Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:10]1[C:15](=[O:16])[C:14]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[C:13]([C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)[CH:12]=[N:11]1)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].[BH4-].[Na+]>C(O)C>[OH:3][CH:2]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH2:1][N:10]1[C:15](=[O:16])[C:14]([C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)=[C:13]([C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)[CH:12]=[N:11]1
Reactant: CS(=O)(=O)c1ccc(-c2cnn(CC(=O)c3ccccc3)c(=O)c2-c2ccc(F)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CS(=O)(=O)c1ccc(-c2cnn(CC(O)c3ccccc3)c(=O)c2-c2ccc(F)cc2)cc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
A mixture of the product from Example 46, 2-phenacyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (700 mg, 1.5 mmol), and sodium borohydride (69 mg, 1.8 mmol) in ethanol (200 mL), was stirred at 40° C. for 2 hours. The reaction mixture was then concentrated in vacuo and the residue was partitioned between ethyl acetate and 2 N aqueous hydrochloric acid. The organic layer was washed with brine, dried over MgSO4, and filtered. The filtrate was concentrated in vacuo to provide a pale yellow solid which was crystallized from ethyl acetate/hexanes to provide the title compound as white crystals (yield: 540 mg, 78%). mp 205-207° C. 1H NMR (300 MHz, CDCl3) δ 3.07 (s, 3H), 3.75 (br s, 1H), 4.63-4.47 (m, 2H), 5.33 (dd, J=9 Hz, 3 Hz, 1H), 7.00 (t, J=9 Hz, 2H), 7.20 (dd, J=9 Hz, 3 Hz, 2H), 7.30-7.45 (m, 5H), 7.52 (d, J=9 Hz, 2H), 7.91 (s, 1H), 7.91 (d, J=9 Hz, 2H). MS (DCI/NH3) m/z 465 (M+H)+. Anal. calc. for C21H21FN2O4S: C, 64.64; H, 4.55; N, 6.03. Found: C, 64.34; H, 4.66; N, 5.93.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:7](=[O:24])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([CH:21]=[O:22])=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:23])=[CH:10][CH:9]=2)=[O:4].P([O-])(O)(O)=[O:33].[Na+].CC(=CC)C.Cl([O-])=O.[Na+]>O.C(O)CCC.C1COCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:7](=[O:24])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([C:21]([OH:33])=[O:22])=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:23])=[CH:10][CH:9]=2)=[O:4]
Reactant: O=P([O-])(O)O
Reactant: COC(=O)c1c(-c2ccc(C=O)cc2)c2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: C1CCOC1
Solvent: CCCCO
Solvent: O
Product: COC(=O)c1c(-c2ccc(C(=O)O)cc2)c2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Yield: 34.2 %

Procedure:
To a mixture of 2-benzyl-6-chloro-4-(4-formylphenyl)-1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (93 mg), sodium dihydrogenphosphate (26 mg), 2-methyl-2-butene (100 μl), THF (2.0 ml), butanol (1.0 ml) and water (2.0 ml) was added sodium chlorite (73 mg) at 0° C. with stirring, and the mixture was stirred for 1 hr. The solvent was removed and the residue was partitioned between 1N hydrochloric acid and ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated. The residue was purified by preparative HPLC to give the title compound (33 mg) as a colorless powder.
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:14].[S].II.[SH2:19]>ClC1C=CC=CC=1Cl>[CH3:14][C:9]1[C:8]2[NH:7][C:2]3[C:3](=[CH:4][CH:5]=[CH:6][C:1]=3[CH3:15])[S:19][C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: Cc1ccccc1Nc1ccccc1C
Reactant: S
Agent: II
Agent: [S]
Solvent: Clc1ccccc1Cl
Product: Cc1cccc2c1Nc1c(C)cccc1S2
Temperature: 180 °C
Yield: 15 %

Procedure:
To a reaction vessel were combined di(2-tolyl)amine (11.7 g, 59.3 mmol), elemental sulfur (3.9 g, 121.65 mmol, 2 eq.), crushed iodine (0.44 g, 1.73 mmol, 3 mol %) followed by o-dichlorobenzene (22 mL). Added an outlet to a dilute bleach solution (for hydrogen sulfide evolution) then put under argon. Refluxed at 180° C. for 4 h and removed solvent under reduced pressure. Purified by column chromatography with 2.0% ethyl acetate/98% hexane to obtain the desired product as white crystals (2 g, 8.8 mmol, 15% yield). Alternatively, the reaction was cooled to about 60° C. then hexane was added for extraction. Repeated hot hexane extractions of reaction until the product was no longer obtained in residue (about four times). Combined hexane extractions and concentrated in vacuo. Purified resulting residue either through repeated hot acetone/isopropanol crystallizations (or triturations) or flash column chromatography using 2% ethyl acetate/98% hexane to obtain product as white crystals (2.92 g, 12.8 mmol, 28% yield).
Reaction SMILES: [C:1]([CH:5]1[C:11](=[O:12])[CH2:10][C@H:9]2[N:13]([CH3:14])[CH:6]1[CH2:7][CH2:8]2)([O:3][CH3:4])=[O:2].[BH4-].[Na+].[ClH:17]>CO.C(O)C>[ClH:17].[C:1]([CH:5]1[CH:11]([OH:12])[CH2:10][C@H:9]2[N:13]([CH3:14])[CH:6]1[CH2:7][CH2:8]2)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)C1C(=O)C[C@@H]2CCC1N2C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: COC(=O)C1C(O)C[C@@H]2CCC1N2C
Reaction time: 4 h

Procedure:
To a solution of (1RS,2RS)-2-carbomethoxy-3-tropanone (17 g, 85 mmol) in 750 ml methanol cooled to -35° C. was added sodium borohydride (17 g, 450 mmol) and the mixture was stirred for 4 hours, The cooled solution was quenched by slow addition of concentrated hydrochloric acid (40 ml) and the mixture was concentrated in vacuo. Water (400 ml) was added and the pH was adjusted to 3 by addition of concentrated hydrochloric acid. After having washed the water phase three times with diethyl ether pH was adjusted to 11 by addition of concentrated ammonium hydroxide and the water phase was extracted three times with methylene chloride. Concentration in vacuo yields an oil which was dissolved in ethanol and added concentrated hydrochloric acid followed by concentration in vacuo. Freeze drying the residue yielded the title compound as an amorphous product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>ClCCl>[CH3:21][S:22]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1)(=[O:24])=[O:23]
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc(NS(C)(=O)=O)cc1
Reaction time: 8 h

Procedure:
The solution of ethyl 2-(4-aminophenyl)acetate (500 mg, 2.79 mmol) and triethylamine (0.58 mL, 4.18 mmol) in dichloromethane (30 mL) was added methanesulfonyl chloride (0.24 mL, 3.07 mmol) dropwise at room temperature and stirred overnight. The mixture was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by a standard method to give desired compound. LC-MS: m/z (M+H)=258.3
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][C:5]2([CH3:12])[CH3:11].N1C=CC=CC=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:19](=[O:21])[CH3:20])[CH2:6][C:5]2([CH3:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)CNc2ccc(Br)cc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N1CC(C)(C)c2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.5 %

Procedure:
To a solution of 5-bromo-3,3-dimethyl-2,3-dihydro-1H-indole (1.6 g, 7.1 mmol) in DCM (40 mL) and pyridine (1.1 mL, 14.2 mmol) was added acetic anhydride (1 mL, 11 mmol). The reaction was stirred at room temperature overnight, then solvent was removed in vacuo and the residue partitioned between water and saturated aqueous NH4Cl. The organic phase was separated, dried (MgSO4), filtered and concentrated to give the title compound (1.8 g), used without further purification. Analytical data were consistent with those reported in Preparation 61.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].[CH3:9][O:10][C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([C:19](O)=[O:20])[CH2:15][CH2:14]1)=[O:12]>C1COCC1>[O:8]=[C:3]1[CH2:4][CH2:5][C:6](=[O:7])[N:2]1[O:1][C:19]([C@H:16]1[CH2:15][CH2:14][C@H:13]([C:11]([O:10][CH3:9])=[O:12])[CH2:18][CH2:17]1)=[O:20]
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)O)CC1
Reactant: O=C1CCC(=O)N1O
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CC[C@H](C(=O)ON2C(=O)CCC2=O)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of N-hydroxysuccinimide (6.18 g, 0.0537 mol) and trans-4-(methoxycarbonyl)cyclohexanecarboxylic acid (10.00 g, 0.05370 mol) in THF (100.00 mL) was charged with (N,N-dicyclohexylcarbodiimide (11.08 g, 0.0537 mol) in THF (16 mL). This reaction was stirred at rt for an additional 16 h then stirred at 45° C. for 1 h. The reaction mixture was filtered while still warm through a fitted funnel. The cake was washed with 3 more portions of THF and the filtrate was concentrated in vacuo and was crystallized from i-PrOH (300 mL) and filtered through a fritted funnel resulting in 11.8 g, (78% yield) of the title compound as a white crystals. 1H NMR (400 MHz, CDCl3) δ ppm 1.45-1.69 (m, 4H), 2.07-2.16 (m, 2H), 2.18-2.28 (m, 2H), 2.29-2.39 (m, 1H), 2.59-2.71 (m, 1H) 2.84 (br. s., 4H) and 3.68 (s, 3H); MS (ES+): m/z 284.09 [MH+].
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.CCN(CC)CC.[C:16](Cl)(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18]>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[CH:3]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1ccnc(N)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccnc(NC(=O)C(C)(C)C)c1
Reaction time: 4 h
Yield: 81.9 %

Procedure:
To a solution of 4-methylpyridin-2-amine (25.0 g, 0.230 mol) and Et3N (35.0 g, 0.350 mmol) in CH2Cl2 (200 ml) was added pivaloyl chloride (33.1 g, 0.270 mol) drop-wise. The mixture was stirred for 4 h under N2 atmosphere. The reaction mixture was quenched with water and was extracted with ethyl acetate (200 mL×3). The combined organic extracts were dried over anhydrous Na2SO4, evaporated under vacuum and purified by chromatography on silica gel (20% ethyl acetate in petroleum ether) to afford N-(4-methylpyridin-2-yl)pivalamide (36.2 g, 82%). 1H NMR (CDCl3, 300 MHz) δ 8.08-8.09 (m, 2H), 8.00 (br s, 1H), 6.83 (dd, J=4.8, 0.6 Hz, 1H), 2.33 (s, 3H), 1.30 (s, 9 H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH2:11].[CH3:12][S:13](Cl)(=[O:15])=[O:14]>N1C=CC=CC=1>[CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:11][S:13]([CH3:12])(=[O:15])=[O:14]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1c(N)cccc1[N+](=O)[O-]
Solvent: c1ccncc1
Product: Cc1c(NS(C)(=O)=O)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-methyl-3-nitro-phenylamine (3 g) and methanesulfonyl chloride (1.6 mL) in pyridine (30 mL, from Mallinckrodt) was stirred at room temperature overnight. Pyridine was removed under reduced pressure. The residue was taken up with dichloromethane (Mallinckrodt) and washed with water and brine. After drying over sodium sulfate and evaporation of the solvent, N-(2-Methyl-3-nitro-phenyl)-methanesulfonamide (4 g) was obtained.
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(N(CC)CC)C.[Br:21][CH:22]([CH3:26])[C:23](Br)=[O:24]>C1(C)C=CC=CC=1>[Br:21][CH:22]([CH3:26])[C:23]([O:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:24]
Reactant: CCCCCCCCCCCCO
Reactant: CC(Br)C(=O)Br
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCOC(=O)C(C)Br
Temperature: 57.5 °C
Reaction time: 3 h
Yield: 93.9 %

Procedure:
To a stirred solution of 1-decanol 2 (10 g, 53.7 mmol) in toluene (100 mL) was added triethylamine (7.5 mL, 53.7 mmol)) and followed by 2-bromo propionyl bromide 58 (12.7 g, 59.1 mmol) at 5-10° C. The reaction mixture was stirred for 3 hour at 55-60° C., and the reaction was monitored by TLC. The reaction mixture was quenched with saturated sodium bicarbonate solution and stirred for 15 minutes at 25-35° C. The aqueous and organic layers were separated, the organic layer was washed with brine, and the combined organic layers were washed with brine solution. The organic layer was dried over Na2SO4 and concentrated under vacuum to afford crude 59 (16.2 g, yield: 94%) as a liquid.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][C:7](=[O:16])[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH:19]1([CH2:22]Br)[CH2:21][CH2:20]1.S([O-])([O-])(=O)=O.[Na+].[Na+]>CN(C)C=O.ClCCl.O>[CH:19]1([CH2:22][N:6]2[C:7](=[O:16])[CH2:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=3)[CH2:21][CH2:20]1
Reactant: O=C1Cc2ccccc2-c2ccccc2N1
Reactant: BrCC1CC1
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C1Cc2ccccc2-c2ccccc2N1CC1CC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
To a solution of 0.5 g (2.4 mmol) of 5H,7H-dibenzo[b,d]azepin-6-one in 6 ml of dimethylformamide at room temperature 0.143 g (3.58 mmol) of sodium hydride was added. After stirring for 1 hour at 60° C. 0.97 g (7.2 mmol) of cyclopropylmethyl bromide were added and stirring was continued at 60° C. overnight. After cooling to room temperature the mixture was was distributed between water and dichloromethane. The combined organic layers were reextracted with sodium sulphate solution and dried (MgSO4). After concentration in vacuo the residue was purified by column chromatography (hexane/ethyl acetate=1:1) to yield 0.6 g (95%) of 5-cyclopropylmethyl-5H,7H-dibenzo[b,d]azepin-6-one as a white crystalline compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[F:12][C:13]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:14]=1[C:15](Cl)=[O:16].S1C=CC=C1C(Cl)=O>>[F:12][C:13]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:14]=1[C:15]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1)=[O:16]
Reactant: O=C(Cl)c1cc(F)ccc1F
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Agent: O=C(Cl)c1cccs1
Product: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1cc(F)ccc1F

Procedure:
4-Fluoro-3-nitro-phenylamine was reacted with 2,5-difluorobenzoyl chloride according to the procedure of Example 256a substituting 2,5-difluorobenzoyl chloride for thiophene-2-carbonyl chloride to provide 2,5-Difluoro-N-(4-fluoro-3-nitro-phenyl)-benzamide which was then reacted according to the procedures of Examples 256b and 256c to provide the title product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([OH:18])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:21][CH2:22][CH2:23][Cl:24].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:21][CH2:22][CH2:23][Cl:24])=[CH:10][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCCCBr
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)Nc1ccc(OCCCCl)c2ccccc12
Temperature: 25 °C

Procedure:
Tert-butyl(4-hydroxy-1-naphthyl)carbamate (3.93 g, 15.1 mmol), 1-bromo-3-chloropropane (5.5 g, 34.8 mmol), and K2CO3 (10.0 g, 75.8 mmol) in acetonitrile (50 ml) are heated to 80° C. with agitation for 8 h. After cooling to room temperature the mixture is filtered and concentrated under vacuum. The residue is purified by column chromatography on silica gel to yield [4-(3-chloropropoxy)-naphthalen-1-yl]-carbamic acid tert-butyl ester. 4 g, 78% is produced as an off-white solid. MS: 336.2 (M+1).
Reaction SMILES: [C:1]1([S:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[F:28][C:29]([F:56])([S:52]([OH:55])(=[O:54])=[O:53])[C:30]([F:51])([F:50])[C:31]([F:49])([F:48])[C:32]([F:47])([F:46])[C:33]([F:45])([F:44])[C:34]([F:43])([F:42])[C:35]([F:41])([F:40])[C:36]([F:39])([F:38])[F:37]>C1(C)C=CC=CC=1>[F:56][C:29]([F:28])([S:52]([O-:55])(=[O:54])=[O:53])[C:30]([F:50])([F:51])[C:31]([F:49])([F:48])[C:32]([F:46])([F:47])[C:33]([F:45])([F:44])[C:34]([F:43])([F:42])[C:35]([F:41])([F:40])[C:36]([F:39])([F:38])[F:37].[CH3:36][C:35]1[CH:30]=[CH:31][C:32]([S+:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:33][CH:34]=1
Reactant: O=S(=O)(O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: O=S(c1ccccc1)c1ccccc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: Cc1ccccc1
Product: Cc1ccc([S+](c2ccccc2)c2ccccc2)cc1
Product: O=S(=O)([O-])C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 2 °C
Reaction time: 0.5 h

Procedure:
Into a four-necked flask were charged 8.0 parts of diphenylsulfoxide and 80.0 parts of toluene, and the mixture was cooled to 2° C. Then, 16.6 parts of trifluoroacetic anhydride and 19.8 parts of perfluorooctanesulfonic acid were added and the mixture was stirred at the same temperature for 30 minutes. After standing, the lower layer was concentrated and diluted with 340 parts of chloroform. The obtained chloroform solution was washed six times with 85 parts of ion-exchange water and concentrated to give 27.7 parts of 4-methylphenyldiphenylsulfonium perfluorooctanesulfonate, which is referred to herein as PAG3.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][C:15]=1[N:16]=[N:17][C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][C:21]([N+:27]([O-:29])=[O:28])=[CH:20][C:19]=1Cl)[N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])(=[O:3])[CH3:2].[C-:31]#[N:32].[Na+].O>C(CCSCCC#N)#N>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][C:15]=1[N:16]=[N:17][C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][C:21]([N+:27]([O-:29])=[O:28])=[CH:20][C:19]=1[C:31]#[N:32])[N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])(=[O:3])[CH3:2]
Reactant: [C-]#N
Reactant: CCN(CC)c1ccc(N=Nc2c(Cl)cc([N+](=O)[O-])cc2[N+](=O)[O-])c(NC(C)=O)c1
Agent: N#CCCSCCC#N
Agent: [Na+]
Solvent: O
Product: CCN(CC)c1ccc(N=Nc2c(C#N)cc([N+](=O)[O-])cc2[N+](=O)[O-])c(NC(C)=O)c1
Reaction time: 0.5 h
Yield: 82.5 %

Procedure:
7.175 parts of cuprous bromide are dissolved in 350 parts of bis(β-cyanoethyl) sulfide. 43.45 parts of 3-acetamido-4-(2'-chloro-4',6'-dinitrophenylazo)-N,N-diethylaniline are introduced, and the mass is brought to 130° C. During 1 hour 30 minutes, in an open reactor, a solution of 6.35 parts of sodium cyanide in 20 parts of water is added to the mixture and the mixture is stirred for 4 hours at 130°-135° C. The product formed is separated as in Example 1; 35.12 parts of 3-acetamido-4-(2'-cyano-4',6'-dinitrophenylazo)-N,N-diethylaniline are obtained. The yield is 82.5%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[CH2:5][C:6]1[C:7]([CH2:13][CH3:14])=[N:8][NH:9][C:10]=1[CH2:11][CH3:12].[O-]CC.[Na+].[CH3:23][O:24][C:25](=[O:29])[CH2:26][CH2:27]Br>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[CH2:5][C:6]1[C:10]([CH2:11][CH3:12])=[N:9][N:8]([CH2:27][CH2:26][C:25]([O:24][CH3:23])=[O:29])[C:7]=1[CH2:13][CH3:14]
Reactant: COC(=O)CCBr
Reactant: CCc1n[nH]c(CC)c1Cc1cc(Cl)cc(Cl)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCc1nn(CCC(=O)OC)c(CC)c1Cc1cc(Cl)cc(Cl)c1

Procedure:
A solution of the pyrazole of Example 11 (198 mg, 0.70 mmol) in ethanol (1 ml) was treated with sodium ethoxide (21% w/v, in EtOH) (261 μL, 0.81 mmol) and then methyl-3-bromopropionate (153 μL, 1.40 mmol) and heated at 70° C. in a sealed Reacti-vial (Trade Mark) for 18 hours. Over a period of 3 days more sodium ethoxide (2.65 eq) and methyl-3-bromopropionate (6.0 eq) were added and the reaction was maintained under the same conditions. After cooling, the solution was concentrated under reduced pressure. The residue was partitioned between dichloromethane and water. The organic phase was dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel eluting with pentane:ethyl acetate (5:1, by volume) to afford two products.
Reaction SMILES: O1CCCC1.[Si]([O:13][CH2:14][C:15]1[CH:16]=[C:17]([C:21]2([OH:44])[CH2:26][CH2:25][N:24]([CH2:27][C:28]34[CH2:43][CH:35]([C:36]5[CH:37]=[CH:38][C:39]([Cl:42])=[CH:40][C:41]=53)[C:34]3[C:29]4=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:23][CH2:22]2)[CH:18]=[N:19][CH:20]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O>[Cl:42][C:39]1[CH:38]=[CH:37][C:36]2[CH:35]3[CH2:43][C:28]([CH2:27][N:24]4[CH2:23][CH2:22][C:21]([C:17]5[CH:18]=[N:19][CH:20]=[C:15]([CH2:14][OH:13])[CH:16]=5)([OH:44])[CH2:26][CH2:25]4)([C:29]4[C:34]3=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:41]=2[CH:40]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1cncc(C2(O)CCN(CC34CC(c5ccccc53)c3ccc(Cl)cc34)CC2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: OCc1cncc(C2(O)CCN(CC34CC(c5ccccc53)c3ccc(Cl)cc34)CC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.3 %

Procedure:
A tetrahydrofuran solution (15 mL) of 4-(5-(tert-butyldimethylsilyl)oxymethyl-3-pyridyl)-1-(2-chloro-9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)piperidin-4-ol (1.70 g, 3.04 mmol) was cooled to 0° C. under nitrogen and treated with tetrabutylammonium fluoride (1.0N in tetrahydrofuran, 3.20 mL, 3.20 mmol, 1.05 eq). The reaction was warmed to room temperature and stirred at that temperature for 3 h. Water (15 mL) was added and the resulting aqueous phase was extracted with ethyl acetate (3×15 mL). Combined organic extracts were dried over anhydrous sodium sulfate, filtered, and reduced to an oil. This procedure resulted in 1.20 g (89%) of the title compound. TLC analysis (Rf 0.11, 5% methanol in diethyl ether). No additional purification was required. 1H NMR (CDCl3, 250 MHz) 8.62 (s, 1H), 8.42 (s, 1H), 7.84 (s, 1H), 7.21 (m, 4H), 6.94 (m, 3H), 4.69 (s, 2H), 4.27 (s, 1H), 3.44 (s, 2H), 2.90 (m, 2H), 2.74 (m, 2H), 2.62 (d, J=1.3 Hz, 2H), 2.11 (m, 2H), 1.76 (m, 2H) MS (CI, CH4) m/z 447 (M+1,100), 449 (32), 475 (M+29,19), 429 (71), 431 (25). The free base was dissolved in ether and acidified with ethereal HCl. The hydrochloride salt was filtered, rinsed with fresh ether and dried in vacuo (room temperature, 10 pascal, 18 h) to yield a white solid, mp 235°-240° C. (dec).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[C:10]1([OH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[Na+].[Na+].O>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1
Reactant: Oc1ccccc1
Reactant: O=C(O)c1ccc(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(-c2ccccc2O)s1
Reaction time: 0.08 h
Yield: 84.3 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (133 mg, 0.12 mmol) is added to a solution of 5-bromothiophene-2-carboxylic acid (850 mg, 4.1 mmol) in degassed THF (10 mL). The resulting solution is stirred for 5 minutes and then 2-(4,4,5,5-tetramethyl)-1,3,2-dioxaborolan-2-yl) phenol (1 g, 4.6 mmol) is added followed by aqueous Na2CO3 (2M, 6.9 mL). The mixture is heated at reflux overnight. The reaction mixture is allowed to cool, poured into water (50 mL), and washed with ether (3×50 mL). The aqueous layer is acidified with concentrated HCl to pH<2. The resulting precipitate is collected by filtration, washed with water and dried in vacuo to yield the desired product (761 mg, 83%). MS for C11H7O3S (ESI) (M−H)+ m/z 219.