Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:12]([Si:14]([CH3:17])([CH3:16])[CH3:15])#[CH:13].C(NC(C)C)(C)C>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.[Cu](I)I.C(#N)C>[CH3:15][Si:14]([C:12]#[C:13][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6])([CH3:17])[CH3:16]
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)c1ccnc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CC(C)NC(C)C
Solvent: CC#N
Product: COC(=O)c1ccnc(C#C[Si](C)(C)C)c1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 81.9 %

Procedure:
Methyl 2-bromoisonicotinate (216 g, 1 mol), dry acetonitrile (1.7 L), ethynyl(trimethyl)silane (117 g, 1.2 mol), diisopropylamine (122 g, 1.2 mol), and dichlorobis(triphenylphosphine)palladium (36 g, 0.05 mol) were placed into a well dried three necked flask which was twice purged with a stream of nitrogen. The reaction mixture was stirred for 0.5 hours, cooled to 10° C., and copper iodide (19 g, 0.1 mol) was added under a stream of nitrogen. At 20° C., the reaction mixture became thick and black and an exotherm was observed which was followed by formation of a precipitate. After the addition of copper iodide, the reaction mixture was stirred for further 2 hours at ambient temperature. The precipitated residue was separated by filtration and twice washed with diethyl ether (800 mL). The filtrate was washed with saturated ammonium chloride (2×300 mL) and brine (2×300 mL). After drying over sodium sulfate, the solvent was evaporated. The residue was purified using a silica gel column, eluting with hexane followed by 5% ethyl acetate in petroleum ether to yield 191 g (82%) of methyl 2-((trimethylsilyl)ethynyl)isonicotinate.
Reaction SMILES: [OH:1][C:2]1[C:11]([O:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:14])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:21][CH2:22][CH2:23]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Br:21][CH2:22][CH2:23][O:1][C:2]1[C:11]([O:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:14])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cccc(OC(=O)c2ccccc2)c1O
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(OC(=O)c2ccccc2)c1OCCBr
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 52.1 %

Procedure:
To a solution of methyl 2-hydroxy-3-[(phenylcarbonyl)oxy]benzoate (42.1 g, 155 mmol) in N,N-dimethylformamide (300 mL) was added 1,2-dibromoethane (135 mL, 1550 mmol) and cesium carbonate (76 g, 232 mmol), and the reaction mixture was stirred at room temperature under nitrogen for 6.5 h. The volume of the reaction mixture was reduced by half in vacuo, and then partitioned between water (500 mL) and ethyl acetate (500 mL). The layers were separated, and the organic layer was washed with brine (200 mL), dried over anhydrous magnesium sulfate and concentrated. The crude precipitate was triturated with 50% diethyl ether/hexanes (200 mL). The solid was washed with 50% diethyl ether/hexanes (2×200 mL) and isolated to give 30.6 g (52% over 2 steps) of methyl 2-[(2-bromoethyl)oxy]-3-[(phenylcarbonyl)oxy]benzoate as an off-white powder: 1H NMR (400 MHz, CDCl3): 8.23-8.21 (m, 2H), 7.77 (dd, J=1.6, 7.6 Hz, 1H), 7.68-7.64 (m, 1H), 7.53 (t, J=6.0 Hz, 2H), 7.39 (dd, J=1.8, 8.0 Hz, 1H), 7.25 (t, J=6.4 Hz, 1H), 4.31 (t, J=6.4 Hz, 2H), 3.93 (s, 3H), 3.52 (t, J=6.4 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([SH:9])[NH:8][C:4]=2[CH:3]=1.[C:12](Cl)(=[O:20])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].O>CC(N(C)C)=O.C(#N)C>[SH:9][C:7]1[NH:8][C:4]2[CH:3]=[C:2]([NH:1][C:12](=[O:20])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:11]=[CH:10][C:5]=2[N:6]=1
Reactant: Nc1ccc2nc(S)[nH]c2c1
Reactant: CCCCCCCC(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: CC#N
Solvent: O
Product: CCCCCCCC(=O)Nc1ccc2nc(S)[nH]c2c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 87.4 %

Procedure:
8.3 g of 5-amino-2-mercaptobenzimidazole was suspended in a mixture of 20 ml of dimethylacetamide and 35 ml of acetonitrile. 8.5 g of octanoyl chloride was dropped into the suspension at 50° C. After stirring at 50° C. for 2 hours, 20 ml of water was added to the reaction mixture. Crystals thus formed were collected by filtration, washed with water and dried to obtain 12.8 g of 2-mercapto-5-octanamidobenzimidazole (yield: 88%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[NH2:12])[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].[Cl:19][C:20]1[CH:29]=[CH:28][C:23]([CH:24]=[CH:25][CH2:26]Cl)=[CH:22][CH:21]=1>CN(C)C=O>[NH2:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[NH:1][CH2:26][CH:25]=[CH:24][C:23]1[CH:28]=[CH:29][C:20]([Cl:19])=[CH:21][CH:22]=1
Reactant: COC(=O)c1ccc(N)c(N)c1
Reactant: ClCC=Cc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N)c(NCC=Cc2ccc(Cl)cc2)c1
Yield: 63.2 %

Procedure:
5.0 g of methyl 3,4-diaminobenzoate was dissolved in 40 ml of dimethylformamide, and to the solution were added 2.07 g of potassium carbonate and 1.87 g of p-chlorocinnamyl chloride, and reaction was carried out according to the procedure in Reference Example 40, to obtain 2.0 g of the title compound as a light brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:10][C:11]2[C:12]([CH3:18])=[N:13][N:14]([CH3:17])[C:15]=2[CH3:16])[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[OH:19]S(O)(=O)=O.[OH-].[Na+]>O>[Br:1][C:2]1[CH:3]=[C:4]([O:10][C:11]2[C:12]([CH3:18])=[N:13][N:14]([CH3:17])[C:15]=2[CH3:16])[C:5]([C:8]([NH2:9])=[O:19])=[N:6][CH:7]=1
Reactant: Cc1nn(C)c(C)c1Oc1cc(Br)cnc1C#N
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1nn(C)c(C)c1Oc1cc(Br)cnc1C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A flask was charged with 5-bromo-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)picolinonitrile (7.0 g, 23 mmol) and H2SO4 (56 g, 570 mmol) and the reaction was stirred at ambient temperature overnight. The reaction was cooled in an ice bath and water (100 mL) was carefully added. 40% NaOH solution was slowly added till the pH was about 12. The mixture was extracted with ethyl acetate and dichloromethane, and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to afford 5-bromo-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)picolinamide (7.4 g, 23 mmol, 100% yield) as light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[C@@H:9]([OH:10])[CH2:8][CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:37](O)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.CCOC(C)=O.CCCCCC>[CH3:1][O:2][C:3]([C@@H:5]1[C@H:9]([O:10][C:37](=[O:44])[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:8][CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: COC(=O)[C@@H]1[C@@H](O)CCN1C(=O)OC(C)(C)C
Reactant: O=C(O)c1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1[C@H](OC(=O)c2ccccc2)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 89.7 %

Procedure:
To a stirred solution of compound 1B (69.1 g, 0.282 mol), triphenylphosphine (88.7 g, 0.338 mol) and benzoic acid (41.3 g, 0.338 mol) in anhydrous THF (1.35 L) cooled to 0° C. was added a solution of DEAD (62.0 mL, 0.330 mol) in anhydrous THF (50 mL) dropwise over 1 h through an addition funnel. After the addition, the resulting light yellow solution was stirred at rt until the reaction was complete (˜8 h). The reaction mixture was then partitioned between EtOAc and aqueous NaHCO3. The organic layer was washed with saturated aqueous NaHCO3, water (2×), brine, dried (Na2SO4) and concentrated under reduced pressure to yield a crude product as a semi-solid. The crude product was suspended in 25% EtOAc/hexane and stirred vigorously for 3 h. The resulting suspension was filtered and the collected white solid (triphenylphosphine oxide) rinsed with 20% EtOAc/hexane (2×). The combined filtrate was concentrated under reduced pressure to yield an oily residue, which was triturated twice with 20% EtOAc/hexane as described above to yield approximately 150 g of the partially purified product as a yellow oil, which was further purified via flash chromatography (silica gel) eluting with 10-20% EtOAc/hexane to furnish pure compound 1C (88.4 g) as a light yellow viscous oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([OH:14])=[CH:12][C:11]([CH2:15][C:16]([O:18][CH3:19])=[O:17])=[N:10]1.[CH3:20][O:21][CH2:22][C:23](Cl)=[O:24].Cl>O1CCOCC1.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([OH:14])=[C:12]([C:23](=[O:24])[CH2:22][O:21][CH3:20])[C:11]([CH2:15][C:16]([O:18][CH3:19])=[O:17])=[N:10]1
Reactant: COCC(=O)Cl
Reactant: COC(=O)Cc1cc(O)n(-c2ccc(F)cc2Cl)n1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COCC(=O)c1c(CC(=O)OC)nn(-c2ccc(F)cc2Cl)c1O
Yield: 74 %

Procedure:
The mixture of the above obtained methyl [1-(2-chloro-4-fluorophenyl)-5-hydroxy-1H-pyrazol-3-yl]acetate (Compound of Formula (IV), 0.600 g, 2.11 mmol, 1 eq.), was suspended in dioxane (10 mL) and Ca(OH)2 (0.313 g, 4.22 mmol, 2eq.) and methoxyacetyl chloride (0.229 g, 2.11 mmol, 1 eq.) under nitrogen, was heated at 70° C. for 45-60 minutes. The resulting solution was concentrated in vacuo and the residue was partitioned between dichloromethane (50 ml) and a mixture of brine (10 ml) and 2N hydrochloric acid (1 ml, 2.00 mmol). The dichloromethane phase was collected. The aqueous phase was extracted with more dichloromethane (50 ml) and then ethyl acetate (50 ml). The combined organic phases were dried over Na2SO4 and the solvent evaporated to give methyl [1-(2-chloro-4-fluorophenyl)-5-hydroxy-4-(methoxyacetyl)-1H-pyrazol-3-yl]acetate as a beige solid (550 mg, 1.55 mmol, 74% yield, 92% HPLC) that can be used in the following step without further purification. MS(ESI+): 357.7; MS(ESI−): 355.8.
Reaction SMILES: [C:1]([C:4]1[C:8]([CH3:9])=[CH:7][O:6][C:5]=1[CH3:10])(=[O:3])[CH3:2].[Br:11]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.O>C1C=CC=CC=1>[C:1]([C:4]1[C:8]([CH3:9])=[C:7]([Br:11])[O:6][C:5]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)c1c(C)coc1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: c1ccccc1
Solvent: O
Product: CC(=O)c1c(C)oc(Br)c1C
Yield: 88 %

Procedure:
A mixture of 3-acetyl-2,4-dimethylfuran (commercially available from Aldrich Chemical Co., Inc., 1 g, 7.24 mmol), N-bromosuccinimide (NBS; 1.3 g, 7.3 mmol), and 2,2'-azobisisobutyronitrile (AIBN; 3 mg) in benzene (10 mL) was heated at reflux temperature for one hour. After cooling, water (50 mL) was added to the mixture. The whole was extracted with benzene (50 mL), the organic layer washed with water, brine, dried over MgSO4, and concentrated in vacuo. Chromatographic purification of the residue eluting with ethyl acetate-hexane (1:10) provided the subtitle compound (1.38 g, 88% yield) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]=[C:10]=[O:11].Cl.[C:13]1([C@H:19]2[CH2:21][C@@H:20]2[N:22]2[C:30](=[O:31])[C@@H:25]3[CH2:26][NH:27][CH2:28][CH2:29][N:24]3[C:23]2=[O:32])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]([N:27]1[CH2:28][CH2:29][N:24]2[C:23](=[O:32])[N:22]([C@H:20]3[CH2:21][C@@H:19]3[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:30](=[O:31])[C@@H:25]2[CH2:26]1)=[O:11]
Reactant: O=C=Nc1cccc(Cl)c1Cl
Reactant: O=C1[C@@H]2CNCCN2C(=O)N1[C@H]1C[C@@H]1c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(Cl)c1Cl)N1CCN2C(=O)N([C@H]3C[C@@H]3c3ccccc3)C(=O)[C@@H]2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
2,3-Dichlorophenyl isocyanate (1.1 eq.) was added to a stirred solution of D2 and DIPEA (3.0 eq.) in DCM (0.09 M) and the mixture was stirred at RT for 1 h. The solvents were removed under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with 10-80% EtOAc/petroleum ether to give the title compound in 67% yield, 92% de by SFC. 1H NMR (400 MHz, DMSO-d6, 300K) δ 8.80 (1H, s), 7.45-7.42 (2H, m), 7.34-7.28 (3H, m), 7.23-7.18 (3H, m), 4.35 (1H, dd, J=12.9, 4.2 Hz), 4.14-4.09 (2H, m), 3.92 (1H, dd, J=13.0, 2.7 Hz), 3.07-2.99 (2H, m), 2.91 (1H, td, J=12.6, 3.0 Hz), 2.68 (1H, m), 2.39 (1H, ddd, J=9.8, 6.8, 3.2 Hz), 1.51 (1H, ddd, J=9.5, 5.7, 4.3 Hz), 1.41 (1H, dd, J=14.0, 7.1 Hz). MS (ES+) C22H20Cl2N4O3 requires 458, 460, found: 459, 461 (M+H+).
Reaction SMILES: Br[C:2]1[N:3]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:4]2[N:5]=[C:6]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)[N:7]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[C:8](=[O:11])[C:9]=2[N:10]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:41]([NH:43][CH3:44])[CH3:42].C(#N)C>C(Cl)Cl>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([N:7]2[C:8](=[O:11])[C:9]3[N:10]=[C:2]([N:43]([CH2:41][CH3:42])[CH3:44])[N:3]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:4]=3[N:5]=[C:6]2[C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:26])([F:27])[F:28])=[CH:21][CH:20]=2)=[CH:17][CH:16]=1
Reactant: O=c1c2nc(Br)n(-c3ccccc3)c2nc(-c2ccc(C(F)(F)F)cc2)n1-c1ccc(Cl)cc1
Reactant: CCNC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: CCN(C)c1nc2c(=O)n(-c3ccc(Cl)cc3)c(-c3ccc(C(F)(F)F)cc3)nc2n1-c1ccccc1
Temperature: 200 °C
Yield: 49.4 %

Procedure:
8-Bromo-1-(4-chloro-phenyl)-9-phenyl-2-(4-trifluoromethyl-phenyl)-1,9-dihydro-purin-6-one (19.0 mg, 0.0348 mmol), potassium carbonate (400 mg, 2.89 mmol), and ethyl-methyl-amine (172 mg, 2.91 mmol) are mixed in a microwave tube with 1 mL of dry acetonitrile. The tube is then capped and heated to 200° C. for 40 min in a microwave reactor. Then the reaction mixture is diluted with CH2Cl2 and filtered. The filtrate is evaporated and the crude product is purified by column chromatography, yielding 9 mg (49%) of the title compound. 1H NMR (CDCl3, 400 MHz) δ 7.54 (m, 4H), 7.47 (m, 1H), 7.42 (d, 2H), 7.30 (d, 4H), 7.08 (d, 2H), 3.17 (q, 2H), 2.90 (s, 3H), 1.03 (t, 3H). HPLC-MS calculated for C27H21ClF3N5O (M+H+) 524.1. Found: 524.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:10][CH:11]([CH3:16])[C:12](=[O:15])[NH:13][N:14]=2)=[CH:5][CH:4]=1>C(#N)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([CH3:16])[C:12](=[O:15])[NH:13][N:14]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C2=NNC(=O)C(C)C2)cc1
Solvent: CC#N
Product: COc1ccc(-c2cc(C)c(=O)[nH]n2)cc1
Temperature: 70 °C
Yield: 73 %

Procedure:
A mixture of the product from step 1 (6-(4-methoxy-phenyl)-4-methyl-4,5-dihydro-2H-pyridazin-3-one; 1.96 g, 9 mmol) and Cu(II) Cl2 (2.48 g, 2 eq.) in of acetonitrile (15 mL) was heated to 70° C. for 2 h. The reaction was quenched with ice-water (˜100 mL), the resulting solid was collected and crystallized from isopropanol to give 1.42 g (73%) of 6-(4-methoxy-phenyl)-4-methyl-2H-pyridazin-3-one: Mp 265-7° C.; MS m/z 217 (M+H).
Reaction SMILES: CCO.[CH3:4][O:5][C:6]([C:8]1[C:9]([OH:34])=[C:10]2[C:15](=[CH:16][N:17]=1)[N:14]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13](=[O:25])[C:12]([C:26]#[C:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[CH:11]2)=[O:7]>[Pd].CCOC(C)=O.CO>[CH3:4][O:5][C:6]([C:8]1[C:9]([OH:34])=[C:10]2[C:15](=[CH:16][N:17]=1)[N:14]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13](=[O:25])[C:12]([CH2:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[CH:11]2)=[O:7]
Reactant: COC(=O)c1ncc2c(cc(C#Cc3ccccc3)c(=O)n2Cc2ccccc2)c1O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CO
Product: COC(=O)c1ncc2c(cc(CCc3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reaction time: 16 h
Yield: 59.3 %

Procedure:
A flask was charged with 10% palladium on carbon (100 mg), EtOH (10 mL), and a solution of 1-benzyl-5-hydroxy-2-oxo-3-phenylethynyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (250 mg, 0.61 mmol) in 10 mL of EtOAc/MeOH (1:1). The mixture was placed under H2 atmosphere and stirred for 16 h. After removal of Pd/C by filtration, the solution was concentrated in vacuo. The residue was purified by silica gel chromatography (0-60% EtOAc/hexanes+2% AcOH) to give 150 mg of the title compound as an off-white solid. MS: (+) m/z 415.12 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:32])[C@H:4]([O:6][C:7]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]2[C:8]=1[C:9]([CH3:31])=[C:10]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=1[Cl:30])[C:11]([O:18][CH:19]([F:21])[F:20])=[N:12]2)[CH3:5].CO.[OH-].[Li+].C(O)(=O)C>O>[Cl:30][C:24]1[CH:25]=[C:26]([Cl:29])[CH:27]=[CH:28][C:23]=1[CH2:22][C:10]1[C:11]([O:18][CH:19]([F:20])[F:21])=[N:12][C:13]2[C:8]([C:9]=1[CH3:31])=[C:7]([O:6][C@H:4]([CH3:5])[C:3]([OH:32])=[O:2])[CH:16]=[CH:15][C:14]=2[F:17]
Reactant: COC(=O)[C@@H](C)Oc1ccc(F)c2nc(OC(F)F)c(Cc3ccc(Cl)cc3Cl)c(C)c12
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: Cc1c(Cc2ccc(Cl)cc2Cl)c(OC(F)F)nc2c(F)ccc(O[C@H](C)C(=O)O)c12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of (R)-2-[3-(2,4-dichlorobenzyl)-2-difluoromethoxy-8-fluoro-4-methylquinolin-5-yloxy]propionic acid methyl ester (0.054 g), methanol (2.0 mL), water (0.1 mL) and 5.0 M aqueous lithium hydroxide solution (0.044 mL) was stirred at room temperature for 15 hours. The mixture was acidified by the addition of glacial acetic acid, diluted with water and the resulting precipitate collected by filtration to afford title compound as a white solid, 0.048 g.
Reaction SMILES: FC(F)(F)C(O)=O.[OH:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]([C:24]([O:26][CH3:27])=[O:25])[CH:17]=[C:18]([CH:23]=2)[C:19]([O:21][CH3:22])=[O:20])[CH2:10]1.N1C=CC=CC=1.CS(C)=O.C1(N=C=NC2CCCCC2)CCCCC1>C1C=CC=CC=1.CCOCC.O>[O:8]=[C:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:23]=[C:18]([C:19]([O:21][CH3:22])=[O:20])[CH:17]=[C:16]([CH:15]=2)[C:24]([O:26][CH3:27])=[O:25])[CH2:10]1
Reactant: COC(=O)c1cc(C(=O)OC)cc(N2CCC(O)C2)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COC(=O)c1cc(C(=O)OC)cc(N2CCC(=O)C2)c1
Reaction time: 8 h
Yield: 45.9 %

Procedure:
Trifluoroacetic acid (0.061 ml, 0.091 g, 0.794 mmol, 0.5 eq) was added dropwise to a stirred solution of dimethyl 5-(3-hydroxypyrrolidin-1-yl)isophthalate (0.4434 g, 1.59 mmol, 1 eq), anhydrous pyridine (0.135 ml, 0.13 g, 1.67 mmol, 1.05 eq), anhydrous DMSO (0.124 ml, 0.13 g, 1.67 mmol, 1.05 eq), and 1,3-dicyclohexylcarbodiimide (0.655 g, 3.18 mmol, 2 eq) in 5 ml anhydrous benzene at ° C. under Ar. After stirring at 0° C. to room temperature overnight the reaction was diluted with Et2O/H2O and stirred for 20 h. The mixture was filtered through cotton and the layers were separated. The organic layer was washed with water (×3), brine (×1), and dried over Na2SO4. The inorganics were filtered off and the solvent was removed in vacuo. Purification via flash chromatography yielded only crude product. Purification via a second column yielded 0.201 g (0.73 mmol, 46% yield) of dimethyl 5-(3-oxopyrrolidin-1-yl)isophthalate.
Reaction SMILES: C1(S(O[C:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=2)(=O)=O)C=CC=CC=1.[NH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH2:26])=[O:25])=[CH:22][CH:21]=1>C(OCC)(=O)C>[CH3:17][C:15]1[CH:16]=[C:11]([NH:19][C:20]2[CH:28]=[CH:27][C:23]([C:24]([NH2:26])=[O:25])=[CH:22][CH:21]=2)[CH:12]=[C:13]([CH3:18])[CH:14]=1
Reactant: Cc1cc(C)cc(OS(=O)(=O)c2ccccc2)c1
Reactant: NC(=O)c1ccc(N)cc1
Solvent: CCOC(C)=O
Product: Cc1cc(C)cc(Nc2ccc(C(N)=O)cc2)c1
Yield: 95.7 %

Procedure:
Following the general procedure, 3,5-dimethylphenyl benzenesulfonate (131 mg, 0.5 mmol) was coupled with 4-aminobenzamide (102 mg, 0.75 mmol) with the reaction time of 6 h. Chromatography on silica gel column with ethyl acetate gave 115 mg (96%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][OH:17])=[N:12][C:11]=2[CH:18]([CH3:20])[CH3:19])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:21][N:22]=[C:23]=[O:24].CCCC[Sn](O[Sn](CCCC)(CCCC)CCCC)(CCCC)CCCC>O1CCCC1>[Cl:8][C:6]1[CH:5]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][O:17][C:23](=[O:24])[NH:22][CH3:21])=[N:12][C:11]=2[CH:18]([CH3:20])[CH3:19])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CC(C)c1nc(CO)n(C)c1Sc1cc(Cl)cc(Cl)c1
Reactant: CN=C=O
Agent: CCCC[Sn](CCCC)(CCCC)O[Sn](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: CNC(=O)OCc1nc(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)n1C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 98 %

Procedure:
In dry tetrahydrofuran (6 ml)was dissolved 0.300 g (0.91 mmol)of [5-(3,5-dichlorophenylthio)-4-isopropyl-1-methyl-1H-imidazol-2-yl]methanol (Compound I-8)and 0.48 ml (8.15 mmol) of methylisocyanate. To this solution was added 0.04 ml of bis(tributyltin)oxide, and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was concentrated under reduced pressure. The residue was fractionated by silica gel chromatography (acetone:methylene chloride=1:4), and recrystallized from isopropyl ether to obtain 0.345 g of (Compound I-43)(yield 98%). mp 112-113° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([F:9])[CH:3]=1.[Mg].[CH3:11][O:12][CH2:13][CH2:14][CH2:15][Si@H:16]1[CH2:21][CH2:20][C@H:19]([CH2:22][CH2:23][C@H:24]2[CH2:29][CH2:28][C@H:27]([C:30]3[CH:35]=[CH:34][C:33](Br)=[CH:32][CH:31]=3)[CH2:26][CH2:25]2)[CH2:18][CH2:17]1>C1COCC1>[CH3:11][O:12][CH2:13][CH2:14][CH2:15][Si@H:16]1[CH2:17][CH2:18][C@H:19]([CH2:22][CH2:23][C@H:24]2[CH2:29][CH2:28][C@H:27]([C:30]3[CH:35]=[CH:34][C:33]([C:2]4[CH:7]=[CH:6][C:5]([F:8])=[C:4]([F:9])[CH:3]=4)=[CH:32][CH:31]=3)[CH2:26][CH2:25]2)[CH2:20][CH2:21]1
Reactant: Fc1ccc(Br)cc1F
Reactant: COCCC[Si@H]1CC[C@H](CC[C@H]2CC[C@H](c3ccc(Br)cc3)CC2)CC1
Agent: [Mg]
Solvent: C1CCOC1
Product: COCCC[Si@H]1CC[C@H](CC[C@H]2CC[C@H](c3ccc(-c4ccc(F)c(F)c4)cc3)CC2)CC1

Procedure:
19.3 g (0.1 mol) of 1-bromo-3,4-difluorobenzene was dripped into a mixture of 2.5 g (0.11 mol) of magnesium and 300 ml of THF to obtain a Grignard's reagent. This solution was then dripped into a 500 ml THF solution of 0.5 g of tetrakis triphenylphosphine palladium and 43.8 g (0.1 mol) of 4-(trans-4-(2-(trans-4-(3-methoxypropyl)-4-silacyclohexyl)ethyl)cyclohexyl)phenyl bromide. After a conventional after treatment, purification was conducted by means of chromatography to obtain 28.9 g (yield 61.3%) of 4-(trans-4-(2-(trans-4-(3-methoxypropyl)-4-silacyclohexyl)ethyl)cyclohexyl)-3',4'-difluorobiphenyl was obtained.