Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH2:5][C:6]1[N:7]=[C:8]([SH:11])[S:9][CH:10]=1)[CH3:2].Br[C:14]([CH3:23])([CH3:22])[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:18]([O:17][C:15](=[O:16])[C:14]([S:11][C:8]1[S:9][CH:10]=[C:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:12])[N:7]=1)([CH3:23])[CH3:22])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Reactant: CCOC(=O)Cc1csc(S)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.6 %

Procedure:
(2-Mercapto-1,3-thiazol-4-yl)acetic acid ethyl ester (88.6 g) synthesized in Example 1 and tert-butyl 2-bromo-2-methylpropionate (105.3 g) were dissolved in N,N-dimethylformamide (700 mL), potassium carbonate (66.3 g) was added, and the mixture was stirred at room temperature for 8 hr. Water (1 L) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (1 L). The organic layer was washed with saturated brine, and dried over hydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (150 g) as a slightly brown oil. The present compound was used in the next step without particular purification.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[N:9]([CH3:10])[C:8]([CH2:11][CH3:12])=[N:7][CH:6]=1.[CH3:13][N:14]1[N:18]=[N:17][C:16]([C:19]2[CH:24]=[CH:23][C:22](O)=[CH:21][CH:20]=2)=[N:15]1.CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:13][N:14]1[N:18]=[N:17][C:16]([C:19]2[CH:20]=[CH:21][C:22]([O:1][CH2:2][CH2:3][CH2:4][C:5]3[N:9]([CH3:10])[C:8]([CH2:11][CH3:12])=[N:7][CH:6]=3)=[CH:23][CH:24]=2)=[N:15]1
Reactant: Cn1nnc(-c2ccc(O)cc2)n1
Reactant: CCc1ncc(CCCO)n1C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCc1ncc(CCCOc2ccc(-c3nnn(C)n3)cc2)n1C
Temperature: 20 °C
Reaction time: 2 h
Yield: 91.9 %

Procedure:
A mixture of 5-(3-hydroxypropyl)-1-methyl-2-ethylimidazole (150 mg, 0.89 mmol), 4-(2-methyl-tetrazol-5-yl)-phenol (172 mg, 0.98 mmol), and DEAD (171 mg, 0.98 mmol) was dissolved in 10 ml of THF under nitrogen at 0° C. To the above solution was added triphenylphosphine (257 mg, 0.89 mmol) at 0° C. and the mixture was stirred for 2 h allowing the mixture to warm to 20° C. The solvent was removed in vacuo, and the residue was purified by silica column chromatography (20 cm column, ethyl acetate/hexane, 1/1-3/1; methylene chloride/methanol 30/1-15/1) to afford 267 mg (92%) of 5-[3-[4-(2-methyl-tetrazol-5-yl)phenoxy]-propyl]-1-methyl-2-ethylimidazole, as a white crystalline solid, m.p. 115°-117° C. (recrystallization from methylene chloride/hexane).
Reaction SMILES: C(O)(C(F)(F)F)=O.[OH:8][C:9]1([CH2:22][N:23]2[CH:27]=[C:26]([C:28]3[CH:33]=[C:32]([NH:34][C:35]4[N:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[CH:37][N:36]=4)[CH:31]=[C:30]([CH3:45])[CH:29]=3)[CH:25]=[N:24]2)[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]1>ClCCl>[CH3:45][C:30]1[CH:29]=[C:28]([C:26]2[CH:25]=[N:24][N:23]([CH2:22][C:9]3([OH:8])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)[CH:27]=2)[CH:33]=[C:32]([NH:34][C:35]2[N:40]=[C:39]([C:41]([F:43])([F:44])[F:42])[CH:38]=[CH:37][N:36]=2)[CH:31]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnn(CC3(O)CCN(C(=O)OC(C)(C)C)CC3)c2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnn(CC3(O)CCNCC3)c2)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
TFA (0.1 mL 1.298 mmol) was added to the solution of racemic tert-butyl 4-hydroxy-4-((4-(3-methyl-5-((4-(trifluoromethyl) pyrimidin-2-yl)amino)phenyl)-1H-pyrazol-1-yl)methyl)piperidine-1-carboxylate (120 mg, 0.23 mmol) in dichloromethane (1 mL). The mixture was stirred at room temperature for 2 days. Additional TFA (0.2 mL) was added and the mixture was stirred for 16 hours. The mixture was purified on reverse phase HPLC (ACN/water with 0.1% TFA modifier) to afford 4-((4-(3-methyl-5-((4-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)-1H-pyrazol-1-yl)methyl)piperidin-4-ol. MS ESI calc'd for C21H24F3N6O [M+H]+433. found 433. 1H NMR (500 MHz, CD3OD) δ 8.65 (d, J=4.8, 1H), 7.96 (s, 1H), 7.86 (s, 1H), 7.83 (s, 1H), 7.31 (s, 1H), 7.06 (s, 1H), 7.05 (d, J=4.2, 1H), 4.20 (s, 2H), 3.31-3.17 (m, 4H), 2.33 (s, 3H), 1.94-1.78 (m, 2H), 1.73-1.65 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][OH:15])=[CH:9][CH:8]=2)=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19].Cl[C:23]1[CH:33]=[C:27]2[N:28]([CH3:32])[CH2:29][CH2:30][CH2:31][N:26]2[C:25](=[O:34])[N:24]=1>>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][O:15][C:23]3[CH:33]=[C:27]4[N:28]([CH3:32])[CH2:29][CH2:30][CH2:31][N:26]4[C:25](=[O:34])[N:24]=3)=[CH:9][CH:8]=2)=[CH:4][C:3]=1[C:18]([F:19])([F:20])[F:21]
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Reactant: OCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Product: CN1CCCn2c1cc(OCCc1ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from 2-(4-(4-chloro-3-(trifluoromethyl)phenoxy)phenyl) ethanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[CH:6]=[CH:7][CH:8]=2)[CH2:3]1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28].C(OCC)C>N1C=CC=CC=1>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH2:3][C@H:2]([NH:1][S:27]([CH3:26])(=[O:29])=[O:28])[CH2:11][CH2:10]3)[CH2:13][CH2:14]1
Reactant: CS(=O)(=O)Cl
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: c1ccncc1
Product: CN1CCN(c2cccc3c2C[C@H](NS(C)(=O)=O)CC3)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.1 %

Procedure:
To an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (120 mg, 0.49 mmol) and triethylamine (0.50 mL, 3.6 mmol) in pyridine (15 mL) was added dropwise methanesulfonyl chloride (62 μL, 0.54 mmol). After the addition the reaction was allowed to stir at ambient temperature for 1 h. The solvent was evaporated in vacuo and the residue was purified on a silica gel column using chloroform/methanol/concentrated ammonium hydroxide (95:5:0.5) as the eluent. This gave, after crystallization from diethyl ether, 100 mg (63% yield) of the title compound as white crystals: mp 135-137° C.; [α]21D +22° (c 0.50, chloroform); EIMS (70 eV) m/z (relative intensity) 323 (59, M+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][Mg]Br.FC1C=CC=CC=1CBr.[Mg].[CH3:21][CH:22]([CH3:30])[C:23](=[O:29])[C:24]([O:26]CC)=[O:25].[NH4+].[Cl-]>C(OCC)C>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][C:23]([OH:29])([CH:22]([CH3:30])[CH3:21])[C:24]([OH:26])=[O:25]
Reactant: CCOC(=O)C(=O)C(C)C
Reactant: Fc1ccccc1C[Mg]Br
Agent: Fc1ccccc1CBr
Agent: [Cl-]
Agent: [Mg]
Solvent: CCOCC
Product: CC(C)C(O)(Cc1ccccc1F)C(=O)O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of (o-fluorobenzyl)magnesium bromide in diethyl ether (100 mL), prepared from the corresponding o-fluorobenzyl bromide (9.45 g, 50.0 mmol) and magnesium turnings (1.32 g, 55.0 mmol), was added to a solution of ethyl 3-methyl-2-oxobutanoate (7.2 g, 50 mmol) in diethyl ether (50 mL) cooled at −78° C. After 30 min at −78° C., the reaction mixture was warmed to 0° C. and poured into saturated aqueous NH4Cl. The organic layer was washed with brine, dried and concentrated. The residue was dissolved in methanol (200 mL) and kept with 2 N KOH (75 mL) for 2 hrs. at 50° C. The reaction mixture was diluted with water and washed with hexane. The aqueous layer was acidified with 2 N HCl, saturated with sodium chloride and extracted with ethyl acetate. Removal of solvents gave the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.C([Li])CCC.[B:17](OC)([O:20]C)[O:18]C.Cl>O1CCCC1>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([B:17]([OH:20])[OH:18])=[CH:3][CH:4]=1
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C

Procedure:
33 g (0.15 mol) of 4-bromotrifluoromethylbenzen was put into a 500-mL three-neck flask, and nitrogen substitution in the system was carried out. Then, 200 mL of tetrahydrofuran (THF) was added thereto, and the mixture was stirred. This mixture solution was stirred at −78° C., and 100 mL (0.16 mol) of n-butyllithium (1.6 mol/L) was dropped into the solution through a dropping funnel. After that, the obtained solution was stirred at the same temperature for 1 hour, and 22.3 mL (0.20 mol) of trimethyl borate was added to be stirred for about 12 hours while the reaction temperature was allowed to gradually increase to the room temperature. Then, 100 mL of dilute hydrochloric acid (1 mol/L) was added to the reaction solution, and the solution was stirred for 1 hour. A water layer of the mixture was extracted using ethyl acetate three times, the extracted solution and an organic layer were washed together one time using saturated saline, and the organic layer was dried with magnesium sulfate. The mixture was filtrated naturally to remove magnesium sulfate, and the filtrate was condensed to obtain a solid. The solid was washed with chloroform, whereby 15 g of a white solid, which was a target matter, was obtained with the yield of 54%.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:9]=[C:10]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:11]3[N:16]=[C:15]([CH2:17][CH:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)[S:14][C:12]=3[N:13]=2)[C:6]2[CH:30]=[CH:31][CH:32]=[CH:33][C:5]=2[N:4]=1)[CH3:2].Cl[C:35]([C:37]([O:40][C:41](=[O:43])[CH3:42])([CH3:39])[CH3:38])=[O:36].CCN(CC)CC>C(Cl)Cl>[CH2:1]([C:3]1[N:7]([C:8]2[N:9]=[C:10]([N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)[C:11]3[N:16]=[C:15]([CH2:17][CH:18]4[CH2:19][CH2:20][N:21]([C:35](=[O:36])[C:37]([O:40][C:41](=[O:43])[CH3:42])([CH3:39])[CH3:38])[CH2:22][CH2:23]4)[S:14][C:12]=3[N:13]=2)[C:6]2[CH:30]=[CH:31][CH:32]=[CH:33][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CCNCC3)sc2n1
Reactant: CC(=O)OC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CCN(C(=O)C(C)(C)OC(C)=O)CC3)sc2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 5-(2-ethylbenzoimidazol-1-yl)-7-morpholin-4-yl-2-piperidin-4-ylmethylthiazolo[5,4-d]pyrimidine (96 mg, 0.21 mmol), acetic acid 1-chlorocarbonyl-1-methylethyl ester (40 μL, 0.28 mmol) and NEt3 (40 μL, 0.31 mmol) in DCM (1 mL) was allowed to stir at r.t. for 30 min then concentrated in vacuo. The resulting residue was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH affording Acetic acid 2-{4-[5-(2-ethylbenzoimidazol-1-yl)-7-morpholin-4-ylthiazolo[5,4-d]pyrimidin-2-ylmethyl]piperidin-1-yl}-1,1-dimethyl-2-oxoethyl ester. LCMS (method A): RT 3.19 min [M+H]+ 592.2
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([OH:25])=O)=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.P([N:44]=[N+:45]=[N-:46])(=O)(OC1C=CC=CC=1)OC1C=CC=CC=1.C(N(CC)CC)C>C(O)(C)C>[F:27][C:2]([F:1])([F:26])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([N:44]=[N+:45]=[N-:46])=[O:25])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: O=C(O)/C=C/c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: [N-]=[N+]=NC(=O)/C=C/c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 79.5 %

Procedure:
To (E)-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)acrylic acid (C22) (1.72 g, 4.59 mmol) in isopropanol (15.3 mL) was diphenyl phosphorazidate (1.3 mL, 6.03 mmol) and triethylamine (0.96 mL, 6.89 mmol) and stirred at room temperature for 6 hours. The white precipitate for filtered, rinsed with isopropanol, and dried to afford the title compound as a white solid (1.46 g, 78%): mp 106° C. (dec); 1H NMR (400 MHz, CDCl3) δ 8.59 (s, 1H), 8.24 (d, J=8.4 Hz, 2H), 7.86-7.73 (m, 3H), 7.66 (d, J=8.3 Hz, 2H), 7.40 (d, J=8.3 Hz, 2H), 6.52 (t, J=14.6 Hz, 1H); 19F NMR (376 MHz, CDCl3) δ −58.02; ESIMS m/z 401 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:16][C:17](=[O:24])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>CN(C=O)C.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:16][C:17](=[O:24])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:4][CH:3]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: CCOC(=O)CC(=O)CCl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC(=O)CSc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.5 %

Procedure:
To a mixture of 4-chlorobenzenethiol (1.75 g, 12.15 mmol) and K2CO3 (3.36 g, 24.30 mmol) in DMF (40 mL) was added ethyl 4-chloro-3-oxobutanoate (2.0 g, 12.15 mmol). The mixture was stirred at RT for 18 hours, diluted with saturated NaHCO3 (40 mL) and extracted with EtOAc (50 mL). The EtOAc layer was dried over Na2SO4 and concentrated. The crude product was purified by flash chromatography (silica gel/hexane-EtOAc 100:0 to 0:100 gradient, using LC-MS to identify fractions containing the desired product) to afford ethyl 4-(4-chlorophenylthio)-3-oxobutanoate 10A (2.07 g, 59% yield). 1H NMR (500 MHz, Chloroform-D) δ ppm 7.22-7.32 (4H, m), 4.18 (2H, q, J=7.15 Hz), 3.79 (2H, s), 3.62 (2H, s), 1.27 (3H, t, J=7.01 Hz).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:13]([OH:15])=[O:14])[CH2:10][CH2:11][OH:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:16](N[C@H](C(O)=O)CO)(OC(C)(C)C)=O>>[C:1]([NH:8][C@H:9]([C:13]([OH:15])=[O:14])[CH2:10][CH2:11][O:12][CH3:16])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCO)C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Product: COCC[C@H](NC(=O)OC(C)(C)C)C(=O)O

Procedure:
Boc-homoserine (0.51 g) was methylated as described for Boc-serine in Example 73. This afforded 0.45 g crude product which was carried on without further purification. NMR (300 MHz, CDCl3) delta 1.40 (s, 9H), 3.16 (s, 3H), 3.90 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13](=[N:15]O)[CH3:14])=[CH:9][CH:8]=2)=[C:4]([F:19])[CH:3]=1.N.[H][H]>CO.[Ni]>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([CH:13]([NH2:15])[CH3:14])=[CH:11][CH:12]=2)=[C:4]([F:19])[CH:3]=1
Reactant: [H][H]
Reactant: CC(=NO)c1ccc(Oc2ccc(Cl)cc2F)cc1
Agent: [Ni]
Agent: N
Solvent: CO
Product: CC(N)c1ccc(Oc2ccc(Cl)cc2F)cc1
Yield: 89 %

Procedure:
2.60 g (9.3 mmol) of 1-[4-(4-chloro-2-fluoro-phenoxy)-phenyl]-ethanone-oxime were dissolved in 20 mL methanol, then combined with 30 mL 7N methanolic ammonia solution and after the addition of 0.2 g Raney nickel hydrogenated at ambient temperature and 50 psi hydrogen pressure. Then the catalyst was filtered off and the filtrate was evaporated down. The crude product thus obtained was reacted further without any further purification.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:14][CH:13]=1.O>C1(C)C(C)=CC=CC=1>[O:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:16][CH:17]=1
Reactant: Clc1nc2ccccc2o1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Solvent: Cc1ccccc1C
Solvent: O
Product: CCOC(=O)Cc1ccc(Nc2nc3ccccc3o2)cc1
Yield: 107.8 %

Procedure:
In xylene (10 mL), 2-chlorobenzoxazole (1.00 g, 6.51 mmol) and ethyl 4-aminophenylacetate (1.67 g, 6.51 mmol) were heated and refluxed for 10 hours. After cooling, water was added to the reaction mixture, followed by extraction with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from hexane-ethyl acetate (3:1, v/v) eluate fractions, ethyl 4-(2-benzoxazolylamino)phenylacetate (2.08 g, 99%) was obtained as a yellow solid.
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([C:9]([NH:11][N:12]([CH2:28][C@H:29]([C:31]([OH:33])=[O:32])[OH:30])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=3[F:27])=[CH:16][CH:15]=2)=[O:10])[N:6]([CH2:34][O:35][C:36](=[O:42])[C@@H:37]([NH2:41])[CH:38]([CH3:40])[CH3:39])[N:5]=1)(=[O:3])[CH3:2].C(Cl)Cl.CCN(CC)CC.Cl[C:54]([O:56][CH3:57])=[O:55]>>[C:1]([C:4]1[CH:8]=[C:7]([C:9]([NH:11][N:12]([CH2:28][C@H:29]([C:31]([OH:33])=[O:32])[OH:30])[CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=3[F:27])=[CH:18][CH:19]=2)=[O:10])[N:6]([CH2:34][O:35][C:36](=[O:42])[C@@H:37]([NH:41][C:54]([O:56][CH3:57])=[O:55])[CH:38]([CH3:39])[CH3:40])[N:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(C(=O)NN(Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@H](O)C(=O)O)n(COC(=O)[C@@H](N)C(C)C)n1
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)OCn1nc(C(C)=O)cc1C(=O)NN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)C[C@@H](O)C(=O)O)C(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 3 %

Procedure:
(S)-2-Amino-3-methylbutyric acid 3-acetyl-5-[N′-((R)-2-carboxy-2-hydroxyethyl)-N′-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)hydrazinocarbonyl]pyrazol-1-ylmethyl ester (21.0 mg, 35 μmol) was combined with DCM (134 μL, 2.1 mmol) and Et3N (15 μL, 0.1 mmol). Methyl chloroformate (2.7 μL, 35 μmol) was added and the mixture was stirred at room temperature for 20 minutes. The solvent was removed in vacuo and the residue was purified by preparative HPLC to yield the title compound (0.7 mg). MS m/z [M+H]+ calc'd for C30H33ClFN5O9, 662.20. found 662.1.
Reaction SMILES: [C:1]1([C:7]2[CH:29]=[CH:28][C:10]([CH2:11][O:12][C:13]3[CH:14]=[CH:15][C:16]4[CH2:22][CH2:21][CH2:20][C:19]([C:23]([O:25]C)=[O:24])=[CH:18][C:17]=4[CH:27]=3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl>CO.C1COCC1>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]([CH2:11][O:12][C:13]3[CH:14]=[CH:15][C:16]4[CH2:22][CH2:21][CH2:20][C:19]([C:23]([OH:25])=[O:24])=[CH:18][C:17]=4[CH:27]=3)=[CH:28][CH:29]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)C1=Cc2cc(OCc3ccc(-c4ccccc4)cc3)ccc2CCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1=Cc2cc(OCc3ccc(-c4ccccc4)cc3)ccc2CCC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 117.5 %

Procedure:
To methyl 2-(4-phenylbenzyloxy)-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (1.22 g, 3.17 mmol) dissolved in a mixed solvent of methanol (20 ml) and THF (35 ml) was added a 1N aqueous solution of sodium hydroxide (10 ml), and the resulting mixture was stirred at room temperature for 18 hours and 60° C. for 2 hours. The reaction mixture was mixed with 1 N hydrochloric acid (12 ml) at room temperature, was concentrated under reduced pressure and was mixed with water, and an insoluble material was collected by filtration. The insoluble material was washed successively with water and hexane, and was dried under reduced pressure to obtain 2-(4-phenylbenzyloxy)-6,7-dihydro-5H-benzocycloheptene-8-carboxylic acid (1.38 g).
Reaction SMILES: [N:1]1[CH:6]=[C:5]([O:7][C:8]2[CH:9]=[C:10]([NH:14]C(=O)OC(C)(C)C)[CH:11]=[N:12][CH:13]=2)[CH:4]=[N:3][CH:2]=1.[ClH:22]>O1CCOCC1>[ClH:22].[N:1]1[CH:6]=[C:5]([O:7][C:8]2[CH:9]=[C:10]([NH2:14])[CH:11]=[N:12][CH:13]=2)[CH:4]=[N:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)Nc1cncc(Oc2cncnc2)c1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1cncc(Oc2cncnc2)c1
Yield: 100 %

Procedure:
Compound 6 (1.1 g, 3.8 mmol, 1.0 eq) was stirred in 4M HCl in Dioxane (19 mL) at rt overnight. The reaction mixture was concentrated in vacuo to give 720 mg (100%) of the title compound as an orange solid: 1H NMR (400 MHz, DMSO-d6) 9.13 (s, 1H), 8.86 (s, 2H), 8.04 (s, 1H), 7.89 (s, 1H), 7.38-7.13 (m, 3H); ES-MS [M+1]+: 189.1
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[Cl:19][C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=1/[CH:27]=[CH:28]/[C:29](O)=[O:30]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:29](=[O:30])/[CH:28]=[CH:27]/[C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([Cl:26])[C:20]=3[Cl:19])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)/C=C/c1cccc(Cl)c1Cl
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)/C=C/c3cccc(Cl)c3Cl)n2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and (E)-3-(2,3-dichloro-phenyl)-acrylic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=2[N+:19]([O-:21])=[O:20])=[CH:4][C:3]=1[F:22].N1C=CC=CC=1.Cl[C:30]([O:32][CH2:33][C:34]([Cl:37])([Cl:36])[Cl:35])=[O:31]>C(Cl)Cl>[F:22][C:3]1[CH:4]=[C:5]([S:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=2[N+:19]([O-:21])=[O:20])[CH:6]=[CH:7][C:2]=1[NH:1][C:30]([O:32][CH2:33][C:34]([Cl:37])([Cl:36])[Cl:35])=[O:31]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: COC(=O)c1ccc(Sc2ccc(N)c(F)c2)c([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(Sc2ccc(NC(=O)OCC(Cl)(Cl)Cl)c(F)c2)c([N+](=O)[O-])c1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
The product of Example 96B (2.0 g, 6.2 mmol) and pyridine (0.55 mL, 6.8 mmol) in CH2Cl2 (20 mL) was reacted with 2,2,2-trichloroethyl chloroformate (0.92 mL, 6.5 mmol) dropwise at 5° C. The mixture was stirred at 5° C. for 30 minutes and concentrated. The residue was diluted with water (50 mL). The resulting crystals were collected by filtration, washed with water and i-Pr2O, and dried at room temperature in vacuum overnight to give the title compound as pale yellow crystals (2.9 g, 93%).
Reaction SMILES: [C:1]([C:3]([C:19]#[N:20])([CH2:13][CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:4][CH:5]1[CH2:10][CH2:9][C:8]([C:11]#[CH:12])=[CH:7][CH2:6]1)#[N:2].ClC1C=CC=C(C(OO)=[O:29])C=1.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[C:1]([C:3]([C:19]#[N:20])([CH2:13][CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:4][CH:5]1[CH2:10][CH2:9][C:8]2([O:29][CH:7]2[CH2:6]1)[C:11]#[CH:12])#[N:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C#CC1=CCC(CC(C#N)(C#N)CCC(F)(F)F)CC1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: C#CC12CCC(CC(C#N)(C#N)CCC(F)(F)F)CC1O2
Temperature: 25 °C
Reaction time: 5 h
Yield: 67.1 %

Procedure:
To a solution of 0.31 g of 4-(2,2-dicyano-5,5,5-trifluoropentyl)-1-ethynylcyclohexene in 3 mL of chloroform was added 0.23 g of m-chloroperbenzoic acid at 0° C., followed by stirring at room temperature for 5 hours. After the reaction mixture was cooled to 0° C., 5 mL of a 10% aqueous sodium sulfite solution was added thereto, followed by extraction twice with 30 mL of chloroform. The combined organic layer was washed sequentially with 30 mL of a 10% aqueous sodium sulfite solution, 30 mL of a saturated aqueous sodium hydrogen carbonate solution and 30 mL of a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.22 g of 4-(2,2-dicyano-5,5,5-trifluoropentyl)-1,2-epoxy-1-ethynylcyclohexane (hereinafter referred to as the present compound (4)) represented by the following formula: