Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.[H-].[Na+].I[CH3:15]>O1CCCC1.[Cl-].[NH4+].O>[Cl:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]2[CH:10]=[CH:9][N:8]([CH3:15])[C:6]=2[N:7]=1
Reactant: CI
Reactant: Clc1nc(Cl)c2cc[nH]c2n1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1ccc2c(Cl)nc(Cl)nc21
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 73.9 %

Procedure:
A solution of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (3.00 g, 16.0 mmol) in anhydrous tetrahydrofuran (45 mL) was cooled to 0° C. and treated with a 60% dispersion of sodium hydride in mineral oil (0.83 g, 20.8 mmol). The reaction was stirred at 0° C. for 20-30 min. The reaction was then treated with iodomethane (3.65 g, 1.6 mL, 25.7 mmol), and the reaction stirred at room temperature overnight. The reaction was diluted with a saturated aqueous ammonium chloride solution (50 mL) and water (50 mL) and was extracted with a 10% methanol in methylene chloride solution (4×50 mL). The combined organic layers were dried over magnesium sulfate, filtered and rinsed with methylene chloride, and concentrated in vacuo onto Celite®. Flash chromatography (80 g silica gel column, 0-15% ethyl acetate/hexanes) afforded 2,4-dichloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidine as a light yellow solid (2.39 g, 74.1%). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.81 (s, 3H) 6.70 (d, J=3.51 Hz, 1H) 7.76 (d, J=3.51 Hz, 1H). LC-MS calcd. for C7H6Cl2N3 [(M+H)+] 202, obsd. 202.0.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]1[CH:21]=[C:22]([C:26]2[O:30][CH:29]=[N:28][C:27]=2[C:31](O)=[O:32])[CH:23]=[CH:24][CH:25]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:31]([C:27]3[N:28]=[CH:29][O:30][C:26]=3[C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([F:19])[CH:21]=3)=[O:32])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)c1ncoc1-c1cccc(F)c1
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3ncoc3-c3cccc(F)c3)cn2)o1

Procedure:
Following general procedure B followed by T, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-(3-fluoro-phenyl)-oxazole-4-carboxylic acid. LC-MS-conditions 01b: tR=0.91 min; [M+H]+=395.12.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][CH2:10][CH:11]([C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[N:23]([S:27]([CH3:30])(=[O:29])=[O:28])[CH:22]=[C:21]2[S:31]([CH3:34])(=[O:33])=[O:32])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)C)(C)(C)C.C(OC(=O)N(CCC(C1C=C2C(=CC=1)N(S(C)(=O)=O)C=C2)C1C=CC=CC=1)C)(C)(C)C>>[CH3:30][S:27]([N:23]1[C:24]2[C:20](=[CH:19][C:18]([CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:10][CH2:9][NH:7][CH3:6])=[CH:26][CH:25]=2)[C:21]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:22]1)(=[O:28])=[O:29]
Reactant: CN(CCC(c1ccccc1)c1ccc2c(c1)c(S(C)(=O)=O)cn2S(C)(=O)=O)C(=O)OC(C)(C)C
Agent: CN(CCC(c1ccccc1)c1ccc2c(ccn2S(C)(=O)=O)c1)C(=O)OC(C)(C)C
Product: CNCCC(c1ccccc1)c1ccc2c(c1)c(S(C)(=O)=O)cn2S(C)(=O)=O

Procedure:
[3-(1,3-Bis-methanesulfonyl-1H-indol-5-yl)-3-phenyl-propyl]-methyl-carbamic acid tert-butyl ester LXXVII was deprotected following the same procedure described above for [3-(1-Methanesulfonyl-1H-indol-5-yl)-3-phenyl-propyl]-methyl-carbamic acid tert-butyl ester LXXVI to afford [3-(1,3-Bis-methanesulfonyl-1H-indol-5-yl)-3-phenyl-propyl]-methyl-amine LXXIX as a colorless oil in quantitative yield.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C:9]1[CH:10]=[C:11]([S:15][C:16]2[C:24]3[C:23](=[O:25])[N:22]([CH3:26])[C:21](=[O:27])[N:20]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:19]=3[S:18][C:17]=2[CH2:32][C:33]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:36]=[CH:35][CH:34]=2)[CH:12]=[CH:13][CH:14]=1.C(N(CC)CC)C>ClCCl>[C:1]([NH:8][C:9]1[CH:10]=[C:11]([S:15][C:16]2[C:24]3[C:23](=[O:25])[N:22]([CH3:26])[C:21](=[O:27])[N:20]([CH2:28][CH:29]([CH3:30])[CH3:31])[C:19]=3[S:18][C:17]=2[CH2:32][C:33]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:36]=[CH:35][CH:34]=2)[CH:12]=[CH:13][CH:14]=1)(=[O:3])[CH3:2]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(Sc3cccc(N)c3)c(Cc3cccc4ccccc34)sc21
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cccc(Sc2c(Cc3cccc4ccccc34)sc3c2c(=O)n(C)c(=O)n3CC(C)C)c1
Reaction time: 1 h

Procedure:
Acetic anhydride (0.034 ml) was added to a solution of 5-[(3-aminophenyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl) thieno[2,3-d]pyrimidine-2,4-(1H, 3H)-dione (60 mg) and triethylamine (0.067 ml ) in anhydrous dichloromethane (2 ml) at room temperature. After 1 hour, work-up and purification as in Example 32 gave the title compound (15 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:18])=[CH:4][C:5]2[C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:8][S:7][C:6]=2[C:16]=1[Cl:17].Br[CH2:20][C:21]([O:23]CC)=[O:22].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[C:3]([O:18][CH2:20][C:21]([OH:23])=[O:22])=[CH:4][C:5]2[C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:8][S:7][C:6]=2[C:16]=1[Cl:17]
Reactant: CCOC(=O)CBr
Reactant: Oc1cc2c(-c3ccccc3)csc2c(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)COc1cc2c(-c3ccccc3)csc2c(Cl)c1Cl
Reaction time: 0.5 h
Yield: 80.5 %

Procedure:
A mixture of 2.7 g of 6,7-dichloro-5-hydroxy-3-phenylbenzo[b]thiophene, 1.6 g of ethyl bromoacetate, 1.3 g of potassium carbonate and 30 ml of dimethylforamide is stirred at 60°-70° for 30 min. The mixture is filtered to remove inorganic salts and the filtrate is concentrated in vacuo to an oily residue. To the residue is added 10 mil of 40% sodium hydroxide and 30 ml of water and the mixture was heated on a steam bath for 30 min. After acidification of the mixture to pH 2, the solid product was extracted into ether, washed and dried. Concentration in vacuo gives 2.6 g of [(6,7-dichloro-3-phenylbenzo[b]thien-5-yl)oxy]acetic acid as crystals which have mp 152°-154° after recrystallization from acetone-hexane.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH:11][C:12]3[CH:17]=[C:16](I)[CH:15]=[CH:14][N:13]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[CH3:19][N:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O)[CH3:21]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COCCOC>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH:11][C:12]3[CH:17]=[C:16]([C:25]4[CH:26]=[CH:27][C:22]([N:20]([CH3:21])[CH3:19])=[CH:23][CH:24]=4)[CH:15]=[CH:14][N:13]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: Ic1ccnc(Nc2ccc3c(c2)OCCO3)c1
Reactant: CN(C)c1ccccc1B(O)O
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: CN(C)c1ccc(-c2ccnc(Nc3ccc4c(c3)OCCO4)c2)cc1
Temperature: 150 °C

Procedure:
Following the same procedure described for Example 401(c), the mixture of (2,3-dihydro-benzo[1,4]dioxin-6-yl)-(4-iodo-pyridin-2-yl)-amine (Example 401(b), 75 mg, 0.2 mmol), tetrakis (triphenylphosphine) palladium (0) (Aldrich Chemical Company) (12 mg, 0.011 mmol), N,N-dimethylaminobenzeneboronic acid (Aldrich Chemical Company) (41 mg, 0.25 mmol) and 1,2-dimethoxyethane (2 mL) gave, after heated in the Microwave Smith Synthesizer at 150° C. for 10 min and purification on a Biotage 40S column (1.5:1 hexane:EtOAc), the title compound as a tan solid. MS (ESI, pos. ion) m/z: 348 (M+1). Mp: 154.0-155.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[CH3:27][C:28]1([C:33]2[CH:40]=[CH:39][C:36]([CH2:37][NH2:38])=[CH:35][CH:34]=2)[O:32][CH2:31][CH2:30][O:29]1>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:38][CH2:37][C:36]1[CH:35]=[CH:34][C:33]([C:28]2([CH3:27])[O:29][CH2:30][CH2:31][O:32]2)=[CH:40][CH:39]=1
Reactant: CC1(c2ccc(CN)cc2)OCCO1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Product: CC1(c2ccc(CNc3c(Cl)ccc4c3CCN(C(=O)C(F)(F)F)CC4)cc2)OCCO1
Yield: 68 %

Procedure:
Use a method similar to the General Procedure 1-3 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (200 mg, 0.47 mmol) with 4-(2-methyl-[1,3]dioxolan-2-yl)-benzylamine (prepared by following the procedure described in J. Med. Chem. 1978, 21, 507) (182 mg, 0.94 mmol). Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0, 19:1 and 9:1) to obtain the desired intermediate as an oil (150 mg, 68%). GC-MS m/z: 468 (M+).
Reaction SMILES: S1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][N:4]([C:12]2[CH:21]=[C:20]([CH:22]([OH:36])[CH:23]3[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]3)[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([CH3:37])[CH:18]=3)[N:13]=2)[CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=O)C=1.[S:49]([O-:53])([O-])(=[O:51])=S.[Na+].[Na+]>ClCCl>[O:51]=[S:49]1(=[O:53])[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:5][N:4]([C:12]2[CH:21]=[C:20]([CH:22]([OH:36])[CH:23]3[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])[CH2:27][CH2:28]3)[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([CH3:37])[CH:18]=3)[N:13]=2)[CH2:3][CH2:2]1
Reactant: O=S([O-])([O-])=S
Reactant: Cc1ccc2nc(N3CCSc4ccccc4C3)cc(C(O)C3CCN(C(=O)OC(C)(C)C)CC3)c2c1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(C(O)C3CCN(C(=O)OC(C)(C)C)CC3)c2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of tert-butyl 4-{[2-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl](hydroxy)methyl}piperidine-1-carboxylate (519 mg, 1.0 mmol) in dichloromethane (10 mL) was added 3-chloroperbenzoic acid (537 mg, 70% purity, 2.2 mmol). After being stirred at room temperature for 4 hours, to the above mixture was added a saturated aqueous solution of sodium thiosulfate (3 mL). The separated organic layer was washed with a saturated aqueous solution of sodium carbonate (5 mL) and brine (5 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with 20-50% ethyl acetate in petroleum ether) to afford 300 mg of the desired product. MS (ESI+) [(M+H)+] 552.
Reaction SMILES: [CH:1]1([C@@H:7]([NH:9][C:10]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[C:14]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:13]=2[CH2:28][N:29]2[CH2:34][CH2:33][N:32]([C:35](=[N:38][S:39]([CH3:42])(=[O:41])=[O:40])SC)[CH2:31][CH2:30]2)=[O:11])[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:43]1[CH2:47][CH2:46][CH2:45][CH2:44]1>>[CH:1]1([C@@H:7]([NH:9][C:10]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[C:14]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:13]=2[CH2:28][N:29]2[CH2:30][CH2:31][N:32]([C:35](=[N:38][S:39]([CH3:42])(=[O:41])=[O:40])[N:43]3[CH2:47][CH2:46][CH2:45][CH2:44]3)[CH2:33][CH2:34]2)=[O:11])[CH3:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CSC(=NS(C)(=O)=O)N1CCN(Cc2c(-c3ccccc3)nc3ccccc3c2C(=O)N[C@@H](C)C2CCCCC2)CC1
Reactant: C1CCNC1
Product: C[C@H](NC(=O)c1c(CN2CCN(C(=NS(C)(=O)=O)N3CCCC3)CC2)c(-c2ccccc2)nc2ccccc12)C1CCCCC1
Yield: 65 %

Procedure:
0.46 g (0.76 mmol) of crude 3-[4-(1-methanesulfonylimino-1-methylsulfanyl-methyl)-piperazin-1-ylmethyl]-2-phenyl-quinoline-4-carboxylic acid ((S)-1-cyclohexyl-ethyl)-amide (compound of Description 16) and 5 ml of pyrrolidine were heated to reflux for 5 h. The excess of pyrrolidine was removed in vacuo and the residue was purified by flash chromatography on silicagel (CH2Cl2/MeOH: 97/3). After concentration of the desired fractions, the residue was crystallised in di-isopropyl ether to afford 0.310 g (yield 65%) of the title compound as white crystals.
Reaction SMILES: C(OC(=O)[CH:5]([CH:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)[C:6]#[N:7])C.[Na].C([O:23][N:24]=O)CC(C)C>C(O)C>[N:10]12[CH2:15][CH2:14][CH:13]([CH2:12][CH2:11]1)[CH:8]([C:5](=[N:24][OH:23])[C:6]#[N:7])[CH2:9]2
Reactant: CCOC(=O)C(C#N)C1CN2CCC1CC2
Reactant: CC(C)CCON=O
Agent: [Na]
Solvent: CCO
Product: N#CC(=NO)C1CN2CCC1CC2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Ethyl(1-azabicyclo[2.2.2]octan-3-yl)cyanoacetate (10 g, 45 mmol) was added to a solution of sodium (1.04 g, 45 mmol) in absolute ethanol (60 ml). The mixture was stirred for 15 min. at room temperature and isoamylnitrite (7.9 ml, 60 mmol) was added. The reaction mixture was stirred for 18 h at 60° C. Evaporation of the reaction mixture gave crude title compound, which was used without further purification.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:23])([CH3:22])[C@@H:11]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:12]=[O:13])(=[O:7])=[O:6].CC(C)=[O:26]>>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:23])([CH3:22])[C@@H:11]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:12]([OH:26])=[O:13])(=[O:7])=[O:6]
Reactant: CC(C)=O
Reactant: CC(C)(COS(=O)(=O)CCCCl)[C@H](C=O)OCc1ccccc1
Product: CC(C)(COS(=O)(=O)CCCCl)[C@@H](OCc1ccccc1)C(=O)O
Yield: 96 %

Procedure:
Following the general procedure of the oxidation of aldehydes to carboxylic acids of Description 13, (3R)-2,2-dimethyl-4-oxo-3-(phenylmethoxy)butyl (3-chloropropyl)sulfonate (11b) (10.0 g, 27.5 mmol) dissolved in 200 mL of acetone was reacted with 13.7 mL of Jones-reagent (2.0 M in water). After work-up, 10.0 g (96% yield) of the title compound (11) was obtained as a colorless oil. 1H NMR (400 MHz, CDCl3): δ=1.11 (s, 3H), 1.13 (s, 3H), 2.27-2.34 (m, 2H), 3.26-3.29 (m, 2H), 3.65-3.68 (m, 2H), 3.91 (s, 1H), 4.04 (d, J=9.6 Hz, 1H), 4.21 (d, J=9.6 Hz, 1H), 4.50 (d, J=10.8 Hz, 1H), 4.69 (d, J=10.8 Hz, 1H), 7.33-7.38 (m, 5H) ppm. 1H NMR (400 MHz, DMSO-d6): δ=0.97 (s, 3H), 1.01 (s, 3H), 2.07-2.16 (m, 2H), 3.41-3.46 (m, 2H), 3.69-3.73 (m, 2H), 3.76 (s, 1H), 3.99 (d, J=9.6 Hz, 1H), 4.14 (d, J=9.2 Hz, 1H), 4.35 (d, J=11.2 Hz, 1H), 4.53 (d, J=11.2 Hz, 1H), 7.27-7.37 (m, 5H), 12.05 (v. br., s, 1H) ppm. MS (ESI) m/z 379.12 (M+H)+, 401.02 (M+Na)+, 376.9 (M−H)−. The analytical data was consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:18](N(OC)C)=[O:19])[N:6]2[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=1.[CH3:24][Mg]Br>O1CCCC1>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:18](=[O:19])[CH3:24])[N:6]2[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=1
Reactant: CON(C)C(=O)c1cc2c(Cl)cccc2n1-c1cccc(F)c1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(=O)c1cc2c(Cl)cccc2n1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
To a mixture of 4-chloro-1-(3-fluorophenyl)-N-methoxy-N-methyl-1H-indole-2-carboxamide (0.44 g, 1.3 mmol) in tetrahydrofuran (10 mL) was added 1.4 M methylmagnesium bromide in tetrahydrofuran (4.7 mL, 6.6 mmol) dropwise. The reaction was stirred at room temperature overnight, then quenched with aqueous saturated NH4Cl solution and extracted with EtOAc. The extracts were dried over MgSO4, concentrated and purified on silica gel (eluting with 0-10% EtOAc in hexane) to give the desired product (0.26 g, 68%). LCMS calculated for C16H12ClFNO(M+H)+: m/z=288.1. Found: 288.0.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH2:14].[CH2:15]([N:17]=[C:18]=[S:19])[CH3:16]>CCOCC>[CH2:15]([NH:17][C:18]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])=[S:19])[CH3:16]
Reactant: CCN=C=S
Reactant: NCCCCCCCCCCCCN
Solvent: CCOCC
Product: CCNC(=S)NCCCCCCCCCCCCN

Procedure:
22 grams (.110 mole) of 1,12-diaminododecane in 300 cc ether was reacted via dropwise addition with 5 grams (0.058 mole) ethyl isothiocyanate. The precipitate was filtered, washed with ether and recrystallized from alcohol yielding 6 grams of the thiourea derivative.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:32][OH:33])[CH2:14][CH2:13][CH2:12][N:11]3[C:15]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5[O:28][C:27]([CH3:29])=[N:26][CH:25]=5)=[C:20]([O:30][CH3:31])[CH:19]=4)=[N:16][N:17]=[C:10]23)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:34][C:35]1[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][CH:36]=1.O>N1C=CC=CC=1>[CH3:34][C:35]1[CH:40]=[CH:39][C:38]([S:41]([O:33][CH2:32][C:9]2([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[CH2:14][CH2:13][CH2:12][N:11]3[C:15]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5[O:28][C:27]([CH3:29])=[N:26][CH:25]=5)=[C:20]([O:30][CH3:31])[CH:19]=4)=[N:16][N:17]=[C:10]23)(=[O:43])=[O:42])=[CH:37][CH:36]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1cc(-c2nnc3n2CCCC3(CO)c2ccc(Cl)c(Cl)c2)ccc1-c1cnc(C)o1
Solvent: c1ccncc1
Solvent: O
Product: COc1cc(-c2nnc3n2CCCC3(COS(=O)(=O)c2ccc(C)cc2)c2ccc(Cl)c(Cl)c2)ccc1-c1cnc(C)o1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of {8-(3,4-dichlorophenyl)-3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridin-8-yl}methanol (178 mg) in pyridine (3 mL) was added 4-methylbenzenesulfonyl chloride under ice-cooling, and the mixture was stirred at room temperature for 4 hr. 4-Methylbenzenesulfonyl chloride (84 mg) was further added, and the mixture was stirred at room temperature for 2 hr, and at 50° C. overnight. Water was added to the reaction mixture, and the precipitated solid was collected by filtration. The solid was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (163 mg).
Reaction SMILES: C(N(C(C)C)CC)(C)C.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.[C:24]([C:26]1[CH:27]=[C:28]([C:32]([OH:34])=O)[NH:29][C:30]=1[CH3:31])#[N:25].Cl.[NH2:36][CH:37]1[CH2:42][CH2:41][N:40]([C:43]2[CH:44]=[C:45]([CH:49]=[C:50]([Cl:52])[N:51]=2)[C:46]([NH2:48])=[O:47])[CH2:39][CH2:38]1>CN(C=O)C>[Cl:52][C:50]1[CH:49]=[C:45]([CH:44]=[C:43]([N:40]2[CH2:41][CH2:42][CH:37]([NH:36][C:32]([C:28]3[NH:29][C:30]([CH3:31])=[C:26]([C:24]#[N:25])[CH:27]=3)=[O:34])[CH2:38][CH2:39]2)[N:51]=1)[C:46]([NH2:48])=[O:47]
Reactant: Cc1[nH]c(C(=O)O)cc1C#N
Reactant: NC(=O)c1cc(Cl)nc(N2CCC(N)CC2)c1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1[nH]c(C(=O)NC2CCN(c3cc(C(N)=O)cc(Cl)n3)CC2)cc1C#N
Reaction time: 8 h
Yield: 7.2 %

Procedure:
Diisopropylethylamine (0.1 ml, 0.56 mmol), EDC (0.09 g, 0.46 mmol) and HOAT (0.064 g, 0.46 mmol) were added to a stirred solution of 4-cyano-5-methyl-1H-pyrrole-2-carboxylic acid (Intermediate 13, 0.07 g, 0.47 mmol) in DMF (1.5 ml) at room temperature. The resultant solution was stirred for 30 mins and a solution of 2-(4-aminopiperidin-1-yl)-6-chloroisonicotinamide hydrochloride (Intermediate 70, 0.16 g, 0.56 mmol) in 1 ml of DMF was added. The reaction was stirred overnight, then concentrated under vacuum and the residue was partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc (×2) and the combined organic extracts were washed with 1 N HCl, water and brine, dried over MgSO4 and concentrated under vacuum. The residue was purified by reverse phase chromatography to give the desired product as a white solid (13 mg).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH3:11][C:12]1[C:16]([CH2:17][OH:18])=[C:15]([CH3:19])[N:14]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[N:13]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:11][C:12]1[C:16]([CH:17]=[O:18])=[C:15]([CH3:19])[N:14]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[N:13]=1
Reactant: Cc1nn(-c2ccccn2)c(C)c1CO
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: Cc1nn(-c2ccccn2)c(C)c1C=O
Temperature: -78 °C
Reaction time: 18 h

Procedure:
Dissolve dimethylsulfoxide (0.324 mL, 4.56 mmol) in DCM (10 mL) and cool the solution to −78° C. Add oxalyl chloride (0.239 mL, 2.74 mmol) to the mixture dropwise and stir at −78° C. for 20 min. Add (3,5-dimethyl-1-pyridin-2-yl-1H-pyrazol-4-yl)-methanol (0.369 g, 1.82 mmol) in DCM (10 mL) and stir the mixture at −78° C. for one hr. Add triethylamine (1.27 mL, 9.12 mmol) to the mixture and warm to room temperature then stir for 18 hr. Add saturated aqueous sodium bicarbonate and extract the aqueous 3 times with DCM, dry organic solution then filter and concentrate. Purify using silica gel chromatography, eluting with 20:80 hexanes:ethyl acetate to give the title preparation as a yellow solid (0.358 g, 97%). MS (APCI): m/z=202 [M+H]+.
Reaction SMILES: [C:1]([C:9]1[N:18]=[CH:17][CH:16]=[CH:15][C:10]=1[C:11]([O:13]C)=[O:12])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[OH-].[NH4+].S([O-])([O-])(=O)=O.[Cu+2].[Zn]>[CH2:1]([C:9]1[N:18]=[CH:17][CH:16]=[CH:15][C:10]=1[C:11]([OH:13])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cccnc1C(=O)c1ccccc1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Product: O=C(O)c1cccnc1Cc1ccccc1
Yield: 32.8 %

Procedure:
Methyl 2-Benzoylnicotinate (2.41 g., 10 mmoles) was dissolved in 250 ml ammonium hydroxide. To this solution was carefully added a catalytic amount of copper (II) sulfate (approx. 100 mg) and zinc powder (7.0 g., 100 mmoles). The mixture was refluxed for 6 days and allowed to cool. The mixture was filtered (pad of celite), acidified to pH 5 with 1N HCl, exhaustively extracted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered, concentrated under vacuum, and purified by column chromatography to give 0.70 grams (33% yield) of 2-benzylnicotinic acid as a white solid. Characteristic analytical data are as follows: mp 180°-182.5° C.; TLC in 20:1.8:0.2 (EtOAc/MeOH/HOAc); 1H NMR (DMSO-d6, 300 MHz) δ4.50 (s, 2H), 7.12-7.48 (m, 5H), 8.18 (dd, 1H, J=8.0, 1.6 Hz), 8.63 (dd, 1H, J=4.8, 1.5 Hz); 13C NMR (75 MHz, DMSO-d6) δ167.84, 160.17, 151.55, 139.85, 138.38, 128.75, 128.04, 126.37, 125.79, 121.57, 41.35, 39.76; mass spectrum (EI) , m/e 213.
Reaction SMILES: [C:1]1([C:7]2[CH2:11][CH:10]([CH2:12][CH2:13][CH:14]=O)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16]1([CH:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH:22]([N:23]1[CH2:28][CH2:27][N:26]([CH2:14][CH2:13][CH2:12][CH:10]2[O:9][N:8]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:11]2)[CH2:25][CH2:24]1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: O=CCCC1CC(c2ccccc2)=NO1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: c1ccc(C2=NOC(CCCN3CCN(C(c4ccccc4)c4ccccc4)CC3)C2)cc1
Yield: 106.8 %

Procedure:
3-(3-Phenyl-4,5-dihydroisoxazol-5-yl)propanal (19.1 mg, 0.087 mmol), 1-(diphenylmethyl)piperazine (20.0 mg, 0.079 mmol), molecular sieve (5 beads) and NaBH(OAc)3 (50.4 mg, 0.237 mmol) were reacted in 3 mL of methylene chloride for about 12 hr. With the following processes the same as in Example 1, 37.1 mg (96.8%) of the target compound was obtained.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][C:9]([NH:18][N:19]=[C:20]2[C:24]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=3)=[N:23][NH:22][C:21]2=[O:35])=[CH:8][CH:7]=1.[CH3:36][NH:37][CH3:38]>>[CH3:34][O:33][C:27]1[CH:26]=[C:25]([C:24]2[C:20](=[N:19][NH:18][C:9]3[CH:10]=[C:11]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:37]([CH3:38])[CH3:36])=[CH:7][CH:8]=3)[C:21](=[O:35])[NH:22][N:23]=2)[CH:30]=[CH:29][C:28]=1[O:31][CH3:32]
Reactant: CNC
Reactant: COc1ccc(C2=NNC(=O)C2=NNc2ccc(OCCCBr)c(-c3ccccc3)c2)cc1OC
Product: COc1ccc(C2=NNC(=O)C2=NNc2ccc(OCCCN(C)C)c(-c3ccccc3)c2)cc1OC
Temperature: 50 °C

Procedure:
5-(3,4-Dimethoxy-phenyl)-4-{[6-(3-dimethylamino-propoxy)-biphenyl-3-yl]-hydrazono}-2,4-dihydro-pyrazol-3-one (compound 121) was prepared by dissolving 4-{[6-(3-bromo-propoxy)-biphenyl-3-yl]-hydrazono}-5-(3,4-dimethoxy-phenyl)-2,4-dihydro-pyrazol-3-one (s) in 1 mL of a dimethylamine solution (2 M in THF) and heating to 50° C. for one hour. The solvent was then evaporated and the residue was purified by silica gel chromatography (eluent: 10% methanol/DCM) to afford 6 mg product (compound 121): HPLC (Rt): 5.490 minutes; m/e: 501.23, MS (ES+): 502.2.