Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH2:7]([N:14]([CH2:35][CH2:36][O:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[C:40]([C:52](=[O:54])[NH2:53])[CH:39]=1)[CH2:15][CH:16]([OH:34])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[NH:26][CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[N:29]=2)=[CH:21][CH:20]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CI>CN(C)C=O>[CH2:7]([N:14]([CH2:35][CH2:36][O:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[C:40]([C:52](=[O:54])[NH2:53])[CH:39]=1)[CH2:15][CH:16]([OH:34])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[N:26]([CH3:1])[CH:27]=[C:28]([C:30]([F:31])([F:32])[F:33])[N:29]=2)=[CH:21][CH:20]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)[O-]
Reactant: NC(=O)c1cc(OCCN(Cc2ccccc2)CC(O)COc2ccc(-c3nc(C(F)(F)F)c[nH]3)cc2)ccc1OCc1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1cc(C(F)(F)F)nc1-c1ccc(OCC(O)CN(CCOc2ccc(OCc3ccccc3)c(C(N)=O)c2)Cc2ccccc2)cc1
Reaction time: 0.33 h

Procedure:
At 0°, 0.18 g of potassium tert.-butoxide is added to a solution of 1.0 g of 1-[N-benzyl-2-(3-carbamoyl-4-benzyloxyphenoxy)-ethylamino]-3-[4-[4-(trifluoromethyl)-1H-imidazol-2-yl]-phenoxy]-2-propanol in 5 ml of dimethylformamide and the mixture is stirred for 20 minutes in an ice bath. At 0°-5°, a solution of 0.12 ml of methyl iodide in 3 ml of dimethylformamide is added and the mixture is then stirred for 4 hours at room temperature. The reaction solution is concentrated by evaporation, the residue is dissolved in water and the solution is extracted with ethyl acetate. After drying the organic phase over sodium sulphate, this is concentrated to dryness by evaporation, yielding the crude 1-[N-benzyl-2-(3-carbamoyl-4-benzyloxyphenoxy)-ethylamino]-3-[4-[1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl]-phenoxy]-2-propanol which is further processed in that form.
Reaction SMILES: FC1C=C2C(=CC=1)N=C(C(NC(=O)OC(C)(C)C)C)C(C1C=CC=CN=1)=C2C1C(C)=CC=CN=1.FC(F)(F)C(O)=O.NC1C(C#N)=C(Cl)N=CN=1.C(N(C(C)C)CC)(C)C.[NH2:61][C:62]1[C:67]([C:68]#[N:69])=[C:66]([NH:70][C@H:71]([C:73]2[C:82]([C:83]3[CH:88]=[CH:87][CH:86]=[CH:85][N:84]=3)=[C:81]([C:89]3[C:94]([CH3:95])=[CH:93][CH:92]=[CH:91][N:90]=3)[C:80]3[C:75](=[CH:76][CH:77]=[C:78]([F:96])[CH:79]=3)[N:74]=2)[CH3:72])[N:65]=[CH:64][N:63]=1>C(Cl)Cl>[NH2:61][C:62]1[C:67]([C:68]#[N:69])=[C:66]([NH:70][CH:71]([C:73]2[C:82]([C:83]3[CH:88]=[CH:87][CH:86]=[CH:85][N:84]=3)=[C:81]([C:89]3[C:94]([CH3:95])=[CH:93][CH:92]=[CH:91][N:90]=3)[C:80]3[C:75](=[CH:76][CH:77]=[C:78]([F:96])[CH:79]=3)[N:74]=2)[CH3:72])[N:65]=[CH:64][N:63]=1
Reactant: Cc1cccnc1-c1c(-c2ccccn2)c([C@H](C)Nc2ncnc(N)c2C#N)nc2ccc(F)cc12
Agent: Cc1cccnc1-c1c(-c2ccccn2)c(C(C)NC(=O)OC(C)(C)C)nc2ccc(F)cc12
Agent: N#Cc1c(N)ncnc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccnc1-c1c(-c2ccccn2)c(C(C)Nc2ncnc(N)c2C#N)nc2ccc(F)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 1-(6-fluoro-4-(3-methylpyridin-2-yl)-3-(pyridin-2-yl)-quinolin-2-yl)ethylcarbamate (0.23 g, 0.50 mmol) in DCM (5 mL) was added trifluoroacetic acid (0.97 mL, 12.5 mmol) and the resulting solution was stirred at room temperature for one hour. The solution was concentrated under reduced pressure then diluted with 1-butanol (2.5 mL) followed by the addition of 4-amino-6-chloropyrimidine-5-carbonitrile (0.082 g, 0.53 mmol) and diisopropylethylamine (0.26 mL, 1.51 mmol) and 4-amino-6-chloropyrimidine-5-carbonitrile (0.082 g, 0.53 mmol). The solution was stirred at 120° C. for 3 h then purification was attempted by silica gel column chromatography eluting with 0-100% (1:10:90 NH4OH:MeOH:DCM) in DCM). The resulting crude solid was repurified by silica gel column chromatography eluting with a gradient of 0-7% MeOH in DCM to afford a mixture of (R) and (S)-4-amino-6-(1-(6-fluoro-4-(3-methylpyridin-2-yl)-3-(pyridin-2-yl)quinolin-2-yl)ethylamino)pyrimidine-5-carbonitrile as a yellow glass: LC-MS (ESI) m/z 477.2 [M+H]+.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[C:11]([O:15][C:16]([C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21](O)=O)=[O:17])([CH3:14])([CH3:13])[CH3:12].N>>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([C:3]2[N:10]=[C:21]([C:20]3[CH:19]=[C:18]([CH:26]=[CH:25][CH:24]=3)[C:16]([O:15][C:11]([CH3:14])([CH3:12])[CH3:13])=[O:17])[O:1][N:2]=2)[CH:5]=1
Reactant: CC(C)(C)OC(=O)c1cccc(C(=O)O)c1
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: CC(C)(C)OC(=O)c1cccc(-c2nc(-c3cccnc3)no2)c1

Procedure:
N′-Hydroxynicotinimidamide (274 mg, 2.00 mmol) was coupled with 3-(tert-butoxycarbonyl)benzoic acid (Aldrich) according to the procedure described in Example 8. 1H NMR (300 MHz, CD3OD) δ 1.65 (s, 9 H), 7.65 (ddd, J=7.9, 4.8, 0.8 Hz, 1 H), 7.71-7.77 (m, 1 H), 8.26 (ddd, J=7.7, 1.8, 1.6 Hz, 1 H), 8.42-8.46 (m, 1 H), 8.57 (dt, J=7.9, 2.0 Hz, 1 H), 8.73-8.78 (m, 2 H), 9.31 (dd, J=2.2, 1.0 Hz, 1 H) ppm; MS (DCI/NH3) m/z 324 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N+:3]=1[O-:8].[N+:9]([O-])([OH:11])=[O:10]>C(O)(=O)C>[NH2:9][C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[N+:3]([O-:8])[CH:4]=1.[N+:9]([C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[N+:3]([O-:8])[CH:4]=1)([O-:11])=[O:10]
Reactant: [O-][n+]1ccccc1O
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: Nc1ccc(O)[n+]([O-])c1
Product: O=[N+]([O-])c1ccc(O)[n+]([O-])c1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
5-amino-2-hydroxypyridine-N-oxide was prepared as follows. One hundred grams of the 2-hydroxypyridine-N-oxide were dissolved in 500 mL of acetic acid with warming. The solution was cooled to approximately 10° C., and 65 mL of 70% nitric acid was added slowly to keep the temperature below 35° C. The mixture was stirred for an additional 30 min and the product was collected by filtration. After washing with acetic acid, and then water, the product was dried under vacuum at 70° C., to give 5-nitro-2-hydroxypyridine-N-oxide (95.9 g, 68% yield). 1HNMR data for this compound (DMSO) was as follows: δ 9.2 (d, 1H), 8.1 (dd, 1H), 6.6 (d, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1O.[C:12](=O)([O-])[O-].[K+].[K+].S([O:23][CH3:24])(OC)(=O)=O.O>CC(C)=O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:12])=[O:7])=[CH:4][C:3]=1[O:23][CH3:24]
Reactant: O=C([O-])[O-]
Reactant: COS(=O)(=O)OC
Reactant: O=C(O)c1ccc(Br)c(O)c1
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)c1ccc(Br)c(OC)c1
Yield: 98.2 %

Procedure:
A solution of 4-bromo-3-hydroxybenzoic acid of Step A (27 mmol), potassium carbonate (33 mmol) and dimethyl sulfate (32 mmol), in acetone (40 mL) was stirred at reflux temperature under nitrogen atmosphere for three hours. The mixture was cooled and 5 mL of water was added. The acetone was evaporated and 30 mL of water was added. The product was extracted into dichloromethane. The organic solution was dried over anhydrous magnesium sulfate, and evaporated to provide the title compound (6.5 g; 99%) as a hard, white, crystalline solid.
Reaction SMILES: P.C1(P(C2C=CC=CC=2)(C2C=CC3CCCCC=3C=2C2C3CCCCC=3C=CC=2P(C2C=CC=CC=2)(C2C=CC=CC=2)=O)=O)C=CC=CC=1.[Br:50][C:51]1[CH:60]=[CH:59][C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[C:52]=1[C:61]1[C:70]2[C:65](=[CH:66][CH:67]=[CH:68][CH:69]=2)[CH:64]=[CH:63][C:62]=1[Br:71]>[Ru]>[Br:50][C:51]1[CH:60]=[CH:59][C:58]2[CH2:57][CH2:56][CH2:55][CH2:54][C:53]=2[C:52]=1[C:61]1[C:70]2[CH2:69][CH2:68][CH2:67][CH2:66][C:65]=2[CH:64]=[CH:63][C:62]=1[Br:71]
Reactant: Brc1ccc2ccccc2c1-c1c(Br)ccc2ccccc12
Agent: [Ru]
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccc2c(c1-c1c(P(=O)(c3ccccc3)c3ccccc3)ccc3c1CCCC3)CCCC2
Agent: P
Product: Brc1ccc2c(c1-c1c(Br)ccc3c1CCCC3)CCCC2

Procedure:
Of the starting optically active phosphine compounds L1, the optically active compound of formula (III), i.e., 2,2'-bis(diphenylphosphinyl)-5,5',6,6',7,7',8,8'-octahydro-1,1 '-binaphthyl (hereinafter abbreviated as OcH-BINAP) can be synthesized, for example, as follows. 2,2'-Dibromo-1,1'-binaphthyl synthesized by the process disclosed in H. Takaya, et al., J. Org. Chem. Vol. 51, p. 629 (1986) is hydrogenated in the presence of a ruthenium-on-carbon catalyst to obtain 2,2'-dibromo-5,5',6,6',7,7',8,8'-octahydro-1,1'-binaphthyl (2,2'-dibromo-1,1'-bitetrahydronaphthalene), which is then reacted with metallic magnesium to form a Grignard reagent. The resulting Grignard reagent is condensed with diphenylphosphinyl chloride to synthesize racemic OcH-BINAP. The racemate is optically resolved by recrystallization from a mixed solvent of chloroform and ethyl acetate in the presence of optically active dibenzoyltartaric acid as a resolving agent, and the precipitated crystal collected by filtration is treated in 1N sodium hydroxide to obtain a phosphine oxide. The optical purity of the phosphine oxide is determined by high performance liquid chromatography using an optically active column, and the above recrystallization operation is repeated until the product becomes optically pure. The thus obtained optically active phosphine oxide is then reduced by using trichlorosilane to obtain optically active OcH-BINAP.
Reaction SMILES: [C:1]1([C:14]([OH:16])=[O:15])[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.N.[Li]>C(O)C>[CH:1]1([C:14]([OH:16])=[O:15])[CH:13]2[CH:5]([C:6]3[C:11]([CH2:12]2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1cccc2c1Cc1ccccc1-2
Agent: N
Agent: [Li]
Solvent: CCO
Product: O=C(O)C1CCCC2c3ccccc3CC12

Procedure:
A solution of 21.0 g (0.10 mole) of fluorene-1-carboxylic acid in 25 ml of absolute ethanol is added to 500 ml of liquid ammonia and the solution treated portionwise with 4.2 g (0.60 mole) of lithium cut in small pieces. After evaporation of the NH3, the residue is cooled in ice and treated first with water and then with sufficient conc. HCl to render it strongly acidic. The crude partially reduced product is filtered off and dissolved in acetic acid. Reduction of the solution over 1 g of PtO2 under up to 55 psi of H2 is complete after about 1 equivalent of H2 is taken up. The solution is freed of catalyst and taken to dryness. Recrystallization from hexane affords the desired product, mp 138-139°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([Br:8])[CH:7]=1.[Br:10]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.CCCCCC.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([Br:8])[CH:7]=1)[CH2:9][Br:10]
Reactant: Cc1cc(Br)cc(Br)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCCCCC
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cc(Br)cc(Br)c1
Temperature: 25 °C
Yield: 43.5 %

Procedure:
3,5-dibromotoluene (78.92 g, 0.316 mole) was dissolved in 1.27 L of carbon tetrachloride; to this solution was added N-bromosuccinimide (61.65 g, 0.346 mole) at room temperature. A portion of dibenzoyl peroxide (0.6 g, 0.008 equivalents) was added and the solution heated to reflux temperature for 2.5 hours. The reaction mixture was cooled to room temperature, filtered and the solvent removed in vacuo to yield a solid. The solid was dissolved in 200 mL of warm hexane, filtered and cooled to room temperature. Crystallizations ensued; the crystals were filtered off and washed with cold hexane and air dried to give 45.15 g (44%) of 3,5-dibromobenzyl bromide. 1H-NMR(CDCl3); δ7.6 (1H), 7.47 (2H), 4.36 (2H).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:9]([C@H:18]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:8]([CH3:29])=[CH:7][C:5]=2[N:6]=1.[Cl:30][C:31]1[CH:36]=[C:35](B(O)O)[CH:34]=[C:33]([Cl:40])[N:32]=1.O1CCOCC1.C([O-])([O-])=O.[K+].[K+]>CCO.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:25]([O:24][C@@H:18]([C:9]1[C:8]([CH3:29])=[CH:7][C:5]2[N:6]=[C:2]([C:35]3[CH:34]=[C:33]([Cl:40])[N:32]=[C:31]([Cl:30])[CH:36]=3)[S:3][C:4]=2[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])([CH3:28])([CH3:27])[CH3:26]
Reactant: OB(O)c1cc(Cl)nc(Cl)c1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3cc(Cl)nc(Cl)c3)sc2c1-c1ccc(Cl)cc1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A microwave tube was charged with Pd(PPh3)4 (4 mg), (S)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (25 mg), the 2,6-dichloropyridin-4-ylboronic acid (10 mg), dioxane (250 μL) and 2M aq K2CO3 (100 μL). The vessel was sealed and heated to 100° C. overnight. At 16 h, the reaction had only reached ˜60% conversion. The reaction was cooled to 23° C., diluted with absolute EtOH (1.5 mL) and H2O (500 μL), and was purified by reverse phase HPLC, eluting by 5-100% acetonitrile in H2O with 0.1% TFA to give the desired product. LCMS-ESI+: calc'd for C27H25Cl3N2O3S: 563.1, 565.1, 567.1 (M+H+); Found: 563.1, 565.0, 567.1 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:13][CH3:14])=[C:9]([OH:12])[CH:10]=2)[CH2:5][CH2:4][N:3]=1.C([CH:17](Br)[C:18](=O)[C:19]([O-:21])=[O:20])C.[CH3:24][CH2:25]O>>[OH:12][C:9]1[CH:10]=[C:11]2[C:6]([CH2:5][CH2:4][N:3]3[CH:17]=[C:18]([C:19]([O:21][CH2:24][CH3:25])=[O:20])[CH:1]=[C:2]32)=[CH:7][C:8]=1[O:13][CH3:14]
Reactant: COc1cc2c(cc1O)C(C)=NCC2
Reactant: CCO
Reactant: CCC(Br)C(=O)C(=O)[O-]
Product: CCOC(=O)c1cc2n(c1)CCc1cc(OC)c(O)cc1-2
Temperature: 25 °C

Procedure:
To a solution of 1-methyl-7-hydroxy-6-methoxy-3,4-dihydroisoquinoline (100 mg) in EtOH (5 ml) was added dropwise under a nitrogen atmosphere ethylbromopyruvate (0.065 ml) and the reaction mixture was heated under reflux for 2 hours. The reaction mixture was allowed to cool to ambient temperature, quenched with a saturated aqueous NaHCO3 solution and extracted with ethyl acetate. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with heptane and increasing amounts of ethyl acetate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[CH2:7][O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[Cl:18])[C:12]([OH:14])=O)([CH3:4])([CH3:3])[CH3:2].[NH2:20][CH2:21][C@@H:22]([OH:40])[CH2:23][N:24]1[CH2:29][CH2:28][CH:27]([O:30][C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([Cl:38])[C:32]=2[CH3:39])[CH2:26][CH2:25]1>>[C:1]([O:5][C:6](=[O:19])[CH2:7][O:8][C:9]1[CH:10]=[C:11]([C:12]([NH:20][CH2:21][C@@H:22]([OH:40])[CH2:23][N:24]2[CH2:29][CH2:28][CH:27]([O:30][C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([Cl:38])[C:32]=3[CH3:39])[CH2:26][CH2:25]2)=[O:14])[CH:15]=[CH:16][C:17]=1[Cl:18])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)COc1cc(C(=O)O)ccc1Cl
Reactant: Cc1c(OC2CCN(C[C@H](O)CN)CC2)ccc(Cl)c1Cl
Product: Cc1c(OC2CCN(C[C@H](O)CNC(=O)c3ccc(Cl)c(OCC(=O)OC(C)(C)C)c3)CC2)ccc(Cl)c1Cl

Procedure:
Prepared as for Example 15, Step 2 using 3-(2-tert-butoxy-2-oxoethoxy)-4-chlorobenzoic acid and (2R)-1-amino-3-[4-(3,4-dichloro-2-methylphenoxy)piperidin-1-yl]propan-2-ol to yield the subtitle compound as a colourless oil (0.14 g).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:35])[C@H:15]([CH:32]1[CH2:34][CH2:33]1)[C@H:16]([C@H:18]1[CH2:22][O:21][C:20]([CH3:24])([CH3:23])[N:19]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[OH:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:50]([C:53]([CH3:56])([CH3:55])[CH3:54])([CH3:52])[CH3:51])(=O)=O>C(Cl)Cl.ClCCCl>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:35])[C@H:15]([CH:32]1[CH2:33][CH2:34]1)[C@H:16]([C@H:18]1[CH2:22][O:21][C:20]([CH3:23])([CH3:24])[N:19]1[C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[O:17][Si:50]([C:53]([CH3:56])([CH3:55])[CH3:54])([CH3:52])[CH3:51])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1[C@@H]([C@H](O)[C@H](C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)C2CC2)COC1(C)C
Solvent: Cc1cccc(C)n1
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1[C@@H]([C@H](O[Si](C)(C)C(C)(C)C)[C@H](C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)C2CC2)COC1(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94.7 %

Procedure:
To a −40° C. solution of tert-butyl (4R)-4-{(1R,2R)-3-[(4R)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-2-cyclopropyl-1-hydroxy-3-oxopropyl}-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (1.80 g, 3.68 mmol) in anhydrous DCM (10 mL), 2,6-lutidine (0.85 mL, 7.3 mmol) was added under an atmosphere of nitrogen. After 10 min., a solution of tert-butyldimethylsilyl trifluoromethanesulfonate (1.1 mL, 4.9 mmol) in anhydrous DCM (1 mL) was added. The reaction mixture was allowed to warm gradually to ambient temperature while stirring overnight. The crude reaction mixture was diluted with 1,2-dichloroethane and cooled to 0° C. prior to quenching with saturated NaHCO3 (aq.). Upon separation of the two layers that resulted, the organic layer was washed with water and brine, dried over Na2SO4, concentrated under reduced pressure and purified by flash chromatography (120 g silica gel, eluting with 0-30% EtOAc/hexanes) to afford the sub-title compound (2.1 g, 95%). LC/MS (ESI) m/z calc. for C32H50N2O7SiNa: 625.3 [M+Na]+. found 625.1.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[O:6][CH:7]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[C:8]#[N:9].[N-:22]=[N+:23]=[N-:24].[Na+].[Cl-].[NH4+]>CN(C)P(N(C)C)(N(C)C)=O>[F:21][C:2]([F:20])([F:1])[C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[O:6][CH:7]([C:8]1[NH:24][N:23]=[N:22][N:9]=1)[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1
Reactant: N#CC(Oc1cccc(C(F)(F)F)c1)c1ccc(Cl)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: FC(F)(F)c1cccc(OC(c2ccc(Cl)cc2)c2nnn[nH]2)c1
Temperature: 0 °C
Reaction time: 19 h

Procedure:
A mixture of (3-trifluoromethylphenoxy) (4-chlorophenyl)acetonitrile (10.68 g.), sodium azide (2.40 g.), ammonium chloride (1.98 g.) and hexamethylphosphoramide (85 ml.) is stirred at 60°-63°C. overnight (19 hours). The reaction mixture is cooled, poured into one liter of ice water containing 25 ml. of concentrated hydrochloric acid and this solution is extracted with 5 × 100 ml. of ether. The ether extracts are combined, extracted with water and dried over sodium sulfate. The ether solution is filtered, the ether is evaporated in vacuo and the residue is crystallized by trituration with methylcyclohexane. Recrystallization from a butyl chloride and methylcyclohexane mixture (about 1 to 1) affords 5-[α-(3-trifluoromethylphenoxy)-4-chlorobenzyl]tetrazole, m.p. 124.5°-126.5°C.
Reaction SMILES: [CH3:1][N:2]([OH:24])[C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=2[Cl:20])[CH:6]=[CH:5][C:4]=1[N+:21]([O-:23])=[O:22].N1C=CC=CC=1.C1C=CC=CC=1.[Cl:37][C:38]([Cl:43])([CH3:42])[C:39](Cl)=[O:40]>C(Cl)Cl>[CH3:1][N:2]([O:24][C:39](=[O:40])[C:38]([Cl:43])([Cl:37])[CH3:42])[C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:17])([F:19])[F:18])=[CH:12][C:11]=2[Cl:20])[CH:6]=[CH:5][C:4]=1[N+:21]([O-:23])=[O:22]
Reactant: CC(Cl)(Cl)C(=O)Cl
Reactant: CN(O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: c1ccccc1
Product: CN(OC(=O)C(C)(Cl)Cl)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of N-methyl-N-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenyl]hydroxyamine (500 mg, 1.38 mmol) in methylene chloride (2 ml) is added pyridine (0.16 ml, 2.00 mmol) and benzene (3 ml), followed by α,α-dichloropropionyl chloride (328 mg, 1.5 eq.). The mixture is stirred at RT for 2 hours. The resulting reaction mixture is then taken up in methylene chloride, washed, dried and evaporated to dryness. The crude product is purified by prep. TLC to yield N-methyl-N-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenyl]-α,α-dichloropropionyloxyamine. nmr (CDCl3) τ7.77(S,3H,COC Cl2CH3), 6.67(S, 3H, NCH3).
Reaction SMILES: C([Li])CCC.[CH2:6]([O:11][CH:12]1[NH:16][C:15](=[O:17])[CH2:14][CH2:13]1)[CH2:7][CH2:8][CH2:9][CH3:10].[C:18](Cl)(=[O:27])[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1>CCCCCC.O1CCCC1.C1(C)C=CC=CC=1>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]([N:16]2[CH:12]([O:11][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:13][CH2:14][C:15]2=[O:17])=[O:27])=[CH:20][CH:21]=1
Reactant: CCCCCOC1CCC(=O)N1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCCCCOC1CCC(=O)N1C(=O)c1ccc(OC)cc1
Reaction time: 0.25 h
Yield: 71.6 %

Procedure:
15.57 cm3 of a 1.5M solution of n-butyllithium in n-hexane is added at -70° C. to a solution of 4 g of 5-(1-pentyloxy) pyrrolidin-2-one in 80 cm3 of tetrahydrofuran. Agitation is carried out for 15 minutes at -70° C. then while maintaining this temperature, a solution of 3.98 g of para-anisoyl chloride at 58% in toluene is added. After allowing to return to ambient tempera-ture and evaporating under reduced pressure, the residue is chromatographed on silica (eluent: n-hexane-ethyl acetate 2-1). 5.1 g of sought product is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][C:11]([C:13]2[C:18]([CH3:19])=[CH:17][N:16]=[C:15]([NH2:20])[CH:14]=2)=[N:10][C:9]=1[C:21]1[N:25](COCC[Si](C)(C)C)[CH:24]=[N:23][N:22]=1.[CH:34]1([C:37](Cl)=[O:38])[CH2:36][CH2:35]1.CO>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][C:11]([C:13]2[C:18]([CH3:19])=[CH:17][N:16]=[C:15]([NH:20][C:37]([CH:34]3[CH2:36][CH2:35]3)=[O:38])[CH:14]=2)=[N:10][C:9]=1[C:21]1[NH:25][CH:24]=[N:23][N:22]=1
Reactant: Cc1cnc(N)cc1-c1nc(-c2nncn2COCC[Si](C)(C)C)c(-c2ccccc2Cl)o1
Reactant: O=C(Cl)C1CC1
Solvent: ClCCl
Solvent: CO
Product: Cc1cnc(NC(=O)C2CC2)cc1-c1nc(-c2nnc[nH]2)c(-c2ccccc2Cl)o1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 23.8 %

Procedure:
A mixture of 4-[5-(2-chlorophenyl)-4-(4-{[2-(trimethylsilyl)-ethoxy]methyl}-4H-1,2,4-triazol-3-yl)-1,3-oxazol-2-yl]-5-methylpyridin-2-amine (0.12 g, 0.25 mmol) and TEA (0.087 mL, 0.62 mmol) in DCM (2 mL) was allowed to stir at 0° C. for 20 min. To this mixture was added cyclopropanecarbonyl chloride (0.056 mL, 0.62 mmol). The reaction mixture was allowed to stir at 0° C. for 2 h and then MeOH (20 mL) was added. The mixture was allowed to stir at rt for 20 min and was then concentrated. MeOH (25 mL) and aqueous saturated NaHCO3 (4 mL) were added to the residue and the mixture was allowed to stir at rt overnight before NaOH (1M, 3 mL) was added. The reaction mixture was allowed to stir rt for 3 h and then concentrated. EtOAc (30 mL) was added to the residue and the mixture was allowed to stir at rt for 30 min. The mixture was filtered and the filtrate was concentrated. DCM (5 mL) and TFA (2 mL) were added to the residue and the mixture was allowed to stir at rt overnight. The reaction mixture was concentrated and purified by column chromatography to give N-{4-[5-(2-chlorophenyl)-4-(4H-1,2,4-triazol-3-yl)-1,3-oxazol-2-yl]-5-methylpyridin-2-yl}cyclopropanecarboxamide (Compound I-77) (0.025 g, 24%). LCMS (AA): m/z=421 (M+H).