Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH3:11])=[C:8]([NH2:12])[CH:7]=[CH:6][CH:5]=2.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]=[C:22]=[O:23])=[CH:16][CH:15]=1.CCCCCC>C1COCC1>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:20][NH:21][C:22]([NH:12][C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[C:10]([CH3:11])=[C:2]([CH3:1])[NH:3]3)=[O:23])=[CH:18][CH:19]=1
Reactant: O=C=NCc1ccc(Br)cc1
Reactant: Cc1[nH]c2cccc(N)c2c1C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1[nH]c2cccc(NC(=O)NCc3ccc(Br)cc3)c2c1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2,3-Dimethyl-4-aminoindole (0.11 g, 0.7 mmol) in THF (3 mL) was treated with 1-bromo-4-(isocyanatomethyl)benzene (0.17 g, 0.8 mmol) at ambient temperature. After stirring for 3 hours at ambient temperature, hexane was added to the reaction mixture to precipitate the title compound as a tan solid (0.12 g). mp 190° C. 1H NMR (300 MHz, DMSO-d6) δ 2.24 (s, 3H), 2.25 (s, 3H), 4.25 (d, 2H), 6.51 (t, 1H), 6.82 (t, 1H), 6.85 (d, 2H), 6.95 (m, 2H), 7.25 (d, 2H), 7.53 (d, 2H), 7.78 (s, 1H), 11.04 (s, 1H); MS (DCI+) m/z 346 (M+H)+; Anal. Calcd. for C18H18N3BrO: C, 58.08; H, 4.87; N, 11.29. Found: C, 57.97; H, 4.92; N, 11.30.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:7]=[CH:6][C:5]=1[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](O)=[O:28])=[C:22]([F:30])[CH:21]=1)[CH3:2].[Br:31][C:32]1[CH:37]=[C:36]([C:38]([CH3:44])([CH3:43])[C:39]([F:42])([F:41])[F:40])[N:35]=[CH:34][C:33]=1[NH2:45].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CC(=O)OCC>N1C=CC=CC=1>[Br:31][C:32]1[CH:37]=[C:36]([C:38]([CH3:43])([CH3:44])[C:39]([F:40])([F:41])[F:42])[N:35]=[CH:34][C:33]=1[NH:45][C:27](=[O:28])[CH2:26][C:23]1[CH:24]=[CH:25][C:20]([C:5]2[CH:6]=[N:7][C:8]([O:10][CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[CH:9][C:4]=2[O:3][CH2:1][CH3:2])=[CH:21][C:22]=1[F:30]
Reactant: CC(C)(c1cc(Br)c(N)cn1)C(F)(F)F
Reactant: CCOc1cc(OCc2ccc(OC)cc2)ncc1-c1ccc(CC(=O)O)c(F)c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCOc1cc(OCc2ccc(OC)cc2)ncc1-c1ccc(CC(=O)Nc2cnc(C(C)(C)C(F)(F)F)cc2Br)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.1 %

Procedure:
To a mixture of 2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (30 mg, 0.073 mmol) in pyridine (5 mL) was added 4-bromo-6-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-3-amine (20.64 mg, 0.073 mmol) and T3P® (EA solvate) (0.5 mL, 0.073 mmol). The mixture was stirred at 25° C. for 1 h. The mixture was concentrated and purified by preparative TLC (DCM/MeOH=15:1, Rf=0.6) to yield a light yellow solid of N-(4-bromo-6-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-3-yl)-2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide (30 mg, 0.038 mmol, 51.7% yield): 1H NMR (400 MHz, CD3OD): δ 8.84 (s, 1H), 7.99 (s, 1H), 7.90 (s, 1H), 7.46 (d, J=7.6 Hz, 1H), 7.40 (d, J=8.4 Hz, 2H), 7.33 (d, J=9.6 Hz, 2H), 6.94 (d, J=8.4 Hz, 2H), 6.48 (s, 1H), 5.30 (s, 2H), 4.16 (q, J=6.8 Hz, 2H), 3.93 (s, 2H), 3.82 (s, 3H), 1.63 (s, 6H), 1.40 (t, J=7.0 Hz, 3H). ES-LCMS m/z 678.0 (M+H+2).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([N+:14]([O-:16])=[O:15])=[C:8]([NH:10]C(=O)C)[CH:9]=1)[CH3:2]>Cl.O>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([N+:14]([O-:16])=[O:15])=[C:8]([CH:9]=1)[NH2:10])[CH3:2]
Reactant: CCOc1ccc([N+](=O)[O-])c(NC(C)=O)c1
Agent: Cl
Solvent: O
Product: CCOc1ccc([N+](=O)[O-])c(N)c1
Yield: 90.6 %

Procedure:
A suspension of N-(5-ethoxy-2-nitrophenyl)acetamide (2.3 g, 10.3 mmol) in 5 M HCl (50 mL) was stirred at reflux temperature for 8 h. The resulting solution was cooled, diluted with water (200 mL), the resulting precipitate filtered and washed with water (2×10 mL) and dried to give aniline 15 (1.70 g, 90%) as an orange powder, mp (H2O) 101-102° C.; 1H NMR δ 8.06 (d, J=9.5 Hz, 1 H, H-3), 6.27 (dd, J=9.5, 2.6 Hz, 1 H, H-4), 6.13 (d, J=2.6 Hz, 1 H, H-6), 5.80 (br s, 2 H, NH2), 4.04 (q, J=7.0 Hz, 2 H, CH2O), 1.42 (t, J=7.0 Hz, 3 H, CH3); 13C NMR δ 164.8, 147.1, 128.4, 126.8, 106.9, 99.0, 64.1, 14.5. Anal. Calcd for C8H10N2O3: C, 52.7; H, 5.5; N, 15.4. Found: C, 52.6; H, 5.5; N, 15.4%.
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:8]=[CH:9][C:10]2[O:14][CH:13]=[C:12]([CH3:15])[C:11]=2[CH:16]=1.F[S:18]([C:21]1[N:22]=[N:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1)(=[O:20])=[O:19]>C1COCC1>[CH3:28][O:27][C:24]1[N:23]=[N:22][C:21]([S:18]([C:13]2[O:14][C:10]3[CH:9]=[CH:8][C:7]([F:6])=[CH:16][C:11]=3[C:12]=2[CH3:15])(=[O:20])=[O:19])=[CH:26][CH:25]=1
Reactant: COc1ccc(S(=O)(=O)F)nn1
Reactant: Cc1coc2ccc(F)cc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)c2oc3ccc(F)cc3c2C)nn1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
n-Butyl lithium (2.5 M in hexane, 11 mmol, 4.83 mL) was added dropwise over 15 minutes to a solution of 5-fluoro-3-methyl benzofuran (11 mmol, 1.65 mg) in THF (20 mL) cooled to −78° C. To this was added 3-fluorosulfonyl-6-methoxy-pyridazine (11 mmol, 2.11 g) and stirred for 30 minutes. The reaction mixture was allowed to come to room temperature overnight and was then quenched with EtOAc (40 mL) and H2O (10 mL). The organic portion was collected, dried, filtered and the filtrate was evaporated to dryness to obtain a crude product, which was purified by silica gel chromatography (eluent: hexanes:EtOAc::4:1) to obtain the desired product: 3-methoxy-6-(5-fluoro-3-methyl-benzofuran-2-sulfonyl)-pyridazine (22%, 781 mg).
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17]/[CH:18]=[C:19](\[CH3:30])/[CH2:20][N:21]3[CH:26]=[C:25]([CH3:27])[C:24](=[O:28])[NH:23][C:22]3=[O:29])[CH2:13][CH2:12]2)[CH:8]=[C:7]([C:31]([F:34])([F:33])[F:32])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][CH:19]([CH3:30])[CH2:20][N:21]3[CH:26]=[C:25]([CH3:27])[C:24](=[O:28])[NH:23][C:22]3=[O:29])[CH2:15][CH2:16]2)[CH:8]=[C:7]([C:31]([F:33])([F:34])[F:32])[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C/C(=C\CN1CCN(c2cc(C(F)(F)F)nc(C(C)(C)C)n2)CC1)Cn1cc(C)c(=O)[nH]c1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1cn(CC(C)CCN2CCN(c3cc(C(F)(F)F)nc(C(C)(C)C)n3)CC2)c(=O)[nH]c1=O
Reaction time: 6 h

Procedure:
1-((2E)-4-{4-[2-tert-Butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}-2-methylbut-2-en-1-yl)-5-methylpyrimidine-2,4(1H,3H)-dione (Example 36, 1.04 mmol, 0.50 g) in methanol (5 ml) was hydrogenated over Pd (10% on activated carbon) with hydrogen at room temperature for 12 h and then at 40° C. for a further 6 h. The mixture was filtered and the residue was washed with methanol. The filtrate was concentrated and purified on silica gel (mobile phase: dichloromethane/methanol: 97/3 v/v); yield 0.20 g.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[C:10]1(=O)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][C:12](=[O:20])[O:11]1>C(O)(=O)C>[Br:1][C:2]1[C:3]([CH3:9])=[C:4]([N:5]2[C:12](=[O:20])[CH2:13][C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:10]2=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1c(N)cccc1Br
Reactant: O=C1Cc2ccccc2C(=O)O1
Solvent: CC(=O)O
Product: Cc1c(Br)cccc1N1C(=O)Cc2ccccc2C1=O
Temperature: 100 °C
Yield: 35.5 %

Procedure:
Step 1 A mixture of 3-bromo-2-methylaniline (1 g, 5.37 mmol) and isochroman-1,3-dione (0.872 g, 5.37 mmol) in acetic acid (15 mL) was heated overnight at 100° C. in a sealed tube. The mixture was cooled to rt and concentrated, and the residue was purified by column chromatography (eluting with a gradient from 80:20 hexane-EtOAc to EtOAc) to give 2-(3-bromo-2-methylphenyl)isoquinoline-1,3(2H,4H)-dione as a tan solid (630 mg, 36%). Mass spectrum m/z 330, 332 (M+H)+.
Reaction SMILES: [OH-].[Li+].[C:3]([NH:6][CH:7]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:20]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[N:21][N:22]([CH3:24])[CH:23]=2)=[CH:15][CH:14]=1)[C:8](OC)=[O:9])(=[O:5])[CH3:4].C(=O)(O)[O-].[Na+].[NH2:38][CH2:39][CH:40]([OH:47])[CH2:41][C:42]([CH3:46])([CH3:45])[CH2:43][CH3:44].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>O1CCCC1.O.O.C(Cl)Cl>[C:29]([O:28][C:26](=[O:27])[NH:25][C:20]1[C:19]([C:16]2[CH:17]=[CH:18][C:13]([CH2:12][CH:7]([NH:6][C:3](=[O:5])[CH3:4])[C:8]([NH:38][CH2:39][CH:40]([OH:47])[CH2:41][C:42]([CH3:46])([CH3:45])[CH2:43][CH3:44])=[O:9])=[CH:14][CH:15]=2)=[CH:23][N:22]([CH3:24])[N:21]=1)([CH3:31])([CH3:30])[CH3:32]
Reactant: COC(=O)C(Cc1ccc(-c2cn(C)nc2NC(=O)OC(C)(C)C)cc1)NC(C)=O
Reactant: CCC(C)(C)CC(O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCC(C)(C)CC(O)CNC(=O)C(Cc1ccc(-c2cn(C)nc2NC(=O)OC(C)(C)C)cc1)NC(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Lithium hydroxide (444 mg, 10.8 mmol) was added to an ambient temperature solution of methyl 2-(acetylamino)-3-(4-{3-[(tert-butoxycarbonyl)amino]-1-methyl-1H-pyrazol-4-yl}phenyl)propanoate (450 mg, 1.08 mmol) in tetrahydrofuran/water (10:1) (11 mL). After stirring at ambient temperature for 1 h, the reaction mixture was diluted with water and extracted with ethyl acetate. The aqueous phase was acidified with 1.5 N hydrochloric acid and extracted with ethyl acetate. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Sodium bicarbonate (727 mg, 8.66 mmol) was added to an ambient temperature solution of the crude residue, 1-amino-4,4-dimethylhexan-2-ol (314 mg, 2.16 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (415 mg, 2.16 mmol) and 1-hydroxybenzotriazole (292 mg, 2.16 mmol) in methylene chloride (20 mL). After stirring at ambient temperature overnight, the reaction was quenched with water and extracted with methylene chloride and ethyl acetate. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-100% ethyl acetate/hexane afforded tert-butyl[4-(4-{2-(acetylamino)-3-[(2-hydroxy-4,4-dimethylhexyl)amino]-3-oxopropyl}phenyl)-1-methyl-1H-pyrazol-3-yl]carbamate.
Reaction SMILES: [CH:1](=[O:5])[CH:2]([CH3:4])[CH3:3].[Cl:6][CH2:7][CH:8]([OH:13])[CH:9](O)[CH2:10][Cl:11].S(=O)(=O)(O)O>C(Cl)CCl>[CH:2]([CH:1]1[O:13][CH:8]([CH2:7][Cl:6])[CH:9]([CH2:10][Cl:11])[O:5]1)([CH3:4])[CH3:3]
Reactant: OC(CCl)C(O)CCl
Reactant: CC(C)C=O
Agent: O=S(=O)(O)O
Solvent: ClCCCl
Product: CC(C)C1OC(CCl)C(CCl)O1

Procedure:
A three-neck 5-mL flask fitted with a thermometer, mechanical stirrer, addition funnel, condenser and positive nitrogen atmosphere was charged with EDC (200 mL), isobutyraldehyde (11.3 g, 0.157 mole), and 1,4-dichloro-2,3-butanediol (25.0 g, 0.157 mole). Concentrated sulfuric acid (23.2 g) was added dropwise to the agitated mixture over thirty minutes, during which time a slight exotherm was noticed and the flask was immersed in an ice bath to maintain a reaction temperature of 17°-19° C. Stirring was then continued at ambient temperature (20° C.) for five hours.
Reaction SMILES: [Cu]([C:4]#[N:5])C#N.Br[C:7]1[CH:8]=[CH:9][C:10](/[C:15](/[C:34]2[CH:39]=[CH:38][C:37]([C:40]([CH3:43])([CH3:42])[CH3:41])=[CH:36][CH:35]=2)=[CH:16]/[C@@H:17]2[N:21]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=3[O:31][CH3:32])[C:20](=[O:33])[CH2:19][CH2:18]2)=[N:11][C:12]=1[O:13][CH3:14].O>CN(C)C=O>[C:40]([C:37]1[CH:36]=[CH:35][C:34](/[C:15](/[C:10]2[N:11]=[C:12]([O:13][CH3:14])[C:7]([C:4]#[N:5])=[CH:8][CH:9]=2)=[CH:16]\[C@H:17]2[CH2:18][CH2:19][C:20](=[O:33])[N:21]2[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=2[O:31][CH3:32])=[CH:39][CH:38]=1)([CH3:43])([CH3:41])[CH3:42]
Reactant: N#C[Cu]C#N
Reactant: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(C(C)(C)C)cc2)c2ccc(Br)c(OC)n2)c(OC)c1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(C(C)(C)C)cc2)c2ccc(C#N)c(OC)n2)c(OC)c1
Temperature: 180 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
Copper cyanide (27 mg) was added to a solution of (5R)-5-[(E)-2-(5-bromo-6-methoxypyridin-2-yl)-2-(4-tert-butylphenyl)ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one obtained in Reference Example 4-42(1) (90 mg) in N,N-dimethylformamide (5 mL), and the mixture was stirred at an external temperature of 180° C. for two hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saline, dried over magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→1:1) to give 6-{(E)-1-(4-tert-butylphenyl)-2-[(2R)-1-(2,4-dimethoxybenzyl)-5-oxopyrrolidin-2-yl]ethenyl}-2-methoxypyridine-3-carbonitrile (32 mg, 40%).
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]2[C:14](=[O:22])[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:16][N:7]3[C:8]=2[C:3]=1[CH:4](C(O)=O)[CH2:5][N:6]3[CH3:23].O>CN1CCCC1=O>[F:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]2[C:14](=[O:22])[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:16][N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][N:6]3[CH3:23]
Reactant: CCOC(=O)c1cn2c3c(c(F)c(F)c(F)c3c1=O)C(C(=O)O)CN2C
Solvent: CN1CCCC1=O
Solvent: O
Product: CCOC(=O)c1cn2c3c(c(F)c(F)c(F)c3c1=O)CCN2C
Temperature: 160 °C
Yield: 48.4 %

Procedure:
300 mg of the compound (197) obtained in Example 68 was dissolved in 6 ml of N-methylpyrrolidone, and the solution was heated at 160° C. for 3 hours. After air-cooling, the water was added to the reaction solution, and the solution was extracted with chloroform three times. After drying over magnesium sulfate, the solvent was removed by distillation. The residue was separated by column chromatography (silica gel, eluent solvent; chloroform) to obtain 128 mg of the subject compound (198) in a 49% yield.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[CH:15]=[C:14]([CH3:16])[O:13][N:12]=1)=O.C[O:18][C:19](=O)[CH:20]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:8][C:6]1[CH:7]=[C:2]2[C:3]([C:9]([C:11]3[CH:15]=[C:14]([CH3:16])[O:13][N:12]=3)=[CH:20][C:19](=[O:18])[O:1]2)=[CH:4][CH:5]=1
Reactant: Cc1ccc(C(=O)c2cc(C)on2)c(O)c1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1ccc2c(-c3cc(C)on3)cc(=O)oc2c1

Procedure:
A solution of (2-hydroxy-4-methylphenyl)(5-methylisoxazol-3-yl)methanone from step 3 (0.93 g, 4.28 mmol) and methyl(triphenylphosphoranylidene)acetate (1.86 g, 5.57 mmol) in toluene (30 mL) was heated to 90° C. for 2 h, concentrated in vacuo, and the residue washed with Et2O and hot acetone to afford the title compound. 1H NMR (400 MHz, acetone-d6): 8.18 (d, 1H), 7.27-7.19 (m, 2H), 6.77 (s, 1H), 6.67 (s, 1H), 2.60 (s, 3H), 2.52 (s, 3H).
Reaction SMILES: C(N1CCN(C2N=C(Br)C=C3C=CSC=23)CC1)C.[CH2:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27]2[N:28]=[C:29]([C:36]3[CH:41]=[CH:40][C:39]([O:42][CH2:43][C@H:44]([O:46]C(=O)C)[CH3:45])=[CH:38][CH:37]=3)[CH:30]=[C:31]3[CH:35]=[CH:34][S:33][C:32]=23)[CH2:23][CH2:22]1)[CH3:20].[ClH:50]>C(OCC)(=O)C>[ClH:50].[ClH:50].[CH2:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27]2[N:28]=[C:29]([C:36]3[CH:41]=[CH:40][C:39]([O:42][CH2:43][CH:44]([OH:46])[CH3:45])=[CH:38][CH:37]=3)[CH:30]=[C:31]3[CH:35]=[CH:34][S:33][C:32]=23)[CH2:23][CH2:22]1)[CH3:20]
Reactant: CCN1CCN(c2nc(-c3ccc(OC[C@@H](C)OC(C)=O)cc3)cc3ccsc23)CC1
Agent: CCN1CCN(c2nc(Br)cc3ccsc23)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: CCN1CCN(c2nc(-c3ccc(OCC(C)O)cc3)cc3ccsc23)CC1
Reaction time: 0.75 h

Procedure:
The resulting compound and 7-(1-ethylpiperazin-4-yl)-5-bromothieno[2,3-c]pyridine (0.29 g) were reacted in the same manner as in Example 300-4, to give a reaction solution containing 7-(4-ethylpiperazin-1-yl)-5-{4-[2-(R)-acetoxypropoxy]phenyl}thieno[2,3-c]pyridine. Ethyl acetate and 2N hydrochloric acid were added to the reaction solution, and the resulting insoluble matters were filtered off. The aqueous layer was separated, while the organic layer was extracted with 2N hydrochloric acid. The aqueous layers were combined and washed with ethyl acetate twice. The pH of the resulting solution was adjusted to pH 10 by adding a 8N aqueous solution of sodium hydroxide thereto, and subsequently, methanol was added thereto until the reaction solution became homogenous. The reaction solution was left as it was at room temperature for 45 min. The solvent was evaporated, and then water was added thereto and the mixture was extracted with ethyl acetate thrice. After washing with brine and drying over magnesium sulfate, the solvent was evaporated. The resulting residue was purified by NH silica gel column chromatography (ethyl acetate/n-hexane system), to give 0.22 g of the free compound of the title compound as a colorless viscous oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:13]=[C:14]([CH:20]=[CH:21][C:22]=3[CH3:23])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1.[CH2:24]1COCC1.CN1CCCC1=O.C[Mg]Br>CCOC(C)=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Fe+3]>[CH3:23][C:22]1[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][C:12]=1[C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([CH3:24])=[N:3][N:4]=[CH:5]2
Reactant: C1CCOC1
Reactant: CCOC(=O)c1ccc(C)c(-c2ccc3c(Cl)nncc3c2)c1
Agent: [Fe+3]
Agent: CC(=O)/C=C(/C)[O-]
Agent: C[Mg]Br
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(C)c(-c2ccc3c(C)nncc3c2)c1
Reaction time: 0.17 h

Procedure:
A 150-ml round-bottom flask under argon was charged with ethyl 3-(1-chlorophthalazin-6-yl)-4-methylbenzoate (358 mg, 1096 μmol), iron(III) acetylacetonate (38.7 mg, 109.6 □mol), THF (4200 μl), and 1-methyl-2-pyrrolidinone (420 μl). Methylmagnesium bromide (1.4M solution in toluene/tetrahydrofuran (75:25); 1174 μl, 1643 μmol) was then added via a syringe to the resulting orange red suspension, causing an immediate color change to brown, and finally to violet. The resulting mixture was stirred for 10 min, and the reaction (which remained a suspension) was diluted with EtOAc and carefully quenched with a few drops of 10% aqueous HCl solution. The mixture was washed with saturated aqueous NaHCO3 solution and the organic layer was dried (MgSO4), filtered, and concentrated in vacuo. CombiFlash purification (20% to 90% EtOAc in Hexanes) afforded ethyl 4-methyl-3-(1-methylphthalazin-6-yl)benzoate as a light golden brown oil. MS (ES+): 307.1 (M+H)+.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([N:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH2:14][CH:13]([C:27]([OH:29])=O)[CH2:12]2)=[O:10])[CH2:5][CH2:4]1)#[N:2].O[N:31]=[C:32]([C:34]1[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=1)[NH2:33]>>[N:36]1[CH:37]=[CH:38][CH:39]=[C:34]([C:32]2[N:33]=[C:27]([CH:13]3[CH2:14][CH:15]([C:17]4[CH:22]=[CH:21][C:20]([C:23]([F:25])([F:24])[F:26])=[CH:19][CH:18]=4)[CH2:16][N:11]([C:9]([N:6]4[CH2:7][CH2:8][CH:3]([C:1]#[N:2])[CH2:4][CH2:5]4)=[O:10])[CH2:12]3)[O:29][N:31]=2)[CH:35]=1
Reactant: N#CC1CCN(C(=O)N2CC(C(=O)O)CC(c3ccc(C(F)(F)F)cc3)C2)CC1
Reactant: NC(=NO)c1cccnc1
Product: N#CC1CCN(C(=O)N2CC(c3ccc(C(F)(F)F)cc3)CC(c3nc(-c4cccnc4)no3)C2)CC1

Procedure:
100 mg (0.244 mmol) of 1-[(4-cyanopiperidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 100A) and 36.8 mg (0.269 mmol) of N′-hydroxypyridine-3-carboximidamide were reacted according to the General Method 1. Yield: 58.6 mg (46% of theory).
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)=O.[CH:12]1([N:18]2[CH2:27][CH2:26][C:21]3([CH2:25][NH:24][CH2:23][CH2:22]3)[CH2:20][CH2:19]2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>>[CH:12]1([N:18]2[CH2:19][CH2:20][C:21]3([CH2:25][N:24]([CH2:1][C:3]4[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=4)[CH2:23][CH2:22]3)[CH2:26][CH2:27]2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: C1CCC(N2CCC3(CCNC3)CC2)CC1
Reactant: O=Cc1ccc(C(=O)O)cc1
Product: O=C(O)c1ccc(CN2CCC3(CCN(C4CCCCC4)CC3)C2)cc1
Yield: 169.2 %

Procedure:
Except for using 4-formylbenzoic acid (112 mg) in place of 4-(diethoxymethyl)benzaldehyde and using 8-cyclohexyl-2,8-diazaspiro[4.5]decane (170 mg) in place of 8-isobutyl-2,8-diazaspiro[4.5]decane, the same operation as in Example 26 was performed to obtain the title compound (450 mg) having the following physical properties.
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]([O:15][C@H:16]2[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:18]([C:28]([O:30][CH3:31])=[O:29])[CH2:17]2)[CH:12]=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd].CCO>[OH:8][C:9]1[N:14]=[C:13]([O:15][C@H:16]2[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[C@H:18]([C:28]([O:30][CH3:31])=[O:29])[CH2:17]2)[CH:12]=[CH:11][CH:10]=1
Reactant: COC(=O)[C@@H]1C[C@@H](Oc2cccc(OCc3ccccc3)n2)CN1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: COC(=O)[C@@H]1C[C@@H](Oc2cccc(O)n2)CN1C(=O)OC(C)(C)C
Yield: 96 %

Procedure:
A Parr jar was charged with the product of Step 3 (6.50 g, 15.17 mmol), EtOH (100 ml), and 10% Pd/C (0.250 g, 2.349 mmol). Hydrogenated at 48 psi. Reaction complete after 18 hours. Filtered through celite. Evaporation of the filtrate gave the title compound as a white foam. (4.95 g, 14.63 mmol, 96% yield). LCMS (ES+) m/z 339.3 (M+H)+.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([C:12]#[C:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[C:9]([OH:18])=[CH:8][N:7]=1)(=[O:3])[CH3:2]>N1C=CC=CC=1.[Cu]I>[C:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10]2[CH:12]=[C:13]([Si:14]([CH3:16])([CH3:15])[CH3:17])[O:18][C:9]2=[CH:8][N:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1cc(C#C[Si](C)(C)C)c(O)cn1
Agent: [Cu]I
Solvent: c1ccncc1
Product: CC(=O)OCc1cc2cc([Si](C)(C)C)oc2cn1
Yield: 22.4 %

Procedure:
{5-Hydroxy-4-[(trimethylsilyl)ethynyl]-2-pyridinyl}methyl acetate (8.3 g, 22 mmol) was dissolved in pyridine (200 ml) and treated with copper(I) iodide (5.2 g, 27 mmol) then heated under reflux for 18 h. The mixture was allowed to cool then evaporated to dryness. The residue was partitioned between water and ethyl acetate then filtered through kieselguhr. The organic layer was separated washed with more water then saturated brine solution then dried. Chromatography on silica gel eluting with 40-60 petrol and ethyl acetate gradient provided the two title compounds, (1.15 g, 27%) of furo[2,3-c]pyridin-5-ylmethyl acetate and (1.3 g, 22%) of [2-(trimethylsilyl)furo[2,3-c]pyridin-5-yl]methyl acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[NH:4][C:5](=[O:14])[C:6](=[O:13])[NH:7]2.[NH2:15]OS(O)(=O)=O>[OH-].[K+].O>[NH2:15][N:7]1[C:8]2[C:3](=[C:2]([Cl:1])[CH:11]=[C:10]([Cl:12])[CH:9]=2)[NH:4][C:5](=[O:14])[C:6]1=[O:13]
Reactant: O=c1[nH]c2cc(Cl)cc(Cl)c2[nH]c1=O
Reactant: NOS(=O)(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Nn1c(=O)c(=O)[nH]c2c(Cl)cc(Cl)cc21
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 68.6 %

Procedure:
The procedure of Wallace, R. G., Org. Prep. Proc. Int. 14:269 (1982) was adapted. 5,7-Dichloro-1,4-dihydroquinoxaline-2,3-dione (52 mg, 0.225 mmole) was dissolved in 3N KOH (1 mL) at 60° C. for 0.5 h, and NH2OSO3H (30 mg, 0.265 mmole, Aldrich) in distilled water (0.5 mL) was dropwise added into above solution with stirring at 60° C. Some precipitate came out after 15 mins. The mixture was stirred at room temperature overnight. The white precipitate was collected by filtration, washed with cold distilled water (0.5 mL) and dried on rotavapor at 60° C. for 2 h affording crude 1-amino-5,7-dichloro-1,4-dihydro-2,3-quinoxalinedione (38 mg, 69%), which included a little of the isomer (4-amino-5,7-dichloro-2,3-quinoxalinedione) by 1H NMR (it is not known which isomer is present in a greater amount).