Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11](=[O:16])[C:10]([C:17]2[N:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:20]=[CH:19][CH:18]=2)=[N:9]1)C1C=CC=CC=1>C1COCC1.CO.[OH-].[OH-].[Pd+2]>[CH3:15][O:14][C:12]1[C:11]([OH:16])=[C:10]([C:17]2[N:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:20]=[CH:19][CH:18]=2)[N:9]=[N:8][CH:13]=1
Reactant: COc1cn(Cc2ccccc2)nc(-c2ccnn2-c2ccccc2)c1=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cnnc(-c2ccnn2-c2ccccc2)c1O
Yield: 81 %

Procedure:
1-benzyl-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (15.0 g) and palladium hydroxide on carbon (5.88 g, palladium 20%, moistened with 50% water) were suspended in THF (500 mL) and methanol (300 mL), and the suspension was stirred at room temperature for 2 days under a hydrogen atmosphere. The reaction mixture was filtered through celite, the filtrate was concentrated. The residue was solidified with ethanol/hexane to give the title compound (9.10 g).
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:47]=[CH:46][C:27]([O:28][CH2:29][C:30]3[N:31]=[C:32]([C:36]4[CH:45]=[CH:44][CH:43]=[CH:42][C:37]=4[C:38]([O:40]C)=[O:39])[O:33][C:34]=3[CH3:35])=[C:26]([O:48][CH3:49])[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].O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[CH2:7]([O:6][P:4](/[CH:9]=[CH:10]/[C:11]1[C:12]([O:22][CH2:23][C:24]2[CH:47]=[CH:46][C:27]([O:28][CH2:29][C:30]3[N:31]=[C:32]([C:36]4[CH:45]=[CH:44][CH:43]=[CH:42][C:37]=4[C:38]([OH:40])=[O:39])[O:33][C:34]=3[CH3:35])=[C:26]([O:48][CH3:49])[CH:25]=2)=[N:13][N:14]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:15]=1)([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccccc3C(=O)OC)oc2C)c(OC)c1)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccccc3C(=O)O)oc2C)c(OC)c1)OCC
Yield: 67 %

Procedure:
To a mixture of methyl 2-[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]benzoate (0.40 g), tetrahydrofuran (2 mL) and ethanol (2 mL) was added 1N aqueous sodium hydroxide solution (2 mL), and the mixture was heated under reflux 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 2-[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]benzoic acid as colorless amorphous form (0.26 g, yield 67%).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23](C)[CH:22]=3)=[CH:16][C:15]=2F)=[O:12])[N:7]([C:29]2[CH:34]=[CH:33][C:32]([NH:35][C:36](=O)[CH2:37][O:38][CH3:39])=[CH:31][CH:30]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].B.CSC>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[CH:18][CH:19]=2)=[O:12])[N:7]([C:29]2[CH:30]=[CH:31][C:32]([NH:35][CH2:36][CH2:37][O:38][CH3:39])=[CH:33][CH:34]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCC(=O)Nc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccnc(C)c3)cc2F)cc1
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: COCCNc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccncc3)cc2)cc1
Temperature: 25 °C
Yield: 6.8 %

Procedure:
To a solution of N-[4-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]-phenyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)phenyl]-2-methoxyacetamide (500 mg, 0.97 mmol) in anhydrous THF (20 mL) was added borane-methyl sulfide complex (2.0 M solution in THF, 5 mL, 10 mmol), and the reaction was stirred at reflux for 7 h. The reaction mixture was cooled to room temperature, partitioned between EtOAc (50 mL) and water (50 mL), and the organic layer was washed with brine, dried over Na2SO4, and concentrated at reduced pressure. The residue was purified by MPLC (1:1 hexanes/EtOAc) to give 33 mg (7%) of the desired product. 1H-NMR (DMSO-d6) δ 8.65 (s, 1H), 8.42 (d, J=4.8 Hz, 2H), 8.34 (s, 1H), 7.58 (d, J=6.6 Hz, 2H), 7.21 (d, J=6.6 Hz, 2H), 7.06 (d, J=6.9 Hz, 2H), 6.84 (d, J=4.8 Hz, 2H), 6.73 (d, J=6.9 Hz, 2H), 6.43 (s, 1H), 5.23 (s, 1H), 3.57 (t, J=5.7 Hz, 2H), 3.35 to 3.30 (m, 5H), 1.32 (s, 9H); MS LC-MS [M+H]+=529, RT=2.20 min.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[C:3]#N.[Cl:7][C:8]1[CH:9]=[C:10]([N:19]=[C:20]=[O:21])[CH:11]=[CH:12][C:13]=1[O:14][C:15]([F:18])([F:17])[F:16].CC(C)=[O:24]>>[Cl:7][C:8]1[CH:9]=[C:10]([N:19]2[C:3](=[O:24])[C:2]([CH3:6])([CH3:5])[NH:1][C:20]2=[O:21])[CH:11]=[CH:12][C:13]=1[O:14][C:15]([F:18])([F:17])[F:16]
Reactant: CC(C)=O
Reactant: O=C=Nc1ccc(OC(F)(F)F)c(Cl)c1
Reactant: CC(C)(N)C#N
Product: CC1(C)NC(=O)N(c2ccc(OC(F)(F)F)c(Cl)c2)C1=O
Temperature: 45 °C
Reaction time: 1 h

Procedure:
6.5 g (0.077 mol) of α-aminoisobutyronitrile are added dropwise to a solution of 17.1 g (0.072 mol) of 3-chloro-4-trifluoromethoxyphenyl isocyanate in 100 ml of acetone. The temperature increases to about 45° C. during this procedure. After the reaction has ceased, the solvent is evaporated off in vacuo, and the residue is then boiled for 1 hour with 80 ml of semi-concentrated hydrochloric acid. The 3-(3-chloro-4-trifluoromethoxyphenyl)-5,5-dimethyl-hydantoin formed during this process is recrystallized from toluene with the addition of petroleum ether. 16 g of product of melting point 104°-107° C. are obtained.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH:5]([CH2:9][N:10]1[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[N:12]([CH2:19][C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][C:27]=3[CH3:29])[N:22]([CH3:30])[CH:21]=2)[C:11]1=[O:31])[CH2:6][CH2:7][CH3:8])C.O.[OH-].[Li+]>O1CCOCC1.O>[CH3:30][N:22]1[C:23]2[C:28](=[C:27]([CH3:29])[CH:26]=[CH:25][CH:24]=2)[C:20]([CH2:19][N:12]2[C:13]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:10]([CH2:9][CH:5]([CH2:6][CH2:7][CH3:8])[C:4]([OH:32])=[O:3])[C:11]2=[O:31])=[CH:21]1
Reactant: CCCC(Cn1c(=O)n(Cc2cn(C)c3cccc(C)c23)c2cccnc21)C(=O)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCCC(Cn1c(=O)n(Cc2cn(C)c3cccc(C)c23)c2cccnc21)C(=O)O
Reaction time: 8 h
Yield: 30.8 %

Procedure:
To a stirred solution of 2-[1-(1,4-dimethyl-1H-indol-3-ylmethyl)-2-oxo-1,2-dihydro-imidazo[4,5-b]pyridin-3-ylmethyl]-pentanoic acid ethyl ester (85 mg, 0.20 mmol) in dioxane (5 ml) and water (1.5 ml) was added lithium hydroxide monohydrate (41 mg, 0.98 mmol) at room temperature. After stirring overnight the reaction appeared complete. The reaction was concentrated to low volume and diluted with water (˜20 ml). Acidified using HOAc and collected the resulting precipitate via filtration. The product was suspended in 2 ml of 1:1 MeOH/acetonitrile, filtered and washed with acetonitrile. The solid was dried on house vacuum to give 25 mg (31%) of the title compound. LCMS, M++1, m/z: 407.91.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:13](=O)[CH2:14]Br)=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[C:17]([NH2:20])(=[S:19])[CH3:18]>CN(C=O)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:13]3[N:20]=[C:17]([CH3:18])[S:19][CH:14]=3)=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1
Reactant: CC(N)=S
Reactant: O=C(CBr)c1cc(=O)oc2cc(Br)ccc12
Solvent: CN(C)C=O
Product: Cc1nc(-c2cc(=O)oc3cc(Br)ccc23)cs1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of 7-bromo-4-(bromoacetyl)-2H-chromen-2-one (0.605 g, 1.7 mmol) in DMF was added thioacetamide (0.138 g, 1.8 mmol). The mixture was stirred 24 h at rt and at 100° C. overnight. Once cool to rt, it was partitioned between aqueous NH4Cl and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. The solvent was evaporated and the residue swished in hexanes/Et2O to give the title compound.
Reaction SMILES: [S:1]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11](=[O:15])OCC.[CH3:16][NH:17][CH2:18][CH:19]=[O:20]>>[CH3:16][N:17]([CH2:18][CH:19]=[O:20])[C:11]([NH:10][C:2]1[S:1][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=2[N:3]=1)=[O:15]
Reactant: CNCC=O
Reactant: CCOC(=O)Nc1nc2c(s1)CCCC2
Product: CN(CC=O)C(=O)Nc1nc2c(s1)CCCC2
Temperature: 120 °C
Reaction time: 18 h

Procedure:
Ethyl N-(4,5,6,7-tetrahydrobenzothiazol-2-yl)carbamate (13.6 grams; 0.06 mol) and the dimethyl acetal of 2-methylaminoacetaldehyde (20 mol.) were charged into a glass reaction vessel equipped with a stirrer, reflux condenser and gas addition tube. The reaction mixture was blanketed with nitrogen gas and heated at 120° C. for a period of 24 hours. Since starting material remained, the mixture was heated for an additional 48 hours and then for an additional 18 hours. After this time the reaction mixture was distilled to remove excess starting material. The residue was purified by chromatography using ethyl acetate as the eluant on silica gel adsorbant yielding the desired product, dimethyl acetal of 2-[1-methyl-3-(4,5,6,7-tetrahydrobenzothiazol-2-yl)ureido]acetaldehyde; (8.9; melting point 89°-92° C.). The structure of the product was verified by infrared and NMR spectroscopy.
Reaction SMILES: [NH2:1][C:2]1[C:7](I)=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.[C:10](B1OC(C)(C)C(C)(C)O1)([CH3:12])=[CH2:11].C(=O)([O-])[O-].[Na+].[Na+].O>CN(C)C=O.C(OCC)(=O)C>[Br:9][C:5]1[CH:6]=[C:7]([C:10]([CH3:12])=[CH2:11])[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Reactant: Nc1ncc(Br)cc1I
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=C(C)c1cc(Br)cnc1N
Temperature: 65 °C
Reaction time: 6 h

Procedure:
A solution of 2-amino-5-bromo-3-iodopyridine B-78-1 (4.75 g, 15.9 mmol), isopropenylboronic acid pinacol ester (3.28 mL, 2.94 g, 17.5 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]-palladium(II) dichloride dichloromethane complex (1:1) (295 mg, 0.403 mmol) in dimethylformamide (48 mL) was treated with 24 mL of 2.0 M aqueous sodium carbonate solution. The resulting biphasic mixture was stirred under argon in a 65° C. oil bath for 6 hours. After cooling to room temperature, the mixture was diluted with 200 mL ethyl acetate and 75 mL deionized water, then suction-filtered to remove some insoluble black precipitate. After separation, the aqueous layer was back-extracted with 100 mL ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated to 5.87 g brown oil. The crude product was purified by silica gel chromatography (eluting with a 10-50% ethyl acetate in hexanes gradient), to give B-78-2 (2.5501 g, 75.3%) as a tan solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=O.[CH3:13][O:14][CH:15]([O:18][CH3:19])[CH2:16][NH2:17].C([BH3-])#N.[Na+]>CO>[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2[NH:17][CH2:16][CH:15]([O:18][CH3:19])[O:14][CH3:13]
Reactant: O=C1CCc2c(F)cc(F)cc21
Reactant: COC(CN)OC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COC(CNC1CCc2c(F)cc(F)cc21)OC
Temperature: 65 °C
Reaction time: 18 h

Procedure:
A mixture of 4,6-difluoroindan-1-one (11.3 g, 67.26 mmol), 2,2-dimethoxyethylamine (7.07 g, 67.26 mmol) and sodium cyanoborohydride (4.23 g) in 75 mL of methanol was heated at gentle reflux and stirred under nitrogen for approximately 18 hours. Additional sodium cyanoborohydride (2.12 g) was added and the mixture was heated at 65° C. for 20 hours. The solvents were removed by evaporation. Purification of the residue by column chromatography on silica gel (elution: 2.5% methanol/methylene chloride) gave (4,6-difluoroindan-1-yl)-(2,2-dimethoxyethyl)amine.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][C@H:16]1[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=1)=[O:14])([CH3:11])([CH3:10])[CH3:9].CCO.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][C@H:16]1[CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]([C:2]2[N:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:27]=1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: Brc1ncccn1
Reactant: CC(C)(C)OC(=O)N1CCOC[C@H]1Cc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCOC[C@H]1Cc1cccc(-c2ncccn2)c1
Temperature: 80 °C

Procedure:
2-Bromopyrimidine (43 mg, 0.27 mmol) was added in one portion to a RT solution of (R)-3-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-morpholine-4-carboxylic acid tert-butyl ester B-7 (100 mg, 0.25 mmol) in dioxane (0.76 mL) under argon. EtOH (0.38 mL) was then added followed by 2M aq. Na2CO3 (0.38 mL, 0.74 mmol) and argon was bubbled through the resulting suspension for 1 min. Pd(dppf)Cl2.DCM (12 mg, 6 mol %) was added in one portion and the resulting mixture was heated to 80° C. for 2 h. The reaction mixture was cooled to RT, quenched into water and filtered through a celite plug washing with TBME. The layers were separated and the aqueous phase was extracted with TBME (3×). The combined organic extracts were washed with brine, dried over Na2SO4, filtered through a second celite plug and evaporated in vacuo to give the crude product that was purified by prep. HPLC (method E) to give the title compound as a yellow oil. LC-MS B: tR=0.79 min; [M+H]+=356.05.
Reaction SMILES: [CH2:1]([O:4][C:5]([O:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])=[C:14]([CH2:17]O)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9])=[O:6])[CH:2]=[CH2:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:46][N:47]1[C:51]2=[C:52]3[C:57](=[CH:58][CH:59]=[C:50]2[NH:49][S:48]1(=[O:70])=[O:69])[CH:56]=[CH:55][C:54]([CH2:60][O:61][Si:62]([CH2:67][CH3:68])([CH2:65][CH3:66])[CH2:63][CH3:64])=[CH:53]3.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.C(Cl)(Cl)Cl>[CH2:1]([O:4][C:5]([O:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])=[C:14]([CH2:17][N:49]3[C:50]4=[CH:59][CH:58]=[C:57]5[C:52]([CH:53]=[C:54]([CH2:60][O:61][Si:62]([CH2:67][CH3:68])([CH2:63][CH3:64])[CH2:65][CH3:66])[CH:55]=[CH:56]5)=[C:51]4[N:47]([CH3:46])[S:48]3(=[O:70])=[O:69])[C@H:15]([CH3:16])[C@H:11]12)[CH3:9])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CO)[C@H](C)[C@H]12
Reactant: CC[Si](CC)(CC)OCc1ccc2ccc3c(c2c1)N(C)S(=O)(=O)N3
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CN3c4ccc5ccc(CO[Si](CC)(CC)CC)cc5c4N(C)S3(=O)=O)[C@H](C)[C@H]12
Reaction time: 0.5 h

Procedure:
A solution of allyl (1S,5R,6S)-6-[1(R)-allyloxycarbonyloxy-ethyl]-2-hydroxymethyl-1-methyl-carbapen-2-em-3-carboxylate (365 mg, 1.0 mmol), triphenylphosphine (315 mg, 1.2 mmol), and 1-methyl-8-triethylsilanyloxymethyl-1,3-dihydro-2-thia-1,3-diaza-cyclopenta[α]naphthalene 2,2-dioxide (416 mg, 1.1 mmol) in anhydrous tetrahydrofuran (7 mL) is cooled in an ice-bath and stirred under a nitrogen atmosphere while diisopropyl azodicarboxylate (0.24 mL, 1.2 mmol) is added dropwise over a few minutes. The resulting solution is stirred in the cold for 30 minutes, then diluted with chloroform, washed with 5% aqueous sodium bicarbonate and brine, dried over sodium sulfate, filtered and evaporated under vacuum. The residue is purified by silica gel flash chromatography, eluting with hexane-ethyl acetate, to afford allyl (1S,5R,6S)-6-[1(R)-allyloxycarbonyloxy-ethyl]-1-methyl-2-(1-methyl-2,2-dioxo-8-triethylsilanyloxymethyl-1,2-dihydro-2-thia-1,3-diaza-cyclopenta[α]naphthalen-3-ylmethyl)-carbapen-2-em-3-carboxylate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:21][O:22][CH2:23]OC>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:21][O:22][CH3:23]
Reactant: COCOC
Reactant: Oc1ccc(F)cc1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: COCOc1ccc(F)cc1Br
Temperature: 25 °C

Procedure:
To a solution of 2-bromo-4-fluoro-phenol (1 g, 5.23 mmol) in CH2Cl2 (120 mL) was added p-toluenesulphonic acid (0.07 g, mmol), dimethoxymethane (2.31 mL, 26.15 mmol) and the resulting mixture was heated under reflux for 16 h under a soxhlett apparatus charged with freshly dried molecular 4 Å sieves. The reaction was allowed to warm to room temperature and washed with 2M sodium hydroxide (100 mL) then dried (Na2SO4), filtered and the solvent was evaporated under vacuum to give title compound as an oil: 0.567 g, 46%. 1H-NMR (CDCl3, 300 MHz) δ7.31 (dd, 1H, J=2.9, 7.9 Hz, ArH), 7.13 (dd, 1H, J=4.9, 9.1 Hz, ArH), 6.98 (m, 1H, ArH), 5.21 (s, 2H, —OCH2O—), 3.54 (s, 3H, —OCH3)
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[CH2:14][OH:15])=[N:6][CH:7]=1.[CH2:16]([O:18][C:19]([C:21]1[CH:26]=[CH:25][C:24](O)=[CH:23][N:22]=1)=[O:20])[CH3:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH2:16]([O:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([O:15][CH2:14][C:9]2[N:10]([CH3:13])[N:11]=[N:12][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=2)=[CH:23][N:22]=1)=[O:20])[CH3:17]
Reactant: CCOC(=O)c1ccc(O)cn1
Reactant: Cn1nnc(-c2ccc(F)cn2)c1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(OCc2c(-c3ccc(F)cn3)nnn2C)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
To a solution of [5-(5-fluoro-pyridin-2-yl)-3-methyl-3H-[1,2,3]triazol-4-yl]-methanol (416 mg, 2.0 mmol), 5-hydroxy-pyridine-2-carboxylic acid ethyl ester (362 mg, 2.60 mmol) and triphenylphosphine (682 mg, 2.6 mmol) in THF (10 mL) was added diethyl azodicarboxylate (40% in toluene, 1.19 mL, 2.6 mmol) dropwise at 0° C. The reaction mixture was then stirred at room temperature for 1 h and then evaporated. Purification by chromatography (silica, 50 to 100% ethyl acetate in heptane) afforded the title compound (386 mg, 77%) as a white solid after recrystallisation from ethyl acetate. MS: m/e=358.3 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[NH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)=[CH:17][CH:18]=2)[N:13]=1>O.CN(C)C=O.C(#N)C>[F:28][C:24]1[CH:23]=[C:22]([C:16]2[N:15]=[C:14]3[C:19]([CH:20]=[CH:21][C:12]([NH:11][C:5](=[O:7])[C:4]4[CH:8]=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=4)=[N:13]3)=[CH:18][CH:17]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: Nc1ccc2ccc(-c3cccc(F)c3)nc2n1
Reactant: O=C(O)c1cccc(Br)c1
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccc2ccc(-c3cccc(F)c3)nc2n1)c1cccc(Br)c1
Temperature: 4 °C
Yield: 54.3 %

Procedure:
The procedure is analogous to that described in Example 11, but starting with 3-bromobenzoic acid (2.8 g), N,N'-carbonyldiimidazole (2.3 g) and 2-amino-7-(3-fluorophenyl)-1,8-naphthyridine (2.4 g). The product obtained by precipitation in water (3.5 g; m.p. approximately 195° C.) is dissolved in a boiling mixture of dimethylformamide (20 cc) and acetonitrile (200 cc). After cooling for 4 hours at 4° C., the crystallized solid is separated by filtration, washed with acetonitrile (3×10 cc) and dried at 40° C. under reduced pressure (0.07 kPa). N-[7-(3-Fluorophenyl)-1,8-naphthyridin-2-yl]-3-bromobenzamide (2.3 g), m.p. 208° C., is obtained.
Reaction SMILES: C([Li])CCC.[CH2:6]([OH:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([C@H]1COC(=O)N1[C:23](=[O:43])[C@H:24]([CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=1)[CH2:25][C:26](=[O:33])[N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)(C)C.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH3:42][O:41][C:38]1[CH:37]=[CH:36][C:35]([CH2:34][C@H:24]([CH2:25][C:26]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:33])[C:23]([O:13][CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:43])=[CH:40][CH:39]=1
Reactant: COc1ccc(C[C@H](CC(=O)N2CCOCC2)C(=O)N2C(=O)OC[C@@H]2C(C)C)cc1
Reactant: OCc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(C[C@H](CC(=O)N2CCOCC2)C(=O)OCc2ccccc2)cc1
Reaction time: 0.17 h
Yield: 93 %

Procedure:
7.84 ml (12.5 mmoles) of butyllithium (as a 1.6M hexane solution) were added, whilst ice-cooling and under an atmosphere of nitrogen, to a solution of 1.73 ml (16.7 mmoles) of benzyl alcohol in 50 ml of anhydrous tetrahydrofuran. The mixture was stirred for 10 minutes, and then a solution of 3.50 g (8.36 mmoles) of 4(S)-isopropyl-3-[4-oxo-2(R)-(4-methoxybenzyl)-4-morpholinobutyryl]-2-oxazolidinone (prepared as described in Preparation 13) in 10 ml of anhydrous tetrahydrofuran was added dropwise thereto. The mixture was then stirred for 30 minutes, after which a saturated aqueous solution of ammonium chloride was added to the reaction mixture, which was then extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, the solvent was removed by distillation under reduced pressure, and the residue was purified by medium pressure silica gel column .chromatography (using a 4:1 by volume mixture of benzene and ethyl acetate as eluent), followed by recrystallization from diisopropyl ether, to give 3.09 g (yield 93%) of the title compound as white crystals, melting at 77°-79° C.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:22]=[C:21](Br)[CH:20]=[CH:19][C:11]=1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24](C([Sn])=C(CCCC)CCCC)[CH2:25]CC>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.C1(C)C=CC=CC=1>[C:1]([NH:9][C:10]1[CH:22]=[C:21]([CH:24]=[CH2:25])[CH:20]=[CH:19][C:11]=1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1NC(=O)c1ccccc1
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1ccc(C(=O)OC(C)(C)C)c(NC(=O)c2ccccc2)c1
Temperature: 25 °C
Yield: 46.5 %

Procedure:
0.54 g of tetrakis(triphenylphosphine)palladium (0) was added to 35 mL of toluene solution containing 3.5 g of tert-butyl 2-(benzamido)-4-bromobenzoate and 5.0 g of tributylvinyl tin, and the resulting mixture was heated to reflux under nitrogen atmosphere for 2 hours. After the reaction mixture was cooled to room temperature, insoluble were removed by filtration, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [eluent; hexane; ethyl acetate=20:1] to obtain 1.4 g of tert-butyl 2-(benzamido)-4-vinylbenzoate as white solid.