Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]([CH2:27][CH2:28][CH2:29][CH3:30])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[CH2:19][C:18]([CH3:21])([CH3:20])[CH2:17][C:16](=[CH:22][CH:23]=O)[CH:15]=2)=[C:8]([O:25][CH3:26])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:31]([C:33]1[C:34](=[C:44]([C:47]#[N:48])[C:45]#[N:46])[O:35][C:36]([CH3:43])([C:39]([F:42])([F:41])[F:40])[C:37]=1[CH3:38])#[N:32]>C(O)C>[CH2:27]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[CH2:19][C:18]([CH3:20])([CH3:21])[CH2:17][C:16](=[CH:22][CH:23]=[CH:38][C:37]3[C:36]([CH3:43])([C:39]([F:42])([F:40])[F:41])[O:35][C:34](=[C:44]([C:45]#[N:46])[C:47]#[N:48])[C:33]=3[C:31]#[N:32])[CH:15]=2)=[C:8]([O:25][CH3:26])[CH:7]=1)[CH2:28][CH2:29][CH3:30]
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(C)C(F)(F)F
Reactant: CCCCN(CCCC)c1ccc(C=CC2=CC(=CC=O)CC(C)(C)C2)c(OC)c1
Solvent: CCO
Product: CCCCN(CCCC)c1ccc(C=CC2=CC(=CC=CC3=C(C#N)C(=C(C#N)C#N)OC3(C)C(F)(F)F)CC(C)(C)C2)c(OC)c1
Temperature: 50 °C
Yield: 70.9 %

Procedure:
In 6 ml of ethanol were dissolved 200 mg (0.49 mmol) of [3-[2-(4-dibutylamino-2-methoxyphenyl)vinyl]-5,5-dimethyl-2-cyclohexenylidene]acetaldehyde and 136 mg (0.54 mmol) of 2-(3-cyano-4,5-dimethyl-5-trifluoromethyl-2(5H)-furanylidene)propanedinitrile. After the mixture was stirred with heating at 50° C. for 3.5 hours, the solvent was evaporated off. The residue was purified by silica gel column chromatography to give 224 mg of a dark brown crystal (yield: 71.2%; mp: 196-201° C.)
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH2:7][N:8]2[C:13]3[CH:14]=[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[S:16][C:12]=3[C:11](=[O:23])[N:10]([CH:24]3[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]3)[C:9]2=[O:37])=[CH:5][N:6]=1.[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41]>C(Cl)Cl>[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41].[CH3:1][C:2]1[S:3][C:4]([CH2:7][N:8]2[C:13]3[CH:14]=[C:15]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[S:16][C:12]=3[C:11](=[O:23])[N:10]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[C:9]2=[O:37])=[CH:5][N:6]=1
Reactant: Cc1ncc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ncc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)s1

Procedure:
A solution of tert-butyl 4-{1-[(2-methyl-1,3-thiazol-5-yl)methyl]-2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl}piperidine-1-carboxylate (715 mg; compound B20) in DCM (15 ml) is reacted with trifluoroacetic acid (3 ml) according to the procedure described in example B43 to afford the title compound as a solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[CH:8]2)=[CH:2]1.C[O:25][C:26](=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33]Br)[CH:28]=1>>[O:1]1[CH:5]=[CH:4][C:3]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH:18]3[CH2:23][CH2:22][N:21]([CH2:33][C:29]4[CH:28]=[C:27]([CH:32]=[CH:31][CH:30]=4)[C:26]([OH:35])=[O:25])[CH2:20][CH2:19]3)=[CH:8]2)=[CH:2]1
Reactant: COc1ccc2c(c1)c(C1CCNCC1)cn2Cc1ccoc1
Reactant: COC(=O)c1cccc(CBr)c1
Product: COc1ccc2c(c1)c(C1CCN(Cc3cccc(C(=O)O)c3)CC1)cn2Cc1ccoc1

Procedure:
This compound was prepared following the procedure described in example 13 (part D) starting with 3.7 g (11.9 mmol) of 1-furan-3-ylmethyl-5-methoxy-3-piperidin-4-yl-1H-indole (example 92, part B) and 3 g (13 mmol) of 3-bromomethyl-benzoic acid methyl ester. After standard work-up, 2.4 g (45% of yield) of the expected acid were obtained. In this case a p-tolensulfonate derivative salt was prepared affording 2.9 g of white solid.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[S:11][C:10]([C:15]([O:17]CC)=[O:16])=[CH:9][C:8]2=[O:20])[CH:2]=[CH2:3].C(=O)(O)[O-].[Na+].CO>O>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[S:11][C:10]([C:15]([OH:17])=[O:16])=[CH:9][C:8]2=[O:20])[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc2sc(C(=O)OCC)cc(=O)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C=CCOc1ccc2sc(C(=O)O)cc(=O)c2c1

Procedure:
A mixture of 3 parts of ethyl 6-allyloxy-1-thiachromone-2-carboxylate, 0.87 parts of sodium bicarbonate and 4 parts of methanol in 25 parts of water was heated under reflux for several minutes then the methanol was distilled. The aqueous solution was diluted with 25 parts of water, filtered and acidified with concentrated hydrochloric acid to give a precipitate which was filtered off, washed with water and dried to give 2.6 parts of 6-allyloxy-1-thiachromone-2-carboxylic acid, melting point, 200°-200.5°C.
Reaction SMILES: [NH:1]([C:66]([O:68][C:69]([CH3:72])([CH3:71])[CH3:70])=[O:67])[CH2:2][C:3]([NH:5][C@H:6]([C:24]([N:26]1[CH2:65][CH2:64][CH2:63][C@H:27]1[C:28]([NH:30][C@H:31]([C:33]([NH:35][C@H:36]([C:53]([O:55]CC1C=CC=CC=1)=[O:54])[CH2:37][CH2:38][CH2:39][CH2:40][NH:41][C:42]([O:44][CH2:45][C:46]1[CH:52]=[CH:51][CH:50]=[CH:49][C:47]=1[Cl:48])=[O:43])=[O:34])[CH3:32])=[O:29])=[O:25])[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:23])[NH:12][S:13]([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14])=[O:4].[OH-].[Na+].C(Cl)(Cl)Cl.CO>CO>[NH:1]([C:66]([O:68][C:69]([CH3:70])([CH3:72])[CH3:71])=[O:67])[CH2:2][C:3]([NH:5][C@H:6]([C:24]([N:26]1[CH2:65][CH2:64][CH2:63][C@H:27]1[C:28]([NH:30][C@H:31]([C:33]([NH:35][C@H:36]([C:53]([OH:55])=[O:54])[CH2:37][CH2:38][CH2:39][CH2:40][NH:41][C:42]([O:44][CH2:45][C:46]1[CH:52]=[CH:51][CH:50]=[CH:49][C:47]=1[Cl:48])=[O:43])=[O:34])[CH3:32])=[O:29])=[O:25])[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:23])[NH:12][S:13]([C:16]1[CH:17]=[CH:18][C:19]([CH3:20])=[CH:21][CH:22]=1)(=[O:14])=[O:15])=[O:4]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)CNC(=O)OC(C)(C)C)C(=O)N2CCC[C@H]2C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)OCc2ccccc2Cl)C(=O)OCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)CNC(=O)OC(C)(C)C)C(=O)N2CCC[C@H]2C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)OCc2ccccc2Cl)C(=O)O)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 85.7 %

Procedure:
At 0° C. to the solution of 230 mg (0.221 mmol) of Boc-Gly-Arg(Tos)-Pro-Ala-Lys(ClZ)-OBzl (SEQ ID NO: 14) in 6 ml of methanol 5 ml of the solution of NaOH in methanol (2 mol/L) were added. The reaction mixture was stirred at 0° C. for 2 h and TLC (chloroform/methanol, 15:1) indicated complete disappearance of Boc-Gly-Arg(Tos)-Pro-Ala-Lys(ClZ)-OBzl (SEQ ID NO: 14). The reaction mixture was neutralized to pH 7 and evaporated at room temperature to remove methanol. The residue was acidified to pH 1–2 with hydrochloric acid (2 mol/L) to provide 180 mg (86%) of the title compound as a colorless powder.
Reaction SMILES: [ClH:1].[C:2]1([CH:8]2[CH2:12][CH2:11][CH2:10][CH:9]2[NH2:13])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[C:16]1[CH2:17][CH2:18][CH2:19][N:20]=1>CCOCC>[ClH:1].[C:2]1([CH:8]2[CH2:12][CH2:11][CH2:10][CH:9]2[N:13]=[C:16]2[CH2:17][CH2:18][CH2:19][NH:20]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1CCCC1c1ccccc1
Reactant: COC1=NCCC1
Agent: Cl
Solvent: CCOCC
Product: c1ccc(C2CCCC2N=C2CCCN2)cc1
Reaction time: 144 h

Procedure:
A slurry of 3.0 g (0.0152 mole) of powdered 2-phenylcyclopentylamine hydrochloride and 3 ml of O-methylbutyrolactim is allowed to stand at room temperature with occasional stirring for 6 days after which the material is covered with absolute ether. The solution is allowed to stand at room temperature for an additional 6 days. A precipitate forms which is collected and recrystallized from acetone-methanol and dried to give 2-[(2-phenylcyclopentyl)imino]pyrrolidine hydrochloride, M.P. 155°-158° C.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[C:11]([CH3:24])=[N:12][C:13]2[C:18]([CH:19]=1)=[CH:17][C:16]([O:20][CH3:21])=[C:15]([O:22][CH3:23])[CH:14]=2)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[O:25]1CCOCC1>>[CH2:1]([O:3][P:4]([CH2:9][C:10]1[C:11]([CH:24]=[O:25])=[N:12][C:13]2[C:18]([CH:19]=1)=[CH:17][C:16]([O:20][CH3:21])=[C:15]([O:22][CH3:23])[CH:14]=2)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: C1COCCO1
Reactant: CCOP(=O)(Cc1cc2cc(OC)c(OC)cc2nc1C)OCC
Product: CCOP(=O)(Cc1cc2cc(OC)c(OC)cc2nc1C=O)OCC

Procedure:
SeO2 (0.56 g, 5.06 mmol) was added to a solution of 3-(diethylphosphonomethyl)-6,7-dimethoxy-2-methylquinoline (1.79 g, 5.06 mmol) in dioxane (25 ml). The mixture was refluxed for 75 min, filtered and concentrated. The remaining oil was purified by chromatography to give 1.48 g 3-(diethylphosphonomethyl)-6,7-dimethoxyquinoline-2-carboxaldehyde.
Reaction SMILES: C(OC(=O)[N:7]([C:37]1[CH:38]=[N:39][C:40]([O:43][CH2:44][CH3:45])=[CH:41][CH:42]=1)[C:8]1[CH:13]=[CH:12][C:11]([CH:14](O)[C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([CH3:24])[CH:22]=3)[N:17]([Si](C(C)C)(C(C)C)C(C)C)[CH:16]=2)=[C:10]([F:36])[N:9]=1)(C)(C)C.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCCl>[CH2:44]([O:43][C:40]1[N:39]=[CH:38][C:37]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]3[C:23]4[C:18](=[N:19][CH:20]=[C:21]([CH3:24])[CH:22]=4)[NH:17][CH:16]=3)=[C:10]([F:36])[N:9]=2)=[CH:42][CH:41]=1)[CH3:45]
Reactant: CCOc1ccc(N(C(=O)OC(C)(C)C)c2ccc(C(O)c3cn([Si](C(C)C)(C(C)C)C(C)C)c4ncc(C)cc34)c(F)n2)cn1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: CCOc1ccc(Nc2ccc(Cc3c[nH]c4ncc(C)cc34)c(F)n2)cn1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To (6-ethoxy-pyridin-3-yl)-{6-fluoro-5-[hydroxy-(5-methyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-pyridin-2-yl}-carbamic acid tert-butyl ester (70, 108.1 mg, 0.166 mmol) in 4.54 mL of 1,2-dichloroethane, triethylsilane (0.454 mL, 2.84 mmol) and trifluoroacetic acid (0.27 mL, 3.5 mmol) are added and the reaction stirred at 80° C. for 4 hours. The reaction is poured into aqueous potassium carbonate and extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography eluting with 25-100% ethyl acetate in hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (P-3039), which is further purified by additional chromatography.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:9][OH:10])[CH:6]=[CH:7][CH:8]=1.[N+:11]([C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O)([O-:13])=[O:12]>>[OH:1][CH2:2][C:3]1[CH:4]=[C:5]([N+:9]([O-:10])=[CH:17][C:16]2[CH:19]=[CH:20][CH:21]=[C:14]([N+:11]([O-:13])=[O:12])[CH:15]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: OCc1cccc(NO)c1
Product: O=[N+]([O-])c1cccc(C=[N+]([O-])c2cccc(CO)c2)c1
Yield: 69.8 %

Procedure:
The reaction of hydroxylamine 91 (1.36 g, 10 mmol) with 3-nitrobenzaldehyde (57) (1.51 g, 10 mmol) afforded, after workup, a light yellow solid. The crude product was recrystallized from acetone/petroleum ether to obtain 1.90 g (6.98 mmol, 70%) of 92 as a pale yellow crystalline solid: mp 177°-179° C.; IR (Nujol) 3220, 1570, 1530, 1350, 1040, 800 cm-1 ; 1H NMR (Me2SO-d6) δ 4.58 (d, J=5.6 Hz, 2H), 5.39 (t, J=4.8, 2H), 7.45-9.53 (m, 9H); 13C NMR (Me2SO-d6) δ 62.91, 119.87, 120.25, 122.98, 125.19, 128.68, 129.42, 130.47, 132.40, 132.94, 135.30, 144.73, 148.26, 148.73. Anal. Calcd for C14H12N2O4 : C, 61.76; H, 4.41. Found: C, 61.99; H, 4.52.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](=[O:10])[NH2:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:11][C:12]([C:14]1[S:15][C:16]([C:19](=[O:21])[CH3:20])=[CH:17][CH:18]=1)=O.C(O)(=O)C>CN(C)C=O>[C:19]([C:16]1[S:15][C:14]([C:12]2[NH:11][C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([NH2:9])=[O:10])[C:2]=3[N:1]=2)=[CH:18][CH:17]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)c1ccc(C(=O)Nc2cccc(C(N)=O)c2N)s1
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(-c2nc3c(C(N)=O)cccc3[nH]2)s1
Temperature: 125 °C
Yield: 95.1 %

Procedure:
To a solution of EXAMPLE 6A (1.70 g) in hot N,N-dimethylformamide (60 mL) was added acetic acid (50 mL) and the solution heated at 125° C. for 3 hours. After cooling, the resulting yellow solid was collected by filtration, washed with methanol and dried to give the title compound (1.52 g, 95%). MS (APCI): 286 (M+1)+.
Reaction SMILES: [C:1]1([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9](Cl)(=[O:11])[CH3:10].Cl>>[C:9]([O:7][C:6]1[C:1]([CH3:8])=[CH:2][CH:3]=[CH:4][CH:5]=1)(=[O:11])[CH3:10]
Reactant: Cc1ccccc1O
Reactant: CC(=O)Cl
Agent: Cl
Product: CC(=O)Oc1ccccc1C
Reaction time: 3 h
Yield: 95 %

Procedure:
Into a spherical flask provided with a condenser, a dropping funnel and containing 2 moles of o-cresol, 2.4 moles of acetyl chloride are introduced in 15 minutes. The bath is kept at 110° C. until the release of hydrochloric acid is completed, i.e. after about 3 hours, and then the o-cresol acetate as obtained is distilled under vacuum:
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12]OC(=O)[N:9]1[C:14](=[O:36])[CH:15]([CH2:19][C:20]1[C:25]([Cl:26])=[CH:24][C:23]([O:27]CC2C=CC=CC=2)=[CH:22][C:21]=1[Cl:35])[CH2:16][CH:17]=O)[C:2]1C=CC=CC=1.NC1CC[O:41][CH2:40]C1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:26][C:25]1[CH:24]=[C:23]([OH:27])[CH:22]=[C:21]([Cl:35])[C:20]=1[CH2:19][C@@H:15]1[CH2:16][CH2:17][N:9]([CH:8]2[CH2:1][CH2:2][O:41][CH2:40][CH2:12]2)[C:14]1=[O:36]
Reactant: O=CCC(Cc1c(Cl)cc(OCc2ccccc2)cc1Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: NC1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C1[C@H](Cc2c(Cl)cc(O)cc2Cl)CCN1C1CCOCC1
Yield: 71.6 %

Procedure:
Treat a solution of 4-(4-(R)-benzyl-2-oxo-oxazolidin-3-yl)-3-(4-benzyloxy-2,6-dichloro-benzyl)-4-oxo-butyraldehyde (Preparation 27) (10.4 g, 20 mmol) and 4-aminotetrahydropyran (2 g, 20 mmol) in dichloromethane (100 mL) with acetic acid (1 mL, 20 mmol). Stir the reaction 1 hr at room temperature then add sodium triacetoxyborohydride (12.6 g, 60 mmol) and stir for an additional 4 hr at room temperature. Quench with water and separate the organic layer. Wash with brine, dry over magnesium sulfate, filter, and remove the solvent under vacuum. Purify by silica gel column chromatography using hexanes:ethyl acetate to afford 4.93 g (57%) of desired product: MS (m/z): 434 (M+).
Reaction SMILES: [C:1]([C:5]1[CH:24]=[CH:23][C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]2[O:21][N:20]=[C:19]([CH3:22])[CH:18]=2)=[CH:7][CH:6]=1)(=O)[CH2:2][CH3:3].Cl.[NH2:26][OH:27].C([O-])(=O)C.[Na+]>C(O)C.O>[C:1](=[N:26][OH:27])([C:5]1[CH:24]=[CH:23][C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]2[O:21][N:20]=[C:19]([CH3:22])[CH:18]=2)=[CH:7][CH:6]=1)[CH2:2][CH3:3]
Reactant: NO
Reactant: CCC(=O)c1ccc(OCCCCCCCc2cc(C)no2)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCC(=NO)c1ccc(OCCCCCCCc2cc(C)no2)cc1
Yield: 59.8 %

Procedure:
To a solution of 1.6 g of 5-[7-(4-propionylphenoxy)heptyl]-3-methylisoxazole (Example 32) in 40 ml of ethanol was added a solution of 368 mg of hydroxylamine hydrochloride and 730 mg of sodium acetate in 8 ml of water. The reaction mixture was heated at reflux overnight and then concentrated in vacuo. The residue was recrystallized from aqueous ethanol to give 1.0 g of 5-[7-(4-propionylphenoxy)heptyl]-3-methylisoxazole oxime, colorless solid, m.p. 88°-89° C.; MIC vs. rhinovirus Type 2 in vitro=2.6 μg/ml; and vs. polio-2 virus at 0.2 μg/ml.
Reaction SMILES: [CH3:1][Si:2]([CH3:33])([CH3:32])[O:3][C@H:4]1[CH2:27][C@@:26]2([CH3:28])[C@@H:15]([CH2:16][CH:17]=[C:18]2[C:19](=[O:25])[CH2:20][O:21][C:22](=[O:24])[CH3:23])[C@H:14]2[C@H:5]1[C@:6]1([CH3:31])[C:11]([C@@H:12]([F:29])[CH2:13]2)=[CH:10][C:9](=[O:30])[CH2:8][CH2:7]1>O1CCOCC1>[CH3:33][Si:2]([CH3:1])([CH3:32])[O:3][C@H:4]1[CH2:27][C@@:26]2([CH3:28])[C@@H:15]([CH2:16][CH:17]=[C:18]2[C:19](=[O:25])[CH2:20][O:21][C:22](=[O:24])[CH3:23])[C@H:14]2[C@H:5]1[C@:6]1([CH3:31])[C:11]([C@@H:12]([F:29])[CH2:13]2)=[CH:10][C:9](=[O:30])[CH:8]=[CH:7]1
Reactant: CC(=O)OCC(=O)C1=CC[C@H]2[C@@H]3C[C@H](F)C4=CC(=O)CC[C@]4(C)[C@H]3[C@@H](O[Si](C)(C)C)C[C@]12C
Solvent: C1COCCO1
Product: CC(=O)OCC(=O)C1=CC[C@H]2[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O[Si](C)(C)C)C[C@]12C

Procedure:
A mixture of 3.5 g of 11β-trimethylsiloxy-21-acetoxy-6α-fluoropregna-4,16-diene-3,20-dione obtained according to Example 6, 2.65 g of 2,3-dichloro-4,5-dicyanobenzoquinone (DDQ) and 30 ml of dioxan was heated under reflux for 2 hours. The resulting dark colored suspension was cooled, filtered from dichloro-dicyanohydroquinone, and evaporated to dryness. The residue was dissolved in chloroform and passed through a short column of neutral alumina (50 g). The solvent was evaporated under reduced pressure. The residue was crystallized from methanol. The analytical sample of 11β-trimethylsiloxy-21-acetoxy-6α-fluoropregna-1,4,16-triene-3,20-dione (compound 13) was obtained by an additional recrystallization from methanol. The yield was 2.65 g.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]O)=[C:4]([CH3:10])[CH:3]=1.O=S(Cl)[Cl:13]>C(Cl)Cl>[Cl:13][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[CH3:10]
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(F)ccc1CO
Solvent: ClCCl
Product: Cc1cc(F)ccc1CCl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
(4-Fluoro-2-methylphenyl)methanol (11.5 g, 82 mmol) was dissolved in CH2Cl2 (100 mL). The mixture was cooled to 0° C. before adding SOCl2 (10.7 g, 90 mmol), then stirred for 30 min at 0° C. and then at room temperature for 1.5 h. The solvent and excess of SOCl2 were removed by evaporation followed by the addition of CH2Cl2. The solvent and remaining traces of SOCl2 were evaporated once more. There was obtained 13.0 g (100%) of 1-(chloromethyl)-4-fluoro-2-methylbenzene as an oil. 1H NMR (300 MHz, CDCl3): 2.4 (s, 3H), 4.6 (s, 2H), 6.8-7.0 (m, 2H), 7.3 (m, 1H).
Reaction SMILES: [CH:1]([NH:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)([CH3:3])[CH3:2].CCN(CC)CC.[C:25](Cl)(=[O:27])[CH3:26]>C(Cl)Cl>[CH:1]([N:4]([CH:5]1[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])[CH2:9][CH2:10]1)[C:25](=[O:27])[CH3:26])([CH3:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CC(C)NC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N(C(C)C)C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 2.5 h
Yield: 59.6 %

Procedure:
To a 0° C. solution of tert-butyl 4-(isopropylamino)piperidine-1-carboxylate (1.2 g, 5.19 mmol) in CH2Cl2 (18 mL) was added Et3N (1.44 mL, 10.38 mmol) followed by acetyl chloride (0.55 mL, 7.78 mmol). The resulting solution was stirred for 2.5 hours, then concentrated in vacuo. The material was purified by flash chromatography on silica gel, eluting with 0% to 5% of EtOAc/CH2Cl2, to afford tert-butyl 4-(N-isopropylacetamido)piperidine-1-carboxylate (0.88 g, 59%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[N:10]([Si](C)(C)C)=[N+:11]=[N-:12].C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([C:5]2[N:10]=[N:11][NH:12][N:6]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: N#Cc1cccc(Br)c1
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Brc1cccc(-c2nn[nH]n2)c1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
3-Bromobenzonitrile (2.49 g, 13.7 mmol) and azidotrimethylsilane (3.14 g, 27.3 mmol) were stirred in anhydrous toluene (100 mL) under argon at ambient temperature. To this was added dibutyltin oxide (341 mg, 1.37 mmol) and the resulting reaction was fitted with a reflux condenser and heated with stirring at 110° C. for 3 h. Upon cooling, the reaction mixture was concentrated in vacuo, and then concentrated to dryness twice following the addition of MeOH (ca. 25 mL each). The crude reaction mixture was dissolved in EtOAc (300 mL) and washed with H2O (2×100 mL). The organic phase was washed with 1N aqueous NaOH (4×75 mL), the combined basic aqueous portions were treated with 4N HCl to obtain an endpoint of pH=4 and the acidic aqueous phase was extracted with EtOAc (4×100 mL washes). The combined EtOAc layers were dried (MgSO4), filtered, and concentrated in vacuo to obtain 5-(3-bromophenyl)-2H-tetrazole as a white solid.
Reaction SMILES: [OH-].[K+].[N+:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:14])=[O:13])([O-:5])=[O:4].Br[CH2:23][CH2:24][CH:25]=[CH2:26]>CN(C=O)C.CCOC(C)=O>[CH2:26]([N:15]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[S:12]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[N+:3]([O-:5])=[O:4])(=[O:14])=[O:13])[CH2:25][CH:24]=[CH2:23]
Reactant: C=CCCBr
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Nc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCCN(c1ccccc1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 64.7 %

Procedure:
Crushed KOH (0.0484 g, 0.862 mmol, 1.2 equiv) was added to 2-nitro-N-phenylbenzenesulfonamide (0.200 g, 0.719 mmol) in 1 mL DMF, and the mixture was stirred for 30 min. 4-Bromo-1-butene (0.2426 g, 1.80 mmol) in 2 mL DMF solution was added dropwise into the mixture and it was stirred at room temperature overnight. The reaction mixture was diluted with 30 mL EtOAc and washed with 1M HCl 2×10 mL and water 3×10 mL. The organic layer was dried over anhydrous Na2SO4 and evaporated to afford the crude product, which was subjected to silica gel chromatography using Hexanes/EtOAc to afford 0.1546 g white solid, yield 63.5%. 1H NMR (CDCl3, 400 MHz) δppm 2.20 (q, J=6.90 Hz, 2H) 3.83 (t, J=7.15 Hz, 2H) 5.00 (d, J=4.39 Hz, 1H) 5.03 (s, 1H) 5.64-5.83 (m, 1H) 7.14-7.21 (m, 3H) 7.30 (d, J=1.85 Hz, 2H) 7.42-7.46 (m, 2H) 7.52-7.58 (m, 1H) 7.60-7.66 (m, 1H)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH2:27]([N:34]1[CH2:39][CH2:38][O:37][CH:36]([CH2:40]Cl)[CH2:35]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([N:34]1[CH2:39][CH2:38][O:37][CH:36]([CH2:40][N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=3)[C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7]2)[CH2:35]1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC2(CC1)OCc1ccccc12
Reactant: ClCC1CN(Cc2ccccc2)CCO1
Product: O=C(c1cn(CC2CN(Cc3ccccc3)CCO2)c2cc(Cl)ccc12)N1CCC2(CC1)OCc1ccccc12

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidine] (prepared according to example 69) with commercially available 4-benzyl-2-(chloromethyl)morpholine gave the title compound. ES-MS m/e (%): 556.3(M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][OH:10])[CH:6]=[C:5]([CH3:11])[N:4]=1.C1C(=O)N([Br:19])C(=O)C1.[OH-].[Na+]>C(O)(=O)C>[Br:19][C:6]1[C:5]([CH3:11])=[N:4][C:3]([O:2][CH3:1])=[CH:8][C:7]=1[CH2:9][OH:10]
Reactant: COc1cc(CO)cc(C)n1
Reactant: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COc1cc(CO)c(Br)c(C)n1
Yield: 79.2 %

Procedure:
A mixture of (2-methoxy-6-methylpyridin-4-yl)methanol (1.1 g) and NBS (1.34 g) was stirred in an acetic acid solvent (22 mL) at room temperature for 12 hours. A 5 M aqueous sodium hydroxide solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 10% to 50%) to give the title compound (1.32 g).