Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=1.[CH2:23]([N:30]1[CH2:35][CH2:34][C:33](=[O:36])[CH2:32][CH2:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1.O>[CH2:23]([N:30]1[CH2:35][CH2:34][C:33]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)([OH:36])[CH2:32][CH2:31]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: COc1ccc(Br)cc1OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: COc1ccc(C2(O)CCN(Cc3ccccc3)CC2)cc1OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61.5 %

Procedure:
A solution of n-butyllithium in hexane (1.56 M, 93.0 mL, 145 mmol) was added dropwise a solution of 4-bromo-1,2-dimethoxybenzene (34.4 g, 158 mmol) in THF (350 ml) under −70° C. and stirred for 30 minutes under argon atmosphere. A solution of 1-benzyl piperidin-4-one (25.0 g, 132 mmol) in THF (50 ml) was added dropwise to the reaction mixture under −60° C., and the mixture was allowed to warm to 0° C. and stirred under ice cooling for 30 minutes. The reaction mixture was diluted with water, concentrated under reduced pressure, and extracted with ethyl acetate. The organic extract was washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified using silica gel column chromatography and the obtained crystals were washed with hexane to obtain 26.6 g (yield 71%) of the title compound. mp. 112–114° C.
Reaction SMILES: [N+](C1C=CC=CC=1)([O-])=[O:2].N[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:11]1([OH:2])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:11]1(=[O:2])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=[N+]([O-])c1ccccc1
Reactant: Nc1ccccc1
Product: O=C1CCCCC1
Product: Oc1ccccc1

Procedure:
Examples of reactions which can be carried out particularly expediently in the reactors according to the invention are, without this listing being exhaustive: dehydrogenations, for example, of cyclohexylidene-aniline to give diphenylamine and of cyclohexenyl-cyclohexanone to give o-phenylphenol; hydrogenations, for example, of nitrobenzene to give aniline and of phenol to give cyclohexanone; oxidative alcohol dehydrogenations, for example, of 3-methyl-3-buten-1-ol to give 3-methyl-2-buten-1-al; selective oxidations of hydrocarbons, for example, of n-butane to give maleic anhydride, of oxylene to give phthalic anhydride and of propene to give acrolein or acrylic acid and alkylations and halogenations.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17](I)[CH:16]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:16]=[C:17]([C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([O:24][CH3:23])[CH:30]=2)[CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(I)c1
Reactant: COc1cccc(B(O)O)c1
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: COCCOC
Product: COc1cccc(-c2cccc(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)c2)c1
Yield: 87 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-methoxybiphenyl-3-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide (0.075 g; 0.176 mmol), 3-methoxyphenylboronic acid (0.028 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 1 to 20% ethyl acetate in dichloromethane) furnished 0.062 g (87%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-methoxybiphenyl-3-carboxamide as a white solid.
Reaction SMILES: C(=O)(O)[O-].[Na+].[CH3:6][O:7][C:8](=[O:18])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16].Br[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:22]>O.CO.CC(C)=O>[O:22]=[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:20][O:17][C:15](=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:8]([O:7][CH3:6])=[O:18]
Reactant: COC(=O)CCCCCCC(=O)O
Reactant: O=C(CBr)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: CO
Product: COC(=O)CCCCCCC(=O)OCC(=O)c1ccccc1
Reaction time: 0.5 h
Yield: 89.7 %

Procedure:
Add a solution of sodium bicarbonate (2.12 g, 25.2 mmol) in water (10 mL) to a solution of suberic acid monomethyl ester (4.75 g, 25.2 mmol) in methanol (50 mL) at room temperature and stir the mixture for 30 minutes. Remove the solvent under reduced pressure and add the residue to a solution of 2-bromoacetophenone (5.0 g, 25.1 mmol) in acetone (150 mL) at room temperature under nitrogen. Heat the mixture at reflux for 10 hours and then remove the solvent under reduced pressure. Dilute the residue with diethyl ether (300 mL), stir for 20 minutes, filter through a short silica gel column, and wash with diethyl ether (2×50 mL). Remove the solvent under reduced pressure to provide octanedioic acid methyl ester 2-oxo-2-phenylethyl ester (6.9 g, 90%).
Reaction SMILES: [F:1][C:2]1[C:10]([O:11]COC)=[CH:9][CH:8]=[C:7]([F:15])[C:3]=1[C:4]([OH:6])=[O:5].[Si](Cl)(C)(C)[CH3:17]>CO>[F:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[C:7]([F:15])[C:3]=1[C:4]([O:6][CH3:17])=[O:5]
Reactant: C[Si](C)(C)Cl
Reactant: COCOc1ccc(F)c(C(=O)O)c1F
Solvent: CO
Product: COC(=O)c1c(F)ccc(O)c1F
Temperature: 25 °C
Yield: 100.4 %

Procedure:
To a solution of 2,4-difluoro-1-(methoxymethoxy)benzene (2.00 g, 11.5 mmol) in THF (30 mL) under nitrogen at −70° C. was added a solution of n-butyllithium in hexanes (1.4 M, 8.20 mL, 11.48 mmol) dropwise over 10 min. The mixture was stirred at −70° C. for 1.5 hr and was then decanted onto freshly pulverized dry ice (˜20 g). Once the effervescence had subsided the mixture was allowed to warm to RT and water (20 mL) was added. The aq solution was extracted twice with ether and was then acidified to pH 1 by the addition of concentrated hydrochloric acid. The resulting suspension was sonicated for 5 min and was then extracted twice with DCM and the combined DCM extracts were dried (MgSO4) and evaporated in vacuo. The residue was triturated with a mixture of isohexane and ether (50:3 v/v) to furnish 2,6-difluoro-3-(methoxymethoxy)benzoic acid as a white solid (1.99 g, 77% yield); Rt 2.31 min (Method 1, basic); m/z 219 (M+H)+ (ES+), which was used directly in the next step (below). To a solution of 2,6-difluoro-3-(methoxymethoxy)benzoic acid (2.74 g, 12.6 mmol) in MeOH (50 mL) was added TMS-Cl (7.94 mL, 62.8 mmol) dropwise and the resulting colourless solution heated at reflux for 3 hr. The resulting mixture was cooled to RT and was then evaporated in vacuo and the residue was subjected to SCX capture and release to afford methyl 2,6-difluoro-3-hydroxybenzoate as a white solid (2.38 g, 100%); Rt 2.29 min (Method 1, basic); m/z 187 (M−H)− (ES−).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:7][CH:6]([CH2:8][OH:9])[CH:5]=[CH:4]1.[OH-].[Na+].[C:12]([O:16][C:17](F)=[O:18])([CH3:15])([CH3:14])[CH3:13].Cl>O.O1CCOCC1.C(OCC)C>[C:17]([C:3]1([NH2:2])[CH2:7][CH:6]([CH2:8][OH:9])[CH:5]=[CH:4]1)([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:18]
Reactant: NC1C=CC(CO)C1
Reactant: CC(C)(C)OC(=O)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)C1(N)C=CC(CO)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56 %

Procedure:
15 g of crude (±)-1-amino-4-hydroxymethyl-2-cyclopentene hydrochloride were dissolved in a mixture of 150 ml of water and 150 ml of dioxane at room temperature under nitrogen. The solution was adjusted to pH 14 with 1N NaOH, then a diethyl ether solution of tert-butyloxy-carbonyl fluoride (BOC-F, 20% excess) was added, and the mixture was stirred for a further 3 h at room temperature (BOC-F prepared as disclosed in Synthesis 1975, 599). The pH was adjusted to 2 with conc. HCl. After distillation of the organic solvents, 50 ml of water were added to the residue, and the mixture was extracted with 3×100 ml of ethyl acetate. The combined organic phases were completely evaporated. The residue was crystallized in a mixture of 110 ml of diisopropyl ether and 80 ml of n-hexane. 11.95 g of title compound were obtained. The yield was 56%.
Reaction SMILES: N#N.[F:3][C:4]([F:14])([F:13])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#N)=[CH:7][CH:6]=1.C(O)=[O:16]>[Ni].[Al]>[F:3][C:4]([F:14])([F:13])[C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:16])=[CH:7][CH:6]=1
Reactant: O=CO
Reactant: N#Cc1ccc(C(F)(F)F)cc1
Agent: [Ni]
Agent: N#N
Agent: [Al]
Product: O=Cc1ccc(C(F)(F)F)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 87.9 %

Procedure:
A Parr hydrogenation bottle was purges with N2 and then charged with 25 g of 4-trifluoromethyl benzonitrile, 250 mL of 75% aqueous formic acid and 3.0 g of powdered nickel/aluminum alloy catalyst (50/50). The reaction mixture was shaken at 80° C. with H2 gas (3 atmospheres pressure) for 16 hours. The reaction mixture was continuously extracted with CH2Cl2 and analyzed via Internal Standard GLC which indicated 87.9% yield of 4-trifluoromethyl benzaldehyde.
Reaction SMILES: [CH2:1]([S:4]([C:7]1[C:17]2[NH:16][C:15](=S)[CH2:14][N:13]=[C:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]=2[CH:10]=[C:9]([CH3:25])[CH:8]=1)(=[O:6])=[O:5])[CH2:2][CH3:3].[C:26]([NH:30][NH2:31])(=O)[CH2:27][CH3:28]>C(O)C>[CH2:1]([S:4]([C:7]1[C:17]2[N:16]3[C:26]([CH2:27][CH3:28])=[N:30][N:31]=[C:15]3[CH2:14][N:13]=[C:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]=2[CH:10]=[C:9]([CH3:25])[CH:8]=1)(=[O:6])=[O:5])[CH2:2][CH3:3]
Reactant: CCCS(=O)(=O)c1cc(C)cc2c1NC(=S)CN=C2c1ccccc1
Reactant: CCC(=O)NN
Solvent: CCO
Product: CCCS(=O)(=O)c1cc(C)cc2c1-n1c(CC)nnc1CN=C2c1ccccc1
Temperature: 250 °C

Procedure:
In the manner given in Example 2, 9-(propylsulfonyl)-7-methyl-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-thione is heated in ethanol with propionic acid hydrazide and the resulting product heated to 250° C. to give 10-(propylsulfonyl)-8-methyl-1-ethyl-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:6]=[C:5]2[CH2:19][CH2:20][N:21]([CH3:23])[CH3:22].C([Sn](CCCC)(CCCC)[CH:29]1[CH:34]=[CH:33][O:32][CH2:31][CH2:30]1)CCC>C1(C)C=CC=CC=1>[O:32]1[CH:31]=[CH:30][CH:29]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[C:5]3[CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])[CH2:34][CH2:33]1
Reactant: CCCC[Sn](CCCC)(CCCC)C1C=COCC1
Reactant: CN(C)CCc1cn(C(=O)c2ccccc2)c2ccc(Br)cc12
Solvent: Cc1ccccc1
Product: CN(C)CCc1cn(C(=O)c2ccccc2)c2ccc(C3C=COCC3)cc12
Reaction time: 8 h
Yield: 17 %

Procedure:
A solution of 5-bromo-3-[2-(N,N-dimethylamino)ethyl]-1-benzoylindole (Example 5a, 180 mg 0.48 mmol), 4-tributylstannyl-3,4-dihydropyran (180 mg, 0.48 mmol) and tetrakistriphenyphosphine palladium (118 mg, 0.1 mmol) in toluene (3 mL) was stirred at 100-110° C. A second portion of catalyst was added after 1 h and heating was continued overnight. After removal of the solvent in vacuo, flash chromatography on silica gel (2-6% 2M methanolic ammonia in dichloromethane) yielded 5-(3,4-dihydropyran-4-yl)-3-[2-(N,N-dimethylamino)ethyl]-1-benzoylindole (30.5 mg, 17%).
Reaction SMILES: [C:1]1([O:7][C:8](=[O:18])[NH:9][C:10]2[CH:14]=[C:13]([CH:15]3[CH2:17][CH2:16]3)[O:12][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].[CH3:20]CC[CH2-].C(=O)=O.CC(C)=O.CI>C1COCC1>[C:1]1([O:7][C:8](=[O:18])[NH:9][C:10]2[C:14]([CH3:20])=[C:13]([CH:15]3[CH2:17][CH2:16]3)[O:12][N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Nc1cc(C2CC2)on1)Oc1ccccc1
Reactant: [CH2-]CCC
Agent: O=C=O
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: Cc1c(NC(=O)Oc2ccccc2)noc1C1CC1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
(5-Cyclopropyl-isoxazol-3-yl)-carbamic acid phenyl ester (0.368 g, 1.51 mmol) is dissolved in THF (10 mL) and cooled to −78° C. and flushed with nitrogen. N-butyllithium (2.17 mL, 3.47 mmol) is then added. The mixture is stirred in the dry ice/acetone bath for 30 minutes. Methyl iodide (0.10 mL, 1.66 mmol) is added neat and the reaction is stirred for 2 hours at −78° C. The reaction is quenched (0° C.) with 20 mL of a saturated solution of ammonium chloride, diluted with ethyl acetate and the organic layer is removed, dried (sodium sulfate) and concentrated to an oil that is purified via FCC (0-40% ethyl acetate:heptanes) to give the title compound as an oil. MS (ESI) m/z 259.20 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8](Cl)=[O:9])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([NH:19][C:20](=[O:30])[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N:27]([CH3:29])[CH3:28])[CH:22]=2)[CH:15]=[CH:16][C:17]=1[CH3:18].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O.C(Cl)Cl>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([NH:11][C:12]2[CH:13]=[C:14]([NH:19][C:20](=[O:30])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([N:27]([CH3:28])[CH3:29])[CH:22]=3)[CH:15]=[CH:16][C:17]=2[CH3:18])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1N
Reactant: O=C(Cl)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1NC(=O)c1ccc(Cl)nc1
Yield: 14.9 %

Procedure:
6-Chloropyrid-3-ylcarbonyl chloride (0.37 g) was added to a mixture of N-(3-amino-4-methylphenyl)-3-dimethylaminobenzamide (0.54 g), potassium carbonate (0.304 g), DMF (5 ml) and methylene chloride (20 ml) and the resultant mixture was stirred at ambient temperature for 16 hours. The mixture was poured into water and extracted with ethyl acetate. The organic extracts were washed with a saturated aqueous sodium chloride solution, dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using a 3:2:1 mixture of isohexane, ethyl acetate and methylene chloride as eluent. There was thus obtained the title compound as a solid (0.122 g); NMR Spectrum: (DMSOd6) 2.19 (s, 6H), 3.28 (s, 3H), 6.88 (m, 1H), 7.25 (m, 4H), 7.57 (m, 1H), 7.7 (d, 1H), 7.84 (d, 1H), 8.36 (m, 1H), 8.95 (d, 1H), 10.11 (s, 1H), 10.16 (s, 1H); Mass Spectrum: M+H+ 409 and 411.
Reaction SMILES: CC(NC(C)C)C.C([Li])CCC.CCCCCC.[F:19][C:20]([F:34])([F:33])[C:21]([NH:23][C:24]1[CH:28]=[CH:27][S:26][C:25]=1[C:29]([O:31][CH3:32])=[O:30])=[O:22].[Br:35]CCBr.C([O-])(O)=O.[Na+]>C1COCC1>[Br:35][C:27]1[S:26][C:25]([C:29]([O:31][CH3:32])=[O:30])=[C:24]([NH:23][C:21](=[O:22])[C:20]([F:19])([F:33])[F:34])[CH:28]=1
Reactant: COC(=O)c1sccc1NC(=O)C(F)(F)F
Reactant: BrCCBr
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: COC(=O)c1sc(Br)cc1NC(=O)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 39.9 %

Procedure:
To a solution of N-(1-methylethyl)propan-2-amine (20 mL, 142 mmol) in THF (200 mL) was added 1.6 M n-butyl lithium in hexane (84.2 mL, 132 mmol) at 0° C. After stirring at this temperature for 15 min, the mixture was cooled to −78° C. Then, a solution of methyl 3-[(trifluoroacetyl)amino]thiophene-2-carboxylate (10.1 g, 40.0 mmol) in THF (50 mL) was added slowly. After additional stirring at −78° C. for 1 h, 1,2-dibromoethane (20.6 mL, 238 mmol) was added at once. The mixture was stirred at −78° C. for 30 min and at room temperature for 30 min. The mixture was poured into saturated aqueous NaHCO3 (600 mL) and extracted with EtOAc. The combined extracts were washed with brine, and then dried over Na2SO4. After removal of the solvent at reduced pressure, the residue was purified by column chromatography (Purif, silica gel, hexane to 10:90 hexane /EtOAc) to give the title compound (5.30 g, 41%) as a yellow solid:
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:30])[N:4]([C:19]2[CH:24]=[C:23]([C:25](=O)[C:26]#[CH:27])[CH:22]=[CH:21][C:20]=2[CH3:29])[C:5]([CH3:18])=[N:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].Cl.[OH:32][C:33]([CH3:38])([CH3:37])[C:34]([NH2:36])=[NH:35].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[C:3](=[O:30])[N:4]([C:19]2[CH:24]=[C:23]([C:25]3[CH:26]=[CH:27][N:36]=[C:34]([C:33]([OH:32])([CH3:38])[CH3:37])[N:35]=3)[CH:22]=[CH:21][C:20]=2[CH3:29])[C:5]([CH3:18])=[N:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: CC(C)(O)C(=N)N
Reactant: C#CC(=O)c1ccc(C)c(-n2c(C)nc(OCc3ccc(F)cc3F)c(Cl)c2=O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc(-c2ccnc(C(C)(C)O)n2)cc1-n1c(C)nc(OCc2ccc(F)cc2F)c(Cl)c1=O
Temperature: 85 °C
Yield: 48.7 %

Procedure:
To a solution of the 5-chloro-6-(2,4-difluoro-benzyloxy)-2-methyl-3-(2-methyl-5-propynoyl-phenyl)-3H-pyrimidin-4-one of Step D (20 mg, 0.05 mmol) in acetonitrile (1 mL) as added 2-hydroxy-2-methylpropionamidine HCl (9 mg, 0.07 mmol) and potassium carbonate (20 mg, 0.15 mmol) and the slurry was heated at 85° C. for eighteen hours. The reaction was returned to ambient temperature and filtered to remove excess salts. The filtrate was concentrated and purified via normal phase chromatography (ethyl acetate/heptane) to provide the title compound as a white solid (12.5 mg, 50% yield). MS (M+H): 513; 1H NMR (400 MHz, chloroform-d) δ ppm, 1.65 (s, 6H), 2.18 (s, 3H), 2.21 (s, 3H), 5.51-5.60 (m, 2H), 6.88-6.97 (m, 2H), 7.55-7.60 (m, 3H), 7.93 (s, 1H), 8.14 (d, J=8.61 Hz, 1H), 8.78 (d, J=5.09, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([F:14])[CH:8]=1)[CH3:2].[CH3:19][C:20]1[N:21]=[C:22]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[S:23][C:24]=1[CH2:25]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:25][C:24]2[S:23][C:22]([C:27]3[CH:28]=[CH:29][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:31][CH:32]=3)=[N:21][C:20]=2[CH3:19])=[C:9]([F:14])[CH:8]=1)[CH3:2]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CO
Reactant: CCOC(=O)C(Cc1ccc(O)c(F)c1)OCC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)c(F)c1)OCC

Procedure:
In analogy to the procedure described in example 1 d], [rac]-2-ethoxy-3-(3-fluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (example 7 a]) was reacted with [4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methanol in tetrahydrofuran in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate) to yield [rac]-2-ethoxy-3-{3-fluoro-4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenyl}-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 4 e], to yield [rac]-2-ethoxy-3-{3-fluoro-4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenyl}-propionic acid as light yellow solid,
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:10]([C:26]([OH:28])=O)[C:9]1=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl.[Cl-].[F:45][C:46]1[CH:51]=[CH:50][C:49]([CH2:52][NH3+:53])=[C:48]([C:54]([NH:56][CH3:57])=[O:55])[CH:47]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:1]([N:8]1[C:17]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[C:10]([C:26]([NH:53][CH2:52][C:49]2[CH:50]=[CH:51][C:46]([F:45])=[CH:47][C:48]=2[C:54]([NH:56][CH3:57])=[O:55])=[O:28])[C:9]1=[O:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1c(OCc2ccccc2)c2ncccc2n(Cc2ccccc2)c1=O
Reactant: CNC(=O)c1cc(F)ccc1C[NH3+]
Agent: On1nnc2cccnc21
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CNC(=O)c1cc(F)ccc1CNC(=O)c1c(OCc2ccccc2)c2ncccc2n(Cc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-benzyl-4-(benzyloxy)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylic acid (0.15 g, 0.39 mmol) in DMF (4 mL) was added HOAT (0.26 g, 1.94 mmol) and EDC (0.07 g, 0.47 mmol). The solution was stirred for 10 minutes at which time EDC (0.036 g, 0.23 mmol), {4-fluoro-2-[(methylamino)carbonyl]phenyl}methanaminium chloride (0.108 g, 0.47 mmol), and DIEA (0.10 g, 0.78 mmol) were added. The reaction was then stirred at room temperature overnight at which time the solution was purified by preparative reverse phase HPLC eluting with a gradient of 5-95% acetonitrile/water (0.1% TFA). The fractions that contained the desired product were concentrated. Note that during the prep des-O-benzyl product was also obtained. The mixture was taken on to the next step.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)#[N:2].C([O-])([O-])=O.[Na+].[Na+].C(O)C.FC1C=C([C:29]2[C:34](=[O:35])[N:33]3[CH:36]=[CH:37][S:38][C:32]3=[N:31][C:30]=2[CH3:39])C=C(F)C=1>C1(C)C=CC=CC=1.O>[CH3:39][C:30]1[N:31]=[C:32]2[S:38][CH:37]=[CH:36][N:33]2[C:34](=[O:35])[C:29]=1[C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: Cc1nc2sccn2c(=O)c1-c1cc(F)cc(F)c1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: Cc1nc2sccn2c(=O)c1-c1ccc(C#N)cc1

Procedure:
This compound was prepared from Step 2 intermediate (10 g, 34.234 mmol), 4-cyanophenylboronic acid (6.5 g, 44.235 mmol), Pd[(C6H5)3P]4 (1.62 g, 1.401 mmol) and Na2CO3 (21.7 g, 2.051 mmol) in a mixture of toluene (250 ml), ethanol (150 ml) and water (100 ml) according to the procedure described in Intermediate 3, Step 3 to afford a crude product which was purified by silica gel column chromatography using 10% ethyl acetate in chloroform to give 5 g of the product as a light yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 2.19 (s, 3H), 7.53 (d, J=7.8 Hz, 3H), 7.88 (d, J=7.8 Hz, 2H) 8.02 (d, J=4.8 Hz, 1H); ESI-MS (m/z) 265.31 (M−H)−.
Reaction SMILES: O[Li].[OH2:3].Br[CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]=[CH:6]1.[OH2:11]>>[CH2:10]1[CH2:9][CH2:8][CH2:7][CH:6]=[CH:5]1.[C:9]1(=[O:11])[CH2:8][CH2:7][C:5](=[O:3])[CH2:10]1
Reactant: BrC1C=CCCC1
Reactant: O
Agent: [Li]O
Product: C1=CCCCC1
Product: O=C1CCC(=O)C1
Reaction time: 8 h

Procedure:
To a suspension of 1,3-cyclopentandedione (4.00 g, 0.040 mmol) in water (30 ml) were added LiOH.H2O (1.88 g, 0.045 moll) and 3-bromocyclohexene (7.18 g, 0.045 mmol). The solution was stirred overnight, the pH raised to 12-14 (LiOH.H2O) and stirred for 2 h. The solution was washed with Et2O (4×40 ml), acidified to pH 1-2 and resulting solids isolated by filtration, washed and dried to give 2-cyclohexene-1,3-cyclopentanedione. [δH (CD3OD) 5.69 (1H, m), 5.44 (1H, m), 3.20 (1H, m), 2.47 (4H, s), 2.15-1.19 ˜(6H, m). m/z ESI, 70V) 179 (MH+)]. The product was dissolved in EtOH (50 ml) and reduced under an atmosphere of H2 at RT with Pd/C (200 mg). After 5 h the reaction was filtered and the solvent removed to give the title compound as a white solid (890 mg 12%). δH (CD3OD) 2.44 (4H, 2), 2.39 (1H, m), 1.85-1.70 (5H, m), 1.50-1.45 (2H, m), 1.35-1.15 (3H, m). m/z (ESI, 70V) 181 (MH+).