Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([O:18][C:19]3[CH:20]=[C:21]([C:25]4[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH:26]=4)[CH:22]=[N:23][CH:24]=3)[CH:15]=[CH:14][C:12]=2[N:13]=1.[ClH:38].O1CCOCC1>>[NH:28]1[CH2:27][CH:26]=[C:25]([C:21]2[CH:20]=[C:19]([O:18][C:16]3[CH:15]=[CH:14][C:12]4[N:13]=[C:9]([NH:8][C@@H:3]5[CH2:4][CH2:5][CH2:6][CH2:7][C@H:2]5[OH:1])[S:10][C:11]=4[CH:17]=3)[CH:24]=[N:23][CH:22]=2)[CH2:30][CH2:29]1.[ClH:38]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cncc(Oc3ccc4nc(N[C@@H]5CCCC[C@H]5O)sc4c3)c2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Oc3cncc(C4=CCNCC4)c3)cc2s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solid tert-butyl 4-(5-(2-((1R,2R)-2-hydroxycyclohexylamino)benzo[d]thiazol-6-yloxy)pyridin-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate (7.2 mg, 0.0138 mmol, see Example 25 above) was added 4M HCl in Dioxane (1 mL, 4.0 mmol). The reaction mixture was stirred at room temperature for 1 hour. The crude reaction mixture was concentrated to a solid and lyophilized to give title compound as HCl salt (4.8 mg). ES/MS m/z 423.2 (MH+), Rt=1.72 min.
Reaction SMILES: C(SC1C=C(O)C(=O)NC=1)C1C=CC=CC=1.COC[O:20][C:21]1[C:22](=[O:38])[N:23](COC)[CH:24]=[C:25]([S:27][CH2:28][C:29]2[N:30]=[C:31]([CH3:34])[O:32][CH:33]=2)[CH:26]=1>>[OH:20][C:21]1[C:22](=[O:38])[NH:23][CH:24]=[C:25]([S:27][CH2:28][C:29]2[N:30]=[C:31]([CH3:34])[O:32][CH:33]=2)[CH:26]=1
Reactant: COCOc1cc(SCc2coc(C)n2)cn(COC)c1=O
Agent: O=c1[nH]cc(SCc2ccccc2)cc1O
Product: Cc1nc(CSc2c[nH]c(=O)c(O)c2)co1

Procedure:
Prepared as described for 5-(benzylsulfanyl)-3-hydroxypyridin-2(1H)-one (Example 12) from 3-(methoxymethoxy)-1-(methoxymethyl)-5-{[(2-methyl-1,3-oxazol-4-yl)methyl]sulfanyl}pyridin-2(1H)-one (Intermediate 21).
Reaction SMILES: C[O:2][C:3](=[O:47])[CH2:4][CH2:5][NH:6][C:7](=[O:46])[C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:45])[CH:15]([C:33]2[CH:38]=[CH:37][C:36]([CH:39]3[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]3)=[CH:35][CH:34]=2)[CH2:16][C:17]([C:19]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:20]=2)=[O:18])=[CH:10][CH:9]=1.Cl>C1COCC1>[F:26][C:25]([F:27])([F:28])[C:23]1[CH:24]=[C:19]([C:17](=[O:18])[CH2:16][CH:15]([C:33]2[CH:38]=[CH:37][C:36]([CH:39]3[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]3)=[CH:35][CH:34]=2)[C:14]([C:11]2[CH:10]=[CH:9][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:47])=[O:2])=[O:46])=[CH:13][CH:12]=2)=[O:45])[CH:20]=[C:21]([C:29]([F:30])([F:31])[F:32])[CH:22]=1
Reactant: COC(=O)CCNC(=O)c1ccc(C(=O)C(CC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccc(C3CCCCC3)cc2)cc1
Agent: Cl
Solvent: C1CCOC1
Product: O=C(O)CCNC(=O)c1ccc(C(=O)C(CC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccc(C3CCCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3-{4-[4-(3,5-Bis-trifluoromethylphenyl)-2-(4-cyclohexylphenyl)-4-oxobutyryl]benzoylamino}propionic acid methyl ester (6.20 g, 9.38 mmol) was dissolved in THF (75 mL), HCl (6 N, 25 mL) was added and the mixture was heated to reflux, after 2 hours the heat was turned of and the mixture was stirred at room temperature for 16 hours. The mixture was evaporated to dryness to give the title compound. Yield: quantitative.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH3:11].CC(C)([O-])C.[K+].[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=1.C(OCC)(=O)C>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:24][C:23]1[CH:26]=[CH:27][C:20]([O:19][CH3:18])=[CH:21][CH:22]=1)[N:6]=[C:5]2[CH3:11]
Reactant: Cc1n[nH]c2ccc(Br)cc12
Reactant: COc1ccc(CCl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(Cn2nc(C)c3cc(Br)ccc32)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.3 %

Procedure:
To a solution of 5-bromo-3-methylindazole 104 (0.2 g, 0.948 mmol) in anhydrous THF (3 mL), cooled in ice bath, was added potassium t-butoxide (0.127 g, 1.13 mmol) and 4-methoxybenzyl chloride (0.14 mL, 1.04 mmol). The reaction mixture was allowed to warmed to room temperature and was stirred for 16 hours. Ethyl acetate (100 mL) was added and the organic layer was washed with saturated ammonium chloride solution, water and brine. The organic layer was dried over sodium sulfate. The organic solvent was evaporated under reduced pressure. The crude product was purified by flash column chromatography to yield the desired 5-bromo-N-(4-methoxybenzyl)-3-methylindazole 105 (0.29 g, 0.932 mmol) as a mixture of the 1H- and 2H-indazole regioisomers.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[N:10]([O-])=O.[Na+].[Sn].[ClH:15]>O>[ClH:15].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:6][NH2:10])[CH:7]=[CH:8][CH:9]=1
Reactant: O=N[O-]
Reactant: COc1cccc(N)c1
Agent: Cl
Agent: [Na+]
Agent: [Sn]
Solvent: O
Product: COc1cccc(NN)c1

Procedure:
A suspension of 3-methoxyaniline (10 g) in concentrated hydrochloric acid (85 ml) was stirred at ca. 0° and a solution of sodium nitrite (5.75 g) in water (25 ml) was slowly added over a period of 30 min keeping the temperature of the mixture at ca. 0°. After 1 h a solution of tin II chloride dihydrate (59 g) in concentrated hydrochloric acid (50 ml) was added over a period of 1.5 h, to the cooled suspension keeping the temperature below 0° C. The suspension was stirred for a further 30 min, filtered and washed with dried ether to give the title compound as a solid (14 g) m.p. 171°.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([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])=[N:4][CH:3]=1.[ClH:38]>C(Cl)Cl.O1CCOCC1>[ClH:38].[CH3:1][C:2]1[S:6][C:5]([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])=[N:4][CH:3]=1
Reactant: Cc1cnc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)s1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1cnc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of tert-butyl 4-{1-[(5-methyl-1,3-thiazol-2-yl)methyl]-2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl}piperidine-1-carboxylate (980 mg; compound B12) in DCM (5 ml) and 1,4-dioxane (20 ml) is reacted with a solution of hydrogen chloride in 1,4-dioxane (2.3 ml, 4.0 M) under stirring at RT. After 1 h and after 2.5 h additional amounts of a solution of hydrogen chloride in 1,4-dioxane (4.6 ml and 2.3 ml) are added and the reaction mixture is stirred for another 10 min. All volatiles are removed under reduced pressure and the resulting residue is treated with diethyl ether. Removal of the solvent under reduced pressure gives the title compound as a solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1.Cl[C:13]1[CH:23]=[C:17]2[N:18]([CH3:22])[CH2:19][CH2:20][CH2:21][N:16]2[C:15](=[O:24])[N:14]=1>>[CH3:22][N:18]1[CH2:19][CH2:20][CH2:21][N:16]2[C:15](=[O:24])[N:14]=[C:13]([O:1][CH2:2][CH2:3][C:4]3[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=3)[CH:23]=[C:17]12
Reactant: N#Cc1ccc(CCO)cc1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Product: CN1CCCn2c1cc(OCCc1ccc(C#N)cc1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E11 starting from of 4-(2-hydroxyethyl)benzonitrile and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([OH:26])([C:22]([F:25])([F:24])[F:23])[C:18]([F:21])([F:20])[F:19])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-]S(C(F)(F)[F:33])(=O)=O.F[N+]1C=CC=CC=1.[NH4+].[Cl-].CCOCC>ClC(Cl)C>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([OH:26])([C:18]([F:19])([F:20])[F:21])[C:22]([F:25])([F:23])[F:24])=[CH:14][CH:15]=2)[C:10]([F:33])=[C:9]1[CH3:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)([O-])C(F)(F)F
Reactant: Cc1cc2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc2n1Cc1ccccc1
Agent: F[n+]1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CC(Cl)Cl
Product: Cc1c(F)c2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 11.4 %

Procedure:
To a solution of 21 mg (0.054 mmol) of 2-(1-benzyl-2-methyl-1H-indol-5-yl)-1,1,1,3,3,3-hexafluoro-propan-2-ol (example 80) in 1 mL of dichloroethane were added 16 mg (0.065 mmol) of 1-fluoropyridinium triflate. After stirring at RT for 72 hrs, the mixture was poured into a mixture of a saturated aqueous solution of NH4Cl and Et2O. The phases were separated and the aqueous one was extracted with Et2O. The combined organic phases were dried over Na2SO4 and evaporated. Column chromatography on silica gel with n-heptane/EtOAc 4:1 yielded 2.5 mg (11%) of 2-(1-benzyl-3-fluoro-2-methyl-1H-indol-5-yl)-1,1,1,3,3,3-hexafluoro-propan-2-ol, light brown waxy solid. MS: 404 (M−H)−.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([NH:18]S(C(C)(C)C)=O)[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].Cl.CCOCC>CO>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@H:12]([NH2:18])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: CCOc1cc(C(CS(C)(=O)=O)NS(=O)C(C)(C)C)ccc1OC
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: CCOc1cc([C@H](N)CS(C)(=O)=O)ccc1OC
Reaction time: 12 h

Procedure:
Finally, a reaction flask was charged with Compound F in MeOH (10 vol) at 20-25° C. then treated with 2N HCl/Et2O (˜2 mL, 2.0 equiv) and stirred for 12 h. The reaction mixture was concentrated to dryness and the resulting solid was dissolved in water/EtOAc. The aqueous portion was neutralized then extracted with CH2Cl2. The combined organic layers were dried with MgSO4 then concentrated to provide (S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethylamine (Compound B).
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C@H:9]1[C:14]([OH:16])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][CH:18]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:19]([OH:23])[C:20]([NH2:22])=[O:21].O[NH-].O=[N-]>>[NH2:22][C:20](=[O:21])[C:19](=[O:23])[CH:18]([NH:17][C:14]([C@@H:9]1[CH2:10][CH2:11][C:12](=[O:13])[N:8]1[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:16])[CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(O)[C@@H]1CCC(=O)N1Cc1ccccc1
Reactant: NC(=O)C(O)C(N)Cc1ccccc1
Agent: [N-]=O
Agent: [NH-]O
Product: NC(=O)C(=O)C(Cc1ccccc1)NC(=O)[C@@H]1CCC(=O)N1Cc1ccccc1

Procedure:
Coupling of (S)-1-benzyl-5-oxopyrrolidine-2-carboxylic acid with 3-amino-2-hydroxy-4-phenylbutanamide was followed by oxidation of the resulting hydroxyamide intermediate to the corresponding ketoamide.
Reaction SMILES: [H-].[Na+].[Cl:3][CH2:4][CH2:5][CH2:6][CH:7](P(OCC)(OCC)=O)[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[F:23][C:24]1[CH:31]=[C:30]([N:32]2[CH:36]=[C:35]([CH3:37])[N:34]=[CH:33]2)[C:29]([O:38][CH3:39])=[CH:28][C:25]=1[CH:26]=O.O>C1COCC1.C(OCC)(=O)C>[Cl:3][CH2:4][CH2:5][CH2:6]/[C:7](=[CH:26]\[C:25]1[CH:28]=[C:29]([O:38][CH3:39])[C:30]([N:32]2[CH:36]=[C:35]([CH3:37])[N:34]=[CH:33]2)=[CH:31][C:24]=1[F:23])/[C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9]
Reactant: COc1cc(C=O)c(F)cc1-n1cnc(C)c1
Reactant: CCOP(=O)(OCC)C(CCCCl)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(/C=C(\CCCCl)C(=O)OC(C)(C)C)c(F)cc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 106.5 %

Procedure:
Sodium hydride (containing mineral oil at 40%, 0.68 g) was added to a solution of tert-butyl 5-chloro-2-(diethoxyphosphoryl)valerate (5.59 g) in THF (50 mL) in a nitrogen atmosphere at room temperature, and the reaction solution was stirred at room temperature for 30 minutes. A solution of 2-fluoro-5-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (3.19 g) in THF (10 mL) was added to the reaction mixture, and the reaction solution was stirred at room temperature for 4 hours. Water and ethyl acetate were added to the reaction mixture and the organic layer was partitioned. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (elution solvent:heptane-ethyl acetate system) to obtain tert-butyl (E)-5-chloro-2-(2-fluoro-5-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valerate (5.93 g). A solution of tert-butyl (E)-5-chloro-2-(2-fluoro-5-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valerate in trifluoroacetic acid (30 mL) was stirred while cooling with ice. After 2 hours, the reaction solution was concentrated under reduced pressure. Tert-butyl methyl ether was added to the resulting residue, and the resulting deposited solid was filtered to obtain 3 g of the title compound. Properties data of the compound are as follows.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:4][C:3]=1[N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25].[O:30]=[C:31]1[NH:35][C:34](=[O:36])[CH:33]([CH2:37][C:38]2[CH:48]=[CH:47][C:41]([O:42][CH2:43][C:44](O)=[O:45])=[CH:40][CH:39]=2)[S:32]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCCC1>[O:30]=[C:31]1[NH:35][C:34](=[O:36])[CH:33]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:42][CH2:43][C:44]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([O:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[N:15]4[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]4)=[CH:4][C:3]=3[N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:45])=[CH:47][CH:48]=2)[S:32]1
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccccc2N2CCCCC2)ccc1N
Agent: CCOP(=O)(C#N)OCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccccc2N2CCCCC2)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Yield: 91 %

Procedure:
In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-{2-amino-5-[2-(piperidin-1-yl)phenoxy]phenyl}-N-methyl-carbamate (1.19 g), 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid (0.93 g), diethyl cyanophosphonate (0.54 g), triethylamine (0.33 g) and anhydrous tetrahydrofuran (20 ml) and the reaction mixture was purified to give the desired product (1.80 g).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[N:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].F[C:21]1[CH:22]=[CH:23][C:24]([N+:31]([O-:33])=[O:32])=[C:25]([CH:30]=1)[C:26]([O:28][CH3:29])=[O:27].[Cl-].[NH4+]>CN(C)C=O>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[N:12]=[CH:11][C:10]([O:13][C:21]3[CH:22]=[CH:23][C:24]([N+:31]([O-:33])=[O:32])=[C:25]([CH:30]=3)[C:26]([O:28][CH3:29])=[O:27])=[CH:9][CH:8]=2)[N:3]=1
Reactant: Cc1nc(-c2ccc(O)cn2)no1
Reactant: COC(=O)c1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Oc2ccc(-c3noc(C)n3)nc2)ccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 1 h
Yield: 80.8 %

Procedure:
1.54 g of 6-(5-methyl-1,2,4-oxadiazol-3-yl)pyridin-3-ol and 1.86 g of potassium carbonate were added to a dimethylformamide (10 ml) solution of 955 mg of methyl 5-fluoro-2-nitrobenzoate, and stirred at 80° C. for 1 hour. This was restored to room temperature, then aqueous saturated ammonium chloride solution was added to it, extracted with ethyl acetate, and the organic layer was dried, and the solvent was evaporated away under reduced pressure to obtain 1.38 g of methyl 5-{[6-(5-methyl-1,2,4-oxadiazol-3-yl)pyridin-3-yl]oxy}-2-nitrobenzoate as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C@H:3]1[CH2:8][CH2:7][C@H:6]([CH:9]=[O:10])[CH2:5][CH2:4]1.[CH2:13]([CH:16]([CH3:20])[CH:17](O)[OH:18])[CH2:14][CH3:15].C1(C)C=CC=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1>O>[F:1][C:2]([F:11])([F:12])[C@H:3]1[CH2:4][CH2:5][C@H:6]([CH:9]2[O:18][CH2:17][CH:16]([CH2:13][CH2:14][CH3:15])[CH2:20][O:10]2)[CH2:7][CH2:8]1
Reactant: O=C[C@H]1CC[C@H](C(F)(F)F)CC1
Reactant: CCCC(C)C(O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCC1COC([C@H]2CC[C@H](C(F)(F)F)CC2)OC1

Procedure:
A mixture of 0.02 mol of trans-4-trifluoromethyl-1-formylcyclohexane (prepared as in Example 3), 0.02 mol of 2-propylpropanediol, 30 ml of toluene and 0.5 g of pTsOH (sic) is heated for 4 hours on a water separator. The pure product is obtained after customary work-up and crystallization.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:9]12[O:15][CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14]2.S([O-])([O-])(=O)=O.[NH4+].[NH4+]>C1COCC1.BrCCBr.[Cu]Cl>[C:3]1([C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[OH:15])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Brc1ccccc1
Reactant: C1CCC2OC2C1
Agent: Cl[Cu]
Agent: O=S(=O)([O-])[O-]
Agent: [Mg]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: O[C@@H]1CCCC[C@H]1c1ccccc1
Reaction time: 0.17 h
Yield: 24.1 %

Procedure:
Magnesium turnings (706 mg; 29 mmol; 1.45 equiv.) were combined with THF (3.5 mL). Bromobenzene (3.1 mL; 29.4 mmol; 1.47 equiv.) in 5 mL of THF was added slowly dropwise. After approximately 1 mL of the bromobenzene solution had been added 1 drop of 1,2-dibromoethane was added to initiate the reaction. Once all the bromobenzene was added and the magnesium consumed the reaction mixture was diluted with THF (20 mL) and cooled to -30° Copper(I) chloride (130 mg; 1.32 mmol; 0.066 equiv.) was added and the reaction mixture was stirred for 10 min. A solution of cyclohexene oxide (2.1 mL; 20 mmol) in THF (2 mL) was added slowly dropwise. After the addition was complete the reaction mixture was warmed to 0° and stirred for 2 h. The reaction mixture was then treated with saturated aqueous ammonium sulfate (10 mL) and the layers were separated. The organic layer was washed with 5 mL portions of saturated ammonium sulfate until the washes were colorless. The combined aqueous washes were extracted with ether (3×10 mL), and the combined organic solution was dried (MgSO4) and concentrated. The crude product was recrystallized from pentane to afford 850 mg (24%) of 1m as white crystals. 1H nmr (300 MHz, CDCl3): 7.369-7.221 (5H, m); 3.640 (1H, m); 2.438 (1H, dt, J=10.43 Hz, 3.34 Hz); 2.146-2.114 (1H, m); 1.892-1.847 (2H, m); 1.788-1.753 (1H, m); 1.639 (1H, s); 1.530-1.254 (4H, m). IR (KBr, cm-1): 3500 (s); 2900 (s); 1600 (m). FDMS (m/e): 176 (M+).
Reaction SMILES: [OH-:1].[K+].[Sn:3]([Cl:7])([Cl:6])([Cl:5])[Cl:4]>>[OH2:1].[OH2:1].[OH2:1].[OH2:1].[OH2:1].[Sn:3]([Cl:7])([Cl:6])([Cl:5])[Cl:4]
Reactant: [OH-]
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [K+]
Product: O

Procedure:
A tin (IV) chloride pentahydrate (Aldrich) solution was prepared by addition of the solid to distilled water; 20% colloidal alumina (AL-20, PQ Corp.) was stirred into this solution and a white precipitate formed. An aqueous potassium hydroxide (Fisher) solution was added to the tin chloride solution and stirred., colloidal silica (HS-40, DuPont) was added to the mixture (to give a final reactant ratio of 2K2 0:3.8SiO2 :SnO2 :0.1A12O3 :80H2O) and the resulting gel stirred until homogeneous. The gel was reacted in a polytetrafluoroethylene-lined autoclave (Parr) at 200° C. for 21 days to produce a white solid after the reactor was cooled to room temperature. This solid was washed repeatedly with distilled water, filtered, and dried to yield a fine white powder (Phase G). Chemical analysis indicated 13.67% K, 22.82% Sn, 18.69% Si, and 0.92% Al.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6](=[O:8])C)(=[O:4])=[O:3].C(OOOOCO[C:18](=[O:20])C)(=O)C>>[CH3:1][S:2]([O:5][CH2:6][O:8][CH2:18][O:20][S:2]([CH3:1])(=[O:4])=[O:3])(=[O:4])=[O:3]
Reactant: CC(=O)OS(C)(=O)=O
Reactant: CC(=O)OCOOOOC(C)=O
Product: CS(=O)(=O)OCOCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 41.8 %

Procedure:
a mixture of 12.7 g of acetyl methanesulfonate and 9.15 g of trioxymethylene diacetate was prepared at 0° C and then stirred at 25° C for 20 hours. Distillation at 10μ produced 4.5 g of CH3SO3CH2OCH2OSO2CH3 b.p. 110°-115° C (pot temp.); m.p. 57°-59° C.
Reaction SMILES: BrC1C(=O)C(C(O)=O)=CN(C(C)C)C=1C.[Br:16][C:17]1[C:18](=[O:31])[C:19]([C:28]([OH:30])=O)=[CH:20][N:21]([C@H:24]([CH2:26][CH3:27])[CH3:25])[C:22]=1[CH3:23].Cl.CS(C1C=CC(CN)=CC=1)(=O)=O.[CH3:45][S:46]([C:49]1[CH:50]=[CH:51][C:52]([CH2:55][NH2:56])=[N:53][CH:54]=1)(=[O:48])=[O:47].BrBr>>[CH3:45][S:46]([C:49]1[CH:50]=[CH:51][C:52]([CH2:55][NH:56][C:28]([C:19]2[C:18](=[O:31])[C:17]([Br:16])=[C:22]([CH3:23])[N:21]([C@H:24]([CH2:26][CH3:27])[CH3:25])[CH:20]=2)=[O:30])=[N:53][CH:54]=1)(=[O:48])=[O:47]
Reactant: CS(=O)(=O)c1ccc(CN)nc1
Reactant: CC[C@H](C)n1cc(C(=O)O)c(=O)c(Br)c1C
Agent: BrBr
Agent: CS(=O)(=O)c1ccc(CN)cc1
Agent: Cc1c(Br)c(=O)c(C(=O)O)cn1C(C)C
Product: CC[C@H](C)n1cc(C(=O)NCc2ccc(S(C)(=O)=O)cn2)c(=O)c(Br)c1C

Procedure:
Preparation 20 is prepared following the procedure for preparation 5, substituting preparation 3c with preparation 12b and 4-methylsulfonylbenzylamine hydrochloride with C-(5-methanesulfonyl-pyridin-2-yl)-methylamine. ESI mass spectrum: [M+H]+=456 (bromine isotope pattern); Retention time HPLC: 0.87 min (Z018_S04).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([C:20](=[O:35])[N:21]([CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH2:32][CH2:33][OH:34])[CH3:22])[CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[NH2:7][C@H:8]([CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)[C:20]([N:21]([CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH2:32][CH2:33][OH:34])[CH3:22])=[O:35]
Reactant: CN(CCc1ccccc1OCCO)C(=O)[C@@H](Cc1ccc2ccccc2c1)NC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(CCc1ccccc1OCCO)C(=O)[C@H](N)Cc1ccc2ccccc2c1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 51.9 %

Procedure:
A solution of [(1R)-1-(N-{2-[2-(2-hydroxyethoxy)phenyl]ethyl}-N-methylcarbamoyl)-2-(2-naphthyl)ethyl]carbamic acid tert-butyl ester (519 mg, 1.85 mmol) in dichloromethane (3 ml) was cooled to 0° C. Trifluoroacetic acid (3 mL) was added. The reaction mixture was stirred at 0° C. for 40 min. Dichloromethane (20 ml) was added. A saturated solution of sodium hydrogen carbonate (10 ml) was added dropwise. Solid sodium hydrogen carbonate was added, until pH 7 was obtained. The phases were separated. The aqueous phase was extracted with dichloromethane (3×20 ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (60 g), using dichloromethane/methanol/25% aqueous ammonia, to give 377 mg of (2R)-2-amino-N-{2-[2-(2-hydroxyethoxy)phenyl]ethyl}-N-methyl-3-(2-naphthyl)propionamide.