Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[C:5]([F:23])=[C:6]([NH:11][S:12]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])(=[O:14])=[O:13])[CH:7]=[CH:8][C:9]=1[F:10])(=[O:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:33][O:34][CH2:35][CH2:36][O:37][CH2:38]Cl>C(Cl)Cl>[C:1]([C:4]1[C:5]([F:23])=[C:6]([N:11]([CH2:33][O:34][CH2:35][CH2:36][O:37][CH3:38])[S:12]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])(=[O:14])=[O:13])[CH:7]=[CH:8][C:9]=1[F:10])(=[O:3])[CH3:2]
Reactant: CC(=O)c1c(F)ccc(NS(=O)(=O)c2cc(F)ccc2F)c1F
Reactant: COCCOCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCOCN(c1ccc(F)c(C(C)=O)c1F)S(=O)(=O)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.3 %

Procedure:
N-(3-acetyl-2,4-difluoro-phenyl)-2,5-difluoro-benzenesulfonamide (2.88 g, 8.293 mmol) was dissolved in dry DCM (75 mL) under nitrogen atmosphere. DIPEA (1.55 mL, 9.12 mmol, 1.1 eq) was then added, followed by 2-methoxyethoxymethyl chloride (0.98 mL, 9.12 mmol, 1.1 eq) and the mixture was stirred at room temperature for 1 h. It was then diluted with DCM and washed with water and brine, dried over Na2SO4 and evaporated to dryness. The crude product was purified by chromatography on silica gel (n-hexane/ethyl acetate 7:3) to give 2.25 g (62%) of N-(3-acetyl-2,4-difluoro-phenyl)-2,5-difluoro-N-(2-methoxy-ethoxymethyl)-benzene-sulfonamide as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[N:12]=[CH:11][CH:10]=[N:9]2)=[CH:4][C:3]=1[SH:13].[C:14](Cl)(=O)[CH2:15][CH3:16].C(=O)([O-])O.[Na+]>CN1CCCC1=O>[CH2:15]([C:16]1[S:13][C:3]2[CH:4]=[C:5]([N:8]3[N:9]=[CH:10][CH:11]=[N:12]3)[CH:6]=[CH:7][C:2]=2[N:1]=1)[CH3:14]
Reactant: CCC(=O)Cl
Reactant: Nc1ccc(-n2nccn2)cc1S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCc1nc2ccc(-n3nccn3)cc2s1
Temperature: 70 °C
Reaction time: 5 h

Procedure:
The 2-amino-5-(1,2,3-triazol-2-yl)-thiophenol (2.3 g) was dissolved in N-methylpyrrolidone (8 ml), and propionyl chloride (0.472 ml) was added to the solution, followed by heating and stirring at 70° C. for 5 hours. The reaction mixture was poured into a saturated aqueous solution of sodium hydrogencarbonate, and subjected to extraction with dichloromethane. The resultant organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure and then purified through a silica gel column (hexane-ethyl acetate=4:1→1:1), thereby obtaining the intended compound, 2-ethyl-6-(1,2,3-triazol-2-yl)benzothiazole (940 mg). Physical properties of this product are described below.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[NH:6][C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=2[C:13](=[O:15])[CH:14]=1)[CH3:4].[H][H].Br[CH2:19][C:20]1[CH:38]=[CH:37][C:23]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:22][CH:21]=1>CN(C=O)C.O>[CH2:3]([C:5]1[CH:14]=[C:13]([O:15][CH2:19][C:20]2[CH:38]=[CH:37][C:23]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:22][CH:21]=2)[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[N:6]=1)[CH3:4]
Reactant: CCOC(=O)Cc1ccccc1Oc1ccc(CBr)cc1
Reactant: [H][H]
Reactant: CCc1cc(=O)c2c([nH]1)CCCC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1ccccc1Oc1ccc(COc2cc(CC)nc3c2CCCC3)cc1
Reaction time: 20 h
Yield: 41.5 %

Procedure:
Sodium hydride (60% dispersion in mineral oil; 63 mg) was added to a solution of compound D (254 mg) in DMF (5 ml). When evolution of hydrogen ceased, a solution of compound C (500 mg) in DMF (5 ml) was added and the solution was left to stand for 20 hours. Water (50 ml) was added and the mixture was extracted with ethyl acetate (2×25 ml). The combined extracts were washed with water (25 ml), followed by saturated sodium chloride solution (25 ml) and then dried (MgSO4). The solvent was removed by evaporation and the residue purified by flash chromatography, eluting with ethyl acetate/hexane (1:1 v/v), to give ethyl 2-[4-((2-ethyl-5,6,7,8-tetrahydroquinolin-4-yl)oxymethyl)phenoxy]phenylacetate (A) (265 mg), as an oil which solidified on standing, m.p. 89°-90° C. (after trituration with hexane); NMR: 1.1-1.35(2×t, 6H), 1.7-1.9(m, 4H), 2.6(t, 2H), 2.7(q, 2H), 2.85(t, 2H), 4.1-4.3(m, 2H), 5.0(s, 2H), 5.6(s, 1H), 6.5(s, 1H), 7.0(d, 2H), 7.25-7.5(m, 5H), 7.55-7.65(m, 2H).
Reaction SMILES: CS[C:3]1[N:4]=[CH:5][C:6]2[C:15](=[O:16])[N:14]([CH2:17][CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[CH2:13][C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[C:7]=2[N:31]=1.ClC1C=CC=C(C(OO)=O)C=1.C(=O)(O)[O-].[Na+].[CH2:48]([NH2:50])[CH3:49].C1COCC1>ClCCl.C1COCC1>[CH2:48]([NH:50][C:3]1[N:4]=[CH:5][C:6]2[C:15](=[O:16])[N:14]([CH2:17][CH:18]3[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH2:22][CH2:23]3)[CH2:13][C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[C:7]=2[N:31]=1)[CH3:49]
Reactant: CCN
Reactant: CSc1ncc2c(n1)N1CCC[C@H]1CN(CC1CCN(C(=O)OC(C)(C)C)CC1)C2=O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCNc1ncc2c(n1)N1CCC[C@H]1CN(CC1CCN(C(=O)OC(C)(C)C)CC1)C2=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 83.8 %

Procedure:
(S)-9-Methylthio-5-(1-tert-butoxycarbonylpiperidin-4-yl)methyl-1,2,3,3a,4,5-hexahydro-5,8,10,10b-tetraazabenzo[e]azulen-6-one (2.51 g, 5.61 mmol) obtained in Step 1 was dissolved in dichloromethane (40 mL), and the mixture was stirred at room temperature for 20 minutes after adding 3-chloroperbenzoic acid (65%; 1.94 g, 7.29 mmol). Thereafter, an aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted three times with chloroform. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained upon concentration under reduced pressure was dissolved in THF (10 mL), and the mixture was stirred overnight after adding a 2.0 mol/L ethylamine/THF solution (14.0 mL, 28.1 mmol). The residue obtained by concentrating the reaction mixture under reduced pressure was purified by silica gel column chromatography to give the title compound (Compound 23) (2.09 g, 84%) as a yellow oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[N:15]([CH2:16][CH2:17][CH3:18])[N:14]=[C:13]([C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])[C:12]=2[C:26]([F:29])([F:28])[F:27])=[O:10])=[CH:4][C:3]=1[C:30](=[O:37])[NH:31][C:32]1([C:35]#[N:36])[CH2:34][CH2:33]1.C(=O)([O-])[O-].[K+].[K+].I[CH2:45][CH3:46]>CN(C)C=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:45][CH3:46])[C:9]([C:11]2[N:15]([CH2:16][CH2:17][CH3:18])[N:14]=[C:13]([C:19]([F:25])([F:24])[C:20]([F:23])([F:21])[F:22])[C:12]=2[C:26]([F:29])([F:27])[F:28])=[O:10])=[CH:4][C:3]=1[C:30](=[O:37])[NH:31][C:32]1([C:35]#[N:36])[CH2:34][CH2:33]1
Reactant: CCCn1nc(C(F)(F)C(F)(F)F)c(C(F)(F)F)c1C(=O)Nc1ccc(Cl)c(C(=O)NC2(C#N)CC2)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCn1nc(C(F)(F)C(F)(F)F)c(C(F)(F)F)c1C(=O)N(CC)c1ccc(Cl)c(C(=O)NC2(C#N)CC2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
70 mg (0.13 mmol) of N-{4-chloro-3-[(1-cyanocyclopropyl)carbamoyl]phenyl}-3-(pentafluoroethyl)-1-propyl-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide and 35 mg (0.14 mmol) of potassium carbonate are suspended in 1.4 ml of N,N-dimethylformamide p.a. Over a period of 16 h, a total of 29 mg (0.19 mmol) of iodoethane are added gradually to the mixture. After the addition has ended, the reaction solution is stirred at room temperature for 20 h. The reaction mixture is diluted with water, and the aqueous phase is extracted three times with ethyl acetate. The combined organic phases are washed twice with saturated sodium chloride solution, dried over sodium sulphate and filtered. The solvents are removed on a rotary evaporator under reduced pressure.
Reaction SMILES: C([O:8][C:9]([C@H:11]1[CH2:16][CH2:15][C@@H:14]([NH:17][C:18]([C:20]2[C:21]([O:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([S:34][CH3:35])[CH:29]=3)=[N:22][CH:23]=[C:24]([F:26])[CH:25]=2)=[O:19])[CH2:13][CH2:12]1)=[O:10])C1C=CC=CC=1>C(O)=O.CO.[Pd]>[F:26][C:24]1[CH:25]=[C:20]([C:18]([NH:17][C@@H:14]2[CH2:15][CH2:16][C@H:11]([C:9]([OH:10])=[O:8])[CH2:12][CH2:13]2)=[O:19])[C:21]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([S:34][CH3:35])[CH:29]=2)=[N:22][CH:23]=1
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](C(=O)OCc3ccccc3)CC2)c1
Agent: [Pd]
Solvent: O=CO
Solvent: CO
Product: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](C(=O)O)CC2)c1
Reaction time: 2 h
Yield: 48.3 %

Procedure:
cis-4-{[5-Fluoro-2-(3-methylsulfanyl-phenoxy)-pyridine-3-carbonyl]-amino}-cyclohexanecarboxylic acid benzyl ester (1.75 g, 3.54 mmol) was dissolved in a solution of 4.4% formic acid in methanol (40 ml) and this was added dropwise to a suspension of palladium black (2 g) in 4.4% formic acid in methanol (120 ml) at room temperature under nitrogen. The mixture was stirred for 2 h, then filtered through arbocel washing with methanol (5×50 ml). The filtrates were concentrated under reduced pressure and basified to pH10 with 1M sodium hydroxide solution (50 ml). The aqueous phase was extracted with diethylether (3×50 ml) then acidified to pH1 with concentrated hydrochloric acid. After extraction with diethylether (3×50 ml) the combined organic extracts were washed with water (10 ml), dried over MgSO4 and the solvent removed under reduced pressure to give cis-4-{[5-Fluoro-2-(3-methylsulfanyl-phenoxy)-pyridine-3-carbonyl]-amino}-cyclohexanecarboxylic acid (691 mg) as a white solid.
Reaction SMILES: CC(C)([O-])C.[K+].[OH:7][C@@H:8]([C@H:10]1[CH2:14][N:13]([C@@H:15]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[CH3:16])[C:12](=[O:25])[CH2:11]1)[CH3:9].Cl[C:27]1[C:28]2[N:29]([N:45]=[CH:46][C:47]=2[CH3:48])[CH:30]=[C:31]([C:33]2[CH:38]=[CH:37][C:36]([N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[CH:35][CH:34]=2)[N:32]=1>C1COCC1>[CH3:24][O:23][C:20]1[CH:19]=[CH:18][C:17]([C@H:15]([N:13]2[CH2:14][C@H:10]([C@H:8]([O:7][C:27]3[C:28]4[N:29]([N:45]=[CH:46][C:47]=4[CH3:48])[CH:30]=[C:31]([C:33]4[CH:38]=[CH:37][C:36]([N:39]5[CH2:44][CH2:43][O:42][CH2:41][CH2:40]5)=[CH:35][CH:34]=4)[N:32]=3)[CH3:9])[CH2:11][C:12]2=[O:25])[CH3:16])=[CH:22][CH:21]=1
Reactant: Cc1cnn2cc(-c3ccc(N4CCOCC4)cc3)nc(Cl)c12
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)O)CC2=O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3nc(-c4ccc(N5CCOCC5)cc4)cn4ncc(C)c34)CC2=O)cc1
Reaction time: 0.25 h

Procedure:
A solution of 1M potassium tertbutoxide in THF (0.10 mL, 0.10 mmol) was added to a solution of (R)-4-((R)-1-hydroxyethyl)-1-4R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 1.04 (27 mg, 0.1 mmol) in THF (0.5 mL) at room temperature. After 15 minutes, a solution of 4-(4-(4-chloro-3-methylpyrazolo[1,5-a]pyrazin-6-yl)phenyl)morpholine 5.11 (20 mg, 0.06 mmol) in THF (1.2 mL) was added under argon. After 90 minutes, an additional 14 mg of (R)-4-((R)-1-hydroxyethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 1.04 and 0.05 mL of 1M potassium tertbutoxide in THF were added. After 5 hours, mixture was quenched by addition of sat. NH4Cl (aq) and extracted with ethyl acetate. Combined organics were washed with 1:1 water/brine, dried (Na2SO4), filtered, and concentrated under reduced pressure to yield (R)-1-((R)-1-(4-methoxyphenyl)ethyl)-4-((R)-1-(3-methyl-6-(4-morpholinophenyl)pyrazolo[1,5-a]pyrazin-4-yloxy)ethyl)pyrrolidin-2-one 5.12, which was used without further purification.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([NH2:12])=[O:11])=[N:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>CC#N>[C:10]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:1]([CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[N:2]=1)(=[O:11])[NH2:12]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: NC(=O)c1n[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)Cn1nc(C(N)=O)c2ccccc21
Temperature: 25 °C

Procedure:
To a suspension of 1H-indazole-3-carboxamide [90004-04-9](2.00 g, 12.4 mmol) and potassium carbonate (4.12 g, 29.8 mmol) in CH3CN (60 mL) was added tert-butyl bromoacetate (2.20 mL, 14.9 mmol) dropwise at RT, and the resulting mixture was refluxed for 16 h. The mixture was then cooled to RT and filtered, the solid was washed with CH3CN and the filtrate was concentrated under vacuum. The residual oil was used directly in the next step without further purification. MS (LC/MS): 276.0 [M+H]+; tR (HPLC conditions d): 3.22 min.
Reaction SMILES: [CH3:1][C:2]([NH:4][C@@H:5]1[C:15]2[CH:16]=[C:17]([OH:20])[CH:18]=[CH:19][C:14]=2[C:13]2[C:8](=[CH:9][C:10]([O:25][CH3:26])=[C:11]([O:23][CH3:24])[C:12]=2[O:21][CH3:22])[CH2:7][CH2:6]1)=[O:3].[C:27](Cl)(=[O:29])[NH2:28].[N:31]1([CH:37]2[CH2:42][CH2:41]N[CH2:39][CH2:38]2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>N1C=CC=CC=1>[N:31]1([CH:37]2[CH2:42][CH2:41][N:28]([C:27]([O:20][C:17]3[CH:18]=[CH:19][C:14]4[C:13]5[C:12]([O:21][CH3:22])=[C:11]([O:23][CH3:24])[C:10]([O:25][CH3:26])=[CH:9][C:8]=5[CH2:7][CH2:6][CH:5]([NH:4][C:2](=[O:3])[CH3:1])[C:15]=4[CH:16]=3)=[O:29])[CH2:39][CH2:38]2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: COc1cc2c(c(OC)c1OC)-c1ccc(O)cc1[C@@H](NC(C)=O)CC2
Reactant: NC(=O)Cl
Reactant: C1CCN(C2CCNCC2)CC1
Solvent: c1ccncc1
Product: COc1cc2c(c(OC)c1OC)-c1ccc(OC(=O)N3CCC(N4CCCCC4)CC3)cc1C(NC(C)=O)CC2
Yield: 38.8 %

Procedure:
A solution of N-acetyl-colchinol (300 mg, 0.84 mmol), (J. Cech F. Santacy Collect. Czech Comm 1949, 4, 532–539), in pyridine (5 ml) was treated with 4-piperidinopiperidine carbamoyl chloride (346 mg, 1.5 mmol), (K. H. Henegar et al. J. Org. Chem., 1997, 62, 6588–6597) and the solution heated at reflux for 1 hour. The cooled mixture was filtered and the filtrate concentrated under reduced pressure. The residue was purified on silica gel eluting with methanol to give the title compound (180 mg) as a white solid.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].Cl[C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17](Cl)[N:16]=1>[Cu]I.CN(C)C=O>[CH3:22][O:21][C:19]1[CH:18]=[C:17]([O:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=2)[N:16]=[C:15]([O:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:10])[F:11])[CH:4]=2)[CH:20]=1
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: COc1cc(Cl)nc(Cl)c1
Agent: [Cu]I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(Oc2cccc(C(F)(F)F)c2)nc(Oc2cccc(C(F)(F)F)c2)c1

Procedure:
To meta-trifluoromethyl phenol (2.5 g, 0.0028×5.5 mol), 15 ml of dimethylformamide was added, followed by the addition of sodium hydride (0.45 g (ca.60% in mineral oil), 0.0028×4.0 mol) and CuI (0.25 g, 0.0028×0.47 mol). To thus formed mixture was added 2,6-dichloro-4-methoxy-pyridine (0.5 g, 0.0028 mol), and the resultant solution was refluxed for about 8 hours.
Reaction SMILES: N[C:2]1[C:7]([CH2:8][CH3:9])=[C:6]([CH3:10])[N:5]=[C:4]([CH2:11][CH2:12][CH2:13][CH3:14])[N:3]=1.Br[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]([O:31]C(C)(C)C)=[O:30])=[CH:19][CH:18]=1.[NH+]1C=CC=NC=1.[OH-].[Na+].FC(F)(F)C(O)=[O:47]>CN(C=O)C.CO>[CH2:11]([CH:4]1[NH:3][C:2](=[O:47])[C:7]([CH2:8][CH3:9])=[C:6]([CH3:10])[N:5]1[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]([OH:31])=[O:30])=[CH:19][CH:18]=1)[CH2:12][CH2:13][CH3:14]
Reactant: O=C(O)C(F)(F)F
Reactant: CCCCc1nc(C)c(CC)c(N)n1
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Agent: [Na+]
Agent: [OH-]
Agent: c1cnc[nH+]c1
Solvent: CN(C)C=O
Solvent: CO
Product: CCCCC1NC(=O)C(CC)=C(C)N1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Heating 4-amino-2-n-butyl-5-ethyl-6-methylpyrimidine (from Example 19) with 4-bromomethyl-2'-t-butoxycarbonylbiphenyl in an appropriate solvent such as methanol or DMF, followed by treatment of the intermediate pyrimidinium species with aqueous base such as 0.1N sodium hydroxide as described by Brown, Hoeger, and Mason (J. Chem. Soc., 1955, 4035), followed by treatment with neat trifluoroacetic acid to achieve final deprotection of the carboxyl group, would provide the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[CH:11]=[C:10]([CH2:12][CH2:13][O:14]S(C3C=CC(C)=CC=3)(=O)=O)[N:9]([CH2:25][CH2:26][CH3:27])[C:8]2=[O:28])=[CH:4][CH:3]=1.[CH2:31]([O:33][C:34](=[O:47])[C:35]([O:45][CH3:46])([CH3:44])[CH2:36][C:37]1[CH:42]=[CH:41][C:40](O)=[CH:39][CH:38]=1)[CH3:32].C([O-])([O-])=O.[K+].[K+]>CCO.O>[CH2:31]([O:33][C:34](=[O:47])[C:35]([O:45][CH3:46])([CH3:44])[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:14][CH2:13][CH2:12][C:10]2[N:9]([CH2:25][CH2:26][CH3:27])[C:8](=[O:28])[N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:30][CH:29]=3)[CH:11]=2)=[CH:39][CH:38]=1)[CH3:32]
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)OC
Reactant: CCCn1c(CCOS(=O)(=O)c2ccc(C)cc2)cn(Cc2ccc(C)cc2)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCCn1c(CCOc2ccc(CC(C)(OC)C(=O)OCC)cc2)cn(Cc2ccc(C)cc2)c1=O
Temperature: 75 °C
Yield: 43.1 %

Procedure:
A mixture of toluene-4-sulfonic acid 2-[1-(4-methyl-benzyl)-2-oxo-3-propyl-2,3-dihydro-1H-imidazol-4-yl]-ethyl ester (0.079 g, 0.184 mmol), 3-(4-hydroxy-phenyl)-2-methoxy-2-methyl-propionic acid ethyl ester (0.038 g, 0.169 mmol) and K2CO3 (0.047 g, 0.340 mmol) in EtOH (8 mL) was heated at 75° C. under N2 for 16 h. The reaction mixture was cooled to room temperature and quenched with aqueous 1 N HCl (1 mL). The solvent was removed in vacuo to give a residue that was diluted with water and extracted with EtOAc. The organic layer was dried (MgSO4) and the solvent removed in vacuo to afford crude product that was purified by flash chromatography using a 2:1 hexanes:acetone to afford 0.036 g (44%) 2-methoxy-2-methyl-3-(4-{2-[1-(4-methyl-benzyl)-2-oxo-3-propyl-2,3-dihydro-1H-imidazol-4-yl]-ethoxy}-phenyl)-propionic acid ethyl ester.
Reaction SMILES: ClN1C(=O)C[CH2:4][C:3]1=O.C([C:11]1[C:12]([Cl:32])=[C:13](CC)[C:14]([O:24][CH2:25][C:26](=[CH2:29])[CH:27]=[CH2:28])=[C:15]([CH:17]=[N:18][NH:19][P:20](=[O:23])([O-:22])[O-:21])[CH:16]=1)C.[CH2:33](N(CC)CC)[CH3:34]>C(Cl)Cl>[Cl:32][C:12]1[CH:11]=[CH:16][C:15]2[C:17]3[C:26]([CH:27]=[CH2:28])([CH2:25][O:24][C:14]=2[CH:13]=1)[CH2:29][N:19]([P:20](=[O:23])([O:21][CH2:33][CH3:34])[O:22][CH2:3][CH3:4])[N:18]=3
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCN(CC)CC
Reactant: C=CC(=C)COc1c(C=NNP(=O)([O-])[O-])cc(CC)c(Cl)c1CC
Solvent: ClCCl
Product: C=CC12COc3cc(Cl)ccc3C1=NN(P(=O)(OCC)OCC)C2
Temperature: 0 °C
Reaction time: 4 h

Procedure:
N-Chlorosuccinimide (1.0 g, 0.007 mol) was added to a mixture of 2.7 g (0.007 mol) of the product from Step D, 0.75 g of 3A molecular sieves and 120 mL of methylene chloride. The resulting mixture was cooled to 0° C. and was treated with a solution of 1.3 mL of triethylamine and 60 mL of methylene chloride. The resulting mixture was stirred at room temperature for 4 h and then decanted into 100 mL of water. The aqueous layer was extracted with two 50 mL portions of methylene chloride and the combined organic layers were washed with water and saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate and concentrated to give 2.9 g of a brown oil. Flash chromatography on silica gel using 1:3 hexanes-EtOAc afforded 1.0 g of a light yellow oil. 200 MHz 1H NMR (CDCl3): δ1.36 (t, 6H), 3.55 (dd, 1H), 3.9 (d, 1H), 4.1-14.3 (m, 5H), 4.60 (d, 1H), 5.15-5.3 (m, 2H), 5.90-6.05 (m, 1H), 6.9-7.0 (m, 2H), 7.78 (d, 1H).
Reaction SMILES: [C:1]1([CH3:33])[CH:6]=[CH:5][C:4]([N:7]([CH:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][C:23]3([CH2:29][C:30](O)=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:17][CH2:16]2)[C:8]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)=[O:9])=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[C:40]([O:49][CH3:50])(=[O:48])[C:41]1[C:42](=[CH:44][CH:45]=[CH:46][CH:47]=1)[NH2:43].C(N(CC)CC)C>ClCCl.CN(C)C=O>[C:1]1([CH3:33])[CH:6]=[CH:5][C:4]([N:7]([CH:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][C:23]3([CH2:29][C:30]([NH:43][C:42]4[CH:44]=[CH:45][CH:46]=[CH:47][C:41]=4[C:40]([O:49][CH3:50])=[O:48])=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:17][CH2:16]2)[C:8]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)=[O:9])=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccccc1N
Reactant: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCC3(CC(=O)O)CCCCC3)CC2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1NC(=O)CC1(CCN2CCC(N(C(=O)c3ccco3)c3ccc(C)cc3)CC2)CCCCC1
Reaction time: 2 h
Yield: 39.1 %

Procedure:
To a solution of [1-[2-[4-[N-(p-tolyl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]acetic acid (synthesized in Preparation Example 3B-1) (678 mg) in dichloromethane (15 mL) was added N,N-dimethylformamide (2 drops) dropwise. Oxalyl chloride (228 mg) was then added to the solution under ice cooling. The solution was stirred under ice cooling for 2 hours. A 5-mL aliquot of the reaction solution was taken and was added to a solution of methyl anthranilate (99 mg) and triethylamine (182 mg) in dichloromethane (15 mL) dropwise under ice cooling. The reaction solution was stirred for 18 hours while the temperature was allowed to rise to room temperature. NH Silica gel was then added to the reaction solution, and it was concentrated under reduced pressure. The residue was purified by chromatography [silica gel, chloroform-methanol (20:1)] to give methyl 2-[2-[1-[2-[4-[N-(p-tolyl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]acetylamino]benzoate (150 mg).
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O.[Cl:21][C:22]1[C:23]([O:30][CH:31]([F:33])[F:32])=[N:24][CH:25]=[C:26]([CH:29]=1)[CH:27]=O>>[Cl:21][C:22]1[CH:29]=[C:26]([CH2:27][N:1]2[CH:2]([C:11]3[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=3[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]2=[O:9])[CH:25]=[N:24][C:23]=1[O:30][CH:31]([F:33])[F:32]
Reactant: O=Cc1cnc(OC(F)F)c(Cl)c1
Reactant: COC(=O)CCCCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCCCC(=O)N1Cc1cnc(OC(F)F)c(Cl)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 6-amino-6-(2,6-dimethoxyphenyl)hexanoate with 5-chloro-6-(difluoromethoxy)nicotinaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.94 min.; [M+H]+: 441.11 g/mol.
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[N:9]=[CH:8][C:7]1=[O:18].Cl>O1CCCC1.ClCCl>[CH3:17][O:16][C:13]1[CH:14]=[C:15]2[C:10]([N:9]=[CH:8][C:7](=[O:18])[N:6]2[CH2:5][CH2:4][CH:3]=[O:2])=[CH:11][CH:12]=1
Reactant: COc1ccc2ncc(=O)n(CCC(OC)OC)c2c1
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc2ncc(=O)n(CCC=O)c2c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 94.1 %

Procedure:
1-(3,3-Dimethoxypropyl)-7-methoxyquinoxalin-2(1H)-one (300 mg, 1.08 mmol) was dissolved in tetrahydrofuran (3 ml). 1N Hydrochloric acid (3 ml) was added to this solution and the mixture was stirred at room temperature for 3.5 hours. The reaction solution was diluted with dichloromethane and stirred, and the organic layer was then separated. The organic layer was washed with saturated sodium chloride solution, dried over magnesium sulfate and then the solvent was removed under reduced pressure to yield 236 mg (94%) of the title compound in the form of a light brown solid.