Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[C:10]([O:12][C@@H:13]2[CH2:17][CH2:16][O:15][CH2:14]2)[CH:9]=[C:8]([CH3:18])[C:7]=1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][O:26][C:27]2[CH:40]=[CH:39][C:30]3[C@H:31]([CH2:34][C:35]([O:37]C)=[O:36])[CH2:32][O:33][C:29]=3[CH:28]=2)[CH:20]=1)(=O)C.[OH-].[Li+].O.[OH-].[Na+]>CO.O1CCCC1>[OH:4][CH2:5][C:6]1[CH:11]=[C:10]([O:12][C@@H:13]2[CH2:17][CH2:16][O:15][CH2:14]2)[CH:9]=[C:8]([CH3:18])[C:7]=1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][O:26][C:27]2[CH:40]=[CH:39][C:30]3[C@H:31]([CH2:34][C:35]([OH:37])=[O:36])[CH2:32][O:33][C:29]=3[CH:28]=2)[CH:20]=1
Reactant: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(O[C@@H]5CCOC5)cc4COC(C)=O)c3)ccc21
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1cc(O[C@@H]2CCOC2)cc(CO)c1-c1cccc(COc2ccc3c(c2)OC[C@H]3CC(=O)O)c1
Reaction time: 3 h
Yield: 8.5 %

Procedure:
The crude methyl 2-((S)-6-((2′-(acetoxymethyl)-6′-methyl-4′-(((R)-tetrahydrofuran-3-yl)oxy)biphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 35e (189 mg, 0.36 mmol) was dissolved in 10 mL of a mixture of the solvents of methanol and tetrahydrofuran (V/V=1:4), followed by addition of 1M aqueous lithium hydroxide solution (4 mL, 4 mmol). The reaction solution was stirred for 3 hours. The resulting solution was added with 50 mL of water and 5 mL of 2M aqueous sodium hydroxide solution. The aqueous phase was washed with ethyl acetate (30 mL), then 1M hydrochloric acid was added dropwise to adjust the pH to 2-3, and extracted with ethyl acetate (20 mL×2). The combined organic extracts were washed with saturated sodium chloride solution (30 mL), dried with anhydrous magnesium sulphate, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by TLC with elution system A to obtain the title compound 2-((S)-6-((2′-(hydroxymethyl)-6′-methyl-4′-(((R)-tetrahydrofuran-3-yl)oxy)biphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid 35 (15 mg, yield 8.6%) as a white solid.
Reaction SMILES: [Cl:1][C:2]([Cl:23])([Cl:22])[C:3]1[N:8]=[C:7]([C:9]([Cl:12])([Cl:11])[Cl:10])[N:6]=[C:5]([C:13]2[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=2)[N:4]=1.[O:24]1CCCC1.O>C(N(CC)CC)C>[Cl:1][C:2]([Cl:22])([Cl:23])[C:3]1[N:8]=[C:7]([C:9]([Cl:11])([Cl:10])[Cl:12])[N:6]=[C:5]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:18])=[O:24])=[CH:15][CH:14]=2)[N:4]=1
Reactant: O=C(Cl)c1ccc(-c2nc(C(Cl)(Cl)Cl)nc(C(Cl)(Cl)Cl)n2)cc1
Reactant: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(O)c1ccc(-c2nc(C(Cl)(Cl)Cl)nc(C(Cl)(Cl)Cl)n2)cc1
Reaction time: 0.17 h

Procedure:
4-(4,6-Bis(trichloromethyl)-s-triazin-2-yl)-benzoyl chloride pw) is added to a mixture of tetrahydrofuran (10 pw) and water (5 pw). To complete the reaction, 1 pw of triethylamine is added after 6 minutes, and the mixture is stirred for another 10 minutes. The solvent is removed by distillation, and the residue is recrystallized from toluene/benzine. The product is identical with the compounds described in Examples 12 and 16.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:17])[N:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[C:5](=[O:8])[NH:6][N:7]=1.[OH:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O.N1C=CC=CC=1>CN(C=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:1][C:2]1[C:3](=[O:17])[N:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[C:5](=[O:8])[N:6]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH2:19][OH:18])[N:7]=1
Reactant: O=c1[nH]nc(Br)c(=O)n1Cc1ccc(Cl)cc1
Reactant: OCc1ccccc1B(O)O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=c1c(Br)nn(-c2ccccc2CO)c(=O)n1Cc1ccc(Cl)cc1
Reaction time: 8 h
Yield: 60.1 %

Procedure:
According to Scheme 2 Step 3: To a solution of 6-bromo-4-(4-chlorobenzyl)-1,2,4-triazine-3,5(2H,4H)-dione (0.400 g, 1.3 mmol) in DMF (8 mL) were added 2-(hydroxymethyl)phenylboronic acid (0.29 g, 1.9 mmol), copper(II) acetate (0.23 g, 1.3 mmol) and pyridine (0.20 g, 2.5 mmol) and the mixture was left stiffing overnight at 60° C. The reaction mixture was quenched with a saturated sodium bicarbonate solution. The precipitate formed was filtered, washed first with water and then with diethyl ether. 330 mg (Yield=62%) of 6-bromo-4-(4-chlorobenzyl)-2-(2-(hydroxymethyl)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione were recovered. The product was pure enough to be used without any purification.
Reaction SMILES: [N:1]([CH2:4][C:5](Cl)=[O:6])=[N+:2]=[N-:3].[OH:8][CH2:9][CH2:10][O:11][CH2:12][N:13]1[CH:21]=[N:20][C:19]2[C:18](=[O:22])[NH:17][C:16]([NH2:23])=[N:15][C:14]1=2.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>CN(C)C=O>[N:1]([CH2:4][C:5]([O:8][CH2:9][CH2:10][O:11][CH2:12][N:13]1[CH:21]=[N:20][C:19]2[C:18](=[O:22])[NH:17][C:16]([NH2:23])=[N:15][C:14]1=2)=[O:6])=[N+:2]=[N-:3]
Reactant: Nc1nc2c(ncn2COCCO)c(=O)[nH]1
Reactant: [N-]=[N+]=NCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: [N-]=[N+]=NCC(=O)OCCOCn1cnc2c(=O)[nH]c(N)nc21
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 59.6 %

Procedure:
A solution of 0.84 ml (8.4 mmol) azidoacetyl chloride in 5 ml dry dimethylformamide was added dropwise over 10 minutes in an ice-cooled, thoroughly stirred suspension of 1.25 g (5.55 mmol) 9-(2-hydroxyethoxymethyl)guanine and 0.78 ml (5.55 mmol) triethylamine in 40 ml dry dimethylformamide. After 45 minutes of thorough stirring at 0° C., 0.11 ml (1.1 mmol) azidoacetylchloride in 1 ml dimethylformamide was added, and stirring was continued for 15 minutes. The reaction was stopped by the addition of 15 ml 7% NaHCO3 solution whereupon the mixture was evaporated to dryness in vacuo. The residue was triturated with 20 ml of a mixture of methylene chloride:diethyl ether:ethanol (volume ratio 5:5:1). The solid substance obtained was filtered off, thoroughly washed with cold water and recrystallised from hot water, after treatment with active carbon. 1.02 g (62%) of 9-(2-azidoacetoxyethoxy-methyl)guanine m.p. 175°-177° C. (decomposition) was obtained. MS m/e 308 (M30), 151 (base+H); IR (KBr) 2110 (N3), 1745 (COOR) cm-1 ; UV (phosphate buffer, pH=7) λmax 253 nm (ε 8.42× 103), 270 (sh); TLC Rf 0.27 (CHCl3 --MeOH, 8:2), Rf 0.60 (EtOH--HOAc, 8:2).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[O:19][C@@H:20]3[O:46][C@H:45]([CH2:47][O:48]C(=O)C(C)(C)C)[C@@H:37]([O:38]C(=O)C(C)(C)C)[C@H:29]([O:30]C(=O)C(C)(C)C)[C@H:21]3[O:22]C(=O)C(C)(C)C)[CH:12]=[CH:11]2)=[CH:4][CH:3]=1.O.O.[OH-].[Li+]>CO>[C@@H:20]1([O:19][C:17]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:18]=2[N:10]([CH2:9][CH2:8][C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=2)[CH:11]=[CH:12]3)[O:46][C@H:45]([CH2:47][OH:48])[C@@H:37]([OH:38])[C@H:29]([OH:30])[C@H:21]1[OH:22]
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Oc2cccc3ccn(CCc4ccc(O)cc4)c23)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: OC[C@H]1O[C@@H](Oc2cccc3ccn(CCc4ccc(O)cc4)c23)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.4 %

Procedure:
To a solution of 1-[2-(4-hydroxyphenyl)ethyl]-7-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-indole (50 mg) in methanol (1 mL) were added water (0.1 mL) and lithium hydroxide monohydrate (11 mg), and the mixture was stirred at room temperature overnight. The reaction mixture was purified by column chromatography on silica gel (eluent: methylene chloride/methanol=8/1-5/1) to give the title compound (20 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([OH:16])=[O:15])[CH2:9]2)[CH:5]=[C:4](Cl)[N:3]=1.[C:18]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][C:21]=1[F:29])#[N:19].C([O-])(O)=O.[Na+]>O1CCOCC1.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>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([OH:16])=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:23]2[CH:24]=[CH:25][C:20]([C:18]#[N:19])=[C:21]([F:29])[CH:22]=2)[N:3]=1
Reactant: N#Cc1ccc(B(O)O)cc1F
Reactant: Nc1nc(Cl)cc(N2CCC[C@H](C(=O)O)C2)n1
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: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1ccc(-c2cc(N3CCC[C@H](C(=O)O)C3)nc(N)n2)cc1F
Temperature: 140 °C
Reaction time: 0.17 h
Yield: 50 %

Procedure:
A mixture of (3S)-1-(2-amino-6-chloro-4-pyrimidinyl)-3-piperidinecarboxylic acid (1.9 g, 7.40 mmol), (4-cyano-3-fluorophenyl)boronic acid (1.465 g, 8.88 mmol) and NaHCO3 (0.622 g, 7.40 mmol) in 1,4-dioxane (10 mL) and water (2.5 mL) was stirred for 10 minutes under nitrogen. Pd(Ph3P)4 (0.171 g, 0.148 mmol) was added, and the microwave tube was heated at 140° C. for 50 minutes in microwave. LCMS showed 50% desired product. The reaction was then heated at 100° C. overnight. The yellow mixture was filtered and dried. The solid was washed with Et2O (3×), and dried. The filtrate was poured into water. The formed solid was filtered and dried. The solids were combined to afford the title compound (1.8 g) as a yellow solid. LC-MS (ES) m/z=342 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:29])([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[C:21]([CH3:26])([CH3:25])[CH2:20][CH2:19][C:18]2([CH3:28])[CH3:27])[C:3]([NH:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9](O)=[O:10])=[O:4].Cl.[NH2:31][OH:32].O.CCN(CC)CC>O=S(Cl)Cl.CN(C=O)C.C1COCC1>[F:29][C:2]([F:1])([C:15]1[CH:16]=[C:17]2[C:22]([C:21]([CH3:25])([CH3:26])[CH2:20][CH2:19][C:18]2([CH3:27])[CH3:28])=[CH:23][CH:24]=1)[C:3]([NH:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([NH:31][OH:32])=[O:10])=[O:4]
Reactant: CC1(C)CCC(C)(C)c2cc(C(F)(F)C(=O)Nc3cccc(C(=O)O)c3)ccc21
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)CCC(C)(C)c2cc(C(F)(F)C(=O)Nc3cccc(C(=O)NO)c3)ccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 10 %

Procedure:
3-(2,2-Difluoro-2-(1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalen-6-yl)acetamido)benzoic acid 20 (407 mg, 1.02 mmol) was dissolved in SOCl2 (5.7 mL) and two drops of DMF were added at 0° C. This mixture was stirred at 0° C. for 1 h then evaporated under vacuum and the crude product was dissolved in CH2Cl2 (5 mL). B) Hydroxylamine hydrochloride (3.18 g, 45.7 mmol) was dissolved in THF (41.17 mL) and water (8.25 mL) and Et3N (8.25 mL) at 0° C., the mixture was stirred at 0° C. for 1 h. Solution A) was added at 0° C. via syringe in B) and the mixture was stirred at 0° C. for 10 min and abandoned at RT for 19 h. The mixture was evaporated and the residue obtained was extracted with CH2Cl2 (3×50 mL) and washed with water (50 mL). The organic layer was washed with brine (2×50 mL), dried over MgSO4, filtered and evaporated. The crude product was purified by column chromatography eluent (cyclohexane:EtOAc=98:02). 3-(2,2-Difluoro-2-(1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalen-7-yl)acetamido)-N-hydroxybenzamide EHT 9710 was obtained (40 mg, 10% yield) as an orange solid.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[CH2:7][CH2:6][N:5]([CH3:18])[CH2:4]1.[ClH:19].CN1CC[C@@H](C2C=CC([N+]([O-])=O)=CC=2)[C@H](COC2C=CC3OCOC=3C=2)C1.[F:47][C:48]([F:57])([F:56])[C:49]1[CH:50]=[C:51](O)[CH:52]=[CH:53][CH:54]=1>>[ClH:19].[CH3:18][N:5]1[CH2:6][CH2:7][C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[C@H:3]([CH2:2][O:1][C:53]2[CH:52]=[CH:51][CH:50]=[C:49]([C:48]([F:57])([F:56])[F:47])[CH:54]=2)[CH2:4]1
Reactant: CN1CC[C@H](c2ccc([N+](=O)[O-])cc2)[C@H](CO)C1
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: CN1CC[C@@H](c2ccc([N+](=O)[O-])cc2)[C@H](COc2ccc3c(c2)OCO3)C1
Agent: Cl
Product: CN1CC[C@@H](c2ccc([N+](=O)[O-])cc2)[C@H](COc2cccc(C(F)(F)F)c2)C1

Procedure:
Compound (8) was prepared from (+)cis-3-hydroxymethyl-1-methyl-4-(4-nitrophenyl)piperidine as described for compound (1) using 3-trifluoromethylphenol instead of sesamol. The crude product was purified on a silica gel column using CH2Cl2 /CH3OH 9/1 as eluent. Identified by 1H NMR. M.p. 271°-272° C.
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:12]=[CH:13][C:14]([N:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][CH2:19][CH2:18]3)=[N:15][CH:16]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[Cl:27][C:28](Cl)([O:30]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl.C(N(CC)CC)C>[C:1]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:12]=[CH:13][C:14]([N:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]([C:28]([Cl:27])=[O:30])[CH2:19][CH2:18]3)=[N:15][CH:16]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)N1CCN(c2ccc(N3CCNc4ccccc43)nc2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)N1CCN(c2ccc(N3CCN(C(=O)Cl)c4ccccc43)nc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
0.430 g of 1-[5-(4-tert-butyl-piperazin-1-yl)pyridin-2-yl]-1,2,3,4-tetrahydroquinoxaline is put in 12.23 ml of dichloromethane and 0.51 ml of triethylamine, then 0.181 g of triphosgene is added at 0° C. The reaction mixture is stirred at room temperature under nitrogen atmosphere for 15 minutes to form 4-[5-(4-tert-butyl-piperazin-1-yl)pyridin-2-yl]-3,4-dihydro-2H-quinoxaline-1-carbonyl chloride. 0.378 g of trans N-(4-amino-adamantan-1-yl)-methanesulfonamide is prepared in 10 ml of dimethyl formamide and 0.51 ml of triethylamine under nitrogen atmosphere which is heated to dissolve it. The hot mixture is added to the reaction mixture containing 4-[5-(4-tert-butyl-piperazin-1-yl)pyridin-2-yl]-3,4-dihydro-2H-quinoxaline-1-carbonyl chloride and it is stirred for two hours. Water and sodium chloride are added, and it is extracted three times with dichloromethane; the organic phases are combined and then dried over magnesium sulfate, then concentrated under reduced pressure. The 0.829 g of raw product is chromatographed on silica gel, eluting with a gradient of a dichloromethane/(dichloromethane-methanol 90:10) mixture from 0 to 100%. 0.4184 g of trans (5-methanesulfonylamino-adamantan-2-yl)amide of 4-[5-(4-tert-butyl-piperazin-1-yl)pyridin-2-yl]-3,4-dihydro-2H-quinoxaline-1-carboxylic acid is obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[C:5](=[CH:7][CH:8]=[CH:9][CH:10]=1)[NH2:6].[CH2:12](O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[CH2:1]([O:2][C:3](=[O:11])[C:4]1[C:5](=[CH:7][CH:8]=[CH:9][CH:10]=1)[NH2:6])[CH3:12]
Reactant: CCO
Reactant: COC(=O)c1ccccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCOC(=O)c1ccccc1N
Reaction time: 20 h
Yield: 89 %

Procedure:
453 parts of anthranilic acid methyl ester are refluxed with 900 parts of ethanol and 30 parts of potassium carbonate for half an hour. Methanol which is set free during the reaction is then distilled off over a column. The complete transesterification requires about 20 hours. After an intermediate fraction containing methanol and ethanol as well, the excess of ethanol is distilled off. By distillation of the residue under reduced pressure there are obtained 441 parts of anthranilic acid ethyl ester (boiling point 113°-122° C. under 3-5 mm Hg, nD25 1,564; anthranilic acid methyl ester cannot be traced by gas chromatography). The yield is 89% of the theory.
Reaction SMILES: [F:1][C:2]([O:5][CH2:6][CH2:7]OCC1C=CC(Br)=CC=1)([F:4])[F:3].C1(SC)C=CC=CC=1.[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28].C(=O)(O)[O-].[K+].[O-]S([O-])(=O)=O.[Mg+2]>C(Cl)(Cl)Cl>[F:1][C:2]([O:5][CH2:6][CH2:7][O:28][C:27](=[O:29])[C:26]([F:31])([F:30])[F:25])([F:4])[F:3]
Reactant: O=C(O)C(F)(F)F
Reactant: FC(F)(F)OCCOCc1ccc(Br)cc1
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CSc1ccccc1
Product: O=C(OCCOC(F)(F)F)C(F)(F)F
Reaction time: 24 h

Procedure:
Combine 2-(4-bromobenzyloxy)ethyl trifluoromethyl ether (2.4 g, 8.1 mmol), thioanisole (28.5 mL, 243 mmol), and trifluoroacetic acid (30 mL). After 24 hours, add potassium bicarbonate to neutralize. Add MgSO4 and chloroform (30 mL). Filter and distill through a short path distillation apparatus to give 2-(trifluoroacetoxy)ethyl trifluoromethyl ether containing chloroform which can be used without further purification.
Reaction SMILES: [O-]CC.[Na+].[Na].C([S:9][CH2:10][CH:11]1[O:15][C:14]([CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[S:13][CH2:12]1)(=O)C>C(O)C>[SH:9][CH2:10][CH:11]1[O:15][C:14]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])([CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[S:13][CH2:12]1
Reactant: CCOC(=O)CCC1(CCC(=O)OCC)OC(CSC(C)=O)CS1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)CCC1(CCC(=O)OCC)OC(CS)CS1
Yield: 106.5 %

Procedure:
A solution of sodium ethoxide in ethanol (20 mls) [prepared from 0.16 g (0.006 g-atom) of sodium metal] and the thioacetate produced in Example 63 (2.1 g, 0.0055 mol) was stirred for one hour at room temperature under nitrogen. Ethanol was removed in vacuo on the rotary evaporator and the residue dissolved in ethyl acetate. This organic phase was washed with 0.5N sodium bisulfate solution and dried over sodium sulfate. The drying agent was filtered and the filtrate concentrated on the rotary evaporator to give 1.97 g (95%) of the title compound as an oil.
Reaction SMILES: [CH3:1][C:2]([O:41][CH2:42][C@H:43]1[CH2:45][O:44]1)([CH3:40])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=3[F:24])[C:15]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[F:34])([C:25]#[N:26])[CH:14]([CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[NH:13]2)=[O:11])=[N:5]1.[CH3:46][NH:47][CH3:48]>C(O)(C)C>[CH3:46][N:47]([CH3:48])[CH2:45][C@@H:43]([OH:44])[CH2:42][O:41][C:2]([CH3:1])([CH3:40])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=3[F:24])[C:15]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[F:34])([C:25]#[N:26])[CH:14]([CH2:35][C:36]([CH3:37])([CH3:39])[CH3:38])[NH:13]2)=[O:11])=[N:5]1
Reactant: CNC
Reactant: CC(C)(C)CC1NC(C(=O)Nc2ccn(CC(C)(C)OC[C@H]3CO3)n2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Solvent: CC(C)O
Product: CN(C)C[C@@H](O)COC(C)(C)Cn1ccc(NC(=O)C2NC(CC(C)(C)C)C(C#N)(c3ccc(Cl)cc3F)C2c2cccc(Cl)c2F)n1
Yield: 20.1 %

Procedure:
A mixture of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid {1-[2-methyl-2-((R)-1-oxiranylmethoxy)-propyl]-1H-pyrazol-3-yl}-amide (0.69 g, 1.04 mmol), isopropyl alcohol (2 mL), and dimethylamine (1.04 mL, 2.08 mmol, 2 M in THF) was microwaved at 130° C. for 15 min. The mixture was extracted with dichloromethane and water. The organic layer was separated and the solvent evaporated under reduced pressure. The resulting oil was purified by column chromatography (50% ethyl acetate/heptane) to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid {1-[2-((R)-3-dimethylamino-2-hydroxy-propoxy)-2-methyl-propyl]-1H-pyrazol-3-yl)-amide (147.2 mg, 20.05%) as a white powder. HRMS (ES+) m/z Calcd for C35H44Cl2F2N6O3S+H [(M+H)+]: 705.2893. found: 705.2893.
Reaction SMILES: Cl[CH2:2][C:3]([O:7][C:8](=[O:19])[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][CH:17]=[CH2:18])[CH:11]=1)=[N:4][O:5][CH3:6].[CH3:20][S:21]([C:23]1[CH:24]=[C:25]([P:29]([C:32]2[CH:37]=[CH:36][C:35]([S:38][CH3:39])=[CH:34][CH:33]=2)(=[O:31])[O-:30])[CH:26]=[CH:27][CH:28]=1)=[O:22].[K+].[I-].[K+]>C(C(C)=O)C>[CH3:20][S:21]([C:23]1[CH:24]=[C:25]([P:29]([C:32]2[CH:33]=[CH:34][C:35]([S:38][CH3:39])=[CH:36][CH:37]=2)(=[O:30])[O:31][CH2:2][C:3]([O:7][C:8](=[O:19])[NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][CH:17]=[CH2:18])[CH:11]=2)=[N:4][O:5][CH3:6])[CH:26]=[CH:27][CH:28]=1)=[O:22]
Reactant: CSc1ccc(P(=O)([O-])c2cccc(S(C)=O)c2)cc1
Reactant: C=CCc1cccc(NC(=O)OC(CCl)=NOC)c1
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=CCc1cccc(NC(=O)OC(COP(=O)(c2ccc(SC)cc2)c2cccc(S(C)=O)c2)=NOC)c1
Temperature: 25 °C

Procedure:
1-Chloro-2-(N-3-allylphenylcarbamoyloxy)-2-methoxyiminoethane (14.1 grams; 0.05 mole), methyl ethyl ketone (100 ml), potassium 3-methylsulfinylphenyl(4-methylthiophenyl)phosphinate (18.2 grams; 0.05 mole) and a few crystals of potassium iodide are charged into a glass reaction flask equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is then heated at reflux for a period of about 6 hours. After this time the reaction mixture is cooled to room temperature and is filtered to remove inorganic salts. The salts are washed with acetone and the washings combined with the filtrate. The resulting solution is stripped of solvents in a rotary evaporator. The remaining residue is dissolved in ether and the ether solution is washed with water and dried over anhydrous magnesium sulfate. The dried solution is filtered and stripped of ether to yield the desired product O-[2-(N-3-allylphenylcarbamoyloxy)-2-methoxyiminoethyl] 3-methylsulfinylphenyl(4-methylthiophenyl)phosphinate.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:7][O:6][C:5]([CH2:14][S:15][CH2:16][C:17]([OH:19])=O)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:4][CH2:3]1.C1(N=C=NC2CCCCC2)CCCCC1.[C:36]1([C@H:42]2[CH2:46][O:45][C:44](=[O:47])[NH:43]2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:20][C:2]1([CH3:1])[CH2:3][O:4][C:5]([CH2:14][S:15][CH2:16][C:17]([N:43]2[C@@H:42]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH2:46][O:45][C:44]2=[O:47])=[O:19])([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[O:6][CH2:7]1
Reactant: O=C1N[C@@H](c2ccccc2)CO1
Reactant: CC1(C)COC(CSCC(=O)O)(c2ccccc2)OC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1(C)COC(CSCC(=O)N2C(=O)OC[C@@H]2c2ccccc2)(c2ccccc2)OC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
{[(5,5-Dimethyl-2-phenyl-1,3-dioxan-2-yl)methyl]thio}acetic acid (9.9 g, 33.0 mmol) was dissolved in dry CH2Cl2 (250 ml) and cooled to 0° C. N,N′-Dicyclohexylcarbodiimide (DCC, 7.63 g, 37.0 mmol) and 4-(dimethylamino)pyridine (DMAP, 8.57 g, 70.0 mmol) were added and the mixture was stirred at 0° C. for 20 minutes. (S)-(+)-4-Phenyl-2-oxazolidinone (5.38 g, 33.0 mmol) was added and the mixture was stirred at room temperature for 70 h. The mixture was filtered, concentrated under reduced pressure and purified by flash-chromatography (hexane:EtOAc-7:3). This afforded 10.2 g (70%) of the title compound as a white solid. 1H-NMR (CDCl3, 200 MHz): 0.6 (s, 3H), 1.3 (s, 3H), 2.8 (s, 2H), 3.4 (s, 4H), 3.8 (s, 2H), 4.1-4.15 (dd, 1H), 4.6-4.8 (t, 1H), 5.35-5.45 (dd, 1H), 7.25-7.45 (m, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.Cl[C:10]1[C:15]([C:16]#[N:17])=[CH:14][CH:13]=[CH:12][N:11]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([C:10]2[C:15]([C:16]#[N:17])=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:7]=1
Reactant: O=c1ccc(Br)c[nH]1
Reactant: N#Cc1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#Cc1cccnc1-n1cc(Br)ccc1=O
Temperature: 75 °C

Procedure:
To 5-bromo-2-pyridone (1.0 g) and 2-chloro-3-cyanopyridine (1.0 g) in dry N,N-dimethylformamide (20 ml) was added caesium carbonate (2.73 g), and the mixture heated at 75° C. under a nitrogen atmosphere for 24 h. The solvent was removed in vacuo from the mixture and the residue partitioned between ethyl acetate and water. The organic layer was evaporated and the residue purified by chromatography (silica gel, 0 to 4% MeOH/CH2Cl2) to give the title compound, crystallised from diethyl ether/isohexane: 1H NMR (400 MHz, CDCl3) δ 8.81 (1H, dd, J 2.0, 5.1), 8.17 (1H, dd, J 1.8, 7.6), 7.67 (1H, d, J 2.7), 7.56 (1H, dd, J 4.9, 7.6), 7.49 (1H, dd, J 2.5, 10.0), 6.62 (1H, d, J 9.8); MS (ES+) m/z 276 and 278 [M+H]+.