Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([CH:4]=[C:5](SC)[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[NH:15][CH:14]=[N:13][C:12]=1[CH3:16])([O-:3])=[O:2].[NH3:19]>>[N+:1]([CH:4]=[C:5]([NH2:19])[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[NH:15][CH:14]=[N:13][C:12]=1[CH3:16])([O-:3])=[O:2]
Reactant: CSC(=C[N+](=O)[O-])NCCSCc1[nH]cnc1C
Reactant: N
Product: Cc1nc[nH]c1CSCCNC(N)=C[N+](=O)[O-]

Procedure:
Reaction of 1-nitro-2-methylthio-2-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]ethylene (see Example 2(i)) with ammonia by the procedure of Example 2(ii) yields, after recrystallisation from methanol, the title compound, m.p. 193°-195° C.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.C1CCC(N=C=NC2CCCCC2)CC1.CS(O[C:33]1[CH:42]=[CH:41][C:40]2[C:35](=[CH:36][CH:37]=[C:38]([C:43](=[NH:45])[NH2:44])[CH:39]=2)[CH:34]=1)(=O)=O>N1C=CC=CC=1>[CH3:1][N:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:9][C:33]2[CH:42]=[CH:41][C:40]3[C:35](=[CH:36][CH:37]=[C:38]([C:43](=[NH:44])[NH2:45])[CH:39]=3)[CH:34]=2)=[O:8])=[CH:5][CH:4]=1
Reactant: CS(=O)(=O)Oc1ccc2cc(C(=N)N)ccc2c1
Reactant: CN(C)c1ccc(C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Product: CN(C)c1ccc(C(=O)Oc2ccc3cc(C(=N)N)ccc3c2)cc1
Reaction time: 0.5 h
Yield: 20.5 %

Procedure:
To 50 ml of dried pyridine, were added 2.9 g of 4-dimethylaminobenzoic acid and 4.4 g of DCC. The mixture was stirred for 30 minutes while being cooled in ice. After adding 5.0 g of 6-amidino-2-naphthol methanesulfonate, the mixture was further stirred for one hour under cooling in ice, then overnight at room temperature. The reaction mixture was filtered, the collected precipitate was washed with pyridine and ethyl ether and heated in DMF. The insolubles were filtered off and the filtrate was mixed with ethyl ether. The precipitate which was formed was collected by filtration and recrystallized from a mixture of methanol and ethyl ether to obtain 1.2 g of a white powder of 6-amidino-2-naphthyl 4-dimethylaminobenzoate methanesulfonate.
Reaction SMILES: [CH2:1]([OH:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].[C:11](O)(=[O:13])[CH3:12].O.OS(O)(=O)=O>>[C:11]([O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:10])(=[O:13])[CH3:12]
Reactant: CC(=O)O
Reactant: OCCCCCCCCO
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)OCCCCCCCCO
Temperature: 25 °C
Yield: 92.3 %

Procedure:
A solution of 1.987 g (13.7 mmoles) of 1,8-octanediol in 25 ml (441 mmoles) of glacial acetic acid was mixed with 200 ml (11.11 moles) of H2O containing 4 ml (72 mmoles) of conc. H2SO4. This mixture was extracted continuously for 40 hours using hexane. The monoester is not very soluble in hexane and hence a mixture of hexane-cyclohexane (in which the monoester, but not the starting diol, is soluble) should be recommended if one is interested in developing this process for 1,8-octanediol. After cooling the hexane to room temperature, ether was added to make the organic layer homogeneous. The ether-hexane layer was then dried over anhydrous potassium carbonate and filtered. Removal of the solvent under reduced pressure afforded 2.38 g (~92% yield) of product, GC analysis of which indicated the presence of 2% starting diol and 4% diester. The purity of the desired monoester was therefore 94%.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[C:17]([Cl:24])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([O:15][CH3:16])=[C:9]([S:11](Cl)(=[O:13])=[O:12])[CH:10]=1.S([O-])([O-])=O.[Na+].[Na+].C(=O)(O)[O-].[Na+].Cl>O>[Cl:1][C:2]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[C:17]([Cl:24])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([O:15][CH3:16])=[C:9]([S:11]([OH:13])=[O:12])[CH:10]=1
Reactant: COc1ccc(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)cc1S(=O)(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Solvent: O
Product: COc1ccc(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)cc1S(=O)O
Temperature: 25 °C
Yield: 65.7 %

Procedure:
To a solution of 5-(2,6-dichloro-4-nitro-phenoxy)-2-methoxy-benzenesulfonyl chloride (4.26 g, 10.3 mmol) in water (40 mL) was added sodium sulfite (3.89 g, 30.9 mmol) and sodium bicarbonate (5.19 g, 61.8 mmol). The resulting mixture was heated to reflux for 2 h and then cooled to RT. The solution was acidified with conc. HCl (5 mL) followed by addition of water (40 mL). The aqueous solution was extracted with EtOAc (5×80 mL). The combined organic extracts were washed with brine (2×50 mL), dried and concentrated to give the title compound of Step B (2.56 g) as a solid. The title product of Step B was used in the next step without purification. MS (APCl−) Calc.: 376.9. Found: 375.8 (M−1).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:3]=1[O:4][C:5]1[C:10]([C:11]([O-:13])=O)=[CH:9][N:8]=[C:7]([CH3:14])[CH:6]=1.[Li+].C(N(C(C)C)C(C)C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[CH:54]1([N:57]2[C:66]3[C:61](=[CH:62][CH:63]=[CH:64][CH:65]=3)[NH:60][CH2:59][CH2:58]2)[CH2:56][CH2:55]1.C(=O)(O)[O-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH:54]1([N:57]2[C:66]3[C:61](=[CH:62][CH:63]=[CH:64][CH:65]=3)[N:60]([C:11]([C:10]3[CH:9]=[N:8][C:7]([CH3:14])=[CH:6][C:5]=3[O:4][C:3]3[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:2]=3[Cl:1])=[O:13])[CH2:59][CH2:58]2)[CH2:56][CH2:55]1
Reactant: Cc1cc(Oc2cc(Cl)ccc2Cl)c(C(=O)[O-])cn1
Reactant: c1ccc2c(c1)NCCN2C1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(Oc2cc(Cl)ccc2Cl)c(C(=O)N2CCN(C3CC3)c3ccccc32)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.8 %

Procedure:
To a solution of 420 mg (1.381 mmol) lithium 4-(2,5-dichloro-phenoxy)-6-methyl-nicotinate in 6 mL dry N,N-dimethylformamide was added 1.17 mL (6.907 mmol) N-ethyldiisopropylamine and 635 mg (1.658 mmol) O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, commercially available, CAS RN 148893-10-1) and 289 mg (1.658 mmol) 1-cyclopropyl-1,2,3,4-tetrahydro-quinoxaline (Example 8, intermedaite a). The reaction mixture was stirred for 18 hours at room temperature and then poured on 30 mL 10% aqueous sodium bicarbonate solution and 30 mL ethyl acetate. The layers were separated and the aqueous layer was extracted a second time with 30 mL ethyl acetate. The organic layers were washed with 30 mL brine, dried over magnesium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography using a MPLC system (20 g silica gel column, CombiFlash Companion, Isco Inc.) with gradient of n-heptane:ethyl acetate (100:0 to 0:100) to give 375 mg (60%) of the title compound as a light yellow solid. MS (ESI): m/z=454.108 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:10]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:9]([OH:22])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.FC(F)(F)S(O[CH2:29][C:30]([F:33])([F:32])[F:31])(=O)=O.C([O-])([O-])=O.[K+].[K+].[NH4+].[Cl-]>CN(C=O)C>[F:31][C:30]([F:33])([F:32])[CH2:29][O:1][C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:10]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:9]([O:22][CH2:29][C:30]([F:31])([F:32])[F:33])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CCOC(=O)c1c(C(=O)OCC)c(O)c2ncccc2c1O
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C(=O)OCC)c(OCC(F)(F)F)c2ncccc2c1OCC(F)(F)F
Temperature: 25 °C
Yield: 95.5 %

Procedure:
A mixture containing diethyl 5,8-dihydroxyquinoline-6,7-dicarboxylate 2 (57.8 g, 189 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (100 g, 2.28 equiv) and K2CO3 (62.7 g, 2.4 equiv) in DMF (300 ml) was heated to 70 C for an hour. This mixture was cooled down to r.t. and added to half-saturated NH4Cl (1.5 L). After acidification with AcOH (60 ml), the product was extracted with toluene twice and once with 50% EtOAc/toluene. The combined organics were dried over Na2SO4 and filtered through a 1.2 L pad of silica to remove the polar material. The silica was washed with 10% EtOAc/toluene. Evaporation of the solvents afforded 84.68 g (95% yield) of pure product 3.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:22]=[O:23])[CH2:10][N:11]([CH3:21])[C:12](=[O:20])[O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:24]1([Mg]Cl)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:10][N:11]([CH3:21])[C:12]([O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])=[O:20])[C@@H:22]([CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[OH:23])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C[C@H](C=O)NC(=O)OC(C)(C)C)C(=O)OCC[Si](C)(C)C
Reactant: Cl[Mg]C1CCCCC1
Solvent: Cc1ccccc1
Product: CN(C[C@@H](NC(=O)OC(C)(C)C)[C@H](O)C1CCCCC1)C(=O)OCC[Si](C)(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 24 %

Procedure:
To a solution of above crude (2-(trimethylsilyl)ethyl) (R)-2-(t-butoxycarbonylamino)-2-formylethylmethylcarbamate (0.71 g, 2.05 mmol) in toluene (6 mL) at −78° C. was added cyclohexylmagnesium chloride (2 M in ether, 5.13 mL) dropwise. The resulting solution was stirred at −78° C. for 1 h, allowed to warm slowly to rt, and quenched with sat'd aq NH4Cl (5 mL). The organic layer was separated, and aqueous layer was extracted with ether (2×5 mL). The combined organic layers were concentrated in vacuo, and the residue was purified by flash column chromatography to give (1R,2R)-2-(t-butoxycarbonylamino)-1-cyclohexyl-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-1-ol (209.7 mg, 24%). 1H NMR (400 MHz, CDCl3): 4.94 (d, 1 H), 4.16 (m, 2 H), 3.80 (m, 1 H), 3.78 (m, 1H), 3.04 (m, 1H), 2.88 (m, 1 H), 2.86 (s, 3 H), 2.10 (m, 1 H), 1.64 (m, 4 H), 1.42 (m, 1 H), 1.40 (s, 9 H), 1.28-1.02 (m, 4 H), 0.98 (m, 2 H), 0.82 (m, 4 H), 0.02 (s, 9 H); MS m/z 431 (M+H+).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][NH:4][C:5]1[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=1[C:7](=[NH:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:21](Cl)(=O)[O:22]CC.C1C=CC=CC=1>C(N(CC)CC)C>[F:1][C:2]([F:19])([F:20])[CH2:3][N:4]1[C:5]2[C:6](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:14][C:21]1=[O:22]
Reactant: N=C(c1ccccc1)c1ccccc1NCC(F)(F)F
Reactant: CCOC(=O)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: O=c1nc(-c2ccccc2)c2ccccc2n1CC(F)(F)F

Procedure:
To a mixture of 2.8 g of 2-(2,2,2-trifluoroethylamino)-benzophenonimine, 2 ml. of ethyl chlorocarbonate and 20 ml. of benzene was added dropwise 2.0 g of triethylamine, and the mixture was heated under reflux for 3 hours. After cooling, the reaction mixture was washed with water and dried over anhydrous sodium sulfate. Then, the solvent was removed under reduced pressure. The residue was absorbed on a silica gel column, eluted with chloroform to obtain 1-(2,2,2-trifluoroethyl)-4-phenyl-2(1H)-quinazolinone, which was recrystallized from ethanol to give colorless crystals, m.p. 181.5°-182.0° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][CH:29]=1)[CH2:6][N:7]1[CH2:11][CH2:10][C@H:9]([NH:12][S:13]([C:16]2[S:24][C:23]3[C:18](=[N:19][C:20]([Cl:25])=[CH:21][CH:22]=3)[CH:17]=2)(=[O:15])=[O:14])[C:8]1=[O:26])#[N:2].CI.[H-].[Na+].[CH3:34]COC(C)=O>CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][CH:29]=1)[CH2:6][N:7]1[CH2:11][CH2:10][C@H:9]([N:12]([CH3:34])[S:13]([C:16]2[S:24][C:23]3[C:18](=[N:19][C:20]([Cl:25])=[CH:21][CH:22]=3)[CH:17]=2)(=[O:15])=[O:14])[C:8]1=[O:26])#[N:2]
Reactant: CCOC(C)=O
Reactant: N#Cc1cccc(CN2CC[C@H](NS(=O)(=O)c3cc4nc(Cl)ccc4s3)C2=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN([C@H]1CCN(Cc2cccc(C#N)c2)C1=O)S(=O)(=O)c1cc2nc(Cl)ccc2s1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
5-Chlorothieno[3,2-b]pyridine-2-sulfonic acid [1-(3-cyanobenzyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide (0.25 g, 0.56 mmol) is dissolved in 6 mL of DMF and cooled to 0° C. To the solution is added methyl iodide (0.40 g, 2.82 mmol) and sodium hydride (25 mg of a 60% dispersion in mineral oil, 0.62 mmol). The reaction mixture is allowed to warm to room temperature and is stirred for 2 h. At this time, the solution is diluted with and EtOAc and the layers are separated. The organic layer is washed with 1N HCl, H2O, saturated NaHCO3 solution and saturated NaCl. The organic phase is then dried over MgSO4, filtered and concentrated to give the title compound (0.25 g, 0.54 mmol) as a solid.
Reaction SMILES: [CH2:1]([N:10]1[C:15](=[O:16])[C:14]([CH2:17]OS(C)(=O)=O)=[CH:13][C:12]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([CH3:30])[CH:24]=2)=[N:11]1)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:31][NH:32][CH3:33]>>[CH2:1]([N:10]1[C:15](=[O:16])[C:14]([CH2:17][N:32]([CH3:33])[CH3:31])=[CH:13][C:12]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([CH3:30])[CH:24]=2)=[N:11]1)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CNC
Reactant: Cc1cc(-c2cc(COS(C)(=O)=O)c(=O)n(CC=Cc3ccccc3)n2)ccc1F
Product: Cc1cc(-c2cc(CN(C)C)c(=O)n(CC=Cc3ccccc3)n2)ccc1F
Yield: 90.9 %

Procedure:
Following the procedure of Example 7, 2-cinnamyl-6-(4-fluoro-3-methylphenyl)-4-methanesulonyloxymethyl-2H-pyridazin-3-one and dimethylamine were reacted to yield the title compound as a yellow oil (yield: 90.9%).
Reaction SMILES: [CH:1]1[C:13]2[N:12]([CH2:14][CH2:15][CH2:16][P:17](=[O:24])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl[C:30]([CH3:33])([CH3:32])[CH3:31]>>[C:30]([C:8]1[CH:9]=[CH:10][C:11]2[N:12]([CH2:14][CH2:15][CH2:16][P:17](=[O:24])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])[C:13]3[C:5]([C:6]=2[CH:7]=1)=[CH:4][C:3]([C:5]([CH3:6])([CH3:13])[CH3:4])=[CH:2][CH:1]=3)([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)Cl
Reactant: CCOP(=O)(CCCn1c2ccccc2c2ccccc21)OCC
Agent: [Al+3]
Agent: [Cl-]
Product: CCOP(=O)(CCCn1c2ccc(C(C)(C)C)cc2c2cc(C(C)(C)C)ccc21)OCC
Reaction time: 0.42 h

Procedure:
Diethyl 3-(9H-carbazol-9-yl)propylphosphonate (1.00 g, 2.89 mmol) was dissolved in 2-chloro-2-methylpropane (5.0 mL) and flushed with N2 for 5 minutes. To this stirred solution was added aluminum chloride (1.16 g, 8.67 mmol) slowly. The solution turned chunky and black with gas bubbles appearing. The reaction was allowed to stir for 25 minutes after adding all the aluminum chloride. It was then quenched with 25 mL water and an extraction performed with water washings followed by 2×20 mL 1 M NaOH washings, then another water washing. The yellow organic layer was kept and dried and the solvent removed under vacuum. A tlc in ethyl acetate showed 4 spots with the brightest (and desired product) being the third spot from the top. A long column was run and the desired product was obtained as a thick yellow oil (447 mg, 34% yield). 1H NMR (400.14 MHz, CD2Cl2) δ 8.10 (d, J=1.6 Hz, 2H), 7.52 (dd, J=8.80, 2.00 Hz, 2H), 7.35 (d, 8.40 Hz, 2H), 4.36 (t, J=7.00 Hz, 2H), 4.08-3.93 (m, 4H), 2.21-2.07 (m, 2H), 1.71 (dt, J=18.14 Hz, 6.00 Hz, 2H), 1.45 (18H), 1.25 (t, J=7.00 Hz, 6H). 13C{1H} NMR (100.61 MHz, CD2Cl2) δ 142.14 (2C), 139.26 (2C), 123.80 (2C), 123.06 (2C), 116.68 (2C), 108.50 (2C), 61.89 (d, J=6.4 Hz, 2C), 43.36 (d, J=15.8 Hz), 34.92 (2C), 32.19 (6C), 23.35 (d, 142.2 Hz), 22.59 (d, J=4.9 Hz), 16.64 (d, J=5.8 Hz, 2C). 31P{1H} NMR (161.97 MHz, CD2Cl2): δ 31.34.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]2[S:15][C:14]([C:16]([OH:18])=O)=[CH:13][CH:12]=2)=[N:4][O:5][C:6]=1[C:7]([F:10])([F:9])[F:8].[OH:19][C:20]1([C:26]([F:29])([F:28])[F:27])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C1COCC1.N1CCCCC1>C(N(CC)CC)C>[OH:19][C:20]1([C:26]([F:29])([F:27])[F:28])[CH2:25][CH2:24][N:23]([C:16]([C:14]2[S:15][C:11]([C:3]3[C:2]([CH3:1])=[C:6]([C:7]([F:8])([F:9])[F:10])[O:5][N:4]=3)=[CH:12][CH:13]=2)=[O:18])[CH2:22][CH2:21]1
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Reactant: OC1(C(F)(F)F)CCNCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: C1CCNCC1
Product: Cc1c(-c2ccc(C(=O)N3CCC(O)(C(F)(F)F)CC3)s2)noc1C(F)(F)F
Yield: 49 %

Procedure:
Prepared from 5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and 4-hydroxy-4-trifluoromethyl-piperdine by the method described in Example 2 Method B reversing the order of addition such that solid acid chloride was added to a THF solution of triethylamine and piperdine derivative. The reaction mixture was evaporated to a solid, triturated and filtered with the aid of water, then washed with a 1 N aqueous hydrochloric acid solution followed by water. The solid was air dried and then chromatographed on silica gel with EtOAc/hexanes (50%) as eluant to afford product as a colorless solid (53 mg, 49%). 1H NMR (DMSO-d6) 1.70-1.72 (m, 4 H), 2.34 (d, J=1.8, 3 H), 3.24 (br, 2 H), 4.19 (br, 2 H), 6.17 (s, 1 H), 7.56 (d, J=4.0, 1 H), 7.65 (d, J=4.0, 1 H). 19F NMR −83.5, −63.1. LC/MS 6.40 min, [M+1]+429.
Reaction SMILES: BrC1C=C(C(Cl)=O)C=CC=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][CH:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][C:27]=1[F:33].[Br:34][C:35]1[CH:36]=[C:37]([C:41]([N:43]=[C:44]=[S:45])=[O:42])[CH:38]=[CH:39][CH:40]=1>C1(C)C=CC=CC=1.C(O)C>[Br:34][C:35]1[CH:36]=[C:37]([C:41]([N:43]=[C:44]=[S:45])=[O:42])[CH:38]=[CH:39][CH:40]=1.[Br:34][C:35]1[CH:36]=[C:37]([CH:38]=[CH:39][CH:40]=1)[C:41]([NH:43][C:44]([NH:30][C:29]1[CH:31]=[CH:32][C:26]([O:25][C:16]2[C:15]3[C:20](=[CH:21][C:22]([O:23][CH3:24])=[C:13]([O:12][CH3:11])[CH:14]=3)[N:19]=[CH:18][CH:17]=2)=[C:27]([F:33])[CH:28]=1)=[S:45])=[O:42]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Agent: O=C(Cl)c1cccc(Br)c1
Agent: O=C(N=C=S)c1cccc(Br)c1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4cccc(Br)c4)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
3-Bromo-1-benzenecarbonyl isothiocyanate was prepared using commercially available 3-bromo-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 3-bromo-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (79 mg, yield 90%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](OCC)=[O:22])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([C:21](=[O:22])[CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: Cc1ccccn1
Reactant: CCOC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C(=O)Cc3ccccn3)cc2)CC1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
A solution of 4-(4-ethoxycarbonylphenoxy)piperidine-1-carboxylic acid tert-butyl ester (3.5 g, 10 mmol) and 2-methylpyridine (1.9 g, 2.0 mmol) in 50 mL of THF was stirred at 0° C. as LiHMDS (1.0M, 22 mL) was added dropwise. The reaction was stirred at 45° C. overnight, then quenched with ice-water and the solvent evaporated. The residue was extracted with CH2Cl2 (3×30 mL), and the combined CH2Cl2 layers were washed with saturated NaHCO3, saturated NaCl solution, dried over Na2SO4, and concentrated to give the product; Mp 138-140° C.; MS m/z 397 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[CH:4][C:5]([F:30])=[C:6]([S:8]([N:11](CC2C=CC(OC)=CC=2OC)[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1.[CH3:32][N:33]1[C:37]([C:38]2[CH:39]=[C:40]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH:41]=[CH:42][C:43]=2[OH:44])=[CH:36][CH:35]=[N:34]1.C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[Cl:1][C:2]1[C:3]([O:44][C:43]2[CH:42]=[CH:41][C:40]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[CH:39][C:38]=2[C:37]2[N:33]([CH3:32])[N:34]=[CH:35][CH:36]=2)=[CH:4][C:5]([F:30])=[C:6]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][N:13]=2)(=[O:9])=[O:10])[CH:7]=1
Reactant: COc1ccc(CN(c2ccc(F)cn2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Reactant: Cn1nccc1-c1cc(-c2ccccc2)ccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cn1nccc1-c1cc(-c2ccccc2)ccc1Oc1cc(F)c(S(=O)(=O)Nc2ccc(F)cn2)cc1Cl
Reaction time: 2 h
Yield: 63.3 %

Procedure:
5-Chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(5-fluoropyridin-2-yl)benzenesulfonamide (Preparation 105, 23 mg, 0.04 mmol), 3-(1-methyl-1H-pyrazol-5-yl)biphenyl-4-ol (Preparation 107, 9 mg, 0.04 mmol) and potassium carbonate (15 mg, 0.11 mmol) in dimethyl sulfoxide (1 mL) were stirred at room temperature for 2 hours. The mixture was treated with aqueous 2M HCl (3 mL). The resulting mixture was extracted with dichloromethane (3 mL). The dichloromethane layer was dried through a phase separating cartridge followed by treatment with trifluoroacetic acid (500 μL). The mixture was stirred for 2 hours and allowed to stand at room temperature for 18 hours. The mixture was then treated with a saturated solution of ammonium chloride (5 mL). The dichloromethane layer was separated, dried through a phase separating cartridge and evaporated in vacuo. The residue was purified by preparative HPLC to afford the title compound (14 mg, 45%).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:23]([N:25]([CH3:42])[C@@H:26]([C@@H:38]([CH3:41])[CH2:39][CH3:40])[C@H:27]([O:36][CH3:37])[CH2:28][C:29](OC(C)(C)C)=[O:30])=[O:24])[CH:20]([CH3:22])[CH3:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.[CH3:44][O:45][C@@H:46]([C@@H:64]1[CH2:68][CH2:67][CH2:66][NH:65]1)[C@@H:47]([CH3:63])[C:48]([NH:50][C@H:51]([C:59]([O:61][CH3:62])=[O:60])[CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)=[O:49].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>ClCCl>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:23]([N:25]([CH3:42])[C@@H:26]([C@@H:38]([CH3:41])[CH2:39][CH3:40])[C@H:27]([O:36][CH3:37])[CH2:28][C:29]([N:65]3[CH2:66][CH2:67][CH2:68][C@H:64]3[C@H:46]([O:45][CH3:44])[C@@H:47]([CH3:63])[C:48]([NH:50][C@H:51]([C:59]([O:61][CH3:62])=[O:60])[CH2:52][C:53]3[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=3)=[O:49])=[O:30])=[O:24])[CH:20]([CH3:22])[CH3:21])=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)[C@@H](OC)[C@@H]1CCCN1
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)OC(C)(C)C)OC)N(C)C(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC)OC)N(C)C(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 69 %

Procedure:
To a stirring mixture of dimer acid #5 (12.1 g, 23.0 mM) and #67 (11.5 g, 23.0 mM) in 75 mL of dichloromethane under nitrogen, HATU (10.8 g, 27.6 mM) was added followed by Hunig's base (12.1 mL, 69.0 mM). The reaction was allowed to stir at room temperature for 15 hours. Reaction was concentrated to a smaller volume, taken up with ethyl acetate and washed with 1 N HCl two times. The organic layer was then washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. Residue was then purified by silica gel chromatography (Gradient: 0% to 70% acetone in heptanes), producing #113 (12.3 g, 62%) as a white solid. LC-MS (Protocol Q): m/z 855.3 [M+H+], 877.2 [M+Na+], retention time=2.32 minutes; HPLC (Protocol R): /z 855.5 [M+H+], retention time=9.596 minutes (purity >97%).