Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[NH2:2][NH2:3].[C:4]1([CH:10]2[CH2:15][CH2:14][O:13][C:12](=[O:16])[CH2:11]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)C>[OH:13][CH2:14][CH2:15][CH:10]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:11][C:12]([NH:2][NH2:3])=[O:16]
Reactant: O=C1CC(c2ccccc2)CCO1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)CC(CCO)c1ccccc1
Temperature: 25 °C

Procedure:
Hydrazine monohydrate (1.6 mL) was added to a solution of 4-phenyl-tetrahydropyran-2-one (573 mg; CAS No. 61949-75-5) in ethanol (3 mL) at room temperature, and the reaction solution was heated under reflux for three hours. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure. A saturated sodium bicarbonate solution was added to the resulting residue, followed by extraction with chloroform. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate-methanol system) to obtain 492 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[N:24]=[C:25]=[S:26])(=[O:3])[CH3:2].[NH2:27][CH2:28][CH:29]([NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39].C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[NH:24][C:25]([NH:27][CH2:28][CH:29]([NH:40][C:41]([O:42][C:43]([CH3:44])([CH3:46])[CH3:45])=[O:47])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[S:26])(=[O:3])[CH3:2]
Reactant: CCCCCCCCCCC(CN)NC(=O)OC(C)(C)C
Reactant: CC(=O)OC[C@H]1O[C@@H](N=C=S)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCC(CNC(=S)N[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O)NC(=O)OC(C)(C)C
Yield: 98.7 %

Procedure:
2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl isothiocyanate 37 (25.0 mg, 0.0617 mmol), tert-butyl N-[1-(R/S)-(aminomethyl)-undecyl]carbamate (27.8 mg, 0.0927 mmol) and triethylamine (12.5 mg, 0.0124 mmol) were dissolved in abs. CH2Cl2 (5 ml) and stirred at room temperature for 1 hour. Following evaporation, the residue was purified by column chromatography to give 65 (42.0 mg, 94%)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:14]([O-:16])=[O:15])[C:5]([NH:8][CH2:9][CH2:10][CH2:11][O:12][CH3:13])=[N:6][CH:7]=1.[H-].[Na+].I[CH3:20]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([N+:14]([O-:16])=[O:15])[C:5]([N:8]([CH2:9][CH2:10][CH2:11][O:12][CH3:13])[CH3:20])=[N:6][CH:7]=1
Reactant: CI
Reactant: COCCCNc1ncc(Br)cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCCN(C)c1ncc(Br)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A dry round bottom flask containing 5-bromo-N-(3-methoxypropyl)-3-nitropyridin-2-amine (1.0 g, 3.45 mmol) in dry DMF (4.5 mL) was cooled to 0° C., then sodium hydride, 60% dispersion in mineral oil (0.28 g, 7.02 mmol) was added carefully in portions. The mixture was stirred at 0° C. for 15 min, then iodomethane (0.66 mL, 10.6 mmol) was added dropwise. Upon complete addition, the mixture was allowed to warm to 23° C. After 19 h, the reaction was carefully diluted with water then extracted five times with EtOAc. The organic extraction was then washed one time with brine and dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was purified on silica gel (0-25% EtOAc in hexanes) to afford a light yellow oil as 5-bromo-N-(3-methoxy propyl)-N-methyl-3-nitropyridin-2-amine. 1H NMR (400 MHz, CDCl3) δ ppm 8.31 (1H, d, J=2.3 Hz), 8.21 (1H, d, J=2.3 Hz), 3.79 (2H, m), 3.47 (2H, m), 3.33 (3H, s), 2.86 (3H, s), 2.01 (2H, m).
Reaction SMILES: CN(C)C=O.[OH:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.F[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>O>[N:9]1[CH:10]=[CH:11][CH:12]=[C:7]([O:6][C:14]2[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=2)[CH:8]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Oc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(Oc2cccnc2)cc1
Temperature: 70 °C
Reaction time: 17 h
Yield: 27.1 %

Procedure:
To an N,N-dimethylformamide (30.0 mL) solution of 3-hydroxypyridine (3.00 g, 31.5 mmol) and 4-fluorobenzaldehyde (5.08 g, 41.0 mmol) was added potassium carbonate (8.71 g, 63.0 mmol) under nitrogen atmosphere, which was stirred for 17 hours at 70° C. The reaction mixture was then cooled to room temperature and water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:1→3:1) to obtain the title compound (1.70 g, 27.1%).
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]([NH2:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)(O)[O-].[Na+].Br[CH2:18][C:19](=O)[C:20]([O:22][CH2:23][CH3:24])=[O:21].FC(F)(F)C(OC(=O)C(F)(F)F)=O>O1CCCC1>[C:1]1(/[CH:7]=[CH:8]/[C:9]2[O:10][CH:18]=[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: NC(=O)/C=C/c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Product: CCOC(=O)c1coc(/C=C/c2ccccc2)n1
Temperature: 0 °C
Reaction time: 10 h

Procedure:
A mixture of (2E)-3-phenylprop-2-enamide (2.00 g, 13.6 mmol) and sodium bicarbonate (4.57 g, 54.4 mmol) in tetrahydrofuran (48 mL) was cooled to 0° C. Ethyl 3-bromo-2-oxopropanoate (3.16 mL, 25.2 mmol) was added drop-wise, and the reaction mixture was heated at reflux for 4 hours, whereupon it was filtered through diatomaceous earth and concentrated in vacuo. The residue was dissolved in tetrahydrofuran (33 mL), cooled to 0° C., and treated drop-wise with trifluoroacetic anhydride (14.8 mL, 105 mmol). The reaction mixture was stirred at room temperature for 10 hours, then cooled to 0° C. and quenched via addition of saturated aqueous sodium bicarbonate solution. The mixture was extracted three times with ethyl acetate, and the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Chromatography on silica gel (Gradient: 0% to 30% ethyl acetate in heptane) provided partially purified product; this was crystallized from heptane/ethyl acetate to afford the product as pale yellow needles. Yield: 1.52 g, 6.25 mmol, 46%. LCMS m/z 244.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.20 (s, 1H), 7.63 (d, J=16.4 Hz, 1H), 7.51-7.56 (m, 2H), 7.34-7.43 (m, 3H), 6.97 (d, J=16.5 Hz, 1H), 4.42 (q, J=7.1 Hz, 2H), 1.41 (t, J=7.1 Hz, 3H).
Reaction SMILES: [K].[O:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:5][NH:4][C:3]1=[S:12].[CH2:13](I)[CH3:14]>C(O)C>[CH2:13]([S:12][C:3]1[O:2][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:5][N:4]=1)[CH3:14]
Reactant: CCOC(=O)c1n[nH]c(=S)o1
Reactant: CCI
Agent: [K]
Solvent: CCO
Product: CCOC(=O)c1nnc(SCC)o1

Procedure:
A mixture of ethyl 1,3,4-oxadiazole-2-thione-5-carboxylate potassium salt dimethylsulfoxide solvate (11 g., 0.03 mole) and ethyl iodide (7 g., 0.045 mole) in absolute ethanol (100 ml.) was heated at reflux for 45 minutes and then worked up as described previously in Experiment A to yield the title compound (5.59 g.).
Reaction SMILES: [NH:1]1[C:9]2[C:5](=[CH:6][C:7]([P:18]([O:23][CH2:24][CH3:25])(=[O:22])[O:19][CH2:20][CH3:21])([P:10]([O:15][CH2:16][CH3:17])(=[O:14])[O:11][CH2:12][CH3:13])[CH:8]=2)[CH:4]=[CH:3][CH2:2]1.C([N-]C(C)C)(C)C.[Li+].[C:34]([S:37][CH2:38][CH2:39]I)(=[O:36])[CH3:35]>C1COCC1>[C:34]([S:37][CH2:38][CH2:39][C:8]1[C:7]([P:18]([O:23][CH2:24][CH3:25])(=[O:22])[O:19][CH2:20][CH3:21])([P:10]([O:11][CH2:12][CH3:13])(=[O:14])[O:15][CH2:16][CH3:17])[CH:6]=[C:5]2[C:9]=1[NH:1][CH2:2][CH:3]=[CH:4]2)(=[O:36])[CH3:35]
Reactant: CCOP(=O)(OCC)C1(P(=O)(OCC)OCC)C=C2C=CCNC2=C1
Reactant: CC(=O)SCCI
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)C1(P(=O)(OCC)OCC)C=C2C=CCNC2=C1CCSC(C)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of dihydro-1-pyrindine-6,6-bisphosphonic acid, tetraethyl ester (7.0 mmol) [prepared as described in Example A, Part I] in anhydrous THF (100 ml) at -78° C. under argon is added dropwise a pregenerated solution of lithium diisopropyl amide (7.0 mmol) in THF (10 ml). After stirring 30 minutes, to this is added 2-acetylthio-1-iodoethane (7.5 mmol) in THF (25 ml). The reaction mixture is stirred at -78° C. for 5 hours then allowed to warm to room temperature and stirred overnight. The reaction is quenched by the addition of saturated aqueous ammonium chloride and then extracted with diethyl ether. The organic layers are combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The desired product is purified by flash chromatography using a 5-10% isopropanol in methylene chloride gradient on silica gel.
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:28])[NH:6][C:7]1[C:8]([CH3:27])=[C:9]([CH3:26])[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=3)[C:11]=2[C:24]=1[CH3:25].[NH2:31][CH2:32][CH2:33][CH2:34][OH:35]>CCCCCC.C(OCC)(=O)C>[OH:35][CH2:34][CH2:33][CH2:32][NH:31][C:5]([NH:6][C:7]1[C:8]([CH3:27])=[C:9]([CH3:26])[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:16]=[CH:17][C:18]([CH:21]([CH3:22])[CH3:23])=[CH:19][CH:20]=3)[C:11]=2[C:24]=1[CH3:25])=[O:28]
Reactant: Cc1c(C)c2c(c(C)c1NC(=O)OCC(Cl)(Cl)Cl)C(c1ccc(C(C)C)cc1)CO2
Reactant: NCCCO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1c(C)c2c(c(C)c1NC(=O)NCCCO)C(c1ccc(C(C)C)cc1)CO2
Yield: 33 %

Procedure:
Using 2,2,2-trichloroethyl(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamate obtained in Example 138 and 3-amino-1-propanol, the title compound was synthesized in the same manner as in Example 143. Yield: 33%. Melting point: 185-186° C. (hexane-ethyl acetate).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C)C=O>[C:21]1([CH2:20][CH2:19][CH2:18][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)CCc1ccc(O)cc1
Reactant: BrCCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1ccc(OCCCc2ccccc2)cc1
Reaction time: 0.5 h
Yield: 44.2 %

Procedure:
To a solution of ice-cooled ethyl 4-hydroxybenzenepropanoate (0.40 g, 2.1 mmol) in N,N-dimethylformamide (15 mL) was added 60% sodium hydride (0.11 g, 2.7 mmol), and the mixture was stirred for 30 minutes. Then, 1-bromo-3-phenylpropane (0.53 g, 2.7 mmol) was added thereto, and the mixture was stirred at room temperature for 3 hours. To the reaction solution was added water, and the reaction mixture was extracted with ethyl acetate. The extract was washed with water, dried, and then concentrated. The residue was purified with silica gel column chromatography (hexane/ethyl acetate=18:1) to give the title compound (0.29 g, yield 46%).
Reaction SMILES: [N:1]1([C:6]([C:8]2[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH:26]2[CH2:31][CH2:30][N:29]([C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]2)=[CH:20][CH:19]=1>>[N:1]1([C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:18]3[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH:26]4[CH2:27][CH2:28][N:29]([C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33])[CH2:30][CH2:31]4)=[CH:22][CH:23]=3)=[CH:10][CH:9]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(c1ccc(B(O)O)cc1)N1CCCC1
Reactant: CC(C)OC(=O)N1CCC(COc2ccc(Br)cc2)CC1
Product: CC(C)OC(=O)N1CCC(COc2ccc(-c3ccc(C(=O)N4CCCC4)cc3)cc2)CC1
Yield: 19.1 %

Procedure:
The title compound (8.6 mg, 19%) was prepared from [4-(1-pyrrolidinylcarbonyl)phenyl]boronic acid (21.9 mg, 0.1 mmol) and 1-methylethyl 4-{[(4-bromophenyl)oxy]methyl}-1-piperidinecarboxylate (Example 9, Step 2, 36 mg, 0.10 mmol) in a manner similar to Example 9, Step 3. LRMS (ESI), m/z 451 (M+H).
Reaction SMILES: [CH2:1]([O:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:10])[CH3:2].C(O[CH:16](N(C)C)[N:17]([CH3:19])[CH3:18])(C)(C)C>>[CH3:16][N:17]([CH3:19])[CH:18]=[C:6]1[CH2:7][CH2:8][CH2:9][CH:4]([O:3][CH2:1][CH3:2])[C:5]1=[O:10]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: CCOC1CCCCC1=O
Product: CCOC1CCCC(=CN(C)C)C1=O

Procedure:
2-Ethoxy-cyclohexanone (142 mg, 1.0 mmol) was reacted with tert.-butoxy-bis-(dimethylamino)-methane using in analogous manner the procedure described in example 45a) to give crude title compound (232 mg) as a yellow oil which was used directly in the next step.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]3[C:12]([C:22](=O)[CH3:23])=[CH:13][C:14]([F:21])=[C:15]4[C:20]=3[N:19]=[CH:18][CH:17]=[CH:16]4)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:31].[Na+]>CO.C(#N)C>[CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]3[C:12]([CH:22]([NH2:31])[CH3:23])=[CH:13][C:14]([F:21])=[C:15]4[C:20]=3[N:19]=[CH:18][CH:17]=[CH:16]4)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)c1cc(F)c2cccnc2c1N1CCN(C2CCC2)CC1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: CC(N)c1cc(F)c2cccnc2c1N1CCN(C2CCC2)CC1
Temperature: 65 °C

Procedure:
A mixture of 1-[8-(4-cyclobutylpiperazin-1-yl)-5-fluoroquinolin-7-yl]ethanone (16 mg, 0.049 mmol) and ammonium acetate (37.7 mg, 0.489 mmol) in methanol (0.27 mL) and acetonitrile (0.28 mL) was heated at 65° C. in a sealed tube for 30 minutes. After cooling to room temperature, sodium cyanoborohydride (6 mg, 0.01 mmol) was added. The reaction was heated at 65° C. for another 4 hours, then cooled to room temperature and quenched with sat. sodium bicarbonate, extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and evaporated to dryness. The residue was used directly in the next step. LCMS calculated for C19H26FN4 (M+H)+: m/z=329.2; Found: 329.2.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:9][NH2:10])=[N:4][CH:5]=[CH:6][C:7]=1[I:8].C(N(CC)CC)C.[F:18][C:19]([F:25])([F:24])[CH2:20][C:21](Cl)=[O:22].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[C:3]([NH:9][NH:10][C:21](=[O:22])[CH2:20][C:19]([F:25])([F:24])[F:18])=[N:4][CH:5]=[CH:6][C:7]=1[I:8]
Reactant: O=C(Cl)CC(F)(F)F
Reactant: NNc1nccc(I)c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CC(F)(F)F)NNc1nccc(I)c1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of intermediate compound D7 (2.528 g, 9.38 mmol) in dry DCM (15 ml), cooled at 0° C., were added triethylamine (3.244 ml, 23.45 mmol) and 3,3,3,-trifluoropropionyl chloride (1.924 g, 13.132 mmol). The resulting reaction mixture was stirred at r.t. for 3 h. After this period, NaHCO3 (aqueous sat. solution) was added. The resulting solution was then extracted with DCM. The organic layer was separated, dried (MgSO4) and concentrated in vacuo. The residue thus obtained was triturated with DIPE to yield intermediate compound D10 (4 g, 55%).
Reaction SMILES: CN.[Cl:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([N:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)[N:11]=1)[C:7]#[N:8].ClC1C=C(C=C(N2CCC(O)CC2)N=1)[C:23]#[N:24].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[Cl:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([NH:24][CH3:23])[CH2:14][CH2:13]2)[N:11]=1)[C:7]#[N:8]
Reactant: N#Cc1cc(Cl)nc(N2CCC(O)CC2)c1
Reactant: N#Cc1cc(Cl)nc(N2CCC(=O)CC2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CN
Agent: [Na+]
Solvent: C1CCOC1
Product: CNC1CCN(c2cc(C#N)cc(Cl)n2)CC1
Reaction time: 0.5 h

Procedure:
Methylamine (2.65 ml, 5.3 mmol) was added to a solution of 2-chloro-6-(4-oxopiperidin-1-yl)isonicotinonitrile (Intermediate 26; 500 mg, 2.12 mmol) in anhydrous THF (4 ml). The mixture was stirred for 30 minutes and sodium triacetoxyborohydride (674 mg, 3.18 mmol) was added. The mixture was stirred at room temperature for 18 h, then concentrated in vacuo, diluted with EtOAc and washed with 1 N NaOH, water and brine. The organic phase was dried over Na2SO4 then concentrated in vacuo to give a brown oil which was dried under vacuum to yield the title compound (507 mg).
Reaction SMILES: [CH2:1]([N:8]([CH2:28][C:29]([O:31]CC1C=CC=CC=1)=O)[C:9](=[O:27])[C@H:10]([NH:19]C(OC(C)(C)C)=O)[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>ClCCl.O1CCOCC1>[CH2:1]([N:8]1[CH2:28][C:29](=[O:31])[NH:19][C@H:10]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)[C:9]1=[O:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(F)cc1)C(=O)N(CC(=O)OCc1ccccc1)Cc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C1CN(Cc2ccccc2)C(=O)[C@@H](Cc2ccc(F)cc2)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
To an ice-cooled solution of (2R)-N-benzyl-N-benzyloxycarbonylmethyl-2-(tert-butoxycarbonylamino)-3-(4-fluorophenyl)propanamide (9.48 g) in dichloromethane (55 ml) was added 4N hydrogen chloride in dioxane solution (54.6 ml). The mixture was stirred at the same temperature for 15 minutes and at room temperature for one hour. After removal of solvent by evaporation, excess aqueous sodium hydrogen carbonate solution was added to the resulting residue. The mixture was warmed at near 50° C. for several minutes and the resulting precipitates were collected by filtration and washed with water and dried in vacuo to give (3R)-1-benzyl-3-(4-fluorobenzyl)piperazine-2,5-dione (5.00 g).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[Br:13]Br.C([O-])(O)=O.[Na+]>C(OCC)C.O>[Br:13][CH:3]1[C:2](=[O:1])[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4]1
Reactant: BrBr
Reactant: CCOC(=O)C1CCC(=O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)C1CCC(=O)C(Br)C1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a 0° C. solution of ethyl 4-oxocyclohexanecarboxylate (6.0 g, 35.3 mmol) in diethyl ether (200 mL) was added dropwise a solution of bromine (5.3 g, 33.3 mmol) in diethyl ether (20 mL). The resulting mixture was stirred at room temperature for 40 min, then was cooled in an ice/water bath, diluted with water, and neutralized with aqueous NaHCO3 solution. The organic layer was separated and washed with water then brine, then was dried over MgSO4 and concentrated to an oil, which was used in next reaction without purification.
Reaction SMILES: [C:1]([O:4][C@:5]1([C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([C@@H:24]([Cl:28])[CH2:25]2)[C@:21]2([CH3:22])[C:16](=[CH:17][C:18](=[O:29])[CH:19]=[CH:20]2)[CH2:15][CH2:14]3)[CH2:11][C@@H:10]1[CH3:30])[C:6](=[O:9])[CH2:7][OH:8])(=[O:3])[CH3:2].[C:31](Cl)(=[O:34])[CH2:32][CH3:33].O>N1C=CC=CC=1.Cl>[C:1]([O:4][C@:5]1([C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([C@@H:24]([Cl:28])[CH2:25]2)[C@:21]2([CH3:22])[C:16](=[CH:17][C:18](=[O:29])[CH:19]=[CH:20]2)[CH2:15][CH2:14]3)[CH2:11][C@@H:10]1[CH3:30])[C:6](=[O:9])[CH2:7][O:8][C:31](=[O:34])[CH2:32][CH3:33])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@]1(C(=O)CO)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](Cl)C[C@@]21C
Reactant: CCC(=O)Cl
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CCC(=O)OCC(=O)[C@@]1(OC(C)=O)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](Cl)C[C@@]21C
Reaction time: 1 h

Procedure:
A solution of 17-acetoxy-11β-chloro-21-hydroxy-16β-methylpregna-1,4-diene-3,20-dione (67 mg.) in pyridine (1 ml.) at 0° was treated with propionyl chloride (0.03 ml.). After one hour, a little water was added and the solution was diluted with dilute hydrochloric acid. The precipitated solid was collected and recrystallized from methanol to give the title compound, m.p. 213°-215° (K), [α]D + 108.4° (c 0.6, chloroform) λmax 240 nm (ε 15,760) (Found: C, 65.9; H, 7.2. C27H35Cl O6 requires C, 66.0; H, 7.2).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([OH:16])=[O:15])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[Cl:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][C:23]=1[F:24].C([O-])([O-])=O.[Na+].[Na+].Cl>C1(C)C=CC=CC=1.CN(C=O)C>[Cl:17][C:18]1[CH:19]=[C:20]([C:2]2[C:7]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[N:6][CH:5]=[C:4]([CH:3]=2)[C:14]([OH:16])=[O:15])[CH:21]=[CH:22][C:23]=1[F:24]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(Br)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc(F)c(Cl)c2)c1
Temperature: 90 °C
Reaction time: 4 h
Yield: 62.9 %

Procedure:
5-Bromo-6-(2,2,2-trifluoroethoxy)-3-pyridinecarboxylic acid (CAN 1211586-75-2; 1.5 g; 5.0 mmol) was dissolved in toluene (35 mL) an DMF (2 mL). To this solution was added 1,1′-bis(diphenylphosphino)-ferrocene-palladium(II)dichloride dichloromethane complex (204 mg, 250 μmol), followed by 3-chloro-4-fluorophenylboronic acid (CAN 144432-85-9; 959 mg, 5.5 mmol) and 2M-Na2CO3 (20.0 mL 40.0 mmol). The reaction mixture was heated to 90° C. and stirred for 4 h, cooled and poured into 100 mL ice water, acidified with 45 mL 2N—HCl and extracted ethyl acetate. The organic layers were combined, dried with Na2SO4 and concentrated in vacuo. The crude material was crystallized from heptane:ethyl acetate (5:1) to yield 1.1 g (63%) of the title compound as light grey solid; LC-MS (UV peak area/ESI): 97%, 348.0066 (M−H)−.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[N:6][C:7]([CH2:11][CH2:12][CH:13]=O)=[CH:8][CH:9]=2)[CH2:4][O:3]1.[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([CH2:13][CH2:12][CH2:11][C:7]2[N:6]=[C:5]3[CH2:4][O:3][C:2](=[O:1])[C:10]3=[CH:9][CH:8]=2)[CH2:18][CH2:17]1
Reactant: O=CCCc1ccc2c(n1)COC2=O
Reactant: CN1CCNCC1
Product: CN1CCN(CCCc2ccc3c(n2)COC3=O)CC1
Yield: 83.6 %

Procedure:
In a process similar to that described in Preparation 8, 3-(5-Oxo-5,7-dihydro-furo[3,4-b]pyridin-2-yl)-propionaldehyde (63 mg, 0.33 mmol) and 1-methylpiperazine (33 mg, 0.33 mmol) are reacted to provide the title compound as white solid (76 mg, 84%).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:11]=[CH:10][N:9]([C:12]3[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=3[CH3:20])[C:4]=2[C:5](=[O:8])[NH:6][N:7]=1.[H-].[Na+].[CH3:23]I>CN(C=O)C.O>[NH2:1][C:2]1[C:3]2[CH:11]=[CH:10][N:9]([C:12]3[C:13]([CH3:20])=[CH:14][C:15]([CH3:19])=[CH:16][C:17]=3[CH3:18])[C:4]=2[C:5](=[O:8])[N:6]([CH3:23])[N:7]=1
Reactant: CI
Reactant: Cc1cc(C)c(-n2ccc3c(N)n[nH]c(=O)c32)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C)c(-n2ccc3c(N)nn(C)c(=O)c32)c(C)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 49.6 %

Procedure:
To an ice-cooled solution of 4-amino-1-mesityl-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one (268 mg, 1.0 mmol) in DMF (3 ml) was added sodium hydride (60% in oil, 44 mg, 1.1 mmol) and the mixture was stirred for 10 minutes. Methyl iodide (0.081 ml, 1.3 mmol) added and the mixture was stirred at room temperature for 1 hour. Additional sodium hydride (60% in oil, 44 mg, 1.1 mmol) and methyl iodide (0.081 ml, 1.3 mmol) were added and the mixture was stirred for 1 hour. The resulting mixture was diluted with water (30 ml) and extracted with ethyl acetate (30 ml×2). The extracts were combined, washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was subjected to silica gel column chromatography eluting with hexane/ethyl acetate (1:1-2:3) to give 140 mg (50%) of the title compound as crystals.