Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]([O:10][CH3:11])=[O:9])[C:4](=[O:12])[N:3]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1C(=O)N([Br:26])C(=O)C1>C(Cl)(Cl)Cl>[Br:26][CH2:7][C:6]1[N:2]([CH3:1])[N:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:4](=[O:12])[C:5]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1c(C)n(C)n(-c2ccccc2)c1=O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1c(CBr)n(C)n(-c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 32.7 %

Procedure:
Methyl 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylate (7.82 g, 31.8 mmol) was dissolved in CHCl3 (150 ml) and n-bromosuccimide (6.91 g, 38.8 mmol) was added. The reaction was stirred at room temperature, and after 1.5 hours, more NBS (6.23 g, 35.2 mmol) was added. After another hour of stirring, the reaction was filtered, and the solid was washed with chloroform. The filtrate was concentrated, treated with dichlormethane, and refiltered. The filtrate was again concentrated, and filtered through silica gel (˜3 inches, dichlormethane/MeOH). The fractions with product collected, concentrated, and purified on silica gel (dichlormethane/MeOH) to give the desired methyl 5-(bromomethyl)-1-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylate (4.11 g, 82% purity, 10.4 mmol, 33% yield). MS (ESI pos. ion) m/z: 325, 327 (MH+). Calc'd exact mass for C13H13Br79.0N2O3: 324. Calc'd exact mass for C13H13Br81.0N2O3: 326.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].O1CCC[CH2:17]1.C(=O)([O-])[O-].[K+].[K+].CI>>[N:8]1([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([O:12][CH3:17])=[O:11]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: C1CCOC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: COC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Yield: 97.1 %

Procedure:
N-(tert-Butoxycarbonyl)-L-proline (7.05 g, 0.0328 mol) was dissolved in THF (200 mL, 2 mol) and to this solution was added potassium carbonate (10.2 g, 0.0738 mol) and methyl iodide (5.0 mL, 0.08 mol). The resulting heterogeneous solution was heated to reflux for 16 h with vigorous stirring. The mixture was then filtered through a pad of diatomaceous earth and the filter pad was washed thoroughly with tetrahydrofuran (THF). The volatiles were removed in vacuo and the resulting residue was purified by CombiFlash chromatography using a 40 g column and eluting with EtOAc/hexanes (0-25%) to afford the desired product as a yellow oil (7.3 g, 97%). LC-MS: 130.2 (M−Boc+2H)+ and 252.1 (M+Na)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[C:9](C1NC=CN=1)(C1NC=CN=1)=[S:10]>C(#N)C>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([N:1]=[C:9]=[S:10])=[N:3][CH:4]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: S=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CC#N
Product: S=C=Nc1ccc(Cl)cn1
Yield: 36.6 %

Procedure:
2-Amino-5-chloropyridine (10.28 g) was added in portions, with stirring, over a period of 25 minutes to a solution of thiocarbonyl diimidazole (14.26 g) in acetonitrile (100 ml) at ambient temperature. The stirring was continued and the solution/suspension was left at ambient temperature for a few hours. The precipitate was filtered and washed with acetonitrile (3×25 ml). The solid residue was dissolved in hot acetone and filtered. The acetone solution was evaporated in vacuo, the residue was dissolved in hot ethyl acetate and filtered through a pad of silica (diam. 7 cm×3 cm). The silica was washed with another portion of hot ethyl acetate. The combined solutions were evaporated in vacuo to yield a crude product (5 g) of the titled product.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([NH:8][CH3:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[O:12]=[P:13](Cl)([Cl:15])[Cl:14]>C1(C)C=CC=CC=1>[CH3:9][N:8]([C:7]1[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[P:13]([Cl:15])([Cl:14])=[O:12]
Reactant: CNc1ccc([N+](=O)[O-])cc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CN(c1ccc([N+](=O)[O-])cc1)P(=O)(Cl)Cl

Procedure:
p-Nitro-N-methylaniline (9.3 g, 0.061 mol) and 9 mL (0.1 mol) POCl3 were heated in 50 mL toluene to 90°-95° C. overnight. The solution was cooled and filtered. The volatiles were removed from the filtrate, giving 15.3 g of a purple, viscous oil. NMR (CDCl3): AA'XX' quartet from δ7.45-7.35 (4H), 3.37 (d,3H, J=14-15 Hz). No N--H was observed in the NMR. Due to an expected very high boiling point, this material was not distilled but used directly in the preparation of N-Methyl-N-(4-nitrophenyl) phosphoric triamide in the following Example VI.
Reaction SMILES: [C:1]1([CH:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[C:17]([NH2:25])[C:18]([NH:21][CH2:22][CH2:23][CH3:24])=[CH:19][CH:20]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:32](OCC)(OCC)OCC>C(O)(=O)C>[C:26]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:9][CH2:10][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]4[N:21]([CH2:22][CH2:23][CH3:24])[CH:32]=[N:25][C:17]=4[CH:16]=3)[CH2:12][CH2:13]2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CCOC(OCC)OCC
Reactant: CCCNc1ccc(CN2CCN(C(c3ccccc3)c3ccccc3)CC2)cc1N
Solvent: CC(=O)O
Product: CCCn1cnc2cc(CN3CCN(C(c4ccccc4)c4ccccc4)CC3)ccc21

Procedure:
A mixture of 5 parts of 4-[4-(diphenylmethyl)-1-piperazinylmethyl]-N1 -propyl-1,2-benzenediamine, 35 parts of 1,1',1"-[methylidynetris(oxy)]trisethane and 1.5 parts of acetic acid is stirred and refluxed for 2 hours. The reaction mixture is cooled and evaporated. The residue is taken up in 100 parts of water and a hydrochloric acid solution 10 N is added till all solid enters solution. This solution is treated with activated charcoal. The latter is filtered off and the filtrate is alkalized with a sodium hydroxide solution. The product is extracted with dichloromethane. The extract is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 4-methyl-2-pentanone. The product is filtered off, washed with a small amount of 4-methyl-2-pentanone and with 2,2'-oxybispropane, and dried, yielding 2.2 parts of 5-[4-(diphenylmethyl)- 1-piperazinylmethyl]-1-propyl-1H-benzimidazole; mp. 154.8° C.
Reaction SMILES: [OH:1][CH:2](/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1.[H-].[Na+].Cl[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=1[Cl:28]>O1CCCC1>[Cl:28][C:22]1[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=1[CH2:20][O:1][CH:2](/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1
Reactant: ClCc1ccc(Cl)cc1Cl
Reactant: OC(/C=C/c1ccccc1)Cn1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1ccc(COC(/C=C/c2ccccc2)Cn2ccnc2)c(Cl)c1
Temperature: 25 °C

Procedure:
trans-1-[2-Hydroxy-4-phenylbut-3-enyl]imidazole (430 mg.) in 5 ml. dry tetrahydrofuran was treated under nitrogen with stirring with 96 mg. of sodium hydride (56% dispersion in mineral oil) and the mixture heated under reflux for 30 minutes. After cooling in an ice bath the mixture was treated with stirring with 430 mg. of α,2,4-trichlorotoluene in 5 ml. tetrahydrofuran for 30 minutes at 0° C., one hour at 25° C. and overnight under reflux. The resulting mixture was evaporated to dryness, ether (150 ml.) added and the ether extract washed with water, dried over magnesium sulfate and evaporated to afford trans-1-[2-(2,4-dichlorobenzyloxy)-4-phenylbut-3-enyl]imidazole. The nitrate salt precipitated from ether and was crystallized from ethyl acetate, m.p. 133.5°-134.5° C. (foaming).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:19])[CH:9]=2)[N:4]=1.[CH3:20][C:21]1[CH:22]=[C:23]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:24]=[CH:25][CH:26]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:30]2[CH2:31][CH2:32][N:27]([C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([CH3:20])[CH:22]=3)[CH2:28][CH2:29]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:19])[CH:9]=2)[N:4]=1
Reactant: CCOC(=O)Nc1nc2cc(C)ccc2nc1OC
Reactant: Cc1cccc(N2CCNCC2)c1
Product: COc1nc2ccc(C)cc2nc1NC(=O)N1CCN(c2cccc(C)c2)CC1
Yield: 90 %

Procedure:
Ethyl N-(2-methoxy-6-methylquinoxalin-3-yl)carbamate and 1-(3-methylphenyl)piperazine were reacted by the same way with the example 43 to obtain the titled compound (yield, 90%). 1H NMR (300 MHz, CDCl3): δ 2.33-2.46 (m, 6H), 3.14-3.37 (m, 4H), 3.73-3.87 (m, 3H), 4.05-4.18 (m, 4H), 6.72-6.78 (m, 3H), 7.00-7.20 (m, 2H), 7.30-7.38 (m, 1H), 7.49-7.62 (m, 2H).
Reaction SMILES: [O-]CC.[Na+].[NH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH3:20])[C:15](=[O:21])[CH:14]=[CH:13]2.Cl[CH2:23][CH2:24][C:25]([NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH3:34])=[O:26]>C(O)C>[CH3:20][N:16]1[C:17]2[C:12](=[CH:11][C:10]([O:9][CH2:8][CH2:7][CH2:6][NH:5][CH2:23][CH2:24][C:25]([NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])=[O:26])=[CH:19][CH:18]=2)[CH:13]=[CH:14][C:15]1=[O:21]
Reactant: Cc1ccccc1NC(=O)CCCl
Reactant: Cn1c(=O)ccc2cc(OCCCN)ccc21
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccccc1NC(=O)CCNCCCOc1ccc2c(ccc(=O)n2C)c1
Temperature: 60 °C
Reaction time: 5 h
Yield: 58.5 %

Procedure:
Sodium ethoxide (34 mg) was added to an ethanol solution (5 ml) of 6-(3-amino-propoxy)-1-methyl-1H-quinolin-2-one (116 mg) and 3-chloro-N-o-tolyl-propionamide (148 mg). The mixture was stirred at 60° C. for 5 hours. The reaction mixture was condensed under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol=20:1→10:1). The purified product was condensed under reduced pressure to give the title compound (115 mg) as a white powder.
Reaction SMILES: C[O:2][C:3]1[N:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=[O:17])[N:10]2[CH2:13][C@@H:14]2[CH2:16][O:15]2)=[CH:5][CH:4]=1>CN(C=O)C>[OH:15][CH2:16][C@H:14]1[N:12]2[C:11]3[N:10]([C:9](=[O:17])[CH2:8][CH2:7][C:6]=3[CH:5]=[CH:4][C:3]2=[O:2])[CH2:13]1
Reactant: COc1ccc2c(n1)N(C[C@@H]1CO1)C(=O)CC2
Solvent: CN(C)C=O
Product: O=C1CCc2ccc(=O)n3c2N1C[C@H]3CO
Yield: 30.9 %

Procedure:
A solution of 7-(methyloxy)-1-[(2R)-2-oxiranylmethyl]-3,4-dihydro-1,8-naphthyridin-2(1H)-one (1.167 g, 4.98 mmol) in DMF (20 ml) under argon was heated to 120° C. for 6 h. Reaction was then evaporated and chromatographed (0-20% methanol/DCM) to give product as an orange solid (339 mg, 31%).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]2[CH2:6][CH:7]([CH2:9][OH:10])[O:8][C:4]=2[C:3]=1[Cl:13].[H-].[Na+].[CH2:16](Br)[CH3:17]>CN(C=O)C>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]2[CH2:6][CH:7]([CH2:9][O:10][CH2:16][CH3:17])[O:8][C:4]=2[C:3]=1[Cl:13]
Reactant: CCBr
Reactant: OCC1Cc2ccc(Cl)c(Cl)c2O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOCC1Cc2ccc(Cl)c(Cl)c2O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.6 %

Procedure:
To a solution of 2.88 g of 6,7-dichloro-2-hydroxymethyl-2,3-dihydrobenzofuran dissolved in 22 ml of DMF is added 790 mg of sodium hydride (50% suspension) and stirred at room temperature for 30 minutes. After addition of 1.73 g of ethyl bromide, the reaction mixture is stirred at room temperature for 17 hours and extracted with water and ether. The ether layer is washed with water, dried over magensium sulfate, and evaporated under reduced pressure to give a residue, which is chromatographed on silica gel with dichloromethane as an eluent to give 2.0 g of oily 6,7-dichloro-2-ethoxymethyl-2,3-dihydrobenzofuran. To a solution of 2.0 g of the 6,7-dichloro-2-ethoxymethyl-2,3-dihydrobenzofuran dissolved in 5 ml of thionyl chloride is dropwise added 3 g of chlorosulfonic acid under ice-cooling. The reaction mixture is stirred at room temperature for 2 hours, then poured into iced water, and extracted with ethyl acetate. The ethyl acetate layer is washed with water, dried and evaporated under reduced pressure to give an oil, which is then dissolved in 30 ml of dichloromethane. After introduction of 30 ml of ammonia at -30° to -20° C., the mixture is allowed to stand at room temperature for a night and evaporated under reduced pressure to give an oily residue, which is then dissolved in ethyl acetate and washed with water. The ethyl acetate layer is dried and evaporated to dryness to give 2.7 g of an oily product, which is chromatographed on silica gel with dichloromethane (1000 ml) and successively dichloromethane/acetone (20/1) as eluents to give 900 mg of the objective 6,7-dichloro-2-ethoxymethyl-5-sulfamoyl-2,3-dihydrobenzofuran (I j-84) as crystals, yield 24%, m.p. 148°-149° C.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]1[CH:22]=[C:21]([CH:23]=[O:24])[C:20]([O:25][CH3:26])=[CH:19][C:18]=1[O:27][CH3:28])=O)(C)(C)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-].C(Cl)Cl>C1COCC1>[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]1[C:18]([O:27][CH3:28])=[CH:19][C:20]([O:25][CH3:26])=[C:21]([CH:22]=1)[CH:23]=[O:24]
Reactant: COc1cc(OC)c(-c2cc3ccccc3n2C(=O)OC(C)(C)C)cc1C=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1cc(OC)c(-c2cc3ccccc3[nH]2)cc1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.8 %

Procedure:
Ex-32B: 2-(5-Formyl-2,4-dimethoxyphenyl)indole-1-carboxylic acid tert-butyl ester (Ex-32A, 2.0 g, 5.2 mmol) was dissolved in 100 ml of THF, and Bu4NF (6.86 g, 26 mmol) was added. The reaction mixture was stirred at room temperature overnight. No significant reaction occurred under these conditions by HPLC. Then, additional Bu4NF (6.86 g, 26 mmol) was added to the mixture, and the mixture was stirred at reflux for 4 days. The reaction reached about 50% completion (HPLC). The reaction mixture was poured into CH2Cl2, and washed with water and brine. The organic phase was dried over MgSO4, and concentrated. The residue was purified by column chromatography (EtOAc/hexanes, 2:1) to give 0.45 g (30%) of 5-(1H-indol-2-yl)-2,4-dimethoxybenzaldehyde. 1H-NMR (300 MHz, CDCl3) δ 10.37 (s, 1H), 9.25 (br, 1H), 8.28 (s, 1H), 7.63(d, J=8 Hz, 1H), 7.39 (d, J=8 Hz, 1H), 7.08–7.20 (m, 2H), 6.92(d, J=2 Hz, 1H), 6.56 (s, 1H) 4.11(s, 3H), 4.00 (s, 3H). HMRS (EI) calcd. for C17H15NO3: 281.1052 (M+); Found: 281.1049.
Reaction SMILES: [CH3:1][C:2]1([NH2:15])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10][N:9]=2)[CH2:4][CH2:3]1.[C:16](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:17]>ClCCl>[N:15]([C:2]1([CH3:1])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10][N:9]=2)[CH2:4][CH2:3]1)=[C:16]=[S:17]
Reactant: Cc1cc(N2CCC(C)(N)CC2)ncn1
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Solvent: ClCCl
Product: Cc1cc(N2CCC(C)(N=C=S)CC2)ncn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.5 %

Procedure:
To a solution of 4-methyl-1-(6-methylpyrimidin-4-yl)piperidin-4-amine (1.09 g, 5.28 mmol) in dichloromethane (17.2 mL) was added 1,1′-thiocarbonyldipyridin-2(1H)-one (1.84 g, 7.92 mmol) and the reaction mixture was stirred at room temperature for 16 hours. After cooling to room temperature the mixture was evaporated. Purification by chromatography (silica gel, 3×70 g, 50 to 100% ethyl acetate in heptane) afforded the title compound (1.2 g, 91%) as a light yellow solid. MS ISP (m/e): 249.1 [(M+H)+].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[C:14]([CH3:15])=[C:13]([C:16]3[CH:17]=[C:18]([C:22]([NH2:25])([CH3:24])[CH3:23])[CH:19]=[CH:20][CH:21]=3)[N:12]([CH3:26])[N:11]=2)=[CH:4][CH:3]=1.CCN(CC)CC.[F:34][C:35]([F:43])([F:42])[CH2:36][NH:37][S:38](Cl)(=[O:40])=[O:39]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]2[C:14]([CH3:15])=[C:13]([C:16]3[CH:17]=[C:18]([C:22]([NH:25][S:38]([NH:37][CH2:36][C:35]([F:43])([F:42])[F:34])(=[O:40])=[O:39])([CH3:24])[CH3:23])[CH:19]=[CH:20][CH:21]=3)[N:12]([CH3:26])[N:11]=2)=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)NCC(F)(F)F
Reactant: Cc1c(CCc2ccc(F)cc2)nn(C)c1-c1cccc(C(C)(C)N)c1
Solvent: CCN(CC)CC
Product: Cc1c(CCc2ccc(F)cc2)nn(C)c1-c1cccc(C(C)(C)NS(=O)(=O)NCC(F)(F)F)c1

Procedure:
Prepared by the procedure of Example 1 Step 3 using the amine from Step 3 (72 mg, 0.20 mmol), Et3N (114 μL, 0.82 mmol) and 2,2,2-trifluoroethylsulfamoyl chloride (121 mg, 0.61 mmol) to yield, after purification by column chromatography on silica using 80-100% Et2O/iso-hexanes the title sulfamide (23 mg, 22%). 1H NMR (CDCl3, 500 MHz) δ 7.54 (1H, d, J=7.8 Hz), 7.48 (1H, t, J=7.8 Hz), 7.42 (1H, s), 7.23 (1H, d, J=7.5 Hz), 7.19 (2H, dd, J=8.5, 5.6 Hz), 6.97 (2H, t, J=8.5 Hz), 4.71 (1H, s), 4.43 (1H, t, J=7.4 Hz), 3.74 (3H, s), 3.57 (2H, quintet, J=7.4 Hz), 2.98-2.92 (2H, m), 2.87-2.82 (2H, m), 1.87 (3H, s), 1.79 (6H, s). MS (ES+) C24H28F4N4O2S requires: 512, found: 513 (M+H+, 100%).
Reaction SMILES: C([O:3][C:4]([C:6]1([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[O:27][N:26]=[C:25]([CH3:28])[C:24]=4[NH:29][C:30]([O:32][C@@H:33]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH3:34])=[O:31])=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5])C.[Li+].[OH-].CCOC(C)=O>O1CCOCC1>[CH3:28][C:25]1[C:24]([NH:29][C:30]([O:32][C@@H:33]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH3:34])=[O:31])=[C:23]([C:20]2[CH:21]=[CH:22][C:17]([C:14]3[CH:13]=[CH:12][C:11]([C:6]4([C:4]([OH:5])=[O:3])[CH2:10][CH2:9][CH2:8][CH2:7]4)=[CH:16][CH:15]=3)=[CH:18][CH:19]=2)[O:27][N:26]=1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)O[C@H](C)c4ccccc4)cc3)cc2)CCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CCCC4)cc3)cc2)c1NC(=O)O[C@H](C)c1ccccc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
1-{4′-[3-methyl-4-((R)-1-phenyl-ethoxycarbonylamino)-isoxazol-5-yl]-biphenyl-4-yl}-cyclopentanecarboxylic acid ethyl ester (0.060 g, 0.11 mmol) in 1,4-dioxane (2 mL) was treated with 1N aqueous LiOH (1 mL), and the reaction was stirred at 60° C. overnight. Acidic work-up, followed by silica gel chromatography (0-50% EtOAc in hexanes) gave the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:22])OC2C=CC=CC=2)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[F:23][C:24]1[CH:25]=[C:26]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:27]=[C:28]([F:30])[CH:29]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:34]2[CH2:33][CH2:32][N:31]([C:26]3[CH:25]=[C:24]([F:23])[CH:29]=[C:28]([F:30])[CH:27]=3)[CH2:36][CH2:35]2)=[O:22])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: Fc1cc(F)cc(N2CCNCC2)c1
Reactant: COc1nc2ccccc2nc1NC(=O)Oc1ccccc1
Product: COc1nc2ccccc2nc1NC(=O)N1CCN(c2cc(F)cc(F)c2)CC1
Yield: 74.5 %

Procedure:
Phenyl N-(2-methoxyquinoxalin-3-yl)carbamate and 1-(3,5-difluorophenyl)piperazine were reacted by the same way with the example 36 to obtain the titled compound.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.[C:23]1([CH2:29][CH2:30][O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]Cl)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][O:31][CH2:30][CH2:29][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: ClCCCCCOCCc1ccccc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCOCCc2ccccc2)CC1

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (2.0 g) as starting compound and 5-(2-phenylethyloxy)-pentyl chloride were reacted and treated in the same manner as in Example 168 to give 0.69 g of 4-amino-5-chloro-2-methoxy-N-((1-(5-(2-phenylethyloxy)pentyl)piperidin-4-yl)methyl)benzamide.
Reaction SMILES: Br[CH:2]=[CH:3]Br.[Li]CCCC.[CH3:10][O:11][C@H:12]1[CH2:17][CH2:16][C@H:15]2[C@H:18]3[C@H:28]([CH2:29][CH2:30][C@:13]12[CH3:14])[C@:26]1([CH3:27])[C@H:21]([CH2:22][C:23](=[O:31])[CH2:24][CH2:25]1)[CH2:20][CH2:19]3>C1COCC1.C(Cl)Cl>[C:2]([C@@:23]1([OH:31])[CH2:24][CH2:25][C@@:26]2([CH3:27])[C@@H:21]([CH2:20][CH2:19][C@@H:18]3[C@@H:28]2[CH2:29][CH2:30][C@@:13]2([CH3:14])[C@H:15]3[CH2:16][CH2:17][C@@H:12]2[O:11][CH3:10])[CH2:22]1)#[CH:3]
Reactant: CO[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: BrC=CBr
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: C#C[C@@]1(O)CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](OC)CC[C@@H]32)C1
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 4.3 %

Procedure:
A solution of 1,2-dibromoethylene (1.7 mL, 21 mmol) in dry THF (25 mL) was treated with n-BuLi (16.8 mL, 2.5M in THF, 42 mmol) at -65° C. After stirring the mixture at -70° C. for 0.25 hr, a solution of 17β-methoxy-5α-androstan-3-one (2.128 g, 7 mmol) in THF (22 mL) was added and the mixture was stirred at -78° C. for 30 min. The cooling bath was then removed and the mixture was quenched with NH4Cl solution (3 mL). The solvents were removed and the residue was extracted with EtOAc. The organic layer was washed with water, and brine. After drying over anhyd. MgSO4 the solution was filtered and evaporated to yield the crude product. This crude product was then dissolved in a small amount of CH2Cl2 and poured on a column of silica gel. Elution with toluene:acetone mixture (95:5) gave 3β-ethynyl-3-hydroxy-17β-methoxy-5α-androstane (100 mg) as a colorless solid; mp 138-145° C.; TLC Rf (hexane:acetone 7:3)=0.45; and then 3β-ethynyl-3α-hydroxy-17β-methoxy-5α-androstane (1.6 g) as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.[CH3:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:12]([NH2:14])=[O:13])=[CH:7][C:8]=1[C:9]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([CH3:15])=[CH:17][CH:18]=1)=[O:11]
Reactant: Cc1ccc(N)cc1
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Product: COc1ccc(C(N)=O)cc1C(=O)Nc1ccc(C)cc1

Procedure:
The captioned compound was synthesized from 6-methoxyisophthalamic acid and 4-methylaniline by the same procedure as in the manufacturing method described in step C of Example 1-3-1.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N+:11]([O-:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>CN(C)C=O>[N:26]1([CH2:25][CH2:24][CH2:23][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:13]=[CH:12][N+:11]([O-:14])=[CH:10][CH:9]=3)=[CH:6][CH:7]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: [O-][n+]1ccc(-c2ccc(O)cc2)cc1
Reactant: ClCCCN1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: [O-][n+]1ccc(-c2ccc(OCCCN3CCCCC3)cc2)cc1
Temperature: 25 °C

Procedure:
A A mixture of 4-(4-hydroxyphenyl)pyridine 1-oxide (250 mg), potassium carbonate (560 mg) and 1-(3-chloropropyl)piperidine, hydrochloride in N,N-dimethylformamide (10 mL) is heated at a temperature close to 65° C. overnight, then cooled back to room temperature and filtered. The filtrate is concentrated under reduced pressure and the residue purified by chromatography over silica gel (eluent dichloromethane/methanol from 100/0 to 90/10). Fraction containing the compound are pooled and concentrated under reduced pressure. Crude base is diluted with ethanol, oxalic acid (28 mg) is added and solvent removed under reduced pressure to give 40 mg of 4-[4-(3-piperidino-propoxy)phenyl]pyridine 1-oxide, oxalate as a viscous yellow product.