Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[C:5]([C:9]#[C:10][C:11]2[N:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]3=[N:13][C:12]=2[CH2:20][S:21][CH2:22][C:23](O)=[O:24])[CH:6]=[CH:7][CH:8]=1.C(Cl)(=O)C(Cl)=O.C(=O)([O-])[O-].[Na+].[Na+].[NH2:40][C:41]1[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=1>ClCCl.O.CN(C=O)C>[N:43]1[CH:44]=[CH:45][CH:46]=[C:41]([NH:40][C:23](=[O:24])[CH2:22][S:21][CH2:20][C:12]2[N:13]=[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]3[C:11]=2[C:10]#[C:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:26])([F:1])[F:27])[CH:4]=2)[CH:42]=1
Reactant: O=C(O)CSCc1nc2ccccn2c1C#Cc1cccc(C(F)(F)F)c1
Reactant: Nc1cccnc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(CSCc1nc2ccccn2c1C#Cc1cccc(C(F)(F)F)c1)Nc1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.3 %

Procedure:
141 mg (0.358 mmol) of 2-((3-((3-(trifluoromethyl)phenyl)ethynyl)imidazo[1,2-a]-pyridin-2-yl)methylthio)acetic acid were dissolved in 5 ml of dichloromethane followed by the addition of 0.094 ml (1.073 mmol) of oxalyl chloride and a drop of DMF. The solvent was stirred at r.t. for 2 h and then the solvent was evaporated in vacuo. The obtained residue was taken up in 5 ml of tetrahydrofurane, 99 mg (0.715 mmol) of sodium carbonate were added followed by the addition of 40.4 mg (0.429 mmol) of 3-aminopyridine. The solution was stirred at r.t. for 16 h. The mixture was then poured onto 15 ml of water, extracted 3 times with 15 ml of ethyl acetate, the combined organic phases were washed with 20 ml of brine and then were dried on Na2SO4 which was then removed by filtration and the obtained filtrate was concentrated in vacuo. The crude residue was purified by flash chromatography on a silica gel cartridge (eluent: dichloromethane/methanol gradient, 100% to 90% of dichloromethane, v/v). 89 mg of N-(pyridin-3-yl)-2-((3-((3-(trifluoromethyl)-phenyl)-ethynyl)imidazo[1,2-a]pyridin-2-yl)methylthio) acetamide were obtained as a pale yellow solid. LC-MS: m/z=467 (MH+) UV purity at 254 nm=95%. 1H NMR (300 MHz, DMSO) δ 10.13 (s, 1H), 8.76 (dd, J=16.4, 4.5 Hz, 2H), 8.24 (dd, J=4.7, 1.5 Hz, 1H), 8.07 (ddd, J=8.3, 2.5, 1.5 Hz, 1H), 7.79-7.60 (m, 3H), 7.60-7.35 (m, 3H), 7.30 (dd, J=8.3, 4.7 Hz, 1H), 7.16 (td, J=6.8, 1.1 Hz, 1H), 4.90 (s, 2H), 4.26 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([Cl:12])[CH:3]=1.O=S(Cl)Cl.[CH3:17]O>>[Br:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([O:8][CH3:17])=[O:7])=[C:4]([Cl:12])[CH:3]=1
Reactant: CO
Reactant: O=C(O)c1cc(F)c(Br)cc1Cl
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(F)c(Br)cc1Cl
Temperature: 0 °C
Reaction time: 72 h
Yield: 95 %

Procedure:
4-bromo-2-chloro-5-fluorobenzoic acid (Apollo PC9723, 5 g; 19.73 mmol; 1 eq.) was dissolved in MeOH (100 mL). The solution was cooled down to 0° C. SOCl2 (4.29 mL; 59.18 mmol; 3 eq.) was added dropwise (addition took 15 min and IT increased to 9° C.). The reaction mixture was stirred at RT for 3 days. The reaction mixture was concentrated and the crude mixture was dissolved in EtOAc (200 mL) and washed with a saturated aqueous solution of NaHCO3(50 mL), brine (50 mL), dried over MgSO4 and concentrated affording the title compound as a white solid (5.04 g, 95%). 1H NMR (DMSO-d6, 300 MHz) δ 8.10-8.08 (d, J=6.30 Hz), 1H), 7.86-7.83 (d, J=8.82 Hz, 1H), 3.87 (s, 3H). HPLC (Method A) Rt 4.32 min (Purity: 99.7%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[CH2:7]2.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)C(Cl)=O.C(N(CC)CC)C.CN(C)[CH:44]=[O:45]>>[O:21]=[C:15]1[CH:14]([N:8]2[CH2:7][C:6]3[C:10](=[CH:11][CH:12]=[C:4]([CH2:3][NH:2][C:44](=[O:45])[C:25]4[CH:26]=[CH:30][CH:31]=[CH:32][C:24]=4[C:23]([F:22])([F:33])[F:34])[CH:5]=3)[C:9]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: CN(C)C=O
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CCN(CC)CC
Product: O=C1CCC(N2Cc3cc(CNC(=O)c4ccccc4C(F)(F)F)ccc3C2=O)C(=O)N1
Reaction time: 1 h
Yield: 43 %

Procedure:
To a stirred mixture of 3-(5-Aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (1.00 g, 3.20 mmol) and 3-(trifluoromethyl)benzoyl chloride (0.67 g, 3.20 mmol) in N,N-dimethylformamide (25 mL), was added triethylamine (0.90 mL, 6.40 mmol) at room temperature under nitrogen. After 1 h, the solvent was removed in vacuo and the residue was dissolved in ethyl acetate (100 mL). The ethyl acetate layer was washed with 1N aq. HCl (2×100 mL) and water (100 mL), then dried (MgSO4) and concentrated in vacuo to give N-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-2-trifluoromethyl-benzamide as an off-white solid (0.61 g, 43% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 30/70 CH3CN/0.1% H3PO4, 4.89 min (97.35%); mp: 303-305° C.; 1H NMR (DMSO-d6) δ 1.93-2.11 (m, 1H), 2.31-2.46 (m, 1H), 2.55-2.71 (m, 1H), 2.83-3.03 (m, 1H), 4.33 (d, J=17.4 Hz, 1H), 4.47 (d, J=17.4 Hz, 1H), 4.56 (d, J=5.9 Hz, 2H), 5.12 (dd, J=5.0, 13.1 Hz, 1H), 7.49 (d, J=7.7 Hz, 1H), 7.54-7.87 (m, 6H), 9.15 (t, J=5.9 Hz, 1H), 10.99 (s, 1H); 13C NMR (DMSO-d6) δ 22.49, 31.21, 42.61, 47.13, 51.59, 122.14, 122.94, 123.61 (q, J=272 Hz), 125.94 (q, J=31.2 Hz), 126.25 (q, J=4.7 Hz), 127.13, 128.61, 129.82, 130.47, 132.48, 136.18, 142.38, 143.35, 167.16, 167.92, 171.03, 172.88; LCMS: MH=446; Anal Calcd for C22H18N3O4F3+0.3H2O: C, 58.62; H, 4.16; N, 9.32. Found: C, 58.60; H, 3.82; N, 9.20.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]([CH3:28])[C:18]2=[O:29])=[CH:12][C:3]=1[O:4][C:5]1[C:6](=[O:11])[NH:7][CH:8]=[CH:9][CH:10]=1.FC(F)(F)S(O)(=O)=O.ClCCCl.[N+](=[CH:44][C:45]([O:47][CH2:48][CH3:49])=[O:46])=[N-]>CCCCCC.C(OCC)(=O)C>[Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]([CH3:28])[C:18]2=[O:29])=[CH:12][C:3]=1[O:4][C:5]1[C:6]([O:11][CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46])=[N:7][CH:8]=[CH:9][CH:10]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ccc[nH]c3=O)c(Cl)cc2F)c1=O
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCCl
Product: CCOC(=O)COc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Reaction time: 2 h

Procedure:
Into a mixture of 1.0 g of 3-[2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-1,2,3,6-tetrahydropyrimidin-1-yl)phenoxy]-1H-pyridin-2-one, 70 mg of trifluoromethanesulfonic acid and 40 ml of 1,2-dichloroethane, 0.4 ml of ethyl diazoacetate (purity: 90%) is dropped at room temperature over 2 hours. After dropping, the reaction mixture is further stirred for 2 hours, and subjected to silica gel column chromatography (eluent; hexane/ethyl acetate=2/1) to give 3-[2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-1,2,3,6-tetrahydropyrimidin-1-yl)phenoxy]-2-(ethoxycarbonylmethoxy)pyridine.
Reaction SMILES: [CH:1]1([P:7]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[C@@H:8]2[CH2:12][NH:11][C@H:10]([CH2:13][P:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:33]([O:37][C:38](=O)[O:39]C(C)(C)C)([CH3:36])([CH3:35])[CH3:34].C(N(CC)CC)C>C(Cl)Cl>[C:33]([O:37][C:38]([N:11]1[CH2:12][C@@H:8]([P:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:27]2[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]2)[CH2:9][C@H:10]1[CH2:13][P:14]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:39])([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: c1ccc(P(C[C@@H]2C[C@H](P(C3CCCCC3)C3CCCCC3)CN2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@@H](P(C2CCCCC2)C2CCCCC2)C[C@H]1CP(c1ccccc1)c1ccccc1

Procedure:
To a solution of (2S,4S)-4-dicyclohexylphosphino-2-diphenylphosphinomethylpyrrolidine [IV′] (46 mg, 0.1 mmol) dissolved in 1 ml of methylene chloride was added a solution of di-tert-butylcarbonate (24 mg, 0.11 mmol) dissolved in 11 mg (0.11 mmol) of triethylamine and 2 ml of methylene chloride and the resultant mixture was stirred for 2 to 3 hours at room temperature under nitrogen atmosphere. The reaction solution was concentrated under vacuum to afford white crystalline BCPM (50 mg, 86%), mp. 171 to 174° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:9]([C:10]2[CH:15]=[C:14]([S:16][CH2:17][C:18]([F:21])([F:20])[F:19])[C:13]([CH3:22])=[CH:12][C:11]=2[F:23])[N:8]=[C:7]([O:24][C:25]([F:34])([F:33])[C:26]([F:32])([F:31])[C:27]([F:30])([F:29])[F:28])[CH:6]=1)(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:43])C=1>C(Cl)(Cl)Cl>[C:1]([NH:4][C:5]1[N:9]([C:10]2[CH:15]=[C:14]([S:16]([CH2:17][C:18]([F:20])([F:21])[F:19])=[O:43])[C:13]([CH3:22])=[CH:12][C:11]=2[F:23])[N:8]=[C:7]([O:24][C:25]([F:34])([F:33])[C:26]([F:31])([F:32])[C:27]([F:28])([F:29])[F:30])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)Nc1cc(OC(F)(F)C(F)(F)C(F)(F)F)nn1-c1cc(SCC(F)(F)F)c(C)cc1F
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1cc(OC(F)(F)C(F)(F)C(F)(F)F)nn1-c1cc(S(=O)CC(F)(F)F)c(C)cc1F
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
60 mg of 5-acetylamino-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-(1,1,2,2,3,3,3-heptafluoropropoxy)pyrazole was dissolved in 10 mL of chloroform, and 30 mg of m-chloroperbenzoic acid (purity: 75%) was added under cooling with ice. After stirring for 30 minutes under cooling with ice, the solution was washed with an aqueous sodium thiosulfate solution and then washed with an aqueous potassium carbonate solution, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:2) to obtain 53mg of 5-acetylamino-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylsulfinyl)phenyl}-3-(1,1,2,2,3,3,3-heptafluoropropoxy)pyrazole.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:21][OH:22])[CH2:4][O:5][C:6]1[C:13]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[CH:12][C:9]([CH:10]=O)=[C:8]([O:19][CH3:20])[CH:7]=1.[C:23]([C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH2:35])(=[O:34])=[O:33])=[CH:28][CH:27]=1)(=[O:25])[CH3:24]>>[OH:1][CH2:2][CH:3]([CH2:21][OH:22])[CH2:4][O:5][C:6]1[C:13]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[CH:12][C:9](/[CH:10]=[CH:24]/[C:23]([C:26]2[CH:27]=[CH:28][C:29]([S:32]([NH2:35])(=[O:34])=[O:33])=[CH:30][CH:31]=2)=[O:25])=[C:8]([O:19][CH3:20])[CH:7]=1
Reactant: COc1cc(OCC(CO)CO)c(-c2cccs2)cc1C=O
Reactant: CC(=O)c1ccc(S(N)(=O)=O)cc1
Product: COc1cc(OCC(CO)CO)c(-c2cccs2)cc1/C=C/C(=O)c1ccc(S(N)(=O)=O)cc1
Yield: 72 %

Procedure:
The title compound was prepared by condensing 4-(3-hydroxy-2-hydroxymethyl-propoxy)-2-methoxy-5-thiophen-2-yl-benzaldehyde (Ex-50C) and 4-acetyl-benzenesulfonamide (Ex-26A) in a similar manner as described in Ex-22. Yellow solid, 72% yield, mp 191–192° C. 1H-NMR (300 MHz, DMSO-d6) δ 8.29–8.32 (m, 3H), 8.09 (d, 1H, J=16.0 Hz), 7.99 (d, 2H, J=8.1 Hz), 7.92 (d, 1H, J=16.0 Hz), 7.70 (d, 1H, J=3.3 Hz), 7.53–7.56 (m, 3H), 7.14 (dd, 1H, J=5.4, 3.3 Hz), 6.87 (s, 1H), 4.61 (t, 2H, J=5.1 Hz), 4.28 (d, 2H, J=5.1 Hz), 4.00 (s, 3H), 3.60–3.67 (m, 4H), 2.11–2.15 (m, 1H). MS (ESI) m/z=504 ([M+H]+, 100%). Anal. Calcd. for C24H25NO7S2.½H2O: C, 56.23; H, 5.11; N, 2.73; S, 12.51. Found: C, 56.32; H, 5.06; N, 2.83; S, 12.55.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=1.[Br:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]=O>>[Br:11][C:12]1[CH:13]=[C:14]([CH2:15][C:7]2[S:6][C:5]3[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][C:4]=3[CH:8]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: Cc1ccc2sccc2c1
Reactant: O=Cc1cccc(Br)c1
Product: Cc1ccc2sc(Cc3cccc(Br)c3)cc2c1

Procedure:
5-Methylbenzo[b]thiophene and 3-bromobenzaldehyde were treated in a manner similar to Reference Example 7 to give the target compound.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]([N:6]1[C:19]2[C:18](C#N)=[CH:17][CH:16]=[CH:15][C:14]=2[S:13][C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH3:5].I[CH:23]([CH3:25])[CH3:24].C(=O)([O-])O.[Na+].[CH3:31][N:32](C)C=O>C(OCC)(=O)C>[CH3:1][N:2]([CH2:3][CH:4]([N:6]1[C:19]2[CH:18]=[C:17]([C:31]#[N:32])[CH:16]=[CH:15][C:14]=2[S:13][C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH3:5])[CH:23]([CH3:25])[CH3:24]
Reactant: CNCC(C)N1c2ccccc2Sc2cccc(C#N)c21
Reactant: CC(C)I
Reactant: CN(C)C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)N(C)CC(C)N1c2ccccc2Sc2ccc(C#N)cc21
Temperature: 140 °C

Procedure:
A mixture of 10-[(2RS)-1-methylamino-2-propyl]-phenothiazinecarbonitrile (4.55 g), 2-iodopropane (2 cc) and sodium hydrogen carbonate (1.9 g) in dry dimethylformamide (45.5 cc) is heated for 6 hours to a temperature in the region of 140° C. After cooling, the reaction mixture is diluted with ethyl acetate (200 cc), washed with distilled water (4×30 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The oily yellow residue is purified by chromatography on a column (height: 25 cm; diameter: 4 cm) of silica gel (0.04-0.063 mm) with a slight excess pressure of nitrogen (40 kPa) and with a mixture (97.5:2.5 by volume) (1 liter) of methylene chloride and methanol, and collecting 60-cc fractions. Fractions 4 to 12 are combined and concentrated to dryness under reduced pressure (30 mm Hg; kPa) at 40 ° C. The oily yellow residue (2.9 g) is purified again by chromatography on a column (height: 25 cm; diameter: 4 cm) of silica gel (0.2-0.063 mm), eluting with a mixture (80:20 by volume) (1 liter) of cyclohexane and ethyl acetate and collecting 60-cc fractions. Fractions 4 to 12 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. 10-{(2RS)-1-[N-Methyl-N-(1-methylethyl) amino]-2-propyl}-2-phenothiazinecarbonitrile (2.2 g) is thereby obtained in the form of a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[S:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[O:4][C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.O[CH2:20][CH2:21][CH2:22][N:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH3:1][C:2]1[S:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[O:4][C:3]=1[C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:20][CH2:21][CH2:22][N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:16][CH:17]=1
Reactant: CC1=C(c2ccc(O)cc2)Oc2ccccc2S1
Reactant: OCCCN1CCCC1
Product: CC1=C(c2ccc(OCCCN3CCCC3)cc2)Oc2ccccc2S1

Procedure:
The entitled compound was obtained according to the method of Example 3 but using 4-(3-methyl-1,4-benzoxathiin-2-yl)phenol synthesized in Reference Example 1-2 and 1-(3-hydroxypropyl)pyrrolidine as the starting material.
Reaction SMILES: [C:1]([NH:4][CH:5]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)[CH2:6][OH:7])(=[O:3])[CH3:2].[OH2:24].N1[CH:30]=[CH:29]C=CC=1>C(OC(=O)C)(=O)C>[C:29]([O:7][CH2:6][CH:5]([NH:4][C:1](=[O:3])[CH3:2])[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)(=[O:24])[CH3:30]
Reactant: O
Reactant: CC(=O)NC(CO)CCc1ccc(OCc2ccccc2)cc1
Reactant: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)NC(CCc1ccc(OCc2ccccc2)cc1)COC(C)=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 2-acetamido-4-(4-benzyloxyphenyl)butanol (9.48 g) in pyridine (100 ml), acetic anhydride (22.2 ml) was added and the mixture was stirred at room temperature for 5 hours. Then, the solution was poured into water and extracted with ethyl acetate. The extract was washed with a dilute hydrochloric acid, a dilute aqueous sodium hydrogencarbonate solution and a saturated brine, dried over magnesium sulfate and the solvent was distilled away under reduced pressure. The residue obtained was crystallized from ethyl acetate-hexane to give the subject compound (8.32 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9](I)[CH:10]=1)[C:5]([OH:7])=[O:6].B(O)(O)[C:13]1[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(C)C=CC=CC=1.C(O)C.O>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>[Br:1][C:2]1[CH:3]=[C:4]([C:5]([OH:7])=[O:6])[CH:8]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH:10]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: O=C(O)c1cc(Br)cc(I)c1
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: [Cs+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: Cc1ccc(-c2cc(Br)cc(C(=O)O)c2)cc1
Temperature: 85 °C

Procedure:
A pressure vial was charged with 3-bromo-5-iodo-benzoic acid (7.60 g, 23.2 mmol), p-tolylboronic acid (3.16 g, 23.2 mmol), tetrakis(triphenylphosphine)palladium(0) (1.34 g, 1.16 mmol), cesium carbonate (8.33 g, 25.6 mmol), toluene (99.0 mL, 930 mmol), ethanol (27.1 mL, 465 mmol) and water (12.6 mL, 697 mmol) and the reaction stirred at 85° C. over nights. The reaction mixture was filtered over celite and the solvent removed to get the crude product as a brown solid.
Reaction SMILES: Cl.Cl.[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([OH:11])=O)[C:4]=1[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1.[CH2:18]([C:25]1([OH:31])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.O>[CH2:18]([C:25]1([OH:31])[CH2:30][CH2:29][N:28]([C:9]([C:5]2[C:4]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)=[N:3][CH:8]=[CH:7][CH:6]=2)=[O:11])[CH2:27][CH2:26]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: OC1(Cc2ccccc2)CCNCC1
Reactant: O=C(O)c1cccnc1-c1ccncc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(c1cccnc1-c1ccncc1)N1CCC(O)(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.8 %

Procedure:
A suspension of 2,4′-bipyridine-3-carboxylic acid dihydrochloride (5.0 g), 4-benzyl-4-hydroxypiperidine (3.9 g), HATU (10 g) and triethylamine (13 mL) in DMF (50 mL) was stirred overnight at room temperature. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane), and recrystallized from ethyl acetate/hexane to give the title compound (3.2 g).
Reaction SMILES: O.[OH-].[Li+].[O:4]=[C:5]1[C:14]2[NH:15][CH:16]=[CH:17][C:13]=2[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH:6]1.C([C:20]([O-:22])=[O:21])C>C(O)C.O>[O:4]=[C:5]1[C:14]2[NH:15][CH:16]=[C:17]([C:20]([OH:22])=[O:21])[C:13]=2[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH:6]1
Reactant: O=c1[nH]c2ccccc2c2cc[nH]c12
Reactant: CCC(=O)[O-]
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1c[nH]c2c(=O)[nH]c3ccccc3c12
Yield: 101.1 %

Procedure:
1.64 g (39 mmol) of lithium hydroxide monohydrate is added to 1 g (3.9 mmol) of 4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate (synthesis 1) suspended in 45 mL of ethanol and 45 mL of water, and the solution is stirred for 17 h at 70° C. then 5 h at 100° C. The ethanol is evaporated under vacuum and distilled water is added. The aqueous solution is washed with ethyl acetate then acidified with acetic acid to pH 4-5. The precipitate that forms is filtered then dried under vacuum at 55° C. to give 0.9 g (100%) of 4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid in the form of a beige solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:13]=[CH:12][C:11]([Mg]Br)=[CH:10][CH:9]=1.[O:16]1[CH:20]=[CH:19][N:18]=[C:17]1[CH:21]=[O:22]>C1COCC1>[O:16]1[CH:20]=[CH:19][N:18]=[C:17]1[CH:21]([C:11]1[CH:12]=[CH:13][C:8]([O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)=[CH:9][CH:10]=1)[OH:22]
Reactant: Br[Mg]c1ccc(OC2CCCCO2)cc1
Reactant: O=Cc1ncco1
Solvent: C1CCOC1
Product: OC(c1ccc(OC2CCCCO2)cc1)c1ncco1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
4-(2-Tetrahydro-3-H-pyranoxy)phenylmagnesium bromide (6.7 mmol) in THF (0.5 M) was added dropwise to a solution of oxazole-2-carbaldehyde (5.15 mmol) in THF (8 mL). After it was stirred at room temperature for 2.5 hours, the reaction was quenched with water and extracted with EtOAc (200 mL). The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was column chromatographed (silica gel, 1:2 EtOAc/hexane). Compound M11.1 was obtained. MS ESI (pos.) m/e: 276 (M+H). 1H NMR (400 MHz) (DMSO-d6) δ 8.02 (s, 1H); 7.31 (d, J=8.7 Hz, 2H); 7.14 (s, 1H); 6.97-7.01 (m, 2H); 6.27 (d, J=5 Hz, 1H); 5.74 (d, J=5 Hz, 1H); 5.44 (s, 1H); 3.74 (m, 1H); 3.52 (M, 1H); 1.72-1.81 (m, 3H); 1.52-1.60 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10](=[O:15])[C:9]=2[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl.O>[CH3:14][C:11]1([CH3:13])[O:12][C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:1]([S:35]([CH3:34])(=[O:37])=[O:36])[S:35]([CH3:34])(=[O:37])=[O:36])=[CH:3][CH:4]=2)=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)=[CH:18][CH:17]=2)[C:10]1=[O:15]
Reactant: CC1(C)OC(c2ccc(N)cc2)=C(c2ccc(OCc3ccc4ccccc4n3)cc2)C1=O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Product: CC1(C)OC(c2ccc(N(S(C)(=O)=O)S(C)(=O)=O)cc2)=C(c2ccc(OCc3ccc4ccccc4n3)cc2)C1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 56.2 %

Procedure:
To a stirred solution of 5-(4-aminophenyl)-2,2-dimethyl-4-(4-(quinolin-2-ylmethoxy)phenyl)furan-3(2H)-one (60 mg, 0.13 mmol) in DCM (5 mL) were added methane sulfonyl chloride (0.012 g, 0.15 mmol) and TEA (0.04 mL, 0.27 mmol) at 0° C. under N2 atmosphere. The reaction mixture was stirred at RT for 10 min. The reaction mixture diluted with water and extracted with DCM (2×10 mL). The combined organic layers were washed with water (2×5 mL), brine and dried over anhydrous Na2SO4. After filtration and evaporation, the crude material was purified by silica gel column chromatography to afford N-(4-(5,5-dimethyl-4-oxo-3-(4-(quinolin-2-ylmethoxy)phenyl)-4,5-dihydrofuran-2-yl) phenyl)-N-(methylsulfonyl)methane sulfonamide (25 mg, 30%), as a white color solid. 1H NMR (500 MHz, CDCl3): δ 8.22 (d, J=8.5 Hz, 1H), 8.10 (d, J=7.9 Hz, 1H), 7.76 (d, J=8.4 Hz, 1H), 7.80 (d, J=8.2 Hz, 2H), 7.74 (t, J=8.2 Hz, 1H), 7.70 (d, J=8.5 Hz, 1H), 7.56 (d, J=7.5 Hz, 1H), 7.28 (d, J=7.4 Hz, 2H), 7.12 (d, J=7.5 Hz, 2H), 7.08 (d, J=7.6 Hz, 2H), 5.42 (s, 2H), 3.42 (s, 6H), 1.58 (s, 6H). MS: [M+Na]: m/z=615.1, [M+H]: m/z=593.1. HPLC: 98.9% (RT-2.52 min), Column: Acquity BEH-C-18, 50×2.1 mm, 1.7 um. Mobile Phase: 0.025% TFA in Water (A), ACN (B), Flow rate: 0.5 ml/min (Gradient).