Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[C:34](=[O:35])[N:11]2[C:12]([C:18]([O:20][CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])=[C:13]([CH2:16][OH:17])[CH2:14][S:15][C@H:10]12)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:55][O:56][C:57]1[CH:62]=[CH:61][C:60](O)=[CH:59][CH:58]=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][CH:9]1[C:34](=[O:35])[N:11]2[C:12]([C:18]([O:20][CH:21]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])=[C:13]([CH2:16][O:17][C:60]3[CH:61]=[CH:62][C:57]([O:56][CH3:55])=[CH:58][CH:59]=3)[CH2:14][S:15][C@H:10]12)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CO)CS[C@H]12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(OCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)OC(C)(C)C)[C@H]3SC2)cc1
Temperature: 0 °C
Reaction time: 6 h
Yield: 21.2 %

Procedure:
5.00 g (10.1 mmol) of Diphenylmethyl 7-tert-butoxycarbonylamino-3-hydroxymethyl-3-cephem-4-carboxylate, 7.93 g (30.2 mmol) of triphenylphosphine, and 7.28 g (60.2 mmol) of p-methoxyphenol were dissolved in 25 ml of tetrahydrofuran under argon atmosphere, and the reaction solution was cooled to -40°-35° C., and 4.76 ml (30.2 mmol) of diethyl azodicarboxylate were added dropwise, and then the stirring was effected for 6 hrs. at the same temperature. This solution was added to a suspension of 300 ml of ice cold 1N hydrochloric acid and 300 ml of ethyl acetate, and stirred, and then separated, and the layer of ethyl acetate was washed with water and saturated saline solution, and dried over anhydrous magnesium sulfate. Benzene was added to a caramel obtained by evaporating off the solvent so that the insoluble material was removed by filtering off, and the residue obtained by evaporating off the benzene filtrate was dissolved in diethyl ether. This ether solution was washed with 20% potassium carbonate aqueous solution until unreacted p-methoxyphenol was removed, and further washed with saturated potassium dihydrogen phosphate aqueous solution, water, and saturated saline solution. The layer of ether was dried over anhydrous magnesium sulfate, and then, ether was evaporated off to give 2.80 g of a caramel. The caramel was column chromatographed on silica gel by eluting with benzene-acetone (V:V;100:1), and then, powdered with ether-hexane to give 1.29 g of diphenylmethyl 7-tert-butoxycarbonylamino-3-(4-methoxyphenoxymethyl)-3cephem-4-carboxylate.
Reaction SMILES: [Br:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.[CH2:11](Br)[CH:12]=[CH2:13].O1CCOCC1.[OH-].[Na+]>C(OCC)(=O)C>[CH2:13]([N:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[Br:1])[CH:12]=[CH2:11]
Reactant: Brc1nc2ccccc2[nH]1
Reactant: C=CCBr
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C=CCn1c(Br)nc2ccccc21
Temperature: 100 °C
Reaction time: 2 h
Yield: 51.9 %

Procedure:
A mixture of 2-bromo-1H-benzo[d]imidazole (0.400 g, 2.04 mmol), allyl bromide (0.35 mL, 4.08 mmol), 1,4-dioxane (15 mL), and 2 M aqueous sodium hydroxide solution (15 mL, 3.00 mmol) stirred for 2 h at 100° C. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (50 mL). The organic phase was separated and washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified via preparative thin layer chromatography (eluting with 20% ethyl acetate/petroleum ether) to afford 1-allyl-2-bromo-1H-benzo[d]imidazole (0.251 g, 52%) as a yellow oil. MS (ESI, pos. ion) m/z 237, 239 [M+H]+.
Reaction SMILES: [OH-].[Na+].[C:3](OC(=O)C)(=[O:5])[CH3:4].O1CCCC1.Br.[CH2:16]1[CH2:20][O:19][C:18]2[CH:21]=[CH:22][C:23]3[CH2:24][CH2:25][CH:26]([CH2:28][CH2:29][NH2:30])[C:27]=3[C:17]1=2>O>[CH2:16]1[CH2:20][O:19][C:18]2[CH:21]=[CH:22][C:23]3[CH2:24][CH2:25][CH:26]([CH2:28][CH2:29][NH:30][C:3](=[O:5])[CH3:4])[C:27]=3[C:17]1=2
Reactant: NCCC1CCc2ccc3c(c21)CCO3
Reactant: CC(=O)OC(C)=O
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)NCCC1CCc2ccc3c(c21)CCO3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
Aqueous 1N sodium hydroxide solution (1.5 ml) and acetic anhydride (0.050 ml, 0.528 mmols) were added to a tetrahydrofuran (1.5 ml) solution of 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine hydrobromide (0.10 g, 0.352 mmols), and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The extract was washed with a saturated saline solution, then dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from isopropyl ether/hexane to obtain 0.057 g (yield: 66%) of the target compound.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.Cl.[CH3:14][O:15][C:16](=[O:28])[CH2:17][NH:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][CH3:27].[C:29]([O:33][C:34]([NH:36][C@H:37]([C:51](O)=[O:52])[CH:38]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:35])([CH3:32])([CH3:31])[CH3:30].ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>ClCCl>[CH3:14][O:15][C:16](=[O:28])[CH2:17][N:18]([C:51](=[O:52])[C@@H:37]([NH:36][C:34]([O:33][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:35])[CH:38]([C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][CH3:27]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(c1ccccc1)c1ccccc1
Reactant: COC(=O)CNCc1ccccc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)CN(Cc1ccccc1OC)C(=O)[C@@H](NC(=O)OC(C)(C)C)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.7 %

Procedure:
1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.15 g) was added over 5 minutes to a mixture of N-(2-methoxybenzyl)glycine methyl ester hydrochloride (1.72 g), N-(tert-butoxycarbonyl)-3,3-diphenyl-L-alanine (1.71 g), 1-hydroxybenzotriazole (0.81 g) and N,N-diisopropylethylamine (1.22 ml) in dichloromethane (40 ml). After being stirred for 3 hours at room temperature, the resulting mixture was extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixed solvent of hexane and ethyl acetate (4:1) to give N-[(2S)-2-(tert-butoxycarbonylamino)-3,3-diphenylpropionyl]-N-(2-methoxybenzyl)glycine methyl ester (2.34 g) as a colorless powder.
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:32])[CH2:15][NH:16][C:17]([CH:19]2[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20]2)=O)=[CH:10][CH:9]=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>C(Cl)Cl>[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:32][C:17]([CH:19]3[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[CH2:20]3)=[N:16][CH:15]=2)=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)NCC(=O)c2ccc(F)cc2)C1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC(c2ncc(-c3ccc(F)cc3)o2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.6 %

Procedure:
Dry pyridine (0.24 mL, 2.74 mmol) was added dropwise to a solution of tert-butyl 3-((2-(4-fluorophenyl)-2-oxoethyl)carbamoyl)piperidine-1-carboxylate (500 mg, 1.37 mmol) in dry CH2Cl2 (12 mL) at 0° C., followed by trifluoromethanesulfonic anhydride (0.5 mL, 2.74 mmol). The reaction mixture was allowed to warm up to room temperature and stirred for 3 h. The reaction mixture was diluted with CH2Cl2 and the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by purified by column chromatography (silica gel 60-120 mesh, eluent 12-15% EtOAc in petroleum ether) to afford tert-butyl 3-(5-(4-fluorophenyl)oxazol-2-yl)piperidine-1-carboxylate (150 mg, yield 32%). 1H NMR (400 MHz, DMSO-d6) δ 7.75-7.72 (dd, J=9.0 Hz, 5.3 Hz, 2H), 7.55 (s, 1H), 7.33-7.29 (t, J=8.8 Hz, 2H), 3.99-3.90 (m, 1H), 3.69-3.60 (m, 1H), 3.02 (m, 1H), 2.12-2.07 (m, 1H), 1.82-1.76 (m, 2H), 1.64-1.57 (m, 1H), 1.51-1.42 (m, 2H), 1.35 (s, 9H). MS (ESI) m/z: Calculated for C19H23FN2O3: 346.17. found: 347.2 (M+H)+
Reaction SMILES: O[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH:8][C:9]([C:11]1[S:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=1)=[O:10].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.CC1C=CC(C)=CC=1>N1C=CC=CC=1>[N+:16]([C:13]1[S:12][C:11]([C:9]2[O:10][C:2]3[CH:3]=[N:4][CH:5]=[CH:6][C:7]=3[N:8]=2)=[CH:15][CH:14]=1)([O-:18])=[O:17]
Reactant: O=C(Nc1ccncc1O)c1ccc([N+](=O)[O-])s1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: c1ccncc1
Solvent: Cc1ccc(C)cc1
Product: O=[N+]([O-])c1ccc(-c2nc3ccncc3o2)s1
Temperature: 160 °C
Yield: 17.2 %

Procedure:
To a stirred solution of N-(3-hydroxypyridin-4-yl)-5-nitrothiophene-2-carboxamide (1.1 g, 4.1 mmol) in pyridine (5 mL) was added P2O5 (1.2 g, 8.3 mmol) and p-xylene (21 mL). After refluxing at 160° C. overnight, the reaction mixture was concentrated in vacuo and the residue was purified by chromatography on silica gel eluted with 5% of ethyl acetate in CH2Cl2 to give 2-(5-nitrothiophen-2-yl)oxazolo[5,4-c]pyridine as brown solid (174 mg, yield 17%). 1H NMR (400 MHz, CDCl3) δ: 8.97 (1H, s); 8.59 (1H, d, J=5.6); 7.94 (1H, d, J=4.4); 7.86 (1H, d, J=4.4), 7.69 (1H, d, J=5.6,0.8).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[O:8][C:7](=[O:9])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([C@H:16]3[CH2:21][CH2:20][C@H:19]([O:22][CH2:23][S:24][CH3:25])[CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5]1.I([O-])(=O)(=O)=[O:27].[Na+]>CO.O>[CH3:25][S:24]([CH2:23][O:22][C@H:19]1[CH2:20][CH2:21][C@H:16]([C:13]2[CH:12]=[CH:11][C:10]([N:6]3[CH2:5][CH:4]([CH2:3][O:2][CH3:1])[O:8][C:7]3=[O:9])=[CH:15][CH:14]=2)[CH2:17][CH2:18]1)=[O:27]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: COCC1CN(c2ccc([C@H]3CC[C@H](OCSC)CC3)cc2)C(=O)O1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COCC1CN(c2ccc([C@H]3CC[C@H](OCS(C)=O)CC3)cc2)C(=O)O1
Reaction time: 24 h

Procedure:
1.71 g (4.68 mmol) of (RS)-5-methoxymethyl-3-[4-(trans-4-methylsulfanylmethoxy-cyclohexyl)-phenyl]-oxazolidin-2-one were dissolved in 100 ml of methanol, cooled to 0° and treated dropwise while stirring during 40 minutes with a solution of 1.0 g (4.68 mmol) of sodium metaperiodate dissolved in 40 ml of water. The reaction mixture was held at about 4° for 24 hours. Thereafter, it was diluted with water and the product was extracted with methylene chloride. The organic phase was washed with water, dried over sodium sulfate and filtered. The filtrate was filtered through 50 g of silica gel 60 and washed separately with methanol. After evaporation of the methanol eluate the diastereomer mixture, (RS)-3-[4-(trans-4-methanesulfinylmethoxy-cyclohexyl)-phenyl]-5-methoxymethyl-oxazolidin-2-one, was crystallized from benzene. M.p.: 98°-100°.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:11]=1[Cl:17])=[O:9].[N:18](OCCCCC)=[O:19]>C(O)(C)(C)C>[Cl:17][C:11]1[C:12]([Cl:16])=[CH:13][CH:14]=[CH:15][C:10]=1[C:8](=[O:9])[CH:7]=[N:18][OH:19]
Reactant: CCCCCON=O
Reactant: CC(=O)c1cccc(Cl)c1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: O=C(C=NO)c1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.8 %

Procedure:
Potassium t-butoxide (239.7 g, 2.136 mol) was dissolved in t-butanol (1.5 liters) and allowed to stir at room temperature for 30 minutes. 2,3-Dichloroacetophenone (67.26 g, 0.356 mol) was added in one portion and the resulting mixture stirred overnight at room temperature. Amyl nitrite (83.41 g, 0.712 mol) was added slowly dropwise, with stirring. When the addition was complete the reaction mixture was stirred at room temperature for 2 hours and then heated at 50° C. for 2 hours. The solution was allowed to cool and stirred at room temperature overnight. The reaction mixture was poured into ice/water (1.5 liters), and the aqueous solution extracted with diethyl ether (3×500 ml). The aqueous phase was acidified with concentrated hydrochloric acid and allowed to stand at room temperature overnight. The solid which precipitated was filtered at the pump and dried under vacuum over anhydrous phosphorus pentoxide to give 2,3-dichlorophenylglyoxal aldoxime (57.3 g, 73.8%) as a brown solid. T.l.c. (SiO2 ; CHCl3) showed little impurity, but subsequent dehydration of the oxime showed that recrystallisation would be advisable. The oxime may be recrystallised from toluene, m.p. 109° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7](Br)[CH:6]=1)[CH3:2].[OH:13][CH2:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1.C([O-])([O-])=O.[K+].[K+].CO>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1>[OH:13][CH2:14][C:15]1[CH:20]=[C:19]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:12])[CH:6]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: OCc1cccc(B(O)O)c1
Reactant: CCOC(=O)c1cccc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cccc(-c2cccc(CO)c2)c1
Temperature: 80 °C

Procedure:
A mixture of ethyl-3-bromobenzoate (3.0 g, 13 mmol), [3-(hydroxymethyl)-phenyl]boronic acid (3.0 g, 20 mmol), PdCl2(PPh3)2 (0.46 g, 0.66 mmol), K2CO3 (3.6 g, 26 mmol), methanol (4 mL), and toluene (36 mL) was heated at 80° C. for 18 h under N2 and then allowed to cool to rt. The reaction mixture was filtered through Celite and then poured into a mixture of ethyl acetate and brine. The two layers were separated and the aqueous layer was extracted with ethyl acetate (×3). The organic extracts were dried (Na2SO4), filtered, concentrated and purified by silica gel chromatography to give ethyl 3′-(hydroxymethyl)biphenyl-3-carboxylate as an orange oil. A solution of CBr4 (5.8 g, 17 mmol) and CH2Cl2 (20 mL) was added dropwise to a solution of the above alcohol, PPh3 (4.6 g, 18 mmol), and CH2Cl2 (50 mL) at 0° C. under N2. The reaction was allowed to warm to rt, maintained for 2 h, concentrated, and purified by silica gel chromatography to give ethyl 3′-(bromomethyl)biphenyl-3-carboxylate as a clear oil. Ethyl 3′-(bromomethyl)biphenyl-3-carboxylate was used to alkylate 1-(2,2-dimethylpropyl)-4-propyl-1H-indol-5-ol following the procedure outlined in example 1. A mixture of the above indole (0.66 g, 1.4 mmol), 1 N LiOH (8 mL), and THF (8 mL) was heated at 40° C. for 2 d and then cooled to 0° C.—acetone can used in place of THF if faster reaction rates are desired. The reaction was acidified to pH=1 with conc. HCl and extracted with ethyl acetate (×3). The organic extracts were dried (Na2SO4), filtered, concentrated and purified by silica gel chromatography to give a yellow oil. 1H NMR (CDCl3, 500 MHz) δ 8.39 (s, 1H), 8.11 (d, 1H), 7.85 (d, 1H), 7.76 (s, 1H), 7.59-7.48 (m, 4H), 7.12 (d, 1H), 7.05 (d, 1H), 6.96 (d, 1H), 6.46 (d, 1H), 5.16 (s, 2H), 3.84 (s, 2H), 2.95 (t, 2H), 1.76 (m, 2H), 1.01 (t, 3H), 0.99 (s, 9H). MS (ESI): 456 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([SH:12])=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[H-].[Na+].Cl[C:16]1[C:21](Cl)=[N:20][CH:19]=[CH:18][N:17]=1.C(OCC)(=O)C>CN(C)C=O>[N:17]1[C:18]2[NH:1][C:2]3[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[N:4][C:3]=3[S:12][C:19]=2[N:20]=[CH:21][CH:16]=1
Reactant: Clc1nccnc1Cl
Reactant: COC(=O)c1cnc(S)c(N)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cnc2c(c1)Nc1nccnc1S2
Yield: 30.4 %

Procedure:
To a solution of 1.0 g of methyl 5-amino-6-mercaptonicotinate in N,N-dimethylformamide (30 ml) were added 0.52 g of sodium hydride (oily: 60% or more) and 0.97 g of 2,3-dichloropyrazine and the resulting mixture was reacted at 100° C. for 2 hours. Then ethyl acetate was added to the reaction mixture, which was then washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, diethyl ether was added to the residue and the crystals thus precipitated were taken up by filtration to thereby give 0.43 g of crude methyl 10H-pyrazino[2,3-b]pyrido[3,2-e][1,4]thiazin-8-carboxylate as a brown solid. To a solution of 1.43 g of these crude crystals in N,N-dimethylformamide (50 ml) were added 0.26 g of sodium hydride (60% oily) and 0.5 g of chloromethyl methyl ether and the resulting mixture was reacted under ice-cooling for 1 hour. After adding ethyl acetate, the mixture was washed with a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, diethyl ether was added to the residue and the crystals thus precipitated were taken up by filtration to thereby give 1.5 g of the title compound as red crystals.
Reaction SMILES: Br[C:2]1[C:3]([O:14][CH2:15][C:16]2[C:17]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:18][O:19][C:20]=2[CH3:21])=[N:4][CH:5]=[C:6]([CH:13]=1)[C:7]([NH:9][CH:10]([CH3:12])[CH3:11])=[O:8].Br[C:29]1C(OCC2C(C3C=CC=CC=3)=NOC=2C)=NC=C(C=1)C(NC1CCOCC1)=O>>[CH:10]([NH:9][C:7](=[O:8])[C:6]1[CH:13]=[C:2]([CH3:29])[C:3]([O:14][CH2:15][C:16]2[C:17]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:18][O:19][C:20]=2[CH3:21])=[N:4][CH:5]=1)([CH3:12])[CH3:11]
Reactant: Cc1onc(-c2ccccc2)c1COc1ncc(C(=O)NC(C)C)cc1Br
Reactant: Cc1onc(-c2ccccc2)c1COc1ncc(C(=O)NC2CCOCC2)cc1Br
Product: Cc1cc(C(=O)NC(C)C)cnc1OCc1c(-c2ccccc2)noc1C
Yield: 52 %

Procedure:
As described for example 66, 5-bromo-N-isopropyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide (150 mg, 0.35 mmol), instead of 5-bromo-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-(tetrahydro-pyran-4-yl)-nicotinamide was converted to the title compound (73 mg, 52%) which was obtained as an off white gum. MS: m/e=366.0 [M+H]+.
Reaction SMILES: [N:1]12[CH2:9][CH:5]([C:6](=[O:8])[CH2:7]1)[CH2:4][CH2:3][CH2:2]2.[C:10]12([CH2:20][S:21]([OH:24])(=[O:23])=[O:22])[C:17]([CH3:19])([CH3:18])[CH:14]([CH2:15][CH2:16]1)[CH2:13][C:11]2=[O:12]>O>[C:10]12([CH2:20][S:21]([OH:24])(=[O:22])=[O:23])[C:17]([CH3:19])([CH3:18])[CH:14]([CH2:15][CH2:16]1)[CH2:13][C:11]2=[O:12].[N:1]12[CH2:9][C@H:5]([C:6](=[O:8])[CH2:7]1)[CH2:4][CH2:3][CH2:2]2
Reactant: O=C1CN2CCCC1C2
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: O
Product: O=C1CN2CCC[C@@H]1C2

Procedure:
This compound was made in exactly the same manner as described in example 1 using (±)1-azabicyclo[3.2.1]octan-6-one and (-)camphorsulfonic acid. M.p. 267°-268° C. (decomp.) [α]D =-48° (water).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[CH2:12][OH:13].N1C=CN=C1.[CH:19]([Si:22](Cl)([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])([CH3:21])[CH3:20]>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:10])([F:11])[F:9])=[CH:4][C:3]=1[CH2:12][O:13][Si:22]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:19]([CH3:21])[CH3:20]
Reactant: OCc1cc(C(F)(F)F)ccc1Br
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)[Si](OCc1cc(C(F)(F)F)ccc1Br)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 102.7 %

Procedure:
To a solution of (2-bromo-5-(trifluoromethyl)phenyl)methanol (10 g; 39 mmol) in N,N-dimethylformamide (100 mL) was added imidazole (6.82 g; 100.1 mmol) and triisopropylsilyl chloride (9.6 mL; 55.2 mmol) under N2. The reaction was stirred at room temperature for 48 hours. The reaction was diluted with ethyl acetate and washed with water (4×) and brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by 80 g RediSep column (Teledyne Isco Inc., Lincoln Nebr.) (eluted with 5-10% ethyl acetate in heptane) to yield the title compound (16.47 g, 100%) as a colorless oil. MS (GC) Calc: 410.0, Found: 391 (M−F). 1H NMR (400 MHz, CDCl3) δ ppm 7.94 (s, 1H), 7.62 (d, J=8.30 Hz, 1H), 7.39 (d, J=8.30 Hz, 1H), 4.84 (s, 2H), 1.25 (m, 3H), 1.12(d, 18H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[F:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1[S:62](Cl)(=[O:64])=[O:63]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([S:62]([C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][C:56]=2[F:55])(=[O:64])=[O:63])[CH2:49][CH2:48]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: O=S(=O)(Cl)c1ccccc1F
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CCN(S(=O)(=O)c2ccccc2F)CC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 16 %

Procedure:
The desired compound was prepared according to the procedure of Example A42 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 2-fluorobenzenesulfonyl chloride as starting materials in 16% yield. LCMS for C30H30ClFN7O3S (M+H)+: m/z=622.2.
Reaction SMILES: [C:1]([Cl:4])([Cl:3])=[S:2].C(Cl)(Cl)Cl.[CH:9]1([SH:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[OH-].[Na+]>O>[Cl:3][CH:1]([S:2][S:15][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[Cl:4]
Reactant: S=C(Cl)Cl
Reactant: SC1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: ClC(Cl)SSC1CCCCC1
Yield: 67.2 %

Procedure:
To a solution of 20.0 g (0.17 mole) of thiophosgene in 100 ml. of chloroform cooled to 0° C. was added dropwise with stirring 20.2 g (0.17 mole) of cyclohexyl mercaptan. To this mixture was added dropwise a solution of 2.5 g of sodium hydroxide in 25 ml. of water at such a rate as to keep the temperature less than 8° C. When the addition was complete, the chloroform layer was separated and dried over calcium chloride. The solvent was evaporated, and the residue was distilled under reduced pressure to give 26.4 g of yellow cyclohexyl dichloromethyl disulfide, b.p. 118°-125° C. (5 Torr.)
Reaction SMILES: OO[S:3]([O-:5])=[O:4].[K+].[OH:7][CH:8]1[CH2:13][CH:12]([CH2:14][CH2:15][CH3:16])S[C:10]2[S:17][C:18]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:19][C:9]1=2>O.CO>[OH:7][CH:8]1[CH2:13][CH:12]([CH2:14][CH2:15][CH3:16])[S:3](=[O:5])(=[O:4])[C:10]2[S:17][C:18]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:19][C:9]1=2
Reactant: O=S([O-])OO
Reactant: CCCC1CC(O)c2cc(S(N)(=O)=O)sc2S1
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCCC1CC(O)c2cc(S(N)(=O)=O)sc2S1(=O)=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of "oxone"® (196.7 g, 0.32 mol) in water (870 ml) was added to a stirred solution of 5 (56.6 g, 0.19 mol) in methanol (870 ml) over 45 minutes. After stirring at ambient temperature for 20 hours, the mixture was filtered and the solid washed with methanol. The combined filtrate and washings were concentrated in vacuo below 50° C. to remove methanol. The aqueous suspension was extracted with ethyl acetate (1000 ml and 2×600 ml), the combined extracts were washed twice with water, dried over sodium sulfate and evaporated in vacuo to yield 47.37 g of 6.