Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C@H:3]([C:10]([OH:12])=[O:11])[CH2:4][C:5]1[N:9]=[CH:8][NH:7][CH:6]=1.[CH3:13]O>>[CH3:13][O:11][C:10](=[O:12])[C@H:3]([CH2:4][C:5]1[N:9]=[CH:8][NH:7][CH:6]=1)[NH:2][CH3:1]
Reactant: CN[C@@H](Cc1c[nH]cn1)C(=O)O
Reactant: CO
Product: CN[C@@H](Cc1c[nH]cn1)C(=O)OC

Procedure:
One gram of N-methyl-L-histidine was dissolved in methanol and HCl was bubbled in at 0° C. for a few minutes. The mixture was heated at reflux 1.5 hours (more hydrochloric acid was introduced on several occasions) and the cooled solution was concentrated at reduced pressure. HPLC indicated about 7% of unreacted starting material remaining. The product was not additionally purified.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[CH:6][N:5]=[C:4]([CH2:9][S:10][C:11]2[NH:15][C:14]3[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:13]=3[N:12]=2)[CH:3]=1.ClC1C=CC=C(C(OO)=[O:30])C=1>ClCCl>[NH2:1][C:2]1[C:7]([Br:8])=[CH:6][N:5]=[C:4]([CH2:9][S:10]([C:11]2[NH:15][C:14]3[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:13]=3[N:12]=2)=[O:30])[CH:3]=1
Reactant: COc1ccc2[nH]c(SCc3cc(N)c(Br)cn3)nc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccc2[nH]c(S(=O)Cc3cc(N)c(Br)cn3)nc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2 -(4 -amino-5 -bromo-2 -pyridylmethylthio)-5 -methoxy-(1H)-benzimidazole (0.58 g, 0.0016 M) was dissolved in dichloromethane (160 ml) and cooled to -40°. m-Chloroperbenzoic acid (0.33 g, 0.0019 M) in dichloromethane (10 ml) was added dropwise over 20 mins, keeping the temperature at 30 ° to -40°. The solution was stirred at -30 ° for 1 hour and then stored at -20 ° overnight, or until reaction was complete. Ammonia was then bubbled through the solution at 50, the mixture allowed to warm up to room temperature, and then filtered. The filtrate and washings were washed with 10 % Na2CO3 (10 ml) an dried. Back extraction of the aqueous layers with dichloromethane (3×100 ml) gave further organic layers which were dried and combined with layers obtained from the first extraction. Evaporation of the combined organic layers gave a brown solid. Purification, by heating in presence of decolouring charcoal in ethyl acetate/methanol, followed by recrystallisation from methanol gave 2 -(4 -amino-5 -bromo-2 -pyridylmethylsulphinyl)-5 -methoxy-(1H)-benzimidazole, 0.21 g, m.p. 130°-132°.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]3[O:20][CH2:21][O:22][C:16]=3[CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:23])[CH:8]=2)[N:3]=1.[NH3:24]>>[NH2:24][C:2]1[N:11]=[C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]3[O:20][CH2:21][O:22][C:16]=3[CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:23])[CH:8]=2)[N:3]=1
Reactant: Clc1ccc2nc(Cl)nc(NCc3ccc4c(c3)OCO4)c2c1
Reactant: N
Product: Nc1nc(NCc2ccc3c(c2)OCO3)c2cc(Cl)ccc2n1
Reaction time: 18 h

Procedure:
2.0 g of 2.6-dichloro-4-(3,4-methylenedioxybenzyl)aminoquinazoline was heated to 120° C. in 50 ml of ethanolic ammonia put in a pressure vessel for 18 hours, cooled and concentrated under a reduced pressure. The obtained residue was introduced to a silica gel column and eluted with a chloroform/methanol (9:1) mixture to give 830 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=O)[NH:11][C:10]([C:14]3[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])=[N:9]2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:24]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([Cl:24])=[N:11][C:10]([C:14]3[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c(-c2c(F)cccc2Cl)nn1-c1ccc(Br)cc1
Product: Fc1cccc(Cl)c1-c1nc(Cl)n(-c2ccc(Br)cc2)n1

Procedure:
To 2-(4-bromophenyl)-5-(2-chloro-6-fluorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (Intermediate-1, 0.100 g, 0.271 mmol) was added POCl3. The reaction mass was refluxed for 48 h. The reaction mass was quenched in water, basified with NaHCO3 and extracted with ethyl acetate and concentrated. The obtained crude product was purified with column chromatography on silica gel eluting with 0.5% EA:DCM to afford 0.110 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 7.44 (t, J=9.3 Hz, 1H), 7.53 (d, J=7.8 Hz, 1H), 7.60-7.68 (m, 1H), 7.72 (d, J=9.0 Hz, 2H), 7.85 (d, J=8.7 Hz, 2H). MS (m/z): 388.22 (M+H)+.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([Cl:13])[C:7]=1[CH2:14][C:15]([NH:17][CH:18]1[C:26]2[C:21](=[N:22][CH:23]=[CH:24][CH:25]=2)[O:20][CH2:19]1)=[O:16])(=O)C>C1COCC1.[OH-].[Na+].CCOC(C)=O>[Cl:13][C:8]1[CH:9]=[C:10]([Cl:12])[CH:11]=[C:6]([CH2:5][OH:4])[C:7]=1[CH2:14][C:15]([NH:17][CH:18]1[C:26]2[C:21](=[N:22][CH:23]=[CH:24][CH:25]=2)[O:20][CH2:19]1)=[O:16]
Reactant: CC(=O)OCc1cc(Cl)cc(Cl)c1CC(=O)NC1COc2ncccc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(Cc1c(Cl)cc(Cl)cc1CO)NC1COc2ncccc21
Temperature: 30 °C
Reaction time: 3 h

Procedure:
A mixture of rac-3,5-dichloro-2-(2-((2,3-dihydrofuro[2,3-b]pyridin-3-yl)amino)-2-oxoethyl)benzyl acetate (0.097 mmol) in 0.5 mL THF and 0.24 mL of 2M NaOH solution was stirred at 30° C. for 3 h. The reaction mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried over MgSO4 and concentrated in vacuo to give the desired compound as white solid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:25]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][O:21][CH2:20]2)=[C:8]([NH2:27])[N:7]=1)[CH2:2][CH2:3][CH3:4].Cl.O1CCOCC1>CO>[NH2:27][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:25])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][CH2:22][O:21][CH2:20]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCC3CCCOC3)c2n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCC3CCCOC3)c2n1
Reaction time: 18 h
Yield: 38.4 %

Procedure:
To a solution of 2-(butyloxy)-8-(methyloxy)-9-[4-(tetrahydro-2H-pyran-3-yl)butyl]-9H-purin-6-amine (135 mg, 0.358 mmol) in methanol (10 ml) was added 4M HCl in dioxane (2.235 ml, 8.94 mmol) and the mixture was left standing at 20° C. for 18 hours. The solvent was evaporated in vacuo to give a white solid which was loaded in methanol onto a 10 g aminopropyl SPE cartridge and eluted with methanol. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a white solid (50 mg).
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1[C:7]([O:14][CH2:15][CH2:16][O:17][CH:18]2[CH:23]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][CH2:33][O:34][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=4[O:42][CH3:43])=[CH:26][CH:25]=3)[CH2:22][CH2:21][N:20]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:19]2)=[N:8][C:9]([CH3:13])=[N:10][C:11]=1[Cl:12])=[N+]=[N-].O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:71](OC(=O)C)(=[O:73])[CH3:72]>O1CCCC1>[C:71]([NH:1][CH2:4][CH2:5][C:6]1[C:7]([O:14][CH2:15][CH2:16][O:17][CH:18]2[CH:23]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][CH2:33][O:34][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=4[O:42][CH3:43])=[CH:26][CH:25]=3)[CH2:22][CH2:21][N:20]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:19]2)=[N:8][C:9]([CH3:13])=[N:10][C:11]=1[Cl:12])(=[O:73])[CH3:72]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2nc(C)nc(Cl)c2CCN=[N+]=[N-])cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2nc(C)nc(Cl)c2CCNC(C)=O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 1.13 g of tert-butyl 3-{2-[5-(2-azidoethyl)-6-chloro-2-methylpyrimidin-4-yloxy]ethoxy}-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate in 25 ml of tetrahydrofuran is admixed at room temperature successively with 3.1 ml of water, 0.54 g of triphenylphosphine and 0.74 ml of acetic anhydride. The reaction mixture is stirred at room temperature over 16 hours and subsequently concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.10 (3:1 EtOAc-heptane); Rt=5.49.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].N1C=CC=CC=1.Cl.N1C=CC=CC=1C(Cl)=[O:23]>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[N:7]1[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=1[C:1]([NH2:8])=[O:23]
Reactant: O=C(Cl)c1ccccn1
Reactant: Nc1ccccc1N
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: NC(=O)c1ccccn1
Yield: 60 %

Procedure:
Dissolving 5.0 g (17 mmol) of (4-bromo-phenyl)-(2-nitrophenyl)-amine into 50 milliliter of tetrahydrofuran, an aqueous solution prepared by dissolving 15 g (86 mmol) of sodium dithionite into 60 milliliter of water was added. Subsequently, adding 10 milliliter of methanol, the resultant solution was stirred at room temperature for 3 hours. After recognizing that the color (orange) of the resultant solution almost disappeared, water was added, followed by extracting with ethyl acetate. After sufficiently drying an organic layer with sodium sulfate, the solvent was removed by distillation, and as a result, phenylenediamine was obtained. Dissolving the resultant phenylenediamine into 150 milliliter of ethyl acetate, an organic layer was extracted. Further, 5.4 g (68 mmol) of pyridine, 3.6 g (23 mmol) of 2-picolinic acid chloride hydrochloride and catalyst amount of 4-dimethylaminopyridine (DMAP) were added to the organic layer, and the resultant solution was stirred at room temperature for 3 hours, followed by left standing for a night. After completion of the reaction, adding water, separation with filtration was carried out for precipitated solids and then, they were sufficiently washed with water and methanol, thereby obtaining 3.8 g of 2-picolinic acid amide as white solid (yield: 60%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=2)[CH:4]=1.C[O:20]C(OC)N(C)C>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]=[O:20])=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=2)[CH:4]=1
Reactant: COc1ccnc(-c2ccc(C)c([N+](=O)[O-])c2)c1
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: COc1ccnc(-c2ccc(C=O)c([N+](=O)[O-])c2)c1
Temperature: 140 °C
Reaction time: 24 h

Procedure:
To a solution of 4-(4-methoxypyridin-2-yl)-2-nitrotoluene (2.5 g) in N,N-dimethylformamide (15 ml) was added N,N-dimethylformamide dimethyl acetal (2.72 ml), and the mixture was stirred at 140° C. for 24 hours under a nitrogen atmosphere. The reaction mixture was evaporated under reduced pressure, and the residue was suspended in tetrahydrofuran (60 ml) and water (60 ml). Sodium metaperiodate (6.57 g) was added to the suspension, and the mixture was stirred at ambient temperature for 3 hours. The reaction mixture was filtered, and the filtrate was extracted with ethyl acetate. The separated organic layer was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 150 g, 25-45% ethyl acetate in n-hexane) to give 4-(4-methoxypyridin-2-yl)-2-nitrobenzaldehyde (1.99 g).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[S:3]([C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[CH:9]=[O:10])(=[O:5])=[O:4].[BH4-].[Na+]>C1COCC1>[CH3:1][N:2]([CH3:16])[S:3]([C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[CH2:9][OH:10])(=[O:4])=[O:5]
Reactant: COc1ccc(C=O)cc1S(=O)(=O)N(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(CO)cc1S(=O)(=O)N(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 62.7 %

Procedure:
To a solution of OBS02049 (5.5 g, 21.21 mmol) in anhydrous THF (50 mL) was added sodium borohydride (0.88 g, 23.33 mmol). The mixture was stirred at room temperature for 4 h, quenched with water (CARE!!) and filtered through a Celite pad. The filtrate was concentrated in vacuo and re-dissolved in DCM (200 n-L). The organic layer was washed with brine (2×200 mL), dried (Na2SO4) and filtered. Concentration in vacuo of the combined filtrates gave OBS02053 as a golden-yellow oil (3.26 g, 59%). TLC [SiO2, EtOAc-n-hexane (1:1)] Rf=0.36; 1H-NMR (270 MHz, CDCl3)=1.73 (1H, bs, OH), 2.97 (6H, s), 3.88 (3H, s), 4.62 (2H, s), 6.95 (1H, d, J=8.4), 7.23 (1H, dd, J=2.2, 8.4), 7.36 (1H, d, J=2.2).
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=1.[CH:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.S(=O)(=O)(O)O>>[CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CC1=CCCCC1
Reactant: c1ccccc1
Agent: O=S(=O)(O)O
Product: CC1(c2ccccc2)CCCCC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 36.5 %

Procedure:
A mixed solution of 75.0 ml (632 mmol) of 1-methyl-1-cyclohexene and 56.4 ml (632 mmol) of benzene was added at 0° C. dropwise to 225.6 ml (2.53 mol) benzene solution of 231 g (2.36 mol) of sulfuric acid spending 1.5 hours, followed by stirring at 0° C. for 1.5 hours. The reaction solution was quenched by adding 300 ml of water, and the water layer was separated. The thus obtained organic layer was washed with 100 ml of saturated sodium hydrogen carbonate aqueous solution, 100 ml of water and 100 ml of saturated brine and dried with anhydrous sodium sulfate. After filtering the desiccant, the filtrate was concentrated to obtain crude 1-methylcyclohexylbenzene. By purifying the thus obtained crude 1-methylcyclohexylbenzene by distillation under a reduced pressure (from 110 to 113° C./10 mmHg), 40.2 g of the specified substance was obtained with a yield of 36.5%.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([N:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=4)=[CH:16][C:15]3=[O:30])=[CH:11][CH:12]=2)[CH:7]=[N:6]1.C([O-])([O-])=O.[K+].[K+].[NH:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1>CN(C=O)C.O>[N:37]1([CH2:2][CH2:3][CH2:4][N:5]2[C:13]3[C:8](=[CH:9][C:10]([N:14]4[CH:19]=[CH:18][C:17]([C:20]5[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=5)=[CH:16][C:15]4=[O:30])=[CH:11][CH:12]=3)[CH:7]=[N:6]2)[CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: O=c1cc(-c2ccc(C(F)(F)F)cc2)ccn1-c1ccc2c(cnn2CCCCl)c1
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1cc(-c2ccc(C(F)(F)F)cc2)ccn1-c1ccc2c(cnn2CCCN2CCCC2)c1
Temperature: 50 °C
Yield: 91.7 %

Procedure:
To a solution of 1-(1H-indazol-5-yl)-4-(4-(trifluoromethyl)phenyl)pyridin-2(1H)-one (278 mg, 0.783 mmol) in DMSO (4.0 mL) was added 3-bromo-1-chloropropane (1.23 g, 7.83 mmol) and Cs2CO3 (765 mg, 2.35 mmol), and the reaction was stirred at ambient temperature for 18 h. The reaction mixture was diluted with H2O (25 mL) and extracted with EtOAc (3×25 mL). The extracts were washed with brine (25 mL), dried over Na2SO4, and concentrated. Flash chromatography (silica gel, CH2Cl2/MeOH, 100:1) yielded the intermediate 1-(1-(3-chloropropyl)-1H-indazol-5-yl)-4-(4-(trifluoromethyl)phenyl)pyridin-2(1H)-one. To a solution of 1-(1-(3-chloropropyl)-1H-indazol-5-yl)-4-(4-(trifluoromethyl)phenyl)pyridin-2(1H)-one (78 mg, 0.18 mmol) in DMF (1.0 mL) was added K2CO3 (0.12 g, 0.90 mmol), pyrrolidine (130 mg, 1.8 mmol) and KI (30 mg, 0.18 mmol), and the reaction was heated to 50° C. for 18 h. The reaction mixture was cooled and diluted with H2O (25 mL). The resulting solids were collected by filtration and washed with H2O (10 mL). The collected solid was dissolved in EtOAc (20 mL) and washed with brine (10 mL). The washed organic solution was dried over Na2SO4, filtered and concentrated to provide the title compound (77 mg, 91%): 1H NMR (500 MHz, CDCl3) δ 8.05 (s, 1H), 7.77-7.74 (m, 5H), 7.60-7.42 (m, 3H), 6.92 (d, J=2.0 Hz, 1H), 6.53-6.51 (m, 1H), 4.51 (t, J=7.0 Hz, 2H), 2.48-2.44 (m, 6H), 2.16-2.12 (m, 2H), 1.79-1.77 (m, 4H).
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[C:21]([F:30])=[C:22]4[C:26](=[CH:27][CH:28]=3)[NH:25][C:24]([CH3:29])=[CH:23]4)=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:31][CH3:32])C1C=CC=CC=1.C([O-])=O.[NH4+]>CN(C=O)C.[Pd].C(OCC)(=O)C>[F:30][C:21]1[C:20]([O:19][C:13]2[C:12]3[C:17](=[CH:18][C:9]([OH:8])=[C:10]([O:31][CH3:32])[CH:11]=3)[N:16]=[CH:15][N:14]=2)=[CH:28][CH:27]=[C:26]2[C:22]=1[CH:23]=[C:24]([CH3:29])[NH:25]2
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
A suspension of 7-benzyloxy-4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxyquinazoline (8.2 g, 19.1 mmol), ammonium formate (12 g, 190 mmol) in DMF (50 ml) containing 10% palladium on carbon (2 g) was stirred at ambient temperature for 1.5 hours. The mixture was diluted with ethyl acetate and filtered over diatomaceous earth. A solid precipitated out of the filtrate. The solid was filtered off. The filtrate was washed with aqueous sodium hydrogen carbonate, followed by brine and dried over magnesium sulphate. The volatiles were removed under vacuum. The residual solid was combined with the solid previously isolated from the filtrate and was then triturated with acetonitrile under cooling. The precipitate was filtered, washed with acetonitrile followed by diethyl ether and dried under vacuum to give 4-(4-fluoro-2-methylindol-5-yloxy)-7-hydroxy-6-methoxyquinazoline (6.48 g, quant.).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([C:10]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=3)=[CH:8][CH:7]=[CH:6][N:5]2[CH:17]=1.[H-].[Na+].Cl[C:21]1[N:25]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:24]2[CH:34]=[CH:35][CH:36]=[CH:37][C:23]=2[N:22]=1.O>CN(C=O)C>[CH3:1][C:2]1[N:3]=[C:4]2[C:9]([C:10]3[CH:15]=[CH:14][C:13]([O:16][C:21]4[N:25]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:32])([CH3:33])[CH3:31])[C:24]5[CH:34]=[CH:35][CH:36]=[CH:37][C:23]=5[N:22]=4)=[CH:12][CH:11]=3)=[CH:8][CH:7]=[CH:6][N:5]2[CH:17]=1
Reactant: C[Si](C)(C)CCOCn1c(Cl)nc2ccccc21
Reactant: Cc1cn2cccc(-c3ccc(O)cc3)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cn2cccc(-c3ccc(Oc4nc5ccccc5n4COCC[Si](C)(C)C)cc3)c2n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 68.5 %

Procedure:
To a solution of 4-(2-methylimidazo[1,2-a]pyridin-8-yl)phenol (0.40 g) in DMF (5 ml) was added sodium hydride (60% in oil, 0.086 g), and the mixture was stirred at room temperature for 5 min. To the reaction mixture was added 2-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole (0.50 g), and the mixture was stirred under microwave irradiation at 150° C. for 1 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate) to give the title compound (0.57 g).
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([CH2:15][CH2:16][CH3:17])[CH:9]=2)[S:6][CH:7]=1)[CH3:2].O.[Br:19][CH2:20][CH2:21]Br>CN(C=O)C>[Br:19][CH2:20][CH2:21][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[S:6][CH:7]=[C:3]([CH2:1][CH3:2])[N:4]=2)=[CH:9][C:10]=1[CH2:15][CH2:16][CH3:17]
Reactant: BrCCBr
Reactant: CCCc1cc(-c2nc(CC)cs2)ccc1O
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1cc(-c2nc(CC)cs2)ccc1OCCBr
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 4-(4-ethyl-1,3-thiazol-2-yl)-2-propylphenol (0.24 g, 0.97 mmol) (Example 33) in DMF (2 mL, containing 1% v/v of water) was added 1,2-dibromoethane (1.09 g, 5.82 mmol), and the mixture was stirred at rt for 12 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude residue was suspended in EtOAc, filtered through a small plug of silica, and the filtrate was concentrated. The crude material was used in the next step without further purification. 1H NMR (400 MHz, CDCl3): δ 7.79-7.68 (m, 2H), 6.88-6.78 (m, 2H), 4.34 (t, 2H), 3.69 (t, 2H), 2.95-2.82 (m, 2H), 2.72-2.60 (m, 2H), 1.80-1.64 (m, 2H), 1.36 (t, 3H), 1.02 (t, 3H).
Reaction SMILES: [C:1]([NH:3][C@@H:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C@@H:5]1[NH:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH3:21])[CH:19]=2)[N:14]=[C:13]([C:22]([NH:24][CH2:25][CH2:26][O:27][CH3:28])=[O:23])[N:12]=1)#[N:2].Cl.[CH3:30][O:31][NH2:32].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[NH2:2][C:1]([NH:3][C@@H:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C@@H:5]1[NH:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH3:21])[CH:19]=2)[N:14]=[C:13]([C:22]([NH:24][CH2:25][CH2:26][O:27][CH3:28])=[O:23])[N:12]=1)=[N:32][O:31][CH3:30]
Reactant: CON
Reactant: COCCNC(=O)c1nc(N[C@H]2CCCC[C@H]2NC#N)c2cc(C)ccc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: COCCNC(=O)c1nc(N[C@H]2CCCC[C@H]2NC(N)=NOC)c2cc(C)ccc2n1
Temperature: 0 °C
Yield: 77.7 %

Procedure:
To a solution of 1.96 g of 4-{[(1S,2R)-2-(cyanoamino)cyclohexyl]amino}-N-(2-methoxyethyl)-6-methylquinazolin-2-carboxamide and 8.56 g of methoxyamine hydrochloride in 80 ml of ethanol, 10.86 g of sodium carbonate was added and the mixture was heated at reflux for 1 hour. The reaction solution was added to 400 ml of ice water, and the deposited substance was collected by filtration. After the collected deposited substance was washed with water, it was dried under reduced pressure. The obtained powder was washed with a mixed solution of (chloroform:diisopropyl alcohol=1:1), whereby 1.71 g of a desired compound was obtained as a white powder.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@:9]([CH3:19])([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:10]=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:21][OH:22].C(N(CC)CC)C>C(O)C>[C:1]([O:5][C:6]([NH:8][C@:9]([CH3:19])([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:10]=[N:21][OH:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@](C)(C=O)Cc1ccccc1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@](C)(C=NO)Cc1ccccc1

Procedure:
A solution of (R)-2-tert-butoxycarbonylamino-2-methyl-3-phenylpropanal (80 mg, 0.30 mmol), hydroxylamine hydrochloride (25 mg, 0.36 mmol) and triethylamine (0.125 mL, 0.9 mmol) in 3.4 mL ethanol was heated to reflux temperature overnight. Additional hydroxylamine hydrochloride (25 mg, 0.36 mmol) and triethylamine (0.125 mL, 0.9 mmol) were added and the reaction continued at reflux temperature for 4.5 h. Concentration and flash chromatography (0-25% EtOAc/hexanes) gave (R)-2-tert-butoxycarbonylamino-2-methyl-3-phenylpropanal oxime. 1H NMR (CDCl3) δ 7.95 (bs, 1H), 7.52 (bs, 1H), 7.25 (m, 3H), 7.10 (d, J=6.7 Hz, 2H), 5.01 (s, 1H), 3.14 (m, 2H), 1.46 (s, 9H), 1.42 (s, 3H).
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][CH2:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)C(=O)C2=CC=CC=C12.O.NN>CO>[NH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]#[N:14])=[CH:15][CH:16]=1
Reactant: N#Cc1ccc(CCCN2C(=O)c3ccccc3C2=O)cc1
Agent: NN
Solvent: CO
Solvent: O
Product: N#Cc1ccc(CCCN)cc1
Temperature: 25 °C
Yield: 90 %

Procedure:
To a 10 g (30 mmols) portion of 4-(3-phthalimidopropyl)benzonitrile were added 1.89 ml (39 mmols) of hydrazine hydrate and 130 ml of methanol, and the mixture was refluxed for 3 hours, cooled to room temperature and then concentrated. The residue was dissolved in 200 ml of 1 mol dm-3NaOH, followed by extraction with ether. The extract was dried over K2CO3 and concentrated, giving 4.32 g (yield 90%) of 4-(3-aminopropyl)benzonitrile.