Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]([CH3:24])[C:6]([C:8]1[CH:9]=[C:10]([C:21](O)=[O:22])[CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[CH:13]=1)=[O:7])[CH:2]([CH3:4])[CH3:3].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[F:48][C:49]([F:60])([F:59])[C:50]1[N:55]=[CH:54][C:53]([C@H:56]([NH2:58])[CH3:57])=[CH:52][CH:51]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH2:1]([N:5]([CH3:24])[C:6]([C:8]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[CH:11]=[C:10]([C:21]([NH:58][C@@H:56]([C:53]2[CH:54]=[N:55][C:50]([C:49]([F:59])([F:48])[F:60])=[CH:51][CH:52]=2)[CH3:57])=[O:22])[CH:9]=1)=[O:7])[CH:2]([CH3:4])[CH3:3]
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)N(C)CC(C)C)c2)cc1
Reactant: C[C@@H](N)c1ccc(C(F)(F)F)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(-c2cc(C(=O)N[C@H](C)c3ccc(C(F)(F)F)nc3)cc(C(=O)N(C)CC(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 5-(isobutyl(methyl)carbamoyl)-4′-methylbiphenyl-3-carboxylic acid (21 mg, 0.064 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (25 mg, 0.13 mmol), 1-hydroxybenzotriazole hydrate (9.9 mg, 0.064 mmol), and CH2Cl2 (3 mL) were added (R)-1-(6-(trifluoromethyl)pyridin-3-yl)ethanamine (18 mg, 0.097 mmol) (WO 2008/130481) and N,N-diisopropylethylamine (17 μL, 0.097 mmol). The mixture was stirred at room temperature overnight, and then concentrated in vacuo. The residue was purified by preparative HPLC (100×21.2 mm C18 column, 40-80% MeCN/water[10 mM Et2NH]) to afford a white foam.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][O:11][C@@H:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9]1)=O)(C)(C)C>Cl.O1CCOCC1>[C:14]1([C@@H:10]2[O:11][CH2:12][CH2:13][NH:8][CH2:9]2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccccc2)C1
Agent: Cl
Solvent: C1COCCO1
Product: c1ccc([C@H]2CNCCO2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.8 %

Procedure:
1.280 g (S)-2-Phenyl-morpholine-4-carboxylic acid tert-butyl ester was dissolved in 31 mL 4N HCl in dioxane and stirred at room temperature overnight. Concentrated in vacuo and diluted with 1N HCl. The aqueous was extracted with ether and then basicified to pH 12-14 with 2N NaOH followed by extraction with DCM. The organic layers were dried over Na2SO4, filtered and concentrated in vacuo to afford 617 mg of product by H NMR. 78% yield.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]=[N+:14]=[N-:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:16]#[C:17][CH2:18][CH3:19]>C(O)C.CCCCCC.C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]2[C:18]([CH3:19])=[C:17]([CH3:16])[N:15]=[N:14]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=NC1CCN(Cc2ccccc2)C1
Reactant: C#CCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCO
Product: Cc1nnn(C2CCN(Cc3ccccc3)C2)c1C

Procedure:
To a solution of N-benzyl-3-azidopyrrolidine (2.02 g, 0.01 mole) in 30 ml of 98% ethanol was added 15 ml of butyne and heated in a sealed steel reaction vessel at 105°-110° C. for 24 hr. Removal of the solvent under reduced pressure afforded 2.55 g of the crude which contained 50% starting material. Chromatography over silica gel using hexane/ethyl acetate (1:1) as solvent yielded 0.88 g of the desired product. 1H NMR (CDCl3) δ: 7.36-7.2 (m, 5H), 4.95-4.8 (m, 1H), 3.7 (S, 2H), 3.2-3.1 (m, 1H), 2.93-2.76 (m, 3H), 2.48-2.3 (m, 2H), 2.24 (s, 3H), 2.21 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][C:28]=1[N+:29]([O-:31])=[O:30])[C:6]([N:8]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=1[O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=O)[CH3:9])=[O:7].[CH3:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(OCC)(=O)C.C(Cl)(Cl)Cl.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][C:28]=1[N+:29]([O-:31])=[O:30])[C:6]([N:8]([CH3:9])[C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=1[O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([N:36]1[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]1)=[O:25])=[O:7]
Reactant: CN1CCNCC1
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)O)ccc1[N+](=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.1 %

Procedure:
3-Methoxy-4-nitro-N-[2-(5-carboxypent-1-yloxy)-4-methylphenyl]-N-methylbenzamide (5.2 g), 1-methylpiperazine (1.45 g) and 1-hydroxybenzotriazole (1.96 g) were dissolved in N,N-dimethylformamide (50 ml) and the solution was cooled in an ice bath. To the mixture was added N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide hydrochloride (2.78 g) and the solution was stirred at the same temperature for 30 minutes. The reaction mixture was allowed to warm to ambient temperature and stirring was continued for additional 20 hours. The reaction mixture was diluted with ethyl acetate and the solution was washed successively with saturated sodium hydrogen carbonate and brine, and dried over sodium sulfate. The sodium sulfate was removed and the solvent was removed by evaporation to give oil. The crude material was subjected to a silica gel column chromatography (SiO2 ; 120 g, 2% methanol in chloroform) to give 3-methoxy-4-nitro-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-ylcarbonyl)pent-1-yloxy]phenyl]benzamide (6.2 g).
Reaction SMILES: Cl.[C:2]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:15](=[O:16])[CH:14]=[C:13]([O:17][CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:12]([C:24]#[N:25])=[N:11]2)=[CH:6][C:5]=1[F:26])#[N:3].[C:27](Cl)(=[O:32])[O:28][CH:29]([CH3:31])[CH3:30]>C(Cl)Cl>[C:24]([C:12]1[C:13]([O:17][CH:18]2[CH2:19][CH2:20][N:21]([C:27]([O:28][CH:29]([CH3:31])[CH3:30])=[O:32])[CH2:22][CH2:23]2)=[CH:14][C:15](=[O:16])[N:10]([C:7]2[CH:8]=[CH:9][C:4]([C:2]#[N:3])=[C:5]([F:26])[CH:6]=2)[N:11]=1)#[N:25]
Reactant: CC(C)OC(=O)Cl
Reactant: N#Cc1ccc(-n2nc(C#N)c(OC3CCNCC3)cc2=O)cc1F
Agent: Cl
Solvent: ClCCl
Product: CC(C)OC(=O)N1CCC(Oc2cc(=O)n(-c3ccc(C#N)c(F)c3)nc2C#N)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
To a stirring solution of 1-(4-cyano-3-fluorophenyl)-6-oxo-4-(piperidin-4-yloxy)-1,6-dihydropyridazine-3-carbonitrile HCl salt (Example 36, step A) (19 mg, 0.05 mmol) in DCM (3 mL) at room temperature under argon was added TEA (0.014 mL, 0.10 mmol) and isopropyl carbonochloridate (12 mg, 0.10 mmol). The reaction mixture was stirred at room temperature overnight. Solvent was removed in vacuo and the crude product was dissolved in a small amount of DCM (˜2 ml) and loaded onto a 40 g ISCO silica gel column which was eluted with a 20 min gradient from 0% to 100% EtOAc/Hexanes. 15 mg (43%) of isopropyl 4-(3-cyano-1-(4-cyano-3-fluorophenyl)-6-oxo-1,6-dihydropyridazin-4-yloxy)piperidine-1-carboxylate was obtained as white solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.72-7.81 (1H, m), 7.56-7.72 (2H, m), 6.30 (1H, s), 4.82-5.04 (1H, m, J=6.6, 6.3, 6.2, 6.2 Hz), 4.65 (1H, ddd, J=7.0, 3.4, 3.3 Hz), 3.65-3.84 (2H, m), 3.37-3.61 (2H, m), 1.96-2.12 (2H, m), 1.81-1.96 (2H, m), 1.13-1.33 (6H, m). MS (ESI) 426 (M+H).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=O.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:28])[CH2:24][C:25](=[O:27])[CH3:26])=[CH:19][CH:18]=1.C(O)(=O)C.N1CCCCC1>ClCCl>[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([C:23](=[O:28])[C:24](=[CH:13][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[O:3][C:2]([CH3:1])=[CH:11][C:10]3=[O:12])[C:25](=[O:27])[CH3:26])=[CH:21][CH:22]=1
Reactant: Cc1cc(=O)c2cccc(C=O)c2o1
Reactant: COc1ccc(C(=O)CC(C)=O)cc1
Solvent: C1CCNCC1
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccc(C(=O)C(=Cc2cccc3c(=O)cc(C)oc23)C(C)=O)cc1

Procedure:
250 mg (1.32 mmol) of 2-methyl-4-oxo-4H-chromene-8-carbaldehyde are dissolved with 281 mg (1.46 mmol) of 1-(4-methoxyphenyl)butane-1,3-dione, 100 mg (1.66 mmol) of acetic acid and 11 mg (0.13 mmol) of piperidine in 5 ml of dichloromethane and, after addition of molecular sieves, heated under reflux under argon for 4 h. The solvent is removed after filtration in vacuo. 480 mg (99% of theory) of the title compound are obtained and are employed without further purification in the next stage.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12](Br)[CH:13]=2)[N:8]([CH3:16])[CH:7]=1)=[O:5])[CH3:2].[CH3:17][C:18]1(C)C(C)(C)OB(C=C)O1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH:17]=[CH2:18])[CH:13]=2)[N:8]([CH3:16])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(C)c2ccc(Br)cc12
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1CCOC1
Solvent: O
Product: C=Cc1ccc2c(c1)c(C(=O)OCC)cn2C
Temperature: 75 °C
Reaction time: 4 h
Yield: 95.8 %

Procedure:
To a solution of 5-bromo-1-methyl-1H-indole-3-carboxylic acid ethyl ester (1.2 g) described in Reference Example 52 (2) in tetrahydrofuran (14 ml) were added 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (983 mg), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (S-Phos) (349 mg), palladium acetate (96 mg) and tripotassium phosphate (2.26 g) at room temperature, and stirred at 75° C. for 4 hours. After completion of the reaction, the mixture was cooled to room temperature, water was added thereto, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated. The obtained residue was purified with silica gel column chromatography (n-hexane/ethyl acetate) to give 1-methyl-5-vinyl-1H-indole-3-carboxylic acid ethyl ester (934 mg) as a yellow solid.
Reaction SMILES: [CH2:1]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19]([OH:22])(=O)=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(OCC)(=O)C.P(Cl)(Cl)([Cl:31])=O.[Cl-].[Na+]>O.CN(C)C=O>[CH2:1]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19]([Cl:31])(=[O:22])=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCCCCCCCCCc1ccccc1S(=O)(=O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCc1ccccc1S(=O)(=O)Cl
Reaction time: 0.17 h

Procedure:
To a solution composed of 32.7 g (0.1 mol) of dodecylbenzenesulfonic acid, 80 ml of ethyl acetate, and 12 ml of dimethylformamide (DMF) was added dropwise 12.4 ml (0.15 mol) of phosphorus oxychloride with stirring over a period of 10 minutes and then while heating the mixture so as to maintain the temperature thereof at 40° C., the reaction was performed for 60 minutes. After the reaction was over, the reaction mixture was cooled to 5° to 10° C. and then a solution composed of 16 g of sodium chloride and 160 ml of water was added dropwise to the reaction mixture over a period of 15 minutes. After removing an aqueous layer, an ethyl acetate layer thus formed was washed once with 100 ml of an aqueous 10% sodium chloride solution. The ethyl acetate solution of dodecylbenzenesulfonyl chloride obtained was used for the subsequent reaction as it was.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[S:23][C:22]([C:24]3([OH:34])[CH2:33][CH2:32][C:27]4(OCC[O:28]4)[CH2:26][CH2:25]3)=[N:21][CH:20]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1.[N-:35]=[N+]=[N-].[Na+].CS(O)(=O)=O.O>C(Cl)(Cl)Cl>[OH:34][C:24]1([C:22]2[S:23][C:19]([C:4]3[CH:5]=[C:6]([NH:8][C:9]4[N:14]=[C:13]([C:15]([F:17])([F:16])[F:18])[CH:12]=[CH:11][N:10]=4)[CH:7]=[C:2]([CH3:1])[CH:3]=3)=[CH:20][N:21]=2)[CH2:33][CH2:32][NH:35][C:27](=[O:28])[CH2:26][CH2:25]1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(O)CCC4(CC3)OCCO4)s2)c1
Agent: CS(=O)(=O)O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(O)CCNC(=O)CC3)s2)c1
Temperature: 65 °C
Yield: 63.9 %

Procedure:
A mixture of 8-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]-1,4-dioxaspiro[4.5]decan-8-ol (60 mg, 0.122 mmol), sodium azide (23.76 mg, 0.365 mmol) and methanesulfonic acid (95 μL, 1.462 mmol) in CHCl3 (1.2 mL) was heated at 65° C. for 1 h and cooled to room temperature. The mixture was treated with water, and extracted with ethyl acetate. The combined organics were dried, filtered, concentrated and purified by flash chromatography to afford 5-hydroxy-5-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]azepan-2-one (36 mg, 0.078 mmol). APCI: [M+H]+ m/z 464.2. 1H NMR (600 MHz, CDCl3): δ 8.63 (d, J=4.9, 1H), 7.89 (s, 1H), 7.83 (s, 1H), 7.62 (s, 1H), 7.26 (s, 1H), 7.05 (s, 1H), 7.03 (d, J=4.9, 1H), 6.21 (s, 1H), 3.81 (s, 1H), 3.46 (s, 1H), 3.21-3.03 (m, 2H), 2.41 (dd, J=7.5, 14.4, 1H), 2.37 (s, 3H), 2.24 (t, J=13.3, 1H), 2.18-2.04 (m, 3H). rhSYK activity=+++
Reaction SMILES: CN(C)C(=O)C.[F:7][C:8]1[CH:26]=[CH:25][C:11]([NH:12][C:13]2[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:14]=2[C:15]([OH:17])=[O:16])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:34]([CH3:37])([CH3:36])[CH3:35]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(OCC)(=O)C.O>[F:7][C:8]1[CH:26]=[CH:25][C:11]([NH:12][C:13]2[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:14]=2[C:15]([O:17][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:16])=[CH:10][CH:9]=1
Reactant: CC(C)(C)Br
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1Nc1ccc(F)cc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc([N+](=O)[O-])cc1Nc1ccc(F)cc1
Temperature: 55 °C
Reaction time: 4 h

Procedure:
To N,N-dimethylacetamide 15 mL solution of 2-(4-fluoroanilino)-4-nitrobenzoic acid 1.0 g, were added potassium carbonate 9.9 g, benzyltriethylammonium chloride 0.82 g and 2-bromo-2-methylpropane 21 mL at room temperature, and it was stirred at 55° C. for 4 hours. After the reaction mixture was cooled to room temperature,2-bromo-2-methylpropane 21 mL was added to it, and it was stirred at 55° C. for 12 hours. After the reaction mixture was cooled to room temperature, water and ethyl acetate were added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after sequential washing with water and 10% citric acid aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [eluent; hexane:ethyl acetate=8:1] to give tert-butyl 2-(4-fluoroanilino)-4-nitrobenzoate 1.1 g of red oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[CH:12][C:11]([C:14]([NH:16][CH:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH:35]=[CH:34][C:26]([C:27]([O:29]C(C)(C)C)=[O:28])=[CH:25][N:24]=4)[CH2:19][CH2:18]3)=[O:15])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(Cl)Cl.C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[CH:12][C:11]([C:14]([NH:16][CH:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH:35]=[CH:34][C:26]([C:27]([OH:29])=[O:28])=[CH:25][N:24]=4)[CH2:19][CH2:18]3)=[O:15])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N2CCC(NC(=O)c3ccc(-c4cccc(F)c4)nc3)CC2)nc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(N2CCC(NC(=O)c3ccc(-c4cccc(F)c4)nc3)CC2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a round-bottom flask containing tert-butyl 6-[4-({[6-(3-fluorophenyl)pyridin-3-yl]carbonyl}amino)piperidin-1-yl]nicotinate was added DCM (50 mL) and TFA (18 mL). After stirring at rt overnight the reaction was diluted with toluene (10 mL) and the solvent removed to give 6-[4-({[6-(3-fluorophenyl)pyridin-3-yl]carbonyl}amino)piperidin-1-yl]nicotinic acid, as a white solid (30 mg, 78%). 1H NMR (400 MHz, DMSO-d6) □ ppm 9.06 (1H, s), 8.62 (1H, s), 8.47 (1H, d, J=7.9 Hz), 8.22-8.32 (1H, m), 8.10 (1H, d, J=8.1 Hz), 7.85-8.01 (3H, m), 7.47-7.60 (1H, m), 7.29 (1H, t, J=7.8 Hz), 6.89 (1H, d, J=9.3 Hz), 4.42 (2H, d, J=13.2 Hz), 3.10 (2H, t, J=12.7 Hz), 2.33-2.54 (2H, m), 1.91 (2 h, d, J=13.2 Hz), 1.41-1.63 (2H, m). HRMS (TOF, ES+) calculated: 421.1676; observed 421.1722.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([C:17]([C:19]2[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([O:27][CH3:28])[CH:20]=2)=O)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(OP([CH2:37][C:38]#[N:39])(=O)OCC)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].O1C2C=CC(C(C3C=C(OC)C=C(OC)C=3)=CC#N)=CC=2OCC1>C1COCC1>[C:4]([Si:1]([CH3:2])([CH3:3])[O:8][C:9]1[CH:10]=[C:11]([C:17]([C:19]2[CH:20]=[C:21]([O:27][CH3:28])[CH:22]=[C:23]([O:25][CH3:26])[CH:24]=2)=[CH:37][C:38]#[N:39])[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])([CH3:6])([CH3:5])[CH3:7]
Reactant: COc1cc(OC)cc(C(=O)c2ccc(OC)c(O[Si](C)(C)C(C)(C)C)c2)c1
Reactant: CCOP(=O)(CC#N)OCC
Agent: COc1cc(OC)cc(C(=CC#N)c2ccc3c(c2)OCCO3)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(OC)cc(C(=CC#N)c2ccc(OC)c(O[Si](C)(C)C(C)(C)C)c2)c1
Yield: 74.1 %

Procedure:
[3-(tert-butyldimethylsilanyloxy)-4-methoxyphenyl]-(3,5-dimethoxyphenyl) methanone (0.74 g, 1.84 mmol), cyanomethylphosphonic acid diethyl ester (0.58 ml, 3.68 mmol) in anhydrous THF (10 ml), and lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 3.70 ml, 3.68 mmol) were treated in the same manner as described above for the synthesis of 3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-3-(3,5-dimethoxyphenyl)-acrylonitrile. The crude was purified via flash column chromatography (100% hexane gradient to 20% EtOAc in hexane in about 40 min.) to give 3-[3-(tert-butyl-dimethyl-silanyloxy)-4-methoxy-phenyl]-3-(3,5-dimethoxy-phenyl)-acrylonitrile as an clear colorless oil (0.58 g, 74%): 1HNMR (CDCl3) δ 7.09-6.78 (m, 3H, Ar), 6.53-6.51 (m, 2H, Ar), 6.41 (d, J=2 Hz, 1H, Ar), 5.60 (s, 1H, CH), 3.86-3.76 (multiple singlets, 9H), 0.97 (s, 9H, 3OCH3), 0.14 (s, 6H, 2OCH3). The product was carried over to the next step.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[N:6]([CH3:21])[C:7](/[CH:9]=[CH:10]/[C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=3)=[N:8][C:4]=2[CH:3]=1.BrC1C=CC2N=C(/C=C/C3C=CC(C(F)(F)F)=CC=3)N(C)C=2C=1.[CH3:47][S:48]([NH:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=1B(O)O)(=[O:50])=[O:49]>>[CH3:21][N:6]1[C:5]2[CH:22]=[C:23]([C:53]3[CH:54]=[CH:55][CH:56]=[CH:57][C:52]=3[NH:51][S:48]([CH3:47])(=[O:50])=[O:49])[CH:2]=[CH:3][C:4]=2[N:8]=[C:7]1/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:13][CH:12]=1
Reactant: Cn1c(/C=C/c2ccc(C(F)(F)F)cc2)nc2cc(Br)ccc21
Reactant: CS(=O)(=O)Nc1ccccc1B(O)O
Agent: Cn1c(/C=C/c2ccc(C(F)(F)F)cc2)nc2ccc(Br)cc21
Product: Cn1c(/C=C/c2ccc(C(F)(F)F)cc2)nc2ccc(-c3ccccc3NS(C)(=O)=O)cc21

Procedure:
Using the procedure of Example 1, Step B, the title compounds were prepared from a mixture of (E)-5-bromo-1-methyl-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazole and (E)-6-bromo-1-methyl-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazole and 2-methylsulfonylaminophenyl boronic acid.
Reaction SMILES: [NH2:1][C@H:2]([CH2:8][CH2:9][S:10][CH3:11])[CH:3]([OH:7])[C:4]([OH:6])=[O:5].C(N(CC)CC)C.[C:19]([O:23][C:24](ON=C(C1C=CC=CC=1)C#N)=[O:25])([CH3:22])([CH3:21])[CH3:20]>O1CCOCC1>[C:19]([O:23][C:24]([NH:1][C@H:2]([CH2:8][CH2:9][S:10][CH3:11])[CH:3]([OH:7])[C:4]([OH:6])=[O:5])=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: CSCC[C@@H](N)C(O)C(=O)O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CSCC[C@@H](NC(=O)OC(C)(C)C)C(O)C(=O)O
Temperature: 25 °C
Yield: 46.4 %

Procedure:
A solution of Example 1C (2.68 g, 12.5 mmol), triethylamine (3.47 ml, 75.0 mmol), and 2-(tert-butyoxycarbonyloxyimino)-2-phenylacetonitrile (3.22 g, 13.0 mmol) in 30% aqueous dioxane was heated to 50° C. for 6 hours, cooled to ambient temperature, and concentrated. The residue was diluted with aqueous sodium hydroxide (0.25M, 50 mL) and extracted twice with ethyl acetate. The aqueous layer was acidified to pH 3 with 1M H3PO4 and extracted five times with chloroform. The combined extracts were washed with brine, dried (MgSO4), filtered, and concentrated to provide the desired product (1.62 g). MS (ESI) m/e 278 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:30](=[O:31])[CH2:29][C:28](=[O:32])[NH:27][C:26]3[C:33]4[C:38]([CH:39]=[CH:40][C:25]2=3)=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:20][CH:19]=1.C(=O)([O-])O.[Na+]>ClCCl.C(N(CC)CC)C.O1CCCC1.CN(C=O)C>[Cl:1][C:2]1[C:3]([C:4]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[C:30](=[O:31])[CH2:29][C:28](=[O:32])[NH:27][C:26]4[C:33]5[C:38]([CH:39]=[CH:40][C:25]3=4)=[CH:37][CH:36]=[CH:35][CH:34]=5)=[CH:20][CH:19]=2)=[O:6])=[CH:7][CH:8]=[CH:9][N:10]=1
Reactant: O=C(O)c1cccnc1Cl
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C1CC(=O)N(c2ccc(NC(=O)c3cccnc3Cl)cc2)c2ccc3ccccc3c2N1
Temperature: 25 °C
Reaction time: 20 h
Yield: 61.3 %

Procedure:
2-Chloronicotinic acid (63 mg, 0.4 mmol) was suspended in dry dichloromethane (2 mL), the suspension was added with DMF (0.08 mL) and oxalyl dichloride (0.05 mL, 0.6 mmol), and the mixture was stirred at room temperature for 20 hours. The solvent was evaporated under reduced pressure, and the residue was concentrated twice from dry dichloromethane (1 mL) under reduced pressure. The resultant was added with 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (63 mg, 0.2 mmol) obtained in Example 1, (3), dry tetrahydrofuran (4 mL) and triethylamine (0.11 mL), and the mixture was stirred at room temperature for 22 hours, and then refluxed by heating for 4 hours. This reaction mixture was added with saturated aqueous sodium hydrogencarbonate, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was recrystallized from chloroform to obtain the title compound (56 mg, yield 60%) as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]2[CH2:14][CH2:13][CH2:12][C:11](=[C:15]([CH3:17])[CH3:16])[S:10]2)=[CH:4][CH:3]=1.C([N-]C(C)C)(C)C.[Li+].[CH:26](OCC)=[O:27].[Cl-].[NH4+]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:10][C:11](=[C:15]([CH3:17])[CH3:16])[CH2:12][CH2:13][C:14]=2[CH:26]=[O:27])=[CH:4][CH:3]=1
Reactant: CC(C)=C1CCCC(=Nc2ccc(Cl)cc2)S1
Reactant: CCOC=O
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)=C1CCC(C=O)=C(Nc2ccc(Cl)cc2)S1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 37 %

Procedure:
In a dehydrated tetrahydrofuran (20 ml) solution of (4-chloro-phenyl)-[6-isopropylidene-tetrahydro-thiopyran-2-ylidene]-amine (1.1 g), 3.6 ml of lithium diisopropylamide (1.5 mol/l, tetrahydrofuran/cyclohexane solution) was added dropwise at −78° C. under a nitrogen atmosphere. After stirring at −78° C. for 30 minutes, a tetrahydrofuran (2 ml) solution of ethyl formate (0.39 g) was added dropwise. After raising the temperature to room temperature and further stirring for 1 hour, an aqueous saturated ammonium chloride solution was added and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 0.45 g of the target compound.