Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.Cl[Pd]Cl>[O:11]=[C:5]1[C:6]([C:7]([OH:9])=[O:8])=[CH:10][C:2]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:3][NH:4]1
Reactant: OB(O)c1ccccc1
Reactant: O=C(O)c1cc(Br)cnc1O
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(O)c1cc(-c2ccccc2)c[nH]c1=O
Temperature: 110 °C
Yield: 18.1 %

Procedure:
A mixture of 5-bromo-2-hydroxynicotinic acid (436 mg, 2.00 mmol, Syn. Comm., 19 (3&4), 553-559 (1989)), phenylboronic acid (248 mg, 2.03 mmol), Cs2CO3 (1.20 g) and PdCl2 [(t-Bu) 2P(OH)] 2 (170 mg, CombiPhos Catalysts, Inc. Princeton, N.J.) in DMF (10 mL) and water (1.0 mL) was purged with Ar gas and heated at 110° C. for 6 h. Additional phenylboronic acid (75 mg) was added and the mixture was heated at 110° C. for 5 h. To the reaction was added TFA (3 mL), and the mixture was concentrated in vacuo to a volume of ˜12 mL. The mixture was purified by preparative HPLC to afford the desired product (78 mg, 18%). 1H NMR (DMF-d7) δ 14.8 (br s, 1H), 13.8 (br s, 1H), 8.73 (s, 1H), 8.46 (s, 1H), 7.74 (d, 1H, J=7.2 Hz), 7.53-7.42 (m, 3H), 5.81 (s, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16]O)[CH2:10][CH:9]1[C:18](=[O:35])[NH:19][CH:20]([CH:24]1[CH:29]([OH:30])[CH:28]([OH:31])[CH:27]([OH:32])[CH:26]([S:33][CH3:34])[O:25]1)[CH:21]([CH3:23])[CH3:22])=O)(C)(C)C.[C-:36]#[N:37].[Na+]>>[CH3:22][CH:21]([CH3:23])[CH:20]([NH:19][C:18]([CH:9]1[CH2:10][CH:11]([CH2:14][CH2:15][CH2:16][C:36]#[N:37])[CH2:12][CH2:13][NH:8]1)=[O:35])[CH:24]1[CH:29]([OH:30])[CH:28]([OH:31])[CH:27]([OH:32])[CH:26]([S:33][CH3:34])[O:25]1
Reactant: CSC1OC(C(NC(=O)C2CC(CCCO)CCN2C(=O)OC(C)(C)C)C(C)C)C(O)C(O)C1O
Reactant: [C-]#N
Agent: [Na+]
Product: CSC1OC(C(NC(=O)C2CC(CCCC#N)CCN2)C(C)C)C(O)C(O)C1O

Procedure:
The title compound of example 23 was prepared from protected tosylate intermediate prepared in example 19, 11h according to the procedure used in examples 19-21 using sodium cyanide nucleophile in the displacement step; MS (ESPOS): 430.3 [M+H]+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)Br.[Cl:25][C:26]1[CH:27]=[C:28]([CH:47]=[CH:48][C:49]=1[Cl:50])[CH2:29][N:30]1[C:38]2[C:33](=[C:34]([O:39][CH2:40]CO)[CH:35]=[CH:36][CH:37]=2)[CH:32]=[C:31]1[C:43]([O:45][CH3:46])=[O:44]>ClCCl>[Cl:25][C:26]1[CH:27]=[C:28]([CH:47]=[CH:48][C:49]=1[Cl:50])[CH2:29][N:30]1[C:38]2[C:33](=[C:34]([O:39][CH2:40][CH2:20][Br:24])[CH:35]=[CH:36][CH:37]=2)[CH:32]=[C:31]1[C:43]([O:45][CH3:46])=[O:44]
Reactant: COC(=O)c1cc2c(OCCO)cccc2n1Cc1ccc(Cl)c(Cl)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1cc2c(OCCBr)cccc2n1Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.3 %

Procedure:
Triphenylphosphine (0.55 g) was added in small portions over 2 hours to a stirred solution of carbon tetrabromide (0.47 g) and methyl N-(3,4-diclilorobenzyl)-4-(hydroxyethyloxy)indole-2-carboxylate (0.28 g) in dichloromethane (10 ml). The reaction was stirred for 3 hours at room temperature, concentrated in vacuo and the residue purified by column chromatography using dichloromethane as eluent to give methyl N-(3,4-dichlorobenzyl)-4-(bromoethyloxy)indole-2-carboxylate as a white solid (0.29 g, 90%); NMR d (CD3SOCD3) 3.80 (s, 3H), 3.89 (t, 2H), 4.46 (t, 2H), 5.80 (s, 2H), 6.62 (d, 1H), 6.88 (dd, 1H), 7.17 (d, 1H), 7.25 (t, 1H), 7.30-7.36 (m, 2H), 7.52 (d, 1H), M/z (+) 456, 458 (MH+).
Reaction SMILES: CCN(C(C)C)C(C)C.[NH2:10][C:11]1[C:12]([F:23])=[C:13]([CH2:20][CH2:21][OH:22])[C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=1.[C:24](Cl)(=[O:26])[CH3:25]>C1COCC1>[C:24]([O:22][CH2:21][CH2:20][C:13]1[C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=[C:11]([NH2:10])[C:12]=1[F:23])(=[O:26])[CH3:25]
Reactant: CC(=O)Cl
Reactant: Nc1ccc([N+](=O)[O-])c(CCO)c1F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OCCc1c([N+](=O)[O-])ccc(N)c1F
Reaction time: 1.5 h
Yield: 68.5 %

Procedure:
To a solution of DIEA (1.80 mL, 10.6 mmol) and 2-(3-amino-2-fluoro-6-nitrophenyl)ethanol (0.88 g, 4.40 mmol), as prepared in the preceding step, in THF (10 mL) in an ice-bath was added a solution of acetyl chloride (319 μL, 4.49 mmol) in THF (5 mL). After stirring for 1.5 hour, the ice-bath was removed and the mixture was continued to stir at ambient temperature overnight. Additional acetyl chloride (63 μL, 0.88 mmol) was added, and the mixture was stirred for another 16 hours. The solvents were removed, and the mixture was partitioned between DCM and H2O. The organic layer was separated, and the aqueous layer was back-extracted with DCM. The organic layers were combined, washed with H2O (twice), dried over Na2SO4, concentrated, and flash chromatographed on silica gel eluting with EtOAc/DCM (0, 1, 2, and 5%) to give the title compound (0.73 g, 69% yield) as a yellow solid. 1H-NMR (400 MHz, CDCl3) δ 7.85 (dd, J=9.0, 1.5 Hz, 1H), 6.68 (t, J=8.9 Hz, 1H), 4.38-4.35 (m, 4H), 3.38 (dt, J=6.6, 2.8 Hz, 2H), 2.03 (s, 3H).
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[S:2].[CH3:13][C:14]([C:17]1[CH:18]=[C:19]([C:34]([NH:36][NH2:37])=[NH:35])[CH:20]=[C:21]([C:30]([CH3:33])([CH3:32])[CH3:31])[C:22]=1[O:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29])([CH3:16])[CH3:15].C(N(CC)CC)C>O1CCCC1>[CH3:32][C:30]([C:21]1[CH:20]=[C:19]([C:34]2[N:36]=[N:37][C:1](=[S:2])[N:35]=2)[CH:18]=[C:17]([C:14]([CH3:13])([CH3:15])[CH3:16])[C:22]=1[O:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29])([CH3:31])[CH3:33]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: COCCOCOc1c(C(C)(C)C)cc(C(=N)NN)cc1C(C)(C)C
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCCOCOc1c(C(C)(C)C)cc(C2=NC(=S)N=N2)cc1C(C)(C)C

Procedure:
1,1'-Thiocarbonyldiimidazole (0.64 g, 0.0036 mole) is added portionwise to a stirred 0° C. solution of 3,5-bis(1,1-dimethylethyl)-4-[(2-methoxyethoxy)methoxy]benzene carboximidic acid hydrazide (1.0 g, 0.0028 mole) and triethylamine (0.43 ml, 0.003 mole) in tetrahydrofuran (5.0 ml). After the addition is complete the mixture is heated to reflux for 1.5 hours. The solution is cooled and concentrated in vacuo. The residue is dissolved in ether (20 ml) and the solution washed with aqueous 2M HCl, saturated aqueous NaHCO3, saturated aqueous NaCl, and dried over MgSO4. Filtration and concentration in vacuo gives 0.94 g (1.1 g theor., 86%) product after recrystallization from ethyl acetate/isopropyl ether, mp 187° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:30])=[C:7]([S:9]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][C:16]=2[O:24][CH2:25][C:26]([NH:28][NH2:29])=[O:27])(=[O:11])=[O:10])[CH:8]=1)#[N:2].Cl[C:32](Cl)([O:34]C(=O)OC(Cl)(Cl)Cl)Cl.O>O1CCCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:30])=[C:7]([S:9]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][C:16]=2[O:24][CH2:25][C:26]2[O:27][C:32](=[O:34])[NH:29][N:28]=2)(=[O:10])=[O:11])[CH:8]=1)#[N:2]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)c1ccc(CCNS(=O)(=O)c2cc(C#N)ccc2O)c(OCC(=O)NN)c1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1ccc(CCNS(=O)(=O)c2cc(C#N)ccc2O)c(OCc2n[nH]c(=O)o2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.1 %

Procedure:
5-Cyano-N-[2-(2-hydrazinocarbonylmethoxy-4-isopropylphenyl)ethyl]-2-hydroxybenzenesulfonamide (0.258 g) was dissolved in 10 mL of tetrahydrofuran. To the stirred solution was added 0.177 g of triphosgene under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 0.26 g of 5-cyano-2-hydroxy-N-[2-[4-isopropyl-2-(5-oxo-4,5-dihydro[1,3,4]-oxadiazol-2-ylmethoxy)phenyl]ethyl]benzenesulfonamide.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([I:15])=[C:11]([F:16])[CH:10]=2)[CH2:4]1.[F:17][CH:18]([F:22])[C:19](O)=[O:20].C(N(CC)C(C)C)(C)C.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[F:17][CH:18]([F:22])[C:19]([NH:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([I:15])=[C:11]([F:16])[CH:10]=2)[CH2:4]1)=[O:20]
Reactant: NC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Reactant: O=C(O)C(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1)C(F)F
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 91.5 %

Procedure:
A suspension of (5S)-5-Aminomethyl-3-(3-fluoro-4-iodo-phenyl)-oxazolidin-2-one (1022, 5.0 g, 14.88 mmol) in methylene chloride (CH2Cl2, 50 mL) was treated with difluoroacetic acid (2.14 g, 1.41 mL, 22.32 mmol, 1.5 equiv) and N,N-diisopropylethylamine (DIEA or Hunig's base, 3.85 g, 5.18 mL, 29.76 mmol, 2.0 equiv), and the resulting reaction mixture was cooled down to 0-5° C. before being treated with EDCl (4.30 g, 22.32 mmol, 1.5 equiv) at 0-5° C. The reaction mixture was subsequently stirred at 0-5° C. for 1 h before being gradually warmed up to room temperature for 12 h. When TLC and HPLC/MS showed that the reaction was complete, the reaction mixture was quenched with H2O (50 mL) and CH2Cl2 (50 mL). The two layers were then separated, and the aqueous layer was extracted with CH2Cl2 (2×50 mL). The combined organic extracts were washed H2O (50 mL) and the saturated aqueous NaCl solution (50 mL), dried over MgSO4, and concentrated in vacuo to afford the crude (5 S) 2,2-difluoro-N-[3-(3-fluoro-4-iodo-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide (1026, 5.64 g, 6.16 g theoretical, 91.6%) as off-white powders, which by HPLC/MS and 1H NMR was found to be essentially pure and was directly used in the subsequent reactions without further purification. For 1026: 1H NMR (300 MHz, DMSO-d6) δ 3.54 (t, 2H, J=5.5 Hz), 3.77 (dd, 1H, J=6.3, 9.2 Hz), 4.15 (t, 1H, J=9.2 Hz), 4.77-4.86 (m, 1H), 6.25 (t, 1H, J=53.52 Hz, —CHCF2), 7.18 (dd, 1H, J=2.4, 8.7 Hz), 7.55 (dd, 1H, J=2.4, 8.7 Hz), 7.84 (t, 1H, J=8.5 Hz), 9.19 (t, 1H, J=5.5 Hz, —CONH); C12H10F3IN2O3, LCMS (EI) m/e 415 (M++H), 456 (M++H+CH3CN).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][OH:23])[CH:17]=2)=[C:11]([CH3:24])[CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].O[C:26]1[CH:39]=[CH:38][C:29]2[C@H:30]([CH2:33][C:34]([O:36][CH3:37])=[O:35])[CH2:31][O:32][C:28]=2[CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[Si:1]([O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][O:23][C:26]3[CH:39]=[CH:38][C:29]4[C@H:30]([CH2:33][C:34]([O:36][CH3:37])=[O:35])[CH2:31][O:32][C:28]=4[CH:27]=3)[CH:17]=2)=[C:11]([CH3:24])[CH:10]=1)([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:3])[CH3:2]
Reactant: Cc1cc(O[Si](C)(C)C(C)(C)C)cc(C)c1-c1cccc(CO)c1
Reactant: COC(=O)C[C@@H]1COc2cc(O)ccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(O[Si](C)(C)C(C)(C)C)cc4C)c3)ccc21
Temperature: 0 °C
Reaction time: 4 h
Yield: 177.6 %

Procedure:
(4′-((tert-Butyldimethylsilyl)oxy)-2′,6′-dimethylbiphenyl-3-yl)methanol 3f (1.19 g, 3.48 mmol), methyl (S)-2-(6-hydroxyl-2,3-dihydrobenzofuran-3-yl)acetate (660 mg, 3.17 mmol) and triphenylphosphine (1.34 g, 4.75 mmol) were dissolved in 10 mL of dichloromethane. The reaction solution was cooled down to 0° C., followed by addition of diisopropyl azodicarboxylate (960 mg, 4.75 mmol), then warmed up to room temperature and stirred for 4 hours. The resulting solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system B to obtain the title compound (S)-methyl 2-(6-((4′-((tert-butyldimethylsilyl)oxy)-2′,6′-dimethylbiphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 3 g (1.28 g, yield 76.0%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([OH:25])=[C:5]([C:14]([N:16]([CH2:23][CH3:24])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:15])[C:6](=[O:13])[N:7]2[CH3:12].[OH-].[Na+:27]>C(O)C>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([O-:25])=[C:5]([C:14](=[O:15])[N:16]([CH2:23][CH3:24])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:6](=[O:13])[N:7]2[CH3:12].[Na+:27]
Reactant: CCN(C(=O)c1c(O)c2c(Cl)cccc2n(C)c1=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCN(C(=O)c1c([O-])c2c(Cl)cccc2n(C)c1=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39 %

Procedure:
The pH value of a solution of 5-chloro-N-ethyl-4-hydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide (170 mg, 0.48 mmol, 1.00 equiv) in ethanol (5 ml) was adjusted to 9-10 with a solution of 5M sodium hydroxide. The mixture then was stirred for about 30 min at ambient temperature. The resulting solids were collected by filtration and washed with ethanol to give the title compound as a white solid (70 mg, yield: 39%). 1H NMR (300 MHz, DMSO) δ: 6.84˜7.31 (m, 8H), 3.68 (q, 2H), 3.34 (s, 3H), 1.02 (t, 3H). LC-MS: m/z=357 (M-Na+2H)+
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1>CC(O)=O>[Br:1][C:9]1[CH:8]=[CH:7][C:6]([N:11]2[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH2:16]2)=[C:5]([O:4][CH3:3])[CH:10]=1
Reactant: BrBr
Reactant: COc1ccccc1N1CCN(C)CC1
Solvent: CC(=O)O
Product: COc1cc(Br)ccc1N1CCN(C)CC1
Temperature: 25 °C

Procedure:
A bromine solution (1.24 ml, 24.2 mmol) in 9.7 ml AcOH is added dropwise to a cooled solution (ca. 5° C.) of 1-(2-Methoxy-phenyl)-4-methyl-piperazine (as obtained in preparation 71, 5 g, 24.2 mmol) in AcOH (87 ml). After complete addition, the cooling bath is removed and reaction mixture allowed to warm up to RT. The dark violet solution is concentrated in vacuo, 20 ml de-ionized water is added and the pH is adjusted basic with a 20% NaOH solution. The mixture is extracted several times with CH2Cl2 and the combined organic layers are washed with brine, dried over Na2SO4, filtered and the filtrate is concentrated in vacuo. The residue is purified by chromatography on a 120 g silica gel column on a Combiflash Companion™ (Isco Inc.) apparatus (gradient CH2Cl2/CH2Cl2:EtOH:NH3 90:9:1 from 1:0=>0:1) to afford the title compound as a dark brown oil, Rt=0.767 min (Acquity HPLC BEH C18, 2.1×50 mm, 1.7 micron, detection 215 nM, 0.1 min 2% CH3CN in H2O, 2% to 100% CH3CN in H2O in 1.5 min, 0.4 min 100% CH3CN+0.1% TFA, flow rate 1.0 ml/min); MS: 285 (M+1, 79Br)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]2[N:9]([S:13]([C:16]3[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[C:10](I)=[CH:11][C:3]=12.CC1(C)C(C)(C)OB([C:31]2[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH:32]=2)O1.C(=O)([O-])O.[Na+]>CN(C)C=O.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]2[N:9]([S:13]([C:16]3[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[C:10]([C:31]3[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH:32]=3)=[CH:11][C:3]=12
Reactant: Cc1ccc(S(=O)(=O)n2c(I)cc3c(Cl)c(Cl)cnc32)cc1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2c(C3=CCN(C(=O)OC(C)(C)C)CC3)cc3c(Cl)c(Cl)cnc32)cc1
Temperature: 72 °C
Reaction time: 0.5 h

Procedure:
A mixture of Example 229B (0.808 g, 1.730 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (Frontier Scientific, 0.588 g, 1.903 mmol) and sodium hydrogencarbonate (0.436 g, 5.19 mmol) in degassed N,N-dimethylformamide (10.81 mL) and water (3.6 mL) was treated with bis(triphenylphosphine)palladium(II) chloride (0.121 g, 0.173 mmol) under nitrogen and the mixture was heated at 72° C. for 24 hours. The mixture was cooled to ambient temperature, suspended in 80 mL water, stirred for 30 minutes and filtered. Purification by flash chromatography on silica gel (AnaLogix IntelliFlash 280) eluting with a gradient of 0-20% ethyl acetate in hexanes afforded the title compound. MS (ESI+) m/z 522.2 (M+H)+.
Reaction SMILES: C([O:4][CH2:5][C:6]([N:8]([CH2:10][C:11]1[C:12]([CH:36](OC)[O:37]C)=[N:13][C:14]2[N:15]([C:21](=[O:35])[NH:22][C:23]3[CH:28]=[C:27]([O:29][CH:30]([CH3:32])[CH3:31])[C:26]([C:33]#[N:34])=[CH:25][N:24]=3)[CH2:16][CH2:17][CH2:18][C:19]=2[CH:20]=1)[CH3:9])=[O:7])(=O)C.Cl>C1COCC1.O>[C:33]([C:26]1[C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[CH:28][C:23]([NH:22][C:21]([N:15]2[C:14]3[C:19](=[CH:20][C:11]([CH2:10][N:8]([CH3:9])[C:6](=[O:7])[CH2:5][OH:4])=[C:12]([CH:36]=[O:37])[N:13]=3)[CH2:18][CH2:17][CH2:16]2)=[O:35])=[N:24][CH:25]=1)#[N:34]
Reactant: COC(OC)c1nc2c(cc1CN(C)C(=O)COC(C)=O)CCCN2C(=O)Nc1cc(OC(C)C)c(C#N)cn1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Oc1cc(NC(=O)N2CCCc3cc(CN(C)C(=O)CO)c(C=O)nc32)ncc1C#N
Temperature: 25 °C
Reaction time: 9.5 h

Procedure:
To a solution of 2-(((8-((5-cyano-4-isopropoxypyridin-2-yl)carbamoyl)-2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)(methyl)amino)-2-oxoethyl acetate (intermediate 195, 378 mg, 0.682 mmol) in THF (1.7 ml) and water (1.7 ml) was added 37% aqueous HCl (1.12 mL, 13.64 mmol) at room temperature. The reaction mixture was stirred for 9.5 h at room temperature, quenched by the addition of saturated aqueous NaHCO3 and extracted with DCM (3×). The combined organic layers were dried using Na2SO4, filtered and evaporated. The crude product was dissolved in DMF, filtered to remove insoluble impurities and purified by reversed phase preparative HPLC eluting with a gradient of MeCN and water (RP 5, H2O/MeCN 95:05 to 00:100 in 20 min). Fractions containing the product were collected, concentrated, diluted with water and basified with NaHCO3. The mixture was extracted with DCM (2×), dried using Na2SO4, filtered and concentrated. The resulting reddish solid was triturated in MeCN, filtered and dried to yield the title compound as a white solid.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[N:9][N:10]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[C:11](=[O:13])[CH:12]=1)(=O)=O.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1>>[O:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH:14]1[N:10]1[C:11](=[O:13])[CH:12]=[C:7]([C:27]2[CH:28]=[CH:29][C:24]([C:23]([F:34])([F:33])[F:22])=[CH:25][CH:26]=2)[CH:8]=[N:9]1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: O=c1cc(OS(=O)(=O)C(F)(F)F)cnn1C1CCCCO1
Product: O=c1cc(-c2ccc(C(F)(F)F)cc2)cnn1C1CCCCO1
Yield: 20.6 %

Procedure:
6-Oxo-1-(tetrahydro-2H-pyran-2-yl)-1,6-dihydropyridazin-4-yl trifluoromethanesulfonate (2.47 g, 7.5 mmol) and 4-trifluoromethylphenylboronic acid (2.56 g, 15 mmol) were reacted according to the procedure of Example 31 (step a) to provide the title compound (500 mg, 20%) as a white solid: ESI MS m/z 325 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:4]([C:8](I)=[C:9]([CH:11]3[CH2:13][CH2:12]3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[F:15][C:16]1[CH:17]=[CH:18][C:19]2=[C:20]([CH:36]=1)[O:21][CH2:22][C:23]1[CH:33]=[C:32]([CH:34]=[O:35])[CH:31]=[CH:30][C:24]=1/[C:25]/2=[C:26](/[CH3:29])\[C:27]#[N:28]>>[Br:1][C:2]1[C:3]2[N:4]([C:8]([CH:34]([OH:35])[C:32]3[CH:31]=[CH:30][C:24]4/[C:25](=[C:26](/[CH3:29])\[C:27]#[N:28])/[C:19]5[CH:18]=[CH:17][C:16]([F:15])=[CH:36][C:20]=5[O:21][CH2:22][C:23]=4[CH:33]=3)=[C:9]([CH:11]3[CH2:13][CH2:12]3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Brc1cccn2c(I)c(C3CC3)nc12
Reactant: C/C(C#N)=C1/c2ccc(C=O)cc2COc2cc(F)ccc21
Product: C/C(C#N)=C1/c2ccc(C(O)c3c(C4CC4)nc4c(Br)cccn34)cc2COc2cc(F)ccc21
Yield: 81.5 %

Procedure:
[step 3] Using 8-bromo-2-cyclopropyl-3-iodoimidazo[1,2-a]pyridine (2.2 g, 5.9 mmol) obtained in step 2 and (E)-2-(3-fluoro-8-formyldibenzo[b,e]oxepin-11(6H)-ylidene)propanenitrile (1.1 g, 3.7 mmol) obtained in Reference Example 5, and in the same manner as in Reference Example 14A, step 3, (E)-2-{8-[(8-bromo-2-cyclopropylimidazo[1,2-a]pyridin-3-yl)(hydroxy)methyl]-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene}propanenitrile (1.6 g, 80%) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:10](O)[CH2:11][OH:12].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]1[O:12][CH2:11][CH2:10][O:5]1
Reactant: O=Cc1ccccc1Br
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Brc1ccccc1C1OCCO1
Reaction time: 4 h

Procedure:
To a solution of 50.0 g of 2-bromobenzaldehyde in 50 ml of toluene was added ;b 25.0 ml of ethylene glycol plus 500 mg of p-toluenesulfonic acid. The mixture was heated at reflux with a Dean Stark Trap for 18 hours. Then an additional 10 ml of ethylene glycol was added to the mixture and reflux was continued for 4 hours longer. The solvent was evaporated in vacuo and the residue was dissolved in ether. The organic solution was washed with 5% sodium bicarbonate, dried over magnesium sulfate and filtered. The filtrate was evaporated to an oil which was distilled through a Kugelrohr apparatus. The fraction boiling at 130° C., 0.1 mm was collected giving 60.3 g of 2-(2-bromophenyl)-1,3-dioxolane.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([N:19]2[C@H:23]([CH2:24][O:25][CH3:26])[CH2:22][O:21][C:20]2=[O:27])[CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:12])(=[O:4])=[O:3].Cl[C:29]1[C:34]([Cl:35])=[CH:33][C:32]([Cl:36])=[CH:31][N:30]=1>>[Cl:35][C:34]1[C:29]([N:16]2[CH2:17][CH2:18][N:13]([C:11]([C:10]3[CH:9]=[CH:8][C:7]([N:19]4[C@H:23]([CH2:24][O:25][CH3:26])[CH2:22][O:21][C:20]4=[O:27])=[CH:6][C:5]=3[S:2]([CH3:1])(=[O:3])=[O:4])=[O:12])[CH2:14][CH2:15]2)=[N:30][CH:31]=[C:32]([Cl:36])[CH:33]=1
Reactant: COC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCNCC2)c(S(C)(=O)=O)c1
Reactant: Clc1cnc(Cl)c(Cl)c1
Product: COC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(c3ncc(Cl)cc3Cl)CC2)c(S(C)(=O)=O)c1
Yield: 45.5 %

Procedure:
By reaction and treatment in the same manner as in Example 147 and using (R)-3-[3-methanesulfonyl-4-(piperazine-1-carbonyl)phenyl]-4-methoxymethyloxazolidin-2-one (1.19 g) described in Preparation Example 172 and 2,3,5-trichloropyridine (1.09 g), the title compound (740 mg) was obtained.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.[NH2:13][CH:14]([CH2:17][CH3:18])[CH2:15][OH:16]>O1CCCC1>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([NH:13][CH:14]([CH2:17][CH3:18])[CH2:15][OH:16])=[O:4]
Reactant: CCC(N)CO
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Solvent: C1CCOC1
Product: CCC(CO)NC(=O)c1ccccc1N
Yield: 82.7 %

Procedure:
10.0 g (61 mmol) of isatoic anhydride and 11 g (123.6 mmol) of 2-amino-1-butanol in 200 ml of tetrahydrofuran were heated under reflux for 8 hours. The tetrahydrofuran was then removed under reduced pressure and the resulting residue was distributed between 2M aqueous sodium hydroxide solution and ethyl acetate. The ethyl acetate phase was dried and concentrated under reduced pressure. 10.5 g (82%) of the product were obtained.