Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][C:17]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:18][CH:19]=3)[O:14]2)(=O)=O)=CC=1.[NH2:27][CH2:28][CH2:29][OH:30]>C(#N)C>[CH3:26][S:23]([C:17]1[CH:16]=[C:15]2[C:20]([CH2:21][CH2:22][CH:13]([CH2:12][NH:27][CH2:28][CH2:29][OH:30])[O:14]2)=[CH:19][CH:18]=1)(=[O:24])=[O:25]
Reactant: Cc1ccc(S(=O)(=O)OCC2CCc3ccc(S(C)(=O)=O)cc3O2)cc1
Reactant: NCCO
Solvent: CC#N
Product: CS(=O)(=O)c1ccc2c(c1)OC(CNCCO)CC2

Procedure:
Preparation according to Example 25: [7-(methylsulfonyl)-3,4-dihydro-2H-chromen-2-yl]methyl 4-methylbenzenesulfonate (0.020 g, 0.0504 mmol), 2-aminoethanol (0.5 ml), ACN (3 ml). 1H-NMR (400 MHz, CDCl3): δ 7.37-7.39 (2H, m), δ 7.23 (1H, d, J=8 Hz), δ 4.18-4.24 (1H, m), δ 3.63-3.72 (2H), δ 3.02 (3H, s), δ 2.81-3.00 (6H, m), δ 1.97-2.08 (1H, m), δ 1.83-1.87 (1H, m).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:14])[C:11]=1[O:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:14][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:11]=1[O:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6]
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cc(O)c(OC)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(F)c(OC)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 67.4 %

Procedure:
To a solution of methyl 3-fluoro-5-hydroxy-4-(methyloxy)benzoate (3.63 g, 18.1 mmol.) in DMF (25 mL) was added cesium carbonate (8.9 g, 27.2 mmol.) followed by benzyl bromide (2.8 mL, 23.6 mmol.) and the mixture was stirred at room temperature over 12 hours. The mixture was then partitioned with ethyl ether and water and the organic phase washed with water (3×) then saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. Filtration and concentration followed by purification of the residue by silica gel flash chromatography using 50% hexanes in chloroform as eluent afforded methyl 3-fluoro-4-(methyloxy)-5-[(phenylmethyl)oxy]benzoate (3.54 g, 67% yield) as a colorless solid after concentration of the pure fractions and drying in vacuo.
Reaction SMILES: [Br:1][C:2]1([CH2:5][CH2:6][OH:7])[CH2:4][CH2:3]1.N1C=CC=CC=1.[Si:14](OS(C(F)(F)F)(=O)=O)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>C(Cl)Cl>[Br:1][C:2]1([CH2:5][CH2:6][O:7][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:4][CH2:3]1
Reactant: OCCC1(Br)CC1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCC1(Br)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of the cyclopropyl alcohol (Step A) (1.303 g, 7.95 mmoles) in 30 ml anhydrous DCM was added anhydrous pyridine (1.2 ml, 1.1736 g, 14.8 mmoles), TBSOTf (2.7 ml, 3.1077 g, 11.76 mol) and the solution was stirred at room temperature for 16 h. It was extracted with CHCl3/brine and the organic fraction was dried with MgSO4. The solvent was reduced and the crude product purified using flash-column chromatography (CHCl3/hexanes 1:10, Rf=0.4). Yield: 0.796 g, 36%. 1H-NMR (500 MHz, CDCl3): δ=3.95-3.75 (t, 2H), 1.95-1.85 (t, 2H), 1.15-1.05 (m, 2H), 0.95-0.80 (m, 11H), 0.15-0.05 (s, 6H).
Reaction SMILES: [Cl:1]C(Cl)(Cl)C(Cl)(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[CH3:35][Si:36]([CH3:48])([CH3:47])[NH:37][S:38]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)(=O)=[O:39]>>[CH3:35][Si:36]([CH3:48])([CH3:47])[N:37]=[S:38]([Cl:1])([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:39]
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: C[Si](C)(C)NS(=O)(=O)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)N=S(=O)(Cl)c1ccccc1

Procedure:
The reactants used in the general procedure were hexachloroethane (0.1353 mol, 32.68 g), triphenylphosphine (0.1367 mol, 36.22 g), triethylamine (0.1353 mol, 19.2 ml), and N-trimethylsilylsulfonamide (3b) (0.1353 mol, 31.0 g).
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[C:11]([OH:15])(=[O:14])[CH:12]=[O:13]>CC(C)=O>[C:1]([NH:9][CH:12]([OH:13])[C:11]([OH:15])=[O:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccccc1
Reactant: O=CC(=O)O
Solvent: O
Solvent: CC(C)=O
Product: O=C(NC(O)C(=O)O)c1ccccc1
Yield: 100 %

Procedure:
The titled compound 65 was prepared according to a procedure described by Zoller et al.209 A mixture of benzamide 35 (5.00 g, 41.3 mmol) and glyoxylic acid monohydrate 41 (4.32 g, 46.9 mmol) in anhydrous acetone (70 mL) was heated at reflux for 19 h. The reaction mixture was evaporated under reduced pressure to afford the desired product 65 as a colourless solid (8.06 g, 100%), m.p. 198-200° C. (lit.209 200-201° C. (dec)) Spectroscopic data indicated the crude product 65 did not require purification and was used directly in the subsequent reaction (Section 7.11.4). νmax (KBr): 3310 bs, 3058w, 1728s, 1646s, 1602w, 1582w, 1535s, 1491w, 1452w, 1315m, 1292w, 1254m, 1161m, 1097s, 1040m, 1002w, 957m, 805w, 770w, 728m, 692m, 654m, 609w, 515m, 483w cm−1. 1H n.m.r. (300 MHz, D6-DMSO): δ 5.60 (d, J=7.8 Hz, 1H, H2), 7.41-7.49 (m, 2H, H3′, 5′), 7.55 (m, 1H, H4′), 7.86-7.92 (m, 2H, H2′, 6′), 9.26 (d, J=7.8 Hz, 1H, NH), two exchangeable OH protons not observed. 13C n.m.r. (75 MHz, D6-DMSO): δ 71.7 (C2), 127.6, 128.3, 131.7 (Arom CH), 133.7 (C1′), 166.0, 171.5 (C1, CONH). Mass Spectrum (ESI+, MeOH): m/z 218.2 (M+Na)+, C9H9NNaO4 requires 218.2.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C[O:8][C:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:11]=1[CH3:17].O>C1COCC1>[Cl:16][C:12]1[C:11]([CH3:17])=[C:10]([CH2:9][OH:8])[CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)c1cccc(Cl)c1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(Cl)cccc1CO
Reaction time: 1 h
Yield: 103.9 %

Procedure:
LAH (61.00 mL, 1.0 M in THF, 61.00 mmol) was added to a solution of 3-chloro-2-methyl-benzoic acid methyl ester (4.50 g, 24.40 mmol) in THF at 0° C. The reaction mixture was stirred for 1 hour, water was added to quench the reaction. The aqueous layer was extracted with Et2O (3×150 mL), and the combined organic phases were washed with brine (1×150 mL) and dried over MgSO4. Purification by column chromatography using hex:EtOAc (4:1) as the eluant afforded 3.97 g of the title compound. Spectroscopic data: 1H NMR (300 MHz, CDCl3.) δ 1.94 (br s, 1H), 2.36 (s, 3H), 4.67 (br s, 2H), 7.11 (t, J=7.765 Hz, 1H), 7.245 (d, J=7.03 Hz, 1H), 7.30 (d, J=7.91 Hz, 1H).
Reaction SMILES: C(O)(=O)C.[N:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11](=[N:20]O)[CH2:12][CH2:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH:6]=1>C(O)C.[Zn]>[N:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([NH2:20])[CH2:12][CH2:13][CH:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)[CH:6]=1
Reactant: ON=C(CCC1CCOCC1)c1cccnc1
Agent: [Zn]
Solvent: CCO
Solvent: CC(=O)O
Product: NC(CCC1CCOCC1)c1cccnc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93 %

Procedure:
Acetic acid (16 mL) was added to a suspension of 1-(3-pyridyl)-3-(4-oxanyl)propan-1-one oxime (1.60 g, 6.83 mmol) in 95% ethanol (40 mL) over a period of 15 min. Zinc dust (12 g, 180 mmol) was added and the reaction mixture was stirred at ambient temperature for 4 h. The reaction mixture was filtered through a Celite plug, which was then washed with ethanol (50 mL). The combined filtrates were concentrated by rotary evaporation. The solid residue was made basic by addition of 50% aqueous NaOH (with ice bath cooling), saturated with solid NaCl and extracted with chloroform (5×30 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated by rotary evaporation to give pure product as a colorless viscous liquid (1.40 g, 82% yield).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:11][CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:19]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11]([I:19])[CH:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: c1ccc(Cn2nccc2-c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Ic1cnn(Cc2ccccc2)c1-c1ccccc1
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 65E (270 mg) in N,N-dimethylformamide (5 mL) was added N-iodosuccinimide (259 mg). The mixture was stirred overnight. The mixture was diluted with ethyl acetate (200 mL) and washed with aqueous sodium bisulfite, water, and brine. The organic layers were combined, and evaporation of the solvent provided the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]([CH3:11])[CH3:10])[CH:5]=[C:4]([CH3:12])[C:3]=1[OH:13].[C:14]([N:17]1[CH2:22]CNC[CH2:18]1)(=[O:16])[CH3:15]>C1(C)C(C)=CC=CC=1>[C:14]([N:17]1[CH2:22][CH2:11][N:9]([CH2:8][C:6]2[CH:7]=[C:2]([CH3:1])[C:3]([OH:13])=[C:4]([CH3:12])[CH:5]=2)[CH2:10][CH2:18]1)(=[O:16])[CH3:15]
Reactant: CC(=O)N1CCNCC1
Reactant: Cc1cc(CN(C)C)cc(C)c1O
Solvent: Cc1ccccc1C
Product: CC(=O)N1CCN(Cc2cc(C)c(O)c(C)c2)CC1

Procedure:
A solution of 35.8 g=0.2 mole of 2,6-dimethyl-4-(N,N-dimethylaminomethyl)-phenol and 25.6 g=0.2 mole of acetylpiperazine in 100 ml of xylene is boiled under reflux for 5 hours, in the course of which nitrogen is passed through the solution. After cooling, the precipitate is filtered off, washed with ethyl acetate and dried over phosphorus pentoxide in vacuo. This gives 46.1 g (88% of theory), melting point: 150°-151° C.
Reaction SMILES: C(Cl)(Cl)Cl.Br[CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1)=[O:8].[C:19]1([CH:25]2[CH2:30][C:29](=[O:31])[CH2:28][C:27](=[O:32])[CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[OH:32][C:27]1[CH2:26][CH:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:30][C:29](=[O:31])[C:28]=1[CH2:6][C:7](=[O:8])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1
Reactant: O=C(CBr)c1cccc(C(F)(F)F)c1
Reactant: O=C1CC(=O)CC(c2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: O=C1CC(c2ccccc2)CC(O)=C1CC(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 34.4 %

Procedure:
To a chloroform solution (2 mL) of 2-bromo-3′-trifluoromethylacetophenone (534.1 mg, 2 mmol) and 5-phenyl-1,3-cyclohexanedione (376.5 mg, 2 mmol) was added potassium carbonate (276.4 mg, 2 mmol) and stirred under suspension at room temperature over night. The reaction liquid was added with ethyl acetate (5 mL), to filter off undissolved substance, followed by concentration of thus obtained organic layer under reduced pressure and purification of concentrated residue using silica gel column chromatography (hexane/ethyl acetate=1/1) to obtain a crude product, which was further purified by suspension (hexane 1 ml/ethyl acetate about 0.2 ml) to obtain an objective compound (257.8 mg, 35.0%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([SH:8])=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C@@H:20]2[O:26][C@H:21]2[C:22]([O:24][CH3:25])=[O:23])=[CH:16][CH:15]=1>C1(C)C=CC=CC=1.O.O.C([O-])(=O)C.[Zn+2].C([O-])(=O)C>[Cl:1][C:2]1[C:7]([S:8][C@@H:20]([C:17]2[CH:16]=[CH:15][C:14]([O:13][CH3:12])=[CH:19][CH:18]=2)[C@@H:21]([OH:26])[C:22]([O:24][CH3:25])=[O:23])=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H]1O[C@H]1c1ccc(OC)cc1
Reactant: O=[N+]([O-])c1cccc(Cl)c1S
Agent: CC(=O)[O-]
Agent: [Zn+2]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)[C@H](O)[C@@H](Sc1c(Cl)cccc1[N+](=O)[O-])c1ccc(OC)cc1

Procedure:
In a 25 ml flask equipped with thermometer and nitrogen admission, there are introduced 22 mg of zinc acetate dihydrate, 948 mg of 6-chloro-2-nitrothiophenol and 5 ml of toluene. To the suspension are added dropwise, within 5 mn, a solution of 1.093 g of methyl (-) (2R,3S) 3-(4-methoxyphenyl)-2,3-epoxy-propionate in 7.5 ml of toluene at 25° C. The temperature rises to 27°-28° C., whilst stirring is maintained for 1.5 hour. The mixture is evaporated in vacuo, and a yellow oil is obtained, which is used as it is in the subsequent example.
Reaction SMILES: [Cl-].[NH4+].[Br:3][C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[C:6]([N+:13]([O-])=O)[CH:5]=1>C(O)C.O.[Fe]>[Br:3][C:4]1[CH:5]=[C:6]([NH2:13])[CH:7]=[C:8]([NH2:10])[CH:9]=1
Reactant: O=[N+]([O-])c1cc(Br)cc([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1cc(N)cc(Br)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 38.1 %

Procedure:
Ammonium chloride (5.20 g, 97 mmol) was added to a stirred, cooled (room temperature) mixture of 1-bromo-3,5-dinitrobenzene (20 g, 81 mmol) and iron (54.3 g, 972 mmol) in ethanol:water (2:1) and the mixture was stirred at 80° C. for 1 h. The heterogeneous reaction was filtered on celite while hot, concentrated, and diluted with brine. The product was extracted with ethyl acetate, the organic layer washed with brine and dried over Na2SO4. The residue was dissolved in boiling ethyl acetate (˜75 mL), a bit of hexanes was added to form a layer on top of ethyl acetate (˜7.5 mL) and the mixture was left to crystallize overnight. The crystals were filtered, washed with diethyl ether and air-dried to give 5.77 g of 5-bromobenzene-1,3-diamine as a grey solid. MS ESI: [M+H]+ m/z 187.0 and 189.0.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:21]=[CH:20][C:11]2[C:12]([C:16]([NH:18][CH3:19])=[O:17])=[C:13]([CH3:15])[O:14][C:10]=2[CH:9]=1.[Cl:22][C:23]1[N:28]=[C:27](Cl)[CH:26]=[CH:25][N:24]=1.O>CN(C=O)C>[Cl:22][C:23]1[N:28]=[C:27]([O:7][C:8]2[CH:21]=[CH:20][C:11]3[C:12]([C:16]([NH:18][CH3:19])=[O:17])=[C:13]([CH3:15])[O:14][C:10]=3[CH:9]=2)[CH:26]=[CH:25][N:24]=1
Reactant: CNC(=O)c1c(C)oc2cc(O)ccc12
Reactant: Clc1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1c(C)oc2cc(Oc3ccnc(Cl)n3)ccc12
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
Potassium carbonate (1.5 mmol) was added to a solution of 6-hydroxy-N,2-dimethylbenzofuran-3-carboxamide (1 mmol) in 5 ml DMF. After 30 mins, 2,4-dichloropyrimidine (1 mmol) was added and the reaction mixture was stirred overnight at 60° C. Water was added. The resultant solid was filtered, washed with water, and dried to give 6-(2-chloropyrimidin-4-yloxy)-N,2-dimethylbenzofuran-3-carboxamide in a yield of 82%, as a solid, which was used in the next step without further purification.
Reaction SMILES: [C:1]([C:3]1[C:8]([F:9])=[C:7]([F:10])[C:6]([OH:11])=[C:5]([F:12])[C:4]=1[F:13])#[N:2].[C:14](Cl)(=[O:18])[C:15]([CH3:17])=[CH2:16].C(=O)([O-])[O-].[Ca+2].Cl>C1C=CC=CC=1>[C:14]([O:11][C:6]1[C:5]([F:12])=[C:4]([F:13])[C:3]([C:1]#[N:2])=[C:8]([F:9])[C:7]=1[F:10])(=[O:18])[C:15]([CH3:17])=[CH2:16]
Reactant: N#Cc1c(F)c(F)c(O)c(F)c1F
Reactant: C=C(C)C(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: c1ccccc1
Product: C=C(C)C(=O)Oc1c(F)c(F)c(C#N)c(F)c1F
Yield: 63.9 %

Procedure:
In 30 ml of benzene, 3.0 g (0.0157 mol) of 4-cyano-2,3,5,6-tetrafluorophenol and 1.80 g (0.0173 mol) of methacrylic acid chloride were dissolved. The resultant solution, and 1.73 g (0.0173 mol) of calcium carbonate added thereto as a hydrogen chloride trapping agent were stirred under reflux for 32 hours. The resultant reaction mixture was cooled off and filtered to separate calcium carbonate. The filtrate was dried with magnesium sulfate and then evaporated with a rotary evaporator. Consequently, there was obtained 2.6 g of 4-cyano-2,3,5,6-tetrafluorophenyl methacrylate (yeild 63.9% and purity 95.4%). The analyses obtained of the novel substance for the determination of its chemical structure were the same as those of Example 2.
Reaction SMILES: [Li]CCCC.[S:6]1[CH:10]=[CH:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]1=2.[Sn:15](Cl)([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19]>>[CH2:24]([Sn:15]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:20][CH2:21][CH2:22][CH3:23])[C:10]1[S:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH:9]=1)[CH2:25][CH2:26][CH3:27]
Reactant: c1ccc2sccc2c1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Product: CCCC[Sn](CCCC)(CCCC)c1cc2ccccc2s1

Procedure:
2.5 M of n-BuLi (3.1 mL/hexane, 7.67 mmol) was added to benzo[b]thiophene (1.05 g, 7.67 mmol/THF (20 mL)) and reacted at 0° C. for 1 hour under a dry and anaerobic operation condition to form a solution. SnBu3Cl (2.38 mL, 8.44 mmol) was then added to the solution and reacted at 0° C. for 30 minutes. After returning to room temperature, the solution was continuously reacted for 8 hours. After the reaction was completed, the solution was extracted by ether (30 mL) and deionized water (50 mL). An organic phase was collected. After removal of ether by a rotary concentrator, the organic phase was purified by reduced-pressure distillation to form a transparent pale yellow oily product (23, 1.76 g, 54%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])[CH:18]=2)[CH2:9][CH:10]([OH:15])[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[F:37][C:38]1[CH:43]=[CH:42][C:41]([S:44](Cl)(=[O:46])=[O:45])=[CH:40][CH:39]=1>ClCCl>[F:37][C:38]1[CH:43]=[CH:42][C:41]([S:44]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([N:8]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:28])([F:29])[CH:25]([F:26])[F:27])[CH:18]=3)[CH2:9][CH:10]([OH:15])[C:11]([F:14])([F:13])[F:12])[CH:3]=2)(=[O:46])=[O:45])=[CH:40][CH:39]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: Nc1cccc(N(Cc2cccc(OC(F)(F)C(F)F)c2)CC(O)C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(Nc1cccc(N(Cc2cccc(OC(F)(F)C(F)F)c2)CC(O)C(F)(F)F)c1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 29 %

Procedure:
The 3-[(3-aminophenyl)[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol from EX-528C (50 mg, 0.12 mmol) was dissolved in 1 mL of dichloromethane. Triethylamine (25 μL, 0.18 mmol) followed by 4-fluorobenzene-sulfonyl chloride were added. The solution was stirred at room temperature for 5 hours, at which time HPLC analysis indicated that no free amine starting material remained. The reaction was quenched with water and filtered through pre-wetted celite eluting with ethyl acetate. The solvent was evaporated, and the residue was purified by reverse phase HPLC eluting with 10% to 90% acetonitrile in water to afford 20.1 mg (29%) of the desired 4-fluoro-N-[3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]-(3,3,3-trifluoro-2-hydroxypropyl)amino]phenyl]benzenesulfonamide product as a yellow oil, which was greater than 98% pure by reverse phase HPLC analysis. HRMS calcd. for C24H21F8N2O4S: 585.1094 [M+H]+, found: 585.1083. 1H NMR (CDCl3) δ 3.6 (m, 2H), 3.8 (dd, 1H), 4.3 (m, 1H), 4.6 (s, 2H), 5.9 (tt, 1H), 6.4 (d, 1H), 6.5-6.6 (m, 3H), 6.9-7.4 (m, 7H), 7.6 (m, 1H).
Reaction SMILES: O[C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[N:5]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:3]=1.P(Br)(Br)[Br:19].[OH-].[Na+].Cl>CN(C)C=O>[Br:19][C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[N:5]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:3]=1
Reactant: BrP(Br)Br
Reactant: Cc1nc(Nc2ccc(F)cc2)nc(O)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1nc(Nc2ccc(F)cc2)nc(Br)c1C
Temperature: 65 °C
Reaction time: 0.33 h
Yield: 64.6 %

Procedure:
5 g (21.44 mmole) of 2-(4-fluorophenylamino)-4-hydroxy-5,6-dimethylpyrimidine produced in Example 1 was suspended in 40 ml of N,N-dimethylformamide and the resulting suspension was warmed to 65° C. 8.1 g (30 mmole) of phosphorus tribromide was added dropwise thereto over 20 minutes and the resulting mixture was allowed to react at 75° C. for 30 minutes. The reaction solution was cooled to room temperature, poured onto 500 g of ice-water, adjusted to pH 11 with sodium hydroxide solution, stirred for 30 minutes and then adjusted again to pH 5.5 with dilute hydrochloric acid. The resulting yellow solid product was washed with 100 ml of water and the dried to obtain 4.1 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:9][CH3:10])=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].[Cl:11][C:12]1[N:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](Cl)=[O:15].C(N(CC)C(C)C)(C)C>CCOC(C)=O>[Cl:11][C:12]1[C:13]([C:14]([NH:1][C:2]2[C:3]([O:9][CH3:10])=[N:4][CH:5]=[CH:6][C:7]=2[CH3:8])=[O:15])=[CH:17][CH:18]=[CH:19][N:20]=1
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: COc1nccc(C)c1N
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1nccc(C)c1NC(=O)c1cccnc1Cl
Reaction time: 10 h
Yield: 86.9 %

Procedure:
To a solution of 0.4 g (2.9 mmol) of 3-amino-2-methoxy-4-methylpyridine and 0.5 g (2.9 mmol) of 2-chloronicotinoyl chloride in EtOAc at 0° C. was added 0.4 g (3.0 mmol) of N,N-diisopropylethylamine. Stirring was continued for 10 h at which point the mixture was washed with 0.1N HCl , dried (MgSO4), concentrated and purified by flash chromatography on silica gel (1:1 EtOAc:hexanes) to yield 0.7 g (88%) of the desired material. m.p.: 145°-146° C. (Recrystallized from ethyl acetate).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH3:11][C:12]1[CH:36]=[CH:35][C:15]([CH2:16][C:17]2([C:30](OCC)=[O:31])[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]2)=[CH:14][CH:13]=1>C1COCC1.CCOCC>[OH:31][CH2:30][C:17]1([CH2:16][C:15]2[CH:35]=[CH:36][C:12]([CH3:11])=[CH:13][CH:14]=2)[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[CH2:18]1
Reactant: CCOC(=O)C1(Cc2ccc(C)cc2)CCCN(C(=O)OC(C)(C)C)C1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1ccc(CC2(CO)CCCN(C(=O)OC(C)(C)C)C2)cc1
Temperature: -20 °C
Reaction time: 0.33 h

Procedure:
A solution of diisobutylaluminum hydride (12.0 ml, 12.0 mmol, 1M in THF) was added dropwise to a solution of the product from STEP 2 (1.5 g, 6.0 mmol) in 15 ml THF at −20° C. The resulting mixture was stirred at −20° C. for 20 min and allowed to warm to room temperature. After 3 h, the reaction was diluted with ether (70 ml) and washed with 50 ml of aqueous 1M tartaric acid. The organic extracts were dried with MgSO4, filtered and concentrated. The residue was purified by chromatography (SiO2, ethyl acetate/hexane=1/3) to afford 0.58 g of a viscous. The 1H NMR spectrum of the product was consistent for the proposed structure.
Reaction SMILES: [Cl-].[C:2]([OH:8])(=O)[CH2:3][CH2:4][C:5]#[CH:6].[Cl:9][C:10]1[CH:11]=[C:12]([NH:16][CH3:17])[CH:13]=[CH:14][CH:15]=1>C(Cl)Cl>[Cl:9][C:10]1[CH:11]=[C:12]([N:16]([CH3:17])[C:2](=[O:8])[CH2:3][CH2:4][C:5]#[CH:6])[CH:13]=[CH:14][CH:15]=1
Reactant: CNc1cccc(Cl)c1
Reactant: C#CCCC(=O)O
Agent: [Cl-]
Solvent: ClCCl
Product: C#CCCC(=O)N(C)c1cccc(Cl)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 88.2 %

Procedure:
Oxayl chloride (89 μL, 1.02 mmol) was added to a solution of pent-4-ynoic acid (50 mg, 0.51 mmol) in DCM (3 mL). The reaction mixture was stirred at 50° C. for 1 hour, was cooled to 0° C. and was added dropwise to a solution of (3-chloro-phenyl)-methyl-amine (62 μL, 0.51 mmol). The reaction mixture was stirred for 2 hours at room temperature. After evaporation of the solvent, the crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 100 mg (0.45 mmol, 88%) of pent-4-ynoic acid (3-chloro-phenyl)-methyl-amide.