Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:10][C:9]=1[NH2:22])([CH3:4])([CH3:3])[CH3:2].C([O:26][C:27](=O)[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]#[N:38])[CH:32]=1)=[O:30])C>>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:10][C:9]=1[NH:22][C:27](=[O:26])[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]#[N:38])[CH:32]=1)=[O:30])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(=O)c2ccccc2)cc1N
Reactant: CCOC(=O)CC(=O)c1cccc(C#N)c1
Product: CC(C)(C)OC(=O)Nc1ccc(C(=O)c2ccccc2)cc1NC(=O)CC(=O)c1cccc(C#N)c1
Yield: 29.3 %

Procedure:
Prepared from (2-amino-4-benzoyl-phenyl)-carbamic acid tert.-butyl ester (Example G24) (375 mg, 1.20 mmol) and 3-(3-cyano-phenyl)-3-oxo-propionic acid ethyl ester (Pol. J. Chem.1978, 25) (313 mg, 1.44 mmol) according to the general procedure K. Obtained as a light yellow solid (170 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[C:6]=2[C:18]([OH:20])=O.[CH3:21][N:22](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[C:6]=2[C:18]([NH:22][CH3:21])=[O:20]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1c2ccc(Br)cc2nn1-c1ccc(F)cc1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1c2ccc(Br)cc2nn1-c1ccc(F)cc1
Temperature: 25 °C
Yield: 57.4 %

Procedure:
To a stirred solution of compound (xvi) (50 mg, 0.15 mmol) in DMF (5 mL) were added HATU (85 mg, 0.22 mmol) DIPEA (0.1 mL, 0.45 mmol) and methyl amine solution (0.26 mL, 0.15 mmol) at 0° C. and the reaction mixture was stirred at RT. After 12 h the reaction mixture was diluted with water and the precipitated solid was filtered to give 6-bromo-2-(4-fluorophenyl)-N-methyl-2H-indazole-3-carboxamide (xvii) (30 mg, 58%) as a white solid. ESI-MS m/z calculated for [M+H]+: 348.01; found: 347.90.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[N:18]3[N:25]=[CH:26][C:27]([C:28](O)=[O:29])=[C:17]3[N:16]=2)[CH:8]=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12].[CH3:33][S:34]([C:37]1[CH:38]=[C:39]([NH2:43])[CH:40]=[CH:41][CH:42]=1)(=[O:36])=[O:35].Cl>>[CH3:33][S:34]([C:37]1[CH:38]=[C:39]([NH:43][C:28]([C:27]2[CH:26]=[N:25][N:18]3[C:19]([C:21]([F:22])([F:23])[F:24])=[CH:20][C:15]([C:7]4[CH:8]=[CH:9][C:10]([C:11]([F:13])([F:14])[F:12])=[C:5]([O:4][CH2:3][C:2]([F:1])([F:32])[F:31])[CH:6]=4)=[N:16][C:17]=23)=[O:29])[CH:40]=[CH:41][CH:42]=1)(=[O:35])=[O:36]
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)c(OCC(F)(F)F)c3)nc12
Reactant: CS(=O)(=O)c1cccc(N)c1
Agent: Cl
Product: CS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)c(OCC(F)(F)F)c4)nc23)c1

Procedure:
The title compound was prepared from 5-[3-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.10) and 3-methanesulfonyl-phenylamine [commercially available as hydrochloride] according to general procedure II. Yellow solid. MS (EI) 626.3 [M]; mp 227° C.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][C:24]([O:26]CC)=O)[CH:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+:29].[OH-]>CO>[NH2:29][C:24]([CH2:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[O:16][CH2:15][CH2:14][N:11]1[CH2:12][CH2:13][CH:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][CH2:10]1)=[O:26]
Reactant: [NH4+]
Reactant: CCOC(=O)Cc1cccc(OCCN2CCC(Cc3ccccc3)CC2)c1
Agent: [OH-]
Solvent: CO
Product: NC(=O)Cc1cccc(OCCN2CCC(Cc3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 62 %

Procedure:
To a solution of 4-benzyl-1-(2-(3-(ethoxycarbonylmethyl)phenoxy)ethyl)piperidine (0.382 g, 1.00 mmol) in 5 mL of MeOH was added 5 mL of 30% NH4OH solution. The resulting solution was allowed to stir at rt for 12 hr. The MeOH was evaporated in vacuo and water (10 mL) was added. A colorless solid precipitated. The solid was collected by filtration and dried in vacuo giving the title product (218 mg, 62%): mp 100-101° C.; 1H NMR (CDCl3) 1.31 (m, 2 H), 1.60 (m, 1 H), 1.609 (m, 2 H), 2.04 (m, 2 H), 2.53 (d, J=6.6 Hz, 2 H), 2.80 (t, J=4.8 Hz, 2 H), 2.95 (d, J=11.4 Hz, 2 H), 3.55 (s, 2 H), 4.08 (t, J=6 Hz, 2 H), 5.35 (s, 2 H), 6.82 (m, 2 H), 7.13-7.27 (m, 6 H).
Reaction SMILES: C[O:2][C:3](=[O:39])[C@@H:4]([C:9]1[CH:10]=[C:11]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=2)[CH:12]=[C:13]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]2[CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[OH-].[Na+]>CO>[CH3:7][CH:6]([CH3:8])[CH2:5][C@H:4]([C:9]1[CH:10]=[C:11]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:37])([F:36])[F:38])=[CH:31][CH:30]=2)[CH:12]=[C:13]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]2[CH2:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:14]=1)[C:3]([OH:39])=[O:2]
Reactant: COC(=O)[C@H](CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(N2CCCCC2CCc2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)C[C@@H](C(=O)O)c1cc(-c2ccc(C(F)(F)F)cc2)cc(N2CCCCC2CCc2ccccc2)c1
Temperature: 60 °C

Procedure:
To a solution of (R)-4-methyl-2-[5-(2-phenethyl-piperidin-1-yl)-4′-trifluoromethyl-biphenyl-3-yl]-pentanoic acid methyl ester (14 mg, 0.03 mmol) in MeOH (2 mL) was added 1N NaOH (0.100 mL) and heated to 60° C. for 2 h. The reaction was concentrated in vacuo to remove MeOH. The thick liquid was acidified to pH=2 by 2N HCl. The resulting acidic solution was extracted with EtOAc. The organic fraction was dried (MgSO4) and concentrated in vacuo. The crude mixture was purified by Gilson reverse phase column chromatography to obtain (R)-4-methyl-2-[5-(2-phenethyl-piperidin-1-yl)-4′-trifluoromethyl-biphenyl-3-yl]-pentanoic acid. 1H-NMR (MeOD-d4): δ 0.84 (m, 6H), 1.40 (m, 1H), 1.60-1.76 (m, 5H), 1.93 (m, 4H), 2.28-2.41 (m, 2H), 2.59 (m, 1H), 3.56-3.73 (m, 3H), 3.78 (q, 1H), 6.85 (s, 1H), 6.87 (s, 1H), 6.98 (m, 1H), 7.04 (m, 2H), 7.47-7.57 (m, 2H), 7.71 (s, 5H); Calcd for C32H36F3NO2 (M+H) 524.63, Found 524.3
Reaction SMILES: [NH2:1][OH:2].[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]2[CH2:16][O:15][CH2:14][CH2:13][N:12]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:7][CH:6]=1)=O>C(O)C>[OH:2][N:1]=[CH:3][C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]2[CH2:16][O:15][CH2:14][CH2:13][N:12]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:7][CH:6]=1
Reactant: NO
Reactant: CC(C)(C)OC(=O)N1CCOC[C@H]1c1ccc(C=O)cc1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCOC[C@H]1c1ccc(C=NO)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.6 %

Procedure:
Hydroxylamine (2.513 mL of 50% w/v, 38.04 mmol) was added to a stirred solution of tert-butyl (3R)-3-(4-formylphenyl)morpholine-4-carboxylate 11 (5.54 g, 19.02 mmol) in ethanol (29.66 mL) and the resulting mixture stirred at rt for 1 h. The reaction mixture was concentrated in vacuo and then redissolved in EtOAc (50 mL) and sequentially washed with water (2×20 mL) and brine (1×20 mL), dried over MgSO4, filtered and concentrated in vacuo to leave product as a white foam (5.57 g, 96% yield); 1H NMR (400.0 MHz, DMSO) d 1.39 (9H, s), 3.08 (1H, m), 3.49 (1H, m), 3.69-3.83 (4H, m), 4.28 (1H, m), 4.98 (1H, s), 7.36 (2H, m), 7.58 (2H, m), 8.13 (1H, s) and 11.23 (1H, s) ppm.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([NH:15][NH2:16])=O)=[CH:11][CH:10]=2)[CH:5]=[C:4]([NH2:19])[N:3]=1.I.CS[C:23](=[NH:36])[NH:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=1>N1C=CC=CC=1>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([NH:24][C:23]2[NH:36][C:13]([C:12]3[CH:17]=[CH:18][C:9]([O:8][C:6]4[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([NH2:19])[CH:5]=4)=[CH:10][CH:11]=3)=[N:15][N:16]=2)=[CH:26][C:27]=1[C:32]([F:33])([F:34])[F:35]
Reactant: CSC(=N)Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: NNC(=O)c1ccc(Oc2cc(N)nc(N)n2)cc1
Agent: I
Solvent: c1ccncc1
Product: Nc1cc(Oc2ccc(-c3nnc(Nc4ccc(Cl)c(C(F)(F)F)c4)[nH]3)cc2)nc(N)n1
Temperature: 25 °C
Yield: 50.6 %

Procedure:
4-[(2,6-diaminopyrimidin-4-yl)oxy]benzohydrazide (1.48 g, 5.68 mmol) and S-methyl N-[4-chloro-3-(trifluoromethyl)phenyl]isothiourea hydroiodide (2.33 g, 5.89 mmol) were suspended in 30 mL of anhydrous pyridine. The reaction mixture was refluxed for 18 hours under Ar atmosphere. The formed yellow solution was cooled down to ambient temperature and pyridine was removed in vacuo. The resulting yellow foamy solid was re-dissolved in 50 mL of 5:1 EtOAc/MeOH; ca. 15 g of silica gel was added and solvent was removed in vacuo. The impregnated silica gel was packed into ISCO column and the product was purified using ISCO system (80 g pre-packed column, 50 min run, 0% to 10% gradient of solvent B in solvent A [Solvent A—4 mL of MeOH, 4 ml, of Et3N in 4 L of CH2Cl2; Solvent B—4 mL of Et3N in 4 L of MeOH]). Solvent was removed in vacuo to give the title product as a white solid (1.33 g). Yield 50.5%.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][O:13][C@H:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C@@H:15]1[OH:20]>>[F:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([O:20][C@H:15]2[CH2:16][CH2:17][CH2:18][CH2:19][C@@H:14]2[O:13][CH3:12])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: CO[C@H]1CCCC[C@@H]1O
Product: CO[C@H]1CCCC[C@@H]1Oc1cc(F)ccc1[N+](=O)[O-]

Procedure:
Prepared analogously to III.1 from 926 μl 2,4-difluor-nitrobenzene and 1 g (1S,2S)-2-methoxycyclohexanol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:17]2[CH2:21][C@H:20]([CH2:22][OH:23])[O:19][C:18]2=[O:24])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH3:15])[C:10](=[O:16])[CH2:9]1.C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([N:17]2[CH2:21][C@H:20]([CH2:22][O:23][S:33]([CH3:32])(=[O:35])=[O:34])[O:19][C:18]2=[O:24])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH3:15])[C:10](=[O:16])[CH2:9]1
Reactant: CCN1CCN(c2ccc(N3C[C@H](CO)OC3=O)cc2F)CC1=O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CCN1CCN(c2ccc(N3C[C@H](COS(C)(=O)=O)OC3=O)cc2F)CC1=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(5R)-3-(3-Fluoro-4-{4-ethyl-3-oxopiperazin-1-yl}phenyl)-5-hydroxymethyloxazolidin-2-one (830 mg) was dissolved in pyridine (20 ml), and cooled to 0° C. Triethylamine (0.41 ml) and methanesulfonyl chloride (0.21 ml) were added, and stirring continued at ambient temperature for 2 hours. Solvent was evaporated and the residue dissolved in ethyl acetate. The resulting solution was washed with water, dried (MgSO4), and evaporated to give (5R)-3-(3-fluoro-4-{4-ethyl-3-oxopiperazin-1-yl}phenyl)-5-(methanesulfonyloxymethyl)-oxazolidin-2-one (1.0 g) which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=2)[CH2:15][CH2:14]1.Cl.[C:33]1([NH:43]N)[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][CH:34]=1>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:43][C:33]2[C:34]([C:9]=1[CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]1)=[CH:35][CH:36]=[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:42]=21
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccccc3Br)CC2)c1
Reactant: NNc1cccc2ccccc12
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccccc4Br)[nH]c4c3ccc3ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(2-bromophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1-naphthylhydrazine hydrochloride: ESMS m/e: 608.0 (M+H)+.
Reaction SMILES: C1O[C:4]2([C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:6][C:5]32[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]3)OC1.O.NN.[OH-].[K+].[CH2:25](O)[CH2:26][OH:27]>>[CH2:25]1[O:18][C:15]2([CH2:14][CH2:13][C:5]3([CH2:4][C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[CH2:6]3)[CH2:17][CH2:16]2)[O:27][CH2:26]1
Reactant: O=C1CCC2(CC1)Cc1ccccc1C21OCCO1
Reactant: OCCO
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: c1ccc2c(c1)CC1(CCC3(CC1)OCCO3)C2
Yield: 85 %

Procedure:
A mixture of 5g. (0.0194 M) of spiro(cyclohexane 1,2'-indan)-1',4-dione 4-ethylene ketal [9](prepared as in Example 16B), 2.6ml. of hydrazine hydrate and 3.76 g. of potassium hydroxide in 50 ml. of ethylene glycol is heated at reflux for about 1.5 hours. Material is then removed by distillation to bring the pot temperature to 200° C. After about 5 hours of additional heating at reflux, the mixture is allowed to cool and diluted with water. The precipitated solid is collected on a filter, dried and recrystallized from petroleum ether to give 4 g. (85% yield) of spiro(cyclohexane-1,2'-indan)-4-one ethylene ketal [10], having a melting point of 70° to 74° C.
Reaction SMILES: O=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[OH-].[Na+].[CH3:14][C:15]([CH3:17])=[O:16]>>[CH3:14][C:15](/[CH:17]=[CH:2]/[C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1)=[O:16]
Reactant: COc1cc(C=O)ccc1O
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Product: COc1cc(/C=C/C(C)=O)ccc1O
Temperature: 25 °C
Reaction time: 96 h
Yield: 85 %

Procedure:
To a solution of vanillin (5 g) in acetone (20 mL) was added 10% sodium hydroxide solution (20 mL). The reaction mixture was stirred at room temperature for 4 days (Normura, 1917). After acidification the product was extracted with EtOAc twice and washed with water. Evaporation of solvent left a dark brown liquid which on crystallisation from EtOAc-petroleum afforded the title compound (85%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([N:11]2[CH2:16][CH2:15][NH:14][C@H:13]([CH3:17])[CH2:12]2)=[N:6][CH:5]=1.Cl[C:20]1[NH:24][C:23]2[CH:25]=[C:26]([C:38]([F:41])([F:40])[F:39])[CH:27]=[C:28]([C:29]3[CH:34]=[C:33]([F:35])[C:32]([F:36])=[C:31]([F:37])[CH:30]=3)[C:22]=2[N:21]=1>>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([N:11]2[CH2:16][CH2:15][N:14]([C:20]3[NH:21][C:22]4[C:28]([C:29]5[CH:30]=[C:31]([F:37])[C:32]([F:36])=[C:33]([F:35])[CH:34]=5)=[CH:27][C:26]([C:38]([F:41])([F:39])[F:40])=[CH:25][C:23]=4[N:24]=3)[C@H:13]([CH3:17])[CH2:12]2)=[N:6][CH:5]=1
Reactant: COC(=O)c1cnc(N2CCN[C@H](C)C2)c(Cl)c1
Reactant: Fc1cc(-c2cc(C(F)(F)F)cc3[nH]c(Cl)nc23)cc(F)c1F
Product: COC(=O)c1cnc(N2CCN(c3nc4cc(C(F)(F)F)cc(-c5cc(F)c(F)c(F)c5)c4[nH]3)[C@H](C)C2)c(Cl)c1

Procedure:
5-Chloro-6-[(3R)-3-methyl-piperazin-1-yl]-nicotinic acid methyl ester from step (b) above (271 mg, 1.0 mmol) and 2-chloro-6-trifluoromethyl-4-(3,4,5-trifluoro-phenyl)-1H-benzoimidazole (350 mg, 1.0 mmol, Example 51b) reacted under the conditions of Example 3c to give the title compound as a white solid. MS ESI, pos. ion) m/e: 584 (M+1).
Reaction SMILES: [C:1]([C:4]1([O:10][CH2:9]1)[CH2:5][C:6]([OH:8])=[O:7])(=[O:3])[NH2:2].[OH-].[Na+].[C-:13]#[N:14].[Na+].Cl>O>[C:1]([C:4]([OH:10])([CH2:9][C:13]#[N:14])[CH2:5][C:6]([OH:8])=[O:7])(=[O:3])[NH2:2]
Reactant: [C-]#N
Reactant: NC(=O)C1(CC(=O)O)CO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N#CCC(O)(CC(=O)O)C(N)=O
Reaction time: 27 h
Yield: 101 %

Procedure:
43.5 g (0.3 mol) of the 3-carbamoyl-3,4-epoxybutyric acid was placed in 150 ml of water and 50.2 ml of 5.98 M NaOH solution (0.3 mol) added at 15°C. The pH of the solution was 12.07. 16.2 g of NaCN (0.33 mol) dissolved in 50 ml of water was then added at 15°C. The pH changed to 12.28. The temperature was then raised to 33°-35°C over about 10 min. 6.73 N HCl (approximately 0.3 mol) was then added slowly to maintain the pH at 11. After 27 hrs the solution was assayed by NMR analysis and showed a 101±2 percent yield of the 3-carbamoyl-3-hydroxy-4-cyanobutyric acid salt.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[N:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:11]([C:18]#[N:19])=[CH:10][C:9]=2[CH:20]([OH:22])[CH3:21])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[CH3:30][S:31]([O:22][CH:20]([C:9]1[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[N:16]2)=[C:11]([C:18]#[N:19])[CH:10]=1)[CH3:21])(=[O:33])=[O:32]
Reactant: CC(O)c1cc(C#N)c2cccnc2c1-c1cccc(F)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(OS(C)(=O)=O)c1cc(C#N)c2cccnc2c1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 8-(3-fluorophenyl)-7-(1-hydroxyethyl)quinoline-5-carbonitrile (20 mg, 0.07 mmol) in methylene chloride (1 mL) was added triethylamine (0.28 mL, 2.0 mmol) followed by methanesulfonyl chloride (0.12 mL, 1.5 mmol). The reaction was stirred at room temperature for 30 minutes, quenched with water and then extracted with dichloromethane. The combined organic layers were washed with brine and dried over magnesium sulfate and concentrated to dryness under reduced pressure. The residue was used directly in the next step (28 mg, 100%). LCMS calculated for C19H16FN2O3S (M+H)+: m/z=371.1; Found: 371.1.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([S:13]([N:16]2[C:20]3=[N:21][CH:22]=[C:23]([OH:25])[CH:24]=[C:19]3[CH:18]=[C:17]2[C:26]([C:33]2[CH:38]=[CH:37][C:36]([S:39]([CH3:42])(=[O:41])=[O:40])=[CH:35][CH:34]=2)=[CH:27][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:43][O:44][CH2:45][CH2:46]Br>CN(C)C=O.C(OCC)(=O)C>[C:7]1([S:13]([N:16]2[C:20]3=[N:21][CH:22]=[C:23]([O:25][CH2:46][CH2:45][O:44][CH3:43])[CH:24]=[C:19]3[CH:18]=[C:17]2[C:26]([C:33]2[CH:34]=[CH:35][C:36]([S:39]([CH3:42])(=[O:40])=[O:41])=[CH:37][CH:38]=2)=[CH:27][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)(=[O:14])=[O:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CS(=O)(=O)c1ccc(C(=CC2CCCC2)c2cc3cc(O)cnc3n2S(=O)(=O)c2ccccc2)cc1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCOc1cnc2c(c1)cc(C(=CC1CCCC1)c1ccc(S(C)(=O)=O)cc1)n2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.1 %

Procedure:
Potassium carbonate (246 mg, 1.78 mmol) was added to a solution of 1-benzenesulfonyl-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-ol (prepared as in Example 13, 310 mg, 0.59 mmol) in N,N-dimethylformamide (2 mL) at room temperature and the mixture was then stirred at room temperature for 30 min and then treated with 2-bromoethyl methyl ether (0.06 mL, 0.59 mmol). The mixture was then heated at 80° C. for 1 h. The resulting reaction mixture was diluted with ethyl acetate (150 mL), washed with brine, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 1-benzenesulfonyl-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-5-(2-methoxy-ethoxy)-1H-pyrrolo[2,3-b]pyridine (343 mg, quant.) as a light yellow solid which was used in the next step without further purification: LC/MS m/e calcd for C30H32N2O6S2 [M+H]+ 581.73, observed 581.1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][CH:19]1[CH:26]2[CH2:27][C:22]3([OH:29])[CH2:23][CH:24]([CH2:28][CH:20]1[CH2:21]3)[CH2:25]2>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([NH:18][CH:19]1[CH:20]2[CH2:28][CH:24]3[CH2:23][C:22]([OH:29])([CH2:27][CH:26]1[CH2:25]3)[CH2:21]2)=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1C2CC3CC1CC(O)(C3)C2
Reactant: O=C(O)c1cccc(OCc2ccccc2)c1
Product: O=C(NC1C2CC3CC1CC(O)(C3)C2)c1cccc(OCc2ccccc2)c1

Procedure:
Prepared from 3-(benzyloxy)benzoic acid and 4-amino-1-hydroxyadamantane to give the title compound as a mixture of two isomers. 1H NMR (300 MHz, CDCl3): δ 7.69-7.74 (m, 1H), 7.29-7.48 (m, 7H), 7.20-7.24 (m, 0.5H), 7.09-7.13 (m, 0.5H), 6.27 (d, 1H), 5.12 (s, 2H), 4.18-4.23 (m, 1H), 2.16-2.27 (m, 3H), 1.91-1.98 (m, 2H), 1.71-1.84 (m, 6H), 1.54-1.61 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[C@@H:6]([CH2:14][CH3:15])[N:5]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:4]=2[N:3]=1.Cl.[NH2:22][C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1>C(O)(C)C.O1CCOCC1>[CH:16]1([N:5]2[C:4]3[N:3]=[C:2]([N:26]4[CH:27]=[CH:28][C:23](=[NH:22])[CH:24]=[CH:25]4)[N:11]=[CH:10][C:9]=3[N:8]([CH3:12])[C:7](=[O:13])[C@H:6]2[CH2:14][CH3:15])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Nc1ccncc1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Cl)nc2N1C1CCCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: CC[C@@H]1C(=O)N(C)c2cnc(-n3ccc(=N)cc3)nc2N1C1CCCC1
Temperature: 160 °C

Procedure:
To a solution of the Intermediate B (400 mg, 1.36 mmol) in 5 mL of isopropanol in a microwave vial, 4N HCl in dioxane (0.43 mL) and 4-aminopyridine (320 mg, 2 eq) were added and the vial was heated in a microwave oven at 160° C. for 1 hour. Solvent was removed under reduced pressure and the resulting yellow solid was purified by reversed phase HPLC to give the title compound. 1H NMR (CDCl3) δ: 9.62 (bs, 1H), 8.91 (d, J=7.7 Hz, 2H), 7.81 (s, 1H), 7.37 (d, J=7.8 Hz, 2H), 4.44-4.36 (m, 2H), 3.41 (s, 3H), 2.08-1.71 (m, 10H), 0.89 (t, J=7.5 Hz, 3H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1.BrCCBr.[Mg].[CH3:14][Si:15]([CH3:18])([CH3:17])Cl.C([O-])(O)=O.[Na+]>C1COCC1>[CH3:14][Si:15]([CH3:18])([CH3:17])[C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(Cl)c1
Reactant: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Mg]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: Cc1cccc([Si](C)(C)C)c1
Reaction time: 0.5 h
Yield: 91.6 %

Procedure:
A solution of m-chlorotoluene (12.66 g, 0.100 mol) and 1,2-dibromoethane (0.5 ml) in THF (20 ml) was added to magnesium turnings (2.67 g, 0.110 mol). The mixture was heated under reflux for 4 h, after which the heating bath was removed and trimethylchlorosilane (11.08 g, 0.102 mol) was added so that gentle reflux was maintained. The mixture was stirred for another 0.5 h and 5% NaHCO3 (100 ml) was then added. The resulting mixture was extracted with CH2Cl2 (3×50 ml), the organic phase was washed with brine and dried (MgSO4). Filtration and evaporation provided 15.05g (92%) of 36 as a pale yellow liquid. Spectroscopic data were identical to those previously reported in the literature.40
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C@H:10]2[C:14]3([CH2:16][CH2:15]3)[C:13](=O)[NH:12][CH2:11]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCCC1>[H-].[Al+3].[Li+].[H-].[H-].[H-]>[C:1]1([C@@H:7]([NH:9][C@H:10]2[C:14]3([CH2:16][CH2:15]3)[CH2:13][NH:12][CH2:11]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@H](N[C@@H]1CNC(=O)C12CC2)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H](N[C@@H]1CNCC12CC2)c1ccccc1

Procedure:
A flask was charged with 200 mg of (S)-7-[(S)-1-phenylethyl]amino-4-oxo-5-azaspiro[2.4]heptane, and the atmosphere in the flask was replaced with nitrogen. Next, 5 ml of tetrahydrofuran was added to dissolve the compound in the flask, 5.0 ml of lithium aluminum hydride (1 M solution in tetrahydrofuran) was added dropwise to the resulting solution at 0° C. and then the mixture was heated under reflux for 1 hour. After confirming completion of the reaction, the reaction was terminated by adding saturated ammonium chloride solution and then the insoluble matter was removed by filtration. The resulting filtrate was concentrated under a reduced pressure and distributed between ethyl acetate and saturated brine, and the resulting organic layer was dried over anhydrous sodium sulfate. Thereafter, the insoluble matter was removed by filtration and the resulting filtrate was concentrated under a reduced pressure to obtain 181 mg (96%) of colorless oily substance.