Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[O:36])[C:12]2[CH:17]=[C:16]([CH2:18][C:19]3[C:20](=[O:31])[C:21]([O:29][CH3:30])=[C:22]([O:27][CH3:28])[C:23](=[O:26])[C:24]=3[CH3:25])[CH:15]=[CH:14][C:13]=2[O:32]C(=O)C)=[N:8][CH:9]=1)=[O:3].C(=O)([O-])O.[Na+]>CO.Cl>[OH:3][C:2]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[O:36])[C:12]2[CH:17]=[C:16]([CH2:18][C:19]3[C:20](=[O:31])[C:21]([O:29][CH3:30])=[C:22]([O:27][CH3:28])[C:23](=[O:26])[C:24]=3[CH3:25])[CH:15]=[CH:14][C:13]=2[OH:32])=[N:8][CH:9]=1)=[O:1]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccc(C(=O)O)cn3)c2)=C(C)C1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)Nc3ccc(C(=O)O)cn3)c2)=C(C)C1=O
Yield: 79.7 %

Procedure:
N-(5-Hydroxycarbonylpyridin-2-yl)-5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzamide (0.085 g, 0.172 mmol) was dissolved in methanol (6 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (2 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with a 2N hydrochloric acid solution and the aqueous layer was rendered acidic (pH=3 to 4) and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was recrystallized from ether to obtain the titled compound (0.062 g, 0.137 mmol, 79%).
Reaction SMILES: [CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[NH:5]1)([CH3:3])[CH3:2].[C:10]1([CH2:16][CH2:17][CH2:18][C:19](Cl)=[O:20])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:19](=[O:20])[CH2:18][CH2:17][CH2:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:3])[CH3:2]
Reactant: CC(C)[C@H]1COC(=O)N1
Reactant: O=C(Cl)CCCc1ccccc1
Product: CC(C)[C@H]1COC(=O)N1C(=O)CCCc1ccccc1
Yield: 98.6 %

Procedure:
Following the procedure described in Referential Example 3, but using 4-(S)-isopropyl-2-oxazolidinone (6.88 g) and 4-phenylbutyryl chloride (6.88 g), the desired compound (10.23 g) was obtained as a colorless oil.
Reaction SMILES: [CH2:1]([N:3]1[C:15]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:14]2[C:5]([C:6](N)=[N:7]C3C=CC=CC=32)=[N:4]1)[CH3:2].[CH3:25][C:26]([CH3:42])([CH3:41])[C:27]([NH:29][C:30]1[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:31]=1B(O)O)=[O:28]>>[C:6]([C:5]1[C:14]([C:31]2[CH:32]=[CH:33][C:34]([O:36][CH3:37])=[CH:35][C:30]=2[NH:29][C:27](=[O:28])[C:26]([CH3:42])([CH3:41])[CH3:25])=[C:15]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:3]([CH2:1][CH3:2])[N:4]=1)#[N:7]
Reactant: COc1ccc(B(O)O)c(NC(=O)C(C)(C)C)c1
Reactant: CCn1nc2c(N)nc3ccccc3c2c1CCc1ccccc1
Product: CCn1nc(C#N)c(-c2ccc(OC)cc2NC(=O)C(C)(C)C)c1CCc1ccccc1

Procedure:
Using a modification on the method described in Part B of Example 573, 4-bromo-1-ethyl-5-(2-phenylethyl)-1H-pyrazole-3-carbonitrile (prepared as described in Part E of Example 41, 10.3 g, 33.9 mmol) was coupled with 2-[(2,2-dimethylpropanoyl)amino]-4-methoxyphenylboronic acid (prepared as described in Part A of Example 573, 15.3 g, 60.9 mmol). The reaction was worked up and purified as described in Part B of Example 573 to yield 1.7 g of N-{2-[3-cyano-1-ethyl-5-(2-phenylethyl)-1H-pyrazol4-yl]-5-methoxyphenyl}-2,2-dimethylpropanamide as a colorless liquid, MS (ESI) m/z 431.17 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:13]=1[C:14]([OH:16])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:23][NH:24][O:25][CH3:26].Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>[Cl-]>[CH3:23][N:24]([O:25][CH3:26])[C:14](=[O:16])[C:13]1[CH:17]=[C:18]([OH:21])[CH:19]=[CH:20][C:12]=1[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: O=C(Nc1ccc(O)cc1C(=O)O)OCc1ccccc1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1cc(O)ccc1NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Benzyloxycarbonylamino-5-hydroxybenzoic acid (6.0 g) and N,O-dimethylhydroxylamine hydrochloride (2.5 g) were dissolved in methylenb chloride (80 ml). To the solution were added 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (4.6 g) and triethylamine (5 ml). The mixture was stirred for 2 hours at room temperature. The reaction mixture was concentrated under reduced pressure. To the concentrate was added water, which was subjected to extraction with ethyl acetate (200 ml). The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by means of a silica gel column chromatography to give N-methyl-N-methyloxy-2-benzyloxycarbonylamino-5-hydroxybenzamide as a yellow oily product (5.0 g).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)(=[O:21])=[O:20])[CH:14]=1.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([NH:34][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)(=[O:21])=[O:20])[CH:14]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: NCc1ccccc1
Reactant: O=S(=O)(c1cccc(CCCCOCCCCCCBr)c1)C1CCCC1
Product: O=S(=O)(c1cccc(CCCCOCCCCCCNCc2ccccc2)c1)C1CCCC1

Procedure:
1-{4-[(6-Bromohexyl)oxy]butyl}-3-(cyclopentylsulfonyl)benzene (Example 11ii) (50 mg) was dissolved in benzylamine (0.5 ml), and heated in a microwave oven at 150° for 10 min. Excess benzylamine was removed in vacuo and the residue purified on a silica SPE bond elut cartridge, eluting with EtOAc-cyclohexane mixtures, to give the title compound, (40 mg) LCMS RT=2.74 min
Reaction SMILES: [OH:1][CH:2]1[CH:6]([OH:7])[CH:5]([N:8]2[CH:16]=[N:15][C:14]3[C:13](=[O:17])[NH:12][C:11]([NH:18]C(=O)C(C)C)=[N:10][C:9]2=3)[O:4][CH:3]1[CH:24]=[CH:25][P:26](=[O:29])([OH:28])[OH:27]>[NH4+].[OH-]>[NH2:18][C:11]1[NH:12][C:13](=[O:17])[C:14]2[N:15]=[CH:16][N:8]([CH:5]3[O:4][CH:3]([CH:24]=[CH:25][P:26](=[O:27])([OH:29])[OH:28])[CH:2]([OH:1])[CH:6]3[OH:7])[C:9]=2[N:10]=1
Reactant: CC(C)C(=O)Nc1nc2c(ncn2C2OC(C=CP(=O)(O)O)C(O)C2O)c(=O)[nH]1
Agent: [NH4+]
Agent: [OH-]
Product: Nc1nc2c(ncn2C2OC(C=CP(=O)(O)O)C(O)C2O)c(=O)[nH]1
Yield: 53.8 %

Procedure:
Compound 18.8 (180 mg, 54% yield) was synthesized from compound 18.5 (400 mg, 0.932 mmol) by treating 18.5 with concentrated NH4OH (10 ml) at 45° C. for 30 min. 1H NMR (D2O, 300 MHz) 7.98 (s, 1H), 6.41 (m, 1H), 5.95 (m, 1H), 5.75 (d, J=5.4 Hz, 1H), 4.63 (m, 1H), 4.49 (m, 1H), 4.19 (t, J=4.5 Hz, 1H), 31P NMR (D2O, 121.4 MHz) 9.7; MS (ESI) m/z 360 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]=[C:9](Cl)[N:10]=[C:11]([N:12]3[CH2:17][CH2:16][S:15](=[O:18])[CH2:14][CH2:13]3)[C:6]=2[N:5]=[CH:4][N:3]=1.[OH:20][CH2:21][CH2:22][NH2:23]>>[NH2:1][C:2]1[C:7]2[N:8]=[C:9]([NH:23][CH2:22][CH2:21][OH:20])[N:10]=[C:11]([N:12]3[CH2:17][CH2:16][S:15](=[O:18])[CH2:14][CH2:13]3)[C:6]=2[N:5]=[CH:4][N:3]=1
Reactant: NCCO
Reactant: Nc1ncnc2c(N3CCS(=O)CC3)nc(Cl)nc12
Product: Nc1ncnc2c(N3CCS(=O)CC3)nc(NCCO)nc12

Procedure:
This compound was prepared analogous to Example 2 from 8-amino-2-chloro-4-(1-oxido-thiomorpholino)-pyrimido[5,4-d]pyrimidine (melting point: 270°-272° C.; decomposition) and 2-hydroxyethyl-amine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[CH:6]2.C([O-])([O-])=O.[K+].[K+].Br[CH2:19][CH:20]([CH3:22])[CH3:21]>CN(C=O)C>[CH2:19]([N:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)[CH:6]=[N:7]1)[CH:20]([CH3:22])[CH3:21]
Reactant: COc1ccc2[nH]ncc2c1
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2c(cnn2CC(C)C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 36.5 %

Procedure:
A solution of 5-methoxy-1H-indazole (5.00 g, 33.7 mmol) in DMF (100 mL) was treated with K2CO3 (5.83 g, 42.2 mmol) and stirred at room temperature for 15 minutes. To this solution was added 1-bromo-2-methylpropane (5.09 g, 37.1 mmol) and the resulting mixture was heated to 110° C. for 18 hours. Another equivalent of 1-bromo-2-methyl-propane was added and the mixture continued to heat for 48 hours more. The mixture was concentrated under reduced pressure and dissolved in dichloromethane. The solution was washed with 1N HCl, filtered, and concentrated under reduced pressure. The residue was chromatographed on Biotage eluting with hexanes/ether (5:1) to afford 2.51 g of orange oil (36% yield).
Reaction SMILES: [CH2:1]([OH:7])[CH2:2]/[CH:3]=[CH:4]\[CH2:5][CH3:6].[H-].[Na+].Cl[C:11]1[C:12]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:13][S:14][N:15]=1.O>O1CCCC1>[CH2:1]([O:7][C:11]1[C:12]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:13][S:14][N:15]=1)[CH2:2]/[CH:3]=[CH:4]\[CH2:5][CH3:6]
Reactant: CC/C=C\CCO
Reactant: Clc1nsnc1-c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC/C=C\CCOc1nsnc1-c1cccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of cis-3-hexen-1-ol (900 mg, 9 mmol) and sodium hydride (310 mg, 9 mmol) in dry tetrahydrofuran was added a solution of 3-(4-chloro-1,2,5-thiadiazol-3yl) pyridine (590 mg, 3 mmol) in dry tetrahydrofuran. The reaction mixture was stirred at room temperature for 1 h. Water was added and the mixture was extracted with ether. The ether phase was dried and evaporated to give the title compound.
Reaction SMILES: [C-:1]#[N:2].[Na+].[F:4][C:5]([S:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Cl)=[CH:11][CH:10]=1)([F:7])[F:6]>O.[Cl-].C([N+](CC)(CC)CC)C>[F:4][C:5]([S:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][C:1]#[N:2])=[CH:11][CH:10]=1)([F:7])[F:6]
Reactant: FC(F)(F)Sc1ccc(CCl)cc1
Reactant: [C-]#N
Agent: CC[N+](CC)(CC)CC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: N#CCc1ccc(SC(F)(F)F)cc1
Temperature: 110 °C
Reaction time: 1 h
Yield: 123.3 %

Procedure:
75 g of sodium cyanide were dissolved in 200 ml of water, and 15 g of tetraethylammonium chloride after 450 g of 4-trifluoromethylmercapto-benzyl chloride were added. The reaction mixture was stirred at 110° C. for 1 hour and then cooled. The cold mixture was diluted with 200 ml of water and then extracted twice with methylene chloride. After drying the organic phase, the solvent was distilled off and the crude product was purified by distillation. 410 g of 4-trifluoromethylmercapto-benzyl cyanide were obtained. Boiling point=95°-97° C./1.5 mm Hg; nD20 =1.5025.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=C(C)C(O)=[CH:14][CH:15]=2)[C:10]([CH2:20][C:21]([N:23]([CH3:25])[CH3:24])=[O:22])([OH:19])[C:9]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[O-2].[O-2].[Mn+4].ClCCl>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:16][C:11]([CH:10]=[O:19])=[CH:14][CH:15]=2)[C:10]([CH2:20][C:21]([N:23]([CH3:24])[CH3:25])=[O:22])([OH:19])[C:9]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(O)ccc2c1C(O)(CC(=O)N(C)C)C(=O)N2Cc1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CN(C)C(=O)CC1(O)C(=O)N(Cc2ccccc2)c2ccc(C=O)cc21
Yield: 198.6 %

Procedure:
Under inert atmosphere, a flask is charged with manganese dioxide (8.7 g, 0.1 mol) and 2-(1-benzyl-3-hydroxy-5-hydroxy-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl)-N,N-dimethyl-acetamide (Example 23) (3.54 g, 0.01 mol). To this, mol sieve (4 A, 2 g) and dichloromethane (100 mL) are added, and the mixture is heated under reflux for six hours. The mixture is then filtered, and evaporation of the solvent leaves 3.5 g of a dark brown foam. This is chromatographed on silica (ethyl acetate) to give 1.8 g (50%) of the title product as pale yellow foam. 1H-NMR (CDCl3, 300 MHz) δ 2.82, 3.13 (AB, 2H, 2J=16.1 Hz, CH2NMe2); 2.95, 2.98 (2 s, 3H each, N(CH3)2); 4.93, 4.94 (AB, 2H, 2J=16 Hz, NCH2Ph); 6.11 (s, 1H, OH); 6.82 (d, 1H, 3J=7.9 Hz, H-7); 7.23-7.38 (m, 5H, Ph); 7.72 (dd, 1H, 4J=1.5 Hz, H-6); 8.00 (d, 1H, H-4); 9.83 (s, 1H, CHO). 13C-NMR (CDCl3, 75 MHz) δ 35.76, 37.70 (N(CH3)2); 38.72 (CH2CONMe2); 44.42 (NCH2Ph); 74.06 (C-3); 109.80 (C-7); 125.38 (C-4); 127.42 (Bn ortho-C); 128.14 (Bn para-C); 129.16 (Bn meta-C); 132.00, 132.31 (C-5, C-9); 133.49 (C-6); 135.04 (Ph ipso-C); 148.24 (C-8); 170.22 (CONMe2); 176.69 (C-2); 190.80 (CHO).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10]([N:12]1[C:16]2([CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH2:15][CH2:14][CH:13]1[C:22]([O:24]CC)=[O:23])=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4].O.[OH-].[Li+].Cl>C1COCC1.O.CO>[CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10]([N:12]1[C:16]2([CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)[CH2:15][CH2:14][CH:13]1[C:22]([OH:24])=[O:23])=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4]
Reactant: CCOC(=O)C1CCC2(CCOCC2)N1C(=O)[C@@H](NC(=O)OC)C(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)N[C@H](C(=O)N1C(C(=O)O)CCC12CCOCC2)C(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 77.4 %

Procedure:
To a solution of ethyl 1-{N-[(methyloxy)carbonyl]-L-valyl}-8-oxa-1-azaspiro[4.5]decane-2-carboxylate (167) (80 mg, 0.2 mmol) in THF/water/methanol (1.0 mL/0.5 mL/0.5 mL) was added lithium hydroxide monohydrate (13 mg, 0.3 mmol) and the reaction stirred at room temperature for 72 h. The reaction was treated with 1N HCl (0.5 mL) and the reaction partitioned between EtOAc and 0.1 N HCl. The organic layer was separated and dried over MgSO4 and concentrated in vacuo to afford the title compound as a white solid (53 mg, 72% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.88 (br. s., 1H) 7.45-7.61 (m, 1H) 4.89-5.03 (m, 1H) 3.70-3.87 (m, 2H) 3.65 (t, J=9.2 Hz, 1H) 3.53 (s, 3H) 3.02 (td, J=12.9, 4.9 Hz, 1H) 2.71-2.90 (m, 1H) 2.22-2.38 (m, 1H) 1.87-2.19 (m, 3H) 1.53-1.73 (m, 1H) 1.32-1.42 (m, 1H) 1.06-1.15 (m, 1H) 0.61-0.98 (m, 8H). LC-MS ESI (M+H)+=342.95.
Reaction SMILES: [C:1](/[C:3](=[CH:9]\OCC)/[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].Cl.[F:14][C:15]([F:26])([F:25])[O:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][NH2:24])=[CH:19][CH:18]=1.CC([O-])=O.[Na+]>CC(O)=O.O>[NH2:2][C:1]1[N:23]([C:20]2[CH:19]=[CH:18][C:17]([O:16][C:15]([F:25])([F:26])[F:14])=[CH:22][CH:21]=2)[N:24]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCO/C=C(\C#N)C(=O)OCC
Reactant: NNc1ccc(OC(F)(F)F)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1cnn(-c2ccc(OC(F)(F)F)cc2)c1N
Temperature: 100 °C
Yield: 94.1 %

Procedure:
A mixture of ethyl (2E)-2-cyano-3-ethoxy-2-propenoate (113) (1.87 g, 11.1 mmol), 4-(trifluoromethoxy)phenylhydrazine hydrochloride (114) (2.286 g, 10.00 mmol) and NaOAc (0.90 g, 11.0 mmol) in AcOH (7.5 mL) and water (2.5 mL) was heated to 100° C. under N2 for 15 h. The mixture was poured onto ice, and the resulting precipitate was filtered and recrystallised (MeOH/water) to give ethyl 5-amino-1-[4-(trifluoromethoxy)phenyl]-1H-pyrazole-4-carboxylate (115) (2.965 g, 94%) as white flakes: mp 102-103° C.; 1H NMR [(CD3)2SO] δ 7.73 (s, 1H), 7.68 (d, J=9.1 Hz, 2H), 7.53 (d, J=9.1 Hz, 2H), 6.41 (br s, 2H), 4.22 (q, J=7.1 Hz, 2H), 1.27 (t, J=7.1 Hz, 3H). APCI MS m/z 316 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].C(N(CC)CC)C.C(OC(N1C[C@@H](S)C[C@H]1CN[C:32]([C:34]1[S:35][C:36]([C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:37][CH:38]=1)=[O:33])=O)C=C>C(#N)C>[CH2:42]([O:41][C:39]([C:36]1[S:35][C:34]([C:32](=[O:33])[NH:6][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=2)=[CH:38][CH:37]=1)=[O:40])[CH3:43]
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: C=CCOC(=O)N1C[C@@H](S)C[C@H]1CNC(=O)c1ccc(C(=O)OCC)s1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C(=O)NCc2ccc(Cl)c(Cl)c2)s1
Temperature: 25 °C
Reaction time: 22 h
Yield: 90 %

Procedure:
Starting material (12(e)) was prepared as follows. To a stirring solution of 3,4-dichlorobenzylamine (0.53 mL; 4.0 mmole) in acetonitrile (10 mL) was added triethylamine (1.67 mL; 12.0 mmole) and a solution of (11(a)) (0.87 g; 4.0 mmole. see Example 11) in acetonitrile (20 mL). The solution was stirred at ambient temperature, under argon, for 22 hours. The solvent and excess triethylamine were removed in vacuo and the residue partitioned between chloroform and water. The organic phase was washed with water and brine, dried over magnesium sulphate and vacuumed to dryness to give 5-(3,4-dichlorobenzyl-carbamoyl)-thiophene-2-carboxylic acid ethyl ester (12(a)) as a cream solid (90%).
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH:8]([CH2:12][S:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:15])=[O:14])[C:9](O)=[O:10])[CH:2]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.Cl.[NH2:44][CH2:45][C:46]#[N:47].CN1CCOCC1>>[C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH:8]([CH2:12][S:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:15])=[O:14])[C:9]([NH:47][CH2:46][C:45]#[N:44])=[O:10])[CH:2]=1
Reactant: N#CCN
Reactant: O=C(O)C(Cc1cccc(-c2ccccc2)c1)CS(=O)(=O)Cc1ccccc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: N#CCNC(=O)C(Cc1cccc(-c2ccccc2)c1)CS(=O)(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-Biphenyl-3-yl-2-benzylsulfonylmethyl-propionic acid (300 mg, 0.76 mmol), prepared as in Reference 9, was combined with EDC (300 mg, 1.57 mmol), HOBt (300 mg, 1.96 mmol), and aminoacetonitrile hydrochloride (150 mg, 1.6 mmol). Dichloromethyl (4 mL) was added and then 4-methylmorpholine (0.5 mL). The mixture was stirred at ambient temperature for 2 hours. After dilution with ethyl acetate (150 mL), the solution was washed with water (30 mL), saturated aqueous NaHCO3 solution and brine, dried with magnesium sulfate and evaporated under vacuum. The product, 3-biphenyl-3-yl-N-cyanomethyl-2-benzylsulfonylmethyl-propionamide (273 mg), was crystallized from ethyl acetate/hexane as a white solid; 1H NMR: (DMSO) 8.87 (t, J=5.5 Hz, 1H), 7.68–7.14 (m, 14H), 4.45 (d, J=13.8 Hz, 1H), 4.38 (d, J=13.8 Hz, 1H), 4.13 (m, 2H), 3.49 (dd, J=9.4 Hz, J=14.1 Hz, 1H), 3.28–3.11 (m, 1H), 3.04–2.76 (m, 3H). MS: (M++1) 433.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH:27]([CH3:28])[C:26](=[O:29])[NH:25][C:24]4=[O:30])=[CH:19][C:18]=3[F:31])=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:32]I>>[CH3:1][C:2]1[C:3]([N:9]2[CH2:10][CH2:11][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH:27]([CH3:28])[C:26](=[O:29])[N:25]([CH3:32])[C:24]4=[O:30])=[CH:19][C:18]=3[F:31])=[O:16])[CH2:13][CH2:14]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: CI
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)NC(=O)C4C)cc3F)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)N(C)C(=O)C4C)cc3F)CC2)c(C)c1

Procedure:
Using 1-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-3-fluorophenyl}-5-methylimidazolidine-2,4-dione (80 mg) described in Example 515 and methyl iodide (12 μl) and by the reaction and treatment in the same manner as in Example 36, the title compound (12 mg) was obtained.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1.[C:16]1([C:22]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:23][CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:16]1([C:22]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:23][CH:24]2[CH2:25][CH2:26][N:27]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)[CH2:28][CH2:29]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: ClCCCCCCCCc1cccnc1
Reactant: C(=C(c1ccccc1)c1ccccc1)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C(=C(c1ccccc1)c1ccccc1)C1CCN(CCCCCCCCc2cccnc2)CC1
Reaction time: 8 h

Procedure:
A 5-L flask equipped with a magnetic stirrer, condenser, and argon inlet tube was charged with the 191.3 g of crude, overweight 3-(8-chlorooctyl)-pyridine, 184.4 g of 4-(2,2-diphenylethenyl)piperidine, 1.0 L of N,N-dimethylformamide, 116.3 g of potassium iodide, and 74.2 g of potassium carbonate. The mixture was stirred and heated at 75° for 18 hours and then cooled to 20°. Most of the solvent was removed on a rotary evaporator at 50°/0.5 mm. The residual yellow-brown semi-solid was partitioned between 2.0 L of ether and 1.0 L of deionized water. The aqueous layer was extracted with 2×1.0 L=2.0 L of ether. The combined ether solutions were washed with 500 mL of deionized water and 500 mL of brine and dried over sodium sulfate, to which was added 20 g of Norit SG Extra charcoal. This mixture was filtered through Celite and concentrated on a rotary evaporator at 45° to an oil which solidified upon standing. The solid was triturated with 500 mL of warm hexanes. The suspension was stored overnight at -20° and filtered. The solid was washed with a total of 100 mL of cold hexanes and dried at 20°/0.1 mm over phosphorus pentoxide to give 205.9 g of 3-[8-[4-(2,2-diphenylethenyl)-1-piperidinyl]octyl]pyridine as a pale tan solid, mp 53°-54°. Liquid chromatography analysis indicated this material to be homogeneous.
Reaction SMILES: [Cl:1][C:2]1[C:8]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]([F:18])([F:17])[F:16])[CH2:11][CH2:10]2)=[CH:7][C:5]([NH2:6])=[C:4]([N+:19]([O-])=O)[CH:3]=1.C1COCC1>CO>[Cl:1][C:2]1[C:8]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]([F:16])([F:17])[F:18])[CH2:11][CH2:10]2)=[CH:7][C:5]([NH2:6])=[C:4]([NH2:19])[CH:3]=1
Reactant: Nc1cc(N2CCC(C(F)(F)F)CC2)c(Cl)cc1[N+](=O)[O-]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1cc(Cl)c(N2CCC(C(F)(F)F)CC2)cc1N
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A mixture of 4-chloro-2-nitro-5-(4-trifluoromethyl-piperidin-1-yl)aniline (0.63 g, 1.9 mmol), THF (10 mL), MeOH (20 mL) and 50%-Pt-on-carbon (60 mg) was stirred for 22 h at rt under a hydrogen atmosphere (3 bar). The catalyst was removed by filtration and the mixture was concentrated to give the sub-title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].C([O-])(=O)C.[Na+].[S:17]1[CH2:21][CH2:20][NH:19][CH2:18]1>C(O)C>[C:6]1([C:4](=[O:5])[CH2:3][CH2:2][N:19]2[CH2:20][CH2:21][S:17][CH2:18]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(CCCl)c1ccccc1
Reactant: C1CSCN1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C(CCN1CCSC1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.4 %

Procedure:
A solution containing 8.43 g (0.05 mol) of β-chloropropiophenone, 4.10 g (0.05 mol) of anhydrous sodium acetate and 4.01 g (0.045 mol) of thiazolidine in 30 ml of ethanol is stirred at 25° C. for 8 hours. After filtering off the precipitate and evaporating the solvent from the solution, the oily yellowish residue weighing 9.3 g is converted to the hydrochloride in a mixture of acetone and ether in the usual way to give 9.9 g of product. After recrystallization from methanol, the hydrochloride of the title product thus obtained melts at 170°-171° C.; it is identical to the hydrochloride described in Examples 1 and 43.