Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[CH2:5][C@@H:6]2[C@H:9]([CH:10]=1)[C:8](=[CH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]2)[CH2:2][CH3:3].N12CCCN=C1CCCCC2.P([O-])(O)(O)=O.[K+].[N+:36]([CH3:39])([O-:38])=[O:37]>>[CH2:1]([C:4]1[CH2:5][C@@H:6]2[C@H:9]([CH:10]=1)[C@@:8]([CH2:11][C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])([CH2:39][N+:36]([O-:38])=[O:37])[CH2:7]2)[CH2:2][CH3:3]
Reactant: CCCC1=C[C@@H]2C(=CC(=O)OC(C)(C)C)C[C@@H]2C1
Reactant: C[N+](=O)[O-]
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: C1CCC2=NCCCN2CC1
Product: CCCC1=C[C@H]2[C@@H](C1)C[C@]2(CC(=O)OC(C)(C)C)C[N+](=O)[O-]
Temperature: 55 °C
Reaction time: 8 h

Procedure:
Tert-butyl(±)-(1S,5R)-3-propyl-bicyclo[3.2.0]hept-3-en-6-ylideneacetate (1.81 g, 7.29 mmol) was dissolved in nitromethane (7 mL). To the solution, 1,8-diazabicyclo[5.4.0]undec-7-ene (1.5 mL, 10.2 mmol) was added, and the mixture was heated with stirring at 50 to 60° C. for 8 hours. The mixture was allowed to cool, and a saturated aqueous solution of potassium dihydrogen phosphate was then added thereto, followed by extraction with ethyl acetate. Then, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain the compound of interest as a colorless oil substance (2.22 g, 95%).
Reaction SMILES: [Na].[C:2]1([C:8](=O)[CH2:9][CH2:10][C:11](=O)[CH3:12])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:15]1[CH2:19][CH:18]=[CH:17][CH:16]=1.O>CO>[CH3:12][C:11]1[CH:10]=[CH:9][C:8]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:15]2[C:16]=1[CH:17]=[CH:18][CH2:19]2
Reactant: CC(=O)CCC(=O)c1ccccc1
Reactant: C1=CCC=C1
Agent: [Na]
Solvent: O
Solvent: CO
Product: Cc1ccc(-c2ccccc2)c2c1C=CC2
Temperature: 0 °C

Procedure:
5 g (0.21 mol}of sodium were dissolved in 100 ml of methanol in a Schlenk tube and the solution was cooled to 0° C. A mixture of 15.8 g (0.84 mol) of 1-phenyl-1,4-pentanedione and 7.3 ml (5.8 g, 0.08 mol) of cyclopentadiene was added dropwise in the course of 15 minutes. The red solution was stirred at room temperature overnight, hydrolyzed with 200 ml of water and extracted five times with 75 ml of petroleum ether each time. The combined organic extracts were filtered and concentrated to dryness and the residue was subjected to fractional distillation.
Reaction SMILES: [Mn]([O-])(=O)(=O)=[O:2].[K+].[OH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH:17]2[O:29][CH2:30][C:31]2[CH:40]=[CH:39][C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:32]=2)=[CH:12][CH:11]=1>O.C(O)(=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C1C=CC=CC=1>[C:25]([O:24][C:22]([N:19]1[CH2:20][CH2:21][CH:16]([C:13]2[CH:14]=[CH:15][C:10]([CH2:9][C:8]([OH:2])=[O:7])=[CH:11][CH:12]=2)[CH:17]([O:29][CH2:30][C:31]2[CH:40]=[CH:39][C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:32]=2)[CH2:18]1)=[O:23])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CCO)cc2)C(OCc2ccc3ccccc3c2)C1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(CC(=O)O)cc2)C(OCc2ccc3ccccc3c2)C1
Reaction time: 48 h
Yield: 50.5 %

Procedure:
6.95 g (44 mmol) of powdered potassium permanganate dissolved in a mixture of 100 ml of water and 100 ml of glacial acetic acid as well as 0.73 g (2 mmol) of tetrabutylammonium iodide were added to a solution of 5.0 g (10.83 mmol) of tert-butyl (3RS,4RS)-4-[4-(2-hydroxy-ethyl)-phenyl]-3-naphthalen-2-ylmethoxy-piperidine-1-carboxylate in 500 ml of benzene. The reaction mixture was stirred intensively for 48 hours. For the working-up, the phases were separated. The organic phase was washed with 100 ml of saturated sodium thiosulphate solution. The aqueous phase was decolorized by the addition of saturated sodium thiosulphate solution and subsequently extracted twice with 100 ml of ethyl acetate and 100 ml of methylene chloride each time. The organic phases were combined, dried over sodium sulphate and evaporated under reduced pressure. For purification, the crude material was chromatographed on silica gel using a 9:1 mixture of methylene chloride and methanol as the eluent after the column had previously been prepared with a 90:10:0.1 mixture of methylene chloride, methanol and ammonia. There were obtained 2.6 g (50% of theory) of (3RS,4RS)-[4-(1-tert-butoxycarbonyl-3-naphthalen-2-ylmethoxy-piperidin-4-yl)-phenyl]-acetic acid as a colourless, amorphous solid; MS: 476 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.C(=O)(O)[O-].[Na+].[C:16](Cl)(Cl)=[S:17].[CH2:20]([CH2:22][NH2:23])[OH:21]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:16]([NH:23][CH2:22][CH2:20][OH:21])=[S:17])[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: S=C(Cl)Cl
Reactant: Cn1cc(Br)cc(N)c1=O
Reactant: NCCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cn1cc(Br)cc(NC(=S)NCCO)c1=O
Reaction time: 1 h
Yield: 68.4 %

Procedure:
To a solution of 5-bromo-3-amino-1-methyl-2-pyridone (500 mg, 2.46 mmol) in chloroform (12 mL) was added a solution of saturated aqueous sodium bicarbonate (12 mL). To the vigorously stirred mixture was added thiophosgene (0.2 mL, 2.7 mmol) via drop-wise addition. The mixture was stirred for 1 hour and then transferred to a separatory funnel. The chloroform phase was collected and the aqueous phase was back extracted with methylene chloride (10 mL). The organic phases were combined in a 100 mL round bottom flask. To the rapidly stirred solution was added ethanolamine (0.16 mL, 2.7 mmol) via slow drop-wise addition. The material was stirred for 1.5 hours and the precipitated product was collected by filtration. The solid was dried in a vacuum oven providing the desired product as a light white-yellow solid (515 mg). (M−H)−=304/306 m/e.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][C:10]2=O)=[CH:5][CH:4]=1.C1C=CC=CC=1.C[Si]([C:24]#[N:25])(C)C.P(Cl)(Cl)(Cl)=O>[I-].[Zn+2].[I-].N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]=[C:10]2[C:24]#[N:25])=[CH:5][CH:4]=1
Reactant: C[Si](C)(C)C#N
Reactant: COc1ccc2c(c1)C(=O)CCC2
Agent: [I-]
Agent: [Zn+2]
Solvent: c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COc1ccc2c(c1)C(C#N)=CCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 7-methoxy-1-tetralone (39.65 g, 0.23 mol), zinc iodide (1.73 g, 5.4 mmol), and benzene (100 mLs) was added trimethylsilylcyanide (25.0 g. 0.25 mol). The mixture was stirred overnight at room temperature. Pyridine (350 mL) was added and phosphorous oxychloride (100 mL) was then added dropwise, with a slight temperature increase. The mixture was heated to reflux and held for 6 hr. TLC showed one mid-Rf spot for the desired product. The mixture was stirred overnight at room temperature. The mixture was carefully poured onto ice/hydrochloric acid (about 1.5 liter of 10% HCl). The total volume was 2 liters. This mixture was extracted with ethyl acetate (3×500 mLs), the organics combined and washed with water (2×500 mLs) and then brine (500 mLs). The ethyl acetate was dried over magnesium sulfate and evaporated off provide a liquid which on standing solidified. This crude solid was slurried in hexane and filtered to give 31.3 g (74%) of a tan solid. Some of this material, was purified by silica gel chromatography (10% ethyl acetate-hexanes) to provide a solid: mp 47–49° C.; 1H NMR (DMSO-d6): δ 2.44–2.50 (2H, m), 2.72 (2H, t, J=8.4 Hz), 6.81 (1 H, d, J=2.6 Hz), 6.90 (1H, dd, J=2.9 Hz, J=8.2 Hz), 7.17–7.19 (2H, m); MS m/z 168 ([M−H]−);
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[NH:10][C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=3)=[C:12]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[N:20]=[CH:19][CH:18]=[CH:17]4)[N:13]=2)=[CH:4][C:3]=1[OH:31].ClC[CH2:34][C:35]([O:37][CH3:38])=[O:36].C([O-])([O-])=O.[K+].[K+]>CC(C)=O.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[NH:10][C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=3)=[C:12]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[N:20]=[CH:19][CH:18]=[CH:17]4)[N:13]=2)=[CH:4][C:3]=1[O:31][CH2:34][C:35]([O:37][CH3:38])=[O:36]
Reactant: Cc1cccc(-c2[nH]c(Cc3ccc(F)c(O)c3)nc2-c2ccc3ncccc3c2)n1
Reactant: COC(=O)CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)COc1cc(Cc2nc(-c3ccc4ncccc4c3)c(-c3cccc(C)n3)[nH]2)ccc1F
Temperature: 60 °C
Reaction time: 20 h
Yield: 75.1 %

Procedure:
To a stirred solution of 2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)phenol (Example 81) (100 mg, 0.244 mmol) in acetone (5 mL) were added methyl 3-chloropropanoate (32 uL, 0.366 mmol) and K2CO3 (67 mg, 0.488 mmol) and the mixture was stirred at 60° C. for 20 hours. The reaction mixture was cooled to room temperature, diluted with H2O (20 mL), and extracted with CH2Cl2 (5 mL, 3 times). The organic layer was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by MPLC on NH silica gel (MeOH:CH2Cl2=1:50 (v/v)) to afford the title compound (88.4 mg, 75%). (300 MHz, CDCl3) δ 2.50 (3H, s), 3.74 (3H, s), 4.16 (2H, s), 4.71 (2H, s), 6.91-6.97 (3H, m), 7.06 (1H, td), 7.24 (1H, s), 7.37 (1H, d), 7.42 (1H, dd), 7.97 (1H, d), 8.10-8.18 (3H, m), 8.92 (1H, dd), 10.35 (1H, bs). MS (ESI) m/z 483 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].[N:11]([O-])=O.[Na+].[ClH:15]>O>[Cl-:15].[N+:1]([C:4]1[CH:10]=[CH:9][C:7]([N+:8]#[N:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=N[O-]
Reactant: Cl
Reactant: Nc1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Solvent: O
Product: N#[N+]c1ccc([N+](=O)[O-])cc1
Product: [Cl-]
Reaction time: 0.25 h

Procedure:
4-Nitroaniline (0.14 g) was dissolved in 2N-hydrochloric acid (3 mL) under heating and the solution was ice-cooled. To this solution was added a solution of sodium nitrite (72 mg) in water (0.5 mL) dropwise, and the mixture was stirred for 15 minutes. The aqueous solution of 4-nitrobenzenediazonium chloride thus obtained was added to a solution of (S)-1-[(2,3-dihydro-2,4,6,7-tetramethylbenzofuran-2yl)methyl]-N-(diphenylmethyl)-4-piperidinamine (0.43 g) in acetic acid (3 mL) under cooling and the mixture was stirred at room temperature for 12 hours. This reaction mixture was poured into saturated aqueous sodium carbonate solution and extracted with ethyl acetate. The extract was washed with water and saturated aqueous sodium chloride solution, dried over MgSO4, and concentrated under reduced pressure. To the (S)-1-[[2,3-dihydro-2,4,6,7-tetramethyl-5-(4-nitrophenyl-azo)benzofuran-2-yl]methyl]-N-(diphenylmethyl)-4-piperidinamine thus obtained were added ethanol (30 mL) and Raney nickel (Kawaken Fine Chemical NDHT-90) (0.6 g) and the mixture was stirred in a hydrogen atmosphere at 5 atm. and room temperature for 1 hour. This reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to provide 0.32 g of the title compound. Yield 71%.
Reaction SMILES: O[N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([O:13]C)=O.[ClH:15].[NH2:16][C:17]([NH2:19])=[NH:18].C[O-:21].[Na+]>CO>[ClH:15].[OH:21][NH:18][C:17]([NH2:19])=[N:16][C:11]([C:3]1[NH:2][C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2)=[O:13]
Reactant: COC(=O)c1cc2ccccc2n1O
Reactant: C[O-]
Reactant: N=C(N)N
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: NC(=NC(=O)c1cc2ccccc2[nH]1)NO

Procedure:
The reaction was carried out in a manner similar to Example 1 except for using 1.00 g (5.23 mmol) of methyl 1-hydroxy-2-indolecarboxylate, 5.00 g (52.3 mmol) of guanidine hydrochloride and 50 ml of a methanol solution of 2.82 g (52.3 mmol) of sodium methoxide. 1-Hydroxy-2-indoloylguanidine hydrochloride was obtained in an amount of 0.56 g (42.0%).
Reaction SMILES: CS(O[CH2:6][C:7]1[C:8]([CH:32]([O:35][CH3:36])[O:33][CH3:34])=[N:9][C:10]2[N:11]([C:17](=[O:31])[NH:18][C:19]3[CH:24]=[C:23]([O:25][CH:26]([CH3:28])[CH3:27])[C:22]([C:29]#[N:30])=[CH:21][N:20]=3)[CH2:12][CH2:13][CH2:14][C:15]=2[CH:16]=1)(=O)=O.C(N(CC)CC)C.[C:44]([N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1)(=[O:46])[CH3:45]>C(Cl)Cl.O>[C:44]([N:47]1[CH2:52][CH2:51][N:50]([CH2:6][C:7]2[CH:16]=[C:15]3[C:10](=[N:9][C:8]=2[CH:32]([O:33][CH3:34])[O:35][CH3:36])[N:11]([C:17]([NH:18][C:19]2[CH:24]=[C:23]([O:25][CH:26]([CH3:28])[CH3:27])[C:22]([C:29]#[N:30])=[CH:21][N:20]=2)=[O:31])[CH2:12][CH2:13][CH2:14]3)[CH2:49][CH2:48]1)(=[O:46])[CH3:45]
Reactant: CC(=O)N1CCNCC1
Reactant: COC(OC)c1nc2c(cc1COS(C)(=O)=O)CCCN2C(=O)Nc1cc(OC(C)C)c(C#N)cn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COC(OC)c1nc2c(cc1CN1CCN(C(C)=O)CC1)CCCN2C(=O)Nc1cc(OC(C)C)c(C#N)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (8-((5-cyano-4-isopropoxypyridin-2-yl)carbamoyl)-2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl methanesulfonate (intermediate 167, 188 mg, 0.362 mmol) in DCM (1 ml) was added triethylamine (0.176 mL, 1.267 mmol) followed by 1-acetylpiperazine (71.0 mg, 0.543 mmol) and the reaction mixture was stirred at room temperature for approximately 2 h. The reaction mixture was diluted with DCM and water and extracted. The water phase was extracted with DCM (2×), the combined organic layers were dried using Na2SO4, filtered and concentrated. The crude product was purified via silica gel column chromatography, eluting with a gradient of MeOH (1-5%) in DCM. Product fractions were combined and concentrated to yield the title compound as a white solid. (UPLC-MS 3) tR 0.97 min, ESI-MS 552.3 [M+H]+. 1H NMR (600 MHz, CDCl3) δ 14.01 (s, 1H), 8.38 (s, 1H), 7.96 (s, 1H), 7.62 (s, 1H), 5.68 (s, 1H), 4.88-4.80 (m, 1H), 4.07-4.02 (m, 2H), 3.66-3.58 (m, 4H), 3.47-3.42 (m, 8H), 2.86 (t, 2H), 2.45 (t, 2H), 2.41 (t, 2H), 2.09 (s, 3H), 2.04-1.96 (m, 2H), 1.44 (d, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[S:11][CH:12]=2)=[CH:5][CH:4]=1.[Li]CCCC.[I:24]I>C1COCC1>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[S:11][C:12]=2[I:24])=[CH:5][CH:4]=1
Reactant: COc1ccc(Oc2csc3ccccc23)cc1
Reactant: II
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(Oc2c(I)sc3ccccc23)cc1
Temperature: 25 °C

Procedure:
A solution of 133 mg (0.52 mmol) of 3-(4-methoxyphenoxy)benzo[b]thiophene (Part A) in 3 mL of THF was treated with 0.33 mL of 1.6 M n-BuLi in hexanes (0.54 mmol) at −78° C. for 15 min and then treated with 138 mg (0.54 mmol) of I2 in 3 mL of THF. The reaction was allowed to gradually warm to room temperature and then partitioned between brine and EtOAc/hexanes. The two phases were separated, the organic phase was washed with H2O, dried over Na2SO4, and concentrated in vacuo. The residue was crystallized from hexanes to afford 143 mg (0.37 mmol; 72%) of the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([N:10]2[CH2:15][CH2:14][CH:13](NC(=O)OC(C)(C)C)[CH2:12]C2)[N:3]=1.ClC1N=C(Cl)C=C(OC)N=1.N[C@@H]1CCC[N:37]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:36]1>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][C@@H:15]2[CH2:14][CH2:13][CH2:12][N:37]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:36]2)[N:3]=1
Reactant: COc1cc(Cl)nc(N2CCC(NC(=O)OC(C)(C)C)CC2)n1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Agent: COc1cc(Cl)nc(Cl)n1
Product: COc1cc(Cl)nc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)n1

Procedure:
The title compound was prepared according to the procedure for compound 276a, using 2,4-dichloro-6-methoxypyrimidine and (R)-tert-butyl 3-aminopiperidine-1-carboxylate.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[NH:10][NH2:11].CN([CH:15]=[N:16][C:17](=[O:19])[CH3:18])C.CCOCC>N1C=CC=CC=1>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[NH:10]/[N:11]=[CH:15]/[NH:16][C:17](=[O:19])[CH3:18]
Reactant: CC(=O)N=CN(C)C
Reactant: NNc1cc(F)ccc1Br
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(=O)N/C=N/Nc1cc(F)ccc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.2 %

Procedure:
To a solution of (2-bromo-5-fluoro-phenyl)-hydrazine hydrochloride (1.21 g, 5 mmol) in pyridine (3 mL) was added a solution of N-((dimethylamino)methylene)acetamide (600 mg, 5.26 mmol) in pyridine (2 mL) and the mixture stirred at room temperature under nitrogen for 1 h. The precipitate formed was collected, washed with CH2Cl2 and then with ether to obtain 1.15 g (3.16 mmol, 63% yield) of the title compound which was contaminated with 1 mole of dimethylamine hydrochloride as a white crystalline powder: HPLC: 2.22 min (AP 84% at 220 nm); LC/MS m/z 274/276 (M+H); 1H NMR (DMSO-d6, 500 MHz) δ ppm 2.00 (3H, s, 9-Me), 2.51 (6H, s, 2 N—CH3), 6.45 (1H, dt, J=8.5, 3 Hz, 5-CH), 6.89 (1H, dd, J=12, 3 Hz, 3-CH), 7.43 (1H, dd, J=8.5, 6 Hz, 6-CH), 8.68 (1H, d, J=9.5 Hz, 7-CH), 8.88 (2H, br.s, NH2+), 9.24 (1H, s, 7-NH), 10.54 (1H, d, J=9.5 Hz, 2-NH); No signals from the rotational isomer were observed; 13C NMR (CDCl3, 125.8 Hz) δppm 22.6 (9-CH3), 33.9 (2 NCH3), 99.6 (d, J=28 Hz, 3-CH), 99.7 (1-C), 105.0 (d, J=24 Hz, 5-CH), 133.5 (d, J=10.6 Hz, 6-CH), 137.1 (7-CH), 144.9 (d, J=11.6 Hz, 2-C), 162.4 (d, J=244 Hz, 4-CF), 168.5 (8-C═O). No signals from the rotational isomer were observed; Anal. calcd for C9H9BrFN3O.Me2NH.HCl.1/2H2O: C36.24, H4.99, N15.37, found C35.88, H4.87, N15.23. An analytical sample of the title compound without contamination of dimethylamine hydrochloride was obtained by column purification (SiO2, 10-15% EtOAc—CH2Cl2): TLC Rf 0.55 (20% EtOAc—CH2Cl2); HPLC: 2.17 min (AP 88% at 220 nm); LC/MS m/z 274/276 (M+H); 1H NMR (DMSO-d6, 500 MHz) δ ppm 1.99 (3H, s, 9-Me), 6.45 (1H, dt, J=8.5, 3 Hz, 5-CH), 6.88 (1H, dd, J=12, 3 Hz, 3-CH), 7.43 (1H, dd, J=9, 6 Hz, 6-CH), 8.69 (1H, d, J=9.5 Hz, 7-CH), 9.23 (1H, s, 7-NH), 10.52 (1H, d, J=9.5 Hz, 2-NH); About 16% of rotational isomer was also observed as a set of minor peaks: 1H NMR (DMSO-d6, 500 MHz) δ ppm 2.11 (3H, s, 9′-Me), 6.58 (1H, dt, J=8.5, 3 Hz, 5′-CH), 7.10 (1H, dd, J=11.6, 3 Hz, 3′-CH), 7.29 (1H, d, J=2.4 Hz, 7′-CH), 7.50 (1H, dd, J=8.7, 6 Hz, 6′-CH), 8.35 (1H, s, 2′-NH), 10.70 (1H, s, 7′-NH); 13C NMR (DMSO-d6, 125.8 Hz) δppm 22.6 (9-CH3), 99.7 (d, J=29 Hz, 3-CH), 99.8 (d, J=3 Hz, 1-C), 105.0 (d, J=24 Hz, 5-CH), 133.6 (d, J=10.6 Hz, 6-CH), 137.1 (7-CH), 144.9 (d, J=11.6 Hz, 2-C), 162.5 (d, J=241 Hz, 4-CF), 168.5 (8-C═O); 13C NMR (DMSO-d6, 125.8 Hz) δ ppm 22.9 (9′-CH3), 100.7 (d, J=3 Hz, 1′-C), 101.6 (d, J=29 Hz, 3′-CH), 106.8 (d, J=24 Hz, 5′-CH), 133.6 (d, J=9.6 Hz, 6′-CH), 162.4 (d, J=242 Hz, 4′-CF), 168.6 (8′-C═O); HRMS (ESI) calcd for C9H10BrFN3O (M+H) 273.9991, found 274.0004 (δ+4.6 ppm); Anal. calcd for C9H9BrFN3O: C39.43, H3.31, N29.15, found C39.67, H2.99, N29.09.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[N+:8]([C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][OH:14])([O-:10])=[O:9]>>[N+:8]([C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][O:14][C:4](=[O:5])[CH2:3][CH2:2][C:1]([OH:6])=[O:7])([O-:10])=[O:9]
Reactant: O=C1CCC(=O)O1
Reactant: O=[N+]([O-])c1ccccc1CO
Product: O=C(O)CCC(=O)OCc1ccccc1[N+](=O)[O-]

Procedure:
Succinic acid mono-o-nitrobenzyl ester was prepared from succinic anhydride and o-nitrobenzyl alcohol by the procedure similar to that described in Example 174.
Reaction SMILES: F[C:2]1[CH:3]=[C:4](C[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:5]=[CH:6][C:7]=1OCC1C(C)=CC(C)=CC=1C.[OH-].[Na+].Cl>C(O)C>[C:21]([O:23][CH2:24][CH3:25])(=[O:22])[CH3:20].[CH3:4][CH2:3][CH2:2][CH2:7][CH2:6][CH3:5]
Reactant: CCOC(=O)CCc1ccc(OCc2c(C)cc(C)cc2C)c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCC
Product: CCOC(C)=O
Yield: 99.1 %

Procedure:
A mixture of ethyl 3-fluoro-4-[(2,4,6-trimethylphenyl)methoxy]benzenepropanoate (363 mg, 1.1 mmol), a 2 N aqueous sodium hydroxide solution (1.5 mL) and ethanol (5 mL) was stirred at 60° C. for 1.5 hours. The reaction solution was ice-cooled and acidified with 1 N hydrochloric acid, and then the solvent was distilled off under reduced pressure. The residue was dissolved in methylene chloride, and the mixture was washed with water and saturated brine and dried over magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the resulting crystals were recrystallized from ethyl acetate/hexane (190 mg, yield 57%).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[CH:6]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[C:7]3[C:12]([CH2:13][S:14][C:4]=2[CH:3]=1)=[CH:11][CH:10]=[CH:9][N:8]=3.[C:23](O)(=[O:31])[C:24]1[CH:29]=[CH:28][N+:27]([O-])=[CH:26][CH:25]=1.O.[OH:34]N1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>ClCCl>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[CH:6]([N:15]3[CH2:16][CH2:17][N+:18]([O-:34])([C:23]([C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)=[O:31])[CH2:19][CH2:20]3)[C:7]3[C:12]([CH2:13][S:14][C:4]=2[CH:3]=1)=[CH:11][CH:10]=[CH:9][N:8]=3
Reactant: O=C(O)c1cc[n+]([O-])cc1
Reactant: On1nnc2ccccc21
Reactant: Clc1ccc2c(c1)SCc1cccnc1C2N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: O=C(c1ccncc1)[N+]1([O-])CCN(C2c3ccc(Cl)cc3SCc3cccnc32)CC1

Procedure:
To a stirred suspension of 8-chloro-5,11-dihydro-11-(1-piperazinyl)[1]benzothiepino[4,3-b]pyridine (251 mg, 0.762 mmol) and isonicotinic acid N-oxide (128 mg, 0.918 mmol) in dry dichloromethane (20 mL), add 1-hydroxybenzotriazole hydrate (123 mg, 0.909 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (175 mg, 0.912 mmol). Stir the resultant mixture at room temperature for 3 hours. Wash the reaction mixture successively with 2.5M aqueous sodium hydroxide (5 mL), water (4×10 mL), and brine (15 mL). Dry the washed solution over anhydrous magnesium sulfate, filter out the drying agent, and remove solvent from the filtrate under reduced pressure. Flash chromatograph the residue on silica gel, eluting with methanol/dichloromethane (1:9) to obtain the title compound as a 3/4 hydrate (240 mg, 70% yield): mp 162°-165.5° C. (melts to a viscous gum); MS (FAB) m/z 450 [M+ +1].
Reaction SMILES: [Cl:1][C:2]([F:20])([F:19])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([OH:18])[CH:4]=1.[C:21]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[Cl:1][C:2]([F:19])([F:20])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:10])[F:11])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([O:18][CH3:21])[CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1c(O)cc(C(F)(F)Cl)nc1C(F)(F)F
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CCOC(=O)c1c(OC)cc(C(F)(F)Cl)nc1C(F)(F)F
Yield: 88.4 %

Procedure:
This compound was prepared using the procedure of Example 8, 12.0 g (0.038 mol) of product of Example 5, 5.8 g (0.042 mol) of K2CO3, 12 ml (0.190 mol) of methyl iodide in 200 ml of acetone were reacted affording 11.21 g of solid which was purified by HPLC using 25% ethyl acetate/cyclohexane as eluting solvent to give 9.33 g (73.6%) of product as a white solid; mp 62°-64° C.
Reaction SMILES: C(N(CC)CC)C.[OH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18].[P:21](Cl)([Cl:24])([Cl:23])=[O:22]>CCOCC>[Cl:23][P:21]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])([Cl:24])=[O:22]
Reactant: COC(=O)CCc1ccccc1O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COC(=O)CCc1ccccc1OP(=O)(Cl)Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dry triethylamine (0.38 mL, 2.8 mmol) and methyl 3-(2-hydroxyphenyl)propanoate, 80 (0.5 g, 2.77 mmol) in dry ether (9.2 mL) were added dropwise to a solution of dry ether (5 mL) containing phosphorus oxychloride (0.25 mL, 2.8 mmol) at −78° C. under nitrogen. Following the addition, the reaction mixture was slowly allowed to warm to rt, and stirred for 1 h. The solvent was removed under reduced pressure to give crude product as an oil containing a significant amount of solid.