Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][C:7]1[CH:20]=[CH:19][C:10]([CH2:11][CH:12]2[S:16][C:15](=[O:17])[NH:14][C:13]2=[O:18])=[CH:9][CH:8]=1)=[N+]=[N-]>CO.[Pd]>[NH2:1][CH2:4][CH2:5][O:6][C:7]1[CH:20]=[CH:19][C:10]([CH2:11][CH:12]2[S:16][C:15](=[O:17])[NH:14][C:13]2=[O:18])=[CH:9][CH:8]=1
Reactant: [N-]=[N+]=NCCOc1ccc(CC2SC(=O)NC2=O)cc1
Agent: [Pd]
Solvent: CO
Product: NCCOc1ccc(CC2SC(=O)NC2=O)cc1

Procedure:
A solution of 5-[4-(2-Azidoethoxy)Benzyl]2,4-Thiazolidinedione (5 g) in Methanol (100 ml) was reduced under hydrogen at ambient temperature and pressure in the presence of 10% palladium on charcoal (5 g) for 18 hours. The mixture was filtered through diatomaceous earth and the filter pad was washed exhaustively with Methanol. The combined filtrates was evaporated to dryness under reduced pressure and the title compound (m.p. 175°-6° C.) was obtained as a dihydrate following crystallisation from methanol.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:22].O1CCOCC1>>[ClH:22].[S:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[C:11]1([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)=O)(c2cccs2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: NC(=O)C1(c2cccs2)CCNCC1

Procedure:
Prepare by the method of example 20.10 using 1-tert-butoxycarbonyl-4-(thiophen-2-yl)-piperidine-4-carboxylic acid amide (3 mmol) and HCl in dioxane (40 mmol, 4N) to give the title compound.
Reaction SMILES: C([NH:8][CH:9]([CH3:28])[CH2:10][N:11]1[CH:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:27])C1C=CC=CC=1.C(O)(=O)C.[H][H]>[C].[Pd].C(O)C>[NH2:8][CH:9]([CH3:28])[CH2:10][N:11]1[CH:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:27]
Reactant: [H][H]
Reactant: CC(Cn1cc(-c2ccccc2)c2ccccc2c1=O)NCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(N)Cn1cc(-c2ccccc2)c2ccccc2c1=O
Yield: 75.2 %

Procedure:
36.8 g of 2-(2-benzylaminopropyl)-4-phenyl-1(2H)-isoquinolone preapred as described above, 12 g of 5% palladium-carbon, 50 ml of glacial acetic acid and 200 ml of ethanol were mixed, and the mixture was catalytically reduced while introducing hydrogen gas into the mixture at 60° to 70° C. After completion of the reduction reaction, the mixture was filtered, and the solvent was distilled off from the filtrate. The resulting residue was dissolved in 5% hydrochloric acid and the solution was washed with ethyl acetate. The aqueous layer was separated and rendered neutral with a 10% aqueous solution of sodium hydroxide. The resulting precipitate was filtered and recrystallized from a mixture of ethyl acetate and petroleum ether to obtain 20.9 g (75% yield) of 2-(2-aminopropyl)-4-phenyl-1(2H)-isoquinolone having a melting point of 104° C. as colorless prisms.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([N:10]2[CH:14]=[C:13]([Br:15])[N:12]=[CH:11]2)[C:7]([C:16]([F:19])([F:18])[F:17])=[CH:6][C:5]=1[N+:20]([O-])=O>CO.[Pd]>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([N:10]2[CH:14]=[C:13]([Br:15])[N:12]=[CH:11]2)[C:7]([C:16]([F:19])([F:17])[F:18])=[CH:6][C:5]=1[NH2:20]
Reactant: COC(=O)c1cc(-n2cnc(Br)c2)c(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(-n2cnc(Br)c2)c(C(F)(F)F)cc1N
Yield: 58.3 %

Procedure:
In a similar way a solution of 5-(4-bromo-imidazol-1-yl)-2-nitro-4-trifluoromethyl-benzoic acid methyl ester (300 mg, 0.8 mmol) in 50 ml methanol is hydrogenated over 43 mg of 10% palladium on charcoal to obtain after the usual workup procedure 160 mg (0.466 mmol, 58%) of 2-amino-5-(4-bromo-imidazol-1-yl)-4-trifluoromethyl-benzoic acid methyl ester, m.p. 163-165° C., ES-MS: m/z 365 [M+H]+.
Reaction SMILES: N[C:2]1[S:3][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:5][N:6]=1.N([O-])=O.[Na+].[ClH:17]>C(O)(=O)C.O.[Cu]>[Cl:17][C:2]1[S:3][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:5][N:6]=1
Reactant: Nc1nnc(-c2ccccc2)s1
Reactant: Cl
Agent: [Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Clc1nnc(-c2ccccc2)s1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A stirred suspension of 2-amino-5-phenyl-[1,3,4]thiadiazole (6.45 g, 36.4 mmol; Aldrich) and copper (230 mg, 3.6 mmol; Aldrich) in hydrochloric acid (36 mL, 12 M) and glacial acetic acid (180 mL) was chilled to 0° C. and treated with a solution of sodium nitrite (2.64 g, 38.2 mmol; Aldrich) in water (12 mL), added dropwise over 40 minutes. After stirring at room temperature for 4 hours, the mixture was poured into ice water. The aqueous solution was extracted with chloroform (3×), and the combined extracts were washed sequentially with 5% sodium bicarbonate and brine, and dried over sodium sulfate. The crude product was filtered through a short silica gel plug with chloroform to afford the title product: 1H NMR (300 MHz, CDCl3) δ ppm 7.46-7.55 (m, 3H), 7.85-7.93 (m, 2H). MS (DCI/NH3) m/e 197/199 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:39]=[CH:38][C:6]([CH2:7][NH:8][C:9]2[C:14]([C:15]([OH:17])=O)=[C:13]([NH:18][C@H:19]([C:21]3[N:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:25](=[O:33])[C:24]4=[C:34]([CH3:37])[CH:35]=[CH:36][N:23]4[N:22]=3)[CH3:20])[N:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:73][O:74][C:75]1[CH:76]=[C:77]([CH:79]=[CH:80][CH:81]=1)[NH2:78]>CN(C)C=O.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9]2[C:14]([C:15]([NH:78][C:77]3[CH:79]=[CH:80][CH:81]=[C:75]([O:74][CH3:73])[CH:76]=3)=[O:17])=[C:13]([NH:18][C@H:19]([C:21]3[N:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:25](=[O:33])[C:24]4=[C:34]([CH3:37])[CH:35]=[CH:36][N:23]4[N:22]=3)[CH3:20])[N:12]=[CH:11][N:10]=2)=[CH:38][CH:39]=1
Reactant: COc1ccc(CNc2ncnc(N[C@@H](C)c3nn4ccc(C)c4c(=O)n3-c3ccccc3)c2C(=O)O)cc1
Reactant: COc1cccc(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(CNc2ncnc(N[C@@H](C)c3nn4ccc(C)c4c(=O)n3-c3ccccc3)c2C(=O)Nc2cccc(OC)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.4 %

Procedure:
(S)-4-((4-Methoxybenzyl)amino)-6-((1-(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carboxylic acid (300 mg, 0.51 mmol) was dissolved in 7 mL dimethylformamide. N,N-Diisopropylethylamine (150 μl, 1.10 mmol) and HATU (400 mg, 1.05 mmol) were added and the reaction mixture was stirred at room temperature for 30 min. Then, 3-methoxyaniline (95 μl, 0.85 mmol) was added and the reaction mixture stirred at room temperature overnight. The crude was diluted with water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulphate and concentrated under reduced pressure. A semi-solid was obtained and purified using SP1® Purification System (0% to 50%, hexane-ethyl acetate) to obtain 265 mg (82% yield) of the title compound. Purity 100%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([CH2:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:6]=1[CH3:20])=[O:4].[Br:21]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([CH2:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:6]=1[CH2:20][Br:21])=[O:4]
Reactant: COC(=O)c1cc(Br)c(=O)n(CC2CCOCC2)c1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(Br)c(=O)n(CC2CCOCC2)c1CBr
Yield: 45.9 %

Procedure:
A mixture of 5-bromo-2-methyl-6-oxo-1-(tetrahydro-pyran-4-ylmethyl)-1,6-dihydro-pyridine-3-carboxylic acid methyl ester (0.906 g, 2.63 mmol), N-bromosuccinimide (0.516 g, 2.89 mmol), and benzoyl peroxide (64 mg, 0.26 mmol) in CCl4 (30 mL) was refluxed for 16 h. The solvent was evaporated in vacuo, and the residue was chromatographed (0-60% EtOAc/hexanes) to give 511 mg of the title compound. MS: (+) m/z 424.10 (M+1).
Reaction SMILES: CON(C)[C:4](=[O:23])[C:5]1[CH:10]=[C:9]([S:11]([F:16])([F:15])([F:14])([F:13])[F:12])[CH:8]=[C:7]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH:6]=1.[CH3:25][Mg]Br.Cl>C1COCC1.O>[N:17]1([C:7]2[CH:6]=[C:5]([C:4](=[O:23])[CH3:25])[CH:10]=[C:9]([S:11]([F:12])([F:16])([F:15])([F:13])[F:14])[CH:8]=2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: CON(C)C(=O)c1cc(N2CCOCC2)cc(S(F)(F)(F)(F)F)c1
Reactant: C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1cc(N2CCOCC2)cc(S(F)(F)(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-Methoxy-N-methyl-3-morpholin-4-yl-5-(pentafluorosulfanyl)benzamide (2.38 g) was dissolved in THF (50 ml), methylmagnesium bromide (4.22 ml, 3 M in ether) was added dropwise at 0° C. and then the mixture was stirred at RT for 2 h. Then 1N hydrochloric acid (100 ml) was added, and the mixture was diluted with water and extracted by shaking three times with EA. Thereafter, the combined EA phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified using silica gel (80 g cartridge, n-heptane/EA gradient of 0-70% within 40 min). 1.1 g of the title compound were obtained.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[S:14][C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:12][CH:11]=1)(=[O:3])[CH3:2].[BH4-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C>[OH:3][CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[S:14][C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:12][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(-c2ccccc2C(C)=O)s1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1ccc(-c2ccccc2C(C)O)s1
Temperature: 0 °C
Reaction time: 8 h
Yield: 93.1 %

Procedure:
Ethyl 5-(2-acetylphenyl)thiophene-2-carboxylate (3.52 g) obtained in Step 2 was dissolved in ethanol (30 ml) and the mixture was cooled to 0° C. Sodium borohydride was added and the mixture was stirred overnight at 0° C.—room temperature. The reaction mixture was cooled to 0° C., 10% aqueous citric acid was added dropwise and ethanol was evaporated. The reaction mixture was extracted with ethyl acetate, washed successively with water, saturated aqueous sodium hydrogencarbonate and brine, and dried over sodium sulfate. The organic layer was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to give the title compound (3.30 g).
Reaction SMILES: O.[OH-].[C:3]1([CH2:9][C:10](=[O:12])[CH3:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(O)C>[C:3]1([CH2:9][CH:10]([OH:12])[CH3:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(=O)Cc1ccccc1
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(O)Cc1ccccc1
Temperature: 80 °C

Procedure:
In a 4 liter three-necked flask fitted with a mechanical stirrer and a reflux condenser, were placed 1500 ml of water, 150 g ofsodium hydroxide (pellets), 190 ml of ethanol and 180 g of phenylacetone. The mixture was stirred and heated to 80° C., and 150 g of Raney alloy was added very cautiously by small amounts over about 1 hour. During the addition, heating was discontinued and the temperature was maintained at 85°-87° C.
Reaction SMILES: [C:1]1([C:7]2[C:12]([C:13](O)=O)=[CH:11][N:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:16].[Na+]>>[C:11]1(=[O:16])[C:12]2[C:7]([C:1]3[C:6]([CH:13]=2)=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:8][CH:9]=[N:10]1
Reactant: O=C(O)c1cnccc1-c1ccccc1
Reactant: [OH-]
Agent: [Na+]
Product: O=C1N=CC=C2C1=Cc1ccccc12
Temperature: 200 °C
Reaction time: 5 h

Procedure:
4-Phenylnicotinic acid (4.7 g, 23.8 mmol) from the previous step was suspended in polyphosphoric acid (160.3 g) and slowly heated to 200° C. with stirring. After 5 hours, the mixture was cooled to 140° C. and slowly poured over crushed ice and stirred for 24 hours. The mixture was then neutralized to pH=4 with 50% sodium hydroxide solution and extracted 3 times with dichloromethane. The dichloromethane extracts were combined and the solvent was removed under reduced pressure to yield the yellow solid of 2-azafluorenone (3.1 g, HPLC RT=2.16 min, method A; LC-MS m/z=182), 1H NMR, 400 MHz, CHCl3, 8.72 ppm (s, 1H), 8.75 ppm (d, 1H), 7.75 ppm (d, 1H), 7.65 ppm (d, 1H), 7.62-7.55 ppm (m, 1H), 7.51-7.46 ppm (m, 2H).
Reaction SMILES: C([O:9][CH2:10][C:11]1[N:20]=[C:19]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]3[O:29][CH2:30][O:31][C:25]=3[CH:24]=2)[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:32][CH3:33])[CH:17]=2)[N:12]=1)(=O)C1C=CC=CC=1.[H][H]>[Pd].C(OCC)(=O)C.C(O)C>[OH:9][CH2:10][C:11]1[N:20]=[C:19]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]3[O:29][CH2:30][O:31][C:25]=3[CH:24]=2)[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:32][CH3:33])[CH:17]=2)[N:12]=1
Reactant: [H][H]
Reactant: COc1ccc2nc(COC(=O)c3ccccc3)nc(NCc3ccc4c(c3)OCO4)c2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc2nc(CO)nc(NCc3ccc4c(c3)OCO4)c2c1
Yield: 89.5 %

Procedure:
1.5 g of 10% palladium/carbon powder was added to a solution of 1.26 g (2.93 mmol) of 2-benzoyloxymethyl-4-(3,4-methylenedioxybenzyl)amino-6-methoxyquinazoline in an ethyl acetate/ethanol (20 ml-20 ml) mixture. The obtained mixture was stirred at room temperature in a stream of hydrogen for 24 hours and filtered through Celite. The filter cake was washed with hot ethyl acetate/ethanol. The filtrate and the washings were distilled under a reduced pressure to remove the solvent. Thus 0.89 g of the title compound was obtained as a pale-yellow crystal.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]#[N:23])[CH:17]=1)[CH2:10][C:9]2([CH3:25])[CH3:24])=[O:5])C.[OH-].[Na+].O.Cl>C(#N)C>[C:22]([C:18]1[CH:17]=[C:16]([CH:11]2[CH2:10][C:9]([CH3:25])([CH3:24])[C:8]3[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=3)[NH:12]2)[CH:21]=[CH:20][CH:19]=1)#[N:23]
Reactant: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1cccc(C#N)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: CC1(C)CC(c2cccc(C#N)c2)Nc2ccc(C(=O)O)cc21
Temperature: 60 °C
Reaction time: 4 h
Yield: 67.7 %

Procedure:
A mixture of 2-(3-cyano-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (3.0 g, 7.96 mmol), sodium hydroxide (1.8 g, 44.9 mmol), water (15 mL) in acetonitrile (30 mL) was stirred at 60° C. for 4 h. The mixture was neutralized with a 3 mol/L aqueous hydrochloric acid solution and extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-(3-cyano-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (1.65 g, 60%) as a white solid which was used for next step without further purification: MS (ESI) M+1=307.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[CH2:14])[CH2:10][CH2:11][CH:12]=[O:13].[CH3:15][Mg]I.Cl>C(OCC)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH2:10][CH2:11][CH:12]([OH:13])[CH3:15])[CH3:14]
Reactant: C[Mg]I
Reactant: C=C(CCC=O)c1ccc(Cl)cc1Cl
Agent: Cl
Solvent: CCOCC
Product: CC(O)CCC(C)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 315.8 %

Procedure:
A solution of 4-(2,4-dichlorophenyl)pent-4-enal (26.0 g) in dry diethyl ether was added dropwise to a stirred solution of methylmagnesium iodide [from magnesium (4.09 g) and methyl iodide (24.14 g)] in diethyl ether (total volume of diethyl ether ca. 200 ml). Following the addition, the reaction mixture was stirred at room temperature for 1 hour then poured into a mixture of ice and dilute hydrochloric acid, and extracted with ether. The extracts were washed with water, dried over magnesium sulphate, concentrated under reduced pressure, and chromatographed on a column of silica gel (eluting with dichloromethane: 60°-80° petrol, 1:1) to give 2-(2,4-dichlorophenyl)hexan-5-ol (19.2 g, 69%) as an almost colourless oil.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:12][CH:11]=2)[C:5]([C:23]2[CH:42]=[CH:41][C:26]([O:27][C@H:28]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:29]([O:31]CC)=[O:30])=[CH:25][CH:24]=2)=[CH:4][CH:3]=1.[OH-].[K+].Cl>C1COCC1.CO>[CH3:1][C:2]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:12][CH:11]=2)[C:5]([C:23]2[CH:42]=[CH:41][C:26]([O:27][C@H:28]([CH2:34][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:29]([OH:31])=[O:30])=[CH:25][CH:24]=2)=[CH:4][CH:3]=1
Reactant: CCCCCCCc1ccc(CCCn2c(C)ccc2-c2ccc(O[C@H](Cc3ccccc3)C(=O)OCC)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCCc1ccc(CCCn2c(C)ccc2-c2ccc(O[C@H](Cc3ccccc3)C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a mixed solution of ethyl (2R)-2-{4-[5-methyl-1-(4-heptylphenylpropyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate (1.03 g, 1.76 mmol) in THF (15 ml) and methanol (7 ml) was added 1N aqueous potassium hydroxide (5.3 ml, 5.3 mmol) and the mixture was stirred for 1 hour at room temperature. The reaction solution was neutralized with 1N aqueous hydrochloric acid, extracted with ethyl acetate, washed with saturated brine and dried over magnesium sulfate anhydride. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate) to give the object compound as an oily substance. 969 mg, (yield 99%)
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][C:3]1=[O:9].[Cl:11][C:12]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:13]=1[C:14](C#N)=[O:15].C(N(CC)CC)C.Cl>C(Cl)Cl.[Cl-].[Zn+2].[Cl-]>[CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][C:5](=[O:8])[CH:4]([C:14](=[O:15])[C:13]2[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:12]=2[Cl:11])[C:3]1=[O:9]
Reactant: N#CC(=O)c1ccc(Cl)cc1Cl
Reactant: CC1(C)CCC(=O)CC1=O
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)CCC(=O)C(C(=O)c2ccc(Cl)cc2Cl)C1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 40 %

Procedure:
4,4-Dimethyl-1,3-cyclohexanedione [14.0 grams (g), 0.1 mole], 20.0 g (0.1 mole) 2,4-dichlorobenzoyl cyanide and 13.6 g (0.11 mole) anhydrous, powdered zinc chloride were combined in 100 milliliters (ml) methylene chloride. Triethylamine (10.1 g, 0.12 mole) was slowly added with cooling. The reaction mixture was stirred at room temperature for 5 hours and then poured into 2N hydrochloric acid. The aqueous phase was discarded and the organic phase was washed with 150 ml 5% Na2CO3 four times. The aqueous washings were combined and acidified with HCl, extracted with methylene chloride, dried and concentrated to yield 25.3 g of crude product. The crude product was chromatographed (2% AcOH/CH2Cl2) in 5 g aliquots then reduced on rotavap under reduced pressure at 50° C. for 30 minutes to remove AcOH. This yielded an oil (40% yield). The structure was confirmed by instrumental analysis.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[N:12]1[CH:17]=[CH:16][CH:15]=[N:14][C:13]=1[S:18][CH2:19][N:20]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[S:21]1(=[O:23])=[O:22]>>[N:14]1[CH:15]=[CH:16][CH:17]=[N:12][C:13]=1[S:18]([CH2:19][N:20]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[S:21]1(=[O:23])=[O:22])=[O:9]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C1c2ccccc2S(=O)(=O)N1CSc1ncccn1
Product: O=C1c2ccccc2S(=O)(=O)N1CS(=O)c1ncccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of m-chloroperbenzoic acid (0.9 g, 5.37 mmol) and 2-(2-pyrimidylthiomethyl) saccharin prepared by procedures similar to those of Examples 9 and 11 (1.5 g, 4.8 mmol) in MDC (75 ml) was stirred overnight at room temperature. The reaction mixture was washed with sodium bicarbonate solution, dried (Na2SO4) and freed of solvent under vacuum. Part of this crude product (0.5 g) was saved for direct conversion to the sulfone; the remaining material was chromatographed (silica gel-95:5 CH2Cl2 :acetone). Recrystallization from ethanol:acetonitrile afforded 0.95 g of 2-(2-pyrimidylsulfinylmethyl)saccharin as white crystals, mp 197°-198 ° C. decomp. 1H nmr (90 MHz, CDCl3, DMSO-d6) :5.1-5.5 (2H, q) .
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:10]=[CH:9][C:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[C:19]([O:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:20]=2)[NH:17][C:16]([C:28]([OH:30])=O)=[CH:15]3)=[CH:7][CH:6]=1)(=[O:4])=[O:3].O.O[N:33]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.N.Cl>CN(C)C=O>[CH3:1][S:2]([C:5]1[N:10]=[CH:9][C:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[C:19]([O:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:20]=2)[NH:17][C:16]([C:28]([NH2:33])=[O:30])=[CH:15]3)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C(=O)O)cc3c2)cn1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)c1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C(N)=O)cc3c2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.1 %

Procedure:
To a solution of 5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-7-(tetrahydro-2H-pyran-4-yloxy)-1H-indole-2-carboxylic acid (3 g) in N,N-dimethylformamide (20 mL) were added 1-hydroxybenzotriazole monohydrate (1.6 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2 g), and 10% aqueous ammonia (27 mL), and the mixture was stirred at room temperature for 1 hr. 1N HCl was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was crystallized from diethyl ether to give the title compound (1.35 g, yield 45%) as yellow powder.
Reaction SMILES: [N+]([O-])(O)=O.Cl.[C:6]12([NH2:16])[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][CH:8]([CH2:9]3)[CH2:7]1)[CH2:13]2.[OH-:17].[Na+]>S(=O)(=O)(O)O>[OH:17][C:8]12[CH2:9][CH:10]3[CH2:11][CH:12]([CH2:13][C:6]([NH2:16])([CH2:15]3)[CH2:7]1)[CH2:14]2
Reactant: NC12CC3CC(CC(C3)C1)C2
Reactant: [OH-]
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O=[N+]([O-])O
Product: NC12CC3CC(C1)CC(O)(C3)C2
Temperature: 10 °C
Reaction time: 4 h

Procedure:
To a mixture of 150 ml of concentrated sulfuric acid and 15 ml of concentrated nitric acid, cooled to 10° C. is added 10 g (0.053 moles) of 1-adamantanamine hydrochloride over 5 minutes. This mixture is stirred in an ice bath for 4 hours. The reaction is then poured over ice and the pH adjusted to pH 10 using 50% NaOH. The product is extracted into chloroform which is dried over MgSO4 and then evaporated to dryness. The residue is recrystallized from ethyl acetate to give 3-hydroxytricyclo[3.3.1.13,7 ]decan-1-amine (m.p. 260°-264° C.) which is used directly in step B.