Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11][CH2:10][C:4]=2[N:5]=[C:6]([S:8][CH3:9])[N:7]=1.[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>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.[Pd].C1(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[C:2]1[C:3]2[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11][CH2:10][C:4]=2[N:5]=[C:6]([S:8][CH3:9])[N:7]=1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: CSc1nc(Cl)c2c(n1)CCN(C(=O)OC(C)(C)C)C2
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CSc1nc2c(c(-c3ccc(Cl)cc3Cl)n1)CN(C(=O)OC(C)(C)C)CC2
Yield: 104.2 %

Procedure:
A mixture of tert-butyl 4-chloro-2-methylthio-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidine-6-carboxylate (334 mg, 1.06 mmol), 2,4-dichlorobenzeneboronic acid (222 mg, 1.16 mmol), bis(dibenzylideneacetone)palladium(0) (48 mg, 0.053 mmol) and 1,4-bis(diphenylphosphino)butane (45 mg, 0.11 mmol) in toluene (2 ml), aqueous 1M sodium carbonate solution (1 ml) and ethanol (0.5 ml) was heated under reflux for 19 h under nitrogen. The reaction mixture was then cooled, water was added, and the toluene layer was separated. The aqueous layer was extracted with ethyl acetate and the combined organic extracts were dried (MgSO4), filtered, and the filtrate concentrated in vacuo. The crude product was purified by column chromatography using 15% acetone in hexanes as eluent, giving tert-butyl 4-(2,4-dichlorophenyl)-2-methylthio-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidine-6-carboxylate (471 mg, yield>100%) as a light yellow sticky foam.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:25]([O:27]CC)=O)[C:5]2[C:6](=O)[CH:7]([C:18]3[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=3)[CH:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:9][C:10]=2[CH:11]=1.O.[NH2:31][NH2:32]>CO>[F:1][C:2]1[CH:11]=[C:10]2[NH:9][CH:8]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:7]([C:18]3[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=3)[C:6]3=[N:31][NH:32][C:25](=[O:27])[C:4]([CH:3]=1)=[C:5]23
Reactant: NN
Reactant: CCOC(=O)c1cc(F)cc2c1C(=O)C(c1nccn1C)C(c1ccccc1)N2
Solvent: CO
Solvent: O
Product: Cn1ccnc1C1c2n[nH]c(=O)c3cc(F)cc(c23)NC1c1ccccc1
Temperature: 45 °C
Reaction time: 8 h
Yield: 9 %

Procedure:
A mixture of ethyl 7-fluoro-3-(1-methyl-1H-imidazol-2-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate (141 mg) in 85% hydrazine monohydrate (10 mL) and methanol (10 mL) was stirred at 45° C. for overnight. Methanol was removed under reduced pressure. The mixture was filtered and washed with water to give 5-fluoro-9-(1-methyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (11 mg, yield: 9%). 1H-NMR (400 MHz, CD3OD) δ (ppm): 3.34 (s, 3H), 4.65 (d, J=8.0 Hz, 1H), 4.94 (d, J=8.0 Hz, 1H), 6.81 (s, 1H), 6.88-7.02 (m, 2H), 7.18 (dd, 1H), 7.28-7.29 (m, 3H), 7.34-7.36 (m, 2H); 19F-NMR (400 MHz, CD3OD) δ: −105.70 (s); LC-MS (ESI) m/z: 362 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[CH3:27][N:28]([CH3:40])[C:29]([S:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][NH2:37])=[CH:34][CH:33]=1)=[O:30]>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:14])([F:15])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:37][CH2:36][C:35]1[CH:34]=[CH:33][C:32]([S:31][C:29](=[O:30])[N:28]([CH3:27])[CH3:40])=[CH:39][CH:38]=1
Reactant: CN(C)C(=O)Sc1ccc(CN)cc1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Product: CN(C)C(=O)Sc1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1
Yield: 43.7 %

Procedure:
Use a method similar to the General Procedure 1-2 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (348 mg, 0.8 mmol) with 4-dimethylcarbamoylthio-benzylamine (345 mg, 1.6 mmol). Purify by chromatography on silica gel eluting with hexane/EtOAc (4:1) to obtain the desired intermediate (170 mg, 43%).
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5](=[O:31])[CH:6]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22](=[O:30])[C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.[Br:32][CH2:33][CH2:34]Br>C(O)C>[CH3:3][O:4][C:5](=[O:31])[CH:6]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22](=[O:30])[C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1)[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:34][CH2:33][Br:32])=[CH:12][CH:13]=1
Reactant: BrCCBr
Reactant: COC(=O)C(Cc1ccc(O)cc1)Nc1ccccc1C(=O)c1ccc(C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COC(=O)C(Cc1ccc(OCCBr)cc1)Nc1ccccc1C(=O)c1ccc(C)cc1
Yield: 53.3 %

Procedure:
To a solution of potassium hydroxide (0.17 g, 2.95 mmol) in ethanol (20 ml) is added 2-[(2-(4-methylbenzoyl)phenyl)amino]-3-(4-hydroxyphenyl)-propionic acid methyl ester (1.15 g, 2.95 mmol) and 1,2-dibromoethane (5.54 g, 29.50 mmol). Then the mixture is heated to reflux for 8 hours. After cooled, the reaction mixture is filtered to remove the solid formed, and then the filtrate is evaporated under a vacuum. The crude product is purified by silica gel chromatography using hexane/EtOAc (4:1) as eluent to give the title compound (0.78 g, 53%).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH2:4][S:5](=[O:22])[C@@H:6]2[CH:17]([NH:18][CH:19]=[O:20])[C:16](=[O:21])[N:7]2[C:8]=1[C:9]([O:11]C(C)(C)C)=[O:10]>FC(F)(F)C(O)=O>[Br:1][CH2:2][C:3]1[CH2:4][S:5](=[O:22])[C@@H:6]2[CH:17]([NH:18][CH:19]=[O:20])[C:16](=[O:21])[N:7]2[C:8]=1[C:9]([OH:11])=[O:10]
Reactant: CC(C)(C)OC(=O)C1=C(CBr)CS(=O)[C@@H]2C(NC=O)C(=O)N12
Solvent: O=C(O)C(F)(F)F
Product: O=CNC1C(=O)N2C(C(=O)O)=C(CBr)CS(=O)[C@H]12
Yield: 99.6 %

Procedure:
10 g of t-butyl 3-bromomethyl-7-formamido-3-cephem-4-carboxylate-1-oxide in 40 ml of trifluoroacetic acid were stirred for 15 minutes at room temperature and after evaporation to dryness under vacuo, 25 ml of dichloromethane were added to the residue and evaporation to dryness was repeated. Ether was added to the residue and the formed crystals were vacuum filtered and washed with ether and the almost colorless solid was dried under vacuo to obtain 8.54 g of 3-bromomethyl-7-formamido-3-cephem-4-carboxylic acid-1-oxide having the following characteristics:
Reaction SMILES: [C:1]([O:5][CH2:6][C@@H:7]1[C:12](=[O:13])[NH:11][CH2:10][CH2:9][N:8]1[C:14](=[O:38])[CH2:15][C@H:16]([NH:27]C(=O)OCC1C=CC=CC=1)[CH2:17][C:18]1[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20][C:19]=1[F:26])([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C>CO.[Pd]>[NH2:27][C@H:16]([CH2:17][C:18]1[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20][C:19]=1[F:26])[CH2:15][C:14]([N:8]1[CH2:9][CH2:10][NH:11][C:12](=[O:13])[C@H:7]1[CH2:6][O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:38]
Reactant: CC(C)(C)OC[C@@H]1C(=O)NCCN1C(=O)C[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC[C@@H]1C(=O)NCCN1C(=O)C[C@H](N)Cc1cc(F)c(F)cc1F
Reaction time: 2 h
Yield: 70.7 %

Procedure:
65.7 g of benzyl(R)-4-[(R)-2-(t-butoxymethyl)-3-oxopiperazine-1-yl]-4-oxo-1-(2,4,5-trifluorophenyl)butane-2-ylcarbamate of the above Step 1 was dissolved in 409 mL of methanol; a solution in which 13.1 g of palladium/carbon was wetted with 92 ml of ethyl acetate was added; and then stirred for 2 hours under hydrogen pressure of 15 bar. The resulting reaction solution was filtered with diatomite, and then concentrated under reduced pressure to obtain 34.8 g of a title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([O:4][C:5](=[O:21])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([CH3:20])[C:16]([O:18]C)=[O:17])=[CH:10][CH:9]=1)[CH3:3]>C(OCC)C.P([O-])([O-])([O-])=O>[CH3:22][C:2]([CH3:3])([O:4][C:5](=[O:21])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([CH3:20])[C:16]([OH:18])=[O:17])=[CH:10][CH:9]=1)[CH3:1]
Reactant: COC(=O)C(C)Cc1ccc(OCC(=O)OC(C)(C)C)cc1
Agent: O=P([O-])([O-])[O-]
Solvent: CCOCC
Product: CC(Cc1ccc(OCC(=O)OC(C)(C)C)cc1)C(=O)O
Reaction time: 16 h
Yield: 93 %

Procedure:
Dissolve (+)-4-[[2-(1,1-dimethylethoxy)-2-oxoethyl]oxy]-alpha-methyl-benzenepropanoic acid, methyl ester (5.74 g, 18.6 mmol) in ethyl ether and adsorb onto silica gel (18 g). Evaporate the solvent in vacuo to leave a white powder. Suspend the powder in pH 7 phosphate buffer (600 mL of a 0.1M solution). Add lipase P-30 (5.74 g) and stir for 16 hours. Filter and extract with ethyl ether (3×400 mL). Dry (MgSO4), evaporate the solvent in vacuo and purify by flash chromatography (5→10% methanol/chloroform) to give the title compound (5.09 g, 98% ee after reesterification with diazomethane); [α]d 20 =+18.9° (C=0.97, CHCl3).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:10](=[O:19])[NH:9][N:8]=1)[CH3:2].[H-].[Na+].[CH3:23][S:24](Cl)(=[O:26])=[O:25].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:10](=[O:19])[N:9]([S:24]([CH3:23])(=[O:26])=[O:25])[N:8]=1)[CH3:2]
Reactant: CCOC(=O)CCc1n[nH]c(=O)c2cc(OC)ccc12
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CCc1nn(S(C)(=O)=O)c(=O)c2cc(OC)ccc12
Temperature: 55 °C
Reaction time: 8 h
Yield: 17.5 %

Procedure:
A suspension of 3-(6-methoxy-4-oxo-3,4-dihydro-phthalazin-1-yl)-propionic acid ethyl ester (4 g, 0.0145 mole), prepared as described in example 119, and NaH (0.638 g, 0.016 mole) in acetonitrile (80 ml) was heated at 55° C. After 2 hours the mixture was cooled, added with methanesulfonyl chloride (1.35 ml, 0.017 mole), and stirred at room temperature overnight. K2CO3 (2 g, 0.0145 mole) and methanesulfonyl chloride (1.12 ml, 0.0145 mole) were added, and the mixture was stirred overnight, then dried and partitioned between water and CHCl3. The organic phase was washed with a K2CO3 solution, anhydrified and dried to give a residue which was chromatographed (eluent: CH2Cl2/ethyl acetate 95:5). The resultant solid was crystallised from acetonitrile (5 ml) to give 0.9 g of the title compound (yield: 17.5%).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[N:12]=[C:11]([N:13]([CH2:15][CH:16]2[CH2:18][CH2:17]2)[CH3:14])[CH:10]=[N:9][CH:8]=1.O.CN([CH:23]=[O:24])C>>[Cl:6][C:7]1[C:8]([CH:23]=[O:24])=[N:9][CH:10]=[C:11]([N:13]([CH2:15][CH:16]2[CH2:18][CH2:17]2)[CH3:14])[N:12]=1
Reactant: CN(CC1CC1)c1cncc(Cl)n1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CN(CC1CC1)c1cnc(C=O)c(Cl)n1
Reaction time: 0.25 h
Yield: 71 %

Procedure:
Phosphoryl chloride (0.43 mL) was added dropwise to DMF (1 mL) at 0° C. The mixture was stirred for 15 min, and a solution of 6-chloro-N-(cyclopropylmethyl)-N-methylpyrazin-2-amine (0.46 g) in DMF (1 mL) was added dropwise thereto. The mixture was stirred at 50° C. for 16 hr, water (5 mL) was added at 0° C., and the mixture was stirred at room temperature for 1.5 hr. The mixture was extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient: 5→20% ethyl acetate/hexane) to give the title compound (0.37 g, 71%) as a pale-yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[C:17]([C:20]1[CH:21]=[C:22]([N:26]=[C:27]=[O:28])[CH:23]=[CH:24][CH:25]=1)(=[O:19])[CH3:18]>C(Cl)Cl>[C:17]([C:20]1[CH:21]=[C:22]([NH:26][C:27]([NH:16][C:10]2[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:8]([C:3]3[N:4]([CH3:7])[N:5]=[CH:6][C:2]=3[Br:1])[CH:9]=2)=[O:28])[CH:23]=[CH:24][CH:25]=1)(=[O:19])[CH3:18]
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C
Reactant: CC(=O)c1cccc(N=C=O)c1
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2cccc(C(C)=O)c2)cc1-c1c(Br)cnn1C
Yield: 81.8 %

Procedure:
3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.031 g, 0.11 mmol) was treated with 3-acetylphenyl isocyanate (0.019 g, 15.8 μL, 0.11 mmol, 1.05 equiv.) in CH2Cl2 (1 mL), in a similar manner as described in Example 1.2 to afford Compound 17 (0.038 g, 0.09 mmol, 79%) as a white solid. LCMS m/z (%)=443 (M+H79Br, 99), 466 (M+H81Br, 100). 1H NMR (400 MHz, acetone-d6) δ: 8.30 (s, 1H), 8.19 (s, 1H), 8.13 (t, J=1.8 Hz, 1H), 7.80 (dd, J=1.4, 8.1 Hz, 1H), 7.70 (dd, J=2.7, 9.0 Hz, 1H), 7.62 (d, J=7.7 Hz, 1H), 7.49 (s, 1H), 7.44 (d, J=2.7 Hz, 1H), 7.41 (t, J=7.9 Hz, 1H), 7.15 (d, J=9.0 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][CH3:16])[CH2:12][CH:13]=2)=[C:4]([F:17])[CH:3]=1.C1(C)C=CC=CC=1>[Pd].CC(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH3:16])[CH2:10][CH2:9]2)=[C:4]([F:17])[CH:3]=1
Reactant: CCCC1CC=C(c2ccc(Br)cc2F)CC1
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: CCCC1CCC(c2ccc(Br)cc2F)CC1
Yield: 78 %

Procedure:
A mixture of compound (69) (39.2 g, 131.9 mmol) and 5%-palladium on carbon (0.5% sulfur, 50% water-containing article) (1.18 g, 3 wt %) was agitated for 18 hours under a hydrogen atmosphere in a toluene (200 mL)-IPA (100 mL) solvent. The reaction mixture was filtered and a solvent in a filtrate was distilled off by an evaporator. The residue was passed through silica gel column chromatography and then a low-boiling-point material was distilled off by distillation, and thus 4-bromo-2-fluoro-1-(4-propylcyclohexyl)benzene (70) (30.8 g, yield 78.1%) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15][CH2:16]OS(C)(=O)=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1.O>C(#N)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15][CH2:16][N:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCNC1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCOS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCCC2)CC1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A mixture of methanesulfonic acid trans-2-(4-tert-butoxycarbonylamino-cyclohexyl)-ethyl ester (3.2 g, 10 mmol), potassium carbonate (1.4 g, 10 mmol) and pyrrolidine (1.25 mL, 15 mmol) in acetonitrile (40 mL) was stirred at 60° C. for 2 hours. The mixture was cooled to room temperature and poured into water (200 mL). The precipitated white crystals were filtered off and washed with water to yield 1.9 g (64%) of the title compound.
Reaction SMILES: [C:1](=O)([O:17]N1C(=O)CCC1=O)[O:2][CH2:3][C:4]1[C:16]2[CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[CH:7]=[CH:6][CH:5]=1.[C:26]([O:30][C:31]([NH:33][CH2:34][CH2:35][NH2:36])=[O:32])([CH3:29])([CH3:28])[CH3:27]>C(#N)C.C([O-])([O-])=O.[Na+].[Na+]>[C:26]([O:30][C:31]([NH:33][CH2:34][CH2:35][NH:36][C:1]([O:2][CH2:3][C:4]1[C:16]2[CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[CH:7]=[CH:6][CH:5]=1)=[O:17])=[O:32])([CH3:29])([CH3:28])[CH3:27]
Reactant: O=C(OCc1cccc2c1Cc1ccccc1-2)ON1C(=O)CCC1=O
Reactant: CC(C)(C)OC(=O)NCCN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCNC(=O)OCc1cccc2c1Cc1ccccc1-2

Procedure:
A solution of fluorenylmethyl succinimidyl carbonate (31.0 g, 0.092 mol) in acetonitrile (300.0 ml) was slowly added to mono tert-butyloxycarbonylethylenediamine (10.0 g, 0.063 mol) dissolved in 10% aq. Na2CO3 (250 ml). Acetonitrile was evaporated and the product was extracted with ethyl acetate, organic phase was dried over Na2CO3, concentrated and the product was allowed to crystallize by adding petroleum ether. The product was collected on filter, washed with petroleum ether. Yield 20.0 g (84%). TLC petroleum ether--diethylether 88:12 Rf 0.64. NMR (300 MHz, DMSO-d6, 25° C.) d: 1.37 (s, 9H, tBu), 2.99 (m, 4H, CH2CH2), 4.20-4.29 (m, 3H, Fmoc OCH2CH--), 6.76 (t, 1H, NH), 7.25 (t, 1H, NH), 7.33-7.89 (m, 8H, Fmoc). M.p. 146°-148° C.
Reaction SMILES: [C:1]1([B:7]([CH:9]([O:16][CH:17]([B:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[OH:25])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:32][N:33]([CH3:37])[CH2:34][CH2:35]O>C(O)C>[C:1]1([B:7]([CH:9]([O:16][CH:17]([B:24]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[O:25][CH2:35][CH2:34][N:33]([CH3:37])[CH3:32])[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:8][CH2:35][CH2:34][N:33]([CH3:37])[CH3:32])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN(C)CCO
Reactant: OB(c1ccccc1)C(OC(B(O)c1ccccc1)c1ccccc1)c1ccccc1
Solvent: CCO
Product: CN(C)CCOB(c1ccccc1)C(OC(B(OCCN(C)C)c1ccccc1)c1ccccc1)c1ccccc1

Procedure:
The entitled compound (60 mg) was obtained by allowing 95 mg of bis(4,4′-(phenylhydroxyboryl)benzyl) ether and 55 mg of N,N-dimethylethanolamine to act in 0.7 mL of ethanol at room temperature.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[O:16]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17]1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([C:18]3[CH:19]=[CH:20][O:16][CH:17]=3)[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc(C#Cc2cccc(Cl)c2)c[nH]1
Reactant: OB(O)c1ccoc1
Solvent: ClCCl
Product: Cc1nc(C#Cc2cccc(Cl)c2)cn1-c1ccoc1
Reaction time: 8 h

Procedure:
4-(3-Chloro-phenylethynyl)-2-methyl-1H-imidazole (200 mg, 0.92 mmol) was dissolved in 10 mL dichloromethane. Powdered molecular sieves (3 A, 200 mg), 3-furaneboronic acid (207 mg, 1.85 mmol) and [Cu(OH)TMEDA]2Cl2 (43 mg, 0.093 mmol) were added. Oxygen was bubbled through the reaction mixture for 10 minutes and stirring was continued at room temperature overnight. The reaction mixture was filtered through a dicalite speed plus pad and washed with 50 mL dichloromethane. The filtrate was washed with 50 mL water, dried with magnesium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (dichloromethane/methanol 100:0->90:10 gradient) and the desired compound was as a brown oil (21 mg, 8%), MS: m/e=283.1 (M+H+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][NH:16][S:17]([C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1)(=[O:19])=[O:18])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[NH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][NH:16][S:17]([C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1)(=[O:19])=[O:18]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CCNS(=O)(=O)c1cccc2ccccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: O=S(=O)(NCCC1CCCCN1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 20 h
Yield: 96.3 %

Procedure:
To a solution of the product of step c (3.29 g, 7.89 mmol) in CHCl3 (8 ml) was added trifluoroacetic acid (16 ml) and the reaction mixture was stirred at ambient temperature for 20 h. The excess trifluoroacetic acid was removed at reduced pressure and the residue partitioned between aqueous 10% potassium carbonate (50 ml) and CHCl3 (50 ml). The CHCl3 layer was removed and the aqueous phase was extracted with further CHCl3 (50 ml). The combined organic phases were washed with brine and dried over anhydrous sodium sulfate. The filtrate was evaporated at reduced pressure to afford the title compound (2.42 g, 97%). 1H NMR (CHCl3) 8.43 (1H, d, 1.5), 7.98-7.86 (4H, m), 7.76-7.60 (2H, m), 3.20-3.01 (5H, m), 2.60-2.55 (2H, m), 1.60-1.19 (8H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.Cl.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[N:25][CH:24]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:16][CH2:17][N:18]([C:22]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)=[O:29])[CH2:19][CH2:20]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCNCC1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)c1cc(Cl)c2cccnc2c1N1CCN(C(=O)c2cccnc2)CC1
Reaction time: 2 h
Yield: 98.8 %

Procedure:
1-(5-Chloro-8-piperazin-1-ylquinolin-7-yl)ethanone (0.030 g, 0.10 mmol, from Example 47, Step 1) was combined with nicotinoyl chloride hydrochloride (0.028 g, 0.16 mmol) and triethylamine (0.058 mL, 0.41 mmol) in methylene chloride (1.0 mL) at room temperature and stirred for 2 hours. The reaction was diluted with dichloromethane, washed with water, dried over MgSO4, concentrated and purified on silica gel (eluting with 0 to 5% methanol in dichloromethane) to give the desired product (39 mg, 95%). LCMS calculated for C21H20ClN4O2 (M+H)+: m/z=395.1; Found: 395.1.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:17]([I:18])=[CH:16][N:15]([CH2:19][C:20]3[C:25]([CH3:26])=[C:24]([O:27][CH3:28])[C:23]([CH3:29])=[CH:22][N:21]=3)[C:4]=2[N:5]=[C:6]([NH:8]C(=O)C(C)(C)C)[N:7]=1.CCO.O>[Cl-].[Cl-].[Zn+2].O>[Cl:1][C:2]1[C:3]2[C:17]([I:18])=[CH:16][N:15]([CH2:19][C:20]3[C:25]([CH3:26])=[C:24]([O:27][CH3:28])[C:23]([CH3:29])=[CH:22][N:21]=3)[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1
Reactant: COc1c(C)cnc(Cn2cc(I)c3c(Cl)nc(NC(=O)C(C)(C)C)nc32)c1C
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCO
Solvent: O
Product: COc1c(C)cnc(Cn2cc(I)c3c(Cl)nc(N)nc32)c1C
Temperature: 80 °C
Reaction time: 8 h
Yield: 79.9 %

Procedure:
A mixture of N-[4-chloro-5-iodo-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]-2,2-dimethyl-propionamide (1.0 g, 1.89 mmol), ZnCl2 (1.29 g, 9.47 mol, 5.0 eq.), and EtOH/H2O solution (25 mL, volumetric ratio 100:5) was stirred at 80° C. overnight. The reaction mixture poured into water, and the solid was collected by filtration, washed with water (10 mL×3), and recrystallized from MeOH to give the title product (0.67 g, 85% yield; HPLC purity 98%). tR: 5.39 min. 1H-NMR (DMSO-d6) δ 8.07 (s, 1H), 7.28 (s, 1H), 6.75 (br. s, 2H), 5.29 (s, 2H), 3.73 (s, 3H), 2.26 (s, 3H), 2.17 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1>O.[OH-].[Na+].[Ni]>[CH3:1][C:2]1[O:6][C:5]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C=CC(=O)O)o1
Agent: [Ni]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(CCC(=O)O)o1
Yield: 45.3 %

Procedure:
14.6 g of β-(5-methyl-2-furyl) acrylic acid, prepared in accordance with the procedures of Example 1, were dissolved in 100 ml H2O containing 4 g of NaOH. 10 g of Raney nickel alloy were then added. The resulting suspension was stirred in an ice-bath and a solution of 8 g of NaOH and 30 ml H2O was slowly added to the stirred solution, while the temperature thereof is maintained at below 20° C. On completion of the addition of the NaOH to the reaction mixture the temperature was permitted to rise slowly to 30° C. The reaction mixture was maintained at this temperature for 2 hours. Thereafter the reaction mixture was filtered with the filtrate being acidified with diluted HCl and extracted with ethyl acetate. The resulting extract was washed with water until neutral, dried and evaporated. The residue, on recrystallization from petroleum ether (boiling point--40°-60° C.), yielded 6.7 g (45% yield) of β-(5-methyl-2-furyl) propionic acid. Chromatography on the mother liquor on a column of silica gel and eluting with petroleum ether (boiling point--40°-60° C.) gave a further yield of 2.5 g (17%) of the pure acid melting at 56°-58° C.