Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)\[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1.[C:21]([C:23]([C:31]1[CH:36]=[CH:35][C:34](O)=[CH:33][CH:32]=1)([CH3:30])[CH2:24][C:25]([O:27]CC)=[O:26])#[N:22]>>[C:21]([C:23]([C:31]1[CH:36]=[CH:35][C:34]([O:14][CH2:13][C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5]/[C:4](=[N:3]\[O:2][CH3:1])/[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:8][CH:9]=2)=[CH:33][CH:32]=1)([CH3:30])[CH2:24][C:25]([OH:27])=[O:26])#[N:22]
Reactant: CO/N=C(\COc1ccc(CO)cc1)c1ccccc1
Reactant: CCOC(=O)CC(C)(C#N)c1ccc(O)cc1
Product: CO/N=C(\COc1ccc(COc2ccc(C(C)(C#N)CC(=O)O)cc2)cc1)c1ccccc1
Yield: 57.47 %

Procedure:
Compound 59 was synthesized from (1Z)-2-[4-(hydroxymethyl)phenoxy]-1-phenylethanone O-methyloxime (2.34 g, 8.66 mmol) and ethyl 3-cyano-3-(4-hydroxyphenyl)butanoate (2.4 g, 9.6 mmol) by following the procedure described in scheme 18 (0.15 g, yield: 57.47%); Purity: 98.34%.
Reaction SMILES: [CH2:1]([C:4]1[C:13]([OH:14])=[C:12]([N+:15]([O-:17])=[O:16])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])[CH:2]=[CH2:3].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>ClCCCl>[CH3:3][CH:2]1[CH2:1][C:4]2=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:10]=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[C:13]2[O:14]1
Reactant: C=CCc1c(C(=O)OC)ccc([N+](=O)[O-])c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: COC(=O)c1ccc([N+](=O)[O-])c2c1CC(C)O2
Reaction time: 48 h
Yield: 12.8 %

Procedure:
Methyl 2-allyl-3-hydroxy-4-nitro-benzoate 1d (800 mg, 3.30 mmol) was dissolved in 10 mL of 1,2-dichloroethane followed by the addition of 1 mL of p-toluenesulfonic acid. The reaction solution was stirred for 48 hours. The resulting solution was added with 10 mL of saturated sodium bicarbonate solution and extracted with dichloromethane (20 mL×3). The combined organic phase was washed with water (20 mL) and saturated sodium chloride solution (20 mL) successively, then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound methyl 2-methyl-7-nitro-2,3-dihydrobenzofuran-4-carboxylate 30a (100 mg, yield: 12.5%) as a yellow solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][CH2:7][CH2:8][CH2:9][OH:10])=[CH:2]1.N1C=CC=CC=1.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C(Cl)(Cl)Cl>[CH3:17][S:18]([O:10][CH2:9][CH2:8][CH2:7][CH2:6][C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCCc1ccsc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)OCCCCc1ccsc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 96.2 %

Procedure:
To a solution of 1.05 g (6.7×10-3 mol) of 4-(3-thienyl)-butanol in 25 ml of dry, freshly distilled pyridine was added 0.85 g (1.1 equiv.) of methane-sulfonyl chloride at 25° C. The addition was gradual and carried out over a several minute period. The reaction mixture was stirred for 6 hr at room temperature and quenched by pouring into a separtory funnel containing water-HCl and ether. The layers were separated and the aqueous layer was extracted once with 10% hydrochloric acid, followed by extraction with water and drying with Na2SO4. Evaporation of the solvent afforded 1.51 g of a light brown oil (95% yield), tlc (CHCl3) showed a single spot. El. Anal. Calcd. for C9H14O3S2 : C, 46.13; H, 6.02; S, 27.36. Found: C, 45.92; H, 5.94; S, 27.15. Nmr (CDCl3, δ rel TMS) 2.0-1.5 brs, 4H; 2.67 brt, 2H; 2.97s, 3H; 4.22 t, 2H; 7.07-6.80 d, 2H; 7.37-7.13, H.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:43])[C@@H:12]([NH:21][C:22](=[O:42])[C@H:23]([NH:34]C(OC(C)(C)C)=O)[C:24]2[CH:33]=[CH:32][C:27]3[O:28][CH2:29][CH2:30][O:31][C:26]=3[CH:25]=2)[C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])[S:8][CH:9]=1)=[O:4].FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:43])[C@@H:12]([NH:21][C:22](=[O:42])[C@H:23]([NH2:34])[C:24]2[CH:33]=[CH:32][C:27]3[O:28][CH2:29][CH2:30][O:31][C:26]=3[CH:25]=2)[C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])[S:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1csc(NC(=O)[C@@H](NC(=O)[C@H](NC(=O)OC(C)(C)C)c2ccc3c(c2)OCCO3)[C@@H](C)c2ccccc2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1csc(NC(=O)[C@@H](NC(=O)[C@H](N)c2ccc3c(c2)OCCO3)[C@@H](C)c2ccccc2)n1
Reaction time: 2 h
Yield: 94 %

Procedure:
2-{(2S,3S)-2-[(R)-2-tert-Butoxycarbonylamino-2-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-acetylamino]-3-phenyl-butyrylamino}-thiazole-4-carboxylic acid methyl ester (0.49 g, 0.80 mmol) was stirred in dichloromethane (8 mL) in an ice bath. Trifluoroacetic acid (8 mL) was added and the solution was stirred for 2 hours. The reaction mixture was evaporated and the residue was precipitated with hexanes/ether. The mixture was stirred vigorously for 10 minutes and then filtered. The resulting solid was partitioned between aqueous sodium bicarbonate and dichloromethane. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic extracts were washed with brine and dried (sodium sulfate). Evaporation of the solvents gave 2-{(2S,3S)-2-[(R)-2-amino-2-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-acetylamino]-3-phenyl-butyrylamino}-thiazole-4-carboxylic acid methyl ester (0.384 g, 94%).
Reaction SMILES: [CH3:1][CH:2]1[N:7]([CH3:8])[CH2:6][CH2:5][N:4]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=O)=[CH:11][CH:10]=2)[CH2:3]1.[NH2:19][C:20]1[N:24](C(OC(C)(C)C)=O)[N:23]=[C:22]([CH2:32][CH2:33][C:34]2[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[C:36]([O:42][CH3:43])[CH:35]=2)[CH:21]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH3:41][O:40][C:38]1[CH:39]=[C:34]([CH2:33][CH2:32][C:22]2[NH:23][N:24]=[C:20]([NH:19][C:13](=[O:15])[C:12]3[CH:11]=[CH:10][C:9]([N:4]4[CH2:5][CH2:6][N:7]([CH3:8])[CH:2]([CH3:1])[CH2:3]4)=[CH:18][CH:17]=3)[CH:21]=2)[CH:35]=[C:36]([O:42][CH3:43])[CH:37]=1
Reactant: COC(=O)c1ccc(N2CCN(C)C(C)C2)cc1
Reactant: COc1cc(CCc2cc(N)n(C(=O)OC(C)(C)C)n2)cc(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(CCc2cc(NC(=O)c3ccc(N4CCN(C)C(C)C4)cc3)n[nH]2)cc(OC)c1
Yield: 19.4 %

Procedure:
N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-(3,4-dimethylpiperazin-1-yl)benzamide was prepared as for Example 94, but starting from methyl 4-(3,4-dimethylpiperazin-1-yl)benzoate (221 mg, 0.84 mmol), tert-butyl 5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazole-1-carboxylate (244 mg, 0.7 mmol) and 1M NaHMDS (1.13 ml, 1.13 mmol) in THF (5 ml). The crude product was purified by reverse phase prep. HPLC (basic) using a 38-58% gradient of acetonitrile in water containing 1% 0.880 ammonium hydroxide. The clean fractions were taken and evaporated to afford the title compound as a white solid (63 mg, 19%); 1H NMR (500.13 MHz, DMSO-d6) δ 1.12 (3H, d), 1.89-1.90 (3H, m), 2.32 (3H, s), 2.35-2.40 (1H, m), 2.64-2.68 (1H, m), 2.86-2.91 (1H, m), 2.89 (4H, t), 3.00 (1H, s), 3.64-3.68 (2H, m), 3.74 (6H, s), 6.32 (1H, s), 6.33 (1H, t), 6.42 (2H, d), 6.94-6.96 (2H, m), 7.86-7.88 (2H, m). MS: m/z 464 (MH+).
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([O:13][CH3:14])=[CH:9][CH:10]=2)[C:5]1=O.[C:16]([NH:19][CH2:20][CH2:21][NH2:22])(=[O:18])[CH3:17]>C1(C)C=CC=CC=1>[CH3:14][O:13][C:8]1[CH:7]=[C:6]2[C:11]([CH2:12][C:4]3[CH:3]=[CH:2][N:22]([CH2:21][CH2:20][NH:19][C:16](=[O:18])[CH3:17])[C:5]=32)=[CH:10][CH:9]=1
Reactant: CC(=O)NCCN
Reactant: COc1ccc2c(c1)C(=O)C(CC=O)C2
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)-c1c(ccn1CCNC(C)=O)C2
Yield: 15.1 %

Procedure:
A solution of 4.5 g of (RS)-2-(2-oxoethyl)-6-methoxy-1-indanone and 2.3 g of N-acetylethylenediamine in 100 ml of toluene was boiled under reflux for 10 minutes. The reaction mixture was evaporated in a vacuum, taken up in dichloromethane, dried with magnesium sulfate and again evaporated. After purification on silica gel (ethyl acetate), 0.9 g (15%) of N-[2-(7-methoxy-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-ethyl]-acetamide was obtained as a yellowish solid.
Reaction SMILES: [OH:1][C:2]([CH3:17])([CH3:16])[CH2:3][C:4]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][NH:7][C:6](=O)[CH2:5]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:17][C:2]([OH:1])([CH3:16])[CH2:3][C:4]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5][CH2:6][NH:7][CH2:8]1
Reactant: CC(C)(O)CC1(c2ccccc2)CNC(=O)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(O)CC1(c2ccccc2)CCNC1
Yield: 90 %

Procedure:
To a solution of 4-(2-hydroxy-2-methylpropyl)-4-phenylpyrrolidin-2-one (crude, 2.17 g, 9.3 mmol) in anhydrous THF (40 mL) was added LiAlH4 (1.42 g, 37.3 mmol) at −10° C. in a dry-ice/acetone bath. The reaction mixture was refluxed overnight. LC-MS showed that about 90% of desired product was produced. The reaction mixture was diluted with anhydrous THF (200 mL) and filtered through Celite. The filter cake was washed several times with anhydrous THF. The filtrate was concentrated to dryness to give crude 2-methyl-1-(3-phenylpyrrolidin-3-yl)propan-2-ol (1.34 g, 67%), which was used directly for next step without purification. 1H NMR (CDCl3 400 MHz): δ 7.28-7.22 (m, 4H), 7.16-7.12 (m, 1H), 3.82 (s, br, 1H), 3.24-3.16 (m, 2H), 3.11 (m, 1H), 2.95 (m, 1H), 2.26-2.13 (m, 2H), 1.98 (s, 2H), 1.09 (s, 3H), 1.05 (s, 3H).
Reaction SMILES: Cl.[C:2]1([C:8]2[S:12][C:11]([CH2:13][C:14]3[CH:26]=[CH:25][C:17]([O:18][CH2:19][C@H:20]4[CH2:24][CH2:23][CH2:22][NH:21]4)=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:28][CH2:29][CH2:30][C:31]([O:33]C)=[O:32]>>[C:2]1([C:8]2[S:12][C:11]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([O:18][CH2:19][C@H:20]4[CH2:24][CH2:23][CH2:22][N:21]4[CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[CH:25][CH:26]=3)=[CH:10][CH:9]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCCBr
Reactant: c1ccc(-c2ccc(Cc3ccc(OC[C@H]4CCCN4)cc3)s2)cc1
Agent: Cl
Product: O=C(O)CCCN1CCC[C@@H]1COc1ccc(Cc2ccc(-c3ccccc3)s2)cc1
Yield: 35.3 %

Procedure:
The title compound (60 mg, 36%) was prepared from the product of Example 159 (0.15 g, 0.39 mmol) and methyl 4-bromobutyrate (84 mg, 0.47 mmol) using the procedure of Example 147; 1HNMR (400 MHz, CD3OD) δ 7.50 (d, J=8.8 Hz, 2H), 7.32 (t, J=6 Hz, 2H), 7.24 (m, 3H), 7.18 (d, J=3.6 Hz, 1H), 6.98 (d, J=8.8 Hz, 2H), 6.77 (d, J=3.6 Hz, 1H), 4.36 (dd, J=7.2, 3.6 Hz, 1H), 4.18 (m, 1H), 4.10 (s, 2H), 4.00 (m, 1H), 3.71 (m, 1H), 3.55 (m, 1H), 3.25 (m, 2H), 2.50-2.30 (m, 4H), 2.19-1.98 (m, 4H), LC/MS (ESI+) m/z: 90%; 437 (M+1, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:3]=1[C:4](O)=[O:5].O1CCCC1.B>C1COCC1>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:3]=1[CH2:4][OH:5]
Reactant: COc1cccc(Cl)c1C(=O)O
Agent: B
Solvent: C1CCOC1
Product: COc1cccc(Cl)c1CO
Yield: 96.6 %

Procedure:
To a stirred solution of 2-chloro-6-(methyloxy)benzoic acid (0.252 g, 1.35 mmol, Arkpharminc) in dry THF (15 ml) at ambient temperature under nitrogen was added 1 M borane tetrahydrofuran complex (4.1 ml of solution in THF, 4.1 mmol, Aldrich) dropwise. The solution was then heated at reflux for 24 h and allowed to cool. The reaction mixture was quenched by the dropwise addition of methanol (4 ml), then heated at reflux for 30 min and allowed to cool. The solvent was removed in vacuo and the residue was partitioned between dilute aqueous ˜1M aqueous HCl and chloroform, the aqueous phase being extracted with more chloroform and the chloroform solutions being filtered through a phase separator. The combined chloroform solutions were evaporated in vacuo to give the title compound as a pale yellow solid (0.225 g); LCMS: (System 4) MH+=173, tRET=1.86 min.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]N([Si](C)(C)C)[Si](C)(C)C.COC(=O)[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:33]=1[F:39].Cl>C1COCC1>[C:1]1([S:7]([N:10]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:33]=3[F:39])=[O:18])=[CH:11]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1cccc(F)c1F
Reactant: O=C(O)Cc1ccn(S(=O)(=O)c2ccccc2)c1
Agent: Cl
Agent: [Li]N([Si](C)(C)C)[Si](C)(C)C
Solvent: C1CCOC1
Product: O=C(Cc1ccn(S(=O)(=O)c2ccccc2)c1)c1cccc(F)c1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 62.1 %

Procedure:
To a solution of (1-benzenesulfonyl-1H-pyrrol-3-yl)-acetic acid (1.3 g, 4.90 mmol) in THF was added LiN(TMS)2 (12 mL, 1.0M in THF, 12 mmol) at −78° C. The resulting solution was stirred at this temperature for 1 hour and 0° C. for 1 hour and then was cooled to −78° C. again. To this solution was added 2,3-difluoro-benzoic acid methyl ester (1.1 g, 6.40 mmol) and the reaction was stirred at room temperature for 14 hours. The solution was poured into 2N HCl and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and evaporated. The crude product was purified by flash column eluting with 20% of EtOAc in hexanes to afford the title compound as a yellow oil (1.1 g, 58%). 1H NMR (500 MHz, CDCl3) δ7.77 (d, 2H), 7.50 (m, 2H), 7.42 (t, 2H), 7.28 (m, 1H), 7.05 (m, 3H), 6.18 (m, 1H), 3.98 (s, 2H) ppm. MS (ES+): m/e=362.1 (M+H); LC/Method A/3.98 min.
Reaction SMILES: I[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][N:12]=[N:11][CH:10]=2)=[CH:4][C:3]=1[CH3:15].[F:16][C:17]1[CH:18]=[CH:19][C:20](B2OC(C)(C)C(C)(C)O2)=[C:21]2[C:25]=1[C@H:24]([O:26][C:27]1[CH:40]=[CH:39][C:30]3[C@H:31]([CH2:34][C:35]([O:37][CH3:38])=[O:36])[CH2:32][O:33][C:29]=3[CH:28]=1)[CH2:23][CH2:22]2.BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:15][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[N:11][CH:10]=2)[CH:6]=[C:7]([CH3:8])[C:2]=1[C:20]1[CH:19]=[CH:18][C:17]([F:16])=[C:25]2[C:21]=1[CH2:22][CH2:23][C@H:24]2[O:26][C:27]1[CH:40]=[CH:39][C:30]2[C@H:31]([CH2:34][C:35]([O:37][CH3:38])=[O:36])[CH2:32][O:33][C:29]=2[CH:28]=1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Reactant: Cc1cc(-c2ccnnc2)cc(C)c1I
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-c6ccnnc6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from 4-(4-iodo-3,5-dimethylphenyl)pyridazine and methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 15): tR=1.20 min; Mass spectrum (ESI+): m/z=525 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:23])[N:5](C2C=CC(OC)=CC=2)[CH2:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)[CH3:2].S([O-])([O-])=O.[Na+].[Na+].C(=O)(O)[O-].[Na+]>O.C(#N)C>[CH2:1]([C:3]1[C:4](=[O:23])[NH:5][CH2:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)[CH3:2]
Reactant: CCC1=C(c2ccc(F)cc2)CN(c2ccc(OC)cc2)C1=O
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCC1=C(c2ccc(F)cc2)CNC1=O
Reaction time: 0.5 h

Procedure:
A solution of ceric ammonium nitrate (542 g, 0.99 mol) in water (1L) is added dropwise over 45 minutes to a suspension of 3-ethyl-4-(4-fluorophenyl)-1,5-dihydro-1-(4-methoxyphenyl)-2H-pyrrol-2-one (103 g, 0.33 mol) in acetonitrile (2 L), while the temperature of the reaction mixture is maintained at 0°-10° C. After stirring 30 minutes sodium sulfite (125 g) is added. The mixture is stirred 30 minutes more and sodium bicarbonate (83 g) is added. After stirring an additional 30 minutes the mixture is concentrated to 1L and extracted with methylene chloride and ethyl acetate. The extracts are dried with magnesium sulfate, evaporated, and recrystallized from ethanol. Chromatography of this material on silica gel followed by drying under vacuum at 60° C. for 18 hr affords the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2B(O)O)=[CH:4][CH:3]=1.Br[C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1-c1ccc(F)cc1
Reactant: NS(=O)(=O)c1ccc(Br)cc1
Product: NS(=O)(=O)c1ccc(-c2ccccc2-c2ccc(F)cc2)cc1
Yield: 46 %

Procedure:
Following the general procedure outlined in Synthetic Scheme IX, 1.5 g (6.9 mmol) of 2-(4-fluorophenyl)phenylboronic acid (Step 1) was reacted with 2.5 g (10.4 mol) of 4-bromobenzenesulfonamide (Lancaster). Purification by silica gel chromatography (Waters LC-2000) with ethyl acetate/hexane (3:7) and subsequent recrystallization from ethyl acetate/hexane gave 1.04 g (46%) of 4-[2-(4-fluorophenyl)phenyl]benzenesulfonamide as a colorless solid: mp 187.3-188.2° C.; NMR (CDCl3) δ 4.83 (s, 2H), 6.92 (t, J=9 Hz, 2H), 7.02-7.11 (m, 2H), 7.27 (d, J=9 Hz, 2H), 7.36-7.50 (m, 4H), 7.78 (d, J=8 Hz, 2H) MS (EI): m/e (rel intensity) 327 (75) 245 (100); HRMS Calc'd for C18H14FNO2S: 327.0729. Found: 327.0743. Anal. Calc'd for C18H14FNO2S: C, 66.04; H, 4.31; N, 4.28. Found: C, 65.86; H, 4.51; N, 4.34.
Reaction SMILES: [Cl:1]C(OCC)=O.[CH3:7][C:8]1[CH2:9][C:10]([CH2:23]N2CCOCC2)=[C:11]([CH2:15][O:16][N:17]=[CH:18][C:19]([O:21][CH3:22])=[O:20])[CH2:12][C:13]=1[CH3:14]>C1COCC1>[CH3:22][O:21][C:19](=[O:20])[CH:18]=[N:17][O:16][CH2:15][C:11]1[CH2:12][C:13]([CH3:14])=[C:8]([CH3:7])[CH2:9][C:10]=1[CH2:23][Cl:1]
Reactant: CCOC(=O)Cl
Reactant: COC(=O)C=NOCC1=C(CN2CCOCC2)CC(C)=C(C)C1
Solvent: C1CCOC1
Product: COC(=O)C=NOCC1=C(CCl)CC(C)=C(C)C1

Procedure:
1.4 ml of ethyl chloroformate are added to a solution of 2.3 g methyl (4,5-dimethyl-2-morpholin-4-ylmethylcyclohexa-1,4-dienyl)methoxyiminoacetate in 25 ml of THF. The mixture is now heated for 20 hours at 70°. After the mixture has been evaporated, the residue is chromatographed on silica gel (ether/hexane 1:2). This gives 1.5 g of crystals of the title compound of melting point 65-68°.
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH3:7])[CH2:4][NH2:5])[CH3:2].C1(CN)CCCCC1.[O:16]=[C:17]1[C:25]2([CH2:29][O:28][C:27]3[CH:30]=[C:31]4[C:35](=[CH:36][C:26]2=3)[CH2:34][CH2:33][O:32]4)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]1[CH2:37][C:38]1[CH:46]=[CH:45][C:41]([C:42](O)=[O:43])=[CH:40][CH:39]=1.O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC1C=C(C=CC=1)C(O)=O>>[CH2:1]([CH:3]([CH2:6][CH3:7])[CH2:4][NH:5][C:42](=[O:43])[C:41]1[CH:45]=[CH:46][C:38]([CH2:37][N:18]2[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:25]3([CH2:29][O:28][C:27]4[CH:30]=[C:31]5[C:35](=[CH:36][C:26]3=4)[CH2:34][CH2:33][O:32]5)[C:17]2=[O:16])=[CH:39][CH:40]=1)[CH3:2]
Reactant: CCC(CC)CN
Reactant: O=C(O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1
Agent: NCC1CCCCC1
Agent: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Product: CCC(CC)CNC(=O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1

Procedure:
Following the procedure as described in EXAMPLE 12 and making non-critical variations using 2-ethyl-n-butylamine to replace cyclohexanemethylamine, and 4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid to replace 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid, N-(2-ethylbutyl)-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide was obtained (60%) as a colorless solid: mp 211-213° C.; 1H NMR (300 MHz, CDCl3) δ7.78-7.70 (m, 2H), 7.44-7.37 (m, 2H), 7.24-7.15 (m, 2H), 7.08-7.00 (m, 1H), 6.77-6.71 (m, 1H), 6.47 (s, 1H), 6.44 (s, 1H), 6.08-5.99 (m, 1H), 4.99 (ABq, 2H), 4.85 (ABq, 2H), 4.59-4.50 (m, 2H), 3.44-3.36 (m, 2H), 3.10-2.91 (m, 2H), 1.55-1.30 (m, 5H), 0.97-0.87 (m, 6H); MS (ES+) m/z 497.0 (M+1).
Reaction SMILES: Cl.[OH:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][C:4]=1[O:11][CH3:12].[OH-].[Na+].[C:15](Cl)(=[O:33])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].O>CN(C)C=O.CCOCC>[CH2:7]([NH:8][C:15](=[O:33])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]#[C:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:6]1[CH:9]=[CH:10][C:3]([OH:2])=[C:4]([O:11][CH3:12])[CH:5]=1
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: COc1cc(CN)ccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: CCCCCCCCC#CCCCCCCCC(=O)NCc1ccc(O)c(OC)c1

Procedure:
2.4 g of 4-hydroxy-3-methoxybenzylamine-HCl was suspended in 35 ml of N,N-dimethylformamide (DMF), and stirred. Added were 5 ml of a 5N solution of NaOH, and the mixture was stirred for an additional 10 to 15 minutes. The DMF mixture was chilled in an ice bath, and the stearoyl chloride, prepared above and dissolved in ether, was added dropwise. The mixture was then stirred for 3 hours, allowing it to come to room temperature. The mixture was then poured into 300 ml water, layers separated, and the aqueous layer extracted with ethyl ether. The extracts were washed with HCl, sodium bicarbonate, water, and brine, and then dried and filtered. 5.3 g of crude N-vanillyl-9-octadecynamide was obtained. Purification by recrystallization from toluene and hexane, and then benzene and hexane, gave 2.8 g of analytically pure product. Its structure was confirmed via nuclear magnetic resonance and infrared spectroscopy.
Reaction SMILES: Br[C:2]1[C:3](=[O:21])[N:4]([C:9]2[CH:10]=[C:11]([CH:16]=[C:17]([F:20])[C:18]=2[CH3:19])[C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([Br:8])[N:7]=1.[CH2:22]([O:29][CH2:30][CH2:31][S:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]([NH2:42])([CH3:41])[CH3:40])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([O:29][CH2:30][CH2:31][S:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]([NH:42][C:2]1[C:3](=[O:21])[N:4]([C:9]2[CH:10]=[C:11]([CH:16]=[C:17]([F:20])[C:18]=2[CH3:19])[C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([Br:8])[N:7]=1)([CH3:40])[CH3:41])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(N)c1ccccc1SCCOCc1ccccc1
Reactant: COC(=O)c1cc(F)c(C)c(-n2cc(Br)nc(Br)c2=O)c1
Product: COC(=O)c1cc(F)c(C)c(-n2cc(Br)nc(NC(C)(C)c3ccccc3SCCOCc3ccccc3)c2=O)c1

Procedure:
The subtitle compound was prepared using a similar method to Example 252h from methyl 3-(3,5-dibromo-2-oxopyrazin-1(2H)-yl)-5-fluoro-4-methylbenzoate (Example 252g) and 2-(2-{[2-(benzyloxy)ethyl]sulfanyl}phenyl)propan-2-amine (Example 320c).
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][CH:12]2[C:20]3[C:15](=[CH:16][C:17]([C:21]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:22])=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[O:35](C(OC(C)(C)C)=O)[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:39]([O:38][C:36]([N:11]([C@H:8]1[CH2:9][CH2:10][C@H:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:6][CH2:7]1)[CH:12]1[C:20]2[C:15](=[CH:16][C:17]([C:21]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:22])=[CH:18][CH:19]=2)[CH2:14][CH2:13]1)=[O:35])([CH3:42])([CH3:41])[CH3:40]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CCCCOC(=O)c1ccc2c(c1)CCC2N[C@H]1CC[C@H](C(C)(C)C)CC1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCOC(=O)c1ccc2c(c1)CCC2N(C(=O)OC(C)(C)C)[C@H]1CC[C@H](C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of butyl 1-[(trans-4-tert-butylcyclohexyl)amino]indane-5-carboxylate (1.0 g, 2.8 mmol) in CH2Cl2 (50 mL) was added Et3N (2.0 mL, 14.3 mmol), BOC2O (3.1 mL, 13.5 mmol) and catalytic amount of DMAP. After stirring at room temperature for 18 h, the reaction was quenched with saturated aqueous NaHCO3 (50 mL). The layers were separated and the aqueous layer was extracted once with EtOAc (50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. Chromatography (5% EtOAc in Hexane) gave butyl 1-[(tert-butoxycarbonyl)(trans-4-tert-butylcyclohexyl)amino]indane-5-carboxylate. HPLC/MS: m/z=416.3 (M−56+1), 438.3 (M−56+23), Rt=3.07 min. 1H NMR (CDCl3): δ 7.90 (1H, d, J=8.5 Hz), 7.89 (1H, s), 7.16 (1H, m), 4.75 (1H, br s), 4.35 (2H, t, J=6.5 Hz), 4.19 (1H, br s), 3.10-3.05 (1H, m), 2.97-2.87 (1H, m), 2.36 (2H, m), 1.91-1.77 (5H, m), 1.52 (2H, m), 1.07-1.00 (8H, m), 0.90 (9H, s), 0.89 (9H, s).