Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C:7]2=[N:12][S@@:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[O:14])#[N:2].[BH4-].[Na+]>C1COCC1>[C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C@H:7]2[NH:12][S@@:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[O:14])#[N:2]
Reactant: CC(C)(C)[S@@](=O)N=C1CCc2c(C#N)cccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)[S@@](=O)N[C@@H]1CCc2c(C#N)cccc21
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a flask containing the crude suspension of (R)-N-(4-cyano-2,3-dihydro-1H-indene-1-ylidene)-2-methylpropane-2-sulfinamide INT-48 under N2 was added THF (1.0 L) and the reaction mixture cooled to −78° C. Sodium borohydride (40.9 g, 1.08 mol) was added portion-wise over 30 mins. (The internal temperature did not rise during the addition.) The reaction mixture was stirred at −78° C. for 30 mins, half out of the bath for 30 mins, then warmed to 0° C. over 1 h. The 0° C. reaction mixture was placed in an ice bath and quenched with brine (100 mL) followed by saturated sodium potassium tartrate (420 mL) and the Ti salts precipitated. The reaction mixture was diluted with EA (1.5 L) and stirred at room temperature overnight. The organic layers were decanted and washed successively with saturated NH4Cl, water, and brine. The organic layers were dried over MgSO4 and filtered through a pad of MgSO4. The filtrate was concentrated to produce 52.9 g of crude (R)-N-((R)-4-cyano-2,3-dihydro-1H-inden-1-yl)-2-methylpropane-2-sulfinamide INT-49 as a brown oil, which was used directly in the next step. LCMS-ESI (m/z) calculated for C14H18N2OS: 262.3; found 263.1 [M+H]+, tR=2.99 min. 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J=7.7, 1H), 7.56 (t, J=6.8, 1H), 7.36 (t, J=7.7, 1H), 4.97 (q, J=7.5, 1H), 3.50 (d, J=7.6, 1H), 3.22 (ddd, J=16.9, 8.8, 3.9, 1H), 3.01 (dt, J=22.4, 6.9, 1H), 2.70-2.53 (m, 1H), 2.15-1.95 (m, 1H), 1.33-1.20 (m, 9H).
Reaction SMILES: [Na+].[CH2:2]([S:6]([NH-:9])(=[O:8])=[O:7])[CH2:3][CH2:4][CH3:5].CC(C)=O.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][CH:16]=1>O>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:9][S:6]([CH2:2][CH2:3][CH2:4][CH3:5])(=[O:8])=[O:7])=[O:23])=[CH:17][CH:16]=1
Reactant: CCCCS([NH-])(=O)=O
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CCCCS(=O)(=O)NC(=O)Nc1ccc(Cl)cc1
Reaction time: 1 h
Yield: 65.7 %

Procedure:
1-butanesulfonamide sodium salt (9.1 g, 57 mmole) was dissolved in water (40 ml) and acetone (40 ml) was added. To the resulting mixture was added dropwise 40 ml of acetone containing 4-chlorophenyl isocyanate (8.6 g). After two hours solid was removed from the reaction mixture by filtration. The solid was washed with water and the combined filtrate was treated with 1N HCl (57 ml). After about one hour, precipitate was collected from the filtrate and washed with water. After drying at 65° C. under vacuum, 10.7 g of product were obtained.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.C(N(CC)CC)C.Cl[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]>C(Cl)Cl>[OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:3]1
Reactant: O[C@@H]1CCNC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CC[C@@H](O)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
3-Hydroxy-(R)-pyrrolidine (8.71 g, 0.1 mol) was dissolved in CH2Cl2 (260 mL) and cooled to 0° C. Triethylamine (33.5 mL, 0.24 mol) and benzyl chloroformate (14.9 mL, 0.11 mol) were added, and the resulting solution was stirred for 2 h at 0° C. The solution was gradually warmed to room temperature and allowed to stir overnight. The solution was washed with 1 M HCl, saturated NaHCO3, and brine. The organic solution was dried over MgSO4 and concentrated. The crude product was purified by column chromatography eluting with ethyl acetate to afford 13.7 g (62% yield, 2 steps) of the desired product as a purple oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([NH:11][C:12](=[O:27])[CH:13]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[S:9][CH:10]=1)=[O:5])C.S(=O)(=O)(O)O>CO>[CH3:1][O:3][C:4]([C:6]1[N:7]=[C:8]([NH:11][C:12](=[O:27])[CH:13]([C:20]2[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=2)[CH2:14][CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19]2)[S:9][CH:10]=1)=[O:5]
Reactant: CCOC(=O)c1csc(NC(=O)C(CC2CCCC2)c2ccc(Cl)cc2)n1
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1csc(NC(=O)C(CC2CCCC2)c2ccc(Cl)cc2)n1
Yield: 42 %

Procedure:
A solution of 2-[2-(4-chloro-phenyl)-3-cyclopentyl-propionylamino]-thiazole-4-carboxylic acid ethyl ester (prepared as in Example 31(B)(a), 105 mg, 0.25 mmol) in methanol (10 mL) was treated with a catalytic amount of sulfuric acid. The reaction mixture was heated under reflux for 68 h. The reaction was concentrated in vacuo. High pressure liquid chromatography (Chromegasphere SI-60, 10 μm, 60 Å, 25 cm×23 cm ID, 75/25 heptane/ethyl acetate) afforded 2-[2-(4-chloro-phenyl)-3-cyclopentyl-propionylamino]-thiazole-4-carboxylic acid methyl ester (41.3 mg, 40.7%) as a white solid: mp 156-157° C.; EI-HRMS m/e calcd for C19H21ClN2O3S (M+) 392.0961, found 392.0956.
Reaction SMILES: [C:1]([NH:6][C:7]1[NH:8][C:9](=[O:24])[C:10]2[N:11]=[CH:12][N:13]([C:22]=2[N:23]=1)[C@@H:14]1[O:21][C@H:18]([CH2:19][OH:20])[C@@H:16]([OH:17])[CH2:15]1)(=[O:5])[CH:2]([CH3:4])[CH3:3].CC(N(C)C)=O.[C:31](Cl)(=[O:47])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46].C(=O)(O)[O-].[K+]>N1C=CC=CC=1>[C:31]([O:20][CH2:19][C@H:18]1[O:21][C@@H:14]([N:13]2[C:22]3[N:23]=[C:7]([NH:6][C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])[NH:8][C:9](=[O:24])[C:10]=3[N:11]=[CH:12]2)[CH2:15][C@@H:16]1[OH:17])(=[O:47])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: CC(C)C(=O)Nc1nc2c(ncn2[C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCC(=O)OC[C@H]1O[C@@H](n2cnc3c(=O)[nH]c(NC(=O)C(C)C)nc32)C[C@@H]1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To an oven-dried 100 mL round-bottomed flask containing a stir bar was added N2-isobutyryl-2′-deoxyguanosine (0.75 g, 1 eq.). The flask was fitted with a septum and dry dimethylacetamide (DMA, 32 mL) and dry pyridine (16 mL) were added via cannula, with swirling and stirring. The flask was purged with argon gas, the slurry was allowed to cool 10 min. in an ice bath, and palmitoyl chloride (2.5 eq.) was added dropwise over 5 min. The mixture was allowed to stir while it slowly warmed to 25° C. After 24 h, the mixture was poured into 200 mL of 0.5 M potassium bicarbonate solution giving a white solid which was isolated by suction filtration, washed with 3×30 mL H2O, air dried, and finally dried under high vacuum giving a white powder. This crude product was purified by flash chromatography (silica gel bed, eluted with chloroform-methanol) giving a white powder. 1H-NMR and elemental analysis data were consistent with the assigned structure.
Reaction SMILES: [Li+].[OH-].[CH3:3][CH:4]([CH3:34])[CH2:5][CH2:6][CH:7]([N:13]1[CH2:18][CH2:17][C@@H:16]([CH2:19][C:20]([O:22]C)=[O:21])[CH2:15][C@H:14]1[C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1)[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11].Cl>O.C1COCC1>[CH3:11][CH:10]([CH3:12])[CH2:9][CH2:8][CH:7]([N:13]1[CH2:18][CH2:17][C@@H:16]([CH2:19][C:20]([OH:22])=[O:21])[CH2:15][C@H:14]1[C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:26][CH:25]=1)[CH2:6][CH2:5][CH:4]([CH3:3])[CH3:34]
Reactant: COC(=O)C[C@@H]1CCN(C(CCC(C)C)CCC(C)C)[C@H](c2ccc(C(F)(F)F)cc2)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CCC(CCC(C)C)N1CC[C@@H](CC(=O)O)C[C@H]1c1ccc(C(F)(F)F)cc1
Temperature: 60 °C
Yield: 97.8 %

Procedure:
A solution of LiOH (1.6 g, 67 mmol) in H2O (15 ml) was added to a stirred solution of methyl {(2S,4R)-1-[4-methyl-1-(3-methylbutyl)pentyl]-2-[4-(trifluoromethyl)phenyl]piperidin-4-yl}acetate (Step 1, 6.0 g, 13.2 mmol) in THF (15 ml) at RT. The mixture was stirred and heated at 60° C. for 18 hrs. After cooling to RT 2N HCl (35 ml) was added and the THF was removed in vacuo. The residue was partitioned between CH2Cl2/H2O. The pH of the aqueous layer was adjusted to pH7 with saturated aqueous NaHCO3. The aqueous layer was extracted with CH2Cl2 (×3). The combined extracts were dried (Na2SO4) filtered and evaporated. The residue was purified by chromatography (silica, 4-8% MeOH/CH2Cl2) to give the acid (5.7 g) as a colourless solid. 1H NMR (500 MHz, CD3OD): δ 0.68-0.75 (1H, m), 0.83-0.87 (12H, m), 0.97-1.09 (2H, m), 1.10-1.17 (1H, m), 1.32-1.50 (7H, m), 1.69-1.75 (1H, m), 1.86-2.00 (3H, m), 2.16-2.24 (2H, m), 2.25-2.31 (1H, m), 2.54 (1H, t, J 11.6), 3.17 (1H, d, J 11.8), 3.93 (1H, d, J 10.3), 7.54 (2H, brd, J 7), 7.65 (2H, d, J 8.2); M/Z (ES+) 442 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19]CC2C=CC=CC=2)[N:8]=1)=[O:5]>C(OCC)(=O)C.[Pd].CCOCC>[F:1][C:2]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:8]=1)=[O:5]
Reactant: O=C(Nc1ccn(Cc2ccccc2OCc2ccccc2)n1)c1c(F)cccc1F
Agent: [Pd]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: O=C(Nc1ccn(Cc2ccccc2O)n1)c1c(F)cccc1F

Procedure:
A solution of 2,6-difluoro-N-[1-({2-[(phenylmethyl)oxy]phenyl}methyl)-1H-pyrazol-3-yl]benzamide (for a preparation see Example 59)(2.34 g, 5.58 mmol) in ethyl acetate (20 ml) was stirred overnight with 10% palladium on carbon (wet) (0.594 g, 0.279 mmol) under an atmosphere of hydrogen. The reaction mixture was filtered and the filtrate evaporated in vacuo to give a colourless oil. The oil was dissolved in ether and the solution evaporated in vacuo to give the title compound as a white foam (1.82 g); LCMS: (System 3) MH+=330, tRET=0.92 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:10])=[C:4]([C:6]([F:9])=[CH:7][CH:8]=1)[NH2:5].Cl[C:12](=[O:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14]>C1COCC1>[Cl:1][C:2]1[C:3]([F:10])=[C:4]([NH:5][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:18])[C:6]([F:9])=[CH:7][CH:8]=1
Reactant: Nc1c(F)ccc(Cl)c1F
Reactant: CCOC(=O)C(=O)Cl
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)Nc1c(F)ccc(Cl)c1F
Reaction time: 0.5 h
Yield: 72 %

Procedure:
To a solution of 3-chloro-2,6-difluoroaniline (430 mg, 2.55 mmol) and TEA (0.5 mL, 3.59 mmol) in THF (5 mL) was added ethyl 2-chloro-2-oxoacetate (0.3 mL, 2.63 mmol). A white precipitate was formed immediately. After 30 min, the reaction mixture was filtered and rinsed with ether. The filtrate was concentrated to yield a crude yellow oil, which was purified by silica gel chromatography to yield the desired product (484 mg, 72%) as a white solid. 1H NMR (500 MHz, CDCl3) δ 8.42 (br. s., 1H), 7.35 (m, 1H), 6.98 (m, 1H), 4.45 (q, J=7.2 Hz, 2H), 1.45 (t, J=7.2 Hz, 3H). MS (ESI) m/z: 263.9 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:44])[CH2:5][CH2:6][C:7]1[CH:42]=[CH:41][C:10]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][N:20]3[CH2:25][CH2:24][C:23]4([C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[N:27]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:26]4)[CH2:22][CH2:21]3)=[CH:15][CH:14]=2)=[CH:9][C:8]=1[F:43])C.[OH-].[K+]>C(O)C.O>[C:37]([O:36][C:34]([N:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:23]2([CH2:22][CH2:21][N:20]([CH2:19][C:16]3[CH:15]=[CH:14][C:13]([CH2:12][O:11][C:10]4[CH:41]=[CH:42][C:7]([CH2:6][CH2:5][C:4]([OH:44])=[O:3])=[C:8]([F:43])[CH:9]=4)=[CH:18][CH:17]=3)[CH2:25][CH2:24]2)[CH2:26]1)=[O:35])([CH3:40])([CH3:38])[CH3:39]
Reactant: CCOC(=O)CCc1ccc(OCc2ccc(CN3CCC4(CC3)CN(C(=O)OC(C)(C)C)c3ccccc34)cc2)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC2(CCN(Cc3ccc(COc4ccc(CCC(=O)O)c(F)c4)cc3)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.2 %

Procedure:
A mixture of tert-butyl 1′-[[4-[[4-(3-ethoxy-3-oxo-propyl)-3-fluoro-phenoxy]methyl]phenyl]methyl]spiro[indoline-3,4′-piperidine]-1-carboxylate (0.32 g, 0.53 mmol) and KOH (0.148 g, 2.65 mmol) in ethanol:water (3:1, 4 mL) is stirred at room temperature for 16 hours. The reaction mixture is evaporated to dryness. The residue is re-dissolved in water (8 mL), cooled to 0° C., acidified with 1.5 N HCl to pH˜6, and extracted with EtOAc (3×15 mL). The combined organic layer is washed with water (15 mL) and saturated brine solution (15 mL), dried with a drying agent, filtered, and evaporated to dryness to give the title compound as an off-white solid (0.22 g, 72.1%). ESI/MS m/z 575.6 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][C:24]=2[O:25][CH3:26])[N:21]=[CH:20][N:19]=[C:18]3[NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:29]=2[F:35])[CH2:10][C@@H:9]1[C:36]([OH:38])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N:40]1CCOCC1.N>C1COCC1.C(Cl)Cl>[NH2:40][C:36]([C@H:9]1[CH2:10][C@H:11]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][C:24]=2[O:25][CH3:26])[N:21]=[CH:20][N:19]=[C:18]3[NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:29]=2[F:35])[CH2:12][CH2:13][N:8]1[C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])=[O:38]
Reactant: CN1CCOCC1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@@H]1CCN(C(=O)OC(C)(C)C)[C@@H](C(=O)O)C1
Agent: N
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@@H]1CCN(C(=O)OC(C)(C)C)[C@@H](C(N)=O)C1
Temperature: 25 °C
Reaction time: 0.12 h
Yield: 102.6 %

Procedure:
A stirred solution of (2R,4R)-1-(tert-butoxycarbonyl)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)piperidine-2-carboxylic acid (7) (0.13 g, 0.232 mmol) in THF (5 ml) was cooled to −15° C. (acetone/ice). NMM (0.035 g, 0.348 mmol) was added to the solution followed by IBCF (0.041 g, 0.301 mmol). The reaction mixture was held at −15° C. (the formation of the mixed anhydride was monitored by TLC (THF)). After 5-10 minutes, the reaction mixture was treated with aqueous ammonia in THF (0.2 ml) at −15° C. and allowed to warm to room temperature. The reaction mixture was diluted with DCM (20 ml), washed with water (2×2 ml) and concentrated to give tert-butyl (2R,4R)-2-(aminocarbonyl)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)piperidine-1-carboxylate (8) (0.13 g, 100%) as a pale yellow foam which was used without further purification; Mass Spectrum: (M+H)+ 544.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:10]=3[C:9]=2[C:19]([OH:21])=O)=[CH:4][CH:3]=1.C1C=[N:26][C:25]2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.Cl.CN.CCN=C=NCCCN(C)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:10]=3[C:9]=2[C:19]([NH:26][CH3:25])=[O:21])=[CH:4][CH:3]=1
Reactant: On1nnc2cccnc21
Reactant: COc1ccc2sc(-c3ccc(F)cc3)c(C(=O)O)c2c1
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)sc2ccc(OC)cc12
Temperature: 25 °C

Procedure:
To a solution containing 2-(4-fluorophenyl)-5-methoxybenzo[b]thiophene-3-carboxylic acid (0.57 g, 1.9 mmol), HOAT (0.28 g, 2.1 mmol), diisopropylethylamine (2.3 mL, 13.2 mmol), methylamine hydrochloride (0.20 g, 2.8 mmol) and dichloromethane (20 mL) was added EDCI (0.51 g, 13.2 mmol). The solution was maintained at room temperature for 6 h, diluted with additional DCM (20 mL), washed with water (20 mL), washed with aqueous HCl (2×20 mL, 0.1 N), dried over MgSO4, filtered and concentrated to afford 2-(4-fluorophenyl)-5-methoxy-N-methylbenzo[b]thiophene-3-carboxamide which was used without further purification. 1H NMR (500 MHz, DMSO-D6) δ ppm 8.30 (d, J=4.27 Hz, 1H), 7.90 (d, J=8.85 Hz, 1H), 7.60 (dd, J=8.70, 5.34 Hz, 2H), 7.34 (t, J=8.85 Hz, 2H), 7.16 (d, J=2.14 Hz, 1H), 7.07 (dd, J=8.85, 2.44 Hz, 1H), 3.81 (s, 3H), 2.74 (d, J=4.58 Hz, 3H). LCMS: retention time: 2.513 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, C18, 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 5% CH3CN/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% CH3CN/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 316 (MH+).
Reaction SMILES: [Cl-].CC([O-])(C)C.[K+].[CH2:8]([CH:11]1[CH2:15][CH2:14][CH:13]([CH:16]2[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]2)[CH2:12]1)[CH2:9][CH3:10].C1[CH2:27][O:26][CH2:25]C1>>[CH3:25][O:26][CH:27]=[C:19]1[CH2:20][CH2:21][CH:16]([CH:13]2[CH2:14][CH2:15][CH:11]([CH2:8][CH2:9][CH3:10])[CH2:12]2)[CH2:17][CH2:18]1
Reactant: C1CCOC1
Reactant: CCCC1CCC(C2CCC(=O)CC2)C1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Product: CCCC1CCC(C2CCC(=COC)CC2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
THF (100 ml) was added to methoxymethyltriphenylphophnium chloride (29.3 g) in a reaction vessel under an atmosphere of nitrogen, and the solution was cooled to −15° C. t-BuOK (10.5 g) in a THF (50 ml) solution was added, and the stirring was continued for another 1 hour. 4-(3-Propylcyclopentyl)-cyclohexanone (15.0 g) in a THF (50 ml) solution was added dropwise, and the stirring was continued for another 2 hours. The reaction mixture was warmed to room temperature and was extracted with toluene after the addition of water (200 ml) The resulting organic layer was washed with water and dried over anhydrous sulfate, and the toluene was concentrated to a volume of about 100 ml under reduced pressure. The concentrate was poured into n-hexane (500 ml) and solids deposited were filtered off. The solvent of the resulting solution was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (eluent: ethyl acetate/n-heptane=1/9 by volume) to give 1-methoxymethylene-4-(3-propylcyclopentyl)cyclohexane (17.0 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4](O)([C:20]([F:23])([F:22])[F:21])[C:5]1[C:9](=[O:10])[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])[NH:7][C:6]=1[CH3:19].S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:25])[C:4](=[C:5]1[C:9](=[O:10])[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])[N:7]=[C:6]1[CH3:19])[C:20]([F:23])([F:21])[F:22]
Reactant: COC(=O)C(O)(c1c(C)[nH]n(-c2ccccc2OC)c1=O)C(F)(F)F
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)C(=C1C(=O)N(c2ccccc2OC)N=C1C)C(F)(F)F

Procedure:
To a toluene solution (5 ml) of 2,5-dihydro-α-hydroxy-1-(2-methoxyphenyl)-3-methyl-5-oxo-α-trifluoromethyl-1H-pyrazole-4-acetic acid methyl ester (180 mg, 0.5 mmol), thionyl chloride (0.365 ml, 5.0 mmol) was added and the mixture was stirred under reflux for 3 hours. After concentrating the liquid reaction mixture under reduced pressure, the title compound was obtained as a reddish brown solid (171 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][C:17]([CH:24]=[O:25])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[C:19]([C:20]([F:23])([F:21])[F:22])=[CH:18][C:17]([CH2:24][OH:25])=[CH:16][N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(C=O)cc2C(F)(F)F)CC1
Agent: [BH4-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(CO)cc2C(F)(F)F)CC1

Procedure:
4-(5-Formyl-3-trifluoromethyl-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester from step (c) above (1.44 g, 4.0 mmol) reacted with NaBH4 (180 mg, 4.8 mmol, Aldrich) under the conditions of Example 183f to give the title compound as a gum. MS (ESI, pos. ion) m/e: 262 (M−Bu+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[CH2:8][C:9]3[C:21]4[NH:20][C:19]5[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=5)[C:13]=4[C:12]4[C:22](=[O:25])[NH:23][CH2:24][C:11]=4[C:10]=3[C:4]=2[CH:3]=1.[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:26]1([C:2]2[CH:7]=[CH:6][C:5]3[CH2:8][C:9]4[C:21]5[NH:20][C:19]6[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=6)[C:13]=5[C:12]5[C:22](=[O:25])[NH:23][CH2:24][C:11]=5[C:10]=4[C:4]=3[CH:3]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C1NCc2c3c(c4[nH]c5ccccc5c4c21)Cc1ccc(Br)cc1-3
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: O=C1NCc2c3c(c4[nH]c5ccccc5c4c21)Cc1ccc(-c2ccccc2)cc1-3
Temperature: 25 °C
Yield: 76.6 %

Procedure:
A solution of 3-bromo-5H, 6H, 12H, 13H-indeno[2,3-a]pyrrolo[3,4-c]carbazole-7(7H)one (Compound I-9) (100 mg, 0.26 mmol), phenylboronic acid (35 mg, 0.29 mmol) and bis(triphenylphosphine)palladium(II) chloride (25 mg) in DMF (5 ml) was heated in a sealed reaction tube at 100°-110° C. for 24 hours. The mixture was cooled to ambient temperature, filtered through a pad of Celite® and concentrated at reduced pressure. The product was triturated with THF to give 77 mg of a brown solid which contained product and starting material. HPLC purification gave Compound I-27 as a tan solid. The melting point was greater than 300 ° C. The following NMR data were obtained: 1H NMR (DMSO-d6, 300 MHz): 4.2 (s, 2H), 5.05 (s, 2H), 7.3-7.55 (m, 5H), 7.7 (d, 2H, J=8 Hz), 7.8-7.9 (m, 3H), 8.2 (s, 1H); 8.6 (s, 1H), 9.4 (d, 1H, J=9 Hz), 12.0 (s, 1H). MS(FAB): m/e 387 (m+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:12]([O-:14])=[O:13])=[C:7]([CH:11]=1)[C:8](O)=[O:9]>C1COCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:12]([O-:14])=[O:13])=[C:7]([CH2:8][OH:9])[CH:11]=1
Reactant: COc1ccc([N+](=O)[O-])c(C(=O)O)c1
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc([N+](=O)[O-])c(CO)c1
Yield: 9.8 %

Procedure:
To the solution of 5-methoxy-2-nitrobenzoic acid (20 g, 1.0 mol) in THF (100 mL) was added BH3 (1.0 M in THF, 30.4 mL, 3.0 eq) at 0° C. The mixture was refluxed for 3 h, diluted with water (200 mL) and extracted with DCM (100 ml*3). The combined organic lays were dried over MgSO4, evaporated to afford (5-methoxy-2-nitrophenyl)methanol (18 g, yield: 97%), as a white solid. 1HNMR (400 MHz, DMSO-d6) δ: 8.13 (d, J=6.4 Hz, 1H), 7.34 (d, J=6.4 Hz, 1H), 7.02 (s, 1H), 5.60˜5.58 (m, 1H), 4.84 (d, J=8.0 Hz, 2H), 3.89 (s, 3H); ESI-MS: m/z 184.1 ([M+1]+).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[Br:12]Br.S([O-])([O-])(=O)=S.[Na+].[Na+].CO>C(Cl)Cl>[Br:12][C:11]1[CH:10]=[C:5]([CH:4]=[CH:3][C:2]=1[OH:1])[C:6]([O:8][CH3:9])=[O:7]
Reactant: BrBr
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1ccc(O)c(Br)c1
Temperature: 25 °C
Reaction time: 36 h
Yield: 106.1 %

Procedure:
To a stirred suspension of methyl 4-hydroxybenzoate (180 g, 1183 mmol) in DCM (3 L) was added dropwise bromine (64 mL, 1242 mmol) under nitrogen and at 0° C. and the reaction mixture was left to stir at room temperature for 36 h. A solution of sodium thiosulfate (500 mL of a 10% solution) was then added while keeping the temperature around 15° C. followed by addition of MeOH (250 mL). The organic layer was washed with water, then brine, dried over MgSO4, filtered and concentrated to dryness to afford methyl 3-bromo-4-hydroxybenzoate (290 g) as a white solid. Mass Spectrum: m/z [M−H]−=229.