Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:4][C@H:3]1[NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].Cl[CH2:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.[I-].[K+]>[C:30]([C:29]([CH2:28][N:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:4][C@@H:3]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:2]1=[O:1])=[O:34])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)C(=O)CCl
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN(C2CCCCC2)c2ccccc2NC1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N[C@@H]1CN(C2CCCCC2)c2ccccc2N(CC(=O)C(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.8 %

Procedure:
To a solution of 50 g of (R)-(−)-2-oxo-3-tert-butoxycarbonylamino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine in 200 ml of dimethylsulfoxide were added 28.1 g of 1-chloropinacolone, 28.8 g of potassium carbonate (powder), 1.15 g of potassium iodide and 1.35 g of tetrabutylammonium bromide. The mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into ice water. The precipitate thus formed was collected by filtration with suction, washed with water and then dried, whereby 63.5 g of the title compound was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([NH:10][CH3:11])[C:7]([C:12]([F:15])([F:14])[F:13])=[CH:6][C:5]=1[N+:16]([O-])=O>CO.O1CCCC1.[Pd]>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([NH:10][CH3:11])[C:7]([C:12]([F:13])([F:15])[F:14])=[CH:6][C:5]=1[NH2:16]
Reactant: CNc1cc(C(=O)OC)c([N+](=O)[O-])cc1C(F)(F)F
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CNc1cc(C(=O)OC)c(N)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 103 %

Procedure:
2-Nitro-5-methylamino-4-trifluoromethyl-benzoic acid methyl ester is dissolved in methanol/tetrahydrofuran and after addition of 10% Pd-C, the mixture is stirred for 45 min. at room temperature under hydrogen. The mixture is filtrated over celite and evaporated under reduced pressure to give 2-amino-5-methylamino-4-trifluoromethyl-benzoic acid methyl ester as an orange oil (240 mg, 103% yield). The product is used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[C:15]([CH3:16])=[N:14][CH:13]=[CH:12][N:11]3[CH:17]=2)=[CH:4][CH:3]=1.I[C:19]1[CH:24]=[CH:23][N:22]=[C:21]([S:25][CH3:26])[N:20]=1.C([O-])([O-])=O.[Cs+].[Cs+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>O.CC([O-])=O.CC([O-])=O.[Pd+2].CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[C:15]([CH3:16])=[N:14][CH:13]=[CH:12][N:11]3[C:17]=2[C:19]2[CH:24]=[CH:23][N:22]=[C:21]([S:25][CH3:26])[N:20]=2)=[CH:6][CH:7]=1
Reactant: CSc1nccc(I)n1
Reactant: Cc1nccn2cc(-c3ccc(F)cc3)nc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1nccc(-c2c(-c3ccc(F)cc3)nc3c(C)nccn23)n1
Temperature: 100 °C
Yield: 58.3 %

Procedure:
Into a flask was added 2-(4-fluorophenyl)-8-methylimidazo[1,2-a]pyrazine (Preparation #K.1; 4.8 g, 21.0 mmol), 4-iodo-2-(methylthio)pyrimidine (Frontier, 9.4 g, 31.7 mmol), Cs2CO3 (10.3 g, 31.7 mmol), PPh3 (2.2 g, 8.4 mmol), and DMF (50 mL). The mixture was degassed under vacuum and back-filled with N2. The mixture was charged with Pd(OAc)2 (0.95 g, 4.2 mmol) and heated at about 100° C. for about 16 h. The mixture was cooled to ambient temperature, diluted with water (200 mL), and extracted with DCM (3×200 mL). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by flash column chromatography (0-5% MeOH:DCM) followed by trituration in EtOAc yielded the title compound (4.30 g, 58% yield): LC/MS (Table 1, Method b) Rt=2.2 min; MS m/z: 352.3 (M+H)+.
Reaction SMILES: C([O:5][C:6](=[O:42])[CH2:7][CH:8]1[C:17]2[C:12](=[C:13]([CH3:34])[C:14]([C:18]3[N:22]=[C:21]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH:30]([CH3:32])[CH3:31])=[C:25]([Cl:33])[CH:24]=4)[O:20][N:19]=3)=[CH:15][CH:16]=2)[CH2:11][CH2:10][N:9]1[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])CCC.[OH-].[Na+]>C(O)C>[Cl:33][C:25]1[CH:24]=[C:23]([C:21]2[O:20][N:19]=[C:18]([C:14]3[C:13]([CH3:34])=[C:12]4[C:17](=[CH:16][CH:15]=3)[CH:8]([CH2:7][C:6]([OH:42])=[O:5])[N:9]([C:35]([O:37][C:38]([CH3:39])([CH3:41])[CH3:40])=[O:36])[CH2:10][CH2:11]4)[N:22]=2)[CH:28]=[CH:27][C:26]=1[O:29][CH:30]([CH3:32])[CH3:31]
Reactant: CCCCOC(=O)CC1c2ccc(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)c(C)c2CCN1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(-c2noc(-c3ccc(OC(C)C)c(Cl)c3)n2)ccc2c1CCN(C(=O)OC(C)(C)C)C2CC(=O)O
Temperature: 25 °C
Yield: 89.9 %

Procedure:
To a solution of 1,1-dimethylethyl 1-[2-(butyloxy)-2-oxoethyl]-6-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-5-methyl-3,4-dihydro-2(1H)-isoquinolinecarboxylate (Preparation 20; 92 mg, 0.154 mmol) in ethanol (3 ml) was added sodium hydroxide (0.154 ml, 0.308 mmol) and the resulting mixture was stirred at room temperature for ca 3.5 h. Most of the solvent was removed and the residue partitioned between ether and water (with dropwise addition of 2N sodium hydroxide to keep the mixture basic). The layers were separated, and the aqueous layer acidified with 2N aqueous hydrochloric acid and extracted twice with ethyl acetate. The combined ethyl acetate fractions were dried over MgSO4 and concentrated in vacuo to give the title compound (75 mg) as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].I[CH2:13][CH3:14].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:13]([O:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1)[CH3:14]
Reactant: CCI
Reactant: Cc1ccc(O)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc(C)c([N+](=O)[O-])c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
4-Methyl-3-nitrophenol (10.0 g) was mixed with iodoethane (10.5 mL), potassium carbonate (13.5 g) and DMF (130 mL), and the obtained mixture was stirred at 60° C. overnight. Water was added to the reaction mixture, and the mixture was extracted twice with diethyl ether. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a yellow oil (11.8 g).
Reaction SMILES: [C:1]([Mg]Br)#[C:2][CH3:3].[CH3:6][C:7]1([CH3:31])[O:12][C:11](=[O:13])[C:10](=[CH:14][C:15]2[CH:20]=[CH:19][C:18]([S:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[CH:17][CH:16]=2)[C:9](=[O:30])[O:8]1.[NH4+].[Cl-]>C1COCC1>[CH3:6][C:7]1([CH3:31])[O:12][C:11](=[O:13])[CH:10]([CH:14]([C:15]2[CH:16]=[CH:17][C:18]([S:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[CH:19][CH:20]=2)[C:1]#[C:2][CH3:3])[C:9](=[O:30])[O:8]1
Reactant: Cc1ccccc1CSc1ccc(C=C2C(=O)OC(C)(C)OC2=O)cc1
Reactant: CC#C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CC(c1ccc(SCc2ccccc2C)cc1)C1C(=O)OC(C)(C)OC1=O
Temperature: 0 °C
Yield: 15 %

Procedure:
An oven-dried 100 mL pear-shaped flask, fitted with an oven-dried stir bar, was charged with a 0.5 M solution of 1-propynyl magnesium bromide in THF (12.5 mL, 6.27 mmol) via cannula. The solution was cooled to 0° C., and then a solution of 28.2 (1.05 g, 2.85 mmol) in anhydrous THF (6 mL) was added over 3 minutes via cannula. The reaction was stirred at 0° C. for 5 minutes and then stirred at room temperature for 1.5 hours. The reaction mixture was poured into saturated NH4Cl(aq) and extracted with ethyl acetate. The combined organic layers were washed with water, followed by brine. The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified via radial chromatography (20% ethyl acetate in hexanes) followed by recrystalization from hot ethyl acetate and hexanes to yield 162 mg (15%) of 2,2-Dimethyl-5-{1-[4-(2-methyl-benzylsulfanyl)-phenyl]-but-2-ynyl}-[1,3]dioxane-4,6-dione (28.3). LC/MSD m/e: 409.1 (M+H).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:12]=[CH:11][C:7]2[NH:8][N:9]=[N:10][C:6]=2[CH:5]=1.CC(N(C)C)=O.C(N(CC)CC)C.[C:26](Cl)(=[O:34])[O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>N1C=CC=CC=1>[O:27]([C:26]([NH:3][C:4]1[CH:12]=[CH:11][C:7]2[NH:8][N:9]=[N:10][C:6]=2[CH:5]=1)=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Nc1ccc2[nH]nnc2c1
Reactant: O=C(Cl)Oc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc2[nH]nnc2c1)Oc1ccccc1
Temperature: 5 °C
Reaction time: 2 h
Yield: 88.5 %

Procedure:
To 62.1 g of 5-aminobenzotriazole dihydrochloride was added 500 ml of dimethylacetamide, and 83,7 ml of triethylamine was added dropwise thereto while being cooled in an ice bath. To the mixture was further added dropwise 21.0 ml of pyridine, and 42.3 g of phenyl chlorocarbonate was then added dropwise thereto while maintaining the system at 5° C. or lower, followed by stirring at room temperature for 2 hours. After the reaction, the reaction mixture was poured into 2 (of ice-water for crystallization, followed by filtration to obtain 60.8 g of 5-phenoxycarbonylaminobenzotriazole.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([F:16])[C:13]([F:15])=[CH:14][C:9]=2[N:8]=[C:7]1[C:17]1[C:18]([O:23][CH2:24][C:25]2[CH:30]=C[CH:28]=[CH:27][C:26]=2Cl)=[N:19][CH:20]=[CH:21][CH:22]=1.C1(CO)CCCC1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([F:16])[C:13]([F:15])=[CH:14][C:9]=2[N:8]=[C:7]1[C:17]1[C:18]([O:23][CH2:24][CH:25]2[CH2:26][CH2:27][CH2:28][CH2:30]2)=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: Fc1cc2nc(-c3cccnc3OCc3ccccc3Cl)n(Cc3cccc(Cl)c3)c2cc1F
Agent: OCC1CCCC1
Product: Fc1cc2nc(-c3cccnc3OCC3CCCC3)n(Cc3cccc(Cl)c3)c2cc1F

Procedure:
The title compound was prepared in analogy to Example 1, from 1-(3-chloro-benzyl)-2-(2-chloro-pyridin-3-yl)-5,6-difluoro-1H-benzoimidazole (Example 11, intermediate) and cyclopentyl-methanol (CAS Reg. No. 3637-61-4). Colorless powder (52%). MS (Turbo Spray): m/z=454.1 (M+H).
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.[CH2:10]([O:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C(=O)([O-])[O-].[Na+].[Na+].C(O)C>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.O>[Br:9][C:5]1[CH:6]=[C:7]([F:8])[C:2]([C:22]2[CH:23]=[CH:24][C:19]([O:18][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:20][CH:21]=2)=[N:3][CH:4]=1
Reactant: Fc1cc(Br)cnc1Br
Reactant: CCCCCCCCOc1ccc(B(O)O)cc1
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: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CCCCCCCCOc1ccc(-c2ncc(Br)cc2F)cc1
Yield: 70 %

Procedure:
12.74 g (50.00 mmol) of 2,5-dibromo-3-fluoropyridine, 12.51 g (50.00 mmol) of 4-octyloxybenzeneboronic acid, 0.58 g (0.50 mmol) of tetrakis(triphenylphosphine)palladium(0) and 10.60 g (100 mmol) of sodium carbonate are heated at 80° C. for 3 hours in 375 ml of toluene, 250 ml of ethanol and 125 ml of water. The mixture is subsequently partitioned between aqueous sodium chloride solution and ether, and the organic phase is washed with aqueous sodium chloride solution, dried over sodium sulfate, evaporated and purified by chromatography (silica gel/hexane : ethyl acetate =9:1), giving 13.31 g of 5-bromo-3-fluoro-2-(4-octyloxyphenyl)pyridine. ##STR15##
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:20]=[CH:19][C:11]([C:12]([NH:14][CH2:15][C:16]([OH:18])=O)=[O:13])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[NH:54]1[CH2:59][CH2:58][CH:57]([NH:60][C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=2[C:67]([F:70])([F:69])[F:68])[CH2:56][CH2:55]1>CN(C=O)C.O>[O:18]=[C:16]([N:54]1[CH2:55][CH2:56][CH:57]([NH:60][C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=2[C:67]([F:68])([F:69])[F:70])[CH2:58][CH2:59]1)[CH2:15][NH:14][C:12](=[O:13])[C:11]1[CH:10]=[CH:9][C:8]([NH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:20][CH:19]=1
Reactant: FC(F)(F)c1ccccc1NC1CCNCC1
Reactant: O=C(O)CNC(=O)c1ccc(Nc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCC(Nc2ccccc2C(F)(F)F)CC1)c1ccc(Nc2ccccc2)cc1
Reaction time: 8 h
Yield: 63.6 %

Procedure:
To a stirred solution of (4-phenylamino-benzoylamino)-acetic acid (0.058 g, 0.00021 mol) in DMF (5 mL) was added DIPEA (0.069 g, 0.00054 mol), HOBt (0.028 g, 0.0002142 mol) and EDCI.HCl (0.085 g, 0.00045 mol) at ambient temperature. After 2 minutes piperidin-4-yl-(2-trifluoromethyl-phenyl)-amine dihydrochloride (0.050 g, 0.00019 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the product was extracted with ethyl acetate. The ethyl acetate layer was collected, washed with brine solution, dried over sodium sulfate and concentrated under reduced. The resulting residue was purified by column chromatography using silica gel 60-120 mesh (60% ethyl acetate in hexane) to afford 0.06 g (68%) of N-{2-oxo-2-[4-(2-trifluoromethyl-phenylamino)-piperidin-1-yl]-ethyl}-4-phenylamino-benzamide. LCMS: 497.21 (M+1)+, 95.3%, 1H NMR (DMSO-d6): δ 8.6 (s, 1H), 8.2 (t, 1H), 7.8 (d, 2H), 7.4 (m, 4H), 7.2 (d, 2H), 7.1 (m, 3H), 6.9 (t, 1H), 6.7 (t, 1H), 4.7 (d, 1H), 4.3 (d, 1H), 4.1 (s, 2H), 3.9 (d, 1H), 3.7 (s, 1H), 2.8 (t, 1H), 2.0 (t, 2H), 1.5 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]2=[N:4][C:3]=1[CH3:13].[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH:19]=O.[O-]CC.[Na+]>C(O)C>[Br:1][C:2]1[C:7](=[O:8])[N:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]2=[N:4][C:3]=1/[CH:13]=[CH:19]/[C:15]1[S:14][CH:18]=[CH:17][CH:16]=1
Reactant: O=Cc1cccs1
Reactant: Cc1nc2ccccn2c(=O)c1Br
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: O=c1c(Br)c(/C=C/c2cccs2)nc2ccccn12

Procedure:
The title compound was prepared from 3-bromo-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (500 mg, 2.091 mmol) and thiophene-2-carboxaldehyde (351 mg, 3.129 mmol) in the presence of sodium ethoxide (284 mg, 4.175 mmol) in absolute ethanol (25 ml) as described in Intermediate 1 to give 283 mg of the product as a light yellow solid; 1H NMR (300 MHz, CDCl3) δ 7.06 (s, 2H), 7.31-7.43 (m, 3H), 7.63 (dd, J=2.4, 16.2 Hz, 2H), 8.15 (d, J=14.7 Hz, 1H), 8.94 (d, J=6.9 Hz, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:30])[NH:17][C:18]1[S:19][CH:20]=[C:21]([C:23]2[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=2)[N:22]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCOCC1.[Si]([N:41]=[C:42]=[O:43])(C)(C)C>>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16](=[O:30])[NH:17][C:18]1[S:19][CH:20]=[C:21]([C:23]2[CH:24]=[CH:25][C:26]([NH:29][C:42]([NH2:41])=[O:43])=[CH:27][CH:28]=2)[N:22]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)N=C=O
Reactant: Nc1ccc(-c2csc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)n2)cc1
Solvent: C1COCCO1
Product: NC(=O)Nc1ccc(-c2csc(NC(=O)C3CCCN3C(=O)OCc3ccccc3)n2)cc1
Temperature: 70 °C

Procedure:
2-[4-(4-Amino-phenyl)-thiazol-2-ylcarbamoyl]-pyrrolidine-1-carboxylic acid benzyl ester (Compound 5050, Example 50, 40 mg, 0.095 mmol) was dissolved in 4 ml of 1:1 dioxane/TMS isocyanate. Reaction mixture was heated at 70° C. for 7 hours. It was then evaporated to dryness. The crude was redissolved in 10 ml of DMF and purified on reverse phase HPLC. MS: 466.1 (M+H+); H1 NMR (DMSO-d6): δ(ppm) 12.39 (d, 1H), 7.72 (d, 2H), 7.42 (d, 3H), 7.35 (s, 2H), 7.10 (dd, 2H), 5.88 (br s, 2H), 5.02 (m, 2H), 4.50 (m, 1H), 2.25 (m, 2H), 1.90 (m, 4H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Br[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[O:18][CH3:19].C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1.C1(C)C=CC=CC=1.[Cu]Br>[CH3:19][O:18][C:10]1[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:9]=1[N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: COc1cc([N+](=O)[O-])ccc1Br
Reactant: CN1CCNCC1
Agent: [Cu]Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COc1cc([N+](=O)[O-])ccc1N1CCN(C)CC1
Temperature: 100 °C
Yield: 14.8 %

Procedure:
A mixture of N-methylpiperazine (216 mg, 2.15 mmol), 2-bromo-5-nitroanisole (1 g, 4.3 mmol), potassium carbonate (447 mg, 3.23 mmol), copper (I) bromide (86.6 mg, 0.30 mmol) in pyridine (0.5 ml) and toluene (2 ml) was heated at 100° C. overnight. After cooling, the mixture was partitioned between water and ether and the aqueous phase was further extracted with ethyl acetate. The combined organic phases were dried (Na2SO4) and evaporated under reduced pressure, to give the crude product. This was purified by chromatography on silica gel, eluting with methanol and dichloromethane, to give the title compound (D34) as a yellow/brown oil (80 mg, 15%) MH+=252.
Reaction SMILES: [Si:1]([O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[C:24]([CH2:29][O:30][CH:31]=C1C3CC4CC(C[C-]1C4)C3)[CH:23]=[CH:22]2)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(N(CC)CC)C.[Si](C1C=CC2C(=CC=CC=2)C=1C(OC)=[O:83])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.C12CC3CC(CC(C3)C1=O)C2>C1COCC1>[Si:1]([O:18][C:19]1[CH:28]=[C:27]2[C:26](=[CH:21][CH:20]=1)[CH:25]=[C:24]([C:29]([O:30][CH3:31])=[O:83])[CH:23]=[CH:22]2)([C:14]([CH3:16])([CH3:15])[CH3:17])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](Oc1ccc2cc(COC=C3[C-]4CC5CC(C4)CC3C5)ccc2c1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1c([Si](c2ccccc2)(c2ccccc2)C(C)(C)C)ccc2ccccc12
Agent: O=C1C2CC3CC(C2)CC1C3
Agent: [Al+3]
Agent: [H-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1ccc2cc(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc2c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
[(6-tert-Butyldiphenylsilyloxy-2-naphthyl)methoxymethylene]adamantane 1d). Approximately 7 g of a 2:1 mixture of TiCl3 and lithium aluminum hydride (Aldrich) was cautiously added to a 250 mL dry three-neck round bottom flask containing 150 mL of dry THF maintained at 0° C. by an ice bath. The resulting black mixture was stirred at 0° C. for 10 minutes and triethylamine (3.3 mL, 24 mmol) was added. The mixture was refluxed for 1 hour and a solution of methyl tert-butyldiphenylsilylnaphthoate (1.76 g, 4 mmol) and adamantanone (600 mg, 4 mmol) in 40 mL of dry THF was added over 6 hours. Reflux was continued for an additional 4 hours and the mixture cooled to room temperature.
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])=[CH:9][C:8]=1[CH3:14])[CH3:2].Cl[CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:32]=[CH:31][C:30]([CH:33]([CH3:35])[CH3:34])=[CH:29][CH:28]=2)[O:24][C:25]=1[CH3:26].C(C1C=CC(C=O)=CC=1)(C)C.O=P(Cl)(Cl)Cl.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>>[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][CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:28]=[CH:29][C:30]([CH:33]([CH3:35])[CH3:34])=[CH:31][CH:32]=3)[O:24][C:25]=2[CH3:26])=[CH:9][C:8]=1[CH3:14])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1C)OCC
Reactant: Cc1oc(-c2ccc(C(C)C)cc2)nc1CCl
Agent: CC(C)c1ccc(C=O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)C(Cc1ccc(OCc2nc(-c3ccc(C(C)C)cc3)oc2C)cc1C)OCC

Procedure:
In analogy to the procedure described in example 1 f], [rac]-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester (example 34 b]) was reacted with 4-chloromethyl-2-(4-isopropyl-phenyl)-5-methyl-oxazole (prepared from 4-isopropyl-benzaldehyde and diacetyl monoxyme followed by treatment with POCl3 in analogy to the procedures described in examples 5 a] and 2 b]) in the presence of cesium carbonate and potassium iodide to yield [rac]-2-ethoxy-3-{4-[2-(4-isopropyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionic acid ethyl ester as colorless liquid.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:9][C@@H:8]([O:10][CH3:11])[CH2:7][N:6]1C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:4].C(Cl)Cl.C(O)(C(F)(F)F)=O>O>[CH3:1][O:2][C:3]([C@H:5]1[CH2:9][C@@H:8]([O:10][CH3:11])[CH2:7][NH:6]1)=[O:4]
Reactant: COC(=O)[C@H]1C[C@@H](OC)CN1C(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: COC(=O)[C@H]1C[C@@H](OC)CN1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a flask containing 3 (4.67 g, 11.6 mmol) was added a solution of CH2Cl2 (27 mL), water (0.3 mL), and TFA (3.0 mL, 38.9 mmol). The solution was stirred at RT for 3 h before concentrating under reduced pressure to reveal impure 4. MS: APCI (AP+): 160.1 (M)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[NH:6][CH:7]([CH3:14])[CH2:8][C:9]([O:11]CC)=[O:10].[OH-].[Na+].CO>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[NH:6][CH:7]([CH3:14])[CH2:8][C:9]([OH:11])=[O:10]
Reactant: CCOC(=O)CC(C)Nc1ccc(OC)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(NC(C)CC(=O)O)cc1OC

Procedure:
A 54-g sample of the unpurified ester product of Example 2 was combined with 17.5 g of sodium hydroxide, 550 ml of methanol and 130 ml of water, and refluxed for 1.5 hrs. The reaction mixture was cooled, concentrated under reduced pressure, diluted with water and neutralized with 6N hydrochloric acid to give an oily mixture which was extracted with chloroform. The combined organic extracts were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 48 g of an oily product. This material was used in the next step without further purification.
Reaction SMILES: O/[CH:2]=[C:3](\[CH2:8][C:9]1[CH:10]=[N:11][CH:12]=[N:13][CH:14]=1)/[C:4]([O:6]C)=O.OS(C(F)(F)F)(=O)=O.[C:23](=[NH:46])([O:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[C:37]([C:42]([F:45])([F:44])[F:43])[CH:36]=2)=[CH:30][CH:29]=1)[NH2:24].C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[Cl:41][C:38]1[CH:39]=[CH:40][C:35]([O:34][C:31]2[CH:32]=[CH:33][C:28]([CH2:27][CH2:26][O:25][C:23]3[NH:46][CH:2]=[C:3]([CH2:8][C:9]4[CH:10]=[N:11][CH:12]=[N:13][CH:14]=4)[C:4](=[O:6])[N:24]=3)=[CH:29][CH:30]=2)=[CH:36][C:37]=1[C:42]([F:43])([F:44])[F:45]
Reactant: COC(=O)/C(=C/O)Cc1cncnc1
Reactant: N=C(N)OCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)C(F)(F)F
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=c1nc(OCCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)[nH]cc1Cc1cncnc1
Temperature: 160 °C
Yield: 24.9 %

Procedure:
To the suspension of methyl (2E)-3-hydroxy-2-(5-pyrimidinylmethyl)-2-propenoate (302 mg, 1.557 mmol) and 2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)ethyl imidocarbamate triflate (527 mg, 1.038 mmol) in NMP (12 mL) was added K2CO3 (430 mg, 3.11 mmol). The mixture was heated with a microwave reactor at 160° C. for 1 h. Purification via MDAP then afforded the title compound (130 mg, 24.91% yield). LCMS: rt=3.43 min, [M+H+]=503