Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][CH2:5][N:6]1[C:18]2[CH2:17][CH2:16][C@@H:15]([NH:19][S:20]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH2:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)([OH:3])=[O:2].S(=O)(=O)(O)O.C(=O)([O-])O.[Na+].O.[CH2:40](O)[CH3:41]>>[CH2:40]([O:2][C:1]([CH2:4][CH2:5][N:6]1[C:18]2[CH2:17][CH2:16][C@@H:15]([NH:19][S:20]([C:23]3[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=3)(=[O:21])=[O:22])[CH2:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)=[O:3])[CH3:41]
Reactant: CCO
Reactant: O=C(O)CCn1c2c(c3ccccc31)C[C@H](NS(=O)(=O)c1ccncc1)CC2
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CCOC(=O)CCn1c2c(c3ccccc31)C[C@H](NS(=O)(=O)c1ccncc1)CC2
Temperature: 25 °C

Procedure:
0.9 g (2.3 mmol) of 9-(2-carboxyethyl)-3(R)-(4-pyridylsulphonamido)-1,2,3,4-tetrahydrocarbazole is dissolved in 50 ml of ethanol p.a., 3 ml of concentrated sulphuric acid are added and the mixture is boiled under reflux for 1.5 hours with stirring. After cooling to room temperature, 12.0 g of sodium hydrogen carbonate are added, water is added after the evolution of gas has ended and the mixture is extracted several times with ethyl acetate. The combined organic phases are dried with sodium sulphate and the solvent evaporated therefrom. The crude product is purified by chromatography on silica gel 60 (40-63 μm, Merck, eluant: CH2Cl2 :CH3OH=10:1). Rf =0.63 (CH2Cl2 :CH3OH=10:1)
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[S:8][CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13].CC(C)([O-])C.[K+]>CN(C=O)C.CCOCC>[N+:12]([C:11]1[CH:10]=[CH:9][S:8][C:7]=1[N:1]1[CH:5]=[N:4][CH:3]=[N:2]1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1ccsc1Cl
Reactant: c1nc[nH]n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=[N+]([O-])c1ccsc1-n1cncn1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
1H-1,2,4-triazole (582 mg, 8.43 mmol), 2-chloro-3-nitrothiophene (1.15 g, 7.03 mmol) and potassium t-butoxide (944 mg, 8.43 mmol) were dissolved in DMF (30 mL). The resulting solution was stirred at 90° C. for 2 h, after which the reaction mixture was cooled to room temperature and diluted with Et2O. The solution was washed with brine and the organic phase was separated, dried (Na2SO4), filtered, concentrated under vacuum to give 1-(3-nitrothiophen-2-yl)-1H-1,2,4-triazole. Retention time (min)=1.073, method [1], MS(ESI) 197.0 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:24][C:25]1[CH:31]=[C:30]([S:32]([CH3:35])(=[O:34])=[O:33])[CH:29]=[CH:28][C:26]=1[NH2:27]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([NH:27][C:26]4[CH:28]=[CH:29][C:30]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:31][C:25]=4[F:24])=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)c1ccc(N)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Nc4ccc(S(C)(=O)=O)cc4F)ncnc32)CC1

Procedure:
4-[4-(2-Fluoro-4-methanesulfonyl-phenylamino)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester was prepared according to General Procedure C by the reaction of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19) with 2-fluoro-4-(methylsulfonyl)aniline (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA). 1H NMR (400 MHz, DMSO-d6) δ 1.43 (s, 9H), 1.90-2.00 (m, 4H), 2.95-3.05 (m, 2H), 3.30 (methyl sulfonyl and water peak), 4.03-4.09 (m, 2H), 4.90-4.93 (m, 1H), 7.79-7.81 (m, 1H), 7.88-7.91 (m, 1H), 8.21-8.24 (m, 1H), 8.40-8.42 (m, 2H), 10.36 (s, 1H). Mass spectrum MH+=491.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][CH:36]1[CH2:40][CH2:39][CH2:38][O:37]1.CN(C)C=O>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:35][CH:36]2[CH2:40][CH2:39][CH2:38][O:37]2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: BrCC1CCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(CC2CCCO2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.22 g), potassium carbonate (0.94 g), 2-(bromomethyl)tetrahydrofuran (0.56 g) and N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless viscous substance (0.94 g, 55%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8](O)=[N:7][C:6]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[CH:5][C:4]=2[N:3]=1.P(Cl)(Cl)([Cl:23])=O>>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[N:7][C:8]=2[Cl:23])[N:3]=1
Reactant: COc1ccc(-c2cc3nc(Cl)ccc3c(O)n2)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc(-c2cc3nc(Cl)ccc3c(Cl)n2)cc1
Yield: 96.2 %

Procedure:
2-Chloro-7-(4-methoxyphenyl)-[1,6]naphthyridin-5-ol (135 mg, 0.47 mmol) was dissolved in phosphorus oxychloride (2 mL, 21.5 mmol) and refluxed for 3 hours. An orange solid precipitated. The reaction mixture was diluted with dichloromethane (25 mL) and concentrated to an orange solid. The solid was re-dissolved in EtOAc (300mL) and washed with saturated sodium bicarbonate solution (100 mL), brine (100 mL) and dried over magnesium sulfate. Filtration and concentration yielded 2,5-dichloro-7-(4-methoxy-phenyl)-[1,6]naphthyridine (138 mg, 86%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][CH2:15][C@H:14]([NH:18]C(=O)OC(C)(C)C)[CH2:13]3)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.Cl.O1CCOCC1>CO>[NH2:18][C@H:14]1[CH2:15][CH2:16][CH2:17][N:12]([C:10]2[CH:9]=[CH:8][C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=3[N:11]=2)[CH2:13]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccc3ncnc(N)c3n2)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Nc1ncnc2ccc(N3CCC[C@H](N)C3)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 107.5 %

Procedure:
To a 40 mL screw-cap vial was added tert-butyl N-[(3S)-1-(4-aminopyrido[3,2-d]pyrimidin-6-yl)-3-piperidyl]carbamate 43 (2.53 g, 7.35 mmol) followed by methanol (7 mL), then HCl in dioxane (4 mol/L, 7.5 equiv., 55.1 mmol, 13.8 mL). The reaction was stirred at room temperature for 2 hours. Resulting precipitate was collected by filtration, and washed 2× with ethyl acetate, yielding 1.93 g of product as an orange solid, 3×HCl salt. 25 mg was purified by reverse phase HPLC, yielding 5 mg of neutralized product. 1H NMR (400 MHz, DMSO) δ 8.17-8.13 (s, 1H), 7.77-7.73 (d, J=9.3 Hz, 1H), 7.46-7.39 (d, J=9.4 Hz, 1H), 7.39-7.07 (s, 2H), 4.48-4.26 (m, 2H), 3.03-2.90 (m, 1H), 2.73-2.62 (m, 2H), 1.93-1.82 (m, 1H), 1.82-1.67 (m, 1H), 1.52-1.36 (m, 1H), 1.34-1.16 (m, 1H). LCMS M?Z (M+H)=245.
Reaction SMILES: O1CCCC1.C([N-]C(C)C)(C)C.[Li+].[Cl:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[Cl:25])[N:21]=[C:20]([O:26][CH3:27])[C:19]([O:28][CH3:29])=[N:18]2.[B:30](OC)([O:33]C)[O:31]C.Cl>O1CCCC1.O>[Cl:25][C:24]1[C:15]([Cl:14])=[CH:16][C:17]2[N:18]=[C:19]([O:28][CH3:29])[C:20]([O:26][CH3:27])=[N:21][C:22]=2[C:23]=1[B:30]([OH:33])[OH:31]
Reactant: COB(OC)OC
Reactant: COc1nc2cc(Cl)c(Cl)cc2nc1OC
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1nc2cc(Cl)c(Cl)c(B(O)O)c2nc1OC
Reaction time: 1 h
Yield: 26.1 %

Procedure:
Lithium diisopropylamide mono(tetrahydrofuran) (1.5M in cyclohexane, 6.18 mL, 9.26 mmol) was added to a stirred suspension of 6,7-dichloro-2,3-dimethoxyquinoxaline (Preparation 1, 2.0 g, 7.72 mmol) in dry tetrahydrofuran (150 mL) at −78° C., under nitrogen. After 1 hour at −78° C., trimethyl borate (1.47 mL, 2.0 g, 19.3 mmol) was added. The solution was stirred for a further 1 hour and then left to reach room temperature over 18 hours. Water (50 mL) was added, the solution was acidified to pH 1 with 2M aqueous hydrochloric acid solution and extracted with dichloromethane (3×150 mL). The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, by gradient elution using dichloromethane:methanol (100:0 changing to 99:1, by volume) as the eluent to afford 6,7-dichloro-2,3-dimethoxyquinoxaline-5-boronic acid (0.610 g, 26%) as a light brown solid.
Reaction SMILES: [NH:1]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@@H:2]([C:4]([N:6]([CH3:21])[C@H:7]([C:12](CC1C=CC=CC=1)=[O:13])[CH2:8][CH:9]([CH3:11])[CH3:10])=[O:5])[CH3:3].C([OH:31])C>>[NH:1]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@@H:2]([C:4]([N:6]([CH3:21])[C@H:7]([C:12]([OH:13])=[O:31])[CH2:8][CH:9]([CH3:10])[CH3:11])=[O:5])[CH3:3]
Reactant: CC(C)C[C@@H](C(=O)Cc1ccccc1)N(C)C(=O)[C@@H](C)NC(=O)OC(C)(C)C
Reactant: CCO
Product: CC(C)C[C@@H](C(=O)O)N(C)C(=O)[C@@H](C)NC(=O)OC(C)(C)C

Procedure:
32.45 g (79.92 m mol) BOC-(D)-Ala-MeLeu-Bzl in 800 ml ethanol containing 1.6 g 10% palladium/charcoal are debenzylated by hydrogenation for 2 hours at room temperature. After uptake of the calculated quantity of hydrogen the suspension is filtered through talc, the solvent evaporated off and the residue crystallised from hexane to yield the title compound with a rotation of [α]D25 =-36.7° (c=0.8 in chloroform).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[N:6][CH:7]=1.[C:12]1([C:18]#[CH:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C1COCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:11][S:8]([C:5]1[N:4]=[CH:3][C:2]([C:19]#[C:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][N:6]=1)(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1ncc(Br)cn1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ncc(C#Cc2ccccc2)cn1
Temperature: 65 °C
Reaction time: 4 h
Yield: 56.9 %

Procedure:
Bis-(triphenylphosphine)-palladium(II)dichloride (1.48 g, 2.11 mmol, 0.05 equiv.) was dissolved in 200 ml THF. (10 g, 42.2 mmol) 5-Bromo-2-(methylsulfonyl)pyrimidine and phenylacetylene (9.26 ml, 84.4 mmol, 2 equiv.) were added at room temperature. Triethylamine (17.6 ml, 127 mmol, 3 equiv.), triphenylphosphine (330 mg, 1.3 mmol, 0.03 equiv.) and copper(I)iodide (80 mg, 420 μmol, 0.01 equiv.) were added and the mixture was stirred for 4 hours at 65° C. The reaction mixture was cooled and extracted with saturated NaHCO3 solution and two times with EtOAc. The organic layers were extracted with water, dried over sodium sulfate and evaporated to dryness. The crude product was purified by flash chromatography on a silica gel column and eluting with an ethyl acetate:heptane gradient 0:100 to 100:0. The desired 2-methanesulfonyl-5-phenylethynyl-pyrimidine (6.2 g, 57% yield) was obtained as a yellow solid, MS: m/e=259.1 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][N:7]([CH:9]2[CH2:12][CH2:11][CH:10]2[CH2:13][N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:8]=1)([O-])=O.[F:19][C:20]1[CH:21]=[C:22]([CH2:27][C:28]([NH:30][CH:31]([CH2:35][CH2:36][CH3:37])[C:32](O)=[O:33])=[O:29])[CH:23]=[C:24]([F:26])[CH:25]=1>>[N:14]1([CH2:13][CH:10]2[CH2:11][CH2:12][CH:9]2[N:7]2[CH:8]=[C:4]([NH:1][C:32](=[O:33])[C@@H:31]([NH:30][C:28](=[O:29])[CH2:27][C:22]3[CH:23]=[C:24]([F:26])[CH:25]=[C:20]([F:19])[CH:21]=3)[CH2:35][CH2:36][CH3:37])[N:5]=[CH:6]2)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=[N+]([O-])c1cn(C2CCC2CN2CCCC2)cn1
Reactant: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Product: CCC[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C2CCC2CN2CCCC2)cn1

Procedure:
4-Nitro-1-(2-pyrrolidin-1-ylmethyl-cyclobutyl)-1H-imidazole was reduced and then coupled with 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid (U.S. Ser. No. 11/078,898 filed Mar. 11, 2005) to afford the title compound: MS 474.6 m/z (M+1).
Reaction SMILES: C(Cl)(C(Cl)=O)=O.[C:7]([OH:34])(=O)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].[NH2:35][C@@H:36]([C@@H:49]([OH:66])[C@@H:50]([OH:65])[CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH3:64])[CH2:37][O:38][C@@H:39]1[CH2:45][CH2:44][CH2:43][C@H:42]([OH:46])[C@H:41]([OH:47])[C@H:40]1[OH:48]>C1COCC1.CC([O-])=O.[Na+]>[OH:66][C@@H:49]([C@@H:50]([OH:65])[CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH3:64])[C@H:36]([NH:35][C:7](=[O:34])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:37][O:38][C@H:39]1[CH2:45][CH2:44][CH2:43][C@H:42]([OH:46])[C@H:41]([OH:47])[C@H:40]1[OH:48]
Reactant: CCCCCCCCCCCCCC[C@H](O)[C@H](O)[C@H](N)CO[C@@H]1CCC[C@H](O)[C@H](O)[C@H]1O
Reactant: CCCCCCCCCCCCCCCCCCCCCCCCCC(=O)O
Agent: CC(=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCCCCCCCCC(=O)N[C@H](CO[C@H]1CCC[C@H](O)[C@H](O)[C@H]1O)[C@@H](O)[C@@H](O)CCCCCCCCCCCCCC
Temperature: 70 °C

Procedure:
(COCl)2 (2 mL) was added to hexacosanoic acid (139 mg, 0.39 mmol) and heated at 70° C. for 2 h, after which time the solution was cooled to rt, and the (COCl)2 removed under a stream of dry argon. The residual volatiles were removed under reduced pressure. The resulting crude acyl chloride was dissolved in THF (0.5 mL) and added with vigorous stirring to a solution of amine 72 (81 mg, 0.18 mmol) in THF/NaOAc(aq) (8M) (1:1, 2 mL). Vigorous stirring was maintained for 2 h, after which time the reaction mixture was left to stand and the layers were separated. The aqueous layer was extracted with THF (3×2.0 mL) and the organic layers were combined and concentrated under reduced pressure. The crude product was purified by column chromatography (10% MeOH in CHCl3) to give amide 73 as a white solid.
Reaction SMILES: [C:1]([NH:4][CH:5]([CH3:8])[CH2:6][NH2:7])(=[O:3])[CH3:2].C(N(CC)CC)C.[CH:16]1[C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([S:26](Cl)(=[O:28])=[O:27])[C:20]=2[CH:19]=[CH:18][N:17]=1>C(Cl)(Cl)Cl>[C:1]([NH:4][CH:5]([CH3:8])[CH2:6][NH:7][S:26]([C:21]1[C:20]2[CH:19]=[CH:18][N:17]=[CH:16][C:25]=2[CH:24]=[CH:23][CH:22]=1)(=[O:27])=[O:28])(=[O:3])[CH3:2]
Reactant: CC(=O)NC(C)CN
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(=O)NC(C)CNS(=O)(=O)c1cccc2cnccc12
Reaction time: 2 h
Yield: 82.9 %

Procedure:
In 50 ml of a chloroform solution containing 2.0 g of 2-acetylaminopropylamine and 2.6 g of triethylamine was added dropwise 50 ml of a chloroform solution containing 3.28 g of 5-isoquinolinesulfonyl chloride under cooling with ice. The mixed solution was stirred at a temperature of 15° C. to 25° C. for two hours, and then the reaction solution was washed with water and dried with anhydrous sodium sulfate. The chloroform was distilled therefrom under reduced pressure. The crystalline residue thus obtained was recrystallized from methanol to give 3.67 g of N-(2-acetylaminopropyl)-5-isoquinolinesulfonamide in a yield of 83%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2/[C:10](=[CH:18]/[C:19]2[NH:20][CH:21]=[CH:22][CH:23]=2)/[C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.CCN(CC)CC.[F:31][S:32]([C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=[O:40])=[CH:37][CH:36]=1)(=[O:34])=[O:33]>C(Cl)(Cl)Cl>[O:17]=[C:11]1[NH:12][C:13]2[C:9](/[C:10]/1=[CH:18]/[C:19]1[NH:20][CH:21]=[CH:22][CH:23]=1)=[C:8]([C:4]1[CH:3]=[C:2]([NH:1][C:39](=[O:40])[C:38]3[CH:42]=[CH:43][C:35]([S:32]([F:31])(=[O:34])=[O:33])=[CH:36][CH:37]=3)[CH:7]=[CH:6][CH:5]=1)[CH:16]=[CH:15][CH:14]=2
Reactant: Nc1cccc(-c2cccc3c2/C(=C/c2ccc[nH]2)C(=O)N3)c1
Reactant: O=C(Cl)c1ccc(S(=O)(=O)F)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C1Nc2cccc(-c3cccc(NC(=O)c4ccc(S(=O)(=O)F)cc4)c3)c2/C1=C/c1ccc[nH]1
Temperature: -78 °C
Reaction time: 1 h
Yield: 52.5 %

Procedure:
A solution of (Z)-4-(3-aminophenyl)-1,3-dihydro-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (30 mg, 0.100 mmol) (from Example 4 supra) and Et3N (14 μL, 0.100 mmol) in 5 mL of chloroform was cooled to −78° C. and then treated with 4-(fluorosulfonyl)benzoyl chloride (24 mg, 0.109 mmol) (Aldrich). The reaction mixture was stirred at −78° C. under a nitrogen atmosphere for 1 hr and then heated at reflux. The reaction mixture was allowed to cool to room temperature and then diluted with chloroform. The organic phase was then washed, in sequence, as follows: with a saturated aqueous sodium bicarbonate solution, with distilled water, with a 1N aqueous hydrochloric acid solution, and finally with a saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 30% ethyl acetate-hexanes elution) yielded pure (Z)-N-[3-[2,3-dihydro-2-oxo-3-[(1H-pyrrol-2-yl)methylene]-1H-indol-4-yl]-phenyl]-4-(fluorosulfonyl)benzamide (yield: 25.6 mg, 53%) as a yellow solid (mp: 148-151° C.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:18])=[C:6]([C:8](=[O:17])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[CH:7]=1.[C:19]([O-])(=O)[CH3:20].[Na+]>C(OC(=O)C)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:18][C:19]([CH3:20])=[C:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16])[C:8]2=[O:17]
Reactant: O=C(Cc1ccccc1F)c1cc(Br)ccc1O
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: Cc1oc2ccc(Br)cc2c(=O)c1-c1ccccc1F
Temperature: 25 °C
Yield: 70.7 %

Procedure:
Intermediate 23 (5 g, 16.17 mmoles) was taken in a RB flask and to this acetic anhydride (40 ml) and sodium acetate (9.2 g, 82.03 mmoles) were added and the mixture was refluxed for 12 h. After cooling to RT, the reaction mixture was quenched by the addition of ice cold water. The solid formed was filtered and washed with water. The product was dried under vacuum to afford the title compound as off-white solid (3.81 g, 71% yield). 1H-NMR (δ ppm, CDCl3, 400 MHz): δ 8.34(d, J=2.3Hz, 1H), 7.76(dd, J=8.8, 2.2Hz, 1H), 7.41(m, 2H), 7.24(m, 2H), 7.18(t, J=8.9Hz, 1H), 2.30(s, 3H).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7](=[O:15])[C@@H:6]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:5]1.[CH3:24]I>C1COCC1>[CH3:24][N:8]1[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:4]([CH3:3])[CH2:5][C@H:6]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21])[C:7]1=[O:15]
Reactant: CN1C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc2ccccc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1C[C@H](NC(=O)OC(C)(C)C)C(=O)N(C)c2ccccc21
Yield: 115.2 %

Procedure:
36 mg of sodium hydride in suspension at 60% in oil (0.90 mmol) are introduced at −10° C. into a 50 mL round-bottomed flask, with stirring and under an argon atmosphere, containing 10 mL of THF and 265 mg of 11 (0.91 mmol). The medium is stirred for 1 h, and then 148 mg (1.04 mmol) of methyl iodide are added. The medium is kept stirring at RT for 24 h. The mixture is concentrated, and 320 mg of crude product are obtained, which product is chromatographed on a silica cartridge (50 g, eluent heptane/AcOEt—in an AcOEt gradient: 10 to 50%). 235 mg of expected product 17 are recovered.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24]Br)[CH:6]=1.[CH3:27][C@@H:28]1[C@H:32]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:31][C:30](=[O:39])[NH:29]1>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][N:29]2[C@H:28]([CH3:27])[C@H:32]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[O:31][C:30]2=[O:39])[CH:6]=1
Reactant: C[C@H]1NC(=O)O[C@H]1c1ccccc1
Reactant: COC(=O)Cc1ccc(OC)c(Oc2ccc(C(F)(F)F)cc2CBr)c1
Product: COC(=O)Cc1ccc(OC)c(Oc2ccc(C(F)(F)F)cc2CN2C(=O)O[C@@H](c3ccccc3)[C@H]2C)c1

Procedure:
Prepared according to the procedure described in Example 6, Step 5, using the following starting materials: [3-(2-bromomethyl-4-trifluoromethyl-phenoxy)-4-methoxy-phenyl]-acetic acid methyl ester and (4R,5S)-4-methyl-5-phenyl-2-oxazolidinone.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[N+:9]([O-])([OH:11])=[O:10]>>[OH:1][C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1
Reactant: Cc1ccc(O)cn1
Reactant: O=[N+]([O-])O
Product: Cc1ccc(O)c([N+](=O)[O-])n1
Temperature: 6 °C

Procedure:
To 40 ml. of ice cold concentrated sulfuric acid was added 10.9 g. of 3-hydroxy-6-methylpyridine. Maintaining the temperature at 6° C., 4.7 ml. of fuming nitric acid was added dropwise with stirring. The mixture was allowed to warm to room temperature overnight. Ice (200 g.) was added with stirring. After the ice had melted, the precipitate was collected, washed with water and dried to give 3-hydroxy-6-methyl-2-nitropyridine, m.p. 103°-105° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:23])[N:7]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:8]([CH3:14])=[N:9]2.[C:24]([CH2:28][C:29](Cl)=[O:30])([CH3:27])([CH3:26])[CH3:25].C(N(CC)C(C)C)(C)C>C(#N)C>[O:22]=[C:16]1[CH:15]([N:7]2[C:6](=[O:23])[C:5]3[C:10](=[CH:11][CH:12]=[CH:13][C:4]=3[CH2:3][NH:2][C:29](=[O:30])[CH2:28][C:24]([CH3:27])([CH3:26])[CH3:25])[N:9]=[C:8]2[CH3:14])[CH2:20][CH2:19][C:18](=[O:21])[NH:17]1
Reactant: CC(C)(C)CC(=O)Cl
Reactant: Cc1nc2cccc(CN)c2c(=O)n1C1CCC(=O)NC1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1nc2cccc(CNC(=O)CC(C)(C)C)c2c(=O)n1C1CCC(=O)NC1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 20.1 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.49 g, 1.5 mmol) in acetonitrile (10 mL), was added t-butylacetyl chloride (0.31 mL, 2.2 mmol) and N,N-diisopropyl ethylamine (0.60 mL, 3.7 mmol). The mixture was stirred at room temp for 15 minutes. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-3,3-dimethyl-butyramide as a light yellow solid (120 mg, 22% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, gradient to 95/5 in 5 min, kept for 5 min, 5.74 min (98.4%); mp, 212-214° C.; 1HNMR (DMSO-d6) 0.96 (s, 9H, 3CH3), 2.08 (s, 2H, CH2Me3), 2.12-2.19 (m, 1H, CHH), 2.57-2.86 (m, 6H, CHCH2, CH3), 4.68-4.85 (m, 2H, CH2NH), 5.24 (dd, J=6, 11 Hz, 1H, CH), 7.34-7.76 (m, 3H, Ar), 8.11 (t, J=6 Hz, 1H, CH2NH), 11.02 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.76, 23.28, 29.69, 30.47, 30.58, 41.43, 48.76, 56.47, 117.65, 124.64, 125.42, 133.77, 141.19, 148.42, 154.75, 160.93, 169.51, 170.97, 172.60. LCMS MH=399; Anal Calcd For C21H26N4O4+0.1H2O: C, 63.02; H, 6.60; N, 14.00. Found: C, 62.86; H, 6.70; N, 13.92.