Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:21][CH2:20][N:19]([C:22](=[O:31])[C:23]3[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=3[F:30])[CH2:18][CH2:17]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:32])[CH:11]=2)[CH:6]=1.O.[OH-].[Li+]>C1COCC1.O>[F:30][C:24]1[CH:25]=[CH:26][C:27]([F:29])=[CH:28][C:23]=1[C:22]([N:19]1[CH2:20][CH2:21][CH:16]([C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([F:32])[CH:11]=3)[CH:6]=[C:5]([CH2:4][C:3]([OH:33])=[O:2])[C:14]=2[CH3:15])[CH2:17][CH2:18]1)=[O:31]
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C2CCN(C(=O)c3cc(F)ccc3F)CC2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(CC(=O)O)cc2ccc(F)cc2c1C1CCN(C(=O)c2cc(F)ccc2F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.4 %

Procedure:
To a solution of {4-[1-(2,5-difluoro-benzoyl)-piperidin-4-yl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (73 mg, 0.160 mmol) in THF (8.0 mL) was added a solution of lithium hydroxide monohydrate (76.6 mg, 1.8 mmol) in water (2 mL). The reaction mixture was stirred at room temperature overnight. After this time, the reaction mixture was concentrated. Water (˜20 mL) was added and the mixture was acidified with 1.0 N aqueous HCl (3.2 mL). The resulting white precipitate was collected by vacuum filtration, washed with hexanes, and then further dried under vacuum to give {4-[1-(2,5-difluoro-benzoyl)-piperidin-4-yl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid (57.5 mg, 81%). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.46 (br. s, 1H), 7.80-8.20 (m, 1H), 7.90 (dd, J=9.00, 6.50 Hz, 1H), 7.69 (s, 1H), 7.31-7.52 (m, 4H), 4.62-4.77 (m, 1H), 3.68-4.08 (m, 4H), 3.48-3.60 (m, 1H), 2.95-3.21 (m, 1H), 2.43 (br. s., 3H), 2.11-2.34 (m, 2H), 1.57-1.82 (m, 2H). MS cald. for C25H23F3NO3 [(M+H)+]: 442, obsd. 442.2.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:14][N:15]=[C:16]=[S:17]>ClCCl>[C:3]1([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:16]([NH:15][CH3:14])=[S:17]
Reactant: CN=C=S
Reactant: Nc1ccccc1-c1ccccc1
Solvent: ClCCl
Product: CNC(=S)Nc1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of 2-aminobiphenyl (6.3 g), methylisothiocyanate (3.8 g) and dichloromethane (45 ml) was stirred at ambient temperature for four days to give N-(2-biphenylyl)-N'-methylthiourea (m.p. 152°-153° C.).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[Li]CCCC.CCCCCC.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[CH:29][C:30]([C:33](=[O:35])[CH3:34])=[N:31][CH:32]=2)=[CH:23][CH:22]=1>C1COCC1>[CH3:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[CH:28]=[CH:29][C:30]([C:33]([C:2]3[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=3)([OH:35])[CH3:34])=[N:31][CH:32]=2)=[CH:25][CH:26]=1
Reactant: Ic1ccncc1
Reactant: COc1ccc(-c2ccc(C(C)=O)nc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc(-c2ccc(C(C)(O)c3ccncc3)nc2)cc1
Reaction time: 0.5 h
Yield: 33.9 %

Procedure:
To cooled (−78° C.) 4-iodopyridine (270 mg, 1.3 mmol) [Albrecht, et al., US Patent Application Publication No. 2009/0318436] in THF (15 mL) was added slowly 1.6 M n-BuLi in hexane (1.65 mL, 2.6 mmol). Stirring was continued for an additional 30 minutes at the same temperature, followed by the addition of a THF (5 mL) solution of 1-(5-(4-methoxyphenyl)pyridin-2-yl)ethanone (300 mg, 1.3 mmol). After stirring for 2 hours at the same temperature, the reaction mixture was quenched with saturated aqueous NH4Cl solution (10 mL). The aqueous layer was extracted with ethylacetate (2×150 mL). The combined organic layers were washed with brine (20 mL). Finally, the organic phase was dried over Na2SO4 and concentrated under reduced pressure to give crude product. The crude product was purified by flash chromatography (silica gel 60-120μ) using 20% ethyl acetate and hexane as eluent to afford racemic 1-(5-(4-methoxyphenyl)pyridin-2-yl)-1-(pyridin-4-yl)ethanol as an off-white solid (135 mg, 33% yield) in 99.6% HPLC purity. 1H NMR (400 MHz, DMSO-d6): δ 8.74 (d, 1H), 8.45 (dd, 2H), 7.98 (dd, 1H), 7.68 (d, 1H), 7.62 (d, 2H), 7.48 (dd, 2H), 7.02 (d, 2H), 6.15 (s, 1H), 3.78 (s, 3H), 1.88 (s, 3H); LC-MS m/z calculated for [M+H]+ 307.14, found 307.3.
Reaction SMILES: [Br-:1].[CH:2]1([C:8]([OH:34])([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30]C=2)[C:9]([O:11][CH:12]2[CH2:17][CH2:16][N+:15]([CH2:19][C:20](=[O:27])[NH:21][C:22]3[CH:26]=[CH:25][O:24][N:23]=3)([CH3:18])[CH2:14][CH2:13]2)=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C1(C(C2C=CC=CC=2)(O)C(O)=O)CCCC1>>[Br-:1].[CH:28]1([C:8]([OH:34])([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]([O:11][CH:12]2[CH2:17][CH2:16][N+:15]([CH2:19][C:20](=[O:27])[NH:21][C:22]3[CH:26]=[CH:25][O:24][N:23]=3)([CH3:18])[CH2:14][CH2:13]2)=[O:10])[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: C[N+]1(CC(=O)Nc2ccon2)CCC(OC(=O)C(O)(c2ccccc2)C2CCCCC2)CC1
Agent: O=C(O)C(O)(c1ccccc1)C1CCCC1
Agent: [Br-]
Product: C[N+]1(CC(=O)Nc2ccon2)CCC(OC(=O)C(O)(c2ccccc2)C2CCCC2)CC1

Procedure:
This compound is prepared by an analogous method to 4-(2-cyclohexyl-2-hydroxy-2-phenyl-acetoxy)-1-(isoxazol-3-ylcarbamoylmethyl)-1-methyl-piperidinium bromide (Example 3) by replacing cyclohexyl-hydroxy-phenyl-acetic acid with cyclopentyl-mandelic acid.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH2:17][CH2:16][NH:15][CH2:14][C:10]=2[N:11]=[CH:12][N:13]=1.[CH3:18][O:19][C:20]1[CH:25]=[N:24][C:23]([N:26]2[CH:30]=[N:29][C:28]([CH3:31])=[N:27]2)=[C:22]2[NH:32][CH:33]=[C:34]([C:35](=[O:39])[C:36](O)=[O:37])[C:21]=12.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH3:18][O:19][C:20]1[CH:25]=[N:24][C:23]([N:26]2[CH:30]=[N:29][C:28]([CH3:31])=[N:27]2)=[C:22]2[NH:32][CH:33]=[C:34]([C:35](=[O:39])[C:36]([N:15]3[CH2:16][CH2:17][C:9]4[C:8]([C:3]5[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=5)=[N:13][CH:12]=[N:11][C:10]=4[CH2:14]3)=[O:37])[C:21]=12
Reactant: c1ccc(-c2ncnc3c2CCNC3)nc1
Reactant: COc1cnc(-n2cnc(C)n2)c2[nH]cc(C(=O)C(=O)O)c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COc1cnc(-n2cnc(C)n2)c2[nH]cc(C(=O)C(=O)N3CCc4c(ncnc4-c4ccccn4)C3)c12
Temperature: 25 °C
Reaction time: 18 h
Yield: 49.2 %

Procedure:
Part E: To a solution of 4-(pyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine hydrochloride (0.137 g, 0.55 mmol) in DMF (15 mL) at 25° C. was added sequentially 2-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid (0.151 g, 0.50 mmol), N-methylmorpholine (0.220 mL, 2.00 mmol), and TBTU (0.177 g, 0.55 mmol), and the mixture was stirred at 25° C. for 18 h. The reaction mixture was concentrated under vacuum, and the residue dissolved in hot methanol. The solution was allowed to cool slowly to room temperature. The precipitate was recovered by filtration, washed with methanol, and dried under vacuum to provide 1-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(pyridin-2-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)ethane-1,2-dione (0.122 g, 49%) as an off-white solid; HRMS: 496.1835 (M+H)+ [calc'd: 496.1840]; 1H NMR (500 MHz, DMSO-d6) δ 12.44 (br s, 1H), 9.24 (m, 1H), 9.17 (s, 2/3H), 9.08 (s, 1/3H), 8.77 (m, 1/3H), 8.67 (m, 2/3H), 8.34 (s, 2/3H), 8.26 (s, 1/3H), 8.12-8.00 (m, 2H), 7.87 (m, 1H), 7.58 (m, 1/3H), 7.53 (m, 2/3H), 4.92 (s, 4/3H), 4.72 (s, 2/3H), 3.93 (m, 1/3H), 3.91 (s, 1H), 3.85 (s, 2H), 3.70 (m, 2/3H), 3.32 (m, 1/3H), 3.18 (m, 2/3H), 2.50 (s, 2H), 2.49 (s, 1H).
Reaction SMILES: C(O)(C(F)(F)F)=O.C([SiH](C(C)C)C(C)C)(C)C.[N:18]([CH2:21][C@H:22]1[O:26][C:25](=[O:27])[N:24]([C:28]2[CH:33]=[CH:32][C:31]([S:34][C:35](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[C:30]([F:54])[CH:29]=2)[CH2:23]1)=[N+:19]=[N-:20].IC.C(N(CC)CC)C>C(Cl)Cl>[N:18]([CH2:21][C@H:22]1[O:26][C:25](=[O:27])[N:24]([C:28]2[CH:33]=[CH:32][C:31]([S:34][CH3:35])=[C:30]([F:54])[CH:29]=2)[CH2:23]1)=[N+:19]=[N-:20]
Reactant: [N-]=[N+]=NC[C@@H]1CN(c2ccc(SC(c3ccccc3)(c3ccccc3)c3ccccc3)c(F)c2)C(=O)O1
Agent: CC(C)[SiH](C(C)C)C(C)C
Solvent: ClCCl
Solvent: CI
Solvent: O=C(O)C(F)(F)F
Product: CSc1ccc(N2C[C@@H](CN=[N+]=[N-])OC2=O)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.6 %

Procedure:
5% TFA and 2.5% triisopropylsilane in DCM (4 ml) was added to 5-(S)-azidomethyl-3-[4′-triphenylmethylthio-3′-fluorophenyl]oxazolidine-2-one (0.250 g, 0.490 mmol; prepared as described above for Example 6), and the mixture stirred for 1 h at r.t. Solvent was removed under vacuum and the residue dissolved in DMF (2 ml). Iodomethane (0.046 ml, 0.735 mmol) was added followed by dropwise addition of triethylamine (0.136 ml, 0.979 mmol). The mixture was stirred at r.t. for 2 h, evaporated, and the residue purified by PTLC (50% ethyl acetate in DCM) to give the product as a white solid (0.124 g, 90%). MS (m/z): [M+H]+=283.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](Cl)=[O:9])=[CH:6][C:5]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[N:3]=1.[NH2:26][N:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>C(Cl)Cl>[N:27]1([NH:26][C:8]([C:7]2[C:2]([Cl:1])=[N:3][C:4]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])=[C:5]([C:11]3[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=3)[CH:6]=2)=[O:9])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: O=C(Cl)c1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc1Cl
Reactant: NN1CCCCC1
Solvent: ClCCl
Product: O=C(NN1CCCCC1)c1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a portion of the methylene chloride (1 mL) solution of 2-(chloro)-6-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyridine-3-carbonyl chloride (0.068 mmol) from Step B was added a solution of 1-aminopiperidine (0.010 mL, 0.088 mmol) and TEA (0.014 mL, 0.10 mmol) in methylene chloride (1 mL). The reaction was stirred at rt for 16 h and was then evaporated. The residue was purified by preparative TLC (40% ethyl acetate in hexanes) to yield N-(piperidin-1-yl)-2-(chloro)-6-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyridine-3-carboxamide. HPLC/MS: 494 (M+1), 496 (M+3); Rt=3.97 min
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH:5]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21](OC)=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)[CH2:6][C:7]#[C:8][CH3:9])[CH3:2].[CH3:27]C1C=CC=CC=1CBr.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:26])[CH:5]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:27])=[CH:12][CH:11]=1)[CH2:6][C:7]#[C:8][CH3:9])[CH3:2]
Reactant: Cc1ccccc1CBr
Reactant: CC#CCC(C(=O)OCC)c1ccc(OCc2ccc(OC)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC#CCC(C(=O)OCC)c1ccc(OCc2ccccc2C)cc1
Temperature: 80 °C

Procedure:
Ester 15.1 (3.19 g, 9 mmol) was taken up in glacial acetic acid (100 mL) in a 250 mL RB Flask, and the suspension was heated to reflux for 16 h. The solvent was removed under reduced pressure, and the residue was re-dissolved in ethyl acetate (200 mL). The solution was washed with 1 N HCl(aq) (200 mL) and saturated brine (200 mL), dried over MgSO4 and concentrated to a thick yellow oil, to which was added 2-methylbenyl bromide (2.57 g, 13.9 mmol), cesium carbonate (6.03 g, 18.5 mmol) and DMF (20 mL). The suspension was heated to 80° C. for overnight. After cooling, the reaction was quenched with water (200 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with NaHCO3 (sat. 2×100 mL), and NaCl (sat. 3×100 mL), dried over MgSO4, and concentrated to a white powder (2.41 g, 79%).
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]3[NH:23][C:22]4[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=4[N:20]=3)[CH:13]=2)[CH2:7]1)=[O:5])C>Cl>[ClH:18].[NH:20]1[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=[C:19]1[C:14]1[CH:13]=[C:12]([N:8]2[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]2)[CH:17]=[CH:16][C:15]=1[Cl:18]
Reactant: CCOC(=O)[C@@H]1CCCN(c2ccc(Cl)c(-c3nc4ccccc4[nH]3)c2)C1
Agent: Cl
Product: O=C(O)[C@@H]1CCCN(c2ccc(Cl)c(-c3nc4ccccc4[nH]3)c2)C1
Temperature: 120 °C
Yield: 145 %

Procedure:
Method 2—Step e A mixture of (R)-1-[3-(1H-Benzoimidazol-2-yl)-4-chloro-phenyl]-piperidine-3-carboxylic acid ethyl ester (0.81 g, 2.11 mmol) in 6N HCl (4.0 mL) was heated in microwave at 120° C. for 20 minutes; 2 cycles were needed to complete conversion. Then solvent was removed and the crude triturated with a mixture of acetone/ethyl acetate (1:1), the solid filtered off and dried under vacuum, to obtain 0.60 g of the title compound (80%).
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]1[C:13]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)=[C:14]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[NH:15][CH:16]=1)=O)(C)(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[F:23][C:20]1[CH:19]=[CH:18][C:17]([C:14]2[NH:15][CH:16]=[C:12]([CH2:11][CH2:10][CH2:9][NH:8][CH3:6])[C:13]=2[C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)NCCCc1c[nH]c(-c2ccc(F)cc2)c1-c1ccncc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNCCCc1c[nH]c(-c2ccc(F)cc2)c1-c1ccncc1
Yield: 96 %

Procedure:
400 mg (1.01 mmol) of 4-[3-(t-butoxycarbonylamino)propyl]-2-(4-fluorophenyl)-3-(pyridin-4-yl)-1H-pyrrole [prepared as described in step 4(i) above] were added to a suspension of 154 mg of lithium aluminum hydride in 8 ml of tetrahydrofuran. The resulting mixture was heated under reflux for 2 hours. At the end of this time, the reaction mixture was worked up and then purified in the same manner as that described in Example 1(vi) above to give 300 mg (yield 96%) of the title compound as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][N:11]=[N:10][CH:9]=2)=[CH:4][C:3]=1[CH2:13][NH:14][C:15](=[O:18])[O:16][CH3:17].[Cl:19][C:20]1[CH:25]=[CH:24][C:23](I)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Fe+3].[Cu]=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][N:11]([C:23]3[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=3)[N:12]=2)=[CH:4][C:3]=1[CH2:13][NH:14][C:15](=[O:18])[O:16][CH3:17]
Reactant: COC(=O)NCc1cc(-c2cnn[nH]2)ccc1Cl
Reactant: Clc1ccc(I)cc1
Agent: O=[Cu]
Agent: [Fe+3]
Agent: CC(=O)/C=C(/C)[O-]
Solvent: CN(C)C=O
Product: COC(=O)NCc1cc(-c2cnn(-c3ccc(Cl)cc3)n2)ccc1Cl
Temperature: 110 °C

Procedure:
A mixture of methyl N-[[2-chloro-5-(1H-1,2,3-triazol-5-yl)phenyl]methyl]carbamate (i.e. the product of Step E, Example 9) (0.53 g, 2.0 mmol), 1-chloro-4-iodobenzene (0.57 g, 2.4 mmol), iron(III) acetylacetonate (0.21 g, 0.6 mmol), copper(II) oxide (0.016 g, 0.2 mmol) and cesium carbonate (1.29 g, 4.0 mmol) in N,N-dimethylformamide (4 mL) was heated at 110° C. for 14 h and then concentrated under reduced pressure. The resulting residue was suspended in ethanol and then concentrated onto silica gel (2 g). The silica gel mixture was purified by flash column chromatography using a Supelco (division of Sigma-Aldrich Co., 595 North Harrison Road, Bellefonte, Pa. 16823, U.S.A.) tube prepacked with 10 g of silica gel (50 μm particle diameter, 70 Å pore size) and 3:1 hexanes-ethyl acetate as eluant to provide methyl N-[[2-chloro-5-[2-(4-chlorophenyl)-2H-1,2,3-triazol-4-yl]phenyl]methyl]carbamate, a compound of the present invention, as a beige solid (0.105 g)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[P:18](Cl)([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19]>N1C=CC=CC=1>[CH3:9][C:8]([C:11]1[CH:12]=[CH:13][C:14]([O:17][P:18]([O:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([O:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[O:19])=[CH:15][CH:16]=1)([C:5]1[CH:4]=[CH:3][C:2]([O:1][P:18]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:19])=[CH:7][CH:6]=1)[CH3:10]
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Solvent: c1ccncc1
Product: CC(C)(c1ccc(OP(=O)(Oc2ccccc2)Oc2ccccc2)cc1)c1ccc(OP(=O)(Oc2ccccc2)Oc2ccccc2)cc1

Procedure:
Bisphenol A bis(diphenyl phosphate) was prepared by the reaction of 11.4 g of bisphenol A with 29.6 g of diphenyl chlorophosphate in 100 ml of pyridine, which was performed by the protocol of Example 2. Recrystallization from isopropanol gave 12 g of the title compound of mp=56°-58° C. Mass spectrum: m/e 692. Elemental analysis found weight percent C=68.2 and weight percent H=5.04.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[C:5]([CH3:10])=[CH:4][C:3]=1[OH:11].[CH3:12][N:13]([CH3:17])[C:14](Cl)=[O:15]>N1C=CC=CC=1>[CH3:9][S:8][C:6]1[CH:7]=[C:2]([CH3:1])[C:3]([O:11][C:14](=[O:15])[N:13]([CH3:17])[CH3:12])=[CH:4][C:5]=1[CH3:10]
Reactant: CSc1cc(C)c(O)cc1C
Reactant: CN(C)C(=O)Cl
Solvent: c1ccncc1
Product: CSc1cc(C)c(OC(=O)N(C)C)cc1C
Temperature: 100 °C

Procedure:
A mixture of 25.2 g 2,5-dimethyl-4-(methylthio)phenol and 20.3 ml dimethylcarbamoyl chloride in 70 ml dry pyridine was heated for 24 hours at 100° C. Addition to excess of ice-cold dilute hydrochloric acid gave an oil. The oil product was extracted into ether and washed three times with cold dilute sodium hydroxide and once with water, dried, and the ether removed by evaporation to give 4-dimethylcarbamoyloxy-2,5-dimethylphenyl methyl sulphide, boiling point 146° C. at 0.6 mm to 150° C. to 0.9 mm.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[Cl:14][C:15]1[C:16]([CH3:25])=[C:17]([S:21](Cl)(=[O:23])=[O:22])[CH:18]=[CH:19][CH:20]=1>>[Cl:14][C:15]1[C:16]([CH3:25])=[C:17]([S:21]([NH:1][C:2]2[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)(=[O:23])=[O:22])[CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(=O)C(=O)c1csc(N)n1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Product: CCOC(=O)C(=O)c1csc(NS(=O)(=O)c2cccc(Cl)c2C)n1

Procedure:
The title compound was prepared from ethyl (2-amino-4-thiazolyl)glyoxylate and 3-chloro-2-methylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a yellow solid (32.5 mg) with purity >90%. LCMS (pos) m/z 389.0.B
Reaction SMILES: [O:1]=[C:2]1[C:11]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][CH:21]([C:36]3[N:37]([CH2:41][C:42]4[CH:47]=[C:46]([F:48])[CH:45]=[C:44]([F:49])[CH:43]=4)[CH:38]=[CH:39][N:40]=3)[CH2:22][C:23]3[CH:31]=[C:30]([CH3:32])[C:29]4[C:25](=[CH:26][N:27](COC)[N:28]=4)[CH:24]=3)=[O:19])[CH2:14][CH2:13]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.C(Cl)(=O)C>CO>[O:1]=[C:2]1[C:11]([CH:12]2[CH2:13][CH2:14][N:15]([C:18]([O:20][C@@H:21]([C:36]3[N:37]([CH2:41][C:42]4[CH:47]=[C:46]([F:48])[CH:45]=[C:44]([F:49])[CH:43]=4)[CH:38]=[CH:39][N:40]=3)[CH2:22][C:23]3[CH:24]=[C:25]4[C:29](=[C:30]([CH3:32])[CH:31]=3)[NH:28][N:27]=[CH:26]4)=[O:19])[CH2:16][CH2:17]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1
Reactant: COCn1cc2cc(CC(OC(=O)N3CCC(c4cc5ccccc5[nH]c4=O)CC3)c3nccn3Cc3cc(F)cc(F)c3)cc(C)c2n1
Solvent: CO
Solvent: CC(=O)Cl
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(c3cc4ccccc4[nH]c3=O)CC2)c2nccn2Cc2cc(F)cc(F)c2)cc2cn[nH]c12
Temperature: 25 °C

Procedure:
1-(1-(3,5-difluorobenzyl)-1H-imidazol-2-yl)-2-(2-(methoxymethyl)-7-methyl-2H-indazol-5-yl)ethyl 4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxylate (72.0 mg, 0.108 mmol) and acetyl chloride (0.18 mL) were combined in methanol (2.0 mL) and heated at reflux for 1 h. After cooling to room temperature, the solvents were removed in vacuo. Column chromatography afforded 47 mg (70%). 1H-NMR (CD3OD, 500 MHz) δ 1.38-2.05 (m, 3H), 2.45 (s, 3H), 2.70-3.05 (m, 3H), 3.24 (dd, J=7.3, 7.3, 1H), 3.45-3.55 (m, 1H), 4.05-4.40 (m, 2H), 5.05-5.45 (m, 2H), 5.50 (s, 1H), 5.95 (bs, 1H), 6.34-6.90 (m, 4H), 7.17 (s, 1H), 7.25 (m, 2H), 7.34 (d, J=8.2, 1H), 7.45-7.75 (m, 3H), 7.90 (s, 1H). Mass spec.: 623.3 (MH)+.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[C:14]([CH3:17])[CH:13]=[C:12]2[NH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=1.[C:28](Cl)(=[O:30])[CH3:29]>>[Cl:27][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][C:23]=1[Cl:26])[CH2:19][NH:18][C:12]1[C:11]2[C:16](=[C:7]([O:6][CH2:5][CH2:4][NH:3][C:28](=[O:30])[CH3:29])[CH:8]=[CH:9][CH:10]=2)[N:15]=[C:14]([CH3:17])[CH:13]=1
Reactant: Cc1cc(NCc2ccc(Cl)c(Cl)c2)c2cccc(OCCN)c2n1
Reactant: CC(=O)Cl
Agent: Cl
Product: CC(=O)NCCOc1cccc2c(NCc3ccc(Cl)c(Cl)c3)cc(C)nc12

Procedure:
Preparation was made using a similar procedure as described in example 21. Starting materials were [8-(2-aminoethoxy)-2-methylquinolin-4-yl]-(3,4-dichlorobenzyl)-amine dihydrochloride and acetylchloride.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13].[Cl:16][CH2:17][CH:18](OS(C)(=O)=O)[CH3:19].O>C1(C)C=CC=CC=1>[Cl:16][CH2:17][CH:18]([N:11]([C:5]1[C:6]([CH3:10])=[CH:7][CH:8]=[CH:9][C:4]=1[CH3:3])[S:12]([CH3:15])(=[O:14])=[O:13])[CH3:19]
Reactant: CC(CCl)OS(C)(=O)=O
Reactant: Cc1cccc(C)c1NS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cccc(C)c1N(C(C)CCl)S(C)(=O)=O
Temperature: 100 °C
Reaction time: 12 h
Yield: 60 %

Procedure:
5.2 g of a 80% mineral oil dispersion of sodium hydride are added in small portions, at room temperature, to a suspension of 31.5 g (0.158 moles) of N-(2,6-dimethylphenyl)-methanesulfonamide in 400 ml of dry toluene. The resulting mixture is heated slowly, within about one hour, to 100° C., and then 27.3 g (0.158 moles) of 1-chloro-2-methanesulfonyloxy-propane are added dropwise to the mixture at the same temperature within 0.5 hours. The reaction mixture is stirred at 100°-110° C. for 12 hours, thereafter it is cooled, placed into an ice bath, and 100 ml of water are introduced dropwise. The aqueous phase is separated, the toluene phase is washed with 100 ml of water, twice with 100 ml of 1 n aqueous sodium hydroxide and finally with 100 ml of water, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The thick, yellow, oily residue, weighing 33.9 g, is distilled under reduced pressure. 26.15 g of 1-chloro-2-[N-(2,6-dimethylphenyl)-methanesulfonamido]-propane are obtained as a slightly opalescent oil; b.p.: 150°-154° C./26.6 Pa.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17](I)[CH:16]=1.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:16]=[C:17]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[F:23])[CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(I)c1
Reactant: OB(O)c1ccccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(-c2ccccc2F)c1
Yield: 73.8 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-fluorobiphenyl-3-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide (0.075 g; 0.176 mmol), 2-fluorophenylboronic acid (0.026 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in dichloromethane) furnished 0.051 g (73%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-fluorobiphenyl-3-carboxamide as a white solid.