Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]2[CH:13]([OH:28])[N:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[C:15](=O)[CH:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH3-]C#N.[Na+]>FC(F)(F)C(O)=O>[CH2:1]([N:8]1[CH2:9][CH:10]2[CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:25])[F:26])=[CH:19][CH:18]=3)[C:13](=[O:28])[CH:11]2[CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C2CN(Cc3ccccc3)CC2C(O)N1c1ccc(OC(F)(F)F)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: O=C1C2CN(Cc3ccccc3)CC2CN1c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.5 %

Procedure:
To a solution of 5-Benzyl-3-hydroxy-2-(4-trifluoromethoxy-phenyl)-hexahydro-pyrrolo[3,4-c]pyrrol-1-one (6.0 g, 15.3 mmol) in trifluoroacetic acid (50 mL) was added NaCNBH3 (1.0 g, 15.3 mmol) and the mixture was stirred at room temperature overnight. Trifluoroacetic acid was removed by reduced pressure and the residue was added to dichloromethane (50 mL). Saturate solution of Na2CO3 (70 mL) was added. The mixture was extracted with dichloromethane (2×60 mL), washed with brine (100 mL), dried over Na2SO4. The solvent was removed and the crude product was purified by column chromatography on silica gel with petroleum ether:ethyl acetate (10:1 to 5:1) to yield the title compound (4.0 g, 70%). 1H NMR (300 MHz, CDCl3): δ 7.73-7.69 (m, 2H), 7.31-7.22 (m, 7H), 4.04 (t, 1H, J=9.5 Hz), 3.74-3.54 (m, 3H), 3.28-3.17 (m, 2H), 2.95 (bs, 1H), 2.76-2.74 (m, 1H), 2.63-2.53 (m, 2H); LC-MS: [M+1]+ 376.9.
Reaction SMILES: [CH2:1]=O.[C:3]([O:7][C:8](=[O:26])[NH:9][CH:10]1[CH2:15][CH2:14][N:13]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:12][CH2:11]1)([CH3:6])([CH3:5])[CH3:4].C[O-].[Na+].[BH4-].[Na+]>CO.C(Cl)Cl>[C:3]([O:7][C:8](=[O:26])[NH:9][CH:10]1[CH2:11][CH2:12][N:13]([S:16]([C:19]2[CH:20]=[CH:21][C:22]([NH:25][CH3:1])=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH2:14][CH2:15]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2ccc(N)cc2)CC1
Reactant: C=O
Agent: C[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CNc1ccc(S(=O)(=O)N2CCC(NC(=O)OC(C)(C)C)CC2)cc1
Temperature: 70 °C
Yield: 103.5 %

Procedure:
Paraformaldehyde (0.15 g, 0.5 mmol) was added in one portion to pressure vessel containing [1-(4-amino-benzenesulfonyl)-piperidin-4-yl]-carbamic acid tert-butyl ester (0.12 g, 0.34 mmol) in Methanol (5 ml) at room temperature. To this mixture was added sodium methoxide (0.055 g, 1.02 mmol) in one portion, the pressure vessel was sealed and heated at 70° C. for 12 hours. After this time the reaction was cooled to room temperature and sodium borohydride (0.031 g, 0.82 mmol) added in one portion, the pressure vessel was re-sealed and heated at 70° C. for 1 hour. The reaction was then cooled to room temperature, diluted with DCM (20 ml) and washed with water (20 ml). The organic layer was separated, dried (MgSO4), filtered and concentrated to give the title compound (0.13 g, 99% yield) as a white solid which was taken on without further purification. Tr=1.96 min m/z (ES+) (M+Na+) 392.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:7][C:8]1[N:13]=[CH:12][C:11]([C:14]([N:16]2[C@@H:21]([CH3:22])[CH2:20][O:19][CH2:18][C@@H:17]2[CH3:23])=[O:15])=[CH:10][CH:9]=1.Br[C:25]1[C:26](=[O:33])[N:27]([CH3:32])[N:28]=[C:29]([Cl:31])[CH:30]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Cl:31][C:29]1[CH:30]=[C:25]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]([N:16]3[C@@H:21]([CH3:22])[CH2:20][O:19][CH2:18][C@@H:17]3[CH3:23])=[O:15])=[CH:12][N:13]=2)[C:26](=[O:33])[N:27]([CH3:32])[N:28]=1
Reactant: Cn1nc(Cl)cc(Br)c1=O
Reactant: C[C@H]1COC[C@H](C)N1C(=O)c1ccc(N)nc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: C[C@H]1COC[C@H](C)N1C(=O)c1ccc(Nc2cc(Cl)nn(C)c2=O)nc1
Temperature: 25 °C
Yield: 31.1 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 1,4-dioxane (8 mL), cesium carbonate (221 mg, 0.68 mmol), 324a (80 mg, 0.34 mmol), and 4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (80 mg, 0.36 mmol). After bubbling nitrogen through the suspension for 5 minutes, Xantphos (40 mg, 0.068 mmol) and tris(dibenzylideneacetone)dipalladium(0) (24 mg, 0.034 mmol) were added. The system was subjected to three cycles of vacuum/nitrogen flush and heated at reflux for 2.5 h. It was then cooled to room temperature and filtered. The solid was washed with dichloromethane (3×10 mL). The combined filtrate was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with petroleum ether/ethyl acetate (2/1 to 100% ethyl acetate) to afford 324b (40 mg, 31%) as a yellow solid. MS-ESI: [M+H]+ 378.3
Reaction SMILES: Cl[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][CH2:12][CH2:13][C:14]2[CH:27]=[CH:26][CH:25]=[CH:24][C:15]=2[O:16][CH2:17][CH2:18][NH:19][C:20]([CH3:23])([CH3:22])[CH3:21])[NH:4][CH:3]=1.Cl.[OH-:29].[Na+]>C(O)C.O>[CH3:21][C:20]([NH:19][CH2:18][CH2:17][O:16][C:15]1[CH:24]=[CH:25][CH:26]=[CH:27][C:14]=1[CH2:13][CH2:12][CH2:11][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH2:2][C:3](=[O:29])[NH:4]2)([CH3:23])[CH3:22]
Reactant: CC(C)(C)NCCOc1ccccc1CCCc1cccc2[nH]cc(Cl)c12
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)NCCOc1ccccc1CCCc1cccc2c1CC(=O)N2
Reaction time: 19 h

Procedure:
A mixture of 3.76 g of the product of Step A in 94 ml of 94% ethanol and 94 ml of aqueous N hydrochloric acid was stirred under an inert atmosphere for 19 hours and was diluted with water and iced. The mixture was made alkaline by addition of 32% sodium hydroxide solution and was extracted with ethyl acetate. The organic phase was washed with water, dried over a deshydrant, filtered and evaporated to dryness. The residue was chromatographed over silica and eluted with a 9-1 ethyl acetate-triethylamine mixture to obtain 2.18 g of 1,3-dihydro-4-[3-(2-{2-[1,1-dimethylethylamino]-ethoxy}-phenyl)-propyl]-2H-indol-2-one.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]2[O:12][CH:11]=[N:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[CH3:13][O:14][C:15]1[C:20](B2OC(C)(C)C(C)(C)O2)=[C:19]([CH3:30])[CH:18]=[CH:17][N:16]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CN(C1C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=CC=CC=1)C>CC(O)C.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:13][O:14][C:15]1[C:20]([C:2]2[CH:7]=[C:6]([C:8]3[O:12][CH:11]=[N:10][CH:9]=3)[CH:5]=[CH:4][N:3]=2)=[C:19]([CH3:30])[CH:18]=[CH:17][N:16]=1
Reactant: COc1nccc(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: Brc1cc(-c2cnco2)ccn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: CC(C)O
Product: COc1nccc(C)c1-c1cc(-c2cnco2)ccn1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
An oven-dried flask under argon was charged with the 2-bromo-4-oxazol-5-yl-pyridine (Intermediate II-c, 461 mg, 2.07 mmol), 2-methoxy-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine V-d (510 mg, 2.07 mmol), K3PO4 (2.82 g, 13.3 mmol), Pd(OAc)2 (51 mg, 0.225 mmol), Davephos (89 mg, 0.225 mmol) in iPrOH (5 mL) and water (3 mL). After 40 min at 100° C., the mixture was cooled to room temperature, diluted with water and extracted with EtOAc then washed with brine. The organics were dried (MgSO4), filtered and evaporated before purification by column chromatography (SiO2, 30% to 100% EtOAc in cyclohexane) to afford the desired product V-e as an off-white solid (240 mg, 43%). 1H NMR (300 MHz, CDCl3) δ 8.78 (d, J=4.8 Hz, 1H), 8.10 (d, J=4.8 Hz, 1H), 8.01 (s, 1H), 7.59 (d, J=4.9 Hz, 2H), 7.51 (d, J=4.9 Hz, 1H), 6.86 (d, J=4.9 Hz, 1H), 3.88 (s, 3H), 2.16 (s, 3H).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[C:20](=[CH:28]O)[C:21](=[O:27])[NH:22]2>>[CH3:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[C:20](=[CH:28][NH:16][C:13]1[CH:12]=[CH:11][C:10]([O:9][CH2:8][CH2:7][N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[CH:15][CH:14]=1)[C:21](=[O:27])[NH:22]2
Reactant: Cc1cccc2c1C(=CO)C(=O)N2
Reactant: Nc1ccc(OCCN2CCCCC2)cc1
Product: Cc1cccc2c1C(=CNc1ccc(OCCN3CCCCC3)cc1)C(=O)N2
Yield: 49.1 %

Procedure:
In a manner similar to that described in Example 231, 4-(2-piperidin-1-yl-ethoxy)-phenylamine (754 mg, 1.2 equiv.) and 4-methyl-3-hydroxymethylene-1,3-dihydro-indol-2-one (500 mg, 2.86 mmol, 1 equiv.) are reacted to give the named compound as a yellow solid (530 mg, 49%).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:17]=[C:18]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:24][CH:23]=3)[CH:19]=[CH:20][CH:21]=1)[C:10]([CH3:33])([CH3:32])[CH2:9]2)=[O:5])C.O.[OH-].[Li+].Cl>CO.O1CCCC1.O>[C:28]([C:25]1[CH:24]=[CH:23][C:22]([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([CH:11]3[C:10]([CH3:33])([CH3:32])[CH2:9][C:8]4[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=4)[NH:12]3)[CH:17]=2)=[CH:27][CH:26]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(-c3ccc(C(C)(C)C)cc3)c1)N2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(-c2cccc(C3Nc4ccc(C(=O)O)cc4CC3(C)C)c2)cc1
Temperature: 60 °C
Reaction time: 12 h
Yield: 69.1 %

Procedure:
A mixture of 2-(4′-tert-butyl-biphenyl-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.28 g, 0.63 mmol) in methanol (7 mL) and tetrahydrofuran (5 mL), lithium hydroxide hydrate (0.27 g, 6.3 mmol) in water (0.5 mL) was stirred at 60° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-(4′-tert-butyl-biphenyl-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (0.18 g, 70%) as a white solid which was used for next step without further purification: LC/MS m/e calcd for C28H31NO2 (M+H)+: 414.6, observed: 414.1;
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1.O=[C:12]1[CH2:17][CH2:16][CH:15]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:14][CH2:13]1.[BH4-].[Na+]>[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC.ClCCl>[N:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[NH:4][CH2:3][CH2:2][NH:1][CH:12]1[CH2:17][CH2:16][CH:15]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:14][CH2:13]1
Reactant: CCOC(=O)CC1CCC(=O)CC1
Reactant: NCCNc1ccccn1
Agent: [Ti+4]
Agent: CC[O-]
Agent: [BH4-]
Solvent: ClCCl
Product: CCOC(=O)CC1CCC(NCCNc2ccccn2)CC1
Temperature: -78 °C
Reaction time: 4 h

Procedure:
To a mixture of 2-(N-[2-(amino)-ethyl]-amino)-pyridine (685 mg, 5 mmol) and ethyl 2-(4-oxocyclohexyl)acetate (786 mg, 4 mmol) was added dichloromethane (4 mL) followed by titanium ethoxide (420 μL, 2 mmol, technical grade). The resulting mixture was stirred for 4 hr then concentrated under reduced pressure. The residue was taken up in methanol (10 mL) and cooled to −78° C. To this solution was added sodium borohydride (228 mg, 6 mmol). On complete addition, the cold bath was removed and stirring continued for 1.25 hr. The mixture was diluted with dichloromethane and poured into saturated sodium carbonate solution (15 mL). The organic phase was separated, dried over magnesium sulfate and concentrated to give the crude title compound as a 6:1 mixture trans:cis isomers. This mixture was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:12][CH2:11][N:10](CC2C=CC=CC=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:12][CH2:11][NH:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccccc2)CCN(Cc2ccccc2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NC1(c2ccccc2)CCNC1
Yield: 99.9 %

Procedure:
(1-Benzyl-3-phenylpyrrolidin-3-yl)carbamic acid tert-butyl ester (Hagen S. E., Domagala J. M., Heifetz C. L., Sanchez J. P., Solomon M., J. Med. Chem., 1990; 33(2):849–854) (2.79 g, 7.9 mmol) in 100 mL of methanol is treated with 1.0 g of 20% Pd/C and shaken for 17 hours under 50 psi of hydrogen. The solution is filtered and concentrated to afford 2.07 g of the title compound as a foam; MS EI+: m/z 263 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[C:17]([NH:24][C:25]3[S:26][C:27]([C:37](=[O:39])[NH2:38])=[C:28]([C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=4)[N:29]=3)[CH:16]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+]>[Zn].O1CCCC1>[C:1]([O:5][C:6](=[O:40])[NH:7][CH:8]1[CH2:9][CH2:10][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[C:17]([NH:24][C:25]3[S:26][C:27]([C:37](=[O:39])[NH2:38])=[C:28]([C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=4)[N:29]=3)[CH:16]=2)[CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCN(Cc2ccc([N+](=O)[O-])c(Nc3nc(-c4cccc(Cl)c4)c(C(N)=O)s3)c2)CC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCN(Cc2ccc(N)c(Nc3nc(-c4cccc(Cl)c4)c(C(N)=O)s3)c2)CC1
Reaction time: 0.25 h
Yield: 97 %

Procedure:
To a suspension of 0.250 g of (1-{3-[5-carbamoyl-4-(3-chloro-phenyl)-thiazol-2-ylamino]-4-nitro-benzyl}-piperidin-4-yl)-carbamic acid tert-butyl ester (VI.12a), 10 mL of tetrahydrofuran, and 10 mL of saturated ammonium chloride solution was added 0.15 g (6.9 mg-atom) of zinc powder. After 15 minutes, another 0.15 g of zinc powder was added. The mixture was stirred for another 10 minutes, then 0.15 g of zinc powder was added. The mixture was filtered, and 30 mL of saturated ammonium chloride solution plus 30 mL of tetrahydrofuran were added to the filtrate. The tetrahydrofuran layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 0.23 g of (1-{4-amino-3-[5-carbamoyl-4-(3-chloro-phenyl)-thiazol-2-ylamino]-benzyl}-piperidin-4-yl)-carbamic acid tert-butyl ester (VII.12), which was used directly in the next step.
Reaction SMILES: [H-].COCCO[Al+]OCCOC.[Na+].[H-].[OH-].[Na+].O.[Cl:18][C:19]1[CH:20]=[C:21]([CH2:26][C:27]([N:29]2[CH2:37][C@H:36]3[C@H:31]([CH2:32][CH:33]=[CH:34][CH2:35]3)[CH2:30]2)=O)[CH:22]=[CH:23][C:24]=1[Cl:25]>C1(C)C=CC=CC=1>[Cl:18][C:19]1[CH:20]=[C:21]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:26][CH2:27][N:29]1[CH2:37][C@H:36]2[C@H:31]([CH2:32][CH:33]=[CH:34][CH2:35]2)[CH2:30]1
Reactant: O=C(Cc1ccc(Cl)c(Cl)c1)N1C[C@H]2CC=CC[C@H]2C1
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Clc1ccc(CCN2C[C@H]3CC=CC[C@H]3C2)cc1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 0.70 g of this intermediate and 3 mL of toluene was added at 0° 2 mL of 3.4 M sodium bis(2-methoxyethoxy)aluminum hydride in toluene and the mixture was stirred in an ice bath for 1 hour and at room temperature for 4 hours. Aqueous sodium hydroxide solution (15%, 5 mL) and water (10 mL) were added with cooling. From the toluene layer there was obtained 0.66 g of crude product which was partitioned into a neutral and basic fraction. The latter was short-path distilled (140° bath temperature, 0.003 mm) to give 0.48 g of cis-2-(3,4-dichlorophenethyl)-3a,4,7,7a-tetrahydroisoindoline. 'H NMR (in CDCl3) : δ7.3 (AB quartet, 2H);7.0 (d/d, 1H); 5.8 (m, 2H); 3.0 (m, 2H); 2.8 (m, 4H), among others. The hydrochloride had m.p. 201°-202° after recrystallization from ethanol.
Reaction SMILES: N(OC(C)(C)C)=O.[CH2:8]([O:10][C:11]([C:13]1[NH:14][C:15]2[C:20]([CH:21]=1)=[C:19]([O:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[C:25]([F:30])[C:24]=1N)[CH:18]=[CH:17][CH:16]=2)=[O:12])[CH3:9]>CN(C)C=O.C(OCC)C>[CH2:8]([O:10][C:11]([C:13]1[NH:14][C:15]2[C:20]([CH:21]=1)=[C:19]([O:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[C:25]([F:30])[CH:24]=1)[CH:18]=[CH:17][CH:16]=2)=[O:12])[CH3:9]
Reactant: CCOC(=O)c1cc2c(Oc3cc(F)cc(F)c3N)cccc2[nH]1
Agent: CC(C)(C)ON=O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)c1cc2c(Oc3cc(F)cc(F)c3)cccc2[nH]1
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
Tert-butyl nitrite (0.547 ml, 4.6 mmol) is dissolved in 5 ml of dimethylformamide and heated to 65° C. A solution of 155 (1.5 g, 4.6 mmol) in 5 ml of dimethylformamide is added dropwise and the mixture is stirred of additional 10 minutes. The brown solution is cooled to room temperature, diluted with diethyl ether and washed with 2N HCl and brine. The organic layers are dried over sodium sulphate and evaporated. The crude product (1.5 g of a brown oil) is further purified by flash-chromatography (hexane/ethyl acetate 9:1).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:37]2[CH:42]=[CH:41][C:40]([O:43][CH2:44][O:45][CH3:46])=[CH:39][CH:38]=2)[C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]=2[S:21]([N:24]2[CH2:29][CH2:28][N:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[Cl:36])[CH2:26][CH2:25]2)(=[O:23])=[O:22])=[CH:7][CH:6]=1.Cl.[O:48]1[CH2:53][CH2:52][N:51]([CH2:54][CH2:55]Cl)[CH2:50][CH2:49]1>>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:37]2[CH:38]=[CH:39][C:40]([O:43][CH2:44][O:45][CH3:46])=[CH:41][CH:42]=2)[C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:55][CH2:54][N:51]3[CH2:52][CH2:53][O:48][CH2:49][CH2:50]3)[C:13]=2[S:21]([N:24]2[CH2:29][CH2:28][N:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[Cl:36])[CH2:26][CH2:25]2)(=[O:22])=[O:23])=[CH:7][CH:6]=1
Reactant: COCOc1ccc(C(c2ccc(OCOC)cc2)c2c(S(=O)(=O)N3CCN(c4ccccc4Cl)CC3)[nH]c3ccccc23)cc1
Reactant: ClCCN1CCOCC1
Agent: Cl
Product: COCOc1ccc(C(c2ccc(OCOC)cc2)c2c(S(=O)(=O)N3CCN(c4ccccc4Cl)CC3)n(CCN3CCOCC3)c3ccccc23)cc1

Procedure:
Substantially the same procedure as in Example 243 was repeated using Compound 241 (1.1 g, 1.66 mmol) obtained in Example 242 and 2-morpholinoethylchloride hydrochloride (310 mg, 1.66 mmol) to give 1.3 g (quantitative) of the title compound.
Reaction SMILES: ClC(OCC)=O.[CH2:7]([C:9]1[CH:19]=[CH:18][C:12]([CH:13]=[CH:14][C:15](O)=[O:16])=[CH:11][CH:10]=1)[CH3:8].C(N(CC)CC)C.[BH4-].[Na+].Cl>C1COCC1.O>[CH2:7]([C:9]1[CH:19]=[CH:18][C:12](/[CH:13]=[CH:14]/[CH2:15][OH:16])=[CH:11][CH:10]=1)[CH3:8]
Reactant: CCc1ccc(C=CC(=O)O)cc1
Agent: CCOC(=O)Cl
Agent: Cl
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CCc1ccc(/C=C/CO)cc1
Reaction time: 0.5 h

Procedure:
General Procedure G. A solution of ethyl chloroformate (1.1 ml, 11.4 mmol) in THF (5 ml) was added to a solution of 4-ethylcinnamic acid (2 g, 11.4 mmol) and triethylamine (1.6 ml, 11.4 mmol) in THF (50 ml) at −5° C. to −10° C., and the solution was stirred for 30 min. The resulting white precipitate was filtered off, rinsed with THF (10 ml), and the combined filtrates were added to a solution of NaBH4 (945 mg, 24.9 mmol) in H2O (20 ml) slowly in order to maintain an internal temperature of 10° C. to 15° C. After the addition was completed, the reaction was stirred at room temperature for 4 hours, and then it was made acidic with HCl (20%). The layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with NaHCO3 (aq), and water, and brine, and dried over Na2SO4. The filtered solution was concentrated in vacuo, and the residue was purified by column chromatography (20% ethyl acetate in hexane) to yield a white solid.
Reaction SMILES: [OH:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11]O)[OH:10])O)O)=O.CCCCCCCCCCCC[N+](CC([O-])=O)(C)C.[Na+].[Cl-:33].O.Cl>C1(C)C=CC=CC=1>[Cl:33][CH2:11][C:9]1[O:10][C:3]([CH:2]=[O:1])=[CH:5][CH:7]=1
Reactant: [Cl-]
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: CCCCCCCCCCCC[N+](C)(C)CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=Cc1ccc(CCl)o1
Reaction time: 3 h

Procedure:
To a three-necked flask equipped with a condenser and a stirrer were added 5 g (0.028 mole) of a commercially available D-(-)-fructose and a surface active agent, 82.3 mg (0.00028 mole) of lauryldimethylbetaine. Then, 5 ml of water and 30 ml of toluene were added thereto and the mixture was stirred. Thereafter, a molar excess of hydrogen chloride was passed through the mixture at room temperature for about 30 minutes with thorough stirring. After the reaction was continued at room temperature for a further 3 hours, the upper toluene layer was separated from the lower aqueous layer. Thirty milli-liters of toluene and the above surface active agent in the same amount as above were then freshly added to the aqueous layer. After the reaction was carried out at room temperature for 3 hours, the upper toluene layer was again separated. This toluene extraction operation was repeated three times in total. All the toluene layers were combined and filtered through Celite. The filtrate was neutralized with an aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate and concentrated. Thus, about 2.9 g of 5-chloromethylfurfural was obtained as a crude product.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:21]1[N:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:23][N:22]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)C>[CH2:28]([O:27][C:24]1[CH:23]=[N:22][C:21]([C:14]2[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:12][CH:13]=2)=[N:26][CH:25]=1)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: OB(O)c1ccc(CCOCc2ccccc2)cc1
Reactant: CCCCCCCCCCOc1cnc(Cl)nc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCCCCCCCCOc1cnc(-c2ccc(CCOCc3ccccc3)cc2)nc1
Yield: 62 %

Procedure:
8.62 g (33.7 mmol) of 4-(2-benzyloxyethyl) phenyl boronic acid, 9.13 g (33.7 mmol) of 2-chloro-5-decyloxypyrimidine, 1.29 g of tetrakis (triphenylphosphine) palladium, 54 ml of 2M-sodium carbonate solution, 54 ml of toluene and 27 ml of ethanol were heated at 80° C. for 4 hours under presence of nitrogen. After reactions had been completed, extraction with toluene was performed. Then, the extracted solution was dried with anhydrous sodium sulfate. The solvent was removed by filtration, and then refining was performed by recrystallization (toluene/methanol) so that 9.30 g of 2-{4-(5-decyloxypyrimidine-2-yl) phenyl}ethylbenzylether was obtained (yield 62%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([S:16][C:17]2[CH:18]=[CH:19][C:20]3[N:24]=[C:23]([CH2:25][O:26][C:27]4[CH:32]=[CH:31][C:30]([CH2:33][CH:34]([O:39][CH2:40][C:41]5[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=5)[C:35]([O:37]C)=[O:36])=[CH:29][CH:28]=4)[N:22]([CH3:48])[C:21]=3[CH:49]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([C:5]1[CH:6]=[C:7]([S:16][C:17]2[CH:18]=[CH:19][C:20]3[N:24]=[C:23]([CH2:25][O:26][C:27]4[CH:32]=[CH:31][C:30]([CH2:33][CH:34]([O:39][CH2:40][C:41]5[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=5)[C:35]([OH:37])=[O:36])=[CH:29][CH:28]=4)[N:22]([CH3:48])[C:21]=3[CH:49]=2)[CH:8]=[C:9]([C:12]([CH3:14])([CH3:15])[CH3:13])[C:10]=1[OH:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)C(Cc1ccc(OCc2nc3ccc(Sc4cc(C(C)(C)C)c(O)c(C(C)(C)C)c4)cc3n2C)cc1)OCc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1c(COc2ccc(CC(OCc3ccc(F)cc3)C(=O)O)cc2)nc2ccc(Sc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)cc21
Yield: 60.3 %

Procedure:
Reaction and isolation were conducted in a similar procedure to that described in Example 2 using methyl 3-[4-[6-(3,5-di-t-butyl4-hydroxyphenylthio)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyl]-2-(4-fluorobenzyloxy)propionate (0.22 g), aqueous 2N sodium hydroxide solution (2 ml) and methanol (5 ml) to afford the title compound (0.13 g, mp 40-46° C.).