Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6](Br)=[CH:5][CH:4]=1)[CH3:2].C([Li])CCC.B(OCCCC)(OCCCC)OCCCC.S(=O)(=O)(O)O.Br[C:37]1[CH:38]=[CH:39][C:40]2[O:46][CH2:45][CH2:44][C:43]([C:47]([O:49][CH2:50][CH3:51])=[O:48])=[CH:42][C:41]=2[CH:52]=1.B([O-])([O-])OC1C=CC(CC)=CC=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.C1(C)C(CCO)=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:37]2[CH:38]=[CH:39][C:40]3[O:46][CH2:45][CH2:44][C:43]([C:47]([O:49][CH2:50][CH3:51])=[O:48])=[CH:42][C:41]=3[CH:52]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCOC(=O)C1=Cc2cc(Br)ccc2OCC1
Reactant: CCc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCCOB(OCCCC)OCCCC
Agent: CCc1ccc(OB([O-])[O-])cc1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C1=Cc2cc(-c3ccc(CC)cc3)ccc2OCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.5 %

Procedure:
Under argon atmosphere, to a solution of 4-ethylbromobenzene (10.0 g) in tetrahydrofuran (60 ml) was added n-butyllithium (1.6M hexane solution) (37.2 ml) at -78° C., and the mixture was stirred for 1 hour. To the reaction mixture was dropwise added a solution of tributyl borate (13.68 g) in tetrahydrofuran (30 ml), and the reaction mixture was warmed to room temperature and stirred at room temperature for 2 hours. To the reaction mixture was added 10% sulfuric acid (100 ml), and the mixture was stirred for 1 hour. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in acetone (30 ml), and to the mixture was added 10% sulfuric acid (50 ml). The mixture was stirred at room temperature for 16 hours, and under reduced pressure acetone was evaporated. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate/hexane=1:2) to give crude 4-ethylphenyl borate (0.91 g) as colorless solid. Under argon atmosphere, a solution of ethyl 7-bromo-2,3-dihydro-1-benzoxepine-4-carboxylate (500 mg), the above crude 4-ethylphenyl borate (0.32 g) and potassium carbonate (0.49 g) in toluene-ethanol-water (20-2-2 ml) was stirred at room temperature for 1 hour. To the reaction mixture was added tetrakistriphenyl-phosphinepalladium (0.06 g), and the mixture was refluxed for 18 hours and cooled to room temperature. The organic layer was washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate/hexane=1:15) to give ethyl 7-(4-ethylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxylate (464 mg) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[N:3]([S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=2)(=[O:20])=[O:19])[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][C:6]=1[C:7](OCC)=[O:8].C1(C)C=CC=CC=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1>[CH3:1][C:2]1[N:3]([S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=2)(=[O:19])=[O:20])[C:4]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:5][C:6]=1[CH:7]=[O:8]
Reactant: CCOC(=O)c1cc(-c2ccccc2)n(S(=O)(=O)c2cccc(C)c2)c1C
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1cccc(S(=O)(=O)n2c(-c3ccccc3)cc(C=O)c2C)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
A solution (10 mL) of ethyl 2-methyl-1-[(3-methylphenyl)sulfonyl]-5-phenyl-1H-pyrrole-3-carboxylate (588 mg) in tetrahydrofuran was cooled to −78° C., a 1.5 mol/L toluene solution (3.00 mL) of diisobutylaluminum hydride was added dropwise. After completion of the dropwise addition, the mixture was stirred at −78° C. for 30 min, and at room temperature for 30 min. 1 mol/l Hydrochloric acid (10 mL) was added to the reaction mixture and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. A solution (10 mL) of the residue in acetonitrile was cooled to 0° C., tetra-n-propylammonium perruthenate (53 mg), N-methylmorpholine N-oxide (358 mg) and molecular sieves 4A powder (1.0 g) were added, and the mixture was stirred at room temperature for 2.5 hr. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in ethyl acetate (30 mL) and filtered through celite. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→2:1) to give the title compound as a pale-yellow oil (yield 250 mg, 48%).
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][SH:4].O=[CH:9][C@@H:10]([C@H:12]([C@H:14]([C@@H:16]([CH2:18][OH:19])[OH:17])[OH:15])[OH:13])[OH:11].N1C=CC=CC=1>O>[OH:11][CH:10]([CH:9]1[NH:1][CH:2]([C:5]([OH:7])=[O:6])[CH2:3][S:4]1)[CH:12]([OH:13])[CH:14]([OH:15])[CH:16]([OH:17])[CH2:18][OH:19]
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Reactant: N[C@@H](CS)C(=O)O
Solvent: O
Solvent: c1ccncc1
Product: O=C(O)C1CSC(C(O)C(O)C(O)C(O)CO)N1
Temperature: 65 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
Under an argon atmosphere, L-cysteine (2.42 g, 20.0 mmol), D-galactose (3.60 g, 20.0 mmol), and pyridine (0.40 ml, 5.0 mmol) were added to water (340 ml), and the solution was heated at 65° C. for 1 hour, and left standing at room temperature for 2 hours. The precipitated solid was collected by filtration, and dried under reduced pressure to give 2-(1,2,3,4,5-pentahydroxypentyl)thiazolidine-4-carboxylic acid (4.70 g) as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]([C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:5]O.CCCCCC.C1(C)C=CC=CC=1>O>[CH3:1][O:2][C:3]([C:4]1[C:7]2[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=2[O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH:5]=1)=[O:21]
Reactant: COC(=O)C(=CO)c1cc(Cl)ccc1Oc1ccccc1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)C1=Cc2ccccc2Oc2ccc(Cl)cc21
Temperature: 20 °C
Reaction time: 2 h
Yield: 86.8 %

Procedure:
A slurry of 2-(5-chloro-2-phenoxy-phenyl)-3-hydroxy-acrylic acid methyl ester (210 g, 691 mmol) was heated in pyrophosporic acid (420 g) to 60° C. After two hours, the reaction was cooled to 20° C. and hexane (250 mL), toluene (500 mL), and water (500 mL) were added to quench the reaction. The organic layer was separated and washed with saturated aqueous sodium bicarbonate (500 mL) and saturated brine (500 mL). The organic fraction was concentrated and the resulting oil was crystallized from n-butanol (500 mL; 20° C. for one hour and −10° C. for two hours), which provided the titled compound as off-white crystals (172 g, 85% yield for steps A and B). 1H NMR (400 MHz, CDCl3) 3.9 (s, 3H), 7.1-7.2 (m, 3H), 7.3 (m, 2H), 7.4 (t, 1H), 7.6 (d, 1H), 8.0 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-])=O)[CH:3]=1.Cl[Sn]Cl.C([O-])(O)=O.[Na+]>C(O)C.O>[NH2:9][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][C:5]=1[OH:8]
Reactant: O=[N+]([O-])c1cc(Br)ccc1O
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1cc(Br)ccc1O
Temperature: 70 °C
Reaction time: 2 h
Yield: 89.2 %

Procedure:
A mixture of compound 4-bromo-2-nitrophenol (1 g, 4.59 mmol) and SnCl2 (5.2 g, 22.9 mmol) in ethanol (10 mL) was stirred at 70° C. for 2 h. After cooled down, the mixture was diluted with water (100 mL), adjusted to pH 7 with saturated aqueous NaHCO3 and extracted with ethyl acetate (100 mL). The organic layer was washed with brine (50 mL), dried over Na2SO4, concentrated to give 2-amino-4-bromophenol (770 mg, 89%) as a grey solid. LCMS: 188 [M+1]+. 1H NMR (400 MHz, DMSO-d6) δ 4.79 (s, 2H), 6.48 (dd, J1=2.4 Hz, J2=8.4 Hz, 1H), 6.55 (d, J=8.4 Hz, 1H), 6.71 (d, J=2.4 Hz, 1H), 9.26 (s, 1H).
Reaction SMILES: [N:1]([CH:4]1[CH2:10][CH2:9][N:8]([C:11]2[N:15]([CH3:16])[N:14]=[CH:13][C:12]=2[N+:17]([O-:19])=[O:18])[CH2:7][CH:6]([OH:20])[CH2:5]1)=[N+:2]=[N-:3].[H-].[Na+].I[CH3:24].O>CN(C=O)C>[N:1]([CH:4]1[CH2:10][CH2:9][N:8]([C:11]2[N:15]([CH3:16])[N:14]=[CH:13][C:12]=2[N+:17]([O-:19])=[O:18])[CH2:7][CH:6]([O:20][CH3:24])[CH2:5]1)=[N+:2]=[N-:3]
Reactant: CI
Reactant: Cn1ncc([N+](=O)[O-])c1N1CCC(N=[N+]=[N-])CC(O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC1CC(N=[N+]=[N-])CCN(c2c([N+](=O)[O-])cnn2C)C1
Reaction time: 0.17 h

Procedure:
To a solution of 5-azido-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-3-ol, Intermediate 18 (0.85 g, 3.0 mmol) in DMF (5 mL) cooled to 0° C. under nitrogen, was added sodium hydride (60% in mineral oil, 133 mg, 3.3 mmol) and the resulting mixture was stirred for 10 min. Iodomethane (0.37 mL, 6.0 mmol) was added and the mixture stirred at room temperature for 16 hr. Water (200 mL) was added and the mixture extracted with EtOAc (2×50 mL). The combined organic layers were dried over Na2SO4 and the solvent removed under reduced pressure. Purification via silica gel column chromatography (0-50% EtOAc/isohexane) gave 5-azido-3-methoxy-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepane as an oil (0.76 g). This azide (0.76 g, 2.6 mmol) in THF (15 mL) and water (3 mL) was treated with triphenylphosphine (0.71 g, 2.7 mmol). The mixture was heated at 65° C. for 16 hr and the solvents were removed under reduced pressure to afford 6-methoxy-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-amine. This amine was suspended in DCM (40 mL) and di-tert-butyl dicarbonate (1.13 g, 5.2 mmol) and DIPEA (1.36 mL, 7.8 mmol) were added. After stirring at room temperature for 16 hr the solvent was removed under reduced pressure and the residue dissolved in DCM (40 mL). Water (20 ml) was added and the organic layer was separated, dried over Na2SO4 and the solvent removed under reduced pressure. Purification via silica gel column chromatography (0-50% EtOAc/isohexane) gave tert-butyl 6-methoxy-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-ylcarbamate (0.84 g, 74% over three steps) as an oil. 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J=4.3 Hz, 1H), 5.39 (d, J=7.9 Hz, 1H), 4.21-3.94 (m, 1H), 3.84 (s, 3H), 3.56-3.42 (m, 2H), 3.35-3.03 (m, 6H), 2.28-1.89 (m, 4H), 1.46 (s, 9H).
Reaction SMILES: Br[CH2:2][C:3]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([OH:14])[CH2:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:7])=[O:6].[I-:21].[Na+].O.CCOCC>CC(C)=O>[I:21][CH2:2][C:3]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([OH:14])[CH2:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:7])=[O:6]
Reactant: O=S(=O)(CC(O)(CBr)c1ccccc1)c1ccccc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOCC
Solvent: O
Product: O=S(=O)(CC(O)(CI)c1ccccc1)c1ccccc1
Yield: 31.1 %

Procedure:
1-Bromo-2-phenyl-3-phenylsulphonyl-2-propanol (1.3 g, 0.004 mole) is dissolved in acetone (30 cc). Sodium iodide (0.9 g, 0.006 mole) is added and heated under reflux for 15 h. The reaction mixture is poured into water (100 cc), reextracted with ether (3×50 cc), washed with a 15% strength NaHSO3 solution (50 cc) and then with water (50 cc) and is dried over MgSO4. The crystallized crude (0.9 g) is recrystallized from carbon tetrachloride to give yellow crystals of 1-iodo-2-phenyl-3-phenylsulphonyl-2-propanol (0.5 g, 31%). Mp=98° C.
Reaction SMILES: [S:1]1[C:5]([C@H:6]([O:25][Si:26]([C:39]([CH3:42])([CH3:41])[CH3:40])([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)/[CH:7]=[CH:8]/[C@H:9]2[C:13](=[CH2:14])[CH2:12][C@H:11]([OH:15])[C@@H:10]2[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:4][C:3]2[CH:43]=[CH:44][CH:45]=[CH:46][C:2]1=2.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O.C(OCC)(=O)C>[S:1]1[C:5]([C@H:6]([O:25][Si:26]([C:39]([CH3:41])([CH3:42])[CH3:40])([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)/[CH:7]=[CH:8]/[C@H:9]2[C:13]([CH3:14])=[CH:12][C:11](=[O:15])[C@@H:10]2[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:4][C:3]2[CH:43]=[CH:44][CH:45]=[CH:46][C:2]1=2
Reactant: C=C1C[C@H](O)[C@H](C/C=C\CCCC(=O)O)[C@H]1/C=C/[C@@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1cc2ccccc2s1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CC1=CC(=O)[C@H](C/C=C\CCCC(=O)O)[C@H]1/C=C/[C@@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1cc2ccccc2s1
Temperature: -25 °C

Procedure:
(Z)-7-((1R,2R,5S)-2-((R,E)-3-(Benzo[b]thiophen-2-yl)-3-(tert-butyldiphenylsilyloxy)prop-1-enyl)-5-hydroxy-3-methylenecyclopentyl)hept-5-enoic acid (23a) is dissolved in acetone (0.1 M) and cooled to −25° C. Jones reagent (1 molar equivalent) is added dropwise with stirring. Upon completion, as judged by TLC, the reaction is quenched with isopropyl alcohol and the crude reaction mixture is diluted with ethyl acetate, washed three times with brine, and dried over magnesium sulfate. After filtration and solvent evaporation, the product is purified by flash chromatography using hexanes-ethyl acetate as eluent to afford the title intermediate.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:16]=4[C:15](=[O:23])[N:14]4[CH2:24][CH2:25][C@H:13]4[C:12]=23)[N:4]=1.[CH2:26]([NH2:29])[CH2:27][CH3:28]>CN(C)C=O>[F:22][C:20]1[CH:19]=[CH:18][C:17]2[N:11]3[CH:10]=[N:9][C:8]([C:5]4[N:4]=[C:3]([CH2:2][NH:29][CH2:26][CH2:27][CH3:28])[O:7][N:6]=4)=[C:12]3[C@@H:13]3[CH2:25][CH2:24][N:14]3[C:15](=[O:23])[C:16]=2[CH:21]=1
Reactant: CCCN
Reactant: O=C1c2cc(F)ccc2-n2cnc(-c3noc(CCl)n3)c2[C@@H]2CCN12
Solvent: CN(C)C=O
Product: CCCNCc1nc(-c2ncn3c2[C@@H]2CCN2C(=O)c2cc(F)ccc2-3)no1
Yield: 73.2 %

Procedure:
1.8 g (5 mmol) of (S)-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-7-fluoro-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one were stirred at room temperature for 2 hours with 2 g (34 mmol) of propylamine and 20 ml of N,N-dimethylformamide. By evaporation of the solvent and chromatography of the residue on silica gel while eluting with ethyl acetate/methanol 9/1 there were obtained 1.4 g (73%) of (S)-7-fluoro-1-(5-propylaminomethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one, which was converted into the hydrochloride (amorphous).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.S([O-])([O-])=O.[Na+].[Na+].C(=O)(O)[O-].[Na+].Cl>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([OH:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Solvent: O
Product: O=S(O)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 87 %

Procedure:
A mixture of 4-fluorobenzenesulfonyl chloride (50.0 g, 257 mmol), sodium sulfite (48.6 g, 386 mmol), and sodium bicarbonate (108 g, 1.28 mol) in water was heated to 100° C. The resulting solution was stirred for 1.5 h at 100° C., then cooled to RT and acidified by careful addition of concentrated hydrochloric acid. The resulting precipitate was extracted with EtOAc (3×250 mL). The combined extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. Drying in vacuo gave the title compound of Step A as a solid (35.8 g). MS (APCl−) Calc.: 160.0. Found: 195.1 (M+35, Cl− adduct).
Reaction SMILES: C([O:8][C:9]1[C:14]2[N:15]([CH:18]([F:20])[F:19])[CH:16]=[N:17][C:13]=2[CH:12]=[C:11](Cl)[N:10]=1)C1C=CC=CC=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][C:29]=1[O:30][CH3:31].C([O-])([O-])=O.[K+].[K+].B(O)O.C([O-])=O.[NH4+]>C1(C)C=CC=CC=1.O.CCOC(C)=O.CCO.CN(C=O)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl.[OH-].[OH-].[Pd+2]>[F:20][CH:18]([F:19])[N:15]1[C:14]2[C:9](=[O:8])[NH:10][C:11]([C:27]3[CH:26]=[CH:25][C:24]([O:23][CH3:22])=[C:29]([O:30][CH3:31])[CH:28]=3)=[CH:12][C:13]=2[N:17]=[CH:16]1
Reactant: COc1ccc(B(O)O)cc1OC
Reactant: FC(F)n1cnc2cc(Cl)nc(OCc3ccccc3)c21
Agent: Cl[Pd]Cl
Agent: [Pd+2]
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1ccc(-c2cc3ncn(C(F)F)c3c(=O)[nH]2)cc1OC
Temperature: 90 °C
Reaction time: 3.5 h

Procedure:
4-(benzyloxy)-6-chloro-3-(difluoromethyl)-3H-imidazo[4,5-c]pyridine 2.28 (113 mg, 0.365 mmol), 3,4-dimethoxyphenylboronic acid (107 mg, 0.588 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (14.5 mg, 0.0205 mmol) and K2CO3 (164 mg, 1.19 mmol) were taken up in toluene (3 mL) and water (0.6 mL) under Ar. The stirred mixture was heated to 90° C. After 3.5 h, additional boronic acid (35 mg, 0.19 mmol), catalyst (4.5 mg, 0.0064 mmol), and K2CO3 (53 mg, 0.38 mmol) were added as a suspension in toluene (1 mL) and water (0.3 mL). After an additional 1 h, the reaction mixture was cooled to r.t. and was diluted with EtOAc (20 mL) and water (20 mL). The phases were separated, and the aqueous phase was extracted with EtOAc (20 mL). The organic phase was dried over Na2SO4, filtered, and concentrated onto silica gel. Purification by silica gel chromatography (20% to 50% acetone in hexanes) provided a residue that was dissolved in EtOH (3 mL) and DMF (2 mL). Ammonium formate (260 mg, 4.1 mmol) and Pd(OH)2 on carbon (20 wt. % Pd, 40 mg) were added and the mixture was heated to 70° C. and stirred for 20 min. The mixture was diluted with DMF (5 mL) and filtered through Celite. The filtrate was concentrated in vacuo and the resulting crude solid was purified by silica gel chromatography (0% to 10% MeOH in DCM) to provide 3-(difluoromethyl)-6-(3,4-dimethoxyphenyl)-3H-imidazo[4,5-c]pyridin-4(5H)-one 2.29.
Reaction SMILES: C([O:4][C:5]([C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[CH:10]=[C:9]([NH:19][C:20]2[CH:24]=[C:23]([CH3:25])[NH:22][N:21]=2)[N:8]=1)=[O:6])(C)C.[OH-].[K+]>CO>[CH3:18][O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[C:7]([C:5]([OH:6])=[O:4])=[N:8][C:9]([NH:19][C:20]1[CH:24]=[C:23]([CH3:25])[NH:22][N:21]=1)=[CH:10]2
Reactant: COc1ccc2c(C(=O)OC(C)C)nc(Nc3cc(C)[nH]n3)cc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc2c(C(=O)O)nc(Nc3cc(C)[nH]n3)cc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.5 %

Procedure:
A mixture of 6-methoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinoline-1-carboxylic acid isopropyl ester (0.7 g), 1M KOH (10 ml) and methanol (30 ml) was stirred at room temperature overnight, and then it was concentrated. The residue was acidified to pH=1 by 1M HCl and yielded 0.42 g of crude 6-methoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinoline-1-carboxylic acid. LC-MS: 299 (MH+).
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1.[O:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1>CCO>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[C:15]2[CH2:16][CH2:17][O:12][CH2:13][CH2:14]2)[C:10]#[N:11])=[CH:5][CH:4]=1
Reactant: N#CCc1ccc(Cl)cc1
Reactant: O=C1CCOCC1
Agent: [Na]
Solvent: CCO
Product: N#CC(=C1CCOCC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 38.9 %

Procedure:
Sodium (152 mg, 6.6 mmol) was added into EtOH (10 ml) and stirred at room temperature for 20 minutes. 2-(4-Chlorophenyl)acetonitrile (500 mg, 3.3 mmol) was added to the solution, after all the sodium had dissolved, and the reaction was stirred at room temperature for 0.5 h. To the resulting mixture was added dihydro-2H-pyran-4(3H)-one (330 mg, 3.3 mmol) and stifled at room temperature for 1.5 h. The solvent was removed. To the residue was added water and extracted with EtOAc (3×20 mL). The combined organic solution were dried over Na2SO4 and concentrated to give crude product, which was purified by flash column chromatography (petroleum ether: EtOAc=10:1) to give compound 2-(4-chlorophenyl)-2-(dihydro-2H-pyran-4(3H)-ylidene)acetonitrile (300 mg) which was used for the next step without further purification.
Reaction SMILES: Cl[C:2]1[C:11]([O:12][CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=1B(O)O.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)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]>[F:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=1[C:2]1[C:11]([O:12][CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1
Reactant: COc1ccc(F)c(B(O)O)c1
Reactant: COC(=O)c1cnc(Cl)c(OCC(C)C)c1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cnc(-c2cc(OC)ccc2F)c(OCC(C)C)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 72.3 %

Procedure:
Under an argon atmosphere, to a solution of methyl 6-chloro-5-isobutoxynicotinate (1.84 g) in toluene (25 mL) were added 2-fluoro-5-methoxyphenylboronic acid (2.21 g), tris(dibenzylideneacetone)dipalladium(0) (318 mg), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (570 mg) and 2.0 M aqueous sodium carbonate solution (13.0 mL), and the mixture was stirred at 100° C. for 1 hr. The reaction mixture was filtered through celite, and water was added at room temperature. The reaction mixture was extracted with ethyl acetate, and the extract was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.82 g) as a yellow oil.
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:7][NH:8][C:9]([C:11]1[N:18]2[C:14]([S:15][CH:16]=[CH:17]2)=[N:13][C:12]=1[CH3:19])=[O:10].[NH2:20][C:21]1[S:22][C:23]([C:29]2[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=2)=[C:24]([C:26](O)=[O:27])[N:25]=1>>[NH2:20][C:21]1[S:22][C:23]([C:29]2[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=2)=[C:24]([C:26]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:6]3)[C@H:2]2[CH2:7][NH:8][C:9]([C:11]2[N:18]3[C:14]([S:15][CH:16]=[CH:17]3)=[N:13][C:12]=2[CH3:19])=[O:10])=[O:27])[N:25]=1
Reactant: Cc1cccc(-c2sc(N)nc2C(=O)O)c1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2C[C@@H]21
Product: Cc1cccc(-c2sc(N)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)c1

Procedure:
prepared by reaction of 6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid[(1S,2S,5R)-1-(3-aza-bicyclo[3.1.0]hex-2-yl)methyl]-amide with 2-Amino-5-m-tolyl-thiazole-4-carboxylic acid. LC-MS (basic): tR=1.24 min; [M+H]+=493.1.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[CH3:25]>>[F:17][C:4]1[CH:3]=[C:2]([C:21]2[CH:22]=[CH:23][C:24]([CH3:25])=[C:19]([F:18])[CH:20]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: Cc1c2n(c3c(Br)cc(F)cc13)CCNC2=O
Reactant: Cc1ccc(B(O)O)cc1F
Product: Cc1ccc(-c2cc(F)cc3c(C)c4n(c23)CCNC4=O)cc1F

Procedure:
The title compound, light yellow solid (71 mg, 87%), MS (ISP) m/z=327.5 [(M+H)+], mp 206° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 14) (74.3 mg, 0.25 mmol) and commercially available 3-fluoro-4-methyl-phenylboronic acid (50.0 mg, 0.325 mmol).