Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH2:22][CH:23]3[CH2:26][CH2:25][CH2:24]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:33][C:34]1[C:39]([F:40])=[C:38]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH:37]=[CH:36][C:35]=1B(O)O>COCCOC.[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>[CH:23]1([CH2:22][O:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][O:14][C:11]2[CH:12]=[CH:13][C:8]([C:5]3[C:4]([C:35]4[CH:36]=[CH:37][C:38]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])=[C:39]([F:40])[C:34]=4[F:33])=[CH:3][CH:2]=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)[CH2:26][CH2:25][CH2:24]1
Reactant: CCCCCCCCOc1ccc(B(O)O)c(F)c1F
Reactant: Brc1ccc(-c2ccc(OCCCCCCOCC3CCC3)cc2)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCCCCCCCOc1ccc(-c2ccccc2-c2ccc(OCCCCCCOCC3CCC3)cc2)c(F)c1F

Procedure:
4-Bromo-4′-[6-(cyclobutylmethoxy)hexyloxy]biphenyl (0.70 g, 1.7 mmol) from step 3 and a 2M-aqueous solution of sodium carbonate (40 ml) were mixed in DME (60 ml) and with tetrakis(triphenylphosphine)-palladium(0) (0.12 g, 0.12 mmol) under dry nitrogen; to which 2,3-difluoro-4-octyloxyphenylboronic acid (prepared as described in Example 1 step 4) (0.58 g, 2.0 mmol) was added. The stirred reaction mixture was heated under reflux overnight. The product was extracted into DCM and washed with brine, water and dried (MgSO4). The solvent was removed under reduced pressure and the residue was purified by column chromatography [DCM-hexane, 1:5] and recrystallised from hexane to give white crystals.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:46]1[N:47]=[C:48]([NH2:51])[S:49][CH:50]=1)[C:5]([NH:7][CH:8]1[C:44](=[O:45])[N:10]2[C:11]([C:28]([O:30][CH:31]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:29])=[C:12]([CH2:15][O:16][C:17](=[O:27])[C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=3)[CH2:13][S:14][C@H:9]12)=[O:6]>C(O)C.O1CCCC1>[CH3:1][O:2][N:3]=[C:4]([C:46]1[N:47]=[C:48]([NH2:51])[S:49][CH:50]=1)[C:5]([NH:7][CH:8]1[C:44](=[O:45])[N:10]2[C:11]([C:28]([O:30][CH:31]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:29])=[C:12]([CH2:15][O:16][C:17](=[O:27])[C:18]3[CH:19]=[CH:20][C:21]([NH2:24])=[CH:22][CH:23]=3)[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(COC(=O)c3ccc([N+](=O)[O-])cc3)CS[C@H]12)c1csc(N)n1
Solvent: C1CCOC1
Solvent: CCO
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(COC(=O)c3ccc(N)cc3)CS[C@H]12)c1csc(N)n1
Reaction time: 3 h
Yield: 72.8 %

Procedure:
Platinic oxide (0.4 g.) was added to a solution of benzhydryl 7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(4-nitrobenzoyloxymethyl)-3-cephem-4-carboxylate (syn isomer) (4.3 g.) in a mixture of ethanol (50 ml.) and tetrahydrofuran (50 ml.), and the suspension was subjected to catalytic reduction at ambient temperature under ordinary pressure for 3 hours. After removing the catalyst from the resultant mixture by filtration, the filtrate was evaporated under reduced pressure. The residue was dissolved in ethyl acetate and the solution was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The residue was pulverized with diethyl ether to give benzhydryl 7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(4-aminobenzoyl-oxymethyl)-3-cephem-4-carboxylate (syn isomer) (3.0 g.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[CH:15]1[CH2:20][CH2:19][N:18]([C:21](Cl)=[O:22])[CH2:17][CH2:16]1.[N:24]1([C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.CCN(C(C)C)C(C)C>O1CCOCC1>[N:24]1([C:31]2[CH:32]=[CH:33][C:34]([NH:37][C:21]([N:18]3[CH2:19][CH2:20][CH:15]([C:6]4[C:5]5[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=5)[N:9]=[CH:8][N:7]=4)[CH2:16][CH2:17]3)=[O:22])=[CH:35][CH:36]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: COc1cc2ncnc(C3CCN(C(=O)Cl)CC3)c2cc1OC
Reactant: Nc1ccc(N2CCCCCC2)cc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(C3CCN(C(=O)Nc4ccc(N5CCCCCC5)cc4)CC3)c2cc1OC
Temperature: 100 °C
Reaction time: 3 h
Yield: 6.1 %

Procedure:
4-(6,7-Dimethoxy-quinazolin-4-yl)-piperidine-1-carbonyl chloride (37 mg, 0.11 mmol), prepared as described in Example 3a, was dissolved in anhydrous dioxane (2 mL) and to it was added 4-azepan-1-yl-phenylamine (19 mg, 0.1 mmol) followed by DIEA (20 uL, 0.11 mmol) and the mixture was stirred at 100° C. for 3 h. It was then concentrated in vacuo and the residue was purified by Preparative TLC (silica gel, 5% MeOH/DCM) to obtain 3 mg (6%) of pure 4-(6,7-dimethoxy-quinazolin-4-yl)-piperidine-1-carboxylic acid (4-azepan-1-yl-phenyl)-amide. 1H-NMR (300 MHz, CDCl3) 9.08 (s, 1H), 7.55-7.23 (m, 4H), 7.18 (d, 1H), 6.77 (d, 1H), 6.37 (s, 1H), 4.27 (m, 2H), 4.07 (s, 6H), 3.68-3.32 (m, 3H), 3.30-2.90 (m, 2H), 2.24-1.88 (m, 4H), 1.86-1.38 (m, 10H). LC/MS (ESI): 490.3 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH2:25][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[CH3:28][O:29][CH2:30][C:31](Cl)=[O:32]>>[CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:22])[F:21])=[CH:15][C:14]=2[CH2:23][N:24]([CH2:25][CH3:26])[C:31](=[O:32])[CH2:30][O:29][CH3:28])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC
Reactant: COCC(=O)Cl
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC)C(=O)COC

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and methoxyacetyl chloride.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:6][C:5]([C:15]#[N:16])=[CH:4][C:3]=1[NH:17]C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:17][C:3]1[CH:4]=[C:5]([CH:6]=[C:7]([N:8]2[CH2:9][CH2:10][N:11]([CH3:14])[CH2:12][CH2:13]2)[C:2]=1[Cl:1])[C:15]#[N:16]
Reactant: CN1CCN(c2cc(C#N)cc(NC(=O)OC(C)(C)C)c2Cl)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCN(c2cc(C#N)cc(N)c2Cl)CC1
Yield: 84.9 %

Procedure:
To a solution of tert-butyl 2-chloro-5-cyano-3-(4-methylpiperazin-1-yl)phenylcarbamate (135 mg, 0.385 mmol) in DCM (1.4 mL) was added TFA (0.6 mL, 3.89 mmol). The mixture was stirred at reaction mixture. The solvent was evaporated under vacuum, the residue was dissolved in EtOAc, washed with small amount of sat NaHCO3, and brine, dried over MgSO4, filtered, concentrated, and the residue was purified by ISCO (12 g, EtOAc/DCM=0-60%) to give 82 mg of 3-amino-4-chloro-5-(4-methylpiperazin-1-yl)benzonitrile
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[C:7]1[CH:19]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32]C)=[O:31])[CH:17]=[C:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].CCOC(C)=O.Cl>C1COCC1>[C:1]([O:5][C:6](=[O:34])[C:7]1[CH:19]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])[CH:17]=[C:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:8]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)CCCCCCCCCOc1cc(C(=O)OC(C)(C)C)cc(C(=O)OC(C)(C)C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1cc(OCCCCCCCCCC(=O)O)cc(C(=O)OC(C)(C)C)c1

Procedure:
To a solution of 5-(9-methoxycarbonyl-nonyloxy)-isophthalic acid di-tert-butyl ester (162 mg, 0.34 mmol) in THF (2 ml) was added 1 N NaOH (0.35 ml). The mixture was refluxed for 7 h. The mixture was left at room temperature over night before concentration. To the residue EtOAc and 0.1N HCl was added. The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4) and concentrated to give a clear syrup.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][S:14]([CH2:17][C:18](NC1N=NN(CCCCCCCCCCCC)N=1)=[O:19])(=[O:16])=[O:15])([CH3:3])[CH3:2].[CH2:38]([SH:46])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]>>[CH2:38]([S:46][C:18](=[O:19])[CH2:17][S:14](=[O:15])(=[O:16])[NH:13][C:5]1[C:4]([CH:1]([CH3:2])[CH3:3])=[CH:9][CH:8]=[CH:7][C:6]=1[CH:10]([CH3:12])[CH3:11])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]
Reactant: CCCCCCCCS
Reactant: CCCCCCCCCCCCn1nnc(NC(=O)CS(=O)(=O)Nc2c(C(C)C)cccc2C(C)C)n1
Product: CCCCCCCCSC(=O)CS(=O)(=O)Nc1c(C(C)C)cccc1C(C)C

Procedure:
This compound was prepared in the same manner as for the title compound of Example 2, except that 2-DAT was replaced with octanthiol, mp 51°-52° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])/[CH:7]=[CH:8]/[C:9]1[CH:13]=[CH:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23]Br)=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[C:1]([O:5][C:6](=[O:25])/[CH:7]=[CH:8]/[C:9]1[CH:13]=[CH:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)/C=C/c1ccn(S(=O)(=O)c2ccc(CBr)cc2)c1
Reactant: C1COCCN1
Product: CC(C)(C)OC(=O)/C=C/c1ccn(S(=O)(=O)c2ccc(CN3CCOCC3)cc2)c1

Procedure:
Starting from compound D2 and morpholine the title compound can be obtained analogously as described for compound C5.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH:8]([S:14][C:15]2[CH:16]=[N:17][C:18]([NH:28][C:29]3[S:30][CH:31]=[C:32]([CH3:34])[N:33]=3)=[C:19]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:20]=2)[C:9](OCC)=[O:10])[CH2:4][CH2:3]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[NH4+].[Cl-]>C1COCC1>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH:8]([S:14][C:15]2[CH:16]=[N:17][C:18]([NH:28][C:29]3[S:30][CH:31]=[C:32]([CH3:34])[N:33]=3)=[C:19]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:20]=2)[CH2:9][OH:10])[CH2:4][CH2:3]1
Reactant: CCOC(=O)C(Sc1cnc(Nc2nc(C)cs2)c(Oc2ccccc2)c1)C1CCN(C)CC1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1csc(Nc2ncc(SC(CO)C3CCN(C)CC3)cc2Oc2ccccc2)n1
Temperature: 0 °C
Yield: 85 %

Procedure:
Placed ethyl 2-(1-methylpiperidin-4-yl)-2-(6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)acetate (prepared in Example 235; 0.405 g, 0.812 mmol) in THF (8 mL) and cooled to 0° C. added LiAlH4 (2.44 mL, 2.44 mmol) and warmed to ambient temperature for 30 minutes. Saturated NH4Cl was slowly added and extracted with CH2Cl2. The organic layer was dried, filtered, and concentrated to give the title compound (0.315 g, 84.9% yield). 1H NMR (d6-DMSO) δ 10.92 (bs, 1H), 8.16 (d, 1H), 7.41 (t, 2H), 7.33 (d, 1H), 7.17 (t, 1H), 7.05 (d, 2H), 6.60 (s, 1H), 4.82 (t, 1H), 3.49 (m, 2H), 2.87 (m, 1H), 2.80 (m, 2H), 2.23 (s, 3H), 2.15 (s, 3H), 1.86-1.53 (m, 6H), 1.29 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:12])[CH:9]=[N+]=[N-])=[CH:4][C:3]=1[S:13](=[O:16])(=[O:15])[NH2:14].[ClH:17].C(O)(C)C>COCCOCCOC>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:12])[CH2:9][Cl:17])=[CH:4][C:3]=1[S:13](=[O:16])(=[O:15])[NH2:14]
Reactant: Cc1ccc(C(=O)C=[N+]=[N-])cc1S(N)(=O)=O
Reactant: Cl
Solvent: CC(C)O
Solvent: COCCOCCOC
Product: Cc1ccc(C(=O)CCl)cc1S(N)(=O)=O

Procedure:
10 g of 4'-methyl-3'-sulfamoyl-diazoacetophenone were reacted as prescribed in Example 66(b) in diethylene glycol dimethyl ether with 37% HCl and worked up. Colorless crystals, melting point: 166° C. (from isopropanol).
Reaction SMILES: [H-].[Na+].[C:3]([NH:11][C:12]1[CH:21]=[CH:20][C:19]2[N:18]([CH3:22])[C:17]3=[CH:23][C:24]([C:26]([O:28]CC)=[O:27])=[N:25][N:16]3[C:15](=[O:31])[C:14]=2[CH:13]=1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.I[CH3:33]>CN(C=O)C>[C:3]([N:11]([CH3:33])[C:12]1[CH:21]=[CH:20][C:19]2[N:18]([CH3:22])[C:17]3=[CH:23][C:24]([C:26]([OH:28])=[O:27])=[N:25][N:16]3[C:15](=[O:31])[C:14]=2[CH:13]=1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)c1cc2n(C)c3ccc(NC(=O)c4ccccc4)cc3c(=O)n2n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)c1ccccc1)c1ccc2c(c1)c(=O)n1nc(C(=O)O)cc1n2C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 57.3 %

Procedure:
To a stirring suspension of sodium hydride (0.05 9, 1.25 mmol, 60% dispersion in mineral oil) in 20 mL of DMF was added dropwise a solution of 7-(benzoylamino)-4,9-dihydro-4-methyl-9-oxopyrazolo-[5,1-b]quinazoline-2-carboxylic acid, ethyl ester (0.40 g, 1.02 mmol, Example 2) in 30 mL of DMF. The mixture was stirred for 30 minutes at 0° C. followed by dropwise addition of iodomethane (0.07 mL, 1.12 mmol). The ice-bath was removed, the mixture was stirred at room temperature for 2 hours, then concentrated to a yellow solid. The solid was dissolved into water, acidified to a pH of about 7 with a saturated solution of potassium phosphate, monobasic, and extracted into chloroform (2×50 mL). The combined chloroform extract was dried (MgSO4), filtered, and concentrated. Medium pressure chromatography (silica gel, 2.5% methanol in chloroform) of the crude afforded 0.22 g (52%) of the title compound as its ethyl ester; yellow solid, mp 214°-217° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[CH2:5][N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]#[CH:19])=[CH:13][CH:14]=2)[C:9]([C:20]2[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=2)=[N:8][C:7]1=[O:29].[H-].[Na+].Br[CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH3:42]>CN(C=O)C>[CH:26]([C:23]1[CH:24]=[CH:25][C:20]([C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[C:12]([O:16][CH2:17][C:18]#[CH:19])[CH:11]=3)[N:6]([CH2:5][C:4]3[CH:30]=[CH:31][CH:32]=[C:2]([O:1][CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH3:42])[CH:3]=3)[C:7](=[O:29])[N:8]=2)=[CH:21][CH:22]=1)([CH3:27])[CH3:28]
Reactant: C#CCOc1ccc2c(c1)c(-c1ccc(C(C)C)cc1)nc(=O)n2Cc1cccc(O)c1
Reactant: COCCOCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCOc1ccc2c(c1)c(-c1ccc(C(C)C)cc1)nc(=O)n2Cc1cccc(OCCOCCOC)c1
Temperature: 60 °C

Procedure:
To a solution of 100 mg (0.236 mmol) of 1-(3-hydroxy-benzyl)-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one in anhydrous DMF (5 mL) is added NaH (11 mg, 0.471 mmol) and the solution is allowed to stir until evolution of gas ceases. 1-bromo-2-(2-methoxyethoxy)-ethane (34 μl, 0.247 mmol) is added and the mixture is heated for 20 hours at 60° C. After cooling to room temperature, the reaction mixture is quenched with water and extracted with dichloromethane (2×20 ml). The combined organic layers are washed with brine, dried (Na2SO4), filtered and evaporated in vacuo to provide a yellow solid which is purified by flash chromatography on silica gel using petroleum ether/ethyl acetate (1:1) to provide the title compound as a yellow oil. Yield: 111 mg (85%).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[N:9]=[C:10]([OH:26])[C:11]3[N:12]=[CH:13][N:14]([C:24]=3[N:25]=2)[C@@H:15]2[O:23][C@H:20]([CH2:21][OH:22])[C@@H:18]([OH:19])[C@H:16]2[OH:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O[C:31](=[O:33])[CH3:32])(=O)C>>[CH:1]1([NH:7][C:8]2[N:9]=[C:10]([OH:26])[C:11]3[N:12]=[CH:13][N:14]([C:24]=3[N:25]=2)[C@@H:15]2[O:23][C@H:20]([CH2:21][O:22][C:31](=[O:33])[CH3:32])[C@@H:18]([O:19][C:18](=[O:19])[CH3:20])[C@H:16]2[O:17][C:16](=[O:17])[CH3:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(=O)OC(C)=O
Reactant: OC[C@H]1O[C@@H](n2cnc3c(O)nc(NC4CCCCC4)nc32)[C@H](O)[C@@H]1O
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(O)nc(NC4CCCCC4)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
By a procedure similar to that of Example 4(a), 1 part by weight of 2-cyclohexylaminoinosine is reacted with 5 parts by volume of acetic anhydride to obtain 1.1 parts by weight of 2-cyclohexylamino-2',3',5'-tri-O-acetylinosine as a colorless resinous product.
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[NH:4][CH2:3][CH2:2]2.C(S[C:18]1[O:19][C:20]([C:23]2[O:24][C:25]([Br:28])=[CH:26][CH:27]=2)=[N:21][N:22]=1)C1C=CC=CC=1.C(N(CC)C(C)C)(C)C>[OH-].[Na+]>[Br:28][C:25]1[O:24][C:23]([C:20]2[O:19][C:18]([N:4]3[CH:5]4[CH2:8][CH2:9][N:1]([CH2:7][CH2:6]4)[CH2:2][CH2:3]3)=[N:22][N:21]=2)=[CH:27][CH:26]=1
Reactant: Brc1ccc(-c2nnc(SCc3ccccc3)o2)o1
Reactant: C1CN2CCC(CC2)N1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Product: Brc1ccc(-c2nnc(N3CCN4CCC3CC4)o2)o1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
A mixture of 1,4-diazabicyclo[3.2.2]nonane (4.05 g, 32.1 mmol), 2-benzylsulfanyl-5-(5-bromo-furan-2-yl)-[1,3,4]oxadiazole (10.3 g, 30.5 mmol) and N,N-diisopropylethylamine (8.29 g, 64.1 mmol) was stirred at 100° C. for 4 hours. Aqueous sodium hydroxide (30 ml, 1 M) was added followed by extraction with chloroform (3×30 ml). The organic phase was dried and evaporated. The crude solid mixture was solved in hot ethyl acetate (100 ml), some red, glue-like impurities where removed by filtration. The filtrate was evaporated and finally the crystalline product was triturated with diethylether. Yield 3.43 g (33%). LC-ESI-HRMS of [M+H]+ shows 339.0453 Da. Calc. 339.045664 Da, dev. −1.1 ppm.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[O:4][N:3]=1.C([Li])CCC.[CH2:13]1[O:15][CH2:14]1>O1CCCC1>[CH3:1][C:2]1[CH:6]=[C:5]([CH2:7][CH2:13][CH2:14][OH:15])[O:4][N:3]=1
Reactant: Cc1cc(C)on1
Reactant: C1CO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(CCCO)on1
Temperature: -75 °C
Yield: 45.9 %

Procedure:
3,5-Dimethylisoxazole (220 g, 2.27 moles) in 2.2 L tetrahydrofuran under nitrogen was cooled with stirring to -75° C. and 908 mL of 2.5M n-butyllithium (2.27 moles) in hexanes were added over 1 hour keeping the temperature at or less than 65° C. The chilled solution was stirred for thirty minutes after addition was complete and was then treated at about -70° C. with a solution of 112 g (2.54 moles) of ethylene oxide in 390 ml tetrahydrofuran over a period of 1.5 hours, keeping the temperature at about -65° C. and stirred overnight. The mixture at 8° C. was quenched with continued cooling in an 8° C. bath by adding 1.2 L of 2.5M hydrochloric acid over a period of 20 minutes, during which time the temperature rose to 23° C., and was stirred for 10 minutes. The organic phase was separated, washed with 500 ml of water and concentrated to give 147 g of title compound as a brown oil. The combined aqueous phases (original+wash phase) were extracted with methyl tert-butyl ether (3×200 ml) and the combined organic extracts were concentrated to give an additional 125 g of title compound as a brown oil.
Reaction SMILES: C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O.[C:12]([Si:16]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[O:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22])([CH3:15])([CH3:14])[CH3:13]>C(Cl)Cl>[C:12]([Si:16]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[O:17][CH2:18][CH2:19][CH2:20][CH:21]=[O:22])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)[Si](OCCCCO)(c1ccccc1)c1ccccc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)[Si](OCCCC=O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.7 %

Procedure:
To a suspension of 9.0 g silica gel and PCC (7.7 g, 35.7 mmol) in 300 mL DCM was added 4-(tert-Butyl-diphenyl-silanyloxy)-butan-1-ol (6.0 g, 18.3 mmol) in 50 mL DCM. The mixture was stirred for 3 h at room temperature and then the resulting suspension filtered thorough a pad of celite/florisil and rinsed with DCM. The solvent was evaporated and the product was isolated by flash column chromatography eluting with 0% to 30% ethyl acetate/hexane to give the title compound (4.7 g) as a light yellow oil.
Reaction SMILES: [C:1]([C:5]1[CH:29]=[CH:28][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[C:19]4[CH:26]=[CH:25][NH:24][C:20]=4[N:21]=[CH:22][N:23]=3)[C:13]=2[CH3:27])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[C:32]1([S:38](Cl)(=[O:40])=[O:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1COCC1>[C:32]1([S:38]([N:24]2[C:20]3[N:21]=[CH:22][N:23]=[C:18]([C:14]4[C:13]([CH3:27])=[C:12]([NH:11][C:9](=[O:10])[C:8]5[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:29][CH:28]=5)[CH:17]=[CH:16][CH:15]=4)[C:19]=3[CH:26]=[CH:25]2)(=[O:40])=[O:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1ncnc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1ncnc2c1ccn2S(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of Intermediate 51 (7.51 g, 19.54 mmol) in THF (500 ml) at 0° C. was added NaH (1.172 g, 29.3 mmol) portionwise. The mixture was stirred at 0° C. for 3 hrs, then benzenesulfonyl chloride (3.70 ml, 25.4 mmol) was added and stirring was continued at r.t. overnight. The reaction mixture was quenched with sat. aqueous NH4Cl solution, and extracted with EtOAc. The organic layer was dried, filtered, and evaporated to dryness. Purification by flash chromatography (silica gel, cyclohexane/EtOAc gradient) yielded Intermediate 52.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:12]([CH3:14])[CH3:13])[CH:8]=2)[CH:3]=1.[OH-].[Na+].[CH3:17]OS(OC)(=O)=O>O>[CH3:17][O:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:12]([CH3:14])[CH3:13])[CH:8]=2)[CH:3]=1
Reactant: CC(C)c1ccc2cc(O)ccc2c1
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc2cc(C(C)C)ccc2c1
Temperature: 60 °C

Procedure:
To a suspension of 31.71 g 2-hydroxy-6-(1-methylethyl)naphthalene in 500 ml water and under a nitrogen atmosphere was added 61.5 g of 14.4% (by weight) sodium hydroxide (NaOH). The mixture was heated to 60° C. and 30.02 g of dimethylsulfate was added in one portion to the dark cloudy solution. In 20 minutes the pH of the reaction had dropped from 13 to 2. Another 20 g 14.4% NaOH was added. After 45 minutes 10 g additional dimethylsulfate was added. After 1 hour 20 g of 14.4% NaOH was added and the reaction was heated at 80° C. overnight. The brown suspension was then extracted with toluene and the extract was dried over magnesium sulfate (MgSO4), filtered, and concentrated in vacuum to give a crude solid which was recrystallized from isopropanol to give 2-methoxy-6-isopropylnaphthalene, melting point 63.5° to 64.5° C.
Reaction SMILES: [CH:1]1([NH:6][S:7]([C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[C:12]([N+:17]([O-])=O)[C:11]=2[OH:20])(=[O:9])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>[Pd]>[CH:1]1([NH:6][S:7]([C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[C:12]([NH2:17])[C:11]=2[OH:20])(=[O:9])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)NC2CCCC2)c1O
Agent: [Pd]
Product: Nc1ccc(Cl)c(S(=O)(=O)NC2CCCC2)c1O
Yield: 91 %

Procedure:
Following the general hydrogenation procedure outlined in example 15, (N-cyclopentyl)-6-chloro-2-hydroxy-3-nitrobenzenesulfonamide (0.54 g, 1.7 mmol) was reduced with hydrogen and 10%,Pd/C (0.54 g) to form the desired product (0.45 g, crude). LC-MS m/z 291(M+).