Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]=O)[CH:14]=1.N1CCCCC1>C(O)(=O)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[CH:19][C:15]3[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=3)[C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: O=C1CCCc2ccc(Br)cc21
Reactant: O=Cc1cccnc1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: O=C1C(=Cc2cccnc2)CCc2ccc(Br)cc21
Reaction time: 18 h
Yield: 81.6 %

Procedure:
A mixture of 7-bromo-1-tetralone (11.25 g), pyridin-3-carboxaldehyde (5.35 g), acetic acid (5 ml) and piperidine (6 ml) was heated on a stream bath for 6 hours and then allowed to stand for 18 hours. The volatile material was evaporated and the residue was dissolved in ethyl acetate. The solution was extracted several times with dilute hydrochloric acid and the combined extracts were made just alkaline with dilute sodium hydroxide solution. The solid was filtered off, washed with water and crystallised from methanol to give 7-bromo-2-(3-pyridylmethylene)-1-tetralone (12.8 g), m.p. 124°-125°.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[OH:19][CH2:20][C:21]1[CH:42]=[CH:41][C:24]([C:25]([O:27][N:28]=[C:29]([C:31]2[CH:36]=[CH:35][C:34]([CH2:37][CH:38]([CH3:40])[CH3:39])=[CH:33][CH:32]=2)[NH2:30])=O)=[CH:23][CH:22]=1.C1COCC1>C(OCC)(=O)C>[CH2:37]([C:34]1[CH:35]=[CH:36][C:31]([C:29]2[N:30]=[C:25]([C:24]3[CH:41]=[CH:42][C:21]([CH2:20][OH:19])=[CH:22][CH:23]=3)[O:27][N:28]=2)=[CH:32][CH:33]=1)[CH:38]([CH3:40])[CH3:39]
Reactant: CC(C)Cc1ccc(C(N)=NOC(=O)c2ccc(CO)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)Cc1ccc(-c2noc(-c3ccc(CO)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 45.8 %

Procedure:
Tetrabutylammonium fluoride (1.0 M solution in THF, 10 mL) was added to a solution of N′-{[4-(hydroxymethyl)benzoyl]oxy}-4-isobutylbenzenecarboximidamide (3.07 g, 9.42 mmol) and THF (50 mL) and stirred at room temperature for 20 hours. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (1.33 g, 46% yield) as a crude solid.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:24]=[CH:23][C:22]([C:25]([O:27]C)=[O:26])=[CH:21][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[S:13][CH2:12][CH2:11]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl.O>O1CCCC1.CO>[CH:1]1([C:7]2[C:8]3[CH:24]=[CH:23][C:22]([C:25]([OH:27])=[O:26])=[CH:21][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[S:13][CH2:12][CH2:11]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCSc1ccccc1-3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCSc1ccccc1-3
Temperature: 25 °C
Reaction time: 13 h
Yield: 88.5 %

Procedure:
To a solution of methyl 12-cyclohexyl-6,7-dihydro-5-thia-7a-azadibenzo[a,e]azulene-9-carboxylate (186 mg, 0.470 mmol) in tetrahydrofuran (2 ml) and methanol (2 ml) was added 4N aqueous sodium hydroxide solution (2 ml), and the mixture was stirred at room temperature for 13 hr. 2N hydrochloric acid and water were added to the reaction mixture. The precipitated solid was collected by filtration and dried in vacuo to give 12-cyclohexyl-6,7-dihydro-5-thia-7a-azadibenzo[a,e]azulene-9-carboxylic acid (157 mg, yield 87.7%).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:12]1[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=1)[N:6]2[CH3:11].[CH3:18][C:19]1[CH:20]=[C:21]([CH:38]=[CH:39][CH:40]=1)[C:22]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)=[O:23].C(N(CC)CC)C>C(O)(C)C>[CH3:18][C:19]1[CH:20]=[C:21]([CH:38]=[CH:39][CH:40]=1)[C:22]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[CH2:33][CH2:34][N:35]([C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[C:5]([C:12]2[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=2)[N:6]3[CH3:11])[CH2:36][CH2:37]1)=[O:23]
Reactant: Cc1cccc(C(=O)NCc2ccccc2N2CCNCC2)c1
Reactant: Cn1cc(-c2nc3c(Cl)ncnc3n2C)cn1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: Cc1cccc(C(=O)NCc2ccccc2N2CCN(c3ncnc4c3nc(-c3cnn(C)c3)n4C)CC2)c1
Temperature: 25 °C
Yield: 50.3 %

Procedure:
A stirred solution of 6-chloro-9-methyl-8-(1-methyl-1H-pyrazol-4-yl)-9H-purine (30 mg, 0.12 mmol), 3-methyl-N-(2-(piperazin-1-yl)benzyl)benzamide (46.4 mg, 0.15 mmol), and triethylamine (84.0 uL, 0.60 mmol) in isopropyl alcohol (2.0 mL) were heated to 80° C. for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The product was purified by preparatory HPLC (reverse-phase, acetonitrile/water with 0.1% formic acid) to give 31.5 mg (50% yield) of the title compound.
Reaction SMILES: [C:1]1([C:7]2[CH2:16][C:15](=[O:17])[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:18]([OH:20])=[O:19])[CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:21](O)[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.S(=O)(=O)(O)O.CCOCC>C(O)C.O>[C:1]1([C:7]2[CH2:16][C:15](=[O:17])[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:18]([O:20][CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[O:19])[CH:13]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCCc1ccccc1
Reactant: O=C(O)c1ccc2c(c1)C(=O)CC(c1ccccc1)=N2
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOCC
Solvent: CCO
Product: O=C(OCCc1ccccc1)c1ccc2c(c1)C(=O)CC(c1ccccc1)=N2

Procedure:
2-Phenyl-4-quinolone-6-carboxylic acid (1.5 grams) obtained in Example 2 is stirred for fifteen hours at 110° C. with 50 ml of phenethyl alcohol and 1 ml of concentrated sulfuric acid. After cooling, 1.5 liters of ether is added to the mixture, the mixture is cooled with ice, oil which separates out therefrom is taken out. The mixture is then dissolved in 5 ml of ethanol. Then 3 ml of water is added thereto, and crystal which separates out therefrom are collected by filtration, and washed with a 5% sodium bicarbonate solution, then with water, and finally with methanol, and dried to give 0.9 gram of phenethyl 2-phenyl-4-quinolone-6-carboxylate, colorless powder, melting point 282°to 284° C.
Reaction SMILES: O[O:2][S:3]([O-:5])=O.[K+].[C:7]1([CH:13]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:14][NH:15][C:16]2[N:24]=[C:23](SC)[N:22]=[C:21]3[C:17]=2[N:18]=[CH:19][N:20]3[CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][O:28]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:39](=O)([O-])O.[Na+]>O.CC(C)=O>[C:33]1([CH:13]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:14][NH:15][C:16]2[N:24]=[C:23]([S:3]([CH3:39])(=[O:5])=[O:2])[N:22]=[C:21]3[C:17]=2[N:18]=[CH:19][N:20]3[CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][O:28]2)[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: O=S([O-])OO
Reactant: O=C([O-])O
Reactant: CSc1nc(NCC(c2ccccc2)c2ccccc2)c2ncn(C3CCCCO3)c2n1
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CS(=O)(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn(C3CCCCO3)c2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 75.7 %

Procedure:
A solution of Oxone (trade mark) (potassium peroxymonosulphate) (44 g, 71.7 mmol) in water (200 ml) was added dropwise over 2 hours to a solution of N-(2,2-diphenylethyl)-2-(methylsulfanyl)-9-tetrahydro-2H-pyran-2-yl-9H-purin-6-amine (Preparation 3) (25 g, 56.2 mmol) and sodium hydrogen carbonate (20 g, 238 mmol) in acetone (1000 ml) and water (250 ml). The resulting mixture was stirred at room temperature for 24 hours, filtered and the residue washed with acetone. The acetone was removed from the filtrate under reduced pressure and the resulting aqueous residue extracted with ethyl acetate and then dichloromethane. The combined organic layers were washed with brine, dried with anhydrous magnesium sulphate, filtered and evaporated under reduced pressure. The residue was triturated with diethyl ether, filtered, washed with diethyl ether and pentane and then dried to afford the title compound as a white solid (20.32 g).
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Li]CCCC.[CH3:29][C:30]1([CH3:37])[CH2:35][CH2:34][C:33](=O)[CH2:32][CH2:31]1>C1COCC1.[Cl-].[NH4+].C(OCC)(=O)C>[CH3:29][C:30]1([CH3:37])[CH2:35][CH2:34][C:33](=[CH:2][O:3][CH3:4])[CH2:32][CH2:31]1
Reactant: CC1(C)CCC(=O)CC1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC=C1CCC(C)(C)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a mixture of methoxymethyl triphenylphosphonium chloride (35.5 g, 0.104 mol) in THF (400 mL) at 0° C. was added n-BuLi (33.1 mL of a 2.8M solution in hexanes; 0.095 mol). The mixture was stirred at 0° C. for 30 min., cooled to −78° C. and a solution of 4,4-dimethyl cyclohexanone (10.0 g, 0.079 mol) in THF (100 mL) was added, dropwise. After 1 hr at −78° C. the mixture was slowly warmed to 0° C., diluted with satd ammonium chloride (400 mL) and ethyl acetate (100 mL) and stirred at room temperature for 48 hr. Layers were separated and the aqueous phase was extracted with ethyl acetate. Combined organics were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was triturated with hexanes, solids were removed by filtration and the filtrated was concentrated in vacuo. The residue was dissolved in dichloromethane (40 mL), PS-TsNHNH2 (8 g; ca. 3.7 mmol/g) and acetic acid (2 drops) were added and the mixture was stirred at room temperature for 24 hr. Resin was removed by filtration and washed (CH2Cl2, MeOH, CH2Cl2). Combined filtrate/washings were concentrated in vacuo, affording (4,4-dimethyl cyclohexylidene)methyl methyl ether as an oil.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH2:11][N:12]3[C:16]4[CH:17]=[C:18]([O:23][CH3:24])[C:19]([O:21][CH3:22])=[CH:20][C:15]=4[N:14]=[CH:13]3)[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH:25]1([CH2:31][NH2:32])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[CH:25]1([CH2:31][NH:32][C:2]2[S:3][C:4]3[CH:10]=[C:9]([CH2:11][N:12]4[C:16]5[CH:17]=[C:18]([O:23][CH3:24])[C:19]([O:21][CH3:22])=[CH:20][C:15]=5[N:14]=[CH:13]4)[CH:8]=[CH:7][C:5]=3[N:6]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: NCC1CCCCC1
Reactant: COc1cc2ncn(Cc3ccc4nc(Br)sc4c3)c2cc1OC
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncn(Cc3ccc4nc(NCC5CCCCC5)sc4c3)c2cc1OC
Temperature: 100 °C
Yield: 33.1 %

Procedure:
A stirred mixture of 2-bromo-6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazole (70 mg, 0.173 mmol) from Example 2, cyclohexanemethylamine (39 mg, 0.346 mmol) and DIEA (67 mg, 0.519 mmol) in anhydrous DMA (1.5 mL) was heated at 100° C. for 2.5 h. After cooling to rt, the mixture was purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C-18 column as the stationary phase to afford N-(cyclohexylmethyl)-6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-amine (25 mg, 33%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.15 (br s, 1H), 8.04 (t, J=5.4 Hz, 1H), 7.63 (s, 1H), 7.31 (m, 1H), 7.12-7.24 (m, 3H), 5.40 (s, 2H), 3.76 (s, 6H), 3.17 (t, J=6.1 Hz, 2H), 1.49-1.78 (m, 6H), 1.07-1.27 (m, 3H), 0.84-1.02 (m, 2H). LCMS (ESI) m/z 437 (M+H)+.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([C:20]#[N:21])[CH:18]=4)[N:13]([CH3:22])[CH:12]=3)[CH2:7][CH2:6]2)[O:4]CC1.C(=O)(O)[O-].[Na+]>O1CCCC1.Cl>[C:20]([C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH3:22])[CH:12]=[C:11]2[CH:8]1[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH2:7]1)#[N:21]
Reactant: Cn1cc(C2CCC3(CC2)OCCO3)c2cc(C#N)ccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1cc(C2CCC(=O)CC2)c2cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 44 %

Procedure:
A solution of 3-(1,4-dioxa-spiro[4,5]dec-8-yl)-5-cyano-1-methyl-indole (5.5 g) in 150 ml (1:1) tetrahydrofuran-hydrochloric acid (1N) was allowed to stir at room temperature for 16 hours, followed by the addition of 4.49 g sodium bicarbonate. The mixture was extracted with methylene chloride (3×100 ml), washed with brine (3×150 ml). The organic layer was dried over anhydrous magnesium sulfate and filtered. The solvent was removed to afford a light brown solid which was boiled in ethyl acetate-hexanes (1:1). The mixture was cooled to room temperature and solid was collected and dried under vacuum to afford 2.06 g of the title compound as a solid: mp 150-152° C.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.Cl[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].[CH:20]1([Mg]Cl)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C1COCC1>[CH:20]1([CH:7]2[CH2:8][C:3](=[O:2])[CH:4]=[CH:5][N:6]2[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: COc1ccncc1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Cl[Mg]C1CCCCC1
Solvent: C1CCOC1
Product: O=C1C=CN(C(=O)OCc2ccccc2)C(C2CCCCC2)C1
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
4-methoxypyridine (17.56 ml, 173 mmol) in THF (577 ml) at −30° C. was added benzyl chloroformate (24.70 ml, 173 mmol) dropwise. Stirred at −30° C. for 30 minutes and then added cyclohexylmagnesium chloride (200 ml, 260 mmol). Stirred for 30 minutes at −30° C. and quenched with 1N HCl. Extracted 3 times with diethyl ether. The combined organic fractions were combined, dried (Naz SO4), filtered and the solvent was evaporated under reduced pressure. Purified on silica gel 30% EtOAc/Hexanes affording 35.25 g.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[N:7]=[CH:6][NH:5][N:4]=1.Cl[C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][N:12]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:17][C:16]1[C:11]([N:5]2[CH:6]=[N:7][C:3]([C:2]([F:9])([F:8])[F:1])=[N:4]2)=[N:12][CH:13]=[CH:14][CH:15]=1
Reactant: FC(F)(F)c1nc[nH]n1
Reactant: Clc1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1ncn(-c2ncccc2Cl)n1
Temperature: 120 °C
Reaction time: 27 h
Yield: 11.3 %

Procedure:
A mixture of 3.5 g of 3-trifluoromethyl-1H-1,2,4-triazole, 3.8 g of 2,3-dichloropyridine, 6.0 g of potassium carbonate and 30 ml of N,N-dimethylformamide was stirred at 120° C. for 27 hours. After the reaction mixture was allowed to cool to room temperature, water was poured and the mixture was extracted with ethyl acetate two times. The organic layers were combined, washed successively with water and an aqueous saturated sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 0.72 g of 3-chloro-2-(3-trifluoromethyl-1H-1,2,4-triazol-1-yl)pyridine of the formula:
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[CH:9]=[C:10](Br)[C:5]=2[NH:4][N:3]=1.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[NH2:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[CH:9]=[C:10]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[F:20])[C:5]=2[NH:4][N:3]=1
Reactant: OB(O)c1ccccc1F
Reactant: Nc1n[nH]c2c(Br)cn(-c3ccccc3Cl)c(=O)c12
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: COCCOC
Solvent: O
Product: Nc1n[nH]c2c(-c3ccccc3F)cn(-c3ccccc3Cl)c(=O)c12
Temperature: 90 °C
Reaction time: 8 h
Yield: 24.4 %

Procedure:
A mixture of 3-amino-7-bromo-5-(2-chlorophenyl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one obtained in Step B of Example 18 (150 mg), 2-fluorophenylboronic acid (93 mg), tetrakis(triphenylphosphine)palladium(0) (51 mg), potassium carbonate (122 mg), 1,2-dimethoxyethane (5.0 mL) and water (0.5 mL) was stirred overnight at 90° C. under argon atmosphere. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, methanol/ethyl acetate) to give the title compound (38.3 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:32][C:33]([OH:36])([CH3:35])[CH3:34])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20](B4OC(C)(C)C(C)(C)O4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[C:38]1[N:43]=[C:42]([C:44]#[N:45])[CH:41]=[N:40][CH:39]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:32][C:33]([OH:36])([CH3:34])[CH3:35])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:18]=[CH:19][C:20]([C:38]4[N:43]=[C:42]([C:44]#[N:45])[CH:41]=[N:40][CH:39]=4)=[CH:21][CH:22]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: N#Cc1cncc(Cl)n1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccc(F)cc2)OC1=O
Product: C[C@@H](c1ccc(-c2cncc(C#N)n2)cc1)N1CC[C@](CC(C)(C)O)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from (S)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 6-chloropyrazine-2-carbonitrile following a procedure analogous to that described in Example 459 Step 4. LC-MS Method 1 tR=1.61 min, m/z=497 (M+Na); 1H NMR (CDCl3) 8.98 (d, 2H), 7.87 (d, 2H), 7.26 (m, 1H), 7.18 (m, 3H), 7.04 (t, 2H), 5.72 (q, 1H), 2.99 (m, 1H), 1.59 (d, 3H), 1.14 (d, 6H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][NH:12][CH3:13])=[CH:8][C:6]=2[N:7]=1.[CH3:20][N:21]1[CH2:26][CH2:25][CH:24]([CH:27]=O)[CH2:23][CH2:22]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][N:12]([CH3:13])[CH2:27][CH:24]3[CH2:23][CH2:22][N:21]([CH3:20])[CH2:26][CH2:25]3)=[CH:8][C:6]=2[N:7]=1
Reactant: CN1CCC(C=O)CC1
Reactant: CNCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Product: CN1CCC(CN(C)Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1

Procedure:
Reaction between (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methyl-amine and 1-methylpiperidine-4-carbaldehyde using standard reductive amination conditions yielded (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methyl-(1-methyl-piperidin-4-ylmethyl)-amine, which was reacted with 2-aminopyrimidine-5-boronic acid in General Procedure A. Acid/base work-up and trituration with ether yielded 335. 400 MHz 1H NMR CDCl3: 9.30 (s, 2H), 7.26 (s, 1H), 5.30 (br s, 2H, NH2), 4.04 (t, 4H, J4.5), 3.90 (t, 4H, J4.5), 3.80 (s, 2H), 2.87 (d, 2H, J11.5), 2.33 (d, 2H, J7.1), 2.30 (s, 3H), 2.28 (s, 3H), 1.93 (t, 2H, J11.7), 1.83 (d, 2H, J13.1), 1.57-1.51 (m, 1H), 1.32-1.22 (m, 2H). LC-MS (m+1)=469.35
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[N:14][C:15]([C:18]([O:20]CC)=O)=[C:16]([OH:17])[C:11]=3[O:10][N:9]=2)=[CH:4][CH:3]=1.[NH2:23][CH2:24][C:25]([OH:27])=[O:26].[O-]CC.[Na+].Cl>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[CH:13]=[N:14][C:15]([C:18]([NH:23][CH2:24][C:25]([OH:27])=[O:26])=[O:20])=[C:16]([OH:17])[C:11]=3[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1ncc2c(-c3ccc(F)cc3)noc2c1O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)CNC(=O)c1ncc2c(-c3ccc(F)cc3)noc2c1O
Temperature: 25 °C
Yield: 57.9 %

Procedure:
Ethyl 3-(4-fluorophenyl)-7-hydroxyisoxazolo[4,5-c]pyridine-6-carboxylate (0.11 g, 0.36 mmol) was dissolved in 10 mL of DMF. Glycine (0.55 g, 7.28 mmol) and sodium ethoxide (0.37 g, 5.46 mmol) were added and the mixture was refluxed for 14 h. The mixture was cooled to room temperature and diluted with 60 mL of water. Concentrated hydrochloric acid was added dropwise until pH was 3. The resulting suspension was filtered and the solid was dried under vacuum to give 69 mg of the title compound. MS: (+) m/z 332.00 (M+1).
Reaction SMILES: [N+](C1C=CC(C([O:10][CH2:11][C@@H:12]2[C@@H:17]([CH2:18][O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:16]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[C@@H:15]([O:34][C@@H:35]([C:37]3[CH:42]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:40]=[C:39]([C:47]([F:50])([F:49])[F:48])[CH:38]=3)[CH3:36])[O:14][CH2:13]2)=O)=CC=1)([O-])=O.[OH-].[Na+]>CO.C(O)C.CCOC(C)=O>[CH2:20]([O:19][CH2:18][C@H:17]1[C@H:16]([C:27]2[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=2)[C@@H:15]([O:34][C@@H:35]([C:37]2[CH:42]=[C:41]([C:43]([F:46])([F:44])[F:45])[CH:40]=[C:39]([C:47]([F:50])([F:48])[F:49])[CH:38]=2)[CH3:36])[O:14][CH2:13][C@@H:12]1[CH2:11][OH:10])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: C[C@@H](O[C@H]1OC[C@H](COC(=O)c2ccc([N+](=O)[O-])cc2)[C@@H](COCc2ccccc2)[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Solvent: CCOC(C)=O
Product: C[C@@H](O[C@H]1OC[C@H](CO)[C@@H](COCc2ccccc2)[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 45 °C

Procedure:
The intermediate from example 1 step H (4.57 g, 6.22 mmol) was dissolved in a 1:1 mixture of methanol/ethanol (60 mL) followed by the addition of 5 N NaOH (12.0 mL). The vessel was heated to 45° C. for 1 hr. The reaction mixture was cooled to ambient temperature and diluted with 400 mL EtOAc. The EtOAc solution was washed twice with 2 N NaOH, dried over Na2SO4, filtered through a fritted funnel and concentrated in vacuo. The crude residue was purified on silica gel and eluted a combination of EtOAc/hexanes (1-30% EtOAc/hexanes linear gradient). This provided the title compound. 1H-NMR (CDCl3): δ 1.38 (d, 3H, J=6.5 Hz), 1,90-2.22 (m, 2H), 2.34-2.42 (m, 1H), 2.72 (dd, 1H, J=8.5, 10.5 Hz), 3.12-3.18 (m, 1H), 3.24-3.31 (m, 1H), 3.46-3.56 (m, 2H), 3.55-3.62 (m, 1H), 3.65-3.74 (m, 1H), 4.09 (dd, 1H, J=4.0, 11.5 Hz), 4.21 (d, 1H, J=8.5 Hz), 4.31 (s, 21H), 4.96 (q, 1H, J=6.5 Hz), 6.90-7.02 (m, 4H), 7.14-7.22 (m, 4H), 7.25-7.34 (m, 3H), 7.69 (s, 1H) ppm.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:8]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)=[N:7][C:6]=1[CH:26]1[CH2:28][CH2:27]1)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH:26]1([C:6]2[C:5]([CH2:4][OH:3])=[C:10]([C:11]([F:12])([F:14])[F:13])[CH:9]=[C:8]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:23])[F:24])=[CH:17][CH:16]=3)[N:7]=2)[CH2:28][CH2:27]1
Reactant: CCOC(=O)c1c(C(F)(F)F)cc(-c2ccc(OC(F)(F)F)cc2)nc1C1CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCc1c(C(F)(F)F)cc(-c2ccc(OC(F)(F)F)cc2)nc1C1CC1

Procedure:
In analogy to the procedure described in example 16 c], 2-cyclopropyl-6-(4-trifluoromethoxy-phenyl)-4-trifluoromethyl-nicotinic acid ethyl ester was treated with lithium aluminium hydride to give the title compound as colorless crystals.
Reaction SMILES: CC1[O:11][C:10]2[C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3NCCC=2N=1.S(Cl)(Cl)=O.Cl.[F:21][C:22]([F:31])([F:30])[C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1.C([N:34]([CH2:37][CH3:38])CC)C>C1(C)C=CC=CC=1.ClCCl>[C:37]([C:38]1[CH:13]=[CH:12][C:9]([C:10]([NH:27][C:26]2[CH:28]=[CH:29][C:23]([C:22]([F:30])([F:31])[F:21])=[CH:24][CH:25]=2)=[O:11])=[CH:8][C:15]=1[CH3:14])#[N:34]
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: Cc1nc2c(o1)-c1ccccc1NCC2
Reactant: CCN(CC)CC
Agent: Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: Cc1cc(C(=O)Nc2ccc(C(F)(F)F)cc2)ccc1C#N
Temperature: 25 °C
Reaction time: 48 h
Yield: 80.7 %

Procedure:
A mixture of 4-cyano-3-methyl-benzoic acid from Example E6 (750 mg, 4.6 mmol) and thionyl chloride (1.02 ml, 14.0 mmol) in toluene (40 ml) was heated at reflux for 2 h. After cooling at room temperature, solvents were re-moved in vacuo and azeotroped with toluene. The residue was redissolved in dichloromethane (25 ml) then 4-trifluoromethylaniline hydrochloride (1.11 g, 5.6 mmol) in dichloromethane (5 ml) and triethylamine (1.95 ml, 14.0 mmol) was added. The mixture was stirred at room temperature for 2 days, washed with brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel through an isolute (eluant; 20% EtOAc:80% cyclohexane) to yield the title compound (1.13 g, 80%).