Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[C:16](Br)=[C:17](Br)[N:18]3[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]#[N:30])[C:7]([C:10]([OH:12])=[O:11])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].O.[OH-].[Na+].[H][H].O>C(O)C.[OH-].[OH-].[Pd+2].CO>[CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[CH:17][N:18]3[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]#[N:30])[C:7]([C:10]([OH:12])=[O:11])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(C(=O)O)n1Cc1cccc2c1c(Br)c(Br)n2-c1ccccc1C#N
Reactant: [H][H]
Agent: [Pd+2]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CO
Product: CCCCc1ncc(C(=O)O)n1Cc1cccc2c1ccn2-c1ccccc1C#N
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To 2-butyl-1-[[2,3-dibromo-1-(2-cyanophenyl)-1H-indol-4-yl]methyl]-1H-imidazole-5carboxylic acid in ethanol (26 ml, 0.032M), sodium hydroxide water solution (1N, 2.923 ml, 2,923 mmol, 3.5 eq.), and palladium hydroxide on carbon (186 mg) were added. The mixture was placed under a balloon of hydrogen gas and stirred at room temperature. After 1.5 hours, 20 ml water and 40 ml methanol were added and the reaction was filtered. The filtrate was concentrated to about 20 ml and acidified with 1N HCl to pH~2. The mixture was extracted with 10% methanol in methylene chloride. The extract was washed with brine and concentrated. The residue was chromatographed on silica gel eluting with EtOAc: Pyridine:AcOH:H2O (40:1:1:0.5) to give the title B compound (200 mg).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12](=[O:40])[CH:13]([C:23]3[CH:28]=[CH:27][C:26]([O:29][Si](C(C)C)(C(C)C)C(C)C)=[CH:25][CH:24]=3)[CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].CCOC(C)=O>C1COCC1>[OH:29][C:26]1[CH:27]=[CH:28][C:23]([CH:13]([C:12]([NH:11][C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[CH:1]=[N:2][CH:3]=[CH:4]3)=[O:40])[CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[CH:24][CH:25]=1
Reactant: CC(C)[Si](Oc1ccc(C(CNC(=O)OC(C)(C)C)C(=O)Nc2ccc3cnccc3c2)cc1)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(C(=O)Nc1ccc2cnccc2c1)c1ccc(O)cc1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To tert-butyl 3-(isoquinolin-6-ylamino)-3-oxo-2-(4-(triisopropyl silyloxy)phenyl)propylcarbamate (E7) in THF at 0° C. was added TBAF, and the solution was stirred for 45 min at 0° C. The compound was poured into EtOAc and washed with NH4Cl(sat), dried (Na2SO4), filtered, and evaporated. Column chromatography 6% MeOH/CH2Cl2 gave pure tert-butyl 2-(4-hydroxyphenyl)-3-(isoquinolin-6-ylamino)-3-oxopropylcarbamate (E8).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.N1C=CC=CC=1.[C:18](Cl)(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20]>ClCCl>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:5][CH:4]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1ccc(C(F)(F)F)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 97.3 %

Procedure:
To a stirred solution of 4-trifluoromethylaniline (25 g, 0.155 mol) and pyridine (62 ml, 0.775 mol) in dichloromethane (300 ml) cooled to 0° C. under nitrogen was added dropwise pivaloyl chloride (19 ml, 0.155 mol). The reaction mixture was stirred at room temperature for 3.5 hr, then diluted with dichloromethane (300 ml). The resulting solution was washed sequentially with 1N aqueous hydrochloric acid solution (2×), saturated aqueous sodium bicarbonate solution, water and brine, dried (anhydrous sodium sulfate)and concentrated in vacuo to yield the title compound as a white solid (37 g, 97% yield).
Reaction SMILES: [C:1]1([N:7]2[C:15]3[CH2:14][CH2:13][NH:12][CH2:11][C:10]=3[N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:16][C:17]1[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](O)=[O:20].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:16][C:17]1[C:25]([C:26]([F:28])([F:29])[F:27])=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([N:12]1[CH2:13][CH2:14][C:15]2[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=[N:9][C:10]=2[CH2:11]1)=[O:20]
Reactant: c1ccc(-n2nnc3c2CCNC3)cc1
Reactant: O=C(O)c1cccc(C(F)(F)F)c1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCc2c(nnn2-c2ccccc2)C1
Reaction time: 8 h
Yield: 92.5 %

Procedure:
A solution of 1-phenyl-4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine (17 mg, 0.085 mmol) and 2-chloro-3-(trifluoromethyl)benzoic acid (21 mg, 0.093 mmol) in DCM (8 mL) was treated with Et3N (35 μL, 0.25 mmol) followed by HATU (38 mg, 0.1 mmol). The reaction was stirred overnight, then concentrated to minimum volume and purified on 16 g SiO2 with 0-3.5% NH3 in MeOH/CH2Cl2 to give 32 mg (91%) of 5-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-1-phenyl-4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine. MS (ESI): mass calcd. for C19H14ClF3N4O, 406.1. m/z found, 407.1 [M+H]+. 1H NMR (400 MHz, CDCl3): δ 7.84-7.75 (m, 1H), 7.62-7.43 (m, 7H), 5.11 (q, J=16.5 Hz, 1H), 4.64-4.45 (m, 1H), 4.32 (dt, J=13.2, 5.4 Hz, 0.5H), 4.05-3.95 (m, 0.5H), 3.65-3.48 (m, 1H), 3.04 (t, J=5.9 Hz, 1H), 3.01-2.76 (m, 1H).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].[C:10](Cl)(=[O:13])[CH2:11][CH3:12].Cl>ClCCl.N1C=CC=CC=1>[C:10]([O:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[F:1])(=[O:13])[CH2:11][CH3:12]
Reactant: Oc1cccc(F)c1F
Reactant: CCC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(=O)Oc1cccc(F)c1F
Reaction time: 2 h
Yield: 105.2 %

Procedure:
20 g (153.7 mmol) of 2,3-difluorophenol in 150 ml of dichloromethane and 17.5 ml of pyridine are admixed dropwise at 0° C. with 14 ml (161 mmol) of propionyl chloride. The mixture is stirred for two hours and 100 ml of 2 M hydrochloric acid are added. The mixture is extracted with dichloromethane and the extracts are washed with water. Drying over sodium sulphate and the removal of the solvent in vacuo give 30.1 g of 2,3-difluorophenyl propionate.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]([CH:11]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]([NH:20][NH2:21])=[O:19])[C:13]2[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:12]1=2)[C:8](=[O:10])[CH3:9].Cl[C:37]([O:39][CH2:40][CH3:41])=O>CO.CCOC(C)=O>[F:33][C:30]([F:31])([F:32])[C:28]1[CH:27]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:34])[F:35])[CH:29]=1)[CH2:6][N:7]([CH:11]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]2[O:19][C:37]([O:39][CH2:40][CH3:41])=[N:21][N:20]=2)[C:13]2[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:12]1=2)[C:8](=[O:10])[CH3:9]
Reactant: CCOC(=O)Cl
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)NN)c2cc(Cl)ccc21
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOc1nnc(N2CCCC(N(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)C(C)=O)c3ccc(Cl)cc32)o1

Procedure:
To a stirring solution of N-(3,5-Bistrifluoromethyl-benzyl)-N-(8-chloro-1-hydrazinocarbonyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-acetamide (0.13 mmol, 73 mg) in MeOH (1 mL) was added ethyl chloroformate (0.41 mmol, 45.0 μL) and the reaction mixture was refluxed for 12 h. After completion (by TLC), the mixture was cooled, diluted with EtOAc (20 mL), washed with water and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to afford the crude product as viscous oil. Purification by flash silica gel column chromatography gave the title compound as colorless foam; Rf 0.40 (EtOAc/Hexane, 1:1, v/v); MS (ES+): 599 (M+Na+).
Reaction SMILES: C(#N)C.CS(C)=O.[CH:8]([O-:10])=O.[Na+].Br[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([NH:23][CH3:24])[N:17]=[C:16]2[O:25][CH2:26][CH3:27]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH2:26]([O:25][C:16]1[C:15]2[C:20](=[CH:21][CH:22]=[C:13]([CH:8]=[O:10])[CH:14]=2)[N:19]=[C:18]([NH:23][CH3:24])[N:17]=1)[CH3:27]
Reactant: CCOc1nc(NC)nc2ccc(Br)cc12
Reactant: O=C[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CC#N
Product: CCOc1nc(NC)nc2ccc(C=O)cc12
Reaction time: 48 h
Yield: 30.1 %

Procedure:
To a combined solution of acetonitrile (40 mL) and DMSO (40 mL) was added tetrakis(triphenylphosphine)palladium(0) (1.65 g, 1.43 mmol), anhydrous sodium formate (5.82 g, 85.6 mmol) followed by powder (6-bromo-4-ethoxy-quinazolin-2-yl)-methyl-amine (4 g, 14.3 mmol) and the resultant mixture was heated to 85° C., 50 psi under CO atmosphere. After being stirred for 48 hours, the cooled mixture was poured to water and extracted with DCM (3×200 mL). The combined organic phase was washed with brine, dried over Na2SO4, evaporated to give a brown solid which was purified by column to afford 4-ethoxy-2-methylamino-quinazoline-6-carbaldehyde (1 g, 4.3 mmol, 30%) as a pale solid. 1H NMR (DMSO-d6): δ 9.95 (s, 1H), 8.38 (s, 1H), 8.00-7.97 (d, 1H), 7.59-7.56 (m, 1H), 7.46-7.44 (d, 1H), 4.53-4.48 (q, 2H), 2.89-2.87 (d, 3H), 1.44-1.40 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH:21]([C:24]1[CH:28]=[C:27]([NH2:29])[NH:26][N:25]=1)([CH3:23])[CH3:22]>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:29][C:27]2[NH:26][N:25]=[C:24]([CH:21]([CH3:23])[CH3:22])[CH:28]=2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: CC(C)c1cc(N)[nH]n1
Product: CC(C)c1cc(NC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)[nH]n1

Procedure:
Prepared according to the procedure described for example 44 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (35 mg, 0.1 mmol) and 3-isopropyl-1H-pyrazol-5-amine (12.5 mg, 0.1 mmol). The title compound was obtained as a solid (7.1 mg, 16% yield). MS m/z: 458.00, 460.00 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:3]=1[CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([C@H:10]2[CH2:19][CH2:18][C:13]3(OCC[O:14]3)[CH2:12][C@H:11]2[CH3:20])[C:6]1=[O:21].CC1C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[Cl:1][C:2]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:3]=1[CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([C@@H:10]2[CH2:19][CH2:18][C:13](=[O:14])[CH2:12][C@@H:11]2[CH3:20])[C:6]1=[O:21]
Reactant: C[C@@H]1CC2(CC[C@@H]1N1CCC(Cc3ccc(Cl)cc3Cl)C1=O)OCCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: C[C@H]1CC(=O)CC[C@H]1N1CCC(Cc2ccc(Cl)cc2Cl)C1=O
Yield: 93.8 %

Procedure:
Dissolve 3-(2,4-dichloro-benzyl)-1-(cis-7-methyl-1,4-dioxa-spiro[4.5]dec-8-yl)-pyrrolidin-2-one (2.34 g, 5.87 mmol) in acetone (100 mL) and add TsOH (1.01 g, 5.87 mmol). Stir the reaction at room temperature for 24 hours until the starting material has been gone. Add saturated NaHCO3 (100 mL) and extract the aqueous layer with ethyl acetate (3×200 mL). Combine the organic layers and dry with Na2SO4, filter and concentrate to give 1.95 g (94%) of the crude title compound as a white solid: Mass spectrum (ion spray): m/z=354.2, 356.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)=[N:10][NH:11][C:12]=2[C:13]([F:16])([F:15])[F:14])=[CH:4][CH:3]=1.[CH2:27](I)[CH3:28].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH2:27]([N:11]1[C:12]([C:13]([F:16])([F:14])[F:15])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:9]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:24])=[O:25])=[CH:19][CH:18]=2)=[N:10]1)[CH3:28]
Reactant: CS(=O)(=O)c1ccc(-c2n[nH]c(C(F)(F)F)c2-c2ccc(F)cc2)cc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCn1nc(-c2ccc(S(C)(=O)=O)cc2)c(-c2ccc(F)cc2)c1C(F)(F)F

Procedure:
4-(4-Fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)-1H-pyrazole from step 3 (1.81 g, 4.3 mmol) and ethyl iodide (0.86 g, 5.5 mmol) were stirred vigorously in 20 mL dry dimethylformamide (DMF) with finely powdered potassium carbonate (0.58 g, 4.2 mmol) under nitrogen at 25° C. for 18 hours. The mixture was diluted with ethyl acetate and filtered to remove solids. The organic filtrate was washed with two portions of water followed by brine, dried over MgSO4 and concentrated in vacuo. The desired 1-ethyl-4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)-1H-pyrazole was isolated by chromatography on silica gel using ethyl acetate/toluene (10/90) as the eluant, giving 0.65 g (69%) of a white solid: mp 133-135.5° C.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:10][CH3:11])[CH2:4][CH:5]=[CH:6][N+:7]([O-:9])=[O:8].[CH2:12]=[CH:13][CH:14]=[CH2:15]>C1C2NC3C(=CC=CC=3)SC=2C=CC=1.C1(C)C=CC=CC=1>[CH3:11][O:10][CH:3]([O:2][CH3:1])[CH2:4][C@H:5]1[C@H:6]([N+:7]([O-:9])=[O:8])[CH2:15][CH:14]=[CH:13][CH2:12]1
Reactant: C=CC=C
Reactant: COC(CC=C[N+](=O)[O-])OC
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: Cc1ccccc1
Product: COC(C[C@@H]1CC=CC[C@H]1[N+](=O)[O-])OC
Reaction time: 30 h
Yield: 125.4 %

Procedure:
214 g (1.0 mole) 75% 4,4-dimethoxy-1-nitro-1-butene and 0.1 g phenothiazine were put in an autoclave at room temperature, together with 850 ml toluene. Then 216 g (4.0 mole) butadiene were added under pressure. Subsequently stirring was conducted under the own pressure (approx. 6 bar) for 30 hours at 100° C. The pressure was released and the temperature reduced. Finally toluene and unreacted butadiene were distilled off. 270 g of an oily residue were obtained, containing about 39% reaction product and about 10% educt, as confirmed by GC. The crude product was employed without any further purification in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[CH2:26][C:25](=[N:28][O:29][CH2:30][CH2:31][N:32](C(OC(C)(C)C)=O)[CH2:33][CH3:34])[CH:24]=[CH:23][C:22]=3[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[CH2:26][C:25](=[N:28][O:29][CH2:30][CH2:31][NH:32][CH2:33][CH3:34])[CH:24]=[CH:23][C:22]=3[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: CCN(CCON=C1C=Cc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2C1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CCNCCON=C1C=Cc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.6 %

Procedure:
In chloroform (1.8 ml) was dissolved 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(2-(N-(t-butoxycarbonyl)-N-ethylamino)ethyloxyimino)quinazoline (V-16, 54 mg), and trifluoroacetic acid (1.8 ml) was added, followed by stirring at room temperature for 1 hour. After completion of the reaction, the reaction mixture was concentrated, and diluted with ethyl acetate. The mixture was sequentially washed with aqueous saturated sodium bicarbonate solution, water, and aqueous sodium chlorite solution, and dried over magnesium sulfate. After concentration, the crystalline residue was washed with a mixture of dichloromethane-hexane (1:4) to obtain 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(2-(N-ethylamino)ethyloxyimino)quinazoline (V-17, 28 mg) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:21][O:22][CH2:23][CH3:24])[N:14]([CH2:15][CH2:16][CH2:17][C:18](=O)[CH3:19])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[ClH:25].[CH2:26]([O:33][NH2:34])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[ClH:25].[CH2:26]([O:33][N:34]=[C:18]([CH2:17][CH2:16][CH2:15][N:14]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:1])[C:11]=2[N:12]=[C:13]1[CH2:21][O:22][CH2:23][CH3:24])[CH3:19])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CCCC(C)=O
Reactant: NOCc1ccccc1
Agent: Cl
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CCCC(C)=NOCc1ccccc1

Procedure:
By the general methods described in Example 35, 5-(4-amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)pentan-2-one was reacted with O-benzylhydroxylamine hydrochloride to provide 5-(4-amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)pentan-2-one O-benzyloxime hydrochloride in about a 16 to 1 mixture of E and Z isomers as a white solid after recrystallization of the hydrochloride salt from a mixture of toluene and methanol, mp 184-186° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].S(Cl)(Cl)=O.Cl[C:17](SCl)=[O:18]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]=[C:17]=[O:18])(=[O:10])=[O:9]
Reactant: NS(=O)(=O)c1ccccc1Cl
Reactant: O=C(Cl)SCl
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: O=C=NS(=O)(=O)c1ccccc1Cl

Procedure:
In a flask equipped with a stirrer, reflux condenser and nitrogen bubbling apparatus, were mixed 5 g (0.03 mole) o-chlorobenzenesulfonamide, 50 ml (0.686 mole) thionyl chloride and 2 drops of pyridine. Then 3.9 g (0.03 mole) chlorocarbonylsulfenyl chloride was slowly added.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](Br)=[CH:10][CH:9]=[C:8]([CH:13]2[CH2:15][CH2:14]2)[N:7]=1)=[O:5])[CH3:2].[NH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1>[Pd]>[CH2:1]([O:3][C:4]([C:6]1[C:11]([NH:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[CH:10][CH:9]=[C:8]([CH:13]2[CH2:15][CH2:14]2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(C2CC2)ccc1Br
Reactant: Nc1cccnc1
Agent: [Pd]
Product: CCOC(=O)c1nc(C2CC2)ccc1Nc1cccnc1

Procedure:
Palladium catalysed arylation of 3-Bromo-6-cyclopropyl-pyridine-2-carboxylic acid ethyl ester with 3-Aminopyridine according to the general procedure described in example 78 step 3 yielded the title compound as a light yellow solid, MS (ISP): m/e=284.4 (M+H+).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=O.ClCC(=N)OCC.[NH2:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[NH:22][CH2:23][CH2:24][CH3:25])[C:17]#[N:18].C(N(CC)CC)C>C(OCC)(=O)C.O.C(O)(=O)C>[CH2:23]([N:22]1[C:21]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][C:14]=2[N:13]=[C:3]1[CH2:2][Cl:1])[CH2:24][CH3:25]
Reactant: O=C(Cl)CCl
Reactant: CCCNc1ccc(C#N)cc1N
Agent: CCOC(=N)CCl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCn1c(CCl)nc2cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Alternatively, chloroacetylchloride rather than ethyl chloroacetimidate can by used: To a solution of 3-amino-4-n-propylaminobenzonitrile (5.15 g, 29.4 mmol) and triethylamine (4.51 mL) in ethyl acetate (52 mL) at room temperature, chloroacetyl chloride (2.57 mL) is added slowly. After stirring the reaction mixture for 30 minutes at room temperature, acetic acid (5 mL) is added and the reaction mixture heated to reflux. After heating for 20 h, the reaction mixture is cooled to room temperature and diluted with water (50 mL). The organic solution is washed twice with 1.0 M sodium hydroxide (2×50 mL), then washed with an aqueous solution of 0.25 M KH2PO4 (50 mL), followed by brine (50 mL). The organic layer is dried (sodium sulfate), concentrated in vacuo, and the solid recrystallized by heating in ethyl acetate (20 mL), adding hexane (40 mL) and cooling to room temperature with stirring to afford 1-n-Propyl-2-chloromethyl-5-cyanobenzimidazole as brown crystals. 1H NMR (CDCl3): δ 8.08 (d, J=0.8 Hz, 1H), 7.57 (dd, J=1.65, 8.52 Hz, 1H), 7.45 (d, J=8.24 Hz, 1H), 7.26 (s, 1H), 4.84 (s, 2H) 4.24 (t, J=7.6 Hz, 2H), 1.94 (pentet, J=7.4. 7.6 Hz, 2H) 1.03 (t, J=7.4 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]([NH:12][C:13]1[CH:18]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[CH:16]=[CH:15][C:14]=1[Cl:23])=[CH:6][C:7]([O:9]CC)=O)[CH3:2]>C1(C2C=CC=CC=2)C=CC=CC=1.CCOCC>[CH3:22][O:21][C:19]([C:17]1[C:18]2[C:7](=[O:9])[CH:6]=[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:24])[NH:12][C:13]=2[C:14]([Cl:23])=[CH:15][CH:16]=1)=[O:20]
Reactant: CCOC(=O)C=C(Nc1cc(C(=O)OC)ccc1Cl)C(=O)OCC
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: CCOCC
Product: CCOC(=O)c1cc(=O)c2c(C(=O)OC)ccc(Cl)c2[nH]1
Temperature: 250 °C
Reaction time: 3 h

Procedure:
A suspension of 23 (9.00 g, 25.4 mmol) in biphenyl ether (100 mL) was heated to 250° C. and stirred for 3 h. Then the reaction mixture was cooled to room temperature and purified by flash chromatography (hexanes to EtOAc) to afford a colorless oil (24, 3.88 g, 49.4%). 1H NMR (CDCl3, 300 MHz) δ 9.39 (br s, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.24 (d, J=8.0 Hz, 1H), 6.96 (s, 1H), 4.54 (q, J=7.0 Hz, 2H), 4.00 (s, 3H), 1.46 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]([C:5]([NH:7][C:8]1[N:17]=[C:16]([NH:18][C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])=[O:20])[C:15]2[CH2:14][C:13](=O)[CH2:12][CH2:11][C:10]=2[N:9]=1)=[O:6])([CH3:4])[CH3:3].[Cl:26][C:27]1[CH:28]=[C:29]([O:34][NH2:35])[CH:30]=[C:31]([Cl:33])[CH:32]=1>C(O)C>[CH3:4][C:2]([C:5]([NH:7][C:8]1[N:17]=[C:16]([NH:18][C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])=[O:20])[C:15]2[CH2:14][C:13](=[N:35][O:34][C:29]3[CH:28]=[C:27]([Cl:26])[CH:32]=[C:31]([Cl:33])[CH:30]=3)[CH2:12][CH2:11][C:10]=2[N:9]=1)=[O:6])([CH3:1])[CH3:3]
Reactant: NOc1cc(Cl)cc(Cl)c1
Reactant: CC(C)(C)C(=O)Nc1nc2c(c(NC(=O)C(C)(C)C)n1)CC(=O)CC2
Solvent: CCO
Product: CC(C)(C)C(=O)Nc1nc2c(c(NC(=O)C(C)(C)C)n1)CC(=NOc1cc(Cl)cc(Cl)c1)CC2

Procedure:
A solution of 3.5 grams (0.010 mole) of 2,4-di[(1,1-dimethylethyl)carbonylamino]-5,6,7,8-tetrahydro-6-quinazolinone (prepared in Step C of this Example) in 30 mL of ethanol is stirred, and a solution of 2.1 grams (0.012 mole) of O-(3,5-dichlorophenyl)hydroxylamine in 15 mL of ethanol is added dropwise. Upon completion of addition, the reaction mixture is heated to reflux, where it is stirred for about four hours. After this time the reaction mixture is cooled and concentrated under reduced pressure to a residue. The residue is dissolved in diethyl ether and washed with two portions of an aqueous solution saturated with sodium chloride. The organic layer is dried with sodium sulfate and filtered. The filtrate is concentrated under reduced pressure, yielding 2,4-di[(1,1-dimethylethyl)carbonylamino]-6-(3,5-dichlorophenoxyimino)-5,6,7,8-tetrahydroquinazoline.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([O:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[CH3:13].Cl[CH2:21][C:22]1[S:26][C:25]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)=[N:24][C:23]=1[CH3:37].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([O:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:21][C:22]2[S:26][C:25]([C:27]3[CH:28]=[CH:29][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:31][CH:32]=3)=[N:24][C:23]=2[CH3:37])=[CH:8][C:7]=1[CH3:13]
Reactant: CCCCOC(Cc1ccc(O)cc1C)C(=O)OC
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Product: CCCCOC(Cc1ccc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C)C(=O)OC

Procedure:
In analogy to the procedure described in example 14 b], [rac]-2-butoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid methyl ester was reacted with 5-chloromethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole [PCT Int. Appl. (2002), WO 0292590 A1] in the presence of cesium carbonate and potassium iodide to yield [rac]-2-butoxy-3-{2-methyl-4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenyl}-propionic acid methyl ester as colorless liquid.