Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([CH3:10])[NH:9][C:5]=2[C:4]=1[N:13]1[CH2:17][CH:16]([CH2:18][N:19]=[N+]=[N-])[O:15][C:14]1=[O:22])[CH3:2].[H][H]>[Pd].C(OCC)(=O)C>[CH2:1]([C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([CH3:10])[NH:9][C:5]=2[C:4]=1[N:13]1[CH2:17][CH:16]([CH2:18][NH2:19])[O:15][C:14]1=[O:22])[CH3:2]
Reactant: CCc1ccc2nc(C)[nH]c2c1N1CC(CN=[N+]=[N-])OC1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCc1ccc2nc(C)[nH]c2c1N1CC(CN)OC1=O

Procedure:
A mixture of (±)-3-(5'-1-ethyl-2-methylbenzimidazolyl)-5-(azidomethyl)oxazolidin-2one (XXXIX, EXAMPLE 70, 0.190 g) and palladium on carbon (10%, 0.065 g) is stirred in ethyl acetate (70 ml) for 15.5 hrs under 1 atm (balloon) hydrogen. The mixture is then filtered and the filtrate concentrated to give the crude product as a solid in an oil. The crude sample is placed on a silica gel column (5 cm×0.5 cm, 40.63 μ) and eluted with ethyl acetate followed by methanol/ethyl acetate mixtures (1/9 10 ml, 1/3 20 ml, 1/1 20 ml. The 1/3 and 1/1 methanol/ethyl acetate fractions are combined and concentrated to give the title compound as a foamy solid. NMR (CDCl3, 300 MHz) 7.64, 7.55, 7.24, 4.70, 4.10, 3.87, 3.12, 3.01, 2.57 and 1.36 δ; CMR (CDCl3, 75.47 MHz) 13.60, 14.77, 38.46, 44.80, 48.61, 73.57, 109.06, 109.17, 114.63, 131.64, 132.86, 142.52, 152.05 and 155.09 δ.
Reaction SMILES: [N:1]1[CH:9]=[C:8]2[C:4]([N:5]=[C:6]([NH2:10])[NH:7]2)=[N:3][CH:2]=1.[C:11]([C:13]1[CH:28]=[CH:27][C:16]([CH:17]=[C:18]([C:24](=O)[CH3:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:15][CH:14]=1)#[N:12].C(=O)(O)[O-].[Na+]>CN(C=O)C>[C:11]([C:13]1[CH:28]=[CH:27][C:16]([CH:17]2[N:7]3[C:6](=[N:5][C:4]4[N:3]=[CH:2][N:1]=[CH:9][C:8]=43)[NH:10][C:24]([CH3:25])=[C:18]2[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:15][CH:14]=1)#[N:12]
Reactant: CCOC(=O)C(=Cc1ccc(C#N)cc1)C(C)=O
Reactant: Nc1nc2ncncc2[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1=C(C)Nc2nc3ncncc3n2C1c1ccc(C#N)cc1
Temperature: 55 °C
Reaction time: 12 h

Procedure:
Under an atmosphere of argon, 7H-purine-8-amine (300 mg, 2.2 mmol) and ethyl 2-(4-cyanobenzylidene)-3-oxobutanoate (702 mg, 2.9 mmol, 1.3 eq.) were dissolved in DMF (5 ml), and solid sodium bicarbonate (932 mg, 11.1 mmol, 5 eq.) was added. The mixture was stirred at 55° C. for 12 h. The mixture was then filtered, and the DMF from the filtrate was distilled off under reduced pressure. The residue was purified by preparative HPLC (Gromsil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA 10:90→90:10). After lyophilization of the appropriate fractions, the title compound was obtained as a solid (430 mg, 54% of theory). The isomeric compound (rac)-ethyl 9-(4-cyanophenyl)-7-methyl-6,9-dihydropyrimido[1,2-e]purine-8-carboxylate (see Example 23A) was obtained as a byproduct.
Reaction SMILES: [C:1]([C:3]([C:14]1[CH:19]=[CH:18][C:17]([S:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:16][CH:15]=1)([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:4][N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1)#[N:2].ClC1C=C(C=CC=1)C(OO)=[O:32].[N+]([O-])(O)=O.CCOCC>C(Cl)Cl>[C:1]([C:3]([C:14]1[CH:15]=[CH:16][C:17]([S:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:32])=[CH:18][CH:19]=1)([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:4][N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1)#[N:2]
Reactant: CCCCC(C#N)(Cn1ccnc1)c1ccc(Sc2ccccc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: O=[N+]([O-])O
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCC(C#N)(Cn1ccnc1)c1ccc(S(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.7 %

Procedure:
To a solution of 4 g (0.01 mole) of 1-[2-cyano-2-(4-phenylthiophenyl) hexyl]imidazole in 25 ml of methylene chloride is added 2.5 g (0.012 mole) of 85% m-chloroperoxybenzoic acid in small portions at 0°. The mixture is stirred at room temperature overnight. To the reaction mixture is added conc. nitric acid until it is strongly acidic. To this solution is added 150 ml of anhydrous ether. The gummy solid precipitates are washed with ether and back neutralized with dilute NH4OH solution. The free base (3.5 g) thus obtained is a yellow solid, mp 55°-61°.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH2:7]([C:14]1[CH:15]=[C:16]([CH2:21][CH:22]([O:26][CH2:27][CH3:28])[C:23]([OH:25])=[O:24])[CH:17]=[CH:18][C:19]=1[OH:20])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CN(C=O)C.[CH2:34](O)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(Cl)Cl>[CH2:34]([O:24][C:23](=[O:25])[CH:22]([O:26][CH2:27][CH3:28])[CH2:21][C:16]1[CH:17]=[CH:18][C:19]([OH:20])=[C:14]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:15]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CCOC(Cc1ccc(O)c(Cc2ccccc2)c1)C(=O)O
Reactant: OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(Cc1ccc(O)c(Cc2ccccc2)c1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 49 %

Procedure:
Oxalyl chloride (0.364 g, 2.87 mmol) was added dropwise to a mixture of 3-(3-benzyl-4-hydroxy-phenyl)-2-ethoxy-propionic acid (0.345 g, 1.15 mmol) and a catalytic amount of DMF in dry DCM (2.0 mL). The mixture was stirred for 17 h at room temperature before the excess oxalyl chloride was evaporated in vacuo. The remaining carboxylic acid chloride was redissolved in dry DCM (3.0 mL) and benzyl alcohol (0.15 g, 1.38 mmol) was added under nitrogen atmosphere. After stirring for 24 h at room temperature the solvent was removed in vacuo and the resulting oil was purified by column chromatography using DCM/MeOH (96:4) as the eluent to afford the title compound as an oil (0.22 g, 36.8%). Mass Spectrum: M−H+ 388.94.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:28]([F:31])([F:30])[F:29])[CH2:14][CH2:13][N:12]([C:15]3[N:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[C:18]([C:25](O)=[O:26])=[CH:17][N:16]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].S(Cl)(Cl)=O>CN(C)C=O.ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:28]([F:29])([F:30])[F:31])[CH2:14][CH2:13][N:12]([C:15]3[N:20]=[C:19]([C:21]([F:23])([F:24])[F:22])[C:18]([CH2:25][OH:26])=[CH:17][N:16]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8]
Reactant: O=C(O)c1cnc(N2CCC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)nc1C(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: O=S(Cl)Cl
Product: OCc1cnc(N2CCC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)nc1C(F)(F)F
Yield: 84.8 %

Procedure:
2-[3-(3,4,5-Trichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]-4-(trifluoro-methyl)pyrimidine-5-carboxylic acid (2.0 g) was added to 1,2-dichloroethane (50 mL). To the resulting mixture, thionyl chloride (1.0 g), and one drop of N,N-dimethylformamide was added and the mixture was refluxed under heating for 5 hours. After removing the solvent by evaporation, the residues were dissolved in 1,4-dioxane (20 mL), and the resulting solution was added dropwise to the mixture solution comprising water (30 mL), 1,4-dioxane (30 mL), and sodium borohydride (0.4 g) under ice cooling. After the dropwise addition was completed, the solution was refluxed under heating for one hour. After cooling, the reaction solution was poured over ice water and then extracted with ethyl acetate. After cooling, the extraction was carried out by adding water and ethyl acetate to the solution. The organic layer was dried over magnesium sulfate. The solvent was evaporated off under reduced pressure, and the residue was then purified by a silica gel chromatography to obtain the title compound (1.65 g, 86%).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:33])[N:10]([CH2:31][CH3:32])[CH2:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=1B1OC(C)(C)C(C)(C)O1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:35]1[CH:36]=[C:37]([C@H:42]([CH3:58])[C:43](N2[C@H](C)[C@H](C3C=CC=CC=3)OC2=O)=[O:44])[CH:38]=[C:39]([Cl:41])[CH:40]=1.[O:59]1CCNC1=O>>[CH2:1]([NH:8][C:9](=[O:33])[N:10]([CH2:11][C:12]1[CH:17]=[C:16]([C:18]([F:19])([F:20])[F:21])[CH:15]=[CH:14][C:13]=1[C:35]1[CH:40]=[C:39]([Cl:41])[CH:38]=[C:37]([CH:42]([CH3:58])[C:43]([OH:44])=[O:59])[CH:36]=1)[CH2:31][CH3:32])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1)C(=O)NCc1ccccc1
Reactant: O=C1NCCO1
Reactant: C[C@H](C(=O)N1C(=O)O[C@@H](c2ccccc2)[C@H]1C)c1cc(Cl)cc(Br)c1
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(Cl)cc(C(C)C(=O)O)c1)C(=O)NCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: 3-benzyl-1-ethyl-1-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-urea and (4R,5S)-3-[(S)-2-(3-bromo-5-chloro-phenyl)-propionyl]-4-methyl-5-phenyl-oxazolidin-2-one; under the coupling conditions, the oxazolidinone was hydrolyzed to the acid and the stereocenter racemized. M+H is 519.
Reaction SMILES: [BH4-].[Na+].C([Se][Se]CC1C=CC=CC=1)C1C=CC=CC=1.ClC(Cl)(Cl)C([C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[CH:25][CH:24]=1)O.[OH-:38].[Na+].[CH2:40]([OH:42])[CH3:41]>>[CH3:35][N:32]1[CH2:33][CH2:34][N:29]([C:26]2[CH:27]=[CH:28][C:23]([CH2:41][C:40]([OH:38])=[O:42])=[CH:24][CH:25]=2)[CH2:30][CH2:31]1
Reactant: CCO
Reactant: [OH-]
Reactant: CN1CCN(c2ccc(C(O)C(Cl)(Cl)Cl)cc2)CC1
Agent: [BH4-]
Agent: [Na+]
Agent: c1ccc(C[Se][Se]Cc2ccccc2)cc1
Product: CN1CCN(c2ccc(CC(=O)O)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.559 g (14.77 mmol) of sodium borohydride is added quickly to 2.294 g (7.35 mmol) of dibenzyl diselenide in 28 ml of ethanol. The reaction mixture is stirred at room temperature for 1 hour. 2.266 g (7 mmol) of 2,2,2-trichloro-1-(4-(4-methylpiperazine-1-yl)phenyl)ethanol and 1.680 g (42.0 mmol) of sodium hydroxide are then added. The reaction mixture is stirred at 35° C. for 24 hours. The solvent is concentrated and the crude product extracted with ethyl acetate after adding a pH 5 aqueous phase. The organic phases are combined, dried on magnesium sulfate and then concentrated to yield 2-(4-(4-methylpiperazine-1-yl)phenyl)acetic acid which is used without additional purification.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]([O:22][CH3:23])=[O:21])[CH:18]=2)[CH:13]=[CH:12]1.[Cl-].C([Al+]CC)C>ClCCCl>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:13]2[C:14]3[C:19](=[CH:18][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:15]=3)[NH:11][CH:12]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: CC[Al+]CC
Agent: [Cl-]
Solvent: ClCCCl
Product: COC(=O)c1ccc2c(C(=O)c3ccc(F)cc3)c[nH]c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.1 %

Procedure:
A solution of 4-fluorobenzoyl chloride 43b (2 mmol, 0.24 mL) in 8 mL of DCE was added dropwise to an ice-cold solution of methyl 1H-indole-6-carboxylate 43a (1.43 mmol, 250 mg) and diethylaluminum chloride (1M in hexanes, 1.86 mmol, 1.86 mL) in 8 mL of DCE. After 2 h at 0° C., the mixture was warmed to room temperature and was stirred overnight. To the mixture was added pH 7 buffer; the resulting solid was filtered and washed with CH2Cl2 to give 162 mg (38%) of methyl 3-(4-fluorobenzoyl)-1H-indole-6-carboxylate 43c. MS m/z (M+H+) 298.0.
Reaction SMILES: C(N=C=O)CN=[C:4]=[O:5].[CH2:9]([CH2:16][CH2:17]N=C=O)[CH2:10][CH2:11][CH2:12][N:13]=C=O.N(C1CCCC1CN=C=O)=C=O.N(C1CC(C)(CN=C=O)CC(C)(C)C1)=C=O.C1(CN=C=O)C=CC(CN=C=O)=CC=1>C1CCCCC1>[NH2:13][C:12]1[CH:11]=[CH:10][CH:9]=[CH:16][CH:17]=1.[CH2:4]=[O:5]
Reactant: O=C=NCCCCCCN=C=O
Reactant: O=C=NCCN=C=O
Agent: CC1(C)CC(N=C=O)CC(C)(CN=C=O)C1
Agent: O=C=NCC1CCCC1N=C=O
Agent: O=C=NCc1ccc(CN=C=O)cc1
Solvent: C1CCCCC1
Product: C=O
Product: Nc1ccccc1

Procedure:
Examples of suitable polyisocyanates which may be used include ethylene diisocyanate, 1,4-tetramethylene diisocyanate, 1,6-hexamethylene diisocyanate, 2,4,4-trimethyl-1,6-hexamethylene diisocyanate, 1,12-dodecane diisocyanate, cyclobutane-1,3-diisocyanate, cyclohexane- 1,3- and/or -1,4-d iisocyanate, 1-isocyanato-2-isocyanatomethyl cyclopentane, 1-isocyanato-3,3,5-trimethyl-5-isocyanatomethyl cyclohexane(isophorone diisocyanate or IPDI), 2,4- and/or 2,6-hexahydrotoluylene diisocyanate, 2,4′- and/or 4,4′-dicyclohexylmethane diisocyanate, α,α,α′,α-tetramethyl-1,3- and/or -1,4-xylylene diisocyanate, 1,3- and 1,4-xylylene dilsocyanate, 1-isocyanato-1-methyl-4(3)-isocyanatomethyl-cyclohexane, 1,3- and 1,4-phenylene diisocyanate, 2,4- and/or 2,6-toluylene diisocyanate, diphenyl methane-2,4′- and/or -4,4′-diisocyanate, naphthalene-1,5-diisocyanate, triphenyl methane-4,4′,4″-triisocyanate, polyphenyl polymethylene polyisocyanates of the type obtained by condensing aniline with formaldehyde followed by phosgenation, and mixtures of the above-mentioned polyisocyanates.
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[C:15]([F:22])[CH:14]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCO>CCOC(C)=O>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:14][C:15]=1[F:22]
Reactant: CCOC(=O)C(c1ccccc1)c1ccc([N+](=O)[O-])c(F)c1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)C(c1ccccc1)c1ccc(N)c(F)c1
Yield: 97.5 %

Procedure:
The ethyl 2-phenyl-2-(3-fluoro-4-nitrophenyl)acetate was dissolved in a 1:1 mix of EtOH and EtOAc (465 ml) and hydrogenated in an H-cube (1 bar, 25° C., 1 ml/min and 0.25 mol/L). After removal of the solvent and drying, 5.2 g (97.5%) of product could be obtained.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([NH2:5])[CH3:4].[F:6][C:7]1[CH:8]=[CH:9][C:10]([C:30]([F:33])([F:32])[F:31])=[C:11]([CH:29]=1)[C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:28]=[CH:27][C:23]([C:24](O)=O)=[CH:22][N:21]=2)[CH2:16][CH2:15]1)=[O:13]>>[F:6][C:7]1[CH:8]=[CH:9][C:10]([C:30]([F:32])([F:33])[F:31])=[C:11]([C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:28]=[CH:27][C:23]([C:24]4[NH:5][CH:3]([CH3:4])[CH2:2][N:1]=4)=[CH:22][N:21]=3)[CH2:16][CH2:15]2)=[O:13])[CH:29]=1
Reactant: O=C(O)c1ccc(N2CCN(C(=O)c3cc(F)ccc3C(F)(F)F)CC2)nc1
Reactant: CC(N)CN
Product: CC1CN=C(c2ccc(N3CCN(C(=O)c4cc(F)ccc4C(F)(F)F)CC3)nc2)N1
Yield: 46 %

Procedure:
Following the procedure as described in Example 10, making variations only as required to use 1,2-diaminopropane in place of 1,2-diaminopentane to react with 6-[4-(5-fluoro-2-trifluoromethylbenzoyl)piperazin-1-yl]nicotinic acid, the title compound was obtained as a pale yellow solid in 46% yield (0.260 g). 1H NMR (300 MHz, CD3OD) δ 8.63 (d, J=2.3 Hz, 1H), 7.98-7.86 (m, 2H), 7.48-7.35 (m, 2H), 6.99 (d, J=9.2 Hz, 1H), 4.55-4.41 (m, 1H), 3.98-3.33 (m, 10H), 1.44 (d, J=6.3 Hz, 3H). MS (ES+) m/z 436 (M+1).
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([N:16]2[CH:20]=[C:19]([C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[N:18]=[CH:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH:50]1[CH2:53][CH:52]([O:54][C:55]2[CH:56]=[C:57]([CH:60]=[CH:61][C:62]=2[CH3:63])[C:58]#[N:59])[CH2:51]1>CN(C=O)C>[C:58]([C:57]1[CH:60]=[CH:61][C:62]([CH3:63])=[C:55]([CH:56]=1)[O:54][CH:52]1[CH2:51][N:50]([C:25](=[O:27])[CH2:24][NH:23][C:21]([C:19]2[N:18]=[CH:17][N:16]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:20]=2)=[O:22])[CH2:53]1)#[N:59]
Reactant: Cc1ccc(C#N)cc1OC1CNC1
Reactant: O=C(O)CNC(=O)c1cn(-c2ccccc2)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(C#N)cc1OC1CN(C(=O)CNC(=O)c2cn(-c3ccccc3)cn2)C1
Reaction time: 0.03 h
Yield: 18.7 %

Procedure:
DIPEA (193.9 mg, 1.5 mmol) was added to a stirred solution of [(1-phenyl-1H-imidazole-4-carbonyl)-amino]-acetic acid (prepared from Intermediate 68 by means of Step 3 of the General Scheme) (92 mg, 0.37 mmol) in DMF (3 mL) followed by HOBt (53.2 mg, 0.39 mmol) and EDCI (75.5 mg, 0.39 mmol). After 2 minutes of stirring, 3-(azetidin-3-yloxy)-4-methyl-benzonitrile hydrochloride (prepared by the method used for the synthesis of Intermediate 71) (84 mg, 0.37 mmol) was added and the resulting mixture was stirred at ambient temperature overnight. Partitioning with cold water and ethyl acetate and concentration of the organic layer after drying over sodium sulfate afforded a residue which was purified by preparative HPLC to afford 29 mg (18.7% Yield) of 1-phenyl-1H-imidazole-4-carboxylic acid {2-[3-(5-cyano-2-methyl-phenoxy)-azetidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 416, 98.6%. 1H NMR (300 MHz, DMSO-d6): δ 8.38 (d, 1H), 8.28 (d, 1H), 8.12 (t, 1H), 7.7 (d, 2H), 7.5 (t, 2H), 7.38 (m, 3H), 7.16 (s, 1H), 5.2 (m, 1H), 4.7 (t, 1H), 4.4 (m, 1H), 4.2 (m, 1H), 3.8 (m, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH2:16])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[C:18](OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.C(=O)([O-])O.[Na+]>O1CCOCC1.O>[CH2:1]([O:3][C:4](=[O:17])[C:5]([CH3:7])([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH3:18])[CH:10]=1)[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1cccc(CN)c1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)C(C)(C)Oc1cccc(CNC)c1

Procedure:
In analogy to the procedures described in example 5D], 5E] and 5F], 2-(3-aminomethyl-phenoxy)-2-methyl-propionic acid ethyl ester was converted into the corresponding tert-butoxycarbonylamino derivative by treatment with di-tert-butyl dicarbonate and sodium hydrogen carbonate in dioxane/water at r.t., methylated at N and deprotected again to yield the title compound as a yellow oil.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([O:21][C:22]([F:25])([F:24])[F:23])[CH:5]=[C:6]2[C:11]=1[O:10][CH:9]([C:12]([F:15])([F:14])F)[C:8]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:7]2.[CH2:26]([CH:30]([Sn])C=C(CCCC)CCCC)[CH2:27]CC.[NH4+].[F-:43]>C1(C)C=CC=CC=1.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>[CH2:30]([C:2]1[CH:3]=[C:4]([O:21][C:22]([F:25])([F:24])[F:23])[CH:5]=[C:6]2[C:11]=1[O:10][CH:9]([C:12]([F:14])([F:15])[F:43])[C:8]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:7]2)[CH:26]=[CH2:27]
Reactant: CCOC(=O)C1=Cc2cc(OC(F)(F)F)cc(I)c2OC1C(F)(F)F
Reactant: CCCCC(=CC([Sn])CCCC)CCCC
Reactant: [F-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: C=CCc1cc(OC(F)(F)F)cc2c1OC(C(F)(F)F)C(C(=O)OCC)=C2
Reaction time: 1 h
Yield: 94 %

Procedure:
To a mixture of ethyl 8-iodo-6-(trifluoromethoxy)-2-(trifluoromethyl)-2H-chromene-3-carboxylate prepared as in Example 21a, Step 2 (1.00 g, 2.07 mmole) and Pd(PPh3)4 (0.239 g, 0.207 mmole) in anhydrous toluene (50 mL) under a dry N2 atmosphere was added tributylallyltin (0.707 mL, 2.28 mmole). The mixture was refluxed for 16 h and 20% NH4F solution (50 mL) was added. The mixture was stirred for 1 h and extracted with EtOAc (200 mL). The extract was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated in vacuo. Purification by silica chromatography (9:1 hexanes:EtOAc) gave 0.770 g (94% yield) of the product as a yellow oil: EIHRMS m/z 396.0769 (M+, C17H14F6O4, Calc'd 396.0796).
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:12]([NH:15][C:16]1[CH:17]=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=1)(=[O:14])[CH3:13]>CC(N(C)C)=O.[Cu-]=O>[C:12]([NH:15][C:16]1[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=1)[O:22][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])(=[O:14])[CH3:13]
Reactant: CC(=O)Nc1cccc(O)c1
Reactant: COC(=O)c1ccccc1I
Agent: O=[Cu-]
Solvent: CC(=O)N(C)C
Product: COC(=O)c1ccccc1Oc1cccc(NC(C)=O)c1
Temperature: 180 °C
Yield: 55 %

Procedure:
To a stirred solution of methyl 2-iodobenzoate (10 g, 38.2 mmole) in dimethylacetamide (50 mL) was added 3-acetamidophenol (5 g, 33 mmole) and copper(I) oxide (2.5 g, 17 mmole), and the mixture was heated at reflux under argon (180° C. oil bath). After 24 h the reaction was cooled to RT and most of the solvent was distilled off. The remaining residue was purified by flash chromatography on silica gel (50% EtOAc/hexane) to give the crude title compound (4.95, 55%): MS (ES) m/e 286.2 (M+H)+. The title compound prepared in this way contained approximately 45% N,O-diarylated acetamidophenol as a contaminant: MS (ES) m/e 420.4 (M+H)+. The mixture was used without further purification.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C[O-].[Na+].[Cl:27][C:28]1[C:29]([CH3:40])=[C:30]([C:34](=O)[C:35]([O:37][CH3:38])=[O:36])[CH:31]=[CH:32][CH:33]=1>CN(C)C=O>[Cl:27][C:28]1[C:29]([CH3:40])=[C:30]([C:34](=[CH:2][O:3][CH3:4])[C:35]([O:37][CH3:38])=[O:36])[CH:31]=[CH:32][CH:33]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)C(=O)c1cccc(Cl)c1C
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC=C(C(=O)OC)c1cccc(Cl)c1C
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
92.3 g of methoxymethyltriphenylphosphonium chloride were suspended in 500 ml of anhydrous dimethylformamide, and 42.3 g of 30% strength sodium methanolate solution were added. After 20 minutes, a solution of 30 g of methyl 3-chloro-2-methylphenylglyoxylate in 200 ml of dimethylformamide was added dropwise to the pale yellow suspension. After a further 3 hours at room temperature, the mixture was poured into ice-water and extracted three times using methyl tert-butyl ether. It was dried over sodium sulfate, concentrated, and the crude product was applied to 100 g of silica gel. The product was eluted through a silica gel column using methyl tert-butyl ether. This gave 29 g of a colorless solid.
Reaction SMILES: [C:1]1([C:11]([OH:13])=O)[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=C[CH:2]=1.C([O:16][C:17]([C:19]1([NH2:30])[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24](OC)[CH:25]=2)[CH2:20]1)=[O:18])C.C[N:32](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1]([C:11]([NH:30][C:19]2([C:17]([OH:16])=[O:18])[CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20]2)=[O:13])=[CH:2][N:32]=1
Reactant: O=C(O)c1cccc2c1CCCC2
Reactant: CCOC(=O)C1(N)Cc2ccc(OC)cc2C1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NC1(C(=O)O)Cc2ccccc2C1)c1cncc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.4 %

Procedure:
To a solution of 5,6,7,8-tetrahydro-naphthalene-1-carboxylic acid (400 mg, 2.27 mmol), 2-amino-5-methoxy-indan-2-carboxylic acid ethyl ester (639 mg, 2.72 mmol), HATU (1.3 g, 3.41 mmol) in anhydrous DMF (15 mL) is added DIPEA (563 μL, 3.41 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (50 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (115 g silica gel, gradient elution: 5%-40% EtOAc in heptane) to give a pure product (52) as white solid (622 mg, 70%).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[NH:6][C:5](=[O:7])[N:4]([C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[O:9])[C:3]1=[O:20].[H-].[Na+].[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28]Br.C(OCC)(=O)C>CN(C=O)C>[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][N:6]1[C:2]([CH3:21])([CH3:1])[C:3](=[O:20])[N:4]([C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[O:9])[C:5]1=[O:7]
Reactant: Clc1cccc(CBr)c1
Reactant: CC1(C)NC(=O)N(C(=O)c2cccc3ccccc23)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)C(=O)N(C(=O)c2cccc3ccccc23)C(=O)N1Cc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.8 %

Procedure:
5,5-Dimethyl-3-naphthylcarbonylimidazolidine-2,4-dione (35 mg) was dissolved in DMF (0.4 mL), and sodium hydride (60%, in oil) (5 mg) was added. Then, 3-chlorobenzyl bromide (26 mg) was added, and the mixture was stirred at room temperature overnight. Ethyl acetate (9.5 mL) was added to the reaction solution, separated out white precipitates were filtered, and the filtrate was concentrated and purified by silica gel chromatography (hexane:ethyl acetate=2:1) to obtain 14 mg of white crystals.