Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[N:4][N:3]=[N:2]1.[H-].[Na+].[CH2:8]([N:14]1[C:23]2[C:18](=[CH:19][C:20]([CH3:24])=[CH:21][CH:22]=2)[C:17]([O:25][CH3:26])=[C:16]([CH2:27]Br)[C:15]1=[O:29])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]>CN(C)C=O.C(OC(=O)C)C>[CH2:8]([N:14]1[C:23]2[C:18](=[CH:19][C:20]([CH3:24])=[CH:21][CH:22]=2)[C:17]([O:25][CH3:26])=[C:16]([CH2:27][C:5]2[NH:4][N:3]=[N:2][N:1]=2)[C:15]1=[O:29])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCn1c(=O)c(CBr)c(OC)c2cc(C)ccc21
Reactant: c1nnn[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCn1c(=O)c(Cc2nnn[nH]2)c(OC)c2cc(C)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.2 %

Procedure:
A solution of tetrazole (0.17 g) in dimethylformamide (2 ml) at ice-bath temperature under nitrogen was stirred with 60% sodium hydride (0.1 g) for 5 mins and then a solution of 1-hexyl-3-bromomethyl-4-methoxy-6-methyl-2(1H)-quinolinone (Example 14, 0.73 g) in dimethylformamide (8 ml) was added to it. The reaction mixture was stirred at room temperature for 2 hours, diluted with ethylacetate and then washed several times with water. The organic layer was dried and evaporated under reduced pressure. The resulting crude reaction product was chromatographed on silica-gel (30 g). Elution with 10% to 20% ethylacetatedichloromethane gave 1-hexyl-3-(1-tetrazolylmethyl)-4-methoxy-6-methyl-2(1H)-quinolinone (0.37 g). That this compound was obtained was confirmed by the spectral data: MS: m/e 355 (M.+); NMR (CDCl3): δ4.18 (s, 3H, OCH3), 5.68 (s, 2H, CH2), 9.14 (s, 1H, CH=).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([CH:25]=[CH:26][C:27]=2[OH:28])[CH2:12][N:13]([CH3:24])[S:14]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:6]=[CH:7][CH:8]=1.[C:31]([O:35][C:36](=[O:40])[C@H:37](O)[CH3:38])([CH3:34])([CH3:33])[CH3:32].N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:31]([O:35][C:36](=[O:40])[C@@H:37]([O:28][C:27]1[CH:26]=[CH:25][C:11]([CH2:12][N:13]([CH3:24])[S:14]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])=[CH:10][C:9]=1[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:29])[F:30])[CH:4]=1)[CH3:38])([CH3:34])([CH3:33])[CH3:32]
Reactant: CN(Cc1ccc(O)c(-c2cccc(C(F)(F)F)c2)c1)S(=O)(=O)c1ccc(F)cc1
Reactant: C[C@@H](O)C(=O)OC(C)(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H](Oc1ccc(CN(C)S(=O)(=O)c2ccc(F)cc2)cc1-c1cccc(C(F)(F)F)c1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 4 h
Yield: 13.9 %

Procedure:
A solution of N-(3-(3-trifluoromethylphenyl)-4-hydroxybenzyl)-4-fluoro-N-methylbenzenesulfonamide (36) (50.0 mg, 0.114 mmol) and (R)-t-butyl-2-hydroxypropanoate (18.3 mg, 0.125 mmol, 1.1 eq, Chem-Impex International, Inc., Wood Dale, Ill., USA) in THF (2 mL) at 0° C. was added diethyl azodicarboxylate (20 μL, 0.125 mmol, 1.1 eq) and triphenylphosphine (33 mg 0.125 mmol, 1.1 eq). After stirring at 0° C. for 4 h the mixture was extracted between saturated sodium bicarbonate and ethyl acetate, dried (Na2SO4) and concentrated in vacuo. This crude product was purified on reversed phase semi-preparative HPLC to give 9 mg of t-butyl-(S)-2-(2-(3-trifluoromethylphenyl)-4-((4-fluoro-N-methylphenylsulfonamido)methyl)phenoxy)propanate. This intermediate was then dissolved in TFA/DCM (1 mL/1 mL) and stirred at room temperature for 30 min. Solvent was removed in vacuo and the residue was purified via reversed phase semi-preparative HPLC to afford 4.9 mg of (S)-2-(2-(3-trifluoromethylphenyl)-4-((4-fluoro-N-methylphenylsulfonamido)methyl)phenoxy)propanoic acid (Example 36). 1HNMR (CDCl3, 400 MHz): δ 7.84 (m, 3H), 7.70 (d, 1H), 7.56 (m, 2H), 7.26 (m, 3H), 7.20 (d, 1H), 6.88 (d, 1H), 4.80 (m, 1H), 4.15 (s, 2H), 2.64 (s, 3H), 1.57 (d, 3H). MS (ESI): MH+=512.1. HPLC (Method B) tR=2.78 min.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[CH:39]=[C:38]([N:40]4[CH2:45][CH2:44][N:43]([CH2:46][C:47]5[CH2:52][C:51](=O)[CH2:50][CH2:49][C:48]=5[C:54]5[CH:59]=[CH:58][C:57]([Cl:60])=[CH:56][CH:55]=5)[CH2:42][CH2:41]4)[CH:37]=[CH:36][C:12]=3[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][CH2:26][CH:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[C:21]([N+:33]([O-:35])=[O:34])[CH:20]=3)(=[O:18])=[O:17])=[O:14])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[NH:61]1[CH2:66][CH2:65][O:64][CH2:63][CH2:62]1>ClCCl.CO>[Cl:60][C:57]1[CH:58]=[CH:59][C:54]([C:48]2[CH2:49][CH2:50][CH:51]([N:61]3[CH2:66][CH2:65][O:64][CH2:63][CH2:62]3)[CH2:52][C:47]=2[CH2:46][N:43]2[CH2:42][CH2:41][N:40]([C:38]3[CH:37]=[CH:36][C:12]([C:13]([NH:15][S:16]([C:19]4[CH:24]=[CH:23][C:22]([NH:25][CH2:26][CH:27]5[CH2:28][CH2:29][O:30][CH2:31][CH2:32]5)=[C:21]([N+:33]([O-:35])=[O:34])[CH:20]=4)(=[O:18])=[O:17])=[O:14])=[C:11]([O:10][C:6]4[CH:7]=[C:8]5[C:9](=[CH:4][CH:5]=4)[NH:1][CH:2]=[CH:3]5)[CH:39]=3)[CH2:45][CH2:44]2)=[CH:55][CH:56]=1
Reactant: O=C1CCC(c2ccc(Cl)cc2)=C(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(NCC5CCOCC5)c([N+](=O)[O-])c4)c(Oc4ccc5[nH]ccc5c4)c3)CC2)C1
Reactant: C1COCCN1
Solvent: ClCCl
Solvent: CO
Product: O=C(NS(=O)(=O)c1ccc(NCC2CCOCC2)c([N+](=O)[O-])c1)c1ccc(N2CCN(CC3=C(c4ccc(Cl)cc4)CCC(N4CCOCC4)C3)CC2)cc1Oc1ccc2[nH]ccc2c1
Reaction time: 8 h

Procedure:
To a mixture of EXAMPLE 249F (120 mg) in dichloromethane (2 mL) and methanol (0.5 mL) was added morpholine (37mg) and 2-picoline borane complex (15.04 mg). The mixture was stirred overnight. The mixture was then diluted with dichloromethane (200 mL) and washed with aqueous NaHCO3, water, and brine, and dried over Na2SO4. The residue, after evaporation of solvent, was dissolved in dichloromethane and chromatographed with 0-10% 7N NH3 in 5% methanol in dichloromethane to give the title compound. 1H NMR (300 MHz, dimethylsulfoxide-d6) δ 11.15 (s, 1H), 8.58 (m, 2H), 7.79 (dd, 1H), 7.53 (m, 1H), 7.35 (m, 4H), 7.17 (m, 1H), 7.07 (m, 2H), 6.85 (dd, 1H), 6.64 (dd, 1H), 6.39 (s, 1H), 6.13 (d, 1H), 3.84 (m, 2H), 3.58 (m, 5H), 3.01 (m, 5H), 2.63 (m, 6H), 2.10 (m, 14H), 1.61 (m, 3H), 1.26 (m, 3H).
Reaction SMILES: [H][H].O.[C:4]([NH:7][C:8]1[C:9]([O:20][CH3:21])=[C:10]([N+:17]([O-])=O)[C:11]([O:15][CH3:16])=[C:12]([Cl:14])[CH:13]=1)(=[O:6])[CH3:5]>[Fe].C(O)(=O)C>[C:4]([NH:7][C:8]1[C:9]([O:20][CH3:21])=[C:10]([NH2:17])[C:11]([O:15][CH3:16])=[C:12]([Cl:14])[CH:13]=1)(=[O:6])[CH3:5]
Reactant: [H][H]
Reactant: COc1c(Cl)cc(NC(C)=O)c(OC)c1[N+](=O)[O-]
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: COc1c(Cl)cc(NC(C)=O)c(OC)c1N
Temperature: 80 °C

Procedure:
253 g of powdered iron which had been reduced with hydrogen were added to 760 ml of water containing 13 ml of acetic acid and which had been previously heated to 80° C., and then 0.46 mole (126.5 g) of 5-acetamido-2,4-dimethoxy-3-nitrochlorobenzene prepared in the previous step was added gradually, with stirring. Upon completion of the additions, the reaction mixture was maintained in a boiling water bath for 15 minutes. After cooling, the reaction mixture was centrifuged. The iron slurries after being separated from the liquid phase were extracted with ethyl acetate. The ethyl acetate phase which was washed with water and then dried over sodium sulphate was diluted with 100 ml of a 7N hydrochloric acid solution in absolute ethanol. The expected product, which precipitated n the form of hydrochloride, was thoroughly drained. It was dissolved in the minimum amount of water. After neutralization, the expected product precipitated. Recrystallized from alcohol, it melted at 113° C.
Reaction SMILES: [C:1]1([CH3:22])[CH:6]=[CH:5][C:4]([S:7]([NH:10][C@@H:11]([C:19]([OH:21])=[O:20])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1>C(OCC)(=O)C.C(OCC)C>[C:1]1([CH3:22])[CH:2]=[CH:3][C:4]([S:7]([NH:10][C@H:11]([C:19]([OH:21])=[O:20])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:9])=[O:8])=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)N[C@H](Cc2ccccc2)C(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)N[C@@H](Cc2ccccc2)C(=O)O)cc1
Yield: 100 %

Procedure:
In a mixture of 50 ml of ethyl acetate and 50 ml of diethylether were dissolved under heating 7.4 g of 2,4-cis-4-ethoxycarbonyl-2-(4-fluoro-2-methylphenyl)piperidine and 4.0 g of N-p-toluenesulfonyl-D-phenylalanine. The solvent was concentrated by heating, 30 ml of diisopropyl ether was added thereto and the mixture was stirred. Precipitated crystals were removed and mother liquor was washed with a concentrated aqueous ammonia solution, dried and concentrated under reduced pressure. To the residue was added 4.0 g of N-p-toluenesulfonyl-L-phenylalanine, and 50 ml of ethyl acetate and 30 ml of diisopropyl ether were added thereto and dissolved by heating, the mixture was stirred at room temperature for 16 hours. Precipitated crystals were collected by filtration, washed with diisopropyl ether, and dried, to give 4.0 g of N-p-toluenesulfonyl-L-phenylalanine salt of (2R,4S)-4-ethoxycarbonyl-2-(4-fluoro-2-methylphenyl)-4-piperidine.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[C:7]([OH:9])[C:6]([O:10][CH2:11][CH2:12][CH3:13])=[CH:5][N:4]=1.CO[CH:16]=[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([N:27]3[CH:31]=[CH:30][CH:29]=[CH:28]3)[CH:25]=2)[C:20](=[O:32])[NH:19][C:18]1=[O:33]>CN(C)C=O>[OH:9][C:7]1[C:6]([O:10][CH2:11][CH2:12][CH3:13])=[CH:5][N:4]=[C:3]([CH2:2][NH:1][CH:16]=[C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([N:27]4[CH:31]=[CH:30][CH:29]=[CH:28]4)[CH:25]=3)[C:20](=[O:32])[NH:19][C:18]2=[O:33])[CH:8]=1
Reactant: CCCOc1cnc(CN)cc1O
Reactant: COC=C1C(=O)NC(=O)c2ccc(-n3cccc3)cc21
Solvent: CN(C)C=O
Product: CCCOc1cnc(CNC=C2C(=O)NC(=O)c3ccc(-n4cccc4)cc32)cc1O

Procedure:
A mixture of 2-aminomethyl-5-propoxy-pyridin-4-ol (137 mg, 0.75 mmole) IN 10 mL of N,N-dimethylformamide is stirred, then 4-methoxymethylene-6-pyrrol-1-yl-4H-isoquinoline-1,3-dione (201 mg, 0.75 mmole) is added and the reaction mixture stirred for one hour. The reaction mixture is evaporated to dryness, triturated with 5% methanol in chlororform, filtered, washed with fresh 5% methanol in chloroform, washed with acetonitrile and dried to give a grey solid, 290 mg, (92%); MS (ES+): m/z 419.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[S:24][CH:25]=[CH:26][C:27]=3[O:28][CH2:29][CH3:30])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[CH3:33][S:34]([CH2:37][CH2:38][N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)(=[O:36])=[O:35]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:42]3[CH2:41][CH2:40][N:39]([CH2:38][CH2:37][S:34]([CH3:33])(=[O:35])=[O:36])[CH2:44][CH2:43]3)=[O:21])[C:10]([C:23]3[S:24][CH:25]=[CH:26][C:27]=3[O:28][CH2:29][CH3:30])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)CCN1CCNCC1
Reactant: CCOc1ccsc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Product: CCOc1ccsc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CCS(C)(=O)=O)CC1

Procedure:
2-{4-[(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-(2-methanesulfonylethyl)piperazine dihydrochloride (example 3) to give [(4S,5R)-4,5-bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro-imidazol-1-yl]-[4-(2-methanesulfonyl-ethyl)-piperazin-1-yl]-methanone in an analogous manner as described in example 1. LR-MS: 635.1 [(M+H)+].
Reaction SMILES: C([O:8][C:9]1[C:10]2[N:11]([C:20]([CH3:24])=[C:21]([CH3:23])[N:22]=2)[CH:12]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:14]=1)C1C=CC=CC=1>C(O)C.[Pd]>[CH2:18]([O:17][C:15]([CH:13]1[CH2:12][N:11]2[C:20]([CH3:24])=[C:21]([CH3:23])[N:22]=[C:10]2[CH:9]([OH:8])[CH2:14]1)=[O:16])[CH3:19]
Reactant: CCOC(=O)c1cc(OCc2ccccc2)c2nc(C)c(C)n2c1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1CC(O)c2nc(C)c(C)n2C1
Yield: 14.5 %

Procedure:
3 g of 8-benzyloxy-6-ethoxycarbonyl-2,3-dimethylimidazo[1,2-a]pyridine, suspended in 50 ml of ethanol, are treated with 0.5 g of 10% strength palladium/active carbon and hydrogenated under a hydrogen pressure of 50 bar for 20 hours at an oil bath temperature of 75° C. After cooling, the catalyst is filtered off, the filtrate is concentrated to ⅕ of the volume in vacuo and the colorless precipitate formed here is filtered off. The filtrate from the precipitate is concentrated to dryness and chromatographed on silica gel (eluent: methylene chloride/methanol 100/3). 0.32 g of 6-ethoxycarbonyl-8-hydroxy-2,3-dimethyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine is obtained. For conversion into the title compound, it is dissolved in chloroform, treated with 1.6 g of manganese dioxide and stirred at room temperature for 20 h. It is then filtered off, the filtrate is concentrated to dryness in vacuo and the residue obtained is purified on silica gel (eluent: methylene chloride/methanol 13/1). 0.2 g of the title compound of melting point 138-40° C. (diethyl ether) is obtained.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:50]1[C:58]2[C:53](=[CH:54][C:55]([C:59]3[CH:60]=[C:61]([NH2:65])[CH:62]=[CH:63][CH:64]=3)=[CH:56][CH:57]=2)[CH:52]=[CH:51]1>CN(C=O)C>[NH:50]1[C:58]2[C:53](=[CH:54][C:55]([C:59]3[CH:60]=[C:61]([NH:65][C:23]([C:18]4[C:19](=[O:22])[O:20][C:21]5[C:16]([CH:17]=4)=[CH:15][CH:14]=[CH:13][C:12]=5[O:11][CH3:10])=[O:25])[CH:62]=[CH:63][CH:64]=3)=[CH:56][CH:57]=2)[CH:52]=[CH:51]1
Reactant: Nc1cccc(-c2ccc3[nH]ccc3c2)c1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc2cc(C(=O)Nc3cccc(-c4ccc5[nH]ccc5c4)c3)c(=O)oc12
Temperature: 25 °C
Yield: 62.8 %

Procedure:
DIEA (0.014 mL, 0.073 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.016 g, 0.066 mmol) and HATU (0.030 g, 0.073 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(1H-Indol-5-yl)-phenylamine (0.015 g, 0.066 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.017 g of product in 56% yield: LCMS (ESI) m/z 411 (MH+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[S:9][CH:10]=[CH:11][N:12]=1.[Br:13]Br.OS([O-])=O.[Na+]>C(Cl)(Cl)Cl>[Br:13][C:10]1[S:9][C:8]([NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[N:12][CH:11]=1
Reactant: BrBr
Reactant: c1ccc(Nc2nccs2)nc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Brc1cnc(Nc2ccccn2)s1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a stirred suspension of N-(pyridin-2-yl)thiazol-2-amine (9.76 g, 55.07 mmol) in degassed chloroform (180 mL) was added bromine (3.11 mL, 60.6 mmol, 1.1 eq) at 23° C. The reaction was stirred for 15 minutes and followed by LC/MS. Bromine (2×0.3 mL) was added until reaction completed. The mixture was cooled to 0° C. and 10% aq. NaHSO3 (150 mL) was added. The suspension changed color and the solid was filtered, washed with water and vacuum dried overnight. The title compound was obtained as a solid (10.79 g, 77%). 1H NMR (400 MHz, DMSO-d6) δ ppm 6.94-6.99 (1H, m), 7.04 (1H, d, J=8.34 Hz) 7.45 (1H, s), 7.74 (1 H, td, J=7.83, 1.77 Hz), 8.31 (1 H, d, J=5.31 Hz), 11.54 (1 H, s). LC/MS (M+H)+: 256, 258; (M−H)−: 254, 256.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:39])[NH:5][C:6]1[S:7][C:8]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[CH:13][C:12]([C:21]3[CH:22]=[C:23]([N:27]4[CH2:32][CH2:31][C:30]([CH3:38])([C:33]([O:35]CC)=[O:34])[CH2:29][CH2:28]4)[N:24]=[N:25][CH:26]=3)=[CH:11][C:9]=2[N:10]=1)[CH3:2].CC(C)([O-])C.[K+].O>CS(C)=O>[CH2:1]([NH:3][C:4](=[O:39])[NH:5][C:6]1[S:7][C:8]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[CH:13][C:12]([C:21]3[CH:22]=[C:23]([N:27]4[CH2:32][CH2:31][C:30]([CH3:38])([C:33]([OH:35])=[O:34])[CH2:29][CH2:28]4)[N:24]=[N:25][CH:26]=3)=[CH:11][C:9]=2[N:10]=1)[CH3:2]
Reactant: CCNC(=O)Nc1nc2cc(-c3cnnc(N4CCC(C)(C(=O)OCC)CC4)c3)cc(-c3ccccn3)c2s1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCNC(=O)Nc1nc2cc(-c3cnnc(N4CCC(C)(C(=O)O)CC4)c3)cc(-c3ccccn3)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.5 %

Procedure:
To an ice-cold solution of ethyl 1-(5-(2-(3-ethylureido)-7-(pyridin-2-yl)benzo[d]thiazol-5-yl)pyridazin-3-yl)-4-methylpiperidine-4-carboxylate (0.05 g, 0.092 mmol) in DMSO (2 mL) was added potassium tert-butoxide (0.051 g, 0.45 mmol) and the mixture stirred at rt for 2 h. After completion of reaction (by TLC), water (10 mL) was added followed by extraction with EtOAc (3×50 mL) and the organic layer discarded. The pH of the aqueous layer was adjusted up to 4-5, extracted with EtOAc (3×50 mL) and the combined organic layer dried over Na2SO4, filtered and evaporated under reduced pressure. The residue thus obtained was triturated with ether to obtain Compound 195 as an off-white solid (0.025 g, 53%). 1H NMR (DMSO-d6): δ 9.15 (s, 1H), 8.82 (m, 1H), 8.55 (d, J=8.0 Hz, 1H), 8.38 (s, 1H), 8.21 (s, 1H), 8.02 (t, J=8.0 Hz, 1H), 7.90 (m, 1H), 7.64 (s, 1H), 7.46 (m, 1H), 7.17 (br s, 1H), 4.20 (m, 2H), 3.19-3.24 (m, 4H), 2.10 (m, 2H), 1.43 (m, 2H), 1.22 (s, 3H) and 1.01 (t, J=7.2 Hz, 3H). MS: 518.29 [M+H]+.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(OCC)(=O)C>[C:13]1([NH:12][C:2]2[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=2[N+:8]([O-:10])=[O:9])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: Nc1ccccc1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(O)cc1Nc1ccccc1
Temperature: 140 °C
Reaction time: 3 h

Procedure:
14 g of 3-fluoro-4-nitrophenol and 24 ml of aniline were mixed and stirred for 3 hours at 140° C. After cooling, it was dissolved in ethyl acetate and extracted six times with 2N aqueous hydrochloric acid. The organic phase was washed with saturated sodium chloride solution, dried on sodium sulfate, concentrated by evaporation in a vacuum, and the residue was crystallized from diisopropyl ether. 20.8 g was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([NH2:12])=[CH:7]2.C(N(CC)CC)C.[CH3:20][O:21][CH2:22][C:23](Cl)=[O:24]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([NH:12][C:23](=[O:24])[CH2:22][O:21][CH3:20])=[CH:7]2
Reactant: COCC(=O)Cl
Reactant: Nc1cnc2c(Cl)ccnc2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC(=O)Nc1cnc2c(Cl)ccnc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.3 %

Procedure:
A round bottom flask under nitrogen was charged with 8-chloro-1,5-naphthyridin-3-amine (41 mg, 0.23 mmol), triethylamine (64 μl, 0.46 mmol), and dichloromethane (1 mL). To this was added 2-methoxyacetyl chloride (42 μl, 0.46 mmol) dropwise via syringe and reaction allowed to stir overnight at room temperature. Next day reaction mixture was diluted with dichloromethane and washed with aqueous sodium bicarbonate solution. Layers separated and organic layer dried over sodium sulfate to afford yellow oil. This was purified by ISCO silica gel chromatography (2-5% MeOH/DCM) to afford N-(8-chloro-1,5-naphthyridin-3-yl)-2-methoxyacetamide (43 mg, 75% yield) as light yellow solid. MS[M+H]=251.9. Calc'd for C11H10ClN3O2=251.7.
Reaction SMILES: N[C:2]1[C:7]([I:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.N([O-])=[O:11].[Na+].[OH-].[Na+]>S(=O)(=O)(O)O>[Br:9][C:5]1[CH:6]=[C:7]([I:8])[C:2](=[O:11])[NH:3][CH:4]=1
Reactant: O=N[O-]
Reactant: Nc1ncc(Br)cc1I
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=c1[nH]cc(Br)cc1I
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Amino-5-bromopyridine (CAS No. 1072-97-5) (300 g) was dissolved in a mixed solvent consisting of 1000 ml of acetic acid and 200 ml of water, 30 ml of concentrated sulfuric acid were gradually dropped thereinto under stirring. Then, 79.1 g of periodic acid hydrate and 176 g of iodine were added thereto, followed by stirring at 80° C. for 4 hours. To the reaction mixture were added periodic acid hydrate (40 g) andiodine (22 g), followed by further stirring at 80° C. for 2 hours. After cooling to room temperature, the reaction mixture was poured onto ice (3000 ml) and neutralized to pH 7.0 with 5N aqueous sodium hydroxide. The resulting crystals were collected by filtration, dissolved in a mixed solvent of ethyl acetate/diethyl ether, successively washed with aqueous sodium thiosulfate, water, 1N aqueous sodium hydroxide and brine, and dried over anhydrous magnesium sulfate. Then, the solvent was evaporated, to give 392 g of 2-amino-5-bromo-3-iodopyridine (yield: 76%). 2-Amino-5-bromo-3-iodopyridine (100 g) was gradually added to 300 ml of concentrated sulfuric acid under ice-cooling. After the reaction mixture was stirred at room temperature for 2 hours, it was ice-cooled again. 35 g of sodium nitrite were gradually added thereto, followed by stirring at room temperature for 3 days and nights. The reaction solution was poured onto ice (3000 ml) and neutralized to pH 4.0 with sodium hydroxide. The resulting crystals were collected by filtration, washed with water and warm air-dried at 60° C. for one day and night, to give 102 g (quantitative) of the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]3[CH2:24][CH2:23]3)[N:17]=2)=[O:15])[CH2:10][C:9]1([CH3:26])[CH3:25])=O)(C)(C)C.[C:27]([OH:33])([C:29]([F:32])([F:31])[F:30])=[O:28]>>[F:30][C:29]([F:32])([F:31])[C:27]([OH:33])=[O:28].[CH:22]1([C:18]2[N:17]=[C:16]([C:14]([N:11]3[CH2:12][CH2:13][NH:8][C:9]([CH3:26])([CH3:25])[CH2:10]3)=[O:15])[CH:21]=[CH:20][CH:19]=2)[CH2:23][CH2:24]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cccc(C3CC3)n2)CC1(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CN(C(=O)c2cccc(C3CC3)n2)CCN1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a mixture of 190 mg (0.529 mmol) 4-(6-cyclopropyl-pyridine-2-carbonyl)-2,2-dimethyl-piperazine-1-carboxylic acid tert-butyl ester was added 500 μl (6.48 mmol) TFA. The resulting mixture was stirred at RT for 3.5 h. The solvent was evaporated.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)#[N:2].Br[C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([Cl:20])[CH:14]=1>>[Cl:20][C:15]1[CH:14]=[C:13]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH:18]=[CH:17][C:16]=1[OH:19]
Reactant: Oc1ccc(Br)cc1Cl
Reactant: N#Cc1ccc(B(O)O)cc1
Product: N#Cc1ccc(-c2ccc(O)c(Cl)c2)cc1
Yield: 62 %

Procedure:
4-Cyanophenylboronic acid and 4-bromo-2-chlorophenol were processed as described in Example 167A to provide the title compound (62% yield). 1HNMR (300 MHz, DMSO) δ7.12 (m, 1H), 7.58 (m, 1H), 7.80 (m, 5H); MS (CDI) m/z 247(M+NH4)+.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:11]3[N:12]=[C:13]([NH2:21])[N:14]=[C:15]([C:16]4[O:17][CH:18]=[CH:19][CH:20]=4)[C:10]=3[N:9]=[N:8]2)=[CH:4][C:3]=1[CH3:24].Cl[C:26]([O:28][CH2:29][CH3:30])=[O:27].O>N1C=CC=CC=1>[NH2:21][C:13]1[N:14]=[C:15]([C:16]2[O:17][CH:18]=[CH:19][CH:20]=2)[C:10]2[N:9]=[N:8][N:7]([CH2:6][C:5]3[CH:22]=[CH:23][C:2]([NH:1][C:26](=[O:27])[O:28][CH2:29][CH3:30])=[C:3]([CH3:24])[CH:4]=3)[C:11]=2[N:12]=1
Reactant: CCOC(=O)Cl
Reactant: Cc1cc(Cn2nnc3c(-c4ccco4)nc(N)nc32)ccc1N
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)Nc1ccc(Cn2nnc3c(-c4ccco4)nc(N)nc32)cc1C
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
A suspension of 3-(4-amino-3-methylbenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine (260 mg, 0.812 mmol) in pyridine (5 mL) at room temperature was treated dropwise with ethyl chloroformate (0.155 mL, 1.62 mmol), stirred for 30 min, poured into water (30 mL), extracted with EtOAc (2×10 mL) and the combined organic phase was dried (MgSO4) and concentrated in vacuo to give the title compound (318 mg, 100%) as a beige solid.