Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8](Cl)[N:7]=[C:6]1[N:14]1[CH2:19][CH2:18][CH:17]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16][CH2:15]1.[C:29]([C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][C:32]=1[F:40])#[N:30].C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C.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>[CH3:1][O:2][C:3](=[O:28])[CH2:4][N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([C:34]2[CH:35]=[CH:36][C:31]([C:29]#[N:30])=[C:32]([F:40])[CH:33]=2)[N:7]=[C:6]1[N:14]1[CH2:19][CH2:18][CH:17]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:22])[CH2:16][CH2:15]1
Reactant: N#Cc1ccc(B(O)O)cc1F
Reactant: COC(=O)Cn1c(N2CCC(NC(=O)OC(C)(C)C)CC2)nc(Cl)c(Cl)c1=O
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: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cn1c(N2CCC(NC(=O)OC(C)(C)C)CC2)nc(-c2ccc(C#N)c(F)c2)c(Cl)c1=O
Yield: 35 %

Procedure:
A mixture of [2-(4-tert-butoxycarbonylamino-piperidin-1-yl)-4,5-dichloro-6-oxo-6H-pyrimidin-1-yl]-acetic acid methyl ester (5.76 g, 13.2 mmol), 4-cyano-3-fluoro benzeneboronic acid (2.24 g, 16.1 mmol), Pd(PPh3)4 (306 mmol, 0.26 mmol) and Na2CO3 (2.8 g, 26.5 mmol) in DMF:H2O (50 mL:10 mL) was stirred at 65° C. overnight under nitrogen atmosphere. The reaction mixture was concentrated, and the residue was purified by silica chromatography (1:20 to 1:0, EA:PE) to give 2.4 g of the title product (43%). 1H NMR (400 MHz, CDCl3): δ 1.27-1.37 (m, 2H), 1.45 (s, 9H), 1.99-2.02 (m, 2H), 2.99-3.06 (m, 2H), 3.68-3.76 (m, 1H), 3.78 (s, 3H), 4.42-4.52 (m, 3H), 4.90 (s, 2H), 7.63-7.66 (m, 1H), 7.67-7.71 (m, 2H). [M+H] Calc'd for C24H27ClFN5O5, 520. Found, 520.
Reaction SMILES: Cl.C(O[C:7]([N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19])[C:11](=[O:20])[CH:10]1[CH3:21])=[O:8])(C)(C)C.CN1CCOCC1.[Cl:29][C:30]1[CH:31]=[C:32]([CH:38]=[CH:39][C:40]=1[Cl:41])[CH:33]=[CH:34]C(O)=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[Cl:29][C:30]1[CH:31]=[C:32](/[CH:33]=[CH:34]/[C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19])[C:11](=[O:20])[CH:10]2[CH3:21])=[O:8])[CH:38]=[CH:39][C:40]=1[Cl:41]
Reactant: C=CCCCN1CCN(C(=O)OC(C)(C)C)C(C)C1=O
Reactant: O=C(O)C=Cc1ccc(Cl)c(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Product: C=CCCCN1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)C(C)C1=O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 86.1 %

Procedure:
Hydrogen chloride solution (4 M in 1,4-dioxane, 8 ml) was added to a solution of 2-methyl-3-oxo-4-pent-4-enyl-piperazine-1-carboxylic acid tert-butyl ester (200 mg, 0.71 mmol). The reaction mixture was stirred at room temperature for 3.5 h, then volatile material was removed by rotary evaporation. The residue was taken up in dichlormethane (10 ml), treated with 4-methylmorpholine (358 mg, 3.54 mmol), and the mixture obtained concentrated in vacuo. The residue was taken up in N,N-dimethylformamide (8 ml), then 4-methylmorpholine (358 mg, 3.54 mmol), 3,4-dichlorocinnamic acid (161 mg, 0.71 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate (404 mg, 1.06 mmol) were added. The solution was stirred at room temperature for 48 h, then the mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2; heptane-ethyl acetate gradient) produced the title compound (233 mg, 86%). Light yellow oil, MS (ISP)=381.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([C:12]([O:14][CH3:15])=[O:13])[CH2:7][CH2:8][O:9]2)=[CH:4][CH:3]=1.[Br:16]N1C(=O)CCC1=O>CN(C=O)C.C(OCC)(=O)C>[Br:16][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[F:1])[O:9][CH2:8][CH2:7][CH:6]2[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)C1CCOc2cc(F)ccc21
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C1CCOc2cc(F)c(Br)cc21
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 89.7 %

Procedure:
Methyl 7-fluoro-3,4-dihydro-2H-chromene-4-carboxylate (336 mg, 1.60 mmol) was diluted with DMF (5 mL) followed by the addition of N-bromosuccinimide (313 mg, 1.76 mmol). The reaction was heated at 50° C. and stirred for 2.5 hours. The reaction was cooled, diluted with ethyl acetate and washed with water, saturated sodium bicarbonate, water, and brine. The organic layer was dried over MgSO4, filtered and concentrated. The material was purified using a Biotage 40M cartridge, gradient 5% ethyl acetate/hexane to 50% to yield the title compound (415 mg, 89.8% yield).
Reaction SMILES: [CH3:1][C:2](=[N:4][OH:5])[CH3:3].Cl[CH:7]([C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:17]=[C:18]([C:23]3([O:29][CH3:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:19]=[C:20]([F:22])[CH:21]=2)=[CH:11][CH:10]=1)[CH3:8]>>[F:22][C:20]1[CH:19]=[C:18]([C:23]2([O:29][CH3:30])[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)[CH:17]=[C:16]([S:15][C:12]2[CH:11]=[CH:10][C:9]([CH:7]([O:5][N:4]=[C:2]([CH3:3])[CH3:1])[CH3:8])=[CH:14][CH:13]=2)[CH:21]=1
Reactant: COC1(c2cc(F)cc(Sc3ccc(C(C)Cl)cc3)c2)CCOCC1
Reactant: CC(C)=NO
Product: COC1(c2cc(F)cc(Sc3ccc(C(C)ON=C(C)C)cc3)c2)CCOCC1
Temperature: 60 °C
Yield: 58 %

Procedure:
Using an analogous procedure to that described in Example 1 except that the reactants were heated to 60° C. for 2 hours, acetone oxime was reacted with 4-{3-[4-(1-chloroethyl)phenylthio]-5-fluorophenyl}-4-methoxytetrahydropyran to give acetone O-{4-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenylthio)-α-methylbenzyl}oxime as an oil in 58% yield.
Reaction SMILES: [CH:1]1([C@H:6]([N:11]=[C:12]=[O:13])[C:7]([O:9][CH3:10])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:14]([C@@H:19]1[CH2:23][CH2:22][CH2:21][C@H:20]1[OH:24])[CH2:15][CH2:16][CH:17]=[CH2:18]>C1(C)C=CC=CC=1.CN(C1C=CN=CC=1)C.CCOC(C)=O.Cl>[CH:1]1([C@H:6]([NH:11][C:12]([O:24][C@@H:20]2[CH2:21][CH2:22][CH2:23][C@H:19]2[CH2:14][CH2:15][CH2:16][CH:17]=[CH2:18])=[O:13])[C:7]([O:9][CH3:10])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)[C@@H](N=C=O)C1CCCC1
Reactant: C=CCCC[C@@H]1CCC[C@H]1O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=CCCC[C@@H]1CCC[C@H]1OC(=O)N[C@H](C(=O)OC)C1CCCC1
Temperature: 85 °C
Reaction time: 5 h
Yield: 75 %

Procedure:
A solution of methyl (2S)-cyclopentyl(isocyanato)acetate (1.57 g, 8.56 mmol) and (1R,2R)-2-pent-4-en-1-ylcyclopentanol (Intermediate A9) (1.20 g, 7.78 mmol) in PhMe (56 mL) was treated portionwise with DMAP (0.95 g, 7.78 mmol). The resulting mixture was stirred for 5 hours at 85° C., then cooled to 20° C., and diluted with EtOAc and HCl(aq.) (1N). The organic layer was separated, washed with brine, and dried over Na2SO4. Filtration and removal of the volatiles gave a residue that was purified by column chromatography (gradient elution, 4-40% Et2O/petroleum ether) to afford the title compound (1.97 g, 76%) as an oil. LCMS (ES+) m/z, 338 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:35])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[C:22](=[O:26])[N:21]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])[CH2:20]4)=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.NC1C=CC(C2C=C3C(=CC=2)C(=O)N([C@@H](C(C)C)C(OC)=O)C3)=CC=1.[F:61]C1C=C(F)C=CC=1N=C=O>>[F:61][C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[NH:8][C:9](=[O:35])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[C:22](=[O:26])[N:21]([C@@H:27]([CH:32]([CH3:33])[CH3:34])[C:28]([O:30][CH3:31])=[O:29])[CH2:20]3)=[CH:13][CH:12]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=O)Nc4ccc(F)cc4)cc3)ccc2C1=O
Reactant: O=C=Nc1ccc(F)cc1F
Agent: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(N)cc3)ccc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=O)Nc4ccc(F)cc4F)cc3)ccc2C1=O

Procedure:
The compound of example 236 was prepared analogous to compound of example 224 by reaction of compound of example 223 with 2,4-difluorophenyl isocyanate. The compound of example 236 was used directly without isolation for the preparation of compound of example 237.
Reaction SMILES: C([O:4][C@@H:5]1[NH:8][C:7](=O)[C@H:6]1[NH:10][C:11](=[O:26])[C:12]([C:16]1[N:17]=[C:18]([NH:21][C:22](=[O:25])[CH2:23][Cl:24])[S:19][CH:20]=1)=[N:13][O:14][CH3:15])(=O)C.[N-:27]=[N+:28]=[N-:29].[Na+].O>CN(C=O)C>[N:27]([CH:7]1[NH:8][C:5](=[O:4])[C@H:6]1[NH:10][C:11](=[O:26])[C:12]([C:16]1[N:17]=[C:18]([NH:21][C:22](=[O:25])[CH2:23][Cl:24])[S:19][CH:20]=1)=[N:13][O:14][CH3:15])=[N+:28]=[N-:29]
Reactant: [N-]=[N+]=[N-]
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N[C@H]1OC(C)=O)c1csc(NC(=O)CCl)n1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CON=C(C(=O)N[C@@H]1C(=O)NC1N=[N+]=[N-])c1csc(NC(=O)CCl)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.2 %

Procedure:
To a solution of 0.308 g of (3S,4S)-4-acetoxy-3-[2-(2-chloroacetamidothiazol-4-yl)-2-methoxyiminoacetamido]-2-oxoazetidine in 3 ml of DMF is added under ice-cooling a solution of 0.061 g of sodium azide is 2 ml of water. The mixture is stirred for 18 hours at room temperature, to which is added water, then the resulting precipitates are collected by filtration to give 0.216 g of (3S)-4-azido-3-[2-(2-chloroacetamidothiazol-4-yl)-2-methoxyiminoacetamido]-2-oxoazetidine.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:13]2C(=O)NC(=O)[C:14]2([O:23]CCC)C=CC=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.C[NH2:33]>C(O)C>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][O:23][NH2:33])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN
Reactant: CCCOC12C=CC=C(NC(=O)OCc3ccccc3)C1C(=O)NC2=O
Solvent: C1CCOC1
Solvent: CCO
Product: NOCCCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To a solution of N-[3-(benzyloxycarbonylamino)-1-propoxylphthalimide (1.42 g, 4.0 mmol), as prepared in the preceding step, in ethanol (20 mL) and tetrahydrofuran (20 mL) was added 40% methylamine (2 mL, 25 mmol). The solution was stirred at room temperature for 1 h. The solvent was evaporated and the residue passed through silica gel (3:1 ethyl acetate:hexane to ethyl acetate) to give the title compound as a white solid (870 mg, 97%). 1H-NMR (300 MHz, CDCl3) δ7.36 (m, 5H), 5.38 (br s, 2H), 5.09 (s, 2H), 5.08 (br s, 1H), 3.73 (t, J=5.9 Hz, 2H), 3.29 (q, J=6.2 Hz, 2H), 1.79 (pentet, J=6.2 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]3[CH2:21][CH:20]([OH:22])[CH2:19]3)=[O:17])[CH:10]=2)[C:5]([F:23])=[CH:4][C:3]=1[NH:24][C:25]([C:27]1([C:30]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)=[O:31])[CH2:29][CH2:28]1)=[O:26].Cl.[CH3:41][N:42]([CH3:47])[CH2:43][C:44](O)=[O:45].C(N(CC)CC)C.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]3[CH2:19][CH:20]([O:22][C:44](=[O:45])[CH2:43][N:42]([CH3:47])[CH3:41])[CH2:21]3)=[O:17])[CH:10]=2)[C:5]([F:23])=[CH:4][C:3]=1[NH:24][C:25]([C:27]1([C:30]([NH:32][C:33]2[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=2)=[O:31])[CH2:28][CH2:29]1)=[O:26]
Reactant: O=C(Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1)N1CC(O)C1
Reactant: CN(C)CC(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)CC(=O)OC1CN(C(=O)Nc2cc(Oc3cc(F)c(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)ccn2)C1
Reaction time: 8 h
Yield: 46.9 %

Procedure:
N-{2,5-Difluoro-4-[(2-{[(3-hydroxyazetidin-1-yl)carbonyl]amino}pyridin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (38.9 mg) was dissolved in N,N-dimethylformamide (1.0 ml) under a nitrogen atmosphere, and N,N-dimethylglycine hydrochloride (20 mg), triethylamine (0.050 ml) and BOP reagent (63.5 mg) were added at room temperature, followed by stirring overnight. N,N-Dimethylglycine hydrochloride (20 mg), triethylamine (0.050 ml) and BOP reagent (63.5 mg) were added again at room temperature, and the reaction mixture was stirred for 5 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with a saturated aqueous solution of sodium hydrogencarbonate (twice) and brine, dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate), and fractions containing the target compound were concentrated under reduced pressure. To the resultant residue was added tert-butyl methyl ether (1 ml)—heptane (2 ml) to precipitate a solid. The solid was collected by filtration and dried under aeration to provide the titled compound as white powder (21.1 mg, 47%).
Reaction SMILES: B(Br)(Br)Br.[CH2:5]([NH:7][C:8](=[O:10])[O-:9])[CH3:6].C[O:12][C:13]1[C:14]([Cl:26])=[CH:15][C:16]2[CH:17]([CH3:25])[CH:18]3[CH2:22][NH:21][CH2:20][CH:19]3[C:23]=2[CH:24]=1>>[CH2:5]([NH:7][C:8](=[O:9])[O-:10])[CH3:6].[OH:12][C:13]1[C:14]([Cl:26])=[CH:15][C:16]2[CH:17]([CH3:25])[CH:18]3[CH2:22][NH:21][CH2:20][CH:19]3[C:23]=2[CH:24]=1
Reactant: COc1cc2c(cc1Cl)C(C)C1CNCC21
Agent: BrB(Br)Br
Agent: CCNC(=O)[O-]
Product: CC1c2cc(Cl)c(O)cc2C2CNCC12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
BBr3 (0.3 mL, 0.30 mmol, 1 M in CH2Cl2) was added to a solution of N-Ethylcarbamate-5-methoxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 3, Step A) (46 mg, 0.15 mmol) at 0 ° C., and stirred overnight at room temperature. The reaction solution was quenched with H2O and filtered through an Extrelut column. The column was washed with CH2Cl2, and the filtrate was concentrated. The crude product was obtained without further purification. MS calculated for C15H18ClNO3+H: 296, observed: 296.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5](=O)[CH2:4][CH:3]1[C:8]([O:10][CH2:11][CH3:12])=[O:9].CC(O)=O.[CH2:17]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[CH2:25]([N:24]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:5]1[CH2:4][CH:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:2]([CH3:1])[CH2:6]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: CCOC(=O)C1CC(=O)CC1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCOC(=O)C1CC(N(Cc2ccccc2)Cc2ccccc2)CC1C
Temperature: 0 °C
Reaction time: 20 h
Yield: 75 %

Procedure:
A round bottom flask was charged with ethyl 2-methyl-4-oxocyclopentanecarboxylate (10.0 g, 58.8 mmol) and DCE (180 mL). The solution was cooled to about 0° C. and AcOH (5.7 mL, 100 mmol) and dibenzylamine (11.3 mL, 58.8 mmol) were added dropwise, resulting in formation of a thick suspension. The reaction mixture was warmed to about 10° C. and sodium triacetoxyborohydride (21.2 g, 100 mmol) was added portionwise and the reaction mixture was stirred at ambient temperature for about 20 h. The reaction mixture was slowly poured into stirred saturated aqueous NaHCO3 (300 mL) and was stirred for about 20 min. The layers were separated and the aqueous phase was extracted with DCM (3×100 mL). The combined organic extracts were washed with brine (2×100 mL), dried over anhydrous Na2SO4, and concd under reduced pressure. The crude yellow oil was purified via flash column chromatography eluting with a gradient of 0-30% EtOAc in heptane to give ethyl 4-(dibenzylamino)-2-methylcyclopentanecarboxylate (15.5 g, 75%) as a colorless oil: 1H NMR (pyridine-d5) δ 7.53 (dd, J=0.9, 7.9 Hz, 4H), 7.43-7.35 (m, 4H), 7.33-7.25 (m, 2H), 4.22-4.06 (m, 2H), 3.79 (d, J=14.2 Hz, 2H), 3.70 (d, J=14.2 Hz, 2H), 3.34-3.22 (m, 1H), 2.76 (dd, J=7.9, 16.6 Hz, 1H), 2.25-2.13 (m, 1H), 2.09-1.94 (m, 2H), 1.88-1.79 (m, 1H), 1.52 (dd, J=10.5, 22.5 Hz, 1H), 1.16 (t, J=7.1 Hz, 3H), 0.98 (d, J=7.0 Hz, 3H).
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][N:9]=2)[CH2:3]1.[F:16][C:17]([F:33])([F:32])[C:18]1[O:22][N:21]=[C:20]([C:23]2[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=2)[C:26](O)=[O:27])[N:19]=1>>[CH3:1][CH:2]1[N:7]([C:26](=[O:27])[C:25]2[CH:29]=[CH:30][CH:31]=[C:23]([C:20]3[N:19]=[C:18]([C:17]([F:33])([F:32])[F:16])[O:22][N:21]=3)[CH:24]=2)[CH2:6][CH2:5][N:4]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][N:9]=2)[CH2:3]1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: CC1CN(c2ccc(C#N)cn2)CCN1
Product: CC1CN(c2ccc(C#N)cn2)CCN1C(=O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Yield: 39 %

Procedure:
This compound was synthesized from 6-(3-methylpiperazin-1-yl)nicotinonitrile and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described for example 37 step 3 (75 mg, yield 39%). 1H NMR (400 MHz, MeOD) δ 8.41 (d, J=2.0 Hz, 1H), 8.27-8.25 (m, 1H), 8.18 (s, 1H), 7.77-7.72 (m, 3H), 6.89 (d, J=9.0 Hz, 1H), 4.39 (m, 3H), 3.48 (m, 2H), 3.22-3.15 (m, 1H), 1.29 (m, 3H). MS (ESI) m/z: Calculated for C21H17F3N6O2: 442.14. found: 443.2 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[C:9](=[O:10])[C:8]([OH:11])=[CH:7][C:6]([CH:12]([CH3:14])[CH3:13])=[CH:5][CH:4]=1)=[O:2].[CH2:15]([Li])[CH2:16][CH2:17]C>O1CCCC1.CCCCCC>[OH:2][CH:1]([C:3]1[C:9](=[O:10])[C:8]([OH:11])=[CH:7][C:6]([CH:12]([CH3:14])[CH3:13])=[CH:5][CH:4]=1)[CH2:15][CH2:16][CH3:17]
Reactant: CC(C)c1ccc(C=O)c(=O)c(O)c1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCC(O)c1ccc(C(C)C)cc(O)c1=O
Temperature: -78 °C

Procedure:
7-formyl-4-isopropyl-2-hydroxy-2,4,6-cycloheptatrien-1-one (1.95 g, 10 mmol) was dissolved in tetrahydrofuran (30 ml) and the resultant was cooled to -78° C. in a dry ice/acetone bath. A solution of n-butyllithium in hexane (1.6M, 14 ml) was added dropwise to the solution, then, the dry ice/acetone bath was removed and the resultant was stirred until insoluble matter was dissolved. An aqueous saturated ammonium chloride was added to the reaction mixture and the resultant was extracted with methylene chloride. The methylene chloride layer was washed with water, then dried over anhydrous sodium sulfate. Solvent was distilled off to give 2.72 g of 7-(α-hydroxybutyl)-4-isopropyl-2-hydroxy-2,4,6-cycloheptatrien-1-one as a reddish brown oil (yield: quantitative).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:12]2[C:13]([Cl:21])=[N:14][CH:15]=[C:16]([CH:18]3[CH2:20][CH2:19]3)[CH:17]=2)[C:10]=1[CH3:11])=[O:5])C.[OH-].[Na+].O>O1CCCC1>[Cl:21][C:13]1[C:12]([N:9]2[C:10]([CH3:11])=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]2)=[CH:17][C:16]([CH:18]2[CH2:20][CH2:19]2)=[CH:15][N:14]=1
Reactant: CCOC(=O)c1cnn(-c2cc(C3CC3)cnc2Cl)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)cnn1-c1cc(C2CC2)cnc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.8 %

Procedure:
To a solution of 1-(2-chloro-5-cyclopropylpyridin-3-yl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (1.13 g) in tetrahydrofuran (30 ml) were added 4 N aqueous solution of sodium hydroxide (30 ml) and water (20 ml), and stirred at room temperature overnight. After completion of the reaction, the organic solvent was evaporated in vacuo, then water and diethyl ether were added thereto, and the aqueous layer was separated. To the aqueous layer was added concentrated hydrochloric acid under ice-cooling to adjust the layer to pH 5, the precipitated solid was collected by filtration, washed, and then dried at 60° C. under air blow to give the titled compound (922 mg) as a white solid. MS (ESI) m/z: 278 (M+H)+.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH:11][S:12]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]([OH:25])=O)[CH:18]=[CH:19][CH:20]=1)(=[O:14])=[O:13].[Cl:26]CCl>CN(C)C=O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH:11][S:12]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]([Cl:26])=[O:25])[CH:18]=[CH:19][CH:20]=1)(=[O:14])=[O:13]
Reactant: ClCCl
Reactant: O=C(O)C=Cc1cccc(S(=O)(=O)Nc2ccc3ccccc3c2)c1
Solvent: CN(C)C=O
Product: O=C(Cl)C=Cc1cccc(S(=O)(=O)Nc2ccc3ccccc3c2)c1
Temperature: 40 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
To a suspension of 3-[3-(naphthalen-2-ylsulfamoyl)-phenyl]-acrylic acid (15e) (0.21 g, 0.57 mmol) in dichloromethane (2.5 ml) oxalyl chloride (0.15 ml, 1.71 mmol) and one drop of dimethylformamide were added. The reaction mixture was stirred at 40° C. for one hour and concentrated under reduced pressure to give crude title compound (0.21 g, 95%).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]1[CH:6]=[C:7]([S:11]([NH2:14])(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=1.[CH:15](I)([CH3:17])[CH3:16].Cl>CN(C=O)C.O>[OH:3][CH2:4][C:5]1[CH:6]=[C:7]([S:11]([NH:14][CH:15]([CH3:17])[CH3:16])(=[O:12])=[O:13])[CH:8]=[CH:9][CH:10]=1
Reactant: CC(C)I
Reactant: NS(=O)(=O)c1cccc(CO)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)NS(=O)(=O)c1cccc(CO)c1
Reaction time: 0.17 h

Procedure:
Sodium hydride (60% oil dispersion, 0.177 g) was added to 3-hydroxymethylbenzenesulfonamide (0.77 g) with stirring in DMF (15 ml) under nitrogen at 21°. After 10 min, isopropyl iodide (0.45 ml) was added followed by a further 0.3 ml after 1 h. After an additional 2 h more isopropyl iodide (0.2 ml) was added. After 3 days more sodium hydride oil dispersion (0.08 g) was added. After another day, the solution was poured into water acidified with 2M hydrochloric acid and the product was extracted with ethyl acetate twice. The combined extracts were washed with brine and evaporated to an oil. This oil was loaded onto a column of silica gel (60 g) and the column was eluted successively with 30%, 50% and 70% ethyl acetate in 40-60 petroleum ether to give the title compound (0.527 g) LCMS RT=2.22 min.
Reaction SMILES: C([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.Cl[C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][N:29]=1.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>ClCCl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[C:32]([C:31]1[CH:34]=[CH:35][C:28]([N:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:17][CH2:16][C:14]2[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:5])=[O:26])[S:12][CH:13]=2)=[N:29][CH:30]=1)#[N:33]
Reactant: N#Cc1ccc(Cl)nc1
Reactant: CCCCCCCNCCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)c1ccc(C#N)cn1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A compound obtained using 2-({4-[2-(heptylamino)ethyl]-1,3-thiazol-2-yl}thio)-2-methylpropionic acid tert-butyl ester synthesized in Example 303-2 and 6-chloronicotinonitrile as starting materials and by an operation similar to that of Example 303-3 was treated with dichloromethane and trifluoroacetic acid, and the mixture was stirred at room temperature for 12 hr. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; chloroform:methanol=50:1) to give the title compound.
Reaction SMILES: CO[N:3]=[C:4]1[CH2:13][CH2:12][C:11]2[CH:10]=[C:9]([CH2:14][C:15](OCC)=[O:16])[CH:8]=[CH:7][C:6]=2[CH2:5]1.C(O)C.[ClH:23].C(O)C>O1CCCC1>[ClH:23].[NH2:3][CH:4]1[CH2:13][CH2:12][C:11]2[CH:10]=[C:9]([CH2:14][CH2:15][OH:16])[CH:8]=[CH:7][C:6]=2[CH2:5]1
Reactant: CCOC(=O)Cc1ccc2c(c1)CCC(=NOC)C2
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Product: NC1CCc2cc(CCO)ccc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5.5 ml of 2M borane-methylsulfide complex in tetrahydrofuran are added to a solution of 1.31 g of ethyl 6-methoxyimino-5,6,7,8-tetrahydronaphthalene-2-acetate in tetrahydrofuran under argon at -5° to 0° C., and the mixture is stirred at room temperature overnight. Ethanol and 9% hydrogen chloride-ethanol are added to the mixture under cooing and stirring, and the mixture is stirred at room temperature for 30 minutes. After the solvent is distilled off, the residue is crystallized with a mixture of ethanol and ether to give 990 mg of 2-(6-amino-5,6,7,8-tetrahydronaphthalene-2-yl)ethanol hydrochloride as colorless solid.