Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1[C:4]([C:26]([F:29])([F:28])[F:27])=[C:5]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[C:19]4[CH2:25][NH:24][CH2:23][C:20]=4[NH:21][N:22]=3)=[O:17])[CH2:12][CH2:11]2)[CH:6]=[CH:7][C:8]=1[F:9].Cl[C:31]([N:33]1[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]1)=[O:32]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:2][C:3]1[C:4]([C:26]([F:27])([F:28])[F:29])=[C:5]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[C:19]4[CH2:25][N:24]([C:31]([N:33]5[CH2:34][CH2:35][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:37][CH2:38]5)=[O:32])[CH2:23][C:20]=4[NH:21][N:22]=3)=[O:17])[CH2:12][CH2:11]2)[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Cl)CC1
Reactant: O=C(c1n[nH]c2c1CNC2)N1CCC(c2ccc(F)c(F)c2C(F)(F)F)CC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)N2Cc3[nH]nc(C(=O)N4CCC(c5ccc(F)c(F)c5C(F)(F)F)CC4)c3C2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 71.2 %

Procedure:
A solution of (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl) methanone hydrochloride salt (50 mg, 0.11 mmol), N,N,N-diisopropylethylamine (0.05 mL, 0.3 mmol) and DMAP (0.5 mg, 0.004 mmol) in anhydrous CH2Cl2 (1 mL) was cooled to 0° C. under an atmosphere of N2, treated with tert-butyl 4-(chlorocarbonyl)piperazine-1-carboxylate (30 mg, 0.12 mmol) and stirred at 0° C. for 1 h. The cooling bath was then removed and the reaction stirred at room temperature for a further 4 h. After this time, the mixture was chromatographed over silica gel (Isco CombiFlash Rf unit, 12 g Redisep gold column, 0% to 10% CH3OH in CH2Cl2) to provide tert-butyl 4-(3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carbonyl)piperazine-1-carboxylate as a white solid (48 mg, 71%): 1H NMR (500 MHz, CDCl3) δ 10.76 (br s, 1H), 7.33 (dd, J=17.0, 9.0 Hz, 1H), 7.11 (dd, J=9.0, 4.0 Hz, 1H), 4.88-4.52 (m, 2H), 4.69 (br s, 2H), 4.62 (s, 2H), 3.49 (apparent t, J=4.5 Hz, 4H), 3.32 (apparent t, J=4.5 Hz, 4H), 3.25 (apparent t, J=12.5 Hz, 1H), 3.14-2.88 (m, 2H), 1.94 (d, J=12.5 Hz, 2H), 1.72-1.66 (m, 2H), 1.48 (s, 9H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:40])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:39])[CH2:16][N:17]([C:27](=[O:38])[C@H:28]([CH3:37])[NH:29]C(OC(C)(C)C)=O)[CH:18]1[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)C.O1CCOCC1.[ClH:52]>>[ClH:52].[CH2:1]([O:8][C:9](=[O:40])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:39])[CH2:16][N:17]([C:27](=[O:38])[C@H:28]([CH3:37])[NH2:29])[CH:18]1[CH2:19][C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:26]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N(CC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)C1Cc2ccccc2C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: C[C@H](N)C(=O)N(CC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)C1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
N-t-butyloxycarbonyl-L-alanyl-N-(2-indanyl)glycyl-L-proline benzylester (2.72 g, 4.95 m mole) was dissolved in 4N hydrogen chloride dioxane solution (50 ml) and the mixture was stirred for 1 hour at room temperature. The solvent was distilled under reduced pressure from the solution, and thereby a sticky residue was obtained. After addition of ethyl ether the solution was filtered and a crystalline residue was obtained on the filter paper, and immediately dried in a desiccator to obtain a white powder of L-alanyl-N-(2-indanyl)glycyl-L-proline benzylester hydrochloride (2.31 g, 4.76 m mole, yield: 96%). This product had a hygrospic nature, and gave a single spot with Rf =0.42 by silica gel thin layer chromatography (developing solvent, chloroform:methanol:triethylamine=40:2:1, Colour forming method: spraying of 0.1% ninhydrin and heating).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[CH:3]=1.[H-].[Na+].[CH:21]1([CH2:27][C:28](Cl)=[O:29])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.O>CN(C=O)C>[CH:21]1([CH2:27][C:28]([O:1][C:2]2[C:11]3[C:6](=[N:7][CH:8]=[CH:9][CH:10]=3)[N:5]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:4](=[O:18])[CH:3]=2)=[O:29])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=C(Cl)CC1CCCCC1
Reactant: O=c1cc(O)c2cccnc2n1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CC1CCCCC1)Oc1cc(=O)n(-c2ccccc2)c2ncccc12
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
In accordance with a process described in JP-61-246183A, 4-hydroxy-1-phenyl-1,8-naphthyridin-2(1H)-one was synthesized. To a suspension of the synthesized compound (953 mg, 4.0 mmol) in DMF (32 mL) was added sodium hydride (purity of about 60%, 176 mg, 4.4 mmol, 1.1 eq.), and the mixture was stirred at a room temperature for 35 minutes. Then, cyclohexylacetyl chloride (4.8 mmol, 1.2 eq.) was added thereto with cooling in an ice bath, and the mixture was stirred at a room temperature for 80 minutes. Thereafter, water was added to the reaction mixture, and the precipitate was separated by filtration and dried to give 4-cyclohexylacetoxy-1-phenyl-1,8-naphthyridin-2(1H)-one as a form of crystal (1.33 g, yield 91%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:15]=[C:14]([C:23]([F:26])([F:25])[F:24])[CH:13]=2)=[O:10])=[CH:4][C:3]=1[C:27]1[C:38](=[O:39])[N:37]([CH3:40])[C:30]2[N:31]=[C:32](SC)[N:33]=[CH:34][C:29]=2[CH:28]=1.[CH3:41][NH2:42].C1COCC1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:15]=[C:14]([C:23]([F:26])([F:25])[F:24])[CH:13]=2)=[O:10])=[CH:4][C:3]=1[C:27]1[C:38](=[O:39])[N:37]([CH3:40])[C:30]2[N:31]=[C:32]([NH:42][CH3:41])[N:33]=[CH:34][C:29]=2[CH:28]=1
Reactant: CN
Reactant: CSc1ncc2cc(-c3cc(NC(=O)Nc4cc(C(F)(F)F)nn4-c4ccccc4)ccc3C)c(=O)n(C)c2n1
Solvent: C1CCOC1
Product: CNc1ncc2cc(-c3cc(NC(=O)Nc4cc(C(F)(F)F)nn4-c4ccccc4)ccc3C)c(=O)n(C)c2n1
Yield: 77.8 %

Procedure:
Using a procedure analogous to example A1, 1-(4-methyl-3-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)urea (0.1231 g, 0.218 mmol) and 2.0M MeNH2/THF (1.088 ml, 2.177 mmol) were combined to afford 1-(4-methyl-3-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)urea (93 mg, 78% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 9.08 (s, 1H), 8.69 (s, 1H), 8.59 (s, 1H), 7.81 (brq, J=4.4 Hz, 1H), 7.66 (s, 1H), 7.63-7.52 (m, 5H), 7.30 (d, J=2.0 Hz, 1H) 7.21 (dd, J=2.0 and 8.4 Hz, 1H), 7.13 (d, J=8.4 Hz, 1H), 6.85 (s, 1H), 3.59 (s, 3H), 2.90 (brd, J=4.8 Hz, 3H), 2.05 (s, 3H); MS (ESI) m/z: 549.3 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][NH2:24])[CH:21]=4)[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:27](Cl)(=[O:31])[CH:28]([CH3:30])[CH3:29]>C(N(CC)CC)C>[F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][CH2:7][N:8]2[CH2:9][CH2:10][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][NH:24][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])[CH:21]=4)[CH2:16][CH2:15]3)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)Cl
Reactant: NCc1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2
Solvent: CCN(CC)CC
Product: CC(C)C(=O)NCc1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2
Yield: 55.9 %

Procedure:
1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-aminomethylindoline (300 mg), triethylamine (80 mg) and isobutyryl chloride (90 mg) were treated as in Example 133 to give the title compound (200 mg) as white needles (yield: 58%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:11]([F:12])=[C:10](Cl)[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4].[NH:14]1[CH2:19][CH:18]=[CH:17][CH2:16][CH2:15]1>>[CH2:1]([O:5][C:6]1[N:7]=[CH:8][N:9]=[C:10]([N:14]2[CH2:15][CH:16]=[CH:17][CH2:18][CH2:19]2)[C:11]=1[F:12])[C:2]#[C:3][CH3:4]
Reactant: C1=CCNCC1
Reactant: CC#CCOc1ncnc(Cl)c1F
Product: CC#CCOc1ncnc(N2CC=CCC2)c1F
Reaction time: 3 h
Yield: 101.4 %

Procedure:
0.2 g of 4-(2-butynyloxy)-6-chloro-5-fluoropyrimidine and 0.25 g of 1,2,3,6-tetrahydropyridine were mixed and left for 3 hours at room temperature. The reaction mixture was subjected to silica gel column chromatography to obtain 0.25 g of 1-(6-(2-butynyloxy)-5-fluoropyrimidin-4-yl)-1,2,3,6-tetrahydropyridine (hereinafter, referred to as Compound (53)).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9](=[O:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>C(Cl)Cl>[S:26]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9](=[O:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])([CH3:25])(=[O:28])=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCCCCC(=O)NCCCCCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCC(=O)NCCCCCCOS(C)(=O)=O
Yield: 107.2 %

Procedure:
To a solution of 2.00 g (7.37 mmol) of N- (6-hydroxyhexyl)caprylamide and 1.23 ml of triethylamine in 50 ml of methylene chloride was added 0.68 ml (8.84 mmol) of methanesulfonyl chloride under ice-cooling with stirring and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution and water and dried. The solvent was distilled off. The residue was washed with hexane to obtain 2.54 g of the desired compound (98.6%, colorless powder), mp: 62.0°-63.0° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[C:13]2[C:8](=[C:9]([O:16]C)[C:10]([O:14]C)=[CH:11][CH:12]=2)[CH2:7][CH:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:5]=1.B(Cl)(Cl)[Cl:25].CO>ClC(Cl)C>[ClH:25].[NH2:2][CH2:3][C:4]1[C:13]2[C:8](=[C:9]([OH:16])[C:10]([OH:14])=[CH:11][CH:12]=2)[CH2:7][CH:6]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:5]=1
Reactant: COc1ccc2c(c1OC)CC(c1ccccc1)C=C2CN
Reactant: ClB(Cl)Cl
Agent: Cl
Solvent: CO
Solvent: CC(Cl)Cl
Product: NCC1=CC(c2ccccc2)Cc2c1ccc(O)c2O
Temperature: 25 °C
Reaction time: 18 h
Yield: 56 %

Procedure:
A slurry of 10 g (25 mmol) of 1-aminomethyl-3,4-dihydro-5,6-dimethoxy-3-phenyl-naphthalene hydrochloride, from Step 2, in 150 mL of dichloroethane was cooled to 10° C. under a nitrogen atmosphere. Boron trichloride was passed through the reaction mixture until 27 g (230 mmol) had been added. The reaction mixture was allowed to warm to ambient temperature and stirred for 18 h. The reaction mixture was then recooled in ice and 100 mL of methanol was added dropwise. The reaction mixture was again allowed to warm to ambient temperature and concentrated in vacuo. Twice, 500 mL portions of methanol were added to the residue and it was reconcentrated. The resultant foam was dissolved in 40 mL of ethanol, filtered and the solution was treated with 40 mL of methylene chloride and 80 mL of heptane. Off-white crystals of 1-aminomethyl-3,4-dihydro-5,6-dihydroxy-3-phenyl naphthalene hydrochloride (5.1 g, 56% yield) were collected by filtration, m.p. 204°-205° C. The 1H NMR spectrum was identical to the spectrum for the product of Example 2A.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:15])[CH2:10][CH2:9]2)[N:3]=1.[F:21][CH:22]([F:38])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B1OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[K+].[K+].O>C(#N)C.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>[F:21][CH:22]([F:38])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:15])[CH2:10][CH2:9]2)[N:3]=1
Reactant: CC1(C)OB(c2ccccc2C(F)F)OC1(C)C
Reactant: CC(C)COC(=O)N1CCN(c2nccc(Cl)n2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)COC(=O)N1CCN(c2nccc(-c3ccccc3C(F)F)n2)CC1
Temperature: 120 °C

Procedure:
To a solution of the isobutyl 4-(4-chloropyrimidin-2-yl)piperazine-1-carboxylate 8a and 2-(2-(difluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 11a (1.2 eq) in acetonitrile was added Pd(PPh3)4 (0.10 eq), K2CO3 (2 eq) and water. The vial was sealed and heated by microwave irradiation at 120° C. for 15 minutes. The solvent was evaporated and the residue was dissolved in DMF and purified by reverse phase HPLC (using 10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA) to give 24. m/z 391.1 (M+1), r.t: 3.59 (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [CH2:1]([C:6]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:7][CH:8]=[CH:9][C:10]([OH:12])=[O:11])[CH2:2][CH2:3][CH2:4][CH3:5].[N+:18]([C:21]1[CH:26]=[CH:25][C:24](O)=[CH:23][CH:22]=1)([O-:20])=[O:19].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:18]([C:21]1[CH:26]=[CH:25][C:24]([O:11][C:10](=[O:12])[CH:9]=[CH:8][CH:7]=[C:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:23][CH:22]=1)([O-:20])=[O:19]
Reactant: CCCCCC(=CC=CC(=O)O)CCCCC
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCCC(=CC=CC(=O)Oc1ccc([N+](=O)[O-])cc1)CCCCC
Temperature: 25 °C
Reaction time: 18 h
Yield: 40.6 %

Procedure:
As in Example 115, 5-pentyl-2,4-decadienoic acid (4.0 g) and 4-nitrophenol (2.8 g) in 30 mL of dichloromethane was treated with 1,3-dicyclohexylcarbodiimide (3.48 g) and the mixture was stirred at room temperature for 18 hours. After the usual work up, the crude ester was purified by HPLC (ether-hexane; 1:24) to furnish 2.45 g of 5-pentyl-2,4-decadienoic acid 4-nitrophenyl ester as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:12]([N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)=[N:13][N:14]=[C:7]1[N:6]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:5]2=[O:27].C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C(Cl)Cl>[CH2:20]([N:6]1[C:5](=[O:27])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([N:1]([S:36]([CH3:35])(=[O:38])=[O:37])[S:36]([CH3:35])(=[O:38])=[O:37])[CH:3]=2)[N:8]2[C:12]([N:15]3[CH2:16][CH2:17][CH2:18][CH2:19]3)=[N:13][N:14]=[C:7]12)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Nc1ccc2c(c1)c(=O)n(Cc1ccccc1)c1nnc(N3CCCC3)n21
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N(c1ccc2c(c1)c(=O)n(Cc1ccccc1)c1nnc(N3CCCC3)n21)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 83.9 %

Procedure:
In a 20 ml balloon flask, we resuspend 0.55 g (1.5 mmol) of 7-amino-4-benzyl-1-(pyrrolidin-1-yl)-4H-[1,2,4]triazolo[4,3-a]quinazolin-5-one (described in example 225) in 10 ml methylene chloride. We add 0.42 ml (3.0 mmol) of triethylamine then 0.24 ml (3.0 mmol) of methanesulfonyl chloride. The obtained solution is shaken for 24 hours at ambient temperature. After cooling down, the obtained solution is washed in water, dried on Na2SO4 then evaporated under vacuum. The crude mixture of the 2 obtained compounds (0.85 g) is chromatographied on silica column by elution with the mixture CH2Cl2 99/CH3OH 1/NH4OH 0.1. The fractions containing the first product by elution order are joined and evaporated under vacuum to give 0.65 g of 4-benzyl-7-(N,N-dimethylsulfonylamino)-1-(pyrrolidin-1-yl)-4H-[1,2,4]triazolo[4,3-a]quinazolin-5-one.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[CH:9]=[C:10](/[C:15](/[CH3:25])=[CH:16]\[CH:17]=[CH:18]\[C:19](\[CH3:24])=[CH:20]\[C:21]([OH:23])=O)[CH:11]=[C:12]([Br:14])[CH:13]=1.C[Si](C)(C)[O:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][Si](C)(C)C)=[CH:31][CH:30]=1.[F-].[K+]>CN(C=O)C.CCOCC>[OH:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:21](=[O:23])/[CH:20]=[C:19](\[CH3:24])/[CH:18]=[CH:17]/[CH:16]=[C:15](\[C:10]2[CH:11]=[C:12]([Br:14])[CH:13]=[C:8]([Br:7])[CH:9]=2)/[CH3:25])=[CH:31][CH:30]=1
Reactant: C[Si](C)(C)Nc1ccc(O[Si](C)(C)C)cc1
Reactant: C/C(=C/C=C/C(C)=C/C(=O)O)c1cc(Br)cc(Br)c1
Agent: O=C(Cl)C(=O)Cl
Agent: [F-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C/C(=C/C=C/C(C)=C/C(=O)Nc1ccc(O)cc1)c1cc(Br)cc(Br)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of dry ether (30 mL) and DMF (0.5 g, 7 mmol) was cooled to 15° C. and then treated with oxalyl chloride (0.2 g, 1.5 mmol) and stirred for 15 min. All solvent was then removed and dimethylchloroformamidinium chloride (Helv. Chim. Acta 42, 1653 (1959)) as a white solid was suspended in DMF (5 mL). To this was added (2E,4E,6Z)-7-(3,5-dibromophenyl)-3,7-dimethyl-2,4,6-heptatrienoic acid (0.30 g, 0.8 mmol) and the mixture was stirred at room temperature for 3-4 h. The reaction was cooled to 0° C. and treated over a 10 min period with a solution of O,N-bis(trimethylsilyl)-4-aminophenol (0.6 g, 2.4 mmol) in DMF (5 mL). Once the addition was complete stirring was continued for 1 h and then it was poured into 5% aqueous KF (10 mL) and stirred a further 1 h. The aqueous mixture was extracted with ether, purified by HPLC using 35% EtOAc/hexanes as eluent to give N-(4-hydroxyphenyl)-(2E,4E,6Z)-7-(3,5-dibromophenyl)-3,7-dimethyl-2,4,6-heptatrienamide.
Reaction SMILES: Cl[C:2]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:3]=1[C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=O.[NH2:17][C:18]([NH2:20])=[S:19]>C(O)C>[NH2:20][C:18]1[S:19][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:4]([C:3]2[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][CH:2]=2)[N:17]=1
Reactant: CCOC(=O)CC(=O)c1ccc(Cl)cc1Cl
Reactant: NC(N)=S
Solvent: CCO
Product: CCOC(=O)c1sc(N)nc1-c1ccc(Cl)cc1
Yield: 75.2 %

Procedure:
To a cold (5° C.) vigorously stirred mixture of 121.87 g (0.936 mole) of ethyl acetoacetate, 314 ml. of benzene and 626 ml. of water was added 41.25 ml. of 33% sodium hydroxide. To the above mixture was added simultaneously, in two dropping funnels, 177.0 g (1.01 mole) of p-chlorobenzoyl chloride and 188.8 ml. of 33% sodium hydroxide in 2 hours. The reaction mixture became pasty. The reaction mixture was heated at 35° C. for 1 hour, cooled and filtered to give 170.0 g of sodium salt of ethyl 2-benzoylacetoacetate. Part (150 g) of this salt was added to a mixture of 39.0 g (0.729 mole) of ammonium chloride and 78 ml. of concentrated ammonium hydroxide in 780 ml. of water. The mixture was stirred at 40°-50° C. for 3 hours and cooled in an ice bath. The precipitate was filtered to give 115.5 g of yellow solid which was Kugelrohr distilled to give 76.0 g (38% based on ethyl acetoacetate) of crude ethyl p-chlorobenzoylacetate. A mixture of 40.0 g (0.175 mole) of crude ethyl p-chlorobenzoylacetate, 24.2 g (0.18 mole) of sulfuryl chloride and some chloroform was held at reflux for 6 hours, cooled and concentrated to give 49.0 g of crude ethyl 2-chloro-p-chlorobenzoylacetate. A mixture of 46.0 g (0.174 mole) of crude ethyl 2-chloro-p-chlorobenzoylacetate, 13.25 g (0.174 mole) of thiourea, and 174 ml. of ethanol was held at reflux for 2 hours and cooled. The precipitate was filtered and neutralized with saturated sodium bicarbonate. The insoluble material was filtered to give 37.0 g (80%) of ethyl 2-amino-4-p-chlorophenyl-5-thiazolecarboxylate, m.p. 198°-200° C.
Reaction SMILES: CO[C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([CH3:16])([CH3:15])[C:13](=[O:17])[N:12]([C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([C:26]([F:29])([F:28])[F:27])[CH:19]=3)[C:11]2=[S:30])=[CH:6][CH:5]=1.[CH3:32][NH2:33]>>[C:24]([C:21]1[CH:22]=[CH:23][C:18]([N:12]2[C:13](=[O:17])[C:14]([CH3:15])([CH3:16])[N:10]([C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH:33][CH3:32])=[O:31])=[CH:5][CH:6]=3)[C:11]2=[S:30])=[CH:19][C:20]=1[C:26]([F:29])([F:28])[F:27])#[N:25]
Reactant: COC(=O)c1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C2(C)C)cc1
Reactant: CN
Product: CNC(=O)c1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C2(C)C)cc1
Reaction time: 15 h
Yield: 51 %

Procedure:
A mixture of 4-[3-(4-cyano-3-trifluoromethylphenyl)-5,5 -dimethyl-4-oxo-2-thioxo-imidazolidin-1-yl]benzoic acid methyl ester (49c) (0.02 g, 0.0435 mmol) and methylamine (2 ml distilled from its 40% aqueous solution) was kept at −20° C. for 15 hours. After evaporation of the methylamine, the mixture was chromatographed (dichloromethane:acetone, 80:20) to yield 4-[3-(4-cyano-3-trifluoromethylphenyl)-5,5-dimethyl-4-oxo-2-thioxo-imidazolidin-1-yl]-N-methylbenzamide (49d) [RD153](0.01 g, 0.0224, 51%), the structure of which is illustrated in Formula 20. The ester 4-[3-(4-cyano-3-trifluoromethylphenyl)-5,5-dimethyl-4-oxo-2-thioxo-imidazolidin -1-yl]benzoic acid methyl ester (49c) (0.08 g, 0.0179 mmol, 41%) was also recovered.
Reaction SMILES: [CH2:1]([S:3][C:4]1[N:8]=[CH:7][NH:6][N:5]=1)[CH3:2].[CH2:9]([N:13]([CH2:17][CH2:18][CH3:19])[C:14](Cl)=[O:15])[CH2:10][CH2:11][CH3:12].O1CCCC1>C(N(CC)CC)C>[CH2:9]([N:13]([CH2:17][CH2:18][CH3:19])[C:14]([N:6]1[CH:7]=[N:8][C:4]([S:3][CH2:1][CH3:2])=[N:5]1)=[O:15])[CH2:10][CH2:11][CH3:12]
Reactant: CCCCN(CCC)C(=O)Cl
Reactant: CCSc1nc[nH]n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCN(CCC)C(=O)n1cnc(SCC)n1

Procedure:
A mixture of 5.16 g. 3-ethylthio-1,2,4-triazole, 7.8 g. N-n-butyl-N-propylcarbamoyl chloride, 35 ml. dry tetrahydrofuran and 8 ml. dry triethylamine was refluxed under anhydrous conditions for 24 hours. The reaction mixture was worked up as described in Example 1 to give a residual oil. This oil was distilled under reduced pressure to give 1-(N-n-butyl-N-propylcarbamoyl)-3-ethylthio-1,2,4-triazole, b.p. 127° C./0.2 mm. (91.2% 1-isomer by GLC assay). Elemental analysis satisfactory.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH2:6][CH:7]=O)[CH2:3][CH:4]=O.S([O-])([O-])(=O)=O.[Mg+2].[C:16]1([NH:22][C:23]([NH2:25])=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][C:2]1([CH3:9])[CH:6]=[CH:7][N:25]([C:23]([NH:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:24])[CH:4]=[CH:3]1
Reactant: CC(C)(CC=O)CC=O
Reactant: NC(=O)Nc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)C=CN(C(=O)Nc2ccccc2)C=C1
Reaction time: 0.67 h
Yield: 100.1 %

Procedure:
A mixture of 4.57 g (0.036 mole) of 3,3-dimethylglutaraldehyde, 0.20 g (0.001 mole) of p-toluenesulfonic acid monohydrate and 8.64 g (0.072 mole) of anhydrous magnesium sulfate in 300 ml of dry THF was heated to reflux under nitrogen. 4.89 g (0.036 mole) of phenylurea in 125 ml of dry THF was added over a period of 1 hour. Refluxing was continued for an additional 40 minutes before the reaction mixture was filtered and the filtrate evaporated in vacuo to yield 8.23 g of a brown oil. The crude product was purified by silica gel column chromatography on 410 g of CC-7 silica gel eluting with a 7.5% ethyl acetate/hexane solution. The eluate was evaporated in vacuo to yield 4.74 g of the title compound, a white solid, mp 128°-130° C.
Reaction SMILES: Br[C:2]1[NH:22][C:5]2=[N:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[CH:13]=3)[N:9]=[C:4]2[CH:3]=1.[CH3:23][N:24]([CH3:37])[C:25]([C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][C:32]=1[F:33])=[O:26]>>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([CH:17]=[C:16]([O:18][CH3:19])[CH:15]=1)[CH2:11][CH2:10][C:8]1[N:9]=[C:4]2[CH:3]=[C:2]([C:29]3[CH:30]=[CH:31][C:32]([F:33])=[C:27]([CH:28]=3)[C:25]([N:24]([CH3:37])[CH3:23])=[O:26])[NH:22][C:5]2=[N:6][CH:7]=1
Reactant: CN(C)C(=O)c1cc(B(O)O)ccc1F
Reactant: COc1cc(CCc2cnc3[nH]c(Br)cc3n2)cc(OC)c1
Product: COc1cc(CCc2cnc3[nH]c(-c4ccc(F)c(C(=O)N(C)C)c4)cc3n2)cc(OC)c1

Procedure:
The compound was prepared by using procedure analogous to those described for the synthesis of Example 53, Step 2 starting from 6-bromo-2-[2-(3,5-dimethoxyphenyl)ethyl]-5H-pyrrolo[2,3-b]pyrazine and 3-(dimethylcarbamoyl)-4-fluorophenylboronic acid (from Combi-Blocks). LCMS calculated for C25H26FN4O3 (M+H)+: m/z=449.2. Found 449.1.