Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].Br[C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[O:33]1[CH2:34][CH2:35][N:30]([C:27]2[CH:28]=[CH:29][C:24]([NH:1][C:2]3[CH:14]=[C:13]([CH2:15][CH2:16][C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:12]=[CH:11][C:3]=3[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])=[CH:25][CH:26]=2)[CH2:31][CH2:32]1
Reactant: CC(C)(C)OC(=O)c1ccc(CCc2ccccc2)cc1N
Reactant: Brc1ccc(N2CCOCC2)cc1
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1ccc(CCc2ccccc2)cc1Nc1ccc(N2CCOCC2)cc1
Temperature: 110 °C
Reaction time: 6 h

Procedure:
To toluene 3.0 mL solution of tert-butyl 2-amino-4-phenethylbenzoate 0.10 g were added 4-(4-bromophenyl)morpholine 0.21 g, cesium carbonate 0.23 g, tris(dibenzylideneacetone)dipalladium(0) 3.2 mg and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 8.3 mg at room temperature, and it was stirred at 110° C. for 6 hours. After the reaction mixture was cooled to room temperature, palladium acetate 1.6 mg, tris(dibenzylideneacetone)dipalladium(0) 3.2 mg and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 8.3 mg were added, and it was stirred at 110° C. for 12 hours. After the reaction mixture was cooled to room temperature, 4-(4-bromophenyl)morpholine 0.21 g, cesium carbonate 0.23 g, palladium acetate 1.6 mg, tris(dibenzylideneacetone)dipalladium(0) 3.2 mg and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 8.3 mg were added, and it was stirred at 110° C. for 4 hours. After the reaction mixture was cooled to room temperature, insoluble matter was filtrated, ethyl acetate and 10% citric acid aqueous solution were added to it. The organic layer was separated and collected, dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate=4:1] to give tert-butyl 2-(4-morpholinoanilino)-4-phenethylbenzoate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]2[CH3:14])[CH:5]=[CH:6][CH:7]=1.[Li]CCCC.[CH3:20][C:21]([CH3:23])=[O:22]>C1COCC1>[CH3:14][C:9]1[N:8]([C:4]2[CH:3]=[C:2]([C:21]([OH:22])([CH3:23])[CH3:20])[CH:7]=[CH:6][CH:5]=2)[C:12]([CH3:13])=[CH:11][CH:10]=1
Reactant: CC(C)=O
Reactant: Cc1ccc(C)n1-c1cccc(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(C)n1-c1cccc(C(C)(C)O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.1 %

Procedure:
A solution of 1-(3-bromophenyl)-2,5-dimethyl-1H-pyrrole (1.50 g, 6.00 mmol) in THF (25 mL) was cooled to −78° C. under an atmosphere of argon. To this solution was added n-BuLi (2.50 M in hexane, 2.76 mL, 6.90 mmol) dropwise via syringe. After 30 min, acetone (0.572 mL, 7.8 mmol) was added to the cold solution dropwise via syringe. After 10 min, the cold bath was removed and the reaction mixture was allowed to warm to rt. After 5.5 h, the reaction was quenched by the addition of water. The mixture was extracted with EtOAc and the organic solutions dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography to give the desired product (0.84 g, 61%). LCMS: (FA) ES+ 230.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:8][NH:7][CH2:6]1)=[O:4].[CH2:9]([N:11]([CH2:38][CH3:39])[C:12]1[CH:17]=[C:16]([C:18]2[O:22][N:21]=[C:20]([C:23]3[CH:28]=[C:27]([CH3:29])[C:26]([O:30][CH2:31][C@@H:32]4[CH2:34][O:33]4)=[C:25]([CH2:35][CH3:36])[CH:24]=3)[N:19]=2)[CH:15]=[C:14]([CH3:37])[N:13]=1)[CH3:10].C(N(CC)CC)C.CC(=O)OCC>CO>[CH3:1][O:2][C:3]([CH:5]1[CH2:8][N:7]([CH2:34][C@H:32]([OH:33])[CH2:31][O:30][C:26]2[C:27]([CH3:29])=[CH:28][C:23]([C:20]3[N:19]=[C:18]([C:16]4[CH:15]=[C:14]([CH3:37])[N:13]=[C:12]([N:11]([CH2:38][CH3:39])[CH2:9][CH3:10])[CH:17]=4)[O:22][N:21]=3)=[CH:24][C:25]=2[CH2:35][CH3:36])[CH2:6]1)=[O:4]
Reactant: COC(=O)C1CNC1
Reactant: CCc1cc(-c2noc(-c3cc(C)nc(N(CC)CC)c3)n2)cc(C)c1OC[C@@H]1CO1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CO
Product: CCc1cc(-c2noc(-c3cc(C)nc(N(CC)CC)c3)n2)cc(C)c1OC[C@@H](O)CN1CC(C(=O)OC)C1

Procedure:
A solution of azetidine-3-carboxylic acid methyl ester (40 mg, 0.355 mmol) and diethyl-{4-[3-((S)-3-ethyl-5-methyl-4-oxiranylmethoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-6-methyl-pyridin-2-yl}-amine (300 mg, 0.71 mmol, Example 18 step a)) in methanol (5 mL) and triethylamine (0.1 mL) is stirred at 60° C. for 2 days. The mixture is dissolved with EA and washed with sat. aq. NaHCO3-solution. The org. extract is collected and concentrated. The crude product is purified by prep. HPLC to give the title compound (60 mg) as pale yellow oil; LC-MS: tR=0.79 min; [M+1]+=538.04; 1H NMR (CDCl3): δ 1.25 (t, J=6.8 Hz, 6H), 1.32 (t, J=7.5 Hz, 3H), 2.40 (s, 3H), 2.50 (s, 3H), 2.71-2.80 (m, 4H), 3.06 (s br, 1H), 3.35-3.46 (m, 2H), 3.48-3.54 (m, 2H), 3.58-3.72 (m, 6H), 3.75 (s, 3H), 3.81-3.86 (m, 2H), 3.93-4.00 (m, 1H), 7.01 (s, 1H), 7.10 (s, 1H), 7.87 (s, 1H), 7.88 (s, 1H).
Reaction SMILES: CON(C)[C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[NH:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5].[H-].[H-].[H-].[H-].[Li+].[Al+3].[NH4+].[Cl-].ClCCl>C1COCC1>[N:19]1[CH:18]=[CH:17][C:16]([NH:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH:4]=[O:5])=[CH:21][CH:20]=1
Reactant: CON(C)C(=O)c1[nH]c2ccccc2c1Nc1ccncc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=Cc1[nH]c2ccccc2c1Nc1ccncc1
Temperature: 0 °C
Yield: 36.3 %

Procedure:
At 0° C. stir a suspension of 3-(pyridin-4-ylamino)-1H-indole-2-carboxylic acid methoxy-methyl-amide (2.72 g, 7.2 mmol) in THF (35 mL), and add a 1M solution of LAH in THF (14.5 mL, 14.5 mmol). Allow warming to room temperature and continue to stir for 20 h. Add aqueous NH4Cl followed by dichloromethane. Filter the aluminum salts, separate the organic phase and concentrate it under vacuum to obtain a brown oil. Flash chromatograph the oil to obtain 0.62 g (36%) of the title compound as a yellow solid. 1H NMR (DMSO-d6) δ 11.8 (1H, s), 9.95 (1H, s), 9.1 (1H, s), 8.18 (2H, brs), 7.4 (3H, m), 7.1 (1H, dd), 6.7 (2H, brd).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH:21]([OH:24])[CH2:22][OH:23])[C:10]([NH:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[Si:30](Cl)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31].O>ClCCl.CN(C)C=O.[Cl-].[Na+].O>[C:1]([O:5][C:6]([NH:8][CH:9]([CH:21]([OH:24])[CH2:22][O:23][Si:30]([CH3:32])([CH3:31])[C:33]([CH3:36])([CH3:35])[CH3:34])[C:10]([NH:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(C(=O)NOCc1ccccc1)C(O)CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Cl-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC(C(=O)NOCc1ccccc1)C(O)CO[Si](C)(C)C(C)(C)C
Yield: 44.6 %

Procedure:
[(Tert-butoxy)carbonylamino]-3,4-dihydroxy-N-(phenylmethoxy) butanamide (47 g, 138 mmol), imidazole (37.5 g, 552 mmol) and tert-butyldimethylsilyl chloride (57.7 g, 386.4 mmol) were stirred at 0° C. for 1 h and the room temperature for an additional 1 h in a mixture of dichloromethane (1.7 L) and dimethylformamide (17 mL). Water (250 mL) was added and after decantation, water (2×250 mL) and brine (250 mL) was used for washing the organic phases, which was dried over Na2SO4. After evaporation of the solvent, the residue was purified by column chromatography using a mixture of ethyl acetate/hexane (1/4) as eluent to get 28 g of the desired product.
Reaction SMILES: CO[C:3](=[O:18])[CH:4]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH3:17])[C:5]([O:7]C)=O.C[O-].[Na+].Cl.[C:23]([NH2:26])(=[NH:25])[CH3:24]>CO>[CH3:17][O:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[O:9][C:4]1[C:3]([OH:18])=[N:25][C:23]([CH3:24])=[N:26][C:5]=1[OH:7]
Reactant: CC(=N)N
Reactant: COC(=O)C(Oc1ccccc1OC)C(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1ccccc1Oc1c(O)nc(C)nc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.3 %

Procedure:
A solution of dimethyl-(o-methoxyphenoxy)malonate (10 g) in dry methanol (80 ml) was cooled to 0° C. Sodium methylate (6.71 g) was added portionwise. To the suspension was added of acetamidine hydrochloride (2.84 g) and the mixture was stirred overnight at r.t. The solvent was removed under reduced pressure and the residue was suspended in diethyl ether (100 ml). The solid was filtered off, washed with another portion of diethyl ether (100 ml) and dissolved in water (50 ml). The pH was adjusted to 4 by adding glacial acetic acid (25 ml). The white precipitate that formed was filtered off, washed with water and dried to yield 5-(o-methoxyphenoxy)-4,6-dihydroxy-2-methyl-pyrimidine (5.17 g) (or a tautomer) as a white powder.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[C:21]4[C:16](=[N:17][CH:18]=[C:19]([C:22]5[CH:27]=[CH:26][C:25]([N:28]6[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]6)=[CH:24][CH:23]=5)[CH:20]=4)[NH:15][CH:14]=3)[CH:10]=[N:9]2)[CH:2]=1.Cl>CCOCC.CO>[N:28]1([C:25]2[CH:26]=[CH:27][C:22]([C:19]3[CH:20]=[C:21]4[C:13]([C:11]5[CH:10]=[N:9][N:8]([CH2:7][C:3]6[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=6)[CH:12]=5)=[CH:14][NH:15][C:16]4=[N:17][CH:18]=3)=[CH:23][CH:24]=2)[CH2:29][CH2:30][NH:31][CH2:32][CH2:33]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6cccnc6)c5)c4c3)cc2)CC1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: c1cncc(Cn2cc(-c3c[nH]c4ncc(-c5ccc(N6CCNCC6)cc5)cc34)cn2)c1
Yield: 11.1 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(4-(3-(1-(pyridin-3-ylmethyl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazine-1-carboxylate (100 mg, 0.186 mmol) was deprotected with HCl in ether/methanol (2/3 ml). This afforded 9 mg (11.0% yield) of the titled compound. 1H NMR (CD3OD, 300 MHz): δ 8.54 (s, 1H), 8.34-8.28 (d, 1H), 8.50-8.49 (d, 1H), 8.43-8.42 (d, 1H), 8.307-8.300 (d, 1H), 8.23 (s, 1H), 7.93 (s, 1H), 7.79-7.77 (d, 1H), 7.64-7.61 (m, 3H), 7.45-7.41 (m, 1H), 7.14-7.11 (m, 2H), 5.49 (s, 2H), 3.38-3.31 (m, 4H), 3.30-3.23 (m, 4H). MS: m/z=436.2 (M+1), HPLC: 97.13% in method A.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[NH:10][NH2:11].C(N(CC)CC)C.C(O[CH:22]=[C:23]([C:29]([C:31]([F:34])([F:33])[F:32])=O)[C:24]([O:26][CH2:27][CH3:28])=[O:25])C>C(O)C>[F:32][C:31]([F:33])([F:34])[C:29]1[N:10]([C:4]2[CH:5]=[CH:6][C:7]([Cl:9])=[CH:8][C:3]=2[Cl:2])[N:11]=[CH:22][C:23]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: NNc1ccc(Cl)cc1Cl
Reactant: CCOC=C(C(=O)OCC)C(=O)C(F)(F)F
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnn(-c2ccc(Cl)cc2Cl)c1C(F)(F)F
Temperature: -10 °C
Reaction time: 8 h

Procedure:
2,4-Dichlorophenylhydrazine hydrochloride salt (15.68 grams, 0.068 mole) was dissolved in a minimum amount of ethanol and the solution was cooled to -10° C. Triethylamine (9.44 ml., 0.068 mole) was added followed by ethyl (ethoxymethylene)trifluoroacetoacetate (16.27 grams, 0.068 mole). The addition of this last reactant was made over thirty minutes, keeping the reaction temperature below -10° C. The reaction mixture was allowed to rise to room temperature overnight (about 16 hours). The solvent was removed in vacuo and the resiude was dissolved in equal parts of ethyl acetate and water. The organic phase was separated, washed with 1N HCl, water, saturated sodium bicarbonate solution, water, and brine. It was then dried and evaporated to 7.85 grams of an oil which slowly crystallized. The 5-(trifluoromethyl)-1-(2,4-dichlorophenyl)-1H-pyrazole-4-carboxylic acid, ethyl ester, was recrystallized from petroleum ether, mp=81°-83° C.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][C:22]4[C:23]5[CH2:31][CH2:30][NH:29][CH2:28][C:24]=5[N:25]=[CH:26][N:27]=4)=[CH:18][CH:19]=3)[CH:14]=[CH:13]2)=[O:11])[CH:6]=[CH:7][CH:8]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[CH2:68]([N:70]([CH2:76][CH3:77])[CH2:71][CH2:72][C:73](O)=[O:74])[CH3:69]>CN(C=O)C>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][C:22]4[C:23]5[CH2:31][CH2:30][N:29]([C:73](=[O:74])[CH2:72][CH2:71][N:70]([CH2:76][CH3:77])[CH2:68][CH3:69])[CH2:28][C:24]=5[N:25]=[CH:26][N:27]=4)=[CH:18][CH:19]=3)[CH:14]=[CH:13]2)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)n1ccc2cc(Oc3ncnc4c3CCNC4)ccc21
Reactant: CCN(CC)CCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN(CC)CCC(=O)N1CCc2c(ncnc2Oc2ccc3c(ccn3C(=O)Nc3cccc(C(F)(F)F)c3)c2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-(5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide, Example 31-C, (120 mg, 0.26 mmol), HATU (198 mg, 0.52 mmol), DIEA (0.2 mL, 1.30 mmol) and DMF (5 mL) is added 3-diethylamino-propionic acid hydrochloride (47 mg, 0.26 mmol). After stirring at rt for 2 h the contents of the flask are partitioned between DCM and 10% aqueous LiCl. Organic layer is removed, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is then separated via semi-prep HPLC (C18; 10-100% I/H2O with 0.1% NH4OH) to give the title compound. MS (ESI) m/z 581.2 (M+1); 1H NMR (400 MHz, MeOD) δ ppm 8.40-8.48 (m, 1H), 8.33 (d, J=8.8 Hz, 1H), 8.06 (s, 1H), 7.94 (d, J=3.5 Hz, 1H), 7.89 (d, J=8.6 Hz, 1H), 7.57 (t, J=8.1 Hz, 1H), 7.36-7.47 (m, 2H), 7.10 (dd, J=9.0, 2.1 Hz, 1H), 6.74 (d, J=3.8 Hz, 1H), 4.71-4.79 (m, 2H), 3.85-4.05 (m, 2H), 3.20 (d, J=5.8 Hz, 2H), 2.84-3.08 (m, 8H), 1.23 (q, J=7.1 Hz, 6H).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:14]([N:21]=[C:22]=[S:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(#N)C.CN(C)C1C=CN=CC=1>[CH:8]1([N:7]([C:22]([NH:21][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[S:23])[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: S=C=NCc1ccccc1
Reactant: c1ccc(NC2CCCCC2)cc1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: S=C(NCc1ccccc1)N(c1ccccc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of N-cyclohexylaniline (0.1 ml, 0.57 mmol) in acetonitrile (4 ml) was added a catalytic amount of 4-(dimethylamino)pyridine (5 mg, 0.04 mmol). To this mixture was added benzyl isothiocyanate (0.11 ml, 0.83 mmol) dropwise, and the mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure, and the residue purified on preparative silica gel plates, developing with 20% ethyl acetate/hexanes, to furnish (cyclohexylphenylamino)-N-benzylthiocarboxamide as a white solid, (M+1)=324.8.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([OH:18])[CH2:9][CH2:10][NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH:5]=[CH:6][CH:7]=1.[CH2:19]([CH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1)[CH2:20][C:21]#[CH:22]>>[CH:23]1([CH2:19][CH2:20][C:21]#[C:22][C:2]2[CH:3]=[C:4]([CH:8]([OH:18])[CH2:9][CH2:10][NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH:5]=[CH:6][CH:7]=2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C(NCCC(O)c1cccc(Br)c1)C(F)(F)F
Reactant: C#CCCC1CCCC1
Product: O=C(NCCC(O)c1cccc(C#CCCC2CCCC2)c1)C(F)(F)F

Procedure:
Sonogashira reaction of 25 with but-3-ynyl-cyclopentane yielded N-(3-(3-(4-cyclopentylbut-1-ynyl)phenyl)-3-hydroxypropyl)-2,2,2-trifluoroacetamide as a dark brown oil. Yield (690 mg, 69%): 1H NMR (400 MHz, CDCl3) δ 7.22-7.57 (m, 4H),
Reaction SMILES: [CH2:1](O)[CH:2]=[CH2:3].S(=O)(=O)(O)O.[Cl:10][C:11]1[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:12]=1[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]([OH:27])=[O:26])=[CH:20][CH:19]=1.O>C1C=CC=CC=1>[Cl:10][C:11]1[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:12]=1[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]([O:27][CH2:3][CH:2]=[CH2:1])=[O:26])=[CH:20][CH:19]=1
Reactant: C=CCO
Reactant: O=C(O)Cc1ccc(-c2ccc(O)cc2Cl)cc1
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Solvent: O
Product: C=CCOC(=O)Cc1ccc(-c2ccc(O)cc2Cl)cc1

Procedure:
After allyl alcohol (7.0 ml, 103 mmol) and concentrated sulfuric acid (0.1 ml) were successively added to a solution of (2′-chloro-4′-hydroxy-1,1′-biphenyl-4-yl)acetic acid (1.93 g, 7.35 mmol) obtained in Example (13-1) in benzene (30 ml), the mixture was heated under reflux for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate (twice). The organic layer was successively washed with water (twice) and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=90/10-65/35) to give allyl (2′-chloro-4′-hydroxy-1,1′-biphenyl-4-yl)acetate as a white powder (1.97 g, yield: 899.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][C:19](Br)=[CH:18][CH:17]=1)[C:10]([CH3:24])([CH3:23])[CH2:9]2)=[O:5])[CH3:2].[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.Cl.CN(C)CC(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][C:19]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[CH:18][CH:17]=1)[C:10]([CH3:24])([CH3:23])[CH2:9]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(Br)cc1)N2
Reactant: C1COCCN1
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(N3CCOCC3)cc1)N2
Temperature: 120 °C
Yield: 19.5 %

Procedure:
A mixture of 2-(4-bromo-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (1.0 g, 2.6 mmol), morpholine (2.24 g, 25.8 mmol), copper (I) iodide (0.29 g, 1.55 mmol), N,N-dimethylglycine hydrochloride (0.29 g, 2.06 mmol) and potassium carbonate (1.07, 7.74 mmol) in DMSO (10 mL) was heated for 3 hours at 120° C. After cooling to room temperature, the mixture was treated with ethyl acetate (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. Purification on flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company) (20% ethyl acetate/hexanes) to afford 3,3-dimethyl-2-(4-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.20 g, 20%) as a white solid: LC/MS m/e calcd for C24H30N2O3 (M+H)+: 395.5, observed: 395.2.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[CH:25]1([S:31](Cl)(=[O:33])=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>N1C=CC=CC=1>[O:16]=[C:12]1[NH:11][C:10]2[C:17]3[C:22]([CH:23]=[CH:24][C:9]=2[N:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:31]([CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)(=[O:33])=[O:32])=[CH:3][CH:4]=2)[C:14](=[O:15])[CH2:13]1)=[CH:21][CH:20]=[CH:19][CH:18]=3
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: O=S(=O)(Cl)C1CCCCC1
Solvent: c1ccncc1
Product: O=C1CC(=O)N(c2ccc(NS(=O)(=O)C3CCCCC3)cc2)c2ccc3ccccc3c2N1
Yield: 34.1 %

Procedure:
5-(4-Aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (30 mg, 0.095 mmol) obtained in Example 1, (3), and cyclohexanesulfonyl chloride (69 μL, 0.47 mmol) were treated by heating in pyridine (3 mL). A post-treatment was performed in a conventional manner to give the title compound (15 mg, yield 34%) as brown amorphous.
Reaction SMILES: Br[CH2:2][C:3]1[NH:7][C:6](=[O:8])[NH:5][C:4]=1[C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1.[C:19]1([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].[ClH:37]>CC(O)C.O.C(O)C>[ClH:37].[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([C:9]([C:4]2[NH:5][C:6](=[O:8])[NH:7][C:3]=2[CH2:2][N:28]2[CH2:29][CH2:30][CH:25]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:26][CH2:27]2)=[O:18])=[CH:11][CH:12]=1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: COc1ccc(C(=O)c2[nH]c(=O)[nH]c2CBr)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: CC(C)O
Product: COc1ccc(C(=O)c2[nH]c(=O)[nH]c2CN2CCC(c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4.7 g (15 mmole) of 5-(bromomethyl)-1,3-dihydro-4-(4-methoxybenzoyl)-2H-imidazol-2-one, 2.5 g (16 mmole) of 4-phenylpiperidine, 2.1 g (15 mmole) of potassium carbonate and 75 ml of ethanol is stirred at 25° C. for 16 hours. Water (100 ml) is added and a precipitate forms. This is separated by filtration and washed with water. It is then suspended in 2-propanol and 1 equivalent of hydrogen chloride in 2-propanol is added. The resulting solid is separated by filtration and recrystallized from 2-propanol containing a little water to give 1,3-dihydro-4-(4-methoxybenzoyl)-5-[(4-phenyl-1-piperidinyl)methyl]-2H-imidazol-2-one hydrochloride melting at about 230° C. with decomposition.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:16]=[CH:15][C:8]2[S:9][C:10]([C:12]([OH:14])=O)=[CH:11][C:7]=2[CH:6]=1)=[O:4].[C:17]([O:36][NH2:37])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[CH:16]=[CH:15][C:8]2[S:9][C:10]([C:12](=[O:14])[NH:37][O:36][C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2sc(C(=O)O)cc2c1
Reactant: NOC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2sc(C(=O)NOC(c3ccccc3)(c3ccccc3)c3ccccc3)cc2c1
Temperature: 25 °C

Procedure:
A solution of benzo[b]thiophene-2,5-dicarboxylic acid 5-methyl ester (2.592 g, 10.97 mmol), O-trityl -hydroxylamine (3.020 g, 10.97 mmol), EDC (3.150 g, 16.48 mmol), HOBt (1.482 g, 10.97 mmol) and DIEA (4.80 mL, 27.6 mmol) in anhydrous THF (100 mL) was allowed to stir at rt for one week and then concentrated. To the residue was added MeOH (10 mL) and water (100 mL). The syrup obtained was washed with water (10 mL) and triturated with water (90 mL) to give 2-trityloxycarbamoyl-benzo[b]thiophene-5-carboxylic acid methyl ester as a pale solid. MS (EI): cal'd 243.1 (M-benzothiophene moiety+H+), exp 243.2 (M-benzothiophene moiety+H+).