Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[CH2:5][NH:6][C:7](=[O:12])[C:8]([F:11])([F:10])[F:9].[Cl:16][S:17](O)(=[O:19])=[O:18]>>[F:1][C:2]1[CH:15]=[CH:14][C:13]([S:17]([Cl:16])(=[O:19])=[O:18])=[C:4]([CH2:5][NH:6][C:7](=[O:12])[C:8]([F:10])([F:11])[F:9])[CH:3]=1
Reactant: O=C(NCc1cccc(F)c1)C(F)(F)F
Reactant: O=S(=O)(O)Cl
Product: O=C(NCc1cc(F)ccc1S(=O)(=O)Cl)C(F)(F)F
Temperature: 70 °C

Procedure:
3-Fluoro-N-trifluoroacetylbenzylamine (Intermediate 105, 1.11 g) was added portionwise to chlorosulfonic acid (5 mL), while stirring and cooling in an ice bath. On completion of the addition, the ice bath was removed and the mixture was allowed to come to room temperature then heated to 70° C. for 3 hours. After cooling, the mixture was slowly added to ice and the resultant suspension was extracted with ethyl acetate, washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness to give 4-fluoro-2-(trifluoroacetylaminomethyl)benzenesulfonyl chloride (1.53 g) as a brown solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C(O[C:10]([N:12]1[CH2:17][CH2:16][C@H:15]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[C@H:14]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:13]1)=O)C.[C:32]([OH:39])(=[O:38])/[CH:33]=[CH:34]/[C:35]([OH:37])=[O:36].C(O)C>O1CCCC1.CCOCC>[C:32]([OH:39])(=[O:38])/[CH:33]=[CH:34]/[C:35]([OH:37])=[O:36].[CH3:10][N:12]1[CH2:17][CH2:16][C@H:15]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[C@H:14]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:13]1
Reactant: CCOC(=O)N1CC[C@H](Oc2ccccc2C)[C@H](c2ccccc2)C1
Agent: O=C(O)/C=C/C(=O)O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCOCC
Product: Cc1ccccc1O[C@H]1CCN(C)C[C@H]1c1ccccc1
Reaction time: 1.17 h

Procedure:
To a stirred suspension of 1.49 g of lithium aluminum hydride in 80 ml of anhydrous tetrahydrofuran is added, under nitrogen, a solution of 4.84 g of cis-1-ethoxycarbonyl-3-phenyl-4-(2-tolyloxy)piperidine. After 70 minutes at room temperature, the mixture is cooled, 80 ml of ether is added and the excess hydride is destroyed by the continuous addition of saturated sodium sulfate solution of 0°-10° C. until a flocculent white precipitate forms. The solid is filtered, washed with ether and the filtrate is concentrated in vacuo. The residue is partitioned between ether (200 ml) and water (100 ml). The ether phase is washed with saturated sodium chloride solution (100 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford a light yellow oil. The oil is dissolved in ether (50 ml) and treated with a solution of 1.77 g of fumaric acid in a mixture of ether (160 ml) and absolute ethanol (25 ml). After stirring overnight, the precipitate is filtered, washed with ether and dried to afford a colorless solid. Recrystallization from 90 ml of isopropanol affords product as a colorless solid, mp 169.5°-170.5° C. dec.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:21])[CH2:13][CH2:12][N:11]([C:14]3[N:19]=[CH:18][NH:17][C:16](=[O:20])[N:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.OC1(C2C=CC=CC=2)CCN(C2N=CNC(=O)N=2)CC1.CC1C=CC(S(O[CH2:53][C:54]2[S:55][C:56]([C:59]([F:62])([F:61])[F:60])=[CH:57][CH:58]=2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:21])[CH2:13][CH2:12][N:11]([C:14]3[N:19]=[CH:18][N:17]([CH2:53][C:54]4[S:55][C:56]([C:59]([F:62])([F:61])[F:60])=[CH:57][CH:58]=4)[C:16](=[O:20])[N:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCc2ccc(C(F)(F)F)s2)cc1
Reactant: O=c1nc(N2CCC(O)(c3ccc(Cl)cc3)CC2)nc[nH]1
Agent: O=C([O-])[O-]
Agent: O=c1nc(N2CCC(O)(c3ccccc3)CC2)nc[nH]1
Agent: [K+]
Product: O=c1nc(N2CCC(O)(c3ccc(Cl)cc3)CC2)ncn1Cc1ccc(C(F)(F)F)s1

Procedure:
A mixture (100 mg) of 4-[4-(4-Chlorophenyl)-4-hydroxypiperidin-1-yl]-1,3,5-triazin-2(1H)-one synthesized in Reference Synthesis Example 22a and 4-(4-hydroxy-4-phenylpiperidin-1-yl)-1,3,5-triazin-2(1H)-one, [5-(trifluoromethyl)thiophen-2-yl]methyl 4-methylbenzenesulfonate (558 mg, 0.65 mmol) synthesized in Reference Synthesis Example 51, and potassium carbonate (180 mg, 1.30 mmol) were used to obtain a mixture of compounds in Reference Synthesis Examples 92a and 92b being the title compounds (21 mg) by synthesis in a similar manner to Reference Synthesis Example 91.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:22][C:23]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:24]=1[C:25]([NH2:27])=[O:26]>>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][C:23]2[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:24]=2[C:25]([NH2:27])=[O:26])[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)nc(Cl)nc32)cc1
Reactant: COc1ccc(C(N)=O)c(N)c1
Product: COc1ccc(C(N)=O)c(Nc2nc(Cl)nc3c2ccn3S(=O)(=O)c2ccc(C)cc2)c1
Yield: 29 %

Procedure:
Using General Protocol II and starting with 2,4-dichloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine (4.0 g, 11.7 mmol) and 2-amino-4-(methyloxy)benzamide (4.5 g, 26.8 mmol), 2-({2-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-4-(methyloxy)benzamide was isolated as a yellow solid (0.1.58 g, 29% yield); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.33 (s, 3 H), 4.28 (s, 3 H), 6.62 (t, J=3.48 Hz, 1 H), 6.68 (ddd, J=6.00, 2.88, 2.66 Hz, 1 H), 7.41-7.46 (m, 2 H), 7.64 (s, 1 H), 7.74 (t, J=3.48 Hz, 1 H), 7.81-7.87 (m, 1 H), 7.92-7.98 (m, 2 H), 8.22 (s, 1 H), 8.32 (t, J=2.66 Hz, 1 H), 13.13 (s, 1 H).
Reaction SMILES: C(CCC[NH:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([Br:16])[CH:10]=1)=O)#N.[Si]([N:21]=[N+:22]=[N-:23])(C)(C)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O.[OH-].[Na+]>C1COCC1>[Br:16][C:11]1[CH:10]=[C:9]([C:7]2[NH:6][N:23]=[N:22][N:21]=2)[CH:14]=[CH:13][C:12]=1[CH3:15]
Reactant: Cc1ccc(C(=O)NCCCC#N)cc1Br
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc(-c2nnn[nH]2)cc1Br
Reaction time: 24 h

Procedure:
A solution of 1.0 mmol of this amide, 4.0 mmol of TMSN3, 4.0 mmol of PPh3, and 4.0 mmol of DEAD in 4 mL of THF at 0° C. was stirred 24 h and then concentrated. The residue was mixed with 5 mL of THF and 12.0 mmol of 1N NaOH. After stirring for 24 h and processing by extraction, 5-(3'-bromo-4'-methylphenyl)tetrazole was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Br:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[Cl:16])[C:3]=1[CH3:17].[Br:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>ClCCCl>[Br:1][C:2]1[CH:7]=[C:6]([Br:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[Cl:16])[C:3]=1[CH2:17][Br:18]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(Br)cc(Br)nc1-c1ccc(F)cc1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCCl
Product: Fc1ccc(-c2nc(Br)cc(Br)c2CBr)c(Cl)c1
Temperature: 0 °C

Procedure:
To a solution of 4,6-dibromo-2-(2-chloro-4-fluorophenyl)-3-methylpyridine (3.55 g, 9.35 mmol, 1 eq) in 1,2-dichloroethane (90 mL) was added N-bromosuccinimide (2.0 g, 11.22 mmol, 1.2 eq) and benzoyl peroxide (226 mg, 0.9 mmol, 0.1 eq). The resulting mixture was degassed with argon then warmed to and maintained at reflux for 5.5 h. The mixture was cooled solvent was removed under reduced pressure, and the material was purified by flash column chromatography eluting with 2% Et2O in hexanes. The material was re-dissolved in CCl4 and N-bromosuccinimide (667 mg) and benzoyl peroxide (75 mg) were added. The mixture was brought to and maintained at reflux for 6.5 h. The mixture was cooled to 0° C., filtered to remove the succinimide, and concentrated under reduced pressure. The product was purified by flash column chromatography on silica gel eluting with 2% Et2O in hexanes to give 4,6-dibromo-3-(bromomethyl)-2-(2-chloro-4-fluorophenyl)pyridine. Mass spectrum (ESI) 456.1 (M+1); 458.0 (M+3); 460.1 (M+5); 462.1 (M+7). 1H NMR (500 MHz, CDCl3) δCHCl3: 7.85 (1H, s); 7.46 (1H, dd, J=8.5 Hz, J=5.7 Hz); 7.27 (1H, dd, J=8.5 Hz, J=2.5 Hz); 7.16 (1H, ddd, J=8.5 Hz, J=8.3 Hz, J=2.5 Hz); 4.55 (1H, ½ ABq, J=10.8 Hz); 4.17 (1H, ½ ABq, J=10.8 Hz,
Reaction SMILES: [OH:1][C:2]1[C:10]([CH2:11][CH2:12][CH3:13])=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[C:21]#[CH:22]>CC(C)=O.C1(C)C=CC=CC=1>[CH2:22]([O:1][C:2]1[C:10]([CH2:11][CH2:12][CH3:13])=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[CH:3]=1)[C:21]#[CH:20]
Reactant: CCCc1cc2c(cc1O)OCO2
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: C#CCOc1cc2c(cc1CCC)OCO2

Procedure:
Following the same procedure as in Example 3 a) and b), but using 7.2 g (0.04 moles) of 5-hydroxy-6-propyl-benzo[1.3]dioxole, 5.92 g (0.04 moles) of anhydrous potassium carbonate in 40 ml of acetone were reacted with 5.95 g (0.04 moles) of a solution of propargyl bromide in toluene, (80% w/w).
Reaction SMILES: [C:1]([NH:4][C:5]1[NH:6][C:7](=[O:33])[C:8]2[S:13][C:12](=[O:14])[N:11]([C@@H:15]3[O:27][C@H:26]([CH2:28][O:29][C:30](=[O:32])[CH3:31])[C@@H:21]([O:22][C:23](=[O:25])[CH3:24])[C@H:16]3[O:17][C:18](=[O:20])[CH3:19])[C:9]=2[N:10]=1)(=[O:3])[CH3:2].[CH:34]([C:37]1[CH:42]=[C:41]([CH:43]([CH3:45])[CH3:44])[CH:40]=[C:39]([CH:46]([CH3:48])[CH3:47])[C:38]=1[S:49](Cl)(=[O:51])=[O:50])([CH3:36])[CH3:35]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([NH:4][C:5]1[N:6]=[C:7]([O:33][S:49]([C:38]2[C:39]([CH:46]([CH3:47])[CH3:48])=[CH:40][C:41]([CH:43]([CH3:45])[CH3:44])=[CH:42][C:37]=2[CH:34]([CH3:36])[CH3:35])(=[O:51])=[O:50])[C:8]2[S:13][C:12](=[O:14])[N:11]([C@@H:15]3[O:27][C@H:26]([CH2:28][O:29][C:30](=[O:32])[CH3:31])[C@@H:21]([O:22][C:23](=[O:25])[CH3:24])[C@H:16]3[O:17][C:18](=[O:20])[CH3:19])[C:9]=2[N:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc2c(sc(=O)n2[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]2OC(C)=O)c(=O)[nH]1
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)Cl)c(C(C)C)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1nc(OS(=O)(=O)c2c(C(C)C)cc(C(C)C)cc2C(C)C)c2sc(=O)n([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]3OC(C)=O)c2n1
Reaction time: 1 h
Yield: 92 %

Procedure:
The intermediate from Step 1 above (500 mg, 0.98 mmol) was dissolved in DCM (15 mL) at ambient temperature. DMAP (7.3 mg, 0.06 mmol), and TEA (16 ml, 11 mmol) were added to the solution, followed by 2,4,6-triisopropylbenzenesulfonyl chloride (454 mg, 1.5 mmol). After 1 h the reaction had gone to completion, the crude mixture was concentrated, and then purified by flash chromatography (SiO2, 10% EtOAc—CHCl3), affording 690 mg (92%) of 5-acetylamino-7-(2,4,6-triisopropyl-benzenesulfonyloxy)-3-(2′,3′,5′-tri-O-acetyl-β-D-ribofuranosyl)thiazolo[4,5-d ]pyrimidin-2-one as a foaming white solid 17: 74.5-76.3° C.; Rf=0.7 (SiO2, 20% EtOAc—CHCl3); 1H (400 MHz, d6-DMSO) δ 10.83 (s, 1H), 7.39 (s, 2H), 6.03 (d, J=4.0, 1H), 5.91-5.96 (m, 1H), 5.69 (t, J=6.4, 1H), 4.30-4.70 (m, 1H), 4.22-4.26 (m, 1H), 4.16-4.20 (m, 1H), 3.90-4.00 (m, 2H), 2.97-3.01 (m, 1H), 2.07 (s, 3H), (s, 3H), 2.04 (s, 3H), 1.88 (s, 3H), 1.17-1.25 (m, 18H).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([C@@H:18]3[CH2:20][C@H:19]3[CH2:21][OH:22])[CH:9]=2)[N:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([C@@H:18]3[CH2:20][C@H:19]3[CH:21]=[O:22])[CH:9]=2)[N:3]=1
Reactant: Cc1nc(C)n(-c2cc([C@@H]3C[C@H]3CO)nc(C(F)(F)F)n2)n1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: Cc1nc(C)n(-c2cc([C@@H]3C[C@H]3C=O)nc(C(F)(F)F)n2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of trans-(2-(6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)cyclopropyl)methanol (16-5, 409 mg, 1.30 mmol, 1.0 eq.) in anhydrous DCM (10.0 mL) at 0° C. was added Dess-Martin periodinane (610 mg, 1.44 mmol, 1.1 eq.). The resulting mixture was stirred for 2 hours at room temperature under an atmosphere of nitrogen gas. The mixture was then quenched with saturated aqueous NaHCO3 solution (10 mL) and 10% aqueous Na2S2O3 solution (10 mL) and vigorously stirred at room temperature for 1 hour until it formed a clear two phase solution. The separated aqueous layer was extracted with DCM (2×50 mL). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. The resulting residue was purified by silica gel column chromatography (0-50% ethyl acetate in hexanes) to give trans-2-(6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)cyclopropanecarbaldehyde (16-6) as an off-white solid. 1H NMR (300 MHz, CDCl3) δ 9.55 (d, 1H, J=3.6 Hz), 7.99 (s, 1H), 2.92 (s, 3H), 2.86-2.73 (m, 2H), 2.43 (s, 3H), 1.97 (ddd, 1H, J=9.9, 5.7, 4.2 Hz), 1.85 (ddd, 1H, J=9.9, 5.7, 4.2 Hz). LRMS m/z (M+H) 312 found, 312 required.
Reaction SMILES: [CH:1]([N:4]=[C:5]=[O:6])([CH3:3])[CH3:2].[Cl:7][C:8]1[C:9]([C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([Cl:20])[CH:14]=2)=[N:10][NH:11][CH:12]=1.C(N(CC)CC)C.O>CN(C=O)C>[CH:1]([NH:4][C:5]([N:11]1[CH:12]=[C:8]([Cl:7])[C:9]([C:13]2[CH:14]=[C:15]([Cl:20])[CH:16]=[C:17]([Cl:19])[CH:18]=2)=[N:10]1)=[O:6])([CH3:3])[CH3:2]
Reactant: Clc1cc(Cl)cc(-c2n[nH]cc2Cl)c1
Reactant: CC(C)N=C=O
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)NC(=O)n1cc(Cl)c(-c2cc(Cl)cc(Cl)c2)n1
Reaction time: 2 h
Yield: 63.1 %

Procedure:
0.95 g (0.011 mol) of isopropyl isocyanate are added, dropwise and at 0° C., to a solution of 2.55 g (0.01 mol) of 4-chloro-3-(3,5-dichlorophenyl)-1H-pyrazole and 1.55 ml (0.011 mol) of triethylamine in 20 ml of anhydrous DMF. Stirring is continued for 2 h at room temperature. The reaction mixture is poured into 100 ml of water and extracted with ethyl acetate. After drying the organic phase and concentration under vacuum, the residue is triturated with 50 ml of heptane, filtered and dried. We obtain 2.10 g of 1-isopropylaminocarbonyl-4-chloro-3-(3,5-dichlorophenyl)pyrazole, melting at 127° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C@H:2]1[CH2:7][OH:8].Cl[C:10]([O:12][CH3:13])=[O:11].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[OH:8][CH2:7][C@H:2]1[NH:1][CH2:6][CH2:5][N:4]([C:10]([O:12][CH3:13])=[O:11])[CH2:3]1
Reactant: OC[C@@H]1CNCCN1
Reactant: COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)N1CCN[C@H](CO)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.4 %

Procedure:
A solution of the product of stage (ii) (0.080 g) in dry acetonitrile (10 ml) was treated with a solution of methyl chloroformate (71 mg; 0.75 mmol) in dry acetonitrile (3 ml) over a 5 min period. The mixture was stirred at ambient temperature for 30 min and aqueous sodium carbonate solution (1 ml) was added. The solvent was removed in vacuo and the aqueous residue was extracted with dichloromethane (3×25 ml) and chloroform (3×25 ml). The extract was washed with aqueous sodium carbonate solution (5 ml: 1M), and the combined extracts were dried and evaporated in vacuo to give the title compound as an oil (0.1 g).
Reaction SMILES: [OH:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([CH3:12])[C:6]=2[CH:5]=[C:4]([C:13]([N:15]([CH3:17])[CH3:16])=[O:14])[CH:3]=1.Cl[CH:19]1[C:28]2[C:23](=[CH:24][C:25]([F:29])=[CH:26][CH:27]=2)[O:22][CH2:21][CH2:20]1>>[F:29][C:25]1[CH:24]=[C:23]2[C:28]([CH:19]([O:1][C:2]3[C:10]4[N:9]=[C:8]([CH3:11])[N:7]([CH3:12])[C:6]=4[CH:5]=[C:4]([C:13]([N:15]([CH3:16])[CH3:17])=[O:14])[CH:3]=3)[CH2:20][CH2:21][O:22]2)=[CH:27][CH:26]=1
Reactant: Cc1nc2c(O)cc(C(=O)N(C)C)cc2n1C
Reactant: Fc1ccc2c(c1)OCCC2Cl
Product: Cc1nc2c(OC3CCOc4cc(F)ccc43)cc(C(=O)N(C)C)cc2n1C
Yield: 45 %

Procedure:
The title compound was prepared as a white solid in 45% yield (0.96 g) from 4-hydroxy-N,N,1,2-tetramethyl-1H-benzimidazole-6-carboxamide (1.3 g, 5.5 mmol, WO 2004054984) and 4-chloro-7-fluorochromane (2.0 g, 11 mmol, STEP 2) by the same manner in STEP 1 of Example 1:
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:18])[CH2:13][CH2:14][C:15]([OH:17])=O)=[CH:8][CH:7]=1)(=[O:4])=[O:3].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[CH2:44]([NH:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[CH3:45]>CN(C=O)C>[CH2:44]([N:46]([CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[C:15](=[O:17])[CH2:14][CH2:13][C:12](=[O:18])[C:9]1[CH:8]=[CH:7][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:11][CH:10]=1)[CH3:45]
Reactant: CCCCCCCNCC
Reactant: CS(=O)(=O)Nc1ccc(C(=O)CCC(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCCCCCCN(CC)C(=O)CCC(=O)c1ccc(NS(C)(=O)=O)cc1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
A stirred solution of 4-[(methylsulfonyl)amino]-γ-oxobenzenebutanoic acid as prepared in Preparation 2 (12.0 g, 0.044 mol) in DMF (100 ml) under N2 is cooled in an ice bath to 5° C. and treated with 1-hydroxybenzotriazole (5.94 g, 0.044 mol) and N,N'-dicyclohexylcarbodiimide (9.08 g, 0.044 mol). After 1 hour, ethylheptylamine (6.3 g, 0.044 mol) is added; after an additional 30 minutes the ice bath is removed and the mixture is kept at ambient temperature for 18 hours. The reaction mixture is filtered over a Celite filter aid and the filtrate is concentrated under vacuum. The resulting material is dissolved in CH2Cl2 ; washed with dilute HCl, NaHCO3 and brine; dried (Na2SO4) and concentrated. The residue is chromatographed over silica gel (1.25 kg) with 5% MeOH:1% NH4OH:CH2Cl2. The N-ethyl-N-heptyl-γ-oxo-4-[(methylsulfonyl)amino]benzenebutanamide thus obtained is crystallized from EtOAc:SSB to yield 10.77 g, mp 100°-102° C. and 2.32 g, mp 99°-101° C. The analytical sample has a mp 102°-103° C.
Reaction SMILES: C([O:3][C:4](=[O:48])[CH2:5][CH:6]([O:8][C:9]1[C:14]([CH2:15][CH2:16][CH:17]([C:38](=[O:40])[CH3:39])[CH2:18][CH:19]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]2[CH:37]=[CH:36][C:31]3[O:32][CH2:33][CH2:34][O:35][C:30]=3[CH:29]=2)[CH3:20])=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:41][CH2:42][C:43]([O:45]CC)=[O:44])[CH3:7])C>[OH-].[Na+]>[C:38]([CH:17]([CH2:18][CH:19]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[CH:37]=[CH:36][C:31]2[O:32][CH2:33][CH2:34][O:35][C:30]=2[CH:29]=1)[CH3:20])[CH2:16][CH2:15][C:14]1[C:9]([O:8][CH:6]([CH3:7])[CH2:5][C:4]([OH:48])=[O:3])=[C:10]([CH2:41][CH2:42][C:43]([OH:45])=[O:44])[CH:11]=[CH:12][CH:13]=1)(=[O:40])[CH3:39]
Reactant: CCOC(=O)CCc1cccc(CCC(CC(C)Oc2ccccc2-c2ccc3c(c2)OCCO3)C(C)=O)c1OC(C)CC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)C(CCc1cccc(CCC(=O)O)c1OC(C)CC(=O)O)CC(C)Oc1ccccc1-c1ccc2c(c1)OCCO2
Yield: 66.1 %

Procedure:
A similar procedure as described in Example 43, step 5 was used, starting from 4-[3-[6-(3-acetyl-5-(2,3-dihydro-benzo[1,4]-dioxin-6-yl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (330 mg, 0.5 mmol) and 1.0 N aqueous sodium hydroxide (10 mL) to afford 4-[3-[6-(3-acetyl-5-(2,3-dihydro-benzo[1,4]dioxin-6-yl-phenoxy)-hexyl]-2-(2-carboxy-ethyl)-phenoxy]-butyric acid (200 mg, 61%) as a off-white solid: ES(+)-HRMS m/e calcd for C35H40O9 (M+Na)+ 627.2564. found 627.2560.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][CH2:34][O:35][CH3:36])=[N:11][C:12]([N:16]2C(C)=CC=C2C)=[CH:13][C:14]=1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.NO.[OH-].[K+].O>C(O)C.O>[CH2:1]([O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([NH2:16])=[N:11][C:10]=1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][CH2:34][O:35][CH3:36])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCOCCCCCCCCCCc1nc(-n2c(C)ccc2C)cc(C)c1OCc1ccccc1
Agent: Cl
Agent: NO
Agent: [K+]
Solvent: O
Solvent: CCO
Product: COCOCCCCCCCCCCc1nc(N)cc(C)c1OCc1ccccc1

Procedure:
To stirred solution containing 240 mg (0.49 mmol) of 3-(benzyloxy)-6-(2,5-dimethyl-1H-pyrrol-1-yl)-2-(10-(methoxymethoxy)decyl)-4-methylpyridine in 10 mL of 9:1 ethanol-water were added 338 mg (4.87 mmol) of hydroxylamine hydrochloride followed by 273 mg (4.87 mmol) of potassium hydroxide. The reaction mixture was then stirred at reflux 6 h. then a second portion of 338 mg (4.87 mmol) of hydroxylamine hydrochloride followed by 273 mg (4.87 mmol) of potassium hydroxide was added and the mixture was stirred at reflux 16 h. The reaction mixture was then poured into 50 mL of water and extracted with two 50-mL portions of dichloromethane. The combined organic layer was washed with a 60-mL portion of brine, dried (MgSO4) and then concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column (10×3 cm). Elution with 9:1 dichloromethane-methanol afforded the expected product as a yellowish oil: yield 113 mg (56%); silica gel TLC Rf 0.45 (9:1 dichloromethane-methanol); 1H NMR (CDCl3) δ 1.24-1.31 (br m, 12H), 1.63-1.53 (m, 4H), 2.16 (s, 3H), 2.62 (dd, 2H, J=8.0, 8.0 Hz), 3.28 (s, 3H), 3.48 (t, 2H, J=6.8 Hz), 4.59 (s, 2H), 4.71 (s, 2H), 5.24 (br s, 2H), 6.16 (s, 1H) and 7.31-7.43 (m, 5H); 13C NMR (CDCl3) δ 16.73, 29.19, 29.40, 29.46, 29.46, 29.48, 29.56, 29.72, 29.84, 32.24, 53.41, 67.85, 75.43, 96.34, 108.08, 127.73, 128.00, 128.00, 128.50, 128.50, 137.41, 142.46, 144.91, 153.46 and 154.13; mass spectrum (APCI), m/z 415.2957 (M+H)+ (C25H39N2O3 requires 415.2961).
Reaction SMILES: NCCC(O)=O.[Br:7][C:8]1[N:13]=[C:12]([CH:14]=O)[CH:11]=[CH:10][CH:9]=1.[C:16]([CH2:18][C:19]([NH:21][CH:22]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][O:34][CH3:35])=[CH:28][CH:27]=1)[CH2:23][CH2:24][CH3:25])=[O:20])#[N:17]>C(O)C.O.CCOC(C)=O.CCCCCC>[Br:7][C:8]1[N:13]=[C:12](/[CH:14]=[C:18](\[C:16]#[N:17])/[C:19]([NH:21][CH:22]([C:26]2[CH:27]=[CH:28][C:29]([O:32][CH2:33][O:34][CH3:35])=[CH:30][CH:31]=2)[CH2:23][CH2:24][CH3:25])=[O:20])[CH:11]=[CH:10][CH:9]=1
Reactant: CCCC(NC(=O)CC#N)c1ccc(OCOC)cc1
Reactant: O=Cc1cccc(Br)n1
Agent: NCCC(=O)O
Solvent: CCCCCC
Solvent: CCO
Solvent: O
Product: CCCC(NC(=O)/C(C#N)=C/c1cccc(Br)n1)c1ccc(OCOC)cc1
Yield: 186.8 %

Procedure:
β-Alanine (1.42 g, 16 mmol) and 6-bromopyridine-2-carboxaldehyde (744 mg, 4 mmol) were added successively to a stirred solution of 2-cyano-N-(1-(4-(methoxymethoxy)phenyl)butyl)acetamide (276 mg, 1.0 mmol) in ethanol/water (28 mL/17 mL) at room temp. After 72 hours TLC (in 25% EtOAc/Hexane) showed a single product and some starting materials. The mixture was partitioned between aqueous sodium bicarbonate and ethyl acetate. The separated organic layer was washed with sat. brine and dried with sodium sulfate and concentrated to give a light amber oil (830 mg) as crude product. The crude material was purified by flash chromatography to afford the title compound as a yellow oil (253 mg) in 57% yield. 1H NMR (500 MHz, CDCl3) δ 7.59 (dd, J=7.9, 7.5 Hz, 1H), 7.52 (d, J=8.0 Hz, 1H), 7.27 (d, J=8.6 Hz, 2H), 7.22 (d, J=7.4 Hz, 1H), 6.96 (d, J=8.6 Hz, 2H), 6.82 (s, 1H), 5.19 (s, 2H), 3.85 (t, J=7.6 Hz, 1H), 3.49 (s, 3H), 1.67 (m, 2H), 1.39 (m, 2H), 0.94 (t, J=7.3 Hz, 3H); Mass spec ES+; m/z=444.0 (m+1) and 466.0 (m+Na+).
Reaction SMILES: [NH2:1][C:2](=[S:14])[CH2:3][N:4]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[N:5]1.Br[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)=O>C(O)C>[N+:25]([C:22]1[CH:23]=[CH:24][C:19]([C:17]2[N:1]=[C:2]([CH2:3][N:4]3[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[N:5]3)[S:14][CH:16]=2)=[CH:20][CH:21]=1)([O-:27])=[O:26]
Reactant: CCOC(=O)c1cnn(CC(N)=S)c1
Reactant: O=C(CBr)c1ccc([N+](=O)[O-])cc1
Solvent: CCO
Product: CCOC(=O)c1cnn(Cc2nc(-c3ccc([N+](=O)[O-])cc3)cs2)c1
Temperature: 25 °C
Yield: 89.1 %

Procedure:
A solution (8 mL) of the compound (1.0 g, 4.7 mmol) obtained in Example 1b and 2-bromo-1-(4-nitrophenyl)ethanone (1.4 g, 5.6 mmol) in ethanol was heated under reflux overnight, and cooled to room temperature. The solvent was evaporated under reduced pressure, and the resulting crude title compound was recrystallized (ethyl acetate-hexane) to give the title compound (1.5 g, 89%) as colorless crystals.