Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]=[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[SH:4](=[O:17])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:3]1.[C:18](Cl)(=[O:21])[CH2:19][CH3:20].C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:18]([N:1]=[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[SH:4](=[O:17])([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:3]1)(=[O:21])[CH2:19][CH3:20]
Reactant: CCC(=O)Cl
Reactant: N=C1N[SH](=O)(c2ccccc2)c2ccccc21
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCC(=O)N=C1N[SH](=O)(c2ccccc2)c2ccccc21

Procedure:
From 12 g. 3-imino-1-phenyl-3H-1,2-benzisothiazole-1-oxide, 5 g. propionyl chloride and 6.6 g. triethylamine in chloroform, there is obtained, after heating under reflux for 3 hours and then working up the reaction mixture in the usual manner, the desired 3-(propionyl-imino)-1-phenyl-3H-1,2-benzisothiazole-1-oxide which, after recrystallisation from ethyl acetate, melts at 170°C.
Reaction SMILES: [CH2:1]([O:3][C@H:4]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][S:34]([CH3:37])(=[O:36])=[O:35])=[CH:29][CH:28]=2)=[CH:20][CH:19]=1)[C:5]([NH:7][C@H:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:9][OH:10])=[O:6])[CH3:2]>CCCCCCC>[CH2:1]([O:3][C@@H:4]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][C:27]2[CH:28]=[CH:29][C:30]([O:33][S:34]([CH3:37])(=[O:35])=[O:36])=[CH:31][CH:32]=2)=[CH:20][CH:19]=1)[C:5]([NH:7][C@H:8]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH2:9][OH:10])=[O:6])[CH3:2]
Reactant: CCO[C@H](Cc1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)cc1)C(=O)N[C@@H](CO)c1ccccc1
Solvent: CCCCCCC
Product: CCO[C@@H](Cc1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)cc1)C(=O)N[C@@H](CO)c1ccccc1
Yield: 38 %

Procedure:
A solution of 2-ethoxy-3-[4-(2-{4-methanesulfonyloxyphenyl} ethoxy)phenyl]propanoic acid (10.5 g; 25.7 mmole) in dry dichloromethane (150 ml) was cooled on an ice-bath and EDC (5.42 g; 28.3 mmole), diisopropylethylamine (4.8 ml; 28.3 mmole) and HOBtxH2O (3.82 g; 28.3 mmole) were added. After 20 minutes the ice-bath was removed and (R)-phenylglycinol (3.88 g; 28.3 mmole) was added. After stirring at room temperature over night dichloromethane (100 ml), citric acid (60 ml, 10%) and ethyl acetate were added and the phases were separated. The organic phase was washed with citric acid (60 ml), sodium bicarbonate (2×60 ml) and brine (60 ml), dried (sodium sulfate), filtered and the solvent evaporated in vacuo. The crude product was crystallized twice in ethyl acetate/heptan to give 4.43 g of (R)-2-ethoxy-N-(2-hydroxy-(R)-1-phenylethyl)-3-[4-(2-{4-methanesulfonyloxyphenyl}ethoxy)phenyl]propanoic amide. The mother liquids were combined, the solvent was evaporated in vacuo and the residue was purified by chromatography on silica gel using ethyl acetate:heptan (gradient 25 to 100% ethyl acetate) to give 5.14 g (yield 38%) of (S)-2-ethoxy-N-(2-hydroxy-(R)-1-phenylethyl)-3-[4-(2-{4-methanesulfonyloxyphenyl}ethoxy)-phenyl]propanoic amide and 0.51 g (totally 4.94 g, yield 36%) of (R)-2-ethoxy-N-(2-hydroxy-(R)-1-phenylethyl)-3-[4-(2-{4-methanesulfonyloxyphenyl}-ethoxy)phenyl]propanoic amide.
Reaction SMILES: [Si:1]([O:8][C@H:9]([CH2:27][OH:28])[C@@H:10]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(Cl)Cl.N1C=CC=CC=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O>CCOC(C)=O>[Si:1]([O:8][C@H:9]([CH:27]=[O:28])[C@@H:10]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccc(F)c1)[C@@H](CO)O[Si](C)(C)C(C)(C)C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cccc(F)c1)[C@@H](C=O)O[Si](C)(C)C(C)(C)C
Temperature: 23 °C
Reaction time: 0.03 h

Procedure:
To a 150 mL RBF containing tert-butyl(2S,3S)-3-(tert-butyldimethylsilyloxy)-1-(3-fluorophenyl)-4-hydroxybutan-2-ylcarbamate (170.00 mg, 411 μmol) was added DCM (10 mL) and the mixture was allowed to stir at 23° C. for 2 minutes. At this time, pyridine (299 μl, 3699 μmol) was added via syringe before the addition of Dess-MartinPeriodinane (262 mg, 617 μmol) in one portion. The reaction stayed a clear solution and was allowed to stir 1 h before loading directly to a silica gel column (20% EtOAc). The purified product was concentrated to give the title compound as a colorless oil.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH:17][C:18](=[O:28])[CH2:19][O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:14]=2O)[CH2:9][CH2:8]1)(=[O:3])[CH3:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C(C)=CC=CC=1>[CH2:21]([O:20][CH2:19][C:18]1[O:28][C:14]2[C:15]3[CH:7]([CH2:6][CH2:5][NH:4][C:1](=[O:3])[CH3:2])[CH2:8][CH2:9][C:10]=3[CH:11]=[CH:12][C:13]=2[N:17]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(=O)NCCC1CCc2ccc(NC(=O)COCc3ccccc3)c(O)c21
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1C
Product: CC(=O)NCCC1CCc2ccc3nc(COCc4ccccc4)oc3c21
Yield: 23.5 %

Procedure:
N-{3-[2-(Acetylamino)ethyl]-4-hydroxy-2,3-dihydro-1H-inden-5-yl}-2-(benzyloxy)acetamide (280 mg, 0.732 mmol) and pyridinium p-toluenesulfonate (36.6 mg, 0.146 mmol) were heated under reflux in xylene (15 mL) for 2.5 hr. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane=30/70→60/40) to give the title compound (62.8 mg, yield 23%).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Cl.[NH2:8][OH:9].[CH3:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14]Br>CN(C)C=O>[CH3:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14][N:8]([CH2:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:13]([CH3:14])[CH:12]=1)[OH:9]
Reactant: Cc1cccc(CBr)c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(CN(O)Cc2cccc(C)c2)c1
Yield: 49.4 %

Procedure:
The procedure of Example 1 is repeated using 21.2 g of sodium carbonate, 3.47 g of hydroxylamine hydrochloride and 18.51 g m-methylbenzyl bromide in 75 ml of dimethylformamide. Recrystallization from ethanol affords 5.95 g of the title hydroxylamine as a white solid, mp 70°-73° C.
Reaction SMILES: Cl.Cl.[C@H:3]1([CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:16][CH2:15]2)[C@@H]2N(CCCC2)CCC1.Cl.Cl.Cl.NC1CCN(CC[N:55]2[CH2:60][CH2:59][C@H:58]([OH:61])[C@@H:57]([CH3:62])[CH2:56]2)CC1>>[OH:61][C@H:58]1[CH2:59][CH2:60][N:55]([CH2:3][CH2:13][N:14]2[CH2:15][CH2:16][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:18][CH2:19]2)[CH2:56][C@@H:57]1[CH3:62]
Reactant: O=C(NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1)c1cc2c(OCc3coc4ccccc34)cccc2[nH]1
Reactant: C[C@H]1CN(CCN2CCC(N)CC2)CC[C@@H]1O
Agent: Cl
Product: C[C@H]1CN(CCN2CCC(NC(=O)c3cc4c(OCc5coc6ccccc56)cccc4[nH]3)CC2)CC[C@@H]1O

Procedure:
This compound is synthesized analogously to example 1 from 4-(benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (105, see example 50) and amine 14.
Reaction SMILES: [Br:1][CH:2]1[CH:12]([Br:13])[CH2:11][CH2:10][CH:4]2[C:5]([NH:7][C:8](=[O:9])[CH:3]12)=[O:6].N1C=CC=CC=1.[Br:20][C:21]1[C:29]([Br:30])=[CH:28][C:27]([Br:31])=[CH:26][C:22]=1[C:23](Cl)=[O:24]>C1C=CC=CC=1>[Br:20][C:21]1[C:29]([Br:30])=[CH:28][C:27]([Br:31])=[CH:26][C:22]=1[C:23]([N:7]1[C:8](=[O:9])[CH:3]2[CH:2]([Br:1])[CH:12]([Br:13])[CH2:11][CH2:10][CH:4]2[C:5]1=[O:6])=[O:24]
Reactant: O=C(Cl)c1cc(Br)cc(Br)c1Br
Reactant: O=C1NC(=O)C2C1CCC(Br)C2Br
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: O=C(c1cc(Br)cc(Br)c1Br)N1C(=O)C2CCC(Br)C(Br)C2C1=O
Temperature: 25 °C

Procedure:
3,4-Dibromohexahydrophthalimide (0.10 mole), benzene (300 ml) and pyridine (0.11 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2,3,5-Tribromobenzoyl chloride (0.10 mole) is then added dropwise to the flask with stirring at room temperature. After the addition is completed the reaction mixture is heated at reflux with continued stirring for a period of about 1 hour. After this time the reaction mixture is filtered and the filtrate is washed with water. The washed filtrate is then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product N-(2,3,5-tribromobenzoyl)-3,4-dibromohexahydrophthalimide.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6](Cl)=[N:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:21][CH3:22])=[O:4].[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH2:21]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:8]=1[N:7]=[C:6]([N:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)[C:5]([C:3]([OH:4])=[O:2])=[C:14]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:22]
Reactant: C1CCNC1
Reactant: CCc1cccc2c(-c3ccccc3)c(C(=O)OC)c(Cl)nc12
Product: CCc1cccc2c(-c3ccccc3)c(C(=O)O)c(N3CCCC3)nc12

Procedure:
The title compound was prepared in analogy to example 43 step E from 2-chloro-8-ethyl-4-phenyl-quinoline-3-carboxylic acid methyl ester (prepared as described in example 43 step D) and pyrrolidine. Yellow solid. MS (ESI): 347.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3]([C:22](OCC)=[O:23])=[CH:4][N:5]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1.C1(C)C=CC=CC=1>[F:1][C:2]1[C:3]([CH2:22][OH:23])=[CH:4][N:5]([S:13]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)(=[O:15])=[O:14])[C:6]=1[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(=O)c1cn(S(=O)(=O)c2ccccc2)c(-c2ccccc2)c1F
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccccc1)n1cc(CO)c(F)c1-c1ccccc1
Temperature: -70 °C
Reaction time: 1 h
Yield: 75.1 %

Procedure:
A solution (10 mL) of ethyl 4-fluoro-5-phenyl-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate (60 mg) in tetrahydrofuran was cooled to −70° C., and a 1.5 mol/L solution (0.5 mL) of diisobutylaluminum hydride in toluene was added dropwise by small portions. The mixture was further stirred at −70° C. for 1 hr, 1 mol/L hydrochloric acid (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=7:3) to give the title compound as a colorless oil (yield 40 mg, 75%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]=[C:3]([C:7]2[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=2)[CH2:2]1>C1COCC1.[Pd]>[F:13][C:8]1[C:7]([CH:3]2[CH2:4][CH2:5][CH2:6][O:1][CH2:2]2)=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: Fc1ncccc1C1=CCCOC1
Agent: [Pd]
Solvent: C1CCOC1
Product: Fc1ncccc1C1CCCOC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Palladium (0.005 g, 0.005 mmol, 10% wt. on activated carbon) was added to a stirred solution of 3-(5,6-dihydro-2H-pyran-3-yl)-2-fluoropyridine (0.10 g, 0.558 mmol) in THF (2 mL). The reaction mixture was placed under a hydrogen atmosphere (balloon) and stirred at room temperature for 4 h. The reaction mixture was filtered through Celite, and the filtrate was concentrated in vacuo to give 2-fluoro-3-(tetrahydro-2H-pyran-3-yl)pyridine. MS (ESI, pos. ion) m/z: 182.1 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[N:4][CH:3]=1.[Cl:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[C:22]([F:27])[CH:21]=1>CN(C=O)C>[Cl:19][C:20]1[CH:26]=[CH:25][C:23]([NH:24][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[N:4][CH:3]=2)=[C:22]([F:27])[CH:21]=1
Reactant: Nc1ccc(Cl)cc1F
Reactant: COCCOc1cc2nncc(Cl)c2cc1OC
Solvent: CN(C)C=O
Product: COCCOc1cc2nncc(Nc3ccc(Cl)cc3F)c2cc1OC

Procedure:
A solution of 4-chloro-6-methoxy-7-(2-methoxyethoxy)cinnoline (0.4 g, 1.5 mmol), (prepared as described for the starting material in Example 2), and 4-chloro-2-fluoroaniline (282 μl, 2.5 mmol) in DMF (5 ml) was treated as described in Example 2, to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-methoxyethoxy)cinnoline as the hydrochloride salt (450 mg, 72%).
Reaction SMILES: [C:1](Cl)(=O)[C:2](Cl)=O.[Na].O[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]1=[S:15]>C1C=CC=CC=1.CN(C=O)C.CN(C1C=CN=CC=1)C>[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15][C:2]1[CH:1]=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: On1ccccc1=S
Reactant: O=C(Cl)C(=O)Cl
Agent: CN(C)c1ccncc1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: c1ccc(Sc2ccccn2)nc1
Yield: 72 %

Procedure:
360 mg (1 mmol) of peracetoquinic acid (32) are taken into solution with stirring in 5 ml of benzene with the addition of 1 ml of oxalyl chloride and 1 drop of DMF for 3 hours. After evaporation to dryness, the residue is taken up in 5 ml of benzene and added with stirring to a suspension of 180 mg (1.1 mmol) of the sodium salt of N-hydroxypyridine-2-thione and 12 mg (0.1 mmol) of DMAP. The reaction mixture is kept refluxing in 10 ml of toluuene under an atmosphere of nitrogen. After 2 hours of heating under reflux, the cooled reaction mixture is filtered on Celite and evaporated to dryness. By flash chromatography on silica (90% of CH2Cl2 ; 10% EtOAc), 306 mg of pyridyl sulfide of formula (34) are obtained in the form of a yellowish oil. Yield 72%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:26]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:27])[C:5]([C:17]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:18])=[C:6]([C:8]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])[CH:7]=1.[Cl:35][C:36]1[C:45]2[C:44]([S:46](Cl)(=[O:48])=[O:47])=[CH:43][C:42]([S:50](Cl)(=[O:52])=[O:51])=[CH:41][C:40]=2[C:39]([S:54](Cl)(=[O:56])=[O:55])=[CH:38][CH:37]=1>N1C=CC=CC=1>[Cl:35][C:36]1[CH:37]=[CH:38][C:39]([S:54]([NH:1][C:2]2[CH:7]=[C:6]([C:8]([O:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:9])[C:5]([C:17]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:18])=[C:4]([C:26]([O:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[O:27])[CH:3]=2)(=[O:56])=[O:55])=[C:40]2[C:45]=1[C:44]([S:46]([NH:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[O:9])[C:5]([C:17]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:18])=[C:4]([C:26]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:27])[CH:3]=1)(=[O:48])=[O:47])=[CH:43][C:42]([S:50]([NH:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[O:9])[C:5]([C:17]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:18])=[C:4]([C:26]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:27])[CH:3]=1)(=[O:52])=[O:51])=[CH:41]2
Reactant: Nc1cc(C(=O)Oc2ccccc2)c(C(=O)Oc2ccccc2)c(C(=O)Oc2ccccc2)c1
Reactant: O=S(=O)(Cl)c1cc(S(=O)(=O)Cl)c2c(Cl)ccc(S(=O)(=O)Cl)c2c1
Solvent: c1ccncc1
Product: O=C(Oc1ccccc1)c1cc(NS(=O)(=O)c2cc(S(=O)(=O)Nc3cc(C(=O)Oc4ccccc4)c(C(=O)Oc4ccccc4)c(C(=O)Oc4ccccc4)c3)c3c(Cl)ccc(S(=O)(=O)Nc4cc(C(=O)Oc5ccccc5)c(C(=O)Oc5ccccc5)c(C(=O)Oc5ccccc5)c4)c3c2)cc(C(=O)Oc2ccccc2)c1C(=O)Oc1ccccc1

Procedure:
To a stirred solution of 13.6 g. of 5-amino-1,2,3-benzenetricarboxylic acid, triphenyl ester (U.S. Pat. No. 4,087,613) in 45 ml. of dry pyridine is added 4.58 g. of 8-chloro-1,3,5-naphthalenetrisulfonyl chloride, and the mixture is heated at 60°-70° C. for three hours. The cooled solution is added slowly with vigorous stirring to 300 ml. of ice-water, and the resulting solid is collected by filtration, washed with water, and dried. The solid is dissolved in methylene chloride, washed with water, and dried. The extract is concentrated to a volume of 80 ml. and passed through a bed of hydrous magnesium silicate. Evaporation of the filtrate with the addition of ether gives a solid, which is purified by chromatography on silica gel giving 7.8 g. of a light yellow solid.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([S:19][C:20]2[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][CH:21]=2)[C:6]([NH:9][C:10]2[S:11][C:12]3[C:17]([N:18]=2)=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:7][CH:8]=1.[OH-].[Na+]>CO>[Br:2][C:3]1[CH:4]=[C:5]([S:19][C:20]2[CH:29]=[CH:28][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=2)[C:6]([NH:9][C:10]2[S:11][C:12]3[C:17]([N:18]=2)=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:7][CH:8]=1
Reactant: COC(=O)c1ccc(Sc2cc(Br)cnc2Nc2nc3cccnc3s2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(Sc2cc(Br)cnc2Nc2nc3cccnc3s2)cc1
Yield: 70 %

Procedure:
Heated a mixture of methyl 4-(5-bromo-2-(thiazolo[5,4-b]pyridin-2-ylamino)pyridin-3-ylthio)benzoate hydrochloride (0.570 g, 1.12 mmol), 1N aqueous sodium hydroxide (2.80 mL, 2.80 mmol), and methanol (6 mL) at 65° C. for an hour. Cooled, and partitioned between saturated NH4Cl (30 mL), 1N HCl (3 mL), water (10 mL) and chloroform. The mixture was filtered, washed with water, and dried to afford the title compound (0.360 g, 70.1% yield). 1H NMR (d-DMSO) δ 7.35 (dd, 1H), 7.43 (d, 2H), 7.50 (s, 1H), 7.67 (d, 1H), 7.94 (d, 2H), 8.44 (s, 1H).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:15]=[CH:14][C:8]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:7][CH:6]=1.I[CH3:17]>>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]([CH3:17])[C:11](=[O:13])[CH3:12])=[CH:14][CH:15]=1
Reactant: COc1ccc(CNC(C)=O)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(CN(C)C(C)=O)cc1
Reaction time: 8 h
Yield: 90 %

Procedure:
Sodium hydride (60% in mineral oil) (1.11 grams, 27.4 mmol) was measured into a round bottom flask and triturated with hexanes. To this was added pure N-(4-methoxybenzyl)-acetamide (1.23 grams, 6.9 mmol) followed by iodomethane (1.95 grams, 13.7 mmol)and the resulting mixture stirred overnight. The reaction was filtered and the solvent removed under vacuum. The crude product was purified by flash column chromatography (SiO2, 2% EtOH in methylene chloride) to yield 1.2 grams of a colorless oil. HRMS (M+H) calcd for C11H16NO2: 194.1181; found: 194.1177. 1H NMR and 13C NMR show a mixture of rotamers at room temperature. 1H NMR (500 MHz, CDCl3) δ: 2.13 (s), 2.15 (s), 2.89 (s), 2.90 (s), 3.78 (s), 3.80 (s), 4.45 (s), 4.50 (s), 6.86 (m), 7.08 (d, J=9), 7.17 (d, J=9). 13C NMR (125 MHz, CDCl3) δ: 21.50, 21.91, 33.49, 35.33, 49.95, 53.72, 55.28, 113.95, 114.32, 127.66, 128.46, 129.44, 129.52, 158.95, 159.13, 170.63, 170.91.
Reaction SMILES: [CH2:1]([C:4]1[C:12]([O:13][CH3:14])=[CH:11][C:10]([CH3:15])=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:2]=[CH2:3]>C(O)(C(F)(F)F)C(F)(F)F.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:14][O:13][C:12]1[C:4]([CH:1]=[CH:2][CH3:3])=[C:5]2[C:9](=[C:10]([CH3:15])[CH:11]=1)[N:8]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH:7]=[CH:6]2
Reactant: C=CCc1c(OC)cc(C)c2c1ccn2C(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: OC(C(F)(F)F)C(F)(F)F
Product: CC=Cc1c(OC)cc(C)c2c1ccn2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of tert-Butyl 4-allyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (9.8 g, 32.5 mmol) in 1,1,1,3,3,3-hexafluoro-propanol (HFIPA) (40.6 mL) was added to palladium(II) acetate (0.073 g, 0.325 mmol) in 4 mL of HFIPA. The reaction was stirred at room temperature for 4 hours. The reaction was concentrated and absorbed onto silica and then purified by silica gel flash chromatography (0-30% ethyl acetate/heptanes) to provide the title compound. MS (ESI+) m/z 302.25 (M+H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][CH2:7][CH2:8][O:9][C:10]1[N:15]=[C:14]([C:16]([NH:18][O:19][CH3:20])=[O:17])[CH:13]=[C:12]([N:21]2[CH2:26][CH2:25][CH:24]([NH:27][C:28]([C:30]3[NH:31][C:32]([CH3:37])=[C:33]([Cl:36])[C:34]=3[Cl:35])=[O:29])[CH2:23][CH2:22]2)[N:11]=1>CN(C=O)C>[Cl:35][C:34]1[C:33]([Cl:36])=[C:32]([CH3:37])[NH:31][C:30]=1[C:28]([NH:27][CH:24]1[CH2:23][CH2:22][N:21]([C:12]2[N:11]=[C:10]([O:9][CH2:8][CH2:7][NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[N:15]=[C:14]([C:16]([NH:18][O:19][CH3:20])=[O:17])[CH:13]=2)[CH2:26][CH2:25]1)=[O:29]
Reactant: CS(=O)(=O)Cl
Reactant: CONC(=O)c1cc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)nc(OCCN)n1
Solvent: CN(C)C=O
Product: CONC(=O)c1cc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)nc(OCCNS(C)(=O)=O)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 30.1 %

Procedure:
Methane sulfonyl chloride (0.032 ml, 0.412 mmol) was added dropwise to a solution of 2-(2-aminoethoxy)-6-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-N-methoxypyrimidine-4-carboxamide (Example 319, 0.20 g, 0.412 mmol), TEA (0.11 ml, 0.824 mmol) and DMF (3 ml) at 0° C. The reaction was stirred for 15 minutes at 0° C. then quenched with water. The aqueous phase was extracted with EtOAc, washed with saturated sodium bicarbonate solution, water and brine. It was dried over magnesium sulfate and concentrated to give brown solid, which was purified by reverse phase HPLC (30% to 35% acetonitrile in water, 0.1% TFA) affording the title compound (70 mg).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:21][C:22]1[N:27]=[CH:26][C:25]2[C:28](=O)[O:29][CH:30]([CH2:31][CH3:32])[C:24]=2[CH:23]=1.Cl>C1COCC1>[Cl:21][C:22]1[N:27]=[CH:26][C:25]2[C:28](=[C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][C:2]3=[O:10])[O:29][CH:30]([CH2:31][CH3:32])[C:24]=2[CH:23]=1
Reactant: CCC1OC(=O)c2cnc(Cl)cc21
Reactant: O=C1Cc2ccccc2N1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC1OC(=C2C(=O)Nc3ccccc32)c2cnc(Cl)cc21
Temperature: 95 °C
Reaction time: 4.5 h
Yield: 67.4 %

Procedure:
A solution of 1,3-dihydro-indol-2-one (650 mg, 4.77 mmol.) in THF (10 mL) is cooled to 0° C. under an argon atmosphere and treated with a solution of lithium bis(trimethylsilyl)amide (9.6 mL of a 1 M solution in THF, 9.6 mmol) dropwise. The ice bath is removed and 6-chloro-1-ethyl-1H-furo[3,4-c]pyridin-3-one (630 mg, 3.18 mmol) is added directly as a solid. The resulting solution is stirred for 4.5 h. The reaction mixture is poured into aqueous 10% HCl solution (100 mL) and stirred at room temperature for 10 min and then heated at 90-100° C. for 2 h. The reaction mixture is cooled to room temperature for 36 h during which time a precipitate formed. The precipitate which formed is collected by filtration and dried to give the title compound as an orange solid (670 mg, 67%).
Reaction SMILES: [N+:1]([CH2:4][CH3:5])([O-:3])=O.C(N(CC)CC)C.[C:13]([C:15]1[CH:24]=[C:23]2[C:18]([C:19](=[O:37])[C:20]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:21][N:22]2[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[CH:17][CH:16]=1)#[CH:14].C1(N=C=O)C=CC=CC=1>C(Cl)(Cl)Cl>[F:31][C:28]1[CH:27]=[CH:26][C:25]([N:22]2[C:23]3[C:18](=[CH:17][CH:16]=[C:15]([C:13]4[O:3][N:1]=[C:4]([CH3:5])[CH:14]=4)[CH:24]=3)[C:19](=[O:37])[C:20]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:21]2)=[CH:30][CH:29]=1
Reactant: C#Cc1ccc2c(=O)c(C(=O)OCC)cn(-c3ccc(F)cc3)c2c1
Reactant: CC[N+](=O)[O-]
Solvent: ClC(Cl)Cl
Solvent: O=C=Nc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn(-c2ccc(F)cc2)c2cc(-c3cc(C)no3)ccc2c1=O
Yield: 70.2 %

Procedure:
A solution of 9.8 g nitroethane and 13 ml triethylamine in 130 ml chloroform was added dropwise to a solution of 10.47 g ethyl 1,4-dihydro-7-ethynyl-1-(4- fluorophenyl)-4-oxo-3-quinolinecarboxylate and 15.5 g phenyl isocyanate in 80 ml chloroform over a period ofconcentrated in vacuo. The residue was crystallized in ether and recrystallized from acetonitrile to give 8.60 g ethyl 1,4-dihydro-1-(4-fluorophenyl)-7-(3-methyl-5-isoxazolyl)4 -oxo-3-quinolinecarboxylate (yellow solid, m.p. 214°-216° C.).