Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][OH:3].O.O.O.C([O-])(=O)C.[Na+].[OH:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([OH:20])[C:14]=1[C:21](=O)[CH3:22]>CCO.O.O>[OH:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([OH:20])[C:14]=1[C:21](=[N:2][OH:3])[CH3:22]
Reactant: NO
Reactant: CC(=O)c1c(O)cc(C)cc1O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(=NO)c1c(O)cc(C)cc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.9 %

Procedure:
A solution of hydroxylamine hydrochloride (470 mg, 6.76 mmol) and sodium acetate trihydrate (590 mg, 4.34 mmol) dissolved in 20 ml of a mixture of EtOH/H2O (7/3) was added to a solution of 1-(2,6-dihydroxy-4-methylphenyl)ethanone (Intermediate 16, 940 mg) in 15 ml of a mixture of EtOH/H2O (7/3). After refluxing and stirring under N2 for 2 hours, additional hydroxylamine hydrochloride (159 mg, 2.29 mmol) and sodium acetate trihydrate (199 mg) dissolved in 5 ml of water were added. The reaction mixture was heated at reflux overnight. After cooling down to room temperature, the volatiles were removed. Water was added and the solid afforded was filtered, washed with water and dried giving 829 mg of the title compound.
Reaction SMILES: [Na].CO[C:4](=O)[CH2:5][CH2:6][S:7][C:8]1[C:17]([C:18](=[O:26])[NH:19][CH2:20][C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:27]([F:30])([F:29])[F:28])[CH:14]=2)[N:9]=1.I[CH2:33][CH2:34]CCC>CO>[CH2:6]([S:7][C:8]1[C:17]([C:18]([NH:19][CH2:20][C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)=[O:26])=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:27]([F:30])([F:29])[F:28])[CH:14]=2)[N:9]=1)[CH2:5][CH2:4][CH2:33][CH3:34]
Reactant: COC(=O)CCSc1nc2ccc(C(F)(F)F)cc2cc1C(=O)NCc1cccs1
Reactant: CCCCCI
Agent: [Na]
Solvent: CO
Product: CCCCCSc1nc2ccc(C(F)(F)F)cc2cc1C(=O)NCc1cccs1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 40 %

Procedure:
198 mg (8.6 mmol) sodium were added slowly to MeOH (86 ml) and the solution was stirred for 5 min at RT. Then a solution of 455 mg (1.0 mmol) 3-(3-(thiophen-2-ylmethylcarbamoyl)-6-(trifluoromethyl)quinolin-2-ylthio)propanoic acid methyl ester (Example 26) in MeOH (10 ml) was added at RT. The reaction solution was then heated for 30 min at 70° C. Then 396 μl (3.0 mmol) 1-iodopentane were added at RT and the mixture was stirred for 1 h at RT. Then the mixture was concentrated to small volume under vacuum and the residue was taken up with EE. It was washed with water and brine and the organic phase was dried over Na2SO4, filtered and concentrated to small volume under vacuum. 167 mg (0.4 mmol, 38%) 2-(pentylthio)-N-(2-thienylmethyl)-6-(trifluoromethyl)-3-quinoline carboxamide were obtained as residue. MS: m/z 439.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]#[C:14][Si](C)(C)C)[CH:10]=[N:9]2)[CH:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.C(OCC)(=O)C.O>[C:13]([C:11]1[CH:10]=[N:9][N:8]([CH2:7][C:4]2[CH:3]=[C:2]([CH3:1])[O:6][N:5]=2)[CH:12]=1)#[CH:14]
Reactant: Cc1cc(Cn2cc(C#C[Si](C)(C)C)cn2)no1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C#Cc1cnn(Cc2cc(C)on2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70 %

Procedure:
5-Methyl-3-((4-((trimethylsilyl)ethynyl)-1H-pyrazol-1-yl)methyl)isoxazole (31) (0.55 g, 2.12 mmol) was dissolved in 3 ml THF and stirred at RT. To the stirred solution was then added a 1M solution of TBAF in THF (3 ml, 3 mmol). After 10 minutes, the reaction was diluted with ethyl acetate (20 ml) and water (20 ml). The organic solution was collected, dried and concentrated. The crude product was purified on a short silica column eluting with 5% ethyl acetate in DCM. The pure fractions provided the title compound as a pale brown solid (278 mg, 70%). 1H-NMR (500 MHz, CDCl3) 2.38 (s, 3H), 3 (s, 1H), 5.29 (s, 2H), 5.9 (s, 1H), 7.61 (s, 1H), 7.63 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:10]=[C:9]([Br:11])[C:8]2[N:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:14][C:7]=2[C:6]=1[OH:21])=[O:4].[CH3:22][C:23]([CH3:28])([CH3:27])[C:24](Cl)=[O:25].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[N:10]=[C:9]([Br:11])[C:8]2[N:12]=[C:13]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[O:14][C:7]=2[C:6]=1[O:21][C:24](=[O:25])[C:23]([CH3:28])([CH3:27])[CH3:22])=[O:4]
Reactant: COC(=O)c1nc(Br)c2nc(-c3ccccc3)oc2c1O
Reactant: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1nc(Br)c2nc(-c3ccccc3)oc2c1OC(=O)C(C)(C)C
Yield: 41.2 %

Procedure:
A solution of 4-bromo-7-hydroxy-2-phenyl-oxazolo[4,5-c]pyridine-6-carboxylic acid methyl ester (0.1 g, 0.286 mmol; example 3a), trimethylacetyl chloride (42.3 μL, 0.344 mmol), triethylamine (79.7 μL, 0.572 mmol), and 4-(dimethylamino)pyridine (3.5 mg, 0.03 mmol) in methylene chloride (2.5 mL) was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate solution, brine, saturated ammonium chloride solution, and brine. The organic fraction was dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by flash chromatography eluting from silica gel with a gradient of 0-70% ethyl acetate in hexanes to give 51 mg of the title compound as a white solid. MS: (+) m/z 432.8, 434.8 (M+1, 79Br/81Br).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:10]([CH3:12])[N:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH2:18]([C:20]1[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([CH3:29])[C:21]=1[CH2:22]Br)[CH3:19].[C:30](=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(#N)C>[CH:16]([O:15][CH:27]([CH3:26])[CH3:20])([CH3:17])[CH3:30].[C:13]([C:9]1[N:4]2[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([NH:1][CH2:22][C:21]3[C:24]([CH3:29])=[CH:25][C:26]([F:28])=[CH:27][C:20]=3[CH2:18][CH3:19])[C:3]2=[N:11][C:10]=1[CH3:12])([O:15][CH2:16][CH3:17])=[O:14]
Reactant: O=C([O-])[O-]
Reactant: CCc1cc(F)cc(C)c1CBr
Reactant: CCOC(=O)c1c(C)nc2c(N)cc(C)cn12
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)OC(C)C
Product: CCOC(=O)c1c(C)nc2c(NCc3c(C)cc(F)cc3CC)cc(C)cn12
Yield: 35 %

Procedure:
A stirred mixture of (0.7 g, 3.0 mmol) 8-amino-3-carboethoxy-2,6-dimethylimidazo[1,2-a]pyridine, (0.8 g, 3.5 mmol) 2-ethyl-4-fluoro-6-methylbenzylbromide, (0.7 g, 4.8 mmol) potassium carbonate and (0.1 g) sodium iodide in 15 ml acetonitrile was refluxed over night. After evaporation of the solvent under reduced pressure the residue was dissolved in dichloromethane and washed with water, the organic layer was separated dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluent petroleum ether (40-60):isopropyl ether 7:3 to give 0.4 g, (35%) of the title compound.
Reaction SMILES: [N:1]([C:4]1[C:5](=[O:20])[CH2:6][CH2:7][C@@:8]2([CH3:19])[C:17]=1[CH2:16][CH2:15][C:14]1[C:9]2=[CH:10][CH:11]=[C:12]([Cl:18])[CH:13]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[NH2:1][C:4]1[C:5](=[O:20])[CH2:6][CH2:7][C@@:8]2([CH3:19])[C:17]=1[CH2:16][CH2:15][C:14]1[C:9]2=[CH:10][CH:11]=[C:12]([Cl:18])[CH:13]=1
Reactant: C[C@]12CCC(=O)C(N=[N+]=[N-])=C1CCc1cc(Cl)ccc12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: C[C@]12CCC(=O)C(N)=C1CCc1cc(Cl)ccc12
Yield: 22 %

Procedure:
To a solution of (R) -1-azido-7-chloro-4,4a, 9,10-tetrahydro-4a-methyl-2 (3H) -phenanthreneone (0.210 g, 0.730 mmol) in tetrahydrofuran (8 mL) and water (1 mL) was added triphenylphosphine (0.325 g, 1.24 mmol). After refluxing for 20 minutes the mixture was cooled and the tetrahydrofuran evaporated. The resulting system was diluted with toluene (8 mL) and refluxed for 16 hours. The mixture was evaporated and the residue was purified by chromatography (Chromatotron, Harrison Research, Palo Alto, Calif.) (15% ethyl acetate/hexane) twice to give 42 mg (22%) of the title amine as a white powder. IR (KBr) 1648 (CO)cm-1 ; 1H NMR (300 MHz, CDCl3) δ7.23 (s, 2H), 7.15 (s, 1H), 2.98-3.07 (m, 1H), 2.75-2.93 (m, 3H), 2.48-2.67 (m, 2H), 2.36-2.47 (m, 1H), 2.05-2.16 (m, 1H), 1.49 (s,3H); MS (FD)m/z 261 (M+); UV λmaxEtOH (nm) (ε) 203 (20595), 294 (6036).
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C@H:9]1[CH2:14][CH2:13][C@@H:12]([N:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH:22]3[CH2:24][CH2:23]3)[CH2:17][CH2:16]2)[CH2:11][CH2:10]1)C1C=CC=CC=1.C(O)(=O)C.[H][H].[O-2].[Al+3].[O-2].[O-2].[Al+3]>ClCCl.CO.[Pd]>[CH:22]1([CH2:21][N:18]2[CH2:19][CH2:20][N:15]([C@@H:12]3[CH2:13][CH2:14][C@H:9]([NH2:8])[CH2:10][CH2:11]3)[CH2:16][CH2:17]2)[CH2:23][CH2:24]1
Reactant: [H][H]
Reactant: c1ccc(CN(Cc2ccccc2)[C@H]2CC[C@@H](N3CCN(CC4CC4)CC3)CC2)cc1
Agent: [Pd]
Agent: [Al+3]
Agent: [O-2]
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: N[C@H]1CC[C@@H](N2CCN(CC3CC3)CC2)CC1
Yield: 172 %

Procedure:
(cis)-N,N-Dibenzyl-4-[4-(cyclopropylmethyl)piperazin-1-yl]cyclohexanamine 12d (2.44 g, 5.83 mmol) was dissolved in 30 mL mixture solvent of dichloromethane and methanol (V/V=1:2) followed by the addition of palladium/carbon (1.22 g, 10%) and 0.1 mL acetic acid, filled with hydrogen three times. The reaction mixture was reacted at 3 atmosphere for 12 hours. The resulting solution was added with 4 g alkaline aluminum oxide (200-300 mesh) and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (cis)-4-[4-(cyclopropylmethyl)piperazin-1-yl]cyclohexanamine 12e (2.38 g, yield: 98.0%) as a colorless solid.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([NH:12][C:13]([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[C:20]([NH:25][C:26]([C:28]1[C:29]([C:34]3[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][CH:35]=3)=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:27])[CH:19]=[CH:18]2)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1>[NH2:1][CH2:4][C@@H:5]([NH:12][C:13]([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[C:20]([NH:25][C:26]([C:28]1[C:29]([C:34]3[CH:35]=[CH:36][C:37]([C:40]([F:43])([F:41])[F:42])=[CH:38][CH:39]=3)=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:27])[CH:19]=[CH:18]2)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: [N-]=[N+]=NC[C@@H](NC(=O)c1ccc2nc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: NC[C@@H](NC(=O)c1ccc2nc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1)c1ccccc1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
(S)-2-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-6-carboxylic acid (2-azido-1-phenyl-ethyl)amide (M, 0.722 mg, 1.22 mM) was dissolved in dioxane (10 mL). Triphenyl phosphine (0.35 g, 1.34 mM) was added and the mixture was stirred at 50° C. for 4 h. The mixture was removed from the heat and treated with an aqueous solution of NaOH (1N, 5 mL). The resulting mixture was stirred at room temperature for 2 h. The mixture was treated with 1N HCl (10 mL) and stirred for 12 h. The precipitate was collected by filtration and washed with ether. The solid was dried under high vacuum to provide (S)-2-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-6-carboxylic acid (2-amino-1-phenyl-ethyl)-amide. ESMS (m+1), 555; calc. Mw, 554
Reaction SMILES: F[C:2]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=1)=[O:5].[F:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[OH:30].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[F:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[O:30][C:2]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=1)=[O:5]
Reactant: O=C(Nc1cc[nH]c(=O)c1)c1ccc(C(F)(F)F)cc1F
Reactant: Oc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(Nc1cc[nH]c(=O)c1)c1ccc(C(F)(F)F)cc1Oc1ccc(F)cc1F
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide (30 mg, 0.1 mmol) in DMF (1 mL) was added 2,4-difluorophenol (130 mg, 1.0 mmol) and Cs2CO3 (325.8 mg, 1.0 mmol) and the reaction mixture was stirred at 100° C. for 1 hour. The reaction was cooled to 25° C., filtered and purified by reverse phase chromatography using a gradient of acetonitrile in water (10-99%) and HCl as a modifier to yield 2-(2,4-difluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide (16). ESI-MS m/z calc. 410.07, found 411.2 (M+1)+; Retention time: 1.55 minutes (3 minutes run).
Reaction SMILES: [Cl:1][C:2]1[N:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[C:4]#[N:5].[H-].[Na+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CN(C=O)C>[CH2:13]([O:10][C:7]1[CH:8]=[N:9][C:2]([Cl:1])=[C:3]([CH:6]=1)[C:4]#[N:5])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: N#Cc1cc(O)cnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cc(OCc2ccccc2)cnc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.1 %

Procedure:
To a flame dried flask under N2 was placed 2-chloro-5-hydroxynicotinonitrile (2.0 g, 0.012 mol), DMF (60 mL), NaH (50% oil dispersion, 0.75 g, 0.013 mol) and the mixture cooled to 0°-4° C. A solution of benzyl bromide (1.5 mL, 0.013 mol) in DMF (2 mL) was then added and the solution allowed to stir at room temperature overnight. The mixture was poured into H2O and extracted with Et2O (3×). The organic layer was concentrated to yield 2.0 g (100%) of 5-benzyloxy-2-chloronicotinonitrile. An analytical sample of 5-benzyloxy-3-chloronicotinonitrile was prepared by trituration with C6H14, mp 114°-15° C.; 1H NMR (CDCl3) δ5.2 (2H, s) 7.4 (5H, s), 7.5 (1H, d, J=3) and 8.35 (1H, d, J=3); IR (nujol) 2220 cm-1 ; MS m/e M+ 244.
Reaction SMILES: C([O:5][C:6]1[C:7](=[O:24])[C:8](=O)[C:9]=1[CH:10]=[C:11]1[C:19]([CH3:21])([CH3:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]1[CH3:22])CCC.[N:25]#[C:26][NH2:27].[CH2:28]([N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])[CH3:29]>C(O)C>[CH2:28]([NH+:30]([CH2:33][CH3:34])[CH2:31][CH3:32])[CH3:29].[C:26]([N:27]=[C:8]1[C:7](=[O:24])[C:6]([O-:5])=[C:9]1[CH:10]=[C:11]1[C:19]([CH3:21])([CH3:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]1[CH3:22])#[N:25]
Reactant: N#CN
Reactant: CCCCOc1c(C=C2N(C)c3ccccc3C2(C)C)c(=O)c1=O
Reactant: CCN(CC)CC
Solvent: CCO
Product: CC[NH+](CC)CC
Product: CN1C(=Cc2c([O-])c(=O)c2=NC#N)C(C)(C)c2ccccc21

Procedure:
A mixture of 1 g (3.1 mmol) of 3-butoxy-4-(1,3,3-trimethyl-2,3-dihydro-1H-2-indolylidenmethyl)-3-cyclobutene-1,2-dione (18), 200 mg (4.8 mmol) of cyanamide and 0.5 ml (3.6 mmol) of triethylamine is refluxed with stirring in 10 ml of absolute ethanol for 12 h. The solvent is removed under reduced pressure by a rotary evaporator. The obtained gum is column purified (Silica gel 60, 0–5% methanol-chloroform) to give triethylammonium-3-cyanimino-4-oxo-2-(1,3,3-trimethyl-2,3-dihydro-1H-2-indolylidenmethyl)-1-cyclobuten -1-olate (19) as an oily, yellow solid. Yield: 0.96 g (78%).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5](C=O)=[CH:4][C:3]=1[CH3:9].S([CH2:20][N+:21]#[C-:22])(C1C=CC(C)=CC=1)(=O)=O.[C:23]([O-:26])([O-])=O.[K+].[K+]>CO>[Br:1][C:2]1([C:23]2[O:26][CH:22]=[N:21][CH:20]=2)[S:6][CH2:5][CH:4]=[C:3]1[CH3:9]
Reactant: Cc1cc(C=O)sc1Br
Reactant: O=C([O-])[O-]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: [K+]
Solvent: CO
Product: CC1=CCSC1(Br)c1cnco1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 83 %

Procedure:
The mixed solution of 5-bromo-4-methyl-thiophene-2-carbaldehyde (k) (0.93 mmol) in methanol (4 mL) was added tosylmethyl isocyanide (1.02 mmol) and K2CO3 (1.88 mmol). The reaction was stirred at room temperature for 5 min before heated to 80° C. in the sealed tube. After 30 min, the solution was cooled to room temperature and concentrated. Column chromatography afforded 5-bromo-4-methyl-5-(oxazol-5-yl)-thiophene (l) (190 mg, 80%). Compound (n) was prepared using a Suzuki Coupling reaction analogous to step B of the preparation of Example 1. 1-(2,6-difluoro-phenyl)-3-[4-(5-oxazol-5-yl-3-methyl-thiophen-2-yl)-phenyl]-urea was prepared by reacting (n) with 2,6-difluorophenyl isocyanate by an analogous procedure as that described for Example 4.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]=[C:6]=[O:7])=[O:4].[NH2:8][C:9]1[S:10][C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=1>C(Cl)Cl>[S:10]1[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=[C:9]1[NH:8][C:6](=[O:7])[NH:5][C:3]([O:2][CH3:1])=[O:4]
Reactant: Nc1nc2ccccc2s1
Reactant: COC(=O)N=C=O
Solvent: ClCCl
Product: COC(=O)NC(=O)Nc1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 12 h
Yield: 40 %

Procedure:
Three and one half parts by weight of methoxycarbonyl isocyanate was added gradually with stirring to a solution at room temperature of 41/2 parts by weight of 2-aminobenzothiazole dissolved in 150 parts by weight of methylene chloride. After stirring the reaction mixture at room temperature for 12 hours, the product was isolated by filtration giving a 40% yield of essentially pure methyl 4-(benzothiazol-2-yl)allophanate having a melting point of 338°-340° C with decomposition.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]=[C:18]([CH2:20][OH:21])[O:17][N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N=C[N:24]([C:27](N2C=NC=C2)=[O:28])C=1.[OH-].[NH4+]>C1COCC1>[CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]=[C:18]([CH2:20][O:21][C:27](=[O:28])[NH2:24])[O:17][N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1cc(-c2ccc(NCc3ccccc3)cc2)no1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)OCc1cc(-c2ccc(NCc3ccccc3)cc2)no1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
[3-(4-benzylamino-phenyl)-isoxazol-5-yl]-methanol (178 mg, 0.63 mmol) was dissolved in THF (20 ml, 0.03 M), to which was added CDI (154 mg, 0.95 mmol). After the mixture was stirred at room temperature for about 1 hour, 1 ml of ammonium hydroxide was added and the resulting mixture was stirred for another 3 hours. The completion of the reaction was confirmed by liquid chromatography, and the THF was distilled under reduced pressure to obtain a pale yellow solid compound. The solid compound was extracted three times with water and ethyl acetate, the organic solvent layer was dried under reduced pressure, and then a crude compound was purified by column chromatography on silica gel using ethyl acetate/hexane (1:3) to obtain carbamic acid 3-(4-benzylamino-phenyl)-isoxazol-5-ylmethyl ester as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]3[N:15]=[C:16]([CH3:19])[C:17](I)=[C:13]3[N:12]=[C:11]([N:20]3[CH2:24][CH2:23][CH2:22][C@H:21]3[CH2:25][OH:26])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.[F:27][CH:28]([F:38])[C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C1(C)C=CC=CC=1.C([O-])(O)=O.[Na+]>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.C(O)C>[F:27][CH:28]([F:38])[C:29]1[CH:34]=[CH:33][C:32]([C:17]2[C:16]([CH3:19])=[N:15][N:14]3[C:9]([C:4]4[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=4)=[CH:10][C:11]([N:20]4[CH2:24][CH2:23][CH2:22][C@H:21]4[CH2:25][OH:26])=[N:12][C:13]=23)=[CH:31][CH:30]=1
Reactant: Cc1nn2c(-c3cc(F)cc(F)c3)cc(N3CCC[C@H]3CO)nc2c1I
Reactant: OB(O)c1ccc(C(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1nn2c(-c3cc(F)cc(F)c3)cc(N3CCC[C@H]3CO)nc2c1-c1ccc(C(F)F)cc1
Temperature: 85 °C
Reaction time: 4 h
Yield: 92.7 %

Procedure:
(S)-(1-(7-(3,5-Difluorophenyl)-3-iodo-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidin-2-yl)methanol (55 mg), 4-(difluoromethyl)phenylboronic acid (34 mg) and tetrakis(triphenylphosphine)palladium (10 mg) are added to toluene (8 mL), ethanol (3 mL) and 1 N NaHCO3 aqueous solution (1.5 mL) and stirred at 85° C. for 4 hours under argon atmosphere. After cooling to room temperature, the reaction solvent is removed by distillation under reduced pressure. The remainder is extracted with ethyl acetate and water. The organic layer is washed with brine and dehydrated with anhydrous MgSO4. The dehydrated organic layer is concentrated by distillation under reduced pressure and purified by column chromatography to yield the target compound (51 mg).
Reaction SMILES: C[O-].[Na+].C([O:7][C@@H:8]1[CH2:36][N:11]2[C@H:12]([CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][C@@H:10]2[CH2:9]1)(=O)C.O>CO>[CH:23]([C@H:12]1[N:11]2[CH2:36][C@@H:8]([OH:7])[CH2:9][C@H:10]2[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]1)([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(=O)O[C@H]1C[C@H]2CN(C(=O)OC(C)(C)C)C[C@@H](C(c3ccccc3)c3ccccc3)N2C1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H](O)CN2[C@H](C(c2ccccc2)c2ccccc2)C1
Reaction time: 1 h
Yield: 91.5 %

Procedure:
Sodium methoxide in methanol (5M, 27 μl ) was added into a solution of tert-butyl (4R,7S,8aS)-7-acetoxy-4-benzhydrylhexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate (628 mg) in methanol (10 ml) at room temperature. After being stirred for 1 hour at the same temperature, the reaction mixture was poured into water (10 ml). The whole was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography with a mixture of hexane and ethyl acetate (1:1) as an eluent to give tert-butyl (4R,7S,8aS)-4-benzhydryl-7-hydroxyhexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate (521 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH:13]=[C:12]3[NH:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:4][CH:3]=1.Cl[S:35]([C:38]1[CH:46]=[CH:45][C:41]([C:42]([OH:44])=[O:43])=[CH:40][CH:39]=1)(=[O:37])=[O:36].C(N(CC)CC)C.ClCCl>>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH:13]=[C:12]3[NH:20][CH:21]2[CH2:22][CH2:23][N:24]([S:35]([C:38]3[CH:39]=[CH:40][C:41]([C:42]([OH:44])=[O:43])=[CH:45][CH:46]=3)(=[O:37])=[O:36])[CH2:25][CH2:26]2)=[CH:32][CH:31]=1
Reactant: O=c1cc(NC2CCNCC2)c2cc(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)ccc2[nH]1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)c1ccc(S(=O)(=O)N2CCC(Nc3cc(=O)[nH]c4ccc(C(c5ccc(Cl)cc5)c5ccc(Cl)cc5)cc34)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 25-mL round-bottom flask, was placed 6-[bis(4-chlorophenyl)methyl]-4-[(piperidin-4-yl)amino]-1,2-dihydroquinolin-2-one (150 mg, 0.31 mmol, 1.00 equip, 98%), 4-(chlorosulfonyl)benzoic acid (103.77 mg, 0.47 mmol, 1.50 equip), triethylamine (98.28 mg, 0.95 mmol, 3.00 equip, 98%), dichloromethane (3 g, 35.32 mmol, 114.96 equip). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The resulting residue was purified by Prep-HPLC with the following conditions: Column, Sunfire Prep C18 OBD 5 um, 19×150 mm; mobile phase, Phase A: water (0.05% NH4HCO3), Phase B:CH3CN (20% CH3CN up to 65% in 8 min, up to 100% in 0.1 min, hold 100% for 1.9 min, down to 20% in 0.1 min, hold 20% for 1.9 min); Detector, UV 220 & 254 nm to yield 4-[4-([6-[bis(4-chlorophenyl)methyl]-2-oxo-1,2-dihydroquinolin-4-yl]amino)piperidine-1-sulfonyl]benzoic acid as an off-white solid.