Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[C:13]([N:23]4[CH:28]=[CH:27][C:26](=[O:29])[NH:25][C:24]4=[O:30])[CH:14]=[C:15]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:16]=3[O:17][CH3:18])[CH:8]=[CH:7][C:5]=2[N:6]=1.[C:31](OC(=O)C)(=[O:33])[CH3:32]>>[C:19]([C:15]1[C:16]([O:17][CH3:18])=[C:11]([C:9]2[CH:8]=[CH:7][C:5]3[N:6]=[C:2]([NH:1][C:31](=[O:33])[CH3:32])[S:3][C:4]=3[CH:10]=2)[CH:12]=[C:13]([N:23]2[CH:28]=[CH:27][C:26](=[O:29])[NH:25][C:24]2=[O:30])[CH:14]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: COc1c(-c2ccc3nc(N)sc3c2)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Product: COc1c(-c2ccc3nc(NC(C)=O)sc3c2)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Temperature: 100 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
A mixture of the product from Example 83 (30 mg, 0.071 mmol) and acetic anhydride (3 mL) was stirred at 100° C. for 2 h, and then allowed to cool to room temperature. The resulting solid was collected by filtration, washed with H2O, and dried to give the title compound as an off-white solid (29 mg, 88%). 1H NMR (300 MHz, DMSO-d6) δ 12.42 (s, 1H) 11.41 (d, J=2.21 Hz, 1H) 8.12 (d, J=1.47 Hz, 1H) 7.82 (d, J=8.46 Hz, 1H) 7.78 (d, J=8.09 Hz, 1H) 7.61 (dd, J=8.46, 1.84 Hz, 1H) 7.31 (q, J=2.70 Hz, 2H) 5.64 (dd, J=8.09, 2.21 Hz, 1H) 3.24 (s, 3H) 2.22 (s, 3H) 1.41 (s, 9H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][C:10]=1[CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])C=CC=CC=1>ClCCl>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[CH:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:11][C:10]=1[CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(OCc2ccccc2)c(C2CCCC2)c1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CCOC(=O)C=Cc1ccc(OCc2ccccc2)c(C2CCCC2)c1
Temperature: 25 °C
Yield: 73.8 %

Procedure:
A mixture of 4-benzyloxy-3-cyclopentyl-benzaldehyde (1.3 g, 4.64 mmol) and ethyl 2-triphenylphosphoranylideneacetate (1.6 g, 4.64 mmol) in dichloromethane (12 mL) was heated at reflux for 24 h. The reaction was cooled to room temperature and concentrated in vacuo. Purification by silica gel chromatography (0-10% ethyl acetate/hexanes) yielded ethyl 3-(4-benzyloxy-3-cyclopentyl-phenyl)prop-2-enoate (1.2 g, 81% yield). 1H NMR (400.0 MHz, DMSO-d6) δ 7.61-7.57 (m, 2H), 7.52 (dd, J=2.1, 8.5 Hz, 1H), 7.46-7.39 (m, 4H), 7.33 (t, J=7.1 Hz, 1H), 7.06 (d, J=8.5 Hz, 1H), 6.49 (d, J=16 Hz, 1H), 5.18 (s, 2H), 4.16 (q, J=7.1 Hz, 2H), 3.32-3.27 (m, 1H), 1.99-1.92 (m, 2H), 1.74-1.67 (m, 2H), 1.65-1.58 (m, 4H), 1.24 (t, J=7 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH2:28][C:29](O)=[O:30])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:32][NH:33][C@H:34]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH3:35]>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:16]=[CH:17][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH2:28][C:29](=[O:30])[N:33]([CH3:32])[C@H:34]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[CH3:35])=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)[CH2:7][CH2:8]1)=[O:5])[CH3:2]
Reactant: CN[C@@H](C)c1ccccc1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCC(=O)O)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCC(=O)N(C)[C@@H](C)c4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 33, Step 4, using 1-{4′-[4-(2-carboxy-ethyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and methyl-((S)-1-phenyl-ethyl)-amine.
Reaction SMILES: [CH:1]([N:4]([CH3:27])[C:5]1[C:6](OS(C(F)(F)F)(=O)=O)=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:10][CH:9]=2)([CH3:3])[CH3:2].[N+:28]([C:31]1[CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=[CH:34][C:32]=1[NH2:33])([O-:30])=[O:29].C([O-])([O-])=O.[Na+].[Na+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:33][C:32]1[CH:34]=[CH:35][C:36]([C:6]2[C:5]([N:4]([CH:1]([CH3:3])[CH3:2])[CH3:27])=[N:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:15]([O:17][CH3:18])=[O:16])[CH:12]=3)[N:7]=2)=[CH:37][C:31]=1[N+:28]([O-:30])=[O:29]
Reactant: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N(C)C(C)C)nc2c1
Reactant: CC1(C)OB(c2ccc(N)c([N+](=O)[O-])c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1ccc2nc(-c3ccc(N)c([N+](=O)[O-])c3)c(N(C)C(C)C)nc2c1
Temperature: 90 °C
Reaction time: 0.67 h
Yield: 92.5 %

Procedure:
To a solution of methyl 3-(isopropyl(methyl)amino)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate (1.0 g, 2.46 mmol) in DME (10 mL) was added 2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.97 g, 3.69 mmol), Pd(PPh3)4 (90 mg, 0.12 mmol), Na2CO3 (781 mg, 7.38 mmol) and water (2 mL) with stirring for 40 minutes at 90° C. under an inert atmosphere of nitrogen in an oil bath. The reaction mixture was concentrated under vacuum to give the residue, which was purified via silica gel chromatography (1% to 5% ethyl acetate in petroleum ether) to afford methyl 2-(4-amino-3-nitrophenyl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate as a yellow solid (900 mg, 93%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH:7]C(=O)OC(C)(C)C)[N:4]=[C:3]1[CH3:15].[ClH:16]>ClCCl.O1CCOCC1>[ClH:16].[CH3:1][N:2]1[CH:6]=[C:5]([NH2:7])[N:4]=[C:3]1[CH3:15]
Reactant: Cc1nc(NC(=O)OC(C)(C)C)cn1C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1nc(N)cn1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 55 %

Procedure:
To a solution of 337b (1.2 g, 5.68 mmol) in dichloromethane (5.0 mL) was added 3M HCl in dioxane (5.0 mL). This mixture was stirred at room temperature for 4 h and concentrated under reduced pressure. The crude product was washed by ethyl acetate to afford 337c (450 mg, 55%) as a pale yellow solid, which was used in the next step without further purification. MS-ESI: [M+H]+ 112.2
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:25][C:26]1[CH:27]=[CH:28][C:29]2[C:33]([CH3:35])([CH3:34])[O:32][B:31]([OH:36])[C:30]=2[CH:37]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[OH:36][B:31]1[C:30]2[CH:37]=[C:26]([NH:25][C:10](=[O:12])[C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:17][CH:16]=3)[CH:27]=[CH:28][C:29]=2[C:33]([CH3:35])([CH3:34])[O:32]1
Reactant: CC1(C)OB(O)c2cc(N)ccc21
Reactant: CC(C)(C)OC(=O)N[C@H](CCc1ccc(C(F)(F)F)cc1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](CCc1ccc(C(F)(F)F)cc1)C(=O)Nc1ccc2c(c1)B(O)OC2(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.6 %

Procedure:
To a suspension of (R)-2-(tert-butoxycarbonylamino)-4-(4-(trifluoromethyl)phenyl)butanoic acid (LXXI) (1 g, 2.88 mmol) and 6-amino-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol (XCVIII) (0.615 g, 2.88 mmol) in dry DCM (10 mL) was added DIPEA (1.47 mL, 8.64 mmol). To this solution was added HATU (1.09 g, 2.88 mmol) and the mixture was stirred at room temperature overnight. The mixture was washed with 2 N aqueous HCl, 1 M aqueous K2CO3, brine, dried over MgSO4 and evaporated under vacuum to give (R)-tert-butyl 1-(1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-ylamino)-1-oxo-4-(4-(trifluoromethyl)phenyl)butan-2-ylcarbamate (1.44 g, 2.84 mmol, 99% yield). ESIMS found for C25H30BF3N2O5 m/z 507.5 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]([CH3:12])[C:8]([NH:10][CH3:11])=[S:9])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:17]I>C1COCC1>[CH3:17][S:9][C:8](=[N:10][CH3:11])[N:7]([CH2:6][C:5]1[CH:13]=[CH:14][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH3:12]
Reactant: CI
Reactant: CNC(=S)N(C)Cc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN=C(SC)N(C)Cc1ccc(Cl)cc1
Temperature: 0 °C

Procedure:
In 50 ml of dry THF was dissolved 4.69 g (0.0205 mole) of N-(4-chlorobenzyl)-N-methyl-N'-methylthiourea, followed by addition of 0.82 g of 60% sodium hydride (oil). The mixture was refluxed for 1 hour. Then, under cooling with ice-water and stirring, 1.277 ml of methyl iodide was added dropwise and after completion of dropwise addition, the mixture was further stirred at room temperature for 45 minutes. The THF was distilled off and the residue was diluted with water (about 50 ml), saturated with sodium chloride, and extracted with AcOEt (100 ml×3). The extract was dried over MgSO4 and the solvent was distilled off to give 5.11 g of crude S-methyl-N-(4-chlorobenzyl)-N-methyl-N'-methylisothiourea as a colorless--pale yellow oil.
Reaction SMILES: [C:1]([C:3]1(O)[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1)#[N:2].CCN(S(F)(F)[F:23])CC>C(Cl)Cl>[C:1]([C:3]1([F:23])[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1)#[N:2]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCCC(O)(C#N)C1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC(F)(C#N)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
To a solution of tert-butyl 3-cyano-3-hydroxypiperidine-1-carboxylate (5.7 g, 25.1 mmol) in DCM (50 mL) cooled to −78° C., DAST (4.85 g, 30.1 mmol) was added drop-wise and the resulting solution stirred at −78° C. for 1 hour. The reaction was warmed to 0° C. and stirred for an additional 1 hour. The reaction mixture was diluted with DCM and quenched with sat. aq. NaHCO3. The combined extracts were dried by Na2SO4, filtered and concentrated in vacuo to afford crude title compound as a pale yellow oil 5.5 g. MS (m/z): 129 (M+H-Boc)+
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:24]([NH:26][C@H:27]([C:34]([NH:36][C@H:37]([CH:42]=NNC(N)=O)[CH2:38][CH:39]([CH3:41])[CH3:40])=[O:35])[CH2:28][C:29]1[N:33]=[CH:32][NH:31][CH:30]=1)=[O:25])[CH2:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([OH:52])CCC.C(O)(=O)C>O>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:24]([NH:26][C@H:27]([C:34]([NH:36][C@H:37]([CH:42]=[O:52])[CH2:38][CH:39]([CH3:40])[CH3:41])=[O:35])[CH2:28][C:29]1[N:33]=[CH:32][NH:31][CH:30]=1)=[O:25])[CH2:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCO
Reactant: CC(C)C[C@@H](C=NNC(N)=O)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1cccc2ccccc12)NC(=O)OCc1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: CC(C)C[C@@H](C=O)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1cccc2ccccc12)NC(=O)OCc1ccccc1

Procedure:
A solution of 200 mg. of N-benzyloxycarbonyl-3-(1-naphthyl)-L-alanyl-L-histidyl-L-leucinal semicarbazone in 2 ml. of the upper layer of a 4:1:5 by volume mixture of 1-butanol, glacial acetic acid and water was subjected to partition chromatography on a Sephadex (trade mark) G-25 column (column size: 2.5 cm. inner diameter×100.5 cm. length) and eluted with the same solvent as above. Fractions coloured with Pauli's reagent and 2,4-dinitrophenylhydrazine were collected and the solvent was removed under reduced pressure from the collected fractions. When diethyl ether was added to the residue, there were obtained 96 mg. of the desired compound as a white powdery solid, melting at 106°-108° C.; [α]22 -49.0° (C=0.5, methanol).
Reaction SMILES: CS(O[CH2:6][C@@H:7]1[CH2:11][C@H:10]([S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][N:8]1[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=1)=[O:33])(=O)=O.[N-:45]=[N+:46]=[N-:47].[Na+].[Cl-].[NH4+]>CN(C)C=O>[N:45]([CH2:6][C@@H:7]1[CH2:11][C@H:10]([S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:9][N:8]1[C:32]([O:34][CH2:35][C:36]1[CH:37]=[CH:38][C:39]([N+:42]([O-:44])=[O:43])=[CH:40][CH:41]=1)=[O:33])=[N+:46]=[N-:47]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OC[C@@H]1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC[C@@H]1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 79.9 %

Procedure:
To a solution of (2S,4S)-2-(methanesulfonyloxy)methyl-1-(4-nitrobenzyloxycarbonyl)-4-(triphenylmethylthio)pyrrolidine (7.1 g) in dimethylformamide (70 ml) was added sodium azide (1.09 g) and ammonium chloride (0.90 g) and the mixture was stirred at 80°-90° C. for 3 hours. The reaction mixture was poured into ice-water (200 ml) and extracted twice with ethyl acetate (200 ml). The extract was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (200 g) eluting with n-hexane and ethyl acetate (2:1, V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4S)-2-azidomethyl-1-(4-nitrobenzyloxycarbonyl)-4-(triphenylmethylthio)pyrrolidine (5.20 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:22])=[C:11]([CH2:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH:17]([OH:21])[CH2:16]3)[N:12]=2)=[CH:4][CH:3]=1.[C:23]([C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](Cl)=[O:29])#[N:24]>N1C=CC=CC=1>[C:23]([C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28]([O:21][C@H:17]1[CH2:18][CH2:19][CH2:20][C@@H:15]([O:14][CH2:13][C:11]2[N:12]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[O:9][C:10]=2[CH3:22])[CH2:16]1)=[O:29])#[N:24]
Reactant: Cc1oc(-c2ccc(F)cc2)nc1COC1CCCC(O)C1
Reactant: N#Cc1cccc(C(=O)Cl)c1
Solvent: c1ccncc1
Product: Cc1oc(-c2ccc(F)cc2)nc1CO[C@@H]1CCC[C@H](OC(=O)c2cccc(C#N)c2)C1
Temperature: 50 °C

Procedure:
0.1 g of 3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexanol is dissolved in 3 ml of pyridine and, at 0° C., 0.1 g of 3-cyanobenzoyl chloride is added. The reaction mixture is then heated at 50° C. for 10 minutes. The reaction is checked (LCMS), showing the formation of the desired product in addition to unreacted alcohol cis-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexanol. After addition of a further 0.9 g of 3-cyanobenzoyl chloride and 30 minutes of stirring at room temperature, the reaction is terminated by addition of 5 ml of concentrated hydrochloric acid, the mixture is extracted with ethyl acetate and the organic phase is washed with saturated sodium bicarbonate and sodium chloride solution and dried over magnesium sulfate. Purification by HPLC gives 0.1 g of the compound cis-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl 3-cyanobenzoate as a brown solid.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[OH:26][CH2:27][C:28]([NH:32][S:33]([C:36]1[S:40][C:39]([NH2:41])=[N:38][C:37]=1[CH3:42])(=[O:35])=[O:34])([CH2:30][OH:31])[CH3:29]>>[OH:31][CH2:30][C:28]([NH:32][S:33]([C:36]1[S:40][C:39]([NH:41][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:25])[F:1])=[CH:4][C:5]([C:15]4[CH:16]=[CH:17][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:19][CH:20]=4)=[N:6][C:7]=23)=[O:13])=[N:38][C:37]=1[CH3:42])(=[O:35])=[O:34])([CH2:27][OH:26])[CH3:29]
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Cc1nc(N)sc1S(=O)(=O)NC(C)(CO)CO
Product: Cc1nc(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)sc1S(=O)(=O)NC(C)(CO)CO

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 2-amino-4-methyl-thiazole-5-sulfonic acid (2-hydroxy-1-hydroxymethyl-1-methyl-ethyl)-amide (example B.9) according to general procedure II. Yellow solid. MS (ISP) 619.2 [(M−H)−]; mp 248° C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([O:27][CH3:28])=[C:8]([CH:26]=1)[NH:9][C:10]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)=[O:11].Br[C:30]([CH3:37])([CH3:36])[C:31]([O:33][CH2:34][CH3:35])=[O:32]>CCOCC.CN(C)C=O>[CH3:36][C:30]([O:25][C:22]1[CH:23]=[CH:24][C:19]([C:16]2[CH:15]=[CH:14][C:13]([CH2:12][C:10]([NH:9][C:8]3[CH:26]=[C:4]([Cl:3])[CH:5]=[CH:6][C:7]=3[O:27][CH3:28])=[O:11])=[CH:18][CH:17]=2)=[CH:20][CH:21]=1)([CH3:37])[C:31]([O:33][CH2:34][CH3:35])=[O:32]
Reactant: COc1ccc(Cl)cc1NC(=O)Cc1ccc(-c2ccc(O)cc2)cc1
Reactant: CCOC(=O)C(C)(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)C(C)(C)Oc1ccc(-c2ccc(CC(=O)Nc3cc(Cl)ccc3OC)cc2)cc1
Temperature: 20 °C

Procedure:
A 55% suspension of 2.57 gm (58.8 millimols) of sodium hydride in oil was washed free of oil with absolute ether, and the residual sodium hydride was suspended in 60 ml of absolute dimethylformamide. While stirring the resulting suspension at 20° C in an atmosphere of nitrogen, a solution of 10.8 gm (about 29.4 millimols) of raw 4-(5-chloro-2-methoxyanilinocarbonyl-methyl)-4'-hydroxy-biphenyl in 40 ml of dimethylformamide was added dropwise thereto. The resulting mixture was stirred on a bath at 80° C for 11/2 hours more, and then 11.5 gm (58.8 millimols) of ethyl 2-bromo-2-methylpropionate were added and the mixture was stirred at 100° C for 3 hours. After evaporation in vacuo, water was added, and the mixture was extracted with ethyl acetate/ether (2:1). The organic extract was washed with water, dried over sodium sulfate, filtered and evaporated to dryness in vacuo. The dark brown, viscous evaporation residue was purified by chromatography on silicagel with toluene/ethyl acetate (4:1). The combined uniform fractions were evaporated and dried at 80° C/1 mm Hg, yielding 1.7 gm (12% of theory) of a bright red, viscous substance, m.p. < 20° C, which was identified to be the compound of the formula ##STR14##
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:36])=[C:7]([C:9]2[NH:13][C:12](=[O:14])[N:11]([C:15]3[CH:33]=[CH:32][C:18]([C:19]([NH:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=4)=[O:20])=[C:17]([O:34][CH3:35])[CH:16]=3)[N:10]=2)[CH:8]=1.[CH:37]1([C:40](Cl)=[O:41])[CH2:39][CH2:38]1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:36][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:40]([CH:37]2[CH2:39][CH2:38]2)=[O:41])=[CH:8][C:7]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:33]=[CH:32][C:18]([C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)=[O:20])=[C:17]([O:34][CH3:35])[CH:16]=2)[N:10]=1
Reactant: COc1cc(-n2nc(-c3cc(CN)ccc3Cl)[nH]c2=O)ccc1C(=O)Nc1cccc(C(F)(F)F)c1
Reactant: O=C(Cl)C1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc(-n2nc(-c3cc(CNC(=O)C4CC4)ccc3Cl)[nH]c2=O)ccc1C(=O)Nc1cccc(C(F)(F)F)c1
Yield: 31 %

Procedure:
The title compound was prepared by following the procedure as described for step-2 of Intermediate-30 by using 4-(3-(5-(aminomethyl)-2-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxy-N-(3-(trifluoromethyl)phenyl)benzamide (Intermediate-26, 0.060 g, 0.11 mmol), cyclopropylcarbonyl chloride (0.019 g, 0.17 mmol), DIPEA (1 mL) and THF (5 mL) to afford 0.020 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 1.06 (m, 2H), 1.22 (m, 2H), 3.17 (m, 1H), 3.95 (s, 3H), 4.34 (d, J=6.0 Hz, 2H), 7.44-7.84 (m, 8H), 7.95 (d, J=9.0 Hz, 1H), 8.25 (s, 1H), 8.70 (m, 1H), 10.43 (m, 1H), 12.05 (m, 1H); MS (m/z): 584.35 (M+H+).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C@@H:4]([OH:13])[CH2:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:7].[CH3:21][C:22]([Si:25](Cl)([CH3:27])[CH3:26])([CH3:24])[CH3:23].N1C=CN=C1>CN(C=O)C.CCOC(C)=O>[NH2:2][C@@H:3]([CH2:14][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)[C@@H:4]([O:13][Si:25]([C:22]([CH3:24])([CH3:23])[CH3:21])([CH3:27])[CH3:26])[CH2:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:7]
Reactant: CCCCNC(=O)C[C@H](O)[C@@H](N)CC1CCCCC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCNC(=O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](N)CC1CCCCC1
Yield: 78.5 %

Procedure:
A solution of the HCl salt of (3S,4S)-4-amino-N-butyl-5-cyclohexyl-3-hydroxypentanamide (279 mg, 1.03 mmol), TBSCl (311 mg, 2.06 mmol) and imidazole (281 mg, 4.12 mmol) in dry DMF (2 mL) was stirred at rt for 2 d. The mixture was diluted with EtOAc (90 mL), washed with 1:1 water/brine (3×20 mL), dried over Na2SO4 and concentrated to leave crude (3S,4S)-4-amino-N-butyl-3-(tertbutyldimethylsilyloxy)-5-cyclohexylpentanamide (311 mg, 78%) as a yellow syrup.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:36])[C@@H:12]([NH:21][C:22](=[O:35])[C@@H:23]([C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:34])[CH3:33])=[CH:27][CH:26]=2)[NH2:24])[C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])[S:8][CH:9]=1)=[O:4].[O:37]=[C:38](Cl)OC(Cl)(Cl)Cl>ClCCl.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:36])[C@@H:12]([N:21]2[C:22](=[O:35])[C@@H:23]([C:25]3[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:34])[CH3:33])=[CH:27][CH:26]=3)[NH:24][C:38]2=[O:37])[C@H:13]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH3:14])[S:8][CH:9]=1)=[O:4]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)c1csc(NC(=O)[C@@H](NC(=O)[C@H](N)c2ccc(NC(C)=O)cc2)[C@@H](C)c2ccccc2)n1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1csc(NC(=O)[C@H]([C@@H](C)c2ccccc2)N2C(=O)N[C@H](c3ccc(NC(C)=O)cc3)C2=O)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 119.9 %

Procedure:
Crude 2-{(2S,3S)-2-[(R)-2-(4-acetylamino-phenyl)-2-amino-acetylamino]-3-phenyl-butyrylamino}-thiazole-4-carboxylic acid methyl ester (≈0.175 mmol) was dissolved in dichloromethane (10 mL) and diisopropylethyllamine (72 μL, 0.41 mmol) was added. The resulting mixture was added to an ice cooled solution of diphosgene (13 μL, 0.109 mmol) in dichloromethane (10 mL). The reaction mixture was stirred for 15 minutes, diluted with ethyl acetate (100 mL) and washed with 0.2M aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, brine and dried over sodium sulfate. The solution was filtered and the solvent removed in vacu. The residue was purified by chromatography over silica gel gradient eluted from 50% to 100% ethyl acetate in hexanes to afford 2-{(2S,3S)-2-[(R)-4-(4-acetylamino-phenyl)-2,5-dioxo-imidazolidin-1-yl]-3-phenyl-butyrylamino}-thiazole-4-carboxylic acid methyl ester (70 mg, 74%).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=O)=[CH:14][CH:13]=2)[N:4]=1.[CH3:24][NH:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH3:24][N:25]([CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:19](=[O:21])[CH2:18][C:15]1[CH:14]=[CH:13][C:12]([N:5]2[C:6]3[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=3[C:3]([C:2]([F:23])([F:22])[F:1])=[N:4]2)=[CH:17][CH:16]=1
Reactant: O=C(O)Cc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1
Reactant: CNCCc1ccccc1
Product: CN(CCc1ccccc1)C(=O)Cc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1

Procedure:
The title compound was prepared from {4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}acetic acid and N-methylphenethylamine using a similar procedure to that described for Example 13, but purified by flash column chromatography eluting from 0-88% ethyl acetate in hexane, followed by mass directed auto-prep.