Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:27])=[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[H-].[Na+:29].[S:30]1([O:36][CH2:35][CH2:34][O:33]1)(=[O:32])=[O:31].CCOCC>O1CCCC1.O>[S:30]([O-:36])([O:33][CH2:34][CH2:35][N:3]1[C:4]([CH3:27])=[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:2]1[CH3:1])(=[O:32])=[O:31].[Na+:29]
Reactant: O=S1(=O)OCCO1
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)C1=C(C)N(CCOS(=O)(=O)[O-])C(C)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Temperature: -10 °C
Reaction time: 3 h

Procedure:
In 160 ml of tetrahydrofuran was dissolved 40 g of diethyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5 -dicarboxylate and after adding to the solution 5.2 g of 50% oil dispersion of sodium hydride at room temperature, the resultant mixture was stirred for 30 minutes at room temperature. Then, the mixture was cooled to temperatures of from -10° C. to -20° C., and after adding dropwise thereto a solution of 20 g ethylene sulfate in 80 ml of tetrahydrofuran, the mixture was stirred for 1 hr. at -10° C., and the temperature of the system was raised gradually till room temperature. After further adding 4.0 g of 50% oil dispersion of sodium hydride, the mixture was stirred for 3 hrs. at room temperature. The reaction mixture was cooled to -10° C., and after adding dropwise a solution of 5.0 g ethylene sulfate in 10 ml of tetrahydrofuran, the mixture was stirred for 1 hr. at the same temperature. The reaction mixture was cooled and 800 ml of ether was added thereto and further 100 ml of water was added. The separated aqueous layer was subjected to a silica gel column chromatography (12 cm × 5.0 cm). After eluting the small amount of raw material using 50 ml of ethyl acetate as an elute, the product was then developed by using 1:1 ethyl acetate-methanol mixed solvent as an elute. The solvent of the effluent was distilled away under reduced pressure, and to the residue obtained was added 30 ml of water and after cooling, the crystal formed was filtered to provide 35 g of sodium β-[2,6-dimethyl-3,5-bis(ethoxycarbonyl)-4-(3-nitrophenyl)- 1,4-dihydropyridine-1-yl]-ethyl sulfate. By recrystallizing this product from water, scale-shaped yellow crystal was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][C:13]1[N:18]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)[C:17](=[O:29])[C:16]([C:30]([NH:32][CH2:33][C:34]2[CH:39]=[CH:38][C:37]([S:40]([CH3:43])(=[O:42])=[O:41])=[CH:36][N:35]=2)=[O:31])=[CH:15][C:14]=1[C:44]1[N:48]([CH3:49])[N:47]=[CH:46][CH:45]=1.[S:50]([C:54]1C=CC(C)=C[CH:55]=1)([O-:53])(=[O:52])=[O:51].C(S(O)(=O)=O)C>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:6][CH:7]=1.[CH3:12][C:13]1[N:18]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:27])([F:26])[F:28])[CH:20]=2)[C:17](=[O:29])[C:16]([C:30]([NH:32][CH2:33][C:34]2[CH:39]=[CH:38][C:37]([S:40]([CH3:43])(=[O:42])=[O:41])=[CH:36][N:35]=2)=[O:31])=[CH:15][C:14]=1[C:44]1[N:48]([CH3:49])[N:47]=[CH:46][CH:45]=1.[S:50]([CH2:54][CH3:55])([O-:53])(=[O:52])=[O:51]
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: CCS(=O)(=O)O
Agent: Cc1c(-c2ccnn2C)cc(C(=O)NCc2ccc(S(C)(=O)=O)cn2)c(=O)n1-c1cccc(C(F)(F)F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCS(=O)(=O)[O-]

Procedure:
Compound (I) esylate was synthesized using an analogous method to that described for the synthesis of compound (I) tosylate in Example 8a from compound (I) (50 mg, 0.092 mmol) and ethane sulfonic acid (9.3 mg, 0.092 mmol). No precipitation was obtained after stirring over night. The solvent was evaporated and ethyl acetate (2 ml) was added. A suspension was formed. The suspension was stirred over night, was filtered and dried under vacuum at 50° C. to give the title product; yield 49 mg, 0.075 mmol, 81%
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:20]([F:23])([F:22])[F:21])=[N:7]2.[NH2:24][CH2:25][CH2:26][CH2:27][NH2:28]>C1(C)C=CC=CC=1>[NH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:20]([F:23])([F:22])[F:21])=[N:7]2
Reactant: COc1ccc(-c2cc3nc(C(F)(F)F)ccc3c(Cl)n2)cc1
Reactant: NCCCN
Solvent: Cc1ccccc1
Product: COc1ccc(-c2cc3nc(C(F)(F)F)ccc3c(NCCCN)n2)cc1
Temperature: 100 °C

Procedure:
A mixture of 5-chloro-7-(4-methoxy-phenyl)-2-trifluoromethyl-[1,6]naphthyridine (55 mg, 0.2 mmol) and 1,3-diaminopropane (2.5 mL) in a sealed reaction vessel was heated at 100° C. for 3 hours. The mixture was diluted with toluene and concentrated three times to azeotropically remove excess 1,3-diaminopropane. The residue was diluted with EtOAc, washed sequentially with sat. NaHCO3, H2O, sat. NaCl, dried over Na2SO4, and concentrated giving the title compound (60 mg, quantitative) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[N:14]=[C:13]([C:15]([OH:17])=[O:16])[CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.S(Cl)(Cl)=O.[CH2:22](N(CC)CC)C.CO>O.CCCCCC.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[N:14]=[C:13]([C:15]([O:17][CH3:22])=[O:16])[CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=C(O)c1cccc(Oc2ccnc(Cl)c2)n1
Reactant: CCN(CC)CC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1cccc(Oc2ccnc(Cl)c2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.2 %

Procedure:
A mixture of 6-[(2-chloro-4-pyridyl)oxy]picolinic acid (28 g, 0.11 mol) and thionyl chloride (50 mL) is refluxed for two hours and concentrated in vacuo to remove residual thionyl chloride. A solution of the resultant acid chloride in ethyl acetate is cooled, treated with triethylamine (55 mL, 0.4 mol) and anhydrous methanol (5.4 mL, 0.13 mol), stirred at room temperature for three hours, and diluted with water. The organic layer is separated, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a residue. Flash column chromatography of the residue using silica gel and a 1:1 hexane/ethyl acetate solution gives the title product as light green crystals (18.1 g, 62.3%, mp 89° C.). Using essentially the same procedure, the following compounds are obtained:
Reaction SMILES: N1C=CC=CC=1.[C:7]1([CH3:17])[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1.[CH3:18][C:19]1[CH:23]([CH3:24])[CH:22]=[C:21]([CH3:25])[C:20]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH2:32].Cl>>[CH3:18][C:19]1[CH:23]([CH3:24])[CH:22]=[C:21]([CH3:25])[C:20]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32][S:13]([C:10]1[CH:11]=[CH:12][C:7]([CH3:17])=[CH:8][CH:9]=1)(=[O:15])=[O:14]
Reactant: CC1=CC(C)C(C)=C1c1ccccc1N
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CC1=CC(C)C(C)=C1c1ccccc1NS(=O)(=O)c1ccc(C)cc1
Yield: 63.9 %

Procedure:
0.131 g (1.505 mmol) of pyridine and 0.316 g (1.656 mmol) of p-toluenesulfonyl chloride were added to 0.300 g (1.505 mmol) of 2-(2,3,5-trimethylcyclopenta-1,4-dienyl)phenylamine melted in 3 mL of MC, and then reacted at room temperature for 12 hours. 3 mL of 2 N HCl was added to the reaction product and strongly stirred for a few minutes. The organic layer was collected. The collected organic layer was neutralized with 3 mL of H2O without delay and dried over MgSO4. The product was filtered using a column chromatography with hexane/ethylacetate (v/v=3:1). The solvent contained in the puried product was dried in vacuum, thereby obtaining white solid (0.340 g, 64%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][NH2:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH:20]1[C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([S:30](Cl)(=[O:32])=[O:31])[C:24]=2[CH:23]=[CH:22][N:21]=1>ClCCl>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][S:30]([C:25]1[CH:26]=[CH:27][CH:28]=[C:29]2[C:24]=1[CH:23]=[CH:22][N:21]=[CH:20]2)(=[O:31])=[O:32])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCNS(=O)(=O)c1cccc2cnccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of N-(tert-butoxycarbonyl)-1,3-propylenediamine (2.09 g, Tokyo Kasei Kogyo) and triethylamine (3.4 ml, Tokyo Kasei Kogyo) in dichloromethane (20 ml) was added with a solution of isoquinoline-5-sulfonyl chloride (2.73 g, prepared according to Japanese Patent Unexamined Publication (Kokai) No. 61-227581) in dichloromethane (15 ml) with stirring and ice cooling and stirred at room temperature for 14 hours and 30 minutes. The reaction mixture was washed successively with saturated aqueous sodium hydrogencarbonate and saturated brine. The organic layer was dried, and then the solvent was evaporated under reduced pressure. Then, the residue was purified by flash column chromatography (chloroform:methanol=50:1) to obtain the title compound (4 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[O:18]C)[C:5]([C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=1)=[O:6].B(Br)(Br)Br.[OH-].[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[OH:18])[C:5]([C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=1)=[O:6]
Reactant: COc1ccc(C(=O)c2ccc(C#N)cc2)cc1F
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: N#Cc1ccc(C(=O)c2ccc(O)c(F)c2)cc1
Temperature: 25 °C
Yield: 72 %

Procedure:
A solution of 50 g of 4-(3-fluoro-4-methoxy-benzoyl)benzonitrile in 550 ml of methylene chloride is treated with 70 ml of BBr3 at 5° C. and stirred at room temperature. 1 l of 1M NaOH is added dropwise while cooling with ice. Then, the mixture is extracted with saturated aqueous NH4Cl solution and methylene chloride. The organic phase is washed with water and dried. After recrystallization from ether, there are obtained 34 g of 4-(3-fluoro-4-hydroxy-benzoyl)-benzonitrile, m.p. 168.5°-169.5° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[C:6]([NH:11][C:12](=[O:18])[CH:13](Cl)[C:14]([CH3:16])=O)[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[C:20]([NH2:23])(=[S:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+].O>O1CCCC1>[CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[C:6]([NH:11][C:12]([C:13]3[S:22][C:20]([CH3:21])=[N:23][C:14]=3[CH3:16])=[O:18])[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CC(=O)C(Cl)C(=O)Nc1cccc2c1CCC2(C)C
Reactant: CC(N)=S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(C)c(C(=O)Nc2cccc3c2CCC3(C)C)s1
Reaction time: 4 h
Yield: 42.4 %

Procedure:
1.14 g (4.08 mmol) of N-(1,1-dimethyl-4-indanyl)-2-chloroacetoacetamide and 0.30 g (4.08 mmol) of thioacetamide were dissolved in 10 ml of tetrahydrofuran and was refluxed for 3 hours. To the reaction mixture was added 0.56 g (4.08 mmol) of anhydrous potassium carbonate and reaction was effected for 4 hours under reflux. The resulting solution was added to water and extracted with ethyl acetate. The organic layer was concentrated and then purified by column chromatography (eluent; n-hexane:ethyl acetate=50:50 V/V) to obtain 0.52 g of N-(1,1-dimethyl-4-indanyl)-2,4-dimethylthiazole-5-carboxamide (yield 43%).
Reaction SMILES: [CH2:1]([C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Br:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]1[S:33][C:32]([NH2:34])=[N:31][N:30]=1.Cl>N1C=CC=CC=1>[Br:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]1[S:33][C:32]([NH:34][S:19]([C:16]2[CH:17]=[CH:18][C:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:14][CH:15]=2)(=[O:21])=[O:20])=[N:31][N:30]=1
Reactant: Nc1nnc(CCCCCBr)s1
Reactant: CCCCCCCCCCCCc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCc1ccc(S(=O)(=O)Nc2nnc(CCCCCBr)s2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 60 %

Procedure:
To a solution of 4-dodecylbenzenesulfonyl chloride (1.53 g, 4.42 mmol) in pyridine (15 mL) was added 5-(5-bromopentyl)-1,3,4-thiadiazol-2-amine. (1.00 g, 4.02 mmol). The reaction mixture was stirred at room temperature for 5 h, then 2 mol/L HCl (25 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (3×50 mL). The organic extracts were washed with water (50 mL) and brine (50 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography over silica gel 60 (70-230 mesh) eluted with CH2Cl2:MeOH 49:1 to give 1.39 g of product as a solid contaminated with N-(5-(5-chloropentyl)-1,3,4-thiadiazol-2-yl)-4-dodecyl benzenesulfonamide in about 60% yield. 1H NMR (300 MHz, CDCl3) δ 0.87 (t, 3, J=6.9 Hz), 1.25-1.30 (m, 18), 1.55-1.58 (m, 4), 1.73-1.88 (m, 4), 2.64 (t, 2, J=7.8 Hz), 2.83 (t, 2, J=7.8 Hz), 3.42 (t, 1, J=6.6), 3.55 (t, 1, J=6.3 Hz), 7.27 (d, 2, J=8.1 Hz), 7.84 (d, 2, J=8.1 Hz); 13C NMR (75 MHz, CDCl3) δ 14.1, 22.6, 26.0, 27.3, 27.4, 27.5, 29.3, 29.4, 29.5, 29.6, 29.7, 30.5, 31.1, 31.8, 31.9, 32.0, 33.2, 35.8, 44.5, 126.5, 128.9, 138.3, 148.3, 158.5, 168.2; HRMS (ESI+, m/z) calculated for C25H41BrN3O2S2 558.1824, observed 558.1819 (M+H)+; HRMS (ESI+, m/z) calculated for C25H41ClN3O2S2 514.2329, observed 514.2330 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.[CH2:12]([NH2:15])[CH:13]=[CH2:14]>C(Cl)Cl>[Cl:11][C:4]1[N:3]=[C:2]([NH:15][CH2:12][CH:13]=[CH2:14])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: C=CCN
Solvent: ClCCl
Product: C=CCNc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: -15 °C
Reaction time: 18 h

Procedure:
2,6-Dichloro-3-nitropyridine (71-1, 10 g, 51.8 mmol, 1.0 equiv) was added to anhydrous DCM (207 mL) and cooled to −15° C. TEA (7.57 mL, 53.9 mmol, 1.04 equiv) was then added followed by allyl amine (4.05 mL, 53.9 mmol, 1.04 equiv) over 12 h via syringe pump. Following this duration, the reaction vessel was removed from the −15° C. bath and allowed to gradually warm to RT. After 18 h, the reaction was quenched with 0.2M citric acid (100 mL) and diluted with CH2Cl2 (40 mL). The layers were separated and the organics were washed an additional time with 1×100 mL 0.2M citric acid. Washed combined organics with 2×100 mL sat. NaHCO3, dried over Na2SO4, filtered and concentrated to give an orange oil. The crude material was carried onward without further purification. LRMS (M+H)+: observed=214.0, calculated=213.6.
Reaction SMILES: [C:1]([OH:18])(=[O:17])[C:2]1[C:3](=[CH:7][C:8](=[C:12]([CH:16]=1)[C:13]([OH:15])=[O:14])[C:9]([OH:11])=O)[C:4]([OH:6])=O>C1(OC)C=CC=CC=1>[CH:16]1[C:12]2[C:13]([O:14][C:9](=[O:11])[C:8]=2[CH:7]=[C:3]2[C:4]([O:18][C:1](=[O:17])[C:2]=12)=[O:6])=[O:15]
Reactant: O=C(O)c1cc(C(=O)O)c(C(=O)O)cc1C(=O)O
Solvent: COc1ccccc1
Product: O=c1oc(=O)c2cc3c(=O)oc(=O)c3cc12

Procedure:
50.0 g pyromellitic acid were boiled under reflux with 400 ml anisole and 3.0 g activated carbon, Merck Art. No. 2184, under the same conditions as in example 1 and then processed. 4.3 g (60.6% of the theory) water separated in the course of 2.5 hours. 27.3 g (=64% of the theory) pyromellitic acid anhydride were obtained and the remainder of 18.0 g, (36%) was filtered off as unchanged pyromellitic acid, together with the activated carbon.
Reaction SMILES: O[CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13]1[S:14][CH:15]=[CH:16][CH:17]=1.[C:18]([O:22][CH3:23])(=[O:21])[CH2:19][SH:20].C(=O)(O)[O-].[Na+]>ClCCl>[CH3:23][O:22][C:18](=[O:21])[CH2:19][S:20][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13]1[S:14][CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)CS
Reactant: O=C1c2ccccc2C(O)N1Cc1cccs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)CSC1c2ccccc2C(=O)N1Cc1cccs1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.6 %

Procedure:
To a solution of 12 (500 mg, 2.04 mmol) in dichloromethane (15 mL) at room temperature was added methyl thioglycolate (204 μL, 2.24 mmol) and the resulting reaction mixture was stirred at room temperature for 18 hours in a sealed tube. The reaction mixture was poured onto saturated sodium bicarbonate and extracted with ethyl acetate (3×30 mL). The combined ethyl acetate extracts were dried over anhydrous sodium sulfate and concentrated in vacuo. Chromatography (SiO2, 5% EtOAc-Hexanes eluant) provided 650 mg of 13 as a white solid (679 mg theoretical, 96% yield).
Reaction SMILES: NC(N)=O.[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][CH2:29][CH3:30])=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4CCN(C(OCC)=O)C[CH2:35]4)[N:32]=[CH:33][C:14]=13)[CH2:6]2.[CH3:45][O:46][C:47]1[CH:52]=CC(N)=[CH:49][CH:48]=1.NC1C=CC=CC=1>>[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:20]=[CH:21][C:22]([NH:25][C:26]([NH:28][C:29]4[CH:49]=[CH:48][C:47]([O:46][CH3:45])=[CH:52][CH:30]=4)=[O:27])=[CH:23][CH:24]=3)[N:16]=[C:15]3[N:31]([CH2:34][CH3:35])[N:32]=[CH:33][C:14]=13)[CH2:6]2
Reactant: COc1ccc(N)cc1
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(C(=O)OCC)CC4)c3n2)cc1
Agent: NC(N)=O
Solvent: Nc1ccccc1
Product: CCn1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc(NC(=O)Nc4ccc(OC)cc4)cc3)nc21

Procedure:
A urea formation procedure similar to that used for the synthesis of ethyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-ethylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate is used, utilizing p-anisidine as the aniline component. (20%, MS=500.2 (M+H))
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([S:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([N:22]4[CH2:27][CH2:26][CH2:25][CH:24]([C:28]([O:30]CC)=[O:29])[CH2:23]4)=[O:21])=[CH:14][C:13]=3[Cl:33])=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[OH-].[K+].[OH-].[Na+]>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([S:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([N:22]4[CH2:27][CH2:26][CH2:25][CH:24]([C:28]([OH:30])=[O:29])[CH2:23]4)=[O:21])=[CH:14][C:13]=3[Cl:33])=[CH:8][CH:9]=2)[CH:4]=[CH:3]1
Reactant: CCOC(=O)C1CCCN(C(=O)/C=C/c2ccc(Sc3ccc4c(ccn4C)c3)c(Cl)c2)C1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Product: Cn1ccc2cc(Sc3ccc(/C=C/C(=O)N4CCCC(C(=O)O)C4)cc3Cl)ccc21

Procedure:
The title compound was prepared by the procedures described in Example 155, substituting the ethyl nipecotate from Example 137 with ethyl ester from Example 283, and KOH with NaOH, to provide a white solid. 1H NMR (CDCl3, 300 MHz) δ 1.45-1.69 (m, 1H), 1.69-1.98 (m, 2H), 1.98-2.22 (m, 1H), 2.51-2.70 (m, 1H), 3.05-3.47 (m, 1H), 3.80-4.20 (m, 2H), 3.85 (s, 3H), 4.47-4.68 (m, 1H), 6.53 (d, J=3.0 Hz, 1H), 6.57 (d, J=8.1 Hz, 1H), 6.87 (d, J=15.3 Hz, 1H), 7.08 (d, J=8.1 Hz, 1H), 7.14 (d, J=3.0 Hz, 1H), 7.37 (d, J=9.0 Hz, 1H), 7.42 (d, J=9.0 Hz, 1H), 7.51 (s, 1H), 7.52 (d, J=15.3 Hz, 1H), 7.89 (br s, 1H). MS (ESI+) (M−H+H)+ at m/z 453, 455.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[CH2:5][C:6](=O)[C@@H:7]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=1)[O:8]2.COC1C=C(OC)C=C2C=1C[C@H](O)[C@@H](C1C=CC(OC)=C(OC)C=1)O2.[Sn](Cl)(Cl)(Cl)Cl>ClCCl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=1)[O:8]2
Reactant: COc1cc(OC)c2c(c1)O[C@H](c1ccc(OC)c(OC)c1)C(=O)C2
Agent: COc1cc(OC)c2c(c1)O[C@H](c1ccc(OC)c(OC)c1)[C@@H](O)C2
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1cc(OC)c2c(c1)OC(c1ccc(OC)c(OC)c1)C=C2
Reaction time: 24 h
Yield: 10.3 %

Procedure:
Dried (2R)-5,7,3′,4′-tetrakis(methyloxy)flavan-3-one (1) (200 mg, 0.581 mmol) and (2R,3S)-5,7,3′,4′-tetrakis(methyloxy)flavan-3-ol (5) (400 mg, 1.162 mmol, 2 eq.) was dissolved in dry dichloromethane (10 mL) and the mixture was cooled in ice/NaCl bath. Then tin(IV)chloride (1 M solution in dichloromethane, 1 mL, 1 mmol, 1.7 eq.) was added dropwise and the reaction mixture was stirred under argon in thawing ice/NaCl bath for 24 hours (TLC monitoring of consumption of starting materials). The reaction mixture was then filtered on a basic aluminium oxide and washed with ethyl acetate. Purification on silica preparative TLC plates (hexane-ethyl acetate 4:6) afforded (2R)-3-[(2R,3S)-5,7,3′,4′-tetrakis(methyloxy)-3-hydroxyflavan)]-5,7,3′,4′-tetramethoxyflavan-3-ene (6) (Rf 0.20, 40.1 mg, 0.060 mmol, 10%).
Reaction SMILES: [CH:1]1([C@H:4]2[O:10][C@H:5]2[C:6]([O:8][CH3:9])=[O:7])[CH2:3][CH2:2]1.C(OC)=O.[N-:15]=[N+:16]=[N-:17].[Na+]>CO.O>[CH:1]1([C@H:4]([N:15]=[N+:16]=[N-:17])[C@@H:5]([OH:10])[C:6]([O:8][CH3:9])=[O:7])[CH2:3][CH2:2]1
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)[C@@H]1O[C@@H]1C1CC1
Agent: [Na+]
Solvent: COC=O
Solvent: O
Solvent: CO
Product: COC(=O)[C@H](O)[C@@H](N=[N+]=[N-])C1CC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 69.3 %

Procedure:
To a solution of 2.89 g of methyl (2R,3R)-3-cyclopropyl-2,3-epoxypropionate in 112.5 ml of methanol-water (8:1) are added 14 ml of methyl formate and 16.60 g of sodium azide. Then, the reaction mixture is stirred at 50° C. overnight. The reaction mixture is cooled to room temperature and evaporated to remove methanol. The residue is dissolved in ethyl acetate. The solution is washed with brine and dried. The solvent is removed in vacuo. The residue is purified by silica gel column chromatography (solvent; hexane:ethyl acetate=4:1) to give 2.61 g of methyl (2R,3S)-3-cyclopropyl-3-azido-2-hydroxypropionate.
Reaction SMILES: [C:1]1([CH2:11][C:12]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(C(OC(C)(C)C)=O)[C:13]([O:15]C(C)(C)C)=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl>C1COCC1>[C:1]1([CH2:11][CH:12]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:13]([OH:15])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)C(Cc1ccccc1)(Cc1cccc2ccccc12)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1CCOC1
Product: O=C(O)C(Cc1ccccc1)Cc1cccc2ccccc12
Temperature: 2000 °C
Yield: 82.5 %

Procedure:
A solution of 20.0 g (0.045 mol) of di-t-butyl (1-naphthylmethyl)benzylmalonate in 350 mL THF was treated repeatedly with HCl gas over a 3-hour period. The solvent was removed under reduced pressure and the residue heated at 2000° C. for 25 minutes. The residue was taken up in Et2O and extracted with 1N NaOH. The NaOH solution was acidified with dilute HCl and extracted with Et2O. The Et2O was washed with saturated NaCl, dried over MgSO4, and the solvent removed under reduced pressure leaving 10.78 g (82% yield) of the product as a white solid. The structure was confirmed by NMR and mass spectroscopy.
Reaction SMILES: [C:1]([O:4][CH:5]1[CH:9]([N:10]2[C:14]3[CH:15]=[C:16]([Cl:20])[C:17]([Cl:19])=[CH:18][C:13]=3[N:12]=[CH:11]2)[CH2:8][CH:7]([CH2:21][O:22][C:23](=[O:25])[CH3:24])[CH:6]1[O:26][C:27](=[O:29])[CH3:28])(=[O:3])[CH3:2].[Br:30]N1C(=O)CCC1=O>O1CCOCC1>[C:1]([O:4][CH:5]1[CH:9]([N:10]2[C:14]3[CH:15]=[C:16]([Cl:20])[C:17]([Cl:19])=[CH:18][C:13]=3[N:12]=[C:11]2[Br:30])[CH2:8][CH:7]([CH2:21][O:22][C:23](=[O:25])[CH3:24])[CH:6]1[O:26][C:27](=[O:29])[CH3:28])(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)OCC1CC(n2cnc3cc(Cl)c(Cl)cc32)C(OC(C)=O)C1OC(C)=O
Solvent: C1COCCO1
Product: CC(=O)OCC1CC(n2c(Br)nc3cc(Cl)c(Cl)cc32)C(OC(C)=O)C1OC(C)=O
Yield: 62.6 %

Procedure:
(±)(1R*, 2S*, 3S*, 5S*)-3-(Acetoxymethyl)-5-(5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyl diacetate (4.20 g, 9.48 mmol) was refluxed in dry dioxane (25 mL) while freshly recrystallized N-bromosuccinimide (3.37 g, 18.9 mmol) was added all at once. After 5 minutes of reflux, volatiles were removed in vacuo. The residue was partitioned between water and chloroform. The chloroform layer was dried (sodium sulfate), and evaporated to an oil which was chromatographed on silica gel with elution by 1:1 hexanes-ethyl acetate. Resolidification from ethanol-water gave title compound as white powder (3.10 g, 63%), m.p. 157°-158.5° C.; 1H-NMR(DMSO-d6) identical to that of the sample described in Example 3.