Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]([OH:13])=O)=[CH:5][CH:4]=1.[CH3:14][CH:15]([CH3:22])[CH2:16][CH:17]([NH2:21])[CH2:18][CH2:19][CH3:20]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]=[CH:10][C:11]([NH:21][CH:17]([CH2:18][CH2:19][CH3:20])[CH2:16][CH:15]([CH3:22])[CH3:14])=[O:13])=[CH:7][CH:8]=1
Reactant: CCCC(N)CC(C)C
Reactant: COc1ccc(C=CC(=O)O)cc1
Product: CCCC(CC(C)C)NC(=O)C=Cc1ccc(OC)cc1
Yield: 65 %

Procedure:
Prepared in a similar manner to example 4 using 3-(4-methoxy-phenyl)-acrylic acid and 3-methyl-1-propyl-butylamine (example 2a). Yield: 65%. 1H NMR (500 MHz, CDCl3): δ 0.90-0.95 (m, 9H), 1.30-1.39 (m, 5H), 1.49-1.50 (m, 1H), 1.64-1.67 (m, 1H), 3.82 (s, 3H), 4.17-4.18 (m, 1H), 5.18-5.20 (d, 1H), 6.22-6.26 (d, 1H), 6.86-6.89 (d, 2H), 7.42-7.45 (d, 2H), 7.56-7.59 (d, 1H). MS (M+H, 290.1).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[C:9]1[C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[C:27]([O:32]C)[CH:28]=2)[CH:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br.[OH-].[Na+]>C(Cl)Cl>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[C:9]1[C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[C:27]([OH:32])[CH:28]=2)[CH:23]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCc1c(-c2ccc3cc(OC)ccc3c2)n(Cc2ccccc2)c2ccccc12
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCCCCc1c(-c2ccc3cc(O)ccc3c2)n(Cc2ccccc2)c2ccccc12
Temperature: 0 °C
Yield: 81.7 %

Procedure:
1-benzyl-2-(6-methoxynaphthalen-2-yl)-3-pentyl-1H-indole (210.0 g, 0.484 mol) was dissolved in methylene chloride (620 mL), the solution was cooled to 0° C., and 1.0 M boron tribromide in methylene chloride (363 mL, 0.363 mole) was added to the solution over 30 minutes. The reaction mixture was stirred for twelve hours at 20° C. to 25° C., at which point in time HPLC analysis indicated that no starting material was present. The solution was cooled to 0° C.-10° C. and a 5% aqueous sodium hydroxide solution (462 mL, 0.605 mole) was added to the solution over 30 minutes. The mixture was stirred for 30 minutes and the layers were separated. The organic layer was washed with 15% aqueous sodium chloride (170 mL) and passed through a silica gel pad (210 g). The pad was washed with two 250 mL portions of methylene chloride. The combined filtrate was concentrated by atmospheric distillation to a volume of 500 mL, toluene (260 mL) was added, and distillation was resumed until the volume reached 500 mL. The temperature increased to 75° C.-80° C. during the distillation. Heptane (1040 mL) was then added while maintaining the temperature. The mixture was cooled to 55° C. over 50 min. Approximately 10 grams of the solution were withdrawn from the reactor, subjected to low-temperature crystallization, and returned to the solution as a seeding suspension at 55° C. Crystallization began at 43° C.-45° C. The suspension was cooled to 0° C.-5° C. and stirred at that temperature for two hours. The solid was filtered, washed with 500 mL heptane, and dried at 50° C./50 torr for 24 hours to produce 166.0 g (81.7% yield) of the title compound as an off-white solid with 99.89% ar. HPLC purity.
Reaction SMILES: Cl.[F:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[NH:10][C:9]2=[O:19])=[CH:5][C:4]=1[C:22]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)=[O:23].[C:30]([O:34][C:35]([N:37]1[CH2:41][CH2:40][CH2:39][C@:38]1([CH3:45])[C:42](O)=[O:43])=[O:36])([CH3:33])([CH3:32])[CH3:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(#N)C>[O:19]=[C:9]1[NH:10][C:11](=[O:18])[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:8]1[CH2:7][C:6]1[CH:20]=[CH:21][C:3]([F:2])=[C:4]([CH:5]=1)[C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:42]([C@@:38]2([CH3:45])[CH2:39][CH2:40][CH2:41][N:37]2[C:35]([O:34][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:36])=[O:43])[CH2:26][CH2:25]1)=[O:23]
Reactant: O=C(c1cc(Cn2c(=O)[nH]c(=O)c3ccccc32)ccc1F)N1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCC[C@]1(C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC[C@]1(C)C(=O)N1CCN(C(=O)c2cc(Cn3c(=O)[nH]c(=O)c4ccccc43)ccc2F)CC1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
1-(4-fluoro-3-(piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione hydrochloric acid (30b, 37 mg) was suspended in acetonitrile (1.5 mL), treated with (R)-1-(tert-butoxycarbonyl)-2-methylpyrrolidine-2-carboxylic acid (40a, 30 mg), HATU (47 mg), and Et3N (0.5 mL) sequentially. The reaction mixture was stirred at ambient temperature (25° C.) for 19 hrs. The reaction mixture was directly purified by flash chromatography with MeOH—CH2Cl2 (0-20% gradient elution) to afford the desired product, (R)-tert-butyl 2-(4-(5-((2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl)methyl)-2-fluorobenzoyl)piperazine-1-carbonyl)-2-methylpyrrolidine-1-carboxylate (40b) as the major fraction (colorless oil, 50 mg). MS (ESI): m/z=594 (M+H+)
Reaction SMILES: [Cl:1]/[CH:2]=[C:3]1/[C@:4]2([CH2:20][CH2:19][C@H:18]3[C@@H:9]([CH2:10][CH2:11][C:12]4[C@@H:17]3[CH2:16][CH2:15][C:14](=[O:21])[CH:13]=4)[C@@H:6]2[CH2:7][CH2:8]/1)[CH3:5].[OH:22]O.[OH-].[Na+]>CO.C(Cl)Cl>[Cl:1]/[CH:2]=[C:3]1/[C@:4]2([CH2:20][CH2:19][C@H:18]3[C@@H:9]([CH2:10][CH2:11][C:12]45[O:22][CH:13]4[C:14](=[O:21])[CH2:15][CH2:16][C@@H:17]53)[C@@H:6]2[CH2:7][CH2:8]/1)[CH3:5]
Reactant: OO
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC/C2=C\Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: C[C@]12CC[C@H]3[C@@H](CCC45OC4C(=O)CC[C@H]35)[C@@H]1CC/C2=C\Cl
Temperature: 0 °C

Procedure:
3.93 mmol (1.2 9) of E-17-chloromethylen-estr-4-en-3-one is dissolved in a mixture of 12 ml of methanol and 10 ml of methylene chloride under a cover gas (argon) and cooled to 0° C. 9.2 mmol (0.94 ml) of hydrogen peroxide (30%) and 1.65 mmol (0.4 ml) of sodium hydroxide solution (c=4 mol/l) are added in drops in succession to the cooled solution while being stirred. After dropwise addition is completed, the temperature is slowly increased to room temperature. After about 1.5 hours of reaction time, the mixture is added to ice water and extracted with methylene chloride. The combined extracts are dried on sodium sulfate and concentrated by evaporation. 1.1 g of a white, sticky foam is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[N:10][C:9]=1[N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(C(C)C)C(C)C)C.Cl.[NH2:44][C@@H:45]1[CH2:50][CH2:49][CH2:48][CH2:47][C@H:46]1[OH:51].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C.C(OCC)(=O)C>[OH:51][C@@H:46]1[CH2:47][CH2:48][CH2:49][CH2:50][C@H:45]1[NH:44][C:14]([C:12]1[CH:11]=[N:10][C:9]([N:17]2[CH2:18][CH2:19][CH2:20][CH2:21]2)=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[N:13]=1)=[O:16]
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: O=C(O)c1cnc(N2CCCC2)c(-c2ccccc2Cl)n1
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(N2CCCC2)c(-c2ccccc2Cl)n1
Reaction time: 72 h
Yield: 41.7 %

Procedure:
To a solution of 0.10 g 6-(2-chloro-phenyl)-5-pyrrolidin-1-yl-pyrazine-2-carboxylic acid in 3.0 ml of DMF is added at room temperature 0.082 g 1,1′-carbonyl-diimidazole, 0.22 ml N-ethyldiisopropylamine and 0.057 g (1R,2R)-2-amino-cyclohexanol hydrochloride and stirred for 72 hours. To the mixture is added citric acid 10% solution and ethyl acetate. The organic layer is washed with sodium bicarbonate 10% solution and sodium chloride saturated solution. The organic layer is separated and dried over sodium sulfate and evaporated at the rotary evaporator. The residue is purified by chromatography on silica gel with heptane/ethyl acetate 40/60 to yield 0.055 g of the title compound as white solid, MS (ISP) 401.3 (M+H)+.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[C:17]2[C:12](=[N:13][CH:14]=[N:15][C:16]=2[NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)=[C:21]([CH2:33][CH3:34])[CH:20]=2)[NH:11][N:10]=1)(=O)=O.[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[CH2:33]([C:21]1[CH:20]=[C:19]([NH:18][C:16]2[N:15]=[CH:14][N:13]=[C:12]3[NH:11][N:10]=[C:9]([O:8][CH2:7][CH2:6][N:39]4[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]4)[C:17]=23)[CH:24]=[CH:23][C:22]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)[CH3:34]
Reactant: CCc1cc(Nc2ncnc3[nH]nc(OCCOS(C)(=O)=O)c23)ccc1OCc1ccccn1
Reactant: CN1CCNCC1
Product: CCc1cc(Nc2ncnc3[nH]nc(OCCN4CCN(C)CC4)c23)ccc1OCc1ccccn1
Yield: 44 %

Procedure:
The procedure described in Example 55 was repeated using 2-[(4-{[3-ethyl-4-(pyridin-2-ylmethoxy)phenyl]amino}-1H-pyrazolo[3,4-d]pyrimidin-3-yl)oxy]ethyl methanesulfonate (prepared as described in Example 19) and N-methylpiperazine to give the title compound in 44% yield; NMR Spectrum: 1.20 (t, 3H), 2.10 (s, 3H), 2.20-2.35 (m, 4H), 2.40-2.55 (m, 4H), 2.65 (q, 2H), 2.77 (t, 2H), 4.40 (t, 2H), 5.20 (s, 2H), 7.01 (d, 1H), 7.34-7.40 (m, 2H), 7.48-7.54 (m, 2H), 7.85 (td, 1H), 8.23 (s, 1H), 8.26 (s, 1H), 8.59 (d, 1H); Mass Spectrum: 489 (MH+).
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([CH2:10][N:11]3[C:19]4[CH:18]=[CH:17][C:16]([F:20])=[C:15](C(O)=O)[C:14]=4[C:13]([CH3:24])=[N:12]3)[CH:7]=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.C1(P([N:39]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>CN(C=O)C.O>[CH:1]1([C:4]2[N:9]=[C:8]([CH2:10][N:11]3[C:19]4[CH:18]=[CH:17][C:16]([F:20])=[C:15]([NH2:39])[C:14]=4[C:13]([CH3:24])=[N:12]3)[CH:7]=[CH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: Cc1nn(Cc2cccc(C3CC3)n2)c2ccc(F)c(C(=O)O)c12
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nn(Cc2cccc(C3CC3)n2)c2ccc(F)c(N)c12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 57.3 %

Procedure:
1-((6-Cyclopropylpyridin-2-yl)methyl)-5-fluoro-3-methyl-1H-indazole-4-carboxylic acid (0.205 g, 0.630 mmol) was dissolved in 6 mL of DMF. To this was added diphenylphosphoryl azide (0.260 g, 0.945 mmol) and TEA (0.263 mL, 1.89 mmol) and the mixture was stirred at ambient temperature for 1.5 hours. Water (5 mL) was added and the mixture was warmed to 80° C. for 2 hours, then allowed to stir at ambient temperature for 16 hours. The reaction mixture was diluted with water and extracted twice with EtOAc. The combined organic extracts washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. Column chromatography (1:1 EtOAc:Hexanes) of the crude material afforded 0.107 g (57%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:19][C:20]([O:22]C)=[O:21])[CH:5]=[CH:6][C:7]=1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:12]=2[N:13]=1.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:19][C:20]([OH:22])=[O:21])[CH:5]=[CH:6][C:7]=1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: COC(=O)Cc1ccc(Nc2nc3ccc(C)cc3s2)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc2nc(Nc3ccc(CC(=O)O)cc3Cl)sc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 76.8 %

Procedure:
Methyl (3-chloro-4-(6-methyl-2-benzothiazolyl)aminophenyl)acetate (274 mg, 0.79 mmol) was dissolved in THF (5 ml). To the resulting solution was added 0.5N NaOH (5.0 ml, 2.50 mmol), followed by stirring at room temperature for 15 hours. The reaction mixture was poured in ice-1N HCR. The crystals thus precipitated were collected by filtration under reduced pressure, washed with water and dried under reduced pressure to give (3-chloro-4-(6-methyl-2-benzothiazolyl)aminophenyl)acetic acid (202 mg, 77%) as a pale yellow solid.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:12]=[C:11]([CH3:13])[C:10]([C:14](=[O:16])[CH3:15])=[C:9]([CH3:17])[CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br-:18].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(#N)C>[Br:18][CH2:15][C:14]([C:10]1[C:11]([CH3:13])=[CH:12][C:7]([O:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:8][C:9]=1[CH3:17])=[O:16]
Reactant: [Br-]
Reactant: CC(=O)c1c(C)cc(OC2CCCC2)cc1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Product: Cc1cc(OC2CCCC2)cc(C)c1C(=O)CBr
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.6 %

Procedure:
To a solution of 1-(4-(cyclopentyloxy)-2,6-dimethylphenyl)ethanone (4.60 g, 19.8 mmol) in acetonitrile (39.6 mL) was added tetrabutylammoniumtribromide (TBABr3, 10.5 g, 21.8 mmol). The reaction was stirred at room temperature overnight. The solution was concentrated under reduced pressure, added with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure to give 2-bromo-1-(4-(cyclopentyloxy)-2,6-dimethylphenyl)ethanone (6.2 g), which was used directly for the next step without further purification.
Reaction SMILES: Cl[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11])[CH3:3].[CH3:13][CH:14]([S-:16])[CH3:15].[Na+]>C(#N)C>[CH:14]([S:16][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11])[CH3:3])([CH3:15])[CH3:13]
Reactant: CC(C)[S-]
Reactant: CC(Cl)c1ccccc1[N+](=O)[O-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)SC(C)c1ccccc1[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 16 h
Yield: 63.2 %

Procedure:
In a 1 liter three-necked flask equipped with a stirrer, dropping funnel and thermometer, 63 g 1-(1-chlorethyl)-2-nitrobenzene (VIII-1) (purity 99.4%, 0.337 mols) in 20 ml acetonitrile are added dropwise at 30-40° C. to 34.8 g (0.354 mol) sodium 2-propanethiolate in 450 ml acetonitrile. The suspension is stirred at 40° C. for another 16 hours, then cooled, and the solvent is removed under vacuum. The residue remaining is dissolved in dichloromethane, washed, dried over sodium sulfate, and the solvent is removed under vacuum. The crude product is purified by column chromatography (silica gel, 29:1 hexane/acetone). 48 g (98.8% purity by HPLC, 62.4% theoretical yield) of 1-[1-(isopropylthio)ethyl]-2-nitrobenzene are obtained as a yellow oil [logP (pH 2.3)=3.89].
Reaction SMILES: [CH3:1][N:2]1[C:15]([C:16]([O:18]C)=O)=[C:14]([OH:20])[C:5]2[N:6]([CH3:13])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[S:3]1(=[O:22])=[O:21].[NH2:23][C:24]1[S:25][CH:26]=[C:27]([CH3:29])[N:28]=1>>[CH3:1][N:2]1[C:15]([C:16]([NH:23][C:24]2[S:25][CH:26]=[C:27]([CH3:29])[N:28]=2)=[O:18])=[C:14]([OH:20])[C:5]2[N:6]([CH3:13])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[S:3]1(=[O:22])=[O:21]
Reactant: Cc1csc(N)n1
Reactant: COC(=O)C1=C(O)c2c(c3ccccc3n2C)S(=O)(=O)N1C
Product: Cc1csc(NC(=O)C2=C(O)c3c(c4ccccc4n3C)S(=O)(=O)N2C)n1
Yield: 88 %

Procedure:
2,5-Dihydro-2,5-dimethyl-4-hydroxy-N-(4-methyl-2-thiazolyl)-1, 2-thiazino[5,6-b]indole-3-carboxamide-1,1-dioxide was prepared analogous to Example 1 from methyl 2,5-Dihydro-2,5-dimethyl-4-hydroxy-1,2-thiazino[5,6-b]indole-3-carboxylate 1,1-dioxide and 2-amino-4-methyl-thiazole with a yield of 88% of theory; M.p.: 270° C. (decomposition).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:22])=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:5]2[N:6]([N:8]=[C:9]([NH2:11])[N:10]=2)[CH:7]=1.[C:23](Cl)(=[O:25])[CH3:24].ClCC(NC1N=C2C(C3C=CC=C(C(F)(F)F)C=3)=C(C)C(C3N(C4C=CC(C#N)=CC=4)N=CC=3)=CN2N=1)=O>>[Br:1][C:2]1[C:3]([CH3:22])=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:5]2[N:6]([N:8]=[C:9]([NH:11][C:23](=[O:25])[CH3:24])[N:10]=2)[CH:7]=1
Reactant: Cc1c(Br)cn2nc(N)nc2c1-c1cccc(C(F)(F)F)c1
Reactant: CC(=O)Cl
Agent: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(NC(=O)CCl)nc2c1-c1cccc(C(F)(F)F)c1
Product: CC(=O)Nc1nc2c(-c3cccc(C(F)(F)F)c3)c(C)c(Br)cn2n1

Procedure:
The title compound was prepared from 6-bromo-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (Int. 2, 6.7 g, 18.06 mmol) and acetyl chloride (2.83 mL, 39.7 mmol) using a similar method to that employed for Intermediate 17 (5.65 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C@H:13]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14]1)[CH:6]=[CH:5]2.[F:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[F:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[C:7]([NH:12][C@H:13]2[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH2:15][CH2:14]2)[CH:6]=[CH:5]3)(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 6.4 %

Procedure:
(6-Amino-quinolin-2-yl)-(R)-indan-1-yl-amine (0.05 g, 0.18 mmol) and 4-fluoro-benzenesulfonyl chloride (0.035 g, 0.18 mmol) were dissolved in pyridine (1 mL). The reaction mixture was stirred for 16 h at ambient temperature. Saturated sodium bicarbonate solution was added then and the aqueous phase extracted with ethyl acetate (3×10 mL). The combined organic phases were dried over sodium sulfate, filtered and the filtrate was evaporated. The residual oil was subjected to column chromatography (silica gel, heptane, ethyl acetate; 9:1=>1:1) to yield the title compound as a brown solid (5 mg, 6%); MS 434.7 [(M+H)+].
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]2[C:8]([O:13][C:14]3[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=3)=[N:9][CH:10]=[CH:11][N:12]=2)[CH2:2]1.Cl[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1>C(=O)(O)[O-].[Na+]>[O:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]2[C:8]([O:13][C:14]3[CH:20]=[CH:19][C:17]([NH:18][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)=[CH:16][CH:15]=3)=[N:9][CH:10]=[CH:11][N:12]=2)[CH2:2]1
Reactant: Nc1ccc(Oc2nccnc2C2CCCOC2)cc1
Reactant: Clc1ccccn1
Agent: O=C([O-])O
Agent: [Na+]
Product: c1ccc(Nc2ccc(Oc3nccnc3C3CCCOC3)cc2)nc1
Temperature: 120 °C
Reaction time: 0.75 h

Procedure:
4-(3-(Tetrahydro-2H-pyran-3-yl)pyrazin-2-yloxy)aniline (0.10 g, 0.38 mmol) and 2-chloropyridine (0.072 mL, 0.76 mmol) were mixed together neat in a microwave tube. The tube was sealed and stirred at 120° C. for 45 min before being warmed to 160° C. and stirred for 2 h. The reaction mixture was cooled to room temperature, diluted with sat. sodium bicarbonate, and extracted with EtOAc (2×). The combined organic layers were washed with sat. sodium chloride, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting crude product was purified by silica gel chromatography to give N-(4-(3-(tetrahydro-2H-pyran-3-yl)pyrazin-2-yloxy)phenyl)pyridin-2-amine. MS (ESI, pos. ion) m/z: 349.1 (M+1). IC50 (uM) 0.021.
Reaction SMILES: [CH:1]([C:3](Cl)([CH3:10])[CH2:4][C:5]([CH3:9])(Cl)[C:6]#[N:7])=O.[ClH:12]>>[Cl:12][C:6]1[C:5]([CH3:9])=[CH:4][C:3]([CH3:10])=[CH:1][N:7]=1
Reactant: CC(Cl)(C#N)CC(C)(Cl)C=O
Reactant: Cl
Product: Cc1cnc(Cl)c(C)c1

Procedure:
19.4 g of the 4-formyl-2-methyl-2,4-dichlorovaleronitrile obtained in Example 7(a) are heated for 4 hours to 160°-170° C. while introducing a weak stream of dry HCl gas. After it has cooled, the dark melt is subjected to steam distillation. The distillate is extracted with diethyl ether and the extract is dried and evaporated to dryness in vacuo. The residual light brown oil is distilled, affording 7.36 g of 2-chloro-3,5-dimethylpyridine in the form of a light brown oil which boils at 110° C./2500 Pa.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)C#N)=[CH:4][CH:3]=1.C(C=C)=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[N:11][C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CSc1ccc(NC(C#N)c2ccc(Cl)cc2)cc1
Agent: C=CC=O
Product: CSc1ccc(N=Cc2ccc(Cl)cc2)cc1

Procedure:
Following a procedure similar to that described in Example 21(iii), but using α-(4-chlorophenyl)-α-(4-methylthioanilino)acetonitrile [prepared as described in step (ii) above] and acrolein as starting materials, the title compound was obtained as an orange-colored powder (yield 32%), melting at 203-205° C.
Reaction SMILES: [CH3:1]C1(C)CCCNC1=O.[CH3:10][C:11]1([CH3:18])[NH:16][C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1.[H-].[Na+].CI>C1COCC1>[CH3:1][N:16]1[C:11]([CH3:18])([CH3:10])[CH2:12][CH2:13][CH2:14][C:15]1=[O:17]
Reactant: CC1(C)CCCNC1=O
Reactant: CC1(C)CCCC(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CN1C(=O)CCCC1(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
To a solution of a 3 to 1 mixture of 3,3-dimethylpiperidin-2-one and 6,6-dimethylpiperidin-2-one (4.72 g, 37.1 mmol) in 60 ml of THF was added 60% sodium hydride suspension (1.93 g, 48.2 mmol). The grey reaction mixture was stirred at room temperature for 30 minutes. Then methyl iodide (3.02 ml, 48.2 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with water, and worked up with ethyl acetate/water. The orange oil was chromatographed over a prepacked 70 g silica column After elution with a 50% to 100% ethyl acetate in heptane gradient, the fractions containing the desired product were collected to yield 2.46 g (47%) of the title compound as a light yellow solid; and 0.91 g (17%) of isomeric 1,3,3-trimethyl-piperidin-2-one as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=O)=[C:7]([CH3:15])[CH:6]=1)=[O:4].[C:16]1([CH:23]=[CH:22][CH:21]=[C:19]([OH:20])[CH:18]=1)[OH:17]>>[OH:17][C:16]1[CH:18]=[C:19]([OH:20])[CH:21]=[CH:22][C:23]=1[C:12](=[O:14])[CH2:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][C:7]=1[CH3:15]
Reactant: COC(=O)c1ccc(CC(=O)O)c(C)c1
Reactant: Oc1cccc(O)c1
Product: COC(=O)c1ccc(CC(=O)c2ccc(O)cc2O)c(C)c1
Yield: 69.6 %

Procedure:
2-(4-(methoxycarbonyl)-2-methylphenyl)acetic acid (295 mg) was treated with resorcinol (190 mg) in BF3Et2O at 90° C. over night. After aqueous work-up with ethyl acetate and column purification, the desired product (296 mg) was isolated as an oil.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([CH2:9][CH:10]=O)=[CH:7][CH:6]=[CH:5][C:4]=1[C:12]1[S:16][C:15]([C:17]2[CH:18]=[CH:19][C:20]([O:25][CH:26]([CH3:28])[CH3:27])=[C:21]([CH:24]=2)[C:22]#[N:23])=[N:14][CH:13]=1)[CH3:2].[NH:29]1[CH2:36][CH2:35][CH2:34][C@H:30]1[C:31]([OH:33])=[O:32].C(O)(=O)C.C([BH3-])#N.[Na+]>>[C:22]([C:21]1[CH:24]=[C:17]([C:15]2[S:16][C:12]([C:4]3[C:3]([CH2:1][CH3:2])=[C:8]([CH2:9][CH2:10][N:29]4[CH2:36][CH2:35][CH2:34][C@H:30]4[C:31]([OH:33])=[O:32])[CH:7]=[CH:6][CH:5]=3)=[CH:13][N:14]=2)[CH:18]=[CH:19][C:20]=1[O:25][CH:26]([CH3:28])[CH3:27])#[N:23]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: CCc1c(CC=O)cccc1-c1cnc(-c2ccc(OC(C)C)c(C#N)c2)s1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CCc1c(CCN2CCC[C@H]2C(=O)O)cccc1-c1cnc(-c2ccc(OC(C)C)c(C#N)c2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 14.6 %

Procedure:
A solution of 5-{5-[2-ethyl-3-(2-oxoethyl)phenyl]-1,3-thiazol-2-yl}-2-[(1-methylethyl) oxy]benzonitrile (D76) (60 mg, 0.154 mmol), L-proline (35.4 mg, 0.307 mmol) and acetic acid (0.1 ml, 1.747 mmol) was stirred at room temperature for 15 min, then sodium cyanoborohydride (29.0 mg, 0.461 mmol) was added. The mixture was stirred at room temperature for 2 h. After concentration, the residue was partitioned between ethyl acetate and aqueous HCl (2M). The organic phase was washed with saturated brine, concentrated and purified by Mass Directed AutoPrep to afford 1-{2-[3-(2-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazol-5-yl)-2-ethylphenyl]ethyl}-L-proline (E88) (11 mg) as a TFA salt.