Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:30]=[CH:29][C:8]([O:9][C:10]2[C:11]([C:16]3[CH2:17][CH2:18][CH2:19][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:21]=3)=[N:12][CH:13]=[CH:14][N:15]=2)=[CH:7][CH:6]=1)=[O:4].C1COCC1>[Pd].CCO>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([O:9][C:10]2[C:11]([CH:16]3[CH2:17][CH2:18][CH2:19][N:20]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[CH2:21]3)=[N:12][CH:13]=[CH:14][N:15]=2)=[CH:29][CH:30]=1)=[O:4]
Reactant: COC(=O)c1ccc(Oc2nccnc2C2=CN(C(=O)OC(C)(C)C)CCC2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Oc2nccnc2C2CCCN(C(=O)OC(C)(C)C)C2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a rb flask containing tert-butyl 5-(3-(4-(methoxycarbonyl)phenoxy)pyrazin-2-yl)-3,4-dihydropyridine-1(2H)-carboxylate (900 mg, 2.187 mmol) and palladium on carbon (233 mg, 0.219 mmol) (10 wt %) under N2 is added THF (5.5 mL) and EtOH (5.5 mL). The flask is purged with H2 (3×), then stirred under H2 at rt 3 h. The reaction was filtered through celite and the filter cake washed with Teac (2×10 mL). The combined filtrates were concentrated and the residue purified by ISCO (12 g SiO2, 0-50% Teac/Hexane) to give tert-butyl 3-(3-(4-(methoxycarbonyl)phenoxy)pyrazin-2-yl)piperidine-1-carboxylate as a brown solid.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:9][N:10]=2)[NH:5][C:4](=[O:19])[C:3]=1[C:20](OCC)=[O:21].[CH3:25][CH:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:9][N:10]=2)[NH:5][C:4](=[O:19])[C:3]=1[C:20]([NH:33][CH:26]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH3:25])=[O:21]
Reactant: CC(N)c1ccccc1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccccc3)cc2[nH]c1=O
Product: CC(NC(=O)c1c(O)c2ncc(Cc3ccccc3)cc2[nH]c1=O)c1ccccc1

Procedure:
This compound was prepared from ethyl 4-hydroxy-2-oxo-7-(phenylmethyl)-1,2-dihydro-1,5-naphthyridine-3-carboxylate and α-methylbenzylamine employing methods similar to those described in Example 2 and was obtained as a white solid: 1H NMR (d6-DMSO) δ 12.40 (1H, br), 10.80 (1H, br), 8.35 (1H, br), 7.35-7.24 (1H, m), 5.14 (1H, m), 4.05 (2H, br s), 1.46 (3H, br); HRMS calcd for C24H21N3O3+H+: 400.1661. Found: 400.1670.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[N+:8]([O-])[CH:7]=[CH:6]2.C(OC(=O)C)(=[O:16])C>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:16])[NH:8][CH:7]=[CH:6]2
Reactant: COc1ccc2c[n+]([O-])ccc2c1
Reactant: CC(=O)OC(C)=O
Product: COc1ccc2c(=O)[nH]ccc2c1
Temperature: 100 °C

Procedure:
5.2 g of 6-Methoxy-isoquinoline 2-oxide (58) was heated in 120 mL of acetic anhydride at 100° C. for 3 h. The reaction mixture was evaporated and the residue was taken up in 2 M NaOH and heated at 100° C. for another hour. The mixture was allowed to cool down and the pH was adjusted by addition of 2N HCl to 6. The aqueous layer was extracted several times with methyl-tert.butyl ether, the combined organic layer was dried over sodium sulphate and evaporated. The crude material was purified by silica gel chromatography to yield 3.26 g of the desired product.
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[C:23]([C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24].[H-].[Na+].CN(C)P(N(C)C)(N(C)C)=O>O1CCCC1>[CH3:6][O:5][C:3](=[O:4])[CH:2]([O:33][C:30]1[CH:31]=[CH:32][C:27]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:28][CH:29]=1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[CH:9][CH:8]=1
Reactant: COC(=O)C(Br)c1ccc(OCOc2ccc(Cl)cc2)cc1
Reactant: CC(C)(C)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: COC(=O)C(Oc1ccc(C(C)(C)C)cc1)c1ccc(OCOc2ccc(Cl)cc2)cc1
Yield: 105.3 %

Procedure:
As described in Example 3, 8.92 g of methyl bromo{p-[(p-chlorophenoxy)methoxy]phenyl}acetate, 3,45 g of p-tert.-butylphenol and 9.17 g of 60% sodium hydride-oil dispersion are reacted in 75 ml of tetrahydrofuran containing 1 ml of hexamethylphosphoramide and worked-up to give 11 g of product as an oil. Chromatography over silica gel with dichloromethane as eluent gives 7.1 g of gum which is crystallized from methanol to give 4.9 g of white crystals. Recrystallization gives white crystals, mp 64°-65° C.
Reaction SMILES: [Na].[C:2]([O:10]CC)(=[O:9])[CH2:3][C:4]([O:6]CC)=[O:5].Br[CH2:14][C:15]1[C:16]([CH2:21]Br)=[CH:17][CH:18]=[CH:19][CH:20]=1>C(O)C.C(OCC)C>[CH2:21]1[C:16]2[C:15](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:14][C:3]1([C:4]([OH:6])=[O:5])[C:2]([OH:10])=[O:9]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: BrCc1ccccc1CBr
Agent: [Na]
Solvent: CCOCC
Solvent: CCO
Product: O=C(O)C1(C(=O)O)Cc2ccccc2C1

Procedure:
Sodium (3.7 g) was dissolved in 80 ml of ethyl alcohol, followed by the addition of 150 ml of diethyl ether. Diethyl malonate (12.5 ml) was added followed by 20 g of α,α'-dibromo-o-xylene in 150 ml of diethyl ether with overhead stirring. The reaction was heated to reflux for 5 hours. The reaction was cooled, filtered, and the solvent was removed under vacuum. The residue was treated with a potassium hydroxide solution (20 g in 125 ml of water) and heated to reflux for 15 hours. The reaction was then cooled and rinsed with 200 ml of diethyl ether. The aqueous phase was acidified with 30% hydrochloric acid. The precipitate was collected and dried under vacuum over Drieruite for 5 hours to yield 8.86 g of indan-2,2-dicarboxylic acid.
Reaction SMILES: CCCCCC.C([Li])CCC.[C:12]1([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:17]=[CH:16][C:15]([C:18]2[N:23]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:26][CH:25]=3)[N:21]=[C:20]([C:36]3[CH:41]=[CH:40][C:39](Br)=[CH:38][CH:37]=3)[N:19]=2)=[CH:14][CH:13]=1.Br[C:50]1[CH:51]=[CH:52][C:53]([C:56]2[CH:61]=[CH:60][N:59]=[CH:58][CH:57]=2)=[N:54][CH:55]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCCC1>[C:12]1([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:17]=[CH:16][C:15]([C:18]2[N:23]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:26][CH:25]=3)[N:21]=[C:20]([C:36]3[CH:41]=[CH:40][C:39]([C:50]4[CH:51]=[CH:52][C:53]([C:56]5[CH:61]=[CH:60][N:59]=[CH:58][CH:57]=5)=[N:54][CH:55]=4)=[CH:38][CH:37]=3)[N:19]=2)=[CH:14][CH:13]=1
Reactant: Brc1ccc(-c2nc(-c3ccc(-c4ccccc4)cc3)nc(-c3ccc(-c4ccccc4)cc3)n2)cc1
Reactant: Brc1ccc(-c2ccncc2)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: c1ccc(-c2ccc(-c3nc(-c4ccc(-c5ccccc5)cc4)nc(-c4ccc(-c5ccc(-c6ccncc6)nc5)cc4)n3)cc2)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 54.2 %

Procedure:
Under a stream of argon, 2.2 ml of a hexane solution containing 3.3 mmol of butyl lithium was slowly added to 60 ml of tetrahydrofuran cooled to −78° C. in which 1.62 g of 2,4-bis(4-biphenylyl)-6-(4-bromophenyl)-1,3,5-triazine obtained in Reference Example 3 had been dissolved. After stirring at −78° C. for 15 minutes, 0.91 g of dichloro(tetramethylethylenediamine)zinc(II) was added thereto and stirred at −78° C. for 10 minutes and then at room temperature for 2 hours. A 30 ml portion of tetrahydrofuran prepared by dissolving 0.71 g of 5-bromo-2,4′-bipyridyl and 0.14 g of tetrakis(triphenylphosphine)palladium(0) therein was added to this solution and stirred under heating reflux for 14 hours. The reaction solution was concentrated under a reduced pressure and the thus obtained solid was recrystallized from dichloromethane-methanol. The thus obtained crude product was purified by a silica gel column chromatography (eluting solution hexane:chloroform=2:1 to chloroform) and an alumina gel column chromatography (eluting solution hexane:chloroform=1:1) and then recrystallized from dichloromethane-methanol to obtain a white solid of the intended 5-{4-[4,6-bis(4-biphenylyl)-1,3,5-triazin-2-yl]phenyl}-2,4′-bipyridyl (1.00 g, yield 54%).
Reaction SMILES: [C:1]([C:5]([C:7]1[N:12]2[C:13](=[S:17])[C@H:14]([O:15][CH3:16])[C@H:11]2[S:10](=[O:19])(=[O:18])[CH:9]([C:20]2[N:24]([CH3:25])[N:23]=[N:22][N:21]=2)[C:8]=1[CH3:26])=[O:6])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH2:34](Br)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CS(C)=O.C(OCC)(=O)C>[CH2:34]([C:9]1([C:20]2[N:24]([CH3:25])[N:23]=[N:22][N:21]=2)[C:8]([CH3:26])=[C:7]([C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[O:6])[N:12]2[C:13](=[S:17])[C@H:14]([O:15][CH3:16])[C@H:11]2[S:10]1(=[O:19])=[O:18])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CO[C@H]1C(=S)N2C(C(=O)C(C)(C)C)=C(C)C(c3nnnn3C)S(=O)(=O)[C@H]12
Reactant: BrCc1ccccc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CO[C@H]1C(=S)N2C(C(=O)C(C)(C)C)=C(C)C(Cc3ccccc3)(c3nnnn3C)S(=O)(=O)[C@H]12
Reaction time: 8 h

Procedure:
415 mg of 4-tert-butylcarbonyl-7α-methoxy-3-methyl-2-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-3-cephem 1,1-dioxide was dissolved in dimethyl sulphoxide (3 ml) and triethylamine (0.153 ml) and benzyl bromide (0.360 ml) were added. The reaction mixture was left overnight at room temperature, diluted with ethyl acetate, washed with a dilute solution of hydrochloric acid and eventually with brine. Drying over Na2SO4 and removal of the organic solvent left a residue which was then purified by flash chromatography affording the title compound as a white solid (270 mg).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)=[CH:10][NH:9][N:8]=2)=[CH:4][CH:3]=1.Br[CH2:19][CH:20]([CH3:22])[CH3:21].C(=O)([O-])[O-].[Cs+].[Cs+].ClCCl>CN(C)C=O.O>[CH2:19]([N:9]1[CH:10]=[C:11]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[C:7]([C:5]2[S:6][C:2]([Br:1])=[CH:3][CH:4]=2)=[N:8]1)[CH:20]([CH3:22])[CH3:21]
Reactant: Brc1ccc(-c2n[nH]cc2-c2ccncc2)s1
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Cn1cc(-c2ccncc2)c(-c2ccc(Br)s2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.8 %

Procedure:
To a solution of 4-[3-(5-bromo-2-thienyl)-1H-pyrazol-4-yl]pyridine (1 eq, 8.8 mmol) in 50 mL N,N-dimethylformamide were added 1-bromo-2-methylpropane (1.5 eq, 13.2 mmol) and cesium carbonate (1.1 eq, 9.7 mmol). The reaction mixture was stirred overnight at room temperature and poured in 500 mL of water. The resulting precipitate was filtered and dried. The solid was then recristallised in a mixture diisopropylether:dichloromethane to afford 1.81 g of 4-[1-isobutyl-3-(5-bromo-2-thienyl)-1H-pyrazol-4-yl]pyridine (53% yield).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[C:5]([NH2:17])=[CH:4][N:3]=1.[C:18]([N:25]1[CH2:31][CH2:30][CH2:29][C@H:26]1[CH:27]=O)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C(Cl)Cl>[C:21]([O:20][C:18]([N:25]1[CH2:31][CH2:30][CH2:29][C@H:26]1[CH2:27][NH:17][C:5]1[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)=[N:7][C:2]([Cl:1])=[N:3][CH:4]=1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: COc1ccc(Oc2nc(Cl)ncc2N)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1ccc(Oc2nc(Cl)ncc2NC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Reaction time: 3 h
Yield: 85 %

Procedure:
To a solution of Compound 1c (4.45 g, 17.7 mmol) in 1,2-dichloroethane (80 mL) was added Boc-L-prolinal (Compound 1d) (5.0 g; 24.4 mmol) and glacial acetic acid (4.5 mL) at ambient temperature, and the mixture was stirred under a nitrogen atmosphere for 3 h. The mixture was then treated with NaB(OAc)3H (9.37 g; 44.2 mmol) and continually stirred at room temperature for 20 h. The resultant mixture was diluted with CH2Cl2, and washed with saturated NaHCO3(aq) and H2O. The organic phase was washed sequentially with H2O and brine, and then dried over Na2SO4. The mixture was filtered and the filtrate was evaporated under reduced pressure to give the crude material. The crude material was purified by flash column chromatography (SiO2), eluting with a Et2O—CH2Cl2 gradient to afford Compound 1e (6.54 g; 85% yield) as a pale-yellow solid. 1H-NMR (400 MHz, CDCl3): δ 7.73-7.79 (m, 1H), 7.07-7.14 (m, 2H), 6.91-6.98 (m, 2H), 5.73 (br. s, 0.6H), 4.77 (br. s, 0.4H), 4.20-4.30 (m, 1H), 3.85 (s, 3H), 3.21-3.58 (m, 4H), 1.81-2.11 (m, 4H), 1.46-1.49 (m, 9H); MS: m/z 435.1 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O.Br[CH:33]=[C:34]([C:36]1[S:37][CH:38]=[CH:39][CH:40]=1)[CH3:35]>CN(C=O)C.[Cu]I>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6](/[CH:33]=[C:34](/[C:36]3[S:37][CH:38]=[CH:39][CH:40]=3)\[CH3:35])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: CC(=CBr)c1cccs1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: C/C(=C\n1c2c(c3cc(C)ccc31)CN(C)CC2)c1cccs1
Temperature: 85 °C

Procedure:
2,3,4,5-Tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (50 mg, 0.25 mmol) was dissolved in DMF (3 mL), potassium phosphate (106 mg, 0.5 mmol), copper (I) iodide (4.75 mg, 0.025 mmol) and L-proline (5.75 mg, 0.05 mmol) were added. 2-(1-Bromoprop-1-en-2-yl)thiophene (55 mg, 0.275 mmol) was dissolved in DMF (2 mL) and added dropwise to the reaction mixture. The reaction mixture was purged with nitrogen for 2 min. and heated at 85° C. overnight. DMF was evaporated under reduced pressure and water was added to the residue. The product was extracted with EtOAc (3×25 mL), the organic layer was washed with water (3×25 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by HPLC. Yield: 0.4 mg as the TFA salt. 1H NMR (CDCl3, TFA salt) δ (ppm):7.30-7.20 (m, 3H), 7.10 (m, 3H), 7.0 (s, 1H), 4.78 (m, 1H), 4.15 (m, 1H), 3.82 (m, 1H), 3.30 (m, 2H), 3.05 (s, 3H), 2.90 (m, 1H), 2.42 (s, 3H), 1.98 (s, 3H).
Reaction SMILES: C([O:3][C:4]([C@H:6]1[C@@H:11]([N:12]([CH2:33][CH2:34][CH:35]2[CH2:37][CH2:36]2)[C:13](=[O:32])[CH2:14][C:15]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[CH:24][C:18]=3[S:17](=[O:31])(=[O:30])[N:16]=2)[C@H:10]2[CH2:38][C@@H:7]1[CH2:8][CH2:9]2)=O)C.[O-]CC.[Na+].Cl>C(O)C>[CH:35]1([CH2:34][CH2:33][N:12]2[C:13](=[O:32])[C:14]([C:15]3[NH:20][C:19]4[CH:21]=[CH:22][C:23]([NH:25][S:26]([CH3:29])(=[O:27])=[O:28])=[CH:24][C:18]=4[S:17](=[O:30])(=[O:31])[N:16]=3)=[C:4]([OH:3])[C@H:6]3[C@@H:11]2[C@H:10]2[CH2:38][C@@H:7]3[CH2:8][CH2:9]2)[CH2:36][CH2:37]1
Reactant: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1N(CCC1CC1)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)[C@@H]3[C@H]4CC[C@H](C4)[C@@H]3N(CCC3CC3)C1=O)N2
Temperature: 25 °C
Reaction time: 23 h
Yield: 22.9 %

Procedure:
To a solution of the crude (1S,2R,3S,4R)-3-{(2-cyclopropyl-ethyl)-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-amino}-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester in absolute ethanol (11 mL) was added a 21 wt. % solution of sodium ethoxide in ethanol (2.4 mL, 7.41 mmol). After shaking at 25° C. for 23 h, additional 21 wt. % solution of sodium ethoxide in ethanol (1.0 mL, 3.09 mmol) was added. After shaking at 25° C. for 6 h, additional 21 wt. % solution of sodium ethoxide in ethanol (1.0 mL, 3.09 mmol) was added and the mixture was shaken for another 24 h. The mixture was then acidified with 1.0 M aqueous hydrochloric acid solution (22 mL) and was extracted with ethyl acetate (3×60 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude mixture was purified by prep-HPLC [Column Luna 5μ C18 (2) 100 Å AXIA 150×21.2 mm, 5 micron, 30%-95% in 7 min @ 30 mL/min flow rate, 0.05% trifluoroacetic acid in acetonitrile/0.05% trifluoroacetic acid in water] to afford the desired product, N-{3-[(1R,2S,7R,8S)-3-(2-cyclopropyl-ethyl)-6-hydroxy-4-oxo-3-aza-tricyclo[6.2.1.02,7]undec-5-en-5-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (160.7 mg, 0.309 mmol, 22.9% over two steps), as a solid. 1H NMR (400 MHz, CDCl3) δ: 0.09-0.15 (2H, m), 0.49-0.54 (2H, m), 0.64-0.73 (1H, m), 1.27-1.31 (2H, m), 1.48-1.78 (6H, m), 2.55-2.56 (1H, m), 2.74-2.80 (1H, m), 2.85 (1H, d, J=9.2 Hz), 3.06 (3H, s), 3.10-3.17 (1H, m), 3.57 (1H, d, J=9.2 Hz), 3.80-3.87 (1H, m), 6.99 (1H, s), 7.22-7.25 (1H, m), 7.62-7.68 (2H, m). LC-MS (ESI) calcd for C23H28N4O6S2 520.15, found 521.4 [M+H+].
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:22])=[C:8]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[N:13][S:12][C:9]2=[CH:10][N:11]=1)=[O:5])C.[NH2:23][CH2:24][C:25]([OH:27])=[O:26].C[O-].[Na+]>>[F:21][C:18]1[CH:17]=[CH:16][C:15]([C:14]2[C:8]3[C:9](=[CH:10][N:11]=[C:6]([C:4]([NH:23][CH2:24][C:25]([OH:27])=[O:26])=[O:5])[C:7]=3[OH:22])[S:12][N:13]=2)=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1ncc2snc(-c3ccc(F)cc3)c2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CNC(=O)c1ncc2snc(-c3ccc(F)cc3)c2c1O
Temperature: 25 °C
Yield: 89.4 %

Procedure:
A mixture of 3-(4-Fluoro-phenyl)-4-hydroxy-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester (150 mg, 0.47 mmol), glycine (1.06 g, 14.1 mmol), and NaOMe (23.5 mL, 11.75 mmol, 0.5 M solution in MeOH) was refluxed for 24 h. After cooling to r.t. the mixture was concentrated in vacuo. The residue was dissolved in water (50 mL), and the solution washed with CH2Cl2 (2×30 mL) before it was acidified by addition of aqueous 1N HCl solution. The resulting precipitate was sucked off, washed with water, and dried in vacuo to give the title compound (146 mg) as white solid: MS (m/z) 346.1 (M−1)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1B(O)O.C1(C)C=CC=CC=1.[CH2:17]([O:21][C:22]([C:24]1[N:25]=[C:26](Br)[C:27]2[C:32]([C:33]=1[O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:23])[CH2:18][CH2:19][CH3:20].C([O-])([O-])=O.[Na+].[Na+]>CCO.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>[CH2:17]([O:21][C:22]([C:24]1[N:25]=[C:26]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[C:27]2[C:32]([C:33]=1[O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:23])[CH2:18][CH2:19][CH3:20]
Reactant: CCCCOC(=O)c1nc(Br)c2ccccc2c1OCc1ccccc1
Reactant: OB(O)c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCCOC(=O)c1nc(-c2ccccn2)c2ccccc2c1OCc1ccccc1
Reaction time: 24 h

Procedure:
To a solution of Pyridin-2-ylboronic acid (323 mg, 2.5 mmol) in EtOH (2.5 ml) was added subsequently toluene (15 ml), 4-Benzyloxy-1-bromo-isoquinoline-3-carboxylic acid butyl ester (1.035 mg, 2.5 mmol, see example D-86a), Pd(PPh3)4 (292 mg, 0.25 mmol), and aq. 2 M Na2CO3 solution (2.5 ml, 5 mmol). The mixture was then refluxed with stirring under N2 protection for 24 h. Subsequently, the mixture was concentrated in vacuo. To the residue was added water (15 ml) and the mixture was extracted with EtOAc (30 ml). The organic phase was dried over MgSO4 and evaporated in vacuo. Purification of the residue by flash column chromatography on silica gel using CH2Cl2 MeOH=982 as the eluent gave a dark oil that was further purified by flash column chromatography on silica gel using CH2Cl2 MeOH=991 as the eluent and subsequently by preparative TLC using CH2Cl2 MeOH=982 as the eluent (had to be repeated several times) to give the title compound as a yellow oil (19 mg); MS-(+)-ion M+1=413.2.
Reaction SMILES: C[O:2][C:3](=[O:39])[CH2:4][N:5]([CH2:34][C:35]([O:37]C)=[O:36])[C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:9]=[C:8]([N+:31]([O-:33])=[O:32])[CH:7]=1.[OH-].[Na+]>CO.O1CCOCC1.O>[C:3]([CH2:4][N:5]([C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:9]=[C:8]([N+:31]([O-:33])=[O:32])[CH:7]=1)[CH2:34][C:35]([OH:37])=[O:36])([OH:39])=[O:2]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(N(CC(=O)OC)CC(=O)OC)cc([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: CCCCCCCCCCCCCCCCCCOc1cc(N(CC(=O)O)CC(=O)O)cc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 80.9 %

Procedure:
A solution of 1.44 g (2.6 mmol) of N-(2-methoxy-2-oxoethyl)-N-[3-nitro-5-(octadecyloxy)phenyl]glycine methyl ester and 15 ml of 1N NaOH in 65 ml of methanol, 10 ml of dioxane and 20 ml of water was stirred reflux for 5 hours. The solvents were removed at reduced pressure and the residue was dissolved in 400 ml of hot water. After cooling to room temperature, 6N HCl was added to acidify and the resultant precipitate was filtered. Purification by chromatography on 40 g of silica gel using 20% methanol-chloroform gave 1.1 g (81% yield, mp 131°-134°) of N-(carboxymethyl)-N-[3-nitro-5-(octadecyloxy)phenyl]glycine.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[CH:11]=[C:10](B2OC(C)(C)C(C)(C)O2)[CH:9]=[N:8]1.[F:21][C:22]([F:64])([F:63])[C:23]1[CH:24]=[C:25]([CH:56]=[C:57]([C:59]([F:62])([F:61])[F:60])[CH:58]=1)[CH2:26][N:27]([C:49]1[N:54]=[CH:53][C:52](Br)=[CH:51][N:50]=1)[C@@H:28]1[CH2:32][N:31]([C:33]2[C:38]([Cl:39])=[CH:37][N:36]=[C:35]([N:40]3[CH2:45][CH2:44][CH:43]([OH:46])[CH2:42][CH2:41]3)[N:34]=2)[C@H:30]([CH2:47][CH3:48])[CH2:29]1.N#N.C([O-])([O-])=O.[Na+].[Na+]>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.ClCCl.O.COCCOC>[F:62][C:59]([F:60])([F:61])[C:57]1[CH:56]=[C:25]([CH:24]=[C:23]([C:22]([F:21])([F:63])[F:64])[CH:58]=1)[CH2:26][N:27]([C:49]1[N:54]=[CH:53][C:52]([C:10]2[CH:9]=[N:8][N:7]([CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)[CH:11]=2)=[CH:51][N:50]=1)[C@@H:28]1[CH2:32][N:31]([C:33]2[C:38]([Cl:39])=[CH:37][N:36]=[C:35]([N:40]3[CH2:41][CH2:42][CH:43]([OH:46])[CH2:44][CH2:45]3)[N:34]=2)[C@H:30]([CH2:47][CH3:48])[CH2:29]1
Reactant: CC1(C)OB(c2cnn(C3CCCCO3)c2)OC1(C)C
Reactant: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(Br)cn2)CN1c1nc(N2CCC(O)CC2)ncc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Solvent: ClCCl
Product: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(-c3cnn(C4CCCCO4)c3)cn2)CN1c1nc(N2CCC(O)CC2)ncc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 25 ml round-bottom flask is charged with 1-(tetrahydro-pyran-2-yl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (56 mg, 0.2 mmol), 1-(4-{(2R,4S)-4-[(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-2-ethyl-pyrrolidin-1-yl}-5-chloro-pyrimidin-2-yl)-piperidin-4-ol (110 mg, 0.15 mmol) under N2. Pd(PPh3)4 (34 mg, 0.03 mmol) is added promptly and the flask is recharged with N2. Then DME (0.5 ml), Na2CO3 (1 M in H2O, 0.3 ml, 0.3 mmol) are added. The mixture is then heated to 95 degree for 2 hours. After cooling down to rt, NaIO4 (103 mg, 0.48 mmol) is added into reaction mixture. Stirring is continued for 1 h to give white suspension. H2O and dichloromethane are added, then organic layer is collected with phase separator. Removal of solvent gave 1-{4-[(2R,4S)-4-((3,5-bis-trifluoromethyl-benzyl)-{5-[1-(tetrahydro-pyran-2-yl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-amino)-2-ethyl-pyrrolidin-1-yl]-5-chloro-pyrimidin-2-yl}-piperidin-4-ol which is used without further purification.