Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20](F)=[C:21]([F:24])[CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>C1COCC1.CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[C:21]([F:24])[CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(F)c(F)cc23)CC1
Reactant: C1COCCN1
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(N4CCOCC4)c(F)cc23)CC1
Yield: 89.4 %

Procedure:
A solution of 4-(6,7-Difluoro-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester (37.8 mg, 108 μmol) (preparation in Example 90c) and morpholine (19.8 μL, 227 μmol) in THF (100 μL) and DMSO (50 μL) was heated at 100° C. for 1 hr. The crude reaction was loaded onto a flash silica cartridge (1 :1 hexanes/EtOAc eluent) to provide the title compound (40.2 mg, 89%). NOe experiments support the assigned regioisomer. Select 1H-NMR resonances and nOes (300 MHz, CDCl3) δ 7.68 (d, J=13.7 Hz, 1H), 7.37 (d, J=8.4 Hz, 1H), 3.45 (tt, 1H), 3.31 (m, 4H). Irradiation of the diagnostic methine proton at δ 3.45 generates an nOe to the quinazoline C5 proton at δ 7.68, but not to the quinazoline C8 proton at δ 7.37. The C5 proton has a larger coupling constant than the C8 proton, indicating fluorine substitution at C6 of the quinazoline. Furthermore, irradiation of the C8 proton at δ 7.37 generates an nOe only to the morpholine C3 protons at δ 3.31, while irradiation of the C5 proton generates an nOe only to the methine proton at δ 3.45. These data indicate morpholine substitution at the quinazoline C7 carbon. LC/MS (ESI): calcd mass 416.2, found 417.3 (MH)+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:6]=1[C:7]([NH:9][C:10]1[N:14]([CH3:15])[N:13]=[N:12][N:11]=1)=[O:8])(=[O:4])=[O:3].[H-].[Na+].Cl[C:27]([O:29][CH3:30])=[O:28].C(=O)([O-])O.[Na+]>C1COCC1.O>[CH3:1][S:2]([C:5]1[CH:19]=[C:18]([C:20]([F:23])([F:21])[F:22])[CH:17]=[CH:16][C:6]=1[C:7]([N:9]([C:10]1[N:14]([CH3:15])[N:13]=[N:12][N:11]=1)[C:27](=[O:28])[O:29][CH3:30])=[O:8])(=[O:3])=[O:4]
Reactant: COC(=O)Cl
Reactant: Cn1nnnc1NC(=O)c1ccc(C(F)(F)F)cc1S(C)(=O)=O
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)N(C(=O)c1ccc(C(F)(F)F)cc1S(C)(=O)=O)c1nnnn1C
Reaction time: 0.17 h

Procedure:
To a solution of 175 mg (0.5 mmol) of 2-(methylsulfonyl)-N-(1-methyl-1H-tetrazol-5-yl)-4-(trifluoromethyl)benzamide in 4 ml of THF (abs.) under protective gas at 0° C. are added 14 mg (0.55 mmol) of sodium hydride (95%). After stirring for 10 min, 46 μl (0.6 mmol) of methyl chloroformate are added at 0° C. The reaction mixture is stirred at RT for 1 h. Subsequently, the reaction mixture is adjusted to pH 7 with an aqueous sat. sodium hydrogencarbonate solution, and 10 ml of water are added. Then the mixture is extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and concentrated. Yield: 231 mg (57%)
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([C:13]([NH:15][N:16]=[C:17]([C:19]2[C:23]([OH:24])=[C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:27][CH:26]=3)[S:21][CH:20]=2)[CH3:18])=[O:14])[CH:10]=[CH:9][C:5]=1[C:6](O)=[O:7])([O-:3])=[O:2].C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH3:50][N:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1.Cl>CN1CCCC1=O>[C:31]([C:28]1[CH:27]=[CH:26][C:25]([C:22]2[S:21][CH:20]=[C:19]([C:17](=[N:16][NH:15][C:13](=[O:14])[C:11]3[CH:10]=[CH:9][C:5]([C:6]([N:54]4[CH2:55][CH2:56][N:51]([CH3:50])[CH2:52][CH2:53]4)=[O:7])=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=3)[CH3:18])[C:23]=2[OH:24])=[CH:30][CH:29]=1)([CH3:34])([CH3:32])[CH3:33]
Reactant: CN1CCNCC1
Reactant: CC(=NNC(=O)c1ccc(C(=O)O)c([N+](=O)[O-])c1)c1csc(-c2ccc(C(C)(C)C)cc2)c1O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CC(=NNC(=O)c1ccc(C(=O)N2CCN(C)CC2)c([N+](=O)[O-])c1)c1csc(-c2ccc(C(C)(C)C)cc2)c1O
Reaction time: 2 h
Yield: 10 %

Procedure:
To a N-methyl-2-pyrrolidinone (1.0 mL) solution of 2-nitro-4-[(2-{1-[5-(4-t-butylphenyl)-4-hydroxy-3-thienyl]-ethylidene}hydrazino)carbonyl]benzoic acid (50 mg, 0.10 mmol, see the synthetic example 47) and triethylamine (16 μL, 0.11 mmol) was added isobutyl chloroformate (26 μL, 0.20 mmol) at 0° C. The reaction mixture was stirred for 2 hours at this temperature, and then N-methyl piperazine (45 μL, 0.40 mmol) was added. After stirring for 1 hour at room temperature, the reaction mixture was acidified with 1M aqueous HCl solution (1.0 mL) and concentrated under the reduced pressure. To the residue was added water, then the precipitate was collected by filtration, washed with water, isopropanol and methanol, then dried by means of a vacuum pump to give the desired product as a pale yellow solid (yield 10%).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=4)=[O:19])=[CH:13][CH:12]=3)=[CH:9][S:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[I:28]I.[OH-].[K+]>N1C=CC=CC=1.O1CCCC1>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=4)=[O:19])=[CH:13][CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([I:28])=[CH:4][N:3]=1
Reactant: II
Reactant: Nc1nccc2scc(-c3ccc(NC(=O)Nc4cccc(F)c4)cc3)c12
Agent: [K+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Nc1ncc(I)c2scc(-c3ccc(NC(=O)Nc4cccc(F)c4)cc3)c12

Procedure:
As shown in the Scheme above, 1-(4-(4-aminothieno[3,2-c]pyridin-3-yl)phenyl)-3-(3-fluorophenyl)urea ((1), prepared as described in WO2005/10009), in a mixture of pyridine and tetrahydrofuran can be treated with iodine at room temperature, followed by treatment with potassium hydroxide at elevated temperature to provide 1-(4-(4-amino-7-iodothieno[3,2-c]pyridin-3-yl)phenyl)-3-(3-fluorophenyl)urea (2). Methyl 4-amino-3-(4-(3-(3-fluorophenyl)ureido)phenyl)thieno[3,2-c]pyridine-7-carboxylate (3) can be prepared by reacting 1-(4-(4-amino-7-iodothieno[3,2-c]pyridin-3-yl)phenyl)-3-(3-fluorophenyl)urea (2) with carbon monoxide gas in the presence of a catalyst such as but not limited to [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane, and a base such as but not limited to triethylamine. The reaction is typically performed under pressure and at an elevated temperature. Methyl 4-amino-3-(4-(3-(3-fluorophenyl)ureido)phenyl)thieno[3,2-c]pyridine-7-carboxylate (3) can be reacted with aqueous lithium hydroxide to provide 4-amino-3-(4-(3-(3-fluorophenyl)ureido)phenyl)thieno[3,2-c]pyridine-7-carboxylic acid (4). The reaction is typically performed at elevated temperature in a solvent such as but not limited to tetrahydrofuran and methanol. 4-Amino-3-(4-(3-(3-fluorophenyl)ureido)phenyl)thieno[3,2-c]pyridine-7-carboxylic acid (4) can be reacted with N,N-diethyl-1,3-propanediamine in the presence of a coupling agent such as but not limited to 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride, an auxiliary coupling reagent such as but not limited to 1-hydroxybenzotriazole hydrate, and a base such as but not limited to N-methylmorpholine to provide 4-amino-N-[3-(diethylamino)propyl]-3-(4-{[(3-fluorophenyl)carbamoyl]amino}phenyl)thieno[3,2-c]pyridine-7-carboxamide (5). The reaction is typically performed in a solvent such as but limited to N,N-dimethylformamide.
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[C:10]([C:12]3[CH2:13][CH2:14][NH:15][CH2:16][CH:17]=3)[N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(Cl)Cl.[C:22]([N:26]=[C:27]=[O:28])([CH3:25])([CH3:24])[CH3:23]>N1C=CC=CC=1>[C:22]([NH:26][C:27]([N:15]1[CH2:14][CH:13]=[C:12]([C:10]2[N:9]=[N:8][N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:11]=2)[CH2:17][CH2:16]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: C1=C(c2cn(-c3ccccc3)nn2)CCNC1
Reactant: CC(C)(C)N=C=O
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)NC(=O)N1CC=C(c2cn(-c3ccccc3)nn2)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
4-[1-Phenyl-1H-[1,2,3]triazol-4-yl]-1,2,3,6-tetra-hydropyridine (35 mg) prepared in Example 49 was dissolved in 1 ml of pyridine and 1 ml of chloroform and 26 μl of tert-butyl isocyanate was added thereto followed by stirring at room temperature for 6 hours. The reaction solution was concentrated in vacuo and the resulting residue was separated and purified by a preparative thin-layer chromatography (chloroform/methanol=10/1+0.3% aqueous ammonia) and then recrystallized from chloroform-hexane to give 42 mg of the title compound as a white solid.
Reaction SMILES: ClC[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[Br:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)=[CH:14][CH:13]=1
Reactant: ClCCCN1CCOCC1
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccc(OCCN2CCOCC2)cc1
Temperature: 62.5 °C
Reaction time: 17.5 h
Yield: 2180.8 %

Procedure:
A 50 L jacketed reactor equipped with a reflux condenser and temperature probe was charged with 4-(3-chloropropyl)morpholine (2.44 kg, 0.54 mol), 4-bromophenol (2.27 kg, 0.54 mol, 1.0 equiv.), powdered potassium carbonate (6.331 kg, 1.88 mol, 3.50 equiv.), and DMF (12.2 L) and stirred. The reaction mixture was then heated to 60-65° C. and stirred overnight. After 17.5 h, the reaction mixture was cooled to 20-25° C. The reaction mixture was charged to a different reactor equipped with bottom valve for the work-up. While maintaining a temperature between 20-30° C., DI water (48.7 L) was charged to the reactor. The phases were separated. The aqueous layer was extracted with MTBE (3×24.4 L). To the combined organics, DI water (18.3 L) and then 6M sodium hydroxide (18.2 L) were added. The mixture was stirred for 2-5 minutes and the phases were separated. The organic phase was washed with water (24.4 L) and brine (24.4 L), dried over magnesium sulfate, filtered, and concentrated to give 3370 g of a yellow oil (89% crude yield, 99.4% AUC by HPLC).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[C:10]([CH2:12]O)[CH:9]=[CH:8][C:7]=1[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[F:22])[CH2:2][CH2:3][CH3:4].S(Cl)([Cl:25])=O>C(Cl)Cl>[CH2:1]([O:5][C:6]1[CH:11]=[C:10]([CH2:12][Cl:25])[CH:9]=[CH:8][C:7]=1[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[F:22])[CH2:2][CH2:3][CH3:4]
Reactant: O=S(Cl)Cl
Reactant: CCCCOc1cc(CO)ccc1-c1cc(OC)ccc1F
Solvent: ClCCl
Product: CCCCOc1cc(CCl)ccc1-c1cc(OC)ccc1F
Reaction time: 8 h
Yield: 85.5 %

Procedure:
To a stirred solution of 5.3 (0.8800 g, 2.891 mmol) in DCM (15 mL) at 23° C. was added thionyl chloride (0.4218 mL, 5.783 mmol). The reaction mixture was then stirred overnight. The reaction was concentrated and then purified by combiflash (0 to 10% EtOAc/Hexanes) to provide 5.4 (0.7980 g, 85.50% yield).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[C@H:20]([CH3:25])[CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:29][CH2:30][CH2:31][OH:32]>>[OH:32][CH2:31][CH2:30][CH2:29][N:22]1[CH2:21][C@@H:20]([CH3:25])[N:16]2[C:17]3[CH:18]=[CH:19][C:11]([O:10][CH:7]4[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]4)=[CH:12][C:13]=3[CH:14]=[C:15]2[C:23]1=[O:24]
Reactant: OCCCBr
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@H](C)CNC2=O)CC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@H](C)CN(CCCO)C2=O)CC1
Yield: 58 %

Procedure:
The title compound was synthesized in analogy to example 17, from (R)-8-(1-isopropyl-piperidin-4-yloxy)-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 8), sodium hydride and 3-bromo-1-propanol, to give the desired product as a colorless oil (58%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.S(Cl)(Cl)=O.[NH3:17]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH2:17])=[O:12])=[CH:5][CH:4]=1
Reactant: COc1ccc(CC(=O)O)cc1
Reactant: N
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(CC(N)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
A solution of 2-(4-methoxyphenyl)acetic acid (500 mg, 3.00 mmol) in DCM (30 ml) was added thionyl chloride (0.4 ml, 4.5 mmol) at 0° C. The reaction mixture was allowed to warm up to room temperature and continued to stirred overnight. Then aqueous ammonia (2 ml) was added to the reaction mixture. The white solid forming was filtered and dried under vacuum to obtained 350 mg (70%) of 2-(4-methoxyphenyl)acetamide as a white solid.
Reaction SMILES: [N:1]([CH:4]([C:6]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:10]=[N:11][CH:12]=[CH:13][C:8]=2[N:7]=1)[CH3:5])=[N+]=[N-]>[Pd].CCOC(C)=O>[C:15]1([N:14]2[C:9]3[CH:10]=[N:11][CH:12]=[CH:13][C:8]=3[N:7]=[C:6]2[CH:4]([NH2:1])[CH3:5])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(N=[N+]=[N-])c1nc2ccncc2n1-c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(N)c1nc2ccncc2n1-c1ccccc1
Temperature: 20 °C
Reaction time: 3 h
Yield: 65.6 %

Procedure:
A mixture of 2-(1-azidoethyl)-3-phenyl-3H-imidazo[4,5-c]pyridine (0.89 g, 3.39 mmol) and 10% palladium on carbon (0.20 g) in EtOAc (40 mL) was stirred under an atmosphere of hydrogen at atmospheric pressure and 20° C. for 3 h. The catalyst was removed by filtration and the filtrate concentrated in vacuo. The resulting residue was purified by chromatography (SiO2 0-10% (2M ammonia in methanol) in DCM) to give the title compound as a white solid (0.53 g, 65%). LCMS (method H): Rt 0.25 min, [M+H]+ 239.
Reaction SMILES: Br[CH:2]=[CH:3][CH:4]=[C:5]([CH3:14])[CH2:6][CH:7]([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10].[CH3:15][C:16]1[CH2:21][CH2:20][CH2:19][C:18]([CH3:23])([CH3:22])[C:17]=1/[CH:24]=[CH:25]/[C:26]([CH3:28])=[O:27]>>[CH3:15][C:16]1[CH2:21][CH2:20][CH2:19][C:18]([CH3:22])([CH3:23])[C:17]=1[CH:24]=[CH:25][C:26]([CH3:28])([OH:27])[CH:2]=[CH:3][CH:4]=[C:5]([CH3:14])[CH2:6][CH:7]([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10]
Reactant: CCOC(CC(C)=CC=CBr)OCC
Reactant: CC(=O)/C=C/C1=C(C)CCCC1(C)C
Product: CCOC(CC(C)=CC=CC(C)(O)C=CC1=C(C)CCCC1(C)C)OCC
Yield: 73 %

Procedure:
The procedure is as in Example 1, but employs 6-bromo-3-methyl-1,1-diethoxy-3,5-hexadiene (0.56 g; 2.12 mmol) and β-ionone (0.33 g; 1.716 mmol, i.e. 0.8 equivalent). After flash chromatography, 9-(2,6,6-trimethyl-1cyclohexenyl)-1,1-diethoxy-3,7-dimethyl-7-hydroxy-3,5,8-nonatriene, or C20 diethyl hydroxyacetal, (0.47 g) is obtained. The yield is 73%. The structure of the product obtained is confirmed by the infrared spectrum and the proton nuclear magnetic resonance spectrum.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[CH:9]2[CH2:10][CH2:11][N:6]([CH2:7][CH2:8]2)[CH2:5]1.CO.C[O-].[Na+].[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([C:26]2[O:30][C:29]([C:31](Cl)=[O:32])=[CH:28][CH:27]=2)=[CH:22][CH:21]=1)([O-:19])=[O:18]>ClCCl>[N:6]12[CH2:11][CH2:10][CH:9]([CH2:8][CH2:7]1)[CH:4]([NH:3][C:31]([C:29]1[O:30][C:26]([C:23]3[CH:22]=[CH:21][C:20]([N+:17]([O-:19])=[O:18])=[CH:25][CH:24]=3)=[CH:27][CH:28]=1)=[O:32])[CH2:5]2
Reactant: NC1CN2CCC1CC2
Reactant: O=C(Cl)c1ccc(-c2ccc([N+](=O)[O-])cc2)o1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: O=C(NC1CN2CCC1CC2)c1ccc(-c2ccc([N+](=O)[O-])cc2)o1

Procedure:
A mixture of (±)3-aminoquinuclidine dihydrochloride, methanol (250 ml), sodium methoxide (5.1 g, 95 mmol) was stirred at reflux for 1 hour. The mixture was evaporated and was mixed with methanol (150 ml) and dichloromethane (100 ml) was added and cooled on ice, and 5-(4-nitrophenyl)-2-furoyl chloride (11.2 g, 44.5 mmol), solved in dichloromethane (200 ml) was added drop-wise at 0° C. The mixture was stirred at room temperature for 21 hours. The mixture was evaporated, water (200 ml) was added and the pH was adjusted to 8.5 with triethylamine. The mixture was extracted with ethyl acetate (3×200 ml) and the pure product was isolated as free base. Yield 5.0 g (33%).
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([CH2:7][OH:8])[NH:4][N:3]=1.[Cl:9][CH:10]([CH:13]=O)[CH:11]=O>C(O)(=O)C>[Cl:9][C:10]1[CH:11]=[N:1][C:2]2[N:3]([N:4]=[C:5]([CH2:7][OH:8])[N:6]=2)[CH:13]=1
Reactant: O=CC(Cl)C=O
Reactant: Nc1n[nH]c(CO)n1
Solvent: CC(=O)O
Product: OCc1nc2ncc(Cl)cn2n1
Temperature: 80 °C

Procedure:
To a slurry of (3-amino-1H-1,2,4-triazol-5-yl)methanol (28.5 g, 150 mmol) in acetic acid was added chloromalonaldehyde (16 g, 150 mmol). The mixture was heated to 80° C. for 4 hours. Upon cooling of the reaction to room temperature, the product crystallized out as a white solid (25.5 g, 92%). 1H NMR (300 MHz, DMSO-D6) δ: 4.67 (s, 2 H), 5.62 (s, 1 H), 8.94 (d, J=2.45 Hz, 1 H), 9.81 (d, J=2.45 Hz, 1 H). MS (APCI): 185.0 (M+H+).
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:17][CH3:18])[C:10]([C:19](=[S:21])[NH2:20])=[CH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:22][CH2:23][C:24]([CH2:26]Cl)=O>C(O)C>[Cl:22][CH2:23][C:24]1[N:20]=[C:19]([C:10]2[C:11]3[C:16](=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][CH:12]=3)[N:8]([CH2:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[CH:9]=2)[S:21][CH:26]=1
Reactant: O=C(CCl)CCl
Reactant: COc1cccc2c(C(N)=S)cn(CC3CCCCC3)c12
Solvent: CCO
Product: COc1cccc2c(-c3nc(CCl)cs3)cn(CC3CCCCC3)c12
Temperature: 60 °C
Reaction time: 1 h
Yield: 80.8 %

Procedure:
A mixture of 1-(cyclohexyl)methyl-7-methoxy-1H-indole-3-carboxylic acid amide (prepared from 7-methoxyindole as described in Example 1; 5.10 g, 17.8 mmol), Lawesson's reagent (7.92 g, 19.6 mmol), and toluene (150 ml) was stirred at room temperature for 4 days. The reaction mixture was concentrated in vacuo and the obtained reside was purified by column chromatography eluting with dichloromethane to afford 1-(cyclohexyl)methyl-7-methoxy-1H-indole-3-carbothioic acid amide (3.58 g). A mixture of 1-(cyclohexyl)methyl-7-methoxy-1H-indole-3-carbothioic acid amide (200 mg, 0.66 mmol), 1,3-dichloroacetone (126 mg, 0.99 mmol), and ethanol (2.0 ml) was stirred at 60° C. for 1 h. The reaction mixture was concentrated in vacuo, and the obtained residue was mixed with 5% aqueous sodium carbonate (100 ml). The resulting mixture was extracted with dichloromethane (4×100 ml). The organic layers were combined, washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The obtained residue was purified by column chromatography eluting with 25% (v/v) ethyl acetate in n-heptane to give 3-[4-(chloromethyl)thiazol-2-yl]-1-(cyclohexyl)methyl-7-methoxy-1H-indole (200 mg).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[OH:15].[Cl:16][CH:17]([F:24])[C:18]([F:23])([F:22])[C:19](Cl)=[O:20]>Cl>[Cl:16][CH:17]([F:24])[C:18]([F:23])([F:22])[C:19]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[OH:15])=[O:20]
Reactant: O=C(Cl)C(F)(F)C(F)Cl
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(Nc1ccc([N+](=O)[O-])cc1O)C(F)(F)C(F)Cl
Temperature: 20 °C
Reaction time: 3 h

Procedure:
146.8 g (1.1 mole) of anhydrous aluminium chloride were added with stirring to a suspension of 154 g (1 mole) of 2-amino-5-nitrophenol. The brownish black solution was cooled down to 20° C. In 20 min 181 g (1 mole) of 3-chloro-2,2,3-trifluoro-propionyl chloride were added thereto, the temperature being kept at 30° C. by cooling. After 3 hours of stirring at room temperature the solution was poured out in 2 l of icewater and 200 ml of concentrated hydrochloric acid. Stirring was continued for 1 hour. The precipitate was collected and rinsed with water until free from acid.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][N:4]=1)[NH2:2].[CH:15](OCC)(OCC)OCC>>[N:12]1[CH:13]=[CH:14][C:9]([C:7]2[CH:6]=[CH:5][N:4]3[CH:15]=[N:2][N:1]=[C:3]3[CH:8]=2)=[CH:10][CH:11]=1
Reactant: NNc1cc(-c2ccncc2)ccn1
Reactant: CCOC(OCC)OCC
Product: c1cc(-c2ccn3cnnc3c2)ccn1

Procedure:
A 1.0 g portion of 2-hydrazino-4,4'-bipyridine and 50 ml of triethyl orthoformate was refluxed 18 hours, then chilled and the crystals collected. These crystals were dissolved in acetone-ethyl acetate, treated with activated carbon, filtered and the filtrate concentrated while hexane was added. Cooling gave the desired product as white crystals, mp 194°-196° C.
Reaction SMILES: C(OC(=O)[C:5](=[C:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)[C:6]#[N:7])C.[C-:22]#[N:23].[K+]>CCO.O>[CH2:14]([N:11]1[CH2:10][CH2:9][C:8]([CH2:5][C:6]#[N:7])([C:22]#[N:23])[CH2:13][CH2:12]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(=O)C(C#N)=C1CCN(Cc2ccccc2)CC1
Reactant: [C-]#N
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N#CCC1(C#N)CCN(Cc2ccccc2)CC1
Reaction time: 24 h
Yield: 81.2 %

Procedure:
To a solution of (1-benzyl-piperidin-4-ylidene)-cyano-acetic acid ethyl ester (112.9 g, 0.40 mol) in EtOH (500 ml) and H2O (100 ml), potassium cyanide (64.6 g, 0.99 mol) is added at ambient temperature. The reaction mixture is stirred at 65 C.° for 24 h. After removal of EtOH, H2O is added to the residue. The waster phase is extracted with diethyl ether. The combined extracts are washed with H2O and brine, dried over sodium sulfate and evaporated down to give 77.7 g of 1-benzyl-4-cyanomethyl-piperidine-4-carbonitrile.
Reaction SMILES: [SH:1][CH2:2][CH2:3][NH:4][C:5](=[O:12])[CH2:6][CH2:7][CH2:8][C:9](O)=[O:10].[NH3:13]>>[SH:1][CH2:2][CH2:3][NH:4][C:5](=[O:12])[CH2:6][CH2:7][CH2:8][C:9]([NH2:13])=[O:10]
Reactant: O=C(O)CCCC(=O)NCCS
Reactant: N
Product: NC(=O)CCCC(=O)NCCS

Procedure:
A solution of 9.1 g (44 mmol) of methyl ester of N-(2-mercaptoethyl)glutaramic acid obtained in Example 4a), in 100 cm3 of aqueous 20% solution of aqueous ammonia was stirred for 4 hours at ambient temperature under argon atmosphere. After evaporation to dryness and recrystallization from isopropanol 7 g of N-(2-mercaptoethyl)glutaramide were obtained in the form of a white solid with a melting point of 127° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:7][CH:6]([C:8]2[N:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]2[CH:14]=[C:15]([C:18]#[N:19])[CH:16]=[CH:17][C:4]=2[O:3]1.ClC1C=CC=C(C(OO)=[O:29])C=1>ClCCl.C(OCC)C>[C:18]([C:15]1[CH:16]=[CH:17][C:4]2[O:3][C:2]([CH3:20])([CH3:1])[CH2:7][CH:6]([C:8]3[N:9]=[CH:10][CH:11]=[CH:12][N+:13]=3[O-:29])[C:5]=2[CH:14]=1)#[N:19]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1(C)CC(c2ncccn2)c2cc(C#N)ccc2O1
Solvent: CCOCC
Solvent: ClCCl
Product: CC1(C)CC(c2nccc[n+]2[O-])c2cc(C#N)ccc2O1
Reaction time: 8 h
Yield: 9.7 %

Procedure:
242 mg of 3,4-dihydro-2,2-dimethyl-4-(2-pyrimidinyl)-2H-1-benzopyran-6-carbonitrile were dissolved in 5 ml of dichloromethane at room temperature and 450 mg of m-chloroperbenzoic acid were added. After stirring overnight the mixture was washed with sodium bisulphite solution and sodium bicarbonate solution. The organic phase was dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using ethyl acetate/ethanol/formic acid (40:4:1) for the elution. The product was obtained in the form of an oil which was dissolved in diethyl ether and washed with sodium bicarbonate solution. The organic phase was dried over sodium sulphate and evaporated. The resulting oil was crystallized from t-butyl methyl ether to give 25 mg of 2-(6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)pyrimidine 1-oxide of melting point 98°-100° C.