Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[S:4]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)(=[O:6])=[O:5])[CH3:2].C([O-])(O)=O.[Na+].[Na+].[I-].Cl[CH2:29][CH2:30][NH:31][C:32]([NH:34][C:35]1[CH:40]=[C:39]([CH3:41])[N:38]=[C:37]([CH3:42])[CH:36]=1)=[O:33]>C1COCC1>[CH3:41][C:39]1[CH:40]=[C:35]([NH:34][C:32](=[O:33])[NH:31][CH2:30][CH2:29][N:18]2[CH2:19][CH2:20][CH:15]([N:3]([CH2:1][CH3:2])[S:4]([C:7]3[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=3)(=[O:5])=[O:6])[CH2:16][CH2:17]2)[CH:36]=[C:37]([CH3:42])[N:38]=1
Reactant: Cc1cc(NC(=O)NCCCl)cc(C)n1
Reactant: CCN(C1CCNCC1)S(=O)(=O)c1ccc(OC)cc1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(C1CCN(CCNC(=O)Nc2cc(C)nc(C)c2)CC1)S(=O)(=O)c1ccc(OC)cc1
Temperature: 50 °C
Reaction time: 648 h

Procedure:
A suspension of N-ethyl-4-methoxy-N-piperidin-4-yl-benzenesulfonamide (Example A4., 2.09 g, 7.0 mmol), NaHCO3 (3.4 g, 40 mmol), NaI (0.75 g, 5 mmol) and 1-(2-chloro-ethyl)-3-(2,6-dimethyl-pyridin-4-yl)-urea (Example D1, 1.14 g 5 mmol) in THF (30 mL) is stirred at 50° C. for 27 days. The mixture is quenched with Na2CO3 (150 mL) and extracted with CH2Cl2 (3×100 mL). The organic extracts are washed with sat. aq. Na2CO3 (70 mL), dried (Na2SO4), filtered and evaporated. The residue is purified by MPLC to provide the title compound.
Reaction SMILES: C(SC1N=C(C)C=CC=1C(O)=O)C=C.[CH2:15]([O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C@H:26]([NH:35][C:36](=[O:48])[C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[N:39][C:38]=2[S:44][CH2:45][CH:46]=[CH2:47])[C:27]([NH:29][C:30]2([C:33]#[N:34])[CH2:32][CH2:31]2)=[O:28])=[CH:21][C:20]=1[Cl:49])C=C>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1>[C:33]([C:30]1([NH:29][C:27]([C@H:26]2[NH:35][C:36](=[O:48])[C:37]3[C:38](=[N:39][C:40]([CH3:43])=[CH:41][CH:42]=3)[S:44][CH2:45][CH:46]=[CH:47][CH2:15][O:18][C:19]3=[CH:24][CH:23]=[C:22]([CH:21]=[C:20]3[Cl:49])[CH2:25]2)=[O:28])[CH2:31][CH2:32]1)#[N:34]
Reactant: C=CCOc1ccc(C[C@H](NC(=O)c2ccc(C)nc2SCC=C)C(=O)NC2(C#N)CC2)cc1Cl
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Agent: [Ti+4]
Agent: C=CCSc1nc(C)ccc1C(=O)O
Product: Cc1ccc2c(n1)SCC=CCOc1ccc(cc1Cl)C[C@@H](C(=O)NC1(C#N)CC1)NC2=O
Temperature: 50 °C
Reaction time: 72 h

Procedure:
The title compound was prepared in analogy to example 8 starting from 2-(allylthio)-6-methylnicotinic acid with the exception of the macroccyclisation: in a 10 mL round-bottomed flask, (S)—N-(3-(4-(allyloxy)-3-chlorophenyl)-1-(1-cyanocyclopropylamino)-1-oxopropan-2-yl)-2-(allylthio)-6-methylnicotinamide (50 mg, 97.8 μmol, Eq: 1.00) was combined with dry degassed DCM (50 mL) under argon atmosphere and titanium (IV) isopropoxide (16.7 mg, 17.2 μL, 58.7 μmol, Eq: 0.60) was added. This solution was added dropwise (20 min) to a solution of Grubbs II (24.9 mg, 29.4 μmol, Eq: 0.30) dissolved in dry degassed DCM (35 ml) under argon atmosphere at 50° C. (reflux). After the addition, the reaction mixture was heated to 50° C. and stirred for 3 days under argon atmosphere. The crude material was purified by flash chromatography (silica gel, 20 g, n-heptane/AcOEt 2/1, 1/1) to yield a brown solid (4 mg; 6%). m/z=483.0 [M+H]+.
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C:12]4[CH2:13][CH2:14][C:15](=[O:20])[CH2:16][C:17]=4[CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C:4]2=[O:21])[CH3:2].CO.Cl.C(=O)(O)[O-].[Na+]>O>[CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C@@H:12]4[C:17]([CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C:4]2=[O:21])=[CH:16][C:15](=[O:20])[CH2:14][CH2:13]4)[CH3:2]
Reactant: CC[C@]12CC[C@@H]3C4=C(CC[C@H]3[C@@H]1CCC2=O)CC(=O)CC4
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Reaction time: 2 h

Procedure:
Add 13β-ethyl-gon-5(10)-en-3,17 -dione (1 g.) with stirring under nitrogen to methanol (25 cc.) containing 11N hydrochloric acid (1.75 cc.) and water (1.1 cc.). Stir for 2 hours, add sodium bicarbonate (1.75 g.) and filter the mixture. Evaporate the filtrate to dryness and recrystallize the residue from ethyl acetate to obtain the title compound; ultraviolet absorption peak at 240 mμ (ε 17,800); infrared absorption peaks at 5.78, 6.00, 6.17 μ.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[CH:4]=[N:3]1.CC[N:12]([CH2:15][CH3:16])[CH2:13]C.N1CCC1>CN(C=O)C>[N:12]1([C:7]([C:5]2[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=2)=[O:9])[CH2:13][CH2:16][CH2:15]1
Reactant: Cn1cc(C(=O)O)cn1
Reactant: CCN(CC)CC
Agent: C1CNC1
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)N2CCC2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl-1H-pyrazole-4-carboxylic acid (1.0 g, 7.93 mmol; CAS Nr. 5952-92-1) was combined with DMF (10.0 ml) to give a colorless solution. Et3N (2.41 g, 3.32 ml, 23.8 mmol) and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate (TBTU, 2.8 g, 8.72 mmol) were added and the reaction mixture was stirred at RT for 1 h. Azetidine (475 mg, 8.33 mmol) was added and the stirring was continued overnight. DMF was partially removed under high vacuum, H2O and 10% NaHCO3 aq. solution were added to the residue, and the compound was extracted with EtOAc. After drying over Na2SO4, filtration and concentration under vacuum, the crude product was purified by flash chromatography (50 g SiO2—NH2 cartridge; eluent: CH2Cl2/MeOH 95:05). More product was isolated from the aqueous phase by full evaporation and a second chromatography. White solid (971 mg, 74%).
Reaction SMILES: [F:1][CH:2]([C:7]([O:9][CH3:10])=[O:8])[C:3]([O:5][CH3:6])=[O:4].C=O.FF.C1N2CN3CN(C2)CN1C3.[O:25]1COCO[CH2:26]1.C(=O)(O)[O-].[K+].C(=O)(O)[O-].[Na+]>>[OH:25][CH2:26][C:2]([F:1])([C:7]([O:9][CH3:10])=[O:8])[C:3]([O:5][CH3:6])=[O:4]
Reactant: C1OCOCO1
Reactant: COC(=O)C(F)C(=O)OC
Agent: C1N2CN3CN1CN(C2)C3
Agent: C=O
Agent: FF
Product: COC(=O)C(F)(CO)C(=O)OC

Procedure:
In the first process stage, dimethyl α-fluoromalonate is subjected to hydroxymethylation with formaldehyde. (Dimethyl α-fluoromalonate is a known compound; see Journal of Fluorine Chemistry 25 (1984), 203-212.) The formaldehyde is preferably employed in the form of an aqueous solution having a formaldehyde content of 30 to 40% by weight. The formaldehyde is employed in an amount of 1 to 10 mot, preferably 1.1 to 3 mot (relative to 1 mol of dimethyl α-fluoromalonate). It is also possible to use paraformaldehyde, hexamethylenetetramine or 1,3,5-trioxane instead of formaldehyde. It is advantagous to carry out the reaction in the presence of a basic catalyst, which is then used in an amount of 2 to 50, preferably 5 to 15, mol % (relative to the dimethyl α-fluoromalonate). The catalyst used is, in particular, an alkali metal bicarbonate, for example potassium bicarbonate and sodium bicarbonate. The reaction is carried out at a temperature of 5° to 40° C., preferably 15° to 30° C. The dimethyl α -hydroxymethyl-α-fluoromalonate formed is then isolated from the reaction mixture, preferably by salting out or extraction by means of a water-immiscible organic solvent. A suitable solvent is, above all, an aliphatic chlorinated hydrocarbon having 1 to 4 carbon atoms, for example methylene dichloride, chloroform, carbon tetrachloride, 1,1-dichloroethane or 1,2-dichloroethane. A combination of salting out and extraction is particularly advantageous; a saturated salt solution (ammonium sulfate or sodium chloride) is then first added to the reaction mixture, and this mixture is then extracted. Dimethyl α-hydroxymethyl-α-fluoromalonate is obtained in the form of a colorless solid by evaporating the solvent.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[S:23]1[CH:27]2[NH:28][C:29](=O)[CH:30]=[CH:31][N:26]2[CH:25]=[CH:24]1>CC#N>[S:23]1[CH:27]2[NH:28][C:29](=[S:10])[CH:30]=[CH:31][N:26]2[CH:25]=[CH:24]1
Reactant: O=C1C=CN2C=CSC2N1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: CC#N
Product: S=C1C=CN2C=CSC2N1
Reaction time: 1.5 h
Yield: 121.9 %

Procedure:
Lawesson's reagent (5.26 g.) was added to a boiling solution of 8H-thiazolo[3,2-a]pyrimidin-7-one (4.0 g.) in CH3CN(200 ml.) and the mixture was heated under reflux with stirring for 1.5 h. On cooling silica gel (70-230 mesh, 15 g.) was added and the mixture was evaporated to dryness. The residue was applied to a column of silica gel (300 g.) and eluted with MeOH/CH2Cl2 (5-10% to give 8H-thiazolo[3,2-a]-pyrimidin-7-thione (2.7 g.). Trimethyloxonium tetrafluoroborate (2.0 g.) was added to a stirred suspension of 8H-thiazolo[3,2-a]pyrimidin-7-thione (1.5 g.) in dry CH3CN (50 ml.). After stirring for 2 h, the solution was concentrated to about 20 ml., and with vigorous stirring anhydrous ether (100 ml.) was added to precipitate 7-methylthiothiazolo[3,2-a]-pyrimidinium tetrafluoroborate (1.3 g.), having nmr in d6DMSO:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:13]=[C:12]([O:14][CH:15]([F:17])[F:16])[NH:11][N:10]=1.S(OC)(O[CH3:22])(=O)=O.[NH4+].[Cl-]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:13]=[C:12]([O:14][CH:15]([F:16])[F:17])[N:11]([CH3:22])[N:10]=1
Reactant: FC(F)Oc1cc(-c2ccc(Cl)cc2Cl)n[nH]1
Reactant: COS(=O)(=O)OC
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: Cn1nc(-c2ccc(Cl)cc2Cl)cc1OC(F)F
Reaction time: 1 h
Yield: 78.7 %

Procedure:
457.2 g of 3-(2,4-dichlorophenyl)-5-difluoromethoxy-1H-pyrazole from Example 3.2 were initially charged in 2300 ml of toluene. 227.3 g of dimethyl sulfate were added dropwise, and the mixture was heated at reflux for 3 h. After cooling, 500 ml of saturated aqueous NH4Cl solution were added, the mixture was stirred for 1 h and the organic phase was separated off and washed with water until neutral. Drying over Na2SO4 and concentration gave 377.8 g of 3-(2,4-dichlorophenyl)-5-difluoromethoxy-1-methyl-1H-pyrazole of a purity of 92.9% (GC). Yield: 73.1%. M.p.: 35° C.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:13])C)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(OC(=O)C)(=[O:16])C.C(O)(=O)C>>[C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([OH:13])=[O:16])=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)Oc1ccc(C(C)=O)cc1
Solvent: CC(=O)O
Product: CC(=O)Oc1ccc(C(=O)O)cc1
Reaction time: 0.5 h
Yield: 73 %

Procedure:
The oxidation of p-acetoxyacetophenone proceeded as in Example I, except that the reaction was run for 30 minutes and a total of 150 g (1.47 moles) of acetic anhydride and 37 g (0.62 mole) of acetic acid was added through the pump. The reaction mixture was concentrated from 772 g to 413 g by evaporation of acetic acid. The slurry was filtered to remove precipitated p-acetoxybenzoic acid. After drying, 128.2 g of p-acetoxybenzoic acid of 95 mole % purity (73% yield) were obtained. Remaining in the filtrate were: p-acetoxybenzoic acid, 8.5 mole % yield, p-acetoxyacetophenone, 1.8 mole % yield, p-hydroxybenzoic acid, 0.6 mole % yield. Analysis of the reactor wash showed 2.6 mole % p-acetoxybenzoic acid. Total reaction yield of p-acetoxybenzoic acid was 84 mole %.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[OH:10].[NH2:28][C:29](=[O:51])[CH2:30][N:31]([C:36]1[CH:37]=[C:38]([CH:46]=[CH:47][C:48]=1[O:49][CH3:50])[C:39]([O:41][CH2:42][C:43](O)=[O:44])=[O:40])[S:32]([CH3:35])(=[O:34])=[O:33].C(Cl)CCl>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[NH2:28][C:29](=[O:51])[CH2:30][N:31]([C:36]1[CH:37]=[C:38]([CH:46]=[CH:47][C:48]=1[O:49][CH3:50])[C:39]([O:41][CH2:42][C:43]([O:10][C@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[CH2:8][C:7]1[C:6]([Cl:26])=[CH:5][N+:4]([O-:27])=[CH:3][C:2]=1[Cl:1])=[O:44])=[O:40])[S:32]([CH3:35])(=[O:34])=[O:33]
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: COc1ccc(C(=O)OCC(=O)O)cc1N(CC(N)=O)S(C)(=O)=O
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)OCC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1N(CC(N)=O)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 36.6 %

Procedure:
(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (30 mg, 0.071 mmol), 2-(3-(N-(2-amino-2-oxoethyl)methylsulfonamido)-4-methoxybenzoyloxy)acetic acid (51.4 mg, 0.143 mmol), DMAP (15 mg, 0.123 mmol), and EDC (100 mg, 0.522 mmol) were dissolved in DMF (2 ml). The reaction was stirred at RT for 3 hours to achieve completion. The reaction mixture was diluted with Water, and the precipitate was washed with water, dissolved in EtOAc and extracted with HCl 1N, Na2CO3 sat. sol. and brine. The organic phase was dried over Na2SO4 and concentrated under vacuum. The crude product was crystallized in EtOH to give (S)-4-(2-(2-(3-(N-(2-amino-2-oxoethyl)methylsulfonamido)-4-methoxybenzoyloxy)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (20 mg, 0.026 mmol, 36.7% yield).
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Cl.[C:6]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)([CH3:9])([CH3:8])[CH3:7].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:6]([C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:1][CH:3]2[CH2:4][O:5]2)=[CH:14][CH:15]=1)([CH3:9])([CH3:7])[CH3:8]
Reactant: ClCC1CO1
Reactant: CC(C)(C)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)c1ccc(OCC2CO2)cc1
Yield: 76.4 %

Procedure:
A mixture of epichlorohydrin (15.3 g; 0.165 mol), 4-tert-butylphenol (5.0 g; 0.033 mol) and potassium carbonate (6.9 g; 0.050 mol) in acetonitrile (50 mL) was refluxed for 5 h. The resulting heterogeneous mixture was cooled to below reflux temperature and vacuum filtered through fritted glass. The organics were concentrated to give the crude product (7.9 g) as a liquid. Flash chromatography on silica gel (CH2Cl2:EtOAc; 19:1) gave the desired product (5.2 g; 76%) as a liquid.
Reaction SMILES: [K].C1C2C(=CC=CC=2)C=CC=1.[CH2:12]1[C:21]2[C:16]3[C:17](=[CH:22][CH:23]=[CH:24][C:15]=3[CH2:14][O:13]1)[CH:18]=[CH:19][CH:20]=2>C1COCC1>[CH3:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:17]2[C:16]=1[C:21]([CH2:12][OH:13])=[CH:20][CH:19]=[CH:18]2
Reactant: c1cc2c3c(cccc3c1)COC2
Agent: [K]
Solvent: C1CCOC1
Solvent: c1ccc2ccccc2c1
Product: Cc1cccc2cccc(CO)c12
Temperature: 60 °C
Reaction time: 0.33 h

Procedure:
A 3-L 4-neck flask equipped with an overhead stirrer, a thermocouple, a condenser, a nitrogen inlet, and a 1-L addition funnel was charged with potassium (30 g, 0.764 mol) and THF (1 L). The metal suspension was heated to 60° C. for 30 min and then stirred to room temperature. To the reaction mixture was then added naphthalene (2 g, 0.015 mol), the suspension was stirred at room temperature for 10 min and then cooled to −20° C. to afford a blue suspension. A solution of 1H,3H-Benzo[de]isochromene (26 g, 0.153 mol) in THF (500 ml) was slowly added via the addition funnel, with addition controlled so that the reaction temperature did not exceed −15° C. After stirring for 5 h at −20° C., the suspension was removed from the cooling bath, warmed with stirring to 0° C., and then allowed to stand without stirring (potassium metal settling). The solution was decanted and the residual potassium was cooled and carefully decomposed with isopropyl alcohol (IPA) under N2. The decanted solution was carefully treated with water (20 mL) under nitrogen and stirring was continued for 20 min. Additional water and ether were added and the organic layer was separated. The aqueous layer was extracted with CH2Cl2 and the combined organics were dried over MgSO4 and condensed in vacuo to yield a crude material. The crude material was purified by flash chromatography (7.5/2.5 hexane/EtOAc) to yield 8-methyl-1-napthalenemethanol as a solid.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([C:18]4[CH:31]=[CH:30][C:21]([CH2:22][NH:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:20][CH:19]=4)=[C:13]([C:14]([F:17])([F:16])[F:15])[C:8]=3[N:7]=[N:6]2)[CH2:3][CH2:2]1.Cl.[O-:33][C:34]#[N:35].[K+].C(=O)(O)[O-].[Na+]>O.ClCCl>[C:34]([N:23]([CH2:22][C:21]1[CH:30]=[CH:31][C:18]([C:12]2[CH:11]=[CH:10][C:9]3[N:5]([CH2:4][CH:1]4[CH2:2][CH2:3]4)[N:6]=[N:7][C:8]=3[C:13]=2[C:14]([F:15])([F:16])[F:17])=[CH:19][CH:20]=1)[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])(=[O:33])[NH2:35]
Reactant: N#C[O-]
Reactant: CCOC(=O)CNCc1ccc(-c2ccc3c(nnn3CC3CC3)c2C(F)(F)F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)CN(Cc1ccc(-c2ccc3c(nnn3CC3CC3)c2C(F)(F)F)cc1)C(N)=O
Reaction time: 1.5 h

Procedure:
Ethyl N-{4-[1-(cyclopropylmethyl)-4-(trifluoromethyl)-1H-benzotriazol-5-yl]benzyl}glycinate (42 mg, 0.097 mmol) was added to a dichloromethane:1 N hydrochloric acid solution (400 μL:80 μL) and the mixture placed into an ice-bath at 0° C. Potassium cyanate (24 mg, 0.29 mmol) was dissolved in deionized water (300 uL) and this solution was added to the mixture over 5 minutes. The mixture was vigorously stirred for 1.5 hours, at which time the mixture was treated with sodium bicarbonate (aqueous saturated) and extracted with ethyl acetate (3×40 mL). The organic layers were combined, dried with sodium sulfate, filtered and concentrated in vacuo to provide the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]([CH2:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:18]3[S:19][CH:20]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:22]=3)=[CH:12][CH:11]=2)[CH:5]=[C:4]([F:37])[C:3]=1[CH2:38][CH2:39][C:40]([O:42]CC)=[O:41].[OH-].[K+]>O1CCCC1.C(O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]([CH2:29][CH2:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:18]3[S:19][CH:20]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:22]=3)=[CH:12][CH:11]=2)[CH:5]=[C:4]([F:37])[C:3]=1[CH2:38][CH2:39][C:40]([OH:42])=[O:41]
Reactant: CCOC(=O)CCc1c(F)cc(OCc2ccc(CN(CCc3ccccc3)c3nc(-c4ccccc4)cs3)cc2)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(O)CCc1c(F)cc(OCc2ccc(CN(CCc3ccccc3)c3nc(-c4ccccc4)cs3)cc2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.6 %

Procedure:
That is, ethyl 3-[2,6-difluoro-4-[[4-[[(2-phenylethyl)(4-phenyl-1,3-thiazol-2-yl)amino]methyl]benzyl]oxy]phenyl]-propanoate (300 mg, 0.49 mmol) was dissolved in a mixed solvent of tetrahydrofuran (8 mL) and ethanol (8 mL). Thereto was added an aqueous solution (5 mL) of 85% potassium hydroxide (100 mg, 1.51 mmol), and the mixture was stirred at room temperature for 18 hr. The reaction solution was diluted with ethyl acetate, washed successively with aqueous citric acid solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and crystallized from diethyl ether-hexane to give the title compound (271 mg, yield 94%) as colorless prism crystals.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].C(=O)([O-])[O-].[K+].[K+].[CH:16]1[C:21]([C:22]#[N:23])=[CH:20][N:19]=[C:18](Cl)[CH:17]=1.O>CC(N(C)C)=O>[OH:6][CH2:5][C:4]1[CH:3]=[C:2]([CH:9]=[CH:8][CH:7]=1)[O:1][C:18]1[CH:17]=[CH:16][C:21]([C:22]#[N:23])=[CH:20][N:19]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: OCc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: N#Cc1ccc(Oc2cccc(CO)c2)nc1
Temperature: 100 °C
Yield: 99.8 %

Procedure:
Add 3-hydroxybenzyl alcohol (0.99 g, 7.94 mmol) and potassium carbonate (1.50 g, 10.83 mmol) to 6-chloronicotinitrile (1.00 g, 7.22 mmol) in dimethylacetamide (25 mL) and stir. Heat to 100° C. for 4 hrs. Let cool to ambient temperature and pour into water (100 mL). Extract with diethyl ether (3×100 mL). Combine the organic layers and wash with 1N NaOH (2×50 mL) and dry over magnesium sulfate. Filter and concentrate under reduced pressure to give the product (1.63 g, 99%): 1H NMR (CDCl3) 8.49 (d, J=2.2 Hz, 1H), 7.95 (dd, J=2.2 Hz, 8.7 Hz, 1H), 7.47 (t, J=7.9 Hz, 1H), 7.29 (s, 1H), 7.21 (s, 1H), 7.10 (d, J=8.2 Hz, 1H), 7.06 (d, J=8.7 Hz, 1H), 4.77 (s, 2H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9]([C@H:11]1[C@@H:15]([C:16](OC)=[O:17])[CH2:14][N:13]([CH3:20])[CH2:12]1)=O>O1CCCC1>[CH3:20][N:13]1[CH2:14][C@H:15]([CH2:16][OH:17])[C@H:11]([CH2:9][OH:8])[CH2:12]1
Reactant: COC(=O)[C@H]1CN(C)C[C@H]1C(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1C[C@@H](CO)[C@@H](CO)C1
Reaction time: 1 h
Yield: 92.3 %

Procedure:
To a suspension of 3.8 gm (100 mMol) lithium aluminum hydride in 200 mL tetrahydrofuran were added dropwise a solution of 10.0 gm (50.0 mMol) 1-methyl-cis-3,4-pyrrolidinedicarboxylic acid dimethyl ester in 50.0 mL tetrahydrofuran. The reaction mixture was stirred at ambient for about 1 hour and was then quenched by the sequential addition of 3.8 mL water, 3.8 mL 15% aqueous sodium hydroxide solution and 11.4 mL of water. The resultant mixture was stirred at ambient for 20 hours. At this point the suspension was filtered through a bed of Celite and the filter cake was washed with tetrahydrofuran. The combined liltrates were concentrated in vacuo to give 6.7 gm of the desired compound as a light yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[C:7]([F:15])[C:8]([F:14])=[CH:9][CH:10]=2)[C:5]=1[F:16])[CH3:2].C([Li])CCC.CCCCCC.[CH2:28]([C@H:32]1[CH2:37][CH2:36][C@H:35]([C@H:38]2[CH2:43][CH2:42][C@H:41]([CH2:44][CH:45]=[O:46])[CH2:40][CH2:39]2)[CH2:34][CH2:33]1)[CH2:29][CH2:30][CH3:31].Cl>O1CCCC1>[CH2:1]([O:3][C:4]1[C:5]([F:16])=[C:6]2[C:11]([CH:10]=[C:9]([CH:45]([OH:46])[CH2:44][C@H:41]3[CH2:40][CH2:39][C@H:38]([C@H:35]4[CH2:36][CH2:37][C@H:32]([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:33][CH2:34]4)[CH2:43][CH2:42]3)[C:8]([F:14])=[C:7]2[F:15])=[CH:12][CH:13]=1)[CH3:2]
Reactant: CCOc1ccc2ccc(F)c(F)c2c1F
Reactant: CCCC[C@H]1CC[C@H]([C@H]2CC[C@H](CC=O)CC2)CC1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCC[C@H]1CC[C@H]([C@H]2CC[C@H](CC(O)c3cc4ccc(OCC)c(F)c4c(F)c3F)CC2)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A tetrahydrofuran (50 ml) solution of 2-ethoxy-1,7,8-trifluoronaphthalene (9.4 g) was cooled to −60° C. Then, a 1.58 M butyllithium/hexane solution (47 ml) was added dropwise to this solution, followed by stirring for 2 hours. A tetrahydrofuran (50 ml) solution of trans-4-(trans-4-butylcyclohexyl)cyclohexylacetoaldehyde (13.2 g) was added dropwise at −50° C. . After stirring for 2 hours, the reaction temperature was increased to 0° C. 10% hydrochloric acid was added to the reaction solution. The reaction solution was extracted with ethyl acetate, washed with brine, and concentrated. The residue was recrystallized from ethyl acetate, and 7-ethoxy-3-[2-[trans-4-(trans-4-butylcyclohexyl)cyclohexyl]-1-hydroxyethyl]-1,2,8-trifluoronaphthalene was obtained.
Reaction SMILES: C(OC(=O)C1C=CC(NC(=O)C(N2C3C=C(F)C(F)=CC=3N=C2C2C=CC(Cl)=CC=2)C2CCCCC2)=CC=1)C.[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]2[N:51]([CH:52]([CH:56]3[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]3)[C:53]([OH:55])=O)[C:50]3[CH:62]=[CH:63][CH:64]=[CH:65][C:49]=3[N:48]=2)=[CH:43][CH:42]=1.[CH3:66][O:67][C:68]([C:70]1([O:73][C:74]2[CH:79]=[CH:78][C:77]([NH2:80])=[C:76]([F:81])[CH:75]=2)[CH2:72][CH2:71]1)=[O:69]>>[CH3:66][O:67][C:68]([C:70]1([O:73][C:74]2[CH:79]=[CH:78][C:77]([NH:80][C:53](=[O:55])[CH:52]([N:51]3[C:50]4[CH:62]=[CH:63][CH:64]=[CH:65][C:49]=4[N:48]=[C:47]3[C:44]3[CH:45]=[CH:46][C:41]([Cl:40])=[CH:42][CH:43]=3)[CH:56]3[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]3)=[C:76]([F:81])[CH:75]=2)[CH2:72][CH2:71]1)=[O:69]
Reactant: COC(=O)C1(Oc2ccc(N)c(F)c2)CC1
Reactant: O=C(O)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2ccccc21
Agent: CCOC(=O)c1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)cc1
Product: COC(=O)C1(Oc2ccc(NC(=O)C(C3CCCCC3)n3c(-c4ccc(Cl)cc4)nc4ccccc43)c(F)c2)CC1

Procedure:
The title compound was prepared in analogy to example 22, intermediate d), from [2-(4-chloro-phenyl)-benzoimidazol-1-yl]-cyclohexyl-acetic acid (Ex. 39/40, int. b) and 1-(4-amino-3-fluoro-phenoxy)-cyclopropanecarboxylic acid methyl ester to give the product as a light yellow foam (21%).