Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C@@:7]([Cl:28])([C@H:8]([Cl:27])[CH2:9][C@@H:10]3[C@@H:21]2[CH2:20][CH2:19][C@@:18]2([CH3:26])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C:15](=[O:17])[CH3:16])[CH2:6]1)(=[O:3])[CH3:2].[F:29]C(F)(F)C([O-])=O.[Na+].[F-].[Na+].FF>FC(Cl)(Cl)Cl.C(Cl)(Cl)Cl>[C:1]([O:4][C@H:5]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C@@:7]([Cl:28])([C@H:8]([Cl:27])[CH2:9][C@@H:10]3[C@@H:21]2[CH2:20][CH2:19][C@@:18]2([CH3:26])[C@@:11]3([F:29])[CH2:12][CH2:13][C@@H:14]2[C:15](=[O:17])[CH3:16])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: O=C([O-])C(F)(F)F
Reactant: CC(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@]4(C)[C@@H](C(C)=O)CC[C@H]4[C@@H]3C[C@@H](Cl)[C@@]2(Cl)C1
Agent: FF
Agent: [F-]
Agent: [Na+]
Solvent: FC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CC(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@]4(C)[C@@H](C(C)=O)CC[C@@]4(F)[C@@H]3C[C@@H](Cl)[C@@]2(Cl)C1

Procedure:
3β-Acetoxy-5α,6β-dichloropregnan-20-one (1.4 g) was dissolved in fluorotrichloromethane (250 ml) and chloroform (200 ml) containing sodium trifluoroacetate (ca. 2 g) and sodium fluoride (ca. 2 g). The resulting solution was cooled to -78° and vigourously stirred, whereupon fluorine from four 750 cc bottles (10% v/v fluorine in nitrogen) was bubbled through the solution over a period of 8 hours. The reaction solution was then poured into aqueous sodium thiosulphate and the organic layer was separated, washed with water, dried over potassium carbonate and evaporated to dryness to yield crude 3β-acetoxy-5α,6β-dichloro-14α-fluoropregnan-20-one.
Reaction SMILES: [F:1][C:2]([F:21])([C:17]([F:20])([F:19])[F:18])[C:3]([F:16])([F:15])[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[OH:14])=[O:5].N1C=CC=CC=1.C(#N)C.[C:31](Cl)(=[O:35])[C:32]([CH3:34])=[CH2:33]>O>[F:1][C:2]([F:21])([C:17]([F:18])([F:19])[F:20])[C:3]([F:16])([F:15])[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:31](=[O:35])[C:32]([CH3:34])=[CH2:33])=[CH:9][C:8]=1[OH:14])=[O:5]
Reactant: Nc1ccc(NC(=O)C(F)(F)C(F)(F)C(F)(F)F)c(O)c1
Reactant: C=C(C)C(=O)Cl
Solvent: O
Solvent: CC#N
Solvent: c1ccncc1
Product: C=C(C)C(=O)Nc1ccc(NC(=O)C(F)(F)C(F)(F)C(F)(F)F)c(O)c1
Yield: 61.8 %

Procedure:
To 64 g (0.2 mol) of 2-heptafluorobutanamido-5-aminophenol were added 18 g (0.22 mol) of pyridine and 500 ml of acetonitrile and mixture was cooled with stirring. To the solution was added dropwise 23 g (0.22 mol) of methacrylic chloride. After the completion of the reaction, 500 ml of water was added to the reaction solution and the crystals thus deposited were collected and recrystallized from acetonitrile to obtain 48 g of Monomer Coupler (15).
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]1=[O:20].[C:21]1([CH:27]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:28][C:29](O)=[O:30])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:7]([N:4]1[CH2:5][CH2:6][CH:2]([NH:1][C:29](=[O:30])[CH2:28][CH:27]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:3]1=[O:20])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NC1CCN(C(c2ccccc2)c2ccccc2)C1=O
Reactant: O=C(O)CC(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(CC(c1ccccc1)c1ccccc1)NC1CCN(C(c2ccccc2)c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
To a solution of 3-amino-1-benzhydryl-pyrrolidin-2-one (42) (0.2 g, 0.75 mmol) in dry CH2Cl2 (20 ml)was added 3,3-diphenylpropionic acid (0.19 g, 0.82 mmol) under nitrogen. To the reaction was added EDC (0.18 g, 0.9 mmol) and DMAP (cat), and the reaction mixture was stirred under nitrogen at room temperature overnight. The reaction was then concentrated under reduced pressure. The residue was dissolved in ethyl acetate: water (10:1) (100 ml). The organic was washed with water (25 ml, 2×) and 10% NaOH (25 ml), dried over MgSO4 and evaporated to dryness. The resulting residue was purified by column chromatography using hexane:ethyl acetate (2:1) to give the desired product in 70% yield
Reaction SMILES: [Cl:1][C:2]1[C:11]([NH2:12])=[C:10]([NH:13][C@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[N:22]#[C:23][Br:24]>C(O)C>[BrH:24].[Cl:1][C:2]1[C:11]2[N:12]=[C:23]([NH2:22])[N:13]([C@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:15])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: C[C@H](Nc1c(N)c(Cl)nc2ccccc12)c1ccccc1
Reactant: N#CBr
Solvent: CCO
Product: Br
Product: C[C@@H](c1ccccc1)n1c(N)nc2c(Cl)nc3ccccc3c21
Temperature: 80 °C
Reaction time: 8 h
Yield: 53.3 %

Procedure:
A solution of 2-chloro-N4-[(1S)-1-phenylethyl]quinoline-3,4-diamine (13.0 g, 43.7 mmol) in ethanol (100 mL) was heated to 80° C. for 30 minutes. Cyanogen bromide (4.6 g, 44 mmol) was added, and the dark solution was heated at 80° C. for one hour. An analysis by LC/MS indicated the presence of starting material. Additional cyanogen bromide (4.6 g, 44 mmol) was added, and the reaction was stirred overnight at 80° C. The reaction was still incomplete, and additional cyanogen bromide (4.6 g, 44 mmol) was added. The reaction was heated overnight at 100° C. after a fourth equivalent of cyanogen bromide (4.6 g, 44 mmol) was added. The solvent was removed under reduced pressure, and aqueous sodium hydroxide (200 mL of 2 N) was slowly added to the resulting oil. The mixture was stirred for two hours at room temperature, and a precipitate formed, which was isolated by filtration. The solid was then purified by automated flash chromatography (silica cartridge, eluting with aqueous ammonium hydroxide:methanol:dichloromethane in a gradient from 0:0:100 to 0.3:4.7:95) to provide 9.4 g of 4-chloro-1-[(1S)-1-phenylethyl]-1H-imidazo[4,5-c]quinolin-2-amine hydrobromide as a brown solid. A portion of the product was purified again by automated flash chromatography (silica cartridge, eluting with aqueous ammonium hydroxide:methanol:dichloromethane in a gradient from 0:0:100 to 0.2:3.8:96) to provide a sample of the product as gray needles, mp 170-172° C.
Reaction SMILES: [ClH:1].[OH:2][C@H:3]1[C@@H:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH2:8][C:7]2[CH:18]=[C:19]([C:22]([F:25])([F:24])[F:23])[CH:20]=[CH:21][C:6]=2[N:5]([CH2:26][CH2:27][N:28]([CH3:30])[CH3:29])[C:4]1=[O:31].[H-].[Na+].I[CH3:35]>CN(C)C=O>[ClH:1].[CH3:35][O:2][C@H:3]1[C@@H:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH2:8][C:7]2[CH:18]=[C:19]([C:22]([F:23])([F:25])[F:24])[CH:20]=[CH:21][C:6]=2[N:5]([CH2:26][CH2:27][N:28]([CH3:30])[CH3:29])[C:4]1=[O:31]
Reactant: CI
Reactant: COc1ccc([C@H]2Cc3cc(C(F)(F)F)ccc3N(CCN(C)C)C(=O)[C@H]2O)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc([C@H]2Cc3cc(C(F)(F)F)ccc3N(CCN(C)C)C(=O)[C@H]2OC)cc1
Reaction time: 0.5 h

Procedure:
A solution of (cis)-3-(hydroxy)-1-[2-(dimethylamino)ethyl]-1,3,4,5-tetrahydro-4-(4-methoxyphenyl)-7-(trifluoromethyl)-2H-1-benzazepin-2-one, monohydrochloride (0.81 g, 1.92 mmol) in 21 ml of dimethylformamide was treated with sodium hydride (0.23 g, 5.76 mmol of a 60% mineral oil dispersion) at room temperature under argon. Stirring was continued for 30 minutes. The temperature was lowered to 0° C., iodomethane was added (0.13 ml, 2.11 mmol) and the reaction was continued for 11/2 hours at 0° C. The reaction was quenched at 0° C. with water. Dimethylformamide and water were removed in vacuo. Hexane and 1M hydrochloric acid were added, the aqueous layer was washed twice with hexane, made basic with saturated aqueous potassium carbonate solution and washed three times with ethyl acetate. The ethyl acetate layers were washed with brine, dried over sodium sulfate, and evaporated in vacuo to yield 0.95 g of an oil. This material was dissolved in a minimal amount of chloroform, treated with saturated hydrogen chloride-ether solution, evaporated in vacuo and triturated with ether/ethyl acetate/methanol (80:15:5) to yield 0.67 g of a white solid, melting point 148° C. (dec).
Reaction SMILES: [OH:1][C:2]1[O:9][C@H:8]([CH2:10][OH:11])[CH2:7][C@H:5]([OH:6])[C:3]=1[OH:4].[S:12](Cl)([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)(=[O:14])=[O:13]>N1C=CC=CC=1>[S:12]([O:11][CH2:10][C@H:8]1[O:9][C:2]([OH:1])=[C:3]([OH:4])[C@@H:5]([OH:6])[CH2:7]1)([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)(=[O:14])=[O:13]
Reactant: OC[C@@H]1C[C@H](O)C(O)=C(O)O1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@H](O)C(O)=C(O)O2)cc1

Procedure:
Dissolve 10 gm. of the alcohol and 15.4 gm. of tosyl chloride in 100 ml. of dry pyridine and let the solution stand at 25°C. for 17 hours. Add ethanol and evaporate the solution to a residue and then azeotrope with toluene. Chromatograph the residue on a silica gel column (110 × 2.5 cm) using 10% acetone in hexane as the eluant to obtain 4-deoxy-6O-tosyl-D-threo-hex-1-enopyranose.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:13]([Cl:14])=[CH:12][C:11]([O:15][CH3:16])=[C:10]([C:17]([OH:19])=O)[CH:9]=1.[N:20]1([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:13]([Cl:14])=[CH:12][C:11]([O:15][CH3:16])=[C:10]([C:17]([N:23]2[CH2:22][CH2:21][N:20]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][CH2:24]2)=[O:19])[CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1cc(Cl)c(-c2ccccc2Cl)cc1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(Cl)c(-c2ccccc2Cl)cc1C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.3 %

Procedure:
To a stirred solution of 2′,6-dichloro-4-methoxy-[1,1′-biphenyl]-3-carboxylic acid (500 mg, 1.68 mmol) in DMF (10 mL) at room temperature, tert-butyl piperazine-1-carboxylate (345 mg, 1.85 mmol), BOP (892 mg, 2.02 mmol) and DIEA (542 mg, 4.2 mmol) were added and the resulting mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (dichloromethane/methanol=50:1) to afford the desired product (550 mg, 70% yield). ESI-MS m/z: 465.4[M+H]+.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[C:20]1([C@H:26]([NH2:28])[CH3:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:20]1([C@H:26]([NH:28][C:5]2[N:10]=[C:9]([N:11]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[N:13]=[CH:12]3)[CH:8]=[CH:7][N:6]=2)[CH3:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Reactant: C[C@@H](N)c1ccccc1
Product: C[C@@H](Nc1nccc(-n2cnc3ccccc32)n1)c1ccccc1

Procedure:
2-methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine was reacted with (R)-1-phenylethylamine according to the procedure described in EXAMPLE 1, Step C to afford the title compound. Mass Spectrum (CI): m/e 316.1 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.49 (br s, 1H); 8.37 (d, J=5.1 Hz, 1H); 7.83 (d, J=8.0 Hz, 1H); 7.3-7.5 (m, 8H); 6.77 (d, J=5.3 Hz, 1H); 6.03 (br s, 1H); 5.22 (br s, 1H); 1.65 (d, J=7.0 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[Cl:20])[C:6]([CH3:12])=[N:7]2.[Br:21]N1C(C)(C)C(=O)N(Br)C1=O.C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>>[Br:21][CH2:12][C:6]1[C:5]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[Cl:20])=[N:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[Cl:1])[N:7]=1
Reactant: Cc1nc2cccc(Cl)c2nc1-c1cc(F)ccc1Cl
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(Cl)c(-c2nc3c(Cl)cccc3nc2CBr)c1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
5-chloro-3-(2-chloro-5-fluorophenyl)-2-methylquinoxaline (0.3013 g, 0.981 mmol) and 1,3-dibromo-5,5-dimethylhydantoin (0.280 g, 0.981 mmol) were suspended in carbon tetrachloride (9.81 m/L, 0.981 mmol). To the mixture was added benzoyl peroxide (0.0317 g, 0.0981 mmol) and the mixture was heated at reflux. After 22 h, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography on a 80 g of Redi-Sep™ column using 0 to 5% gradient of EtOAc in hexane over 10 min, then 5% isocratic of EtOAc for 25 min, then 5 to 20% gradient of EtOAc in hexane over 20 min, then 20% isocratic of EtOAc for 4 min as eluent to give 2-(bromomethyl)-5-chloro-3-(2-chloro-5-fluorophenyl)-quinoxaline as a light yellow syrupy solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.12-8.21 (2H, m), 7.92-8.00 (1H, m), 7.76 (1H, dd, J=9.0, 5.1 Hz), 7.71 (1 H, dd, J=8.6, 3.1 Hz), 7.49-7.58 (1H, m), 4.74 (2H, br. s.); LC-MS (ESI) m/z 387.0 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][O:11][C:10]([CH3:14])([CH3:13])[O:9]2)=[CH:4][N:3]=1.CCCCCC.C([Li])CCC.CN(C)[CH:28]=[O:29].O>C(OCC)C>[CH3:13][C:10]1([CH3:14])[O:9][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([CH:28]=[O:29])=[N:3][CH:4]=2)[CH2:12][O:11]1
Reactant: CC1(C)OCC(c2ccc(Br)nc2)O1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Solvent: O
Product: CC1(C)OCC(c2ccc(C=O)nc2)O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27.2 %

Procedure:
To a solution of 2-bromo-5-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridine (4.12 g) in diethyl ether (100 mL) was slowly added a 1.6M n-butyllithium hexane solution (10 mL) at −78° C. The reaction mixture was stirred for 30 min, and N,N-dimethylformamide (1.40 g) was added. The reaction mixture was warmed to room temperature over 1 hr, and stirred overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (900 mg, yield 27%) was obtained as a pale-yellow oil from a fraction eluted with ethyl acetate-hexane (1:4, volume ratio). MS: 208 (MH+).
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=O)[C:2]1=[O:3].[C:12]([C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)(=O)[CH3:13].[OH-].[K+].CC[OH:24]>O>[S:16]1[CH:17]=[CH:18][CH:19]=[C:15]1[C:12]1[CH:13]=[C:4]([C:2]([OH:24])=[O:3])[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:1]=1
Reactant: CC(=O)c1cccs1
Reactant: O=C1Nc2ccccc2C1=O
Reactant: CCO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc(-c2cccs2)nc2ccccc12

Procedure:
5 g (34.0 mmol) of isatin, 4.4 ml (40.8 mmol) of 2-acetylthiophene and 6.3 g (112.2 mmol) of potassium hydroxide were dissolved in 40 ml of abs. EtOH and the slurry heated at 80° C. for 16 hours. After cooling of the reaction mixture, 50 ml of water were added and the solution extracted with 50 ml of Et2O. The ice-cooled aqueous phase was acidified to pH 1 with 37% HCl and the precipitate collected by filtration and washed with water. The crude product obtained was dried in-vacuo at 40° C. and triturated with EtOAc to yield 4.8 g of the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][N:10]([C@@H:13]([C:55]([CH3:58])([CH3:57])[CH3:56])[C:14]([NH:16][C@@H:17]([CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C@@H:18]([OH:47])[CH2:19][C@@H:20]([NH:34][C:35]([C@@H:37]([NH:42][C:43](=[O:46])[O:44][CH3:45])[C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[CH:24][CH:23]=2)=[O:15])[C:9]1=[O:59])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:60][S:61][CH3:62].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.O>C(#N)C.C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:12][CH2:11][N:10]([C@@H:13]([C:55]([CH3:58])([CH3:57])[CH3:56])[C:14]([NH:16][C@@H:17]([CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C@@H:18]([O:47][CH2:60][S:61][CH3:62])[CH2:19][C@@H:20]([NH:34][C:35](=[O:36])[C@H:37]([C:38]([CH3:41])([CH3:40])[CH3:39])[NH:42][C:43]([O:44][CH3:45])=[O:46])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[CH:24][CH:23]=2)=[O:15])[C:9]1=[O:59])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CSC
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2ccccc2)C1=O)C(C)(C)C)C(C)(C)C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](OCSC)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2ccccc2)C1=O)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.4 %

Procedure:
To a solution of the compound of Example 111 (1.4 g, 1.74 mmol) and methyl sulfide (3.2 mL, 43.3 mmol) in acetonitrile (18 mL) at 0° C. was added benzoyl peroxide (1.7 g), and the mixture was warmed to room temperature and stirred for 30 minutes. The reaction was cooled to 0° C. and benzoyl peroxide (1.7 g) was added, and the mixture was warmed to room temperature and stirred for 30 minutes. Water was added and the reaction was diluted with ethyl acetate and washed with 10% Na2CO3 and brine. The organic was dried over MgSO4, filtered and evaporated. The residue was chromatographed on silica gel eluting with a gradient starting with dichloromethane and ending with ethyl acetate to give the title compound (1.24 g, 83% yield).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:10]3[CH2:23][CH2:22][N:21]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([N:30]5[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]5)[CH:25]=4)[C:11]=3[N:12]=[C:13]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[N:14]=2)[CH:6]=[CH:7][CH:8]=1.C([S-])C.[Na+].O>CN(C)C=O>[CH3:36][N:33]1[CH2:34][CH2:35][N:30]([C:26]2[CH:25]=[C:24]([N:21]3[C:11]4[N:12]=[C:13]([N:15]5[CH2:16][CH2:17][O:18][CH2:19][CH2:20]5)[N:14]=[C:9]([C:5]5[CH:4]=[C:3]([OH:2])[CH:8]=[CH:7][CH:6]=5)[C:10]=4[CH2:23][CH2:22]3)[CH:29]=[CH:28][N:27]=2)[CH2:31][CH2:32]1
Reactant: COc1cccc(-c2nc(N3CCOCC3)nc3c2CCN3c2ccnc(N3CCN(C)CC3)c2)c1
Agent: CC[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCN(c2cc(N3CCc4c(-c5cccc(O)c5)nc(N5CCOCC5)nc43)ccn2)CC1
Temperature: 150 °C
Reaction time: 8 h
Yield: 17.3 %

Procedure:
4-(3-Methoxyphenyl)-7-[2-(4-methylpiperazin-1-yl)-pyridin-4-yl]-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine (107 mg, 0.22 mmol) was heated at 150° C. in dimethylformamide (1 ml), and sodium ethanethiolate (275 mg, 3.3 mmol) was added at 15 minutes intervals in 3 portions. After heating at 150° C. for further 15 minutes followed by cooling, water (1 ml) was added, followed by washing with ethyl acetate (2 ml). After the aqueous layer was left overnight, the deposited precipitate was filtered off, and washed with water followed by drying, whereby a colorless solid was obtained (18 mg, 17.3% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:10]2[O:15][CH2:14][CH2:13][CH2:12][O:11]2)[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[F:16][C:17]([F:25])([F:24])[C:18]([F:23])([F:22])C([O-])=O.[Na+].CN(C=O)C>[Cu]I.C1(C)C=CC=CC=1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:18]([F:23])([F:22])[C:17]([F:25])([F:24])[F:16])=[CH:3][C:4]=1[CH:10]1[O:15][CH2:14][CH2:13][CH2:12][O:11]1
Reactant: O=C([O-])C(F)(F)C(F)(F)F
Reactant: COc1ccc(Br)cc1C1OCCCO1
Agent: [Cu]I
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc(C(F)(F)C(F)(F)F)cc1C1OCCCO1
Temperature: 140 °C
Yield: 93.6 %

Procedure:
A 50 ml round bottom flask equipped with Dean-Stark trap and reflux condenser was charged with Compound 38 (1.0 g, 3.66 mmol), sodium pentafluoropropionate (1.29 g, 6.95 mmol) and copper(I) iodide (1.46 g, 7.69 mmol), DMF (15 ml) -toluene (6 ml). The slurry was heated to 120-140° C. (bath temperature) and toluene (6 ml) was removed by distillation. The reaction mixture was heated at 140° C. (inner temperature) for 15 h. The mixture was diluted with water (40 ml) —toluene (15 ml) —ethyl acetate (60 ml). The mixture was filtered through a pad of celite and the filter cake was washed with ethyl acetate. The filtrate was washed with water, and brine, dried(MgSO4) and concentrated in vacuo to give crude product. The crude product was purified by column chromatography on silica gel with hexane-ethyl acetate(10:1-5:1) to give Compound 39 (1.07 g) as a pale yellow oil
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:27]([F:30])([F:29])[F:28])=[N:10][N:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C(O)(=[O:33])C.OO.[OH2:37]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:27]([F:28])([F:29])[F:30])=[N:10][N:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:12]=2[C:13]2[CH:14]=[CH:15][C:16]([S:19]([CH3:20])(=[O:33])=[O:37])=[CH:17][CH:18]=2)=[CH:4][CH:3]=1
Reactant: CSc1ccc(-c2c(-c3ccc(F)cc3)c(C(F)(F)F)nn2-c2ccccc2)cc1
Reactant: CC(=O)O
Reactant: O
Agent: OO
Product: CS(=O)(=O)c1ccc(-c2c(-c3ccc(F)cc3)c(C(F)(F)F)nn2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 140 mg of 4-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-1-phenyl-3-(trifluoromethyl)pyrazole and 30 mL of glacial acetic acid was added 4.1 g of 30% hydrogen peroxide. The reaction mixture was stirred at room temperature for 18 hours, heated at 80 ° C. for 8 hours, and poured into water. The insoluble solid was filtered and air dried to give 150 mg of solid, mp 201.5°-203 ° C.
Reaction SMILES: Cl[C:2]1[C:3]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[F:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1.CC(N(C)C)=O>CO>[F:22][C:23]1[CH:29]=[CH:28][C:26]([NH:27][C:2]2[C:3]([NH:12][S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)(=[O:15])=[O:14])=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:25][CH:24]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=S(=O)(Nc1nc2ccccc2nc1Cl)c1ccccc1
Solvent: CO
Solvent: CC(=O)N(C)C
Product: O=S(=O)(Nc1nc2ccccc2nc1Nc1ccc(F)cc1)c1ccccc1
Temperature: 120 °C
Yield: 61.8 %

Procedure:
A CEM microwave reaction vessel was charged with N-(3-chloroquinoxalin-2-yl)benzenesulfonamide (52 mg, 0.16 mmol), prepared using procedures similar to those described in the above step, 4-fluoroaniline (36 mg, 0.32 mmol), and 0.8 mL of dimethylacetamide. The vessel was sealed and the reaction mixture was heated under microwave radiation for 25 m at 120° C. in a CEM Discover microwave instrument. Methanol (1 mL) was added to the reaction mixture and after 20 minutes the product precipitated out of the solution. Filtration yielded N-(3-(4-fluorophenylamino)quinoxalin-2-yl)benzenesulfonamide (39 mg, 62%). 1H-NMR (400 MHz, do-DMSO): δ 12.30 (s, 1H), 9.11 (s, 1H), 8.16-8.10 (d, 2H), 8.02-7.90 (m, 3H), 7.68-7.58 (m, 3H), 7.55-7.51 (m, 1H), 7.41-7.32 (m, 2H), 7.25-7.16 (m, 2H); MS (EI) m/z C20H15FN4O2S: 395.0 (MH+).
Reaction SMILES: C[S-:2].[Na+].[CH:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=2)=[CH:6][CH:5]=1.[OH-].[Na+]>CN(C)C=O>[O:10]([C:11]1[CH:16]=[CH:15][C:14]([SH:2])=[CH:13][CH:12]=1)[C:7]1[CH:8]=[CH:9][CH:4]=[CH:5][CH:6]=1
Reactant: C[S-]
Reactant: Brc1ccc(Oc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Sc1ccc(Oc2ccccc2)cc1

Procedure:
A solution of sodium thiomethoxide (25 g) and 4-bromodiphenyl ether (25 g) in N,N-dimethylformamide (DMF) (150 ml) was refluxed overnight. The mixture was cooled and added to dilute aqueous sodium hydroxide. The water layer was washed with ether to remove by-products and acidified with hydrochloric acid. The product, 4-(phenoxy)thiophenol, was extracted with ether, and the ether layer dried and evaporated to give 4-(phenoxy)thiophenol (19-20 g) as a red oil. This material can be used without further purification.