Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC[O:4][C:5]1[C:10]2[C:11]([CH3:22])=[C:12]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])[C:13]([CH3:16])([CH3:15])[O:14][C:9]=2[CH:8]=[C:7]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:6]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(O)(C)(C)C>[OH:4][C:5]1[C:10]2[C:11]([CH3:22])=[C:12]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])[C:13]([CH3:16])([CH3:15])[O:14][C:9]=2[CH:8]=[C:7]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:6]=1
Reactant: CCCCCc1cc(OCOC)c2c(c1)OC(C)(C)C(CCC(=O)O)=C2C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: c1cc[nH+]cc1
Solvent: CC(C)(C)O
Product: CCCCCc1cc(O)c2c(c1)OC(C)(C)C(CCC(=O)O)=C2C

Procedure:
To a solution of 0.55 g (1.65 mmol) of 5-(Methoxymethoxy)-2,2,4-trimethyl-7-pentyl-2H-1-benzopyran-3-propanoic acid in 60 mL of tert-butyl alcohol (MCB Chem. Co.) under argon was added 4.16 g (10 eq.) of pyridinium para-toluenesulfonic acid (Aldrich) and the reaction mixture boiled under reflux for 1 hr. The reaction mixture was cooled with an ice-water bath and then partitioned between 500 mL of EtOAc and 100 mL of water. The phases were separated and the organic phase washed with water (5×100 mL), half-sat. aq. NaCl (1×100 mL), sat. aq. NaCi (1×100 mL), dried (Na2SO4), evaporated under reduced pressure and the residue dried under high vacuum to give discolored solids. The solids were redissolved and subjected to column chromatography on flash-grade silica gel, eluting with 10% MeOH-CHCl3. The fractions containing product were combined and solvent removed under reduced pressure to give, after drying under high vacuum, 143 mg of 5-Hydroxy-2,2,4-trimethyl-7-pentyl-2H-1-benzopyran-3-propanoic acid as a glass/amorphous solid. HR EI MS: Calc M+, 332.1988; Observed, 332.1985.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[Cl:10].[Na+].[CH3:12][S:13]([O-:15])=[O:14].O>CS(C)=O>[Cl:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[S:13]([CH3:12])(=[O:15])=[O:14])[CH:6]=[O:7]
Reactant: CS(=O)[O-]
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CS(=O)(=O)c1ccc(C=O)cc1Cl
Temperature: 90 °C

Procedure:
To a solution containing 1.0 g of 4,3-dichlorobenzaldehyde in 45 ml of DMSO was added 1.93 g of methanesulfinicacid sodium salt with stirring at 90° C. The solution was stirred for 6 hours at 90° C. and then poured into water. Sodiumhydrogencarbonate was added and the product was extracted with ethyl acetate. The extract was evaporated to dryness in vacuo. The residue was triturated with 2-propanol, yield 1.06 g. 1H-NMR (DMSO-d6,400 MHz): 3.45 (s, 3 H, CH3), 8.09-8.27 (m, 3 H, Ar), 10.01 (d, 1 H, CHO).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@H:14]([N:15]([CH3:25])[C:16](=[O:24])[C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:26]([N:29]1[CH2:34][CH2:33][CH:32]([C:35](O)=[O:36])[CH2:31][CH2:30]1)(=[O:28])[CH3:27]>>[C:26]([N:29]1[CH2:30][CH2:31][CH:32]([C:35]([N:11]2[CH2:12][CH2:13][C@@H:14]([N:15]([CH3:25])[C:16](=[O:24])[C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[C@H:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[CH2:10]2)=[O:36])[CH2:33][CH2:34]1)(=[O:28])[CH3:27]
Reactant: CC(=O)N1CCC(C(=O)O)CC1
Reactant: CN(C(=O)c1ccc(F)cc1)[C@@H]1CCNC[C@H]1c1ccc(Cl)c(Cl)c1
Product: CC(=O)N1CCC(C(=O)N2CC[C@@H](N(C)C(=O)c3ccc(F)cc3)[C@H](c3ccc(Cl)c(Cl)c3)C2)CC1

Procedure:
Using the compound obtained in Example 26 and 1-acetylpiperidine-4-carboxylic acid, and by the reaction and purification in the same manner as in Example 3, the title compound was obtained.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:11][C:12]([NH:14][C@@:15]1([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[C@H:20]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=2)[C@@H:19]([O:31]C(C2C=CC([N+]([O-])=O)=CC=2)=O)[C@@H:18]2[C@H:16]1[C@H:17]2[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[O:13])([CH3:10])([CH3:9])[CH3:8].CO>C(OCC)(=O)C>[C:7]([O:11][C:12]([NH:14][C@@:15]1([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[C@H:20]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=2)[C@@H:19]([OH:31])[C@@H:18]2[C@H:16]1[C@H:17]2[C:43]([O:45][C:46]([CH3:48])([CH3:47])[CH3:49])=[O:44])=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)N[C@]1(C(=O)OC(C)(C)C)[C@@H]2[C@@H](C(=O)OC(C)(C)C)[C@@H]2[C@H](OC(=O)c2ccc([N+](=O)[O-])cc2)[C@H]1OCc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@]1(C(=O)OC(C)(C)C)[C@@H]2[C@@H](C(=O)OC(C)(C)C)[C@@H]2[C@H](O)[C@H]1OCc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.9 %

Procedure:
Potassium carbonate (5.11 g, 36.60 mmol) is added to a solution of di-tert-butyl (1S,2R,3S,4S,5R,6R)-2-[(tert-butoxycarbonyl)amino]-3-[(3,4-dichlorobenzyl)oxy]-4-{[(4-nitrophenyl)carbonyl]oxy}bicyclo[3.1.0]hexane-2,6-dicarboxylate (9.00 g, 12.20 mmol) and methanol (122.01 mL, 3.01 moles), and then stirred at room temperature. After 1 hour, dilute the reaction mixture with ethyl acetate, wash with water (75 mL), brine (75 mL), dry over sodium sulfate, and concentrate under reduced pressure to give a residue. The residue is purified by flash chromatography, eluting with 10-60% ethyl acetate:hexanes to give the title compound (5.3 g, 9.01 mmol, 74%). MS (m/z): 610/612 (M+1).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.II.C(N(CC)CC)C.O=[C:30]([CH2:48][CH3:49])[CH2:31][NH:32][C:33]([CH2:35][CH2:36][NH:37][C:38](=[O:47])[O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:34]>ClCCl>[CH2:40]([O:39][C:38](=[O:47])[NH:37][CH2:36][CH2:35][C:33]1[O:34][C:30]([CH2:48][CH3:49])=[CH:31][N:32]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CCC(=O)CNC(=O)CCNC(=O)OCc1ccccc1
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1cnc(CCNC(=O)OCc2ccccc2)o1
Temperature: 25 °C
Reaction time: 0.1 h

Procedure:
23.07 g (49.60 mmol) PS-triphenylphosphine are in 200 ml dichloromethane suspended, 12.65 g (49.82 mmol) iodine are added. It is stirred for 0.1 hours at ambient temperature, then 13.80 ml (99.28 mmol) triethylamine are added dropwise. 5.80 g (19.84 mmol) benzyl [2-(2-oxo-butylcarbamoyl)-ethyl]-carbamate dissolved in 150 ml dichloromethane are added. The reaction mixture is stirred for 72 hours at ambient temperature, then the precipitate is filtered off. The filtrate is extracted with water, the organic phase is dried and evaporated to dryness.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:9]=[C:8]([NH2:10])[NH:7][N:6]=1)=O.[NH3:11]>CO>[NH2:10][C:8]1[NH:7][N:6]=[C:5]([C:3]([NH2:11])=[O:2])[CH:9]=1
Reactant: N
Reactant: COC(=O)c1cc(N)[nH]n1
Solvent: CO
Product: NC(=O)c1cc(N)[nH]n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1.0 g (7 mmol) of 5-amino-1H-pyrazole-3-carboxylic acid methyl ester in 10 mL of methanol (MeOH) in a sealed tube was saturated with ammonia (NH3), and the sealed tube mixture was stirred at rt overnight. Since analysis by thin layer chromatography (TLC) revealed that the reaction was not complete, the mixture was then heated at 80° for 1 day. The reaction mixture was then cooled, the sealed tube was opened, and the solvent was evaporated to give 0.9 g of desired 5-amino-1H-pyrazole-3-carboxylic acid amide as indicated by 1H NMR; LC-MS—calcd for C4H6N4O [M++H]+: 127.05, found: 127.2.
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH2:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])(=[O:15])=[O:14])=[CH:9][CH:8]=1.[CH:25](=[O:29])[CH2:26][CH2:27][CH3:28].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH:16]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])[CH:25]([OH:29])[CH2:26][CH2:27][CH3:28])(=[O:15])=[O:14])=[CH:9][CH:8]=1
Reactant: CCCC=O
Reactant: O=S(=O)(Cc1cc(F)ccc1F)c1ccc(Cl)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCC(O)C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
In an argon gas stream and at −78° C., n-butyl lithium (a 1.57M hexane solution, 7.01 ml, 11.0 mmol) was added to a tetrahydrofuran (50 ml) solution of the 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (3.03 g, 10.0 mmol) obtained in Example 5 and the mixture was stirred at −78° C. for 1 hour. Butanal (1.08 ml, 12.0 mmol) was added dropwise to the reaction mixture. The mixture was stirred for 15 hours while elevating its temperature to room temperature. After cooling to 0° C. and addition of a saturated aqueous ammonium chloride solution, the mixture was extracted with diethyl ether. The extracts were combined, washed successively with water and brine, dried over MgSO4, and then concentrated. The solid thus precipitated was collected by filtration and washed with hexane. The filtrate and washing with hexane were combined, followed by concentration. The residue was purified by medium-pressure chromatography on a silica gel column (10% ethyl acetate-hexane) as a high-polarity isomer to yield a colorless solid. The resulting colorless solid was recrystallized from hexane, whereby the title compound (396 mg, 11%) was obtained as colorless needle crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](=[N:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[NH:6][CH:7]=1.CCN(C(C)C)C(C)C.I[CH2:29][C:30]([NH2:32])=[O:31].O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[N:6]([CH2:29][C:30]([NH2:32])=[O:31])[CH:7]=1
Reactant: NC(=O)CI
Reactant: Cc1ccc(S(=O)(=O)N=c2ccc(Br)c[nH]2)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)NC2C=CC(Br)=CN2CC(N)=O)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 97.6 %

Procedure:
To a suspension of N-(5-bromopyridin-2(1H)-ylidene)-4-methylbenzenesulfonamide (step 1) (11.3 g, 34.5 mmol) in DMF (70 mL) was added Huenig's base (N-ethyldiisopropyl amine) (6.62 mL, 38.0 mmol) and 2-iodoacetamide (7.03 g, 38.0 mmol). The mixture was stirred at room temperature for 15 h. The mixture was poured into 750 mL of water. The mixture was stirred for 90 min and the solid precipitate was collected by filtration. The filter-cake was washed with water and then ether, and then dried at 70° C. under vacuum for 1 h to afford 2-(5-bromo-2-(4-methylphenylsulfonamido)pyridin-1(2H)-yl)acetamide (13.0 g, 98.0% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.37 (d, J=2.2 Hz, 1H), 7.88 (dd, J=9.7 Hz, 2.5 Hz, 1H), 7.79 (s, 1H), 7.65 (d, J=8.2 Hz, 2H), 7.39 (s, 1H), 7.29 (t, J=9.3 Hz, 3H), 4.79 (s, 2H), 2.34 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:10][C:11]([CH3:17])=[C:12]([C:14]([OH:16])=[O:15])[N:13]=2)=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22].CCN(CC)CC>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C:21](=[O:22])[C:20]2[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:19]=2[Cl:18])[C:9]2[S:10][C:11]([CH3:17])=[C:12]([C:14]([OH:16])=[O:15])[N:13]=2)=[CH:6][CH:7]=1
Reactant: Cc1sc(Nc2ccc(Cl)cc2)nc1C(=O)O
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1sc(N(C(=O)c2ccc(Cl)cc2Cl)c2ccc(Cl)cc2)nc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2.0 g (7.4 mmol) 2-(4-Chloro-phenylamino)-5-methyl-thiazole-4-carboxylic acid, 1.56 ml (11.1 mmol) 2,4-Dichlorobenzoyl chloride and 3.09 ml (22.3 mmol) NEt3 in 30 ml DCM was stirred at room temperature for 2 h. After removal of all volatiles the resulting yellow foam was used without further purification in the consecutive step. MS (m/e): 441.0 (MH+, 100%)
Reaction SMILES: [CH:1]([O:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:22][CH2:23][N:24]1[C:28](=[O:29])[C:27]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]2[C:25]1=[O:34].C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>CC(=O)CC>[CH:1]([O:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:22][CH2:23][N:24]2[C:25](=[O:34])[C:26]3[C:27](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]2=[O:29])[CH2:17][CH2:16]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(C(OC2CCNCC2)c2ccccc2)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C1c2ccccc2C(=O)N1CCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Yield: 100 %

Procedure:
The mixture of 4-benzhydryloxy-piperidine (1.85 g, 3.4 mmol, 1.0 eq.), N-(2-bromoethyl)phthalimide (0.855 g, 3.4 mmol, 1.0 eq.), K2CO3 (0.705 g, 5.1 mmol, 1.5 eq.), and NaI (0.713 g, 4.8 mmol, 1.4 eq.) in 2-butanone (20 ml) was refluxed for 2-3 hours. The mixture was then cooled to room temperature. The white solid was filtered off and was washed with small amount of CHCl3. The filtrates were combined and concentrated. The resulted residue was dissolved in CHCl3 (100 ml). The solution was washed with water (3×10 ml), then dried over anhydrous Na2SO4. After removed all solvent, the crude product, 2-[2-(4-benzhydryloxy-piperidin-1-yl)-ethyl]-isoindole-1,3-dione was yielded (1.5 g, 100% yield). 1H-NMR (CDCl3, ppm): 7.84 (m, 2H), 7.70 (m, 2H), 7.20-7.40 (m, 10H), 5.50 (s, 1H), 3.80 (t, 2H), 3.39 (m, 1H), 2.82 (m, 2H), 2.59 (t, 2H), 2.18 (m, 2H), 1.83 (m, 2H) 1.67 (m, 2H). ESMS 441.2 (M+1), 463.2 (M+23).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:15]3[C:14]([CH3:16])=[N:13][N:12]([C:17]4[C:18]([O:23][CH3:24])=[N:19][CH:20]=[CH:21][CH:22]=4)[C:11]=3[C:10](=[O:25])[NH:9]2)=[CH:4][CH:3]=1.Cl[C:27]1[CH:28]=[C:29]([CH3:37])[C:30]2[N:31]([C:33]([CH3:36])=[N:34][N:35]=2)[N:32]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:15]3[C:14]([CH3:16])=[N:13][N:12]([C:17]4[C:18]([O:23][CH3:24])=[N:19][CH:20]=[CH:21][CH:22]=4)[C:11]=3[C:10](=[O:25])[N:9]2[C:27]2[CH:28]=[C:29]([CH3:37])[C:30]3[N:31]([C:33]([CH3:36])=[N:34][N:35]=3)[N:32]=2)=[CH:4][CH:3]=1
Reactant: COc1ncccc1-n1nc(C)c2c1C(=O)NC2c1ccc(Cl)cc1
Reactant: Cc1cc(Cl)nn2c(C)nnc12
Product: COc1ncccc1-n1nc(C)c2c1C(=O)N(c1cc(C)c3nnc(C)n3n1)C2c1ccc(Cl)cc1

Procedure:
The title product was prepared in analogy to the procedure described in Example 110 using 4-(4-chlorophenyl)-1-(2-methoxypyridin-3-yl)-3-methyl-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one (Step 71.4) and 6-chloro-3,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazine (Step 111.2). The crude material was first purified by silica gel column chromatography (CH2Cl2/MeOH 1-5%), followed by preparative achiral SFC (column Propyl-pyridyl-urea, gradient 9-14% in 6 min_total 11 min). tR: 4.71 min (HPLC 1); tR: 1.10 min (LC-MS 2); ESI-MS: 501 [M+H]+ (LC-MS 2); Rf=0.44 (CH2Cl2/MeOH 9:1); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.03 (s, 3H) 2.51-2.57 (m, 6H) 3.92 (s, 3H) 6.61 (s, 1H) 7.20 (dd, J=7.8, 5.1 Hz, 1H) 7.37-7.44 (m, 2H) 7.47-7.54 (m, 2H) 7.97-8.06 (m, 2H) 8.32 (d, J=4.3 Hz, 1H).
Reaction SMILES: C(OC([NH:8][C@H:9]([CH2:45][CH:46]([CH3:48])[CH3:47])[CH2:10][O:11][C:12]1[CH:44]=[CH:43][C:15]([CH2:16][CH:17]2[S:21][C:20](=[O:22])[N:19](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:18]2=[O:42])=[CH:14][CH:13]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][C@H:9]([CH2:45][CH:46]([CH3:48])[CH3:47])[CH2:10][O:11][C:12]1[CH:44]=[CH:43][C:15]([CH2:16][CH:17]2[S:21][C:20](=[O:22])[NH:19][C:18]2=[O:42])=[CH:14][CH:13]=1
Reactant: CC(C)C[C@H](COc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@@H](N)COc1ccc(CC2SC(=O)NC2=O)cc1
Yield: 128.1 %

Procedure:
A procedure similar to that described in Preparation 2, above, was followed, but using 1.03 g of 5-{4-[2(R)-t-butoxycarbonylamino-4-methylpentyloxy]benzyl}-3-triphenylmethylthiazolidine-2,4-dione [prepared as described in Preparation 16], 10 ml of methylene chloride and 10 ml of trifluoroacetic acid. After completion of the reaction, the methylene chloride and trifluoroacetic acid were removed by distillation under reduced pressure, and the residue was washed with toluene to give 640 mg of the title compound.
Reaction SMILES: O.C(=O)([O-])[O-].[Na+].[Na+].Br[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])[CH2:16][C:17]([C:19]2[CH:24]=[CH:23][N:22]=[N:21][CH:20]=2)=[O:18])=[CH:11][CH:10]=1.B([C:35]1[CH:43]=[CH:42][C:38]([C:39]([OH:41])=[O:40])=[CH:37][CH:36]=1)(O)O>O1CCOCC1>[O:18]=[C:17]([C:19]1[CH:24]=[CH:23][N:22]=[N:21][CH:20]=1)[CH2:16][CH:15]([C:12]1[CH:11]=[CH:10][C:9]([C:35]2[CH:43]=[CH:42][C:38]([C:39]([OH:41])=[O:40])=[CH:37][CH:36]=2)=[CH:14][CH:13]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:31]
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: Cc1ccccc1C(CC(=O)c1ccnnc1)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccccc1C(CC(=O)c1ccnnc1)c1ccc(-c2ccc(C(=O)O)cc2)cc1
Temperature: 80 °C

Procedure:
Water (1 mL) and 2 M aq. sodium carbonate solution (0.39 mL, 0.78 mmol) were added at room temperature to a degassed solution of 3-(4-bromophenyl)-1-(pyridazin-4-yl)-3-o-tolylpropan-1-one (100 mg, 262 μmol), 4-boronobenzoic acid (53.8 mg, 315 μmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (11 mg, 13 μmol) in 1,4-dioxane (1.5 mL). After heating at 80° C. for 4 h the reaction mixture was partitioned between ethyl acetate and sat. aq. ammonium chloride solution. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. After chromatography (SiO2; gradient heptane/ethyl acetate 1:1 to ethyl acetate) the title compound was obtained (33 mg, 30%). Light yellow solid, MS: 423.2 [M+H]+.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([CH2:10][O:11][CH3:12])=[CH:4][C:3]=1[O:13][CH3:14].C([Li])CCC.CCCCCC.C[O:27][B:28]([O:31]C)[O:29]C.Cl>O1CCCC1>[CH3:14][O:13][C:3]1[CH:4]=[C:5]([CH2:10][O:11][CH3:12])[CH:6]=[C:7]([O:8][CH3:9])[C:2]=1[O:27][B:28]([OH:31])[OH:29]
Reactant: COB(OC)OC
Reactant: COCc1cc(OC)c(Br)c(OC)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COCc1cc(OC)c(OB(O)O)c(OC)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66.9 %

Procedure:
To a solution of 2-bromo-1,3-dimethoxy-5-(methoxymethyl)benzene (20.0 g, 76.6 mmol) in tetrahydrofuran (200 mL) which had been cooled in a dry ice-acetone bath was added 1.58M n-butyllithium in hexane (50.9 mL, 80.4 mmol) under a nitrogen stream, and the reaction mixture was stirred for 30 minutes. A solution of trimethoxyborane (8.75 g, 84.2 mmol) in tetrahydrofuran (20 mL) was then added to the reaction mixture, and the reaction temperature was increased to 0° C. while stirring. After adding 1N hydrochloric acid (200 mL) to the reaction mixture, it was stirred for 30 minutes at room temperature. After the reaction terminated, toluene (200 mL) was added to the reaction mixture and the organic layer was separated off, after which the aqueous layer was extracted with toluene (100 mL). The combined organic extracts were washed with water (100 mL) and then concentrated under reduced pressure. The residue was dissolved in tert-butyl methyl ether (75 mL) and the reaction mixture was stirred for 30 minutes, after which heptane (223 mL) was added thereto and the reaction mixture was further stirred for 2 hours. The precipitate was filtered out and washed with a mixed solution of tert-butyl methyl ether and heptane (1:3, 3.75 mL), and then dried at 40° C. for 24 hours to afford 12.4 g of the title compound (71.8% yield).
Reaction SMILES: [CH3:1][C:2]([O:4][CH2:5][C@H:6]1[O:11][C@H:10](Br)[C@H:9]([O:13][C:14]([CH3:16])=[O:15])[C@@H:8]([O:17][C:18]([CH3:20])=[O:19])[C@@H:7]1[O:21][C:22]([CH3:24])=[O:23])=[O:3].[N+:25]([C:28]1[CH:33]=[CH:32][C:31]([O-:34])=[CH:30][CH:29]=1)([O-:27])=[O:26].[Na+].CC(C)=O.[OH-].[Na+]>O>[C:14]([O:13][C@@H:9]1[C@@H:8]([O:17][C:18](=[O:19])[CH3:20])[C@H:7]([O:21][C:22](=[O:23])[CH3:24])[C@@H:6]([CH2:5][O:4][C:2](=[O:3])[CH3:1])[O:11][C@H:10]1[O:34][C:31]1[CH:32]=[CH:33][C:28]([N+:25]([O-:27])=[O:26])=[CH:29][CH:30]=1)(=[O:15])[CH3:16]
Reactant: O=[N+]([O-])c1ccc([O-])cc1
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](Oc2ccc([N+](=O)[O-])cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 18 h
Yield: 24.9 %

Procedure:
To a mixture of 15 g of acetobromoglucose, 7.92 g of sodium 4-nitrophenolate and 50 ml of acetone was added 300 mg of sodium hydroxide in 15 ml of water. This mixture was stirred for 18 hours, poured into 400 ml of water and the precipitate was filtered off. The residue was dissolved in 200 ml of methylene chloride, washed with 100 ml of aqueous sodium bicarbonate solution, dried and passed through a pad of hydrous magnesium silicate. Evaporation of the solvent and crystallization yielded 4.26 g of 4-nitrophenyl (2,3,4,6-tetra-O-acetyl)-β-D-glucopyranoside as white crystals, mp 173°-175° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[C:10]([CH2:12][C:13](O)=[O:14])#[N:11].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>O1CCOCC1>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:13](=[O:14])[CH2:12][C:10]#[N:11])=[CH:4][CH:3]=1
Reactant: N#CCC(=O)O
Reactant: NCc1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1COCCO1
Product: N#CCC(=O)NCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.6 %

Procedure:
According to the Scheme 1 Step 1: A mixture of 4-chlorobenzylamine (10.0 g, 71 mmol), cyanoacetic acid (6.13 g, 72 mmol), HOBt (11 g, 72 mmol), EDCI.HCl (20 g, 106 mmol) in 100 mL of dioxane was stirred for 3 h at room temperature. The solvent was removed under vacuum and 300 mL of DCM was added. The organic layer was successively washed with 2×100 mL of water, 2×50 mL of a solution 1N of NaOH, 4×100 mL of water until neutral pH. The organic layer was dried over Na2SO4, filtered and concentrated to afford N-(4-chlorobenzyl)-2-cyanoacetamide 1(A) (13.12 g, 89%) as a brown solid.
Reaction SMILES: [CH:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[CH3:2].C[Si](C)(C)[N-][Si](C)(C)C.[K+].F[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[N:27]=1>O1CCCC1>[F:32][C:28]1[N:27]=[C:26]([C:1]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=2)[CH3:2])[CH:31]=[CH:30][CH:29]=1
Reactant: Fc1cccc(F)n1
Reactant: CC(c1ccccn1)c1ccccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CC(c1ccccn1)(c1ccccn1)c1cccc(F)n1

Procedure:
26.8 g (145 mmol) of 2,2′-(ethane-1,1-diyl)dipyridine were dissolved in 400 ml of tetrahydrofurane. A solution of 32 g (160 mmol) of potassium hexamethyldisilazide in 240 ml tetrahydrofuran was added. Meanwhile the solution coloured to dark red. After stirring for one hour 16.8 g (145 mmol) of 2,6-difluoropyridine was added in one batch. The mixture was heated under reflux for 1 hour.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:25]=[CH:24][N:23]=[C:22]([CH2:26][CH2:27][CH2:28]O)[CH:21]=2)=[CH:16][CH:15]=1.[O:30]1[CH2:34][C:33](=[O:35])[NH:32][C:31]1=[O:36].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.O1CCCC1.C(OCC)(=O)C.O>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[N:25]=[CH:24][N:23]=[C:22]([CH2:26][CH2:27][CH2:28][N:32]3[C:33](=[O:35])[CH2:34][O:30][C:31]3=[O:36])[CH:21]=2)=[CH:18][CH:19]=1
Reactant: O=C1COC(=O)N1
Reactant: OCCCc1cc(-c2ccc(Cl)cc2)ncn1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1COC(=O)N1CCCc1cc(-c2ccc(Cl)cc2)ncn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.5 %

Procedure:
0.4 ml of a 40% solution of diethyl azodicarboxylate (0.9 mmol) in toluene is added to a solution, cooled with an ice bath, of 0.111 g (0.44 mmol) of 3-[6-(4-chlorophenyl)pyrimidin-4-yl]propan-1-ol, prepared in stage 5.4., of 0.077 g (0.76 mmol) of 1,3-oxazolidine-2,4-dione and of 0.235 g (0.89 mmol) of triphenylphosphine in 4 ml of tetrahydrofuran. The mixture is subsequently stirred at ambient temperature overnight. It is taken up in a mixture of ethyl acetate and of water. The organic phase is washed with a saturated aqueous sodium chloride solution, dried over sodium sulphate and evaporated. The residue is purified by chromatography on silica gel, elution being carried out with a 97/3 mixture of dichloromethane and of methanol, to produce 0.117 g (0.35 mmol) of product in the solid form.