Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:19])[CH2:10][S:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=1.[CH3:20][CH:21]([Si:23](Cl)([CH:27]([CH3:29])[CH3:28])[CH:24]([CH3:26])[CH3:25])[CH3:22].N1C=CN=C1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:19])[CH2:10][S:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][Si:23]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:22])[CH3:20])[CH:13]=1
Reactant: O=C(CSc1cccc(O)c1)c1ccc(F)cc1F
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)[Si](Oc1cccc(SCC(=O)c2ccc(F)cc2F)c1)(C(C)C)C(C)C
Reaction time: 24 h
Yield: 96 %

Procedure:
To a 100 mL three-neck round bottom flask was added 9n (1.4 g, 5 mmol) and TIPSCl (1.15 g, 6 mmol) in CH2Cl2 (40 mL) under nitrogen at room temperature. Then a solution of imidazole (816 mg, 12 mmol) in CH2Cl2 (20 mL) was added dropwise. The resulting mixture was stirred for 24 h. The mixture was filtered and the solvents were removed under reduced pressure. The residue was purified by flash column chromatography eluted by hexane:ethyl acetate (6:1) and the correct product was obtained as a slightly yellow oil; yield 96% (2.1 g); H NMR (400 MHz, CDCl3): d 1.13 (m, 18H, 6×CH3), 1.29 (m, 3H, CH), 4.26 (s, 2H, SCH2), 6.75 (m, 1H, Ar), 6.89-6.97 (m, 4H, Ar), 7.15 (m, 1H, Ar), 7.95 (m, 1H, Ar); CNMR (100 MHz, CDCl3): δ 21.6, 17.7, 29.3, 104.3, 111.5, 118.5, 119.2, 121.5, 122.7, 129.5, 131.4, 135.9, 153.6, 156.3, 159.5, 162.3, 164.9; IR ν (cm−1) 2944, 2983, 2866, 1682, 1610, 1584, 1475, 1423, 1266, 1245, 1186, 1145, 1095, 997, 970, 943, 881, 852, 776, 683; ESI HRMS m/z calcd for C23H31F2O3SSi (M+OH)+ 453.17258, found 453.17226.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([CH:25]2[CH2:27][CH2:26]2)[OH:24])=[CH:4][CH:3]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[F:59][CH:60]([F:63])[CH2:61]O>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([CH:25]2[CH2:27][CH2:26]2)[O:24][CH2:61][CH:60]([F:63])[F:59])=[CH:4][CH:3]=1
Reactant: OC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C1CC1
Reactant: OCC(F)F
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: FC(F)COC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C1CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 48.5 %

Procedure:
To a solution of [9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl](cyclopropyl)methanol (183 mg, 0.433 mmol), 1,1′-(azodicarbonyl)dipiperidine (219 mg, 0.868 mmol) in tetrahydrofuran (5.0 mL) was added tri(n-butyl)phosphine (0.217 mL, 0.869 mmol) at room temperature. After the mixture was stirred at room temperature for 10 min under nitrogen atmosphere, 2,2-difluoroethanol (0.272 mL, 4.30 mmol) was added to the reaction mixture. The mixture was stirred at 50° C. for 14 hr under nitrogen atmosphere. The mixture was concentrated in vacuo and diethyl ether was added to the residue. The solid was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 10-40% ethyl acetate/n-hexane gradient mixture and recrystallization from 2-propanol/n-hexane to give the title compound (102 mg, 0.21 mmol, 48%) as colorless crystals.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([NH:5][C:6]1[C:11](Br)=[CH:10][C:9]([CH3:13])=[CH:8][C:7]=1[Br:14])=[O:4].C([Li])CCC.[CH3:22][S:23]SC.Cl>C(OCC)C.CCCCCC>[F:1][C:2]([F:16])([F:15])[C:3]([NH:5][C:6]1[C:11]([S:23][CH3:22])=[CH:10][C:9]([CH3:13])=[CH:8][C:7]=1[Br:14])=[O:4]
Reactant: CSSC
Reactant: Cc1cc(Br)c(NC(=O)C(F)(F)F)c(Br)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CSc1cc(C)cc(Br)c1NC(=O)C(F)(F)F
Reaction time: 0.5 h
Yield: 78 %

Procedure:
Under an atmosphere of argon, 69.3 g (95% by weight pure, 182 mmol) of N-(trifluoroacetyl)-2,6-dibromo-4-methylaniline in 900 ml of dry diethyl ether were cooled to a temperature of −70° C. At this temperature, 153 ml of a 2.5M solution (382.5 mmol) of n-butyllithium in hexane were added dropwise. The mixture was subsequently stirred at this temperature for another 30 minutes. At this temperature, a solution of 51.5 g (547 mmol) of dimethyl disulfide in 100 ml of dry diethyl ether was then added dropwise. The contents were stirred at this temperature for 1 h and then at RT for 3 h and subsequently poured into 1000 ml of 1M hydrochloric acid. After phase separation, the aqueous phase was extracted with diethyl ether, the combined organic phases were dried and the filtrate was freed of the solvents. The residue was stirred with heptane for 30 minutes and then filtered. 46.6 g of N-(trifluoroacetyl)-2-bromo-4-methyl-6-(methylthio)aniline were obtained as residue.
Reaction SMILES: CON(C)[C:4]([C@@H:6]1[CH2:10][C:9](=[O:11])[N:8]([C@@H:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[CH2:7]1)=[O:5].[CH3:23][Mg]Br>C1COCC1>[C:4]([C@H:6]1[CH2:7][N:8]([C@@H:12]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[CH3:13])[C:9](=[O:11])[CH2:10]1)(=[O:5])[CH3:23]
Reactant: COc1ccc([C@@H](C)N2C[C@H](C(=O)N(C)OC)CC2=O)cc1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: COc1ccc([C@@H](C)N2C[C@H](C(C)=O)CC2=O)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of (R)-N-methoxy-1-((R)-1-(4-methoxyphenyl)ethyl)-N-methyl-5-oxopyrrolidine-3-carboxamide 1.02 (6.87 g, 22.4 mmol) in THF (70 mL) was cooled to an internal temperature of 19° C. under Ar. Methylmagnesium bromide (3 M in Et2O, 14.9 mL, 44.7 mmol) was added in portions over ca. 10 min to keep the internal temperature below 10° C. The resulting mixture was stirred for 1 h, by which time the internal temperature had reached −12° C., and was then warmed in an ice bath to 0° C. After an additional 50 min, the reaction was quenched with saturated aqueous NH4Cl (150 mL) and was diluted with EtOAc (150 mL) and water to dissolve solids. The phases were separated, and the aqueous phase was extracted with EtOAc (100 mL). The combined organic phase was dried over Na2SO4, filtered, and concentrated onto 25 g silica gel. The product was purified by silica gel chromatography (15% to 45% acetone in hexanes) to afford (R)-4-acetyl-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 1.03.
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:11](=[CH:12][NH:13][N:14]=2)[CH:10]=[C:9]([CH3:16])[C:8]=1[NH:17][C:18]([C:20]1[N:21]([C:27]2[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][N:28]=2)[N:22]=[C:23]([O:25][CH3:26])[CH:24]=1)=[O:19])=[O:6])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>ClCCl>[CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:11](=[CH:12][N:13]([S:42]([CH3:41])(=[O:44])=[O:43])[N:14]=2)[CH:10]=[C:9]([CH3:16])[C:8]=1[NH:17][C:18]([C:20]1[N:21]([C:27]2[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][N:28]=2)[N:22]=[C:23]([O:25][CH3:26])[CH:24]=1)=[O:19])=[O:6])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(C(=O)Nc2c(C)cc3c[nH]nc3c2C(=O)NC(C)C)n(-c2ncccc2Cl)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C(=O)Nc2c(C)cc3cn(S(C)(=O)=O)nc3c2C(=O)NC(C)C)n(-c2ncccc2Cl)n1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
To a suspension of 6-{[2-(3-chloro-pyridin-2-yl)-5-methoxy-2H-pyrazole-3-carbonyl]-amino}-5-methyl-2H-indazole-7-carboxylic acid isopropylamide (0.800 g, 1.71 mmol) in dichloromethane (5.0 mL) was added triethylamine (0.476 mL, 3.42 mmol), followed by methanesulphonyl chloride (0.265 mL, 3.42 mmol). The dark colored homogeneous reaction mixture was stirred for 1 h at 20° C. The reaction mixture was then concentrated in vacuo and the residue was purified by flash-chromatography (SiO2, CH2Cl2/ethyl acetate 4:1) yielding a brown solid that was recrystallized from ethyl acetate to afford the title compound as colourless crystals with a melting range of 135-175° C. (with decomposition).
Reaction SMILES: C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:30][C:31]1[C:35]([C:36]([OH:38])=O)=[CH:34][O:33][N:32]=1.[CH3:39][O:40][C:41]1[CH:61]=[CH:60][C:44]([O:45][C:46]2[CH:59]=[CH:58][C:49]([CH2:50][NH:51][C:52]([C:54]3([NH2:57])[CH2:56][CH2:55]3)=[O:53])=[CH:48][CH:47]=2)=[C:43]([C:62]([F:65])([F:64])[F:63])[CH:42]=1>CN(C=O)C>[CH3:39][O:40][C:41]1[CH:61]=[CH:60][C:44]([O:45][C:46]2[CH:59]=[CH:58][C:49]([CH2:50][NH:51][C:52]([C:54]3([NH:57][C:36]([C:35]4[C:31]([CH3:30])=[N:32][O:33][CH:34]=4)=[O:38])[CH2:55][CH2:56]3)=[O:53])=[CH:48][CH:47]=2)=[C:43]([C:62]([F:63])([F:64])[F:65])[CH:42]=1
Reactant: Cc1nocc1C(=O)O
Reactant: COc1ccc(Oc2ccc(CNC(=O)C3(N)CC3)cc2)c(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(Oc2ccc(CNC(=O)C3(NC(=O)c4conc4C)CC3)cc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
37 μL (0.26 mmol) of triethylamine and 84.4 mg (0.26 mmol) of TBTU were added to a solution of 33.4 mg (0.26 mmol) of 3-methylisoxazole-4-carboxylic acid in 5 mL DMF and the mixture was stirred for 10 min at RT. Then 100 mg (0.26 mmol) of 1-amino-cyclopropanecarboxylic acid 4-(4-methoxy-2-trifluoromethyl-phenoxy)-benzylamide (from 85a) was added and the mixture was stirred for 4 h at ambient temperature and overnight at 40° C. The reaction mixture was purified by chromatography (reversed phase).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[C:14](=O)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[O:16][CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:7]1=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].C1COCC1>>[CH3:1][O:2][C:3]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[O:16][CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[CH2:7]1
Reactant: COc1ccc(CN2C(=O)c3cccc(OCCN(C)C)c3C2=O)c(OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN2Cc3cccc(OCCN(C)C)c3C2)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.6 %

Procedure:
2-(2,4-Dimethoxy-benzyl)-4-(2-dimethylamino-ethoxy)-isoindole-1,3-dione (201 mg, 0.52 mmol) was treated with a 1M solution of lithium aluminium hydride in THF (5 mL, 5 mmol). After 7.5 hours at r.t. a further portion of lithium aluminium hydride solution (5 mL, 5 mmol) was added and the mixture maintained for further 18 hours. The mixture was then cooled in ice and quenched by the dropwise addition of water (0.4 mL), 2N sodium hydroxide solution (0.8 mL) and water (0.8 mL). Magnesium sulfate was added, followed by ethyl acetate and then the mixture was stirred at r.t. for 1 hour. The solids were removed by filtration, being well washed with ethyl acetate. Concentration of the filtrate gave the title compound (192 mg, 103%) as a brown oil which was carried forward without further purification. 1H NMR (methanol-d4) 7.24 (1H, d), 7.16 (1H, t), 6.82-6.78 (2H, m), 6.55 (1H, d), 6.51 (1H, dd), 4.12 (2H, t), 3.92 (4H, s), 3.86 (2H, s), 3.82 (3H, s), 3.80 (3H, s), 2.76 (2H, t), 2.33 (6H, s). MS: [M+H]+ 357.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=1)[OH:4].O=[C:14]([CH3:28])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:19][CH:18]=1.C1C=CC=CC=1.C([BH3-])#N.[Na+]>CO>[CH3:27][O:26][C:24]([CH2:23][C:20]1[CH:19]=[CH:18][C:17]([O:16][CH2:15][CH:14]([NH:1][CH2:2][CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=2)[OH:4])[CH3:28])=[CH:22][CH:21]=1)=[O:25]
Reactant: COc1cccc(C(O)CN)c1
Reactant: COC(=O)Cc1ccc(OCC(C)=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)Cc1ccc(OCC(C)NCC(O)c2cccc(OC)c2)cc1
Yield: 55.7 %

Procedure:
Following a procedure similar to that described in Example 3, but using 2.5 g of 2-amino-1-(3-methoxyphenyl)ethanol (prepared as described in Preparation 43), 4.0 g of methyl 4-(2-oxopropoxy)phenylacetate (prepared as described in Preparation 3), 80 ml of benzene, 60 ml of absolute methanol and 2.75 g of sodium cyanoborohydride, and then purifying the reaction product by column chromatography through silica gel, using ethyl acetate as the eluent, 3.11 g of the title compound were obtained having an Rf=0.21 (thin layer chromatography over silica gel, using ethyl acetate as the developing solvent).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].[CH3:13][C:14]([OH:18])([C:16]#[CH:17])[CH3:15].C(NC(C)C)(C)C>CN(C)C=O.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:17]#[C:16][C:14]([OH:18])([CH3:15])[CH3:13])=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10]
Reactant: C#CC(C)(C)O
Reactant: Nc1ccc(Br)cc1S(N)(=O)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: CC(C)(O)C#Cc1ccc(N)c(S(N)(=O)=O)c1
Temperature: 100 °C
Yield: 45.4 %

Procedure:
2-Amino-5-bromobenzenesulfonamide (2 g, 7.96 mmol), copper(I) iodide (0.076 g, 0.40 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.280 g, 0.40 mmol) were slurried in anhydrous N,N-dimethylformamide (6 mL) in a microwave vial. 2-Methyl-3-butyn-2-ol (2.316 mL, 23.89 mmol) followed by diisopropylamine (3.37 mL, 23.89 mmol) were added, the vial was capped, purged with argon and the mixture was heated in a microwave at 100° C. for 30 min. The mixture was filtered and the solvent was evaporated in vacuo. Purification by column chromatography, using a gradient of 60-70% ethyl acetate in heptane as the eluent, gave 0.92 g (46% yield) of the title compound.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])=[CH:9][CH:8]=2)OCC[O:3]1.Cl.CC(C)=O.C(=O)([O-])O.[Na+]>O>[CH2:13]([C:10]1[CH:9]=[CH:8][C:7]([C:2](=[O:3])[CH3:1])=[CH:12][CH:11]=1)[CH:14]=[C:15]([CH3:17])[CH3:16]
Reactant: CC(C)=CCc1ccc(C2(C)OCCO2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)c1ccc(CC=C(C)C)cc1
Yield: 97.6 %

Procedure:
A solution of 69.0 g of 2-methyl-2-(p-prenylphenyl)-1,3-dioxolane, 8 ml of 6 N hydrochloric acid and 400 ml of acetone was stirred at room temperature for 3 hours. A solution of 5.0 g of sodium hydrogen carbonate and 200 ml of water was added to the solution, which was extracted with ethyl ether after removal of the acetone. The ethereal solution was washed with water, dried, concentrated and distilled to give 54.6 g of p-prenylacetophenone, b.p. 110-112 °C/0.05 mmHg.
Reaction SMILES: [CH3:1][CH:2]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Na].[Br:14][C:15]1[CH:22]=[CH:21][C:18](CBr)=[CH:17][CH:16]=1>C(O)C>[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:1][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:17][CH:16]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: CCOC(=O)C(C)C(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(Cc1ccc(Br)cc1)C(=O)OCC
Reaction time: 72 h
Yield: 91.7 %

Procedure:
A solution of diethyl methylmalonate (87 g) in absolute ethanol (100 ml) was added to a pre-formed solution of sodium (11.5 g) in ethanol (400 ml) under argon. A hot solution of p-bromobenzylbromide (125 g) in absolute alcohol (200 ml) was added rapidly with vigorous stirring, which was continued for 3 days and the solid so formed was removed by filtration. The filtrate was evaporated and the residue dissolved in ethyl acetate (11), washed with brine (250 ml), dried (MgSO4) and evaporated. The residual oil was distilled under vacuum to give diethyl (4-bromophenyl)methylmalonate (150.7 g) b.p. 130-133/0.03 mm Hg; 1H NMR (d6 -DMSO): 1.33 (t, 6H), 1.4 (s, 3H), 3.27 (s, 2H), 4.30 (q, 4H), 7.23 (d, 2H), 7.6 (d, 2H),
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:30])[NH:17][C:18]1[S:19][CH:20]=[C:21]([C:23]2[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=2)[N:22]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:38](Cl)(=[O:43])[CH2:39][CH2:40][CH2:41][CH3:42]>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16](=[O:30])[NH:17][C:18]1[S:19][CH:20]=[C:21]([C:23]2[CH:24]=[CH:25][C:26]([NH:29][C:38](=[O:43])[CH2:39][CH2:40][CH2:41][CH3:42])=[CH:27][CH:28]=2)[N:22]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(-c2csc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)n2)cc1
Reactant: CCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC(=O)Nc1ccc(-c2csc(NC(=O)C3CCCN3C(=O)OCc3ccccc3)n2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
80 mg (0.19 mmol)) of Compound 5050 was dissolved in 5 mL of dry methylene chloride. To this solution at 0° C. was added triethylamine (0.19 mmol, 25 μL) followed by pentanoyl chloride (0.19 mmol, 22 μL). Reaction mixture was stirred at 0° C. for 15 minutes. Reaction mixture was quenched using water and evaporated. It was redissolved in 5 mL of DMF and purified using reverse phase HPLC. MS: 507.2 (M+H+).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:7]2[C:8]([F:28])=[C:9]([N:13]([CH2:25][O:26][CH3:27])[S:14]([C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=3[F:24])(=[O:16])=[O:15])[CH:10]=[CH:11][CH:12]=2)=[N:4][NH:5][CH:6]=1.[H-].[Na+].Br[CH2:32][CH2:33][O:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][O:36]1>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[C:3]([C:7]2[C:8]([F:28])=[C:9]([N:13]([CH2:25][O:26][CH3:27])[S:14]([C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=3[F:24])(=[O:16])=[O:15])[CH:10]=[CH:11][CH:12]=2)=[N:4][N:5]([CH2:32][CH2:33][O:34][CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][O:36]2)[CH:6]=1
Reactant: COCN(c1cccc(-c2n[nH]cc2Br)c1F)S(=O)(=O)c1cc(F)ccc1F
Reactant: BrCCOC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCN(c1cccc(-c2nn(CCOC3CCCCO3)cc2Br)c1F)S(=O)(=O)c1cc(F)ccc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55.4 %

Procedure:
A solution of N-[3-(4-Bromo-1H-pyrazol-3-yl)-2-fluoro-phenyl]-2,5-difluoro-N-methoxymethyl-benzenesulfonamide (346 mg, 0.726 mmol)(prepared as described in Preparation 1) in anhydrous DMF (4 mL) was cooled to 0° C. under an argon atmosphere and sodium hydride (60% in mineral oil, 87 mg, 2.179 mmol, 3 eq) was added. The mixture was stirred at 0° C. for 30 minutes, then 2-(2-bromo-ethoxy)-tetrahydro-pyran (0.165 mL, 1.089 mmol, 1.5 eq) was added dropwise and the mixture was stirred at 0° C. for 1 hour. The reaction mixture was then diluted with AcOEt and washed with water and brine. The organic layer was dried over Na2SO4 and evaporated to dryness. The crude product was purified by flash chromatography on silica gel (cyclohexane/AcOEt 55:45) affording 243 mg (55%) of the desired regioisomer N-(3-{4-Bromo-1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazol-3-yl}-2-fluoro-phenyl)-2,5-difluoro-N-methoxymethyl-benzenesulfonamide. HPLC (254 nm): Rt: 7.21 min; 1H NMR (DMSO-d6) Shift (selected signals): 8.07 (s, 1H), 7.55-7.69 (m, 2H), 7.47-7.53 (m, 2H), 7.39-7.45 (m, 1H), 7.30-7.35 (m, 1H), 5.09 (s, 2H), 4.51-4.57 (m, 1H), 4.29-4.35 (m, 2H), 3.89-3.97 (m, 1H), 3.70-3.78 (m, 1H), 3.42-3.51 (m, 1H), 3.38 (s, 3H), 1.29-1.69 (3 m, 6H); HRMS (ESI) calcd for C24H26BrF3N3O5S [M+H]+ 604.0723. found 604.0693.
Reaction SMILES: FC(F)(F)C1C=C([C@H]2OC(=O)N(C[C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[CH:31]=[C:32]([C:38]4[CH:43]=[CH:42][C:41]([C:44]([O:46]C)=[O:45])=[CH:40][C:39]=4C)[CH:33]=[CH:34][C:35]=3OC)[C@H]2C)C=C(C(F)(F)F)C=1.[OH-].[K+].C(O)C>C(O)(=O)C>[F:27][C:26]([F:28])([F:29])[C:24]1[CH:23]=[CH:22][C:21]([C:30]2[CH:31]=[C:32]([C:38]3[CH:43]=[CH:42][C:41]([C:44]([OH:46])=[O:45])=[CH:40][CH:39]=3)[CH:33]=[CH:34][CH:35]=2)=[CH:20][CH:25]=1
Reactant: COC(=O)c1ccc(-c2ccc(OC)c(-c3ccc(C(F)(F)F)cc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c2)c(C)c1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: O=C(O)c1ccc(-c2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1

Procedure:
methyl 2″-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4′-methoxy-2-methyl-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylate (20 mg, 0.0276 mmol), aqueous potassium hydroxide (300 μL, 3M, 0.90 mmol) and ethanol (2 mL) were stirred at 20° C. for 2 hours and 20 minutes to complete the hydrolysis. The reaction mixture was acidified by acetic acid. The mixture was purified by preparative TLC on silica gel, (eluted with AcOH/EtOAc/hexanes=5/25/70, v/v) to afford 2″-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4′-methoxy-2-methyl)-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylic acid. LCMS calc.=711.17; found=712.10 (M+1)+. 1H NMR signals are doubled because of atropoisomerism. 1H NMR (CDCl3, 500 MHz) δ 7.99 (d, J=8.0 Hz, 1H), 7.92 (d, J=8.5 Hz, 1H), 7.85 (d, J=5 Hz, 1H), 7.72-7.68 (m, 1.5H), 7.67-7.60 (m, 2.5H), 7.47-7.36 (m, 2H), 7.32 (d, J=8.0 Hz, 0.5H), 7.28 (d, J=8.0 Hz, 0.5H), 7.15 (s, 1H), 7.08 (d, J=8.5, 7.0 Hz, 1H), 5.58 (d, J=8.0 Hz, 0.5H), 5.29 (d, J=6.5 Hz, 0.5H), 4.97 (d, J=15.5 Hz, 0.5H), 4.94 (d, J=14 Hz, 0.5H), 4.16 (d, J=16 Hz, 0.5H), 3.96 (d, J=15.5 Hz, 0.5H), 3.87 (s, 3H), 3.83-3.74 (m, 1H), 2.38, 2.33 (s, 3H), 0.55 (d, J=6.5 Hz, 1.5H), 0.42 (d, J=7 Hz, 1.5H).
Reaction SMILES: [F:1][C:2]1[CH:23]=[C:22](I)[CH:21]=[CH:20][C:3]=1[NH:4][C:5]1[C:6]([C:13]([NH:15][O:16][CH2:17][CH2:18][OH:19])=[O:14])=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1.[CH2:25]([OH:28])[C:26]#[CH:27]>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[F:1][C:2]1[CH:23]=[C:22]([C:27]#[C:26][CH2:25][OH:28])[CH:21]=[CH:20][C:3]=1[NH:4][C:5]1[C:6]([C:13]([NH:15][O:16][CH2:17][CH2:18][OH:19])=[O:14])=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1
Reactant: Cn1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)cc1=O
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Product: Cn1cc(C(=O)NOCCO)c(Nc2ccc(C#CCO)cc2F)cc1=O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
4-(2-Fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide (330 mg, 0.74 mmol), CuI (3 mg, 0.01 mmol) and (Ph3P)2PdCl2 (104 mg, 0.01 mmol) were dissolved dry THF (2 mL) in a flask which was then flushed with nitrogen. A solution of propargyl alcohol (47 mg, 0.81 mmol) in TEA (2 mL) was added to the reaction, which was stirred at R.T. for 15 h. The solvent was removed under reduced pressure, then the residue purified by chromatography on silica gel (10% MeOH/CH2Cl2 as eluant), giving 4-[2-fluoro-4-(3-hydroxy-1-propynyl)anilino]-N-(2-hydroxyethoxy)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide as a viscous, transparent oil (44%). 1H NMR [(CD3)2SO, 400 MHz] δ 11.50 (v br s, 1H), 9.60 (s, 1H), 8.16 (s, 1H), 7.49 (t, J=8.3 Hz, 1H), 7.40 (dd, J=10.1, 1.9 Hz, 1H), 7.28 (dd, J=8.3, 1.4 Hz, 1H), 5.67 (s, 1H), 5.37 (t, J=5.1 Hz, 1H), 4.73 (br s, 1H), 4.30 (d, J=4.8 Hz, 2H), 3.91 (t, J=4.8 Hz, 2H), 3.62 (br t, J=4.8 Hz, 2H), 3.36 (s, 3H). LCMS (APCI+) calcd for C18H19N3O5F 376 (MH+), found 376.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([OH:12])[C:4]=1[CH3:13])#[N:2].[Br:14]N1C(=O)CCC1=O.O>CN(C=O)C>[Br:14][C:11]1[C:3]([C:1]#[N:2])=[C:4]([CH3:13])[C:5]([OH:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(C#N)ccc(C(=O)O)c1O
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(O)c(C(=O)O)cc(Br)c1C#N
Temperature: 15 °C
Reaction time: 16 h
Yield: 93.5 %

Procedure:
To a solution of 4-cyano-2-hydroxy-3-methylbenzoic acid (5.50 g) in DMF (50.0 mL) was added N-bromosuccinimide (5.50 g) under ice-cooling, and the mixture was stirred at 15° C. for 16 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (7.40 g: containing DMF).