Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([SiH](CC)CC)C.FC(F)(F)C(O)=O.ClC(Cl)C.[C:19]1([N:25](COCC[Si](C)(C)C)[S:26]([C:29]2[C:34]([CH:35]=O)=[CH:33][CH:32]=[CH:31][N:30]=2)(=[O:28])=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[CH3:45][O:46][C:47](=[O:60])[CH2:48][N:49]1[C:57]2[C:52](=[CH:53][C:54]([F:58])=[CH:55][CH:56]=2)[CH:51]=[C:50]1[CH3:59]>>[CH3:45][O:46][C:47](=[O:60])[CH2:48][N:49]1[C:57]2[C:52](=[CH:53][C:54]([F:58])=[CH:55][CH:56]=2)[C:51]([CH2:35][C:34]2[C:29]([S:26](=[O:27])(=[O:28])[NH:25][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[N:30][CH:31]=[CH:32][CH:33]=2)=[C:50]1[CH3:59]
Reactant: COC(=O)Cn1c(C)cc2cc(F)ccc21
Reactant: C[Si](C)(C)CCOCN(c1ccccc1)S(=O)(=O)c1ncccc1C=O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC(Cl)Cl
Product: COC(=O)Cn1c(C)c(Cc2cccnc2S(=O)(=O)Nc2ccccc2)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.6 %

Procedure:
A mixture of triethylsilane (3.1 mL), trifluoroacetic acid (0.88 mL) and dichloroethane (12 mL) at −15° C. was treated dropwise with a mixture of 3-formylpyridine-2-sulfonic acid phenyl[2-(trimethylsilanyl)ethoxymethyl]amide (0.55 g), (5-fluoro-2-methylindol-1-yl)acetic acid methyl ester (0.29 g) and dichloroethane (18 mL), and the resulting mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure and the residue was dissolved in dichloromethane. The mixture was washed with saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane, cyclohexane, ethyl acetate and methanol (9:1:0:0 to 0:0:9:1 by volume) to afford the title compound (0.20 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[C:4]([F:11])[C:3]=1[O:12][CH3:13].Br[C:15]1[N:16]=[CH:17][C:18]([NH2:21])=[N:19][CH:20]=1.CCO.C([O-])([O-])=O.[Na+].[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.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:15]2[N:16]=[CH:17][C:18]([NH2:21])=[N:19][CH:20]=2)=[C:4]([F:11])[C:3]=1[O:12][CH3:13]
Reactant: COc1c(Br)ccc(B(O)O)c1F
Reactant: Nc1cnc(Br)cn1
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: COc1c(Br)ccc(-c2cnc(N)cn2)c1F
Temperature: 80 °C

Procedure:
A mixture of (4-bromo-2-fluoro-3-methoxyphenyl)boronic acid (940 mg, 1.69 mmol) and 5-bromopyrazin-2-amine (1.31 g, 7.56 mmol) was treated with EtOH (12.4 ml), toluene (12.8 ml), and aqueous Na2CO3 (2.0 N, 9.44 ml, 18.9 mmol), and the resulting mixture deoxygenated by sparging with for 10 minutes. Pd(PPh3)4 (218 mg, 0.189 mmol) was then added, and the mixture heated at 80° Celsius for 17 h. The reaction was cooled to rt and then partitioned between saturated aqueous NH4Cl and EtOAc. The organic layer was isolated, dried over MgSO4, and concentrated to dryness. The resultant residue was suspended in DCM and the title compound isolated by filtration (300 mg, 27%), which was used without further purification. Additional product was obtained by concentrating the filtrate to dryness and subjecting the residue to FCC (560 mg, 50%). MS (ESI): mass calcd. for C11HgBrFN3O, 296.99; m/z found, 298.0 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 8.34 (dd, J=2.6, 1.5, 1H), 8.00 (d, J=1.5, 1H), 7.54-7.49 (m, 2H), 6.78 (s, 2H), 3.90 (d, J=0.6, 3H).
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([C:6]([NH:20][C:21]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:22])=[N:7][N:8]2COCC[Si](C)(C)C)=[CH:4][C:3]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.Cl>CO>[F:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([C:6]([NH:20][C:21]([N:23]3[CH2:24][CH2:25][CH2:26][CH2:27]3)=[O:22])=[N:7][NH:8]2)=[CH:4][C:3]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: C[Si](C)(C)CCOCn1nc(NC(=O)N2CCCC2)c2cc(-c3ccccc3)c(F)c(F)c21
Agent: Cl
Solvent: CO
Product: O=C(Nc1n[nH]c2c(F)c(F)c(-c3ccccc3)cc12)N1CCCC1

Procedure:
75 mg of pyrrolidine-1-carboxylic acid (6,7-difluoro-5-phenyl-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl)amide in 3 ml of methanol are treated with 0.82 ml of 2N HCl for 1 hour at reflux. After evaporation and purification by preparative LC/MS (acetonitrile/pH 9 buffer), 36 mg of pyrrolidine-1-carboxylic acid (6,7-difluoro-5-phenyl-1H-indazol-3-yl)amide are obtained.
Reaction SMILES: B.[Cl:2][C:3]1[C:11]([Cl:12])=[C:7]([C:8](O)=[O:9])[C:6]([NH2:13])=[CH:5][CH:4]=1.Cl>O1CCCC1>[NH2:13][C:6]1[C:7]([CH2:8][OH:9])=[C:11]([Cl:12])[C:3]([Cl:2])=[CH:4][CH:5]=1
Reactant: Nc1ccc(Cl)c(Cl)c1C(=O)O
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: Nc1ccc(Cl)c(Cl)c1CO
Yield: 76 %

Procedure:
A solution of borane (0.55 mol) in 550 ml of tetrahydrofuran was slowly added, over a period of 1 hour, to a solution of 5,6-dichloroanthranilic acid (44.5 g, 0.216 mol) in tetrahydrofuran (1200 ml). The solution was heated at reflux for 18 hours, cooled and treated slowly with 550 ml of 1N HCl. The tetrahydrofuran was removed in vacuo at 30° and the aqueous mixture was washed with ether and then made basic with concentrated NH4OH. The resulting solid was extracted with ether, dried (K2CO3) and the solvent was evaporated to leave 31.5 g. (76%) of the title compound as light pinkish needles, m.p. 133.5°-135°. An analytical sample was prepared by recrystallization from benzene; white needles, m.p. 134°-135.5°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][S:8][C:9]2[C:10](F)=[C:11]([F:27])[C:12]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])=[C:13]([CH:18]=2)[C:14]([O:16][CH3:17])=[O:15])=[CH:5][CH:4]=1.[N-:31]=[N+:32]=[N-:33].[Na+].O>CN(C=O)C>[N:31]([C:10]1[C:9]([S:8][CH2:7][C:6]2[CH:29]=[CH:30][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])[C:11]=1[F:27])=[N+:32]=[N-:33]
Reactant: COC(=O)c1cc(SCc2ccc(OC)cc2)c(F)c(F)c1Nc1ccccc1F
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(SCc2ccc(OC)cc2)c(N=[N+]=[N-])c(F)c1Nc1ccccc1F
Temperature: 90 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
To a solution of methyl 5-(4-methoxybenzylthio)-3,4-difluoro-2-((2-fluorophenyl)amino)benzoate (24.35 g, 56.18 mmol) in DMF (200 mL) was added NaN3 (4.38 g, 67.41 mmol) at ambient temperature. The mixture was stirred at 90° C. for 3 h. Then water (200 mL) was added. The solution was extracted with ethyl acetate (100 mL×3). The combined organic extracts were washed with water (100 mL) and brine (100 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate, 10:1, v/v) and gave the desired product (white solid, 21.04 g, 82.1% yield). 1H NMR (400 MHz, CDCl3): δ 8.98 (s, 1H), 7.75 (s, 1H), 7.10 (m, 6H), 6.84 (m, 2H), 4.03 (s, 2H), 3.92 (s, 3H), 3.81 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:12])[CH:8]=2)[N:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([SH:20])=[CH:16][CH:15]=1>CN(C1C=CN=CC=1)C>[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20][C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([Cl:12])[CH:8]=3)[N:3]=2)=[CH:16][CH:15]=1
Reactant: Clc1ccc2nc(Cl)ccc2c1
Reactant: Nc1ccc(S)cc1
Agent: CN(C)c1ccncc1
Product: Nc1ccc(Sc2ccc3cc(Cl)ccc3n2)cc1
Yield: 0 %

Procedure:
2,6-Dichloroquinoline (15.2 moles, 3.0 g), 4-aminothiophenol (15.2 moles, 1.9 g), and DMAP (15.2 moles, 1.85 g) were stirred at room temperature for 3 days. The solvent was removed, diluted with ethyl acetate, washed with water, dried over sodium sulfate and concentrated. The product was purified by HPLC over silica gel eluted with 25% ethyl acetate in hexane to yield 2-(4-aminophenylthio)-6-chloroquinoline 830 mg, 19%. Mass spec (FD) 286. Calculated for C15H11ClN2S: C, 62.82 H, 3.87; N, 9.77. Found: C, 63.09; H, 3.94; N, 9.61.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1.[Cl:17][CH2:18][C:19](Cl)=[O:20]>CC(O)C.CCCCCC>[Cl:17][CH2:18][C:19]([N:9]([C:3]1[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[C:10]1[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=1)=[O:20]
Reactant: Cc1ccc(Nc2c(F)cccc2Cl)cc1
Reactant: O=C(Cl)CCl
Solvent: CCCCCC
Solvent: CC(C)O
Product: Cc1ccc(N(C(=O)CCl)c2c(F)cccc2Cl)cc1
Temperature: 37.5 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
20.4 g of crude (2′-chloro-6′-fluorophenyl)-(4-methylphenyl)-amine are heated to about 80° C. and treated with 10.75 g of chloroacetylchlonde. The mixture is stirred for 2 hours and diluted with 10 ml of 2-propanol. The solution is cooled to 35-40° C. and seeded. The precipitated suspension is diluted with 30 ml of hexane, cooled to 0-5° C. and stirred for about 1 hour. The crystals are isolated by filtration, washed with a cold solution of 2-propanol/hexane ⅓. After drying, 22.7 g of 2-chloro-N-(2′-chloro-6′-fluorophenyl)-N-(4-methylphenyl)acetamide are obtained. HPLC purity: 99%. Melting point: 79-80° C. 1H-NMR(DMF-d7, 400 MHz, 393K) δ 2.44(s, 3H, CH3); 4.32 (s, 2H, CH2), 7.35[d, J=8.0 Hz, 2H, HC(3) and HC(5)], 7.43[ddd, J=8.0, 2.0 Hz, JH-F=8.0, 1H, HC(5′)], 7.48[d, J=8.0 Hz, 2H, HC(2) and HC(6)], 7.55[d, J=8.0 Hz, 1H, HC(3′)], 7.60[ddd, J=8.0 Hz, JH-F=5.5, 1H, HC(4′)].
Reaction SMILES: C(OC([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][CH:15]=[C:14]([F:22])[CH:13]=3)[CH2:9]1)=O)(C)(C)C.C([Li])(C)(C)C.[Cl:28]C(Cl)(Cl)C(Cl)(Cl)Cl>C1(C)C=CC=CC=1.CCCCC>[Cl:28][C:15]1[N:16]=[C:17]2[C:12](=[CH:13][C:14]=1[F:22])[CH2:11][C@H:10]1[N:18]2[C@H:19]([CH3:21])[CH2:20][NH:8][CH2:9]1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3cc(F)cnc3N21
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: Cc1ccccc1
Product: C[C@@H]1CNC[C@H]2Cc3cc(F)c(Cl)nc3N21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 8.8 %

Procedure:
To a solution of 0.23 g (4R,9aR)-7-fluoro-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester (intermediate h of examples 54–61) in 5 mL toluene was added dropwise at −78° C. 1.4 mL of a ca 1.3 M solution of t-butyllithium in pentane. The mixture was stirred at −78° C. for 30 min. To the resulting mixture was added 0.3 g hexachloroethane and the mixture was stirred at −78° C. for 30 min and then allowed to thaw to 0° C. over ca 30 min. The reaction was quenched with 10% citric acid and the organic phase was separated and evaporated and the residue purified by chromatography on silica gel with heptane:ethyl acetate (4:1). The product fractions containing the two isomers and some starting material were evaporated and the residue was taken up in 1 mL trifluoroacetic acid and kept at room temperature for 30 min. The solvent was evaporated and the residue was purified by chromatography on silica gel with dichloromethane:methanol:ammonia (9:1:0.1). The product fractions containing the more polar isomer were collected evaporated and dried under high vacuum to yield 0.016 g (4R,9aR)-6-chloro-7-fluoro-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene as light brown gum.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:5](=[O:12])[NH:6][C:7]([SH:11])=[N:8][C:9]=1[CH3:10].C[O-].[Na+].[I-].[CH3:17][CH3:18]>CO>[CH2:17]([S:11][C:7]1[NH:6][C:5](=[O:12])[C:4]([CH2:3][CH2:2][OH:1])=[C:9]([CH3:10])[N:8]=1)[CH3:18]
Reactant: CC
Reactant: Cc1nc(S)[nH]c(=O)c1CCO
Agent: C[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: CCSc1nc(C)c(CCO)c(=O)[nH]1
Reaction time: 0.5 h
Yield: 61 %

Procedure:
A mixture of intermediate 1 (37.2 g) and sodium methylate (36 g) in methanol (250 ml) was stirred for 30 min. Ethane iodide (31.2 g) was added dropwise. The reaction mixture was stirred and refluxed for 3 hours. The solvent was evaporated and the residue was stirred in water, filtered and recrystallized from CH3CN. The precipitate was filtered off and dried, yielding 26 g (60%) of 2-(ethylthio)-5-(2-hydroxyethyl)-6-methyl-4(3H)-pyrimidinone (intermediate 2).
Reaction SMILES: Cl.[C:2]1([CH3:18])[CH:7]=[CH:6][C:5]([C:8]([N:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)N)=[O:9])=[CH:4][CH:3]=1.[CH3:19][CH2:20][O:21][C:22]([CH:24]1[CH2:30][CH2:29][C:27](=O)[CH2:26][CH2:25]1)=[O:23].C(O)(=O)C.Cl>O>[C:2]1([CH3:18])[CH:7]=[CH:6][C:5]([C:8]([N:10]2[C:27]3[CH2:29][CH2:30][CH:24]([C:22]([O:21][CH2:20][CH3:19])=[O:23])[CH2:25][C:26]=3[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][CH:16]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)N(N)c2ccccc2)cc1
Reactant: CCOC(=O)C1CCC(=O)CC1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C1CCc2c(c3ccccc3n2C(=O)c2ccc(C)cc2)C1

Procedure:
1-(4-Toluoyl)-1-phenylhydrazine hydrochloride (13 g.) and 8.7 g. of ethyl cyclohexanone-4-carboxylate (prepared in situ from the corresponding ethylene ketal) in 40 ml. glacial acetic acid, and 5 ml. glacial acetic acid saturated with hydrogen chloride was warmed on a steam bath for thirty minutes, diluted with water and extracted with ether. The ether extracts were washed with potassium bicarbonate solution and water, dried, and evaporated to dryness. The residue was chromatographed on silica gel using 10% ether-pentane as eluant to give 12.7 g. of the title compound; m.p. 70°-72°C. (hexane-ether).
Reaction SMILES: C([O:3][C:4](=[O:30])[CH:5]([C:17]1[CH:22]=[C:21]([O:23][CH2:24][CH3:25])[CH:20]=[C:19]([O:26][CH2:27][CH3:28])[C:18]=1[F:29])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[NH:16])[NH:14][OH:15])=[CH:9][CH:8]=1)C.[OH-].[Na+].Cl>C1COCC1>[CH2:27]([O:26][C:19]1[C:18]([F:29])=[C:17]([CH:5]([NH:6][C:7]2[CH:8]=[CH:9][C:10]([C:13](=[NH:16])[NH:14][OH:15])=[CH:11][CH:12]=2)[C:4]([OH:30])=[O:3])[CH:22]=[C:21]([O:23][CH2:24][CH3:25])[CH:20]=1)[CH3:28]
Reactant: CCOC(=O)C(Nc1ccc(C(=N)NO)cc1)c1cc(OCC)cc(OCC)c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOc1cc(OCC)c(F)c(C(Nc2ccc(C(=N)NO)cc2)C(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
The (RS)-(3,5-diethoxy-2-fluoro-phenyl)-[4-(N-hydroxycarbamimidoyl)-phenylamino]-acetic acid ethyl ester (44 mg) described in example 2.5 was dissolved in THF (0.5 ml). IM NaOH (0.21 ml) was added and the mixture was stirred for 2 h at room temperature. The mixture was neutralized with 1 M HCl, concentrated and purified by column chromatography to give 23 mg of (RS)-(3,5-diethoxy-2-fluoro-phenyl)-[4-(N-hydroxycarbamimidoyl)-phenylamino]-acetic acid as a colorless solid. MS: 392 ([M+H]+) This compound was separated into the enantiomers by preparative HPLC on a chiral stationary phase (Chiralpak AD) using heptane/isopropanol/trifluoroacetic acid (60:40:0.2) as a mobile phase to give, after neutralisation, (R)-(3,5-diethoxy-2-fluoro-phenyl)-[4-(N-hydroxycarbamimidoyl)-phenylamino]-acetic acid and (S)-(3,5-diethoxy-2-fluoro-phenyl)-[4-(N-hydroxycarbamimidoyl)-phenylamino]-acetic acid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:25])[N:5]([CH2:12][CH:13]([C:19]1([CH3:24])OCC[O:20]1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6]2=[O:11].N1C=CC=CC=1.[C:32](Cl)(=[O:34])[CH3:33]>ClCCl>[C:32]([O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:25])[N:5]([CH2:12][CH:13]([C:19](=[O:20])[CH3:24])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6]2=[O:11])(=[O:34])[CH3:33]
Reactant: CCOC(=O)C(CN1C(=O)c2cccc(O)c2C1=O)C1(C)OCCO1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C(CN1C(=O)c2cccc(OC(C)=O)c2C1=O)C(C)=O
Reaction time: 0.17 h
Yield: 54.2 %

Procedure:
Ethyl 3-(4-hydroxy-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (102.4 mg, 0.34 mmol) was dissolved in dichloromethane, and pyridine (55 μl, 0.682 mmol) and acetyl chloride (49 μl, 0.68 mmol) were then slowly added dropwise to the obtained solution at 0° C. The resulting mixture was then stirred at the same temperature for 10 minutes. After the reaction was completed, the reaction mixture was washed with water and then the aqueous layer was extracted with dichloromethane. The combined organic layer was dried with anhydrous sulfate and distilled under a reduced pressure. The desired product (64 mg, 54%) was obtained by performing column chromatography (eluent: n-hexane/ethyl acetate=3/1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[N:12]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=3)[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=3)=[O:10])[CH:5]=[CH:4][N:3]=1.Br[CH2:33][C:34](=O)[C:35]([O:37][CH2:38][CH3:39])=[O:36]>C(#N)C>[CH2:38]([O:37][C:35]([C:34]1[N:1]=[C:2]2[CH:7]=[C:6]([NH:8][C:9]([C:11]3[N:12]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=4)[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([C:20]([F:23])([F:21])[F:22])=[CH:15][CH:14]=4)=[O:10])[CH:5]=[CH:4][N:3]2[CH:33]=1)=[O:36])[CH3:39]
Reactant: Nc1cc(NC(=O)c2cc3cc(C(F)(F)F)ccc3n2Cc2cccc(F)c2)ccn1
Reactant: CCOC(=O)C(=O)CBr
Solvent: CC#N
Product: CCOC(=O)c1cn2ccc(NC(=O)c3cc4cc(C(F)(F)F)ccc4n3Cc3cccc(F)c3)cc2n1
Yield: 67.8 %

Procedure:
The compound is prepared according to a process similar to that described in step 15.3, by reacting 0.23 g (0.54 mmol) of N-[2-aminopyrid-4-yl]-5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide, prepared according to the protocol described in step 17.2, with 0.21 g (1.07 mmol) of ethyl 3-bromo-2-oxopropionate in 4 mL of acetonitrile. 192 mg of the expected product are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[CH:17]OCC)[C:9]2=[O:21])[CH:5]=[CH:6][CH:7]=1.[CH2:22]([NH:24][CH2:25][CH3:26])[CH3:23]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[CH:17][N:24]([CH2:25][CH3:26])[CH2:22][CH3:23])[C:9]2=[O:21])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC=C1C(=O)N(c2cccc(Cl)c2)c2ccccc21
Reactant: CCNCC
Solvent: CCO
Product: CCN(C=C1C(=O)N(c2cccc(Cl)c2)c2ccccc21)CC
Reaction time: 24 h

Procedure:
1-(3-Chlorophenyl)-3-(ethoxymethylene)-2(1H,3H)-indolone (0.15 g, 0.5 mmole), diethylamine (5 ml, 48 mmole) and ethanol (30 ml) were combined and stirred 24 hours at 25°. The reaction mixture was concentrated in vacuo to an oil. The oil was taken up in ethyl acetate, washed with H2O and then brine, dried over MgSO4 and evaporated to yield title product which crystallized on cooling and trituration with ether/pentane, 96 mg. m.p. 74°-75.5°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21](=[O:28])[N:22]([CH3:27])[CH:23]=[C:24]([Br:26])[CH:25]=2)=[CH:16][CH:15]=1)[NH:5]C(OC(C)(C)C)=O.[ClH:30]>O1CCOCC1>[ClH:30].[CH3:1][O:2][C:3](=[O:29])[C@H:4]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[C:21](=[O:28])[N:22]([CH3:27])[CH:23]=[C:24]([Br:26])[CH:25]=2)=[CH:18][CH:19]=1)[NH2:5]
Reactant: COC(=O)[C@H](Cc1ccc(-c2cc(Br)cn(C)c2=O)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)[C@@H](N)Cc1ccc(-c2cc(Br)cn(C)c2=O)cc1

Procedure:
A solution of N-[(1,1-dimethylethoxyl)carbonyl]-4-(5-bromo-1-methyl-2-oxo-3-pyridinyl)-L-phenylalanine methyl ester (135 mg, 0.29 mmol) in 4 N HCl in dioxane (5 mL) was stirred for 2 hr and was concentrated. The residue was triturated with several portions of ether to give 4-(5-bromo-1-methyl-2-oxo-3-pyridinyl)-L-phenylalanine methyl ester hydrochloride (120 mg, quant) as a white powder. LRMS-Electrospray: m/z positive ion 729, 2M+H (2 Br), 406 (M+H+CH3CN), 397 (M+H+CH3CN (1 Br)), 365 (M+H (1 Br)). HRMS: Obs. Mass 365.0504. Calcd. Mass 365.0501 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([Sn](C)(C)C)=[CH:4][CH:3]=1.Br[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19](=[O:21])[CH3:20]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19](=[O:21])[CH3:20])=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccccc1Br
Reactant: Cc1ccc([Sn](C)(C)C)cc1
Product: CC(=O)c1ccccc1-c1ccc(C)cc1

Procedure:
Prepared from 4-methylphenyltrimethylstannane (Example 69, Step A) and 2'-bromoacetophenone by the procedure described in Example 69, Step B. 1H NMR (200 MHz,CDCl3): 1.98 (s,3H), 2.37 (s,3H), 7.20 (s,4H), 7.3-7.5 (m,4H). FAB-MS: calculated for C15H14O 210; found 211 (M+H,100%).
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10]O)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[Br:12]Br>CCOCC>[CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][Br:12])[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CCC[C@H]1CC[C@H](CO)CC1
Reactant: BrBr
Solvent: CCOCC
Product: CCC[C@H]1CC[C@H](CBr)CC1
Temperature: 180 °C

Procedure:
Trans-4-n-propylcyclohexylmethanol (0.12 mole) was added to red phosphorus (0.03 g atom) and warmed gently (ca 30° C.) using an oil bath. Bromine (0.14 mole) was added dropwise to the mixture. When addition was complete (about 1/2 hour) the temperature of the oil bath was raised to 180° C. for one hour. After this time, the mixture was allowed to cool, shaken with ether and filtered. The filtrate was washed with water, then dried (Na2SO4). The ether was removed by distillation and the residue distilled. The product boiled at 112° C. at a pressure of 15 mm Hg.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15])[O:5][CH2:6][CH2:7][N:8]([CH3:10])[CH3:9].[C:17]1([OH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:9][N:8]([CH3:10])[CH2:7][CH2:6][O:5][C:4]1[CH:11]=[CH:12][C:13]([N+:14]([O-:16])=[O:15])=[C:2]([O:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:3]=1
Reactant: Oc1ccccc1
Reactant: CN(C)CCOc1ccc([N+](=O)[O-])c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)CCOc1ccc([N+](=O)[O-])c(Oc2ccccc2)c1
Temperature: 110 °C
Reaction time: 4 h
Yield: 84 %

Procedure:
A mixture of [2-(3-fluoro-4-nitro-phenoxy)-ethyl]-dimethyl-amine (2.8 g, 12 mmol) and phenol (1.4 g, 15 mmol) in DMF (100 mL) was treated with potassium carbonate (3.4 g, 25 mmol) and the mixture heated at 110° C. under N2 with stirring. After 4 hours, the mixture was cooled to ambient temperature. The mixture was evaporated in vacuo, and the residue was partitioned between ethyl acetate (100 mL) and water (100 mL), and the aqueous phase was extracted with ethyl acetate (100 mL). The combined organic phases were washed with 10% potassium carbonate (2×100 mL) and water (2×100 mL), and were then extracted with dilute aqueous HCl (3×75 mL). The combined aqueous extracts were washed with CH2Cl2 (2×100 mL), basified (NaOH), and extracted into ethyl acetate (3×75 mL). The combined organic phases were washed with water (2×100 mL), dried (MgSO4) and evaporated, providing 3.1 g, in 84% yield; 1H NMR (CDCl3) δ 2.29 (s, 6H), 2.67 (t, J=5.8 Hz, 2H), 4.00 (t, J=5.8 Hz, 2H), 6.46 (d, J=2.6 Hz, 1H), 6.68 (dd, J=9.2 Hz, J=2.6 Hz, 1H), 7.03-7.07 (m, 2H), 7.18-7.22 (m, 1H), 7.35-7.42 (m, 2H), 8.06 (d, J=9.2 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH:4]=O.C(N(CC)CC)C.C([NH:21][C:22](=[CH2:27])[C:23]([O:25][CH3:26])=[O:24])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C=O>[F:10][C:7]1[CH:6]=[C:3]2[C:2]([CH:27]=[C:22]([C:23]([O:25][CH3:26])=[O:24])[N:21]=[CH:4]2)=[CH:9][CH:8]=1
Reactant: C=C(NC(C)=O)C(=O)OC
Reactant: O=Cc1cc(F)ccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1cc2ccc(F)cc2cn1
Temperature: 110 °C
Yield: 39.8 %

Procedure:
A sealed tube was charged with 2-bromo-5-fluorobenzaldehyde (300 mg, 1.47 mmol), dry dimethylformamide (1.5 ml), triethylamine (0.7 ml, 5.02 mmol), methyl 2-acetamidoacrylate (273 mg, 1.91 mmol), tris-o-tolyl-phosphine (89 mg, 0.29 mmol) and palladium acetate (33 mg, 0.14 mmol). The solution was degassed with Argon for 10 min. and then warmed at 110° C. for 4.5 hours. The mixture was cooled to room temperature and poured onto an aqueous solution of ammonium chloride. The mixture was extracted with ethyl acetate, washed with brine, dried over sodium sulfate and concentrated. The residue was purified by flash chromatography over silica gel (gradient cyclohexane/dichloromethane: 0-80%) to yield methyl 7-fluoro-isoquinoline-3-carboxylate (120 mg, 39%) as beige solid.