Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:9]([N:11]1[C:19]2[CH:18]=[C:17]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)[CH:16]=[C:15]([C:26]([O:28]C)=[O:27])[C:14]=2[CH2:13][CH2:12]1)=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].C1COCC1>O>[C:1]([O:5][C:6]([C@@H:8]([CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:9]([N:11]1[C:19]2[CH:18]=[C:17]([C:20]3[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=3)[CH:16]=[C:15]([C:26]([OH:28])=[O:27])[C:14]=2[CH2:13][CH2:12]1)=[O:10])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc(-c2ccncc2)cc2c1CCN2C(=O)[C@H](Cc1ccccc1)C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@@H](Cc1ccccc1)C(=O)N1CCc2c(C(=O)O)cc(-c3ccncc3)cc21
Temperature: 50 °C
Reaction time: 3 h
Yield: 47.4 %

Procedure:
To a 20 ml vial were added (S)-methyl 1-(2-(tert-butoxycarbonyl)-3-phenylpropanoyl)-6-(pyridin-4-yl)indoline-4-carboxylate 54.8.A (900 mg, 1.8 mmole), LiOH)(376 mg, 9.0 mmole), 40 ml of THF, and 10 ml of water. The reaction was stirred at 50° C. for 3 hour at which time the solvent was removed by a stream of nitrogen. The crude product was purified using a silica gel column (eluting with 10% MeOH in DCM) to give (S)-1-(2-(tert-butoxycarbonyl)-3-phenylpropanoyl)-6-(pyridin-4-yl)indoline-4-carboxylic acid 60.A as a yellow solid (403 mg, 46% yield).
Reaction SMILES: [CH2:1]1[O:3][CH:2]1[CH2:4][OH:5].[C:6]([O:10]C)(=[O:9])[CH:7]=[CH2:8]>CC(OC)(C)C>[CH2:1]1[O:3][CH:2]1[CH2:4][OH:5].[C:6]([O-:10])(=[O:9])[CH:7]=[CH2:8]
Reactant: C=CC(=O)OC
Agent: OCC1CO1
Solvent: COC(C)(C)C
Product: C=CC(=O)[O-]

Procedure:
In a screw-top glass container, in each case 5 mMol of glycidol (370 mg) were agitated with 10 or 50 mMol of methyl acrylate, 50 mg of Novozym® 435 (supported lipase from Candida antarctica B, from Novozymes, Denmark), 5.0 ml of MTBE (tert-butyl methyl ether) and, in some cases, 1.0 g of 5 Å molecular sieve at 20 or 40° C. for 24 h. Thereafter, the enzyme was filtered off and the excess of methyl acrylate was removed on a rotary evaporator. A colorless acrylate was obtained.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9]([S:19]([O-:22])(=O)=[O:20])=[C:10]2[O:15][C:16](=[O:18])[CH3:17])(=[O:3])[CH3:2].[Na+].P(Cl)(Cl)([Cl:26])=O.CNC=O>>[C:1]([NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9]([S:19]([Cl:26])(=[O:22])=[O:20])=[C:10]2[O:15][C:16](=[O:18])[CH3:17])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc2c(OC(C)=O)c(S(=O)(=O)[O-])ccc12
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Solvent: CNC=O
Product: CC(=O)Nc1cccc2c(OC(C)=O)c(S(=O)(=O)Cl)ccc12
Reaction time: 1 h

Procedure:
The 5-acetamido-1-acetoxynaphthalene-2-sulfonyl chloride was prepared by dropwise treatment of a suspension of dry sodium 5-acetamido-1-acetoxynaphthalene-2-sulfonate in 100 ml. phosphoryl chloride with 5.5 ml. dry methylformamide in a nitrogen atmosphere. The reaction mixture was stirred 1 hour and then poured over 600 ml. of crushed ice. The crude product was filtered and dissolved immediately in 500 ml. chloroform. The solution was treated with activated charcoal and dried over anhydrous magnesium sulfate to give 10.8 g. (44%) of a resinous yellow product which showed a single spot on a thin-layer chromotography.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[F:20])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:16])[CH:14]=2)[N:9]=[CH:8][N:7]=1.[O:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29]Cl)[CH2:23][CH2:22]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[F:20])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH2:29][CH2:28][CH2:27][N:24]3[CH2:25][CH2:26][O:21][CH2:22][CH2:23]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1
Reactant: Oc1ccc2ncnc(Nc3ccc(F)c(Cl)c3)c2c1
Reactant: ClCCCN1CCOCC1
Product: Fc1ccc(Nc2ncnc3ccc(OCCCN4CCOCC4)cc23)cc1Cl
Temperature: 100 °C
Yield: 58 %

Procedure:
Using an analogous procedure to that described in Example 1 except that the reaction mixture was heated to 100° C. for 2 hours. 4-(3'-chloro-4'- fluoroanilino)-6-hydroxyquinazoline was reacted with 3-morpholinopropyl chloride to give 4-(3'-chloro-4'-fluoranilino)-6-(3-morpholinopropoxy)quinazoline in 58% yield; NMR Spectrum: 1.97 (m, 2H), 2.4 (broad t, 4H), 2.48 (t, 2H), 3.58 (t, 4H), 4.2 (t, 2H), 7.44 (t, 1H), 7.53 (m, 1H) 7.74 (d, 1H), 7.85 (m, 1H), 7.9 (d, 1H), 8.17 (m, 1H), 8.53 (s, 1H), 9.67 (broad s, 1H); Elemental Analysis: Found C, 60.0; H, 5.4; N, 13.2; C21H22ClFN4O2 0.2H2O requires C, 60.0; H, 5.3; N, 13.3%.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[N:9]([CH2:15][C:16]([F:19])([F:18])[F:17])[C:8]2=[O:20])(=[O:4])=[O:3].CO>O>[OH:20][CH:8]1[C:7]2[C:11](=[CH:12][CH:13]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=2)[C:10](=[O:14])[N:9]1[CH2:15][C:16]([F:19])([F:17])[F:18]
Reactant: CS(=O)(=O)c1ccc2c(c1)C(=O)N(CC(F)(F)F)C2=O
Solvent: CO
Solvent: O
Product: CS(=O)(=O)c1ccc2c(c1)C(O)N(CC(F)(F)F)C2=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 40.9 %

Procedure:
3.4 g of 5-methanesulfonyl-2-(2,2,2-trifluoro-ethyl)-isoindole-1,3-dione were dissolved using 240 ml of MeOH. 0.63 g of KBH4 were then added in small portions at ambient temperature. The reaction mixture was stirred for 20 h at ambient temperature and subsequently poured into 1 l of water at 0° C. The aqueous layer was then extracted three times using 300 ml of CH2Cl2 each time. Then, the aqueous layer was extracted four times using 300 ml of EA each time. Each organic layer was dried separately over Na2SO4. The solvents were removed in vacuo. The EA layer yielded 1.4 g pure product as a pale yellow oil. The CH2Cl2 layer was chromatographed on silica gel using EA/HEP 1:2 yielding another 1.5 g of product (Rf(EA/HEP 1:2)=0.035; MS (DCI): 310 (M+1)+)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[F:20][C:21]([F:33])([F:32])[C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][S:28]([C:25]2[CH:24]=[CH:23][C:22]([C:21]([F:20])([F:32])[F:33])=[CH:27][CH:26]=2)(=[O:30])=[O:29])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: Nc1cnc(Oc2cc3ccccc3cn2)c(Cl)c1
Product: O=S(=O)(Nc1cnc(Oc2cc3ccccc3cn2)c(Cl)c1)c1ccc(C(F)(F)F)cc1

Procedure:
The title compound was prepared by reacting 5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 2) and 4-(trifluoromethyl)benzene-1-sulfonyl chloride.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][C:13]([F:16])([F:15])[F:14])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:17])[CH:3]=1.[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH2:22][NH2:23]>>[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH2:22][NH:23][C:2]1[C:11]2[C:6](=[C:7]([O:12][C:13]([F:16])([F:15])[F:14])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:17])[CH:3]=1
Reactant: Cc1cc(Cl)c2cccc(OC(F)(F)F)c2n1
Reactant: NCc1ccc(Cl)c(Cl)c1
Product: Cc1cc(NCc2ccc(Cl)c(Cl)c2)c2cccc(OC(F)(F)F)c2n1

Procedure:
Preparation was made using a similar procedure as described in example 1, method 1.3. Starting materials were 4-chloro-2-methyl-8-trifluoromethoxyquinoline and 3,4-dichlorobenzylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([C:8]2[CH:20]=[CH:19][C:11]([O:12][C:13]([CH3:18])([CH3:17])[C:14](Cl)=[O:15])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[NH:23]([CH2:27][CH2:28][OH:29])[CH2:24][CH2:25][OH:26]>CC(C)=O>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([C:8]2[CH:20]=[CH:19][C:11]([O:12][C:13]([CH3:18])([CH3:17])[C:14]([N:23]([CH2:27][CH2:28][OH:29])[CH2:24][CH2:25][OH:26])=[O:15])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: CC(C)(Oc1ccc(C(=O)c2ccc(Cl)cc2)cc1)C(=O)Cl
Reactant: OCCNCCO
Solvent: CC(C)=O
Product: CC(C)(Oc1ccc(C(=O)c2ccc(Cl)cc2)cc1)C(=O)N(CCO)CCO

Procedure:
A solution of 3.36 g (10 millimoles) of 2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropionoyl chloride in 15 ml of acetone were added, slowly under stirring at room temperature, to a solution of 2.1 g (20 millimoles) of diethanolamine in 30 ml of acetone.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][CH2:6][SH:7].Cl[C:9]1[CH:14]=[CH:13][N+:12]([O-:15])=[C:11]([CH3:16])[C:10]=1[CH3:17]>CN1CCCC1=O>[CH3:16][C:11]1[C:10]([CH3:17])=[C:9]([S:7][CH2:6][CH2:5][CH2:4][OH:3])[CH:14]=[CH:13][N+:12]=1[O-:15]
Reactant: Cc1c(Cl)cc[n+]([O-])c1C
Reactant: OCCCS
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Cc1c(SCCCO)cc[n+]([O-])c1C
Reaction time: 0.25 h

Procedure:
6 g of (60% strength) NaH are added in portions to 50 ml of dry N-methylpyrrolidone (NMP), the mixture is stirred 15 min, 9.5 g (0.11 mol) of 3-hydroxypropyl mercaptan are metered in in the course of 20 min and the mixture is stirred again for 30 min until evolution of gas has ended. A solution of 14.4 g (0.1 mol) of 4-chloro-2,3-dimethylpyridine-N-oxide in 100 ml of NMP is then added dropwise in the course of 20 min, and the reaction mixture is stirred for 1 h at RT, then for 1 h at 70° C. and after this for a further 1 h at 100° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([CH3:11])[C:8](Br)=[CH:7][N:6]=1)=[O:4].[O:13]([C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1)[CH3:14].C(=O)([O-])[O-].[K+].[K+]>C1COCC1.[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[CH3:14][O:13][C:15]1[CH:20]=[CH:19][C:18]([C:8]2[C:9]([CH3:11])=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[N:6][CH:7]=2)=[CH:17][CH:16]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: COC(=O)c1cc(C)c(Br)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: C1CCOC1
Product: COC(=O)c1cc(C)c(-c2ccc(OC)cc2)cn1
Temperature: 60 °C
Yield: 100 %

Procedure:
To a solution of 5-bromo-4-methylpyridine-2-carboxylic acid methyl ester (2.207 g, 9.59 mmol), 4-methoxylphenylboronic acid (1.604 g, 10.55 mmol) and 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (0.313 g, 0.480 mmol) in THF (30 mL) was added potassium carbonate (2.0 M in water, 10.1 mL, 20.15 mmol). The mixture was purged with nitrogen and heated at 50° C. for 1 hour and at 60° C. for 5 hours. The reaction was poured into ethyl acetate and was washed with brine, dried over sodium sulfate, filtered and concentrated. It was purified by column chromatography to yield methyl 5-(4-methoxyphenyl)-4-methylpyridine-2-carboxylate (2.47 g, 9.59 mmol) as a pink solid. MS ESI calc'd. for C15H16NO3 [M+H]+ 258.1. found 258.1.
Reaction SMILES: [NH2:1][C:2]1[C:18]([F:19])=[C:17]([F:20])[C:16]([F:21])=[C:15]([F:22])[C:3]=1[C:4]([NH:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5].[C:23](Cl)(Cl)=[O:24]>O1CCOCC1.C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:8]([O:7][N:6]1[C:4](=[O:5])[C:3]2[C:2](=[C:18]([F:19])[C:17]([F:20])=[C:16]([F:21])[C:15]=2[F:22])[NH:1][C:23]1=[O:24])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Nc1c(F)c(F)c(F)c(F)c1C(=O)NOCc1ccccc1
Reactant: O=C(Cl)Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: O=c1[nH]c2c(F)c(F)c(F)c(F)c2c(=O)n1OCc1ccccc1
Temperature: 80 °C
Yield: 51 %

Procedure:
A solution of 2-amino-N-benzyloxy-3,4,5,6-tetrafluoro-benzamide (Example V-3, 1.72 g, 5.47 mmol) in 1,4-dioxane (50 mL) was reacted with a 20% solution of phosgene (4.25 mL, 8.00 mmol) in toluene and heated to 80° C. in a sealed tube for 18 hours. The mixture was then cooled, diluted with ethyl acetate, and washed with saturated aqueous NaHCO3. The organic layer was dried with magnesium sulfate and concentrated. The residue was triturated with diethyl ether and filtered to provide 0.95 g of the title compound as a solid.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[CH:2]([CH2:4][C:5]([OH:7])=[O:6])[OH:3].[CH2:10](O)[CH2:11][CH2:12][CH2:13][CH3:14]>>[CH2:10]([O:8][C:1](=[O:9])[CH:2]([CH2:4][C:5]([O:7][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:6])[OH:3])[CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCO
Reactant: O=C(O)CC(O)C(=O)O
Product: CCCCCOC(=O)CC(O)C(=O)OCCCCC
Temperature: 115 °C
Yield: 55.6 %

Procedure:
To the reaction flask, DL-malic acid (100.43 g), 1-pentanol (325 mL) and Amberlyst® 15 ion exchange resin (14.2 g) were added. The mixture was placed under nitrogen and heated to reflux. At 108° C., two phases started to collect in the Dean-Stark trap. The reaction was maintained at 110-120° C. for 4 hr 15 min and water was continuously removed. The product was separated from the catalyst via filtration over silica using 300 mL diethyl ether. The organic layer was washed 4 times with saturated sodium bicarbonate, washed once with water, and dried over magnesium sulfate. Diethyl ether was removed via rotary evaporation. Dipentyl-DL-malate was obtained as a low viscosity, slightly hazy, very light yellow liquid with a slight pleasant odor (116.5 g, 55.6% yield) after pumping on the sample in vacuo to remove residual 1-pentanol.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([NH2:12])[CH2:8][CH2:7]1)=[O:5].[O-]S([O-])(=O)=O.[Mg+2].[CH:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[BH4-].[Na+]>CO.O>[CH3:2][O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([NH:12][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:8][CH2:7]1)=[O:5]
Reactant: O=Cc1ccccc1
Reactant: COC(=O)[C@H]1CC[C@H](N)CC1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Solvent: CO
Solvent: O
Product: COC(=O)C1CCC(NCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
To a solution of trans-4-amino-cyclohexylcarboxylic acid methyl ester hydrochloride (4.5 g, 23.24 mmol) in MeOH (30 mL) is added TEA (1.3 mL, 9.339 mmol), MgSO4 (4.2 g, 34.88 mmol), and benzaldehyde (2.5 mL, 24.74 mmol). The mixture stirs 1 h. The mixture is then cooled to 0° C. and NaBH4 (5.0 g, 132.2 mmol) is added portionwise over 0.5 h. The mixture stirs 1 h at ambient temperature. Then H2O (200 mL) is added and the mixture is extracted with EtOAc (2×500 mL), dried and concentrated. The resulting solid is purified by flash chromatography (gradient elution: 0-100% EtOAc/Hep) which affords 2.7 g of 4-benzylamino-cyclohexanecarboxylic acid methyl ester. LC/MS: [M+H]+ 248, Rt=0.82 min (method 11).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([NH2:18])=[O:17])=[N:14][CH:15]=1.ClC1C=CC=C(C(OO)=[O:36])C=1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)=[O:36])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([NH2:18])=[O:17])=[N:14][CH:15]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cc(C(N)=O)ncc1C(Sc1ccc(F)cc1)c1cc(F)ccc1F
Solvent: ClCCl
Product: Cc1cc(C(N)=O)ncc1C(c1cc(F)ccc1F)S(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59 %

Procedure:
To a solution of 5-[(2,5-difluorophenyl) [(4-fluorophenyl)thio]methyl]-4-meth ylpyridine-2-carboxamide (152 mg, 0.39 mmol) in methylene chloride (5 ml), 3-chloroperbenzoic acid (104 mg, 0.39 mmol) was added at 0° C. After stirring for 2 hours at room temperature, the reaction mixture was washed with 1 N aqueous sodium hydroxide. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to flash silica gel chromatography. The fraction obtained from an elution with hexane:ethyl acetate=7:3 was concentrated under reduced pressure, and the resulting residue was washed with a mixed solvent of ethanol and hexane, and was collected by filtration to obtain the title compound (91 mg, 0.23 mmol, 58%) as a white solid.
Reaction SMILES: [C:1]([O:4][C@:5]1([C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15](=[CH:16][C:17](=[O:27])[O:18][CH2:19]2)[C@H:14]([Cl:28])[C@H:13]3OS(C)(=O)=O)[CH2:10][CH2:9]1)[C:6](=[O:8])[CH3:7])(=[O:3])[CH3:2].C([O-])(=O)C.[K+].CS(C)=O>O>[C:1]([O:4][C@:5]1([C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15](=[CH:16][C:17](=[O:27])[O:18][CH2:19]2)[C:14]([Cl:28])=[CH:13]3)[CH2:10][CH2:9]1)[C:6](=[O:8])[CH3:7])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3[C@H](OS(C)(=O)=O)[C@@H](Cl)C4=CC(=O)OC[C@]4(C)[C@H]3CC[C@@]21C
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3C=C(Cl)C4=CC(=O)OC[C@]4(C)[C@H]3CC[C@@]21C
Temperature: 25 °C
Reaction time: 12 h
Yield: 72.1 %

Procedure:
A mixture of 2.35 g of 17α-acetoxy-6β-chloro-7α-mesyloxy-2-oxa-4-pregnene-3,20-dione, 0.83 g of potassium acetate and 0.88 ml of dimethyl sulfoxide was stirred at room temperature for 12 hours. Ice-cooled water was poured into the reaction mixture, and the precipitated crystals were collected by filtration to give 1.37 g of 17α-acetoxy-6-chloro-2-oxapregna-4,6-diene-3,20-dione. The 1H NMR spectrum of this compound was the same as that of the compound produced in Example 1.
Reaction SMILES: Cl.C([O:4][CH:5](OCC)[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10][CH:9]=1)C>O1CCOCC1.O>[OH:16][CH2:15][CH2:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][CH2:6][CH:5]=[O:4])=[CH:9][CH:10]=1
Reactant: CCOC(COc1ccc(CCO)cc1)OCC
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: O=CCOc1ccc(CCO)cc1
Reaction time: 1 h

Procedure:
Concentrated hydrochloric acid (5 mL) was added to a solution of 2-(4-(2,2-diethoxyethoxy)phenyl)ethanol (example 3, step a) (0.76 g) in 1,4-dioxane (10 mL) and the resulting mixture was stirred for 1 h. The reaction was diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic solutions were washed with water (50 mL) and brine (50 mL), then dried over sodium sulphate, filtered and evaporated in vacuo to give the subtitled compound, which was used directly. Yield 0.35 g.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][C:6]1[CH:7]=[C:8]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=2[CH:30]=O)[C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:11]=1)[CH3:2].[CH2:33]([NH2:35])[CH3:34]>>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][C:6]1[CH:7]=[C:8]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:22][C:21]=2[CH2:30][NH:35][CH2:33][CH3:34])[C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OCc2ccccc2)c(-c2ccc(C(F)(F)F)cc2C=O)c1
Reactant: CCN
Product: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OCC)ccc1OCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 1, Step 5, using the following starting materials: (6-benzyloxy-2′-formyl-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester and ethylamine (2M in THF).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([CH2:13][C:14]([O:16]C)=[O:15])[CH:10]=[CH:11][CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O.[OH-].[Li+]>CO.O>[N:1]1([C:7]2[CH:8]=[C:9]([CH2:13][C:14]([OH:16])=[O:15])[CH:10]=[CH:11][CH:12]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: COC(=O)Cc1cccc(N2CCOCC2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)Cc1cccc(N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
To a solution of methyl 3-(morpholin-4-yl)phenylacetate (0.50 g, 2.1 mmol) in methanol (5 mL) and H2O (1 mL) was added lithium hydroxide monohydrate (0.18 g, 2 eq.). After the reaction mixture was stirred at room temperature overnight, it was concentrated to dryness. Acetic acid was then added to the residue and the resulting mixture was partitioned between EtOAc and H2O. The organic layer was washed with NaCl (sat.), dried over Na2SO4, and evaporation under vacuo to give 3-(morpholin-4-yl)phenylacetic acid (0.42 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH:10]1OCC[O:11]1>C1COCC1.Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH:10]=[O:11]
Reactant: COc1ccc(C)c(C2OCCO2)c1
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc(C)c(C=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.1 %

Procedure:
A solution of 2-(2-methyl-5-methoxyphenyl)-1,3-dioxolane (4.2 g; 21.6 mmol; from step (ii) above) in a mixture of THF (60 mL) and HCl/aq (5%; 30 mL) was stirred overnight at room temperature. The solution was concentrated, and the mixture was extracted with ether. The organic phase was dried (Na2SO4) and concentrated yielding 2.956 g (91%) of a dark brown liquid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:65]([O:67][C:68](=[O:77])[C:69]1[CH:74]=[C:73]([NH2:75])[CH:72]=[CH:71][C:70]=1[F:76])[CH3:66]>C(Cl)Cl>[CH2:65]([O:67][C:68](=[O:77])[C:69]1[CH:74]=[C:73]([NH:75][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:25])([CH3:26])[CH3:27])[NH:10]2)=[O:30])[CH:72]=[CH:71][C:70]=1[F:76])[CH3:66]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: CCOC(=O)c1cc(N)ccc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)ccc1F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 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 (100 mg, 0.17 mmol) in methylene chloride (10 mL), HATU (Aldrich, 98 mg, 0.26 mmol) was added followed by the addition of DIPEA (0.150 mL, 0.855 mmol) and 5-amino-2-fluoro-benzoic acid ethyl ester (Oakwood, 63 mg, 0.34 mmol). The mixture was stirred at rt for 1.5 hr. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (50 g column, eluent EtOAc/Hexanes, 5-20%) to give a white solid. 64 mg.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:37]=[N:38][C:39]([CH3:42])=[CH:40][CH:41]=2)[CH:31]=1)=[O:29])(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:37]=[N:38][C:39]([CH3:42])=[CH:40][CH:41]=2)[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: Cc1ccc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cn1
Product: Cc1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(C)cc3NC(=O)OC(C)(C)C)c2)cn1

Procedure:
The title compound was prepared from (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J20) (218 mg, 0.75 mmol) and 3-[3-(6-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K4) (234 mg, 0.75 mmol) according to the general procedure M. Obtained as an amorphous off-white substance (331 mg, 84%).