Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([O:14][C:13]([C:12]1[CH:11]=[CH:10][C:9]([CH2:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[CH:17][CH:16]=1)=[O:15])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)Cc1ccc(C(=O)O)cc1
Reactant: BrCc1ccccc1
Product: CC(C)(C)OC(=O)Cc1ccc(C(=O)OCc2ccccc2)cc1

Procedure:
In a manner similar to Example 7(a), by reaction of 3 g (12.7 mmol) of 4-(tert-butoxycarbonylmethyl)benzoic acid prepared in Example 29(a) with 1.6 ml (14 mmol) of benzyl bromide, 3.2 g (77%) of the benzyl ester are obtained in the form of a slightly yellow oil.
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[C:4]([C:7]2[N:11]3[C:12]4[C:17]([N:18]=[C:19]([NH:20][CH2:21][CH2:22][CH2:23][OH:24])[C:10]3=[N:9][CH:8]=2)=[CH:16][C:15]([C:25]([F:28])([F:27])[F:26])=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[C:29](Cl)(=[O:31])[CH3:30]>ClCCl>[OH:24][CH2:23][CH2:22][CH2:21][NH:20][C:19]1[C:10]2[N:11]([C:7]([C:4]3[CH2:3][CH2:2][N:1]([C:29](=[O:31])[CH3:30])[CH2:6][CH:5]=3)=[CH:8][N:9]=2)[C:12]2[C:17]([N:18]=1)=[CH:16][C:15]([C:25]([F:26])([F:28])[F:27])=[CH:14][CH:13]=2
Reactant: OCCCNc1nc2cc(C(F)(F)F)ccc2n2c(C3=CCNCC3)cnc12
Reactant: CC(=O)Cl
Solvent: ClCCl
Product: CC(=O)N1CC=C(c2cnc3c(NCCCO)nc4cc(C(F)(F)F)ccc4n23)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 36 %

Procedure:
To a solution of 3-[1-(1,2,3,6-tetrahydro-pyridin-4-yl)-7-trifluoromethyl-imidazo[1,2-a]quinoxalin-4-ylamino]-propan-1-ol prepared in the previous example (50.0 mg; 0.132 mmol; 1 eq) in anhydrous dichloromethane (660 μL) are successively added N,N′-dimethylaminopyridine (16.1 mg; 0.132 mmol; 1 eq) and acetyl chloride (9.4 μL; 0.132 mmol; 1 eq). The solution is allowed to stir for 17 hours at room temperature until completion of the reaction. The reaction mixture is concentrated under vacuum and the resulting residue is taken-up in ethyl acetate (10 mL). The resulting organic solution is washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated in vacuum. The resulting residue is passed through a silica gel column (dichloromethane/methanol 95:5) to afford the title compound as an off-white solid (20 mg; 0.048 mmol; 36%)
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]2[CH3:18])[C:5]2[CH2:10][N:9]([CH3:11])[CH2:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:27]2[CH:32]=[CH:31][C:30]([NH:33][C:34]([NH2:36])=[O:35])=[CH:29][CH:28]=2)O1>>[CH3:11][N:9]1[CH2:10][C:5]2[C:4]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]3[CH3:18])=[N:3][C:2]([C:27]3[CH:32]=[CH:31][C:30]([NH:33][C:34]([NH2:36])=[O:35])=[CH:29][CH:28]=3)=[N:7][C:6]=2[CH2:8]1
Reactant: CC1(C)OB(c2ccc(NC(N)=O)cc2)OC1(C)C
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1CN(C)C2
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(N)=O)cc2)nc2c1CN(C)C2

Procedure:
Method as intermediate 5 using (S)-4-(2-chloro-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)-3-methylmorpholine (intermediate 12) and 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea as starting materials.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH2:11])[CH:6]=1)[CH3:2].[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=1[S:21](Cl)(=[O:23])=[O:22].N1C=CC=CC=1>C(Cl)Cl>[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=1[S:21]([NH:11][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:12])(=[O:23])=[O:22]
Reactant: CCOC(=O)c1cccc(N)c1
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1cccc(NS(=O)(=O)c2c(F)cccc2F)c1
Temperature: 25 °C
Reaction time: 36 h
Yield: 94.9 %

Procedure:
To a solution of ethyl-3-aminobenzoate (50 mL, 333 mmol) and 2,6-difluorobenzenesulfonyl chloride (44.2 mL, 333 mmol) in DCM (300 mL) at 0° C. was added pyridine (32.2 mL, 400 mmol). The reaction mixture was warmed to rt, stirred for 36 h, and quenched with 2 mL NH3 (7 M in MeOH). The suspension washed with 10% NaHSO4 and the organic extracts combined and passed through a short column of silica gel. Residual material was flushed from the column with 10% MeOH/EtOAc. The organic extracts were combined and the solvent removed under reduced pressure to provide 107.9 g (95%) of the title compound of Step A. 1H-NMR (400 MHz, DMSO-d6) δ ppm 11.20 (s, 1H), 7.77 (s, 1H), 7.71 (t, J=7.4 Hz, 1H), 7.63 (d, J=7.3 Hz, 1H), 7.35-7.49 (m, 2H), 7.29 (t, J=9.3 Hz, 2H), 4.28 (q, J=7.1 Hz, 2H), and 1.29 (t, J=7.1 Hz, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[C:6]([F:13])[CH:5]=1)([O-:3])=[O:2].Cl.[CH3:15][NH:16][O:17][CH3:18].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>N1C=CC=CC=1>[CH3:18][O:17][N:16]([CH3:15])[C:8](=[O:9])[C:7]1[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=1[F:13]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1F
Reactant: CNOC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CON(C)C(=O)c1ccc([N+](=O)[O-])cc1F
Temperature: 60 °C
Reaction time: 15 h
Yield: 85.2 %

Procedure:
4-Nitro-2-fluorobenzoic acid (5.03 g) was dissolved in pyridine (60.0 ml), and N,O-dimethylhydroxylamine hydrochloride (7.95 g), HOBt (5.50 g), and EDC (7.79 g) were added thereto. The obtained mixture was stirred at 60° C. for 15 hours. After the reaction mixture was allowed to cool, the solvent was distilled off under reduced pressure. Water and ethyl acetate were added to the obtained residue, and extraction and washing were carried out. The organic layer was sequentially washed with a 1N hydrochloric acid aqueous solution, saturated sodium-bicarbonate aqueous solution, and saturated sodium chloride solution, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was recrystallized with a mixed solvent of tert-butylmethylether and n-heptane to obtain Compound 14a (5.28 g, 85%) as an opalescent solid.
Reaction SMILES: [C:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([C@@H:10]1[C@H:15]2[CH2:16][C@H:12]([C@H:13]([O:17][CH2:18][C:19]([O:21]CC)=[O:20])[CH2:14]2)[N:11]1[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:9])#[N:2].O.[OH-].[Li+]>O1CCOCC1.O>[C:27]([O:26][C:24]([N:11]1[C@H:10]([C:8]([N:4]2[CH2:5][CH2:6][CH2:7][C@H:3]2[C:1]#[N:2])=[O:9])[C@H:15]2[CH2:16][C@@H:12]1[C@H:13]([O:17][CH2:18][C:19]([OH:21])=[O:20])[CH2:14]2)=[O:25])([CH3:30])([CH3:28])[CH3:29]
Reactant: CCOC(=O)CO[C@@H]1C[C@@H]2C[C@H]1N(C(=O)OC(C)(C)C)[C@@H]2C(=O)N1CCC[C@H]1C#N
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H](C[C@H]2OCC(=O)O)[C@H]1C(=O)N1CCC[C@H]1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 112.3 %

Procedure:
To a solution of tert-butyl (1R,3S,4S,6R)-3-{[(2S)-2-cyano-1-pyrrolidinyl]carbonyl}-6-(2-ethoxy-2-oxoethoxy)-2-azabicyclo[2.2.1]heptane-2-carboxylate obtained in Example 15-1 (249 mg) in dioxane (3 mL) and water (1 mL), was added lithium hydroxide monohydrate (302 mg). The mixture was stirred at room temperature for 1 hr. The resulting mixture was evaporated in vacuo. 1N Hydrochloric acid (1.2 mL) was added to the residue, and the mixture was extracted with ethyl acetate. The combined organic phase was washed with brine, dried over sodium sulfate, and evaporated in vacuo to give the target compound (261 mg).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([Cl:16])[C:7]=1[N+:17]([O-])=O)[CH2:2][CH2:3][CH3:4]>[Pt].C1(C)C=CC=CC=1>[NH2:17][C:7]1[C:8]([Cl:16])=[N:9][C:10]2[C:15]([C:6]=1[NH:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:14][CH:13]=[CH:12][CH:11]=2
Reactant: CCCCNc1c([N+](=O)[O-])c(Cl)nc2ccccc12
Agent: [Pt]
Solvent: Cc1ccccc1
Product: CCCCNc1c(N)c(Cl)nc2ccccc12
Reaction time: 0.5 h
Yield: 66.7 %

Procedure:
4-Butylamino-2-chloro-3-nitroquinoline (33 g, 0.12 mole, Example 112) was combined with toluene (200 mL) and 5% platinum on carbon (1 g). The mixture was hydrogenated on a Parr apparatus at an initial pressure of 38 psi (2.7 Kg/cm2). When the hydrogenation was complete, the catalyst was removed by filtration and the filtrate was concentrated to provide a brown liquid. The liquid was chilled in an ice bath to provide an orange solid. The solid was collected by filtration, slurried with diethyl ether for 30 minutes then filtered to provide 20 g of the desired product as a tan solid. The structure was confirmed by nuclear magnetic resonance spectroscopy.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:5]=1[NH2:6].[CH:12](=O)/[CH:13]=[CH:14]/[CH3:15].[OH-].[Na+]>>[CH3:15][C:14]1[CH:13]=[CH:12][C:7]2[C:5](=[C:4]([O:3][CH3:2])[CH:10]=[CH:9][C:8]=2[CH3:11])[N:6]=1
Reactant: C/C=C/C=O
Reactant: COc1ccc(C)cc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(C)c2ccc(C)nc12
Temperature: 80 °C
Yield: 65 %

Procedure:
To a solution of 0.34 l concentrated HCl at 40° C. was added 275 parts 2-methoxy-5-methylaniline and further heated to 80° C. Then 154 parts crotonaldehyde was added dropwise, heated to 100° C. for 1 hour. The reaction was cooled to 30° C. and poured into 2.5 l ice water and neutralized with 50% NaOH. The product was filtered, washed with water, water pressed, washed with hexane and air dried to give 65% yield of 2,5-dimethyl-8-methoxyquinoline.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:15]([N+:16]([O-])=O)=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[Cl-].[NH4+]>O1CCCC1.O.[Zn]>[F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:15]([NH2:16])=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(Nc2ncccc2[N+](=O)[O-])cc1F
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(Nc2ncccc2N)cc1F
Reaction time: 0.17 h
Yield: 110.9 %

Procedure:
Zinc dust (14.3 g, 219 mmol) was added to a stirring mixture of N-(3-fluoro-4-methylphenyl)-3-nitropyridin-2-amine (C1) (6.78 g, 27.4 mmol) and ammonium chloride (11.7 g, 219 mmol) in tetrahydrofuran (55 mL) and water (55 mL), which caused the temperature of the mixture to rise to 45° C. The reaction mixture was stirred for 10 minutes, and then filtered through a pad of Celite, rinsing with ethyl acetate. The organic layer from the filtrate was further diluted with ethyl acetate, washed with aqueous ammonium chloride solution and with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and filtered. The filtrate was concentrated in vacuo to afford the product as a black solid (6.6 g), the bulk of which was taken directly to the following step. LCMS m/z 218.1 [M+H]+. 1H NMR (400 MHz, CDCl3), characteristic product peaks: δ 7.84 (dd, J=4.9, 1.6 Hz, 1H), 7.01 (dd, J=7.6, 1.6 Hz, 1H), 6.82 (br dd, J=8, 2 Hz, 1H), 6.77 (dd, J=7.6, 4.9 Hz, 1H), 2.20 (d, J=2 Hz, 3H).
Reaction SMILES: [C:1]12([C:12]([O:14]C)=[O:13])[CH2:7][C:4]([C:8]([O:10][CH3:11])=[O:9])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[OH-].[K+].O>CO>[CH3:11][O:10][C:8]([C:4]12[CH2:7][C:1]([C:12]([OH:14])=[O:13])([CH2:6][CH2:5]1)[CH2:2][CH2:3]2)=[O:9]
Reactant: COC(=O)C12CCC(C(=O)OC)(CC1)C2
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)C12CCC(C(=O)O)(CC1)C2
Temperature: 25 °C
Yield: 63.6 %

Procedure:
To a solution of dimethyl bicyclo[2.2.1]heptane-1,4-dicarboxylate (2.00 g, 9.44 mmol, as prepared in Aust. J. Chem., 1985, 38, 1705-18) in MeOH (47 mL) was added KOH (0.475 g, 8.46 mmol) and water (2.5 mL). The reaction was stirred at reflux for about 16 h and then cooled to room temperature and concentrated to dryness under reduced pressure. Water (25 mL) was added to the remaining residue and the mixture was extracted with Et2O (2×25 mL). The aqueous layer was acidified to about pH 4 using aqueous 6 N HCl and was extracted with DCM (3×20 mL). The combined DCM extracts were dried over anhydrous MgSO4, filtered, and concentrated to provide 4-(methoxycarbonyl)bicyclo[2.2.1]heptane-1-carboxylic acid as an off-white solid (1.19 g, 71%): 1H NMR (400 MHz, DMSO-d6) δ 12.19 (s, 1H), 3.61 (s, 3H), 1.92 (d, J=6.6 Hz, 4H), 1.76 (s, 2H), 1.65-1.54 (m, 4H).
Reaction SMILES: [O:1]=[C:2]([C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[C:17]([F:23])[CH:16]=1)[CH2:3][CH2:4][CH2:5][CH2:6][NH:7]C(=O)OC(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[NH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]([C:15]1[CH:16]=[C:17]([F:23])[C:18]([F:22])=[C:19]([F:21])[CH:20]=1)=[O:1]
Reactant: CC(C)(C)OC(=O)NCCCCC(=O)c1cc(F)c(F)c(F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCCCC(=O)c1cc(F)c(F)c(F)c1
Yield: 88.1 %

Procedure:
Tert-butyl 5-oxo-5-(3,4,5-trifluorophenyl)pentylcarbamate (0.18 g, 0.54 mmol) was stirred in trifluoroacetic acid/dichloromethane 1:1 (8 mL) for 1 hour then concentrated. The residue was dissolved in ethyl acetate (40 mL) and washed with saturated sodium chloride/2M aqueous sodium hydroxide 10:1 (11 mL), then dried over anhydrous sodium sulfate, filtered and concentrated to provide 5-amino-1-(3,4,5-trifluorophenyl)pentan-1-one (0.11 g, 88% yield) as an oil. MS (EI) for C11H12F3NO: 232 (MH+).
Reaction SMILES: [C:1](=[O:40])([O:36][CH:37](I)[CH3:38])[O:2][CH:3]([CH2:20][O:21][C:22](=[O:35])[C@H:23]([CH:32]([CH3:34])[CH3:33])[NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:4][O:5][C:6](=[O:19])[C@H:7]([CH:16]([CH3:18])[CH3:17])[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[CH3:41][C:42]([O:44][CH2:45][C:46]1[CH2:67][S:66][C@@H:49]2[C@H:50]([NH:53][C:54](/[C:56](/[C:60]3[N:64]=[C:63]([NH2:65])[S:62][CH:61]=3)=[N:57]\[O:58][CH3:59])=[O:55])[C:51](=[O:52])[N:48]2[C:47]=1[C:68]([O-:70])=[O:69])=[O:43].[Na+]>CN(C=O)C>[C:42]([O:44][CH2:45][C:46]1[CH2:67][S:66][C@@H:49]2[C@H:50]([NH:53][C:54](=[O:55])/[C:56](/[C:60]3[N:64]=[C:63]([NH2:65])[S:62][CH:61]=3)=[N:57]\[O:58][CH3:59])[C:51](=[O:52])[N:48]2[C:47]=1[C:68]([O:70][CH:37]([O:36][C:1]([O:2][CH:3]([CH2:20][O:21][C:22](=[O:35])[C@H:23]([CH:32]([CH3:34])[CH3:33])[NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:4][O:5][C:6](=[O:19])[C@H:7]([CH:16]([CH3:18])[CH3:17])[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:40])[CH3:38])=[O:69])(=[O:43])[CH3:41]
Reactant: CC(I)OC(=O)OC(COC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)COC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(COC(C)=O)CS[C@H]12)c1csc(N)n1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(C)OC(=O)OC(COC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)COC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)=C(COC(C)=O)CS[C@H]12)c1csc(N)n1

Procedure:
A solution of 1,3-bis(N-tert-butoxycarbonyl-L-valyloxy)-2-propyl 1-iodoethyl carbonate (0.156 mmol) and cefotaxime sodium (67.8 mg, 0.142 mmol) in 3.2 mL dry N,N′-dimethylformamide was stirred under argon for 22 h. The reaction mixture was concentrated and subjected to column chromatography (silica, 2/1 petroleum ether—ethyl acetate, and then 20/1 CH2Cl2-methanol) to yield an oil enriched in the desired product. The oil was dissolved in 10 mL ethyl acetate, washed with water, dried, and concentrated. A second chromatography (silica, 40/1 CH2Cl2-methanol) gave the title compound (59.7 mg) as cream-colored solids.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([CH2:7][CH:8]=O)[CH2:2]1.[CH3:10][NH2:11]>CCOCC>[O:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([CH2:7]/[CH:8]=[N:11]/[CH3:10])[CH2:2]1
Reactant: O=CC[C@H]1CCCOC1
Reactant: CN
Solvent: CCOCC
Product: C/N=C/C[C@H]1CCCOC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
To a magnetically stirred solution of (R)-2-(tetrahydro-2H-pyran-3-yl)acetaldehyde (11 g, 85.8 mmol) in Et2O (215 mL) at room temperature was added MeNH2 (2M in THF, 215 mL, 429.2 mmol) and molecular sieves (4 Å, powdered, activated, 21.5 g). The reaction was stirred at room temperature for 1 h. The resulting mixture was then filtered and concentrated under reduced pressure to furnish (R,E)-N-(2-(tetrahydro-2H-pyran-3-yl)ethylidene)methanamine as a yellow oil (11.3 g, 80 mmol, 93%). The crude material was carried on without further purification. 1H NMR (400 MHz, CDCl3) δ 7.67 (m, 1H), 3.86-3.91 (m, 2H), 3.36-3.43 (m, 1H), 3.29 (s, 3H), 3.13 (dd, J=11.0, 9.8 Hz, 1H), 1.95-2.14 (m, 2H), 1.86-1.91 (m, 2H), 1.62-1.68 (m, 2H), 1.21-1.30 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[C:14]([CH2:15][CH2:16][NH2:17])=[C:6]2[C:7]3[CH2:13][CH2:12][O:11][C:8]=3[CH:9]=[CH:10][N:5]2[N:4]=1.C(N(CC)CC)C.[C:27](Cl)(=[O:29])[CH3:28]>O1CCCC1.C(=O)([O-])O.[Na+]>[F:19][C:2]([F:1])([F:18])[C:3]1[C:14]([CH2:15][CH2:16][NH:17][C:27](=[O:29])[CH3:28])=[C:6]2[C:7]3[CH2:13][CH2:12][O:11][C:8]=3[CH:9]=[CH:10][N:5]2[N:4]=1
Reactant: CC(=O)Cl
Reactant: NCCc1c(C(F)(F)F)nn2ccc3c(c12)CCO3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)NCCc1c(C(F)(F)F)nn2ccc3c(c12)CCO3
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.9 %

Procedure:
To a solution of 2-[2-(trifluoromethyl)-8,9-dihydrofuro[3,2-c]pyrazolo[1,5-a]pyridin-1-yl]ethanamine (70 mg, 0.26 mmol) and triethylamine (72 μL, 0.52 mmol) in tetrahydrofuran (3 mL) was added acetyl chloride (22 μL, 0.31 mmol) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. The reaction solution was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=70/30→100/0) and recrystallization (ethyl acetate/hexane) to give the title compound (61.8 mg, yield 76%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18].CCN(C(C)C)C(C)C>C(OCC)(=O)C>[Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18])=[O:5]
Reactant: Nc1ccccc1O
Reactant: O=C(Cl)c1cccnc1Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccccc1O)c1cccnc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.4 %

Procedure:
A solution of 2-chloronicotinoyl chloride (2.91 g, 16.6 mmol) in ethyl acetate (50 mL) was added to a mixture of 2-aminophenol (2.00 g, 18.3 mmol) and DIPEA (4.8 mL, 27.5 mmol) in ethyl acetate (50 mL) at 4° C. The reaction mixture was stirred for 1 hour. The organic mixture was washed with water and brine then concentrated under reduced pressure. The residue was dissolved in ethanol/THF 1:1 (75 mL) and 15% sodium hydroxide (25 mL) and the mixture was stirred at 50° C. for 45 min. The mixture was cooled down to room temperature and concentrated in vacuo to one third volume and then acidified to pH=2 with 3M HCl. The solid was filtered, washed with water and dried to afford title compound 13 (3.69 g, 81%) as a beige solid. LRMS (ESI): (calc) 248.04. (found) 249.2 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([CH3:20])([CH3:19])[CH2:10][C:11]([OH:18])([C:14]([F:17])([F:16])[F:15])[CH:12]=O.[NH2:21][C:22]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:23]=1[CH2:24][O:25][C:26]2=[O:27].B(Br)(Br)Br>>[OH:18][C:11]1([C:14]([F:15])([F:17])[F:16])[CH2:10][C:9]([CH3:19])([CH3:20])[C:4]2[C:5](=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH:12]1[NH:21][C:22]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:23]=1[CH2:24][O:25][C:26]2=[O:27]
Reactant: COc1ccccc1C(C)(C)CC(O)(C=O)C(F)(F)F
Reactant: Nc1cccc2c1COC2=O
Agent: BrB(Br)Br
Product: COc1cccc2c1C(C)(C)CC(O)(C(F)(F)F)C2Nc1cccc2c1COC2=O
Yield: 19 %

Procedure:
Analogously to Example 10, the corresponding imine is produced starting from 600 mg of 4-(2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 308 mg of 4-amino-phthalide (Bull. Soc. Sci. Bretagne 26, 1951, Special Edition 5, p. 7, 96). As in Example 2, 650 mg of the imine is reacted by reaction with 7.7 ml of BBr3 (1 M in dichloromethane), and 165 mg of the title compound is obtained.
Reaction SMILES: [CH:1]([C:4]1[C:13]2[C:8](=[CH:9][C:10](OS(C(F)(F)F)(=O)=O)=[CH:11][CH:12]=2)[CH:7]=[C:6]([NH:22][C:23]2[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=2)[N:5]=1)([CH3:3])[CH3:2].[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[CH:1]([C:4]1[C:13]2[C:8](=[CH:9][C:10]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[CH:11][CH:12]=2)[CH:7]=[C:6]([NH:22][C:23]2[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=2)[N:5]=1)([CH3:3])[CH3:2]
Reactant: C1COCCN1
Reactant: Cc1cc(Nc2cc3cc(OS(=O)(=O)C(F)(F)F)ccc3c(C(C)C)n2)n[nH]1
Product: Cc1cc(Nc2cc3cc(N4CCOCC4)ccc3c(C(C)C)n2)n[nH]1

Procedure:
Similar procedure as described in the example 363 was used, starting from Trifluoro-methanesulfonic acid 1-isopropyl-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-6-yl ester and morpholine to give 5 mg of (1-Isopropyl-6-morpholin-4-yl-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine as a yellow solid. LC-MS m/e 352 (MH+).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C@@H:4]([Cl:12])[C@H:3]1[OH:13].[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)(O)[O-].[Na+]>O.C1(C)C=CC=CC=1>[C:14]([NH:1][C@@H:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C@@H:4]([Cl:12])[C@H:3]1[OH:13])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: N[C@@H]1Cc2ccccc2[C@@H](Cl)[C@H]1O
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(N[C@@H]1Cc2ccccc2[C@@H](Cl)[C@H]1O)c1ccccc1
Temperature: 25 °C
Yield: 45.3 %

Procedure:
To a mixture of (±)-(1R,2S,3R)-3-amino-1-chloro-1,2,3,4-tetrahydro-2-naphthalenol (547 mg) in water (10 ml) and benzoylchloride (367 mg) in toluene (6 ml) was added dropwise a solution of sodium bicarbonate (420 mg) in water (10 ml) over a period of 30 minutes. Stirring was maintained at room temperature for an additional period of 30 minutes. The mixture was extracted with chloroform, washed with saturated aqueous sodium chloride and evaporated in vacuo. Recrystallization of the residue from a cyclohexane/ethyl acetate mixture yielded the title compound (357 mg) as a white solid.
Reaction SMILES: C1(O[C:8](=[O:30])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[C:19]([F:25])[C:18]=3[F:26])[C:11]=2[C:27](=[O:29])[NH2:28])C=CC=CC=1.[NH2:31][CH2:32][CH2:33][CH:34]([OH:41])[CH2:35][CH2:36][NH:37][CH:38]([CH3:40])[CH3:39]>>[OH:41][CH:34]([CH2:35][CH2:36][NH:37][CH:38]([CH3:40])[CH3:39])[CH2:33][CH2:32][NH:31][C:8](=[O:30])[NH:9][C:10]1[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]2[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[C:19]([F:25])[C:18]=2[F:26])[C:11]=1[C:27]([NH2:28])=[O:29]
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)c(F)c1F
Reactant: CC(C)NCCC(O)CCN
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCC(O)CCNC(C)C)c2C(N)=O)c(F)c1F

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and 1-amino-5-isopropylamino-pentan-3-ol by the procedure analogous to Example 1. MS (APCl, m/z): 504 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:9]=[N:10][N:11]([C:13]([CH3:17])([CH3:16])[CH2:14][OH:15])[CH:12]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>O>[CH3:26][S:27]([O:15][CH2:14][C:13]([N:11]1[CH:12]=[C:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:18])[CH:9]=[N:10]1)([CH3:17])[CH3:16])(=[O:29])=[O:28]
Reactant: CC(C)(C)OC(=O)Nc1cnn(C(C)(C)CO)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cnn(C(C)(C)COS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To tert-butyl(1-(1-hydroxy-2-methylpropan-2-yl)-1H-pyrazol-4-yl)carbamate (3.4 g) obtained in Step A of Example 114 were added successively triethylamine (2.4 mL) and methanesulfonyl chloride (1.2 mL) in an ice bath, and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the crude title compound (2.2 g).