Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:25])[CH2:7][CH2:6][C:5]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])(O)[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[F:35][CH:36]1[CH2:40][NH:39][CH:38]([CH2:41][OH:42])[CH2:37]1>>[F:1][C:2]1([F:25])[CH2:7][CH2:6][CH:5]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:39]4[CH2:40][CH:36]([F:35])[CH2:37][CH:38]4[CH2:41][OH:42])=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:4][CH2:3]1
Reactant: OCC1CC(F)CN1
Reactant: O=C(NCC1(O)CCC(F)(F)CC1)c1c(Cl)ccc2nc(Cl)ccc12
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(N3CC(F)CC3CO)ccc12

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluoro-1-hydroxycyclohexylmethyl)-amide, DIPEA and 4-fluoro-2-hydroxymethyl-pyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.75 (1H), 7.48 (2H), 6.69 (1H), 5.33-5.52 (1H), 4.31 (m, 1H), 3.89 (m, 1H), 3.70 (m, 3H), 3.55 (m, 1H), 3.26 (m, 2H), 2.44 (m, 2H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27-1.32 (m, 2H). m/z: 456 [M+H]
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([NH:15]C(=O)OCC2C=CC=CC=2)[C@H:11](/[CH:26]=[CH:27]\[CH3:28])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:29]([NH:39][C@H:40]([C:45]([OH:47])=O)[CH2:41][CH2:42][S:43][CH3:44])([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30].CN1CCOCC1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CCO.[OH-].[Pd+2].[OH-].CCOC(C)=O>[Si:1]([O:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([NH:15][C:45](=[O:47])[C@@H:40]([NH:39][C:29](=[O:30])[O:31][CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:41][CH2:42][S:43][CH3:44])[C@H:11]([CH2:26][CH2:27][CH3:28])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: CSCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: C/C=C\[C@@H]1C[C@H](O[Si](C)(C)C(C)(C)C)CC[C@@H]1NC(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCC[C@@H]1C[C@H](O[Si](C)(C)C(C)(C)C)CC[C@@H]1NC(=O)[C@H](CCSC)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 22 h
Yield: 62.9 %

Procedure:
A solution of benzyl (1S,2S,4R)-4-(tert-butyldimethylsilyloxy)-2-((Z)-prop-1-enyl)cyclohexylcarbamate (0.3 g, 0.74 mmol) in 10 mL of 7:3 EtOH:EtOAc was charged with palladium hydroxide and stirred under hydrogen atmosphere for 22 h. The palladium was removed by filtration and the solution was charged with fresh palladium hydroxide before again being placed under hydrogen atmosphere (5 kg pressure). After 3 h, the mixture was filtered through celite with EtOAc washings and concentrated in vacuo. The residue was dissolved in DMF (3 mL) and the resultant solution was cooled to 0° C. before being charged successively with (S)-Cbz methionine (0.31 g, 1.1 mmol), N-methyl morpholine (0.24 mL, 2.2 mmol), and BOP reagent (0.48 g, 1.1 mmol). The reaction was slowly warmed to 30° C. and then stirred for 12 h before being quenched water. The mixture was extracted with EtOAc, and the combined organic phases were washed with brine, dried, filtered, and concentrated in vacuo. The residue was purified by flash chromatography to afford benzyl (S)-1-((1S,2R,4R)-4-(tert-butyldimethylsilyloxy)-2-propylcyclohexylamino)-4-(methylthio)-1-oxobutan-2-ylcarbamate (0.25 g). blah, blah. MS found: (M+H)+=537.
Reaction SMILES: [P:1]([O:19][CH2:20][C:21]([CH3:26])([CH3:25])[CH2:22][CH2:23][OH:24])([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:28].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[CH2:4]([O:3][P:1]([O:19][CH2:20][C:21]([CH3:26])([CH3:25])[CH2:22][C:23]([OH:28])=[O:24])([O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:2])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: CC(C)(CCO)COP(=O)(OCc1ccccc1)OCc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Product: CC(C)(COP(=O)(OCc1ccccc1)OCc1ccccc1)CC(=O)O
Reaction time: 48 h
Yield: 85.1 %

Procedure:
To a solution of the product from Example 9B (0.396 g, 1.0 mmol) in DMF (10 mL) at room temperature was added pyridinium dichromate (2.3 g), and the mixture was stirred for 48 hours. 10% citric acid was added and the reaction was extracted twice with ethyl acetate. The combined organic layer was washed with brine, dried over MgSO4, filtered and evaporated. The residue was purified by chromatography on silica gel, eluting with a gradient of 0-5% methanol in chloroform, to give the title compound (0.334 g, 81%).
Reaction SMILES: C12(COC3C(C4CC4)=CC(C(O)=O)=CN=3)CC3CC(CC(C3)C1)C2.[C@@H:25]12[CH2:31][C@@H:28]([CH2:29][CH2:30]1)[CH2:27][C@H:26]2[O:32][C:33]1[C:41]([CH:42]2[CH2:44][CH2:43]2)=[CH:40][C:36]([C:37](O)=[O:38])=[C:35]([F:45])[CH:34]=1.COC[CH2:49][S:50]([NH2:53])(=[O:52])=[O:51].CS(N)(=O)=O>>[C@@H:25]12[CH2:31][C@@H:28]([CH2:29][CH2:30]1)[CH2:27][C@H:26]2[O:32][C:33]1[C:41]([CH:42]2[CH2:44][CH2:43]2)=[CH:40][C:36]([C:37]([NH:53][S:50]([CH3:49])(=[O:52])=[O:51])=[O:38])=[C:35]([F:45])[CH:34]=1
Reactant: O=C(O)c1cc(C2CC2)c(O[C@@H]2C[C@@H]3CC[C@H]2C3)cc1F
Reactant: COCCS(N)(=O)=O
Agent: CS(N)(=O)=O
Agent: O=C(O)c1cnc(OCC23CC4CC(CC(C4)C2)C3)c(C2CC2)c1
Product: CS(=O)(=O)NC(=O)c1cc(C2CC2)c(O[C@@H]2C[C@@H]3CC[C@H]2C3)cc1F
Yield: 64 %

Procedure:
Following the procedure as described in Example 271 and making variations as required to replace 6-(adamantan-1-ylmethoxy)-5-cyclopropylnicotinic acid with 4-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-yloxy)-5-cyclopropyl-2-fluorobenzoic acid and to replace 2-methoxyethanesulfonamide with methyl sulfonamide. Purification by silica gel column chromatography (2:1 hexanes:ethyl acetate (+0.2% acetic acid v/v)) gave the title compound as a colorless solid (0.080 g, 64%): 1H NMR (300 MHz, DMSO-d6) δ 11.82 (br s, 1H), 7.10 (d, J=8.3 Hz, 1H), 6.83 (d, J=13.1 Hz, 1H), 4.81-4.72 (m, 1H), 3.29 (s, 3H), 2.59-2.54 (m, 1H), 2.25-2.19 (m, 1H), 2.17-2.05 (m, 1H), 2.04-1.92 (m, 1H), 1.91-1.78 (m, 1H), 1.61-1.48 (m, 1H), 1.46-1.17 (m, 4H), 0.97-0.80 (m, 3H), 0.67-0.60 (m, 2H); MS (ES+) m/z 368.09 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:19])[N:8]([CH3:18])[C:9]2[C:14]([C:15]=1Cl)=[CH:13][C:12]([Cl:17])=[CH:11][CH:10]=2)=[O:5])[CH3:2].[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>O>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:19])[N:8]([CH3:18])[C:9]2[C:14]([C:15]=1[N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)=[CH:13][C:12]([Cl:17])=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(Cl)c2cc(Cl)ccc2n(C)c1=O
Reactant: C1COCCN1
Solvent: O
Product: CCOC(=O)c1c(N2CCOCC2)c2cc(Cl)ccc2n(C)c1=O

Procedure:
A solution of 200 mg. of 4,6-dichloro-1,2-dihydro-1-methyl-2-oxo-3-quinolinecarboxylic acid ethyl ester, (prepared in Example 4) in 1 ml. of morpholine was heated in a test tube for a few minutes and then was poured into 40 ml. of water. The resulting precipitate was collected and washed with water. Recrystallization from ethanol gave the title compound with m.p. 167°-169° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[S:10]([NH:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[S:21][CH2:22][C:23]1[CH:24]=[C:25]([NH:29][C:30](=[O:32])[CH3:31])[CH:26]=[CH:27][CH:28]=1)(=[O:12])=[O:11].C1C=C(Cl)C=C(C(OO)=[O:41])C=1>C(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[S:10]([NH:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[S:21]([CH2:22][C:23]1[CH:24]=[C:25]([NH:29][C:30](=[O:32])[CH3:31])[CH:26]=[CH:27][CH:28]=1)=[O:41])(=[O:11])=[O:12]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)Nc1cccc(CSc2ccc(Cl)cc2NS(=O)(=O)c2cc3ccccc3o2)c1
Solvent: ClCCl
Product: CC(=O)Nc1cccc(CS(=O)c2ccc(Cl)cc2NS(=O)(=O)c2cc3ccccc3o2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.6 %

Procedure:
To a solution of N-{3-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfanyl)methyl]phenyl}acetamide (105 mg, 0.216 mmol) in CH2Cl2 (3 ml) was added mCPBA (52 mg, ˜0.216 mmol) and the reaction was stirred at room temperature for 1 hour. The reaction mixture was directly loaded onto Celite and purified by flash column chromatography on silica gel (50-100% EtOAc in hexane) to yield the title compound (55 mg, 51%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][S:14][C:15]2[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=2)[C:8]=1[CH3:24].[OH-].[Na+].ClN1C(=[O:33])CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C([O-])(=O)C.[NH4+].[Cl-].[Na+]>CN(C)C=O.O.C(OCC)(=O)C>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][S:14]([C:15]2[NH:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)=[O:33])[C:8]=1[CH3:24]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COCCCOc1ccnc(CSc2nc3ccccc3[nH]2)c1C
Agent: CC(=O)[O-]
Agent: O=S([O-])([O-])=S
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COCCCOc1ccnc(CS(=O)c2nc3ccccc3[nH]2)c1C
Reaction time: 0.03 h
Yield: 90.6 %

Procedure:
2-{[4-(3-Methoxypropoxy)-3-methylpyridin-2-yl]methylthio}-1H-benzimidazole (5.0 g 14.6 mmol; referred to as Compound I hereinafter) was dissolved in 20 ml of N,N-dimethylformamide, followed by the addition of a 2N aqueous solution of sodium hydroxide (18 ml). A solution (10 ml) of N-chlorosuccinimide (2.71 g, 20.3 mmol) in N,N-dimethylformamide was added dropwise to the solution at −20° C. to −10° C. The reaction mixture was reacted at −15° C. to −7° C. for 1.5 hr. To the reaction mixture was added a 10% aqueous solution of sodium thiosulfate (5 ml), stirred for 2 min and then, a solution (60 ml) of ammonium acetate (23.1 g) in water was added thereto. 60 ml of ethyl acetate and 10 g of sodium chloride were added thereto to extract the reaction mixture, and the aqueous layer was further extracted with ethyl acetate (40 ml). The organic layers were combined, washed with a 15% aqueous solution of sodium chloride (80 ml) for three times and then, the solvent was evaporated. To the resulting oil was added 12 ml of ethyl acetate, 28 ml of hexane and 10 ml of toluene, followed by stirring at room temperature for 1 hr. The resulting crystals were collected by filtration, washed with a solvent mixture (10 ml) of 30% ethyl acetate and hexane for two times and then, dried under reduced pressure, to give the title compound (4.7 g, yield; 90.6%) as grayish white crystals.
Reaction SMILES: C[O:2][CH2:3][C@@H:4]([O:6][C:7]1[CH:8]=[C:9]([C:24]2[NH:28][C:27]([C:29]3[O:30][CH2:31][C@@H:32]([CH:34]([OH:36])[CH3:35])[N:33]=3)=[CH:26][CH:25]=2)[CH:10]=[C:11]([O:13][C:14]2[CH:19]=[N:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][N:15]=2)[CH:12]=1)[CH3:5].B(Br)(Br)Br.C(=O)([O-])O.[Na+]>C(Cl)Cl>[OH:36][C@@H:34]([C@@H:32]1[CH2:31][O:30][C:29]([C:27]2[NH:28][C:24]([C:9]3[CH:8]=[C:7]([CH:12]=[C:11]([O:13][C:14]4[CH:19]=[N:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][N:15]=4)[CH:10]=3)[O:6][C@@H:4]([CH3:5])[CH2:3][OH:2])=[CH:25][CH:26]=2)=[N:33]1)[CH3:35]
Reactant: COC[C@H](C)Oc1cc(Oc2cnc(S(C)(=O)=O)cn2)cc(-c2ccc(C3=N[C@H](C(C)O)CO3)[nH]2)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H](CO)Oc1cc(Oc2cnc(S(C)(=O)=O)cn2)cc(-c2ccc(C3=N[C@H]([C@@H](C)O)CO3)[nH]2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 71 %

Procedure:
(1R)-1-{[(4S)-2-(5-(3-{[(2S)-1-Methoxypropan-2-yl]oxy}-5-{[5-(methylsulfonyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-yl}ethanol (213 mg, 0.412 mmol) synthesized in Example (114d) was dissolved in methylene chloride (5.0 mL), and boron tribromide (1.0 mol/L methylene chloride solution, 0.80 mL, 0.80 mmol) was added dropwise at −78° C., followed by stirring at room temperature for 1.5 hours under nitrogen atmosphere. To this reaction solution, a saturated aqueous sodium hydrogencarbonate solution (10 mL) was added, and extraction was carried out with methylene chloride (20 mL). The organic layer was washed with 1N aqueous sodium hydroxide solution (10 mL), and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=4%-5%) to afford the desired compound (147 mg, yield 71%) as a white solid.
Reaction SMILES: CO/[CH:3]=[C:4]1/[C:5](=[O:15])[NH:6][C:7](=[O:14])[C:8]2[C:13]/1=[CH:12][CH:11]=[CH:10][CH:9]=2.[N:16]1([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>>[N:16]1([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([NH:29]/[CH:3]=[C:4]3\[C:5](=[O:15])[NH:6][C:7](=[O:14])[C:8]4[C:13]\3=[CH:12][CH:11]=[CH:10][CH:9]=4)=[CH:25][CH:24]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccccc21
Reactant: Nc1ccc(CN2CCOCC2)cc1
Product: O=C1NC(=O)c2ccccc2/C1=C/Nc1ccc(CN2CCOCC2)cc1
Yield: 18.7 %

Procedure:
Using the procedure described for the preparation of example 14, 100 mg (15% yield) of a yellow solid from 300 mg (1.47 mmol) of (4E)-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione and 4-morpholin-4-ylmethyl-phenylamine 283.5 mg (1.47 mmol); mp 221-2MS (ESI) m/z 463.1 (M−1).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([OH:20])=[C:12]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:11]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:2]1([CH2:1][O:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([O:20][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:12]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:11]=2[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1c(C(=O)OCC)c(O)c2ccccc2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1c(C(=O)OCC)c(OCc2ccccc2)c2ccccc2c1OCc1ccccc1
Yield: 109.4 %

Procedure:
Benzylbromide (2.95 ml, 24.7 mmol) was added to a stirred solution of diethyl 1,4-dihydroxy-2,3-naphthalenedicarboxylate (3 g, 9.87 mmol) and potassium carbonate (3.40 g, 24.7 mmol) in acetone (100 ml). The reaction mixture was refluxed for 18 hours under an atmosphere of argon. The resulting mixture was evaporated and the reaction mixture triturated with water. The resulting tan coloured solid was collected by filtration and washed with water then dried under vacuum to give the title compound (5.23 g, 10.8 mmol). LC/MS: Rt=4.13, [MH]+ 485.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[CH:6][C:7]=1[F:8].[N+:10]([O-])([O-:12])=[O:11].[NH4+].FC(F)(F)C(O)=O.[OH-].[Na+]>>[F:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([N+:10]([O-:12])=[O:11])[C:7]=1[F:8]
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1ccc(F)c(F)c1
Agent: [NH4+]
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(F)c(F)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 38 %

Procedure:
3,4-Difluorotoluene (9.00 g, 70.3 mmol), ammonium nitrate (6.75 g, 84.3 mmol) and trifluoroacetic acid (25 ml) were stirred at ambient temperature for 18 h. The resulting solution was made basic to pH>10 with 5 N sodium hydroxide and, after cooling to ambient temperature, extracted with diethyl ether (3×40 ml). The combined organic layers were washed with brine (40 ml) and dried over anhydrous sodium sulfate. The filtrate was concentrated in vacuo. The crude product was purified by silica gel column chromatography, eluting with hexanes/ethyl acetate (9:1), to afford 3,4-difluoro-5-nitrotoluene (4.63 g, 40%) as a light yellow oil. 1H-NMR δ(400 MHz, CDCl3) 7.94 (1H, dd, J=9.9, 7.3 Hz), 7.17 (1H, dd, J=10.3, 7.6 Hz), 2.61 (3H, s).
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]1[CH:30]=[CH:29][C:7]([CH2:8][CH2:9][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:6][CH:5]=1.[Li]CCCC.[CH:36]([C:39]1[CH:40]=[C:41]([CH:45]([CH3:49])[CH2:46][CH:47]=O)[CH:42]=[CH:43][CH:44]=1)([CH3:38])[CH3:37]>>[CH:36]([C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([CH:45]([CH2:46][CH:47]=[CH:9][CH2:8][C:7]2[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:30][CH:29]=2)[CH3:49])[CH:40]=1)([CH3:38])[CH3:37]
Reactant: CC(C)c1cccc(C(C)CC=O)c1
Reactant: COc1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Li]CCCC
Product: COc1ccc(CC=CCC(C)c2cccc(C(C)C)c2)cc1
Yield: 25.8 %

Procedure:
Starting from p-methoxyphenethyltriphenylphosphonium bromide (1.20 g, 2.51 mmol, 1.0 equiv.), n-BuLi (1.6 M in hexanes, 1.6 mL, 2.51 mmol, 1.0 equiv.) and 3-(3-isopropylphenyl)butanal (0.72 g, 3.77 mmol, 1.5 equiv.), 0.20 g (26%) of the title compound as a yellow oil was obtained after purification by flash chromatography on SiO2 (cyclohexane/EtOAc 99:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][CH2:11][C:12]([CH3:15])([CH3:14])[N:13]=2)=[CH:5][CH:4]=1.N#N.C([Li])CCC.[Li].[C:24](Cl)(=[O:27])[CH2:25][CH3:26]>C(OCC)C.CCCCCC.[Cl-].[Cl-].[Zn+2].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:14][C:12]1([CH3:15])[CH2:11][O:10][C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][C:7]=2[C:24](=[O:27])[CH2:25][CH3:26])=[N:13]1
Reactant: CCC(=O)Cl
Reactant: COc1ccc(C2=NC(C)(C)CO2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: N#N
Solvent: CCCCCC
Solvent: CCOCC
Product: CCC(=O)c1cc(OC)ccc1C1=NC(C)(C)CO1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 115.3 %

Procedure:
A solution of 2-(4-methoxy-phenyl)-4,4-dimethyl-4,5-dihydro-oxazole (4.5 g, 21.9 mmoles), prepared as described in example 1, in dry ethyl ether (90 ml), under stirring and N2 at 0° C., was added with 2.5M n-butyl lithium (9.6 ml, 24.1 mmoles) in hexane. The reaction went on for 4 hours. In another flask a suspension of ZnCl2 (4.48 g, 33 mmoles) in dry ethyl ether (60 ml) was prepared and, at 0° C., dropwise added with the solution of the lithium derivative. At the end of the addition, the mixture was left at room temperature for 1.5 hours, then cooled to 0° C. and sequentially added with palladium acetate (0.25 g, 1.09 mmoles), triphenylphosphine (0.57 g, 2.19 mmoles) and, after 5 minutes, with propanoyl chloride (2.13 g, 23.02 mmoles). The mixture was left to stand for 20 hours, then poured into water/ice and extracted with ethyl acetate. The organic phase was anhydrified, discoloured and brought to dryness to give 6.6 g of the title compound (yield: 75%)
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH2:13][CH2:12]1.C(N(C(C)C)CC)(C)C.[Cl:32][C:33](Cl)([O:35]C(=O)OC(Cl)(Cl)Cl)Cl.ClC(Cl)C.Cl>O1CCOCC1>[ClH:32].[O:35]=[C:33]1[NH:1][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[N:10]1[CH:11]1[CH2:12][CH2:13][N:14]([CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH2:15][CH2:16]1
Reactant: N#Cc1ccc(N)c(NC2CCN(C3CCOCC3)CC2)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: CC(Cl)Cl
Product: N#Cc1ccc2[nH]c(=O)n(C3CCN(C4CCOCC4)CC3)c2c1
Reaction time: 0.08 h

Procedure:
4-Amino-3-{[1-(tetrahydro-2H-pyran-4-yl)-4-piperidinyl]amino}benzonitrile (D59, 240 mg, 0.0008 mol, 1 eq), diisopropylethylamine (140 mg, 0.00104 mol, 1.3 eq), triphosgene (70 mg, 0.00024 mol, 0.3 eq), and dichloroethane (20 ml) were combined. After 5 min, 4 ml of 4M HCl in dioxane were added, the reaction evaporated, the residue dissolved in methanol and purified exactly as in Example 1, where A=H2O and B=CH3CN to produce the title compound as a white solid. MS (ESI): 327 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[C:9](/[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:10]/[CH:11]=O)=[CH:5][CH:4]=1.[C:19]([CH:23]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:21][CH3:22])=[O:20]>C(Cl)(Cl)(Cl)Cl.ClCCl>[CH3:22][O:21][C:19](=[O:20])/[CH:23]=[CH:11]/[CH:10]=[C:9](/[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)\[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COc1ccc(/C(=C/C=O)c2ccccc2)cc1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)/C=C/C=C(\c1ccccc1)c1ccc(OC)cc1
Yield: 80 %

Procedure:
As described in Example 99, (E)-3-(4-methoxyphenyl)-3-phenyl-2-propenal (8.7 g) was reacted with (carbomethoxymethylene)triphenylphosphorane (14.2 g) in carbon tetrachloride (50 mL) and dichloromethane (5 mL) overnight at room temperature. The crude ester was isolated in the usual manner and was purified by HPLC (ether-hexane; 3:17) to yield 8.6 g of (E,E)-5-(4-methoxyphenyl)-5-phenyl-2,4-pentadienoic acid methyl ester. Crystallization of a portion from ethyl acetate-hexane gave the analytical specimen, mp 88°-89.5° C. Anal. Calcd for C19H18O3 : C, 77.53; H, 6.19 Found: C, 77.40; H. 6.18
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)=[CH:13][CH:12]=2)=[O:7])CCC.[NH2:27][C@H:28]([C:30]([OH:32])=[O:31])[CH3:29]>>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([O:19][C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[CH:10]=[N:9][C:8]([C:6]([NH:27][C@@H:28]([CH3:29])[C:30]([OH:32])=[O:31])=[O:7])=[C:17]3[OH:18])=[CH:21][CH:22]=1
Reactant: CCCCOC(=O)c1ncc2ccc(Oc3ccc(Cl)cc3)cc2c1O
Reactant: C[C@H](N)C(=O)O
Product: C[C@H](NC(=O)c1ncc2ccc(Oc3ccc(Cl)cc3)cc2c1O)C(=O)O

Procedure:
Prepared in analogy to Example A-50 by reacting 6-(4-Chloro-phenoxy)-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester (compound of Example A-60 b) with L-alanine in a microwave reactor for 25 min at 130° C. MS-(−)-ion: M−1=385.1
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][C@H:11]3[CH2:15][N:14](C(OC(C)(C)C)=O)[C@H:13]([CH2:23][NH:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH2:12]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[ClH:30]>ClCCl.O1CCOCC1>[ClH:30].[CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][C@H:11]3[CH2:15][NH:14][C@H:13]([CH2:23][NH:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH2:12]3)=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: COC(=O)CNC[C@@H]1C[C@@H](Oc2cnc(C3CC3)cn2)CN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=O)CNC[C@@H]1C[C@@H](Oc2cnc(C3CC3)cn2)CN1
Reaction time: 0.5 h

Procedure:
A solution of the product from Example 174E (1.10 g, 2.71 mmol) in dichloromethane (3 mL) was treated with hydrochloric acid in 1,4-dioxane (4 M, 3 mL). The mixture was stirred for 30 minutes, during which time a solid formed. The volatiles were removed in vacuo to give the title compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[CH2:14][CH2:13][N:12]=[C:11]2[NH2:15])=[CH:5][CH:4]=1.[N:16](=[C:18]([C:24]#[N:25])[C:19](OCC)=[O:20])[OH:17]>>[NH2:25][C:24]1[N:15]=[C:11]2[N:10]([CH2:9][C:6]3[CH:5]=[CH:4][C:3]([Cl:2])=[CH:8][CH:7]=3)[CH2:14][CH2:13][N:12]2[C:19](=[O:20])[C:18]=1[N:16]=[O:17]
Reactant: CCOC(=O)C(C#N)=NO
Reactant: NC1=NCCN1Cc1ccc(Cl)cc1
Agent: Cl
Product: Nc1nc2n(c(=O)c1N=O)CCN2Cc1ccc(Cl)cc1

Procedure:
The product of Procedure 91 was condensed with ethyl oximinocyanoacetate according to the method described in Procedure 1. The crude product, 1.6 g., from 2.9 g. of the product of Procedure 91, was a blue solid, m.p. 273°-275° d, recrystallized from dimethylformamide, m.p. 290°-291° d.