Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([OH:15])[CH2:9][CH2:10][C:11](OC)=[O:12])=[CH:4][C:3]=1[CH3:16]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:15][C:11](=[O:12])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[CH3:16]
Reactant: COC(=O)CC[C@@H](O)c1ccc(F)c(C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc([C@H]2CCC(=O)O2)ccc1F
Temperature: 40 °C
Reaction time: 16 h
Yield: 112.5 %

Procedure:
To a solution of (R)-methyl 4-(4-fluoro-3-methyl-phenyl)-4-hydroxy-butanoate (289 mg) in 20 mL DCM was added 4 drops TFA at room temperature and the resulting solution warmed to 40° C. After stirring for 16 h the reaction was cooled to room temperature and concentrated under reduced pressure. The product was isolated by flash column chromatograph eluting with 0% to 30% ethyl acetate/hexane gradient solvent to give 279 mg of (R)-5-(4-fluoro-3-methyl-phenyl)-dihydro-furan-2-one as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].[C:14](=O)([O:17]C)[O:15][CH3:16].C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O>[C:10]([CH:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[C:14]([O:15][CH3:16])=[O:17])#[N:11]
Reactant: COc1cccc(CC#N)c1
Reactant: COC(=O)OC
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C(C#N)c1cccc(OC)c1

Procedure:
Twenty five grams of (3-methoxyphenyl)acetonitrile are dissolved in 200 ml of anhydrous THF in an Erlermeyer ground-necked flask. 60% sodium hydride (8.88 g; 0.37 mol) is added to the solution and the reaction mixture is heated at reflux for 30 minutes with stirring. Dimethyl carbonate (58 ml; 0.6814 mol) is then added dropwise in the course of half an hour and the reaction mixture is subsequently heated at reflux for 2 hours with stirring. The reaction mixture is poured into cold and slightly acidic water. The aqueous phase is extracted with ether, and then the ethereal phase is washed with water before being evaporated. A solution of potassium carbonate (47.15 g; 0.34 mol ) is added to the oil obtained above. After stirring, the mixture is washed with ether. The ethereal phase obtained is rewashed with a solution of potassium carbonate (12.02 g; 0.08 mol). The two aqueous phases are combined, immediately acidified, and extracted with ether. The organic phase so obtained is washed with a 10% sodium hydrogen carbonate solution, dried over magnesium sulphate and evaporated under reduced pressure to yield the title product in the form of an orangey yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([CH:14]([CH3:16])[CH3:15])[C:12](SC)=[N:11][CH:10]=2)=[CH:5][CH:4]=1>[Ni].C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([CH:14]([CH3:16])[CH3:15])[CH:12]=[N:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cnc(SC)n2C(C)C)cc1
Agent: [Ni]
Solvent: CCO
Product: COc1ccc(-c2cncn2C(C)C)cc1

Procedure:
A mixture of 7.5 parts of 5-(4-methoxyphenyl)-1-(1-methylethyl)-2-(methylthio)-1H-imidazole, 10 parts of Raney-nickel catalyst and 80 parts of ethanol is stirred and refluxed for 2 h. The catalyst is filtered off and another 10 parts of Raney-nickel catalyst is added. The whole is stirred for 2 hours at reflux temperature. The Raney-nickel catalyst is filtered off and the filtrate is evaporated, yielding 4 parts of 5-(4-methoxyphenyl)-1-(1-methylethyl)-1H-imidazole as a solid residue.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8](=S)[NH:7][C:6]=2[CH:17]=1.[NH2:18][CH2:19][CH2:20][CH2:21][N:22]1[CH:26]=[CH:25][N:24]=[CH:23]1>C(OCCO)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8]([NH:18][CH2:19][CH2:20][CH2:21][N:22]3[CH:26]=[CH:25][N:24]=[CH:23]3)=[N:7][C:6]=2[CH:17]=1
Reactant: S=C1Nc2cc(Cl)ccc2Nc2ccccc21
Reactant: NCCCn1ccnc1
Solvent: CCOCCO
Product: Clc1ccc2c(c1)N=C(NCCCn1ccnc1)c1ccccc1N2
Yield: 62.5 %

Procedure:
A solution of 0.6 g (2.3 mmol) of 8-chloro-5,10-dihydro-dibenzo[b,e][1,4]diazepin-11-thione in 15 mL of 2-ethoxyethanol was treated with 0.6 mL (4.6 mmol) of 1-(3-aminopropyl)imidazole and heated at reflux for 3 days. The solvent was removed under reduced pressure and the residue taken up in EtOAc and washed four times with H2O, then saturated NaHCO3 solution, and saturated NaCl solution. Drying over MgSO4 and removal of the solvent under reduced pressure left the crude product. Trituration with EtOAc/hexane followed by recrystallization from acetone/water gave 506 mg (62.6% yield) of the pure product as a golden solid, mp 228-230° C. The structure was confirmed by NMR and mass spectroscopy. (m+H)+ =352.
Reaction SMILES: [CH2:1]([O:17][CH2:18][CH:19]([O:22][CH3:23])[CH2:20][OH:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[P:24](Cl)([Cl:33])([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:25].ClCCl>C(N(CC)CC)C>[P:24]([Cl:33])(=[O:25])([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[O:21][CH2:20][CH:19]([O:22][CH3:23])[CH2:18][O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCOCC(CO)OC
Reactant: O=P(Cl)(Cl)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCOCC(COP(=O)(Cl)Oc1ccccc1)OC
Temperature: 5 °C
Reaction time: 1 h

Procedure:
A 1 mmol portion of 3-(hexadecyloxy)-2-methoxy propanol is added to a 0°-5° C. solution of 1 mmol of phenyl dichlorophosphate in 2 ml of anhydrous dichloromethane containing 1.2 mmol of triethylamine. The mixture is stirred under argon for 1 hour at 5° C., then for 2.5 hours at room temperature and then used as is.
Reaction SMILES: [CH3:1][C@@H:2]1[C@H:20]([OH:21])[C@@H:19]([CH3:22])[C:17](=[O:18])[C:16]([CH3:24])([CH3:23])[C@@H:15]([OH:25])[CH2:14][C:12](=[O:13])[O:11][C@H:10](/[C:26](/[CH3:35])=[CH:27]/[C:28]2[N:32]=[C:31]([CH2:33]O)[S:30][CH:29]=2)[CH2:9][C@@H:7]2[O:8][C@:6]2([CH3:36])[CH2:5][CH2:4][CH2:3]1.C1(P([N:51]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2.[NH4+].[Br-].[NH4+].[OH-].CP(C)C>O1CCCC1.CCOC(C)=O>[CH3:1][C@@H:2]1[C@H:20]([OH:21])[C@@H:19]([CH3:22])[C:17](=[O:18])[C:16]([CH3:24])([CH3:23])[C@@H:15]([OH:25])[CH2:14][C:12](=[O:13])[O:11][C@H:10](/[C:26](/[CH3:35])=[CH:27]/[C:28]2[N:32]=[C:31]([CH2:33][NH2:51])[S:30][CH:29]=2)[CH2:9][C@@H:7]2[O:8][C@:6]2([CH3:36])[CH2:5][CH2:4][CH2:3]1
Reactant: C/C(=C\c1csc(CO)n1)[C@@H]1C[C@@H]2O[C@]2(C)CCC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: CP(C)C
Agent: [Br-]
Agent: [NH4+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C/C(=C\c1csc(CN)n1)[C@@H]1C[C@@H]2O[C@]2(C)CCC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1
Temperature: 35 °C
Reaction time: 0.08 h
Yield: 100.3 %

Procedure:
To a stirred suspension of epothilone F (2.5 g, 4.77 mmol, 86.2% potency) in tetrahydrofuran (25 ml) was added diphenylphosphoryl azide (1.14 ml, 1.45 g, 5.25 mmol, 1.1 equivalents) at room temperature. The mixture was stirred for approximately 5 min. 1,8-diazabicyclo[5.4.0]undec-7-ene (0.86 ml, 0.87 g, 5.73 mmol, 1.2 equivalents) was then added over 10 min. The mixture was stirred for 10 min. and then allowed to warm to 35° C. and stirred for 6.5 hours. The mixture was cooled to 10° C., and a mixture of aqueous solution of NH4Br (2M, 5 ml) and NH4OH (2M, 5 ml) was added. After the mixture was stirred for 5 min, trimethylphosphine (1M in tetrahydrofuran, 5.01 ml, 5.01 mmol, 1.05 equivalents) was added over 10 min at 10° C. The mixture was allowed to stir at 35° C. for 4 hours and then cooled to room temperature. EtOAc (80 ml) and aqueous NH4OH (1 M, 10 ml) were added. The organic layer was washed with aqueous NH4OH (1 M, 20 ml). The combined aqueous layers were extracted with EtOAc (20 ml). The combined organic layers were washed with H2O (20 ml) and dried over MgSO4. The solvents were removed on a rotary evaporator, and the residue dried in vacuo to provide the crude 21-amino epothilone B (2.5 g) as an off-white solid. The crude 21-amino epothilone B (2.45 g) was crystallized from EtOAc/heptane to give 21-amino epothilone B (1.95 g, 90% yield corrected for input potency) as a white solid.
Reaction SMILES: [CH2:1]([N:13]([CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26](=[O:31])[C:27]([F:30])([F:29])[F:28])=[C:20]([O:32]C)[CH:19]=1)[CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].Br>O>[CH2:1]([N:13]([CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]2[CH2:24][CH2:25][C:26]([C:27]([F:30])([F:29])[F:28])([OH:31])[O:32][C:20]=2[CH:19]=1)[CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCN(C)CCOc1ccc(CCC(=O)C(F)(F)F)c(OC)c1
Agent: Br
Solvent: O
Product: CCCCCCCCCCCCN(C)CCOc1ccc2c(c1)OC(O)(C(F)(F)F)CC2
Temperature: 25 °C
Yield: 39.6 %

Procedure:
A mixture of 4-[4-[2-(N-dodecyl-N-methylamino)ethoxy]-2-methoxyphenyl]-1,1,1-trifluoro-2-butanone (157 mg, 0.33 mmol) and hydrobromic acid (47%, 3 ml) was refluxed for 3.5 h. After cooling to r.t., the mixture was diluted with water, extracted with dichloromethane. The organic layer was washed with sat. sodium bicarbonate, brine, dried over magnesium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel (ethyl acetate/acetone 3:1) to afford the title compound (60 mg, 40%) as a clear oil.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][N:8]=2)=[C:4]([CH3:18])[CH:3]=1.[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][N:8]=2)=[C:4]([CH3:18])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1Oc1ccc([N+](=O)[O-])cn1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(Cl)ccc1Oc1ccc(N)cn1

Procedure:
2-(4-chloro-2-methyl-phenoxy)-5-nitropyridine (203 mg, 0.77 mmol) was dissolved in 95% ethanol (3 mL) and treated with 20% palladium hydroxide on carbon (50 mg). The reaction mixture was shaken in a hydrogen atmosphere (40 psi) for 1 hour. The solution was filtered through celite and concentrated in vacuo . MS (m/z): 234/236 (M+H)+; C12H11N2OCl requires 234.7.
Reaction SMILES: [CH3:1][Si:2]([CH3:17])([CH3:16])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[N:10][N:9]=[C:8]1[C:12]([O:14]C)=[O:13].[OH-].[K+]>CCO>[CH3:1][Si:2]([CH3:17])([CH3:16])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[N:10][N:9]=[C:8]1[C:12]([OH:14])=[O:13]
Reactant: COC(=O)c1nncn1COCC[Si](C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: C[Si](C)(C)CCOCn1cnnc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 127.4 %

Procedure:
To a solution of methyl 4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazole-3-carboxylate (225 mg, 0.874 mmol, 1.00 equiv) in EtOH (1.5 mL) was added aq. KOH (2N, 0.9 mL, 0.87 mmol, 1.0 equiv). After stirring at rt for 1 hr, the reaction mixture was concentrated affording the title compound as a colorless solid (271 mg) (Table 8-30).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:7]([CH2:11][CH3:12])([CH3:10])[CH2:8][CH3:9])=[N:5][N:6]=1.[CH2:13]([C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH3:25])[C:16]=1[C:17](Cl)=[O:18])[CH3:14]>C1(C)C=CC=CC=1>[CH2:8]([C:7]([C:4]1[S:3][C:2]([NH:1][C:17](=[O:18])[C:16]2[C:20]([CH2:24][CH3:25])=[CH:21][CH:22]=[CH:23][C:15]=2[CH2:13][CH3:14])=[N:6][N:5]=1)([CH3:10])[CH2:11][CH3:12])[CH3:9]
Reactant: CCc1cccc(CC)c1C(=O)Cl
Reactant: CCC(C)(CC)c1nnc(N)s1
Solvent: Cc1ccccc1
Product: CCc1cccc(CC)c1C(=O)Nc1nnc(C(C)(CC)CC)s1
Yield: 36.2 %

Procedure:
A solution of 1.85 g of 2-amino-5-(1-ethyl-1-methylpropyl)-1,3,4-thiadiazole and 2.21 g of 2,6-diethylbenzoyl chloride in 50 ml of toluene was heated at reflux for sixteen hours and then cooled and the solvent was removed by evaporation under reduced pressure to provide a solid residue. The solid was crystallized from 2B ethanol to give 1.25 g of N-[5-(1-ethyl-1-methylpropyl)-1,3,4-thiadiazol-2-yl]-2,6-diethylbenzamide.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH:4]1[CH2:9]C[CH2:7][CH2:6][N:5]1[S:10]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1)(=[O:12])=[O:11].OCCC1C[S:30]CCN1.C1(S(Cl)(=O)=O)C2C(=CC=CC=2)C=CC=1>>[Cl:1][CH2:2][CH2:3][CH:4]1[CH2:9][S:30][CH2:7][CH2:6][N:5]1[S:10]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1)(=[O:12])=[O:11]
Reactant: O=S(=O)(c1cccc2ccccc12)N1CCCCC1CCCl
Reactant: OCCC1CSCCN1
Agent: O=S(=O)(Cl)c1cccc2ccccc12
Product: O=S(=O)(c1cccc2ccccc12)N1CCSCC1CCCl
Yield: 70 %

Procedure:
The title compound (300 mg, 70%) was prepared according to the procedure outlined in D1 using 3-(2-hydroxyethyl)thiomorpholine and 1-naphthalenesulfonyl chloride.
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].[CH3:9][C:10](O)([CH3:12])[CH3:11].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:1]([O:8][C:10]([CH3:12])([CH3:11])[CH3:9])(=[O:7])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6]
Reactant: CC(C)(C)O
Reactant: C#CCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C#CCCCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Hex-5-ynoic acid (Compound SP424) (8.0 g, 71.3 mmol), 2-methylpropan-2-ol (10.6 g, 143.0 mmol) and 4-(dimethylamino)pyridine (0.44 g, 3.60 mmol) were dissolved in DCM (17.5 ml), a solution of dicyclohexylcarbodiimide (16.2 g, 78.5 mmol) in DCM (17.5 ml) was added, and the mixture was stirred at room temperature overnight. The white solid in the reaction solution was removed by filtration, after which the filtrate was washed with a 0.5 M aqueous hydrochloric acid solution and a saturated aqueous sodium bicarbonate solution and dried over anhydrous magnesium sulfate. The residue obtained by filtration and concentration under reduced pressure was purified by column chromatography (hexane:ethyl acetate=100:0-90:10) to afford the title compound SP423 (6.73 g, 56.1%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[C:13]([C:20]([O:22]C)=[O:21])=[CH:12][N:11]=1.[OH-].[K+]>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]=[C:14]([C:16]([F:17])([F:18])[F:19])[C:13]([C:20]([OH:22])=[O:21])=[CH:12][N:11]=1
Reactant: COC(=O)c1cnc(Nc2ccc(Cl)cc2Cl)nc1C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cnc(Nc2ccc(Cl)cc2Cl)nc1C(F)(F)F
Yield: 76.1 %

Procedure:
To a solution of methyl 2-(2,4-dichlorophenylamino)-4-trifluoromethyl-pyrimidine-5-carboxylate (0.358 g) in ethanol (8 ml) was added a solution of potassium hydroxide (190 mg) in ethanol (8 ml) and the solution stirred at reflux for 24 h. Ethanol was removed under reduced pressure and water (15 ml) added. The solution was washed with ether and concentrated hydrochloric acid was added to adjust the acidity to pH 1. The precipitated solid was filtered, washed with water and dried in vacuo at 50° C. to afford 2-(2,4-dichlorophenylamino)-4-trifluoromethyl-pyrimidine-5-carboxylic acid (262 mg).
Reaction SMILES: [F:1][C:2]([F:49])([F:48])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[CH:35]=[C:34](B4OC(C)(C)C(C)(C)O4)[CH:33]=[CH:32][C:31]=3[O:45][CH3:46])[C@H:14]2[CH3:47])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Br[C:51]1[CH:60]=[CH:59][C:54]([C:55]([O:57][CH3:58])=[O:56])=[CH:53][C:52]=1[CH3:61].[OH-].[K+]>ClCCl.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[F:1][C:2]([F:48])([F:49])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:28])([F:27])[F:29])[CH:23]=[CH:22][C:21]=3[C:30]3[CH:35]=[C:34]([C:51]4[CH:60]=[CH:59][C:54]([C:55]([O:57][CH3:58])=[O:56])=[CH:53][C:52]=4[CH3:61])[CH:33]=[CH:32][C:31]=3[O:45][CH3:46])[C@H:14]2[CH3:47])[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: COC(=O)c1ccc(Br)c(C)c1
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [K+]
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2ccc(OC)c(-c3ccc(C(F)(F)F)cc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c2)c(C)c1

Procedure:
A mixture of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[2′-methoxy-5′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (60 mg, 0.085 mmol), methyl 4-bromo-3-methylbenzoate (29 mg, 0.128 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium dichloride dichloromethane adduct (28 mg, 30%), aqueous potassium hydroxide (57 μL, 3M, 0.171 mmol) and 1,4-dine (1 mL) was placed in a sealed tube and subjected to microwave irradiation at 140° C. for 15 minutes. The crude reaction was purified by preparative TLC on SiO2 (eluted with 30% EtOAc in hexanes) to afford methyl 2″-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4′-methoxy-2-methyl-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylate as a solid foam. LCMS calc.=725.18; found=726.49 (M+1)+. 1H NMR signals are doubled because of atropoisomerism. 1H NMR (CDCl3, 500 MHz) 7.94 (d, J=8.5 Hz, 1H), 7.88-7.83 (m, 2H), 7.71 (s, 0.5H), 7.69 (s, 0.5H), 7.68-7.60 (m, 2H), 7.45-7.39 (m, 2H), 7.38, 7.37 (d, J=2 Hz, 1H), 7.28 (d, J=8 Hz, 0.5H), 7.24 (d, J=8 Hz, 0.5H), 7.14 (d, J=2 Hz, 1H), 7.07 (t, J=8 Hz, 1H), 5.58 (d, J=8.5 Hz, 0.5H), 5.28 (d, J=8 Hz, 0.5H), 4.96 (d, J=10 Hz, 0.5H), 4.93 (d, J=9.5 Hz, 0.5H), 4.16 (d, J=15.5 Hz, 0.5H), 3.96 (d, J=16 Hz, 0.5H), 3.92 (s, 3H), 3.86 (s, 3H), 3.82-3.93 (m, 1H), 2.37 (s, 1.5H), 2.31 (s, 1.5H), 0.54 (d, J=6.5 Hz, 1.5H), 0.42 (d, J=6.5 Hz, 1.5H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[CH2:17][CH2:18][OH:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[Cl:53][C:54]1[CH:63]=[C:62]2[C:57]([C:58](O)=[C:59]([C:65]3[CH:70]=[C:69]([CH3:71])[CH:68]=[C:67]([CH3:72])[CH:66]=3)[C:60](=[O:64])[NH:61]2)=[CH:56][C:55]=1[N+:74]([O-:76])=[O:75]>>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[CH2:17][CH2:18][O:19][C:58]1[C:57]2[C:62](=[CH:63][C:54]([Cl:53])=[C:55]([N+:74]([O-:76])=[O:75])[CH:56]=2)[NH:61][C:60](=[O:64])[C:59]=1[C:65]1[CH:66]=[C:67]([CH3:72])[CH:68]=[C:69]([CH3:71])[CH:70]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(C)cc(-c2c(O)c3cc([N+](=O)[O-])c(Cl)cc3[nH]c2=O)c1
Reactant: O=C(OCc1ccccc1)N1CCCCC1CCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OCc3ccccc3)c3cc([N+](=O)[O-])c(Cl)cc3[nH]c2=O)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 64 %

Procedure:
To a solution of 7-chloro-3-(3,5-dimethylphenyl)-4-hydroxy-6-nitro-1H-quinolin-2-one (13.5 g in 600 mL of N,N-dimethylformamide) was added 9.2 g of 2-(2-hydroxyethyl)-piperidine-1-carboxylic acid benzyl ester and 14 g of triphenylphosphine followed by 10.4 mL of diisopropyl azodicarboxylate and the mixture stirred at room temperature. After 24 hours, the solvents were removed in vacuo and the residue resolvated in methylene chloride, washed with water and purified by flash chromatography on silica gel (hexane:ethyl acetate, 90:10; then methylene chloride:ethyl acetate, 95:5) to give the title compound (13.2 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[NH:17][N:18]=[CH:19][CH:20]=3)=[N:13][C:12]=2[CH3:21])=[O:10])[CH:2]=1.Br[CH2:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[CH:25]=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[CH:20]=[CH:19][N:18]([CH2:23][C:24]4[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[CH:25]=4)[N:17]=3)=[N:13][C:12]=2[CH3:21])=[O:10])[CH:2]=1
Reactant: Fc1cc(F)cc(CBr)c1
Reactant: Cc1nc(-c2ccn[nH]2)sc1C(=O)NCc1cccnc1
Product: Cc1nc(-c2ccn(Cc3cc(F)cc(F)c3)n2)sc1C(=O)NCc1cccnc1

Procedure:
The title compound was prepared from 4-methyl-2-(2H-pyrazol-3-yl)-thiazole-5-carboxylic acid (pyridin-3-ylmethyl)-amide and 1-bromomethyl-3,5-difluoro-benzene as described in Example 49 and isolated as a white solid (0.071 mg, 51% yield). 1H NMR (400 MHz, CDCl3) δ 8.61 (s, 1H), 8.56 (d, J=4 Hz, 1H), 7.71 (d, J=8 Hz, 1H), 7.45 (d, J=2 Hz, 1H), 7.28-7.34 (m, 1H), 6.89 (d, J=2 Hz, 1H), 6.70-6.79 (m, 3H), 6.12-6.18 (m, 1H), 5.32 (s, 2H), 4.63 (d, J=8 Hz, 2H), 2.75 (s, 3H); MS (M+H)+=425.9; Rt=1.25 min; HRMS (M+H)+=426.12.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([OH:27])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][C:23]([F:26])([F:25])[F:24])[CH2:9]1)C1C=CC=CC=1.[ClH:34].C(O)C.C1(C)C=CC=CC=1>CO.[Pd]>[ClH:34].[NH:8]1[CH2:13][CH2:12][O:11][C@@H:10]([C@:14]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)([OH:27])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][C:23]([F:26])([F:25])[F:24])[CH2:9]1
Reactant: OC(Cc1ccccc1OC(F)(F)F)(c1ccccc1)C1CN(Cc2ccccc2)CCO1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: CO
Product: O[C@@](Cc1ccccc1OC(F)(F)F)(c1ccccc1)[C@H]1CNCCO1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
Alternatively, the following method may be used. A stainless steel Buchi hydrogenation reactor was loaded with 1-(4-Benzyl-morpholin-2-yl)-1-phenyl-2-(2-trifluoromethoxy-phenyl)-ethanol (230 g, 0.503 mole), methanol (1 L), a suspension of Pd/C (10%, 46 g, 20% loading) in methanol (500 ml), and methanol (500 ml) from equipment rinses. A solution of HCl in ethanol (1.6N, 460 ml, 0.736 mole, 1.5 eq.) was added and the reactor was pressurized with H2 (3 Bar). The reaction mixture was heated to 40° C. and stirred for 3 hours. The reaction mixture was cooled to 20° C. and flushed with N2. The catalyst was filtered off and washed with methanol (0.5 L). The filtrates were concentrated under vacuum to a yellow solid. The yield of crude title compound was 198 g (97.5%). A reactor was loaded with crude title compound (190 g, 0.47 mole) and toluene (6.65 L) under N2. The suspension was heated under reflux and toluene (150 ml) was added until all solid dissolved. The solution was stirred for 15 minutes more under reflux and then cooled slowly to 20° C. The suspension was stirred for 1 hour at 20° C. The solid was filtered, washed with toluene (680 ml), and dried at 40° C. under vacuum. The yield of pure anhydrous title compound was 158.5 g (83.4%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=4[O:27][CH2:28][CH2:29][O:30][CH3:31])[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1.[C:32](Cl)(=[O:34])[CH3:33]>>[C:32]([N:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=4[O:27][CH2:28][CH2:29][O:30][CH3:31])[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1)(=[O:34])[CH3:33]
Reactant: CC(=O)Cl
Reactant: COCCOc1cc(OC)ccc1-c1ncnc2c(C(=O)NC3CCNCC3)c[nH]c12
Product: COCCOc1cc(OC)ccc1-c1ncnc2c(C(=O)NC3CCN(C(C)=O)CC3)c[nH]c12

Procedure:
Starting from 4-[4-methoxy-2-(2-methoxy-ethoxy)-phenyl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide (example A184) and acetyl chloride the title compound was obtained as colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([NH2:15])[C:7]([C:16]([NH2:18])=[O:17])=[CH:6]2.[C:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])#N>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]1[N:15]=[C:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[NH:18][C:16](=[O:17])[C:7]1=[CH:6]2
Reactant: CCOC(=O)C#N
Reactant: COc1cc2cc(C(N)=O)c(N)nc2cc1OC
Solvent: c1ccccc1
Product: CCOC(=O)c1nc2nc3cc(OC)c(OC)cc3cc2c(=O)[nH]1

Procedure:
Still further, a mixture of 6,7-dimethoxy-2-aminoquinoline-3-carboxamide (0.5 g., 2 millimoles), ethyl cyanoformate (0.43 g., 44 millimiles) and benzene (30 ml.) is refluxed for three days. The mixture is then cooled, filtered and the solid extracted with chloroform. Concentration of the chloroform extract affords the product which is recrystallized from chloroform.