Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)=[O:4].[C:16]1(=[O:26])[NH:20][C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12.[K].C(OCC)(=O)C>O>[CH3:14][CH:13]([CH3:15])[CH2:12][CH:2]([N:20]1[C:16](=[O:26])[C:17]2[C:18](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:19]1=[O:21])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)=[O:4]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1ccc(C(=O)C(Br)CC(C)C)cc1
Agent: [K]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)C(CC(C)C)N2C(=O)c3ccccc3C2=O)cc1
Temperature: 160 °C
Yield: 72.7 %

Procedure:
2-Bromo-4-methyl-1-(4-methylphenyl)pentane-1-one (13.5 g, 50 mmol) and potassium phthalimide (9.26 g, 50 mmol) were thoroughly mixed and heated at 160° C. for 2 hours. After being cooled, the reaction mixture was added with ethyl acetate (100 ml) and with water (50 ml). The resulting organic layer was separated and washed with brine. The organic solution was then dried over sodium sulfate and evaporated under reduced pressure. The residue was crystallized by treatment with hexane and the resulting crystals were recrystallized from hexane to obtain 12.2 g of the intended compound as white crystals (yield: 73%).
Reaction SMILES: [CH3:1][C:2]1[CH:32]=[CH:31][CH:30]=[CH:29][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([N:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][N:18]3[CH:26]=[CH:27][CH:28]=[C:17]3[CH2:16]2)=[O:14])=[CH:9][CH:8]=1)=[O:5].[Cl:33]N1C(=O)CCC1=O>O1CCCC1>[Cl:33][C:26]1[N:18]2[C:17]([CH2:16][N:15]([C:13]([C:10]3[CH:9]=[CH:8][C:7]([NH:6][C:4](=[O:5])[C:3]4[CH:29]=[CH:30][CH:31]=[CH:32][C:2]=4[CH3:1])=[CH:12][CH:11]=3)=[O:14])[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19]2)=[CH:28][CH:27]=1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3ccc(Cl)n3Cc3ccccc32)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 68.8 %

Procedure:
To an ice-water cooled suspension of 211 mg of 2-methyl-N-[4-(5H-pyrrolo[2,1-c][1,4]-benzodiazepin-10(11H)-ylcarbonyl)-phenyl]benzamide in 5 ml of tetrahydrofuran is added 67 mg of N-chlorosuccinimide followed by continued stirring in the cold for 10 minutes. The bath is removed and stirring continued for 2.25 hours. The reaction mixture is added to ice-water and extracted with ether. The organic layer is dried and concentrated in vacuo to give a foam which is crystallized from ethyl acetate-hexane to give 157 mg of the desired product as an orange-pink solid, m.p. 185°-187° C.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH2:7][CH2:8][C:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=1)[C:3]([O:5]C)=O.[NH2:22][CH2:23][C:24]([OH:26])=[O:25].C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH3:21][C:2]1([CH3:1])[CH2:7][CH2:8][CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:22]([CH2:23][C:24]([OH:26])=[O:25])[C:3]1=[O:5]
Reactant: NCC(=O)O
Reactant: COC(=O)C(C)(C)CCC(=O)c1cccc(C(F)(F)F)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC1(C)CCC(c2cccc(C(F)(F)F)c2)N(CC(=O)O)C1=O
Temperature: 140 °C

Procedure:
To a stirred solution of methyl 2,2-dimethyl-5-oxo-5-[3-(trifluoromethyl)phenyl]pentanoate from Step A (45.0 mg, 0.149 mmol) and glycine (99.0 mg, 1.32 mmol) in MeOH (2 mL) and acetic acid (0.045 mL) was added sodium cyanoborohydride (50.0 mg, 0.794 mmol). The reaction mixture was heated to reflux for 18 h. To the resulting mixture was added xylenes (3 mL) and heated to 140° C. for 4 h. The solvent was removed in vacuo and the crude solid dissolved in DMSO (1 mL). The crude product was purified by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. Lyophilization provided the title compound. MS: m/z=330 (M+1).
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.[C:31]([NH:39][C:40]1[C:41]2[N:42]=[CH:43][N:44]([C:53]=2[N:54]=[CH:55][N:56]=1)[C@@H:45]1[O:52][C@H:49]([CH2:50]O)[C@@H:47]([OH:48])[CH2:46]1)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.ClCCl>[C:20]1(=[O:30])[N:24]([CH2:50][C@H:49]2[O:52][C@@H:45]([N:44]3[C:53]4[N:54]=[CH:55][N:56]=[C:40]([NH:39][C:31](=[O:38])[C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[C:41]=4[N:42]=[CH:43]3)[CH2:46][C@@H:47]2[OH:48])[C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12
Reactant: O=C(Nc1ncnc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1)c1ccccc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(Nc1ncnc2c1ncn2[C@H]1C[C@H](O)[C@@H](CN2C(=O)c3ccccc3C2=O)O1)c1ccccc1
Reaction time: 2 h
Yield: 30.9 %

Procedure:
To a stirred solution of 13.11 g (50 mmol) Ph3P, 6.99 g (47.5 mmol) phthalimide and 17.77 g (50 mmol) N6-benzoyl-2′-deoxyadenosine in 400 mL dry THF was added 9.84 mL (50 mmol) of diisopropyl azodicarboxylate under a nitrogen atmosphere. The resulting mixture was stirred for 2 h in an ice water bath and then 4 h at room temperature. After most of the THF was evaporated under reduced pressure, the oily residue was added 100 ml of dichloromethane. The precipitate, which was formed after the addition of dichloromethane, was filtered and washed with small amounts of THF/dichloromethane mixture (1:1). The filtrate was concentrated and purified with a silica gel column chromatography (dichloromethane/THF=2:1 then dichloromethane/methanol=19:1) to give 7.1 g of compound 2.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[Si:9]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][N:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[C:32]1[C:40]1[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=1)([C:22]([CH3:25])([CH3:24])[CH3:23])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)C.O>[Si:9]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][N:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]([Cl:1])=[C:32]1[C:40]1[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=1)([C:22]([CH3:24])([CH3:25])[CH3:23])([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)[Si](OCCCCn1c(-c2cccnc2)cc2ccccc21)(c1ccccc1)c1ccccc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCO
Solvent: O
Product: CC(C)(C)[Si](OCCCCn1c(-c2cccnc2)c(Cl)c2ccccc21)(c1ccccc1)c1ccccc1
Yield: 60.9 %

Procedure:
N-Chlorosuccinimide (504 mg) was dissolved in an ethanol (9 ml) and water (1 ml) mixture of the 1-[4-(tert-butyldiphenylsilyloxy)butyl]-2-(3-pyridyl)indole (1.99 g) obtained in the same way as in Example 2(1), and the mixture was reacted at room temperature for 4.5 hours. After the reaction, water was added and the mixture was extracted with ethyl acetate, and the organic phase was washed with brine, then dried over magnesium sulfate, then the solvent was evaporated in vacuo and the residue was purified by silica gel column chromatography to obtain 1-[4-(tert-butyldiphenylsilyloxy)butyl]-3-chloro-2-(3-pyridyl)indole (1.24 g).
Reaction SMILES: [OH:1][CH:2]([CH2:24][OH:25])[CH2:3][O:4][C:5](=[O:23])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[C:26]1([C:32](Cl)([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>ClCCl.N1C=CC=CC=1>[OH:1][CH:2]([CH2:24][O:25][C:32]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[CH2:3][O:4][C:5](=[O:23])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(O)CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 88 %

Procedure:
A solution of 2 (21 mmol) in 80 ml of dichloromethane/pyridine (1:1) is added dropwise with triphenylmethyl chloride (27 mmol) and stirred at room temperature for 48 hours. The solvent is removed, and the residue is added twice with 50 ml of toluene and concentrated. The residue is diluted with 100 ml of H2O and extracted three times with 50 ml of dichloromethane. The combined organic phases are washed with 50 ml of cold 5% HCl and 50 ml of saturated NaCl solution, dried over MgSO4, filtrated and concentrated. The residue is purified by chromatography on silica gel using heptane/ethyl acetate (5:1). Yield: 88% of a colorless oil.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([OH:8])[CH:4]([CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:3]1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.CC(O)C>CC(C)=O>[O:1]=[C:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH:4]([CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:3]1
Reactant: O=C1CCC(O)C(C(c2ccccc2)c2ccccc2)N1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: CC(C)=O
Product: O=C1CCC(=O)C(C(c2ccccc2)c2ccccc2)N1
Reaction time: 4 h
Yield: 85.2 %

Procedure:
To a stirred solution of 2-oxo-5-hydroxy-6-benzhydryl piperidine (18.15 gm, 64.5 mmole) in acetone (150 ml) at -5° C. was added Jones reagent (2.67 M, 94 mmole), and the reaction mixture was further stirred for 4 hrs. At the end of this period, the excess reactant was decomposed with 2-propanol and the solution concentrated under vacuum to half of its volume. The contents of the flask were then dilutes with water (1000 ml) and extracted with methylene chloride (3×1000 ml). the combined organic phases were dried (anhyd. magnesium sulfate) and the methylene chloride was removed under vacuum to afford 2,5-dioxo-6-benzhydrylpiperidine (15.35 gm, 85%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([OH:14])[C:3]=1[C:15]1[CH:23]=[CH:22][C:18]2[O:19][CH2:20][O:21][C:17]=2[CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:30]([O:33][CH2:34][CH2:35]Br)(=[O:32])[CH3:31]>CN(C)C=O>[C:30]([O:33][CH2:34][CH2:35][O:14][C:4]1[C:3]([C:15]2[CH:23]=[CH:22][C:18]3[O:19][CH2:20][O:21][C:17]=3[CH:16]=2)=[C:2]([NH2:1])[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=1)(=[O:32])[CH3:31]
Reactant: Nc1c(-c2ccc3c(c2)OCO3)c(O)nn1Cc1ccccc1
Reactant: CC(=O)OCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=O)OCCOc1nn(Cc2ccccc2)c(N)c1-c1ccc2c(c1)OCO2
Reaction time: 8 h
Yield: 58.7 %

Procedure:
To a stirred mixture of 5-amino-4-(1,3-benzodioxol-5-yl)-1-benzyl-1H-pyrazol-3-ol (30 g) (Preparation 59) and cesium carbonate (94.8 g) in anhydrous dimethylformamide (340 ml), under an atmosphere of nitrogen, 2-bromoethyl acetate (16.2 g) was added drop-wise over 10 minutes and the reaction was stirred overnight. The reaction was quenched by the addition of an aqueous solution of HCl (2N, 260 ml) then ethyl acetate (600 ml) and water (100 ml) were added. The aqueous phase was extracted with ethyl acetate (3×500 ml) and the combined organic fractions were washed with brine (500 ml) and dried over Na2SO4. The dark oil was purified by flash chromatography (heptane/EtOAc; 1/1) (silica, 1000 g) yielding of the title compound as a dark oil (22.5 g).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([F:10])[C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:6]([F:16])[CH:5]=1)(=O)[CH3:2].[CH3:17][C:18]([S@:21]([NH2:23])=[O:22])([CH3:20])[CH3:19]>C1COCC1.[Cl-].[Na+].O>[F:10][C:8]1[CH:9]=[C:4]([C:1](=[N:23][S:21]([C:18]([CH3:20])([CH3:19])[CH3:17])=[O:22])[CH3:2])[CH:5]=[C:6]([F:16])[C:7]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13]
Reactant: CC(=O)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Reactant: CC(C)(C)[S@](N)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=NS(=O)C(C)(C)C)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 84.6 %

Procedure:
To a solution of N-(4-acetyl-2,6-difluoro-phenyl)-methanesulfonamide (1.84 g, 7.38 mmol) and (R)-(+)-2-methyl-2-propanesulfinamide (1.07 g, 8.86 mL) in THF (15 mL) was added dropwise Ti(OEt)4 (2.61 mL, 12.6 mmol) at room temperature. The mixture was stirred overnight at 90° C. The mixture cooled to room temperature and then was added brine. After the mixture was extracted three times with EtOAc, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by chromatography to yield N-{2,6-difluoro-4-[1-(2-methyl-propane-2-sulfinylimino)-ethyl]-phenyl}-methanesulfonamide (2.2 g, 85%). To a solution of N-{2,6-difluoro-4-[1-(2-methyl-propane-2-sulfinylimino)-ethyl]-phenyl}-methanesulfonamide (2.2 g, 6.24 mmol) in THF (20 mL) was added portionwise NaBH4 (944 mg, 24.9 mmol) dissolved in THF (2 mL) at −48° C. The mixture was stirred for 10 hours at −48° C. room temperature, and then CH3OH was added dropwise until gas was no longer evolved. The mixture was concentrated under reduced pressure, and then was purified by chromatography to afford N-{2,6-difluoro-4-[1-(2-methyl-propane-2-sulfinylamino)-ethyl]-phenyl}-methanesulfonamide (1.89 g, 50%).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:9]=[C:10]([CH:23]2[CH2:28][CH2:27][N:26]([C:29](OCC3C=CC=CC=3)=O)[CH2:25][CH2:24]2)[N:11]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C=O.[H][H]>CO.C(O)(=O)C.[Pd]>[F:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][CH2:14][N:11]2[C:10]([CH:23]3[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]3)=[CH:9][C:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])=[C:12]2[CH3:13])=[CH:21][CH:20]=1
Reactant: Cc1c(C(=O)OC(C)(C)C)cc(C2CCN(C(=O)OCc3ccccc3)CC2)n1CCc1ccc(F)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: C=O
Solvent: CO
Solvent: CC(=O)O
Product: Cc1c(C(=O)OC(C)(C)C)cc(C2CCN(C)CC2)n1CCc1ccc(F)cc1

Procedure:
A 340 mg portion of benzyl 4-{4-(tert-butoxycarbonyl)-1-[2-(4-fluorophenyl)ethyl]-5-methyl-1H-pyrrol-2-yl}piperidine-1-carboxylate was dissolved in 7 ml of methanol, and 159 μl of 37% formalin, 3 drops of acetic acid and 45 mg of 10% palladium-activated carbon were added, followed by stirring at room temperature for 2 hours in an atmosphere of hydrogen. The reaction liquid was filtered through celite, the filtrate was concentrated under a reduced pressure, 50 ml of a saturated sodium bicarbonate aqueous solution was added to the residue, and the resulting solid was collected by filtration to obtain 232 mg of tert-butyl 1-[2-(4-fluorophenyl)ethyl]-2-methyl-5-(1-methylpiperidin-4-yl)-1H-pyrrole-3-carboxylate as a colorless solid.
Reaction SMILES: P(Br)(Br)[Br:2].[CH2:5]([C:7]1[CH:8]=[C:9]([CH2:13]O)[CH:10]=[CH:11][CH:12]=1)[CH3:6].O>C1C=CC=CC=1>[Br:2][CH2:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([CH2:5][CH3:6])[CH:8]=1
Reactant: BrP(Br)Br
Reactant: CCc1cccc(CO)c1
Solvent: c1ccccc1
Solvent: O
Product: CCc1cccc(CBr)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Phosphorous tribromide (5.3 ml) was added to a solution of the product from step (i) (7.6 g) in benzene (150 ml) at 0° C. After 3 hours, water (40 ml) was added and the mixture warmed to room temperature and extracted with ethyl acetate. The organic phase was dried (MgSO4) and evaporated. Purified by chromatography eluting with 2% ethyl acetate in isohexane. Yield 8.0 g.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[CH2:6][C@H:5]1[CH3:15])(=[O:3])[CH3:2].[N:16]([O-:18])=[O:17].[Na+].O>C(O)(C(F)(F)F)=O>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[C:10]([N+:16]([O-:18])=[O:17])[CH:11]=2)[CH2:6][C@H:5]1[CH3:15])(=[O:3])[CH3:2]
Reactant: O=N[O-]
Reactant: COc1ccc2c(c1)C[C@@H](C)N2C(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1cc2c(cc1[N+](=O)[O-])N(C(C)=O)[C@H](C)C2
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.7 %

Procedure:
A solution of (2R)-1-acetyl-2-methyl-5-(methyloxy)-2,3-dihydro-1H-indole (100 mg, 0.487 mmol)—see (Arp, Forrest O.; Fu, Gregory C. Kinetic Resolutions of Indolines by a Nonenzymatic Acylation Catalyst. Journal of the American Chemical Society (2006), 128(44), 14264-14265.)—in TFA (2 mL) at 0° C. was treated with sodium nitrite (33.6 mg, 0.487 mmol). The resulting red solution was stirred at 0° C. for 1 h. H2O (20 mL) was added, the resulting slurry was filtered and the solids were washed with water to afford (2R)-1-acetyl-2-methyl-5-(methyloxy)-6-nitro-2,3-dihydro-1H-indole as a yellow solid (85 mg, 70%). 1H NMR (400 MHz, DMSO-d8) δ ppm 1.22 (d, J=6.41 Hz, 3H), 2.22 (s, 3H), 2.76 (d, J=17.21 Hz, 1H), 3.45 (dd, J=17.12, 8.88 Hz, 1H), 3.89 (s, 3H), 4.59-4.74 (m, 1H), 7.35 (s, 1H), 8.40 (s, 1H); ESIMS (M+H)+=251.00.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:9][CH2:8][C@H:7]([OH:10])[CH2:6]1)(=[O:3])[CH3:2].[CH3:11][S:12](Cl)(=[O:14])=[O:13].C(N(CC)CC)C>COC(C)(C)C>[CH3:11][S:12]([O:10][C@@H:7]1[CH2:8][CH2:9][C@H:5]([O:4][C:1](=[O:3])[CH3:2])[CH2:6]1)(=[O:14])=[O:13]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)O[C@@H]1CC[C@H](O)C1
Solvent: CCN(CC)CC
Solvent: COC(C)(C)C
Product: CC(=O)O[C@H]1CC[C@@H](OS(C)(=O)=O)C1
Temperature: -8 °C
Yield: 95.8 %

Procedure:
Dissolve (1S,3R)-cis-3-acetoxy-cyclopentanol (9.75 g, 67.6 mmol, prepared in example 23) in tert-butyl methyl ether (80 mL, anhydrous) and cool to -8° C. with stirring. Add methanesulfonyl chloride (5.7 mL, 73.6 mmol, mesyl chloride) over 5 minutes, followed by dropwise addition of triethylamine (11.4 mL, 81.2 mL), over about 30 minutes, maintaining the temperature below -2° C. The ice bath is then removed and the mixture is stirred for 2 hours. The mixture is poured into a water/brine mixture (50 mL/50 mL). The layers are separated and the aqueous layer extracted with tert-butyl methyl ether (100 mL). The organic layer and extract is combined, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide the title compound (14.4 g) as a yellow oil; 1H NMR (CDCl3) δ 8 5.1 (m, 2 H), 3.02 (s, 3 H), 2.41 (m, 1 H), 2.05 (s, 3 H), 2.0 (m, 5 H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[N:33]=[C:34]([N:37]2[CH:41]=[C:40]([CH3:42])[N:39]=[CH:38]2)[S:35][CH:36]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[N:33]=[C:34]([N:37]2[CH:41]=[C:40]([CH3:42])[N:39]=[CH:38]2)[S:35][CH:36]=1)=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cn(-c2nc(C(=O)CC(=O)OC(C)(C)C)cs2)cn1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1N
Product: Cc1cn(-c2nc(C(=O)CC(=O)Nc3cc(-c4ccccc4F)ccc3NC(=O)OC(C)(C)C)cs2)cn1

Procedure:
Prepared from (3-amino-2′-fluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G37) (151 mg, 0.5 mmol) and 3-[2-(4-methyl-imidazol-1-yl)-thiazol-4-yl]-3-oxo-propionic acid tert.-butyl ester (Example H20) (154 mg, 0.5 mmol) according to the general procedure K. Obtained as a yellow amorphous substance (157 mg).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[C:9]([O:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[F:39])[C:10]([C:14]3[CH:15]=[N:16][N:17]([CH:19]4[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]4)[CH:18]=3)=[CH:11][CH:12]=2)[CH2:7][CH2:6][C@@H:5]1[CH3:40])(=[O:3])[CH3:2].FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[F:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[O:32][C:9]1[C:10]([C:14]2[CH:15]=[N:16][N:17]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[CH:18]=2)=[CH:11][CH:12]=[C:13]2[C:8]=1[CH2:7][CH2:6][C@H:5]([CH3:40])[N:4]2[C:1](=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(-c3cnn(C4CCN(C(=O)OC(C)(C)C)CC4)c3)c(Oc3ccccc3F)c2CC[C@@H]1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)N1c2ccc(-c3cnn(C4CCNCC4)c3)c(Oc3ccccc3F)c2CC[C@@H]1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.9 %

Procedure:
A 100-mL round-bottom flask was charged with (S)-tert-butyl 4-(4-(1-acetyl-5-(2-fluorophenoxy)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (370 mg, 0.67 mmol), dichloromethane (10 mL) and trifluoroacetic acid (4 mL). The resulting solution stirred for 2 h at room temperature. The pH value of the solution was adjusted to 8 with saturated aqueous potassium carbonate solution. The resulting mixture was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting with 5:1, ethyl acetate/petroleum ether) to afford (S)-1-(5-(2-fluorophenoxy)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone (141 mg, 47%) as a white solid. 1H NMR (300 MHz, CD3OD) δ ppm 1.15 (d, J=6.60 Hz, 3H), 1.25-1.45 (m, 1H), 1.75-1.95 (m, 2H), 1.97-2.08 (m, 2H), 2.15-2.35 (m, 5H), 2.65-2.89 (m, 3H), 3.09-3.20 (m, 2H), 4.15-4.29 (m, 1H), 4.65-4.85 (m, 1H), 6.35-6.48 (m, 1H), 6.85-6.98 (m, 2H), 7.13-7.22 (m, 1H), 7.27-7.42 (m, 1H), 7.61 (d, J=8.40 Hz, 1H), 7.81 (s, 1H), 7.99 (s, 1H). MS (ESI, pos. ion) m/z 449 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH:3]1[C:13]2[CH2:12][O:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl[C@H:19]1[CH2:24][CH2:23][CH2:22][N:21]([CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=2)[CH2:20]1>CS(C)=O>[CH3:36][O:35][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][C:30]=1[O:33][CH3:34])[CH2:26][CH2:25][N:21]1[CH2:22][CH2:23][CH2:24][C@@H:20]1[CH2:19][N:8]1[C:7]2[CH:6]=[CH:5][CH:4]=[CH:3][C:13]=2[CH2:12][O:11][C:10]2[CH:14]=[CH:15][CH:16]=[CH:17][C:9]1=2
Reactant: COc1ccc(CCN2CCC[C@H](Cl)C2)cc1OC
Reactant: c1ccc2c(c1)COc1ccccc1N2
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(CCN2CCC[C@@H]2CN2c3ccccc3COc3ccccc32)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
Sixty-percent sodium hydride (470 mg, 12 mmols) was washed with petroleum ether, and then suspended in 50 ml of dimethyl sulfoxide. To the suspension were added 1.5 g (7.5 mmols) of 5,11-dihydrodibenzo[b,e][1,4]oxazepine. The mixture was stirred in a nitrogen atmosphere at room temperature for 30 minutes. To this reaction solution was added dropwise a solution of 3.2 g (11 mmols) of (S)-(+)-3-chloro-1-(3,4-dimethoxyphenethyl)piperidine[[α]D25=+20.3 ° (c=0.9, ethano 1)] in 30 ml of dimethyl sulfoxide, and the mixed solution was stirred at 50° C. for 5 hours. The reaction solution was poured into ice water, and extracted with ethyl acetate. The organic layer was washed with water and with a saturated aqueous solution of sodium chloride in this order, and dried. Subsequently, the solvent was distilled off under reduced pressure. The resulting residue was subjected to column chromatography, and eluted with a mixed solvent of ethyl acetate and hexane at a ratio of 1:3. This mixed solvent was distilled off under reduced pressure. Further, the thus-obtained residue was subjected to column chromatography, and eluted with a mixed solvent of chloroform and methanol at a ratio of 300:1. The mixed solvent was then distilled off under reduced pressure to give 2.8 g of (R)-(+)-5,11-dihydro-5-[1-(3,4-dimethoxyphenethyl)-2-pyrrolidinylmethyl]dibenzo[b,e][1,4]oxazepine as a pale yellow oil in a yield of 85%.