Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:11]2[N:12]=[N:13][C:14]3[C:19]([C:20]=2[OH:21])=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:10])[CH:5]=[CH:6][CH:7]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23].N1C=CC=CC=1>CN(C)C=O>[C:22]([NH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:11]2[N:12]=[N:13][C:14]3[C:19]([C:20]=2[OH:21])=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:10])[CH:5]=[CH:6][CH:7]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc(NC(=O)c2nnc3ccccc3c2O)c1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(=O)Nc1cccc(NC(=O)c2nnc3ccccc3c2O)c1
Temperature: 0 °C

Procedure:
N-(3-Amino-phenyl)-4-hydroxy-cinnoline-3-carboxamide (1 g) is reacted with acetic anhydride (5 ml) in dimethylformamide (50 ml) in the presence of pyridine (5 ml) at 80° C. for 2 hours. After cooling the reaction mixture is diluted with ice water and the precipitate is filtered and washed with water: washing with hot ethanol gives 0.75 g of N-(3-acetylamino-phenyl)-4-hydroxy-cinnoline-3-carboxamide.
Reaction SMILES: [CH:1]1([CH2:4][C:5]#[N:6])[CH2:3][CH2:2]1.[Li]CCCC.[O:12]=[C:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:29][C@H:28]([CH2:30][NH:31][C:32](=[O:34])[CH3:33])[O:27][C:26]3=[O:35])=[CH:21][C:20]=2[F:36])[CH2:15][CH2:14]1>O1CCCC1>[CH:1]1([CH:4]([C:13]2([OH:12])[CH2:14][CH2:15][N:16]([C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH2:29][C@H:28]([CH2:30][NH:31][C:32](=[O:34])[CH3:33])[O:27][C:26]4=[O:35])=[CH:21][C:20]=3[F:36])[CH2:17][CH2:18]2)[C:5]#[N:6])[CH2:3][CH2:2]1
Reactant: N#CCC1CC1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(=O)CC3)c(F)c2)C(=O)O1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(O)(C(C#N)C4CC4)CC3)c(F)c2)C(=O)O1
Reaction time: 1 h
Yield: 64 %

Procedure:
A mixture of cyclopropyl acetonitrile (28 mmol) and was treated with n-BuLi (28 mmol) at −78° C. in tetrahydrofuran and was stirred for 1 hour. Addition of (S)-N-{3-[4-(4-oxo-piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (14.32 mmol) was done to the reaction mixture and stirred overnight. The reaction mixture was quenched with saturated ammonium chloride solution and was extracted with ethyl acetate. The organic layer was concentrated, dried and evaporated to afford a residue which was purified on silica gel column chromatography to provide title compound in 64% yield. M.P. 170-72° C. and MS (M+1)=431 (H+, 100%) for M.F.=C22H27FN4O4.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].Br[CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=1[O:25][CH3:26]>O1CCOCC1.[Ag-]=O>[CH3:26][O:25][C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][C:15]=1[CH2:14][C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[NH:9][CH:8]=1)[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Agent: O=[Ag-]
Solvent: C1COCCO1
Product: COC(=O)c1ccc(Cc2c[nH]c3ccc([N+](=O)[O-])cc23)c(OC)c1
Temperature: 60 °C
Reaction time: 20 h
Yield: 43.8 %

Procedure:
Silver (I) oxide (7.15 g.) was added to a solution of 5-nitroindole (5 g.) and methyl 4-bromomethyl-3-methoxybenzoate (B) (7.99 g.) in dioxane (30 ml.), under a nitrogen atmosphere. The mixture was stirred at 60° C. for 20 hours, dioxane removed by evaporation and ethyl acetate (50 ml.) added to the residue. The resulting suspension was separated by filtration through diatomaceous earth. The filtrate was evaporated to give a dark viscous oil, which was purified by flash chromatography on silica gel (600 ml.), eluting with 3:7 v/v ethyl acetate:hexane. The viscous yellow oil obtained was crystallized from a mixture of dichloromethane and hexane to give methyl 3-methoxy-4-(5-nitroindol-3-ylmethyl)benzoate (C) (4.6 g., 45%) as yellow needles, m.p. 153°-155° C. NMR: 3.83(s,3H, COOCH3), 3.93(s,3H, OCH3), 4.12(s,2H, CH2. Ar), 7.25(d,1H), 7.43(d,1H), 7.49(m,3H), 7.95(dd, 1H, H6 -indole), 8.47(d,1H, H4 -indole), 11.65(broad s,1H, H1 -indole).
Reaction SMILES: C[O:2][C:3](=[O:51])[CH2:4][N:5]([C:11]1[CH:16]=[C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:14]=[C:13]([O:36][CH2:37][CH2:38][CH2:39][O:40][C:41]2[CH:46]=[CH:45][C:44]([C:47]([CH3:50])([CH3:49])[CH3:48])=[CH:43][CH:42]=2)[CH:12]=1)[CH2:6][C:7]([O:9]C)=[O:8].[OH-].[Na+].O1CCOCC1>CO>[C:3]([CH2:4][N:5]([C:11]1[CH:16]=[C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:14]=[C:13]([O:36][CH2:37][CH2:38][CH2:39][O:40][C:41]2[CH:46]=[CH:45][C:44]([C:47]([CH3:48])([CH3:50])[CH3:49])=[CH:43][CH:42]=2)[CH:12]=1)[CH2:6][C:7]([OH:9])=[O:8])([OH:51])=[O:2]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(OCCCOc2ccc(C(C)(C)C)cc2)cc(N(CC(=O)OC)CC(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: CCCCCCCCCCCCCCCCCCOc1cc(OCCCOc2ccc(C(C)(C)C)cc2)cc(N(CC(=O)O)CC(=O)O)c1
Yield: 92.3 %

Procedure:
A solution of 0.815 g (1.14 mmol) of N-[3-[3-[4-(1,1-dimethylethyl)phenoxy]propoxy]-5-(octadecyloxy)phenyl]-N-(2-methoxy-2-oxoethyl)glycine methyl ester and 0.76 mL of 6N NaOH in 20 mL of methanol-10 mL of dioxane was stirred at reflux under argon for 5 hours. The solvents were removed at reduced pressure, the residue was acidified with dilute HCl and the product was extracted with ethyl acetate. The dried extract was concentrated at reduced pressure and the residue was crystallized from methanol-water to give 0.72 g (92% yield, mp99°-101°) of N-(carboxymethyl)-N-[3-[3-[4-(1,1-dimethylethyl)phenoxy]propoxy]-5-(octadecyloxy) phenyl]glycine.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8][CH2:9][CH2:10][CH2:11][C:12]([NH2:14])=[O:13])[N:3]=1.[NH3:15]>O>[NH2:15][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8][CH2:9][CH2:10][CH2:11][C:12]([NH2:14])=[O:13])[N:3]=1
Reactant: NC(=O)CCCSc1cccc(Br)n1
Reactant: N
Solvent: O
Product: NC(=O)CCCSc1cccc(N)n1

Procedure:
A mixture of 4-(2-bromopyrid-6-ylthio)butyramide (5 g.) and concentrated aqueous ammonia (25 ml.) was heated in a sealed tube at 180° for 24 hours. The mixture was cooled and diluted with water, and then extracted twice with EtOAc. The combined extracts were extracted twice with N aqueous HCl and the aqueous acid extracts were combined, basified with 10N aqueous NaOH, and extracted with EtOAc. The EtOAc extract was dried and evaporated to dryness to give 4-(2-aminopyrid-6-ylthio)butyramide.
Reaction SMILES: [C:1](=[O:26])([O:7][C:8]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:11]=[C:10]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21](I)[CH:20]=2)[CH:9]=1)[O:2][C:3]([CH3:6])([CH3:5])[CH3:4].C(=O)(OC(C)(C)C)OC1N(C2C=CC=CN=2)N=C([C:40]2[CH:45]=[CH:44][C:43](Br)=[CH:42][CH:41]=2)C=1>>[C:1](=[O:26])([O:2][C:3]([CH3:6])([CH3:5])[CH3:4])[O:7][C:8]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:11]=[C:10]([C:19]2[CH:20]=[C:21]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH:22]=[CH:23][CH:24]=2)[CH:9]=1
Reactant: CC(C)(C)OC(=O)Oc1cc(-c2cccc(I)c2)nn1-c1ccccn1
Reactant: CC(C)(C)OC(=O)Oc1cc(-c2ccc(Br)cc2)nn1-c1ccccn1
Product: CC(C)(C)OC(=O)Oc1cc(-c2cccc(-c3ccccc3)c2)nn1-c1ccccn1
Yield: 89 %

Procedure:
The title compound was prepared in the same manner as in Example C-1, except that an equimolar amount of 3-(3-iodophenyl)-1-(pyridin-2-yl)-1H-pyrazol-5-yl tert-butyl carbonate (23) prepared in Example B-4 was used in place of Compound 21 prepared in Example B-2.
Reaction SMILES: [F:1][C:2]([F:51])([F:50])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[S:30][C:29]([C:31]5[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=5[CH3:40])=[N:28][C:27]=4[C:41]([CH3:44])([CH3:43])[CH3:42])=[CH:24][N:23]=[C:22](S(C)(=O)=O)[N:21]=3)[C@H:14]2[CH3:49])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl.[F:53][CH:54]1[CH2:57][NH:56][CH2:55]1.CCN(C(C)C)C(C)C>C1COCC1>[F:11][C:9]([F:10])([F:12])[C:7]1[CH:6]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[S:30][C:29]([C:31]5[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=5[CH3:40])=[N:28][C:27]=4[C:41]([CH3:44])([CH3:42])[CH3:43])=[CH:24][N:23]=[C:22]([N:56]4[CH2:57][CH:54]([F:53])[CH2:55]4)[N:21]=3)[C@H:14]2[CH3:49])[CH:4]=[C:3]([C:2]([F:1])([F:51])[F:50])[CH:8]=1
Reactant: FC1CNC1
Reactant: Cc1cc(C(=O)O)ccc1-c1nc(C(C)(C)C)c(-c2cnc(S(C)(=O)=O)nc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)s1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)O)ccc1-c1nc(C(C)(C)C)c(-c2cnc(N3CC(F)C3)nc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)s1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 93 %

Procedure:
To a solution of 4-{5-[4-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2-(methylsulfonyl)pyrimidin-5-yl]-4-tert-butyl-1,3-thiazol-2-yl}-3-methylbenzoic acid (INTERMEDIATE 52, 180 mg, 0.106 mmol) in THF (5 mL) was added 3-fluoroazetidine hydrochloride (35.4 mg, 0.317 mmol) and DIEA (0.092 mL, 0.529 mmol). It was stirred at 60° C. for 15 minutes to see complete conversion by LCMS. The solvent was evaporated, and the residue was purified on reverse phase HPLC, eluting with water and acetonitrile (10% to 100%), to give the title compound as a yellowish solid after lyophilization (74 mg, 93% yield). LCMS (M+H)+: 752.05. 1H NMR (CDCl3, 500 MHz): δ8.36 (s, 1H), 8.08 (s, 1H), 8.00 (s, 1H), 7.93 (s, 1H), 7.87 (m, 1H), 7.79 (s, 2H), 5.80 (d, 9.0 Hz, 1H), 4.75 (m, 4H), 4.61-4.53 (m, 4H), 4.47 (m, 1H), 4.09 (m, 1H), 3.76 (s, 3H), 1.33 (s, 9H), 0.82 (d, 7.0 Hz, 3H). RTA IC50: 197 nM.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([N:13]3[CH2:20][CH:19]4[CH:15]([CH2:16][NH:17][CH2:18]4)[CH2:14]3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][O:22][C:23]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:24]=1[C:25](O)=[O:26]>>[CH3:21][O:22][C:23]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:24]=1[C:25]([N:17]1[CH2:16][CH:15]2[CH:19]([CH2:20][N:13]([C:9]3[N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:12]=[CH:11][N:10]=3)[CH2:14]2)[CH2:18]1)=[O:26]
Reactant: COc1ccc(C(=O)O)c(OC)c1
Reactant: c1ccc(-c2ccnc(N3CC4CNCC4C3)n2)cc1
Product: COc1ccc(C(=O)N2CC3CN(c4nccc(-c5ccccc5)n4)CC3C2)c(OC)c1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 26 and 2,4-dimethoxybenzoic acid. MS (ESI) mass calcd. for C25H26N4O3, 430.51; m/z found, 431.2 [M+H]+.
Reaction SMILES: [N:1]1([C:11]([C:13]2[CH:17]=[C:16]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[S:15][CH:14]=2)=[O:12])[C@@H:10]2[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1.Cl[C:25](OC1C=CC([N+]([O-])=O)=CC=1)=[O:26].[NH2:37][CH2:38][CH2:39][OH:40]>C(Cl)Cl>[OH:40][CH2:39][CH2:38][NH:37][C:25]([N:21]1[CH2:20][CH2:19][CH:18]([C:16]2[S:15][CH:14]=[C:13]([C:11]([N:1]3[C@@H:10]4[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]4)[CH2:4][CH2:3][CH2:2]3)=[O:12])[CH:17]=2)[CH2:23][CH2:22]1)=[O:26]
Reactant: NCCO
Reactant: O=C(c1csc(C2CCNCC2)c1)N1CCC[C@@H]2CCCC[C@@H]21
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Product: O=C(NCCO)N1CCC(c2cc(C(=O)N3CCC[C@@H]4CCCC[C@@H]43)cs2)CC1
Yield: 50.4 %

Procedure:
cis-(octahydro-quinolin-1-yl)-(5-piperidin-4-yl-thiophen-3-yl)-methanone (CC-033) (0.095 g, 0.28 mmol) and 4-nitrophenyl chloroformate (0.29 mmol) were dissolved in DCM (4 mL) and TEA (0.3 mmol) and the resulting mixture stirred overnight. The mixture was diluted with DCM (25 mL) and washed with aqueous citric acid (10% w/v) and saturated aqueous sodium hydrogen carbonate and then brine. After drying with magnesium sulphate, the mixture was filtered and the solvent evaporated to give a clear gum. DCM (3 mL) was added together with 2-aminoethanol (0.26 mmol). The mixture was refluxed overnight and then diluted with DCM (10 mL) and washed with aqueous citric acid (10% w/v) and 2M aqueous sodium carbonate and then brine. After drying with magnesium sulphate, the mixture was filtered and the solvent evaporated to give a yellow gum which was purified by HPLC eluting with 10%-98% acetonitrile in water (0.1% formic acid). The fractions containing the desired product were concentrated under vacuum to give the title compound (0.055 g). LCMS m/z 420.30 [M+H]+ RT=8.68 min (Analytical Method 2).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1.[NH2:35][C:36]1[CH:44]=[C:43]([O:45][CH3:46])[CH:42]=[C:41]([O:47][CH3:48])[C:37]=1[C:38]([NH2:40])=[O:39]>CC(N(C)C)=O.O>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:18]=[CH:17][C:14]([C:15]3[NH:40][C:38](=[O:39])[C:37]4[C:36](=[CH:44][C:43]([O:45][CH3:46])=[CH:42][C:41]=4[O:47][CH3:48])[N:35]=3)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Reactant: CC(C)N1CCN(Cc2ccc(C=O)cc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(CN4CCN(C(C)C)CC4)cc3)nc2c1
Temperature: 130 °C
Reaction time: 8 h
Yield: 29.8 %

Procedure:
A mixture of 4-((4-isopropylpiperazin-1-yl)methyl)benzaldehyde (0.240 g, 0.97 mmol), NaHSO3 (0.155 g, 1.50 mmol), and p-TsOH (0.019 g, 0.10 mmol) was added to a solution of 2-amino-4,6-dimethoxybenzamide (0.190 g, 0.97 mmol) in DMA (7 mL). The reaction was stirred at 130° C. overnight. Then, the mixture was diluted with H2O and extracted with CH2Cl2. The organics were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 2% to 10% MeOH/CH2Cl2, afforded the title compound (0.122 g, 30%) as a light yellow solid. 1H NMR (300 MHz, DMSO-d6): δ 12.02 (s, 1H), 8.12 (d, J=8.0 Hz, 2H), 7.43 (d, J=8.0 Hz, 2H), 6.74 (s, 1H), 6.53 (s, 1H), 3.89 (s, 3H), 3.85 (s, 3H), 3.51 (s, 2H), 2.54-2.71 (m, 1H), 2.27-2.44 (m, 8H), 0.95 (d, J=6.4 Hz, 6H). ESI MS m/z 423 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)#[C:2][CH2:3][CH3:4].[C:11]1([CH3:24])[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[C:12]=1[S:19]([O:22][NH2:23])(=[O:21])=[O:20].C(OCC)C>ClCCl>[C:11]1([CH3:24])[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[C:12]=1[S:19]([O-:22])(=[O:21])=[O:20].[NH2:23][N+:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:1]#[C:2][CH2:3][CH3:4]
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Reactant: CCC#Cc1ccccn1
Solvent: CCOCC
Solvent: ClCCl
Product: CCC#Cc1cccc[n+]1N
Product: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Reaction time: 0.5 h
Yield: 39.1 %

Procedure:
To a solution of 2-(1-butynyl)pyridine (12.8 g) dissolved in dichloromethane (60 mL) was added a solution of O-mesitylenesulfonylhydroxylamine (Reference; Synthesis, 1997, 1) (20 g) in dichloromethane (132 mL) while cooling with ice, and the reaction mixture was stirred for 30 minutes. Diethyl ether (2 L) was added to the reaction mixture to precipitate crystals, which were filtered off and then dried under reduced pressure to afford a crude product of N-amino-2-(1-butynyl)pyridinium mesitylenesulfonate (12.6 g) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[N+:26]([O-])=O)=[CH:16][CH:15]=3)[C:9]([CH2:11][CH3:12])=[N:10][C:5]2=[C:4]([CH3:29])[CH:3]=1.[H][H]>C(O)C.[Pd]>[NH2:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:17]1[CH:18]=[CH:19][C:14]([CH2:13][N:8]2[C:6]3=[N:7][C:2]([CH3:1])=[CH:3][C:4]([CH3:29])=[C:5]3[N:10]=[C:9]2[CH2:11][CH3:12])=[CH:15][CH:16]=1
Reactant: [H][H]
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(-c2ccccc2[N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(-c2ccccc2N)cc1
Reaction time: 1.5 h
Yield: 95.6 %

Procedure:
To a solution of 0.340 g (0.88 mmol) of the product of Step 1 in 15 mL of absolute ethanol was added 35 mg of 10% palladium on carbon catalyst and the mixture was hydrogenated at 40 psi of hydrogen on a Parr apparatus. Reduction was complete after 1.5 hours and the reaction mixture was filtered and evaporated in vacuo to afford a tan solid (0.300 g, 95%) which was used in the subsequent step without further purification: NMR (CDCl3) δ 1.33 (t, J=10 Hz, 3H), 2.59 (s, 3H), 2.64 (s, 3H), 2.84 (q, J=10 Hz, 2H), 3.70 (br s, 2H), 5.48 (s, 2H), 6.70-6.82 (m, 2H), 6.90 (s, 1H), 7.03-7.22 (m, 4H), 7.36 (d, J=10 Hz, 2H); MS (FAB) m/e 357 (MH+).
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([O:6][CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)=[CH:4][CH:3]=1.[CH:15]([C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1)=[O:16].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH:7]1[O:6][C:5]1[CH:13]=[CH:14][C:2]([C:20]2[CH:21]=[CH:22][C:17]([CH:15]=[O:16])=[CH:18][CH:19]=2)=[CH:3][CH:4]=1
Reactant: Brc1ccc(OC2CCCCO2)cc1
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=Cc1ccc(-c2ccc(OC3CCCCO3)cc2)cc1
Temperature: 95 °C
Yield: 45.2 %

Procedure:
2-(4-Bromophenoxy)tetrahydropyran (3.0 g) was dissolved in N,N-dimethylformamide (30 ml). 4-Formylphenylboronic acid (2.1 g), tetrakis(triphenylphosphine)palladium (0) (1.35 g) and tripotassium phosphate (4.95 g) were added thereto, and the resulting mixture was heated at 90 to 100° C. under a nitrogen atmosphere for 3 hours. After completion of the reaction, ethyl acetate was added to the reaction mixture and filtered through Celite. The filtrate was separated into layers. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→50:50) to afford the title compound as a white powder (1.49 g).
Reaction SMILES: C([O:8][C:9]1[CH:30]=[CH:29][C:12]([CH2:13][C:14]2[CH:18]=[C:17]([C:19]3[C:20]([NH2:28])=[N:21][C:22]([CH2:25][O:26][CH3:27])=[CH:23][CH:24]=3)[O:16][N:15]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.ClCCl.B(Br)(Br)Br>CO>[NH2:28][C:20]1[C:19]([C:17]2[O:16][N:15]=[C:14]([CH2:13][C:12]3[CH:29]=[CH:30][C:9]([OH:8])=[CH:10][CH:11]=3)[CH:18]=2)=[CH:24][CH:23]=[C:22]([CH2:25][O:26][CH3:27])[N:21]=1
Reactant: COCc1ccc(-c2cc(Cc3ccc(OCc4ccccc4)cc3)no2)c(N)n1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: COCc1ccc(-c2cc(Cc3ccc(O)cc3)no2)c(N)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 19.7 %

Procedure:
To a mixture of 3-(3-(4-benzyloxy-benzyl)-isoxazol-5-yl)-6-methoxymethyl-pyridin-2-ylamine (30 mg, 0.075 mmol) described in Example 26 and dichloromethane (1 mL) was added boron tribromide (220 μL, 1 M dichloromethane solution, 0.22 mmol) at −78° C., which was stirred for 1 hour at 0° C. The reaction mixture was cooled to −78° C., methanol was added at the same temperature, and the excess boron tribromide was quenched. The reaction mixture was gradually allowed to room temperature, a sodium acetate aqueous solution was added to the reaction mixture at room temperature, which was neutralized, after which water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and was concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=2:1) to obtain the title compound (4.6 mg, 20%).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.C(=O)([O-])[O-:9].C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])[O-].[K+].[K+].[C:24]([O-:27])(=[O:26])[CH3:25].[C:28]([O-:31])(=[O:30])[CH3:29].[Na+].C([O-])(=O)C.[K+]>O1CCCC1.C(#N)C.CC(C)=O>[C:1]([O-:6])(=[O:7])/[CH:2]=[CH:3]\[C:4]([O-:9])=[O:5].[C:28]([O-:31])(=[O:30])/[CH:29]=[CH:25]/[C:24]([O-:27])=[O:26]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)[O-]
Reactant: O=C1C=CC(=O)O1
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CC#N
Solvent: C1CCOC1
Product: O=C([O-])/C=C/C(=O)[O-]
Product: O=C([O-])/C=C\C(=O)[O-]

Procedure:
Specifically, the procedure is as follows. First, vitamin E (II) is reacted with maleic anhydride (III) in the presence of an alkaline carbonate (sodium carbonate, potassium carbonate or the like) or an alkaline acetate (sodium acetate, potassium acetate or the like) in a nonpolar solvent such as acetone, acetonitrile or tetrahydrofuran (THF) for about 1 to 3 hours while heating to give mono-tocopheryl maleate (or fumarate) (IV) (which is a novel compound not found in publications so far). The compound (IV) thus produced may further be subjected to a condensation reaction with an amino acid (glycine, β-alanine, γ-aminobutyric acid, 5-aminovaleric acid, ε-aminocaproic acid, anthranilic acid, tranexamic acid, proline, one of their esters, aminoethylsulfonic acid, or aminoethylsulfinic acid) or an amine (serotonin) in a solvent such as chloroform or tetrahydrofuran in the presence of an organic amine (pyridine, triethylamine or the like) according to the mixed anhydride method using ethyl chloroformate or the like to give a corresponding acid amide (V) of mono-tocopheryl maleate (or fumarate) (IV). The compound (IV) or (V) then is subjected to an addition reaction with an SH compound (glutathione, γ-glutamylcysteine, cysteine, penicillamine, an ester thereof, or cysteamine), a component of the present compound, at room temperature for about 3 to 6 hours and then about 1 to 3 hours while warming to give the present compound (I). A reaction solvent for this may be water or a solvent miscible with water, e.g., alcohol, acetonitrile or dioxane, which preferably is used as a mixture with water.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([NH:25][CH:26]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27]2)=[N:23][CH:24]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:18][C:19]1[CH:20]=[CH:21][C:22]([NH:25][CH:26]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27]2)=[N:23][CH:24]=1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(N)cn2)C1
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)C1
Yield: 81.5 %

Procedure:
Following General procedure C, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (311 mg, 1 mmol) was reacted with tert-butyl 3-(5-aminopyridin-2-ylamino)pyrrolidine-1-carboxylate (417 mg, 1.5 mmol) to afford the desired product (450 mg, 98%) as a yellow solid: ESI MS m/z 552 [C27H30BrN5O3+H]+.
Reaction SMILES: [CH:1]([NH:4]/[C:5](/SC)=[CH:6]/[C:7]#[N:8])([CH3:3])[CH3:2].O.[NH2:12][NH2:13]>CCO>[CH:1]([NH:4][C:5]1[CH:6]=[C:7]([NH2:8])[NH:13][N:12]=1)([CH3:3])[CH3:2]
Reactant: CS/C(=C\C#N)NC(C)C
Reactant: NN
Solvent: CCO
Solvent: O
Product: CC(C)Nc1cc(N)[nH]n1
Temperature: 25 °C
Yield: 62.4 %

Procedure:
A mixture of (Z)-3-(isopropylamino)-3-(methylthio)acrylonitrile (0.413 g, 2.64 mmol) and hydrazine monohydrate (0.38 mL, 7.93 mmol) in EtOH (6 mL) was heated to reflux for 16 hours. After cooling to room temperature, the reaction mixture was concentrated. The residue was purified by column chromatography, eluting with ethyl acetate, DCM/MeOH (9:1) to give N3-isopropyl-1H-pyrazole-3,5-diamine (0.231 g, 62% over 2 steps) as an oil.