Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH2:5][C@@H:6]1[C@@H:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:10]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@@H:9]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@H:8]([C:36]2[CH:41]=[C:40]([CH2:42][C:43]3[CH:48]=[CH:47][C:46]([O:49][CH2:50][CH3:51])=[CH:45][CH:44]=3)[C:39]([Cl:52])=[CH:38][C:37]=2[O:53][CH2:54][CH:55]=[CH2:56])[O:7]1)(=O)C.C[O-].[Na+].C(O)(=O)C>CO>[CH2:54]([O:53][C:37]1[CH:38]=[C:39]([Cl:52])[C:40]([CH2:42][C:43]2[CH:44]=[CH:45][C:46]([O:49][CH2:50][CH3:51])=[CH:47][CH:48]=2)=[CH:41][C:36]=1[C@@H:8]1[O:7][C@H:6]([CH2:5][OH:4])[C@@H:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:10]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C@H:9]1[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH:55]=[CH2:56]
Reactant: C=CCOc1cc(Cl)c(Cc2ccc(OCC)cc2)cc1[C@@H]1O[C@H](COC(C)=O)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: C=CCOc1cc(Cl)c(Cc2ccc(OCC)cc2)cc1[C@@H]1O[C@H](CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 98 %

Procedure:
To a solution of ((2R,3R,4R,5S,6S)-6-(2-(allyloxy)-4-chloro-5-(4-ethoxybenzyl)phenyl)-3,4,5-tris(benzyloxy)tetrahydro-2H-pyran-2-yl)methyl acetate (20, 7.8 g, 10 mmol) from Step 4 in methanol (130 mL) was added sodium methoxide (25% in methanol, 13 mL) and the reaction mixture was vigorously stirred at ambient temperature for 5 h. The solution was cooled to 0° C. prior to neutralizing with acetic acid (6.5 mL). After removal of organic volatiles under reduced pressure, the residue was diluted ethyl acetate and water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with sodium hydrogen carbonate and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude residue was purified on Biotage® purification apparatus (silica gel, 5 to 30% tetrahydrofuran in hexanes) to yield the title compound (21, 7.2 g, 9.8 mmol, 98%) as a white solid.
Reaction SMILES: [CH2:1]([OH:6])[CH:2](O)[CH2:3][CH3:4].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[C:18]1([CH3:33])[CH:23]=[CH:22][C:21]([S:24]([O:27][CH2:28][CH:29]([OH:32])[CH2:30][CH3:31])(=[O:26])=[O:25])=[CH:20][CH:19]=1>N1C=CC=CC=1>[C:1]([O:32][CH:29]([CH2:30][CH3:31])[CH2:28][O:27][S:24]([C:21]1[CH:20]=[CH:19][C:18]([CH3:33])=[CH:23][CH:22]=1)(=[O:25])=[O:26])(=[O:6])[CH2:2][CH2:3][CH3:4]
Reactant: CCC(O)CO
Reactant: CCC(O)COS(=O)(=O)c1ccc(C)cc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CCCC(=O)OC(CC)COS(=O)(=O)c1ccc(C)cc1

Procedure:
Using 1,2-butanediol, pyridine and p-toluenesulfonyl chloride, (RS)-1-p-toluenesulfonyloxy-2-butanol 2b ##STR24## was prepared in the same manner as Example 1 of Production.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[OH:20][C:21]1[C:30]([CH3:31])=[C:29]2[C:24]([CH:25]=[C:26]([C:36]([O:38][CH3:39])=[O:37])[CH:27]([C:32]([F:35])([F:34])[F:33])[O:28]2)=[CH:23][CH:22]=1.[CH2:40]([CH:42]([CH2:45][CH3:46])[CH2:43]O)[CH3:41].N(C(OCC)=O)=NC([O-])=O>C1COCC1>[CH2:40]([CH:42]([CH2:45][CH3:46])[CH2:43][O:20][C:21]1[C:30]([CH3:31])=[C:29]2[C:24]([CH:25]=[C:26]([C:36]([O:38][CH3:39])=[O:37])[CH:27]([C:32]([F:35])([F:33])[F:34])[O:28]2)=[CH:23][CH:22]=1)[CH3:41]
Reactant: CCC(CC)CO
Reactant: COC(=O)C1=Cc2ccc(O)c(C)c2OC1C(F)(F)F
Agent: CCOC(=O)N=NC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCC(CC)COc1ccc2c(c1C)OC(C(F)(F)F)C(C(=O)OC)=C2
Reaction time: 0.25 h

Procedure:
Polymer bound PPh3 was suspended in THF for 15 min. Methyl 7-hydroxy-8-methyl-2-(trifluoromethyl)-2H-chromene-3-carboxylate from Step 1 (1.5 g, 5.21 mmole) and 2-ethyl butanol (0.96 mL, 7.81 mmole) were added to the above slurry and stirred for 15 min. Ethyl azodicarboxylate (1.23 mL, 7.81 mmole) was added to above mixture dropwise and the mixture was stirred at room temperature overnight. LCMS indicated product formation and that there was no starting material present. The polymer was filtered off through celite pad and the pad was washed with ether. The filtrate was concentrated and the product mixture was suspended in hexane. The undissolved solid was removed by filtration and the filtrate was evaporated and dried in vacuo to afford yellow solid, (1.76 g, 98%): LCMS m/z395.15 (M+Na). 1H NMR (CDCl3/400 MHz) 7.68 (s, 1H), 7.00 (d, 1H, J=8.4 Hz), 6.48 (d, 1H, J=8.4 Hz), 5.68 (q, 1H, J=7.2 Hz), 3.89 (m, 2H), 3.82 (s, 3H), 2.09 (s, 3H), 1.72 (m, 1H), 1.53 (m, 4H), 0.95 (m, 6H). This ester was of suitable purity to use without further purification.
Reaction SMILES: CS(OC[CH:7]([C:16]1[CH:17]=[N:18][C:19]([NH:22][C:23]([C:25]2([C:28]3[CH:36]=[CH:35][C:31]4[O:32][CH2:33][O:34][C:30]=4[CH:29]=3)[CH2:27][CH2:26]2)=[O:24])=[CH:20][CH:21]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH3:15])(=O)=O.C[O:38][CH2:39][CH2:40][N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1.O1C2C=CC(C3(C(NC4C=CC(C(N(C)C)C5C=CC=CC=5OC)=CN=4)=O)CC3)=CC=2OC1>>[O:32]1[C:31]2[CH:35]=[CH:36][C:28]([C:25]3([C:23]([NH:22][C:19]4[CH:20]=[CH:21][C:16]([CH:7]([N:44]5[CH2:45][CH2:46][N:41]([CH2:40][CH2:39][OH:38])[CH2:42][CH2:43]5)[C:8]5[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=5[O:14][CH3:15])=[CH:17][N:18]=4)=[O:24])[CH2:26][CH2:27]3)=[CH:29][C:30]=2[O:34][CH2:33]1
Reactant: COc1ccccc1C(COS(C)(=O)=O)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1
Reactant: COCCN1CCNCC1
Agent: COc1ccccc1C(c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1)N(C)C
Product: COc1ccccc1C(c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1)N1CCN(CCO)CC1

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(5-((4-(2-hydroxyethyl)piperazin-1-yl)(2-methoxyphenyl)methyl)pyridin-2-yl)cyclopropanecarboxamide was prepared from (6-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)pyridin-3-yl)(2-methoxyphenyl)ethyl methanesulfonate and 1-(2-methoxyethyl)piperazine in a manner analogous to that of 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-((dimethylamino)(2-methoxyphenyl)methyl)pyridin-2-yl)cyclopropanecarboxamide.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8]CC)=O)=[CH:2]1.[Br-].S(=O)(=O)(O)O.[CH2:17](OCC)[CH3:18]>>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2([OH:8])[CH2:18][CH2:17]2)=[CH:2]1
Reactant: CCOCC
Reactant: CCOC(=O)c1ccoc1
Agent: O=S(=O)(O)O
Agent: [Br-]
Product: OC1(c2ccoc2)CC1
Reaction time: 1.5 h

Procedure:
2.50 g (17.84 mmol) ethyl furan-3-carboxylate and 0.53 ml (1.82 mmol) titanium tetra-isopropyloxide are placed in 56 ml diethyl ether, 12.61 ml (37.82 mmol) ethylmagnesum bromide (Grignard reagent in tetrahydrofuran) in 28 ml diethyl ether are added dropwise within 1 hour, while the temperature should not rise above 20° C. The reaction mixture is stirred for 1.5 hours, then hydrolysed with 180 ml 10% sulphuric acid. The aqueous phase is extracted with diethyl ether, the combined organic phases are dried and evaporated to dryness. The residue is purified by chromatography. Yield: 1.05 g (47% of theoretical)
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]([OH:16])=O)=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([CH2:12][CH3:13])[CH:6]=2.[NH2:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:23]=1[CH:24]1[CH2:29][CH2:28][CH2:27][CH:26]([N:30]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:25]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[OH-].[Na+].NN>CN(C=O)C.CO>[NH2:1][C:2]1[C:3]([C:14]([NH:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][C:23]=2[CH:24]2[CH2:29][CH2:28][CH2:27][CH:26]([NH2:30])[CH2:25]2)=[O:16])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([CH2:12][CH3:13])[CH:6]=2
Reactant: Nc1cnccc1C1CCCC(N2C(=O)c3ccccc3C2=O)C1
Reactant: CCc1ccc2cc(N)c(C(=O)O)nc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NN
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CN(C)C=O
Product: CCc1ccc2cc(N)c(C(=O)Nc3cnccc3C3CCCC(N)C3)nc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 3-amino-7-ethylquinoline-2-carboxylic acid (0.040 g, 0.18 mmol), 2-[3-(3-aminopyridin-4-yl)cyclohexyl]-1H-isoindole-1,3(2H)-dione (0.055 g, 0.17 mmol), HATU (0.22 g, 0.58 mmol), DMF (0.65 mL) and DIPEA (0.076 g, 0.59 mmol) was stirred at room temperature for 16 h. Aq. NaOH (1 M) was added to the reaction mixture, and a precipitate formed, which was collected by vacuum filtration. The collected solid was washed with 1 M NaOH, followed by water and dried under vacuum to afford an intermediate. The intermediate was dissolved in DMF (0.15 mL) and hydrazine (0.15 mL) was added. The resulting reaction mixture was stirred at room temperature for 16 h, diluted with MeOH, filtered and purified by preparative LC MS (XBridge™ preparative C18 5 μm 30×10 mm OBD™ column, flow rate 60 mL/min., eluting with a gradient of MeCN and water with 0.15% NH4OH) to give title compound. LCMS calc. for C23H28N5O (M+H)+: m/z=390.2. Found: 390.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[C:11]([CH2:25][OH:26])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:10]=1.[CH3:27]I.[H-].[Na+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[C:11]([CH2:25][O:26][CH3:27])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:10]=1
Reactant: CN(C)C(=O)N1CC(c2cc(F)ccc2F)=CC1(CO)c1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCC1(c2ccccc2)C=C(c2cc(F)ccc2F)CN1C(=O)N(C)C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To 25 mg (0.07 mmol) of 1-9 in 1 mL of DMF was added a small amount of MeI and NaH (60% suspension in oil) and the mixture was left to stir for 15 h at room temperature. The reaction was quenched with 1 drop of water and loaded directly onto a RP HPLC and eluted with CH3CN/H2O with 0.1% TFA to provide 2-1 as a white solid. Data for 2-1: 1HNMR (500 MHz, CDCl3) δ 7.4-7.2 (m, 5H), 7.1-6.9 (m, 3H), 6.4 (s, 1H), 4.8 (d, 1H), 4.7 (d, 1H), 4.45 (d, 1H), 4.35 (d, 1H), 3.4 (s, 3H), 2.8 (s, 6H) ppm. HRMS (MS) calc'd M+H for C21H22F2N2O2: 373.1722. Found: 373.1722.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[OH:9].[C:10]1([CH2:16][O:17][CH2:18][CH:19](O)[CH:20](O)[CH2:21][O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CN(C)C=O.C(=O)([O-])[O-].[Cs+].[Cs+]>C(OC(C)C)(C)C.O>[F:1][C:2]1[C:3]2[O:9][C@@H:19]([CH2:18][O:17][CH2:16][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C@H:20]([CH2:21][O:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[O:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: OC(COCc1ccccc1)C(O)COCc1ccccc1
Reactant: Oc1cccc(F)c1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CC(C)OC(C)C
Solvent: O
Product: Fc1cccc2c1O[C@@H](COCc1ccccc1)[C@H](COCc1ccccc1)O2

Procedure:
A mixture of 3-fluorobenzene-1,2-diol (5.12 g) and (R*, R*)-(±)-1,4-bis (phenylmethoxy)-2,3-butanediol, bis (4-methylbenzenesulphonate) (24.4 g) was stirred with dimethylformamide (DMF) (160 ml) under a nitrogen stream for 45 min. Anhydrous cesium carbonate (13.0 g) was added and the mixture was heated to 150° under reflux for 18 hours. The dark brown mixture was cooled to 30° and diluted with di-isopropyl ether (370 ml) and water (30 ml). The layers were separated and the aqueous layer was re-extracted with di-isopropyl ether (150 ml and then 100 ml). The extracts were sequentially washed within 1M hydrochloric acid (300 ml), 30% aqueous sodium chloride (100 ml) and were combined and evaporated in vacuo to a dark brown oil (12.6 g) which was dissolved in a light petroleum-dichloromethane (3:1) (40 ml) and chromatographed over Sorbsil (Trade Mark) (126 g) using light petroleum-dichloromethane mixtures of gradually increasing polarity. Combination of appropriate fractions and evaporation of the solvents gave the title compound as a yellow oil (7.0 g), NMR (CDCl3) 2.6-2.8 (10H, m, Ph), 3.18-3.38 (3H, m, 6-H, 7-H, 8-H), 5.32-5.58 (4H, m, CH2Ph), 5.64 (2H, m, 2-H, 3-H), 6.06-6.32 (4H, m, CH2O).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]2[C:5]([N:6]=[C:7]3[C:12](=[C:13]2[CH:16]([F:18])[F:17])[CH:11]=[CH:10][CH:9]=[N:8]3)=[CH:4][CH:3]=1.[C-:19]#[N:20].[Na+].CCOC(C)=O.CCCCCC>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[N:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]([C:19]#[N:20])([CH:16]([F:18])[F:17])[C:14]=2[CH:15]=1
Reactant: [C-]#N
Reactant: FC(F)c1c2cc(Cl)ccc2nc2ncccc12
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: N#CC1(C(F)F)c2cc(Cl)ccc2Nc2ncccc21
Reaction time: 15 h
Yield: 52.9 %

Procedure:
Method KKK To a stirred solution of 7-chloro-9-(difluoromethyl)-4-azaacridine (91) (1.28 g, 4.84 mmol) in anhydrous DMF (30 mL) at room temperature was added NaCN (711 mg, 14.51 mmol). After 15 h at room temperature, the reaction was quenched with H2O (150 mL), and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Flash chromatography (SiO2, 30% EtOAc-hexane) furnished 92 (747 mg, 53% yield) as a brown solid.
Reaction SMILES: ClC1C=CC(C(OC)=O)=CC=1.COC1C=C(C=CC=1)C(OC)=O.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:42]=[CH:43][CH:44]=1)[C:29]([C:31]1[C:32]([OH:41])=[CH:33][C:34]2[C:39]([CH:40]=1)=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:30]>>[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:42]=[CH:43][CH:44]=1)[C:29]([C:31]1[C:40]2[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:34]=[CH:33][C:32]=1[OH:41])=[O:30]
Reactant: COc1cccc(C(=O)c2cc3ccccc3cc2O)c1
Agent: COC(=O)c1ccc(Cl)cc1
Agent: COC(=O)c1cccc(OC)c1
Product: COc1cccc(C(=O)c2c(O)ccc3ccccc23)c1

Procedure:
Following the procedure of Example 4, but using in place of the methyl p-chlorobenzoate used therein, an approximately equivalent amount of methyl m-methoxybenzoate, there is accordingly obtained 3-(m-methoxybenzoyl)-2-naphthol.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:9][C:10]1[CH:18]=[C:17]([Br:19])[CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13].C([O-])([O-])=O.[Cs+].[Cs+]>C(Cl)Cl>[CH2:1]([O:14][C:12](=[O:13])[C:11]1[CH:15]=[CH:16][C:17]([Br:19])=[CH:18][C:10]=1[F:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1F
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Product: O=C(OCc1ccccc1)c1ccc(Br)cc1F
Yield: 102.4 %

Procedure:
Benzyl bromide (2.80 mL, 23.6 mmol) was added to a solution of 2-fluro-4-bromobenzoic acid (4.34 g, 19.8 mmol) and Cs2CO3 (9.79 g, 30.0 mmol) in CH2Cl2 (50 mL). The mixture was heated to reflux for 4 hr. The reaction was quenched with H2O (150 mL) and extracted with CH2Cl2 (150 mL). The organic layer was dried over MgSO4 and concentrated. The residue was purified by flash column chromatograph eluting with 10% EtOAc in hexanes to give a colorless oil (6.27 g, 100% yield). 1H NMR (400 MHz, CDCl3) δ 7.82-7.88 (m, 1 H) 7.44-7.47 (m, 2 H) 7.34-7.42 (m, 5 H) 5.38 (s, 2 H).
Reaction SMILES: CC1C=CC(S(Cl)(=O)=O)=CC=1.[CH2:12]([OH:16])[CH2:13][C:14]#[CH:15].N1C=CC=CC=1.CC1C=CC(S(OCCC#C)(=O)=O)=CC=1.[O:38]=[CH:39][C:40]1[CH:48]=[CH:47][C:45](O)=[C:42]([O:43][CH3:44])[CH:41]=1>C(Cl)Cl>[CH2:12]([O:16][C:45]1[CH:47]=[CH:48][C:40]([CH:39]=[O:38])=[CH:41][C:42]=1[O:43][CH3:44])[CH2:13][C:14]#[CH:15]
Reactant: COc1cc(C=O)ccc1O
Reactant: C#CCCO
Agent: C#CCCOS(=O)(=O)c1ccc(C)cc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: C#CCCOc1ccc(C=O)cc1OC
Yield: 33.5 %

Procedure:
4-Methylbenzenesulfonyl chloride (5.7 g, 30 mmol), 3-butyn-1-ol (1.5 mL, 20 mmol) and pyridine (3.2 mL, 40 mmol) in CH2Cl2 (20 mL) were treated according to Procedure 4 giving but-3-ynyl 4-methylbenzenesulfonate (4.15 g, 93%) as a colourless oil. Vanillin (0.86 g, 5.7 mmol) was alkylated with but-3-ynyl 4-methylbenzenesulfonate (1.9 g, 8.5 mmol) according to Procedure 4 and the crude product was recystallised from EtOAc/petrol to provide 4-(but-3-ynyloxy)-3-methoxybenzaldehyde (0.39 g, 34%) as a colourless crystalline solid; mp 101-102° C.; δH (400 MHz, CDCl3) 2.07 (t, J=2.8 Hz, 1H, C≡CH), 2.79 (td, J=7.2, 2.8 Hz, 2H, CH2C≡CH), 3.93 (s, 3H, OCH3), 4.25 (t, J=7.2 Hz, 2H, OCH2), 7.00 (d, J5,6=8.0 Hz, 1H, H5), 7.42 (d, J2,6=2.0 Hz, 1H, H2), 7.45 (dd, J5,6=8.0, J2,6=2.0 Hz, 1H, H6), 9.86 (s, 1H, CHO); δC (100 MHz, CDCl3) 13.3, 56.1, 67.0, 70.5, 79.6, 109.6, 112.0, 126.6, 130.5, 149.9, 153.3, 190.9; vmax 1021, 1269, 1586, 1677, 2940, 3246 cm−1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]2[CH:12]=[C:13]([CH3:15])[N:14]=[C:10]2[CH:9]=[CH:8][CH:7]=1)=[O:5])[CH3:2].[Cl:16][C:17]([Cl:22])([Cl:21])[C:18](Cl)=[O:19]>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:11]2[C:12]([C:18](=[O:19])[C:17]([Cl:22])([Cl:21])[Cl:16])=[C:13]([CH3:15])[N:14]=[C:10]2[CH:9]=[CH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cccc2nc(C)cn12
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cccc2nc(C)c(C(=O)C(Cl)(Cl)Cl)n12
Yield: 60.3 %

Procedure:
To a solution of 8.03 g (39.3 mmol) of 5-ethoxycarbonyl-2-methylimidazo[1,2-a]pyridine and 14.41 g (118 mmol) of 4-dimethylaminopyridine in 80 ml of chloroform was added dropwise 21.45 g (118 mmol) of trichloroacetyl chloride. The mixture was heated for 15 hours under reflux. After cooling, the reaction mixture was washed with an aqueous solution of sodium hydrogencarbonate, drid over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (eluent:ethyl acetate/n-hexane=2:1) to give 8.29 g of the desired compound (60.3%, pale yellow solid).
Reaction SMILES: C([N:4]1[CH:9]([CH2:10][C:11]#[N:12])[C:8](=[O:13])[NH:7][CH:6]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:5]1=[O:21])(=O)C.O.NN>CN(C)C=O>[CH2:14]([CH:6]1[NH:7][C:8](=[O:13])[CH:9]([CH2:10][C:11]#[N:12])[NH:4][C:5]1=[O:21])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(=O)N1C(=O)C(Cc2ccccc2)NC(=O)C1CC#N
Agent: NN
Solvent: O
Solvent: CN(C)C=O
Product: N#CCC1NC(=O)C(Cc2ccccc2)NC1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
5.51 g (0.0193 mol) of 1-acetyl-3-benzyl-6-cyanomethyl-2,5-dioxopiperazine was dissolved in 80 ml of dimethylformamide, 3.86 g of hydrazine monohydrate added and the resulting solution stirred for 3 hours at room temperature. The reaction solution was concentrated under reduced pressure, and the residue washed with water to obtain 3.52 g of 3-benzyl-6-cyanomethyl-2,5-dioxopiperazine. Yield: 72.7%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([OH:13])=O)=[CH:7][N:6]=1)=[O:4].S(Cl)([Cl:16])=O.CN(C)C=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([Cl:16])=[O:13])=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(C(=O)O)cn1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(=O)Cl)cn1
Temperature: 70 °C

Procedure:
14.5 g (80 mmol) of 2-methoxycarbonylpyridine-5-carboxylic acid are treated with 6.48 ml of thionyl chloride and 2 ml of anhydrous N,N-dimethylformamide in 200 ml of anhydrous toluene. The mixture is heated at 70° C. for 3 h with stirring. It is then concentrated in vacuo and the residue is dissolved in 150 ml of tetrahydrofuran.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:15])[CH:6]([C:11]([F:14])([F:13])[F:12])[C:7]([O:9][CH3:10])=[O:8].Cl>CN(C)C=O>[F:12][C:11]([C:6]([C:7]([O:9][CH3:10])=[O:8])([C:5]([O:4][CH3:3])=[O:15])[C:11]([F:13])([F:14])[F:12])=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]([O:4][CH3:3])=[O:15]
Reactant: COC(=O)C(C(=O)OC)C(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(C(=O)OC)=C(F)C(C(=O)OC)(C(=O)OC)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.5 %

Procedure:
Into a mixture of sodium hydride (0.36 g, 15 mmol) and N,N-dimethylformamide (5 ml), a solution of dimethyl(trifluoromethyl)malonate (2.00 g, 10 mmol) in N,N-dimethylformamide (5 ml) was added dropwise with cooling the vessel in an ice-bath. After being stirred for 2 h at room temperature, the reaction mixture was poured into dilute aqueous HCl, and worked up as usual. Distillation under vacuum gave tetramethyl 2,4,4,4-tetrafluoro-1-butene-1,1,3,3-tetra-carboxylate (1.27 g, 70%), b.p. 122°-124° C./0.3 mmHg. Found: C: 40.74; H: 3.53%. Calcd.for C8H12O8F4 : C: 40.01; H: 3.36%. 19F NMR: δ--15.1 (d. CF3), +10.7 (q, =CF--). 1H NMR: δ 3.77 (s, CH3), 3.87 (s, CH3), 3.90 (COCH3)). IR: 1665 (C=C), 1750 (C=O) cm-1
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH2:12](Br)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CC(C)=O>[CH2:25]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)OC)cc1
Temperature: 0 °C
Yield: 8.1 %

Procedure:
A well stirred mixture of 100 g of methyl 4-hydroxybenzoate, 182.25 g of tetradecylbromide, 136.26 g of potassium carbonate and 4.93 g of sodium iodide in 1-liter of acetone is refluxed for 48 hours. The mixture is poured into ice water, the solid collected and washed with water. The solid is dissolved in chloroform and washed with 1N sodium hydroxide, dried and evaporated to a residue which is crystallized from hexanes to give 18.5 g of the desired product as a white solid, m.p. 64°-66° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](OS(C2C=CC(C)=CC=2)(=O)=O)[C:5]([N+:19]([O-:21])=[O:20])=[C:4]([C:22]2[O:23][CH:24]=[CH:25][CH:26]=2)[N:3]=1.C(N(CC)CC)C.[N:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH2:40][NH2:41].O>C(COC)OC>[O:23]1[CH:24]=[CH:25][CH:26]=[C:22]1[C:4]1[N:3]=[C:2]([NH2:1])[N:7]=[C:6]([NH:41][CH2:40][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][N:34]=2)[C:5]=1[N+:19]([O-:21])=[O:20]
Reactant: NCc1ccccn1
Reactant: Cc1ccc(S(=O)(=O)Oc2nc(N)nc(-c3ccco3)c2[N+](=O)[O-])cc1
Solvent: COCCOC
Solvent: O
Solvent: CCN(CC)CC
Product: Nc1nc(NCc2ccccn2)c([N+](=O)[O-])c(-c2ccco2)n1
Reaction time: 16 h
Yield: 69.3 %

Procedure:
A solution of (2-amino-6-(2-furyl)-5-nitropyrimidin-4-yl)4-methylbenzenesulphonate (478 mg, 1.27 mmol) in dimethoxyethane (15 mL) was treated with triethylamine (0.531 mL, 3.81 mmol) and 2-pyridinemethylamine (0.393 mL, 3.81 mmol), stirred for 16 h, poured into water (100 mL) and the resulting solid was filtered to give the title compound (275 mg, 69%) as a yellow solid; NMR δH (400 MHz, CDCl3) 8.70-8.58 (2H, m), 7.70-7.66 (1H, m), 7.55-7.54 (1H, m), 7.28 (1H, d, J 8.0 Hz), 7.24-7.20 (1H, m), 7.07-7.06 (1H, m), 6.54-6.52 (1H, m), 5.26 (2H, br s) and 4.83 (2H, d, J 5.0 Hz); Retention time 1.44 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[N:7]=[C:8]([C:11]2[CH:16]=[CH:15][C:14](OS(C(F)(F)F)(=O)=O)=[CH:13][CH:12]=2)[O:9][CH:10]=1)[CH3:2].[CH3:26][S:27]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)(=[O:29])=[O:28].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F-].[Cs+]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[N:7]=[C:8]([C:11]2[CH:12]=[CH:13][C:14]([C:33]3[CH:34]=[CH:35][C:30]([S:27]([CH3:26])(=[O:29])=[O:28])=[CH:31][CH:32]=3)=[CH:15][CH:16]=2)[O:9][CH:10]=1)[CH3:2]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CCOC(=O)Cc1coc(-c2ccc(OS(=O)(=O)C(F)(F)F)cc2)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1coc(-c2ccc(-c3ccc(S(C)(=O)=O)cc3)cc2)n1
Temperature: 110 °C
Yield: 11.8 %

Procedure:
A suspension of [2-(4-Trifluoromethanesulfonyloxy-phenyl)-oxazol-4-yl]-acetic acid ethyl ester (See Intermediate 69) (0.83 g, 2.2 mmol), 4-(methanesulfonyl)phenyl boronic acid (0.48 g, 2.4 mmol), triphenylphosphine (69 mg, 0.26 mmol), cesium fluoride (0.67 g, 4.4 mmol) and palladium acetate (15 mg, 0.066 mmol) in DMF (10 mL) is heated at 110° C. for 24 h. The suspension is cooled to room temperature and filtered. The filtrate is partitioned between EtOAc and water. The aqueous phase is extracted with EtOAc. The combined organic phase is washed with brine, dried (Na2SO4), and concentrated. The residue is purified by flash chromatography (40 g SiO2, elute 20% to 80% EtOAC/hexane) to yield the title compound (0.10 g, 12%). MS (m/e): 386.2 (M+1)