Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(O)(O)(=O)=O.[CH3:6][N:7]1[C:11]([NH2:12])=[C:10]([NH2:13])[CH:9]=[N:8]1.[CH2:14]([O:21][C:22]([NH:24][C@@H:25]([CH2:29][CH2:30][CH2:31][NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:26](O)=[O:27])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>C(Cl)(Cl)Cl>[NH2:12][C:11]1[N:7]([CH3:6])[N:8]=[CH:9][C:10]=1[NH:13][C:26]([C@@H:25]([NH:24][C:22](=[O:23])[O:21][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:29][CH2:30][CH2:31][NH:32][C:33](=[O:34])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:27]
Reactant: Cn1ncc(N)c1N
Reactant: CC(C)(C)OC(=O)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cn1ncc(NC(=O)[C@H](CCCNC(=O)OC(C)(C)C)NC(=O)OCc2ccccc2)c1N
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a suspension of 1-methyl-1H-pyrazole-4,5-diamine sulfate (2.10 g), (2S)-2-[(benzyloxycarbonyl)amino]-5-[(tert-butoxycarbonyl)amino]pentanoic acid (3.66 g) and triethylamine (3.04 g) in chloroform (50 ml) was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.91 g), and the mixture was stirred at room temperature for 15 hours. The reaction mixture was washed successively with 10% aqueous citric acid solution, brine and saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a crude product of 1-benzyl 4-tert-butyl {(1S)-1-[(5-amino-1-methyl-1H-pyrazol-4-yl)carbamoyl]tetramethylene}biscarbamate as an oil. The crude product was used directly in the next step without further purification.
Reaction SMILES: [C:1]([C:4]1[CH:29]=[CH:28][C:7]([C:8]([NH:10][C:11]2[CH:27]=[CH:26][CH:25]=[CH:24][C:12]=2[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[O:14])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:30][Mg]Br.C(OCC)C>O1CCCC1>[OH:3][C:1]([C:4]1[CH:29]=[CH:28][C:7]([C:8]([NH:10][C:11]2[CH:27]=[CH:26][CH:25]=[CH:24][C:12]=2[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[O:14])=[O:9])=[CH:6][CH:5]=1)([CH3:30])[CH3:2]
Reactant: COc1ccc(NC(=O)c2ccccc2NC(=O)c2ccc(C(C)=O)cc2)cc1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(NC(=O)c2ccccc2NC(=O)c2ccc(C(C)(C)O)cc2)cc1
Reaction time: 1 h
Yield: 14 %

Procedure:
To a solution of 2-(4-acetylbenzoylamino)-N-(4-methoxyphenyl)benzamide (161 mg, 0.410 mmol) in tetrahydrofuran (10 mL) cooled to 0° C. was added 3 M methyl magnesium bromide in diethyl ether (0.2 mL, 0.6 mmol). After 1 h, the reaction mixture was quenched with saturated aqueous ammonium chloride solution (2 mL), diluted with ether, and washed with water. The organic layer was dried (magnesium sulfate), filtered, and concentrated in vacuo. The residue was chromatographed (silica gel, 15% ethyl acetate/85% hexanes to 35% ethyl acetate/65% hexanes) to give 24 mg (14%) of the title compound as a white solid.
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[CH:5][CH:4]=1)=O.[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[BH4-].[Na+]>CO>[CH2:19]([NH:26][CH2:1][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[CH:5][CH:4]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NCc1ccccc1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1ccc(Oc2ccc(CNCc3ccccc3)cc2)nc1
Reaction time: 18 h

Procedure:
Combine 6-(4-Formyl-phenoxy)-nicotinamide (0.097 g, 0.4 mmol) in 5 mL of methanol with benzylamine (0.4 mmol), and 1 g of 3 {acute over (Å)} molecular sieves. Stir for 18 h. Add sodium borohydride (0.076 g, 2 mmol), and stir for 18 h. Flush the reactions down through a 5 g SCX column, first wash with 1:1 chloroform/methanol, then collect washes with 1:1 chloroform/2 M ammonia in methanol. Adsorb the collected material on silica, then purify via a ISCO® Combiflash 16× system (use a 10 g silica cartridge, and elute with 98:2:0.2 chloroform/ethanol/ammonium hydroxide, gradient to 90:10:1 chloroform/ethanol/ammonium hydroxide). 1H NMR (DMSO-d6): 8.58 (d, 1H), 8.22 (m, 1H), 8.0 (s, 1H), 7.46 (s, 1H), 7.27-7.38 (m, 6H), 7.20 (m, 1H) 7.02-7.08 (m, 3H), 3.67-3.68 (d, 4H). TLC Rf (90:10:1 chloroform/ethanol/ammonium hydroxide): 0.31.
Reaction SMILES: [K+].[NH:2]1[CH2:6][CH2:5][C@@H:4]([S:7][C:8]2[C@H:9]([CH3:22])[C@@H:10]3[C@@H:17]([C@H:18]([OH:20])[CH3:19])[C:16](=[O:21])[N:11]3[C:12]=2[C:13]([O-:15])=[O:14])[C:3]1=[S:23].[C:24]([O:29][CH2:30]I)(=[O:28])[CH:25]([CH3:27])[CH3:26].C(OCC)(=O)C>CN(C)C=O>[C:24]([O:29][CH2:30][O:14][C:13]([C:12]1[N:11]2[C:16](=[O:21])[C@H:17]([C@H:18]([OH:20])[CH3:19])[C@H:10]2[C@@H:9]([CH3:22])[C:8]=1[S:7][C@@H:4]1[CH2:5][CH2:6][NH:2][C:3]1=[S:23])=[O:15])(=[O:28])[CH:25]([CH3:27])[CH3:26]
Reactant: CC(C)C(=O)OCI
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S[C@@H]3CCNC3=S)[C@H](C)[C@H]12
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)C(=O)OCOC(=O)C1=C(S[C@@H]2CCNC2=S)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Reaction time: 0.5 h
Yield: 24.1 %

Procedure:
(1R, 5S, 6S)-2-[(3R)-Pyrrolidine-2-thion-3-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid potassium salt (0.5 g) is suspended in N,N-dimethylformamide (5 ml). To the suspension is added isobutyryloxymethyl iodide (338 mg) under ice cooling, and the mixture is stirred at the same temperature for 30 minutes. To the reaction mixture is added ethyl acetate, and the mixture is washed with water, dried and concentrated to dryness under reduced pressure. The residue is purified by silica gel flash column chromatography (eluent, chloroform:methanol=20:1) to give (1R, 5S, 6S)-2-[(3R)-pyrrolidine-2-thion-3-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid isobutyryloxymethyl ester (0.14 g) as an amorphous powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH3:12])[CH:6]=[CH:5]2.[CH2:13]([O:20][C:21]([N:23]1[C@H:25]([CH3:26])[C@@H:24]1[C:27]([O:29][CH3:30])=[O:28])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.B(F)(F)F.CCOCC>C(Cl)Cl>[CH3:30][O:29][C:27](=[O:28])[C@@H:24]([C@H:25]([CH3:26])[C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=2)[N:7]([CH2:11][CH3:12])[CH:6]=1)[NH:23][C:21]([O:20][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:22]
Reactant: COC(=O)[C@H]1[C@@H](C)N1C(=O)OCc1ccccc1
Reactant: CCn1ccc2cc(Cl)ccc21
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCn1cc([C@@H](C)[C@@H](NC(=O)OCc2ccccc2)C(=O)OC)c2cc(Cl)ccc21
Reaction time: 0.08 h
Yield: 28.3 %

Procedure:
To a solution of 5-chloro-1-ethylindole (6.17 g) and methyl (2R,3R)-N-benzyloxycarbonyl-3-methyl-2-aziridinecarboxylate (9.87 g) in dry methylene chloride (100 ml) which was cooled on an ice bath, was added boron trifluoride etherate (4 ml). The mixture was stirred for five minutes and washed with saturated sodium bicarbonate solution, treated with active charcoal, and dried over magnesium sulfate. After removal of the solvent, the crude residue was chromatographed on silica gel (100 g) (toluene as eluent) to give (αR,βR)-N-benzyloxycarbonyl-5-chloro-1-ethyl-β-methyltryptophan methyl ester (4.17 g) as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[C:16](Br)[CH:17]=[N:18][CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([Mg]Cl)[CH2:22][CH3:23]>C1COCC1.C(OCC)C>[CH2:21]([C:16]1[CH:15]=[C:14]([O:13][CH2:12][C@@H:9]2[CH2:10][CH2:11][N:8]2[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:19]=[N:18][CH:17]=1)[CH2:22][CH3:23]
Reactant: CCC[Mg]Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(Br)c1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCc1cncc(OC[C@@H]2CCN2C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Yield: 22 %

Procedure:
To a solution of 5-(N-t-butyloxycarbonyl-(2S)-azetidinylmethoxy)-3-bromopyridine (1.50 g, 4.37 mmol, Example 12a above) in THF (30 mL) at 0° C. was added [1,3-bis(diphenylphosphino)-propane]nickel(II) (14.0 mg) followed by propylmagnesium chloride (5.50 mL of a 2 M solution in diethyl ether, Aldrich). The reaction mixture was refluxed for 3 h, cooled to ambient temperature and then quenched with saturated aqueous ammonia chloride. The desired product was extracted with CH2Cl2. The organic phase was dried over MgSO4, filtered and concentrated. The residue was chromatographed (silica gel; hexane/EtOAc, 10:1 to 1:1) to afford 5-propyl-3-(N-t-butyloxycarbonyl-(2S)-azetidinylmethoxy)pyridine as an oil (292 mg, 22%): MS (CI/NH3) m/z: 307 (M+H)+; 1H NMR (CDCl3, 300 MHz) δ0.95 (t, J=8.3 Hz, 3H), 1.42 (s, 4.5H), 1.46 (s, 4.5H), 1.60-1.70 (m, 2H), 2.22-2.40 (m, 2H), 2.56 (t, J=8.3 Hz, 2H), 3.70-3.80 (m, 2H), 3.90 (m, 1H), 4.13 (m, 1H), 4.51 (m, 1H), 7.04 (s, 1H), 8.06 (s, 1H), 8.18 (d, J=3.3 Hz, 1H). To a 0° C. solution of 5-propyl-3-(N-t-butyloxycarbonyl-(2S)-azetidinylmethoxy)pyridine (290 mg, 0.950 mmol) in CH2Cl2 (3 mL) was added TFA (3 mL). After stirring for 30 min the reaction mixture was basified with 15% aqueous NaOH and extracted with CH2Cl2 (3×). The combined organic extracts were dried over MgSO4, filtered and concentrated. Purification by chromatography (silica gel; CH2Cl2/MeOH, 10:0.5) afforded the free base of the title compound as an oil (103 mg, 53%): MS (CI/NH3) m/z: 207 (M+H)+; 1H NMR (CDCl3, 300 MHz) δ0.94 (t, J=8.3 Hz, 3H), 1.58-1.70 (m, 2H), 2.30-2.48 (m, 2H), 2.55 (t, J=8.3 Hz, 2H), 3.57 (m, 1H), 3.76 (q, J=8.3 Hz, 1H), 4.04-4.10 (m, 2H), 4.39 (m, 1H), 7.03 (t, J=3.0 Hz, 1H), 8.04 (s, 1H), 8.14 (d, J=3.3 Hz, 1H). The free base was dissolved in Et2O and a saturated solution of HCl in Et2O was added dropwise carefully. The solvent was removed, and the resultant solid was recrystallized from MeOH/Et2O to afford the title compound as a yellow hygroscopic solid: mp 79-80° C.; MS (CI/NH3) m/z: 207 (M+H)+; 1H NMR (D2O, 300 MHz) δ1.01 (t, J=3.05 Hz, 3H), 1.68-1.80 (m, 2H), 2.62-2.78 (m, 2H), 2.80 (t, J=7.1 Hz, 2H), 4.04-4.21 (m, 3H), 4.44-4.60 (m, 2H), 7.40 (s, 1H), 8.04 (s, 1H), 8.14 (s, 1H). Anal. Calcd for C12H18N2O.2 HCl.H2O: C, 48.49; H, 7.46; N, 9.43. Found: C, 48.35; H, 7.23; N, 9.48.
Reaction SMILES: [CH2:1]([C@H:8]([NH:23][C:24](=[O:33])[C:25]1[CH:30]=[CH:29][C:28](F)=[C:27]([Br:32])[CH:26]=1)[C@@H:9]([OH:22])[CH2:10][C@H:11]([C:13](=[O:21])[NH:14][CH2:15][CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C12CC(CC1)CC2NC(=O)[C@H](C)C[C@H:45]([OH:55])[C@@H](N)CC1C=CC=CC=1.BrC1C=C(C=C(OC)C=1)C(O)=O>>[CH2:1]([C@H:8]([NH:23][C:24](=[O:33])[C:25]1[CH:30]=[C:29]([O:55][CH3:45])[CH:28]=[C:27]([Br:32])[CH:26]=1)[C@@H:9]([OH:22])[CH2:10][C@H:11]([C:13](=[O:21])[NH:14][CH2:15][CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](C[C@H](O)[C@@H](N)Cc1ccccc1)C(=O)NC1CC2CCC1C2
Reactant: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1ccc(F)c(Br)c1)C(=O)NCCC(C)(C)C
Agent: COc1cc(Br)cc(C(=O)O)c1
Product: COc1cc(Br)cc(C(=O)N[C@@H](Cc2ccccc2)[C@@H](O)C[C@@H](C)C(=O)NCCC(C)(C)C)c1

Procedure:
Prepared as for D3 from (2R,4S,5S)-5-amino-4-hydroxy-2-methyl-6-phenylhexanoic acid (bicyclo[2.2.1]hept-2-yl)amide (D29) and 3-bromo-5-methoxybenzoic acid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([Cl:19])=[CH:10][C:9]=1[NH:20][C:21](=[O:44])[CH2:22][C:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N:30]2[C:34]([CH2:35][O:36]C3CCCCO3)=[CH:33][N:32]=[N:31]2)[CH:25]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:19][C:11]1[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:13][C:8]2[N:7]=[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([N:30]4[C:34]([CH2:35][OH:36])=[CH:33][N:32]=[N:31]4)[CH:25]=3)[CH2:22][C:21](=[O:44])[NH:20][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCCC2)c(Cl)cc1NC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(-n3nncc3CO)c2)=Nc2cc(N3CCCC3)c(Cl)cc2N1

Procedure:
The title compound was prepared from (RS)-[4-chloro-2-(3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionylamino)-5-pyrrolidin-1-yl-phenyl]-carbamic acid tert.-butyl ester (Example M30) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (58 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[N:13]1[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14]1)[C:6]([NH:8][NH2:9])=O.[F:19][C:20]1[CH:21]=[C:22]([C:27]2([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:32][CH2:31][CH2:30][N:29]=[C:28]2SC)[CH:23]=[CH:24][C:25]=1[F:26]>C(O)C.C(OCC)(=O)C>[F:19][C:20]1[CH:21]=[C:22]([C:27]2([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:32][CH2:31][CH2:30][N:29]3[C:6]([C:5]4[CH:10]=[CH:11][C:12]([N:13]5[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14]5)=[C:3]([O:2][CH3:1])[CH:4]=4)=[N:8][N:9]=[C:28]23)[CH:23]=[CH:24][C:25]=1[F:26]
Reactant: CCOC(=O)C1(c2ccc(F)c(F)c2)CCCN=C1SC
Reactant: COc1cc(C(=O)NN)ccc1-n1cnc(C)c1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(c2ccc(F)c(F)c2)CCCn2c(-c3ccc(-n4cnc(C)c4)c(OC)c3)nnc21
Temperature: 90 °C
Reaction time: 48 h
Yield: 45.9 %

Procedure:
3-Methoxy-4-(4-methyl-1H-imidazol-1-yl)benzohydrazide (236 mg) was added to a mixture of ethyl 3-(3,4-difluorophenyl)-2-(methylsulfanyl)-3,4,5,6-tetrahydropyridine-3-carboxylate (300 mg) in ethanol (3 mL) at room temperature, and the mixture was stirred at 90° C. for 2 days. The reaction mixture was diluted with ethyl acetate, the mixture was washed with water and saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (217 mg).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([CH2:7]P(OC)(OC)=O)=[O:6].[OH:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]2)=[CH:17][CH:16]=1.O>O1CCCC1>[CH3:3][O:4][C:5](=[O:6])[CH:7]=[C:24]1[CH2:23][CH2:22][CH:21]([C:18]2[CH:19]=[CH:20][C:15]([OH:14])=[CH:16][CH:17]=2)[CH2:26][CH2:25]1
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: O=C1CCC(c2ccc(O)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C=C1CCC(c2ccc(O)cc2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 97.8 %

Procedure:
60% suspension mixed with NaH mineral oil (7.6 g, 0.19 mol) was added to trimethyl phosphonoacetate (22.8 mL, 0.15 mol) solution dissolved in anhydrous tetrahydrofuran (655 mL) under 0° C. nitrogen gas. 4-(4-hydroxyphenyl)cyclohexanone (25 g, 0.13 mol) solution dissolved in tetrahydrofuran (525 mL) was slowly added thereto at 25° C. Then, the reaction mixture was stirred at room temperature for 5 hours, cooled with water, and extracted with ethyl acetate. The mixed organic phase was washed with brine and dried with Na2SO4. The solvent was reduced under reduced pressure to obtain [4-(4-hydroxyphenyl)cyclohexylidene]acetic acid methyl ester as a white solid (31.3 g, 97%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH:14]=[CH2:15])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:16]([N:23]1[CH2:28][CH2:27][NH:26][CH:25]([CH:29]=[CH2:30])[CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCN(CC)CC>C(Cl)Cl>[CH2:16]([N:23]1[CH2:28][CH2:27][N:26]([C:10]([C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:13][CH:14]=[CH2:15])=[O:12])[CH:25]([CH:29]=[CH2:30])[CH2:24]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: C=CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: C=CC1CN(Cc2ccccc2)CCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCN(Cc2ccccc2)CC1C=C
Temperature: 25 °C

Procedure:
(2S)-2-[(tert-butoxycarbonyl)amino]-4-pentenoic acid (466 mg, 2.17 mmol) and 1-benzyl-3-vinylpiperazine (436 mg, 2.17 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiinide hydrochloride (HOBT, 622 mg, 3.26 mmol) were combined with anhydrous CH2Cl2 (10 mL) at room temperature. Et3N (0.74 mL, 5.43 mmol) was added in one portion. The resulted solution was maintained at room temperature for 18 h at which time it was concentrated in vacuo to a volume of approximately 5 mL. Then the solution was purified by silica gel chromatography (SGC) eluting with 2:1 hex-EtOAc. The title compound (a pair of diastereomers) was obtained (171 mg, 20%) as a pale-yellow oil. 1H NMR (300 MHz, CDCl3) δ 7.31 (s, 5H), 5.99-5.82 (m, 1H), 5.81-5.65 (m, 1H), 5.50-5.00 (m, 6H), 4.75-4.23 (m, 2H), 3.70-3.37 (m, 3H), 3.11-2.79 (m, 2H), 2.59-2.00 (m, 4H), 1.42 (s, 9H) ppm. MS (CI) 400.6 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([NH:19][NH2:20])=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][N:22]=[C:23]=[S:24]>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([C:17]([NH:19][NH:20][C:23]([NH:22][CH3:21])=[S:24])=[O:18])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN=C=S
Reactant: NNC(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Solvent: Cc1ccccc1
Product: CNC(=S)NNC(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Yield: 95.9 %

Procedure:
N-Benzyloxycarbonyl-4-(hydrazinocarbonyl)piperidine (231 g) was dissolved in toluene (500 ml) and a solution of methyl isothiocyanate (90 g) in toluene (50 ml) was added with stirring. After lhr the resulting precipitate was separated, washed with ether and dried to give the title compound (280 g).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[CH:10]=[C:9]([C:20]([F:23])([F:22])[F:21])[N:8]=2)[CH:6]=1.[NH2:24][C:25]1[CH:30]=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][N:26]=1>>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[CH:10]=[C:9]([C:20]([F:23])([F:22])[F:21])[N:8]=[C:7]([N:5]3[CH:6]=[C:2]([C:28]4[CH:29]=[CH:30][C:25]([NH2:24])=[N:26][CH:27]=4)[N:3]=[CH:4]3)[N:12]=2)=[CH:14][CH:15]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc(-n2cnc(Br)c2)n1
Product: Nc1ccc(-c2cn(-c3nc(-c4ccc(Cl)cc4)cc(C(F)(F)F)n3)cn2)cn1

Procedure:
The title compound was prepared from 2-(4-bromo-imidazol-1-yl)-4-(4-chloro-phenyl)-6-trifluoromethyl-pyrimidine (example E.2) (0.40 g, 1.0 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.22 g, 1.0 mmol) according to the general procedure VI. Obtained as a yellow solid (0.095 g, 23%). MS (ISP) 417.3 [(M+H)+]; mp 254° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.[NH2:32][C:33]1[CH:37]=[CH:36][N:35]([CH2:38][C@@H:39]([OH:44])[CH2:40][N:41]([CH3:43])[CH3:42])[N:34]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:43][N:41]([CH3:42])[CH2:40][C@H:39]([OH:44])[CH2:38][N:35]1[CH:36]=[CH:37][C:33]([NH:32][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10]2)=[O:29])=[N:34]1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: CN(C)C[C@H](O)Cn1ccc(N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C[C@H](O)Cn1ccc(NC(=O)C2NC(CC(C)(C)C)C(C#N)(c3ccc(Cl)cc3F)C2c2cccc(Cl)c2F)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (200 mg, 0.43 mmol), (S)-1-(3-amino-pyrazol-1-yl)-3-dimethylamino-propan-2-ol (158 mg, 0.86 mmol), 2-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluorophosphate (HATU, 243.3 mg, 0.64 mmol) and iPr2NEt (0.3 mL, 1.67 mmol) in CH2Cl2 (10 mL) was stirred at rt overnight. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, dried over Na2SO4 and filtered. The mixture was then concentrated and purified flash column chromatography (1-100% ethyl acetate/heptane) to afford rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [1-((S)-3-dimethylamino-2-hydroxy-propyl)-1H-pyrazol-3-yl]-amide as an off white powder (63.2 mg, 43.6%). HRMS (ES m/z Calcd. for C31H36Cl2F2N6O2+H [(M+H)+]: 633.2318. found: 633.2313.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:8]([C:12]([F:15])([F:14])[F:13])[O:9]2)=[CH:4][CH:3]=1.[Br:21]Br.C(OCC)(=O)C>ClC(Cl)(Cl)Cl>[Br:21][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[F:1])[O:9][CH:8]([C:12]([F:14])([F:15])[F:13])[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:6]2
Reactant: CCOC(=O)C1=Cc2ccc(F)cc2OC1C(F)(F)F
Reactant: BrBr
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C1=Cc2cc(Br)c(F)cc2OC1C(F)(F)F
Reaction time: 24 h
Yield: 44.6 %

Procedure:
To the solution of ethyl 7-fluoro-2-(trifluoromethyl)-2H chromene-3-carboxylate (5 g, 34 mmol) in 100 mL of tetrachloromethane was added dropwise at room temperature a solution of bromine(10.5 mL, 204 mmol) in 20 mL of tetrachloromethane. The resulting solution was stirred for 24 hrs. To the reaction was added 500 mL of ethyl acetate. The resulting organic phase was then washed with aqueous sodium thiosulfite to remove excess bromine, and brine, then dried over anhydrous magnesium sulfate. After removing the volatiles, the residue was purified on silica gel column with 1:9 EtOAc/hexane. It gave 5.6 g product. A small fraction of the product was further purified on reverse phase HPLC for analytica characterization. It gave a white solid. m.p.=98.5-100.0° C. 1H NMR(CDCl3/300 MHz) 7.67(s, 1H), 7.46(d, J=7.5 Hz, 1H), 6.83(d, J=9 Hz, 1H), 5.74(q, J=6.6 Hz, 1H), 4.36(m, 2H), 1.39(t, J=7.2 Hz, 3H). 19F NMR(CDCl3/300 MHz): −78.82(d, J=6.5 Hz), −98.7(t, J=7.9 Hz). 13C NMR(CDCl3/300 MHz): 163.6, 163.1, 159.7,154.0(d, J=11.5 Hz), 135.1, 133.4, 123.4(q, J=287.3 Hz), 117.3, 105.6(d, J=26.7 Hz), 102.2(d, J=22.3 Hz), 71.1(q, J=33.3 Hz), 61.9, 14.4. LC-MS(ES+): 369.2(M+1, 100). HRMS (EI+): m/z calc. For C13H9BrF4O3: 367.9671(M+), found: 367.9675.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][O:25]4)=[CH:19][CH:18]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH:37]1([C:43](Cl)=[O:44])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>C(Cl)Cl>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([N:15]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][O:25]4)=[CH:19][CH:18]=3)[C:43]([CH:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)=[O:44])=[CH:13][CH:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: c1cc(OC2CCCCO2)ccc1CNc1ccc(OCCN2CCCC2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(C1CCCCC1)N(Cc1ccc(OC2CCCCO2)cc1)c1ccc(OCCN2CCCC2)cc1
Reaction time: 1 h

Procedure:
To a solution of [4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-[4-(tetrahydro-pyran-2-yloxy)-benzyl]-amine (1.70 g, 4.29 mmol) and triethylamine (2.40 mL, 17.2 mmol) in methylene chloride (8–10 mL) at 0° C. was added cyclohexanecarbonyl chloride (1.72 mL, 12.87 mmol) in methylene chloride (30 mL) dropwise. The reaction mixture was stirred for 1 hr. and was quenched with water/saturated sodium bicarbonate (1/1, 40–50 mL). The layers were separated and the aqueous solution was washed with methylene chloride (2×25 mL). The combined organic solutions were dried (magnesium sulfate), filtered, and concentrated. Medium pressure chromatography using a solvent gradient (methylene chloride to 10% methanol/methylene chloride) afforded the title compound of Step A. MS 507 (M+1)+