Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[CH3:2][O-:3].[Na+].[O:5]1[C@H:7]2[CH2:8][C@H:9]3[C@:24]([CH3:26])([CH2:25][C@@H:6]12)[C@@H:23]1[C@H:12]([C@H:13]2[C@:20]([CH3:28])([CH2:21][C:22]1=[O:27])[C@@H:16]([C:17](=[O:19])[CH3:18])[CH2:15][CH2:14]2)[CH2:11][CH2:10]3.Cl>CO.O>[OH:3][C@@H:2]1[C@@H:6]([O:5][CH3:7])[CH2:25][C@@:24]2([CH3:26])[C@@H:9]([CH2:10][CH2:11][C@@H:12]3[C@@H:23]2[C:22](=[O:27])[CH2:21][C@@:20]2([CH3:28])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C:17](=[O:19])[CH3:18])[CH2:8]1
Reactant: C[O-]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H]5O[C@@H]5C[C@]4(C)[C@H]3C(=O)C[C@]12C
Agent: Cl
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CO
Product: CO[C@H]1C[C@@]2(C)[C@@H](CC[C@H]3[C@@H]4CC[C@H](C(C)=O)[C@@]4(C)CC(=O)[C@@H]32)C[C@@H]1O

Procedure:
Sodium (70 mg.) was dissolved in dry methanol (5 ml.), and to the resulting solution of sodium methoxide (about 166 mg,) was added 2α,3α-epoxy-5α-pregnane-11,20-dione (100 mg). The solution was refluxed for 5 days, then water was added, and the mixture was neutralised with dilute hydrochloric acid and extracted into chloroform. The extract was dried over sodium sulphate and evaporated to a brown oil which was purified by preparative TLC in ethyl acetate/petrol (1/1). The title compound was recrystallised from ethyl acetate/petrol (21 mg).
Reaction SMILES: [CH2:1]([C:13]1[CH:18]=[CH:17][C:16]([N:19]=[N:20][C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Br:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]Br.[OH-].[K+]>C(O)C>[Br:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][O:27][C:24]1[CH:23]=[CH:22][C:21]([N:20]=[N:19][C:16]2[CH:15]=[CH:14][C:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:18][CH:17]=2)=[CH:26][CH:25]=1
Reactant: BrCCCCCCCCCCBr
Reactant: CCCCCCCCCCCCc1ccc(N=Nc2ccc(O)cc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCCCc1ccc(N=Nc2ccc(OCCCCCCCCCCBr)cc2)cc1
Temperature: 25 °C

Procedure:
A 3000 ml three-necked round bottom flask was equipped with magnetic stirring, a heating mantle, a reflux condenser, and a nitrogen atmosphere. The flask was charged with 4-dodecyl-4'-hydroxyazobenzene (60.0 g, 0.164 mol), 1,10-dibromodecane, (66.95 g, 0.223 mol), potassium hydroxide (9.75 g, 0.174 mol), and ethanol (1260 ml). The stirring mixture was refluxed for seven hours. During the course of the reaction, a yellow precipitate formed in the reaction mixture. The reaction mixture then was cooled to room temperature and chilled in an ice-water bath. A crude product was isolated by suction filtration, washed with water, then with hexane. The product was recrystallized from ethyl acetate.
Reaction SMILES: [N:1]1([C:6]2[NH:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:16]1[N:24]=[C:23]2[C:19]([N:20]=[C:21]([CH2:26][N:27]3[CH2:32][CH2:31][CH:30]([C:33]([OH:36])([CH3:35])[CH3:34])[CH2:29][CH2:28]3)[N:22]2[CH3:25])=[C:18]([N:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)[N:17]=1>>[CH3:25][N:22]1[C:21]([CH2:26][N:27]2[CH2:32][CH2:31][CH:30]([C:33]([OH:36])([CH3:35])[CH3:34])[CH2:29][CH2:28]2)=[N:20][C:19]2[C:23]1=[N:24][C:16]([N:10]1[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]=[C:6]1[N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[N:17][C:18]=2[N:37]1[CH2:38][CH2:39][O:40][CH2:41][CH2:42]1
Reactant: c1ccc2[nH]c(N3CCCC3)nc2c1
Reactant: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Product: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(-n3c(N4CCCC4)nc4ccccc43)nc21

Procedure:
Following General Procedure I for Buchwald coupling, 2-(pyrrolidin-1-yl)-1H-benzo[d]imidazole and 2-(1-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol were reacted to give 261. LCMS m/z: 560.3 (MH+)
Reaction SMILES: [CH2:1]([S:8][C:9]1[C:14]2[N:15]=[C:16](OC3C=CC=CC=3)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:32][CH2:33][CH2:34][NH2:35]>>[CH2:1]([S:8][C:9]1[C:14]2[N:15]=[C:16]([NH:35][CH2:34][CH2:33][OH:32])[N:17]=[C:18]([N:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCO
Reactant: c1ccc(CSc2ncnc3c(N4CCOCC4)nc(Oc4ccccc4)nc23)cc1
Product: OCCNc1nc(N2CCOCC2)c2ncnc(SCc3ccccc3)c2n1

Procedure:
The same substance was also obtained in analogous manner by heating 8-benzylthio-4-morpholino-2-phenoxypyrimido[5,4-d]pyrimidine (melting point: 159°-161° C.) at 90° C. with 2-hydroxyethyl-amine.
Reaction SMILES: [O:1]=[S:2]1(=[O:25])[N:9]([C:10]2[C:15]([Cl:16])=[CH:14][C:13]([Cl:17])=[CH:12][C:11]=2[Cl:18])[CH2:8][C:5]2([CH2:7][CH2:6]2)[CH2:4][N:3]1[CH2:19][C:20]([O:22]CC)=[O:21].C(OCC)(=O)C.Cl>C1COCC1.CO.O>[O:25]=[S:2]1(=[O:1])[N:9]([C:10]2[C:11]([Cl:18])=[CH:12][C:13]([Cl:17])=[CH:14][C:15]=2[Cl:16])[CH2:8][C:5]2([CH2:6][CH2:7]2)[CH2:4][N:3]1[CH2:19][C:20]([OH:22])=[O:21]
Reactant: CCOC(=O)CN1CC2(CC2)CN(c2c(Cl)cc(Cl)cc2Cl)S1(=O)=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)CN1CC2(CC2)CN(c2c(Cl)cc(Cl)cc2Cl)S1(=O)=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To ethyl 2-(6,6-dioxido-7-(2,4,6-trichlorophenyl)-6-thia-5,7-diazaspiro[2,5]-octane-5-yl)acetate (60 mg, 0.14 mmol) in THF (5 mL) and MeOH (5 mL), was added LiOH monohydrate (25 mg, 0.58 mmol) in water (1 mL) and agitated for 5 hr at room temperature. After addition of ethyl acetate (30 mL) and water (30 mL), pH of the resultant was adjusted to 3 with 1 N HCl and extracted to the organic layer. The resultant was dried over MgSO4, concentrated under reduced pressure, and crystallized with ethyl acetate (1 mL) and hexane (10 mL), giving the compound of interest (50 mg, 89%, white solid). 1H NMR (300 MHz, CDCl3): δ 7.39 (s, 2H), 4.39 (s, 2H), 3.73 (s, 2H), 3.57 (s, 2H), 0.66-0.64 (m, 4H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH:18]([CH3:20])[CH3:19])[CH:12]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+].[N+:26]([CH3:29])([O-:28])=[O:27]>C(O)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11](/[CH:12]=[CH:29]/[N+:26]([O-:28])=[O:27])[CH:14]=[CH:15][C:16]=1[O:17][CH:18]([CH3:20])[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)Oc1ccc(C=O)cc1OCc1ccccc1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: CC(C)Oc1ccc(/C=C/[N+](=O)[O-])cc1OCc1ccccc1
Temperature: 130 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
3-(Benzyloxy)-4-isopropoxybenzaldehyde described in Production Example 17-2 (2.59 g, 9.59 mmol) was dissolved in acetic acid (7.5 mL), then ammonium acetate (887 mg, 11.5 mmol) and nitromethane (1.25 mL, 23.1 mmol) were added under nitrogen atmosphere at room temperature, and the mixture was heated and stirred at 130° C. for 2 hours. The mixture was cooled to room temperature, and the precipitate was collected by filteration and washed with ethanol to obtain the title compound (2.20 g, 73%).
Reaction SMILES: [N:1]1([C:6]2[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.N1N=CN(C2C=[C:20]3C(=CC=2)NC=[C:21]3[CH2:27][CH2:28][OH:29])C=1>CS(C)=O>[N:1]1([C:6]2[CH:12]=[C:11]3[C:9](=[CH:8][CH:7]=2)[NH:10][CH:20]=[C:21]3[CH2:27][CH2:28][OH:29])[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: Nc1ccc(-n2cncn2)cc1
Reactant: OCCc1c[nH]c2ccc(-n3cnnc3)cc12
Solvent: CS(C)=O
Product: OCCc1c[nH]c2ccc(-n3cncn3)cc12

Procedure:
Prepared from 4-(1,2,4-triazol-1-yl)aniline (EP497512) as described for Intermediate 3, δ (250 MHz, D6 -DMSO) 2.89 (2H, t, J=7.2 Hz, CH2), 3.64-3.74 (2H, m, CH2), 4.67 (1H, t, J=5.3 Hz, OH), 7.29 (1H, d, J=2.3 Hz, Ar--H), 7.47 (1H, dd, J=8.7 and 1.5 Hz, Ar--H), 7.53 (1H, dd, J=8.7 and 2.3 Hz, Ar--H), 7.95 (1H, d, J=1.9 Hz, Ar--H), 8.19 (1H, s, Ar--H), 9.19 (1H, s, Ar--H), 11.10 (1H, s, NH).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@@H:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C@H:14]([CH:20]=[C:21]([CH2:27][CH2:28][O:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)[C:22]([O:24]CC)=[O:23])[O:13][C:12]1([CH3:37])[CH3:36])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.Cl>CCCCCC.C(OCC)(=O)C.[OH-].[K+]>[CH2:1]([O:8][C:9]([N:11]1[C@@H:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C@H:14]([CH:20]=[C:21]([CH2:27][CH2:28][O:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)[C:22]([OH:24])=[O:23])[O:13][C:12]1([CH3:37])[CH3:36])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=C[C@@H]1OC(C)(C)N(C(=O)OCc2ccccc2)[C@H]1CC(C)C)CCOC1CCCCO1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)C[C@H]1[C@H](C=C(CCOC2CCCCO2)C(=O)O)OC(C)(C)N1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
400 mg of ethyl 3-[(4S,5S)-3-benzyloxycarbonyl-2,2-dimethyl-4-isobutyloxazolidin-5-yl]-2-[2-(2-tetrahydropyranyloxy)ethyl]-2-propenoate was dissolved in 1.93 ml of an ethanol/water (10/1) solution of 2N potassium hydroxide, and the solution was stirred overnight at room temperature. 24 ml of water was added thereto, and the mixture was cooled to 0° C., then neutralized with 1N hydrochloric acid and extracted three times with 15 ml of ethyl acetate. The ethyl acetate layer was washed sequentially with water and a saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate. Then the solvent was distilled off under reduced pressure to obtain 3-[(4S,5S)-3-benzyloxycarbonyl-2,2-dimethyl-4-isobutyloxazolidin-5yl]-2-[2-(2-tetrahydropyranyloxy)ethyl]-2-propenoic acid as a colorless oily substance.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=[O:5].[Cl:7][C:8]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][N:11]=[C:10]2[NH:18][CH:19]=[C:20]([NH2:21])[C:9]=12.[Li+].[OH-]>N1C=CC=CC=1.C1COCC1>[Cl:7][C:8]1[C:13]([C:14]([F:17])([F:15])[F:16])=[CH:12][N:11]=[C:10]2[NH:18][CH:19]=[C:20]([NH:21][C:4](=[O:5])[CH2:3][O:2][CH3:1])[C:9]=12
Reactant: COCC(=O)Cl
Reactant: Nc1c[nH]c2ncc(C(F)(F)F)c(Cl)c12
Agent: [Li+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COCC(=O)Nc1c[nH]c2ncc(C(F)(F)F)c(Cl)c12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 98.1 %

Procedure:
2-Methoxyacetyl chloride (0.074 mL, 0.76 mmol) was added to a solution of 4-chloro-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-amine (120 mg, 0.51 mmol, Example 12, Steps A-G) in pyridine (5 mL) at 0° C. The reaction was stirred at 0° C. for 10 minutes, and the pyridine was removed in vacuo. The residue obtained was dissolved in THF (5 mL), treated with 2N LiOH (3 mL) and stirred for 20 minutes. THF was then removed under reduced pressure, and the aqueous slurry obtained was extracted with water (20 mL) and ethyl acetate (50 mL). The organic layer was separated, washed with brine, dried (Na2SO4) and concentrated in vacuo to provide N-(4-chloro-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methoxyacetamide (154 mg, 98% yield) as a solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH:12]=[CH:13][C:14](=O)[CH3:15])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23]1[CH:29]=[CH:28][C:26]([N:27]2[C:11]([C:8]3[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=3)=[CH:12][CH:13]=[C:14]2[CH3:15])=[CH:25][CH:24]=1
Reactant: Nc1ccc(-c2ccco2)cc1
Reactant: CC(=O)C=CC(=O)c1ccc(S(C)(=O)=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(-c2ccco2)cc1
Yield: 24.3 %

Procedure:
A mixture of 1-[4-(methylsulfonyl)phenyl]pentene-1,4-dione (0.305 g, 1.2 mmol prepared according to the method of J. Med. Chem., 1997, 40, 1619), 4-(2-furyl)aniline (0.35 g, 2 mmol), and p-toluenesulfonic acid monohydrate (0.015 g) in toluene (40 mL) was heated at reflux temperature for 16 hours using Dean-Stark apparatus. After cooling, volatiles were removed by evaporation. The residue was purified by flash chromatography eluting with hexane/ethyl acetate (4/1). The resulting solid was recrystallized from CH2Cl2/hexane to give the title compound (0.11 g, 24.3% yield).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:25][CH2:24][C@@:23]2([CH3:26])[C@H:4](/[C:5](=[CH:29]/[CH3:30])/[C:6](=[O:28])[C@@H:7]3[C@@H:22]2[CH2:21][CH2:20][C@@:19]2([CH3:27])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:18])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH2:3]1.[OH-].[Na+]>[Pd].O>[OH:1][C@@H:2]1[CH2:25][CH2:24][C@@:23]2([CH3:26])[C@H:4]([C@@H:5]([CH2:29][CH3:30])[C:6](=[O:28])[C@@H:7]3[C@@H:22]2[CH2:21][CH2:20][C@@:19]2([CH3:27])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:18])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH2:3]1
Reactant: C/C=C1\C(=O)[C@@H]2[C@H](CC[C@]3(C)[C@@H]([C@H](C)CCC(=O)O)CC[C@@H]23)[C@@]2(C)CC[C@@H](O)C[C@@H]12
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC[C@H]1C(=O)[C@@H]2[C@H](CC[C@]3(C)[C@@H]([C@H](C)CCC(=O)O)CC[C@@H]23)[C@@]2(C)CC[C@@H](O)C[C@@H]12

Procedure:
In one embodiment in Step 5, E/Z-3α-hydroxy-6-ethylidene-7-keto-5β-cholan-24-oic acid (5A), water, NaOH solution (e.g. 50% wt.), and Pd/C are mixed at about 5 bar of H2 gas and at a temperature at about 100° C. to about 105° C. until H2 uptake has ceased. The reaction mixture is cooled to about 40° C. to about 50° C. and Pd/C is filtered off. Then n-butyl acetate and HCl are added to the solution containing compound 6. In one embodiment, the aqueous phase is separated and discarded. The organic phase containing compound 6 is treated with activated carbon. The carbon is filtered off and the filtrate is moved to another reactor where it is reduced down by distillation, and then the suspension is cooled to about 5° C. to about 20° C. In one embodiment, compound 6 is isolated via filtration and the filtrate is dried on the pressure filter under vacuum at about 80° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[C:13]3[CH3:20])=[CH:4][N:3]=1.[N+:21]([O-])([OH:23])=[O:22].[OH-].[NH4+]>S(=O)(=O)(O)O>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:11]=[C:12]3[C:17](=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=2)[N:16]=[CH:15][CH:14]=[C:13]3[CH3:20])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1ccnc2ccc(Cc3cnc(N)nc3N)cc12
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: Cc1ccnc2c([N+](=O)[O-])cc(Cc3cnc(N)nc3N)cc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 53.2 %

Procedure:
The product of Example 11 (0.53 g, 2 mmol) was dissolved in 7 ml of concentrated sulfuric acid, and chilled to 0°. Then 0.3 ml (6.4 mmol) of fuming nitric acid (d=1.5) in 0.5 ml of concentrated sulfuric acid was added dropwise to the solution. The reaction was stirred at 0°-5° for 30 minutes, then at 25° for 1 hour. It was then poured onto 50 ml of ice and neutralised to pH 9 with concentrated ammonium hydroxide. The precipitate which formed was filtered and dried, and then purified on a silica gel column which was eluted with methylene chloride:methanol/12:1, giving 0.33 g (53%) of the title compound, which melted at 256°-258° after recrystallisation from beta methoxyethanol:water/2:1. NMR (Me2SO-d6) δ 2.72 (s, 3, Me), 3.90 (s, 2, CH2), 5.77 (br s, 2, NH2), 6.24 (br s, 2, NH2), 7.55 (d, 1, pyridine-beta H, J=4.1), 7.71 (s, 1, pyrimidine-H6), 8.05 (d, 1, ArH5, J=1.8), 8.28 (d, 1, ArH7, J=1.6), 8.81 (d, 1, pyridine-alpha H, J=4.4). Anal. Calcd. for C15H14N6O2 0.5H2O: C, 56.42; H, 4.73; N, 26.32. Found: C, 56.34; H, 4.82; N, 26.21.
Reaction SMILES: C([O:5][C:6](=[O:25])[CH2:7][N:8]([C:14](=[S:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21](=[O:23])[CH3:22])[CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)(C)(C)C.[I-].[Na+].Cl[Si](C)(C)C>C(#N)C>[C:21]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:14]([N:8]([CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13]1)[CH2:7][C:6]([OH:25])=[O:5])=[S:24])(=[O:23])[CH3:22]
Reactant: CC(=O)c1ccccc1C(=S)N(CC(=O)OC(C)(C)C)C1CCCC1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)c1ccccc1C(=S)N(CC(=O)O)C1CCCC1
Reaction time: 0.43 h

Procedure:
The crude ester (28.2 g) was combined with sodium iodide (16.5 g, 0.11 m) in acetonitrile (100 ml) and the mixture brought to 45° C. Chlorotrimethylsilane (11.9 g, 0.11 m) was introduced and heating was continued at 45°-52° for 26 min. The mixture was cooled, quenched with water (60 ml) and diluted with methylene chloride. The organic layer was removed, washed with water, sodium thiosulfate solution and brine, and concentrated in vacuo. Treatment of the residue with saturated sodium bicarbonate solution was followed by filtration of insoluble matter. The filtrate was washed with ethyl acetate, acidified (concentrated hydrochloric acid) and extracted (ethyl acetate). Drying and concentration of the extracts gave a residue which was purified by column chromatography or HPLC. The product was isolated as an amorphous solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[NH:16][CH:15]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:14]3([C:29]4[C:24](=[CH:25][C:26]([Br:30])=[CH:27][CH:28]=4)[NH:23][C:22]3=[O:31])[CH:13]2[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=2[F:39])=[O:11])=[CH:5][CH:4]=1)#[N:2].[OH:40]O.[OH-].[Na+]>CS(C)=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([CH:12]2[NH:16][CH:15]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:14]3([C:29]4[C:24](=[CH:25][C:26]([Br:30])=[CH:27][CH:28]=4)[NH:23][C:22]3=[O:31])[CH:13]2[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=2[F:39])=[O:11])=[CH:7][CH:8]=1)(=[O:40])[NH2:2]
Reactant: OO
Reactant: CC(C)(C)CC1NC(C(=O)Nc2ccc(C#N)cc2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Br)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(C(N)=O)cc2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Br)ccc12
Temperature: 10 °C
Reaction time: 1 h
Yield: 79.6 %

Procedure:
To the solution of rac-(2′S,3′R,4′S,5′R)-6-bromo-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-cyano-phenyl)-amide (0.16 g, 0.26 mmol) prepared in Example 93 in DMSO (1 mL) at 0° C. was added an aqueous solution (30% Aldrich) of H2O2 (0.45 g, 3.9 mmol), then aqueous solution (1N) of NaOH (1.3 mL, 1.3 mmol) was added dropwise. The reaction mixture was stirred at 10° C. for 1 h. The mixture was partitioned between ethyl acetate and saturated aqueous Na2SO3 solution. The organic layer was separated, washed with water, brine, dried over MgSO4, and concentrated. The residue was triturated with dichlormethane and hexanes to give rac-(2′S,3′R,4′S,5′R)-6-bromo-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-carbamoyl-phenyl)-amide as a white solid (Yield 0.13 g, 76%)
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([C:17]1[O:18][C:19]2[C:25]([O:26][CH2:27][CH2:28][O:29][CH3:30])=[CH:24][CH:23]=[CH:22][C:20]=2[CH:21]=1)=[O:16])(C)(C)C.NC1C=CC=CC=1NC(C1SC2C=CC(OCCOCCOC)=CC=2C=1)=O>>[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([C:17]1[O:18][C:19]2[C:25]([O:26][CH2:27][CH2:28][O:29][CH3:30])=[CH:24][CH:23]=[CH:22][C:20]=2[CH:21]=1)=[O:16]
Reactant: COCCOc1cccc2cc(C(=O)Nc3ccccc3NC(=O)OC(C)(C)C)oc12
Agent: COCCOCCOc1ccc2sc(C(=O)Nc3ccccc3N)cc2c1
Product: COCCOc1cccc2cc(C(=O)Nc3ccccc3N)oc12

Procedure:
was prepared from (2-{[7-(2-Methoxy-ethoxy)-benzofuran-2-carbonyl]-amino}-phenyl)-carbamic acid tert-butyl ester (34) in an analogous manner to that described for the preparation of (27) example 11, step 2; exact MW [M+H] calc'd: 327.13; MW found [M+H]: 327.0.
Reaction SMILES: [F:1][CH2:2][C:3]1([C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])[CH2:6][C:5](OC)([O:7]C)[CH2:4]1.Cl>>[F:1][CH2:2][C:3]1([C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])[CH2:6][C:5](=[O:7])[CH2:4]1
Reactant: COC1(OC)CC(CF)(C(=O)OC(C)C)C1
Agent: Cl
Product: CC(C)OC(=O)C1(CF)CC(=O)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.3 %

Procedure:
To a stirred solution of Intermediate 302B (0.6 g, 2.56 mmol) was added a conc. aq. solution of HCl (1.576 mL, 20.49 mmol) and the reaction mass was stirred at RT for 16 h. The reaction was extracted with DCM (3×10 mL) and the organic layer was washed with water and a 10% aq. solution of NaHCO3, and then dried over Na2SO4, filtered and concentrated to afford Intermediate 302C as a pale yellow liquid (0.3 g, 62%). 1H NMR (400 MHz, chloroform-d) δ ppm 5.12 (s, 1H), 4.67-4.87 (m, 2H), 3.44-3.64 (m, 2H), 3.12-3.31 (m, 2H), 1.29 (d, J=6.53 Hz, 6H).
Reaction SMILES: [Mg].II.Br[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:13][Si:14](OCC)([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17].C(C1C=C(O)C(C(C)(C)C)=CC=1O)(C)(C)C>C(OCC)C.CCCCCCC>[CH:6]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][SiH:14]([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17])=[CH:9][CH:8]=1)=[CH2:5]
Reactant: BrC=Cc1ccccc1
Reactant: CCO[Si](C)(OCC)OCC
Agent: CC(C)(C)c1cc(O)c(C(C)(C)C)cc1O
Agent: II
Agent: [Mg]
Solvent: CCCCCCC
Solvent: CCOCC
Product: C=Cc1ccc(C[SiH](OCC)OCC)cc1
Temperature: 2 °C
Reaction time: 8 h
Yield: 70.4 %

Procedure:
In a three-neck flask under argon and while being stirred mechanically, 11.7 g (480 mmol) of magnesium chips and some iodine crystals in 40 ml of a solution A (55% diethyl ether, 45% tetrahydrofuran) are mixed together. Then, a solution of 80.0 g (436 mmol) of bromostyrene, dissolved in 210 ml of solvent mixture A, is slowly added in drops, and thus a continuous exothermic reaction is achieved. The solution is stirred under reflux. After the end of the exothermic reaction, the reaction mixture is cooled to 2° C., and then 155.5 g (872 mmol) of methyltriethoxysilane in 160 ml of dry diethyl ether is added; the temperature must not exceed 15° C. After the end of the substitution reaction, stirring is continued at room temperature overnight. Approximately 200 ml of n-heptane is then added, thus the magnesium salts precipitate. The latter are filtered off, 9.7·10−2 g (0.44 mmol) of 2,5-di-tert-butylhydroquinone is added to the filtrate, the solvent is drawn off in a rotary evaporator, and the residue is distilled in fractionated form under vacuum. 72.5 g (307 mmol) of the product was obtained with a yield: 70.3%, and a boiling point of 65-66° C. (0.05 mbar)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:10]3([C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[NH:12][C:11]3=[O:19])[CH2:9]2)=[CH:4][CH:3]=1.ClC1C=[CH:25][C:24]([C@H:27]2[C@@:29]3(C4C(=CC=CC=4)N[C:30]3=[O:38])[CH2:28]2)=CC=1.[H-].[Na+].BrCC1CCOCC1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C@@:10]3([C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]([CH2:28][CH:27]4[CH2:29][CH2:30][O:38][CH2:25][CH2:24]4)[C:11]3=[O:19])[CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=C1Nc2ccccc2C12CC2c1ccc(Cl)cc1
Reactant: O=C1Nc2ccccc2[C@]12C[C@H]2c1ccc(Cl)cc1
Agent: BrCC1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1N(CC2CCOCC2)c2ccccc2[C@]12C[C@H]2c1ccc(Cl)cc1
Reaction time: 1 h
Yield: 70 %

Procedure:
Racemic (1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3′-indolin]-2′-one and (1R,2S)-2-(4-chlorophenyl)spiro[cyclopropane-1,3′-indolin]-2′-one (270 mg, 1.0 mmol, 1.0 equiv.) were added to a stirred solution of sodium hydride (60%, 60 mg, 1.5 mmol) in 5 mL of DMF under argon atmosphere at 0° C. After stirring for 1 hour, 4-bromomethyl-tetrahydropyran (215 mg, 1.2 mmol) was added. The reaction mixture was stirred for 14 hours at room temperature. The crude product was purified by HPLC to give the title compound as a white solid (258 mg, 70%). LC/MS m/e calcd. for C22H22ClNO2: 367, observed (M+H)+: 368.2 1H NMR (400 MHz, MeOD-d4) δppm 1.39-1.55 (m, 2 H) 1.65 (dd, J=13.14, 1.77 Hz, 2 H) 2.11-2.25 (m, 3 H) 3.22 (t, J=8.46 Hz, 1 H) 3.37-3.47 (m, 2 H) 3.79 (d, J=7.33 Hz, 2 H) 3.94-4.04 (m, 2 H) 6.09 (d, J=7.58 Hz, 1 H) 6.76 (t, J=7.58 Hz, 1 H) 7.11 (d, J=7.83 Hz, 1 H) 7.17-7.25 (m, 3 H) 7.33 (d, J=8.34 Hz, 2 H). MS calcd. For C22H22ClNO2 367, obsd. (ESI+) [(M+H)+] 368.