Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[S:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[C:12]=3[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[I-:21].[Na+].CNC1CCCCC1NC>[Cu]I.O1CCOCC1>[I:21][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[S:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[C:12]=3[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Brc1cccc(-c2cccc3c2sc2ccccc23)c1
Reactant: [I-]
Agent: [Cu]I
Agent: CNC1CCCCC1NC
Agent: [Na+]
Solvent: C1COCCO1
Product: Ic1cccc(-c2cccc3c2sc2ccccc23)c1
Yield: 91.2 %

Procedure:
4-(3-bromophenyl)dibenzo[b,d]thiophene (9.00 g, 26.5 mmol), sodium iodide (7.95 g, 53.1 mmol), copper(I) iodide (1.516 g, 7.96 mmol), and dioxane (265 ml) were added into a 500 mL 3-necked flask. N1,N2-dimethylcyclohexane-1,2-diamine (2.092 ml, 13.26 mmol) was added. The mixture was degassed by bubbling nitrogen for 30 minutes and the reaction mixture was heated and refluxed overnight. After completion of the reaction, the heating was stopped and the mixture was filtered through a pad of Celite® and washed several times with DCM. The crude material was purified via column chromatography using hexane/DCM (80/20). The target 4-(3-iodophenyl)dibenzo[b,d]thiophene (9.33 g, 24.16 mmol, 91% yield) was afforded as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:10]([CH2:14][CH3:15])[C:11]([OH:13])=O)=[O:9])=[CH:4][CH:3]=1.[NH2:16][CH:17]1[C:35](=[O:36])[N:19]2[C:20]([C:32]([OH:34])=[O:33])=[C:21]([CH:24]([S:26][C:27]3[NH:31][N:30]=[N:29][N:28]=3)[CH3:25])[CH2:22][S:23][C@H:18]12>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:10]([CH2:14][CH3:15])[C:11]([NH:16][CH:17]2[C:35](=[O:36])[N:19]3[C:20]([C:32]([OH:34])=[O:33])=[C:21]([CH:24]([S:26][C:27]4[NH:28][N:29]=[N:30][N:31]=4)[CH3:25])[CH2:22][S:23][C@H:18]23)=[O:13])=[O:9])=[CH:6][CH:7]=1
Reactant: CC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: CCC(C(=O)O)S(=O)c1ccc(O)cc1
Product: CCC(C(=O)NC1C(=O)N2C(C(=O)O)=C(C(C)Sc3nnn[nH]3)CS[C@H]12)S(=O)c1ccc(O)cc1

Procedure:
456 mg. of 2-(p-hydroxyphenylsulfinyl)butyric acid and 7-amino-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid were reacted in the same manner as described in Example 28 and 237 mg. of 7-[2-(p-hydroxyphenylsulfinyl)butyramido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid were obtained.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)=O.[C:12]([NH2:15])(=[S:14])[CH3:13].[OH-].[Na+]>O1CCOCC1>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:15]=[C:12]([CH3:13])[S:14][CH:2]=2)=[CH:6][CH:7]=1
Reactant: CC(N)=S
Reactant: O=C(CBr)c1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1nc(-c2ccc(Br)cc2)cs1
Temperature: 25 °C
Yield: 103.4 %

Procedure:
To a stirred solution of 2,4′-dibromoacetophenone (5 g, 18 mmol) in dioxane (180 ml) was added thioacetamide (6.76 g, 90 mmol), and the mixture was heated at reflux temperature for 8 hours. The reaction mixture was cooled down to room temperature, and made basic by addition of 2N NaOH aqueous solution. The whole was extracted with diethyl ether. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate-hexane (1:5) to give title compound (4.73 g, 99% yield).
Reaction SMILES: [C@@H:1]1([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.C(N(CC)CC)C.[C:25]([Si:29]([CH3:32])([CH3:31])Cl)([CH3:28])([CH3:27])[CH3:26]>CN(C)C=O.C(OCC)(=O)C>[Si:29]([O:7][CH2:6][C@H:5]1[O:8][C@@H:1]([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[CH2:2][C@@H:3]1[OH:4])([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:32])[CH3:31]
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1cn([C@H]2C[C@H](O)[C@@H](CO[Si](C)(C)C(C)(C)C)O2)c(=O)[nH]c1=O
Reaction time: 6 h
Yield: 88.4 %

Procedure:
5'-O-tert-Butyldimethylsilylthymidine (Compound 2, Table I) was prepared by dissolving thymidine (25 g, 0.10 mole), 4-N,N-dimethylaminopyridine (3.15 g, 0.026 mole) and triethylamine (13.5 g, 18.6 ml, 0.13 mole) in 200 ml of dry N,N-dimethylformamide under a stream of argon. 19.4 g (0.13 mol) tert-butyldimethylchlorosilane was added to the dissolved mixture, with the entire mixture then being stirred for six hours before evaporation of the solvent. The resulting gum was dissolved in 30 ml ethyl acetate and the solution extracted with 10 ml saturated sodium bicarbonate solution, 30 ml water and 30 ml brine. Following drying of the organic layer, the residue was purified by flash chromatography using dichloromethane/ethanol (50/1) as eluent. Evaporation of the product-containing fractions yielded 31.5 g of the desired 5'-O-tert-butyldimethylsilylthymidine as a white foam (86% yield).
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[NH:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][CH2:8][CH2:7][CH2:6]1>O.CC(O)=O>[N:1]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:3]
Reactant: c1ccc2c(c1)CCCCN2
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=NN1CCCCc2ccccc21
Temperature: 5 °C
Reaction time: 1 h
Yield: 90.5 %

Procedure:
A solution of sodium nitrite (1.35 g, 19.6 mmol) in water (4.0 mL) was added dropwise to a solution of 2,3,4,5-tetrahydro-1H-1-benzazepine (2.40 g, 16.3 mmol) in AcOH (10 mL) at 0-10° C. The mixture was stirred at 5° C. for 10 min, room temperature for 1 h and extracted with CH2Cl2 (3×20 mL). The organic layer was dried (MgSO4), concentrated in vacuo and flash column chromatography (EtOAc:hexane/1:9) gave 1-nitroso-2,3,4,5-tetrahydro-1H-1-benzazepine (2.60 g, 91%) as a brown liquid. 1H NMR (CDCl3, 300 MHz) δ1.70-1.85 (m, 4H), 2.70-2.82 (m, 2H), 3.92 (br, 2H), 7.25-7.32 (m, 1H), 7.32-7.40 (m, 2H), 7.40-7.48 (m, 1H) ppm.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH2:12]([N:14]1[C:20]2[N:21]=[CH:22][C:23]([CH2:25][CH2:26][O:27][C:28]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:31]=[CH:30][CH:29]=3)=[CH:24][C:19]=2[C:18](=[O:38])[NH:17][C:16]2[C:39]([CH3:43])=[CH:40][CH:41]=[N:42][C:15]1=2)[CH3:13]>C(Cl)Cl>[CH2:12]([N:14]1[C:20]2[N:21]=[CH:22][C:23]([CH2:25][CH2:26][O:27][C:28]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[N+:31]([O-:9])=[CH:30][CH:29]=3)=[CH:24][C:19]=2[C:18](=[O:38])[NH:17][C:16]2[C:39]([CH3:43])=[CH:40][CH:41]=[N:42][C:15]1=2)[CH3:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCN1c2ncc(CCOc3ccnc4ccccc34)cc2C(=O)Nc2c(C)ccnc21
Solvent: ClCCl
Product: CCN1c2ncc(CCOc3cc[n+]([O-])c4ccccc34)cc2C(=O)Nc2c(C)ccnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
Solid mCPBA (163 mg, 0.75 mmol) was added to a solution of 5,11-dihydro-11-ethyl-4-methyl-8-{2-(4-quinolinyloxy)ethyl}-6H-dipyrido[3,2-b:2′,3′-e] [1,4]diazepin-6-one (144 mg, 0.34 mmol) in CH2Cl2 (7.5 mL). The solution was stirred at room temperature for 2 h. The mixture was diluted with CH2Cl2 (125 mL), washed successively with aqueous 10% Na2S2O3 (2×25 mL), aqueous saturated NaHCO3 (2×25 mL) and brine (25 mL), then was dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (CH2Cl2:MeOH, 10:1) to give the title compound (102 mg, 68% yield) as a white solid: MS (ESI) m/z 442 (MH)+.
Reaction SMILES: [OH-].[Li+].COC([C:7]1[C:12]([NH2:13])=[N:11][C:10]([NH2:14])=[C:9]([Cl:15])[N:8]=1)=O.Cl>CO.O.O1CCOCC1>[Cl:15][C:9]1[C:10]([NH2:14])=[N:11][C:12]([NH2:13])=[CH:7][N:8]=1
Reactant: COC(=O)c1nc(Cl)c(N)nc1N
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Solvent: O
Product: Nc1cnc(Cl)c(N)n1
Temperature: 90 °C
Yield: 81.8 %

Procedure:
Lithium hydroxide (12.4 g, 0.30 mol) was added to a stirred suspension of 3,5-diamino-6-chloro-pyrazine-2-carboxylic acid methyl ester (20 g, 99 mmol) in methanol (300 ml) and water (120 ml) and the reaction heated at 90° C. for 1.5 hours before allowing to cool to room temperature. The reaction was concentrated in vacuo to afford a yellow slurry and this was suspended in 1,4-dioxane (350 ml) and 2M aqueous HCl solution (200 ml) was added. The mixture was heated at 100° C. for 2 hours and then allowed to cool before removing the 1,4-dioxane in vacuo. The resulting aqueous solution was taken to pH 8 using sodium carbonate (saturated aqueous) and extracted into ethyl acetate (3×300 ml). The combined organic layers were washed with brine (300 ml), dried (Na2SO4) and concentrated in vacuo to afford a yellow solid (11.7 g, 82%).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[CH3:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][NH:33]1>>[CH3:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][N:33]1[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[CH:19][C:20]([C:23]([N:25]4[CH2:26][CH2:27][O:28][CH2:29][CH2:30]4)=[O:24])=[CH:21][CH:22]=3)=[CH:13][C:11]=2[CH:12]=1
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cc3)ccc2o1
Reactant: CC1CCCCN1
Product: CC1CCCCN1CCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cc3)ccc2o1

Procedure:
The product from Example 23D and 2-methyl-piperidine were processed as described in Example 1D to provide the titled compound. 1H NMR (300 MHz, CD3OD) δ 7.82 (m, 1H), 7.74 (d, J=8.1, 2H), 7.56 (m, 2H), 7.52 (d, J=8.1 Hz, 2H), 6.80 (s, 1H), 3.4-3.78 (m, 15H), 1.6-2.1 (m, 6H), 1.46 (d, J=6.3 Hz, 3H); MS (DCI) m/z 433 (M+H)+;
Reaction SMILES: [C:1]([C:5]1[C:6]([NH2:14])=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:3])[CH3:2].[C:15]12([CH2:25][C:26](Cl)=[O:27])[CH2:24][CH:19]3[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]3)[CH2:16]1)[CH2:22]2>>[C:15]12([CH2:25][C:26]([NH:14][C:6]3[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[C:9]4[N:10]=[CH:11][CH:12]=[CH:13][N:8]4[N:7]=3)=[O:27])[CH2:22][CH:21]3[CH2:20][CH:19]([CH2:18][CH:17]([CH2:23]3)[CH2:16]1)[CH2:24]2
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Reactant: CC(C)(C)c1c(N)nn2cccnc12
Product: CC(C)(C)c1c(NC(=O)CC23CC4CC(CC(C4)C2)C3)nn2cccnc12

Procedure:
The product from Example 105B and 1-adamantylacetyl chloride were processed using the method analogous to that described in Example 105C to afford the title compound. 1H NMR (300 MHz, DMSO-d6): δ ppm 1.45 (s, 9H), 1.59-1.67 (m, 12H), 1.95 (br s, 3H), 2.06 (s, 2H), 6.98 (dd, J=6.8, 4.1 Hz, 1H), 8.47 (dd, J=4.1, 1.7 Hz, 1H), 8.95 (dd, J=7.0, 1.9 Hz, 1H), 9.56 (s, 1H); MS (DCI) m/z 367 (M+H)+.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[C:13]1([CH2:19][O:20][C:21]2[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=2[C:23]([OH:25])=O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.ON1C2C=CC=CC=2N=N1.[CH2:40]([CH2:42][NH2:43])[OH:41]>C1COCC1>[OH:41][CH2:40][CH2:42][NH:43][C:23]([C:22]1[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=1[O:20][CH2:19][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:25]
Reactant: O=C(O)c1ccccc1OCc1ccccc1
Reactant: NCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(NCCO)c1ccccc1OCc1ccccc1
Temperature: 25 °C
Yield: 101 %

Procedure:
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDAC) (1.3 g, 6.57 mmol) was slowly added to a solution of 2-(phenylmethoxy)benzoic acid (1.5 g, 6.57 mmol), 1-hydroxybenzotriazole (HOBt) (0.89 g, 6.57 mmol), and ethanolamine (0.40 mL, 6.57 mmol) in 50 mL of anhydrous THF at 0° C. The suspension was stirred and warmed up slowly to room temperature over 24 hrs. The reaction mixture was concentrated to dryness under reduced pressure and the resulting residue was diluted with dichloromethane and washed with 0.5N HCl twice followed by the addition of a saturated NaHCO3 solution and brine. The organic layer was separated, dried through a MgSO4 pad and concentrated under reduced pressure to afford 1.8 g (100%) of N-(2-Hydroxyethyl)[2-(phenylmethoxy)phenyl]carboxamide.
Reaction SMILES: [H-].[Li+].[NH2:3][C:4]1[N:12]=[C:11]2[C:7]([NH:8][CH:9]=[N:10]2)=[C:6]([O:13][CH2:14][CH2:15][O:16][CH3:17])[N:5]=1.[CH2:18]([O:20][P:21]([CH2:26][O:27][CH2:28][CH2:29][CH2:30]Br)([O:23][CH2:24][CH3:25])=[O:22])[CH3:19].O>CN(C)C=O>[NH2:3][C:4]1[N:12]=[C:11]2[C:7]([N:8]=[CH:9][N:10]2[CH2:30][CH2:29][CH2:28][O:27][CH2:26][P:21]([O:23][CH2:24][CH3:25])([O:20][CH2:18][CH3:19])=[O:22])=[C:6]([O:13][CH2:14][CH2:15][O:16][CH3:17])[N:5]=1
Reactant: CCOP(=O)(COCCCBr)OCC
Reactant: COCCOc1nc(N)nc2nc[nH]c12
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(COCCCn1cnc2c(OCCOC)nc(N)nc21)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of lithium hydride (560 mg, 60 mmol) in dry dimethylformamide (DMF, 200 ml) was added 2-amino-6-methoxyethoxy purine (8.0 g, 40 mmol) [prepared according to the literature procedure: J. Kjellberg, M. Liljenberg and N. G. Johansson, Tetrahedron Lett. 877, 1986] and stirred for 60 min at 25° C. To this solution was added over 3 min a solution of 3-(diethylphosphonomethoxy)-1-bromopropane (12.0 g, 41.5 mmol) in DMF (5 mL) and the solution was heated at 55° C. for 4 h. The reaction mixture was then cooled to room temperature and water (50 mL) was added dropwise. Insoluble material was removed by filtration. The filtrate was concentrated in vacuo to give a viscous oil which was purified by column chromatography on silica gel (5% methanol in CH2 CL2) to afford 2-amino-9-[3-(diethylphosphonomethoxy)-propyl]-6-methoxyethoxy purine as a white crystalline solid: yield 3.45 g (21%); mp 78°-79° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([OH:16])[CH:7]=1)[CH3:2].F[C:19]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:20]=1[CH:21]=[O:22]>>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[CH:11]=[C:10]([C:12]([F:13])([F:15])[F:14])[CH:9]=[C:8]([O:16][C:19]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:20]=2[CH:21]=[O:22])[CH:7]=1)[CH3:2]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1F
Reactant: CCOC(=O)Cc1cc(O)cc(C(F)(F)F)c1
Product: CCOC(=O)Cc1cc(Oc2ccc([N+](=O)[O-])cc2C=O)cc(C(F)(F)F)c1

Procedure:
(3-Hydroxy-5-trifluoromethyl-phenyl)-acetic acid ethyl ester and 2-fluoro-5-nitrobenzaldehyde were reacted according to the procedure described in Example 21, Step 5, to give [3-(2-formyl-4-nitro-phenoxy)-5-trifluoromethyl-phenyl]-acetic acid ethyl ester.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:13]2=[CH:14][N:15]([C:17]3[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:24])[N:16]=[C:12]2[C:11]([Cl:25])=[CH:10][N:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:25][C:11]1[C:12]2[C:13](=[CH:14][N:15]([C:17]3[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:24])[N:16]=2)[C:8]([NH2:7])=[N:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ncc(Cl)c2nn(-c3c(Cl)cccc3Cl)cc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncc(Cl)c2nn(-c3c(Cl)cccc3Cl)cc12
Yield: 24845.2 %

Procedure:
A solution of [7-chloro-2-(2,6-dichlorophenyl)-2H-pyrazolo[4,3-c]pyridin-4-yl]-carbamic acid tert-butyl ester (531 mg, contaminated with residual tert-butyl carbamate) and TFA (10 mL) in DCM (10 mL) was stirred at room temperature for 2 h and then concentrated under reduced pressure. The residue was partitioned between ethyl acetate and sodium bicarbonate (sat. aq.). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to afford the title compound as a beige solid (100 g, 30% yield over 2 steps). LCMS (Method D): RT=2.15 min, m/z: 313 [M+H+].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:14])([CH3:13])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[CH2:15]([O:22][CH2:23][C@@H:24]1[NH:29][CH2:28][CH2:27][N:26]([S:30]([C:33]2[S:34][CH:35]=[CH:36][CH:37]=2)(=[O:32])=[O:31])[CH2:25]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CC(C)([O-])C.[Na+].COC(C)(C)C>O.C1(C)C=CC=CC=1>[CH2:15]([O:22][CH2:23][C@H:24]1[CH2:25][N:26]([S:30]([C:33]2[S:34][CH:35]=[CH:36][CH:37]=2)(=[O:31])=[O:32])[CH2:27][CH2:28][N:29]1[C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:14])([CH3:13])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(O)(c1ccc(Br)cc1)C(F)(F)F
Reactant: O=S(=O)(c1cccs1)N1CCN[C@@H](COCc2ccccc2)C1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: COC(C)(C)C
Solvent: Cc1ccccc1
Product: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2COCc2ccccc2)cc1)C(F)(F)F
Temperature: 65 °C
Yield: 74 %

Procedure:
A 1-L pressure vessel was charged with 2-(4-bromophenyl)-1,1,1-trifluoropropan-2-ol (43.8 g, 163 mmol, Example 27, Step 1), (3R)-3-((benzyloxy)methyl)-1-(2-thiophenylsulfonyl)piperazine (47.8 g, 136 mmol), 200 mL of toluene, and sodium tert-butoxide (32.6 g, 339 mmol). After bubbling nitrogen gas through the solution for 5 min, chloro(2-dicyclohexylphosphino-2′,6′-di-1-propoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(II), methyl-t-butylether adduct (RuPhos Palladacycle) (0.99 g, 1.36 mmol, Strem Chemicals, Newburyport, Mass.) and 2-dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (RuPhos) (0.63 g, 1.36 mmol, Strem Chemicals, Newburyport, Mass.) were added. The vessel was sealed and heated at 65° C. for 12 h. After that time, the mixture was diluted with water and extracted with EtOAc, dried (MgSO4), filtered, and concentrated. Purification by column chromatography on silica gel (0 to 60% EtOAc in hexanes) gave 2-(4-((2R)-2-((benzyloxy)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol (54.4 g) as a yellow foam.
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].CC(C)([O-])C.[K+].[Cl:18][C:19]1[N:20]=[CH:21][N:22]([CH2:46][O:47][CH2:48][CH2:49][Si:50]([CH3:53])([CH3:52])[CH3:51])[C:23]=1[C:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([O:35][C:36]2[CH:41]=[C:40]([CH:42]=O)[CH:39]=[C:38]([Cl:44])[CH:37]=2)[C:29]=1[F:45])=[O:25]>C1COCC1.CCOC(C)=O>[Cl:18][C:19]1[N:20]=[CH:21][N:22]([CH2:46][O:47][CH2:48][CH2:49][Si:50]([CH3:53])([CH3:52])[CH3:51])[C:23]=1[C:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([O:35][C:36]2[CH:41]=[C:40](/[CH:42]=[CH:3]/[C:1]#[N:2])[CH:39]=[C:38]([Cl:44])[CH:37]=2)[C:29]=1[F:45])=[O:25]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)NCc1ccc(Cl)c(Oc2cc(Cl)cc(C=O)c2)c1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)NCc1ccc(Cl)c(Oc2cc(Cl)cc(/C=C/C#N)c2)c1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
To a solution of diethyl cyanomethylphosphonate (56.1 mg, 0.317 mmol) in THF (5 mL) at 0° C. was added potassium t-butoxide (1.0 M solution in THF) (0.317 ml, 0.317 mmol) and the mixture was stirred at 0° C. for 30 minutes. Next, 4-chloro-N-({4-chloro-3-[(3-chloro-5-formylphenyl)oxy]-2-fluorophenyl}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (165 mg, 0.288 mmol) was added and the reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with EtOAc and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give 4-chloro-N-{[4-chloro-3-({3-chloro-5-[(E)-2-cyanoethenyl]phenyl}oxy)-2-fluorophenyl]methyl}-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (113 mg, 0.190 mmol, 66% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.74 (t, 1H), 7.95 (s, 1H), 7.54 (d, 2H), 7.41-7.48 (m, 1H), 7.36 (t, 1H), 7.23 (s, 1H), 6.97 (s, 1H), 6.58 (d, 1H), 5.47 (s, 2H), 4.45 (d, 2H), 3.36 (t, 2H), 0.72 (t, 2H), −0.12 (s, 9H).
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:6][S:7]([C:10]1[CH:29]=[CH:28][C:13]([NH:14][C:15]2[N:20]=[C:19]([C:21]3[N:25]([CH3:26])[C:24]([CH3:27])=[N:23][CH:22]=3)[CH:18]=[CH:17][N:16]=2)=[CH:12][CH:11]=1)(=[O:9])=[O:8])([CH3:5])[CH3:4].[C:30]1([CH3:40])[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1>N1C=CC=CC=1.O>[C:30]1([CH3:40])[CH:35]=[CH:34][C:33]([S:36]([O:1][CH2:2][C:3]([NH:6][S:7]([C:10]2[CH:29]=[CH:28][C:13]([NH:14][C:15]3[N:20]=[C:19]([C:21]4[N:25]([CH3:26])[C:24]([CH3:27])=[N:23][CH:22]=4)[CH:18]=[CH:17][N:16]=3)=[CH:12][CH:11]=2)(=[O:8])=[O:9])([CH3:5])[CH3:4])(=[O:38])=[O:37])=[CH:32][CH:31]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ncc(-c2ccnc(Nc3ccc(S(=O)(=O)NC(C)(C)CO)cc3)n2)n1C
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCC(C)(C)NS(=O)(=O)c2ccc(Nc3nccc(-c4cnc(C)n4C)n3)cc2)cc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 60.1 %

Procedure:
2-{4-[N-(1-Hydroxy-2-methylprop-2-yl)sulphamoyl]anilino}-4-(1,2-dimethylimidazol-5-yl)pyrimidine (Example 59; 2.36 g, 5.66 mmol) was dissolved in dry pyridine (55 ml) and the solution stirred and cooled to 0° C. under inert gas. Solid p-toluenesulphonyl chloride (5.61 g, 29.4 mmol) was added portionwise over 2 minutes. The reaction was stirred at 0° C. for 10 minutes and then at room temperature for 18 hr. The reaction mixture was diluted with water (200 ml) and the precipitated oil allowed to settle out. The supernatant water layer was decanted off and the residual oil was washed with more water and this was decanted off. This process was repeated and then the oil partitioned between EtOAc (100 ml) and water (50 ml). The layers were separated and the organic layer washed with water (50 ml), dried and the solvent evaporated in vacuo to yield the title compound as a gum (1.94 g, 60%) NMR 1.0 (s, 6H), 2.36 (s, 3H), 2.38 (s, 3H), 3.77 (s, 2H), 3.93 (s, 3H), 7.20 (d, 1H), 7.43 (d, 2H), 7.55 (s, 1H), 7.65 (m, 5H), 7.87 (d, 2H), 8.45 (d, 1H), 9.9 (s, 1H); m/z 571.
Reaction SMILES: [CH2:1]([C:5]1[CH:27]=[CH:26][C:8]([CH:9]=[CH:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:15][CH:14]=2)=[O:12])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]>CO.[Pd]>[CH2:1]([C:5]1[CH:27]=[CH:26][C:8]([CH2:9][CH2:10][CH:11]([C:13]2[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:17][CH:18]=2)[OH:12])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C=CC(=O)c2ccc(CCCC(=O)OC)cc2)cc1
Agent: [Pd]
Solvent: CO
Product: CCCCc1ccc(CCC(O)c2ccc(CCCC(=O)OC)cc2)cc1
Reaction time: 3.5 h
Yield: 97.6 %

Procedure:
To a solution of 4.40 g of methyl 4-[4-(4-butylcinnamoyl)phenyl]butyrate in 44 ml of methanol, 0.24 g of 10% palladium on carbon was added, and hydrogenation was carried out at an ordinary temperature and under ordinary pressure for 3.5 hours. After the catalyst was removed by filtration, 0.27 g of sodium borohydride was added to the filtrate under ice-cooling, and then stirring was continued at room temperature for 2 hours. After the reaction solvent was removed under reduced pressure, the residue was added with water and extracted with ether. The ether layer was washed with water, dried, and then the solvent was removed under reduced pressure to yield 4.34 g of colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH:4]([CH3:21])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13]CC2C=CC=CC=2)=[CH:9][CH:8]=1)[OH:6].[H][H]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:22])[CH:4]([CH3:21])[CH:5]([OH:6])[C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1
Reactant: COC(=O)C(C)C(O)c1ccc(OCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(C)C(O)c1ccc(O)cc1
Reaction time: 2.5 h
Yield: 104.6 %

Procedure:
10% Pd/C was added to a degassed solution of 3-(4-benzyloxy-phenyl)-3-hydroxy-2-methyl-propionic acid methyl ester (0.335 g, 1.1 mmol) in methanol (30 mL) and charged to 50 PSI hydrogen, then shaken for 2.5 h. The reaction was filtered to remove the catalyst and concentrated to give 3-hydroxy-3-(4-hydroxy-phenyl)-2-methyl-propionic acid methyl ester (0.242 g, 100%) as an oil. MS found: (M+H)+=211.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.[Cl:9][C:10]1[CH:17]=[C:16](F)[CH:15]=[CH:14][C:11]=1[CH:12]=[O:13]>>[Cl:9][C:10]1[CH:17]=[C:16]([S:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH:15]=[CH:14][C:11]=1[CH:12]=[O:13]
Reactant: O=Cc1ccc(F)cc1Cl
Reactant: Sc1cccc(Cl)c1
Product: O=Cc1ccc(Sc2cccc(Cl)c2)cc1Cl

Procedure:
3-Chlorobenzenethiol and 2-chloro-4-fluorobenzaldehyde were reacted according to the same experiment procedures as in Reference Example 1 of the pamphlet of WO 03029205 to obtain the target product as a colorless oil.