Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.S(Cl)(Cl)=O.CN(C)C=O.[Cl:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1>C1(C)C=CC=CC=1>[Cl:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH:26][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:23][CH:22]=1
Reactant: O=[N+]([O-])c1cccnc1O
Reactant: NCc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: O=[N+]([O-])c1cccnc1NCc1ccc(Cl)cc1
Temperature: 85 °C
Reaction time: 4 h

Procedure:
A mixture of 10.3 g of 2-hydroxy-3-nitropyridine and 25.5 ml of thionyl chloride was heated under reflux for 2.5 hours, after which 1.1 ml of dimethylformamide were rapidly added to the mixture, which was then heated under reflux for 2.5 hours. At the end of this time, the reaction mixture was freed from the solvent by evaporation under reduced pressure. 80 ml of toluene and 19.1 g of sodium carbonate were added to the residue thus obtained, and then a solution of 12.3 ml of 4-chlorobenzylamine in 20 ml of toluene was added dropwise to the resulting mixture, which was then stirred at 85° C. for 4 hours. At the end of this time, the insoluble material in the reaction mixture was removed by filtration. The filtrate was washed with water and dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The resulting residue was crystallized by trituration with 2-propanol, to give 12.0 g of the title compound, melting at 95°-96° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11].O1CCCC1.C([Li])CCC.[CH2:25]([N:28]=[CH:29][C:30]1[S:31][CH:32]=[CH:33][C:34]=1[CH3:35])[CH2:26][CH3:27]>CCCCCC.O>[CH3:12][C:10]([CH3:11])([CH3:13])[C:9]([NH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH2:1][CH:29]([C:30]1[S:31][CH:32]=[CH:33][C:34]=1[CH3:35])[NH:28][CH2:25][CH2:26][CH3:27])=[O:14]
Reactant: Cc1ccccc1NC(=O)C(C)(C)C
Reactant: CCCN=Cc1sccc1C
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCNC(Cc1ccccc1NC(=O)C(C)(C)C)c1sccc1C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a stirred, chilled (-10° C.) solution of 10.14 g of N-[(2-methyl)-phenyl]-2,2-dimethylpropanamide and 80 ml of tetrahydrofuran, was added over 45 min 48 ml of 2.5M n-butyllithium in hexane, maintaining the temperature below 0° C. The solution was stirred for 2 hr, with cooling. To the suspension, was added a solution of 10.6 g of 3-methyl-2-thiophene carboxaldehyde-n-propylimine and 45 ml of tetrahydrofuran, with stirring and cooling over 15 min. The solution was stirred for 1.5 hr, with cooling, and then 150 ml of water was added. The mixture was concentrated. The residue was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. Purification of the residue was accomplished by Preparative HPLC (Water Associates Prep LC/System 500, silica gel, eluted with ethyl acetate, flow rate 200 ml/min, Gow Mac model 80-800 UV detector). The appropriate fractions were combined and concentrated to give 15.2 g of product, as an oil.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[NH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20].[OH-].[Na+].O1CCCC1>O>[CH3:1][N:2]([CH3:13])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: NCCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)c1ccc(S(=O)(=O)NCCCCC(=O)O)cc1
Reaction time: 4 h
Yield: 61.7 %

Procedure:
4.4 g of 4-dimethylaminobenzenesulphonyl chloride (Chem. Ber. 43, 3038, (1910)) are added to a solution comprising 2.34 g of 5-aminovaleric acid and 2.4 g of sodium hydroxide dissolved in 24 cm3 of water, followed by the addition of 24 cm3 of tetrahydrofuran in order to obtain a solution. The temperature rises to 36° C. The mixture is kept stirring for 4 hours, the tetrahydrofuran is evaporated off, the reaction medium is acidified using acetic acid and extracted with chloroform, the organic phase is dried and the solvents are removed under reduced pressure. 3.7 g of expected product are obtained. M.p. 105°-110° C. After crystallization in an isopropanol/water mixture (1:1), the product, melting point 118°-120° C., is obtained.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([CH2:11][CH3:12])[NH:10][C:5]2=[C:4]([CH3:13])[CH:3]=1.[C:14]1([C:20]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[N:21]2[C:25]([C:26]3[C:31]([C:32]4[CH:37]=[CH:36][C:35]([CH2:38]Br)=[CH:34][CH:33]=4)=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:24][N:23]=[N:22]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[H-].[Na+]>>[CH3:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:38][C:35]3[CH:34]=[CH:33][C:32]([C:31]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:25]4[N:21]([C:20]([C:46]5[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=5)([C:40]5[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=5)[C:14]5[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=5)[N:22]=[N:23][N:24]=4)=[CH:37][CH:36]=3)[C:9]([CH2:11][CH3:12])=[N:10][C:5]2=[C:4]([CH3:13])[CH:3]=1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCc1nc2nc(C)cc(C)c2[nH]1
Agent: [H-]
Agent: [Na+]
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1

Procedure:
5,7-Dimethyl-2-ethyl-3-(2'-(N-triphenylmethyltetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine was prepared according to the procedure described in Example 7, Part A from 5,7-dimethyl-2-ethylimidazo[4,5-b]pyridine (1.51 g, 8.62 mmol), N-triphenylmethyl-5-(4'-bromomethylbiphen-2-yl)tetrazole (5.29 g, 9.48 mmol), and NaH (17.2 mmol). Yield: 4.25 g white solid: 1H NMR (300 MHz, CDCl3) δ 7.86 (dd, 1H, J=7, 2 Hz), 7.50-7.41 (m, H), 7.36-7.21 (m, 10 H), 7.05 (d, 2 H, J=4.5 Hz), 6.95-6.89 (m, 7 H), 6.86 (d, 2 H, J=4.5 Hz), 5.35 (s, 2H), 2.67 (q, 2 H, J=7.5 Hz), 2.65 (s, 3 H), 2.58 (s, 3 H), 1.25 (t, 3 H, J=7.5 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[NH:10][CH:11]=[C:12]([C:13](=[O:25])[C:14]3[C:19]([F:20])=[CH:18][CH:17]=[C:16]([N+:21]([O-])=O)[C:15]=3[F:24])[C:3]=12.[Sn](Cl)Cl.O1CCCC1.C(=O)(O)[O-].[Na+]>C(O)C.C(OCC)(=O)C.O>[NH2:21][C:16]1[C:15]([F:24])=[C:14]([C:19]([F:20])=[CH:18][CH:17]=1)[C:13]([C:12]1[C:3]2[C:4](=[N:5][CH:6]=[C:7]([C:8]#[N:9])[C:2]=2[Cl:1])[NH:10][CH:11]=1)=[O:25]
Reactant: N#Cc1cnc2[nH]cc(C(=O)c3c(F)ccc([N+](=O)[O-])c3F)c2c1Cl
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#Cc1cnc2[nH]cc(C(=O)c3c(F)ccc(N)c3F)c2c1Cl
Temperature: 60 °C
Yield: 88 %

Procedure:
In a round bottom flask, 4-chloro-3-(2,6-difluoro-3-nitro-benzoyl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (51, 0.15 g, 0.42 mmol) in 10 mL of ethanol and 10 mL of tetrhydrofuran, tin(II) chloride (0.1 mL, 2.1 mmol) is added. An additional 10 mL of tetrahydrofuran is added to give a clear solution, and the reaction is heated at 60° C. for 24 hours. The reaction is combined with 10 mL of water and 10 mL of saturated aqueous sodium bicarbonate and 20 mL of ethyl acetate is added. Celite is added with mixing, and then filtered. Brine is added to the filtrate and the layers are separated. The organic layer is washed with water, brine, dried with magenesium sulfate, filtered and the filtrate is concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with 0-80% ethyl acetate in hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (52, 123 mg). MS (ESI) [M+H+]+=332.8 and 334.8.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH2:13][C@@H:14]3[CH2:18][CH2:17][CH2:16][O:15]3)=[CH:9][CH:10]=2)[CH2:5][CH2:4][N:3]1[C@H:19]1[CH2:28][CH2:27][C:26]2[CH:25]=[C:24]([CH:29]=O)[CH:23]=[CH:22][C:21]=2[CH2:20]1.[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1>>[N:31]1([CH2:29][C:24]2[CH:25]=[C:26]3[C:21](=[CH:22][CH:23]=2)[CH2:20][C@@H:19]([N:3]2[CH2:4][CH2:5][C:6]4[C:11](=[CH:10][CH:9]=[C:8]([O:12][CH2:13][C@@H:14]5[CH2:18][CH2:17][CH2:16][O:15]5)[CH:7]=4)[C:2]2=[O:1])[CH2:28][CH2:27]3)[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: C1CCNC1
Reactant: O=Cc1ccc2c(c1)CC[C@H](N1CCc3cc(OC[C@@H]4CCCO4)ccc3C1=O)C2
Product: O=C1c2ccc(OC[C@@H]3CCCO3)cc2CCN1[C@H]1CCc2cc(CN3CCCC3)ccc2C1

Procedure:
According to method H-1, (S)-6-{1-oxo-6-[(S)-1-(tetrahydrofuran-2-yl)methoxy]-3,4-dihydro-1H-isoquinolin-2-yl}-5,6,7,8-tetrahydronaphthalene-2-carbaldehyde was reacted with pyrrolidine. The product was thus obtained with the molecular weight of 460.62 (C29H36N2O3); MS (ESI): 461 (M+H+).
Reaction SMILES: C(=S)=S.[Br:4]Br.O.[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH3:15]>>[Br:4][C:12]1[CH:11]=[CH:10][C:9]([O:14][CH3:15])=[C:8]([F:7])[CH:13]=1
Reactant: BrBr
Reactant: COc1ccccc1F
Solvent: O
Solvent: S=C=S
Product: COc1ccc(Br)cc1F

Procedure:
To 50 ml of carbon disulfide in which 50 g of o-fluoroanisole was dissolved, a solution prepared by mixing 27 g of carbon dislufide with 63.8 g of bromine was slowly added dropwise at a temperature of -5° C. to 5° C. in 1 hour with stirring. After the dropping of the solution was finished, it was further stirred at 5° C. for 30 min, added with 125 ml of water, and subjected to extraction with chloroform. The chloroform layer was washed with an aqueous sodium thiosulfate (Na2S2O3) solution and an aqueous sodium hydrogencarbonate (NaHCO3) solution in turn. Then, the solvent was distilled off with an evaporator under a reduced pressure to obtain 70.9 of 4-bromo-2-fluoroanisole.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C@@H:13]1[C@@H:17]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[CH2:16][N:15]([CH2:25][C:26]2([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH2:14]1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH:12]([C@@H:13]1[C@@H:17]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[CH2:16][N:15]([CH2:25][C:26]2([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:33])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)[CH2:14]1)=[O:11]
Reactant: O=C(OCc1ccccc1)C1(CN2C[C@H](CO)[C@@H](c3cccc(F)c3)C2)CCCCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=C[C@H]1CN(CC2(C(=O)OCc3ccccc3)CCCCC2)C[C@@H]1c1cccc(F)c1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A solution of 2.1 mL (24.2 mmol) of oxalyl chloride in 110 mL of CH2Cl2 at −78° C. was treated with 2.6 mL (36.8 mmol) of DMSO maintaining the temperature at less than −60° C. The resulting mixture was stirred cold for 5 min. A solution of 4.5 g (10.5 mmol) of 1-{[(3R,4S)-3-(hydroxymethyl)-4-(3-fluorophenyl)pyrrolidin-1-yl]methyl}cyclohexanecarboxylic acid, benzyl ester (from Step B) in 10 mL of CH2Cl2 was added maintaining the temperature at less than −60° C. The resulting mixture was stirred cold for 60 min. The mixture was treated with 15 mL (84.0 mmol) of N,N-diisopropylethylamine maintaining the temperature at less than −60° C. The reaction was warmed to 0° C., stirred for 20 min and quenched with 20 mL 0.5 N KHSO4. The mixture was partitioned between 250 mL of CH2Cl2 and 100 mL of H2O and the layers were separated. The aqueous layer was extracted with 250 mL of CH2Cl2. The combined organic phases were dried over MgSO4 and concentrated. Purification by Biotage Flash 40 using a 40 M cartridge and 1.0 L each of 95:5 to 90:10 v/v hexane/ethyl acetate as the eluant afforded the title compound: 1H NMR (500 MHz, CDCl3) δ 1.24–3.48 (18H), 5.16 (ABq, J=12.2, 2H), 6.90–7.02 (3H), 7.22–7.39 (6H), 9.59 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.[C:9](=O)(OCC)OCC.C([O-])([O-])=O.[K+].[K+]>C1OCCOCCOCCOCCOCCOC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8][CH3:9])[CH:3]=1
Reactant: Fc1cccc(S)c1
Reactant: CCOC(=O)OCC
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CSc1cccc(F)c1
Temperature: 100 °C
Yield: 96.9 %

Procedure:
To a solution of 3-fluorothiophenol (4.73 g, 37.0 mmol) in diethyl carbonate (11 mL, 129 mmol) was added K2CO3 (7.67 g, 55.5 mmol) and 18-crown-6 ether (100 mg, 0.37 mmol). The reaction mixture was refluxed at 100° C. for 12 h. The reaction mixture was cooled to 20° C. then quenched by addition of H2O and extracted with Et2O. The combine organic solution washed with H2O and brine, dried over MgSO4 to give 1-fluoro-3-(methylsulfanyl)benzene (5.10 g, 97%) as a colorless oil.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[N:11]=1>C(#N)C>[Br:9][C:10]1[C:15]([Br:8])=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[N:11]=1
Reactant: COc1cccc(Br)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: COc1ccc(Br)c(Br)n1
Temperature: 85 °C
Reaction time: 24 h

Procedure:
NBS (302 g) was added to the compound of Example 259 (295 g) in acetonitrile (575 mL) and the mixture was stirred at 80 to 90° C. for 1 day in a nitrogen atmosphere. After cooling, the crystallized imide was removed by filtration and the filtrate was concentrated. Purification of the resulting residue by silica gel column chromatography (ether:petroleum ether=1:1) gave a 6:1 mixture of the title compound and 2,5-dibromo form. This product was crystallized from cold petroleum ether to afford the title compound as a colorless powder (223 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:13][C:12]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])=[N:11][C:10]=1[C:22]([OH:24])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:25][C:26]1[C:27]([N:35]2[CH2:40][CH2:39][CH2:38][C@H:37]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:36]2)=[C:28]2[CH2:34][CH2:33][O:32][C:29]2=[N:30][CH:31]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CCOC(C)=O.CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C:9]1[S:13][C:12]([C:14]2[C:15]([F:21])=[CH:16][CH:17]=[CH:18][C:19]=2[F:20])=[N:11][C:10]=1[C:22]([NH:25][C:26]1[C:27]([N:35]2[CH2:40][CH2:39][CH2:38][C@H:37]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:46])([CH3:45])[CH3:47])[CH2:36]2)=[C:28]2[CH2:34][CH2:33][O:32][C:29]2=[N:30][CH:31]=1)=[O:24])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c(N)cnc3c2CCO3)C1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)Nc1cnc2c(c1N1CCC[C@H](NC(=O)OC(C)(C)C)C1)CCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.9 %

Procedure:
To a mixture of 5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylic acid (Example 1, Step 6, 418.2 mg, 1.174 mmol), tert-butyl [(3S)-1-(5-amino-2,3-dihydrofuro[2,3-b]pyridin-4-yl)piperidin-3-yl]carbamate (377.4 mg, 1.128 mmol) and HATU (1308 mg, 3.440 mmol), DMF (15.0 mL) was added, followed by DIPEA (1.00 mL, 5.74 mmol). The mixture was stirred at room temperature for 2 h. The reaction mixture was then diluted with EtOAc (150 mL), washed with saturated aq. NaHCO3 (150 mL) and brine (2×75 mL), then dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (0-100% EtOAc in hexanes) to give the sub-title compound as a yellow solid (720.2 mg, 95%). LCMS calc. for C32H39F2N6O6S (M+H)+: m/z=673.3. found 673.2.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][O:6][CH:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[O:4][CH2:3]1.[CH3:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18]Cl>>[CH3:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][O:1][CH:2]1[CH2:7][O:6][CH:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[O:4][CH2:3]1
Reactant: Cc1ccccc1CCl
Reactant: OC1COC(c2cccc(Cl)c2)OC1
Product: Cc1ccccc1COC1COC(c2cccc(Cl)c2)OC1
Yield: 39.2 %

Procedure:
Using the procedure of Example 9, 5-hydroxy-2-(3-chlorophenyl)-1,3-dioxane (21.5 g, 0.1 mole) was reacted with 2-methylbenzyl chloride (14.0 g, 0.1 mole) to give a heavy oil, which on distillation under 1 × 10-4 mm pressure gave 12.5 g of product which distilled at a pot temperature of 160°-170° C. Analysis by nmr indicated this product to contain 18% cis-5-(2-methylbenzyloxy)-2-(3-chlorophenyl)-1,3-dioxane.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][O:22][CH2:23][CH2:24][NH2:25]>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:25][CH2:24][CH2:23][O:22][CH3:21])=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: COCCN
Product: COCCNC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (100 mg, 0.28 mmol) and 2-Methoxy ethylamine (25 mg, 0.32 mmol). The title compound was obtained as a solid (52 mg, 46% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.99 (2H, m), 8.95 (1H, m), 8.46 (1H, m), 3.39 (2H, m), 3.35 (2H, m), 3.24 (3H, s). MS m/z: 405.99, 407.99 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.Cl.[C:22](N)(=[NH:24])[CH3:23].CC1NC=CN=1>C(Cl)(Cl)Cl>[NH2:24][C:22](=[N:13][NH:12][C:10]1[CH2:9][N:8]=[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]2[CH:20]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[N:11]=1)[CH3:23]
Reactant: CC(=N)N
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Agent: Cc1ncc[nH]1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CC(N)=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 2.8 parts of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine, 2.8 parts of acetamidine hydrochloride, 2.5 parts of 2-methylimidazole and 100 parts by volume of chloroform is stirred at room temperature for 24 hours. The chloroform layer is washed with water, dried over sodium sulfate and the solvent is evaporated. After treating the residue with diethyl ether, the resulting crystals are subjected to extraction with hot methanol. Evaporation of the methanol gives 2-(α-aminoethylidene) hydrazino-7-chloro-5-phenyl-3H-1,4-benzodiazepine as crystals. Recrystallization from acetone yields pale yellow needles melting at 203° C to 205° C (effervescence).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].CON(C)[C:10]([C:12]1[S:20][C:15]2[N:16]=[CH:17][N:18]=[CH:19][C:14]=2[CH:13]=1)=[O:11].[Cl-].[NH4+]>C1COCC1>[N:16]1[C:15]2[S:20][C:12]([CH:10]=[O:11])=[CH:13][C:14]=2[CH:19]=[N:18][CH:17]=1
Reactant: CON(C)C(=O)c1cc2cncnc2s1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: O=Cc1cc2cncnc2s1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 69.7 %

Procedure:
LiAlH4 (1M in THF, 0.26 mL) was added dropwise to N-methoxy-N-methylthieno[2,3-d]pyrimidine-6-carboxamide (intermediate 12) (117 mg) in THF (6 mL) at −78° C. under an inert atmosphere. The reaction was allowed to stir at −78° C. for 30 minutes and then allowed to warm to 0° C. Saturated aqueous-ammonium chloride (2 mL) was added and allowed to stir at 0° C. for 10 minutes. The organic layer was separated and the aqueous layer extracted with diethyl ether (2×15 mL). The combined organics were dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica eluting with hexane:EtOAc (1:4) afforded the title compound as a white solid (60 mg, 70%);
Reaction SMILES: C([CH:4]1[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:12]2[C:11](=[O:23])[CH2:10][CH2:9][CH2:8][C:7]=2[NH:6][C:5]1([C:25]([F:28])([F:27])[F:26])O)(O)=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:28][C:25]([F:26])([F:27])[C:5]1[NH:6][C:7]2[CH2:8][CH2:9][CH2:10][C:11](=[O:23])[C:12]=2[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[CH:4]=1
Reactant: O=C1CCCC2=C1C(c1cccc([N+](=O)[O-])c1)C(C(=O)O)C(O)(C(F)(F)F)N2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1CCCC2=C1C(c1cccc([N+](=O)[O-])c1)C=C(C(F)(F)F)N2
Yield: 31 %

Procedure:
A suspension of 3-carboxy-2-trifluoromethyl-2-hydroxy-4-(3-nitrophenyl)-4,6,7,8-tetrahydro-5(1H)-quinolone (3.17 g) in toluene (150 mL) was treated with p-toluenesulfonic acid monohydrate (0.32g), the mixture refluxed vigorously under Dean-Stark conditions for 4 hours and then partitioned between water and ethyl acetate. The organic phase was washed (water and brine) and evaporated. The residue was purified by chromatography (hexane/ethyl acetate, 1:1 and methylene chloride/acetonitrile 95:5) to yield the title compound (0.83 g) as a pale yellow solid; mp 215°-216° C.; NMR: 1.77-2.00 (m,2, CH2), 2.16-2.36 (m,2, CH2), 2.50-2.71 (m,2, CH2), 4.79 (d,1, J=4.1 , CH), 5.67 (d,1, J=5.4, CH), 7.57-7.67 (m,2, Ar), 8.04 (m,2, Ar), 9.48 (s,1, NH); MS: m/z=338(M). Analysis for C16H13F3N2O3 : Calculated: C, 56.81; H, 3.87; N, 8.28; Found: C, 56.74; H, 4.02; N, 8.28.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30]C(=O)C)[C@@H:22]([O:23]C(=O)C)[C@H:17]([O:18]C(=O)C)[C@H:12]1[O:13]C(=O)C.[CH2:34]([C:36]1[S:40][C:39]([C:41](Cl)=O)=[CH:38][CH:37]=1)[CH3:35]>>[CH2:34]([C:36]1[S:40][C:39]([CH2:41][C:4]2[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[F:1])[N:6]([C@@H:11]3[O:28][C@H:27]([CH2:29][OH:30])[C@@H:22]([OH:23])[C@H:17]([OH:18])[C@H:12]3[OH:13])[CH:5]=2)=[CH:38][CH:37]=1)[CH3:35]
Reactant: CCc1ccc(C(=O)Cl)s1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ccc3c(F)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: CCc1ccc(Cc2cn([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c3cccc(F)c23)s1

Procedure:
4-Fluoro-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)indole obtained in Example 2-(3) and 5-ethylthiophen-2-carbonyl chloride were treated in a manner similar to Example 2-(4), (5), (6) and (7) to give the titled compound as a colorless powder. APCI-Mass m/Z 439 (M+NH4). 1H-NMR (DMSO-d6) δ 1.17 (t, J=7.5 Hz, 3H), 2.69 (q, J=7.5 Hz, 2H), 3.20-3.48 (m, 4H), 3.67 (m, 2H), 4.20 (s, 2H), 4.53 (br, 1H), 5.08 (br, 1H), 5.20 (br, 2H), 5.38 (d, J=9.2 Hz, 1H), 6.60 (d, J=3.3 Hz, 1H), 6.65 (d, J=3.2 Hz, 1H), 6.77 (dd, J=11.1, 7.8 Hz, 1H), 7.09 (m, 1H), 7.31 (s, 1H), 7.39 (d, J=8.3 Hz, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)=[CH:3]1>CO.CCOC(C)=O.[Pd]>[CH3:1][N:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)=[CH:3]1
Reactant: Cn1cc(-c2ccc([N+](=O)[O-])cc2)c2ncccc21
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cn1cc(-c2ccc(N)cc2)c2ncccc21
Reaction time: 4 h
Yield: 98.7 %

Procedure:
A mixture of 1-methyl-3-(4-nitrophenyl)-1H-pyrrolo[3,2-b]pyridine (85 mg) and 10% Pd—C (50% wet, 100 mg) in MeOH (4 mL) and AcOEt (4 ml) was stirred under H2 atmosphere (balloon) for 4 h. After this time, the reaction was filtered and the filtrate was concentrated under reduced pressure to give the title compound (74 mg).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:12]([OH:15])[CH2:13][OH:14].[Br:16][CH2:17][CH2:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=O>C1C=CC=CC=1>[CH2:13]1[CH2:12][O:15][C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([CH2:18][CH2:17][Br:16])[O:14]1
Reactant: OCCO
Reactant: O=C(CCBr)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: BrCCC1(c2ccccc2)OCCO1
Yield: 49.9 %

Procedure:
p-Toluenesulfonic acid in a catalytic amount and ethylene glycol (2.9 g) were added to a solution of 3-bromo-1-phenyl-1-propanone (10 g) in benzene (100 ml), and the mixture was stirred at refluxing temperature for 70 hr. The reaction mixture was washed successively with 10% aqueous potassium carbonate solution and brine, and dried. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give 6.0 g of 3,3-ethylenedioxy-3-phenylpropyl bromide.