Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[CH2:2]([CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=2)[CH2:12][CH2:11][C:10]1=[N+]1CCCC1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CC(O)=[O:28]>C(Cl)Cl.O.CO>[CH2:2]([CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=2)[CH2:12][CH2:11][C:10]1=[O:28])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(=O)O
Reactant: COc1ccc2c(c1)C(Cc1ccccc1)C(=[N+]1CCCC1)CC2
Agent: [Br-]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: COc1ccc2c(c1)C(Cc1ccccc1)C(=O)CC2
Yield: 53 %

Procedure:
A solution of 1-(1-benzyl-7-methoxy-3,4-dihydro-1H-naphthalen-2-ylidene)-pyrrolidinium bromide and AcOH (300 mL) in DCM (500 mL), H2O (3000 mL) and MeOH (500 mL) was stirred at reflux for 10 hrs. The aqueous layer was washed with DCM (1000 mL), and the combined organic layers were washed with water, dried over Na2SO4 and concentrated to give crude product, purified by silica gel chromatography to give 1-benzyl-7-methoxy-3,4-dihydro-1H-naphthalen-2-one (195 g, yield 53%) as yellow solid.
Reaction SMILES: C([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH:10]([N:21]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[C:26]([F:34])[CH:25]=2)[CH3:22])[CH2:9]1)C1C=CC=CC=1.ClC(OCC(Cl)(Cl)Cl)=O>CC#N>[Cl:20][C:15]1[CH:14]=[C:13]([CH:11]2[CH2:12][NH:8][CH2:9][CH:10]2[N:21]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:32])([F:33])[F:31])=[C:26]([F:34])[CH:25]=2)[CH3:22])[CH:18]=[CH:17][C:16]=1[Cl:19]
Reactant: CN(Cc1ccc(C(F)(F)F)c(F)c1)C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Agent: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: CC#N
Product: CN(Cc1ccc(C(F)(F)F)c(F)c1)C1CNCC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.6 %

Procedure:
To a stirred solution of [(3RS,4SR)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-(3-fluoro-4trifluoromethyl-benzyl)-methyl-amine (3.30 g, 6.45 mmol) in CH3CN (45 ml) at RT, was added 2,2,2-trichloroethyl chloroformate (1.30 ml, 9.67 mmol). The reaction mixture was stirred at RT for 3 hours, concentrated under vacuo. The residue was dissolved in AcOH (10 ml) and zinc dust (1.0 g) was added portion wise over 3 hours. The solvent was evaporated, the residue diluted in EtOAc and the organic phase was washed with an aqueous solution of NaHCO3. The organic phase was dried over Na2SO4, concentrated under vacuo to afford 1.43 g (53%) of the tile compound as a colorless oil. ES-MS m/e: 421.0 (M+H+).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([NH:7][C:8]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:6].[H-].[Na+]>C1COCC1>[C:14]1([C:8]2([N:7]3[CH2:2][CH2:3][CH2:4][C:5]3=[O:6])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(CCCCl)NC1(c2ccccc2)CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1CCCN1C1(c2ccccc2)CCCCC1
Temperature: 70 °C
Yield: 124.1 %

Procedure:
Dissolve 4-chloro-N-(1-phenyl-cyclohexyl)-butyramide (Preparation 29) (0.15 g, 0.53 mmol) in THF (20 mL) and add NaH (0.21 g, 5.29 mmol. 65% wt). Stir and heat the reaction mixture to 70° C. under nitrogen. Continue to heat the reaction at 70° C. for over night then cool it to room temperature. Add water (20 mL), and extract the aqueous layer with dichloromethane (3×50 mL). Combine the organic layers and dry with Na2SO4, filter, concentrate and purify by flash column chromatography (silica gel, 10-40% of EtOAc/Hexane) to give 0.16 g (89%) of the title compound as a colorless oil: Mass spectrum (ion spray): m/z=243.9 (M+).
Reaction SMILES: [C:1]1([CH:7]([C:9]2[CH:10]=[N:11][C:12]3[C:17]([C:18]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:16][CH:15]=[CH:14][C:13]=3[C:25]([F:28])([F:27])[F:26])[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:36](Cl)(=[O:38])[CH3:37]>C(Cl)Cl>[C:36]([O:8][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:25]([F:28])([F:26])[F:27])(=[O:38])[CH3:37]
Reactant: CC(=O)Cl
Reactant: OC(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OC(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1ccccc1
Reaction time: 2 h
Yield: 79.1 %

Procedure:
Phenyl[4-phenyl-8-(trifluoromethyl)quinolin-3-yl]methanol (Example 34, 0.050 g, 0.132 mmol) was taken into CH2Cl2 (3 mL). Next, triethylamine (0.1 mL, 0.70 mmol) was added followed by acetyl chloride (0.05 mL, 0.70 mmol). The reaction was allowed to stir for 2 hours. The solvent was removed and the resulting material was taken up into an Ether/water/5% HCl solution. The layers were separated and the organic layer was washed once more with 5% HCl, dried over magnesium sulfate and concentrated. The product was purified via column chromatography using 7% ethyl acetate in hexane as the eluent to afford the product as a white solid (0.044 g, 79.4%). MS (ESI) m/z 422 ([M+H]+); Anal. Calcd. for C25H18F3NO2: C, 71.25; H, 4.31; N, 3.32. Found: C, 71.15; H, 4.11; N, 3.21.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:10]=[C:11]([CH:21]=[CH:22][CH:23]=2)[CH2:12]P(=O)(OCC)OCC)=[N:6][CH:7]=1.[H-].[Na+].[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][C:36](=O)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].O>C1COCC1.O1CCOCCOCCOCCOCC1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:10]=[C:11]([CH:21]=[CH:22][CH:23]=2)[CH:12]=[C:36]2[CH2:37][CH2:38][N:33]([C:31]([O:30][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:32])[CH2:34][CH2:35]2)=[N:6][CH:7]=1
Reactant: CCOP(=O)(Cc1cccc(Oc2ccc(C)cn2)c1)OCC
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(Oc2cccc(C=C3CCN(C(=O)OC(C)(C)C)CC3)c2)nc1
Reaction time: 0.5 h
Yield: 62.4 %

Procedure:
Diethyl 3-(5-methylpyridin-2-yloxy)benzylphosphonate (1.75 g, 5.22 mmol) from Step 3 and 1,4,7,10,13-pentaoxacyclopentadecane (15-Crown-5, 0.02 mL, 0.10 mmol) were combined in THF (5 mL). Sodium hydride (230 mg, 60% dispersion in mineral oil, 5.74 mmol) was added. The reaction was stirred for 30 min and then a solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (1.14 g, 5.74 mmol) in THF (5 mL) was added. After 16 h, water was added and the layers were separated. The aqueous layer was extracted with EtOAc (2×200 mL) and the combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-30%, EtOAc:heptane) to afford the title compound (1.24 g, 62% yield) as a thick oil.
Reaction SMILES: C([O:8][N:9]1[C:46](=[O:47])[CH:45]=[C:12]2[N:13]([CH:42]3[CH2:44][CH2:43]3)[C:14]3[CH:19]=[C:18]([N:20]4[CH2:25][CH2:24][N:23]([C:26]([C@@H:28]([NH:30]C(=O)OCC5C=CC=CC=5)[CH3:29])=[O:27])[CH2:22][CH2:21]4)[C:17]([F:41])=[CH:16][C:15]=3[N:11]2[C:10]1=[O:48])C1C=CC=CC=1>CN(C=O)C.[Pd]>[NH2:30][C@H:28]([C:26]([N:23]1[CH2:22][CH2:21][N:20]([C:18]2[C:17]([F:41])=[CH:16][C:15]3[N:11]4[C:10](=[O:48])[N:9]([OH:8])[C:46](=[O:47])[CH:45]=[C:12]4[N:13]([CH:42]4[CH2:44][CH2:43]4)[C:14]=3[CH:19]=2)[CH2:25][CH2:24]1)=[O:27])[CH3:29]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCN(c2cc3c(cc2F)n2c(=O)n(OCc4ccccc4)c(=O)cc2n3C2CC2)CC1
Agent: [Pd]
Solvent: CN(C)C=O
Product: C[C@H](N)C(=O)N1CCN(c2cc3c(cc2F)n2c(=O)n(O)c(=O)cc2n3C2CC2)CC1
Yield: 74.2 %

Procedure:
Benzyl [(S)-1-[[4-[2-(benzyloxy)-5-cyclopropyl-8-fluoro-1,2,3,5-tetrahydro-1,3-dioxopyrimido[1,6-a]benzimidazol-7-yl]-1-piperazinyl]carbonyl]ethyl]carbamate (127 mg, 0.194 mmol) is dissolved in DMF (15 ml) and hydrogenated over 5 percent Pd/C. After completion of the reduction the catalyst is filtered off and the filtrate is evaporated. The residue is taken up in methanol (50 ml) and treated with active charcoal. After filtering off the charcoal the filtrate is concentrated to a volume of 25 ml. The separated crystals are filtered off. There are obtained 62 mg (84%) of 7-(4-L-alanyl-1-piperazinyl)-5-cyclopropyl-8-fluoro-2-hydroxypyrimido[1,6-a]benzimidazole-1,3(2H,5H)-dione.
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([C:16]2[O:20][C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=3)=[N:18][C:17]=2[CH:32]([CH3:34])[CH3:33])[CH3:15])=[CH:8][C:7]=1[CH3:35].[OH-].[Na+].Cl>CO.C1COCC1>[CH:32]([C:17]1[N:18]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]([F:30])([F:31])[F:29])=[CH:23][CH:22]=2)[O:20][C:16]=1[CH:14]([CH3:15])[CH2:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:36])=[O:2])=[C:7]([CH3:35])[CH:8]=1)([CH3:33])[CH3:34]
Reactant: COC(=O)CCc1ccc(OCC(C)c2oc(-c3ccc(OC(F)(F)F)cc3)nc2C(C)C)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(OCC(C)c2oc(-c3ccc(OC(F)(F)F)cc3)nc2C(C)C)ccc1CCC(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 86.9 %

Procedure:
A solution of 3-(4-{2-[4-isopropyl-2-(4-trifluoromethoxy-phenyl)-oxazol-5-yl]-propoxy}-2-methyl-phenyl)-propionic acid methyl ester (239 mg, 0.473) in MeOH (1.0 mL) and THF (0.5 mL) is treated with NaOH (1.5 mL, 2.0 M) and stirred at room temperature for 12 hours. The mixture is neutralized to pH=4 with HCl (5 N) and extracted with EtOAc (20 mL×2), and the combined organics are dried (Na2SO4), concentrated and purified on silica gel chromatography column with EtOAc/Hexanes (50/50) to yield the acid as white solid (202 mg, 87%). MS (ES): 492.2; the structure is also confirmed by proton NMR.
Reaction SMILES: [CH3:1]N(C)C=O.[H-].[Na+].[Cl:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][N:17]=2)[CH:12]=[CH:11][C:10]=1[NH:30][C:31](=[O:41])[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[Cl:40].CI>O>[Cl:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][N:17]=2)[CH:12]=[CH:11][C:10]=1[N:30]([CH3:1])[C:31](=[O:41])[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[Cl:40]
Reactant: COc1cc2ncnc(Oc3ccc(NC(=O)OCc4ccccc4Cl)c(Cl)c3)c2cc1OC
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: COc1cc2ncnc(Oc3ccc(N(C)C(=O)OCc4ccccc4Cl)c(Cl)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 85 %

Procedure:
Dimethylformamide (5 ml) was added to sodium hydride (11 mg), and 2-chlorobenzyl N-{2-chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]phenyl}carbamate (65 mg) was added to the mixture. Subsequently, a dimethylformamide solution (2 ml) of methyl iodide (77 mg) was added thereto, and the mixture was stirred at room temperature for 10 min. Water was added to stop the reaction, and the reaction solution was then extracted with ethyl acetate, followed by washing with water and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (57 mg, yield 85%).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:17])[C:14]([OH:16])=O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1>C(OCC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([C:13](=[O:17])[C:14]([NH:26][C:25]3[CH:27]=[CH:28][C:22]([O:21][CH3:20])=[CH:23][CH:24]=3)=[O:16])[CH2:11][CH2:12]2)=[CH:18][CH:19]=1
Reactant: COc1ccc(N)cc1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccc(F)cc2)CC1
Solvent: CCOCC
Product: COc1ccc(NC(=O)C(=O)N2CCC(Cc3ccc(F)cc3)CC2)cc1

Procedure:
The title compound is prepared from [4-(4-fluoro-benzyl)-piperidin-1-yl]-oxo-acetic acid (Example 1b) and 4-methoxy-aniline (Aldrich) according to the method described in Example 94. Melting Point: 105-107° C. (diethylether
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6](=[O:18])[C:7]1[CH:12]=[C:11]([F:13])[C:10]([F:14])=[C:9]([O:15][CH3:16])[C:8]=1[F:17])[CH3:2].[CH:20]([O-])([O-])[O:21][CH2:22][CH3:23].C(OC(=O)C)(=O)C>>[CH3:16][O:15][C:9]1[C:8]([F:17])=[C:7]([CH:12]=[C:11]([F:13])[C:10]=1[F:14])[C:6]([C:5](=[CH:20][O:21][CH2:22][CH3:23])[C:4]([O:3][CH2:1][CH3:2])=[O:19])=[O:18]
Reactant: CCOC([O-])[O-]
Reactant: CCOC(=O)CC(=O)c1cc(F)c(F)c(OC)c1F
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(OC)c1F
Temperature: 110 °C
Reaction time: 12 h
Yield: 98.6 %

Procedure:
A mixture of ethyl-3-methoxy-2,4,5-trifluorobenzoylacetate (500 mg, 1.8 mmol), ethyl orthoformate (0.45 mL, 2.72 mmol) and acetic anhydride (460 mg, 4.5 mmol, 2.5 eq) was stirred at 110° C. for 12 hours and the excess reagents were removed by distillation under high vacuum (0.1 mmHg) to give 590 mg of a yellow-orange oil. This material was used directly in the next step without further purification or characterization.
Reaction SMILES: [CH:1]12[CH2:9][CH:4]([CH2:5][C:6]1=NO)[C:3]1[CH:10]=[CH:11][CH:12]=[CH:13][C:2]2=1.[Na].[OH2:15]>C(O)C.C(Cl)(Cl)Cl>[CH:1]12[CH2:9][CH:4]([CH2:5][C:6]1=[O:15])[C:3]1[CH:10]=[CH:11][CH:12]=[CH:13][C:2]2=1
Reactant: ON=C1CC2CC1c1ccccc12
Reactant: O
Agent: [Na]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: O=C1CC2CC1c1ccccc12
Temperature: 25 °C

Procedure:
A solution of benzonorbornen-2-one oxime (2g.) in absolute ethanol (120ml.) was heated to reflux under nitrogen and sodium metal (12 g.) was added in small portions with continuous stirring. The reaction mixture was then refluxed for 30 minutes. This viscous suspension was then cooled to room temperature, 100 ml. of water added and the reaction mixture agitated until a clear solution was obtained. This was extracted with ether and the ether extract worked up to give an oil which was dissolved in chloroform and extracted with 10% HCl solution. Removal of water and excess HCl under vacuum from this extract gave a white solid (1g., 40%). The white solid was analyzed by infra-red, nuclear magnetic resonance and elemental analysis techniques and was determined to be the 1,2,3,4-tetrahydro-1,4-methanonaphthalen-endo-2-amine hydrochloride, C11H14NCl (m.p. 230°-231°C). Basification of a sample of this material with 10% NaOH gave, on ether extraction, the required amine as a pale yellow oil which was also analyzed by infra-red, and nuclear magnetic resonance techniques, and the empirical formula was determined to be C11H13N.
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[C:34]([O:37][CH2:38][C:39](Cl)=[O:40])(=[O:36])[CH3:35]>CC#N>[C:34]([O:37][CH2:38][C:39](=[O:40])[NH:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24])(=[O:36])[CH3:35]
Reactant: CC(=O)OCC(=O)Cl
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(=O)OCC(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.33 h
Yield: 75.4 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.62 g, 4.08 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.600 g, 1.85 mmol) in CH3CN (50 ml). After stirring for 20 min, acetoxyacetyl chloride (0.28 g, 2.03 mmol) was added. The mixture was stirred at room temperature for 17 hours. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 (70 ml). The CH2Cl2 solution was washed with 1N HCl (30 ml), H2O (30 ml), brine (30 ml) and dried (MgSO4). The solvent was removed in vacuo and the residue was purified by chromatography (SiO2, CH2Cl2:CH3OH 100:2.5) to give (N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}carbamoyl)methyl acetate (0.54 g, 75%) as a white solid: mp 108-110° C.; 1H NMR (DMSO-d6) δ d 11.14 (s, 1H), 8.68 (t, J=6.0 Hz, 1H), 7.87-7.79 (m, 2H), 7.71-7.65 (m, 1H), 5.19-5.12 (dd, J=5.3 and 12.4 Hz, 1H), 4.77 (d, J=5.9 Hz, 2H), 4.56 (s, 2H), 2.96-2.83 (m, 1H), 2.63-2.47 (m, 2H), 2.11 (s, 3H), 2.08-1.98 (m, 1H); 13C NMR (DMSO-d6) δ d 172.66, 169.96, 169.72, 167.46, 167.37, 166.36, 138.80, 134.68, 133.01, 132.47, 127.04, 121.87, 62.36, 48.84, 37.46, 30.38, 21.93, 20.49; Anal. Calcd. For C18H17N3O7+0.15H2O: C, 55.43; H, 4.47; N, 10.77. Found: C, 55.43; H, 4.54; N, 10.44.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[NH:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(=O)(O)[O-].[Na+].Br[CH2:26][C:27](=[O:32])[C:28]([F:31])([F:30])[F:29]>C(O)(C)C>[OH:32][C:27]1([C:28]([F:31])([F:30])[F:29])[CH2:26][N:11]([C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][CH:9]=2)[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:13]1
Reactant: O=C(CBr)C(F)(F)F
Reactant: CS(=O)(=O)c1ccc(NC(=N)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CS(=O)(=O)c1ccc(N2CC(O)(C(F)(F)F)N=C2c2ccccc2)cc1

Procedure:
To a mixture of N-[4-(methylsulfonyl)phenyl]benzenecarboximidamide (Step 1) (10 mmol) and sodium bicarbonate (20 mmol) in isopropanol (100 mL), 3-bromo-1,1,1-trifluoroacetone (20 mmol) is added. After heating the reaction mixture at 70°-75° C. for 20 hours, the solvent is removed. The residue is redissolved in methylene chloride and washed with water. The organic fractions are combined, dried over sodium sulfate, filtered and concentrated in vacuo. The crude mixture is chromatographed (silica gel, toluene/ethyl acetate, 7/3) to give 4-hydroxy-1-[4-(methylsulfonyl)phenyl]-2-phenyl -4-trifluoromethyl-4,5-dihydro-1H-imidazole.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:13]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[N:8]=[C:7]2[C:32]#[C:33][Si](C)(C)C)([O-:3])=[O:2].[F-].C([NH+](CCCC)CCCC)CCC>C1COCC1>[C:32]([C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:9]([C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:8]=1)#[CH:33]
Reactant: C[Si](C)(C)C#Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccc([N+](=O)[O-])cc12
Agent: CCCC[NH+](CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.1 %

Procedure:
To a solution of 5-nitro-3-trimethylsilanylethynyl-1-trityl-1H-indazole (700 mg, 1.4 mmol) in THF (5 mL) was added tributylammonium fluoride (1M, 2.8 mL, 2.8 mmol). The resulted solution was stirred at room temperature for 2 hours. TLC showed the completion of reaction. After removal the solvent under vacuum, the product was purified using silica (20 hexane in dichloromethane) to give 560 mg of titled product (93% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([NH:13][CH:14]2[CH2:17]C[CH2:15]2)[C:5]([C:6]([O:8]CC)=O)=[CH:4][N:3]=1.C(Cl)(=O)C(Cl)=O.[NH2:24][CH:25]([C:31](=[O:33])[CH3:32])[C:26]([O:28][CH2:29][CH3:30])=[O:27].CN1CCOCC1>C(Cl)Cl.CN(C=O)C.C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:12]=[C:11]([NH:13][CH:14]([CH3:15])[CH3:17])[C:5]([C:6]([NH:24][CH:25]([C:31](=[O:33])[CH3:32])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:8])=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cnc(Cl)cc1NC1CCC1
Reactant: CCOC(=O)C(N)C(C)=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C(NC(=O)c1cnc(Cl)cc1NC(C)C)C(C)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred solution of 6-chloro-4-(isopropylamino)nicotinic acid (2) in DCM (15 mL) was cooled to 0° C., oxalyl chloride (2 equiv) was added, followed by addition of 2 drops of DMF. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated to remove excess of oxalyl chloride. The acyl chloride, generated in-situ was dissolved in THF and added dropwise to a cool, stirred solution of ethyl 2-amino-3-oxobutanoate (1.1 equiv.) and NMM (5 equiv.) in THF. The reaction temperature was slowly brought to room temperature and stirred overnight. The reaction mixture was diluted with EtOAc and washed with water, followed by brine solution. The EtOAc layer was collected, dried over Na2SO4, filtered and concentrated. The crude material obtained was purified by column chromatography through silica gel and EtOAc: Pet. Ether as eluent to afford the title compound, ethyl 2-(6-chloro-4-(isopropylamino)nicotinamido)-3-oxobutanoate.
Reaction SMILES: C1(C)C=C(C)C=C(C)C=1S(O[NH2:13])(=O)=O.[C:15]([NH:34][C:35]1[S:36][CH:37]=[C:38]([C:40](=[N:44][O:45][CH3:46])[C:41]([OH:43])=[O:42])[N:39]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(Cl)Cl>[C:15]([N:34]=[C:35]1[N:39]([NH2:13])[C:38]([C:40](=[N:44][O:45][CH3:46])[C:41]([OH:43])=[O:42])=[CH:37][S:36]1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CON=C(C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Solvent: ClCCl
Product: CON=C(C(=O)O)c1csc(=NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1N

Procedure:
O-mesitylenesulfonylhydroxylamine (1.3 g.) was added at room temperature to a stirred suspension of 2-(2-tritylamino-4-thiazolyl)-2-methoxyimino acetic acid (2.15 g) in methylene chloride (40 ml), thus giving in a few minutes the complete dissolution of the reaction mixture. Stirring was maintained for 18 hours, during which time the mesitylenesulfonic salt of the title compound slowly separates as a white solid. The product was filtered and washed with ethyl ether, thus giving 2.98 g (92%) of 2-(2-tritylimino-3-amino-4-thiazolinyl)-2-methoxyimino acetic acid, mesitylene sulfonate, m.p.=161°-163° dec.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][O:12][C:11](=[O:14])[N:10]2[C:15]([O:17]C2C=CC([N+]([O-])=O)=CC=2)=O)[CH:5]=[CH:6][C:7]=1[F:8].CO[C:29]1([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:34][CH2:33][CH:32]([NH:35][CH2:36][CH2:37][NH2:38])[C:31](=C=O)[CH2:30]1>ClCCl>[C:41]1([C:29]2([C:11]([O:12][CH3:13])=[O:14])[CH2:30][CH2:31][CH:32]([NH:35][CH2:36][CH2:37][NH:38][C:15]([N:10]3[CH:9]([C:4]4[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=4)[CH2:13][O:12][C:11]3=[O:14])=[O:17])[CH2:33][CH2:34]2)[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: O=C1OCC(c2ccc(F)c(F)c2)N1C(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: COC1(c2ccccc2)CCC(NCCN)C(=C=O)C1
Solvent: ClCCl
Product: COC(=O)C1(c2ccccc2)CCC(NCCNC(=O)N2C(=O)OCC2c2ccc(F)c(F)c2)CC1
Temperature: 25 °C

Procedure:
A mixture of 4-(3,4-difluorophenyl)-3-(4-nitrophenyloxy-carbonyl)-2-oxo-oxazolidine (50 mg, 0.123 mmol) and 2-[4-methoxy-carbonyl-4-phenylcyclohex-1-yl]aminoethylamine (75 mg) in dichloromethane (6 mL) was stirred at room temperature and the product formed was purified by preparative TLC on silica gel using ethyl acetate as the eluent. There were two bands for the two isomers, the higher band was the minor product (1H-NMR confirmed it to be the cis isomer with respect to methoxycarbonyl and amine groups) and the lower band was the major product (1H-NMR confirmed it to be the trans isomer with respect to methoxycarbonyl and amine groups). The HCl salt was made by treatment with 1N HCl in ether.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:15])[CH:5]=[C:6]([F:14])[C:7]=1[N:8]1[CH2:13][CH:12]2[CH:10]([O:11]2)[CH2:9]1.N1C=CC=CC=1.Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>ClCCl>[CH2:26]([O:25][C:23](=[O:24])[NH:15][C:4]1[CH:5]=[C:6]([F:14])[C:7]([N:8]2[CH2:13][CH:12]3[CH:10]([O:11]3)[CH2:9]2)=[C:2]([F:1])[CH:3]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Nc1cc(F)c(N2CC3OC3C2)c(F)c1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1cc(F)c(N2CC3OC3C2)c(F)c1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3,5-Difluoro-4-(6-oxa-3-aza-bicyclo[3.1.0]hex-3-yl)-phenylamine (0.14 g, 0.66 mmol) was dissolved in dichloromethane (1.0 mL) and pyridine (0.11 mL, 1.32 mmol) and stirred at 0° C. Benzyl chloroformate (0.1 mL, 0.72 mmol) was added and the mixture was stirred at 0° C. for one hour. The reaction mixture was allowed to warm to room temperature, washed with water, brine and dried (MgSO4). The title compound was isolated by silica gel chromatography (0-1% MeOH-DCM) as a pale yellow solid.