Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Br[CH:10]([CH2:15][CH2:16][CH2:17][Br:18])[C:11](OC)=[O:12].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)C>[Br:18][CH2:17][CH2:16][CH2:15][CH:10]1[C:11](=[O:12])[NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[O:8]1
Reactant: COC(=O)C(Br)CCCBr
Reactant: Nc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOCC
Product: O=C1Nc2ccccc2OC1CCCBr
Yield: 20.3 %

Procedure:
24 g of 2-aminophenol, 55 g of methyl 2,5-dibromovalerate and 30 g of potassium carbonate were heated to reflux for 5 hours in 250 ml of acetone. For work-up, the reaction mixture was diluted with 250 ml of diethyl ether, washed with 200 ml of water and acidified to pH=1 using 12N hydrochloric acid solution. The organic phase was separated, washed twice with 100 ml of water each time, dried and evaporated. The residue was crystallized from methanol. 11 g of 2-(3-bromopropyl)-2H-1,4-benzoxazin-3(4H)one were obtained.
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].[O:10]1[CH2:14][CH2:13][CH2:12][C:11]1=[O:15]>C(O)C>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH2:14][CH2:13][CH2:12][C:11]([OH:15])=[O:10]
Reactant: Oc1ccccc1Cl
Reactant: O=C1CCCO1
Agent: [Na]
Solvent: CCO
Product: O=C(O)CCCOc1ccccc1Cl
Temperature: 150 °C
Reaction time: 0.08 h
Yield: 80.4 %

Procedure:
To a solution of sodium (405 mg, 1.08 mmol) in ethanol (11.1 mL) was added 2-chlorophenol and the reaction mixture was stirred for 5 minutes before adding dihydro-furan-2-one (1.4 g, 16.1 mmol). The reaction mixture was stirred for 5 hours at 100° C. after which time the ethanol was slowly evaporated by continuous heating to 150° C. for another 12 hours. After such time the residue was dissolved in water (7 mL) and aqueous hydrochloric acid (1N) was added until precipitation occurred. The precipitate was isolated by filtration, washed with water and dried in vacuo to yield the title compound as yellow solid (2.79 g, 80.4%).
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:16][CH:15]=1.B(OC)(OC)[O:30]C.OO>C1COCC1.C(O)(=O)C>[F:6][C:7]1[C:12]([F:13])=[C:11]([OH:30])[CH:10]=[CH:9][C:8]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:16][CH:15]=1
Reactant: COB(OC)OC
Reactant: CCCCCCCCOc1ccc(-c2cccc(F)c2F)cc1
Agent: OO
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCCCCCCOc1ccc(-c2ccc(O)c(F)c2F)cc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 68.8 %

Procedure:
A solution of n-butyllithium (1.60 ml, 10.0 M in hexanes, 0.016 mol) was added dropwise to a stirred, cooled (−78° C.) solution of 2,3-difluoro-4′-octyloxybiphenyl [see M. Hird and K. L. Toyne, J. Mater. Chem., 1995, 5, 2239] (4.70 g, 0.015 mol) in dry THF (250 ml) under dry nitrogen. The mixture was stirred at −78° C. for 2 hr and a solution of trimethyl borate (3.15 g, 0.030 mol) in dry THF (10 ml) was added. The mixture was allowed to warm to room temperature overnight and a solution of 30% hydrogen peroxide (50 ml) in acetic acid (500 ml) was added dropwise at room temperature. The mixture was extracted into ether (3 times) and the combined ethereal extracts were washed with water and dried over MgSO4. The solvent was removed in vacuo and the residue was recrystallised from ethanol to yield colourless crystals (3.45 g, 69%), mp 145° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]2[O:13][CH:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:14]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:23])[CH3:15]>Cl.C(Cl)Cl>[CH2:14]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][C@@H:11]1[CH2:12][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][C@H:10]1[OH:13])[CH3:15]
Reactant: c1ccc(CN2CC3OC3C2)cc1
Reactant: CCOc1ccccc1O
Agent: Cl
Solvent: ClCCl
Product: CCOc1ccccc1O[C@@H]1CN(Cc2ccccc2)C[C@H]1O

Procedure:
A mixture of 45.5 g. (0.26 mole) of 1-benzyl-3,4- epoxypyrrolidine (60 g. of 76% epoxide), 48 g. (0.35 mole) of o-ethoxyphenol and 8 drops of concentrated hydrochloric acid was heated at 145° C. for 16 hr. The mixture was cooled, dissolved in methylene chloride and washed with dilute sodium hydroxide solution. The methylene chloride layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was chromatographed on 1 kg. of silica gel using 20% acetone in benzene as the eluent. Two recrystallizations from cyclohexane gave 8.0 g. (10%) of tan needles, m.p. 88.5°-90.0° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[CH:8][C:7]=1[O:15][CH3:16].FC(F)(F)C(=O)CI(C1C=CC=CC=1)CC(C(F)(F)F)=[O:24].O.C(C(O)=O)(F)(F)F>CC#N>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH2:13][OH:24])=[CH:8][C:7]=1[O:15][CH3:16]
Reactant: COc1cc(C(C)=O)ccc1OCCCCl
Reactant: O=C(CI(CC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1cc(C(=O)CO)ccc1OCCCCl
Yield: 32.8 %

Procedure:
A solution of 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (4.3 g, 17.7 mmol), [bis(trifluoroacetony)iodo]benzene (15.6 g, 36.2 mmol), H2O (18 ml), CF3CO2H (2.8 ml) and CH3CN (90 ml) was refluxed for 3 hours. The CH3CN was removed under reduced pressure and the resulting yellow liquid was partitioned between H2O and CH2Cl2. The biphasic mixture was filtered, the organic phase collected, washed with saturated NaHCO3 solution and concentrated to afford 1.5 g of an amorphous brown solid. The solid was flash chromatographed on silica gel, eluting the column with 5% EtOAc/CH2Cl2. Concentration of similar fractions afforded 0.7 g of the compound as a pale yellow solid, m.p. 99-101° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]([N:20]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([N+:29]([O-])=O)[CH:27]=3)[CH2:22][CH2:21]2)=[O:19])[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]([N:20]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([NH2:29])[CH:27]=3)[CH2:22][CH2:21]2)=[O:19])[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N[C@H]1CC[C@H](C(=O)N2CCc3ccc([N+](=O)[O-])cc32)CC1)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Nc1ccc2c(c1)N(C(=O)[C@H]1CC[C@H](NC(=O)OCc3ccccc3)CC1)CC2

Procedure:
17.33 g of stannous chloride was added to a hydrated ethanol (120 ml of ethanol+1.2 ml of water) suspension containing 6.08 g of N-benzyloxycarbonyl-trans-4-[(6-nitro-1-indolinyl)carbonyl]cyclohexylamine (the compound obtained in the same manner as in Reference Example 13-1 before deprotection), and the mixture was refluxed under argon atmosphere for 4.5 hours. An aqueous 10% sodium hydroxide solution was added to the reaction mixture to adjust pH of the mixture to pH 9 to 10, the mixture was diluted with 300 ml of chloroform and dried over anhydrous magnesium sulfate, and then, the insolubles were removed by filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (solvent: chloroform-ethyl acetate (2:1)) to obtain 4.72 g of N-benzyloxycarbonyl-trans-4-[(6-amino-1-indolinyl)carbonyl]cyclohexylamine. (2) 0.12 ml of pyridine and 0.104 ml of acetic anhydride were added to 10 ml of a methylene chloride solution containing 396 mg of the compound obtained in the above (1), and the mixture was stirred for 5 hours. 5% hydrochloric acid was added to the reaction mixture and the mixture was extracted with chloroform. The extracted layer was successively washed with water and an aqueous saturated sodium bicarbonate solution and dried over anhydrous sodium sulfate, and then, the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (solvent: chloroform-ethyl acetate (1:1)).
Reaction SMILES: [CH3:1][C:2]1[C:3]2[C:8]([CH:9]3[C:14]=1[CH2:13][CH2:12][NH:11][CH2:10]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[CH:15]1([NH:21][C:22](=[O:25])[CH:23]=[CH2:24])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH:15]1([NH:21][C:22](=[O:25])[CH2:23][CH2:24][N:11]2[CH2:12][CH2:13][C:14]3=[C:2]([CH3:1])[C:3]4[C:8]([CH:9]3[CH2:10]2)=[CH:7][CH:6]=[CH:5][CH:4]=4)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CC1=C2CCNCC2c2ccccc21
Reactant: C=CC(=O)NC1CCCCC1
Product: CC1=C2CCN(CCC(=O)NC3CCCCC3)CC2c2ccccc21

Procedure:
1,3,4,9b-Tetrahydro-5-methyl-2H-indeno[1,2-c]pyridine and N-cyclohexyl acrylamide are reacted in accordance with the process described in Example 6. Reaction period 8 hours. M.P. of the title compound 162.5°-163.5° from acetone.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([N:5]([CH:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([OH:19])=[CH:14][CH:15]=2)[CH2:10]1)[CH2:6][CH2:7][CH3:8])=[O:4].[CH3:22][C:23](C)([O-])C.[K+].C(I)C>CS(C)=O>[CH2:22]([O:19][C:13]1[CH:12]=[C:11]2[C:16]([CH2:17][CH2:18][CH:9]([N:5]([CH2:6][CH2:7][CH3:8])[C:3](=[O:4])[C:2]([F:20])([F:21])[F:1])[CH2:10]2)=[CH:15][CH:14]=1)[CH3:23]
Reactant: CCCN(C(=O)C(F)(F)F)C1CCc2ccc(O)cc2C1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCI
Product: CCCN(C(=O)C(F)(F)F)C1CCc2ccc(OCC)cc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.4 %

Procedure:
To a solution of 2,2,2-trifluoro-N-(7-hydroxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-N-propyl-acetamide (1.0 g, 3.32 mmol) in DMSO (30 mL) under an inert atmosphere was added a slurry of potassium t-butoxide (392 mg, 3.49 mmol, 1.05 eq.) in DMSO (10 mL). The reaction was stirred at room temperature for 30 min. and then ethyl iodide (0.32 mL, 3.98 mmol, 1.2 eq.) was added dropwise. The reaction mixture was stirred for 2 h, quenched with water, and extracted with EtOAc (2×50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated onto silica gel (10 g). This was placed on top of a flash column and eluted with 20% acetone in hexanes to afford N-(7-ethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-2,2,2-trifluoro-N-propyl-acetamide as an oil (660 mg).
Reaction SMILES: CC(C)([O-])C.[K+].[O:7]1[CH2:11][CH2:10][NH:9][C:8]1=[O:12].Cl[C:14]1[S:15][CH:16]=[CH:17][C:18]=1[N+:19]([O-:21])=[O:20]>CN(C=O)C.[Cl-].[Na+].O>[N+:19]([C:18]1[CH:17]=[CH:16][S:15][C:14]=1[N:9]1[CH2:10][CH2:11][O:7][C:8]1=[O:12])([O-:21])=[O:20]
Reactant: O=C1NCCO1
Reactant: O=[N+]([O-])c1ccsc1Cl
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1OCCN1c1sccc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
Potassium tert-butoxide (1.86 g, 16.6 mmol) and oxazolidin-2-one (1.90 g, 21.8 mmol) in DMF (50 ml) was stirred for 30 min. 2-chloro-3-nitrothiophene (1.64 g, 10.0 mmol) was added and after 1 h, the solution was placed into a preheated oil bath at 100° C. After stirring for 1 h, the solution was diluted with brine and extracted with diethyl ether. The combined organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was flash chromatographed with 9:1, 4:1, 7:3, 3:2, and 1:1 hexane:ethyl acetate as the eluant to yield impure 3-(3-nitrothiophen-2-yl)oxazolidin-2-one. Method [3] Retention time 2.50 min by HPLC (MH+ 215) and (M+Na=237).
Reaction SMILES: [C:1]([C:3]1[O:4][C:5]2[C:11]([C:12]3[CH:35]=[CH:34][C:15]([O:16][CH2:17][C:18]4[CH:19]=[C:20]([CH:31]=[CH:32][CH:33]=4)[C:21]([N:23]4[CH2:30][CH2:29][CH2:28][C@H:24]4[C:25]([OH:27])=[O:26])=[O:22])=[CH:14][CH:13]=3)=[CH:10][C:9]([F:36])=[C:8]([F:37])[C:6]=2[CH:7]=1)#[N:2].Cl.[NH2:39][OH:40].C(N(CC)CC)C>C(O)C>[NH2:2][C:1](=[N:39][OH:40])[C:3]1[O:4][C:5]2[C:11]([C:12]3[CH:13]=[CH:14][C:15]([O:16][CH2:17][C:18]4[CH:19]=[C:20]([CH:31]=[CH:32][CH:33]=4)[C:21]([N:23]4[CH2:30][CH2:29][CH2:28][C@H:24]4[C:25]([OH:27])=[O:26])=[O:22])=[CH:34][CH:35]=3)=[CH:10][C:9]([F:36])=[C:8]([F:37])[C:6]=2[CH:7]=1
Reactant: N#Cc1cc2c(F)c(F)cc(-c3ccc(OCc4cccc(C(=O)N5CCC[C@H]5C(=O)O)c4)cc3)c2o1
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: NC(=NO)c1cc2c(F)c(F)cc(-c3ccc(OCc4cccc(C(=O)N5CCC[C@H]5C(=O)O)c4)cc3)c2o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 20 %

Procedure:
The compound (20 mg, 0.04 mmol) of Example 54 was dissolved in ethanol (5 mL), and hydroxylamine hydrochloride (14 mg, 0.21 mmol) and triethylamine (0.058 mL, 0.42 mmol) were added thereto, and stirred at room temperature for 2 hours. After that, the solvent was distilled away, and the resulting residue was purified by reversed-phase HPLC in the same manner as in Step 2 of Example 1 to thus obtain the title compound.
Reaction SMILES: [CH3:1][NH2:2].Br.[CH3:4][O:5][C:6]([C:8]1[C:9]([CH3:23])=[N:10][S:11][C:12]=1[NH:13][C:14]([O:16]C1C=CC=CC=1)=O)=[O:7]>C(O)C.O>[CH3:4][O:5][C:6]([C:8]1[C:9]([CH3:23])=[N:10][S:11][C:12]=1[NH:13][C:14]([NH:2][CH3:1])=[O:16])=[O:7]
Reactant: COC(=O)c1c(C)nsc1NC(=O)Oc1ccccc1
Reactant: CN
Agent: Br
Solvent: O
Solvent: CCO
Product: CNC(=O)Nc1snc(C)c1C(=O)OC

Procedure:
A warm solution of methyl 3-aminocrotonate (prepared according to the method of Conrad and Epstein, Chemische Berichte, 1887, 20, 3054, 10.4 g.) in toluene (20 ml.) was added with stirring to a solution of phenoxycarbonylisothiocyanate (16 g.) in toluene (50 ml.). The temperature of the mixture rose from 20° C. to 35° C. The mixture was then stirred for 11/2 hours at ambient temperature, filtered and the solid residue washed with light petroleum (b.p. 40°-60° C.) to give 3-imino-2-methoxycarbonyl-N-phenoxycarbonylthiobutyramide (8.6 g.) in the form of an orange solid, which was then dissolved in ethyl acetate (100 ml.). To this solution, a solution of bromine (1.67 ml.) in ethyl acetate (5 ml.) was added over 15 minutes at 2°-5° C. The mixture was stirred at ambient temperature for 11/2 hours and the solid product filtered off to give 4-methoxycarbonyl-3-methyl-5-phenoxycarbonylaminoisothiazole hydrobromide (9.6 g.) m.p. 170°- 173° C. A solution of methylamine in ethanol (30% w/v; 20 ml.) was added to 4-methoxycarbonyl-3-methyl-5-phenoxycarbonylaminoisothiazole hydrobromide (9.0 g.). The mixture was heated under reflux for 15 minutes, diluted with water (30 ml.), filtered and the solid residue dried at 100° C., to give 1-(4-methoxycarbonyl-3-methylisothiazol-5-yl)-3-methylurea (4.1 g.), m.p. 236°-237° C.
Reaction SMILES: Cl.C[O:3][C:4]1[C:20]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:19][C:7]2[CH:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:9][NH:10][CH2:11][CH2:12][C:6]=2[CH:5]=1.[BrH:25]>>[BrH:25].[OH:3][C:4]1[C:20]([S:21](=[O:23])(=[O:24])[NH2:22])=[CH:19][C:7]2[CH:8]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:9][NH:10][CH2:11][CH2:12][C:6]=2[CH:5]=1
Reactant: COc1cc2c(cc1S(N)(=O)=O)C(c1ccccc1)CNCC2
Agent: Br
Agent: Cl
Product: NS(=O)(=O)c1cc2c(cc1O)CCNCC2c1ccccc1

Procedure:
7-Methoxy-1-phenyl-8-sulfamoyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride is treated with hydrobromic acid by the procedure of Example 2 to give 7-hydroxy-1-phenyl-8-sulfamoyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[F:19][C:20]1[CH:25]=[C:24]([S:26][C:27]2[CH:32]=[CH:31][C:30]([S:33][CH3:34])=[CH:29][CH:28]=2)[CH:23]=[CH:22][C:21]=1[NH:35][C:36](=[O:54])[C:37]([O:46][Si](C(C)(C)C)(C)C)([C:42]([F:45])([F:44])[F:43])[C:38]([F:41])([F:40])[F:39].C(OCC)(=O)C>C1COCC1>[F:19][C:20]1[CH:25]=[C:24]([S:26][C:27]2[CH:32]=[CH:31][C:30]([S:33][CH3:34])=[CH:29][CH:28]=2)[CH:23]=[CH:22][C:21]=1[NH:35][C:36](=[O:54])[C:37]([OH:46])([C:38]([F:39])([F:40])[F:41])[C:42]([F:44])([F:45])[F:43]
Reactant: CSc1ccc(Sc2ccc(NC(=O)C(O[Si](C)(C)C(C)(C)C)(C(F)(F)F)C(F)(F)F)c(F)c2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CSc1ccc(Sc2ccc(NC(=O)C(O)(C(F)(F)F)C(F)(F)F)c(F)c2)cc1
Yield: 89.4 %

Procedure:
Tetra-n-butylammonium fluoride (0.48 ml of a 1M solution in THF) was added to a stirred solution of N-[2-fluoro-4-(4-methylsulphanylphenylsulphanyl)phenyl]-2-(t-butyldimethylsilyloxy)-2-trifluoromethyl-3,3,3-trifluoropropanamide (0.278 g) (Method 55) in anhydrous THF (5 ml) at −78° C. under argon. After 30 minutes ethyl acetate (50 ml) was added and the mixture was washed with aqueous hydrochloric acid (2M, 30 ml) and brine (30 ml) then dried. Volatile material was removed by evaporation and the residue was purified on a silica gel Mega Bond Elut column eluting with 10-30% ethyl acetate/iso-hexane to give the title compound (0.199 g) as a pale yellow solid. NMR (CDCl3): 2.50 (s, 3H), 5.12 (s, 1H), 6.98 (d, 1H), 7.05 (d, 1H), 7.23 (d, 2H), 7.35 (d, 2H), 8.05-8.08 (m, 1H); MS (ESP−): 458,
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][OH:14])=[CH:11][CH:10]=1.CC(C)([O-])C.[K+].CN1CCCC1=O>O>[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][O:14][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:11][CH:10]=1
Reactant: Fc1ccccn1
Reactant: OCc1ccc(Br)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Brc1ccc(COc2ccccn2)cc1
Temperature: 100 °C

Procedure:
A mixture of 2-fluoropyridine (1.6 g), 4-bromobenzyl alcohol (3.08 g), potassium tert-butoxide (2.03 g) and N-methylpyrrolidone (12.8 ml) was heated at 100° C. by microwave irradiation for one minute. The mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and concentrated. 2-(4-Bromobenzyloxy)pyridine was obtained in this way.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[C:18](=[O:19])[CH2:17][C@@H:16]([C:20](O)=[O:21])[CH2:15]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:25]([N:27](CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.CN>CN(C)C=O>[CH3:25][NH:27][C:20]([C@@H:16]1[CH2:17][C:18](=[O:19])[N:14]([C:11]2[CH:12]=[CH:13][C:8]([O:7][CH2:6][C:5]3[CH:23]=[CH:24][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:9][CH:10]=2)[CH2:15]1)=[O:21]
Reactant: O=C(O)[C@@H]1CC(=O)N(c2ccc(OCc3ccc(F)cc3)cc2)C1
Reactant: CCN(CC)CC
Agent: CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CNC(=O)[C@@H]1CC(=O)N(c2ccc(OCc3ccc(F)cc3)cc2)C1
Reaction time: 0.5 h
Yield: 65.6 %

Procedure:
A solution of 1.82 mmol of (R)-1-[4-(4-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid in 37 ml of N,N-dimethylformamide was cooled to 0° C., was treated consecutively with 2.0 mmol of triethylamine, 1.82 mmol of HBTU, 2.2 mmol of methylamine hydrochloride, and 2.0 mmol of triethylamine. The ice-bath was removed, and stirring continued at RT. The reaction was stopped after 30 min, and the orange coloured solution was evaporated under reduced pressure. The residue obtained was triturated in 1 ml of ethyl acetate; the white solid product was filtered, thereafter dissolved in dichloromethane; and the solution washed three times with water. The organic phase was dried over sodium sulfate, then evaporated under reduced pressure to yield 409 mg (66% of theory) of the (R)-1-[4-(4-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid methylamide a white solid. MS: m/e=343 (M+H)+; enantiomeric excess >99.5%.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[I:34][C:35]1[CH:36]=[C:37]([CH2:41][OH:42])[CH:38]=[CH:39][CH:40]=1.[Cl:43][C:44]1[C:45]([OH:54])=[C:46]([C:51](=[O:53])[CH3:52])[CH:47]=[CH:48][C:49]=1O>ClCCl.O1CCCC1>[Cl:43][C:44]1[C:45]([OH:54])=[C:46]([C:51](=[O:53])[CH3:52])[CH:47]=[CH:48][C:49]=1[O:42][CH2:41][C:37]1[CH:38]=[CH:39][CH:40]=[C:35]([I:34])[CH:36]=1
Reactant: CC(=O)c1ccc(O)c(Cl)c1O
Reactant: OCc1cccc(I)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)c1ccc(OCc2cccc(I)c2)c(Cl)c1O
Reaction time: 18 h
Yield: 64.5 %

Procedure:
Add triphenylphosphine (13.6 g, 51.7 mmol) and DIAD (10.5 g, 51.7 mmol) to a solution of (3-iodo-phenyl)-methanol (11.0 g, 47.0 mmol) and 1-(3-Chloro-2,4-dihydroxy-phenyl)-ethanone (8.77 g, 47.0 mmol) in dichloromethane:tetrahydrofuran (250 ml:250 ml) and stir. After 18 hours, concentrate the reaction, and load directly onto silica. Purify the residue by flash chromatography eluting with acetone:hexanes to yield the title product as a white solid (12.2 g, 64%): 1H NMR (DMSO-d6) δ 2.62 (s, 3H), 5.34 (s, 2H), 6.88 (d, 1H), 7.23 (t, 1H), 7.48 (d, 1H), 7.72 (d, 1H), 7.87 (s, 1H), 7.96 (d, 1H), 13.14 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:13]([C:14]3[N:15]=[CH:16][NH:17][CH:18]=3)=[C:12]([CH3:19])[O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].Cl[C:21]1[N:26]=[CH:25][CH:24]=[CH:23][N:22]=1>>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:13]([C:14]3[N:15]=[CH:16][N:17]([C:21]4[N:26]=[CH:25][CH:24]=[CH:23][N:22]=4)[CH:18]=3)=[C:12]([CH3:19])[O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Clc1ncccn1
Reactant: Cc1onc(-c2ccc(F)c(F)c2)c1-c1c[nH]cn1
Product: Cc1onc(-c2ccc(F)c(F)c2)c1-c1cn(-c2ncccn2)cn1
Yield: 47 %

Procedure:
As described for Example 53, 3-(3,4-difluoro-phenyl)-4-(1H-imidazol-4-yl)-5-methyl-isoxazole (78 mg, 0.3 mmol) using 2-chloropyrimidine instead of 4-fluoroacetophenone was converted to the title compound (48 mg, 47%) which was obtained as an off-white solid. MS: m/e=406.3 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[N:19]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:18]=[N:17][N:16]=2)=[CH:5][CH:4]=1.[NH2:39][C@@H:40]([CH3:43])[CH2:41][OH:42].C(=O)([O-])[O-].[K+].[K+].O>C1COCC1>[C:20]([N:19]1[C:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:6]2[CH:5]=[CH:4][C:3]([CH2:2][NH:39][C@@H:40]([CH3:43])[CH2:41][OH:42])=[CH:8][CH:7]=2)=[N:16][N:17]=[N:18]1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: C[C@H](N)CO
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](CO)NCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5-(4′-bromomethylbiphenyl-2-yl)-1-trityl-1H-tetrazole made as described in Preparation 1 (9.7 g, 17.4 mmol), (2S)-2-aminopropan-1-ol (3.9 g, 52.3 mmol), and potassium carbonate (2.4 g, 17.4 mmol), in THF (170 mL) was stirred at room temperature overnight. Water (100 mL) was added, and the aqueous phase was extracted with EtOAc (3×100 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. Silica gel chromatography gave intermediate (5a).
Reaction SMILES: [C:1]([O:9][C@@H:10]1[C@@H:14]([CH2:15][OH:16])[CH2:13][C@@H:12]([NH:17]C(OC(C)(C)C)=O)[C@@H:11]1[O:25][C:26](=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:34].O1CCOCC1>>[ClH:34].[C:1]([O:9][C@@H:10]1[C@@H:14]([CH2:15][OH:16])[CH2:13][C@@H:12]([NH2:17])[C@@H:11]1[O:25][C:26](=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H](CO)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@H]1C[C@H](CO)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Reaction time: 0.58 h
Yield: 90 %

Procedure:
(1R,2S,3R,5R)-3-[(tert-Butoxycarbonyl)amino]-5-(hydroxymethyl)-cyclopentane-1,2-diyl dibenzoate (1.42 g, 3.11 mmol) was treated with a 4.00 M solution of HCl in 1,4-dioxane (17.0 mL, 69.3 mmol) and the reaction was stirred for 35 min. The reaction mixture was concentrated in vacuo and Et2O was added to precipitate the product, which was washed with Et20 to afford the title compound as a white solid (1.05 g, 90%). LC/MS: Rt=1.06 min, ES+ 356 (FA standard).