Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([C:17]3[CH:18]=[C:19]([N:23]4[CH2:28][CH2:27][CH:26]([C:29]([OH:31])=O)[CH2:25][CH2:24]4)[CH:20]=[CH:21][CH:22]=3)(=[O:16])=[O:15])[C@H:10]([CH3:32])[CH2:9]2)=[C:4]([C:33]([F:36])([F:35])[F:34])[CH:3]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)[N:55]([CH3:57])[CH3:56])C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([C:17]3[CH:18]=[C:19]([N:23]4[CH2:24][CH2:25][CH:26]([C:29]([N:55]([CH3:57])[CH3:56])=[O:31])[CH2:27][CH2:28]4)[CH:20]=[CH:21][CH:22]=3)(=[O:16])=[O:15])[C@H:10]([CH3:32])[CH2:9]2)=[C:4]([C:33]([F:34])([F:36])[F:35])[CH:3]=1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1cccc(N2CCC(C(=O)O)CC2)c1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1cccc(N2CCC(C(=O)N(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-[3-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-yl}sulfonyl)phenyl]piperidine-4-carboxylic acid (200 mg, 0.38 mmol) in DMF (4.0 mL) was added BOP (202 mg, 0.46 mmol), DIPEA (0.33 mL, 1.9 mmol), and finally N′N-dimethylamine (0.6 mL, 1.1 mmol). The reaction was allowed to stir at ambient temperature over a 16 hour period, after which it was judged complete by LCMS. The reaction mixture was diluted with EtOAc (50 mL), and washed with saturated NaHCO3(aq) (3×25 mL). The organic layer was dried over Na2SO4, decanted, and concentrated in vacuo. The resultant crude oil was purified on a normal phase SiO2 column (20%-80% EtOAc/Hexanes) affording the desired amide in >95% purity. HRMS: calcd for C26H32F4N4O3S+H+, 557.22040. found ([M+H]+), 557.22195.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][CH:4]([C:7]([O:9]C)=[O:8])[CH:3]1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1.[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[H-].[Na+]>CN(C=O)C.CCOCC>[CH2:18]([O:1][CH:2]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH:3]1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)C1CCC(O)C1c1ccc(F)cc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C(O)C1CCC(OCc2ccccc2)C1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 106.1 %

Procedure:
To a solution of 10.0 gm of methyl 3-(SR)-(hydroxy)-2-(RS)-(4-fluorophenyl)cyclopentane-1-(RS)-carboxylate prepared as in Example 32 (lower isomer) and 10.8 gm of benzyl bromide in 50 mL of DMF was added in portions over 30 min 2.0 gm of 60% NaH in mineral oil. The reaction was stirred for 2 h at room temperature and was then diluted with ether and quenched by slow addition to water containing 25 mL of 2N HCl. The mixture was extracted twice with ether and the organic layers were washed with a portion of brine, combined, dried over sodium sulfate and evaporated. By T.l.c. and NMR the crude product consisted of a mixture of desired benzylated starting material and dimer derived from transesterification. The crude product was taken up in 100 mL of methanol and 45 mL of 5N NaOH was added. The mixture was stirred at room temperature for 40 h residue was diluted with waste. The residue was diluted with water and extracted twice with ether and the ether layers washed with dilute NaOH. The combined aqueous layers were acidified with HCl (c) and extracted twice with ethyl acetate. The organic layers were washed with a portion of brine, combined, dried over sodium sulfate and evaporated to give 14 gm of title compound contaminated with some 3-(SR)-(hydroxy)-2-(RS)-(4-fluorophenyl)cyclopentane-1-(RS)-carboxylic acid. This could be further purified by flash chromatography eluting with 20% ethyl acetate in hexanes followed by 1% HOAc/20% ethyl acetate in hexanes. T.l.c. (1% HOAc/20% ethyl acetate in hexanes) Rf =0.4.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:5]=[C:6]([CH3:9])[S:7][CH:8]=1.[C-:10]#[N:11].[K+].O>C(=O)(O)[O-].[Na+].CCOC(C)=O>[C:10]([CH2:3][C:4]1[N:5]=[C:6]([CH3:9])[S:7][CH:8]=1)#[N:11]
Reactant: [C-]#N
Reactant: Cc1nc(CCl)cs1
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nc(CC#N)cs1
Temperature: 25 °C
Yield: 24.1 %

Procedure:
4-Chloromethyl-2-methyl thiazole hydrochloride (1 g, 5.4 mmol) was taken up in sodium bicarbonate saturated aqueous solution and extracted with EtOAc, dried (MgSO4), and concentrated in vacuo. The residue was dissolved in 95% ethanol (50 mL) and potassium cyanide (353 mg, 5.4 mmol) followed by water (5 mL) were added to the reaction mixture. The mixture was refluxed for 18 hours and cooled to room temperature. The reaction mixture was taken up in EtOAc and washed with water, dried (MgSO4), and concentrated in vacuo. The residue was purified on silica with a gradient of heptane to 1:1 heptane/EtOAc to give 4-cyanomethyl-2-methyl thiazole (180 mg, 24%).
Reaction SMILES: [CH:1]1([N:7]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[C:8](=[O:23])[NH:9][C:10]2[S:11][C:12]([S:15]([NH:18][CH2:19][C:20]([OH:22])=[O:21])(=[O:17])=[O:16])=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:30]1(NC2CCCCC2)CCCCC1.COC(=O)CN(S(C1SC(N)=NC=1)(=O)=O)C>>[CH:24]1([N:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:8](=[O:23])[NH:9][C:10]2[S:11][C:12]([S:15]([N:18]([CH2:19][C:20]([OH:22])=[O:21])[CH3:30])(=[O:16])=[O:17])=[CH:13][N:14]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C(O)CNS(=O)(=O)c1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Reactant: C1CCC(NC2CCCCC2)CC1
Agent: COC(=O)CN(C)S(=O)(=O)c1cnc(N)s1
Product: CN(CC(=O)O)S(=O)(=O)c1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1

Procedure:
Prepared in a similar manner to [2-(3,3-dicyclohexyl-ureido)-thiazole-5-sulfonylamino]-acetic acid via dicyclohexylamine and [(2-amino-thiazole-5-sulfonyl)-methyl-amino]-acetic acid methyl ester to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[O:33][C:32]([C:34](O)=[O:35])=[CH:31][CH:30]=2)=[CH:25][CH:24]=1>C1COCC1>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[O:33][C:32]([C:34]([NH:1][C:2]3[CH:7]=[C:6]([C:8]4[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]5[CH2:20][CH2:19]5)=[O:15])=[CH:10][CH:9]=4)[C:5]([CH3:21])=[CH:4][CH:3]=3)=[O:35])=[CH:31][CH:30]=2)=[CH:25][CH:24]=1
Reactant: O=C(O)c1ccc(-c2ccc(Cl)cc2)o1
Reactant: Cc1ccc(N)cc1-c1ccc(C(=O)NCC2CC2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)c2ccc(-c3ccc(Cl)cc3)o2)cc1-c1ccc(C(=O)NCC2CC2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 10.9 %

Procedure:
5′-Amino-N-(cyclopropylmethyl)-2′-methyl-1,1′-biphenyl-4-carboxamide (53 mg, 0.189 mmol) and 5-(4-chlorophenyl)-2-furoic acid (84.2 mg, 0.378 mmol) were mixed in THF (5 ml) and the mixture shaken in a varian tube for 15 min at room temperature. Carbodiimde resin (500 mg) was added and shaking continued for 18 h. The solution was filtered off and concentrated under vacuum. The residue was dissolved in methanol, filtered through an SCX SPE and the solvent evaporated under vacuum to give 5-(4-chlorophenyl)-N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-2- furamide (10 mg, 11%). NMR; δH CDCl3 8.07,(1H, b), 7.85,(2H, d), 7.69-7.65,(3H, m), 7.52,(1H, d), 7.44-7.41,(4H, m), 7.31-7.29,(2H, m), 6.98,(1H, b), 6.79,(1H, d), 3.36,(2H, m), 2.25,(3H, s), 1.10,(1H, m), 0.60,(2H, m), 0.31,(2H, m). LCMS: retention time 3.92 min, MH+485.
Reaction SMILES: [OH:1][CH:2]1[C:6](=[CH2:7])[CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[H-].[Na+].[CH3:17]I>C1COCC1>[CH3:17][O:1][CH:2]1[C:6](=[CH2:7])[CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1
Reactant: C=C1CN(C(=O)OC(C)(C)C)CC1O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=C1CN(C(=O)OC(C)(C)C)CC1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
A solution of tert-butyl 3-hydroxy-4-methylenepyrrolidine-1-carboxylate (0.257 g, 1.29 mmol; prepared as described by Alcaraz, Lilian; Cridland, Andrew; Kinchin, Elizabeth Organic Letters, 2001, vol. 3, #25 p. 4051-4054) in 8 mL of THF, stirred at r.t. under a nitrogen atmosphere was added NaH. After 0.5 h stirring at r.t., methyl iodide (0.057 g, 1.42 mmol) was added and the resulting mixture stirred at r.t. for 2 h. After overnight resting, the reaction was quenched with water, extracted with EtOAc which was washed with brine, dried over Na2SO4 and evaporated to dryness affording a crude, purified by means of automated flash chromatography (SP01®TM-Biotage; gradient Petroleum Ether-EtOAc from 9:1 to 7:3) giving 165 mg of the title compound. Yield: 60%.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=3[O:20][CH3:21])[C:14](O)=[O:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.S(Cl)([Cl:24])=O>>[C:1]12([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=3[O:20][CH3:21])[C:14]([Cl:24])=[O:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: COc1ccc(C(=O)O)cc1C12CC3CC(CC(C3)C1)C2
Reactant: O=S(Cl)Cl
Product: COc1ccc(C(=O)Cl)cc1C12CC3CC(CC(C3)C1)C2
Yield: 100 %

Procedure:
In a round bottom flask, there are introduced 200 ml of thionyl chloride and there are then added, in small fractions, 35 g (122 mmoles) of the acid obtained in stage (a), above. The reaction mixture is heated to reflux until the emission of gases ceases. The reaction mixture is evaporated to dryness, taken up in 100 ml of anhydrous benzene and again evaporated to dryness, yielding 37 g of the expected product (100% yield) having a melting point of 153°-154° C.
Reaction SMILES: CS(O[CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)(=O)=O.[N:19]1[C:27]2[N:22]3[C:23](=[N:28][CH:29]=[C:21]3[C:20]=1[SH:30])[CH:24]=[CH:25][CH:26]=2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[N:19]1[C:27]2[N:22]3[C:23](=[N:28][CH:29]=[C:21]3[C:20]=1[S:30][CH:6]1[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:10][CH2:11]1)[CH:24]=[CH:25][CH:26]=2
Reactant: Sc1nc2cccc3ncc1n32
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Sc2nc3cccc4ncc2n43)CC1
Temperature: 80 °C
Reaction time: 11 h
Yield: 56 %

Procedure:
To a solution of tert-butyl 4-[(methylsulfonyl)oxy]-1-piperidinecarboxylate (3.5 g, 12.5 mmol) in DMF (60 ml) were added 1,4,7b-triazacyclopenta[cd]inden-2-thiol (3.7 g, 21.3 mmol) and DBU (3.7 ml, 25 mmol), and the mixture was stirred at 80° C. for 11 hours. The reaction mixture was concentrated under reduced pressure, and to the concentrate was added water (200 ml) The mixture was extracted with a mixed solution of THF and ethyl acetate (3/2, 500 ml). The organic layer was washed with saturated aqueous solution of sodium chloride (200 ml), successively, and dried over anhydrous sodium sulfate, concentrated under reduced pressure. The concentrate was subjected to flash column chromatography (silica gel 30 g, ethyl acetate/hexane=1/2 to 1/0), and the desired fraction was concentrated under reduced pressure. To the concentrate was added disopropyl ether and the precipitates were collected by filtration to give the titled compound (2.5 g, 7 mmol) as yellowish powdery crystals.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[C:14]([C:16]([O:18]CC)=[O:17])[CH:13]=[CH:12][C:11]=2[C:21]2[C:26]([O:27][CH3:28])=[CH:25][CH:24]=[CH:23][C:22]=2[O:29][CH3:30])=[CH:6][C:5]=1[O:31][CH2:32][CH2:33][CH2:34][N:35]([CH3:37])[CH3:36].Cl>CCO>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[C:14]([C:16]([OH:18])=[O:17])[CH:13]=[CH:12][C:11]=2[C:21]2[C:26]([O:27][CH3:28])=[CH:25][CH:24]=[CH:23][C:22]=2[O:29][CH3:30])=[CH:6][C:5]=1[O:31][CH2:32][CH2:33][CH2:34][N:35]([CH3:37])[CH3:36]
Reactant: CCOC(=O)c1ccc(-c2c(OC)cccc2OC)c(-c2ccc(Cl)c(OCCCN(C)C)c2)n1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1cccc(OC)c1-c1ccc(C(=O)O)nc1-c1ccc(Cl)c(OCCCN(C)C)c1
Yield: 98.8 %

Procedure:
Add 3.16 g (56.38 mmol) of potassium hydroxide to a solution of 5.63 g (11.28 mmol) of ethyl 6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridine-2-carboxylate in 132 mL of EtOH. Reflux the reaction mixture for 2 h and then concentrate under reduced pressure. Take up the residue obtained in 10 mL of water, then neutralize with 56.5 mL (56.5 mmol) of a 1N HCl aqueous solution. The precipitate obtained is filtered on a frit and rinsed with 2×10 mL of water. After drying under reduced pressure, we obtain 5.25 g of 6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridine-2-carboxylic acid in the form of white powder.
Reaction SMILES: [C:1]1([S:11]([NH2:14])(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:22]([O:24][CH2:25][CH3:26])=[O:23]>CC(=O)CC.O.CCOC(C)=O>[C:1]1([S:11]([NH:14][C:22](=[O:23])[O:24][CH2:25][CH3:26])(=[O:12])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)Cl
Reactant: NS(=O)(=O)c1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)NS(=O)(=O)c1cccc2ccccc12
Yield: 65.8 %

Procedure:
A mixture of 1-naphthalene sulfonamide (769 mg, 3.67 mmol) and potassium carbonate (563 mg, 4.07 mmol) in 2-butanone (9 ml) was heated under reflux for 30 min. Ethyl chloroformate (430 mg, 3.96 mmol) was added dropwise and the resulting solution was heated under reflux for 3 h. The mixture was cooled and diluted with H2O (30 ml) and AcOEt (10 ml). The aqueous layer was collected and adjusted to pH 2 by addition of 1N HCl (aq). Extraction with AcOEt (2×20 ml) and concentration of the dried organic extracts afforded ethyl 1-naphthylsulfonylcarbamate (674 mg, 67%) as a white solid. 1H NMR (DMSO-d6): δ 12.35 (bs, 1H), 8.57 (1H, d, J 8.6), 8.29 (2H, m), 8.11 (1H, d, J 7.7), 7.71 (3H, m), 3.90 (2H, q, J 7.1), 0.99 (3H, t, J 7.1).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][CH2:8][CH2:9][OH:10].C(N(CC)CC)C.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:28][C:18]1[CH:23]=[CH:22][C:21]([S:24]([O:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:2]2[O:3][CH2:4][CH2:5][O:1]2)(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCCCC1OCCO1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCCCC2OCCO2)cc1
Reaction time: 8 h

Procedure:
To a stirred solution of the alcohol of step 4 (0.50 g, 3.4 mmol, 1.0 equiv.) in CH2Cl2 (50 mL) at room temperature was added triethylamine (0.62 mL, 4.4 mmol, 1.3 equiv.) followed by p-toluenesulfonylchloride (TsCl, 0.71 g, 3.7 mmol, 1.1 equiv.) and 4-dimethylaminopyridine (50 mg, 0.4 mmol, 0.1 equiv.). The resulting mixture was stirred at that temperature for 8 h. The mixture was diluted with CH2Cl2 (100 mL) washed with sat. aq. NaHCO3 (100 mL) and brine (2×100 mL), dried (MgSO4), filtered, and concentrated under reduced pressure. While concentrating, the temperature was maintained below 40° C., as the compound had been reported as unstable above this temperature (Wennekes et al. 2008). Due to this instability, the compound was used in the next step crude. 1H NMR (500 MHz, CDCl3) δ=7.79 (d, J=8.3 Hz, 2H), 7.34 (d, J=8.4 Hz, 2H), 4.80 (t, J=4.6 Hz, 1H), 4.03 (t, J=6.5 Hz, 2H), 3.96-3.88 (m, 2H), 3.87-3.78 (m, 2H), 2.45 (s, 3H), 1.75-1.65 (m, 2H), 1.65-1.57 (m, 2H), 1.50-1.41 (m, 2H) ppm; 13C NMR (125 MHz, CDCl3) δ=144.9, 133.5, 130.0, 128.1, 104.4, 70.6, 65.1, 33.3, 29.0, 20.1, 14.4 ppm.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([B:10]([OH:12])[OH:11])=[CH:6][CH:5]=1)([OH:3])=O.C(Cl)(=O)C(Cl)=O.[OH:19][C:20]([CH3:24])([CH3:23])[CH2:21][NH2:22].C(N(CC)CC)C>ClCCl.CN(C)C=O.Cl>[OH:19][C:20]([CH3:24])([CH3:23])[CH2:21][NH:22][C:1]([C:4]1[CH:9]=[CH:8][C:7]([B:10]([OH:12])[OH:11])=[CH:6][CH:5]=1)=[O:3]
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: CC(C)(O)CN
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(O)CNC(=O)c1ccc(B(O)O)cc1
Reaction time: 3 h

Procedure:
4-Carboxyphenylboronic acid (0.5 g, 3.0 mmol) is suspended in dry dichloromethane (8 mL) and oxalylchloride (2 M in dichloromethane, 3.0 mL, 6.0 mmol) is added followed by 2 drops of N,N-dimethylformamide. The mixture is stirred for 3 hours then the solvent removed under vacuum. 2-Hydroxy-2-methylpropylamine (step 1, 800 mg, 9.0 mmol) and triethylamine (2.0 mL, 13.8 mmol) in dichloromethane (12 mL) are added to the residue and the mixture stirred for 30 minutes. The mixture is diluted with 1 M HCl and the phases separated. The aqueous layer is extracted several times with ethyl acetate. The combined organic phases are dried and the solvent removed to give the title compound as a crude product. LC (METHOD 5): tR=0.55 min; Mass spectrum (ES+): m/z=238 [M+H]+.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][CH2:16][C@H:17]([OH:30])[CH2:18][O:19][C:20]1[C:28]2[NH:27][C:26](=[O:29])[NH:25][C:24]=2[CH:23]=[CH:22][CH:21]=1.[CH3:31][O:32][C:33]1[CH:34]=[C:35]([CH:52]=[CH:53][C:54]=1[O:55][CH3:56])[C:36]([NH:38][C:39]1[CH:44]=[CH:43][C:42]([N:45]2[CH2:50][CH2:49][C:48](=O)[CH2:47][CH2:46]2)=[CH:41][CH:40]=1)=[O:37].C(O)(=O)C>CN(C)C=O>[OH:30][C@H:17]([CH2:18][O:19][C:20]1[C:28]2[NH:27][C:26](=[O:29])[NH:25][C:24]=2[CH:23]=[CH:22][CH:21]=1)[CH2:16][NH:15][CH:48]1[CH2:47][CH2:46][N:45]([C:42]2[CH:43]=[CH:44][C:39]([NH:38][C:36](=[O:37])[C:35]3[CH:52]=[CH:53][C:54]([O:55][CH3:56])=[C:33]([O:32][CH3:31])[CH:34]=3)=[CH:40][CH:41]=2)[CH2:50][CH2:49]1
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Reactant: COc1ccc(C(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COc1ccc(C(=O)Nc2ccc(N3CCC(NC[C@H](O)COc4cccc5[nH]c(=O)[nH]c45)CC3)cc2)cc1OC
Reaction time: 2 h

Procedure:
Sodium triacetoxyborohydride (0.044 g, 2.1 mmol) was added to a solution of 4-((2S)-3-amino-2-hydroxy-propoxy)-1,3-dihydro-benzoimidazol-2-one (U.S. Pat. No. 5,786,356) (0.23 g, 1.05 mmol), 3,4-dimethoxy-N-[4-(4-oxo-piperidin-1-yl)-phenyl]-benzamide (which was obtained in Example 369) (0.41 g, 1.16 mmol), and acetic acid (0.07 mL, 1.16 mmol) in anhydrous dimethylforamide (8 mL). The reaction was stirred for 2 hours. The reaction was quenched with 50% water/saturated aqueous NaHCO3 (20 mL). The solids were captured on a filter and washed with ethyl acetate, diethyl ether, and hexanes to afford 0.31 g of the desired product as a brown solid; 1H NMR (300 MHz, DMSO-d6) δ 1.32 (m, 2H), 1.89 (m, 2H), 2.54 (m, 1H), 2.65 (m, 2H), 2.84(m, 2H), 3.56 (m, 2H), 3.83(s, 3H), 3.84 (s, 3H), 3.95 (m, 2H), 4.02 (s, 1H), 5.06(brs, 1H), 6.52 (d, 1H, J=7.1), 6.51(d, 1H, J=8.1 Hz), 6.88 (m, 2H), 7.08 (d, 1H, J=8.7 Hz), 7.58 (m, 5H), 8.87 (s, 1 H), 10.59 (brs, 1 H), 10.72 (brs, 1 H); MS (ES) m/z: 561.2 (MH+).
Reaction SMILES: CCC(=O)CC(=O)CC.CC(=O)CC(=O)C.CCCCC(=O)CC(=O)CCCC.CC(C)(C(=O)CC(=O)C(C)(C)C)C.BrCCCCCCC(C(=O)C)C(=O)C.[Br:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH:64]([C:71](=[O:76])[CH2:72][CH2:73]CC)[C:65](=[O:70])[CH2:66][CH2:67]CC.BrCCCCCCC(C(=O)C(C)(C)C)C(=O)C(C)(C)C>>[Br:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH:64]([C:65](=[O:70])[CH2:66][CH3:67])[C:71](=[O:76])[CH2:72][CH3:73]
Reactant: CCCCC(=O)C(CCCCCCBr)C(=O)CCCC
Agent: CC(=O)C(CCCCCCBr)C(C)=O
Agent: CC(C)(C)C(=O)C(CCCCCCBr)C(=O)C(C)(C)C
Agent: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Solvent: CC(=O)CC(C)=O
Product: CCC(=O)C(CCCCCCBr)C(=O)CC

Procedure:
By replacing the 3,5-heptanedione in the foregoing preparation by a molar equivalent amount of 2,4-pentanedione, 5,7-undecanedione or 2,2,6,6-tetramethyl-3,5-heptanedione, it is contemplated that there can be obtained, respectively, 3-(6-bromohexyl)-2,4-pentanedione, 6-(6-bromohexyl)-5,7-undecanedione, or 4-(6-bromohexyl)-2,2,6,6-tetramethyl-3,5-heptanedione.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[O:5])[CH3:2].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.O.[CH:69]([O-:71])=[O:70].[Li+].[Cl-].[Li+].C(N(CC)C(C)C)(C)C.C(OC(=O)C)(=O)C>C(OCC)(=O)C.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.CN(C)C=O>[CH3:2][CH2:1][O:3][C:4]([C:6]1[N:7]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:69]([OH:71])=[O:70])=[CH:10][CH:9]=2)=[O:5]
Reactant: CCOC(=O)c1cc2cc(Br)ccc2n1S(=O)(=O)c1ccc(C)cc1
Reactant: O=C[O-]
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc2cc(C(=O)O)ccc2n1S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 5-bromo-1-(toluene-4-sulfonyl)-1H-indole-2-carboxylic acid ethyl ester (948.4 mg, 2.24 mmol), Tris(dibenzylideneacetone) dipalladium (0) (0.112 mmol, 103 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (0.225 mmol, 130 mg), lithium formate monohydrate (5.6 mmol, 394 mg), lithium chloride (286 mg, 6.75 mmol), and anhydrous N,N-dimethylformamide (DMF) (5.9 ml) was evacuated, and backfilled with argon. Then, N,N-diisopropylethyl amine (4.5 mmol, 0.78 ml) and acetic anhydride (4.5 mmol, 0.43 ml) were added to the mixture, and deaeration and argon replacement was performed again. The reaction container was placed in a reaction device preheated at 80° C. and the reaction mixture was stirred for 20 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and an aqueous solution of 1 M hydrochloric acid, and filtered through Celite. The resulting filtrate was washed with 1 M hydrochloric acid, water, and a saturated aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate. The desiccant was removed by filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1 to 1/3, and finally ethyl acetate/methanol=15/1) to give 1-(toluene-4-sulfonyl)-1H-indole-2,5-dicarboxylic acid 2-ethyl ester as a yellow amorphous material (930 mg).
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH2:12]([OH:15])[C:13]#[CH:14]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I.C(NCC)C>[OH:15][CH2:12][C:13]#[C:14][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: C#CCO
Reactant: COC(=O)c1ccccc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCNCC
Product: COC(=O)c1ccccc1C#CCO
Reaction time: 18 h

Procedure:
Step 1--A mixture of methyl o-iodobenzoate (9.17 g), propargyl alcohol (3.06 ml) and diethyl amine (90 ml) is treated with bis(triphenylphosphine)palladium chloride (1.23 g) and copper iodide (333 mg) and the reaction is stirred at 20°-25° under nitrogen for 18 hrs. The reaction is then filtered through a filter agent and concentrated. The resulting residue is partitioned between water and dichloromethane. The combined organic phases are washed once with saline, dried over magnesium sulfate, filtered and concentrated to an oil. Purification by silica gel chromatography gives methyl o-(1-hydroxy-2-propyn-3-yl)benzoate (CXIX).