Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[OH:22])[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH3:23][C:24](C)=[CH:25][CH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][C:31]([C:34](O)=[O:35])=[CH:30][CH2:29]1.C1(N=C=NC2CCCCC2)CCCCC1.CN(C1C=CC=CN=1)C>O.O1CCCC1>[CH2:27]([CH:28]1[CH2:33][CH2:32][C:31]([C:34]([O:22][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][CH2:14][CH2:13][CH2:12][CH:9]2[CH2:8][CH2:7][CH:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:11][CH2:10]2)=[O:35])=[CH:30][CH2:29]1)[CH2:26][CH2:25][CH2:24][CH3:23]
Reactant: CC(C)=CCCC1CC=C(C(=O)O)CC1
Reactant: CCCCC[C@H]1CC[C@H](CCCCc2ccccc2O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: O
Solvent: C1CCOC1
Product: CCCCCC1CC=C(C(=O)Oc2ccccc2CCCCC2CCC(CCCCC)CC2)CC1
Reaction time: 8 h

Procedure:
To a round-bottom flask equipped with a stirbar is added phenol 3H (R=pentyl) (5 g), (4-(4-Methyl-3-pentenyl)-1-cyclohexenyl)carboxylic acid (R=n-pentyl) (3.3 g), dicyclohexylcarbodiimide (5.11 g), dimethylaminopyridine (202 mg), and anhydrous tetrahydrofuran (50 mL). The reaction is stirred overnight, at which time the solution is poured into water and extracted with 1:1 hexanes:ethyl acetate. The combined organic layers are washed with brine and dried over potassium carbonate, and the solution is concentrated in vacuo. Filtration through silica gel using 10% ethyl acetate in hexanes gives the pure product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[C:18](Br)=[CH:19][CH:20]=[CH:21][C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:25]=1B(O)O.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-]>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>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[C:18]([C:25]4[C:26]([CH3:30])=[CH:27][CH:28]=[CH:29][C:24]=4[CH3:23])=[CH:19][CH:20]=[CH:21][C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3c(Br)cccc3O2)cc1
Reactant: Cc1cccc(C)c1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCC2Cc3c(cccc3-c3c(C)cccc3C)O2)cc1
Yield: 167.4 %

Procedure:
Treatment of (±)-(4-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (1.5 g, 3.32 mmol) with 2,6-dimethylphenylboronic acid (2.35 g, 15.66 mmol), tetrakis(triphenylphosphine)palladium(0) (0.452 g, 0.394 mmol), and barium hydroxide octahydrate (6.17 g, 19.57 mmol) generally according to the procedure described for Intermediate 50 provided 2.27 g (71%) of (±)-[4-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a colorless oil. Anal. calcd. for C24H24O4S: C, 70.56; H, 5.92. Found: C, 69.72; H, 5.87.
Reaction SMILES: C(#N)C1C=CC=CC=1.C(=O)([O-])[O-:10].[K+].[K+].OO.[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([C:26](=[CH2:31])[C:27]([O:29][CH3:30])=[O:28])=[CH:22][CH:21]=1)([O-:19])=[O:18]>CO.C(Cl)(Cl)Cl.O>[O:10]1[CH2:31][C:26]1([C:23]1[CH:22]=[CH:21][C:20]([N+:17]([O-:19])=[O:18])=[CH:25][CH:24]=1)[C:27]([O:29][CH3:30])=[O:28]
Reactant: O=C([O-])[O-]
Reactant: C=C(C(=O)OC)c1ccc([N+](=O)[O-])cc1
Agent: OO
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: O
Product: COC(=O)C1(c2ccc([N+](=O)[O-])cc2)CO1
Reaction time: 17 h

Procedure:
Benzonitrile (1 ml.), potassium carbonate (0.2 g.) and 30% aqueous hydrogen peroxide solution (1.5 ml.) were added to a solution of methyl 2-p-nitrophenylprop-2-enoate (1.0 g.) in a mixture of methanol (15 ml.) and chloroform (15 ml.) and the mixture was stirred at laboratory temperature for 17 hours and then poured into water. The mixture was extracted three times with diethyl ether and the combined extracts were washed successively with water, aqueous ferrous sulphate solution and saturated aqueous sodium chloride solution, dried over magnesium sulphate and evaporated to dryness under reduced pressure. There was thus obtained as solid residue methyl 2,3-epoxy-2-p-nitrophenylpropionate which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[BH4-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:13])[C:9]([F:11])([F:12])[F:10])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Br)cc1)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OC(c1ccc(Br)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
To 4′-bromo-2,2,2-trifluoroacetophenone (5.0 g, 19.76 mmol) in THF (50 mls) at 0° C. was added NaBH4 (1.5 g, 39.52 mmol). The mixture was warmed to room temperature and stirred for 1 hour. The reaction was complete by TLC(CH2Cl2). The mixture was quenched with H2O, rotary evaporated to remove most of the THF, and extracted 2 times with CH2Cl2. The organics were combined, washed with brine, concentrated to a small volume and filtered through a plug of silica gel. The silica was washed with CH2Cl2 to elute the product, and the resulting solution was concentrated to give 4.65 g of 1-(4-bromophenyl)-2,2,2-trifluoroethanol. Yield 92%.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([NH:9][C:10]1[C:15]([NH2:16])=[CH:14][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:12][N:11]=1)([CH3:8])[CH3:7])(=[O:3])[CH3:2].[C:21](N1C=CN=C1)(N1C=CN=C1)=[O:22]>C(#N)C>[C:1]([O:4][CH2:5][C:6]([N:9]1[C:10]2=[N:11][CH:12]=[C:13]([C:17]([F:18])([F:20])[F:19])[CH:14]=[C:15]2[NH:16][C:21]1=[O:22])([CH3:8])[CH3:7])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(C)(C)Nc1ncc(C(F)(F)F)cc1N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: CC(=O)OCC(C)(C)n1c(=O)[nH]c2cc(C(F)(F)F)cnc21
Temperature: 50 °C
Reaction time: 2 h
Yield: 45.1 %

Procedure:
To a solution of 2-(2-acetoxy-1,1-dimethylethylamino)-3-amino-5-(trifluoromethyl)pyridine (1.5 g) in acetonitrile (15 mL) was added 1,1′-carbonyldiimidazole (1.25 g), and the mixture was stirred at 50° C. under nitrogen atmosphere for 2 hours. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The separated organic layer was washed successively with 1 N-hydrochloric acid, water, an aqueous saturated sodium hydrogencarbonate solution and brine. The organic layer was dried over magnesium sulfate and evaporated in vacuo. The residue was subjected to a silica gel column chromatography eluting with a mixture of chloroform and methanol (20:1). The obtained substance was triturated with diethyl ether to give 3-(2-acetoxy-1,1-dimethylethyl)-6-trifluoromethyl-2,3-dihydro-1H-imidazo[4,5-b]pyridin-2-one (736.5 mg) as a pale brown solid.
Reaction SMILES: [CH3:1][C:2]1([OH:12])[CH:9]2[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2.C(N(CC)CC)C.[C:20](Cl)(=[O:23])[CH:21]=[CH2:22].CO>C(C(C)=O)C(C)C.O>[C:20]([O:12][C:2]1([CH3:1])[CH:3]2[CH2:11][CH:7]3[CH2:6][CH:5]([CH2:10][CH:9]1[CH2:8]3)[CH2:4]2)(=[O:23])[CH:21]=[CH2:22]
Reactant: C=CC(=O)Cl
Reactant: CC1(O)C2CC3CC(C2)CC1C3
Solvent: CO
Solvent: O
Solvent: CCN(CC)CC
Product: C=CC(=O)OC1(C)C2CC3CC(C2)CC1C3
Reaction time: 2 h
Yield: 100.6 %

Procedure:
Into a reaction vessel were charged 2.1 liters of methyl isobutyl ketone, 665.2 g (4.0 mol) of 2-methyl-2-adamantanol and 607.29 g (6.0 mol) of triethylamine, and their temperature was elevated to 60° C. under stirring. To the mixture, a solution prepared by dissolving 434.55 g (4.8 mol) of acryloyl chloride in 0.4 liter of methyl isobutyl ketone was added dropwise. At the end of the dropwise addition, the temperature was reached about 80° C. with the reaction heat. The mixture was kept at 80° C. for 2 hours with stirring to complete the reaction. After cooling, 64.02 g (2.0 mol) of methanol was added dropwise to deactivate the unreacted acryloyl chloride while keeping the temperature below 40° C. Then, 3.3 liters of water was added thereto to wash the mixture, followed by separation of the mixture into layers. Thereafter, 2.8 liters of a saturated aqueous sodium chloride solution was added to the organic layer to wash it again, and the mixture was separated into layers. To the organic layer after separation was added 204 g of active carbon “Carborafin” manufactured by Takeda Chemical Industries, Ltd. and stirred for 1 hour. The mixture was filtered thereafter and the residue was washed with 2 liters of methyl isobutyl ketone. The filtrate and the washing effluents were combined and concentrated at a bath temperature of 45° C. to obtain 886.17 g of crude 2-methyl-2-adamantyl acrylate.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C@@H:9]([O:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]2[N:37]=[C:22]3[CH:23]=[CH:24][CH:25]=[C:26]([C:27]4[CH:36]=[CH:35][C:30]5[O:31][CH2:32][CH2:33][O:34][C:29]=5[CH:28]=4)[N:21]3[N:20]=2)=[CH:14][CH:13]=1)C)(C)(C)C.[CH3:39]C1C=CC(S(O)(=O)=O)=CC=1>ClCCl>[NH2:7][C@@H:8]([CH3:39])[CH2:9][O:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]2[N:37]=[C:22]3[CH:23]=[CH:24][CH:25]=[C:26]([C:27]4[CH:36]=[CH:35][C:30]5[O:31][CH2:32][CH2:33][O:34][C:29]=5[CH:28]=4)[N:21]3[N:20]=2)=[CH:14][CH:13]=1
Reactant: C[C@@H](CNC(=O)OC(C)(C)C)Oc1ccc(Nc2nc3cccc(-c4ccc5c(c4)OCCO5)n3n2)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: C[C@H](N)COc1ccc(Nc2nc3cccc(-c4ccc5c(c4)OCCO5)n3n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
((S)-2-{4-[5-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-phenoxy}-propyl)-carbamic acid tert-butyl ester (100 mg, 0.196 mmol) was dissolved in dichloromethane (4 ml) and MP-TsOH (1 g, 3.23 mmol) added. The mixture was shaken overnight at room temperature. The resin was collected by filtration and washed with methanol. The product was then cleaved from the resin with 2M ammonia in methanol. The eluant was concentrated in vacuo and the product was purified by prep LCMS.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[CH2:5]O.P(Br)(Br)[Br:13].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[CH2:5][Br:13]
Reactant: BrP(Br)Br
Reactant: COc1cc(Br)cc(CO)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc(Br)cc(CBr)c1
Reaction time: 0.17 h
Yield: 214.3 %

Procedure:
11 Grams (51 mmole) of 3-bromo-5methoxy benzyl alcohol was dissolved in 100 ml methylene chloride and cooled in an ice-bath. 2.0 ml (20 mmole) of phosphorus tribromide was added dropwise to this solution at room temperature, and the mixture was allowed to stir for 10 minutes. Saturated sodium bicarbonate solution was then added, and the mixture was extracted with ether and washed with sodium bicarbonate solution. Evaporation of the ether yielded 12 grams of 3-Bromo-5-methoxy-benzyl bromide as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:15]([F:18])([F:17])[F:16].S(=O)(=O)(O)O.[I:24]N1C(=O)CCC1=O>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([OH:14])=[C:12]([I:24])[CH:13]=2)=[CH:4][C:3]=1[C:15]([F:16])([F:17])[F:18]
Reactant: Oc1ccc(-c2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: O=C1CCC(=O)N1I
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Oc1ccc(-c2ccc(Cl)c(C(F)(F)F)c2)cc1I
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.4 %

Procedure:
4′-Chloro-3′-(trifluoromethyl)biphenyl-4-ol (Preparation 54, 150 mg, 0.55 mmol) was dissolved in acetic acid (5 mL) and concentrated sulphuric acid (0.032 μL) was added followed by N-iodosuccinimide (124 mg, 0.55 mmol). The reaction was stirred at room temperature for 18 hours and then partitioned between ethyl acetate (50 mL) and water (20 mL). The ethyl acetate was separated, dried over MgSO4, filtered and evaporated. The crude product was chromatographed on silica eluting with a gradient of heptane:ethyl acetate 100:0 to 85:15 to give the title compound (167 mg, 0.42 mmol, 76%) as a gum.
Reaction SMILES: [OH:1][CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][NH:4][C:5](=[O:7])[CH3:6].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[O:1]=[C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][NH:4][C:5](=[O:7])[CH3:6]
Reactant: CC(=O)NCC(O)c1ccccc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(=O)NCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 52.5 %

Procedure:
A mixture of N-(2-hydroxy-2-phenyl-ethyl)-acetamide (7.68 g, 43 mmol), prepared in the previous step, and pyridinium chlorochromate (14.0 g, 65 mmol) in 800 ml of methylene chloride was stirred at room temperature for 5 hours. The organic phase was decanted from a black oily residue in the flask. This black residue was triturated with methylene chloride and then with 10% methanol-methylene chloride. The organic phases were concentrated under reduced pressure and the residue chromatographed on 400 g of silica gel (230-400 mesh) using ethyl acetate-methylene chloride as the eluent. Isolation of the desired component gave N-(2-oxo-2-phenyl-ethyl)-acetamide (4.0 g, 53%) as a white solid. The material was used in the following reaction without additional purification, MS m/e (M+H)+ 178.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][C:5]=1CN1C(C2C(C)=CC=CN=2)CCCC1C1C(C)=CC=CN=1.[Li+].[BH4-]>CO>[OH:2][CH2:3][C:4]1[CH:9]=[C:8]([CH:7]=[CH:6][CH:5]=1)[C:10]#[N:11]
Reactant: COC(=O)c1cc(C#N)ccc1CN1C(c2ncccc2C)CCCC1c1ncccc1C
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Product: N#Cc1cccc(CO)c1
Reaction time: 3.5 h
Yield: 86 %

Procedure:
To a stirred, room temperature solution of the ester from above (2.05 g, 4.6 mmol) in MeOH (50 mL) was added LiBH4 (1.0 g, 50 mmol) in three portions. Effervescence was observed, and the mixture was stirred for 3.5 hours. The mixture was concentrated and 1 N NaOH (50 mL) was added to the resultant residue. The aqueous mixture was extracted with CH2Cl2 (3×50 mL). The organic extracts were combined, dried (Na2SO4), and concentrated. Purification of the crude material by column chromatography on silica gel (40 g, eluted with 5% NH4OH/5% MeOH/CH2Cl2) provided 4-3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-3-hydroxymethyl-benzonitrile (1.63 g, 86%) as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH3:25])=[C:11]2[C:16](=[C:17]([CH3:20])[C:18]=1[CH3:19])[O:15][C@:14]([CH3:24])([CH2:21][CH2:22][OH:23])[CH2:13][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28].N1C=CC=CC=1.C.C(OC1C(C)=C2C(=C(C)C=1C)O[C@](C)(CCO)CC2)C1C=CC=CC=1>C1C=CC=CC=1>[CH3:26][S:27]([O:23][CH2:22][CH2:21][C@:14]1([CH3:24])[CH2:13][CH2:12][C:11]2[C:16](=[C:17]([CH3:20])[C:18]([CH3:19])=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:10]=2[CH3:25])[O:15]1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CC[C@@](C)(CCO)O2
Agent: C
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CC[C@@](C)(CCOS(C)(=O)=O)O2
Temperature: 0 °C

Procedure:
A solution of 0.5 g. (1.47 mmoles) of (S)-(-)-6-benzyloxy-2,5,7,8-tetramethylchroman-2-ethanol and 0.25 ml. (0.37 g.; 3.2mmoles) of methanesulfonyl chloride in 5 ml. of anhydrous pyridine was kept at 0° C. for 45 hours then poured into 100 ml. of ice-water and the resulting mixture was stirred for 15 minutes. The mixture was then extracted three times with ether and the combined ether extracts were washed with cold 1 N aqueous HCl followed by water and saturated brine. After drying and filtration, the ether extracts were concentrated in vacuo giving 0.587 g. (95.6%) of (S)-6-benzyloxy-2,5,7,8-tetramethylchroman-2-ethanol methane as a colorless solid, m.p. 81°-83° C.; [α]25D - 0.36°(c 0.82, C6H6).
Reaction SMILES: [CH3:1][NH:2][C:3]([O:5][CH2:6][CH2:7][CH2:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12][C@@H:13]1[C@@H:17](/[CH:18]=[CH:19]/[C@@H:20]([O:26]C2CCCCO2)[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C@H:16]([O:33]C2CCCCO2)[CH2:15][C@@H:14]1[O:40][Si](CC1C=CC=CC=1)(CC1C=CC=CC=1)CC1C=CC=CC=1)=[O:4]>C(O)(=O)C.O.O1CCCC1>[CH3:1][NH:2][C:3]([O:5][CH2:6][CH2:7][CH2:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12][C@@H:13]1[C@@H:17](/[CH:18]=[CH:19]/[C@@H:20]([OH:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C@H:16]([OH:33])[CH2:15][C@@H:14]1[OH:40])=[O:4]
Reactant: CCCCC[C@@H](/C=C/[C@@H]1[C@@H](C/C=C\CCCCOC(=O)NC)[C@@H](O[Si](Cc2ccccc2)(Cc2ccccc2)Cc2ccccc2)C[C@H]1OC1CCCCO1)OC1CCCCO1
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: CCCCC[C@H](O)/C=C/[C@@H]1[C@@H](C/C=C\CCCCOC(=O)NC)[C@@H](O)C[C@H]1O

Procedure:
At 50°, 250 mg. of (5Z,13E)-(8R,9S,11R,12R,15S)-1-(N-methylcarbamoyloxy)-11,15-bis(tetrahydropyran-2-yloxy)-9-tribenzylsilyloxy-5,13-prostadiene was stirred for 5 hours in 15 ml. of a mixture of glacial acetic acid/water/tetrahydrofuran (65/35/10). The mixture was evaporated under vacuum and the residue purified by chromatography on silica gel with ether/dioxane (7+3), thus obtaining 105 mg. of the title compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:14]3[CH:15]=[N:16][CH:17]=[CH:18][C:13]=3[N:12]([C:19]([CH3:30])([CH3:29])[CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[F:31][C:32]([F:43])([F:42])[C:33]1[N:34]=[N:35][N:36]([CH2:38][C:39](O)=[O:40])[CH:37]=1>>[Si:22]([O:21][CH2:20][C:19]([N:12]1[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:10]([C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:39](=[O:40])[CH2:38][N:36]3[CH:37]=[C:33]([C:32]([F:42])([F:31])[F:43])[N:34]=[N:35]3)[CH:7]=[N:6][CH:5]=2)=[O:9])=[CH:11]1)([CH3:30])[CH3:29])([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:23])[CH3:24]
Reactant: O=C(O)Cn1cc(C(F)(F)F)nn1
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(N)c2)c2cnccc21
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(NC(=O)Cn3cc(C(F)(F)F)nn3)c2)c2cnccc21

Procedure:
Prepared according to Method Z (Preparation 8) using (5-Amino-pyridin-3-yl)-{1-[2-(tert-butyl-dimethyl-silanyloxy)-1,1-dimethyl-ethyl]-1H-pyrrolo[3,2-c]pyridin-3-yl}-methanone (Preparation 28) and [4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]acetic acid (Preparation 90).
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH2:5][OH:6].[H-].[Na+].[CH3:10][O:11][CH2:12][CH2:13][O:14][CH2:15]Cl.O>CN(C)C=O>[CH3:10][O:11][CH2:12][CH2:13][O:14][CH2:15][O:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:7]
Reactant: COCCOCCl
Reactant: OCCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOCOCCCCCO
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.4 %

Procedure:
A solution of 50.00 g of 1,5-pentanediol dissolved in 100 ml of dimethylformamide was added dropwise to a mixture of 23.00 g of sodium hydride (as a 55% w/w dispersion in mineral oil) in 300 ml of dimethylformamide, whilst ice-cooling at 5° to 7° C. The mixture was stirred at room temperature for 1 hour, after which 65.79 g of 2-methoxyethoxymethyl chloride dissolved in 100 ml of dimethylformamide were added dropwise, whilst ice-cooling at 5° to 7° C. The mixture was stirred at room temperature for 3 hours, after which it was poured into 2.5 liters of water and then extracted five times with methylene chloride. The combined extracts were washed with water, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The residue was subjected to column chromatography through 850 g of silica gel, and 48.40 g of the title compound were obtained, as a colorless oil, from those fractions eluted with mixtures of methylene chloride and methanol ranging from 98:2 to 95:5 by volume.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:12])[C:5](=[CH:10][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7].[CH3:13][N:14]([CH3:18])[C:15](Cl)=[S:16].N12CCN(CC1)CC2.C(OCC)(=O)C>CN(C=O)C.O>[CH3:13][N:14]([CH3:18])[C:15]([O:12][C:4]1[CH:3]=[C:2]([F:1])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])=[S:16]
Reactant: COC(=O)c1ccc(F)cc1O
Reactant: CN(C)C(=S)Cl
Agent: C1CN2CCN1CC2
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(F)cc1OC(=S)N(C)C
Temperature: 25 °C
Reaction time: 7 h
Yield: 81.1 %

Procedure:
4-Fluorosalicylic acid (10.0 g, 64 mmol) was dissolved in methanol (300 ml), and concentrated sulfuric acid (6.3 g, 64 mmol) was added thereto. The reaction mixture was refluxed for 48 hrs. The solvent was evaporated, and the residue was neutralized with 2 N aqueous sodium hydroxide solution. Ethyl acetate was added to the mixture. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated to give methyl 4-fluorosalicylate (10.0 g, 92%) as white crystals. Methyl 4-fluorosalicylate (10.0 g, 58 mmol) and N,N-dimethylthiocarbamoyl chloride (9.6 g, 77 mmol) were dissolved in DMF (100 ml), and 1,4-diazabicyclo[2.2.2]octane (8.5 g, 75 mmol) was added thereto. The reaction mixture was stirred at room temperature for 7 hrs. The reaction mixture was combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated. The residue was subjected to a silica gel column chromatography. The fractions eluted with ethylacetate-hexane (1:5, v/v) were collected, concentrated and recrystallized from ethyl acetate-hexane to give the titled compound (12.1 g, 80%) as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:30][CH2:31][CH2:32][OH:33])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][C:26](=[O:29])[NH:25][N:24]=4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:34]C([Si](Cl)(C)C)(C)C.[H-].[Na+].CI.[N+](CC)(CC)(CC)CC.[F-]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@:8]2([CH2:30][CH2:31][CH2:32][OH:33])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][C:26](=[O:29])[N:25]([CH3:34])[N:24]=4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@@H](c1ccc(-c2ccc(=O)[nH]n2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Agent: CC[N+](CC)(CC)CC
Agent: [F-]
Agent: [H-]
Solvent: CI
Product: C[C@@H](c1ccc(-c2ccc(=O)n(C)n2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from (R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(6-oxo-1,6-dihydropyridazin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one by treatment with Ii) TBSCl, (ii) NaH, MeI and (iii) Et4NF. LC-MS Method 2 tR=1.111, m/z=488; 1H NMR (CDCl3) 1.27-1.40 (m, 1H), 1.49 (d, 3H), 1.64 (m, 1H), 1.85-1.99 (m, 3H), 2.10-2.33 (m, 4H), 2.89 (m, 1H), 3.51 (t, 2H), 3.80 (s, 3H), 5.68 (m, 1H), 6.90-7.02 (m, 5H), 7.18 (m, 2H), 7.21 (m, 1H), 7.48 (d, 2H), 7.52 (d, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:3]=1[CH2:4][NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[Cl:16])[N:12]=[C:11]([N:17]1[CH:21]=[C:20]([C:22]([O:24]CC)=[O:23])[CH:19]=[N:18]1)[NH:10][C:9]2=O.[CH:33]1([NH2:36])[CH2:35][CH2:34]1>>[CH:33]1([NH:36][C:9]2[C:8]3[C:13](=[CH:14][C:15]([Cl:16])=[C:6]([NH:5][CH2:4][C:3]4[C:2]([CH3:1])=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:32])[CH:7]=3)[N:12]=[C:11]([N:17]3[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[N:18]3)[N:10]=2)[CH2:35][CH2:34]1
Reactant: NC1CC1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(Cl)c(NCc4c(C)cccc4C)cc3c(=O)[nH]2)c1
Product: Cc1cccc(C)c1CNc1cc2c(NC3CC3)nc(-n3cc(C(=O)O)cn3)nc2cc1Cl

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-((2,6-dimethylbenzyl)amino)-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and cyclopropyl amine in step E. MS (ESI): predicted mass calcd. for C24H23ClN6O2, 462.9