Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC[OH:46]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH2:15][OH:46])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Reactant: OCCBr
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(CCO)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-bromoethanol and isolated as white solid (5.8 mg, 43%). MS (m/e): 327.3 (MH+).
Reaction SMILES: [Br-].[Mg+2].[Br-].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[C:12]2[O:16][C:15]3[CH:17]=[C:18]([O:21][CH3:22])[CH:19]=[CH:20][C:14]=3[C:13]2([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:26][CH:25]=2)O)=[CH:7][CH:6]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[H][H]>CCOCC.C(OCC)(=O)C>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[O:16][C:15]3[CH:17]=[C:18]([O:21][CH3:22])[CH:19]=[CH:20][C:14]=3[C:13]=2[C:24]2[CH:25]=[CH:26][C:27]([O:30][CH2:31][CH2:32][N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)=[CH:28][CH:29]=2)=[CH:7][CH:6]=1
Reactant: [H][H]
Reactant: COc1ccc2c(c1)OC(=Cc1ccc(Cl)cc1)C2(O)c1ccc(OCCN2CCOCC2)cc1
Agent: [Al+3]
Agent: [Br-]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COc1ccc2c(-c3ccc(OCCN4CCOCC4)cc3)c(Cc3ccc(Cl)cc3)oc2c1
Reaction time: 1 h

Procedure:
Magnesium bromide etherate (0.194 g, 0.75 mmol) was dissolved in 20 ml ether in a two-necked flask under oxygen-free nitrogen atmosphere at room temperature. After stirring for 1 hour, 2-(p-chlorophenylmethylene)-3-[p-(2-morpholinoethoxy)phenyl]-6-methoxy- 2,3-dihydrobenzo[b]furan-3-ol (5) (0.247 g, 0.5 mmol) in ether (10 ml) was added dropwise to the mixture. After stirring for 4 hours, LiAlH4 (0.076 g, 2.0 mmol) was added to the above reaction mixture. The reaction mixture was left overnight at room temperature. After stirring overnight, ethyl acetate was added dropwise till hydrogen evolution ceased. The above mixture was washed with water followed by brine (2×20 ml), dried (anhydrous magnesium sulfate) and the solvent was evaporated off to give an oil which was chromatographed on silica. Elution with (chloroform: hexane: triethylamine=1:1:0.2) yielded a white solid of the free base (Rf =0.4). Yield (60%); m.p. 126°-128° C.; 1H-NMR (CDCl3) (δ) 2.60-2.63 (m, 4H, N(CH2CH2)2O (ring)), 2.85 (t, 2H, OCH2CH2N), 3.74-3.77 (m, 4H, N(CH2CH2)2O (ring)), 3.84 (s, 3H, OCH3), 4.11 (CH2 at C-2), 4.17 (t, 2H, OCH2CH2N), 6.84-7.44 (m, 11H, ArH); m/z (%) 479 (10), 491 (35), 100 (100).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][OH:14])=[C:11]([CH3:15])[O:10][N:9]=2)=[N:6][CH:7]=1>C(Cl)Cl.[O-2].[Mn+4].[O-2]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH:13]=[O:14])=[C:11]([CH3:15])[O:10][N:9]=2)=[N:6][CH:7]=1
Reactant: Cc1onc(-c2ccc(F)cn2)c1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cc1onc(-c2ccc(F)cn2)c1C=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 40.6 %

Procedure:
To a solution of [3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-methanol (2.10 g, 10.1 mmol) in DCM (240 mL) was added manganese(IV) oxide (activated 85%, 20.63 g, 201 mmol) and the reaction mixture was stirred vigorously at room temperature for 3 days. The reaction mixture was filtered through dicalite and then fresh manganese(IV) oxide (activated 85%, 20.63 g, 201 mmol) was added and the reaction mixture stirred vigorously at room temperature for another 4 days. The reaction mixture was filtered through dicalite and evaporated. The combined DCM extracts were then dried over sodium sulfate, filtered and evaporated. Purification by chromatography (silica, 0 to 50% ethyl acetate in heptane) gave the title compound (845 mg, 40%) as a white solid. MS: m/e=207.0 [M+H]+.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:30])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([C:24]#[C:25][CH2:26][N:27]([CH3:29])[CH3:28])[CH:20]=4)[N:15]=[CH:14]3)[CH:7]=2)[CH2:3][CH2:2]1.CO>[Pd].C(O)C>[CH:1]1([NH:4][C:5](=[O:30])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([CH2:24][CH2:25][CH2:26][N:27]([CH3:28])[CH3:29])[CH:20]=4)[N:15]=[CH:14]3)[CH:7]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(C#CCN(C)C)cc2c1=O
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(CCCN(C)C)cc2c1=O
Yield: 69.4 %

Procedure:
N-Cyclopropyl-3-[6-[3-(dimethylamino)prop-1-yn-1-yl]-4-oxoquinazolin-3(4H)-yl]-4-methylbenzamide (0.097 g) and 10% Palladium on carbon (0.01 g) were stirred in ethanol (2 ml) and methanol (0.5 ml) under an atmosphere of hydrogen for 2 hours. The catalyst was removed by filtration through diatomaceous earth (Celite®) and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on a silica column eluting with 10% methanol/ethyl acetate followed by 10% methanol/ethyl acetate+1% aqueous ammonia solution to give the title compound (0.068 g) as a white foam solid; NMR Spectrum: (DMSOd6) 0.56 (m, 2H), 0.70 (m, 2H), 1.78 (m, 2H), 2.15 (s, 9H), 2.23 (t, 2H), 2.78 (t, 2H), 2.86 (m, 1H), 7.53 (d, 1H), 7.71 (d, 1H), 7.78 (d, 1H), 7.83 (s, 1H), 7.91 (d, 1H), 8.02 (s, 1H), 8.25 (s, 1H), 8.42 (d, 1H); Mass Spectrum: M+H+ 405.
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[C:10]([C:12]3[CH2:13][CH2:14][N:15](C(OC(C)(C)C)=O)[CH2:16][CH:17]=3)[N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)=O>[C:1]1([N:7]2[CH:11]=[C:10]([C:12]3[CH2:13][CH2:14][NH:15][CH2:16][CH:17]=3)[N:9]=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cn(-c3ccccc3)nn2)CC1
Solvent: O=CO
Product: C1=C(c2cn(-c3ccccc3)nn2)CCNC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 101 %

Procedure:
tert-Butyl 4-[1-phenyl-1H-[1,2,3]triazol-4-yl]-1,2,3,6-tetrahydropyridine-1-carboxylate (50 mg) was dissolved in 1 ml of formic acid followed by stirring at room temperature for 4 hours. After formic acid was evaporated in vacuo, the residue was dissolved in chloroform and washed with a saturate aqueous solution of sodium bicarbonate and then with a saturated saline solution. After the organic layer was dried over sodium sulfate, the solvent was evaporated in vacuo to give 35 mg of crude product of the title compound as an oily substance.
Reaction SMILES: C[O:2][C:3](=[O:38])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([NH:23][C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([S:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=2)=[O:25])[C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=2)=[CH:6][CH:5]=1.[OH-].[Na+]>C(O)C>[CH:17]1([C:14]2[CH:13]=[CH:12][C:11]([CH:10]([NH:23][C:24]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([S:33][C:34]([F:37])([F:35])[F:36])=[CH:29][CH:28]=3)=[O:25])[C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:38])=[O:2])=[CH:5][CH:6]=3)=[CH:16][CH:15]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: COC(=O)c1ccc(C(NC(=O)Nc2ccc(SC(F)(F)F)cc2)c2ccc(C3CCCCC3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(Nc1ccc(SC(F)(F)F)cc1)NC(c1ccc(C(=O)O)cc1)c1ccc(C2CCCCC2)cc1
Reaction time: 8 h
Yield: 65.6 %

Procedure:
4-[1-(4-Cyclohexylphenyl)-3-(4-trifluoromethylsulfanylphenyl)ureidomethyl]benzoic acid methyl ester (0.53 g, 0.98 mmol) was dissolved in ethanol (96%, 11 mL) and sodium hydroxide (4 N, 1.47 mL) was added. The mixture was stirred overnight. The reaction was concentrated to dryness and added water (15 mL) and acidified with hydrochloric acid (4 N, 1.6 mL) to pH 2-3 and extracted with ethyl acetate (25 mL). The aqueous phase was extracted once more with ethyl acetate (15 mL) and the combined organic phases were washed 3 times with water (10 mL), dried over magnesium sulphate, filtered and concentrated in vacuo. Crystallisation from ethyl acetate:n-heptane gave 0.34 g of 4-[1-(4-cyclohexylphenyl)-3-(4-trifluoromethylsulfanylphenyl)ureidomethyl]benzoic acid.
Reaction SMILES: C([N:8]1[CH2:12][C@:11]2([O:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][C@@H:10]2[CH2:9]1)C1C=CC=CC=1>CCO.[OH-].[OH-].[Pd+2]>[C:27]([O:26][C:24]([O:23][C@@:11]12[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][C@@H:10]1[CH2:9][NH:8][CH2:12]2)=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)O[C@]12CN(Cc3ccccc3)C[C@H]1CN(C(=O)OC(C)(C)C)C2
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)O[C@]12CNC[C@H]1CN(C(=O)OC(C)(C)C)C2
Reaction time: 18 h

Procedure:
To a solution of tert-butyl(cis)-5-benzyl-3a-[(tert-butoxycarbonyl)oxy]hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (274 mg, 0.861 mmol) in EtOH (8.61 mL) purged with nitrogen was added Pd(OH)2/C (27 mg) and the resulting mixture stirred under a H2 balloon for 18 hrs. The reaction mixture was filtered and then concentrated under reduced pressure to obtain the crude title compound that was carried forward to the next step without further purification. m/z (APCI+) for C16H28N2O5 429.20 (M+H)+.
Reaction SMILES: [CH:1]1([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH2:10](Br)[C:11]#[CH:12]>>[CH2:8]([O:7][C:5]([C:1]1([CH2:12][C:11]#[CH:10])[CH2:4][CH2:3][CH2:2]1)=[O:6])[CH3:9]
Reactant: CCOC(=O)C1CCC1
Reactant: C#CCBr
Product: C#CCC1(C(=O)OCC)CCC1

Procedure:
In analogy to the procedure described in example 24C], reaction of ethyl cyclobutanecarboxylate and propargyl bromide gave the title compound as brown liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=O)[CH2:18][O:19][C:20]3[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=3)[C:23]([O:25][CH3:26])=[O:24])=[C:12]([NH:31][CH3:32])[CH:11]=2)[CH:6]=[CH:5][N:4]=1>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]3[N:16]=[C:17]([CH2:18][O:19][C:20]4[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=4)[C:23]([O:25][CH3:26])=[O:24])[N:31]([CH3:32])[C:12]=3[CH:11]=2)[CH:6]=[CH:5][N:4]=1
Reactant: CNc1cc(Oc2ccnc(OC)c2)ccc1NC(=O)COc1cccc(C(=O)OC)c1
Solvent: CC(=O)O
Product: COC(=O)c1cccc(OCc2nc3ccc(Oc4ccnc(OC)c4)cc3n2C)c1
Yield: 71.8 %

Procedure:
Methyl 3-[2-({4-[(2-methoxypyridin-4-yl)oxy]-2-(methylamino)phenyl}amino)-2-oxoethoxy]benzoate produced in Example (16e) (4.52 g, 10.3 mmol) and acetic acid (50 mL) was stirred at 80° C. for two hours. The reaction mixture was concentrated and then water (100 mL) and sodium bicarbonate were added, followed by extraction with ethyl acetate (100 mL). The organic layer was washed with a saturated sodium bicarbonate aqueous solution (100 mL) twice and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel chromatography (hexane/ethyl acetate, 1:1) to obtain the title compound (3.10 g, 72%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](Br)[C:20]([C:24]#[N:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[Br-].[C:29]([C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[CH2:34][Zn+])#[N:30]>>[CH3:1][O:2][C:3](=[O:27])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:34][C:33]5[CH:36]=[CH:37][CH:38]=[C:31]([C:29]#[N:30])[CH:32]=5)[C:20]([C:24]#[N:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: N#Cc1cccc(C[Zn+])c1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C#N)c4Br)ccc21
Agent: [Br-]
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C#N)c4Cc3cccc(C#N)c3)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-bromo-5-cyano-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 3-cyano-benzylzinc bromide following a procedure analogous to that described in Step 6 of Intermediate 1. LC (method 4): tR=1.18 min; Mass spectrum (ESI+): m/z=487 [M+Na]+.
Reaction SMILES: C(O)(=O)C.[NH2:5][C:6]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([NH2:15])[NH:8][N:7]=1.CN(C)[CH:18]=[CH:19][CH:20]=O>CCO>[NH2:15][C:9]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:6]2[N:5]=[CH:18][CH:19]=[CH:20][N:7]2[N:8]=1
Reactant: COC(=O)c1c(N)n[nH]c1N
Reactant: CN(C)C=CC=O
Solvent: CCO
Solvent: CC(=O)O
Product: COC(=O)c1c(N)nn2cccnc12
Temperature: 25 °C

Procedure:
Acetic acid (0.013 mL, 0.221 mmol) was added to a mixture of methyl 3,5-diamino-1H-pyrazole-4-carboxylate (689 mg, 4.41 mmol, prepared as described in J. Prakt. Chem. 1965, 27, 239-250) and 3-dimethylaminoacrylaldehyde (531 mg, 5.36 mmol) in EtOH (9 mL), and the mixture was heated at reflux for 22 hours, and then cooled to room temperature. The slurry was concentrated under vacuum, and the residue was dissolved in hot methanol (20 mL), allowed to cool to room temperature, then filtered and dried to provide the title compound, in sufficient purity for use in the next step. MS (ESI) m/z 193 (M+H)+.
Reaction SMILES: [N:1]([CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][C@@H:8]([CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)=[O:20])[CH2:15][CH2:14]2)[CH2:7]1)=[N+:2]=[N-:3].[CH:30]12CC(C=C1)C=[CH:31]2>O1CCOCC1>[Cl:29][C:24]1[CH:23]=[C:22]([NH:21][C:19]([N:16]2[CH2:17][CH2:18][N:13]([CH2:12][C@@H:8]3[CH2:9][CH2:10][CH2:11][N:6]([CH2:5][CH2:4][N:1]4[CH:31]=[CH:30][N:3]=[N:2]4)[CH2:7]3)[CH2:14][CH2:15]2)=[O:20])[CH:27]=[CH:26][C:25]=1[Cl:28]
Reactant: [N-]=[N+]=NCCN1CCC[C@@H](CN2CCN(C(=O)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Reactant: C1=CC2C=CC1C2
Solvent: C1COCCO1
Product: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCN(C[C@@H]2CCCN(CCn3ccnn3)C2)CC1
Temperature: 180 °C

Procedure:
4-{[(3R)-1-(2-Azidoethyl)piperidin-3-yl]methyl}-N-(3,4-dichlorophenyl)piperazine-1-carboxamide (100 mg, 0.23 mmol) was dissolved in 1,4-dioxane (4 ml). Bicyclo(2.2.1)hepta-2,5-diene (0.5 ml) was added and the mixture heated in the microwave at 180° C. for 20 minutes. The reaction mixture was poured onto a bond elut column (SiO2, 20 g) and the product eluted with a gradient of dichloromethane through to 20% methanolic ammonia/dichloromethane to yield the title compound as a white solid (80.1 mg)
Reaction SMILES: [C:1](F)(=[O:5])[CH:2]([CH3:4])[CH3:3].[CH3:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=1>>[C:1]([C:13]1[CH:12]=[CH:11][C:10]2[C:15](=[CH:16][CH:17]=[C:8]([CH3:7])[CH:9]=2)[CH:14]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C(=O)F
Reactant: Cc1ccc2ccccc2c1
Product: Cc1ccc2cc(C(=O)C(C)C)ccc2c1

Procedure:
In the BF3 absorption tank, the isobutyryl fluoride solution absorbed BF3 contained in gas released from the acylation reactor, and no BF3 was detected in the analysis of gas purged from the BF3 absorption tank. In the complex preparation tank, the isobutyryl fluoride synthesis solution from the BF3 absorption tank further absorbed BF3 recovered from the distillation column, and in the acylation reactor, the resultant isobutyryl fluoride synthesis solution reacted with 2-methylnaphthalene to give 2-isobutyryl-6-methylnaphthalene.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10](Br)=[CH:9][N:8]=[C:7]([CH3:12])[N:6]=1)=[O:4].[NH2:13][C:14]1[CH:15]=[N:16][CH:17]=[N:18][CH:19]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd].CCCCCCC.C(OCC)(=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[C:10]([NH:13][C:14]2[CH:15]=[N:16][CH:17]=[N:18][CH:19]=2)=[CH:9][N:8]=[C:7]([CH3:12])[N:6]=1)=[O:4]
Reactant: Nc1cncnc1
Reactant: COC(=O)c1nc(C)ncc1Br
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Solvent: ClC(Cl)Cl
Product: COC(=O)c1nc(C)ncc1Nc1cncnc1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
A suspension of 5-bromo-2-methylpyrimidine-4-carboxylic acid methyl ester (89.1 mg, 386 μmol), 5-aminopyrimidine (55.0 mg, 578 μmo) and potassium phosphate tribasic (115 mg, 540 μmol) in toluene (3 mL) was evacuated and flushed with argon. 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos; 73.6 mg, 127 μmol) and tris(dibenzylideneacetone)-dipalladium(0) chloroform adduct (39.9 mg, 38.6 μmol) were added and the reaction mixture was stirred at 120° C. for 16 h. The reaction mixture was poured into ethyl acetate (50 mL) and extracted with water. The organic phase was washed brine and the aqueous layers were back-extracted with ethyl acetate. The organic layers were dried and the solvent was removed. The product was obtained after silica gel chromatography using a heptane/ethyl acetate gradient as light yellow solid (55 mg, 58%).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:16])[NH:10][O:11][CH2:12][C:13]([OH:15])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][C@@H:18]([CH3:42])[C:19]([N:21]([C@@H:33]([CH3:41])[CH:34]([O:38][CH2:39][CH3:40])[O:35][CH2:36][CH3:37])[CH2:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)=[O:20]>>[CH2:1]([NH:8][C:9]([NH:10][O:11][CH2:12][C:13]([NH:17][C@@H:18]([CH3:42])[C:19]([N:21]([C@@H:33]([CH3:41])[CH:34]([O:38][CH2:39][CH3:40])[O:35][CH2:36][CH3:37])[CH2:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)=[O:20])=[O:15])=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CONC(=O)NCc1ccccc1
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](C)N
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](C)NC(=O)CONC(=O)NCc1ccccc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(3-benzylureidooxy)acetic acid (Compound VI-1) 94 mg (0.42 mmol) was coupled with (S)-2-amino-N—((S)-1,1-diethoxypropan-2-yl)-N-(naphthalen-1-ylmethyl)propanamide Compound IV-10) 100 mg (0.28 mmol) to obtain the title compound.
Reaction SMILES: [C:1]([C:3]([OH:10])([CH2:7][CH2:8][CH3:9])[CH2:4][CH2:5][CH3:6])#[CH:2].Br[C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[C:15]#[N:16]>>[OH:10][C:3]([CH2:7][CH2:8][CH3:9])([CH2:4][CH2:5][CH3:6])[C:1]#[C:2][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[C:15]#[N:16]
Reactant: C#CC(O)(CCC)CCC
Reactant: N#Cc1cccc(Br)c1
Product: CCCC(O)(C#Cc1cccc(C#N)c1)CCC

Procedure:
Coupling of 4-ethynylheptan-4-ol with 3-bromobenzonitrile following the method described in Example 12 gives 3-(3-hydroxy-3-propylhex-1-ynyl)benzonitrile.
Reaction SMILES: [H-].[Na+].[OH:3]/[N:4]=[C:5](\[C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:13][CH:12]=1)/[C:6]([O:8]CC)=[O:7].Cl[CH2:25][C:26]1[CH:45]=[CH:44][C:29]([O:30][CH2:31][C:32]2[N:33]=[C:34]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[O:35][C:36]=2[CH3:37])=[CH:28][CH:27]=1.Cl.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:37][C:36]1[O:35][C:34]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)=[N:33][C:32]=1[CH2:31][O:30][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][O:3]/[N:4]=[C:5](\[C:11]2[CH:12]=[CH:13][C:14]([O:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:15][CH:16]=2)/[C:6]([OH:8])=[O:7])=[CH:45][CH:44]=1
Reactant: CCOC(=O)/C(=N/O)c1ccc(Oc2ccccc2)cc1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [H-]
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(/C(=O)O)c2ccc(Oc3ccccc3)cc2)cc1
Reaction time: 1 h
Yield: 81 %

Procedure:
Sodium hydride (60% in oil, 127 mg) was added under a nitrogen atmosphere to a solution of ethyl E-2-hydroxyimino-2-(4-phenoxylphenyl)acetate (910 mg) and 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (1.00 g) in N,N-dimethylformamide (10 ml) at room temperature and the mixture was stirred for 1 hour. After adding 1N HCl (5 ml), aqueous sodium bicarbonate was added, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride, dried (MgSO4) and then concentrated. The residue was subjected to column chromatography on silica gel to obtain an oil from a fraction eluted with ethyl acetate-hexane (1:3, v/v). This oil was dissolved in tetrahydrofuran (10 ml)-methanol (5 ml), and 1N aqueous solution of sodium hydroxide (5 ml) was added and the mixture was stirred at 40° C. for 2 hours. 1N HCl (5.5 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride, dried (MgSO4) and then concentrated. The residual crystal was recrystallized from ethyl acetate-hexane to obtain E-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-2-(4-phenoxyphenyl)acetic acid (1.38 g, yield 81%) as colorless crystals. m.p. 152-153° C. (decomposition)
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH:17]([O:24]C(=O)C3C=CC=CC=3)[C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[N:9][N:8]=2)=[CH:4][CH:3]=1.O.[OH-].[Li+]>O1CCOCC1.CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH:17]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[OH:24])=[N:9][N:8]=2)=[CH:33][CH:34]=1
Reactant: O=C(OC(c1ccncc1)c1nnc(Nc2ccc(Cl)cc2)c2ccccc12)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: OC(c1ccncc1)c1nnc(Nc2ccc(Cl)cc2)c2ccccc12
Reaction time: 16 h

Procedure:
100 mg (0.214 mMol) of rac benzoic acid-[4-(4-chloroanilino)phthalazin-1-yl](pyridin-4-yl)-methyl ester in 2 ml dioxane, 1 ml methanol and 1 ml water are saponified with 9.9 mg (0.235 mmol) lithium hydroxide monohydrate. After 16 h, the title compound is filtered off: m.p. 196-197° C., FAB MS (M+H)+=363.
Reaction SMILES: C1(C)C=CC(S(Cl)(=O)=O)=CC=1.C1(C)C=CC(S(O[CH2:22][CH2:23][CH:24]=[C:25]([CH3:34])[CH2:26][CH:27]([OH:33])[CH:28]=[CH:29][C:30]([CH3:32])=[CH2:31])(=O)=O)=CC=1>N1C=CC=CC=1>[CH3:34][C:25]1[CH2:26][CH:27]([CH:28]=[CH:29][C:30]([CH3:32])=[CH2:31])[O:33][CH2:22][CH2:23][CH:24]=1
Reactant: C=C(C)C=CC(O)CC(C)=CCCOS(=O)(=O)c1ccc(C)cc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: C=C(C)C=CC1CC(C)=CCCO1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61.6 %

Procedure:
To an ice-cool solution of the diol prepared according to g) (2.0 g, 10.2 mmole) in pyridine (22 ml) was added p-toluenesulfonyl chloride (2.13 g, 11.2 mmole) in small portions and over 30 min. The mixture was stirred at 0° for 30 min and then stored overnight at 3°. The usual extraction with ether and treatment of the organic phase gave 2.85 g of a crude product which, on thin layer chromatographic analysis, showed two components. The further purification of this product by MPLC [LOBAR® column (origin: Merck), mixture of hexane-ethyl acetate as elution agent] gave 2.20 g (yield: 61.6%) of the desired product, i.e. 6-hydroxy-4,9-dimethyl-3,7,9-decatrienyl p-toluenesulfonate, and 220 mg of an unidentified by-product.