Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[C:6](=[N:7][C:8](SC)=[N:9][CH:10]=2)[N:5]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=1)[CH:2]=[CH2:3].[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][N:33]([CH2:36][C:37]([N:39]([CH3:41])[CH3:40])=[O:38])[CH2:32][CH2:31]2)=[CH:26][CH:25]=1>>[CH3:40][N:39]([CH3:41])[C:37](=[O:38])[CH2:36][N:33]1[CH2:32][CH2:31][N:30]([C:27]2[CH:28]=[CH:29][C:24]([NH:23][C:8]3[N:7]=[C:6]4[N:5]([C:16]5[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=5)[N:4]([CH2:1][C:2]#[CH:3])[C:12](=[O:13])[C:11]4=[CH:10][N:9]=3)=[CH:25][CH:26]=2)[CH2:35][CH2:34]1
Reactant: C=CCn1c(=O)c2cnc(SC)nc2n1-c1cccc(C)n1
Reactant: CN(C)C(=O)CN1CCN(c2ccc(N)cc2)CC1
Product: C#CCn1c(=O)c2cnc(Nc3ccc(N4CCN(CC(=O)N(C)C)CC4)cc3)nc2n1-c1cccc(C)n1

Procedure:
34.3 mg of the entitled compound was obtained as a yellow solid in the same manner as in Example 113-1 to 113-2, for which, however, 2-allyl-1-(6-methylpyridin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one was used in place of 2-allyl-1-[6-(1-hydroxy-1-methylethyl)-2-pyridinyl]-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one used in Example 113-1, and 2-[4-(4-aminophenyl)piperazin-1-yl]-N,N-dimethylacetamide was used in place of 4-(4-methylpiperazin-1-yl) aniline used in Example 113-2.
Reaction SMILES: O[CH2:2][C:3]1[CH:15]=[CH:14][C:6]2[S:7][C:8]([C:11]([OH:13])=[O:12])=[C:9]([CH3:10])[C:5]=2[CH:4]=1.[ClH:16].[CH3:17]O>>[CH3:17][O:13][C:11]([C:8]1[S:7][C:6]2[CH:14]=[CH:15][C:3]([CH2:2][Cl:16])=[CH:4][C:5]=2[C:9]=1[CH3:10])=[O:12]
Reactant: CO
Reactant: Cl
Reactant: Cc1c(C(=O)O)sc2ccc(CO)cc12
Product: COC(=O)c1sc2ccc(CCl)cc2c1C

Procedure:
5-Hydroxymethyl-3-methylbenzo[b]thiophene-2-carboxylic acid (4.4 g.) was dissolved in methanol (150 ml.) and the solution was saturated with hydrogen chloride gas. It was then heated under reflux for 4 hours and cooled. The solid which crystallized out was filtered off and dried. The product (3.54 g.) was shown by n.m.r. to consist of a mixture of 5-chloromethyl-3-methylbenzo[b]thiophene-2-carboxylic acid methyl ester (65%) and 5-methoxymethyl-3-methylbenzo[b]thiophene-2-carboxylic acid methyl ester. The product was chromatographed on silica gel. Elution with toluene first gave 5-chloromethyl-3-methylbenzo[b]thiophene-2-carboxylic acid methyl ester, m.p. 115°-116° C. (from petrol b.p. 40°-60° C.).
Reaction SMILES: C=C[C@@H]1[C@@H]2C[C@@H]([C@H](O)C3C4C(=CC=CC=4)N=CC=3)N(CC2)C1.[CH2:23]([CH:29]([N:33]1[CH:37]=[C:36]([N+:38]([O-:40])=[O:39])[N:35]=[CH:34]1)[C:30]([OH:32])=[O:31])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].Cl>O.C(N(CC)CC)C.C(O)C>[CH2:23]([C@@H:29]([N:33]1[CH:37]=[C:36]([N+:38]([O-:40])=[O:39])[N:35]=[CH:34]1)[C:30]([OH:32])=[O:31])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCC(C(=O)O)n1cnc([N+](=O)[O-])c1
Agent: C=C[C@H]1CN2CC[C@H]1C[C@H]2[C@H](O)c1ccnc2ccccc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: O
Product: CCCCCC[C@H](C(=O)O)n1cnc([N+](=O)[O-])c1
Temperature: 85 °C

Procedure:
To a suspension of 5.89 g (0.02 mol) of (-)-cinchonidine in 80 mL water was added 2.78 mL (2.02 g, 0.02 mol) triethylamine. The mixture was warmed to about 40°-45° C. A solution of 10.21 g (0.04 mol) of a racemic mixture of α-hexyl-4-nitro-1H-imidazole-1-acetic acid in 40 mL technical grade ethanol was added to the warm suspension with stirring. (The pH of the mixture was adjusted to 6.9-7.4 by addition of triethylamine or aqueous hydrochloric acid as required.) The resulting suspension was then heated to about 85° C. The resulting solution was allowed to cool gradually to ambient temperature with slow stirring. The precipitated salt was filtered, washed with about 30 mL of ethanol --H2O(1:2), and dried at 50° C. in vacuo to constant weight. The reaction produced 9 g of (R)-α-hexyl-4-nitro-1H-imidazole-1-acetic acid)-cinchonidine salt. A portion of the product was converted to the free acid and then derivatized as the methyl ester (diazomethane) and analyzed by HPLC on a chiral column. The analysis indicated that the acid derived from the product had an ee of 94%. Recrystallization of the product salt from ethanol--water 1:1 (13:1 volumes) provided 7.4 g of the pure salt, ee>99% (HPLC), M.Pt. 205° C. (dec). (NMR).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[NH2:14][C:15]1[C:16](=[O:23])[C:17](=[O:22])[C:18]=1OCC.O>N1C=CC=CC=1>[NH2:14][C:15]1[C:16](=[O:23])[C:17](=[O:22])[C:18]=1[NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: Nc1ccc(-c2cccnc2)cc1
Reactant: CCOc1c(N)c(=O)c1=O
Solvent: O
Solvent: c1ccncc1
Product: Nc1c(Nc2ccc(-c3cccnc3)cc2)c(=O)c1=O
Yield: 41.8 %

Procedure:
A solution of 3-(4-aminophenyl)pyridine (0.51 g) and 3-amino-4-ethoxy-3-cyclobutene 1,2-dione (0.42 g) in pyridine (2 ml) is stirred at 80° for 20 hours. The cool mixture is treated with water (15 ml), and the solid filtered off and washed with water and hot methanol. Recrystallation from dimethylformamide gives 0.33 g of the title compound, mp 3224° C. dec.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([Br:9])[N:3]=1.[C:10]([N:18]=[C:19]=[S:20])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([NH:8][C:19]([NH:18][C:10](=[O:17])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[S:20])[CH:5]=[C:4]([Br:9])[N:3]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Nc1cc(Br)nc(Br)c1
Solvent: C1CCOC1
Product: O=C(NC(=S)Nc1cc(Br)nc(Br)c1)c1ccccc1
Temperature: 70 °C
Reaction time: 16 h
Yield: 85 %

Procedure:
To a solution of 2,6-dibromopyridin-4-amine in THF (250 mL) was added benzoylisothiocyanate (3.50 mL, 26.0 mmol)) and the resulting reaction mixture heated to 70° C. for 16 h. A further 1.50 mL (11.20 mmol) of benzoylisothiocyanate was added to complete the reaction and the reaction stirred at 70° C. for 16 h. After completion (by TLC), the solvent was distilled under reduced pressure, the residue treated with 10% MeOH-ether solution then filtered to obtain the desired product as a yellow solid (7.60 g, 85%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[C:9]2[C:5]([CH2:6][C:7]([CH2:13][CH3:14])([CH3:12])[CH2:8]2)=[C:4]([CH3:15])[C:3]=1[CH:16]1[CH2:21][C:20](=[O:22])[C:19]([C:23](=O)[CH2:24][CH3:25])=[CH:18][CH2:17]1.C([O-])(=[O:29])C.[Na+].Cl.[O:33]([NH2:36])[CH2:34][CH3:35]>C(O)C>[Cl:1][C:2]1[C:10]([CH3:11])=[C:9]2[C:5]([CH2:6][C:7]([CH2:13][CH3:14])([CH3:12])[CH2:8]2)=[C:4]([CH3:15])[C:3]=1[CH:16]1[CH2:17][C:18](=[O:29])[C:19]([C:23](=[N:36][O:33][CH2:34][CH3:35])[CH2:24][CH3:25])=[C:20]([OH:22])[CH2:21]1
Reactant: CCC(=O)C1=CCC(c2c(C)c3c(c(C)c2Cl)CC(C)(CC)C3)CC1=O
Reactant: CCON
Reactant: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCON=C(CC)C1=C(O)CC(c2c(C)c3c(c(C)c2Cl)CC(C)(CC)C3)CC1=O
Temperature: 25 °C
Reaction time: 10 h
Yield: 66.4 %

Procedure:
To a solution 0.15 g of the 5-(6-chloro-2-ethyl-2,4,7-trimethylindan-5-yl)-2-propionyl-cyclohex-2-en-1-one in 10 ml of ethanol was added 0.9 g of sodium acetate (NaOAc.3H2O) and 0.64 g of ethoxylamine hydrochloride. After stirring at room temperature for 10 hours, the reaction mixture extracted with diethyl ether. The combined organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica-gel column chromatography to afford 0.1153 g of the title compound as yellow oil.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:41])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[O:39][N:38]=[C:37]([CH3:40])[CH:36]=2)[CH:30]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:16]([N:14]([CH3:15])[C:12]1[C:11]([C:20]([F:21])([F:23])[F:22])=[CH:10][C:9]2[NH:24][C:25](=[O:41])[CH2:26][C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]4[O:39][N:38]=[C:37]([CH3:40])[CH:36]=4)[CH:30]=3)=[N:7][C:8]=2[CH:13]=1)[CH:17]([CH3:18])[CH3:19]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(N(C)CC(C)C)cc3NC(=O)OC(C)(C)C)c2)on1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2cccc(C3=Nc4cc(N(C)CC(C)C)c(C(F)(F)F)cc4NC(=O)C3)c2)on1

Procedure:
The title compound was prepared from (5-(isobutyl-methyl-amino)-2-{3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M105) (0.42 g, 0.71 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (161 mg, 48%).
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH:34]=[CH:35][CH:36]=1)[C:6]([NH:8][CH2:9][C:10]([NH:12][C@@H:13]1[CH2:17][CH2:16][N:15]([CH:18]2[CH2:23][CH2:22][N:21](C(OCC3C=CC=CC=3)=O)[CH2:20][CH2:19]2)[CH2:14]1)=[O:11])=[O:7].[H][H]>CO.[Pd]>[O:11]=[C:10]([NH:12][C@@H:13]1[CH2:17][CH2:16][N:15]([CH:18]2[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]2)[CH2:14]1)[CH2:9][NH:8][C:6](=[O:7])[C:5]1[CH:34]=[CH:35][CH:36]=[C:3]([C:2]([F:38])([F:37])[F:1])[CH:4]=1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCN(C2CCN(C(=O)OCc3ccccc3)CC2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCN(C2CCNCC2)C1
Yield: 96.7 %

Procedure:
In a round-bottom flask, a slurry of benzyl 4-{(3R)-3-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]pyrrolidin-1-yl}piperidine-1-carboxylate (0.690 g, 1.30 mmol) and Palladium (10%) on Carbon (0.200 g) in methanol (10 mL) was purged with hydrogen gas for 2 min.; the reaction was then subjected to 1 atm of hydrogen gas for 3 h. The flask was purged with Argon, then the mixture was filtered and concentrated to afford N-(2-oxo-2-{[(3R)-1-piperidin-4-ylpyrrolidin-3-yl]amino}ethyl)-3-(trifluoromethyl)benzamide (0.501 g, 97%) as an off-white solid. 1H-NMR (CDCl3) δ: 1.32-1.53 (m, 2H), 1.52-2.04 (m, 6H), 2.15-2.40 (m, 2H), 2.40-2.70 (m, 3H), 2.80-3.00 (m, 3H), 4.00-4.20 (m, 2H), 4.42 (bs, 1H), 6.77 (m, 1H), 7.40-7.55 (m, 1H), 7.53 (t, J=7.8 Hz, 1H), 7.73 (d, J=7.2 Hz, 1H), 7.98 (d, J=7.5 Hz, 1H), 8.08 (s, 1H). MS m/z: 399 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].Cl[C:12]1[C:13]2[CH:26]=[C:25]([Cl:27])[S:24][C:14]=2[N:15]=[C:16]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[N:17]=1>>[N:21]1[CH:20]=[CH:19][C:18]([C:16]2[N:17]=[C:12]([NH:6][CH2:5][C:4]3[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=3)[C:13]3[CH:26]=[C:25]([Cl:27])[S:24][C:14]=3[N:15]=2)=[CH:23][CH:22]=1
Reactant: Clc1cc2c(Cl)nc(-c3ccncc3)nc2s1
Reactant: NCc1ccc(Cl)c(Cl)c1
Product: Clc1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(-c3ccncc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 4-chloro-2-(pyridin-4-yl)-6-chloro-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-(3,4-dichlorobenzylamino)-6-chloro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:41])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH:34](Cl)[C:35](OCC)=[O:36])=[CH:29][CH:28]=1)([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:9][CH2:8]2)(=[O:3])[CH3:2].[NH2:42][C:43](N)=[S:44].S1(CCCC1)(=O)=[O:47]>C1C=CC=CC=1>[C:1]([O:4][C:5]1[C:6]([CH3:41])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH:34]3[S:44][C:43](=[O:47])[NH:42][C:35]3=[O:36])=[CH:29][CH:28]=1)([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:9][CH2:8]2)(=[O:3])[CH3:2]
Reactant: NC(N)=S
Reactant: CCCCCCCCC1(COc2ccc(CC(Cl)C(=O)OCC)cc2)CCc2c(C)c(OC(C)=O)c(C)c(C)c2O1
Reactant: O=S1(=O)CCCC1
Solvent: c1ccccc1
Product: CCCCCCCCC1(COc2ccc(CC3SC(=O)NC3=O)cc2)CCc2c(C)c(OC(C)=O)c(C)c(C)c2O1

Procedure:
A mixture of 2.1 g of ethyl 3-[4-(6-acetoxy-5,7,8-trimethyl-2-octylchroman-2-ylmethoxy)phenyl]-2-chloropropionate (prepared as described in Preparation 18), 0.35 g of thiourea and 2.5 ml of sulfolane was heated for 7 hours at 120°-130° C. under a nitrogen atmosphere. The reaction mixture was then dissolved in benzene. The benzene solution was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography, eluted with a 10:1 by volume mixture of benzene and ethyl acetate, to give the title compound as a slightly yellow, foamy solid.
Reaction SMILES: COC1C=CC(C[N:8]2[CH2:14][CH:13]([CH3:15])[CH2:12][O:11][CH2:10][CH2:9]2)=CC=1.[Cl:18]C(OC(Cl)C)=O.CO>ClCCCl>[ClH:18].[CH3:15][CH:13]1[CH2:12][O:11][CH2:10][CH2:9][NH:8][CH2:14]1
Reactant: CC(Cl)OC(=O)Cl
Reactant: COc1ccc(CN2CCOCC(C)C2)cc1
Solvent: CO
Solvent: ClCCCl
Product: CC1CNCCOC1
Product: Cl
Temperature: 25 °C
Yield: 82.7 %

Procedure:
To a solution of 4-(4-methoxy-benzyl)-6-methyl-[1,4]oxazepane (3.24 g, 13.8 mmol) in 1,2-dichloroethane (23 ml) was added 1-chloroethyl chloroformate (4.93 g, 34.5 mmol) at room temperature. The mixture was refluxed for 7 hours. The reaction mixture was cooled to room temperature and then methanol (30 ml) was added. The mixture was refluxed for 5 hours and concentrated in vacuo. This crude product was washed with hexane, dried under reduced pressure to afford 6-methyl-[1,4]oxazepane hydrochloride as white solid (1.73 g, 83%).
Reaction SMILES: [C:1]([C:4]1[C:9](=[O:10])[C:8]([O:11][CH3:12])=[CH:7][N:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=3)[C:14]=2[F:25])[N:5]=1)(=O)[CH3:2].[CH3:26]C(O)=O.[C:30]1([NH:36][NH2:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>COC(OC)N(C)C.Cl>[F:25][C:14]1[C:15]([C:19]2[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=2)=[CH:16][CH:17]=[CH:18][C:13]=1[N:6]1[CH:7]=[C:8]([O:11][CH3:12])[C:9](=[O:10])[C:4]([C:1]2[N:36]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:37]=[CH:26][CH:2]=2)=[N:5]1
Reactant: COc1cn(-c2cccc(-c3cnn(C)c3)c2F)nc(C(C)=O)c1=O
Reactant: NNc1ccccc1
Reactant: CC(=O)O
Agent: COC(OC)N(C)C
Agent: Cl
Product: COc1cn(-c2cccc(-c3cnn(C)c3)c2F)nc(-c2ccnn2-c2ccccc2)c1=O
Yield: 62 %

Procedure:
A mixture of 3-acetyl-1-[2-fluoro-3-(1-methyl-1H-pyrazol-4-yl)phenyl]-5-methoxypyridazin-4(1H)-one (243 mg, 0.708 mmol) in N,N-dimethylformamide dimethyl acetal (2.4 mL) was heated to reflux for 2 h. The mixture was concentrated in vacuo. To the residue were added AcOH (2.4 mL) and phenylhydrazine (0.139 mL, 1.42 mmol). The mixture was heated to reflux for 2 h. The mixture was diluted with 1 M HCl aqueous solution, extracted with AcOEt, washed with saturated NaHCO3 aqueous solution, dried over Na2SO4, filtered, concentrated in vacuo, purified by column chromatography on basic silica gel (hexane/AcOEt=20/80 to 0/100) and recrystallized with EtOH/AcOEt/hexane to yield the title compound (193 mg, 62% yield) as a pale yellow solid: mp 218-221° C. 1H NMR (DMSO-d6, 300 MHz): δ ppm 3.78 (3H, s), 3.91 (3H, s), 6.97 (2H, d, J=1.9 Hz), 7.13-7.50 (6H, m), 7.72-7.84 (2H, m), 7.93 (1H, s), 8.18 (1H, d, J=2.3 Hz), 8.55 (1H, d, J=1.9 Hz).
Reaction SMILES: [F:1][CH2:2][C:3]([CH2:7][F:8])([OH:6])[C:4]#[CH:5].[H-].[Na+].[CH2:11]([S:14](Cl)(=[O:16])=[O:15])[CH2:12][CH3:13].O>O1CCCC1>[CH2:11]([S:14]([O:6][C:3]([CH2:7][F:8])([C:4]#[CH:5])[CH2:2][F:1])(=[O:16])=[O:15])[CH2:12][CH3:13]
Reactant: CCCS(=O)(=O)Cl
Reactant: C#CC(O)(CF)CF
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C#CC(CF)(CF)OS(=O)(=O)CCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
An amount (2.4 g) of 1-fluoro-2-fluoromethyl-3-butyn-2-ol was dissolved in tetrahydrofuran (20 ml); to the solution under cooling with ice, 60% oily sodium hydride (0.96 g) was added under a nitrogen atmosphere. After stirring for 30 minutes under cooling with ice, propanesulfonyl chloride (2.2 ml) was added dropwise. The mixture was stirred for 5 hours while its temperature was raised to room temperature. Water was added to the reaction mixture, followed by extraction with ether. The extract was washed with water and a saturated aqueous solution of sodium chloride, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluent; 30% ethyl acetate/hexane) to give the titled compound (4.1 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:12][N:11]=[N:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl[CH2:14][C:15]([O:17][CH3:18])=[O:16]>>[CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[N:10]=[N:11][N:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(-c2nnn[nH]2)c1
Reactant: COC(=O)CCl
Product: COC(=O)Cn1nnnc1-c1cccc(C)c1

Procedure:
Feed materials: 5-(3-methylphenyl)tetrazole and methyl chloroacetate.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[C:10]([F:17])[CH:9]=1.CC1(C)C(C)(C)OB([C:26]2[CH:27]=[N:28][C:29]([NH2:32])=[N:30][CH:31]=2)O1>O.C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:32][C:29]1[N:30]=[CH:31][C:26]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[C:10]([F:17])[CH:9]=2)=[CH:27][N:28]=1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: O=C(O)c1ccc(Br)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: Nc1ncc(-c2ccc(C(=O)O)c(F)c2)cn1
Temperature: 120 °C

Procedure:
A solution of sodium carbonate (1.4 g, 0.014 mol) in water (8 mL) was added to a mixture of 4-bromo-2-fluorobenzoic acid (1.0 g, 0.0046 mol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (1.5 g, 6.8 mmol), and tetrakis(triphenylphosphine)palladium (0.3 g, 0.2 mmol) in toluene (16 mL) and ethanol (8 mL). The resulting mixture was heated at 120° C. for 15 min. The reaction mixture was washed with ether (3×10 mL) to remove impurity. The aqueous layer was adjusted with 1N HCl to pH 7.0, and purified by RP-HPLC (pH 10) to afford the desired product. LCMS: (M+H)=234.1.
Reaction SMILES: [C:1]1([N:7]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:8]([C:10]2[CH:31]=[CH:30][C:13]3[N:14]([CH:27]4[CH2:29][CH2:28]4)[C:15]([CH2:17][NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:39].C(O)C.C(=O)([O-])[O-].[NH4+:47].[NH4+]>ClCCl.CO>[ClH:39].[C:1]1([N:7]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:8]([C:10]2[CH:31]=[CH:30][C:13]3[N:14]([CH:27]4[CH2:28][CH2:29]4)[C:15]([CH2:17][NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25](=[NH:47])[NH2:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [NH4+]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C#N)cc1)n2C1CC1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCO
Solvent: CO
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C1CC1)c1ccccc1
Yield: 31 %

Procedure:
Prepared analogously to Example 25d from 1-cyclopropyl-2-[N-(4-cyanophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)amide, ethanolic hydrochloric acid, ethanol, and ammonium carbonate. Yield: 31% of theory, C30H33N6O3 (524.6); Rf value: 0.40 (silica gel; dichloromethane/methanol=5:1); EKA mass spectrum: (M+H)+=525; (M+H+Na)++=274; (M+2H)++=263.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:10][N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([OH:17])[CH2:12]1>>[CH3:10][N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([O:17][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH2:12]1
Reactant: CN1CCCC(O)C1
Reactant: N#Cc1ccccc1F
Product: CN1CCCC(Oc2ccccc2C#N)C1

Procedure:
2-Fluoro-benzonitrile was reacted with 1-methyl-piperidin-3-ol according to the method of Example 85A to provide the title compound. MS (DCI/NH3) m/z 217 (M+1)+.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([F:16])[C:10]=1[CH3:17].N1C=CC=CC=1.[C:24](OCC)(=[O:26])[CH3:25]>>[C:1]([O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:24](=[O:26])[CH3:25])=[C:10]([CH3:17])[C:11]=1[F:16])(=[O:3])[CH3:2]
Reactant: Cc1c(N)ccc(O)c1F
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(OC(C)=O)c(F)c1C
Temperature: 65 °C
Reaction time: 0.75 h
Yield: 15 %

Procedure:
Acetic anhydride (4.49 ml, 47.6 mmol) was added dropwise to a solution of 4-amino-2-fluoro-3-methylphenol (2.80 g, 1.91 mmol) and pyridine (3.53 ml, 43.6 mmol) in ethyl acetate (60 ml) at room temperature, and the resulting mixture was slowly heated to 65° C. and stirred for 45 minutes while being maintained at this temperature. The resulting reaction solution was cooled to room temperature and partitioned by the use of water and ethyl acetate to find that an insoluble material was present. The insoluble material was collected by filtration and dried to obtain 4-(acetylamino)-2-fluoro-3-methylphenyl acetate (679 mg, 15%). The filtrate was concentrated and then extracted with chloroform to obtain a crude product, and the crude product was washed with ethyl acetate (8 ml)-hexane (24 ml) by repulping, collected by filtration and then dried to obtain 4-(acetylamino)-2-fluoro-3-methylphenyl acetate (3.54 g, 79%).
Reaction SMILES: [CH2:1]([NH:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[CH3:2].C=O.[CH3:12]CCCC=C>>[CH3:12][N:3]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[CH2:1][CH3:2]
Reactant: CCNC1CCCCC1
Reactant: C=CCCCC
Agent: C=O
Product: CCN(C)C1CCCCC1
Yield: 391 %

Procedure:
In a similar manner to Example 1, 190.8 g (1.5 mol) of N-ethylcyclohexylamine and 247.6 g (2.4 mol) of formaldehyde (29.1%) are reacted in a 1 l autoclave; a maximum pressure of 2.6 MPa is established at a temperature of 160° C. After the end of the reaction, 30 g of hexene-1 are added and the organic phase is removed from the aqueous phase. The remaining organic phase is subsequently fractionally distilled. 196.9 g of N-methyl-N-ethylcyclohexylamine having a purity of 98.7% are isolated, corresponding to a yield of 91.8% of theory.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=2[F:19])=[N:9][NH2:10])=[N:4][CH:5]=[CH:6][N:7]=1.C1N=CN([C:25](N2C=NC=C2)=[O:26])C=1>C1COCC1>[NH2:1][C:2]1[C:3]([C:8]2[N:11]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=3[F:19])[C:25]([OH:26])=[N:10][N:9]=2)=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NN=C(Nc1cccc(F)c1F)c1nccnc1N
Solvent: C1CCOC1
Product: Nc1nccnc1-c1nnc(O)n1-c1cccc(F)c1F
Reaction time: 8 h
Yield: 91.2 %

Procedure:
3-Amino-N-(2,3-difluorophenyl)-N′-aminopyrazine-2-carboxamidine (500 mg, 1.89 mmol) was dissolved in dry THF (10 mL) and CDI (340 mg, 2.10 mmol) was added at RT. The solution was kept at RT for overnight. After the solvent was removed by evaporation, the residue was added to saturated NaHCO3 solution and filtered. After washing with water, the crude yellow solid product (500 mg, 91%) was obtained after drying under vacuum. LC-MS m/e=290.8 (M+H). Using the same procedure, 5-(3-aminopyrazin-2-yl)-4-(2,3-dichlorophenyl)-4H-1,2,4-triazol-3-ol, 5-(3-aminopyrazin-2-yl)-4-(3-chloro-2-fluorophenyl)-4H-1,2,4-triazol-3-ol, 5-(2-aminopyridin-3-yl)-4-(2,3-difluorophenyl)-4H-1,2,4-triazol-3-ol, 5-(2-aminopyridin-3-yl)-4-(2,3-dichlorophenyl)-4H-1,2,4-triazol-3-ol, and 5-(2-aminopyridin-3-yl)-4-(3-chloro-2-fluorophenyl)-4H-1,2,4-triazol-3-ol can be produced from 3-amino-N-(2,3-dichlorophenyl)-N′-aminopyrazine-2-carboxamidine, 3-amino-N-(3-chloro-2-fluorophenyl)-N′-aminopyrazine-2-carboxamidine, 2-amino-N-(2,3-difluorophenyl)-N′-aminopyridine-3-carboxamidine, 2-amino-N-(2,3-dichlorophenyl)-N′-aminopyridine-3-carboxamidine, and 2-amino-N-(3-chloro-2-fluorophenyl)-N′-aminopyridine-3-carboxamidine, respectively.