Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ON=[C:3]([CH3:17])[C:4](=[N:12][NH:13][C:14]([NH2:16])=[S:15])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[CH:6]=1.C(=O)([O-])[O-].[K+].[K+].C>O.CO>[CH3:17][C:3]1[C:4]([C:5]2[CH:6]=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=2)=[N:12][NH:13][C:14](=[S:15])[N:16]=1
Reactant: CC(=NO)C(=NNC(N)=S)c1cccc(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1cccc(-c2n[nH]c(=S)nc2C)c1
Yield: 115.2 %

Procedure:
A mixture of 2-hydroxyimino-3'-methylpropiophenone thiosemicarbazone (5 g) and potassium carbonate (6.1 g) in water (44 ml) was refluxed for 4 hours under nitrogen atmosphere. The reaction mixture was treated with activated charcoal and filtered by suction. The filtrate was acidified with diluted hydrochloric acid, and the resultant precipitates were collected by filtration, washed with water and dried. The above obtained crude product was dissolved in methanol (150 ml), and the solution was filtered by suction. The filtrate was concentrated under reduced pressure, and the residue was crystallized from diisopropyl ether, collected by filtration, washed with a mixture of methanol and diisopropyl ether, and dried to give 5-methyl-6-(m-tolyl)-1,2,4-triazine-3(2H)-thione (5 g).
Reaction SMILES: [N:1]1([C:5]([C:7]2[N:8]=[CH:9][C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:20]=[C:21]([O:23][C@H:24]4[CH2:28][CH2:27][O:26][CH2:25]4)[CH:22]=3)[C:17]([OH:19])=O)=[N:11][CH:12]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:53][C:54]1[S:55][CH:56]=[C:57]([CH3:59])[N:58]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[N:1]1([C:5]([C:7]2[N:8]=[CH:9][C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:20]=[C:21]([O:23][C@H:24]4[CH2:28][CH2:27][O:26][CH2:25]4)[CH:22]=3)[C:17]([NH:53][C:54]3[S:55][CH:56]=[C:57]([CH3:59])[N:58]=3)=[O:19])=[N:11][CH:12]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1csc(N)n1
Reactant: O=C(O)c1cc(Oc2cnc(C(=O)N3CCC3)cn2)cc(O[C@H]2CCOC2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1csc(NC(=O)c2cc(Oc3cnc(C(=O)N4CCC4)cn3)cc(O[C@H]3CCOC3)c2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 28 %

Procedure:
3-{[5-(Azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-[(3S)-tetrahydrofuran-3-yloxy]benzoic acid (200 mg, 0.52 mmol), HATU (475 mg, 1.25 mmol) and 2-amino-4-methylthiazole (119 mg, 1.04 mmol) were suspended in DMF (2 mL). DIPEA (0.220 mL, 1.26 mmol) was then added and the reaction mixture stirred at RT for 16 hours. The DMF was removed in vacuo and water (15 mL) added. The mixture was extracted with ethyl acetate (3×20 mL) and the extracts combined, washed with water (15 mL), 1N hydrochloric acid (10 mL), water (10 mL), a saturated aqueous solution of sodium bicarbonate (10 mL), brine (10 mL), dried (MgSO4), filtered, and evaporated in vacuo. The residue was chromatographed on silica, eluting with a gradient of 60-100% ethyl acetate in isohexane, to give the desired compound (70 mg).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2)#[N:2].C([O-])(O)=O.[Na+].[NH2:17][OH:18].Cl>CCO>[OH:18][NH:17][C:1]([C:3]1[C:4]2[CH:5]=[CH:6][NH:7][C:8]=2[CH:9]=[CH:10][CH:11]=1)=[NH:2]
Reactant: N#Cc1cccc2[nH]ccc12
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: N=C(NO)c1cccc2[nH]ccc12
Temperature: 70 °C
Reaction time: 8 h
Yield: 93.6 %

Procedure:
4-Cyanoindole (850 mg) was dissolved in EtOH (25 ml). To this solution was added NaHCO3 (2.51 g) and NH2OH.HCl (831 mg). The mixture was heated to 70° C. and stirred overnight. The reaction was incomplete so was heated at 80° C. for a further 4 hours. The reaction mixture was filtered and evaporated to give the title compound (980 mg) as a yellow semisolid. No purification attempted.
Reaction SMILES: C([O:6][C:7]1[CH:12]=CC(OC)=[CH:9][C:8]=1[CH:15](C)C(C)=C)(=O)CCC.[C:20]([O:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)(=[O:24])[CH2:21][CH2:22][CH3:23].ClC1C=CC=C(C(OO)=O)C=1.[OH-].[Ca+2].[OH-]>ClCCl>[C:20]([O:25][C:26]1[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][C:31]=1[C:8]([CH3:15])([CH3:9])[CH:7]1[O:6][CH2:12]1)(=[O:24])[CH2:21][CH2:22][CH3:23]
Reactant: C=C(C)C(C)c1cc(OC)ccc1OC(=O)CCC
Reactant: CCCC(=O)Oc1ccc(OC)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Ca+2]
Agent: [OH-]
Solvent: ClCCl
Product: CCCC(=O)Oc1ccc(OC)cc1C(C)(C)C1CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
To a mixture of E61, o-(1,2-dimethylallyl)-p-methoxyphenyl n-butyrate and p-methoxyphenyl n-butyrate (39.5 gm) in dichloromethane (900 mL) was added in portions metachloroperbenzoic acid (52 gm; 300 mmoles). The mixture was stirred at room temperature overnight. The reaction mixture was cooled in an ice-water bath and calcium hydroxide (150 gm) was added. After stirring for 15 minutes the mixture was filtered through a celite pad and the filtrate concentrated in vacuo. The residue was chromatographed in silica gel using 10% ethyl acetate in hexane to obtain 20 gm (47%) of o-(1,1-dimethyl-2,3-epoxypropyl)-p-methoxyphenyl n-butyrate, E62, as an oil.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH2:6][C:5]2[CH:9]=[C:10]3[C:15](=[CH:16][C:4]=2[S:3]1(=[O:18])=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11]3.C(N(CC)CC)C.[C:26]1([N:32]=[C:33]=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CS(C)=O>[CH3:1][N:2]1[C:7](=[O:8])[CH:6]([C:33]([NH:32][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:34])[C:5]2[CH:9]=[C:10]3[C:15](=[CH:16][C:4]=2[S:3]1(=[O:17])=[O:18])[CH:14]=[CH:13][CH:12]=[CH:11]3
Reactant: O=C=Nc1ccccc1
Reactant: CN1C(=O)Cc2cc3ccccc3cc2S1(=O)=O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CN1C(=O)C(C(=O)Nc2ccccc2)c2cc3ccccc3cc2S1(=O)=O
Reaction time: 20 h
Yield: 36.8 %

Procedure:
To a solution of 1.3 g (5 mmol) 3,4-dihydro-2-methyl-3-oxo-2H-naphtho[2,3-e]-1,2-thiazine 1,1-dioxide and 0.7 ml (5 mmol) triethylamine dissolved in 10 ml DMSO at room temperature was added 0.6 g (5 mmol) phenylisocyanate. After stirring for 20 hr the resulting mixture was quenched with dilute HCl in an ice bath and then extracted with ether (2 times). The combined ether extracts were washed, dried and concentrated to give 1.9 g crude product. This material was recrystallized from ethanol followed by recrystallization from ethylacetate to give 0.7 g 3,4-dihydro-2-methyl-3-oxo-2H-naphtho[2,3-e]-1,2-thiazine-4-carboxanilide 1,1-dioxide.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[CH3:5][O:6][C:7]1[CH:32]=[CH:31][CH:30]=[CH:29][C:8]=1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]2[CH2:27][CH3:28])=[CH:13][CH:12]=1)=[O:10].[Cl-].[NH4+]>CCOCC>[CH2:27]([CH:22]1[CH2:23][CH2:24][CH2:25][CH2:26][N:21]1[CH2:20][CH2:19][CH2:18][O:17][C:14]1[CH:13]=[CH:12][C:11]([C:9]([C:8]2[CH:29]=[CH:30][CH:31]=[CH:32][C:7]=2[O:6][CH3:5])([OH:10])[CH2:1][CH3:2])=[CH:16][CH:15]=1)[CH3:28]
Reactant: CCC1CCCCN1CCCOc1ccc(C(=O)c2ccccc2OC)cc1
Reactant: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CCC1CCCCN1CCCOc1ccc(C(O)(CC)c2ccccc2OC)cc1
Reaction time: 1 h

Procedure:
To 80 ml. of a 2.5 molar ethereal ethyl magnesium bromide solution a solution of 19.1 g. of 2-methoxy-4'-[3-(2-ethyl-piperid-1-yl)-propoxy]-benzophenone in 150 ml. of ether is added dropwise, with stirring at a temperature between 0° C. and 5° C., whereupon the reaction mixture is slightly boiled for one hour. After cooling the mixture is decomposed with a 10% aqueous ammonium chloride solution, and the aqueous phase is extracted with ether. The organic phase is washed to neutral with water, dried over anhydrous magnesium sulfate, and ether is distilled off under reduced pressure. Fractionation of the residue in vacuum yields 14.6 g. of the named compound, boiling at 224° to 226° C./13.3 Pa.
Reaction SMILES: [I:1][C:2]1[C:3]([O:14][CH3:15])=[N:4][N:5]([C@H:7]2[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9][CH2:8]2)[CH:6]=1.N1C=CN=C1.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Si:21]([O:13][C@H:10]1[CH2:9][CH2:8][C@H:7]([N:5]2[CH:6]=[C:2]([I:1])[C:3]([O:14][CH3:15])=[N:4]2)[CH2:12][CH2:11]1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1nn([C@H]2CC[C@H](O)CC2)cc1I
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: COc1nn([C@H]2CC[C@H](O[Si](C)(C)C(C)(C)C)CC2)cc1I
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of trans-4-(4-iodo-3-methoxy-1H-pyrazol-1-yl)cyclohexanol (0.359 g, 1.11 mmol), 1H-imidazole (0.228 g, 3.34 mmol), and 4-dimethylaminopyridine (0.0272 g, 0.223 mmol) in anhydrous DCM (10.8 mL) was charged with tert-butyldimethylsilyl chloride (0.336 g, 2.23 mmol) and stirred at rt for 20 min. The reaction was partitioned between CHCl3 and 1M NaHCO3 and separated. The aqueous was re-extracted with CHCl3 (3×) and the combined organic fraction were washed with brine (1×), dried over Na2SO4, filtered and concentrated in vacuo resulting in a crude colorless oil. The crude material was purified by chromatography on silica gel [eluting with 5% EtOAc in hexanes] resulting in the title compound as a clear colorless oil. 1H NMR (400 MHz, CD3OD): δ=0.09 (d, J=0.51 Hz, 6H), 0.91 (s, 9H), 1.41-1.54 (m, 2H), 1.74-1.87 (m, 2H), 1.93-2.09 (m, 4H), 3.68-3.77 (m, 1H), 3.86 (d, J=0.5 Hz, 3H), 3.96 (tt, J=3.9, 12 Hz, 1H), 7.48 (s, 1H). MS (ES+): m/z 437.17 (100) [MH+]. HPLC: tR=4.98 min (vvnonpolar—5 min, ZQ3).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[N:13][C:14]([CH3:18])=[C:15]([NH2:17])[CH:16]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:20]([O:27][C:28]([NH:30][C:31](=[N:34][C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36])SC)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl.[Hg](Cl)Cl>[CH2:38]([O:37][C:35](=[O:36])[NH:34]/[C:31](/[NH:17][C:15]1[C:14]([CH3:18])=[N:13][CH:12]=[C:11]([CH2:10][CH2:9][CH2:8][NH:7][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:19])[CH:16]=1)=[N:30]\[C:28](=[O:29])[O:27][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: CSC(=NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Reactant: Cc1ncc(CCCNC(=O)OC(C)(C)C)cc1N
Agent: Cl[Hg]Cl
Solvent: ClCCl
Product: Cc1ncc(CCCNC(=O)OC(C)(C)C)cc1N/C(=N/C(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
To a solution of tert-butyl[3-(5-amino-6-methylpyridin-3-yl)propyl]carbamate (2.99 g, 11.3 mmol), 1,3,-bis(benzyloxycarbonyl)-2-methyl-2-thiopseudourea (3.41 g, 9.51 mmol), and mercury(II)chloride (3.37 g, 12.4 mmol) in DCM (100 mL) was added TEA (5.19 mL, 37.3 mmol) dropwise via syringe. The reaction mixture was allowed to stir at rt overnight. The reaction mixture was filtered over a pad of Celite® and the resulting filtrate was concentrated. The residue was purified by column chromatography to give dibenzyl{(Z)-[(5-{3-[(tert-butoxycarbonyl)amino]propyl}-2-methylpyridin-3-yl)amino]methylylidene}biscarbamate (3.34 g, 61%) as a white solid. LCMS (FA): Rt=1.90 min, m/z=576.0 (M+H).
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[C:11]([O:15][C:16]([NH:18][C@H:19]1[CH2:23][C@@H:22]([C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:20]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].Cl[CH2:29][O:30][CH2:31][CH3:32]>O1CCCC1>[C:11]([O:15][C:16]([NH:18][C@H:19]1[CH2:23][C@@:22]([CH2:29][O:30][CH2:31][CH3:32])([C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:20]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: COC(=O)[C@H]1C=C[C@@H](NC(=O)OC(C)(C)C)C1
Reactant: CCOCCl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC[C@]1(C(=O)OC)C=C[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 662 %

Procedure:
To a 1.0 M solution of lithium hexamethyldisilazide in tetrahydrofuran (36.7 mL, 36.7 mmol) was added a solution of methyl (1R,4S)-4-[(tert-butoxycarbonyl)amino]cyclopent-2-ene-1-carboxylate (4.00 g, 1.66 mmol) in tetrahydrofuran (6.0 mL) at −78° C. The resulting light brown solution was stirred at −78° C. for 30 min before (chloromethoxy)ethane (1.88 g, 19.9 mol) was added in one portion. The mixture was stirred at −78° C. for 1 h and then kept in a freezer reading at −25° C. overnight. The reaction was then quenched with saturated NH4Cl (50 mL). The organic layer was separated and the aqueous layer was extracted with CH2Cl2 three times. The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated, and purified by flash chromatography (0 to 15% EtOAC in hexanes) to provide the desired product (3.29 g, 66%) as a cis/trans (3:2) mixture based on the analysis on reverse phase HPLC. MS calculated for C15H26NO5: (M+H) 300.2; found 200.2 (M+H-Boc).
Reaction SMILES: [CH3:1][N:2]([CH3:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=S)[NH:8][NH2:9].Cl.[Cl:13][CH:14]([C:20]([CH3:22])=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16]>C(O)C>[ClH:13].[CH2:18]([O:17][C:15]([C:14]1[C:7]([NH:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:11])[CH3:1])=[N:8][NH:9][C:20]=1[CH3:22])=[O:16])[CH3:19]
Reactant: CN(C)CCCNC(=S)NN
Reactant: CCOC(=O)C(Cl)C(C)=O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1c(NCCCN(C)C)n[nH]c1C
Yield: 71.4 %

Procedure:
A stirred solution of 7.05 g (0.04 mole) of 4-(3-dimethylaminopropyl)-3-thiosemicarbazide in 50 mL of absolute ethanol under nitrogen atmosphere was treated with 40 mL of 2N ethanolic hydrogen chloride and then with 6.6 g (0.04 mole) of ethyl 2-chloroacetoacetate, stirred at ambient temperature for 2 hr and heated at reflux for 5 hr. The reaction mixture was filtered hot to remove some crystalline sulfur and the filtrate solidified on cooling to give 8.3 g of crude product. After 5 recrystallizations from methyl ethyl ketone/methanol with charcoal treatment of the final recrystallization, a crystalline product was obtained, 3,4 g, mp 195°-196° C. After drying at 82° C. under reduced pressure, it was submitted for elemental analysis.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[C:7]([CH3:12])[C:3]=1[C:4]([OH:6])=[O:5].[C:13](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[CH3:13][O:5][C:4](=[O:6])[C:3]1[C:7]([CH3:12])=[CH:8][C:9]([Cl:11])=[N:10][C:2]=1[Cl:1]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(Cl)nc(Cl)c1C(=O)O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1c(C)cc(Cl)nc1Cl
Yield: 98.4 %

Procedure:
To a solution of 8.05 g (39.1 mmol) of 2,6-dichloro-4-methyl-nicotinic acid [Lamm, G. Ger. Offen. (1977), DE 2538950] in 100 ml of DMF was added 8.10 g (58.6 mmol) of potassium carbonate. While stirring, 12.16 ml=27.7 g (195.4 mmol) of iodomethane was added drop by drop and the reaction mixture was stirred for 6 hours at RT. It was then poured into crashed ice and extracted twice with EtOAc; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated to give 8.47 g (99%) of the title compound as light yellow solid. MS: 219.0 (M+, 2Cl).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]([O:18]CC)=[O:17])[O:9][N:8]=1.O.[OH-].[Li+].Cl>CO.O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:11]([C:12]([F:14])([F:15])[F:13])=[C:10]([C:16]([OH:18])=[O:17])[O:9][N:8]=1
Reactant: CCOC(=O)c1onc(-c2ccccn2)c1C(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1onc(-c2ccccn2)c1C(F)(F)F
Reaction time: 1 h
Yield: 98.7 %

Procedure:
To a solution of ethyl 3-(pyridin-2-yl)-4-(trifluoromethyl)isoxazole-5-carboxylate (511 mg, 1.79 mmol) in methanol (12 mL) and water (3 mL) at room temperature was added lithium hydroxide, hydrate (74.9 mg, 1.79 mmol). The reaction mixture was stirred for 1 hr. A 1N aqueous solution of hydrochloric acid (1.8 mL) was added, and the solvent were removed under reduced pressure to afford 3-(pyridin-2-yl)-4-(trifluoromethyl)isoxazole-5-carboxylic acid+1LiCl (531 mg, 1.767 mmol, 99% yield) as a white solid. The compound had an HPLC ret. time=0.725 min.-Column: CHROMOLITH® SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=258.8. 1H NMR (400 MHz, CD3OD) δ ppm 7.59 (dd, J=7.03, 5.02 Hz, 1H), 7.82 (d, J=7.78 Hz, 1H), 8.01 (td, J=7.78, 1.76 Hz, 1H), and 8.73 (d, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8](F)=[CH:7][CH:6]=1)[CH3:2].[C:13]1([CH:19]2[CH2:24][CH2:23][N:22]([C:25]3[CH:30]=[CH:29][C:28]([N:31]4[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]4)=[CH:27][CH:26]=3)[CH2:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([N:34]2[CH2:33][CH2:32][N:31]([C:28]3[CH:29]=[CH:30][C:25]([N:22]4[CH2:21][CH2:20][CH:19]([C:13]5[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=5)[CH2:24][CH2:23]4)=[CH:26][CH:27]=3)[CH2:36][CH2:35]2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: c1ccc(C2CCN(c3ccc(N4CCNCC4)cc3)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(N2CCN(c3ccc(N4CCC(c5ccccc5)CC4)cc3)CC2)cc1
Temperature: 150 °C
Reaction time: 12 h
Yield: 46 %

Procedure:
A mixture of 4-fluorobenzoic acid ethyl ester (1.25 g), 1-[4-(4-phenylpiperidin-1-yl)phenyl]piperazine (1.19 g) and potassium carbonate (1.53 g) in dimethylsulfoxide (18 ml) was stirred for 12 hours at 150° C. The reaction mixture was pulverized with water. The mixture was extracted with dichloromethane. The organic layer was separated, washed with brine, dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography over silica using dichloromethane/methyl alcohol (200:1) as the elution. The powder was recrystallized from toluene (60 ml). The crystal was collected by filtration, and dried under reduced pressure to give 4-[4-[4-(4-phenylpiperidin-1-yl)phenyl]piperazin-1-yl]benzoic acid ethyl ester (0.80 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](=[O:12])[N:9]([CH3:11])[CH3:10])[CH:5]=[CH:4][C:3]=1[N:13]([CH3:33])[C:14]([C:16]1[S:32][C:19]2[C:20]3[CH:28]=[CH:27][C:26]([C:29]([OH:31])=O)=[CH:25][C:21]=3[O:22][CH2:23][CH2:24][C:18]=2[CH:17]=1)=[O:15].[NH2:34][CH2:35][CH2:36][NH:37][C:38](=[O:40])[CH3:39].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1>[C:38]([NH:37][CH2:36][CH2:35][NH:34][C:29]([C:26]1[CH:27]=[CH:28][C:20]2[C:19]3[S:32][C:16]([C:14]([N:13]([C:3]4[CH:4]=[CH:5][C:6]([C:8](=[O:12])[N:9]([CH3:10])[CH3:11])=[CH:7][C:2]=4[Cl:1])[CH3:33])=[O:15])=[CH:17][C:18]=3[CH2:24][CH2:23][O:22][C:21]=2[CH:25]=1)=[O:31])(=[O:40])[CH3:39]
Reactant: CN(C)C(=O)c1ccc(N(C)C(=O)c2cc3c(s2)-c2ccc(C(=O)O)cc2OCC3)c(Cl)c1
Reactant: CC(=O)NCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)NCCNC(=O)c1ccc2c(c1)OCCc1cc(C(=O)N(C)c3ccc(C(=O)N(C)C)cc3Cl)sc1-2

Procedure:
Following the procedures in Examples 47 and 235, 2-((2-chloro-4-(dimethylcarbamoyl)phenyl)(methyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carboxylic acid was reacted with N-(2-aminoethyl)acetamide, HATU and DIPEA in THF to give 333 as a colorless solid after reverse phase HPLC. MS: (ESI+) 569.1
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:20]=[C:19]([C:21](O)=[O:22])[CH:18]=[CH:17][CH:16]=2)=[CH:11][C:10]=1[CH:24]1[C:37]2[C:36](=[O:38])[CH2:35][C:34]([CH3:40])([CH3:39])[CH2:33][C:32]=2[O:31][C:30]2[CH2:29][C:28]([CH3:42])([CH3:41])[CH2:27][C:26](=[O:43])[C:25]1=2.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>CN(C=O)C.O>[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][CH:18]=[C:19]([C:21]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:22])[N:20]=2)=[CH:11][C:10]=1[CH:24]1[C:25]2[C:26](=[O:43])[CH2:27][C:28]([CH3:41])([CH3:42])[CH2:29][C:30]=2[O:31][C:32]2[CH2:33][C:34]([CH3:40])([CH3:39])[CH2:35][C:36](=[O:38])[C:37]1=2
Reactant: COc1ccc(-c2cccc(C(=O)O)n2)cc1C1C2=C(CC(C)(C)CC2=O)OC2=C1C(=O)CC(C)(C)C2
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2cccc(C(=O)N3CCOCC3)n2)cc1C1C2=C(CC(C)(C)CC2=O)OC2=C1C(=O)CC(C)(C)C2
Reaction time: 24.5 h
Yield: 78.4 %

Procedure:
Morpholine (0.0625 ml, 0.72 mmol) was added to a solution of the 6-[4-methoxy-3-(3,3,6,6-tetramethyl-1,8-dioxo-2,3,4,5,6,7,8,9-octahydro-1H-xanthen-9-yl)phenyl]pyridine-2-carboxylic acid produced in Example 1-2 (180 mg, 0.36 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (138 mg, 0.72 mmol), and 1-hydroxybenzotriazole monohydrate (55.0 mg, 0.36 mmol) in DMF (4 ml) at room temperature, and the mixture thus obtained was then stirred at the same temperature as above for 24.5 hours. Thereafter, water was added to the reaction solution, and the mixed solution was then extracted with ethyl acetate. The organic layer thus obtained was washed with water, and was then dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, and the residue thus obtained was then purified by silica gel column chromatography (ethyl acetate). The solid thus obtained was washed with a mixed solution of diethyl ether and hexane, followed by collection by filtration and drying, to obtain the title compound (161 mg, yield: 79%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].Br[CH2:13][CH2:14]Br.[OH-].[K+].O>CN(C)C=O>[N+:8]([C:7]1[C:2]2[NH:1][CH2:14][CH2:13][O:11][C:3]=2[CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Reactant: BrCCBr
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc2c1NCCO2
Temperature: 200 °C
Reaction time: 48 h
Yield: 14.3 %

Procedure:
To a solution of 2-amino-3-nitrophenol (15.0 g, 97 mmol) and 1,2-dibromoethane (29.1 g, 155 mmol) in dimethylformamide (80 mL) was added KOH (10.9 g, 194 mmol) at 180° C. After stirring at 200° C. for 2 days, the mixture was poured to 150 g water. The mixture was concentrated under reduced pressure. The crude product was purified using column chromatography to give the title compound (2.50 g) as a red solid. MS (ESI): m/z 181 [M+H]+
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:13]=[CH:14][C:15]3[N:19]=[C:18]([C@@H:20]4[CH2:25][C@@H:24]5[C@@H:22]([CH2:23]5)[N:21]4[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[NH:17][C:16]=3[CH:33]=1)[CH:6]=[N:5]2.CC([O-])=O.[K+].[B:39]1(B2OC(C)(C)C(C)(C)O2)[O:43]C(C)(C)C(C)(C)[O:40]1>O1CCOCC1.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:29]([O:28][C:26]([N:21]1[C@H:20]([C:18]2[NH:17][C:16]3[CH:33]=[C:12]([C:7]4[CH:6]=[N:5][C:4]5[C:9](=[CH:10][CH:11]=[C:2]([B:39]([OH:43])[OH:40])[CH:3]=5)[N:8]=4)[CH:13]=[CH:14][C:15]=3[N:19]=2)[CH2:25][C@@H:24]2[C@H:22]1[CH2:23]2)=[O:27])([CH3:32])([CH3:31])[CH3:30]
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1nc2ccc(-c3cnc4cc(Br)ccc4n3)cc2[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1nc2ccc(-c3cnc4cc(B(O)O)ccc4n3)cc2[nH]1
Temperature: 83 °C
Reaction time: 16 h
Yield: 60.2 %

Procedure:
Pd(Ph3P)4 (23.28 mg, 0.020 mmol) was added to a degassed solution of (1R,3S,5R)-tert-butyl 3-(6-(6-bromoquinoxalin-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (102 mg, 0.201 mmol), KOAc (49.4 mg, 0.504 mmol) and bis(pinacolato)diboron (113 mg, 0.443 mmol) in dioxane (2 mL) and the reaction was stirred at 83° C. for 16 h. The reaction mixture was partitioned between EtOAc (20 mL) and sat. NH4Cl(aq.) (5 mL). The organic layer was dried (MgSO4), filtered and concentrated to an orange oil, which was purified by prep HPLC (H2O-MeOH with 0.1% TFA buffer) to yield 2-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazol-6-yl)quinoxalin-6-ylboronic acid (57 mg, 0.121 mmol, 60.0% yield) as orange solid. LC-MS retention time 1.94 min; m/z 472 [M+H]+. (Column PHENOMENEX® Luna 3.0×50 mm S10. Solvent A=90% water: 10% methanol: 0.1% TFA. Solvent B=10% water: 90% methanol: 0.1% TFA. Flow Rate=4 mL/min. Start % B=0. Final % B=100. Gradient Time=3 min. Wavelength=220).