Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[C:18]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[O:9])=[N:4][CH:3]=1.[CH3:25][O:26][C:27](=[O:35])[C:28]1[CH:33]=[CH:32][CH:31]=[N:30][C:29]=1[SH:34]>>[CH3:25][O:26][C:27](=[O:35])[C:28]1[CH:33]=[CH:32][CH:31]=[N:30][C:29]=1[S:34][C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[C:18]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[O:9])=[N:4][CH:3]=1
Reactant: COC(=O)c1cccnc1S
Reactant: Cc1ccc(NC(=O)Nc2ncc(Br)s2)c(C(=O)C2CCCC2)c1
Product: COC(=O)c1cccnc1Sc1cnc(NC(=O)Nc2ccc(C)cc2C(=O)C2CCCC2)s1
Yield: 25 %

Procedure:
2-{2-[3-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-nicotinic acid methyl ester (124 mg, 25%) was prepared from 1-(5-bromo-thiazol-2-yl)-3-(2-cyclo pentanecarbonyl-4-methyl-phenyl)-urea (408 mg, 1 mmol) and 2-mercapto-nicotinic acid methyl ester (340 mg, 2 mmol) following the general procedure Q.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]([NH2:15])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:16]([O:19]C(=O)C)(=[O:18])[CH3:17]>N1C=CC=CC=1>[C:16]([O:19][NH:15][CH:7]([C:3]1[S:4][CH:5]=[CH:6][C:2]=1[CH3:1])[CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccsc1C(N)Cc1ccccc1
Solvent: c1ccncc1
Product: CC(=O)ONC(Cc1ccccc1)c1sccc1C
Reaction time: 8 h
Yield: 68.1 %

Procedure:
To a stirred solution of 10 g (0.047 mol) of α-(3-methyl-2-thienyl)benzeneethanamine in 50 ml of pyridine at ambient temperature was added dropwise 6.6 ml (0.07 mol) of acetic anhydride. Mixture was allowed to stand overnight, diluted with 500 ml of ETOAC, washed with 1N HCl until acidic, water, brine and dried. The resulting dark oil obtained from concentration of the organics was purified by chromatography on silica gel to give 8.2 g ( 0.032 mol) of N-acetoxy-α-(3-methyl-2-thienyl)benzeneethanamine as a light brown solid. To a stirred suspension of this solid in 45 ml of THF at 0° C. was added dropwise 64 ml (0.064 mol) of a 1.M solution of borane in THF. The resulting mixture was allowed to warm to ambient temperature and stirred overnight. The reaction was quenched by carefully adding 100 ml of 6N HCl and was then warmed at 75° C. for 40 hours. The mixture was cooled, made basic with 50% aqueous NaOH, and extracted with CH2Cl2 (3×200 ml). The organic extracts were combined, washed with water, brine, and dried. The resulting oil obtained from concentration of organics was dissolved in 50 ml isopropanol and made acidic with hydrochlorinated isopropanol. The white solid was collected by filtration and dried giving 5. g of product as a white solid (mp 226°-228° C.).
Reaction SMILES: [CH3:1][NH:2][NH2:3].F[C:5]1[CH:12]=[C:11]([N:13]2[CH2:17][CH2:16][N:15]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][C:23]=3[CH3:24])[C:14]2=[O:25])[CH:10]=[CH:9][C:6]=1[C:7]#[N:8].CO>COCCO.C(Cl)(Cl)Cl>[NH2:8][C:7]1[C:6]2[C:5](=[CH:12][C:11]([N:13]3[CH2:17][CH2:16][N:15]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][C:23]=4[CH3:24])[C:14]3=[O:25])=[CH:10][CH:9]=2)[N:2]([CH3:1])[N:3]=1
Reactant: Cc1ccncc1N1CCN(c2ccc(C#N)c(F)c2)C1=O
Reactant: CNN
Solvent: ClC(Cl)Cl
Solvent: COCCO
Solvent: CO
Product: Cc1ccncc1N1CCN(c2ccc3c(N)nn(C)c3c2)C1=O
Temperature: 170 °C
Reaction time: 12 h
Yield: 69.2 %

Procedure:
Methyl hydrazine (10 mL) was added to a stirred solution of 2-fluoro-4-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-benzonitrile (I-123a: 240 mg, 0.80998 mmol) in 2-methoxy ethanol (20 mL). The resulting mixture was stirred at 170° C. for 12 hours. The reaction was monitored by TLC (10% MeOH in CHCl3). The reaction mixture was cooled to room temperature and concentrated. Ice was added to the concentrate and the precipitate formed was collected and dried under reduced pressure to afford 180 mg of the product (69.2% yield).
Reaction SMILES: [C:1](/[CH:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)([O:3][CH3:4])=[O:2].[Br:14]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[C:1](/[CH:5]=[CH:6]/[C:7]1[CH:8]=[CH:9][C:10]([CH2:13][Br:14])=[CH:11][CH:12]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)/C=C/c1ccc(C)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)/C=C/c1ccc(CBr)cc1
Yield: 99.3 %

Procedure:
A mixture of 4-{(E)-2-carbomethoxyethenyl}toluene (17.6 g), N-bromosuccinimide (17.8 g) and a trace of dibenzoxylperoxide was refluxed in carbon tetrachloride under illumination until the brown-red colour disappeared. Filtration and evaporation of the solvent gave 4-{(E)-2-carbomethoxyethenyl}benzyl bromide (25.3 g). This was dissolved in dry tetrahydrofuran, heated with the sodium salt of ethyl acetoacetate (15.2 g) and a trace of potassium iodide and refluxed for 1.5 days. The solvent was removed the residue partitioned between ether and water and the ether layer dried. Removal of the solvent gave an oil (26.6 g). This was stirred with sodium hydroxide (10 g) in water (400 ml) for 2 days. The solution was extracted with ether, the aqueous layer made acidic with hydrochloric acid and this was heated on a steam bath for 1 h. The solution was extracted with chloroform and the organic layer dried (MgSO4). Removal of the solvent gave the acid of the title compound (11.0 g). This was esterified with methanol-sulphuric acid to give the title compound. τ(CDCl3) 7.9 (3H, s), 7.0-7.5 (4H, m), 6.25 (3H, s), 3.65 (1H, d, J= 16 Hz), 2.85 (2H, d, J=8 Hz), 2.6 (2H, d, J=8 Hz), 2.4 (1H, d, J=16 Hz).
Reaction SMILES: [N:1]([C@H:4]([CH3:20])[CH2:5][N:6]1[C:10]2=[CH:11][C:12]3[C:17]([CH2:16][CH:15]=[CH:14][C:13]=3[O:18][CH3:19])=[C:9]2[CH:8]=[N:7]1)=[N+]=[N-].[C:21]([OH:28])(=[O:27])/[CH:22]=[CH:23]/[C:24]([OH:26])=[O:25]>C(O)C.C(OCC)C.CO.[Pt]=O>[C:21]([OH:28])(=[O:27])/[CH:22]=[CH:23]/[C:24]([OH:26])=[O:25].[CH3:19][O:18][C:13]1[CH:14]=[CH:15][CH2:16][C:17]2[C:12]=1[CH:11]=[C:10]1[C:9]=2[CH:8]=[N:7][N:6]1[CH2:5][C@H:4]([NH2:1])[CH3:20]
Reactant: COC1=C2C=c3c(cnn3C[C@@H](C)N=[N+]=[N-])=C2CC=C1
Agent: O=[Pt]
Agent: O=C(O)/C=C/C(=O)O
Solvent: CO
Solvent: CCO
Solvent: CCOCC
Product: COC1=C2C=c3c(cnn3C[C@@H](C)N)=C2CC=C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 82.7 %

Procedure:
0.5 g (1.85 mmol) of (R)-1-(2-azido-propyl)-7-methoxy-1,4-dihydro-indeno[2,1-c]pyrazole dissolved in 50 ml of anhydrous ethanol were hydrogenated over 50 mg of platinum oxide for 2 hours. The catalyst was subsequently filtered off, rinsed with ethanol and the solvent was removed in a vacuum. The colorless oil obtained was dissolved in 70 ml of anhydrous diethyl ether, filtered and treated while stirring with a solution of 215 mg(1.85 mmol) of fumaric acid in 5 ml of methanol. The mixture was stirred at room temperature for 15 hours and the white crystals were subsequently filtered off. 0.55 g (83%) of (R)-2-(7-methoxy-1,4-dihydro-indeno[2,1-c]pyrazol-1 -yl)-1-methyl-ethylamine fumarate (1:1) with m.p. 180° was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[C:10]3[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][N:15](COCC[Si](C)(C)C)[C:11]=3[N:12]=[CH:13][N:14]=2)[CH:6]=[C:5]([NH:31][C:32](=[O:36])[C:33]([CH3:35])=[CH2:34])[N:4]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[C:10]3[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][NH:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:6]=[C:5]([NH:31][C:32](=[O:36])[C:33]([CH3:35])=[CH2:34])[N:4]=1
Reactant: C=C(C)C(=O)Nc1cc(-c2ncnc3c2c(C(=O)OCC)cn3COCC[Si](C)(C)C)cc(OC)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=C(C)C(=O)Nc1cc(-c2ncnc3[nH]cc(C(=O)OCC)c23)cc(OC)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To ethyl 4-{2-methoxy-6-[(2-methylacryloyl)amino]pyridine-4-yl}-7-{[2 (trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (20 mg, 0.039 mmol) in DCM (0.50 mL) was added TFA (500 μL, 6.49 mmol) and the reaction was stirred for 2 hours at room temperature. The reaction was then concentrated in vacuo, and the residue dissolved in acetonitrile (1.0 mL) and ammonium hydroxide (1.0 mL) was added. The reaction was stirred for an additional 1 hour at room temperature before being concentrated in vacuo and purified by reverse phase HPLC using an acetonitrile gradient in water with 0.1% TFA modifier. The products were collected and lyophilized to afford a colorless solid. LRMS calcd for C19H20N5O4[M+H]+: 382, found 382. 1H NMR (600 MHz, DMSO-D6) δ 13.08 (bs, 1H), 10.05 (s, 1H), 8.92 (s, 1H), 8.33 (d, 1H, J=3.1 Hz), 7.87 (d, 1H, J=0.9 Hz), 6.67 (d, 1H, J=1.1 Hz), 5.87 (s, 1H), 5.52 (s, 1H), 3.90 (q, 2H, J=7.2 Hz), 3.89 (s, 3H), 1.91 (s, 3H), 0.92 (t, 3H, J=7.2 Hz).
Reaction SMILES: C([O:4][CH2:5][CH2:6][O:7][C:8](=[O:36])[C:9]1[CH:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=2)[C:13]([C:24](=[O:33])[CH2:25][S:26](=[O:32])(=[O:31])[NH:27][CH:28]([CH3:30])[CH3:29])=[C:12]([CH3:34])[NH:11][C:10]=1[CH3:35])(=O)C.[OH-].[Na+]>C(O)C>[OH:4][CH2:5][CH2:6][O:7][C:8](=[O:36])[C:9]1[CH:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=2)[C:13]([C:24](=[O:33])[CH2:25][S:26](=[O:32])(=[O:31])[NH:27][CH:28]([CH3:30])[CH3:29])=[C:12]([CH3:34])[NH:11][C:10]=1[CH3:35]
Reactant: CC(=O)OCCOC(=O)C1=C(C)NC(C)=C(C(=O)CS(=O)(=O)NC(C)C)C1c1cccc([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1=C(C(=O)CS(=O)(=O)NC(C)C)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OCCO)=C(C)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.6 %

Procedure:
A suspension of 2.09 g of 1,4-dihydro-5-[(isopropylsulfamoyl)acetyl]-2,6-dimethyl-4-(3-nitrophenyl)nicotinic acid 2-acetoxyethyl ester in 20 ml of ethanol was treated dropwise at room temperature with a solution of 0.36 g of sodium hydroxide in 24 ml of ethanol. The dark orange solution obtained was subsequently stirred at room temperature for 1 hour. The ethanol was thereupon evaporated off at 25°-30° under reduced pressure and the residue was dissolved in 20 ml of water. The mixture was acidified cautiously with 2N hydrochloric acid, extracted several times with a mixture of methylene chloride/ethyl acetate (9:1) and the extract was dried over sodium sulfate. After evaporation of the solvent the solid residue was recrystallized from ethanol. There were obtained 1.55 g of 1,4-dihydro-5-[(isopropylsulfamoyl)acetyl]-2,6-dimethyl-4-(3-nitrophenyl)nicotinic acid 2-hydroxyethyl ester in the form of pale yellow crystals, m.p. 185°-188°.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[S:3]([CH2:6][C:7]([O:9][CH3:10])=[O:8])(=[O:5])=[O:4].[H-].[Na+].Br[C:15]1[CH:16]=[CH:17][C:18]2[CH:29]=[CH:28][C:22]3=[N:23][CH:24]=[C:25]([Cl:27])[CH:26]=[C:21]3[C:20](=[O:30])[C:19]=2[CH:31]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Cl:27][C:25]1[CH:26]=[C:21]2[C:20](=[O:30])[C:19]3[CH:31]=[C:15]([CH:6]([S:3]([N:2]([CH3:11])[CH3:1])(=[O:4])=[O:5])[C:7]([O:9][CH3:10])=[O:8])[CH:16]=[CH:17][C:18]=3[CH:29]=[CH:28][C:22]2=[N:23][CH:24]=1
Reactant: O=c1c2cc(Br)ccc2ccc2ncc(Cl)cc12
Reactant: COC(=O)CS(=O)(=O)N(C)C
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [H-]
Solvent: C1COCCO1
Product: COC(=O)C(c1ccc2ccc3ncc(Cl)cc3c(=O)c2c1)S(=O)(=O)N(C)C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A 200 mL round bottom flask was charged with methyl [(dimethylamino)sulfonyl]acetate (5.26 g, 29.0 mmol) and dioxane (77 ml), cooled to 0° C. and then sodium hydride (2.321 g, 58.0 mmol) was added in one portion. After 15 min., the mixture was warmed to room temperature and 7-bromo-3-chloro-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (6.20 g, 19.34 mmol) was added followed by Pd2(dba)3 (0.708 g, 0.774 mmol) and triphenylphosphine (1.217 g, 4.64 mmol). The resulting suspension was degassed by sparging with nitrogen for 30 min. Then, the mixture was heated to 70° C. and left to stir overnight. The reaction was then cooled to room temperature, poured into brine (500 mL) and extracted with dichloromethane (3×150 mL). The combined organics were then dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (EtOAc/Hexanes gradient) to afford the title compound as a yellow oil that solidified to a yellow solid upon standing. 1H NMR (600 MHz, DMSO-D6) δ 9.00 (d, 1H); 8.49 (d, 1H); 8.47 (d, 1H); 8.07 (dd, 1H); 7.88 (d, 1H); 7.48 (d, 1H); 7.34 (d, 1H); 6.05 (s, 1H); 3.75 (s, 3H); 2.68 (s, 6H). LRMS (APCI) calculated for C19H18ClN2O5S [M+H]+, 421.1; found 421.0.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][CH:20]([CH3:22])[CH3:21])[CH:13]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:30][CH:31]([CH3:33])[CH3:32]>CN(C=O)C>[CH2:19]([O:18][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[O:11][CH2:10][C:2]1[N:3]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=1)[CH:20]([CH3:22])[CH3:21]
Reactant: CC(C)COc1cccc(OCc2nc3ccccc3[nH]2)c1
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)COc1cccc(OCc2nc3ccccc3n2CC(C)C)c1
Temperature: 90 °C
Yield: 84 %

Procedure:
A 100 mL flask fitted with a stir-bar, condenser, and an Ar inlet was charged with benzimidazole 73 (1.73 g, 5.84 mmol) and K2CO3 (1.62 g, 11.7 mmol). DMF (25 mL) was added followed by 1-bromo-2-methylpropane (1.20 g, 0.95 mL, 8.73 mmol), and the mixture was heated in a 90° C. bath for 5 hr. Another 0.3 mL of 1-bromo-2-methylpropane was added and the mixture was heated overnight. The suspension was cooled, and the solids were filtered off and rinsed with EtOAc (100 mL). The filtrate was washed with saturated aqueous NH4Cl (2×60 mL), H2O (2×60 mL), and brine (50 mL), filtered through phase separation paper, and concentrated in vacuo to a yellow oil. The crude oil was chromatographed on silica gel with the product eluting with 10-12% EtOAc in hexanes. The product fractions were concentrated to give 1.73 g of Compound #17 as a colorless oil (84%). 1H NMR (300 MHz, CDCl3): δ 7.81 (m, 1H), 7.40 (m, 1H), 7.36-7.24 (m, 2H), 7.20 (t, 1H), 6.71-6.63 (m, 2H), 6.56 (dd, 1H), 5.37 (s, 2H), 4.12 (d, 2H), 3.72 (d, 2H), 2.36 (nonet, 1H), 2.08 (nonet, 1H), 1.03 (d, 6H), 0.98 (d, 6H) ppm. HPLC analysis (5:10:85 H2O:A1:MeOH) showed a purity of 99% with a retention time of 8.0 min.
Reaction SMILES: [OH:1][CH:2]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15](I)[CH:14]=1)[CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[C:20]([CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][O:23]1)#[CH:21]>>[OH:1][CH:2]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:21]#[C:20][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH:14]=1)[CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)NCCC(O)c1cccc(I)c1
Reactant: C#CC1CCCCO1
Product: CC(C)(C)OC(=O)NCCC(O)c1cccc(C#CC2CCCCO2)c1

Procedure:
Sonogashira reaction of 106 with 2-ethynyltetrahydro-2H-pyran yielded tert-butyl 3-hydroxy-3-(3-((tetrahydro-2H-pyran-2-yl)ethynyl)phenyl)propylcarbamate (107) as dark brown oil. Yield (1.21 g, 83%): 1H NMR (400 MHz, CDCl3) δ 7.45 (s, 1H), 7.27-7.35 (m, 3H), 4.87 (bs, 1H), 4.69-4.71 (m, 1H), 4.49-4.51 (m, 1H), 4.02-4.07 (m, 1H), 3.50-3.52 (m, 1H), 3.56-3.61 (m, 1H), 3.13-3.18 (m, 1H), 1.91-1.93 (m, 2H), 1.74-1.86 (m, 4H), 1.51 (m, 2H), 1.43 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH2:16][CH:15]([C:17]([F:20])([F:19])[F:18])[N:14]3[N:21]=[C:22]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([C:30](O)=[O:31])[CH:25]=4)[CH:23]=[C:13]3[NH:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH2:33][CH:34]1[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH2:16][CH:15]([C:17]([F:18])([F:19])[F:20])[N:14]3[N:21]=[C:22]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([C:30]([NH:33][CH:34]5[CH2:35][CH2:36][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:38][CH2:39]5)=[O:31])[CH:25]=4)[CH:23]=[C:13]3[NH:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2CC(C(F)(F)F)n3nc(-c4ccnc(C(=O)O)c4)cc3N2)cc1OC
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Product: COc1ccc(C2CC(C(F)(F)F)n3nc(-c4ccnc(C(=O)NC5CCN(C(=O)OC(C)(C)C)CC5)c4)cc3N2)cc1OC
Yield: 39.3 %

Procedure:
Example ER-897037 was prepared in two steps from 4-(5-(3,4-dimethoxyphenyl)-7-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-2-yl)picolinic acid (25 mg, 0.056 mmol) and commercially available tert-butyl 4-aminopiperidine-1-carboxylate (33 mg, 0.167 mmol) in a manner similar to that of example D-6 to afford intermediate tert-butyl 4-(4-(5-(3,4-dimethoxyphenyl)-7-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-2-yl)picolinamido)piperidine-1-carboxylate (14 mg, 0.022 mmol, 40% yield). Then, this intermediate (13 mg, 0.021 mmol) was treated with HCl in a manner similar to that of example ER-897560 to afford the desired product ER-897037 (11 mg, 90% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([CH:23]=[CH:24][CH:25]=3)[O:17][CH:18]([CH3:22])[C:19]([NH2:21])=O)=[N:9]2)=[CH:4][CH:3]=1.C(#N)C>ClCCl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([CH:23]=[CH:24][CH:25]=3)[O:17][CH:18]([CH3:22])[C:19]#[N:21])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(Oc1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1)C(N)=O
Solvent: ClCCl
Solvent: CC#N
Product: CC(C#N)Oc1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1

Procedure:
Using (+)-2-(3-(2-(7-Chloroquinolin-2-yl)ethenyl)phenoxy)propanoamide from Example 75 in place of the (+)-enantiomer in example 76, gave the title compound, mp 147°-149° C. (ex acetonitrile), D -134.4° (c 0.98 in dichloromethane).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH2:14].[CH3:15][O:16][C:17]1[CH:27]=[CH:26][CH:25]=[CH:24][C:18]=1[CH:19]=[CH:20][C:21](Cl)=O.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1.[C:51]([OH:56])(=[O:55])[C:52]([OH:54])=[O:53]>C(OCC)(=O)C>[C:51]([OH:56])(=[O:55])[C:52]([OH:54])=[O:53].[CH3:15][O:16][C:17]1[CH:27]=[CH:26][CH:25]=[CH:24][C:18]=1/[CH:19]=[CH:20]/[C:21]1[N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]=1
Reactant: COc1ccccc1C=CC(=O)Cl
Reactant: Nc1ccccc1Nc1ccccn1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Product: COc1ccccc1/C=C/c1nc2ccccc2n1-c1ccccn1

Procedure:
Free base of the titled compound was prepared from N-(2-pyridyl)-o-phenylenediamine and 2-methoxycinnamoyl chloride (Vallaerda, J.; Appelberg, U.; Csoeregh, I.; Hacksell, U. J. Chem. Soc. Perkin Trans.I; 1994, 17, 461) according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). The free base and oxalic acid were dissolved into ethyl acetate. Concentration and recrystallization from ethyl acetate/n-hexane yielded the titled compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[C:13](Cl)[C:12]([F:16])=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:17][C:18]([F:28])([F:27])[C:19]1[CH:20]=[C:21]([NH:25][NH2:26])[CH:22]=[CH:23][CH:24]=1.C(O)C.C(N(CC)CC)C>CCOCC>[CH2:1]([O:8][C:9]1[N:14]=[C:13]([NH:26][NH:25][C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([C:18]([F:17])([F:28])[F:27])[CH:20]=2)[C:12]([F:16])=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NNc1cccc(C(F)(F)F)c1
Reactant: Fc1cnc(OCc2ccccc2)nc1Cl
Solvent: CCOCC
Solvent: CCO
Solvent: CCN(CC)CC
Product: Fc1cnc(OCc2ccccc2)nc1NNc1cccc(C(F)(F)F)c1
Temperature: 50 °C
Yield: 76.9 %

Procedure:
A 25 mL vial was charged with 2-(benzyloxy)-4-chloro-5-fluoropyrimidine (153 mg, 0.639 mmol), (3-(trifluoromethyl)phenyl)hydrazine (338 mg, 1.92 mmol), ethanol (8 mL), and triethylamine (140 μL, 1.00 mmol). The resulting yellow solution was heated at 50° C. on an orbital shaker for 16 h. The crude material was then diluted with Et2O (100 mL) and washed with 1.0 M aqueous NaH2PO4 (50 mL) and then water (50 mL). The organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by flash column chromatography (EtOAc/hexane gradient) to afford 2-(benzyloxy)-5-fluoro-4-(2-(3-(trifluoromethyl)phenyl)hydrazinyl)pyrimidine (186 mg, 77%) as a brown oil: 1H NMR (300 MHz, DMSO-d6) δ 9.74 (bs, 1H), 8.38 (s, 1H), 8.07 (s, 1H), 7.36 (m, 1H), 7.26 (bs, 5H), 7.01 (m, 3H), 5.14 (s, 2H); MS (ESI) m/z 379 (M+H)+, 377 (M−H)−.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([F:11])([F:10])[F:9].[Li]CCCC.CCCCCC.[CH2:23]([N:25]([CH2:44][CH3:45])[CH2:26][CH2:27][N:28]1[C:38]2[C:33](=[C:34]([C:40]([F:43])([F:42])[F:41])[CH:35]=[C:36]([I:39])[CH:37]=2)[C:31](=[O:32])[C:29]1=[O:30])[CH3:24]>C1COCC1>[CH2:44]([N:25]([CH2:23][CH3:24])[CH2:26][CH2:27][N:28]1[C:38]2[C:33](=[C:34]([C:40]([F:42])([F:43])[F:41])[CH:35]=[C:36]([I:39])[CH:37]=2)[C:31]([OH:32])([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]([F:11])([F:10])[F:9])[C:29]1=[O:30])[CH3:45]
Reactant: CCN(CC)CCN1C(=O)C(=O)c2c1cc(I)cc2C(F)(F)F
Reactant: FC(F)(F)c1ccccc1Br
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCN(CC)CCN1C(=O)C(O)(c2ccccc2C(F)(F)F)c2c1cc(I)cc2C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 20.5 %

Procedure:
To a solution of 2-bromobenzotrifluoride (0.3 mL, 2.23 mmol) in THF (1.5 mL) was added dropwise 1.53 N BuLi in hexane (1.45 mL, 2.22 mmol) over 10 min at −78° C. and the mixture was stirred for 10 min. The resulting solution (1.2 mL, 0.82 mmol) was then added dropwise to the cooled solution of 1-(2-diethylaminoethyl)-4-trifluoromethyl-6-iodoisatin (352 mg, 0.8 mmol) in THF (4 mL) at −78° C. via a syringe. The mixture was allowed to warm to room temperature and stirred for 30 min. The reaction was quenched with aqueous NaHCO3. The mixture was extracted with ethyl acetate, dried over MgSO4, and concentrated. The residue was purified by silica gel column chromatography with 50:1 to 40:1 chloroform/methanol to give the title compound (96.3 mg, 21%).
Reaction SMILES: [Br-].[C:2]1(C([PH3+])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([Li])CCC.[C:27]([C:32]([C:41]([O:43][CH2:44][CH3:45])=[O:42])([CH2:38][CH:39]=[CH2:40])[CH2:33][CH2:34][C:35](=O)[CH3:36])([O:29][CH2:30][CH3:31])=[O:28]>C1COCC1>[CH2:38]([C:32]([CH2:33][CH2:34][C:35]([CH3:2])=[CH2:36])([C:41]([O:43][CH2:44][CH3:45])=[O:42])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:39]=[CH2:40]
Reactant: C=CCC(CCC(C)=O)(C(=O)OCC)C(=O)OCC
Reactant: [PH3+]C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CCC(CCC(=C)C)(C(=O)OCC)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.1 %

Procedure:
To a THF suspension (4.2 ml) containing triphenylmethylphosphonium bromide (0.536 g, 1.5 mmol) was added dropwise at 0° C. butyl lithium (1.4 mmol in 0.88 ml of 1.6M hexane solution). The reaction liquid was stirred at 0° C. for 30 minutes and then given 5,5-dicarboethoxy-7-octen-2-on (0.27 g, 1.0 mmol), followed by stirring at 0° C. for 1 hour. After treatment and purification as in Referential Example 9, there was obtained 0.239 g of diethyl allyl(3-methyl-3-butenyl)malonate (yields: 89%). Characteristic Values of allyl(3-methyl-3-butenyl)malonate
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1.C(OC(=O)[NH:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[CH:51][CH:52]=[CH:53][C:54]=4[F:58])[O:49][C:48]=3[C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38]1)(C)(C)C>>[NH2:36][C:37]1([C:41]2[CH:42]=[CH:43][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[CH:51][CH:52]=[CH:53][C:54]=4[F:58])[O:49][C:48]=3[C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)=[CH:45][CH:46]=2)[CH2:38][CH2:39][CH2:40]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4cccc(F)c4c3=O)cc2)CCC1
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Product: NC1(c2ccc(-c3c(-c4ccccc4)oc4cccc(F)c4c3=O)cc2)CCC1
Yield: 73.2 %

Procedure:
Following the procedure used to prepare 3-[4-(1-amino-cyclobutyl)-phenyl]-6-fluoro-2-phenyl-chromen-4-one, {1-[4-(5-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (19 mg, 0.039 mmol) was reacted to give the title compound (11 mg, 73%). LCMS (Method F): RT=8.60 min, [M+H]+=386. 1H NMR (400 MHz, CDCl3): δ 7.63-7.54 (m, 1H), 7.38-7.27 (m, 6H), 7.27-7.20 (m, 2H), 7.15 (d, J=8.6 Hz, 2H), 7.03 (t, J=8.6 Hz, 1H), 2.57-2.47 (m, 2H), 2.24-2.12 (m, 2H), 2.12-1.99 (m, 1H), 1.78-1.66 (m, 1H).