Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH2:16][C@H:17]1[CH2:21][CH2:20][C:19](=[O:22])[NH:18]1)[CH2:9][CH2:10]OS(C)(=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+]>CC#N>[CH2:1]([N:8]1[CH2:9][CH2:10][N:18]2[C:19](=[O:22])[CH2:20][CH2:21][C@@H:17]2[CH2:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OCCN(Cc1ccccc1)C[C@H]1CCC(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: O=C1CC[C@@H]2CN(Cc3ccccc3)CCN12
Reaction time: 4 h
Yield: 84.9 %

Procedure:
Methanesulfonic acid 2-[benzyl-((R)-5-oxo-pyrrolidin-2-ylmethyl)-amino]-ethyl ester (3.5 g, 10.74 mmol) was dissolved in CH3CN (20 ml) and then 60% NaH (558 mg, 13.96 mmol) was added portionwise at room temperature. After stirring for 4 hours, the solvent was removed under vacuum and the residue was treated with water and extracted with ethyl acetate. The organic phase was washed with brine, dried (Na2SO4) and evaporated under vacuum. The residue was purified by flash chromatography (DCM/abs EtOH/Petroleum Ether/33% NH4OH/Et2O 300/180/900/9.9/360 respectively) to afford the title compound as yellow oil (2.1 g, 85% yield).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]([OH:9])=O)=[N:4][O:5][N:6]=1.[Cl:10][C:11]1[N:16]=[C:15]([NH2:17])[CH:14]=[CH:13][CH:12]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.C([O-])(O)=O.[Na+]>CN(C)C=O>[NH2:1][C:2]1[C:3]([C:7]([NH:17][C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:10])[N:16]=2)=[O:9])=[N:4][O:5][N:6]=1
Reactant: Nc1cccc(Cl)n1
Reactant: Nc1nonc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nonc1C(=O)Nc1cccc(Cl)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-amino-1,2,5-oxadiazole-3-carboxylic acid (0.4 g, 3.1 mmol) and 6-chloropyridin-2-amine (0.56 g, 4.3 mmol) in N,N-dimethylformamide (6.2 mL) was treated with N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (1.4 g, 3.7 mmol) followed by N,N-diisopropylethylamine (0.76 mL, 4.3 mmol) at 0° C. The reaction mixture was stirred at 25° C. for 2 h, poured into saturated NaHCO3 (50 mL) and extracted with ethyl acetate (100 mL). The organic layer was separated and washed with brine (25 mL), dried with sodium sulfate, filtered, and concentrated to a crude solid. The crude solid was washed with ethyl acetate and filtered. The filtrate was concentrated and purified on silica gel to give the desired product with some impurities. The impurities were removed by washing the solid with chloroform to yield the desired product (65 mg, 9%). LCMS for C8H7ClN5O2 (M+H)+: m/z=240.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[CH2:7][CH2:6]2.CC1C=CC(N=[CH:21][C:22]2[C:23]([NH2:31])=[CH:24][C:25]3[O:29][CH2:28][O:27][C:26]=3[CH:30]=2)=CC=1>C(O)C.[OH-].[Na+].C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]2[C:8]3=[N:31][C:23]4[CH:24]=[C:25]5[O:29][CH2:28][O:27][C:26]5=[CH:30][C:22]=4[CH:21]=[C:7]3[CH2:6][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)CCC2=O
Reactant: Cc1ccc(N=Cc2cc3c(cc2N)OCO3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc2c(c1)Cc1cc3cc4c(cc3nc1-2)OCO4
Temperature: 100 °C
Yield: 134.9 %

Procedure:
To 5-methoxyindan-1-one (350 mg, 2 mmol) is added 6[[(4-methylphenyl)imino]methyl]-1,3-benzodioxol-5-amine (512 mg, 1 mmol) in ethanol (4 mL) and 2N sodium hydroxide (1 mL). The reaction mixture is heated at reflux (about 100° C.) for 16 hrs. Upon cooling the reaction product is dissolved in methylene chloride (200 mL) and extracted with a saturated sodium chloride solution (200 mL). The organic layer is dried with a rotatory evaporator. The resulting residue is chromatographed on silica gel with 2:3 ethyl acetate/hexanes to yield 8-Methoxy-10H-1,3-dioxolo[4,5-g]indeno[1,2-b]quinoline (393 mg, 67.4% of theory).
Reaction SMILES: [NH2:1][C:2]1[C:29]([Cl:30])=[CH:28][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:31][CH3:32])[CH:3]=1.[CH:33](=O)[CH3:34].C([BH3-])#N.[Na+]>>[NH2:1][C:2]1[C:29]([Cl:30])=[CH:28][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:33][CH3:34])[CH:22]3[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]3)[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:31][CH3:32])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCNC2CCCCC2)CC1
Reactant: CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCN(CCCCCN1CCC(CNC(=O)c2cc(Cl)c(N)cc2OC)CC1)C1CCCCC1

Procedure:
4-Amino-5-chloro-N-((1-(5-cyclohexylaminopentyl)piperidin-4-yl)-methyl)-2-methoxybenzamide (1.1 g) as starting compound, acetaldehyde (0.15 ml) and sodium cyanoborohydride (0.33 g) were reacted and treated in the same manner as in Example 136 to give 1.0 g of 4-amino-5-chloro-N-((1-(5-(N-ethyl-N-cyclohexylamino)pentyl)piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: CO[C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.COC(=O)C1C=CC(OC[C:37]2[C:38]([C:43]3C=C(C)C=CC=3)=[N:39]OC=2C)=NC=1>>[CH:38]([NH:39][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1)([CH3:43])[CH3:37]
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(C)cc3)noc2C)nc1
Reactant: COC(=O)c1ccc(OCc2c(-c3cccc(C)c3)noc2C)nc1
Product: Cc1ccc(-c2noc(C)c2COc2ccc(C(=O)NC(C)C)cn2)cc1
Yield: 78 %

Procedure:
As described for example 250, 6-(5-methyl-3-p-tolyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (250 mg, 0.73 mmol) was converted, instead of 6-(5-methyl-3-m-tolyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester, to the title compound (210 mg, 78%) which was obtained as a white solid. MS: m/e=366.3 [M+H]+.
Reaction SMILES: [CH2:1]([C@H:3]1[C@@H:7]([C:8]([NH:10][NH:11][C:12]2[N:13]=[C:14]3[CH:20]=[CH:19][N:18]([S:21]([C:24]4[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=4)(=[O:23])=[O:22])[C:15]3=[N:16][CH:17]=2)=O)[CH2:6][C@@H:5]([NH:31][C:32](=[O:34])[CH3:33])[CH2:4]1)[CH3:2].S(Cl)(Cl)=O.C([O-])(O)=O.[Na+].CCOC(C)=O>O1CCOCC1>[CH2:1]([C@H:3]1[C@@H:7]([C:8]2[N:13]3[C:14]4[CH:20]=[CH:19][N:18]([S:21]([C:24]5[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=5)(=[O:22])=[O:23])[C:15]=4[N:16]=[CH:17][C:12]3=[N:11][N:10]=2)[CH2:6][C@@H:5]([NH:31][C:32](=[O:34])[CH3:33])[CH2:4]1)[CH3:2]
Reactant: CC[C@@H]1C[C@H](NC(C)=O)C[C@@H]1C(=O)NNc1cnc2c(ccn2S(=O)(=O)c2ccc(C)cc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC[C@@H]1C[C@H](NC(C)=O)C[C@@H]1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Temperature: 80 °C
Yield: 66.3 %

Procedure:
To a mixture of (1S,2R,4S)-4-acetamido-2-ethylcyclopentanecarboxylic acid (3.03 g, 15.2 mmol) in DCM (90 mL) was added 2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (4.20 g, 13.8 mmol, Example #4, Step D), HATU (5.53 g, 14.5 mmol) and TEA (7.72 mL, 55.4 mmol). After stirring at ambient temperature for about 2 h, the reaction was diluted with water (60 mL). The layers were separated and the aqueous layer was extracted with DCM (3×50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous MgSO4, filtered, and concd under reduced pressure. The crude material was purified by silica gel chromatography eluting with a gradient of 0-5% MeOH in DCM to give N-((1S,3R,4S)-3-ethyl-4-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)cyclopentyl)acetamide (7.0 g, 90%, 87% purity) as a tan foam: LC/MS (Table 1, Method a) Rt=1.96 min; MS m/z: 485 (M+H)+. To a solution of impure N-((1S,3R,4S)-3-ethyl-4-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)-cyclo-pentyl)acetamide (9.40 g, 19.4 mmol) in 1,4-dioxane (100 mL) was added TEA (8 mL, 58 mmol) and thionyl chloride (1.9 mL, 27.1 mmol). The reaction mixture was heated at about 80° C. for about 2 h, and then cooled to about 0° C. and saturated aqueous NaHCO3 and EtOAc (100 mL each) were added. The layers were separated and the aqueous layer was extracted with additional EtOAc (2×100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous MgSO4, filtered, and concd under reduced pressure. The crude material was purified by silica gel chromatography eluting with a gradient of 50-100% EtOAc/MeOH/Et2NH (90:9:1) in EtOAc to give N-((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)acetamide (6.00 g, 66%): LC/MS (Table 1, Method a) Rt=2.03 min; MS m/z: 467 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[C:7]([C:10]3[CH:11]=[N:12][N:13]([CH:15]4[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]4)[CH:14]=3)[CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[NH2:30]Cl.S([O-])([O-])(=O)=S.[Cl-].[NH4+]>CN(C=O)C.CCOCC>[NH2:30][N:1]1[C:9]2[C:4](=[N:5][CH:6]=[C:7]([C:10]3[CH:11]=[N:12][N:13]([CH:15]4[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:20]4)[CH:14]=3)[CH:8]=2)[CH:3]=[CH:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc4cc[nH]c4c3)cn2)CC1
Reactant: NCl
Agent: O=S([O-])([O-])=S
Agent: [Cl-]
Agent: [H-]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc4ccn(N)c4c3)cn2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 45 %

Procedure:
To a solution of tert-butyl 4-[4-(1H-pyrrolo[3,2-b]pyridin-6-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate: (0.73 g, 2.0 mmol) in 4.0 mL of DMF at −20° C. was added NaH (60% in oil, 96 mg, 2.4 mmol) in one portion. After 15 min, the mixture was stirred at room temperature for 30 min. A solution of NH2Cl in Et2O (prepared according to the procedure described in J. Org. Chem. 2004, 1371: ˜0.15 M, 16 ml) was added. The mixture was poured into a saturated solution of thiosulfate and ammonium chloride, and extracted with ethyl acetate. The organic layer was concentrated and the product was purified by column chromatography (EtOAc:MeOH=100:5). The entitled intermediate was isolated as a light brown solid (350 mg, 45% yield) (starting material (220 mg) was also recovered).
Reaction SMILES: [OH:1][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:21]=[C:20]([C:22]3[O:26][N:25]=[C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:23]=3[C:33]([F:36])([F:35])[F:34])[O:19][N:18]=2)=[CH:13][CH:12]=1)[C:3]([NH:5][CH2:6][CH2:7]C(O)=O)=[O:4].Cl.CNC.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:72][N:73]([CH:75]=[O:76])[CH3:74]>>[OH:1][CH:2]([C:11]1[CH:12]=[CH:13][C:14]([C:17]2[N:21]=[C:20]([C:22]3[O:26][N:25]=[C:24]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:23]=3[C:33]([F:34])([F:35])[F:36])[O:19][N:18]=2)=[CH:15][CH:16]=1)[C:3]([NH:5][CH2:6][CH2:7][C:75]([N:73]([CH3:74])[CH3:72])=[O:76])=[O:4]
Reactant: CN(C)C=O
Reactant: O=C(O)CCNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNC
Agent: Cl
Solvent: CN1CCOCC1
Product: CN(C)C(=O)CCNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 36.4 %

Procedure:
(R/S)-3-(2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)propanoic acid (Example 22, 22 mg, 0.044 mmol), dimethylamine-HCl (5.36 mg, 0.066 mmol), 4-methylmorpholine (17.72 mg, 0.175 mmol), and HATU (21.65 mg, 0.057 mmol) were added to DMF (1 mL). This was stirred for 1 h and then purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 12 min, 20 mL/min, 220 nM, product retention=13.4 min) to provide (R/S)-3-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)-N,N-dimethylpropanamide (9 mg, 0.016 mmol, 36.4% yield): LCMS=530.3 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.14-8.19 (2 H, m), 7.55-7.71 (7 H, m), 5.11 (1 H, s), 3.51 (2 H, t, J=6.60 Hz), 2.98 (3 H, s), 2.92 (3 H, s), 2.60 (2 H, t, J=6.49 Hz); HPLC peak RT=8.8 min (Method A).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]([CH2:8][CH:9]1[CH2:14][N:13]([C:15]2[C:25]([F:26])=[CH:24][C:18]([C:19]([O:21]CC)=[O:20])=[C:17]([F:27])[C:16]=2[F:28])[CH2:12][CH2:11][O:10]1)[CH3:7])=[O:5])[CH3:2].[OH-].[Na+]>CO.O>[CH2:1]([O:3][C:4]([N:6]([CH2:8][CH:9]1[CH2:14][N:13]([C:15]2[C:25]([F:26])=[CH:24][C:18]([C:19]([OH:21])=[O:20])=[C:17]([F:27])[C:16]=2[F:28])[CH2:12][CH2:11][O:10]1)[CH3:7])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(F)c(N2CCOC(CN(C)C(=O)OCC)C2)c(F)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCOC(=O)N(C)CC1CN(c2c(F)cc(C(=O)O)c(F)c2F)CCO1
Yield: 68.6 %

Procedure:
To a solution of 19.1 g of ethyl 4-[2-(N-ethoxycarbonyl-N-methylaminomethyl)morpholino]-2,3,5-trifluorobenzoate in 100 ml of methanol is added dropwise a solution of 7.56 g of sodium hydroxide in 100 ml of water under ice-cooling. After stirring under ice-cooling for 20 minutes, the methanol is distilled off under reduced pressure. The solution is washed with ethyl acetate, made acid with 6 N hydrochloric acid and then extracted with ethyl acetate. After drying over anhydrous magnesium sulfate, the ethyl acetate is distilled off under reduced pressure. To the residue is added isopropyl ether. The obtained crystals are filtered with suction and dried to give 12.2 g of 4-[2-(N-ethoxycarbonyl-N-methylaminomethyl)-morpholino]-2,3,5-trifluorobenzoic acid in 68% yield, melting at 170°-172° C.
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH2:13][C:14]3=[O:19])=[C:6]([OH:20])[C:5]=1[O:21][CH3:22].C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32]([CH3:36])([CH3:35])[CH2:33][OH:34]>C(#N)C>[F:1][CH:2]([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH2:13][C:14]3=[O:19])=[C:6]([O:20][CH2:31][C:32]([CH3:36])([CH3:35])[CH2:33][OH:34])[C:5]=1[O:21][CH3:22]
Reactant: CC(C)(CO)CBr
Reactant: COc1c(OC(F)F)ccc(-c2cccc3c2CCC3=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1c(OC(F)F)ccc(-c2cccc3c2CCC3=O)c1OCC(C)(C)CO
Temperature: 80 °C
Yield: 29.5 %

Procedure:
To a stirring solution of 4-(4-(difluoromethoxy)-2-hydroxy-3-methoxyphenyl)-2,3-dihydro-1H-inden-1-one (80 mg, 0.25 mmol) in acetonitrile (10 mL) was added potassium carbonate (104 mg, 0.75 mmol) and followed by 3-bromo-2,2-dimethyl-propan-1-ol (125 mg, 0.75 mmol) and the resultant reaction mixture was heated to 80° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 0-70% ethyl acetate in pet ether) to afford title compound as a solid (30 mg, 30%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](O)=[O:7])#[N:2].B.C1COCC1>C1COCC1>[OH:7][CH2:6][C:5]1[CH:4]=[C:3]([CH:11]=[CH:10][CH:9]=1)[C:1]#[N:2]
Reactant: N#Cc1cccc(C(=O)O)c1
Agent: B
Solvent: C1CCOC1
Product: N#Cc1cccc(CO)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.4 %

Procedure:
3-Cyanobenzoic acid (5 g, 34.0 mmol) was dissolved in THF (50 mL) at ambient temperature. To this solution was added borane/THF complex (1M in THF, 68 mL, 68.0 mmol) in three portions and borane trifluoride/diethyl etherate complex (4.3 mL, 34.0 mmol). The reaction mixture was stirred at ambient temperature for 2 hours, quenched with methanol and stirred for 10 minutes. The solution was diluted with ethyl acetate and washed with saturated NaHCO3 (3×). The organic layer was separated, dried (MgSO4), filtered and concentrated in vacuo to give the title compound (2.19 g, 48% yield) as a solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[S:7][C:8]([CH3:11])=[CH:9][CH:10]=1)=[O:5].[F:12][C:13]([F:24])([F:23])[C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1.[OH-].[Na+]>C(Cl)Cl>[CH3:11][C:8]1[S:7][C:6]([C:4](=[O:5])[CH2:3][NH:2][C:18](=[O:19])[C:17]2[CH:21]=[CH:22][C:14]([C:13]([F:12])([F:23])[F:24])=[CH:15][CH:16]=2)=[CH:10][CH:9]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: Cc1ccc(C(=O)CN)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1ccc(C(=O)CNC(=O)c2ccc(C(F)(F)F)cc2)s1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A stirred suspension of 2-amino-1-(5-methylthienyl)ethanone hydrochloride (3.0 g of a mixture containing approximately 60% 2-amino-1-(5-methylthienyl)ethanone hydrochloride) in methylene chloride (100 ml) was cooled in an ice bath. To this cold mixture was added 4-(trifluoromethyl)benzoyl chloride (2.8 g, 0.013 mole), followed by the slow addition of a 2N solution of sodium hydroxide (9.4 ml). After complete addition, the mixture was stirred at room temperature for three days. The mixture was washed first with an aqueous 5% hydrochloric acid solution, followed by water. The organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure, yielding 3.9 g of N-[2-(5-methylthienyl)-2-oxoethyl]-4-trifluoromethylbenzamide as a solid. A small portion was recrystallized from ethanol for analysis, m.p. 182°-183° C.
Reaction SMILES: [C:1]([NH:9][C@@H:10]1[CH2:19][CH2:18][C:13]2([O:17][CH2:16][CH2:15][O:14]2)[CH2:12][C@@H:11]1[C:20]([O:22]CC)=[O:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-].O>C1COCC1>[C:1]([NH:9][C@@H:10]1[CH2:19][CH2:18][C:13]2([O:17][CH2:16][CH2:15][O:14]2)[CH2:12][C@@H:11]1[C:20]([OH:22])=[O:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)[C@H]1CC2(CC[C@H]1NC(=O)c1ccccc1)OCCO2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(N[C@@H]1CCC2(C[C@@H]1C(=O)O)OCCO2)c1ccccc1
Yield: 100 %

Procedure:
(7S,8R)-Ethyl 8-benzamido-1,4-dioxaspiro[4.5]decane-7-carboxylate (740 mg, 2.22 mmol) was dissolved in THF (10 mL) at 25° C. with stirring. 0.5N LiOH (8.88 mL, 4.44 mmol) was then added thereto and the mixture stirred for 3 hours. The reaction was worked up by adding water and then removing the THF in vacuo. The remaining basic aqueous mixture was then acidified to pH=3 with 1N HCl. The aqueous mixture was extracted (2×) with methylene chloride. The methylene chloride extracts were combined, dried over sodium sulfate and concentrated to give (7S,8R)-8-benzamido-1,4-dioxaspiro[4.5]decane-7-carboxylic acid (678 mg, 2.22 mmol, 100% yield) as a white glass. MS (ESI+)=306.19 (M+H)+.
Reaction SMILES: [Cl:1][CH:2]([O:6][C:7]([NH:9][CH2:10][C:11]1([CH2:17][C:18]([OH:20])=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:8])[CH:3]([CH3:5])[CH3:4].[CH:21]1C=CC=CC=1.C[Si](C=[N+]=[N-])(C)C>CO>[Cl:1][CH:2]([O:6][C:7]([NH:9][CH2:10][C:11]1([CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1)=[O:8])[CH:3]([CH3:4])[CH3:5]
Reactant: c1ccccc1
Reactant: CC(C)C(Cl)OC(=O)NCC1(CC(=O)O)CCCCC1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC(=O)CC1(CNC(=O)OC(Cl)C(C)C)CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
A mixture of (93) (1.0 g, 3.3 mmol), benzene (90 mL), and methanol (10 mL) was cooled to 0° C. Trimethylsilyldiazomethane was added slowly at 0° C. until the yellow color persisted. The mixture was stirred at 0° C. for 30 min until the reaction was complete (monitored by TLC). After removing the solvent under reduced pressure, chromatography of the resulting residue on silica gel, eluting with 10% ethyl acetate/hexane gave 760 mg (72%) of the title compound. MS (ESI) m/z 320.24 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]2[NH:6][C:7](=[O:29])[CH:8]([CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=3)[N:9]=[C:10]([N:11]3[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]3)[C:4]=2[CH:3]=1.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([Mg]Br)=[CH:36][CH:35]=1>O1CCCC1>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]2[NH:6][C:7](=[O:29])[CH:8]([CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=3)[N:9]=[C:10]([N:11]3[CH2:12][CH2:13][C:14]([OH:17])([C:37]4[CH:38]=[CH:39][C:34]([O:33][CH3:32])=[CH:35][CH:36]=4)[CH2:15][CH2:16]3)[C:4]=2[CH:3]=1
Reactant: COc1ccc([Mg]Br)cc1
Reactant: O=C1CCN(C2=NC(Cc3ccc4ccccc4c3)C(=O)Nc3ccc(Cl)cc32)CC1
Solvent: C1CCOC1
Product: COc1ccc(C2(O)CCN(C3=NC(Cc4ccc5ccccc5c4)C(=O)Nc4ccc(Cl)cc43)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.3 %

Procedure:
7-Chloro-3-(naphthalen-2-ylmethyl)-5-(4-oxopiperidin-1-yl)-1H-benzo[e][1,4]diazepin-2(3H)-one (18 mg, 0.04 mmol) was dissolved in anhydrous tetrahydrofuran (0.2 mL) under nitrogen, 4-methoxyphenylmagnesium bromide (0.5M solution in tetrahydrofuran, 0.5 mL, 0.25 mmol) was added dropwise. After stirring at ambient temperature for 1 hour the reaction was quenched with water (1 mL), diluted with ethyl acetate, separated, washed with water, dried with sodium sulfate, decanted, and concentrated. The residue was redissolved in ethyl acetate (0.5 mL) and hexanes added slowly (total of 6 mL). A solid precipitated and was collected by filtration. Washing with hexanes provided 7-chloro-5-(4-hydroxy-4-(4-methoxyphenyl)piperidin-1-yl)-3-(naphthalen-2-ylmethyl)-1H-benzo[e][1,4]diazepin-2(3H)-one (10 mg, 43% yield). ESI m/z measured 540.2062 [M+H]+. calculated 540.2054.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([Cl:33])[C:19]=1[CH2:20][CH:21]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=1)[OH:22].[CH2:34]([C:38]1[CH:43]=[CH:42][C:41]([C@H:44]([CH3:48])[C:45](O)=[O:46])=[CH:40][CH:39]=1)[CH:35]([CH3:37])[CH3:36].[NH4+].[Cl-]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:33][C:18]1[CH:17]=[N:16][CH:15]=[C:14]([Cl:13])[C:19]=1[CH2:20][CH:21]([O:22][C:45](=[O:46])[C@H:44]([C:41]1[CH:42]=[CH:43][C:38]([CH2:34][CH:35]([CH3:37])[CH3:36])=[CH:39][CH:40]=1)[CH3:48])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=1
Reactant: CC(C)Cc1ccc([C@H](C)C(=O)O)cc1
Reactant: COc1ccc(C(O)Cc2c(Cl)cncc2Cl)cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc(C(Cc2c(Cl)cncc2Cl)OC(=O)[C@@H](C)c2ccc(CC(C)C)cc2)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.3 %

Procedure:
(1-Ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride) (EDC.HCl) (345 mg, 3 eq.) is added to a solution of 2-(3,5-dichloro-pyridin-4-yl)-1-(3,4-dimethoxy-phenyl)-ethanol (200 mg, 1 eq.), (S)-2-(4-isobutyl-phenyl)-propionic acid (148 mg, 1.2 eq.) and 4-dimethylaminopyridine (DMAP) (37 mg, 0.5 eq.) in dry CH2Cl2 (8 mL) at room temperature under nitrogen atmosphere. The mixture is stirred at room temperature overnight, then it is treated with a saturated solution of NH4Cl (20 ml) and extracted with EtOAc (2×20 ml). The combined organic layer are dried over Na2SO4 and the solvent is evaporated. The crude is purified by flash chromatography on silica gel in gradient elution (from petroleum ether/EtOAc 9/1 v/v to petroleum ether/EtOAc 7/3 v/v) to yield 259 mg of pure compound.
Reaction SMILES: [OH:1][C@:2]1([CH3:27])[CH2:24][CH2:23][C@@:22]2([CH3:25])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:21]2[CH2:20][CH2:19][C@@:18]2([CH3:26])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12]2(OCC[O:14]2)[CH3:13])[CH2:3]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[OH:1][C@:2]1([CH3:27])[CH2:24][CH2:23][C@@:22]2([CH3:25])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:21]2[CH2:20][CH2:19][C@@:18]2([CH3:26])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1
Reactant: CC1([C@H]2CC[C@H]3[C@@H]4CC[C@H]5C[C@](C)(O)CC[C@]5(C)[C@H]4CC[C@]23C)OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@](C)(O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
A solution of 3α-hydroxy-3β-methyl-20,20-ethylenedioxy-5α-pregnane and p-toluene sulfonic acid (catalytic) in wet acetone was heated at reflux overnight. The reaction was concentrated in vacuo and taken up in chloroform. The organic phase was washed with sodium bicarbonate, dried over magnesium sulfate, concentrated, and recrystallized from methanol to give the title compound.