Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[Cl:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].N1C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[C:16]([Cl:15])[CH:17]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: Nc1cccc(Cl)c1
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(S(=O)(=O)Nc2cccc(Cl)c2)ccc1Cl
Temperature: 25 °C

Procedure:
A mixture of 4-chloro-3-nitrobenzenesulfonylchloride (1g, 3.9 mmol), 3-chloroaniline (0.5 mL, 4.7 mmol) and pyridine (1.6 mL) in CH2Cl2 (2 mL) was stirred at room temperature. The reaction was quenched with NaHCO3 (sat aq solution, 30 mL×3). The organic phase was separated, dried (MgSO4), and filtered. The volatiles were evaporated and the residue was purified by column chromatography (SiO2, pentane:EtOAc, 4:1) to give 4-chloro-N-(3-chlorophenyl)-3-nitrobenzenesulfonamide; MS (posESI) m/z=349.2 (M+H+). 1H NMR (CDCl3) δ 7.00-7.40 (m, 3H), 7.60-7.90 (m, 3H), 8.70 (bs, 1H). 4-Chloro-N-(3-chlorophenyl)-3-nitrobenzenesulfonamide (0.45 g, 1.3 mmol), N-methylpiperazine (0.191 mL, 1.73 mmol) and K2CO3 (359 mg, 2.6 mmol) in CH3CN (2.5 mL) as the filtrated was concentrated to give a residue which was purified by column (SiO2, CHCl3:MeOH: NH3 9:1:0.4%) to give 420 mg of N-(3-chlorophenyl)-4-(4-methyl-1-piperazinyl)-3-nitrobenzenesulfonamide (85%). Purity>95% according to HPLC analysis. The compound was dissolved in THF (1 mL) and ethanol (5 mL) was added. The solution was treated with Raney-Ni (50 mg) and hydrazine monohydrate (0.05 mL) overnight. The Raney-Ni was filtered (celite pad), the volatiles were evaporated and the residue was purified by column chromatography (SiO2, CHCl3:MeOH: NH3 9:1:0.4%). The product was isolated as hydrochloride salt by treatment with HCl gas in diethyl ether to yield 170 mg of final product (32%).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([PH:11](=[O:15])[O:12][CH2:13][CH3:14])([O:8][CH2:9][CH3:10])[CH3:7])[CH3:4].Cl[CH:17]([F:19])[F:18]>O1CCCC1>[CH2:9]([O:8][C:6]([P:11]([CH:17]([F:19])[F:18])(=[O:15])[O:12][CH2:13][CH3:14])([O:5][CH2:3][CH3:4])[CH3:7])[CH3:10]
Reactant: FC(F)Cl
Reactant: CCO[PH](=O)C(C)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(C)(OCC)P(=O)(OCC)C(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 15.8 g of sodium hydride (dispersion in oil) in 500 ml of tetrahydrofuran are added dropwise 67 g (300 mMol) of ethyl 1,1-diethoxyethylphosphinate at such a rate so that the temperature does not exceed 25° C. This mixture is stirred for one hour at room temperature, then cooled to -10° C. and 77.8 g (900 mMol) of chlorodifluoromethane are introduced. Stirring is continued for another 2 hours at room temperature, then 100 ml of ice-cold water are added. The mixture is extracted three times with dichloromethane and the combined extracts dried over magnesium sulphate. Removal of the solvent in vacuo gives ethyl 1,1-diethoxyethyl(difluoromethyl)phosphinate as a viscous oil, Rf=0.44 (CH2Cl2 /CH3COOH, 9+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH2:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.Cl[CH2:13][CH2:14][N:15]([CH2:26][CH2:27]Cl)[S:16]([C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)(=[O:18])=[O:17]>C(N(C(C)C)CC)(C)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:11]2[CH2:27][CH2:26][N:15]([S:16]([C:19]3[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=3)(=[O:18])=[O:17])[CH2:14][CH2:13]2)([CH3:9])[CH3:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)N(CCCl)CCCl)cc1
Reactant: CC(C)(N)c1ccc(Br)cc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)N2CCN(C(C)(C)c3ccc(Br)cc3)CC2)cc1

Procedure:
To a solution of 1-(4-bromo-phenyl)-1-methyl-ethylamine (400 mg, 1.84 mmol) in diisopropylethylamine (4 mL) was added N,N-bis(2-chloroethyl)-4-methylbenzene sulphonamide (500 mg, 1.68 mmol) and the reaction subjected to microwave irradiation at 150° C. for 9 h afterwhich time the reaction was concentrated in vacuo and the crude residue purified by reverse phase preparative HPLC-MS to afford 1-[1-(4-bromo-phenyl)-1-methyl-ethyl]-4-(toluene-4-sulfonyl)-piperazine as a peach solid (375 mg, 47%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[N:7]=[C:6]([O:14][CH:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)[CH:5]=1.Cl.O1CCOCC1>C(Cl)Cl>[CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:11])[F:12])[N:7]=[C:6]([O:14][CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH:5]=1
Reactant: COCc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)nc(C(F)(F)F)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COCc1cc(OC2CCNCC2)nc(C(F)(F)F)c1
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-{[4-(methoxymethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidine-1-carboxylate (40. mg, 0.10 mmol, from Step C) in Methylene chloride (1.0 mL) was added 4.0M Hydrogen chloride in dioxane (0.50 mL, 2.0 mmol). The reaction mixture was stirred for one hour. The solvent was removed in vacuo. The residue was dissolved in DCM, and this solution was washed with saturated sodium bicarbonate, water (2×), brine, dried over sodium sulfate, filtered and concentrated to give product which was used without further purification (30 mg, 100%). 1H NMR (400 MHz, CDCl3) δ 7.18 (s, 1H), 6.84 (s, 1H), 5.19 (tt, J=8.4, 3.6 Hz, 1H), 4.45 (s, 2H), 3.44 (s, 3H), 3.19-3.03 (m, 2H), 2.88-2.70 (m, 2H), 2.13-1.97 (m, 2H), 1.73-1.53 (m, 2H); 19F NMR (376 MHz, CDCl3) δ−68.89 (s); LCMS (M+H)+: 291.1.
Reaction SMILES: Cl[C:2]1[C:3](=[O:18])[N:4]([CH:15]([CH3:17])[CH3:16])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:19][C:20]1[C:24]([CH2:25][CH2:26][NH2:27])=[C:23]([CH3:28])[O:22][N:21]=1>>[CH3:19][C:20]1[C:24]([CH2:25][CH2:26][NH:27][C:2]2[C:3](=[O:18])[N:4]([CH:15]([CH3:17])[CH3:16])[S:5](=[O:14])(=[O:13])[C:6]=2[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:23]([CH3:28])[O:22][N:21]=1
Reactant: Cc1noc(C)c1CCN
Reactant: CC(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Product: Cc1noc(C)c1CCNC1=C(c2ccccc2)S(=O)(=O)N(C(C)C)C1=O

Procedure:
The title compound was prepared from 4-chloro-2-isopropyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide and [2-(3,5-dimethylisoxazol-4-yl)ethyl]amine in a similar manner as described for Example 24. 1H NMR (500 MHz, CDCl3): δ 7.54-7.50 (m, 2H), 7.49-7.45 (m, 3H), 5.32 (t, 1H), 4.47 (sept, 1H), 3.04 (q, 2H), 2.33 (t, 2H), 2.14 (s, 3H), 2.01 (s, 3H), 1.59 (d, 6H); 13C NMR (125 MHz, CDCl3): δ 166.1, 159.4, 158.6, 134.9, 131.4, 130.2, 129.2, 125.1, 109.7, 107.9, 47.9, 43.3, 23.0, 20.4, 11.1, 10.2; Mass Spectrum: M+H+ 390
Reaction SMILES: [CH3:1][C:2]1[N:3]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH:4]=[C:5]([C:7](=[O:9])[CH3:8])[CH:6]=1.[Br:19]Br>C(Cl)(Cl)Cl>[CH3:1][C:2]1[N:3]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:11])=[O:12])[CH:4]=[C:5]([C:7](=[O:9])[CH2:8][Br:19])[CH:6]=1
Reactant: BrBr
Reactant: CC(=O)c1cc(C)n(S(=O)(=O)c2ccccc2)c1
Solvent: ClC(Cl)Cl
Product: Cc1cc(C(=O)CBr)cn1S(=O)(=O)c1ccccc1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 58.4 %

Procedure:
A solution of 13.3 g (50 mmole) of 1-(2-methyl-1-phenylsulfonyl-pyrrol-4-yl)-1-ethanone in 320 ml of chloroform was stirred at -10° C. and a solution of 2.56 ml (8.0 g, 50 mmole) of bromine in 40 ml of chloroform was added dropwise over six hours. After the addition was completed, the mixture was stirred at -10° C. for 0.5 hours, then allowed to warm to room temperature. The mixture was concentrated, and the residue was chromatographed over silica gel using 1:1:0.1 hexane/toluene/ethyl acetate as eluent to give 10.0 g (59%) of the product as a white solid; m.p. 86°-88° C.
Reaction SMILES: [CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH:2]([CH3:4])[CH3:3].[C:25]([NH:33][C@H:34]([C:39](O)=[O:40])[CH2:35][C:36](=[O:38])[NH2:37])(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH3:24][C:21]1[CH:22]=[CH:23][C:18]([S:15]([N:5]([C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:39]([C@@H:34]([NH:33][C:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:32])[CH2:35][C:36]([NH2:37])=[O:38])=[O:40])[CH2:1][CH:2]([CH3:3])[CH3:4])(=[O:17])=[O:16])=[CH:19][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCN)C(=O)O)cc1
Reactant: NC(=O)C[C@H](NC(=O)c1ccccc1)C(=O)O
Product: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)[C@H](CC(N)=O)NC(=O)c2ccccc2)C(=O)O)cc1

Procedure:
The title compound was prepared from Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-L-lysine (100 mg, 0.29 mmol, example 1, step E) as described in general procedure Bc using Nα-benzoyl-L-asparagine (70 mg, 0.3 mmol) which was prepared in step A this example. The final product was purified by preparative HPLC to yield 14 mg (9%) of the desired material.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]2[C:6]([O:11][CH2:12][CH3:13])=[N:7][S:8](=[O:10])(=[O:9])[C:4]=2[CH:3]=1.[C:16](OC=O)(=[O:18])C>>[CH:16]([NH:1][C:2]1[CH:15]=[CH:14][C:5]2[C:6]([O:11][CH2:12][CH3:13])=[N:7][S:8](=[O:10])(=[O:9])[C:4]=2[CH:3]=1)=[O:18]
Reactant: CC(=O)OC=O
Reactant: CCOC1=NS(=O)(=O)c2cc(N)ccc21
Product: CCOC1=NS(=O)(=O)c2cc(NC=O)ccc21

Procedure:
Following the procedures outlined in Description 4a, 6-amino-3-ethoxy-benzoisothiazole-1,1-dioxide was reacted with formic-acetic anhydride to give the title compound.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4]Br.C(=O)([O-])[O-].[K+].[K+].[Cl:12][C:13]1[CH:18]=[C:17]([O:19][CH2:20][CH:21]=[C:22]([Cl:24])[Cl:23])[CH:16]=[C:15]([Cl:25])[C:14]=1[OH:26].O>CN(C)C=O>[Cl:12][C:13]1[CH:18]=[C:17]([O:19][CH2:20][CH:21]=[C:22]([Cl:24])[Cl:23])[CH:16]=[C:15]([Cl:25])[C:14]=1[O:26][CH2:4][CH2:3][CH2:2][Br:1]
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: ClC(Cl)=CCOc1cc(Cl)c(OCCCBr)c(Cl)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 51.7 %

Procedure:
A reaction vessel was charged with 10.6 g of 1,3-dibromopropane, 5.53 g of potassium carbonate and 100 ml of N,N-dimethylformamide, to which a solution of 30.5 g of 2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenol dissolved in 40 ml of N,N-dimethylformamide was slowly added dropwise. After stirring at room temperature for 24 hours, the reaction mixture was poured into water, and extracted twice with 150 ml of diethyl ether. The combined ether layer was washed with water, dried with anhydrous magnesium sulfate, and concentrated to obtain a crude product. The crude product was subjected to silica gel chromatography, which afforded 11.1 g of 3,5-dichloro-4-(3-bromopropyloxy)-1-(3,3-dichloro-2-propenyloxy)benzene (77% yield), nD24.0 1.5693.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([C:13]([OH:16])([CH3:15])[CH3:14])[CH:10]=[CH:9][C:8]=2[NH:17][C:18]([C:20]2[NH:21][CH:22]=[C:23]([C:25]#[N:26])[N:24]=2)=[O:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.OS(O)(=O)=O.CO.[C:34]([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]1([C:7]2[CH:12]=[C:11]([C:13]([O:16][CH3:34])([CH3:15])[CH3:14])[CH:10]=[CH:9][C:8]=2[NH:17][C:18]([C:20]2[NH:21][CH:22]=[C:23]([C:25]#[N:26])[N:24]=2)=[O:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: O=C([O-])O
Reactant: CC(C)(O)c1ccc(NC(=O)c2nc(C#N)c[nH]2)c(C2=CCCCC2)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COC(C)(C)c1ccc(NC(=O)c2nc(C#N)c[nH]2)c(C2=CCCCC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44 %

Procedure:
To a solution of 4-cyano-1H-imidazole-2-carboxylic acid [2-cyclohex-1-enyl-4-(1-hydroxy-1-methyl-ethyl)-phenyl]-amide (as prepared in example 12, 18.0 mg, 0.0514 mmol) in 1 mL of DCM was added conc H2SO4 (50 μL) followed by 50 μL of MeOH. The resulting mixture was stirred at RT for 0.5 h and then treated with 10 mL of saturated NaHCO3 aqueous solution. The mixture was extracted with EtOAc (2×20 mL). The combined organic layers were washed with H2O (10 mL), brine (10 mL) and dried (Na2SO4). Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (1% MeOH/DCM) gave 8.2 mg (44%) of the title compound as a white solid. 1H-NMR (CDCl3; 400 MHz): δ 12.31 (s, 1H), 9.65 (s, 1H), 8.30 (d, 1H, J=8.6 Hz), 7.76 (s, 1H), 7.35 (dd, 1H, J=8.6, 2.3 Hz), 7.25 (d, 1H, J=2.3 Hz), 5.88 (m, 1H), 3.11 (s, 3H), 2.23-2.37 (m, 4H), 1.75-1.90 (m, 4H), 1.55 (s, 6H).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH:17]=O.O>C1(C)C=CC=CC=1>[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH:17]=[N:6][C:5]1[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=Cc1ccccn1
Reactant: Nc1ccccc1[N+](=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=[N+]([O-])c1ccccc1N=Cc1ccccn1

Procedure:
27.6 g of o-nitroaniline and 21.4 g of 2-pyridine aldehyde are heated in 200 ml of toluene for 10 hours, and the water formed is collected by means of a water separator. 500 ml of diethyl ether are then added to the solution, and the crystals which precipitate are filtered off with suction.
Reaction SMILES: [Br:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[F:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][C:18]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[C:15]1[CH:16]=[CH:17][C:18]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[C:13]([F:12])[CH:14]=1
Reactant: Clc1ccc2[nH]ncc2c1Br
Reactant: OB(O)c1ccc(OCc2ccccc2)c(F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Fc1cc(-n2ncc3c(Br)c(Cl)ccc32)ccc1OCc1ccccc1
Reaction time: 120 h

Procedure:
A mixture of 4-bromo-5-chloro-1H-indazole (D22) (0.361 g, 1.56 mmol), {3-fluoro-4-[(phenylmethyl)oxy]phenyl}boronic acid (0.57 g, 2.32 mmol), copper (II) acetate (0.42 g, 2.31 mmol) and pyridine (0.25 mL, 3.10 mmol) in dichloromethane (50 mL) were stirred together vigorously under an air atmosphere with powdered 4A molecular sieves (1.5 g). After 5 days, the mixture was filtered through celite and the solvent evaporated. The concentrate was chromatographed (silica, dichloromethane/hexane) to give the title compound (D23) as an off white solid (0.32 g)
Reaction SMILES: [CH3:1][C:2]([CH3:27])([CH3:26])[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]([OH:12])=[O:11])=[C:7]([N:13]([CH:23]([CH3:25])[CH3:24])[C:14]([C@H:16]2[CH2:21][CH2:20][C:19]([CH3:22])=[CH:18][CH2:17]2)=[O:15])[CH:6]=1.[CH3:28]C(C)(C)C#CC1SC(C(OC)=O)=C(NC(C)C)C=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CCOC(C)=O>ClC(Cl)C>[CH3:1][C:2]([CH3:26])([CH3:27])[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]([O:12][CH3:28])=[O:11])=[C:7]([N:13]([CH:23]([CH3:24])[CH3:25])[C:14]([C@H:16]2[CH2:21][CH2:20][C:19]([CH3:22])=[CH:18][CH2:17]2)=[O:15])[CH:6]=1
Reactant: CC1=CC[C@@H](C(=O)N(c2cc(C#CC(C)(C)C)sc2C(=O)O)C(C)C)CC1
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1NC(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@@H]1CC=C(C)CC1)C(C)C
Temperature: 90 °C
Reaction time: 16 h
Yield: 50.7 %

Procedure:
4-Methyl-cyclohex-3-enecarbonyl chloride (S) (0.71 mmol), methyl 5-(3,3-dimethylbut-1-ynyl)-3-(isopropylamino)thiophene-2-carboxylate (80 mg, 0.29 mmol) and potassium phosphate tribasic (152 mg, 0.71 mmol) were suspended in dichloroethane (0.75 mL), sealed with a cap and heated to 90° C. After 16 h, the reaction mixture was cooled and partitioned between ethyl acetate and water. The organic layer was separated and the aqueous extracted again with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated. Flash chromatography (10-35% EtOAc:Hexanes) afforded 59 mg (51% yield) of the desired (S)-methyl 5-(3,3-dimethylbut-1-ynyl)-3-(N-isopropyl-4-methylcyclohex-3-enecarboxamido)thiophene-2-carboxylate as a white foam.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:8]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[N:9][C:10]3[C:15]([N:16]=2)=[CH:14][C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].I[CH3:31]>O1CCCC1>[CH:1]1([N:6]([CH3:31])[C:7]2[C:8]([C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)=[N:9][C:10]3[C:15]([N:16]=2)=[CH:14][C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CI
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(NC3CCCC3)nc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N(C)C3CCCC3)nc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 3-(cyclopentylamino)-2-(4-fluorophenyl)quinoxaline-6-carboxylate (200 mg, 0.55 mmol) in tetrahydrofuran (15 mL) was added sodium hydride (96 mg, 4.00 mmol) at 0° C. After stirring for 1 h at room temperature, iodomethane (141.94 mg, 1.00 mmol) was added at 0° C. and the reaction mixture was stirred overnight. The reaction was then quenched by the addition of water (3 mL), extracted with dichloromethane (3×15 mL), and the organic layers combined, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give methyl 3-(cyclopentyl(methyl)amino)-2-(4-fluorophenyl)quinoxaline-6-carboxylate as a yellow oil (120 mg, crude).
Reaction SMILES: [F:1][C:2]([F:37])([C:33]([F:36])([F:35])[F:34])[C:3]([F:32])([F:31])[C:4]([F:30])([F:29])[C:5]([F:28])([F:27])[C:6]([F:26])([F:25])[C:7]([F:24])([F:23])[C:8]([F:22])([F:21])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]O.[BrH:38].S(=O)(=O)(O)O>O>[Br:38][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:8]([F:21])([F:22])[C:7]([F:23])([F:24])[C:6]([F:25])([F:26])[C:5]([F:27])([F:28])[C:4]([F:29])([F:30])[C:3]([F:31])([F:32])[C:2]([F:1])([F:37])[C:33]([F:34])([F:35])[F:36]
Reactant: Br
Reactant: OCCCCCCCCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: O
Product: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)CCCCCCCCCCCBr
Temperature: 100 °C

Procedure:
To a mixture of 29.0 g of crude 11-(heptadecafluorooctyl)-1-undecanol and 250 mL of 48% hydrobromic acid was slowly added 25 mL of concentrated sulfuric acid. The reaction mixture was heated at 100° C. for 18 hr and poured into 1 liter of water. The mixture was extracted with hexanes, and the combined organic phases were washed with saturated aqueous sodium bicarbonate and dried over anhydrous magnesium sulfate. The solution was concentrated to a dark liquid, which was eluted through 3 inches of silica with hexanes. Concentration of the eluent afforded 20.2 g of crude 1-bromo-11-(heptadecafluorooctyl)undecane as a nearly white solid, which was used without further purification.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:12])[C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6]Cl.[CH3:13][C:14]1([CH3:21])[NH:18][C:17](=[S:19])[NH:16][C:15]1=[S:20]>C(Cl)(Cl)Cl>[CH3:2][N:3]([CH3:12])[C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][S:19][C:17]1[NH:18][C:14]([CH3:21])([CH3:13])[C:15](=[S:20])[N:16]=1
Reactant: CN(C)c1ccccc1CCl
Reactant: CC1(C)NC(=S)NC1=S
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CN(C)c1ccccc1CSC1=NC(=S)C(C)(C)N1
Reaction time: 0.5 h

Procedure:
Initially, 11 g of 2-dimethylaminobenzylchloride hydrochloride was added to a solution of 8 g of 5,5-dimethyl-2,4-dithiohydantoin in 200 mL of chloroform (CHCl3) at about 60° C. The reaction mixture was stirred for 30 minutes and washed with an aqueous solution of NaHCO3, dried over MgSO4, and concentrated in vacuo. The residue was treated following the procedure used for the compound (a). As a result, the desired compound of 2-(2-dimethylaminobenzylthio)-5,5-dimethylimidazolin-4-thione was isolated by column chromatography. The yield of this compound was 9.1 g with a yield ratio of 62.1%. Further, the desired compound of 2,4-bis(2-dimethylaminobenzylthio)-5,5-dimethyl-5H-imidazole was isolated. The yield of this compound was 1.2 g with a yield ratio of 5.6%.
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][C:4]([C:7]2[O:8][C:9]3[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:10]=3[CH:11]=2)=[CH:3][CH:2]=1.[CH:19](=NC1C=CC=CC=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:1]1([CH:18]=[CH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:2]=[CH:3][C:4]([C:7]2[O:8][C:9]3[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:10]=3[CH:11]=2)=[CH:5][CH:6]=1
Reactant: COc1ccc2cc(-c3ccc(C)cc3)oc2c1
Reactant: C(=Nc1ccccc1)c1ccccc1
Product: COc1ccc2cc(-c3ccc(C=Cc4ccccc4)cc3)oc2c1

Procedure:
Following the procedure given in Example 1b 2-(p-tolyl)-6-methoxybenzofuran was interacted with an equimolar quantity or benzalaniline to produce 2-(4-stilbenyl)-6-methoxybenzofuran, which, when recrystallized from toluene, melted at 223.5°-225.5° C. The wavelength of maximum excitation of this compound was 371 nm., and the wavelength of maximum emission was 446 nm.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[O:3][C:4]1[CH:5]=[C:6]([CH2:10][N:11]2[C:23]3[CH:22]=[CH:21][CH:20]=[C:19]([OH:24])[C:18]=3[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][C:16]=3[C:25](=[O:27])[NH2:26])[CH:7]=[CH:8][CH:9]=1.Br[CH2:31][C:32]([O:34][CH3:35])=[O:33]>CN(C=O)C.C(OCC)(=O)C>[F:29][C:2]([F:28])([F:1])[O:3][C:4]1[CH:5]=[C:6]([CH2:10][N:11]2[C:23]3[CH:22]=[CH:21][CH:20]=[C:19]([O:24][CH2:31][C:32]([O:34][CH3:35])=[O:33])[C:18]=3[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][C:16]=3[C:25](=[O:27])[NH2:26])[CH:7]=[CH:8][CH:9]=1
Reactant: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc(OC(F)(F)F)c1
Reactant: COC(=O)CBr
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1cccc(OC(F)(F)F)c1
Reaction time: 0.05 h
Yield: 82.5 %

Procedure:
40% Methanolic Triton B (0.15 mL, 0.34 mM) was added to a solution of the 9-[(3-trifluoromethoxyphenyl)methyl]-4-hydroxy-5-carbamoyl carbazole (115 mg, 0.28 mM) in 8 mL DMF at room temperature. After 3 minutes, methyl bromoacetate (65 mg, 0.41 mM) was added and the resultant mixture stirred at room temperature for 23 hours. The mixture was diluted with ethyl acetate, washed with H2O, and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with ethyl acetate) to afford 112 mg (83%) of the {9-[(3-trifluoromethoxyphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester as a white solid. 1H NMR (DMSO-d6) δ 7.6 (d, 1H, J=8 Hz), 7.55 (br s, 1H), 7.5-7.0 (m, 9H), 6.6 (d, 1H, J=8 Hz), 5.7 (s, 2H), 4.9 (s, 2H), and 3.75 (s, 3H). IR (KBr, cm−1) 3488, 3141, 1763, 1674, 1501, 1444, 1269, 1215, 1178, 1102, 772, and 714. MS (FD) m/e 472.
Reaction SMILES: Cl.[F:2][C:3]([F:35])([C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][N:29]=2)=[CH:24][CH:23]=1)[C:4]([C:6]1[N:7](S(N(C)C)(=O)=O)[CH:8]=[C:9]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[N:10]=1)=[O:5].C[OH:37]>>[CH3:14][C:12]([CH3:13])([CH3:15])[CH2:11][C:9]1[N:10]=[C:6]([C:4]([OH:5])([OH:37])[C:3]([F:2])([F:35])[C:22]2[CH:23]=[CH:24][C:25]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][N:29]=3)=[CH:26][CH:27]=2)[NH:7][CH:8]=1
Reactant: CN(C)S(=O)(=O)n1cc(CC(C)(C)C)nc1C(=O)C(F)(F)c1ccc(-c2ccc(F)cn2)cc1
Reactant: CO
Agent: Cl
Product: CC(C)(C)Cc1c[nH]c(C(O)(O)C(F)(F)c2ccc(-c3ccc(F)cn3)cc2)n1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
Hydrogen chloride (4 M in 1,4-dioxane) (1 mL, 4 mmol) was added to an ambient temperature solution of 2-{difluoro[4-(5-fluoropyridin-2-yl)phenyl]acetyl}-4-(2,2-dimethylpropyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (20 mg, 0.04 mmol) in methanol (2 mL). After stirring at 70° C. for 1 h, volatiles were removed. The residue was partitioned between ethyl acetate and 10% aqueous sodium hydroxide. The aqueous phase was extracted with ethyl acetate. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-50% ethyl acetate/hexane afforded the title compound. LCMS: 406 (M+H).