Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[Cl:12][C:13]([Cl:30])([Cl:29])[C:14]([N:16]1[CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[C:21]([S:25](Cl)(=[O:27])=[O:26])[CH:22]=2)[CH2:17]1)=[O:15]>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:30][C:13]([Cl:12])([Cl:29])[C:14]([N:16]1[CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[C:21]([S:25]([NH:7][C:6]3[CH:8]=[CH:9][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:4][CH:5]=3)(=[O:27])=[O:26])[CH:22]=2)[CH2:17]1)=[O:15]
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: O=C(N1Cc2ccc(S(=O)(=O)Cl)cc2C1)C(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=C(N1Cc2ccc(S(=O)(=O)Nc3ccc(C(F)(F)F)cc3)cc2C1)C(Cl)(Cl)Cl
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 70.7 %

Procedure:
To a solution of 4-trifluoromethyl aniline (213 μL, 1.70 mmol) in pyridine (270 μL) was added 2-(trichloroacetyl)-2,3-dihydro-1 H-isoindole-5-sulfonyl chloride (617 mg, 1.70 mmol) at room temperature, and the mixture was stirred at 60° C. for 1.5 hr. The reaction mixture was allowed to cool to room temperature and diluted with ethyl acetate. The mixture was washed with 1 mol/L hydrochloric acid, brine and water. The organic layer was dried over anhydrous sodium sulfate and then the desiccant was filtered off, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→2:1) to afford the title compound as a colorless powder (586 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[O:10])=[C:4]([F:25])[CH:3]=1.[CH3:26][N:27]1[CH2:31][CH2:30][NH:29][C:28]1=[O:32]>>[CH3:23][C:22]1[C:17]([N:14]2[CH2:15][CH2:16][N:11]([C:9]([C:5]3[C:6]([F:8])=[CH:7][C:2]([N:29]4[CH2:30][CH2:31][N:27]([CH3:26])[C:28]4=[O:32])=[CH:3][C:4]=3[F:25])=[O:10])[CH2:12][CH2:13]2)=[N:18][CH:19]=[C:20]([CH3:24])[CH:21]=1
Reactant: CN1CCNC1=O
Reactant: Cc1cnc(N2CCN(C(=O)c3c(F)cc(Br)cc3F)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3c(F)cc(N4CCN(C)C4=O)cc3F)CC2)c(C)c1
Yield: 85.5 %

Procedure:
Using (4-bromo-2,6-difluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (410 mg) described in Preparation Example 111 and 1-methylimidazolidin-2-one (120 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (367 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[F:15])[C:5]([NH:7][CH2:8][C:9]([OH:11])=[O:10])=O.CN1CCOCC1.ClC(OC)=O.ClC([O-])=O>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:5]2[O:10][C:9](=[O:11])[CH2:8][N:7]=2)[CH:12]=[CH:13][C:14]=1[F:15]
Reactant: O=C(O)CNC(=O)c1ccc(F)c(F)c1
Agent: COC(=O)Cl
Agent: O=C([O-])Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: O=C1CN=C(c2ccc(F)c(F)c2)O1
Temperature: -10 °C
Reaction time: 1 h
Yield: 94.7 %

Procedure:
To a solution of 2-(3,4-difluorobenzamido)acetic acid (5.18 g, 24.1 mmol) in THF (25 mL) in a 100 mL round-bottomed flask was added 4-methylmorpholine (2.44 g, 24.1 mmol) to give a colorless solution. The solution was cooled to −10° C. and methyl chloroformate (2.28 g, 24.1 mmol) was added slowly over the course of thirty minutes while maintaining the solution at −10° C. A white precipitate started to form almost immediately and the solution became increasingly orange in color. Once the addition of chloroformate was complete the solution was stirred at −10° C. for 1 hour and warmed to room temperature over the course of an hour. The solution was filtered through a glass frit and the remaining solid was washed thoroughly with THF until colorless. The combined filtrate was evaporated under reduced pressure to provide 2-(3,4-difluoro-phenyl)oxazol-5(4H)-one as a light orange solid (4.5 g, 95%). LCMS (+ESI) m/z 198.2 [M+H]+. 1H-NMR (CDCl3) δ 7.85 (m, 1H), 7.78 (m, 1H), 7.30 (m, 1H), 4.45 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][CH2:6][C:7]#[C:8][CH2:9][N:10]1[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][C@@H:11]1/[CH:17]=[CH:18]/[CH:19]([OH:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[H][H]>[Pd].CO>[CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][N:10]1[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][C@@H:11]1/[CH:17]=[CH:18]/[CH:19]([OH:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCC(O)/C=C/[C@H]1CCCC(=O)N1CC#CCCCC(=O)OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCCCCC(O)/C=C/[C@H]1CCCC(=O)N1C/C=C\CCCC(=O)OC
Reaction time: 23 h
Yield: 97.6 %

Procedure:
Palladium on carbon (10 wt. %, 3 mg) was added to a solution of solution of 7-[(R)-2-((E)-3-hydroxy-oct-1-enyl)-6-oxo-piperidin-1-yl]-hept-5-ynoic acid methyl ester (13.5 mg, 0.037 mmol) in MeOH (2.0 mL). A hydrogen atmosphere was established by evacuating and refilling with hydrogen (3×) and the reaction mixture was stirred under a balloon of hydrogen for 23 h. The reaction mixture was filtered through celite, washing with ethanol, and the filtrate was concentrated in vacuo to afford 13.2 mg (97%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][N:6]([CH2:17][C:18]([N:20]([N:22]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23]1)[CH3:21])=[O:19])[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[CH3:16])[NH:12][N:11]=[CH:10]2)[CH3:2].[H-].[Na+].[CH3:34]I>CN(C)C=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][N:6]([CH2:17][C:18]([N:20]([N:22]1[CH2:23][C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:30]1)[CH3:21])=[O:19])[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[CH3:16])[N:12]([CH3:34])[N:11]=[CH:10]2)[CH3:2]
Reactant: CCOC(=O)CN(CC(=O)N(C)N1Cc2ccccc2C1)c1cc2cn[nH]c2cc1C
Reactant: CI
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN(CC(=O)N(C)N1Cc2ccccc2C1)c1cc2cnn(C)c2cc1C
Yield: 73 %

Procedure:
The compound (871 mg, 2.07 mmol) of step B was dissolved in N,N-dimethylformamide (19 ml), 60% sodium hydride (109 mg, 2.73 mmol) was added under ice-cooling with stirring, and the mixture was stirred at the same temperature for 1 hr. Then, methyl iodide (0.44 ml) was added, and the mixture was stirred under ice-cooling for 90 min. The reaction mixture was diluted with 10% citric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure. The obtained oil was purified by silica gel column chromatography (ethyl acetate-hexane→ethyl acetate-methanol) to give the title compound (653 mg, yield 73%) as a colorless amorphous solid.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH3:12][C:13]1[C:17](B2OC(C)(C)C(C)(C)O2)=[C:16]([CH3:27])[O:15][N:14]=1.O>CCOC(C)=O>[CH3:12][C:13]1[C:17]([C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=2)=[C:16]([CH3:27])[O:15][N:14]=1
Reactant: Cc1noc(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1noc(C)c1-c1ccc(N)c([N+](=O)[O-])c1
Temperature: 120 °C

Procedure:
4-bromo-2-nitroaniline (1 g, 4.6 mmol) and 3,5-Dimethylisoxazole-4-boronic acid pinacol ester (2 g, 9.2 mmol) was added to a solvent mixture of 1,2-dimethoxymethane (12 ml) and water (6 ml). To the above mixture were added PEPPSI-Ipr (312 mg, 0.46 mmol) and CsCO3 (4.5 g, 13.8 mmol). The reaction mixture was heated at 120° C. for 30 min. The reaction mixture was then diluted with EtOAc (100 ml), washed with bring (50 ml×2). The organic solvent was evaporated and the residue was dissolved in DCM and purified with flash column chromatography (50% EtOAc/Hexane) to afford 4-(3,5-dimethylisoxazol-4-yl)-2-nitroaniline.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([N:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[S:4][N:3]=1.[Cl:14][C:15]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:16]=1[CH2:17][N:18]1[CH:22]=[CH:21][C:20]([NH2:23])=[N:19]1>>[Cl:14][C:15]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:16]=1[CH2:17][N:18]1[CH:22]=[CH:21][C:20]([NH:23][CH:10]2[CH2:11][CH2:12][N:7]([C:5]3[S:4][N:3]=[C:2]([CH3:1])[N:6]=3)[CH2:8][CH2:9]2)=[N:19]1
Reactant: Cc1nsc(N2CCC(=O)CC2)n1
Reactant: Nc1ccn(Cc2ccc(Cl)cc2Cl)n1
Product: Cc1nsc(N2CCC(Nc3ccn(Cc4ccc(Cl)cc4Cl)n3)CC2)n1

Procedure:
Prepared in analogy to example 1 step h) starting from 1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-one (example 1c) and 1-(2,4-dichloro-benzyl)-1H-pyrazol-3-ylamine. The title compound was obtained as a colorless oil (yield=56%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH2:9](Br)[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: Oc1ccc(Cl)cc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(COc1ccc(Cl)cc1)c1ccccc1
Reaction time: 2 h
Yield: 98.4 %

Procedure:
To a solution of 4-chlorophenol (0.774 g) and phenacyl bromide (1 g) in N,N-dimethyl formamide (10 ml) potassium carbonate (3.5 g) was added. The mixture was refluxed with stirring for 2 h. After cooling the reaction mixture was poured into water (50 ml) and extracted with dichloromethane (3×20 ml). The combined organic layers were washed with water (20 ml) and brine (20 ml), dried (MgSO4), and evaporated. The crude was purified by flash chromatography on silica gel (petrol ether/ethyl acetate 10:1) to give 2-(4-chlorophenoxy)-1-phenylethanone (1.22 g) as pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][C:3]=1[F:12].ClS([N:17]=[C:18]=[O:19])(=O)=O.O>C(#N)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[N:8]2[C:18]([NH2:17])=[O:19])=[CH:4][C:3]=1[F:12]
Reactant: O=C1Cc2cc(F)c(Cl)cc2N1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: O
Solvent: CC#N
Product: NC(=O)N1C(=O)Cc2cc(F)c(Cl)cc21
Reaction time: 0.75 h
Yield: 10.1 %

Procedure:
To a slurry of 6-chloro-5-fluoro-2-oxindole (0.04 mole) in acetonitrile (80 ml) was added chlorosulfonyl isocyanate (6.65 g, 0.047 mole) and the mixture was stirred for 45 minutes. Water (100 ml) was then added and the aqueous mixture was stirred for one hour. The precipitate which formed was filtered off and recrystallized from acetonitrile to give 0.92 g of the title product. Extraction of the filtrate from the aqueous reaction mixture with ethyl acetate (300 ml) followed by drying the extract over MgSO4 and then evaporating it under reduced pressure gave additional product. Recrystallization from acetonitrile gave an additional 2.2 g of product, m.p. 229°-231° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH:6]([OH:8])[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.N1(O)CCCC[CH2:13]1.C=O.[OH-].[K+]>C(O)=O>[CH3:13][N:3]1[C:4]([CH3:10])([CH3:9])[CH2:5][CH:6]([OH:8])[CH2:7][C:2]1([CH3:11])[CH3:1]
Reactant: ON1CCCCC1
Reactant: CC1(C)CC(O)CC(C)(C)N1
Agent: C=O
Agent: [K+]
Agent: [OH-]
Solvent: O=CO
Product: CN1C(C)(C)CC(O)CC1(C)C
Yield: 91 %

Procedure:
1,2,2,6,6-pentamethy-4-piperidinol was synthesized upon reductive-amination of 2,2,6,6-tetramethy-4-piperidinol. A mixture of 2,2,6,6-tetramethyl]-piperidinol (3.55 g, 0.02 M), 37% formalin (3.3 mL) and 1 mL formic acid was heated under a reflux condensor on the steam bath for 5 h. The reaction mixture was made basic with (1.0 M) potassium hydroxide solution and the product was extracted with ether (5×50 mL). The combined extract was washed with saturated solution of potassium carbonate (2×20 mL) and dried over anhydrous magnesium sulfate and finally the solvent was evaporated under vacuum. The residue was then sublimed at 0.05 mm, bath temperature 85° C. The white sublimate weighed 3.5 g to give 91% yield, mp=72-74° C.
Reaction SMILES: [OH:1][C:2]([C:5]([CH3:11])([CH:9]=[CH2:10])[C:6]([OH:8])=[O:7])([CH3:4])[CH3:3].N1C(C)=CC=CC=1C.[C:20]([Si:24]([CH3:27])([CH3:26])Cl)([CH3:23])([CH3:22])[CH3:21]>ClCCl>[C:20]([Si:24]([CH3:27])([CH3:26])[O:1][C:2]([C:5]([CH3:11])([CH:9]=[CH2:10])[C:6]([OH:8])=[O:7])([CH3:4])[CH3:3])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=CC(C)(C(=O)O)C(C)(C)O
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: C=CC(C)(C(=O)O)C(C)(C)O[Si](C)(C)C(C)(C)C
Reaction time: 1 h
Yield: 95.8 %

Procedure:
A cooled (0° C.) solution of 2-(1-hydroxy-1-methyl-ethyl)-2-methyl-but-3-enoic acid (2.0 g, 12.6 mmol) and 2,6-lutidine (13.5 g, 126.4 mmol) in dichloromethane (150 mL) was treated with tert-butyldimethylchlorosilane (16.7 g, 63.2 mmol). After stirring for 1 h, the volatiles were removed in vacuo, the residue was taken in methanol (100 mL) and water (50 mL) and treated with potassium carbonate (20 g). After stirring for 16 h, the volatiles were removed in vacuo, the residue was diluted with water (50 mL), acidified to pH 2 with potassium hydrogen sulfate, and extracted with dichloromethane (3×25 mL). All the organics were combined and the volatiles were removed in vacuo to afford the title compound (3.288 g, 95%) as a clear oil. 1H NMR (300 MHz, CDCl3) δ 0.24 (s, 3H), 0.25 (s, 3H), 0.94 (s, 9H), 1.34 (s, 3H), 1.37 (s, 3H), 1.38 (s, 3H), 5.29 (m, 2H), 6.17 (dd, J=17.6, 10.9 Hz, 1H), 10.99 (br s, 1H).
Reaction SMILES: [C:1]1([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li].I[CH2:15][C:16]#[N:17].Cl>C1COCC1.O>[CH2:11]([O:10][C:8]([CH:7]([CH2:15][C:16]#[N:17])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:9])[CH3:12]
Reactant: CCOC(=O)Cc1ccccc1
Reactant: N#CCI
Agent: Cl
Agent: [Li]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(CC#N)c1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 86.4 %

Procedure:
In this example 10 g of ethyl phenylacetate in 10 ml of THF was added dropwise to 61 ml of a 1 molar solution lithium bis[trimethylsilvllamide in tetrahydrofuran, under nitrogen, at -78° C. The mixture was stirred for one hour at -78° C. A solution containing 10.2 g of iodoacetonitrile in 10 ml of tetrahydrofuran was added dropwise. The reaction mixture was stirred at -78° C. for about one-half hour and then stirred for two hours and allowed to warm toward room temperature during this period. The reaction mixture was then added to water and the pH adjusted to pH 1 by the addition of aqueous 10% hydrochloric acid. The mixture was washed with saturated aqueous sodium chloride solution and extracted three times with ethyl ether. The extracts were combined, washed twice with aqueous saturated sodium bicarbonate, dried over magnesium sulfate and evaporated affording 10.7 g of the title compound is an oil. The oil was further purified by chromatography over silica gel eluting with 20% vol. ethyl acetate petroleum ether.
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][C:13]=1[Cl:24]>C1(C)C(C)=CC=CC=1.C(Cl)(Cl)Cl>[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:17]=[CH:16][C:15]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:14][C:13]=1[Cl:24]
Reactant: Clc1nc2ccccc2o1
Reactant: CCOC(=O)Cc1ccc(N)c(Cl)c1
Solvent: Cc1ccccc1C
Solvent: ClC(Cl)Cl
Product: CCOC(=O)Cc1ccc(Nc2nc3ccccc3o2)c(Cl)c1
Temperature: 25 °C
Yield: 78.9 %

Procedure:
In xylene (10 ml), 2-chlorobenzoxazole (743 μl, 6.51 mmol) and ethyl 4-amino-3-chlorophenylacetate (1.30 g, 6.51 mmol) were heated under reflux for 2 hours. After cooling to room temperature, the reaction mixture was diluted with chloroform (50 ml). The mixture was washed with water, dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from n-hexane/ethyl acetate (9:1, v/v) eluate fractions, ethyl (4-(2-benzoxazolyl)amino-3-chlorophenyl)acetate (1.70 g, 79%) was obtained as a pale yellow solid.
Reaction SMILES: CC1C=C(C2C=CC(OC(F)(F)[F:15])=CC=2)SC=1CO.F[C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[C:24]([F:31])=[CH:23][C:22]=1[C:32]1[S:36][C:35]([CH2:37][O:38][Si](C(C)C)(C(C)C)C(C)C)=[C:34]([CH3:49])[CH:33]=1>>[F:15][C:23]1[C:24]([F:31])=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=[CH:21][C:22]=1[C:32]1[S:36][C:35]([CH2:37][OH:38])=[C:34]([CH3:49])[CH:33]=1
Reactant: Cc1cc(-c2ccc(OC(F)(F)F)cc2)sc1CO
Reactant: Cc1cc(-c2cc(F)c(C(F)(F)F)cc2F)sc1CO[Si](C(C)C)(C(C)C)C(C)C
Product: Cc1cc(-c2ccc(C(F)(F)F)c(F)c2F)sc1CO

Procedure:
The title compound was prepared using a method analogous to that used for the preparation of {3-methyl-5-[4-(trifluoromethoxy)phenyl]thien-2-yl}methanol (intermediate 118) using ({5-[2,5-difluoro-4-(trifluoromethyl)phenyl]-3-methylthien-2-yl}methoxy)(triisopropyl)silane (intermediate 121).
Reaction SMILES: FC(F)[C:3]1[N:7](C2N=C(N3CCOCC3)N=C(OC3CCN(C(OC(C)(C)C)=O)CC3)N=2)[C:6]2[CH:34]=[CH:35][CH:36]=[C:37](OC)[C:5]=2[N:4]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:4]1[C:5]2[CH:37]=[CH:36][CH:35]=[CH:34][C:6]=2[N:7]=[CH:3]1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(OC2CCN(C(=O)OC(C)(C)C)CC2)nc(N2CCOCC2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc2[nH]cnc2c1

Procedure:
Treatment of tert-butyl 4-(4-(2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yloxy)piperidine-1-carboxylate (112 mg, 0.2 mmol) with TFA (5 mL) in CH2Cl2 (10 mL), followed by quenching with aqueous NH3 gave 2-(difluoromethyl)-4-methoxy-1-(4-morpholinyl)-6-(4-piperidinyloxy)-1,3,5-triazin-2-yl]-1H-benzimidazole: 1H NMR (DMSO-d6) δ 7.96 (dd, J=8.4, 0.5 Hz, 1H), 7.71 (t, JHF=52.8 Hz, 1H), 7.44 (t, J=8.3 Hz, 1H), 6.98 (d, J=7.7 Hz, 1H), 5.11 (m, 1H), 3.98 (s, 3H), 3.83 (m, 4H), 3.71 (m, 4H), 3.00 (m, 2H), 2.62 (m, 2H), 2.00 (m, 2H), 1.58 (m, 2H).
Reaction SMILES: [C:1]([N:8]([CH2:10][CH2:11][CH2:12][S:13]([C:16]1[CH:17]=[C:18]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]3[N:32]([C:33]4[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=4[F:40])[N:31]=[C:30]([C:41]([F:47])([F:46])[C:42]([F:45])([F:44])[F:43])[CH2:29]3)[CH:23]=2)[CH:19]=[CH:20][CH:21]=1)(=[O:15])=[O:14])C)(OC(C)(C)C)=O.FC(F)(F)C(O)=O>ClCCl>[F:40][C:34]1[CH:35]=[C:36]([F:39])[CH:37]=[CH:38][C:33]=1[N:32]1[CH:28]([C:24]2[CH:23]=[C:22]([C:18]3[CH:19]=[CH:20][CH:21]=[C:16]([S:13]([CH2:12][CH2:11][CH2:10][NH:8][CH3:1])(=[O:14])=[O:15])[CH:17]=3)[CH:27]=[CH:26][CH:25]=2)[CH2:29][C:30]([C:41]([F:46])([F:47])[C:42]([F:45])([F:43])[F:44])=[N:31]1
Reactant: CN(CCCS(=O)(=O)c1cccc(-c2cccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)c2)c1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCCCS(=O)(=O)c1cccc(-c2cccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)c2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-{3′[3-(N-BOC-N-methyl-amino)-propane-1-sulfonyl]-biphenyl-3-yl}-1-(2,4-difluoro-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole (20.0 mg, 0.03 mmol) prepared in Example 85 and trifluoroacetic acid (22.3 uL, 0.29 mmol) were added at 0° C. to dichloromethane (1.0 mL). The reaction mixture was stirred at room temperature for 1 hour, quenched with a saturated solution of sodium hydrogen carbonate, and then extracted with dichloromethane three times. The combined extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a residue as a white liquid. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/2) to give 5.0 mg of the titled compound as a white solid.
Reaction SMILES: [C:1]([O:9][CH:10]([CH3:12])[CH3:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:14].C1(C)C(C)=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>C1C=CC=CC=1.O.CC(C)=O>[S:14]=[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]1[C:1]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8]
Reactant: CC(C)OC(=O)c1ccccc1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1C
Solvent: CC(C)=O
Product: CC(C)OC(=O)C1C=CC=CC1=S
Temperature: 0 °C
Yield: 227.6 %

Procedure:
CAUTION—The reaction and workup should be conducted in a good fume hood. A mixture of isopropyl benzoate (8.13 ml, 50 mmol), P4S10 (7.40 grams, 16.7 mmol), HMDO (17.7 mL, 83.3 mmol), and xylene (50 mL, dried over 3A molecular sieves) was mechanically stirred and refluxed under argon for 8 hours. The reaction mixture was cooled in an ice-bath and treated with aqueous K2CO3 solution (21 mL of 5.3 M, 111 mmol). Acetone (25 mL) was added and the mixture was stirred vigorously for 30 minutes in the ice-bath. Water and benzene were then added, the layers separated, and the aqueous phase extracted with benzene. The combined organic phase was washed with dilute K2CO3 solution, water and brine, and dried over anhydrous Na2SO4. Evaporation of the solvent and distillation of the residue through a short Vigreaux column gave 7.46 grams (83%) of isopropyl thionobenzoate, bp 54–61° C./0.01 mm:1H NMR CDCl3) δ1.52 (d,J=6.6 Hz, 6H), 5.94(heptuplet, j-6.6 Hz, 1H)), 7.41 (m,2H), 7.55 (m,1H), 8.23 (m,2H); 13C NMR (CDCl3) δ21.32, 75.60, 128.05, 128.85, 132.59, 139.00, 210.68. Analysis by gas chromatography showed 98.3% purity, with 1.5% of the starting ester as the major impurity.
Reaction SMILES: [CH:1]([S:4]([C:7]1[CH:20]=[CH:19][C:10]([NH:11][CH2:12][CH2:13][N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:9]([N+:21]([O-])=O)[CH:8]=1)(=[O:6])=[O:5])([CH3:3])[CH3:2].C(O)(=O)C>C(OCC)(=O)C.[C].[Pd]>[NH2:21][C:9]1[CH:8]=[C:7]([S:4]([CH:1]([CH3:2])[CH3:3])(=[O:5])=[O:6])[CH:20]=[CH:19][C:10]=1[NH:11][CH2:12][CH2:13][N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CC(C)S(=O)(=O)c1ccc(NCCN2CCCC2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)S(=O)(=O)c1ccc(NCCN2CCCC2)c(N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
A mixture of crude 4-(isopropylsulfonyl)-2-nitro-N-(2-pyrrolidin-1-ylethyl)aniline (Step A), 10% palladium carbon (20 mg) and acetic acid (0.2 mL) in ethyl acetate (5 mL) was stirred for 2 h at room temperature under H2 atmosphere then the reaction mixture was filtered. The filtrate was evaporated under reduced pressure. The residue was purified by amine coated silica gel column chromatography (hexane:ethyl acetate=1:2) to give the title compound as an orange solid (122.9 mg, 52%, 2 steps).
Reaction SMILES: [Cl:1][SiH:2]([Cl:4])[Cl:3].[CH2:5]([O:9][C:10]1[CH:32]=[CH:31][C:13]([C:14]([O:16][C:17]2[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[C:25]([O:27][CH3:28])=[O:26])=[CH:19][C:18]=2[O:29][CH3:30])=[O:15])=[CH:12][CH:11]=1)[CH2:6][CH:7]=[CH2:8]>O1CCCC1>[Cl:1][Si:2]([Cl:4])([Cl:3])[CH2:8][CH2:7][CH2:6][CH2:5][O:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([O:16][C:17]2[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[C:25]([O:27][CH3:28])=[O:26])=[CH:19][C:18]=2[O:29][CH3:30])=[O:15])=[CH:31][CH:32]=1
Reactant: Cl[SiH](Cl)Cl
Reactant: C=CCCOc1ccc(C(=O)Oc2ccc(/C=C/C(=O)OC)cc2OC)cc1
Solvent: C1CCOC1
Product: COC(=O)/C=C/c1ccc(OC(=O)c2ccc(OCCCC[Si](Cl)(Cl)Cl)cc2)c(OC)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
5 ml of trichlorosilane are added while stirring to a solution of 0.1 g of H2PtCl6 in 20 ml of dry tetrahydrofuran. A solution of 14.8 g of 2-methoxy-4-[(E)2-methoxycarbonylvinyl]phenyl 4-(3-butenyloxy)benzoate dissolved in 20 ml of dry tetrahydrofuran is cautiously added dropwise thereto. Thereafter, the mixture is stirred at room temperature for 5 hrs. and then at 50° C. for 16 hrs. The reaction mixture is concentrated in a water-jet vacuum and completely freed from residual solvent and trichlorosilane on an oil pump with a cooling trap under reduced pressure. This gives crude 2-methoxy-4-[(E)2-methoxycarbonylvinyl]phenyl 4-(4-trichlorosilanylbutyloxy)benzoate, which is dissolved in dry tetrahydrofuran for storage.