Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:24][NH:25][C:26](=[O:30])[N:27]([CH3:29])[CH3:28]>>[CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:25]([CH3:24])[C:26]([N:27]([CH3:29])[CH3:28])=[O:30])=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Reactant: CNC(=O)N(C)C
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N(C)C(=O)N(C)C)cc3)CC2)c(C)c1
Yield: 64.1 %

Procedure:
Using [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (211 mg) described in Preparation Example 113 and trimethylurea (77 mg) and by the reaction and treatment in the same manner as in Example 262, the title compound (127 mg) was obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([Cl:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[CH:22]=[CH:23][C:24]2[CH2:30][CH2:29][C:28](=[O:31])[NH:27][CH2:26][C:25]=2[CH:32]=1>>[Cl:19][C:5]1[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])=[N:7][C:2]([NH:20][C:21]2[CH:22]=[CH:23][C:24]3[CH2:30][CH2:29][C:28](=[O:31])[NH:27][CH2:26][C:25]=3[CH:32]=2)=[N:3][CH:4]=1
Reactant: Nc1ccc2c(c1)CNC(=O)CC2
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CNC(=O)CC3)ncc1Cl

Procedure:
Following a procedure analogous to Example 1742a, 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methylbenzamide and 8-amino-1,2,4,5-tetrahydro-benzo[c]azepin-3-one were converted to give 2-[5-chloro-2-(3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide: 1H NMR (300 MHz, CDCl3) δ 8.54 (d, 1H), 8.03 (s, 1H), 7.6 (m, 2H), 7.4 (m, 2H), 7.08 (m, 3H), 7.26 (m, 1H), 7.1 (t, 1H), 7.05 (d, 1H). 4.25 (s, 2H), 3.05 (t, 2H), 2.95 (d, 3H), 2.86 (t, 2H); MS (m/e): 437.3 (M+1).
Reaction SMILES: [C:1]1([S:7]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][N:10]1[CH2:14][CH2:13][NH:12][C:11]1=[CH:15][N+:16]([O-:18])=[O:17]>N1C=CC=CC=1>[CH3:9][N:10]1[CH2:14][CH2:13][NH:12][C:11]1=[C:15]([N+:16]([O-:18])=[O:17])[S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN1CCNC1=C[N+](=O)[O-]
Reactant: ClSc1ccccc1
Solvent: c1ccncc1
Product: CN1CCNC1=C(Sc1ccccc1)[N+](=O)[O-]
Reaction time: 8 h

Procedure:
14.6 g of phenylsulfenyl chloride was added dropwise to a cooled, stirred solution of 14.3 g of Compound 1 in 250 ml of pyridine. The mixture was allowed to stand overnight at room temperature, then excess pyridine was recovered on a rotary evaporator. The residue was treated with 250 ml of water and the mixture extracted with methylene chloride. The combined extracts were dried and the solvent evaporated to give a crystalline solid which was triturated with ethyl acetate, then ethanol, to yield 25, as a yellow solid, melting point: 170° - 173°.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.[N:21]1([C:27]2[N:32]=[CH:31][C:30]([C:33](O)=[O:34])=[CH:29][N:28]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>>[Cl:14][C:8]1[CH:7]=[C:6]2[C:11]([C:12](=[O:13])[C:3]([CH2:2][NH:1][C:33]([C:30]3[CH:31]=[N:32][C:27]([N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)=[N:28][CH:29]=3)=[O:34])=[CH:4][N:5]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:10][CH:9]=1
Reactant: O=C(O)c1cnc(N2CCOCC2)nc1
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1cnc(N2CCOCC2)nc1

Procedure:
2-Morpholin-4-yl-pyrimidine-5-carboxylic acid (7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-amide was prepared starting from intermediate D and 2-morpholin-4-yl-pyrimidine-5-carboxylic acid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.67 (s, 2H) 8.55 (t, J=5.50 Hz, 1H) 8.21 (d, J=8.78 Hz, 1H) 7.90 (s, 1H) 7.56-7.67 (m, 3H) 7.49-7.55 (m, 2H) 7.39 (dd, J=8.66, 1.88 Hz, 1H) 6.84 (d, J=2.01 Hz, 1H) 4.29 (d, J=5.52 Hz, 2H) 3.67-3.76 (m, 3H) 1.52-1.61 (m, 2H) 1.39-1.48 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:5]([CH2:12][CH3:13])[NH:4][N:3]=1.CN(C)[CH:16]=[CH:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=1)=O>>[CH2:12]([C:5]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:2]2[N:1]=[CH:16][CH:17]=[C:18]([C:20]3[CH:21]=[C:22]([C:26]([F:27])([F:28])[F:29])[CH:23]=[CH:24][CH:25]=3)[N:3]2[N:4]=1)[CH3:13]
Reactant: CN(C)C=CC(=O)c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)c1c(N)n[nH]c1CC
Product: CCOC(=O)c1c(CC)nn2c(-c3cccc(C(F)(F)F)c3)ccnc12

Procedure:
As for Example 1, ethyl 3-amino-5-ethyl-pyrazole-4-carboxylate is reacted with 3-dimethylamino-3'-(trifluoromethyl)acrylophenone to give the product as crystals, m.p. 142°-143° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([O:15][CH3:16])=[C:11](Br)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:18][S:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([O:15][CH3:16])=[C:11]([C:23]3[CH:24]=[CH:25][C:20]([S:19][CH3:18])=[CH:21][CH:22]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: COc1c(Br)cnn(-c2ccc(F)cc2)c1=O
Reactant: CSc1ccc(B(O)O)cc1
Product: COc1c(-c2ccc(SC)cc2)cnn(-c2ccc(F)cc2)c1=O

Procedure:
The title compound was prepared according to the method of Example 6 starting with 2-(4-fluorophenyl)-4-methoxy-5-bromo-3(2H)-pyridazinone in place of 2-benzyl-4-bromo-5-methoxy-3(2H)-pyridazinone and substituting 4-(methylthio)benzeneboronic acid in place of 4-fluorobenzeneboronic acid (yield: 70 mg, 61%). 1H NMR (500 MHz, DMSO-d6) δ 2.54 (s, 3H), 4.02 (s, 3H), 7.35 (dd, J=9.0, 9.0 Hz, 2H), 7.39 (d, J=8.5 Hz, 2H), 7.61 (d, J=8.5 Hz, 2H), 7.65 (dd, J=9.0, 5.0 Hz, 2H), 8.14 (s, 1H). MS (APCI+) m/z 343 (M+H)+.
Reaction SMILES: [Na:1].[CH3:2][CH2:3][C@@H:4]([C:23]([C@H:25]([C@@H:27]([OH:43])[C@@H:28]([CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[C:34]([OH:39])[C:33]=1[C:40]([OH:42])=[O:41])[CH3:29])[CH3:26])=[O:24])[C@H:5]1[O:9][C@@:8]([C@@H:12]2[O:17][C@@H:16]([CH3:18])[C@@:15]([OH:21])([CH2:19][CH3:20])[CH2:14][CH2:13]2)([CH2:10][CH3:11])[CH2:7][C@@H:6]1[CH3:22].[C:44](Cl)(=[O:47])[CH2:45][CH3:46].O>N1C=CC=CC=1>[CH3:38][C:35]1[C:34]([O:39][C:44](=[O:47])[CH2:45][CH3:46])=[C:33]([C:32]([CH2:31][CH2:30][CH:28]([CH3:29])[CH:27]([OH:43])[CH:25]([CH3:26])[C:23](=[O:24])[CH:4]([CH2:3][CH3:2])[CH:5]2[CH:6]([CH3:22])[CH2:7][C:8]([CH2:10][CH3:11])([CH:12]3[CH2:13][CH2:14][C:15]([CH2:19][CH3:20])([OH:21])[CH:16]([CH3:18])[O:17]3)[O:9]2)=[CH:37][CH:36]=1)[C:40]([OH:42])=[O:41].[Na:1]
Reactant: CC[C@@H](C(=O)[C@@H](C)[C@@H](O)[C@H](C)CCc1ccc(C)c(O)c1C(=O)O)[C@H]1O[C@](CC)([C@H]2CC[C@](O)(CC)[C@H](C)O2)C[C@@H]1C
Reactant: CCC(=O)Cl
Agent: [Na]
Solvent: c1ccncc1
Solvent: O
Product: CCC(=O)Oc1c(C)ccc(CCC(C)C(O)C(C)C(=O)C(CC)C2OC(CC)(C3CCC(O)(CC)C(C)O3)CC2C)c1C(=O)O
Reaction time: 2 h

Procedure:
6.12 g. of the sodium salt of antibiotic X-537A was dissolved in pyridine (10 ml.) by warming slightly. The solution was cooled in an ice bath and treated with propionyl chloride, then allowed to stand at room temperature for 2 hours. The mixture was poured into water, extracted with ethyl acetate, and the organic phase washed in succession with 1N hydrochloric acid (several times) and sodium carbonate solution (twice). Evaporation of the ethyl acetate solution left a residue which was crystallized from methylene chloride/hexane to afford 3-methyl-2-propionyloxy-6-{7-ethyl-4-hydroxy-3,5-dimethyl-6-oxo- 7[5-ethyl-3-methyl-5-(5-ethyl-5-hydroxy-6-methyl-2-tetrahydropyranyl)-2-tetrahydrofuryl]heptyl}benzoic acid, sodium salt, m.p. 185°-186.5° [α]D25 -20.00° (C=1.00 in methanol).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][C:8]2[O:9][C:10]([CH3:15])([CH3:14])[CH:11]3[O:13][CH:12]3[C:7]=2[CH:6]=1)(=[O:3])[CH3:2].[NH3:21]>C(O)C>[C:1]([NH:4][C:5]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][C:8]2[O:9][C:10]([CH3:15])([CH3:14])[C@@H:11]([OH:13])[C@H:12]([NH2:21])[C:7]=2[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])OC(C)(C)C1OC21
Reactant: N
Solvent: CCO
Product: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])OC(C)(C)[C@@H](O)[C@@H]2N
Temperature: 25 °C
Reaction time: 120 h

Procedure:
6-Acetamido-3,4-epoxy-3,4-dihydro-2,2-dimethyl-7-nitro-2H-benzo[b]pyran (1.0 g) was dissolved in dry ethanol (150 ml) and saturated with ammonia during 3 h, with cooling. The reaction mixture was stirred at room temperature for 5 days and evaporated. The crude residue was purified on the chromatotron (80% ethyl acetate-pentane to 20% methanol-ethyl acetate gradient elution), to give the title compound (410 mgm). A small portion was converted to the hydrochloride salt and recrystallised from ethanol-diethyl ether, with m.p. 258°-261° C.
Reaction SMILES: [CH2:1]([N:5]1[C:9]([CH3:10])=[CH:8][C:7]([C:11]([O:13]CC)=O)=[N:6]1)[CH2:2][CH2:3][CH3:4].[OH-].[NH4+:17]>CO>[CH2:1]([N:5]1[C:9]([CH3:10])=[CH:8][C:7]([C:11]([NH2:17])=[O:13])=[N:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1nc(C(=O)OCC)cc1C
Reactant: [NH4+]
Agent: [OH-]
Solvent: CO
Product: CCCCn1nc(C(N)=O)cc1C

Procedure:
A solution of ethyl 1-butyl-5-methyl-1H-pyrazole-3-carboxylate (18.1 g, 86.1 mmol) in methanol (25 mL) was treated with ammonium hydroxide (25 mL) according to a modification of the method described in Part D of Examples 1-4. At the end of the reaction, the methanol was removed under reduced pressure, and the remaining solution was cooled in a refrigerator. A precipitate formed, was isolated by filtration, and was washed with water. The solid (9 g) was recrystallized from hexane (300 mL) and ethyl acetate (30 mL), isolated by filtration, washed with hexane, and air-dried to provide 6.95 g of 1-butyl-5-methyl-1H-pyrazole-3-carboxamide as colorless plates, mp 113.5-114.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C@@H:10]3[O:22][C@H:21]([CH3:23])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]3[O:12][C:13](=[O:15])[CH3:14])[C:6]=2[CH:24]=1.[Br:25]N1C(=O)CCC1=O.C([O-])(O)=O.[Na+].C(Cl)(Cl)Cl>C1COCC1>[Br:25][C:8]1[N:7]([C@@H:10]2[O:22][C@H:21]([CH3:23])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]2[O:12][C:13](=[O:15])[CH3:14])[C:6]2[CH:24]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[N:9]=1
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C)O[C@H]1n1cnc2ccc(Cl)cc21
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C)O[C@H]1n1c(Br)nc2ccc(Cl)cc21
Temperature: 0 °C

Procedure:
To a refluxing solution of 0.76 g (2.2 mmol) of 6-chloro-1-(2,3-di-O-acetyl-5-deoxy-beta-D-ribofuranosyl)-1H-benzimidazole in 30 mL of THF was added 0.77 g (4.3 mmol) of N-bromosuccinimide. The resultant mixture was further refluxed for 15 min. The reaction mixture was then poured into an ice-cooled mixture of 20 mL sat. NaHCO3 solution and 20 mL CHCl3. The CHCl3 layer was separated and was further washed with sat. NaHCO3. After drying (MgSO4) and solvent removal, a crude product was obtained which was purified by flash column chromatography on silica with EtOAc/hexane (2:3) as the eluent. This gave 0.73 g (79%) of the title compound as an oil. 1H NMR (DMSO-d6) δ1.42 (d, 3H, CH3), 2 (s, 3H, COCH3), 2.1 (s, 3H, COCH3), 4.2 (quintet, 1H, CH), 5.2 (t, 1H, CH), 5.6 (t, 1H, CH), 6.1 (d, 1H, CH), 7.3 (d, 1H, aromatic), 7.6 (d, 1H, aromatic), 7.82 (s, 1H, aromatic).
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:19]=[C:18]2[C:9]([O:10][CH2:11][CH2:12][N:13]3[C:17]2=[N:16][C:15]([C:20]2[N:24]([CH:25]([CH3:27])[CH3:26])[N:23]=[CH:22][N:21]=2)=[CH:14]3)=[CH:8][CH:7]=1)=[O:5].[CH3:29][Mg]Cl>C1COCC1>[CH3:27][CH:25]([N:24]1[C:20]([C:15]2[N:16]=[C:17]3[N:13]([CH:14]=2)[CH2:12][CH2:11][O:10][C:9]2[C:18]3=[CH:19][C:6]([C:4](=[O:5])[CH3:29])=[CH:7][CH:8]=2)=[N:21][CH:22]=[N:23]1)[CH3:26]
Reactant: CON(C)C(=O)c1ccc2c(c1)-c1nc(-c3ncnn3C(C)C)cn1CCO2
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: CC(=O)c1ccc2c(c1)-c1nc(-c3ncnn3C(C)C)cn1CCO2
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.4 %

Procedure:
To a solution of N-methoxy-N-methyl-4-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaene-13-carboxamide (800 mg, 2.09 mmol) in THF (80 mL) was added methylmagnesium chloride (3.5 mL, 10.5 mmol) dropwise at 0° C. The mixture was further stirred at 0° C. for 1 h. After being quenched with aqueous NH4Cl (20 mL), most of THF was removed by rotate evaporate. The residue was extracted with ethyl acetate (3×20 mL), washed with water (3×20 mL), and sat. NaCl (20 mL). The organic phase was dried and concentrated to give the crude product, which was purified by silica gel chromatography eluting with EtOAc/petroleum ether (1:1) to give 1-{4-[1-(Propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaen-13-yl}ethan-1-one (560 mg, 80% yield) as a white solid. LCMS (ESI) m/z: 338.2 [M+H+]
Reaction SMILES: C(N(CC)CC)C.ClC(OCC(C)C)=O.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH:24]1[C:36](O)=[O:37])=[O:22])([CH3:19])([CH3:18])[CH3:17]>O1CCCC1>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH:24]1[CH2:36][OH:37])=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C(C(=O)O)C1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C(CO)C1
Reaction time: 3 h
Yield: 68.7 %

Procedure:
Triethylamine (6.06 g) and isobutyl chloroformate (7.51 g) were added to a solution of piperazine-1,2,4-tricarboxylic acid 1,4-di-tert-butyl ester (16.52 g) in tetrahydrofuran (200 ml) at −10° C., and the mixture was stirred for 3 hours. The reaction solution was filtered, and treated with 20 ml aqueous solution of sodium borohydride (7.72 g) at −10° C. After the mixture was stirred for 1 hour, ethyl acetate (500 ml) and water (200 ml) were added thereto, and excessive sodium borohydride was quenched with 1 N hydrochloric acid. The organic layer was washed with water (200 ml), followed by saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. Then, the solvent was removed by distillation at reduced pressure. The residue was purified by silica gel column chromatography to obtain 10.87 g of the title compound from a fraction eluted with hexane-ethyl acetate (1:1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]1[C@H:13]([NH2:14])[CH2:12][CH2:11][O:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.[C:20]1(=O)[CH2:24][CH2:23][CH2:22][CH2:21]1.C([BH3-])#N.[Na+]>CO>[C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]1[C@H:13]([NH:14][CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:12][CH2:11][O:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1COCC[C@H]1N
Reactant: O=C1CCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@@H]1COCC[C@H]1NC1CCCC1
Temperature: 45 °C
Reaction time: 8 h
Yield: 61.9 %

Procedure:
trans-(4-Amino-tetrahydro-pyran-3-yl)-carbamic acid tert-butyl ester (intermediate G, 1.0 g, 4.63 mmol) was dissolved in 90 mL methanol. Acetic acid (1.4 g, 23 mmol) and cyclopentanone (1.18 g, 14 mmol) were added and the reaction mixture was stirred at 45° C. overnight. Sodium cyanoborohydride (612 mg, 9.7 mmol) was added and stirring was continued at 45° C. for 2 h. The mixture was extracted with 2N sodium carbonate solution and ethyl acetate. The combined organic phases were dried on sodium sulfate, filtered and evaporated. Purification of the residue by flash chromatography on silica gel (dichloromethane/methanol/ammonia 100:0:0→90:10:1) yielded the title compound as a yellow solid (815 mg, 62%), MS: m/e=229.4 [(M-butene)+].
Reaction SMILES: [Si:1]([O:18][C@H:19]1[C:24](=[CH2:25])[C@@H:23]([F:26])[CH2:22]/[C:21](=[CH:27]/[C:28](OC)=[O:29])/[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C>ClCCl.C1(C)C=CC=CC=1>[Si:1]([O:18][C@H:19]1[C:24](=[CH2:25])[C@@H:23]([F:26])[CH2:22]/[C:21](=[CH:27]/[CH2:28][OH:29])/[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C1[C@@H](F)C/C(=C/C(=O)OC)C[C@H]1O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: C=C1[C@@H](F)C/C(=C/CO)C[C@H]1O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 90.1 %

Procedure:
The compound of Example 18B (130 mg, 0.3 mmol) was dissolved in 1 mL of 1:1 dichloromethane/toluene and cooled to −78° C. Diisobutylaluminum hydride (1 M in hexanes, 0.7 mL, 2.5 equivalents) was added, and the mixture was stirred for 30 minutes. Reaction was quenched by the addition of methanol, followed by saturated aqueous NH4Cl; the mixture was warmed to ambient temperature and extracted with ethyl acetate. The organics were washed with brine and dried over Na2SO4. The solvents were removed in vacuo; the residue was purified by chromatography on an Analogix Intelliflash 280™, eluting with 15% ethyl acetate in hexanes, to give the titled compound (111 mg, 95%).
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([S:8][C:9]2[CH:17]=[C:16]3[C:12]([CH2:13][O:14][C:15]3=[O:18])=[CH:11][C:10]=2[N+:19]([O-])=O)[S:6][CH:7]=1)[CH3:2].[NH4+].[Cl-]>CCO.O.[Fe]>[NH2:19][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][C:9]=1[S:8][C:5]1[S:6][CH:7]=[C:3]([CH2:1][CH3:2])[N:4]=1)[C:15](=[O:18])[O:14][CH2:13]2
Reactant: CCc1csc(Sc2cc3c(cc2[N+](=O)[O-])COC3=O)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CCc1csc(Sc2cc3c(cc2N)COC3=O)n1

Procedure:
A mixture of 6-(4-ethyl-2-thiazolylthio)-5-nitro-3H-isobenzofuran-1-one (750 mg, 2.33 mmol), Fe powder (600 mg, 10.7 mmol) and NH4Cl (150 mg, 2.8 mmol) in 45 mL of EtOH:H2O (2:1) was refluxed for 1.5 h. The hot mixture was filtered through celite and the celite was washed several times with hot EtOH:THF (4:1). Solvent was evaporated in vacuo and the residue was partitioned between H2O and EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated. The solid title compound so obtained was used without purification in the next step.
Reaction SMILES: C(Cl)Cl.[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:6]=1[CH2:12][OH:13].C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>CCOCC>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:6]=1[CH:12]=[O:13]
Reactant: OCc1cc(I)ccc1Cl
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: O=Cc1cc(I)ccc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.5 %

Procedure:
A methylene chloride solution (99 mL) of (2-chloro-5-iodophenyl)methanol (9.01 g, 33.5 mmol) and PCC (8.67 g, 40.2 mmol) were combined and stirred at rt. After 16 h, Et2O was added and the solution stirred for 30 minutes. The solution was then filtered and the organic layer was washed with H2O (2×), NaHCO3 (3×), and brine. The organic layer was dried (Na2SO4), concentrated, and purified by Biotage chromatography (0%-20% EtOAc/hexanes) to afford 5.94 g of product (67%). 1H NMR (400 MHz, chloroform-d) δ ppm 10.38 (s, 1 H) 8.22 (d, J=2.02 Hz, 1 H) 7.83 (dd, J=8.46, 2.15 Hz, 1 H) 7.21 (d, J=8.59 Hz, 1 H).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.[F:23][C:24]1[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=1[C@@H:31]1[CH2:42][CH2:41][C@@H:40]([OH:43])[C:34]2=[N+:35]([O-:39])[CH:36]=[CH:37][CH:38]=[C:33]2[CH2:32]1>C(Cl)Cl>[F:23][C:24]1[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=1[C@@H:31]1[CH2:42][CH2:41][C:40](=[O:43])[C:34]2=[N+:35]([O-:39])[CH:36]=[CH:37][CH:38]=[C:33]2[CH2:32]1
Reactant: [O-][n+]1cccc2c1[C@H](O)CC[C@@H](c1cccc(F)c1F)C2
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=C1CC[C@@H](c2cccc(F)c2F)Cc2ccc[n+]([O-])c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dess-MartinPeriodinane (1.227 g, 2.89 mmol) was added to the CH2Cl2 (8 mL) solution of (6R,9R)-6-(2,3-difluorophenyl)-9-hydroxy-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine 1-oxide (0.7662 g, 2.63 mmol) at rt. The reaction was stirred at rt for 1 hour. The reaction was directly load to a column and separated with 10% methanol in CH2Cl2 (0 to 10% gradient) (0.54 g, 42%). MS (ESI)[M+H+]=290.03.
Reaction SMILES: [CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[NH:9][C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Br[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][C:34]=1[O:41][CH3:42])=[O:32].CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[CH3:42][O:41][C:34]1[CH:35]=[C:36]([O:39][CH3:40])[CH:37]=[CH:38][C:33]=1[C:31](=[O:32])[CH2:30][N:9]1[C:10](=[O:11])[C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[S:28][C:6]=2[N:7]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:16][CH:15]=2)[C:8]1=[O:12]
Reactant: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Reactant: COc1ccc(C(=O)CBr)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1cc2c(=O)n(CC(=O)c3ccc(OC)cc3OC)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.3 %

Procedure:
To a mixture of 4′-[(6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)methyl]biphenyl-2-carbonitrile (1 g), 2-bromo-1-(2,4-dimethoxyphenyl)ethanone (0.83 g) and N,N-dimethylformamide (50 mL) was added 60% sodium hydride (0.15 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% potassium hydrogensulfate and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.91 g, 62%).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:12])=[C:4]([C:10]#[N:11])[C:5](=[O:9])[NH:6][C:7]=1[CH3:8].[BH4-].[Na+].Cl>CO>[NH2:11][CH2:10][C:4]1[C:5](=[O:9])[NH:6][C:7]([CH3:8])=[C:2]([Br:1])[C:3]=1[CH3:12]
Reactant: Cc1[nH]c(=O)c(C#N)c(C)c1Br
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1[nH]c(=O)c(CN)c(C)c1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.6 %

Procedure:
To a stirred solution of 5-bromo-4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (1 g, 4.44 mmol) and NiCl2.6H2O (0.21 g, 0.89 mmol) in methanol at 0° C., NaBH4 (0.68 g, 17.78 mmol) was added portion wise. Reaction mixture was then stirred at rt for overnight period. On completion, it was acidified using 3N HCl and stirred at rt for 3 h. Solvent was removed under reduced pressure. Residue was washed with diethyl ether and basified with aq. NH4OH. Compound was extracted in 10% MeOH in DCM and dried over anhydrous Na2SO4 to give the title compound (0.96 g, 94%) which was used as such for coupling reaction.