Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](Cl)=[O:4].[NH2:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][C:2]([CH3:7])([CH3:6])[C:3]([NH:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1)=[O:4]
Reactant: N#Cc1ccc(N)cc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Nc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
Add dropwise trimethylacetyl chloride (3.3 mL, 27 mmol) to a mixture of 4-aminobenzonitrile (2.92 g, 24.7 mmol) and triethylamine (3.8 mL, 27 mmol) in anhydrous DCM (25 mL) at 0° C. Stir the mixture to room temperature overnight. Partition the reaction mixture between DCM (500 mL) and water (250 mL) and extract the aqueous phase with DCM (250 mL). Wash the combined organic extracts with water (3×250 mL), dry over Na2SO4, filter and concentrate in vacuo to obtain the desired intermediate (5 g, 100%). MS (ES+) m/z: 203.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:32]=[CH:31][C:15]3[N:16]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:18][C:14]=3[CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:35][O:36][C:37](=[O:45])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]Br.O>CN(C)C=O>[CH3:35][O:36][C:37](=[O:45])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][N:11]([S:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])[C:12]1[CH:32]=[CH:31][C:15]2[N:16]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:18][C:14]=2[CH:13]=1
Reactant: O=S(=O)(Nc1ccc2c(c1)nc(-c1ccccc1)n2-c1ccccc1)c1ccc(Cl)cc1
Reactant: COC(=O)CCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCCCCCN(c1ccc2c(c1)nc(-c1ccccc1)n2-c1ccccc1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
100 mg of 4-chloro-N-(1,2-diphenyl-1H-benzimidazol-5-yl)benzenesulfonamide was suspended in 0.5 ml of N,N-dimethylformamide, mixed with 8 mg of sodium hydride, and stirred for 30 minutes at 20° C. 70 mg of 7-bromoheptanoic acid methyl ester was added, it was allowed to stir for 15 hours, mixed with water, extracted three times with ethyl acetate, the extracts were dried on sodium sulfate, concentrated by evaporation in a vacuum, and the residue was chromatographed on silica gel.
Reaction SMILES: [BH4-].[Na+].[N:3]1[C:12]2[C:7](=[CH:8][C:9]([CH2:13][N:14]3[C:18]4=[N:19][C:20]([C:23]5[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=5)[CH:26]=[O:27])=[CH:21][CH:22]=[C:17]4[N:16]=[N:15]3)=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1>CO>[N:3]1[C:12]2[C:7](=[CH:8][C:9]([CH2:13][N:14]3[C:18]4=[N:19][C:20]([C:23]5[CH:24]=[C:25]([CH2:26][OH:27])[CH:28]=[CH:29][CH:30]=5)=[CH:21][CH:22]=[C:17]4[N:16]=[N:15]3)=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: O=Cc1cccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1cccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 24.3 %

Procedure:
Sodium borohydride (0.018 g, 0.493 mmol) was added to a solution of example 3 (0.180 g, 0.493 mmol) in methanol (4 ml), cooled to 0° C., and stirred 1 h. Ice-cold water was added to the mixture, extracted with ethyl acetate, washed with brine, dried over sodium sulphate and concentrated. The crude product was purified by column chromatography with methanol: dichloromethane to afford the title compound as a yellow solid (0.044 g, 24%). M.P. 191-193° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.88 (dd. J=4.2, 1.7 Hz, 1H), 8.63 (d, J=8.7 Hz, 1H), 8.38 (d, J=8.3 Hz, 1H), 8.21 (d, J=8.3 Hz, 2H), 8.12 (d, J=8.8 Hz, 1H), 8.02 (s, 1H), 8.02 (d, J=8.8 Hz, 1H), 7.83 (dd, J=8.7, 2.0 Hz, 1H), 7.53 (m, 3H), 6.20 (s, 2H), 5.30 (t, J=5.7 Hz, 1H), 4.58 (d, J=5.4 Hz, 2H). MS (m/z): 368.37 (M30+1).
Reaction SMILES: [C:1]([NH2:4])(=[S:3])[CH3:2].Br[CH:6]([CH:14]([CH3:16])[CH3:15])[C:7](=O)[C:8]([O:10][CH2:11][CH3:12])=[O:9]>C(O)C>[CH3:2][C:1]1[S:3][C:6]([CH:14]([CH3:16])[CH3:15])=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:4]=1
Reactant: CCOC(=O)C(=O)C(Br)C(C)C
Reactant: CC(N)=S
Solvent: CCO
Product: CCOC(=O)c1nc(C)sc1C(C)C
Temperature: 80 °C
Yield: 62.4 %

Procedure:
To a solution of thioacetamide (158 mg) in ethanol (20 ml) was added ethyl 3-bromo-4-methyl-2-oxopentanoate (500 mg) in ethanol (0.5 ml). Molecular sieves (100 mg) were added and the mixture was heated at 80° C. for 18 h. The mixture was filtered, washing with ethanol (5 ml) and the solvent removed in vacuo. The residue triturated with DCM and the solid removed by filtration. The filtrate was concentrated to ˜5 ml and purified by column chromatography on silica gel (10 g silica), eluting with a gradient of 0-100% ethyl acetate in cyclohexane to give the title compound as a yellow oil (280 mg).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.S([O-])([O-])(=O)=O.[Mg+2].C(N(CC)CC)C>C(Cl)Cl>[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[N:6]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=Cc1ccccc1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccccc1)N=Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
L-phenylalanine methyl ester hydrochloride (4.31 g), benzaldehyde (2.05 ml), anhydrous magnesium sulfate (5.19 g) and triethylamine (2.90 ml) were added to methylene chloride (200 ml), and the mixture was stirred overnight at room temperature. The solid was filtered off from the reaction solution, and the solvent was distilled off under reduced pressure. Then, ethyl acetate (150 ml) was added to the residue. The solid was separated again by filtration, and the solvent was distilled off under reduced pressure to obtain desired N-(phenylmethylene)-L-phenylalanine methyl ester (5.18 g) in a yield of 97.0%.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[CH2:15]1[CH:17](N)[CH2:16]1>>[CH:17]1([C:10]2[CH:5]=[C:4]([NH:1][C:8]3[CH:7]=[CH:6][C:5]4[C:4]([NH2:1])=[CH:13][CH:12]=[CH:11][C:10]=4[N:9]=3)[CH:13]=[CH:12][CH:11]=2)[CH2:16][CH2:15]1
Reactant: NC1CC1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Product: Nc1cccc2nc(Nc3cccc(C4CC4)c3)ccc12

Procedure:
The title compound, MS: m/e=276.4 (M+H+), was prepared in accordance with the general method of example 1 from 5-nitro-2-chloroquinoline and 3-cyclopropylamine.
Reaction SMILES: CS(O[CH2:6][C:7]1[N:12]=[CH:11][C:10]2[N:13]=[CH:14][N:15]([C:16]3[S:17][C:18]([C:34](=[O:36])[NH2:35])=[C:19]([O:21][C@@H:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]([F:33])([F:32])[F:31])[CH3:23])[CH:20]=3)[C:9]=2[CH:8]=1)(=O)=O.[C:37]([N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)(=[O:39])[CH3:38]>ClCCl>[C:37]([N:40]1[CH2:45][CH2:44][N:43]([CH2:6][C:7]2[N:12]=[CH:11][C:10]3[N:13]=[CH:14][N:15]([C:16]4[S:17][C:18]([C:34]([NH2:35])=[O:36])=[C:19]([O:21][C@@H:22]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=5[C:30]([F:32])([F:33])[F:31])[CH3:23])[CH:20]=4)[C:9]=3[CH:8]=2)[CH2:42][CH2:41]1)(=[O:39])[CH3:38]
Reactant: CC(=O)N1CCNCC1
Reactant: C[C@@H](Oc1cc(-n2cnc3cnc(COS(C)(=O)=O)cc32)sc1C(N)=O)c1ccccc1C(F)(F)F
Solvent: ClCCl
Product: CC(=O)N1CCN(Cc2cc3c(cn2)ncn3-c2cc(O[C@H](C)c3ccccc3C(F)(F)F)c(C(N)=O)s2)CC1

Procedure:
In a similar manner as described for example 58, 108 mg of [1-(5-carbamoyl-4-{(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy}-2-thienyl)-1H-imidazo[4,5-c]pyridin-6-yl]methyl methanesulfonate and 128.2 mg of 1-acetylpiperazine in 2.5 ml dichloromethane give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([NH2:10])[CH2:7][N:6]1[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:4].[OH:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[C:29](O)=[O:30]>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([NH:10][C:29]([C:20]2[CH:21]=[CH:22][C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:19]=2[OH:18])=[O:30])[CH2:7][N:6]1[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:4]
Reactant: COC(=O)[C@@H]1C[C@H](N)CN1Cc1ccccc1
Reactant: O=C(O)c1ccc2ccccc2c1O
Product: COC(=O)[C@@H]1C[C@H](NC(=O)c2ccc3ccccc3c2O)CN1Cc1ccccc1

Procedure:
(2S,4S)-1-Benzyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylic acid methyl ester was prepared from (2S,4S)-4-amino-1-benzyl-pyrrolidine-2-carboxylic acid methyl ester and 1-hydroxy-naphthalene-2-carboxylic acid in an analogous manner to example 1. MS calcd. for C24H25N2O4 [(M+H)+] 405.0, obsd. 405.0.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([NH2:22])([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:23](OC(=O)C)(=[O:25])[CH3:24].N1C=CC=CC=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([NH:22][C:23](=[O:25])[CH3:24])([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccccc1CC1(N)CCN(C(=O)OC(C)(C)C)CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)NC1(Cc2ccccc2C)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 8 h

Procedure:
A mixture of N-t-butoxycarbonyl-4-amino-4-(2-methylbenzyl)piperidine (305 mg, 1.0 mmol), acetic anhydride (0.38 ml, 4.0 mmol), and pyridine (0.1 ml, 1.2 mmol) in CH2Cl2 is stirred at room temp. overnight. Then concentrate the reaction mixture in vacuo and purify the residue by column chromatography on silica to afford the product.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:25])=[C:5]([C:21]([O:23][CH3:24])=[O:22])[N:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-])=O)[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9]>CO.O.Cl.[Fe]>[NH2:18][C:14]1[CH:13]=[C:12]([N:6]2[C:5]([C:21]([O:23][CH3:24])=[O:22])=[C:4]([CH3:25])[NH:3][C:2]([CH3:1])=[C:7]2[C:8]([O:10][CH3:11])=[O:9])[CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)N1c1cccc([N+](=O)[O-])c1
Agent: [Fe]
Agent: Cl
Solvent: CO
Solvent: O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)N1c1cccc(N)c1
Reaction time: 3.5 h
Yield: 88 %

Procedure:
1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyrazinedi-carboxylic acid, dimethyl ester (219 mg, 0.63 mmol) was dissolved in 30 mL methanol containing 3 mL of water in a flask equipped with a mechanical stirrer. Iron powder (300 mg) was added, followed by one drop of 37% hydrochloric acid. The whole mixture was refluxed moderately with mechanical stirring for 3.5 hours. Usual extractive work up furnished the title compound as yellow solid (176 mg, 88%): mp 212-213° C.; 1H-NMR (CDCl3) δ 6.91 (t, 1H, J=8.0 Hz), 6.20 (dd, 1H, J=7.8, 2.0 Hz), 6.11 (dd, 1H, J=8.2, 2.3 Hz), 6.00 (t, 1H, J=2.2 Hz), 5.93 (s, 1H), 3.77 (s, 6H), and 2.38 (s, 6H); 13C-NMR (CDCl3) δ 166.8, 152.0, 148.5, 146.9, 129.6, 109.5, 107.8, 104.2, 100.3, 51.8, and 17.9.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([F:22])=[C:17]([C:19](=[O:21])[CH3:20])[CH:18]=1.CCOC(C)=O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH2:5]([O:4][C:2](=[O:3])[NH:12][C:13]1[CH:14]=[CH:15][C:16]([F:22])=[C:17]([C:19](=[O:21])[CH3:20])[CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(=O)c1cc(N)ccc1F
Reactant: O=C(Cl)OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)c1cc(NC(=O)OCc2ccccc2)ccc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 83.5 %

Procedure:
Benzyl chloroformate (3 mL, 21.5 mmol) was added to a mixture of 1-(5-amino-2-fluorophenyl)ethanone (3 g, 19.6 mmol) and tetrabutylammonium bromide at room temperature. The reaction was stirred at room temperature for 24 hours, the crude was treated with AcOEt (50 mL) and H2O (50 mL), the organic phase was separated and evaporated in vacuo. The crude was purified by column chromatography (silica gel; MeOH/DCM). The desired fractions were collected and the solvents evaporated in vacuo to afford intermediate A40 as a cream solid (4.7 g, 84%). LCMS: 286 [M−H]−; Rt: 2.81 min (method 3).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH:5]([NH2:7])C.[OH-].[Na+].[C:10](Cl)([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]>CN(C=O)C.O>[NH2:7][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:10](=[O:11])[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(N)CCCN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: NCCCCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 27.2 %

Procedure:
To a solution of 1,4-diaminopentane (25 g, 155 mmol) in 100 mL DMF/H2O (1:1) was added 5N NaOH to adjust the pH to 9. CBZ-Cl (3.7 mL, 26 mmol) was added as one portion and stirred at room temperature for 16 hrs. The reaction was acidified to pH 1.25 and washed with diethyl ether. The pH of the reaction was then adjusted to 9.5 and the reaction extracted with EtOAc. The organic layer was washed with H2O, brine, dried over Na2SO4 and evaporated to give title compound (1.57 g, 30%).
Reaction SMILES: [C:1]1([C:7]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH:14]([C:20]3[CH:25]=[CH:24][C:23]4[O:26][CH2:27][O:28][C:22]=4[CH:21]=3)[C:15]([O:17]CC)=[O:16])[N:10]=[CH:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.C(OCC)(=O)C>[OH-].[Na+].C(O)C>[C:35]1([C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH:14]([C:20]3[CH:25]=[CH:24][C:23]4[O:26][CH2:27][O:28][C:22]=4[CH:21]=3)[C:15]([OH:17])=[O:16])[N:10]=[CH:9]2)[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CCOC(=O)C(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1ccc2c(c1)OCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(O)C(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
The mixture of ethyl 3-[1-(triphenylmethyl)imidazol-4-yl]-2-(3,4-methylenedioxyphenyl)propionate (730 mg) in 1N sodium hydroxide aqueous solution (4.1 ml) and ethanol (10 ml) was stirred at ambient temperature for 3 hours. The resulting solution was neutralized with 1N hydrochloric acid (4 ml) followed by dilution with ethyl acetate, and then the organic layer was washed with brine. Drying, filtering and removal of the solvents afforded 3-[1-(triphenylmethyl)-imidazol-4-yl]-2-(3,4-methylenedioxyphenyl)propionic acid (650 mg) as a white solid.
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[C:17]([CH3:18])=[CH:16][N:15]=[C:14]3[NH:19][N:20]=[CH:21][C:13]=23)[CH:7]=1)([CH3:5])[C:3]#[N:4].[H-].[Al+3].[Li+].[H-].[H-].[H-].CC#N>C1COCC1>[CH3:5][C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[C:17]([CH3:18])=[CH:16][N:15]=[C:14]3[NH:19][N:20]=[CH:21][C:13]=23)[CH:7]=1)([CH3:1])[CH2:3][NH2:4]
Reactant: Cc1cnc2[nH]ncc2c1-c1cccc(C(C)(C)C#N)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CC#N
Solvent: C1CCOC1
Product: Cc1cnc2[nH]ncc2c1-c1cccc(C(C)(C)CN)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 31 %

Procedure:
To a cooled solution of 2-methyl-2-(3-(5-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)phenyl)propanenitrile (108 mg, 0.3908 mmol) at 0° C. in THF (20 ml) was added slowly a solution of lithium aluminium hydride (781.5 μL of 2 M, 1.563 mmol). The reaction mixture was allowed to stir at 0° C. for 2 hours and then allowed to warm to RT and stirred for 16 hours. The mixture was then cooled to 0° C. and quenched with water. EtOAc was added and the mixture passed through a celite pad. The organics were separated, washed with saturated NaCl, dried over Na2SO4, filtered and concentrated under reduced pressure to give a semi solid which was lyophilized from MeCN/H20 (34 mg, Yield=31%).
Reaction SMILES: CS(Cl)(=O)=O.O[CH2:7][CH2:8][CH2:9][NH:10][C:11]([C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[CH:18][NH:19]2)=[C:15]([Br:22])[CH:14]=1)=[O:12].C(N(CC)CC)C.[NH:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[CH2:35][OH:36]>C1COCC1>[OH:36][CH2:35][C@@H:31]1[CH2:32][CH2:33][CH2:34][N:30]1[CH2:7][CH2:8][CH2:9][NH:10][C:11]([C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[CH:18][NH:19]2)=[C:15]([Br:22])[CH:14]=1)=[O:12]
Reactant: OC[C@@H]1CCCN1
Reactant: O=C(NCCCO)c1cc(Br)c2cc[nH]c2c1
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NCCCN1CCC[C@H]1CO)c1cc(Br)c2cc[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.3 %

Procedure:
A solution methanesulfonyl chloride (0.13 mL, 1.68 mmol) in THF (1 mL) was added to a solution of 4-bromo-1H-indole-6-carboxylic acid (3-hydroxy-propyl)-amide (0.50 g, 1.68 mmol) and triethylamine (0.25 mL, 1.84 mmol) in tetrahydrofuran (5 mL) at 0° C. and slowly warmed to room temperature over 30 minutes. (S)-(+)-2-pyrrolidinemethanol (1.0 g, 9.88 mmol) was added and stirred at room temperature overnight. The reaction was concentrated in vacuo and purified by column chromatography (5% methanol in dichloromethane) to yield 0.50 g (78%) of (S)-4-bromo-1H-indole-6-carboxylic acid [3-(2-hydroxymethyl-pyrrolidin-1-yl)-propyl]-amide. Mass spectrum (LCMS, ESI pos.): Calcd for C17H22BrN3O2 379.09. Found 380.0; (M+H).
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[S:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH:15]=[C:14]1[C:22]([OH:24])=O.[C:25]1([CH2:31][O:32][C:33]([C:35]2([NH2:41])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)=[O:34])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.ON1C2C=CC=CC=2N=N1>C(Cl)Cl>[C:25]1([CH2:31][O:32][C:33]([C:35]2([NH:41][C:22]([C:14]3[S:13][C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[CH:15]=3)=[O:24])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]2)=[O:34])[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: NC1(C(=O)OCc2ccccc2)CCCCC1
Reactant: O=C(O)c1cc2ccccc2s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(NC1(C(=O)OCc2ccccc2)CCCCC1)c1cc2ccccc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.8 %

Procedure:
Under ice-cooling, 5.9 g (31 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added to a solution of 5 g (28 mmol) of 2-benzothiophenecarboxylic acid, 6.5 g (28 mmol) of 1-aminocyclohexanecarboxylic acid phenylmethyl ester and 4.5 g (29 mmol) of 1-hydroxybenzotriazole in methylene chloride. After the mixture was stirred at room temperature overnight, the reaction solvent was distilled off under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate twice. The obtained organic layer was washed with a 10% aqueous potassium hydrogensulfate solution, a saturated aqueous sodium hydrogencarbonate solution and then saturated brine, and it was dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, diethyl ether was added to the obtained residue, and the mixture was stirred overnight. The crystal was collected by filtration and heated/dried under reduced pressure to obtain 10 g (91%) of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:15])[CH:11]=2)[CH2:6]1)[CH3:3].[H-].[Na+].[Br:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1.O>CN(C=O)C>[Br:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][O:15][C:10]2[CH:11]=[C:12]3[C:7](=[CH:8][CH:9]=2)[CH2:6][CH:5]([CH2:4][N:2]([CH3:1])[CH3:3])[CH2:14][CH2:13]3)=[CH:21][CH:20]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: CN(C)CC1CCc2cc(O)ccc2C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CC1CCc2cc(OCc3ccc(Br)cc3)ccc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.3 %

Procedure:
2-(N,N-Dimethylamino)methyl-6-hydroxytetralin (5.0 g; obtained in Reference Example 16) was dissolved in DMF (130 ml), to which was added 60% oily sodium hydride (1.46 g) at 0° C. The reaction mixture was warmed to room temperature, and stirred for 1 hour. This was again cooled to 0° C., to which was added a DMF solution (20 ml) of 4-bromobenzyl bromide (10.0 g). The reaction mixture was stirred at room temperature for 2 hours, and water was added thereto, which was then extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, then dried, and concentrated. The residue was purified by alumina column chromatography (eluent: ethyl acetate/hexane=1/10) to obtain the entitled compound (3.4 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([CH3:14])[CH:9]=2)[CH:5]=[CH:4][C:3]=1[OH:15].[NH2:16][C@@H:17]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:18](NC1C=C(C2C=CN=CC=2)C=CC=1OCC1C=CC=CC=1)=[O:19]>>[NH2:16][C@@H:17]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:18]([NH:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([CH3:14])[CH:9]=2)[CH:5]=[CH:4][C:3]=1[OH:15])=[O:19]
Reactant: Cc1cc(-c2ccc(O)c(N)c2)ccn1
Reactant: N[C@@H](Cc1ccccc1)C(=O)Nc1cc(-c2ccncc2)ccc1OCc1ccccc1
Product: Cc1cc(-c2ccc(O)c(NC(=O)[C@@H](N)Cc3ccccc3)c2)ccn1

Procedure:
64.0 was prepared from 64.B analogous to the preparation of 13.F. LC-MS (+esi, M+H+=348.1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][O:11][CH2:12][CH2:13][OH:14].[CH3:15][S:16](Cl)(=[O:18])=[O:17]>ClCCl.C(N(CC)CC)C>[CH3:15][S:16]([O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])(=[O:18])=[O:17]
Reactant: OCCOCCc1ccc(F)cc1F
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCOCCc1ccc(F)cc1F
Reaction time: 0.25 h
Yield: 100 %

Procedure:
The 2-[2-(2,4-difluorophenyl)ethoxy]ethanol obtained according to the preceding paragraph was dissolved in 40 ml of dichloromethane containing 1.13 g of triethylamine and the solution was treated with 1.28 g of methanesulfonyl chloride. After stirring for 15 minutes, the solution was washed well with water, the organic layer was separated, dried over sodium sulfate, filtered and evaporated to give 3.12 g (100%) of 2-[2-(2,4-difluorophenyl)ethoxy]ethyl methanesulfonate in the form of an oil which was homogeneous according to chromatography.