Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[S:18][C:17]([C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>CO>[C:19]([C:17]1[S:18][C:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:15][N:16]=1)(=[O:26])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cnc(C(=O)c3ccccc3)s2)CC1
Agent: Cl
Solvent: CO
Product: O=C(c1ccccc1)c1ncc(C2CCNCC2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 111.9 %

Procedure:
To 11 mg of 1-t-butyloxycarbonyl-4-(2-benzoyl-thiazol-5-yl)piperidine (step A) was added 1.5 ml of saturated HCl in MeOH. The reaction was stirred at room temperature overnight. The solvent was evaporated under reduced pressure to give 9 mg of the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:2]=1.Br[CH2:14][CH2:15]Br>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:15][CH2:14]2)[CH:2]=1
Reactant: BrCCBr
Reactant: CCOC(=O)Cc1cccnc1
Product: CCOC(=O)C1(c2cccnc2)CC1

Procedure:
Prepared in a similar manner to that described above by reacting ethyl 2-pyridin-3-ylacetate with 1,2-dibromoethane to give ethyl 1-pyridin-3-ylcyclopropane-1-carboxylate which was then hydrogenated to give the desired compound as a brown oil (quantitative reaction).
Reaction SMILES: [CH3:1][C:2]1([CH3:46])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][C:29]4[CH:30]=[C:31]([NH:35][C:36]([NH:38][C:39]5[CH:44]=[CH:43][CH:42]=[C:41](I)[CH:40]=5)=[O:37])[CH:32]=[CH:33][CH:34]=4)[CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1.[C:47]1([C:53]#[CH:54])[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][C:2]1([CH3:46])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][C:29]4[CH:30]=[C:31]([NH:35][C:36]([NH:38][C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([C:54]#[C:53][C:47]6[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=6)[CH:40]=5)=[O:37])[CH:32]=[CH:33][CH:34]=4)[CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc(NC(=O)Nc5cccc(I)c5)c4)C(=O)O3)ccc2O1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc(NC(=O)Nc5cccc(C#Cc6ccccc6)c5)c4)C(=O)O3)ccc2O1
Reaction time: 0.08 h
Yield: 86.5 %

Procedure:
A solution of N-[3-({2-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)ethoxy}methyl)phenyl]-N′-(3-iodophenyl)urea (393 mg) and phenylacetylene (77 mg) in DMF (6 ml) was treated with diisopropylethylamine (5 ml) and nitrogen was passed through the solution for 5 min. Copper (I) iodide (10 mg) and dichlorobis(triphenylphosphine)palladium(II) (47 mg) were added and the mixture was stirred under nitrogen at 200 for 21.5 h. The solvent was evaporated in vacuo and EtOAc (15 ml) was added. The supernatent solution was collected and the solvent evaporated in vacuo to give a residue which was purified by Biotage. Elution with dichloromethane-ethanol-ammonia (325:8:1) gave the title compound (328 mg). LCMS RT=3.93 min, ES+ve 718 (MH)+.
Reaction SMILES: COC1C(OC)=NS(=O)(=O)N=1.C(N)C#C.CO[C:18]1[C:22]([NH:23][C:24]#[C:25][CH3:26])=[N:21][S:20](=[O:28])(=[O:27])[N:19]=1.[CH3:29][C:30]1[NH:34][CH:33]=[N:32][C:31]=1[CH2:35][S:36][CH2:37][CH2:38][NH2:39]>>[CH3:29][C:30]1[NH:34][CH:33]=[N:32][C:31]=1[CH2:35][S:36][CH2:37][CH2:38][NH:39][C:18]1[C:22]([NH:23][CH2:24][C:25]#[CH:26])=[N:21][S:20](=[O:28])(=[O:27])[N:19]=1
Reactant: CC#CNC1=NS(=O)(=O)N=C1OC
Reactant: Cc1[nH]cnc1CSCCN
Agent: C#CCN
Agent: COC1=NS(=O)(=O)N=C1OC
Product: C#CCNC1=NS(=O)(=O)N=C1NCCSCc1nc[nH]c1C

Procedure:
Reaction of a methanolic suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide wth one equivalent of 2-propynylamine and treating the resultant 3-methoxy-4-propynylamino-1,2,5-thiadiazole 1,1-dioxide with one equivalent of 2-[(5-methyl-1H-imidazol-4-yl)methylthio]ethylamine yields the title compound; identical to the product of Example 1.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[NH:27]1[CH2:32][CH2:31][CH:30]([NH2:33])[CH2:29][CH2:28]1>CCO>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[C:2]([NH:33][CH:30]2[CH2:31][CH2:32][NH:27][CH2:28][CH2:29]2)[CH:3]=1)=[O:15]
Reactant: NC1CCNCC1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2cnn3C(C)C)c(=O)[nH]1
Solvent: CCO
Product: Cc1cc(C)c(CNC(=O)c2cc(NC3CCNCC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Reaction time: 1.5 h
Yield: 35 %

Procedure:
In a 25 mL sealable tube under nitrogen were combined 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (60 mg, 0.16 mmol) and 4-piperidinamine (2 mL) in EtOH (3 mL). The vessel was sealed and the reaction mixture was irradiated (microwave) at 125° C. for 5 hr and then at 160° C. for 90 min. The mixture was evaporated under vacuum and the resulting residue was partitioned between EtOAc and water. Organics were washed with water (2×) and brine, dried over MgSO4, filtered and evaporated. The residue was purified by silica gel chromatography (eluent: gradient 0 to 90:10:1 DCM/MeOH/NH4OH). The isolated product was treated with EtOAc/ether (1:1) and allowed to stand at room temperature overnight. The solids that had precipitated were triturated, filtered, and dried to afford the title compound as a pale yellow solid 25 mg (35%). LCMS E-S (M+H)=438.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.66 (t, J=4.67 Hz, 1 H) 7.98 (s, 1 H) 7.12 (s, 1 H) 5.89 (s, 1 H) 4.98 (dt, J=13.33, 6.60 Hz, 1 H) 4.30-4.41 (m, 4 H) 3.01 (t, J=11.62 Hz, 2 H) 2.85 (br. s., 1 H) 2.20 (s, 3 H) 2.12 (s, 3 H) 1.80 (d, J=10.36 Hz, 2 H) 1.44 (s, 3 H) 1.43 (s, 3 H) 1.18-1.30 (m, 3 H) 0.79-0.91 (m, 1 H)
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH2:11](O)[CH3:12].S(=O)(=O)(O)O>>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:11][CH3:12])=[O:7])=[CH:4][CH:3]=1
Reactant: CCO
Reactant: O=C(O)c1ccc(I)cc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(I)cc1
Temperature: 25 °C

Procedure:
To a suspension of 24.9 g (100.4 mmol) of 4-iodobenzoic acid in 46.25 g (58.9 mL, 1.0 mol) of ethanol was added 3 mL of c. sulfuric acid. The resulting mixture was refluxed for 60 minutes, distilled until a clear, homogeneous solution was obtained and then allowed to cool to room temperature. The reaction mixture was extracted and partitioned between pentane (250 mL) and water (250 mL) and the layers were separated. The aqueous phase was washed with 3×100 mL-portions of pentane. All organic phases were combined, washed with brine, dried over MgSO4, filtered and concentrated in vacuo to a dark yellow oil. Purification by flash chromatography (silica, 10% ethyl acetate in hexane) yielded the title compound as a clear, light yellow oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([CH2:10][OH:11])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1>ClCCl.[O-2].[Mn+4].[O-2]>[NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1
Reactant: OCc1cccc2[nH]ccc12
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1cccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.9 %

Procedure:
To a dissolved solution of (1H-Indol-4-yl)-methanol (100 mg, 0.69 mmole) in dichloromethane (0.500 ml), manganese (IV) oxide (597 mg, 6.9 mmol) is added. The reaction mixture stirred at room temperature for 8 hours and then passed through Celite. The reaction mixture is then concentrated to give a yellow oil (90 mg). MS (ESI) m/z 146.1 (M+1).
Reaction SMILES: [C:1]([NH:4][NH:5][C:6](=[O:8])[CH3:7])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:15][CH2:16][O:17][CH2:18][CH:19](Cl)Cl>CS(C)=O>[C:1]([N:4]1[N:5]([C:6](=[O:8])[CH3:7])[CH:19]=[CH:18][O:17][CH:16]=[CH:15]1)(=[O:3])[CH3:2]
Reactant: CCOCC(Cl)Cl
Reactant: CC(=O)NNC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(=O)n1ccoccn1C(C)=O
Temperature: 20 °C

Procedure:
A mixture of 35 g of diacetylhydrazine (0.3 mol), 124.4 g or 165.8 g of ground potassium carbonate (0.9 or 1.2 mol, respectively), 85.8 g of 2,2-dichlorodiethyl ether (0.6 mol) and 560 ml of solvent (see Table 2) is heated to 125° C. and maintained at 125-130° C. or 80-90° C. (in the case of DMSO) for 5 hours. The mixture is then cooled to 20° C. and filtered, and the filtration residue is washed with the solvent. The yield is given by the content of title compound in the combined filtrate.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][OH:8].O1COCO[CH2:10]1>[Cl-].[In+3].[Cl-].[Cl-].C(#N)CCC>[S:1]1[C:2]2[CH2:6][CH2:7][O:8][CH2:10][C:3]=2[CH:4]=[CH:5]1
Reactant: OCCc1cccs1
Reactant: C1OCOCO1
Agent: [Cl-]
Agent: [In+3]
Solvent: CCCC#N
Product: c1cc2c(s1)CCOC2
Temperature: 25 °C
Yield: 121.2 %

Procedure:
10.0 g of 2-thiopheneethanol, 3.5 g of 1,3,5-trioxane, and 862 mg of indium(III) chloride were added to 1,500 mL of butyronitrile, and the resulting mixture was refluxed for 6 hours. The reaction product solution was cooled to room temperature and concentrated by evaporation under reduced pressure. The residue was distilled under reduced pressure to obtain 6.6 g (yield of 60%) of the title compound, of which analysis data were the same as obtained in Example 14.
Reaction SMILES: Cl[CH:2]([C:4]1[C:5]([CH:20]2[CH2:22][CH2:21]2)=[N:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[N:8][CH:9]=1)[CH3:3].[CH2:23]([O:25][C:26](=[O:37])[CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][C:30]=1[CH3:36])[CH3:24].[H-].[Na+]>CN(C=O)C>[CH2:23]([O:25][C:26](=[O:37])[CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH:2]([C:4]2[C:5]([CH:20]3[CH2:22][CH2:21]3)=[N:6][C:7]([C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=3)=[N:8][CH:9]=2)[CH3:3])=[CH:31][C:30]=1[CH3:36])[CH3:24]
Reactant: CCOC(=O)COc1ccc(O)cc1C
Reactant: CC(Cl)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(OC(C)c2cnc(-c3ccc(C(F)(F)F)cc3)nc2C2CC2)cc1C
Yield: 56.9 %

Procedure:
180 mg (0.551 mmol) of [rac]-5-(1-chloro-ethyl)-4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine (example 28H), 116 mg (0.551 mmol) of (4-hydroxy-2-methyl-phenoxy)-acetic acid ethyl ester (WO02092590) and 31 mg (0.71 mmol) sodium hydride (55% in oil) were stirred in 3 ml DMF over night. The reaction mixture was partitioned between ether and water. The crude product was purified by chromatography over silica gel with AcOEt/heptane 1:4 to give 157 mg of pure [rac]-(4-{1-[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-ethoxy}-2-methyl-phenoxy)-acetic acid ethyl ester.
Reaction SMILES: [S@@:1]1(=[O:10])[N:5]2[CH2:6][CH2:7][CH2:8][CH2:9][CH:4]2[CH2:3][O:2]1.[O-:11]I(=O)(=O)=O.[Na+].O>C(#N)C.C([O-])(O)=O.[Na+].CCOC(C)=O.O.[Ru](Cl)(Cl)Cl>[S:1]1(=[O:11])(=[O:10])[N:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C@H:4]2[CH2:3][O:2]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: O=[S@@]1OCC2CCCCN21
Agent: Cl[Ru](Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: O=S1(=O)OC[C@@H]2CCCCN21
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of (S)-Hexahydro-[1,2,3]oxathiazolo[3,4-a]pyridine 1-oxide (1.31 g, 8.125 mmol) in anhydrous acetonitrile (10 mL) was added sodium (meta)periodate (1.91 g, 8.9375 mmol), followed by ruthenium(III) chloride hydrate (17 mg, 0.08125 mmol), and then H2O (10 mL). The mixture was stirred at 0° C. for 10 min and at rt for 20 min, then diluted with saturated NaHCO3 (30 mL) and EtOAc (100 mL). The aqueous layer was extracted with EtOAc (80 mL) and DCM (80 mL). The combined organic layer was dried over Na2SO4, concentrated in vacuo, and purified by flash column chromatography (silica gel, 2% EtOAc in DCM) to afforded the title product as a clear, colorless oil (1.1 g, 76%).
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[N:7]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:6](=[O:25])[N:5]([CH2:26][C:27]3[N:28]=[N:29][N:30]([CH2:32][CH3:33])[N:31]=3)[C:4]=2[CH:3]=1.[F:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.Cl[Pd]Cl>[CH2:32]([N:30]1[N:29]=[N:28][C:27]([CH2:26][N:5]2[C:4]3[CH:3]=[C:2]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=4[F:34])[S:10][C:9]=3[C:8](=[O:11])[N:7]([CH:12]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[CH2:16][CH2:17]3)[C:6]2=[O:25])=[N:31]1)[CH3:33]
Reactant: OB(O)c1ccccc1F
Reactant: CCn1nnc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(Br)cc32)n1
Agent: Cl[Pd]Cl
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: CCn1nnc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4F)cc32)n1

Procedure:
Tert-butyl 4-{6-bromo-1-[(2-ethyl-2H-tetrazol-5-yl)methyl]-2,4-dioxo-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl}piperidine-1-carboxylate (405 mg, compound B101), (2-fluorophenyl)boronic acid (116 mg), dichlorobis(tricyclohexylphosphine)palladium (55 mg) and aqueous cesium carbonate solution (0.563 ml, 2.0 M) in DME (10 ml) are reacted according to the procedure described in example B55 to afford the title compound after two times purification by flash column chromatography [silica gel, elution gradient: cyclohexane/EtOAc, 100/0 to 50/50 to 30/70 (v/v)] as a solid.
Reaction SMILES: [N+]([O-])([O-])=[O:2].[NH4+].[Ce].[F:7][C:8]1[C:21]2[C:20]([OH:22])=[C:19]3[C:14]([CH:15]=[CH:16][N:17]=[CH:18]3)=[CH:13][C:12]=2[C:11]([O:23][CH3:24])=[CH:10][CH:9]=1>O.C(#N)C>[F:7][C:8]1[C:21]2[C:20](=[O:22])[C:19]3[CH:18]=[N:17][CH:16]=[CH:15][C:14]=3[C:13](=[O:2])[C:12]=2[C:11]([O:23][CH3:24])=[CH:10][CH:9]=1
Reactant: O=[N+]([O-])[O-]
Reactant: COc1ccc(F)c2c(O)c3cnccc3cc12
Agent: [Ce]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: COc1ccc(F)c2c1C(=O)c1ccncc1C2=O
Temperature: 60 °C

Procedure:
A solution of cerium ammonium nitrate (CAN; 13.70 g) in water (50 mL) is added during twenty minutes to a stirred suspension of 9-fluoro-10-hydroxy-6-methoxybenzo[g]isoquinoline in acetonitrile (150 mL). At the end of the addition the obtained suspension is heated at 60° C. for two hours to give a clear, dark solution which is cooled to room temperature and diluted with water (100 mL). Following removal of acetonitrile by distillation at reduced pressure the aqueous phase is saturated with sodium chloride and extracted with methylene chloride (3×150 mL). The combined organic solutions are dried over anhydrous sodium sulphate and the solvent is removed at reduced pressure. The obtained residue is purified by silica-gel column chromatography (eluant: methylene chloride/ethyl acetate from 85/15 to 75/25 v/v) to give 9-fluoro-6-methoxybenzo[g]isoquinoline5,10-dione as a brown-yellow solid (0.48 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](Cl)=[N:6][CH:7]=1.[NH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:6][CH:7]=1
Reactant: C1CNCCN1
Reactant: Clc1ccc(Br)cn1
Product: Brc1ccc(N2CCNCC2)nc1
Temperature: 130 °C
Reaction time: 8 h
Yield: 75.7 %

Procedure:
A mixture of 5-bromo-2-chloropyridine (110 g, 573 mmol) and piperazine (99.1 g, 1.15 mol) was stirred overnight at 130° C. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water (200 mL) and then extracted with DCM (3×200 mL). The combined organic layers were concentrated under reduced pressure to obtain compound 90a as a white solid (105 g, 76% yield). Mass Spectrum (LCMS, ESI pos.): Calcd. for C9H12BrN3: 242.0 (M+H). found 242.0.
Reaction SMILES: CO[C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=3)=[N:14][O:15][CH:16]=2)[CH:9]=1)=[O:4].COC(C1NN=C(OCC2C(C3C=CC=CC=3)=NOC=2C)C=1)=O.[NH2:47][N:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1>>[N:48]1([NH:47][C:3]([C:5]2[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]3[C:13]([C:17]4[CH:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=4)=[N:14][O:15][CH:16]=3)[CH:9]=2)=[O:4])[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1
Reactant: NN1CCOCC1
Reactant: COC(=O)c1cc(OCc2conc2-c2ccc(F)cn2)n[nH]1
Agent: COC(=O)c1cc(OCc2c(-c3ccccc3)noc2C)n[nH]1
Product: O=C(NN1CCOCC1)c1cc(OCc2conc2-c2ccc(F)cn2)n[nH]1
Yield: 38 %

Procedure:
As described for example 1b, 5-[3-(5-fluoro-pyridin-2-yl)-isoxazol-4-ylmethoxy]-2H-pyrazole-3-carboxylic acid methyl ester (70 mg, 0.22 mmol), instead of 5-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-2H-pyrazole-3-carboxylic acid methyl ester, was converted, using 4-aminomorpholine instead of morpholine, to the title compound (32 mg, 38%) which was obtained as a white solid. MS: m/e=389.1 [M+H]+.
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][NH:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].C(OCC)(=O)C>CN(C=O)C>[CH2:29]([N:2]1[CH2:3][CH2:4][CH2:5][C:6]2[CH:11]=[C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)[CH:9]=[CH:8][C:7]=2[CH2:1]1)[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCCNC3)nc1
Reactant: CCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCN1CCCc2cc(Oc3ccc(C(N)=O)cn3)ccc2C1
Temperature: 70 °C

Procedure:
Mix 6-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide (Example 447, Part E, 0.300 g, 1.06 mmol), K2CO3 (0.366 g, 2.65 mmol), and 1-bromohexane (0.192 g, 1.16 mmol) in DMF (5.3 mL). Heat at 70° C. overnight, then increase the temperature to 100° C. for additional two hours. Cool the reaction mixture to room temperature and add ethyl acetate (150 mL). Wash with 1.0 N NaOH (1×50 mL), brine (1×50 mL), dry the organic layer over Na2SO4, filter and concentrate. Purify by flash chromatography eluting with 7% to 15% (2.0 M NH3 in methanol) in ethyl acetate to give the title compound: MS ES+368.2 (M+H)+, HRMS calcd for C22H30N3O2 368.2338 (M+H)+, found 368.2334, time 0.53 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18 min], tR=11.6 min, 97.8% purity.
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][NH:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)=[O:8])C.CO.O.O[Li].O>C1COCC1>[C:12]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:13]=[CH:14][C:9]([C:7]([NH:6][CH2:5][C:4]([OH:21])=[O:3])=[O:8])=[CH:10][CH:11]=1
Reactant: CCOC(=O)CNC(=O)c1ccc(-c2ccccc2)cc1
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CNC(=O)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.3 %

Procedure:
To a stirred solution of biphenyl-4-carboxylic acid (10 g, 0.05044 mole) in DMF (50 mL), was added DIPEA (22.82 g, 0.176 mol), HOBt (7.496 g, 0.0554 mol) and EDCI.HCl (17.4 g, 0.09 mol) at ambient temperature. After 2 minutes glycine ethyl ester hydrochloride (8.45 g, 0.06 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was diluted with cold water and the resulting precipitate was isolated by filtration and dried to afford 14.26 g (99.8%) of [(biphenyl-4-carbonyl)-amino]-acetic acid ethyl ester. 1H NMR (DMSO-d6): δ9.0 (t, 1H), 8.0-7.9 (d, 2H), 7.84-7.7 (dd, 4H), 7.5 (t, 2H), 7.46-7.36 (m, 1H), 4.2-4.1 (q, 2H), 4.0 (d, 2H), 1.25 (t, 3H). To a stirred solution of [(biphenyl-4-carbonyl)-amino]-acetic acid ethyl ester (14.26 g, 0.05 mol) in a mixture of THF (60 mL), methanol (60 mL) and H2O (30 mL) was added LiOH.H2O (12.68 g, 0.3023 mol) and the resulting mixture was stirred at ambient temperature for 1 hour. The volatiles were then evaporated and the residue was acidified with 10% aqueous HCl solution. The resulting precipitate was isolated by filtration washed with water followed by hexane and dried to afford 12.8 g (99%) of [(biphenyl-4-carbonyl)-amino]-acetic acid. 1H NMR (DMSO-d6): δ 8.0-7.85 (m, 3H), 7.8-7.7 (m, 4H), 7.55-7.45 (t, 2H), 7.45-7.35 (t, 1H), 3.5 (d, 2H).
Reaction SMILES: [SH:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]2[C:19](=[O:41])[NH:20][C:21](=[O:40])[C:22]=2[C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]([CH2:32][CH2:33][CH2:34]OS(C)(=O)=O)[CH:24]=2)=[CH:10]1>>[CH3:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]2[C:19](=[O:41])[NH:20][C:21](=[O:40])[C:22]=2[C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]([CH2:32][CH2:33][CH2:34][S:1][C:2]3[N:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[CH:24]=2)=[CH:10]1
Reactant: Cn1cc(C2=C(c3cn(CCCOS(C)(=O)=O)c4ccccc34)C(=O)NC2=O)c2ccccc21
Reactant: Sc1ncccn1
Product: Cn1cc(C2=C(c3cn(CCCSc4ncccn4)c4ccccc34)C(=O)NC2=O)c2ccccc21
Yield: 43.5 %

Procedure:
In an analogous manner to that described in Example 59, from 25 mg of 2-mercaptopyrimidine and 100 mg of the product of Example 58, there were obtained 45 mg of 3-(1-methyl-3-indolyl)-4-[1-[3-(2-pyrimidinylthio)propyl]-3-indolyl]-1H-pyrrole-2,5-dione, m.p. 125°-127° C.
Reaction SMILES: C([O:8][C:9]1[CH:38]=[CH:37][C:36]([C:39]2[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=2)=[CH:35][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH3:34])[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12])C1C=CC=CC=1.O1CCCC1>C(OCC)(=O)C.CO.[C].[Pd]>[OH:8][C:9]1[CH:38]=[CH:37][C:36]([C:39]2[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=2)=[CH:35][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH3:34])[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])=[O:12]
Reactant: COc1ccccc1-c1ccc(C(=O)OC(C)(C)C)c(NC(=O)c2cc(-c3cccnc3)ccc2OCc2ccccc2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccccc1-c1ccc(C(=O)OC(C)(C)C)c(NC(=O)c2cc(-c3cccnc3)ccc2O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution mixture of the obtained tert-butyl 2-(2-(benzyloxy)-5-(pyridin-3-yl)benzamido)-4-(2-methoxyphenyl)benzoate (0.19 g) in ethyl acetate (5.0 mL) and methanol (5.0 mL), 10% palladium-carbon (39 mg) was added, followed by stirring under a hydrogen atmosphere at room temperature for 2 hours. To the reaction mixture, 10% palladium-carbon (39 mg) was added, followed by stirring under a hydrogen atmosphere at room temperature for 2 hours and 30 minutes. Tetrahydrofuran was added to the reaction mixture, and the insoluble substance was removed by filtration. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), PSQ100B (spherical), eluent: 100-91% chloroform/methanol] to obtain tert-butyl 2-(2-hydroxy-5-(pyridin-3-yl)benzamido)-4-(2-methoxyphenyl)benzoate as a white solid.