Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:10]=[C:9]([N:17]3[CH:21]=[C:20](I)[N:19]=[CH:18]3)[N:8]=2)=[CH:4][CH:3]=1.[C:23]([NH:27][S:28]([C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)(=[O:30])=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[C:23]([NH:27][S:28]([C:31]1[CH:32]=[CH:33][CH:34]=[C:35]([C:20]2[N:19]=[CH:18][N:17]([C:9]3[N:8]=[C:7]([C:5]4[S:6][C:2]([Cl:1])=[CH:3][CH:4]=4)[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:10]=3)[CH:21]=2)[CH:36]=1)(=[O:30])=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)s2)nc(-n2cnc(I)c2)n1
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2cn(-c3nc(-c4ccc(Cl)s4)cc(C(F)(F)F)n3)cn2)c1

Procedure:
N-tert-Butyl-3-{1-[4-(5-chloro-thiophen-2-yl)-6-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-benzenesulfonamide was prepared from 4-(5-chloro-thiophen-2-yl)-2-(4-iodo-imidazol-1-yl)-6-trifluoromethyl-pyrimidine (example B.1) (0.46 g, 1.0 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.28 g, 1.1 mmol) according to the general procedure III. Obtained as a light yellow solid (0.3 g) which was subsequently deprotected.
Reaction SMILES: [CH2:1]([C:8]1[S:9][C:10]2[CH:16]=[C:15]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:14]=[CH:13][C:11]=2[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33](Cl)(=[O:35])[CH3:34]>>[C:33]([N:30]1[CH2:31][CH2:32][CH:27]([C:19]2[N:20]3[C:25]([C:24]([NH2:26])=[N:23][CH:22]=[N:21]3)=[C:17]([C:15]3[CH:14]=[CH:13][C:11]4[N:12]=[C:8]([CH2:1][C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)[S:9][C:10]=4[CH:16]=3)[CH:18]=2)[CH2:28][CH2:29]1)(=[O:35])[CH3:34]
Reactant: Nc1ncnn2c(C3CCNCC3)cc(-c3ccc4nc(Cc5ccccc5)sc4c3)c12
Reactant: CC(=O)Cl
Product: CC(=O)N1CCC(c2cc(-c3ccc4nc(Cc5ccccc5)sc4c3)c3c(N)ncnn23)CC1
Yield: 54.8 %

Procedure:
In a manner similar to the procedure described for the preparation of Example 331 and using 5-(2-benzyl-1,3-benzothiazol-6-yl)-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine and acetyl chloride as starting material, 27 mg (54.8%) of the desired product was isolated. 1H NMR (400 MHz, CD2Cl2) δ 8.04 (d, 1H), 7.91 (s, 1H), 7.89 (s, 1H), 7.59 (d, 1H), 7.41-7.29 (m, 5H), 7.56 (s, 1H), 4.76-4.68 (m, 1H), 4.44 (s, 2H), 3.96-3.90 (m, 1H), 3.56-3.44 (m, 1H), 3.30-3.24 (m, 1H), 2.70-2.80 (m, 1H), 2.22-2.12 (m, 2H), 2.10 (s, 3H), 1.76-1.60 (m, 2H) LC-MS m/z [M+H]+ 483.3, RT 2.76 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][CH:12]=[C:13]2[C:18](=[O:19])OC(C)(C)OC2=O)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.CCCCCC>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[C:5]2[C:6]=1[C:18](=[O:19])[CH:13]=[CH:12][NH:11]2
Reactant: COc1cc(NC=C2C(=O)OC(C)(C)OC2=O)cc(OC)c1
Solvent: CCCCCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COc1cc(OC)c2c(=O)cc[nH]c2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5-[(3,5-Dimethoxyphenylamino)-methylene]-2,2-dimethyl[1,3]dioxane-4,6-dione (400 mg, 1.30 mmol) in diphenyl ether (5 mL) and heated at 200° C. for 30 min. The reaction mixture was cooled to rt and hexane was added and stirred for 30 min. The brown solid was filtered and dried to yield 5,7-dimethoxy-1H-quinolin-4-one LCMS m/z=206 (M+1).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:28])[C:7]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:8][N:9]2[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=2[O:21][CH3:22])=[CH:4][C:3]=1F.[NH:30]1[CH2:36][CH2:35][CH2:34][C@H:31]1[CH2:32][OH:33].C(N(C(C)C)CC)(C)C.O>C(#N)C>[CH3:22][O:21][C:14]1[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:13]=1[CH2:12][N:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([N:30]3[CH2:36][CH2:35][CH2:34][C@H:31]3[CH2:32][OH:33])[N:11]=2)[C:6](=[O:28])[C:7]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:8]1
Reactant: OC[C@@H]1CCCN1
Reactant: CCOC(=O)c1cn(Cc2ccc(OC)cc2OC)c2nc(Cl)c(F)cc2c1=O
Solvent: CC#N
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cn(Cc2ccc(OC)cc2OC)c2nc(N3CCC[C@H]3CO)ccc2c1=O

Procedure:
A mixture of EXAMPLE 1B (2.96 g), (S)-prolinol (850 μL), and diisopropylethylamine (4 mL) in acetonitrile (70 mL) at 25° C. was stirred for 3 days, treated with water, and extracted with dichloromethane. The extract was washed with 1M hydrochloric acid, water, saturated NaHCO3, and water, and concentrated.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][N:6]1[C:10](=[O:11])[C:9]([C:12]#[N:13])=[C:8]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=[C:7]12)[CH3:2].[OH:20]S(O)(=O)=O>>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][N:6]1[C:10](=[O:11])[C:9]([C:12]([NH2:13])=[O:20])=[C:8]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=[C:7]12)[CH3:2]
Reactant: CCOC(=O)Cn1c2cccccc-2c(C#N)c1=O
Reactant: O=S(=O)(O)O
Product: CCOC(=O)Cn1c2cccccc-2c(C(N)=O)c1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3-Cyano-1,2-dihydro-2-oxocyclohepta[b]pyrrole-1-acetic acid ethyl ester (2.56 g, described in example 12), was suspended in concentrated H2SO4 (10 ml). The mixture was stirred at 25° C. for 3 hr and then poured into ice water (20 ml). After 5 minutes, the resulting solid was collected on a filter, washed with water and then diethyl ether, air dried and recrystallized from ethanoldiethyl ether to give 1.75 g of 3-(aminocarbonyl)-1,2-dihydro-2-oxocyclohepta[b]pyrrole-1-acetic acid ethyl ester; mp 215°-220° C.; nmr (DMSO-d6) δ1.20 (t,J=7.5 Hz, 3H), 3.25 (broad, 2H), 4.15 (q, J=7.5 Hz, 2H), 5.0 (s, 2H), 7.6 (m, 4H), 9.3 (d, J=10 Hz, 1H); ir (white mineral oil) 3360, 3160, 1743, 1734, 1667, 1590 cm-1 ; uvλmax (MeOH) 276 nm (ε32,100), 232 (17,200), 223 (17,100); Anal Calc for C14H14N2O4 : C, 61.36% H, 5.15% N, 10.21%; Found: C, 61.12% H, 5.26% N, 10.24%.
Reaction SMILES: [N+]([O-])(O)=[O:2].[CH3:5][C:6]1([CH3:15])[CH2:11][CH2:10][CH2:9][C@@H:8]([CH3:12])[C@@H:7]1[CH:13]=[O:14]>>[CH3:15][C:6]1([CH3:5])[CH2:11][CH2:10][CH2:9][C@@H:8]([CH3:12])[C@@H:7]1[C:13]([OH:2])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: C[C@@H]1CCCC(C)(C)[C@H]1C=O
Product: C[C@@H]1CCCC(C)(C)[C@H]1C(=O)O
Temperature: 55 °C
Reaction time: 2 h
Yield: 98.7 %

Procedure:
In a 300-ml 4-necked flask equipped with a condenser, a thermometer, a dropping funnel, and a stirrer was placed 38 g of nitric acid (aqueous 60% solution) and heated to 55° C. Then, 90 g of (1S,6R)-2,2,6-trimethylcyclohexanecarbaldehyde (14) [composition: 91% of the (1S,6R)-form, 9% of the (1R,6R)-form] synthesized in Synthesis Example 5-A) was added dropwise thereto with stirring over a period of 2 hours. After carrying out the reaction for 3 hours at the same temperature, the reaction mixture was washed with water with 90 g of toluene and 100 g of water at room temperature, followed by separating an organic layer formed from an aqueous layer. The organic layer was washed thrice with 100 g of a saturated aqueous sodium chloride solution, followed by separating the organic layer from an aqueous layer. The toluene was distilled off from an organic layer by an evaporator under reduced pressure to provide 98 g of crude (1S,6R)-2,2,6-trimethylcyclohexanecarboxylic acid (15) [composition: 91% of the (1S,6R)-form, 9% of the (1R,6R)-form]. The product was recrystallized from methylene chloride as a solvent to provide 46 g of pure (1S,6R)-2,2,6-trimethylcyclohexanecarboxylic acid (15) [melting point: 67° C. to 68° C.; optical rotation; [α]D25 =-14.40°].
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13](OCC)=[O:14])[C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[O:35][CH:36]=[CH:37][CH:38]=4)[O:31][C:32]=3[CH3:33])=[CH:22][CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][OH:14])[C:10]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[O:35][CH:36]=[CH:37][CH:38]=4)[O:31][C:32]=3[CH3:33])=[CH:24][CH:25]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1oc(-c2ccco2)nc1COc1ccc(COc2nn(Cc3ccccc3)cc2CO)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.7 %

Procedure:
To a solution of ethyl 1-benzyl-3-[(4{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1H-pyrazole-4-carboxylate (0.80 g) in tetrahydrofuran (10 mL) was added lithium aluminum hydride (0.06 g) at 0° C. and the mixture was stirred at room temperature for 1 hr. Sodium sulfate decahydrate (0.51 g) was added to the reaction mixture and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate and the precipitate was filtered off and the filtrate was concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:2, v/v) to give {1-benzyl-3-[(4{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1H-pyrazol-4-yl}methanol as a colorless oil (0.49 g, yield 65%).
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[C:6]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[Cl:31])[CH2:7][NH:8][C@H:9]([C:20]([O:22][CH3:23])=[O:21])[CH2:10][CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])C>C(#N)C>[CH3:23][O:22][C:20](=[O:21])[C@@H:9]([N:8]1[CH2:7][C:6]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])=[CH:5][C:4]1=[O:3])[CH2:10][CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:14])[CH3:15]
Reactant: CCOC(=O)C=C(CN[C@@H](CCO[Si](C)(C)C(C)(C)C)C(=O)OC)Oc1ccccc1Cl
Solvent: CC#N
Product: COC(=O)[C@H](CCO[Si](C)(C)C(C)(C)C)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 140 °C
Yield: 56.8 %

Procedure:
A solution of 4-[(S)-3-(t-butyl-dimethyl-silanyloxy)-1-methoxycarbonyl-propylamino]-3-(2-chloro-phenoxy)-but-2-enoic acid ethyl ester (495 mg, 1.02 mmol) in acetonitrile (4 mL) was placed in a sealed microwave reaction tube and heated in a microwave reactor at 140° C. for 3 h. After this time, the mixture was cooled to room temperature and concentrated in vacuo with silica gel (2 g). Purification by Biotage flash chromatography (Aspire 40 g column, 16% ethyl acetate/hexanes to 50% ethyl acetate/hexanes) afforded (S)-4-(t-butyl-dimethyl-silanyloxy)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-butyric acid methyl ester (255 mg, 49% over two steps) as a golden oil: HR-ES-MS m/z calculated for C21H30NO5ClSi [M+Na]+ 462.1474, observed 462.1473.
Reaction SMILES: [N:1]1([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][C:8]=2[N+:15]([O-:17])=[O:16])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:18][CH:19]([CH3:35])[C:20]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:24]=1)=[O:21]>>[CH3:18][CH:19]([CH3:35])[C:20]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]2[CH2:34][CH2:33][N:32]([CH2:11][C:10]3[CH:13]=[CH:14][C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[C:8]([N+:15]([O-:17])=[O:16])[CH:9]=3)[CH2:31][CH2:30]2)[CH:24]=1)=[O:21]
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=Cc1ccc(N2CCOCC2)c([N+](=O)[O-])c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc(N4CCOCC4)c([N+](=O)[O-])c3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 4-(4-morpholinyl)-3-nitrobenzaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 467.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH3:3].CI.[C]=O.[C:8](O)(=O)[CH3:9]>>[C:1]([O:2][C:3]1[CH:9]=[CH:8][CH:3]=[CH:9][CH:8]=1)(=[O:2])[CH3:1]
Reactant: COC
Reactant: CC(=O)O
Agent: [C]=O
Solvent: CI
Product: CC(=O)Oc1ccccc1

Procedure:
A 300-ml autoclave equipped with an agitator was charged with 23 g of dimethyl ether, 56.4 g of phenyl, 30 g of acetic acid, 1.0 g of RhCl(CO)(Pφ3)2 and 14.2 g of methyl iodide, following which the reaction was carried out at 190° C. and a carbon monoxide pressure of 30 kg/cm2 gauge (total pressure of 50 kg/cm2 gauge). The yields of acetic acid and phenyl acetate were 97.3% and 97.2%, respectively. The reaction was repeated several times, and the resulting reaction product liquids were collected and used in Example 14.
Reaction SMILES: C([O:5][C:6]([N:8]1[C:19]2[C:11](=[C:12]3[C:16](=[C:17]([OH:20])[CH:18]=2)[NH:15][C:14]([C:21]([F:24])([F:23])[F:22])=[C:13]3[C:25]([O:27][CH3:28])=[O:26])[CH:10]([CH2:29][Cl:30])[CH2:9]1)=O)(C)(C)C.C(OCC)(=O)C.Cl.[CH3:38][O:39][C:40]1[CH:41]=[C:42]2[C:46](=[C:47]([O:51][CH3:52])[C:48]=1[O:49][CH3:50])[NH:45][C:44](C(O)=O)=[CH:43]2.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.O>[Cl:30][CH2:29][CH:10]1[C:11]2=[C:12]3[C:16](=[C:17]([OH:20])[CH:18]=[C:19]2[N:8]([C:6]([C:44]2[NH:45][C:46]4[C:42]([CH:43]=2)=[CH:41][C:40]([O:39][CH3:38])=[C:48]([O:49][CH3:50])[C:47]=4[O:51][CH3:52])=[O:5])[CH2:9]1)[NH:15][C:14]([C:21]([F:24])([F:22])[F:23])=[C:13]3[C:25]([O:27][CH3:28])=[O:26]
Reactant: COC(=O)c1c(C(F)(F)F)[nH]c2c(O)cc3c(c12)C(CCl)CN3C(=O)OC(C)(C)C
Reactant: COc1cc2cc(C(=O)O)[nH]c2c(OC)c1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1c(C(F)(F)F)[nH]c2c(O)cc3c(c12)C(CCl)CN3C(=O)c1cc2cc(OC)c(OC)c(OC)c2[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 42.6 mg(95 μmol) of methyl 3-t-butoxycarbonyl-1-chloromethyl-5-hydroxy-7-trifluoromethyl-1,2,3,6-tetrahydropyrrolo[3,2-e]indole-8-carboxylate, 1.6 ml of 3M hydrogen chloride-ethyl acetate was added, and the mixture was stirred at room temperature for one hour. Then the solvent was distilled off. The residue with 23.8 mg (95 mol) of 5,6,7-trimethoxyindole-2-carboxylic acid, and 54.6 mg (285 μmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride was stirred in 0.95 ml of anhydrous dimethylformamide at room temperature under atmosphere of argon overnight. Water was added to the liquid reaction mixture. The resulting mixture was extracted with methylene chloride, and the extract solution was washed with water, 10% sodium hydrogencarbonate, and saturated sodium chloride solution successively, and dried over anhydrous sodium sulfate. Therefrom the solvent was distilled off. The residue was purified by silica gel column chromatography (chloroform:methanol=20:1) to obtain methyl 1-chloromethyl-5-hydroxy-7-trifluoromethyl-3-(5,6,7-trimethoxy-1H-indol-2-ylcarbonyl)-1,2,3,6-tetrahydropyrrolo[3,2-e]indole-8-carboxylate in a yield of 45.3 mg (82%).
Reaction SMILES: [CH3:1][N:2]([CH3:29])[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](/[CH:13]=[CH:14]/[C:15](=[O:28])[CH2:16][C:17](=[O:27])/[CH:18]=[CH:19]/[C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)=[CH:5][CH:4]=1.CN(C)C1C=CC(/C=C/C(=O)CC(=O)/C=C/C2C=CC(O)=C(OC)C=2)=CC=1>>[CH3:29][N:2]([CH3:1])[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:13][CH2:14][C:15](=[O:28])[CH2:16][C:17](=[O:27])[CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(/C=C/C(=O)CC(=O)/C=C/c2ccc(O)cc2)c2ccccc12
Agent: COc1cc(/C=C/C(=O)CC(=O)/C=C/c2ccc(N(C)C)cc2)ccc1O
Product: CN(C)c1ccc(CCC(=O)CC(=O)CCc2ccc(O)cc2)c2ccccc12

Procedure:
The title compound was synthesized using the same procedure employed for Example 372, but with (1E,6E)-1-(4-dimethylaminonaphthalen-1-yl)-7-(4-hydroxyphenyl)hepta-1,6-diene-3,5-dione (20 mg, 52 μmol, synthesized in Example 94) as the starting material instead of (1E,6E)-1-(4-dimethylaminophenyl)-7-(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione, and was purified by silica gel column chromatography eluting with hexane/ethyl acetate=90/10 to 80/20. The product was obtained as a gum (16.5 mg, 82%) having the following characteristics.
Reaction SMILES: [CH2:1](Br)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].[NH:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[C:12]1[C:20]1[C:21]([NH2:25])=[N:22][O:23][N:24]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([N:13]1[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:11]=[C:12]1[C:20]1[C:21]([NH2:25])=[N:22][O:23][N:24]=1)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: Nc1nonc1-c1nc2ccccc2[nH]1
Reactant: O=C(CBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1nonc1-c1nc2ccccc2n1CC(=O)c1ccccc1

Procedure:
Phenacylbromid (0.1 g, 0.49 mmol) is added to an efficiently stirred suspension of 4-(1H-benzimidazol-2-yl)-furazan-3-ylamine (0.1 g, 0.4 mmol) [A. V. Sergievskii, O. A. Krasnoshek, S. F. Mel'nikova, I. V. Tselinskii, Russian Journal of Organic Chemistry, 2002, 38, 915-917] and potassium carbonate (0.172 g, 1.24 mmol) in dry DMF (5 ml) at room temperature. After 4 hours the reaction mixture is diluted with ethyl acetate and the organic phase is washed repeatedly with brine. Drying of the solvent, filtering and evaporation of the solvent under reduced pressure gives the title compound in crude form. The title compound is obtained in pure form by chromatography over silicagel, m.p. 202-204° C.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.[H-].[Na+].Cl[C:13]1[N:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][N:14]=1>CN(C)C=O>[CH3:20][O:19][C:17]1[CH:16]=[CH:15][N:14]=[C:13]([N:1]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=[CH:2]2)[N:18]=1
Reactant: COc1ccnc(Cl)n1
Reactant: c1ccc2[nH]cnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccnc(-n2cnc3ccccc32)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 41.8 %

Procedure:
Benzimidazole (0.50 g) was dissolved in dimethylformamide (10 ml), and sodium hydride (60% purity, oily) (0.18 g) was added thereto at room temperature. After stirring for 1 hour, 2-chloro-4-methoxypyrimidine (0.62 g) was added at room temperature, followed by stirring for 3 hours. Ice water was added, followed by extraction with ethyl acetate, washing with a saturated sodium chloride aqueous solution and drying over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain 0.40 g of the desired product as a white powder (m.p. 114-116° C.).
Reaction SMILES: Br[C:2]#[N:3].CC#N.[Cl:7][C:8]1[C:9]([NH2:17])=[C:10]([NH2:16])[CH:11]=[C:12]([Cl:15])[C:13]=1[Cl:14]>O.CO>[NH2:3][C:2]1[NH:17][C:9]2[C:8]([Cl:7])=[C:13]([Cl:14])[C:12]([Cl:15])=[CH:11][C:10]=2[N:16]=1
Reactant: N#CBr
Reactant: Nc1cc(Cl)c(Cl)c(Cl)c1N
Solvent: CO
Solvent: CC#N
Solvent: O
Product: Nc1nc2cc(Cl)c(Cl)c(Cl)c2[nH]1
Reaction time: 2 h

Procedure:
To a stirred solution of 3.62 mL of 5M BrCN/MeCN in 35 mL of H2O, was added dropwise a solution of 3,4,5-trichloro-1,2-phenylenediamine (13a) (3.478 g, 16.446 mmol) in 35 mL of MeOH, After the addition had been completed, stirring was continued at room temperature for 2 hr. The reaction mixture was concentrated to ~ 35 mL and was washed with EtOAc (50 mL). The EtOAc phase was extracted with H2O (50 mL). The combined H2O phase was neutralized with sat. NaHCO3 solution to ~ pH 8 and the resulting suspension was extracted with EtOAc (150 mL). The EtOAc phase was washed with a mixture of sat. NaHCO3 and sat. NaCl solution (20 mL/130 mL), dried (Na2SO4), and evaporated. The residue was dissolved in MeOH, decolorized with charcoal, and then recrystallized from MeCN to give 3.098 g (2 crops, 80%) of 13b as a slightly grey crystals. MP: 255°-258° C. MS: (EI) m/e 234.9473 (100%, M+ =234.9471). 1H NMR (DMSO-d6): d 11.25 (br s, 1, 1-NH), 7.29 {s, 1, 7(4)-H}, 6.75 (br s, 2, 2-NH2). Anal. Calcd. for C7H4Cl3N3 : C 35.55, H 1.70, N 17.77, Found: C 35.72, H 1.78, N 17.89.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([OH:17])=[CH:7][CH:8]=2)[N:3]=1.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24]Cl>>[CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([O:17][CH2:24][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=3)=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1cc(N2CCCC2)c2ccc(O)cc2n1
Reactant: ClCc1ccccn1
Product: Cc1cc(N2CCCC2)c2ccc(OCc3ccccn3)cc2n1

Procedure:
In analogy to example 6 there was prepared: on reaction of 2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol with 2-picolyl choride, whereby the product was isolated as free base, 2-methyl-7-(pyridin-2-ylmethoxy)-4-pyrrolidin-1-yl-quinoline as a light brown solid. ISP mass spectrum, m/e: 320.4 (M+1 calculated for C20H21N3O: 320).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Br:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[CH3:16])[NH:12][CH:11]=[CH:10]2.[OH-].[Na+].CN([CH:22]=[O:23])C>>[Br:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[CH3:16])[NH:12][CH:11]=[C:10]2[CH:22]=[O:23]
Reactant: CN(C)C=O
Reactant: Cc1cc2[nH]ccc2cc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc2[nH]cc(C=O)c2cc1Br
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 85 %

Procedure:
Phosphorus oxychloride (0.73 g, 4.79 mmol) and DMF (5.0 mL) were mixed together and stirred for 5 min. A solution of 5-bromo-6-methyl-1H-indole (500 mg, 2.39 mmol) in DMF (3.0 mL) was added to the solution slowly and complete solid was formed which stopped stirring. The solution was adjusted to pH=10 with 1 N NaOH, then heated to 100° C. for 1 min. The reaction was cooled to room temperature. The precipitated solids were filtered and dried to give the title compound (480 mg, 85%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 12.2 (s, 1 H), 9.88 (s, 1 H), 8.28 (s, 1 H), 8.23 (s, 1 H), 7.49 (s, 1 H), 2.44 (s, 3 H).
Reaction SMILES: C([NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]1[CH2:23][CH2:22][CH2:21][CH:20]1[CH3:24])=[S:11])(=O)C1C=CC=CC=1.[OH-].[Na+]>O>[CH3:24][CH:20]1[CH2:21][CH2:22][CH2:23][N:19]1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[NH:12][C:10]([NH2:9])=[S:11]
Reactant: CC1CCCN1c1ccccc1NC(=S)NC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1CCCN1c1ccccc1NC(N)=S

Procedure:
A mixture of 1-benzoyl-3-[2-(2-methyl-1-pyrrolidinyl)phenyl]thiourea (9 g), sodium hydroxide (1 g, as pellets) and water (10 ml) was heated at 90°-95° C. for 48 hours to give 1-[2-(2-methyl-1-pyrrolidinyl)phenyl]thiourea (m.p. 145°-148° C.) which was purified by column chromatography on silica gel using a 1:1 mixture of ethylacetate and hexane as eluant.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][C:18]([F:21])([F:20])[F:19])[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:22]([N:10]1[C:11]2[C:16](=[CH:15][C:14]([O:17][C:18]([F:21])([F:19])[F:20])=[CH:13][CH:12]=2)[C:8]([C:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH:6]=2)=[CH:9]1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CN1CC=C(c2c[nH]c3ccc(OC(F)(F)F)cc23)CC1
Product: CN1CC=C(c2cn(C(=O)c3ccccc3)c3ccc(OC(F)(F)F)cc23)CC1

Procedure:
(9.3 mg, 32%); from 3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-5-trifluoromethoxy-1H-indole (Example 4h, 20 mg, 0.068 mmol) and benzoyl chloride (15.0 mg, 0.107 mmol), HRMS-FAB+ for C22H19N2O2F3, calculated MH+ : 401.14767; found: 401.14761.