Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:18]3[CH2:20][CH2:19]3)[C:10](=[O:17])[N:11]([CH2:13][C:14]([OH:16])=O)[CH:12]=2)=[CH:4][CH:3]=1.[C:21]1([C@H:31]([NH2:33])[CH3:32])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([CH:18]3[CH2:20][CH2:19]3)[C:10](=[O:17])[N:11]([CH2:13][C:14]([NH:33][C@H:31]([C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][CH:22]=3)[CH3:32])=[O:16])[CH:12]=2)=[CH:6][CH:7]=1
Reactant: C[C@@H](N)c1cccc2ccccc12
Reactant: O=C(O)Cn1cc(-c2ccc(Cl)cc2)n(C2CC2)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)Cn1cc(-c2ccc(Cl)cc2)n(C2CC2)c1=O)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
150 mg (0.512 mmol) of [4-(4-chlorophenyl)-3-cyclopropyl-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-acetic acid from Example 130A, 96.5 mg (0.564 mmol) of (1R)-1-(1-naphthyl)ethylamine, 128 mg (0.67 mmol) of EDC hydrochloride and 83.1 mg (0.62 mmol) of HOBt are dissolved in 2 ml of dry DMF and stirred overnight at room temperature. The crude product is purified by flash chromatography on silica gel (eluent: first dichloromethane, then dichloromethane/methanol 100:1). The target compound is obtained in a yield of 172 mg (75% of theory).
Reaction SMILES: [CH:1]1([N:4]2[C:12]3[CH:11]=[CH:10][N:9]=[CH:8][C:7]=3[C:6]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=3[F:21])=[C:5]2[C:22](O)=[O:23])[CH2:3][CH2:2]1.[CH3:25][C:26]1([CH3:34])[O:30][CH:29]([CH2:31][O:32][NH2:33])[CH2:28][O:27]1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:25][C:26]1([CH3:34])[O:30][CH:29]([CH2:31][O:32][NH:33][C:22]([C:5]2[N:4]([CH:1]3[CH2:2][CH2:3]3)[C:12]3[CH:11]=[CH:10][N:9]=[CH:8][C:7]=3[C:6]=2[NH:13][C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=2[F:21])=[O:23])[CH2:28][O:27]1
Reactant: O=C(O)c1c(Nc2ccc(I)cc2F)c2cnccc2n1C1CC1
Reactant: CC1(C)OCC(CON)O1
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: CN(C)C=O
Product: CC1(C)OCC(CONC(=O)c2c(Nc3ccc(I)cc3F)c3cnccc3n2C2CC2)O1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a heterogeneous mixture of 1-cyclopropyl-3-(2-fluoro-4-iodo-phenylamino)-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid (160.0 mg, 0.37 mmol) and O-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-hydroxylamine (113.1 mg, 0.77 mmol, 2.1 eq) in anhydrous N,N-dimethylformamide (5.7 mL) was added N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (278.3 mg, 0.74 mmol, 2.0 eq) and N,N-diisopropylethylamine (0.25 mL, 1.46 mmol, 4.0 eq), and the resulting homogeneous reaction mixture was stirred under N2 at RT for 16 h. The reaction mixture was quenched with MeOH (2 mL), and the crude material was absorbed onto silica. The crude mixture was purified by flash column chromatography (silica, ISCO, 45 mL/min, 25 to 100% EtOAc in hexane) to afford the product as an orange waxy solid (75.4 mg; 36.4%). LC-MS (method C): [M+H]+=567.2, RT=0.73 min.
Reaction SMILES: [C:1]1([CH:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=3)[C:10]([C:20]3[C:28]([OH:29])=[CH:27][C:23]4[O:24][CH2:25][O:26][C:22]=4[CH:21]=3)([CH2:18]O)[C:9]2=[O:30])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(P(CCCC)CCCC)CCC.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C(OCC)(=O)C>[C:31]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=3)[C:10]3([C:20]4=[CH:21][C:22]5[O:26][CH2:25][O:24][C:23]=5[CH:27]=[C:28]4[O:29][CH2:18]3)[C:9]2=[O:30])[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: Cc1ccc2c(c1)C(CO)(c1cc3c(cc1O)OCO3)C(=O)N2C(c1ccccc1)c1ccccc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: CCCCP(CCCC)CCCC
Solvent: CCOC(C)=O
Product: Cc1ccc2c(c1)C1(COc3cc4c(cc31)OCO4)C(=O)N2C(c1ccccc1)c1ccccc1
Reaction time: 0.17 h
Yield: 78.1 %

Procedure:
To a solution of 1-(diphenylmethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-5-methyl-1,3-dihydro-2H-indol-2-one (1.31 g, 2.72 mmol) in ethyl acetate (50.0 mL) was added tributylphosphine (0.82 g, 4.07 mmol). A solution of di-tert-butyl azodicarboxylate (0.94 g, 4.07 mmol) in ethyl acetate (45.0 mL) was added to the above reaction mixture over a period of 5 minutes. After stirring for 10 minutes under N2, the reaction was quenched with saturated aqueous ammonium chloride (60.0 mL). The organic layer was separated and washed with 1.0 N hydrochloric acid solution (3×100 mL), dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography eluting with ethyl acetate/hexane (10-50%) to afford the title compound (0.98 g, 78% yield): 1H NMR (300 MHz, CDCl3) δ 7.40-7.25 (m, 10H), 7.02, (s, 1H), 6.96 (s, 1H), 6.79 (d, 1H), 6.50 (s, 1H), 6.36 (d, 1H), 6.08 (s, 1H), 5.86 (d,2H), (4.82 (ABq, 2H), 2.20 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.Cl[C:11](=[O:16])[C:12]([O:14][CH3:15])=[O:13]>>[CH3:15][O:14][C:12](=[O:13])[C:11]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][C:4]=1[CH3:9])=[O:16]
Reactant: COC(=O)C(=O)Cl
Reactant: Cc1cc(Cl)ccc1N
Product: COC(=O)C(=O)Nc1ccc(Cl)cc1C

Procedure:
In a manner similar to that employed in Referential Example 242, the title compound was prepared from 4-chloro-2-methylaniline and methyl chlorooxoacetate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=2)(=[O:14])=[O:13])[C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33][CH3:34].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>>[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]([CH3:34])[C:8]([C:5]1[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:24])([F:25])[F:23])[CH:16]=2)(=[O:14])=[O:13])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10]
Reactant: CNc1ccccc1Cl
Reactant: O=C(O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1)c1ccccc1Cl

Procedure:
5-Chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)picolinic acid (50 mg, 0.12 mmol), (2-chloro-phenyl)-methyl-amine (50 mg, 0.36 mmol), BOP (69 mg, 0.36 mmol), DIEA (130 L, 0.72 mmol) were reacted according to the procedure D to provide the title compound. HPLC purification (20→90% gradient of MeCN-water) provided 5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylic acid (2-chloro-phenyl)-methyl-amide: MS m/z: (M+H) 537.4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([S:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[N:15]=2)=[CH:11][C:10]([CH:21]=O)=[N:9]1.[CH3:23][NH2:24].CO.CO.[BH4-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([S:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[N:15]=2)=[CH:11][C:10]([CH2:21][NH:24][CH3:23])=[N:9]1
Reactant: CN
Reactant: Cc1cccc(Sc2cc(C=O)nn2-c2ccccc2Cl)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CNCc1cc(Sc2cccc(C)n2)n(-c2ccccc2Cl)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 1-(2-chlorophenyl)-5-[(6-methylpyridin-2-yl)thio]-1H-pyrazole-3-carbaldehyde (415 mg) in tetrahydrofuran (4 mL) were added 40% methylamine-methanol solution (1.5 mL) and methanol (4 mL) at 0° C., and the mixture was stirred at room temperature for 4 hr. Sodium borohydride (905 mg) was added to the reaction mixture at 0° C. and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound as a yellow oil (yield 450 mg, yield quantitative).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N+:12]([O-])=[CH:11][N:10]([CH3:14])[C:9]=2[C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[CH:4][CH:3]=1.CC1(C)C(=[S:26])C(C)(C)C1=O>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11](=[S:26])[N:10]([CH3:14])[C:9]=2[C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[CH:4][CH:3]=1
Reactant: Cn1c[n+]([O-])c(-c2ccc(F)cc2)c1-c1ccncc1
Reactant: CC1(C)C(=O)C(C)(C)C1=S
Solvent: ClC(Cl)Cl
Product: Cn1c(-c2ccncc2)c(-c2ccc(F)cc2)[nH]c1=S
Temperature: 0 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
0.5 g of 5-(4-fluorophenyl)-4-(4-pyridyl)-3-methylimidazole N-oxide from example 1d were dissolved in 20 ml of CHCl3, and the reaction mixture was cooled in an ice-bath. An equimolar solution of 2,2,4,4-tetramethyl-3-thionocyclobutanone in CHCl3 was slowly added dropwise to the initial charge, and the mixture was then stirred in the ice-bath for 30 min. The ice-bath was removed, and stirring was continued at room temperature for 1 h. The solvent was then removed using a rotary evaporator, and the solid residue was triturated in diethyl ether. The precipitate was filtered off and dried under reduced pressure. The yield was 98%.
Reaction SMILES: C([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[CH:15]=[CH:16][C:17]3[O:22][CH2:21][CH2:20][NH:19][C:18]=3[CH:23]=2)=[O:13])=[CH:7][CH:6]=1)C.[F:25][C:26]1[CH:27]=[C:28]([S:32](Cl)(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1>N1C=CC=CC=1>[F:25][C:26]1[CH:27]=[C:28]([S:32]([N:19]2[C:18]3[CH:23]=[C:14]([C:12]([NH:11][C:8]4[CH:9]=[CH:10][C:5]([C:4]([OH:3])=[O:24])=[CH:6][CH:7]=4)=[O:13])[CH:15]=[CH:16][C:17]=3[O:22][CH2:21][CH2:20]2)(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)NCCO3)cc1
Solvent: c1ccncc1
Product: O=C(O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(F)c2)CCO3)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 44.1 %

Procedure:
Step 7 and 8. A solution of 4-[(3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl)-amino]-benzoic acid ethyl ester (27 mg, 0.085 mmol) in pyridine (0.4 mL) was treated with a solution of 3-fluoro-benzenesulfonyl chloride (25 mg, 0.13 mmol) in pyridine (0.2 mL). The resulting mixture was stirred at room temperature for 18 hours. The pyridine was evaporated, and the residual crude 4-{[4-(3-fluoro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoic acid ethyl ester was dissolved in ethanol (0.6 mL) and treated with KOH 3N (0.15 mL). The resulting mixture was stirred at room temperature overnight. The mixture was acidified with HCl 3N and evaporated. The residue was purified by preparative HPLC (ZORBAX Eclipse XDB-C18, 21.2×50 mm, 5 μm, gradient acetonitrile/water +0.1% formic acid). 4-{[4-(3-Fluoro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoic acid (17.1 mg, 44%) was obtained as an off-white solid, MS (ISP): m/e=455.0 (M−H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:11]([CH3:14])([CH3:13])[CH3:12].CN(C)CCN(C)C.C([Li])CCC.[I:28]I>CCOCC.O1CCCC1>[CH3:10][O:9][C:6]1[CH:5]=[C:4]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:3]([O:2][CH3:1])=[CH:8][C:7]=1[I:28]
Reactant: COc1ccc(OC)c(C(C)(C)C)c1
Reactant: II
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cc(C(C)(C)C)c(OC)cc1I
Temperature: 22 °C
Reaction time: 18 h

Procedure:
A stirred solution of 3.00 g (15.5 mmol) of 1,4-dimethoxy-2-t-butyl-benzene (obtained by methylation of t-butyl hydroquinone with sodium hydride and methyl iodide in tetrahydrofuran) and 2.52 g (21.7 mmol) of tetramethylethylenediamine in 50 mL of anhydrous ether under nitrogen is cooled to 0° C. and 8.66 mL (21.7 mmol) of n-butyllithium (2.5 M in hexane) is added over a 5 minute period. The mixture is warmed to 22° C., stirred for 18 hours and then cooled back to 0° C. The reaction is quenched with 7.86 g (30.9 mmol) of iodine in 30 mL of tetrahydrofuran and partitioned between ethyl acetate (200 mL) and 10% NaHSO3 (300 mL). The organic layer is washed with water (50 mL), brine (50 mL), dried (MgSO4) and evaporated to give a brown, partially crystalline oil which is chromatographed on silica gel (eluting with 98:2 hexane/ethyl acetate) to give crude product which is recrystallized from hexane to obtain 2,5-dimethoxy-4-t-butylphenyl iodide m p 80.5-82.5° C.)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C([Li])CCC.[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([OH:39])=[C:30]([C:32](=[O:38])[C:33](OCC)=[O:34])[CH:31]=1.Cl>ClCCl.O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([NH:19][C:33](=[O:34])[C:32](=[O:38])[C:30]3[CH:31]=[C:26]([Cl:25])[CH:27]=[CH:28][C:29]=3[OH:39])=[CH:17][CH:18]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCc2ccc(N)cc2)cc1OC
Reactant: CCOC(=O)C(=O)c1cc(Cl)ccc1O
Agent: Cl
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc(CCc2ccc(NC(=O)C(=O)c3cc(Cl)ccc3O)cc2)cc1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 60.3 %

Procedure:
Under an argon atmosphere, a tetrahydrofuran (20 ml) solution of 4-[2-(3,4-dimethoxyphenyl)ethyl]benzenamine (2.50 g, 9.72 mmol) is cooled to 0° C. n-Butyllithium (2.3M, 4.2 ml, 9.72 mmol) is added, and the resulting solution is stirred for 15 minutes. A tetrahydrofuran (10 ml) solution of ethyl 5-chloro-2-hydroxy-α-oxobenzenacetate (0.74 g, 3.24 mmol) is then added, after which the solution is allowed to warm to ambient temperature over a 30 minute period. The contents are then poured into 5% hydrochloric acid (100 ml) and extracted into ethyl acetate. The organics are washed with 10% sodium bicarbonate and brine, then dried (sodium sulfate), and concentrated to give 1.51 g of a crude solid. Chromatography (Kieselgel 60, dichloromethane) affords N-[4-[2-(3,4-dimethoxyphenyl)ethyl]phenyl]-2-hydroxy-5-chloro-α-oxobenzeneacetamide (0.86 g, 61%), mp 128°-130° C.
Reaction SMILES: [CH3:1][Mg]Br.[CH2:4]([N:6]1[C:10]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]=[O:19])=[CH:14][CH:13]=2)=[CH:9][C:8]([C:20]2[CH:21]=[C:22]([C:26]([NH:29][S:30]([CH2:33][C:34]([F:37])([F:36])[F:35])(=[O:32])=[O:31])([CH3:28])[CH3:27])[CH:23]=[CH:24][CH:25]=2)=[N:7]1)[CH3:5].[Cl-].[NH4+]>O1CCCC1>[CH2:4]([N:6]1[C:10]([O:11][C:12]2[CH:13]=[CH:14][C:15]([CH:18]([OH:19])[CH3:1])=[CH:16][CH:17]=2)=[CH:9][C:8]([C:20]2[CH:21]=[C:22]([C:26]([NH:29][S:30]([CH2:33][C:34]([F:37])([F:35])[F:36])(=[O:31])=[O:32])([CH3:28])[CH3:27])[CH:23]=[CH:24][CH:25]=2)=[N:7]1)[CH3:5]
Reactant: C[Mg]Br
Reactant: CCn1nc(-c2cccc(C(C)(C)NS(=O)(=O)CC(F)(F)F)c2)cc1Oc1ccc(C=O)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCn1nc(-c2cccc(C(C)(C)NS(=O)(=O)CC(F)(F)F)c2)cc1Oc1ccc(C(C)O)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 76.5 %

Procedure:
Methylmagnesium bromide (3.00 M in diethyl ether, 0.135 mL, 0.404 mmol, 2.00 equiv) was added to a solution of N-(1-{3-[1-ethyl-5-(4-formylphenoxy)-1H-pyrazol-3-yl]phenyl}-1-methylethyl)-2,2,2-trifluoroethanesulfonamide (100 mg, 0.202 mmol, 1 equiv) in tetrahydrofuran (2.0 mL) at 0° C. The reaction mixture was stirred at 0° C. for 5 minutes, then was treated with saturated aqueous ammonium chloride solution. The biphasic mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride solution, and the washed solution was dried over sodium sulfate. The dried solution was filtered, and the filtrate was concentrated. The residue was purified by flash-column chromatography (hexanes, grading to 90% ethyl acetate-hexanes) to afford N-[1-(3-{1-ethyl-5-[4-(1-hydroxyethyl)phenoxy]-1H-pyrazol-3-yl}phenyl)-1-methylethyl]-2,2,2-trifluoroethanesulfonamide (79 mg, 77%). Calcd (M+1)+: 512.2. Found: 512.1.
Reaction SMILES: O1CCCC1.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:14]#[N:15])=[CH:9][CH:8]=1.CC(C)([O-])C.[K+].[CH3:31][N:32]=[C:33]=[S:34]>O>[CH3:31][NH:32][C:33](=[S:34])[C:13]([C:10]1[CH:11]=[CH:12][C:7]([Cl:6])=[CH:8][CH:9]=1)([C:14]#[N:15])[CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: N#CC(CCCc1ccccc1)c1ccc(Cl)cc1
Reactant: CN=C=S
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CNC(=S)C(C#N)(CCCc1ccccc1)c1ccc(Cl)cc1
Reaction time: 0.5 h
Yield: 52.6 %

Procedure:
To a tetrahydrofuran solution containing 1.78 g (6.6 mmole) of 2-(4-chlorophenyl)-5-phenylvaleronitrile was added a tetrahydrofuran solution containing 0.77 g (6.9 mmole) of potassium tert-butoxide at 0° C. After stirring for 30 minutes, a tetrahydrofuran solution containing 0.5 g (6.8 mmol) of methyl isothiocyanate was added to the mixture and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, dried and condensed under reduced pressure, and then purified by silica gel chromatography to obtain 1.19 g (yield: 52.4 %) of N-methyl-2-(4-chlorophenyl)-2-cyano-5-phenylthiovaleroamide as a crystal.
Reaction SMILES: [CH:1]1([CH2:7][OH:8])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.N1C=CN=C1.[C:14]([Si:18](Cl)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:17])([CH3:16])[CH3:15].CO>CN(C)C=O>[Si:18]([O:8][CH2:7][CH:1]1[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OCC1CC=CCC1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C)(C)[Si](OCC1CC=CCC1)(c1ccccc1)c1ccccc1
Reaction time: 22 h

Procedure:
3-Cyclohexene-1-methanol (5.0 g) was dissolved in N,N-dimethylformamide (50 ml), and imidazole (3.93 g) and tert-butylchlorodiphenylsilane (14 ml) were added to stir the mixture for 22 hours. After adding methanol, the solvent was distilled off under reduced pressure, and water was added to the residue to conduct extraction with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (hexane:ethyl acetate=30:1) to obtain (±)-4-(tert-butyldiphenylsilyloxy-methyl)-1-cyclohexene (16.1 g) as a colorless oil.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][O:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:20]=2)[CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][O:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:20]=2)[CH2:11][C:12]([OH:14])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)COCc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)COCc1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.5 %

Procedure:
A solution of tert-butyl (3R)-6-cyclohexyl-3-{3-[(2-ethoxy-2-oxoethoxy)methyl]-1,2,4-oxadiazol-5-yl}hexanoate (Preparation 86) (500 mg, 1.08 mmol) in dichloromethane (7 ml) was treated with trifluoroacetic acid (3 ml) and stirred at room temperature for 5 hours. The solvent was removed under reduced pressure and the residue azeotroped from toluene and dichloromethane. The oil was purified by column chromatography on silica gel eluting with a gradient system of 100:0:0 (dichloromethane:methanol:acetic acid) gradually changing to 90:10:1 (dichloromethane:methanol:acetic acid) to afford the title compound as a colourless oil (374 mg).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[C:22]2[CH2:21][CH2:20][N:19]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[C:18](=[O:29])[C:17]=2[C:16]([CH3:30])=[C:15]1[C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1.I[CH2:39][CH2:40][CH2:41][C:42]([F:45])([F:44])[F:43].O>CN(C=O)C>[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[C:22]2[CH2:21][CH2:20][N:19]([N:23]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]3)[C:18](=[O:29])[C:17]=2[C:16]([CH3:30])=[C:15]1[C:31]1[CH:32]=[CH:33][C:34]([O:37][CH2:39][CH2:40][CH2:41][C:42]([F:45])([F:44])[F:43])=[CH:35][CH:36]=1
Reactant: FC(F)(F)CCCI
Reactant: Cc1c2c(n(-c3ccccc3Cl)c1-c1ccc(O)cc1)CCN(N1CCCCC1)C2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c2c(n(-c3ccccc3Cl)c1-c1ccc(OCCCC(F)(F)F)cc1)CCN(N1CCCCC1)C2=O
Temperature: 80 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
Potassium carbonate (0.19 g, 1.38 mmol) was added to a solution of 1-(2-chlorophenyl)-2-(4-hydroxyphenyl)-3-methyl-5-piperidin-1-yl-1,5,6,7-tetrahydropyrrolo[3,2-c]pyridine-4-one, from Ex. 1, Step 8 (0.50 g, 1.15 mmol) in DMF (30 ml) followed by 1-iodo-4,4,4-trifluorobutane (328 mg, 1.38 mmol). The reaction mixture was heated at 80° C. overnight. TLC showed very little conversion to starting material; 656 mg (2 eqv.) 1-iodo-4,4,4-trifluorobutane and 380 mg (2 eqv.) K2CO3 were added and heating continued for one hour. After cooling to rt, water was added and the product extracted with EtOAc (×3). The combined organic extracts were washed with brine (×2), dried (Na2SO4), filtered and concentrated. Flash chromatography (heptane:EtOAc gradient) afforded 250 mg (40%) of the title compound as a colorless solid.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([B:20]3[O:24][C:23](C)(C)C(C)(C)[O:21]3)=[C:16](C=O)[CH:15]=2)=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6])#[N:2].[BH4-].[Na+].Cl>CO>[C:1]([C:3]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]3[B:20]([OH:21])[O:24][CH2:23][C:16]=3[CH:15]=2)=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6])#[N:2]
Reactant: COC(=O)c1cc(Oc2ccc(B3OC(C)(C)C(C)(C)O3)c(C=O)c2)ccc1C#N
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(Oc2ccc3c(c2)COB3O)ccc1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.2 %

Procedure:
To a solution of methyl 2-cyano-5-(3-formyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)benzoate (15.7 g) in methanol (150 mL) was added sodium borohydride (646 mg, 17.0 mmol) portionwise at 0° C. The mixture was stirred at room temperature for 1 h. The mixture was acidified with 6 M HCl, and extracted with ethyl acetate. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography (6:4 to 4:6 hexane/ethyl acetate) followed by recrystallization from methanol/water to give 5-(4-cyano-3-methoxycarbonylphenoxy)-1-hydroxy-2,1-benzoxaborole (6.34 g, 62%).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[O:14][CH:13]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:12][C:11]2=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N:29]=[C:30]=[N:31][Si](C)(C)C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[O:1]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[O:14][CH:13]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:12]/[C:11]/2=[N:31]/[C:30]#[N:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CC(c2ccccc2)Oc2ccc(Oc3ccccc3)cc21
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: N#C/N=C1/CC(c2ccccc2)Oc2ccc(Oc3ccccc3)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 6-phenoxy-2-phenylchroman-4-one (316 mg, 1. mmol) in anhydrous DCM (7.8 mL) was added TiCl4 (1 M solution in DCM, 2 mL, 2 mmol) dropwise within 15 minutes at room temperature. After addition, the mixture was stirred for 1 h. To this mixture was added bis-trimethylsilylcarbodiimide (0.41 g, 0.49 mL, 2.2 mmol) dropwise. The resulting mixture was stirred for another 18 h after the addition. The reaction mixture was poured into ice-water (50 g) and extracted with DCM (3×30 mL). The combined organic phases were dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated to give (Z)—N-(6-phenoxy-2-phenylchroman-4-ylidene)cyanamide (340 mg, 90%), which was used in the next step without further purification.