Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][CH2:11][CH2:12][OH:13])[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[CH3:21][S:22]([O:13][CH2:12][CH2:11][CH2:10][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH3:9])(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: CN(CCCO)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(CCCOS(C)(=O)=O)C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 110.4 %

Procedure:
A solution of 3-(N-t-butoxycarbonyl-N-methylamino)propanol (2.40 g) and triethylamine (2.07 g) in methylene chloride (25 ml) was cooled to 0° C. and treated with methanesulfonyl chloride (1.883 g). After being stirred for 1 hour at 0°-4° C., the solution was evaporated in vacuo. The residue was partitioned between ethyl acetate (25 ml) and water (50 ml). The separated organic layer was washed with 0.5N hydrochloric acid (50 ml), water (50 ml), aqueous sodium bicarbonate (50 ml), water (50 ml) and brine (50 ml) successively, and dried over magnesium sulfate. The evaporation of the solvent gave 3-(N-t-butoxycarbonyl-N-methylamino)propyl methanesulfonate (3.742 g) as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21]Cl)[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:26]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21][N:32]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCNCCCCCC
Reactant: O=C1c2c(Cl)cccc2-n2cnc(-c3noc(CCl)n3)c2[C@@H]2CCN12
Solvent: CN(C)C=O
Product: CCCCCCN(CCCCCC)Cc1nc(-c2ncn3c2[C@@H]2CCN2C(=O)c2c(Cl)cccc2-3)no1
Yield: 56.5 %

Procedure:
1.13 g (3 mmol) of (S)-8-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one were stirred at room temperature overnight with 1.7 g (9 mmol) of dihexylamine and 15 ml of N,N-dimethylformamide. By evaporation of the reaction mixture and chromatography of the residue on silica gel while eluting with ethyl acetate there was obtained 0.89 g (56%) of (S)-8-chloro-1-(5-dihexylaminomethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one, which was converted into the hydrochloride (amorphous).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C@@H:4]([NH2:12])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(N(CC)C(C)C)(C)C.C([O:25][C:26](=O)/[CH:27]=[C:28](/[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[S:38][CH3:39])\[CH2:29]Br)C>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C@@H:4]([N:12]1[CH2:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[S:38][CH3:39])=[CH:27][C:26]1=[O:25])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)[C@@H](N)CC1CCCCC1
Reactant: CCOC(=O)/C=C(\CBr)Oc1ccccc1SC
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2ccccc2SC)=CC1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 12.8 %

Procedure:
To a stirred solution of (S)-2-amino-3-cyclohexyl-propionic acid methyl ester (1.10 g, 0.006 mol) in N,N-dimethylformamide (10 mL) was added N,N-diisopropylethylamine (3.51 g, 0.027 mol) slowly at room temperature, under nitrogen. The resulting mixture was stirred for 5 min and then treated with (E)-4-bromo-3-(2-methylsulfanyl-phenoxy)-but-2-enoic acid ethyl ester (1.80 g, 0.005 mol) and the reaction mixture was heated at 110° C.-120° C. for 16 h. After this time, ice water was added and the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (silica gel (100-200 mesh)) afforded (S)-3-cyclohexyl-2-[4-(2-methylsulfanyl-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester (250 mg, 11%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]([CH:16]([CH3:18])[CH3:17])[C:7]([N:9]3[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]3)=[N:8][C:4]=2[CH:3]=1.[N+:21]([O-])([OH:23])=[O:22].O.[OH-].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][C:5]2[N:6]([CH:16]([CH3:18])[CH3:17])[C:7]([N:9]3[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]3)=[N:8][C:4]=2[CH:3]=1
Reactant: CC(C)n1c(N2CCN(C)CC2)nc2cc(Cl)ccc21
Reactant: O=[N+]([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)n1c(N2CCN(C)CC2)nc2cc(Cl)c([N+](=O)[O-])cc21
Temperature: 60 °C
Reaction time: 1 h

Procedure:
5-Chloro-1-isopropyl-2-(4-methyl-1-piperazinyl)benzimidazole (2.7 g) was dissolved in acetic acid (15 ml). To the solution was added fuming nitric acid (3 ml) at 0° C. and then the mixture was stirred at 60° C. for 1 hour. The reaction mixture was poured into water and the mixture was made basic with an aqueous sodium hydroxide solution and extracted with chloroform. The chloroform layer was washed with water and dried over anhydrous magnesium sulfate and then the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography [eluted with chloroform-methanol (10:1, v/v)] to give 5-chloro-1-isopropyl-2-(4-methyl-1-piperazinyl)-6-nitrobenzimidazole (1.8 g). A part of the obtained product was recrystallized from acetonitrile, which showed the following physical properties:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[CH:8]=[C:9]([CH:38]=[CH:39][CH:40]=1)[C:10]([CH2:12][NH:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([O:22][C:23](=[O:37])[NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:18][CH2:17]1)=[O:11])=[O:6].[BH-](O[C:51]([CH3:53])=[O:52])(OC(C)=O)OC(C)=O.[Na+]>CO>[OH:52][C:51]1[CH:53]=[CH:5][C:7]([CH2:8][NH:1][CH2:2][CH2:3][NH:4][C:5]([C:7]2[CH:8]=[C:9]([CH:38]=[CH:39][CH:40]=2)[C:10]([CH2:12][NH:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([O:22][C:23](=[O:37])[NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:18][CH2:17]2)=[O:11])=[O:6])=[CH:40][CH:39]=1
Reactant: NCCNC(=O)c1cccc(C(=O)CNCCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)c1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: O=C(Nc1ccccc1-c1ccccc1)OC1CCN(CCNCC(=O)c2cccc(C(=O)NCCNCc3ccc(O)cc3)c2)CC1

Procedure:
A solution of biphenyl-2-ylcarbamic acid 1-(2-{[3-(2-aminoethylcarbamoyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester (9.31 g, 17.1 mmol; prepared as described in Preparation 8) and 4-hydroxybenzaldehyde10,411,879 (2.30 g, 18.8 mmol, 1.1 eq) in 125 mL MeOH was stirred at room temperature for 2 hours. Na(OAc)3BH (7.26 g, 34.2 mmol, 2.0 eq) was added to the reaction at room temperature in two portions separated in one hour interval. The reaction was stirred for an additional hour before being concentrated under vacuum. The residue was taken up in 100 mL DCM and stirred with 100 mL of 1.0 N HCl for 1 hour. The aqueous phase was adjusted to pH 9 using 10.0 N NaOH. The mixture was stirred for an additional 10 minutes. The organic phase was separated, dried over Na2SO4, filtered and concentrated under vacuum. The crude material was purified using silica gel chromatography (7% MeOH in CH2Cl2 with 1% NH4OH as eluent). The title compound was obtained as an off-white solid (8.08 g, 73%). MS m/z: [M+H+] calcd for C38H43N5O5, 650.34. Found, 650.2.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[CH2:3][CH2:4][N:5]1[C:21](=[O:22])[C:20]2[C:19]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([O:23][CH3:24])[CH:17]=4)[NH:12][C:11]=3[CH:10]=[CH:9][C:8]=2[C:6]1=[O:7].[H-].[Na+].S(OC)(O[CH3:32])(=O)=O>CN(C)C=O>[CH3:1][N:2]([CH3:25])[CH2:3][CH2:4][N:5]1[C:21](=[O:22])[C:20]2[C:19]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([O:23][CH3:24])[CH:17]=4)[N:12]([CH3:32])[C:11]=3[CH:10]=[CH:9][C:8]=2[C:6]1=[O:7]
Reactant: COS(=O)(=O)OC
Reactant: COc1ccc2[nH]c3ccc4c(c3c2c1)C(=O)N(CCN(C)C)C4=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c1c3c(ccc1n2C)C(=O)N(CCN(C)C)C3=O
Temperature: 40 °C
Reaction time: 0.33 h
Yield: 51.3 %

Procedure:
In 10 ml of N,N-dimethylformamide was dissolved 380 mg of N-(2-dimethylaminoethyl)-6-methoxycarbazole-3,4-dicarboximide. Thereto was added 45 mg of 60% sodium hydride. The mixture was stirred at 40° C. for 20 minutes and then cooled to 20° C. Thereto was added 140 mg of dimethyl sulfate, and the resulting mixture was stirred at the same temperature for 2 hours. The solvent was removed by distillation under reduced pressure. The residue was mixed with 50 ml of ethyl acetate and 25 ml of water to dissolve the residue. The organic layer was separated, washed with an aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was recrystallized from n-propanol to obtain 200 mg (yield: 50%) of N-(2-dimethylaminoethyl)-6-methoxy-9-methylcarbazole-3,4-dicarboximide as yellow crystals.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[CH2:6]([N:10]=[C:11]=[O:12])[CH2:7][CH2:8][CH3:9]>[N+](C1C=CC=CC=1)([O-])=O.C(Cl)(Cl)(Cl)Cl>[CH2:6]([NH:10][C:11]([C:2]1[NH:1][CH:5]=[CH:4][N:3]=1)=[O:12])[CH2:7][CH2:8][CH3:9]
Reactant: CCCCN=C=O
Reactant: c1c[nH]cn1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O=[N+]([O-])c1ccccc1
Product: CCCCNC(=O)c1ncc[nH]1
Yield: 18 %

Procedure:
A solution of 0.10 mol of imidazole and 0.10 mol of n-butyl isocyanate in 40 ml of nitrobenzene was heated under reflux for 8 hours. After cooling the reaction mixture, it was diluted with carbon tetrachloride and the solid was filtered off and washed with carbon tetrachloride until the carbon tetrachloride runnings were colourless. After drying, imidazole-2-carboxylic acid n-butylamide was obtained in 18% yield. Melting point: 188°-190° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:12])[N:10]=2)[CH2:3]1.[CH3:18][S:19](Cl)(=[O:21])=[O:20].C(N(CC)CC)C>C(Cl)Cl>[CH3:18][S:19]([O:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11]([N:13]3[CH2:14][CH2:15][CH2:16][CH2:17]3)=[O:12])[N:10]=2)[CH2:3]1)(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(c1csc(N2CC(O)C2)n1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CN(c2nc(C(=O)N3CCCC3)cs2)C1
Reaction time: 1 h
Yield: 88.7 %

Procedure:
To a solution of 3-hydroxy-1-(4-pyrrolidinocarbonyl-1,3-thiazol-2-yl)azetidine (290 mg, 1.14 mmol) (obtained as described in Reference Example 26(2)) in methylene chloride (9 ml) were added methanesulfonyl chloride (0.30 ml, 5.12 mmol) and triethylamine (0.70 ml, 5.12 mmol) in an ice bath, and the mixture was stirred for 1 hour. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using methylene chloride:ethyl acetate (1:1)→ethyl acetate as the eluant to afford 3-methanesulfonyloxy-1-(4-pyrrolidinocarbonyl-1,3-thiazol-2-yl)azetidine (335 mg, yield 89%) as a pale yellow solid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)=[CH:6][CH:5]=[C:4]([Cl:17])[N:3]=1.[CH2:18]([NH2:20])[CH3:19]>C1COCC1>[Cl:17][C:4]1[N:3]=[C:2]([NH:20][CH2:18][CH3:19])[C:7]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)=[CH:6][CH:5]=1
Reactant: O=C(c1cccc(Cl)c1)c1ccc(Cl)nc1Cl
Reactant: CCN
Solvent: C1CCOC1
Product: CCNc1nc(Cl)ccc1C(=O)c1cccc(Cl)c1

Procedure:
To a THF solution of 2,6-dichloro-3-(3-chlorobenzoyl)pyridine was added a 70% ethylamine aqueous solution, followed by reaction at room temperature. Thereafter, the reaction mixture was worked up and purified in a usual manner to obtain 6-chloro-3-(3-chlorobenzoyl)-2-ethylaminopyridine. NMR1: 8.95 (1H, brs), 6.48 (1H, d, J=7.8 Hz), 1.31 (3H, t, J=7.1 Hz).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([NH2:15])[C:13]=1[Cl:14])[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl>[OH-].[Na+].O>[CH2:16]([NH:15][C:12]1[CH:11]=[C:7]([CH:6]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[C:13]=1[Cl:14])[C:8]([OH:10])=[O:9])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(N)c1Cl
Reactant: BrCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CS(=O)(=O)c1cc(C(=O)O)cc(NCc2ccccc2)c1Cl

Procedure:
To a solution of 3-methylsulfonyl-4-chloro-5-aminobenzoic acid (1.25 g.) in 1N sodium hydroxide (5 ml.) is added benzyl bromide (1 ml.). The stirred reaction is heated at 45°-50° C. for 6 hours with the occasional addition of a few drops of 1N sodium hydroxide to maintain a pH of 9. The reaction mixture is diluted with water (50 ml.) and acidified with 1N hydrochloric acid to give 0.9 g. (53 %) of 3-benzylamino-4-chloro-5-methylsulfonylbenzoic acid, m.p. 254°-256.5° C. after recrystallization from nitromethane.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH2:20])(C)(C)C.CC1(C)O[C:27](=[O:29])[CH:26]=[C:25]([C:30]2[S:31][CH:32]=[CH:33][CH:34]=2)O1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:14]1([C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:25]([C:30]4[S:31][CH:32]=[CH:33][CH:34]=4)[CH2:26][C:27](=[O:29])[NH:20][C:9]=3[CH:10]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)cc1N
Reactant: CC1(C)OC(=O)C=C(c2cccs2)O1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccs2)=Nc2ccc(-c3ccccc3)cc2N1
Yield: 59.5 %

Procedure:
Prepared from (3-amino-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G9) (69 mg, 0.243 mmol) and 2,2-dimethyl-6-thiophen-2-yl-[1,3]dioxin-4-one (Example J1) (54 mg, 0.257 mmol) according to the general procedure K. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a brown solid (46 mg).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([C:6]2[N:2]([CH3:1])[C:3]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:5]=2)=[O:19])=[CH:16][CH:15]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)Cc1cccn1C
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CCOC(=O)Cc1ccc(C(=O)c2ccc(Cl)cc2)n1C
Reaction time: 0.33 h
Yield: 15.7 %

Procedure:
To a solution of (22.0 g. (0.131 mole) of ethyl N-methylpyrrole-2-acetate and 24.5 g. (0.14 mole) of p-chlorobenzoyl chloride in 120 ml. of carbon disulfide is added 35.0 g. (0.262 mole) of anhydrous aluminum chloride over a period of 20 minutes with intermittant cooling to keep the temperature at 25° C. The mixture is stirred for an additional 20 minutes. The carbon disulfide solvent is then decanted and discarded. The red gummy residue is washed with hexane and dilute hydrochloric acid and ice is added to the mixture. The mixture is extracted with ether. The ether solution is shaken with an aqueous solution of dimethylaminopropylamine and washed with dilute hydrochloric acid followed by brine. The solution is dried over magnesium sulfate and treated with charcoal. After removal of the charcoal, the solvent is evaporated in vacuo leaving a partially crystalline red oil as a residue. This material is extracted with three 500 ml. portions of boiling pentane. The combined pentane extracts are evaporated in vacuo, and the residue is crystallized from 60 ml. of cold methanol. The resulting solid is collected and washed with cold methanol; there is obtained about 6.3 g of a white crystalline solid, ethyl 5-(p-chlorobenzoyl)-1-methylpyrrole-2-acetate, m.p. 74-76° C. Recrystallization from methyl cyclohexane raises the melting point to 78-80° C.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5].[NH:12]1[CH:16]=[N:15][CH:14]=[N:13]1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:2]([N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)=[C:3]([CH:6]=1)[CH:4]=[O:5]
Reactant: c1nc[nH]n1
Reactant: COc1ccc(F)c(C=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(-n2cncn2)c(C=O)c1
Temperature: 100 °C
Yield: 20.2 %

Procedure:
To a solution of 2-fluoro-5-methoxybenzaldehyde (200 mg, 1.29 mmol) in DMSO (10 mL) are added 1,2,4-triazole (134 mg, 1.95 mmol) and K2CO3 (359 mg, 2.60 mmol) at room temperature. The solution is heated to 100° C. for 2 hours. The solution is cooled and is extracted with H2O (30 mL) and EtOAc (3×15 mL). The combined organic layer is dried with MgSO4 and is filtered. The filtrate is concentrated and the residue is purified by silica gel flash column chromatography with 50% EtOAc in heptane as the eluent to afford 5-methoxy-2-1,2,4-triazol-1-yl-benzaldehyde (53 mg, 20%) as a white foam.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[C:7]#[N:8].[NH4+]=[S:12].C(N(CC)CC)C>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([C:7](=[S:12])[NH2:8])[CH:9]=1
Reactant: N#Cc1cc(Br)ccc1F
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: NC(=S)c1cc(Br)ccc1F
Temperature: 50 °C
Yield: 97.8 %

Procedure:
5-bromo-2-fluoro-benzonitrile (12.4 mmol, 2470 mg) in pyridine (6.5 mL) was treated with ammonium sulfide (40 mass % in water, 1.1 equiv., 13.6 mmol, 2.32 mL) and triethylamine (1.1 equiv., 13.6 mmol, 1.90 mL). The reaction mixture was heated at 50° C. for 3 hours, then cooled to room temperature. The reaction mixture was partitioned between EtOAc and water. The organic later was washed with water (3×), and brine (3×), dried with MgSO4, then concentrated. The residue was purified on silica eluted with 0 to 50% EtOAc in Heptane to provide 5-bromo-2-fluoro-benzenecarbothioamide (2.84 g, 94% yield).
Reaction SMILES: [Na].Cl[C:3]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:6][S:5][N:4]=1.[CH2:14]([OH:20])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>>[CH2:14]([O:20][C:3]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:6][S:5][N:4]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCO
Reactant: Clc1nsnc1-c1cccnc1
Agent: [Na]
Product: CCCCCCOc1nsnc1-c1cccnc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of sodium (230 mg, 10 mmol) in 1-hexanol (15 ml) was added 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (490 mg, 2.5 mmol). The mixture was stirred at 50° C. for 2 h and evaporated. The residue was dissolved in water and extracted with ether. The combined organic phases were dried and evaporated to give the wanted compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]=[C:4]([CH2:8][C:9](=O)[CH3:10])[CH2:3]1.Cl.[CH2:13]([O:16][NH2:17])[CH:14]=[CH2:15]>C(O)C>[CH2:13]([O:16][N:17]=[C:8]([C:4]1[CH2:3][N:2]([CH3:1])[CH2:7][CH2:6][CH:5]=1)[CH2:9][CH3:10])[CH:14]=[CH2:15]
Reactant: CC(=O)CC1=CCCN(C)C1
Reactant: C=CCON
Agent: Cl
Solvent: CCO
Product: C=CCON=C(CC)C1=CCCN(C)C1
Yield: 52.8 %

Procedure:
1-(1,2,5,6-Tetrahydro-1-methyl-3-pyridinyl)propanone (3.06 g, 20 mmol, prepared as described in Example 8 above) was reacted with 3.27 g (30 mmol) of O-2-propenylhydroxylamine hydrochloride in 20 ml of ethanol to prepare 2.2 g (53%) of the title compound, isolated as the ethanedioate salt, mp 117°-120° C.
Reaction SMILES: [CH2:1]([N:3]([CH3:25])[C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:20]=[C:19]([CH3:21])[C:18]([OH:22])=[C:17]([CH3:23])[CH:16]=3)[N:11]=2)[CH:7]=[C:6]([CH3:24])[N:5]=1)[CH3:2].Cl[CH2:27][C@H:28]([OH:31])[CH2:29][OH:30]>C(O)(C)C.[OH-].[Na+].CC(=O)OCC>[CH2:1]([N:3]([CH3:25])[C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:20]=[C:19]([CH3:21])[C:18]([O:22][CH2:27][C@H:28]([OH:31])[CH2:29][OH:30])=[C:17]([CH3:23])[CH:16]=3)[N:11]=2)[CH:7]=[C:6]([CH3:24])[N:5]=1)[CH3:2]
Reactant: OC[C@@H](O)CCl
Reactant: CCN(C)c1cc(-c2nc(-c3cc(C)c(O)c(C)c3)no2)cc(C)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CCN(C)c1cc(-c2nc(-c3cc(C)c(OC[C@H](O)CO)c(C)c3)no2)cc(C)n1
Yield: 37.2 %

Procedure:
To a solution of 4-{5-[2-(ethyl-methyl-amino)-6-methyl-pyridin-4-yl]-[1,2,4]oxadiazol-3-yl}-2,6-dimethyl-phenol (55 mg, 0.163 mmol) in isopropanol (3 mL) and 3 N aq. NaOH (0.5 mL), (R)-3-chloro-1,2-propanediol (98 mg, 0.894 mmol) is added. The mixture is stirred at 65° C. for 72 h before another portion of (R)-3-chloro-1,2-propanediol (98 mg, 0.894 mmol) is added. Stirring is continued at 65° C. for 4 days before a third portion of (R)-3-chloro-1,2-propanediol (98 mg, 0.894 mmol) is added. After stirring for another 48 h, the mixture is diluted with EA (50 mL) and washed with 1 N aq. NaOH (10 mL) followed by brine (10 mL), dried over MgSO4, filtered and concentrated. The crude product is purified on prep. TLC plates with DCM containing 10% of 7 N NH3 in methanol and 5% of methanol to give (R)-3-(4-{5-[2-(ethyl-methyl-amino)-6-methyl-pyridin-4-yl]-[1,2,4]oxadiazol-3-yl}-2,6-dimethyl-phenoxy)-propane-1,2-diol (25 mg) as a yellow solid; LC-MS: tR=0.73 min; [M+1]+=413.14.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([OH:14])=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].O1[CH2:21][CH2:20][CH2:19][CH2:18]1>>[CH:18]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([OH:14])=[CH:10][N:9]=2)=[CH:4][CH:3]=1)=[CH:19][CH2:20][CH2:21][CH2:6][CH2:7][CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: C1CCOC1
Reactant: Oc1cnc(-c2ccc(Br)cc2)nc1
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCC=Cc1ccc(-c2ncc(O)cn2)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 75 %

Procedure:
After replacing inner atmosphere of a four-necked flask equipped with a stirring device and a thermometer with nitrogen gas, the flask was charged with 1.26 g (5 mmol) of 2-(4-bromophenyl)-5-hydroxypyrimidine, 0.01 g (0.008 mmol) of tetrakis-triphenylphosphine-palladium, 0.6 g (15 mmol) of sodium hydroxide and 20 ml of tetrahydrofuran. Then, 19.5 ml of a solution prepared by dissolving 7.5 mmol of E-1-nonenylcatecholborane, prepared in the same manner as in Example 2, in tetrahydrofuran was dropwise added at room temperature. The resulting mixture was heated under reflux with stirring for 7 hours. After cooling the mixture to room temperature, the mixture was extracted with 30 ml of toluene, and the organic layer was twice washed with each 10 ml portion of saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After distilling off the solvent, purification of the residue by silica gel column chromatography gave 1.16 g (yield 75%) of 2-{4-(1-decenyl)-phenyl}-5-hydroxypyrimidine.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][N:16]3[C:20]4[CH:21]=[CH:22][C:23]([CH3:25])=[CH:24][C:19]=4[N:18](C(C)=C)[C:17]3=[O:29])[CH2:9][CH2:8]2)[C:5]2[CH:30]=[CH:31][CH:32]=[CH:33][C:4]=2[NH:3]1.[ClH:34].O>C(O)C>[OH2:1].[ClH:34].[O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][N:16]3[C:20]4[CH:21]=[CH:22][C:23]([CH3:25])=[CH:24][C:19]=4[NH:18][C:17]3=[O:29])[CH2:9][CH2:8]2)[C:5]2[CH:30]=[CH:31][CH:32]=[CH:33][C:4]=2[NH:3]1
Reactant: C=C(C)n1c(=O)n(CCCN2CCC(n3c(=O)[nH]c4ccccc43)CC2)c2ccc(C)cc21
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1ccc2c(c1)[nH]c(=O)n2CCCN1CCC(n2c(=O)[nH]c3ccccc32)CC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
A mixture of 6 parts of 1-{3-[4-(2,3-dihydro-2-oxo-1H-benzimidazol-1yl)-1-piperidinyl]propyl}-1,3-dihydro-5-methyl-3-(1-methylethenyl)-2H-benzimidazol-2-one, 12 parts of a hydrochloric acid solution, 30 parts of water and 40 parts of ethanol is stirred first for a while at 50° C and further for 1 hour at room temperature. The reaction mixture is evaporated and the residue is crystallized from a mixture of 4-methyl-2-pentanone and 2-propanol. The product is filtered off and dried, yielding 3.7 parts (40%) of 1-{3-[4-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-1-piperidinyl]propyl}-1,3-dihydro-5-methyl-2H-benzimidazol-2-one hydrochloride hydrate; m.p. 251.4° C.