Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]#[N:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[F:13][C:14]([F:21])([F:20])[C:15]1[CH:19]=[CH:18][NH:17][N:16]=1.C1(C)C=CC=CC=1.CN(C)C=O.CN[C@H]1CCCC[C@@H]1NC.C(=O)([O-])[O-].[K+].[K+]>CCOC(C)=O.[Cu]I>[F:13][C:14]([F:21])([F:20])[C:15]1[CH:19]=[CH:18][N:17]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3([C:11]#[N:12])[CH2:10][CH2:9]3)=[CH:4][CH:3]=2)[N:16]=1
Reactant: N#CC1(c2ccc(Br)cc2)CC1
Reactant: FC(F)(F)c1cc[nH]n1
Agent: [Cu]I
Agent: CN[C@H]1CCCC[C@@H]1NC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#CC1(c2ccc(-n3ccc(C(F)(F)F)n3)cc2)CC1

Procedure:
To a solution of 1-(4-bromophenyl)cyclopropanecarbonitrile (600 mg, 0.003 mol), 3-(trifluoromethyl)-1H-pyrazole (441 mg, 0.00324 mol) in toluene (2 mL, 0.02 mol) and N,N-dimethylformamide (3 mL, 0.04 mol) were added (1S,2S)—N,N′-dimethylcyclohexane-1,2-diamine (77 mg, 0.00054 mol), copper(I) iodide (51 mg, 0.00027 mol), and potassium carbonate (784 mg, 0.00567 mol). The mixture was microwave irradiated at 200° C. for 60 minutes and then filtered. The filtrate was diluted with methanol, and the product from the filtrate was isolated and purified using prep-HPLC. Additional product could be obtained from the precipitate by dissolving the precipitate in EtOAc, washing with satd. NaHCO3, brine, drying with MgSO4, and concentrating for purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:17])[CH2:12][C:13]([F:16])([F:15])[F:14])=[CH:4][C:3]=1[CH:18]=O.CCN(CC)CC.[CH:27]1([NH2:30])[CH2:29][CH2:28]1.[BH4-].[Na+].C([O-])(O)=O.[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:17])[CH2:12][C:13]([F:16])([F:15])[F:14])=[CH:4][C:3]=1[CH2:18][NH:30][CH:27]1[CH2:29][CH2:28]1
Reactant: O=Cc1cc(CCNC(=O)CC(F)(F)F)ccc1Cl
Reactant: NC1CC1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(CC(F)(F)F)NCCc1ccc(Cl)c(CNC2CC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.2 %

Procedure:
A mixture of N-[2-(4-chloro-3-formyl-phenyl)-ethyl]-3,3,3-trifluoro-propionamide (175 mg, 0.596 mmol), Et3N (0.125 mL, 0.896 mmol) and cyclopropylamine (0.063 mL, 0.90 mmol) in MeOH (2.00 mL) was heated to reflux for 4 h. The mixture was allowed to cool to rt, and NaBH4 (56.4 mg, 1.49 mmol) was added in portions. The mixture was stirred for 1 h, and aq. sat. NaHCO3 was added. The mixture was extracted with EtOAc several times, and the combined org. extracts were washed with brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (CH2Cl2/MeOH 95:5) yielded the title compound (130 mg, 65%). LC-MS: tR=0.65 min; ES+: 335.12.
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][N:11]=2)[N:3]=1.[O:16]1[CH2:22][C@@H:21]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=2)[CH2:20][NH:19][CH2:18][CH2:17]1.C(N(CC)CC)C>>[CH3:8][N:7]1[C:6](=[O:9])[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][N:11]=2)[N:3]=[C:2]1[N:19]1[CH2:20][C@H:21]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=2)[CH2:22][O:16][CH2:17][CH2:18]1
Reactant: N#Cc1ccc([C@H]2CNCCOC2)cc1
Reactant: Cn1c(Cl)nc(-c2ccncn2)cc1=O
Solvent: CCN(CC)CC
Product: Cn1c(N2CCOC[C@@H](c3ccc(C#N)cc3)C2)nc(-c2ccncn2)cc1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 73.2 %

Procedure:
To a solution of 2-chloro-3-methyl-6-(pyrimidin-4-yl)-3H-pyrimidin-4-one (73.4 mg, 0.330 mmol) and (S)-4-([1,4]oxazepan-6-yl)benzonitrile (70.0 mg, 0.346 mmol) was added triethylamine (100 mg, 0.989 mmol) at room temperature. The mixture was stirred at room temperature for 5 hours and partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=1/9) to afford (S)-4-(4-(1,6-dihydro-1-methyl-6-oxo-4-(pyrimidin-4-yl)pyrimidin-2-yl)-[1,4]oxazepan-6-yl)benzonitrile (A076) as white solid (93.8 mg, 70%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([NH:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)=[O:14])[C:9]([OH:11])=O.[CH:23]([N:26]1[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28][CH2:27]1)([CH3:25])[CH3:24]>>[CH:23]([N:26]1[CH2:31][CH2:30][CH:29]([NH:32][C:9](=[O:11])[CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[O:14])[CH2:28][CH2:27]1)([CH3:25])[CH3:24]
Reactant: CC(C)N1CCC(N)CC1
Reactant: Cc1ccccc1C(NC(=O)Nc1ccc(Cl)cc1)C(=O)O
Product: Cc1ccccc1C(NC(=O)Nc1ccc(Cl)cc1)C(=O)NC1CCN(C(C)C)CC1

Procedure:
The titled compound was prepared analogously as describe in EXAMPLE 82, using 2-(2-methylphenyl)-2-(4-chlorophenylaminocarbonylamino)-acetic acid and 1-isopropyl-4-aminopiperidine. MS 443.2 and 445.2 (M+H, Cl pattern).
Reaction SMILES: [CH3:1][C:2]1([CH3:40])[S:7](=[O:9])(=[O:8])[C@H:6]2[CH2:10][C:11]([CH3:23])([CH3:22])[O:12][C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][C:14]=3[C@@:5]2([CH3:24])[N:4]=[C:3]1[N:25]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29]>CCOC(C)=O.CO.[Pd]>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]2[O:12][C:11]([CH3:23])([CH3:22])[CH2:10][C@@H:6]3[S:7](=[O:8])(=[O:9])[C:2]([CH3:40])([CH3:1])[C:3]([N:25]([C:26]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:32])[C:33](=[O:34])[O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[N:4][C@:5]3([CH3:24])[C:14]=2[CH:15]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@]2(C)c3cc([N+](=O)[O-])ccc3OC(C)(C)C[C@@H]2S(=O)(=O)C1(C)C
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@]2(C)c3cc(N)ccc3OC(C)(C)C[C@@H]2S(=O)(=O)C1(C)C
Reaction time: 16 h
Yield: 100 %

Procedure:
A mixture of tert-butyl N-[(4aS,11bR)-3,3,6,6,11b-pentamethyl-10-nitro-4,4-dioxo-4a,5-dihydro-[1]benzoxepino[4,5-b][1,4]thiazin-2-yl]-N-tert-butoxycarbonyl-carbamate (70 mg, 0.120 mmol) (Prepared following the procedure for Intermediate 31 (trans), Step 1 and 2) and 10% Pd/C (38.6 mg, 0.036 mmol) in EtOAc (1.1 mL) and MeOH (1.1 mL) was stirred under hydrogen atmosphere for 16 hours. The mixture was passed through a celite cake and rinsed with ethyl acetate and ethanol. The filtrate was concentrated in vacuo to afford the title compound (66 mg, 0.120 mmol, 100% yield) as a white foam. MS m/z=574.3 (M+Na).
Reaction SMILES: C12[N:8]([C:9]3C=N[C:16]4[C:11](=[CH:12]C=[CH:14][CH:15]=4)[N:10]=3)CC1CCNC2.[CH:19]12[CH2:25][NH:24][CH:23]1[CH2:22][N:21]([C:26]([C:28]1[CH:33]=[C:32]([CH3:34])[CH:31]=[CH:30][C:29]=1[N:35]1[N:39]=[CH:38][CH:37]=[N:36]1)=[O:27])[CH2:20]2.ClC1N=C(C)C=C(C)N=1>>[CH3:12][C:11]1[CH:16]=[C:15]([CH3:14])[N:8]=[C:9]([N:24]2[CH2:25][CH:19]3[CH:23]2[CH2:22][N:21]([C:26]([C:28]2[CH:33]=[C:32]([CH3:34])[CH:31]=[CH:30][C:29]=2[N:35]2[N:39]=[CH:38][CH:37]=[N:36]2)=[O:27])[CH2:20]3)[N:10]=1
Reactant: c1ccc2nc(N3CC4CCNCC43)cnc2c1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CC3CNC3C2)c1
Agent: Cc1cc(C)nc(Cl)n1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CC3CN(c4nc(C)cc(C)n4)C3C2)c1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 2, Step A, using Intermediate 26 and 2-chloro-4,6-dimethylpyrimidine. MS (ESI) mass calcd. for O21H23N7O, 389.46; m/z found, 390.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[C:5]([F:14])=[C:4](Cl)[N:3]=1.Cl.[F:17][C:18]1[CH:19]=[CH:20][C:21]([C@@H:24]([NH2:26])[CH3:25])=[N:22][CH:23]=1.CCN(C(C)C)C(C)C>C(O)CCC>[Cl:1][C:2]1[N:3]=[C:4]([NH:26][C@H:24]([C:21]2[CH:20]=[CH:19][C:18]([F:17])=[CH:23][N:22]=2)[CH3:25])[C:5]([F:14])=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:7]=1
Reactant: Fc1c(Cl)nc(Cl)nc1N1CCOCC1
Reactant: C[C@H](N)c1ccc(F)cn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1nc(Cl)nc(N2CCOCC2)c1F)c1ccc(F)cn1
Temperature: 130 °C
Yield: 42 %

Procedure:
A mixture of 4-(2,6-dichloro-5-fluoropyrimidin-4-yl)morpholine (Preparation 11a, 1.18 g, 4.68 mmol), (S)-1-(5-fluoropyridin-2-yl)ethanamine hydrochloride (prepared as described in WO2006/123113, 1.00 g, 4.69 mmol) and N,N′-diisopropylethylamine (3.27 mL, 18.77 mmol) in n-butanol (20 mL) was heated at 130° C. for two days. The solvent was evaporated under reduced pressure and the residue was purified by flash chromatography (0-5% ethyl acetate in hexanes to 5:94:1 ethyl acetate/hexanes/triethylamine) to give the title compound (0.700 g, 42%) as one major regioisomer. The chemical structures of both regioisomers were confirmed by NMR experiments (gHSQCAD and gHMBCAD).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Br[CH2:11][CH2:12][CH2:13][Cl:14]>>[Cl:14][CH2:13][CH2:12][CH2:11][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: ClCCCBr
Reactant: c1ccc2[nH]ccc2c1
Product: ClCCCn1ccc2ccccc21

Procedure:
Prepared by Procedure AH, and Scheme P using 1H-indole and 1-bromo-3-chloropropane: 1H NMR (400 MHz, CDCl3) δ 7.70-7.04 (m, 5H), 6.50 (d, 1H, J=2.8 Hz), 4.31 (t, 2H, J=6.8 Hz), 3.42 (t, 2H, J=6.4 Hz), 2.28-2.20 (m, 2H).
Reaction SMILES: O.[OH-].[Li+].[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][C:15]=1[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([N+:26]([O-:28])=[O:27])[CH:24]=2)[NH:19][CH:18]=1)[C:9]([O:11]C)=[O:10].Cl>O.CO>[N+:26]([C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[NH:19][CH:18]=[C:17]2[CH2:16][C:15]1[CH:14]=[CH:13][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[O:5][CH3:4])([O-:28])=[O:27]
Reactant: COC(=O)c1ccc(Cc2c[nH]c3ccc([N+](=O)[O-])cc23)c(OC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc(C(=O)O)ccc1Cc1c[nH]c2ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of lithium hydroxide monohydrate (1.2 g.) in water (20 ml.) was added to a suspension of nitro ester (C) (2.0 g.) in methanol (30 ml.). The mixture was stirred at ambient temperature for 18 hours and then acidified with hydrochloric acid (1N, 50 ml.). The yellow precipitate was isolated by filtration, washed with water, and dried to give 4-(5-nitroindol-3-ylmethyl)-3-methoxybenzoic acid; partial NMR (250 MHz, DMSO-d6): 3.92(s,3H, OMe); 4.12(s,2H, ArCH2); 11.64(br s,1H, NH).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10](Br)=[CH:11][CH:12]=2)[CH:7]([NH:15][C:16](=[O:21])[O:17][CH:18]([CH3:20])[CH3:19])[CH2:6][CH:5]1[CH3:22])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:29][N:30]1[C:34]([CH3:35])=[C:33](B2OC(C)(C)C(C)(C)O2)[C:32]([CH3:45])=[N:31]1.C(O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH3:19][CH:18]([O:17][C:16](=[O:21])[NH:15][C@H:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([C:33]3[C:32]([CH3:45])=[N:31][N:30]([CH3:29])[C:34]=3[CH3:35])[CH:9]=2)[N:4]([C:1](=[O:3])[CH3:2])[C@@H:5]([CH3:22])[CH2:6]1)[CH3:20]
Reactant: Cc1nn(C)c(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: CC(=O)N1c2ccc(Br)cc2C(NC(=O)OC(C)C)CC1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(=O)N1c2ccc(-c3c(C)nn(C)c3C)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 25 °C
Yield: 29 %

Procedure:
A flask was charged with 1-methylethyl (1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl)carbamate (for a preparation see Example 61) (100 mg, 0.271 mmol), potassium carbonate (74.9 mg, 0.542 mmol), 1,3,5-trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (77 mg, 0.325 mmol) and tetrakis(triphenylphosphine)palladium(0) (15.65 mg, 0.014 mmol) then filled with ethanol (1 mL) and toluene (1 mL) and the resulting mixture was refluxed under nitrogen for 18 h then cooled to room temperature and partitioned between water (40 mL) and EtOAc (40 mL). The layers were separated and the aqueous phase was extracted with EtOAc (40 mL). The combined organic phases were washed with brine, dried over Na2SO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (gradient: 0 to 50% AcOEt in Hexanes) gave 1-methylethyl[(cis)-1-acetyl-2-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (33 mg, 0.078 mmol, 29%) as a dark yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][C:10]2[C:11]([NH2:24])=[CH:12][C:13]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])=[CH:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1.N1C=CC=CC=1.[CH2:33]([C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=[O:41])=[CH:38][CH:37]=1)[CH2:34][CH3:35]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:24][C:40](=[O:41])[C:39]3[CH:43]=[CH:44][C:36]([CH2:33][CH2:34][CH3:35])=[CH:37][CH:38]=3)=[CH:12][C:13]([O:16][Si:17]([C:20]([CH3:23])([CH3:21])[CH3:22])([CH3:19])[CH3:18])=[CH:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1
Reactant: CCCc1ccc(C(=O)Cl)cc1
Reactant: COc1ccc(C(=O)Nc2ccc(O[Si](C)(C)C(C)(C)C)cc2N)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCc1ccc(C(=O)Nc2cc(O[Si](C)(C)C(C)(C)C)ccc2NC(=O)c2ccc(OC)cc2)cc1
Reaction time: 4 h

Procedure:
To a solution of N1-(4-methoxybenzoyl)-4-(tert-butyldimethylsilyloxy)-1,2-benzenediamine (300 mg, 0.81 mmol) in methylene chloride (20 mL) was added pyridine (0.13 mL, 1.6 mmol) followed by 4-propylbenzoyl chloride (0.15 mL, 0.89 mmol). The reaction mixture was stirred for 4 h, diluted with methylene chloride, washed with saturated aqueous cupric sulfate solution, dried (magnesium sulfate), filtered, and concentrated in vacuo. The residue was chromatographed (silica gel, methylene chloride to 20% ethyl acetate/80% methylene chloride) to give 400 mg (95%) of the the title compound as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.Cl[CH2:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:18][CH2:17]1)=[O:15]>C(OCC)C>[CH2:22]([CH:19]1[CH2:18][CH2:17][N:16]([C:14](=[O:15])[CH2:13][NH:1][C:2]2[CH:11]=[CH:10][C:5]3[NH:6][C:7](=[O:9])[NH:8][C:4]=3[CH:3]=2)[CH2:21][CH2:20]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Nc1ccc2[nH]c(=O)[nH]c2c1
Reactant: O=C(CCl)N1CCC(Cc2ccccc2)CC1
Solvent: CCOCC
Product: O=C(CNc1ccc2[nH]c(=O)[nH]c2c1)N1CCC(Cc2ccccc2)CC1

Procedure:
The title compound is prepared from 5-amino-1,3-dihydro-benzimidazol-2-one and 2-chloro-1-(4-benzyl-piperidin-1-yl)-ethanone (Example 200a) according to the method described in Example 142b. Melting Point: 237-238° C. (diethylether)
Reaction SMILES: C([O:8][C:9]([C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:44])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH2:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@@H:30]1[C:34]([O:36]CC1C=CC=CC=1)=[O:35])=[O:28])=[O:10])C1C=CC=CC=1>C(O)C.[Pd]>[C:34]([C@H:30]1[CH2:31][CH2:32][CH2:33][N:29]1[C:27](=[O:28])[CH2:26][O:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[O:18][CH2:17][C:16]([N:12]1[CH2:13][CH2:14][CH2:15][C@@H:11]1[C:9]([OH:10])=[O:8])=[O:44])([OH:36])=[O:35]
Reactant: O=C(OCc1ccccc1)[C@H]1CCCN1C(=O)COc1ccccc1OCC(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: O=C(O)[C@H]1CCCN1C(=O)COc1ccccc1OCC(=O)N1CCC[C@@H]1C(=O)O
Yield: 125.2 %

Procedure:
230 mg (0.38 mmol) (R)-1-[[2-[2-[(R)-2-benzyloxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-phenoxy]acetyl)-pyrrolidine-2-carboxylic acid benzyl ester in 100 ml ethanol were hydrogenated in the presence of 30 mg 5% Pd on carbon. Filtration and evaporation of the solvent yielded 0.2 g (R)-1-[[2-[2-[(R)-2-carboxy-pyrrolidin-1-yl]-2-oxo-ethoxy]-phenoxy]-acetyl]-pyrrolidine-2-carboxylic acid as colorless glass (that still contained small amounts of ethanol)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH:9]([F:11])[CH3:10])[CH:3]=1.C([Li])CCC.C(O[B:21]1[O:25][C:24]([CH3:27])([CH3:26])[C:23]([CH3:29])([CH3:28])[O:22]1)(C)C.Cl>C(OCC)C.O>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([B:21]2[O:25][C:24]([CH3:27])([CH3:26])[C:23]([CH3:29])([CH3:28])[O:22]2)=[CH:3][C:4]=1[CH:9]([F:11])[CH3:10]
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: CC(F)c1cc(Br)ccc1Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: CC(F)c1cc(B2OC(C)(C)C(C)(C)O2)ccc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 50.7 %

Procedure:
4-Bromo-1-chloro-2-(1-fluoroethyl)benzene (2.55 g, 10.74 mmol) was dissolved in dry diethyl ether (50 mL) and cooled to −75° C. n-Butyllithium (4.72 mL, 11.81 mmol) was added dropwise keeping the temperature below −70° C. The reaction mixture was then stirred for 15 min, then 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.197 g, 11.81 mmol) was added and the reaction mixture was allowed to warm to room temperature. The reaction mixture was then diluted with water and diethyl ether. The aqueous phase was acidified with 12N HCl and the product was then extracted with diethyl ether. The organic phase was dried and concentrated under vacuum to yield the title compound (1.55 g, 5.45 mmol, 50.7% yield) as a white solid: 1H NMR (CDCl3): δ 7.94 (d, 1H), 7.65 (m, 1H), 7.36 (m, 1H), 5.96 (dq, 1H), 1.64 (dd, 3H), 1.34 (s, 12H).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH2:7][O:8][C:9]2[CH:20]=[CH:19][C:12]([CH:13]=[CH:14][C:15](OC)=[O:16])=[CH:11][CH:10]=2)=[N:4][C:3]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[H-].C([Al+]CC(C)C)C(C)C>>[CH3:1][C:2]1[S:6][C:5]([CH2:7][O:8][C:9]2[CH:20]=[CH:19][C:12](/[CH:13]=[CH:14]/[CH2:15][OH:16])=[CH:11][CH:10]=2)=[N:4][C:3]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)C=Cc1ccc(OCc2nc(-c3ccccc3)c(C)s2)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: Cc1sc(COc2ccc(/C=C/CO)cc2)nc1-c1ccccc1

Procedure:
According to the method described for Reference Example 23, methyl 4-(5-methyl-4-phenyl-2-thiazolylmethoxy)cinnamate was subjected to reduction with diisobutylaluminum hydride to give (E)-3-[4-(5-methyl-4-phenyl-2-thiazolylmethoxy)phenyl]-2-propen-1-ol. Recrystallization from ethyl acetate--isopropyl ether gave colorless prisms, m.p.125°-126° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[CH3:26][C:27]1([CH3:33])[CH2:31][NH:30][CH2:29][C@@H:28]1[OH:32]>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([N:30]3[CH2:31][C:27]([CH3:33])([CH3:26])[C@@H:28]([OH:32])[CH2:29]3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: CC1(C)CNC[C@@H]1O
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(N3C[C@H](O)C(C)(C)C3)c2c1

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and (3R)-4,4-dimethylpyrrolidin-3-ol. MS obsd. (ESI+) [(M+H)+] 452, 1H NMR (400 MHz, CD3OD) δ ppm 7.94 (dd, J=7.83, 1.01 Hz, 1 H), 7.83-7.73 (m, 2 H), 7.58 (td, J=7.58, 1.26 Hz, 1 H), 7.47-7.37 (m, 2 H), 7.23 (dd, J=8.59, 1.77 Hz, 1 H), 6.03 (s, 1 H), 5.11 (s, 2 H), 4.02 (dd, J=10.36, 5.31 Hz, 1 H), 3.93 (dd, J=5.05, 3.79 Hz, 1 H), 3.61-3.47 (m, 4 H), 2.37 (s, 3 H), 1.15 (s, 3 H), 1.10-1.05 (m, 3 H).
Reaction SMILES: C([O:4][CH2:5][C:6](=[O:28])[C@:7]1([OH:27])[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C:21](=[CH:22][CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:26])[CH2:17][CH2:18]2)[CH2:13][CH2:12]3)[CH2:9][CH2:8]1)(=O)C.[OH-].[K+]>CO.C(Cl)Cl>[OH:27][C@:7]1([C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C:21](=[CH:22][CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:26])[CH2:17][CH2:18]2)[CH2:13][CH2:12]3)[CH2:9][CH2:8]1)[C:6](=[O:28])[CH2:5][OH:4]
Reactant: CC(=O)OCC(=O)[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)C3=CC[C@@]21C
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: C[C@]12CCC(=O)C=C1CC[C@@H]1C2=CC[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CO
Temperature: 0 °C
Yield: 89.8 %

Procedure:
At room temperature, 1.5 g of 21-acetoxy-17-hydroxy-4,9(11)-pregnadiene-3,20-dione in 40 ml of methanol is agitated for 2 hours at room temperature with 15 ml of 0.2N methanolic potassium hydroxide solution. The reaction mixture is introduced into ice water. The precipitated product is suctioned off, dissolved in methylene chloride, washed with water, and dried over sodium sulfate, thus obtaining 1.2 g of 17,21-dihydroxy-4,9(11)-pregnadiene-3,20-dione; mp 248.2° C.
Reaction SMILES: [F:1][CH:2]([F:15])[O:3][N:4]=[C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:14])[C:6]#[N:7].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:34]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:34][CH2:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:5](=[N:4][O:3][CH:2]([F:15])[F:1])[C:6]#[N:7]
Reactant: Cc1ccccc1C(C#N)=NOC(F)F
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: N#CC(=NOC(F)F)c1ccccc1CBr
Temperature: 25 °C

Procedure:
A solution of 8.0 g of α-difluoromethoxyimino-o-tolylacetonitrile and 0.07 g of dibenzoyl peroxide in 50 ml of carbon tetrachloride is heated to reflux. With radiation from a lamp, 6.77 g of N-bromosuccinimide are added thereto in several small portions and the mixture is left to react for 0.5 hour. The reaction mixture is cooled to room temperature, the succinimide is filtered off and the residue is concentrated by evaporation. Chromatography on silica gel with hexane/ethyl acetate (15:1) yields pure 2-(2-bromomethylphenyl)-2-difluoromethoxyimino-acetonitrile in the form of a pale yellow oil.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10][CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O.[C:27]([O:34]C([O-])=O)([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=O>ClC(Cl)C.CO.C(N(CC)CC)C>[C:30]([O:29][C:27]([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10][CH2:9]1)=[O:34])([CH3:31])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: CCOC(=O)C=C1CCN(Cc2ccccc2)CC1
Agent: CC(Cl)OC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Solvent: CO
Product: CCOC(=O)C=C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.7 %

Procedure:
51.0 g of ethyl (1-benzylpiperidin-4-ylidene)acetate was dissolved in 200 ml of dichloroethane. After adding 36.5 g of 1-chloroethyl chloroformate under ice-cooling, the resulting mixture was heated under reflux for 2 hours. After adding 100 ml of methanol, the resulting mixture was further heated under reflux for 40 minutes and then allowed to stand at room temperature overnight. Then 60 g of triethylamine was added to the reaction mixture under ice-cooling. Further, 300 ml of methanol was added thereto and the system was made homogeneous. Next, 47.2 g of tert-butyl dicarbonate was added and the resulting mixture was stirred at room temperature for 20 minutes. The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate, washed successively with 1 N hydrochloric acid, water, a saturated aqueous solution of sodium chloride and saturated sodium hydrogencarbonate and dried over anhydrous magnesium sulfate followed by filtration. After distilling off the solvent under reduced pressure, the crude crystals thus obtained were ground and washed with hexane to thereby give 15.2 g of the title compound. The filtrate was concentrated and the residue was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate) to thereby give 37.8 g of the additional title compound as colorless crystals.