Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.[H-].[Na+].[Cl:10][C:11]1[N:16]=[C:15](Cl)[C:14]([Cl:18])=[CH:13][N:12]=1>CN(C=O)C.C1COCC1>[Cl:10][C:11]1[N:16]=[C:15]([O:7][CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[C:14]([Cl:18])=[CH:13][N:12]=1
Reactant: OC1CCOCC1
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Clc1ncc(Cl)c(OC2CCOCC2)n1
Temperature: 25 °C

Procedure:
To a solution of tetrahydro-4-pyranol (0.36 g, 3.54 mmol) in DMF (5 mL) was added sodium hydride (60% dispersion, 0.17 g, 4.25 mmol). The resulting mixture was added to a solution of 2,4,5-trichloropyrimidine (650 mg, 3.5 mmol) in THF at 0° C. The combined mixture was then allowed to warm to room temperature. To the reaction was then added water and the product was extracted with a 1:1 EtOAc-Heptane mixture. The extract was then dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography (0-30% EtOAc in heptane) to give 2,5-dichloro-4-(tetrahydro-2H-pyran-4-yloxy)pyrimidine. 1H-NMR (CDCl3): δ 8.33 (s, 1H), 5.42 (m, 1H), 4.09-3.90 (m, 2H), 3.65 (m, 2H), 2.19-1.99 (m, 2H), 1.87 (m, 2H).
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][CH:28]=[C:4]2[N:3]1[C@H:29]1[CH2:34][CH2:33][C@H:32]([O:35][CH2:36][C:37](=[O:39])[CH3:38])[CH2:31][CH2:30]1.[CH:40](N(C(C)C)CC)(C)C.FC(F)(F)S(O[Si:55]([C:58]([CH3:61])([CH3:60])[CH3:59])([CH3:57])[CH3:56])(=O)=O.C(=O)([O-])O.[Na+]>C(Cl)Cl.C(OCC)(=O)C>[Si:55]([O:39][C:37]1([CH2:36][O:35][C@H:32]2[CH2:31][CH2:30][C@H:29]([N:3]3[C:2](=[O:1])[C:7]([CH2:8][C:9]4[CH:10]=[CH:11][C:12]([C:15]5[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=5)=[CH:13][CH:14]=4)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]4[N:26]=[CH:27][CH:28]=[C:4]34)[CH2:34][CH2:33]2)[CH2:40][CH2:38]1)([C:58]([CH3:61])([CH3:60])[CH3:59])([CH3:57])[CH3:56]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)=O)CC2)c2ccnn12
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC3(O[Si](C)(C)C(C)(C)C)CC3)CC2)c2ccnn12
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 4′-({5-oxo-4-[trans-4-(2-oxopropoxy)cyclohexyl]-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.93 g) and diisopropylethylamine (0.77 mL) in methylene chloride (10 mL) was added dropwise tert-butyldimethylsilyl trifluoromethanesulfonate (1.02 mL) at −78° C., and the mixture was stirred for 3 hr while warming to 0° C. To the reaction mixture were added ethyl acetate and saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was crudely purified by silica gel column chromatography, and dissolved in methylene chloride (5 mL), and the mixture was added dropwise to a solution of diethylzinc (1 M hexane solution, 7.5 mL) and chloroiodomethane (0.55 mL) in methylene chloride (10 mL) at 0° C., and the mixture was stirred for 2 hr. To the reaction mixture were added ethyl acetate and then saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.67 g, 68%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6](N)=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1.[C:13]([C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:25]=1[OH:26])[C:20](O)=[O:21])([CH3:16])([CH3:15])[CH3:14].C1([N:37]=C=NC2CCCCC2)CCCCC1>ClCCl>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([C:18]2[C:17]([C:13]([CH3:16])([CH3:15])[CH3:14])=[C:25]([OH:26])[C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:23][C:19]=2[C:20]([NH2:37])=[O:21])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Solvent: ClCCl
Product: COc1ccc(-c2c(C(N)=O)cc(C(C)(C)C)c(O)c2C(C)(C)C)c([N+](=O)[O-])c1
Yield: 39 %

Procedure:
4-methoxy-2-nitroaniline (1.68 g), 3,5-di-t-butyl-4-hydroxybenzoic acid (2.50 g) and dicyclohexylcarbodiimide (2.06 g) were stirred in dichloromethane (12 ml) at room temperature for 6 days. After filtering off the insolubles and distilling off the solvent, the residue was purified by a silica gel column chromatography (hexane:ethyl acetate=20:1) and crystallized from hexane-ethyl acetate to give N-(4-methoxy-2-nitrophenyl-3,5-di-t-butyl-4-hydroxybenzamide (1.56 g, 39%).
Reaction SMILES: CS(C)=O.[CH3:5][C:6]1[CH:7]=[C:8]([OH:20])[C:9]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=2)=[N:10][C:11]=1[CH3:12].Cl[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O>[CH3:5][C:6]1[CH:7]=[C:8]([O:20][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:9]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=2)=[N:10][C:11]=1[CH3:12]
Reactant: Clc1ccnc2ccccc12
Reactant: Cc1ccc(-c2nc(C)c(C)cc2O)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc(-c2nc(C)c(C)cc2Oc2ccnc3ccccc23)nc1
Temperature: 140 °C
Reaction time: 5 h
Yield: 71.5 %

Procedure:
Dimethyl sulfoxide (2 ml) was added to 5,6,5′-trimethyl-[2,2′]bipyridin-3-ol (50 mg), 4-chloroquinoline (115 mg), and cesium carbonate (228 mg), and the mixture was stirred at 140° C. for 5 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (57 mg, yield 72%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]([C:28]([CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:29])[CH2:15][CH:16]=[CH:17][C:18]3[C:23]([OH:24])=[CH:22][CH:21]=[C:20]([C:25](=[NH:27])[NH2:26])[CH:19]=3)=[CH:10][C:9]=2[C:35]([F:38])([F:37])[F:36])[CH2:3][CH2:2]1.[C:39](=[NH:44])(OCC)[CH3:40].C(N(CC)CC)C.FC(F)(F)C(O)=O>C(O)C>[NH:44]=[C:39]([N:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]([C:28]([CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:29])[CH2:15][CH:16]=[CH:17][C:18]3[C:23]([OH:24])=[CH:22][CH:21]=[C:20]([C:25](=[NH:26])[NH2:27])[CH:19]=3)=[CH:10][C:9]=2[C:35]([F:36])([F:37])[F:38])[CH2:3][CH2:2]1)[CH3:40]
Reactant: CCOC(C)=N
Reactant: N=C(N)c1ccc(O)c(C=CCN(C(=O)CCC(=O)O)c2ccc(OC3CCNCC3)c(C(F)(F)F)c2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(=N)N1CCC(Oc2ccc(N(CC=Cc3cc(C(=N)N)ccc3O)C(=O)CCC(=O)O)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 4-(piperidin-4-yl)oxy-3-trifluoromethyl-N-(2-(carboxy)ethylcarbonyl)-N-(3-(6-(hydroxy)-3-amidinophenyl)prop-2-en-1-yl)benzenamine (2.5 g) and ethyl acetimidate (2 g) in ethanol (100 mL) was added triethylamine and the solution was stirred at ambient temperature for 4 hours. The solution was acidified with trifluoroacetic acid, concentrated, separated on HPLC (CH3CN/H2O, gradient) and freeze-dried to afford 4-(N′-(1-iminoethyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(2-(carboxy)ethylcarbonyl)-N-(3-(6-(hydroxy)-3-amidinophenyl)prop-2-en-1-yl)benzenamine.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[C@H:15]([OH:24])[CH2:16][C@H:17]([OH:23])[CH2:18][C:19]([O:21]C)=[O:20])=[C:11]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH3:3].[OH-].[Na+:33].CC(OC)(C)C>C(O)C>[CH3:3][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[CH:15]([OH:24])[CH2:16][CH:17]([OH:23])[CH2:18][C:19]([O-:21])=[O:20])=[C:11]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2)[CH3:1].[Na+:33]
Reactant: COC(=O)C[C@@H](O)C[C@@H](O)/C=C/c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: CCO
Product: CC(C)n1c(/C=C/C(O)CC(O)CC(=O)[O-])c(-c2ccc(F)cc2)c2ccccc21
Temperature: 70 °C
Reaction time: 1.75 h
Yield: 71.2 %

Procedure:
Fluvastatin methyl ester (2.0 g) was added to a solution of NaOH (1 eq.) in ethanol (15 ml). The mixture was stirred at about 70° C. for 1.75 h, after which the starting material was no longer detectable by HPLC. Then, 40 ml of MTBE was dripped into the solution. The mixture was cooled slowly to room temperature and stirred overnight. The product could not be filtrated so another 100 ml of MTBE was added and the mixture was stirred over the weekend. The product was isolated by filtration under nitrogen and dried at 50° C. in a vacuum oven for 24 h to obtain 1.45 g (71.2%) of fluvastatin sodium Form XIV.
Reaction SMILES: [C:1]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([Cl:15])[CH:11]=[C:10]([Cl:16])[CH:9]=2)([O:3][CH2:4][CH3:5])=[O:2].CN(C)[CH:19]=[O:20].P(Cl)(Cl)(Cl)=O>ClC(Cl)C>[CH:19]([C:14]1[C:13]2[C:8](=[CH:9][C:10]([Cl:16])=[CH:11][C:12]=2[Cl:15])[NH:7][C:6]=1[C:1]([O:3][CH2:4][CH3:5])=[O:2])=[O:20]
Reactant: CCOC(=O)c1cc2c(Cl)cc(Cl)cc2[nH]1
Reactant: CN(C)C=O
Solvent: CC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1C=O
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
Combine 2-carboethoxy-4,6-dichloroindole (20.0 g, 0.077 mol), and dimethylformamide (9.0 mL, 0.117 mol) in dichloroethane (100 mL). Add phosphoryl chloride (18.0 g, 0.117 mmol). Heat to reflux. After 3.5 hours, cool the reaction mixture to ambient temperature to obtain a solid. Collect the solid by filtration, rinse with dichloromethane. Combine the solid with aqueous 1 M sodium acetate solution and stir. After 1 hour, filter, rinse with water, and dry to give the title compound.
Reaction SMILES: [Cl:1][SiH2:2][Cl:3].[CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]=1>[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[CH:4]1([SiH:2]([Cl:3])[Cl:1])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: Cl[SiH2]Cl
Reactant: C1=CCCCC1
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Product: Cl[SiH](Cl)C1CCCCC1
Temperature: 100 °C

Procedure:
Dichlorosilane in an amount of 83.5 g (0.827 mol), 82.3 g of cyclohexene (1.00 mol), 0.05 mol % of chloroplatinic acid (relative to dichlorosilane) were charged in a 500 ml pressure-proof stainless steel reactor and after sealing, reaction was carried out by heating in an oil bath at 100° C. for 30 hours. After reaction, the seal of the reactor was broken and the reacted liquid was discharged and subjected to vacuum distillation to obtain 139.3 g (0.761 mol) of cyclohexyldichlorosilane having a boiling point of 110°~112° C./155 mmHg.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-])=O)=[CH:8][CH:9]=2)[NH:4][N:3]=1.C([O-])=O.[NH4+]>C(O)C.O.CCOC(C)=O.[Fe]>[NH2:11][C:7]1[CH:6]=[C:5]2[C:10]([C:2]([CH3:1])=[N:3][NH:4]2)=[CH:9][CH:8]=1
Reactant: Cc1n[nH]c2cc([N+](=O)[O-])ccc12
Agent: [Fe]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1n[nH]c2cc(N)ccc12
Temperature: 90 °C
Yield: 81.9 %

Procedure:
To a solution of 3-methyl-6-nitroindazole (0.4 g, 2.24 mmol) in ethanol (EtOH) (10 mL) and H2O (5 mL) was added Iron (0.63 g, 11.22 mmol) and ammonium formate (1.4 g, 22.4 mmol). After heating at 90° C. for 2 h, the mixture was diluted with EtOAc, excess iron was removed by filtration, and the filtrate was washed sequentially with water, sat. NaHCO3, and brine, before it was dried and concentrated to give 6-amino-3-methylindazole (0.27 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16](=[O:17])[CH:15]2[CH:10]([CH:11]3[CH2:18][CH:14]2[CH:13]=[CH:12]3)[CH:9]1[C:19](C)(C)[O:20][SiH2]C(C)(C)C)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C:16](=[O:17])[CH:15]2[CH:10]([CH:11]3[CH2:18][CH:14]2[CH:13]=[CH:12]3)[CH:9]1[CH2:19][OH:20])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C(=O)C2C3C=CC(C3)C2C1C(C)(C)O[SiH2]C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C(=O)C2C3C=CC(C3)C2C1CO
Reaction time: 16 h
Yield: 80 %

Procedure:
A solution of 28 (3.2 g; 8.1 mmol) in 60 mL of THF and acetic acid (1.16 mL; 20.3 mmol) was treated with TBAF 1M in THF. The reaction mixture was stirred for 16 h then was diluted with CH2Cl2 (120 mL) and washed with water (75 mL). The organic layer was dried with sodium sulfate and concentrated in vacuo to a yellow oil. Flash chromatography (60% EtOAc/40% hexanes) afforded 1.81 g (81%) of the desired product 29. 1H NMR (CDCl3) δ 6.2 (bs, 1H), 6.1 (bs, 1H), 3.8 (d, 1H), 3.6 (m, 2H), 3.3 (s, 1H), 3.15 (dd, 1H), 3.1 (s, 1H), 2.5 (dd, 1H), 1.5 (app.t, 3H), 1.35 (s, 9H) ppm.
Reaction SMILES: CO[C:3]1[C:7]2[CH:8]=[CH:9][C:10](OC)=[CH:11][C:6]=2[O:5][C:4]=1[C:14]([OH:16])=O.O.N[C:19]1[NH:23][N:22]=[N:21][N:20]=1.Cl.C[N:26](C)C=O>>[NH:20]1[C:19]([C:3]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[O:5][C:4]=2[C:14]([NH2:26])=[O:16])=[N:23][N:22]=[N:21]1
Reactant: Nc1nnn[nH]1
Reactant: CN(C)C=O
Reactant: COc1ccc2c(OC)c(C(=O)O)oc2c1
Agent: Cl
Solvent: O
Product: NC(=O)c1oc2ccccc2c1-c1nnn[nH]1
Temperature: 25 °C
Yield: 43 %

Procedure:
A mixture of 5.0 g (0.023 mole) of 3,6-dimethoxy-2-benzofurancarboxylic acid and 8.0 g (0.049 mole) of 1,1-carbonylbis(1H-imidazole) in 60 ml of N,N-dimethylformamide is stirred and warmed on the steam bath for 20 minutes. The mixture is cooled to room temperature, 2.5 g (0.024 mole) of 5-aminotetrazole monohydrate is added, and the new mixture is again heated for 20 minutes. The reaction mixture is cooled, added to 350 g of ice/water and acidified with 4.0 N hydrochloric acid to precipitate the tetrazole product. The precipitate is filtered, washed with 50% aqueous ethanol, and recrystallized from aqueous N,N-dimethylformamide to yield 2.8 g (43% yield) of the analytically pure 3,6-dimethoxy-N- 1Htetrazol-5-yl-2-benzofurancarboxamide, mp 238° C.-dec.
Reaction SMILES: CS[C:3]1[C:4]2[CH:12]=[N:11][CH:10]=[CH:9][C:5]=2[N:6]=[CH:7][N:8]=1.[Br:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17]>>[Br:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH:17][C:3]1[C:4]2[CH:12]=[N:11][CH:10]=[CH:9][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: CSc1ncnc2ccncc12
Reactant: Nc1cccc(Br)c1
Product: Brc1cccc(Nc2ncnc3ccncc23)c1
Temperature: 10 °C
Yield: 10 %

Procedure:
A mixture of 4-methylthiopyrido[4,3-d]pyrimidine (171 mg, 0.96 mmol), (see previous experimental) and 3-bromoaniline (1 mL) is heated to 10° C. for 2 h. A solid precipitates on cooling and is collected by vacuum filtration and then recrystallized from EtOH to yield 4-(3-bromoanilino)pyrido[4,3-d]pyrimidine (30 mg, 10%). 1H NMR (DMSO) δ 10.33 (1H, s), 9.86 (1H, s), 8.84 (1H, d, J=5.8 Hz), 8.79 (1H, s), 8.22 (1H, s), 7.89 (1H, d, J=7.2 Hz), 7.69 (1H, d, J=5.8 Hz), 7.40 (2H, dt, Jd=8.0 Hz, Jt=1.5 Hz).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:5]2[N:10]([CH2:11][O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[Br:28]N1C(=O)CCC1=O>C(Cl)Cl>[NH2:1][C:2]1[N:3]=[C:4]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:5]2[N:10]([CH2:11][O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:9]=[C:8]([Br:28])[C:6]=2[N:7]=1
Reactant: Nc1nc(OCc2ccccc2)c2c(ccn2COCc2ccccc2)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: Nc1nc(OCc2ccccc2)c2c(n1)c(Br)cn2COCc1ccccc1
Yield: 94.3 %

Procedure:
A solution of 2-amino-4-benzyloxy-5-N-benzyloxymethylpyrrolo[3,2-d]pyrimidine (1.0 g) in methylene chloride (30 mL) was stirred in an ice bath while N-bromosuccinimide (0.5 g) was added portion-wise. The solution was concentrated and chromatography afforded 2-amino-4-benzyloxy-5-N-benzyloxymethyl-7-bromopyrrolo[3,2-d]pyrimidine (1.15 g) as a white solid. 13C NMR (CDCl3), δ 158.8, 157.2, 150.9, 137.3, 136.6, 131.8, 129.0, 128.8, 128.6, 128.5, 128.3, 127.9, 111.3, 90.3, 77.8, 70.7, 68.4.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14](=[O:31])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[CH:17][CH:16]=2)[CH2:6][CH2:5][CH2:4]1.[CH3:32][S:33](Cl)(=[O:35])=[O:34].N1C=CC=CC=1>ClCCl.C(#N)C>[CH3:32][S:33]([O:1][CH2:2][CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14](=[O:31])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[CH:17][CH:16]=2)[CH2:6][CH2:5][CH2:4]1)(=[O:35])=[O:34]
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(CO)c3ccccc32)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CC#N
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(COS(C)(=O)=O)c3ccccc32)cc1
Reaction time: 2 h

Procedure:
5-Hydroxymethyl-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.70 g) is dissolved in a mixture (30 ml) of dichloromethane/acetonitrile (1:1) and thereto are added methanesulfonyl chloride (0.8 ml) and pyridine (1.0 ml), and the mixture is refluxed with stirring for 2 hours. After cooling, the reaction solution is evaporated under reduced pressure and to the resulting residue is added water and then extracted with ethyl acetate. The extract is washed successively with diluted hydrochloric acid and saturated saline solution, and dried over magnesium sulfate. The solvent is distilled off and the resulting residue is recrystallized from ethyl acetate/n-hexane to give 5-methanesulfonyloxymethyl-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.72 g) as white powder, m.p. 189°-190° C.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][N:15]=1.[F:21][C:22]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:23]=1[CH:24]=[O:25].[Cl-].[NH4+]>C(OCC)(=O)C.O1CCCC1>[Cl:13][C:14]1[CH:19]=[C:18]([CH:24]([C:23]2[CH:26]=[C:27]([F:30])[CH:28]=[CH:29][C:22]=2[F:21])[OH:25])[C:17]([Cl:20])=[CH:16][N:15]=1
Reactant: Clc1ccc(Cl)nc1
Reactant: O=Cc1cc(F)ccc1F
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: OC(c1cc(F)ccc1F)c1cc(Cl)ncc1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 66.5 %

Procedure:
To a tetrahydrofuran solution (14 ml) of diisopropylamine (1.4 ml, 10 mmol) was added n-butyl lithium (6.3 ml, 1.59M hexane solution) at −78° C. After stirring for 10 minutes, 2,5-dichloropyridine (1.48 g, 10 mmol) was added. Thirty minutes later, 2,5-difluorobenzaldehyde (1.09 ml, 10 mmol) was added to the mixture. The resulting mixture was warmed gradually to 0° C. and stirring was conducted for further 10 minutes. An aqueous solution of ammonium chloride was added and the mixture was diluted with ethyl acetate (80 ml). The organic layer was separated, washed with brine and dried. After filtration, the filtrate was concentrated under reduced pressure. The precipitate thus obtained was triturated with ethanol to yield the title compound (1.93 g, 67%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH:38]([NH:41][CH3:42])([CH3:40])[CH3:39]>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([N:41]([CH:38]([CH3:40])[CH3:39])[CH3:42])[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Reactant: CNC(C)C
Product: CC(C)N(C)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and N-isopropylmethylamine according to conditions described in general procedure C. Mp: 94-96° C.; 1H NMR (400 MHz, CDCl3) δ 1.06-1.14(m, 6 H), 2.84(s, 3 H), 3.25(t, J=4.0 Hz, 4 H), 3.87(t, J=4.8 Hz, 4H), 5.95(d, J=5.2 Hz, 1 H), 6.78(d, J=11.2 Hz, 1 H), 7.07(d, J=8.0 Hz, 1H), 7.31(d, J=8.0 Hz, 1 H), 7.49-7.59(m, 3 H), 7.89(d, J=8.8 Hz, 1 H), 7.96(d, J=7.6 Hz, 1H), 8.01(d, J=8.0 Hz, 1 H), 8.14-8.17(m, 2 H).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=3)[S:8][C:4]=2[CH:3]=1.O.O.Cl[Sn]Cl>C(O)C>[F:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]=[C:7]([C:9]3[CH:10]=[CH:11][C:12]([NH2:15])=[CH:13][CH:14]=3)[S:8][C:4]=2[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(-c2nc3ccc(F)cc3s2)cc1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Nc1ccc(-c2nc3ccc(F)cc3s2)cc1
Temperature: 80 °C
Yield: 27.5 %

Procedure:
To a stirred solution of 4-fluoro aniline (16a, 4g, 32.7 mmol) in pyridine as solvent and base to this 4-nitrobenzoyl chloride (17, 6.69 g, 36.0 mmol) is added slowly and reflux for 2h, after completion of the reaction, reaction mixture is poured in water, filter and washed with dil HCl to afford compound N-(4-fluorophenyl)-4-nitrobenzamide (18a). To a stirred solution of amide (18a, 8g, 30.7 mmol) taken in toluene lawessons reagent (2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide) (10.18 g, 25.2 mmol) is added and refluxed at 110° C. for 7h. After completion of the reaction toluene is evaporated under vacuum and water is added and extracted into chloroform finally purification by column chromatography to afford pure compound N-(4-fluorophenyl)-4-nitrobenzothioamide (19a). Treating the thioamide product (19a, 4g, 14.49 mmol) with potassium ferricyanide (4 eq) in aqueous sodium hydroxide (8 eq) solution at 90° C. for 3h cyclization takes place to obtain the 6-fluoro-2-(4-nitrophenyl)benzo[d]thiazole (20a) solid is precipitated from the reaction mixture filtered and washed with water to get 20a. Reduction of the nitro compound (20a, 1 g, 3.64 mmol) is proceeded with SnCl2.2H2O in ethanol and reflux at 80° C. for 2h. After completion of reaction ethanol is evaporated under vacuum and to this saturated sodium bicarbonate solution is added to quench the excess stannous chloride and filtered in celite bed and purified in silica column (60-120) to afforded pure compound (21a) The compound 4-(6-fluorobenzo[d]thiazol-2-yl)benzenamine (21a, 244 mg, 1 mmol) on reaction with 4-fluoro 3-methoxy benzaldehyde (22c, 152 mg, 1 mmol) in ethanol using catalytic amount of acetic acid and refluxed for 2h after completion reaction mixture is cooled to 0° C. solid is precipitated from the reaction mixture it is filtered and washed with ethanol to gave the enamine product, and immediately proceeded for the next reaction with using (p-tolylsulfonyl) methyl isocyanide (tosmic) (1.5 eq), and potassium carbonate (2 eq) as base, in 10 mL of methanol and 5 mL of DME was heated under reflux for 12 h after completion of reaction as monitored by TLC. It was cooled to room temperature (27° C.); the solution was concentrated in vacuo and partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc and Hexane to gave compound 4c as a light yellow solid (68%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([CH3:13])[C:11]=1[OH:12].S(OC)(O[CH3:21])(=O)=O>[OH-].[Na+]>[CH3:21][O:12][C:11]1[C:10]([CH3:13])=[CH:9][CH:8]=[CH:7][C:6]=1[O:5][C:4]1[CH:14]=[CH:15][CH:16]=[C:2]([Cl:1])[CH:3]=1
Reactant: Cc1cccc(Oc2cccc(Cl)c2)c1O
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Product: COc1c(C)cccc1Oc1cccc(Cl)c1

Procedure:
An aqueous solution (40 ml) of sodium hydroxide (10 g) and a mixture of 6-(3-chlorophenoxy)-o-cresol (13.9 g) and dimethyl sulfate (11 ml) were treated in a similar manner to that of Example 6-(2) to give oily 3-chlorophenyl 2-methoxy-3-methylphenyl ether (14.6 g).