Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:10]([NH:20][C:21]([C:23]2[CH:40]=[CH:39][C:26]([CH2:27][NH:28]C(=O)OCC3C=CC=CC=3)=[CH:25][CH:24]=2)=[O:22])=[N:11][N:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[OH-].[OH-].[Pd+2]>[NH2:28][CH2:27][C:26]1[CH:25]=[CH:24][C:23]([C:21]([NH:20][C:10]2[C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:13][N:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:11]=2)=[O:22])=[CH:40][CH:39]=1
Reactant: CC(C)(C)OC(=O)Nc1cn(-c2ccccc2)nc1NC(=O)c1ccc(CNC(=O)OCc2ccccc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1cn(-c2ccccc2)nc1NC(=O)c1ccc(CN)cc1
Reaction time: 1.5 h

Procedure:
A solution of benzyl {4-[({4-[(tert-butoxycarbonyl)amino]-1-phenyl-1H-pyrazol-3-yl}amino)carbonyl]benzyl}carbamate (0.75 g, 1.38 mmol) in methanol (150 mL) was treated with palladium hydroxide on carbon (75 mg) and placed under a hydrogen atmosphere for 1.5 hours. The reaction was filtered, evaporated in vacuo and purified by flash column chromatography (1-18% methanol/methylene chloride) to give title compound as an off-white solid. 1H NMR (DMSO-d6) δ 8.37 (s, 1H), 7.99 (d, J=8.2 Hz, 2H), 7.71 (d, J=7.9 Hz, 2H), 7.50 (d, J=8.2 Hz, 2H), 7.45 (t, J=7.6 Hz, 2H), 7.27 (t, J=7.3 Hz, 1H), 3.90 (s, 2H), 1.50 (s, 9H); ESIMS calcd 408.2 (M++H), found 408.1 (M++H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C(O[C:12](=O)[NH:13][CH:14]1[CH:21]2[CH2:22][CH:17]3[CH2:18][C:19]([OH:24])([CH2:23][CH:15]1[CH2:16]3)[CH2:20]2)(C)(C)C>C1COCC1>[CH3:12][NH:13][CH:14]1[CH:21]2[CH2:22][CH:17]3[CH2:18][C:19]([OH:24])([CH2:23][CH:15]1[CH2:16]3)[CH2:20]2
Reactant: CC(C)(C)OC(=O)NC1C2CC3CC1CC(O)(C3)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNC1C2CC3CC1CC(O)(C3)C2
Temperature: 0 °C
Yield: 89.5 %

Procedure:
Lithium aluminium hydride (0.711 g, 0.018 mol) was added to a solution of (5-hydroxy-adamantan-2-yl)carbamic acid tert-butyl ester (1 g, 0.0037 mol) in THF (50 ml) at 0° C. under a nitrogen atmosphere. The slurry was heated under reflux for 5 h. It was then cooled to 0° C. and quenched with 30% NaOH solution (12 ml) and filtered. The filtrate was concentrated to give 2-methylaminoadamantan-5-ol as a white solid (0.6 g, 90%). LC-MS (m/z): 181.9 (M+1). 1HNMR (300 MHz, DMSO-d5): δ 4.3 (s, 1H), 4.2 (s, 1H), 2.4 (s, 0.7H), 2.3 (s, 0.3H), 2.2 (s, 3H), 1.8-2.0 (m, 5H), 1.5-1.6 (m, 5H), 1.4-1.5 (m, 2H), 1.2 (m, 2H).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14](Br)[N:15]=2)[N:10]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26][N:27]1[C:35]2[C:30](=[CH:31][C:32]([C:36]#[N:37])=[CH:33][CH:34]=2)[C:29]([Sn](CCCC)(CCCC)CCCC)=[N:28]1.O.C(OCC)C>CN(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.[Cu]I>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:29]3[C:30]4[C:35](=[CH:34][CH:33]=[C:32]([C:36]#[N:37])[CH:31]=4)[N:27]([CH3:26])[N:28]=3)[N:15]=2)[N:10]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2ccc(C#N)cc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)c2cc(C#N)ccc21
Temperature: 80 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
In a 50 ml round-bottomed flask, 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (300 mg, 0.70 mmol) and 1-methyl-3-tributylstannyl-1H-indazole-5-carbonitrile (crude from Step 3, 847 mg, 1.14 mmol) were dissolved in DMF (6.6 ml). The reaction mixture was evacuated and backfilled with argon then tetrakis(triphenylphosphine)palladium (0) (41 mg, 0.036 mmol) and copper (I) iodide (27 mg, 0.14 mmol) were added. The reaction mixture was stirred at 80° C. overnight then cooled to room temperature and water and diethyl ether were added. The resulting brown precipitate was collected via filtration washing with water and diethyl ether. The brown powder was absorbed on silica gel and chromatographed with MeOH/CH2Cl2/0.5% NH4OH (gradient: 0-2% MeOH) to afford 254 mg (72%) of 2-(5-cyano-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide as a light yellow solid.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5](C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:6]2.FC(F)(F)C(O)=O>>[I:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][NH:5][CH2:6]2
Reactant: Ic1cccc2c1CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2
Solvent: O=C(O)C(F)(F)F
Product: Ic1cccc2c1CNC2

Procedure:
Prepared in analogy to Example A2 (c) from 4-Iodo-2-trityl-2,3-dihydro-1H-isoindole and trifluoroacetic acid. Light yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:17]=[CH:18][C:19]2[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][N:20]=2)[CH:5]=[N:6][C:7]=1[N:8]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[N:9]1.[CH2:29]([Mg]Br)[CH:30]([CH3:32])[CH3:31].[Cl-].[NH4+]>O1CCCC1>[CH3:29][CH:30]([CH3:32])[CH2:31][CH:18]([C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][N:20]=1)[NH:17][C:4]1[CH:5]=[N:6][C:7]([N:8]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[N:9]2)=[C:2]([CH3:1])[CH:3]=1
Reactant: CC(C)C[Mg]Br
Reactant: COC(=O)c1ccc(C=Nc2cnc(-n3cc(C(F)(F)F)cn3)c(C)c2)nc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(CC(C)C)Nc2cnc(-n3cc(C(F)(F)F)cn3)c(C)c2)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 36.8 %

Procedure:
To a 0° C. solution of methyl 6-((5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-ylimino)methyl)nicotinate (592 mg, 1.52 mmol) in anhydrous tetrahydrofuran (8 mL) was added isobutylmagnesium bromide (1.0 mL, 2.0M in THF, 2.0 mmol). The reaction mixture was allowed to warm to room temperature and stir for 3 hours. Saturated aqueous ammonium chloride (10 mL) was added and the mixture extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by preparative TLC gave methyl 6-(3-methyl-1-(5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-ylamino)butyl)nicotinate (250 mg). 1H NMR (400 MHz, CDCl3, δ): 9.18-9.17 (m, 1H), 8.26-8.23 (m, 1H), 8.16 (s, 1H), 7.81 (s, 1H), 7.69-7.68 (m, 1H), 7.40-7.38 (m, 1H), 6.79-6.78 (m, 1H), 4.65-4.58 (m, 1H), 4.00 (s, 3H), 2.27 (s, 3H), 1.78-1.66 (m, 3H), 1.02 (d, 3H), 0.96 (d, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:16](=[O:17])[CH:15]2[CH:10]([CH:11]3[C:18](=[C:19]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:14]2[C:13]([C:32]([OH:45])([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:12]3)[C:8]1=[O:9])=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].ClCC(O[CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62]CC)=O>CN(C)C=O>[OH:45][C:32]([C:13]1[CH:14]2[C:18](=[C:19]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:11]([CH:12]=1)[CH:10]1[C:8]([N:7]([CH2:6][C:4]([O:3][CH2:1][CH2:2][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62])=[O:5])[C:16](=[O:17])[CH:15]21)=[O:9])([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CCOC(=O)CN1C(=O)C2C3C=C(C(O)(c4ccccc4)c4ccccn4)C(C3=C(c3ccccc3)c3ccccn3)C2C1=O
Reactant: CCCCCCCCOC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCOC(=O)CN1C(=O)C2C3C=C(C(O)(c4ccccc4)c4ccccn4)C(C3=C(c3ccccc3)c3ccccn3)C2C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
A similar procedure (Hursthouse, M. B.; Khan, A.; Marson, C. M.; Porter, R. A. Tetrahedron Lett. 1995, 36, 33, 5979-5982) to that described for the preparation of 207 was followed using NRB (0.37 g, 0.7 mmol) and potassium carbonate (0.25 g, 1.8 mmol) in dimethylformamide (5 mL), and octyl chloroacetate (0.32 g, 1.5 mmol) in dimethylformamide (2 mL), and the mixture stirred at room temperature for 2 h. Purification by flash chromatography (hexane/ethyl acetate 2:1) afforded 369 as a white solid (0.34 g, 0.5 mmol, 71%). 1H NMR (400 MHz, CDCl3) δ 0.87-0.90 (3H, m, O(CH2)7CH3), 1.26-1.30 (10H, m, OCH2CH2(CH2)5CH3), 1.61-1.63 (2H, m, OCH2CH2(CH2)5CH3), 3.40-4.56 (8H, m, OCH2(CH2)6CH3, NCH2, H-1, H-2, H-3, H-4), 5.48 (0.5H, s, OH), 5.52 (0.3H, m, V/H-6), 5.53 (0.5H, s, OH), 5.55 (0.4H, m, Y/H-6), 6.02 (0.1H, m, U/H-6), 6.04 (0.2H, m, W/H-6), 6.70-7.60 (16H, m, Ar), 8.40-8.60 (2H, m, αPyr).
Reaction SMILES: [ClH:1].O[CH:3]1[O:11][C@H:10]([CH2:12][OH:13])[C@@H:8]([OH:9])[C@H:6]([OH:7])[C@H:4]1[NH2:5]>C(N)CC>[ClH:1].[CH2:4]([NH:5][CH:3]1[O:11][C@H:10]([CH2:12][OH:13])[C@@H:8]([OH:9])[C@H:6]([OH:7])[C@H:4]1[NH2:5])[CH2:6][CH3:8]
Reactant: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: Cl
Solvent: CCCN
Product: CCCNC1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1N
Temperature: 25 °C

Procedure:
21.5 g of glucosamine hydrochloride were suspended in 17.7 g of n-propylamine and the suspension was warmed to 70°, until a clear solution was formed. On cooling to room temperature, the product precipitated.
Reaction SMILES: [CH:1]([C:3]1[CH:7]=[C:6]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])[N:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:4]=1)=[O:2].[C:24](=O)([O-])[O-].[K+].[K+].IC.O>CN(C)C=O>[CH:1]([C:3]1[CH:7]=[C:6]([N:8]([CH3:24])[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])[N:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:4]=1)=[O:2]
Reactant: O=Cc1cc(NS(=O)(=O)c2ccccc2)n(-c2ccccc2)n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: CN(c1cc(C=O)nn1-c1ccccc1)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
To a solution of N-(3-formyl-1-phenyl-1H-pyrazol-5-yl)benzenesulfonamide (331 mg) in N,N-dimethylformamide (5 mL) were added potassium carbonate (182 mg) and iodomethane (215 mg) at room temperature. After stirring at room temperature for 1 hr, the mixture was further stirred at 80° C. for 1 hr, and allowed to cool to room temperature. Water was added and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=7:1→3:1) to give the title compound as a pale-yellow amorphous (yield 297 mg, yield 86%).
Reaction SMILES: [CH:1]1([C:4](=[O:11])[CH2:5][C:6]([O:8]CC)=O)[CH2:3][CH2:2]1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[CH:1]1([C:4](=[O:11])[CH2:5][C:6]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][CH:14]=2)=[O:8])[CH2:2][CH2:3]1
Reactant: CCOC(=O)CC(=O)C1CC1
Reactant: Nc1ccc(C(F)(F)F)cc1
Solvent: Cc1ccccc1
Product: O=C(CC(=O)C1CC1)Nc1ccc(C(F)(F)F)cc1
Yield: 93.2 %

Procedure:
A mixture of 10.14 g (65 mmol) of ethyl 3-cyclopropyl-3-oxopropanoate and 10.47 g (65 mmol) of 4-aminobenzotrifluoride in 100 ml of dry toluene was refluxed for 8 hours using a Dean-Stark condenser to remove the ethanol formed during the reaction. The reaction mixture was cooled and petroleum ether (b.p. 40°-60° C.) was added to obtain 16.44 g (93%) of 3-cyclopropyl-3-oxo-N-[4-(trifluoromethyl)phenyl]-propanamide as a white crystalline solid, melting at 131°-2° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:10][C@@H:9]([OH:11])[CH2:8][NH:7]1)=[O:5])[CH3:2].C(N([CH2:17][CH3:18])CC)C.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>N1C=CC=CC=1>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:10][C@@H:9]([O:11][S:25]([C:22]2[CH:23]=[CH:24][C:19]([CH3:29])=[CH:20][CH:21]=2)(=[O:27])=[O:26])[CH2:8][N:7]1[S:25]([C:22]1[CH:23]=[CH:24][C:17]([CH3:18])=[CH:20][CH:21]=1)(=[O:27])=[O:26])=[O:5])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)[C@H]1C[C@@H](O)CN1
Reactant: CCN(CC)CC
Solvent: c1ccncc1
Product: CCOC(=O)[C@H]1C[C@@H](OS(=O)(=O)c2ccc(C)cc2)CN1S(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a cold solution of 4-hydroxy-pyrrolidine-2-carboxylic acid ethyl ester (1) (1.4 g, 7.1 mmol) and triethyl amine (0.998 mL, 7.1 mmol) in pyridine (14 mL) at −5° C. was added portion-wise 4-toluenesulfonyl chloride (3.42 g, 17.9 mmol). The cold solution was then stirred for 1 h at 0° C. and stored overnight in the refrigerator. Then the mixture was further stirred at room temperature for 5 h and poured into ice water (10 mL). The precipitate separated out was filtered, washed with water (2×5 mL), and dried to give compound (2) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:14][CH2:15][CH2:16][C@@H:17]2[CH2:19][C@@H:18]2[CH:20]2[CH2:25][CH2:24][N:23](C(OCC3C=CC=CC=3)=O)[CH2:22][CH2:21]2)=[N:4][CH:5]=[C:6]([N:8]2[CH2:12][CH2:11][NH:10][C:9]2=[O:13])[CH:7]=1.[H][H]>CCO.[Pd]>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][NH:10][C:9]2=[O:13])[CH:5]=[N:4][C:3]=1[O:14][CH2:15][CH2:16][C@@H:17]1[CH2:19][C@@H:18]1[CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1
Reactant: [H][H]
Reactant: Cc1cc(N2CCNC2=O)cnc1OCC[C@@H]1C[C@@H]1C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(N2CCNC2=O)cnc1OCC[C@@H]1C[C@@H]1C1CCNCC1

Procedure:
Benzyl 4-[(1R,2S)-2-(2-{[3-methyl-5-(2-oxoimidazolidin-1-yl)pyridin-2-yl]oxy}ethyl)cyclopropyl]piperidine-1-carboxylate (18 mg, 0.041 mmol) in 1 mL of EtOH was treated with 10% palladium on carbon (10 mg) for 2.5 hrs under 1 atm. of hydrogen gas. The catalyst was filtered off via Gilsen 0.045 μM PTFE syringe filter and the filtrate was concentrated in vacuo to give the product used for the next reaction without further purification. LCMS (ESI) m/z 345 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH2:4].[Br:10]Br>CC(O)=O>[Br:10][C:7]1[C:6]([F:9])=[CH:5][C:3]([NH2:4])=[C:2]([F:1])[CH:8]=1
Reactant: Nc1cc(F)ccc1F
Reactant: BrBr
Solvent: CC(=O)O
Product: Nc1cc(F)c(Br)cc1F
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
To a stirred solution of 100 g of 2,5-difluoroaniline and 1150 mL of AcOH is added over 1.3 hours a solution of 40.2 mL of Br2 in 350 mL of AcOH at a temperature of 15°-20°. The pink suspension is stirred 30 minutes longer and then evaporated in vacuo. The residue is basified with 50% NaOH (ice is added to keep the temperature below 35°). Extraction of the free base with 1 L of CH2Cl2 and washing of the extract with 2×100 mL of H2O, drying with Na2SO4 and evaporation in vacuo gives 157 g (97.5% yield) of 4-bromo-2,5-difluoroaniline, m.p. 73°-75°. The mass spectrum had a M+1 ions at 208,210.
Reaction SMILES: C([N:4]1[C:8]2=[N:9][CH:10]=[CH:11][C:12]([CH2:13][NH:14]C(=O)C)=[C:7]2[CH2:6][CH2:5]1)(=O)C.[ClH:18]>CCO>[ClH:18].[NH:4]1[C:8]2=[N:9][CH:10]=[CH:11][C:12]([CH2:13][NH2:14])=[C:7]2[CH2:6][CH2:5]1
Reactant: CC(=O)NCc1ccnc2c1CCN2C(C)=O
Agent: Cl
Solvent: CCO
Product: NCc1ccnc2c1CCN2
Temperature: 70 °C

Procedure:
A mixture of N-(1-acetyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl)-acetamide (0.50 g, Step A), HCl (conc., 3 mL) and EtOH (12 mL) was heated to 70° C. for overnight. Additional 3 mL of conc. HCl was added to the reaction and the heating was continued for 3 more days. Solvent was evaporated to give a white residue as crude C-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-methylamine HCl salt, which was used without further purification.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:23])=[C:16]([NH:20][CH:21]=[O:22])[C:17]([CH3:19])=[CH:18][C:13]=3[O:12][CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].CCCCCC.[C:30](OCC)(=[O:32])C>>[CH:30]([C:18]1[C:13]2[O:12][CH2:11][CH:10]([C:7]3[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=3)[C:14]=2[C:15]([CH3:23])=[C:16]([NH:20][CH:21]=[O:22])[C:17]=1[CH3:19])=[O:32]
Reactant: Cc1cc2c(c(C)c1NC=O)C(c1ccc(C(C)C)cc1)CO2
Reactant: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1c(C=O)c2c(c(C)c1NC=O)C(c1ccc(C(C)C)cc1)CO2
Yield: 92 %

Procedure:
Using (3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)formamide obtained in Example 58, the title compound was synthesized in the same manner as in Example 20. Yield: 92%. Melting point: 123-124° C. (hexane-ethyl acetate).
Reaction SMILES: Cl.[NH:2]([C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1)[C:3]([NH2:5])=[NH:4].[C:15]([O:19][C:20](=[O:41])[CH2:21][C@@:22]1([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[O:26][N:25]=[C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=2)[CH2:23]1)([CH3:18])([CH3:17])[CH3:16].N1C=CC=CC=1.CC(N(C)C)=O>O>[C:15]([O:19][C:20](=[O:41])[CH2:21][C@@:22]1([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[O:26][N:25]=[C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][C:10](=[O:11])[C:9]3[CH:8]=[CH:7][C:6]([NH:2][C:3]([NH2:5])=[NH:4])=[CH:14][CH:13]=3)[CH:28]=2)[CH2:23]1)([CH3:17])([CH3:18])[CH3:16]
Reactant: N=C(N)Nc1ccc(C(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)C[C@]1(C(=O)OC(C)(C)C)CC(c2cccc(O)c2)=NO1
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)OC(=O)C[C@]1(C(=O)OC(C)(C)C)CC(c2cccc(OC(=O)c3ccc(NC(=N)N)cc3)c2)=NO1
Reaction time: 3 h
Yield: 56.4 %

Procedure:
4-Carbamimidamidobenzoyl chloride hydrochloride (2.158 g) was added to a mixture of tert-butyl (5S)-5-(2-tert-butoxy-2-oxoethyl)-3-(3-hydroxyphenyl)-4,5-dihydro-1,2-oxazole-5-carboxylate (1.74 g), pyridine (2.2 mL), and DMA (2.2 mL) at 50 C, and the obtained mixture was stirred at 50 C for 3 hours. Further, 4-carbamimidamidobenzoyl chloride hydrochloride (2.158 g), DMA (1.1 mL), and pyridine (1.1 mL) were added thereto, and the obtained mixture was stirred at 50 C for 2 hours. To the reaction mixture, water was added, followed by extraction with ethyl acetate and ethyl acetate/THF (1/1). The extract was washed with brine and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate, subsequently acetonitrile/acetic acid), and then, the obtained fraction was concentrated under reduced pressure. The residue was added to a saturated aqueous solution of sodium bicarbonate, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (1.40 g).
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]Br)[CH2:2][CH2:3][CH3:4].[CH3:14][NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(O)CCC>[CH3:14][N:15]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[O:13])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CNc1ccccc1
Reactant: CCCCOC(=O)CCCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCCCO
Product: CCCCOC(=O)CCCCCN(C)c1ccccc1
Reaction time: 60 h

Procedure:
A mixture of 111 g (0.44 mol) of butyl-6-bromohexanoate (Example 21), 50 g (0.46 mol) of N-methylaniline, 63.9 g (0.46 mol) of anhydrous potassium carbonate, 3.6 g (0.022 mol) of potassium iodide, and 500 mL of butanol was heated at reflux with stirring for 60 hours. The resulting suspension was cooled and filtered, and the solid was extracted with ethyl acetate. The extract was combined with the filtrate and the solvents were removed by rotary evaporation. The residue was distilled in vacuo, bp 183°-188° C. (0.1 mm). A slightly yellow oil was obtained, mass 60 g (50%).
Reaction SMILES: [N:1]1([C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[C@@H:17]([O:22][C:23]2[N:28]=[C:27]([NH2:29])[N:26]=[C:25]([N:30]3[CH2:42][CH2:41][C:33]4([CH2:37][NH:36][C@H:35]([C:38]([OH:40])=[O:39])[CH2:34]4)[CH2:32][CH2:31]3)[CH:24]=2)[C:18]([F:21])([F:20])[F:19])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2N=C1.[NH:43]1[C:51]2C(=CC=CC=2)C=N1>>[NH2:29][C:27]1[N:26]=[C:25]([N:30]2[CH2:31][CH2:32][C:33]3([CH2:37][NH:36][C@H:35]([C:38]([OH:40])=[O:39])[CH2:34]3)[CH2:41][CH2:42]2)[CH:24]=[C:23]([O:22][C@H:17]([C:11]2[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:10]=2[N:1]2[C:5]3[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:51]=[N:43]2)[C:18]([F:20])([F:19])[F:21])[N:28]=1
Reactant: Nc1nc(O[C@H](c2ccc(Cl)cc2-n2cnc3ccccc32)C(F)(F)F)cc(N2CCC3(CC2)CN[C@H](C(=O)O)C3)n1
Reactant: c1ccc2[nH]ncc2c1
Product: Nc1nc(O[C@H](c2ccc(Cl)cc2-n2ncc3ccccc32)C(F)(F)F)cc(N2CCC3(CC2)CN[C@H](C(=O)O)C3)n1

Procedure:
The title compound was prepared as described for (S)-8-(6-((R)-1-(2-(1H-benzo[d]imidazol-1-yl)-4-chlorophenyl)-2,2,2-trifluoroethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 36b) starting with 1H-indazole and obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][CH2:7][C@H:8]([OH:21])[CH2:9][N:10]2[C:14](=[O:15])[C:13]3=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]3[C:11]2=[O:20])=[C:4]([O:24][C:25](=[O:27])[CH3:26])[CH:3]=1.C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][CH2:7][C@H:8]([O:21][S:36]([CH3:35])(=[O:38])=[O:37])[CH2:9][N:10]2[C:14](=[O:15])[C:13]3=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]3[C:11]2=[O:20])=[C:4]([O:24][C:25](=[O:27])[CH3:26])[CH:3]=1
Reactant: CC(=O)Oc1cc(Cl)ccc1OC[C@H](O)CN1C(=O)c2ccccc2C1=O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)Oc1cc(Cl)ccc1OC[C@@H](CN1C(=O)c2ccccc2C1=O)OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.6 %

Procedure:
To a reaction vessel were added crude (R)-1-(4-chloro-2-acetoxyphenoxy)-3-phthalimido-2-propanol 364 mg (0.90 mmol), triethylamine 137 mg (1.36 mmol) and ethyl acetate 2 mL. To this mixture was slowly dropped methanesulfonyl chloride 134 mg (1.18 mmol) in an ice bath and then the mixture was stirred at room temperature for 3 hours. After washing with an aqueous 5% HCl solution and water successively, the organic layer was taken and the solvent was evaporated to give crude (R)-1-(4-chloro-2-acetoxyphenoxy)-2-methanesulfonyloxy-3-phthalimidopropane 213 mg (yield 98%, chemical purity 97%) as a brown solid.
Reaction SMILES: [BH4-].[K+].[OH:3][C:4]1([CH2:16][OH:17])[CH2:8][S:7][C:6](=[S:9])[N:5]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.Cl>O.C(#N)C>[N:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[NH:5][C:6](=[S:9])[S:7][CH2:8][CH:4]([OH:3])[CH2:16][OH:17]
Reactant: OCC1(O)CSC(=S)N1c1ccccn1
Agent: Cl
Agent: [BH4-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: OCC(O)CSC(=S)Nc1ccccn1
Temperature: 2 °C
Reaction time: 0.5 h
Yield: 42.5 %

Procedure:
A solution of potassium borohydride (5.4 g) in distilled water (35 cc) is added, at a maximum of 20° C., to a suspension of 4-hydroxy-4-hydroxymethyl-3-(pyrid-2-yl)-thiazolidine-2-thione (23.8 g) in anhydrous acetonitrile (240 cc). The reaction is allowed to proceed for 30 minutes at 20° C. An 8.5 N aqueous solution of hydrochloric acid (12 cc) is added at a maximum of 20° C. The acetonitrile is evaporated off under reduced pressure (20 mm Hg) at 45° C. The aqueous phase is extracted 3 times with chloroform (500 cc in total). The organic solution is washed with distilled water (100 cc), dried over sodium sulphate and evaporated. The resulting product (21.2 g) is purified by crystallisation from a mixture of methylene chloride (100 cc) and isopropyl ether (50 cc). After drying in the atmosphere for 16 hours, yellow crystals (13 g), which melt at 96° C., are obtained and these are purified again by recrystallisation from a boiling mixture of acetonitrile (75 cc) and isopropyl ether (20 cc). After filtering the boiling solution and then cooling for 2 hours at 2° C., the crystals which have appeared are filtered off, washed with an ice-cooled mixture (25 cc in total) of acetonitrile (20 cc) and isopropyl ether (5 cc) and dried under reduced pressure (0.1 mm Hg) at 45° C. 2,3-Dihydroxy-propyl pyrid-2-yldithiocarbamate (10.2 g), which melts at 98° C., is thus obtained.