Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:10](Cl)(=[O:12])=[O:11])=[CH:5][CH:4]=1.C[Si](C)(C)[O:16][C:17]([CH3:19])=[CH2:18].C(N(CC)CC)C>C(#N)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:10]([CH2:18][C:17](=[O:16])[CH3:19])(=[O:12])=[O:11])=[CH:5][CH:4]=1
Reactant: COc1ccc(NS(=O)(=O)Cl)cc1
Reactant: C=C(C)O[Si](C)(C)C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(NS(=O)(=O)CC(C)=O)cc1
Temperature: 25 °C

Procedure:
4-Methoxyphenylsulfamoyl chloride (11.0 g, crude from Step B) in acetonitrile (5.0 mL) was added to a mixture of trimethyl(prop-1-en-2-yloxy)silane (0.85 g, 85% purity, 5.56 mmol) and triethylamine (2.0 mL) in acetonitrile (10 mL) at rt. Upon addition, the reaction was warmed up and refluxed for 2 hrs. After cooling to rt., solvent was removed under reduced pressure and product was purified by flash chromatography (silica gel, ethyl acetate/hexanes gradient) to give N-(4-methoxyphenyl)-2-oxopropane-1-sulfonamide as a solid. LC-MS found: (M+1)+=244.2.
Reaction SMILES: C([O:3][C:4](=[O:13])[C:5]([C:7]1[S:8][C:9]([Cl:12])=[CH:10][CH:11]=1)=[O:6])C.[OH-].[Na+].Cl>O.CO>[Cl:12][C:9]1[S:8][C:7]([C:5](=[O:6])[C:4]([OH:13])=[O:3])=[CH:11][CH:10]=1
Reactant: CCOC(=O)C(=O)c1ccc(Cl)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C(=O)c1ccc(Cl)s1

Procedure:
(5-Chlorothiophen-2-yl)-oxo-acetic acid ethyl ester (8.62 g, 39.4 mmol) was dissolved in a mixture of 100 ml water and 100 ml methanol, then treated with 10 N NaOH (5.9 ml, 59 mmol) at room temperature for 20 hours. The reaction was then poured into 200 ml 3N HCl, and extracted with ethyl acetate (2×100 ml). The combined ethyl acetate extracts were dried over Na2SO4 and concentrated under vacuum to provide Preparation 1b (6.89 g, 92%). The product was then recrystallized from hexane/ether. MS (M−H)−: 189.10; 1H NMR (300 MHz, CDCl3) δ9.07 (1H, br s), 8.32 (1H, d, J=4.2 Hz), 7.10 (1H, d, J=4.2 Hz). IR (KBr) 3270, 3099, 1765, 1744, 1675, 1514, 1411, 1325 cm−1.
Reaction SMILES: [CH:1]([O:4][C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:12][C@@H:13]([CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[OH:14])([CH3:3])[CH3:2].CO[CH:23](OC)[CH2:24][NH:25][CH:26]=[O:27].B(F)(F)F>C(Cl)Cl>[CH:1]([O:4][C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]2[C:6]=1[CH2:12][C@@H:13]([CH:15]1[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]1)[O:14][C@H:23]2[CH2:24][NH:25][CH:26]=[O:27])([CH3:3])[CH3:2]
Reactant: COC(CNC=O)OC
Reactant: Cc1cccc(C[C@H](O)C2CCNCC2)c1OC(C)C
Agent: FB(F)F
Solvent: ClCCl
Product: Cc1ccc2c(c1OC(C)C)C[C@@H](C1CCNCC1)O[C@H]2CNC=O
Reaction time: 15 h

Procedure:
Dissolve (S)-2-(2-Isopropoxy-3-methylphenyl)-1-(4-piperidinyl)ethanol (21.5 g, 78 mmol), N-(2,2,-dimethoxyethyl)formamide (15.5 g, 117 mmol) and BF3□Et2O (66.1 g, 466 mmol) in CH2Cl2 (350 mL). Heat the solution to reflux for 3 hr and then allow to stand 15 hr at room temperature. Evaporate the solvent and dissolve the residue in CH2Cl2. Treat the resulting solution with 50% aqueous NaOH to obtain a pH of 13. Separate the phases and extract the aqueous phase with CH2Cl2. Combine the organic phases, wash with brine and dry over MgSO4. Evaporate the solvent to afford a residue. Purify the residue by chromatography over SiO2 using CHCl3:2M NH3/MeOH (8:2). Evaporate the product-containing fractions and triturate with 1:1 Et2O:heptane to afford a crystalline solid; 1H-NMR (CDCl3) δ 8.2, 7.9 (2s, 1H), 7.0-6.7 (m, 2H), 6.2 (m, 1H), 4.8 (m, 1H). 4.2 (m, 1H), 4.1 (m, 1H), 3.3 (m, 2H), 3.2 (m, 2H), 2.9 (m, 1H), 2.7, (m, 2H), 2.5 (m, 2H), 2.2 (s, 3H), 2.0-1.4 (m, 5H), 1.3-1.2 (2d, 6H).
Reaction SMILES: [C:1]([CH:5]([CH:21]1[CH2:24][C:23](=[O:25])[C:22]1(Cl)Cl)[C:6]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[O:7][SiH3:8])([CH3:4])([CH3:3])[CH3:2].C(OCC)C>C(O)(=O)C.[Zn]>[C:1]([CH:5]([CH:21]1[CH2:22][C:23](=[O:25])[CH2:24]1)[C:6]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[O:7][SiH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C(C1CC(=O)C1(Cl)Cl)C(O[SiH3])(c1ccccc1)c1ccccc1
Agent: [Zn]
Solvent: CCOCC
Solvent: CC(=O)O
Product: CC(C)(C)C(C1CC(=O)C1)C(O[SiH3])(c1ccccc1)c1ccccc1
Temperature: 60 °C
Yield: 44 %

Procedure:
Zinc dust (15.7 g, 0.24 mol) was added to a solution of 3-(tert-butyl -diphenyl-siloxyethyl) -2,2-dichlorocyclobutanone (17 g, 0.04 mol) in glacial acetic acid (68 mL) at room temperature. The reactants were heated at 60° C. for 1 hr, after which time dry diethyl ether was added to the cooled products, which were then filtered. The residue was washed with diethyl ether and the combined filtrate and washings were concentrated under reduced pressure. The residue was dissolved in CH2Cl2, which was washed with saturated NaHCO3 twice and water once. The organic phase was dried over MgSO4 and the solvent was evaporated to give an oily product, which was purified by silica gel flash chromatography (Hexane: EtOAc=12:1) to give a colorless oil (6.2 g, 43.7%). 1H NMR (CDCl 3, 400 MHz): δ 1.06 (s, 9H), 1.82-1.87 (m, 2H), 2.48-2.60 (m, 1H), 2.65-2.71 (m, 2H), 3.07-3.14 (m, 2H), 3.69-3.73 (t, J=6.0, 6.4, 2H), 7.37-7.46 (m, 6H), 7.65-7.73 (m, 4H). 13C NMR (CDCl3, 100 MHz): δ 19.37, 26.76, 27.06, 39.02, 52.87, 62.87, 127.91, 129.88, 129.92, 133.86, 208.89. IR (neat) νmax 2957, 2930, 2857, 1784, 1472, 1428, 1388, 1112, 822, 739, 702.
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH2:9][CH2:10][CH3:11])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[Br:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.N1CCCCC1.C(O)(=O)C>C1(C)C=CC=CC=1>[Br:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[C:3]([C:2](=[O:1])[CH2:8][CH2:9][CH2:10][CH3:11])[C:4]([O:6][CH3:7])=[O:5])=[CH:15][CH:14]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: CCCCC(=O)CC(=O)OC
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: CCCCC(=O)C(=Cc1ccc(Br)cc1)C(=O)OC

Procedure:
A mixture of 1.58 g (10 mmol) of methyl 3-oxoheptanoate, 1.85 g (10 mmol) of 4-bromobenzaldehyde, 0.04 ml of piperidine, 0.12 ml of acetic acid and 10 ml of toluene is heated to the refluxing temperature in a 25-ml round-bottomed flask equipped with a Dean and Stark apparatus. After two hours of heating, the theoretical amount of water is recovered and the toluene is evaporated off under vacuum.
Reaction SMILES: CI.[NH2:3][C:4]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:5]=1[CH2:6][NH:7][C:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=1)=S>C(O)C>[CH3:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:4]2[C:5]=1[CH2:6][NH:7][C:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=1)=[N:3]2
Reactant: Cc1cccc(N)c1CNC(=S)Nc1cccc(C(F)(F)F)c1
Solvent: CCO
Solvent: CI
Product: Cc1cccc2c1CNC(Nc1cccc(C(F)(F)F)c1)=N2
Yield: 8.9 %

Procedure:
A mixture of methyl iodide (167 mg, 1.18 mmol) and 1-(2-amino-6-methyl-benzyl)-3-(3-trifluoromethyl-phenyl)-thiourea (50 mg, 0.147 mmol) in ethanol (3 ml) was heated to reflux for 3 h. The solvent was evaporated under reduced pressure, the residue was taken up in ethyl acetate, washed (water), and dried (Na2SO4). After evaporation of the solvent under reduced pressure, the title compound (4 mg, 8.9%, MS: m/e=306.1 [M+H+]) was obtained by HPLC purification of the residue (YMC CombiPrep C18 column 50×20 mm, solvent gradient 5-95% CH3CN in 0.1% TFA(aq) over 6.0 min, λ=230 nm, flow rate 40 ml/min).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+]([O-])=O)[CH:5]=[CH:4][N:3]=1.[O-:11][CH2:12][CH3:13].[Na+]>C(O)C.ClCCl>[Br:1][C:2]1[CH:7]=[C:6]([O:11][CH2:12][CH3:13])[CH:5]=[CH:4][N:3]=1
Reactant: CC[O-]
Reactant: O=[N+]([O-])c1ccnc(Br)c1
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: CCOc1ccnc(Br)c1

Procedure:
To a suspension of 2-bromo-4-nitropyridine (1.0 g) in ethanol (5 ml) was added a solution of sodium ethoxide in ethanol (20%, 2 ml), and the resultant mixture was stirred at 85° C. for 1.5 hours. After cooling, the mixture was diluted with dichloromethane and washed with water and brine. The separated organic layer was dried over sodium sulfate and evaporated under reduced pressure to give 2-bromo-4-ethoxypyridine (927 mg).
Reaction SMILES: [CH:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:15][C:16]3[CH:26]=[CH:25][CH:24]=[CH:23][C:17]=3[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:11]([CH3:14])[CH:12]=2)[C:7]([CH3:28])([CH3:27])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH2:29]1[CH:31]([CH:32](O)C#N)[CH2:30]1.C([BH3-])#N.[Na+].[OH-].[Na+]>C(O)(=O)C.C(#N)C>[CH:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([N:15]([C:16]3[CH:26]=[CH:25][CH:24]=[CH:23][C:17]=3[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:32][CH:31]3[CH2:29][CH2:30]3)=[C:11]([CH3:14])[CH:12]=2)[C:7]([CH3:28])([CH3:27])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: N#CC(O)C1CC1
Reactant: CCOC(=O)c1ccccc1Nc1cc2c(cc1C)N(C(C)C)CCC2(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CC(=O)O
Product: CCOC(=O)c1ccccc1N(CC1CC1)c1cc2c(cc1C)N(C(C)C)CCC2(C)C
Yield: 49 %

Procedure:
Ethyl [(1-isopropyl-4,4,7-trimethyl-1,2,3,4-tetrahydroquinolin-6-yl)amino)benzoate (Compound 20, 0.18 g, 0.47 mmol) was dissolved in a 10% acetic acid in acetonitrile solution (6.0 mL). The solution was treated with cyclopropylcarboxaldehyde (0.10 mL, 1.3 mmol) and then sodium cyanoborohydride (35 mg, 0.55 mmol) and the reaction was stirred at room temperature for 7 hours. 1M aqueous NaOH was added until pH=6 was reached and the solution was extracted with ether (2×), washed with brine, and dried (Na2SO4). The filtered solution was concentrated under reduced pressure and the residue purified using flash column chromatography (10% ethyl acetate in hexanes) to give the title compounds (0.1 g) as an oil.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]([C:9]1[CH:28]=[CH:27][C:12]([CH2:13][N:14]2[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].FC(F)(F)C(O)=O>ClCCl>[F:29][C:2]([F:1])([F:30])[C:3]([C:9]1[CH:10]=[CH:11][C:12]([CH2:13][N:14]2[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]2)=[CH:27][CH:28]=1)([OH:8])[C:4]([F:7])([F:6])[F:5]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: OC(c1ccc(CN2CCNCC2)cc1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.6 %

Procedure:
To a solution of tert-butyl 4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazine-1-carboxylate (16.09 mmol, 7.12 g) in dichloromethane (30 mL) was added trifluoroacetic acid (5 mL) and the reaction stirred at room temperature for 2 hours. The reaction mixture was concentrated under vacuum and purified by SCX chromatography to afford the title compound (3.5 g). MS (ESI) m/z 343.1 [M+H]+
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[N:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][N:19]=2)[CH:5]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:7]=1.C([O-])([O-])=O.[Na+].[Na+].Br[C:35]1[CH:36]=[N:37][CH:38]=[C:39]([F:41])[CH:40]=1>CC1CCCO1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[F:41][C:39]1[CH:40]=[C:35]([C:6]2[CH:5]=[C:4]([NH:17][C:18]3[N:23]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:21]=[CH:20][N:19]=3)[CH:3]=[C:2]([CH3:1])[CH:7]=2)[CH:36]=[N:37][CH:38]=1
Reactant: Fc1cncc(Br)c1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(B2OC(C)(C)C(C)(C)O2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CC1CCCO1
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cncc(F)c2)c1
Temperature: 80 °C

Procedure:
A mixture of N-[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (1.00 g, 2.64 mmol), Na2CO3 (2.64 mL, 5.27 mmol, 2.0 M), and 3-bromo-5-fluoropyridine (0.511 g, 2.90 mmol) in 2-methyl tetrahydrofuran (13.0 mL) was purged with argon (3×), then Pd(dppf)Cl2—CH2Cl2 (0.108 g, 0.132 mmol) was added. The reaction was purged with argon (3×) and heated to 80° C. The reaction was monitored by LC/MS and upon completion was cooled to ambient temperature. The reaction mixture was filtered through a CELITE plug and washed with dichloromethane. The eluent was diluted with water and the organic layer was extracted, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography (acetone/hexanes) to afford N-[3-(5-fluoropyridin-3-yl)-5-methylphenyl]-4-(trifluoromethyl)pyrimidin-2-amine. MS APCI calc'd for C17H19F4N4 [M+H]+ 349. found 349.
Reaction SMILES: O.O[N:3]1C2C=CC=CC=2N=N1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([CH:25]2[CH2:30][CH2:29][N:28]([C:31]3[CH:36]=[CH:35][C:34]([CH2:37][C:38](O)=[O:39])=[CH:33][CH:32]=3)[CH2:27][CH2:26]2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(Cl)CCl>N.CO.CN(C=O)C>[C:12]([O:16][C:17]([N:19]1[CH2:20][CH2:21][CH:22]([CH:25]2[CH2:30][CH2:29][N:28]([C:31]3[CH:32]=[CH:33][C:34]([CH2:37][C:38]([NH2:3])=[O:39])=[CH:35][CH:36]=3)[CH2:27][CH2:26]2)[CH2:23][CH2:24]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCC(C2CCN(c3ccc(CC(=O)O)cc3)CC2)CC1
Agent: N
Solvent: ClCCCl
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C2CCN(c3ccc(CC(N)=O)cc3)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-Hydroxybenzotriazole hydrate (53 mg; 0.388 mmol) was dissolved in a solution of ammonia in methanol (5 mL; 7M). The solution was evaporated to a white solid. A solution of {4-[1′-(tert-butoxycarbonyl)-4,4′-bipiperidin-1-yl]phenyl}acetic acid (52 mg; 0.129 mmol) in DMF (2 mL) was added, followed by EDC (75 mg; 0.388 mmol). The mixture was stirred at ambient temperature for 1 hr. The reaction was partitioned between iPrOAc (50 mL) and aq. sodium bicarbonate (10 mL). The organic was washed twice more with water (2×10 mL). The organic was dried over magnesium sulfate, filtered and evaporated to a solid. The solid was chromatographed (PTLC; 40:1 CH2Cl2/MeOH), affording the title compound.
Reaction SMILES: Br[C:2]1[C:3]([Cl:9])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C([Mg]Cl)(C)C.[Br:15][C:16]1[N:21]=[C:20]([CH:22]=[O:23])[CH:19]=[CH:18][CH:17]=1>C1COCC1>[Br:15][C:16]1[N:21]=[C:20]([CH:22]([C:2]2[C:3]([Cl:9])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=2)[OH:23])[CH:19]=[CH:18][CH:17]=1
Reactant: O=Cc1cccc(Br)n1
Reactant: Clc1ncc(Br)c(Cl)n1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: OC(c1cccc(Br)n1)c1cnc(Cl)nc1Cl
Temperature: -30 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 5-bromo-2,4-dichloropyrimidine (11.4 g, 50 mmol) in THF (200 mL) at −30° C., was added dropwise isopropyl magnesium chloride (25 mL, 2 M in THF, 50 mmol) and the mixture was stirred at −30° C. for 20 minutes. Then a solution of 6-bromopicolinaldehyde (9.3 g, 50 mmol) in THF (10 mL) was added and the mixture was warmed to 0° C. and stirred for another 40 minutes. The reaction was quenched by adding saturated aqueous NH4Cl solution and the resulting mixture was extracted with ethyl acetate (3×300 mL). The organic solutions were then washed with brine. The organic phase was dried with anhydrous MgSO4, filtered and concentrated under reduced pressure to give crude (6-bromo-pyridin-2-yl)-(2,4-dichloro-pyrimidin-5-yl)-methanol as a light yellow oil. (Yield 16.1 g)
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].C([N:21](CC)CC)C.C(Cl)(=O)OCC>C1COCC1>[CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([NH2:21])=[O:15])=[CH:12][CH:11]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: CCOP(=O)(Cc1ccc(C(=O)O)cc1)OCC
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Product: CCOP(=O)(Cc1ccc(C(N)=O)cc1)OCC

Procedure:
To a solution of 1.36 g of 4-diethoxyphosphinylmethylbenzoic acid and 0.56 g of triethylamine in 15 ml of dry THF was slowly added a solution of 0.60 g of ethyl chlorocarbonate in 2 ml of dry THF under ice-cooling with stirring. After stirring for 30 minutes under ice-cooling, ammonia gas was slowly bubbled into the mixture for 15 minutes, stirred for 2 hours at room temperature. After adding 30 ml of water, the reaction mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate and the solvent was evaporated. The residue was subjected to silica gel column chromatography (eluent; chloroform:methanol=10:1) to give 4-diethoxyphosphinylmethylbenzamide. it was recrystallized from chloroform-benzene mixture to give 0.80 g of colorless plate crystals. mp: 177.0°-177.5° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:22])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([C:19]([CH3:21])=[CH2:20])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[Cl:23][C:24]1[N:25]=[CH:26][NH:27][C:28]=1[C:29](O)=[O:30].CCN(C(C)C)C(C)C.C(Cl)CCl>C1COCC1>[Cl:23][C:24]1[N:25]=[CH:26][NH:27][C:28]=1[C:29]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([O:10][C:11]2[CH:18]=[C:17]([C:19]([CH3:21])=[CH2:20])[CH:16]=[C:13]([C:14]#[N:15])[CH:12]=2)[C:4]=1[F:22])=[O:30]
Reactant: O=C(O)c1[nH]cnc1Cl
Reactant: C=C(C)c1cc(C#N)cc(Oc2c(Cl)ccc(CN)c2F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: C1CCOC1
Product: C=C(C)c1cc(C#N)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)c1
Yield: 13.5 %

Procedure:
3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-(1-methylethenyl)benzonitrile (0.068 g, 0.215 mmol), 4-chloro-1H-imidazole-5-carboxylic acid (0.040 g, 0.273 mmol), and DIPEA (0.075 mL, 0.429 mmol) were combined in THF (6 mL) and treated with EDC (0.082 g, 0.429 mmol) at 50° C. for three days. The reaction mixture was concentrated to dryness and partitioned between EtOAc and brine. The organic phase was isolated, washed with saturated aqueous NaHCO3, dried over MgSO4, filtered and concentrated to dryness. The residue was purified on 40 g silica gel eluted with 40 to 100% EtOAc/hexanes to give impure product. This material was repurified by mass-directed HPLC on a SunFire prep C-18 column eluted with 30 to 85% CH3CN/H2O (0.1% formic acid buffer). Appropriate fractions were combined, concentrated to dryness, chased twice with ethanol and twice with toluene to remove residual water to give 4-chloro-N-[(4-chloro-3-{[3-cyano-5-(1-methylethenyl)phenyl]oxy}-2-fluorophenyl)methyl]-1H-imidazole-5-carboxamide (0.013 g, 0.029 mmol, 13.60% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.20 (br. s., 1H), 8.30 (br. s., 1H), 7.73-7.78 (m, 2H), 7.50 (d, J=8.52 Hz, 1H), 7.43 (s, 1H), 7.36 (t, J=7.76 Hz, 1H), 7.26 (s, 1H), 5.57 (s, 1H), 5.25 (s, 1H), 4.52 (d, J=5.36 Hz, 2H), 2.10 (s, 3H). LC-MS (ES−) m/z 443.08, 445.16 [M−1]. LC-MS (ES+) m/z 445.07, 447.07 [M+H].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:34])[CH2:9][C:10]2[N:11](C(OC(C)(C)C)=O)[C@H:12]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.C(=O)(O)[O-].[Na+]>ClCCl>[C:21]1([C@H:12]2[C@@H:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[NH:14][C:10]([CH2:9][C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[O:34])=[N:11]2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1C(CC(=O)c2ccc(F)cc2)=N[C@@H](c2ccccc2)[C@H]1c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(CC1=N[C@@H](c2ccccc2)[C@@H](c2ccccc2)N1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 47.4 %

Procedure:
To a cold (0° C.) solution of 257 (458 mg, 1.0 mmol) in dichloromethane (25 mL) is added TFA (1.5 mL). The reaction mixture is stirred for 20 min. at 0° C., and at RT for 30 min. The solution is poured into cold sat. sodium bicarbonate solution, and the mixture extracted with EtOAc. The organic layer is separated, dried (MgSO4), and filtered. The filtrate is rotary evaporated, and the residue is recrystallized from Et2O to give 170 mg of the product 258. 1H NMR (CDCl3) δ 10.60-8.80 (bs, 1H), 8.00-7.80 (m, 2H), 7.20-7.00 (m, 9H), 7.00-6.85 (m, 4H), 5.50 (bs, 1H), 5.30 (s, 2H); MS: m/z 359 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[F:18])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][NH2:14])[CH2:8][CH2:7]1.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[S:29][C:28]([S:30](Cl)(=[O:32])=[O:31])=[CH:27][CH:26]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[F:18])[O:5][CH:6]1[CH2:7][CH2:8][N:9]([CH2:12][CH2:13][NH:14][S:30]([C:28]2[S:29][C:25]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=3)=[CH:26][CH:27]=2)(=[O:31])=[O:32])[CH2:10][CH2:11]1
Reactant: NCCN1CCC(Oc2ccc(F)c(F)c2)CC1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccn2)s1
Product: O=S(=O)(NCCN1CCC(Oc2ccc(F)c(F)c2)CC1)c1ccc(-c2ccccn2)s1
Reaction time: 12 h
Yield: 7.6 %

Procedure:
To a solution of 5-pyridin-2-yl-thiophene-2-sulfonyl chloride (0.213 g) [in CH2Cl2 (10 ml)] was added a solution of the product of Example 4, Step (b) (0.210 g) [in CH2Cl2 (5 ml) and pyridine (0.066 ml)]. The reaction was left to stir for 12 hrs. The reaction mixture was washed with saturated aqueous NaCl solution and the organics separated and dried and then filtered. The solvents were evaporated and the product purified by using reverse phase HPLC {with a gradient eluent system [25% MeCN/NH4OAcaq (0.1%) to 95% MeCN//NH4OAcaq (0.1%)]} give the title compound as a solid (0.03 g).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:21]=[CH:20][C:10]([N:11]([Si](C)(C)C)[Si](C)(C)C)=[CH:9][CH:8]=1.[CH3:22][C:23]([S:26]([N:28]=[C:29]1[CH2:32][O:31][CH2:30]1)=[O:27])([CH3:25])[CH3:24]>C1COCC1>[NH2:11][C:10]1[CH:20]=[CH:21][C:7]([C:29]2([NH:28][S:26]([C:23]([CH3:25])([CH3:24])[CH3:22])=[O:27])[CH2:32][O:31][CH2:30]2)=[CH:8][CH:9]=1
Reactant: CC(C)(C)S(=O)N=C1COC1
Reactant: C[Si](C)(C)N(c1ccc(Br)cc1)[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)NC1(c2ccc(N)cc2)COC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
A solution of n-butyllithium in hexanes (1.65 M, 5.14 mL) was added dropwise to a solution of 4-bromo-N,N-bis(trimethylsilyl)aniline (2.52 mL) in THF (14 mL) at −78° C. The resulting mixture was stirred for 1 h at −78° C. before a solution of 2-methyl-N-oxetan-3-ylidenepropane-2-sulfinamide in THF (2.8 mL) was added dropwise over the course of 15 minutes at −78° C. The reaction mixture was stirred for an additional 1 h at −78° C. then allowed to warm to room temperature. After being stirred for 18 h at room temperature, the reaction mixture was poured into ice cooled saturated sodium bicarbonate solution. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with saturated sodium bicarbonate solution and brine and then dried over anhydrous sodium sulfate. The dried solution was filtered and the filtrate was concentrated to dryness. The residue was diluted with diisopropylether and extracted with 1 M citric acid solution. The aqueous extracts were combined and basified with sodium bicarbonate solid to pH>7. The basic aqueous layer was extracted with ethyl acetate and the organic layer was washed with brine. The organics were dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by recrystallization with ethyl acetate and column chromatography (30-100% ethyl acetate in hexanes) gave the product (1.37 g, 90%). 400 M Hz 1H-NMR (DMSO-d6) δ: 7.07 (d, J=8.7 Hz, 2H), 5.56 (d, J=8.7 Hz, 2H), 6.05 (s, 1H), 5.10 (brs, 2H), 4.94 (dd, J=6.0 and 2.3 Hz, 2H), 4.83 (d, J=6.0 Hz, 1H), 4.60 (d, J=6.0 Hz, 1H), 1.08 (s, 9H).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:22]#[C:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:12]2[C:17](=[O:18])[O:16][C:15]([CH3:20])([CH3:19])[O:14][C:13]=2[CH:21]=1)C1C=CC=CC=1>CCO.[OH-].[OH-].[Pd+2]>[CH3:20][C:15]1([CH3:19])[O:14][C:13]2[CH:21]=[C:9]([OH:8])[CH:10]=[C:11]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:12]=2[C:17](=[O:18])[O:16]1
Reactant: CCCCCC#Cc1cc(OCc2ccccc2)cc2c1C(=O)OC(C)(C)O2
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCc1cc(O)cc2c1C(=O)OC(C)(C)O2

Procedure:
Compound (12) (500 mg, 1.32 mmol) was hydrogenated over Pd(OH)2 (20%, 95 mg, ca. 0.1 eq.) in EtOH (15 mL) at atmospheric pressure for 12 hrs. Filtration through Celite™ and concentration left 387 mg (100%) of white solids. m.p. 100°-102° C. IR (CHCl3) 3100-3400, 3020, 2930, 1715, 1615, 1590, 1450, 1390, 1295, 1170, 1050 cm-1 ; 1H NMR (CDCl3, 250 MHz) δ6.42 (d, 1H, J=2.4 HZ, ArH), 6.27 (d, 1H, J=2.4 Hz, ArH), 5.50 (br s, 1H, OH), 3.04 (br t 2H, J=7.7 Hz), 1.69 (s, 6H, CH3), 1.20-1.65 (m, 1OH), 0.88 (t, 3H, J=7.2 Hz, CH3).