Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][C@@H:19]1[CH2:28][CH2:27][C:26]2[C:21](=[C:22]([N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)[CH:23]=[CH:24][CH:25]=2)[CH2:20]1.C(N(CC)CC)C>S(Cl)(Cl)=O.C(Cl)Cl>[CH3:35][N:32]1[CH2:33][CH2:34][N:29]([C:22]2[CH:23]=[CH:24][CH:25]=[C:26]3[C:21]=2[CH2:20][C@H:19]([NH:18][C:13](=[O:15])[C:12]2[CH:11]=[CH:10][C:9]([C:1](=[O:8])[C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:17][CH:16]=2)[CH2:28][CH2:27]3)[CH2:30][CH2:31]1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Reactant: O=C(O)c1ccc(C(=O)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(C(=O)c4ccccc4)cc2)CC3)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-Benzoylbenzoic acid (0.50 g, 2.2 mmol) was dissolved in thionyl chloride (15 mL) and heated at reflux for 15 min. The excess of thionyl chloride was evaporated in vacuo, the residue was treated with toluene and again the solvent was removed in vacuo. Crude acid chloride (150 mg, 0.60 mmol) was dissolved in methylene chloride (5 mL) and added dropwise to an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (140 mg, 0.57 mmol) and triethylamine (120 μL, 0.86 mmol) in methylene chloride (30 mL). After the addition, the reaction was allowed to stir at ambient temperature for 15 min and was then washed with dilute aqueous sodium hydrogen carbonate. The phases were separated and the organic phase was dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:3) as the eluent. Yield: 120 mg (48%) of the title compound as white crystals: mp 194-195° C.; [α]21D −51° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 453 (2, M+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([O:9][CH2:10][CH3:11])[CH:3]=1.Br[CH2:13][CH2:14][O:15][CH2:16][CH3:17].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:13][CH2:14][O:15][CH2:16][CH3:17])=[C:4]([O:9][CH2:10][CH3:11])[CH:3]=1
Reactant: CCOCCBr
Reactant: CCOc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOCCOc1ccc(Br)cc1OCC
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A suspension of 4-bromo-2-ethoxyphenol (8 g), bromoethylethyl ether (5 ml), sodium iodide (5.5 g) and potassium carbonate (10.2 g) in DMF (10 ml) was stirred under nitrogen atmosphere at 90° C. overnight. The solvent was evaporated, and to the residue was added water. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated, and the residue was distilled under reduced pressure to give 1-bromo-3-ethoxy-4-(2-ethoxyethoxy)benzene (8.1 g) as yellow oil.
Reaction SMILES: [F:1][CH:2]([F:19])[C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[CH:11][CH:10]=2)[CH:6]=[CH:5][N:4]=1.[N:20]1[CH:25]=[CH:24][N:23]=[CH:22][C:21]=1[C:26]1[CH:27]=[CH:28][C:29]([NH2:32])=[N:30][CH:31]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C>[F:19][CH:2]([F:1])[C:3]1[CH:8]=[C:7]([C:9]2[CH:10]=[CH:11][C:12]([CH2:15][C:16]([NH:32][C:29]3[CH:28]=[CH:27][C:26]([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][N:20]=4)=[CH:31][N:30]=3)=[O:18])=[CH:13][CH:14]=2)[CH:6]=[CH:5][N:4]=1
Reactant: Nc1ccc(-c2cnccn2)cn1
Reactant: O=C(O)Cc1ccc(-c2ccnc(C(F)F)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cc1ccc(-c2ccnc(C(F)F)c2)cc1)Nc1ccc(-c2cnccn2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(4-(2-(difluoromethyl)pyridin-4-yl)phenyl)acetic acid 203-5 (70 mg, 0.27 mmol), 5-(pyrazin-2-yl)pyridin-2-amine (55 mg, 0.32 mmol), N,N-diisopropylethylamine (139 μL, 0.80 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (152 mg, 0.40 mmol) in DMF (2 mL) was stirred at room temperature overnight. The solvent was removed by rotary evaporation. The crude product was purified by reverse phase HPLC to give 2-(4-(2-(difluoromethyl)pyridin-4-yl)phenyl)-N-(5-(pyrazin-2-yl)pyridin-2-yl)acetamide 203. MS m/z 418.2 (M+1); 1H NMR 400 MHz (CDCl3) δ 8.99 (d, 1H), 8.90 (dd, 1H), 8.70 (d, 1H), 8.63 (dd, 1H), 8.53 (d, 1H), 8.40-8.33 (m, 2H), 8.30 (s, 1H), 7.84 (s, 1H), 7.70-7.68 (m, 2H), 7.62-7.60 (m, 1H), 7.50-7.49 (m, 2H), 6.70 (t, 1H), 3.87 (s, 2H).
Reaction SMILES: O.[NH2:2][NH2:3].[CH3:4][N:5]1[C:11](=[O:12])[C:10]2[S:13][CH:14]=[CH:15][C:9]=2[N:8]2[CH:16]=[N:17][C:18]([C:19]([O:21]CC)=O)=[C:7]2[CH2:6]1>C(O)C>[CH3:4][N:5]1[C:11](=[O:12])[C:10]2[S:13][CH:14]=[CH:15][C:9]=2[N:8]2[CH:16]=[N:17][C:18]([C:19]([NH:2][NH2:3])=[O:21])=[C:7]2[CH2:6]1
Reactant: CCOC(=O)c1ncn2c1CN(C)C(=O)c1sccc1-2
Reactant: NN
Solvent: O
Solvent: CCO
Product: CN1Cc2c(C(=O)NN)ncn2-c2ccsc2C1=O
Yield: 97 %

Procedure:
13 ml of hydrazine hydrate were added to a suspension of 7.0 g (24 mmol) of ethyl 5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a]thieno[2,3-f][1,4]diazepine-3-carboxylate in 70 ml of ethanol and the mixture was heated at reflux for 3 hours. After cooling to 0° the crystals obtained were filtered off and there were obtained 6.5 g (97%) of 5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a]thieno[2,3-f][1,4]diazepine-3-carboxylic acid hydrazide as colourless needles of m.p. >260°.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[C:10]3=[O:17])=[C:5]([CH3:18])[O:4][N:3]=1.[N:19]1([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[Mg]Br)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.[Cl-].[NH4+]>C1COCC1>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[C:10]3([OH:17])[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[CH2:25][N:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)=[C:5]([CH3:18])[O:4][N:3]=1
Reactant: Br[Mg]c1ccccc1CN1CCOCC1
Reactant: Cc1noc(C)c1-c1ccc2c(c1)C(=O)C(=O)N2
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1noc(C)c1-c1ccc2c(c1)C(O)(c1ccccc1CN1CCOCC1)C(=O)N2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-(3,5-Dimethyl-isoxazol-4-yl)-1H-indole-2,3-dione (100 mg, 0.41 mmol) is dissolved in anhydrous THF (1 mL) and cooled to 0° C. (2-(4-Morpholinylmethyl)phenyl)magnesium bromide (4.0 mL, 1.0 mmol) is added dropwise and then the mixture stirred at room temperature for 2 hours. The mixture is poured onto saturated aqueous ammonium chloride solution. The aqueous phase is extracted with ethyl acetate. The organic phase is dried over magnesium sulfate. The solvent is concentrated to dryness and purified using column chromatography on silica gel using a cyclohexane/ethyl acetate gradient. The product fractions are combined and concentrated to dryness in vacuo.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:9]1[C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1>C(OC(=O)C)(=O)C>[CH:1](=[C:17]1[C:18]2[N:9]=[CH:10][CH:11]=[CH:12][C:13]=2[CH2:14][CH2:15][CH2:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: c1cnc2c(c1)CCCC2
Solvent: CC(=O)OC(C)=O
Product: C(=C1CCCc2cccnc21)c1ccccc1
Yield: 57.6 %

Procedure:
Benzaldehyde (3.59 mL, 35.30 mmole) was added to a solution of 5,6,7,8-tetrahydro-quinoline (4.70 g, 35.30 mmole) in acetic anhydride (25 mL), and the solution was heated to reflux under a nitrogen atmosphere. After overnight at reflux, the reaction was concentrated in vacuo. The residue was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated. The residue was purified by flash chromatography on silica gel (33% EtOAc/hexanes) to give the title compound (4.50 g, 58%) as a waxy yellow solid after drying in vacuo: MS (ES) m/e 222 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([C:19]3[N:23]([CH3:24])[N:22]=[CH:21][CH:20]=3)=[N:11][N:10]=2)[CH2:5][CH2:4]1.C(N(CC)CC)C.[F:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[C:35]([C:42]([F:45])([F:44])[F:43])[CH:34]=1>C(Cl)Cl>[F:32][C:33]1[CH:41]=[CH:40][C:36]([C:37]([N:2]([CH3:1])[CH:3]2[CH2:4][CH2:5][N:6]([C:9]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]([C:19]4[N:23]([CH3:24])[N:22]=[CH:21][CH:20]=4)=[N:11][N:10]=3)[CH2:7][CH2:8]2)=[O:38])=[C:35]([C:42]([F:45])([F:44])[F:43])[CH:34]=1
Reactant: CNC1CCN(c2nnc(-c3ccnn3C)c3ccccc23)CC1
Reactant: O=C(Cl)c1ccc(F)cc1C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C(=O)c1ccc(F)cc1C(F)(F)F)C1CCN(c2nnc(-c3ccnn3C)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.1 %

Procedure:
Treat a solution of N-methyl-1-(4-(1-methyl-1H-pyrazol-5-yl)phthalazin-1-yl)piperidin-4-amine (2.8 g, 8.68 mmol) and triethylamine (3.36 mL, 26.1 mmol) in CH2Cl2 (30 mL) with 4-fluoro-2-(trifluoromethyl)benzoyl chloride (2.14 mL, 10.42 mmol). Stir for 3 h at ambient temperature. Concentrate the reaction mixture under reduced pressure. Purify the resulting residue by flash silica gel chromatography (hexane:ethyl acetate:2 M NH3 in MeOH=20:5:1) to provide the free base as a yellow foam (3.83 g, 86%). ES/MS m/z 513.0 (M+1).
Reaction SMILES: Br[C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[O:7][CH:6]=[CH:5]2.[CH:16]1(B(O)O)[CH2:18][CH2:17]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=CC=1>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:16]1([C:2]2[C:3]([N+:13]([O-:15])=[O:14])=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8](=[O:12])[O:7][CH:6]=[CH:5]3)[CH2:18][CH2:17]1
Reactant: OB(O)C1CC1
Reactant: O=c1occc2c([N+](=O)[O-])c(Br)ccc12
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=c1occc2c([N+](=O)[O-])c(C3CC3)ccc12

Procedure:
A microwave vial was charged with 6-bromo-5-nitro-1H-isochromen-1-one (500.00 mg, 0.0018516 mol), cyclopropylboronic acid (206.8 mg, 0.002407 mol), palladium acetate (21 mg, 0.000092 mol), tricyclohexylphosphine (52 mg, 0.00018 mol), potassium phosphate (1376 mg, 0.006481 mol), toluene (10 mL, 0.09 mol) and water. The mixture was heated using microwave irradiation at 100° C. for 30 minutes. The rection mixture was then diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried and evaporated. The resultant residue was purified by flash chromatography to afford the product. The product was used as such for the syntheses of 6-cyclopropyl compounds of this invention without further purification.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][CH2:9][C:10]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[O:11])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[C:22](#[N:25])[CH:23]=[CH2:24].[Cl-].[NH4+]>CN(C)C=O>[C:22]([CH2:23][CH2:24][CH:9]([NH:8][C:6](=[O:7])[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:19][CH:18]=1)[C:10]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[O:11])#[N:25]
Reactant: O=C(CNC(=O)c1ccc(F)cc1)c1cccnc1
Reactant: C=CC#N
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: N#CCCC(NC(=O)c1ccc(F)cc1)C(=O)c1cccnc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 83 %

Procedure:
To a solution of 3-[2-(4-fluorobenzoyl)aminoacetyl]-pyridine (500 mg) in N,N-dimethylformamide (10 ml) were added sodium hydride (81.3 mg, 60% mineral oil) and acrylonitrile (113 mg) under dry ice-acetone cooling, and the mixture was stirred at the same temperature under argon atmosphere for 10 minutes. The mixture was warmed slowly to 0° C. and stirred at the same temperature for 30 minutes. To the reaction mixture was added a saturated aqueous ammonium chloride solution and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to obtain a crude product of 4-cyano-2-(4-fluorobenzoylamino)-1-(3-pyridyl)-1-butanone (500 mg).
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=2)[C:11](OS(C(F)(F)F)(=O)=O)=[C:10]([C:27]2[O:31][N:30]=[C:29]([CH3:32])[CH:28]=2)[C:9]1=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:34]([C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1)[CH3:35].C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.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]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=2)[C:11]([C:39]2[CH:40]=[CH:41][C:36]([CH2:34][CH3:35])=[CH:37][CH:38]=2)=[C:10]([C:27]2[O:31][N:30]=[C:29]([CH3:32])[CH:28]=2)[C:9]1=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(-c2c(OS(=O)(=O)C(F)(F)F)c3cc(Cl)ccc3n(Cc3ccccc3)c2=O)on1
Reactant: CCc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCc1ccc(-c2c(-c3cc(C)no3)c(=O)n(Cc3ccccc3)c3ccc(Cl)cc23)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 81.1 %

Procedure:
A mixture of trifluoro-methanesulfonic acid 1-benzyl-6-chloro-3-(3-methyl-isoxazol-5-yl)-2-oxo-1,2-dihydro-quinolin-4-yl ester (40 mg, 0.080 mmol), 4-ethylbenzeneboronic acid (14.4 mg, 0.096 mmol), Pd(PPh3)4 (9.2 mg, 0.0080 mmol) and Na2CO3 (80 ul, 0.16 mmol, 2.0 M)in 1 ml of 1,4-dioxane was stirred at 100° C. for 1 h, then cooled to rt. Treated with 40 ml of EtOAc, the mixture was washed with H2O (2×10 ml), brine (10 mL) and dried (Na2SO4). Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (25% EtOAc/hexane) gave 29.5 mg (81%) of product as a white solid: 1H-NMR (CDCl3; 400 MHz) δ7.41 (dd, 1H, J=9.0, 2.2 Hz), 7.24-7.38 (m, 8H), 7.15 (d, 2H, J=8.0 Hz), 6.48 (s, 1H), 5.64 (s, 2H), 3.71 (s, 1H), 2.74 (q, 2H, J=7.6 Hz), 2.23 (s, 3H), 1.31 (t, 2H, J=7.6 Hz),. Mass spectrum (ESI, m/z): Calcd. for C28H23ClN2O2, 455.1 (M+H), found 455.1.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:9][C:10]([O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1)=[O:11])[CH2:6][CH2:7][CH3:8]>C(Cl)(Cl)(Cl)Cl>[CH2:5]([O:9][C:10]([O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([Cl:3])=[O:18])=[CH:15][CH:14]=1)=[O:11])[CH2:6][CH2:7][CH3:8]
Reactant: O=S(Cl)Cl
Reactant: CCCCOC(=O)Oc1ccc(C(=O)O)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCOC(=O)Oc1ccc(C(=O)Cl)cc1

Procedure:
On the other hand, 15 ml of carbon tetrachloride (solvent) and 3 ml of thionyl chloride were added to 2.16 g (0.0158 mol) of 4-n-butoxycarbonyloxy benzoic acid, and the mixture was heated and refluxed. After sufficiently reacting them, excess thionyl chloride and carbon tetrachloride (solvent) were distilled off under reduced pressure to obtain 4-butoxycarbonyloxy benzoic acid chloride (one having Formula 7 wherein R2 is a n-butyl group).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:10][C:11]1[CH:12]=[C:13]([CH:26]=[C:27]([O:29][CH2:30][CH2:31][C:32]2[S:36][CH:35]=[N:34][C:33]=2[CH3:37])[CH:28]=1)[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([OH:25])=[O:24])=[CH:19][N:18]=1)=[O:15].C([BH3-])#N.[Na+]>CO>[CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH:10][C:11]1[CH:12]=[C:13]([CH:26]=[C:27]([O:29][CH2:30][CH2:31][C:32]2[S:36][CH:35]=[N:34][C:33]=2[CH3:37])[CH:28]=1)[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([OH:25])=[O:24])=[CH:19][N:18]=1)=[O:15]
Reactant: Cc1ccccc1C=O
Reactant: Cc1ncsc1CCOc1cc(N)cc(C(=O)Nc2ccc(C(=O)O)cn2)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Cc1ccccc1CNc1cc(OCCc2scnc2C)cc(C(=O)Nc2ccc(C(=O)O)cn2)c1
Reaction time: 40 h
Yield: 96 %

Procedure:
2-Methylbenzaldehyde (0.035 ml, 0.3 mM) was added to a solution of 2-[3-amino-5-(4-methyl-thiazol-5-yl) ethoxy benzoyl]amino-5-pyridine carboxylic acid (0.10 g 0.25 mM) and 4A molecular sieves (0.25 g) in methanol (15 ml), under an inert atmosphere at room temperature. After 1 hr sodium cyanoborohydride (0.019 g, 0.3 mM) was added and the reaction mixture stirred for 40 hrs. The reaction mixture was filtered, concentrated in vacuo, 2M NaOH added to pH=11–12 then acidified with 2M HCl to precipitate a colourless solid. The solid was filtered, washed with water to give the title compound as a colourless solid (0.12 g, 96%); 1H NMR δ (d6-DMSO): 2.33 (m, 6H), 3.19 (dd, 2H), 4.13 (dd, 2H), 4.26 (s, 2H), 6.33 (s, 1H), 6.83 (s, 1H), 6.90 (s, 1H), 7.09–7.19 (m, 3H), 7.26 (s, 1H), 8.28 (s, 2H), 8.83 (s, 1H), 8.88 (s, 1H), 10.87 (s, 1H), 13.09 (bs, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][N:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]2=[O:18])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[N+:19]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)([O-:21])=[O:20].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CCOCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C(O)C.C(COC)OC>[CH3:9][O:8][C:7]1[C:2]([C:26]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:19]([O-:21])=[O:20])[CH:27]=2)=[CH:3][C:4]([CH2:10][CH2:11][N:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]2=[O:18])=[CH:5][CH:6]=1
Reactant: COc1ccc(CCn2ccccc2=O)cc1Br
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Solvent: CCO
Product: COc1ccc(CCn2ccccc2=O)cc1-c1cccc([N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 18 h
Yield: 31.1 %

Procedure:
Into a 40 mL vial were added 1-[2-(3-bromo-4-methoxy-phenyl)-ethyl]-1H-pyridin-2-one (I-166, 210 mg, 0.68 mmol), 3-nitrophenylboronic acid (125 mg, 0.75 mmol), PPh3 (36 mg, 0.014 mmol), potassium carbonate (283 mg, 2.04 mmol), dimethoxyethane (10 mL), ethanol (1 mL), and water (1 mL). The suspension was degassed with N2 for 5 minutes and then palladium(II) acetate (15 mg, 0.068 mmol). After degassing for an additional 2 minutes the reaction was stirred at 80° C. for 18 hours. To the reaction was added 5 mL of water and 10 mL of ethyl acetate. The layers were separated and the aqueous was extracted with ethyl acetate (3×10 mL). The organics were combined and concentrated. The residue was purified by flash column chromatography eluting with 10-20% acetone/dichloromethane. The yellow oil which was obtained (136 mg) was dissolved in 1 mL of ether and allowed to stand at room temperature for 3 days. The tan solid which formed was filtered, washed with ether, and dried to afford 74 mg of P-244 in 31% yield. 1H NMR (400 MHz, CDCl3) δ 8.30-8.29 (m, 1H), 8.18-8.15 (m, 1H), 7.81-7.79 (m, 1H), 7.54 (t, J=8.0 Hz), 7.37-7.33 (m, 1H), 7.19 (dd, J=8.2, 2.2 Hz, 1H), 7.05 (d, J=2.4 Hz, 1H), 6.95-6.93 (m, 2H), 6.61 (d, J=9.2 Hz, 1H), 6.06 (td, J=6.6, 1.2 Hz, 1H), 4.15 (t, J=7.0 Hz, 2H), 3.82 (s, 3H), 3.07 (t, J=7.0 Hz, 2H) ppm. LC/MS=99.4%, 351.6 (ESI+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]=[C:12]=[S:13])=[O:10])=[CH:4][CH:3]=1.[NH2:14][C:15]1[CH:43]=[CH:42][C:18]([O:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27]([N:29]3[CH2:34][CH2:33][CH:32]([N:35]4[CH2:40][CH2:39][CH:38]([OH:41])[CH2:37][CH2:36]4)[CH2:31][CH2:30]3)=[O:28])[CH:21]=2)=[CH:17][CH:16]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1(C)C=CC=CC=1.C(O)C>[OH:41][CH:38]1[CH2:39][CH2:40][N:35]([CH:32]2[CH2:33][CH2:34][N:29]([C:27]([NH:26][C:22]3[CH:21]=[C:20]([O:19][C:18]4[CH:17]=[CH:16][C:15]([NH:14][C:12]([NH:11][C:9](=[O:10])[CH2:8][C:5]5[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=5)=[S:13])=[CH:43][CH:42]=4)[CH:25]=[CH:24][N:23]=3)=[O:28])[CH2:30][CH2:31]2)[CH2:36][CH2:37]1
Reactant: O=C(Cc1ccc(F)cc1)N=C=S
Reactant: Nc1ccc(Oc2ccnc(NC(=O)N3CCC(N4CCC(O)CC4)CC3)c2)cc1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=C(Cc1ccc(F)cc1)NC(=S)Nc1ccc(Oc2ccnc(NC(=O)N3CCC(N4CCC(O)CC4)CC3)c2)cc1
Reaction time: 4 h
Yield: 19 %

Procedure:
After adding a solution of 2-(4-fluorophenyl)acetyl isothiocyanate in toluene (0.25 M, 3.0 ml) to a solution of 4-(4-aminophenoxy)-2-{[4-(4-hydroxypiperidin-1-yl)piperidin-1-yl]carbonylamino}pyridine (214 mg) and (+)-10-camphorsulfonic acid (105 mg) in ethanol (4.0 ml) at room temperature, the mixture was stirred for 4 hours. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate and brine and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate:methanol=100:0 to 97:3) to provide the title compound (58.6 mg, 19%) as white powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18](Br)[CH:17]=1)[C:10]([CH3:24])([CH3:23])[CH2:9]2)=[O:5])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.Cl.[Cl:74][C:75]1[CH:80]=[CH:79][C:78]([N:81]2[CH2:86][CH2:85][NH:84][CH2:83][CH2:82]2)=[CH:77][CH:76]=1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:84]3[CH2:83][CH2:82][N:81]([C:78]4[CH:77]=[CH:76][C:75]([Cl:74])=[CH:80][CH:79]=4)[CH2:86][CH2:85]3)[CH:17]=1)[C:10]([CH3:24])([CH3:23])[CH2:9]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(Br)c1)N2
Reactant: Clc1ccc(N2CCNCC2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(N3CCN(c4ccc(Cl)cc4)CC3)c1)N2
Temperature: 120 °C
Reaction time: 12 h
Yield: 39.7 %

Procedure:
To a mixture of 2-(3-bromo-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (388 mg, 1 mmol), palladium acetate (6.73 mg, 0.03 mmol), cesium carbonate (0.65 g, 2 mmol), xantphos (23 mg, 0.04 mmol) and 1-(4-chloro-phenyl)-piperazine hydrochloride (350 mg, 1.5 mmol) in toluene (10 mL) was stirred at 120° C. for 12 hours. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×100 mL), washed with saturated aqueous sodium chloride (2×50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. Purification on flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company)(20% ethyl acetate/hexanes) to afford 2-{3-[4-(4-chloro-phenyl)-piperazin-1-yl]-phenyl}-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.20 g, 40%) as a white solid: LC/MS m/e calcd for C30H34ClN3O2 M+: 504.08, observed: 504.2.
Reaction SMILES: C[O:2][C:3]1[CH:11]=[CH:10][C:9]([S:12](=[O:15])(=[O:14])[NH2:13])=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].Br.C(O)(=O)C>C(OC(=O)C)C.CO>[NH2:13][S:12]([C:9]1[CH:10]=[CH:11][C:3]([OH:2])=[C:4]([CH:8]=1)[C:5]([OH:7])=[O:6])(=[O:14])=[O:15]
Reactant: COc1ccc(S(N)(=O)=O)cc1C(=O)O
Agent: Br
Solvent: CC(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: NS(=O)(=O)c1ccc(O)c(C(=O)O)c1
Reaction time: 8 h

Procedure:
A mixture of 2-methoxy-5-sulfamoylbenzoic acid (58 g, 0.25 mole), 48% hydrobromic acid (150 ml), and acetic acid (150 ml) was heated to reflux for five hours. The progress of reaction was checked by thin layer chromatography (silica gel, 7:2:1 ethylacetate/methanol/29% ammonium hydroxide). Upon cooling, a solid crystallized out which was collected by filtration, and rinsed with cold water. This solid was dissolved in hot water (≤85° C.) and filtered through Celite® and recrystallized from the cool filtrate. Some of the recrystallized material was crystallized once more by dissolving in methanol, filtering, and mixing with excess amount of 1,1,1-trichloroethane. The mixture was evaporated to remove most of the methanol, and the resulting crystallizing mixture was stirred in ice bath. The solid was collected by filtration and rinsed with 1,1,1-trichloroethane, vacuum pumped at room temperature overnight to give a white solid, mp 234°-235° C.