Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1([NH:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si](C)(C)[N-][Si](C)(C)C.[K+].[C:44]([Si:48]([O:51][CH2:52][CH2:53][CH2:54]I)([CH3:50])[CH3:49])([CH3:47])([CH3:46])[CH3:45].C[SiH2]C>CN(C)C=O>[CH2:1]([O:8][C:9]([C:11]1([N:16]([CH2:54][CH2:53][CH2:52][O:51][Si:48]([C:44]([CH3:45])([CH3:47])[CH3:46])([CH3:49])[CH3:50])[S:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OCCCI
Reactant: O=C(OCc1ccccc1)C1(NS(=O)(=O)c2ccc(Oc3ccc(F)cc3)cc2)CCCC1
Agent: C[SiH2]C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCN(C1(C(=O)OCc2ccccc2)CCCC1)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 103.7 %

Procedure:
To a solution of 1-[4-(4-fluorophenoxy)benzenesulfonylamino]-cyclopentanecarboxylic acid benzyl ester (199 grams, 0.42 mole) in dry N,N-dimethylformamide (2.5 L) at room temperature was added potassium hexamethyldisilazide (100 grams, 0.50 mole) and, after 3 hours, tert-butyl-(3-iodopropoxy)dimethylsilane (150 grams, 0.50 mole). The resulting mixture was stirred at room temperature for 16 hours. Additional tert-butyl-3-iodopropoxy)-dimethylsilane (20 grams, 0.067 mole) was then added. Stirring at room temperature was continued for a further 3.5 hours. The mixture was quenched by addition of saturated ammonium chloride solution. The N,N-dimethylformamide was removed by evaporation under vacuum. The residue was taken up in diethyl ether and washed with water and brine. After drying over magnesium sulfate, the diethyl ether was evaporated to afford crude 1-{[3-(tert-butyl-dimethylsilanyloxy)-propyl]-[4-(4-fluorophenoxy)benzenesulfonyl]-amino}cyclopentanecarboxylic acid benzyl ester as an amber oil (279.6 grams).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([N:28]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([C:47]([CH3:50])([CH3:49])[CH3:48])=[CH:43][CH:42]=2)[CH2:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:32][CH:31]=2)[C:17]([NH:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH:16]([N:28]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([C:47]([CH3:50])([CH3:49])[CH3:48])=[CH:43][CH:42]=2)[CH2:29][C:30]2[CH:31]=[CH:32][C:33]([C:36]([CH3:37])([CH3:38])[CH3:39])=[CH:34][CH:35]=2)[CH2:17][NH:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)c1ccc(CN(Cc2ccc(C(C)(C)C)cc2)C(Cc2ccc(OCc3ccccc3)cc2)C(=O)NCCN2CCCCC2)cc1
Agent: [Li]
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(CN(Cc2ccc(C(C)(C)C)cc2)C(CNCCN2CCCCC2)Cc2ccc(OCc3ccccc3)cc2)cc1
Yield: 72 %

Procedure:
A solution of 900 mg (1.75 mmol) 3-(4-benzyloxy-phenyl)-2-[bis-(4-tert-butyl-benzyl)-amino]-N-(2-piperidin-1-yl-ethyl)-propionamide (Example 10) in 36 mL dry THF was treated portionwise with 332 mg (8.76 mmol) lithium tetrahydriodoaluminate, and the resulting suspension was heated under reflux for 16 hours. The mixture was then carefully quenched with 0.4 mL H2O, followed by 2.0 mL 2N NaOH solution, and finally 0.8 mL H2O. The mixture was filtered and the solids washed with chloroform. The filtrate was treated with 50 mL H2O, and after layers separated, the aqueous layer was extracted with an additional 50 mL chloroform. The combined organic extracts were washed with brine, dried over anhydrous magnesium sulphate, and concentrated at reduced pressure to give 832 mg of an amber oil. The oil was purified by column chromatography on silica gel (230-400 mesh) using 2% to 5% methanol in chloroform as eluant to give 612 mg (69%) of the title compound as a viscous, pale yellow liquid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[N:9]=[C:10](I)[C:3]=12.[F:25][C:26]1[CH:41]=[CH:40][CH:39]=[CH:38][C:27]=1[O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[N:9]=[C:10]([C:32]3[CH:31]=[CH:30][C:29]([O:28][C:27]4[CH:38]=[CH:39][CH:40]=[CH:41][C:26]=4[F:25])=[CH:34][CH:33]=3)[C:3]=12
Reactant: OB(O)c1ccc(Oc2ccccc2F)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC(n2nc(I)c3c(N)ncnc32)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCCC(n2nc(-c3ccc(Oc4ccccc4F)cc3)c3c(N)ncnc32)C1
Temperature: 100 °C
Reaction time: 8 h
Yield: 58.3 %

Procedure:
Into a 100 mL, 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of tert-butyl 3-[4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate (300 mg, 0.68 mmol, 1.00 equiv) in dioxane/H2O(7/3=V/V) (30 mL), [4-(2-fluorophenoxy)phenyl]boronic acid (500 mg, 2.16 mmol, 6.99 equiv), sodium carbonate (200 mg, 1.89 mmol, 0.26 equiv), and Pd(PPh)4 (500 mg, 0.43 mmol, 3.19 equiv). The resulting solution was stirred overnight at 100° C. in an oil bath an then concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (100:1) to give 0.2 g (59%) of tert-butyl 3-[4-amino-3-[4-(2-fluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate as a light yellow solid.
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]2[CH2:17][CH2:16][CH:15]([NH:18][CH:19]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[C:20]([NH2:22])=[O:21])[CH2:14][CH2:13]2)=[CH:4]1.[C:29](O)(=[O:38])/[CH:30]=[CH:31]/[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]2[CH2:17][CH2:16][CH:15]([NH:18][CH:19]([CH:23]3[CH2:24][CH2:25][N:26]([C:29](=[O:38])/[CH:30]=[CH:31]/[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH2:27][CH2:28]3)[C:20]([NH2:22])=[O:21])[CH2:14][CH2:13]2)=[CH:4]1
Reactant: NC(=O)C(NC1CCC(c2c[nH]c3ccccc23)CC1)C1CCNCC1
Reactant: O=C(O)/C=C/c1ccccc1
Agent: Cl
Product: NC(=O)C(NC1CCC(c2c[nH]c3ccccc23)CC1)C1CCN(C(=O)/C=C/c2ccccc2)CC1

Procedure:
The title compound was prepared from the product of Example 1, step J, and trans-cinnamic acid, by the method of Example 1, step K, giving a solid that was a mixture of cyclohexyl diastereomers by LCMS. Mass spectrum (LCMS, ESI pos.) calcd. for C30H36N4O2: 484 (M+H). Found: 484
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:11][CH3:12])[CH:3]=1.C(Cl)(=O)C(Cl)=O.CN(C=O)C.C(N(CC)CC)C.O[CH2:32][P:33](=[O:40])([O:37][CH2:38][CH3:39])[O:34][CH2:35][CH3:36]>C(Cl)Cl.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:32][P:33]([O:37][CH2:38][CH3:39])([O:34][CH2:35][CH3:36])=[O:40])=[O:7])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: COc1cc(Cl)ccc1C(=O)O
Reactant: CCOP(=O)(CO)OCC
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: CCOP(=O)(COC(=O)c1ccc(Cl)cc1OC)OCC
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 4-chloro-2-methoxybenzoic acid (1 mmol), oxalyl chloride (1 mmol) and DMF (0.05 mmol) in 2 mL of CH2Cl2 was stirred at rt for 6 h and then evaporated. To the residue was added 2 mL of CH2Cl2, triethylamine (2 mmol) and diethyl (hydroxymethyl)phosphonate (0.33 mmol) and this mixture was stirred at rt for 16 h and then diluted with water and CH2Cl2. The organic layer was dried (MgSO4) and evaporated. Purification of the residue by silica gel chromatography provided diethylphosphonomethyl 4-chloro-2-methoxybenzoate as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[NH2:18][CH:19]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:20]1>>[CH2:24]([N:21]1[CH2:22][CH2:23][CH:19]([NH:18][C:7](=[O:9])[C:6]2[CH:10]=[C:2]([Cl:1])[C:3]([N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:4][C:5]=2[O:11][CH3:12])[CH2:20]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CCN(CC)c1cc(OC)c(C(=O)O)cc1Cl
Reactant: NC1CCN(Cc2ccccc2)C1
Product: CCN(CC)c1cc(OC)c(C(=O)NC2CCN(Cc3ccccc3)C2)cc1Cl

Procedure:
Following the procedure set forth in general method A supra using 1.29 g. of 5-chloro-4-diethylamino-2-methoxybenzoic acid and 0.97 g. of 3-amino-1-benzylpyrrolidine, 0.93 g. of oily N-(1-benzyl-3-pyrrolidinyl)-5-chloro-4-diethylamino-2-methoxybenzamide was obtained (purified by a silica gel column chromatography using a mixture of chloroform, ether and methanol (volume ratio 5:2:1) as an eluting solution).
Reaction SMILES: [N:1]1([CH2:7][CH:8]2[CH2:13][NH:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[O:9]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl.[N:19]([O-])=[O:20].[Na+]>O>[N:1]1([CH2:7][CH:8]2[CH2:13][N:12]([N:19]=[O:20])[C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[O:9]2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: c1ccc2c(c1)NCC(CN1CCOCC1)O2
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=NN1CC(CN2CCOCC2)Oc2ccccc21

Procedure:
Similarly 8 g (0.034 mole) of racemic 2-(4-morpholinylmethyl)-3,4-dihydro-2H-1,4-benzoxazine in about 130 ml. of 2N aqueous hydrochloric acid was treated with 1.3 g (0.019 mole) of sodium nitrite in about 100 ml of water at 0° C. to produce racemic 2-(4-morpholinylmethyl)-4-nitroso-3,4-dihydro-2H-1,4-benzoxazine, which was used as such in the next synthetic step without further purification or characterization.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH:13]([CH2:14][N:15]([C@@H:23]([C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=[CH:27][CH:26]=3)[CH3:24])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:12][CH2:11][NH:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Cl[C:38]1[O:39][C:40]2[CH:46]=[CH:45][C:44]([C:47]([O:49][CH3:50])=[O:48])=[CH:43][C:41]=2[N:42]=1.O>CS(C)=O>[C:18]([O:17][C:16]([N:15]([CH2:14][CH:13]1[CH2:12][CH2:11][N:10]([C:38]2[O:39][C:40]3[CH:46]=[CH:45][C:44]([C:47]([O:49][CH3:50])=[O:48])=[CH:43][C:41]=3[N:42]=2)[CH2:9][CH:8]1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)[C@@H:23]([C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1)[CH3:24])=[O:22])([CH3:19])([CH3:21])[CH3:20]
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CCNCC1c1cccc(F)c1)C(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc2oc(Cl)nc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1ccc2oc(N3CCC(CN(C(=O)OC(C)(C)C)[C@H](C)c4cccc5ccccc45)C(c4cccc(F)c4)C3)nc2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 12.9 %

Procedure:
To a solution of 185 mg of tert-butyl {[3-(3-fluorophenyl)piperidin-4-yl]methyl}[(1R)-1-(1-naphthyl)ethyl]carbamate in 2.00 mL of DMSO was added 18 mg of sodium hydride (55% dispersion) at room temperature, followed by stirring for 10 minutes. 89 mg of methyl 2-chloro-1,3-benzoxazole-5-carboxylate was added thereto, followed by stirring at 100° C. overnight. 55 mg of methyl 2-chloro-1,3-benzoxazole-5-carboxylate was further added thereto, followed by stirring at 100° C. overnight. The reaction mixture was cooled to room temperature, and water was then added thereto, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate and chloroform-methanol) to obtain 33 mg of methyl 2-[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-(3-fluorophenyl)piperidin-1-yl]-1,3-benzoxazole-5-carboxylate as a colorless resinous compound. ESI+: 638
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[C:6]([C:13]#[N:14])=[C:5]2[CH3:15].[N-:16]=[N+:17]=[N-:18].[NH4+]>CCO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[C:6]([C:13]1[NH:18][N:17]=[N:16][N:14]=1)=[C:5]2[CH3:15]
Reactant: Cc1c(C#N)c(=O)oc2ccc(Cl)cc12
Reactant: [N-]=[N+]=[N-]
Agent: [NH4+]
Solvent: CCO
Product: Cc1c(-c2nnn[nH]2)c(=O)oc2ccc(Cl)cc12

Procedure:
The reaction of 6-Chloro-3-cyano-4-methyl coumarin with ammonium azide as described in Example 1 yielded the title product, m.p. (EtOH) 219°-223° C. (Found: C, 50.30; H, 2.69; N, 21.33; C11H7ClN4O2 requires; C, 50.04; H, 2.84; N, 21.63%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([NH:11][C:12]([C:15]2[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][N:16]=2)([CH3:14])[CH3:13])=[N:9][CH:10]=1)=O.[CH2:22]([O:24][C:25]([C:27]1[N:28]=[C:29]([NH2:32])[S:30][CH:31]=1)=[O:26])[CH3:23]>CC(CC)=O>[Cl:21][C:20]1[C:15]([C:12]([NH:11][C:8]2[N:7]=[CH:6][C:5]([C:3]3[N:32]=[C:29]4[N:28]([CH:2]=3)[C:27]([C:25]([O:24][CH2:22][CH3:23])=[O:26])=[CH:31][S:30]4)=[CH:10][N:9]=2)([CH3:14])[CH3:13])=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(Nc1ncc(C(=O)CBr)cn1)c1ncccc1Cl
Reactant: CCOC(=O)c1csc(N)n1
Solvent: CCC(C)=O
Product: CCOC(=O)c1csc2nc(-c3cnc(NC(C)(C)c4ncccc4Cl)nc3)cn12
Temperature: 90 °C
Reaction time: 8 h
Yield: 26.6 %

Procedure:
To a 20 dram vial was added 2-bromo-1-(2-(2-(3-chloropyridin-2-yl)propan-2-ylamino)pyrimidin-5-yl)ethanone (103 mg, 0.28 mmol), ethyl-2-aminothiazole-4-carboxylate (48 mg, 0.28 mmol), and methylethylketone (2 mL). The mixture was heated to 90° C. in a sealed tube and stirred overnight. The reaction was then concentrated and purified by silica gel chromatography (EtOAc/hex) to afford 33 mg of ethyl 6-(2-(2-(3-chloropyridin-2-yl)propan-2-ylamino)pyrimidin-5-yl)imidazo[2,1-b]thiazole-3-carboxylate as a tan solid. This compound was dissolved in methanol (1 mL) and ammonium hydroxide (3 mL) was added. The resulting mixture was heated in a microwave reactor to 135° C. and stirred for 15 min. The reaction was concentrated, followed by the addition of HBTU (68 mg, 179 μmol), HOBt (24 mg, 179 μmol), NH4Cl (48 mg, 1.1 mmol), DIPEA (78 μL, 441 μmol), and NMP (2 mL). The reaction was stirred for 2 h and then purified directly by reverse phase chromatography to afford 18 mg of 6-(2-(2-(3-chloropyridin-2-yl)propan-2-ylamino)pyrimidin-5-yl)imidazo[2,1-b]thiazole-3-carboxamide as an off-white solid (M+H=414.1).
Reaction SMILES: [CH3:1]OP(C(=[N+]=[N-])C(=O)C)(=O)OC.[C:13]([C:15]1[CH:16]=[N:17][C:18]2[C:23]([CH:24]=1)=[CH:22][C:21]([O:25][CH:26]([S:37][CH3:38])[C:27]([NH:29][C:30]([CH2:34][O:35][CH3:36])([CH3:33])[CH:31]=O)=[O:28])=[CH:20][CH:19]=2)#[CH:14].C([O-])([O-])=O.[K+].[K+]>CO.C(OCC)(=O)C>[C:13]([C:15]1[CH:16]=[N:17][C:18]2[C:23]([CH:24]=1)=[CH:22][C:21]([O:25][CH:26]([S:37][CH3:38])[C:27]([NH:29][C:30]([CH2:34][O:35][CH3:36])([CH3:33])[C:31]#[CH:1])=[O:28])=[CH:20][CH:19]=2)#[CH:14]
Reactant: C#Cc1cnc2ccc(OC(SC)C(=O)NC(C)(C=O)COC)cc2c1
Reactant: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: C#Cc1cnc2ccc(OC(SC)C(=O)NC(C)(C#C)COC)cc2c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 87.6 %

Procedure:
A mixture of (1-diazo-2-oxo-propyl)-phosphonic acid dimethyl ester (Bestmann's reagent) (43 mg) and 2-(3-ethynyl-quinolin-6-yloxy)-N-(1-methoxymethyl-1-methyl-2-oxo-ethyl)-2-methylsulfanyl-acetamide (60 mg) in MeOH (6 ml) was cooled to 0° C. Solid K2CO3 (40 mg) was added and the mixture stirred during 16 hour allowing the temperature raising to 25° C. The reaction mixture was diluted with ethyl acetate and poured onto brine. The water phase was extracted twice with ethyl acetate and the combined organic phases dried over sodium sulfate, filtered and evaporated. The crude residue was purified by column chromatography to give 2-(3-ethynyl-quinolin-6-yloxy)-N-(1-methoxymethyl-1-methyl-prop-2-ynyl)-2-methylsulfanyl-acetamide (52 mg) as a light brown oil as a mixture of diastereoisomers.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.S([O-])(O[O-])(=O)=[O:19].[K+].[K+]>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13]([C:14]([OH:19])=[O:15])=[CH:16][CH:17]=2)=[CH:6][CH:7]=1
Reactant: O=S(=O)([O-])O[O-]
Reactant: O=Cc1ccc(C#Cc2ccc(F)cc2)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1ccc(C#Cc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.8 %

Procedure:
To a solution of 4-[(4-fluorophenyl)ethynyl]benzaldehyde (10.39 g; 46.37 mmol, intermediate which may be obtained according to methods disclosed in EP03 103780.7) in DMF (400 mL) was added potassium peroxomonosulfate (28.5 g, 46.4 mmol) in one portion at rt. The reaction mixture was stirred at rt overnight. The reaction mixture was poured in water (2 L) and the resulting precipitate was filtered off, washed with water and dried under reduced pressure to give 10.45 g (94%) of the title compound as a white powder. HPLC, Rt: 3.98 min (purity: 98.6%). 1H NMR (DMSO-d6) δ: 13.15 (brs, 1H), 7.96 (d, J=8.1 Hz, 2H), 7.64 (m, 4H), 7.29 (t, J=8.9 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[S:16]1C2C=CC=CC=2[N:18]=[C:17]1NC(=O)C(O)=O>>[NH2:18][C:17]1[S:16][C:3]2[C:4]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[CH:5][CH:6]=[C:7]([O:8][CH3:9])[C:2]=2[N:1]=1
Reactant: COc1ccc(-c2ccccc2)cc1N
Reactant: O=C(O)C(=O)Nc1nc2ccccc2s1
Product: COc1ccc(-c2ccccc2)c2sc(N)nc12

Procedure:
The title compound was prepared from 3-amino-4-methoxy-biphenyl, according to the patent literature N-(Benzothiazol-2-yl)oxamic acid derivatives. W. Winter, M. Thiel, A. Roesch and O. H. Wilhelms, German Patent, DE 2656468, 1978. and is obtained as a white solid, MS: m/e=256 (M+), mp. 207-208° C.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([NH:7][C@H:8]1[CH2:12][CH2:11][O:10][CH2:9]1)=[O:6].[H-].[Na+]>C1COCC1>[O:10]1[CH2:11][CH2:12][C@H:8]([N:7]2[CH2:2][CH2:3][NH:4][C:5]2=[O:6])[CH2:9]1
Reactant: O=C(NCCCl)N[C@H]1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1NCCN1[C@H]1CCOC1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 29.2 %

Procedure:
A −20° C. solution of (S)-1-(2-chloroethyl)-3-(tetrahydrofuran-3-yl)urea (0.11 g, 0.571 mmol) in THF (6 mL) was treated with NaH (60% in mineral oil, 0.057 g, 1.428 mmol), stirred at −20° C. for 0.5 h, then at RT for 1 h. The mixture was treated with satd. NH4Cl and H2O, extracted with EtOAc (3×) and THF (2×) and the combined organics were washed with brine (1×), dried over MgSO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford (S)-1-(tetrahydrofuran-3-yl)imidazolidin-2-one (26 mg, 29%). 1H NMR (400 MHz, DMSO-d6): δ 6.32 (brs, 1 H), 4.36-4.30 (m, 1 H), 3.83-3.77 (m, 1 H), 3.63-3.53 (m, 4 H), 3.31-3.26 (m, 1 H), 3.24-3.21 (m, 2 H); 2.05-1.96 (m, 1 H); 1.84-1.76 (m, 1 H). MS (ESI) m/z: 157.1 (M+H+).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH:11]=[O:12])[C:2]=1[CH:13]=[O:14].O[C:16]1[C:25]2[C:20](=CC=CC=2)[C:19](O)=[CH:18][CH:17]=1>>[CH:16]1[C:25]2[C:13](=[O:14])[C:2]3[C:3](=[CH:4][C:5]4[C:10]([CH:1]=3)=[CH:9][C:8]3[C:7](=[CH:10][CH:1]=[CH:2][CH:3]=3)[CH:6]=4)[C:11](=[O:12])[C:20]=2[CH:19]=[CH:18][CH:17]=1
Reactant: O=Cc1cc2ccccc2cc1C=O
Reactant: Oc1ccc(O)c2ccccc12
Product: O=C1c2ccccc2C(=O)c2cc3cc4ccccc4cc3cc21
Temperature: 120 °C

Procedure:
To a flame-dried flask was added 2,3-naphthalenedicarboxaldehyde (1 molar equivalent (0.29 g, 1.57 mmol)) and 1,4-dihydroxynaphthalene (1 molar equivalent (0.25 g, 1.57 mmol)) these reagents were flushed with nitrogen for 15 minutes before anhydrous pyridine (5 ml) was added. The resulting solution was stirred at 120° C. with stirring for 24 hours. On cooling, the solid product was filtered off and washed successively with methanol (10 ml), 10% copper sulphate solution (10 ml), water (10 ml) and acetone (10 ml) and dried in vacuum oven. The product was an orange/brown solid (0.14 g, 29%) and was greater than 90% pure by HPLC. 1H NMR (D8-THF) δ 9.09 (2H, s, H—Ar), 8.87 (2H, s, H—Ar), 8.38 (2H, m, H—Ar), 8.15 (2H, m, H—Ar), 7.87 (2H, m, H—Ar) and 7.61 ppm (2H, m, H—Ar).
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH3:12])[NH:9][C:8](=[O:13])[CH:7]=1.[CH2:19](Br)[C:20]#[CH:21]>>[F:1][C:2]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH3:12])[N:9]([CH2:21][C:20]#[CH:19])[C:8](=[O:13])[CH:7]=1
Reactant: Cc1cc(OCc2ccc(F)cc2F)cc(=O)[nH]1
Reactant: C#CCBr
Product: C#CCn1c(C)cc(OCc2ccc(F)cc2F)cc1=O
Yield: 44.9 %

Procedure:
The title compound was prepared by alkylation of 4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one (2.5 g, 10 mmol) with propargyl bromide (1.3 ml, 11.0 mmol) as described above to give 1.3 g (44%) of the desired product. 1H-NMR (DMSOd6/300 MHz) δ 7.60 (app q, J=8.4 hz, 1H), 7.35-7.27 (m, 1H); 7.16-7.10 (m, 1H); 5.94 (d, J=2.1 Hz, 1H), 5.88 (d, J=3.0 Hz, 1H), 5.03 (s, 2H), 4.76 (d, J=2.4, Hz, 2H), 3,31 (s, 3H), 3.24 (t, J=2.4 Hz, 1H), 2.39 (s, 3H); ES-HRMS m/z 290.0994 (M+H calcd for C16H14F2NO2=290.0993).
Reaction SMILES: [CH2:1]([O:3][P:4](/[CH:9]=[CH:10]/[C:11]1[C:12]([O:22][CH2:23][C:24]2[CH:48]=[CH:47][C:27]([O:28][CH2:29][C:30]3[N:31]=[C:32]([C:36]4[CH:37]=[CH:38][C:39]([CH3:46])=[C:40]([CH:45]=4)[C:41]([O:43]C)=[O:42])[O:33][C:34]=3[CH3:35])=[C:26]([O:49][CH3:50])[CH:25]=2)=[N:13][N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:15]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].O1CCC[CH2:52]1.[OH-].[Na+].Cl>O.C(O)C>[CH2:1]([O:3][P:4](/[CH:9]=[CH:10]/[C:11]1[C:12]([O:22][CH2:23][C:24]2[CH:48]=[CH:47][C:27]([O:28][CH2:29][C:30]3[N:31]=[C:32]([C:36]4[CH:37]=[CH:38][C:39]([CH3:46])=[C:40]([CH:45]=4)[C:41]([OH:43])=[O:42])[O:33][C:34]=3[CH2:35][CH3:52])=[C:26]([O:49][CH3:50])[CH:25]=2)=[N:13][N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:15]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: C1CCOC1
Reactant: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccc(C)c(C(=O)OC)c3)oc2C)c(OC)c1)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccc(C)c(C(=O)O)c3)oc2CC)c(OC)c1)OCC
Temperature: 60 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To a mixture of methyl 5-[4-({4-[({4-[(E)-2-(diethoxyphosphoryl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]-2-methylbenzoate (0.46 g), tetrahydrofuran (2 mL) and ethanol (2 mL) was added 1N aqueous sodium hydroxide solution (2 mL), and the mixture was stirred at 60° C. for 1 hr. To the reaction mixture were added 1N hydrochloric acid (2 mL) and water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 5-[4-({4-[({4-[(E)-2-(diethoxyphosphoryl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-ethyl-1,3-oxazol-2-yl]-2-methylbenzoic acid as colorless crystals (0.39 g, yield 87%). Recrystallization from acetone-hexane gave colorless prism crystals. melting point: 165-166° C.