Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:4]=1[NH2:5].[Cl:12][C:13]1[N:18]=[C:17](Cl)[C:16]([F:20])=[CH:15][N:14]=1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:12][C:13]1[N:18]=[C:17]([NH:5][C:4]2[CH:6]=[CH:7][C:8]([O:10][CH3:11])=[CH:9][C:3]=2[O:2][CH3:1])[C:16]([F:20])=[CH:15][N:14]=1
Reactant: COc1ccc(N)c(OC)c1
Reactant: Fc1cnc(Cl)nc1Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Nc2nc(Cl)ncc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2,4-dimethoxyaniline (4.1 g, 24.6 mmol) was added to a solution of 2,4-dichloro-5-fluoropyrimidine (4.1 g, 24.6 mmol) in isopropanol (16 mL). N,N-Diisopropyl-ethylamine (6.30 g, 8.50 mL, 48.8 mmol) was added and the mixture was allowed to stir at room temperature for 24 h. The solution was partitioned between ethyl acetate and water. The organic phase was separated and washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to afford an oil. This oil was purified via column chromatography on silica gel (gradient elution with 0-10% methanol-methylenechloride) to afford (2-chloro-5-fluoro-pyrimidin-4-yl)-(2,4-dimethoxy-phenyl) amine. MS (MH+) 284; Calculated 283.69 for C12H11ClFN3O2.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C1(P(=[CH:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[N:5]1[CH:6]=[CH:7][C:2](/[CH:1]=[CH:28]/[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:3][CH:4]=1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccncc1
Solvent: ClCCl
Product: CCOC(=O)/C=C/c1ccncc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 96.3 %

Procedure:
To a solution of isonicotinaldehyde (0.811 mL, 8.61 mmol) in DCM (30 mL) was added ethyl (triphenylphosphoranylidene)acetate (3.00 g, 8.61 mmol) in DCM (5 mL) dropwise. The reaction mixture was allowed to stir at rt for 5 h and then concentrated. The residue was purified by column chromatography to give ethyl (2E)-3-pyridin-4-ylacrylate (1.47 g, 96%). LCMS: (FA) ES+ 178.3.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:16])[C:7]2=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]2[N:5]=1)[CH3:3].[NH2:21][C:22]1[C:27]([C:28]([O:30][C:31]2[CH:36]=[CH:35][C:34]([S:37](=[O:41])(=[O:40])[NH:38][CH3:39])=[CH:33][CH:32]=2)=[O:29])=[C:26](Cl)[N:25]=[CH:24][N:23]=1.CCN(C(C)C)C(C)C.[F-].[Cs+]>C(O)(C)(C)C>[NH2:21][C:22]1[C:27]([C:28]([O:30][C:31]2[CH:32]=[CH:33][C:34]([S:37](=[O:41])(=[O:40])[NH:38][CH3:39])=[CH:35][CH:36]=2)=[O:29])=[C:26]([NH:1][C@H:2]([C:4]2[N:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:8](=[O:16])[C:7]3=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]3[N:5]=2)[CH3:3])[N:25]=[CH:24][N:23]=1
Reactant: CNS(=O)(=O)c1ccc(OC(=O)c2c(N)ncnc2Cl)cc1
Reactant: Cc1ccn2nc([C@H](C)N)n(-c3ccccc3)c(=O)c12
Agent: [Cs+]
Agent: [F-]
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CNS(=O)(=O)c1ccc(OC(=O)c2c(N)ncnc2N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)cc1
Temperature: 80 °C
Yield: 14 %

Procedure:
(S)-2-(1-Aminoethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (81 mg, 0.27 mmol), 4-(N-methylsulfamoyl)phenyl 4-amino-6-chloropyrimidine-5-carboxylate (135 mg, 0.39 mmol), DIEA (344 μl, 1.97 mmol) and cesium fluoride (150 mg, 0.99 mmol) were suspended in tert-butanol (10 ml) and the mixture was heated at 80° C. in a sealed tube for 24 h. The solvent was evaporated under reduced pressure and the reaction mixture was diluted with ethyl acetate and washed with saturated ammonium chloride solution and brine. After evaporation of the solvent, the residue was purified by reverse phase chromatography using SP1® Purification System to give 27 mg (14% yield) as a solid. Purity 99%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[CH2:25][NH:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:7]=1)[CH3:2].[C:35](Cl)(=[O:37])[CH3:36]>>[CH2:1]([O:3][C:4](=[O:34])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][C:16]=2[CH2:25][N:26]([C:35](=[O:37])[CH3:36])[CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:7]=1)[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(C(F)(F)F)cc2CNCc2ccccc2)c1
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(C(F)(F)F)cc2CN(Cc2ccccc2)C(C)=O)c1

Procedure:
Prepared according to the procedure described in Example 3, Step 3, using the following starting materials: {3-[2-(benzylamino-methyl)-4-trifluoromethyl-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester and acetyl chloride.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C(O[C:10]([NH:12][CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]([C:26]3[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[C:28]([O:36][CH3:37])[CH:27]=3)[CH:21]=2)[CH2:15][CH2:14]1)=O)C.[Cl-].[NH4+]>C1COCC1>[CH3:10][NH:12][CH:13]1[CH2:14][CH2:15][N:16]([CH2:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]([C:26]3[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[C:28]([O:36][CH3:37])[CH:27]=3)[CH:21]=2)[CH2:17][CH2:18]1
Reactant: CCOC(=O)NC1CCN(Cc2ccnc(-c3cc(OC)c(OC)c(OC)c3)c2)CC1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: CNC1CCN(Cc2ccnc(-c3cc(OC)c(OC)c(OC)c3)c2)CC1

Procedure:
To a suspension of lithium aluminum hydride (100 mg) in dry THF (50 mL) was added a solution of 4-(ethoxycarbonylamino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (566 mg) in dry THF (50 mL) under an argon atmosphere. The mixture was then refluxed overnight, then cooled down. Saturated aqueous ammonium chloride was added to the mixture and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was subjected to silica gel column chromatography using chloroform-ammonia saturated methanol (9:1) to give the title compound as yellow oil.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[C-:9]#[N:10].[Na+].O>CS(C)=O>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([C:9]#[N:10])=[N:3][CH:4]=1
Reactant: Cc1ccc(F)nc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc(C#N)nc1
Yield: 30 %

Procedure:
A solution of 2-fluoro-5-methylpyridine (CAN: 2369-19-9, 10 g, 90 mmol) and sodium cyanide (8.8 g, 180 mmol) in DMSO (15 mL) was heated to 150° C. for 48 h. Then water was added, the resulting mixture was extracted with ethyl acetate (3×50 mL) and the combined extracts were washed with sodium hypochlorite solution and brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography (silica gel, 40 g, 10% ethyl acetate in petroleum ether) to yield the title compound (3.2 g, 27 mmol, 30.1%) as yellow solid; MS (EI): m/e=119.1 [M+H]+.
Reaction SMILES: CO.[CH3:3][CH:4]([CH3:16])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-])=O.Cl.C(=O)([O-])O.[Na+]>O>[CH3:3][CH:4]([CH3:16])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH2:13]
Reactant: CC(C)CCc1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)CCc1ccccc1N
Temperature: 60 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
To a mixture composed of 10 ml of methanol, 1.3 g (6.4 mmol) of the above 2-(3-methylbutyl)nitrobenzene, and 6.4 ml of concentrated aqueous hydrochloric acid solution, 1.4 g (25.1 mmol) of reduced iron was added in portions and heated to 60° C. with stirring for 1 hour. The reaction mass was poured into water, neutralized with a saturated aqueous sodium hydrogen carbonate solution and filtered to move precipitated iron hydroxide. The filtrate was extracted with ethyl acetate, washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 0.95 g of the desired product as oil. Yield was 85%.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[CH:5][CH:6]=[N:7]2.[Br:12]N1C(C)(C)C(=O)N(Br)C1=O.C1(C(OO)=O)C=CC=CC=1>ClC(Cl)(Cl)Cl>[Br:12][CH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[CH:5][CH:6]=[N:7]2
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: Cc1cccc2nccnc12
Agent: O=C(OO)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cccc2nccnc12
Reaction time: 16 h
Yield: 100 %

Procedure:
A mixture of 10 parts of 5-methylquinoxaline, 10 parts of 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione, 1.7 parts of benzenecarboperoxoic acid and 318 parts of tetrachloromethane was stirred for 16 hours at reflux temperature under 2 lamps of 250 Watt. The reaction mixture was cooled and the organic layer was decanted. The product was filtered off and dried, yielding 15.5 parts (100%) of 5-(bromomethyl)quinoxaline (interm. 1).
Reaction SMILES: [BH4-].[Na+].CC(O)C.[CH:7]([C:9]1[C:17]2[C:12](=[C:13]([N+:18]([O-])=O)[CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)=O.[CH3:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1)(=[O:24])=[O:23]>[C].[Pd].O>[CH3:7][C:9]1[C:17]2[C:12](=[C:13]([NH:18][S:31]([C:28]3[CH:27]=[CH:26][C:25]([S:22]([CH3:21])(=[O:24])=[O:23])=[CH:30][CH:29]=3)(=[O:33])=[O:32])[CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1
Reactant: CS(=O)(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: O=Cc1c[nH]c2c([N+](=O)[O-])cccc12
Agent: [Pd]
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: Cc1c[nH]c2c(NS(=O)(=O)c3ccc(S(C)(=O)=O)cc3)cccc12
Yield: 61 %

Procedure:
580 mg (15.3 mmol) of sodium borohydride and 150 mg of 10% palladium-carbon were added to a 2-propanol suspension (25 ml) containing 300 mg (1.58 mmol) of 3-formyl-7-nitro-1H-indole, followed by refluxing for 6 hours. After water was added to the reaction system, the catalyst was filtered off. The filtrate was extracted with ethyl acetate, and the extract was washed with brine and then dried over magnesium sulfate. The solvent was evaporated, and the residue was dissolved in 5 ml of pyridine. The mixture was reacted and treated with 170 mg (0.67 mmol) of 4-(methylsulfonyl)benzenesulfonyl chloride in the same manner as in Example 1a, to give 149 mg of the title compound.
Reaction SMILES: [C:1](=[N:9][OH:10])([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:18][CH2:19][C:20](Cl)=O>C1(C)C=CC=CC=1>[Cl:18][CH2:19][C:20]1[O:10][N:9]=[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:8]=1
Reactant: O=C(Cl)CCl
Reactant: NC(=NO)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: ClCc1nc(-c2ccccc2)no1
Temperature: 25 °C

Procedure:
A solution of benzamidoxime (0.77 g, 5.68 mmol) and triethylamine (0.95 mL, 0.82 mmol) in toluene (10 mL) was treated with 0.45 mL (5.65 mmol) of chloroacetyl chloride at room temperature for 30 min., refluxed for 18 hours, cooled to room temperature and concentrated in vacuo. The residue was diluted with water, and extracted with ethyl acetate. The organic extracts were then washed with water and dried with MgSO4. Concentration in vacuo gave an oil which was chromatographed on silica gel using ethyl acetate, hexanes (1.9), giving 0.24 of the title compound as a light yellow oil which solidified on standing. 1H NMR (250 MHz, CDCl3) δ 8.1 (m, 2H), 7.5 (m, 3H), 4.8 (s, 2H).
Reaction SMILES: C[Si](Br)(C)C.C([O:8][P:9]([CH2:14][CH2:15][C:16]([F:28])([F:27])[C:17]([F:26])([F:25])[C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20])(=[O:13])[O:10]CC)C.O>C(Cl)Cl>[F:28][C:16]([F:27])([C:17]([F:25])([F:26])[C:18]([F:23])([F:24])[C:19]([F:21])([F:22])[F:20])[CH2:15][CH2:14][P:9](=[O:8])([OH:13])[OH:10]
Reactant: CCOP(=O)(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)OCC
Agent: C[Si](C)(C)Br
Solvent: O
Solvent: ClCCl
Product: O=P(O)(O)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
Neat 1,1,1,2,2,3,3,4,4-nonafluoro-6-iodohexane (10 mmol) was added to 50 mmol of triethyl phosphate. The reaction mixture was heated at 160° C. overnight to produce diethyl(3,3,4,4,5,5,6,6,6-nonafluorohexyl)phosphonate, which was isolated by fractional distillation (90-95% yield). Neat trimethylsilyl bromide (21 mmol) was added slowly to a solution of diethyl(3,3,4,4,5,5,6,6,6-nonafluorohexyl)phosphonate (7 mmol) in dry CH2Cl2 (25 mL) at 0° C. The reaction mixture was stirred overnight at room temperature, after which time water (30 mmol) was added to the reaction mixture. Volatiles were removed in vacuo leaving (3,3,4,4,5,5,6,6,6-nonafluorohexyl)phosphonic acid as a white crystal (>95% yield). The procedure for producing the phosphonic acid salt was similar as described for Intermediate 1.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][CH2:7][CH3:8])[CH2:3][CH2:4][OH:5].[NH2:9][C:10]1[N:15]=[C:14](Cl)[C:13]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C:25]#[N:26])=[CH:20][C:19]=2[F:27])=[C:12]([CH3:28])[N:11]=1>C(O)CCC>[NH2:9][C:10]1[N:15]=[C:14]([NH:1][C@@H:2]([CH2:6][CH2:7][CH3:8])[CH2:3][CH2:4][OH:5])[C:13]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C:25]#[N:26])=[CH:20][C:19]=2[F:27])=[C:12]([CH3:28])[N:11]=1
Reactant: Cc1nc(N)nc(Cl)c1Cc1ccc(CC#N)cc1F
Reactant: CCC[C@H](N)CCO
Solvent: CCCCO
Product: CCC[C@@H](CCO)Nc1nc(N)nc(C)c1Cc1ccc(CC#N)cc1F
Reaction time: 2 h

Procedure:
(S)-3-Aminohexan-1-ol (0.966 g) was added to a suspension of the product of example 33 step (iii) (1.2 g) in butan-1-ol (9 mL). The reaction was performed in the CEM Microwave, at 180° C. for 2 h. The solvent was evaporated under reduced pressure and the crude product was purified by flash silica chromatography, to give the subtitle compound as an orange solid, 0.98 g.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].CO.C(O)C.C([O:15][CH:16]1[CH:20]([N:21]2[C:25]3[CH:26]=[C:27]([Cl:31])[C:28]([Cl:30])=[CH:29][C:24]=3[N:23]=[C:22]2[I:32])[CH2:19][CH:18]([CH2:33][O:34]C(=O)C)[CH:17]1[O:38]C(=O)C)(=O)C>O.C(O)(=O)C>[Cl:30][C:28]1[C:27]([Cl:31])=[CH:26][C:25]2[N:21]([CH:20]3[CH:16]([OH:15])[CH:17]([OH:38])[CH:18]([CH2:33][OH:34])[CH2:19]3)[C:22]([I:32])=[N:23][C:24]=2[CH:29]=1
Reactant: CC(=O)OCC1CC(n2c(I)nc3cc(Cl)c(Cl)cc32)C(OC(C)=O)C1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: OCC1CC(n2c(I)nc3cc(Cl)c(Cl)cc32)C(O)C1O
Reaction time: 2 h
Yield: 93.3 %

Procedure:
Sodium carbonate (40 mg, 0.37 mmol) was dissolved in water (0.7 mL) and methanol (3 mL) and ethanol (3 mL) were added. To this stirred mixture was added (±)(1R*, 2S*, 3S*, 5S*)-3-(acetoxymethyl)-5-(5,6-dichloro-2-iodo-1H-benzimidazol-1-yl)-1,2-cyclopentanediyl diacetate (215 mg, 0.37 mmol). After 2 hours at ambient temperature, acetic acid was added to adjust the pH to 7 and volatiles were evaporated in vacuo. Resolidification of the residual solid from 3:1 ethanol-water gave (±)-(1R*, 2S*, 3S*, 5S*)-5-(5,6-dichloro-2-iodo-1H-benzimidazol-1-yl)-3-(hydroxymethyl)-1,2-cyclopentanediol as a white powder (153 mg, 94%), m.p. 209°-210° C. dec.; 1H-NMR(DMSO-d6)δ: 8.22 and 7.91 (both s, 2, 2 aromatic CH), 5.12 (t, J=4.5 Hz, 1, OH), 4.95 (d, J=6.2 Hz, 1, OH), 4.9-4.8 (m, 1, NCH), 4.70 (t, J=3.5 Hz, 1, OH), 4.6-4.5 (m, 1, OCH), 3.9-3.8 (m, 1, OCH), 3.7-3.6 and 3.55-3.45 (both m, 1 each, OCH2), 2.2-2.0 (m, 3, CH2 and CH); mass spectrum(CI): 443 (M+1).
Reaction SMILES: [Si:1]([N:8]1[CH:11]([S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][C:9]1=[O:32])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li+].CC([N-]C(C)C)C.[Li]CCCC.C(NC(C)C)(C)C.[C:53]1([CH2:59][C:60](OCC)=[O:61])[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1.Cl>C1COCC1.CCOCC>[Si:1]([N:8]1[C@@H:11]([S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C@H:10]([C:60](=[O:61])[CH2:59][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[C:9]1=[O:32])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCOC(=O)Cc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)CC1SC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: CC(C)NC(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)N1C(=O)[C@@H](C(=O)Cc2ccccc2)[C@@H]1SC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 79.2 %

Procedure:
1-t-Butyldimethylsilyl-4-tritylthio-2-azetidinone (18.32 g, 40 mmol) in dry THF (100 ml) was added dropwise under N2 to a cooled (-78° C.) LDA solution [prepared under N2, at -78° C. from dropwise addition of 1.6 M n-BuLi (101.25 ml, 162 mmol) to diisopropyl amine (22.95 ml, 162 mmol) in dry THF (150 ml) and stirred at -78° C. for 30 min]. The mixture was stirred at -78° C. for 30 min and ethyl phenylacetate (15.66 g, 15.12 ml 15.12 ml, 93.6 mmol) in dry THF (50 ml) was added and the reaction mixture was stirred at -78° C. for 2 h. It was poured onto ice-1 N HCl (pH 5-6) and extracted with ether several times. The ether solution was washed with brine and dried (Na2SO4 ). It was evaporated to dryness to give 33.7 g of a crude solid. This was dissolved in ether (10 ml) and triturated with pentane (200 ml). The solid was filtered and washed several times with pentane to give 18.3 g of a white solid (79.6%) mp 141-143. 1Hmr (CDCl3 δ: 7.0-7.6 (20H, m), 4.8 (H, d), 3.7 (H, d), 3.53 (H, s), 3.43 (H, s) 1.5 (9H, s) and 0.3 ppm (6H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[C:5]([NH:7][CH2:8][C:9]([N:11]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12]1)=[O:10])=[O:6].[CH3:21][S:22](Cl)(=[O:24])=[O:23]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[C:5]([NH:7][CH2:8][C:9]([N:11]1[CH2:15][CH2:14][CH:13]([O:16][S:22]([CH3:21])(=[O:24])=[O:23])[CH2:12]1)=[O:10])=[O:6]
Reactant: O=C(NCC(=O)N1CCC(O)C1)c1ccc(Cl)c(Cl)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)OC1CCN(C(=O)CNC(=O)c2ccc(Cl)c(Cl)c2)C1
Temperature: 50 °C
Yield: 0.1 %

Procedure:
A suspension of 3,4-dichloro-N-[2-(3-hydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-benzamide (2.00 g, 6.30 mol) in pyridine (40 mL) was heated at about 50° C. until the solution became homogenous and then cooled to about 0° C. Methanesulfonyl chloride (1.46 mL, 18.9 mol) was added to the reaction mixture dropwise. The reaction mixture was allowed to warm to room temperature and then concentrated in vacuo. The residue was dissolved in DCM (50 mL), washed with brine (2×50 mL), and the organic portion was separated, dried over MgSO4, filtered, and concentrated in vacuo to give methanesulfonic acid 1-[2-(3,4-dichloro-benzoylamino)-acetyl]-pyrrolidin-3-yl ester (2.46 g, 98%) as a brown oil which was used in subsequent reactions without further purification. RP-HPLC (Table 1, Method n) Rt 1.76 min; m/z: (M+H)+ 395.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6]([OH:8])=O.N1C=CC=CC=1.C(Cl)(=O)C(Cl)=O.[CH3:30][O:31][C:32]1[CH:51]=[CH:50][C:35]([CH2:36][C@@H:37]2[CH2:42][N:41]([CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[CH2:40][CH2:39][NH:38]2)=[CH:34][CH:33]=1>O1CCCC1.ClCCl.C(N(CC)CC)C>[F:16][C:2]([F:1])([F:17])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6]([N:38]1[CH2:39][CH2:40][N:41]([CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:42][C@H:37]1[CH2:36][C:35]1[CH:34]=[CH:33][C:32]([O:31][CH3:30])=[CH:51][CH:50]=1)=[O:8]
Reactant: O=C(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COc1ccc(C[C@@H]2CN(Cc3ccccc3)CCN2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc(C[C@@H]2CN(Cc3ccccc3)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1
Temperature: 55 °C
Reaction time: 0.08 h
Yield: 80.1 %

Procedure:
To a solution of 3,5-bis(trifluoromethyl)benzoic acid (3.04 g) and pyridine (0.030 ml) in tetrahydrofuran (9 ml) was added dropwise oxalyl chloride. (1.80 g) over 5 minutes, and the reaction mixture was heated at 55° C. with stirring for one hour. After cooling, the solution was added dropwise to a solution of (2R)-2-(4-methoxybenzyl)-4-benzylpiperazine (3.47 g) and triethylamine (3.55 g) in dichloromethane (35 ml) below 5C over 30 minutes under nitrogen atmosphere. The reaction mixture was stirred at room temperature for one hour, and concentrated under reduced pressure. To the residue were added ethyl acetate (40 ml) and water (20 ml) with stirring. The organic layer was separated, washed with brine, and dried over magnesium sulfate. After removal of the solvent by evaporation, the resulting residue was purified by column chromatography on silica gel (70 g) using a mixed solvent of toluene and ethyl acetate (5:1). The fractions containing the objective compound were collected and evaporated under reduced pressure to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(4-methoxybenzyl)-4-benzylpiperazine (5.03 g) as syrup.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:17]2[CH2:18][CH2:19][CH:9]1[C:10]1[C:11]([OH:28])=[C:12]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:13]=[CH:14][C:15]=1[CH2:16]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].S(OC)(O[CH3:33])(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>O>[C:1]([O:5][C:6]([N:8]1[CH:17]2[CH2:18][CH2:19][CH:9]1[C:10]1[C:11]([O:28][CH3:33])=[C:12]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:13]=[CH:14][C:15]=1[CH2:16]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1O)C1CCC(C2)N1C(=O)OC(C)(C)C
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: COc1c(NC(=O)OC(C)(C)C)ccc2c1C1CCC(C2)N1C(=O)OC(C)(C)C

Procedure:
4-tert-Butoxycarbonylamino-3-hydroxy-12-aza-tricyclo[7.2.1.0*2,7*]dodeca-2(7),3,5-triene-12-carboxylic acid tert-butyl ester (260 mg, 0.67 mmol), dimethyl sulfate (0.13 mL, 1.3 mmol), cesium carbonate (430 mg, 1.3 mmol) and dioxane (3 mL) were stirred together at 90° C. for 20 h. The reaction mixture was then diluted with water (5 mL), extracted with CH2Cl2 (2×5 mL), dried over MgSO4, filtered and concentrated. The resulting residue was purified with silica gel chromatography (0-50% EtOAc in hexanes) to obtain 4-tert-Butoxycarbonylamino-3-methoxy-12-aza-tricyclo[7.2.1.0*2,7*]dodeca-2(7),3,5-triene-12-carboxylic acid tert-butyl ester as a yellow, foamy residue (198 mg, 74%). 1HNMR (400 MHz, CDCl3) δ 7.6 (s, 1H), 7.4 (d, 1H, J=8.0 Hz), 7.1 (d, 1H, J=8.0 Hz), 4.5 (m, 1H), 4.1 (m, 1H), 3.3 (s, 3H), 3.1 (dd, 1H, J=14.4, 4.8 Hz), 2.9 (dd, 1H, J=14.5, 5.0 Hz), 2.7 (dd, 1H, J=17.9, 7.8 Hz), 2.6 (dd, 1H, J=18.4, 10.4 Hz), 2.2 (m, 1H), 1.5-1.4 (m, 19H); MS (m/e) 349 (M-C4H7).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[CH:17]([CH2:21][CH:22]=[CH2:23])[C:18](=O)[CH3:19]>C(O)C>[CH2:9]([O:8][C:7]1[C:2]2[N:3]([C:17]([CH2:21][CH:22]=[CH2:23])=[C:18]([CH3:19])[N:1]=2)[CH:4]=[CH:5][CH:6]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Nc1ncccc1OCc1ccccc1
Reactant: C=CCC(Cl)C(C)=O
Solvent: CCO
Product: C=CCc1c(C)nc2c(OCc3ccccc3)cccn12
Yield: 7.4 %

Procedure:
A solution of 2-amino-3-benzyloxypyridine (3 g) and 3-chloro-5-hexen-2-one (2.981 g) in ethanol (15 ml) was stirred and refluxed for 45 hours and then evaporated in vacuo. To the residue was added an aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and evaporated in vacuo. The oily residue was purified by column chromatography on silica gel (50 g) using methylene chloride and then chloroform as eluents. The eluate with chloroform was evaporated in vacuo and the residual solid was recrystallized from diisopropyl ether to give 8-benzyloxy-3-allyl-2-methylimidazo[1,2-a]pyridine (0.31 g).