Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(OCC)OCC)C.[CH:17]([C@H:20]1[CH2:24][O:23][C:22](=[O:25])[N:21]1[C:26]1[CH:31]=[CH:30][N:29]=[C:28]([NH:32][C@@H:33]([CH3:38])[C:34]([NH:36][NH2:37])=[O:35])[N:27]=1)([CH3:19])[CH3:18].C(OCC)(=O)C>CCCCCCC>[CH:17]([C@H:20]1[CH2:24][O:23][C:22](=[O:25])[N:21]1[C:26]1[CH:31]=[CH:30][N:29]=[C:28]([NH:32][C@H:33]([C:34]2[O:35][C:4]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:37][N:36]=2)[CH3:38])[N:27]=1)([CH3:19])[CH3:18]
Reactant: CC(C)[C@H]1COC(=O)N1c1ccnc(N[C@@H](C)C(=O)NN)n1
Reactant: CCOC(OCC)(OCC)c1ccccc1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CC(C)[C@H]1COC(=O)N1c1ccnc(N[C@@H](C)c2nnc(-c3ccccc3)o2)n1
Yield: 17.9 %

Procedure:
A solution of (triethoxymethyl)benzene (360 mg, 1.6 mmol, 5.0 equiv. in 5 mL of benzene and 0.5 mL of glacial AcOH) was added to (S)-2-((4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-yl)amino)propanehydrazide (99 mg, 0.30 mmol, 1.0 equiv.), the reaction mixture was stirred at reflux for 1.5 hours, the solvent was removed to yield the crude product. Silica gel column chromatography (ethyl acetate in heptane 10 to 90%) to yield (S)-4-isopropyl-3-(2-(((S)-1-(5-phenyl-1,3,4-oxadiazol-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one (21.2 mg, white solid) in 15.9% yield. HRMS(B) m/z 395.1820, (M+H)+, RT=2.42 min
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:12]=[C:11]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:10]=1.Br[CH2:28][CH2:29][OH:30].[OH-].[Na+].Cl>CN(C)C=O>[OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:28][CH2:29][OH:30])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:12]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:14]=1
Reactant: OCCBr
Reactant: Oc1ccc(-c2nc(-c3ccccc3)nc(-c3ccccc3)n2)c(O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: OCCOc1ccc(-c2nc(-c3ccccc3)nc(-c3ccccc3)n2)c(O)c1
Yield: 79.9 %

Procedure:
To 17.0 g (0.05 mol) of the resulting 2-(2,4-dihydroxyphenyl)-4,6-diphenyl-s-triazine were added 94.8 g (0.75 mol) of 2-bromoethanol and 85 g of dimethylformamide, and 29.2 g (0.35 mol) of a 48% aqueous solution of sodium hydroxide was added thereto dropwise at 85° C. The mixture was allowed to react at 85° C. for 10 hours, followed by cooling. The reaction mixture was neutralized with concentrated hydrochloric acid, and the precipitate was collected by filtration, washed with water, and dried to give 15.4 g (80%) of 2-hydroxy-4-(2-hydroxyethyloxy)phenyl-4,6-diphenyl-s-triazine (hereinafter referred to as HETr). To 15 g (0.039 mol) of the resulting HETr were added 6.8 g (0.047 mol) of octylic acid, 45 g of xylene, and 0.6 g of p-toluenesulfonic acid, and the mixture was heated under reflux at 140° C. for 10 hours. The reaction mixture was washed with water and recrystallized from a 1:3 mixed solvent of xylene and methanol to give 16.9 g (85%) of a pale yellow solid having a melting point of 109° C.
Reaction SMILES: [Br:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([NH:13][C:14]([C:16]1[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[O:18][C:17]=1[CH2:25][CH2:26][CH2:27][CH3:28])=[O:15])=[CH:7]2.Br[CH2:30][C:31]#[N:32].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[C:11]([O:12][CH2:30][C:31]#[N:32])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([NH:13][C:14]([C:16]1[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[O:18][C:17]=1[CH2:25][CH2:26][CH2:27][CH3:28])=[O:15])=[CH:7]2
Reactant: CCCCc1oc2ccccc2c1C(=O)Nc1ccc2c(Br)c(O)ccc2c1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCc1oc2ccccc2c1C(=O)Nc1ccc2c(Br)c(OCC#N)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.2 %

Procedure:
A mixture of 2-butyl-benzofuran-3-carboxylic acid (5-bromo-6-hydroxy-naphthalen-2-yl)-amide (351 mg, 0.801 mmol), prepared in the previous step, bromoacetonitrile (67 μL, 0.962 mmol) and potassium carbonate (559 mg, 4.05 mmol) in 15 mL of DMF was stirred under nitrogen at room temperature for 19 h (overnight). The reaction was partitioned between ethyl acetate and water. The organic layer was separated, washed five times with water, dried (MgSO4) and the solvent removed under reduced pressure to give 2-butyl-benzofuran-3-carboxylic acid (5-bromo-6-cyanomethoxy-naphthalen-2-yl)-amide (364 mg, 95%) as a yellow solid, mp 155-159° C.
Reaction SMILES: [CH3:1][C:2]([CH3:15])([O:4][C:5]([N:7]1[CH2:12][CH2:11][C:10](=[CH2:13])[CH:9](O)[CH2:8]1)=[O:6])[CH3:3].S(Cl)([Cl:18])=O.C([O-])(O)=O.[Na+]>C1C=CC=CC=1>[CH3:1][C:2]([CH3:15])([O:4][C:5]([N:7]1[CH2:12][CH2:11][C:10]([CH2:13][Cl:18])=[CH:9][CH2:8]1)=[O:6])[CH3:3]
Reactant: C=C1CCN(C(=O)OC(C)(C)C)CC1O
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)N1CC=C(CCl)CC1
Temperature: 60 °C
Yield: 76.4 %

Procedure:
The intermediate obtained from Step A (400 mg, 1.88 mmole) was dissolved in 10 mL benzene and thionyl chloride (165 ml, 2.26 mmole) was added and heated to 60° C. for 25 minutes. The resulting mixture was poured into NaHCO3 (aq.) and extracted with ether. The ether layer was dried over magnesium sulfate and concentrated to give title compound (333 mg, 77%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12]Br)=[CH:10][CH:9]=1.[NH2:16][C:17]1[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=1[C:19]([O:21][CH3:22])=[O:20]>C(C(C)=O)C>[F:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][NH:16][C:17]2[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=2[C:19]([O:21][CH3:22])=[O:20])=[CH:10][CH:9]=1
Reactant: COC(=O)c1ccccc1N
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)c1ccccc1NCc1ccc(F)cc1
Temperature: 25 °C
Yield: 85 %

Procedure:
A suspension of 77 g of potassium carbonate in a mixture of 100 mL of methyl ethyl ketone, 50 g of 4-fluorobenzyl bromide and 26 mL of the methyl 2-aminobenzoate was refluxed for 8 h, cooled to room temperature, filtered and concentrated. Filtration on 600 mL of silica gel and washing with 10% ethyl acetate in hexane afforded the desired material as a yellow oil (41 g, 85% purity). This material was used as such for the next step.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:24])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=1[CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Cl[CH2:35][O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:24])[C@H:15]([C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=1[CH3:23])[CH2:35][O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(Br)ccc1CC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: ClCOCc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Br)ccc1[C@H](COCc1ccccc1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
To a solution of 16C (2.0 g, 5.15 mmol) in CH2Cl2 (20 ml) was added TiCl4 (6.18 ml, 6.18 mmol) at 0° C. to form a yellow solution. DIEA (1.080 ml, 6.18 mmol) was added at 0° C. to form a blue solution. The mixture was stirred at 0° C. for 1 h. Benzyl chloromethyl ether (1.428 ml, 10.30 mmol) was added and stirring was continued for 2 h at 0° C. at which point the blue turn to brownish red solution. The reaction was quenched with water, diluted with EtOAc. The aqueous layer was extracted with EtOAc. The combined organic extracts were washed with sat. NaHCO3 and brine, dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography (0-50% ethyl acetate/hexanes). The fractions containing the product was combined, concentrated to give 16D (2.4 g, 4.72 mmol, 92% yield) as a semi solid. 1H NMR (400 MHz, chloroform-d) δ ppm 2.41 (d, J=6.05 Hz, 3H) 2.78-2.93 (m, 1H) 3.30 (d, J=13.19 Hz, 1H) 3.43-3.57 (m, 1H) 4.01-4.23 (m, 3H) 4.46-4.81 (m, 3H) 5.36-5.53 (m, 1H) 7.01-7.16 (m, 1H) 7.18-7.41 (m, 12H).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[C:9]([NH:11][C:12](=[O:25])[C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=2)[N:8]2[N:26]=[C:27]([CH3:29])[CH:28]=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4].C1C(=O)N([Cl:37])C(=O)C1.O>C(Cl)(Cl)Cl>[CH2:1]([C:5]1[CH:10]=[C:9]([NH:11][C:12](=[O:25])[C:13]2[CH:14]=[C:15]([O:23][CH3:24])[C:16]([O:21][CH3:22])=[C:17]([O:19][CH3:20])[CH:18]=2)[N:8]2[N:26]=[C:27]([CH3:29])[C:28]([Cl:37])=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc(NC(=O)c2cc(OC)c(OC)c(OC)c2)n2nc(C)cc2n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCCCc1cc(NC(=O)c2cc(OC)c(OC)c(OC)c2)n2nc(C)c(Cl)c2n1

Procedure:
5-n-Butyl-2-methyl-7-(3,4,5-trimethoxybenzoyl-amino) pyrazolo[1,5-a]pyrimidine (the compound of Example 53; 0.78 g) was dissolved in 10 ml of chloroform. After addition of 0.28 g of NCS, the mixture was refluxed with heating for 1 hour and allowed to cool. After addition of some water, the reaction mixture was extracted with chloroform. The organic layer was collected, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate:n-hexane=1:2) and recrystallized from ethanol-n-hexane to provide 0.61 g of the object compound as colorless crystals. Table 3 shows the structure and melting point of the compound obtained.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][C:13](=[O:15])[NH:12][N:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[OH-:16].[Na+]>ClCCl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][C:13](=[O:15])[N:12]([CH2:1][C:4]3[CH:9]=[CH:8][C:7]([C:10]([O:14][CH3:13])=[O:16])=[CH:6][CH:5]=3)[N:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: [OH-]
Reactant: CC(C)c1ccc(-c2n[nH]c(=O)o2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1ccc(Cn2nc(-c3ccc(C(C)C)cc3)oc2=O)cc1
Yield: 184.5 %

Procedure:
5-(4-Isopropylphenyl)-1,3,4-oxadiazol-2(3H)-one (0.41 g, 2.0 mmol) is dissolved in dichloromethane (5 mL) and stirred vigorously with methyl 4-bromomethylbenoate (0.50 g, 2.2 mmol) in the presence of sodium hydroxide (1.25 N, 1.76 mL, 2.2 mmol) and tetra-n-butylammonium bromide (0.07 g, 0.022 mmol) at room temperature overnight. The solvent is removed in vacuum, and the residue is treated with water. The precipitate is collected by filtration, washed with hexanes thoroughly and dried in the air to provide methyl 4-{[5-(4-isopropylphenyl)-2-oxo-1,3,4-oxadiazol-3(2H)-yl]methyl}benzoate (0.65 g, 93%). (ES+): m/e 353.
Reaction SMILES: CON(C)[C:4]([CH2:6][C@@H:7]1[CH2:11][C:10]([F:13])([F:12])[CH2:9][N:8]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:5].[CH3:22][C:23]([CH3:27])=[CH:24][Mg]Br>C1COCC1>[F:13][C:10]1([F:12])[CH2:9][N:8]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[C@H:7]([CH2:6][C:4](=[O:5])[CH:22]=[C:23]([CH3:27])[CH3:24])[CH2:11]1
Reactant: CC(C)=C[Mg]Br
Reactant: CON(C)C(=O)C[C@@H]1CC(F)(F)CN1C(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)=CC(=O)C[C@@H]1CC(F)(F)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.5 %

Procedure:
To a THF (23 ml) solution of (R)-tert-butyl 2-((N-methoxy-N-methylcarbamoyl)methyl)-4,4-difluoropyrrolidine-1-carboxylate (1.4 g, 4.54 mmol) over ice bath, 2-methyl-1-propenylmagnesium bromide solution (0.5 M in THF, 45 ml, 22.7 mmol) was added dropwise over 1 hour. Remove ice bath, stifling was continued for another 3 hours. The reaction was quenched with 1N HCl (aq., 30 ml) at 0° C., and was stirred at room temperature for 30 minutes. Two layers were separated, aqueous layer was extracted with EtOAc (25 ml×2), organic layers were combined, dried (Na2SO4), filtered, solvent was removed in vacuo. Product was purified by silica gel chromatography (Hexane/EtOAc, linear gradient from 100:0 to 80:20). Compound (R)-tert-butyl 4,4-difluoro-2-(4-methyl-2-oxopent-3-enyl)pyrrolidine-1-carboxylate was obtained as a light yellow oil: 1.10 g (79.5% yield).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[O:8])[CH2:3]1.[CH3:20][S:21](Cl)(=[O:23])=[O:22].C(N(CC)CC)C>C(Cl)Cl>[CH3:20][S:21]([O:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[O:8])[CH2:3]1)(=[O:23])=[O:22]
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)N1CC[C@H](O)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)O[C@H]1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 103.2 %

Procedure:
To a solution of (3S)-3-hydroxy-1-(p-nitrobenzyloxycarbonyl)pyrrolidine (4.00 g, 15.0 mmol) (obtained as described in Reference Example 53(2)) in methylene chloride (120 ml) were added methanesulfonyl chloride (1.28 ml, 16.5 mmol) and triethylamine (2.31 ml, 16.5 mmol) in an ice bath. After stirring the mixture in the ice bath for 10 minutes, the mixture was stirred at room temperature for 2.5 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (1:2)→ethyl acetate as the eluant to afford (3S)-3-methanesulfonyloxy-1-(p-nitrobenzyloxycarbonyl)pyrrolidine (5.33 g, yield 100%) as a colorless and transparent syrup.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:22]=1.O.C1(C)C(S(O)(=O)=O)=CC=CC=1.[NH2:35][C:36]1[CH:49]=[CH:48][C:39]([C:40]([NH:42][CH2:43][CH2:44][N:45]([CH3:47])[CH3:46])=[O:41])=[CH:38][CH:37]=1>C(O)(C)C>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:35][C:36]4[CH:49]=[CH:48][C:39]([C:40]([NH:42][CH2:43][CH2:44][N:45]([CH3:46])[CH3:47])=[O:41])=[CH:38][CH:37]=4)=[N:22][C:6]2=3)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CN(C)CCNC(=O)c1ccc(N)cc1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCCC2)c2nc(Cl)ncc21
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: O
Solvent: CC(C)O
Product: CN(C)CCNC(=O)c1ccc(Nc2ncc3c(n2)N(C2CCCCC2)CC(F)(F)C(=O)N3C)cc1
Yield: 66.8 %

Procedure:
A mixture of 0.0562 g (0.18 mmole) 2-chloro-9-cyclohexyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-246), 0.0514 g (0.27 mmole) of toluenesulfonic acid monohydrate, 0.0373 g (0.18 mmole) of 4-amino-N-(2-dimethylamino-ethyl)-benzamide and 1 mL of isopropanol was heated in a sealed vessel at 140 degrees for 15.5 hours, cooled and concentrated under reduced pressure. The residue taken up in ethyl acetate and washed successively with 50 mL of saturated aqueous sodium bicarbonate, 50 mL of water, 50 mL of brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with acetonitrile-methanol-triethylamine (80:20:1) to give 0.0603 g of 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(2-dimethylamino-ethyl)-benzamide (I-264)
Reaction SMILES: [Cl:1][C:2]1[C:3](OS(O)(=O)=O)=[C:4]2[C:9](=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[NH:8][C:7](=[O:16])[C:6]([C:17](=[O:20])[CH2:18][CH3:19])=[C:5]2C.[Cl:27][C:28](=[CH2:31])[CH2:29][NH2:30]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]([F:14])([F:13])[F:15])[CH:11]=1)[NH:8][C:7](=[O:16])[C:6]([C:17](=[O:20])[CH2:18][CH3:19])=[C:5]2[NH:30][CH2:29][C:28]([Cl:27])=[CH2:31]
Reactant: CCC(=O)c1c(C)c2c(OS(=O)(=O)O)c(Cl)cc(C(F)(F)F)c2[nH]c1=O
Reactant: C=C(Cl)CN
Product: C=C(Cl)CNc1c(C(=O)CC)c(=O)[nH]c2c(C(F)(F)F)cc(Cl)cc12
Yield: 71 %

Procedure:
6- Chloro-4-methylsulfoxy-3-propionyl-8-trifluoromethyl-2-quinolinone (365 mg, 1 mmol) and 2-chloroallylamine (92 mg, 1 mmol) were used and the reaction was carried out as in the above process of example 1 to obtain the desired product (279 mg, yield: 71%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:17][CH2:16]1)=[CH:11][C:10](Br)=[CH:9][CH:8]=2)(=[O:3])[CH3:2].[Cl:30][C:31]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[C:33]([F:46])[C:32]=1[OH:47]>>[C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:17][CH2:16]1)=[CH:11][C:10]([C:35]1[CH:34]=[C:33]([F:46])[C:32]([OH:47])=[C:31]([Cl:30])[CH:36]=1)=[CH:9][CH:8]=2)(=[O:3])[CH3:2]
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Product: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1

Procedure:
Following general procedure D, tert-butyl (trans-4-((3-acetyl-6-bromoquinolin-4-yl)amino)cyclohexyl)carbamate (46 mg, 0.10 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (41 mg, 0.15 mmol) to afford the desired product (38 mg, 72%) as a light brown solid. ESI MS m/z 528 [C28H31ClFN3O4+H]+
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:8]=[C:9]([C:11](=[O:13])[CH3:12])[CH:10]=1)[NH2:7])(=[O:3])[CH3:2].Cl[C:15]1[N:23]=[CH:22][N:21]=[C:20]2[C:16]=1[NH:17][CH:18]=[N:19]2.Cl.[OH-].[K+]>O>[C:1]([C:4]1[CH:5]=[C:6]([NH:7][C:15]2[N:23]=[CH:22][N:21]=[C:20]3[C:16]=2[NH:17][CH:18]=[N:19]3)[CH:8]=[C:9]([C:11](=[O:13])[CH3:12])[CH:10]=1)(=[O:3])[CH3:2]
Reactant: Clc1ncnc2nc[nH]c12
Reactant: CC(=O)c1cc(N)cc(C(C)=O)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(=O)c1cc(Nc2ncnc3nc[nH]c23)cc(C(C)=O)c1
Reaction time: 0.17 h
Yield: 90.4 %

Procedure:
Compound No. 16: A suspension of 3,5-diacetylaniline (0.531 g) in water (10 mL) was treated with 6-chloropurine (0.464 g) and concentrated HCl (0.25 mL) and heated at reflux for 30 min. After cooling the mixture was treated with 6 mL of aqueous 1N KOH. The mixture was stirred for 10 min and the solid was filtered out, washed with water, and dried, to give 0.80 g of 6-[(3,5-diacetylphenyl)amino]purine, mp dec 340°-350° C.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][C:5]#[N:6].N[NH:9][C:10]([NH2:12])=[S:11].C(=O)([O-])[O-].[K+].[K+]>FC(F)(F)C(O)=O.O>[CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][C:5]1[S:11][C:10]([NH2:12])=[N:9][N:6]=1
Reactant: CN(C)CCC#N
Reactant: NNC(N)=S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CCc1nnc(N)s1
Temperature: 25 °C
Yield: 32.8 %

Procedure:
A solution of 2.00 ml (17.7 mmol) of 3-(dimethylamino)propanenitrile and 1.70 g (18.6 mmol) of thiosemicarbazide in trifluoroacetic acid (5 ml) was heated at 80° C. for 6 hr. The reaction solution was cooled to room temperature and was then diluted with water. The diluted solution was rendered weakly basic by the addition of a 10% aqueous potassium carbonate solution. The solution was extracted with chloroform, and the extract was dried over anhydrous sodium sulfate. The filtrate was concentrated, and the residue was washed with diethyl ether-ethyl acetate to give 1.00 g (yield 33%) of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][OH:7])([O-:3])=[O:2].C1C=CC=CC=1.[CH2:18]([S:34](Cl)(=[O:36])=[O:35])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>C(N(CC)CC)C>[CH2:18]([S:34]([O:7][CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:36])=[O:35])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: O=[N+]([O-])c1ccccc1CO
Reactant: CCCCCCCCCCCCCCCCS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCCCCCCCCCCCCCCCS(=O)(=O)OCc1ccccc1[N+](=O)[O-]
Reaction time: 4 h

Procedure:
To a stirred solution of 7.65 g (0.05 mol) of 2-nitrobenzyl alcohol in 75 ml of benzene containing 5.05 g (0.05 mol) of triethylamine was added 16.25 g (0.05 mol of hexadecanesulfonyl chloride. The mixture was stirred an additional four hours. The mixture was evaporated to dryness in vacuo and the solid taken up into a mixture of ether and water. The ether layer was separated and dried over MgSO4. Evaporation of the ether gave a solid which was crystallized from absolute ethanol (yield 14.3 g, m.p. 63°-65° C.).
Reaction SMILES: [F:1][C:2]([F:18])([C:9]([F:17])([F:16])[C:10]([F:15])([F:14])[CH:11]([F:13])[F:12])[CH2:3][CH:4]([C:7]#[N:8])[C:5]#[N:6].I[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[F:1][C:2]([F:18])([C:9]([F:16])([F:17])[C:10]([F:14])([F:15])[CH:11]([F:13])[F:12])[CH2:3][C:4]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])([C:7]#[N:8])[C:5]#[N:6]
Reactant: CCCCCI
Reactant: N#CC(C#N)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCCCCC(C#N)(C#N)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.4 %

Procedure:
1.4 g of 2-(2,2,3,3,4,4,5,5-octafluoropentyl)malononitrile and 1.0 g of iodopentane were dissolved in 10 ml of dimethyl sulfoxide, 0.70 g of potassium carbonate was added, and the mixture was stirred at room temperature for 3 hours. Thereafter, dilute hydrochloric acid was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed successively with water and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.90 g of 2-(2,2,3,3,4,4,5,5-octafluoropentyl)-2-pentylmalononitrile (hereinafter, referred to as the present compound (51)).
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[N:8]=[N:7][C:6]([C:9]([O:11]CCCC)=O)=[CH:5][CH:4]=1>CO>[Cl:2][C:3]1[N:8]=[N:7][C:6]([C:9]([NH2:1])=[O:11])=[CH:5][CH:4]=1
Reactant: CCCCOC(=O)c1ccc(Cl)nn1
Reactant: N
Solvent: CO
Product: NC(=O)c1ccc(Cl)nn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.5 %

Procedure:
Excess gaseous ammonia was added to an ice bath cooled solution of n-butyl 6-chloropyridazine-3-carboxylate (40 g) in methanol (280 ml). The mixture was stirred at ambient temperature for 4 hours and the resulting residue filtered off, washed with methanol (20 ml) and dried to give 6-chloropyridazine-3-carboxamide (28.05 g, 95.5% yield), mpt. 243°-5° C.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][NH:5][CH3:6].[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][N:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][N:23]=3)[C:20]=2[OH:21])=[C:12]([CH3:31])[CH:11]=1)#[N:9].C(O)=O>>[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][N:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26]([N:5]([CH2:4][CH2:3][N:2]([CH3:7])[CH3:1])[CH3:6])=[O:28])=[CH:24][N:23]=3)[C:20]=2[OH:21])=[C:12]([CH3:31])[CH:11]=1)#[N:9]
Reactant: CNCCN(C)C
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Solvent: O=CO
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)N(C)CCN(C)C)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 284 using N1,N1,N2-trimethylethane-1,2-diamine and 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid to give a formic acid salt (61 mg, 0.135 mmol, 72.3%) as an off-white solid. MS: 405 (M+H). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.42 (s, 3H) 2.53-2.70 (m, 4H) 3.02 (s, 3H) 3.11-3.80 (m, 6H) 7.53 (d, J=8.3 Hz, 1H) 7.58 (s, 1H) 7.89-7.99 (m, 2H) 8.10 (br. s., 1H) 8.50 (m, 2H).