Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([OH:8])=[N:6][CH:7]=1.[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:22][C:12]1[CH:17]=[CH:16][C:15]([S:18]([O:8][C:5]2[C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=[N+]([O-])c1cc(Br)cnc1O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)Oc2ncc(Br)cc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5-Bromo-3-nitropyridin-2-ol (30.00 g, 0.137 mmol) and p-toluenesulfonyl chloride (30.03 g, 0.158 mmol) were suspended in CH2Cl2 under N2 and treated dropwise with triethylamine (38.2 mL, 0.274 mmol) prior to the addition of DMAP (3.35 g, 0.027 mmol). After stirring at rt for 16 h the mixture was diluted with CH2Cl2 (500 mL) then washed with 1M HCl(aq) (2×500 mL) and brine (500 mL). The aqueous layer was back-extracted with CH2Cl2 (200 mL) and the combined organic layers dried over Na2SO4, and concentrated in vacuo. The crude material thus isolated was chromatographed over silica gel eluting with 50% EtOAc/hexane to give, on evaporation, a solid which was crystallized from 50% EtOAc/hexane to afford 5-bromo-3-nitropyridin-2-yl 4-methylbenzenesulfonate. 1H NMR (400 MHz, CDCl3) δ 2.51 (s, 3H), 7.43 (dd, 2H, J=8.4, 0.4 Hz), 7.99 (dt, 2H, J=6.8, 2.0 Hz), 8.52 (d, 1H, J=2.4 Hz), 8.60 (d, 1H, J=2.4 Hz).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4](=[CH:8]N(C)C)[C:5](=O)[CH3:6].Cl.[C:14]([NH:18][NH2:19])([CH3:17])([CH3:16])[CH3:15].C([O-])(=O)C.[Na+].ClCCl>C(O)C>[CH3:1][O:2][C:3]([C:4]1[CH:8]=[N:19][N:18]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:5]=1[CH3:6])=[O:12]
Reactant: COC(=O)C(=CN(C)C)C(C)=O
Reactant: CC(C)(C)NN
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: COC(=O)c1cnn(C(C)(C)C)c1C
Temperature: 90 °C
Yield: 70.9 %

Procedure:
A solution of 2-dimethylaminomethylene-3-oxo-butyric acid methyl ester (7.43 g, 43.40 mmol) in absolute ethanol (70 mL) was treated with tert-butylhydrazine hydrochloride (5.52 g, 44.29 mmol) and sodium acetate (4.42 g, 53.88 mmol). The resulting mixture was heated to 90° C. for 18 h. At this time, the reaction was cooled to 25° C. The reaction was poured onto ice using dichloromethane to assist the transfer (50 mL). The mixture was transferred to a separatory funnel at which time the layers were shaken and separated. The aqueous layer was further extracted with dichloromethane (1×50 mL). The combined organics were washed with a saturated aqueous sodium bicarbonate solution (1×50 mL), water (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. ISCO CombiFlash (120 g column; 0-10% ethyl acetate/hexanes) afforded 1-tert-butyl-5-methyl-1H-pyrazole-4-carboxylic acid methyl ester (6.04 g, 71%) as a yellow oil.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[F:28][C:29]1[CH:30]=[CH:31][C:32]([CH3:38])=[C:33](B(O)O)[CH:34]=1>>[Cl:20][C:17]([F:19])([F:18])[O:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:21]=[C:2]([C:31]3[CH:30]=[C:29]([F:28])[CH:34]=[CH:33][C:32]=3[CH3:38])[C:3]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[N:4][CH:5]=2)=[CH:11][CH:12]=1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: Cc1ccc(F)cc1B(O)O
Product: Cc1ccc(F)cc1-c1cc(C(=O)Nc2ccc(OC(F)(F)Cl)cc2)cnc1N1CC[C@@H](O)C1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 290 using (R)-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Stage 171.1) and 5-Fluoro-2-methylphenylboronic acid to afford a white solid. HPLC (Condition 10) tR=6.424 min, UPLC-MS (Condition 11) m/z=492.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.60-1.92 (m, 2H) 1.94-2.11 (m, 3H) 2.78-3.03 (m, 1H) 3.07-3.28 (m, 3H) 4.11-4.23 (m, 1H) 4.76-4.94 (m, 1H) 7.10-7.19 (m, 1H) 7.23-7.31 (m, 1H) 7.33 (d, J=8.99 Hz, 3H) 7.86 (d, J=8.99 Hz, 2H) 7.91 (m, J=2.30 Hz, 1H) 8.73-8.79 (m, 1H) 10.08-10.17 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]([CH:23]3[CH2:27][CH2:26][NH:25][CH2:24]3)[C:7]([CH2:9][N:10]3[C:14]4=[CH:15][N:16]=[CH:17][CH:18]=[C:13]4[C:12]([S:19]([CH3:22])(=[O:21])=[O:20])=[N:11]3)=[N:8][C:4]=2[CH:3]=1.[OH:30][CH2:31][C:32](O)=[O:33].C(OC(=O)C)(=O)C>>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]([CH:23]3[CH2:27][CH2:26][N:25]([C:31](=[O:30])[CH2:32][OH:33])[CH2:24]3)[C:7]([CH2:9][N:10]3[C:14]4=[CH:15][N:16]=[CH:17][CH:18]=[C:13]4[C:12]([S:19]([CH3:22])(=[O:20])=[O:21])=[N:11]3)=[N:8][C:4]=2[CH:3]=1
Reactant: O=C(O)CO
Reactant: CS(=O)(=O)c1nn(Cc2nc3cc(Cl)ccc3n2C2CCNC2)c2cnccc12
Solvent: CC(=O)OC(C)=O
Product: CS(=O)(=O)c1nn(Cc2nc3cc(Cl)ccc3n2C2CCN(C(=O)CO)C2)c2cnccc12

Procedure:
The title compound was prepared in analogy to Example 2-16 by using 1-((5-chloro-1-(pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)methyl)-3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridine and 2-hydroxyacetic acid instead of 1-{[5-chloro-1-(pyrrolidin-3-yl)-1H-benzimidazol-2-yl]methyl}-3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridine and acetic anhydride.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[S:16][C:17]([C:21](O)=[O:22])=[C:18]([CH3:20])[N:19]=2)[C:11](=[O:24])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[S:55]1[C:59]([CH2:60][NH2:61])=[CH:58][C:57]2[CH:62]=[CH:63][CH:64]=[CH:65][C:56]1=2>CN(C)C=O>[S:55]1[C:59]([CH2:60][NH:61][C:21]([C:17]2[S:16][C:15]([N:12]3[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:10][C:11]3=[O:24])=[N:19][C:18]=2[CH3:20])=[O:22])=[CH:58][C:57]2[CH:62]=[CH:63][CH:64]=[CH:65][C:56]1=2
Reactant: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)O
Reactant: NCc1cc2ccccc2s1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)NCc1cc2ccccc2s1
Reaction time: 0.5 h
Yield: 78 %

Procedure:
To a solution of 2-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylic acid (0.20 g, 0.58 mmol) in anhydrous N,N-dimethylformamide (10 mL) was added N,N-diisopropylethylamine (0.27 g, 2.10 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (0.18 g, 0.93 mmol). The mixture was stirred for 30 minutes, followed by the addition of 1-hydroxybenzotriazole (0.11 g, 0.81 mmol) and benzo[b]thiophen-2-ylmethanamine (0.14 mL, 0.87 mmol). The reaction mixture was stirred at ambient temperature for 24 hours. The solvent was removed in vacuo and the residue was dissolved in dichloromethane (50 mL), washed with saturated aqueous sodium bicarbonate (2×5 mL) and brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was recrystallized from ethyl acetate and hexane. The solid was collected by filtration and washed with methanol and hexane. The title compound was obtained as a colorless solid in 78% yield (0.22 g): 1H NMR (300 MHz, DMSO-d6) δ 8.98 (t, J=5.8 Hz, 1H), 8.61 (d, J=8.1 Hz, 1H), 7.82-7.85 (m, 1H), 7.76-7.73 (m, 1H), 7.51-7.23 (m, 8H), 6.34 (dd, J=8.1, 2.7 Hz, 1H), 6.23 (d, J=2.7 Hz, 1H), 5.16 (s, 2H), 4.65-4.63 (m, 2H), 2.56 (s, 3H); MS (ES+) m/z 488.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([Br:37])[C:5]([C@@H:8]([NH:18][C:19](=[O:36])[CH2:20][N:21]2[C:25]3[C:26]([F:31])([F:30])[C@@H:27]4[CH2:29][C@@H:28]4[C:24]=3[C:23]([C:32]([F:35])([F:34])[F:33])=[N:22]2)[CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=2)=[N:6][CH:7]=1.N1C=CC=CC=1.[CH3:44][S:45](Cl)(=[O:47])=[O:46]>C(Cl)Cl>[Br:37][C:4]1[C:5]([C@@H:8]([NH:18][C:19](=[O:36])[CH2:20][N:21]2[C:25]3[C:26]([F:31])([F:30])[C@@H:27]4[CH2:29][C@@H:28]4[C:24]=3[C:23]([C:32]([F:33])([F:34])[F:35])=[N:22]2)[CH2:9][C:10]2[CH:11]=[C:12]([F:17])[CH:13]=[C:14]([F:16])[CH:15]=2)=[N:6][CH:7]=[C:2]([NH:1][S:45]([CH3:44])(=[O:47])=[O:46])[CH:3]=1
Reactant: Nc1cnc([C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)(F)F)c3c2C(F)(F)[C@@H]2C[C@H]32)c(Br)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cnc([C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)(F)F)c3c2C(F)(F)[C@@H]2C[C@H]32)c(Br)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Compound 41C (35.6 mg, 0.06 mmol) was dissolved in 1 mL of methylene chloride and cooled to 0° C. To it was added 0.2 mL of pyridine followed by methanesulfonyl chloride (0.007 mL, 0.09 mmol). The reaction mixture was stirred at 0° C. for one hour. LCMS showed complete reaction. It was then partitioned between EtOAc and brine. The organic layer was separated, dried and concentrated to afford the title product. MS (m/z) 670.27 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[NH:3][CH:4]=[C:5]([CH3:7])[N:6]=1.F[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[C:10]=1[N+:17]([O-:19])=[O:18].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Br:1][C:2]1[N:3]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[C:10]=2[N+:17]([O-:19])=[O:18])[CH:4]=[C:5]([CH3:7])[N:6]=1
Reactant: Cc1c[nH]c(Br)n1
Reactant: COc1cccc(F)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc(-n2cc(C)nc2Br)c1[N+](=O)[O-]
Temperature: 90 °C

Procedure:
2-bromo-4-methyl imidazole (3.7 g, 23.4 mmol) and 2-fluoro-6-methoxy-nitrobenzene were dissolved in DMF (80 mL). To this was then added potassium carbonate (6.3 g, 46.8 mmol). The reaction was heated to 90° C. for 16 hrs then poured into water and extracted with ethyl acetate. The organic layer was separated and washed with water then brined, dried over magnesium sulfate and filtered. The solvent was removed under reduced pressure and the crude purified by flash chromatography on silica gel in 20:1 ethyl acetate/methylene chloride. A tan solid (2.6 g) was recovered. MS (ES) m/z 311.9 [M+1]+
Reaction SMILES: I[C:2]1[S:6][C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[N:9]=2)=[C:4]([C:15]([NH2:17])=[O:16])[CH:3]=1.[CH3:18][N:19]1[CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:21]=[N:20]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[CH3:18][N:19]1[CH:23]=[C:22]([C:2]2[S:6][C:5]([NH:7][C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[N:9]=3)=[C:4]([C:15]([NH2:17])=[O:16])[CH:3]=2)[CH:21]=[N:20]1
Reactant: Cc1cccc(Nc2sc(I)cc2C(N)=O)n1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1cccc(Nc2sc(-c3cnn(C)c3)cc2C(N)=O)n1
Temperature: 100 °C

Procedure:
A suspension of 5-iodo-2-[(6-methylpyridin-2-yl)amino]thiophene-3-carboxamide (300 mg, 0.84 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (619 mg, 2.97 mmol), dichlorobis(triphenylphosphine)palladium (29.3 mg, 0.04 mmol), and sodium carbonate (7.5 mL, 15.0 mmol) in 1,2-dimethoxyethane (7.5 mL) sealed in a 20 mL microwave reaction vessel was purged of oxygen by doing 5 vacuum/argon flush cycles. The reaction solution was heated in a microwave for five minutes at 100° C., and then partitioned between ethyl acetate (50 mL) and water (30 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. Purification by silica gel chromatography (12-100% ethyl acetate/hexanes) yielded the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:20]=[CH:19][C:5]([CH:6]2[CH2:15][C:14](=[O:16])[C:13]3[C:8](=[CH:9][C:10]([OH:18])=[CH:11][C:12]=3[OH:17])[O:7]2)=[CH:4][CH:3]=1.C(O[C:25](=[O:27])[CH3:26])(=O)C>S(=O)(=O)(O)O.O>[C:2]([O:1][C:2]1[CH:20]=[CH:19][C:5]([CH:6]2[CH2:15][C:14](=[O:16])[C:13]3[C:8](=[CH:9][C:10]([O:18][C:25](=[O:27])[CH3:26])=[CH:11][C:12]=3[O:17][C:6](=[O:7])[CH3:5])[O:7]2)=[CH:4][CH:3]=1)(=[O:1])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1CC(c2ccc(O)cc2)Oc2cc(O)cc(O)c21
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)Oc1ccc(C2CC(=O)c3c(OC(C)=O)cc(OC(C)=O)cc3O2)cc1

Procedure:
4',5,7-Trihydroxyflavanone (10.5 g) was stirred with acetic anhydride (50 ml) and sulphuric acid (5 drops) for 2 hr at room temperature, then poured into iced water. The product was extracted into ether and the extracted washed with water, followed by sodium bicarbonate solution. 4',5,7-Triacetoxyflavanone was obtained on evaporation of the ether, and this was dissolved in a mixture of tetrahydrofuran (250 ml) and ethanol (250 ml). Sodium borohydride (1.2 g) was added over 5 min, and the solution stirred for 30 min. Further borohydride (1.8 g) was then added and stirring continued for a further 30 min. The solution was acidifed by cautious addition of glacial acetic acid (8 ml). The solvent was evaporated off and the residual oil extracted into chloroform, washed with water, dried and evaporated.
Reaction SMILES: [O:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=O.[CH3:11][O:12][C:13](=[O:34])[CH:14]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:11][O:12][C:13](=[O:34])[CH2:14][C:2]1[O:1][C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[CH:3]=1
Reactant: O=C1Cc2ccccc2O1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)Cc1cc2ccccc2o1
Reaction time: 5 h

Procedure:
A solution of 2-coumaranone (5.0 g, 37 mmol) and methyl(triphenylphosphoranylideneacetate) (13.5 g. 40 mmol) in toluene (70 mL) was heated to reflux for 25 hours. More toluene was added (10 mL), and after a further 5 hours, more methyl(triphenylphosphoranylideneacetate) (0.5 g, 1.5 mmol). After another 19 hours, a further 1.0 g (3.0 mmol) was added, and after a further 21 hours, the solvent was removed in vacuo. Column chromatography (heptane:ethyl acetate 4:1) gave the product as a brown oil, 28 mmol, 75%.
Reaction SMILES: [F:1][C@H:2]1[CH2:6][NH:5][C@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.[CH2:10]=O.Cl>[Pd]>[F:1][C@H:2]1[CH2:6][N:5]([CH3:10])[C@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1
Reactant: O=C(O)[C@@H]1C[C@@H](F)CN1
Reactant: C=O
Agent: [Pd]
Agent: Cl
Product: CN1C[C@H](F)C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 72 h
Yield: 54.2 %

Procedure:
A solution of (2S,4R)-4-fluoropyrrolidine-2-carboxylic acid (1.00 g, 7.52 mmol), formaldehyde (37% wt in water, 1.00 mL, 30.8 mmol), 12N HCl (0.5 mL) in IMS (38 mL) was purged with argon. To the solution was added Pd/C (100 mg), then the flask was evacuated and filled with H2 the resulting suspension was stirred at RT for 3 d. The reaction mixture was passed through a pad of Celite and the mixture was concentrated in vacuo to give the title compound as a pale yellow gum (600 mg, 54%). 1H NMR (300 MHz, d6-DMSO): 2.29-2.37 (1H, m), 2.63-2.67 (1H, m), 2.97 (3H, s), 3.44-3.53 (1H, m), 4.00-4.04 (1H, m), 4.58 (1H, dd, J 11.6, 7.11), 5.41-5.45 (1H, m).
Reaction SMILES: [CH:1]1([C@H:6]2[C:31](=[O:32])[N:30]3[CH2:33][C@@H:27]([CH2:28][C@H:29]3[C:34]([O:36][CH3:37])=[O:35])[O:26][C:25]3[N:20]([C:21](=[O:38])[CH:22]=[CH:23][CH:24]=3)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]3[C@@H:10]([CH2:11][CH2:12][CH2:13]3)[O:9][C:8](=[O:39])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1C(=O)N([Br:47])C(=O)C1>C(#N)C>[Br:47][C:22]1[C:21](=[O:38])[N:20]2[C:25]([O:26][C@H:27]3[CH2:33][N:30]([C:31](=[O:32])[C@H:6]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)[NH:7][C:8](=[O:39])[O:9][C@H:10]4[C@H:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)[CH2:13][CH2:12][CH2:11]4)[C@H:29]([C:34]([O:36][CH3:37])=[O:35])[CH2:28]3)=[CH:24][CH:23]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1CCCC1)NC(=O)O[C@@H]1CCC[C@H]1CCCCCn1c(cccc1=O)O2
Solvent: CC#N
Product: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1CCCC1)NC(=O)O[C@@H]1CCC[C@H]1CCCCCn1c(ccc(Br)c1=O)O2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82 %

Procedure:
A 25 mL round bottom flask under nitrogen was charged with the product of Example 82 Step 1 (238 mg, 0.438 mmol), NBS (39.0 mg, 0.219 mmol), and acetonitrile (15 ml). Stirred at room temperature 10 minutes. HPLC/MS shows mainly desired; little starting material. Added an additional 10 mg NBS. Still a little starting material remaining. Added another 10 mg NES. HPLC/MS looks good. Cooled. Evaporated. Subjected to ISCO chromatography eluting with a hexane/ethyl acetate gradient. Evaporated fractions containing product to give the title compound as a white solid. (224 mg, 0.360 mmol, 82% yield). LCMS (ES+) m/z 623.3 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13].[CH2:15]([O:17][C:18]([CH2:20][CH2:21][NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:19])[CH3:16].C(N(CC)CC)C>O1CCCC1>[C:23]1([N:22]([CH2:21][CH2:20][C:18]([O:17][CH2:15][CH3:16])=[O:19])[C:7](=[O:8])[C:6]2[CH:10]=[CH:11][C:3]([NH:2][CH3:1])=[C:4]([N+:12]([O-:14])=[O:13])[CH:5]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CNc1ccc(C(=O)Cl)cc1[N+](=O)[O-]
Reactant: CCOC(=O)CCNc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CCN(C(=O)c1ccc(NC)c([N+](=O)[O-])c1)c1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 24.7 g (0.115 mol) of 4-methylamino-3-nitrobenzoic acid chloride and 22.3 g (0.115 mol) of N-(2-ethoxycarbonylethyl)aniline in 300 mL of tetrahydrofuran, 13.1 g (0.13 mol) of triethylamine were added dropwise in 15 minutes, with stirring, at room temperature. After 2 hours stirring, the solvent was distilled off in a water-jet vacuum and the residue was mixed with 700 mL of water with stirring. The mixture was extracted 3 times with 200 mL of dichloromethane, the organic extract was washed twice with 200 mL of 2N hydrochloric acid and twice with 300 mL of water and dried over sodium sulfate. The solvent was then distilled off and the oily product thus obtained was purified by column chromatography (1 kg silica gel; eluant: petroleum ether/ethyl acetate=2:1). Yield: 35.0 g (82% of theory); Rf value: 0.28 (silica gel; dichloromethane/ethanol=50:1).
Reaction SMILES: C([O:3][C:4]([C:6]1([C:9]2[N:27]=[C:12]3[C:13]([O:25][CH3:26])=[CH:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([C:23]#[N:24])[CH:18]=4)[N:11]3[N:10]=2)[CH2:8][CH2:7]1)=[O:5])C.[Li+].[OH-]>O1CCOCC1.O>[C:23]([C:19]1[CH:18]=[C:17]([C:16]2[N:11]3[N:10]=[C:9]([C:6]4([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]4)[N:27]=[C:12]3[C:13]([O:25][CH3:26])=[CH:14][CH:15]=2)[CH:22]=[CH:21][CH:20]=1)#[N:24]
Reactant: CCOC(=O)C1(c2nc3c(OC)ccc(-c4cccc(C#N)c4)n3n2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(-c2cccc(C#N)c2)n2nc(C3(C(=O)O)CC3)nc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-[5-(3-Cyano-phenyl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-cyclopropanecarboxylic acid ethyl ester (compound 188) (0.32 g, 0.88 mmol) was dissolved in 1,4-dioxan (10 mL) by heating. LiOH (0.06 g, 1.4 mmol) in H2O (2.5 mL) was added at RT. The suspension was stirred at RT overnight. The reaction mixture was concentrated in vacuo and H2O was added. The aqueous phase was washed with EtOAc and acidified with 4N HCl to pH 1. The aqueous phase was extracted with DCM (×2) and dried over MgSO4, filtered and concentrated in vacuo. This afforded the title compound as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[NH:8]C(=O)[C:6]2=[O:16].[OH:17]O.Cl>[OH-].[Na+]>[NH2:8][C:9]1[C:10]([N+:12]([O-:14])=[O:13])=[CH:11][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[C:6]([OH:16])=[O:17]
Reactant: OO
Reactant: COc1cc2c(c([N+](=O)[O-])c1)NC(=O)C2=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1cc(C(=O)O)c(N)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a slurry of 5-methoxy-7-nitro-1H-indole-2,3-dione (3 g, 13.5 mmol) in aqueous 2N NaOH solution (30 mL), was added an aq. Solution of 33% hydrogen peroxide (3 mL) slowly at 0° C. After completion of the addition, the reaction mixture was stirred at room temperature for 4 h. After completion of the reaction, the reaction mixture was acidified with 2N HCl at 0° C. The resulting precipitate was filtered, washed with water (2-3 times) and dried under vacuum to obtain the title compound as yellow solid which was directly used for the next reaction.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:13](=[O:14])[CH2:12][CH2:11][CH:10]2[C:15]([OH:17])=O)[CH:5]=[CH:6][CH:7]=1.S(Cl)(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[C:15](=[O:17])[CH:10]3[CH2:11][CH2:12][C:13](=[O:14])[N:9]3[CH2:8][C:4]=2[CH:3]=1
Reactant: O=C(O)C1CCC(=O)N1Cc1cccc(F)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C1c2ccc(F)cc2CN2C(=O)CCC12
Temperature: 5 °C
Reaction time: 8 h

Procedure:
To a solution of 50.00 g of (±)-1-[(3-fluorophenyl)methyl]-5-oxo-2-pyrrolidine carboxylic acid in sieve dried dichloromethane (450 ml), 27.48 g of thionyl chloride was added, and the resultant solution was stirred and refluxed for 5 hours. An infrared spectrum of the solution indicated the presence of the acid chloride. After standing overnight at ambient temperature, the solution was chilled to 5° C. and 84 g of aluminum chloride was added in portions with vigorous stirring. The reaction was exothermic and there was a slow evolution of gas. The mixture was stirred at ambient temperature for 3 hours. The reaction was quenched by the addition of ice chips and water. The two phases of the mixture were separated and the aqueous phase was extracted with dichloromethane (4×150 ml). The combined organic phase was dried (Na2SO4) and concentrated to a solid (69.73 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][O:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][C:12]([CH2:18][N:19]1[C:24](=[O:25])[CH:23]=[CH:22][C:21]([CH:26]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:20]1)=[CH:13]2)=[O:5])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:44]>ClCCl>[CH2:1]([O:3][C:4]([CH2:6][O:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][C:12]([CH2:18][N:19]1[C:24](=[O:25])[CH:23]=[CH:22][C:21]([CH:26]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:20]1)([OH:44])[CH2:13]2)=[O:5])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)COc1cccc2c1CCC(Cn1nc(C(c3ccccc3)c3ccccc3)ccc1=O)=C2
Solvent: ClCCl
Product: CCOC(=O)COc1cccc2c1CCC(O)(Cn1nc(C(c3ccccc3)c3ccccc3)ccc1=O)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.6 %

Procedure:
A solution of 2-[(3,4-dihydro-5-ethoxycarbonylmethoxy-2-naphthyl)methyl]-6-diphenylmethyl-3(2H)-pyridazinone (0.20 g) and 3-chloroperoxybenzoic acid (94 mg) in dichloromethane (5 ml) was allowed to stand in a freezer (about -15° C.) for overnight. The reaction mixture was evaporated in vacuo and the residue was partitioned between ethyl acetate and sodium hydrogencarbonate solution. The organic layer was separated and washed with water, brine, dried over magnesium sulfate and evaporated in vacuo. The residue and 10% palladium on carbon in ethyl acetate (5 ml) and acetic acid (one drop) were stirred under hydrogen (1 atm) at room temperature for 4 hours. The catalyst was filtered off and the filtrate was evaporated in vacuo. The residue was purified by silica gel column chromatography (n-hexane -ethyl acetate=2:1~1:1) to give 2-[(1,2,3,4-tetrahydro-5-ethoxycarbonylmethoxy-2-hydroxy-2-naphthyl)methyl]-6-diphenylmethyl-3(2H)-pyridazinone (0.08 g) as a pale yellow oil.