Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:18]=[CH:17][C:7]2[O:8][CH2:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[NH:12][C:6]=2[CH:5]=1.Cl[C@@H:20]1[CH2:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]3[O:34][CH2:35][O:36][C:30]=3[CH:29]=2)[CH2:21]1.C(=O)([O-])O.[Na+]>CCCCCC.CS(C)=O.C(OCC)(=O)C>[Cl:3][C:4]1[CH:18]=[CH:17][C:7]2[O:8][CH2:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]([CH2:24][C@H:23]3[CH2:25][CH2:20][CH2:21][N:22]3[CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]4[O:34][CH2:35][O:36][C:30]=4[CH:29]=3)[C:6]=2[CH:5]=1
Reactant: Cl[C@@H]1CCCN(CCc2ccc3c(c2)OCO3)C1
Reactant: Clc1ccc2c(c1)Nc1ccccc1CO2
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Clc1ccc2c(c1)N(C[C@H]1CCCN1CCc1ccc3c(c1)OCO3)c1ccccc1CO2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
60% sodium hydride (48 mg, 1.2 mmol) was washed with hexane in argon gas stream and then suspended in dimethyl sulfoxide (8 ml). The obtained suspension was stirred at room temperature for 30 minutes. 7-Chloro-5,11-dihydrodibenzo[b,e][1,4]oxazepine (232 mg, 1 mmol) was added to the suspension, and they were stirred at room temperature for 30 minutes and then at 50° C. for 30 minutes. A solution of (R)-3-chloro-1-(3,4-methylenedioxyphenethyl)piperidine (308 mg, 1.15 mmol) in dimethyl sulfoxide (3 ml) was added dropwise to the obtained solution, and they were stirred at 50° C. for 4 hours. The reaction mixture was distributed into saturated aqueous sodium hydrogencarbonate solution and ethyl acetate. The organic layer was dried and the solvent was evaporated under reduced pressure. The residue was subjected to the silica gel column chromatography. After the elution with hexane and ethyl acetate (10:1) as the eluent, suitable fractions were collected and the solvent was evaporated under reduced pressure to obtain (R)-7-chloro-5,11-dihydro-5-[1-(3,4-methylenedioxyphenethyl)pyrrolidin-2-ylmethyl]-dibenzo[b,e][1,4]oxazepine in the form of a light yellow solid (362 mg, 78%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].BrC[CH2:16][OH:17].[C:18]([O-])([O-])=O.[K+].[K+]>CC#N>[OH:17][CH2:16][CH2:13][O:12][C:10]1[CH:9]=[C:4]([CH:3]=[C:2]([O:1][CH3:18])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(O)cc(OC)c1
Reactant: O=C([O-])[O-]
Reactant: OCCBr
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cc(OC)cc(OCCO)c1
Temperature: 80 °C
Yield: 44.2 %

Procedure:
To a solution of methyl 3-hydroxy-5-methoxybenzoate (1.82 g, 10 mmol) and 2-bromoethanol (2.5 g, 20 mmol) in CH3CN (20 ml) was added K2CO3 (4.2 g, 0.03 mol) and the reaction mixture was heated to 80° C. overnight. After to cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified using normal phase chromatography eluting with petroleum ether and increasing amounts of ethyl acetate to give compound methyl 3-(2-hydroxyethoxy)-5-methoxybenzoate (1.0 g).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[CH2:8][C@@H:7]([C:9]2[O:13][N:12]=[C:11]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[N:10]=2)[N:6]([C:20]([C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:24][CH:23]=2)=[O:21])[CH2:5]1.[CH2:34](N(CC)CC)C.CI.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[CH3:1][O:2][N:3]=[C:4]1[CH2:8][C@@H:7]([C:9]2[O:13][N:12]=[C:11]([CH:14]3[CH2:19][CH2:18][N:17]([CH3:34])[CH2:16][CH2:15]3)[N:10]=2)[N:6]([C:20]([C:22]2[CH:23]=[CH:24][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:26][CH:27]=2)=[O:21])[CH2:5]1
Reactant: CCN(CC)CC
Reactant: CON=C1C[C@@H](c2nc(C3CCNCC3)no2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CI
Solvent: ClCCl
Product: CON=C1C[C@@H](c2nc(C3CCN(C)CC3)no2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 50 %

Procedure:
(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[3-(4-piperidinyl)-1,2,4-oxadiazol-5-yl]-3-pyrrolidinone O-methyloxime (Example 12) was dissolved in dry DCM at 0° C. in presence of 1.5 equivalent of triethyl amine and treated with 1 equivalent of methyl iodide. The reaction mixture was stirred at room temperature for 12 hours. The reaction was hydrolysed and then made basic with a sodium carbonate solution (10%) and extracted with DCM. It was then dried with magnesium sulfate and solvent removal afforded a residue, which was purified by flash-chromatography using dichloromethane/methanol (98/2) as eluent to give (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[3-(1-methyl-4-piperidinyl)-1,2,4-oxadiazol-5-yl]-3-pyrrolidinone O-methyloxime as a mixture of E-/Z-isomers in 50% yield (96.8% purity by HPLC).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][C:33]([C:36]([O:38]CC)=[O:37])([CH3:35])[CH3:34])=[C:6]([CH:8]2[C:13]3([C:21]4[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=4)[NH:15][C:14]3=[O:23])[CH:12]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[CH2:11][C:10](=[O:31])[NH:9]2)[CH:7]=1.[OH-].[Na+]>CO.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][C:33]([C:36]([OH:38])=[O:37])([CH3:34])[CH3:35])=[C:6]([CH:8]2[C:13]3([C:21]4[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=4)[NH:15][C:14]3=[O:23])[CH:12]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[CH2:11][C:10](=[O:31])[NH:9]2)[CH:7]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(Br)cc1C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(Oc1ccc(Br)cc1C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12)C(=O)O
Temperature: 60 °C
Yield: 91.3 %

Procedure:
To a mixture of racemic (2′R,3R,4′S)-2′-[5-bromo-2-(1-ethoxycarbonyl-1-methyl-ethoxy)-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (700 mg, 1.08 mmol) in methanol (20 mL) was added a solution of NaOH (120 mg, 3 mmol) in water (10 mL). The mixture was heated at 60° C. for 1.5 h, evaporated to remove most of methanol, cooled to room temperature, and acidified to “pH” 2 with aqueous HCl solution. The precipitate was collected and dried to give product as a white solid (610 mg). m/z (M+H)+: 617
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11](F)[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:22][CH:23]1[CH2:28][NH:27][CH2:26][CH2:25][NH:24]1>CS(C)=O>[CH3:22][CH:23]1[NH:24][CH2:25][CH2:26][N:27]([C:11]2[C:12]([O:14][CH3:15])=[C:13]3[N:4]([CH:1]4[CH2:3][CH2:2]4)[CH:5]=[C:6]([C:19]([OH:21])=[O:20])[C:7](=[O:18])[C:8]3=[CH:9][C:10]=2[F:17])[CH2:28]1
Reactant: CC1CNCCN1
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Solvent: CS(C)=O
Product: COc1c(N2CCNC(C)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 55 °C
Reaction time: 8 h
Yield: 33.7 %

Procedure:
Thirty five grams of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinoline carboxylic acid and 24.9 g (2.1 eq) of 2-methyl piperazine were put in suspension in DMSO (700 mL) under nitrogen atmosphere. The mixture was heated to 55° C. during 24 hours. The reaction mixture was then stirred at 20° C. overnight. Half of this solution (408 g, assay 4.8%) was filtrated and dried under vacuum to obtain 15.0 g (66% yield) of gatifloxacin.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=CC(S(Cl)(=O)=O)=C[CH:3]=1.N1C=CC=CC=1.[Cl:18][C:19]1[N:27]=[C:26]([Cl:28])[C:25]([F:29])=[CH:24][C:20]=1[C:21]([OH:23])=[O:22].C(=O)([O-])O.[Na+]>C(O)(C)(C)C>[Cl:18][C:19]1[N:27]=[C:26]([Cl:28])[C:25]([F:29])=[CH:24][C:20]=1[C:21]([O:23][C:2]([CH3:7])([CH3:3])[CH3:1])=[O:22]
Reactant: O=C(O)c1cc(F)c(Cl)nc1Cl
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)c1cc(F)c(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
P-toluenesulfonyl chloride (53.5 g) was added to a pyridine (100 ml)/tert-butanol (300 ml) solution of 2,6-dichloro-5-fluoronicotinic acid (24.5 g), and stirred overnight at room temperature. The reaction liquid was poured into aqueous 10% sodium hydrogencarbonate solution, stirred at room temperature for 2 hours, and then extracted with ethyl acetate. The extract was washed with saturated saline water, dried with anhydrous magnesium sulfate, the solvent was evaporated off, the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1) to obtain the entitled compound (29.5 g).
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[I:28][C:29]1[N:30]=[C:31]([CH3:34])[NH:32][CH:33]=1>C(Cl)Cl>[I:28][C:29]1[N:30]=[C:31]([CH3:34])[N:32]([C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:33]=1
Reactant: Cc1nc(I)c[nH]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc(I)cn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Triethylamine (13.4 mL, 96.2 mmol) followed by trityl chloride (20.1 g, 72.1 mmol) were added to an ambient temperature solution of 4-iodo-2-methyl-1H-imidazole (ca. 10 g, 48.1 mmol) in methylene chloride (90 mL). After stirring at ambient temperature for 2 days, the reaction mixture was diluted with methylene chloride and washed with water and brine, dried (sodium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-15% acetone/methylene chloride afforded the title compound.
Reaction SMILES: C([O:5][C:6](=[O:27])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:23]2[C:18]([CH:19]=[N:20][C:21]([S:24]([CH3:26])=[O:25])=[N:22]2)=[CH:17][CH:16]=1)(C)(C)C.C(Cl)Cl.FC(F)(F)C(O)=O>>[CH3:26][S:24]([C:21]1[N:20]=[CH:19][C:18]2=[CH:17][CH:16]=[C:15]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[O:8][CH2:7][C:6]([OH:27])=[O:5])[N:23]2[N:22]=1)=[O:25]
Reactant: CS(=O)c1ncc2ccc(-c3ccccc3OCC(=O)OC(C)(C)C)n2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)c1ncc2ccc(-c3ccccc3OCC(=O)O)n2n1
Reaction time: 18 h
Yield: 77.3 %

Procedure:
[2-(2-Methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenoxy]-acetic acid tert-butyl ester (0.298 g, 0.769 mmol), Methylene chloride (11 mL, 170 mmol), and Trifluoroacetic Acid (2.20 mL, 28.5 mmol) were combined and stirred for 18 hours. The product was extracted into dichloromethane and purified by normal phase silica gel chromatography eluting with methanol/dichloromethane to yield a brown solid, [2-(2-Methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenoxy]-acetic acid (197 mg, 77%). LCMS: m/z=332.06 (M+H+); 1H NMR (400 MHz, DMSO-d6) δ 9.30 (s, 1H), 7.86 (d, 1H, J=7.6 Hz), 7.54 (d, 1H, J=4.7 Hz), 7.46 (m, 1H), 7.31 (d, 1H, J=4.7 Hz), 7.14 (m, 2H), 4.77 (s, 2H), 2.92 (s, 3H).
Reaction SMILES: [N:1]([O-:3])=O.[Na+].C(O)(C(F)(F)F)=O.[F:12][C:13]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:14]=1[O:15][C:16]1([CH2:22][OH:23])[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]1.[OH-].[Na+]>O.C(O)(=O)C>[F:12][C:13]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:14]=1[O:15][C:16]1([CH2:22][OH:23])[CH2:21][CH2:20][CH2:19][N:18]([N:1]=[O:3])[CH2:17]1
Reactant: O=N[O-]
Reactant: OCC1(Oc2cc(F)ccc2F)CCCNC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CC(=O)O
Product: O=NN1CCCC(CO)(Oc2cc(F)ccc2F)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of sodium nitrite (2 mmol, 138 mg) in water (3 mL) was added dropwise to a solution of TFA salt of (3-(2,5-difluorophenoxy)piperidin-3-yl)methanol (1 mmol, 243 mg) in acetic acid (5 mL) and water (2 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hour, and then heated to 60° C. and stirred for 4 hours. The reaction mixture was cooled to room temperature. Sodium hydroxide aqueous solution was added to adjust the pH of the solution slightly basic. The organics were extracted with EtOAc. The product, (3-(2,5-difluorophenoxy)-1-nitrosopiperidin-3-yl)methanol, was obtained after removal of the solvent.
Reaction SMILES: C(OC(=O)[N:7]([C:19]1[CH:24]=[CH:23][C:22]([CH:25](O)[C:26]2[C:34]3[C:29](=[N:30][CH:31]=[CH:32][CH:33]=3)[NH:28][CH:27]=2)=[C:21]([CH3:36])[N:20]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)(C)(C)C.C(OC(=O)N(C1C=CC(C(OC)C2C3C(=NC=CC=3)NC=2)=C(C)N=1)CC1C=CC(C(F)(F)F)=CC=1)(C)(C)C.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(#N)C>[CH3:36][C:21]1[N:20]=[C:19]([NH:7][CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:13][CH:14]=2)[CH:24]=[CH:23][C:22]=1[CH2:25][C:26]1[C:34]2[C:29](=[N:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1
Reactant: Cc1nc(N(Cc2ccc(C(F)(F)F)cc2)C(=O)OC(C)(C)C)ccc1C(O)c1c[nH]c2ncccc12
Agent: CC[SiH](CC)CC
Agent: COC(c1ccc(N(Cc2ccc(C(F)(F)F)cc2)C(=O)OC(C)(C)C)nc1C)c1c[nH]c2ncccc12
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: Cc1nc(NCc2ccc(C(F)(F)F)cc2)ccc1Cc1c[nH]c2ncccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The combined materials of {5-[Hydroxy-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-6-methyl-pyridin-2-yl}-(4-trifluoromethyl-benzyl)-carbamic acid tert-butyl ester (37) and {5-[Methoxy-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-6-methyl-pyridin-2-yl}-(4-trifluoromethyl-benzyl)-carbamic acid tert-butyl ester (38) (194 mg, 0.378 mmol) were dissolved in acetonitrile (3 mL) and triethylsilane (0.30 mL, 1.9 mmol) and trifluoroacetic acid (0.17 mL, 2.3 mmol) were added. After stirring at 25° C. for overnight, TLC analysis indicated that the reaction was about 50% complete. To the reaction mixture was added triethylsilane (0.30 mL, 1.9 mmol), and trifluoroacetic acid (0.17 mL, 2.3 mmol). The mixture was allowed to stir for another 48 hours at 25° C. and the solvent, excess triethylsilane and trifluoroacetic acid were removed by evaporation. Ethyl acetate was added and washed with saturated sodium bicarbonate. The organic layer was dried over magnesium sulfate, filtered and concentrated at reduced pressure to afford a brown oil. Purification of 80 mg of the crude material was carried out using preparatory chromatography (50% ethyl acetate in hexanes) to afford the compound as an off-white solid (P-0013, 10 mg, 0.025 mmol). MS (ESI) [M+H+]+=397.2.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[C:17](OC(=O)C)(=[O:19])[CH3:18]>C(OC(C)C)(=O)C.O>[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH:10][C:17](=[O:19])[CH3:18])=[CH:5][CH:4]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(NN)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)C
Solvent: O
Product: CC(=O)NNc1ccc(C)cc1
Temperature: 57.5 °C

Procedure:
104.8 g of 1-(4-methylphenyl)hydrazine hydrochloride are suspended in 525 ml of isopropyl acetate, a solution of 104.8 g of potassium carbonate in 300 ml of water is added and then the mixture is stirred until the solid has disappeared. 77.4 g of acetic anhydride are added while maintaining the temperature below 20° C. and then the mixture is left stirring at 20° C. A precipitate is observed to form, which precipitate disappears when the mixture is heated at approximately 55-60° C. The organic phase is washed twice with 200 ml of water and is then cooled at 0-5° C. overnight. The product formed is recovered by filtration and is then washed twice with 100 ml of MTBE.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:40])[C:16]([N:18]2[CH2:31][CH2:30][C@:21]3([NH:25][C@@H:24]([C:26]([O:28]C)=O)[CH2:23][CH2:22]3)[CH2:20][C@@H:19]2[C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=2[CH3:39])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CO.[NH3:45]>>[F:10][C:9]([F:12])([F:11])[C:7]1[CH:6]=[C:5]([C@H:13]([N:15]([CH3:40])[C:16]([N:18]2[CH2:31][CH2:30][C@:21]3([NH:25][C@@H:24]([C:26]([NH2:45])=[O:28])[CH2:23][CH2:22]3)[CH2:20][C@@H:19]2[C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=2[CH3:39])=[O:17])[CH3:14])[CH:4]=[C:3]([C:2]([F:1])([F:41])[F:42])[CH:8]=1
Reactant: N
Reactant: COC(=O)[C@H]1CC[C@@]2(CCN(C(=O)N(C)[C@H](C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H](c3ccc(F)cc3C)C2)N1
Solvent: CO
Product: Cc1cc(F)ccc1[C@H]1C[C@]2(CC[C@H](C(N)=O)N2)CCN1C(=O)N(C)[C@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
In a sealed tube a solution of Methyl (2R,5S,7R)-8-{[{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-7-(4-fluoro-2-methylphenyl)-1,8-diazaspiro[4.5]decane-2-carboxylate (Intermediate 12, 21.6 mg, 0.036 mmol) in 7N Ammonia in MeOH (5 mL, 35.0 mmol) was stirred at 25° C. for 1 day. The solvent was evaporated to dryness and the crude was purified by silica cartridge (2 g) (at first EtOAc and then 97.5:2.5 DCM/0.5 M NH3 in MeOH) to give 17.8 mg of the title compound as a white foam. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.00 (s, 1H) 7.70 (s, 2 H) 7.28 (d, 1H) 7.15 (dd, 1H) 7.03 (d, 1H) 6.92 (dd, 1H) 6.78 (t, 1H) 5.31 (q, 1H) 4.14 (dd, 1H) 3.47 (t, 1H) 3.27-3.38 (m, 1H) 2.75 (s, 3H) 2.76 (t, 1H) 2.32 (s, 3H) 2.05-2.15 (m, 1H) 1.68-1.85 (m, 3H) 1.52-1.68 (m, 3H) 1.47 (d, 3H) 1.39-1.54 (m, 1H).
Reaction SMILES: [C:1]([CH2:3][CH:4]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[O:9][CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5]1)#[N:2].Cl.C(O)C>C(OCC)(=O)C>[ClH:17].[Cl:18][C:13]1[CH:12]=[C:11]([CH:10]2[O:9][CH2:8][CH2:7][NH:6][CH2:5][CH:4]2[CH2:3][C:1]#[N:2])[CH:16]=[CH:15][C:14]=1[Cl:17]
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(CC#N)C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: N#CCC1CNCCOC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 171.5 %

Procedure:
To a solution of tert-butyl (6RS,7RS)-6-(cyanomethyl)-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (88 mg) in ethyl acetate (0.5 mL) was added 2 N hydrogen chloride-ethanol solution (3 ml), and the mixture was stirred at room temperature for 18 hr. The reaction mixture was crystallized from ethyl acetate and diisopropyl ether to give the title compound (63 mg).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[O:13]1[C:17]2([CH2:22][CH2:21][CH:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:19][CH2:18]2)[O:16][CH2:15][CH2:14]1.Cl[C:29]([O:31][CH2:32][CH3:33])=[O:30]>O1CCCC1>[O:13]1[C:17]2([CH2:22][CH2:21][C:20]([C:29]([O:31][CH2:32][CH3:33])=[O:30])([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:19][CH2:18]2)[O:16][CH2:15][CH2:14]1
Reactant: CCOC(=O)Cl
Reactant: CCOC(=O)C1CCC2(CC1)OCCO2
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C1(C(=O)OCC)CCC2(CC1)OCCO2
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A 500 mL round-bottomed flask was charged with diisopropylamine (16 mL) and tetrahydrofuran (311 mL). The solution was cooled to −78° C. under N2 and n-BuLi (2.5 M in hexanes, 44.8 mL)) was added. The reaction was stirred for 30 minutes at −78° C. and ethyl 1,4-dioxaspiro[4.5]decane-8-carboxylate (20 g) was added as a tetrahydrofuran solution (ca. 10 mL). The solution was stirred at −78° C. for 1 hour and ethyl chloroformate (9 mL) was added neat. After stirring at −78° C. for 10 minutes, the reaction was warmed to room temperature over 2 hours. The reaction was quenched with saturated aqueous NH4Cl and was diluted with diethyl ether. The layers were separated, the aqueous layer was extracted with diethyl ether and the combined organics were dried (Na2SO4), filtered and concentrated by rotary evaporation. The residue was purified by regular phase flash column chromatography (Analogix, 0-65% hexanes/ethyl acetate).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13]([C:14]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])=[O:15])=[CH:12][C:11]([C:26]([F:29])([F:28])[F:27])=[N:10]2)[CH:6]=[CH:7][CH:8]=1.[CH3:30][N:31]([CH2:39][CH:40]=O)[C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH3:25][O:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][NH:16][C:14]([C:13]1[N:9]([C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[CH2:2][NH:1][CH2:40][CH2:39][N:31]([CH3:30])[C:32](=[O:38])[O:33][C:34]([CH3:36])([CH3:35])[CH3:37])[N:10]=[C:11]([C:26]([F:28])([F:29])[F:27])[CH:12]=1)=[O:15]
Reactant: CN(CC=O)C(=O)OC(C)(C)C
Reactant: COc1ccccc1CNC(=O)c1cc(C(F)(F)F)nn1-c1cccc(CN)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccccc1CNC(=O)c1cc(C(F)(F)F)nn1-c1cccc(CNCCN(C)C(=O)OC(C)(C)C)c1
Reaction time: 0.5 h
Yield: 37.4 %

Procedure:
To a stirred solution of 58 (200 mg, 0.386 mmol) in MeOH (2.0 mL) was added tert-butyl methyl(2-oxoethyl)carbamate (100 mg, 0.579 mmol) followed by acetic acid (44.2 μl, 0.772 mmol). After stirring for 30 min, sodium cyanoborohydride (61 mg, 0.964 mmol) was added and the resulting solution was allowed to stir at 21° C. for 16 h. The solvent was removed by evaporation and the residue taken in saturated NaHCO3. It was then extracted three times with CH2Cl2, dried over Na2SO4 and evaporated. The residue was purified via silica gel flash chromatography (40% to 100% EtOAc/hexanes). The title product 59 (81 mg, 37% yield) was isolated as a yellow solid. LRMS (ESI): calc. 561.6; found 562.7 (MH)+.
Reaction SMILES: [N:1]1([C:13]2C=CC(C(Cl)=O)=C[CH:14]=2)[C:5]2C3C(C[C:4]=2C=N1)=CC=CC=3.[NH:22]1[C:26]2[C:27]3[C:32]([CH2:33][C:25]=2[C:24]([C:34]2[CH:42]=[CH:41][C:37]([C:38]([OH:40])=[O:39])=[CH:36][CH:35]=2)=[N:23]1)=[CH:31][CH:30]=[CH:29][CH:28]=3.[C:43](Cl)(=[O:47])[C:44](Cl)=O>ClCCl.CN(C=O)C>[NH:22]1[C:26]2[C:27]3[C:32]([CH2:33][C:25]=2[C:24]([C:34]2[CH:42]=[CH:41][C:37]([C:38]([O:40][CH2:4][CH2:5][N:1]4[CH2:44][CH2:43][O:47][CH2:14][CH2:13]4)=[O:39])=[CH:36][CH:35]=2)=[N:23]1)=[CH:31][CH:30]=[CH:29][CH:28]=3
Reactant: O=C(Cl)c1ccc(-n2ncc3c2-c2ccccc2C3)cc1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(-c2n[nH]c3c2Cc2ccccc2-3)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(OCCN1CCOCC1)c1ccc(-c2n[nH]c3c2Cc2ccccc2-3)cc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A mixture of 4-(1,4-dihydroindeno[1,2-c]pyrazol-yl)benzoyl chloride [(500 mg) prepared by reaction of the product of Example 8 (1.45 g) with oxalyl chloride (1.5 ml) in dichloromethane (100 ml) and DMF (8 drops) followed by evaporation of the solvent], dichloromethane (50 ml), 2-morpholinoethanol (0.22 ml) and triethylamine (0.5 ml) was stirred at ambient temperature for 3.5 hours. The mixture was washed with water then with saturated sodium bicarbonate solution, then dried, filtered and evaporated to give an oil which was purified by flash column chromatography on silica using dichloromethane/IMS (10:1) as the mobile phase to give an oil which was purified again by flash column chromatography using dichloromethane/IMS (25:1) as the mobile phase to give the product 2-morpholinoethyl 4-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)- benzoate as a solid, m.p. 168-172° C.