Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47](O)=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][CH:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=[O:29])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44].O.O[N:52]1[C:56]2[CH:57]=[CH:58][CH:59]=[CH:60][C:55]=2N=N1.NC1C=CC=CC=1>C1COCC1>[OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47]([NH:52][C:56]1[CH:55]=[CH:60][CH:59]=[CH:58][CH:57]=1)=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][CH:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=[O:29])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44]
Reactant: CO[C@@H]1[C@@H](O)[C@@H](OC)C(NC2=CC(=O)c3c(cc4c(c3O)C(=O)[C@]3(OC)[C@H](O)Cc5cc(C)c(C(=O)O)c(O)c5[C@]3(O)C4=O)C2=O)O[C@H]1C
Reactant: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Solvent: Nc1ccccc1
Product: CO[C@@H]1[C@@H](O)[C@@H](OC)C(NC2=CC(=O)c3c(cc4c(c3O)C(=O)[C@]3(OC)[C@H](O)Cc5cc(C)c(C(=O)Nc6ccccc6)c(O)c5[C@]3(O)C4=O)C2=O)O[C@H]1C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of (6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylic acid (100 mg, 0.14 mmol) in THF (3 mL) was added polystyrene-carbodiimide (261 mg, 0.29 mmol), 1-hydroxybenzotriazole hydrate (39 mg, 0.29 mmol) and aniline (127 mg, 1.43 mmol). The reaction mixture was stirred at room temperature under nitrogen for 6 h. The reaction was filtered through a micro filter. The crude material was purified by preparative TLC (silica gel, 90:10 chloroform/methanol) and preparative HPLC (10:90 acetonitrile/water to 100% acetonitrile with 0.05% TFA over 50 min) to afford (6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-N-phenyl-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxamide as a mixture of diastereomers (5.0 mg, 4%) and as a red solid: 1H NMR (500 MHz, CDCl3) δ 14.25 (s, 0.3H), 14.19 (s, 0.7H), 11.64 (br s, 1H), 8.28 (s, 0.3H), 8.24 (s, 0.7H), 7.50-7.42 (m, 3H), 7.38-7.32 (m, 3H), 7.16 (t, J=14.0 Hz, 2H), 6.91 (d, J=8.5 Hz, 0.3H), 6.86 (d, J=8.5 Hz, 0.7H), 6.54 (s, 1H), 6.20 (s, 0.3H), 6.18 (s, 0.7H), 5.85 (s, 1H), 5.18-5.13 (m, 1H), 4.98 (d, J=8.5 Hz, 1H), 4.67-4.62 (m, 1H), 3.81 (s, 3H), 3.79 (s, 2H), 3.60 (s, 3H), 3.56-3.51 (m, 2H), 3.44 (s, 2H), 3.38 (s, 1H), 3.15-3.10 (m, 1H), 2.51 (s, 3H), 1.37 (d, J=6.0 Hz, 3H); MS (ESI−) m/z 757 (M−H); HPLC 97.0% (AUC), tR 12.95 min.
Reaction SMILES: Cl[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7](O)=O.C(N1C=CN=C1)(N1C=CN=C1)=[O:11].[NH:22]1[CH2:26][CH2:25][CH2:24][C@H:23]1[CH2:27][OH:28].[H-].[Na+]>CN(C)C=O.O>[S:4]1[CH:3]2[CH2:7][N:22]3[CH:26]=[CH:25][CH:24]=[C:23]3[C:27](=[O:11])[O:28][C@H:2]2[CH2:6][CH2:5]1
Reactant: OC[C@@H]1CCCN1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1sccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1O[C@H]2CCSC2Cn2cccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 11.3 %

Procedure:
To a solution of 3-chlorothiophene-2-carboxylic acid (0.5 g; 6.325 mmol) in dimethylformamide (5 ml) was added 1,1′-carbonyldiimidazole (1.07 g; 6.64 mmol) and the solution stirred at room temperature for 1 h, followed by the addition of (S)-(+)-2-pyrrolidinemethanol (0.655 ml; 6.64 mmol). The reaction was stirred at room temperature overnight whereupon 60% sodium hydride in mineral oil (0.507 g; 12.7 mmol) was carefully added and the mixture was heated slowly to 150° C. with the progress of the reaction being monitored by thin layer chromatography. The reaction was cautiously diluted with water and extracted with ethyl acetate and the organic layer washed with water then dried (Na2SO4) and evaporated to give the crude product. Purification by flash chromatography eluting with 0-10% (v/v) methanol in dichloromethane followed by crystalisation from ethyl acetate-petroleum ether (40-60) afforded the title compound (0.15 g). M.p.: 167-167.5° C.; EIMS: m/z=222.2 [M+H]+
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]([NH:5][C:6]1[S:7][C:8]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])=[C:9]([CH3:18])[C:10]=1[C:11]([O:13]C(C)(C)C)=[O:12])=[O:4].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:22]([O:21][C:19]([C:8]1[S:7][C:6]([NH:5][C:3]([C:2]([F:1])([F:29])[F:30])=[O:4])=[C:10]([C:11]([OH:13])=[O:12])[C:9]=1[CH3:18])=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cc1c(C(=O)OCc2ccccc2)sc(NC(=O)C(F)(F)F)c1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(C(=O)OCc2ccccc2)sc(NC(=O)C(F)(F)F)c1C(=O)O
Reaction time: 18 h
Yield: 98.7 %

Procedure:
The compound prepared in Example 5 (155 mg, 0.34 mmol) was dissolved in DCM (2.5 ml) and TFA (3 ml) was added dropwise. After 18 h, the reaction was concentrated. The crude solid was partitioned between CHCl3 and H2O. The layers were separated and the aqueous layer was extracted with CHCl3 (2×). The combined organic layers were dried over MgSO4, filtered and concentrated to yield 130 mg of a white solid (99%). 1H-NMR (CDCl3) 2.83 (s, 3H), 5.34 (s, 2H), 7.40 (m, 5H); 13C-NMR (CDCl3)); mp-179-183° C.
Reaction SMILES: CCCCCC[CH2:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13](O)=[CH:14][CH:15]=1.N(CCO)(CCO)[CH2:18]CO.C([O:39][S:40](C1C=CC=CC=1)(=[O:42])=[O:41])CCCCCCCCCCC.[Na].[Na]>C(O)C>[S:40](=[O:39])([OH:42])[O-:41].[CH2:9]1[CH:10]2[CH:15]3[CH:14]=[CH:13][CH:12]([CH:11]2[CH:7]=[CH:8]1)[CH2:18]3
Reactant: CCCCCCCCCCCCOS(=O)(=O)c1ccccc1
Reactant: CCCCCCCCCc1ccc(O)cc1
Reactant: OCCN(CCO)CCO
Agent: [Na]
Solvent: CCO
Product: C1=CC2C3C=CC(C3)C2C1
Product: O=S([O-])O

Procedure:
The composition of claim 1 wherein the nonionic surfactant is the 8.5 molar ethoxylate of nonylphenol in a 6:1 (wt:wt) blend with triethanolamine in an amount of about 25 wt. %; the anionic surfactant is sodium dodecylbenzene sulfonate in an amount of about 5 wt. %; the solvent is ethanol in an amount of about 4 wt. % and the hydrotrope is the sodium salt of dicyclopentadiene sulfonate formed by bisulfite addition to dicyclopentadiene in alcohol/water solution at a pH of about 7.2 and in an amount of about 2 wt. %.
Reaction SMILES: [NH2:1][C@@H:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4].[OH:9][CH2:10][CH2:11][N:12]1[C:17](=[O:18])[CH2:16][CH2:15][CH:14]([N:19]2[C:27](=[O:28])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]2=[O:29])[C:13]1=[O:30].[Br:31][CH2:32][C:33](ON1C(=O)CCC1=O)=[O:34]>C(Cl)Cl>[Br:31][CH2:32][C:33]([NH:1][C@@H:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4])=[O:34].[OH:9][CH2:10][CH2:11][N:12]1[C:17](=[O:18])[CH2:16][CH2:15][CH:14]([N:19]2[C:20](=[O:29])[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:27]2=[O:28])[C:13]1=[O:30]
Reactant: O=C(CBr)ON1C(=O)CCC1=O
Reactant: CC(C)[C@H](N)C(=O)O
Agent: O=C1CCC(N2C(=O)c3ccccc3C2=O)C(=O)N1CCO
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)CBr)C(=O)O
Temperature: 25 °C

Procedure:
2-(1-(2-hydroxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione (S)-2-amino-3-methylbutanoate (1.8 g) was dissolved in DCM (20 mL). 2,5-Dioxopyrrolidinyl bromoacetate (1.04 g) was added to the mixture. The mixture was stirred with a magnetic stirrer at room temperature, and reacted overnight. The solvent was stripped in vacuo. White solid (1.3 g) was obtained after purification of the crude product on silica gel column (eluted with acetic ether:petroleum ether=1:1).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1.CO.[NH3:15]>>[CH3:12][O:11][C:4]1[N:3]=[C:2]([NH2:15])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Reactant: N
Solvent: CO
Product: COc1ccc([N+](=O)[O-])c(N)n1
Yield: 84 %

Procedure:
A solution/suspension of 2-chloro-6-(methyloxy)-3-nitropyridine (65.7 g, 348 mmol) in 2M ammonia in MeOH (500 ml, 1000 mmol) and aqueous ammonia (500 ml, 348 mmol) was stirred at 65° C. for 18 h. The reaction was cooled down and the solid filtered off and washed with water (2×100 ml). The solid was dried in the vacuum oven at 40° C. overnight to afford the product as a bright yellow solid (52.14 g, 84% purity by NMR, 74%).
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([NH:12]C(=O)C)=[CH:8][CH:7]=1)(=[O:5])=[O:4].Cl>CO>[CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1)(=[O:4])=[O:5]
Reactant: CNS(=O)(=O)c1ccc(NC(C)=O)cc1
Agent: Cl
Solvent: CO
Product: CNS(=O)(=O)c1ccc(N)cc1
Yield: 91.9 %

Procedure:
The acetamide (1.6 g) was dissolved in methanol (5 ml) and refluxed, with an addition of 4 N hydrochloric acid (7 ml), for 1 hour. After an evaporation of methanol under a reduced pressure, the residue was made basic with an addition of 1 N sodium hydroxide, and extracted with ethyl acetate (30 ml), followed by drying over anhydrous sodium sulfate. Evaporation of the solvent under a reduced pressure gave N-methyl-4-(amino)benzenesulfonamide (1.2 g) (m.p. 110.9° C.-112° C.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[C:6]([F:8])[CH:7]=1.[CH3:12][Mg]Br>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:9]([OH:11])([CH3:12])[CH3:10])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC(=O)c1cc(F)cc(F)c1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(C)(O)c1cc(F)cc(F)c1
Temperature: 25 °C

Procedure:
A solution of 1-(3,5-difluoro-phenyl)-ethanone (156 g, 1 mol, 1 eq) in THF (500 mL) was added dropwise under argon to the commercially available solution of methymagnesium bromide (143 g, 1.2 mol, 1.2 eq) in THF at such a rate that gentle refluxing was maintained. After the addition was complete the reaction mixture was stirred at ambient temperature for an hour and poured into ice-cold aqueous saturated ammonium chloride. Phases were separated and aqueous layer extracted two times with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous magnesium sulfate. After removal of the solvent title compound was purified by distillation under reduced pressure (145 g, 0.84 mol, 84%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[NH:10][C:9](=[O:11])[N:8]([C@@H:12]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]3)[C:5]2=[N:6][CH:7]=1.[H-].[Na+].[CH3:26]I>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[N:10]([CH3:26])[C:9](=[O:11])[N:8]([C@@H:12]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]3)[C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](n2c(=O)[nH]c3cc(Cl)cnc32)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1c(=O)n([C@@H]2CCN(C(=O)OC(C)(C)C)C2)c2ncc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 93.6 %

Procedure:
To a stirred solution of (R)-tert-butyl 3-(6-chloro-2-oxo-1H-imidazo[4,5-b]pyridin-3(2H)-yl)pyrrolidine-1-carboxylate (110 mg, 0.33 mmol) in dry THF (5 mL) was added 60% NaH in oil (20 mg, 0.5 mmol). The mixture was stirred at rt for 5 min and MeI (0.02 mL, 0.33 mmol) was added. The mixture was stirred overnight, diluted with EtOAc (100 mL), washed with brine (2×10 mL) and dried over Na2SO4. Removal of the solvent left an oil (118 mg) which was applied to a 2-g silica SPE cartridge. The cartridge was eluted sequentially with 0, 25, 50, 75 and 100% EtOAc in hexanes (15 mL of each) to afford 5 fractions. Fractions 2 & 3 were pooled and concentrated to give (R)-tert-butyl 3-(6-chloro-1-methyl-2-oxo-1H-imidazo[4,5-b]pyridin-3(2H)-yl)pyrrolidine-1-carboxylate (109 mg, 95%) as a red oil. LC-MS Method 1 tR=1.82 min, m/z=353, 279.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:26]=[O:27])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[C:16]([O:24][CH3:25])=[N:17][C:18]([CH3:23])=[N:19][C:20]=3[O:21][CH3:22])[CH2:12][CH2:13][CH2:14][N:7]21.C[Si](C)(C)[C:30]([F:33])([F:32])[F:31].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([O:24][CH3:25])=[N:17][C:18]([CH3:23])=[N:19][C:20]=4[O:21][CH3:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:26]([OH:27])[C:30]([F:33])([F:32])[F:31])=[CH:4][CH:3]=1
Reactant: COc1nc(C)nc(OC)c1N1CCCn2c1nc1c(Cl)ccc(C=O)c12
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1nc(C)nc(OC)c1N1CCCn2c1nc1c(Cl)ccc(C(O)C(F)(F)F)c12
Reaction time: 0.5 h
Yield: 86.8 %

Procedure:
To a stirred solution of 9-chloro-1-(4,6-dimethoxy-2-methylpyrimidin-5-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbaldehyde (433 mg, 1.12 mmol) and trimethyl(trifluoromethyl)silane (495 μL, 3.35 mmol) in tetrahydrofuran (6.0 mL) was added a solution of tetrabutylammonium fluoride in tetrahydrofuran (1.0 M, 112 μL, 0.112 mmol) at 0° C. After 30 min, hydrochloric acid (1.0 M, 2.5 mL) was added. After 1 h, the reaction mixture was diluted with ethyl acetate, washed with aqueous sodium hydrogen carbonate and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting solid was washed with diisopropyl ether to give the title compound as a pale yellow solid (445 mg, 0.972 mmol, 87%).
Reaction SMILES: O.[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]([OH:14])=O)[N:3]=1.Cl.[CH3:16][O:17][NH:18][CH3:19].C(N(CC)CC)C.O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>C(#N)C>[CH3:16][O:17][N:18]([CH3:19])[C:12]([C:4]1[N:3]=[CH:2][C:11]2[C:6]([CH:5]=1)=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:14]
Reactant: CNOC
Reactant: O=C(O)c1cc2ccccc2cn1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: CON(C)C(=O)c1cc2ccccc2cn1
Reaction time: 48 h
Yield: 37.4 %

Procedure:
In 50 mL of acetonitrile was dissolved 0.49 g (2.60 mmol) of isoquinoline-3-carboxylic acid monohydrate. To this 0.28 g (2.87 mmol) of O,N-dimethyl-hydroxylamine hydrochloride, 0.4 mL (2.87 mmol) triethylamine and 0.921 g (3.13 mmol) of 4-(4,6-dimethoxy-[1,3,5]triazin-2-yl)-4-methyl-morpholin-4-ium chloride hydrate were added and stirred for 2 days and then evaporated. A mixture of dichloromethane and water was added to it and the organic layer was evaporated and purified using flash chromatography (0-20% methanol in dichloromethane). Fractions containing pure product were evaporated to yield 210 mg of the free base as a white solid. LC-MSD, m/z for C12H12N2O2 [M+H]+: 217.4, [M+Na]+: 239.4
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]1[C:7](=[O:21])[O:8][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=2[O:19][CH3:20])[CH:10]=1)=[O:4]>O=O>[CH3:1][O:2][C:3]([NH:5][CH:6]([CH2:10][CH2:9][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=1[O:19][CH3:20])[C:7]([OH:21])=[O:8])=[O:4]
Reactant: COC(=O)NC1=CC(c2cccc(OC)c2OC)OC1=O
Agent: O=O
Product: COC(=O)NC(CCc1cccc(OC)c1OC)C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 3-methoxycarbonylamino-5-(2,3-dimethoxyphenyl)-2,5-dihydrofuran-2-one (500 mg, 1.7 mmoles) in oxygen free methanol (0.25M) is placed into a Parr hydrogenator, the catalyst (RR)-EtDiPhos(COD)OTs (1.5 μmoles) is added and the mixture is stirred for 1.5 hr at room temperature under hydrogen pressure (30 psi).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:8]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:7]2=[N:6][C:5]=1[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1.[N:21]1[CH:26]=[N:25][CH:24]=[N:23][C:22]=1[NH2:27]>>[CH3:13][C:10]1[CH:11]=[CH:12][C:7]2[N:8]([C:4]([CH2:3][NH:27][C:22]3[N:23]=[CH:24][N:25]=[CH:26][N:21]=3)=[C:5]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)[N:6]=2)[CH:9]=1
Reactant: Nc1ncncn1
Reactant: Cc1ccc(-c2nc3ccc(C)cn3c2CCl)cc1
Agent: Cl
Product: Cc1ccc(-c2nc3ccc(C)cn3c2CNc2ncncn2)cc1

Procedure:
The title compound was prepared according to Method A and the experimentals described for compound 139 from 3-(chloromethyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridine hydrochloride and 1,3,5-triazin-2-amine. M/e+ 331 for C19H19N6 (M+H)+; 1H-NMR (400 MHz, CDCl3) δ 8.71 (s, 1H), 8.51 (s, 1H), 8.24 (s, 1H), 7.94 (s, 1H), 7.65 (d, J=9.1 Hz, 1H), 7.58 (d, J=8.4 Hz, 2H), 7.26 (d, J=8.4 Hz, 2H), 7.14 (dd, J=9.1, 1.4 Hz, 1H), 5.06 (d, J=5.1 Hz, 2H), 2.39 (s, 3H), 2.32 (s, 3H) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:9](Cl)=[CH:10][C:11]([C:13]1[C:14]([Cl:20])=[N:15][C:16]([Cl:19])=[CH:17][CH:18]=1)=[O:12]>O1CCOCC1>[NH:1]([C:9]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[CH:10][C:11]([C:13]1[C:14]([Cl:20])=[N:15][C:16]([Cl:19])=[CH:17][CH:18]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(C=C(Cl)Cl)c1ccc(Cl)nc1Cl
Reactant: Nc1ccccc1
Solvent: C1COCCO1
Product: O=C(C=C(Nc1ccccc1)Nc1ccccc1)c1ccc(Cl)nc1Cl
Temperature: 0 °C
Reaction time: 8 h
Yield: 48.7 %

Procedure:
A solution of aniline (1.01 mL, 11.1 mmol) in TEA (1.55 mL, 11.1 mmol) was added slowly to a cooled (0° C.) and stirred solution of 3,3-dichloro-1-(2,6-dichloro-3-pyridinyl)-2-propen-1-one (1.0 g, 3.69 mmol) in dioxane (20 mL). The reaction was allowed to warm to room temperature and was stirred overnight. The mixture was concentrated in vacuo until most of the solvent was removed. The residue was diluted with water and extracted with EtOAc (3×). The combined organic extracts were washed with water, dried over Na2SO4 and concentrated in vacuo. Silica gel flash chromatography of the residue using 6:1 EtOAc:Hex gave 3,3-dianilino-1-(2,6-dichloro-3-pyridinyl)-2-propen-1-one as pale yellow solid (0.69 g, 49%): LCMS RT: 3.81 min; MH+: 384.2.
Reaction SMILES: [N:1]([CH:4]1[CH:7]([CH2:8][C:9](=[O:23])[C:10]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])=[N+]=[N-])[NH:6][C:5]1=[O:24])=[N+:2]=[N-:3]>C1C=CC=CC=1.C([O-])(=O)C.[Rh+3].C([O-])(=O)C.C([O-])(=O)C>[N:1]([CH:4]1[C:5](=[O:24])[N:6]2[CH:7]1[CH2:8][C:9](=[O:23])[CH:10]2[C:13]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:14])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NC1C(=O)NC1CC(=O)C(=[N+]=[N-])C(=O)OCc1ccccc1
Agent: [Rh+3]
Agent: CC(=O)[O-]
Solvent: c1ccccc1
Product: [N-]=[N+]=NC1C(=O)N2C(C(=O)OCc3ccccc3)C(=O)CC12
Temperature: 80 °C

Procedure:
A suspension of rhodium acetate (2 mg) and 3-azido-4-(3-benzyloxycarbonyl-3-diazo-2-oxopropyl)-azetidin-2-one (1 mmol) in anhydrous benzene (20 ml) is deoxygenated by bubbling nitrogen through it for 15 mins. The suspension is then stirred with heating in an oil bath at 80° C. for 30 min. After cooling to room temperature, the mixture is filtered and the filtrate is evaporated under vacuum to provide benzyl 6-azido-1-azabicyclo[3.2.0]heptan-3,7-dione-2-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([OH:11])=[N:7][NH:8]2)=[CH:4][CH:3]=1.Br[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N:19]=[C:20]=[O:21])[CH:14]=1>N1C=CC=CC=1.CCOC(C)=O>[CH:14]1[C:13]2[C:18](=[CH:10][CH:2]=[CH:3][CH:4]=2)[CH:17]=[CH:16][C:15]=1[NH:19][C:20]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)[C:6]([OH:11])=[N:7]1)=[O:21]
Reactant: Oc1n[nH]c2cc(Cl)ccc12
Reactant: O=C=Nc1cccc(Br)c1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=C(Nc1ccc2ccccc2c1)n1nc(O)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 157 %

Procedure:
2-Amino-4-chloro-benzoic acid (17.16 g, 100 mmol) was suspended in 90 ml of water and 20 ml of concentrated HCl. NaNO2 (6.9 g, 100 mmol) was dissolved in 15 ml water and added slowly at 0° C. The mixture was stirred at 0° C. for 30 minutes and Na2SO3 (34.0 g, 270 mmol) were added, dissolved in 150 ml water. The mixture was then stirred for 2 hours at room temperature. 30 ml of concentrated HCl were added and the mixture stirred overnight at room temperature and then at 80° C. for 2 hours. The solution is treated with aqueous NaOH until the pH is 5.5 and the precipitated was filtered and triturated with ethanol to yield 13.8 g (82%) of 6-chloro-1H-indazol-3-ol. 6-Chloro-1H-indazol-3-ol (700 mg, 4.15 mmol) was dissolved in 25 ml pyridine together with 1-bromo-3-isocyanato-benzene (990 mg, 5 mmol) and stirred at RT for 4 hours. The mixture was then diluted with EtOAc (100 ml) and washed 2× with 1 M HCl. The organic phase was dried with Na2SO4 and reduced under vacuum. The residue was now dissolved in 1 M NaOH and washed with EtOAc and then precipitated with HCl and the precipitate extracted into EtOAc, dried and reduced under vacuum. The product was then recrystallised from EtOAc and heptane to yield 1.1 g (79%) of crystalline solid (m.p. 223-225° C.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:12]\[C:13]1[NH:17][C:16]([CH3:18])=[C:15]([C:19](O)=[O:20])[C:14]=1[CH3:22].Cl.O[N:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33]C=2N=N1.[NH2:34][CH2:35][CH2:36]C1C=CC=CN=1>CN(C=O)C.C([O-])(O)=O.[Na+].O.C(Cl)CCl>[N:25]1([CH2:36][CH2:35][NH:34][C:19]([C:15]2[C:14]([CH3:22])=[C:13](/[CH:12]=[C:5]3\[C:6](=[O:11])[NH:7][C:8]4[C:4]\3=[CH:3][C:2]([F:1])=[CH:10][CH:9]=4)[NH:17][C:16]=2[CH3:18])=[O:20])[CH:29]=[CH:30][CH:31]=[CH:32][CH2:33]1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)O
Reactant: NCCc1ccccn1
Reactant: On1nnc2ccccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)NCCN1C=CC=CC1

Procedure:
5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (120 mg, 0.4 mmol) was shaken with EDC, HCl (96 mg, 0.5 mmol), anhydrous 1-hydroxy-benztriazole (68 mg, 0.5 mmol), and 2-(2-aminoethylpyridine purchased from Aldrich in anhydrous DMF (3 mL) for 2–3 days at room temperature. The reaction mixture was diluted with 1M NaHCO3 (1.5 ml), then with 8 ml of water. The precipitated crude product was collected by filtration, washed with water, dried and purified by crystallization or chromatography to give 5-[5-fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid [2-(pyridin-1-yl)-ethyl]amide.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:6])[CH2:4]Cl.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([SH:15])[CH:12]=[CH:13][CH:14]=1.[OH-].[Na+]>CO.O.O>[Cl:1][CH2:2][C:3](=[O:6])[CH2:4][S:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH3:7])[CH:10]=1
Reactant: O=C(CCl)CCl
Reactant: COc1cccc(S)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cccc(SCC(=O)CCl)c1
Temperature: 0 °C
Reaction time: 10 h

Procedure:
To a stirred solution of 1,3-dichloro-2-propanone (12.70 g, 0.1 mol) in methanol/water (100 ml, 1:3) at 0° C. is added a suspension of 3-methoxybenzenethiol (14.02 g, 0.1 mol) and sodium hydroxide (4.00 g, 0.10 g) in water (100 ml). The mixture is stirred at 0° C. for 7 h and at mom temperature for 10 h. The precipitated product is extracted with dichloromethane (100 ml), washed with water (80 ml), and dried with sodium sulfate. After removal of the solvent, we obtained the good product (oil, 18.70 g).