Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:18]([N+:19]([O-])=O)=[CH:17][CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[NH2:19][C:18]1[C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cccc(N)c1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 45402.3 %

Procedure:
To a suspension of methyl 2-[(tert-butoxycarbonyl)amino]-3-nitrobenzoate (103 g, 0.348 mmol) in methanol (800 mL) was added 10% palladium on carbon (50% wet; 10 g), and the mixture was purged with hydrogen and stirred under balloon pressure hydrogen at room temperature for 5 hr. The catalyst was removed by filtration, and the filtrate was concentrated in vacuo. The residual solid was suspended in diisopropyl ether (300 mL), and the suspension was stirred at room temperature for 3 hr. The resulting solid was collected by filtration and washed with diisopropyl ether to give the title compound (42.0 g, 158 mmol, 45%). The mixture of the removed catalyst described above and a colorless solid (the title compound) was suspended in tetrahydrofuran (200 mL), and the suspension was stirred at room temperature for 30 minutes. The insoluble material (the catalyst) was removed by filtration, and the filtrate was concentrated in vacuo. The residual solid was suspended in diisopropyl ether (300 mL), and the suspension was refluxed for 30 min. The resulting solid was collected by filtration and washed with diisopropyl ether to give the title compound (33.9 g, 127 mmol, 36%) as a colorless solid. Total amount: 75.9 g, 285 mmol, 82%.
Reaction SMILES: Br[C:2]([F:9])([F:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[O:10]=[C:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.C(OCC)(=O)C.Cl>O1CCCC1.[Zn]>[CH2:6]([O:5][C:3]([C:2]([F:9])([F:8])[C:11]1([OH:10])[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:15][CH2:16]1)=[O:4])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCOC(=O)C(F)(F)Br
Agent: Cl
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(F)(F)C1(O)CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Powdered zinc (2.82 g, 0.043 mol) was suspended in tetrahydrofuran (50.0 mL) under flow of argon gas, and the suspension was mixed with ethyl bromodifluoroacetate (7.31 g, 0.036 mol) at room temperature, followed by stirring under reflux for five minutes. The mixture was further mixed with a solution of tert-butyl 4-oxopiperidinecarboxylate in tetrahydrofuran (3.00 mol/L, 10.0 mL, 0.030 mol), followed by stirring under reflux for two hours. After checking the completion of the reaction by thin layer chromatography, the reaction mixture was mixed with ethyl acetate and diluted hydrochloric acid (1.00 mol/L), followed by separation. The organic layer was sequentially washed with a saturated aqueous sodium bicarbonate solution and brine, was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: chloroform=1:9) and thereby yielded tert-butyl 4-(ethoxycarbonyldifluoromethyl)-4-hydroxy-piperidinecarboxylate (7.39 g, 76%).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[S:20][CH:21]=[CH:22][C:23]=3[S:24][CH3:25])=[CH:15][CH:14]=2)=[C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[NH:6][CH:7]=1)#[N:2].[I:26]NC(=O)CCC(N)=O>>[C:1]([C:3]1[C:4]([C:13]2[CH:14]=[CH:15][C:16]([C:19]3[S:20][CH:21]=[CH:22][C:23]=3[S:24][CH3:25])=[CH:17][CH:18]=2)=[C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[NH:6][C:7]=1[I:26])#[N:2]
Reactant: CCOC(=O)c1[nH]cc(C#N)c1-c1ccc(-c2sccc2SC)cc1
Reactant: NC(=O)CCC(=O)NI
Product: CCOC(=O)c1[nH]c(I)c(C#N)c1-c1ccc(-c2sccc2SC)cc1

Procedure:
In a manner analogous to the procedure set forth in example A-237, the title compound is prepared by iodinating ethyl 4-cyano-3-[4-(3 methylthio(2-thienyl))phenyl]pyrrole-2-carboxylate, prepared directly above, with N-iodo-succinamide.
Reaction SMILES: [Cl:1][S:2]([CH2:5][C:6](Cl)=[O:7])(=[O:4])=[O:3].[CH3:9][OH:10]>CCOCC>[CH3:9][O:10][C:6](=[O:7])[CH2:5][S:2]([Cl:1])(=[O:4])=[O:3]
Reactant: CO
Reactant: O=C(Cl)CS(=O)(=O)Cl
Solvent: CCOCC
Product: COC(=O)CS(=O)(=O)Cl
Reaction time: 3 h

Procedure:
To a solution of chlorosulfonylacetyl chloride (419 μL, 3.955 mmol, 1 eq.) in Et2O (4 mL), at 0° C. was added MeOH (160 μL, 3.955 mmol, 1 eq.). The reaction mixture is strirred at 0° C. for 3 h, then concentrated in vacuo to give chlorosulfonyl-acetic acid methyl ester.
Reaction SMILES: [CH:1]1([NH:7][NH:8]C(OC(C)(C)C)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:16][C:17]1[C:22]([C:23]([N:25]=[C:26]=[O:27])=O)=[C:21]([F:28])[C:20]([CH2:29][NH:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:19][CH:18]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:29][NH:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])=[C:21]([F:28])[C:22]=1[C:23]1[NH:25][C:26](=[O:27])[N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[N:8]=1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)N=C=O)c1F
Reactant: CC(C)(C)OC(=O)NNC1CCCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(-c2nn(C3CCCCC3)c(=O)[nH]2)c1F

Procedure:
The title compound was prepared by following the procedure as described for Example-83 by using tert-butyl 2-(cyclohexyl)hydrazinecarboxylate (Intermediate-64, 0.050 g, 0.23 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoyl isocyanate (Intermediate-51, 0.225 g, 0.70 mmol), DCM (10 mL) and TFA (3 mL) to afford 0.015 g of pure product. 1H NMR (400 MHz, DMSO d6): δ 1.13 (s, 9H), 1.22-1.23 (m, 2H), 1.30-1.37 (m, 2H), 1.62-1.64 (m, 2H), 1.78-1.81 (m, 4H), 3.90-3.92 (m, 1H), 4.27-4.28 (d, J=4.8 Hz, 2H), 7.37-7.41 (t, 1H), 7.46-7.48 (d, 1H), 8.17 (br s, 1H); MS (m/z): 409.36 (M+H+).
Reaction SMILES: [C:1]1([N:7]2[C:19](=[O:20])[C:10]3=[CH:11][NH:12][C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[C:9]3=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:22][O:23]C1C=CC(NN)=CC=1>>[CH3:22][O:23][C:4]1[CH:3]=[CH:2][C:1]([N:7]2[C:19](=[O:20])[C:10]3=[CH:11][NH:12][C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[C:9]3=[N:8]2)=[CH:6][CH:5]=1
Reactant: COc1ccc(NN)cc1
Reactant: O=c1c2c[nH]c3ccccc3c-2nn1-c1ccccc1
Agent: Cl
Product: COc1ccc(-n2nc3c4ccccc4[nH]cc-3c2=O)cc1

Procedure:
The title compound was prepared following the procedure described in Step 3 for the synthesis of 4a, but using 4-methoxyphenyl hydrazine hydrochloride instead of phenyl hydrazine hydrochloride. 1H NMR (DMSO-d6) δ (ppm): 3.76 (3H, s), 6.98 (1H, q, J=5.50 Hz), 7.01 (1H, d, J=9.33 Hz), 7.55 (1H, m), 7.70 (2H, m), 8.05 (1H, q, J=5.09 Hz), 8.08 (1H, d, J=9.33 Hz), 8.19 (1H, d, J=7.96 Hz), 8.70 (1H, d, J=6.31 Hz). m/z 292.4 (MH+).
Reaction SMILES: [NH3:1].[CH2:2]([C:4]1[N:13]=[C:12]([CH2:14][CH3:15])[CH:11]=[C:10]2[C:5]=1[CH:6]=[C:7]([C:54]([O:56]CC)=O)[C:8](=[O:53])[N:9]2[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]2[N:30]=[N:31][N:32]([C:34]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[N:33]=2)=[CH:19][CH:18]=1)[CH3:3]>CO.ClCCl>[CH2:2]([C:4]1[N:13]=[C:12]([CH2:14][CH3:15])[CH:11]=[C:10]2[C:5]=1[CH:6]=[C:7]([C:54]([NH2:1])=[O:56])[C:8](=[O:53])[N:9]2[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]2[N:30]=[N:31][N:32]([C:34]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)[N:33]=2)=[CH:21][CH:22]=1)[CH3:3]
Reactant: N
Reactant: CCOC(=O)c1cc2c(CC)nc(CC)cc2n(Cc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c1=O
Solvent: CO
Solvent: ClCCl
Product: CCc1cc2c(cc(C(N)=O)c(=O)n2Cc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c(CC)n1
Reaction time: 72 h

Procedure:
Concentrated aqueous ammonia solution (d 0.88 ) was added dropwise to a solution of ethyl 5,7-diethyl-2-oxo-1-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl)methyl]-1,2-dihydro-1,6-naphthyridin-3-carboxylate (600 mg) in a mixture of methanol (7 ml) and dichloromethane (1.5 ml) until the solution became cloudy. Dichloromethane (2 ml) was added to give a clear solution and the mixture was stirred for 3 days. Volatile material was then removed by evaporation to give 5,7-diethyl-2-oxo-1-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl)methyl]-1,2-dihydro-1,6-naphthyridin-3-carboxamide as a solid (500 mg), which was used without further purification or characterisation.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][C:6]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]([CH3:23])[CH2:13][C:12]=23)=[N:5][N:4]=1.[CH2:24]([NH:28][CH2:29][CH:30]([CH3:32])[CH3:31])[CH:25]([CH3:27])[CH3:26]>CN(C)C=O>[CH2:24]([N:28]([CH2:2][C:3]1[O:7][C:6]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]([CH3:23])[CH2:13][C:12]=23)=[N:5][N:4]=1)[CH2:29][CH:30]([CH3:32])[CH3:31])[CH:25]([CH3:27])[CH3:26]
Reactant: CC(C)CNCC(C)C
Reactant: CN1Cc2c(-c3nnc(CCl)o3)ncn2-c2ccccc2C1=O
Solvent: CN(C)C=O
Product: CC(C)CN(Cc1nnc(-c2ncn3c2CN(C)C(=O)c2ccccc2-3)o1)CC(C)C
Yield: 77.2 %

Procedure:
1.64 g (5 mmol) of 3-(5-chloromethyl-1,3,4-oxadiazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one were stirred at room temperature overnight with 1.62 g (12.5 mmol) of diisobutylamine and 20 ml of N,N-dimethylformamide. After evaporation of the reaction mixture and chromatography of the residue on silica gel while eluting with ethyl acetate there were obtained 1.63 g (77%) of 3-(5-diisobutylaminomethyl-1,3,4-oxadiazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one of m.p. 138°-140°, which was converted into the hydrochloride of m.p. 177°-180°.
Reaction SMILES: C(O[C:4](=[O:19])[C:5]([F:18])([F:17])[CH:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15])[OH:7])C.[CH:20]([NH2:23])([CH3:22])[CH3:21]>CCO>[CH3:21][CH:20]([NH:23][C:4](=[O:19])[C:5]([F:17])([F:18])[CH:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15])[OH:7])[CH3:22]
Reactant: CCOC(=O)C(F)(F)C(O)c1ccccc1[N+](=O)[O-]
Reactant: CC(C)N
Solvent: CCO
Product: CC(C)NC(=O)C(F)(F)C(O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
To a solution of the ester from Step 1 (1.50 g, 5.45 mmol) in EtOH (20 mL) was added isopropylamine (1.86 mL, 21.8 mmol). The solution was heated to reflux for 20 h and cooled to ambient temperature. Concentration under a nitrogen atmosphere afforded the amide quantitatively: Anal. Calc'd. for C12H14F2N2O4 plus 0.15 mol H2O: C, 49.54; H, 4.95; N, 9.63. Found: C, 49.52; H, 5.52; N, 9.46.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:52][C:53]1[N:54]=[N:55][CH:56]=[CH:57][CH:58]=1>CN(C)C=O>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([NH:52][C:53]2[N:54]=[N:55][CH:56]=[CH:57][CH:58]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Reactant: Nc1cccnn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccnn1)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Yield: 62.2 %

Procedure:
A solution of 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid (prepared in Example 38, 625.2 mg, 2.18 mmol), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (908.3 mg, 2.39 mmol), N,N-diisopropylethylamine (1.1 mL, 6.53 mmol), and 3-aminopyridazine (310.6 mg, 3.27 mmol) in dry N,N-dimethylformamide (11 mL) was stirred at 25° C. under nitrogen for 72 h. The reaction mixture was concentrated in vacuo to remove N,N-dimethylformamide. The resulting residue was diluted with ethyl acetate (200 mL). The organic layer was washed with a 10% aqueous hydrochloric acid solution and washed with a saturated aqueous sodium chloride solution. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-pyridazin-3-yl-propionamide (493.8 mg, 62%) as a white foam: mp 70-71° C.; EI-HRMS m/e calcd for C18H19Cl2N3O (M+) 363.0905, found 363.0908.
Reaction SMILES: N[C@H](C(O)=O)CC[C:5]([OH:7])=[O:6].[CH3:11][N:12]([C:26]1[CH:27]=[CH:28][C:29](C(N[C@H](C(O)=O)CCC(O)=O)=O)=[CH:30][CH:31]=1)[CH2:13][C:14]1[CH:15]=[N:16][C:17]2[N:23]=[C:22]([NH2:24])[N:21]=[C:20]([NH2:25])[C:18]=2[N:19]=1>>[NH2:24][C:22]1[N:21]=[C:20]([NH2:25])[C:18]2[C:17](=[N:16][CH:15]=[C:14]([CH2:13][N:12]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:5]([OH:7])=[O:6])[CH3:11])[N:19]=2)[N:23]=1
Reactant: CN(Cc1cnc2nc(N)nc(N)c2n1)c1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Product: CN(Cc1cnc2nc(N)nc(N)c2n1)c1ccccc1C(=O)O

Procedure:
The title compound was prepared by carboxypeptidase G cleavage of glutamic acid from methotrexate as described in the literature (J. Med. Chem. 24, 1450-1455 (1981)). The yield of I obtained was virtually quantitative.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH2:23][C:22](=[O:24])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[O:25][CH3:26])[N:15]=2)=[CH:10][CH:9]=1.Cl[CH2:28][C:29]([N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)=[O:30]>CC(=O)CC>[CH3:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:23]=[C:22]([O:24][CH2:28][C:29]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[O:30])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[O:25][CH3:26])[N:15]=2)=[CH:12][CH:13]=1
Reactant: O=C(CCl)N1CCOCC1
Reactant: COc1cccc2c1C(=O)CC(c1ccc(C)cc1)=N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COc1cccc2nc(-c3ccc(C)cc3)cc(OCC(=O)N3CCOCC3)c12
Temperature: 20 °C
Yield: 71 %

Procedure:
anhydrous potassium carbonate (2.28 g) is added to a stirred suspension of 2-(4-methylphenyl)-5-methoxy-4-quinolone (2.19 g) and 4-(2-chloroacetyl)morpholine (1.62 g) in 2-butanone (76 cc). The mixture is heated to reflux for 4 hours 20 minutes and cooled to room temperature (approximately 20° C.) and the solvent is evaporated off under reduced pressure. The residue is taken up with water and ethyl acetate and the organic phase is separated after settling has taken place, dried over magnesium sulphate and evaporated under reduced pressure. The residue obtained is chromatographed on silica gel, using a chloroform/acetone mixture (95:5 by volume). The solid collected is stirred in 40°-60° petroleum ether (50 cc). 4-{[2-(4-Methylphenyl)-5-methoxy-4-quinolyl]oxyacetyl}morpholine (2.3 g), m.p. 132° C., is thereby isolated.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]3[CH:15]=[N:16][CH:17]=[C:13]3[CH:12]=[CH:11][C:10]=2[C:18]([OH:20])=O)=[C:4]([F:21])[CH:3]=1.[CH:22]([O:24][CH2:25][CH2:26][O:27][NH2:28])=[CH2:23].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:22]([O:24][CH2:25][CH2:26][O:27][NH:28][C:18]([C:10]1[CH:11]=[CH:12][C:13]2[N:14]([CH:15]=[N:16][CH:17]=2)[C:9]=1[NH:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[F:21])=[O:20])=[CH2:23]
Reactant: C=COCCON
Reactant: O=C(O)c1ccc2cncn2c1Nc1ccc(Br)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=COCCONC(=O)c1ccc2cncn2c1Nc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.6 %

Procedure:
To a solution of 5-(4-Bromo-2-fluorophenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid (2.0 g, 5.7 mmol) and O-(2-vinyloxyethyl)-hydroxylamine (0.71 g, 6.8 mmol) in DMF (44 mL) was added EDCI hydrochloride (1.42 g, 7.41 mmol), HOBt (1.0 g, 7.41 mmol) and DIPEA (0.97 mL, 5.69 mmol). The reaction mixture was stirred at room temperature for 3 hours before being concentrated in vacuo. The resultant residue was dissolved in 1:1 diethylether:ethyl acetate (30 mL) and aqueous saturated sodium hydrogen carbonate solution (30 mL) was added. The resultant mixture was sonicated until a precipitate formed. The precipitate was collected by filtration and washed with 1:1 diethylether:ethyl acetate to yield the title compound as a tan solid (1.33 g, 53%). LCMS (Method B): RT=2.78 min, M+H+=435/437.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22](O)=[O:23])[CH:17]=1)[CH2:10][C:9]2([CH3:26])[CH3:25])=[O:5])[CH3:2].CN(C(ON1N=NC2[CH:38]=[CH:39][CH:40]=[N:41]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.C1(N)CC1>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[O:23])[NH:41][CH:40]3[CH2:38][CH2:39]3)[CH:17]=1)[CH2:10][C:9]2([CH3:25])[CH3:26])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1cccc(C(=O)O)c1)N2
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1cccc(C(=O)NC3CC3)c1)N2
Yield: 100.4 %

Procedure:
The mixture solution of 2-(3-carboxy-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (1.2 g, 3.3 mmol), o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (1.52 g, 4.0 mmol), triethylamine (2.0 mL), cyclopropylamine (330.6 mg, 5.8 mmol) in dry dichloromethane (20.0 mL) was stirred at room temperature for 1 hour, LC/MS showed that reaction finished completely. The reaction mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-(3-cyclopropylcarbamoyl-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (1.3 g, quant.) as a light yellow solid which was used for next step without further purification: MS (ESI) M+1=393.1.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][C:3]=1[C:14]([CH3:17])([CH3:16])[CH3:15].[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.[OH-].[Na+]>COCCOC.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>[C:14]([C:3]1[CH:4]=[C:5]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:6]=[C:7]([O:8][CH3:9])[C:2]=1[C:22]1[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: COc1cc(C(C)(C)C)cc(C(C)(C)C)c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Product: COc1cc(C(C)(C)C)cc(C(C)(C)C)c1-c1ccc(Cl)cc1
Temperature: 75 °C

Procedure:
A solution of 9.0 g (30.1 mmol) of 2-bromo-1,5-di-tert-butyl-3-methoxybenzene (Zhang, H.; Kwong, F. Y.; Tian, Y.; Chan, K. S. J. Org. Chem. 1998, 63, 6886-6890) in 100 mL of DME was purged with nitrogen for 15 min and 1.5 g (0.13 mmol) of tetrakis(triphenylphosphine)palladium(0) was added. After stirring 20 min 5.0 g (31.9 mmol) of 4-chlorobenzeneboronic acid was added. The reaction mixture was stirred at 75° C. and 15 mL of 5 N sodium hydroxide was added dropwise. The resulting mixture was then stirred overnight at 80° C. The reaction mixture was then cooled to room temperature and the DME was removed in vacuo. The residue was partitioned between water and hexane containing 10% EtOAc and extracted. The organic layer was dried, filtered and evaporated to afford the title compound suitable for use in the next step.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH3:16][C:17]1([CH3:33])[C@@H:19]([C:20]#[C:21][C:22]([O:24][CH2:25][C:26]([Cl:29])([Cl:28])[Cl:27])=[O:23])[C@H:18]1[C:30]([OH:32])=[O:31].C(Cl)Cl.[C:37]([C@@H:39](O)[C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([O:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:41]=1)#[N:38]>N1C=CC=CC=1>[CH3:16][C:17]1([CH3:33])[C@@H:19]([C:20]#[C:21][C:22]([O:24][CH2:25][C:26]([Cl:28])([Cl:29])[Cl:27])=[O:23])[C@H:18]1[C:30]([O:32][C@H:39]([C:37]#[N:38])[C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([O:46][C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH:41]=1)=[O:31]
Reactant: CC1(C)[C@H](C(=O)O)[C@@H]1C#CC(=O)OCC(Cl)(Cl)Cl
Reactant: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1C#CC(=O)OCC(Cl)(Cl)Cl
Reaction time: 0.5 h

Procedure:
6.2 g of dicyclohexylcarbodiimide were added to a mixture of 9.5 g of the product of Step B, 30 ml of methylene chloride and 3 ml of pyridine and after stirring for 30 minutes, 6.8 g of (S)α-cyano-3-phenoxy-benzyl alcohol were added to the mixture. The mixture was stirred for 90 minutes and was filtered and the filtrate was washed with N hydrochloric acid and then with water until the wash water was neutral, dried and evaporated to dryness. The 16.3 g of oil residue were chromatographed over silica gel and eluted with a 97-3 benzene-ethyl acetate mixture to obtain 12 of (S)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3-(2,2,2-trichloroethoxycarbonyl-ethynyl]-cyclopropane-carboxylate melting at 101° C.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1.Cl.O1CCOCC1>C(Cl)Cl>[F:27][C:2]([F:1])([F:26])[O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=S(=O)(c1ccc(OC(F)(F)F)cc1)N1CCNCC1
Reaction time: 2 h
Yield: 84.9 %

Procedure:
1,1-Dimethylethyl 4-({4-[(trifluoromethyl)oxy]phenyl}sulfonyl)-1-piperazinecarboxylate (may be prepared as described in Intermediate 10; 5.450 g, 13.28 mmol) was dissolved in DCM (80 ml) and then 4M hydrochloric acid in dioxane (33.2 mL, 133 mmol) was added at room temperature and the reaction mixture was stirred for two hours. The reaction mixture was partitioned between DCM and aqueous sodium bicarbonate (30 ml). The organic phase was washed with further sodium bicarbonate (2×20 ml) and water (2×20 ml). The aqueous phase (pH 1) was basified by adding sodium hydroxide then the aqueous phase was extracted with DCM (2×20 ml). The solvent was removed under vacuum to give the title compound (3.5 g) as a white solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[CH:12]1([C:17]#[N:18])[CH2:16][CH2:15][CH2:14][CH2:13]1.C[Si]([N-][Si](C)(C)C)(C)C.[K+]>C1(C)C=CC=CC=1>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([C:12]2([C:17]#[N:18])[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:3][CH:4]=1
Reactant: Fc1ccc(C(F)(F)F)cc1
Reactant: N#CC1CCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Product: N#CC1(c2ccc(C(F)(F)F)cc2)CCCC1
Temperature: 70 °C
Reaction time: 14 h
Yield: 103.3 %

Procedure:
To a stirred solution of 4-fluorobenzotrifluoride (5.0 g, 30.47 mmol) in toluene (40 mL) was added cyclopentanecarbonitrile (10.5 mL, 100.55 mmol) followed by a solution of 0.5 M KHMDS in toluene (92 mL, 45.71 mmol). The reaction mixture was heated to 70° C. and stirred for 14 hours. After cooling to RT, the reaction mixture was quenched with 1 M HCl until pH<7. The layers were separated and the organic layer was washed with saturated NaHCO3, water, brine, dried over MgSO4, filtered, and concentrated in vacuo. Purification via silica gel chromatography (6:1 hexanes:EtOAc) afforded 7.53 g of a mixture of compound A and residual cyclopentanecarbonitrile. Because these two compounds were not easily separable by chromatography, this mixture was carried directly to the next step.