Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]([S:27][C:28]1[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=1)[CH2:21][N:22]1[CH:26]=[CH:25][N:24]=[CH:23]1.C(Cl)(Cl)Cl>C(Cl)Cl>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]([S:27]([C:28]1[CH:29]=[CH:30][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:36][CH:37]=1)=[O:9])[CH2:21][N:22]1[CH:26]=[CH:25][N:24]=[CH:23]1
Reactant: COC(=O)c1ccc(SC(Cn2ccnc2)c2ccccc2OC)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(S(=O)C(Cn2ccnc2)c2ccccc2OC)cc1
Reaction time: 0.5 h

Procedure:
5 ml of dry methylene chloride containing 304 mg of 3-chloroperbenzoic acid were added to 368 mg of methyl 4-[1-(2-methoxyphenyl)-2-(imidazol-1-yl)ethylthio]benzoate (prepared as described in Example 9) in 7 ml of dry methylene chloride, and the resulting mixture was stirred at 0°-5° C. for 30 minutes. At the end of this time, chloroform was added to the reaction mixture, and the resulting mixture was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography eluted with a 10:1 volume mixture of ethyl acetate and methanol, to give 263 mg of the title compound as colorless crystals, melting at 113°-115° C.
Reaction SMILES: C([O:4][C@@H:5]1[CH:11]=[CH:10][C@H:9]([N:12]2[C:16]3[N:17]=[C:18]([S:31][CH2:32][CH2:33][CH3:34])[N:19]=[C:20]([NH:21][C@@H:22]4[CH2:24][C@H:23]4[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:15]=3[N:14]=[N:13]2)[C:6]21[CH2:8][CH2:7]2)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[CH2:32]([S:31][C:18]1[N:19]=[C:20]([NH:21][C@@H:22]2[CH2:24][C@H:23]2[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:15]2[N:14]=[N:13][N:12]([C@@H:9]3[C:6]4([CH2:7][CH2:8]4)[C@H:5]([OH:4])[CH:11]=[CH:10]3)[C:16]=2[N:17]=1)[CH2:33][CH3:34]
Reactant: CCCSc1nc(N[C@@H]2C[C@H]2c2ccccc2)c2nnn([C@H]3C=C[C@@H](OC(C)=O)C34CC4)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCCSc1nc(N[C@@H]2C[C@H]2c2ccccc2)c2nnn([C@H]3C=C[C@@H](O)C34CC4)c2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the product of step g) (0.5 g) in methanol (10 ml) was added potassium carbonate (0.5 g) and the resulting suspension was stirred at ambient temperature for 2 hours. The reaction mixture was absorbed onto silica and purified by chromatography (SiO2; 3:1 isohexane:ethyl acetate) to give the subtitle compound (0.4 g).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7][CH:8]([NH2:11])[CH2:9][CH3:10].N1C=CC=CC=1.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.C(N(CC)CC)C>C(Cl)Cl.C(OCC)C>[Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7][C@H:8]([NH:11][S:25]([C:22]1[CH:23]=[CH:24][C:19]([Br:18])=[CH:20][CH:21]=1)(=[O:27])=[O:26])[CH2:9][CH3:10]
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: CCC(N)Cc1sccc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC[C@H](Cc1sccc1Cl)NS(=O)(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
Five grams of 3-chloro-2-(2-aminobutyl)thiophene is dissolved in 10 ml of methylene chloride in a 3-neck round bottomed flask blanketed with an inert atmosphere at 0° C. Pyridine (2.2 ml) is added in one portion followed by 6.74 g of 4-bromobenzenesulfonyl chloride which had been previously dissolved in 10 ml of methylene chloride. After the addition is complete, the mixture is stirred at ambient temperature for 3 hours and then at reflux for 2 hours. Two equivalents of triethylamine are added and the mixture is allowed to stir for 14 hours at ambient temperature before diluting with 100 ml of diethyl ether. The solution is poured into a separatory funnel and washed with water, dilute 1N HCl, saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered and concentrated in vacuo to provide (R)-N-[1-[(3-chlorothien-2-yl)methyl]propyl]-4-bromobenzenesulfonamide (8.3 g) as an orange oil which solidifies on standing. MS: m/z (E1, 70EV) 410 (15%). 1H NMR (200 MHz; CDCl3): δ 0.9 (3H, t, CH3), 1.6 (2H, m, CH2), 2.85 (2H, d, CH2), 3.45 (1H, m, CH), 6.75 (1H, d, CH), 7.1 (1H, d, CH), 7.4-7.8 (4H, m, Ph).
Reaction SMILES: [Cl:1][C:2](OC1C=CC(Cl)=CC=1)=[CH:3][C:4]([CH3:16])([CH3:15])[CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.C([OH:27])C>Cl>[Cl:1][CH2:2][C:3](=[O:27])[C:4]([CH3:16])([CH3:15])[CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1
Reactant: CC(C)(C=C(Cl)Oc1ccc(Cl)cc1)CCOc1ccc(Cl)cc1
Reactant: CCO
Agent: Cl
Product: CC(C)(CCOc1ccc(Cl)cc1)C(=O)CCl
Yield: 88 %

Procedure:
580 g (1.5 mols) of 1-chloro-3,3-dimethyl-1,5-di-(4-chlorophenoxy)-1-pentene in 1,000 ml of ethanol and 300 ml of concentrated hydrochloric acid are heated under reflux for 4 hours. The ethanol is removed in vacuo, and the residue is diluted with methylene chloride and extracted by shaking with water, and then three times with dilute sodium hydroxide solution. The dried solution is freed of solvent in vacuo. 363 g (88% of theory) of 1-chloro-5-(4-chlorophenoxy)-3,3-dimethyl-2-pentanone are obtained as an oil.
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]([F:35])([F:34])[C:10]1[N:14]2[N:15]=[C:16]([N:19]3[CH2:25][C@H:24]4[N:26](C(OC(C)(C)C)=O)[C@H:21]([CH2:22][CH2:23]4)[CH2:20]3)[CH:17]=[CH:18][C:13]2=[N:12][N:11]=1>C(Cl)Cl.CO>[C@@H:24]12[NH:26][C@@H:21]([CH2:22][CH2:23]1)[CH2:20][N:19]([C:16]1[CH:17]=[CH:18][C:13]3[N:14]([C:10]([C:9]([F:35])([F:34])[F:8])=[N:11][N:12]=3)[N:15]=1)[CH2:25]2
Reactant: CC(C)(C)OC(=O)N1[C@@H]2CC[C@H]1CN(c1ccc3nnc(C(F)(F)F)n3n1)C2
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: FC(F)(F)c1nnc2ccc(N3C[C@H]4CC[C@@H](C3)N4)nn12
Temperature: 25 °C
Reaction time: 18 h
Yield: 101.5 %

Procedure:
TFA (2.42 ml, 31.4 mmol) was added to a stirred solution of (1R,5S)-tert-butyl 3-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (443 mg, 1.11 mmol) in DCM (4.50 ml) at 25° C. The resulting solution was stirred at ambient temperature for 18 hours. The reaction mixture was diluted with methanol and the crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted using 7M ammonia in methanol and evaporated to dryness to afford 6-[(1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (336 mg, 100%) as a white solid.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH:9]1[CH:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH2:12][N:11]([C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:10]1)C)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH:13]2[CH:9]([NH:7][CH3:6])[CH2:10][N:11]([C:21]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:28])[CH2:12]2)=[CH:15][CH:16]=1
Reactant: CN(C(=O)OC(C)(C)C)C1CN(C(=O)c2ccccc2)CC1c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC1CN(C(=O)c2ccccc2)CC1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 107 %

Procedure:
To a stirred solution of [(3RS,4SR)-1-benzoyl-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid tert-butyl ester (80 mg, 0.19 mmol) in CH2Cl2 (1 ml) was added TFA (0.2 ml). The reaction mixture was stirred at RT for 2 hours, aqueous NaHCO3 was added until pH=8 and the product was extracted with CH2Cl2. The combined organic phase were dried over Na2SO4. Concentration under vacuo gave 64 mg (95%) of the title product as a colorless oil. ES-MS m/e: 315.1 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.I[C:12]1[CH:13]=[C:14]([CH3:19])[CH:15]=[C:16]([CH3:18])[CH:17]=1>>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:8][C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[CH:13]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1cc(C)cc(I)c1
Reactant: NC(=O)c1ccc(N)cc1
Product: Cc1cc(C)cc(NC(=O)c2ccc(N)cc2)c1
Yield: 98.4 %

Procedure:
Using general procedure A, 4-aminobenzamide (170 mg, 1.25 mmol) was coupled with 5-iodo-m-xylene (150 μL, 1.04 mmol). The crude product was purified by flash chromatography on silica gel (2×20 cm; hexane-ethyl acetate 2:3; 15 mL fractions). Fractions 9-18 provided 246 mg (98% yield) of the product as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.74-7.69 (m, 2H), 7.66 (br s, 1H), 7.28 (s, 2H), 6.78 (s, 1H), 6.74-6.69 (m, 2H), 4.05 (br s, 2H), 2.33 (s, 6H). 13C NMR (100 MHz, CDCl3): δ 165.7, 150.3, 139.1, 138.6, 129.2, 126.2, 124.8, 118.2, 114.6, 21.8.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4](C#CC(O)=O)C=[CH:6][C:7]=1C1CCCCC1.[Cl:19][CH:20]1[CH:25]([C:26]#[C:27][C:28](O)=O)[CH2:24][CH2:23][CH2:22][CH2:21]1>>[Cl:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=1[C:26]#[C:27][CH:28]1[CH2:4][CH2:3][CH2:2][CH2:7][CH2:6]1
Reactant: O=C(O)C#Cc1ccc(C2CCCCC2)c(Cl)c1
Reactant: O=C(O)C#CC1CCCCC1Cl
Product: Clc1ccccc1C#CC1CCCCC1

Procedure:
When 3-chloro-4-cyclohexylphenylpropiolic acid in the above example is replaced by the propiolic acids of Example 27, then the corresponding acetylene is prepared.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7](=[O:9])[CH3:8])[CH2:2]1.CCN(C(C)C)C(C)C.[CH:19]1[CH:24]=[CH:23][C:22]([CH2:25][O:26][C:27](Cl)=[O:28])=[CH:21][CH:20]=1>C(Cl)Cl>[C:7]([CH:3]1[CH2:4][CH2:5][CH2:6][N:1]([C:27]([O:26][CH2:25][C:22]2[CH:23]=[CH:24][CH:19]=[CH:20][CH:21]=2)=[O:28])[CH2:2]1)(=[O:9])[CH3:8]
Reactant: CC(=O)C1CCCNC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)C1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 1-(piperidin-3-yl)ethanone (53, 2.6 g, 20 mmol) in DCM (100 ml) at room temperature was added DIEA (5.2 ml, 30 mmol). A solution of Cbz-Cl (4.4 ml, 30 mmol) in DCM (20 ml) was added dropwise over 2 hrs. The mixture was stirred at room temperature for 17 hrs, washed with water, saturated sodium bicarbonate (aq.), water, 1N HCl (aq.) and brine, dried over anhydrous sodium sulfate. The drying agent was removed by filtration. The filtrate was concentrated under vacuum to give the benzyl 3-acetylpiperidine-1-carboxylate (54) which was used in the next step without further purification. LC-MS for C15H19NO3 calcd: 261; found: 262.
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:22][CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][CH2:32][CH:33]([CH3:35])[CH3:34])=[O:30])[CH2:25][CH2:24]2)=[N:4][CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][O:19][S:18](=[O:21])[O:17][CH2:16]2)=[CH:11][CH:10]=1.C([O:38]CC)C>C(#N)C.O>[O:21]=[S:18]1(=[O:38])[O:19][CH2:20][CH:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][C:7]3[N:6]=[CH:5][N:4]=[C:3]([O:22][CH:23]4[CH2:24][CH2:25][N:26]([C:29]([O:31][CH2:32][CH:33]([CH3:35])[CH3:34])=[O:30])[CH2:27][CH2:28]4)[C:2]=3[CH3:1])=[CH:10][CH:11]=2)[CH2:16][O:17]1
Reactant: CCOCC
Reactant: Cc1c(Oc2ccc(C3COS(=O)OC3)cc2)ncnc1OC1CCN(C(=O)OCC(C)C)CC1
Solvent: O
Solvent: CC#N
Product: Cc1c(Oc2ccc(C3COS(=O)(=O)OC3)cc2)ncnc1OC1CCN(C(=O)OCC(C)C)CC1
Temperature: 30 °C
Reaction time: 0.5 h

Procedure:
To a solution of iso-butyl 4-((5-methyl-6-(4-(2-oxido-1,3,2-dioxathian-5-yl)phenoxy)pyrimidin-4-yl)oxy)piperidine-1-carboxylate (100 mg, 0.000198 mole) in acetonitrile (1.2 mL) were added NaIO4 (59 mg, 0.000277 mole) and RuCl3.3H2O (0.5 mg, 0.0000198 mole) in 0.2 mL water. After stirring the suspension at 30° C. for 30 minutes, 0.8 mL water and 1.2 mL diethyl ether were added. The layers were separated, and the aqueous layer was extracted with diethyl ether. The combined ether layer was dried over sodium sulfate, the solvents were evaporated to yield 50 mg product as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([NH:13][CH2:14][C:15]2([CH3:31])[CH2:30][CH2:29][CH2:28][C:17]3([O:21][C:20](=[O:22])[N:19]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:18]3)[CH2:16]2)[C:9]=1[N+:10]([O-])=O)[C:5]#[N:6].[CH:32](OC)(OC)OC.C(O)=O.C(O)(C(F)(F)F)=O>CO.[Fe]>[Cl:1][C:2]1[C:9]2[N:10]=[CH:32][N:13]([CH2:14][C:15]3([CH3:31])[CH2:30][CH2:29][CH2:28][C:17]4([O:21][C:20](=[O:22])[N:19]([CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[CH2:18]4)[CH2:16]3)[C:8]=2[CH:7]=[C:4]([C:5]#[N:6])[CH:3]=1
Reactant: CC(C)(C)CN1CC2(CCCC(C)(CNc3cc(C#N)cc(Cl)c3[N+](=O)[O-])C2)OC1=O
Reactant: COC(OC)OC
Agent: [Fe]
Solvent: O=CO
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CN1CC2(CCCC(C)(Cn3cnc4c(Cl)cc(C#N)cc43)C2)OC1=O
Temperature: 65 °C
Reaction time: 26 h
Yield: 80.1 %

Procedure:
To an orange suspension containing 3-chloro-5-(((7-methyl-3-neopentyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)amino)-4-nitrobenzonitrile (0.132 g, 0.294 mmol) in MeOH (5.44 mL) was added iron (325 mesh) (0.164 g, 2.94 mmol), trimethyl orthoformate (0.325 mL, 2.94 mmol), and formic acid (0.113 mL, 2.94 mmol). The resulting solution was stirred at 65° C. for 26 h. Additional trimethyl orthoformate (0.325 mL, 2.94 mmol) and formic acid (0.113 mL, 2.94 mmol) was added, and stirring was continued at 65° C. for 24 h. The reaction was cooled to rt and concentrated. The resulting residue was suspended in MeCN (2 mL) and DMSO (4 mL) and filtered through a Hirsch funnel to remove any remaining solids. The filtrate was purified using reverse-phase HPLC (Sunfire Prep C18 column (30×150 mm); 14 minute run; 25 mL/min flow rate with at-column dilution; Solvent A: MeCN/0.1% TFA, Solvent B: water/0.1% TFA, gradient: 40-90% solvent A) to provide the title compound (0.101 g, 62% yield) as a TFA salt. 1H NMR (400 MHz, DMSO-d6) δ 8.55 (s, 1H), 8.41 (d, J=1.25 Hz, 1H), 7.81 (d, J=1.25 Hz, 1H), 4.15 (s, 2H), 3.29 (dd, J=9.03, 20.33 Hz, 2H), 2.87 (s, 2H), 1.80 (d, J=13.55 Hz, 1H), 1.49-1.74 (m, 4H), 1.22-1.48 (m, 3H), 1.02 (s, 3H), 0.85 (s, 9H). MS (m/z) 429.2 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:8][CH2:9][C:10]([NH2:12])=O)[CH:5]=[N:6][CH:7]=1.[F:13][C:14]1[CH:15]=[C:16]([NH:26][C:27](=[O:32])[CH2:28][C:29](=O)[CH3:30])[CH:17]=[CH:18][C:19]=1[N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.CCOC(C)=O.O>C1(C)C(C)=CC=CC=1.C([O-])(C)C.C([O-])(C)C.C([O-])(C)C.C([O-])(C)C.[Ti+4]>[F:13][C:14]1[CH:15]=[C:16]([N:26]2[C:27](=[O:32])[CH:28]=[C:29]([CH3:30])[N:12]=[C:10]2[CH2:9][O:8][C:4]2[CH:5]=[N:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH:17]=[CH:18][C:19]=1[N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: CC(=O)CC(=O)Nc1ccc(N2CCOCC2)c(F)c1
Reactant: NC(=O)COc1cncc(F)c1
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Product: Cc1cc(=O)n(-c2ccc(N3CCOCC3)c(F)c2)c(COc2cncc(F)c2)n1
Temperature: 25 °C
Yield: 26.6 %

Procedure:
To a mixture of 2-((5-fluoropyridin-3-yl)oxy)acetamide (200 mg, 1.18 mmol) and N-(3-fluoro-4-morpholinophenyl)-3-oxobutanamide (330 mg, 1.18 mmol) in xylene (10 mL) was added titanium tetraisopropanolate (2.7 mg, 9.5 mmol) and the mixture was refluxed for 50 h. The mixture was cooled to rt and 60 mL of EtOAc and 10 mL of water were added. The resulting mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:1) to give the title compound as a yellow solid (130 mg, 27%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:11]2[S:12][C:13]([S:19][C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=3)=[C:14]([N+:16]([O-])=O)[CH:15]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.[Cl-].[NH4+].O.C(O)C>O1CCCC1.[Fe]>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:11]2[S:12][C:13]([S:19][C:20]3[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=3)=[C:14]([NH2:16])[CH:15]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Nc1cccc(Br)c1)c1cc([N+](=O)[O-])c(Sc2ccc(O)cc2)s1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: Nc1cc(C(=O)Nc2cccc(Br)c2)sc1Sc1ccc(O)cc1
Temperature: 25 °C

Procedure:
To a solution of the product from Example 351D (1 equiv), iron powder (5 equiv) and ammonium chloride (3 equiv) in a mixture of tetrahydrofuran, water and ethanol was heated to reflux for 3 hours. The mixture was cooled to room temperature, filtered through a pad of celite, which was washed with ethanol and the resultant filtrate concentrated under vacuum. The material was then dissolved in water and extracted with ethyl acetate, the organic layer dried and concentrated under vacuum to provide the title product.
Reaction SMILES: [Na].C[CH:3]([C:9]([O:11]CC)=O)[C:4]([O:6]CC)=O.[C:14]([C:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=1)(=O)[CH3:15].[OH-].[K+]>C(O)C.O>[CH3:15][CH:14]1[CH:17]2[CH:18]([CH2:19][CH2:20][CH2:21][CH2:22]2)[C:4](=[O:6])[CH2:3][C:9]1=[O:11]
Reactant: CC(=O)C1=CCCCC1
Reactant: CCOC(=O)C(C)C(=O)OCC
Agent: [K+]
Agent: [Na]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC1C(=O)CC(=O)C2CCCCC12
Reaction time: 0.5 h

Procedure:
Sodium metal (2.31 g, 101.0 mmol) is dissolved in 50 ml of ethanol, and diethyl methylmalonate (17.6 g, 101.0 mmol) is added, after which the mixture is stirred for approx. 30 min. under reflux. 1-Acetyl-1-cyclohexene (12.50 g, 101.0 mmol) is added and the mixture is stirred under reflux overnight. Potassium hydroxide (12.47 g, 222.2 mmol) dissolved in 40 ml of water is added and the mixture is heated under reflux for 4 hr. The ethanol is removed by rotary evaporation, and the residue is dissolved in water and washed with ether. The aqueous layer is acidified with conc. HCl and extracted with ether. The combined extracts are dried and the solvent is removed to give 4a,5,6,7,8,8a -hexahydro-4-methylnaphthalene-1,3(2H,4H)-dione.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][O:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:7][CH:6]=1)C=C.[C:18]1(OC2C=CC=CC=2)[CH:23]=CC=C[CH:19]=1>>[CH2:23]([C:10]1[CH:9]=[C:8]([CH2:11][O:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:7]=[CH:6][C:5]=1[OH:4])[CH:18]=[CH2:19]
Reactant: c1ccc(Oc2ccccc2)cc1
Reactant: C=CCOc1ccc(COCC(=O)OC)cc1
Product: C=CCc1cc(COCC(=O)OC)ccc1O
Temperature: 200 °C

Procedure:
A mixture of methyl 4-allyloxyphenylmethyloxyacetate (2.00 g) and diphenyl ether (14 ml) was heated at 200° C. in an atmosphere of argon for 9 hours. The mixture was cooled to ambient temperature and purified by flash column chromatography on silica gel using a 4:1 (v/v) mixture of hexane and ethyl acetate as eluent to give methyl (3-allyl-4-hydroxyphenyl)methyloxyacetate (435 mg) as a colourless oil; NMR(CDCl3): 3.38(2H,d), 3.75(3H,s), 4.07(2H,s), 4.52(2H,s), 5.12(2H,m), 6.00(1H,m), 6.78(1H,m) and 7.08(2H,m); m/z 236(M).
Reaction SMILES: C([O:4][Si:5]([CH2:10][CH3:11])([CH2:8][CH3:9])[CH2:6][CH3:7])(=O)C.S[C:13]1[CH:18]=CN=CC=1>C(#N)C>[CH2:6]([Si:5]([O:4][Si:5]([CH2:6][CH3:7])([CH2:8][CH3:9])[CH2:10][CH3:11])([CH2:18][CH3:13])[CH2:8][CH3:9])[CH3:7]
Reactant: Sc1ccncc1
Reactant: CC[Si](CC)(CC)OC(C)=O
Solvent: CC#N
Product: CC[Si](CC)(CC)O[Si](CC)(CC)CC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
This solution of resulting mesylate (4) is mixed with 4-mercaptopyridine (803 mg; 1.25 equivalents) and acetonitrile (22 ml), warmed to room temperature, and stirred for 2 hours to give a solution of pyridylsulfide (7).
Reaction SMILES: Cl.[CH:2]1([NH:5][C:6](=[O:38])[C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]5[CH2:33][CH2:34][NH:35][CH2:36][CH:37]=5)=[CH:28][CH:27]=3)[CH:18]=[CH:17]4)[CH:8]=2)[CH2:4][CH2:3]1>C(O)C.[Pd]>[CH:2]1([NH:5][C:6](=[O:38])[C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([CH:32]5[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]5)=[CH:28][CH:27]=3)[CH:18]=[CH:17]4)[CH:8]=2)[CH2:3][CH2:4]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(Cc3ccc(C4=CCNCC4)cc3)ccc2c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(Cc3ccc(C4CCNCC4)cc3)ccc2c1
Reaction time: 2 h

Procedure:
10% Pd/C (20 mg) was added to a solution of Example 7 (60 mg) in ethanol (20 mL) and the mixture subjected to hydrogenation at 3 Barr for 2 hours. The reaction mixture was filtered and evaporated under reduced pressure to give the title compound as the hydrochloride salt as a solid (50 mg).
Reaction SMILES: [CH:1]1([C:6]2([CH3:19])[CH2:14][C:13]3[C:8](=[C:9]([Cl:17])[C:10]([Cl:16])=[C:11]([OH:15])[CH:12]=3)[C:7]2=[O:18])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-:20].[Na+].C(Cl)(Cl)Cl>CC(C)=O>[CH3:1][C:6]([O:15][C:11]1[CH:12]=[C:13]2[C:8](=[C:9]([Cl:17])[C:10]=1[Cl:16])[C:7](=[O:18])[C:6]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)([CH3:19])[CH2:14]2)([CH3:14])[C:7]([OH:18])=[O:20]
Reactant: CC1(C2CCCC2)Cc2cc(O)c(Cl)c(Cl)c2C1=O
Reactant: [OH-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Product: CC(C)(Oc1cc2c(c(Cl)c1Cl)C(=O)C(C)(C1CCCC1)C2)C(=O)O

Procedure:
To a refluxing solution of 2-cyclopentyl-2-methyl-5-hydroxy-6,7-dichloro-1-indanone (15.5 g., 0.05 mole) in acetone (500 ml.) in an inert atmosphere is added solid sodium hydroxide (12.6 g., 0.25 mole). Chloroform (7.6 g., 0.69 mole) in acetone (50 ml.) is addded dropwise during a ten-minute period. The reaction mixture is refluxed for five hours, then evaporated to dryness at reduced pressure. The residue is dissolved in water, filtered and acidified with hydrochloric acid affording α,α-dimethyl-(1-oxo-2-cyclopentyl-2-methyl-6,7-dichloro-5-indanyloxy)acetic acid.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[OH:5][C:6]1[C:15]([OH:16])=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1.N1C=CC=CC=1>C(OCC)(=O)C>[OH:5][C:6]1[C:15]([O:16][C:1](=[O:3])[CH3:2])=[CH:14][C:13]2[C:8]([CH:7]=1)=[CH:9][CH:10]=[CH:11][CH:12]=2
Reactant: Oc1cc2ccccc2cc1O
Reactant: CC(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1cc2ccccc2cc1O
Temperature: 25 °C

Procedure:
Acetylchloride (0.71 ml) was added to a solution of 2,3-dihydroxynaphthalene (1.6 g) and pyridine (0.81 ml) in ethyl acetate (20 ml) at 0° C. The mixture was stirred for few hours at room temperature and then washed with water, dried and evaporated to dryness. The crude product was recrystallized from ether. Yield: 0.52 g.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:15]=2)[C:10]([CH3:25])([CH3:24])[CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1.C(OCC)C>CO.C(Cl)Cl>[CH2:17]([C:14]1[CH:15]=[C:16]2[NH:8][CH2:9][C:10]([CH3:25])([CH3:24])[C:11]2=[N:12][CH:13]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CC(C)(C)c2ncc(Cc3ccccc3)cc21
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: CO
Product: CC1(C)CNc2cc(Cc3ccccc3)cnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.8 %

Procedure:
6-Benzyl-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-b]pyridine-1-carboxylic acid tert-butyl ester (1.66 g, 4.9 mmol) was dissolved in methanol (16 mL) and placed under a nitrogen atmosphere. 4M HCl in 1,4-dioxane (18.5 mL, 74 mmol) was added and the reaction was stirred at room temperature overnight. The reaction was concentrated in vacuo giving a sticky gum. The residue was stripped down from diethyl ether (2×30 mL) giving a sticky solid. The solid was dissolved in DCM (25 mL) and concentrated, to give the title compound (1.2 g), MS: [M+H]+=239.