Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[C:5](=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=1)[NH2:6].C(N(CC)CC)C.[C:22]([C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23]>C(Cl)Cl.[Cl-].[Na+].O>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:5]=1[NH:6][C:30](=[O:31])[C:29]1[CH:33]=[CH:34][C:26]([C:22]([CH3:24])([CH3:23])[CH3:25])=[CH:27][CH:28]=1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1N
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccc([N+](=O)[O-])cc1NC(=O)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a solution of 4-nitro-anthranilic acid methyl ester (5.060 g, 25.8 mmol) in CH2Cl2 (200 mL) was added triethylamine (8 mL) and 4-tert-butyl benzoyl chloride and the reaction was stirred overnight at rt. It was then poured into brine, extracted with ethyl acetate, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography using ethyl acetate/hexanes (20/80) to afford 2-(4-tert-butyl-benzoylamino)-4-nitro-benzoic acid methyl ester (1.841 g, 86%) as a yellow solid. mp=146.0-148.4° C.; mass spectrum (−ES, M−H) m/z 355. 1H NMR (400 MHz, DMSO-d6); δ 11.60 (bs, 1H), 9.35 (d, 1H), 8.20 (d, 1H), 8.02 (dd, 1H), 7.90 (d, 2H), 7.64 (d, 2H), 3.95 (s, 3H), 1.36 (s, 9H). Elemental analysis: Calcd. for C19H20N2O5: C, 64.04; H, 5.66; N, 7.86. Found: C, 64.04; H, 5.79; N, 7.76.
Reaction SMILES: [C-:1]#[N:2].[K+].CS(O[CH2:9][CH2:10][CH:11]([C:22]1[C:30]2[C:25](=[C:26]([CH2:31][S:32][CH3:33])[CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1)[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1)(=O)=O>CN(C=O)C>[CH3:33][S:32][CH2:31][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]2[C:25]=1[NH:24][CH:23]=[C:22]2[CH:11]([C:12]1[CH:13]=[CH:14][C:15]([C:18]([F:20])([F:21])[F:19])=[CH:16][CH:17]=1)[CH2:10][CH2:9][C:1]#[N:2]
Reactant: [C-]#N
Reactant: CSCc1cccc2c(C(CCOS(C)(=O)=O)c3ccc(C(F)(F)F)cc3)c[nH]c12
Agent: [K+]
Solvent: CN(C)C=O
Product: CSCc1cccc2c(C(CCC#N)c3ccc(C(F)(F)F)cc3)c[nH]c12
Temperature: 80 °C
Reaction time: 2 h

Procedure:
28.5 g (0.44 mmol) of potassium cyanide were added to 100 mg (0.22 mmol) of the compound from Example 51A in 5 ml of DMF. The mixture was stirred at 80° C. for 2 h and then concentrated, and the residue was taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. Purification by preparative HPLC (RP18 column; mobile phase: acetonitrile-water gradient with addition of 0.1% formic acid) resulted in 77 mg (91% of theory) of the title compound.
Reaction SMILES: C[Si](C)(C)[NH:3][Si](C)(C)C.CO.[ClH:12].[CH3:13][N:14]1[CH2:46][C@@H:45]2[C@H:16]([CH2:17][C:18]3[N:19]([CH2:44]2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=2[C:26]=3[C:27]2[C:28](=[O:43])[O:29][C:30](=O)[C:31]=2[C:32]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:34]([CH3:41])[CH:33]=2)[CH2:15]1>CN(C=O)C.C(OCC)(=O)C>[ClH:12].[CH3:13][N:14]1[CH2:46][C@@H:45]2[C@H:16]([CH2:17][C:18]3[N:19]([CH2:44]2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=2[C:26]=3[C:27]2[C:28](=[O:43])[NH:3][C:30](=[O:29])[C:31]=2[C:32]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:34]([CH3:41])[CH:33]=2)[CH2:15]1
Reactant: CN1C[C@H]2Cc3c(C4=C(c5cn(C)c6ccccc56)C(=O)OC4=O)c4ccccc4n3C[C@@H]2C1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CO
Product: CN1C[C@H]2Cc3c(C4=C(c5cn(C)c6ccccc56)C(=O)NC4=O)c4ccccc4n3C[C@@H]2C1
Temperature: 45 °C
Reaction time: 48 h
Yield: 58.9 %

Procedure:
A mixture of 1.21 g of 1,1,1,3,3,3-hexamethyldisilazane and 132 mg of methanol was added to a solution of 400 mg of trans-3-(2,3,3a,4,11,11a-hexahydro-2-methyl-1H-pyrrolo[3',4':4,5]-pyrido[1,2-a]indol-10-yl)-4-(1-methyl-3-indolyl)furan-2,5-dione hydrochloride in 30 ml of DMF and stirred for 48 hours. A further 100 mg of methanol and 0.95 g of 1,1,1,3,3,3-hexamethyldisilazane were added, the mixture was heated to 45° C. for 2 hours and then left to stand at room temperature. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate, dichloromethane and methanol. The solution obtained was washed with saturated sodium bicarbonate solution and the organic layer was concentrated. A saturated solution of hydrogen chloride in ethyl acetate was added and the precipitate obtained was filtered off. The solid was suspended in water and stirred, then filtered off and dried. The solid obtained was suspended in ethyl acetate and stirred, then filtered off and dried to give 235 mg of trans-3-(2,3,3a,4,11,11a-hexahydro-2-methyl-1H-pyrrolo[3',4':4,5]pyrido[1,2-a]indol-10-yl)-4 -(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione hydrochloride of melting point >330° C.
Reaction SMILES: [I-].ClC1C=CC=C[N+]=1C.CCN(C(C)C)C(C)C.[NH2:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][N:21]=1.[Br:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][N:32]=1>C1COCC1>[Br:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([NH:19][C:20]2[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][N:21]=2)=[O:36])=[CH:33][N:32]=1
Reactant: COC(=O)c1ccc(N)nc1
Reactant: O=C(O)c1ccc(Br)nc1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(NC(=O)c2ccc(Br)nc2)nc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 63.7 %

Procedure:
2-Chloro-1-methylpyridinium iodide (2.2 g, 9.8 mmol) and DIPEA (1 ml) were added to a mixture of 5-fluoropyridin-2-amine 1 (554 mg, 4.9 mmol) and 6-bromonicotinic acid 2 (1 g, 4.9 mmol) in THF. The reaction mixture was stirred at rt for 2 days. At the conclusion of the reaction, the reaction mixture was concentrated to ⅓ of its volume and the precipitated product was filtered off. The filtrate was concentrated, diluted with chloroform (100 ml), washed with water and brine and then dried over Na2SO4. Evaporation of the solvent gave a crude yellow product, which crystallized in EtOAc to give 6-bromo-N-(5-fluoropyridin-2-yl)nicotinamide 3 (1.05 g, 71%) as a white solid. Mp. 173-174° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[C:13]([Cl:33])=[CH:14][C:15]([F:32])=[C:16]([NH:18][C:19](=[O:31])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[CH:21]=3)[CH:17]=1)[N:5]=2.C([O:37][CH2:38][C:39](Cl)=[O:40])(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:33][C:13]1[C:12]([O:11][C:6]2[N:5]=[C:4]3[S:3][C:2]([NH:1][C:38](=[O:37])[CH2:39][OH:40])=[N:10][C:9]3=[CH:8][CH:7]=2)=[CH:17][C:16]([NH:18][C:19](=[O:31])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[CH:21]=2)=[C:15]([F:32])[CH:14]=1
Reactant: CC(=O)OCC(=O)Cl
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cc(Oc3ccc4nc(N)sc4n3)c(Cl)cc2F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)CO)sc4n3)c(Cl)cc2F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 56.4 %

Procedure:
To a solution of N-{5-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-4-chloro-2-fluorophenyl}-3-(1-cyano-1-methylethyl)benzamide (100 mg, 0.207 mmol) produced in Example C52(v) in pyridine (2.0 mL) was added acetoxyacetyl chloride (48.9 μL, 0.455 mmol), and the mixture was stirred at room temperature for 4 hr. The reaction mixture was diluted with ethyl acetate (10 mL), washed with 5% aqueous sodium hydrogen carbonate solution (10 mL) and saturated brine (10 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in methanol (2.0 mL), sodium carbonate (100 mg, 0.943 mmol) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in ethyl acetate (10 mL). The obtained suspension was washed with 5% aqueous ammonium chloride solution (10 mL), 5% aqueous sodium hydrogen carbonate solution (10 mL) and saturated brine (10 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate/methanol=100/0→85/15), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/hexane to give the title compound (63.0 mg, 56%) as a colorless powder.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[C:3]([C:14]([O:16]CC)=O)[N:2]=1.[H-].[Na+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[NH2:29][OH:30]>CN(C=O)C.CO.O>[CH2:21]([N:12]1[C:13]2[CH:1]=[N:2][C:3]([C:14]([NH:29][OH:30])=[O:16])=[CH:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1cc2c(cn1)[nH]c1ccccc12
Reactant: NO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: O=C(NO)c1cc2c3ccccc3n(Cc3ccccc3)c2cn1
Reaction time: 21 h
Yield: 39.1 %

Procedure:
To a stirred solution of ethyl 9H-β-carboline-3-carboxylate (290 mg, 1.21 mmol) in DMF (4 mL) under a nitrogen atmosphere was added NaH (53 mg, 60% in mineral oil, 1.33 mmol) portionwise, followed by benzyl bromide (173 μL, 1.45 mmol). Stirring was continued for 21 hours at ambient temperature, water (50 mL) was then added to the mixture. The precipitate was filtered, washed with water and dried to give a solid that was dissolved in methanol (25 mL). To the resulting solution, H2NOH (25 mL, 50 wt. % solution in H2O, 0.38 mol) was added. The suspension was stirred for 3 days at ambient temperature. The mixture was then filtered, and the solid was boiled in methanol (25 mL). After filtration, the title product (0.15 g, 39%) was obtained. 1H NMR (400 MHz, DMSO-d6): δ 11.32 (1H, s), 9.10 (1H, s), 9.05 (1H, s), 8.89 (1H, s), 8.52 (1H, d, J=8 Hz), 7.26–7.87 (8H, m), 5.90 (2H, s). HRMS (M+H)+ found: 318.1249. Calcd for C19H16N3O2: 318.1243.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([OH:13])=O)[C:5]=2[C:4]2([C:25]3[C:16](=[CH:17][C:18]4[O:23][CH2:22][CH2:21][O:20][C:19]=4[CH:24]=3)[O:15][CH2:14]2)[C:3]1=[O:26].O[C:28]1[C:36]2N=N[NH:33][C:32]=2[CH:31]=[CH:30][CH:29]=1.[B-](F)(F)(F)F.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.C(N(CC)C(C)C)(C)C.C(N)CCCCC>CN(C)C=O>[CH2:32]([NH:33][C:11]([C:6]1[C:5]2[C:4]3([C:25]4[C:16](=[CH:17][C:18]5[O:23][CH2:22][CH2:21][O:20][C:19]=5[CH:24]=4)[O:15][CH2:14]3)[C:3](=[O:26])[N:2]([CH3:1])[C:10]=2[CH:9]=[CH:8][CH:7]=1)=[O:13])[CH2:31][CH2:30][CH2:29][CH2:28][CH3:36]
Reactant: CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2c(C(=O)O)cccc21
Reactant: Oc1cccc2[nH]nnc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCCCCCN
Product: CCCCCCNC(=O)c1cccc2c1C1(COc3cc4c(cc31)OCCO4)C(=O)N2C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 72.9 %

Procedure:
To a stirred solution of 1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxylic acid (0.200 g, 0.566 mmol) in N,N-dimethylformamide (12 mL) were added hydroxybenzotriazole (0.151 g, 1.13 mmol), 0-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.364 g, 1.13 mmol) and N,N-diisopropylethylamine (0.81 mL, 4.5 mmol). The reaction mixture was stirred at ambient temperature for 15 min and N-hexylamine (0.15 mL, 1.1 mmol) was added. The reaction mixture stirred for 72 h at ambient temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate and was washed with water (3×150 mL), 1 M aqueous sodium hydroxide (2×100 mL) and brine (2×100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was recrystallized from hexanes/ethyl acetate to afford N-hexyl-1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxamide (0.180 g, 73%) as a colorless solid: mp 172-173° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.42-7.36 (m 1H), 7.26-7.22 (m, 1H), 6.99-6.96 (m, 1H), 6.49 (s, 1H), 6.20 (s, 1H), 5.30-5.26 (m, 1H), 4.92 (ABq, 2H), 4.25-4.07 (m, 4H), 3.27-2.97 (m, 5H), 1.30-1.18 (m, 8H), 0.87 (t, J=6.8 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 177.6, 167.0, 155.8, 145.0, 144.1, 137.9, 134.4, 129.5, 127.8, 122.9, 120.6, 110.7, 109.9, 99.8, 78.8, 64.5, 64.0, 58.1, 40.0, 31.4, 28.9, 26.9, 26.5, 22.5, 14.0; MS (ES+) m/z 437.1 (M+1).
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]2[N:13]([S:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)(=[O:16])=[O:15])[CH:12]=[C:11]([CH2:23][N:24](C)[C:25](=O)OC(C)(C)C)[C:10]=2[F:33])=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].[C:34]([O:37]CC)(=[O:36])[CH3:35].Cl.[C:41]([O:44]CC)(=[O:43])[CH3:42]>CC(O)C>[C:41]([OH:44])(=[O:43])/[CH:42]=[CH:35]/[C:34]([OH:37])=[O:36].[F:33][C:10]1[C:11]([CH2:23][NH:24][CH3:25])=[CH:12][N:13]([S:14]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)(=[O:15])=[O:16])[C:9]=1[C:8]1[C:3]([C:1]#[N:2])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(C)=O
Reactant: CN(Cc1cn(S(=O)(=O)c2cccnc2)c(-c2cccnc2C#N)c1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CC(C)O
Product: CNCc1cn(S(=O)(=O)c2cccnc2)c(-c2cccnc2C#N)c1F
Product: O=C(O)/C=C/C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl {[5-(2-cyanopyridin-3-yl)-4-fluoro-1-(pyridine-3-sulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (421 mg) in ethyl acetate (3 mL) and 2-propanol (2 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (6 mL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=3:7→ethyl acetate) to give a free base of the title compound as a pale-yellow solid (yield 242 mg). A solution of the obtained free base in ethyl acetate (3 mL) was added dropwise to a solution of fumaric acid (74 mg) in ethanol (3 mL) and the mixture was concentrated under reduced pressure. The residue was recrystallized from a mixed solvent of ethanol and water to give the title compound as a white solid (yield 259 mg, 61%).
Reaction SMILES: C([N:8]1[CH2:17][CH2:16][C:15]2[N:14]=[C:13]([C:18]([F:21])([F:20])[F:19])[C:12]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:11][C:10]=2[CH2:9]1)C1C=CC=CC=1.[Cl:27]C(OC(Cl)C)=O>ClCCl>[ClH:27].[F:21][C:18]([F:19])([F:20])[C:13]1[C:12]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:11][C:10]2[CH2:9][NH:8][CH2:17][CH2:16][C:15]=2[N:14]=1
Reactant: CCOC(=O)c1cc2c(nc1C(F)(F)F)CCN(Cc1ccccc1)C2
Reactant: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Product: CCOC(=O)c1cc2c(nc1C(F)(F)F)CCNC2
Product: Cl
Temperature: 45 °C
Reaction time: 20 h

Procedure:
A solution of the product (140 mg, 0.385 mmol) from Step B in 1.5 mL of dry dichloromethane was treated with 1-chloroethyl chloroformate (0.050 mL, 0.46 mmol). The reaction mixture was warmed to 45° C. After 20 h, the solution was cooled to room temperature and concentrated under a stream of nitrogen. The resultant residue was dissolved in 3 mL of methanol and the solution was warmed at 40° C. for 2.5 h. The resultant solution was cooled and concentrated under a stream of nitrogen, and the residue was triturated with 4 mL of ethyl acetate. The solid precipitate was collected and dried in vacuo to afford the title compound as a white crystalline solid. LC/MS 275.0 (M+1).
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH:12]=[CH:13][CH:14]=[C:15]2[S:20](Cl)(=[O:22])=[O:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=1>ClCCl>[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([NH:39][S:20]([C:15]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:16]=2[CH:17]=[CH:18][CH:19]=[C:10]3[NH:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)(=[O:22])=[O:21])=[CH:35][CH:34]=1
Reactant: O=C(Nc1cccc2c(S(=O)(=O)Cl)cccc12)c1ccccc1
Reactant: COc1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(NS(=O)(=O)c2cccc3c(NC(=O)c4ccccc4)cccc23)cc1

Procedure:
To a solution of 5-benzoylamino-naphthalene-1-sulfonyl chloride 44 (0.1 g, 0.29 mmol) in dichloromethane (0.5 mL) was added triethylamine (0.06 ml, 0.43 mmol) and p-anisidine (0.05 g, 0.3 mmol). The resultant solution stirred at room temperature for 3 hours. The reaction mixture was quenched with water and the compound extracted into ethyl acetate. The organic extracts were washed with brine, dried over MgSO4, filtered and concentrated to provide the crude product as a yellow oil. 1H NMR (300 MHz, DMSO) δ 8.65 (d, 1H), 8.19 (d, 1H), 8.06 (m, 3H), 7.70 (m, 2H), 7.54 (m, 2H), 6.84 (d, 2H), 6.69 (d, 2H), 3.56 (s, 3H); LC/MS (M+H)+ m/z 433.
Reaction SMILES: [C:1]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9](=[O:36])/[C:10](=[CH:21]/[C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH:32]=[C:31]([CH3:33])[N:30]=[CH:29]3)=[C:24]([O:34][CH3:35])[CH:23]=2)/[CH2:11][CH2:12][CH2:13][O:14]C2CCCCO2)[CH:2]=1>CO>[C:1]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9](=[O:36])/[C:10](=[CH:21]/[C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH:32]=[C:31]([CH3:33])[N:30]=[CH:29]3)=[C:24]([O:34][CH3:35])[CH:23]=2)/[CH2:11][CH2:12][CH2:13][OH:14])[CH:2]=1
Reactant: COc1cc(/C=C(\CCCOC2CCCCO2)C(=O)NCc2cccc(-c3ccccc3)c2)ccc1-n1cnc(C)c1
Solvent: CO
Product: COc1cc(/C=C(\CCCO)C(=O)NCc2cccc(-c3ccccc3)c2)ccc1-n1cnc(C)c1
Temperature: 45 °C
Reaction time: 5 h
Yield: 83.9 %

Procedure:
To the methanol (5 mL) solution of (E)-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)-5-(tetrahydropyran-2-yloxy)valeric acid (biphenyl-3-ylmethyl)amide (168 mg), Dow-XM50W X-8 (300 mg) was added, and the reaction solution was agitated at 45° C. for 5 hours. The resin was filtered off, the ammonia water (1 mL) was added to the filtrate, and the solution was concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: ethyl acetate->ethyl acetate:methanol=9:1), and 120 mg of the title compound was obtained. The physical properties of the compound are as follows.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.Cl[C:26](Cl)([O:28][C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[CH:37]1(O)[CH2:41]C[CH2:39][CH2:38]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:28][CH:26]2[CH2:39][CH2:38][CH2:37][CH2:41]2)=[C:18]([CH3:24])[CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: OC1CCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc2nccc(Oc3cc(C)c(NC(=O)OC4CCCC4)cc3C)c2cc1OC
Yield: 104 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 1-cyclopentanol (20 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (70 mg, yield 99%).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:6]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[CH3:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][NH2:1])=[CH:6][C:7]=1[S:12]([CH3:15])(=[O:14])=[O:13]
Reactant: Cc1ccc(CN=[N+]=[N-])cc1S(C)(=O)=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(CN)cc1S(C)(=O)=O
Temperature: 25 °C

Procedure:
A round bottom flask was charged with 4-(1-azidomethyl)-1-methyl-2-(methylsulfonyl)benzene (5.0 g, 22.17 mmol), THF (40 mL), triphenylphosphine (6.4 g, 24.3 mmol) and water (1.6 mL, 34.2 mmol) at 0° C., and the reaction mixture was stirred at room temperature over night. The solvents were removed and the residue was dissolved in MTBE and 20% HCl in dioxane was added dropwise at 0° C. and the resulting salt was collected and washed with EtOAc. The salt was then neutralized with 6N aq. NaOH and extracted with CH2Cl2. The organic layers were concentrated under reduced pressure to get the title compound as a very thick oil. 1H NMR (400 MHz, CDCl3): 7.98 (s, 1H), 7.50 (d, 1H, J=8.0 Hz), 7.32 (d, 1H, J=8.0 Hz), 3.93 (s, 2H), 3.08 (s, 3H), 2.69 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]#[N:13])=[CH:10][C:9]2[C:8](=[O:14])[CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1.[NH:15]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(N(CC)CC)C.O>C(O)C>[N:15]1([C:2]2[C:11]([C:12]#[N:13])=[CH:10][C:9]3[C:8](=[O:14])[CH2:7][CH2:6][CH2:5][C:4]=3[N:3]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: C1CCCNCC1
Reactant: N#Cc1cc2c(nc1Cl)CCCC2=O
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCO
Product: N#Cc1cc2c(nc1N1CCCCCC1)CCCC2=O
Yield: 38.2 %

Procedure:
A solution of 2-chloro-5-oxo-5,6,7,8-tetrahydro-quinoline-3-carbonitrile (0.07 g, 0.34 mmol), azepane (0.07 g, 0.7 mmol) and triethylamine (0.052 ml, 0.07 g, 0.07 mmol) in ethyl alcohol (3 ml) was heated at reflux for 5 h. Then water (10 ml) was added and the precipitated solid was filtered off and recrystallized from ethyl alcohol to give the title compound (0.035 g, 38%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1.[NH2:30][C:31]1[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=1[C:33]([NH2:35])=[O:34]>>[C:33]([C:32]1[CH:36]=[CH:37][CH:38]=[CH:39][C:31]=1[NH:30][C:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1)(=[O:34])[NH2:35]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Reactant: NC(=O)c1ccccc1N
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccccc3C(N)=O)n2)c(OC)c1)OCC

Procedure:
The title compound was prepared according to the procedure for Example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate and the commercially available 2-aminobenzamide. 1H NMR (400 MHz, DMSO-d6) δ 1.19 (t, J=7.07 Hz, 6H), 3.25 (d, J=21.50 Hz, 2H), 3.76 (s, 3H), 3.93-4.03 (m, 4H), 6.85 (dt, J=8.08, 2.15 Hz, 1H), 7.02 (s, 1H), 7.06 (t, J=7.83 Hz, 1H), 7.38 (t, J=8.21 Hz, 1H), 7.52 (d, J=8.34 Hz, 1H), 7.75 (dd, J=7.96, 1.39 Hz, 1H), 7.77 (br. s., 1H), 8.27 (br. s., 1H), 8.36 (s, 1H), 8.47 (br. s., 1H), 8.80 (s, 1H), 11.82 (s, 1H). MS (ES+): m/z 406.04 (100) [MH+]. HPLC: tR=4.01 min (ZQ3, polar—5 min).