Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:7]([NH2:8])=[N:6][C:4](=[O:5])[CH2:3]1.[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[N:14]=[C:15]=[O:16]>CN(C=O)C.C1(C)C=CC=CC=1>[CH3:1][N:2]1[CH2:3][C:4](=[O:5])[NH:6][C:7]1=[N:8][C:15]([NH:14][C:10]1[S:9][CH:13]=[CH:12][CH:11]=1)=[O:16]
Reactant: CN1CC(=O)N=C1N
Reactant: O=C=Nc1cccs1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CN1CC(=O)NC1=NC(=O)Nc1cccs1
Temperature: 55 °C
Reaction time: 1 h
Yield: 30.3 %

Procedure:
To 9.4 g (83 mM) of creatinine in 100 ml of anhydrous DMF was added with stirring of solution of 9.2 g (75 mM) 2-thienyl isocyanate in 60 ml of toluene. After the addition was completed, the mixture was stirred at 55° C. for 1 hr., cooled, and the solvents removed in vacuo. The residue was recrystallized first from ethanol and then ethyl acetate (treated with charcoal) to give 5.3 g of the above urea as an off-white solid, m.p. 191°-192° C. (dec.).
Reaction SMILES: S(Cl)(Cl)=O.N.[N:6]([CH2:9][CH2:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][CH:12]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(O)C>[NH2:6][CH2:9][CH2:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][CH:12]=1
Reactant: [N-]=[N+]=NCCc1ccc(C(N)=O)cc1
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: O=S(Cl)Cl
Product: NCCc1ccc(C(N)=O)cc1

Procedure:
For the preparation of the starting material of Example 10a, p-(2-bromoethyl)-acetophenone was reacted with sodium azide in dimethylsulfoxide to give p-(2-azidoethyl)acetophenone. Oxidation with sodium hypobromite gave p-(2-azidoethyl)benzoic acid (m.p. 130°-131°, from acetone-hexane), which was converted with thionyl chloride into the corresponding acid chloride and subsequently with ammonia into p-(2-azidoethyl)benzamide. Treatment with triphenylphosphine and hydrolysis gave p-(2-aminoethyl)benzamide, m.p. 132°-133° (from ethanol).
Reaction SMILES: [N-:1]=[C:2]=[O:3].[F:4][C:5]1[C:6]([Si:14]([CH3:17])([CH3:16])[CH3:15])=[C:7]([CH:11]=[CH:12][CH:13]=1)C(O)=O.C(Cl)(=O)C(Cl)=O>C(Cl)Cl.O.CC(C)=O>[F:4][C:5]1[C:6]([Si:14]([CH3:17])([CH3:16])[CH3:15])=[C:7]([N:1]=[C:2]=[O:3])[CH:11]=[CH:12][CH:13]=1
Reactant: [N-]=C=O
Reactant: C[Si](C)(C)c1c(F)cccc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CC(C)=O
Product: C[Si](C)(C)c1c(F)cccc1N=C=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Preparation of the intermediate isocyanate was carried out via a Curtius rearrangement. See Capson, T. L. et al., Tetrahedron Lett., 25, 3515 (1984) and references herein. To a solution of the compound prepared in (2) (3.03 g, 14.3 mmol) in CH2Cl2 (20 mL) was added oxalylchloride (130 mL, 15.0 mmol) and the resulting mixture was stirred 3 h at room temperature. The residue obtained after evaporation of the solvent was diluted with THF (10 mL) and injected with vigorous stirring to a ice-cooled solution of Na2N3 (3.70 g, 57 mmol) in H2O (20 mL) and acetone (50 mL). After 15 min at 0° C. and 1 min at room temperature, the solution was extracted with Et2O (4×50 mL) and dried (Na2SO4). The residue obtained after evaporation of solvents was refluxed in toluene for 1 h 30 to provide, upon solvent removal, 2.85 g (79%) of a slightly yellow oil: IR (neat, cm-1) 2269, 1598, 1433, 1252, 1228, 846, 788; 1H NMR (300 MHz, CDCl3) δ 0.38 (d, J=1.9 Hz, 9H), 6.82 (br t, J=8.3 Hz, 1H), 6.90 (br d, J=8.2 Hz, 1H), 7.25 (ddd, J1 =J2 =8.1 Hz, J3 =6.6 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 0.4, 112.6 (d, JCF =26 Hz), 120.5, 122.5, 131.5, 139.2, 167.4 (d, JCF =241 Hz)
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:5]=2[N:6]=1.[Br:12]Br>C(Cl)(Cl)Cl>[Br:12][C:7]1[C:5]2[N:6]=[C:2]([CH3:1])[S:3][C:4]=2[CH:10]=[CH:9][C:8]=1[CH3:11]
Reactant: Cc1ccc2sc(C)nc2c1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: Cc1nc2c(Br)c(C)ccc2s1
Temperature: 25 °C

Procedure:
A mixture of 2,5-dimethyl-1,3-benzothiazole (10.00 g, 61.26 mmol, Aldrich) and bromine (6.94 mL, 134.8 mmol) in chloroform (200 mL) was heated at reflux overnight. After cooling to room temperature, the mixture was washed with 1 N NaOH, followed by saturated sodium thiosulfate and brine, then dried over sodium sulfate and evaporated to dryness. The residue was purified on silica gel, eluting with 0 to 50% EtOAc in hexane. The first peak had a retention time of 2.51 minutes, LCMS calculated for C9H9BrNS(M+H)+: m/z=242.0; found: 241.9. 1H NMR shown to be the desired product B (980 mg, 6.61%). 1H NMR (CDCl3, 400 MHz) 7.63 (1H, d, J=8.4 Hz), 7.22 (1H, d, J=8.4 Hz), 2.87 (3H, s), 2.55 (3H, s) ppm. The second peak had a retention time of 2.758 minutes, LCMS (M+H)+m/z=241.9; found: 242. 1H NMR showed no coupling for the two phenyl hydrogens confirming the 6-bromo isomer.
Reaction SMILES: [Br:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1Br.[CH2:13]([Sn](CCCC)(CCCC)CCCC)[CH:14]=[CH2:15].[Cl-].[Li+]>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.C1(C)C=CC=CC=1>[CH2:15]([C:3]1[CH:4]=[CH:5][C:6]2[C:7](=[O:11])[O:8][CH2:9][C:10]=2[C:2]=1[Br:1])[CH:14]=[CH2:13]
Reactant: O=C1OCc2c1ccc(Br)c2Br
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: C=CCc1ccc2c(c1Br)COC2=O

Procedure:
To a flask charged with 4,5-dibromo-2-benzofuran-1(3H)-one (170 mg, 0.59 mmol) and a stir bar was added allyl tri-n-butyltin (0.18 mL, 0.59 mmol), palladium tetrakis (68 mg, 0.059 mmol), lithium chloride (50 mg, 1.2 mmol), and toluene (5 mL). The mixture was sealed with a condensor, purged three times with nitrogen, and heated to reflux for 16 hours. The reaction was diluted with EtOAc (50 mL), adsorbed onto silica gel, and purified by silica gel flash chromatography to afford 5-allyl-4-bromo-2-benzofuran-1(3H)-one. LC-MS (IE, m/z): 253 [M+1]+;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=2[Cl:19])=[O:10])=[C:4]([OH:20])[C:3]=1[S:21]([NH:24][CH2:25][CH2:26][CH2:27][S:28][CH3:29])(=[O:23])=[O:22].I([O-])(=O)(=O)=[O:31].[Na+]>C(#N)C.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=2[Cl:19])=[O:10])=[C:4]([OH:20])[C:3]=1[S:21]([NH:24][CH2:25][CH2:26][CH2:27][S:28]([CH3:29])=[O:31])(=[O:22])=[O:23]
Reactant: CSCCCNS(=O)(=O)c1c(Cl)ccc(NC(=O)Nc2cccc(Cl)c2Cl)c1O
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CS(=O)CCCNS(=O)(=O)c1c(Cl)ccc(NC(=O)Nc2cccc(Cl)c2Cl)c1O
Yield: 81.6 %

Procedure:
A solution of N-[4chloro-2-hydroxy-3-[N″-(3-methylthiopropyl)aminosulfonyl]-phenyl]-N′-(2,3-dichlorophenyl) urea (50 mg, 0.10 mmol) and sodium periodate (26 mg, 0.12mmol) in acetonitrile (6 mL) and water (2 mL) was stirred for 3 days at room temperature. The mixture was diluted with ethyl acetate and washed with water to give the crude material. Recrystallization from acetone and hexane gave the desired product (42 mg, 81%). 1H NMR (DMSO-d6): δ 9.32 (s, 1H), 9.27 (s, 1H), 8.59 (s, 1H), 8.29 (d, 1H), 8.07 (m, 1H), 7.33 (m, 2H), 7.13 (d, 1H), 3.00 (m, 2H), 2.75 (m, 1H), 2.65 (m, 1H), 2.47 (s, 3H), 1.79 (m, 2H).
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[N:16]2)=[CH:11][CH:10]=1.[NH2:23][CH2:24][C:25]([CH3:28])([OH:27])[CH3:26]>ClCCl>[Br:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:23][CH2:24][C:25]([CH3:28])([OH:27])[CH3:26])=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[N:16]2)=[CH:11][CH:10]=1
Reactant: CC(C)(O)CN
Reactant: O=[N+]([O-])c1cnc2cc(Br)ccc2c1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(O)CNc1c([N+](=O)[O-])cnc2cc(Br)ccc12
Temperature: 0 °C
Reaction time: 8 h
Yield: 78.5 %

Procedure:
Triethylamine (17.35 mL, 124 mmol) was added to a solution of 7-bromo-4-chloro-3-nitroquinoline (29.84 g, 104 mmol) in dichloromethane (253 mL), and the reaction was cooled to 0° C. 1-Amino-2-methylpropan-2-ol (10.17 g, 114 mmol) was added dropwise, and then the reaction was allowed to warm to ambient temperature and stirred overnight. A precipitate formed and was isolated by filtration and washed with water. The crude solid was recrystallized from a mixture of isopropanol and acetonitrile to provide 27.78 g of 1-(7-bromo-3-nitroquinolin-4-ylamino)-2-methylpropan-2-ol as a solid.
Reaction SMILES: CO[C:3](=[O:14])[C:4]1[C:9]([I:10])=[CH:8][C:7]([Cl:11])=[CH:6][C:5]=1[CH2:12]Br.[F:15][C:16]([F:27])([F:26])[O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH2:23])=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[Cl:11][C:7]1[CH:6]=[C:5]2[C:4](=[C:9]([I:10])[CH:8]=1)[C:3](=[O:14])[N:23]([CH2:22][C:21]1[CH:24]=[CH:25][C:18]([O:17][C:16]([F:15])([F:26])[F:27])=[CH:19][CH:20]=1)[CH2:12]2
Reactant: COC(=O)c1c(I)cc(Cl)cc1CBr
Reactant: NCc1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C1c2c(I)cc(Cl)cc2CN1Cc1ccc(OC(F)(F)F)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 38.1 %

Procedure:
A mixture of 4-chloro-2-bromomethyl-6-iodo-benzoic acid methyl ester (0.78 g, 2.0 mmol), 4-trifluoromethoxy-benzylamine (0.458 mL, 3.0 mmol), and K2CO3 (0.552 g, 4.0 mmol) in toluene (5 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography of the product using 30% ethyl acetate in hexane afforded 5-chloro-7-iodo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.356 g, 38%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.17 (s, 2H), 4.78 (s, 2H) 7.20 (d, 2H), 7.37 (t, 3H), 7.93 (s, 1H). GC-MS: m/z 467 (M)+, 382 (M−85)+.
Reaction SMILES: [CH2:1]([S:3][C@@H:4]1[NH:7][C:6](=[O:8])[C@H:5]1[CH2:9][CH2:10][CH2:11][NH:12][C:13]([NH:25][C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])=[N:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:46](Cl)(=[O:48])[CH3:47]>C1COCC1>[CH2:1]([S:3][C@@H:4]1[N:7]([C:46](=[O:48])[CH3:47])[C:6](=[O:8])[C@H:5]1[CH2:9][CH2:10][CH2:11][NH:12][C:13]([NH:25][C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])=[N:14][C:15]([O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16])[CH3:2]
Reactant: CCS[C@@H]1NC(=O)[C@H]1CCCNC(=NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Reactant: CC(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCS[C@H]1[C@H](CCCNC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)C(=O)N1C(C)=O
Reaction time: 0.17 h
Yield: 90282.5 %

Procedure:
To a -78° C. THF (10 mL) solution of compound 17 (718 mg, 1.26 mmol) was added 1N THF solution (1.5 mL) of lithium bis(trimethylsilyl)amide (1.5 mmol), followed by stirring the solution for 10 min. Acetyl chloride (0.1 mL, 1.5 mmol) was added, and the resultant solution was warmed to room temperature, followed by an additional hour of stirring. The reaction mixture was concentrated, and the residue was partitioned between pH 7.0 aqueous buffer and ethyl acetate. The organic phase was washed with brine, dried (Na2SO4), and concentrated. The residue was purified by silica gel chromatography (1:1/Et2O:hexane) to afford 615 g (90%) of the title product.
Reaction SMILES: C1(C[N:8](CC2C=CC=CC=2)[C:9]2[C:18]3[N:19]=[C:20]([CH2:26][CH:27]([CH3:29])[CH3:28])[N:21]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:17]=3[C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[N:10]=2)C=CC=CC=1>[OH-].[OH-].[Pd+2].C(O)=O>[CH3:24][CH:23]([CH3:25])[CH2:22][N:21]1[C:17]2[C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[N:10]=[C:9]([NH2:8])[C:18]=2[N:19]=[C:20]1[CH2:26][CH:27]([CH3:29])[CH3:28]
Reactant: CC(C)Cc1nc2c(N(Cc3ccccc3)Cc3ccccc3)nc3c(c2n1CC(C)C)CCCC3
Agent: [Pd+2]
Agent: [OH-]
Solvent: O=CO
Product: CC(C)Cc1nc2c(N)nc3c(c2n1CC(C)C)CCCC3
Temperature: 25 °C
Yield: 65.6 %

Procedure:
N,N-Bis(phenylmethyl)-6,7,8,9-tetrahydro-1,2-di(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.61 g, 3.3 mmole), palladium hydroxide on carbon (0.50 g, Pearlman's catalyst) and formic acid (10 mL) were combined and heated at reflux for 20 hours. The reaction mixture was cooled to ambient temperature, filtered through a layer of celite and diluted with water (about 20 mL). The resulting mixture was cooled to 0° C., made basic by the addition of 28% ammonium hydroxide then extracted with methylene chloride (3×50 mL). The extracts were combined, dried over magnesium sulfate and concentrated to provide a white solid. The solid was purified by silica gel chromatography eluting with methylene chloride:methanol 90:10 to provide 0.65 g of the desired product as a white solid, m.p. 160°-161° C. Analysis: Calculated for C18H28N4 : % C, 71.96; % H, 9.39; % N, 18.65; Found: % C, 71.66; % H, 9.37; % N, 18.46.
Reaction SMILES: C1([PH+](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][O:21][C:22]([C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[C:29](C=O)[CH:30]=2)[CH:25]=1)=[O:23].[H][H]>O1CCCC1>[CH3:20][O:21][C:22]([C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1)=[O:23]
Reactant: [H][H]
Reactant: COC(=O)c1ccc2cc(C=O)ccc2c1
Agent: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc2ccccc2c1

Procedure:
For example, 4'-alkoxy-4-bromobiphenyl (17) is reacted with triphenylphosphin to obtain triphenylphosphonium salt of 4'-alkoxybiphenyl (21). The thus obtained triphenylphosphonium salt of 41 -alkoxybiphenyl (21) is reacted with 6-formyl-2-naphthalenecarboxylic acid methyl ester as a solution in such as methylene chrolide and then the resulting compound is reacted with hydrogen in the presence of the reducing catalyst such as paradium carbon in a solvent such as tetrahydrofuran (THF) to obtain 6-[4'-alkoxy-4-biphenyl)ethyl]-2-naphthalenecarboxylic acid methyl ester. The resulting 6-[4'-alkoxy-4-biphenyl)ethyl]-2-naphthalenecarboxylic acid methyl ester is hydrolysised to obtain 6-[4'-alkoxy-4-biphenyl)ethyl]-2-naphthalenecarboxylic acid (22).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[C:11]2[CH:18]=[CH:17][N:16]([CH:19]([CH3:21])[CH3:20])[C:12]=2[N:13]=[CH:14][N:15]=1>C(Cl)Cl>[Br:1][C:18]1[C:11]2[C:10]([Cl:9])=[N:15][CH:14]=[N:13][C:12]=2[N:16]([CH:19]([CH3:21])[CH3:20])[CH:17]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)n1ccc2c(Cl)ncnc21
Solvent: ClCCl
Product: CC(C)n1cc(Br)c2c(Cl)ncnc21
Yield: 93.4 %

Procedure:
N-Bromosuccinimide (165 g, 926 mmol) was added to a solution of 4-Chloro-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine (151 g, 772 mmol) in CH2Cl2 (1 L). After 12 h the reaction was quenched with saturated aqueous NaHCO3 (500 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (2×500 mL). The combined organic layers were washed with water (3×500 mL) and brine (1×500 mL), dried (Na2SO4), filtered, and concentrated in vacuo to afford the title compound as a white solid (198 g, 94%). MS: 275.5 (MH+); HPLC Rf: 5.99 min. (HPLC method 4).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH:5]=[CH:6][CH:7]=1.C[O-].[Na+].[CH2:21]1[O:23][CH:22]1[CH2:24][OH:25].CS(O)(=O)=O>CO>[OH:23][CH:22]([CH2:24][OH:25])[CH2:21][O:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(-c2cccc(O)c2)oc2ccccc12
Reactant: OCC1CO1
Agent: CS(=O)(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1c(-c2cccc(OCC(O)CO)c2)oc2ccccc12
Temperature: 200 °C

Procedure:
The ester which results from the condensation of 2'-hydroxyacetophenone and m-anisic acid is converted to 2-(3-methoxyphenyl)-3-methylbenzofuran by reductive cyclization in dioxane with a titanium tetrachloride/zinc metal catalyst according to the method of Banerji and Nayak, J. Chem. Soc., Chem. Comm., (1990), 150. The 2-(3-methoxyphenyl)-3-methylbenzofuran (47.6 gm, 0.198 mol) is treated with several volumes of pyridine hydrochloride at 200° C. for about 6 hours to cleave the methyl ether moiety to the free hydroxyl group. Three volumes of water are added to the cooled reaction mixture and the system is extracted twice with ether. The ether extracts are combined, washed once with water and then dried over sodium sulfate. Removal of solvent by rotary evaporation affords the desired product, 2-(3-hydroxyphenyl)-3-methylbenzofuran. 2-(3-hydroxyphenyl)-3-methylbenzofuran (22.4 gm 0.1 mol) is dissolved in 100 mL of methanol in a 250 ml round bottom flask under an atmosphere of argon. To this well stirred solution is added sodium methoxide (0.54 gm, 0.01 mol). Glycidol (Aldrich, 8.14 gm, 0.11 mol) is added and the system is gradually heated and held at reflux for 18 hours. The solution is neutralized with methanesulfonic acid. The solvent is removed by rotary evaporation. The resulting product is heated on a Kugelrohr apparatus at 200° C. under a vacuum of 1 mm Hg, to remove any 3-methoxy-1,2-propanediol by-product, affording 2-[3-(2,3-dihydroxypropoxy)phenyl]-3-methylbenzofuran having the structure: ##STR55##
Reaction SMILES: [CH3:1][Si](Cl)(C)C.[NH2:6][C:7]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([F:19])[C:8]=1[F:20]>CO>[NH2:6][C:7]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:10]([C:11]([O:13][CH3:1])=[O:12])=[C:9]([F:19])[C:8]=1[F:20]
Reactant: Nc1c([N+](=O)[O-])cc(C(=O)O)c(F)c1F
Reactant: C[Si](C)(C)Cl
Solvent: CO
Product: COC(=O)c1cc([N+](=O)[O-])c(N)c(F)c1F
Yield: 91.4 %

Procedure:
TMSCl (132 g, 1.21 mol, 2.0 equiv) was added over 5 minutes to a slurry of 4-amino-2,3-difluoro-5-nitrobenzoic acid (3) (132.3 g, 0.607 mol, 1 equiv) in 325 mL of MeOH. The mixture was heated at reflux for 15 hours. Once the reaction was complete by HPLC, the reaction mixture was cooled in an ice-water bath for 45 minutes. Then the reaction mixture was filtered and the cake was washed with 65 mL of MeOH. The wet cake was dried overnight at 55° C. under high vacuum to provide 128.8 g (92%) of 4-amino-2,3-difluoro-5-nitrobenzoic acid methyl ester (4). HPLC was 97.9 a % (220 nm) and 99.2 a % (254 nm). 1H NMR (400 MHz, d6 DMSO) δ 3.84 (3H, s, OMe), 8.1 (2H, br s, NH2), 8.43 (1H, apparent dd, J 1.9, 7.2, Ar—H). 19F NMR (376 MHz, d6 DMSO) δ −153.6, −129.2. 13C NMR (100 MHz, d6 DMSO) δ 52 (CH3O), 105 (C, d, J 10), 125 (CH, t, J 2.7), 128 (CH, d, J 5), 140 (C—F, dd, J 244, 15), 141 (C, dd, J 14, 5), 152 (C—F, dd, J 263, 11), 162 (COO, t, J 3). IR νmax/cm−1 3433, 3322, 1699, 1637, 1548, 1342, 1234. MS APCI (−) m/z 231 (M−1) detected.
Reaction SMILES: [CH:1]1([CH2:7][C:8]([OH:10])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:26][C:27]1[C:31]([C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)=[C:30]([C:38]2[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=2)[NH:29][N:28]=1>O1CCCC1.O>[CH:1]1([CH2:7][C:8]([NH:26][C:27]2[C:31]([C:32]3[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=3)=[C:30]([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)[NH:29][N:28]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)CC1CCCCC1
Reactant: Nc1n[nH]c(-c2ccc(F)cc2)c1-c1ccncc1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: O
Product: O=C(CC1CCCCC1)Nc1n[nH]c(-c2ccc(F)cc2)c1-c1ccncc1
Temperature: -10 °C
Yield: 29.1 %

Procedure:
220 mg of cyclohexylacetic acid was dissolved in 10 ml of tetrahydrofuran. While this solution was being cooled at −10° C., 160 mg of N-methylmorpholine and 220 mg of isobutyl chloroformate were added thereto with stirring. The resulting mixture was stirred for 15 minutes. After the addition of 127 mg of 3-amino-5-(4-fluorophenyl)-4-(4-pyridyl)pyrazole, the mixture was stirred for 30 minutes and then stirred at room temperature for 4 days. After the addition of water, the reaction mixture was extracted with ethyl acetate. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. After the resulting residue was dissolved in 10 ml of methanol, 1 ml of 2N sodium hydroxide was added thereto, followed by stirring at room temperature for 90 minutes. Then, the solvent was distilled off under reduced pressure. After the addition of water, this mixture was extracted with ethyl acetate. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography using 30 g of silica gel [with an elution solvent comprising chloroform-methanol (30:1)]. Thus, 55 mg (29% yield) of the title compound was obtained as colorless crystals.
Reaction SMILES: [P:1]([O-:39])([O:35][CH2:36][CH2:37]Br)([O:3][CH2:4][CH:5]([O:29][C:30]1[CH:34]=[CH:33][O:32][N:31]=1)[CH2:6][O:7][C:8]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[O:10][N:9]=1)=[O:2].[CH3:40][N:41]1[CH:45]=[CH:44][N:43]=[CH:42]1>>[P:1]([O-:39])([O:35][CH2:36][CH2:37][N+:43]1[CH:44]=[CH:45][N:41]([CH3:40])[CH:42]=1)([O:3][CH2:4][CH:5]([O:29][C:30]1[CH:34]=[CH:33][O:32][N:31]=1)[CH2:6][O:7][C:8]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[O:10][N:9]=1)=[O:2]
Reactant: CCCCCCCCCCCCCCCCc1cc(OCC(COP(=O)([O-])OCCBr)Oc2ccon2)no1
Reactant: Cn1ccnc1
Product: CCCCCCCCCCCCCCCCc1cc(OCC(COP(=O)([O-])OCC[n+]2ccn(C)c2)Oc2ccon2)no1

Procedure:
21(b) Following the procedure described in Example 17, 0.730 g of (2RS)-3-(5-hexadecyl-3-isoxazolyloxy)-2-(3-isoxazolyloxy)propyl 2-bromoethyl phosphate [prepared as described in step (a) above] was reacted with 0.91 ml of N-methylimidazole, to give 0.477 g of the title compound as a pale-yellow resinous material.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([C:11]([Cl:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:6])=[O:5].C(OCCCCCC)(=O)[C:15]1[CH:23]=[CH:22]C(C([O-])=O)=[CH:17][CH:16]=1.[K+].S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH2:1]([C:2]1[CH:10]=[C:9]([C:11]([Cl:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:6])=[O:5])[CH2:17][CH2:16][CH2:15][CH2:23][CH3:22]
Reactant: Cc1cc(C(=O)Cl)ccc1C(=O)Cl
Reactant: CCCCCCOC(=O)c1ccc(C(=O)[O-])cc1
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CCCCCCc1cc(C(=O)Cl)ccc1C(=O)Cl

Procedure:
This compound was prepared by the method described for monomethyl terephthaloyl chloride. Typical reagent levels were as follows: potassium monohexyl terephthalate (18.6 g, 0.64 mole), thionyl chloride (9.21 g, 0.774 mole) and 100 ml of toluene. The product was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[C:13]([CH3:20])=[N:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=3)[N:7]([CH2:21][CH2:22][CH2:23]O)[C:6]=2[C:5]([C:25]([O:27][CH3:28])=[O:26])=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]([O:27][CH3:28])=[O:26])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:12]3[C:13]([CH3:20])=[N:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=3)[CH2:23][CH2:22][CH2:21][N:7]21
Reactant: COC(=O)c1ccc(Cl)c2nc(Nc3ccc(OC)nc3C)n(CCCO)c12
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(OC)nc1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 89.9 %

Procedure:
To a solution of methyl 4-chloro-1-(3-hydroxypropyl)-2-[(6-methoxy-2-methylpyridin-3-yl)amino]-1H-benzimidazole-7-carboxylate (Reference example 156, 6.40 g, 15.81 mmol) in tetrahydrofuran (42.0 mL) were added triethylamine (4.42 mL, 31.62 mmol) and methanesulfonyl chloride (1.84 mL, 23.71 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1.5 hrs. The mixture was quenched with aqueous sodium hydrogen carbonate and extracted with ethyl acetate (×3). The combined organic layer was washed with brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The resulting mesylate was dissolved into N,N-dimethylformamide (67.0 mL) and to the solution was added potassium carbonate (4.27 g, 31.62 mmol). The mixture was stirred at 70° C. for 4 hrs. After cooling, the mixture was diluted with water. The generated precipitate was collected by filtration and washed with diisopropyl ether to give the title compound as a colorless solid (5.50 g, 14.22 mmol, 90%).