Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:12]/[C:13]1[NH:14][CH:15]=[CH:16][CH:17]=1)/[C:5](=[O:11])[NH:6]2.C([O-])([O-])=O.[Na+].[Na+].[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2/[C:4](=[CH:12]/[C:13]2[NH:14][CH:15]=[CH:16][CH:17]=2)/[C:5](=[O:11])[NH:6]3)=[CH:28][CH:27]=1
Reactant: O=C1Nc2cccc(I)c2/C1=C/c1ccc[nH]1
Reactant: COc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccc(-c2cccc3c2/C(=C/c2ccc[nH]2)C(=O)N3)cc1
Temperature: 100 °C
Yield: 94.7 %

Procedure:
A solution of (Z)-1,3-dihydro-4-iodo-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (100 mg, 0.298 mmol) (Starting Material 1), 2M aqueous Na2CO3 solution (342 μL, 0.684 mmol), (Ph3P)4Pd (17 mg, 0.015 mmol) (Aldrich), and 4-methoxyphenylboronic acid (52 mg, 0.342 mmol) (Aldrich) in 3 mL of a 2:1 mixture of 1,2-dimethoxyethane:distilled water was heated at 100° C. under a nitrogen atmosphere for 20 h. The reaction mixture was diluted with ethyl acetate, and the organic layer was washed with distilled water. The organic layer was concentrated in vacuo to provide a crude yellow-brown solid. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 25% ethyl acetate-hexanes elution) yielded pure (Z)-1,3-dihydro-4-(4-methoxyphenyl)-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (89.3 mg, 82%) as a yellow solid (mp 222-223° C.).
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[CH2:15]([O:17][C:18]([C:20]1[C:21]([CH2:26][CH2:27][C:28]([OH:30])=O)=[CH:22][NH:23][C:24]=1[CH3:25])=[O:19])[CH3:16]>>[CH2:15]([O:17][C:18]([C:20]1[C:21]2[CH2:26][CH2:27][C:28](=[O:30])[C:22]=2[NH:23][C:24]=1[CH3:25])=[O:19])[CH3:16]
Reactant: CCOC(=O)c1c(CCC(=O)O)c[nH]c1C
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: CCOC(=O)c1c(C)[nH]c2c1CCC2=O
Temperature: 70 °C
Reaction time: 20 h
Yield: 84.8 %

Procedure:
Polyphosphoric acid (20 g) and P2O5 (1.0 g) were mixed together and heated at 70° C. for 20 min. To the mixture was added 3-(4-ethoxycarbonyl-5-methyl-3-pyrrolyl)propanoic acid (1.0 g, 4.44 mmol) and heating was continued for 20 hours. The reaction was poured into ice-water, extracted with EtOAc. The organic layer was washed with brine and sat. NaHCO3, and dried (MgSO4). After removal of the solvent, the crude product was recrystallized from CH2CI2-hexane to give (0.78 g, 85%) of 2-methyl-6-oxo-1,4,5,6-tetrahydro-cyclopenta[b]pyrrole-3-carboxylic acid ethyl ester as a white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10](=[O:11])[CH2:9][CH2:8][CH2:7][C:5]=2[N:6]=1.CO[CH:14]([N:17]([CH3:19])[CH3:18])OC>>[CH3:14][N:17]([CH3:19])/[CH:18]=[C:9]1/[C:10](=[O:11])[C:4]2[S:3][C:2]([N:1]=[CH:14][N:17]([CH3:19])[CH3:18])=[N:6][C:5]=2[CH2:7][CH2:8]/1
Reactant: COC(OC)N(C)C
Reactant: Nc1nc2c(s1)C(=O)CCC2
Product: CN(C)C=Nc1nc2c(s1)C(=O)/C(=C/N(C)C)CC2
Temperature: 100 °C
Reaction time: 65 h

Procedure:
A suspension of 2-amino-5,6-dihydro-4H-benzothiazol-7-one (3.5 g, 20.81 mmol) in dimethoxymethyldimethylamine (12 mL, 90 mmol) was heated at 100° C. with stirring for 65 h. The RM was then evaporated to dryness in vacuo and the residue was suspended in EtOAc. After 1 h at 4° C., the solid was filtered off, washed with EtOAc and then dried under high vacuum at 60° C. to give the pure title product as brown crystals. LC: tR 3.25 min (method D). MS: M+H=279. 1H-NMR in DMSO-d6: 8.40 (s, 1H); 7.23 (s, 1H); 3.15 (s, 3H); 3.05 (s, 6H); 2.97 (s, 3H); 2.91 (t, 2H); 2.67 (t, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N-:4][N:3]=1.[CH2:8]([O:15][C:16]([NH:18][C@@H:19]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH:20]([OH:24])[C:21]([OH:23])=[O:22])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[O:29]1[CH:34]=[CH:33][CH2:32][CH2:31][CH2:30]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(Cl)(Cl)Cl>ClCCl>[CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N-:4][N:3]=1.[CH2:8]([O:15][C:16]([NH:18][C@@H:19]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH:20]([O:24][CH:30]1[CH2:31][CH2:32][CH2:33][CH2:34][O:29]1)[C:21]([OH:23])=[O:22])=[O:17])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(O)C(=O)O
Reactant: C1=COCCC1
Agent: Cc1cc(C)[n-]n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(OC1CCCCO1)C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
162 mg of (2RS,3S)-3-benzyloxycarbonylamino-2-hydroxy-5-methylhexanoic acid 3,5-dimethylpyrazolide was dissolved in 1 ml of dry dichloromethane, and 102 μl of dihydropyran and 0.8 mg of p-toluenesulfonic acid monohydrate were added thereto. The mixture was stirred at room temperature for 1.5 hours. Then, 10 ml of chloroform was added to the mixture, and the mixture was washed with a 4% sodium hydrogencarbonate and a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure to obtain 207 mg of (2RS,3S)-3-benzyloxycarbonylamino-2-(2-tetrahydropyranyloxy)-5-methylhexanoic acid 3,5-dimethylpyrazolide as a colorless oily substance.
Reaction SMILES: [C:1]([C:9]1[O:10][C:11]2[C:16]([C:17](=O)[CH:18]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]1([S:26]([N:29]=C=O)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(#N)C>[C:1]([C:9]1[O:10][C:11]2[C:16]([C:17](=[N:29][S:26]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)(=[O:28])=[O:27])[CH:18]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1cc(=O)c2ccccc2o1
Reactant: O=C=NS(=O)(=O)c1ccccc1
Solvent: CC#N
Product: O=C(c1ccccc1)c1cc(=NS(=O)(=O)c2ccccc2)c2ccccc2o1

Procedure:
Combine 2-Benzoyl-chromone (0.17 g, 0.68 mmol) and benzenesulfonyl isocyanate (1.02 mL, 2.03 mmol) in acetonitrile (7.0 mL). Heat at reflux for 48 hours. Add methanol (5 mL) to quench the reaction. Evaporate in vacuo to obtain a solid. Recrystallize from methanol to give the title compound as a solid: mp, 159°-160° C. Elem. Anal calcd. for C22H15NO4S: C, 67.85; H, 3.88; N, 3.60. Found: C, 67.47; H, 3.70; N, 3.56.
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[C:8]1[CH:9]=[C:10]([C:14]2[N:22]3[C:17]([CH:18]=[N:19][C:20]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([CH:30]5[CH2:35][CH2:34][N:33]([CH2:36][C:37]([NH2:39])=[O:38])[CH2:32][CH2:31]5)=[CH:26][CH:25]=4)=[N:21]3)=[CH:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1)(C)(C)C.O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[OH:6][CH2:7][C:8]1[CH:9]=[C:10]([C:14]2[N:22]3[C:17]([CH:18]=[N:19][C:20]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([CH:30]5[CH2:31][CH2:32][N:33]([CH2:36][C:37]([NH2:39])=[O:38])[CH2:34][CH2:35]5)=[CH:26][CH:25]=4)=[N:21]3)=[CH:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cccc(-c2ccc3cnc(Nc4ccc(C5CCN(CC(N)=O)CC5)cc4)nn23)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: NC(=O)CN1CCC(c2ccc(Nc3ncc4ccc(-c5cccc(CO)c5)n4n3)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 38.8 %

Procedure:
2-[4-(4-{7-[3-(tert-Butyl-dimethyl-silanyloxymethyl)-phenyl]-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino}-phenyl)-piperidin-1-yl]-acetamide (100 mg, 0.175 mmol) was dissolved in tetrahydrofuran (10.0 mL, 123 mmol) and 1.00 M tetra-n-butylammonium fluoride in tetrahydrofuran (0.193 mL, 0.193 mmol) was added. The reaction was stirred at room temperature for 3 hours and was then concentrated under reduced pressure. The residue was taken up in DMSO (2 mL) and purified by prep-HPLC using a gradient of 0-55% AcN/water both containing 0.1% TFA as the eluting solvent. The product was then taken up in MeOH (30 mL) and MP-carbonate (1.2 g) and stirred for 2 hours. The reaction was then filtered and concentrated under reduced pressure to obtain the title compound as a yellow foam (31 mg, 39%). LCMS (m/e) 457 (M+H); 1H-NMR (d6-DMSO, 400 MHz) δ 9.42 (s, 1H), 8.97 (s, 1H), 8.18 (s, 1H), 7.98 (d, 1H, J=7.7 Hz), 7.71 (d, 2H, J=8.3 Hz), 7.54-7.46 (m, 1H), 7.38 (d, 1H, J=7.6 Hz), 7.28-7.08 (m, 5H), 6.95 (d, 1H, J=4.6 Hz), 5.31 (bs, 1H), 4.62 (s, 2H), 2.97-2.88 (m, 2H), 2.88 (s, 2H), 2.49-2.38 (m, 1H), 2.22-2.08 (m, 2H), 1.79-1.67 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7](=[O:16])[N:8]2[CH2:11][CH2:12][CH2:13][CH2:14][OH:15])=[C:4]([Cl:17])[N:3]=1.[H-].[Na+].[CH2:20](Br)[CH:21]=[CH2:22]>CN(C=O)C>[CH2:22]([N:6]1[C:5]2[C:9](=[N:10][C:2]([NH2:1])=[N:3][C:4]=2[Cl:17])[N:8]([CH2:11][CH2:12][CH2:13][CH2:14][OH:15])[C:7]1=[O:16])[CH:21]=[CH2:20]
Reactant: Nc1nc(Cl)c2[nH]c(=O)n(CCCCO)c2n1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCn1c(=O)n(CCCCO)c2nc(N)nc(Cl)c21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
To a solution of 2-amino-6-chloro-9-(4-hydroxybutyl)-8-oxo-7H-purine (0.8 g, 3.1 mM) in DMF (15 mL) was added NaH (0.12 g, 60% oil dispersion, 3 mM) all at once at zero degrees C. under nitrogen and stirred for 30 minutes. To this was added allyl bromide (0.37 g, 3.1 mM) and the resulting mixture was allowed to warm to room temperature and stirred overnight. Most of solvent was removed in vacuo and the residue was purified by column chromatography on silica gel (120 g, CH2Cl2 /CH3OH/conc. NH4OH, 100/5/0.1) to give 7-allyl-2-amino-6-chloro-9-(4-hydroxybutyl)-8-oxo-7H-purine as an off-white powder (40 percent) mp 132°-133° C. IR (KBr) 3320, 1715, 1640, 1585, 1460 cm-1. 1H NMR (DMSO-d6) δ 6.70 (bs, 2H, exchangeable, NH2), 5.95 (m, 1H), 3.70 (t:, J=6.5 Hz, 2H, NCH2), 3.35 (m, 2H, CH2OH), 1.50 (m, 4H, CH2CH2).
Reaction SMILES: [OH:1][C:2]1[C:3]2[N:4]([C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:10]([CH3:12])[N:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.CS(O[CH2:23][CH:24]1[CH2:27][C:26]([F:29])([F:28])[CH2:25]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[F:28][C:26]1([F:29])[CH2:27][CH:24]([CH2:23][O:1][C:2]2[C:3]3[N:4]([C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:10]([CH3:12])[N:11]=3)[CH:5]=[C:6]([CH3:8])[CH:7]=2)[CH2:25]1
Reactant: CS(=O)(=O)OCC1CC(F)(F)C1
Reactant: CCOC(=O)c1c(C)nc2c(O)cc(C)cn12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)nc2c(OCC3CC(F)(F)C3)cc(C)cn12
Temperature: 60 °C
Reaction time: 8 h

Procedure:
1.85 g (7.89 mmol) of ethyl 8-hydroxy-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxylate Example 87A and 2.37 g (9.47 mmol) of (3,3-difluorocyclobutyl)methyl methanesulphonate Example 105A were initially charged in 104 ml of DMF, and 10.28 g (31.56 mmol) of caesium carbonate were added. The reaction mixture was stirred at 60° C. overnight. After cooling, the reaction mixture was filtered, the solid was washed thoroughly with ethyl acetate, the filtrate was concentrated and about 150 ml of water were added to the residue. The solid formed was filtered off and dried under high vacuum. This gave 2.51 g (89% of theory; purity 95%) of the title compound.
Reaction SMILES: O.[NH2:2][C:3]1[C:8]([C:9](=[S:17])[C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:18][C:19]([OH:21])=[O:20].[Na].[CH2:23](I)[CH3:24].O>CN(C)C=O>[NH2:2][C:3]1[C:8]([C:9](=[S:17])[C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:18][C:19]([O:21][CH2:23][CH3:24])=[O:20]
Reactant: CCI
Reactant: Cc1ccc(C(=S)c2cccc(CC(=O)O)c2N)cc1
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cccc(C(=S)c2ccc(C)cc2)c1N
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Seventeen grams (0.05 mole) of sodium 2-amino-3-(4-methylthiobenzoyl)phenylacetic acid monohydrate are dissolved in approximately 150 ml of dimethylformamide and the solution treated with 33 g ethyl iodide. The solution is stirred at room temperature for 2.5 hrs. and added to water and the mixture extracted several times with benzene. The combined benzene extracts are washed with dilute base and water, dried over sodium sulfate and concentrated to obtain the titled compound.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[F:31])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.O[N:33]1[C:37]2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.Cl.CN>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:33][CH3:37])=[O:27])=[CH:24][C:23]=4[F:31])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: On1nnc2ccccc21
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3F)ncc21
Agent: CN
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccc(Nc2ncc3c(n2)N(C2CCCC2)CC(F)(F)C(=O)N3C)c(F)c1
Reaction time: 0.17 h
Yield: 72.4 %

Procedure:
To a mixture of 0.070 g (0.161 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-fluoro-benzoic acid (I-182) and 4 mL of dimethylformamide was added 0.0346 g (0.256 mmole) of 1-hydroxybenzotriazole, 0.0950 g (0.250 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 0.1253 g (0.936 mmole) of diisopropylethylamine. The mixture was stirred for 10 minutes, then 0.0236 g (0.346 mmole) of methylamine hydrochloride was added. The reaction mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of ethyl acetate and washed three times with 10 mL of 1M sodium hydroxide, twice with 15 mL of brine, dried, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-90:10) gave 0.0523 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-fluoro-N-methyl-benzamide (I-228) as a white solid.
Reaction SMILES: [CH:1](/[OH:6])=[CH:2]/[CH2:3][CH2:4][OH:5].N1C=CN=C1.[Si:12](Cl)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]>C(Cl)Cl>[Si:12]([O:6][CH2:1]/[CH:2]=[CH:3]\[CH2:4][OH:5])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O/C=C\CCO
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC/C=C\CO
Temperature: 0 °C
Reaction time: 6 h
Yield: 73 %

Procedure:
To a solution of cis-1,4-butene diol (6) (20.0 g, 227.27 mmol) in dry CH2Cl2 (700 mL) at 0° C. was added imidazole (23.21 g, 340.91 mmol) and tert-butyldimethylsilyl chloride (37.68 g, 250.0 mmol). The reaction mixture was stirred at 0° C. for 6 h. After completion of reaction (monitored by TLC), it was diluted with CH2Cl2 (500 mL) washed with water, brine and dried over anhydrous Na2SO4. Removal of solvent under reduced pressure gave the crude product which was then purified by column chromatography with petroleum ether/EtOAc (9:1 v/v) to give (7) as a colorless liquid.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7]([O:9]CC)=[O:8])[N:4]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.[OH-].[Na+]>C(O)C>[Br:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=[O:8])[N:4]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1
Reactant: CCOC(=O)c1cc(Br)nn1-c1ncccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc(Br)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.8 %

Procedure:
To a 500 mL flask, ethyl 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylate (15.00 g, 85%, 38.57 mmol) and ethanol (80 mL) were added. Sodium hydroxide solution (1.54 g, 38.57 mmol, dissolved in water (80 mL)) were added dropwise. The reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated by rotary evaporator to remove ethanol. The residue was extracted with ethyl acetate (30 mL) and acidified with concentrated hydrochloric acid to pH=3. Aqueous solution was extracted with ethyl acetate (3×100 mL) again. The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous magnesium sulfate and concentrated by rotary evaporator to give the product (10.83 g) as a yellow solid in 91% yield. HPLC area normalization method content is 98%.
Reaction SMILES: [CH2:1]1[O:27][C:4]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])([C:5]2[C:10]([CH2:11]SC3C=CC=CC=3)=[CH:9][CH:8]=[C:7]([Cl:19])[CH:6]=2)[O:3][CH2:2]1.C[I:29]>>[CH2:1]1[O:27][C:4]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])([C:5]2[C:10]([CH2:11][I:29])=[CH:9][CH:8]=[C:7]([Cl:19])[CH:6]=2)[O:3][CH2:2]1
Reactant: CI
Reactant: Fc1ccccc1C1(c2cc(Cl)ccc2CSc2ccccc2)OCCO1
Product: Fc1ccccc1C1(c2cc(Cl)ccc2CI)OCCO1

Procedure:
The starting material is obtained as follows: The solution of 10 g of 3-chloro-2'-fluoro-6-phenylmercaptomethyl-benzophenone ethylene ketal (Example 2) in 50 ml of methyl iodide is refluxed under nitrogen for 5 days. It is evaporated and the formed methyl phenyl thioether distilled off at 60°10.1 mm Hg, to yield the 3-chloro-2'-fluoro-6-iodomethyl-benzophenone ethylene ketal.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:10][CH2:9]1)C1C=CC=CC=1.C1CCCCC=1>C(O)C.[OH-].[OH-].[Pd+2]>[CH2:14]([N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCN1CCN(Cc2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: C1=CCCCC1
Product: CCCCCCCCCN1CCNCC1

Procedure:
A mixture of 1-benzyl-4-nonylpiperazine (0.54 g, 1.80 mmol) (prepared by reacting 1-benzylpiperazine, Aldrich, with 1-bromononane, Aldrich, and Nail in DMF), palladium hydroxide on carbon (0.14 g) and cyclohexene (7 mL) in ethanol (15 mL) was heated at reflux overnight. After filtration, the filtrate was concentrated in vacuo to dryness to give the title compound as an oil, 0.38 g, 100%.
Reaction SMILES: [H-].[Na+].Br[CH2:4][C:5]([NH2:7])=[O:6].[F:8][C:9]1([F:45])[CH2:10][CH2:11][N:12]([C:31]([C:33]2[S:37][C:36]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[N:35][C:34]=2[CH3:44])=[O:32])[C:13]2[CH:30]=[CH:29][CH:28]=[CH:27][C:14]=2/[C:15]/1=[CH:16]/[C:17]([N:19]1[CH2:24][CH2:23][C:22](=[N:25][OH:26])[CH2:21][CH2:20]1)=[O:18]>O1CCCC1.C(OCC)(=O)C>[F:45][C:9]1([F:8])[CH2:10][CH2:11][N:12]([C:31]([C:33]2[S:37][C:36]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)=[N:35][C:34]=2[CH3:44])=[O:32])[C:13]2[CH:30]=[CH:29][CH:28]=[CH:27][C:14]=2/[C:15]/1=[CH:16]/[C:17]([N:19]1[CH2:20][CH2:21][C:22](=[N:25][O:26][CH2:4][C:5]([NH2:7])=[O:6])[CH2:23][CH2:24]1)=[O:18]
Reactant: NC(=O)CBr
Reactant: Cc1nc(-c2ccccc2)sc1C(=O)N1CCC(F)(F)/C(=C\C(=O)N2CCC(=NO)CC2)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1nc(-c2ccccc2)sc1C(=O)N1CCC(F)(F)/C(=C\C(=O)N2CCC(=NOCC(N)=O)CC2)c2ccccc21
Temperature: 0 °C
Reaction time: 3 h
Yield: 66.3 %

Procedure:
Sodium hydride (47 mg) and 58 mg of bromoacetamide were added to a solution of 150 mg of (Z)-4,4-difluoro-5-{2-[4-(hydroxyimino)piperidino]-2-oxoethylidene}-1-(4-methyl-2-phenylthiazole-5-carbonyl)-2,3,4,5-tetrahydro-1H-1-benzoazepine in 10 ml of tetrahydrofuran, and the mixture was stirred at 0° C. for three hours. The reaction solution was diluted with ethyl acetate and washed with a saturated aqueous solution of NaCl and dried over magnesium sulfate, and the solvent was evaporated therefrom. The residue was purified by silica gel column chromatography (eluting with chloroform-methanol). The resulting residue was crystallized from diethyl ether to give 110 mg of (Z)-[(1-{[4,4-difluoro-1-(4-methyl-2-phenylthiazole-5-carbonyl)-2,3,4,5-tetrahydro-1H-1-benzoazepin-5-ylidene]acetyl}piperidin-4-ylidene)aminoxy]acetamide as a pale yellow powder.
Reaction SMILES: C1(C)C=CC(S([O:10][C@H:11]2[CH2:30][CH2:29][C@@:28]3([CH3:31])[C@@H:13]([CH2:14][CH2:15][C@@H:16]4[C@@H:27]3[C:26](=[O:32])[CH2:25][C@@:24]3([CH3:33])[C@H:17]4[CH2:18][CH:19]=[C:20]3[C:21](=[O:23])[CH3:22])[CH2:12]2)(=O)=O)=CC=1.C([O-])(=O)C.[K+].CN(C)C=O>O>[OH:10][C@@H:11]1[CH2:30][CH2:29][C@@:28]2([CH3:31])[C@@H:13]([CH2:14][CH2:15][C@@H:16]3[C@@H:27]2[C:26](=[O:32])[CH2:25][C@@:24]2([CH3:33])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C:21](=[O:23])[CH3:22])[CH2:12]1
Reactant: CC(=O)C1=CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](OS(=O)(=O)c5ccc(C)cc5)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)C1=CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Reaction time: 8 h
Yield: 50.3 %

Procedure:
A stirred mixture of 3β-toluene-p-sulphonyloxy-5α-pregn-16-ene-11,20-dione (627 g.), potassium acetate (918 g.), dimethylformamide (4.25 l.) and water (425 ml.) was heated on the steam bath for 4 hr. Most of the dimethylformamide was removed under reduced pressure and water was added to the residue with stirring. The solid (420 g.) was collected, washed and dried at 40° in vacuo. This material in peroxide free dioxan (7 l.) was flushed with nitrogen and a solution of potassium hydroxide (200 g.) in water (2 l.) was added. The mixture was stirred and heated at 50°-60° for 7 hr. and then left at room temperature overnight. Acetic acid (50 ml.) was added and the precipitated solid was filtered off, washed with water and dried. The dry solid was heated under reflux with benzene (2 l.) for 2 hr. the mixture cooled and filtered to give 3α-hydroxy-5α-pregn-16-ene-11,20-dione (215 g.).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:8]=[CH:7][NH:6][N:5]=1.[F:9][C:10]1[CH:15]=[C:14](F)[CH:13]=[CH:12][C:11]=1[C:17]([N:19]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[NH:23][C:22]2[N:30]=[CH:31][CH:32]=[CH:33][C:21]=2[CH2:20]1)=[O:18]>CCCCCC>[F:9][C:10]1[CH:15]=[C:14]([N:6]2[CH:7]=[CH:8][C:4]([CH3:3])=[N:5]2)[CH:13]=[CH:12][C:11]=1[C:17]([N:19]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[NH:23][C:22]2[N:30]=[CH:31][CH:32]=[CH:33][C:21]=2[CH2:20]1)=[O:18]
Reactant: O=C(c1ccc(F)cc1F)N1Cc2cccnc2Nc2ccccc21
Reactant: Cc1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Product: Cc1ccn(-c2ccc(C(=O)N3Cc4cccnc4Nc4ccccc43)c(F)c2)n1
Reaction time: 1 h

Procedure:
Sodium hydride (60% suspension in oil, 0.48 g, 12.0 mmol) was washed with hexane, dried under nitrogen and resuspended in dry dimethylformamide (60 mL). Neat 3-methylpyrazole (0.48 mL, 6.0 mmol) was added. Stirring was continued until the gas evolution subsided. The (2,4-difluoro-phenyl)-(6,11-dihydro-1H-pyrido[2,3-b][1,5]benzodiazepin-10-yl)-methanone of Step B (2.0 g, 5.9 mmol) was added in one portion to the clear solution. The mixture was placed in an oil bath (preheated at 130° C.) for 1 hour, cooled and partitioned between water and ethyl acetate. The organic extracts were dried over sodium sulfate and evaporated to dryness. The crude material was dissolved in dichloromethane and absorbed onto a silica Merck-60 flash column. Elution with hexane-ethyl acetate (gradient from 9:1 to 1:1) provided the title compound along with the more polar 4-fluoro regioisomer of Example 9. The title compound (0.30 g) was obtained as a foam which crystallized by sonication from hexane-ethanol, m.p. 122-125° C.