Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[CH:4]([O:13]CC)[C:5]1[CH:10]=[CH:9][C:8](Br)=[C:7]([CH3:12])[CH:6]=1)C.C([Li])CCC.[CH:21]([C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)=[O:22]>C(OCC)C.CCCCCC>[CH3:12][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][C:8]=1[CH:21]([C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)[OH:22])[CH:4]=[O:13]
Reactant: O=Cc1cccnc1
Reactant: CCOC(OCC)c1ccc(Br)c(C)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: Cc1cc(C=O)ccc1C(O)c1cccnc1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 76.7 %

Procedure:
To a solution of 1.88 g of 4 -bromo-3-methylbenzaldehyde diethylacetal in 20 ml of diethyl ether was added dropwise 5.0 ml of a 1.4M solution of butyllithium in hexane at -70° C. to 0° C., and the mixture was stirred at 0° C. to -50° C. for 50 minutes. To it was added dropwise 0.89 g of 3-formylpyridine at -30° C. to -20° C., and the reaction mixture allowed to warm to room temperature with stirring. After concentration under reduced pressure the residue was stirred with 10 ml of tetrahydrofuran and 10 ml of 2N hydrochloric acid at room temperature for 45 minutes. The reaction mixture was basified with sodium bicarbonate, extracted with diethyl ether, and the extract was washed with a saturated aqueous solution of sodium chloride, dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of cyclohexane and ethyl acetate (1:2) as eluent to give 1.20 g of the title compound having the following physical characteristics:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:23])=[C:7]([C:9]2[NH:10][C:11](=[O:22])[N:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([F:21])[CH:15]=3)[N:13]=2)[CH:8]=1.[C:24](Cl)(=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26].CCN(C(C)C)C(C)C>C1COCC1>[Cl:23][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:8][C:7]=1[C:9]1[NH:10][C:11](=[O:22])[N:12]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([F:21])[CH:15]=2)[N:13]=1
Reactant: NCc1ccc(Cl)c(-c2nn(-c3ccc(Cl)c(F)c3)c(=O)[nH]2)c1
Reactant: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(-c2nn(-c3ccc(Cl)c(F)c3)c(=O)[nH]2)c1

Procedure:
The title compound was prepared according to the procedure described in Example-108 by using 5-(5-(aminomethyl)-2-chlorophenyl)-2-(4-chloro-3-fluorophenyl)-2H-1,2,4-triazol-3(4H)-one (Intermediate-76, 0.250 g), pivaloyl chloride (1.0 mL), DIPEA (2.0 mL), dry THF (5 mL) to afford 0.110 g of the desired product. 1H NMR (400 MHz, DMSO d6): δ 1.24 (s, 9H), 4.30 (d, J=14.7 Hz, 2H), 7.40 (dd, J=4.5 Hz, 3.6 Hz, 1H), 7.43 (d, 1H), 7.60 (d, J=5.4 Hz, 1H), 7.74 (d, 1H), 7.98 (d, 1H), 8.18 (t, J=15.0 Hz, 11H), 12.70 (s, 1H); MS (m/z): 437.59 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([S@:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1.[OH-].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[Br:8][C:9]1[CH:16]=[CH:15][C:12](/[CH:13]=[N:7]\[S@@:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[O:6])=[CH:11][CH:10]=1
Reactant: CC(C)(C)[S@](N)=O
Reactant: O=Cc1ccc(Br)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(C)(C)[S@@](=O)/N=C\c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89.9 %

Procedure:
Add (R)-2-methylpropane-2-sulfinamide (40.5 g, 0.33 mol) portion-wise to a solution of 4-bromobenzaldehyde (65.57 g, 0.35 mol) in toluene (283 mL). Stir the mixture at ambient temperature for 15 minutes and then add sodium hydroxide (1.34 g, 0.33 mol). Stir the suspension at ambient temperature for 12 h. Add sodium sulphate (16 g) and Celite® (16 g) and stir the suspension for 15 min. Filter and concentrate the filtrate under reduced pressure. Purify the residue by silica gel chromatography eluting with hexane/EtOAc (100% to 70% hexane) to afford the title compound as a white solid (85.5 g, 88% yield). MS (m/z): 288 (M+1).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[C:19]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:20]([CH3:22])[NH:21][C:14]=23)[CH2:3][CH2:2]1.Cl[CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34]>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[C:19]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:20]([CH3:22])[N:21]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:14]=23)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1c(C)[nH]c2c(-c3ccc(F)cc3OCC3CC3)ccnc12
Reactant: C[Si](C)(C)CCOCCl
Product: CCOC(=O)c1c(C)n(COCC[Si](C)(C)C)c2c(-c3ccc(F)cc3OCC3CC3)ccnc12

Procedure:
Starting from ethyl 7-[2-(cyclopropylmethoxy)-4-fluorophenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxylate (example D.a2) and commercially available (2-chloromethoxy-ethyl)-trimethyl-silane the title compound is prepared as pale yellow viscous oil.
Reaction SMILES: Br[CH2:2]/[C:3](/[C:11]([O:13][CH3:14])=[O:12])=[CH:4]\[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[S:15]([O-:18])([O-:17])=[O:16].[Na+:19].[Na+].[Br-].[Na+].[K+].[Br-]>CO>[Na+:19].[C:11](/[C:3](=[CH:4]/[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)/[CH2:2][S:15]([O-:18])(=[O:17])=[O:16])([O:13][CH3:14])=[O:12]
Reactant: COC(=O)/C(=C/c1ccccc1)CBr
Reactant: O=S([O-])[O-]
Agent: [Br-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Product: COC(=O)/C(=C/c1ccccc1)CS(=O)(=O)[O-]
Temperature: 50 °C
Reaction time: 0.75 h

Procedure:
To a 12L, 3-neck round bottom flask fitted with a mechanical stirrer, thermometer and an addition funnel was added the resultant product from Example 3B (400 g, 1.57 mol) and methanol (4L). The mixture was warmed to 50° C. and a solution of sodium sulfite (199 g, 1.57 mol) dissolved in water (4L) was added over 75 min while the internal temperature of the flask was maintained at 50° C. After the addition was complete, the clear solution was allowed to stir at 50° C. for an additional 45 min. The reaction mixture in solution was taken to the next step without additional purification. The compound can be isolated by concentration to an amorphous powder, which is contaminated with an equivalent of sodium bromide: IR (KBr) 1711, 1628, 1215 cm-1 ; 1H NMR (DMSO D-6) delta 3.70 (s, 3H), 3.77 (s, 2H), 7.33-7.41 (m, 3H), 7.48 (s, 1H), 7.87-7.89 (m, 2H); 13C NMR (75 MHz, DMSO D-6) delta 49.88, 51.93, 127.36, 128.33, 128.91, 129.82, 134.75, 139.06, 168.60.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][CH:3]=1.C1N2CCN(CC2)C1.[C:18]([O:22][CH3:23])(=[O:21])[CH:19]=[CH2:20].O1CCOCC1>[Cl-].[Na+].O.O>[CH3:23][O:22][C:18](=[O:21])[C:19]([CH:8]([OH:9])[C:5]1[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=1)=[CH2:20]
Reactant: C=CC(=O)OC
Reactant: Cc1ccc(C=O)cn1
Agent: C1CN2CCN1CC2
Agent: [Cl-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: C=C(C(=O)OC)C(O)c1ccc(C)nc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 43.8 %

Procedure:
A mixture of 6-methylpyridine-3-carboxaldehyde, 97% (500 mg, 4.0 mmol, 1 eq), DABCO (458 mg, 1 eq) and methyl acrylate (1.80 ml, 5 eq) in a 1,4-dioxane (20 ml)/water (20 ml) solvent mixture was stirred at room temperature for 4 days. The resulting mixture was poured in 150 ml of brine and the organics were extracted with DCM (3×300 ml). The gathered DCM layers were dried, solvent was evaporated and the obtained crude was purified by chromatography on Biotage SP1 purification device using 25 g normal phase silica SNAP column and DCM/MeOH solvent system (gradient 1-6% of MeOH in 20 CV). Solvent from gathered fractions of appropriate composition was evaporated and the resulting crude was triturated with cyclohexane to obtain 2-[hydroxy-(6-methyl-pyridin-3-yl)-methyl]-acrylic acid methyl ester in form of white powder (375 mg, yield=43.8%, purity=95%). MS: [M+H]+=208.17 1H NMR (300 MHz; CDCl3) δ/ppm 2.55 (s, 3H), 3.11 (d, J=5.86 Hz, 1H), 3.74 (s, 3H), 5.58 (d, J=5.58 Hz, 1H), 5.87 (s, 1H), 6.38 (s, 1H), 7.15 (d, J=8.13 Hz, 1H), 7.61 (dd, J=8.13 Hz, J=2.45 Hz, 1H), 8.48 (d, J=2.45 Hz, 1H)
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([S-:6])=[S:5].[K+].[NH2:8][C:9]1[N:14]=[C:13]([CH2:15]Cl)[CH:12]=[C:11]([O:17][CH3:18])[N:10]=1>C(O)C.O>[NH2:8][C:9]1[N:10]=[C:11]([O:17][CH3:18])[CH:12]=[C:13]([CH2:15][S:5][C:4]([O:3][CH2:2][CH3:1])=[S:6])[N:14]=1
Reactant: COc1cc(CCl)nc(N)n1
Reactant: CCOC(=S)[S-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCOC(=S)SCc1cc(OC)nc(N)n1

Procedure:
16.0 g of potassium ethylxanthogenate and 17.4 g of 2-amino-4-chloromethyl-6-methoxy-pyrimidine are refluxed in 100 ml of ethanol for 30 minutes. After the reaction solution has cooled, it is diluted with about 1 liter of water, and the product which precipitates is separated and dried. The yield is 22.5 g (87% of theory) of 2-amino-4-methoxy-6-ethoxythiocarbonylthiomethyl-pyrimidine, m.p. 91°-93° C.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[N:7][NH:8][C:9]2=[O:14])([O-])=O.C(N(CC)CC)C.[H][H]>[Pd].C(OCC)(=O)C>[NH2:1][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[N:7][NH:8][C:9]2=[O:14]
Reactant: O=c1[nH]ncc2c([N+](=O)[O-])cccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Nc1cccc2c(=O)[nH]ncc12
Yield: 100.5 %

Procedure:
980 mg of 5-nitro-phthalazin-1-one (Example 66) and 100 mg of palladium on activated carbon are suspended in 50 ml of ethyl acetate and 1 ml of triethylamine and hydrogenated with hydrogen under normal pressure. It is filtered through diatomaceous earth, and the solvent is removed in a vacuum. As a crude product, 830 mg of 5-amino-phthalazin-1-one is obtained as a solid.
Reaction SMILES: [F:1][C:2]1[C:10]([NH:11][S:12](=[O:18])(=[O:17])[NH:13][CH2:14][CH2:15][CH3:16])=[CH:9][CH:8]=[C:7]([F:19])[C:3]=1[C:4]([OH:6])=O.[NH:20]1[C:24]2=[N:25][CH:26]=[C:27]([NH2:29])[CH:28]=[C:23]2[CH:22]=[CH:21]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[C:10]([NH:11][S:12](=[O:18])(=[O:17])[NH:13][CH2:14][CH2:15][CH3:16])=[CH:9][CH:8]=[C:7]([F:19])[C:3]=1[C:4]([NH:29][C:27]1[CH:28]=[C:23]2[CH:22]=[CH:21][NH:20][C:24]2=[N:25][CH:26]=1)=[O:6]
Reactant: CCCNS(=O)(=O)Nc1ccc(F)c(C(=O)O)c1F
Reactant: Nc1cnc2[nH]ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCNS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]ccc3c2)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.9 %

Procedure:
2,6-Difluoro-3-(N-propylsulfamoylamino)benzoic acid (0.095 g, 0.32 mmol), 1H-pyrrolo[2,3-b]pyridin-5-amine (0.043 g, 0.32 mmol), HOBt (0.044 g, 0.32 mmol), and EDCI (0.062 g, 0.32 mmol) were dissolved in DMF (1.6 mL) and stirred at room temperature for 16 hours. The mixture was diluted with EtOAc (30 mL) and washed with a mixture of 1:1:1 water:bicarbonate:brine (3×20 mL). The organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified via column chromatography eluting with 1:1 then 8:2 EtOAc:hexanes to provide 2,6-difluoro-3-(N-propylsulfamoylamino)-N-(1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide (0.060 g, 0.15 mmol, 45% yield). 1H NMR (400 MHz, CD3OD) δ 8.36-8.40 (m, 2H), 7.64-7.72 (m, 1H), 7.41-7.43 (m, 1H), 7.06-7.13 (m, 1H), 6.50-6.52 (m, 1H), 2.96-3.02 (m, 2H), 1.47-1.57 (m, 2H), 0.87-0.93 (m, 3H); m/z (APCI-pos) M+1=410.2.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[C:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]=1)=[O:4].[OH-].[Li+].Cl>O1CCCC1.O>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([C:7]2[N:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:10]=[CH:9][C:8]=2[O:11][CH2:12][C:13]([F:16])([F:14])[F:15])=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
To a solution of 3.0 g 6-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid methyl ester in 30 mL tetrahydrofuran was added 14 mL of a 1M solution of lithium hydroxide in water and the mixture was stirred at room temperature for 1 h. The reaction mixture was acidified by addition of 1M hydrochloric acid. The precipitate was collected by filtration washed with water and dried to constant weight under high vacuum to yield 2.36 g of the title compound as white solid, MS 330.3 (M−H)−.
Reaction SMILES: [CH:1]([N:4]=[C:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[CH2:8]([O:10][C:11](=[O:22])[C:12](=[CH:18]OCC)[C:13](OCC)=[O:14])[CH3:9]>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH:5]([N:4]1[C:1]([CH3:3])=[CH:2][CH:18]=[C:12]([C:11]([O:10][CH2:8][CH3:9])=[O:22])[C:13]1=[O:14])([CH3:7])[CH3:6]
Reactant: CC(C)=NC(C)C
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1ccc(C)n(C(C)C)c1=O
Temperature: 185 °C
Reaction time: 18 h
Yield: 70 %

Procedure:
A mixture of isopropyl(1-methylethylidene)amine (7.94 g, 80.0 mmol, prepared according to Newcomb, Martin et al., J. Amer. Chem. Soc., 1990, 112, 5186) and diethyl(ethoxymethylene)malonate (17.31 g, 80.0 mmol) in diphenyl ether (48 mL) was stirred in a sealed tube at 180-190° C. for 18 h. After cooling, the mixture was chromatographed on a column of silica gel eluting with n-hexane/ethyl acetate (v/v=1/1˜1/2) to give 12.5 g (70%) of the title compound as brown oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([CH2:10][NH:11][C:12]2[CH:13]=[C:14]([NH:19][C:20](=[O:31])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[CH:15]=[CH:16][C:17]=2[CH3:18])=[CH:4][N:3]=1.C(N(CC)CC)C.ClC(Cl)([O:42]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]2[NH:8][C:9](=[O:42])[N:11]([C:12]3[CH:13]=[C:14]([NH:19][C:20](=[O:31])[C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[CH:22]=4)[CH:15]=[CH:16][C:17]=3[CH3:18])[CH2:10][C:5]2=[CH:4][N:3]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CNc1nc(Cl)ncc1CNc1cc(NC(=O)c2cccc(C(F)(F)F)c2)ccc1C
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1N1Cc2cnc(Cl)nc2NC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 185.6 %

Procedure:
To a stirred solution of N-{3-[(2-chloro-4-methylaminopyrimidin-5-ylmethyl)amino]-4-methylphenyl}-3-trifluoromethylbenzamide (559 mg, 1.24 mmol) and triethylamine (693 μL, 4.97 mmol) in THF (15 mL) is added triphosgene (147 mg, 0.49 mmol) in THF (5 mL) at 0° C., and the mixture is stirred for 30 minutes at room temperature. The precipitate is filtered off and the filtrate is stirred for 3 hours at 110° C. The reaction mixture is then diluted with EtOAc and washed with saturated NaHCO3. The organic layer is dried over MgSO4 and concentrated under reduced pressure to give crude oil which is purified by flash column chromatography (SiO2, EtOAc/hexane=1/2) to give N-[3-(7-chloro-2-oxo-1,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-3-yl)-4-methylphenyl]-3-trifluoromethylbenzamide (420 mg, 71%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].F[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1>C(#N)C>[F:1][C:2]1[CH:3]=[N:4][N:5]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[CH:6]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Fc1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(-n2cc(F)cn2)cc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 66.6 %

Procedure:
To a solution of 4-fluoro-1H-pyrazole (250 mg, 2.90 mmol) and potassium carbonate (803 mg, 5.81 mmol) in acetonitrile (3 mL) was added 4-fluoronitrobenzene (430 mg, 3.05 mmol). The resulting mixture was stirred at 70° C. for 2 hours. The reaction was then filtered and concentrated. Purification by column chromatography gave 4-fluoro-1-(4-nitrophenyl)-1H-pyrazole (400 mg, 67%). 1H NMR (400 MHz, CDCl3, δ): 8.34 (d, 2H), 7.91 (d, 1H), 7.81 (d, 2H), 7.67 (d, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:22][CH2:23][CH2:24]OS(C)(=O)=O)[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:9]2[C:14]=1[CH:13]=[CH:12][C:11]([Cl:15])=[CH:10]2)=[O:5])[CH3:2].[CH3:30][NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C)P(=O)(N(C)C)N(C)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:22][CH2:23][CH2:24][N:31]([CH3:30])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:9]2[C:14]=1[CH:13]=[CH:12][C:11]([Cl:15])=[CH:10]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c2ccc(Cl)cc2c(-c2ccccc2)n1CCCOS(C)(=O)=O
Reactant: CNc1ccccc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1c2ccc(Cl)cc2c(-c2ccccc2)n1CCCN(C)c1ccccc1

Procedure:
A solution of 4.36 g. of 5-chloro-2-{3-[(methylsulfonyl)oxy]propyl}-3-phenylisoindole-1-carboxylic acid ethyl ester in 25 ml. of hexamethylphosphoric acid triamide is treated with 25 ml. of N-methylaniline and heated at 80° C. for 24 hours. The mixture is then evaporated to dryness under reduced pressure, and the residue treated with 250 ml. of ice-water. The oily precipitate is taken up in methylene chloride and the extract washed with a saturated solution of sodium chloride, dried over sodium sulfate and concentrated to dryness. The resulting oil is purified by chromatography on 150 g. of aluminum oxide [neutral; Brockmann activityI]. By elution with methylene chloride and evaporation of the solvent, there is obtained 5-chloro-2-[3-(N-methylanilino)propyl]-3-phenylisoindole- 1-carboxylic acid ethyl ester; melting point 108°-110° C. Crystallization from ether/hexane gives almost colorless crystals of the same melting point.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][O:8][C:9]2[C:14]3[C:15]([OH:18])=[N:16][O:17][C:13]=3[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.O[CH2:22][CH:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2([C:35]([O:37][CH3:38])=[O:36])[CH2:34][CH2:33][CH2:32][CH2:31]2)[CH2:25][CH2:24]1.C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]2[C:14]3[C:15]([O:18][CH2:22][CH:23]4[CH2:28][CH2:27][N:26]([CH2:29][C:30]5([C:35]([O:37][CH3:38])=[O:36])[CH2:31][CH2:32][CH2:33][CH2:34]5)[CH2:25][CH2:24]4)=[N:16][O:17][C:13]=3[CH:12]=[CH:11][CH:10]=2)=[CH:19][CH:20]=1
Reactant: COC(=O)C1(CN2CCC(CO)CC2)CCCC1
Reactant: COc1ccc(COc2cccc3onc(O)c23)cc1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: COC(=O)C1(CN2CCC(COc3noc4cccc(OCc5ccc(OC)cc5)c34)CC2)CCCC1
Temperature: 100 °C
Yield: 61.8 %

Procedure:
To a solution of 4-[(4-methoxybenzyl)oxy]-1,2-benzisoxazol-3-ol (100 mg, 0.369 mmol, EXAMPLE 9, step 2) and methyl 1-{[4-(hydroxymethyl)piperidin-1-yl]methyl}cyclopentanecarboxylate (141 mg, 0.553 mmol, EXAMPLE 9, step 3) in toluene (2.5 mL) was added cyanomethylenetributylphosphorane (178 mg, 0.737 mmol) at room temperature. The reaction mixture was heated at 100° C. for 20 h. After cooling, the mixture was concentrated in vacuo to give a dark brown oil. The residual oil was purified by silica gel column chromatography (hexane/ethyl acetate 5:2 to 3:2) to give 116 mg (62%) of the title compound as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:27]4[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=4)[N:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[CH:5][CH:4]=1.[NH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.O>CN(C)C=O>[CH3:29][O:28][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][C:24]=1[O:30][CH3:31])[N:21]=[CH:20][N:19]=[C:18]2[N:15]1[CH2:14][CH2:13][N:12]([C:10]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)=[CH:4][CH:5]=2)=[O:11])[CH2:17][CH2:16]1
Reactant: COc1cc2ncnc(N3CCN(C(=O)Nc4ccc(CCl)cc4)CC3)c2cc1OC
Reactant: C1CCNCC1
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2ncnc(N3CCN(C(=O)Nc4ccc(CN5CCCCC5)cc4)CC3)c2cc1OC
Temperature: 25 °C
Reaction time: 7 h
Yield: 91.7 %

Procedure:
In 10 ml of toluene was suspended 593.5 mg (2.16 mmol) of 6,7-dimethoxy-4-piperazinylquinazoline obtained by the method described in South African Patent No. 67 06512 (1968), and 362.6 ml (2.16 mmol) of 4-(chloromethyl)phenyl isocyanate was added thereto, followed by stirring at room temperature for 3 hours. After the reaction mixture was filtered, the obtained crystals were washed with diisopropyl ether and dried under reduced pressure to give 916.8 mg (2.08 mmol, 96%) of N-[4-(chloromethyl)phenyl]-4-(6,7-dimethoxy-4-quinazolinyl)-1-piperazinecarboxamide. In 10 ml of dimethylformamide was dissolved 422.9 mg (0.96 mmol) of the obtained N-[4-(chloromethyl)phenyl]-4-(6,7-dimethoxy-4-quinazolinyl)-1-piperazinecarboxamide, and 0.28 ml (2.83 mmol) of piperidine was added thereto, followed by stirring at room temperature for 7 hours. Then, the reaction mixture was poured into water and the precipitated crystals were collected by filtration, followed by purification by silica gel column chromatography to give 430.9 mg (0.88 mmol) of the desired compound as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[C:12](Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN1CCCC1=O>[C:12]([NH:9][NH:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([Br:1])=[CH:3][CH:4]=1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NNC(=O)c1ccc(Br)cc1
Solvent: CN1CCCC1=O
Product: O=C(NNC(=O)c1ccc(Br)cc1)c1ccccc1
Yield: 80 %

Procedure:
Subsequently, 2.0 g (13.9 mmol) of the 4-bromobenzohydrazide obtained in (i) above was put in a 300-mL three-neck flask, 7 mL of N-methyl-2-pyrrolidone (abbreviation: NMP) was added thereto, and the mixture was stirred. Thereafter, a mixture of 2.5 mL of N-methyl-2-pyrrolidone and 2.5 mL (21.5 mmol) of benzoyl chloride was dripped through a 50-mL dropping funnel, and the mixture was stirred at 80° C. for 3 hours. The obtained solid was washed with water and a sodium carbonate aqueous solution in this order and collected by suction filtration. Then, the solid was recrystallized with acetone; thus, 3.6 g of a white solid of 1-benzoyl-2-(4-bromobenzoyl)hydrazine that was an object was obtained in the yield of 80%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[C:9](/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)\[CH2:10][Br:11].ClC1C=C(C=CC=1)C(OO)=[O:23]>C(Cl)(Cl)Cl>[Br:11][CH2:10][C:9]1([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[O:23]1
Reactant: Clc1ccccc1/C=C(\CBr)c1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: Clc1ccccc1C1OC1(CBr)c1ccccc1
Yield: 70.2 %

Procedure:
30 g of Z-1-(2-chlorophenyl)-2-phenyl-3-bromoprop-1-ene were refluxed with 23 of 3-chloroperoxybenzoic acid in 500 ml of chloroform. When the reaction was complete, the chloroform phase was washed acid-free with aqueous sodium bicarbonate solution and water, dried over sodium sulfate and evaporated down under reduced pressure. The residue gave 41.3 g (70.2%) of 2-bromomethyl-2-phenyl--(2-chlorophenyl)-oxirane, which was then further processed with triazole according to the Example below. II. Preparation of the end products