Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].C(=O)(O)[O-].[Na+].[Cl:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][CH:29]=[C:28]2[C:34]1[CH2:35][CH2:36][NH:37][CH2:38][CH:39]=1>CN(C)C=O.O1CCCC1>[Cl:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][CH:29]=[C:28]2[C:34]1[CH2:35][CH2:36][N:37]([CH2:2][CH2:3][CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=34)[S:6]2(=[O:18])=[O:17])[CH2:38][CH:39]=1
Reactant: Clc1ccc2[nH]cc(C3=CCNCC3)c2c1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=S1(=O)c2cccc3cccc(c23)N1CCCN1CC=C(c2c[nH]c3ccc(Cl)cc23)CC1
Temperature: 20 °C
Yield: 51.6 %

Procedure:
The experiment is carried out as in Example 1, starting with 2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (2.4 g), sodium bicarbonate (0.7 g) and 4-(5-chloro-3-indolyl)-1,2,3,6-tetrahydropyridine (2 g) in dimethylformamide (15 cc) and tetrahydrofuran (15 cc). The mixture is heated for 5 hours at boiling point, then cooled to a temperature of about 20° C. Stirring is maintained for 7 hours at this temperature. After purification by crystallization from water (50 cc), then recrystallization from boiling acetonitrile (50 cc), 2-{3-[4-(5-chloro-3-indolyl)-1,2,3,6-tetrahydro-1-pyridyl]propyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (2.1 g) is obtained, m.p. 189° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[O:5][CH2:6][CH2:7][CH2:8][C:9]([O:11]CC)=[O:10].[OH-].[Li+]>C1COCC1.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[O:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10]
Reactant: CCOC(=O)CCCOc1cccc(Br)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCCOc1cccc(Br)c1
Temperature: 50 °C
Yield: 97.4 %

Procedure:
To a solution of ethyl 4-(3-bromophenoxy)butanoate (Preparation 55A, 3.3 g, 11.5 mmol) in THF (5 mL) was added lithium hydroxide (0.550 g, 23.0 mmol) dissolved in water (5 mL) at room temperature. The reaction mixture was heated at 50° C. for 3 h. The reaction mixture was concentrated and partitioned between ethyl acetate (50 mL) and 1N aqueous hydrochloric acid (20 mL) (pH of aqueous layer ˜3). The organic layer was washed with brine (20 mL), dried over sodium sulfate, and concentrated under reduced pressure to yield 4-(3-bromophenoxy)butanoic acid (2.9 g, 11.2 mmol, 97% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ ppm 2.10-2.15 (m, 2H), 2.59 (t, J=7.26 Hz, 2H), 4.01 (t, J=6.05 Hz, 2H), 6.82 (ddd, J=8.14, 2.42, 1.10 Hz, 1H), 7.04-7.06 (m, 1H), 7.07-7.10 (m, 1H), and 7.14 (t, J=8.03 Hz, 1H).
Reaction SMILES: C1(O[C:8](=[O:23])[NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][C:21]=3[CH3:22])[CH:11]=2)C=CC=CC=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][C:34]=1[C:35]([F:38])([F:37])[F:36])[NH:31][CH2:30][CH2:29]2>>[CH3:22][C:21]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[C:12]1[CH:11]=[C:10]([NH:9][C:8]([N:31]2[C:32]3[C:28](=[CH:27][C:26]([O:25][CH3:24])=[C:34]([C:35]([F:37])([F:38])[F:36])[CH:33]=3)[CH2:29][CH2:30]2)=[O:23])[CH:15]=[CH:14][CH:13]=1
Reactant: COc1cc2c(cc1C(F)(F)F)NCC2
Reactant: Cc1ccncc1-c1cccc(NC(=O)Oc2ccccc2)c1
Product: COc1cc2c(cc1C(F)(F)F)N(C(=O)Nc1cccc(-c3cnccc3C)c1)CC2
Yield: 34.2 %

Procedure:
Reaction of phenyl-N-[3-(4-methylpyrid-3-yl)phenyl]carbamate (D28) (0.4 g, 1.3 mmoles) with 5-methoxy-6-trifluoromethylindoline (D11) (0.28 g, 1.3 mmoles) as in the method of Example 28 gave the title compound (E41) (0.19 g, 34%) m.p. 178-180° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.C([Li])CCC.CON(C)[C:17]([C:19]1[CH:27]=[CH:26][C:22]2[O:23][CH2:24][O:25][C:21]=2[CH:20]=1)=[O:18]>C1COCC1>[O:23]1[C:22]2[CH:26]=[CH:27][C:19]([C:17](=[O:18])[CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=3)=[CH:20][C:21]=2[O:25][CH2:24]1
Reactant: Cc1cccc(C)n1
Reactant: CON(C)C(=O)c1ccc2c(c1)OCO2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cccc(CC(=O)c2ccc3c(c2)OCO3)n1
Temperature: -60 °C
Yield: 53.8 %

Procedure:
To a −60° C. of 2,6-dimethyl-pyridine (48.3 mL, 457 mmol, 1.1 equiv) was slowly added n-butyl lithium (183 mL, 2.5 M in hexane, 457 mmol, 1.1 equiv) over 30 minutes. The resulting red solution was stirred at −60° C. for an additional hour, and then treated with a solution of benzo[1,3]dioxole-5-carboxylic acid methoxy-methyl-amide (˜415 mmol) in THF (200 mL) over 1 hour. The reaction was slowly warmed to −20° C. over 3 hours, and then poured into ice (1 kg). The liquid layer was decanted and then washed with brine (3×100 mL), dried over magnesium sulfate, and concentrated in vacuo. Recrystallization from toluene provided 1-Benzo[1,3]dioxol-5-yl-2-(6-methyl-pyridin-2-yl)-ethanone (57 g, 54% over two steps).
Reaction SMILES: O[CH:2]1[C:11]2[C:6](=[C:7]([Cl:18])[CH:8]=[C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]=2[CH3:12])[S:5][CH2:4][CH2:3]1.C(N(CC)CC)C.CS([Cl:30])(=O)=O>C(Cl)Cl>[Cl:30][CH:2]1[C:11]2[C:6](=[C:7]([Cl:18])[CH:8]=[C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]=2[CH3:12])[S:5][CH2:4][CH2:3]1
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1cc(Cl)c2c(c1C)C(O)CCS2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(Cl)c2c(c1C)C(Cl)CCS2
Temperature: 25 °C
Reaction time: 1 h
Yield: 116.1 %

Procedure:
1.0 Gram (3.5 mmol) of 4-hydroxy-5-methyl-6-ethoxycarbonyl-8-chlorothiochroman was dissolved in 5 ml of methylene chloride, and 0.72 ml (5.2 mmol) of triethylamine and 0.4 ml (5.2 mmol) of methanesulfonyl chloride were added with an ice bath cooling. The mixture was stirred at room temperature for 1 hour. After the completion of the reaction, an organic layer was washed with 2N hydrochloric acid and with a saturated sodium hydrogencarbonate aqueous solution and dried over anhydrous sodium sulfate, and the solvent was distilled off to give 1.24 g (yield 100%) of 4,8-dichloro-5-methyl-6-ethoxycarbonylthiochroman.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[C@@H:5]([C:6]2[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][CH:7]=2)[C@H:4]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[C:3]1=[O:26].C1C(=O)N(Br)C(=O)C1>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:27])[C:3](=[O:26])[C:4]([C:16]2[CH:17]=[CH:18][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=2)=[C:5]1[C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:13])=[O:14])=[CH:8][CH:7]=1
Reactant: CC1(C)C(=O)[C@@H](c2ccc(S(C)(=O)=O)cc2)[C@@H]1c1ccc(S(C)(=O)=O)cc1
Agent: O=C1CCC(=O)N1Br
Solvent: c1ccccc1
Product: CC1(C)C(=O)C(c2ccc(S(C)(=O)=O)cc2)=C1c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C

Procedure:
To a solution of cyclobutenone from step 2 (530 mg) in benzene was added NBS (350 mg). The mixture was heated to reflux for 1.5 hr in the presence of a sun lamp, cooled to r.t. and the solvent evaporated. The resulting residue was purified by flash chromatography (silica gel; hexane/EtOAc (70:30)) to provide the title compound as a white solid, m.p. 212° C.
Reaction SMILES: [C:1]([C:5]1[CH:26]=[CH:25][C:8]([C:9]([NH:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:30]>CN(C=O)C.CCOC(C)=O>[C:1]([C:5]1[CH:26]=[CH:25][C:8]([C:9]([N:11]([C@@H:12]2[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]2)[CH3:30])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](NC(=O)c2ccc(C(C)(C)C)cc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C(=O)c1ccc(C(C)(C)C)cc1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of (R)-tert-butyl 3-aminopiperidine-1-carboxylate (8) (6.27 g, 33.5 mmol) in DCM (100 mL) was added DIEA (8.75 mL, 50.3 mmol) and then 4-tert-butylbenzoyl chloride (8.0 mL, 43.6 mmol) in drop-wise manner. The mixture was stirred for 3 h at RT, diluted with DCM, washed with 1N NaOH, dried, and concentrated. The residue was subjected to flash column chromatography with 0 to 10% EtOAc in DCM to give (R)-tert-butyl 3-(4-tert-butylbenzamido)piperidine-1-carboxylate (11.0 g, 91%). To a solution of (R)-tert-butyl 3-(4-tert-butylbenzamido)piperidine-1-carboxylate (850 mg, 2.36 mmol) in DMF (10 mL) was added NaH (60% in mineral oil, 190 mg, 4.72 mmol). The mixture was stirred at RT for 10 min and then iodomethane (0.44 mL, 7.08 mmol) was added. The mixture was stirred at RT for 1 h, and diluted with 150 mL EtOAc. The mixture was washed with water ×2, dried, and concentrated. The residue was subjected to flash column with 0 to 3% MeOH in DCM to afford (R)-tert-butyl 3-(4-tert-butyl-N-methylbenzamido)piperidine-1-carboxylate (9) in quantitative yield. It was treated with 15 mL 4N HCl in dioxane at RT for 1 h. The mixture was concentrated in vacuo to dryness to afford (R)-4-tert-butyl-N-methyl-N-(piperidin-3-yl)benzamide (10) HCl salt in quantitative yield.
Reaction SMILES: [CH:1]([NH:4][C:5]([C@H:7]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]2[C:19]([N+:20]([O-])=O)=[CH:18][N:17]=[C:16]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[Sn](Cl)Cl.C(Cl)Cl>CO>[NH2:20][C:19]1[C:14]([NH:13][C@@H:10]2[CH2:9][CH2:8][C@H:7]([C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:6])[CH2:12][CH2:11]2)=[CH:15][C:16]([S:23]([CH3:26])(=[O:24])=[O:25])=[N:17][CH:18]=1
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(S(C)(=O)=O)ncc2[N+](=O)[O-])CC1
Agent: Cl[Sn]Cl
Solvent: ClCCl
Solvent: CO
Product: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(S(C)(=O)=O)ncc2N)CC1
Temperature: 80 °C

Procedure:
To a solution of cis-N-isopropyl-4-(2-(methylsulfonyl)-5-nitropyridin-4-ylamino)cyclohexanecarboxamide (0.177 g, 0.460 mmol) in MeOH (2 mL) was added anhydrous tin (II) chloride (0.349 g, 1.842 mmol). The reaction mixture was heated at 80° C. for 3 hours and was concentrated under vacuum. The remaining residue was dissolved in EtOAc and washed with 1N aqueous NaOH followed by brine. The organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography, eluting with 0-100% 90/10/1 DCM/MeOH/NH4OH:DCM to afford cis-4-(5-amino-2-(methylsulfonyl)pyridin-4-ylamino)-N-isopropylcyclohexanecarboxamide (0.150 g, 92% yield). MS (ESI pos. ion) m/z: 355.2 [M+H].
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:36]=[CH:35][C:18]([CH2:19][N:20]2[C:24]([CH2:25][CH2:26][CH3:27])=[C:23]([CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])[CH:22]=[N:21]2)=[CH:17][CH:16]=1.[OH-].[Na+].C(O)C.Cl>O1CCCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:36]=[CH:35][C:18]([CH2:19][N:20]2[C:24]([CH2:25][CH2:26][CH3:27])=[C:23]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])[CH:22]=[N:21]2)=[CH:17][CH:16]=1
Reactant: CCCc1c(CCC(=O)OCC)cnn1Cc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCc1c(CCC(=O)O)cnn1Cc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.9 %

Procedure:
A mixture of ethyl 3-[1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-5-propyl-1H-pyrazol-4-yl]propionate (210 mg), 1N aqueous sodium hydroxide solution (1 ml), ethanol (1 ml), and tetrahydrofuran (1 ml) was stirred at room temperature for 2 hours. The reaction mixture was acidified with dilute hydrochloric acid, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The crystals obtained were collected by filtration to yield 3-[1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-5-propyl-1H-pyrazol-4-yl]propionic acid (170 mg, yield: 85%). This was recrystallized from ethyl acetate-hexane. Melting point: 158–159° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10](=[O:11])[O:9][CH2:8][C:5]2=[N:6][CH:7]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.C[O-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>>[Cl:1][C:2]1[CH:7]=[N:6][C:5]([CH2:8][O:19][C:16]2[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][CH:15]=2)=[C:4]([CH:3]=1)[C:10]([OH:9])=[O:11]
Reactant: O=C1OCc2ncc(Cl)cc21
Reactant: Oc1ccc(Cl)cc1
Agent: C[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Product: O=C(O)c1cc(Cl)cnc1COc1ccc(Cl)cc1
Temperature: 130 °C
Yield: 58.3 %

Procedure:
A mixture of 3-chlorofuro[3,4-b]pyridin-5(7H)-one (step 1, 110 mg, 0.65 mmol) and 4-chloro phenol (416 mg, 3.24 mmol) was heated to 130° C. under N2, then sodium methoxide (28% methanol solution, 250 mg, 1.30 mmol) was added dropwise to the mixture at 130° C. The mixture was heated at the same temperature for 4 hours. After cooling, to the mixture was added 10% aqueous citric acid and the mixture was extracted with ethyl acetate. The extracts were dried over sodium sulfate and evaporated. The residue was purified by flash column chromatography on silica gel to afford 113 mg of the title compound:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-])=O.C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O.C(OCC)C>[CH2:18]([O:8][C:5]1[CH:4]=[C:3]([C:2]([Cl:1])=[CH:7][CH:6]=1)[NH2:9])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Nc1cc(OCc2ccccc2)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Chloro-3-nitrophenol (0.13 g) was dissolved in N,N-dimethylformamide (3 mL). To the solution were added potassium carbonate (0.31 g) and benzyl bromide (0.14 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with diethyl ether, and the resulting mixture was washed with water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in tetrahydrofuran (3 mL). To the solution were added methanol (3 mL), nickel(II) bromide (8 mg) and sodium borohydride (85 mg) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. Then the mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate, and the resulting mixture was washed with a saturated aqueous sodium hydrogen carbonate solution, water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound (0.15 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][C:18](=[O:27])[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)=[CH:11][C:10]=1[O:28][CH3:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30]([O:34]C(N(C)C)N(C)C)(C)(C)C.Cl>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][C:18](=[O:27])[C:19]([C:20]2[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=2)=[CH:30][OH:34])=[CH:11][C:10]=1[O:28][CH3:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(CCNC(=O)Cc2ccc(C)cc2)ccc1OCc1ccccc1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Agent: Cl
Solvent: C1CCOC1
Product: COc1cc(CCNC(=O)C(=CO)c2ccc(C)cc2)ccc1OCc1ccccc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 90.2 %

Procedure:
11.68 g (30.0 mmol) of N-[2-(4-benzyloxy-3-methoxyphenyl)ethyl]-2-(4-methylphenyl)acetamide and 15.67 g (90.0 mmol) of t-butoxybis(dimethylamino) methane were mixed and stirred at 80° C. for 2 hours. The reaction mixture was cooled and tetrahydrofuran was added thereto. The reaction mixture was acidified with 5% hydrochloric acid and stirred at room temperature for 2 hours. After the solvent was distilled off under reduced pressure, water and 5% hydrochloric acid were added to the residue, which was followed by extracted with chloroform twice, washed with saturated brine twice, dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was washed with hexane and dried to give 11.30 g of N-[2-(4-benzyloxy-3-methoxyphenyl)ethyl]-3-hydroxy-2-(4-methylphenyl)acrylamide.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[C:14](=[O:18])[CH2:15][CH2:16][CH:17]=1)(=O)=O.[Br-:19].[Li+]>CC(C)=O>[Br:19][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[C:14](=[O:18])[CH2:15][CH2:16][CH:17]=1
Reactant: [Br-]
Reactant: CS(=O)(=O)OCCCCCCCC1=CCCC1=O
Agent: [Li+]
Solvent: CC(C)=O
Product: O=C1CCC=C1CCCCCCCBr
Yield: 79 %

Procedure:
A solution of 988 mg of the crude material prepared in Example XV in 7.5 ml dry acetone was stirred at 25° under argon with 1.80 gm lithium bromide for 18.25 hours at 25°. The acetone was removed in vacuo and water added to the residue. The mixture was extracted with 95:5 hexaneether. The extracts were washed with 10% aqueous sodium thiosulfate and brine, dried over MgSO4, filtered and evaporated in vacuo to afford 737 mg of a yellow oil having the following structure: ##STR39##
Reaction SMILES: C(OC(=O)[NH:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([C:18]([C:20]2[C:28]3[C:23](=[N:24][CH:25]=[C:26]([C:29]#[N:30])[CH:27]=3)[NH:22][CH:21]=2)=[O:19])[C:12]=1[F:31])C1C=CC=CC=1.C(#N)C.C[Si](I)(C)C>CO>[NH2:10][C:11]1[C:12]([F:31])=[C:13]([C:14]([F:17])=[CH:15][CH:16]=1)[C:18]([C:20]1[C:28]2[C:23](=[N:24][CH:25]=[C:26]([C:29]#[N:30])[CH:27]=2)[NH:22][CH:21]=1)=[O:19]
Reactant: N#Cc1cnc2[nH]cc(C(=O)c3c(F)ccc(NC(=O)OCc4ccccc4)c3F)c2c1
Agent: C[Si](C)(C)I
Solvent: CO
Solvent: CC#N
Product: N#Cc1cnc2[nH]cc(C(=O)c3c(F)ccc(N)c3F)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.2 %

Procedure:
To a reaction vessel, [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-carbamic acid benzyl ester (27, 1.78 g, 4.12 mmol), 36 mL of anhydrous acetonitrile and trimethylsilyl iodide (3.29 g, 16.47 mmol) were added under nitrogen and the reaction was stirred at room temperature overnight. The reaction mixture was diluted with 20 mL of methanol and the solvents removed under vacuum. The residue was diluted with 50 mL of 2 M sodium hydroxide, and extracted with 3×50 mL of ethyl acetate. The organic layers were combined and washed with 200 mL of 10% sodium thiosulfate, then 200 mL of brine, dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The crude material was slurried in methanol, the solids collected by filtration and dried to give the desired compound (28, 0.74 g, 60%).
Reaction SMILES: [CH3:1][N:2]([CH3:29])[CH2:3][CH2:4][NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[NH:20][C:19]3[C:18](=[O:21])[N:17]([CH2:22][CH2:23][CH3:24])[C:16](=[O:25])[N:15]([CH2:26][CH2:27][CH3:28])[C:14]=3[CH:13]=2)=[CH:8][CH:7]=1.[F:30][C:31]1[CH:36]=[CH:35][C:34]([N:37]=[C:38]=[O:39])=[CH:33][CH:32]=1>C1COCC1>[CH3:29][N:2]([CH3:1])[CH2:3][CH2:4][N:5]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[NH:20][C:19]3[C:18](=[O:21])[N:17]([CH2:22][CH2:23][CH3:24])[C:16](=[O:25])[N:15]([CH2:26][CH2:27][CH3:28])[C:14]=3[CH:13]=2)=[CH:10][N:11]=1)[C:38]([NH:37][C:34]1[CH:35]=[CH:36][C:31]([F:30])=[CH:32][CH:33]=1)=[O:39]
Reactant: O=C=Nc1ccc(F)cc1
Reactant: CCCn1c(=O)c2[nH]c(-c3ccc(NCCN(C)C)nc3)cc2n(CCC)c1=O
Solvent: C1CCOC1
Product: CCCn1c(=O)c2[nH]c(-c3ccc(N(CCN(C)C)C(=O)Nc4ccc(F)cc4)nc3)cc2n(CCC)c1=O
Temperature: 85 °C
Reaction time: 72 h
Yield: 46.8 %

Procedure:
9c (35 mg) was suspended in THF (3 ml) in a pressure tube, 4-fluorophenyl isocyanate (130 mg) was added and the mixture was stirred at 85° C. for 3 days. After cooling to room temperature, the mixture was evaporated and the solid was stirred with ether and filtered The mother liquid contained most of the product. After removal of the solvent, the residue was purified by column (14 g silica gel, RT Scientific) (CH2Cl2: MeOH=100:0 to 95:5) to give the product (11c) (22 mg). HPLC condition: MeOH 40%-95% gradient in 10 minutes then MeOH 95%. Retention Time=7.20 min. 1H NMR (DMSO, d6): 0.83-0.93 (m, 6H), 1.53-1.71 (m, 4H), 2.28 (s, 6H), 2.50 (s, 4H), 3.87 (m, 4H), 4.14 (t, 1H, J=5.4 Hz), 6.83 (s, 1H), 7.15 (t, 2H, J=8.7 Hz), 7.52 (m, 3H), 8.24 (dd, 1H, J1=8.7 Hz, J2=2.4 Hz), 8.92 (d, 1H, J=2.4 Hz), 11.54 (s, 1H). MS: m/z 536 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7](=[O:32])[N:8]2[C:11]2[CH:16]=[C:15]([O:17][CH2:18][C:19]3[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[C:21]([F:27])[C:20]=3[F:28])[C:14]([O:29][CH3:30])=[CH:13][C:12]=2[Cl:31])=[C:4]([O:33][CH3:34])[N:3]=1.C(N(CC)C(C)C)(C)C.C([O:47][CH2:48][C:49](Cl)=[O:50])(=O)C.Cl>C(OCC)(=O)C>[Cl:31][C:12]1[CH:13]=[C:14]([O:29][CH3:30])[C:15]([O:17][CH2:18][C:19]2[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[C:21]([F:27])[C:20]=2[F:28])=[CH:16][C:11]=1[N:8]1[C:7](=[O:32])[NH:6][C:5]2[C:9]1=[N:10][C:2]([NH:1][C:48](=[O:47])[CH2:49][OH:50])=[N:3][C:4]=2[O:33][CH3:34]
Reactant: CC(=O)OCC(=O)Cl
Reactant: COc1cc(Cl)c(-n2c(=O)[nH]c3c(OC)nc(N)nc32)cc1OCc1c(OC)ccc(F)c1F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1cc(Cl)c(-n2c(=O)[nH]c3c(OC)nc(NC(=O)CO)nc32)cc1OCc1c(OC)ccc(F)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2-amino-9-[2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-6-methoxy-7,9-dihydro-8H-purin-8-one (40 mg) and N,N-diisopropyl-ethylamine (0.15 mL) in ethyl acetate (4 mL) was added acetoxyacetyl chloride (0.078 mL), and the mixture was stirred at room temperature overnight. To the reaction mixture was added 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in methanol (1 mL)-tetrahydrofuran (2 mL). To the solution was added sodium methoxide (28% methanol solution, 0.05 mL), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added 1 mol/L hydrochloric acid, and the mixture was poured into a saturated aqueous ammonium chloride solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1−ethyl acetate) to give the title compound (4 mg).
Reaction SMILES: [NH:1]1[C:5]2=[N+:6]([O-])[CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.N.P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:9]1[CH:8]=[CH:7][N:6]=[C:5]2[NH:1][CH:2]=[CH:3][C:4]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: [O-][n+]1cccc2cc[nH]c21
Agent: N
Product: Clc1ccnc2[nH]ccc12
Temperature: 25 °C

Procedure:
100 mg (0.76 mmol) of 1H-pyrrolo[2,3-b]pyridine 7-oxide (from example XV) in 3 ml of phosphorus oxychloride are heated at reflux until a clear solution is formed. After cooling to room temperature, the reaction mixture is carefully hydrolyzed with ice. The mixture is made alkaline using ammonia and extracted repeatedly with ethyl acetate. The organic phase is washed with water and saturated sodium chloride solution. After drying over magnesium sulfate, the solvent is removed under reduced pressure. This gives a yellow oil which is purified by preparative HPLC.