Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].O[CH2:8][S:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CCOCC>[Cl:2][CH2:8][S:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(SCO)c1ccccc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCOCC
Product: O=C(SCCl)c1ccccc1

Procedure:
42 PARTS OF PHOSPHORUS PENTACHLORIDE IS COVERED WITH A LAYER OF ABSOLUTE ETHER. While stirring and cooling with ice, an ethereal solution of 33.6 parts of hydroxymethylbenzoyl sulfide is dripped in and the whole stirred for 2 hours at room temperature. The solution is filtered, the filtrate concentrated at 0.01 mm and a bath temperature of 40° C, the residue taken up in methylene chloride and washed with cold aqueous NaNHCO3 solution. The organic phase is dried over Na2SO4 and distilled 20 parts of chloromethylbenzoyl sulfide having a boiling point at 0.1 mm of 111° to 113° C is obtained.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([O:13][CH3:14])=[CH:6][C:5]=1F.[C:16]([O:23][CH3:24])(=[O:22])[CH2:17][C:18]([O:20][CH3:21])=[O:19].Cl>CN1CCCC1=O.O>[Cl:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([O:13][CH3:14])=[CH:6][C:5]=1[CH:17]([C:16]([O:23][CH3:24])=[O:22])[C:18]([O:20][CH3:21])=[O:19]
Reactant: COc1cc(F)c(Cl)cc1[N+](=O)[O-]
Reactant: COC(=O)CC(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)C(C(=O)OC)c1cc(OC)c([N+](=O)[O-])cc1Cl
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 91.2 %

Procedure:
Sodium hydroxide (4.49 g, 112.3 mmol) was added at room temperature to a stirred solution of 1-chloro-2-fluoro-4-methoxy-5-nitrobenzene (11.0 g, 53.5 mmol) and dimethyl malonate (8.976 g, 67.9 mmol) in N-methylpyrrolidinone (110 mL). The mixture was heated to 80° C. for 2 hours then cooled to 5° C. The pH of the mixture was adjusted to 2 using aq. 1N HCl solution then water (600 mL) was added gradually with stirring over 15 minute at 5° C. The precipitated solid was collected by filtration and washed with water (2×20 mL). The filtered solid was dissolved in dichloromethane (150 mL), dried (Na2SO4) and concentrated under reduced pressure to give the title compound (15.5 g, 91%).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]([CH:15]=[N:16][C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[CH:19]=[CH:20][C:21]([CH3:27])=[N:22]2)([OH:14])[CH2:4][C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:7])[CH3:6]>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl.C(Cl)Cl>[CH3:27][C:21]1[CH:20]=[CH:19][C:18]2[C:23](=[CH:24][CH:25]=[CH:26][C:17]=2[NH:16][CH:15]2[C:9]3[C:8](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:5]([CH3:6])([CH3:7])[CH2:4][C:3]2([C:2]([F:1])([F:28])[F:29])[OH:14])[N:22]=1
Reactant: Cc1ccc2c(N=CC(O)(CC(C)(C)c3ccccc3)C(F)(F)F)cccc2n1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1ccc2c(NC3c4ccccc4C(C)(C)CC3(O)C(F)(F)F)cccc2n1
Reaction time: 1 h
Yield: 84.7 %

Procedure:
5.1 ml of a 1 M titanium tetrachloride-CH2Cl2 solution is added in drops to a solution of 111 mg of 1,1,1-trifluoro-4-phenyl-2-[(2-methylquinolin-5-yl)iminomethyl]-4-methylpentan-2-ol in 84 ml of CH2Cl2 at −78° C. After 1 hour at −78° C., the batch separated, the aqueous phase is extracted with CH2Cl2, the combined organic phases are dried (Na2SO4) and concentrated by evaporation in a vacuum. Column chromatography on silica gel with cyclohexane-ethyl acetate yields 94 mg of product.
Reaction SMILES: F[B-](F)(F)F.[CH3:6][O:7][C:8]1[C:17]2[O:16][CH2:15][O:14][CH2:13][C:12]=2[CH:11]=[C:10]([CH:18]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[N:33]=[C:32]([CH3:34])[O:31][N:30]=3)=[CH:25][CH:24]=2)[C:19]([NH2:21])=[S:20])[CH:9]=1.[C:35](=O)([O-])O.[Na+].C(OCC)(=O)C>C(#N)C>[CH3:35][S:20][C:19](=[NH:21])[CH:18]([C:10]1[CH:9]=[C:8]([O:7][CH3:6])[C:17]2[O:16][CH2:15][O:14][CH2:13][C:12]=2[CH:11]=1)[NH:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]2[N:33]=[C:32]([CH3:34])[O:31][N:30]=2)=[CH:27][CH:28]=1
Reactant: O=C([O-])O
Reactant: COc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)C(N)=S)cc2c1OCOC2
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)C(=N)SC)cc2c1OCOC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
After adding 10.6 g of Me3O+BF4− to a solution of 28.2 g of a crude product of 2-(8-methoxy-4H-benzo[1,3]dioxin-6-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]thioacetamide in 100 ml of acetonitrile, the mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (27.2 g, crude product) as a light yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[C:11]([N+:18]([O-])=O)[C:10]=1[O:21][CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.O.C([O-])(=O)C.[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[CH2:1]([O:8][C:9]1[C:10]([O:21][CH3:22])=[C:11]([NH2:18])[C:12](=[CH:16][CH:17]=1)[C:13]([OH:15])=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(OCc2ccccc2)ccc(C(=O)O)c1[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Product: COc1c(OCc2ccccc2)ccc(C(=O)O)c1N
Reaction time: 4 h

Procedure:
To a vigorously stirring suspension of 4-benzyloxy-3-methoxy-2-nitrobenzoic acid (10.918 g, 0.036 mol) in water (200 ml) containing sodium acetate trihydrate (4.5 g) was added portionwise of sodium hydrosulfite (31 g, 0.18 mol) for 2 hours at 70 ° C. The reaction mixture was kept at this temperature for an additional 4 hours. After cooling, the precipitates were collected by filtration and washed with water. The product was recrystallized from ethanol to give 4-benzyloxy-3-methoxyanthranilic acid, 6.46 g (65.6%) with mp. 167-8 ° C. 1H-NMR: Analyses: Calculated for C15H15NO4 : C, 65.92; H, 5.53; N, 5.13. Found: C, 66.14; H, 5.55; N, 5.24.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:10]=1[CH2:11][NH:12][C:13]1[C:14]2[N:15]([C:19]([CH:23]=[O:24])=[C:20]([CH3:22])[N:21]=2)[CH:16]=[CH:17][CH:18]=1)=O)(C)(C)C.FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>>[NH2:8][C:9]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:10]=1[CH2:11][NH:12][C:13]1[C:14]2[N:15]([C:19]([CH:23]=[O:24])=[C:20]([CH3:22])[N:21]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: Cc1cccc(NC(=O)OC(C)(C)C)c1CNc1cccn2c(C=O)c(C)nc12
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(N)c1CNc1cccn2c(C=O)c(C)nc12

Procedure:
Starting from 8-(2-tert-butoxycarbonylamino-6-methylbenzylamino)-3-formyl-2-methylimidazo[1,2-a]pyridine (3.6 g), trifluoroacetic acid (15 ml) and anisole (5 ml) according to the procedure described for Example C1 (Method B) gives, after chromatography on silica gel (eluent: toluene/dioxane=9:1) and crystallization from ethyl acetate/cyclohexane, 2.3 g (76%) of the title compound of m.p. 230-234° C.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.[F:7][C:8]([F:20])([F:19])[C:9](=O)[CH2:10][C:11](=O)[CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15]>CCO>[CH2:12]([C:11]1[N:3]2[N:4]=[CH:5][CH:6]=[C:2]2[N:1]=[C:9]([C:8]([F:7])([F:19])[F:20])[CH:10]=1)[CH2:13][CH:14]([CH3:16])[CH3:15]
Reactant: Nc1cc[nH]n1
Reactant: CC(C)CCC(=O)CC(=O)C(F)(F)F
Solvent: CCO
Product: CC(C)CCc1cc(C(F)(F)F)nc2ccnn12

Procedure:
A solution of 2.0 gm of 3-aminopyrazole (0.024 mol) in 50 ml EtOH was refluxed with 5.0 gm of 1,1,1, -trifluoro-7-methyl-2,4-octanedione (0.024 mol) for 2 hours. The mixture was evaporated and distilled to yield 1.6 gm (48%) of a slightly yellowish oil, b.p. 103°-105°/0.5 mm.
Reaction SMILES: C(OC([N:8]([C:16]1[C:21]([CH3:22])=[CH:20][C:19]([C:23]#[N:24])=[CH:18][C:17]=1[NH:25][C:26]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[O:27])C(=O)OC(C)(C)C)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:8][C:16]1[C:21]([CH3:22])=[CH:20][C:19]([C:23]#[N:24])=[CH:18][C:17]=1[NH:25][C:26](=[O:27])[O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: CCCCCCCOC(=O)Nc1cc(C#N)cc(C)c1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCOC(=O)Nc1cc(C#N)cc(C)c1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
t-Butyl t-butoxycarbonyl(4-cyano-2-(((heptyloxy)carbonyl)amino)-6-methylphenyl)carbamate (416 mg, 0.85 mmol) obtained in Step 3 was dissolved in CH2Cl2 (3.0 mL), added with TFA (1.95 mL, 30 eq, 25.5 mmol) and stirred at room temperature for 2 hours. Subsequently, the mixture thus obtained was added with sat. NaHCO3 and extracted with CH2Cl2. The organic layer thus obtained was dried over MgSO4 and concentrated under reduced pressure to obtain the title compound in a white solid (245 mg, yield: 99%).
Reaction SMILES: [C:1]([C:3]1[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=1[O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[CH:8][CH:7]=1)#[N:2].[CH2:24]([S:26](Cl)(=[O:28])=[O:27])[CH3:25]>>[C:1]([C:3]1[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=1[O:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]([CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[S:26]([CH2:24][CH3:25])(=[O:28])=[O:27])=[CH:10][CH:11]=1)#[N:2]
Reactant: CCS(=O)(=O)Cl
Reactant: N#Cc1ccccc1Oc1ccc(NCc2cccnc2)cc1
Product: CCS(=O)(=O)N(Cc1cccnc1)c1ccc(Oc2ccccc2C#N)cc1

Procedure:
Using the method of Example 342 using N-(4-(2-cyanophenoxy)phenyl)pyridin-3-ylmethylamine and ethanesulfonyl chloride (Aldrich) and purifying via preparative HPLC eluting with 98:2 to 96:4 DCM/MeOH. Anal Calcd for C21H19N3O3S.0.2H2O: C, 63.52; H, 4.92; N, 10.58. Found: C, 63.51; H, 4.79; N, 10.55. MS found 394.0 [M+H]+
Reaction SMILES: C(OC(C1C=C(C2C=CC(F)=CC=2)N(C2C=CC=CC=2)C=1C)=O)C.[CH2:25]([O:27][C:28](=[O:40])[CH:29]([C:37](=O)[CH3:38])[CH2:30][C:31](=O)[C:32]([CH3:35])([CH3:34])[CH3:33])[CH3:26].[F:41][C:42]1[CH:48]=[CH:47][C:45]([NH2:46])=[CH:44][CH:43]=1>>[CH2:25]([O:27][C:28]([C:29]1[CH:30]=[C:31]([C:32]([CH3:35])([CH3:34])[CH3:33])[N:46]([C:45]2[CH:47]=[CH:48][C:42]([F:41])=[CH:43][CH:44]=2)[C:37]=1[CH3:38])=[O:40])[CH3:26]
Reactant: Nc1ccc(F)cc1
Reactant: CCOC(=O)C(CC(=O)C(C)(C)C)C(C)=O
Agent: CCOC(=O)c1cc(-c2ccc(F)cc2)n(-c2ccccc2)c1C
Product: CCOC(=O)c1cc(C(C)(C)C)n(-c2ccc(F)cc2)c1C

Procedure:
Prepared in analogy to that of 5-(4-fluoro-phenyl)-2-methyl-1-phenyl-1H-pyrrole-3-carboxylic acid ethyl ester from 2-Acetyl-5,5-dimethyl-4-oxo-hexanoic acid ethyl ester and 4-fluoroaniline. The title compound, ESI MS (m/z): 304 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[C:4]([C:14](=O)[C:15](Cl)=[O:16])=[CH:3]1.Cl.C([O:23][C:24](=[NH:38])[CH2:25][C:26]1[C:34]2[C:29](=[CH:30][C:31]([O:35][CH3:36])=[CH:32][CH:33]=2)[N:28]([CH3:37])[CH:27]=1)(C)C.CCN(CC)CC>C(Cl)Cl>[CH3:36][O:35][C:31]1[CH:30]=[C:29]2[C:34]([C:26]([C:25]3[C:24](=[O:23])[NH:38][C:15](=[O:16])[C:14]=3[C:4]3[C:5]4[C:10](=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=4)[N:2]([CH3:1])[CH:3]=3)=[CH:27][N:28]2[CH3:37])=[CH:33][CH:32]=1
Reactant: Cn1cc(C(=O)C(=O)Cl)c2ccc([N+](=O)[O-])cc21
Reactant: COc1ccc2c(CC(=N)OC(C)C)cn(C)c2c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2c(C3=C(c4cn(C)c5cc([N+](=O)[O-])ccc45)C(=O)NC3=O)cn(C)c2c1
Temperature: 0 °C
Yield: 31 %

Procedure:
A suspension of (1-methyl-6-nitro-1H-indol-3-yl)-oxo-acetyl chloride (251 mg, 0.94 mm) and 2-(6-methoxy-1-methyl-1H-indol-3-yl)-acetimidic acid isopropyl ester hydrochloride (280 mg, 0.94 mm) in CH2Cl2(25 mL) was cooled to 0° C., treated with Et3N (0.53 mL, 3.7 mm), and stirred at room temperature while allowing to warm to room temperature overnight. The mixture was then diluted with CH2Cl2 (25 mL), washed with H2O (20 mL), and 0.5 N HCl (20 mL). The combined organic layers were dried over MgSO4, filtered and evaporated. The residue was then combined with toluene (4 mL), cooled to 0° C., treated with pTsOH (197 mg, 1 mm), and stirred for 3 hours. The red solids which precipitated were collected and partitioned between CH2Cl2 (50 mL), and H2O (25 mL). The organic fraction was washed with saturated NaHCO3 solution (25 mL), then dried over MgSO4, filtered and evaporated. Rinsing the residue with tetrahydrofuran (THF) afforded 3-(6-methoxy-1-methyl-1H-indol-3-yl)-4-(1-methyl-6-nitro-1H-indol-3yl)-pyrrole-2,5-dione; mp=308-310° C.; in 31% yield.
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:22][CH:23]([O:25][C:26]1[N:31]=[CH:30][C:29]([C:32]([OH:34])=O)=[CH:28][C:27]=1[C:35]([F:38])([F:37])[F:36])[CH3:24].O[NH:40]/[C:41](=[N:58]\[H])/[C:42]1[CH:43]=[C:44]2[C:48](=[CH:49][CH:50]=1)[NH:47][C:46]([CH2:51][CH2:52][C:53]([O:55][CH2:56][CH3:57])=[O:54])=[CH:45]2.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH3:24][CH:23]([O:25][C:26]1[N:31]=[CH:30][C:29]([C:32]2[O:34][N:58]=[C:41]([C:42]3[CH:43]=[C:44]4[C:48](=[CH:49][CH:50]=3)[NH:47][C:46]([CH2:51][CH2:52][C:53]([O:55][CH2:56][CH3:57])=[O:54])=[CH:45]4)[N:40]=2)=[CH:28][C:27]=1[C:35]([F:38])([F:37])[F:36])[CH3:22]
Reactant: [H]/N=C(\NO)c1ccc2[nH]c(CCC(=O)OCC)cc2c1
Reactant: CC(C)Oc1ncc(C(=O)O)cc1C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CCOC(=O)CCc1cc2cc(-c3noc(-c4cnc(OC(C)C)c(C(F)(F)F)c4)n3)ccc2[nH]1
Temperature: 120 °C
Reaction time: 1 h
Yield: 75.7 %

Procedure:
EDCI (92 mg) and HOBT (79 mg) were added to a solution of 6-[(1-methylethyl)oxy]-5-(trifluoromethyl)-3-pyridinecarboxylic acid (60 mg) in THF (6 mL). The resulting solution was stirred for 1 hour followed by addition of ethyl 3-{5-[(Z)-(hydroxyamino)(imino)methyl]-1H-indol-2-yl}propanoate (D31) (100 mg). The resulting mixture was stirred for 3 hours followed by addition of TBAF (251 mg). The reaction vessel was sealed. The reaction mixture was heated at 120° C. in the microwave for 2 hours. THF was removed. The residue was dissolved in EtOAc. The organic solution was washed with saturated aqueous sodium bicarbonate solution. The organic solution was dried over anhydrous sodium sulfate. The dried solution was concentrated. The residue was purified by column chromatography to afford ethyl 3-(5-{5-[6-[(1-methylethyl)oxy]-5-(trifluoromethyl)-3-pyridinyl]-1,2,4-oxadiazol-3-yl}-1H-indol-2-yl)propanoate (D117) (89 mg). MS (ES): C24H23F3N4O4 requires 488. found 489.2 (M+H+).
Reaction SMILES: C(O)C.C(O[C:7](=[NH:37])[C:8]1[CH:36]=[CH:35][C:11]([O:12][CH2:13][CH2:14][CH2:15][CH:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][O:25][C:26]3[CH:34]=[CH:33][C:29]([C:30](=[NH:32])[O-:31])=[CH:28][CH:27]=3)[CH2:18][CH2:17]2)=[CH:10][CH:9]=1)C.Cl.[F:39][C:40]([F:45])([F:44])[CH2:41][O:42][NH2:43].C(N(CC)CC)C>O.C(Cl)(Cl)Cl>[NH2:37][C:7](=[N:43][O:42][CH2:41][C:40]([F:45])([F:44])[F:39])[C:8]1[CH:9]=[CH:10][C:11]([O:12][CH2:13][CH2:14][CH2:15][CH:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][O:25][C:26]3[CH:34]=[CH:33][C:29]([C:30]([NH2:32])=[O:31])=[CH:28][CH:27]=3)[CH2:18][CH2:17]2)=[CH:35][CH:36]=1
Reactant: CCOC(=N)c1ccc(OCCCC2CCN(CCCOc3ccc(C(=N)[O-])cc3)CC2)cc1
Reactant: NOCC(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClC(Cl)Cl
Product: NC(=O)c1ccc(OCCCN2CCC(CCCOc3ccc(C(N)=NOCC(F)(F)F)cc3)CC2)cc1

Procedure:
To an ethanol (6 mL) suspension of 0.20 g of ethyl=4-{3-[4-(3-{4-[ethoxy(imino)methyl]phenoxy}propyl)-1-piperidinyl]propoxy}benzimidate were added 0.61 g of O-(2,2,2-trifluoroethyl)hydroxylamine hydrochloride and 0.84 mL of triethylamine at room temperature, which was then stirred at the same temperature for one week. Chloroform and water were added to the reaction solution. The organic layer was separated, washed with a saturated sodium chloride aqueous solution, and then dried with anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The resultant residue was purified using silica gel column chromatography (eluent; chloroform:ethanol=30:1), to which hexane was then added, followed by collecting the solid by filtration to provide 0.12 g of 4-{3-[4-(3-{4-[amino(2,2,2-trifluoroethoxyimino)methyl]phenoxy}propyl)-1-piperidinyl]propoxy}benzamide=O-(2,2,2-trifluoroethyl)oxime as white solid form.
Reaction SMILES: [Cl:1][C:2]1[C:6]([CH2:7][CH3:8])=[C:5]([C:9]2[CH:10]=[C:11]([C:14]([OH:16])=O)[S:12][CH:13]=2)[N:4]([CH3:17])[N:3]=1.[NH2:18][C@@H:19]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]([F:42])([F:41])[F:40])[CH2:20][N:21]1[C:29](=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]1=[O:31].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>ClCCl>[Cl:1][C:2]1[C:6]([CH2:7][CH3:8])=[C:5]([C:9]2[CH:10]=[C:11]([C:14]([NH:18][C@@H:19]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[C:39]([F:42])([F:40])[F:41])[CH2:20][N:21]3[C:29](=[O:30])[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:22]3=[O:31])=[O:16])[S:12][CH:13]=2)[N:4]([CH3:17])[N:3]=1
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Reactant: CCc1c(Cl)nn(C)c1-c1csc(C(=O)O)c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1c(Cl)nn(C)c1-c1csc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.2 %

Procedure:
To a solution of 4-(3-chloro-4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (120 mg, 0.44 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (171 mg, 0.44 mmol)[prepared according to Preparation 6] and n,n-diisopropylethylamine (0.39 ml, 2.22 mmol) in Dichloromethane (4.6 ml) at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (228 mg, 0.49 mmol) in one portion. The solution stirred at 25° C. for 1 h and was then dry loaded onto silica and purified via column chromatography (silica, 30-70% EtOAc in hexanes) yielding 4-(3-chloro-4-ethyl-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide (190 mg, 0.30 mmol, 68% yield) as a white solid: LCMS (ES) m/e 601, 603 (M, M+2)+.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([N:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9]1>C(Cl)Cl>[CH:8]1([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCN(C2CCC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C1CC(N2CCNCC2)C1
Temperature: 0 °C
Reaction time: 24 h
Yield: 30.2 %

Procedure:
Trifluoroacetic acid (7.84 mL, 101.73 mmol) was added to a stirred solution of tert-butyl 4-cyclobutylpiperazine-1-carboxylate (2.445 g, 10.17 mmol) in DCM (25 mL) cooled to 0° C. under nitrogen and stirred at 20° C. for 24 h. The reaction mixture was evaporated to dryness and diluted with DCM (30 mL). This was then washed with saturated NaHCO3 (2×10 mL) and the organic layers evaporated to dryness. Product was still present in the aqueous layer, so this was basified with 2M NaOH and extracted with DCM (3×10 mL) and EtOAc (1×10 mL). Organic fractions were combined and evaporated to dryness to afford 1-cyclobutylpiperazine (0.430 g, 30.1%). 1H NMR (399.9 MHz, DMSO-d6) δ 1.60-1.67 (2H, m), 1.72-1.80 (2H, m), 1.93-1.97 (2H, m), 2.25 (4H, s), 2.57-2.60 (1H, d), 2.82 (4H, t)
Reaction SMILES: [F:1][C:2]1[C:3]([C:8](O)=[O:9])=[N:4][N:5]([CH3:7])[CH:6]=1.C(N(CC)CC)C.C(OC(Cl)=O)C(C)C.[BH4-].[Na+]>C1COCC1>[F:1][C:2]1[C:3]([CH2:8][OH:9])=[N:4][N:5]([CH3:7])[CH:6]=1
Reactant: Cn1cc(F)c(C(=O)O)n1
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1cc(F)c(CO)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 54.2 %

Procedure:
To a 50 mL round-bottomed flask containing 4-fluoro-1-methyl-1H-pyrazole-3-carboxylic acid (344 mg, 1.7 mmol) in THF (17 mL), was added triethylamine (0.23 mL, 1.7 mmol) and the reaction mixture was cooled to 0° Celsius. Isobutylchloroformate (216 μL, 1.7 mmol) was added and the reaction mixture was stirred at 0° Celsius for 30 minutes. The solids were removed by filtration, the filtrate was collected, transferred to a 25 mL round bottomed flask and sodium borohydride (95 mg, 2.5 mmol) and the reaction mixture was stirred at RT for 10 min. The reaction mixture was concentrated to dryness and purified by FCC without additional work up to provide the title compound (120 mg, 55% yield) as a yellow oil. The compound showed very low UV activity and did not ionize by MS.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:14](=[O:15])[C:13]2[CH:16]=[N:17][C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]4)=[CH:23][CH:22]=3)=[N:19][C:12]=2[C:11]([C:34]2[CH:39]=[CH:38][N:37]=[C:36]([C:40]([O:42]C)=[O:41])[CH:35]=2)=[N:10]1.O.[OH-].[Li+].CO.Cl>C1COCC1.O>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[N:9]1[C:14](=[O:15])[C:13]2[CH:16]=[N:17][C:18]([NH:20][C:21]3[CH:22]=[CH:23][C:24]([N:27]4[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]4)=[CH:25][CH:26]=3)=[N:19][C:12]=2[C:11]([C:34]2[CH:39]=[CH:38][N:37]=[C:36]([C:40]([OH:42])=[O:41])[CH:35]=2)=[N:10]1
Reactant: COC(=O)c1cc(-c2nn(-c3c(Cl)cccc3Cl)c(=O)c3cnc(Nc4ccc(N5CCN(C)CC5)cc4)nc23)ccn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CN1CCN(c2ccc(Nc3ncc4c(=O)n(-c5c(Cl)cccc5Cl)nc(-c5ccnc(C(=O)O)c5)c4n3)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of Example 222 (0.36 g, 0.583 mmol) in THF (8 mL) was added lithium hydroxide monohydrate (0.049 g, 1.166 mmol) in water (8 mL). Methanol was added until a transparent solution formed (8 mL). This mixture was stirred at room temperature for 2 hours and acidified to pH 5 with 2N aqueous HCl solution. The mixture was concentrated and the formed solid was collected by filtration, washed with water and dried to give the title compound. MS (DCI/NH3) m/z 604 (M+H)+.
Reaction SMILES: [CH2:1]([CH:4]([C:8]1[C:9]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:10]([CH3:22])[C:11]([C:20]#[N:21])=[C:12]2[C:16]=1[O:15][C:14]([CH:17]1[CH2:19][CH2:18]1)=[N:13]2)[CH2:5][CH:6]=[CH2:7])C=C>Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1.ClCCl>[CH:4]1([C:8]2[C:9]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:10]([CH3:22])[C:11]([C:20]#[N:21])=[C:12]3[C:16]=2[O:15][C:14]([CH:17]2[CH2:19][CH2:18]2)=[N:13]3)[CH2:5][CH:6]=[CH:7][CH2:1]1
Reactant: C=CCC(CC=C)c1c(-c2ccccc2)c(C)c(C#N)c2nc(C3CC3)oc12
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Solvent: ClCCl
Product: Cc1c(-c2ccccc2)c(C2CC=CC2)c2oc(C3CC3)nc2c1C#N
Temperature: 50 °C
Reaction time: 3.5 h
Yield: 76 %

Procedure:
At room temperature, Grubbs catalyst second generation (92 mg, 0.11 mol) was added to a solution of 7-(1-allylbut-3-enyl)-2-cyclopropyl-5-methyl-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-299) (400 mg, 1.09 mmol) dissolved in dichloromethane; (108 ml). Under nitrogen atmosphere, the solution was stirred at 50° C. for 3.5 hours. After cooling to room temperature, the solvent was evaporated away under reduced pressure. The residue was purified by middle-pressure liquid chromatography (eluent, n-hexane:ethyl acetate=9:1, v/v) to obtain the entitled compound (282 mg, 76%) as a white solid.