Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].[CH2:2]([N+:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8][C:7]=1[CH3:13])[CH2:3][CH2:4][CH3:5].[C:14]1([C:24](Cl)=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1>CN(C1C=CN=CC=1)C>[CH2:2]([N:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8]/[C:7]/1=[CH:13]\[C:24]([C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)=[O:25])[CH2:3][CH2:4][CH3:5]
Reactant: O=C(Cl)c1cccc2ccccc12
Reactant: CCCC[n+]1c(C)sc(C)c1C
Agent: CN(C)c1ccncc1
Agent: [I-]
Product: CCCCN1C(C)=C(C)S/C1=C\C(=O)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 3-butyl-2,4,5-trimethylthiazol-3-ium iodide (48 mg in 0.5 mL DMA, 0.16 mmol, 1 equiv.) was added, followed by TEA (38 mg in 0.5 mL DMA, 0.37 mmol, 2.4 equiv.) and the solution went black. DMAP (2 mg in 0.5 mL DMA, 0.016 mmol, 0.1 equiv) was added next, followed by 1-naphthoyl chloride (0.9 mL of 0.2M in DMA, 1.2 equiv). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.89 (t, 3 H) 1.29-1.39 (m, 2 H) 1.59-1.69 (m, 2 H) 2.26 (s, 6H) 4.02-4.07 (m, 2 H) 6.30 (s, 1 H) 7.50-7.59 (m, 3 H) 7.68-7.71 (m, 1 H) 7.94-8.01 (m, 2 H) 8.30-8.34 (m, 1 H); MS (ESI) m/z 338 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[O:10][C:9]([C:11]([NH:13][CH3:14])=O)=[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:7]=1.[H-].[Al+3].[H-].[H-].O>O1CCCC1>[NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[O:10][C:9]([CH2:11][NH:13][CH3:14])=[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:7]=1
Reactant: CNC(=O)c1oc(CSCCN)cc1-c1ccccc1
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CNCc1oc(CSCCN)cc1-c1ccccc1
Reaction time: 6 h
Yield: 33.8 %

Procedure:
A solution of 5-[[2-(amino)ethyl]thio]methyl-N-methyl-3-phenyl-2-furancarboxamide (1.4 g) in dry tetrahydrofuran (100 ml) at 0° was mixed with a 0.5 molar solution of aluminium hydride in tetrahydrofuran (50 ml). After 6 hours boiling at reflux, water (6 ml) was added and the filtered solution was evaporated in vacuo. The residue was purified by column chromatography (silica/methanol) affording the title compound (0.45 g) as an oil,
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[Cl:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[O:18][CH:19]([F:21])[F:20]>C(Cl)(Cl)Cl>[Cl:10][C:11]1[C:12]([O:18][CH:19]([F:20])[F:21])=[CH:13][C:14]([N+:1]([O-:4])=[O:2])=[C:15]([F:17])[CH:16]=1
Reactant: O=[N+]([O-])O
Reactant: Fc1ccc(OC(F)F)c(Cl)c1
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1cc(OC(F)F)c(Cl)cc1F
Temperature: 60 °C
Yield: 89.5 %

Procedure:
To 21 g of conc. nitric acid was dropwise added 28 g of conc. sulfuric acid at 0° C., and the mixture was heated at 60° C. At intervals of 3 minutes, 10 g of 1-chloro-2-difluoromethoxy-5-fluorobenzene was added in 5 portions to the mixture, which was kept at 60° C. for half an hour. After cooling, the reaction mixture was poured on ice water and shaken with chloroform. The chloroform layer was washed with water, dried and concentrated. The residue was chromatographed on a column of silica gel, eluting with n-hexane-ethyl acetate (100:15 v/v). The eluate was concentrated to give 11 g of the titled compound XII-1.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([C:27]#[N:28])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])CCC.[NH2:29][C:30]([CH3:36])([CH3:35])[CH2:31][C:32]([OH:34])=[O:33].C[O-].[Na+].[OH-].[Na+]>CN(C=O)C.O>[C:27]([C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([O:19][C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)[CH:12]=2)[C:17]([OH:18])=[C:8]([C:6]([NH:29][C:30]([CH3:36])([CH3:35])[CH2:31][C:32]([OH:34])=[O:33])=[O:7])[N:9]=1)#[N:28]
Reactant: CC(C)(N)CC(=O)O
Reactant: CCCCOC(=O)c1nc(C#N)c2cc(Oc3ccc(F)cc3)ccc2c1O
Agent: C[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(CC(=O)O)NC(=O)c1nc(C#N)c2cc(Oc3ccc(F)cc3)ccc2c1O
Yield: 35.6 %

Procedure:
To a mixture of 1-cyano-7-(4-fluoro-phenoxy)-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester (60 mg, 0.16 mmol) and 3-amino-3-methyl-butyric acid (92 mg, 0.79 mmol) in DMF (1.5 mL) was added NaOMe solid (34 mg, 0.63 mmol). The resultant mixture was stirred in a 150-160° C. oil bath for 4 h. Reaction mixture was diluted with water (60 mL) and basified by 1 N NaOH to pH=10. It was extracted with EtOAc (30 mL), which was discarded. Aqueous layer was acidified by 1 N HCl to pH=3-4. Precipitate was collected and dried. Crude product was then triturated with MeOH (4 mL). Solid was collected and dried in vacuo to provide the title compound 24 mg (0.057 mmol) in 35% yield. LC-MS ESI−: 422.07 (M−1)−.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[N:3]=1.[CH3:22][C:23]1[O:24][C:25]([C:28]2[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=2)=[CH:26][N:27]=1>>[CH3:22][C:23]1[O:24][C:25]([C:28]2[CH:33]=[CH:32][C:31]([NH:34][C:2]3[N:7]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([C:12]4[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=4)[N:3]=3)=[CH:30][CH:29]=2)=[CH:26][N:27]=1
Reactant: CC(C)(O)c1cc(-c2ccc(C(F)(F)F)cc2)nc(Cl)n1
Reactant: Cc1ncc(-c2ccc(N)cc2)o1
Product: Cc1ncc(-c2ccc(Nc3nc(-c4ccc(C(F)(F)F)cc4)cc(C(C)(C)O)n3)cc2)o1
Yield: 21.3 %

Procedure:
Using in analogous manner the procedure described in example 1e), 2-[2-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yl]-propan-2-ol (95 mg, 0.3 mmol) was reacted with 4-(2-methyl-oxazol-5-yl)-phenylamine (52 mg, 0.3 mmol) to give the title compound as light yellow solid (29 mg, 21%). MS ISP (m/e): 455.2 [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=8.20, 7.78, 7.75 and 7.63 (4 d, 4×2H), 7.31 (s, 2H), 7.16 (s, 1H), 3.93 (s, 1H), 2.53 (s, 3H), 1.61 (s, 6H).
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[S:4][CH:3]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O=[C:29]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:30]([O:32][CH2:33][CH3:34])=[O:31]>>[C:14]([O:13][C:11]([CH2:10][N:7]1[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[S:4][CH:3]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:2]([NH:1][CH:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:8]1=[O:9])=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CCCCCCCCC(=O)C(=O)OCC
Reactant: CC(C)(C)OC(=O)CN1C(=O)C(N)C(c2ccccc2)Sc2ccccc21
Product: CCCCCCCCC(NC1C(=O)N(CC(=O)OC(C)(C)C)c2ccccc2SC1c1ccccc1)C(=O)OCC
Yield: 78 %

Procedure:
1.1 g of the compound obtained in Example 20 was reacted with 3.0 g of ethyl 2-ketodecanoate in the same manner as described in Example 21. The reaction product was fractionated and purified by silica gel column chromatography using a 9:1 mixture of benzene and ethyl acetate as the eluent. Thus, there was obtained 1.3 g of the desired compound in the form of an oily material.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20][C:21]1[CH:22]=[C:23]([C@:27]2([NH:34][C:35]([NH2:37])=[S:36])[CH2:32][CH2:31][O:30][CH2:29][C@@H:28]2O)[CH:24]=[CH:25][CH:26]=1.O>O1CCCC1>[Br:20][C:21]1[CH:22]=[C:23]([C@:27]23[CH2:32][CH2:31][O:30][CH2:29][C@H:28]2[S:36][C:35]([NH2:37])=[N:34]3)[CH:24]=[CH:25][CH:26]=1
Reactant: NC(=S)N[C@@]1(c2cccc(Br)c2)CCOC[C@@H]1O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NC1=N[C@@]2(c3cccc(Br)c3)CCOC[C@H]2S1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.3 %

Procedure:
Diethyl azodicarbonate (13.0 mL) was added dropwise to a solution of triphenylphosphine (7.51 g) in tetrahydrofuran (200 mL) in an ice bath. The mixture was warmed to room temperature and stirred for 30 minutes. The reaction solution was cooled to 0° C., and a solution of (±)-[(3R*,4R*)-4-(3-bromophenyl)-3-hydroxytetrahydropyran-4-yl]thiourea (6.33 g) in tetrahydrofuran (44 mL) was added dropwise. The mixture was stirred overnight while gradually warming to room temperature. Water was added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to obtain a crude product. The resulting crude product was purified by silica gel column chromatography again to obtain the title compound (3.55 g).
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[NH:9][C:10](=O)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([I:19])[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].O=P(Cl)(Cl)[Cl:23]>>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([Cl:23])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([I:19])[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1[nH]c(=O)c2cc(I)ccc2c1O
Reactant: O=P(Cl)(Cl)Cl
Product: CCCCOC(=O)c1nc(Cl)c2cc(I)ccc2c1O

Procedure:
0.215 g of 4-hydroxy-7-iodo-1-oxo-1,2-dihydro-isoquinoline-3-carboxylic acid butyl ester were added to 5 ml of POCl3 at room temperature. The mixture was refluxed for 3 h and POCl3 was removed under vacuum. The residue was dissolved in ethyl acetate and the solution was washed with satd. aqueous sodium bicarbonate, dried (MgSO4), filtered, and concentrated to give 0.205 g of a while solid: Proton NMR (200 MHz, chloroform-d) δ 11.91 (s, 1H), 8.67 (m, 1H), 8.10 (m, 2H), 4.49 (t, J=7 Hz, 2H), 1.95-1.75 (m, 2H), 1.60-1.39 (m, 2H), 1.00 (t, J=7 Hz, 3H).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][C:15](=[O:28])[N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)[CH2:10][CH2:9]1)(C)(C)C.Cl.O1CCOCC1.[OH-].[Na+]>CO>[O:28]=[C:15]([N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:18][CH2:17]1)[CH2:14][C@H:11]1[CH2:10][CH2:9][C@H:8]([NH2:7])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CC(=O)N2CCN(c3ccccc3)CC2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: N[C@H]1CC[C@H](CC(=O)N2CCN(c3ccccc3)CC2)CC1
Reaction time: 22 h

Procedure:
Trans-{4-[2-oxo-2-(4-phenyl-piperazin-1-yl)-ethyl]-cylohexyl}-carbamic acid tert-butyl ester (18.1 g, 0.045 mol) was taken up in MeOH (275 mL) and treated with 4 M HCl in dioxane (56 mL, 0.224 mol) and allowed to stand 22 hours. Concentration to dryness yielded a solid which was treated with 2N NaOH (175 mL) and extracted with CH2Cl2. The extracts were washed with water, brine, and dried (Na2SO4). After evaporation of the solvent, the residue was crystallized in Et2O yielding trans-{4-[2-oxo-2-(4-phenyl-piperazin-1-yl)-ethyl]-cyclohexyl}-amine as a white solid, 11.2 g (83%); mp 90-93° C.
Reaction SMILES: OO.C(OC(C(F)(F)F)=O)(C(F)(F)F)=[O:4].[CH2:16]([NH:18][C:19]1[N:20]=[N+:21]([O-:34])[C:22]2[C:31]([N:32]=1)=[CH:30][C:29]1[CH2:28][N:27]([CH3:33])[CH2:26][CH2:25][C:24]=1[CH:23]=2)[CH3:17].C(O)(C(F)(F)F)=O>C(Cl)Cl.N>[CH2:16]([NH:18][C:19]1[N:20]=[N+:21]([O-:34])[C:22]2[C:31]([N+:32]=1[O-:4])=[CH:30][C:29]1[CH2:28][N:27]([CH3:33])[CH2:26][CH2:25][C:24]=1[CH:23]=2)[CH3:17]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CCNc1nc2cc3c(cc2[n+]([O-])n1)CCN(C)C3
Agent: N
Agent: OO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCNc1n[n+]([O-])c2cc3c(cc2[n+]1[O-])CN(C)CC3
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 7.5 %

Procedure:
H2O2 (70%, 1.7 mL, ca. 17 mmol) was added dropwise to a stirred solution of TFAA (2.4 mL, 17 mmol) in DCM (15 mL) at 0° C. The solution was stirred at 20° C. for 10 min, then cooled to 0° C., added to a solution of 1-oxide 258 (440 mg, 1.7 mmol) and TFA (0.66 mL, 8.5 mmol) in DCM (15 mL) at 0° C. The solution was stirred at 20° C. for 4 h, diluted with dilute aqueous NH3 solution (80 mL) and extracted with DCM (4×125 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (1-10%) of MeOH/DCM, to give 1,4-dioxide 259 (35 mg, 8%) as a red solid: mp 120-124° C.; 1H NMR δ 8.10 (s, 1H, H-10), 7.96 (s, 1H, H-5), 6.95 (br s, 1H, NH), 3.78 (s, 2H, H-6), 3.63 (dq, J=7.2, 6.0 Hz, 2H, CH2N), 3.10 (t, J=6.0 Hz, 2H, H-8), 2.75 (t, J=6.0 Hz, 2H, H-9), 2.50 (s, 3H, NCH3), 1.36 (t, J=7.2 Hz, 3H, CH3); 13C NMR δ 149.3, 145.5, 136.5, 135.3, 129.3, 120.5, 113.9, 58.1, 52.1, 45.8, 36.5, 29.1, 14.8; MS (APCI) m/z 276. (MH+, 100%); HRMS (FAB+) calcd for C13H18N5O2 (MH+) m/z 276.1461, found 276.1456.
Reaction SMILES: S1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]3[C:14]([C:15]4[CH:16]=[C:17]([CH:38]=[CH:39][CH:40]=4)[CH2:18][NH:19][C:20]([C:22]4[C:23](=[O:37])[N:24]([CH2:28][C:29]5[CH:34]=[CH:33][C:32]([F:35])=[C:31]([F:36])[CH:30]=5)[CH:25]=[CH:26][CH:27]=4)=[O:21])=[CH:13][NH:12][C:9]3=[N:10][CH:11]=2)=[CH:2]1.[N:41]1C=CC(B(O)O)=C[CH:42]=1.B(O)O>>[N:41]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]3[C:14]([C:15]4[CH:16]=[C:17]([CH:38]=[CH:39][CH:40]=4)[CH2:18][NH:19][C:20]([C:22]4[C:23](=[O:37])[N:24]([CH2:28][C:29]5[CH:34]=[CH:33][C:32]([F:35])=[C:31]([F:36])[CH:30]=5)[CH:25]=[CH:26][CH:27]=4)=[O:21])=[CH:13][NH:12][C:9]3=[N:10][CH:11]=2)=[CH:2][CH:42]=1
Reactant: OB(O)c1ccncc1
Reactant: O=C(NCc1cccc(-c2c[nH]c3ncc(-c4ccsc4)cc23)c1)c1cccn(Cc2ccc(F)c(F)c2)c1=O
Agent: OBO
Product: O=C(NCc1cccc(-c2c[nH]c3ncc(-c4ccncc4)cc23)c1)c1cccn(Cc2ccc(F)c(F)c2)c1=O

Procedure:
Except where indicated, 1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid 3-(5-pyridin-4-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-benzylamide was synthesized as per Example 91, 1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid 3-(5-thiophen-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-benzylamide using 4-Pyridylboronic acid as boronic acid to yield the product. 1H NMR (400 MHz, DMSO-d6) d ppm 12.280 (s, 1H) 10.090 (t, J=6.0 Hz, 1H) 8.864-8.712 (m, 4H) 8.384 (d, J=7.4 Hz, 1H) 8.302-8.233 (m, 2H) 8.201 (d, J=6.5 Hz, 1H) 7.983 (s, 1H) 7.797 (s, 1H) 7.694 (d, J=7.4 Hz, 1H) 7.458-7.302 (m, 3H) 7.239 (d, J=7.0 Hz, 1H) 7.134-7.079 (m, 1H) 6.567 (t, J=7.0 Hz, 1H) 5.146 (s, 2H) 4.605 (d, J=5.6 Hz, 2H); MS m/z/z=548.29 M+H.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[N:24]=3)[N:19]=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[CH3:27][O:26][C:23]1[CH:22]=[CH:21][C:20]2[C:25](=[C:16]([O:15][CH2:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[CH:17]=[CH:18][N:19]=2)[N:24]=1
Reactant: COc1ccc2nccc(OCC3CCN(C(=O)OC(C)(C)C)CC3)c2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2nccc(OCC3CCNCC3)c2n1
Yield: 100.7 %

Procedure:
A solution of carbamate (a) (0.95 g) in dichloromethane/trifluoroacetic acid (20 ml/20 ml) was stirred for 1 hour then evaporated to dryness, azeotroping with toluene and chloroform. The residue was dissolved in water and extracted with ethyl acetate. The aqueous extract was basified with solid potassium carbonate and evaporated. The residue stirred with 10% methanol in chloroform. Filtration and evaporation afforded an oil (0.7 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[C:10]([CH:13]([OH:15])[CH3:14])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.CN(C=O)C.[H-].[Na+].[CH3:23][N:24]1[C:28](S(C)(=O)=O)=[N:27][N:26]=[C:25]1[C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1>CC(=O)OCC>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[C:10]([CH:13]([O:15][C:28]3[N:24]([CH3:23])[C:25]([C:33]4[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=4)=[N:26][N:27]=3)[CH3:14])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cn1c(-c2ccncc2)nnc1S(C)(=O)=O
Reactant: CC(O)c1cc(-c2cccc(Cl)c2)on1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(Oc1nnc(-c2ccncc2)n1C)c1cc(-c2cccc(Cl)c2)on1
Temperature: 25 °C
Reaction time: 1 h
Yield: 16.1 %

Procedure:
1-[5-(3-chloro-phenyl)-isoxazol-3-yl]-ethanol (63.4 mg, 0.28 mmol), DMF and sodium hydride (60% dispersion in oil, 15.1 mg, 0.38 mmol) were mixed under inert atm. and stirred at r.t for 1 h, followed by addition of 4-[4-methyl-5-(methylsulfonyl)-4H-1,2,4-triazol-3-yl]pyridine (45 mg, 0.19 mmol). After stirring at 80° C. for 24 h, the mixture was cooled to r.t., diluted with EA, sequentially washed with water and brine. The organic phase was dried (Na2SO4), filtered and concentrated, in-vacuo. The crude residue was purified via column chromatagraphy using 5% MeOH in EA to isolate the title compound (11.7 mg). 1H-NMR: 8.81 (bs, 2H), 7.77 (s, 1H), 7.67 (m, 3H), 7.42 (m, 2H), 6.73 (s, 1H), 6.36 (q, 1H), 3.62 (s, 3H), 1.94 (d, 3H).
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:8](OC)=[CH:7][C:3]=1[C:4]([NH2:6])=[NH:5].[C:13](OC)(=[O:19])[CH2:14][C:15](OC)=[O:16]>CS(C)=O>[C:3]1([C:4]2[N:5]=[C:15]([OH:16])[CH:14]=[C:13]([OH:19])[N:6]=2)[CH:2]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)CC(=O)OC
Reactant: COc1ccc(F)c(C(=N)N)c1
Solvent: CS(C)=O
Product: Oc1cc(O)nc(-c2ccccc2)n1
Reaction time: 24 h

Procedure:
A mixture of 2-Fluoro-5-methoxybenzamidine (10.3 g) and dimethyl malonate (8.09 g) in dry dimethyl sulfoxide (7 mL) was allowed to stand at room temperature for 24 h.. The precipitated product was collected and washed with water and ether to afford 2-Phenyl-4,6-dihydroxy-pyrimidine as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[C:15]=2[CH2:29][NH2:30])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.Cl[C:39](Cl)([O:41]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:15]=2[CH2:29][NH:30][C:39](=[O:41])[N:20]3[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(NCc3ccc(F)cc3)c2CN)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3c2CNC(=O)N3Cc2ccc(F)cc2)CC1
Temperature: 0 °C

Procedure:
A solution of 4-[2-aminomethyl-3-(4-fluoro-benzylamino)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester (255 mg, 0.62 mmol) in CH2Cl2 (6 ml) was cooled to 0° C. and NEt3 (0.19) ml, 1.36 mmol) and triphosgen (64 mg, 0.22 mmol) were added. After stirring at 0° C. for half an hour, the reaction mixture was allowed to warm up to room temperature and was partitioned between water and ethyl acetate. The organic layer was washed with water and brine. After drying over MgSO4, the organic fraction was concentrated in vacuo and resulting brown residue was purified by flash chromatography to give 4-[1-(4-fluoro-benzyl)-2-oxo-1,2,3,4-tetrahydro-quinazolin-5-yl]-piperazine-1-carboxylic acid tert-butyl ester as a yellow solid. (179 mg, 66%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](O)=[O:12])=[CH:7][C:6]=1[NH:14][C:15](=[O:33])[CH2:16][CH:17]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[O:31][CH3:32])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:4])([CH3:3])[CH3:2].[C:34]([NH2:42])(=[O:41])[C:35]1[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=1>C(OCC)(=O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([NH:42][C:34]([C:35]2[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=2)=[O:41])=[O:12])=[CH:7][C:6]=1[NH:14][C:15](=[O:33])[CH2:16][CH:17]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[O:31][CH3:32])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCCC(CC(=O)Nc1cc(C(=O)O)ccc1C(C)(C)C)c1ccc(OC)cc1OC
Reactant: NC(=O)c1ccncc1
Solvent: CCOC(C)=O
Product: CCCCCC(CC(=O)Nc1cc(C(=O)NC(=O)c2ccncc2)ccc1C(C)(C)C)c1ccc(OC)cc1OC

Procedure:
Following a similar procedure to that described in Example 139, but using N-(2-t-butyl-5-carboxyphenyl)-3-(2,4-dimethoxyphenyl)octanamide (prepared as described in Preparation 7) and isonicotinamide, the title compound was obtained as crystals, melting at 184-185° C. (from ethyl acetate).
Reaction SMILES: [OH:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]([NH2:36])=[O:35])=[CH:32][CH:31]=1>C(#N)C>[CH3:21][O:20][C:3]1[C:4]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)=[CH:5][CH:6]=[C:7]([O:8][CH3:9])[C:2]=1[O:1][CH2:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]([NH2:36])=[O:35])=[CH:32][CH:31]=1
Reactant: COc1ccc(-c2ccc3c(c2)COC3=O)c(OC)c1O
Reactant: NC(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(-c2ccc3c(c2)COC3=O)c(OC)c1OCc1ccc(C(N)=O)cc1
Temperature: 80 °C
Yield: 17.1 %

Procedure:
To a stirring solution of 5-(3-Hydroxy-2,4-dimethoxy-phenyl)-3H-isobenzofuran-1-one (80 mg, 0.279 mmol) in acetonitrile (10 mL) was added potassium carbonate (154 mg, 1.118 mmol) and 4-bromomethyl-benzamide (89 mg, 0.419 mmol) and the resultant reaction mixture was heated to 80° C. for 4 h. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, 0-25% ethyl acetate in pet ether) to afford the title compound as a solid (20 mg, 17%).
Reaction SMILES: [C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=3)[CH:10]([C:18]3[C:19]([OH:27])=[CH:20][C:21]4[O:25][CH2:24][CH2:23][C:22]=4[CH:26]=3)[C:9]2=[O:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:35]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[C:29]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=3)[C:10]3([CH2:35][O:27][C:19]4[CH:20]=[C:21]5[C:22](=[CH:26][C:18]3=4)[CH2:23][CH2:24][O:25]5)[C:9]2=[O:28])[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Reactant: O=C1C(c2cc3c(cc2O)OCC3)c2ccc(F)cc2N1C(c1ccccc1)c1ccccc1
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2cc(F)ccc2C12COc1cc3c(cc12)CCO3

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 1-(diphenylmethyl)-6-fluoro-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 1′-(diphenylmethyl)-6′-fluoro-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1H)-one was obtained (87%) as a colorless solid: mp 194-196° C. (methanol); 1H NMR (300 MHz, CDCl3) δ7.42-7.25 (m, 10H), 7.10-7.04 (m, 2H), 6.67-6.61 (m, 1H), 6.40-6.39 (m, 2H), 6.23-6.19 (m, 1H), 4.81 (ABq, 2H), 4.53 (t, J=9.0 Hz, 2H), 2.99 (t, J=9.0 Hz, 2H); MS (ES+) m/z 463.8 (M+1).
Reaction SMILES: CCCCCC.C([Li])CCC.[CH2:12]([C:14]1[CH:22]=[CH:21][C:17]2[S:18][CH:19]=[CH:20][C:16]=2[CH:15]=1)[CH3:13].[Br:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[C:26]([CH:34]=[O:35])[CH:25]=1.[Cl-].[NH4+]>C1COCC1>[Br:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[C:26]([CH:34]([C:19]2[S:18][C:17]3[CH:21]=[CH:22][C:14]([CH2:12][CH3:13])=[CH:15][C:16]=3[CH:20]=2)[OH:35])[CH:25]=1
Reactant: O=Cc1cc(Br)c2ccccc2c1
Reactant: CCc1ccc2sccc2c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCc1ccc2sc(C(O)c3cc(Br)c4ccccc4c3)cc2c1
Reaction time: 0.08 h
Yield: 89.6 %

Procedure:
In a nitrogen stream, an n-butyllithium hexane solution (1.6 M, 1.44 ml, 2.30 mmol) was added dropwise to a solution of 5-ethylbenzo[b]thiophene (373 mg, 2.30 mmol) in THF (15 ml) at −78° C., and the reaction solution was stirred at the same temperature for 5 minutes. To this mixture, a solution of 4-bromonaphthalene-2-carbaldehyde (515 mg, 2.19 mmol) in THF (5 ml) was added dropwise at −78° C., and the resulting mixture was stirred at the same temperature for two hours and at −20° C. for 30 minutes, and then a saturated ammonium chloride aqueous solution was added and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:9)] to obtain the title compound (780 mg, 90%).