Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[C:7]([CH:19]=[CH:20][CH2:21][CH2:22][CH3:23])=[C:6]([CH:24]([CH3:26])[CH3:25])[N:5]=1)([CH3:3])[CH3:2]>C(OCC)(=O)C.CCCCCC>[CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[C:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:6]([CH:24]([CH3:25])[CH3:26])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CCCC=Cc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccccc1F
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCCCc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccccc1F

Procedure:
The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl (2-fluorophenyl)-5-(pent-1-enyl)pyridine (Example 137) by the procedure described in Example 126. 1H NMR (300 MHz, CDCl3): δ 0.78 (t, J=7.0 Hz, 3 H), 1.07-1.40 (m, 18 H), 2.29 (m, 2 H), 3.26 (m, 1 H), 3.46 (m, 1 H), 4.34 (m, 2 H), 7.20 (m, 3 H), 7.42 (m, 1 H). Rf=0.24 (10% ethyl acetate/n-hexane).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:25](=[CH:26][CH:27]=1)[CH2:24][C@@:6]1([C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[N:8](COCC[Si](C)(C)C)[C:7]1=[O:23])[CH2:5]2.Cl.C(N)CN.[OH-].[Na+]>CO.O>[NH2:1][C:2]1[CH:3]=[C:4]2[C:25](=[CH:26][CH:27]=1)[CH2:24][C@@:6]1([C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]1=[O:23])[CH2:5]2
Reactant: C[Si](C)(C)CCOCN1C(=O)[C@]2(Cc3ccc(N)cc3C2)c2cccnc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: NCCN
Solvent: CO
Product: Nc1ccc2c(c1)C[C@]1(C2)C(=O)Nc2ncccc21
Reaction time: 0.5 h

Procedure:
A solution of (S)-5-amino-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one from Step B (13.7 g, 35.9 mmol) in methanol (300 mL) was saturated with HCl (g). The mixture was resaturated with HCl (g) every 30 min until the starting material was consumed, and then concentrated in vacuo. The residue was dissolved in MeOH (150 mL) and treated with ethylenediamine (2.4 mL, 35.9 mmol) and 10 N sodium hydroxide (7.2 mL, 72 mmol) to adjust the mixture to pH 10. After 30 min, the mixture was diluted with H2O (400 mL) and extracted with CHCl3 (2×1 L). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was triturated with MeOH (50 mL) to give the title compound. MS: m/z=252 (M+1).
Reaction SMILES: [CH2:1](O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(F)(F)F.C1(CC2C=CC=CC=2)C=CC=CC=1.[CH2:26]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1C=CC=CC=1>[CH2:1]([C:35]1[C:34]([CH2:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)=[C:33]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:38]=[CH:37][CH:36]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(Cc2ccccc2Cc2ccccc2)cc1
Reactant: OCc1ccccc1
Agent: FB(F)F
Solvent: c1ccccc1
Solvent: c1ccc(Cc2ccccc2)cc1
Product: c1ccc(Cc2cccc(Cc3ccccc3)c2Cc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 9 h

Procedure:
Two thousand one hundred and eighty (2,180) grams (2,060 cc) of benzyl alcohol and 1,560 g (1,780 cc) of benzene were introduced into a 10-liter flask, and 940 g of boron trifluoride gas was blown into the flask. The whole mass was transferred into an autoclave, agitated at 60° C. for 9 hours, heated, thereafter cooled and then separated into the lower layer (acid layer) and upper layer (oil layer). The upper layer (oil layer) was incorporated with 1.5 l of a 10% aqueous solution of sodium hydroxide, repeatedly agitated and washed eight times and then distilled to obtain 480 g of a distillate boiling in the range of 173°-176° C. at 72 mm Hg. This distillate had a boiling point of 261° C. at atmospheric pressure, 175° C. at 72 mm Hg, 149° C. at 29 mm Hg or 85° C. at 1 mm Hg, a specific gravity (30/4° C.) of 0.997, a viscosity of 0.01564 g/cm.sec (59° C.) ad a refractive index (nD25) of 1.570, and it was found to be diphenylmethane as the main ingredient from its NMR spectra and gas chromatography. The yield of the diphenylmethane was about 15% (about 460 g), and other distillates having a high boiling point such as dibenzylbenzene and tribenzylbenzene were produced in an amount of 989 g as by-products.
Reaction SMILES: C([O-])(=O)C.[K+].C(O)C.[NH2:9][NH:10][C:11]([NH2:13])=[S:12].Cl[CH2:15][C:16](=O)[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>O>[NH:10]([C:11]1[S:12][CH:15]=[C:16]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:13]=1)[NH2:9]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: NNC(N)=S
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)Cc1csc(NN)n1

Procedure:
Potassium acetate (1.3 g., 12.5 mmoles) was dissolved in 40 ml. of an aqueous ethanol mixture (1:1). With stirring, thiosemicarbazide (1.1 g., 12.5 mmoles) and ethyl 4-chloroacetoacetate (2.0 g., 12.5 mmoles) were introduced. After 3 hours of stirring at room temperature a red oil settled out. The reaction mixture was diluted with water and extracted several times with methylene chloride (total 100 ml.). Combined extracts were dried (calcium chloride), filtered, and concentrated under reduced pressure to approximately 2.0 g. of oily residue. Thin layer chromatography (chloroform) revealed the presence of two compounds. This oil was then chromatographed on a silica gel column using methylene chloride as the eluent. Compound IVA (see Example 12) was in the first few fractions while the latter fractions contained a single component (0.6 g.) characterized as Compound IIA by pmr. Although Compound IIA was chromatographically pure, it would not crystallize; ir (mull): 3450-3200 (N--H), 1725 (C=O), 1620, 1580 (C=N) cm-1 : pmr (deuteriochloroform): δ1.20 (t, 3H, CH3), 3.55 (s, 2H, CH2CO), 4.15 (q, 2H, OCH2), 5.80-6.20 (s-broad, 3H, NH), 6.30 (s, 1H, vinyl); ms: (m/e)201(M+).
Reaction SMILES: [H-].[Na+].[C:3]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Br:17][C:18]([CH2:20]Br)=[CH2:19].O>CN(C=O)C.C(OCC)(=O)C>[C:3]([CH:11]([CH2:20][C:18]([Br:17])=[CH2:19])[C:12]([O:14][CH2:15][CH3:16])=[O:13])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C=C(Br)CBr
Reactant: CCOC(=O)CC(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: C=C(Br)CC(C(=O)OCC)C(=O)c1ccccc1
Reaction time: 0.5 h
Yield: 86.3 %

Procedure:
Sodium hydride (0.26 g, 6.0 mmol) was added under ice cooling to a solution (10 ml) of ethyl benzoylacetate (1.0 ml, 5.77 mmol) in DMF, followed by stirring for 30 minutes, and then 2,3-dibromopropene (0.63 ml, 5.77 mmol) was added. The resulting mixture was stirred at room temperature for 1.5 hours, water was added to the reaction mixture, and extraction with ethyl acetate was performed three times. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=4/1). The solvent was distilled off under reduced pressure, to thereby obtain 1.55 g (yield: 86%) of ethyl 2-benzoyl-4-bromo-4-pentenoate as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH2:9][N:10]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:25])[C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])=[N:11]1.[CH3:26]C(C)([O-])C.[K+].CI>CS(C)=O.CO>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:26])[CH:5]=[CH:4][C:3]=1[CH2:9][N:10]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:25])[C:17]2[C:18]([F:24])=[CH:19][CH:20]=[CH:21][C:22]=2[F:23])=[N:11]1
Reactant: O=C(Nc1ccn(Cc2ccc(O)cc2Cl)n1)c1c(F)cccc1F
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CO
Solvent: CI
Product: COc1ccc(Cn2ccc(NC(=O)c3c(F)cccc3F)n2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-{1-[(2-chloro-4-hydroxyphenyl)methyl]-1H-pyrazol-3-yl}-2,6-difluorobenzamide (for a preparation see Example 31)(30 mg, 0.082 mmol) in DMSO (0.5 ml) was added potassium t-butoxide (9.6 mg, 0.086 mmol) and then methyl iodide (6 μl, 0.096 mmol, Aldrich). The solution was stirred at ambient temperature overnight. The solution was diluted with methanol (0.5 ml) and purified by MDAP on Sunfire C18 column using Acetonitrile-Water with a Formic acid modifier (Method B). The solvent was evaporated in vacuo to give the title compound as a colourless gum (7.3 mg); LCMS: (System 4) MH+=378, tRET=2.85 min.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([Cl:19])=[CH:4][N:3]=1.[F:20][C:21]([F:37])([F:36])[CH2:22][NH:23][CH:24]1[CH2:30][CH2:29][C:28]2[CH:31]=[C:32]([NH2:35])[CH:33]=[CH:34][C:27]=2[CH2:26][CH2:25]1.CC1(C)[C@]2(CS(O)(=O)=O)C(C[C@H]1CC2)=O.C(=O)(O)[O-].[Na+]>CC(O)C.C(Cl)Cl.O>[Cl:19][C:5]1[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])=[N:7][C:2]([NH:35][C:32]2[CH:33]=[CH:34][C:27]3[CH2:26][CH2:25][CH:24]([NH:23][CH2:22][C:21]([F:20])([F:36])[F:37])[CH2:30][CH2:29][C:28]=3[CH:31]=2)=[N:3][CH:4]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: Nc1ccc2c(c1)CCC(NCC(F)(F)F)CC2
Agent: CC1(C)[C@@H]2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CC(C)O
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCC(NCC(F)(F)F)CC3)ncc1Cl
Temperature: 120 °C
Yield: 7.4 %

Procedure:
2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (86.3 mg, 0.290 mmol) and N*7*-(2,2,2-trifluoro-ethyl)-6,7,8,9-tetrahydro-5H-benzocycloheptene-2,7-diamine (75 mg, 0.290 mmol) were combined with DL-10-camphorsulfonic acid (101 mg, 0.436 mmol) in 2 ml IPA and heated in a microwave vial for 40 minutes at 120° C. for 40 minutes. The resulting reaction was poured into 25 ml saturated sodium bicarbonate solution and 50 ml water and extractred with 4×25 ml portions of methylene chloride. The combined organic was dried over magnesium sulfate, filtered and evaporated. The crude product was purified via reverse phase preparative chromatography (Luna C18, 5 μm, 100 mm×21.2 mm column) using a gradient of 0-35% MeCN in water (both containing 0.1% TFA). 2-{5-Chloro-2-[7-(2,2,2-trifluoro-ethylamino)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino]-pyrimidin-4-ylamino}-N-methyl-benzamide (11.18 mg, 7.4% yield) was isolated as an off white solid. 1H-NMR (CDCl3) δ 11.07 (s, 1H), 8.66 (d, J=8.44 Hz, 1H), 7.45 (m, 2H), 7.35 (s, 1H), 7.04 (m, 2H), 6.91 (s, 1H), 6.18 (s, 1H), 3.24 (q, J=19.4, 9.8 Hz, 2H), 3.03 (d, J=4.8 Hz, 3H), 2.87 (m, 3H), 2.66 (m, 2H), 2.06 (m, 2H), 1.32 (m, 5H). LC/MS (ESI+)=519 (M+H). MP=202-203° C.
Reaction SMILES: [CH:1]1[C:6]2[C:7]3[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=3[CH2:9][CH2:10][CH2:11][CH2:12][C:5]=2[C:4]([C:17](O)=[O:18])=[CH:3][CH:2]=1>O1CCCC1>[CH:1]1[C:6]2[C:7]3[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=3[CH2:9][CH2:10][CH2:11][CH2:12][C:5]=2[C:4]([CH2:17][OH:18])=[CH:3][CH:2]=1
Reactant: O=C(O)c1cccc2c1CCCCc1ccccc1-2
Solvent: C1CCOC1
Product: OCc1cccc2c1CCCCc1ccccc1-2
Yield: 86.4 %

Procedure:
The reaction between 5,6,7,8-tetrahydrodibenzo[a,c]cycloocten-4-carboxylic acid (1.7 g, 0.0067 mole) and borane-tetrahydrofuran complex (1.16 g of a 1.05 M solution is tetrahydrofuran) in tetrahydrofuran (50 ml) produced 5,6,7,8-tetrahydrodibenzo[a,c]cycloocten-4-methanol as an oil (1.38 g). The IR and nmr spectra were consistent with the proposed structure.
Reaction SMILES: C([C:5]#[C:6][CH2:7][O:8][CH2:9][C:10]#[C:11][C:12]#CCC)#CCC.[CH3:16][O:17][C:18]([C:20]#[C:21][C:22]([O:24][CH3:25])=[O:23])=[O:19]>C1(C)C=CC=CC=1>[CH2:7]1[C:6]2[CH:5]=[C:21]([C:22]([O:24][CH3:25])=[O:23])[C:20]([C:18]([O:17][CH3:16])=[O:19])=[CH:12][C:11]=2[CH2:10][CH2:9][O:8]1
Reactant: CCC#CC#CCOCC#CC#CCC
Reactant: COC(=O)C#CC(=O)OC
Solvent: Cc1ccccc1
Product: COC(=O)c1cc2c(cc1C(=O)OC)COCC2
Temperature: 105 °C
Yield: 19.2 %

Procedure:
A mixture of 3-butynyl-2-propynyl ether (37.2 g, 0.344 mol), dimethylacetylenedicarboxylate (48.9 g, 0.344 mol) and toluene is divided into 2 portions and transferred to 2 addition funnels connected to the reaction vessel. The apparatus is fitted with a condenser and evacuated 4 times with a Firestone valve and nitrogen. The cobalt catalyst is added in equal amounts to each addition funnel. The reaction vessel which contains approximately 2L toluene is heated to 105° C. under a nitrogen atmosphere with stirring. The contents of the addition funnels are added dropwise at equivalent rates, at 105° C., over a 4 hour period. The reaction mixture is stirred overnight at 100° C. under a heat lamp (Visible light), cooled to room temperature and filtered through diatomaceous earth. The filtrate is concentrated in vacuo to a brown oil, which is flash chromatographed (silica gel, 95% hexane:ether acetate eluent) to afford the title product as a pale orange solid (16.5 g, 19.2%) identified by NMR analysis.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=1[CH:15]([CH3:17])[CH3:16])=[O:4].[NH2:18][CH2:19][C:20]1([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.O>CN(C)C=O>[CH:15]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]([CH3:14])[CH3:13])[C:6]=1[NH:5][C:3](=[O:4])[CH2:2][NH:18][CH2:19][C:20]1([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)([CH3:17])[CH3:16]
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)CCl
Reactant: NCC1(Nc2ccccc2)CCCCC1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CNCC1(Nc2ccccc2)CCCCC1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 56.1 %

Procedure:
620 mg (2.45 mmol) of 2-chloro-N-(2,6-diisopropylphenyl)acetamide are added to 500 mg (2.45 mmol) of (1-aminomethylcyclohexyl)phenylamine in 10 ml of dimethylformamide. The reaction medium is stirred at 100° C. under microwave irradiation for 30 min. It is then poured into water and extracted with ethyl acetate. The organic phases are collected and washed with water. They are dried over sodium sulfate. The solvents are evaporated. The residue is chromatographed on silica gel (heptane/ethyl acetate 80/20, v/v). 580 mg of N-(2,6-diisopropylphenyl)-2-[(1-phenylaminocyclohexyl-methyl)amino]acetamide are obtained in the form of a beige solid. Yield=56%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](CC#N)[CH:5]=[C:6]([Cl:19])[C:7]=1[CH2:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](=[O:18])[NH:11][N:10]=1.[C:23]([O:26]CC)(=[O:25])[CH3:24]>Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:24][C:23]([OH:26])=[O:25])[CH:5]=[C:6]([Cl:19])[C:7]=1[CH2:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:16])[CH3:17])[C:12](=[O:18])[NH:11][N:10]=1
Reactant: CCOC(C)=O
Reactant: CC(C)c1cc(Cc2c(Cl)cc(CC#N)cc2Cl)n[nH]c1=O
Agent: Cl
Product: CC(C)c1cc(Cc2c(Cl)cc(CC(=O)O)cc2Cl)n[nH]c1=O
Temperature: 25 °C
Yield: 13 %

Procedure:
A mixture of [3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-ylmethyl)-phenyl]-acetonitrile (55) (assume 0.180 mmol) in concentrated hydrochloric acid (4 mL) was heated to reflux for 24 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (75 mL) and washed with a saturated aqueous sodium chloride solution (20 mL) and water (10 mL). The water layers were combined and extracted with ethyl acetate (50 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under vacuum. The resulting oil was purified by HPLC (acetonitrile/water with 0.1% trifluoroacetic acid). The desired fractions were collected, concentrated and freeze dried. The resulting solid was purified by flash chromatography using silica gel eluted with 10% methanol in methylene chloride. The desired fractions were collected and concentrated under vacuum to afford a solid which was dried under high vacuum to afford 3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-ylmethyl)-phenyl]-acetic acid (56) (8.6 mg, 13% for 2 steps) as a white solid; EI(+)-HRMS m/z calcd for C16H16Cl2N2O3 (M+H)+ 355.0611, found 355.0611. MW=355.2235, Exact Mass=354.0538
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CC1(C)C(C)(C)OB([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[N:25]=[N:24][CH:23]=[N:22]3)=[CH:17][CH:16]=2)O1.[F:27][C:28]1[C:29](I)=[CH:30][C:31](=[O:52])[N:32]([CH2:34][CH2:35][C@@:36]([CH3:51])([S:47]([CH3:50])(=[O:49])=[O:48])[C:37]([NH:39][O:40][CH:41]2[CH2:46][CH2:45][CH2:44][CH2:43][O:42]2)=[O:38])[CH:33]=1>O1CCOCC1.O.[Pd]>[F:27][C:28]1[C:29]([C:15]2[CH:16]=[CH:17][C:18]([N:21]3[N:25]=[N:24][CH:23]=[N:22]3)=[CH:19][CH:20]=2)=[CH:30][C:31](=[O:52])[N:32]([CH2:34][CH2:35][C@@:36]([CH3:51])([S:47]([CH3:50])(=[O:48])=[O:49])[C:37]([NH:39][O:40][CH:41]2[CH2:46][CH2:45][CH2:44][CH2:43][O:42]2)=[O:38])[CH:33]=1
Reactant: CC1(C)OB(c2ccc(-n3ncnn3)cc2)OC1(C)C
Reactant: C[C@@](CCn1cc(F)c(I)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@@](CCn1cc(F)c(-c2ccc(-n3ncnn3)cc2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Temperature: 80 °C
Reaction time: 8 h
Yield: 98.5 %

Procedure:
Pd EnCat™ (317 mg, 0.10 mmol) was added to a mixture of potassium carbonate (393 mg, 2.84 mmol), 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2H-tetrazole (258.4 mg, 0.95 mmol), and (2R)-4-(5-fluoro-4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (490 mg, 0.95 mmol), T3, in 1,4-dioxane:water (4:1, 10 mL). The reaction was heated to 80° C. and stirred at this temperature overnight. The reaction was filtered through celite, and the filter pad was washed with methanol (250 mL). The combined filtrates were concentrated under reduced pressure, and the resulting crude material was purified via flash chromatography using an eluent of EtOAc in n-heptane (20-100%) and methanol in EtOAc (0-10%) to afford the title compound as a light tan solid (500 mg, 98%). MS (LCMS) m/z 534.4 (M−1). 0
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]1([C:11]2[CH:15]=[C:14]([C:16]([OH:18])=O)[O:13][N:12]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CN(C)C=O>[C:5]1([C:11]2[CH:15]=[C:14]([C:16]([Cl:3])=[O:18])[O:13][N:12]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(O)c1cc(-c2ccccc2)no1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(-c2ccccc2)no1

Procedure:
Added to 500 g (4.2 mol) of thionyl chloride were 110 g (0.58 mol) of 3-phenylisoxazole-5-carboxylic acid prepared above in the procedure (2), followed by the further addition of 2 ml of dimethylformamide. The resulting mixture was heated under reflux for 3 hours. After completion of the reaction, thionyl chloride was distilled off under reduced pressure, followed by the addition of 500 ml of benzene. When the mixture thus obtained was distilled under reduced pressure, the title compound, i.e., 3-phenylisoxazole-5-carboxylic acid chloride was obtained as a solid. It was provided for the next step without purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:21][C:6]2=[C:7]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[S:8][C:9]([S:10]([CH3:13])(=O)=O)=[C:5]2[C:4](=[O:22])[CH2:3]1.[OH-].[Na+].SC1[S:28][CH:29]=[CH:30][N:31]=1>CCO>[CH3:1][C:2]1([CH3:23])[CH2:21][C:6]2=[C:7]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[S:8][C:9]([S:10][C:13]3[S:28][CH:29]=[CH:30][N:31]=3)=[C:5]2[C:4](=[O:22])[CH2:3]1
Reactant: Sc1nccs1
Reactant: CC1(C)CC(=O)c2c(S(C)(=O)=O)sc(C(=O)N3CCCC3)c2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)CC(=O)c2c(Sc3nccs3)sc(C(=O)N3CCCC3)c2C1
Temperature: 70 °C
Yield: 27.8 %

Procedure:
To a suspension of 6,6-dimethyl-3-methanesulphonyl-1-(pyrrolidin-1-ylcarbonyl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one (400 mg, 1.1 mmol) in EtOH (10 mL) was added NaOH (1.1 mL of a 3 M solution, 3.3 mmol) followed by 2-mercaptothiazole (0.39 g, 3.3 mmol). The mixture was heated at 70° C. for 5 h then the solution was evaporated. The residue was partitioned between EtOAc (20 mL) and NaOH (1 M; 30 mL). The organic phase was separated, dried (Na2SO4) and evaporated. The residue was chromatographed on silica gel, eluting with EtOAc:hexane (2:1), to afford the title compound (120 mg. 28%) as a colourless solid. 1H NMR (250 MHz, CDCl3) δ 1.07 (6H, s), 1.90-1.95 (4H, m), 2.45 (2H, s), 2.83 (2H, s), 3.40-3.62 (4H, m), 7.55 (1H, d, J=3.4 Hz), 7.97 (1H, d, J=3.4 Hz). MS (ES+) 393 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[CH2:7][CH2:8][N:9]2[C:12]([C:14]2[CH:18]=[CH:17][S:16][C:15]=2[CH3:19])=[O:13])=[CH:4][CH:3]=1.C(O)C.Cl.[OH:25][NH2:26].N1C=CC=CC=1>O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[N:26][OH:25])[CH2:7][CH2:8][N:9]2[C:12]([C:14]2[CH:18]=[CH:17][S:16][C:15]=2[CH3:19])=[O:13])=[CH:4][CH:3]=1
Reactant: NO
Reactant: Cc1sccc1C(=O)N1CCC(=O)c2ccc(Cl)cc21
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Solvent: O
Product: Cc1sccc1C(=O)N1CCC(=NO)c2ccc(Cl)cc21
Yield: 87.1 %

Procedure:
To a mixture of 7-chloro-2,3-dihydro-l-(2-methyl-3-thienylcarbonyl)-4(lH)-quinolinone (17.5 g), obtained in example 5, and ethanol (250 ml) were added hydroxyl amine hydrochloride (8 g) and pyridine (8.8 g), and the mixture was heated under reflux for 1.5 hours. After cooling, the reaction mixture was poured into 1000 ml of water, and precipitated crystals were separated by filtration, washed, dried and recrystallized with ethanol to obtain 7-chloro-2,3-dihydro-1-(2-methyl-3-thienylcarbonyl)-4(lH)-quinolinone-4-oxime (yield 16 g) as white crystal.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=1)=O.[C:21]1([CH3:30])[CH:26]=[CH:25][C:24]([CH2:27][CH:28]=O)=[CH:23][CH:22]=1>>[CH3:30][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[N:1][C:2]3[C:3]([C:12]=2[C:14]2[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=2)=[CH:4][CH:5]=[CH:6][C:7]=3[C:8]([F:11])([F:10])[F:9])=[CH:23][CH:22]=1
Reactant: Cc1ccc(CC=O)cc1
Reactant: Nc1c(C(=O)c2cccc(O)c2)cccc1C(F)(F)F
Product: Cc1ccc(-c2cnc3c(C(F)(F)F)cccc3c2-c2cccc(O)c2)cc1

Procedure:
The title compound was prepared from [2-amino-3-(trifluoromethyl)phenyl]-(3-hydroxy-phenyl)methanone and p-Tolyl-acetaldehyde following the procedure of Example 457: MS (ESI) m/z 380; HRMS: calcd for C23H16F3NO+H+, 380.12567; found (ESI, [M+H]+), 380.1259.
Reaction SMILES: C([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([C:17]3[C:22]4[O:23][C:24]5[C:29]([C:21]=4[CH:20]=[CH:19][CH:18]=3)=[CH:28][CH:27]=[C:26](C)[N:25]=5)[CH:12]=2)=[CH:7][CH:6]=1)C(C)C.C(O[CH2:34][CH2:35]O)C.[CH3:37]N(C=O)C>>[CH:34]([C:26]1[N:25]=[C:24]2[O:23][C:22]3[C:17]([C:13]4[CH:12]=[C:11]([C:8]5[CH:7]=[CH:6][CH:5]=[CH:10][CH:9]=5)[CH:16]=[CH:15][N:14]=4)=[CH:18][CH:19]=[CH:20][C:21]=3[C:29]2=[CH:28][CH:27]=1)([CH3:35])[CH3:37]
Reactant: CN(C)C=O
Reactant: Cc1ccc2c(n1)oc1c(-c3cc(-c4ccc(CC(C)C)cc4)ccn3)cccc12
Reactant: CCOCCO
Product: CC(C)c1ccc2c(n1)oc1c(-c3cc(-c4ccccc4)ccn3)cccc12
Temperature: 130 °C
Yield: 62.6 %

Procedure:
A mixture of iridium complex (2.3 g, 3.22 mmol), 8-(4-(4-isobutylphenyl)pyridin-2-yl)-2-methylbenzofuro[2,3-b]pyridine (2.53 g, 6.44 mmol), 2-ethoxyethanol (60 mL) and DMF (60 mL) was heated at 130° C. overnight. The solvent mixture was evaporated under vacuum. The residue was run through a short silica plug. The reaction mixture was further purified by silica gel column with DCM/heptane as elute to obtain 1.8 g desired product (62.6% yield).