Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:14][C:13]3[CH:15]=[C:16]([C:19]4[CH:20]=[C:21]5[NH:27][C:26]([CH3:28])=[N:25][C:22]5=[N:23][CH:24]=4)[CH:17]=[CH:18][C:12]=3[O:11][CH2:10][CH2:9]2)[C:3]=1[CH3:29].[CH2:30]([NH2:32])[CH3:31]>CN1CCCC1=O.C(OCC)(=O)C>[CH2:30]([NH:32][C:2]1[C:3]([CH3:29])=[C:4]([N:8]2[CH2:14][C:13]3[CH:15]=[C:16]([C:19]4[CH:20]=[C:21]5[NH:27][C:26]([CH3:28])=[N:25][C:22]5=[N:23][CH:24]=4)[CH:17]=[CH:18][C:12]=3[O:11][CH2:10][CH2:9]2)[N:5]=[CH:6][N:7]=1)[CH3:31]
Reactant: CCN
Reactant: Cc1nc2ncc(-c3ccc4c(c3)CN(c3ncnc(Cl)c3C)CCO4)cc2[nH]1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCNc1ncnc(N2CCOc3ccc(-c4cnc5nc(C)[nH]c5c4)cc3C2)c1C
Yield: 28.4 %

Procedure:
A suspension of 4-(6-chloro-5-methylpyrimidin-4-yl)-7-(2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine (44 mg, 0.11 mmol), and ethylamine (29 mg, 0.65 mmol), in N-methylpyrrolidinone (2 mL) was stirred at 100° C. for 6 h. The reaction mixture was diluted with ethyl acetate (75 mL), washed with saturated sodium bicarbonate (75 mL) and brine (50 mL), and dried over sodium sulfate. Concentration and purification by preparatory HPLC (0.1% aqueous ammonium acetate-acetonitrile) gave N-ethyl-5-methyl-6-[7-(2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]pyrimidin-4-amine (13 mg, 30% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.50 (s, 1H), 8.07 (s, 1H), 8.04 (d, 1H), 7.56-7.48 (m, 2H), 7.11 (d, 1H), 4.57 (s, 2H), 4.33 (d, 2H), 3.79 (d, 2H), 3.53-3.39 (q, 2H), 2.64 (s, 3H), 2.04 (s, 3H), 1.21 (t, 3H); MS (EI) for C23H25N7O: 416 (MH+).
Reaction SMILES: [CH2:1]([N:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O:21][CH3:22])(=[O:20])[CH:18]=[CH2:19].[CH3:23]C(C)([O-])C.[K+]>C(O)C>[CH2:22]([O:21][C:17](=[O:20])[CH2:18][CH2:19][O:9][N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:23]
Reactant: ON(Cc1ccccc1)Cc1ccccc1
Reactant: C=CC(=O)OC
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)CCON(Cc1ccccc1)Cc1ccccc1

Procedure:
The procedure of Example I is repeated using 21.33 g of N,N-dibenzylhydroxylamine, 10.33 g of methyl acrylate and 1.0 g of potassium-tert-butoxide in 100 ml of ethanol, to afford the title compound as a colorless liquid.
Reaction SMILES: C(O[C:4]1[C:7](=[O:8])[C:6](=[O:9])[C:5]=1[NH:10][C:11]1[CH:12]=[C:13]([CH:17]2[C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]([CH3:27])[NH:20][C:19](C)=[C:18]2[C:29]([O:31][CH3:32])=[O:30])[CH:14]=[CH:15][CH:16]=1)C.[CH3:33][O:34][C:35]1[CH:36]=[C:37]([CH:41]2[CH2:46][CH2:45][N:44]([CH2:47][CH2:48][CH2:49][NH2:50])[CH2:43][CH2:42]2)[CH:38]=[CH:39][CH:40]=1.O.[CH3:52]N(C=O)C>>[CH3:33][O:34][C:35]1[CH:36]=[C:37]([CH:41]2[CH2:46][CH2:45][N:44]([CH2:47][CH2:48][CH2:49][NH:50][C:4]3[C:7](=[O:8])[C:6](=[O:9])[C:5]=3[NH:10][C:11]3[CH:12]=[C:13]([CH:17]4[C:18]([C:29]([O:31][CH3:32])=[O:30])=[CH:19][NH:20][CH:21]([CH3:27])[C:22]4([CH3:52])[C:23]([O:25][CH3:26])=[O:24])[CH:14]=[CH:15][CH:16]=3)[CH2:43][CH2:42]2)[CH:38]=[CH:39][CH:40]=1
Reactant: CN(C)C=O
Reactant: COc1cccc(C2CCN(CCCN)CC2)c1
Reactant: CCOc1c(Nc2cccc(C3C(C(=O)OC)=C(C)NC(C)=C3C(=O)OC)c2)c(=O)c1=O
Solvent: O
Product: COC(=O)C1=CNC(C)C(C)(C(=O)OC)C1c1cccc(Nc2c(NCCCN3CCC(c4cccc(OC)c4)CC3)c(=O)c2=O)c1
Temperature: 25 °C

Procedure:
The compound of Example 1 (54.7 mg, 0.124 mmol) and 4-(3-methoxyphenyl)piperidine-1-propanamine (41 mg, 0.165 mmol) were heated together in 2 mL DMF at 100° C. for 16 hours. Water was added into this crude reaction mixture after it was cooled to room temperature and the organic material was extracted with ethyl acetate (3×15 mL). Thin layer chromatography on SiO2 eluted with 10% methanol in methylene chloride showed essentially one single spot. This material was allowed to pass through a short bed of silica gel (Merck Type-H) and the pure product was, recovered as a foam after removal of solvents (43 mg, 54.0%). 1H NMR (DMSO-d6) δ 9.86 (br. s, 1H), 8.93 (br. s, 1H), 7.95 (br. s, 1H), 7.30 (d, 1H, J=7.7 Hz), 7.16 (m, 4H), 6.79 (m, 4H), 4.88 (s, 1H), 3.72 (s, 3H), 3.65 (m, 2H), 3.55 (s, 6H), 3.06 (m, 2H), 2.5 (m, 2H), 2.26 (s, 6H), 1.8 (m, 8H), 13C NMR (DMSO-d6) δ 167.38, 159.31, 145.95, 138.97, 129.36, 118.78, 112.45, 101.08, 54.87, 50.67, 18.28. Anal Calcd. for C36H42N4O7•2.10 H2O: C, 63.53; H, 6.84; N, 8.23. Found: C, 63.48; H, 6.85; N, 8.58.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].O[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=O>C1CCCCC1>[C:6]1(=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][CH2:1]1.[CH:15]1([OH:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: O=C(O)CCCCCO
Reactant: OCCCCCCO
Solvent: C1CCCCC1
Product: O=C1CCCCC1
Product: OC1CCCCC1

Procedure:
A process for preparing 1,6-hexanediol from a carboxylic acid mixture comprising adipic acid, 6-hydroxycaproic acid and small amounts of 1,4-cyclohexanediols which is obtained as by-product in the oxidation of cyclohexane to cyclohexanone/cyclohexanol after water extraction of the reaction mixture followed by extraction with aqueous sodium hydroxide solution, by esterification of the acids and hydrogenation comprises
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:19]([OH:21])=[O:20])=[CH:6][N:7]2[CH:16]1[CH2:18][CH2:17]1.[NH2:23][CH2:24][CH2:25][NH:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:29][N:28]=1.C(N(CC)CC)C.O>CS(C)=O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([NH:23][CH2:24][CH2:25][NH:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:29][N:28]=2)[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:19]([OH:21])=[O:20])=[CH:6][N:7]2[CH:16]1[CH2:18][CH2:17]1
Reactant: CCOC(=O)c1ccc(NCCN)nc1
Reactant: COc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)c1ccc(NCCNc2c(F)c(N)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2OC)nc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 50.3 %

Procedure:
A mixture of 5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid (740 mg, 2.39 mmol), ethyl 2-(2-aminoethylamino)pyridine-5-carboxylate (1.00 g, 4.78 mmol) and triethylamine (0.670 mL, 4.81 mmol) in anhydrous DMSO (7 mL) was stirred at 100° C. for 8 h. After cooling, the reaction mixture was poured into water (300 mL) and extracted with CH2Cl2 (2×100 mL). The organic layers were combined, washed with water, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography (EtOAc) to give 5-amino-1-cyclopropyl-7-[2-[(5-ethoxycarbonyl-2-pyridyl)amino]ethylamino]-6-fluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid (600 mg, 50%) as a yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[C:12](Br)=[C:11]([Br:14])[N:10]=[C:9]1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[F:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[C:28]([F:30])[CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+].CO>C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH2:1]([N:8]1[C:12]([C:26]2[CH:25]=[C:24]([F:23])[CH:29]=[C:28]([F:30])[CH:27]=2)=[C:11]([Br:14])[N:10]=[C:9]1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[F:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: Fc1ccc(-c2nc(Br)c(Br)n2Cc2ccccc2)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Fc1cc(F)cc(-c2c(Br)nc(-c3ccc(F)cc3F)n2Cc2ccccc2)c1
Temperature: 25 °C
Yield: 45.8 %

Procedure:
Reflux a mixture of 1-benzyl-4,5-dibromo-2-(2,4-difluoro-phenyl)-imidazole (0.386 g, 0.90 mmol), 3,5-difluorophenyl boronic acid (0.15 g, 0.945 mmol), trans-dichlorobis(triphenylphosphine) palladium (II) (0.065 g, 0.09 mmol), 2 M sodium carbonate (0.90 mL), methanol (1.5 mL) and toluene (10 mL) for 18 hours, then cool to ambient temperature. Dilute with ethyl acetate and wash with saturated sodium bicarbonate, saturated sodium chloride, dry with magnesium sulfate, filter and remove solvents under reduced pressure. Purify the residue on silica gel eluting with hexane/ethyl acetate mixtures to provide 1-benzyl-4-bromo-5-(3,5-difluoro-phenyl)-2-(2,4-difluoro-phenyl)-1H-imidazole (0.19 g). MS(ES+): m/z=461.0 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:4]=1[NH2:5].C(N(CC)CC)C.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1(C)C=CC=CC=1>[C:20]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:3]=1[O:2][CH3:1])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1cc([N+](=O)[O-])ccc1N
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cc([N+](=O)[O-])ccc1NC(=O)c1ccccc1
Yield: 77.1 %

Procedure:
A mixture of 2-methoxy-4-nitroaniline (2.23 g, 13.3 mmol), triethylamine (2.00 ml, 14.6 mmol) and benzoyl chloride (1.70 ml, 14.6 mmol) were stirred in toluene (50 ml) for 24 hours under an inert atmosphere at ambient temperature. The solid was collected by suction filtration and washed with toluene (3×50 ml) and diethyl ether (50 ml). Purification of the crude product by flash chromatography on silica gel, eluting with dichloromethane, yielded N-benzoyl 2-methoxy-4-nitroaniline (2.79 g, 77% yield) as a white solid:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:6]([OH:8])=O.[CH2:15]([NH2:18])[CH2:16]N.S(Cl)(Cl)=[O:20]>CN(C)C=O.CC(C)=O.O>[OH:20][CH2:16][CH2:15][NH:18][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:11]([N+:12]([O-:14])=[O:13])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: NCCN
Reactant: COc1cc(C(=O)O)ccc1[N+](=O)[O-]
Reactant: O=S(Cl)Cl
Solvent: CC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(=O)NCCO)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
A suspension of 3-methoxy-4-nitro-benzoic acid (1.5 g, 7.61 mmol) in thionyl chloride (20 mL) and N,N-dimethylformamide (2 drops) was heated at reflux for 2 hours. The solvent was then evaporated under reduced pressure to give a light yellow solid. A portion of this residue (3.8 mmol) was dissolved in acetone (previously dried over anhydrous sodium sulfate) (20 mL) and cooled in an ice bath. Then a solution of ethylendiamine (0.46 mL, 7.62 mmol) in water (10 mL) was added at 0° C. and the resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was partitioned between water and ethyl acetate; the aqueous phase was separated and extracted twice with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude residue was purified on a silica gel plug (EtOAc/MeOH, 100/0 to 98/2) to afford 0.42 g (46% 2 steps yield) of N-(2-hydroxy-ethyl)-3-methoxy-4-nitro-benzamide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:27][CH3:28])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C@H:14]([NH:16]S(C3C=C(C)OC=3C)(=O)=O)[CH3:15])=[CH:10][CH:9]=2)[CH:7]=1.[Cl:29][C:30]1[S:31][C:32]([Cl:39])=[CH:33][C:34]=1[S:35](Cl)(=[O:37])=[O:36].FC1C=CC(OC)=C(C2C=CC(C(N)C)=CC=2)C=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:27][CH3:28])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C@H:14]([NH:16][S:35]([C:34]3[CH:33]=[C:32]([Cl:39])[S:31][C:30]=3[Cl:29])(=[O:37])=[O:36])[CH3:15])=[CH:10][CH:9]=2)[CH:7]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)sc1Cl
Reactant: COc1ccc(F)cc1-c1ccc([C@@H](C)NS(=O)(=O)c2cc(C)oc2C)cc1
Agent: COc1ccc(F)cc1-c1ccc(C(C)N)cc1
Product: COc1ccc(F)cc1-c1ccc([C@@H](C)NS(=O)(=O)c2cc(Cl)sc2Cl)cc1

Procedure:
Prepared in a similar manner to (R)-2,5-dimethyl-furan-3-sulfonic acid [1-(5′-fluoro-2′-methoxy-biphenyl-4-yl)-ethyl]-amide (Example 10) starting with 2,5-dichloro-3-thiophenesulfonyl chloride and 1-(5′-fluoro-2′-methoxy-biphenyl-4-yl)-ethylamine. Title compound: 1H NMR (400 MHz, CDCl3): δ 7.40, 7.18 (a/b, 4H), 7.05-6.88 (m, 4H), 5.05 (d, 1H), 4.60 (m, 1H), 3.78 (s, 3H), 1.54 (d, 3H) ppm; MS (ESI) m/z: 482 [M+Na]+.
Reaction SMILES: [ClH:1].[NH2:2][C@@H:3]1[C:23](=[O:24])[N:5]2[C:6]([C:20]([O-:22])=[O:21])=[C:7]([CH2:10][N+:11]3[N:12]([CH3:19])[C:13]([NH:16]C=O)=[CH:14][CH:15]=3)[CH2:8][S:9][C@H:4]12.C(OCC)(=O)C>O1CCCC1.CO>[ClH:1].[ClH:1].[ClH:1].[NH2:2][C@@H:3]1[C:23](=[O:24])[N:5]2[C:6]([C:20]([O-:22])=[O:21])=[C:7]([CH2:10][N+:11]3[N:12]([CH3:19])[C:13]([NH2:16])=[CH:14][CH:15]=3)[CH2:8][S:9][C@H:4]12
Reactant: Cn1c(NC=O)cc[n+]1CC1=C(C(=O)[O-])N2C(=O)[C@@H](N)[C@H]2SC1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cn1c(N)cc[n+]1CC1=C(C(=O)[O-])N2C(=O)[C@@H](N)[C@H]2SC1
Reaction time: 12 h

Procedure:
Concentrated hydrochloric acid (0.353 ml) was added to a mixture of di(trifluoroacetic acid)salt of 7β-amino-3-(3-formamido-2-methyl-1-pyrazolio)methyl-3-cephem-4-carboxylate (0.565 g) in tetrahydrofuran (3 ml) and methanol (3 ml) at ambient temperature. After being stirred at the same temperature for 12 hours, the mixture was added dropwise to ethyl acetate (100 ml). The resultant precipitate was collected by filtration to give 7β-amino-3-(3-amino-2-methyl-1-pyrazolio)methyl-3-cephem-4-carboxylate trihydrochloride (292 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)=[CH:9][N:10]=2)[CH:7]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:29](B3OC(C)(C)C(C)(C)O3)=[CH:28][CH:27]=[N:26]2)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]2[C:29]([C:2]3[CH:3]=[CH:4][C:5]4[N:6]([C:8]([C:11]5[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=5)=[CH:9][N:10]=4)[CH:7]=3)=[CH:28][CH:27]=[N:26]2)=[CH:23][CH:24]=1
Reactant: CC1(C)OB(c2ccnn2-c2ccc(Cl)cc2)OC1(C)C
Reactant: Fc1ccc(-c2cnc3ccc(Br)cn23)cc1
Product: Fc1ccc(-c2cnc3ccc(-c4ccnn4-c4ccc(Cl)cc4)cn23)cc1

Procedure:
The title compound, white solid (27 mg, 20%), MS (ISP) m/z=389.4 [(M+H)+], mp 147° C., was prepared in accordance with the general method of example 1 from 6-bromo-3-(4-fluoro-phenyl)-imidazo[1,2-a]pyridine (intermediate E) (0.1 mg, 0.34 mmol) and 1-(4-chloro-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (intermediate B) (0.13 g, 0.41 mmol).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C[Si](C)(C)[CH2:13][C:14]([O:16][CH3:17])=[O:15].[CH2:20]([O:27][C:28]1[CH:36]=[C:35]2[C:31]([CH2:32][C:33]([CH3:39])([CH3:38])[C:34]2=O)=[CH:30][CH:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1.CCOC(C)=O>[CH2:20]([O:27][C:28]1[CH:36]=[C:35]2[C:31]([CH2:32][C:33]([CH3:39])([CH3:38])/[C:34]/2=[CH:13]\[C:14]([O:16][CH3:17])=[O:15])=[CH:30][CH:29]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC1(C)Cc2ccc(OCc3ccccc3)cc2C1=O
Reactant: COC(=O)C[Si](C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)/C=C1/c2cc(OCc3ccccc3)ccc2CC1(C)C
Temperature: -78 °C
Yield: 45 %

Procedure:
At −78° C., lithium bis(trimethylsilyl)amide (1.0 M in THF) (3.6 mL, 3.6 mmol) was added slowly to a solution of methyl 2-(trimethylsilyl)acetate (0.59 mL, 3.6 mmol) in THF (20 mL). The mixture was maintained at −78° C. for 7 minutes and then 6-(benzyloxy)-2,2-dimethyl-2,3-dihydroinden-1-one (8.3) (0.535 g, 2.0 mmol) was added in one portion. The resulting mixture was stirred at −78° C. and allowed to warm to room temperature overnight. The reaction mixture was then diluted with EtOAc (200 mL), washed with water and brine, and dried over anhydrous sodium sulfate. After removing solvent, the residue was purified by chromatography (silica gel, 1:5 EtOAc/hexane) to give product 8.4 in 45% yield.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][O:14][CH3:15])[C:9]([CH:16]([CH3:18])[CH3:17])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:25](Br)[CH:26]=[CH2:27]>C(#N)C>[CH2:27]([O:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][O:14][CH3:15])[C:9]([CH:16]([CH3:18])[CH3:17])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])[CH:26]=[CH2:25]
Reactant: C=CCBr
Reactant: COCOc1cc(O)c(C(=O)OC)cc1C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCOc1cc(OCOC)c(C(C)C)cc1C(=O)OC
Temperature: 25 °C
Yield: 97.5 %

Procedure:
A mixture of methyl 2-hydroxy-5-isopropyl-4-(methoxymethyloxy)benzoate (995 mg, 3.92 mmol) and anhydrous potassium carbonate (650 mg, 4.71 mmol) in acetonitrile (25 ml) was treated with allyl bromide (0.356 ml, 4.11 mmol) and the mixture was stirred and held at reflux for 16 hours. Upon cooling to room temperature the solvent was removed in vacuo, water (30 ml) was added and the organic material was extracted with dichloromethane (2×30 ml). The combined organic extracts were evaporated to dryness in vacuo to afford methyl 2-allyloxy-5-isopropyl-4-(methoxymethyloxy)benzoate (1125 mg, 97%) as pale yellow oil. 1H NMR (DMSO-d6) 7.58 (1H, s), 6.78 (1H, s), 6.03 (1H, m), 5.52 (1H, dm), 5.33 (2H, s), 5.28 (1H, dm), 4.61 (2H, m), 3.78 (3H, s), 3.42 (3H, s), 3.19 (1H, m), 1.18 (6H, d). MS: [M+Na]+ 317.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([O:9]C)=O.[CH:11]([NH2:13])=O>C(Cl)Cl>[N:1]1[C:2]2[S:3][CH:4]=[CH:5][C:6]=2[C:7](=[O:9])[NH:13][CH:11]=1
Reactant: NC=O
Reactant: COC(=O)c1ccsc1N
Solvent: ClCCl
Product: O=c1[nH]cnc2sccc12
Yield: 40 %

Procedure:
A solution of methyl 2-aminothiophene-3-carboxylate (602.1 mg, 3.83 mmol) in formamide (5 mL) is heated at 200 ° C. for 12 h. The resulting tar is dissolved in CH2Cl2 (10 mL) then placed on a silica plug and eluted with 10% MeOH in CH2Cl2. The filtrate is stripped under reduce pressure and the resulting solid is washed with EtOH to yield 3H-thieno[2,3-d]pyrimid-4-one (231.4 mg, 40%) as an orange solid. 1H NMR (DMSO) δ 12.50 (1H, brs), 8.13 (1H, s), 7.60 (1H, d, J=5.8 Hz), 7.41 (1H, d, J=6.0 Hz).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][N:19]=2)[C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:7][C:8]=1F)#[N:2].[NH2:20][CH2:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>CS(C)=O.C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[C:5]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][N:19]=2)[C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:7][C:8]=1[NH:20][CH2:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)#[N:2]
Reactant: COC(=O)c1ccnc(-c2ccc(F)c(C#N)c2)c1
Reactant: NCC1CCCCC1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccnc(-c2ccc(NCC3CCCCC3)c(C#N)c2)c1
Temperature: 40 °C
Reaction time: 17 h

Procedure:
In 3 ml of DMSO was dissolved 247 mg of methyl 2-(3-cyano-4-fluorophenyl)isonicotinate, and 0.31 ml of aminomethylcyclohexane was added thereto. After being stirred at 40° C. for 17 hours, the reaction solution was diluted with ethyl acetate and washed with water and brine, successively. The organic layer was dried and concentrated under reduced pressure and then recrystallization was performed from a mixed solvent of diisopropyl ether and hexane to obtain 266 mg of methyl 2-{3-cyano-4-[(cyclohexylmethyl)amino]phenyl}isonicotinate. (2) Then, 266 mg of the compound was dissolved in a mixed solvent of 5 ml of methanol and 10 ml of THF, and 1.14 ml of a 1M aqueous sodium hydroxide solution was added thereto, followed by heating at 80° C. for 1 hour. After cooling, the reaction solution was diluted with water and washed with diethyl ether. The resulting aqueous layer was neutralized with 1M hydrochloric acid and extracted with ethyl acetate and the organic layer was dried and concentrated under reduced pressure. The resulting residue was recrystallized from a mixed solvent of ethanol and water to obtain 199 mg of 2-{3-cyano-4-[(cyclohexylmethyl)amino]phenyl}isonicotinic acid. Then, 199 mg of the compound was dissolved in 10 ml of ethanol and 0.59 ml of a 1M aqueous sodium hydroxide solution was added thereto. After stirring at room temperature for 15 minutes, the reaction solution was concentrated. The resulting residue was washed with 2-propanol to obtain 181 mg of sodium 2-{3-cyano-4-[(cyclohexylmethyl)amino]phenyl}isonicotinate.
Reaction SMILES: Cl.[NH2:2][OH:3].[Cl:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=O.C(=O)([O-])[O-].[Na+].[Na+].O>CO>[Cl:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=[N:2][OH:3]
Reactant: O=Cc1ccccc1Cl
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: ON=Cc1ccccc1Cl
Reaction time: 8 h
Yield: 98.5 %

Procedure:
Hydroxylamine hydrochloride (35.6 g) was added to a 0° C. mixture of 2-chlorobenzaldehyde (60.0 g) and sodium carbonate (22.6 g) in methanol (1.0 L)-water (1.0 L). The reaction was stirred overnight and then concentrated to half volume. The mixture was extracted twice with ethyl acetate. The organics were combined, washed with brine, dried over anhydrous magnesium sulfate and concentrated to obtain the title compound (65.4 g) having the following physical data.
Reaction SMILES: [C:1](Cl)([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].[NH2:19][C@@H:20]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1)[C:21]([O:23][CH3:24])=[O:22].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[CH:16]1[C:17]2[CH:5]([CH2:4][O:3][C:1]([NH:19][C@@H:20]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=3)[C:21]([O:23][CH3:24])=[O:22])=[O:2])[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:12]=2[CH:13]=[CH:14][CH:15]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.3 %

Procedure:
Fmoc-Cl (27.6 g, 107.2 mmol) in 1,4-dioxane (950 mL) was added dropwise to a solution of (S)-methyl 2-amino-3-(4-nitrophenyl)propanoate (3A; 20 g, 89.3 mmol) and K2CO3 (14.8 g , 107.2 mmol) in water (80 mL) and 1,4-dioxane (150 mL) on an ice bath. After being stirred for 2 hours at room temperature, the mixture was poured into 1.2 L of water to precipitate a white solid, which was filtered and washed with cold water. The solid was dried under vacuum for 3 hours to give 40 g of (S)-methyl 2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-nitrophenyl)propanoate 3B, which was directly used in step 2.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([O:8][C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:16])=[C:4]([O:17][CH3:18])[CH:3]=1.ClC1C=CC=C(C(OO)=[O:27])C=1>ClCCl>[Cl:1][C:2]1[N+:7]([O-:27])=[N:6][C:5]([O:8][C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:16])=[C:4]([O:17][CH3:18])[CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1cc(Cl)nnc1Oc1c(C)cccc1C
Solvent: ClCCl
Product: COc1cc(Cl)[n+]([O-])nc1Oc1c(C)cccc1C
Temperature: 25 °C
Reaction time: 384 h
Yield: 56.8 %

Procedure:
3.42 g (12.9 mmol) of 6-chloro-3-(2,6-dimethylphenoxy)-4-methoxypyridazine, dichloromethane (110 mL) and 3.34 g (15.4 mmol) of 80% m-chloroperbenzoic acid were mixed, and the mixture was stirred at room temperature for 16 days. The reaction mixture was poured into ice-cold saturated aqueous sodium sulfite solution, and extracted with dichloromethane. The organic layers were combined, washed successively with a saturated aqueous sodium hydrogen carbonate solution, water and brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography to obtain 2.06 g (7.33 mmol, Yield: 56.8%) of 6-chloro-3-(2,6-dimethylphenoxy)-4-methoxypyridazine 1-oxide.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH2:9][CH3:10])[C:6](=[O:11])[NH:5][C:4](=[O:12])[CH:3]=1.Cl.[N:14]([O-])=[O:15].[Na+]>O>[NH2:1][C:2]1[N:7]([CH2:8][CH2:9][CH3:10])[C:6](=[O:11])[NH:5][C:4](=[O:12])[C:3]=1[N:14]=[O:15]
Reactant: O=N[O-]
Reactant: CCCn1c(N)cc(=O)[nH]c1=O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCCn1c(N)c(N=O)c(=O)[nH]c1=O

Procedure:
To 34.3 g (0.20 mol) of 6-amino-1-propyl-2,4-(1H,3H)-pyrimidinedione (II), dissolved in 900 ml hot water, was added 45 ml of 5 N HCl and 15 g of NaNO2 (0.22 mol) which was dissolved in water. After cooling the red crystals were filtered off and washed with water. Yield 33.3 g (83%) (III) NMR.