Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:6]=[N:5][N:4]=1.[CH3:18][C:19]1([CH3:32])[CH2:24][NH:23][CH2:22][CH2:21][N:20]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].C(N(CC)CC)C>C(#N)C>[CH3:18][C:19]1([CH3:32])[CH2:24][N:23]([CH2:2][C:3]2[N:7]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=3)[N:6]=[N:5][N:4]=2)[CH2:22][CH2:21][N:20]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]
Reactant: CC(C)(C)OC(=O)N1CCNCC1(C)C
Reactant: FC(F)(F)c1cccc(-n2nnnc2CCl)c1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(Cc2nnnn2-c2cccc(C(F)(F)F)c2)CC1(C)C
Temperature: 120 °C

Procedure:
To a solution of 5-(chloromethyl)-1-[3-(trifluoromethyl)phenyl]-1H-tetrazole (440 mg, 1.68 mmol, commercially available from Otava, Kiev, Ukraine) in acetonitrile (8 mL) was added 1,1-dimethylethyl 2,2-dimethyl-1-piperazinecarboxylate (359 mg, 1.68 mmol, commercially available, for example from ChemPacific Corp., Baltimore, USA) and triethylamine (0.701 mL, 5.03 mmol). The mixture was then heated to 120° C. for 20 minutes in a microwave reactor.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([C@H:11]([O:13]C1CCCCO1)[CH3:12])=[CH2:10].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[CH2:10])[C@H:11]([OH:13])[CH3:12]
Reactant: C=C(c1ccc(F)cc1F)[C@@H](C)OC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: C=C(c1ccc(F)cc1F)[C@@H](C)O
Temperature: 60 °C
Yield: 53 %

Procedure:
A mixture of compound 5b, (3R)-2-(2,4-Difluorphenyl)-3-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)-1-butene, (40 g, 0.149 mole) and pyridinium-p-toluenesulfonate (24.61 g, 0.098 more) in 400 ml of ethanol was heated at 60° C. for 14.5 hours. The reaction mixture was concentrated in vacuo and co-evaporated with toluene. Toluene was then added to the residue and the resulting solid was removed by filtration. The filtrate was evaporated under reduced pressure and the residue was chromatographed on silica gel. Elution with 10% ethyl acetate in hexane gave the title compound 6b as light yellow oil (14.68 g, 53%).
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl.Cl.[Br:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:40]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)=[O:41].[C:48]1([C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)[CH:53]=[CH:52][C:51]([NH:54][C:55](=[O:61])[CH:56]([CH3:60])[C:57](O)=[O:58])=[CH:50][CH:49]=1>CN(C=O)C.O>[C:48]1([C:62]2[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=2)[CH:53]=[CH:52][C:51]([NH:54][C:55](=[O:61])[CH:56]([CH3:60])[C:57]([N:45]2[CH2:44][CH2:43][N:42]([C:40](=[O:41])[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[Br:33])[CH2:47][CH2:46]2)=[O:58])=[CH:50][CH:49]=1
Reactant: CC(C(=O)O)C(=O)Nc1ccc(-c2ccccc2)cc1
Reactant: O=C(c1ccccc1Br)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C(=O)Nc1ccc(-c2ccccc2)cc1)C(=O)N1CCN(C(=O)c2ccccc2Br)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.7 %

Procedure:
HOBt (60 mg, 0.44 mmol), DIPEA (140 mg, 1.1 mmol), EDCI.HCl (85 mg, 0.44 mmol) followed by (2-bromo-phenyl)-piperazin-1-yl-methanone hydrochloride (136 mg, 0.44 mmol), were added to a stirred solution of N-biphenyl-4-yl-2-methyl-malonamic acid (100 mg, 0.37 mmol) in DMF (2.0 mL). The resulting mixture was stirred at ambient temperature overnight then diluted with water. The product was extracted with ethyl acetate. The ethyl acetate layer was washed with brine and concentrated under reduced pressure to afford 140 mg (73%) of N-biphenyl-4-yl-3-[4-(2-bromo-benzoyl)-piperazin-1-yl]-2-methyl-3-oxo-propionamide. LCMS: 520.12 (M+1)+, 97.32%, 1H NMR (DMSO-d6): δ 10.2 (d, 1H), 7.8-7.3 (m, 13H), 4.0-3.4 (m, 7H), 3.2-3.0 (m, 2H), 1.3 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][CH:12]2[CH2:17][CH2:16][C:15]3([CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[CH2:14][CH2:13]2)=[CH:6][CH:5]=1.[CH3:24][S:25][C:26]1[CH:27]=[C:28]([N:32]=[C:33]=[O:34])[CH:29]=[CH:30][CH:31]=1>C(#N)C>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:5]=[CH:6][C:7]([CH2:10][N:11]([CH:12]2[CH2:17][CH2:16][C:15]3([CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[CH2:14][CH2:13]2)[C:33]([NH:32][C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([S:25][CH3:24])[CH:27]=2)=[O:34])=[CH:8][CH:9]=1
Reactant: CSc1cccc(N=C=O)c1
Reactant: COC(=O)c1ccc(CNC2CCC3(CCCCC3)CC2)cc1
Solvent: CC#N
Product: COC(=O)c1ccc(CN(C(=O)Nc2cccc(SC)c2)C2CCC3(CCCCC3)CC2)cc1
Reaction time: 48 h
Yield: 44.2 %

Procedure:
The above 4-(spiro[5.5]undec-3-ylaminomethyl)benzoic acid methyl ester (1.02 g, 3.2 mmol) was added acetonitrile (50 mL) and 3-(methylthio)phenylisocyanate (668 mg, 4 mmol). Upon stirring for 2 days, the reaction appeared incomplete as shown by HPLC, so another portion of 3-(methylthio)phenylisocyanate (240 mg) was added. After stirring for 2 hours the solvent was evaporated. The residue was taken up in dichloromethane (2 mL) and purified by chromatography on silica using dichloromethane as eluent affording 4-[3-(3-methylsulfanyl-phenyl)-1-spiro[5.5]undec-3-yl-ureidomethyl]benzoic acid methyl ester (680 mg).
Reaction SMILES: Cl[C:2]1[C:3](=[O:30])[N:4]([CH:27]([CH3:29])[CH3:28])[N:5]=[CH:6][C:7]=1[NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:15][C:14]=1[CH2:24][CH2:25][CH3:26].C(O)C>[C].[Pd].C(N(CC)CC)C>[CH2:24]([C:14]1[CH:15]=[C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:17]=[CH:18][C:13]=1[O:12][CH2:11][CH2:10][CH2:9][NH:8][C:7]1[CH:6]=[N:5][N:4]([CH:27]([CH3:28])[CH3:29])[C:3](=[O:30])[CH:2]=1)[CH2:25][CH3:26]
Reactant: CCCc1cc(C(=O)OCC)ccc1OCCCNc1cnn(C(C)C)c(=O)c1Cl
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCCc1cc(C(=O)OCC)ccc1OCCCNc1cnn(C(C)C)c(=O)c1
Reaction time: 3 h

Procedure:
A mixture comprising 0.82 g of 4-chloro-5-[3-(2-n-propyl-4-ethoxycarbonylphenoxy)propylamino]-2-i-propyl-3(2H)pyridazinone (Compound No. 64), 50 ml of ethanol, 1.5 ml of triethylamine and 150 mg of 5% palladium-carbon was subjected to hydrogenation under stirring at a temperature of from 40° to 50° C. for 3 hours. The reaction mixture was filtered, and the filtrate was concentrated. The crude crystals thereby obtained were recrystallized from ethyl ether to obtain 0.58 g of the above identified compound as colorless crystals having a melting point of from 111° to 116° C.
Reaction SMILES: [Cl:1][C:2]1[C:11](Cl)=[CH:10][C:5]([NH:6][CH2:7][CH2:8][NH2:9])=[C:4]([N+:13]([O-:15])=[O:14])[CH:3]=1.[CH3:16][O:17][CH2:18][CH2:19][NH2:20]>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([N+:13]([O-:15])=[O:14])[C:5]([NH:6][CH2:7][CH2:8][NH2:9])=[CH:10][C:11]=1[NH:20][CH2:19][CH2:18][O:17][CH3:16]
Reactant: NCCNc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reactant: COCCN
Product: COCCNc1cc(NCCN)c([N+](=O)[O-])cc1Cl
Product: Cl

Procedure:
0.1 mole (28.6 g) of 4,5-dichloro-2-nitro-N-β-aminoethylaniline prepared in the 1st stage is heated for 4 h 30 min in 60 ml of 2-methoxyethylamine on a steam bath. After cooling and dilution with 200 ml of iced water, the precipitate is recrystallized from isopropanol. After being dissolved in a hot mixture of water and alcohol to which hydrochloric acid has been added, the expected product precipitates as a hydrochloride. It decomposes at 260°-265° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:17]1([C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]([S:32]([C:35]3[CH:43]=[CH:42][C:38]([C:39](O)=[O:40])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[CH:24]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>>[CH:17]1([C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]([S:32]([C:35]3[CH:36]=[CH:37][C:38]([C:39]([NH:7][CH2:6][C:5]4[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=4)=[O:40])=[CH:42][CH:43]=3)(=[O:33])=[O:34])[CH:24]=2)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: O=C(O)c1ccc(S(=O)(=O)n2cc(C3CCCCC3)c3ccccc32)cc1
Reactant: NCc1ccc(F)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Product: O=C(NCc1ccc(F)cc1)c1ccc(S(=O)(=O)n2cc(C3CCCCC3)c3ccccc32)cc1
Yield: 90.8 %

Procedure:
Add 4-Fluoro-benzylamine (72 mg, 0.574 mmol, 1.1 eq) followed by triethylamine (343 mg, 0.472 ml, 3.39 mmol, 6.5 eq) to a CH2CL2 solution (8 ml) of 4-(3-Cyclohexyl-indole-1-sulfonyl)-benzoic acid (200 mg, 0.521 mmol, 1 eq). Add benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (231 mg, 0.521 mmol, 1 eq) and stir at room temperature for 16 hours. Remove solvent on rotovap and purify crude by silica gel chromatography to give 4-(3-Cyclohexyl-indole-1-sulfonyl)-N-(4-fluoro-benzyl)-benzamide (232 mg, 99% yield). Mass Spectrum (m/e): 490.92 (MH+).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]([NH:21][CH3:22])=[O:20])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1.[F:29][CH:30]([F:41])[C:31]1[CH:36]=[C:35](F)[CH:34]=[CH:33][C:32]=1[N+:38]([O-:40])=[O:39].C([O-])([O-])=O.[K+].[K+]>CN(P(N(C)C)(N(C)C)=O)C.CCOC(C)=O.O>[CH:1]1([C:4]2[C:5]([N:24]([C:35]3[CH:34]=[CH:33][C:32]([N+:38]([O-:40])=[O:39])=[C:31]([CH:30]([F:29])[F:41])[CH:36]=3)[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]([NH:21][CH3:22])=[O:20])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(F)cc1C(F)F
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(NS(C)(=O)=O)c(C3CC3)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOC(C)=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc([N+](=O)[O-])c(C(F)F)c3)S(C)(=O)=O)c(C3CC3)cc12
Yield: 101.5 %

Procedure:
A solution of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (1.00 g, 2.49 mmol), 2-(difluoromethyl)-4-fluoro-1-nitrobenzene (1.13 g, 5.91 mmol) and K2CO3 (0.85 g, 6.15 mmol) in HMPA (6.2 mL) was stirred at 60° C. for 15 h. The reaction mixture was diluted with EtOAc and water. The organic layer was washed with brine, dried (Na2SO4), filtered, evaporated and purified by silica gel chromatography (0-80% EtOAc/hexanes) to afford the title compound (1.45 g, 97%) as a yellow solid. LCMS (m/z, ES+)=574.3 (M+H+).
Reaction SMILES: [F:1][CH:2]([F:15])[CH2:3][O:4][C:5]1[N:10]=[CH:9][C:8]([C:11](=O)[CH3:12])=[CH:7][C:6]=1[CH3:14].[CH3:16][C:17]([S@:20]([NH2:22])=[O:21])([CH3:19])[CH3:18]>>[F:1][CH:2]([F:15])[CH2:3][O:4][C:5]1[N:10]=[CH:9][C:8]([CH:11]([NH:22][S@@:20]([C:17]([CH3:19])([CH3:18])[CH3:16])=[O:21])[CH3:12])=[CH:7][C:6]=1[CH3:14]
Reactant: CC(=O)c1cnc(OCC(F)F)c(C)c1
Reactant: CC(C)(C)[S@](N)=O
Product: Cc1cc(C(C)N[S@](=O)C(C)(C)C)cnc1OCC(F)F
Yield: 82 %

Procedure:
The title compound is prepared in 82% yield (1.22 g, colorless oil) from 1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethanone (0.99 g, 4.61 mmol, Step-3) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][CH:14]3[C:22]4[C:17](=[CH:18][C:19]([C:23]([O:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:24])=[CH:20][CH:21]=4)[CH2:16][CH2:15]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:30]CN(C(C)C)C(C)C.C(Cl)(Cl)=S.[CH3:43][NH:44][C:45]1[C:46]([NH2:51])=[CH:47][CH:48]=[CH:49][CH:50]=1.Cl>ClCCl>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([N:13]([C:43]3[N:51]([CH3:30])[C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=4[N:44]=3)[CH:14]3[C:22]4[C:17](=[CH:18][C:19]([C:23]([O:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:24])=[CH:20][CH:21]=4)[CH2:16][CH2:15]3)=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCCCOC(=O)c1ccc2c(c1)CCC2Nc1ccc(C2CCCCC2)cc1
Reactant: CCN(C(C)C)C(C)C
Reactant: CNc1ccccc1N
Agent: Cl
Agent: S=C(Cl)Cl
Solvent: ClCCl
Product: CCCCOC(=O)c1ccc2c(c1)CCC2N(c1ccc(C2CCCCC2)cc1)c1nc2ccccc2n1C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a 0° C. solution of butyl 1-[(4-cyclohexylphenyl)amino]indane-5-carboxylate (0.50 g, 1.27 mmol) and DIEA (0.33 mL, 1.90 mmol) in dry dichloromethane (15 mL) was added thiophosgene (0.10 mL, 1.34 mmol) slowly. After stirring at 0° C. for 10 min and then at room temperature for 1 h, a solution of N-methylbenzene-1,2-diamine (0.23 g, 1.90 mmol) and DIEA (0.33 mL, 1.90 mmol) in dry dichloromethane (5 mL) was added. The reaction mixture was stirred for 1 h at room temperature and then diluted with dichloromethane (30 mL) and poured into aqueous HCl (1N, 30 mL). The organic layer was separated and washed with aqueous HCl (1N, 30 mL), saturated aqueous NaHCO3 (30 mL), brine (30 mL), dried over Na2SO4 and then concentrated to dryness. The residue was dissolved in dichloromethane (30 mL) and excess of mercury (II) trifluoroacetate was added. The reaction mixture was stirred for 30 min at ambient temperature and then filtered through Celite. The organic solution was washed with saturated NaHCO3 (30 mL), dried over Na2SO4 and concentrated. Chromatography (8% to 15% EtOAc in Hexane) afforded butyl 1-[(4-cyclohexylphenyl)(1-methyl-1H-benzimidazol-2-yl)amino]indane-5-carboxylate. HPLC/MS: m/z=552.4 (M+1), Rt=2.58 min. 1H NMR (CDCl3): δ 7.96 (1H, d, J=7.8 Hz), 7.91 (1H, s), 7.70 (1H, d, J=7.5 Hz), 7.55 (1H, d, J=7.5 Hz), 7.27-7.20 (2H, m), 7.18 (1H, d, J=7.5 Hz), 7.01 (2H, d, J=8.5 Hz), 6.67 (2H, d, J=8.5 Hz), 6.20 (1H, t, J=7.5 Hz), 4.37 (1H, t, J=6.5 Hz), 3.21 (3H, s), 2.91-2.85 (1H, m), 2.77-2.64 (2H, m), 2.46-2.34 (2H, m), 1.86-1.75 (8H, m), 1.54 (2H, m), 1.41-1.24 (6H, m), 1.04 (3H, t, J=7.5 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](Cl)=[N:9][OH:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:19]([N:23]1[C:27](=[O:28])[C:26]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]2[C:24]1=[O:33])[CH2:20][C:21]#[CH:22]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:22]=[C:21]([CH2:20][CH2:19][N:23]3[C:27](=[O:28])[C:26]4[C:25](=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:24]3=[O:33])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: C#CCCN1C(=O)c2ccccc2C1=O
Reactant: ON=C(Cl)c1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1CCc1cc(-c2ccc(F)cc2)no1
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.9 %

Procedure:
Under a nitrogen atmosphere, 4-fluoro-N-hydroxybenzenecarboximidoyl chloride (31 g, 180 mmol), prepared as described in Parts A through C of Example 11, was added dropwise to a solution of anhydrous triethylamine (19 mL, 210 mmol) and N-(3-butynyl)phthalimide (19.04 g, 95.58 mmol) in dichloromethane (1 L). The reaction was stirred at room temperature for 24 hours and then diluted with dichloromethane, washed sequentially with aqueous potassium carbonate, water, and brine; dried over potassium sulfate; filtered; and concentrated under reduced pressure. The resulting solid was triturated with ethanol, isolated by filtration, and washed with diethyl ether to provide 29.87 g of 2-{2-[3-(4-fluorophenyl)isoxazol-5-yl]ethyl}-1H-isoindole-1,3(2H)-dione. A portion of the product was recrystallized from isopropyl alcohol and dried to provide an analytically pure sample as white crystals, mp 155.0-156.0° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[C@@H:7]1[CH2:11][CH2:10][CH2:9][NH:8]1)([CH3:4])([CH3:3])[CH3:2].[CH2:13]([O:20][C:21]([NH:23][C@H:24]([C:37](O)=[O:38])[CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.P(C#N)(=O)(OCC)OCC.C(N(CC)CC)C>CN(C)C=O.O>[C:1]([O:5][C:6](=[O:12])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:37](=[O:38])[C@H:24]([CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30]([O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:31])[NH:23][C:21]([O:20][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:22])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 73.5 %

Procedure:
In 30 ml of N,N-dimethylformamide are dissolved 2.4 g of L-proline tert-butyl ester and 5.87 g of Nα -benzyloxycarbonyl-Nε -tert-butoxycarbonyl-L-lysine, and 3 g of diethyl phosphorocyanidate is added dropwise to the solution under ice-cooling. After stirring for 30 minutes, a solution of 1.42 g of triethylamine in 5 ml of N,N-dimethylformamide is added to the mixture, followed by stirring under ice-cooling for 1 hour and then at room temperature for 2 hours. 500 ml of water is added to the reaction mixture, and the mixture is extracted with 300 ml of ethyl acetate. The extract is washed with aqueous dilute phosphoric acid, 0.1N aqueous sodium hydroxide and water, successively, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting oily material is purified by silica gel column chromatography (hexane:ethyl acetate=2:1 to 1:1) to give 5.5 g of N-(Nα -benzyloxycarbonyl-Nε -tert-butoxycarbonyl-L-lysyl)-L-proline tert-butyl ester as a colorless oil.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:15]=[CH:14][C:7]2[B:8]([OH:13])[O:9][C:10]([CH3:12])([CH3:11])[C:6]=2[CH:5]=1.[Cl:17][C:18]1[CH:23]=[C:22]([C:24]([C:26]([F:29])([F:28])[F:27])=[CH2:25])[CH:21]=[C:20]([Cl:30])[CH:19]=1>CN(C=O)C>[Cl:17][C:18]1[CH:23]=[C:22]([C:24]2([C:26]([F:29])([F:27])[F:28])[O:1][N:2]=[C:3]([C:4]3[CH:15]=[CH:14][C:7]4[B:8]([OH:13])[O:9][C:10]([CH3:12])([CH3:11])[C:6]=4[CH:5]=3)[CH2:25]2)[CH:21]=[C:20]([Cl:30])[CH:19]=1
Reactant: CC1(C)OB(O)c2ccc(C(Cl)=NO)cc21
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Solvent: CN(C)C=O
Product: CC1(C)OB(O)c2ccc(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)cc21
Temperature: 0 °C
Reaction time: 12 h
Yield: 64.8 %

Procedure:
To a solution of N,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbimidoyl chloride (8 mg, 0.033 mmol) and 1,3-dichloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (8.9 mg, 0.0367 mmol) in DMF (1 mL) at rt was added TEA (5.1 μL, 0.0367 mmol). The reaction mixture was stirred for 12 h, poured into ice-water and extracted with EA (10 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC to give the title compound 5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-isoxazol-3-yl)-3,3-dimethyl-benzo[c][1,2]oxaborol-1(3H)-ol (9.5 mg; yield 64%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 9.26 (s, 1 H), 7.66-7.85 (m, 6 H), 4.32-4.96 (m, 2 H), 1.51 (s, 6 H) ppm; MS: m/z=444 (M+1, ESI+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[N:7][C:6]([N:9]2[CH:13]=[N:12][C:11]([CH3:14])=[N:10]2)=[C:5]2[NH:15][CH:16]=[C:17]([C:18](=[O:22])[C:19]([OH:21])=O)[C:4]=12.Cl.[NH:24]1[CH2:29][CH2:28][C:27](=[C:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)[C:31]#[N:32])[CH2:26][CH2:25]1.C(OP(ON1C(=O)C2C=CC=CC=2N=N1)(OCC)=O)C.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[N:7][C:6]([N:9]2[CH:13]=[N:12][C:11]([CH3:14])=[N:10]2)=[C:5]2[NH:15][CH:16]=[C:17]([C:18](=[O:22])[C:19]([N:24]3[CH2:29][CH2:28][C:27](=[C:30]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=4)[C:31]#[N:32])[CH2:26][CH2:25]3)=[O:21])[C:4]=12
Reactant: N#CC(=C1CCNCC1)c1ccccn1
Reactant: COc1cnc(-n2cnc(C)n2)c2[nH]cc(C(=O)C(=O)O)c12
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cnc(-n2cnc(C)n2)c2[nH]cc(C(=O)C(=O)N3CCC(=C(C#N)c4ccccn4)CC3)c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 35.4 %

Procedure:
2-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid (1.5 g), 2-(piperidin-4-ylidene)-2-(pyridin-2-yl)acetonitrile hydrochloride (1.5 g), 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one (DEPBT) (2.1 g) and Hunig's Base (2 ml) were combined in 20 ml of DMF. The mixture was stirred at room temperature for 16 hours. DMF was removed via evaporation at reduced pressure and the residue was partitioned with MeOH (80 ml). The precipitate was collected via filtration to provide 0.85 g of the product, 2-(1-(2-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pynolo[2,3-c]pyridin-3-yl)-2-oxoacetyl)piperidin-4-ylidene)-2-(pyridin-2-yl)acetonitrile (IVe). 1H NMR (500 MHz, DMSO-d6) δ12.42 (s, 1H), 9.23 (m, 1H), 8.69 (m, 1H), 8.27 (m, 1H), 7.89 (m, 2H), 7.58 (m, 1H), 7.52 (m, 1H), 3.98 (s, 3H), 3.99-2.70 (m, 8H), 2.60 (m, 3H). MS m/z: (M+H)+ calcd for C25H23N8O3 483.19, found 483.18.
Reaction SMILES: [Cl:1][C:2]1(C2C=CC=C(C(=O)NC)C=2)[CH:7]=[CH:6][C:5]([N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])[C:9](=[O:11])[NH2:10])=[C:4](NC(O)=O)[CH2:3]1.[CH3:36][NH:37][C:38]([C:40]1[CH:41]=[C:42]([CH:44]=[CH:45][CH:46]=1)[NH2:43])=[O:39].C1C=CC2N(O)N=NC=2C=1.CN1CC[O:61][CH2:60]C1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.O>[Cl:1][C:2]1([C:60](=[O:61])[NH:43][C:42]2[CH:44]=[CH:45][CH:46]=[C:40]([C:38](=[O:39])[NH:37][CH3:36])[CH:41]=2)[CH:7]=[CH:6][C:5]([N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:19])([F:21])[F:20])[C:9](=[O:11])[NH2:10])=[CH:4][CH2:3]1
Reactant: CNC(=O)c1cccc(C2(Cl)C=CC(N(C(N)=O)c3ccccc3C(F)(F)F)=C(NC(=O)O)C2)c1
Reactant: CNC(=O)c1cccc(N)c1
Reactant: CN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1cccc(NC(=O)C2(Cl)C=CC(N(C(N)=O)c3ccccc3C(F)(F)F)=CC2)c1
Reaction time: 8 h
Yield: 41 %

Procedure:
To a solution of N-(4-chloro-3-((trifluoromethyl)phenyl)-N′-(4-(3-methylcarbamoylphenyl) carboxyaminophenyl) urea (0.14 g, 0.48 mmol), 3-methylcarbamoylaniline (0.080 g, 0.53 mmol), HOBT.H2O (0.14 g, 1.07 mmol), and N-methylmorpholine (0.5 mL, 1.07 mmol) in DMF (3 mL) at 0° C. was added EDCI.HCl (0.10 g, 0.53 mmol). The resulting mixture was allowed to warm to room temp. and was stirred overnight. The resulting mixture was treated with water (10 mL), and extracted with EtOAc (25 mL). The organic phase was concentrated under reduced pressure. The resulting yellow solids were dissolved in EtOAc (3 mL) then filtered through a pad of silica gel (17 g, gradient from 70% EtOAc/30% hexane to 10% MeOH/90% EtOAc) to give N-(4-chloro-3-((trifluoromethyl)phenyl)-N′-(4-(3-methylcarbamoylphenyl)carbamoylphenyl) urea as a white solid (0.097 g, 41%): mp 225-229; TLC (100% EtOAc) Rf 0.23.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[CH:42]=[C:43]([CH:52]=[CH:53][CH:54]=2)[O:44][CH2:45][CH2:46][O:47]S(C)(=O)=O)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:55]12[NH:62][CH:59]([CH2:60][CH2:61]1)[CH2:58][O:57][CH2:56]2>C1COCC1>[CH:46]([OH:47])=[O:57].[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[CH:54]=[CH:53][CH:52]=[C:43]([O:44][CH2:45][CH2:46][N:62]3[CH:55]4[CH2:61][CH2:60][CH:59]3[CH2:58][O:57][CH2:56]4)[CH:42]=2)[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCOS(C)(=O)=O)c4)c4ccccc43)cn12
Reactant: C1CC2COCC1N2
Solvent: C1CCOC1
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCN5C6CCC5COC6)c4)c4ccccc43)cn12
Product: O=CO
Yield: 88.7 %

Procedure:
A solution of Intermediate 154a (50.5 mg, 66 μmol) and 3-oxa-8-aza-bicyclo[3.2.1]octane (76 mg, 0.68 mmol) in THF (1 mL) was heated at 60° C. for 48 h in a sealed vessel. The reaction mixture was concentrated in vacuo and the residue purified by MDAP (Method 7) to give the title compound as a white solid (24 mg, 46%). LCMS (Method 5): Rt 3.72 min, m/z 774 [MH+]. 1H NMR (400 MHz, d6-DMSO): 0.91 (3H, d, J=6.3 Hz), 1.28 (9H, s), 1.46-1.54 (2H, m), 1.64-1.71 (4H, m), 1.75-2.17 (8H, m), 2.59 (2H, t, J=5.9 Hz), 2.86-2.95 (1H, m), 3.07-3.11 (2H, m), 3.12-3.19 (1H, m), 3.28-3.34 (3H, m, obscured by water peak), 3.49 (2H, d, J=9.6 Hz), 4.09 (2H, t, J=6.3 Hz), 4.78-4.85 (1H, m), 5.52 (1H, t, J=4.3 Hz), 6.33 (1H, s), 6.94-6.99 (1H, m), 7.05-7.14 (3H, m), 7.19 (1H, dd, J=9.6 Hz, 2.4 Hz), 7.24-7.42 (5H, m), 7.64 (1H, d, J=10.0 Hz), 7.69 (1H, d, J=2.2 Hz), 8.15 (1H, s), 8.20 (1H, s).