Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1(O)[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][CH2:11]1>FC(F)(F)C(O)=O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][CH:11]=1
Reactant: OC1(c2cc3ccccc3s2)CCN(Cc2ccccc2)CC1
Solvent: O=C(O)C(F)(F)F
Product: C1=C(c2cc3ccccc3s2)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 114.6 %

Procedure:
4-(Benzothiophen-2-yl)-1-benzyl-4-hydroxypiperidine (4.5 g, 0.01 mol) was dissolved in trifluoroacetic acid (50 ml) and stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue partitioned between aqueous saturated potassium carbonate solution and dichloromethane (3×100 ml). The combined organic layers were washed with brine (200 ml), dried (MgSO4) and concentrated. The crude product was purified by flash chromatography eluting with 10% ethyl acetate in petroleum ether. Concentration of the appropriate fractions gave the title compound as a pale yellow solid (3.5 g, 82%); δH (CDCl3), 2.63 (2H, m, NCH2CH2), 2.73 (2H, m, NCH2 CH2), 3.19 (2H, m, NCH2CH2), 3.64 (2H, s, NCH2Ar), 6.19 (1H, m, NCH2CH), 7.11 (1H, s, ArH), 7.31 (7H, m, ArH), 7.65 (1H, d of d, J 6.4Hz, J 1.9Hz, ArH), 7.72 (1H, d of d, J 6.9Hz, J 1.8Hz, ArH). m/z (ES+) 306 (M+1)+.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:6][C:7]1[CH:14]=[C:13]([OH:15])[C:12]([Cl:16])=[CH:11][C:8]=1[CH:9]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCl>[Cl:16][C:12]1[CH:11]=[C:8]([CH2:9][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:7]([Cl:6])=[CH:14][C:13]=1[OH:15]
Reactant: C1CCNC1
Reactant: O=Cc1cc(Cl)c(O)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Oc1cc(Cl)c(CN2CCCC2)cc1Cl
Yield: 78.3 %

Procedure:
Pyrrolidine (0.48 mL, 5.76 mmol) was added to a suspension of Intermediate 24, 2,5-Dichloro-4-hydroxybenzaldehyde (0.88 g, 4.6 mmol) in dichloromethane (10 mL). The reaction mixture was cooled with an ice bath. Sodium triacetoxyborohydride (1.22 g, 5.76 mmol) was added in portions under stirring. The reaction mixture was stirred for 12 h at room temperature. Water (20 mL) and dichloromethane (10 mL) were added. The reaction mixture was acidified with 5N NAHSO4 to pH˜2. The organic layer was separated. The aqueous one was subjected to extraction with CH2Cl2 (2×30 mL), and the extracts were discarded. The aqueous fraction was alkalized with a saturated solution of potassium carbonate to pH 9-10. The product was extracted with CH2Cl2 (3×20 mL). The organic layer was dried with anhydrous Na2SO4 (5 g). The solvent was evaporated in vacuo, and coevaporated with dioxane to give the title compound (0.89 g, 3.6 mmol, 79%) as pale-yellow crystals. LC/MS data: 248.0, 247.0 and 246.0 (M+H); 174.9 (M-pyrrolidine+H) (calculated for C11H13ClNO 246.1). 1H NMR data (DMSO-d6): 10.52 (br.s., 1H, OH); 7.38 (s, 1H, s Ar—H); 6.98 (s, 1H, Ar—H); 3.54 (s, 2H, CH2Ar); 2.40-2.47 (m, 4H); 1.63-1.74 (m, 4H).
Reaction SMILES: FC(F)(F)C([NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([S:16]([N:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)(=[O:18])=[O:17])[CH:9]=1)=O.C([O-])([O-])=O.[K+].[K+].[ClH:34]>CO.O>[ClH:34].[ClH:34].[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][CH2:6][NH2:5])=[CH:9][C:10]=1[S:16]([N:19]1[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]1)(=[O:17])=[O:18]
Reactant: COc1ccc(CCNC(=O)C(F)(F)F)cc1S(=O)(=O)N1CCN(C)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1ccc(CCN)cc1S(=O)(=O)N1CCN(C)CC1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of 2,2,2-trifluoro-N-(2-{4-methoxy-3-[(4-methylpiperazin-1-yl)sulfonyl]-phenyl}ethyl) acetamide (from Step 2), (1.25 g, 3.05 mmol) in MeOH (30 mL) and H2O (8 mL) was added K2CO3 (2.11 g, 15.3 mmol), and the solution was stirred at 60° C. for 2 h. After cooling to rt, the MeOH was evaporated under reduced pressure. The remaining aqueous mixture was extracted with CH2Cl2 (6×50 mL), and the combined organic phases were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was then dissolved in MeOH, and 4 equivalents of 1 N HCl in MeOH were added causing the formation of a white precipitate. The solvent was removed under reduced pressure, and the resulting solid was recrystallized from MeOH/Et2O to give the title compound [assumed to be the bis-HCl salt] as a white solid (457 mg, 48%). 1H NMR (400 MHz, CD3OD) δ 2.29 (s, 3H), 2.48 (broad t, 4H), 2.78 (dd, 2H), 2.87-2.92 (m, 2H), 3.23 (broad t, 4H), 3.91 (s, 3H) 7.16 (d, 1H), 7.47 (dd, 1H), 7.68 (d, 1H); ES-MS m/z (MH+) 314.2, HPLC RT (min) 0.70.
Reaction SMILES: [C:1]([O:4][CH:5]([C:10]([O:12][CH3:13])=[O:11])[CH2:6][C:7](O)=[O:8])(=[O:3])[CH3:2].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[C:1]([O:4][CH:5]([CH2:6][CH2:7][OH:8])[C:10]([O:12][CH3:13])=[O:11])(=[O:3])[CH3:2]
Reactant: COC(=O)C(CC(=O)O)OC(C)=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Product: COC(=O)C(CCO)OC(C)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 103.9 %

Procedure:
5 g of dl-maleic acid was dissolved in 20 ml of acetyl chloride, and stirred under heat at 45° C. for 3 hours. Acetyl chloride was evaporated away under reduced pressure, the resulting crude product was dissolved in 30 ml of methanol, and stirred overnight. The solvent was evaporated away under reduced pressure to obtain 5.3 g of 3-(acetyloxy)-4-methoxy-4-oxobutanoic acid as a pale yellow oil. In an ice bath, 10 ml of borane-dimethylsulfide complex (10 M) was added to a tetrahydrofuran (25 ml) solution of 5.3 g of 3-(acetyloxy)-4-methoxy-4-oxobutanoic acid, and stirred at room temperature for 24 hours. Aqueous 10% citric acid was added to the reaction liquid, extracted with chloroform, and the organic layer was washed with saturated saline water. After dried, the solvent was evaporated away under reduced pressure to obtain 5.1 g of methyl 2-(acetyloxy)-4-hydroxybutanoate as a colorless transparent oil.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]2[C:22]([O:27]C)=[N:23][CH:24]=[CH:25][CH:26]=2)[CH:18]=[CH:17][C:3]=1[CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:6]1=[O:16]>ClCCl>[Cl:1][C:2]1[CH:20]=[C:19]([C:21]2[C:22]([OH:27])=[N:23][CH:24]=[CH:25][CH:26]=2)[CH:18]=[CH:17][C:3]=1[CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:6]1=[O:16]
Reactant: COc1ncccc1-c1ccc(CC2CCN(C3CCCCC3)C2=O)c(Cl)c1
Solvent: ClCCl
Product: O=C1C(Cc2ccc(-c3cccnc3O)cc2Cl)CCN1C1CCCCC1
Reaction time: 16 h
Yield: 56.3 %

Procedure:
Place 3-(2-chloro-4-(2-methoxypyridin-3-yl)benzyl)-1-cyclohexylpyrrolidin-2-one (Example 105) (120 mg, 0.3 mmol) in dichloromethane (10 mL) and cool to 0° C. Add borontribromide (226 mg, 0.9 mmol) and stir of 16 hours. Add water and extract with dichloromethane. Dry over sodium sulfate, filter, and concentrate. Purify by silica gel (10% methanol in dichloromethane) to yield 65 mg (56%) of the title compound: Mass spectrum (apci) m/z=385.2 (M+H).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[NH:7][CH3:8].[CH3:13][O:14][C:15]1[CH:20]=[C:19]([OH:21])[CH:18]=[CH:17][N:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH3:13][O:14][C:15]1[CH:20]=[C:19]([O:21][C:2]2[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=2)[NH:7][CH3:8])[CH:18]=[CH:17][N:16]=1
Reactant: COc1cc(O)ccn1
Reactant: CNc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CNc1cc(Oc2ccnc(OC)c2)ccc1[N+](=O)[O-]
Yield: 66 %

Procedure:
A solution of 5-fluoro-N-methyl-2-nitroaniline (US2003-675927, 3.30 g, 19.4 mmol), 2-methoxypyridin-4-ol (2.70 g, 21.6 mmol) produced in Example (16b) and cesium carbonate (10.6 g, 32.4 mmol) in DMF (20 mL) was stirred at 80° C. for two hours. After leaving to cool, water (100 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (100 mL). The organic layer was washed with water (100 mL) twice and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel chromatography (hexane/ethyl acetate, 2:1) to obtain the title compound (3.90 g, 66%) as a yellow solid.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[CH:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[C:12](O)[CH:11]=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[C:1]([O:9][C:12]1[CH:11]=[CH:10][C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: O=C(O)c1cccnc1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)c1cccnc1
Reaction time: 1 h
Yield: 57 %

Procedure:
To 9.85 g, 80 mmoles, nicotinic acid and 13.35 g, 96 =moles p-nitrophenol in 250 ml DMF was added 16.5 g, 80 mmoles DCC with stirring in ice-bath. After 1 hour at 0° C. and 3 hours at room temperature the urea was filtered off and the product was precipitated by the addition of an equal volume of water. Filtration, drying in vacuo and recrystallization from i-PrOH gave 11.22 g, 57% of white needles, m.p. 172.5°-173° C. (24)
Reaction SMILES: [N:1]1([CH2:31][CH2:32][C:33]([OH:35])=[O:34])[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH:12]([CH2:21][CH2:22][C:23]([OH:25])=[O:24])[CH2:11]2)[CH2:3][CH:2]1[CH2:26][CH2:27][C:28]([OH:30])=[O:29].C([C:43](C(OC(C)(C)C)=O)([CH2:46][NH2:47])[CH2:44][NH2:45])(OC(C)(C)C)=O.Cl>CO>[N:1]1([CH2:31][CH2:32][C:33]([OH:35])=[O:34])[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH:12]([CH2:21][CH2:22][C:23]([OH:25])=[O:24])[CH2:11]2)[CH2:3][CH:2]1[CH2:26][CH2:27][C:28]([OH:30])=[O:29].[NH2:45][CH2:44][CH2:43][CH2:46][NH2:47]
Reactant: CC(C)(C)OC(=O)C(CN)(CN)C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C(O)CCC1CC(CCCC2CCN(CCC(=O)O)C(CCC(=O)O)C2)CCN1CCC(=O)O
Solvent: CO
Product: NCCCN
Temperature: 50 °C
Reaction time: 10 h

Procedure:
To 0.55 g of 4,4′-trimethylene dipiperidine bispropanoic acid-bis-boc-1,3-diamino propane dissolved in 5 mL of methanol was added 0.5 mL of concentrated HCl and the reaction mixture was stirred at 50° C. for 10 hours. After removal of the solvent under reduced pressure, the residue was dissolved in 10 mL of methanol/water (1:1) and was treated with 5 g of Amberlyst OH 26 resin. After stirring at room temperature for 3 hours, the resin was filtered off. The filtrate was evaporated dryness and the residue was lyophilized yielding 0.5 g of the product as a white solid.
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([NH:13][C:14]3[C:15]([N:20]([CH3:25])[S:21]([CH3:24])(=[O:23])=[O:22])=[N:16][CH:17]=[CH:18][CH:19]=3)[N:6]2[N:5]=1)=O.[CH2:26]1[N:31]([C:32]2[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=2)[CH2:30][CH2:29][O:28][CH2:27]1.C(N(CC)C(C)C)(C)C.COCC(O)C>>[CH3:25][N:20]([C:15]1[C:14]([NH:13][C:12]2[N:6]3[C:7]([CH:8]=[N:9][C:4]([NH:38][C:35]4[CH:34]=[CH:33][C:32]([N:31]5[CH2:26][CH2:27][O:28][CH2:29][CH2:30]5)=[CH:37][CH:36]=4)=[N:5]3)=[CH:10][CH:11]=2)=[CH:19][CH:18]=[CH:17][N:16]=1)[S:21]([CH3:24])(=[O:23])=[O:22]
Reactant: CN(c1ncccc1Nc1ccc2cnc(S(C)=O)nn12)S(C)(=O)=O
Reactant: Nc1ccc(N2CCOCC2)cc1
Solvent: COCC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CN(c1ncccc1Nc1ccc2cnc(Nc3ccc(N4CCOCC4)cc3)nn12)S(C)(=O)=O

Procedure:
N-[3-(2-Methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-ylamino)-pyridin-2-yl]-N-methyl-methanesulfonamide (50.0 mg, 0.131 mmol), 4-(4-morpholino)aniline (46.8 mg, 0.263 mmol) and N,N-Diisopropylethylamine (0.0687 mL, 0.394 mmol) were dissolved in 1-Methoxy-2-propanol (0.500 mL, 5.12 mmol). The reaction was irradiated at 300 watts, 200° C. for 20 minutes. The reaction was then reduced en vacuo and the resulting residue was isolated and purified by Gilson prep HPLC to afford N-Methyl-N-{3-[2-(4-morpholin-4-yl-phenylamino)-pyrrolo[2,1-f][1,2,4]triazin-7-ylamino]-pyridin-2-yl}-methanesulfonamide as a lyophilized powder. (M+H)=495.1. 1H NMR (400 MHz, DMSO, d6) δ 9.26 (s, 1H), 8.77 (s, 1H), 8.03 (m, 2H), 7.52 (d, 2H, J=8.05 Hz), 7.41 (d, 1H, J=8.24 Hz), 7.33 (m, 1H), 6.91 (m, 3H), 6.76 (m, 1H), 3.78 (m, 4H), 3.25 (s, 3H), 3.21 (s, 3H), 3.07 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:12][CH:13]([C:16]3[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=3)[CH2:14][OH:15])[CH:8]=2)[O:3]1.[C:29]1([CH3:39])[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1.N1C=CC=CC=1>ClCCl>[CH3:1][C:2]1([CH3:28])[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:12][CH:13]([C:16]3[CH:17]=[C:18]([O:26][CH3:27])[C:19]([O:24][CH3:25])=[C:20]([O:22][CH3:23])[CH:21]=3)[CH2:14][O:15][S:35]([C:32]3[CH:33]=[CH:34][C:29]([CH3:39])=[CH:30][CH:31]=3)(=[O:37])=[O:36])[CH:8]=2)[O:3]1
Reactant: COc1cc(C(CO)Sc2ccc3c(c2)C=CC(C)(C)O3)cc(OC)c1OC
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(C(COS(=O)(=O)c2ccc(C)cc2)Sc2ccc3c(c2)C=CC(C)(C)O3)cc(OC)c1OC
Temperature: 25 °C

Procedure:
To a stirring solution of 2-(2,2-dimethyl-2H-chromen-6-ylsulfanyl)-2-(3,4,5-trimethoxy-phenyl)-ethanol (29.3 mg, 0.073 mmol) in dichloromethane (1.5 mL) is added p-toluenesulfonylchloride (15.3 mg, 0.080 mmol) and pyridine (6.47 uL, 0.080 mmol). The reaction mixture continues to stir at room temperature. The crude material is purified using silica gel chromatography to yield the desired product.
Reaction SMILES: [C:1]([N:4]1[C:13]2[CH:12]=[CH:11][C:10]([N+:14]([O-])=O)=[CH:9][C:8]=2[C:7]2[N:17]([C:25]3[CH:33]=[CH:32][C:28]4[O:29][CH2:30][O:31][C:27]=4[CH:26]=3)[N:18]=[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:6]=2[CH2:5]1)(=[O:3])[CH3:2]>C(O)(=O)C.[OH-].[OH-].[Pd+2]>[C:1]([N:4]1[C:13]2[CH:12]=[CH:11][C:10]([NH2:14])=[CH:9][C:8]=2[C:7]2[N:17]([C:25]3[CH:33]=[CH:32][C:28]4[O:29][CH2:30][O:31][C:27]=4[CH:26]=3)[N:18]=[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1nn(-c2ccc3c(c2)OCO3)c2c1CN(C(C)=O)c1ccc([N+](=O)[O-])cc1-2
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCOC(=O)c1nn(-c2ccc3c(c2)OCO3)c2c1CN(C(C)=O)c1ccc(N)cc1-2
Temperature: 25 °C
Reaction time: 12 h
Yield: 87 %

Procedure:
The material from Step 4 (930 mg, 0.00206 mol) was dissolved in acetic acid (25 mL), treated with a catalytic amount of 20% Pd(OH)2, and shaken for 12 hours, under 5 psi, at room temperature. The suspension was then filtered, and the filtrate was concentrated in vacuo to give the desired product as the acetic acid salt. 850 mg (MW=480.46, 87% yield). LC/MS m/z=421.6 (m+1).
Reaction SMILES: [CH:1]([N:3]([CH2:5][C:6](O)=O)C)=O.[C:9]([O:13][CH3:14])(=[O:12])[C:10]#[CH:11].C(OC(=O)C)(=O)C>>[CH3:1][N:3]1[CH:5]=[CH:6][C:10]([C:9]([O:13][CH3:14])=[O:12])=[CH:11]1
Reactant: C#CC(=O)OC
Reactant: CN(C=O)CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1ccn(C)c1
Yield: 79.6 %

Procedure:
A mixture of 9.52 g (0.0813 mole) of N-formylsarcosine prepared in the Reference Example 1, 25.56 g (0.304 mole) of methyl propiolate, and 65 ml of acetic anhydride was stirred using a magnetic stirrer over an oil bath at 130° C. for 24 hours. The reaction mixture was concentrated under vacuum. 30 ml of toluene was added to the residue and the mixture was evaporated under reduced pressure. This procedure was repeated to obtain a brown oily substance. This oily substance was distilled under vacuum to obtain 9.01 g (yield 79.6%) of a colorless or light-yellow oil of the title compound as fractions with a boiling point of 93°-96° C. at 4 mmHg.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34](=[O:41])(=[O:40])[NH:35]C(C)(C)C)=[CH:24][C:23]=2[F:42])[C:7](=[O:20])[N:8]([C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=2[Cl:19])[N:9]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>>[CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34](=[O:41])(=[O:40])[NH2:35])=[CH:24][C:23]=2[F:42])[C:7](=[O:20])[N:8]([C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=2[Cl:19])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1F
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1F
Yield: 94 %

Procedure:
By the procedure of Example 28, Step G, 5-n-butyl-4-[[2'-(N-t-butylsulfamoyl)-3-fluorobiphenyl-4-yl]methyl]-2-(2-chloro-5-nitrophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (from Example 36, Step B) was deprotected with trifluoroacetic acid. Flash chromatography of the crude product on silica gel (gradient elution with 0.5-5% MeOH in CH2Cl2) gave a 94% yield of the title compound as a cream-colored solid; homogeneous by TLC in 95:5 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 560 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14](=[O:16])[CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[N+:17]([O-])([OH:19])=[O:18].[OH-].[Na+]>OS(O)(=O)=O>[NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14](=[O:16])[CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[C:5]([N+:17]([O-:19])=[O:18])[CH:4]=2
Reactant: O=[N+]([O-])O
Reactant: Nc1c2c(nc3ccccc13)CCCC2=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Nc1c2c(nc3ccc([N+](=O)[O-])cc13)CCCC2=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 79 %

Procedure:
To 100 ml of cold H2SO4 was added 5.00 g of 9-amino-3,4-dihydroacridin-1(2H)-one. The mechanically stirred solution was cooled to 0° C. and 2.1 ml (1 eq) of concentrated HNO3 (70 wt % solution) was added dropwise. Stirring was continued for 15 minutes after the addition, whereupon the reaction was complete. The reaction mixture was poured into excess crushed ice and made basis with a slight excess of 50% NaOH solution. More ice was added during the neutralization to keep the solution cool. The resulting precipitate was filtered and chromatographed over silica gel (EtOAc). The fractions containing the product were evaporated to a solid which was triturated with pentane to yield 4.77 g (79%) of a solid after drying, melting point 254° C. (with decomposition).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:20]([F:23])([F:22])[F:21])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[C:7]([CH2:17][CH2:18][CH3:19])=[CH:6]2)#[N:2].[Cl:24][C:25]1[C:30]([C:31](Cl)=O)=[CH:29][C:28]([Cl:34])=[CH:27][N:26]=1.C(N(CC)CC)C>C(#N)C>[Cl:24][C:25]1[C:30]([C:31]2[O:15][N:14]=[C:13]([CH2:12][N:8]3[C:9]4[C:5](=[C:4]([C:20]([F:22])([F:23])[F:21])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[C:7]3[CH2:17][CH2:18][CH3:19])[N:16]=2)=[CH:29][C:28]([Cl:34])=[CH:27][N:26]=1
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(=N)NO
Reactant: O=C(Cl)c1cc(Cl)cnc1Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cc(Cl)cnc2Cl)n1
Temperature: 150 °C
Yield: 14.2 %

Procedure:
To a solution of 2-[5-cyano-2-propyl-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide (Example 275A) (0.100 g, 0.308 mmol) in anhydrous acetonitrile (10.0 mL) under N2, was added 2,5-dichloro-3-pyridinecarbonyl chloride (0.223 g, 1.10 mmol) and triethylamine (1.0 mL, 13.6 mmol). The mixture was then heated in a microwave at 150° C. for 30 min. Upon cooling, the mixture was poured onto a biotage prepak column and the mixture was purified by flash chromatography (0-25% EtOAc-hexanes gradient) to give 0.021 g (14% yield) of pure product: MS (ES) m/z 480 (M+1).
Reaction SMILES: [NH:1]([C:8]1[N:9]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[CH:14][C:13](Br)=[C:12]([CH3:20])[N:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li][CH2:28]CCC.CI>C1COCC1>[NH:1]([C:8]1[N:9]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[CH:14][C:13]([CH3:28])=[C:12]([CH3:20])[N:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc2c(cc1Br)c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Reactant: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: Cc1cc2c(=O)cc(Nc3ccccc3)n(-c3ccccc3)c2nc1C
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 32 %

Procedure:
A suspension of 2-anilino-6-bromo-7-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one (203 mg, 0.5 mmol) in THF (10 mL) in an atmosphere of argon was cooled to −78° C. A solution of n-BuLi in hexanes (1.0 mL, 1.6 mmol, 1.6 M) was added and the suspension was stirred for 10 min at 0° C. until it became a clear solution. Excessive MeI (0.2 mL, 3.2 mmol) was added, and the reaction was stirred for another 10 min. The reaction was quenched with saturated aqueous NH4Cl (2.0 mL) and water (10 mL) and the mixture was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by prep-HPLC to afford 2-anilino-6,7-dimethyl-1-phenyl-1,8-naphthyridin-4(1H)-one (55 mg, 32%): LCMS RT: 2.33 min, MH+: 342.4, Rf=0.39 (EtOAc). 2-anilino-7-ethyl-1-(3-methylphenyl)-1,8-naphthyridin-4(1H)-one (13.3 mg, 7.5%) was also obtained as a side product: LCMS RT: 2.54 min, MH+: 356.3, Rf=0.40 (EtOAc). Other electrophiles such as aldehydes, carbon dioxide, disulfides, trifluoroacetates acid chlorides and other alkyl halides can also be used to quench the generated aryl lithium.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[C:5](=[O:19])[N:6]2[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].ClCCl.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:21]([O:25][C:26]([N:28]1[CH2:29][CH:30]=[C:31]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[C:4](=[O:20])[C:5](=[O:19])[N:6]3[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[CH2:32][CH2:33]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: O=C1C(=O)N(Cc2cccc(F)c2)c2cccc(Br)c21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC=C(c2cccc3c2C(=O)C(=O)N3Cc2cccc(F)c2)CC1
Temperature: 80 °C

Procedure:
4-Bromo-1-(3-fluoro-benzyl)-1H-indole-2,3-dione (167 mg) was dissolved in 2.5 mL of dioxane and 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (154 mg) was added, followed by [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (24 mg) and K2CO3 (138 mg). The reaction mixture was heated to 80° C. for 18 hours and then cooled and concentrated under reduced pressure. The resulting residue was purified by chromatography to afford 4-[1-(3-Fluoro-benzyl)-2,3-dioxo-2,3-dihydro-1H-indol-4-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester. MS: 337 (M−Boc+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15]([OH:17])=[O:16])=[CH:13][N:12]=[C:11]([Cl:18])[C:10]=2[Cl:19])=[C:4]([Cl:20])[CH:3]=1.CO.[Si](C=[N+]=[N-])(C)(C)[CH3:24]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15]([O:17][CH3:24])=[O:16])=[CH:13][N:12]=[C:11]([Cl:18])[C:10]=2[Cl:19])=[C:4]([Cl:20])[CH:3]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1Nc1ccc(Br)cc1Cl
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)c1cnc(Cl)c(Cl)c1Nc1ccc(Br)cc1Cl
Yield: 65.9 %

Procedure:
To a suspension of 4-(4-bromo-2-chlorophenylamino)-5,6-dichloronicotinic acid (4.3975 g, 11.2 mmol) in a mixture 70 ml MeOH and 70 ml toluene was added TMS-diazomethane (10 ml, 20 mmol, 2M/hexanes) in small portions at room temperature. At the end of the addition the suspension turned into a solution, and then a precipitate was formed again. The suspension was diluted with hexanes and filtered. And the precipitate was washed with hexanes and dried in vacuo to obtain the title compound 3.03 g (66%).