Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)#[N:2]>C(O)C.[Ni]>[C:9]([NH:2][CH2:1][C:3]1([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)(=[O:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)C1(C#N)CCCCC1
Agent: [Ni]
Solvent: CCO
Product: CCOC(=O)C1(CNC(=O)c2ccccc2)CCCCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 127.9 %

Procedure:
A solution of ethyl 1-cyanocyclohexanecarboxylate (10.0 g, 55.1 mmol) in ethanol (200 ml) was stirred at 40° C. for 12 hrs., in the presence of Raney-nickel (10 g), under a hydrogen atmosphere (4 atm). The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. Ethyl acetate (300 ml) and 10% aqueous sodium carbonate solution (150 ml) were added to the residue, benzoyl chloride (6.34 ml, 55.1 ml) was added dropwise at 0° C., and the mixture was stirred at room temperature for 6 hrs. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and dried over anhydrous MgSO4. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with hexane-ethyl acetate (3:1-1:1, v/v) to give the title compound (10.2 g, 63%) as a colorless oil.
Reaction SMILES: I[CH2:2][CH3:3].[CH2:4]1[O:8][C:7]2[CH:9]=[C:10]([OH:13])[CH:11]=[CH:12][C:6]=2[O:5]1>>[CH2:2]([O:13][C:10]1[CH:11]=[CH:12][C:6]2[O:5][CH2:4][O:8][C:7]=2[CH:9]=1)[CH3:3]
Reactant: CCI
Reactant: Oc1ccc2c(c1)OCO2
Product: CCOc1ccc2c(c1)OCO2

Procedure:
Starting from commercially available iodoethane and sesamol the title compound is obtained as colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8]C)[C:5]([C:10](=[O:23])[CH2:11][CH2:12][CH:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:15][CH2:14]2)=[CH:4][C:3]=1[Cl:24]>Cl>[NH2:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([C:10](=[O:23])[CH2:11][CH2:12][CH:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH:20]([CH3:21])[CH3:22])[CH2:15][CH2:14]2)=[CH:4][C:3]=1[Cl:24]
Reactant: COc1nc(N)c(Cl)cc1C(=O)CCC1CCN(CC(C)C)CC1
Agent: Cl
Product: CC(C)CN1CCC(CCC(=O)c2cc(Cl)c(N)[nH]c2=O)CC1
Temperature: 25 °C
Yield: 40.7 %

Procedure:
A mixture of 1-(6-amino-5-chloro-2-methoxy-3-pyridinyl)-3-(1-isobutyl-4-piperidinyl)-1-propanone (step 1 in example 15, 50 mg, 0.141 mmol) in 10% methanolic hydrochloric acid (1 ml) was refluxed for 4 h. To this mixture, concentrated hydrochloric acid (0.2 ml) was added and the mixture was refluxed for 4 h. After cooling to room temperature, the mixture was concentrated in vacuo, treated with SCX column gave brown oil. This oil was chromatographed on a column of silica gel eluting with 25% ammonium hydroxide/methanol/dichloromethane (0.1:1:10) to give pale yellow solid, which was washed with ethyl acetate to afford 19.5 mg (40%) of the title compound as pale orange solids.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:11][CH:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([CH3:22])[CH:16]=2)[CH2:13][NH2:14])=[CH:5][CH:4]=1.[C:23](N1C=CN=C1)(N1C=CN=C1)=[O:24]>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([CH3:22])[CH:16]=3)[CH2:13][NH:14][C:23]2=[O:24])=[CH:5][CH:4]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc(CCNC(CN)c2ccc(C)c(C)c2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(CCN2C(=O)NCC2c2ccc(C)c(C)c2)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 64.9 %

Procedure:
To a solution of N1-[2-(4-methoxyphenyl)ethyl]-1-(3,4-dimethylphenyl)-1,2-ethanediamine (10.6 g, 0.0356 mol) in dry DMF (55 mL) is added 1,1′-carbonyldiimidazole (6.4 g, 0.0395 mol). The reaction is stirred at 50° C. for 30 minutes, cooled, diluted with ethyl acetate (300 mL), and washed with 0.5 N HCl and brine. The organic phase is dried (MgSO4), and concentrated. The residue is re-crystallized from ethyl acetate (70 mL) to afford 7.5 g (65% yield) of the desired compound. 1H NMR (CDCl3) δ 7.16 (d, J=7.8 Hz, 2H), 7.05 (m, 4H), 6.84 (d, J=7.8 Hz, 2H), 4.50 (t, J=8.1 Hz, 1H), 3.82 (s, 3H), 3.73-3.65 (m, 2H), 3.27 (t, J=8.4 Hz, 1H), 2.91 (m, 1H), 2.78 (m, 1H), 2.68 (m, 1H), 2.30 (s, 6H). MS 325 (MH+). Anal. Calcd. For C20H24N2O2 ¼H2O: C, 73.03; H, 7.51; N, 8.52. Found: C, 73.29; H, 7.19; N, 8.32.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[N:28]1([C:34]2[CH:42]=[CH:41][C:37]([C:38](O)=[O:39])=[CH:36][CH:35]=2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:38](=[O:39])[C:37]5[CH:41]=[CH:42][C:34]([N:28]6[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]6)=[CH:35][CH:36]=5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: O=C(O)c1ccc(N2CCCCC2)cc1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1)c1ccc(N2CCCCC2)cc1

Procedure:
The title compound, off-white solid (100 mg, 77%), MS (ISP) m/z=518.5 [(M+H)+], mp 214.5° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and 4-piperidin-1-yl-benzoic acid.
Reaction SMILES: N[C:2]1[C:10]([O:11][C:12]([F:15])([F:14])[F:13])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[Br:16].C(O)C.S(=O)(=O)(O)O.N([O-])=O.[Na+]>O>[Br:16][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:11][C:12]([F:13])([F:14])[F:15])[CH:2]=1)[C:6]([OH:8])=[O:7]
Reactant: Nc1c(Br)cc(C(=O)O)cc1OC(F)(F)F
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc(Br)cc(OC(F)(F)F)c1
Temperature: 25 °C
Yield: 75.8 %

Procedure:
4-Amino-3-bromo-5-trifluoromethoxybenzoic acid (1.5 g, 5 mmoles) was mixed with ethanol (15 mL) at 0° C. and then concentrated sulfuric acid (2.26 g, 10.2 mmoles) wad added. The sodium nitrite (0.38 g, 5.5 mmoles) water solution (1.2 mL) was added dropwise at 0° C. for 1 hour. After the reaction mixture was warmed to room temperature and then heated to reflux for 45 minutes, water was added. The mixture was extracted with dichloromethane. The dichloromethane layer was dried and concentrated. The residue was dissolved in 1M sodium hydroxide and extracted with ether. The aqueous solution was acidified with 2M HCl to pH=2 to give 3-bromo-5-trifluoromethoxybenzoic acid (1.08 g, 75.5%).
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[C:9]([C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[O:10][C:6]=2[CH:5]=[C:4]([N+:16]([O-])=O)[C:3]=1[O:19][CH3:20].[H][H]>[Pd].C1COCC1.CN(C=O)C>[NH2:16][C:4]1[C:3]([O:19][CH3:20])=[CH:2][C:7]2[CH:8]=[C:9]([C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[O:10][C:6]=2[CH:5]=1
Reactant: COc1c([N+](=O)[O-])cc2oc(C(=O)N(C)C)cc2c1Cl
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cc2cc(C(=O)N(C)C)oc2cc1N
Reaction time: 18 h

Procedure:
4-Chloro-5-methoxy-N,N-dimethyl-6-nitrobenzofuran-2-carboxamide (500 mg, 1.68 mmol), TEA (184 mg, 1.83 mmol) and 10% palladium on charcoal (90 mg) were stirred at room temperature in THF-DMF (2:1) (30 mL) under an atmosphere of hydrogen for 18 h. The reaction was recharged with hydrogen then allowed to stir for an additional 18 h. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to afford a brown solid (400 mg, quant.), which was taken through to the next step with no further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1.Cl[C:17]1[N:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([C:17]3[N:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=3)[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cnc(Cl)nc1
Reactant: Cc1nc(C#Cc2cccc(Cl)c2)c[nH]1
Product: Cc1nc(C#Cc2cccc(Cl)c2)cn1-c1ncc(F)cn1

Procedure:
The title compound, MS: m/e=313.1 (M+H+), was prepared in accordance with the general method of example 1 from 4-(3-chloro-phenylethynyl)-2-methyl-1H-imidazole and 2-chloro-5-fluoro-pyrimidine.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:11]([O:29][CH2:30][CH2:31][OH:32])=[N:12][N:13]([CH3:28])[C:14]=3[NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH:25]([CH3:27])[CH3:26])=[CH:21][N:20]=3)(=[O:18])=[O:17])=[CH:9][C:4]=2[O:3][CH2:2]1.[H-].[Na+].[Br:35][C:36]1[CH:37]=[N:38][C:39](Cl)=[N:40][CH:41]=1>C1COCC1.CC(N(C)C)=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:11]([O:29][CH2:30][CH2:31][O:32][C:39]4[N:40]=[CH:41][C:36]([Br:35])=[CH:37][N:38]=4)=[N:12][N:13]([CH3:28])[C:14]=3[NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH:25]([CH3:27])[CH3:26])=[CH:21][N:20]=3)(=[O:18])=[O:17])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Clc1ncc(Br)cn1
Reactant: CC(C)c1ccc(S(=O)(=O)Nc2c(-c3ccc4c(c3)OCO4)c(OCCO)nn2C)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: CC(C)c1ccc(S(=O)(=O)Nc2c(-c3ccc4c(c3)OCO4)c(OCCOc3ncc(Br)cn3)nn2C)nc1
Reaction time: 0.08 h
Yield: 24.9 %

Procedure:
To a solution of N-[4-(1,3-benzodioxol-5-yl)-3-(2-hydroxyethoxy)-1-methyl-1H-pyrazol-5-yl]-5-isopropyl-2-pyridinesulfonamide (Example 43) (18 mg) in anhydrous THF (0.5 ml) at 0° C. and under an atmosphere of nitrogen was added sodium hydride (60% dispersion in oil, 3.3 mg) and the mixture was stirred for 5 minutes. To the mixture was added 5-bromo-2-chloropyrimidine (Liquid Crystals, 1993, 14(3), 741) (11.3 mg) in dimethylacetamide (0.1 ml). After stirring for 90 min, the reaction mixture was partitioned between ethyl acetate (3 ml) and saturated ammonium chloride solution (5 ml). The ethyl acetate layer was dried (MgSO4) and blown down under nitrogen to afford a gummy residue. Purification of the residue by column chromatography on silica gel (5 g), eluting in an isocratic fashion with ethyl acetate:hexane (7:4) afforded the title compound as a white solid (6 mg) after freeze drying from t-butanol.
Reaction SMILES: [C:1]1([CH3:22])[C:2]([S:7]([N:10]([CH2:18][C:19]([OH:21])=O)[C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)(=[O:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[CH2:23]([NH:25][CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)[CH3:24]>>[CH2:23]([N:25]([CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)[C:19](=[O:21])[CH2:18][N:10]([S:7]([C:2]1[C:1]([CH3:22])=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:8])=[O:9])[C:11]1[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=1)[CH3:24]
Reactant: CCNCc1cccnc1
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccccc2C)cc1
Product: CCN(Cc1cccnc1)C(=O)CN(c1ccc(C)cc1)S(=O)(=O)c1ccccc1C

Procedure:
prepared by reaction of [(toluene-2-sulfonyl)-p-tolyl-amino]-acetic acid with ethyl-pyridin-3-ylmethyl-amine
Reaction SMILES: [CH2:1]([O:8][N:9]=[C:10]([C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[C:15]#N)[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.[Cl-].[NH4+].S(=O)(=O)(O)[OH:33]>C1(C)C=CC=CC=1>[CH2:1]([O:8][N:9]=[C:10]([C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]=[O:33])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=NOCc1ccccc1)c1cccc(C#N)c1
Reactant: O=S(=O)(O)O
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: Cc1ccccc1
Product: CC(=NOCc1ccccc1)c1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 24.15 g (95.0 mmol) of crude 3-(1-(benzyloxyimino)ethyl)benzonitrile in 1 liter of dry toluene was added 77.3 ml (116 mmol) of diisobutylaluminum hydride (1.5 mol/toluene solution) at −70° C. or below under an atmosphere of nitrogen, and the mixture was stirred overnight with gradually warming to room temperature. To the reaction mixture was added 200 ml of an about 20% aqueous solution of ammonium chloride, and the mixture was stirred at room temperature for 0.5 hours. Then, 400 ml of an about 5% aqueous solution of sulfuric acid was add thereto with ice-cooling. The mixture was stirred at the same temperature for 0.5 hours and then stirred at room temperature for 6 hours. The reaction mixture was separated and the aqueous layer was extracted with tert-butyl methyl ether. The organic layers were combined and washed twice with water, then dried and concentrated. The residue was subjected to silica gel column chromatography (eluted with n-hexane:toluene=1:1 and then 1:2) to obtain 18.26 g (72.1 mmol) of 3-(1-(benzyloxyimino)ethyl)benzoaldehyde.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][C:14](=O)[C:15]1[CH:20]=[CH:19][C:18]([C:21]([O:23]C(C)(C)C)=[O:22])=[CH:17][C:16]=1[NH2:28])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.FC(F)(F)C(O)=O.C(OC(OC(OC(C)(C)C)=O)=O)(C)(C)C>CN(C=O)C.C(Cl)Cl.C(N(CC)CC)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([OH:23])=[O:22])=[CH:17][C:16]=2[NH:28][C:10]1=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H](CC(=O)c1ccc(C(=O)OC(C)(C)C)cc1N)C(=O)O
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H]1CCc2ccc(C(=O)O)cc2NC1=O
Temperature: 0 °C
Reaction time: 24 h

Procedure:
To a stirred solution of the above (11) (0.71 mMol) in dry DMF (20 mL) at 0° C. in a dewar flask was added triethylamine (200 mL, 1.42 mMol), NaHCO3 (300 mg, 3.57 mMol), and finally diphenylphosphorylazide (250 mL, 1.2 mMol). After stirring at 0° C. for 24 h the reaction was evaporated under reduced pressure, taken up in ethyl acetate (100 mL), washed with H2O, brine, dried (MgSO4), filtered and evaporated. The remaining residue was purified by silica gel chromatography eluted with ethyl acetate in hexane. The fully protected intermediate obtained was then treated with 50% trifluoroacetic acid in CH2Cl2 (15 mL) for 45 min. at room temperature, evaporated under reduced pressure, triturated with ether, filtered and dried under vacuum to give the fully deprotected intermediate. This was treated with di-t-butyldicarbonate and triethylamine overnight at room temperature in DMF, evaporated under reduced pressure, taken up into ethyl acetate and washed with 1N NaHSO4, water and brine, dried (MgSO4), filtered and evaporated. The residue was purified by silica gel chromatography eluted with ethyl acetate in hexane to give the title product (12).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9]C(=O)[C:7]2=[O:12].[OH-:13].[Na+].OO.Cl>O>[NH2:9][C:10]1[C:2]([I:1])=[CH:3][CH:4]=[CH:5][C:6]=1[C:7]([OH:12])=[O:13]
Reactant: O=C1Nc2c(I)cccc2C1=O
Reactant: [OH-]
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: O
Product: Nc1c(I)cccc1C(=O)O
Temperature: 25 °C

Procedure:
To a ice cold solution of 7-iodoindoline-2,3-dione (2.9 g, 0.0106 mol) in an aq. solution of 2 N NaOH (15 mL) was added drop wise an aq. solution of 35% H2O2 (3 mL) and then allowed to stir at room temperature over night. After the reaction is completed, the reaction mixture was diluted with water (50 mL), adjusted the pH to 2 with conc. HCl.
Reaction SMILES: [O:1]=[C:2]1[CH2:8][O:7][CH:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([F:18])([F:17])[F:16])[C:5]2[CH:19]=[CH:20][CH:21]=[CH:22][C:4]=2[NH:3]1.[Cl:23]CC(Cl)=O>C1C=CC=CC=1>[Cl:23][CH2:8][C:2]([NH:3][C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[C:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]([F:18])([F:17])[F:16])=[O:7])=[O:1]
Reactant: O=C1COC(c2ccccc2C(F)(F)F)c2ccccc2N1
Reactant: O=C(Cl)CCl
Solvent: c1ccccc1
Product: O=C(CCl)Nc1ccccc1C(=O)c1ccccc1C(F)(F)F

Procedure:
To a solution of 2-amino-2'-trifluoromethylbenzophenone 1 [L. H. Sternbach et al. Helv. Chim. Acta., 45, 2226 (1962)] (8 g) in benzene (80 ml) is added chloroacetyl chloride (29 ml), and the mixture is refluxed under heating for 30 minutes. Benzene is evaporated under reduced pressure, and the residue is washed with n-hexane to give crystalline 2-(2-chloroacetyl)amino-2'-trifluoromethylbenzophenone (10.05 g), which is recrystallized from benzene-n-hexane to give the pure crystals, mp. 79°-81° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([NH:16][C:17]3[CH:18]=[C:19]([S:29]([NH:32][CH3:33])(=[O:31])=[O:30])[CH:20]=[CH:21][C:22]=3[O:23][CH2:24][C:25]([F:28])([F:27])[F:26])=[N:11][CH:12]=[N:13]2)=[CH:8][CH:7]=1.[CH3:34][O-:35].[Na+].Cl>CO.C([O-])(O)=O.[Na+]>[CH3:33][NH:32][S:29]([C:19]1[CH:20]=[CH:21][C:22]([O:23][CH2:24][C:25]([F:26])([F:27])[F:28])=[C:17]([NH:16][C:10]2[C:9]3[C:14](=[CH:15][C:6]([O:5][CH2:4][CH2:3][CH2:2][O:35][CH3:34])=[CH:7][CH:8]=3)[N:13]=[CH:12][N:11]=2)[CH:18]=1)(=[O:30])=[O:31]
Reactant: C[O-]
Reactant: CNS(=O)(=O)c1ccc(OCC(F)(F)F)c(Nc2ncnc3cc(OCCCCl)ccc23)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CNS(=O)(=O)c1ccc(OCC(F)(F)F)c(Nc2ncnc3cc(OCCCOC)ccc23)c1
Yield: 25 %

Procedure:
A mixture of 3-({7-[(3-chloropropyl)oxy]-4-quinazolinyl}amino)-N-methyl-4-[(2,2,2-trifluoroethyl)oxy]benzenesulfonamide (150 mg, 0.297 mmol) in MeOH (3 mL) was treated with a solution of 25% sodium methoxide in methanol (3 g, 13.88 mmol) and subjected to microwave irradiation (100° C.) for 10 minutes before being cooled and neutralized with the addition of concentrated HCl. The resulting solution was diluted with saturated aqueous NaHCO3 and extracted with CH2Cl2. The organic extracts were dried (sodium sulfate), concentrated, and subjected to reverse phase HPLC (30-70% MeCN/aq. NH4OH pH 10, XBridge C18 OBD 30×150 mm, 5 μm) to give N-methyl-3-[(7-{[3-(methyloxy)propyl]oxy}-4-quinazolinyl)amino]-4-[(2,2,2-trifluoroethyl)oxy]benzenesulfonamide (37 mg, 25%) as a white solid.
Reaction SMILES: [CH:1]([C@H:14]1[O:19][CH2:18][C@@H:17]([NH2:20])[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:21]([C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1)([O-:23])=[O:22].C(O)(=O)C.[BH3-]C#N.[Na+]>ClCCCl.CO>[CH:1]([C@H:14]1[O:19][CH2:18][C@@H:17]([NH:20][CH2:28][C:27]2[CH:30]=[CH:31][C:24]([N+:21]([O-:23])=[O:22])=[CH:25][CH:26]=2)[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: N[C@H]1CC[C@@H](C(c2ccccc2)c2ccccc2)OC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: ClCCCl
Product: O=[N+]([O-])c1ccc(CN[C@H]2CC[C@@H](C(c3ccccc3)c3ccccc3)OC2)cc1
Yield: 78.5 %

Procedure:
Trans-5-amino-2-diphenylmethyl-tetrahydropyran 15 (0.1 g, 0.38 mmol) was reacted with 4-nitrobenzaldehyde (0.057 g, 0.38 mmol) in the presence of glacial acetic acid (0.023 g, 0.38 mmol) in 1,2-dichloroethane (20 ml), and then reduced by NaCNBH3 (0.03 g, 0.45 mmol) in methanol (5 ml) (Procedure D) to give compound 16d (0.12 g, 80%) as an oil.
Reaction SMILES: COC1C=C2C(=CC=1OC)C(N)CCC2.FC1C=C(F)C=CC=1S(C)(=O)=O.C(N(C(C)C)CC)(C)C.F[C:38]1[CH:39]=[CH:40][C:41]([S:59]([CH3:62])(=[O:61])=[O:60])=[C:42]([NH:44][CH:45]2[C:54]3[C:49](=[CH:50][C:51]([O:57][CH3:58])=[C:52]([O:55][CH3:56])[CH:53]=3)[CH2:48][CH2:47][CH2:46]2)[CH:43]=1.[NH:63]1[CH2:68][CH2:67][NH:66][CH2:65][CH2:64]1>CN(C)C=O.C(#N)C.O>[CH3:58][O:57][C:51]1[CH:50]=[C:49]2[C:54](=[CH:53][C:52]=1[O:55][CH3:56])[CH:45]([NH:44][C:42]1[CH:43]=[C:38]([N:63]3[CH2:68][CH2:67][NH:66][CH2:65][CH2:64]3)[CH:39]=[CH:40][C:41]=1[S:59]([CH3:62])(=[O:61])=[O:60])[CH2:46][CH2:47][CH2:48]2
Reactant: C1CNCCN1
Reactant: COc1cc2c(cc1OC)C(Nc1cc(F)ccc1S(C)(=O)=O)CCC2
Agent: COc1cc2c(cc1OC)C(N)CCC2
Agent: CS(=O)(=O)c1ccc(F)cc1F
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: O
Product: COc1cc2c(cc1OC)C(Nc1cc(N3CCNCC3)ccc1S(C)(=O)=O)CCC2
Temperature: 25 °C
Yield: 16.8 %

Procedure:
A solution of 1,2,3,4-tetrahydro-6,7-dimethoxynaphthalen-1-amine (200.0 mg, 0.96 mmol), 2,4-difluoro-1-(methylsulfonyl)benzene (185.0 mg, 0.96 mmol) and diisopropylethylamine (496.0 mg, 3.84 mmol) in N,N-dimethylformamide (2 mL) was stirred at 110° C. for 16 h. The reaction was cooled to room temperature, poured over water and extracted with diethyl ether. The solvent was concentrated in vacuo and the residue was used without further purification for the following reaction. N-(5-Fluoro-2-(methylsulfonyl)phenyl)-1,2,3,4-tetrahydro-6,7-dimethoxynaphthalen-1-amine (150 mg, 0.40 mmol), piperazine (683 mg, 7.90 mmol), N,N-diisopropylethylamine (510 mg, 4.00 mmol) were stirred at 80° C. in dry acetonitrile (3 mL) for 16 h. The solvent was evaporated and the residue was dissolved in dichloromethane and washed with water. The dichloromethane was evaporated and the crude compound was purified by silica chromatography using 10% methanol in dichloromethane to afford the title compound (30 mg, 17% yield). 1H NMR (400 MHz, CDCl3): δ 7.63 (d, 1H), 6.79 (s, 1H), 6.59 (s, 1H), 6.31 (m, 2H), 6.25 (d, 1H), 4.62 (m, 1H), 3.87 (s, 3H), 3.78 (s, 3H), 3.30 (m, 4H), 3.02 (m, 4H), 2.94 (s, 3H), 2.72 (m, 2H), 1.84 (m, 4H); MS (ESI) m/z: 446.3 (M++1).
Reaction SMILES: NCC(C1NC2C(C=1)=CC=CN=2)OC1CCCCO1.[CH3:20][O:21][C:22]1[CH:30]=[CH:29][N:28]=[C:27]2[C:23]=1[CH:24]=[C:25]([CH:31]([O:44][CH:45]1[CH2:50][CH2:49][CH2:48][CH2:47][O:46]1)[CH2:32][N:33]1C(=O)C3=CC=CC=C3C1=O)[NH:26]2.NN.O>CCO>[NH2:33][CH2:32][CH:31]([C:25]1[NH:26][C:27]2[C:23]([CH:24]=1)=[C:22]([O:21][CH3:20])[CH:30]=[CH:29][N:28]=2)[O:44][CH:45]1[CH2:50][CH2:49][CH2:48][CH2:47][O:46]1
Reactant: COc1ccnc2[nH]c(C(CN3C(=O)c4ccccc4C3=O)OC3CCCCO3)cc12
Agent: NCC(OC1CCCCO1)c1cc2cccnc2[nH]1
Agent: NN
Solvent: O
Solvent: CCO
Product: COc1ccnc2[nH]c(C(CN)OC3CCCCO3)cc12
Yield: 65.2 %

Procedure:
Following the same procedure as for 9a. From 4-Methoxy-2-[2-phthalimido-1-(2,3,5,6-tetrahydropyran-2-yl)oxyethyl]-7-azaindole (2.9 g, 10 mmol) in EtOH (100 ml) and NH2NH2.H2O (420 μl, 15 mmol). After a reaction time of 3 h. a diastereomeric mixture (1:1) of 9b (1.9 g, 95%) was obtained.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:20])=[C:7]([CH3:19])[C:8]2[O:13][C:12]([CH2:15][CH3:16])([OH:14])[CH2:11][CH2:10][C:9]=2[C:17]=1[CH3:18])(=[O:3])[CH3:2].[H-].[Na+].[CH:23]([O:26][C:27](=[O:35])[C:28]([CH3:34])([CH3:33])[CH2:29][CH2:30][CH2:31]Br)([CH3:25])[CH3:24].Cl>C1C=CC=CC=1.CS(C)=O.C(OCC)C.O>[C:1]([O:4][C:5]1[C:6]([CH3:20])=[C:7]([CH3:19])[C:8]([O:13][CH2:31][CH2:30][CH2:29][C:28]([CH3:33])([CH3:34])[C:27]([O:26][CH:23]([CH3:24])[CH3:25])=[O:35])=[C:9]([CH2:10][CH2:11][C:12](=[O:14])[CH2:15][CH3:16])[C:17]=1[CH3:18])(=[O:3])[CH3:2]
Reactant: CCC1(O)CCc2c(C)c(OC(C)=O)c(C)c(C)c2O1
Reactant: CC(C)OC(=O)C(C)(C)CCCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Solvent: CCOCC
Product: CCC(=O)CCc1c(C)c(OC(C)=O)c(C)c(C)c1OCCCC(C)(C)C(=O)OC(C)C
Reaction time: 0.67 h
Yield: 83 %

Procedure:
A solution containing 20.0 g (0.072 moles) of 6-acetoxy-3,4-dihydro-2-ethyl-2-hydroxy-5,7,8-trimethyl-2H-1-benzopyran in 500 ml of benzene is slowly dripped, under nitrogen atmosphere, into a suspension containing 2.07 g (0.086 moles) of 97% sodium hydride in 150 ml of dimethylsulfoxide. After 40 minutes the solution is dripped into a solution containing 21.6 g (0.086 moles) of 2,2-dimethyl-5-bromopentanoic acid isopropyl ester in 100 ml of benzene brought to 60° C. and the mixture is reacted for 3 hours at 60° C. Then the suspension is diluted with ethyl ether and water, acidified with a 10% aqueous solution of hydrochloric acid and the product is recovered by evaporation of the organic solvent and purified by chromatography on column of silica gel with eluent petroleum ether-ethyl ether in 60:40 ratio. After evaporation of the solvent, 16.6 g are obtained with a yield of 83% of an oil having the following chemical-physical characteristics: