Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH3:25][NH:26][CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][N:30]([CH3:34])[CH2:29]1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([N:26]([CH3:25])[CH2:27][CH:28]4[CH2:33][CH2:32][CH2:31][N:30]([CH3:34])[CH2:29]4)=[O:21])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: CNCC1CCCN(C)C1
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)N(C)CC3CCCN(C)C3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and N-methyl-1-(1-methylpiperidin-3-yl)methanamine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.09-1.27 (m, 1H) 1.45-1.92 (m, 3 H) 2.15 (br. s., 2 H) 2.37-2.47 (m, 4 H) 2.57-2.75 (m, 3 H) 2.96 (s, 4H) 3.28 (dd, J=12.88, 5.81 Hz, 3 H) 3.49 (d, J=15.41 Hz, 1 H) 7.47 (d, J=8.53 Hz, 1 H) 7.52 (s, 1 H) 7.84 (s, 1 H) 7.89 (br. s., 1 H) 8.20 (d, J=8.34 Hz, 1 H) 8.49 (br. s., 1 H) 8.52 (d, J=8.84 Hz, 1 H); ESI-MS m/z [M+H]+ 445.2.
Reaction SMILES: C(OC([N:8]1[CH:12]([C:13]([OH:15])=O)[CH2:11][S:10][CH:9]1[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)=O)(C)(C)C.[ClH:22].[CH2:23]([O:25][C:26](=[O:33])[C@@H:27]([CH2:29][CH2:30][S:31][CH3:32])[NH2:28])[CH3:24]>>[ClH:22].[ClH:22].[CH2:23]([O:25][C:26](=[O:33])[C@@H:27]([CH2:29][CH2:30][S:31][CH3:32])[NH:28][C:13]([CH:12]1[CH2:11][S:10][CH:9]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[NH:8]1)=[O:15])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1C(C(=O)O)CSC1c1cccnc1
Reactant: CCOC(=O)[C@H](N)CCSC
Agent: Cl
Product: CCOC(=O)[C@@H](CCSC)NC(=O)C1CSC(c2cccnc2)N1

Procedure:
N-tert-Butoxycarbonyl-2-(3-pyridyl)thiazolidine-4-carboxylic acid and D-methionine ethyl ester hydrochloride were used as the starting materials and treated in the same manner as in Example 4 to give [2-(3-pyridyl)thiazolidine-4-carbonyl]-D-methionine ethyl ester dihydrochloride. Melting point 94°-96° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:19][CH2:20][CH3:21])[C:10]3[C:15]([C:16]=2[CH3:17])=[CH:14][C:13]([OH:18])=[CH:12][CH:11]=3)=[CH:4][CH:3]=1.[CH2:22]([O:24][C:25](=[O:30])[C:26](Br)([CH3:28])[CH3:27])[CH3:23]>>[CH2:22]([O:24][C:25](=[O:30])[C:26]([O:18][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:19][CH2:20][CH3:21])[C:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)=[C:16]2[CH3:17])([CH3:28])[CH3:27])[CH3:23]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: CCCn1c(-c2ccc(Cl)cc2)c(C)c2cc(O)ccc21
Product: CCCn1c(-c2ccc(Cl)cc2)c(C)c2cc(OC(C)(C)C(=O)OCC)ccc21

Procedure:
The above compound was prepared from 2-(4-chloro-phenyl)-3-methyl-1-propyl-1H-indole-5-ol and 2-bromo-2-methyl-propanoic acid ethylester using a procedure analogous to that of Example 10.
Reaction SMILES: C([N:8]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]([CH2:15][OH:16])[CH2:9]1)C1C=CC=CC=1>CO.[Pd]>[NH:8]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]([CH2:15][OH:16])[CH2:9]1
Reactant: OCC1CCCCN(Cc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: OCC1CCCCNC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
(1-Benzyl-azepan-3-yl)-methanol (0.0922 g, 0.4192 mmol) dissolved in MeOH (1 mL) was added to a stirring suspension of 10% Pd/C (14.4 mg) in 5 mL MeOH. The reaction was purged with H2, and the reaction was stirred at room temperature overnight. The reaction was judged complete by 1H-NMR analysis of an aliquot from the reaction. The reaction was filtered through a pad of Celite wet with MeOH and was rinsed with MeOH, and concentrated in vacuo to obtain pure azepan-3-yl-methanol in 60% yield (0.0323 g), which was used in the next step without further purification. 1H NMR (CDCl3, 300 MHz, partial) 3.14-2.70 (4H, m), 1.92-1.73 (4H, m), 1.68-1.42 (3H, m) ppm. 13C NMR (CDCl3, 75 MHz) 67.32, 52.01, 50.33, 41.31, 31.05, 29.76, 25.44 ppm.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)=[CH:3][CH:2]=1.[C:15](Cl)([Cl:17])=[O:16]>C1(C)C=CC=CC=1>[Cl:14][C:10]1[CH:9]=[C:8]([N:7]([C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)[C:15]([Cl:17])=[O:16])[CH:13]=[CH:12][CH:11]=1
Reactant: Clc1cccc(Nc2ccccc2)c1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)N(c1ccccc1)c1cccc(Cl)c1
Yield: 58 %

Procedure:
Following the procedure of Example 15, Step A, 20.4 g (100 mmole) of 3-chlorodiphenylamine i.e., N-(3-chlorophenyl)aniline] and phosgene in toluene gave 15.4 g (58%) of N-(3-chlorophenyl)-N-phenylcarbamoyl chloride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:39]2[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=2)=[C:9]([C:15]2[N:16]=[N:17][N:18]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=2)[C:10](OCC)=[O:11])=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:39]2[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=2)=[C:9]([C:15]2[N:16]=[N:17][N:18]([C:20]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:19]=2)[CH2:10][OH:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=C(c1ccc(F)cc1)c1ccc(F)cc1)c1nnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: OCC(=C(c1ccc(F)cc1)c1ccc(F)cc1)c1nnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 3 h
Yield: 75.5 %

Procedure:
To a stirred solution of 3 g (5 mmol) ethyl 3,3-bis(4-fluorophenyl)-2-[2-triphenylmethyl-2H-tetrazol-5-yl]-2-propenoate in 50 mL of methylene chloride at -70° C., 10 mL (15 mmol) diisobutylaluminum hydride solution (1.5M in methylene chloride) was added and the solution stirred for 3 hours. The reaction is quenched with water and the mixture extracted with methylene chloride. The combined organic fractions were dried with magnesium sulfate and concentrated in vacuo to give 2.1 g of the title compound; m.p.=176°-178° C.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([OH:10])=O)=[C:6]([C:11](=[O:13])[CH3:12])[CH:5]=[CH:4][CH:3]=1.[F:14][C:15]1[CH:16]=[C:17]([NH:22][C:23](=[O:26])[NH:24][NH2:25])[CH:18]=[C:19]([F:21])[CH:20]=1>CO>[F:14][C:15]1[CH:16]=[C:17]([NH:22][C:23](=[O:26])[NH:24][N:25]=[C:8]([OH:10])[C:7]2[C:2]([F:1])=[CH:3][CH:4]=[CH:5][C:6]=2[C:11](=[O:13])[CH3:12])[CH:18]=[C:19]([F:21])[CH:20]=1
Reactant: CC(=O)c1cccc(F)c1C(=O)O
Reactant: NNC(=O)Nc1cc(F)cc(F)c1
Solvent: CO
Product: CC(=O)c1cccc(F)c1C(O)=NNC(=O)Nc1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3 g of 6-fluoro-2-acetyl benzoic acid and 3 g of 4-(3,5-difluorophenyl)-semicarbazide are mixed in 20 ml of methanol and heated until clear. The solution is then stirred at R.T. for 24 hr. A white solid forms which is filtered and dried in vacuum at 60° to yield the title product m.p. 227° (decomp.). The corresponding sodium salt is made by reaction of the free acid with 25% sodium methoxylate/methanol.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21](O)[N:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[CH3:24][OH:25].[OH2:26]>>[OH:25][C@@H:24]1[CH2:2][CH2:1][N:4]([C:21]2[N:20]=[CH:19][C:16]3[C:17]4[N:11]([CH:10]=[C:9]([C:8]5[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[CH:6][N:7]=5)[N:18]=4)[CH2:12][CH2:13][O:14][C:15]=3[CH:22]=2)[C@@H:8]1[C:9]([NH2:18])=[O:26]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(O)cc1OCC2
Reactant: CO
Reactant: O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(N3CC[C@@H](O)[C@H]3C(N)=O)cc1OCC2
Yield: 6 %

Procedure:
Following the procedures of Example 339, 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-ol from Example 93 and 3-cis-hydroxy-L-prolinamide were reacted and the crude product subjected to RPHPLC (C18 column, gradient 15 to 55% methanol in water+0.1% HCO2H) to give 397 as a white powder (11 mg, 6%). LCMS: RT=2.28 min, [M+H]+425. 1H NMR 400 MHz (DMSO-d6) δ: 9.08 (1 H, s), 7.91 (1 H, d, J=0.63 Hz), 7.85 (1 H, s), 7.20 (1 H, br), 6.94 (1 H, br), 6.00-5.98 (1 H, m), 5.94 (1 H, s), 5.25 (1 H, d, J=4.81 Hz), 4.51-4.50 (4 H, m), 4.47 (1 H, m), 4.27 (1 H, m), 3.68 (1 H, m), 3.41 (1 H, m), 2.09-2.08 (1 H, m), 2.04-2.01 (1 H, m), 1.50 (6 H, dd, J=6.59, 3.26 Hz)
Reaction SMILES: [N:1]12[CH2:9][CH:5]([C:6](=O)[CH2:7]1)[CH2:4][CH2:3][CH2:2]2.C(O)(=O)C.C([O-])(=O)C.[NH4+].[C:19]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])#[N:20]>C1(C)C=CC=CC=1.O>[N:1]12[CH2:9][CH:5]([C:6](=[C:21]([C:19]#[N:20])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:7]1)[CH2:4][CH2:3][CH2:2]2
Reactant: O=C1CN2CCCC1C2
Reactant: CCOC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C(C#N)=C1CN2CCCC1C2
Reaction time: 40 h

Procedure:
A solution of 1-azabicyclo[3.2.1]octan-6-one (41.25 g, 0.33 mol), acetic acid (2 ml), ammonium acetate (1.25 g) and ethyl cyanoacetate (37 g, 0.33 mol) in toluene (500 ml) was refluxed with a Dean-Stark water separator for 40 h. The toluene phase was extracted with 3×200 ml 5M HCl solution. The water phase was basified with 28% ammonium hydroxide solution and extracted with ether (4×200 ml). The organic phases were dried over magnesium sulfate and evaporated. The residue was purified by column chromatography (eluent CH2Cl2 /MeOH (9:1), yield 41 g of the title compound.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH:20][CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN(CC)CC.[C:32](OC(=O)C)(=[O:34])[CH3:33]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:20]([C:32](=[O:34])[CH3:33])[CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)CNc1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N(CC(C)C)c1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of N-boc-4-(2-isobutylamino-phenyl)-piperazine (333 mg, 1.0 mmol, 1.0 eq), Et3N (0.42 mL, 3.0 mmol, 3.0 eq) and DMAP (6 mg, 0.05 mmol, 0.05 eq) in DCM (10 mL) was added acetic anhydride (0.14 mL, 1.5 mmol, 1.5 eq). The mixture was stirred at r.t. overnight. The reaction was diluted with DCM (50 mL) and washed with saturated aqueous NaHCO3 (25 mL) and brine (25 mL). The organic layer was separated and aqueous layer was extracted with DCM (2×). The combined organic extracts were dried (Na2SO4), filtered and concentrated to afford the title compound (375 mg, 1.0 mmol, 100%). LRMS (ESI+): 376.18 (M+1)
Reaction SMILES: [N+]([C:4]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:5]=1[CH:12]=[C:13]([N+:15]([O-])=O)[CH3:14])([O-])=O.CCOC(C)=O.C(O)(=O)C>[Pd].CCO>[CH3:14][C:13]1[NH:15][C:4]2[C:5]([CH:12]=1)=[CH:6][CH:7]=[CH:8][C:9]=2[O:10][CH3:11]
Reactant: COc1cccc(C=C(C)[N+](=O)[O-])c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cccc2cc(C)[nH]c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 27.8 %

Procedure:
To a 2 L hydrogenation flask were added 1-(2-Nitro-3-methoxyphenyl)-2-nitropropene (44 g, 0.1850 mol), 10% Pd/C (4.4 g, 50% water wet), EtOAc (600 mL), acetic acid (90 mL) and absolute EtOH (75 mL). The reaction mixture was hydrogenated at <60 psi for 3 h and then filtered. The cake was washed with EtOAc (3×100 mL). The filterate was concentrated to remove EtOAc and EtOH. DI water (200 mL) was then added slowly. The resulting slurry was stirred for 0.5 h at RT and filtered. The cake was washed with 1:2 HOAc/H2O (2×30 mL) 1:4 HOAc/H2O (50 mL), water (2×80 mL) and suction dried for 18 h to give 2-methyl-7-methoxyindole (8.3 g, 62% yield). 1H NMR (CDCl3) δ2.42 (s, 3H), 3.94 (s, 3H), 6.18 (pseudo t, J=1.1 Hz, 1H), 6.57 (d, J=7.7 Hz, 1H), 6.97 (pseudo t, J=7.7 Hz, 1H), 7.12 (d, J=7.7 Hz, 1H), 8.10 (s, 1H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[CH2:17]([O:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]=1[CH:30]=O)[CH3:18].C(N(C(C)C)CC)(C)C.C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([CH2:30][C:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:28]=[CH:29][C:20]=2[O:19][CH2:17][CH3:18])[CH2:13][CH2:12]1
Reactant: c1ccc2sc(NC3CCNCC3)nc2c1
Reactant: CCOc1ccc2ccccc2c1C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Product: CCOc1ccc2ccccc2c1CN1CCC(Nc2nc3ccccc3s2)CC1
Temperature: 40 °C
Reaction time: 1 h
Yield: 8 %

Procedure:
To a solution of benzothiazol-2-yl-piperidin-4-yl-amine (23.3 mg, 0.1 mmol, 1.0 equiv) and 2-ethoxy-naphthalene-1-carbaldehyde (commercially available, 24.0 mg, 0.12 mmol, 1.2 equiv) in ethanol (2 mL) was added diisopropylethylamine (23.42 μL, 25.9 mg, 0.2 mmol, 2.0 equiv) and acetic acid (18.0 mg, 0.3 mmol, 3.0 equiv) and the mixture stirred at 40° C. After 1 h, sodium cyano borohydride (7.54 mg, 0.12 mmol, 1.2 equiv) was added and the mixture stirred at 40° C. over night. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 3.3 mg (8%) of the title compound. MS (ESI): 418.4 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.C(O)(C(F)(F)F)=O.[CH3:19][C:20]1[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[C:21]=1[NH2:22]>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][C:21]2[C:23]([CH3:28])=[CH:24][C:25]([CH3:27])=[CH:26][C:20]=2[CH3:19])[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: Cc1cc(C)c(N)c(C)c1
Reactant: Clc1nc(Cl)c2sccc2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C)c(Nc2nc(Cl)nc3ccsc23)c(C)c1
Temperature: 90 °C
Reaction time: 15 h
Yield: 23.2 %

Procedure:
To a solution of 2,4-dichlorothieno[3,2-d]pyrimidine (148 mg, 0.73 mmol), TFA (0.17 mL, 2.19 mmol) in TFE (2 mL) was added 2,4,6-trimethylaniline (0.15 mg, 1.1 mmol) in a sealed tube. The reaction was stirred at 90° C. for 15 h. The reaction mixture was diluted with CH2Cl2 and washed with saturated NaHCO3 solution (3×20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography eluting with Hexanes:ethyl acetate (4:1) to afford the product as a white solid (51.4 mg, 23%):
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=1[C:13]([F:16])([F:15])[F:14].[C:22]([NH:25][C:26]1[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=1)(=[O:24])[CH3:23]>>[C:9]([C:8]1[CH:11]=[CH:12][C:5]([N:4]([CH2:17][C:18]([F:19])([F:20])[F:21])[CH2:3][CH2:2][O:1][C:29]2[CH:30]=[CH:31][C:26]([NH:25][C:22](=[O:24])[CH3:23])=[CH:27][CH:28]=2)=[C:6]([C:13]([F:15])([F:16])[F:14])[CH:7]=1)#[N:10]
Reactant: N#Cc1ccc(N(CCO)CC(F)(F)F)c(C(F)(F)F)c1
Reactant: CC(=O)Nc1ccc(O)cc1
Product: CC(=O)Nc1ccc(OCCN(CC(F)(F)F)c2ccc(C#N)cc2C(F)(F)F)cc1

Procedure:
Synthesized as described in Example 1C from 4-[(2-hydroxyethyl)(2,2,2-trifluoroethyl)amino]-3-(trifluoromethyl)benzonitrile and 4-acetamidophenol: MS (APCI) m/z 446 (M+1).
Reaction SMILES: ClC(Cl)(OC(=O)[O:6][C:7]([Cl:10])(Cl)Cl)Cl.[N:13]1([C:19](=[O:21])[CH3:20])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.N1C=CC=CC=1>C(Cl)Cl>[C:19]([N:13]1[CH2:18][CH2:17][N:16]([C:7]([Cl:10])=[O:6])[CH2:15][CH2:14]1)(=[O:21])[CH3:20]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N1CCN(C(=O)Cl)CC1
Temperature: 25 °C
Yield: 75.3 %

Procedure:
To a stirred solution of carbonic acid ditrichloromethyl ester (triphosgene) (2.31 g, 7.80 mmol) in CH2Cl2 (30 ml) at 0° C., was added a solution of 1-piperazin-1-yl-ethanone (2.0 g, 15.6 mmol) and pyridine (1.38 ml, 17.2 mmol) in CH2Cl2 (5 ml) over 30 minutes. The temperature was raised to RT, and stirring was continued over night. The organic phase was washed with H2O, dried over Na2SO4. Purification by flash chromatography (SiO2, EtOAc) yielded 1.12 g (38%) of the title compound as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12](=[O:13])[N:11]([C:14]3[CH:15]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:18][CH:19]=3)[NH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:30](I)[CH3:31]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12](=[O:13])[N:11]([C:14]3[CH:15]=[C:16]([C:20]([F:21])([F:22])[F:23])[CH:17]=[CH:18][CH:19]=3)[N:10]([CH2:30][CH3:31])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCI
Reactant: O=c1c(-c2cccc(Cl)c2)c[nH]n1-c1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCn1cc(-c2cccc(Cl)c2)c(=O)n1-c1cccc(C(F)(F)F)c1

Procedure:
A mixture of 4.6 grams of the pyrazolinone prepared above, 4 grams potassium carbonate, 15 ml. ethyl iodide and 50 ml. ethanol was refluxed overnight. The reaction product mixture was worked up in the customary way to yield 1.8 grams of the desired product, m.p.=113°-114° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:3][CH:2]=1.C(N(CC)CC)C.Br[CH2:21][C:22]([C:24]1[CH:25]=[CH:26][C:27]2[O:31][C:30]([C:32]([O:34][CH3:35])=[O:33])=[CH:29][C:28]=2[CH:36]=1)=[O:23]>C(#N)C>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][N:10]([CH2:21][C:22]([C:24]3[CH:25]=[CH:26][C:27]4[O:31][C:30]([C:32]([O:34][CH3:35])=[O:33])=[CH:29][C:28]=4[CH:36]=3)=[O:23])[CH2:11][CH2:12]2)=[CH:3][CH:2]=1
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: COC(=O)c1cc2cc(C(=O)CBr)ccc2o1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)c1cc2cc(C(=O)CN3CCN(c4ccncc4)CC3)ccc2o1
Reaction time: 2 h

Procedure:
To a solution of 1-(4-pyridyl)piperazine (262 mg) and triethylamine (0.1 ml) in acetonitrile (10 ml) was added dropwise over 40 minutes a solution of methyl 5-(2-bromoacetyl)benzofuran-2-carboxylate in acetonitrile (5 ml). The resulting mixture was stirred for 2 hours, concentrated and purified by flash column chromatography on grade III alumina, eluting with methanol/dichloromethane (1:99 to 4:96 v/v) to give the title compound as a solid (138 mg); m.p. 173°-177° C.: NMR 2.66(4H,m), 3.8(4H,m), 3.91(3H,s), 4.00(2H,s), 6.82(2H,m), 7.8-8.5(6H,m); m/e 380 (M+H+); calculated for C21H21N3O4.0.5H2O: C, 64.9; H, 5.7; N, 10.8. Found: C, 65.2; H, 5.7; N, 10.9%. The starting ester was prepared as follows:
Reaction SMILES: [CH:1]([NH2:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]([NH:22][C@:23]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:28](O)=[O:29])[CH2:24][C:25]([OH:27])=[O:26])([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].C1CCC(N=C=NC2CCCCC2)CC1.N[C@H](C(O)=O)CC(O)=O>C(Cl)Cl.CCN(CC)CC>[C:15]([NH:22][C@:23]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:28]([NH:14][CH:1]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:29])[CH2:24][C:25](=[O:26])[OH:27])([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]
Reactant: CC(C)(C)OC(=O)N[C@](CC(=O)O)(Cc1ccccc1)C(=O)O
Reactant: NC(c1ccccc1)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: N[C@@H](CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@](CC(=O)O)(Cc1ccccc1)C(=O)NC(c1ccccc1)c1ccccc1
Reaction time: 0.25 h

Procedure:
Benzhydrylamine resin (10 g., 0.4 mmol/g.) was stirred with 250 ml. of 25% Et3N in CH2Cl2 for 10 minutes and then washed a few times with fresh CH2Cl2. It was then suspended in 240 ml. of CH2Cl2 and stirred with Boc-α-benzyl-L-aspartic acid (3.24 g., 10 mmol) and DCC (2.06 g., 10 mmol) for 17 hours. The amino acylated resin was collected, washed thoroughly with CH2Cl2, DMF and MeOH. It was dried and benzoylated with 1.5 ml. of pyridine and 1.65 ml. of benzoyl chloride in 110 ml. of CH2Cl2 for 15 minutes at 0° C. The resin was washed with CH2Cl2, MeOH to give 10.7 g. of desired material. Amino acid analysis indicated that there was 0.40 mmol/g. of aspartic acid.
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][CH:4]=[O:5].O1[CH2:11][CH2:10][CH2:9][CH2:8]1.[CH:12](O)=O>>[CH3:1][C:2]1[CH2:6][CH2:11][C:10](=[C:9]([CH3:12])[CH3:8])[C:4](=[O:5])[CH:3]=1
Reactant: O=CO
Reactant: CC(C)=CC=O
Reactant: C1CCOC1
Product: CC1=CC(=O)C(=C(C)C)CC1
Yield: 83 %

Procedure:
A mixture of 200 parts of 3,3-dimethylacrolein, 600 parts of tetrahydrofuran and 1 part of formic acid is heated for 2 hours at a pressure of 120 atmospheres and a temperature of 280°C in an autoclave. The reaction product is worked up by distillation. 106 parts of piperitenone is obtained having a boiling point of 120° to 122°C at 14 mm Hg. The yield is 83% of theory at a conversion of 72%.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:50])[C@@H:13]([NH:19][C:20]([C:22]2[CH:26]=[C:25]([O:27][CH2:28][C:29]([N:31]3[CH2:35][CH2:34][CH2:33][C@H:32]3[C:36](=[O:42])[NH:37][CH:38]3[CH2:41][CH2:40][CH2:39]3)=[O:30])[N:24]([C:43]3[CH:48]=[CH:47][CH:46]=[C:45]([F:49])[CH:44]=3)[N:23]=2)=[O:21])[CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(Cl)CCl.[CH2:55]([OH:57])[CH3:56]>ClCCl.CN(C1C=CN=CC=1)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:50])[C@@H:13]([NH:19][C:20]([C:22]2[CH:26]=[C:25]([O:27][CH2:28][C:29]([N:31]3[CH2:35][CH2:34][CH2:33][C@H:32]3[C:36](=[O:42])[NH:37][CH:38]3[CH2:39][CH2:40][CH2:41]3)=[O:30])[N:24]([C:43]3[CH:48]=[CH:47][CH:46]=[C:45]([F:49])[CH:44]=3)[N:23]=2)=[O:21])[CH2:14][CH2:15][C:16]([O:18][O:57][CH2:55][CH3:56])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)O)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3cccc(F)c3)n2)CC1
Reactant: CCO
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CCOOC(=O)CC[C@H](NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2cccc(F)c2)n1)C(=O)N1CCN(C(=O)OCC)CC1

Procedure:
To a solution of 1.60 g 4-((S)-4-Carboxy-2-{[5-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-(3-fluoro-phenyl)-1H-pyrazole-3-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester in 30 ml dichloromethane were added 526 mg EDC, 335 mg DMAP and 676 μl ethanol. After 3 h the reaction mixture was concentrated and the residue purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were lyophilized to yield the pure product. Yield: 295 mg MS (ES+): m/e=728.
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][CH2:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[N:10]=[C:6]2[C:5]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:4][CH:3]=1.CC1(C)C(C)(C)CB([C:37]2[CH:56]=[CH:55][C:40]([C:41]([N:43]3[CH2:47][CH2:46][CH2:45][C@H:44]3[C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])=[O:42])=[CH:39][CH:38]=2)C1>>[O:26]1[CH2:27][CH2:28][N:23]([C:5]2[C:6]3[N:7]([CH:8]=[C:9]([CH2:11][CH2:12][C:13]4[CH:22]=[CH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[N:14]=4)[N:10]=3)[C:2]([C:37]3[CH:56]=[CH:55][C:40]([C:41]([N:43]4[CH2:47][CH2:46][CH2:45][C@H:44]4[C:48]([O:50][C:51]([CH3:52])([CH3:54])[CH3:53])=[O:49])=[O:42])=[CH:39][CH:38]=3)=[CH:3][N:4]=2)[CH2:24][CH2:25]1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)c1ccc(B2CC(C)(C)C(C)(C)C2)cc1
Reactant: Brc1cnc(N2CCOCC2)c2nc(CCc3ccc4ccccc4n3)cn12
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)c1ccc(-c2cnc(N3CCOCC3)c3nc(CCc4ccc5ccccc5n4)cn23)cc1
Yield: 88.7 %

Procedure:
Compound 3a (250 mg, 0.570 mmol) was subjected to Suzuki coupling conditions with (S)-tert-butyl 1-(4-(3,3,4,4-tetramethylborolan-1-yl)benzoyl)pyrrolidine-2-carboxylate (686 mg, 1.71 mmol) using the reaction conditions described in Example 1, Step G to obtain compound 17b as a brown solid (320 mg, 81% yield). Mass Spectrum (LCMS, ESI pos.): Calcd. for C37H40N6O4: 633.3 (M+H). Found 633.2.