Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CN(C=O)C.CN(C)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>O>[CH3:27][S:28]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]3)[CH2:2][CH2:3]1)(=[O:30])=[O:29]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1CCc2cc(N3CCNCC3)ccc2N1
Agent: CN(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)N1CCN(c2ccc3c(c2)CCC(=O)N3)CC1
Temperature: 25 °C
Yield: 14.3 %

Procedure:
6-(1-Piperazinyl)-3,4-dihydrocarbostyril (1.0 g) was added to a mixture of 10 ml of DMF and 0.85 ml of trimethylamine and the mixture was stirred at room temperature while slowly adding dropwise 5 ml of DMF solution containing 440 mg of methanesulfonyl chloride. After completion of addition, the reaction mixture was stirred at the same temperature as above for 30 minutes. The reaction mixture was poured into a large amount of water and extracted with chloroform. The extract was washed with water and dried over anhydrous sodium sulfate. Chloroform was distilled off and residual crystals were recrystallized from methanol to give 0.17 g of 6-(4-methanesulfonyl-1-piperazinyl)-3,4-dihydrocarbostyril, m.p. 241.5°-243° C., colorless granules.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:23])[C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[N:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[CH3:24][O:25][C:26]([C@H:28]1[CH2:33][CH2:32][C@H:31]([C:34](O)=[O:35])[CH2:30][CH2:29]1)=[O:27].COC(C1CCC(C(N2CCN(C3C=CC(C(=O)NC4C=CC=C(C(C)(C)C)C=4)=CN=3)CC2)=O)CC1)=O>>[CH3:24][O:25][C:26]([CH:28]1[CH2:33][CH2:32][CH:31]([C:34]([N:20]2[CH2:19][CH2:18][N:17]([C:14]3[CH:15]=[CH:16][C:11]([C:10](=[O:23])[NH:9][C:4]4[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([I:1])[CH:3]=4)=[CH:12][N:13]=3)[CH2:22][CH2:21]2)=[O:35])[CH2:30][CH2:29]1)=[O:27]
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)O)CC1
Reactant: Cc1ccc(NC(=O)c2ccc(N3CCNCC3)nc2)cc1I
Agent: COC(=O)C1CCC(C(=O)N2CCN(c3ccc(C(=O)Nc4cccc(C(C)(C)C)c4)cn3)CC2)CC1
Product: COC(=O)C1CCC(C(=O)N2CCN(c3ccc(C(=O)Nc4ccc(C)c(I)c4)cn3)CC2)CC1

Procedure:
4-{4-[5-(3-Iodo-4-methyl-phenylcarbamoyl)-pyridin-2-yl]-piperazine-1-carbonyl}-cyclohexanecarboxylic acid methyl ester was prepared from N-(3-iodo-4-methyl-phenyl)-6-piperazin-1-yl-nicotinamide and trans-1,4-cyclohexane dicarboxylic acid monomethyl ester in a manner similar to the one described in the synthesis of 4-{4-[5-(3-tert-butyl-phenylcarbamoyl)-pyridin-2-yl]-piperazine-1-carbonyl}-cyclohexane-carboxylic acid methyl ester above. The product was obtained after a silica gel column purification with a 50-100% EtOAc in hexanes gradient. HRMS m/z calcd for C26H31N4O4I [M+H]+: 591.1463. Found: 591.1461.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:11])[CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:12].[C:13]([O-])([O-])=O.[K+].[K+].IC>CC(C)=O>[CH3:13][O:12][C:2]1[CH:1]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([OH:11])=[CH:9]2)=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc2ccc(O)cc2c1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccc2ccc(O)cc2c1
Temperature: 0 °C
Yield: 36.8 %

Procedure:
To a mixture of naphthalene-2,7-diol (25 g, 156.08 mmol) and K2CO3 (32.3 g, 232.02 mmol) in acetone (300 ml) was added iodomethane (22.2 g, 156.41 mmol) dropwise with stirring at 0° C. The resulting solution was stirred overnight at room temperature. The solids were filtered off and the filtrate was concentrated under vacuum to give a residue, which was purified by silica gel column chromatography using 1%-10% ethyl acetate in petroleum ether to afford 7-methoxynaphthalen-2-ol as a light yellow solid (10 g, 37%). (ES, m/z): [M+H]+ 175.1; 1H NMR (400 MHz, DMSO-d6): δ 9.65 (s, 1H), 7.65 (d, J=8.8 Hz, 2H), 6.79 (dd, J=13.6, 1.6 Hz, 2H), 6.92-6.89 (m, 2H), 3.84 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:14]([F:17])([F:16])[F:15])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.F[C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([C:27]([F:30])([F:29])[F:28])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2([C:14]([F:17])([F:16])[F:15])[CH2:13][CH2:12][N:11]([C:19]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([C:27]([F:28])([F:30])[F:29])[CH:20]=3)[CH2:10]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Reactant: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccc(N2CCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C(F)(F)F
Temperature: 110 °C
Reaction time: 4 h
Yield: 42.5 %

Procedure:
3-(3,5-Dichlorophenyl)-3-(trifluoromethyl)pyrrolidine (5.6 g), 4-fluoro-2-trifluoromethylbenzonitrile (4.5 g) and potassium carbonate (5.4 g) were added to N,N-dimethylformamide (50 mL), and the mixture was stirred at 110° C. for 4 hours. After cooling the mixture to room temperature, the solution was diluted with ethyl acetate and washed with water three times. The organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated off under reduced pressure, and the residue was then purified by a column chromatography to obtain the title compound (3.8 g).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:20])[NH:9][CH:10]([C:12]1[CH:13]=[N:14][C:15]([F:19])=[CH:16][C:17]=1[I:18])[CH3:11])([CH3:6])([CH3:5])[CH3:4].I[CH2:22][CH3:23]>CN(C)C=O>[C:3]([O:7][C:8](=[O:20])[N:9]([CH2:22][CH3:23])[CH:10]([C:12]1[CH:13]=[N:14][C:15]([F:19])=[CH:16][C:17]=1[I:18])[CH3:11])([CH3:4])([CH3:5])[CH3:6]
Reactant: CC(NC(=O)OC(C)(C)C)c1cnc(F)cc1I
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(C(=O)OC(C)(C)C)C(C)c1cnc(F)cc1I
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101.5 %

Procedure:
Add sodium hydride (84.0 mg, 2.1 mmol, 60% dispersion in mineral oil) to a solution of [1-(6-fluoro-4-iodo-pyridin-3-yl)-ethyl]-carbamic acid tert-butyl ester (0.37 g, 1.0 mmol) in dimethylformamide (10 mL). Stir at room temperature for 30 min. Add iodoethane (0.2 mL, 2.1 mmol). Stir for 1 hour. Quench the reaction with water. Extract with CH2Cl2. Wash the organic layer with water and saturated aqueous sodium chloride. Dry over MgSO4. After filtration, afford crude product ethyl-[1-(6-fluoro-4-iodo-pyridin-3-yl)-ethyl]-carbamic acid tert-butyl ester (0.4 g, 97%) with 90% HPLC purity, MS (ES) m/z 395 [M+1]+.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:14]2[N:15]=[C:16](Cl)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:26][CH2:27][CH2:28][NH2:29]>>[CH2:1]([NH:8][C:9]1[C:14]2[N:15]=[C:16]([NH:29][CH2:28][CH2:27][OH:26])[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1nc(N2CCOCC2)c2ncnc(NCc3ccccc3)c2n1
Reactant: NCCO
Product: OCCNc1nc(N2CCOCC2)c2ncnc(NCc3ccccc3)c2n1

Procedure:
This compound was prepared analogous to Example 2 from 8-benzylamino-2-chloro-4-morpholino-pyrimido[5,4-d]pyrimidine (melting point: 139°-141° C.) and 2-hydroxyethylamine.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH:14]([F:16])[F:15])([CH3:13])[CH2:11][OH:12])=[CH:6][CH:5]=1.[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][C:19]=1[O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CCCCCC.C(OCC)(=O)C>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]([CH:14]([F:15])[F:16])([CH3:13])[CH2:11][O:12][CH2:22][C:21]2[CH:24]=[CH:25][C:18]([F:17])=[C:19]([O:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:20]=2)=[CH:8][CH:9]=1
Reactant: Fc1ccc(CBr)cc1Oc1ccccc1
Reactant: CC(CO)(c1ccc(Cl)cc1)C(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(COCc1ccc(F)c(Oc2ccccc2)c1)(c1ccc(Cl)cc1)C(F)F

Procedure:
0.44 g (10 mmol) Sodium hydride dispersion (55%) was freed from oil by washing three times with dry toluene. It was suspended in 10 ml dry dimethoxyethane and then, with stirring, 1.77 g (8.0 mmol) 2-(4-chlorophenyl)-2-difluoromethylpropanol and 2.24 g (8.0 mmol) 4-fluoro-3-phenoxybenzyl bromide added. After stirring for five hours at room temperature a thin layer chromatogram (Merck DC silica gel 60F254 plate, using hexane/ethyl acetate 1:1 as eluant, Rf : 0.57) showed that no starting material was present.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:20]([CH3:21])[C:19](=[O:22])[N:18]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:17](=[O:31])[C:16]=2[CH3:32])=[C:11]([CH3:33])[CH:10]=1)C1C=CC=CC=1.[H][H]>CO.[OH-].[Pd+2].[OH-]>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:20]([CH3:21])[C:19](=[O:22])[N:18]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:17](=[O:31])[C:16]=2[CH3:32])=[C:11]([CH3:33])[CH:10]=1
Reactant: Cc1cc(OCc2ccccc2)ccc1-c1c(C)c(=O)n(COCC[Si](C)(C)C)c(=O)n1C
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(O)ccc1-c1c(C)c(=O)n(COCC[Si](C)(C)C)c(=O)n1C

Procedure:
A mixture of C4 (10 g, 21 mmol) and palladium hydroxide (2 g, dry) in methanol (300 mL) was stirred at room temperature for 24 hours under 40 psi of hydrogen. After filtration of the reaction mixture, the filtrate was concentrated to provide the product as a light yellow solid. Yield: 8.0 g, 21 mmol, 100%. 1H NMR (400 MHz, CDCl3) δ 6.92 (d, half of AB quartet, J=8.2 Hz, 1H), 6.81-6.87 (m, 2H), 5.52 (AB quartet, JAB=9.5 Hz, ΔνAB=2.7 Hz, 2H), 3.73-3.80 (m, 2H), 3.03 (s, 3H), 2.11 (s, 3H), 1.65 (s, 3H), 0.99-1.05 (m, 2H), 0.01 (s, 9H).
Reaction SMILES: [F:1][CH2:2][C@:3]1([C:18]([O:20]C(C)(C)C)=[O:19])[CH:7]([CH3:8])[C:6](=[O:9])[N:5]([C@@H:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:11])[CH2:4]1>ClCCl.FC(F)(F)C(O)=O>[F:1][CH2:2][C@:3]1([C:18]([OH:20])=[O:19])[CH:7]([CH3:8])[C:6](=[O:9])[N:5]([C@@H:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:11])[CH2:4]1
Reactant: CC1C(=O)N([C@H](C)c2ccccc2)C[C@@]1(CF)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1C(=O)N([C@H](C)c2ccccc2)C[C@@]1(CF)C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl (3R)-3-fluoromethyl-4-methyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylate (910 mg, 2.71 mmol) in dichloromethane (9 mL), trifluoroacetic acid (9 mL) was added dropwise in an ice bath, and the mixture was stirred at room temperature for 3 hours. After concentrating the reaction mixture under reduced pressure, saturated aqueous solution of sodium hydrogencarbonate (20 mL) was added to the concentrate in an ice bath, and the aqueous solution was washed with diethylether (50 mL). To the aqueous layer was added 1 mol/l hydrochloric acid to pH 2 to 3 in an ice bath, and the solution was extracted with chloroform (100 mL×2). The organic layer was washed with saturated aqueous solution of sodium chloride (100 mL), and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The concentrate was azeotropically distilled by adding toluene (20 mL), and dried under reduced pressure to obtain 910 mg (quantitative) of the title compound as a white solid.
Reaction SMILES: O[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([O:11][CH3:12])[CH:4]=1.[Cl:13][C:14]1[CH:15]=[CH:16][C:17](=[O:51])[N:18]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]3[N:28]=[CH:29][N:30](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:31]=3)=[CH:22][N:21]=2)[CH:19]=1.CCN(C(C)C)C(C)C.O(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O>C(Cl)Cl>[Cl:13][C:14]1[CH:15]=[CH:16][C:17](=[O:51])[N:18]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]3[N:28]([CH2:2][C:3]4[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([O:11][CH3:12])[CH:4]=4)[CH:29]=[N:30][CH:31]=3)=[CH:22][N:21]=2)[CH:19]=1
Reactant: O=c1ccc(Cl)cn1-c1ccc(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cn1
Reactant: COc1cc(CO)ccc1C#N
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(Cn2cncc2Cc2ccc(-n3cc(Cl)ccc3=O)nc2)ccc1C#N
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a cooled solution (-78° C.) of 4-hydroxymethyl-2-methoxy-benzonitrile from step 2 (100 mg, 0.61 mmol) and 5-chloro-5'-(1-trityl-1H-imidazol-4-ylmethyl)-[1,2']bipyridinyl-2-one from Example 23, Step 5 (325 mg, 0.613 mmol) in CH2Cl2 (3 ml) was added DIEA (235 μl, 1.35 mmol) followed immediately by the addition of Tf2O (103 μl, 0.92 mmol). The reaction mixture was stirred at -78° C. for 1 hour and was then transferred to an ice bath and stirred at 0° C. for another hour. The solvent was removed in vacuo. The residue was then dissolved in MeOH (3 ml) and heated to 60° C. for 8 hours. The MeOH was then removed in vacuo and the residue treated with saturated NaHCO3 (5 mL) and extracted with CH2Cl2 (2×10 mL). The organic layer was washed with brine, dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography [4% MeOH(5% NH4OH)/CH2Cl2) to yield the final product.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([OH:14])=O)=[CH:9][CH:10]=2)[NH:5][N:4]=1)=[O:2].[NH2:15]C1C=CC(O)=CC=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C)C=O>[CH:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([NH2:15])=[O:14])=[CH:9][CH:10]=2)[NH:5][N:4]=1)=[O:2]
Reactant: O=Cc1n[nH]c2cc(C(=O)O)ccc12
Reactant: Nc1ccc(O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC(=O)c1ccc2c(C=O)n[nH]c2c1
Reaction time: 2 h

Procedure:
To a solution of 3-formyl-1H-indazole-6-carboxylic acid (1.6 g, 8.4 mmol) and 4-aminophenol (1.8 g, 16.8 mmol) in dry dimethylformamide (35 mL) was added HATU (3.8 g, 16.8 mmol) followed by triethylamine (1.4 mL, 10.1 mmol). The reaction was stirred at room and monitored by TLC and LC/MS. After two hours the reaction was complete. The solvent was removed by vacuum and the product was purified by flash column chromatography using ethyl acetate: petroleum ether 1:1 to pure ethyl acetate. N-4-Hydroxyphenyl)-3-formyl-1H-indazole-6-carboxamide was isolated as a tan colored solid. 1H NMR (DMSO-d4) δ 6.79 (2H, d, 8.9 Hz), 7.59 (2H, d, 8.9 Hz), 7.94 (1H, d, 9.8 Hz), 8.24 (1H, d, 8.2 Hz), 8.31 (1H, s), 9.31 (1H, br s), 10.27 (2H, s). MS (APCI pos) 282.1.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:18])=[CH:4][C:5]2[CH:9]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[S:7][C:6]=2[C:16]=1[Cl:17].Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].C(=O)(O)[O-].[Na+].CN(C)C=O>CC(=O)CC>[CH2:24]([O:23][C:21](=[O:22])[CH2:20][O:18][C:3]1[C:2]([Cl:1])=[C:16]([Cl:17])[C:6]2[S:7][C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:9][C:5]=2[CH:4]=1)[CH3:25]
Reactant: CCOC(=O)CBr
Reactant: Oc1cc2cc(-c3ccccc3)sc2c(Cl)c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc2cc(-c3ccccc3)sc2c(Cl)c1Cl
Yield: 71.3 %

Procedure:
A mixture of 5.1 g of 6,7-dichloro-5-hydroxy-2-phenylbenzo[b]thiophene. 3.5 g of ethyl bromoacetate and 5 g of sodium bicarbonate in 100 ml of 2-butanone containing 10 ml of dimethylformamide is stirred at 85°-90° for 16 hours. The mixture is concentrated at reduced pressure to remove the sovents and the residue is triturated with 50 g of ice-water. After 30 minutes the solid is filtered and air dried. Recrystallization from ether-hexane gives 4.7 g of ethyl[(6,7-dichloro-2-phenylbenzo[b]thien-5-yl)oxy]acetate as fine needles, mp 116.5°-117°.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][C@@H:5]([C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10])[CH2:4]1.[O:15]1[CH:20]=[CH:19][CH2:18][CH2:17][CH2:16]1.O.C1(C)C(S(O)(=O)=O)=CC=CC=1.C(=O)(O)[O-].[Na+]>ClCCl>[O:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]1[O:1][CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][C@@H:5]([C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10])[CH2:4]1
Reactant: C1=COCCC1
Reactant: CC(C)OC(=O)[C@@H]1CCC[C@H](CO)C1
Agent: Cc1ccccc1S(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)OC(=O)[C@@H]1CCC[C@H](COC2CCCCO2)C1
Reaction time: 8 h

Procedure:
100 g of isopropyl (1R,3S)-3-hydroxymethylcyclohexanecarboxylate and 46.2 g of dihydropyran are dissolved in 500 ml of dichloromethane and, at 0° C., 4.75 g of toluenesulfonic acid monohydrate are added. The solution is stirred overnight and then sat. sodium bicarbonate solution is added. The organic phase is separated off, diluted with MTBE and washed with sat. sodium chloride solution, dried over MgSO4 and concentrated, resulting in 140 g of isopropyl (1R,3S)-3-(tetrahydropyran-2-yloxymethyl)cyclohexanecarboxylate as brown oil.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:17][CH:16]2[CH2:18][CH2:19][CH:6]1[C:7]1[NH:8][C:9]3[C:14]([C:15]=12)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[O:4].C(=O)([O-])[O-].[K+].[K+].CO>O>[CH:6]12[CH2:19][CH2:18][CH:16]([C:15]3[C:14]4[C:9]([NH:8][C:7]=31)=[CH:10][CH:11]=[CH:12][CH:13]=4)[CH2:17][CH:5]2[C:3]([OH:4])=[O:2]
Reactant: COC(=O)C1CC2CCC1c1[nH]c3ccccc3c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C(O)C1CC2CCC1c1[nH]c3ccccc3c12
Temperature: 90 °C
Reaction time: 18 h
Yield: 99.5 %

Procedure:
A mixture of 1,2,3,4-tetrahydro-1,4-ethanocarbazole-2-carboxylic acid methyl ester (13.0 g, 0.05 mole, described in Example 1), potassium carbonate (7.0 g, 0.05 mole), methanol (160 ml) and water (40 ml) was refluxed for 4 hr (oil bath at 90° C.) and stirred at room temperature for 18 hr. The reaction mixture was poured into water (500 ml) and washed with diethyl ether (2×). The aqueous phase was acidified with hydrochloric acid IN (100 ml) and extracted with diethyl ether (3×). Organic layers were washed with a saturated sodium chloride solution, dried and evaporated to dryness to afford the title compound (12 g). Crystallization afforded a total of 7.5 g of title compound: mp 212°-214° C.; NMR (DMSO-d6) δ 1.7 (m, 6H), 2.8 (m, 1H), 3.5 (m, 2H), 6.7-7.5 (m, 4H), 10.9 (s, 1H) and 11.8 (br, 1H); and Anal. Calcd for C15H15O2N: C, 74.66% H, 6.27% N, 5.81% and Found: C, 74.67% H, 6.48% N, 5.80%.
Reaction SMILES: [CH:1]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])OCC.[CH3:11][N:12]1[C:25]2[CH:24]=[CH:23][CH:22]=[C:21](C=O)[C:20]=2[S:19][C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2.C(=O)([O-])O.[Na+].C(OCC)C>CO>[CH2:9]([O:8][CH:1]([O:5][CH2:6][CH3:7])[C:21]1[C:20]2[S:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([CH3:11])[C:25]=2[CH:24]=[CH:23][CH:22]=1)[CH3:10]
Reactant: CCOC(OCC)OCC
Reactant: CN1c2ccccc2Sc2c(C=O)cccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: CCOC(OCC)c1cccc2c1Sc1ccccc1N2C
Temperature: 0 °C
Yield: 96.2 %

Procedure:
15.0 ml of triethyl orthoformate were added at room temperature to a solution of 4.90 g (20.3 mmol) of 10-methyl-phenothiazine-4-carbaldehyde and 50 mg of p-toluenesulphonic aci×1H2O in 15 ml of methanol. The reaction mixture was boiled at reflux for 45 minutes, cooled and poured into 30 g of ice, 30 ml of saturated aqueous sodium hydrogen carbonate solution and 100 ml of diethyl ether. The organic phase was washed with 50 ml of saturated sodium chloride solution, dried over magnesium sulphate and concentrated. The residue was chromatographed on 300 g of silica gel with diethyl ether/hexane (1:4), whereupon, after crystallization from diethyl ether/hexane in a refrigerator, 6.16 g (96.2%) of 4-diethoxymethyl-10-methyl-phenothiazine were obtained as a white solid of m.p. 44.6°-46.2°.
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][CH:33]=[CH:32][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]3[S:20][C:19]([CH2:21][N:22]4[CH2:25][CH:24]([C:26]([O:28]C)=[O:27])[CH2:23]4)=[CH:18][C:17]=3[CH2:30][CH3:31])[N:12]=2)=[CH:7][CH:6]=1.O.[OH-].[Li+].C(O)(=O)C.C(O)(=O)C(O)=O>>[Cl:1][C:2]1[CH:35]=[CH:34][CH:33]=[CH:32][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]3[S:20][C:19]([CH2:21][N:22]4[CH2:23][CH:24]([C:26]([OH:28])=[O:27])[CH2:25]4)=[CH:18][C:17]=3[CH2:30][CH3:31])[N:12]=2)=[CH:9][CH:10]=1
Reactant: CCc1cc(CN2CC(C(=O)OC)C2)sc1-c1noc(-c2ccc(Oc3ccccc3Cl)cc2)n1
Agent: O=C(O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CCc1cc(CN2CC(C(=O)O)C2)sc1-c1noc(-c2ccc(Oc3ccccc3Cl)cc2)n1
Yield: 68.8 %

Procedure:
The title compound (140 mg) was synthesized in a yield of 67% as a white crystalline solid by conducting the reaction similar to that mentioned in Example 1 (1g) using methyl 1-[(5-{5-[4-(2-chlorophenoxy)phenyl]-1,2,4-oxadiazol-3-yl}-4-ethyl-2-thienyl)methyl]azetidine-3-carboxylate (0.21 g, 0.41 mmol) that was obtained in Example 19 (19c), lithium hydroxide monohydrate (38 mg, 0.90 mmol), acetic acid (49 μL, 0.90 mmol), and oxalic acid (18 mg, 0.20 mmol).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]([CH3:13])[C:9](=[O:12])[CH2:10][O:11][C:6]=2[CH:5]=[C:4]([F:14])[C:3]=1[N:15]1[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[N:17]([CH3:26])[C:16]1=[O:27].[CH:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][C:29]=1[C:38](Cl)=[O:39]>O1CCOCC1>[CH:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][C:29]=1[C:38]([NH:1][C:2]1[C:7]2[N:8]([CH3:13])[C:9](=[O:12])[CH2:10][O:11][C:6]=2[CH:5]=[C:4]([F:14])[C:3]=1[N:15]1[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[N:17]([CH3:26])[C:16]1=[O:27])=[O:39]
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: CN1C(=O)COc2cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(N)c21
Solvent: C1COCCO1
Product: CN1C(=O)COc2cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(NC(=O)c3ccc4ccccc4c3)c21
Yield: 43.8 %

Procedure:
3-[5-Amino-7-fluoro-4-methyl-2H-1,4-benzoxazine-3(4H)-on-6-yl]-1-methyl-6-trifluoromethyl-2,4-(1H, 3H)-pyrimidinedione (0.49 g) and 2-naphthoyl chloride (0.26 g) were mixed in dioxane (35 ml), the resulting mixture was refluxed for 7 hr. After evaporation, the residue was purified by silica gel column (hexane to 30% and 50% ethyl acetate) to yield the title compound (0.3 g).
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][C:8](=O)[CH:7]([CH2:12][C:13]#[CH:14])[CH2:6]1)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:16][OH:17].N1C=CC=CC=1>C(O)C>[C:1]([CH:5]1[CH2:10][CH2:9]/[C:8](=[N:16]/[OH:17])/[CH:7]([CH2:12][C:13]#[CH:14])[CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NO
Reactant: C#CCC1CC(C(C)(C)C)CCC1=O
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: C#CCC1CC(C(C)(C)C)CC/C1=N/O
Temperature: 25 °C
Yield: 92.8 %

Procedure:
A mixture of 4-tert-butyl-2-prop-2-ynyl-cyclohexanone (50 mg, 0.26 mmol) (prepared as described in Dufey, P.; Bull. Soc. Chim. Fr.; 1968, 4653-4662) in 1.0 mL of ethanol was refluxed with hydroxylamine hydrochloride (25 mg, 0.36 mmol) and pyridine (0.25 mL, excess) for 3 h. The mixture was then allowed to cool to room temperature and partitioned between ethyl acetate and 3N aq. HCl. The organic layers were washed with saturated aqueous sodium chloride solution, dried over MgSO4, filtered and concentrated to give the titled compound as a light yellow solid (50 mg, 93% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([CH:16]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15])=[O:8].C(N(CC)CC)C.[C:25](#[N:28])[CH:26]=[CH2:27]>Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:7]([C:6]1[CH:16]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[CH:27]=[CH:26][C:25]#[N:28])=[O:8]
Reactant: C=CC#N
Reactant: O=C(c1ccccc1F)c1cc(Cl)ccc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CCN(CC)CC
Product: N#CC=Cc1ccc(Cl)cc1C(=O)c1ccccc1F

Procedure:
A solution of 5.0 g (14 mmol) of 5-chloro-2'-fluoro-2-iodobenzophenone, 2 ml (14.3 mmol) of triethylamine, 2 ml (30 mmol) of acrylonitrile and 35 mg (1.5 mmol) of palladium acetate was refluxed under an atmosphere of argon for 16 hr. The mixture was diluted with 100 ml of 1 N hydrochloric acid and the resulting precipitate was collected by filtration. The precipitate was washed with ether and air dried to give an off-white solid, mp 130°-133°.