Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:13]([NH2:18])[CH2:14][CH:15]([CH3:17])[CH3:16].C(N(CC)CC)C>C(OCC)(=O)C>[CH2:13]([NH:18][C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:14][CH:15]([CH3:17])[CH3:16]
Reactant: CCOC(=O)c1cccnc1Cl
Reactant: CC(C)CCN
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cccnc1NCCC(C)C
Temperature: 140 °C
Yield: 75.7 %

Procedure:
A mixture of ethyl 2-chloronicotinate (3.71 g, 20 mmol), isoamylamine (3.03 mL, 26 mmol) and triethylamine (3.62 mL, 26 mmol) was heated in a sealed tube at 140° C. for 8 hours, cooled to 25C, diluted with ethyl acetate and the mixture washed with water. The organic layer was extracted with 1N aqueous hydrochloric acid. The acidic aqueous layer was adjusted to pH 8.0 with saturated sodium bicarbonate solution then extracted with ethyl acetate (2 portions). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (3.58 g, 76%). MS (DCI/NH3) m/z 237 (M+H)+. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.93 (d, J=6.25 Hz, 6 H) 1.31 (t, J=6.99 Hz, 3 H) 1.47 (q, J=6.99 Hz, 2 H) 1.64 (m, 1 H) 3.47 (m, 2 H) 4.28 (q, J=6.99 Hz, 2 H) 6.59 (dd, J=7.72, 4.78 Hz, 1 H) 7.90 (t, J=5.15 Hz, 1 H) 8.07 (dd, J=7.91, 2.02 Hz, 1 H) 8.28 (dd, J=4.78, 1.84 Hz, 1 H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][N:15]=[C:16](Cl)[C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:4][CH:3]=1.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(N(C(C)C)CC)(C)C>CC(O)C>[Br:1][C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][N:15]=[C:16]([N:22]4[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]4)[C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Clc1nccn2c(-c3cccc(Br)n3)cnc12
Reactant: CN1CCNCC1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2nccn3c(-c4cccc(Br)n4)cnc23)CC1
Temperature: 25 °C

Procedure:
A mixture of 3-(6-bromo-pyridin-2-yl)-8-chloro-imidazo[1,2-a]pyrazine (from Example 38 supra) (1.44 g, 4.65 mmol), 1-methylpiperazine (2.1 g, 21 mmol), and diisopropylethylamine (2.7 g, 21 mmol) in 2-propanol (300 mL) was stirred and heated at reflux overnight. The solution was then cooled to room temperature, concentrated under reduced pressure. The resulted solid was washed with water, partitioned between CH2Cl2 and brine. The organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by chromatography (CH2Cl2:CH3OH, 100:1) to give 3-(6-bromo-pyridin-2-yl)-8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazine. (Yield 1.27 g, 73%).
Reaction SMILES: Cl[C:2]([O:4][CH:5]1[CH:10]([CH:11]([CH3:13])[CH3:12])[CH2:9][CH2:8][CH:7]([CH3:14])[CH2:6]1)=[O:3].[N:15]1C=CC=[CH:17][CH:16]=1.C(N)C.Cl>C1(C)C=CC=CC=1.O>[CH:11]([C@@H:10]1[CH2:9][CH2:8][C@@H:7]([CH3:14])[CH2:6][C@H:5]1[O:4][C:2](=[O:3])[NH:15][CH2:16][CH3:17])([CH3:13])[CH3:12]
Reactant: c1ccncc1
Reactant: CC1CCC(C(C)C)C(OC(=O)Cl)C1
Agent: CCN
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: CCNC(=O)O[C@@H]1C[C@H](C)CC[C@H]1C(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
58.7 g of menthyl chloroformate (80% in toluene) were added to a mixture of 16.6 g of pyridine and 150 mL ethylamine (2M solution in THF) in 100 mL toluene at 0° C. over a period of 30 minutes. After stirring for 12 hours at room temperature, 100 mL of 2M HCl and subsequently 50 mL water were added, the phases separated and the water phase discarded. After washing with saturated NaHCO3-solution and water the organic phase was dried and evaporated to yield 47.1 g of crude product which was recrystallized from 82.4 g n-heptane to give 24.4 g of the analytically pure product as white crystals.
Reaction SMILES: N1C=CC=CC=1.[NH:7]1[CH2:12][CH2:11][CH:10]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[N:14]=2)[CH2:9][CH2:8]1.[CH3:24][C:25]([CH3:31])([CH3:30])[CH2:26][C:27](Cl)=[O:28]>C(Cl)Cl>[CH3:24][C:25]([CH3:31])([CH3:30])[CH2:26][C:27]([N:7]1[CH2:12][CH2:11][CH:10]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[N:14]=2)[CH2:9][CH2:8]1)=[O:28]
Reactant: CC(C)(C)CC(=O)Cl
Reactant: c1cc(-c2noc(C3CCNCC3)n2)ccn1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)CC(=O)N1CCC(c2nc(-c3ccncc3)no2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of pyridine (18 μl, 0.22 mmol) and 4-(5-piperidin-4-yl-[1,2,4]oxadiazol-3-yl)pyridine (Example 51, 50 mg, 022 mmol) in CH2Cl2 (4 ml) was treated with 3,3-dimethylbutanoyl chloride (58 mg, 0.43 mmol). The reaction was stirred at rt for 18 h then quenched with saturated aqueous NaHCO3 (1 ml). The organic phase was separated, evaporated and the residue purified by flash chromatography (IH-EtOAc, 1:1 to 0:1) to afford the title compound: RT=3.1 min, m/z (ES+)=329.3 [M+H]+.
Reaction SMILES: [CH:1]1[C:14]2[C:13]3([CH2:16][CH2:17][C:18]([OH:20])=O)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:23])=O>C1C=CC=CC=1>[CH:1]1[C:14]2[C:13]3([CH2:16][CH2:17][C:18]([Cl:23])=[O:20])[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCC12CC(c3ccccc31)c1ccccc12
Solvent: c1ccccc1
Product: O=C(Cl)CCC12CC(c3ccccc31)c1ccccc12

Procedure:
A solution of β-(9,10-dihydro-9,10-methano-9-anthryl)propionic acid and thionyl chloride in benzene was refluxed for 4 hours. Evaporation of excess thionyl chloride and benzene gave β-(9,10-dihydro-9,10-methano-9-anthryl)-propionic acid chloride, which was dissolved in dry tetrahydrofuran. The solution was added to a 30% aqueous monomethylamine solution at 0°-5° C. The reaction mixture was stirred at 0°-15° C., diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness to give β-(9,10-dihydro-9,10-methano-9-anthryl)-propionic acid monomethylamide. M.P. 200°-201° C.
Reaction SMILES: [F:1][C:2]1[C:3]([N+:10]([O-])=O)=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[CH3:13][Si:14]([CH3:21])([CH3:20])[C:15]#[C:16][CH2:17][CH2:18][NH2:19]>>[F:1][C:2]1[C:3]2[C:4](=[CH:5][N:19]([CH2:18][CH2:17][C:16]#[C:15][Si:14]([CH3:21])([CH3:20])[CH3:13])[N:10]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1cccc(F)c1[N+](=O)[O-]
Reactant: C[Si](C)(C)C#CCCN
Product: C[Si](C)(C)C#CCCn1cc2cccc(F)c2n1
Yield: 37.5 %

Procedure:
The title compound was prepared in accordance with ha the general method of Example 149(A), from 3-fluoro-2-nitro-benzaldehyde (0.2 g, 1.2 mmol) and 4-trimethylsilanyl-but-3-ynylamine (0.22 g, 1.5 mmol). The crude product was purified by flash chromatography (cyclohexane/AcOEt 92.5:7.5) to yield 7-fluoro-2-(4-trimethylsilanyl-but-3-ynyl)-2H-indazole (117 mg, 0.45 mmol) as a yellow oil.
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[OH-].[K+:12].[C:13](=[S:15])=[S:14]>C(O)C>[C:1]([NH:9][NH:10][C:13]([S-:15])=[S:14])(=[O:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[K+:12]
Reactant: S=C=S
Reactant: NNC(=O)c1ccncc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(NNC(=S)[S-])c1ccncc1
Reaction time: 1 h

Procedure:
Isonicotinohydrazide (10.96 g, 79.9 mmol) was dissolved in ethanol (80 ml) containing potassium hydroxide (5.3 g, 94.4 mmol). Carbon disulfide was then added with stirring, which was continued for 1 hr. Filtration gave crude potassium 3-isonicotinoyldithiocarbazate which was washed with ether and then dried in vacuum. This was then added slowly with stirring to concentrated sulfuric acid (25 ml) maintained at −5° C. Stirring was continued for an additional 5 min and then the reaction mixture was poured into crushed ice. After 10 min, the solid was filtered off to give 5-(pyridine-4′yl)-1,3,4-thiadiazole-2(3H)-thione.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH:3]([NH:6][CH2:7][C@@H:8]([NH:10]C(=O)OC(C)(C)C)[CH3:9])[CH2:4][I:5].[C:20]([OH:26])([C:22]([F:25])([F:24])[F:23])=[O:21]>C(Cl)Cl>[F:23][C:22]([F:25])([F:24])[C:20]([OH:26])=[O:21].[F:1][C:2]([F:18])([F:19])[CH:3]([NH:6][CH2:7][C@@H:8]([NH2:10])[CH3:9])[CH2:4][I:5]
Reactant: C[C@@H](CNC(CI)C(F)(F)F)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](N)CNC(CI)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of tert-butyl ((2S)-1-((1,1,1-trifluoro-3-iodopropan-2-yl)amino)propan-2-yl)carbamate (1.6 g, 4.04 mmol) and DCM (8.08 ml) was added TFA (6.22 ml, 81 mmol). Stirred for 1 hour at ambient temperature and then the solution was concentrated. The residue was azeotroped with toluene (3×10 ml) to provide (2S)—N1-(1,1,1-trifluoro-3-iodopropan-2-yl)propane-1,2-diamine 2,2,2-trifluoroacetate as a yellow oil that was used without further purification. LRMS m/z (M+H)+ 297.1 found, 297.0 required.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][CH:4]([CH2:7][CH:8]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)[C:9]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[O:10])[CH2:3]1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH3:26][S:23]([C:20]1[CH:21]=[CH:22][C:17]([CH:8]([CH2:7][CH:4]2[CH2:5][CH2:6][C:2](=[O:1])[CH2:3]2)[C:9]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[O:10])=[CH:18][CH:19]=1)(=[O:24])=[O:25]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCC(O)C2)C(=O)Nc2nccs2)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCC(=O)C2)C(=O)Nc2nccs2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 29.8 %

Procedure:
A solution of 3-(3-hydroxy-cyclopentyl)-2-(4-methanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide (prepared as in Example 37, 155 mg, 0.393 mmol) in methylene chloride (3 mL) was treated with pyridinium chlorochromate (20 wt. % on basic alumina, 508 mg, 0.471 mmol). The resulting reaction mixture was stirred at 25° C. for 3 h, at which time, thin layer chromatography indicated a small amount of the 3-(3-hydroxy-cyclopentyl)-2-(4-methanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide. The reaction mixture was then treated with an additional amount of pyridinium chlorochromate (20 wt. % on basic alumina, 127 mg, 0.118 mmol). The reaction mixture was allowed to stir at 25° C. for 1 h and then filtered through a pad of celite. The pad of celite was washed well with ethyl acetate until the washings indicated the absence of product by thin layer chromatography. The filtrate was then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/3 hexanes/ethyl acetate to 100% ethyl acetate) afforded 2-(4-methanesulfonyl-phenyl)-3-(3-oxo-cyclopentyl)-N-thiazol-2-yl-propionamide (46 mg, 30%) as a white foam: mp 94-97° C.; FAB-HRMS m/e calcd for C18H20N2O4S2 (M+H)+ 393.0943. found 393.0948.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[S:27][C:28]2[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[C:29]=2[N:30]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[S:27][C:28]5[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[C:29]=5[N:30]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: Cc1cccc2sc(Cl)nc12
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cccc2sc(Sc3ccc4c(c3)CC[C@H]3N(C)C(=O)CC[C@]43C)nc12
Yield: 42.5 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 2-chloro-4-methylbenzothiazole (84 mg, 0.46 mmol) and 1 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent) to give 66 mg (43%) of the title compound as an amorphous solid. mp 134°-142° FDMS: m/e =408. α[D]589 =+62.80 (c=0.74, chloroform).
Reaction SMILES: Cl.[N+:2]([C:5]1[N:10]=[CH:9][C:8]([O:11][C@@H:12]2[CH:19]3[CH2:20][N:15]4[CH2:16][CH:17]([CH2:21][CH:13]2[CH2:14]4)[CH2:18]3)=[CH:7][CH:6]=1)([O-])=O>C1COCC1.CO.[Ni]>[NH2:2][C:5]1[N:10]=[CH:9][C:8]([O:11][C@@H:12]2[CH:19]3[CH2:20][N:15]4[CH2:16][CH:17]([CH2:21][CH:13]2[CH2:14]4)[CH2:18]3)=[CH:7][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(OC2C3CC4CC2CN(C4)C3)cn1
Agent: [Ni]
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(OC2C3CC4CC2CN(C4)C3)cn1
Temperature: 50 °C

Procedure:
A solution of the product of Example 16B (380 mg, 1.2 mmol) in THF-MeOH (10 mL, 1:1) was treated with Raney nickel (401 mg, 6.83 mmol) under an atmosphere of hydrogen (60 psi), and the mixture was warmed to 50° C. for 1 hour. After removing the catalyst by filtration, the product was purified by preparative HPLC [Waters® XTerra RP18 column, 5μ, 30×100 mm, flow rate 40 mL/minutes, 5-95% gradient of acetonitrile in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide), with UV detection at 254 nm]. Fractions containing the desired compound were pooled, concentrated under vacuum, diluted with methanol, and filtered to afford the title compound: 1H NMR (300 MHz, methanol-D4) δ ppm 1.66 (s, 1H), 1.80 (d, J=12.5 Hz, 2H), 1.99 (s, 2H), 2.28-2.39 (m, 2H), 3.01-3.12 (m, 4H), 3.24 (ddd, J=14.1, 2.4, 2.2 Hz, 2H), 4.45 (t, J=3.2 Hz, 1H), 6.57 (dd, J=9.2, 0.7 Hz, 1H), 7.27 (dd, J=9.0, 2.9 Hz, 1H), 7.67 (dd, J=3.1, 0.7 Hz, 1H). MS (+ESI) m/z=246 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C:10]1[S:14][C:13]([NH:15][C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)=[N:12][C:11]=1[C:26]([NH2:28])=[O:27])=[O:8].[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>CC(N(C)C)=O>[O:32]1[CH2:33][CH2:34][N:29]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C:10]2[S:14][C:13]([NH:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=3)=[N:12][C:11]=2[C:26]([NH2:28])=[O:27])=[O:8])[CH2:30][CH2:31]1
Reactant: C1COCCN1
Reactant: NC(=O)c1nc(Nc2ccc3ccccc3c2)sc1NC(=O)CCCCCBr
Solvent: CC(=O)N(C)C
Product: NC(=O)c1nc(Nc2ccc3ccccc3c2)sc1NC(=O)CCCCCN1CCOCC1
Temperature: 120 °C
Yield: 90.2 %

Procedure:
A mixture of 5-(6-bromohexanamido)-2-(naphthalen-2-ylamino)thiazole-4-carboxamide (150 mg, 0.32 mmol) and morpholine (0.06 mL, 0.69 mmol) in DMA (0.5 ml) was heated at 120° C. for 1.5 hrs in a sealed tube. The reaction mixture was then diluted with ice-water. The resulting solids were collected by filtration and washed successively with ether and MeOH to give 135 mg (90% yield) of the titled compound.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7]O)[CH2:2][CH3:3].S(Cl)([Cl:15])=O>C1(C)C=CC=CC=1.N1C=CC=CC=1>[CH2:1]([O:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7][Cl:15])[CH2:2][CH3:3]
Reactant: O=S(Cl)Cl
Reactant: CCCOc1ccccc1CO
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCCOc1ccccc1CCl
Yield: 104.6 %

Procedure:
A 2 liter flask was charged with 316 grams (1.9 moles, 1.0 eg.) of 2-propoxybenzyl alcohol and 15 grams of pyridine (0.0126 moles) in 750 ml of toluene. 237 grams (1.99 moles, 1.01 ec.) of thionyl chloride was slowly added dropwise, allowing the reaction mixture to reflux during the addition. The reaction was stirred 4 hours at room temperature after which the toluene and thionyl chloride were removed under reduced pressure. To the remaining oil was added water and ether and washed with saturated NaHCO3 Drying and removal of the solvent gave 367 grams (100% yield) of a red oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([NH2:18])=[O:17])=[N:14][CH:15]=1.[H-].[Na+].[C:32](OC(=O)C)(=[O:34])[CH3:33].O>CN(C)C=O>[C:32]([NH:18][C:16]([C:13]1[CH:12]=[C:11]([CH3:19])[C:10]([CH:9]([C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[F:1])[S:20]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])=[CH:15][N:14]=1)=[O:17])(=[O:34])[CH3:33]
Reactant: Cc1cc(C(N)=O)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Reactant: CC(=O)OC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)NC(=O)c1cc(C)c(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(F)cc2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
To a solution of 5-[(2,5-difluorophenyl)[(4-fluorophenyl)sulfonyl]methyl]-4-methylpyridine-2-carboxamide (150 mg, 0.36 mmol) obtained in Example 15 in N,N-dimethylformamide (7 ml), sodium hydride (60%, 34 mg, 0.79 mmol) was added at 0° C., and the mixture was stirred for 1 hour at room temperature. Subsequently, acetic anhydride (40 μl) was added to the reaction solution at 0° C., and the mixture was stirred for 1 hour at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, and was dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, and the resulting residue was subjected to silica gel chromatography. The fraction obtained from an elution with hexane:ethyl acetate=10:3 was concentrated under reduced pressure, and the resulting residue was washed with diethyl ether and n-hexane, and then was collected by filtration, to obtain the title compound (80 mg, 0.17 mmol, 48%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:15]([Br:16])=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([NH:6][CH2:7][C:8]([F:11])([F:10])[F:9])=[O:5].[C:17](OC(Cl)(Cl)Cl)(OC(Cl)(Cl)Cl)=[O:18]>>[Br:16][C:15]1[CH:14]=[CH:13][CH:12]=[C:3]2[C:2]=1[NH:1][C:17](=[O:18])[N:6]([CH2:7][C:8]([F:9])([F:10])[F:11])[C:4]2=[O:5]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1c(Br)cccc1C(=O)NCC(F)(F)F
Product: O=c1[nH]c2c(Br)cccc2c(=O)n1CC(F)(F)F
Yield: 266.5 %

Procedure:
8-Bromo-3-(2,2,2-trifluoroethyl)quinazoline-2,4(1H,3H)-dione (501b, 1.53 g, 88%) was prepared according to the procedures described for 720 using 2-amino-3-bromo-N-(2,2,2-trifluoroethyl)benzamide (1.6 g, 5.39 mmol, 501a) and tri-phosgene (0.5 g, 1.777 mmol, Sigma Aldrich) as the reagents. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.86 (1H, s) 8.01 (2H, d, J=7.82 Hz) 7.20 (1H, t, J=7.82 Hz) 4.73 (2H, q, J=9.19 Hz). m/z (ESI, +ve) 322.9/324.9 (M+H)+.
Reaction SMILES: C(O[C:5]1([CH3:14])[CH:9]=[CH:8][C:7](=[O:10])[CH:6]1[CH2:11][CH:12]=[CH2:13])(=O)C.[C:15]([O-:18])(=[O:17])[CH3:16].[Na+]>C(O)(=O)C>[C:15]([O:18][CH:9]1[CH2:8][C:7](=[O:10])[C:6]([CH2:11][CH:12]=[CH2:13])=[C:5]1[CH3:14])(=[O:17])[CH3:16]
Reactant: C=CCC1C(=O)C=CC1(C)OC(C)=O
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: C=CCC1=C(C)C(OC(C)=O)CC1=O
Yield: 176.3 %

Procedure:
Into a four necked flask equipped with an agitator and a thermometer, 3-acetoxy-2-allyl-3-methyl-4-cyclopentenone (19.4 g), acetic acid (80 ml) and sodium acetate (4 g) were charged and refluxed for 5 hours with agitation. After the completion of the reaction, acetic acid was evaporated off under reduced pressure. The residue was shaken with toluene (70 ml) and water (40 ml). The organic layer was separated, washed with an aqueous solution of sodium bicarbonate and then water and concentrated. The residue was distilled to obtain 4-acetoxy-2-allyl-3-methyl-2-cyclopentenone (16.7 g). Yield, 86%. B.P., 100°-110° C./0.1-0.3 mmHg.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([CH2:26][O:27][CH3:28])=[N:7][C:8]2[C:13]([C:14]=1O)=[CH:12][CH:11]=[C:10]([C:16]1[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:19]=[CH:18][N:17]=1)[N:9]=2)=[O:4].O=P(Cl)(Cl)[Cl:31]>N1C(C)=CC=CC=1C.C(Cl)(Cl)Cl>[Cl:31][C:14]1[C:13]2[C:8](=[N:9][C:10]([C:16]3[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:11][CH:12]=2)[N:7]=[C:6]([CH2:26][O:27][CH3:28])[C:5]=1[C:3]([O:2][CH3:1])=[O:4]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COCc1nc2nc(-c3ncccc3C(F)(F)F)ccc2c(O)c1C(=O)OC
Solvent: Cc1cccc(C)n1
Solvent: ClC(Cl)Cl
Product: COCc1nc2nc(-c3ncccc3C(F)(F)F)ccc2c(Cl)c1C(=O)OC

Procedure:
Dissolve 4-hydroxy-2-methoxymethyl-7-(3-trifluoromethylpyridin-2-yl)-[1,8]naphthyridine-3-carboxylic acid methyl ester (500 mg, 1.27 mmol) in a solution of POCl3 (0.4 mL), 2,6-lutidine (0.43 mL) and CHCl3 (25 mL). Heat the mixture at reflux overnight. Remove the solvent under reduced pressure. Partition the residue between CH2Cl2 and saturated NaHCO3 (aq). Extract the aqueous layer twice with CH2Cl2 (2×100 mL). Dry the combined organic extracts over Na2SO4. Remove the solvent under reduced pressure. Purify the crude product by preparatory TLC eluting with EtOAc\Hexanes (1:1) to yield the title compound.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[C:9]([F:28])[C:10]([CH3:27])=[C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH2:22][C:23]([O:25]C)=O)[N:17]=[CH:16]4)[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.[CH3:29][C:30]([CH3:34])([CH3:33])[CH2:31][NH2:32]>>[CH:1]1([NH:4][C:5](=[O:6])[C:7]2[CH:8]=[C:9]([F:28])[C:10]([CH3:27])=[C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH2:22][C:23]([NH:32][CH2:31][C:30]([CH3:34])([CH3:33])[CH3:29])=[O:25])[N:17]=[CH:16]4)[CH:12]=2)[CH2:2][CH2:3]1
Reactant: CC(C)(C)CN
Reactant: COC(=O)Cn1ncc2cc(-c3cc(C(=O)NC4CC4)cc(F)c3C)ccc21
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(cnn2CC(=O)NCC(C)(C)C)c1

Procedure:
Example 140 was prepared by General Method D using methyl (5-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-1H-indazol-1-yl)acetate (Example 123) and 2,2-dimethyl-1-propanamine to give the title compound (0.008 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]([OH:16])=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[N:32]=[C:31]([NH:33][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH:30]=[CH:29][CH:28]=2)[CH2:23][CH2:22]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH:24]([C:27]4[CH:28]=[CH:29][CH:30]=[C:31]([NH:33][C:34](=[O:38])[CH:35]([CH3:36])[CH3:37])[N:32]=4)[CH2:23][CH2:22]3)=[O:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)n1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CCCCC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)C3(c4ccc(Cl)cc4)CCCCC3)CC2)n1

Procedure:
Example 67 was prepared from 1-(4-chlorophenyl)cyclohexanecarboxylic acid and N-{6-[1-(3-aminopropyl)-4-piperidinyl]-2-pyridinyl}-2-methylpropanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 8.06 (d, 1H, J=8.4 Hz), 7.78 (br s, 1H), 7.65 (t, 1H, J=8.0 Hz), 7.40–7.38 (m, 2H), 7.30–7.27 (m, 2H), 6.88 (d, 2H, J=7.6 Hz), 3.29 (dd, 2H, J=6.0, 11.6 Hz), 2.96 (m, 2H), 2.56–2.49 (m, 2H), 2.36–2.30 (m, 4H), 2.00–1.75 (m, 8H), 1.64–1.59 (m, 8H), 1.25 (d, 6H, J=6.8 Hz); ESMS m/e: 525.3 (M+H)+.
Reaction SMILES: C(O[C:4]([C:6]1[N:11]=[C:10]([CH3:12])[C:9]2[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[S:15][C:8]=2[C:7]=1[OH:23])=[O:5])C.[NH2:24][CH2:25][C:26]([OH:28])=[O:27]>C[O-].[Na+].CO>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:14]2[S:15][C:8]3[C:7]([OH:23])=[C:6]([C:4]([NH:24][CH2:25][C:26]([OH:28])=[O:27])=[O:5])[N:11]=[C:10]([CH3:12])[C:9]=3[N:13]=2)=[CH:17][CH:18]=1
Reactant: CCOC(=O)c1nc(C)c2nc(-c3ccc(F)cc3)sc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1nc(C(=O)NCC(=O)O)c(O)c2sc(-c3ccc(F)cc3)nc12
Temperature: 25 °C
Yield: 81.7 %

Procedure:
A mixture of 2-(4-fluoro-phenyl)-7-hydroxy-4-methyl-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (70 mg, 0.21 mmol) and glycine (317 mg, 4.23 mmol) in 0.5 M sodium methoxide/methanol (8 mL) was refluxed for four days before it was cooled to room temperature and concentrated in vacuo. The residue was dissolved in water (25 mL) and extracted twice with dichloromethane. The remaining aqueous layer was acidified to pH=3 with 1N HCl (6 mL). The solid precipitate was filtered, washed with water and dried in vacuo to give the title compound as a white solid (62 mg): 1H NMR (DMSO-d6, 200 MHz): δ=13.01 (br s, 1H), 9.22 (br s, 1H), 8.20 (m, 2H), 7.40 (m, 2H), 4.03 (d, J=5.9 Hz, 2H), 2.86 (s, 3H); MS: (+) m/z 361.87 (M+1).