Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]([N+:14]([O-:16])=[O:15])[C:4]=1[C:5]([OH:7])=[O:6].C(OCC)(OCC)O[CH2:19][CH3:20]>CN(C)C=O>[CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]([N+:14]([O-:16])=[O:15])[C:4]=1[C:5]([O:7][CH2:19][CH3:20])=[O:6]
Reactant: CCOC(OCC)OCC
Reactant: COc1ccc([N+](=O)[O-])c(C(=O)O)c1OC
Solvent: CN(C)C=O
Product: CCOC(=O)c1c([N+](=O)[O-])ccc(OC)c1OC

Procedure:
2,3-Dimethoxy-6-nitrobenzoic acid (l, 180.0 g, 0.792 mole) was dissolved in triethyl orthoformate (466.2 g, 3.14 mole) optionally containing dimethylformamide (4 mL) and the mixture was heated to reflux for one hour. The solvent was removed in vacuo, the residue was extracted with chloroform (2 L) and the organic layer was dried over magnesium sulfate. Removal of the solvent in vacuo gave the product as a pale brown oil which crystallized upon standing at room temperature, 202 g (100%, m.p. 70°-72° C.). This material could be recrystallized from isopropanol but was generally reacted in the next step without additional purification.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:30].C1COCC1.[NH2:36][C:37]1[CH:42]=[CH:41][C:40]([CH2:43][C:44]([OH:46])=[O:45])=[CH:39][CH:38]=1>CCOC(C)=O>[CH3:29][N:24]1[C:23]([C:21]([NH:20][C:16]2[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=2)[C:12]([C:8]2[CH:7]=[C:6]3[C:11]([C:3](=[CH:2][NH:36][C:37]4[CH:38]=[CH:39][C:40]([CH2:43][C:44]([OH:46])=[O:45])=[CH:41][CH:42]=4)[C:4](=[O:30])[NH:5]3)=[CH:10][CH:9]=2)=[O:13])=[O:22])=[CH:27][C:26]([CH3:28])=[N:25]1
Reactant: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)n(C)n1
Reactant: Nc1ccc(CC(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(CC(=O)O)cc3)c2)n(C)n1
Temperature: 65 °C
Reaction time: 24 h

Procedure:
A small screw cap test tube was charged with 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 60, 100 mg, 0.249 mmol) and THF (2 mL). To the resulting solution was added (4-Amino-phenyl)-acetic acid (41.4 mg, 0.274 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature. EtOAc (3 mL) was added to the mixture and was washed with 5% HCl(aq) (2 mL) and H2O (2×2 mL). The organic layers were combined dried over anhydrous Na2SO4, filtered and concentrated in vacuo The solid was then recrystallized from EtOAc/Hexanes affording 51% (0.068 g, 0.127 mmol) of the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([NH2:10])=[N:5][C:6]([CH3:9])=[N:7][CH:8]=1.C(N(CC)CC)C.[C:18]1([C:24]2[CH:33]=[C:32]3[C:27]([CH2:28][CH2:29][NH:30][CH2:31]3)=[CH:26][CH:25]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C=O>[CH3:9][C:6]1[N:5]=[C:4]([NH2:10])[C:3]([CH2:2][N:30]2[CH2:29][CH2:28][C:27]3[C:32](=[CH:33][C:24]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:25][CH:26]=3)[CH2:31]2)=[CH:8][N:7]=1
Reactant: Cc1ncc(CCl)c(N)n1
Reactant: c1ccc(-c2ccc3c(c2)CNCC3)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ncc(CN2CCc3ccc(-c4ccccc4)cc3C2)c(N)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.7 %

Procedure:
A suspension of 0.17 g (0.00088 mol) of 5-chloromethyl-2-methyl-pyrimidin-4-ylamine in 10 ml of dimethylformamide was treated with 0.30 ml (0.0021 mol) of triethylamine and 0.184 g (0.00088 mol) of 7-phenyl-1,2,3,4-tetrahydro-isoquinoline and the mixture was stirred at room temperature under argon for 18 hours. The solvent was distilled off in a high vacuum. The residue was partitioned between dichloromethane/water, extracted and dried over MgSO4. After removing the solvent the residue was chromatographed over silica gel with ethyl acetate as the eluent. 0.22 g (76%) of 2-methyl-5-(7-phenyl-3,4-dihydro-1H-isoquinolin-2-ylmethyl)-pyrimidin-4-ylamine was obtained as a light yellowish solid; m.p. 147°-149°.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([CH:19]([OH:22])[CH2:20][OH:21])[CH:18]=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23]1(C)[CH:28]=CC(S(O)(=O)=O)=C[CH:24]=1.COC(OC)(C)C>ClCCl>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([CH:19]4[CH2:20][O:21][C:23]([CH3:28])([CH3:24])[O:22]4)[CH:18]=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(C(O)CO)cnc21
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)OC
Solvent: ClCCl
Product: CC1(C)OCC(c2cnc3c(ccn3S(=O)(=O)c3ccccc3)c2)O1
Yield: 930 %

Procedure:
A solution of 1-(1-benzenesulfonyl-pyrrolo[2,3-b]pyridine-5-yl)-ethane-1,2-diol (3 g, 9.43 mmol), p-toluene sulfonic acid (160 mg, 0.84 mmol) and 2,2-dimethoxy-propane (10 mL) in dichloromethane (20 mL) was stirred at 25° C. for 12 h. The solution was concentrated in vacuo. The residue was diluted with ethyl acetate, washed with a saturated aqueous sodium bicarbonate solution, brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 25% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-5-(2,2-dimethyl-[1,3]dioxolan-4-yl)-1H-pyrrolo[2,3-b]pyridine (2.8 g, 83%) as a white solid: LC/MS m/e calcd for C18H19N2SO4 [M+H]+ 359.42, observed 359.3; 1H NMR (400 MHz, CDCl3) δ ppm 1.49 (s, 3H), 1.56 (s, 3H), 3.73 (dd, J=7.5 Hz, 8.3 Hz, 1H), 4.35 (dd, J=6.4 Hz, 8.3 Hz, 1H), 5.16 (dd, J=6.4 Hz, 7.5 Hz, 1H), 6.60 (d, J=4.0 Hz, 1H), 7.49 (m, 2H), 7.58 (m, 1H), 7.75 (d, J=4.0 Hz, 1H), 7.89 (d, J=2.0 Hz, 1H), 8.19 (d, J=7.6 Hz, 2H), 8.42 (d, J=2.0 Hz, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C@H:6]1[CH2:10][CH2:9][N:8]([S:11]([C:14]2[C:15]3[C:16]([CH3:24])=[CH:17][N:18]=[CH:19][C:20]=3[CH:21]=[CH:22][CH:23]=2)(=[O:13])=[O:12])[CH2:7]1.C(N(CC)CC)C.[C:32]1([N:38]=[C:39]=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(=O)([O-])O.[Na+]>ClCCCl>[CH3:24][C:16]1[C:15]2[C:14]([S:11]([N:8]3[CH2:9][CH2:10][C@H:6]([NH:5][CH2:4][CH2:3][CH2:2][NH:1][C:39]([NH:38][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[O:40])[CH2:7]3)(=[O:13])=[O:12])=[CH:23][CH:22]=[CH:21][C:20]=2[CH:19]=[N:18][CH:17]=1
Reactant: O=C=Nc1ccccc1
Reactant: Cc1cncc2cccc(S(=O)(=O)N3CC[C@H](NCCCN)C3)c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: Cc1cncc2cccc(S(=O)(=O)N3CC[C@H](NCCCNC(=O)Nc4ccccc4)C3)c12
Reaction time: 1 h

Procedure:
A suspension of Intermediate 40a (75 mg) obtained in Step A in 1,2-dichloroethane (3 ml) was cooled on ice, and added with triethylamine (114 μl) and phenyl isocyanate (21 μl, Tokyo Kasei Kogyo), and the mixture was stirred for 1 hour, and then further stirred at room temperature for 10 hours. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate (5 ml), and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (chloroform:methanol=15:1) to obtain the title compound (33 mg).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:5][CH:4]=1)#[N:2].[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1>>[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][N:9]([N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)[C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)=[CH:18][CH:17]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: N#Cc1ccc(Nn2cncn2)cc1
Product: N#Cc1ccc(N(Cc2ccc(F)cc2)n2cncn2)cc1

Procedure:
Starting Compounds: 1-[N-(4-cyanophenyl)amino]-1H-1,2,4-triazole and 4-fluorobenzyl bromide
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][CH:12]=[C:13]2[C:17]([N+:18]([O-])=O)=[C:16]([CH3:21])[N:15]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:14]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].[C:34]([OH:41])(=[O:40])/[CH:35]=[CH:36]/[C:37]([OH:39])=[O:38]>CO.O>[C:34]([OH:41])(=[O:40])/[CH:35]=[CH:36]/[C:37]([OH:39])=[O:38].[NH2:18][C:17]1[C:13]2[C:14](=[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[N:10]=[N:11][CH:12]=2)[N:15]([CH2:22][CH:23]([CH3:24])[CH3:25])[C:16]=1[CH3:21]
Reactant: Cc1c([N+](=O)[O-])c2cnnc(OCc3ccccc3)c2n1CC(C)C
Agent: O=C(O)/C=C/C(=O)O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1c(N)c2cnnc(OCc3ccccc3)c2n1CC(C)C
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
A suspension of 1.0 g (2.94 mmol) of 7-benzyloxy-1-isobutyl-2-methyl-3-nitropyrrolo [2,3-d]pyridazine in 30 ml of methanol is treated with a solution of 2.6 g (14.6 mmol) of sodium dithionite in 30 ml of water and stirred at 70° C. for 30 min. After addition of 100 ml of water, the mixture is extracted with 3×100 ml of ethyl acetate. The organic extracts are washed with 200 ml of water, dried over magnesium sulfate and subsequently treated with a solution of 341 mg (2.94 mmol) of fumaric acid in 10 ml of methanol. The solution is subsequently concentrated to a volume of 30 ml. After filtration, 800 mg (64%) of the title compound are isolated. M.p.: 143° C. (dec.).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[CH:15]=[C:14]([N+:16]([O-])=O)[CH:13]=[CH:12][C:9]=1[C:10]#[N:11]>CCO.C1COCC1.[Pd]>[NH2:16][C:14]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[C:8]([O:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[CH:15]=1
Reactant: COCCOCOc1cc([N+](=O)[O-])ccc1C#N
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: COCCOCOc1cc(N)ccc1C#N
Reaction time: 18 h

Procedure:
To a solution of 2-(2-Methoxy-ethoxymethoxy)-4-nitro-benzonitrile (2.35 g; 9 mmol) in EtOH/THF (25 mL/1 mL) was added a catalytic amount of 5% Pd/C. The reaction mixture was stirred under H2 atmosphere for 18 hours, filtered through kiselguhr evaporated to dryness and purified by column chromatography (SiO2—MeOH/CH2Cl2=0:1 to 5:95) to yield after evaporation 1.8 g (88%).
Reaction SMILES: CN(C)[C:3](=O)[S:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[CH:13]=O.[OH-].[Na+].ClC[C:21]#[N:22]>O.CO>[CH3:12][O:11][C:9]1[CH:8]=[CH:7][C:6]2[CH:13]=[C:3]([C:21]#[N:22])[S:4][C:5]=2[CH:10]=1
Reactant: N#CCCl
Reactant: COc1ccc(C=O)c(SC(=O)N(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc2cc(C#N)sc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.8 %

Procedure:
(Ref: Gallagher, T; Pardoe, D. A.; Porter, R.; Tetrahedron Lett.; 2000, 41(28), 5415–5418.) To a solution of S-(2-formyl-5-methoxyphenyl) dimethylthiocarbamate (1.08 g, 4.5 mmol) in water (4 mL) and methanol (8 mL) was added sodium hydroxide (199 mg, 4.9 mmol), this was heated to reflux for 16 hours. The reaction was cooled to room temperature and chloroacetonitrile (0.28 mL, 4.5 mmol) was added in one portion and the mixture the stirred at room temperature for 1 hour. The methanol was removed in vacuo, and water (10 mL) added. The aqueous layer was extracted with diethyl ether (3×20 mL), dried (MgSO4) and the solvent removed in vacuo. The residue was purified by flash chromatography with a gradient of 0–30% ethyl acetate in iso-hexane to give the title compound as a colourless solid (390 mg, 46%); δH (300 MHz, CDCl3) 7.80–7.70 (1H, m, ArH), 7.29 (2H, m, ArH), 7.11–7.01 (1H, m, ArH) and 3.85 (3H, s, OCH3). M+23=212.0. νmax/cm−1 [film] 2213.50 (m).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:16]=[C:17]([CH:19]=[CH:20][C:21]=3[CH3:22])[NH2:18])[N:9]=2)[CH:5]=[N:6][CH:7]=1.Cl.Cl.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=1[CH2:36][N:37]1[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]1)[C:30](Cl)=[O:31]>>[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=1[CH2:36][N:37]1[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]1)[C:30]([NH:18][C:17]1[CH:19]=[CH:20][C:21]([CH3:22])=[C:15]([NH:14][C:10]2[N:9]=[C:8]([C:4]3[CH:5]=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=3)[CH:13]=[CH:12][N:11]=2)[CH:16]=1)=[O:31]
Reactant: Cc1ccc(N)cc1Nc1nccc(-c2cncc(Br)c2)n1
Reactant: COc1cc(C(=O)Cl)ccc1CN1CCN(C)CC1
Agent: Cl
Product: COc1cc(C(=O)Nc2ccc(C)c(Nc3nccc(-c4cncc(Br)c4)n3)c2)ccc1CN1CCN(C)CC1
Reaction time: 17 h

Procedure:
This compound was prepared in the same manner as in Example 1, except that 3-[4-(5-bromopyridin-3-yl)pyrimidin-2-ylamino]-4-methylaniline (Reference Example 19) and 3-methoxy-4-(4-methylpiperazin-1-ylmethyl)benzoyl chloride dihydrochloride (Reference Example 3) were used, and that the reaction was conducted at room temperature for 17 hours and the crude product was purified by silica gel column chromatography.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]1([OH:19])[CH2:18][CH2:17][CH2:16][CH2:15]1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C(N(CC)CC)C.[CH2:27]([O:29][CH2:30][C:31](Cl)=O)[CH3:28]>ClCCl>[CH2:27]([O:29][CH2:30][C:31]1[N:12]([CH2:13][C:14]2([OH:19])[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH3:28]
Reactant: Nc1cnc2ccccc2c1NCC1(O)CCCC1
Reactant: CCOCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOCc1nc2cnc3ccccc3c2n1CC1(O)CCCC1
Reaction time: 3 h
Yield: 48.6 %

Procedure:
To a solution of 1-{[(3-aminoquinolin-4-yl)amino]methyl}cyclopentanol (approximately 28.8 mmol, prepared as described above) in dichloromethane (200 mL) at 0° C. was added triethylamine (4.41 mL, 31.6 mmol) and ethoxyacetyl chloride (88%, 3.96 g, 30.2 mmol). After 3 h at rt, the solution was concentrated and ethanol (260 mL) and triethylamine (14 mL) were added. The resulting solution was heated at reflux for 18 h and then concentrated in vacuo. The residue was partitioned between dichloromethane and water. The organic layer was washed with brine twice and dried over MgSO4, filtered, and concentrated to an oil that formed a white solid when acetonitrile was added. The mixture was sonicated briefly and filtered. The white powder was dried under vacuum to provide pure 1-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclopentanol (4.55 g, 49% for three steps).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]([O:15][CH3:16])=[O:14])=[CH:9][C:8]=1[NH:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])(=O)=O.[C:30]([Sn](CCCC)(CCCC)CCCC)#[C:31][CH2:32][CH3:33]>>[CH2:21]([O:20][C:18]([NH:17][C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][C:7]=1[C:30]#[C:31][CH2:32][CH3:33])[C:13]([O:15][CH3:16])=[O:14])=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCC#C[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(NC(=O)OCc2ccccc2)c1
Product: CCC#Cc1ccc(C(=O)OC)cc1NC(=O)OCc1ccccc1
Yield: 45.6 %

Procedure:
Methyl 3-benzyloxycarbonylamino-4-(1-butynyl)benzoate (646 mg) was prepared from 2-benzyloxycarbonylamino-4-methoxycarbonylphenyl trifluoromethanesulfonate (1.82 g) and 1-butynyl(tributyl)stannane (1.51 g) in a similar manner to that of Preparation 1 (2).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][C@@H:14]3[CH2:18][CH2:17][N:16]([C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[CH2:15]3)=[N:11][NH:10][C:9]2=[O:24])=[CH:4][CH:3]=1.[NH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31](B(O)O)[CH:32]=2)[CH:27]=[CH:26]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:21]1([C:19]([N:16]2[CH2:17][CH2:18][C@@H:14]([CH2:13][C:12]3[N:8]([C:5]4[CH:6]=[CH:7][C:2]([C:31]5[CH:32]=[C:33]6[C:28]([CH:27]=[CH:26][NH:25]6)=[CH:29][CH:30]=5)=[CH:3][CH:4]=4)[C:9](=[O:24])[NH:10][N:11]=3)[CH2:15]2)=[O:20])[CH2:23][CH2:22]1
Reactant: OB(O)c1ccc2cc[nH]c2c1
Reactant: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(Br)cc2)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(-c3ccc4cc[nH]c4c3)cc2)C1
Yield: 105.1 %

Procedure:
4-(4-Bromophenyl)-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (0.100 g, 0.256 mmol), 1H-indol-6-ylboronic acid (0.082 g, 0.511 mmol), tetrakis(triphenylphosphine)palladium(0) (0.030 g, 0.026 mmol), and K3PO4 (0.217 g, 1.022 mmol) were combined in ethanol (4 mL) and water (4 mL), purged with N2, and irradiated in a microwave reactor for 1 h at 110° C. after which time LCMS indicated complete conversion. The reaction mixture was filtered through Celite, diluted with 100 mL EtOH and concentrated to dryness. The residue was partitioned between dichloromethane and water (a minimal amount of CH3OH was added to achieve complete solubility), and the organic phase was isolated, dried over MgSO4, filtered and concentrated to dryness. The residue was purified on 40 g silica gel eluted with 100% EtOAc to 10% CH3OH/CH2Cl2 to give 5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-4-[4-(1H-indol-6-yl)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (0.115 g, 0.269 mmol, quantitative yield) as a white foam. LC-MS (ES−) m/z 426.51 [M−1]. LC-MS (ES+) m/z 428.30 [M+H]. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.72 (d, J=4.08 Hz, 1H), 11.23 (s, 1H), 7.82 (dd, J=8.49, 2.79 Hz, 2H), 7.69 (s, 1H), 7.64 (d, J=8.27 Hz, 1H), 7.48 (dd, J=8.43, 6.50 Hz, 2H), 7.41 (t, J=2.69 Hz, 1H), 7.36 (dd, J=8.27, 1.50 Hz, 1H), 6.47 (t, J=2.04 Hz, 1H), 3.61-3.86 (m, 1H), 3.47-3.60 (m, 1H), 2.87-3.43 (m, 2H), 2.34-2.66 (m, 3H), 1.91-2.13 (m, 1H), 1.44-1.74 (m, 2H), 0.61-0.73 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][C:12]3[CH:22]=[C:21]4[C:16]([CH:17]=[CH:18][CH:19]=[CH:20]4)=[CH:15][C:13]=3[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH:23]1[C:28]([C:29]([OH:31])=[O:30])=[CH:27][C:26]2[C:32]([O:34][C:35](=O)[C:25]=2[CH:24]=1)=[O:33]>>[CH3:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([C:10]2[O:11][C:12]3[CH:22]=[C:21]4[C:16]([CH:17]=[CH:18][CH:19]=[CH:20]4)=[CH:15][C:13]=3[N:14]=2)=[CH:3][C:2]=1[N:1]1[C:32](=[O:33])[C:26]2[C:25](=[CH:24][CH:23]=[C:28]([C:29]([OH:31])=[O:30])[CH:27]=2)[C:35]1=[O:34]
Reactant: COc1ccc(-c2nc3cc4ccccc4cc3o2)cc1N
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Product: COc1ccc(-c2nc3cc4ccccc4cc3o2)cc1N1C(=O)c2ccc(C(=O)O)cc2C1=O

Procedure:
Prepared by the method of Example 1b), from 2-(3-amino-4-methoxyphenyl)naphth[2,3-d]oxazole (67 mg, 0.23 mmol) and 1,2,4-benzenetricarboxylic anhydride (50 mg, 0.26 mmol) the title compound was obtained, 40 mg (37%). 1H NMR (DMSO) δ 8.34(m, 4H), 8.24(d, 1H), 8.15(s, 1H), 8.01(m, 3H), 8.43(m, 3H), 3.81(s, 3H). MS 463 m/z (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[C:13](=[O:26])[CH2:14][CH2:15][C@@H:16]1[CH2:21][CH2:20][NH:19][CH2:18][C@@H:17]1[C:22]([O:24][CH3:25])=[O:23].[CH:27]1[CH:32]=[C:31]([S:33][CH2:34][CH2:35]Cl)[CH:30]=[C:29]([F:37])[CH:28]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[F:37][C:29]1[CH:30]=[C:31]([S:33][CH2:34][CH2:35][N:19]2[CH2:20][CH2:21][C@@H:16]([CH2:15][CH2:14][C:13]([C:6]3[C:5]4[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[O:26])[C@@H:17]([C:22]([O:24][CH3:25])=[O:23])[CH2:18]2)[CH:32]=[CH:27][CH:28]=1
Reactant: Fc1cccc(SCCCl)c1
Reactant: COC(=O)[C@H]1CNCC[C@H]1CCC(=O)c1ccnc2ccc(OC)cc12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)[C@H]1CN(CCSc2cccc(F)c2)CC[C@H]1CCC(=O)c1ccnc2ccc(OC)cc12
Temperature: 65 °C
Yield: 22.9 %

Procedure:
A mixture of 6.44 g of methyl (3R,4R)-4-[3-(6-methoxyquinolin-4-yl)-3-oxopropyl]piperidine-3-carboxylate in 100 cm3 of acetonitrile, 3.43 g of 2-(3-fluorophenylthio)ethyl-1-chloride, 8.85 g of potassium carbonate, and 1.24 g of potassium iodide was heated at a temperature in the region of 65° C. for 48 hours. After cooling, the insoluble material was filtered off. The filtrate was concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The oily residue was purified by chromatography at atmospheric pressure on a column of silica gel (particle size 20-45 μm; diameter 6 cm; 250 g), elution was carried out with a dichloromethane/ethyl acetate/methanol (50/50/3 by volume) mixture, and 50-cm3 fractions were collected. The fractions from 19 to 25 were collected. These fractions were combined and then concentrated under reduced pressure (5 kPa) at approximately 40° C. 2.1 g of methyl (3R,4R)-1-[2-(3-fluorophenylthio)ethyl]-4-[3-(6-methoxyquinolin-4-yl)-3-oxopropyl]piperidine-3-carboxylate were obtained in the form of a mobile brown oil. Methyl (3R,4R)-4-[3-(6-methoxyquinolin-4-yl)-3-oxopropyl]-piperidine-3-carboxylate was prepared as described in Example 5.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=5)[N:30]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: Brc1cccc(-c2ccccc2)n1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(-c5ccccc5)n4)cc3)cc2)CC1

Procedure:
1-[4′-(4-Amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester (0.250 g, 0.689 mmol), 2-bromo-6-phenyl-pyridine (0.1457 g, 0.62 mmol), cesium carbonate (0.2694 g, 0.826 mmol) and (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.032 g, 0.052 mmol) were dissolved in toluene (3 mL) and the solution was degassed with bubbling N2 (g).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=2[CH2:18][N:19]2[C@@H:23]([CH3:24])[C@@H:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:21][C:20]2=[O:31])=[CH:6][C:5]([CH2:32][C:33]([OH:35])=[O:34])=[CH:4][CH:3]=1.[Cl:36][C:37]1[CH:44]=[CH:43][C:40]([CH2:41]Br)=[CH:39][CH:38]=1>>[Cl:36][C:37]1[CH:44]=[CH:43][C:40]([CH2:41][O:34][C:33](=[O:35])[CH2:32][C:5]2[CH:6]=[C:7]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:15])([F:16])[F:17])=[CH:10][C:9]=3[CH2:18][N:19]3[C@@H:23]([CH3:24])[C@@H:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[O:21][C:20]3=[O:31])[C:2]([O:1][CH2:41][C:40]3[CH:43]=[CH:44][C:37]([Cl:36])=[CH:38][CH:39]=3)=[CH:3][CH:4]=2)=[CH:39][CH:38]=1
Reactant: C[C@H]1[C@@H](c2ccccc2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)O)ccc1O
Reactant: Clc1ccc(CBr)cc1
Product: C[C@H]1[C@@H](c2ccccc2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OCc2ccc(Cl)cc2)ccc1OCc1ccc(Cl)cc1

Procedure:
Prepared according to the procedure described in Example 14, Step 3, using the following starting materials: [6-hydroxy-2′-((4S,5R)-4-methyl-2-oxo-5-phenyl-oxazolidin-3-ylmethyl)-4′-trifluoromethyl-biphenyl-3-yl]-acetic acid and 4-chlorobenzyl bromide.