Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][CH2:9][CH:10]([C:12]1[CH:13]=[CH:14][C:15]([C:28]2[C:29]([N:48]([CH3:53])[S:49]([CH3:52])(=[O:51])=[O:50])=[CH:30][C:31]3[O:35][C:34]([C:36]4[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=4)=[C:33]([C:43]([NH:45][CH3:46])=[O:44])[C:32]=3[CH:47]=2)=[N:16][C:17]=1[C:18]1[NH:19][C:20]2[C:25]([CH:26]=1)=[C:24]([F:27])[CH:23]=[CH:22][CH:21]=2)[F:11])C1C=CC=CC=1>C1COCC1.[OH-].[Pd+2].[OH-]>[F:27][C:24]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:25]=1[CH:26]=[C:18]([C:17]1[N:16]=[C:15]([C:28]3[C:29]([N:48]([CH3:53])[S:49]([CH3:52])(=[O:51])=[O:50])=[CH:30][C:31]4[O:35][C:34]([C:36]5[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=5)=[C:33]([C:43]([NH:45][CH3:46])=[O:44])[C:32]=4[CH:47]=3)[CH:14]=[CH:13][C:12]=1[CH:10]([F:11])[CH2:9][OH:8])[NH:19]2
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(C(F)COCc4ccccc4)c(-c4cc5c(F)cccc5[nH]4)n3)cc12
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(C(F)CO)c(-c4cc5c(F)cccc5[nH]4)n3)cc12
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of 5-(5-(2-(benzyloxy)-1-fluoroethyl)-6-(4-fluoro-1H-indol-2-yl)pyridin-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (530 mg, 0.717 mmol) in THF (10 mL) was added palladium hydroxide (101 mg, 0.717 mmol). The mixture was hydrogenated under a balloon for 2 h. Filtration through a pad of celite removed the solid. After washing with ethyl acetate, the combined filtrate was concentrated in vacuo to give 5-(6-(4-fluoro-1H-indol-2-yl)-5-(1-fluoro-2-hydroxyethyl)pyridin-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (465 mg, yield: 100%). MS (M+H)+: 649.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12]O)=[CH:6][CH:5]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:35]N1C(=O)CCC1=O>C(Cl)Cl>[Br:35][CH2:12][CH2:11][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([O:3][C:2]([F:15])([F:14])[F:1])=[CH:5][CH:6]=1
Reactant: OCCCc1ccc(OC(F)(F)F)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: FC(F)(F)Oc1ccc(CCCBr)cc1
Reaction time: 3 h
Yield: 32.5 %

Procedure:
Compound 52-2 (3.33 g) was dissolved in methylene chloride (30 ml), triphenylphosphine (4.35 g) and N-bromosuccinimide (2.95 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr, and further at room temperature for 3 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (1.39 g) as a yellow oil.
Reaction SMILES: [C:1]([Si:5]([O:18][CH:19]1[CH2:22][C:21](S(C)=O)(SC)[CH2:20]1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].Cl(O)(=O)(=O)=[O:29]>CCOCC.O>[Si:5]([O:18][CH:19]1[CH2:22][C:21](=[O:29])[CH2:20]1)([C:1]([CH3:3])([CH3:4])[CH3:2])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: [O-][Cl+3]([O-])([O-])O
Reactant: CSC1(S(C)=O)CC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)[Si](OC1CC(=O)C1)(c1ccccc1)c1ccccc1
Reaction time: 8 h
Yield: 59 %

Procedure:
A solution of tert-butyl{[3-(methylsulfinyl)-3-(methylthio)cyclobutyl]oxy}diphenylsilane (17.05 g, 40.7 mmol, from Step 2) in ether (350 mL) cooled to 0° C. was treated with a solution of 6M perchloric acid in water (10 mL) that was pre-diluted with water (7 mL). The bath was removed and stirred overnight. The mixture was poured into pH 7 buffer, and the product was extracted with diethyl ether. The combined extracts were dried over sodium sulfate, decanted and concentrated. The reaction was performed again on the same scale and the two batches were combined for purification. Flash chromatography, eluting with a gradient from 0-5% ethyl acetate/hexanes afforded desired product (15.7 g, 59%). 1H NMR (300 MHz, CDCl3): δ 7.75-7.62 (m, 4H), 7.49-7.33 (m, 6H), 4.59 (tt, 1H), 3.22-3.03 (m, 4H), 1.07 (s, 9H).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][C:11](=O)[CH2:10][C:9](=[O:14])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:15][C:16]([F:25])([F:24])[C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20].FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O.CN(C)C=O>O.CO>[C:1]1([CH:7]2[CH2:8][C:9](=[O:14])[CH:10]=[C:11]([NH:20][C:19]3[CH:21]=[CH:22][CH:23]=[C:17]([C:16]([F:15])([F:24])[F:25])[CH:18]=3)[CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CC(=O)CC(c2ccccc2)C1
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: O=C1C=C(Nc2cccc(C(F)(F)F)c2)CC(c2ccccc2)C1
Temperature: 25 °C

Procedure:
A mixture of 5-phenylcyclohexane-1,3-dione (1.51 g, 8.04 mmol), 3-(trifluoromethyl)-aniline (1.00 mL, 1.29 g, 8.04 mmol), Ytterbium(III) trifluormethanesulfonate (25 mg, 40 μmol, 0.5 mol %) and N,N-dimethylformamide (2.5 mL) is stirred at room temperature over night. Methanol and water are added and the mixture is filtered. The precipitate is dissolved in a mixture of N,N-dimethylformamide, methanol and some drops of aqueous ammonia. Water is added and the precipitate is filtered. Yield: 1.51 g; ESI mass spectrum [M+H]+=332, Retention time HPLC: 1.09 min (Z003—001).
Reaction SMILES: [NH2:1][C:2]([CH3:9])=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].N1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>C(O)C>[CH3:9][C:2]1[NH:1][CH:11]=[CH:12][CH:13]([C:14]2[CH:15]=[CH:4][CH:3]=[CH:2][CH:9]=2)[C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: C1CCNCC1
Reactant: CCOC(=O)C=C(C)N
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC=CC1c1ccccc1

Procedure:
(E)-3-Phenyl-2-propanol (13.8 ml, 0.11 mol) and ethyl 3-amino-2-butenoate (12.9 g, 0.1 mol) were dissolved in 150 ml of absolute ethanol containing 0.5 ml of piperidine. The mixture was heated under reflux for 18 hours followed by removal of the solvent under vacuum to yield 17.6 g of ethyl 1,4-dihydro-2-methyl-4-phenyl-3-pyridinecarboxylate as a brown viscous oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH:8]([NH:13][CH3:14])[C:9]([F:12])([F:11])[F:10])=[N:6][CH:7]=1.[F:15][CH:16]([F:43])[C:17]([N:19]1[C@H:23]([CH2:24][F:25])[C@@H:22]([C:26]2[CH:31]=[CH:30][C:29](B3OC(C)(C)C(C)(C)O3)=[CH:28][CH:27]=2)[O:21]C1(C)C)=[O:18].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[F:15][CH:16]([F:43])[C:17]([NH:19][C@H:23]([CH2:24][F:25])[C@H:22]([OH:21])[C:26]1[CH:27]=[CH:28][C:29]([C:2]2[CH:7]=[N:6][C:5]([CH:8]([NH:13][CH3:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=2)=[CH:30][CH:31]=1)=[O:18]
Reactant: CC1(C)O[C@H](c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[C@@H](CF)N1C(=O)C(F)F
Reactant: CNC(c1ccc(Br)cn1)C(F)(F)F
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: CCO
Solvent: Cc1ccccc1
Product: CNC(c1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(F)F)cc2)cn1)C(F)(F)F
Temperature: 80 °C
Yield: 98.8 %

Procedure:
To a stirred solution of [1-(5-Bromo-pyridin-2-yl)-2,2,2-trifluoro-ethyl]-methyl-amine (0.075 g, 0.279 mmol) and 2,2-Difluoro-1-{(4S,5R)-4-fluoromethyl-2,2-dimethyl-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-oxazolidin-3-yl}-ethanone (0.115 g, 0.279 mmol) in toluene:ethanol:water (3:3:3 mL) is added Na2CO3 (0.073 g, 0.697 mmol) at room temperature. Resulting reaction mixture is degassed with nitrogen for 30 minutes followed by addition of Pd(PPh3)4 (0.032 g, 0.028 mmol) and heated to 80° C. for 3 h. The reaction mixture is concentrated in vacuo then is diluted with water and extracted with ethyl acetate. Organic layer is dried over sodium sulphate and evaporated in vacuum. The crude material is purified by Combi-flash eluting in 20% ethyl acetate in hexane afford the title compound (0.120 g). 1H-NMR (400 MHz, DMSO) δ: 1.52 (s, 3H), 1.60 (s, 3H), 2.25 (d, J=5.76 Hz, 3H), 3.01-3.05 (m, 1H), 4.44-4.48 (m, 1H), 4.56-4.58 (m, 0.5H), 4.67-4.72 (m, 1H), 4.81-4.88 (m, 0.5H), 4.90-5.00 (m, 1H), 5.27 (d, J=3.68 Hz, 1H), 6.65 (t, J=52.36 Hz, 1H), 7.60 (d, J=8.24 Hz, 2H), 7.98-8.00 (dd, J1=2.04 Hz, J2=8.2 Hz, 1H), 8.06 (d, J=8.24 Hz, 1H), 8.15 (d, J=8.32, 2H), 8.73 (d, J=1.8 Hz, 1H). LC-MS (m/z): [M−H]=476.0.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][C:7]([NH2:10])=[N:6]1.N1C(C)=CC=CC=1C.[CH:19]1([CH2:24][C@H:25]([C:29]2[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[C:31]([CH3:39])[CH:30]=2)[C:26](Cl)=[O:27])[CH2:23][CH2:22][CH2:21][CH2:20]1>C(Cl)Cl>[CH:19]1([CH2:24][C@H:25]([C:29]2[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[C:31]([CH3:39])[CH:30]=2)[C:26]([NH:10][C:7]2[CH:8]=[CH:9][N:5]([CH2:4][CH2:3][O:2][CH3:1])[N:6]=2)=[O:27])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: COCCn1ccc(N)n1
Reactant: Cc1cc([C@@H](CC2CCCC2)C(=O)Cl)ccc1S(C)(=O)=O
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: COCCn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(C)c2)n1
Temperature: 0 °C
Reaction time: 16 h
Yield: 65 %

Procedure:
In a round bottom flask was placed 1-(2-methoxy-ethyl)-1H-pyrazol-3-ylamine (prepared in Example 72, 30 mg, 0.21 mmol), 2,6-lutidine (34 μL, 0.29 mmol) and methylene chloride (5 mL). This solution was then cooled to 0° C. and to it was added dropwise a solution of 3-cyclopentyl-2(R)-(4-methanesulfonyl-3-methyl-phenyl)-propionyl chloride in methylene chloride (0.096 M solution, 2 mL, 0.19 mmol). The reaction was then allowed to warm up to 25° C. and stirred for 16 h. After this time the reaction was quenched with a saturated aqueous sodium bicarbonate solution (10 mL) and then extracted with methylene chloride (3×10 mL). The organic extracts were then combined and washed with a 1 N aqueous hydrochloric acid solution (1×10 mL) and then dried over magnesium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (4 g column, 30% ethyl acetate/hexanes to 75% ethyl acetate/hexanes) afforded 3-cyclopentyl-2(R)-(4-methanesulfonyl-3-methyl-phenyl)-N-[1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-propionamide (57 mg, 65%) as a white foam: [α]31589=−29.5° (c=0.21, methylene chloride); ES-HRMS m/e calcd for C22H31N3O4S (M+H)+ 434.2108, observed 434.2108; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.02-1.20 (m, 2H, CH2), 1.36-1.82 (m, 8H, 4×CH2), 2.03-2.20 (m, 1H, CH), 2.62 (s, 3H, ArCH3), 3.17 (s, 3H, SO2CH3), 3.19 (s, 3H, OCH3), 3.61 (t, J=5.2 Hz, 2H, OCH2), 3.82-3.94 (m, 1H, ArCH), 4.11 (t, J=5.2 Hz, 2H, NCH2), 6.41 (d, J=2.4 Hz, 1H, Ar), 7.41-7.47 (m, 2H, Ar), 7.54 (d, J=2.4 Hz, 1H, Ar), 7.84 (d, Jo=8.8 Hz, 1H, Ar), 10.75 (s, 1H, NH).
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.Cl.O.[CH2:16]([C:23]1([CH2:27][OH:28])[CH2:26][O:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC(C)=O.[O-2].[Cr+6].[O-2].[O-2].C(O)(C)C>[CH2:16]([C:23]1([C:27]([OH:3])=[O:28])[CH2:24][O:25][CH2:26]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)=O
Reactant: OCC1(Cc2ccccc2)COC1
Agent: O=[Cr](=O)=O
Agent: [Cr+6]
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: O=C(O)C1(Cc2ccccc2)COC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 85 %

Procedure:
Jones reagent, (130 mL of a 2.3 M solution) previously prepared by adding hydrochloric acid (46 mL) to water (150 mL) followed by chromium (VI) oxide (55.5 g), was added dropwise to a solution of (3-benzyloxetan-3-yl)methanol (40 g, 0.2 mol) in acetone (600 mL). The reaction mixture was stirred at room temperature for 5 h. Isopropanol (18 g) was added and the mixture was extracted with ether (4 L), washed with NaH2PO4 (1M in water, 200 mL) and sodium chloride (1 M in water, 200 mL). The organics were dried over sodium sulfate, filtered and concentrated. The residue was triturated with ether (100 mL) to afford the title compound (37 g, 0.2 mol, 85%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 3.22 (s, 2H), 4.49-4.51 (d, 2H), 4.65-4.67 (d, 2H), 7.12-7.27 (m, 5H), 12.85 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][N:7]([C:9]2[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=2)N)=[CH:4][CH:3]=1.O=[C:19]([CH3:32])[CH2:20][CH2:21][C:22]1[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=1[C:24]([O:26][CH3:27])=[O:25].Cl>O1CCOCC1>[Br:15][C:12]1[CH:11]=[C:10]2[C:9](=[CH:14][CH:13]=1)[N:7]([CH2:6][C:5]1[CH:16]=[CH:17][C:2]([Br:1])=[CH:3][CH:4]=1)[C:19]([CH3:32])=[C:20]2[CH2:21][C:22]1[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=1[C:24]([O:26][CH3:27])=[O:25]
Reactant: COC(=O)c1ccccc1CCC(C)=O
Reactant: NN(Cc1ccc(Br)cc1)c1ccc(Br)cc1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1ccccc1Cc1c(C)n(Cc2ccc(Br)cc2)c2ccc(Br)cc12
Temperature: 70 °C
Yield: 39.3 %

Procedure:
To a room temperature solution of N-(4-bromobenzyl)-N-(4-bromophenyl)hydrazine (335 mg, 0.941 mmol) and methyl 2-(3-oxobutyl)benzoate (202 mg, 0.98 mmol) in 6 mL dioxane was added 1.5 mL of 4N HCl solution in dioxane. Heated to 70° C. for 16 h, then concentrated, the residue was partitioned between EtOAc and water, then washed with 1M HCl and brine. Dried over sodium sulfate, filtered and concentrated. Purification by flash chromatography (40% CH2Cl2 /Hexanes) provided 195 mg of the title compound.
Reaction SMILES: C([O:8][C:9](=[O:39])[CH:10]([C:21]1[CH:26]=[CH:25][C:24]([NH:27][S:28]([C:31]2[C:32]([CH3:38])=[N:33][N:34]([CH3:37])[C:35]=2[Cl:36])(=[O:30])=[O:29])=[CH:23][N:22]=1)C(OCC1C=CC=CC=1)=O)C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[Cl:36][C:35]1[N:34]([CH3:37])[N:33]=[C:32]([CH3:38])[C:31]=1[S:28]([NH:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:10][C:9]([OH:39])=[O:8])=[N:22][CH:23]=1)(=[O:30])=[O:29]
Reactant: Cc1nn(C)c(Cl)c1S(=O)(=O)Nc1ccc(C(C(=O)OCc2ccccc2)C(=O)OCc2ccccc2)nc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1nn(C)c(Cl)c1S(=O)(=O)Nc1ccc(CC(=O)O)nc1
Yield: 94 %

Procedure:
A solution of 2-[5-(5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonylamino)-pyridin-2-yl]-malonic acid dibenzyl ester in ethyl acetate was treated with 10% palladium on carbon. The mixture was hydrogenolyzed at 25° C. under hydrogen at 1 atmosphere until no starting material remained. At this time, the reaction mixture was filtered through celite. The filtrate was concentrated in vacuo to afford [5-(5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonylamino)-pyridin-2-yl]-acetic acid (94%) as a colorless solid; LRMS for C12H13ClN4O4S (M+H)+ at m/z=345/347.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[C:13]3[C:8]=2[CH:9]=[CH:10][CH:11]=[N:12]3)[CH2:3][CH2:2]1.[OH-:19].[K+].OO>CO>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:16]=[CH:15][C:14]([C:17]([NH2:18])=[O:19])=[C:13]3[C:8]=2[CH:9]=[CH:10][CH:11]=[N:12]3)[CH2:3][CH2:2]1
Reactant: [OH-]
Reactant: N#Cc1ccc(N2CCOCC2)c2cccnc12
Agent: OO
Agent: [K+]
Solvent: CO
Product: NC(=O)c1ccc(N2CCOCC2)c2cccnc12
Yield: 55.8 %

Procedure:
To 0.8 g of 5-morpholino-8-quinolinecarbonitrile (Compound No. 13) 60 ml of methanol was added and the mixture was stirred at 0° C. with further addition of an aqueous solution of 0.47 g of potassium hydroxide and then 5 ml of 30% hydrogen peroxide aqueous solution. The mixture was heated at 40° to 50° C. for 16 hours with stirring. After evaporation of the solvent, saturated sodium chloride aqueous solution was added to the residue, which was extracted with chloroform, and the extract was dried over anhydrous sodium sulfate. Chloroform was evaporated, and the residue was refined by column chromatography on silica gel using chloroform as an eluent. The crystals thus obtained were recrystallized from ethanol to yield 0.48 g (yield: 56%) of 5-morpholino-8-quinolinecarboxamide (Compound No. 22).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[OH:14])=[CH:5][CH:4]=1.[C:17]([O:20][C@@H:21]1[C@@H:33]([O:34][C:35](=[O:37])[CH3:36])[C@H:32]([O:38][C:39](=[O:41])[CH3:40])[C@@H:31]([CH2:42][O:43][C:44](=[O:46])[CH3:45])[O:30][C@@H:22]1OC(=N)C(Cl)(Cl)Cl)(=[O:19])[CH3:18]>ClCCl>[C:17]([O:20][C@@H:21]1[C@@H:33]([O:34][C:35](=[O:37])[CH3:36])[C@H:32]([O:38][C:39](=[O:41])[CH3:40])[C@@H:31]([CH2:42][O:43][C:44](=[O:46])[CH3:45])[O:30][C@H:22]1[O:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[CH2:7][C:6]1[CH:15]=[CH:16][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)OC[C@H]1O[C@H](OC(=N)C(Cl)(Cl)Cl)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: COc1ccc(Cc2ccccc2O)cc1
Solvent: ClCCl
Product: COc1ccc(Cc2ccccc2O[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.1 %

Procedure:
To a solution of 2-(4-methoxybenzyl)phenol (46 mg) and 2,3,4,6-tetra-O-acetyl-1-O-trichloroacetoimidoyl-α-D-glucopyranose (0.13 g) in dichloromethane (2 mL) was added boron trifluoride diethyl ether complex (0.033 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was purified by column chromatography on aminopropyl silica gel (eluent: dichloromethane) to give 2-(4-methoxybenzyl)phenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (0.11 g).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)([OH:10])[C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[O-][CH2:21]C.[Na+].[Na].CI>C(O)C>[F:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)([OH:10])[C:7]([O:9][CH3:21])=[O:8])=[CH:4][CH:3]=1
Reactant: CC[O-]
Reactant: O=C(O)C(O)(c1ccc(F)cc1)c1ccc(F)cc1
Agent: [Na+]
Agent: [Na]
Solvent: CI
Solvent: CCO
Product: COC(=O)C(O)(c1ccc(F)cc1)c1ccc(F)cc1
Reaction time: 3 h

Procedure:
25.0 g (0.095 mol) of 4,4′-difluorobenzilic acid is added to freshly prepared sodium ethoxide solution containing 2.17 g (0.095 mol) of sodium and 200 ml of ethanol at 20° C. and stirred for 3 hours. The solution is evaporated to dryness, the residue is dissolved in DMF, 22.57 g (0.16 mol) of methyl iodide is added dropwise at 20° C., and the mixture is stirred for 24 hours. It is worked up and purified analogously to compound 3b. Yield: 21.06 g (80% of theory).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)CC)C.[CH3:20][C:21]([NH2:26])([CH3:25])[CH2:22][O:23][CH3:24]>>[CH3:20][C:21]([NH:26][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([Cl:1])[N:11]=1)([CH3:25])[CH2:22][O:23][CH3:24]
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: COCC(C)(C)N
Solvent: CCN(CC)CC
Product: COCC(C)(C)Nc1nc(Cl)nc2ccccc12
Yield: 13.2 %

Procedure:
A mixture of 2,4-dichloroquinazoline (995 mg, 5 mmol), triethylamine (0.7 ml, 5 mmol) and 1,1-dimethyl-2-methoxyethylamine (30 mL, 0.5M methanol sol., 15 mmol) was stood at room temperature for 1 week. The reaction mixture was concentrated and partitioned between ethyl acetate and water. Organic layer was washed with water and brine, dried over MgSO4 and concentrated. The residue was purified on 50 g of silica gel column eluting with 50% ethyl acetate in hexane to obtain the title compound (176 mg) as a white solid.
Reaction SMILES: CC1(C)CO[CH:5]([CH:8]([C@@H:10]2[C@:27]3([CH3:28])[C@H:13]([C:14]4[C@H:24]([CH2:25][CH2:26]3)[C@:22]3([CH3:23])[C:17]([CH2:18][C@@H:19]([O:39][C:40](=[O:43])[NH:41][CH3:42])[CH2:20][C@@H:21]3[O:29][C:30](=[O:38])[NH:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:16][CH:15]=4)[CH2:12][CH2:11]2)[CH3:9])[O:4]C1.Cl>C(O)C>[CH3:42][NH:41][C:40]([O:39][C@H:19]1[CH2:20][C@H:21]([O:29][C:30](=[O:38])[NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@@:22]2([CH3:23])[C:17](=[CH:16][CH:15]=[C:14]3[C@@H:24]2[CH2:25][CH2:26][C@@:27]2([CH3:28])[C@H:13]3[CH2:12][CH2:11][C@@H:10]2[CH:8]([CH:5]=[O:4])[CH3:9])[CH2:18]1)=[O:43]
Reactant: CNC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C5OCC(C)(C)CO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)Nc2ccccc2)C1
Agent: Cl
Solvent: CCO
Product: CNC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)Nc2ccccc2)C1
Temperature: 40 °C
Reaction time: 3 h
Yield: 57.7 %

Procedure:
In 5 ml of ethanol was dissolved 105 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α-(N-phenylcarbamoyl)oxy-3β-(N-methylcarbamoyl)oxypregna-5,7-diene, followed by addition of 1 ml of 3N-hydrochloric acid, and the mixture was stirred in an atmosphere of argon gas at 40° C. for 3 hours. The reaction mixture was then worked up in the same manner as Example 156 to give 52 mg of 3β-(N-methylcarbamoyl)oxy-1α-(N-phenylcarbamoyl)oxypregna-5,7-diene-20-carbaldehyde showing the following physical properties.
Reaction SMILES: [H-].[Na+].[PH4+].[Br-].F[C:6](F)([CH2:28][C:29]([OH:31])=[O:30])[CH2:7][CH2:8][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.S(=O)(=O)(O)[O-].[K+].[OH2:39]>C1C=CC=CC=1.CS(C)=O>[O:39]1[CH2:29][CH2:28][CH2:6][CH2:7][CH:8]1[O:31][CH:29]1[CH2:28][CH2:6][CH2:7][CH2:8][O:30]1
Reactant: O=C(O)CC(F)(F)CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O
Agent: O=S(=O)([O-])O
Agent: [Br-]
Agent: [H-]
Solvent: c1ccccc1
Solvent: CS(C)=O
Product: C1CCC(OC2CCCCO2)OC1
Reaction time: 0.25 h

Procedure:
The free acid prepared from the lactol of Preparation 95 which is of the same epimeric configuration at the 3 position of its side chain as the desired configuration at C-15 position of the prostaglandin-type product of this example. The reaction of this part is carried out under an atmosphere of nitrogen with exclusion of moisture. 20 ml. of dimethyl sulfoxide is added to 0.88 g. of a 50 percent sodium hydride dispersion in mineral oil. The mixture is stirred and heated at 70° to 80° C. for 1 hour, then cooled in an ice bath. 4.4 g. of the phosphonium salt of Example A, (3,3-difluoro-4-carboxybutyl)triphenylphosphonium bromide, is added with stirring. The ice bath is removed and stirring is continued for 15 min. 2 g. of the lactol of Preparation 95 dissolved in 5 ml. of dimethyl sulfoxide and 5 ml. of benzene is added dropwise, followed by 10 ml. of benzene. Stirring is continued for 1.5 hr. The reaction mixture is then diluted with 200 ml. of benzene and a solution of 3 g. of potassium bisulfate in 75 ml. of water. The layers are separated and the aqueous layer is extracted twice with 100 ml. of benzene. The organic solutions are combined and washed twice with 50 ml. of water. The water is backwashed with 100 ml. of benzene, and the combined benzene solutions are then dried over sodium sulfate. Filtration and evaporation of solvent yields the bis-tetrahydropyranyl ether of 2,2-difluoro-PGF2α.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][NH:14][CH2:13][CH:12]([C:16]([O:18][CH3:19])=[O:17])[CH2:11]2)=[CH:6][CH:5]=1.C(N(CC)CC)C.Cl[C:30]([O:32][C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=1)=[O:31]>ClCCl>[F:21][C:2]([F:1])([F:20])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][N:14]([C:30]([O:32][C:33]3[CH:34]=[CH:35][C:36]([N+:39]([O-:41])=[O:40])=[CH:37][CH:38]=3)=[O:31])[CH2:13][CH:12]([C:16]([O:18][CH3:19])=[O:17])[CH2:11]2)=[CH:6][CH:5]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)C1CNCC(c2ccc(CC(F)(F)F)cc2)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1CC(c2ccc(CC(F)(F)F)cc2)CN(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 6.62 g (19.8 mmol, purity 90%) of the compound from Example 42A in dichloromethane (211 ml) was admixed with 9.65 ml (7.00 g, 69.2 mmol) of triethylamine and then admixed at 0° C. with 3.99 g (19.8 mmol) of 4-nitrophenyl chloroformate. The mixture was warmed to RT and stirred for 1 h. The reaction solution was washed with saturated aqueous sodium hydrogencarbonate solution and water, and the organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. Yield: 10.3 g (91% of theory, purity 81%)