Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]([O:10]CC)=[O:9])[CH:4]=1.[OH-].[Na+].Cl.[CH2:16]([OH:18])[CH3:17]>>[CH2:16]([O:18][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]([OH:10])=[O:9])[CH:4]=1)[CH3:17]
Reactant: CCO
Reactant: CCOC(=O)c1cc(CBr)on1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCOCc1cc(C(=O)O)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
To an oily suspension of ethyl 5-(bromomethyl)isoxazole-3-carboxylate (0.680 g; 2.91 mmol) in aqueous 1M sodium hydroxide (6.4 mL; 6.4 mmol) was added 1 mL of ethanol. The oily suspension immediately transformed to a white solid suspension. The mixture was stirred overnight at room temperature. The pH of the solution was adjusted between 2 and 3 by addition of 6N hydrochloric acid. The solution was extracted with ethyl acetate. Organic extracts were dried over magnesium sulfate and evaporated to afford 0.189 g (38%) of 5-(ethoxymethyl)isoxazole-3-carboxylic acid as a white solid, which was directly used in the next step.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:22]=[CH:23][C:24]=1Br)[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:33][Si:34]([C:37]#[CH:38])([CH3:36])[CH3:35]>C1COCC1.C(OCC)(=O)C.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:22]=[CH:23][C:24]=1[C:38]#[C:37][Si:34]([CH3:36])([CH3:35])[CH3:33])[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: O=C(OCc1ccccc1)c1ccc(Br)c(OCc2ccccc2)c1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1ccc(C(=O)OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
3-Benzyloxy-4-bromobenzoic acid, benzyl ester (33.00 g, 83.07 mmol) was placed in a three necked flask and the atmosphere was replaced, under vacuum, with argon using a Firestone valve. The solid was dissolved in THF (215 ml), with stirring, and then triethylamine (396 ml) was added. The mixture was cooled in an ice/water bath and the solution degassed five times as described above. Copper (I) iodide (127 mg, 0.66 mmol) and bis(triphenylphosphine)palladium (II) chloride (933 mg, 1.33 mmol) were quickly added and the solution degassed twice more. Trimethylsilylacetylene (17.6 ml, 124.6 mmol) was then added dropwise, by syringe, over ten minutes. The cooling bath was then removed and the solution allowed to slowly warm to ambient temperature. After 21 h TLC analysis (25% EtOAc/hexane) indicated that essentially all the starting material had been consumed. The solvents were removed by evaporation in vacuo and ethyl acetate (500 ml) and dilute brine (300 ml) were added. The organic fraction was separated and the aqueous phase was back extracted with ethyl acetate (1×250 ml and 1×100 ml). The total organic fraction was dried over sodium sulphate, filtered and evaporated to give a crude brown solid (36.2 g). The solid was dissolved in hot ethyl acetate (80 ml) where upon the title compound crystallised. This solid was removed by filtration, washed with ethyl acetate and dried in a vacuum oven at 40° C. to give pure title compound (13.75 g, yield 39%), mp=110.5-111.5° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH:21]([N:23]4[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]4)[CH3:22])=[C:19]([O:36][CH3:37])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1.Cl>C(Cl)Cl.O1CCOCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH:21]([N:23]4[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]4)[CH3:22])=[C:19]([O:36][CH3:37])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1
Reactant: COc1ccc2c(c1C(C)N1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccc2c(c1C(C)N1CCNCC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
A solution of tert-butyl (Z)-4-(1-{2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}ethyl)piperazine-1-carboxylate (0.10 g, 0.21 mmol) in methylene chloride (2.0 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (2.0 mL), and then the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the mixture was azeotroped twice with toluene under reduced pressure. The residual solid was added with water, and then the mixture was adjusted to pH 9 with saturated aqueous sodium hydrogencarbonate, and extracted with chloroform. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure to obtain (Z)-2-[(1H-indazol-3-yl)methylene]-6-methoxy-7-[1-(piperazin-1-yl)ethyl]benzofuran-3(2H)-one (0.080 g, 97%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][CH2:12][N:11](C(=O)C)[CH2:10][CH2:9]1>[OH-].[Na+].C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1
Reactant: CC(=O)N1CCC(c2ccccc2Cl)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cl
Product: Clc1ccccc1C1CCNCC1
Temperature: 50 °C
Yield: 122.9 %

Procedure:
1-[4-(2-Chloro-phenyl)-piperidin-1-yl]-ethanone (0.2 g) was dissolved in a solution of aqueous sodium hydroxide (1 N, 5 mL) and ethanol (10 mL) and heated to 50° C. for 6 hours. The solvent was removed by evaporation under vacuum, and the products extracted into ethyl acetate, washed with water (20 mL) then dried over magnesium sulphate, filtered and the solvent removed by evaporation under vacuum. The residue was dissolved in a solution of hydrogen chloride in dioxane (4 N, 1 mL) and the solvent evaported to give the title compound as a pale yellow solid (0.12 g). LCMS m/z 196.1 [M+H]+. R.T.=2.46 min (Analytical Method 4).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH:20]=1)[C:8]([N:10]=[S@@:11]([CH3:19])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])#[CH:2].C([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[OH:29])#C>>[OH:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:2]#[C:1][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH:20]=1)[C:8]([N:10]=[S@@:11]([CH3:19])(=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9]
Reactant: C#Cc1cncc(C(=O)N=[S@@](C)(=O)c2ccccc2)c1
Reactant: C#Cc1ccccc1O
Product: C[S@@](=O)(=NC(=O)c1cncc(C#Cc2ccccc2O)c1)c1ccccc1
Yield: 7 %

Procedure:
In a manner similar to that describe in Example 431 a mixture of (S)-5-ethynyl-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide and 1-ethynyl-2-hydroxybenzene were reacted to give the title compound as a white solid (6 mg, 7%).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[C:8]([NH:10][C:11](=[O:23])[NH:12][C:13]3[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=3)[CH:7]=[CH:6][C:5]=12.[OH-].[Li+]>O1CCCC1.CO>[N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[C:8]([NH:10][C:11](=[O:23])[NH:12][C:13]3[CH:14]=[CH:15][C:16]([C:17]([OH:19])=[O:18])=[CH:21][CH:22]=3)[CH:7]=[CH:6][C:5]=12
Reactant: COC(=O)c1ccc(NC(=O)Nc2ccc3nccn3c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Nc1ccc(C(=O)O)cc1)Nc1ccc2nccn2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of methyl 4-(3-imidazo[1,2-a]pyridin-6-ylureido)benzoate (2.1 g, 6.77 mmol) in tetrahydrofuran (18.05 ml) and methanol (9.02 ml) was treated with 2N lithium hydroxide (13.53 ml, 27.1 mmol) and the reaction was allowed to stir at room temperature for 16 hours. The mixture was concentrated, redissolved in 225 mL water and acidified to pH 4 with 3N hydrochloric acid. The suspension was filtered with water washes to give the title compound after vacuum drying.
Reaction SMILES: [CH3:1][NH:2][C:3]([O:5][CH2:6][C@@H:7]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][NH:8]1)=[S:4].[C:17]1([N:23]=[C:24]=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>ClCCl>[CH3:1][NH:2][C:3]([O:5][CH2:6][C@@H:7]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][N:8]1[C:24]([NH:23][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:25])=[S:4]
Reactant: O=C=Nc1ccccc1
Reactant: CNC(=S)OC[C@@H]1Cc2ccccc2CN1
Solvent: ClCCl
Product: CNC(=S)OC[C@@H]1Cc2ccccc2CN1C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 96.8 %

Procedure:
(S)-3-(N-Methyl-thiocarbamoyloxymethyl) -1,2,3,4-tetrahydroisoquinoline (1.0 g, 4.94 mmol) dissolved in 20 mL dichloromethane was combined with PhNCO (1.0 g) and stirred for 24 h at rt. The reaction mixture was evaporated and the crude product was purified by column-chromatography (SiO2, hexanes:EtOAc=3:2) to provide the product as white solid (1.7 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1[CH3:12].[C@@H:13]1([NH2:22])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1>>[C@@H:13]1([NH:22][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4]([CH3:12])[CH:5]=2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1
Reactant: COc1ccc(C(=O)O)cc1C
Reactant: N[C@H]1CCc2ccccc21
Product: COc1ccc(C(=O)N[C@H]2CCc3ccccc32)cc1C
Yield: 63 %

Procedure:
Prepared in a similar manner to example 4 using 4-methoxy-3-methylbenzoic acid and (S)-2,3-dihydro-1H-inden-1-amine. Yield 63%. 1H NMR (500 MHz, dMSO): δ 1.94-1.99 (m, 1H), 2.17 (s, 3H), 2.41-2.46 (m, 1H), 2.82-2.87 (m, 1H), 2.96-3.01 (m, 1H), 3.83 (s, 3H), 5.53-5.57 (dd, 1H), 6.98-6.99 (d, 1H), 7.16-7.23 (m, 3H), 7.26-7.27 (m, 1H), 7.75-7.80 (m, 2H), 8.54-8.55 (d, 1H). MS (M+H, 282).
Reaction SMILES: C([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][C:22]=3[CH2:27]/[CH:28]=[CH:29]/[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C@H:36]([CH2:53][CH2:54][C:55]([F:67])([F:66])[C:56]([F:65])([F:64])[C:57]([F:63])([F:62])[C:58]([F:61])([F:60])[F:59])[C:37]([N:39]3[C@H:43]([C:44]5[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=5)[C@H:42]([CH3:50])[N:41]([CH3:51])[C:40]3=[O:52])=[O:38])([CH3:20])[C@@H:18]([O:68]CC3C=CC=CC=3)[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1)C1C=CC=CC=1.C(OC1C=CC2C3[C@H]([C@H]4[C@@](CC=3C/C=C\CCCCCC[C@H](CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(N3[C@H](C5C=CC=CC=5)[C@H](C)N(C)C3=O)=O)(C)[C@@H](OCC3C=CC=CC=3)CC4)CCC=2C=1)C1C=CC=CC=1>CO.O1CCCC1.[OH-].[OH-].[Pd+2]>[OH:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][C@@H:22]3[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C@H:36]([CH2:53][CH2:54][C:55]([F:67])([F:66])[C:56]([F:64])([F:65])[C:57]([F:62])([F:63])[C:58]([F:59])([F:60])[F:61])[C:37]([N:39]3[C@H:43]([C:44]5[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=5)[C@H:42]([CH3:50])[N:41]([CH3:51])[C:40]3=[O:52])=[O:38])([CH3:20])[C@@H:18]([OH:68])[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1
Reactant: C[C@H]1[C@@H](c2ccccc2)N(C(=O)[C@H](CCCCCC/C=C/CC2=C3c4ccc(OCc5ccccc5)cc4CC[C@H]3[C@@H]3CC[C@H](OCc4ccccc4)[C@@]3(C)C2)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)N1C
Agent: [Pd+2]
Agent: C[C@H]1[C@@H](c2ccccc2)N(C(=O)[C@H](CCCCCC/C=C\CC2=C3c4ccc(OCc5ccccc5)cc4CC[C@H]3[C@@H]3CC[C@H](OCc4ccccc4)[C@@]3(C)C2)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)N1C
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H]1[C@@H](c2ccccc2)N(C(=O)[C@H](CCCCCCCCC[C@H]2C[C@]3(C)[C@@H](O)CC[C@H]3[C@@H]3CCc4cc(O)ccc4[C@@H]23)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)N1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 70 %

Procedure:
The mixture of (4S,5R)-1-{(2R,9E)-11-[3,17β-bis-(benzyloxy)estra-1,3,5(10),9(11)-tetraen-11-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)-9-undecenoyl}-3,4-dimethyl-5-phenylimidazolidin-2-one and (4S,5R)-1-{(2R,9Z)-11-[3,17β-bis(benzyloxy)estra-1,3,5(10),9(11)-tetraen-11-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)-9-undecenoyl}-3,4-dimethyl-5-phenylimidazolidin-2-one (283 mg, 0.27 mmol) was dissolved in a mixed solvent of methanol (12 ml) and tetrahydrofuran (1.2 ml), followed by addition of palladium hydroxide/carbon (85 mg) at room temperature. After purging with hydrogen, the reaction mixture was stirred for 1 day at room temperature. After the reaction mixture was filtered, the solvent was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=3/7) to give (4S,5R)-1-{(2R)-11-[3,17β-dihydroxyestra-1,3,5(10)-trien-11β-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)undecanoyl}-3,4-dimethyl-5-phenylimidazolidin-2-one (164 mg, Yield 70%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[NH:10]1[CH2:18][CH2:17][CH2:16][CH:12]([C:13]([NH2:15])=[O:14])[CH2:11]1.CCN(C(C)C)C(C)C.[NH2:28][C:29]1[CH:37]=[C:36]2[C:32]([CH:33]=[N:34][NH:35]2)=[CH:31][CH:30]=1>CC#N.C(O)CCC>[NH:35]1[C:36]2[C:32](=[CH:31][CH:30]=[C:29]([NH:28][C:2]3[N:7]=[C:6]([N:10]4[CH2:18][CH2:17][CH2:16][CH:12]([C:13]([NH2:15])=[O:14])[CH2:11]4)[C:5]([F:9])=[CH:4][N:3]=3)[CH:37]=2)[CH:33]=[N:34]1
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: NC(=O)C1CCCNC1
Reactant: Fc1cnc(Cl)nc1Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: NC(=O)C1CCCN(c2nc(Nc3ccc4cn[nH]c4c3)ncc2F)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 23.6 %

Procedure:
A mixture of 2,4-dichloro-5-fluoropyrimidine (167 mg, 1.00 mmol), nipecotamide (128 mg, 1.00 mmol) and DIEA (0.350 mL, 2.01 mmol) in CH3CN (4 mL) was stirred at room temperature for 20 h. It was concentrated in vacuo. The residue was dissolved in nBuOH (4 mL). 2 mL of the nBuOH solution was taken, to which 6-aminoindazole (100 mg, 0.75 mmol) was added. The solution was stirred at 116° C. for 6 h. nBuOH was removed in vacuo. The residue was purified by HPLC to give the titled compound (63 mg). MS 356.3 (M+H); UV 206.8, 249.8, 276.8, 291.8 nm.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[F:10][C:11]([F:17])([F:16])[CH2:12][N:13]=[C:14]=[S:15]>CC(C)=O>[OH:6][CH2:5][C:4]1[CH:3]=[C:2]([NH:1][C:14]([NH:13][CH2:12][C:11]([F:17])([F:16])[F:10])=[S:15])[CH:9]=[CH:8][CH:7]=1
Reactant: Nc1cccc(CO)c1
Reactant: FC(F)(F)CN=C=S
Solvent: CC(C)=O
Product: OCc1cccc(NC(=S)NCC(F)(F)F)c1

Procedure:
m-Aminobenzyl alcohol (0.123 g.) and 2,2,2-trifluoroethylisothiocyanate (0.141 g.) were heated under reflux in acetone (5 ml.) for 2 hours. Volatile material was evaporated in vacuo and the crude residue was fractionated on a silica gel column (20 cm.×1 cm. diameter) eluted with ethyl acetate to give 1-(3-hydroxymethylphenyl)-3-(2,2,2-trifluoroethyl)thiourea. The n.m.r. spectrum in CDCl3 using tetramethylsilane as internal standard (δ=0) had the following resonances (δ): 7.2 (4H, multiplet); 4.6 (2H, singlet); 4.3 (2H, multiplet).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([NH:11][C:12](=[O:20])OC2C=CC=CC=2)=[CH:3][N:2]=1.[CH:21]1([S:27][C:28]2[C:33]([CH2:34][NH2:35])=[CH:32][CH:31]=[C:30]([C:36]([F:39])([F:38])[F:37])[N:29]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.C(N(CC)CC)C>CS(C)=O.O>[CH:21]1([S:27][C:28]2[C:33]([CH2:34][NH:35][C:12]([NH:11][C:4]3[C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=[N:2][CH:3]=3)=[O:20])=[CH:32][CH:31]=[C:30]([C:36]([F:38])([F:39])[F:37])[N:29]=2)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: NCc1ccc(C(F)(F)F)nc1SC1CCCCC1
Reactant: O=C(Nc1cncc2ccccc12)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: O=C(NCc1ccc(C(F)(F)F)nc1SC1CCCCC1)Nc1cncc2ccccc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 13.4 %

Procedure:
Phenyl isoquinolin-4-ylcarbamate (68 mg, 0.26 mmol) and (2-(cyclohexylthio)-6-(trifluoromethyl)pyridin-3-yl)methanamine (78 mg, 0.27 mmol) were dissolved in dimethyl sulfoxide. Then triethylamine (0.08 mL, 0.52 mmol) was added to it. The mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure. The crude was purified by column chromatography to give 1-((2-(cyclohexylthio)-6-(trifluoromethyl)pyridin-3-yl)methyl)-3-(isoquinolin-4-yl)urea (example compound 19) (16 mg, 14%).
Reaction SMILES: [O:1]=[C:2]([NH:25][C:26]1[NH:30][C:29]([C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)=[N:28][N:27]=1)[C@@H:3]([N:11]([CH2:19][C:20]1[N:21]=[CH:22][S:23][CH:24]=1)C(=O)OC(C)(C)C)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl.C([O-])(O)=O.[Na+]>O1CCOCC1.O>[C:5]1([CH2:4][C@H:3]([NH:11][CH2:19][C:20]2[N:21]=[CH:22][S:23][CH:24]=2)[C:2]([NH:25][C:26]2[NH:30][C:29]([C:31]3[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=3)=[N:28][N:27]=2)=[O:1])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)N(Cc1cscn1)[C@@H](Cc1ccccc1)C(=O)Nc1nnc(-c2ccncc2)[nH]1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(Nc1nnc(-c2ccncc2)[nH]1)[C@H](Cc1ccccc1)NCc1cscn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 34 %

Procedure:
To a rt solution of 2.E (147 mg, 0.29 mmol) in dioxane (3.0 mL) was added concentrated HCl (0.5 mL). After stirring at rt for 1.5 hr, the reaction mixture was poured into saturated NaHCO3, diluted with water and extracted with 30% iPrOH/chloroform. The organic solvent was removed under reduced pressure. After purification of the residue by preparative HPLC (10-90% CH3CN/water, 45 min), the combined product fractions was treated with saturated NaHCO3, and extracted with 30% i PrOH/CHCl3. After removal of solvent under reduced pressure, the title product 2 (40 mg, 37%) was obtained as colorless solid. MS ESI (positve.) m/e: 406.1 (M+H); 1H NMR (400 MHz, CD3OD) δ ppm 3.22-3.43 (m, 3H), 3.47-(dd, J=13.50, 6.06 Hz, 1H), 4.40-4.63 (m, 3H), 7.21-7.41 (m, 5H), 7.80 (d, J=1.96 Hz, 1H), 8.50 (d, J=6.65 Hz, 2H), 8.86 (d, J=6.65 Hz, 2H), 9.10 (d, J=1.96 Hz, 1H).
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[CH:45]=[CH:44][C:13]([C:14]([NH:16][NH:17][C:18]([C:20]2[CH:34]=[CH:33][C:23]([O:24][CH2:25][C:26]([O:28]C(C)(C)C)=[O:27])=[C:22]([O:35][CH2:36][C:37]([O:39]C(C)(C)C)=[O:38])[CH:21]=2)=[O:19])=[O:15])=[CH:12][CH:11]=1)=O)(C)(C)C.[C:46]([OH:52])([C:48]([F:51])([F:50])[F:49])=[O:47]>O>[F:49][C:48]([F:51])([F:50])[C:46]([OH:52])=[O:47].[NH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([NH:16][NH:17][C:18]([C:20]2[CH:34]=[CH:33][C:23]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[C:22]([O:35][CH2:36][C:37]([OH:39])=[O:38])[CH:21]=2)=[O:19])=[O:15])=[CH:44][CH:45]=1
Reactant: CC(C)(C)OC(=O)COc1ccc(C(=O)NNC(=O)c2ccc(CNC(=O)OC(C)(C)C)cc2)cc1OCC(=O)OC(C)(C)C
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: NCc1ccc(C(=O)NNC(=O)c2ccc(OCC(=O)O)c(OCC(=O)O)c2)cc1
Reaction time: 2 h

Procedure:
A solution of t-butyl 4-[3-(4-t-butoxycarbonylaminomethylbenzoyl)carbazoyl]-2-(t-butoxycarbonylmethoxy)phenoxyacetate (100 mg) in a mixture of TFA (9 ml) and water (1 ml) was stored at ambient temperature for 2 hours. The reaction mixture was evaporated to near dryness and excess dry ether was added. The solvents were again removed in vacuo. The solid product was triturated with dry ether, collected and dissolved in 50% aqueous acetic acid (10 ml) with gentle warming. The solution was diluted with water (10 ml) and washed with ether (2×20 ml). The aqueous solution was filtered, diluted with water (20 ml) and lyophilised overnight to give the title compound (69 mg) as a white fluffy solid; NMR Spectrum (DHSO-d6) 4.08 (2H, s), 4.60 (2H, s), 4.62 (2H, s), 6.95 (1H, m), 7.4-7.6 (4H, m), 7.92 (2H, m); Mass Spectrum m/Z 418 (H +H)+ ;
Reaction SMILES: ClC(Cl)(Cl)C[O:4][C:5](=O)[NH:6][C:7]1[C:8]([CH3:27])=[C:9]([CH3:26])[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=3)[C:11]=2[C:24]=1[CH3:25].[CH2:31]([NH:33][CH2:34][CH3:35])[CH3:32]>>[CH2:31]([N:33]([CH2:34][CH3:35])[C:5]([NH:6][C:7]1[C:8]([CH3:27])=[C:9]([CH3:26])[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=3)[C:11]=2[C:24]=1[CH3:25])=[O:4])[CH3:32]
Reactant: CCNCC
Reactant: Cc1c(C)c2c(c(C)c1NC(=O)OCC(Cl)(Cl)Cl)C(c1ccc(C(C)C)cc1)CO2
Product: CCN(CC)C(=O)Nc1c(C)c(C)c2c(c1C)C(c1ccc(C(C)C)cc1)CO2
Yield: 68 %

Procedure:
Using 2,2,2-trichloroethyl(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamate obtained in Example 138 and diethylamine, the title compound was obtained in the same manner as in Example 143. Yield: 68%. Melting point: 79-81° C. (ethyl acetate-hexane).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[O:11].C(=O)([O-])[O-].[K+].[K+].C([O:28][C:29]1[CH:34]=[N:33][CH:32]=[C:31]([CH:35]=[CH2:36])[N:30]=1)(C)(C)C.O>CN(C)C=O.C(OCC)(=O)C>[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([CH:12]1[CH2:13][CH2:14][N:15]([CH2:36][CH2:35][C:31]2[NH:30][C:29](=[O:28])[CH:34]=[N:33][CH:32]=2)[CH2:16][CH2:17]1)=[O:11]
Reactant: C=Cc1cncc(OC(C)(C)C)n1
Reactant: O=C(Cc1ccccc1F)C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Cc1ccccc1F)C1CCN(CCc2cncc(=O)[nH]2)CC1
Reaction time: 64 h
Yield: 2 %

Procedure:
After dissolving 1.00 g of 2-(2-fluorophenyl)-1-(piperidin-4-yl)ethanone hydrochloride in 8 ml of N,N-dimethylformamide, 643 mg of potassium carbonate and 899 mg of 2-tert-butoxy-6-vinylpyrazine were added while stirring, and the stirring was continued for 64 hours at 100° C. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography (solvent: n-hexane/ethyl acetate). Three milliliters of 4N hydrogen chloride/ethyl acetate was added to the obtained product and the mixture was stirred for 2.5 hours at room temperature. A 1N sodium hydroxide solution was added to the reaction solution and extraction was performed with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: chloroform/methanol/ammonia water) to obtain the title compound (27 mg, 2% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17](=[O:32])[C:18]#[C:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13].N1CCCCC1.C([OH:41])C>CCOCC>[C:23]1([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:22]=[CH:21][C:20]([C:19](=[O:41])[CH2:18][C:17]([NH:16][C:4]2[CH:5]=[CH:6][C:7]([O:8][CH2:9][CH2:10][N:11]([CH2:12][CH3:13])[CH2:14][CH3:15])=[C:2]([Cl:1])[CH:3]=2)=[O:32])=[CH:25][CH:24]=1
Reactant: CCO
Reactant: CCN(CC)CCOc1ccc(NC(=O)C#Cc2ccc(-c3ccccc3)cc2)cc1Cl
Solvent: C1CCNCC1
Solvent: CCOCC
Product: CCN(CC)CCOc1ccc(NC(=O)CC(=O)c2ccc(-c3ccccc3)cc2)cc1Cl
Reaction time: 8 h

Procedure:
0.16 g (0.36 mmol) of 3-biphenyl-4-ylpropynoic acid-[3-chloro-4-(2-diethylaminoethoxy)phenyl]amide (educt XII.1) is dissolved in 10 mL of aqueous ethanol and 0.10 mL (1.0 mmol) of piperidine is added. The mixture is stirred for 8 hours at reflux temperature. After cooling, the solvent is eliminated, and the residue is suspended in ether and filtered off. The residue is dried in vacuo at 50° C. Yield: 75 mg (45% of theory); Rf value: 0.40 (silica gel, methylene chloride/methanol/ammonia=9:1:0.01); m.p. 148° C.-151° C.; C27H29ClN2O3; EII mass spectrum: m/z=465/467 [M+H]+.