Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[C:16]([O:25][CH:26]([CH3:28])[CH3:27])(=[O:24])[C:17]1[C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)[OH:19]>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:19][C:18]1[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=1[C:16]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: CC(C)OC(=O)c1ccccc1O
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3ccccc3C(=O)OC(C)C)c2cc1OC
Temperature: 120 °C
Reaction time: 8 h
Yield: 20.7 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (112 mg), isopropyl salicylate (360 mg), and 4-dimethylaminopyridine (244 mg) were suspended in o-dichlorobenzene (1 ml), and the suspension was stirred at 120° C. overnight. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give the title compound (38 mg, yield 21%).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].[Cl:17][C:18]1[CH:23]=[C:22]([CH2:24][N:25]([CH3:27])[CH3:26])[CH:21]=[C:20](Cl)[N:19]=1>CN(C=O)C.CO>[Cl:17][C:18]1[N:19]=[C:20]([O:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)[CH:21]=[C:22]([CH2:24][N:25]([CH3:27])[CH3:26])[CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CN(C)Cc1cc(Cl)nc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CN(C)Cc1cc(Cl)nc(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (44.2 mg, 0.219 mmol) in DMF (0.7 mL) was added sodium hydride (13.2 mg, 0.329 mmol). After stirring for 30 minutes, 1-(2,6-dichloropyridin-4-yl)-N,N-dimethylmethanamine (45 mg, 0.22 mmol) was added to the reaction vial. The reaction solution was heated at 100° C. overnight. The reaction solution was diluted with methanol and purified with preparative LCMS to give the desired product. LCMS (M+H)+: 370.1.
Reaction SMILES: [CH2:1]([N:8]1[C:16]([C:17]2[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=2)=[C:15]2[C:10]([C:11]([C:24]([F:27])([F:26])[F:25])=[CH:12][CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br-].[CH3:29][O:30][C:31]([C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH2:36][Zn+])=[O:32].Cl.ClCCl>C1COCC1>[CH3:29][O:30][C:31](=[O:32])[C:33]1[CH:40]=[CH:39][CH:38]=[C:35]([CH2:36][C:20]2[CH:21]=[CH:22][C:17]([C:16]3[N:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[N:9]=[C:10]4[C:15]=3[CH:14]=[CH:13][CH:12]=[C:11]4[C:24]([F:26])([F:27])[F:25])=[CH:18][CH:19]=2)[CH:34]=1
Reactant: COC(=O)c1cccc(C[Zn+])c1
Reactant: FC(F)(F)c1cccc2c(-c3ccc(Br)cc3)n(Cc3ccccc3)nc12
Agent: Cl
Agent: [Br-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)c1cccc(Cc2ccc(-c3c4cccc(C(F)(F)F)c4nn3Cc3ccccc3)cc2)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
2-Benzyl-3-(4-bromo-phenyl)-7-trifluoromethyl-2H-indazole (43 mg, 0.1 mmol) and 4 mg of bis[triphenylphosphine]palladium(II) chloride were dissolved in THF. After 5 minutes, 0.4 ml of a 0.5M solution of 3-(methoxycarbonyl)-benzylzinc bromide in THF (0.2 mmol) were added and the reaction mixture was stirred at room temperature overnight. 1M HCl-solution and dichloromethane were added, and the phases were separated. The resulting product was obtained after flash chromatographic purification using n-heptane/ethyl acetate, 90:10, as eluent. Yield: 47 mg.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][NH:5][CH2:4][C@H:3]1[CH2:7][NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH3:19][O:20][C:21]1[CH:30]=[C:29]2[C:24]([CH:25]=[CH:26][C:27](=[O:34])[N:28]2[CH2:31][CH:32]=O)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CO>[OH:1][C@H:2]1[CH2:6][N:5]([CH2:32][CH2:31][N:28]2[C:29]3[C:24](=[CH:23][CH:22]=[C:21]([O:20][CH3:19])[CH:30]=3)[CH:25]=[CH:26][C:27]2=[O:34])[CH2:4][C@H:3]1[CH2:7][NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(NC[C@@H]1CNC[C@@H]1O)OCc1ccccc1
Reactant: COc1ccc2ccc(=O)n(CC=O)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc2ccc(=O)n(CCN3C[C@@H](CNC(=O)OCc4ccccc4)[C@@H](O)C3)c2c1
Reaction time: 1 h

Procedure:
Phenylmethyl {[(3S,4R)-4-hydroxy-3-pyrrolidinyl]methyl}carbamate (300 mg, 1.20 mmol) and [7-(methyloxy)-2-oxo-1(2H)-quinolinyl]acetaldehyde (260 mg, 1.12 mmol) were combined in anhydrous DCM (5 ml) and anhydrous MeOH (1 ml) with a spatula of solid sodium carbonate. The reaction mixture was stirred under nitrogen for 1 h then sodium triacetoxyborohydride (762 mg, 3.6 mmol) was added and stirred overnight. The reaction mixture was concentrated and the title compound was obtained as a pale yellow oil (337 mg, 62%) after column chromatography (90:10:1: DCM:MeOH:NH4OH).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][C:23]([O:25][CH3:26])=[O:24].O>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:10][CH2:11][N:12]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH2:13][CH2:14]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CN1CCC(NC(=O)OC(C)(C)C)CC1
Reaction time: 1 h

Procedure:
4-(tert-butoxycarbonylamino)piperidine (1.2 g) and potassium carbonate (1.2 g) were suspended in dimethylformamide (20 mL), and then methyl bromoacetate (0.62 mL) was added. The reaction solution was stirred for one hour and water was added, followed by extraction with ethyl acetate. The organic layer was washed in turn with water and saturated brine, and dried over anhydrous magnesium sulfate, and then the filtrate was concentrated. The residue was purified by silica gel chromatography (hexane:ethyl acetate=2:10:1) to obtain the title compound (1.36 g) having the following physical properties.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:7].[Li]CCCC.[C:13](OC)(=[O:17])[CH2:14][CH2:15][CH3:16]>C1COCC1>[O:17]=[C:13]([CH2:14][CH2:15][CH3:16])[CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: CCCC(=O)OC
Reactant: Cc1ccccn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC(=O)Cc1ccccn1
Reaction time: 1 h

Procedure:
To a solution of 2-picoline (10 g) in THF (75 mL) was added n-BuLi (113 mmol) at −40° C. Further, methyl butanoate (15.8 mL) was added and the mixture was stirred for 1 hour, and the mixture quenched with water. The mixture was extracted with ethyl acetate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (1:1)) to give 2-(2-oxopentanyl)pyridine (4.8 g) as a yellow oil. A solution of 2-bromo-3-cyanobenzaldehyde (1.5 g), Meldrum's acid (1.0 g), 2-(2-oxopentanyl)pyridine (1.2 g) and ammonium acetate (0.6 g) in acetic acid (7 mL) was heated under reflux for 11 hours. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (1:1)) and the obtained residue was crystallized from ethyl acetate to give colorless crystals (520 mg). To a solution of dimethylformamide (384 mg) in chloroform (5 mL) were added phosphorus oxychloride (805 mg) and a solution of the obtained crystals (520 mg) under ice-cooling, and the mixture was stirred overnight. Under ice-cooling, an aqueous sodium acetate (3.4 g) solution was added and the mixture was stirred for 1 hour. The mixture was extracted with ethyl acetate and the solvent was evaporated under reduced pressure to give oil. The obtained oil was purified by silica gel column chromatography (eluent: chloroform-methanol (9:1)) to give a yellow solid (530 mg). To a solution of the obtained solid in pyridine (10 mL) was added hydrazine (120 mg), and the mixture was stirred with heating for 4 hours. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure to give oil. To the obtained oil was added water and the mixture was extracted with ethyl acetate. The extract was washed a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was crystallized from ethyl acetate to give the title compound (145 mg) as a pale-yellow crystal.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:9]([CH2:20][C:21]3[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=3[C:23]#[N:24])[C:10](=[O:19])[C:11]3[CH:17]=[C:16](Cl)[N:15]=[CH:14][C:12]=3[N:13]=2)[CH2:3]1.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1.C(=O)(O)[O-].[Na+]>CCO.CCOC(C)=O>[NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:9]([CH2:20][C:21]3[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=3[C:23]#[N:24])[C:10](=[O:19])[C:11]3[CH:17]=[C:16]([N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)[N:15]=[CH:14][C:12]=3[N:13]=2)[CH2:3]1
Reactant: C1CCNC1
Reactant: N#Cc1ccccc1Cn1c(N2CCC[C@@H](N)C2)nc2cnc(Cl)cc2c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: N#Cc1ccccc1Cn1c(N2CCC[C@@H](N)C2)nc2cnc(N3CCCC3)cc2c1=O
Yield: 41.9 %

Procedure:
2-[2-(3-(R)-Amino-piperidin-1yl)-6-chloro-4-oxo-4H-pyrido[3,4-d]pyrimidin-3-ylmethyl]-benzonitrile (Example 18) (120 mg, 0.3 mmol), pyrrolidine (75 μL, 0.91 mmol) and sodium bicarbonate (76 mg, 0.91 mmol) were stirred in EtOH in a sealed tube at 150° C. for 16 h. After cooling, the reaction was diluted with EtOAc, washed with brine, dried (MgSO4), and concentrated in vacuo. Purification by preparative HPLC yielded 54 mg (32%) of the title compound as a bright orange solid. 1H NMR (400 MHz, MeOD-d4): δ 8.40 (s, 1H), 7.64 (dd, 1H, J=7.6, 1.2 Hz), 7.48 (dt, 1H, J=7.6, 1.2 Hz), 7.33 (t, 1H, J=7.6 Hz), 7.07 (d, 1H, J=7.6 Hz), 6.67 (s, 1H), 5.43 (s, 2H), 3.20-3.32 (m, 5H), 3.02-3.10 (m, 1H), 2.81-2.90 (m, 1H), 2.69-2.78 (m, 1H), 2.59-2.67 (m, 1H), 1.87-1.99 (m, 5H), 1.51-1.73 (m, 2H), 1.18-1.28 (m, 1H). MS (ES) [m+H] calc'd for C24H27N7O 430; found 430.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:17]=[C:16]([NH:18][NH2:19])[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[CH3:20])=[CH:4][CH:3]=1.[CH3:21][CH:22]([C:26](=O)[CH3:27])[C:23](=O)[CH3:24]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:17]=[C:16]([N:18]3[C:26]([CH3:27])=[C:22]([CH3:21])[C:23]([CH3:24])=[N:19]3)[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[CH3:20])=[CH:4][CH:3]=1
Reactant: Cn1cnc2c(Nc3ccc(Cl)cc3)nc(NN)nc21
Reactant: CC(=O)C(C)C(C)=O
Product: Cc1nn(-c2nc(Nc3ccc(Cl)cc3)c3ncn(C)c3n2)c(C)c1C

Procedure:
Was prepared according to Example 9 from (4-chloro-phenyl)-(2-hydrazino-9-methyl-9H-purin-6-yl)-amine and 3-methyl-2,4-pentanedione.
Reaction SMILES: [CH3:1][C:2]1[S:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[O:4][C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.O[CH2:20][CH2:21][CH2:22][N:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH3:1][C:2]1[S:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[O:4][C:3]=1[C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:20][CH2:21][CH2:22][N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:16][CH:17]=1
Reactant: OCCCN1CCCC1
Reactant: CC1=C(c2ccc(O)cc2)Oc2ccccc2S1
Product: CC1=C(c2ccc(OCCCN3CCCC3)cc2)Oc2ccccc2S1

Procedure:
The entitled compound was obtained according to the method of Example 3 but using 4-(3-methyl-1,4-benzoxathiin-2-yl)phenol synthesized in Reference Example 1-2 and 1-(3-hydroxypropyl)pyrrolidine as the starting material.
Reaction SMILES: [OH-].[K+].C[NH:4][C:5](=[NH:7])S.OS(O)(=O)=O.[CH3:13][C:14]1[CH:27]=[CH:26][C:17]([C:18]([CH2:20][C:21](OCC)=[O:22])=[O:19])=[CH:16][CH:15]=1>O>[NH2:7][C:5]1[O:19][C:18]([C:17]2[CH:26]=[CH:27][C:14]([CH3:13])=[CH:15][CH:16]=2)=[CH:20][C:21](=[O:22])[N:4]=1
Reactant: CNC(=N)S
Reactant: CCOC(=O)CC(=O)c1ccc(C)cc1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(-c2cc(=O)nc(N)o2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 9.5 %

Procedure:
Potassium hydroxide (12.55 g, 224 mmol) was added to the vigorously stirred solution of methylthiopseudourea.H2SO4 (14.57 g, 52 mmol) in water (80 ml). Ethyl (4-methyl)benzoylacetate (20.0 g, 97 mmol) (obtained in preparation 1) was added to it and stirred at room temperature for 18 hours. The solid thus obtained was filtered, washed with water, ether and dried at 60° C. in vacuum to yield the title compound (1.85 g, 9.5%). 1H-NMR (DMSO-d6): δ 2.37 (s, 3H), 6.46 (s, 1H), 7.33-7.35 (d, 2H), 7.76-7.78 (d, 2H), 7.91 (bs, 2H, D2O exchangeable). MS m/z: 203.1 (M+).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:55])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH2:52][CH:53]=[CH2:54])[CH2:45]2)[CH:7]([CH3:56])[CH2:6][CH2:5][C:4]1=[O:57])[CH3:2].C(N(C(C)C)CC)(C)C.[N+:67]([C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][C:71]=1[S:76](Cl)(=[O:78])=[O:77])([O-:69])=[O:68]>C(Cl)Cl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:55])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][S:76]([C:71]3[CH:72]=[CH:73][CH:74]=[CH:75][C:70]=3[N+:67]([O-:69])=[O:68])(=[O:77])=[O:78])[CH:46]([O:51][CH2:52][CH:53]=[CH2:54])[CH2:45]2)[CH:7]([CH3:56])[CH2:6][CH2:5][C:4]1=[O:57])[CH3:2]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: C=CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CCC1O
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CCC1OS(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.2 %

Procedure:
To a solution of 17-ethyl-1-hydroxy-12-[2'-(4"-hydroxy-3"-allyloxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (66 mg) in dry methylene chloride (1.4 ml) was added an excess of diisopropylethyl amine (34 μl) and o-nitrobenzenesulfonyl chloride (36 mg) followed by addition of 4-dimethylaminopyridine (24 mg). The mixture was stirred at room temperature for 18 hours at which time it was diluted with ethyl acetate, extracted from saturated sodium bicarbonate solution and washed with brine. The combined organics were dried over magnesium sulfate and the concentrate purified by flash chromatography on silica gel (ethyl acetate:hexane (1:1)+1% methanol to give the title compound (66 mg).
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[CH:8]2)#[N:4].[S:14](Cl)([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15].O>C1COCC1>[C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([S:14]([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15])[CH:9]=[CH:8]2)#[N:4]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: N#Cc1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ccc3cc(C#N)ccc32)cc1
Reaction time: 0.17 h
Yield: 89.7 %

Procedure:
In a 100 mL round-bottom flask was placed NaH (0.4 g, 60% dipersion in mineral oil, 10 mmol) and anhydrous THF (10 mL) was added. To the suspension was added a solution of 5-cyanoindole (1.0 g, 7 mmol) in anhydrous THF (10 mL) by syringe at 0° C. The mixture was stirred for 10 min, and tosyl chloride (1.6 g, 8.4 mmol) was added. After stirring at room temperature for 2 h, water (100 mL) was added. The mixture was extracted with ethyl acetate (3×50 mL), dried (MgSO4), and concentrated. The residue was purified by column chromatography using hexane: ethyl acetate=2:1 as eluent to yield 1.86 g (92%) of the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=[O:18])[CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([S:16][CH3:17])[N:11]=2)[CH:5]=[CH:6][CH:7]=1.[N:19]([O-])=[O:20].[Na+]>O1CCCC1.O>[Br:1][C:2]1[CH:3]=[C:4]([C:8](=[O:18])[C:9]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([S:16][CH3:17])[N:11]=2)=[N:19][OH:20])[CH:5]=[CH:6][CH:7]=1
Reactant: O=N[O-]
Reactant: CSc1nccc(CC(=O)c2cccc(Br)c2)n1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CSc1nccc(C(=NO)C(=O)c2cccc(Br)c2)n1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
12.75 g (39.5 mmol) C1 were dissolved in a mixture of 173 ml glacial acid, 136 ml tetrahydrofurane and 17 ml water. After cooling to 5° C. a solution of 3.24 g (47.0 mmol) sodium nitrite in 25 ml water was added keeping the temperature between 5° C. and 10° C. The cooling was removed and the mixture stirred for 6 hours at room temperature. After removal of the solvent in vacuo 320 ml water and 320 ml ethyl acetate were added. The pH was adjusted to 8 with 3 N NaOH. The phases were separated and the aqueous layer was extracted with 50 ml ethyl acetate. The combined organic layers were dried over sodium sulphate and the solvent was removed in vacuo. The residue was treated with diethylether, filtered off and dried. Yield: 8.33 g (60%) D1, m.p. 156–158° C.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.[CH3:10][N:11]=[C:12]=[S:13]>C1(C)C=CC=CC=1>[CH3:10][NH:11][C:12]([N:2]([CH3:1])[CH2:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)=[S:13]
Reactant: CNCc1cccnc1
Reactant: CN=C=S
Solvent: Cc1ccccc1
Product: CNC(=S)N(C)Cc1cccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.3 %

Procedure:
In 30 ml of toluene was dissolved 2.5 g (0.02 mole) of N-methyl-N-3-pyridylmethylamine followed by addition of 1.5 g (0.02 mole) of methyl isothiocyanate and the mixture was stirred at room temperature overnight. Finally, the solvent was distilled off to give 3.8 g of N-methyl-N′-methyl-N′-3-pyridylmethylthiourea as a yellow viscous oil. This oily product was purified by silica gel column chromatography using HeOH—CHCl3 (1:10) as an eluent to give crystals.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[S:19][C:20]([C:23]([O:25]CC)=[O:24])=[CH:21][N:22]=3)=[CH:14][CH:13]=2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+]>CO.ClCCl>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[S:19][C:20]([C:23]([OH:25])=[O:24])=[CH:21][N:22]=3)=[CH:14][CH:13]=2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1cnc(-c2ccc(NC(=O)c3nc(Cl)c(CC)[nH]3)cc2)s1
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CCc1[nH]c(C(=O)Nc2ccc(-c3ncc(C(=O)O)s3)cc2)nc1Cl
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 80.8 %

Procedure:
Ethyl 2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}phenyl)-1,3-thiazole-5-carboxylate obtained in Example (91c) (89 mg, 0.22 mmol) was dissolved in methanol (15 mL) and dichloromethane (10 mL). A 2 N aqueous lithium hydroxide solution (3 mL, 6 mmol) was added, and the mixture was stirred at 70° C. for 30 minutes. The organic solvent was evaporated under reduced pressure and 1 N hydrochloric acid was added until the pH of the solution was about 4. The resulting solid was collected by filtration and washed with distilled water to obtain 67 mg of the title compound as a light brown solid (80%).
Reaction SMILES: C1(C)C=CC=CC=1.[CH2:8]([NH:10][CH2:11][CH3:12])[CH3:9].[CH2:13]([O:15][Si:16](OCC)([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19])[CH3:14].C(OCl)C.[Mg]>O1CCCC1>[CH2:8]([N:10]([Si:16]([O:20][CH2:21][CH3:22])([O:17][CH2:18][CH3:19])[O:15][CH2:13][CH3:14])[CH2:11][CH3:12])[CH3:9]
Reactant: CCO[Si](OCC)(OCC)OCC
Reactant: CCNCC
Agent: CCOCl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCO[Si](OCC)(OCC)N(CC)CC
Reaction time: 0.5 h

Procedure:
Diethylaminotriethoxysilane was synthesized as Example 1 in the following manner. First, into a four-necked flask (volume of 1 L) equipped with a magnet seal agitator and a dropping funnel, a 100 mL of toluene, a 10 mL of tetrahydro furan, and a 14.6 g (0.2 mol) of diethylamine were introduced and then mixed and agitated. A Grignard reagent (titer=1.71 mol/L) is on the other hand supplied by 129 mL (0.22 mol) into the dropping funnel. Thereafter, while agitating, the Grignard reagent is dropped from the dropping funnel into the flask at room temperature (air-cooling), spending 30 minutes. After completion of dropping, agitating was performed at 60° C. for one hour for Grignard exchange reaction. Then, a 41.7 g (0.2 mol) of tetraethoxysilane previously introduced into the dropping funnel is dropped into the flask, spending 15 minutes. After completion of dropping, a reaction was performed at 60° C. for 2 hours. At this moment, a solid of magnesium ethoxy chloride deposited in the flask. The reacted solution was partly extracted to confirm the generation of the target product by gas chromatography. Then, in nitrogen ambient, the reacted solution in the flask was entirely transferred therefrom to a container equipped with a G4 glass filter for pressure filtration with low-pressure nitrogen (0.01 MPa). The filtered residue (magnesium ethoxy chloride) was cleansed and filtered with toluene repeatedly until the target product could not be confirmed in the filtrate. The filtrate and the mixed solution of the filtered residue and the cleanser were condensed under reduced pressure to settle and remove solvent constituents such as toluene, and subsequently distilled and purified to restore the target product. The target product is a liquid with a colorless transparent appearance, which has a boiling point of 57.5° C./5 mmHg, and a GC purity of 98.0%. The target product is identified by gas-mass chromatography, of which mass spectrum is shown in FIG. 1, and NMR is shown in FIG. 2.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[NH:18]([CH2:22][CH2:23][OH:24])[CH2:19][CH2:20][OH:21]>C(Cl)(Cl)Cl>[CH2:10]([N:18]([CH2:22][CH2:23][OH:24])[CH2:19][CH2:20][OH:21])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OCCNCCO
Reactant: BrCc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: OCCN(CCO)Cc1ccccc1
Reaction time: 5 h
Yield: 79.5 %

Procedure:
Diisopropylethylamine (2.99 mL, 17.1 mmol) and benzyl bromide (1.36 mL, 11.4 mmol) were added to a chloroform (46 mL) solution of diethanolamine (1.80 g, 17.1 mmol), and the solution was stirred for 5 hours under heat and reflux. The reaction solution was washed with water, saturated sodium bicarbonate water, and saturated brine, dried over magnesium sulfate, and evaporated after filtration. The resulting residue was purified by silica gel column chromatography (methanol/chloroform=0/100 to 12/88) to give N-benzyldiethanolamine (1.77 g, 79.4%).