Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][N:3]=1.[NH2:10][CH:11]([CH3:21])[CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17].C(=O)(O)[O-].[K+]>CN(C=O)C.O>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:10][CH:11]([CH3:21])[CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[N:3][CH:4]=1)#[N:9]
Reactant: CC(N)CNC(=O)OC(C)(C)C
Reactant: N#Cc1ccc(Cl)nc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(CNC(=O)OC(C)(C)C)Nc1ccc(C#N)cn1
Temperature: 90 °C
Reaction time: 12 h

Procedure:
2-Chloro-5-cyanopyridine (477 mg, 3.4 mmol), tert-butyl (2-aminopropyl)carbamate (300 mg, 1.7 mmol) and potassium bicarbonate (345 mg, 3.4 mmol) are dissolved in DMF (10 ml) and stirred at 90° C. under argon for 12 h. The reaction mixture is diluted with water (100 ml) and extracted with ethyl acetate (3×75 ml). The combined organic phases are washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated. After removal of the solvent, the residue is purified by flash chromatography on silica gel (eluent: cyclohexane/ethyl acetate 10:1). 265 mg (55% of theory) of the product are obtained as a solid.
Reaction SMILES: [CH:1]([N:4]1[C:28](=[O:29])[C:27]2[N:12]3[CH2:13][CH2:14][C:15]4[CH:16]=[C:17]([O:25][CH3:26])[C:18]([O:21][CH:22]([CH3:24])[CH3:23])=[CH:19][C:20]=4[C:11]3=[C:10]([C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[C:9]=2[CH2:8][NH:7][CH2:6][CH2:5]1)([CH3:3])[CH3:2].[C:35](OC(=O)C)(=[O:37])[CH3:36]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C.O>[C:35]([N:7]1[CH2:8][C:9]2[C:10]([C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)=[C:11]3[C:20]4[CH:19]=[C:18]([O:21][CH:22]([CH3:23])[CH3:24])[C:17]([O:25][CH3:26])=[CH:16][C:15]=4[CH2:14][CH2:13][N:12]3[C:27]=2[C:28](=[O:29])[N:4]([CH:1]([CH3:2])[CH3:3])[CH2:5][CH2:6]1)(=[O:37])[CH3:36]
Reactant: COc1cc2c(cc1OC(C)C)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)C)CCNC3
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: COc1cc2c(cc1OC(C)C)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)C)CCN(C(C)=O)C3
Reaction time: 0.5 h

Procedure:
A solution of 35 mg of 14e in 250 μl of pyridine was treated with 30 μl of acetic anhydride and a catalytic amount of DMAP. After stirring ½ hr the reaction mixture was diluted with 400 μl of water and stirred for an additional 1 h. The precipitate was filtered, washed with water and dried to give 31 mg of crystalline white 14f;
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[C:9]([CH3:21])=[CH:10][C:11]2[O:15][C:14]([CH3:17])([CH3:16])[C:13](=[O:18])[C:12]=2[C:19]=1[CH3:20])([CH3:4])([CH3:3])[CH3:2].[Br:23]N1C(=O)CCC1=O.O>C(#N)C>[Br:23][C:10]1[C:11]2[O:15][C:14]([CH3:16])([CH3:17])[C:13](=[O:18])[C:12]=2[C:19]([CH3:20])=[C:8]([NH:7][C:6](=[O:22])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[C:9]=1[CH3:21]
Reactant: Cc1cc2c(c(C)c1NC(=O)OC(C)(C)C)C(=O)C(C)(C)O2
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: O
Product: Cc1c(Br)c2c(c(C)c1NC(=O)OC(C)(C)C)C(=O)C(C)(C)O2
Temperature: 25 °C
Yield: 72 %

Procedure:
To a solution of tert-butyl(2,2,4,6-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)carbamate obtained in Reference Example 60 (4.86 g, 15.9 mmol) in acetonitrile (70 mL) was added N-bromosuccinimide (5.67 g, 31.8 mmol) was heated under reflux for 1.5 hours. The reaction solution was cooled to room temperature, followed by addition of water, which was extracted with ethyl acetate, and the organic layer was washed with water and a saturation brine, dried over anhydrous sodium sulfate, and then was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=3:7), and then was recrystallized with ethyl acetate-hexane to obtain 4.40 g (yield 72%) of the title compound. Melting point: 131-132° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH2:27][OH:28])=[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[Cl:29][C:30]1[CH:40]=[CH:39][C:33]([O:34][CH2:35][C:36](Cl)=[O:37])=[CH:32][CH:31]=1.O>N1C=CC=CC=1.C(Cl)Cl>[CH3:1][C:2]1[NH:3][C:4]([CH2:27][O:28][C:36](=[O:37])[CH2:35][O:34][C:33]2[CH:39]=[CH:40][C:30]([Cl:29])=[CH:31][CH:32]=2)=[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C1=C(C)NC(CO)=C(C(=O)OCC)C1c1ccccc1[N+](=O)[O-]
Reactant: O=C(Cl)COc1ccc(Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)C1=C(C)NC(COC(=O)COc2ccc(Cl)cc2)=C(C(=O)OCC)C1c1ccccc1[N+](=O)[O-]
Yield: 94.9 %

Procedure:
To a solution of diethyl 2-methyl-4-(2-nitrophenyl)-6-hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (1.95 g) in pyridine (25 ml) was dropwise added over 5 minutes a solution of p-chlorophenoxyacetyl chloride (3.07 g) in methylene chloride under stirring and ice-cooling. The resultant mixture was stirred overnight under cooling with water at 20° C. After removal of the pyridine, water was added to the residue. The precipitated oily substance was extracted with ethyl acetate. The extract was adjusted to pH 4 to 5 with dil. hydrochloric acid, washed each three times with water and then an aqueous solution of sodium bicarbonate and dried over magnesium sulfate. The solvent was distilled off and the residual oil (4.75 g) was subjected to column chromatography on silica-gel using an eluent (benzene:ethyl acetate=10:1) to give an oil (2.65 g) of diethyl 2-methyl-4-(2-nitrophenyl)-6-(4-chlorophenoxy)acetoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate, m.p. 86° to 88° C. (recrystallized from a mixture of diisopropylether and ethanol).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:11][O:12][CH3:13])[C:8]([OH:10])=O)[N:6]=1.P(Cl)(Cl)(Cl)=O.C[Si](CC(N)=O)(C)C.[NH2:27][CH:28]1[C:49](=[O:50])[N:30]2[C:31]([C:46]([OH:48])=[O:47])=[C:32]([O:35][S:36]([C:39]3[CH:45]=[CH:44][C:42]([CH3:43])=[CH:41][CH:40]=3)(=[O:38])=[O:37])[CH2:33][S:34][C@H:29]12.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.O.CN(C)C=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:11][O:12][CH3:13])[C:8]([NH:27][CH:28]2[C:49](=[O:50])[N:30]3[C:31]([C:46]([OH:48])=[O:47])=[C:32]([O:35][S:36]([C:39]4[CH:40]=[CH:41][C:42]([CH3:43])=[CH:44][CH:45]=4)(=[O:37])=[O:38])[CH2:33][S:34][C@H:29]23)=[O:10])[N:6]=1
Reactant: CON=C(C(=O)O)c1csc(N)n1
Reactant: Cc1ccc(S(=O)(=O)OC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)cc1
Agent: C[Si](C)(C)CC(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(OS(=O)(=O)c3ccc(C)cc3)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Yield: 66.9 %

Procedure:
2-(2-Aminothiazol-4-yl)-2-methoxyiminoacetic acid (syn isomer, 0.76 g.), N,N-dimethylformamide (0.33 g.), phosphoryl chloride (1.46 g.), trimethylsilylacetamide (0.5 g.) and ethyl acetate (10 ml.) were treated to give the activated acid solution in a conventional manner. On the other hand, trimethylsilylacetamide (2.7 g.) was added to a suspension of 7-amino-3-tosyloxy-3-cephem-4-carboxylic acid (1.0 g.) in ethyl acetate (15 ml.) and stirred at room temperature. To the solution was added the activated acid solution obtained above at -15° C. all at once, and stirred at -5°-5° C. for an hour. After the resultant solution was chilled to -20° C., water (30 ml.) was added to the chilled solution and adjusted to pH 6.5 with an aqueous solution of sodium bicarbonate. The insoluble substance was removed by filtration. The aqueous layer was separated and adjusted to pH 3.0 with hydrochloric acid. The precipitates were collected by filtration and dried to give 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-tosyloxy-3-cephem-4-carboxylic acid (syn isomer, 1.0 g.).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([NH:11][C:12]2[CH:17]=[CH:16][N:15]3[N:18]=[CH:19][C:20]([CH:21]=O)=[C:14]3[N:13]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].[NH:23]1[CH2:29][C:27](=[O:28])[NH:26][C:24]1=[O:25].N1CCCCC1>CCO>[CH:1]([O:4][C:5]1[CH:6]=[C:7]([NH:11][C:12]2[CH:17]=[CH:16][N:15]3[N:18]=[CH:19][C:20]([CH:21]=[C:29]4[NH:23][C:24](=[O:25])[NH:26][C:27]4=[O:28])=[C:14]3[N:13]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:2])[CH3:3]
Reactant: CC(C)Oc1cccc(Nc2ccn3ncc(C=O)c3n2)c1
Reactant: O=C1CNC(=O)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: CC(C)Oc1cccc(Nc2ccn3ncc(C=C4NC(=O)NC4=O)c3n2)c1
Temperature: 70 °C

Procedure:
To 5-(3-isopropoxyphenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (80 mg, 0.270 mmol) in EtOH was added hydantoin (27 mg, 0.270 mmol) and piperidine (27 μL, 0.270 mmol). The mixture was heated at 70° C. for several hours. The solid produced was isolated by filtration to yield 5-((5-(3-isopropoxyphenylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione. LCMS (M+1=379)
Reaction SMILES: C(OCC1CSC2N(C(=O)C2NC(=O)CC2N=C(C3C=CC=CC=3O)SC=2)C=1C(O)=O)(=O)C.C1(C([O:47][C:48]([C:50]2[N:51]3[CH:54]([S:55][CH2:56][CH:57]=2)[CH:53]([NH:58][C:59](=[O:74])[CH2:60][C:61]2[N:62]=[C:63]([C:66]4[C:71]([OH:72])=[CH:70][CH:69]=[CH:68][C:67]=4[OH:73])[S:64][CH:65]=2)[C:52]3=[O:75])=[O:49])C2C=CC=CC=2)C=CC=CC=1.[SiH](CC)(CC)CC.FC(F)(F)C(O)=O>C(Cl)CCl>[OH:72][C:71]1[CH:70]=[CH:69][CH:68]=[C:67]([OH:73])[C:66]=1[C:63]1[S:64][CH:65]=[C:61]([CH2:60][C:59]([NH:58][CH:53]2[C:52](=[O:75])[N:51]3[CH:54]2[S:55][CH2:56][CH:57]=[C:50]3[C:48]([OH:49])=[O:47])=[O:74])[N:62]=1
Reactant: O=C(Cc1csc(-c2c(O)cccc2O)n1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=CCSC12
Agent: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3csc(-c4ccccc4O)n3)C2SC1
Agent: CC[SiH](CC)CC
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Cc1csc(-c2c(O)cccc2O)n1)NC1C(=O)N2C(C(=O)O)=CCSC12
Yield: 86.3 %

Procedure:
The procedure used for the preparation of 9a was repeated with 8g (145 mg, 0.242 mmol), Et3SiH (0.387 mL, 2.42 mmol), and trifluoroacetic acid (0.746 mL, 9.68 mmol) in dry ClCH2CH2Cl (6 mL) at 0° C. under nitrogen to give 9g (90.5 mg, 86%) as a white solid after crystallization from THF/CH2Cl2 /hexane. mp 165° C. (dec); IR (KBr) 3550-2550 (br), 3282, 1779, 1725, 1665, 1469, 1235 cm-1 ; 1H NMR (DMSO-d6) δ3.43-3.62 (2H, m), 3.76 (2H, s, CH2), 5.00 (1H, d, J=4.8 Hz), 5.67-5.73 (1H, m), 6.42 (3H, d, J=8.1 Hz), 7.07 (1H, t, J=8.1 Hz), 7.41 (1H, s), 9.11 (1H, d, J=8.2 Hz, NH), 12.17 (2H, br s, OH), 13.16 (1H, br s, CO2H); FDMS m/z 433 (M+), 434 (M+ +1); HRMS m/z Calcd for C18H16N3O6S2 (M+ +1): 434.0481, Found: 434.0448.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:54]1[CH:55]=[CH:56][C:57]([F:62])=[C:58]([CH:61]=1)[C:59]#[N:60].[N:63]1([C:69]([O:71][C:72]([CH3:75])([CH3:74])[CH3:73])=[O:70])[CH2:68][CH2:67][NH:66][CH2:65][CH2:64]1>C1(C)C=CC=CC=1.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[C:59]([C:58]1[CH:61]=[C:54]([N:66]2[CH2:65][CH2:64][N:63]([C:69]([O:71][C:72]([CH3:75])([CH3:74])[CH3:73])=[O:70])[CH2:68][CH2:67]2)[CH:55]=[CH:56][C:57]=1[F:62])#[N:60]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: N#Cc1cc(Br)ccc1F
Agent: [Pd]
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(F)c(C#N)c2)CC1
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
1.24 g of 2,2′-bis (diphenylphosphino)-1,1′-binaphthyl and 229 mg of tris (dibenzylideneacetone) dipalladium were dissolved in toluene and stirred at 80° C. for 10 minutes. The reaction mixture was returned to room temperature, and 2.28 g cesium carbonate, 1.0 g 5-bromo-2-fluorobenzonitrile and 1.09 g t-butyl 1-piperazine carboxylate were added thereto and stirred at 80° C. for 12 hours. The reaction solution was purified by silica gel column chromatography to give the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[CH2:19]([C:23]1[NH:24][C:25]([CH2:29][O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])=[C:26]([Cl:28])[N:27]=1)[CH2:20][CH2:21][CH3:22].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1.[Cl-].[Na+].O>[CH3:18][O:17][C:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:24]2[C:25]([CH2:29][O:30][Si:31]([C:34]([CH3:35])([CH3:36])[CH3:37])([CH3:32])[CH3:33])=[C:26]([Cl:28])[N:27]=[C:23]2[CH2:19][CH2:20][CH2:21][CH3:22])=[CH:4][CH:5]=1)=[O:16]
Reactant: COC(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: CCCCc1nc(Cl)c(CO[Si](C)(C)C(C)(C)C)[nH]1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCc1nc(Cl)c(CO[Si](C)(C)C(C)(C)C)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of methyl 4'-bromomethylbiphenyl-2-carboxylate (2.05 g) in dry THF (10 mL) was added dropwise to a solution of 2-butyl-4-chloro-5-(t-butyldimethylsilyloxymethyl)-1H-imidazole (2.03 g) and NaN(TMS)2 (1.48 g) in dry THF (20 mL) at 0° C. and the reaction mixture was stirred at room temperature overnight. It was diluted with brine and the organic layer was collected, dried over MgSO4, and evaporated under reduced pressure. The residue was purified by flash chromatography (EtOAc, silica) to separate the two regioisomeric alkylation products. The major isomer, 4'-[[2-butyl-4-chloro-5-(t-butyldimethylsilyloxymethyl) -1H-imidazol-1-yl]methyl][1,1'-biphenyl-2-yl]carboxylic acid methyl ester (1.4 g) was used in the next step and the regiochemistry of this alkylation product was proven by NOE experiments at the stage of the hydrazide.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH3:11])[N:3]=1.[NH:19]1[CH2:23][CH2:22][CH2:21][C:20]1=[O:24].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1>[Cl:8][C:6]1[N:5]=[C:4]([NH:9][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH3:11])[N:3]=[C:2]([N:19]2[CH2:23][CH2:22][CH2:21][C:20]2=[O:24])[CH:7]=1
Reactant: C[C@H](Nc1nc(Cl)cc(Cl)n1)c1ccc(F)cc1
Reactant: O=C1CCCN1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: C[C@H](Nc1nc(Cl)cc(N2CCCC2=O)n1)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 90.6 %

Procedure:
100 mg of (S)-4,6-dichloro-N-[1-(4-fluorophenyl)ethyl]pyrimidine-2-amine (Reference Example 1), 33 mg of 2-pyrrolidone, 20 mg of 4,5-bis(diphenylphosphino)-9,9′-dimethylxanthene, 149 mg of tripotassium phosphate and 19 mg of tris(dibenzylideneacetone)(chloroform)dipalladium were added in turn to 3 ml of degassed 1,4-dioxane, and the mixture was stirred at 100° C. for 3 hours under argon atmosphere. The reaction solution was filtrated to remove precipitates, and the solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 106 mg of the objective compound as yellow oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[S:7][C:6]([C:8]([N:10]2[CH:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[OH:21])[CH2:13][C:12]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)=[N:11]2)=[O:9])=[CH:5][CH:4]=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.[N:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[C:54](O)=[O:55]>C(Cl)Cl.O>[OH:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH:14]1[N:10]([C:8]([C:6]2[S:7][C:3]([CH2:2][NH:1][C:54]([C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][N:48]=3)=[O:55])=[CH:4][CH:5]=2)=[O:9])[N:11]=[C:12]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[CH2:13]1
Reactant: NCc1ccc(C(=O)N2N=C(c3cccnc3)CC2c2ccccc2O)s1
Reactant: O=C(O)c1ccccn1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccc(C(=O)N2N=C(c3cccnc3)CC2c2ccccc2O)s1)c1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.5 %

Procedure:
A mixture of 2-(1-{[5-(aminomethyl)-2-thienyl]carbonyl}-3-pyridin-3-yl-4,5-dihydro-1H-pyrazol-5-yl)phenol (0.080 g, 0.21 mmol), EDCI (0.070 g, 0.36 mmol), DIPEA (0.150 mL, 0.86 mmol), and picolinic acid (0.31 g. 0.25 mmol) in DCM (4 mL) was allowed to stir at rt overnight. The reaction mixture was diluted with water and extracted with DCM. The organic solutions were combined, washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography to give N-[(5-{[5-(2-hydroxyphenyl)-3-pyridin-3-yl-4,5-dihydro-1H-pyrazol-1-yl]carbonyl}-2-thienyl)methyl]pyridine-2-carboxamide (I-136) (0.033 g) as a clear oil. LCMS: (FA) ES+ 484.2. 1H NMR (400 MHz, d6-DMSO) δ: 9.53-9.59 (m, 1H), 9.05-9.09 (m, 1H), 8.72-8.76 (m, 1H), 8.65-8.69 (m, 1H), 8.36-8.41 (m, 1H), 8.06-8.11 (m, 1H), 7.98-8.05 (m, 1H), 7.88 (d, 1H), 7.60-7.67 (m, 2H), 7.02-7.12 (m, 2H), 6.86-6.91 (m, 1H), 6.82 (d, 1H), 6.69 (t, 1H), 5.82 (dd, 1H), 4.70 (d, 2H), 3.82-3.92 (m, 1H), and 3.17 (dd, 1H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19](=[S:21])[NH2:20])=[CH:15]2)(=[O:8])=[O:7].Br[CH:23]([CH:26]=O)[CH:24]=[O:25].CN(C)C(=O)C>O>[OH:25][CH2:24][C:23]1[S:21][C:19]([C:16]2[NH:17][C:18]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][C:10]=3[NH:9][S:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)(=[O:7])=[O:8])=[N:20][CH:26]=1
Reactant: O=CC(Br)C=O
Reactant: NC(=S)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=S(=O)(Nc1cccc2cc(-c3ncc(CO)s3)[nH]c12)c1cccs1
Temperature: 90 °C
Reaction time: 1 h
Yield: 53.9 %

Procedure:
A mixture of 7-[(2-thienylsulfonyl)amino]-1H-indole-2-carbothioamide (1.12 g), bromomalonaldehyde (0.90 g) and N,N-dimethylacetamide (15 mL) was stirred at 90° C. for 1 hr. Water was added to the reaction mixture, and the obtained crystals were filtrated, washed with water and dried. To a mixture of the obtained crystals, tetrahydrofuran (10 mL) and methanol (10 mL) was added sodium borohydride (0.13 g) at 0° C., and the mixture was stirred at the same temperature for 1 hr. To the reaction mixture was added 10% aqueous citric acid solution was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography and the title compound (0.70 g, yield 60%) was obtained as pale-yellow crystals from a fraction eluted with tetrahydrofuran-hexane (3:1, volume ratio). melting point 209-210° C.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[N:6][CH:5]=[N:4]1.Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1.Cl>CN(C)C=O.C(OCC)(=O)C.O>[N:3]1([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:31][CH:32]=3)=[CH:20][CH:19]=2)[CH:7]=[N:6][CH:5]=[N:4]1
Reactant: c1nc[nH]n1
Reactant: O=C(O)c1ccc(-c2ccc(OCCCCCCCCBr)cc2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(-c2ccc(OCCCCCCCCn3cncn3)cc2)cc1
Temperature: 120 °C
Reaction time: 5 h
Yield: 83.4 %

Procedure:
To a suspension of sodium hydride (60% suspension in mineral oil) (0.296 g) in N,N-dimethylformamide (14 ml) was added 1,2,4-triazole (0.511 g) and 4-[4-(8-bromooctyloxy)phenyl]benzoic acid (1 g), and was stirred for 5 hours at 120° C. The reaction mixture was added to a mixture of water and ethyl acetate, and adjusted to pH 2.5 with conc. hydrochloric acid. The organic layer was taken and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give 4-[4-[8-(1,2,4-Triazol-1-yl)octyloxy]phenyl]benzoic acid (0.81 g).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([OH:9])=[O:8].[CH3:10]O>>[Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=C(O)c1sccc1Br
Reactant: CO
Product: COC(=O)c1sccc1Br

Procedure:
The 3-bromothiophene-2-carboxylic acid was first protected at the carboxylic group. 3-bromothiophene-2-carboxylic acid was dissolved in methanol containing catalytic DCC. Mixture was reacted by refluxing overnight. After solvent was evaporated, the residues were applied on silica gel. Methyl 3-bromothiophene-2-carboxylate was obtained as a colorless liquid.
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][C@@H:21]4[CH2:26][CH2:25][N:24](C(OCC5C=CC=CC=5)=O)[CH2:23][C@H:22]4[F:37])[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.Cl.C([O-])(O)=O.[Na+].[Na+].[Cl-]>O1CCOCC1.O>[N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][C@@H:21]4[CH2:26][CH2:25][NH:24][CH2:23][C@H:22]4[F:37])[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: O=C(OCc1ccccc1)N1CC[C@@H](Oc2cccc3ccc(-c4nnc5ccccn45)nc23)[C@H](F)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: C1COCCO1
Solvent: O
Product: F[C@@H]1CNCC[C@H]1Oc1cccc2ccc(-c3nnc4ccccn34)nc12
Temperature: 100 °C

Procedure:
Non-racemic (trans)-benzyl 4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-3-fluoropiperidine-1-carboxylate (0.304 g, 0.611 mmol) was dissolved in dioxane (7.6 mL) and treated with 6 M hydrogen chloride (7.64 mL, 45.8 mmol), and the reaction mixture was heated at 100° C. for 15 hours. The reaction was cooled and carefully neutralized with solid NaHCO3. Additional water was added to dissolve the resulting NaCl as the neutralization proceeded. The resulting aqueous layer (pH 8-9) was extracted with methylene chloride and the combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude product was chromatographed on SiO2 eluting with a gradient of 2% NH4OH in isopropanol/methylene chloride. The desired product was isolated as a white foam (62.6 mg). MS APCI (+) m/z 364.2 (M+1) detected.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([Mg]Br)=[CH:19][CH:18]=1>C(OCC)C>[OH:1][C:2]1([C:20]2[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: COc1ccc([Mg]Br)cc1
Solvent: CCOCC
Product: COc1ccc(C2(O)CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 97.6 %

Procedure:
A mixture of commercial tert-butyl 4-oxopiperidine-1-carboxylate (2.0 g, 10.0 mmol) and diethyl ether (30 ml) was cooled to 0° C. To this mixture was added dropwise a solution of (4-methoxyphenyl)magnesium bromide (0.5 M in diethyl ether, 30 ml, 15 mmol). After complete addition, the reaction mixture was allowed to warm to rt and stirred for 2 h. It was then slowly quenched with 150 ml of ice cold water and then the resulting mixture was extracted with 3×150 ml of DCM. The organic layers were combined, dried, filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (30:70 ethyl acetate:hexane) to provide the desired product (3.0 g, 100% yield): LC-MS (ES-API): m/z 305.5 (M−H)+; 1H NMR (400 MHz, DMSO-d6) δ 7.37 (q, J=1.0 Hz, 2H), 6.86 (q, J=1.0 Hz, 2H), 4.94 (s, 1H), 3.82 (d, J=11.5 Hz, 2H), 3.73 (s, 3H), 3.13 (br. s, 2H), 1.75 (td, J=12.9, 4.8 Hz, 2H), 1.56 (d, J=12.3 Hz, 2H), 1.41 (s, 9H).