Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:14]=[C:13]([O:15][CH:16]([F:18])[F:17])[N:12]([CH3:19])[N:11]=2)=[CH:6][CH:5]=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:14]1[C:10]([C:7]2[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=2)=[N:11][N:12]([CH3:19])[C:13]=1[O:15][CH:16]([F:18])[F:17]
Reactant: Cn1nc(-c2ccc(Cl)cc2)cc1OC(F)F
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: Cn1nc(-c2ccc(Cl)cc2)c(Br)c1OC(F)F
Reaction time: 16 h

Procedure:
7.9 g (43 mmol) of bromine were added to a solution of 10.1 g (39 mmol) of 3-(4-chlorophenyl)-5-difluoromethoxy-1-methyl-1H-pyrazole in 100 ml of carbon tetrachloride, and the mixture was then stirred for 16 h. The solution was then washed with sat. aqueous sodium bicarbonate solution, dried over magnesium sulfate and finally concentrated. Yield: 12.9 g. 1H-NMR (270 MHz, in CDCl3): δ[ppm]=3.84 (s, 3H), 6.69 (t, 1H), 7.40 (d, 2H), 7.81 (d, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([S:19]([C:22]2[CH:23]=[N:24][CH:25]=[C:26]([CH:31]=2)[C:27]([NH:29][NH2:30])=[O:28])(=[O:21])=[O:20])[CH2:15][CH2:14]1>CO.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6](/[C:8](=[N:30]/[NH:29][C:27](=[O:28])[C:26]2[CH:31]=[C:22]([S:19]([N:16]3[CH2:15][CH2:14][N:13]([CH3:12])[CH2:18][CH2:17]3)(=[O:21])=[O:20])[CH:23]=[N:24][CH:25]=2)/[CH3:9])[CH:7]=1
Reactant: CN1CCN(S(=O)(=O)c2cncc(C(=O)NN)c2)CC1
Reactant: CC(=O)c1cc(Cl)ccc1O
Solvent: CO
Solvent: CC(=O)O
Product: C/C(=N\NC(=O)c1cncc(S(=O)(=O)N2CCN(C)CC2)c1)c1cc(Cl)ccc1O
Temperature: 70 °C

Procedure:
1-(5-chloro-2-hydroxyphenyl)ethanone (25.07 mg, 0.147 mmol) and 5-((4-methylpiperazin-1-yl)sulfonyl)nicotinohydrazide (40 mg, 0.134 mmol) was dissolved in Methanol (10 ml) in the presence of acetic acid as a catalyst and then the reaction mixture was refluxed for 12 h at 70° C. Reaction was monitored by TLC. After completion of the reaction, following cooling, the solvent was removed by vacuum and the resulting crude material was purified by flash column chromatography (2% CH3OH/CH2Cl2) afforded the title compound (E)-N′-(1-(5-chloro-2-hydroxyphenyl)ethylidene)-5-((4-methylpiperazin-1-yl)sulfonyl)nicotinohydrazide as a solid. 1HNMR (400 MHz, CDCl3): δ 9.21 (s, 1H), 9.00 (s, 1H), 8.48 (s, 1H), 7.41 (d, 1H, J=2.0 Hz), 7.20 (d, 1H, J=8.4 Hz), 6.90 (d, 1H, J=8.4 Hz), 3.08 (m, 4H), 2.48 (m, 4H), 2.40 (s, 3H), 2.25 (5, 3H). ESI-MS: 452.0 [M+H]+
Reaction SMILES: [NH2:1][C:2]1([C:6]2[S:7][C:8]([C:11]3[CH:12]=[C:13]([NH:18][C:19]4[N:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][N:20]=4)[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[CH:9][N:10]=2)[CH2:5][O:4][CH2:3]1.[S:29](N)([NH2:32])(=[O:31])=[O:30]>O1CCOCC1.C(OCC)(=O)C>[CH3:17][C:15]1[CH:16]=[C:11]([C:8]2[S:7][C:6]([C:2]3([NH:1][S:29](=[O:31])(=[O:30])[NH2:32])[CH2:3][O:4][CH2:5]3)=[N:10][CH:9]=2)[CH:12]=[C:13]([NH:18][C:19]2[N:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][N:20]=2)[CH:14]=1
Reactant: NS(N)(=O)=O
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(N)COC3)s2)c1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(NS(N)(=O)=O)COC3)s2)c1
Temperature: 100 °C
Yield: 55.7 %

Procedure:
To a solution of N-{3-[2-(3-aminooxetan-3-yl)-1,3-thiazol-5-yl]-5-methylphenyl}-4-(trifluoromethyl)pyrimidin-2-amine (Example 59, 25 mg, 0.061 mmol) in dioxane (600 uL), sulfamide (70 mg, 0.725 mmol) was added. The reaction mixture was stirred at 100° C. The resulting mixture was stirred at 100° C. for 4 days. The mixture was diluted with ethyl acetate, washed with saturated aqueous NaHCO3, followed by brine, dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography on silica (10-100% ethyl acetate in hexanes) and lyophilized to afford N-{3-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]oxetan-3-yl}sulfuric diamide (16.3 mg, 0.034 mmol, 54.6% yield) as a pale yellow solid. MS ESI: [M H]+ m/z 487.0. 1H NMR (500 MHz, DMSO-d6) δ 10.27 (s, 2H), 8.85 (m, 1H), 8.30 (s, 1H), 8.04 (s, 1H), 7.95 (s, 1H), 7.51 (s, 1H), 7.28 (m, 1H), 7.17 (s, 1H), 6.98 (s, 2H), 5.02 (m, 2H), 4.84 (m, 2H), 2.32 (s, 3H). rhSYK activity=+++
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[CH:8]([C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10])[CH2:7][CH2:6][N:5]2[CH:15]=1.CN(C)[C:18]([C:20]1[N:21]([CH3:25])[CH:22]=[CH:23][CH:24]=1)=[O:19]>>[CH3:25][N:21]1[CH:22]=[CH:23][CH:24]=[C:20]1[C:18]([C:15]1[N:5]2[CH2:6][CH2:7][CH:8]([C:9]([O:11][CH:12]([CH3:13])[CH3:14])=[O:10])[C:4]2=[CH:3][C:2]=1[CH3:1])=[O:19]
Reactant: Cc1cc2n(c1)CCC2C(=O)OC(C)C
Reactant: CN(C)C(=O)c1cccn1C
Product: Cc1cc2n(c1C(=O)c1cccn1C)CCC2C(=O)OC(C)C

Procedure:
In accordance with the method of Example 8, isopropyl 1,2-dihydro-6-methyl-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate is condensed with N,N-dimethyl-1-methylpyrrole-2-carboxamide, to produce isopropyl 5-(N-methyl-2-pyrroyl)-1,2-dihydro-6-methyl-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate (XI, R and R1 = CH3, R2 = iC3H7).
Reaction SMILES: Cl.[I:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:6]#[N:7].[CH2:12]([OH:14])[CH3:13].C(OCC)C>C1C=CC=CC=1>[I:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:6](=[NH:7])[O:14][CH2:12][CH3:13]
Reactant: Cc1ccc(C#N)cc1I
Reactant: CCO
Agent: Cl
Solvent: CCOCC
Solvent: c1ccccc1
Product: CCOC(=N)c1ccc(C)c(I)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 189.8 %

Procedure:
Hydrogen chloride gas was bubbled over a period of 35 minutes into a stirred solution of 3-iodo-4-methylbenzonitrile (preparation 51a, 2.00 g, 8.2 mmol) and ethanol (0.70 mL, 12.3 mmol) in benzene at 0° C. The mixture was stirred for 30 minutes at room temperature and then the mixture was placed in the refrigerator and left overnight. Diethyl ether (200 mL) was then added and a white solid precipitated. After leaving the mixture a further night in the refrigerator the precipitate was filtered. Dichloromethane and saturated aqueous potassium carbonate solution were added to the solid with stirring. The organic layer was dried (MgSO4) and evaporated to give the title compound (4.50 g, 80%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[NH2:9].CO[C:12](OC)(OC)[CH2:13][CH2:14][CH2:15][CH3:16].CC1C=CC(S(O)(=O)=O)=CC=1>COCCO>[CH2:13]([C:12]1[NH:9][C:3]2[C:4](=[N:5][CH:6]=[N:7][C:2]=2[Cl:1])[N:8]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCC(OC)(OC)OC
Reactant: Nc1ncnc(Cl)c1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COCCO
Product: CCCCc1nc2ncnc(Cl)c2[nH]1
Yield: 26.8 %

Procedure:
A mixture of 6-Chloro-4,5-diaminopyrimidine (0.289 g, 2 mmol) (from Step 1 of Example 12), trimethylorthovalerate (0.52 ml, 3 mmol) and p-TsOH (0.04 g) in 2-methoxyethanol (10 ml) was refluxed for 24 hours. The product was isolated and purified as described in Step 2 of Example 12 to give the crystalline titled compound (0.113 g, 23%). NMR (CDCl3): δ0.997 (t, J=9 Hz, 3H), 1.484 (m, 2H), 1.925 (m, 2H), 3.075 (m, 2H), 7.27 (s, 1H) and 8.723 (s, 1H). FAB-MS: m/e 211 and 213 (M+H). Analysis calculated for C9H11N4Cl: C, 51.31; H, 5.26; N, 26.60. Found: C, 51.34; H, 5.30, N, 26.46.
Reaction SMILES: [CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10]1[CH:15]=[CH:14][N:13]2[N:16]=[CH:17][C:18]([C:19]3[CH:28]=[CH:27][C:22]([C:23]([NH:25][NH2:26])=[O:24])=[CH:21][CH:20]=3)=[C:12]2[N:11]=1)([CH3:3])[CH3:2].N1([C:34](N2C=CN=C2)=[O:35])C=CN=C1>CN(C=O)C.CCOC(C)=O>[CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10]1[CH:15]=[CH:14][N:13]2[N:16]=[CH:17][C:18]([C:19]3[CH:28]=[CH:27][C:22]([C:23]4[O:24][C:34](=[O:35])[NH:26][N:25]=4)=[CH:21][CH:20]=3)=[C:12]2[N:11]=1)([CH3:3])[CH3:2]
Reactant: CC(C)[C@H]1COC(=O)N1c1ccn2ncc(-c3ccc(C(=O)NN)cc3)c2n1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)[C@H]1COC(=O)N1c1ccn2ncc(-c3ccc(-c4n[nH]c(=O)o4)cc3)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.1 %

Procedure:
To a solution of (S)-4-(5-(4-isopropyl-2-oxooxazolidin-3-yl)pyrazolo[1,5-a]pyrimidin-3-yl)benzohydrazide (Example 9, Step 2; 91 mg, 0.239 mmol) in DMF (2 mL) was added di(1H-imidazol-1-yl)methanone (40.7 mg, 0.251 mmol). The reaction mixture was allowed to stir for 1 hour at ambient temperature, then dissolved in EtOAc, washed with water and brine, and concentrated. The resulting solid was suspended in dichloromethane, filtered, washed with dichloromethane, then concentrated to give crude product. The residue was purified by silica gel chromatography (0-5% MeOH in dichloromethane) to afford 42.8 mg (44%) of (S)-5-(4-(5-(4-isopropyl-2-oxooxazolidin-3-yl)pyrazolo[1,5-a]pyrimidin-3-yl)phenyl)-1,3,4-oxadiazol-2(3H)-one. LCMS (APCI+) m/z 407.5 [M+H]+.
Reaction SMILES: C([Si](C)(C)[N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:15])[CH:13]=2)[CH:8]=[CH:7]1)(C)(C)C.Cl[C:19]1[CH:24]=[CH:23][N:22]=[C:21]([NH:25][CH:26]2[CH2:31][C:30]([CH3:33])([CH3:32])[NH:29][C:28]([CH3:35])([CH3:34])[CH2:27]2)[N:20]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[Cl:15][C:12]1[CH:13]=[C:14]2[C:9]([C:8]([C:23]3[CH:24]=[CH:19][N:20]=[C:21]([NH:25][CH:26]4[CH2:31][C:30]([CH3:33])([CH3:32])[NH:29][C:28]([CH3:35])([CH3:34])[CH2:27]4)[N:22]=3)=[CH:7][NH:6]2)=[CH:10][CH:11]=1
Reactant: CC(C)(C)[Si](C)(C)n1ccc2ccc(Cl)cc21
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CC1(C)CC(Nc2nccc(-c3c[nH]c4cc(Cl)ccc34)n2)CC(C)(C)N1

Procedure:
The title compound was prepared as described in Example 215, starting from 1-(tert-butyl-dimethyl-silanyl)-6-chloro-1H-indole (prepared by TBDMS protection of 6-chloro-1H-indole using standard procedures) and (4-chloro-pyrimidin-2-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine, followed by in situ cleavage of the TBDMS protecting group with catalytic amounts of TBAF. Yield: 650 mg (77%).
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:10](=[S:14])([NH2:13])[CH2:11][CH3:12]>C(O)C>[CH2:11]([C:10]1[S:14][CH:2]=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:13]=1)[CH3:12]
Reactant: CCC(N)=S
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCO
Product: CCOC(=O)c1csc(CC)n1

Procedure:
Ethyl 3-bromo-2-oxopropanoate (4.10 mL, 32.67 mmol) was added dropwise over 10 min to a stirred solution of propanethioamide (3 g, 33.65 mmol) in ethanol (40 mL) cooled in an ice bath. After 16 h the reaction mixture was evaporated in vacuo. Purification was by silica gel chromatography eluting with EtOAc:iso-hexanes, 1:3 to give the sub-title compound as a yellow oil. Yield: 2.78 g
Reaction SMILES: CO.[ClH:3].Cl.Cl.[CH3:6][O:7][C:8]1[CH:33]=[CH:32][C:11]([CH2:12][CH2:13][NH:14][C:15]([NH:17][C:18]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[NH:19])=[NH:16])=[CH:10][CH:9]=1.[CH3:34][C:35]([CH3:37])=O>>[ClH:3].[CH2:21]([NH:20][C:18]1[NH:17][C:15]([NH:14][CH2:13][CH2:12][C:11]2[CH:10]=[CH:9][C:8]([O:7][CH3:6])=[CH:33][CH:32]=2)=[N:16][C:35]([CH3:37])([CH3:34])[N:19]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CC(C)=O
Reactant: CCCCCCCCCCCNC(=N)NC(=N)NCCc1ccc(OC)cc1
Agent: Cl
Solvent: CO
Product: CCCCCCCCCCCNC1=NC(C)(C)N=C(NCCc2ccc(OC)cc2)N1

Procedure:
100 ml of methanol, 40 ml of acetone and 0.2 ml of concentrated hydrochloric acid were added to 2.0 g (4.3 mmol) of N1-(4-methoxyphenethyl)-N5-undecyl-biguanide dihydrochloride, and the mixture was refluxed for 16 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution with a mixture of chloroform/methanol/acetic acid (8:0.5:0.5)), and dissolved in hydrous ethanol. The solvent was distilled off under reduced pressure, followed by sufficient drying under reduced pressure to obtain 16 g of a colorless resinous solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]=[CH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[O:13][C:12]([CH3:18])([CH3:17])[CH2:11][CH2:10]2)[CH3:2].[H][H]>CO.[Pd]>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH2:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[O:13][C:12]([CH3:18])([CH3:17])[CH2:11][CH2:10]2)[CH3:2]
Reactant: CCOC(=O)C=Cc1ccc2c(c1)CCC(C)(C)O2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CCc1ccc2c(c1)CCC(C)(C)O2
Yield: 78.6 %

Procedure:
A suspension of 3-(2,2-Dimethyl-chroman-6-yl)-acrylic acid ethyl ester (1.2 g, 4.61 mmol) in methanol (25 mL) was hydrogenated with 10% palladium on carbon at 60 psi of hydrogen for 6 hours. The catalyst was removed by filtration, and the solvent was evaporated in vacuo to give the product 0.95 g (79%). MS: m/z 263 (MH+). 1H NMR (CDCl3): δ 1.15 (t, 3 H), 1.24 (s, 6 H), 1.70 (t, 2 H), 2.49 (t, 2 H), 2.65 (t, 2 H), 2.76 (t, 2 H), 4.04 (q, 2 H), 6.62 (d, 1 H) and 6.81-6.86 (m, 2 H).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.C([Li])CCC.[N:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1.[CH2:28]([O:31][C:32]1[CH:43]=[C:42]([O:44][CH2:45][CH2:46][CH3:47])[CH:41]=[CH:40][C:33]=1[C:34](N(OC)C)=[O:35])[CH2:29][CH3:30]>C1COCC1>[N:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:34]([C:33]2[CH:40]=[CH:41][C:42]([O:44][CH2:45][CH2:46][CH3:47])=[CH:43][C:32]=2[O:31][CH2:28][CH2:29][CH3:30])=[O:35])=[CH:23][CH:22]=1
Reactant: CCCOc1ccc(C(=O)N(C)OC)c(OCCC)c1
Reactant: Cc1ccncc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCCOc1ccc(C(=O)Cc2ccncc2)c(OCCC)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 47.9 %

Procedure:
To a cooled solution of lithium diisopropylamide (generated from diisopropylamine (109 mg, 1.07 mmol) and a solution of n-butyllithium in hexanes (0.49 mL of a 2.5M solution, 1.22 mmol)) in THF (0.5 mL) at -78° C. was added 4-picoline (95 μL, 0.98 mmol). Stirred -78° to 0° C. for 1 h. The reaction mixture was cooled to -78° C. and a solution of 2,4-di-n-propyloxy-N-methoxy-N-methyl-benzamide from Step B (274 mg, 0.98 mmol) in THF (0.5 mL) was added dropwise. The reaction was stirred <0° C. for 4 h and then quenched by the addition of a saturated aqueous solution of ammonium chloride. The mixture was extracted with ethyl acetate (2 times). The combined extracts were successively washed with water and saturated salt solution and dried over anhydrous sodium sulfate. The solution was filtered and the solvents removed by rotoevaporation. The residue was purified by flash column chromatography on silica gel eluted with 0-50% ethyl acetate in hexanes to yield the title compound (147 mg, 48% yield), mass spectrum (CI) m/e=314 (M+1)+.
Reaction SMILES: [NH:1]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].[H-].[Na+].CI.[C:19](O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[CH3:12][C:11]([O:10][C:8]([NH:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][O:4][CH3:19])=[O:9])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC[C@H](NC(=O)OC(C)(C)C)C(=O)O

Procedure:
In a DMF solution containing 2.00 g of Boc-Ser-OH, 0.86 g of sodium hydride (60% oily suspension) was added under ice cooling and the resultant mixture was stirred for 30 min. To the resultant solution, 0.72 ml of methyl iodide was added and the resultant solution was stirred for 3 hr. The reaction mixture was neutralized with citric acid and evaporated under reduced pressure. The obtained residue was redissolved in ethyl acetate, and the solution was washed with 5% aqueous citric acid solution and saturated aqueous sodium chloride solution, successively, and dried over anhydrous sodium sulfate. The dried solution was evaporated under reduced pressure. The residue was subjected to a silica gel column chromatography (chloroform:methanol=10:1) and crystallized as its DCHA salt from n-hexane to give 0.79 g of the title compound.
Reaction SMILES: [Mg].[CH2:2]([O:9][C:10]1[CH:11]=[C:12](Br)[CH:13]=[CH:14][CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br-].II.[O:20]=[C:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1>C1COCC1>[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([C:21]2([OH:20])[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])[CH2:25][CH2:26]2)[CH:13]=[CH:14][CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Brc1cccc(OCc2ccccc2)c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: II
Agent: [Br-]
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2cccc(OCc3ccccc3)c2)CC1
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
A suspension of magnesium metal (0.144 g, 6.0 mmol) in THF (10 mL) was rapidly stirred for 30 minutes under nitrogen then a solution of 3-benzyloxybromobenzene (1.58 g, 6.00 mmol) in THF (10 mL) added slowly via dropping funnel. Once approximately 1 mL of the bromide solution had been added a crystal of iodine was added to the reaction and the mixture gently heated until Grignard formation began. The remaining bromide solution was then added at a rate to maintain a reaction temperature range of 50-60° C. Once addition was complete the reaction was heated to gentle reflux for 1 hour then cooled in an ice bath. A solution of tert-Butyl 4-oxopiperidine-1-carboxylate (1.00 g, 5.02 mmol) in THF (10 mL) was the added to the reaction over a period of 30 minutes then the mixture was allowed to warm to room temperature with stirring over a 2 hour period. After this time the reaction was quenched by the addition of 25% ammonium chloride solution (50 mL) and the layers separated. The aqueous was extracted with ethyl acetate (2×10 mL) and the combined organics were washed with water (20 mL) and brine (20 mL) then dried over magnesium sulfate. Subsequent filtration, concentration and purification of the residue by column chromatography (SiO2, 0-25% ethyl acetate/heptanes) afforded a 61% yield of tert-butyl 4-(3-benzyloxyphenyl)-4-hydroxypiperidine-1-carboxylate as a viscous clear oil that became a white solid on standing.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:26]=[CH:25][C:19]([O:20][CH2:21][C:22]([OH:24])=O)=[CH:18][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:10])[NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:20][CH2:21][C:22](=[O:24])[NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:25][CH:26]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)COc1ccc(CCCCNC(=O)OCc2ccccc2)cc1
Reactant: Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(COc1ccc(CCCCNC(=O)OCc2ccccc2)cc1)Nc1ccccc1
Temperature: 25 °C
Reaction time: 66 h
Yield: 99.1 %

Procedure:
A mixture of [4-(4-benzyloxycarbonylaminobutyl)phenoxy]acetic acid (300 mg, 0.84 mmol), aniline (0.15 mL, 1.70 mmol), DMAP (60 mg, 0.50 mmol) and EDC-HCl (320 mg, 1.70 mmol) in CH2Cl2 (30 mL) was stirred at room temperature for 66 h. The reaction mixture was concentrated under vacuum and the residue was subjected to flash silica gel column chromatography eluting with methanol/CH2Cl2 (1:99, v/v) to give the desired amide 18 as a white solid (360 mg, 99% yield). 1H NMR (300 MHz, CDCl3) δ 1.55 (m, 4H), 2.60 (m, 2H), 3.20 (m, 2H), 4.58 (s, 2H), 4.70 (br s, 1H), 5.10 (s, 2H), 6.88 (d, 2H), 7.15 (m, 3H), 7.35 (m, 7H), 7.58 (d, 2H), 8.25 (s, 1H). m/z (ESI): 433 [C26H28N2O4+H]+.
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[CH2:3][CH2:4][C@@H:5]([C:20](=[O:42])[NH:21][CH:22]1[C:28](=[O:29])[NH:27][C:26]2[C:30]([CH3:34])=[CH:31][CH:32]=[CH:33][C:25]=2[C:24]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=2)=[N:23]1)[C@H:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]([O:9]C(C)(C)C)=[O:8].C(O)(C(F)(F)F)=O>ClCCl>[F:44][C:2]([F:1])([F:43])[CH2:3][CH2:4][C@@H:5]([C:20](=[O:42])[NH:21][CH:22]1[C:28](=[O:29])[NH:27][C:26]2[C:30]([CH3:34])=[CH:31][CH:32]=[CH:33][C:25]=2[C:24]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=2)=[N:23]1)[C@H:6]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:7]([OH:9])=[O:8]
Reactant: Cc1cccc2c1NC(=O)C(NC(=O)[C@H](CCC(F)(F)F)[C@@H](C(=O)OC(C)(C)C)c1ccccc1)N=C2c1cccc(F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc2c1NC(=O)C(NC(=O)[C@H](CCC(F)(F)F)[C@@H](C(=O)O)c1ccccc1)N=C2c1cccc(F)c1
Reaction time: 3 h

Procedure:
A solution of (2R,3R)-tert-butyl 6,6,6-trifluoro-3-((5-(3-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)carbamoyl)-2-phenylhexanoate (168 mg, 0.275 mmol) in dichloromethane (2 mL) was treated with TFA (2 mL) and allowed to stand at room temperature for 3 hours. The mixture was diluted with DCM and evaporated to dryness. The residue was dissolved in DCM and washed with water and concentrated to give (2R,3R)-6,6,6-trifluoro-3-((5-(3-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl) carbamoyl)-2-phenylhexanoic acid as a light-yellow off-white solid. MS(ES):m/z=556.1 [M+H+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([C:7]([C:9]2[CH:10]=[C:11]([S:15](Cl)(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=2)=[O:8])=[CH:5][CH:4]=1.[NH3:21]>ClCCl.CO>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([C:7]([C:9]2[CH:10]=[C:11]([S:15]([NH2:21])(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=2)=[O:8])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)c2cccc(S(=O)(=O)Cl)c2)cc1
Reactant: N
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(C(=O)c2cccc(S(N)(=O)=O)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
3-(4-Methoxy-benzoyl)-benzenesulfonyl chloride is dissolved in dichloromethane (10 ml) and treated with 1.7 mL of a 2 M solution of ammonia in methanol. The reaction is stirred at ambient temperature for 2 hours and quenched with 1N HCl. The organic phase is separated and evaporated under reduced pressure to give the crude sulfonamide. Purification by silica gel chromatography (gradient of ethyl acetate in hexanes 5-25%) yielded 100 mg (50% yield) of the title compound. 1H NMR (CDCl3, 300 MHz): 8.3 (t, 1H, J=1.6 Hz), 8.1 (m, 1H), 7.95 (m, 1H), 7.8 (d, 2H, J=6.98 Hz), 7.65 (t, 1H, J=7.8 Hz), 7.0 (d, 2H, J=6.98 Hz), 4.95 (s, 2H), 3.9 (s, 3H). MP: 119-122° C. LCMS Elution time 0.81 MS (m/z): 291 (M+1). CHN Calc C, 57.72; H, 4.50; N, 4.81 Found C, 57.65; H, 4.33; N, 4.69
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]([NH:27][S@](C(C)(C)C)=O)([C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([F:26])[CH:17]=2)[CH2:9][C:10]2[S:11][CH:12]=[C:13]([CH3:15])[N:14]=2)=[N:6][CH:7]=1.Cl.[CH:35]1([N:40]=[C:41]=[O:42])[CH2:39][CH2:38][CH2:37][CH2:36]1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]([NH:27][C:41]([NH:40][CH:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)=[O:42])([C:16]2[CH:21]=[C:20]([C:22]([F:24])([F:23])[F:25])[CH:19]=[C:18]([F:26])[CH:17]=2)[CH2:9][C:10]2[S:11][CH:12]=[C:13]([CH3:15])[N:14]=2)=[N:6][CH:7]=1
Reactant: Cc1csc(C[C@](N[S@@](=O)C(C)(C)C)(c2cc(F)cc(C(F)(F)F)c2)c2ccc(Cl)cn2)n1
Reactant: O=C=NC1CCCC1
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CO
Product: Cc1csc(C[C@](NC(=O)NC2CCCC2)(c2cc(F)cc(C(F)(F)F)c2)c2ccc(Cl)cn2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32.7 %

Procedure:
(S)-N-((S)-1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-(4-methylthiazol-2-yl)ethyl)-2-methylpropane-2-sulfinamide (29 mg, 0.058 mmol) in MeOH (1.0 mL) was added HCl (0.5 mL, 2 mmol, 4N solution in dioxane) and the reaction was stirred at room temperature for 0.5 h. The mixture was concentrated, diluted with EtOAc (20 mL), washed with sat. NaHCO3 (20 mL), dried over Na2SO4, filtered and concentrated. The residue was dissolved in DCM (1 mL) and cyclopentyl isocyanate (9 mg, 0.083 mmol) was added followed by two crystals of citric acid. The reaction was stirred overnight, concentrated and purified by Prep TLC (Uniplate, Silica Gel GF, 20×20 cm, 1000 Microns) using Hexane/EtOAc (1/1) to yield (S)-1-(1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-(4-methylthiazol-2-yl)ethyl)-3 -cyclopentylurea as a clear oil (10 mg, 70% yield) LCMS: 1.91 min [M+1] 527.2 (2 min gradient, MeOH/H2O 0.1% TFA); HPLC: 3.91 min (4 min gradient, MeOH/H2O 0.2% PPA); Purity 100%; NMR: 400 MHz 1H (CDCl3) 8.29 ppm, 1 H, d, J=2.64 Hz; 7.54 ppm, 1 H, dd, J=8.57, 2.42 Hz; 7.40 ppm, 1 H, s; 7.32 ppm, 1 H, s; 7.26 ppm, 1 H, d, J=9.67 Hz; 7.12 ppm, 2 H, d, J=8.35 Hz; 6.60 ppm, 1 H, s; 4.58 ppm, 1 H, d, J=13.62 Hz; 4.43 ppm, 1 H, d, J=7.03 Hz; 4.08 ppm, 1 H, d, J=13.62 Hz; 3.92 ppm, 1 H, m; 2.20 ppm, 3 H, s; 1.93 ppm, 2 H, m; 1.61 ppm, 2 H, m; 1.53 ppm, 2 H, m; 1.40 ppm, 1 H, m; 1.32 ppm, 1 H, dd, J=13.18, 7.03 Hz.