Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC(=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:14]2=[O:37])[CH:5]=1.[C:40]([O:44][C:45](=[O:59])[N:46](CCN(C1C=CC=C(N)C=1)C)[CH3:47])([CH3:43])([CH3:42])[CH3:41]>>[C:40]([O:44][C:45](=[O:59])[N:46]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:17]3[CH2:16][CH2:29][CH2:28][CH2:27][CH2:26]3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:34])([CH3:35])[CH3:33])[C:14]2=[O:37])[CH:5]=1)[CH3:47])([CH3:43])([CH3:42])[CH3:41]
Reactant: CN(CCN(C)c1cccc(N)c1)C(=O)OC(C)(C)C
Reactant: COC(=O)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Product: CN(C(=O)OC(C)(C)C)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1

Procedure:
The title compound was obtained by the method used in the preparation of 3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-benzoic acid methyl ester (Example 1), except that {2-[(3-amino-phenyl)-methyl-amino]-ethyl}-methyl-carbamic acid tert-butyl ester (prepared in three steps from 3-fluoro-1-nitrobenzene and N,N′-dimethylethylenediamine) was used instead of 3-amino-benzoic acid methyl ester in step e, followed by reaction of the product obtained, in place of (3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-phenyl)-methyl-carbamic acid tert-butyl ester (Example 3, step d), according to the method of Example 3, step e. 1H NMR (CDCl3) 8.09 (1H, s), 7.50-7.45 (2H, m), 7.29-7.24 (1H, m), 7.12-7.01 (3H, m), 6.53-6.46 (2H, m), 4.69-4.67 (2H, m), 4.38 (1H, d, 13.8), 4.17 (1H, d, 13.8), 3.50-3.44 (2H, m), 2.93 (3H, s), 2.86-2.74 (3H, m), 2.49 (3H, s), 2.04-1.58 (7H, m), 1.31-1.19 (13H, m). Found: C, 65.52; H, 7.53; N, 14.12%; C32H44N6O5.0.4CH2Cl2 requires: C, 65.58; H, 7.61; N, 14.17%.
Reaction SMILES: [C:1]([NH:8][C:9]1[S:10][C:11](Br)=[C:12]([C:14]([O:16][CH2:17][P:18]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])=[O:19])=[O:15])[N:13]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:27]([Sn](CCCC)(CCCC)C=C)[CH2:28]CC.[F-].[Na+]>CN(C=O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([NH:8][C:9]1[S:10][C:11]([CH:27]=[CH2:28])=[C:12]([C:14]([O:16][CH2:17][P:18]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])=[O:19])=[O:15])[N:13]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CCOP(=O)(COC(=O)c1nc(NC(=O)OC(C)(C)C)sc1Br)OCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=Cc1sc(NC(=O)OC(C)(C)C)nc1C(=O)OCP(=O)(OCC)OCC
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A solution of 2-[N-Boc(amino)]-5-bromo-4-diethylphosphonomethoxycarbonylthiazole (1 mmole) and dichlorobis(triphenylphosphine)palladium(II) (0.1 mmole) in DMF (5 mL) was treated with tributyl(vinyl)tin (2.5 mmole) and the reaction was stirred at 60° C. for 2 h. The solvent was removed and the residue taken up in EtOAc and stirred with 2 mmol NaF in 5 ml water for 1 h. Extraction and chromatography gave 2-[N-Boc(amino)]-5-vinyl-4-diethylphosphonomethoxycarbonylthiazole as a yellow solid.
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH:3]([CH3:5])[CH3:4].Cl.[CH2:9]([N:11]1[C:15]2[N:16]=[CH:17][C:18]([C:27]3[O:31][N:30]=[C:29]([CH2:32][CH:33]4[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]4)[N:28]=3)=[C:19]([NH:20][CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[C:14]=2[CH:13]=[N:12]1)[CH3:10].C(N(C(C)C)CC)(C)C>C(Cl)(Cl)Cl>[CH2:9]([N:11]1[C:15]2[N:16]=[CH:17][C:18]([C:27]3[O:31][N:30]=[C:29]([CH2:32][CH:33]4[CH2:38][CH2:37][N:36]([C:1](=[O:6])[CH2:2][CH:3]([CH3:5])[CH3:4])[CH2:35][CH2:34]4)[N:28]=3)=[C:19]([NH:20][CH:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)[C:14]=2[CH:13]=[N:12]1)[CH3:10]
Reactant: CCn1ncc2c(NC3CCOCC3)c(-c3nc(CC4CCNCC4)no3)cnc21
Reactant: CC(C)CC(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CCn1ncc2c(NC3CCOCC3)c(-c3nc(CC4CCN(C(=O)CC(C)C)CC4)no3)cnc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Isovaleryl chloride (0.04 mmol) was added to a stirred solution of Intermediate 125 (0.033 mmol) and diisopropylethylamine (0.1 mmol) in chloroform (1 ml) at room temperature. After stirring at room temperature for 1.5 h, the reaction mixture was applied to a SPE cartridge (aminopropyl, 1 g) and the cartridge was eluted sequentially with chloroform, ethyl acetate and methanol. Fractions containing the desired product were combined and blown down under nitrogen. The resulting residue was further purified on a SPE cartridge (silica, 1 g) eluting with a gradient of 30-100% ethyl acetate in petroleum ether to afford Example 176. LCMS showed MH+=496, TRET=3.17 min.
Reaction SMILES: C(OC([NH:11][C@H:12]([C:16](O)=[O:17])[CH:13]([CH3:15])[CH3:14])=O)C1C=CC=CC=1.[NH2:19][C@@H:20]([CH2:54][OH:55])[C@@H:21]([OH:53])[C@@H:22]([OH:52])[C@H:23]([OH:51])[C:24]([NH:26][C@H:27]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[CH2:28][C:29]([O:31]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:30])=[O:25].C(N(CC)CC)C>CN(C)C=O.CO.[Pd]>[OH:51][C@@H:23]([C@H:22]([OH:52])[C@H:21]([OH:53])[C@@H:20]([NH:19][C:16](=[O:17])[C@H:12]([CH:13]([CH3:15])[CH3:14])[NH2:11])[CH2:54][OH:55])[C:24]([NH:26][C@H:27]([C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)[CH2:28][C:29]([OH:31])=[O:30])=[O:25]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: N[C@@H](CO)[C@@H](O)[C@@H](O)[C@H](O)C(=O)N[C@@H](CC(=O)OC(c1ccccc1)c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)[C@H](N)C(=O)N[C@@H](CO)[C@@H](O)[C@@H](O)[C@H](O)C(=O)N[C@@H](CC(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 152.8 %

Procedure:
To a solution of N-benzyloxycarbonyl-L-valine (460 mg) and diphenylmethyl (S)-3-[(2S,3R,4R,5S)-5-amino-2,3,4,6-tetrahydroxyhexanoyl]amino-3-phenylpropionate (500 mg) in dimethylformamide (50 ml) were added diethyl cyanophosophonate (298 mg) and triethylamine (0.191 ml) and the whole was stirred at room temperature for 15 hours. Aftert concentration under reduced pressure, to the residue was added 0.1N hydrochloric acid (50 ml) and the whole was extracted with ethyl acetate (100 ml). The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine respectively and dried over anhydrous sodium sulfate. Removal of the organic solvent gave a residue, which was dissolved in methanol (20 ml) and stirred at room temperature with 10% palladium on activated carbon (150 mg) under hydrogen atmosphere for 1 hour. After filtration, the filtrate was concentrated under reduced pressure to give a residue, which was passed through a column of DIAION HP-20SS (Mitsubishi kasei corporation), followed by elution with water-acetonitrile. The effective fractions were combined and concentrated under reduced pressure. The residue was recrystallized from methanol-ethyl acetate to afford the title compound (663 mg).
Reaction SMILES: [CH:1]1([C:6]([O:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br.[Li+].CC([N-]C(C)C)C>C1COCC1>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:1]1([C:6]([O:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: BrCCCCCBr
Reactant: CCCCOC(=O)C1CCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCOC(=O)C1(CCCCCBr)CCCC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 65.2 %

Procedure:
Under a N2 atmosphere at −60° C., a solution of butyl cyclopentanecarboxylate (prepared according to Payne, G. B.; Smith, C. W., J. Org. Chem., 1957, 22, 1680-1682, 40.2 g, 0.236 mol) and 1,5-dibromopentane (64 mL, 0.45 mol) in dry THF (400 mL) was added drop wise to a solution of LDA (2M in THF/heptane/ethylbenzene, 200 mL, 0.40 mol) in 30 min. After 3 h, the reaction mixture was allowed to reach rt in 30 min. Then the reaction mixture was poured out into ice-cold saturated aqueous NH4Cl (1 L). The organic layer was decanted and concentrated in vacuo to a smaller volume. The aqueous layer was extracted with Et2O (3×150 mL). The combined organic layers were washed with saturated aqueous NH4Cl (3×150 mL), brine (150 mL), dried (Na2SO4) and evaporated in vacuo. The remaining residue was purified by fractional distillation to give butyl 1-(5-bromo-pentyl)-cyclopentanecarboxylate (49.1 g, >90% pure by GC, 59%) as a bright yellow liquid. bp: T=123° C. (p=0.001 Torr). 1H NMR (CDCl3): δ=4.06 (t, J=6.6 Hz, 2H), 3.38 (t, J=6.9 Hz, 2H), 2.15-2.07 (m, 2H), 1.89-1.79 (quintet, J=7.1 Hz, 2H), 1.69-1.56 (m, 8H), 1.49-1.32 (m, 6H), 1.28-1.17 (m, 2H), 0.94 (t, J=7.4 Hz, 3H). 13C NMR (CDCl3): δ=177.7, 64.0, 54.0, 39.0, 36.0 (2×), 33.6, 32.5, 30.7, 28.5, 25.1, 24.8 (2×), 19.1, 13.6. HRMS calcd for C15H27BrO2 (M+): 318.1195. found: 318.1192.
Reaction SMILES: [CH2:1]([O:17][CH2:18][C:19](=[CH2:22])[CH2:20][OH:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C1(N=C=NC2CCCCC2)CCCCC1.[Br:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][C:44](O)=[O:45]>CCOCC.CN(C)C1C=CN=CC=1>[CH2:1]([O:17][CH2:18][C:19](=[CH2:22])[CH2:20][O:21][C:44](=[O:45])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][Br:38])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: O=C(O)CCCCCBr
Reactant: C=C(CO)COCCCCCCCCCCCCCCCC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Product: C=C(COCCCCCCCCCCCCCCCC)COC(=O)CCCCCBr
Temperature: 22 °C
Reaction time: 18 h

Procedure:
3-Hexadecyloxy-2-methylenepropan-1-ol (from Preparation 1) (1.8 g) was dissolved in ether (35 ml). Dicyclohexylcarbodiimide (1.5 g), 4-dimethylaminopyridine (0.07 g) and 6-bromohexanoic acid (1.2 g) was added, and the mixture was stirred at 22° C. for 18 hours. The reaction mixture was filtered, and the filtrate was washed with water (35 ml), 5% acetic acid in water (35 ml) and water (35 ml). The ether solution was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The crude product was purified by chromatography on a Waters PrepLC®/System 500A using a PrepPAK®-500/SILICA cartridge first with ether/pentane 1:4 and in a second run with methylene chloride/hexane 1:4 as eluent.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[CH:5][CH:4]=1)#N.[PH2]([O-])=[O:13].[Na+].N1C=CC=CC=1>O.C(O)(=O)C.[Ni]>[NH:9]1[C:10]2[C:6](=[CH:5][CH:4]=[C:3]([CH:1]=[O:13])[CH:11]=2)[CH:7]=[CH:8]1
Reactant: O=[PH2][O-]
Reactant: N#Cc1ccc2cc[nH]c2c1
Agent: [Ni]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: c1ccncc1
Solvent: O
Product: O=Cc1ccc2cc[nH]c2c1
Temperature: 45 °C
Reaction time: 0.75 h
Yield: 88.8 %

Procedure:
To a solution of 6-cyanoindole (15.0 g) and sodium hypophosphite (90 g) in water (326 mL), acetic acid (326 mL), and pyridine (652 mL) was added Raney Nickel catalyst and the mixture stirred at 45° C. for 45 minutes. The mixture was filtered through Celite and the filtrate extracted with ethyl acetate (3×500 mL). The extracts were dried over sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was crystallized from a mixture of dichloromethane and hexanes to provide 13.6 g (89%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH3:13][C:14]1([CH3:22])[CH2:20][C:19](=O)[O:18][C:16](=[O:17])[CH2:15]1.C(Cl)(=O)C>ClCCCl.ClCCl>[CH3:13][C:14]1([CH3:22])[CH2:15][C:16](=[O:17])[N:1]([C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=2)[C:19](=[O:18])[CH2:20]1
Reactant: CC1(C)CC(=O)OC(=O)C1
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CC(=O)Cl
Product: CCOC(=O)c1ccc(N2C(=O)CC(C)(C)CC2=O)cc1
Temperature: 25 °C

Procedure:
A solution of ethyl 4-aminobenzoate (10 g, 6.1 mmol) and 3,3-dimethylglutaric anhydride (0.95 g, 6.7 mmol) in 1,2-dichloroethane (15 mL) was heated to reflux for 1 hour, cooled to room temperature, and treated dropwise with acetyl chloride (0.88 mL, 12.5 mmol). The mixture was heated to reflux for 1 hour, cooled to room temperature, diluted with dichloromethane, washed sequentially with water, saturated NaHCO3, and brine, dried (MgSO4), filtered, and concentrated to provide the desired product. MS (DCI(+)) m/e 290 (M+H)+.
Reaction SMILES: [Mg].Br[C:3]1[C:4]([CH3:11])=[CH:5][C:6]([CH3:10])=[C:7]([CH3:9])[CH:8]=1.Br[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1.[O:21]=[P:22](Cl)(Cl)Cl>C1COCC1.BrCCBr>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([P:22](=[O:21])([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[C:3]2[CH:8]=[C:7]([CH3:9])[C:6]([CH3:10])=[CH:5][C:4]=2[CH3:11])=[CH:14][CH:15]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(Br)cc1
Reactant: Cc1cc(C)c(Br)cc1C
Agent: [Mg]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: COc1ccc(P(=O)(c2ccc(OC)cc2)c2cc(C)c(C)cc2C)cc1
Yield: 79.2 %

Procedure:
A reaction flask under nitrogen containing magnesium turnings (120 g, 4.94 mol) and 412 mL THF was charged with 0.5 g of 1,2-dibromoethane and heated to reflux for 1 h. A separate flask was charged with 5-bromo-1,2,4-trimethylbenzene (300 g, 1.51 mol), dissolved in 568 mL of THF. The heat was removed from the first flask and the 5-bromo-1,2,4-trimethylbenzene solution was added dropwise at a rate to maintain reflux. 4-Bromoanisole (536.7 g, 3.01 mol) was then added over 1.5 h at 75° C. reaction temperature. After holding the reaction mixture overnight, POCl3 (231 g, 1.51 mol) was added dropwise at 40-80° C. The product mixture was isolated by aqueous workup to give 453.6 g (79% yield) of product mixture as a viscous liquid. The structure was consistent with NMR data.
Reaction SMILES: C1(C2C(OCC3(C(F)(F)F)CCCCC3)=CC(F)=C(C=2)C(O)=O)CC1.[CH:26]1([C:29]2[C:30]([O:39][CH2:40][CH:41]3[CH2:46][CH2:45][C:44]([F:48])([F:47])[CH2:43][CH2:42]3)=[CH:31][C:32]([F:38])=[C:33]([CH:37]=2)[C:34](O)=[O:35])[CH2:28][CH2:27]1.CS(N)(=O)=O.[CH:54]1([S:57]([NH2:60])(=[O:59])=[O:58])[CH2:56][CH2:55]1>>[CH:26]1([C:29]2[C:30]([O:39][CH2:40][CH:41]3[CH2:46][CH2:45][C:44]([F:47])([F:48])[CH2:43][CH2:42]3)=[CH:31][C:32]([F:38])=[C:33]([CH:37]=2)[C:34]([NH:60][S:57]([CH:54]2[CH2:56][CH2:55]2)(=[O:59])=[O:58])=[O:35])[CH2:27][CH2:28]1
Reactant: O=C(O)c1cc(C2CC2)c(OCC2CCC(F)(F)CC2)cc1F
Reactant: NS(=O)(=O)C1CC1
Agent: CS(N)(=O)=O
Agent: O=C(O)c1cc(C2CC2)c(OCC2(C(F)(F)F)CCCCC2)cc1F
Product: O=C(NS(=O)(=O)C1CC1)c1cc(C2CC2)c(OCC2CCC(F)(F)CC2)cc1F

Procedure:
Following the procedure as described in Example 158 step 5, and making variations as required to replace 5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)-cyclohexyl)methoxy)-benzoic acid with 5-cyclopropyl-4-((4,4-difluorocyclohexyl)-methoxy)-2-fluorobenzoic acid and to replace methanesulfonamide with cyclopropanesulfonamide, the title compound was obtained (0.144 g, 46%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ8.74-8.63 (m, 1H), 7.64-7.56 (m, 1H), 6.61-6.52 (m, 1H), 3.93-3.84 (m, 2H), 3.16-3.04 (m, 1H), 2.26-2.08 (m, 2H), 2.08-1.66 (m, 6H), 1.60-1.42 (m, 4H), 1.20-1.10 (m, 2H), 0.99-0.89 (m, 2H), 0.70-0.61 (m, 2H); MS (ES+) m/z 432.0 (M+1).
Reaction SMILES: CN(C)CCCN=C=NCC.[NH2:12][CH2:13][CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[OH:15].[CH3:22][O:23][C:24](=[O:34])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31](O)=[O:32].ON1C2C=CC=CC=2N=N1>C1COCC1.C(OCC)(=O)C>[CH3:22][O:23][C:24](=[O:34])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31](=[O:32])[NH:12][CH2:13][CH:14]([OH:15])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)CCCCCCC(=O)O
Reactant: NCC(O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)CCCCCCC(=O)NCC(O)c1ccccc1
Reaction time: 12 h
Yield: 92.1 %

Procedure:
Add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) (8.5 g, 44.3 mL) to a solution of 2-amino-1-phenylethanol (5.0 g, 36.4 mmol), suberic acid monomethyl ester (6.85 g, 36.4 mmol) and 1-hydroxybenzotriazole (HOBt, 5.0 g, 37.0 mmol) in THF (200 mL) at room temperature under nitrogen. Stir the mixture for 12 hours. Dilute the mixture with ethyl acetate (600 mL), wash with 1N HCl (2×150 mL), brine (2×150 mL), NaHCO3 (2×150 mL) and brine (150 mL) solutions and dry over sodium sulfate. Remove the solvent under reduced pressure to provide 7-(2-hydroxy-2-phenylethylcarbamoyl)heptanoic acid methyl ester (10.3 g, 91%), which is used in the following step without purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C@@H:13]3[CH:17]=[C:16]([CH3:18])[CH2:15][NH:14]3)[NH:11][CH:12]=2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH3:28][O:29][C:30]([NH:32][C@@H:33]([CH:37]([CH3:39])[CH3:38])[C:34](O)=[O:35])=[O:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH3:28][O:29][C:30](=[O:31])[NH:32][C@H:33]([C:34]([N:14]1[CH2:15][C:16]([CH3:18])=[CH:17][C@H:13]1[C:10]1[NH:11][CH:12]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[N:9]=1)=[O:35])[CH:37]([CH3:39])[CH3:38]
Reactant: CC1=C[C@@H](c2nc(-c3ccc(Br)cc3)c[nH]2)NC1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
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: COC(=O)N[C@H](C(=O)N1CC(C)=C[C@H]1c1nc(-c2ccc(Br)cc2)c[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(4-bromo-phenyl)-2-((S)-4-methyl-2,5-dihydro-1H-pyrrol-2-yl)-1H-imidazole (1.10 g, 3.62 mmol) in DCM (50 mL) was added DIPEA (2.34 g, 18.1 mmol), (S)-2-methoxycarbonylamino-3-methyl-butyric acid (761 mg, 4.34 mmol) and HATU (1.65 g, 4.34 mmol). The mixture was stirred at RT overnight, washed with water (50 mL) and brine (50 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography (10%-50% EtOAc in petroleum ether) to give the desired product, which was purified by supercritical fluid chromatography (SFC) [mobile phase A: supercritical CO2, phase B: methanol+0.05% diethylamine; flow rate: 80 mL/min] to give the title intermediate (750 mg, 45% yield). m/z): [M+H]+ calcd for C21H25BrN4O3 461.11, 463.11 found 461.1.
Reaction SMILES: [Na].N.[CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH2:13][N:14]1[CH2:19][CH2:18][CH:17]([NH:20][C:21]([NH2:23])=[O:22])[CH2:16][CH2:15]1.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30](OCC)=[O:31]>>[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]([NH:23][C:21]([NH:20][CH:17]1[CH2:18][CH2:19][N:14]([CH2:13][C:4]2[CH:5]=[CH:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:3]=2)[CH2:15][CH2:16]1)=[O:22])=[O:31]
Reactant: CCOC(=O)c1ccccn1
Reactant: NC(=O)NC1CCN(Cc2ccc3ccccc3c2)CC1
Agent: N
Agent: [Na]
Product: O=C(NC(=O)c1ccccn1)NC1CCN(Cc2ccc3ccccc3c2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 32.5 %

Procedure:
Sodium (0.1 g, 4.35 mmol) in liquid ammonia (100-150 cm3) was stirred until the blue colour was discharged. A bomb was charged with [1-(naphth-2-ylmethyl)piperid-4-yl]urea (0.83 g, 2.93 mmol) and the liquid ammonia solution was added. The mixture was stirred at room temperature for 2 days then the bomb was cooled to -78° C., and ethyl picolinate (0.6 g, 3.97 mmol) was added. Stirring was continued for 3 hours at room temperature then the ammonia was allowed to evaporate and the gummy residue triturated with water then ethyl acetate. The ethyl acetate suspension was filtered to give recovered [1-(naphth-2-ylmethyl)piperid-4-yl]urea (0.33 g). The filtrate was evaporated and the residue chromatographed on silica eluting with chloroform then chloroform: ethyl acetate 4:1 to give the title compound (0.37 g).
Reaction SMILES: Cl.[CH2:2]([C:6]1[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:9]=[C:8]([CH2:17][NH:18][C:19]([CH:21]2[CH:26]3[CH:22]2[CH2:23][NH:24][CH2:25]3)=[O:20])[CH:7]=1)[CH:3]([CH3:5])[CH3:4].C(N(CC)CC)C.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.CO>C(Cl)Cl>[C:34]([N:24]1[CH2:25][CH:26]2[CH:22]([CH:21]2[C:19]([NH:18][CH2:17][C:8]2[CH:7]=[C:6]([CH2:2][CH:3]([CH3:5])[CH3:4])[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:9]=2)=[O:20])[CH2:23]1)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)Cc1cc(CNC(=O)C2C3CNCC32)nn1-c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)Cc1cc(CNC(=O)C2C3CN(C(=O)c4ccccc4)CC32)nn1-c1ccccc1
Reaction time: 0.08 h
Yield: 83.1 %

Procedure:
The 6-((5-isobutyl-1-phenyl-1H-pyrazole-3-yl)methylcarbamoyl)-3-azabicyclo[3.1.0]hexane hydrochloride (367 mg, 0.979 mmol) prepared in Example 11 was dissolved in 4.9 mL of methylene chloride and triethylamine (273 μL, 1.96 mmol) was added dropwise at 0° C. After stirring for 5 minutes, benzoyl chloride (125 μL, 1.08 mmol) was added dropwise. 10 minutes later, after stirring at room temperature for 3 hours, the completion of the reaction was confirmed by TLC (CH2Cl2:MeOH=20:1). After the reaction was completed, the reaction mixture was extracted with methylene chloride after adding water, 1 N HCl and saturated sodium bicarbonate. The organic layer was dried with anhydrous magnesium sulfate, filtered, concentrated under reduced pressure and separated by column chromatography (CH2Cl2:MeOH=20:1) to obtain 360 mg (83.2%) of the target compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]([CH2:11]Br)[C:9]=1[Cl:10])=[O:4].[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]([CH2:11][N:17]2[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][CH2:16]2)[C:9]=1[Cl:10])=[O:4]
Reactant: COC(=O)c1scc(CBr)c1Cl
Reactant: CN1CCNCC1
Solvent: ClCCl
Product: COC(=O)c1scc(CN2CCN(C)CC2)c1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 39.8 %

Procedure:
To 2-methoxycarbonyl-3-chloro-4-(bromomethyl)thiophene (0.20 g, 0.74 mmol) in methylene chloride (7.5 mL) was added 1-methylpiperazine (0.095 mL, 0.86 mmol) and the mixture was stirred at ambient temperature. After 16 hours, the mixture was poured onto methylene chloride (20 mL) and washed with dilute aqueous NaHCO3, water and brine, dried over Na2SO4 and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 0.085 g (40% yield) of 2-methoxycarbonyl-3-chloro-4-((4-methylpiperazin-1-yl)methyl)thiophene as a tan solid; NMR (CDCl3) 7.4 (s, 1), 3.9 (s, 3), 3.5 (s, 2), 2.3-2.7 (br m, 8), 2.2 (s, 3) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]([N:13]([C:19]([O:21][CH3:22])=[O:20])[CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:11][NH:10][N:9]=2)=[CH:4][CH:3]=1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1>>[F:23][C:24]([F:34])([F:35])[C:25]1[CH:26]=[CH:27][C:28]([NH:31][C:32]([N:10]2[CH2:11][CH:12]([N:13]([C:19]([O:21][CH3:22])=[O:20])[CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[N:9]2)=[O:33])=[CH:29][CH:30]=1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)CN(C(=O)OC)C1CNN=C1c1ccc(Cl)cc1
Product: COC(=O)CN(C(=O)OC)C1CN(C(=O)Nc2ccc(C(F)(F)F)cc2)N=C1c1ccc(Cl)cc1

Procedure:
By substantially following the procedure given in Example 585f using one third (≤13 mmole) of the solution of 3-(4-chlorophenyl)-4-(N-methoxycarbonyl-N-(carbomethoxymethyl)amino)-4,5-dihydro-1H-pyrazole (Example 487c) and 1.87 g (10 mmole) of 4-trifluoromethylphenyl isocyanate, 2.5 g of the desired compound, mp 198°-200° C. was obtained.