Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=C(N2CCN(CC3C=CC(C(F)(F)F)=CC=3)C2=O)SC=1C(O)=O.[F:27][C:28]1[CH:49]=[CH:48][C:31]([CH2:32][N:33]2[CH2:37][CH2:36][N:35]([C:38]3[S:42][C:41]([C:43]([OH:45])=O)=[C:40]([CH3:46])[CH:39]=3)[C:34]2=[O:47])=[CH:30][CH:29]=1.[NH2:50][CH2:51][C:52]1[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=1>>[F:27][C:28]1[CH:49]=[CH:48][C:31]([CH2:32][N:33]2[CH2:37][CH2:36][N:35]([C:38]3[S:42][C:41]([C:43]([NH:50][CH2:51][C:52]4[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=4)=[O:45])=[C:40]([CH3:46])[CH:39]=3)[C:34]2=[O:47])=[CH:30][CH:29]=1
Reactant: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Reactant: NCc1cccnc1
Agent: Cc1cc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)sc1C(=O)O
Product: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1cccnc1
Yield: 79 %

Procedure:
Following the procedure as described in Example 15, making variations as required to replace 3-methyl-5-(2-oxo-3-(4-(trifluoromethyl)benzyl)imidazolidin-1-yl)thiophene-2-carboxylic acid with 5-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-3-methylthiophene-2-carboxylic acid to react with 3-(aminomethyl)pyridine, the title compound was obtained as a colorless solid in 79% yield: mp 119-120° C.; 1H NMR (300 MHz, CDCl3) δ 8.59 (s, 1H), 8.52 (d, J=4.7 Hz, 1H), 7.69 (d, J=7.8 Hz, 1H), 7.29-7.23 (m, 3H), 7.06-6.99 (m, 2H), 6.14 (t, J=5.7 Hz, 1H), 6.08 (s, 1H), 4.58 (d, J=5.7 Hz, 2H), 4.42 (s, 2H), 3.83-3.75 (m, 2H), 3.47-3.39 (m, 2H), 2.48 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 163.5, 162.4 (d, JC-F=246.4 Hz), 155.8, 149.2, 148.8, 142.5, 141.7, 135.5, 134.1, 131.7, (d, JC-F=3.1 Hz), 130.0 (d, JC-F=8.2 Hz), 123.6, 119.0, 115.7 (d, JC-F=21.5 Hz), 112.4, 47.4, 42.7, 41.4, 41.2, 16.1; MS (ES+) m/z 425.3 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:3]([S:12]CC2C=CC=CC=2)=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(O)(=O)C.Cl.[N:25]([O-])=O.[Na+]>O>[S:12]1[C:3]2[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][CH:10]=[CH:11][C:2]=2[N:1]=[N:25]1
Reactant: COC(=O)c1cccc(N)c1SCc1ccccc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1cccc2nnsc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.4 %

Procedure:
A mixture of methyl 3-amino-2-(benzylthio)benzoate (26.9 g, 98.4 mmol), acetic acid (1.00 L, 1.75 mol), water (200 mL) and concentrated hydrochloric acid (172 mL, 2.06 mol) was stirred at room temperature for 30 min. To the reaction mixture was added a solution of sodium nitrite (7.59 g, 110 mmol) in water (200 mL) at 0° C. and the mixture was stirred at 0-5° C. for 2 hr. The precipitate was collected by filtration, washed with water, and dried under reduced pressure to give the title compound (12.5 g, yield 65%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13].[Br:16]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C([O-])(O)=O.[Na+]>ClCCl.CC(=O)OCC>[Br:16][CH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1ccc(C)c(C(=O)OC)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CBr)c(C(=O)OC)c1
Yield: 72.6 %

Procedure:
To a solution of dimethyl 4-methylisophthlate (Chemical Formula 4) (4 g, 19.2 mmol) in distilled dichloromethane were added N-bromosuccinimide (NBS, 4.8 g, 26.9 mmol) and benzoic peroxyanhydride (0.47 g, 19.2 mmol), followed by reaction at 80° C. for 24 hours in a pressure vessel with constant stirring. The reaction progress was monitored by TLC [Hex:EA=3:1]. When the reaction was detected to have reached completion, saturated NaHCO3 was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer thus formed was dried over anhydrous MgSO4, filtered and concentrated in a vacuum. The purification of the concentrate through column chromatography [Hexane: EtOAc=20:1] produced 4 g of dimethyl 4-(bromomethyl)isophthalate (Chemical Formula 5) (70%).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([NH:13][CH2:14][C:15](O)=[O:16])=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:18][C:19]1[S:20][C:21]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:22]=2[N:23]=1.[CH3:32][O:33][C@@H:34]1[CH2:39][CH2:38][CH2:37][NH:36][CH2:35]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:32][O:33][C@@H:34]1[CH2:39][CH2:38][CH2:37][N:36]([C:15](=[O:16])[CH2:14][NH:13][C:11]([C:9]2[CH:8]=[CH:7][C:6]3[N:2]([CH3:1])[C:3]([NH:18][C:19]4[S:20][C:21]5[CH:27]=[C:26]([C:28]([F:30])([F:29])[F:31])[CH:25]=[CH:24][C:22]=5[N:23]=4)=[N:4][C:5]=3[CH:10]=2)=[O:12])[CH2:35]1
Reactant: Cn1c(Nc2nc3ccc(C(F)(F)F)cc3s2)nc2cc(C(=O)NCC(=O)O)ccc21
Reactant: CO[C@@H]1CCCNC1
Agent: CN(C)C(On1nnc2ccccc21)=[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: CO[C@@H]1CCCN(C(=O)CNC(=O)c2ccc3c(c2)nc(Nc2nc4ccc(C(F)(F)F)cc4s2)n3C)C1
Yield: 30.8 %

Procedure:
1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid [2-((R)-3-methoxy-piperidin-1-yl)-2-oxo-ethyl]amide (30 mg) was prepared by following General Procedure F starting from {[1-methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-acetic acid (80 mg), (R)-3-methoxy-piperidine (100 mg), HBTU (200 mg), and DIEA (100 uL) in DMF (1 mL). LC/MS: m/z 546.7. 1H NMR (DMSO-d6, 400 MHz): δ 8.54-8.53 (m, 1H), 8.28 (s, 1H), 8.12 (s, 1H), 7.83-7.81 (d, 1H), 7.71 (m, 2H), 7.56-7.54 (d, 1H), 4.24-4.18 (m, 1H), 4.12-4.08 (m, 1H), 3.73-3.71 (m, 1H), 3.70 (s, 3H), 3.52-3.47 (m, 1H), 3.38-3.34 (m, 2H), 3.31-3.25 (m, 4H), 1.88-1.81 (m, 1H), 1.71-1.62 (m, 1H), 1.45-1.36 (m, 1H), —NH proton signal was not observed.
Reaction SMILES: [CH3:1][Si:2]([CH3:13])([CH3:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][N:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(P(C(C)(C)C)C(C)(C)C)C1C=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.O1CCOCC1>[CH3:21][C:18]1[CH:19]=[CH:20][C:15]([C:6]2[CH:7]=[CH:8][C:3]([Si:2]([CH3:13])([CH3:12])[CH3:1])=[CH:4][CH:5]=2)=[N:16][CH:17]=1
Reactant: C[Si](C)(C)c1ccc(B(O)O)cc1
Reactant: Cc1ccc(Br)nc1
Agent: [Pd]
Agent: CC(C)(C)P(Cc1ccccc1)C(C)(C)C
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: C1COCCO1
Product: Cc1ccc(-c2ccc([Si](C)(C)C)cc2)nc1

Procedure:
15.0 g (0.0773 mol) of 4-trimethylsilyl-phenylboronic acid, 11.96 g (0.0695 mol) of 2-bromo-5-methyl-pyridine, 15.11 g (0.0464 mol) of cesium carbonate, 0.71 g (0.000776 mol) of tris(dibenzylideneacetone) dipalladium (0), 0.43 g (0.00182 mol) of benzyl-di-tert-butyl-phosphane and 100 ml of dioxane were stirred at room temperature for 12 hr. The reaction mixture was filtered and the solvent was removed under 1 mm vacuum. The resulting mixture was purified by distillation in vacuum. Yield of 5-methyl-2-(4-trimethylsilanyl-phenyl)-pyridine was 8.05 g (48%) as a yellow solid with b.p. 111-114° C./0.02 mm and m.p. 66.07° C. 1H NMR (CD2Cl2) 2.15 (s, 3H, Me) 7.45-8.50 (m, 7H, arom-H). Anal. Found: C, 74.34; H, 7.86; N, 5.85. The structure was confirmed by X-ray analysis.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[Cl:13][CH2:14][C:15]#[C:16][CH2:17]Cl.C([O-])([O-])=O.[K+].[K+]>CCO.O>[Cl:13][CH2:14][C:15]#[C:16][CH2:17][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1
Reactant: ClCC#CCCl
Reactant: O=C1CCc2ccc(O)cc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=C1CCc2ccc(OCC#CCCl)cc2N1
Yield: 66.1 %

Procedure:
A mixture of 7-hydroxy-3,4-dihydroquinolin-2(1H)-one (930 mg, 6 mmol), 1,4-dichlorobut-2-yne (326 mg, 2 mmol) and anhydrous K2CO3 (276 mg, 2 mmol) was dissolved in EtOH and the solution was heated to reflux overnight. The solution was diluted with water and extracted with EtOAc. The combined organic layers were washed with saturated aq NaHCO3, brine, dried over anhydrous Na2SO4, concentrated in vacuo and purified by flash chromatography on silica gel column to give 7-(4-chlorobut-2-ynyloxy)-3,4-dihydroquinolin-2(1H)-one (intermediate 50) (330 mg, 66%) as a yellow solid.
Reaction SMILES: CO.O.[OH-].[Na+].[C:6]([NH:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[CH:20]=[C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:37]=[C:36]3[C:31]([CH:32]=[CH:33][CH:34]=[C:35]3[CH2:38][C:39]([O:41]C)=[O:40])=[CH:30][CH:29]=1)[CH:18]=[CH:17]2)(=[O:8])[CH3:7]>C1COCC1>[C:6]([NH:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[CH:20]=[C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:37]=[C:36]3[C:31]([CH:32]=[CH:33][CH:34]=[C:35]3[CH2:38][C:39]([OH:41])=[O:40])=[CH:30][CH:29]=1)[CH:18]=[CH:17]2)(=[O:8])[CH3:7]
Reactant: COC(=O)Cc1cccc2ccc(OCCCCOc3ccc4cccc(CCNC(C)=O)c4c3)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)NCCc1cccc2ccc(OCCCCOc3ccc4cccc(CC(=O)O)c4c3)cc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In a 100 ml round-bottomed flask, dissolve the compound obtained in Example 43 in THF, and add methanol, water and sodium hydroxide. The reaction mixture is maintained at room temperature, with stirring, for 4 hours. Concentrate the solution, carry out hydrolysis and render acidic with concentrated hydrochloric acid. Suction off the resulting precipitate and recrystallise from a mixture of toluene/cyclohexane (4/1).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].[C:12](=O)([O-])[O-].[K+].[K+].CI.O>CN(C=O)C>[CH3:12][O:11][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[NH2:1]
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COc1cccc([N+](=O)[O-])c1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.1 %

Procedure:
A mixture of 2-amino-3-nitrophenol (7.7 g) and potassium carbonate (7.6 g) in DMF (15 ml) was stirred for 30 minutes at room temperature and there was then added methyl iodide (7.8 g). The mixture was stirred for 5 further hours at room temperature. To the reaction mixture was added water, which was extracted with ethyl acetate. The organic layer was washed with water and, then, dried. The solvent was distilled off to give crude crystals and recrystallization from isopropyl ether gave orange prisms (6.9 g, 82%), m.p. 76-77° C.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][CH:22]([CH3:27])[C:23]([NH:25][NH2:26])=[O:24].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@@H:10]1[CH2:11][CH2:12][C@@H:13]2[C:18]([NH:26][NH:25][C:23](=[O:24])[CH:22]([CH3:27])[CH3:21])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CC(C)C(=O)NN
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)C(=O)NNC(=O)[C@H]1CC[C@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.5 %

Procedure:
To a solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.25 g, 0.90 mmol) in dry DCM (20 mL) were added 2-methylpropanehydrazide 193 (0.14 g, 1.35 mmol), 1-hydroxybenzotriazole (0.19 g, 1.35 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.26 g, 1.35 mmol) and 4-(dimethylamino)pyridine (0.16 g, 1.35 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight, and then concentrated under vacuum. The residue was purified by column chromatography to give (2R,5S)-6-(benzyloxy)-N′-(2-methylpropanoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide 194 (0.30 g, 92.6%) as a white solid.
Reaction SMILES: [OH-].[Na+].C(O)C.[CH2:6]([NH:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[C:16]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Cl-].[Na+]>C(OCC)(=O)C.C(O)(=O)C>[CH2:6]([NH:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([OH:20])=[O:19])=[C:16]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[CH:15]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: COC(=O)c1ccc(NCc2ccccc2)cc1Nc1ccc(F)cc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C(O)c1ccc(NCc2ccccc2)cc1Nc1ccc(F)cc1
Temperature: 25 °C
Yield: 73.8 %

Procedure:
10% Sodium hydroxide aqueous solution 0.82 mL was added to a suspension of ethanol 3.0 mL of methyl 4-(benzylamino)-2-(4-fluoroanilino)benzoate 0.24 g at room temperature, and it was heated and refluxed for 2 hours. After the reaction mixture was cooled to room temperature, 10% sodium hydroxide aqueous solution 0.82 mL was added, and it was heated and refluxed for 3 hours. After the reaction mixture was cooled to room temperature, acetic acid 2.0 mL, saturated sodium chloride aqueous solution and ethyl acetate were added to it. The organic layer was separated and collected, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. Diisopropyl ether and hexane were added to the obtained residue, and solid matter was filtrated to give 4-(benzylamino)-2-(4-fluoroanilino)benzoic acid 0.17 g of white solid.
Reaction SMILES: [C:1]([C:4]1[C:13]([N:14]2[CH2:18][CH2:17][CH:16]([C:19]#[N:20])[CH2:15]2)=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[C:6]([Cl:21])[CH:5]=1)(=O)[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:28].[Na+]>CO.C(#N)C>[NH2:28][CH:1]([C:4]1[C:13]([N:14]2[CH2:18][CH2:17][CH:16]([C:19]#[N:20])[CH2:15]2)=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[C:6]([Cl:21])[CH:5]=1)[CH3:2]
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCC(C#N)C1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: CC(N)c1cc(Cl)c2cccnc2c1N1CCC(C#N)C1
Temperature: 65 °C

Procedure:
A mixture of 1-(7-acetyl-5-chloroquinolin-8-yl)pyrrolidine-3-carbonitrile (0.016 g, 0.053 mmol) and ammonium acetate (0.0411 g, 0.534 mmol) in methanol (1.0 mL) and acetonitrile (1.0 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, sodium cyanoborohydride (0.010 g, 0.16 mmol) was added. The reaction was heated at 65° C. overnight. The mixture was cooled to room temperature, quenched with sat. NaHCO3 solution and extracted with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated to give the desired product. LCMS calculated for C16H18ClN4 (M+H)+: m/z=301.1; Found: 301.1.
Reaction SMILES: S1C=CC(C(Cl)=O)=C1.[S:9]1[CH:13]=[CH:12][C:11]([C:14]([N:16]=[C:17]=[S:18])=[O:15])=[CH:10]1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][C:30]=1[O:31][CH3:32])[N:27]=[CH:26][CH:25]=[C:24]2[O:33][C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[C:36]([F:41])[CH:35]=1.C1(C)C=CC=CC=1>C(O)C>[S:9]1[CH:13]=[CH:12][C:11]([C:14]([N:16]=[C:17]=[S:18])=[O:15])=[CH:10]1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][C:30]=1[O:31][CH3:32])[N:27]=[CH:26][CH:25]=[C:24]2[O:33][C:34]1[CH:40]=[CH:39][C:37]([NH:38][C:17]([NH:16][C:14]([C:11]2[CH:12]=[CH:13][S:9][CH:10]=2)=[O:15])=[S:18])=[C:36]([F:41])[CH:35]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Agent: O=C(Cl)c1ccsc1
Agent: O=C(N=C=S)c1ccsc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccsc4)c(F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
3-Thiophenecarbonyl isothiocyanate was prepared using commercially available 3-thiophenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 3-Thiophenecarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (45 mg, yield 58%).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:20][CH3:21])[C:4]1[C:9]([O:10][CH2:11][O:12][CH3:13])=[C:8]([C:14]([F:17])([F:16])[F:15])[CH:7]=[CH:6][C:5]=1[CH2:18][OH:19].O[C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][C:36]([O:38][CH3:39])=[O:37])[CH:30]=2)=[CH:25][CH:24]=1>>[CH3:21][O:20][CH:3]([O:2][CH3:1])[C:4]1[C:9]([O:10][CH2:11][O:12][CH3:13])=[C:8]([C:14]([F:15])([F:16])[F:17])[CH:7]=[CH:6][C:5]=1[CH2:18][O:19][C:23]1[CH:24]=[CH:25][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][C:36]([O:38][CH3:39])=[O:37])[CH:30]=2)=[CH:27][CH:28]=1
Reactant: COC(=O)Cc1cccc(-c2ccc(O)cc2)c1
Reactant: COCOc1c(C(F)(F)F)ccc(CO)c1C(OC)OC
Product: COCOc1c(C(F)(F)F)ccc(COc2ccc(-c3cccc(CC(=O)OC)c3)cc2)c1C(OC)OC
Yield: 549 %

Procedure:
According to a method similar to Example (6-7), from [2-(dimethoxymethyl)-3-(methoxymethoxy)-4-(trifluoromethyl)phenyl]methanol (1.96 g, 6.32 mmol) obtained in Example (6-6) and methyl (4′-hydroxy-1,1′-biphenyl-3-yl)acetate (1.68 g, 6.95 mmol) obtained in Example (8-1), methyl (4′-{[2-(dimethoxymethyl)-3-(methoxymethoxy)-4-(trifluoromethyl)benzyl]oxy}-1,1′-biphenyl-3-yl)acetate was obtained (1.83 g, yield: 549%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]5([C:28]#[N:29])[CH2:27][CH2:26]5)[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[N:6][N:5]2[CH:31]=1.[Cl:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][N:34]=1.C(N(CC)CC)C>O1CCCC1>[Cl:32][C:33]1[CH:41]=[CH:40][C:36]([C:37]([NH:1][C:2]2[N:3]=[C:4]3[CH:9]=[CH:8][C:7]([O:10][C:11]4[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18](=[O:30])[C:19]5[CH:24]=[CH:23][CH:22]=[C:21]([C:25]6([C:28]#[N:29])[CH2:27][CH2:26]6)[CH:20]=5)[CH:12]=4)=[N:6][N:5]3[CH:31]=2)=[O:38])=[CH:35][N:34]=1
Reactant: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc5nc(N)cn5n4)c3)c2)CC1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc5nc(NC(=O)c6ccc(Cl)nc6)cn5n4)c3)c2)CC1
Yield: 75.3 %

Procedure:
Using N-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(1-cyanocyclopropyl)benzamide (120 mg, 0.292 mmol), 6-chloronicotinoyl chloride (61 mg, 0.350 mmol), triethylamine (62 μL, 0.438 mmol) and tetrahydrofuran (5 mL) as starting materials and in the same manner as in Example 385, the title compound (121 mg, 75%) was obtained as a white powder.
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][NH:8][C:9]([C:11]1[C:16]([OH:17])=[CH:15][CH:14]=[CH:13][N:12]=1)=[O:10])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:17][C:16]1[C:11]([C:9]([NH:8][CH2:7][C:6]([OH:18])=[O:5])=[O:10])=[N:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)CNC(=O)c1ncccc1O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CNC(=O)c1ncccc1O
Reaction time: 5 h
Yield: 99 %

Procedure:
To a solution of [(3-hydroxy-pyridine-2-carbonyl)-amino]-acetic acid tert-butyl ester, 29, (0.070 g, 0.277 mmol) in CH2Cl2 (4 mL) is added TFA (1 mL). The resulting solution is stirred for 5 hours then concentrated under reduced pressure to afford 0.054 g (99% yield) of the desired compound as a colorless solid. 1H NMR (400 MHz, MeOD) δ ppm 8.09 (1H, d, J=3.3 Hz), 7.36-7.59 (2H, m), 4.08 (2H, s). HPLC-MS: m/z 197 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=O)[CH2:6][CH2:5]2.[C:12]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])#[N:13].C([O-])(=O)C.[NH4+].C(O)(=O)C>C1C=CC=CC=1.C(OCC)(=O)C.O>[C:12](/[C:14](=[C:7]1/[CH2:6][CH2:5][C:4]2[C:8]/1=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)/[C:15]([O:17][CH2:18][CH3:19])=[O:16])#[N:13]
Reactant: CCOC(=O)CC#N
Reactant: O=C1CCc2cc(F)ccc21
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)/C(C#N)=C1\CCc2cc(F)ccc21

Procedure:
A mixture of 5-Fluoro-indan-1-one (150 g, 1 mol, commercially available), and ethyl cyanoacetate (125 g, 1.1 mol), ammonium acetate (154 g, 2 mol) and glacial acetic acid (500 ml) in benzene (1 L) was refluxed with a Dean Stark water trap for 16 h. Then ethyl acetate was added to the reaction mixture and washed with water.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[CH:5][C:6]2[O:10][N:9]=[C:8]([NH:11][CH2:12][C:13]([OH:15])=O)[C:7]=2[CH:16]=1.[C:19]([O:23][C:24]([N:26]1[CH2:29][CH:28]([NH2:30])[CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[C:19]([O:23][C:24]([N:26]1[CH2:29][CH:28]([NH:30][C:13](=[O:15])[CH2:12][NH:11][C:8]2[C:7]3[CH:16]=[C:3]([C:2]([F:1])([F:18])[F:17])[CH:4]=[CH:5][C:6]=3[O:10][N:9]=2)[CH2:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Reactant: O=C(O)CNc1noc2ccc(C(F)(F)F)cc12
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(NC(=O)CNc2noc3ccc(C(F)(F)F)cc23)C1

Procedure:
(5-Trifluoromethyl-benzo[d]isoxazol-3-ylamino)-acetic acid (2.6 g, 9.99 mmol), 3-amino-azetidine-1-carboxylic acid tert-butyl ester (1.72 g, 9.99 mmol), EDCI (2.3 g, 12.0 mmol), HOBt (1.62 g, 12.0 mmol) in DCM (20 mL) were stirred at room temperature for 4 hours. The reaction was then partitioned between DCM and water. The aqueous layer was extracted two times with DCM. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give the crude material, which was purified by silica gel column (hexanes:ethyl acetate 1:1) to afford the title compound as white foam.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][NH:7][C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.O1CCCC1.Cl.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[N:34][CH:33]=1>O>[C:12]([C:11]1[CH:14]=[CH:15][C:8]([N:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:17][CH:16]=2)[C:31](=[O:38])[C:32]2[CH:37]=[CH:36][CH:35]=[N:34][CH:33]=2)=[CH:9][CH:10]=1)#[N:13]
Reactant: O=C(Cl)c1cccnc1
Reactant: N#Cc1ccc(NCc2ccc(O)cc2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: N#Cc1ccc(N(Cc2ccc(O)cc2)C(=O)c2cccnc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.8 %

Procedure:
224 mg of 4-[N-(4-hydroxybenzyl)amino]benzonitrile, 0.28 ml of triethylamine, and 7 ml of tetrahydrofuran were mixed, and 178 mg of nicotinoyl chloride hydrochloride was slowly added thereto, followed by stirring at room temperature overnight. After water was added to the reaction mixture, the product was extracted with tetrahydrofuran-diethyl ether (1:1). After the extract was washed with water and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The resulting crude product was purified by TLC (using a 9:1 mixture of chloroform and acetone as the developing solvent) to obtain 292 mg of N-(4-cyanophenyl)-N-(4-hydroxybenzyl)-nicotinamide.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[OH:18][CH2:19][C:20]1[N:25]=[CH:24][C:23]([O:26][C:27](=[O:31])[N:28]([CH3:30])[CH3:29])=[CH:22][CH:21]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([O:18][CH2:19][C:20]2[N:25]=[CH:24][C:23]([O:26][C:27](=[O:31])[N:28]([CH3:29])[CH3:30])=[CH:22][CH:21]=2)[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: CN(C)C(=O)Oc1ccc(CO)nc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: CN(C)C(=O)Oc1ccc(COc2nc(N)nc(-c3ccco3)c2C#N)nc1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, dimethyl-carbamic acid 6-hydroxymethyl-pyridin-3-yl ester and DBU in DME. ES-MS m/e (%): 403 (M+Na+, 45), 381 (M+H+, 100).