Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:40]=[C:41]([F:43])[CH:42]=1)[CH2:5][C@H:6]1[C@@H:10]([C@H:11]2[CH2:20][C:19]3[C:14](=[C:15]([O:21][Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])[CH:16]=[CH:17][CH:18]=3)[CH2:13][N:12]2C(OC(C)(C)C)=O)[O:9][C:8](=[O:39])[NH:7]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:43][C:41]1[CH:40]=[C:4]([CH:3]=[C:2]([F:1])[CH:42]=1)[CH2:5][C@H:6]1[C@@H:10]([C@H:11]2[CH2:20][C:19]3[C:14](=[C:15]([O:21][Si:22]([CH:29]([CH3:30])[CH3:31])([CH:23]([CH3:24])[CH3:25])[CH:26]([CH3:27])[CH3:28])[CH:16]=[CH:17][CH:18]=3)[CH2:13][NH:12]2)[O:9][C:8](=[O:39])[NH:7]1
Reactant: CC(C)[Si](Oc1cccc2c1CN(C(=O)OC(C)(C)C)[C@@H]([C@H]1OC(=O)N[C@H]1Cc1cc(F)cc(F)c1)C2)(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[Si](Oc1cccc2c1CN[C@@H]([C@H]1OC(=O)N[C@H]1Cc1cc(F)cc(F)c1)C2)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of (R)-tert-butyl 3-((4S,5S)-4-(3,5-difluorobenzyl)-2-oxooxazolidin-5-yl)-8-(triisopropylsilyloxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate (Step F (11), 470 mg) in CH2Cl2 (20 mL) was treated with TFA (5 mL). This reaction mixture was stirred at rt for 3 h. The mixture was then concentrated in vacuo. Ethyl acetate (10 mL) was added and removed and toluene (10 mL) was added and removed twice to give the title compound: 1H NMR (CDCl3, 500 MHz) δ 1.10 (18H, m), 1.30 (3H, m), 2.61-2.66 (2H, m), 3.08 (1H, dd, J=5, 15 Hz), 3.18 (1H, m), 3.36 (1H, m), 3.79 (1H, d, J=20 Hz), 4.05-4.09 (1H, m), 4.14 (1H, d, J=20 Hz), 4.39 (1H, m), 5.54 (1H, s), 6.64 (1H, d, J=5 Hz), 6.69-6.72 (2H, m), 6.78 (2H, m), 7.01 (1H, m). MS (ESI) (M+H)+ 517.11.
Reaction SMILES: [Cl:1][C:2]([F:10])([F:9])[C:3]([F:8])([F:7])[C:4](Cl)=[O:5].N1C=CC=CC=1.[CH:17]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH2:18].O>C(Cl)(Cl)Cl>[CH2:20]([O:19][CH:17]=[CH:18][C:4](=[O:5])[C:3]([F:8])([F:7])[C:2]([Cl:1])([F:10])[F:9])[CH2:21][CH2:22][CH3:23]
Reactant: O=C(Cl)C(F)(F)C(F)(F)Cl
Reactant: C=COCCCC
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: c1ccncc1
Product: CCCCOC=CC(=O)C(F)(F)C(F)(F)Cl
Temperature: 0 °C
Reaction time: 15 h

Procedure:
With stirring and at 0° C., 10.0 g (50.2 mmol) of 3-chlorotetrafluoropropionyl chloride—dissolved in ml of chloroform—were added to a mixture of 3.97 g (50.2 mmol) of pyridine and 5.03 g (50.2 mmol) of butyl vinyl ether in 80 ml of chloroform. After the addition, stirring was continued at room temperature for a further 15 h. 100 ml of water were then added to the mixture, and the organic phase was separated off, dried and concentrated. This gave 10.4 g (78% of theory) of a yellowish oil.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:19]([CH2:20][CH2:21][C@:4]12[CH3:5])[C@:17]1([CH3:18])[C@H:12]([CH2:13][C:14](=O)[C@H:15]([CH3:22])[CH2:16]1)[CH2:11][CH2:10]3.Cl.[NH2:25][OH:26].C([O-])(=O)C.[Na+].O>C(O)C>[CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:19]([CH2:20][CH2:21][C@:4]12[CH3:5])[C@:17]1([CH3:18])[C@H:12]([CH2:13][C:14](=[N:25][OH:26])[C@H:15]([CH3:22])[CH2:16]1)[CH2:11][CH2:10]3
Reactant: NO
Reactant: CO[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(=O)[C@H](C)C[C@]4(C)[C@H]3CC[C@]12C
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CO[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(=NO)[C@H](C)C[C@]4(C)[C@H]3CC[C@]12C

Procedure:
A mixture of 17β-methoxy-2α-methyl-5α-androstan-3-one (Acta. Endocrinology 36, 83 (1961), 0.5 g.), hydroxylamine hydrochloride (0.218 g.) and sodium acetate (0.258 g.) in ethanol (20 ml.) is refluxed for 1 hour. Water is then added; a precipitate forms which is filtered, washed, dried and recrystallized from methylene chloride-acetone to give the title compound, m.p. 203°-211°; IR (mull) 3360 and 1650 cm-1 ; MS (me) 333; NMR (CDCl3) 0.75, 0.93, 1.06, 3.15 and 3.33 δ.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([NH:9][CH:10]2[CH2:15][CH2:14][S:13][CH2:12][CH2:11]2)=[CH:4][N:3]=1.Cl.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH:18]1[C:23](O)=[O:24].C(N(C(C)C)CC)(C)C.O>CS(C)=O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:9]([CH:10]3[CH2:15][CH2:14][S:13][CH2:12][CH2:11]3)[C:23](=[O:24])[CH:18]3[CH2:19][O:20][CH2:21][CH2:22][N:17]3[C:6]=2[N:7]=1
Reactant: O=C(O)C1COCCN1
Reactant: Clc1ncc(NC2CCSCC2)c(Cl)n1
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1C2COCCN2c2nc(Cl)ncc2N1C1CCSCC1
Temperature: 95 °C
Reaction time: 4 h
Yield: 7.5 %

Procedure:
To a mixture of 2,4-dichloro-N-(tetrahydro-2H-thiopyran-4-yl)pyrimidin-5-amine (864 mg, 3.27 mmol) and morpholine-3-carboxylic acid hydrochloride (822 mg, 4.91 mmol) in DMSO (15 ml) was added diisopropylethylamine (2.29 ml, 13.1 mmol), and the reaction mixture was stirred at 95° C. for 4 hours. The reaction mixture was poured into water and extracted with EtOAc. The organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give a crude solid. The solid was chromatographed by silica gel (hexane/ethyl acetate, 19:1 to 3:2) to afford partially purified 2-chloro-5-(tetrahydro-2H-thiopyran-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (83.6 mg, 0.245 mmol, 7.5% yield) as a white solid. MS [M+H] found 341.
Reaction SMILES: [C:1]([C:3]1[CH:22]=[CH:21][C:6]([C:7]([N:9]2[CH2:20][CH2:19][C:12]3([NH:16][C:15](=[O:17])[NH:14][C:13]3=[O:18])[CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1)#[N:2].Cl[CH2:24][CH2:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:7]([N:9]2[CH2:20][CH2:19][C:12]3([NH:16][C:15](=[O:17])[N:14]([CH2:24][CH2:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3=[O:18])[CH2:11][CH2:10]2)=[O:8])=[CH:21][CH:22]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)CCCCl
Reactant: N#Cc1ccc(C(=O)N2CCC3(CC2)NC(=O)NC3=O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCCN1C(=O)NC2(CCN(C(=O)c3ccc(C#N)cc3)CC2)C1=O

Procedure:
A mixture of 2.4 g (8.0 mmol) of the compound from Step B, 1.8 g (10.1 mmol) tert.-butyl 4-chlorobutanoate (prepared according to Chem. Ber. 1965, 98, 2312), 2.8 g (20.3 mmol) dry potassium carbonate, and a catalytic amount potassium iodide in 50 ml dry DMF was heated at 100° C. for 6 h until the conversion was complete. It was poured into ice-cold water, and the crude solid title compound was collected by filtration. It was redissolved in hot ethyl acetate and dried over sodium sulfate, which was removed by filtration. The title hydantoin crystallized from the filtrate by addition of hexane.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:29])=[C:5]([C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[CH:6]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][OH:22])[CH:16]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][O:13][CH3:14])=[O:9].[N+:30]([C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH:36]=O)([O-:32])=[O:31]>>[CH3:1][C:2]1[NH:3][C:4]([CH3:29])=[C:5]([C:23]([O:25][CH:26]([CH3:27])[CH3:28])=[O:24])[CH:6]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21](=[CH:36][C:35]3[CH:38]=[CH:39][CH:40]=[C:33]([N+:30]([O-:32])=[O:31])[CH:34]=3)=[O:22])[CH:16]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][O:13][CH3:14])=[O:9]
Reactant: COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc(NO)c1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc(/[N+]([O-])=C/c2cccc([N+](=O)[O-])c2)c1
Product: COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc([N+]([O-])=Cc2cccc([N+](=O)[O-])c2)c1

Procedure:
The reaction of hydroxylamine 55 (0.80 g, 2 mmol) with 3-nitrobenzaldehyde (57) (0.302 g, 2 mmol) afforded, after workup, a yellow solid. The crude product was recrystallized from dichloromethane-petroleum ether to afford 0.82 g (1.53 mmol, 77%) of 68 as a light yellow crystalline solid: mp 175°-178° C.; IR (CH2Cl2) 3440, 2980, 1695, 1620, 1550, 1532, 1470, 1350, 1295, 1210, 1100, 905, 810 cm-1 ; 1H NMR (CDCl3) δ 1.11 (d, J=6.2 Hz, 3H), 1.23 (d, J=6.2 Hz, 3H), 2.29 (s, 6H), 3.32 (s, 3H), 3.58 (t, J=4.8 Hz, 2H), 4.20 (m, 2H), 4.94 (septet, J=6.2 Hz, 1H), 5.09 (s, 1H), 6.46 (s, 1H), 7.32-9.28 (m, 9H); 13C NMR (CDCl3) δ 19.38, 19.48, 21.97, 22.20, 40.09, 58.82, 62.85, 67.28, 70.72, 102.95, 103.74, 119.45, 121.46, 123.39, 124.88, 128.68, 129.76, 130.68, 132.25, 132.37, 134.13, 144.77, 145.57, 148.44, 148.61, 149.94, 166.96, 167.43; mass spectrum, m/e (relative intensity) 537 (M+, 0.1), 296 (100), 254 (66.6), 196 (67.2), 150 (15.8), 59 (20.6), 43 (21.1), 28 (73.7). Anal. Calcd for C28H31N3O8 : C, 62.57; H, 5.77. Found: C, 62.74; H, 5.60.
Reaction SMILES: [Cl:1][C:2]1[C:32]([Cl:33])=[CH:31][C:5]2[N:6]([C@H:13]3[O:25][C@@H:24]([CH2:26][O:27]C(=O)C)[C@H:19]([O:20]C(=O)C)[C@@H:14]3[O:15]C(=O)C)[C:7]([NH:9][CH:10]([CH3:12])[CH3:11])=[N:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].O.CO>C(O)C>[Cl:1][C:2]1[C:32]([Cl:33])=[CH:31][C:5]2[N:6]([C@H:13]3[O:25][C@@H:24]([CH2:26][OH:27])[C@H:19]([OH:20])[C@@H:14]3[OH:15])[C:7]([NH:9][CH:10]([CH3:11])[CH3:12])=[N:8][C:4]=2[CH:3]=1
Reactant: CC(=O)OC[C@@H]1O[C@H](n2c(NC(C)C)nc3cc(Cl)c(Cl)cc32)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCO
Product: CC(C)Nc1nc2cc(Cl)c(Cl)cc2n1[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O
Yield: 84 %

Procedure:
5,6-Dichloro-2-(isopropylamino)1-(2,3,5-tri-O-acetyl-beta-L-ribofuranosyl)-1H-benzimidazole (7.50 g, 14.93 mmol), sodium carbonate (1.72 g, 16.23 mmol), water (29 mL), methanol (100 mL) and ethanol (100 mL) were used according to general procedure III. The product was purified by silica gel chromatography using 55:45 dichloromethane/methanol to afford 4.72 g (84%) of a white foam. Analytical data were consistent with the assigned structure.
Reaction SMILES: [CH:1]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10]>[Cl-].[Zn+2].[Cl-].O>[CH:1]1([C:9](=[O:11])[CH3:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: C1=CCCCCCC1
Reactant: CC(=O)OC(C)=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Product: CC(=O)C1CC=CCCCC1
Temperature: 92.5 °C
Reaction time: 7.5 h
Yield: 26.5 %

Procedure:
To cyclooctene (300 g, 2.73 mol) were added acetic anhydride (556 g, 5.45 mol) and zinc chloride (30 g, 0.22 mol). The reaction mixture was warmed to 90-95° C. within 30 min., stirred at that temperature during 7.5 hours, cooled to 60° C., and treated with caution, within 10 min., with water (400 ml). The resulting mixture was heated at 100° C. during 3 h., cooled to 25° C., and extracted with hexane (3×300 ml). The combined organic phases were washed with aq. sat. NaCl soln. (800 ml), aq. sat. NaHCO3 soln. (800 ml), aq. sat. NaCl soln. (400 ml), and dried (Na2SO4). Evaporation of the solvent led to 375 g of crude material which was distilled under vacuum with a short-path Vigreux column. After collecting the unreacted cyclooctene (65 g, 21.7%) at 40-50° C./100 mbar, the fractions distilling at 110° C./24 mbar were collected (144 g) and redistilled using a microdistillation column (20×1.5 cm, filled with 3×3 mm rolled wire netting) to give 110 g of 1-cyclooct-3-enylethanone (34% based on the reacted cyclooctene, 109° C./20 mbar) as colourless oil.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[Cl:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH:15]=[O:16].FC(F)(F)S(O[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[Si](C)(C)C)(=O)=O.[F-].[K+].C1OCCOCCOCCOCCOCCOC1>C1COCC1>[Cl:11][C:12]1[CH:13]=[C:14]([CH:15]2[O:16][CH:1]3[C:10]4[C:5]([CH:4]=[CH:3][N:2]3[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]2=3)=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: C[Si](C)(C)c1ccccc1OS(=O)(=O)C(F)(F)F
Reactant: c1ccc2cnccc2c1
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: Clc1ccc(C2OC3c4ccccc4C=CN3c3ccccc32)cc1Cl
Yield: 77 %

Procedure:
Following the general procedure, treatment of isoquinoline (0.064 g, 59 μL, 0.50 mmol) and 3,4-dichlorobenzaldehyde (0.130 g, 0.75 mmol) with 2-(trimethylsilyl)phenyl trifluoromethanesulfonate (0.179 g, 146 μL, 0.60 mmol) in the presence of KF (0.070 g, 1.2 mmol) and 18-crown-6 (0.317 g, 1.2 mmol) in THF (2.0 mL) at −10° C. to room temperature for 12 hrs followed by flash column chromatography (Pet. ether/EtOAc=93/07) of the crude reaction mixture afforded 6-(3,4-dichlorophenyl)-4bH,6H-benzo[4,5][1,3]oxazino[2,3-a]isoquinoline as inseparable mixture of diastereomers as a yellow solid (0.146 g, 77% yield, dr determined by 1H NMR analysis of crude reaction mixture is 1:1).
Reaction SMILES: [C:1](=[O:22])([O:3][C@@H:4]([CH:8]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)[C:5]([NH2:7])=O)[NH2:2].C(=O)([O-])O.[Na+].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:29]>COCCOC>[C:1](=[O:22])([O:3][C@@H:4]([CH:8]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)[C:5]([NH2:7])=[S:29])[NH2:2]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CC(C)(C)C(c1c[nH]c2ccccc12)[C@H](OC(N)=O)C(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)C(c1c[nH]c2ccccc12)[C@H](OC(N)=O)C(N)=S
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (S)-tert-butyl-1-amino-3-(1H-indol-3-yl)-1-oxopropan-2-yl carbamate (500 mg, 1.6 mmol) in anhydrous 1,2-dimethoxyethane (10 mL) was mixed in portions with sodium hydrogencarbonate (520 mg, 6.2 mmol) and diphosphorus pentasulphide (730 mg, 3.2 mmol) and stirred overnight at room temperature. The reaction mixture was then concentrated to low volume in a vacuum, the residue taken up in ethyl acetate (30 mL) and washed with water and saturated sodium hydrogencarbonate solution (3×20 mL each). The organic phase was dried with sodium sulphate and concentrated to low volume in a vacuum. The raw product (600 mg) was taken up in diethyl ether/cyclohexane (10 mL each) and concentrated to low volume again. During this a white solid separated out.
Reaction SMILES: [Cl:1][CH2:2][C:3]#[N:4].[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[N:15]=[C:14]2[NH:22][CH:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][C:31]3[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=3)[CH2:25][CH2:24]2)=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)C>[ClH:1].[ClH:1].[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[N:15]=[C:14]2[NH:22][CH:23]2[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][C:31]3[CH:32]=[CH:33][C:34]([O:37][CH2:2][C:3]#[N:4])=[CH:35][CH:36]=3)[CH2:27][CH2:28]2)=[CH:8][CH:7]=1
Reactant: N#CCCl
Reactant: Oc1ccc(CCN2CCC(Nc3nc4ccccc4n3Cc3ccc(F)cc3)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cl
Product: N#CCOc1ccc(CCN2CCC(Nc3nc4ccccc4n3Cc3ccc(F)cc3)CC2)cc1
Yield: 78.6 %

Procedure:
A mixture of 1.2 parts of chloroacetonitrile, 6.7 parts of 4-[2-{4-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-ylamino]-1-piperidinyl}ethyl]phenol, 2.8 parts of potassium carbonate and 160 parts of 2-propanone is stirred and refluxed overnight. The reaction mixture is poured onto water and the product is extracted with methylbenzene. The extract is dried, filtered and evaporated. The residue is converted into the hydrochloride salt in 2-propanone. The salt is filtered off and dried, yielding 7.4 parts (78.6%) of {4-[2-{4-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-ylamino]-1-piperidinyl}ethyl]phenoxy}acetonitrile dihydrochloride. monohydrate; mp. 224.6° C.
Reaction SMILES: C(OC([NH:8][C@H:9]([C@@H:17]([OH:36])[C@H:18]([OH:35])[C@@H:19]([NH:27]C(OC(C)(C)C)=O)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O)(C)(C)C>Cl>[NH2:8][C@H:9]([C@@H:17]([OH:36])[C@H:18]([OH:35])[C@@H:19]([NH2:27])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: Cl
Product: N[C@@H](Cc1ccccc1)[C@@H](O)[C@H](O)[C@@H](N)Cc1ccccc1
Temperature: 90 °C

Procedure:
(2S,3R,4R,5S)-2,5-Di-(N-((t-butyloxy)carbonyl)amino)-3,4-dihydroxy-1,6-diphenylhexane (2.7 g, 5.4 mmol) was treated with 200 ml of 6N aqueous hydrochloric acid and heated to 90° C. until the solid had completely dissolved (30 min). The resulting solution was cooled, concentrated in vacuo, treated with saturated brine and 3N aqueous NaOH, extracted with chloroform, dried over Na2SO4, and concentrated in vacuo. Silica gel chromatography using 3% methanol/2% isopropylamine in chloroform provided the pure desired compound (Rf 0.40, 5% methanol/2% isopropylamine in chloroform) as a white solid, m.p. 86°-89° C. 1H NMR (CDCl3) δ2.72 (dd, J=14, 9 Hz, 2H), 2.92 (dd, J=14, 6 Hz, 2H), 3.03 (dd, J=9, 5 Hz, 2H), 3.69 (s, 2H), 7.15-7.35 (m, 10H). Mass spectrum: (M+H)+ =301.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[C:9]([F:19])[CH:8]=2)[CH2:5][C@H:4]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:3]1.Br[C:26]1[S:27][C:28]([CH3:31])=[N:29][N:30]=1.P([O-])([O-])(O)=O.[K+].[K+]>CS(C)=O.O>[CH3:31][C:28]1[S:27][C:26]([N:16]2[CH2:15][CH:14]=[C:13]([C:10]3[CH:11]=[CH:12][C:7]([N:6]4[CH2:5][C@H:4]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:3][C:2]4=[O:1])=[CH:8][C:9]=3[F:19])[CH2:18][CH2:17]2)=[N:30][N:29]=1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3CCNCC3)c(F)c2)C(=O)O1
Reactant: Cc1nnc(Br)s1
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)NC[C@H]1CN(c2ccc(C3=CCN(c4nnc(C)s4)CC3)c(F)c2)C(=O)O1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of (S)-(-)-N-[[2-oxo-3-[4-(4-piperidinyl)-3-fluorophenyl]-5-oxazolidinyl]methyl]acetamide (EXAMPLE 20, 550 mg), 2-bromo-5-methyl-1,3,4-thiadiazole (EXAMPLE 87, Step 1, 323 mg) and potassium hydrogenphosphate (571 mg) in dimethyl sulfoxide (16 mL) is stirred under N2 at 100° C. for 2 hrs, cooled to ambient temperature, diluted with water (20 mL) and extracted with methylene chloride (3×20 mL). The combined organic phase is washed with water (20 mL) and saline (10 mL), dried over anhydrous sodium sulfate and concentrated to give the crude product which is then chromatographed on silica gel (230-400 mesh, 45 g), eluting with a gradient of methanol/methylene chloride (2/98-3/97). Pooling and concentration of those fractions with an Rf =0.44 by TLC (methanol/chloroform, 10/90) gives the title compound, mp 193-195° C.
Reaction SMILES: [C:1]1(C)[C:2]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[CH3:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][OH:22].N1C=CC=C[CH:24]=1>>[S:7]([O:22][CH2:21][CH2:20][O:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][CH3:12])([C:2]1[CH:1]=[CH:6][C:5]([CH3:24])=[CH:4][CH:3]=1)(=[O:8])=[O:9]
Reactant: COCCOCCOCCO
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: c1ccncc1
Product: COCCOCCOCCOS(=O)(=O)c1ccc(C)cc1
Reaction time: 18 h

Procedure:
A solution of toluene sulfonyl chloride (Aldrich, 38 g) and triethylene glycol monomethyl ether (Aldrich, 16.4 g) in dry pyridine (150 ml) was stirred at 0° C. (icebath) for 4 h, followed by 18 h at ambient temperature. The solution was then poured onto ice water (500 ml) and extracted with diethyl ether extracts were combined, washed with hydrochloric acid (3 N) and water, dried (sodium sulfate), and concentrated to provide triethylene glycol methyl tosyl ether as a colorless oil (20.0 g, 62% based on glycol), 1H-NMR (CDCl3) δ: 7.75 (d, J=8.0 Hz, 2, 2 phenyl CH), 7.30 (d, J=8.1 Hz, 2, 2 phenyl CH), 4.11 (t, J=4.8 Hz, 2, CH2OS), 3.65–3.41 (m, 10, 5 CH2O), 3.32 (s, 3, CH3O) and 2.40 (s, 3, benzylic CH3).
Reaction SMILES: C[CH:2]1N(CC2C=CC=CC=2)C(=O)N(C2C=CC(Cl)=CC=2)[C:3]1=[O:4].[CH2:23]([O:25][C:26](=[O:53])[C@H:27]1[CH2:31][CH:30]([O:32]S(C2C=CC(C)=CC=2)(=O)=O)[CH2:29][N:28]1[S:43]([C:46]1[CH:51]=[CH:50][C:49]([CH3:52])=[CH:48][CH:47]=1)(=[O:45])=[O:44])[CH3:24]>C1(C)C=CC=CC=1.C([O-])(=O)C.C[N+](C)(C)C>[CH2:23]([O:25][C:26](=[O:53])[C@H:27]1[CH2:31][CH:30]([O:32][C:3](=[O:4])[CH3:2])[CH2:29][N:28]1[S:43]([C:46]1[CH:51]=[CH:50][C:49]([CH3:52])=[CH:48][CH:47]=1)(=[O:44])=[O:45])[CH3:24]
Reactant: CC1C(=O)N(c2ccc(Cl)cc2)C(=O)N1Cc1ccccc1
Reactant: CCOC(=O)[C@H]1CC(OS(=O)(=O)c2ccc(C)cc2)CN1S(=O)(=O)c1ccc(C)cc1
Agent: CC(=O)[O-]
Agent: C[N+](C)(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@H]1CC(OC(C)=O)CN1S(=O)(=O)c1ccc(C)cc1
Yield: 72.8 %

Procedure:
To 218 g (466 mmol) of allo-1-(4-toluenesulfonyl)- 4-(4-toluenesulfonyloxy)-D-proline ethyl ester in 1500 ml of toluene was added 81 g (606 mmol) of tetramethyl ammonium acetate and the mixture was heated to reflux for 2 hours. The reaction was cooled, washed with 2x500 ml of water and dried over sodium sulfate. Evaporation of the solvent and drying the resulting solids in a vacuum oven overnight at 30° C. provided 120.6 g of product (72% yield). M.P.=82°-83° C.
Reaction SMILES: [F:1][CH:2]([F:12])[O:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([NH:10][NH2:11])[CH:5]=1.CN([CH:16]=[CH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])C.[CH2:23](O)[CH3:24]>>[F:12][CH:2]([F:1])[O:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([N:10]2[C:23]([CH3:24])=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:16]=[N:11]2)[CH:5]=1
Reactant: Cn1nc(NN)cc1OC(F)F
Reactant: CCOC(=O)C=CN(C)C
Reactant: CCO
Product: CCOC(=O)c1cnn(-c2cc(OC(F)F)n(C)n2)c1C

Procedure:
3.0 g (16.8 mmol) 5-Difluoromethoxy-3-hydrazino-1-methylpyrazole was added to 25 ml ethanol and treated dropwise with 2.96 g (16.0 mmol) ethyl dimethylaminomethylenacetate dissolved in 25 ml ethanol. The mixture was heated under reflux for 2 hours. After cooling the precipitate was suction filtered off.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11](Cl)(=[O:13])=[O:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH:15]([NH:18][CH2:19][CH2:20][CH2:21][NH:22][CH:23]([CH3:25])[CH3:24])([CH3:17])[CH3:16]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11]([N:18]([CH:15]([CH3:17])[CH3:16])[CH2:19][CH2:20][CH2:21][NH:22][CH:23]([CH3:24])[CH3:25])(=[O:13])=[O:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CC(C)NCCCNC(C)C
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Product: COc1ccc(S(=O)(=O)N(CCCNC(C)C)C(C)C)cc1OC

Procedure:
3,4 Dimethoxybenzenesulfonyl chloride was reacted with N,N'-diisopropylpropane-1,3-diamine by procedures following those given in Example 1 and chromatographed on Dry-column alumina with 10% methanol/ethyl acetate to provide the title compound. Treatment of this material with isopropanol/HCl gave the hydrochloride salt, m.p. 132°-135° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][NH:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:24]([O:26][C:27]([C:29]1([C:32]2[CH:37]=[CH:36][C:35](B3OC(C)(C)C(C)(C)O3)=[CH:34][CH:33]=2)[CH2:31][CH2:30]1)=[O:28])[CH3:25]>>[CH2:24]([O:26][C:27]([C:29]1([C:32]2[CH:37]=[CH:36][C:35]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH2:14][NH:15][CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:4][CH:3]=3)=[CH:34][CH:33]=2)[CH2:30][CH2:31]1)=[O:28])[CH3:25]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CNCCc1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CNCCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylmethyl]-phenethyl-amine and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.