Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[C:11]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)([CH3:14])([CH3:13])[CH3:12].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[NH3:8].[C:11]([N:15]1[CH2:20][CH2:19][N:18]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:17][CH2:16]1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)(C)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Product: N
Temperature: 130 °C
Reaction time: 8 h
Yield: 118.5 %

Procedure:
To a solution of 1-fluoro-4-nitro-benzene (314 mg, 2.23 mmol) and 4-tert-butyl-piperazine (1 g, 3.34 mmol) in dioxane (15 mL) is added K2CO3 (1.65 mg, 11.9 mmol) and the reaction is stirred at 130° C. overnight. The solvent is evaporated under vacuum and the residue is partitioned between ethyl acetate and water. The organic layer is washed with brine, dried over MgSO4, filtered and concentrated to give a crude compound. Purification by silica gel column chromatography eluting with DCM followed by 99:1 DCM:NH3 (7M in MeOH) affords the title compound (348 mg, 55.4%). LCMS: Rt 3.87 min (99%).
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.[CH3:12][N:13]([CH3:23])[C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17](O)=[O:18]>>[CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]2[C:20]3[C:16](=[CH:15][C:14]([N:13]([CH3:23])[CH3:12])=[CH:22][CH:21]=3)[C:17](=[O:18])[O:8]2)=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: CN(C)c1cccc(C(=O)O)c1
Product: CN(C)c1ccc(C2OC(=O)c3cc(N(C)C)ccc32)cc1

Procedure:
In a second synthetic route to CVL, which is also a multi-step synthesis, 4-dimethylaminobenzaldehyde is reacted with 3-dimethylaminobenzoic acid to obtain 3-(4-dimethylaminophenyl)-6-dimethylaminophthalide in the first step. In a second step, the 3-(4-dimethylaminophenyl)-6-dimethylaminophthalide from step one is interacted with N,N-dimethylaniline in the presence of a Friedel-Crafts type catalyst to obtain 2-[bis(4-dimethylaminophenyl)methyl]-5-dimethylaminobenzoic acid. In a third step, the benzoic acid from step two is oxidized to obtain 3,3-bis(4-dimethylaminophenyl)-6-dimethylaminophthalide.
Reaction SMILES: [N+:1]([C:4]1[S:5][CH:6]=[C:7]2[C:11](=[O:12])[N:10]([CH:13]3[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]3=[O:20])[C:9](=[O:21])[C:8]=12)([O-])=O.[O-]S(S([O-])=O)=O.[Na+].[Na+]>CC(C)=O.O>[NH2:1][C:4]1[S:5][CH:6]=[C:7]2[C:11](=[O:12])[N:10]([CH:13]3[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]3=[O:20])[C:9](=[O:21])[C:8]=12
Reactant: O=C1CCC(N2C(=O)c3csc([N+](=O)[O-])c3C2=O)C(=O)N1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: Nc1scc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Yield: 52 %

Procedure:
0.309 g of 1-nitro-5-(2,6-dioxopiperidin-3-yl)-5H-thieno(3,4-c)pyrrole-4,6-dione was dissolved in 10 mL of acetone, and a solution obtained by dissolving 0.783 g Na2S2O4 in 10 mL water was added. The reaction mixture was refluxed for 2 h, cooled, and 10 mL of water were added. The aqueous phase was extracted with ethyl acetate (3×50 mL). The organic phases were combined, washed with 40 mL of water and 40 mL of brine, dried over anhydrous MgSO4, filtered, evaporated to dryness. The remaining residue was purified on silica gel column chromatography to obtain a solid (0.145 g).
Reaction SMILES: C[N:2]([CH3:15])/[CH:3]=[CH:4]/[C:5]1[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][C:6]=1[C:7]#[N:8].[CH3:16][O:17][C:18]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:19]=1CN.CN1C(=O)N(C)CCC1>CCOC(C)=O.CCCCCC>[CH3:16][O:17][C:18]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:19]=1[CH2:15][N:2]1[CH:3]=[CH:4][C:5]2[C:6](=[CH:9][CH:10]=[C:11]([C:13]#[N:14])[CH:12]=2)[C:7]1=[NH:8]
Reactant: CN(C)/C=C/c1cc(C#N)ccc1C#N
Reactant: COc1ccc(CN)c(OC)c1
Solvent: CCOC(C)=O
Solvent: CN1CCCN(C)C1=O
Solvent: CCCCCC
Product: COc1ccc(Cn2ccc3cc(C#N)ccc3c2=N)c(OC)c1

Procedure:
The product from Example 147 Part A (1.85 g, 9.38 mmol) and 2,4-dimethoxybenzylamine (2.6 mL, 15.03 mmol) were heated with 5 mL of DMPU at 140° C. for 3 h under N2. The reaction mixture was cooled, and EtOAc/hexane (1:2) was added. The precipitate formed was filtered and dried in vacuo to give 2.5 g of the desired product. 1H-NMR (400 MHz, DMSO-d6) δ 3.72 (s, 3H, 3.81 (s, 3H), 4.95 (s, 2H), 6.10 (d, J=7.03 Hz, 1H, 6.44 (d, J=7.91 Hz, 1H), 6.57 (s, 1H), 7.02 (d, J=8.35 Hz, 1H), 7.22 (d, J=6.15 Hz, 1H) 7.68 (d, J=7.91 Hz, 1H), 7.94 (s, 1H), 8.34 (d, J=7.91 Hz, 1H).
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[C:12]([CH:15]=[CH2:16])[CH:11]=[C:10]([C:17]([NH:19][CH2:20][C:21]4[C:22](=[O:29])[NH:23][C:24]([CH3:28])=[CH:25][C:26]=4[CH3:27])=[O:18])[C:9]=3[CH:8]=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C[N+]1([O-])CC[O:34]CC1.[OH2:38]>C(Cl)Cl.O=[Os](=O)(=O)=O>[CH:1]1([N:6]2[C:14]3[CH:13]=[C:12]([CH:15]([OH:34])[CH2:16][OH:38])[CH:11]=[C:10]([C:17]([NH:19][CH2:20][C:21]4[C:22](=[O:29])[NH:23][C:24]([CH3:28])=[CH:25][C:26]=4[CH3:27])=[O:18])[C:9]=3[CH:8]=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=Cc1cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c2cnn(C3CCCC3)c2c1
Reactant: O
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2cc(C(O)CO)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.3 %

Procedure:
To a stirred solution of 1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-vinyl-1H-indazole-4-carboxamide (0.9 g, 2.3 mmol) in DCM (10 mL), was added N-methylmorpholine-N-oxide (0.81 g, 6.92 mmol) at 0° C., OsO4 (0.147 g, 0.576 mmol, 2.5% solution in t-BuOH) was then added. The resulting solution was stirred at room temperature for 1 h. After completion of reaction, water was added and extraction carried out using 10% MeOH/DCM. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to give title compound 1-cyclopentyl-6-(1,2-dihydroxyethyl)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indazole-4-carboxamide (0.6 g, 61.3%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[CH:3]([C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)[OH:4].[CH2:13]([Si:15](Cl)([CH2:18][CH3:19])[CH2:16][CH3:17])[CH3:14].[Cl-].[NH4+]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[F:12][C:2]([F:1])([F:11])[CH:3]([C:5]1[CH:6]=[CH:7][N:8]=[CH:9][CH:10]=1)[O:4][Si:15]([CH2:18][CH3:19])([CH2:16][CH3:17])[CH2:13][CH3:14]
Reactant: OC(c1ccncc1)C(F)(F)F
Reactant: CC[Si](Cl)(CC)CC
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Product: CC[Si](CC)(CC)OC(c1ccncc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.3 %

Procedure:
To 20 ml of pyridine were added 3.4 g of 2,2,2-trifluoro-1-pyridin-4-yl-ethanol and 1.17 g of 4-dimethylaminopyridine, and 3.76 g of triethylsilyl chloride was added at 0° C. After stirring at room temperature for 4 hours, the mixture was poured into an aqueous saturated ammonium chloride solution, followed by extraction with t-butyl methyl ether three times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 5.5 g of 4-[2,2,2-trifluoro-1-(triethylsilyloxy)ethyl]pyridine.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:14]3[CH:15]=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=3)=[CH:8][C:9]=2[C:11]([OH:13])=O)[C:4]([CH:21]([CH3:23])[CH3:22])=[CH:3]1.[NH2:24][CH2:25][C:26]1[C:27](=[O:34])[NH:28][C:29]([CH3:33])=[CH:30][C:31]=1[CH3:32].ON1C2N=CC=CC=2N=N1.C(Cl)CCl.CN1CCOCC1>CS(C)=O>[CH3:32][C:31]1[CH:30]=[C:29]([CH3:33])[NH:28][C:27](=[O:34])[C:26]=1[CH2:25][NH:24][C:11]([C:9]1[CH:8]=[C:7]([C:14]2[CH:15]=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=2)[CH:6]=[C:5]2[C:10]=1[N:2]([CH3:1])[CH:3]=[C:4]2[CH:21]([CH3:22])[CH3:23])=[O:13]
Reactant: Cc1ccc(-c2cc(C(=O)O)c3c(c2)c(C(C)C)cn3C)cn1
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Agent: On1nnc2cccnc21
Solvent: CS(C)=O
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: Cc1ccc(-c2cc(C(=O)NCc3c(C)cc(C)[nH]c3=O)c3c(c2)c(C(C)C)cn3C)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.4 %

Procedure:
To a 20 mL vial was added 1-methyl-3-(1-methylethyl)-5-(6-methyl-3-pyridinyl)-1H-indole-7-carboxylic acid (0.10 g, 0.324 mmol), 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (0.098 g, 0.519 mmol), 1-hydroxy-7-azabenzotriazole (0.088 g, 0.649 mmol) and EDC (0.124 g, 0.649 mmol). The reagents were diluted with DMSO (3 mL) and N-methylmorpholine (0.178 mL, 1.621 mmol). The mixture was stirred overnight, then slowly poured into ice-water (50 mL). The mixture was stirred for 10 min, then allowed to sit for 10 min. The mixture was then extracted with EtOAc (2×) and the combined organics washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was triturated with MTBE and the resulting solid dried in a vac oven at 45° C. for 4 h. Purified the solid by HPLC (Gilson; Sunfire 30×75 mm column; Gradient B: 10-65%; A: water+0.1% TFA; B: CH3CN+0.1% TFA). The residue was dissolved in 10% MeOH/DCM and treated with Silicycle carbonate resin (0.65 g) at 37° C. for 15 min. The mixture was allowed to cool to RT and was filtered through Celite. Concentrated in vacuo to give N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-methyl-3-(1-methylethyl)-5-(6-methyl-3-pyridinyl)-1H-indole-7-carboxamide (55 mg, 37.6% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.30 (d, J=6.82 Hz, 6H) 2.11 (s, 3H) 2.24 (s, 3H) 3.16-3.28 (m, 1H) 3.33 (s, 3H) 3.68 (s, 3H) 4.36 (d, J=5.05 Hz, 2H) 5.87 (s, 1H) 7.11 (s, 1H) 7.28-7.37 (m, 2H) 7.86 (d, J=1.77 Hz, 1H) 7.98 (dd, J=8.08, 2.53 Hz, 1H) 8.50 (t, J=4.93 Hz, 1H) 8.77 (d, J=2.27 Hz, 1H) 11.50 (s, 1H). MS (ES) [M+H]+ 443.2.
Reaction SMILES: [CH:1](=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[C:9]([O:13][CH3:14])(=[O:12])[CH:10]=O.C(OC(=O)C)(=O)C>C(O)(=O)CC.C(NCCCC)CCC>[CH:1]([C:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[CH:10][C:9]([O:13][CH3:14])=[O:12])=[O:8]
Reactant: CCCCCCC=O
Reactant: COC(=O)C=O
Solvent: CCC(=O)O
Solvent: CCCCNCCCC
Solvent: CC(=O)OC(C)=O
Product: CCCCCC(C=O)=CC(=O)OC
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
A mixture of 57 g (0.5 mol) of n-heptanal and 44 g (0.5 mol) of methyl glyoxylate was added dropwise to a mixture of 1.85 g (0.025 mol) of propionic acid and 3.22 g (0.025 mol) of di-n-butylamine in such a way that the temperature did not exceed 80° C. After the addition was complete the mixture was stirred at 80° C. for 30 min, then 102 g (1 mol) of acetic anhydride were added and the mixture was heated to boiling. Acetic acid slowly distilled out, 51 g being obtained in 2 hours. Fractional distillation of the bottom product yielded 59 g of methyl 3-formyl-3-pentylacrylate with a boiling point of 82°-85° C./1 mbar, corresponding to a yield of 64% of theory. The trans/cis isomer ratio was 78/22.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:21])[C:4](=[O:20])[C:5]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:6]([C:8]([NH:10][CH3:11])=[O:9])[N:7]=1.CN(C=O)C.CC(C)([O-])C.[K+].[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][S:41](Cl)(=[O:43])=[O:42])=[CH:36][CH:35]=1>C1COCC1.CCOC(C)=O>[CH3:11][NH:10][C:8]([C:6]1[N:7]=[C:2]([NH:1][S:41]([CH2:40][C:37]2[CH:38]=[CH:39][C:34]([Cl:33])=[CH:35][CH:36]=2)(=[O:42])=[O:43])[N:3]([CH3:21])[C:4](=[O:20])[C:5]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:9]
Reactant: O=S(=O)(Cl)Cc1ccc(Cl)cc1
Reactant: CNC(=O)c1nc(N)n(C)c(=O)c1OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CNC(=O)c1nc(NS(=O)(=O)Cc2ccc(Cl)cc2)n(C)c(=O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 50.8 %

Procedure:
In a round-bottomed flask, 2-amino-5-(benzyloxy)-N,1-dimethyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide (250 mg, 867 μmol, Eq: 1.00) was combined with THF (20 ml) to give a white suspension. DMF (4 ml) was added followed by potassium tert-butoxide (117 mg, 1.04 mmol, Eq: 1.2). The resulting mixture was stirred at room temperature for 10 min, then cooled with an ice bath. To this was slowly added a solution of (4-chlorophenyl)methanesulfonyl chloride (240 mg, 1.07 mmol, Eq: 1.23) in THF (1 ml). After stirring at room temperature for 14 h, further t-BuOK (234 mgs) was added. The mixture was stirred for 5 min, cooled in the ice bath and then further (4-chlorophenyl)methanesulfonyl chloride (240 mg, 1.07 mmol) was added. The reaction mixture was stirred for 72 hours at RT and then diluted with EtOAc, washed with saturated aqueous NaHCO3 solution and brine. Some solid precipitated in the EtOAc solution and was collected by filtration. The remaining filtrate was evaporated to dryness, purified by flash chromatography (silica gel, 2% to 6% MeOH in DCM) and then triturated by EtOAc/Hex. The solids were combined to give the desired product as a white solid (0.210 g; 51%). LCMS m/z=477 (MH+).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:4][O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].CCN(CC)CC.[Cl:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33](Cl)=[O:34].[Na+].[Cl-]>C(Cl)Cl>[Si:6]([O:5][CH2:4][C@@H:3]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:2][NH:1][C:33](=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29][Cl:28])([C:9]([CH3:11])([CH3:12])[CH3:10])([CH3:8])[CH3:7]
Reactant: O=C(Cl)CCCCCl
Reactant: CC(C)(C)OC(=O)N[C@@H](CN)CO[Si](C)(C)C(C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](CNC(=O)CCCCCl)CO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 4 h
Yield: 86.2 %

Procedure:
(S)-tert-butyl 1-amino-3-(tert-butyldimethylsilyloxy)propan-2-ylcarbamate (1 g, 3.29 mmol) was taken up in 10 mL of CH2Cl2 and cooled to 0° C. To this was added Et3N (0.731 g, 7.24 mmol), followed by 5-chloro-pentanoyl chloride (0.557 g, 3.62 mmol). The reaction mixture was allowed to warm to rt and stirred for 4 h. Upon completion of the reaction, satd NaCl solution was added. The organic layer was extracted with EA, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column to give (S)-tert-butyl 1-(tert-butyldimethylsilyloxy)-3-(5-chloropentanamido)propan-2-ylcarbamate (1.2 g, 86%). 1H NMR (CDCl3, 300 MHz) δ 6.31 (s, 1H), 5.04 (d, 1H), 3.65 (m, 3H), 3.53 (m, 2H), 3.40 (m, 2H), 2.18 (t, 2H), 1.78 (m, 4H), 1.43 (s, 9H), 0.88 (s, 9H), 0.0 (s, 6H).
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])=O.[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl>[CH2:16]([N:23]1[CH2:1][CH:3]2[CH:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH:9]1[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)/C=C/C1CCCCC1C=O
Reactant: NCc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)CC1C2CCCCC2CN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of (E)-ethyl 3-(2-formylcyclohexyl)acrylate, benzyl amine and NaBH(Oac)3 in DCM was stirred at rt for 3 h. The reaction mixture was quenched with saturated NaHCO3. The organic layer was separated and the aqueous layer was extracted with DCM (2×). All organic layers were combined, dried with dried with MgSO4 and concentrated in vacuo to give the crude product which was purified by chromatography to afford desired ethyl 2-(2-benzyloctahydro-1H-isoindol-1-yl)acetate. MS (ESI) 302 (M+H).
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[O:20]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[NH:23][CH2:22][CH2:21]1.Cl.[CH:31]12[CH2:40][CH:35]3[CH2:36][CH:37]([CH2:39][CH:33]([CH2:34]3)[CH:32]1[NH2:41])[CH2:38]2>C(Cl)(Cl)Cl.O>[CH:31]12[CH2:40][CH:35]3[CH2:36][CH:37]([CH2:39][CH:33]([CH2:34]3)[CH:32]1[NH:41][C:5]([N:23]1[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:20][CH2:21][CH2:22]1)=[O:11])[CH2:38]2
Reactant: c1ccc2c(c1)NCCO2
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NC1C2CC3CC(C2)CC1C3
Agent: Cl
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(NC1C2CC3CC(C2)CC1C3)N1CCOc2ccccc21
Reaction time: 0.17 h

Procedure:
To a solution of triphosgene (119 mg) in chloroform (3 ml), a solution of triethylamine (332 μl) and 3,4-dihydro-2H-1,4-benzoxazine obtained in Reference Example 14 (108 mg) in chloroform (2 ml) was added under ice cooling and stirred at the same temperature for 10 minutes. To the reaction mixture, 2-adamantaneamine hydrochloride (150 mg) and triethylamine (166 μl) were then added and stirred at room temperature for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed sequentially with 1M aqueous hydrochloric acid, saturated aqueous sodium bicarbonate and brine. After drying over anhydrous magnesium sulfate, the desiccant was filtered off and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluting solvent: n-hexane:ethyl acetate=4:1). The resulting residue was dissolved in a small volume of chloroform and converted into a powder form by addition of diethyl ether, and then collected by filtration to give the titled compound (Compound 34, 96 mg) as a colorless powder.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)=[O:11])[N:5]=[CH:4][C:3]=1[C:20](=[O:28])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23](I)[CH:22]=1.[C:29]([Cu])#[N:30]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)=[O:11])[N:5]=[CH:4][C:3]=1[C:20](=[O:28])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:29]#[N:30])[CH:22]=1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)c2cccc(I)c2)c1N
Reactant: N#C[Cu]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)c2cccc(C#N)c2)c1N
Temperature: 100 °C
Yield: 33.8 %

Procedure:
To a solution of 3-[5-amino-4-(3-iodobenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide (110 mg, 0.23 mmol) in DMF (5 mL) was added CuCN (40 mg, 0.45 mmol) and tetrakis(triphenylphosphine)palladium (catalytic) and the mixture was heated at 100° C. over night under N2. The solvent was removed and the residue was suspended in EtOAc, and solids were filtered off. The filtrate was washed by water, brine, dried over Na2SO4 and concentrated. The crude product was purified by column chromatography on silica gel (EtOAc). Product was obtained as a beige solid (30 mg, 34%). HPLC (4 minute 10-90 gradient) tR 2.02 min; MS m/z 386.13 [M+H]+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=O.[NH2:18][C:19]1[CH:31]=[C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=2)[CH:29]=[CH:28][C:20]=1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(=O)([O-])O.[Na+]>C(N(CC)CC)C.C(Cl)Cl.CN(C)C=O>[Cl:38][C:34]1[CH:33]=[C:32]([C:30]2[CH:29]=[CH:28][C:20]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])=[C:19]([NH:18][C:10](=[O:12])[C:9]3[CH:13]=[CH:14][CH:15]=[C:16]([CH3:17])[C:8]=3[CH3:7])[CH:31]=2)[CH:37]=[CH:36][CH:35]=1
Reactant: Cc1cccc(C(=O)O)c1C
Reactant: CC(C)(C)OC(=O)c1ccc(-c2cccc(Cl)c2)cc1N
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cccc(C(=O)Nc2cc(-c3cccc(Cl)c3)ccc2C(=O)OC(C)(C)C)c1C
Reaction time: 1 h

Procedure:
1.7 mL of methylene chloride, 1.0 μl of N,N-dimethylformamide and, 0.025 mL of oxalyl chloride were added to 41 mg of 2,3-dimethylbenzoic acid at room temperature sequentially and stirred at the same temperature for 1 hour. The reaction mixture was added to a mixed solution of 49 mg of tert-butyl 2-amino-4-(3-chlorophenyl)benzoate, 2.8 mL of methylene chloride and 0.36 mL of triethylamine and stirred at room temperature for 1 hour. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, and the organic layer was separated, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane: ethyl acetate=4:1]to obtain tert-butyl 4-(3-chlorophenyl)-2-(2,3-dimethylbenzamido)benzoate.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])=[C:7]([O:18][CH3:19])[CH:6]=1)=[O:4].CO.[OH-].[Na+]>O1CCCC1>[CH3:19][O:18][C:7]1[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:10]=[CH:9][C:8]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17]
Reactant: COC(=O)c1ccc(-c2ccccc2C)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(C(=O)O)ccc1-c1ccccc1C
Temperature: 105 °C
Yield: 87.3 %

Procedure:
To the 2-methoxy-2′-methyl-biphenyl-4-carboxylic acid methyl ester of step C (26 mmol) was added methanol (10 mL), tetrahydrofuran (45 mL) and 1 N sodium hydroxide (33 mL). The solution was refluxed vigorously in an oil bath at 105° C. for one hour. The volatile solvents were evaporated and the solution was chilled in ice. 2N hydrochloric acid was added until the pH was ˜1. The product was extracted into ethyl acetate, dried with anhydrous magnesium sulfate, and evaporated to a white solid. This was recrystallized from ethyl acetate/hexane to afford 5.5 g of title compound (86%).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[O:5][C:4](=[O:13])[CH:3]=1.[H-].[Na+].[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[CH2:16]([O:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[O:5][C:4](=[O:13])[CH:3]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: ClCc1ccccc1
Reactant: O=c1cc(O)c2ccc(O)cc2o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1cc(OCc2ccccc2)c2ccc(O)cc2o1
Reaction time: 1 h
Yield: 23.2 %

Procedure:
A solution of 4,7-dihydroxycoumarin (1.78g, 0.01 mole) in dry DMF (7.5ml) was stirred during the addition of 100% sodium hydride (0.24g, 0.01 mole) and the mixture stirred for 1 hour at 100°. A solution of benzyl chloride (1.27g. 0.01 mole) in dry DMF (1 ml) was added dropwise and stirring continued at 100° for a further 4 hours. After removal of the solvent in vacuo water was added and the oily solid which precipitated was separated. Recrystallisation from ethanol gave 0.623g (23%) of title compound of mp 234° νmax (mull) 3150, 3050, 1710, 1630 cm-1, τ(DMSO) 4.67 (2H, s); 4.19 (1H, s); 3.28 (1H near s); 3.20 (1H, d.d., J 2.0 Hz; 5.0Hz) 2.66-2.26 (6H, m), 1 low field broad exchangeable proton. (Found, C, 71.51; H, 4.70; C16H12O4 requires; C, 71.64; H, 4.51%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][NH:10][C:11]([C@@H:13]2[CH2:17][C:16]([F:19])([F:18])[CH2:15][N:14]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=O)=[CH:4][CH:3]=1.C(O)(=O)C.C(O)(=O)C.[NH3:36].C1(C)C(C)=CC=CC=1>CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:36][C:11]([C@@H:13]3[CH2:17][C:16]([F:19])([F:18])[CH2:15][N:14]3[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[N:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC(F)(F)C[C@H]1C(=O)NCC(=O)c1ccc(Br)cc1
Reactant: N
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CC(F)(F)C[C@H]1c1ncc(-c2ccc(Br)cc2)[nH]1
Temperature: 140 °C
Reaction time: 4 h
Yield: 102.8 %

Procedure:
In a 50 mL seal tube, (S)-tert-butyl 2-(2-(4-bromophenyl)-2-oxoethylcarbamoyl)-4,4-difluoropyrrolidine-1-carboxylate (1.8 g, 4.02 mmol) and acetic acid, ammonia acetate salt (1.55 g, 20.1 mmol) were combined with xylene (16 ml). The reaction mixture was heated to 140° C. and stirred for 4 hr. The reaction mixture was cooled and diluted with EtOAc (50 ml). It was washed with water and brine, dried with MgSO4, concentrated and purified on a silica gel column (CH2Cl2, 30%, 50%, 80% EtOAc/CH2Cl2) to afford (S)-tert-butyl 2-(5-(4-bromophenyl)-1H-imidazol-2-yl)-4,4-difluoropyrrolidine-1-carboxylate as a yellow solid (1.77 g, 74%): ESI-LRMS m/e calcd for C18H22BrF2N3O2 [M+] 428. found 429 [M+H+].