Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.N1C=CC=CC=1.Cl[C:15]([O:17][CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20])=[O:16].O>O1CCCC1>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:15](=[O:16])[O:17][CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20]
Reactant: Nc1ccccn1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1ccccn1)OCC(Cl)(Cl)Cl

Procedure:
To a solution of 2-aminopyridine (1.00 g, 10.6 mmol) and pyridine (1.01 ml, 12.7 mmol) in tetrahydrofuran (35 ml) was added, under ice-cooling, 2,2,2-trichloroethyl chloroformate (1.76 ml, 12.7 mmol), and the mixture was stirred at room temperature for 1 hour and half. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Hexane was poured to the residue, and 1.77 g (61.6%) of the desired product as a solid was separated by filtration.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:15](=[O:16])[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][NH:12]2)=[N:9][CH:10]=1.C(N(CC)C(C)C)(C)C.[CH3:32][C:33]([CH3:38])([CH3:37])[C:34]([Cl:36])=[O:35]>ClCCl>[ClH:36].[CH3:32][C:33]([CH3:38])([CH3:37])[C:34]([NH:3][CH2:4][C:5]1[CH:10]=[N:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][NH:12]2)=[CH:7][CH:6]=1)=[O:35]
Reactant: NCc1ccc(-n2[nH]cc(-c3cccnc3)c2=O)nc1
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)C(=O)NCc1ccc(-n2[nH]cc(-c3cccnc3)c2=O)nc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
100 mg (0.3 mmol) of the compound from Example 13 are suspended in 3 ml of dichloromethane. 152 mg (1.2 mmol) of N,N-diisopropylethylamine (Hünig base) are added, and the mixture is stirred at RT for 5 min. 43 mg (0.4 mmol) of 2,2-dimethylpropanoyl chloride are then added, and the mixture is stirred at RT for 16 h. The mixture is then concentrated on a rotary evaporator, the residue is taken up in 5 ml of dioxane and 1 ml 1 N aqueous sodium hydroxide solution is added. This mixture is then purified by preparativer HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% TFA to the water). The product-containing fractions are combined and concentrated on a rotary evaporator. The residue is dissolved in 1 N hydrochloric acid, and the solution is lyophilized. The solid is then stirred in tert-butyl methyl ether for 30 min, filtered off and dried under high vacuum.
Reaction SMILES: [CH:1]([C@@H:4]1[C:9]([O:10][CH3:11])=[N:8][CH2:7][C:6]([O:12][CH3:13])=[N:5]1)([CH3:3])[CH3:2].[Cl:14][CH2:15][Si:16]([CH2:19]Cl)([CH3:18])[CH3:17].C([Li])CCC.[Cl-].[NH4+]>C1COCC1>[Cl:14][CH2:15][Si:16]([CH2:19][C@H:7]1[C:6]([O:12][CH3:13])=[N:5][C@H:4]([CH:1]([CH3:3])[CH3:2])[C:9]([O:10][CH3:11])=[N:8]1)([CH3:18])[CH3:17]
Reactant: COC1=N[C@H](C(C)C)C(OC)=NC1
Reactant: C[Si](C)(CCl)CCl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC1=N[C@H](C(C)C)C(OC)=N[C@H]1C[Si](C)(C)CCl
Temperature: 25 °C
Yield: 43.2 %

Procedure:
To a solution of (R)-2-isopropyl-3,6-dimethoxy-2,5-dihydro-pyrazine (7.0 g, 38 mmol), bis(chloromethyl)dimethylsilane (6.0 g, 38 mmol) in THF (150 mL) was added n-butyl-lithium (20 mL, 50 mmol) at −65 to −75° C. dropwise. The mixture was allowed to gradually warm to RT overnight. An ammonium chloride solution at 0° C. was added and the reaction mixture was extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, concentrated, and purified by silica gel chromatography (2% EtOAc in petroleum ether) to give the title intermediate (5 g, 44% yield) as a clear oil 1H NMR: (MeOD, 400 MHz) δ (ppm): 4.15 (m, 1H), 3.99 (m, 1H), 3.72 (m, 6H), 2.95 (m, 2H), 2.30 (m, 1H), 1.45 (m, 1H), 1.08 (m, 4H), 0.75 (m, 3H), 0.26 (s, 6H).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][N:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][N:25]=2)[CH2:6][C@@H:5]1[CH3:32])(=[O:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:66][CH:67]([CH2:70][OH:71])[CH2:68][OH:69]>CN(C=O)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH:66][CH:67]([CH2:70][OH:71])[CH2:68][OH:69])=[O:19])=[CH:16][N:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][N:25]=2)[CH2:6][C@@H:5]1[CH3:32])(=[O:3])[CH3:2]
Reactant: NC(CO)CO
Reactant: CC(=O)N1c2ccc(-c3ccc(C(=O)O)cn3)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)NC(CO)CO)cn3)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Reaction time: 0.08 h
Yield: 24.67 %

Procedure:
To a flask charged with 6-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)nicotinic acid (for a preparation see Intermediate 7) (90 mg, 0.211 mmol) and HATU (96 mg, 0.253 mmol) was added DMF (3 mL) and the resulting mixture was treated with DIPEA (0.110 mL, 0.632 mmol). After stirring for 5 min, the mixture was treated with 2-aminopropane-1,3-diol (38.4 mg, 0.421 mmol). After stirring for 3 min, the solution was partitioned between EtOAc and saturated aqueous NaHCO3 solution and the layers were separated. The aqueous phase was extracted with EtOAc (×2) and the combined organic layers were washed with saturated aqueous NaHCO3 solution (×3), then dried over MgSO4 and concentrated in vacuo. The residue was purified by MDAP (HpH). The appropriate fractions were collected and concentrated in vacuo. The residue was subsequently dissolved in MeOH and dried (hydrophobic frit). The solvent was removed and the residue triturated in Et2O to give 6-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-N-(1,3-dihydroxypropan-2-yl)nicotinamide (26 mg, 0.052 mmol, 24.67% yield) as a white solid.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Li]CCCC.C(NC(C)C)(C)C.[F:21][C:22]([F:40])([F:39])[C:23]1[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:27]([Cl:34])[CH:26]=[C:25]([C:35]([F:38])([F:37])[F:36])[N:24]=1.Cl[C:42]([O:44][CH2:45][CH3:46])=[O:43]>COCCOC>[F:40][C:22]([F:21])([F:39])[C:23]1[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:27]([Cl:34])[C:26]([C:42]([O:44][CH2:45][CH3:46])=[O:43])=[C:25]([C:35]([F:36])([F:37])[F:38])[N:24]=1
Reactant: CCOC(=O)c1c(Cl)cc(C(F)(F)F)nc1C(F)(F)F
Reactant: CCOC(=O)Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: COCCOC
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)F)c(C(=O)OCC)c1Cl
Reaction time: 0.08 h
Yield: 30 %

Procedure:
To a cold (-78° C.) solution of LDA, from 0.0155 mol of n-BuLi, 0.0157 mol (2.2 ml) of diisopropylamine and 30 ml of dry DME was added a solution of 3.2 g (0.01 mol) of product of Example 9 in 5 ml of DME. The resulting purple solution was stirred for 5 minutes and treated with 4 ml of ethyl chloroformate. The mixture was stirred at -78° C. for 10 minutes, the cooling bath was removed, and the reaction mixture was stirred for an additional 30 minutes, then poured into water. The mixture was extracted with ether. The ether extract was washed with 50 ml of 3N HCl, dried, and concentrated. The residue was kugelrohr distilled at 53 Pa. The low bp distillate (pot temperature 50°-60° C.) was identified as ethyl N,N-diisopropylurethane. The higher bp distillate (pot temperature 100° C.) was 1.64 g of a solid which was recrystallized from hexane at low temperature to give 1.2 g (30%) of product; mp 76°-77° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.CCOCC.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH3:26])=[CH:21][CH:20]=1.CCN(CC)CC>[Cl-].[Cl-].[Zn+2].ClCCCl.CC(O)(C)C>[Cl:8][C:6]1[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=[C:2]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH:25]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH3:26])=[CH:21][CH:20]=2)[N:7]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(N)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(NC(=O)OC(C)(C)C)c1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
2,4-Dichloro-5-(trifluoromethyl)pyrimidine (1.93 g, 8.89 mmol) was stirred in a 1:1 t-BuOH:DCE mixture (200 mL) at room temperature. A 1.0 M ZnCl2 solution in Et2O (10.2 mL, 10.2 mmol) was added cautiously and the mixture was stirred at room temperature for 20 minutes. A 1:1 t-BuOH:DCE mixture (100 mL) was added followed by tert-butyl (1-(4-aminophenyl)ethyl)carbamate (2.00 g, 8.46 mmol) and Et3N (1.42 mL, 10.2 mmol). The mixture was stirred at room temperature overnight before the volatiles were evaporated in vacuo. EtOH (30 mL) was added, the suspension was sonicated for 1 minute before the solid was filtered, washed with EtOH (10 mL) and dried in vacuo to give the title compound A80 as a cream solid (3.2 g, 91%). LCMS-C: rt 4.88 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:17][O:16][C@H:15]([CH3:18])[C@H:14]1[CH2:13][S:12][C:11]([NH:19][C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[N:10]2.C(O)(C(F)(F)F)=O.S(=O)(=O)(O)O.C1C(=O)N([Br:47])C(=O)C1.[OH-].[Na+]>>[Br:47][C:5]1[C:6]([F:8])=[CH:7][C:2]([F:1])=[C:3]([C@:9]23[CH2:17][O:16][C@H:15]([CH3:18])[C@H:14]2[CH2:13][S:12][C:11]([NH:19][C:20](=[O:27])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[N:10]3)[CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: C[C@H]1OC[C@]2(c3ccc(F)cc3F)N=C(NC(=O)c3ccccc3)SC[C@H]12
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]1OC[C@]2(c3cc(Br)c(F)cc3F)N=C(NC(=O)c3ccccc3)SC[C@H]12
Temperature: 60 °C
Reaction time: 1 h

Procedure:
N-((4aS*,5R*,7aS*)-7a-(2,4-Difluorophenyl)-5-methyl-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)benzamide (95 mg, 0.24 mmol) was dissolved in TFA (218 μL, 2.93 mmol) and sulfuric acid (78.2 μl, 1.47 mmol). NBS (39 mg, 0.22 mmol) was added and the reaction was stirred at 60° C. for 1 hour. The reaction mixture was cooled to room temperature, neutralized with 2N NaOH and extracted with EtOAc (×3). The combined organics were dried and concentrated in vacuo. The residue was purified by column chromatography, eluting with 0-30% EtOAc in n-hexane to give the desired compound. (78 mg). 1H NMR (400 MHz, CDCl3) δ ppm: 8.05-8.10 (m, 2H), 7.52-7.62 (m, 2H), 7.44-7.51 (m, 2H), 6.95-7.04 (m, 1H), 4.46-4.53 (m, 2H), 3.95 (dd, J=2.45, 9.41 Hz, 1H), 3.17 (dd, J=3.42, 13.45 Hz, 1H), 2.77-2.83 (m, 1H), 2.70-2.77 (m, 1H), 1.37-1.46 (m, 3H).
Reaction SMILES: O[CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.C(Br)(Br)(Br)[Br:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1CCCCC1>C(Cl)Cl>[Br:17][CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](CO)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCCCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H](CBr)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.8 %

Procedure:
To a solution of 1,1-dimethylethyl (3S)-3-(hydroxymethyl)-1-piperidinecarboxylate (30.0 g, 139 mmol) and carbon tetrabromide (72.0 g, 217 mmol) in methylene chloride (150 mL) was added dropwise a solution of triphenyl phosphine (42.4 g, 162 mmol) in methylene chloride (150 mL). An ice-bath was used to maintain an internal temperature between 20 and 25° C. during the addition. After stirring the mixture at ambient temperature for 1 h, cyclohexane (500 mL) was added. Approximately one-half of the solvent was removed under reduced pressure. The remaining solution was cooled in an ice bath and the resulting precipitate was removed by filtration. The filtrate was concentrated under reduced pressure and the residue subjected to flash chromatography (0% to 25% ethyl acetate/hexanes, silica gel) to give 35.1 g (91% yield) of the desired product as a solid. MS (ES+) m/z 278 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Br:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:24]I>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Br:21])[CH3:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2Br)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(c1ccccc1Br)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 43 %

Procedure:
To a solution of 4-(2-bromophenylamino)-piperidine-1-carboxylic acid tert-butyl ester (2.0 g, 0.00562 mole), in DMF (10 mL) was added NaH (60% w/w dispersion in oil) (0.9 g, 0.02251 mole) and the resulting mixture was stirred at ambient temperature for 10 minutes under an atmosphere of nitrogen. Methyl iodide (3.19 g, 0.0225 mole) was then added and stirring was continued for 30 minutes at ambient temperature. The reaction mixture was quenched with aqueous NH4Cl solution and the product was extracted with ether. The ether layer with washed with aqueous NaHCO3 solution followed by brine solution. The ether layer collected was dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was washed with ether and dried to afford 0.893 g (45%) of 4-[(2-bromo-phenyl)-methyl-amino]-piperidine-1-carboxylic acid tert-butyl ester. 1H NMR (CDCl3): δ 7.6-7.54 (m, 1H), 7.28-7.2 (m, 1H), 7.14-7.08 (m, 1H), 6.96-6.88 (m, 1H), 4.2-4.0 (m, 2H), 3.3-3.2 (m, 1H), 2.8-2.7 (m, 2H), 2.7 (s, 3H), 1.7-1.6 (m, 2H), 1.6 (m, 1H), 1.45 (s, 9H). A solution of 4-[(2-bromo-phenyl)-methyl-amino]-piperidine-1-carboxylic acid tert-butyl ester (0.89 g, 0.0024 mole) in dioxane.HCl was stirred for 30 minutes. The reaction was concentrated under reduced pressure to afford 0.704 g (95%) of (2-bromo-phenyl)-methyl-piperidin-4-yl-amine. 1H NMR (DMSO-d6): δ 9.0 (bd, 3H), 7.6 (m, 1H), 7.4 (m, 2H), 7.0 (m, 1H), 3.2 (m, 3H), 2.9 (m, 2H), 2.6 (s, 3H), 1.9 (m, 3H).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[C:8](=[O:13])[CH2:7][CH2:6][CH2:5]2.C(N(CC)CC)C.[F:21][C:22]1[CH:23]=[C:24]([SH:28])[CH:25]=[CH:26][CH:27]=1.O>CC(OC)(C)C>[F:12][C:10]1[CH:11]=[C:2]([S:28][C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([F:21])[CH:23]=2)[CH:3]=[C:4]2[C:9]=1[C:8](=[O:13])[CH2:7][CH2:6][CH2:5]2
Reactant: Fc1cccc(S)c1
Reactant: O=C1CCCc2cc(F)cc(F)c21
Solvent: O
Solvent: COC(C)(C)C
Solvent: CCN(CC)CC
Product: O=C1CCCc2cc(Sc3cccc(F)c3)cc(F)c21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 6,8-difluoro-3,4-dihydro-2H-naphthalen-1-one (50 g) in N,N′dimethylacetamide (100 ml) was treated with triethylamine (38.2 ml), followed by 3-fluorothiophenol (28.2 ml), keeping the temperature below 20° C. The reaction mixture was allowed to stir at ambient temperature for 18 hours. The reaction was diluted with MTBE (70 ml) and cooled on an ice-bath. Water (300 ml) was slowly added (keeping temperature below 25° C.) and the mixture aged for 1 hour. The product was collected by filtration and washed with water and cyclohexane, and dried to afford 8-fluoro-6-(3-fluoro-phenylsulfanyl)-3,4-dihydro-2H-naphthalen-1-one as a pale yellow solid yield (53.5 g, 95% pure by HPLC): MP=126.0-126.9° C.; MS (M+1)=291; H1 NMR (300 MHz): δ (DMSO): 1.97 (2H, pen, J=6.03 Hz), 2.55 (2H, t, J=6.03 Hz), 2.88 (2H, t, J=6.03), 6.84 (1H, dd, J=1.88, 12.06 Hz) 7.01 (1H, d, J=1.03 Hz), 7.31-7.44 (3H, m), 7.52-7.59 (1H, dd/d, J=6.03, 6.41 Hz).
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([CH2:12][OH:13])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O-][Si]([O-])=O.[Mg+2].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[C:1]1([C:7]2[CH:11]=[C:10]([CH:12]=[O:13])[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCc1cc(-c2ccccc2)no1
Agent: O=[Cr](=O)([O-])Cl
Agent: O=[Si]([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: O=Cc1cc(-c2ccccc2)no1

Procedure:
Dissolved in 500 ml of dichloromethane were 29 g (165.7 mmol) of 3-phenyl-5-hydroxymethylisoxazole prepared in Example 28 and 80 g of "Florisil" (trade mark), followed by the addition of 74 g (342.6 mmol) of pyridinium chlorochromate. They were reacted for 7 hours at room temperature. After an insoluble material was filtered off, the filtrate was added into water and then extracted with dichloromethane. After the solvent was distilled off, the residue was purified by silica gel chromatography (eluent: chloroform) so that 3-phenylisoxazole-5-aldehyde was obtained as crystals.
Reaction SMILES: [F:1][C:2]([F:12])([C:5]([F:11])([F:10])[C:6]([F:9])([F:8])[F:7])[CH2:3][OH:4].N1C=CC=CC=1.[Cl-].[C:20]([O:27][CH2:28][CH:29]([CH2:34][CH3:35])[CH2:30][CH2:31][CH2:32][CH3:33])(=[O:26])/[CH:21]=[CH:22]\[C:23]([O-])=[O:24].C(OCC)(=O)C>C(#N)C>[C:20]([O:27][CH2:28][CH:29]([CH2:34][CH3:35])[CH2:30][CH2:31][CH2:32][CH3:33])(=[O:26])/[CH:21]=[CH:22]\[C:23]([O:4][CH2:3][C:2]([F:12])([F:1])[C:5]([F:10])([F:11])[C:6]([F:7])([F:8])[F:9])=[O:24]
Reactant: OCC(F)(F)C(F)(F)C(F)(F)F
Reactant: CCCCC(CC)COC(=O)/C=C\C(=O)[O-]
Agent: [Cl-]
Solvent: CC#N
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCCCC(CC)COC(=O)/C=C\C(=O)OCC(F)(F)C(F)(F)C(F)(F)F
Temperature: 20 °C
Reaction time: 1 h
Yield: 58.6 %

Procedure:
2,2,3,3,4,4,4-Heptafluorobutanol (66.8 g, 0.334 mol) and pyridine (29.6 mL, 0.367 mol) were dissolved in acetonitrile (180 mL) and added with mono(2-ethylhexyl) maleate chloride (90.6 g, 0.367 mol), while-the internal temperature was maintained at 20° C. or lower on an ice bath. After completion of the addition, the reaction mixture was stirred at room temperature for 1 hour and added with ethyl acetate (1000 mL). The organic phase was washed with 1 mol/L aqueous hydrochloric acid and a saturated sodium chloride aqueous solution. Then, the organic phase was collected, the organic solvent was evaporated under reduced pressure, and residue was purified by silica gel column chromatography (hexane/chloroform=10/0 to 7/3 (v/v)) to obtain the target compound (80.3 g, yield: 59%) as a colorless transparent oily compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[CH:21]=[C:20]([Cl:22])[C:17]([C:18]#[N:19])=[C:16]([CH:23]4[CH2:26][NH:25][CH2:24]4)[C:15]=3[O:27][CH3:28])[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12.C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>ClCCl.CO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[CH:21]=[C:20]([Cl:22])[C:17]([C:18]#[N:19])=[C:16]([CH:23]4[CH2:24][N:25]([S:37]([CH3:36])(=[O:39])=[O:38])[CH2:26]4)[C:15]=3[O:27][CH3:28])[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12
Reactant: CS(=O)(=O)Cl
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1C1CNC1
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1C1CN(S(C)(=O)=O)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
A solution of 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-6-chloro-3-methoxybenzonitrile (chiral intermediate from Example 261) (40 mg, 0.10 mmol) in dichloromethane (1 mL) was treated with triethylamine (35 μL, 0.25 mmol), cooled to 0° C., treated with methanesulfonyl chloride (9.3 μL, 0.12 mmol) and stirred at 0° C. for 1 h. The reaction mixture was diluted with methanol and purified by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (20 mg, 42%). The product was isolated as a single enantiomer. 1H NMR (300 MHz, DMSO-d6) δ 8.12 (s, 1H), 7.55 (s, 1H), 7.35 (br s, 2H), 6.25 (q, J=7.0 Hz, 1H), 4.54-4.40 (m, 1H), 4.27-4.12 (m, 4H), 3.68 (s, 3H), 3.01 (s, 3H), 2.55 (s, 3H), 1.74 (d, J=7.1 Hz, 3H). LCMS for C20H23ClN7O3S (M+H)+: m/z=476.1; Found: 476.1.
Reaction SMILES: [F:1][C:2]1[C:3]([CH:11]=[O:12])=[CH:4][C:5]2[CH:9]=[CH:8][S:7][C:6]=2[CH:10]=1.[Cl:13][CH2:14][CH2:15][O:16][CH2:17][Mg]Cl.[Cl-].[NH4+].Cl.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[Cl:13][CH2:14][CH2:15][O:16][CH2:17][CH:11]([C:3]1[C:2]([F:1])=[CH:10][C:6]2[S:7][CH:8]=[CH:9][C:5]=2[CH:4]=1)[OH:12]
Reactant: ClCCOC[Mg]Cl
Reactant: O=Cc1cc2ccsc2cc1F
Agent: Cl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OC(COCCCl)c1cc2ccsc2cc1F
Temperature: 0 °C

Procedure:
To a solution of 1.6 g of 6-fluorobenzo[b]thiophene-5-carbaldehyde in 30 ml of tetrahydrofuran is dropwise added 10 ml of 1.6 M tetrahydrofuran solution of 2-chloroethoxymethylmagnesium chloride at -30° C. over ten minutes, and thereafter, the resulting mixture is stirred while ice-cooling for one hour. Subsequently, the thus stirred reaction mixture is introduced into a mixture of 50 ml of ice water, 50 ml of ethyl acetate and 2 g of ammonium chloride, and the resulting mixture is adjusted to pH 2 with 6 N hydrochloric acid. Thereafter, the thus pH-adjusted mixture is stirred at the same temperature for five minutes. Subsequently, the thus stirred reaction mixture is adjusted to pH 6 with a saturated aqueous sodium hydrogencarbonate solution. Thereafter, the resulting organic layer is separated, washed successively with water and a saturated saline solution, and then dried over anhydrous magnesium sulfate. The solvent is then removed from the thus dried layer by distillation under reduced pressure. The residue obtained is purified by a column chromatography [eluent:toluene:ethyl acetate=4:1], to obtain 1.3 g of oily 2-(2-chloroethoxy)-1-(6-fluorobenzo[b]thiophen-5-yl)ethanol.
Reaction SMILES: [H-].[Na+].CS(C)=O.Cl.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[Cl:16].[CH2:17]([O:24][C:25]1[CH:34]=[C:33]2[C:28]([C:29](Cl)=[CH:30][CH:31]=[N:32]2)=[CH:27][C:26]=1[O:36][CH3:37])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O>[CH2:17]([O:24][C:25]1[CH:34]=[C:33]2[C:28]([C:29]([O:15][C:12]3[CH:13]=[CH:14][C:9]([NH2:8])=[C:10]([Cl:16])[CH:11]=3)=[CH:30][CH:31]=[N:32]2)=[CH:27][C:26]=1[O:36][CH3:37])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Reactant: Nc1ccc(O)cc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc2c(Oc3ccc(N)c(Cl)c3)ccnc2cc1OCc1ccccc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 65.4 %

Procedure:
Sodium hydride (60 wt %, 320 mg) was added to dimethyl sulfoxide (3.6 ml), and the mixture was stirred at 60° C. for 30 min and was then cooled to room temperature. Next, 4-amino-3-chlorophenol hydrochloride (720 mg) was added thereto, and the mixture was stirred at room temperature for 10 min. 7-(Benzyloxy)-4-chloro-6-methoxyquinoline (600 mg) was then added thereto, and the mixture was stirred at 105° C. for 22 hr. Water was added to the reaction solution, followed by extraction with chloroform. The chloroform layer was then washed with a saturated aqueous sodium hydrogencarbonate solution and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and methanol was added to the residue to prepare a suspension. The precipitated crystal was collected by suction filtration to give 533 mg (yield 66%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1[F:12])[N:8]([C:14]1[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=1)[CH:7]=[C:6]([C:22]([O:24]CC)=[O:23])[C:5]2=[O:27].Br>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1[F:12])[N:8]([C:14]1[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=1)[CH:7]=[C:6]([C:22]([OH:24])=[O:23])[C:5]2=[O:27]
Reactant: CCOC(=O)c1cn(-c2ccc(OC)cc2)c2c(F)c(F)c(F)cc2c1=O
Agent: Br
Product: O=C(O)c1cn(-c2ccc(O)cc2)c2c(F)c(F)c(F)cc2c1=O
Temperature: 120 °C
Yield: 79.1 %

Procedure:
A mixture of ethyl 6,7,8-trifluoro-1-(4-methoxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxylate (0.37 g) and 47% hydrobromic acid (4 ml) is heated at 120° C. for 3 hour. After cooling, the precipitated crystals are separated by filtration, washed with water and with a mixture of ethanol and ether to give 6,7,8-trifluoro-1-(4-hydroxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.26 g).