Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]2[N:5]([C:9]([C:12]3[CH:13]=[C:14]([NH:22][C:23]([NH:25][CH2:26][C:27]([F:30])([F:29])[F:28])=[O:24])[CH:15]=[C:16]([O:18][CH:19]([CH3:21])[CH3:20])[CH:17]=3)=[CH:10][N:11]=2)[CH:6]=[CH:7][CH:8]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:64](O)(=[O:67])[C:65]#[CH:66]>C(Cl)Cl>[CH:19]([O:18][C:16]1[CH:17]=[C:12]([C:9]2[N:5]3[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][NH:1][C:64](=[O:67])[C:65]#[CH:66])[C:4]3=[N:11][CH:10]=2)[CH:13]=[C:14]([NH:22][C:23]([NH:25][CH2:26][C:27]([F:29])([F:30])[F:28])=[O:24])[CH:15]=1)([CH3:21])[CH3:20]
Reactant: CC(C)Oc1cc(NC(=O)NCC(F)(F)F)cc(-c2cnc3c(CN)cccn23)c1
Reactant: C#CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C#CC(=O)NCc1cccn2c(-c3cc(NC(=O)NCC(F)(F)F)cc(OC(C)C)c3)cnc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.5 %

Procedure:
To a solution of 1-(3-(8-(aminomethyl)imidazo[1,2-a]pyridin-3-yl)-5-isopropoxyphenyl)-3-(2,2,2-trifluoroethyl)urea (26 mg, 0.062 mmol) in DCM (3 ml) was added DIEA (0.075 ml, 0.432 mmol) and HATU (35.2 mg, 0.093 mmol) and finally propiolic acid (4.95 μl, 0.080 mmol). Reaction was stirred for 30 minutes at room temperature. Reaction was loaded directly onto silica column and purified by flash chromatography (0-10% CH2Cl2/MeOH) to give the title compound (19 mg, 0.040 mmol, 65.0% yield) as an off white solid. MS (ES+) C23H22F3N5O3 requires: 473. found: 474 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.34 (s, 1H), 8.92 (s, 1H), 8.47 (d, J=6.8 Hz, 1H), 7.74 (s, 1H), 7.17 (d, J=1.9 Hz, 2H), 7.10 (s, 1H), 6.98 (s, 1H), 6.82 (s, 1H), 6.74 (s, 1H), 4.69-4.58 (m, 2H), 3.93 (dd, J=9.7, 6.4 Hz, 2H), 2.72-2.64 (m, 1H), 1.30-1.19 (m, 6H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[C:10]2[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]1=2.N1C=C[CH:26]=[C:25](B(O)O)[CH:24]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH3:40][N:41]([CH:43]=O)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>[CH3:22][N:19]1[CH2:20][CH2:21][C:9]2[N:8]([C:3]3[CH:2]=[CH:26][CH:25]=[CH:24][C:4]=3[C:5]3[CH:40]=[N:41][CH:43]=[CH:7][CH:6]=3)[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]=2[CH2:18]1
Reactant: CN(C)C=O
Reactant: OB(O)c1cccnc1
Reactant: Cc1ccc2c(c1)c1c(n2-c2ccccc2Br)CCN(C)C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2-c2ccccc2-c2cccnc2)CCN(C)C1
Temperature: 95 °C

Procedure:
To a de-aerated solution of 5-(2-bromo-phenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.282 mmol), 3-pyridinylboronic acid (51 mg, 0.420 mmol) and K3PO4 (149 mg, 0.706 mmol) in DMF-water (4:1 mL) was added PdCl2(PPh3)2 (10 mg, 5 mol %). The reaction mixture was heated at 95° C. for 30 min under nitrogen atmosphere. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 2,8-dimethyl-5-(2-pyridin-3-yl-phenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as a semisolid (30 mg). 1H NMR (Oxalate salt, CD3OD) δ (ppm): 8.30 (s, 1H), 8.10 (s, 1H), 7.70 (m, 3H), 7.56 (d, 1H), 7.50 (d, 1H), 7.24 (m, 2H), 6.98 (d, 1H), 6.82 (d, 1H), 4.50 (m, 2H), 3.60 (m, 2H), 3.05 (s, 3H), 2.95 (m, 1H), 2.62 (m, 1H), 2.40 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[CH2:12][OH:13].[OH-].[Na+].S(OC)(O[CH3:20])(=O)=O>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:10])([F:11])[F:9])=[CH:4][C:3]=1[CH2:12][O:13][CH3:20]
Reactant: COS(=O)(=O)OC
Reactant: OCc1cc(C(F)(F)F)ccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COCc1cc(C(F)(F)F)ccc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 93.4 %

Procedure:
A mixture of (2-chloro-5-(trifluoromethyl)phenyl)methanol (COK) (11.55 g, 55 mmol), NaOH (8.00 g, 200 mmol) and dimethyl sulfate (6.25 mL, 65 mmol) in THF (100 mL) was stired for 5 hours at room temperature. The reaction was quenched with water (20 mL) and 25% ammonia (5 mL) and the resulting mixture was stirred overnight at room temperature. The mixture was purred into water (100 mL) and extracted with petroleum ether (100 mL). The organic phase was washed with 1 M NaOH (aq) (100 mL), water (3×100 mL), brine (50 mL), dried over Na2SO4 and filtered. The solvent was removed under reduced pressure to yield 1-chloro-2-(methoxymethyl)-4-(trifluoromethyl)benzene (COMK) as a colorless oil (11.54 g, 94%): 1H NMR (CDCl3) 3.50 (s, 3H), 4.57 (s, 2H), 7.46 (m, 2H), 7.77 (s, 1H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[OH-].[Na+].[O:14]1C=CC=[CH:16][CH:15]1OCCBr.Cl>CO.CC(N(C)C)=O>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:16][CH2:15][OH:14])=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: BrCCOC1C=CC=CO1
Reactant: CS(=O)(=O)c1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Solvent: CO
Product: CS(=O)(=O)c1ccc(OCCO)cc1
Yield: 37.9 %

Procedure:
A mixture of 4-methanesulfonylphenol (1.72 g, 10 mmol), DMA (25 ml) and 4 N sodium hydroxide (7 ml) was stirred under an atmosphere of nitrogen. 2-(2-Pyranyloxy)ethylbromide (2.8 g, 14 mmol) was added dropwise and then the mixture was stirred overnight at ambient temperature. The solvent was evaporated in vacuo and the residue was taken up in water (100 ml). The aqueous mixture was extracted with ethyl acetate (2×100 ml) and the combined organic extracts were washed with a 0.5 N sodium hydroxide solution and brine. The organic phase was concentrated to give an oily residue that was dissolved in methanol (50 ml). A solution of 5 N HCl (20 ml) was added and the mixture was stirred at ambient temperature for 2 hours. The reaction mixture was concentrated and a small portion of ice was added followed by 4 N sodium hydroxide until approximately pH 10. The alkaline mixture was extracted with ethyl acetate (3×75 ml) and the combined organic extracts were washed with water and dried (MgSO4). The solvent was evaporated to give 0.82 g (38%) of 2-(4-methanesulfonylphenoxy)ethanol. M.p. 89–90° C.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24][CH2:23][N:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=[C:14]3[C:13]2=[O:25])=[CH:10][CH:9]=[CH:8][C:7]=1[C:26]1[CH:31]=[C:30]([NH:32][C:33]2[CH:37]=[CH:36][N:35]([CH2:38][CH2:39][N:40]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH3:41])[N:34]=2)[C:29](=[O:49])[N:28]([CH3:50])[CH:27]=1)(=O)C.O.[Li+].[OH-]>CC(O)C.O1CCCC1>[OH:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24][CH2:23][N:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=[C:14]3[C:13]2=[O:25])=[CH:10][CH:9]=[CH:8][C:7]=1[C:26]1[CH:31]=[C:30]([NH:32][C:33]2[CH:37]=[CH:36][N:35]([CH2:38][CH2:39][N:40]([CH3:41])[C:42](=[O:43])[O:44][C:45]([CH3:46])([CH3:47])[CH3:48])[N:34]=2)[C:29](=[O:49])[N:28]([CH3:50])[CH:27]=1
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccn(CCN(C)C(=O)OC(C)(C)C)n3)c(=O)n(C)c2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CN(CCn1ccc(Nc2cc(-c3cccc(N4CCn5c(cc6c5CCCC6)C4=O)c3CO)cn(C)c2=O)n1)C(=O)OC(C)(C)C
Temperature: 30 °C
Reaction time: 2 h
Yield: 70.8 %

Procedure:
To a solution of 206g (750 mg, 1.1 mmol) in propan-2-ol (15 mL), tetrahydrofuran (15 mL), and water (5 mL) was added LiOH (2.6 g, 110 mmol). The mixture was stirred at 30° C. for 2 h. It was then evaporated and the residue was purified by reverse phase Combi-flash eluting with 0.3% NH4HCO3 in 1:3 water/CH3CN to give 206h as a brown solid (500 mg, 71%). MS: (M+H)+ 642
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][NH:5][C@@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.S(Cl)([Cl:12])=O.[CH3:14]O>>[ClH:12].[OH:1][C@H:2]1[CH2:6][NH:5][C@@H:4]([C:7]([O:9][CH3:14])=[O:8])[CH2:3]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)[C@H]1C[C@@H](O)CN1
Reactant: CO
Product: COC(=O)[C@H]1C[C@@H](O)CN1
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 113 %

Procedure:
To a suspension of cis-4-hydroxy-D-proline (16.46 g: 125.5 mmole) in methanol (66 ml), thionylchloride (9.16 ml: 125.5 mmole) is added in a nitrogen atmosphere under ice cooling, and the mixture is stirred at room temperature for 30 minutes. The mixture is further stirred to react at 40° C. for 4 hours to give (2R,4R)-4-hydroxy-2-methoxycarbonylpyrrolidine hydrochloride as crude crystals (25.74 g). Yield: 113%. Colorless crystals. NMR δ(D2O) ppm: 2.3 to 2.6(m, 2H), 3.33(s, 1H), 3.4 to 3.5(m, 2H), 3.84(s, 3H), 4.6 to 4.7(m, 2H). IR ν (KBr) cm-1 : 3320, 2980, 1728.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:5]=[C:6]([C:8]2[O:9][CH:10]=[C:11]([CH2:13][CH2:14][CH2:15]O)[N:12]=2)[CH:7]=1.P(OC1C=CC=CC=1)(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.C[I:45]>>[F:1][C:2]1[CH:3]=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:5]=[C:6]([C:8]2[O:9][CH:10]=[C:11]([CH2:13][CH2:14][CH2:15][I:45])[N:12]=2)[CH:7]=1
Reactant: CI
Reactant: OCCCc1coc(-c2cc(F)cc(C(F)(F)F)c2)n1
Agent: O=P(Oc1ccccc1)(Oc1ccccc1)Oc1ccccc1
Product: Fc1cc(-c2nc(CCCI)co2)cc(C(F)(F)F)c1
Temperature: 130 °C
Yield: 33.6 %

Procedure:
To 3-{2-[5-fluoro-3-(trifluoromethyl)phenyl]-1,3-oxazol-4-yl}propan-1-ol (250.3 mg, 0.865 mmol) was added a mixture of triphenyl phosphate (295.4 mg, 0.952 mmol, 1.1 equiv.) and methyl iodide (184.2 mg, 1.298 mmol, 1.5 equiv.). The mixture was heated at 130° C., while adding a further amount of methyl iodide (184.2 mg, 1.298 mmol, 1.5 equiv.). The reaction mixture was heated for a total of 2 hours, and then purified by column-chromatography (SiO2=25 g, hexane/EtOAc=7:1) followed by preparative TLC (SiO2=6 plates, hexane/EtOAc=15:1) to give 2-[5-fluoro-3-(trifluoromethyl)phenyl]-4-(3-iodopropyl)-1,3-oxazole (116.1 mg, 0.291 mmol, 34%) as a colorless oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:36](=[O:37])[N:12]2[CH:13]([C:20]([O:22][CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[C:14]([C:17](Cl)=[O:18])=[CH:15][S:16][C@H:11]12)=[O:8].[CH3:38][O:39][NH2:40]>O1CCCC1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:36](=[O:37])[N:12]2[CH:13]([C:20]([O:22][CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[C:14]([C:17]([NH:40][O:39][CH3:38])=[O:18])=[CH:15][S:16][C@H:11]12)=[O:8]
Reactant: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(C(=O)Cl)=CS[C@H]12
Reactant: CON
Solvent: C1CCOC1
Product: CONC(=O)C1=CS[C@@H]2C(NC(=O)Cc3cccs3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1

Procedure:
Benzhydryl 7-(2-thienylacetamido)-3-chlorocarbonyl-2-cephem-4-carboxylate reacts with 1.1 equivalents of methoxyamine in tetrahydrofuran at -76° C. to give benzhydryl 7-(2-thienylacetamido)-3-methoxyaminocarbonyl-2-cephem-4-carboxylate. 4'-Methoxybenzyl 7-butyramido-3-methylcarbonyldioxycarbonyl-3-cephem-4-carboxylate reacts with 1.1 equivalents phenylhydroxylamine in methylene chloride at -76° C. to provide 4'-methoxybenzyl 7-butyramido-3-phenylhydroxaminocarbonyl-3-cephem-4-carboxylate.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:25])[CH3:24])=[CH:18][CH:17]=2)[C:7]=1[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:5])[CH3:2].[F:32][C:33]([F:45])([F:44])[O:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:38]3[CH:37]=[CH:36][C:35]([O:34][C:33]([F:32])([F:44])[F:45])=[CH:40][CH:39]=3)[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:24])[CH3:25])=[CH:18][CH:17]=2)[C:7]=1[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:5])[CH3:2]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1ccc(OC(C)C)cc1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3ccc(OC(F)(F)F)cc3)ccc2n1-c1ccc(OC(C)C)cc1

Procedure:
The sub-title compound was prepared in accordance with step (c) Example 1 from 2-ethoxycarbonylmethyl-5-hydroxy-1-(4-isopropoxyphenyl)-indole-3-carboxylic acid ethyl ester (212 mg, 0.50 mmol, see step (b) Example 12) and 4-trifluoromethoxyphenylboronic acid (154 mg, 0.75 mmol). Yield 156 mg (53%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7](Cl)[CH:8]=2)[N:3]=1.[CH3:13][C:14]1[O:18][C:17]([CH2:19][NH2:20])=[CH:16][CH:15]=1.[NH2:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1>>[CH3:13][C:14]1[O:18][C:17]([CH2:19][NH:20][C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([NH:21][C:22]4[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=4)[CH:8]=3)[N:3]=2)=[CH:16][CH:15]=1
Reactant: Nc1cccnc1
Reactant: Clc1ccc2nc(Cl)ccc2c1
Reactant: Cc1ccc(CN)o1
Product: Cc1ccc(CNc2ccc3cc(Nc4cccnc4)ccc3n2)o1

Procedure:
The title compound, MS: m/e=331.3 (M+H+), was prepared in accordance with the general method of example 1 from 2,6-dichloroquinoline, 5-methyl-2-furanmethanamine and 3-aminopyridine.
Reaction SMILES: [NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@@H:2]([C:6]([OH:8])=O)[CH:3]([CH3:5])[CH3:4].C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[CH2:29]1[O:40][C:39]2[CH:38]=[CH:37][C:33]([CH2:34][CH2:35][NH2:36])=[CH:32][C:31]=2[O:30]1.C(N(CC)CC)C>ClCCCl>[C:12]([O:11][C:9](=[O:10])[NH:1][C@@H:2]([C:6](=[O:8])[NH:36][CH2:35][CH2:34][C:33]1[CH:37]=[CH:38][C:39]2[O:40][CH2:29][O:30][C:31]=2[CH:32]=1)[CH:3]([CH3:4])[CH3:5])([CH3:15])([CH3:14])[CH3:13]
Reactant: NCCc1ccc2c(c1)OCO2
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)NCCc1ccc2c(c1)OCO2
Reaction time: 0.5 h
Yield: 94.4 %

Procedure:
Boc-D-Val-OH (282 mg, 1.30 mmol) was dissolved in DCE (5 mL), followed by addition of CDI (253 mg, 1.56 mmol). The reaction solution was stirred for 30 mins to activate the acid. After this period, 3,4-Methylenedioxyphenethylamine HCl (263 mg, 1.30 mmol) and triethylamine (363 μL) were added to the reaction vessel and it was stirred at room temperature for 16 hours. Next, the reaction mixture was concentrated under vacuum. The crude material was dissolved in DCM (50 mL), transferred to a separatory funnel, washed with sat. NaHCO3 (aq) (50 mL), dried over Na2SO4 and concentrated down to yield 447.1 mg (94.6%) of crude product, [1-(2-benzo[1,3]dioxol-5-yl-ethylcarbamoyl)-2-methyl-propyl]-carbamic acid tert-butyl ester, which was taken on crude. [M+H]+ 365.00.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH:6]([CH3:8])[CH2:5][N:4]([C:9](=[O:23])[CH2:10][CH2:11][C:12]2[C:20]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[NH:14][C:13]=2[CH:21]=O)[CH2:3]1.[CH3:24][NH:25][S:26]([C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][C:33](=[O:38])[CH2:32]2)(=[O:28])=[O:27]>>[CH3:24][NH:25][S:26]([C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][C:33](=[O:38])/[C:32]/2=[CH:21]\[C:13]1[NH:14][C:15]2[CH2:16][CH2:17][CH2:18][CH2:19][C:20]=2[C:12]=1[CH2:11][CH2:10][C:9]([N:4]1[CH2:3][CH:2]([CH3:1])[NH:7][CH:6]([CH3:8])[CH2:5]1)=[O:23])(=[O:28])=[O:27]
Reactant: CNS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reactant: CC1CN(C(=O)CCc2c(C=O)[nH]c3c2CCCC3)CC(C)N1
Product: CNS(=O)(=O)c1ccc2c(c1)/C(=C/c1[nH]c3c(c1CCC(=O)N1CC(C)NC(C)C1)CCCC3)C(=O)N2
Yield: 61.5 %

Procedure:
3-[3-(3,5-Dimethylpiperazin-1-yl)-3-oxo-propyl]-4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde (136 mg, 0.3 mmol) was condensed with 5-methylaminosulfonyloxindole (68 mg, 0.3 mmol) following the same procedure used in Example 1 above to give 3-[1-{3-[3-(3,5-dimethyl-piperazin-1-yl)-3-oxo-propyl]-4,5,6,7-tetrahydro-1H-indol-2-yl}-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-1H-indole-5-sulfonic acid methylamide (97 mg, 62% yield).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]([C:6]([OH:8])=O)=[C:4]([CH3:12])[CH:3]=1.C(Cl)(=O)C(Cl)=O.CCN(CC)CC.[N:26]1([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH2:30][CH2:29][CH2:28][CH2:27]1>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([C:6]([N:34]2[CH2:35][CH2:36][CH:31]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[CH2:32][CH2:33]2)=[O:8])=[C:9]([CH3:11])[CH:10]=1
Reactant: C1CCN(C2CCNCC2)C1
Reactant: Cc1cc(Br)cc(C)c1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(Br)cc(C)c1C(=O)N1CCC(N2CCCC2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.6 %

Procedure:
A suspension of 0.344 g (1.5 mmol) 4-bromo-2,6-dimethyl-benzoic acid [Fuson, R. C.; Scott, S. L.; Lindsey, R. V., Jr. Journal of the American Chemical Society (1941), 63, 1679-82] in 5 ml of CH2Cl2 was treated at RT with two drops of DMF; then, a solution of 0.14 ml=0.21 g (1.6 mmol) of oxalyl chloride in 3 ml of CH2Cl2 was added drop by drop below 25° C. and the reaction mixture was stirred of 1 hour. After removal of the solvents by evaporation in a high vacuum, the residue was dissolved again in 10 ml of CH2Cl2 and the solution cooled down to 0° C.; then, 0.42 ml=0.30 g (3.0 mmol) of Et3N was added while stirring, followed by 0.23 g (1.5 mmol) of 4-pyrrolidin-1-yl-piperidine. The reaction mixture was subsequently warmed up to RT. After 60 hours, it was poured into crashed ice and extracted twice with CH2Cl2; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 1:0 to 95:5) to give 0.42 g (76%) of the title compound as light yellow oil. MS: 365.0 (MH+, 1 Br).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=O)=[CH:4][C:3]=1[O:13][CH3:14].O=S(Cl)Cl.[CH3:19][O:20][C:21](=[O:29])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH2:28].CCCCCC>CCOC(C)=O>[CH3:19][O:20][C:21](=[O:29])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH:28][C:9](=[O:11])[CH:8]([C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([O:13][CH3:14])[CH:4]=1)[CH3:12]
Reactant: COC(=O)c1ccccc1N
Reactant: COc1cc(C(C)C(=O)O)ccc1O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccccc1NC(=O)C(C)c1ccc(O)c(OC)c1
Yield: 83.7 %

Procedure:
The objective compound was prepared by the same procedure for the intermediate 1, using a 2-(4-hydroxy-3-methoxy-phenyl)-propionic acid (1.08 g, 5.50 mmol), SOCl2 (1.20 mL, 16.6 mmol), and 2-amino-benzoic acid methyl ester (0.56 g, 3.7 mmol). After normal workup, the pure objective compound (1.02 g, 56%) was obtained as pale yellow syrup by a flash column chromatography (n-hexane:EtOAc=10:1): 1H NMR (200 MHz, CDCl3) δ 1.57 (d, J=7.32 Hz, 3H, CH3), 3.72 (q, J=7.32 Hz, 1H, CH), 3.85 (s, 3H, OCH3), 3.88 (s, 3H, COOCH3), 5.73 (br s, 1H, ArOH), 6.89-7.05 (m, 4H, ArH), 7.45 (t, J=8.55 Hz, 1H, ArH), 7.94 (d, J=7.73 Hz, 1H, ArH), 8.67 (d, J=8.55 Hz, 1H, ArH), 11.07 (br s, 1H, NH).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[N:28]=[C:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:26]([C:36]3[CH:37]=[C:38]4[C:43](=[CH:44][CH:45]=3)[CH2:42][NH:41][CH2:40][CH2:39]4)=[CH:25][CH:24]=1)[CH2:19][CH2:18]2)=[O:12].[CH:46](=O)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.C(O)(=O)C.CO>ClCCl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[N:28]=[C:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:26]([C:36]3[CH:37]=[C:38]4[C:43](=[CH:44][CH:45]=3)[CH2:42][N:41]([CH2:46][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[CH2:40][CH2:39]4)=[CH:25][CH:24]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: O=Cc1ccccc1
Reactant: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)ccc1-c1ccc2c(c1)CCNC2
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)ccc1-c1ccc2c(c1)CCN(Cc1ccccc1)C2

Procedure:
A suspension of EXAMPLE 133A (20 mg), benzaldehyde (6.58 μL), MP-CNBH3 (100 mg, 2.47 mmol/g), acetic acid (2 μL) in dichloromethane (2 mL)/methanol (2 mL) was shaken at room temperature for 18 hours. The reaction mixture was filtered, washed with methanol/dichloromethane, concentrated and purified by RP HPLC(C8, 30-100% CH3CN/water/0.1% TFA) to provide the title compound.
Reaction SMILES: [CH3:1][CH:2]([C:16]([OH:18])=[O:17])[C:3]1[CH:4]=[CH:5][C:6]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[C:7]([F:9])[CH:8]=1.[N:19]1[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)=[CH:21][CH:20]=1>CC(C)=O>[CH3:1][CH:2]([C:16]([OH:18])=[O:17])[C:3]1[CH:4]=[CH:5][C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:7]([F:9])[CH:8]=1.[N:19]1[CH:24]=[CH:23][C:22]([CH:25]=[CH:26][C:27]2[CH:28]=[CH:29][N:30]=[CH:31][CH:32]=2)=[CH:21][CH:20]=1
Reactant: C(=C/c1ccncc1)\c1ccncc1
Agent: CC(C(=O)O)c1ccc(-c2ccccc2)c(F)c1
Solvent: CC(C)=O
Product: C(=Cc1ccncc1)c1ccncc1

Procedure:
25 mg (0.1023 mmol) flurbiprofen and 10 mg (0.0548 mmol) trans-1,2-bis(4-pyridyl) ethylene were dissolved in 3 mL acetone. Slow evaporation of the solvent yielded colorless needles of a 2:1 flurbiprofen/1,2-bis(4-pyridyl) ethylene co-crystal, as shown in FIG. 49A-B.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([NH2:7])[CH2:3][CH2:2]1.[C:8]([O:12][C:13]([NH:15][C@@H:16]([CH3:29])[C:17]([NH:19][N:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25](OC)=[O:26])=[O:18])=[O:14])([CH3:11])([CH3:10])[CH3:9].C[Al](C)C.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O>[O:18]=[C:17]([NH:19][N:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25](=[O:26])[NH:7][CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)[C@@H:16]([NH:15][C:13](=[O:14])[O:12][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:29]
Reactant: COC(=O)c1cccn1NC(=O)[C@H](C)NC(=O)OC(C)(C)C
Reactant: NC1CCOCC1
Agent: C[Al](C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nn1cccc1C(=O)NC1CCOCC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Tetrahydro-2H-pyran-4-amine (900 microl, 8.69 mmols) was added to a solution of (S)-methyl 1-(2-(tert-butoxycarbonylamino)propanamido)-1H-pyrrole-2-carboxylate (900 mg, 2.89 mmols, preparation 109) in toluene (36 ml). A 2M solution of Trimethyl aluminium in toluene (7 ml, 14.00 mmols) was added and it was stirred at 80° C. overnight. Water (50 ml) and a 0.5M solution of sodium tartrate (25 ml) were added. It was extracted with ethylacetate. The combined organic layers were washed with water and brine. It was dried, filtered and concentrated in vacuum. The title compound was obtained (617 mg, 56%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:10][C:11]2[C:17](I)=[CH:16][C:15]([OH:19])=[CH:14][C:12]=2[N:13]=1.[C:20]([Cu])#[N:21].[CH3:23][N:24](C=O)C>C(OCC)(=O)C>[C:23]([C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:10][C:11]2[C:17]([C:20]#[N:21])=[CH:16][C:15]([OH:19])=[CH:14][C:12]=2[N:13]=1)#[N:24]
Reactant: CN(C)C=O
Reactant: Oc1ccc(-c2nc3cc(O)cc(I)c3o2)c(Cl)c1
Reactant: N#C[Cu]
Solvent: CCOC(C)=O
Product: N#Cc1cc(O)ccc1-c1nc2cc(O)cc(C#N)c2o1
Temperature: 150 °C
Reaction time: 0.25 h

Procedure:
To 2-(2-chloro-4-hydroxy-phenyl)-7-iodo-benzooxazol-5-ol (279 mg) in DMF (5 mL) was added CuCN (97 mg). The mixture was placed in an oil bath and heated to 150° C. for 3 h. The mixture was cooled to room temperature and diluted with ethyl acetate and washed with 1N HCl, saturated aqueous EDTA, brine (3×), dried (Na2SO4), and concentrated. Material was purified by preparative LC/MS. MS: 278 (MH+), HPLC tR: 1.92 min. The HPLC conditions used are the following: HPLC Waters Corp. Novapak HR™ C 18 RCM 40×100 mm 6 μm particle; flow rate 40 mL/min, linear gradient from 35% B to 65% B over 15 min; A=water, 0.1% TFA; B=MeOH, UV detection at 254 nm and positive ionization mass spectrometry detection