Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C@@H:2]1[C@H:8]([NH:9]C(=O)OC(C)(C)C)[CH2:7][CH2:6][C@@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[O:4][CH2:3]1.[F:26][C:27]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:29]([F:35])[C:28]=1[C:36]1[N:41]=[C:40]([C:42](O)=[O:43])[CH:39]=[CH:38][C:37]=1[F:45]>>[NH2:9][C@H:8]1[C@@H:2]([F:1])[CH2:3][O:4][C@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[NH:23][C:42](=[O:43])[C:40]2[CH:39]=[CH:38][C:37]([F:45])=[C:36]([C:28]3[C:29]([F:35])=[CH:30][C:31]([O:33][CH3:34])=[CH:32][C:27]=3[F:26])[N:41]=2)[CH2:6][CH2:7]1
Reactant: COc1cc(F)c(-c2nc(C(=O)O)ccc2F)c(F)c1
Reactant: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](F)CO1
Product: COc1cc(F)c(-c2nc(C(=O)Nc3cnn(C)c3[C@@H]3CC[C@@H](N)[C@@H](F)CO3)ccc2F)c(F)c1
Yield: 26 %

Procedure:
Following the procedure for Example 111 starting from tert-butyl ((3R,4R,7S)-3-fluoro-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (Intermediate 24), and replacing 5-((tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid with 6-(2,6-difluoro-4-methoxyphenyl)-5-fluoropicolinic acid (see WO2010/56576) gave 187 as a white solid (22 mg, 26%). 1H NMR (400 MHz, CDCl3) δ 10.40 (s, 1H), 8.31 (dd, J=8.6, 4.0 Hz, 1H), 8.21 (s, 1H), 7.71-7.63 (m, 1H), 6.64 (d, J=10.1 Hz, 2H), 4.84-4.73 (m, 2H), 4.07-3.89 (m, 3H), 3.87 (s, 3H), 3.77 (s, 3H), 3.41 (dd, J=23.1, 9.5 Hz, 1H), 2.67 (br s, 1H), 2.15-2.08 (m, 1H), 2.08-1.94 (m, 1H), 1.95-1.84 (m, 1H), 1.85-1.73 (m, 1H). LCMS (ES+) m/z 494 (M+1).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16](I)=[CH:15][CH:14]=2)[S:9][CH:10]=1)=[O:5])C.[C:20]1(B(O)O)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1>>[C:28]1([C:16]2[CH:15]=[CH:14][C:13]([O:12][CH2:11][C:8]3[S:9][CH:10]=[C:6]([C:4]([OH:3])=[O:5])[N:7]=3)=[CH:18][CH:17]=2)[C:29]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: OB(O)c1cccc2ccccc12
Reactant: CCOC(=O)c1csc(COc2ccc(I)cc2)n1
Product: O=C(O)c1csc(COc2ccc(-c3cccc4ccccc34)cc2)n1

Procedure:
2-(4-Naphthalen-1-yl-phenoxymethyl)-thiazole-4-carboxylic acid was prepared using the procedure described above for the preparation of Example 22 from 2-(4-iodo-phenoxymethyl)-thiazole-4-carboxylic acid ethyl ester (of Intermediate 2) and 1-naphthaleneboronic acid (available from Aldrich Chemical Company, Inc., Milwaukee, Wis.). Mass spectrum MH+=362.
Reaction SMILES: [C:1]([NH:5][C:6]1[N:11]=[C:10]([S:12][CH3:13])[C:9]([C:14]([NH2:16])=[O:15])=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2].C1(C2[O:25]N2S(C2C=CC=CC=2)(=O)=O)C=CC=CC=1.C(OCC)(=O)C>C(Cl)(Cl)Cl>[C:1]([NH:5][C:6]1[N:11]=[C:10]([S:12]([CH3:13])=[O:25])[C:9]([C:14]([NH2:16])=[O:15])=[CH:8][N:7]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CSc1nc(NC(C)(C)C)ncc1C(N)=O
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CS(=O)c1nc(NC(C)(C)C)ncc1C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.3 %

Procedure:
To a stirring solution of 2-(tert-butylamino)-4-(methylthio)pyrimidine-5-carboxamide (0.1 g, 0.416 mmol) in chloroform (12 mL) was added portion-wise 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine (0.130 g, 0.499 mmol). The resulting pale yellow solution was stirred at ambient temperature overnight. The reaction solution was concentrated under reduced pressure to give the crude product as a white solid. Ethyl acetate (1 mL) was added and the slurry was stirred at room temp for 1 h. The solids were filtered, washed with ethyl acetate, and dried under vacuum to afford 2-(tert-butylamino)-4-(methylsulfinyl)pyrimidine-5-carboxamide (0.092 g, 0.359 mmol, 86% yield). MS (ESI) m/z 257.3 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=2)[N:7]=1.[I:18]Cl.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([I:18])=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[N:10]=2)[N:7]=1
Reactant: ClI
Reactant: Fc1ccc(-c2cn3nc(Cl)ccc3n2)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Fc1ccc(-c2nc3ccc(Cl)nn3c2I)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.7 %

Procedure:
To a solution, cooled to 0° C., of 5.20 g (21.0 mmol) of 6-chloro-2-(4-fluorophenyl)imidazo[1,2-b]pyridazine (CAS No.: 244081-70-7) in 130 mL of chloroform is rapidly added dropwise a solution of 6.61 g (40.9 mmol) of iodine monochloride in 40 mL of chloroform. After cooling to room temperature and stirring for 4 hours, the mixture is treated with aqueous 5% sodium thiosulfate solution. The product is extracted with dichloromethane. The organic phase is dried by filtration through a hydrophobic filter cartridge and concentrated under reduced pressure. The residue is triturated in acetonitrile, and the solid is isolated after filtering off and rinsing with diisopropyl ether. 5.7 g of a beige-colored powder are isolated after drying under vacuum.
Reaction SMILES: S(O)(O)(=O)=O.[CH3:6][S:7][C:8](=[NH:10])[NH2:9].CN([CH:14]=[C:15]1[C:20](=O)[CH2:19][CH2:18][N:17]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:16]1)C.[OH-].[Na+]>O>[CH3:6][S:7][C:8]1[N:9]=[CH:14][C:15]2[CH2:16][N:17]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:19][C:20]=2[N:10]=1
Reactant: CSC(=N)N
Reactant: CN(C)C=C1CN(C(=O)OC(C)(C)C)CCC1=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CSc1ncc2c(n1)CCN(C(=O)OC(C)(C)C)C2
Reaction time: 1 h
Yield: 40 %

Procedure:
S-Methylisothiourea sulfate (16.44 g, 59.06 mmol, 1.5 eq.) and tert-butyl 3-((dimethylamino)-methylene)-4-oxopiperidine-1-carboxylate (10.0 g, 39.37 mmol, 1.0 eq.) were taken up in water (40 ml); 1 M NaOH solution (50 ml) was added and stirring was carried out for 1 hour at 80° C. After monitoring by TLC, the reaction mixture was diluted with water (100 ml) and extracted with DCM (2×150 ml). The combined org. phases were washed with sat. NaCl solution (100 ml), dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (silica gel, 25% ethyl acetate in hexane). Yield: 40% (4.5 g, 16.01 mmol)
Reaction SMILES: Cl[CH:2]([C:4]1[CH:5]=[C:6]([C:15]([CH3:19])([CH3:18])[C:16]#[N:17])[CH:7]=[C:8]([C:10]([CH3:14])([CH3:13])[C:11]#[N:12])[CH:9]=1)[CH3:3].N1C=[CH:23][N:22]=[N:21]1.[Na].[CH3:26][N:27](C)C=O>O>[N:22]1([CH:2]([C:4]2[CH:5]=[C:6]([C:15]([CH3:19])([CH3:18])[C:16]#[N:17])[CH:7]=[C:8]([C:10]([CH3:14])([CH3:13])[C:11]#[N:12])[CH:9]=2)[CH3:3])[CH:23]=[N:27][CH:26]=[N:21]1
Reactant: CN(C)C=O
Reactant: c1c[nH]nn1
Reactant: CC(Cl)c1cc(C(C)(C)C#N)cc(C(C)(C)C#N)c1
Agent: [Na]
Solvent: O
Product: CC(c1cc(C(C)(C)C#N)cc(C(C)(C)C#N)c1)n1cncn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 2,2'-[5-(1-chloroethyl)-1,3-phenylene)di(2-methylpropiononitrile), (0.35 g), sodium triazole (0.25 g) and dimethylformamide (3 ml) was stirred at room temperature for 18 h, then water (20 ml) was added and the mixture was extracted twice with ethyl acetate. The extracts were combined and evaporated to dryness, and the residue was purified by flash column chromatography, eluting with ethyl acetate, to give 2,2'-[5-(1-[1H-1,2,4-triazol-1-yl]ethyl)-1,3-phenylene]di(2-methylpropiono nitrile), crystallised as the hydrochloride from acetone, mp. 168°-170°.
Reaction SMILES: [S:1]([OH:5])([OH:4])(=[O:3])=[O:2].CS[C:8](=[NH:10])[NH2:9].CS[C:13](=[NH:15])[NH2:14].[CH:16]([NH2:19])([CH3:18])[CH3:17]>O>[S:1]([OH:5])([OH:4])(=[O:3])=[O:2].[CH:16]([NH:19][C:8]([NH2:10])=[NH:9])([CH3:18])[CH3:17].[CH:16]([NH:19][C:13]([NH2:15])=[NH:14])([CH3:18])[CH3:17]
Reactant: CC(C)N
Reactant: CSC(=N)N
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(C)NC(=N)N
Yield: 82 %

Procedure:
Into a one liter reactor fitted with warming, cooling and stirring means were poured 108.5 g (0.39 mol) of bis (S-methylisothiourea) sulphate, 150 ml of water and 94 ml (or 68 g, i.e. 1.15 mol) of isopropylamine. The mixture was refluxed for two hours and then evaporated to dryness. The residue was taken up in ethanol from which there was obtained, after filtration, washing and drying, 96 g (yield 82%) of product.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:17]2[C:26]([N+:27]([O-])=O)=[CH:25][CH:24]=[CH:23][C:18]=2[C:19]([O:21][CH3:22])=[O:20])=[CH:11][CH:10]=1)#[N:2].C.O.NN>CO.C1COCC1>[NH2:27][C:26]1[C:17]([NH:16][CH2:15][C:12]2[CH:13]=[CH:14][C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:1]#[N:2])=[CH:10][CH:11]=2)=[C:18]([CH:23]=[CH:24][CH:25]=1)[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1NCc1ccc(-c2ccccc2C#N)cc1
Agent: NN
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COC(=O)c1cccc(N)c1NCc1ccc(-c2ccccc2C#N)cc1

Procedure:
A mixture of methyl 2-[[(2′-cyanobiphenyl-4-yl)methyl]amino]-3-nitrobenzoate (10 g), FeCl3.6H2O (0.1 g), activated charcoal (1 g) in a mixture of methanol (100 ml) and THF (50 ml) was heated under reflux for 30 min. Hydrazine hydrate (7.2 ml) was added dropwise to the reaction mixture and the mixture was then heated under reflux for 14 hours. The insoluble material was removed from the reaction mixture by filtration and the filtrate was concentrated to dryness. Aqueous sodium bicarbonate was added to the resulting residue and the mixture was extracted with ethyl acetate. The extract was washed with water, dried and evaporated to dryness. The residue was purified by column chromatography on silica gel to give crystals. Recrystallization from isopropyl ether afforded pale yellow needles (6.0 g, 64%), m.p. 110-111° C.
Reaction SMILES: [CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[N:6]1([NH:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=2)[CH2:10][CH2:9][N:8]=[CH:7]1.[CH3:21][S:22]([O:25][C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([C:36](=[NH:38])[NH2:37])[CH:32]=2)[CH:27]=1)(=[O:24])=[O:23].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[CH3:21][S:22]([OH:25])(=[O:24])=[O:23].[N:6]1([NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:16]([O:18][C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[C:31]([C:36](=[NH:37])[NH2:38])[CH:32]=4)[CH:27]=3)=[O:17])=[CH:19][CH:20]=2)[CH2:10][CH2:9][N:8]=[CH:7]1
Reactant: O=C(O)c1ccc(NN2C=NCC2)cc1
Reactant: CS(=O)(=O)Oc1ccc2cc(C(=N)N)ccc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)O
Solvent: c1ccncc1
Product: N=C(N)c1ccc2cc(OC(=O)c3ccc(NN4C=NCC4)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.4 %

Procedure:
To 1.03 g of 4-(2-imidazolinyl)amino-benzoic acid methanesulfonate, 0.96 g of 6-amidino-2-naphthol methanesulfonate, 42 mg of DMAP and 1.06 g of DCC was added 5 ml of anhydrous pyridine. The resulting mixture was stirred overnight at room temperature. To the mixture was added 50 ml of aceone and the precipitate which was formed was collected by filtration. To the precipitate was added 40 ml of DMF. After stirring the precipitate which was formed was collected by filtration and 20 ml of water was added to the precipitate. The insolubles were removed by filtration. The filtrate was distilled under reduced pressure. To the residue was added 200 ml of acetone. The precipitate which was formed was collected by filtration to obtain 0.8 g of 6-amidino-2-naphthyl 4-(2-imidazolinyl)amino-benzoate dimethanesulfonate.
Reaction SMILES: C[N:2](C)C=O.[OH-].[K+].[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1.NOS(O)(=O)=O>O>[NH2:2][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1
Reactant: CN(C)C=O
Reactant: c1ccc2[nH]ccc2c1
Agent: NOS(=O)(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Nn1ccc2ccccc21
Yield: 32 %

Procedure:
To 50 ml of N,N-dimethylformamide were added 24.55 g(440 mmol) of potassium hydroxide and 3.201 g(27.3 mmol) of 1H-indole, and 6.15 g (54.4 mmol) of hydroxylamine-0-sulfonic acid was added thereto in small amounts under stirring. After stirring the reaction mixture at room temperature for 1 hour, 50 ml of water was added thereto and it was extracted three times with 100 ml of benzene. The extract was washed with water, dried and concentrated under the reduced pressure. Silica gel column chromatography of the residue using 50% dichloromethane/n-hexane as an eluent gave 1.16 g of the desired compound(32%).
Reaction SMILES: [O-2].[Nd+3:2].[O-2].[O-2].[Nd+3].[Nd].[N+]([O-])([O-])=O.[Nd+3].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[CH2:20]([CH:22]([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:23][O:24][P:25](=[O:36])([OH:35])[O:26][CH2:27][CH:28]([CH2:33][CH3:34])[CH2:29][CH2:30][CH2:31][CH3:32])[CH3:21].CC1CCCCC1>O>[CH2:20]([CH:22]([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:23][O:24][P:25]([O-:36])([O:26][CH2:27][CH:28]([CH2:33][CH3:34])[CH2:29][CH2:30][CH2:31][CH3:32])=[O:35])[CH3:21].[Nd+:2]
Reactant: CCCCC(CC)COP(=O)(O)OCC(CC)CCCC
Reactant: [Nd+3]
Agent: O=[N+]([O-])[O-]
Agent: [Nd]
Agent: [O-2]
Solvent: CC1CCCCC1
Solvent: O
Product: CCCCC(CC)COP(=O)([O-])OCC(CC)CCCC
Product: [Nd+]
Reaction time: 0.5 h
Yield: 99 %

Procedure:
2.88 g of neodymium oxide containing 72.4% by weight of neodymium, 0.53 g of an aqueous solution of neodymium nitrate containing 24.4% by weight of neodymium, 17.39 g of di(2-ethylhexyl)phosphoric acid (DEHPA), and 80 g of methylcyclohexane (MCH) are introduced into a reactor made inert beforehand with argon. The mixture is stirred and brought to 80° C. until complete disappearance of the solid, i.e., in this case, 1 h. The mixture is cooled. Three washes with 20 g of water are successively carried out in order to remove the inorganic residues. Each wash comprises a step of stirring for 30 minutes and then a step of separating by settling out, also for 30 minutes, except for the final separating by settling out, which lasts 12 h. The water/MCH azeotrope is subsequently distilled with a Dean Stark apparatus. A clear solution of neodymium di(2-ethylhexyl)phosphate in MCH is thus obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[C:8]([N+:14]([O-:16])=[O:15])[CH:7]=1.[Br-].[NH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([CH2:27][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[N:19]1.C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9](/[CH:10]=[CH:27]/[C:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[NH:18][N:19]=2)=[C:8]([N+:14]([O-:16])=[O:15])[CH:7]=1
Reactant: COCCOc1ccc(C=O)c([N+](=O)[O-])c1
Reactant: c1ccc([P+](Cc2n[nH]c3ccccc23)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CO
Product: COCCOc1ccc(/C=C/c2n[nH]c3ccccc23)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.2 %

Procedure:
A solution of 4-(2-methoxyethoxy)-2-nitrobenzaldehyde (27 mg, 0.12 mmol) obtained in Step 1 in methanol (1.0 mL) was added with (1H-indazol-3-ylmethyl)triphenylphosphonium bromide (57 mg, 0.12 mmol) and potassium carbonate (33 mg, 0.24 mmol), followed by stirring at room temperature for 1.5 hours. The reaction mixture was washed with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The filtrate was purified by silica gel column chromatography (ethyl acetate) to obtain (E)-3-{2-[4-(2-methoxyethoxy)-2-nitrophenyl]vinyl}-1H-indazole (0.04 g, 100%).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13]([OH:24])(=O)[C:14]1[CH:22]=[CH:21][C:20]2[O:19][CH2:18][O:17][C:16]=2[CH:15]=1.[Br:25][C:26]1[C:27]([CH3:43])=[N:28][O:29][C:30]=1[NH:31][S:32]([C:35]1[CH:39]=[CH:38][S:37][C:36]=1[C:40]([NH2:42])=[O:41])(=[O:34])=[O:33].[H-].[Na+]>C1COCC1.O>[Br:25][C:26]1[C:27]([CH3:43])=[N:28][O:29][C:30]=1[NH:31][S:32]([C:35]1[CH:39]=[CH:38][S:37][C:36]=1[C:40]([NH:42][C:13](=[O:24])[C:14]1[CH:22]=[CH:21][C:20]2[O:19][CH2:18][O:17][C:16]=2[CH:15]=1)=[O:41])(=[O:34])=[O:33]
Reactant: O=C(O)c1ccc2c(c1)OCO2
Reactant: Cc1noc(NS(=O)(=O)c2ccsc2C(N)=O)c1Br
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1noc(NS(=O)(=O)c2ccsc2C(=O)NC(=O)c2ccc3c(c2)OCO3)c1Br
Reaction time: 0.25 h
Yield: 3.6 %

Procedure:
Carbonyldiimidazole (213 mg. 1.31 mmol) was added to a solution of piperonylic acid (181.5 mg., 1.09 mmol) in dry THF (10 ml). The resulting mixture was stirred for 15 minutes. N-(4-bromo-3-methyl-5-isoxazolyl)-2-aminocarbonylthiophene-3-sulfonamide (Example 89) (400 mg, 1.09 mmol) and NaH (175 mg, 60% in mineral oil, 4.37 mmol) were added sequentially. The mixture was stirred at room temperature for 8 hours. Water was added to destroy the excess NaH. The solvent was then evaporated and the residue was partitioned between 1N HCl and EtOAc. The organic layer was dried (MgSO4), the solid filtered and the filtrate concentrated. The residue was recrystalized from EtOAc to give N-(4-bromo-3-methyl-5-isoxazolyl)-2-{[(3,4-methylenedioxy)benzoyl]-aminocarbonyl}thiophene-3-sulfonamide (20 mg, 3.6% yield) as a yellowish powder (m.p. 90-93° C.).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=4[Cl:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[N-:30]=[N+:31]=[N-:32].[Na+]>>[N:30]([CH2:12][CH:13]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[Cl:29])[C:15]=2[O:14]1)=[N+:31]=[N-:32]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4ccc(Cl)cc4Cl)c3O2)cc1
Agent: [Na+]
Product: [N-]=[N+]=NCC1Cc2cccc(-c3ccc(Cl)cc3Cl)c2O1

Procedure:
Treatment of (±)-[7-(2,4-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (4.2 g, 9.34 mmol) with sodium azide (2.4 g, 37.38 mmol) generally according to the procedure described for Intermediate 98 gave (±)-2-(azidomethyl)-7-(2,4-dichlorophenyl)-2,3-dihydro-1-benzofuran. Treatment of the azide with sulfided platinum on carbon (0.32 g, 5 wt. %) generally according to the procedure described for Example 1 provided 2.16 g (72%) of (±)-1-[7-(2,4-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp 198-200° C.; Anal. calcd. for C15H13Cl2NOHCl: C, 54.49; H, 4.27; N, 4.24. Found: C, 54.5; H, 4.39; N, 4.16.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)([CH2:13][CH:14]=O)[CH2:9]1)=[O:7].[CH2:31]([O:33][CH2:34][CH2:35][N:36]1[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[N:38]=[C:37]1[N:45]1[CH2:51][CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)[CH3:32].C([BH3-])#N.[Na+].[OH-].[Na+]>CO.C(OCC)(=O)C.CO.ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:48]2[CH2:49][CH2:50][CH2:51][N:45]([C:37]3[N:36]([CH2:35][CH2:34][O:33][CH2:31][CH3:32])[C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=4[N:38]=3)[CH2:46][CH2:47]2)([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[CH2:9]1)=[O:7]
Reactant: CCOCCn1c(N2CCCNCC2)nc2ccccc21
Reactant: COc1cc(C(=O)N2CCC(CC=O)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOCCn1c(N2CCCN(CCC3(c4ccc(Cl)c(Cl)c4)CCN(C(=O)c4cc(OC)c(OC)c(OC)c4)C3)CC2)nc2ccccc21
Reaction time: 72 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-oxoethyl)pyrrolidine (0.51 g, 1.13 mmol), 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (0.40 g, 1.36 mmol), and silica gel (about 2 g) in methanol (24 mL) and stir. After 3 days, add sodium cyanoborohydride (0.71 g, 11.3 mmol) and 3 Å molecular sieves (about 12 g) and stir under an inert atmosphere. After 18 hours, add a solution of 2 M sodium hydroxide and dichloromethane and stir. After 18 hours, filter, separate the layers in the filtrate, and extract the organic layer with brine. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 1/1 ethyl acetate/methanol to give, after drying in vacuo at 82° C., the title compound: mp; 55-65° C. Rf=0.36 (silica gel, 1/1 ethyl acetate/methanol). Elemental Analysis calculated for C38H47Cl2N5O5: C 62.98; H 6.54; N 9.66; Found: C 62.65; H 6.65; N 9.51.
Reaction SMILES: [C:1]1([O:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18]Br)=[C:10]([CH2:20][CH2:21][CH3:22])[CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:23][C:24]1[CH:25]=[C:26]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH:27]=[CH:28][C:29]=1[OH:30].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:20]([C:10]1[CH:9]=[C:8]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:13]=[CH:12][C:11]=1[O:14][CH2:15][CH2:16][CH2:17][CH2:18][O:30][C:29]1[CH:28]=[CH:27][C:26]([CH2:31][C:32]([O:34][CH3:35])=[O:33])=[CH:25][C:24]=1[Cl:23])[CH2:21][CH3:22]
Reactant: COC(=O)Cc1ccc(O)c(Cl)c1
Reactant: CCCc1cc(Oc2ccccc2)ccc1OCCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCc1cc(Oc2ccccc2)ccc1OCCCCOc1ccc(CC(=O)OC)cc1Cl

Procedure:
A solution of 4-(4-bromobutoxy)-3-propylphenyl phenyl ether (5.7 g, 15.75 mmol), methyl 3-chloro-4-hyrdoxyphenylacetate (3.0 g, 15.00 mmol) and cesium carbonate (5.38 g, 16.50 mmol) in DMF (50 mL) was stirred at 40° C. overnight. The reaction mixturewas partitioned between ethyl acetate and 0.2N HCl. The organic layer was washed twice with water, then dried over sodium sulfate. The organic layer was filtered and evaporated to an oil which was chromatographed over silica gel with 10% of ethyl acetate in hexane to afford the title compound.
Reaction SMILES: [C:1]([OH:6])(=O)/[CH:2]=[CH:3]/[CH3:4].O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:18][C:19]1[CH:20]=[C:21]([OH:26])[CH:22]=[CH:23][C:24]=1[CH3:25]>CN(C)C=O.CN(C)C(=O)C>[OH:26][C:21]1[CH:22]=[CH:23][C:24]([CH3:25])=[C:19]([NH:18][C:1](=[O:6])/[CH:2]=[CH:3]/[CH3:4])[CH:20]=1
Reactant: C/C=C/C(=O)O
Reactant: Cc1ccc(O)cc1N
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C/C=C/C(=O)Nc1cc(O)ccc1C
Yield: 59.8 %

Procedure:
In the same manner as in Example 259 and using (2E)-but-2-enoic acid (1680 mg, 19 mmol), tetrahydrofuran (5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride (1670 μL, 19 mmol), 3-amino-4-methylphenol (2000 mg, 16 mmol) and N,N-dimethylacetamide (35 mL) as starting materials, the title compound (1830 mg, 59%) was obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[NH:16][C:15]3[C:10](=[N:11][C:12]([O:17][CH3:18])=[CH:13][CH:14]=3)[CH:9]=2)[C:5]([OH:19])=[CH:4][CH:3]=1.[C:20]([O-])([O-])=O.[Cs+].[Cs+].ClCI>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:19][CH2:20][N:16]3[C:15]4[CH:14]=[CH:13][C:12]([O:17][CH3:18])=[N:11][C:10]=4[CH:9]=[C:8]3[C:6]=2[N:7]=1
Reactant: COc1ccc2[nH]c(-c3nc(Cl)ccc3O)cc2n1
Reactant: O=C([O-])[O-]
Agent: ClCI
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(cc3n2COc2ccc(Cl)nc2-3)n1
Temperature: 100 °C
Reaction time: 1 h
Yield: 52.6 %

Procedure:
To a stirring solution of 6-chloro-2-(5-methoxy-1H-pyrrolo[3,2-b]pyridin-2-yl)pyridin-3-ol (200 mg, 0.727 mmol) and Cs2CO3 (472 mg, 1.45 mmol) in DMF (15 mL) was added chloroiodomethane (192 mg, 1.09 mmol) in DMF (2 mL) dropwise at 100° C. under N2. The mixture was stirred at 100° C. for 1 hour. The mixture was diluted with H2O and extracted with EtOAc. The organics were washed with brine and dried over Na2SO4. After concentrated, the resulting residue was purified using Pre-TLC to provide 2-chloro-10-methoxy-6H-pyrido[2,3-e]pyrido[2′,3′:4,5]pyrrolo[1,2-c][1,3]oxazine (110 mg, yield: 52%). 1H-NMR (CDCl3, 400 MHz) 7.44 (d, J=8.8 Hz, 1H), 7.26 (d, J=8.8 Hz, 1H), 7.16 (s, 1H), 7.10 (d, J=8.8 Hz, 1H), 6.63 (d, J=8.8 Hz, 1H), 5.81 (s, 2H), 3.95 (s, 3H). MS (M+H)+: 288/290.