Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH2:10]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:10]([N:17]1[CH2:22][CH2:21][N:20]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH2:19][CH2:18]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: N#Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Temperature: 120 °C
Reaction time: 13 h
Yield: 57.7 %

Procedure:
To a solution of 4-fluorobenzonitrile (3.0 g, 25 mmol) in N,N-dimethylformamide (15 mL) were added 1-benzylpiperazine (4.3 mL, 25 mmol) and potassium carbonate (3.4 g, 25 mmol). The reaction mixture was stirred at 120° C. for 13 h. The solvent was evaporated in vacuo and the residue was partitioned between ethyl acetate (100 mL) and water (15 mL). The aqueous phase was extracted with ethyl acetate (30 mL) and the combined organic phases were washed twice with brine (10 mL) and dried (MgSO4). Evaporation of the solvent gave 7.6 g of crude product. Purification of the residue on a silica gel column using ethyl acetate/methylene chloride (1:9) as the eluent afforded 4.0 g (59% yield) of the title compound as a white solid: mp 104–105° C.; EIMS (70 eV) m/z (relative intensity) 277 (20, M+).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:17][C:6]2=[C:7]([C:12]3[CH:16]=[CH:15][NH:14][N:13]=3)[S:8][C:9]([S:10][CH3:11])=[C:5]2[C:4](=[O:18])[CH2:3]1.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl.C1COCC1.CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][C:2]1([CH3:19])[CH2:17][C:6]2=[C:7]([C:12]3[CH:16]=[CH:15][N:14]([S:21]([CH3:20])(=[O:23])=[O:22])[N:13]=3)[S:8][C:9]([S:10][CH3:11])=[C:5]2[C:4](=[O:18])[CH2:3]1
Reactant: CSc1sc(-c2cc[nH]n2)c2c1C(=O)CC(C)(C)C2
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CSc1sc(-c2ccn(S(C)(=O)=O)n2)c2c1C(=O)CC(C)(C)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.7 %

Procedure:
To a solution of 6,6-dimethyl-3-methylthio-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one (70 mg, 0.24 mmol) in CH2Cl2:THF (5:1, 6 mL), was added methanesulphonyl chloride (36 μL, 0.48 mmol) and 4-dimethylaminopyridine (58 mg, 0.48 mmol). The mixture was stirred at room temperature overnight then diluted with CH2Cl2 (10 mL) and washed with water (2×10 mL). The organic layer was separated, dried (Na2SO1) and evaporated. The residue was chromatographed on silica gel, eluting with CH2Cl2:MeOH (95:5), to give the title compound (38 mg, 43%) as a pale yellow solid. mp 193-195° C. Found: C, 47.72; H, 4,71; N, 7.16%. C15H18N2S3O3.0.3 (H2O) requires: C, 47.93, H, 4.99; N, 7.45%. 1HNMR (360 Hz, d6-DMSO) δ 1.02 (6H, s), 2.41 (2H, s), 2.64 (3H, s), 2.90 (2H, s), 3.61 (3H, s), 6.91 (1H, d, J=2.8 Hz). MS (ES+) 371 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([CH3:10])[N:3]=1.[N+:11]([C:14]1[CH:15]=[C:16]([S:19]([N:22]=[C:23]=[O:24])(=[O:21])=[O:20])[S:17][CH:18]=1)([O-:13])=[O:12]>C(#N)C>[CH3:9][O:8][C:6]1[N:5]=[C:4]([CH3:10])[N:3]=[C:2]([NH:1][C:23]([NH:22][S:19]([C:16]2[S:17][CH:18]=[C:14]([N+:11]([O-:13])=[O:12])[CH:15]=2)(=[O:21])=[O:20])=[O:24])[N:7]=1
Reactant: O=C=NS(=O)(=O)c1cc([N+](=O)[O-])cs1
Reactant: COc1nc(C)nc(N)n1
Solvent: CC#N
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)c2cc([N+](=O)[O-])cs2)n1
Temperature: 25 °C

Procedure:
To 1.4 g of 2-amino-4methoxy-6-methyl-1,3,5-triazine suspended in 25 ml of anhydrous acetonitrile with stirring at ambient temperature was added 2.4 g of 4-nitrothiophene-2-sulfonyl isocyanate. After stirring for sixteen hours at ambient temperature, the product which was present as a precipitate was removed by filtration and washed with 1-chlorobutane. It melted at 188° with decomposition and showed infrared absorption spectrum peaks at 1740, 1600 and 1560 cm-1 consistent for the desired aminocarbonylsulfonamide structure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[C:18]2[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=2[C:16]1=[O:25].[Cl:26][C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29][NH2:30]>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)=[CH:4][C:3]=1[NH:15][C:16](=[O:25])[C:17]1[CH2:24][CH2:23][CH2:22][CH2:21][C:18]=1[C:19]([NH:30][CH2:29][C:28]1[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=1[Cl:26])=[O:20]
Reactant: NCc1ccccc1Cl
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Solvent: c1ccccc1
Product: O=C(NCc1ccccc1Cl)C1=C(C(=O)Nc2cc(OC3CCCC3)c(Cl)cc2F)CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.2 %

Procedure:
N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide (0.500 g, 1.37 mmol), 2-chlorobenzylamine (0.240 g, 1.69 mmol) and benzene (25 ml) as a solvent were placed into a round bottom flask (50 cc) and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. The crystals were washed with hexane and dried to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-(2-chlorobenzyl)-3,4,5,6-tetrahydrophthalamide as white crystals (0.590 g, 85.4% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([C:16]([NH:18][C:19]3[CH:43]=[CH:42][C:22]([C:23]([N:25]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][C:28]=4[O:34]CC4C=CC=CC=4)[CH3:26])=[O:24])=[CH:21][CH:20]=3)=[O:17])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO.O1CCOCC1.[OH-].[Pd+2].[OH-]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:11]([C:16]([NH:18][C:19]3[CH:43]=[CH:42][C:22]([C:23]([N:25]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][C:28]=4[OH:34])[CH3:26])=[O:24])=[CH:21][CH:20]=3)=[O:17])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: Cc1ccc(N(C)C(=O)c2ccc(NC(=O)c3ccccc3-c3ccc([N+](=O)[O-])cc3)cc2)c(OCc2ccccc2)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: Cc1ccc(N(C)C(=O)c2ccc(NC(=O)c3ccccc3-c3ccc(N)cc3)cc2)c(O)c1
Reaction time: 5 h
Yield: 103 %

Procedure:
A solution of 4-(4′-nitrobiphenyl-2-carboxamido)-N-(2-benzyloxy-4-methylphenyl)-N-methylbenzamide (430 mg), 20% palladium hydroxide (80 mg) in methanol (20 ml) and 1,4-dioxane (30 ml) was stirred under atmospheric pressure of hydrogen at 30° C. After 5 hours, the reaction mixture was filtered through a bed of Celite, and the solvent was removed by evaporation and the crude product was purified by silica gel column chromatography (SiO2; 30 g, 3% methanol in chloroform) to give 4-(4′-aminobiphenyl-2-carboxamido)-N-(2-hydroxy-4-methylphenyl)-N-methylbenzamide (350 mg) as amorphous.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[C:6]([NH:12][CH2:13][C@@H:14]2[CH2:16][C@H:15]2[C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH:5]=[CH:4][N:3]=1.[H-].[Na+].I[CH3:27]>CN(C=O)C>[Cl:1][C:2]1[C:7]([C:8]([F:10])([F:11])[F:9])=[C:6]([N:12]([CH2:13][C@@H:14]2[CH2:16][C@H:15]2[C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)[CH3:27])[CH:5]=[CH:4][N:3]=1
Reactant: CI
Reactant: Fc1ccc([C@@H]2C[C@H]2CNc2ccnc(Cl)c2C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C[C@@H]1C[C@H]1c1ccc(F)cc1)c1ccnc(Cl)c1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 966.7 %

Procedure:
To a solution of trans-2-chloro-N-((2-(4-fluorophenyl)cyclopropyl)methyl)-3-(trifluoromethyl)pyridin-4-amine (1.2 g, 3.48 mmol) in DMF (5 mL) was added 60% sodium hydride in mineral oil (0.153 g, 3.83 mmol) at 0° C. The resulting mixture was stirred at 0° C. under nitrogen for 10 min. Iodomethane (0.022 mL, 0.346 mmol) was added at 0° C. The reaction mixture was stirred at 0° C. for 10 min and then at rt for 30 min. The reaction mixture was poured into ice water and the resulting suspension was extracted with EtOAc (3×20 mL). The combined organic layers were washed with aqueous sodium bicarbonate (2×20 mL) and brine (20 mL), dried over magnesium sulfate, filtered and concentrated under vacuum to give trans-2-chloro-N-((2-(4-fluorophenyl)cyclopropyl)methyl)-N-methyl-3-(trifluoromethyl)pyridin-4-amine (1.2 g, 96% yield) as a yellowish oil, which was used for the next step reaction without further purification. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.07 (d, J=5.8 Hz, 1H), 7.01-6.94 (m, 4H), 6.80 (d, J=6.0 Hz, 1H), 3.38 (dd, J=14.1, 6.0 Hz, 1H), 3.18 (dd, J=14.1, 7.3 Hz, 1H), 3.06-3.00 (m, 3H), 1.75-1.63 (m, 1H), 1.24 (br. s., 1H), 1.03 (dt, J=8.5, 5.3 Hz, 1H), 0.90-0.84 (m, 1H). LCMS: M+1=359.17.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]3[CH2:23][CH2:22][C:21](=[O:24])[C:9]3=[C:10]2[C:13]2[CH:18]=[CH:17][C:16]([CH2:19][OH:20])=[CH:15][CH:14]=2)=[CH:5][CH:4]=1.C1CCC(N=C=NC2CCCCC2)CC1.[C:41](O)(=[O:52])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH:50]=[CH2:51]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:41]([O:20][CH2:19][C:16]1[CH:15]=[CH:14][C:13]([C:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([N:2]([CH3:25])[CH3:1])[CH:12]=3)[CH:7]=[C:8]3[CH2:23][CH2:22][C:21](=[O:24])[C:9]=23)=[CH:18][CH:17]=1)(=[O:52])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH:50]=[CH2:51]
Reactant: CN(C)c1ccc2cc3c(c(-c4ccc(CO)cc4)c2c1)C(=O)CC3
Reactant: C=CCCCCCCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=CCCCCCCCCC(=O)OCc1ccc(-c2c3c(cc4ccc(N(C)C)cc24)CCC3=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.3 %

Procedure:
An oven-dried, 25 mL one-necked round-bottomed flask was charged with compound 15b (0.021 g, 0.060 mmol), DCC (0.014 g, 0.069 mmol), DMAP (0.008 g, 0.069 mmol) and dry CH2Cl2 (7 mL). 10-Undecenoic acid (0.012 mL, 0.060 mmol) was added and the mixture was stirred at rt overnight. The consumption of the starting material was monitored by TLC (AcOEt/n-hexane 1:9). After filtration over a short pad of celite, the reaction was quenched with sat'd aq NaHCO3 solution (30 mL). The layers were separated and the aqueous phase was extracted with Et2O (3×15 mL). The combined organic layers were washed with brine (2×40 mL), dried over MgSO4, gravity filtered, and concentrated under reduced pressure. The reaction residue was purified by silica gel flash chromatography, eluting with AcOEt/n-hexane 1.5:8.5, to provide 0.018 g of the title compound as a yellow solid in 60% yield.
Reaction SMILES: [C:1]1(C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:15]1[CH:16]=[C:17]([CH:30]=[CH:31][CH:32]=1)[O:18][CH2:19][CH:20]([OH:29])[CH2:21][CH2:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1.C1(B(O)O)C=CC=CC=1>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.C(O)C>[C:15]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:32]=[CH:31][CH:30]=[C:17]([O:18][CH2:19][CH:20]([OH:29])[CH2:21][CH2:22][C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[CH:16]=1
Reactant: Cc1ccccc1
Reactant: OC(CCc1cccnc1)COc1cccc(Br)c1
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: OB(O)c1ccccc1
Solvent: CCO
Product: OC(CCc1cccnc1)COc1cccc(-c2ccccc2)c1

Procedure:
Prepared according to the method described in Example 33a) from toluene (5 ml), aqueous sodium carbonate (2 M, 1 ml), (±)-1-(3-bromophenoxy)-4-(3-pyridyl)-2-butanol (0.25 g), ethanol (1 ml), benzeneboronic acid (0.14 g) and tetrakis(triphenylphosphine)palladium(0) (30 mg) with heating at reflux for 4 hours. The residue obtained after work up was purified by column chromatography over silica eluting with ethyl acetate to give (±)-1-(biphenyl-3-yloxy)-4-(3-pyridyl)-2-butanol as a colourless oil (0.178 g). Conversion to the oxalate salt upon treatment with excess saturated ethereal oxalic gave the title compound as a hygroscopic gum. (0.10 g)
Reaction SMILES: [Br:1][C:2]1[C:3]([O:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:4]([CH:7]=[C:8]([S:10][CH3:11])[CH:9]=1)[CH:5]=O.Cl.[NH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]1[NH:32][C:31]2[CH:33]=[CH:34][S:35][C:30]=2[C:29](=[O:36])[CH:28]=1>>[Br:1][C:2]1[C:3]([O:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:4]([CH:7]=[C:8]([S:10][CH3:11])[CH:9]=1)[CH2:5][NH:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]1[NH:32][C:31]2[CH:33]=[CH:34][S:35][C:30]=2[C:29](=[O:36])[CH:28]=1
Reactant: NCCCNc1cc(=O)c2sccc2[nH]1
Reactant: CSc1cc(Br)c(OCCc2ccccc2)c(C=O)c1
Agent: Cl
Product: CSc1cc(Br)c(OCCc2ccccc2)c(CNCCCNc2cc(=O)c3sccc3[nH]2)c1

Procedure:
5-[3-(3-bromo-5-methylsulfanyl-2-phenethyloxy-benzylamino)-propylamino]-4H-thieno[3,2-b]pyridine-7-one was prepared by reductive amination of the aldehyde prepared in Example 3 with amine XVIII following method C.
Reaction SMILES: [NH2:1][C:2]1([C:15]([OH:17])=[O:16])[CH2:7][CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.NC1(C(O)=O)CCN(C(OC(C)(C)C)=O)CC1.[Cl:35][C:36]1[C:37]([F:57])=[C:38]([NH:42][C:43]2[C:52]3[C:47](=[CH:48][C:49]([O:55][CH3:56])=[C:50]([CH:53]=O)[CH:51]=3)[N:46]=[CH:45][N:44]=2)[CH:39]=[CH:40][CH:41]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C>[Cl:35][C:36]1[C:37]([F:57])=[C:38]([NH:42][C:43]2[C:52]3[C:47](=[CH:48][C:49]([O:55][CH3:56])=[C:50]([CH2:53][NH:1][C:2]4([C:15]([OH:17])=[O:16])[CH2:7][CH2:6][CH2:5][NH:4][CH2:3]4)[CH:51]=3)[N:46]=[CH:45][N:44]=2)[CH:39]=[CH:40][CH:41]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(N)(C(=O)O)C1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)(C)OC(=O)N1CCC(N)(C(=O)O)CC1
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CNC1(C(=O)O)CCCNC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Amino-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (Pharmacore, or may be prepared using analogous methodology described for the preparation of 4-Amino-1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid in J. Org. Chem. 1996, 61, 7650-7651, 0.221 g, 0.906 mmol) and molecular sieves 4 Å (ca. 200 mg) were added to a rapidly stirred suspension of 4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazoline-6-carbaldehyde (0.20 g, 0.604 mmol) in a mixture of 5% v/v acetic acid in dichloromethane (2 ml). Sodium triacetoxyborohydride (0.192 g, 0.906 mmol) was added over a period of 3 hours. The reaction mixture was concentrated, dissolved in dichloromethane (1 ml) and treated with trifluoroacetic acid (1 ml). The reaction mixture was stirred for 1 hour at room temperature, concentrated and purified by preparative LCMS (acidic hydrophilic system) to afford the intermediate 3-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)amino]piperidine-3-carboxylic acid as a white foam; Mass Spectrum: (M+H)+ 560. The foam was dissolved in aqueous formaldehyde (1 ml) and acetic acid (0.1 ml) was added followed by sodium cyanoborohydride (100 mg) at 0° C. The reaction mixture was purified directly by preparative LCMS (acidic system) to give 3-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]-1-methylpiperidine-3-carboxylic acid (0.03 g, 10.2%) as a white foam; Mass Spectrum: (M+H)+ 488.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:19]([C:21]3[O:22][C:23]4[C:28]([C:29](=[O:37])[C:30]=3[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH3:20])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17]C)[CH:12]=3)[C:3]=12>ClCCl.B(Br)(Br)Br>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:19]([C:21]3[O:22][C:23]4[C:28]([C:29](=[O:37])[C:30]=3[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH3:20])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=3)[C:3]=12
Reactant: COc1cccc(-c2nn(C(C)c3oc4ccccc4c(=O)c3-c3ccccc3)c3ncnc(N)c23)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(c1oc2ccccc2c(=O)c1-c1ccccc1)n1nc(-c2cccc(O)c2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 55.6 %

Procedure:
To a solution of example 41 (0.130 g, 0.265 mmoles) in dichloromethane (26 ml), BBr3 (1M in dichloromethane, 2.6 ml) was added at 0° C. and the reaction mixture was warmed to RT and then stirred for 12 h. The reaction mixture was quenched with 1.5N HCl solution and extracted with dichloromethane. The organic layer was dried over sodium sulphate and concentrated under reduced pressure to afford the title compound as light yellow solid (0.070 g, 56% yield). MP: 212-216° C. 1H-NMR (δ ppm, DMSO-D6, 400 MHz): δ 9.78(s,1H), 8.24(d, J=7.5 Hz, 1H), 8.05(d, J=7.9 Hz, 1H), 7.85(t, J=8.4 Hz, 1H), 7.65 (d, J=8.6 Hz, 1H), 7.53(t, J=7.7 Hz, 1H), 7.36-7.02 (m, 9H), 6.90(d, J=8.2Hz, 1H), 6.03(q, J=6.9Hz, 1H), 1.91(d, J=7.3 Hz, 3H). Mass: 476.17(M+1).
Reaction SMILES: [C:1]1([N:7]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:8][C@H:9]([NH:14][C:15]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([NH:32][CH3:33])[N:27]=2)=[CH:20]3)=[O:16])[C:10]([NH:12][NH2:13])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:40](Cl)(Cl)=[O:41].C1(C)C=CC=CC=1>C(Cl)Cl>[C:34]1([N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][C@H:9]([NH:14][C:15]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([NH:32][CH3:33])[N:27]=2)=[CH:20]3)=[O:16])[C:10]2[O:11][C:40](=[O:41])[NH:13][N:12]=2)[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: O=C(Cl)Cl
Reactant: CNc1nccc(-c2cc3cc(C(=O)N[C@@H](CN(c4ccccc4)c4ccccc4)C(=O)NN)ccc3[nH]2)n1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CNc1nccc(-c2cc3cc(C(=O)N[C@@H](CN(c4ccccc4)c4ccccc4)c4n[nH]c(=O)o4)ccc3[nH]2)n1

Procedure:
200 mg (0.384 mmol) of N—((S)-2-diphenylamino-1-hydrazinocarbonylethyl)-2-(2-methylaminopyrimidin-4-yl)-1H-indole-5-carboxamide (27) were suspended in 20 ml of methylene chloride, and a 20% solution of phosgene in toluene (0.398 mmol) was added dropwise at 0° C. and while stirring. The mixture was stirred at room temperature for a further 15 h and the solvent was evaporated. The oxadiazolone 28 was then isolated by flash chromatography on silica gel (DCM:MeOH=9:1). Yield: 160 mg (76%)
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([NH2:18])=[O:17].[NH2:19][C:20]1[C:21]([CH3:27])=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=1.C(O)(=O)C.C([O-])(O)=O.[Na+]>CN(C=O)C.O>[OH:26][C:22]1[C:21]([CH3:27])=[C:20]([CH:25]=[CH:24][CH:23]=1)[NH:19][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([NH2:18])=[O:17]
Reactant: COc1cc2ncc(C(N)=O)c(Cl)c2cc1OC
Reactant: Cc1c(N)cccc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COc1cc2ncc(C(N)=O)c(Nc3cccc(O)c3C)c2cc1OC
Temperature: 100 °C

Procedure:
A mixture of 4-chloro-6,7-dimethoxy-3-quinolinecarboxamide (0.046 g, 0.17 mmol), 3-amino-2-methylphenol (0.032 g, 0.26 mmol) and acetic acid (40 μl) in DMF (0.8 ml) was heated at 100° C. for 1.5 h. After cooling, the mixture was diluted with water (15 ml) and made alkaline with saturated NaHCO3. The title compound, which slowly precipitated was filtered off and dried to give 34 mg (55%).
Reaction SMILES: [CH2:1]([NH:8][C:9]1([C:14]#[N:15])[CH2:13][CH2:12][CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[K+]>CCOCC>[NH2:15][CH2:14][C:9]1([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: N#CC1(NCc2ccccc2)CCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: NCC1(NCc2ccccc2)CCCC1
Reaction time: 1 h
Yield: 98.9 %

Procedure:
14.1 g of 1-(benzylamino)cyclopentanecarbonitrile are solubilized in 300 mL of Et2O. The mixture is cooled and then 10.68 g of LiAlH4 are added in fractions, while maintaining the temperature in T° C. to −5° C.-0° C. Stirring is applied and under nitrogen at 0° C. for 1 h. After return to RT, 11 mL H2O and then 11 mL of 15% KOH and finally 33 mL of H2O are added dropwise while maintaining the temperature less than 15° C. The precipitate is filtered on Celite, and then the organic phase is dried on magnesium sulfate. The solvents are dry evaporated. 14.23 g (yield=99%) of 1-(aminomethyl)-N-benzylcyclopentanamine are obtained as a yellowish oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[N:7]([CH3:19])[C:8]1[S:12][C:11]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[N:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:21]N1C(=O)CCC1=O>C(#N)C>[C:1]([O:5][C:6](=[O:20])[N:7]([C:8]1[S:12][C:11]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[N:10][C:9]=1[Cl:21])[CH3:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C(=O)OC(C)(C)C)c1cnc(-c2cccnc2)s1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: CN(C(=O)OC(C)(C)C)c1sc(-c2cccnc2)nc1Cl
Temperature: 45 °C
Reaction time: 16 h
Yield: 62.6 %

Procedure:
To a solution of methyl-(2-pyridin-3-yl-thiazol-5-yl)-carbamic acid tert-butyl ester (3.0 g, 10.29 mmol) in acetonitrile (60 mL) was added N-chlorosuccinimide (2.75 g, 20.58 mmol) in one portion and the reaction mixture was stirred at 45° C. for 16 h. The reaction mixture was concentrated and the crude product was purified by silica gel chromatography (0 to 100% ethyl acetate/hexanes) to give the desired product as a yellow solid (2.10 g, 62%): mp 119-122° C.; IR (KBr) 1718 cm−1; 1H NMR (300 MHz, CDCl3) δ 9.08 (s, 1H), 8.67 (d, J=4.2 Hz, 1H), 8.22-8.16 (m, 1H), 7.39 (dd, J=7.9, 5.0 Hz, 1H), 3.26 (s, 3H), 1.46 (s, 9H); ESIMS m/z 326 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](N(OC)C)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C[Mg]Br.[CH2:17](OCC)[CH3:18]>C1COCC1.Cl>[Cl:1][C:2]1[C:7]([C:8](=[O:9])[CH2:17][CH3:18])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CCOCC
Reactant: CON(C)C(=O)c1cccnc1Cl
Agent: C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: CCC(=O)c1cccnc1Cl
Temperature: 50 °C
Reaction time: 1 h

Procedure:
2-Chloro-N-methoxy-N-methylpyridine-3-carboxamide (1.0 g) was dissolved in THF (30 ml), 3 Methylmagnesium bromide-diethyl ether solution (2.0 ml) was added dropwise at room temperature, and the mixture was stirred at 50° C. for 1 hr. The reaction mixture was diluted with 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (630 mg).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[C:10]([CH3:16])([CH3:15])[CH2:9]1)C1C=CC=CC=1.[H][H]>[Pd].CO>[CH3:15][C:10]1([CH3:16])[C:11](=[O:14])[CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: CC1(C)CN(Cc2ccccc2)CCC1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC1(C)CNCCC1=O
Yield: 98.6 %

Procedure:
1-Benzyl-3,3-dimethyl-4-piperidone 275 g (1.26 mol) prepared as per procedure described in U.S. Pat. No. 5,846,980, was dissolved in 1.0 L. methanol. The solution was transferred to a Parr reactor after adding 10% palladium on carbon (25 g). The reaction mixture was stirred under 300 psi hydrogen pressure at 60° C. until chromatography showed complete conversion. The reaction mixture was filtered and the residue washed with methanol (200 ml). The filtrate was concentrated to dryness to afford 3,3-dimethyl-4-piperidone (158 g) which was used as such for the preparation of either 4-benzyloxycarbonylamino-3,3-dimethylpiperidine or 4-t-butyloxycarbonylamino-3,3-dimethylpiperidine.