Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[OH:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH:32]=[O:33].N(C(OCC)=O)=NC([O-])=O>O1CCCC1>[CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[O:8][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH:32]=[O:33]
Reactant: OC1CC2C=CC1C2
Reactant: O=Cc1cccc(O)c1
Agent: CCOC(=O)N=NC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=Cc1cccc(OC2CC3C=CC2C3)c1
Temperature: 75 °C
Reaction time: 48 h

Procedure:
3 g of bicyclo[2.2.1)hept-5-en-2-ol (27.2 mmol) and then 7.86 g of triphenylphosphine (30 mmol) are introduced at 0° C. into a solution of 3.66 g of 3-hydroxybenzaldehyde (30 mmol) in tetrahydrofuran (40 ml), and 13.6 ml of ethyl azodicarboxylate (40% in toluene, 30 mmol) are then added dropwise. The mixture is stirred at 75° C. for 48 hours, the solvent is then evaporated off, the residue is taken up in dichloromethane and the mixture is washed with normal aqueous sodium hydroxide solution, water and then saturated aqueous sodium chloride solution. The resulting solution is dried over magnesium sulfate, filtered and concentrated. The title product is isolated by chromatography on a column of silica (eluent: 88/12 cyclohexane/ethyl acetate). 0.6 g of a colorless oil is obtained:
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[C:13]([NH:15][C:16]2[C:17]([CH3:31])=[C:18]([CH2:22][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:19]=[CH:20][CH:21]=2)=[O:14])=[CH:8][CH:7]=1)(=O)C>N.CO>[CH:32]1([CH:12]([C:9]2[CH:10]=[CH:11][C:6]([CH2:5][OH:4])=[CH:7][CH:8]=2)[C:13]([NH:15][C:16]2[C:17]([CH3:31])=[C:18]([CH2:22][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:19]=[CH:20][CH:21]=2)=[O:14])[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: CC(=O)OCc1ccc(C(C(=O)Nc2cccc(CCC(=O)OC(C)(C)C)c2C)C2CCCC2)cc1
Agent: N
Solvent: CO
Product: Cc1c(CCC(=O)OC(C)(C)C)cccc1NC(=O)C(c1ccc(CO)cc1)C1CCCC1
Temperature: 35 °C
Reaction time: 2 h

Procedure:
16.0 g (32.41 mmol) of tert-butyl(+/−)-3-(3-{[{4-[(acetyloxy)methyl]phenyl}(cyclopentyl)-acetyl]amino}-2-methylphenyl)propanoate were dissolved in 300 ml of a 2 M solution of ammonia in methanol and initially stirred at 30-40° C. for 2 h and then overnight at RT. The solution was then concentrated under reduced pressure and the residue was purified by chromatography on silica gel (mobile phase dichloromethane/methanol 100:1). This gave 13.6 g (93.1% of theory) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]([CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])[CH:6]([CH3:13])[CH2:5][C:4](=[O:14])[CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.CO>CCCCCC>[CH3:1][C:2]1[CH:7]([CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])[CH:6]([CH3:13])[CH2:5][CH:4]([OH:14])[CH:3]=1
Reactant: CC(C)=CCC1C(C)=CC(=O)CC1C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCCCCC
Solvent: CO
Product: CC(C)=CCC1C(C)=CC(O)CC1C
Reaction time: 2 h
Yield: 97.8 %

Procedure:
A solution of 3,5-dimethyl-4-(3methyl-2-butenyl)-2-cyclohexen-1-one (4 g, 0.02 mol) in hexane (25 mL) was stirred under nitrogen at 0° C. and 1 M diisobutylaluminum hydride (25 mL) was added dropwise over 30 minutes. The mixture was stirred for 2 hours and methanol (60 mL) added to precipitate the salts. The solution was filtered and washed with 15% hydrochloric acid, saturated sodium bicarbonate and brine. Drying (Na2SO4), and solvent removal, followed by Kugelrohr distillation gave 3.8 g of 3,5-dimethyl-4-(3-methyl-2-butenyl)-2-cyclohexen-1-ol, bp 135° -140° C./0.5 mm.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].C[O:10][C:11]1[CH:28]=[CH:27][C:14]2[CH:15]([CH3:26])[CH2:16][N:17]([C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])[CH2:18][CH2:19][C:13]=2[CH:12]=1.Cl>ClCCl.C(Cl)(Cl)Cl.O>[OH:7][C:5]1[C:28]([C:11](=[O:10])[CH3:12])=[CH:27][C:14]2[CH:15]([CH3:26])[CH2:16][N:17]([C:20](=[O:25])[C:21]([F:24])([F:22])[F:23])[CH2:18][CH2:19][C:13]=2[CH:6]=1
Reactant: COc1ccc2c(c1)CCN(C(=O)C(F)(F)F)CC2C
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: CC(=O)c1cc2c(cc1O)CCN(C(=O)C(F)(F)F)CC2C

Procedure:
To a mixed liquid of 9.3 g of aluminum chloride in 30 ml of dichloromethane was added dropwise 1.6 ml of acetyl chloride under ice-cooling, followed by stirring. Then, a solution of 5 g of 7-methoxy-1-methyl-3-(trifluoroacetyl)-2,3,4,5-tetrahydro-1H-3-benzazepine in 70 ml of dichloromethane was added thereto, followed by stirring for 13 hours while slowly elevating the temperature to room temperature. The reaction mixture was ice-cooled, and 30 ml of 1 M hydrochloric acid was added dropwise thereto, followed by addition of water and extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (elution solvent: HEX-EtOAc) to obtain 5.137 g of 1-[8-hydroxy-5-methyl-3-(trifluoroacetyl)-2,3,4,5-tetrahydro-1H-3-benzazepine-7-yl]ethanone as a pale brown solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][NH2:10])([CH3:4])([CH3:3])[CH3:2].[BH3-]C#N.[Na+].CC(O)=O.[CH:20]([CH:22]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[C:27]([C:31]#[N:32])[CH:28]=2)[CH2:23]1)=O.C([O-])([O-])=O.[Na+].[Na+]>CO>[C:31]([C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][CH:26]=1)[CH2:23][CH:22]([CH2:20][NH:10][CH2:9][CH2:8][NH:7][C:6](=[O:11])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:30]2)#[N:32]
Reactant: N#Cc1ccc2c(c1)CC(C=O)C2
Reactant: CC(C)(C)OC(=O)NCCN
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NCCNCC1Cc2ccc(C#N)cc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of (2-amino-ethyl)-carbamic acid tert-butyl ester (400 mg, 2.5 mmol), NaBH3CN (315 mg, 5.0 mmol) and HOAc (300 mg, 5.0 mmol) in 30 mL MeOH was added 2-formyl-2,3-dihydro-1H-indene-5-carbonitrile (430 mg, 2.5 mmol). The mixture was stirred at RT overnight, and then sat. Na2CO3 (50 mL) was added and stirred for 30 min. The mixture was extracted with EtOAc (3×50 mL) and the combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by prep-TLC to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1Cl)=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[O:5])[CH3:2].[Cl:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[C:22]([Cl:24])[CH:23]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Na+].[Na+]>CC#N.CC(O)C.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:20]1[CH:19]=[C:18]([Cl:17])[CH:23]=[C:22]([Cl:24])[CH:21]=1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Reactant: CCOC(=O)c1[nH]c2ccc(Br)cc2c1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: CC(C)O
Solvent: O
Product: CCOC(=O)c1cc2cc(-c3cc(Cl)cc(Cl)c3)ccc2[nH]1
Temperature: 25 °C
Yield: 69.2 %

Procedure:
To a stirred solution of 5-bromo-3-chloro-1H-indole-2-carboxylic acid ethyl ester (500 mg, 1.86 mmol) and 3,5-dichlorophenyl boronic acid (530 mg, 2.78 mmol) in a mixture of MeCN (26 mL) and i-PrOH (3.3 mL) at room temperature under argon, was added Pd(OAc)2 (12 mg, 0.05 mmol), Ph3P (40 mg, 0.15 mmol) and Na2CO3 (2M aq., 16 mL) and the resulting mixture was heated at reflux for 3 h. After cooling to room temperature the reaction was diluted with water (20 mL) and extracted with EtOAc (3×30 mL). The combined organic extracts were washed with water, brine and dried (MgSO4). Solvent removal and purification by chromatography afforded the sub-title compound (430 mg, 69%).
Reaction SMILES: C([O:4][C:5]1[CH:29]=[CH:28][CH:27]=[CH:26][C:6]=1[C:7]([NH:9][C:10]1[S:22][C:13]2[C:14]([CH3:21])([CH3:20])[O:15][C:16]([CH3:19])([CH3:18])[CH2:17][C:12]=2[C:11]=1[C:23]([NH2:25])=[O:24])=[O:8])(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.O1CCOCC1>[OH:4][C:5]1[CH:29]=[CH:28][CH:27]=[CH:26][C:6]=1[C:7]([NH:9][C:10]1[S:22][C:13]2[C:14]([CH3:21])([CH3:20])[O:15][C:16]([CH3:18])([CH3:19])[CH2:17][C:12]=2[C:11]=1[C:23]([NH2:25])=[O:24])=[O:8]
Reactant: CC(=O)Oc1ccccc1C(=O)Nc1sc2c(c1C(N)=O)CC(C)(C)OC2(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1COCCO1
Product: CC1(C)Cc2c(sc(NC(=O)c3ccccc3O)c2C(N)=O)C(C)(C)O1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-(2-acetoxybenzamido)-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxamide (200 mg, 0.48 mmol) in 4 mL of MeOH/dioxane=1:1, cooled to 0° C., is added potassium carbonate (66 mg, 0.52 mmol). The reaction mixture is stirred at room temperature for 90 min, filtered off and filtrate is then acidified with 1M HCl. A precipitate is formed which is separated by filtration to afford the desired compound which is used as such.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13](#[N:16])[CH2:14][CH3:15].Br[C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][N:19]=1>C1COCC1>[Cl:24][C:23]1[C:18]([CH:14]([CH3:15])[C:13]#[N:16])=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCC#N
Reactant: Clc1cccnc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C#N)c1ncccc1Cl
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 91.2 %

Procedure:
To a −78° C. solution of diisopropylamine (3.04 g, 4.28 mL, 30 mmol) was added n-butyl lithium (13.2 mL, 2.5M in hexane, 33 mmol). The reaction mixture was stirred for 20 minutes at −78° C., followed by the addition of propionitrile (1.65 g, 2.15 mL, 30 mmol). The reaction mixture was stirred for an additional 50 minutes, followed by the slow addition of 2-bromo-3-chloropyridine (1.92 g, 10 mmol) in THF (10 mL). The reaction was then allowed to warm to ambient temperature and stirred overnight. The reaction mixture was quenched with water and extracted with two portions of diethyl ether. The combined organic phases were washed with brine, concentrated, and the residue chromatographed on silica gel eluting with 30% ethyl acetate-hexane to obtain the title compound (1.52 g, 91%). 1H NMR (300 MHz, DMSO-d6) δ ppm 8.59 (dd, J=1.5, 4.7, 1H), 8.02 (dd, J=1.5, 8.1, 1H), 7.48 (dd, J=4.7, 8.1, 1H), 4.73 (q, J=7.1, 1H), 1.59 (d, J=7.1, 3H). MS (DCI) m/z 167 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[Si]([C:19]#[N:20])(C)(C)C.[Al+3].[Cl-].[Cl-].[Cl-].CS(O)(=O)=O>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][C:11]([OH:14])([C:19]#[N:20])[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)C#N
Reactant: O=C1CCN(c2ncccc2Cl)CC1
Agent: CS(=O)(=O)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O
Product: N#CC1(O)CCN(c2ncccc2Cl)CC1
Reaction time: 8 h

Procedure:
A solution of N-(3-chloro-2-pyridyl)-4-piperidone (compound 21) (13 g, 62 mmol), TMS-CN (6.2 g, 62 mmol) and AlCl3 (0.1 g) in toluene (100 ml) was heated to 60° C., and stirred overnight. Then 0.1 equivalent of methanesulfonic acid was added, and the reaction mixture was heated to reflux for half an hour. After the reaction was completed, three times of water was added into the reaction solution. The reaction mixture was extracted by ethyl acetate. The organic layer was evaporated to give a crude product, which was purified using column chromatography to give the product. (8 g, 55%)
Reaction SMILES: [OH:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[CH:5]=[C:4]([C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[CH:3]=1.[F:27][C:28]1[CH:37]=[C:36]([F:38])[CH:35]=[C:34]2[C:29]=1[CH:30](O)[CH2:31][CH2:32][O:33]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[F:27][C:28]1[CH:37]=[C:36]([F:38])[CH:35]=[C:34]2[C:29]=1[CH:30]([O:1][C:2]1[C:10]3[N:9]=[C:8]([CH3:11])[N:7]([S:12]([C:15]4[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=4)(=[O:14])=[O:13])[C:6]=3[CH:5]=[C:4]([C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[CH:3]=1)[CH2:31][CH2:32][O:33]2
Reactant: Cc1ccc(S(=O)(=O)n2c(C)nc3c(O)cc(C(=O)N(C)C)cc32)cc1
Reactant: OC1CCOc2cc(F)cc(F)c21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2c(C)nc3c(OC4CCOc5cc(F)cc(F)c54)cc(C(=O)N(C)C)cc32)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred mixture of 4-hydroxy-N,N,2-trimethyl-1-[(4-methylphenyl)sulfonyl]-1H-benzimidazole-6-carboxamide (110 mg, 0.294 mmol, STEP 7), 5,7-difluoro-3,4-dihydro-2H-chromen-4-ol (164 mg, 0.884 mmol, STEP 8-1) and triphenylphosphine (232 mg, 0.884 mmol) in toluene (5 mL) was added diisopropyl azodicarboxylate (DIAD) (179 mg, 0.884 mmol) at room temperature. The reaction mixture was stirred at room temperature for 6 hours and concentrated in vacuum. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane gradient elution from 1:20 to 10:1) to afford a mixture of the title compound and triphenylphosphine oxide (280 mg, crude) as white solids, which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O-])=[O:7])=[C:4]([CH3:11])[CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[F:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][OH:7])=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(F)ccc1C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(F)ccc1CO
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.2 %

Procedure:
4-Fluoro-2-methylbenzoate (15.3 g, 91 mmol) was dissolved in THF under a stream of nitrogen. The mixture was cooled to 0° C. while adding LiAlH4 (4.4 g, 110 mmol) in small portions and then stirred at room temperature for 1 h. Water (4.4 mL), aqueous 15% NaOH (4.4 mL) and then more water (13.2 mL) were added dropwise in the given order while cooling to 0° C. The mixture was stirred for 2 h and then the solid material was filtered off. The solvent was removed by evaporation and there was obtained 11.5 g (90%) of (4-fluoro-2-methylphenyl)methanol as an oil. 1H NMR (300 MHz, CDCl3): 2.4 (s, 3H), 4.6 (s, 2H), 6.8-6.9 (m, 2H), 7.3 (t, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH:12]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:13])[C:5]([O:7]C)=[O:6].O.[OH-].[Li+].O.CO>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH:12]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:13])[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(C(C)Oc2ccccc2)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(Oc1ccccc1)c1ccc(C(=O)O)cc1Cl
Temperature: 20 °C
Reaction time: 5 h
Yield: 66.9 %

Procedure:
A mixture of methyl 3-chloro-4-(1-phenoxyethyl)benzoate (750 mg, 2.7 mmol), lithium hydroxide monohydrate (571 mg, 13.6 mmol), water (5 mL) and methanol (5 mL) in tetrahydrofuran (15 mL) was stirred at 20° C. for 5 hours. The reaction mixture was concentrated. The residue was acidified to pH=2 with concentrated hydrochloride solution. The mixture was extracted with ethyl acetate (20 mL×2). The organic phase was dried over sodium sulfate and filtered. The filtrate was concentrated. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=2:1) to give 3-chloro-4-(1-phenoxyethyl)benzoic acid as a white solid (500 mg, 71%). LRMS (M+H+) m/z: 276.06. found 276.
Reaction SMILES: [Br-].[CH3:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][CH2:8][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:5][CH:4]=1.[Li]CCCC.[CH:35](=O)[CH2:36][CH2:37]/[CH:38]=[CH:39]/[CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]>>[CH2:7]([C:6]1[CH:5]=[CH:4][C:3]([CH3:2])=[CH:29][CH:28]=1)[CH:8]=[CH:35][CH2:36][CH2:37]/[CH:38]=[CH:39]/[CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]
Reactant: CCCCC/C=C/CCC=O
Reactant: Cc1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Li]CCCC
Product: CCCCC/C=C/CCC=CCc1ccc(C)cc1
Yield: 57 %

Procedure:
Starting from p-methylphenethyltriphenylphosphonium bromide (2.90 g, 6.29 mmol, 1.0 equiv.), n-BuLi (1.6 M in hexanes, 3.9 mL, 6.29 mmol, 1.0 equiv.) and (E)-dec-4-enal (1.45 g, 9.43 mmol, 1.5 equiv.), 0.92 g (57%) of the title compound as a colorless oil was obtained after purification by flash chromatography on SiO2 (cyclohexane/EtOAc 997:3).
Reaction SMILES: C([C@H:3]([S:7]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[N:9][C:10]([C:12]1[CH:13]=[N:14][CH:15]=[C:16]([C:18]#[C:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=2)[CH:17]=1)=[O:11])=[O:8])[C:4]([O-:6])=O)C.[CH3:33][NH:34][CH2:35][CH2:36][OH:37]>>[OH:37][CH2:36][CH2:35][N:34]([CH3:33])[C:4](=[O:6])[CH2:3][S@:7](=[O:8])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[N:9][C:10](=[O:11])[C:12]1[CH:17]=[C:16]([C:18]#[C:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=2)[CH:15]=[N:14][CH:13]=1
Reactant: CC[C@@H](C(=O)[O-])S(=O)(=NC(=O)c1cncc(C#Cc2cccc(O)c2)c1)c1ccccc1
Reactant: CNCCO
Product: CN(CCO)C(=O)C[S@@](=O)(=NC(=O)c1cncc(C#Cc2cccc(O)c2)c1)c1ccccc1
Yield: 62.8 %

Procedure:
In a manner similar to that described for Example 471, (S)-Ethyl[N-({5-[(3-hydroxyphenyl)ethynyl]pyridin-3-yl}carbonyl)-S-phenylsulfonimidoyl]acetate (65 mg, 0.14 mmol) and 2-(methylamino)ethanol (0.1 mL, 1.2 mmol) were reacted to give the title as clear oil (42 mg, 61%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH:3]1[CH2:5][O:4]1.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH2:17])=[CH:12][CH:11]=1>C(O)(C)C>[F:1][C:2]([F:7])([F:6])[CH:3]([OH:4])[CH2:5][NH:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][CH3:8])=[CH:11][CH:12]=1
Reactant: COc1ccc(CN)cc1
Reactant: FC(F)(F)C1CO1
Solvent: CC(C)O
Product: COc1ccc(CNCC(O)C(F)(F)F)cc1
Temperature: 80 °C
Yield: 70.6 %

Procedure:
To a solution of 2-(trifluoromethyl)oxirane (2.00 g, 17.8 mmol) in isopropanol (20 mL) in a pressure tube was added (4-methoxyphenyl)methanamine (7.35 g, 53.5 mmol). The reaction vessel was capped and heated at 80° C. for 3 h. The reaction mixture was concentrated and purified by silica gel chromatography (80 g REDISEP® column, eluting with a gradient from 0-60% EtOAc in hexanes). The required fractions were concentrated to obtain Intermediate A125A (3.1 g, 70.6% yield) as a white solid. MS(ES) m/z=287 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 7.29-7.17 (m, 2H), 6.87 (d, J=8.5 Hz, 2H), 6.25 (br. s., 1H), 4.04 (td, J=7.8, 3.3 Hz, 1H), 3.72 (s, 3H), 3.66 (d, J=1.8 Hz, 2H), 2.74-2.55 (m, 2H), 2.08 (br. s., 1H).
Reaction SMILES: [CH3:1][S:2]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14](=[O:22])[C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)=[CH:11][CH:12]=2)[CH:7]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)[CH2:6]1)(=[O:4])=[O:3].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCOCC1>[CH3:1][S:2]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14](=[O:22])[C:15]3[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=3)=[CH:11][CH:12]=2)[C:7]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)=[CH:6]1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)N1CC(c2cccc(Cl)c2)c2cc(C(=O)c3ccc(Cl)cc3)ccc21
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: CS(=O)(=O)n1cc(-c2cccc(Cl)c2)c2cc(C(=O)c3ccc(Cl)cc3)ccc21
Temperature: 95 °C
Yield: 56 %

Procedure:
A solution of 1-methylsulfonyl-3-(3-chlorophenyl)-5-(4-chlorobenzoyl)indoline (350 mg) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (356 mg) in dioxane (6 mL) was refluxed under N2 for about 6 hours and then heated at about 95° C. overnight. The solvent was removed. The residue was purified by column chromatography on silica, eluting with EtOAc/hexane, 1:4. The title compound was obtained as a solid. MS(ES): 443.2, calc. Mw=443.4. Rf=0.38, silica, EtOAc/hexane, 1:2. 195 mg, yield: 56%.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[CH:7][NH:8]2)=[C:4]([I:13])[CH:3]=1.[H-].[Na+].I[CH3:17]>CN(C=O)C>[CH3:17][N:8]1[C:9]2[C:5](=[C:4]([I:13])[CH:3]=[C:2]([CH3:1])[CH:10]=2)[C:6]([CH:11]=[O:12])=[CH:7]1
Reactant: Cc1cc(I)c2c(C=O)c[nH]c2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(I)c2c(C=O)cn(C)c2c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a cold solution (0° C.) of 6-methyl-4-iodo-indole-3-carboxaldehyde (265 mg, 0.92 mmol) in dry DMF (2 mL) was added NaH (60% dispersion in mineral oil, 50 mg, 1.25 mmol). The resulting mixture was stirred at 0° C. for 20 min. Iodomethane (0.5 mL, excess) was added to the reaction mixture in a drop wise fashion. The cooling bath was removed and the resulting mixture was stirred at room temperature for 1.5 h. The mixture was quenched with water and was extracted repeatedly from EtOAc. Combined organic was washed with water (twice) and brine. After drying over magnesium sulfate, solvent was removed. The product, 1,6-dimethyl-4-iodo-indole-3-carboxaldehyde was obtained as a solid was which was suspended in hexane, stirred for few minutes and was filtered. The product was further washed with more hexane and was dried to yield 213 mg (77%) of the desired product. MS: 300 (M+H), 322 (M+Na).
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=1.[CH3:9][Mg]I>C(OCC)C>[CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=1.[CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH2:3]1
Reactant: C[Mg]I
Agent: CC1=CC(=O)CCC1
Solvent: CCOCC
Product: CC1(C)CCCC(=O)C1

Procedure:
First, 3-methyl-cyclohexenone was prepared in accordance with the procedures of Jirgensons et. al., Euro. J. Med. Chem. 35 (2000) 555-565. Then, 3-methyl-cyclohexenone was reacted with methyl magnesium iodide in the presence of cuprous chloride in diethyl ether to obtain the title compound.
Reaction SMILES: [CH2:1]1[CH:5]2[C:6](=[O:15])[NH:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[N:10]=[C:4]2[CH2:3][CH2:2]1.[H-].[Na+].[CH2:18](Br)[CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[Cl-].[NH4+]>CN(C)C=O.O>[C:21]1([CH:20]=[CH:19][CH2:18][N:7]2[C:6](=[O:15])[CH:5]3[CH2:1][CH2:2][CH2:3][C:4]3=[N:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]2=3)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C1Nc2ccccc2N=C2CCCC12
Reactant: BrCC=Cc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1C2CCCC2=Nc2ccccc2N1CC=Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A solution of 2,3,9,10a-tetrahydrobenzo[b]cyclopenta[1,4]diazepin-10(1H)-one (4.0 g, 20 mmol) in N,N-dimethylformamide (20 mL) was cooled at 0° C. To the solution was added sodium hydride (60% liquid paraffin dispersion, 0.84 g, 21 mmol). The mixture was stirred for 5 minutes at the same temperature and, then for 10 minutes at room temperature. The reaction mixture was cooled to 0° C., to which was added dropwise a solution of cinnamyl bromide (4.7 g, 24 mmol) in N,N-dimethylformamide (5 mL). The mixture was stirred for 30 minutes at room temperature. The reaction mixture was poured into a saturated aqueous solution of ammonium chloride (40 mL), which was diluted with water, followed by extraction with ethyl acetate three times. Organic layers were combined, which was washed with water and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, followed by filtration. The filtrate was concentrated under reduced pressure. The concentrate was subjected to a silica-gel column chromatography (hexane-ethyl acetate 5:1, then 2:1) to give a crude product of 9-(3-phenyl-2-propen-1-yl)-2,3,9,10a-tetrahydrobenzo[b]cyclopenta-[e][1,4]diazepin-10(1H)-one. The crude product was dissolved in methanol (10 mL), to which was added bromocresol green. To the mixture was added at 0° C. sodium cyanoborohydride (1.26 g, 20 mmol), to which was slowly added a 10% HCl-methanol solution until no more change was observed in the color of the solution. To the reaction mixture was added water, which was subjected to extraction with ethylacetate three times. Organic layers were combined, which was washed with water and a saturated aqueous solution of sodium chloride, followed by drying over magnesium sulfate and filtration. The filtrate was concentrated under reduced pressure to give the object compound (6.0 g, 94%) as an oily product.