Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][NH:4][C:3](=O)[CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[S:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: O=C1CSc2ccccc2CN1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: c1ccc2c(c1)CNCCS2

Procedure:
4,5-Dihydro-1,4-benzothiazepin-3(2H)-one (12 g, prepared in a similar manner to example 1 of international patent application WO 92/21668) was added to a stirred solution of lithium aluminium hydride (6.3 g) in dry tetrahydrofuran (400 ml). After the addition, the reaction mixture was heated under reflux for ten minutes and cooled. Excess of lithium aluminium hydride was decomposed by adding a saturated aqueous solution of sodium sulphate. The mixture was filtered and the solvent was removed from the filtrate by evaporation to give 2,3,4,5-tetrahydro-1,4-benzothiazepine as an oil which was used without further purification. Yield 9.4 g.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.[OH-].[Na+].ClCCl>BrCCCBr.O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[C:5]([CH2:6][CH2:7][CH2:8][Br:15])([CH2:4][CH2:3][CH2:2][Br:1])[C:4]=2[CH:3]=1
Reactant: Brc1ccc2c(c1)Cc1cc(Br)ccc1-2
Agent: BrCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: O
Solvent: ClCCl
Product: BrCCCC1(CCCBr)c2cc(Br)ccc2-c2ccc(Br)cc21
Reaction time: 6 h
Yield: 30 %

Procedure:
The following products are added, in an inert atmosphere, to a solution of 2,7-dibromofluorene (10.0 g, 31.06 mmoles) in 40 ml of 1,3-dibromopropane: first sodium hydroxide (30.0 g, 750.0 mmoles) dissolved in 60 ml of water and finally 0.2 g of tetrabutylammonium bromide. The temperature is brought to 100° C. After 6 hours, after the addition of water, extraction is effected with dichloromethane. After washing the organic phase with water until neutrality, said organic phase is anhydrified on sodium sulfate. The dichloromethane and 1,3-dibromopropane in excess are removed by distillation at reduced pressure. After purification by elution on a chromatographic silica gel column (eluent: heptane/ethyl acetate=99/1), 5.2 g of 2,7-dibromo-9,9-bis(3′-bromopropyl)fluorene are obtained (yield=30%).
Reaction SMILES: [CH:1]([C:3]1[C:7]2[NH:8][C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:10][C:6]=2[O:5][CH:4]=1)=[CH2:2]>CCOC(C)=O.[Pd]>[CH2:1]([C:3]1[C:7]2[NH:8][C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:10][C:6]=2[O:5][CH:4]=1)[CH3:2]
Reactant: C=Cc1coc2cc(C(=O)OCC)[nH]c12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2occ(CC)c2[nH]1
Yield: 90.8 %

Procedure:
A solution of ethyl 3-vinyl-4H-furo[3,2-b]pyrrole-5-carboxylate (105 mg, 0.51 mmol) in EtOAc (8 mL) in a 40-mL scintillation vial was treated with 10% Pd/C (˜15 mg) and a balloon of H2. The system was evacuated and refilled three times with H2 before hydrogenating at rt for 6 h. The catalyst was removed by filtration over Celite® and the filtrate was concentrated. The crude product was purified by flash chromatography (0-10% EtOAc/heptane) to give ethyl 3-ethyl-4H-furo[3,2-b]pyrrole-5-carboxylate (96 mg, 91%). 1H NMR (400 MHz, CDCl3) δ ppm 1.30 (t, J=7.54 Hz, 3H), 1.36-1.42 (m, 3H), 2.57-2.64 (m, 2H), 4.33-4.40 (m, 2H), 6.76 (d, J=1.66 Hz, 1H), 7.31 (t, J=1.12 Hz, 1H); LCMS-MS (ESI+) 207.83 (M+H).
Reaction SMILES: C([N:4]([CH2:14][C@@H:15]1[O:19][C:18](=[O:20])[N:17]([C:21]2[CH:26]=[CH:25][C:24]([CH:27]3[CH2:32][CH2:31][S:30](=[O:34])(=[O:33])[CH2:29][CH2:28]3)=[C:23]([F:35])[CH:22]=2)[CH2:16]1)[C:5]([O:7][CH2:8][O:9]C(=O)CC)=[O:6])(=O)C.C(Cl)(=O)OC[O:39][C:40](=O)[CH2:41][CH:42]([CH3:44])[CH3:43]>ClCCl>[O:34]=[S:30]1(=[O:33])[CH2:31][CH2:32][CH:27]([C:24]2[CH:25]=[CH:26][C:21]([N:17]3[CH2:16][C@H:15]([CH2:14][NH:4][C:5]([O:7][CH2:8][O:9][C:40](=[O:39])[CH2:41][CH:42]([CH3:44])[CH3:43])=[O:6])[O:19][C:18]3=[O:20])=[CH:22][C:23]=2[F:35])[CH2:28][CH2:29]1
Reactant: CCC(=O)OCOC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(C)=O
Reactant: CC(C)CC(=O)OCOC(=O)Cl
Solvent: ClCCl
Product: CC(C)CC(=O)OCOC(=O)NC[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1
Yield: 93 %

Procedure:
Following general procedure C, (S)-5-aminomethyl-3-[4-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-yl)-3-fluoro-phenyl]-oxazolidin-2-one (2) (760.0 mg, 2.2 mmol) in dichloromethane (21 mL) and 3-methyl-butyroxymethyl carbonochloridate (7d) gave the titled product in 93% yield (1030.0 mg, 2.06 mmol). 1H NMR (400 MHz, CDCl3): δ 7.47 (dd, 1H), 7.23 (t, 1H), 7.16 (dd, 1H), 5.73 (q, 2H), 5.37 (t, 1H) 4.76-4.82 (m, 1H), 4.05 (t, 1H), 3.78 (dd, 1H), 3.67 (ddd, 1H), 3.55 (dt, 1H), 3.12-3.19 (m, 4H), 3.09 (dt, 1H), 2.34-2.45 (m, 2H), 2.14-2.21 (m, 2H), 2.07 (sept, 1H), 0.92 (dd, 6H). MS-APCI (m/z+): 501 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][N:11]=[C:10]([C:13]3(O)[CH2:21][CH:20]4[N:16]([CH2:17][CH2:18][CH2:19]4)[CH2:15][CH2:14]3)[C:9]=2[C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:12][N:11]=[C:10]([C:13]3[CH2:21][CH:20]4[N:16]([CH2:17][CH2:18][CH2:19]4)[CH2:15][CH:14]=3)[C:9]=2[C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[CH:6][CH:7]=1
Reactant: OC1(c2n[nH]c(-c3ccc(F)cc3)c2-c2ccncc2)CCN2CCCC2C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Fc1ccc(-c2[nH]nc(C3=CCN4CCCC4C3)c2-c2ccncc2)cc1
Yield: 37.2 %

Procedure:
The compound prepared as described in Example 2 (720 mg, 1.90 mmol) was dissolved in concentrated hydrochloric acid (14 ml). The resulting solution was heated under reflux for 8 hours. At the end of this time, the reaction mixture was neutralized with an aqueous solution of 1 N sodium hydroxide, and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel (eluent, ethyl acetate:methanol:isopropylamine=10:1:1), to give the title compound (Rf=0.45, 255 mg) as a white powder (yield 37%).
Reaction SMILES: FC(F)(F)C(O)=O.C1N2CN3CN(C2)CN1C3.[CH2:18]([C:30]1[C:35]([CH3:36])=[C:34]([CH2:37][OH:38])[C:33]([OH:39])=[C:32]([CH3:40])[CH:31]=1)[C:19]1[C:24]([CH3:25])=[C:23]([CH2:26][OH:27])[C:22]([OH:28])=[C:21]([CH3:29])[CH:20]=1.O>C1(C)C=CC=CC=1.C(C(C)=O)C(C)C>[CH2:18]([C:19]1[C:24]([CH3:25])=[C:23]([CH:26]=[O:27])[C:22]([OH:28])=[C:21]([CH3:29])[CH:20]=1)[C:30]1[C:35]([CH3:36])=[C:34]([CH:37]=[O:38])[C:33]([OH:39])=[C:32]([CH3:40])[CH:31]=1
Reactant: Cc1cc(Cc2cc(C)c(O)c(CO)c2C)c(C)c(CO)c1O
Agent: C1N2CN3CN1CN(C2)C3
Solvent: CC(=O)CC(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1cc(Cc2cc(C)c(O)c(C=O)c2C)c(C)c(C=O)c1O
Temperature: 80 °C
Reaction time: 20 h
Yield: 96.7 %

Procedure:
171.0 g (1.5 mol) of trifluoroacetic acid was put in a four-way flask with a capacity of 1 liter and the reaction container was substituted by nitrogen, after which 47.3 g (0.34 mol) of hexamethylene tetramine was added at a temperature of approx. 25° C., and then 47.4 g (0.15 mol) of 4,4′-methylene bis(2,5-dimethyl-6-hydroxymethylphenol) was added under agitation over 2.5 hours at a temperature of 50° C. to cause reaction. After the entire amount of the material had been added, the temperature was raised to 80° C., and then the mixture was further agitated for 20 hours as a post-reaction. Next, 150.0 g of water was added to the mixture liquid obtained from the reaction to implement hydrolysis reaction for 1 hour at a temperature of 70° C. (crystal precipitated during this reaction). 245.7 g of 16% aqueous sodium hydroxide solution was added to neutralize the obtained mixture liquid, which was then kept at a temperature of 80° C. for 1 hour. Thereafter, the mixture was cooled and precipitated crystal was filtered out to obtain 72.3 g of coarse crystal. Next, the obtained coarse crystal was put in a four-way flask with a capacity of 1 liter, and then 70.0 g of methyl isobutyl ketone and 50.0 g of toluene were added and the mixture was kept at a temperature of 80° C. for 1 hour (the solution was in a slurry state), after which the mixture was cooled and precipitated crystal was filtered out and dried to obtain 45.3 g of yellow powder having a purity of 94.6% based on HPLC.
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-])=O)[CH:19]=2)=[CH:14][CH2:13]1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6]>CO.[Pd]>[NH2:24][C:20]1[CH:19]=[C:18]([C:15]2[CH2:16][CH2:17][N:12]([CH2:11][CH2:10][N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:6])([CH3:7])[CH3:8])[CH2:13][CH:14]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: CN(CCN1CC=C(c2cccc([N+](=O)[O-])c2)CC1)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CN(CCN1CC=C(c2cccc(N)c2)CC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.1 %

Procedure:
A mixture of 189 (416.2 mg, 1.152 mmol) and 10% Pd/C (300 mg) in Methanol (25 mL) was shaken under H2 (50 psi) for 18 h at room temperature. The catalyst was filtered through Celite and the filtrate was taken to dryness to give 190 (349 mg, 1.05 mmol, 91% yield) as an orange oil. LRMS (ESI): calc. 333.2, found 334.2 (MH)+.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[O-]CC.[Na+].O.[N+:20]([CH3:23])([O-:22])=[O:21]>C(O)C>[OH:1][C:2]1([CH2:23][N+:20]([O-:22])=[O:21])[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1
Reactant: C[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(O)(C[N+](=O)[O-])CC1
Temperature: 25 °C

Procedure:
To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (52.65 g, 264 mmol) in nitromethane (21 mL) and ethanol (8 mL) was added a solution of sodium ethoxide in ethanol (2.67 M, 5.0 mL, 13.4 mmol). The mixture was stirred at rt and more ethanol (30 mL) was added. The mixture was sonicated for 15 min, stirred overnight, then sonicated again. To the mixture was added water (400 mL). The solid was isolated by filtration, washed with water (300 mL), and dried to yield tert-butyl 4-hydroxy-4-(nitromethyl)piperidine-1-carboxylate as a white solid, 67.60 g (98%).
Reaction SMILES: [CH3:1][NH2:2].[CH2:3]([CH:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23]OS(C)(=O)=O)=[CH:16][CH:15]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:5][CH3:6]>CO.C1(C)C=CC=CC=1>[CH2:3]([CH:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][NH:2][CH3:1])=[CH:16][CH:15]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:5][CH3:6]
Reactant: CN
Reactant: CCCCC(Cc1ccc(OCCCOS(C)(=O)=O)cc1)C(=O)OCC
Solvent: Cc1ccccc1
Solvent: CO
Product: CCCCC(Cc1ccc(OCCCNC)cc1)C(=O)OCC
Temperature: 90 °C
Reaction time: 48 h

Procedure:
A solution of methylamine in methanol (40%, 5.0 ml) was added to a solution of ethyl 2-butyl-3-[4-(3-methansulfonyloxypropoxy)phenyl]propionate (500 mg), which is the product of Reference example 21 (c) in toluene (10 ml). The mixture was stirred at 90° C. for 2 days. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water and the layers were separated. The ethyl acetate solution was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified via chromatography on a silica gel column using dichloromethane/methanol=5/1 as the eluant to afford the title compound (389 mg) as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([Cl:9])=[CH:4][C:3]=1[CH3:10].[Br:11]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([Cl:9])=[CH:4][C:3]=1[CH2:10][Br:11]
Reactant: Cc1cc(Cl)c(F)cc1Br
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1cc(Br)c(CBr)cc1Cl

Procedure:
A solution of 75 mmol of 1-bromo-4-chloro-5-fluoro-2-methyl-benzene, 75 mmol of 1-bromo-pyrrolidine-2,5-dione and 0.74 mmol of benzoyl peroxide in 100 ml of carbon tetrachloride is heated to reflux for 15 hours. After evaporation of the solvent, the residue is partitioned between water and ethyl acetate. The organic layer is washed with water, and then with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue is purified by flash chromatography (SiO2 60 F) to afford the title compound which is identified based on the Rf value.
Reaction SMILES: Cl[CH2:2][C:3](=[O:5])[CH3:4].[I-].[K+].[Cl:8][C:9]1[CH:10]=[C:11]([S:16][C:17]2[NH:21][C:20]([CH2:22][O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[N:19][C:18]=2[CH:33]([CH3:35])[CH3:34])[CH:12]=[C:13]([Cl:15])[CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:3]([CH2:2][N:21]1[C:17]([S:16][C:11]2[CH:12]=[C:13]([Cl:15])[CH:14]=[C:9]([Cl:8])[CH:10]=2)=[C:18]([CH:33]([CH3:34])[CH3:35])[N:19]=[C:20]1[CH2:22][O:23][CH2:24][C:25]1[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=1)(=[O:5])[CH3:4]
Reactant: CC(=O)CCl
Reactant: COc1ccc(COCc2nc(C(C)C)c(Sc3cc(Cl)cc(Cl)c3)[nH]2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(COCc2nc(C(C)C)c(Sc3cc(Cl)cc(Cl)c3)n2CC(C)=O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 54.7 %

Procedure:
In acetone (2 ml) was dissolved 111 mg (1.20 mmol) of chloroacetone, followed by addition of 200 mg (1.2 mmol) of potassium iodide, and the mixture was stirred at room temperature for 15 minutes. Then, 437 mg (1.00 mmol) of 5-(3,5-dichlorophenylthio)-4-isopropyl-2-(p-methoxybenzyloxymethyl)-1H-imidazole (16b) and 170 mg (1.20 mmol) of potassium carbonate were added in order, and the mixture was stirred for 5 hours and was left overnight. This reaction mixture was concentrated under reduced pressure and the residue was extracted with methylene chloride. The organic layer was washed with water, dried over anhydrous sodium sulfate and the solvent was concentrated under reduced pressure. The residue was fractionated by silica gel chromatography (ethyl acetate:methylene chloride=1:9). The oil was crystallized from ether to provide 270 mg (yield 62%) of 1-acetylmethyl-5-(3,5-dichlorophenylthio)-4-isopropyl-2-(p-methoxybenzyloxymethyl)-1H-imidazole (17v). mp 87-90° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:12]=[CH:11][NH:10][C:9](=O)[CH2:8][C:7]=2[CH:14]=1.B.[ClH:16]>O1CCCC1>[ClH:16].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][C:7]=2[CH:14]=1
Reactant: COc1ccc2c(c1)CC(=O)NC=C2
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CCNCC2

Procedure:
A suspension of 8-methoxy-2-oxo-1H-3-benzazepine (20.4 g, 0.105 m) in tetrahydrofuran (500 ml) was added to 1M borane in tetrahydrofuran (300 ml) stirred at 5° . The mixture was heated to reflux for 2 hours, cooled, treated with 3N hydrochloric acid (300 ml), concentrated in vacuo to remove tetrahydrofuran and heated to reflux for 1 hour. The mixture was concentrated in vacuo, filtered and the filter cake was dissolved in methanol, heated to reflux, dried with magnesium sulfate and concentrated in vacuo to afford 7-methoxy-2,3,4,5-tetrahydro-1H-3benzazepine hydrochloride, m.p. 229°-231°.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([C@H:16]1[CH2:20][CH2:19][C@H:18]([C:21](=[O:31])[C:22]2[CH:27]=[CH:26][C:25]3[O:28][CH2:29][O:30][C:24]=3[CH:23]=2)[NH:17]1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[BH4-].[Na+].C(O)C>CO>[CH2:8]([CH:16]1[CH2:20][CH2:19][CH:18]([CH:21]([OH:31])[C:22]2[CH:27]=[CH:26][C:25]3[O:28][CH2:29][O:30][C:24]=3[CH:23]=2)[NH:17]1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(c1ccc2c(c1)OCO2)[C@H]1CC[C@H](CCc2ccccc2)N1
Agent: [BH4-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Solvent: CO
Product: OC(c1ccc2c(c1)OCO2)C1CCC(CCc2ccccc2)N1

Procedure:
2-[phenethyl]-5-[(3,4-methylenedioxy)benzoyl]pyrrolidine trifluoroacetate (XIV) is reduced with metal borohydride, preferably with sodium borohydride, in a lower alcohol, preferably ethanol or methanol, at -10° to +20° C. The solvent is removed, the aqueous residue is diluted with the solution of base, preferably saturated sodium carbonate, and the product is extracted to organic halogenated solvent, preferably dichloromethane, to result in ±trans erythro 2-[phenethyl]-5-[(3,4-methylenedioxy)-α-hydroxybenzyl]pyrrolidine compound (XV). ##STR16##
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:17])=[N:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:12]([CH3:13])[C@@H:10]([OH:11])[C@H:8]1[OH:9].[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:18]([NH:17][C:3]1[C:2]([F:1])=[CH:15][N:6]([C@@H:7]2[O:14][C@H:12]([CH3:13])[C@@H:10]([O:11][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C@H:8]2[O:9][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5](=[O:16])[N:4]=1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C[C@H]1O[C@@H](n2cc(F)c(N)nc2=O)[C@H](O)[C@@H]1O
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: C[C@H]1O[C@@H](n2cc(F)c(NC(=O)c3ccccc3)nc2=O)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1

Procedure:
5'-Deoxy-5-fluorocytidine (245 mg), benzoyl chloride (400 μl) and 4-dimethylaminopyridine (122 mg) were dissolved in dry pyridine (5 ml). After stirring for 3 hours at room temperature pyridine was removed under reduced pressure. The residue was partitioned between ethyl acetate and water. The ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from methanol to give N4,2'-O,3'-O-tribenzoyl-5'-deoxy-5-fluorocytidine (280 mg), mp 158°~160° C.; MS 558 (MH+).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[C:12]([CH3:19])[CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.[Zn]>[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([CH3:19])[CH:11]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Cc1cc(OCc2ccccc2)ccc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1cc(OCc2ccccc2)ccc1N
Temperature: 45 °C
Reaction time: 3 h
Yield: 70.3 %

Procedure:
A solution of 190 ml of concentrated hydrochloric acid in 300 ml of ethanol is added dropwise to a mixture of 50 g of 4-benzyloxy-2-methyl-1-nitrobenzene and of 46 g of zinc. The solution is cooled to around 45° C. by means of an ice bath throughout the running-in process. The medium is stirred for 3 hours at ambient temperature. The pH of the solution is adjusted to around pH 8 by adding 500 ml of a saturated potassium carbonate solution. The precipitate is filtered off and washed with 5×500 ml of ethyl acetate. The organic phases are combined and washed with 2×1 liter of distilled water, then with 1 liter of a saturated sodium chloride solution. After drying over magnesium sulfate, the solvent is evaporated off under reduced pressure in a rotary evaporator. The reaction crude is purified by flash chromatography (silica 35-70 μm), eluent: ethyl acetate/cyclohexane 80:20; 75:25; 70:30. 30.81 g of 4-benzyloxy-2-methylphenylamine are isolated.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([N:10]([CH2:14][CH2:15][CH3:16])[CH2:11][CH2:12][CH3:13])[N:5]2[CH:17]=1.[CH3:18][C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=1B(O)O.CC([O-])(C)C.[K+]>COCCOC.CC(O)(C)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:18][C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=1[C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([N:10]([CH2:14][CH2:15][CH3:16])[CH2:11][CH2:12][CH3:13])[N:5]2[CH:17]=1
Reactant: CCCN(CCC)c1cccc2nc(Br)cn12
Reactant: Cc1ccc(B(O)O)c(C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CC(C)(C)O
Product: CCCN(CCC)c1cccc2nc(-c3ccc(C)cc3C)cn12
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 1.7 %

Procedure:
2-Bromo-N,N-dipropylimidazo[1,2-a]pyridin-5-amine (prepared in example 61) (0.17 g, 0.57 mmol) was dissolved in 1,2-dimethoxyethane (DME) (1.5 mL). Pd(PPh3)4 (0.033 g, 0.028 mmol) was added and the reaction was stirred at 50° C. for 15 minutes. The solution was cooled and 2,4-dimethylphenylboronic acid (0.103 g, 0.69 mmol) in DME (1 mL) was added to the reaction mixture. KOtBu (0.128 g, 1.14 mmol) in tBuOH (1 mL) was also added to the reaction. The reaction was heated to 100° C. for 1 hr. The solution was filtered through paper and concentrated. Crude material was purified via reverse phase HPLC (acetonitrile containing 0.1% TFA/water containing 0.1% TFA) to obtain 3.1 mg of the title compound (2% yield).
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:8]([CH3:19])=[C:9]([CH3:18])[C:10]([CH3:17])=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[CH:12]2.[CH:20](N1CCCCC1)=[O:21].S(=O)(=O)(O)O.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[CH3:17][C:10]1[C:9]([CH3:18])=[C:8]([CH3:19])[C:7]([CH:20]=[O:21])=[C:16]2[C:11]=1[CH:12]=[CH:13][CH:14]=[N:15]2
Reactant: Cc1c(C)c(Br)c2ncccc2c1C
Reactant: O=CN1CCCCC1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1c(C)c(C=O)c2ncccc2c1C
Temperature: -40 °C

Procedure:
n-Butyl lithium (2.1 equiv; 1.55M in hexane) was added slowly to a suspension of 8-bromo-5,6,7-trimethylquinoline (4.2 g) in anhydrous THF (40 ml) under nitrogen at -90° C. After 3 hr a solution of N-formylpiperidine (2.1 equiv) in anhydrous THF (10 ml) was added to the mixture was warmed to -40° C. over ca. 2 hr. A dilute sulfuric acid solution (1N; 20 ml) was added and the mixture was warmed to room temperature. The mixture was made basic by the addition of potassium carbonate and was then extracted with ether. The dried (MgSO4) organic fraction was evaporated and the residue was purified by column chromatography over alumina with carbon tetrachloride/dichloromethane (1:1 v/v) elution to give 5,6,7-trimethylquinoline-8-carboxaldehyde as a pale yellow solid, mp 162° C. Pmr specturm (CDCl3 ; δ in ppm): 2.48 (3H,s); 2.68 (3H,s); 2.74 (3H,s); 7.43-8.96 (3H,m); 11.61 (1H,s).
Reaction SMILES: [N:1]1([C:15]([C@H:17]([NH:27][C:28](=[O:40])[C:29]([NH:32]C(OC(C)(C)C)=O)([CH3:31])[CH3:30])[CH2:18][O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:16])[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][CH2:7]2)[CH2:3][CH2:2]1.CN1CCOCC1.[CH2:48]([S:50](Cl)(=[O:52])=[O:51])[CH3:49]>ClCCl>[CH2:48]([S:50]([N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:4]2([CH2:5][CH2:6][N:1]([C:15]([C@H:17]([NH:27][C:28](=[O:40])[C:29]([NH2:32])([CH3:30])[CH3:31])[CH2:18][O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:16])[CH2:2][CH2:3]2)[CH2:7]1)(=[O:52])=[O:51])[CH3:49]
Reactant: CCS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](COCc1ccccc1)C(=O)N1CCC2(CC1)CNc1ccccc12
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCS(=O)(=O)N1CC2(CCN(C(=O)[C@@H](COCc3ccccc3)NC(=O)C(C)(C)N)CC2)c2ccccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 0.158 g the intermediate from Step B in 5 mL of dichloromethane was added 0.053 mL of N-methylmorpholine, and 0.034 mL of ethanesulfonylchloride and stirred at 0° C. for 30 min and RT for 1 h. The reaction mixture was diluted with an additional 5 mL of dichloromethane and washed with 5 mL of saturated sodium bicarbonate solution, brine (5 mL), dried over MgSO4 and concentrated. Flash chromatography of the residue over 10 g of silica gel with CH2Cl2 -ether (3:1) as eluent gave 0.057 g of the desired product.