Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[C@H:2]([C:15]([O:17]C)=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=1.O.[OH-].[Li+]>CO.O>[NH:1]([C:19]([O:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:20])[C@H:2]([C:15]([OH:17])=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=1
Reactant: COC(=O)[C@H](Cc1ccc(O)c(C(C)(C)C)c1)NC(=O)OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)c1cc(C[C@H](NC(=O)OCc2ccccc2)C(=O)O)ccc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.7 %

Procedure:
To a solution of Z-Tyr(3-tBu)-OMe (1.01 g, 2.62 mmol) in methanol/water (12 ml/3 ml), lithium hydroxide monohydrate (0.17 g, 3.93 mmol) was added and stirred at room temperature for 2 hours. The reaction mixture was washed with ether, rendered acidic by 2N hydrochloric acid and extracted with methylene chloride. The extract was dried over anhydrous magnesium sulfate and evaporated to remove the solvent under reduced pressure, giving crude Z-Tyr(3-tBu)-OH (0.98 g).
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][C:11](B3OC(C)(C)C(C)(C)O3)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:24]1[C:32]2[C:27](=[N:28][CH:29]=[N:30][C:31]=2[NH2:33])[N:26]([C@H:34]2[CH2:39][CH2:38][C@@H:37]([N:40]3[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]3)[CH2:36][CH2:35]2)[N:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[NH:7]([C:8]1[CH:9]=[CH:10][C:11]([C:24]2[C:32]3[C:27](=[N:28][CH:29]=[N:30][C:31]=3[NH2:33])[N:26]([CH:34]3[CH2:35][CH2:36][CH:37]([N:40]4[CH2:41][CH2:42][N:43]([CH3:46])[CH2:44][CH2:45]4)[CH2:38][CH2:39]3)[N:25]=2)=[CH:12][CH:13]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC1(C)OB(c2ccc(Nc3ccccc3)cc2)OC1(C)C
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(I)c4c(N)ncnc43)CC2)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: COCCOC
Solvent: O
Product: CN1CCN(C2CCC(n3nc(-c4ccc(Nc5ccccc5)cc4)c4c(N)ncnc43)CC2)CC1
Temperature: 25 °C
Yield: 76.3 %

Procedure:
A mixture of N-phenyl—N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amine (Intermediate AE) (0.33 g, 0.0011 mol), cis-3-iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Intermediate AC) (0.43 g, 0.00097 mol), tetrakis(triphenylphosphine)palladium (0.0067 g, 0.000058 mol) and sodium carbonate (0.26 g, 0.0024 mol) was heated in a mixture of ethylene glycol dimethyl ether (16 mL) and water (8 mL) at 80° C. for 16 hours under an atmosphere of nitrogen. The mixture was allowed to cool to ambient temperature and solvents were removed under reduced pressure. The residue was partitioned between saturated aqueous sodium bicarbonate solution (50 mL) and ethyl acetate (50 mL), the organic layer separated and the aqueous layer further extracted with ethyl acetate twice. The combined organic extracts were dried over magnesium sulfate and evaporated under reduced pressure to give a tan solid which was purified by flash column chromatography on silica using dichloromethane/triethylamine/methanol (92:7:1) as a mobile phase to give 3-(4-anilinophenyl)-1-[4-(4-methylpiperazino)-cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine as a white solid (0.400 g, 0.00074 mol). It was dissolved at reflux in ethanol (17 mL) and a preheated solution of maleic acid (0.342 g, 0.003 mol) in ethanol (8 mL) was added. The mixture was refluxed for 10 min, cooled to ambient temperature and the precipitate collected by filtration, washed with ethyl acetate and dried to give cis-3-(4-anilinophenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine trimaleate (0.44 g, 0.00053 mol) 1H NMR (DMSO-d6, 400 MHz) 8.45 (s, 1H), 8.23 (s, 1H) 7.52 (d, 2H), 7.28 (m, 2H), 7.20 (m, 4H), 6.89 (t, 1H), 6.19 (s, 6H), 4.83 (m, 1H), 3.1 (br, 9H), 2.72 (s, 3H), 2.28 (m, 2H), 2.07 (m, 2H), 1.74 (m, 4H); RP-HPLC (Delta Pak C18, 5μm, 300 A, 15 cm; 5%-85% acetonitrile—0.1M ammonium acetate over 20 min, 1 mL/min) Rt 13.12 min. MH+483.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([CH3:40])([CH3:39])[CH2:11][O:12][C:13]1[CH:37]=[C:36](F)[CH:35]=[CH:34][C:14]=1[C:15]([NH:17][C:18]1[CH:33]=[CH:32][CH:31]=[CH:30][C:19]=1[C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=1)=[O:21])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:41]1[CH2:45][CH2:44][CH2:43][CH2:42]1>>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([CH3:40])([CH3:39])[CH2:11][O:12][C:13]1[CH:37]=[C:36]([N:41]2[CH2:45][CH2:44][CH2:43][CH2:42]2)[CH:35]=[CH:34][C:14]=1[C:15]([NH:17][C:18]1[CH:33]=[CH:32][CH:31]=[CH:30][C:19]=1[C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=1)=[O:21])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(CNC(=O)OC(C)(C)C)COc1cc(F)ccc1C(=O)Nc1ccccc1C(=O)Nc1ccc(Cl)cn1
Reactant: C1CCNC1
Product: CC(C)(CNC(=O)OC(C)(C)C)COc1cc(N2CCCC2)ccc1C(=O)Nc1ccccc1C(=O)Nc1ccc(Cl)cn1
Temperature: 80 °C
Yield: 43 %

Procedure:
Using methods substantially equivalent to those described in Example 4-F, except that the reaction was heated to 80° C., 2-[2-(3-tert-butoxycarbonylamino-2,2-dimethyl-propoxy)-4-(pyrrolidin-1-yl)benzoylamino]-N-(5-chloropyridin-2-yl)benzamide (453 mg, 0.73 mmol, 43%) was prepared from 2-[2-(3-tert-butoxycarbonylamino-2,2-dimethyl-propoxy)-4-fluorobenzoylamino]-N-(5-chloropyridin-2-yl)benzamide and pyrrolidine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:20]([O:22]C)=O)[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)=[C:6]([N+:10]([O-:12])=[O:11])[C:7]=1[C:8]#N.[H-].C([Al+]CC(C)C)C(C)C.CCCCCC.Cl.[OH2:41]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:20][OH:22])[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)=[C:6]([N+:10]([O-:12])=[O:11])[C:7]=1[CH:8]=[O:41]
Reactant: O
Reactant: COC(=O)c1cc(Cl)c(C#N)c([N+](=O)[O-])c1-c1cccc(F)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CCCCCC
Solvent: ClCCl
Product: O=Cc1c(Cl)cc(CO)c(-c2cccc(F)c2)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 52.9 %

Procedure:
To a mixture of methyl 4-chloro-5-cyano-3′-fluoro-6-nitrobiphenyl-2-carboxylate (1.02 g, 3.05 mmol) in methylene chloride (20 mL) was added 1.0 M diisobutylaluminum hydride in hexane (7.6 mL, 7.6 mmol) at −78° C. The reaction was warmed to room temperature over 2 hours with stirring. 5.0 M Hydrogen chloride in water (30 mL, 100 mmol) was slowly added with stirring for 1 hour. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and then concentrated to dryness. The residue was purified on silica gel, eluting with 0 to 50% ethyl acetate in hexane, to give the desired product (0.50 g, 53%). LCMS calculated for C14H10ClFNO4 (M+H)+: m/z=310.0; Found: 310.0.
Reaction SMILES: [CH2:1]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[CH:5]2[CH2:15][CH2:16][N:2]1[CH2:3][CH2:4]2.Br[C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[N:24]=[C:23]([CH3:28])[CH:22]=[CH:21]2>>[CH3:28][C:23]1[CH:22]=[CH:21][C:20]2[C:25](=[CH:26][CH:27]=[C:18]([N:7]3[C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=4[C:14]4[CH2:1][N:2]5[CH2:3][CH2:4][CH:5]([C:6]3=4)[CH2:15][CH2:16]5)[CH:19]=2)[N:24]=1
Reactant: Cc1ccc2cc(Br)ccc2n1
Reactant: c1ccc2c3c([nH]c2c1)C1CCN(CC1)C3
Product: Cc1ccc2cc(-n3c4c(c5ccccc53)CN3CCC4CC3)ccc2n1

Procedure:
The reaction of 3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (212 mg, 1.0 mmol; Example 187A) and 6-bromo-2-methylquinoline (333 mg, 1.5 mmol; Oakwood) was performed as described in Example 68 to afford the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 1.94-2.20 (m, 4H) 2.78 (s, 3H) 2.91-2.98 (m, 1H) 3.09-3.29 (m, 4H) 4.35 (s, 2H) 7.06-7.11 (m, 3H) 7.39-7.45 (m, 1H) 7.53 (d, J=8 Hz, 1H) 7.67 (dd, J=9, 2 Hz, 1H) 7.89 (d, J=2 Hz, 1H) 8.13 (d, J=9 Hz, 1H) 8.33 (d, J=8 Hz, 1H); MS (DCI/NH3) m/z 354 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:7]2[N:12]=[C:11]([C:13]3[S:14][CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:17]=3)[N:10]=[C:9]([OH:22])[CH:8]=2)[S:5][CH:6]=1.[CH3:23][O:24][C:25]([C@@:27]12[CH2:45][C@H:44]1[CH:43]=[CH:42][CH2:41][CH2:40][CH2:39][CH2:38][N:37]([CH3:46])[C:36](=[O:47])[N:35]1[C@@H:30]([CH2:31][C@H:32](O)[CH2:33][CH2:34]1)[C:29](=[O:49])[NH:28]2)=[O:26].COC([C@@]12C[C@H]1C=CCCCCN(C)C(=O)N1[C@@H](C[C@H](OC3C4C(=C(C)C(OC)=CC=4)N=C(C4SC=C(C#C)N=4)C=3)CC1)C(=O)N2)=O>>[CH3:23][O:24][C:25]([C@@:27]12[CH2:45][C@H:44]1[CH:43]=[CH:42][CH2:41][CH2:40][CH2:39][CH2:38][N:37]([CH3:46])[C:36](=[O:47])[N:35]1[C@@H:30]([CH2:31][C@@H:32]([O:22][C:9]3[CH:8]=[C:7]([C:4]4[S:5][CH:6]=[C:2]([CH3:1])[N:3]=4)[N:12]=[C:11]([C:13]4[S:14][CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:17]=4)[N:10]=3)[CH2:33][CH2:34]1)[C:29](=[O:49])[NH:28]2)=[O:26]
Reactant: Cc1csc(-c2cc(O)nc(-c3nc(C(F)(F)F)cs3)n2)n1
Reactant: COC(=O)[C@@]12C[C@H]1C=CCCCCN(C)C(=O)N1CC[C@@H](O)C[C@H]1C(=O)N2
Agent: C#Cc1csc(-c2cc(O[C@@H]3CCN4C(=O)N(C)CCCC/C=C\[C@@H]5C[C@@]5(C(=O)OC)NC(=O)[C@@H]4C3)c3ccc(OC)c(C)c3n2)n1
Agent: C#Cc1csc(-c2cc(O[C@@H]3CCN4C(=O)N(C)CCCCC=C[C@@H]5C[C@@]5(C(=O)OC)NC(=O)[C@@H]4C3)c3ccc(OC)c(C)c3n2)n1
Agent: COC(=O)[C@@]12C[C@H]1/C=C\CCCCN(C)C(=O)N1CC[C@@H](O)C[C@H]1C(=O)N2
Product: COC(=O)[C@@]12C[C@H]1C=CCCCCN(C)C(=O)N1CC[C@H](Oc3cc(-c4nc(C)cs4)nc(-c4nc(C(F)(F)F)cs4)n3)C[C@H]1C(=O)N2
Yield: 97 %

Procedure:
(1S,4R,6S,18S)-18[6-(4-Methylthiazol-2-yl)-2-(4-trifluoromethylthiazol-2-yl)-pyrimidin-4-yloxy]-13-N-methyl-2,14-dioxo-3,13,15-triazatricyclo[13.4.0.0*4,6*]nonadec-7-ene-4-carboxylic acid methyl ester 41b was synthesized from compounds B1 (150 mg, 1.2 eq.) and 36 (44.3 mg, 1 eq), according to the procedure as described for compound 37, as a beige solid in 97% yield. MS (ESI, EI−) m/z=704 (MH−).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](Cl)=[O:10])=[CH:4][CH:3]=1.[CH3:12][C:13]1([CH3:24])[C:18](=[O:19])[C:17]([CH3:21])([CH3:20])[C:16](=[O:22])[CH2:15][C:14]1=[O:23].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([CH:15]2[C:14](=[O:23])[C:13]([CH3:24])([CH3:12])[C:18](=[O:19])[C:17]([CH3:21])([CH3:20])[C:16]2=[O:22])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Reactant: CC1(C)C(=O)CC(=O)C(C)(C)C1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)C(=O)C(C(=O)Cc2ccc(Cl)cc2)C(=O)C(C)(C)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Chlorophenylacetic acid (1.7 g, 10 mmol) and oxalyl chloride (2 ml, 23 mmol) were stirred in 100 ml methylene chloride with two drops of dimethylformamide for two hours. The solvent and excess oxalyl chloride were removed under vacuum to give p-chlorophenylacetyl chloride. The 4-chlorophenylacetyl chloride and 4,4,6,6-tetramethyl-1,3,5-cyclohexanetrione (1.5 g, 8.2 mmol) were dissolved in methylene chloride. Triethylamine (3 ml) was added and the resulting solution stirred at room temperature for 30 minutes. The solution was washed with 1 normal hydrochloric acid (1N HCl), 5% potassium carbonate (5% K2CO3) and saturated sodium chloride (brine), dried over anhydrous magnesium sulfate (MgSO4) and concentrated under vacuum. The residue was dissolved in 15 ml acetonitrile. Triethylamine (3 ml) and acetone cyanohydrin (0.3 g) were added and the mixture stirred at room temperature for 4 hours. Afer dilution with ether, the solution was washed with 1N HCl and extracted with 5% K2CO3. The basic extract was acidified with hydrochloric acid and extracted with ether. The ether extract was washed with brine, dried (MgSO4) and concentrated under vacuum yielding 1.0 g of an oil that solidified on standing (m.p. 57°-61° C). It was identified as such by nuclear magnetic resonance spectroscopy, infrared spectroscopy and mass spectroscopy.
Reaction SMILES: [CH3:1][C:2]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].Cl.[CH3:16][NH:17][O:18][CH3:19].CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>ClCCl>[CH3:19][O:18][N:17]([CH3:16])[C:4]([C:3]1[C:2]([CH3:1])=[N:10][C:9]([C:11]([F:14])([F:13])[F:12])=[CH:8][CH:7]=1)=[O:5]
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)O
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc(C(F)(F)F)nc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-methyl-6-trifluoromethylnicotinic acid (500 mg, 2.44 mmol) and N,O-dimethylhydroxylamine hydrochloride (285 mg, 2.92 mmol) in dichloromethane (10 mL) were added N-methylmorpholine (0.32 mL, 2.92 mmol) and N-(3-dimethylaminopropyl-N′-ethylcarbodiimide hydrochloride (EDC, 560 mg, 2.92 mmol). The mixture was stirred at room temperature for 2 hours and washed with 1 N HCl and water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give N-methoxy-N-methyl-2-methyl-6-trifluoromethyl-3-pyridinecarboxamide quantitatively as oil. The crude product was used directly in the following reaction.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[H-].[Na+].[F:18][C:19]1[CH:24]=[C:23](F)[CH:22]=[CH:21][C:20]=1[N+:26]([O-:28])=[O:27]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:15])[C:5]([C:23]1[CH:22]=[CH:21][C:20]([N+:26]([O-:28])=[O:27])=[C:19]([F:18])[CH:24]=1)([CH2:11][CH:12]([CH3:13])[CH3:14])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: CCOC(=O)C(CC(C)C)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC(C)C)(C(=O)OCC)c1ccc([N+](=O)[O-])c(F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-isobutylmalonic acid diethyl ester (75.0 g, 0.35 mol) in DMF (200 mL) was added sodium hydride (60% in mineral oil, 13.0 g, 0.57 mol) over 20 min. at 0° C. The reaction mixture was stirred at 0° C. for 0.5 h, then warmed to 25° C. The reaction mixture was cooled down to 0° C. again and a solution of 2,4-difluoronitro-benzene (50.0 g, 0.31 mol) in DMF (150 mL) was added dropwise at 0° C. The reaction mixture was stirred at 25° C. for 16 h. After cooling, the reaction mixture was poured into ice water (200 mL) and extracted with EtOAc (3×100 mL). The combined organic phases washed with water (3×100 mL), brine (100 mL), and dried (MgSO4). Evaporation of the solvent under reduced pressure gave a brown oil. The crude product (92.0 g, 82%) was used for the next step without purification. 1H NMR (300 MHz, CDCl3/TMS): δ 8.03 (t, J=8.4 Hz, 1H), 7.70 (dd, J=12.9, 1.7 Hz, 1H), 7.47 (d, J=8.5 Hz, 1H), 4.25-4.18 (m, 4H), 2.28 (d, J=6.3 Hz, 2H), 1.54-1.45 (m, 1H), 1.25 (t, J=7.0 Hz, 6H), 0.82 (d, J=7.0 Hz, 6H); 13C NMR (75 MHz, CDCl3/TMS): δ 169.2, 154.5 (d, 1JCF=263.1 Hz), 146.9 (d, unresolved), 125.3, 124.1 (d, 3JCF=3.6 Hz), 118.6 (d, 2JCF=23.3 Hz), 62.0, 60.3, 44.1, 24.7, 23.6, 13.9.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:23])[C:7]([C:18]([O:20]CC)=[O:19])=[CH:8][N:9]2[C:12]2[C:16]([CH3:17])=[N:15][O:14][N:13]=2)=[CH:4][C:3]=1[F:24].Cl.O>C(O)(=O)C>[Cl:1][C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:23])[C:7]([C:18]([OH:20])=[O:19])=[CH:8][N:9]2[C:12]2[C:16]([CH3:17])=[N:15][O:14][N:13]=2)=[CH:4][C:3]=1[F:24]
Reactant: CCOC(=O)c1cn(-c2nonc2C)c2nc(Cl)c(F)cc2c1=O
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: Cc1nonc1-n1cc(C(=O)O)c(=O)c2cc(F)c(Cl)nc21
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 18.1 %

Procedure:
Compound No. 78 (30 mg) obtained in Example 39 was dissolved in acetic acid (2 ml ) and 6N-HCl (0.5 ml). The solution was stirred at 100° C. for 0.5 hour. After cooling and addition of water (10 ml), the precipitate was filtrated and washed with ethanol and ether. The title compound No. 79 was obtained as a colorless solid (5 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6])#[N:2].[C:10]([C:12]1[CH:17]=[CH:16][C:15]([N:18]=[C:19]=[O:20])=[CH:14][CH:13]=1)#[N:11].O>C(N(CC)CC)C>[C:1]([C:3]1[CH:4]=[C:5]([NH:6][C:19]([NH:18][C:15]2[CH:16]=[CH:17][C:12]([C:10]#[N:11])=[CH:13][CH:14]=2)=[O:20])[CH:7]=[CH:8][CH:9]=1)#[N:2]
Reactant: N#Cc1ccc(N=C=O)cc1
Reactant: N#Cc1cccc(N)c1
Solvent: CCN(CC)CC
Solvent: O
Product: N#Cc1ccc(NC(=O)Nc2cccc(C#N)c2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 103.8 %

Procedure:
m-Cyanoaniline (0.5 g, 3.38 mmol) and p-cyanophenylisocyanate (0.49 g, 3.38 mmol) were dissolved in dimethylformaide (8 ml) and triethylamine (1 ml). The reaction was stirred at ambient temperature under a nitrogen atmosphere for 24 h. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with water (3×), brine, dried (MgSO4) and concentrated to give a amorphous solid. This was triturated to a crystalline white solid with ethyl ether. This solid was filtered and washed with ether to give N-(3-cyanophenyl)-N′-(4-cyanophenyl)urea as a white powder (0.92 g, mp 183-5° C.); LRMS (M+H)+ m/z 280, (M+NH4)+ m/z 297; 1H NMR (DMSO-d6): 9.32(s, 1H), 9.21(s, 1H), 7.97(s, 1H), 7.75-7.6(m, 5H), 7.55-7.4(m, 2H).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH:2]([CH:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3].[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][C:18]12[C:26](=[O:27])[N:25]([CH2:28][C:29]([F:32])([F:31])[F:30])[N:24]=[C:23]1[CH2:22][CH2:21][NH:20][CH2:19]2>CC(C)=O.O>[C:6]([C@H:4]([C@@H:2]([C:1]([OH:10])=[O:9])[OH:3])[OH:5])([OH:8])=[O:7].[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][C:18]12[C:26](=[O:27])[N:25]([CH2:28][C:29]([F:31])([F:32])[F:30])[N:24]=[C:23]1[CH2:22][CH2:21][NH:20][CH2:19]2
Reactant: O=C(O)C(O)C(O)C(=O)O
Agent: O=C1N(CC(F)(F)F)N=C2CCNCC12Cc1ccccn1
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a dry and nitrogen purged 5 L round bottom flask equipped with a mechanical stirrer, D(−) tartaric acid (129 g, 0.86 mol) was added to the product from step C (243 g, 0.78 mol) in acetone/water (9:1, 2430 mL) at about 17° C. The mixture was stirred at room temperature overnight, filtered, the solid was collected and washed with cold acetone and dried under vacuum. The product was obtained as a yellow solid (284 g, yield 78.8%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:11][CH2:12][C:13]([N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:14].[C:20](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[CH3:20][O:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:11][CH2:12][C:13]([N:15]1[CH2:16][CH2:17][CH2:18][CH2:19]1)=[O:14]
Reactant: O=C([O-])[O-]
Reactant: O=C(CCc1ccc([N+](=O)[O-])cc1O)N1CCCC1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc([N+](=O)[O-])ccc1CCC(=O)N1CCCC1
Reaction time: 5 h
Yield: 94.1 %

Procedure:
This amide (900 mg, 3.4 mmol) was dissolved in dimethylformamide (100 ml) and potassium carbonate (516 mg) added, followed by iodomethane (0.6 ml, 3.7 mmol). The solution was stirred for 5 hours, then concentrated in vacuo. The residual oil was partitioned between ethyl acetate (50 ml) and H2O (50 ml), the aqueous layer extracted with ethyl acetate (3×50 ml), the combined organic phases washed with brine (20 ml), dried (MgSO4) and evaporated to yield 3-(2-methoxy-4-nitrophenyl)-1-pyrrolidin-1-yl-propan-1-one as a black oil (900 mg, 3.2 mmol);
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[C:11]#[N:12].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:25]([NH2:28])([CH3:27])[CH3:26]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:28][CH:25]([CH3:27])[CH3:26])=[O:8])=[CH:4][C:3]=1[C:11]#[N:12]
Reactant: N#Cc1cc(C(=O)O)ccc1Cl
Reactant: CC(C)N
Agent: O=C(n1ccnc1)n1ccnc1
Product: CC(C)NC(=O)c1ccc(Cl)c(C#N)c1

Procedure:
The above compound was prepared from the product of step (ii) (0.6 g), carbonyldiimidazole (0.59 g) and isopropylamine (0.51 ml) using the method of example 115 step (i). Yield 0.68 g.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7](O)[C:6](=[O:15])[C:5]2=[O:16])[CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClCCl>CN(C)C=O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6](=[O:15])[C:5]2=[O:16])[CH2:3][CH2:2]1
Reactant: O=c1c(=O)n(C2CC2)c2ccccc2n1O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=c1[nH]c2ccccc2n(C2CC2)c1=O
Temperature: 135 °C
Reaction time: 4 h
Yield: 84.1 %

Procedure:
To a solution of 1-cyclopropyl-4-hydroxy-1,4-dihydro-quinoxaline-2,3-dione (31.0 g, 0.14 mol, 1.0 equiv) in N,N-dimethylformamide (250 mL) was added triphenylphosphine (55.9 g, 0.21 mol, 1.5 equiv; [CAS RN 603-35-0]) and the reaction mixture stirred at 135° C. for 4 hours. The reaction mixture was cooled down to 0° C. and dichloromethane (400 mL) was added. The suspension was stirred for 30 min., filtered and washed with dichloromethane (200 mL) providing 23.8 g (83%) of the title compound as a white solid. MS (ISN): m/z=203.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].[Cl:11][C:12]1[CH:13]=[CH:14][C:15](F)=[C:16]([CH:21]=1)[C:17]([O:19][CH3:20])=[O:18]>CN(C)C=O.CCOCC>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([O:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[C:16]([CH:21]=1)[C:17]([O:19][CH3:20])=[O:18]
Reactant: Oc1ccc(F)cc1
Reactant: COC(=O)c1cc(Cl)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)c1cc(Cl)ccc1Oc1ccc(F)cc1
Temperature: 120 °C
Yield: 64.8 %

Procedure:
To a stirred solution of 4-fluorophenol (1.60 g, 14.3 mmol) and sodium hydride (0.34 g, 14.3 mmol) in N,N-dimethylforamide (30 mL) was added a solution of methyl 5-chloro-2-fluorobenzoate (2.70 g, 14.3 mmol) in N,N-dimethylforamide (30 mL) at 0° C. The resulting mixture was heated at 120° C. for 16 h. After cooling to room temperature, the mixture was diluted with ether (300 mL) and washed with water (150 mL×3). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by flush column chromatography on silica gel eluting with hexane/ethyl acetate (20:1) to afford 2.60 g (65%) of the title compounds as slight yellow oil: 1H-NMR (CDCl3) δ 7.88 (1H, d, J=2.8 Hz), 7.40 (1H, dd, J=8.8, 2.8 Hz), 7.06–6.85 (5H, m), 3.84 (3H, s).
Reaction SMILES: [OH:1][C:2]1[CH:27]=[CH:26][C:5]([C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH:9]=2)=[O:7])=[CH:4][C:3]=1[O:28][CH2:29][CH2:30][CH2:31][Cl:32].Br[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[CH3:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][O:1][C:2]2[CH:27]=[CH:26][C:5]([C:6]([C:8]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]([S:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)(=[O:19])=[O:18])[CH:9]=3)=[O:7])=[CH:4][C:3]=2[O:28][CH2:29][CH2:30][CH2:31][Cl:32])=[CH:37][CH:36]=1
Reactant: Cc1ccc(CBr)cc1
Reactant: O=C(c1ccc(O)c(OCCCCl)c1)c1cn(S(=O)(=O)c2ccccc2)c2ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(COc2ccc(C(=O)c3cn(S(=O)(=O)c4ccccc4)c4ccccc34)cc2OCCCCl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.7 %

Procedure:
3-[4-Hydroxy-3-(3-chloropropoxy)benzoyl]-1-(phenylsulfonyl)indole (0.72 g) obtained in Step 1 was dissolved in N,N-dimethylformamide (7 ml). α-bromo-p-xylene (0.37 g) and potassium carbonate (0.28 g) were added to the resultant solution and stirred for 2 hours at room temperature. 2N HCl was added to the reaction mixture, followed by extraction with ethyl acetate. The resultant extract was sequentially washed with saturated sodium bicarbonate solution and brine and then dried. The solvent was distilled off. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1), obtaining 0.49 g of 3-[4-(4-methylphenylmethoxy)-3-(3-chloropropoxy)benzoyl]-1-(phenylsulfonyl)indole as a yellow oily substance.