Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:23])[CH:9]([C:17]2[S:21][N:20]=[C:19]([CH3:22])[N:18]=2)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]#[N:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[SH2:24]>N1C=CC=CC=1.N1CCCCC1>[C:1]1([NH:7][C:8](=[O:23])[CH:9]([C:17]2[S:21][N:20]=[C:19]([CH3:22])[N:18]=2)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15](=[S:24])[NH2:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1nsc(C(CCCCCC#N)C(=O)Nc2ccccc2)n1
Reactant: S
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: Cc1nsc(C(CCCCCC(N)=S)C(=O)Nc2ccccc2)n1
Temperature: 50 °C
Reaction time: 120 h

Procedure:
To a stirred mixture of 7-cyano-2-(3-methyl[1,2,4]thiadiazol-5-yl)heptanoic acid phenylamide (2021044) (0.55 g, 1.7 mmol) in pyridine (120 mL) and piperidine (30 mL) was slowly bubbled hydrogen sulphide for 15 min. The resultant mixture was then stoppered and stirred at 50° C. for five days. The solvent was removed under reduced pressure, water (150 mL) was added to the residue, and the resultant solution was extracted with dichloromethane (3×150 mL). The crude product (1.6 g) was purified by preparative liquid chromatography to afford 2-(3-methyl-[1,2,4]thiadiazol-5-yl)-7-thiocarbamoyl heptanoic acid phenylamide (2021036) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:18])[CH3:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH:19]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]([CH3:30])[CH3:29])[C:23]=1[N:31]=[C:32]=[O:33])([CH3:21])[CH3:20]>>[CH:19]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]([CH3:29])[CH3:30])[C:23]=1[NH:31][C:32](=[O:33])[N:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[C:10]1[CH:11]=[CH:12][C:13]([CH:16]([CH3:18])[CH3:17])=[CH:14][CH:15]=1)([CH3:20])[CH3:21]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: CC(C)c1ccc(NCc2ccc(F)cc2)cc1
Product: CC(C)c1ccc(N(Cc2ccc(F)cc2)C(=O)Nc2c(C(C)C)cccc2C(C)C)cc1
Yield: 20.3 %

Procedure:
By the reaction and treatment in the same manner as in Example 1 using [(4-fluorophenyl)methyl](4-isopropylphenyl)amine (2.2 g) and 2,6-diisopropylphenyl isocyanate (2.2 g) as starting materials, N′-(2,6-diisopropylphenyl)-N-[(4-fluorophenyl)methyl]-N-(4-isopropylphenyl)urea (0.82 g) was obtained. melting point: 80° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]2([C:23](N)=[O:24])[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)[CH:6]=[CH:7][CH:8]=1.[OH-:26].[K+].Cl.[OH-].[Na+]>O.C(O)CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]2([C:23]([OH:26])=[O:24])[CH2:11][CH2:12][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:14][CH2:15]2)[CH:6]=[CH:7][CH:8]=1
Reactant: [OH-]
Reactant: COc1cccc(NC2(C(N)=O)CCN(Cc3ccccc3)CC2)c1
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: OCCO
Product: COc1cccc(NC2(C(=O)O)CCN(Cc3ccccc3)CC2)c1

Procedure:
A mixture of 100 parts of 4-[N-(3-methoxyphenyl)amino]-1-(phenylmethyl)-4-piperidinecarboxamide, 49.5 parts of potassium hydroxide and 974 parts of 1,2-ethanediol is stirred and refluxed for 24 hours. After cooling, the reaction mixture is poured onto 1500 parts of water and acidified with a concentrated hydrochloric acid solution. The whole is strongly alkalized with a sodium hydroxide solution and the layers are separated. The aqueous phase is concentrated, whereupon the product is separated as an oil. The supernatant aqueous phase is decanted and the residual oil is taken up in a sodium hydroxide solution. The precipitated product is filtered off and dissolved in water. The solution is acidified with acetic acid till pH = 6. The precipitated product is filtered off and warmed in ethanol. It is filtered off again, washed with ethanol and 2,2'-oxybispropane and dissolved in boiling N,N-dimethylformamide. The solution is filtered and the product is allowed to crystallized from the filtrate. It is filtered off, washed successively with N,N-dimethylformamide, water and ethanol, and dried, yielding 4-[N-(3-methoxyphenyl)amino]- 1-(phenylmethyl)-4-piperidinecarboxylic acid; mp. 211.1° C.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].Cl[CH2:6][C:7]1[N:12]=[CH:11][CH:10]=[CH:9][N:8]=1.OCC1N=CC=CN=1.S(Cl)(Cl)=O>>[N:8]1[CH:9]=[CH:10][CH:11]=[N:12][C:7]=1[CH2:6][NH:3][CH2:2][CH2:1][NH2:4]
Reactant: ClCc1ncccn1
Reactant: NCCN
Agent: OCc1ncccn1
Solvent: O=S(Cl)Cl
Product: NCCNCc1ncccn1

Procedure:
By the procedure of Example 34, ethylenediamine is reacted with 2-chloromethylpyrimidine, prepared by treating 2-hydroxymethylpyrimidine with thionyl chloride to give N-(2-pyrimidylmethyl)ethylenediamine.
Reaction SMILES: [CH:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[C:10]([C:19]3[S:20][CH:21]=[C:22]([CH2:24][C:25]([O:27]CC)=[O:26])[N:23]=3)[CH:9]=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C.C1COCC1>[CH:1]1([N:7]2[C:11]([C:12]3[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=3)=[C:10]([C:19]3[S:20][CH:21]=[C:22]([CH2:24][C:25]([OH:27])=[O:26])[N:23]=3)[CH:9]=[N:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)Cc1csc(-c2cnn(C3CCCCC3)c2-c2ccc(F)cc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)Cc1csc(-c2cnn(C3CCCCC3)c2-c2ccc(F)cc2)n1
Yield: 90.2 %

Procedure:
A mixed solution of the compound (269 mg, 0.65 mmol) obtained in step 3 and 1N aqueous sodium hydroxide solution (0.976 mL, 0.98 mmol) in ethanol (4 mL) and THF (4 mL) was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure, and water was added to the residue. 1N Hydrochloric acid was added thereto, and the precipitate was collected by filtration, and crystallized from diethyl ether and hexane to give 2-(2-(1-cyclohexyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl)thiazol-4-yl)acetic acid (226 mg, 0.586 mmol, 90%) as a white powder.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:19])=[C:7]([Cl:18])[CH:8]=2)[N:3]=1.[CH3:20][O:21][CH2:22][CH2:23][CH2:24][NH2:25]>C1(C)C=CC=CC=1>[Cl:18][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[Cl:19])[N:3]=[C:2]([NH:25][CH2:24][CH2:23][CH2:22][O:21][CH3:20])[C:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)=[N:10]2
Reactant: COCCCN
Reactant: Clc1cc2nc(Cl)c(-c3ccccn3)nc2cc1Cl
Solvent: Cc1ccccc1
Product: COCCCNc1nc2cc(Cl)c(Cl)cc2nc1-c1ccccn1
Yield: 76.9 %

Procedure:
A solution of 2,6,7-trichloro-3-pyridin-2-yl-quinoxaline (0.50 g) and 3-methoxy-propylamine (0.28 g) in toluene (20 mL) was refluxed under nitrogen for 16 hours. After refluxing, the reaction mixture was cooled, filtered, and concentrated under vacuum. The residue was recrystallized from methanol and water to give the product as a yellow solid (0.45 g); mp 99.5-100.5° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33]/[CH:34]=[C:35](\[C:39]2[CH:44]=[CH:43][C:42]([S:45]([CH3:48])(=[O:47])=[O:46])=[CH:41][CH:40]=2)/[C:36]([OH:38])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:49][C:50]1[S:51][CH:52]=[CH:53][N:54]=1>C(Cl)Cl>[S:51]1[CH:52]=[CH:53][N:54]=[C:50]1[NH:49][C:36](=[O:38])/[C:35](/[C:39]1[CH:44]=[CH:43][C:42]([S:45]([CH3:48])(=[O:47])=[O:46])=[CH:41][CH:40]=1)=[CH:34]/[CH2:33][CH:28]1[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: Nc1nccs1
Reactant: CS(=O)(=O)c1ccc(/C(=C\CC2CCCC2)C(=O)O)cc1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(/C(=C\CC2CCCC2)C(=O)Nc2nccs2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 34.8 %

Procedure:
A solution of triphenylphosphine (672 mg, 2.56 mmol) in methylene chloride (7.5 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (456 mg, 2.56 mmol). The reaction mixture was stirred at 0° C. for 30 min and then treated with a solution of (E)-4-cyclopentyl-2-(4-methanesulfonyl-phenyl)-but-2-enoic acid (545.5 mg, 1.47 mmol) in methylene chloride (4 mL). The clear solution was stirred for 10 min at 0° C. and then allowed to warm to 25° C. where it was stirred for 1 h. The reaction mixture was then treated with 2-aminothiazole (378 mg, 3.76 mmol), and the resulting suspension was stirred at 25° C. over the weekend. The reaction mixture was concentrated in vacuo to remove methylene chloride, and the residue was diluted with ethyl acetate (75 mL) and a 1N aqueous hydrochloric acid solution (100 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×50 mL). The combined organic extracts were successively washed with a saturated aqueous sodium bicarbonate solution (2×50 mL) and a saturated aqueous sodium chloride solution (1×100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 4/1 to 1/1 hexanes/ethyl acetate) afforded (E)-4-cyclopentyl-2-(4-methanesulfonyl-phenyl)-but-2-enoic acid thiazol-2-ylamide (200 mg, 35%) as a white solid: mp 173-176° C.; EI-HRMS m/e calcd for C19H22N2O3S2 (M+) 390.1071, found 390.1072.
Reaction SMILES: [O:1]=[C:2]([CH2:9][C:10](=[O:13])[C:11]#[CH:12])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].C1C2C(=CC=CC=2)C=CC=1CN1CCC[C@H]1CO>C1COCC1.CO>[OH:1][CH:2]([CH2:9][CH:10]([OH:13])[C:11]#[CH:12])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: C#CC(=O)CC(=O)CC(=O)OCC
Agent: OC[C@@H]1CCCN1Cc1ccc2ccccc2c1
Solvent: C1CCOC1
Solvent: CO
Product: C#CC(O)CC(O)CC(=O)OCC
Reaction time: 20 h

Procedure:
50 mg (0.27 mmnol) of ethyl 3,5-dioxo-6-heptynoate was dissolved in 5 ml of THF and 52 ml of methanol. Then, with or without addition of aluminum tri-i-propoxide as a metal reagent, a reaction was conducted at 20° C. for 20 hours using 5.4 ml of a 1.0M BH3 ·THF solution and 6.2 mg (0.027 mmol) of the (S)-N-(β-naphthyl)methyl-2-pyrrolidine methanol (compound (S)-II-1) obtained in Example 1, to obtain ethyl 3,5-dihydroxy-6-heptynoate (VI-2) as oily desired product.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]1[N:13]=[N:12][C:11]([OH:14])=[CH:10][CH:9]=1.[CH3:15][N:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:17](Cl)=[O:18].N12CCN(CC1)CC2.O>CN(C)C=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]1[N:13]=[N:12][C:11]([O:14][C:17](=[O:18])[N:16]([CH3:15])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:10][CH:9]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: Oc1ccc(Cc2ccccn2)nn1
Agent: C1CN2CCN1CC2
Solvent: O
Solvent: CN(C)C=O
Product: CN(C(=O)Oc1ccc(Cc2ccccn2)nn1)c1ccccc1
Yield: 41.2 %

Procedure:
A solution of 6-(2-pyridinylmethyl)-3-pyridazinol (100 mg, 0.53 mmol), N-methyl-N-phenylcarbamoyl chloride (91 mg, 0.53 mmol) and 1,4-diazabicyclo[2.2.2]octane (60 mg, 0.53 mmol) in dimethylformamide (10 ml) was stirred at room temperature for 2 hours. Water was added and the solution was extracted twice with dichloromethane. The combined organic layers were dried over sodium sulphate, filtered and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, ethyl acetate) yielding the title compound (70 mg, 41% yield) as a yellow oil.
Reaction SMILES: [C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][C:4]([C:7](=[O:17])[CH2:8][N:9]2[CH2:16][CH2:15][CH2:14][C@H:10]2[C:11]([OH:13])=O)=[CH:3][CH:2]=1.C(N1CCOCC1)C.ClCCl.[CH2:35]([NH:42][C:43](=[O:53])[C@H:44]([CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[NH2:45])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(#N)C>[C:1]1([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:2]=[CH:3][C:4]([C:7](=[O:17])[CH2:8][N:9]2[CH2:16][CH2:15][CH2:14][C@H:10]2[C:11]([N:42]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:43](=[O:53])[C@H:44]([CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[NH2:45])=[O:13])=[CH:5][CH:6]=1
Reactant: O=C(CN1CCC[C@H]1C(=O)O)c1ccc(-c2ccccc2)cc1
Reactant: N[C@@H](Cc1ccccc1)C(=O)NCc1ccccc1
Agent: CCN1CCOCC1
Solvent: CC#N
Solvent: ClCCl
Product: N[C@@H](Cc1ccccc1)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)c1ccc(-c2ccccc2)cc1
Yield: 13.7 %

Procedure:
A solution of N-[2-(biphenyl-4-yl)-2-oxoethyl] L-proline (51 mg, 0.16 mmol, 1.0 eq), N-ethylmorpholine (125 uL, 0.98 mmol, 6 eq) in acetonitrile (0.5 mL) was cooled to 0° C. and treated with a 50% solution of 1-n-propylphosphonic acid cyclic anhydride in dichloromethane (170 uL, 0.27 mmol, 1.6 eq) followed by phenylalanine benzylamide (49 mg, 0.19 mmol, 3.1 eq). Purification by HPLC provided 12 mg (14%) of L-phenylalanine, N-[1-(2-(biphenyl-4-yl)-2-oxoethyl)-L-prolyl] benzylamide.
Reaction SMILES: [C:1]1([S:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH2:24][CH2:25][CH2:26]OS(C4C=CC(C)=CC=4)(=O)=O)[CH:21]=3)[NH:16][N:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH:38]1([NH2:43])[CH2:42][CH2:41][CH2:40][CH2:39]1>C1COCC1>[CH:38]1([NH:43][CH2:26][CH2:25][CH2:24][O:23][C:20]2[CH:21]=[C:22]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[C:14]3[S:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)(=[O:12])=[O:13])[CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: Cc1ccc(S(=O)(=O)OCCCOc2ccc3[nH]nc(S(=O)(=O)c4cccc5ccccc45)c3c2)cc1
Reactant: NC1CCCC1
Solvent: C1CCOC1
Product: O=S(=O)(c1cccc2ccccc12)c1n[nH]c2ccc(OCCCNC3CCCC3)cc12
Temperature: 25 °C
Yield: 100 %

Procedure:
A solution of toluene-4-sulfonic acid 3-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-propyl ester (0.080 mg, 0.15 mmol) and cyclopentylamine (0.45-0.75 mmol) in THF (10 mL) was stirred at 90° C. for 2 hours in a sealed tube. After cooling to ambient temperature, the reaction mixture was solvent evaporated. It was partitioned in ethyl acetate and washed twice with aqueous sodium bicarbonate. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography using 0.75% ammonium hydroxide/7.5% methanol in chloroform to give cyclopentyl-{3-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-propyl}-amine as a beige foam (70.6 mg, 100%). This compound was dissolved in methanol, and ethereal hydrochloride was added. Concentrating and drying in vacuo for 12.5 hours at 83° C. gave the hydrochloride as a light brown foam (69.7 mg, 95.6%); Mass Spectrum (+EI, [M+H]+) m/z 450. 1HNMR (500 MHz, DMSO-d6): δ14.15-14.21 (br, 1H), 8.70-8.83 (m, 3H), 8.51-8.53 (m, 1H), 8.27 (d, 1H, J=8.30 Hz), 8.03-8.05 (m, 1H), 7.71-7.75 (m, 1H), 7.54-7.65 (m, 3H), 7.30 (d, 1H, J=2.20 Hz), 7.09 (dd, 1H, J=9.15 Hz and 2.31 Hz), 4.11 (t, 2H, J=6.10 Hz), 3.43-3.49 (m, 1H), 3.06 (br, s, 2H), 2.05-2.14 (m, 2H), 1.88-1.96 (m, 2H), 1.43-1.71 ppm (m, 6H). Elemental Analysis for C25H27N3O3S.1.00 mol HCl.0.75 mol H2O: Calcd: C, 60.11; H, 5.95; N, 8.41; Found: C, 59.71; H, 5.83; N, 8.25.
Reaction SMILES: [CH2:1]([C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1/[CH:17]=[CH:18]/[C:19]([OH:21])=[O:20])[CH2:2][CH2:3][CH3:4].[N+:22]([C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1)([O-:24])=[O:23].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:22]([C:25]1[CH:30]=[CH:29][C:28]([O:20][C:19](=[O:21])/[CH:18]=[CH:17]/[C:6]2[CH:7]=[CH:8][C:9]3[C:14](=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=3)[C:5]=2[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:27][CH:26]=1)([O-:24])=[O:23]
Reactant: CCCCc1c(/C=C/C(=O)O)ccc2cc(OC)ccc12
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCc1c(/C=C/C(=O)Oc2ccc([N+](=O)[O-])cc2)ccc2cc(OC)ccc12
Temperature: 25 °C
Yield: 93.5 %

Procedure:
A stirred mixture of (E)-3-(1-butyl-6-methoxy-2-naphthalenyl)-2-propenoic acid (1.5 g) and 4-nitrophenol (0.81 g) in dichloromethane, was cooled in an ice bath, during the addition of a solution of 1,3-dicyclohexyl- carbodiimide (1.1 g) in dichloromethane (5 mL) then the reaction was stirred at room temperature over the weekend. After the precipitated dicyclohexylurea was removed by filtration, the filtrate was concentrated and applied to a column of silica gel (25 g) made up in dichloromethane-hexane (2:1). Elution with the same solvent mixture and concentration of the appropriate fractions yielded 2 g of (E)-3-(1-butyl-6-methoxy-2-naphthalenyl)-2-propenoic acid 4-nitrophenyl ester. Crystallization of the material from 2-propanol gave 1.85 g of the active ester, mp 140°-141° C. Anal. Calcd for C24H23NO5 : C, 71.10; H, 5.72; N, 3.45 Found: C, 70.98; H, 5.50; N, 3.33
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:16])[CH:14]=2)[CH:9]=[CH:8][CH:7]=1)=[O:4].[C:17]([Si:21]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)Cl)([CH3:20])([CH3:19])[CH3:18].N1C=CN=C1.CCOC(C)=O>CN(C=O)C>[Cl:1][CH2:2][C:3]([NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][Si:21]([C:17]([CH3:20])([CH3:19])[CH3:18])([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:14]=2)[CH:9]=[CH:8][CH:7]=1)=[O:4]
Reactant: O=C(CCl)Nc1cccc2ccc(O)cc12
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](Oc1ccc2cccc(NC(=O)CCl)c2c1)(c1ccccc1)c1ccccc1

Procedure:
A solution of product from Step H (13.6 g, 57.87 mmol), tert-butyldiphenylchlorosilane (14.86 mL, 69.45 mmol), and imidazole (5.9 g, 86.8 mmol) in DMF (250 mL) was stirred at room temperature for 72 hours. The reaction was poured into EtOAc (200 mL), and washed with H2O (3×100 mL). The organic layer was dried with magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by column chromatography (15% ethyl acetate/hexane) to provide the title compound as a brown solid.
Reaction SMILES: [N:1]1([CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]([OH:11])=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:18]12[CH2:25][CH2:24][CH:21]([CH2:22][CH2:23]1)[C@@H:20](O)[CH2:19]2.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1>[N:1]1([CH:8]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:9]([O:11][C@@H:20]2[CH:21]3[CH2:24][CH2:25][N:18]([CH2:23][CH2:22]3)[CH2:19]2)=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O[C@H]1CN2CCC1CC2
Reactant: O=C(O)C(c1ccccc1)N1CCCCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(O[C@H]1CN2CCC1CC2)C(c1ccccc1)N1CCCCCC1
Temperature: 25 °C
Yield: 15.7 %

Procedure:
A mixture of 2-(azepan-1-yl)-2-phenylacetic acid (476 mg, 2.04 mmol), (R)-quinuclidin-3-ol (311 mg, 2.45 mmol), HOBT (375 mg, 2.45 mmol) and DCC (505 mg, 2.45 mmol) in THF (20 ml) was stirred at room temperature over a week-end. THF was evaporated, the crude was taken up with EtOAc and washed twice with 2M K2CO3 and then with brine. The organic phase was dried over Na2SO4, filtered and evaporated to dryness. The crude was purified by flash-chromatography (DCM/MeOH=95/5) to get (R)-quinuclidin-3-yl 2-(azepan-1-yl)-2-phenylacetate (110 mg, 15.7% yield) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:12]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[N:13][CH:14]=[C:7]1[C:6](=[O:21])[NH:5]2.[NH:22]1[CH:26]=[CH:25][CH:24]=[N:23]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>[Cu](I)I.O>[CH:15]1([C:12]2[N:8]3[C:9]4[C:4]([NH:5][C:6](=[O:21])[C:7]3=[CH:14][N:13]=2)=[CH:3][C:2]([N:22]2[CH:26]=[CH:25][CH:24]=[N:23]2)=[CH:11][CH:10]=4)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: c1cn[nH]c1
Reactant: O=c1[nH]c2cc(Br)ccc2n2c(C3CCCCC3)ncc12
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1[nH]c2cc(-n3cccn3)ccc2n2c(C3CCCCC3)ncc12
Temperature: 160 °C
Reaction time: 22 h

Procedure:
7-Bromo-1-cyclohexylimidazo[1,5-a]quinoxalin-4(5H)-one as synthesized in above Example 145, 200 mg, pyrazole 59 mg, potassium carbonate 120 mg, copper iodide 28 mg and N,N-dimethylformamide 4 mL were mixed and stirred for 22 hours at 160° C. The reaction liquid was poured into water, and the precipitated matter was recovered by filtration. The precipitate was mixed with 25% aqueous ammonia and methanol, and heated under stirring. The insoluble matter was recovered by filtration, washed with water and dried by heating under reduced pressure to provide 30 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[N+:12]([O-])([OH:14])=[O:13]>OS(O)(=O)=O>[F:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cc(F)ccc1O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc(F)cc([N+](=O)[O-])c1O
Yield: 95.6 %

Procedure:
To a mixture of 5-fluoro-2-hydroxybenzoic acid (3.08 g, 19.76 mmol) in concentrated H2SO4 (30 mL) below 0° C. was added dropwise a mixture of concentrated HNO3 (2.11 g, 21.74 mmol) and concentrated H2SO4 (6 mL) with stirring below 5° C. After the addition, the mixture was stirred at this temperature for 2 hr. The reaction mixture was poured onto crash ice and the precipitate was collected, then the precipitate was dissolved in ethyl acetate (100 mL), washed with water (50 mL×2), brine (30 mL), dried over anhydrous sodium sulfate and concentrated to give 5-fluoro-2-hydroxy-3-nitrobenzoic acid (3.8 g) as a brown solid. LC-MS (ESI) m/z 202 [M+1]+.
Reaction SMILES: CO[C:3]([CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]3([CH3:19])[O:18]CCO3)[CH:12]=2)[N:7]([CH2:20][CH3:21])[C:6]1=[O:22])=[O:4].[NH2:23][C:24]1[CH:25]=[C:26]([CH:37]=[CH:38][CH:39]=1)[C:27]([NH:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)=[O:28]>>[F:36][C:33]1[CH:34]=[CH:35][C:30]([NH:29][C:27]([C:26]2[CH:25]=[C:24]([NH:23][C:3]([CH:5]3[C:13]4[C:8](=[CH:9][CH:10]=[C:11]([C:14](=[O:18])[CH3:19])[CH:12]=4)[N:7]([CH2:20][CH3:21])[C:6]3=[O:22])=[O:4])[CH:39]=[CH:38][CH:37]=2)=[O:28])=[CH:31][CH:32]=1
Reactant: CCN1C(=O)C(C(=O)OC)c2cc(C3(C)OCCO3)ccc21
Reactant: Nc1cccc(C(=O)Nc2ccc(F)cc2)c1
Product: CCN1C(=O)C(C(=O)Nc2cccc(C(=O)Nc3ccc(F)cc3)c2)c2cc(C(C)=O)ccc21

Procedure:
Prepared as in Example 1 from 1-ethyl-5-(2-methyl-[1,3]dioxolan-2-yl)-2-oxo-2,3-dihydro-1H-indole-3-carboxylic acid methyl ester and 3-amino-N-(4-fluoro-phenyl)-benzamide. Recrystallized from ethyl acetate-hexanes-benzene. Calculated for C26H22FN3O4 : C 67.97; H 4.83; N 9.15; found C 68.34; H 5.31; N 8.80.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([C:12]([OH:14])=O)=[CH:9][C:8]=2[CH:15]=1)([O-:3])=[O:2].Cl.Cl.[NH2:18][C@@H:19]1[CH:24]2[CH2:25][CH2:26][N:21]([CH2:22][CH2:23]2)[CH2:20]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[N:21]12[CH2:26][CH2:25][CH:24]([CH2:23][CH2:22]1)[C@@H:19]([NH:18][C:12]([C:10]1[O:11][C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:15][C:8]=3[CH:9]=1)=[O:14])[CH2:20]2
Reactant: N[C@H]1CN2CCC1CC2
Reactant: O=C(O)c1cc2cc([N+](=O)[O-])ccc2o1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2cc([N+](=O)[O-])ccc2o1
Reaction time: 0.67 h

Procedure:
1248 mg (6.03 mmol) of 5-nitrobenzofuran-2-carboxylic acid, 1000 mg (5.02 mmol) of (R)-3-aminoquinuclidine dihydrochloride, 2291 mg (6.03 mmol) of HATU, 2250 mg (18.08 mmol) of N,N-diisopropylethylamine and 15 ml of DMF are reacted according to the general procedure (variant B). DMF is removed under reduced pressure. The reaction mixture is taken up in methanol and stirred together with acidic ion exchange resin (Dowex WX2-200) for about 40 min. The loaded ion exchanger is washed six times with in each case 100 ml of methanol. It is then eluted using methanol/triethylamine 99:1 to 90:10. The solvent is removed under reduced pressure. The product is taken up in 1N aqueous sodium hydroxide solution and extracted three times with ethyl acetate. The extract is dried on magnesium sulfate. 1100 mg (69% of theory) of the title compound are isolated.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2.[SH:18][C:19]1[N:23]=[CH:22][NH:21][N:20]=1>>[NH:21]1[CH:22]=[N:23][C:19]([S:18][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]3)=[N:20]1
Reactant: Sc1nc[nH]n1
Reactant: O=C1CCc2cc(OCCCCBr)ccc2N1
Product: O=C1CCc2cc(OCCCCSc3nc[nH]n3)ccc2N1

Procedure:
Prepared analogous to Example 122 from 6-(4-bromo-butoxy)-3,4-dihydro-carbostyril (m.p. 142°-147° C.) and 3-mercapto-1,2,4-triazole.