Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([CH2:12][CH3:13])[CH2:10][OH:11])[C:5]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[CH:4][N:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([S@:26]([CH:34]2[CH2:36][CH2:35]2)(=[N:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:27])=[CH:22][CH:21]=1>>[CH2:32]([O:31][C:29]([N:28]=[S@:26]([C:23]1[CH:22]=[CH:21][C:20]([NH:19][C:2]2[N:7]=[C:6]([NH:8][C@@H:9]([CH2:10][OH:11])[CH2:12][CH3:13])[C:5]([C:14]3[S:15][CH:16]=[CH:17][CH:18]=3)=[CH:4][N:3]=2)=[CH:25][CH:24]=1)([CH:34]1[CH2:35][CH2:36]1)=[O:27])=[O:30])[CH3:33]
Reactant: CC[C@H](CO)Nc1nc(Cl)ncc1-c1cccs1
Reactant: CCOC(=O)N=[S@](=O)(c1ccc(N)cc1)C1CC1
Product: CCOC(=O)N=[S@](=O)(c1ccc(Nc2ncc(-c3cccs3)c(N[C@H](CC)CO)n2)cc1)C1CC1
Yield: 40 %

Procedure:
In the reaction of (R)-2-(2-chloro-5-(2-thienyl)pyrimidine-4-ylamino)butan-1-ol (270 mg, 0.95 mmol) with (R)—S-(4-aminophenyl)-N-(ethoxycarbonyl)-S-cyclo-propyl-sulfoximide (224 mg, 0.83 mmol) according to procedure 5c, the desired product is obtained in 40% yield (170 mg) after chromatographic purification (silica gel, dichloromethane/ethanol (0%-20% ethanol)).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[C:3]=1[C:13](=[O:15])[CH3:14].[OH-].[K+].[F:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21]Cl>CS(C)=O.O>[F:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][NH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[C:3]=1[C:13](=[O:15])[CH3:14]
Reactant: Fc1ccccc1CCl
Reactant: CC(=O)c1c(C)nc2ccccc2c1N
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)c1c(C)nc2ccccc2c1NCc1ccccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1-(4-amino-2-methyl-3-quinolinyl)-ethanone in dimethylsulfoxide (150 ml) was added to a stirred slurry of pulverized 85% potassium hydroxide (7 g) in dimethylsulfoxide (40 ml). This mixture was stirred at ambient temperature for twenty minutes, and thereafter a solution of o-fluorobenzylchloride (15.2 g) in dimethylsulfoxide (40 ml) was added dropwise. The mixture was stirred for two hours and allowed to stand overnight at room temperature. Thereafter, it was poured onto ice and diluted with water to form a tacky lump. This was allowed to stand for fifteen minutes, and the aqueous dimethylsulfoxide was decanted. The tacky precipitate was dissolved in dichloromethane, washed with water (3×) and saturated sodium chloride solution, and dried over sodium sulfate. Removal of the sodium sulfate by filtration and the solvent by evaporation gave 26.5 g of viscous oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][N:26]=[N+:27]=[N-:28])[O:22][C:21]3=[O:29])=[CH:16][C:15]=2[F:30])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:31]12CC(CC1)=C[CH:32]=2>O1CCOCC1>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][N:26]4[CH:32]=[CH:31][N:28]=[N:27]4)[O:22][C:21]3=[O:29])=[CH:16][C:15]=2[F:30])[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ccc(N3C[C@H](CN=[N+]=[N-])OC3=O)cc2F)C1
Reactant: C1=C2CCC(=C1)C2
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ccc(N3C[C@H](Cn4ccnn4)OC3=O)cc2F)C1
Yield: 73.7 %

Procedure:
(5R)-3-(4-((3R)-3-(t-Butoxycarbonyl)aminopyrrolidin-1-yl)-3-fluorophenyl)-5-azidomethyl-oxazolidin-2-one (695 mg, 1.65 mM) was dissolved in dioxane (30 ml), treated with norbornadiene (760 mg, 8.25 mM) and heated under reflux for 6 hours. After removal of the solvent, the residue was dissolved in the minimum of dichloromethane and purified by chromatography on a 20 g silica Mega Bond Elut® column, eluting with a gradient increasing in polarity from 0 to 2.5% methanol in dichloromethane. Relevant fractions were combined and evaporated to give the desired product (544 mg).
Reaction SMILES: N#N.[CH3:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:13])[CH3:12])=[CH:7][C:6]=1[NH2:14].[CH2:15](O)[CH3:16]>>[CH3:3][N:4]1[C:5]2[CH:10]=[CH:9][C:8]([CH:11]([CH3:12])[CH3:13])=[CH:7][C:6]=2[N:14]=[C:15]1[CH3:16]
Reactant: CCO
Reactant: CNc1ccc(C(C)C)cc1N
Agent: N#N
Product: Cc1nc2cc(C(C)C)ccc2n1C

Procedure:
A mixture of 6.66 g. (0.041 mole) of N2 -methyl-5-isopropyl-1,2-phenylenediamine and 10.02 g. (0.081 mole) of ethyl methylcarboximidate hydrochloride in 100 ml. of absolute ethanol was stirred at room temperature for 40 hours and then refluxed for 18 hours. The reaction mixture was distilled to dryness under reduced pressure, 100 ml. of 4N HCl was added to the residue and then the mixture refluxed for 22 hours. After cooling, the resultant mixture was filtered and the filtrate added dropwise to 200 ml. of stirred ice and water containing 50 ml. of conc. ammonium hydroxide. The precipitated product was isolated by filtration, washed with water and then air-dried. The crude product was dissolved in 75 ml. of refluxing cyclohexane, filtered and the filtrate allowed to cool. The desired product crystallized from the cooled cyclohexane and was removed by filtration to give 2.73 g. (35.8%), melting at 130°-131° C.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[C:14]([C:16]#[N:17])[CH:13]=[CH:12][C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([I:11])[CH:6]=1.[CH:18](O)=O>>[C:16]([C:14]1[CH:13]=[CH:12][C:3]2[N:4]([C:5]3[CH:10]=[CH:9][CH:8]=[C:7]([I:11])[CH:6]=3)[CH:18]=[N:1][C:2]=2[CH:15]=1)#[N:17]
Reactant: N#Cc1ccc(Nc2cccc(I)c2)c(N)c1
Reactant: O=CO
Product: N#Cc1ccc2c(c1)ncn2-c1cccc(I)c1
Temperature: 90 °C

Procedure:
A suspension of 2-amino-(N-(3-iodophenyl))4-cyanoaniline (1,8 g, 5.36 mmol) in formic acid (20 ml) is heated to 80-100° C. for 1.5 hours. The hot reaction mixture is filtered through a cotton pad into ice-water (100 ml). The precipitate is filtered off, washed with water and dried. This crude product is dissolved in dichloromethane and is brought to precipitation by addition of petroleum ether. The product is filtered off and dried. Yield: 1.38 g (75%) of the title compound. Mp. 177-179° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[N:6][C:5](I)=[CH:4][N:3]=1.C[C:10]1([CH3:17])[CH2:15][CH2:14][NH:13][C:12](=[O:16])[CH2:11]1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[Br:1][C:2]1[N:3]=[CH:4][C:5]([N:13]2[CH2:14][C:10]([CH3:15])([CH3:17])[CH2:11][C:12]2=[O:16])=[N:6][CH:7]=1
Reactant: CC1(C)CCNC(=O)C1
Reactant: Brc1cnc(I)cn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC1(C)CC(=O)N(c2cnc(Br)cn2)C1
Yield: 53.2 %

Procedure:
To a well stirred suspension of 2-bromo-5-iodopyrazine (300 mg, 1.05 mmol), 4,4-dimethylpiperidin-2-one (155 mg, 1.37 mmol, 1.3 equiv.) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (xantphos) (24.4 mg, 0.042 mmol, 0.04 equiv.) in 4 ml of toluene were added under argon atmosphere tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3), (19.3 mg, 0.021 mmol, 0.02 equiv.) and the mixture was stirred for 5 hours at 100° C. The crude mixture was adsorbed on silicagel and purified by flash chromatography over a 20 g silicagel column using a 2:1 heptane/ethyl acetate mixture as eluant. The title compound (151 mg, 53% yield) was obtained as a white solid, MS: m/e=270.1, 272.1 (M+H+).
Reaction SMILES: C([O:4][C:5]1[CH:10]=CC(OC(=O)C)=[CH:7][C:6]=1[O:15]C(=O)C)(=O)C.[CH2:19]([CH:26]([C:32]([CH3:34])=O)[C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.S(=O)(=O)(O)O>>[OH:4][C:5]1[CH:10]=[C:31]2[C:30](=[CH:7][C:6]=1[OH:15])[O:29][C:27](=[O:28])[C:26]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[C:32]2[CH3:34]
Reactant: CCOC(=O)C(Cc1ccccc1)C(C)=O
Reactant: CC(=O)Oc1ccc(OC(C)=O)c(OC(C)=O)c1
Agent: O=S(=O)(O)O
Product: Cc1c(Cc2ccccc2)c(=O)oc2cc(O)c(O)cc12
Temperature: 0 °C
Reaction time: 16 h

Procedure:
1,2,4-triacetoxybenzene (6.3 g, 25 mmol) and ethyl 2-benzylacetoacetate (5.5 g, 25 mmol) were heated together as described in Example 1. 75% sulphuric acid (35 ml) was added to the stirred solution and stirring continued for 16 hours. The dark coloured suspension was poured into ice/water (350 ml) with good stirring and the grey suspension filtered and the residue washed with abundant water. The residual solid was air dried and recrystallised from hot ethanol with subsequent addition of a little water to aid crystallisation. The esculetin derivative formed small white needles (5.5 g, 75.3%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][OH:19])[CH2:14][CH2:13]1.CS(C)=O.[H-].[Na+]>O>[CH3:11][N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][O:19][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:14][CH2:13]1
Reactant: CN1CCC(CO)CC1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CN1CCC(COc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 70 °C
Reaction time: 3 h
Yield: 83.1 %

Procedure:
A mixture of 1-chloro-4-nitrobenzene (23) (2.37 g, 15.0 mmol), alcohol 22 (1.94 g, 15.0 mmol), and DMSO (25 mL) was treated portionwise with NaH (60% in mineral oil, 660 mg, 16.5 mmol) at 40° C. The mixture was stirred at 70° C. for 3 h, poured into water (150 mL), and extracted with Et2O (5×100 mL). The combined organic fractions were washed with water (250 mL) and brine (250 mL), dried (MgSO4), and the solvent was removed in vacuo. The resulting solid was recrystallized from Et2O to give 24 (3.12 g, 83%) as yellow needles. 1H NMR (300 MHz, CDCl3): δ=1.36-1.56 (m, 2 H, 3-Hax, 5-Hax), 1.75-1.91 (m, 3 H, 3-Heq, 4-H, 5-Heq), 1.98 (dt, J=11.9, 1.9 Hz, 2 H, 2-Hax, 6-Hax), 2.30 (s, 3 H, NMe), 2.85-2.98 (m, 2 H, 2-Heq, 6-Heq), 3.90 (d, J=5.8 Hz, 2 H, OCH2), 6.94 (mc, 2 H, 2′-H, 6′-H), 8.19 (mc, 2 H, 3′-H, 5′-H) ppm. —13C NMR (50.3 MHz, CDCl3): δ=28.9 (C-3, C-5), 35.1 (C-4), 46.4 (NMe), 55.3 (C-2, C-6), 73.3 (OCH2), 114.3 (C-2′, C-6′), 125.8 (C-3′, C-5′), 141.3 (C-4′), 164.1 (C-1′) ppm. −MS (70 eV, EI): m/z (%)=250 (79) [M]+, 249 (100) [M−H]+. —C13H18N2O3 (250.29): calcd. C, 62.38; H, 7.25; found C, 62.25; H, 7.40.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18]([OH:20])=O)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH2:26]>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=[O:20])[NH:26][C:25]3[CH:27]=[CH:28][CH:29]=[C:23]([O:22][CH3:21])[CH:24]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: O=C(O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Reactant: COc1cccc(N)c1
Product: COc1cccc(NC(=O)CC2CCc3cc(Br)cc4[nH]c(=O)c(=O)n2c34)c1
Yield: 96.8 %

Procedure:
A procedure similar to that described in Example 5 was carried out with 9-bromo-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (150 mg, 0.442 mmol) and m-methoxyaniline (76 mg, 0.62 mmol) to give 190 mg of the title compound (95%): mp 151°~154° C.; 1H NMR (270 MHz, DMSO-d6) δ12.07 (s, 1H), 10.00 (s, 1H), 7.27 (d, 1H, J=2 Hz), 7.24 (bs, 1H), 7.20 (t, 1H, J=8.1 Hz), 7.16 (bs, 1H), 6.64 (dd, 1H, J=8.1, 2 Hz), 6.88 (d, 2H, J =9 Hz), 5.16~5.17 (m, 1H), 3.72 (s, 3H), 3.05 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.82 (dm, 1H, J=16.8 Hz), 2.55~2.65 (m, 2H), 2.09 (dm, 1H, J=13.5 Hz), 1.80~1.96 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[O:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][OH:18])[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:28]1[O:29][C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[N:32]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[O:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][O:18][C:28]3[O:29][C:30]4[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=4[N:32]=3)[CH2:12][CH2:11]2)=[CH:6][CH:7]=1
Reactant: Clc1nc2ccccc2o1
Reactant: OCCN1CCC(OC(c2ccc(Cl)cc2)c2ccccn2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Clc1ccc(C(OC2CCN(CCOc3nc4ccccc4o3)CC2)c2ccccn2)cc1
Yield: 35 %

Procedure:
To a solution of 2.35 g (6.78 mmol) of 2-[4-[(4-chlorophenyl)-2-pyridylmethoxy]-1piperidyl]ethanol obtained in Example 10 dissolved in 20 ml of toluene was added 0.53 g (13.25 mmol) of sodium hydride (60% dispersion in mineral oil), and 1.25 g (8.14 mmol) of 2-chlorobenzoxazole was added to the mixed solution. The mixture stirred under reflux for 7 hours. After the reaction, the insolubles were filtered off, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography using a mixture of chloroform and methanol in the volume ratio of 40:1 as the developing solvent. The desired fractions was concentrated under reduced pressure to give 1.10 g (35%) of 2-[2-[4-[(4-chlorophenyl)-2-pyridylmethoxy]-1-piperidyl]ethoxy]benzoxazole as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)[CH:5]=[CH:6][C:7]=1[F:8].[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(O)(=[O:41])C>CC(O)(C)C.C(O)C.C(O)(=O)C.[Zn]>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:41])[NH:13]3)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(=O)O
Reactant: Fc1ccc(-c2cccc3[nH]ccc23)cc1Cl
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CC(C)(C)O
Solvent: CCO
Product: O=C1Cc2c(cccc2-c2ccc(F)c(Cl)c2)N1
Temperature: 27 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
To the suspension of 4-(3-chloro-4-fluoro-phenyl)-1H-indole (2.03 g, 8.26 mmol) in t-BuOH-ethanol-acetic acid (3:2:1) (99 mL) was added pyridinium tribromide (7.93 g, 24.79 mmol)) portionwise. The mixture was stirred at 27° C. for 3 hours, and then to the mixture was added acetic acid (40 mL). Zinc dust was added to the reaction mixture portionwise until the color changed from deep red to light yellow, and the reaction mixture was stirred at room temperature for one hour. The unreacted zinc dust was filtered off and washed with ethanol. The filtrate was concentrated, and the syrupy residue was dissolved in ethyl acetate, which was washed with water, 0.5 N HCl, sat. NaHCO3 and brine, and dried over Na2SO4. After filtration and evaporation, the crude product was triturated with diethyl ether to provide product 4-(3-chloro-4-fluoro-phenyl)-1,3-dihydro-indol-2-one (1.39 g, 64%) as a tan solid.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[C:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1.[H-].[Na+].Cl[CH2:20][S:21][CH3:22]>CN(C=O)C>[CH3:20][S:21][CH2:22][N:1]1[C:9]2[CH:8]=[C:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1
Reactant: CSCCl
Reactant: CC(C)(C)OC(=O)c1cc2[nH]ccc2cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSCn1ccc2cnc(C(=O)OC(C)(C)C)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.7 %

Procedure:
To a mixture of tert-butyl 1H-pyrrolo[3,2-c]pyridine-6-carboxylate (1.0 g, 4.6 mmol) in DMF (20 ml) was added sodium hydride (60% in oil) (0.41 g, 10 mmol) and stirred at room temperature for 3 h. To the mixture, (chloromethyl)(methyl)sulfane (0.89 g, 9.2 mmol) was added and stirred at room temperature for 2 h. The reaction mixture was extracted with EtOAc/H2O. The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. The crude mixture was purified by chromatography (SiO2, hexanes:EtOAc=50:50) to give tert-butyl 1-(methylthiomethyl)-1H-pyrrolo[3,2-c]pyridine-6-carboxylate (8A, 920 mg, 3.3 mmol, 72% yield) as a yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.61 (s, 9 H) 1.94 (s, 3 H) 5.15 (s, 2 H) 6.64 (d, J=3.28 Hz, 1 H) 7.34 (d, J=3.28 Hz, 1 H) 8.15 (s, 1 H) 8.93 (d, J=1.01 Hz, 1 H).
Reaction SMILES: [C:1]1(=[O:17])[C:10]2[C:5](=[CH:6][C:7]([O:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[Br:18]Br>C(Cl)(Cl)Cl>[Br:18][CH:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[C:7]([O:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:6]=2)[C:1]1=[O:17]
Reactant: BrBr
Reactant: COC(=O)COc1ccc2c(c1)CCCC2=O
Solvent: ClC(Cl)Cl
Product: COC(=O)COc1ccc2c(c1)CCC(Br)C2=O
Reaction time: 4 h

Procedure:
To a solution of the product from step (ii) (1.3 g) in chloroform (15 ml) was added dropwise a solution of bromine (0.29 ml) in chloroform (1 ml) and the resulting mixture was stirred for 4 hours. The solvent was evaporated to give an oil. Purification by flash column chromatography on silica, eluting with ethyl acetate/hexane (30:70 v/v) gave methyl 2-bromotetralone-6-oxyacetate (1.55 g) as an oil: NMR (d6DMSO) δ 2.3-2.6(m,2H), 2.9-3.1(m,2H), 3.7(s,3H), 4.9(s,2H), 4.9-5.0(m,1H), 6.9-7.0(m,2H), 7.9(d,1H); m/e 313/315(M+H)+ Br pattern.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[OH-].[K+].Br[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:19][C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:21])[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CN1CCc2c(c3cc(Cl)ccc3n2CC(=O)c2ccccc2)C1
Reaction time: 8 h
Yield: 17.7 %

Procedure:
8-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (220 mg, 10 mmol) was dissolved in NMP (2 mL). KOH (560 mg, 0.010 mol) was then added, followed by addition of 2-bromoacetophenone (199 mg, 0.001 mol). The reaction was kept overnight at RT and was monitored by TLC & LC/MS. The reaction was quenched by adding water, and extracted using EtOAc, which was then washed with water (2-3×). The organic layer was dried over sodium sulfate and then concentrated to yield 60 mg of dark brown crude oil that was purified by column chromatography using 100-200 mesh silica gel with 4% MeOH:DCM as eluent. 1HNMR (CDCl3, TFA salt) d (ppm): 8.0 (m, 2H), 7.70 (m, 1H), 7.60 (m, 2H), 7.40 (d, 1H), 7.20 (m, 1H), 7.05 (m, 1H), 5.60 (m, 1H), 5.38 (m, 1H), 4.80 (m, 1H), 4.20 (m, 1H), 3.90 (m, 1H), 3.40 (m, 2H), 3.05 (s, 3H), 1.90 (m, 1H).
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:6]=[C:7]([P:15](=[O:22])([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])[CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12].C([O-])(O)=O.[Na+]>C(O)(=O)C>[Br:1][C:6]1[C:5]([O:4][CH3:3])=[C:10]([O:11][CH3:12])[C:9]([O:13][CH3:14])=[CH:8][C:7]=1[P:15](=[O:22])([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18]
Reactant: BrBr
Reactant: CCOP(=O)(OCC)c1cc(OC)c(OC)c(OC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOP(=O)(OCC)c1cc(OC)c(OC)c(OC)c1Br

Procedure:
A solution of bromine (10 mmol) in 10 mL of acetic acid is added dropwise to a solution of ester 11 (10 mmol) in 10 mL of acetic acid cooled by an ice water bath. After the red color of the resulting mixture is discharged, the mixture is poured into saturated NaHCO3 (100 mL) and extracted with ethyl acetate (3×100 mL). The combined organic phases are washed with 100 mL portions of 5% NaHCO3 until no further gas evolution is apparent. The organic phases are then washed with brine (100 mL), dried over anhydrous MgSO4, and concentrated in vacuo. The mixture is purified by flash chromatography to give the product as a pale yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[Cl:42][C:43]1[CH:44]=[CH:45][C:46]([O:53][CH3:54])=[C:47]([S:49](Cl)(=[O:51])=[O:50])[CH:48]=1>C(#N)C>[CH3:54][O:53][C:46]1[CH:45]=[CH:44][C:43]([Cl:42])=[CH:48][C:47]=1[S:49]([O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34])(=[O:51])=[O:50]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(Cl)cc1S(=O)(=O)Oc1ccc(-c2cc3cc(CN4CCCCC4)ccc3n2C(=O)OC(C)(C)C)c2c1CNC2=O
Yield: 42.7 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0279 g, 0.0604 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0540 mL, 0.390 mmol) and 5-chloro-2-methoxybenzenesulfonyl chloride (0.0470 g, 0.195 mmol) to obtain 4-(2-methoxy-5-chlorobenzenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0172 g, yield 434).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([C:11]#[C:12][Si](C(C)C)(C(C)C)C(C)C)[C:6]3[CH2:23][CH2:24][N:25]([CH3:27])[CH2:26][C:5]=3[C:4]=2[CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([C:11]#[CH:12])[C:6]3[CH2:23][CH2:24][N:25]([CH3:27])[CH2:26][C:5]=3[C:4]=2[CH:3]=1
Reactant: CC(C)[Si](C#Cn1c2c(c3cc(Cl)ccc31)CN(C)CC2)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: C#Cn1c2c(c3cc(Cl)ccc31)CN(C)CC2
Temperature: 0 °C
Reaction time: 1 h
Yield: 143 %

Procedure:
To a cooled solution of 8-chloro-2-methyl-5-((triisopropylsilyl)ethynyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (8.0 g, 0.02 mol) in THF (100 mL) was added tetrabutylammonium fluoride solution (1.0M in THF, 40 mL, 0.04 mol) at 0° C. over 15 min. The reaction mixture was stirred for 1 h at 0° C., after completion of reaction (monitored by TLC), the mixture was diluted with water (100 mL) and extracted with EtOAc (3×100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduce pressure to obtain product as a brown colored oil (7.0 g).
Reaction SMILES: [CH:1]1([C:6](=O)[CH2:7][C:8]#[N:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.O.[NH2:12][NH2:13]>C(O)C>[CH:1]1([C:6]2[CH:7]=[C:8]([NH2:9])[NH:12][N:13]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NN
Reactant: N#CCC(=O)C1CCCC1
Solvent: O
Solvent: CCO
Product: Nc1cc(C2CCCC2)n[nH]1
Temperature: 80 °C
Yield: 46.2 %

Procedure:
To a solution of 3-cyclopentyl-3-oxo-propionitrile (1.0 g, 7.3 mmol, 1 eq) in ethanol (10 mL) was added a 64 wt.-% solution of hydrazine hydrate (1.1 mL, 14.6 mmol, 2 eq). The mixture was heated at 80° C. for 16 h and was evaporated to dryness. The residue was purified by flash chromatography using dichloromethane and methanol (100/0 to 90/10) to afford 5-cyclopentyl-2H-pyrazol-3-ylamine as yellow oil (510 mg, 46% yield).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][S:24](=[O:27])[CH2:23][CH2:22]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:6]=2[N:7]=1.[NH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[O:27]=[S:24]1[CH2:25][CH2:26][N:21]([C:4]2[C:5]3[N:11]=[CH:10][N:9]=[C:8]([S:12][CH2:13][CH2:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:6]=3[N:7]=[C:2]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[N:3]=2)[CH2:22][CH2:23]1
Reactant: O=S1CCN(c2nc(Cl)nc3c(SCCc4ccccc4)ncnc23)CC1
Reactant: C1CNCCN1
Product: O=S1CCN(c2nc(N3CCNCC3)nc3c(SCCc4ccccc4)ncnc23)CC1

Procedure:
This compound was prepared analogous to Example 1 from 2-chloro-4-(1-oxido-thiomorpholino)-8-phenethylthio-pyrimido-[5,4-d]-pyrimidine (m.p.: 232°-234° C.) and piperazine.