Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH:4]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[F:16])[C:5]([OH:7])=[O:6])[CH3:2].[CH2:17](O)[CH3:18].CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.ClCCl>[CH2:17]([O:6][C:5](=[O:7])[CH:4]([O:3][CH2:1][CH3:2])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[F:16])[CH3:18]
Reactant: CCO
Reactant: CCOC(C(=O)O)c1ccc(OC)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C(OCC)c1ccc(OC)cc1F

Procedure:
A solution of (RS)-ethoxy-(2-fluoro-4-methoxy-phenyl)-acetic acid (7.26 g, example 63.1), ethanol (16.7 ml) and DMAP (1.57 g) in dichloromethane (120 ml) was cooled to 0° and treated with EDCI (6.59 g). The reaction stirred was stirred at rt for 18 hrs, then washed with 0.5 N HCl, H2O, saturated NaHCO3 and brine. The organic layer was dried over MgSO4, filtrated and concentrated. The crude product was purified by flash chromatography (cyclohexane=>cyclohexane/EtOAc 85:15) to give (RS)-ethoxy-(2-fluoro-4-methoxy-phenyl)-acetic acid ethyl ester (4.42 g) as yellow oil. MS 256.2 ([M]+)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][C@@H:17]2[CH3:22])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[CH:24]([CH3:26])[CH3:25].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH:24]([N:19]1[CH2:20][CH2:21][N:16]([C:14]([CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][CH2:12]2)=[O:15])[C@@H:17]([CH3:22])[CH2:18]1)([CH3:26])[CH3:25]
Reactant: CC(C)I
Reactant: C[C@H]1CNCCN1C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)N1CCN(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)[C@@H](C)C1

Procedure:
(S)-1-[1-(tert-Butoxycarbonyl)-piperidine-4-carbonyl]-2-methylpiperazine (D21)(0.13 g), 2-iodopropane (0.08 ml) and potassium carbonate (0.1 g) in acetonitrile (2 ml) were heated at 120° C. in an Emerys Optimiser microwave for 45 min. The mixture was then filtered and evaporated. The crude product was redissolved in DCM (30 ml) and washed with saturated sodium hydrogen carbonate solution (3×20 ml) and brine (20 ml). The organic layer was dried (MgSO4) and evaporated to give the title compound (D22) as a clear oil (0.11 g)
Reaction SMILES: [Li]CCCC.[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[F:13].[CH3:14][Si:15](Cl)([CH3:17])[CH3:16].C(OC)(C)(C)C>O1CCCC1.O>[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Si:15]([CH3:17])([CH3:16])[CH3:14])[C:8]=1[F:13]
Reactant: Fc1ccccc1F
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: C[Si](C)(C)c1cccc(F)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
625 ml (1 mol) of 1.6 M BuLi are added dropwise at −78° C. to a solution of 114 g (1 mol) of 1,2-difluorobenzene in 1 l of dry tetrahydrofuran. After 1 hour, 140 ml (120 g, 1.1 mol) of trimethylsilyl chloride are slowly added dropwise at −78° C. The mixture is allowed to warm to room temperature overnight, and then 200 ml of methyl tert-butyl ether and 200 ml of water are added. The organic phase is washed with water (2×100 ml) and sat. NaCl (1×100 ml) and dried using magnesium sulfate, and the solvent is removed under reduced pressure. 170 g (91%) of 5 distil over from the residue at from 100 to 102° C./70 mbar.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:41])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([S:28]([CH2:31][CH3:32])(=[O:30])=[O:29])[CH:25]=[C:24](Br)[CH:23]=2)[C:10]=1[CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH3:2].[F:42][C:43]1[CH:44]=[C:45](B(O)O)[CH:46]=[CH:47][C:48]=1[F:49].C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([O:3][C:4](=[O:41])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:46]3[CH:45]=[CH:44][C:43]([F:42])=[C:48]([F:49])[CH:47]=3)[CH:25]=[C:26]([S:28]([CH2:31][CH3:32])(=[O:30])=[O:29])[CH:27]=2)[C:10]=1[CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH3:2]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(S(=O)(=O)CC)c2)c1CCC(=O)OCC
Reactant: OB(O)c1ccc(F)c(F)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(-c3ccc(F)c(F)c3)cc(S(=O)(=O)CC)c2)c1CCC(=O)OCC
Yield: 93.4 %

Procedure:
A similar procedure as described in Example 41, step 1 was used, starting from 4-[3-[6-(3-bromo-5-ethanesulfonyl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (150 mg, 0.23 mmol), 3,4-difluorophenylboronic acid (72 mg, 0.46 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (29 mg, 0.04 mmol), and cesium carbonate (149 mg, 0.46 mmol) to afford 4-[3-[6-(5-ethanesulfonyl-3′,4′-difluoro-biphenyl-3-yloxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (148 mg, 94%) as a colorless viscous oil: ES(+)-HRMS m/e calcd for C37H46F2O8S (M+Na)+ 711.2773, found 711.2778.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[N:13]=[C:12]2[N:14]=[CH:15][NH:16][C:11]2=[C:10]([Cl:17])[CH:9]=1.Br[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[C:21]=1[CH3:30]>CN(C)C=O>[Cl:7][C:8]1[N:13]=[C:12]2[N:14]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[C:21]=3[CH3:30])[CH:15]=[N:16][C:11]2=[C:10]([Cl:17])[CH:9]=1
Reactant: Clc1cc(Cl)c2[nH]cnc2n1
Reactant: Cc1c(CBr)cccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(Cn2cnc3c(Cl)cc(Cl)nc32)cccc1C(F)(F)F
Reaction time: 0.42 h
Yield: 47.6 %

Procedure:
Potassium carbonate (1139 mg, 8.24 mmol) was added to a solution of 5,7-dichloro-1H-imidazo[4,5-b]pyridine (500 mg, 2.66 mmol) in N,N-Dimethylformamide (DMF) (8.5 mL) and the mixture was stirred for 25 min. 1-(bromomethyl)-2-methyl-3-(trifluoromethyl)benzene (942 mg, 3.72 mmol) was then added and the reaction mixture was stirred at rt overnight. The mixture was partitioned between water and EtOAc. The aqueous layer was extracted with additional EtOAc (2×25 mL). The combined organic extracts were washed with brine, dried over Na2SO4 and evaporated. The residue was purified on silica gel (15 to 30% EtOAc in hexanes) to give 5,7-dichloro-3-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-3H-imidazo[4,5-b]pyridine (456 mg, 1.266 mmol, 47.6% yield) as an off-white powder. MS (ES+) m/e 359 (MH+) 1H NMR (400 MHz, DMSO-d6) δ ppm 8.64 (s, 1H), 7.68 (s, 1H), 7.66 (d, J=8.08 Hz, 1H), 7.33 (t, J=7.71 Hz, 1H), 7.07 (d, J=7.83 Hz, 1H), 5.62 (s, 2H) (Ar—CH3 hidden under DMSO peak).
Reaction SMILES: [Sn].[CH3:2][O:3][C:4]1[C:5]([N+:16]([O-])=O)=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[CH:8]=[C:7]2[CH:14]=[O:15].Cl>CCO>[NH2:16][C:5]1[C:4]([O:3][CH3:2])=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7]([CH:14]=[O:15])=[CH:8][N:9]2[CH3:13]
Reactant: COc1ccc2c(c(C=O)cn2C)c1[N+](=O)[O-]
Agent: Cl
Agent: [Sn]
Solvent: CCO
Product: COc1ccc2c(c(C=O)cn2C)c1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Tin powder (2.65 g, 22.3 mmol) was added to a suspension of nitroindole 44 (600 mg, 2.56 mmol) in EtOH (90 mL). Hydrochloric acid (3 M, 36 mL) was added and the mixture was stirred at room temperature for 2 h. The reaction mixture was decanted from the excess tin and added in portions to saturated sodium bicarbonate (200 mL). The mixture was extracted with EtOAc (4×) and the combined extracts were washed with sodium bicarbonate (1 M, 3×) and saturated NaCl (2×), dried (MgSO4), filtered and evaporated. Compound 45 was isolated as a dark yellow oil (513 mg, 98%) and used in the following reaction without further purification; Rf=0.67 (EtOAc); 1H NMR (CDCl3): δ 9.61 (s, 1H), 7.55 (s, 1H), 6.94 (d, 1H, J=8.6 Hz), 6.53 (d, 1H, J=8.6 Hz), 5.79 (bs, 2H), 3.88 (s, 3H), 3.76 (s, 3H).
Reaction SMILES: Br.[C:2]([O:6][C:7]([CH2:9][N:10]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17][N:16]([CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:15][CH2:14][N:13]([CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:12][CH2:11]1)=[O:8])([CH3:5])([CH3:4])[CH3:3].Br[CH2:39][C:40]([O:42][CH3:43])=[O:41]>C(#N)C>[C:2]([O:6][C:7]([CH2:9][N:10]1[CH2:21][CH2:20][N:19]([CH2:39][C:40]([O:42][CH3:43])=[O:41])[CH2:18][CH2:17][N:16]([CH2:22][C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[CH2:15][CH2:14][N:13]([CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:12][CH2:11]1)=[O:8])([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)CN1CCNCCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC1
Reactant: COC(=O)CBr
Agent: Br
Solvent: CC#N
Product: COC(=O)CN1CCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.3 %

Procedure:
1,4,7-Tri-tertbutoxycarbonylmethyl-1,4,7,10-tetraazacyclododecane hydrobromide (25.0 g, 42 mmol) was slurried in acetonitrile and treated with TMG (70 mL). Methyl bromoacetate (6.5 g, 42 mmol) was added in one portion, and the mixture was refluxed for 3 hours. After stirring at ambient temperature for an additional 18 hours, the solvent and excess TMG were removed by rotary evaporation. The residue was dissolved in CHCl3, washed with water, and dried (Na2SO4). Evaporation of the solvent afforded the title product as a pale oil (23 g, 95%). 1H NMR (CDCl3): 1.4 (s, 27 H) , 2.8 (s, 16 H), 3.2 (s, 6 H), 3.4 (s 2 H), 3.6 (s, 3 H).
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:16])[C:6]1[CH:11]=[CH:10][C:9](F)=[C:8]([N+:13]([O-:15])=[O:14])[CH:7]=1)[CH:2]=[CH2:3].[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].C(N(C(C)C)C(C)C)C.O>CN(C=O)C>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([NH:30][C:9]2[CH:10]=[CH:11][C:6]([C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:16])=[CH:7][C:8]=2[N+:13]([O-:15])=[O:14])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: C=CCOC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: C=CCOC(=O)c1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)c([N+](=O)[O-])c1
Temperature: 70 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
To a solution of 4-fluoro-3-nitro-benzoic acid allyl ester (84.3 g, 0.37 mol, 1.0 equiv) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (75.0 g, 0.37 mol, 1.0 equiv; commercially available) in DMF (500 mL) was added N-ethyldiisopropylamine (111.3 g, 0.86 mol, 2.3 equiv) and the reaction mixture heated at 70° C. for 6 h. The reaction mixture was cooled, poured into water (2 L) and the resulting mixture stirred at rt for 1 h. The precipitate was filtered, washed with water and hexane and finally dried over MgSO4 to obtain 129.1 g (85%) of the title compound. 1H NMR (400 MHz, DMSO): δ 1.46 (s, 9H), 1.46-1.56 (m, 2H), 1.92-1.98 (m, 2H), 2.90-2.98 (m, 2H), 3.88-3.95 (m, 3H), 4.78 (d, J=5.2 Hz, 2H), 5.27 (d, J=10.4 Hz, 1H), 5.38 (d, J=17.3 Hz, 1H), 6.00-6.06 (m, 1H), 7.29 (d, J=9.2 Hz, 1H), 7.99 (dd, J=9.2 Hz, J=1.6 Hz, 1H), 8.24 (d, J=7.8 Hz, 1H), 8.64 (s, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Br:7][C:8]1[C:13]([F:14])=[CH:12][C:11]([S:15](Cl)(=[O:17])=[O:16])=[C:10]([F:19])[CH:9]=1>ClCCl>[Br:7][C:8]1[C:13]([F:14])=[CH:12][C:11]([S:15]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)(=[O:16])=[O:17])=[C:10]([F:19])[CH:9]=1
Reactant: C1COCCN1
Reactant: O=S(=O)(Cl)c1cc(F)c(Br)cc1F
Solvent: ClCCl
Product: O=S(=O)(c1cc(F)c(Br)cc1F)N1CCOCC1
Reaction time: 8 h

Procedure:
Morpholine (0.16 ml) was added to a stirred solution of 4-bromo-2,5-difluoro-benzenesulfonyl chloride (0.18 g) in dichloromethane (6 ml) under nitrogen. The reaction mixture was stirred overnight and then quenched with water. The organic phase was dried (MgSO4) and concentrated in vacuo to give the sub-title compound as a white solid (200 mg).
Reaction SMILES: Br[C:2]1NC=CN=1.C1(S([N:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18](B(O)O)=N2)(=O)=O)C=CC=CC=1.P([O-])([O-])(O)=O.[Na+].[Na+]>O1CCOCC1.O>[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:2]1
Reactant: O=S(=O)(c1ccccc1)n1nc(B(O)O)c2ccccc21
Reactant: Brc1ncc[nH]1
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: c1ccc2[nH]ccc2c1
Temperature: 110 °C

Procedure:
A mixture of bromoimidazole Int-22a (98 mg, 0.20 mmol), 1-(phenylsulfonyl)-3-indazole boronic acid (73 mg, 0.24 mmol) and sodium hydrogen phosphate (86 mg, 0.61 mmol) in 1,4-dioxane (4 mL) and water (2 mL) at r.t. was purged with nitrogen gas for 5 min in a microwave vial. Tetrakistriphenylphosphorous palladium was added. The mixture was heated in a microwave reactor at 110° C. for 1 h. Water and ethyl acetate were added, and the layers were separated. The separated aqueous layer was extracted with ethyl acetate. The separated organic layer was dried (MgSO4) and filtered. The solvents were removed in vacuo and chromatographic purification (ethyl acetate-hexane) of the residue gave indole Int-22b (112 mg, 84%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH:12]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH3:28])[CH:19]=1)[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH2:7]2.[CH:29]1([CH:32]=O)[CH2:31][CH2:30]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH:29]1([CH2:32][NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:10]=2[C:9](=[O:11])[N:8]([C@@H:12]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH3:28])[CH:19]=2)[CH2:13][S:14]([CH3:17])(=[O:15])=[O:16])[CH2:7]3)[CH2:31][CH2:30]1
Reactant: CCOc1cc(C(CS(C)(=O)=O)N2Cc3cccc(N)c3C2=O)ccc1OC
Reactant: O=CC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCOc1cc([C@@H](CS(C)(=O)=O)N2Cc3cccc(NCC4CC4)c3C2=O)ccc1OC
Reaction time: 1.5 h
Yield: 77.5 %

Procedure:
To a solution of 7-amino-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonyl-ethyl]-2,3-dihydro-isoindol-1-one (1.8 g, 4.5 mmol), cyclopropane carboxaldehyde (0.47 mL, 6.3 mmol), and acetic acid (1.6 mL, 28 mmol) in 1,2-dichloroethane (20 mL), was added sodium triacetoxyborohydride (1.4 g, 6.7 mmol) at room temperature. After 1.5 hours, the mixture was extracted with methylene chloride (50 mL) and water (20 mL). The organic layer was washed with sodium hydrogen carbonate (sat, 25 mL) and brine (25 mL), and dried over MgSO4. Removal of solvent gave a yellow oil, which was purified by prep HPLC to give (1S)-7-(Cyclopropylmethyl-amino)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonyl-ethyl]-2,3-dihydro-isoindol-1-one as a white solid (1.6 g, 79% yield): mp 147-149° C.; 1H NMR (CDCl3) δ 0.25-0.31 (m, 2H, CH2), 0.55-0.62 (m, 2H, CH2), 1.09-1.20 (m, 1H, CH), 1.45 (t, J=7 Hz, 3H, CH3), 2.93 (s; 3H, CH3), 3.03-3.08 (m, 2H, CH2), 3.67 (dd, J=5, 15 Hz, 1H, CHH), 3.85 (s, 3H, CH3), 4.08 (q, J=7 Hz, 2H, CH2), 4.18 (d, J=17 Hz, 1H, CHH), 4.29 (dd, J=10, 15 Hz, 1H, CHH), 4.34 (d, J=17 Hz, 1H, CHH), 5.62 (dd, J=5, 10 Hz, 1H, NCH), 6.47-6.55 (m, 2H, Ar), 6.69 (t, J=5 Hz, 1H, NH), 6.83 (d, J=8 Hz, 1H, Ar), 6.91-6.95 (m, 2H, Ar), 7.21-7.30 (m, 1H, Ar); 13C NMR (CDCl3) δ 3.57, 10.63, 14.71, 41.42, 47.52, 48.09, 52.04, 55.98, 56.39, 64.60, 108.35, 109.21, 111.48, 112.32, 113.77, 119.37, 130.45, 133.64, 142.78, 147.50, 148.79, 149.54, 171.16. Analy. calculated for C24H30N2O5S: C, 62.86; H, 6.59; N, 6.11. Found: C, 62.77; H, 6.62; N, 6.13.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]([C:13]2[CH:14]=[N:15][C:16]([C:19]3[CH2:20][CH2:21][N:22](C(OC(C)(C)C)=O)[CH2:23][CH:24]=3)=[CH:17][CH:18]=2)[CH2:11][C:10]([C:32]([C:38]([F:41])([F:40])[F:39])([C:34]([F:37])([F:36])[F:35])[OH:33])=[N:9]1.Cl>C(OCC)(=O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]([C:13]2[CH:14]=[N:15][C:16]([C:19]3[CH2:20][CH2:21][NH:22][CH2:23][CH:24]=3)=[CH:17][CH:18]=2)[CH2:11][C:10]([C:32]([C:34]([F:36])([F:35])[F:37])([C:38]([F:41])([F:39])[F:40])[OH:33])=[N:9]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccccc3Cl)cn2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: OC(C1=NN(c2ccccc2Cl)C(c2ccc(C3=CCNCC3)nc2)C1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 195.9 %

Procedure:
1-(2-Chloro-phenyl)-5-[6-(1-BOC-1,2,3,6-tetrahydropyridin-4-yl)-pyridin-3-yl]-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole (400.0 mg, 0.66 mmol) prepared in Example 354 was added to a saturated solution of hydrochloric acid in ethyl acetate (2.0 mL). The reaction mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure to give 350.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:12](=O)[CH2:13][CH2:14][CH3:15]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([NH:9][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:10][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCC=O
Reactant: CC(C)(C)c1ccc(N)cc1
Product: CCCCNc1ccc(C(C)(C)C)cc1
Yield: 90.9 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 137, 4-tert-butylaniline (400 mg, 2.68 mmol) and butyraldehyde (240 μL, 2.68 mmol) were converted to the title compound (500 mg, 84%). 1H NMR (CDCl3) δ 7.27-7.19 (m, 2H), 6.60 (d, J=8.8 Hz, 2H), 3.61 (br s, 1H), 3.13 (t, J=7.0 Hz, 2H), 1.68-1.53 (m, 2H), 1.50-1.40 (m, 2H), 1.32 (s, 9H), 0.99 (t, J=7.3 Hz, 3H); MS(ESI+) m/z 206.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.Cl.Cl[CH2:32][C:33]1[N:34]=[CH:35][N:36]([CH3:38])[CH:37]=1>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[N:19]([CH2:32][C:33]5[N:34]=[CH:35][N:36]([CH3:38])[CH:37]=5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:27])([F:29])[F:28])[CH:3]=1
Reactant: Cn1cnc(CCl)c1
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Agent: Cl
Product: Cn1cnc(CN2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)c1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(1-methyl-1H-imidazol-4-yl)methyl]-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1) and 4-(chloromethyl)-1-methyl-1H-imidazole hydrochloride following General Procedure H.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:13]=[C:12]([CH:14]=[O:15])[N:11]([CH3:16])[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.[C:17]([O-:20])([O-])=[O:18].[K+].[K+].BrCC(OC(C)(C)C)=O>CC#N.C(Cl)Cl.FC(C(O)=O)(F)F>[CH:14]([C:12]1[N:11]([CH3:16])[CH:10]=[C:9]([S:6]([NH:5][CH2:1][C:17]([OH:20])=[O:18])(=[O:8])=[O:7])[CH:13]=1)=[O:15]
Reactant: Cn1cc(S(=O)(=O)NC(C)(C)C)cc1C=O
Reactant: O=C([O-])[O-]
Agent: CC(C)(C)OC(=O)CBr
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc(S(=O)(=O)NCC(=O)O)cc1C=O
Reaction time: 8 h

Procedure:
A solution of 0.8 g (3.3 mmol) N-(tert-butyl)-5-formyl-1-methyl-1H-pyrrole-3-sulfonamide, 1.2 g (9.8 mmol) K2CO3 and 1.4 g (7.2 mmol) tert-butyl bromoacetate in CH3CN was heated at reflux overnight Solvent was removed, and the residue was partitioned between EtOAc and water. The organic layer was separated and washed with brine. Drying (MgSO4) and removal of solvent gave an oil that was chromatographed by normal phase (100% CH2Cl2 followed by gradient elution to 20 EtOAc in CH2Cl2) to give material that was dissolved in 2 mL 1:1 CH2Cl2-TFA with stirring overnight. Solvent was removed to give the title compound as a solid, 1H NMR (DMSO) δ 9.6 (s, 1H), 7.4 (s, 1H), 7.2 (s, 1H), 4.1 (s, 3H), 3.9 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-])=O)=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([OH:14])[CH:3]=1>CC(O)=O.[Pd]>[NH2:1][C:2]1[C:10]([NH2:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([OH:14])[CH:3]=1
Reactant: Nc1cc(O)c(C(=O)O)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CC(=O)O
Product: Nc1cc(O)c(C(=O)O)cc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under an H2(g) atmosphere, a suspension of 4-amino-2-hydroxy-5-nitrobenzoic acid (200 mg, 1.01 mmol, 1.00 equiv) and Pd/C (anhydrous) (0.1 g) in HOAc (15 mL) in a 50-mL round-bottom flask was allowed to react, with stirring, overnight at room temperature. The resulting solution was directly taken on to the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)[CH2:10][CH3:11].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH2:21][CH2:22][C:23](=[O:26])[NH:24][N:25]=2)=[CH:16][CH:15]=1>CC(N(C)C)=O>[OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[N:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH2:21][CH2:22][C:23](=[O:26])[NH:24][N:25]=2)=[CH:16][CH:15]=1)[CH2:10][CH3:11]
Reactant: Nc1ccc(C2=NNC(=O)CC2)cc1
Reactant: CCC(=O)c1ccc(O)cc1O
Solvent: CC(=O)N(C)C
Product: CCC(=Nc1ccc(C2=NNC(=O)CC2)cc1)c1ccc(O)cc1O
Temperature: 140 °C

Procedure:
A solution containing 1.0 g (0.006 mol) of 2',4'-dihydroxypropiophenone and 0.57 g (0.003 mol) of 6-(4-aminophenyl)-4,5-dihydropyridazin-3(2H)one in 10 ml of DMA was heated for 20 h at 140° C. The solvent was evaporated in vacuo and the residue was crystallized from ethanol. Yield 0.05 g (5%), m.p. 350° C. (decomp).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][C:4]([CH3:19])([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:7]=1[N+:16]([O-])=O)[CH3:5].C(OCC)(=O)C.[H][H]>[Pd].CO>[CH3:20][N:2]([CH3:1])[CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:7]=1[NH2:16])([CH3:19])[CH3:5]
Reactant: CN(C)CC(C)(C)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CN(C)CC(C)(C)c1ccc(C(F)(F)F)cc1N
Reaction time: 12 h

Procedure:
A 50 mL round-bottom flask containing dimethyl-[2-methyl-2-(2-nitro-4-trifluoromethyl-phenyl)-propyl]-amine (0.61 g, 2.1 mmol) was charged with 10% palladium on carbon (0.23 g, 0.21 mmol) under nitrogen. Ethyl acetate (5 mL) and methanol (5 mL) were added sequentially via syringe. The atmosphere was replaced with hydrogen, and the reaction was stirred rapidly under 1 atm hydrogen overnight. After approximately 12 h, the reaction was flushed with nitrogen and filtered through a pad of celite, rinsing with methanol. Removal of the solvent in vacuo gave the title compound as a clear and colorless oil. MS m/z 261=[M+H]+. Calc'd for C13H19F3N2: 260.30.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[F:19][C:20]1[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1COCC1>C(Cl)(Cl)Cl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:24]4[CH:23]=[CH:22][CH:21]=[C:20]([F:19])[C:25]=4[F:26])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: OB(O)c1cccc(F)c1F
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4cccc(F)c4F)cc3CC[C@@H]12
Yield: 50 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis(triphenylphosphine) palladium (0) (23 mg, 0.02 mmol), 2,3-difluorophenylboronic acid (123 mg, 0.78 mmol), 0.65 mL of 2M sodium carbonate solution and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 16 h. Additional palladium reagent was added, and the mixture was heated for an additional 16 h. The mixture was cooled, diluted with chloroform (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent) to give 111 mg (50%) of the title compound as a white solid. mp 147°-148°. FDMS: m/e=341 α[D]589 =+70.44 (c=1.08, chloroform).