Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(Cl)(=O)=O.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[C:15]([CH2:27]O)=[N:16][CH:17]=[C:18]([N:20]3[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[N:21]3)[N:19]=2)=[CH:9][CH:8]=1.[CH2:29]([N:31](CC)[CH2:32]C)C.CNC>ClCCl.O1CCCC1.C(OCC)(=O)C.O>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[C:15]([CH2:27][N:31]([CH3:32])[CH3:29])=[N:16][CH:17]=[C:18]([N:20]3[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[N:21]3)[N:19]=2)=[CH:9][CH:8]=1
Reactant: Cc1cc(C)n(-c2cnc(CO)c(Nc3ccc(Cl)cc3)n2)n1
Reactant: CCN(CC)CC
Agent: CNC
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cc(C)n(-c2cnc(CN(C)C)c(Nc3ccc(Cl)cc3)n2)n1
Reaction time: 0.25 h
Yield: 81 %

Procedure:
Methanesulfonyl chloride (274, 0.35 mmol) was added to a solution of [3-(4-chloro-phenylamino)-5-(3,5-dimethyl-pyrazol-1-yl)-pyrazin-2-yl]-methanol (58 mg, 0.18 mmol) and triethylamine (75 μL, 0.53 mmol) in dichloromethane (5 mL) and tetrahydrofuran (1 mL) and stirred for 15 minutes. Dimethylamine (2M in tetrahydrofuran, 1.32 mL, 2.64 mmol) was added and the solution was stirred overnight. Water and ethyl acetate were added and the organic solvents were evaporated in vacuo. The remaining aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulphate, filtrated and evaporated to give the crude product as a brown oil. Purification by flash chromatography (dichloromethane/methanol as eluent) gave (4-chloro-phenyl)-[3-dimethylaminomethyl-6-(3,5-dimethyl-pyrazol-1-yl)-pyrazin-2-yl]-amine (52 mg, 82%) as a brown solid.
Reaction SMILES: [OH:1][C@@H:2]([CH2:8]O)[CH2:3][C:4]([O:6][CH3:7])=[O:5].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C(=O)N([Cl:36])C(=O)C1>C(Cl)Cl>[Cl:36][CH2:8][C@H:2]([OH:1])[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)C[C@@H](O)CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)C[C@@H](O)CCl
Temperature: 5 °C
Reaction time: 0.33 h
Yield: 23.3 %

Procedure:
To a solution of (R)-methyl 3,4-dihydroxybutanoate (125.1 g, 0.93 mol) in CH2Cl2 (1.8 L) was added PPh3 (244.5 g, 0.93 mol) and slowly added NCS (124.2 g, 0.93 mol) under ice water cooling. The mixture was stirred at 5° C. for 20 min and then stirred for 18 h at room temperature. After evaporating the solvent, the residue was purified by column chromatography (P.E\E.A 20:1-5:1, gradient) to give (R)-methyl 4-chloro-3-hydroxybutanoate (33 g, 26% over 3 steps). 1H NMR (300 MHz, CDCl3) δ 4.18-4.25 (m, 1H), 3.68 (s, 3H), 3.55-3.60 (m, 2H), 3.32-3.33 (d, J=4.2 Hz, 1H), 2.52-2.68 (m, 2H).
Reaction SMILES: N1C=CC=CC=1.[I:7]Cl.[CH3:9][CH2:10][C@@:11]1([OH:38])[C:16](=[O:17])[O:15][CH2:14][C:13]2[C:18]([N:20]3[C:24](=[CH:25][C:12]1=2)[C:23]1[N:26]=[C:27]2[C:32](=[CH:33][C:22]=1[CH2:21]3)[C:31]([CH2:34][CH:35]=[CH2:36])=[C:30]([OH:37])[CH:29]=[CH:28]2)=[O:19]>C(Cl)(Cl)Cl.[N+]([O-])([O-])=O.[Ag+]>[CH2:10]([C@:11]1([OH:38])[C:12]2[CH:25]=[C:24]3[N:20]([CH2:21][C:22]4[C:23]3=[N:26][C:27]3[C:32]([CH:33]=4)=[C:31]4[CH2:34][CH:35]([CH2:36][I:7])[O:37][C:30]4=[CH:29][CH:28]=3)[C:18](=[O:19])[C:13]=2[CH2:14][O:15][C:16]1=[O:17])[CH3:9]
Reactant: ClI
Reactant: C=CCc1c(O)ccc2nc3c(cc12)Cn1c-3cc2c(c1=O)COC(=O)[C@]2(O)CC
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3c4c(ccc3nc2-1)OC(CI)C4
Reaction time: 0.25 h

Procedure:
Silver nitrate (6.8 g, 0.040 mol) in dry, freshly distilled chloroform (50 mL) and dry pyridine (20 mL) was treated, dropwise, with stirring with a solution of iodine monochloride (6.48 g, 0.0400 mol) in dry chloroform (40 mL) over a two min period. After stirring for 15 min, the mixture was centrifuged; the supernatent was then added to a solution of (S)-9-allyl-10-hydroxycamptothecin (3.92 g, 0.00960 mol) in dry chloroform (15 mL) giving a deep amber solution which was stirred overnight at ambient temperature. The solution was concentrated to a small volume and then partitioned between methylene chloride and water. After separation of the layers, the aqueous phase was re-extracted with methylene chloride. The combined organic layer was washed successsively with ice cold 5% aq. HCl, dilute sodium thiosulfate solution, and finally with water. The solution was dried (sodium sulfate) and evaporated to a golden-brown residue which was triturated with a small amount of cold methanol to afford the title compound as a light brown solid. (2.25 g, 44%). 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J=4.3 Hz, 1H), 8.07 (d, J=9.2 Hz, 1H), 7.61 (s, 1H), 7.40 (dd, J=7.1 Hz and J=2.0 Hz, 1H), 5.73 (d, J=16.3 Hz, 1H), 5.29 (d, J=16.3 Hz, 1H), 5.26 (s, 2H), 5.20-5.10 (m, 1H), 3.83-3.81 (m, 1H), 3.72-3.70 (m, 1H), 3.57-3.54 (m, 1H), 3.49-3.46 (m, 1H), 3.39-3.38 (m, 1H), 1.92-1.84 (m, 2H), 1.03 (t, J=7.3 Hz, 3H). Anal.: (C23H19IN2O5.1/2H2O) calcd.: C, 51.22; H, 3.74; N, 5.19 found: C, 51.03; H, 3.56; N, 4.87.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:21])=[C:4]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])/[C:5](=[N:14]\[OH:15])/[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:7]=1[F:13].[C:22](OC(=O)C)(=[O:24])[CH3:23]>>[C:22]([O:15]/[N:14]=[C:5](/[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:7]=1[F:13])\[C:4]1[CH:16]=[CH:17][C:18]([O:19][CH3:20])=[C:2]([Cl:1])[C:3]=1[OH:21])(=[O:24])[CH3:23]
Reactant: COc1ccc(/C(=N\O)c2cccc(F)c2F)c(O)c1Cl
Reactant: CC(=O)OC(C)=O
Product: COc1ccc(/C(=N\OC(C)=O)c2cccc(F)c2F)c(O)c1Cl
Temperature: 60 °C

Procedure:
A mixture of 1.5 g of E-3-chloro-2',3'-difluoro-2-hydroxy-4-methoxybenzophenone oxime and 0.67 g of acetic anhydride are warmed at 60° C. for 30 minutes. The mixture is dissolved and then solidifies. The residue is partitioned between ethyl acetate and 10% NaHCO3. The ethyl acetate extract is washed, dried over Na2SO4 and evaporated to give E-3-chloro-2',3'-difluoro-2-hydroxy-4-methoxybenzophenone O-acetyl oxime, mp 136°-139° C.
Reaction SMILES: C(O[C:4]1[C:5](=[O:16])[C:6](=[O:15])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)C.[Cl:17][C:18]1[CH:32]=[CH:31][C:21]([O:22][C:23]2[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=2)=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:32]=[CH:31][C:21]([O:22][C:23]2[CH:30]=[CH:29][C:26]([CH2:27][NH:28][C:4]3[C:5](=[O:16])[C:6](=[O:15])[C:7]=3[NH:8][C:9]3[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=3)=[CH:25][CH:24]=2)=[CH:20][CH:19]=1
Reactant: NCc1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: CCOc1c(Nc2ccncc2)c(=O)c1=O
Product: O=c1c(NCc2ccc(Oc3ccc(Cl)cc3)cc2)c(Nc2ccncc2)c1=O
Yield: 78 %

Procedure:
The title compound was prepared according to the procedure described in example 1B starting from 3-ethoxy-4-(pyridin-4-yl-amino)-3-cyclobutene-1,2-dione prepared according to example 7A and 4-(4-chlorophenoxy)-benzylamine.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[O:13][N:12]=2)[CH2:7][CH2:6]1)=[O:4].[OH-].[Na+].Cl>O1CCOCC1>[O:13]1[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:11]([C@H:8]2[CH2:7][CH2:6][C@H:5]([C:3]([OH:4])=[O:2])[CH2:10][CH2:9]2)=[N:12]1
Reactant: COC(=O)[C@H]1CC[C@H](c2noc3ccccc32)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)[C@H]1CC[C@H](c2noc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of trans-4-benzo[d]isoxazol-3-yl-cyclohexanecarboxylic acid methyl ester (6.77 g, 26.1 mmol) and aqueous 2 M sodium hydroxide solution (131 ml, 261 mmol) in 1,4-dioxane (261 ml) was stirred at room temperature for 20 h. The reaction mixture was cooled by addition of crushed ice (120 g) and acidified with concentrated hydrochloric acid (21.8 ml, 261 mmol). The reaction mixture was extracted with three 150-ml portions of ethyl acetate. The combined organic layers were washed with one 50-ml portion of brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude acid was crystallized from hot ethyl acetate to give the title compound (4.09 g, 64%) as white crystals. MS m/e: 246 ([M+14]+).
Reaction SMILES: [BH4-].[Na+].[C:3]([C@H:8]1[S:12][CH2:11][C@H:10]([O:13][C:14](=[O:16])[CH3:15])[O:9]1)(OCC)=[O:4].CCOC(C)=O.CCCCCC>CO>[OH:4][CH2:3][C@H:8]1[S:12][CH2:11][C@H:10]([O:13][C:14](=[O:16])[CH3:15])[O:9]1
Reactant: CCOC(=O)[C@@H]1O[C@@H](OC(C)=O)CS1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(=O)O[C@H]1CS[C@H](CO)O1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 49.9 %

Procedure:
Sodium borohydride (27 mg, 0.708 mmol) was added to a magnetically stirred solution of trans-2-carboethoxy-5-acetoxy-1,3-oxathiolane (52 mg, 0.236 mmol) in methanol (1 mL) at 0° C. under an argon atmosphere. The resultant solution was stirred for 25 minutes at 0° C. The reaction was quenched with 2 drops of saturated ammonium chloride solution followed by dilution with diethyl ether (4 mL). This mixture was stirred at room temperature for 15 minutes and then was dried over anhydrous magnesium sulphate. The drying agent was removed by suction filtration and the filtrate was concentrated under reduced pressure. The crude product obtained was subjected to column chromatography (50% EtOAc-hexane) to afford 21 mg (50%) of the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[C:6]([OH:9])[C:5]([C:10]2[C:11]([OH:19])=[C:12]([CH3:18])[C:13](Cl)=[CH:14][C:15]=2[CH3:16])=[C:4]([CH3:20])[CH:3]=1>C(O)C.O.C(N(CC)CC)C.CCOC(C)=O.[OH-].[OH-].[Pd+2]>[CH3:16][C:15]1[CH:14]=[CH:13][C:12]([CH3:18])=[C:11]([OH:19])[C:10]=1[C:5]1[C:6]([OH:9])=[C:7]([CH3:8])[CH:2]=[CH:3][C:4]=1[CH3:20]
Reactant: Cc1cc(Cl)c(C)c(O)c1-c1c(C)cc(Cl)c(C)c1O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(C)c(-c2c(C)ccc(C)c2O)c1O
Yield: 93.8 %

Procedure:
A sample of purified 5,5′-dichloro-3,3′,6,6′-tetramethyl-2,2′-biphenol (15.0 g, 48.4 mmol) was dissolved in 100 mL of ethanol containing 10 mL of water and 20 mL of triethylamine. This solution was added to 1.0 g (dry weight basis) of moist 20% Pd(OH)2/C (Pearlman's catalyst) and hydrogenated at 50 psig for 2 hours at ambient temperature. The product was isolated by filtration of catalyst, concentration, dissolution of the residue in EtOAc, washing with water, and concentration to dryness to give 11.0 g (94%) of product, mp 110-113° C. 1H-NMR (CDCl3) δ 1.95 (s, 3H), 2.25 (s, 3H), 4.71 (s, 1H), 6.81 (d, 1H, J=7.5 Hz), 7.10 (d, 1H, J=7.5 Hz).
Reaction SMILES: [C:1]([O:6][CH2:7][C:8]([Cl:11])([Cl:10])[Cl:9])(=[O:5])[C:2]([CH3:4])=[O:3].[Br:12]Br.C(=O)=O>O>[Br:12][CH2:4][C:2](=[O:3])[C:1]([O:6][CH2:7][C:8]([Cl:9])([Cl:10])[Cl:11])=[O:5]
Reactant: CC(=O)C(=O)OCC(Cl)(Cl)Cl
Reactant: BrBr
Agent: O=C=O
Solvent: O
Product: O=C(CBr)C(=O)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Yield: 354.9 %

Procedure:
Trichloroethyl pyruvate (3.7 g, 1.7 mmole) is heated to 65° and 1.1 ml (17 mmole) of bromine is added dropwise over 1 hour. A stream of carbon dioxide is passed through the reaction mixture during the addition to remove the HBr formed in the reaction. The mixture is cooled to room temperature, diluted with water and extracted with ethyl acetate. The extract is dried over MgSO4, evaporated and distilled in vacuum to give 1.8 g of trichloroethyl bromopyruvate, bp 74°-77° (0.01 mm).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:38])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[N:33]([CH3:37])[N:34]=[CH:35][CH:36]=2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:15][N:14]([CH3:16])[C:12]1[C:11]([C:17]([F:18])([F:19])[F:20])=[CH:10][C:9]2[NH:21][C:22](=[O:38])[CH2:23][C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]4[N:33]([CH3:37])[N:34]=[CH:35][CH:36]=4)[CH:27]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnn3C)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccnn3C)c1)=N2

Procedure:
The title compound was prepared from (5-dimethylamino-2-{3-[3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example M31) (78 mg, 0.14 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (48 mg).
Reaction SMILES: O.NN.O=C1C2C(=CC=CC=2)C(=O)[N:6]1[C@@H:15]1[CH2:20][CH2:19][C@H:18]([O:21][C:22](=[O:32])[C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)[CH2:17][CH2:16]1.CO>C(Cl)Cl>[NH2:6][C@H:15]1[CH2:16][CH2:17][C@H:18]([O:21][C:22](=[O:32])[C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)[CH2:19][CH2:20]1
Reactant: O=C(O[C@H]1CC[C@@H](N2C(=O)c3ccccc3C2=O)CC1)c1ccc([N+](=O)[O-])cc1
Agent: NN
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: N[C@H]1CC[C@H](OC(=O)c2ccc([N+](=O)[O-])cc2)CC1
Reaction time: 8 h

Procedure:
35 wt % Hydrazine hydrate (0.93 g, 10.1 mmol) was added to a solution of compound 5 (2.0 g, 5.1 mmol) in CH2Cl2 (50 mL) followed by MeOH (50 mL) at room temperature. The reaction mixture was allowed to stir overnight. The resulting white precipitates were filtered off and the solvent was removed in vacuo. The resulting white solids were dissolved in aqueous 1N HCl solution and washed with CH2Cl2. Aqueous layer was basified with excess 1N NaOH solution and then extracted with CH2Cl2. After drying with MgSO4, the solvent was evaporated affording crude trans-4-nitro-benzoic acid 4-amino-cyclohexyl ester 6 as a white solid (1.1 g, 89% yield), which was used in the next step without further purification. 1H NMR (DMSO-d6): δ 8.26 (dd, J=44 and 9 Hz, 4H), 6.72 (d, J=7 Hz, 2H), 5.08 (s, 1H), 2.00-1.36 (m, 9H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:10]([CH2:11][C:12]([C:27]3[S:28][C:29]([CH2:33][CH2:34][O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])=[C:30]([CH3:32])[N:31]=3)=[C:13]2[C:24]([OH:26])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:43]1([NH:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[C:50]([O:54][CH3:55])[C:49]=2[CH3:56])[CH2:45][CH2:44]1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:10]([CH2:11][C:12]([C:27]3[S:28][C:29]([CH2:33][CH2:34][O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:37])[CH3:38])=[C:30]([CH3:32])[N:31]=3)=[C:13]2[C:24](=[O:26])[N:46]([CH:43]2[CH2:45][CH2:44]2)[CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[C:50]([O:54][CH3:55])[C:49]=2[CH3:56])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1nc(C2=C(C(=O)O)C3CN(C(=O)OC(C)(C)C)CC(C2)N3C(=O)OC(C)(C)C)sc1CCO[Si](C)(C)C(C)(C)C
Reactant: COc1cccc(CNC2CC2)c1C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(CN(C(=O)C2=C(c3nc(C)c(CCO[Si](C)(C)C(C)(C)C)s3)CC3CN(C(=O)OC(C)(C)C)CC2N3C(=O)OC(C)(C)C)C2CC2)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 73.1 %

Procedure:
A mixture of compound D1 (10.52 g, 13.6 mmol), cyclopropyl-(3-methoxy-2-methylbenzyl)amine (prepared by reductive amination from 3-methoxy-2-methylbenzaldehyde, Comins, D. L.; Brown, J. D., J. Org. Chem., 1989, 54, 3730 and cyclopropylamine, 6.54 g, 34.2 mmol), DIPEA (9.40 mL, 54.9 mmol), DMAP (417 mg, 3.40 mmol), HOBt (2.77 g, 20.5 mmol) and EDC.HCl (7.84 g, 40.9 mmol) in CH2Cl2 (150 mL) was stirred at rt for 3 days. The mixture was diluted with more CH2Cl2, and washed with aq. 1M HCl (3×) and aq. sat. NaHCO3 (1×). The org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (EtOAc/heptane 1:5→1:3→1:2→1:1→3:2) yielded the title compound (7.93 g, 70%). LC-MS: tR=1.30 min, ES+: 797.67.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]2[C:11]3[O:19][C@H:20]4[CH2:25][CH2:24][CH2:23][C@H:21]4[NH:22][C:10]=3[CH:9]=[CH:8][C:7]=2[N:6]=1)([CH3:3])[CH3:2].[BH4-].[Na+].[C:28](O)(=O)[CH3:29]>>[CH2:28]([N:22]1[C:10]2[CH:9]=[CH:8][C:7]3[N:6]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[CH:14]=[C:13]([C:15]([F:17])([F:16])[F:18])[C:12]=3[C:11]=2[O:19][C@H:20]2[CH2:25][CH2:24][CH2:23][C@@H:21]12)[CH3:29]
Reactant: CC(C)Oc1cc(C(F)(F)F)c2c3c(ccc2n1)N[C@@H]1CCC[C@@H]1O3
Reactant: CC(=O)O
Agent: [BH4-]
Agent: [Na+]
Product: CCN1c2ccc3nc(OC(C)C)cc(C(F)(F)F)c3c2O[C@H]2CCC[C@H]21

Procedure:
Compound 134 was prepared according to General Method 5 (EXAMPLE 2) from (7aR,10aS)-7,7a,8,9,10,10a-hexahydro-3-isopropoxy-1-(trifluoromethyl)-cyclopenta[5,6][1,4]oxazino[2,3-f]quinoline (5 mg, 0.014 mmol) and NaBH4 pellets (>10 equiv) in 5 mL acetic acid to afford 5 mg of (7aR,10aS)-7-ethyl-7,7a,8,9,10,10a-hexahydro-3-isopropoxy-1-(trifluoromethyl)-cyclopenta[5,6][1,4]oxazino[2,3-f]quinoline. This material (5 mg, 0.01 mmol) was carried on according to General Method 4 (EXAMPLE 1) by treatment with 4 mL of 1:1 acetic acid:concentrated HCl (3 mM) and heated at 90° C. for 4 h to afford 4 mg (89%) of Compound 134, a yellow solid, after column chromatography (3:1 hexanes:EtOAc to 1:1 hexanes:EtOAc, gradient elution). 1H NMR (500 MHz, CDCl3)δ11.01 (bs, 1H), 7.10 (s, 1H), 7.01 (d, J=8.8, 1H), 6.90 (d, J=8.8, 1H), 4.00 (m, 1H), 3.59 (ddd, J=10.0, 7.1, 3.4 1H), 3.44 (m, 2H), 2.03 (m, 4H), 1.61 (m, 2H), 1.20 (t, J=7.1, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:12]([NH:13][CH3:14])[CH2:11][N:10]([C:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][N:24]=4)[CH2:19][CH2:18]3)=[O:16])[CH2:9]2)=[CH:4][CH:3]=1.Cl[C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33]>>[CH:35]([O:34][C:32](=[O:33])[N:13]([C@H:12]1[C@H:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:9][N:10]([C:15]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][N:24]=3)[CH2:19][CH2:18]2)=[O:16])[CH2:11]1)[CH3:14])([CH3:37])[CH3:36]
Reactant: CN[C@@H]1CN(C(=O)C2CCN(c3ccc(C#N)cn3)CC2)C[C@H]1c1ccc(Cl)cc1
Reactant: CC(C)OC(=O)Cl
Product: CC(C)OC(=O)N(C)[C@@H]1CN(C(=O)C2CCN(c3ccc(C#N)cn3)CC2)C[C@H]1c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described for the synthesis of example 136, the title compound [(3S,4R)-4-(4-chloro-phenyl)-1-(5′-cyano-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid isopropyl ester was prepared from 4-[(3R,4S)-3-(4-chloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-3,4,5,6-tetrahydro-2H-[1,2]bipyridinyl-5′-carbonitrile using isopropyl chloroformate instead of ethyl chloroformate and was obtained as a colorless foam. MS m/e: 510.4 [M]+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][CH3:13])(=[O:11])=[O:10])=[CH:5][CH:4]=1>C(Cl)Cl.O=[Mn]=O>[CH:2]([C:3]1[CH:4]=[CH:5][C:6]([S:9]([NH:12][CH3:13])(=[O:11])=[O:10])=[CH:7][CH:8]=1)=[O:1]
Reactant: CNS(=O)(=O)c1ccc(CO)cc1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CNS(=O)(=O)c1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 40.8 %

Procedure:
A solution of 4-hydroxymethyl-N-methyl-benzenesulfonamide (1.61 g, 8.0 mmol) in DCM (50 mL) is added to a mixture of MnO2 (16.1 g, 167 mmol) in DCM (65 mL). The mixture is stirred at rt for 15 min, filtered over celite and the solvent of the filtrate is evaporated to give 4-formyl-N-methyl-benzenesulfonamide (651 mg) as a white solid; LC-MS: tR=0.68 min; 1H NMR (D6-DMSO): δ 10.08 (s, 1H), 8.12-8.07 (m, 2H), 7.98-7.94 (m, 2H), 7.68 (s br, 1H), 2.42 (s, 3H).
Reaction SMILES: C(OC(C1[C:12]2[NH:13][C:14]3[CH:15]=[C:16]([N:20]([CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:17]=[CH:18][C:19]=3[C:11]=2[C:10](C)(C)[CH2:9][NH:8]C=1)=O)C.C(Br)C1C=CC=CC=1.NC1C=C2C(C(CC#N)=CN2)=CC=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>O.CN(C=O)C>[CH2:28]([N:20]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:15]=[C:14]2[C:19]([C:11]([CH2:10][C:9]#[N:8])=[CH:12][NH:13]2)=[CH:18][CH:17]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CCOC(=O)C1=CNCC(C)(C)c2c1[nH]c1cc(N(Cc3ccccc3)Cc3ccccc3)ccc21
Agent: BrCc1ccccc1
Agent: N#CCc1c[nH]c2cc(N)ccc12
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCc1c[nH]c2cc(N(Cc3ccccc3)Cc3ccccc3)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To prepare 8-dibenzylamino-1,1-dimethyl-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylic acid ethyl ester: Benzyl bromide (10 mL, 84.2 mmol) was added to a stirred mixture of (6-amino-1H-indol-3-yl)acetonitrile (Brown, R. K.; Garrison, R. A., J. Am. Chem. Soc. (1955), Vol. 77, pp. 3839-3842) (5.16 g, 30.14 mmol), potassium carbonate (10.83 g, 78.36 mmol), sodium iodide (560 mg, 3.74 mmol) and anhydrous DMF (150 mL) at ambient temperature under nitrogen. The resulting mixture was stirred at ambient temperature overnight, then poured into a mixture of water, and extracted with ethyl acetate. The combined extracts were washed with ammonium chloride solution, and evaporated in vacuo. The residue was purified by chromatography on silica gel eluting with hexane-ethyl acetate (85:15) to give (6-dibenzylamino-1H-indol-3-yl)-acetonitrile (8.8 g); MS (ES): 352 (MH+), which was then treated in a manner similar to that described in Example 34C-G but replacing (6-benzyloxy-1H-indol-3-yl)acetonitrile with (6-dibenzylamino-1H-indo-3-yl)acetonitrile at Step C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][CH2:6][C:7]([C:9](=[O:24])[N:10]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[CH2:11][CH2:12][CH:13]=C)=C>C(Cl)Cl.[Ru]>[CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][CH2:6][C:7]1[C:9](=[O:24])[N:10]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[CH2:11][CH2:12][CH:13]=1
Reactant: C=CCCN(Cc1ccc(OC)cc1)C(=O)C(=C)CCCC(=O)OC
Agent: [Ru]
Solvent: ClCCl
Product: COC(=O)CCCC1=CCCN(Cc2ccc(OC)cc2)C1=O

Procedure:
5-[(4-methoxy-benzyl)-but-3-enyl-carbamoyl]-hex-5-enoic acid methyl ester (t) prepared by above Step 1 was added to the catalyst solution containing Grubb's (I) catalysis such as ruthenium dissolved in organic solvent such as CH2Cl2 to give 4-[1-(4-methoxy-benzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-butyric acid methyl ester (u).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11](OS(C)(=O)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:19]([O-:22])(=[S:21])[CH3:20].[K+].O.CC(OC)(C)C>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([S:21][C:19](=[O:22])[CH3:20])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: CC(=O)SC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
Crude 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester was dissolved in 200 ml DMF, and potassium thioacetate (18.5 g, 162 mmol) was added. The mixture was stirred overnight under a nitrogen atmosphere at about 65° C. The reaction mixture solidified overnight, and after it was cooled to room temperature, 250 ml water and 250 ml TBME was added, and the mixture was stirred for 10 minutes. The layers were separated, and the aqueous layer was extracted with 200 ml TBME. The combined organic layers were washed with water (2×250 ml) and saturated aqueous NaCl solution (150 ml), dried over sodium sulfate, filtered, and evaporated to dryness (30.3 g, 94%) to give a dark-brown oil identified as the product by 1H-NMR, which was used without purification in the next step.