Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:8])=[O:4].[CH2:16]([NH:18][CH2:19][CH3:20])[CH3:17].Cl.C(NCC)C>C1C=CC=CC=1.CCOCC>[CH2:16]([N:18]([CH2:19][CH3:20])[CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:8])=[O:4])[CH3:17]
Reactant: O=C(CCl)NCC(=O)Nc1ccccc1
Reactant: CCNCC
Agent: Cl
Solvent: c1ccccc1
Solvent: CCOCC
Product: CCN(CC)CC(=O)NCC(=O)Nc1ccccc1

Procedure:
A solution of chloroacetylglycineanilide (10.0 g; 0.0443 mole) and diethylamine (9.7 g; 0.133 mole) in benzene (125 ml) was heated under reflux for 5 hours. The solution was cooled and diluted with ether (125 ml) whereby a crystalline mixture of diethylamine hydrochloride and N,N-diethylglycylglycineanilide (as base) was obtained. The mixture was shaken with cold water (2 × 100 ml) and the crystalline residue was recrystallized from water-isopropanol. The desired compound melted at 162°-164°C. Yield: 2.6 g (22.3 %).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[O:13]1[C:17]2([CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[O:16][CH2:15][CH2:14]1.CC(C)([O-])C.[Na+].C(OCC)(=O)C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:10][C:9]([F:12])([F:11])[O:8][C:5]1[CH:6]=[CH:7][C:2]([N:20]2[CH2:21][CH2:22][C:17]3([O:16][CH2:15][CH2:14][O:13]3)[CH2:18][CH2:19]2)=[CH:3][CH:4]=1
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Reactant: C1CC2(CCN1)OCCO2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: FC(F)(F)Oc1ccc(N2CCC3(CC2)OCCO3)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 82.5 %

Procedure:
A mixture of 1-bromo-4-(trifluoromethoxy)-benzene (6.3 g, 26.14 mmol), 1,4-dioxa-8-azaspiro-[4,5]decane (3.35 ml, 26.14 mmol), palladium acetate (60 mg, 0.26 mmol), (S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP) (244 mg, 0.39 mmol), and sodium tert-butoxide (3.77 g, 39.23 mmol) in toluene (50 ml) was stirred at 80° C. for 1 hour. The reaction mixture was allowed to return to room temperature, to which ethyl acetate (50 ml) was added, and the resulting mixture was then filtered. The filtrate was washed with water and brine, and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=50/1) to afford 8-(4-trifluoromethoxyphenyl)-1,4-dioxa-8-azaspiro[4,5]decane (6.54 g, yield 83%) as a pale yellow powder.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[CH2:5]([O:7][C:8]([C:10]1[C:11]([CH3:25])=[N:12][S:13][C:14]=1[NH:15][C:16]([O:18]C1C=CC=CC=1)=O)=[O:9])[CH3:6]>C(O)C>[CH2:5]([O:7][C:8]([C:10]1[C:11]([CH3:25])=[N:12][S:13][C:14]=1[NH:15][C:16]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:18])=[O:9])[CH3:6]
Reactant: CCOC(=O)c1c(C)nsc1NC(=O)Oc1ccccc1
Reactant: CC(C)N
Solvent: CCO
Product: CCOC(=O)c1c(C)nsc1NC(=O)NC(C)C

Procedure:
A solution of isopropylamine in ethanol (33% w/v; 30 ml.) was added, cautiously with swirling, to 4-ethoxycarbonyl-3-methyl-5-phenoxycarbonylaminoisothiazole (prepared according to the method of Goerdeler and Horn, Chemische Berichte, 1963, 96, 1551; 30 g.). When the initial exothermic reaction had subsided the mixture was heated at reflux for 10 minutes, cooled and filtered. The solid was washed with water, and dried to give 1-(4-ethoxycarbonyl-3-methylisothiazol-5-yl)-3-isopropylurea (20.8 g.), m.p. 175°-176° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][N:10]1[C:14]([CH2:15]Cl)=[CH:13][N:12]=[C:11]1[S:17][CH2:18][CH2:19][CH3:20].[C:21]([NH:24][CH:25](C(OCC)=O)[C:26]([O:28]CC)=[O:27])(=[O:23])[CH3:22].[Na].[H-].[Na+].C(NC(C(OCC)=O)C(OCC)=O)(=O)C.C([O-])(=O)CC([O-])=O.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.C(O)C.O>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][N:10]1[C:14]([CH2:15][C@@H:25]([C:26]([OH:28])=[O:27])[NH:24][C:21](=[O:23])[CH3:22])=[CH:13][N:12]=[C:11]1[S:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCSc1ncc(CCl)n1Cc1ccccc1Cl
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: Cl
Agent: O=C([O-])CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: O
Product: CCCSc1ncc(C[C@H](NC(C)=O)C(=O)O)n1Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Crude 1-(2-chlorophenyl)methyl-5-chloromethyl-2-propylthio-1H-imidazole hydrochloride (0.3 g, 0.853 mmole) in dimethyl formamide (2 mL) was added to sodium diethyl acetamidomalonate (prepared by introducing sodium hydride (2.84 mmol) to a solution of diethyl acetamidomalonate (0.415 g, 1.91 mmol) in dimethyl formamide (3mL)). The mixture was stirred under argon at 25° C. for 18 hours, poured into water and the product was extracted into methylene chloride. The water-washed organic extracts were dried and concentrated in vacuo to a light orange product. This crude product was purified over silica gel with 1:1 hexane/ethyl acetate to afford 0.27 g of the malonate addition product. This product was hydrolyzed in 50% aqueous ethanol (20 mL) and sodium carbonate (0.85 g) in water (20 mL) on the steam bath for 3 hours. The reaction mixture was poured into water and extracted with methylene chloride. The washed, dried, concentrated product (0.23 g) was purified by prep TLC on silica gel with a system of 15% methanol in chloroform containing 0.5% of formic acid to provide 0.13 g of 3-[(2-chlorophenyl)methyl]-2-propylthio-N-acetylhistidine as an amorphous solid; m.p. 182°-184° C.
Reaction SMILES: [C:1]1([C:7](=[O:12])[CH2:8][C:9](=[O:11])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]1([CH3:25])[CH:18]=[CH:17][C:16]([S:19]([N:22]=[C:23]=[O:24])(=[O:21])=[O:20])=[CH:15][CH:14]=1>C1C=CC=CC=1>[C:1]1([C:7](=[O:12])[CH:8]([C:23](=[O:24])[NH:22][S:19]([C:16]2[CH:17]=[CH:18][C:13]([CH3:25])=[CH:14][CH:15]=2)(=[O:20])=[O:21])[C:9](=[O:11])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)CC(=O)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Solvent: c1ccccc1
Product: CC(=O)C(C(=O)NS(=O)(=O)c1ccc(C)cc1)C(=O)c1ccccc1

Procedure:
Reaction of equimolar amounts of 1-phenyl-1,3-butanedione with p-toluenesulfonylisocyanate in benzene according to the procedure of Example 1 affords 1-PHENYL-2-(N-p-TOLUENESULFONYLCARBAMOYL)-1,3-BUTANEDIONE, m.p. 113.5°-116.5° C. (corr.).
Reaction SMILES: S(=O)(=O)(O)[OH:2].[Br:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:18])[CH:15]=NO)=[C:9]([CH2:19][CH3:20])[CH:8]=1>O>[Br:6][C:7]1[CH:12]=[C:11]2[C:10](=[C:9]([CH2:19][CH3:20])[CH:8]=1)[NH:13][C:14](=[O:18])[C:15]2=[O:2]
Reactant: CCc1cc(Br)ccc1NC(=O)C=NO
Reactant: O=S(=O)(O)O
Solvent: O
Product: CCc1cc(Br)cc2c1NC(=O)C2=O
Temperature: 80 °C
Yield: 74 %

Procedure:
To a solution of sulfuric acid (100 mL) and water (10 mL) at 80° C. (oil bath) was added N-(4-bromo-2-ethyl-phenyl)-2-hydroximino-acetoamide (61.0 g, 225 mmol) in small portions over 20 minutes. The reaction mixture was heated at 80° C. (oil bath) for 15 minutes. After cooling to room temperature, ice-water (500 mL) was added and the mixture was extracted with ethyl acetate. Extracts were washed with saturated sodium bicarbonate solution, dried over magnesium sulfate, and concentrated under reduced pressure to give the title compound (42.3 g, 74% yield). 1H NMR (DMSO-d6) δ 8.87 (s, 1H), 7.75 (d, 1H), 7.71 (d, 1H), 2.75 (q, 2H), 1.44 (t, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:7][CH2:8][C:9](Cl)=[O:10]>>[Cl:7][CH2:8][C:9]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:10]
Reactant: O=C(Cl)CCl
Reactant: C1COCCN1
Product: O=C(CCl)N1CCOCC1

Procedure:
7-Oxo-4,7-dihydro[1,3]thiazolo[5,4-b]pyridine-6-carboxamides. Preparation of specific examples of heterocycle W20.1 follows an established literature precedent described in Chart BM (A. Haemers J. Heterocyclic Chem. 1984, 21, 401-406.). Morpholine is condensed with chloroacetyl chloride to afford 4-(chloroacetyl)-morpholine (BM.1) which is transformed to the dithiocarboxylate methyl ester (BM.2) by the reaction with sulfur, an amine base (e.g. triethylamine) and iodomethane. Condensation of BM.2 with aminoacetonitrile bisulfate in the presence of triethylamine affords the thiazole BM.3. Subsequent reduction of the carboxamide with borane provides BM.4 which is condensed with diethyl ethoxymethylenemalonate to give BM.5. Alkylation of the enamine nitrogen with an alkylhalide (e.g. iodomethane) or other suitable electrophile in the presence of an inorganic base affords BM.6. Cyclization of BM.6 by heating in a mixture of Eaton's reagent provides the thiazolopyridine BM.7. The resulting ester is then treated with a benzylamine (e.g. 4-chlorobenzylamine, 4-bromobenzylamine, or 4-fluorobenzylamine) at high temperature or the ester may be saponified to afford the corresponding acid which is then coupled with a benzylamine mediated by 1,1′-carbonyldiimidazole (or other suitable carboxylic acid activating agent) to provide amides of the general formula BM.8.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[C:7]([F:15])[CH:6]=1.[CH2:16]([NH2:18])[CH3:17].Cl>C(O)C>[CH2:16]([NH:18][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[C:7]([F:15])[CH:6]=1)[CH3:17]
Reactant: CCN
Reactant: CS(=O)(=O)c1cc(F)cc(OCCBr)c1
Agent: Cl
Solvent: CCO
Product: CCNCCOc1cc(F)cc(S(C)(=O)=O)c1

Procedure:
Preparation according to Example 1 but performed in one portion: 1-(2-bromoethoxy)-3-fluoro-5-methylsulfonyl-benzene (0.321 g, 1.08 mmol) and ethanamine (4.3 ml, 8.6 mmol 2 M in methanol) in ethanol (6 ml). Yield: 255 mg (90%). The amine was converted to the hydrochloric acid salt and re-crystallized from ethanol/diethyl ether: M.p. 200.8-201.1° C. MS m/z (relative intensity, 70 eV) 261 (M+, 3), 94 (6), 59 (12), 58 (bp), 56 (8).
Reaction SMILES: [C:1]1([CH:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:8]2[CH2:13][CH2:12][N:11]([C:14](OCC)=O)[C:10]([CH3:30])([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=3)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[C:31]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[C:10]([CH3:30])([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=3)[CH2:9]2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CCOC(=O)N1CCN(C(c2ccccc2)c2ccccc2)CC1(C)Cc1ccc(OC)c(OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CC2(C)CN(C(c3ccccc3)c3ccccc3)CCN2C)cc1OC
Reaction time: 2 h
Yield: 97 %

Procedure:
14.5 g of 1-diphenylmethyl-3-methyl-3-(3,4-dimethoxybenzyl)-4-carbethoxy-piperazine (cf. Example 5) are dissolved in 170 ml of dry tetrahydrofuran and added dropwise, with stirring over a period of 2 hours, to a boiling suspension of 3.42 g of lithium aluminum hydride in 150 ml of dry tetrahydrofuran. The batch is kept at the boiling point for a further 2 hours. After careful addition of wter, the mixture is filtered and the filtrate evaporated. The remaining oil is further worked up as in Example 4. 12.4 g (82 percent of theory) of 1-diphenylmethyl-3-methyl-3-(3,4-dimethoxybenzyl)-4-methyl-piperazine are obtained in the form of the dihydrochloride. m.p. = 192° C. (ethanol).
Reaction SMILES: ClCC(C1C=CC(Cl)=CC=1Cl)=O.ClCC(C1C=CC(Cl)=C(Cl)C=1)=O.[Cl:25][CH2:26][C:27]([C:29]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:30]=1[Cl:36])=[O:28].ClCC(C1C=CC(Cl)=CC=1Cl)O.ClCC(C1C=CC(Cl)=C(Cl)C=1)O>>[Cl:25][CH2:26][CH:27]([C:29]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:30]=1[Cl:36])[OH:28]
Reactant: O=C(CCl)c1cc(Cl)ccc1Cl
Agent: O=C(CCl)c1ccc(Cl)c(Cl)c1
Agent: O=C(CCl)c1ccc(Cl)cc1Cl
Agent: OC(CCl)c1ccc(Cl)c(Cl)c1
Product: OC(CCl)c1cc(Cl)ccc1Cl

Procedure:
Cultivation, reaction and purification were carried out in the same way as described in Example 9 except that 2-chloro-1-(2', 4'-dichlorophenyl) ethanon, 2-chloro-1-(3', 4'-dichlorophenyl) ethanone, 2-chloro-1-(2', 5'-dichlorophenyl) ethanone were used as substrate, and (-)-2-chloro-1-(2', 4'-dichlorophenyl) ethanol, (-)-2-chloro-1-(3', 4'-dichlorophenyl) ethanol, (-)-2-chloro-1-(2', 5'-dichlorophenyl) ethanol was obtained. The yield, specific rotation and optical purity determined by high-performance liquid chromatography were shown in Table 6.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:13]([C@@H:14]([O:40]CC2C=CC=CC=2)[C@@H:15]([N:25](CC2C=CC=CC=2)CC2C=CC=CC=2)[CH2:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=2)[CH2:12][O:11][C@@H:10]([O:48][CH2:49][C:50]([CH3:53])([CH3:52])[CH3:51])[C@@H:9]1[CH3:54])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]([N:8]1[C@@H:13]([C@@H:14]([OH:40])[C@@H:15]([NH2:25])[CH2:16][C:17]2[CH:18]=[C:19]([F:24])[CH:20]=[C:21]([F:23])[CH:22]=2)[CH2:12][O:11][C@@H:10]([O:48][CH2:49][C:50]([CH3:53])([CH3:52])[CH3:51])[C@@H:9]1[CH3:54])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: C[C@H]1[C@H](OCC(C)(C)C)OC[C@H]([C@@H](OCc2ccccc2)[C@H](Cc2cc(F)cc(F)c2)N(Cc2ccccc2)Cc2ccccc2)N1C(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: C[C@H]1[C@H](OCC(C)(C)C)OC[C@H]([C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)N1C(=O)OC(C)(C)C
Yield: 97.3 %

Procedure:
Stir (2R,3S,5R)-5-[(1S,2S)-1-benzyloxy-2-dibenzylamino-3-(3,5-difluorophenyl)-propyl]-2-(2,2-dimethylpropoxy)-3-methylmorpholine-4-carboxylic acid tert-butyl ester (645 mg, 0.87 mmol) and 20% palladium hydroxide on carbon (60% moisture, 645 mg) in ethyl acetate (10 mL) under one-atmosphere of hydrogen gas at room temperature overnight. Filter the suspension through a pad of filtering agent, wash with ethyl acetate and concentrate to give the desired compound (400 mg, 97%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:41]([O:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][O:50][C:51]2[CH:56]=[CH:55][C:54]([C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)=[CH:53][CH:52]=2)=[O:42])[C:7]([C:10]2[C:11]([C:19]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:31][CH:30]=3)=[O:20])=[CH:12][C:13]([N+:16]([O-])=O)=[CH:14][CH:15]=2)=[CH:8][CH:9]=1)([O-])=O>[Pd].O1CCCC1>[NH2:16][C:13]1[CH:12]=[C:11]([C:19]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][C:29]2[CH:30]=[CH:31][C:32]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)=[CH:33][CH:34]=2)=[O:20])[C:10]([C:7]2[C:6]([C:41]([O:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][O:50][C:51]3[CH:56]=[CH:55][C:54]([C:57]4[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=4)=[CH:53][CH:52]=3)=[O:42])=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=2)=[CH:15][CH:14]=1
Reactant: O=C(OCCCCCCOc1ccc(-c2ccccc2)cc1)c1cc([N+](=O)[O-])ccc1-c1ccc([N+](=O)[O-])cc1C(=O)OCCCCCCOc1ccc(-c2ccccc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1ccc(-c2ccc(N)cc2C(=O)OCCCCCCOc2ccc(-c3ccccc3)cc2)c(C(=O)OCCCCCCOc2ccc(-c3ccccc3)cc2)c1
Reaction time: 24 h

Procedure:
Bis{6-[4-biphenyloxy]hexyl} 4,4′-dinitro-2,2′-biphenyldicarboxylate (8) (2.26 g, 2.70 mol), palladium on activated carbon (5%, 0.31 g), and tetrahydrofuran (50 ml) were added to a hydrogenation bottle. The bottle was secured on a Parr hydrogenation apparatus, flushed five times with hydrogen, then pressurized with hydrogen to 56 psi. The pressure was maintained and the vessel was agitated for 24 hours. After the reaction mixture was filtered and about 100 ml of hexanes were added to recrystallize the products directly to afford 1.7 g (80%) of light yellow crystals. mp: 122–124° C. 1H-NMR (CDCl3) δ (ppm) 1.2–1.8 (m, 16H), 3.9 (m, 8H), 6.8–7.6 (m, 24H).
Reaction SMILES: C([NH:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O.N1CCCCC1.[CH:30]([C:32]1[CH:40]=[CH:39][C:35]([C:36]([OH:38])=O)=[CH:34][CH:33]=1)=[O:31].C1C=CC2N(O)N=NC=2C=1.C(N=C=NC(C)C)(C)C>CN(C=O)C.C(#N)C>[CH:30]([C:32]1[CH:33]=[CH:34][C:35]([C:36]([NH:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[O:38])=[CH:39][CH:40]=1)=[O:31]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: O=C(O)CCNC(=O)OCC1c2ccccc2-c2ccccc21
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCNCC1
Solvent: CC#N
Solvent: CN(C)C=O
Product: O=Cc1ccc(C(=O)NCCC(=O)O)cc1
Reaction time: 0.5 h

Procedure:
To the above resin bound Fmoc β-alanine was added 500 μL of a 20% solution of piperidine in DMF. After 30 min of shaking, the resin was drained and washed with 1 mL DMF containing 1-hydroxybenzotriazole (50 mg/mL) and DMF (2×1 mL). Then 200 μmol 4-formylbenzoic acid (30 mg) and 200 μmol HOBt (31 mg) dissolved in DMF (500 μL) were added to the resin followed by 200 μmol diisopropyl carbodiimide (DIC, 25.2 mg) dissolved in acetonitrile (500 μL). The mixture was shaken for 4 hours at 25° C. followed by filtration and washing of the resin with DMF (3×1 mL).
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[S:24][C:25]([C:28](=[O:30])[CH3:29])=[CH:26][CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:31].[NH2:32][C:33]1[CH:34]=[CH:35][C:36]([O:40][CH3:41])=[C:37]([OH:39])[CH:38]=1>C1COCC1>[OH:39][C:37]1[CH:38]=[C:33]([NH:32][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([C:14]4[CH:15]=[C:16]([NH:20][C:21]([C:23]5[S:24][C:25]([C:28](=[O:30])[CH3:29])=[CH:26][CH:27]=5)=[O:22])[CH:17]=[CH:18][CH:19]=4)=[O:13])=[CH:9][CH:10]=3)[NH:5][C:4]2=[O:31])[CH:34]=[CH:35][C:36]=1[O:40][CH3:41]
Reactant: COc1ccc(N)cc1O
Reactant: CC(=O)c1ccc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)s1
Solvent: C1CCOC1
Product: COc1ccc(NC=C2C(=O)Nc3cc(C(=O)c4cccc(NC(=O)c5ccc(C(C)=O)s5)c4)ccc32)cc1O
Temperature: 65 °C
Reaction time: 24 h
Yield: 58.9 %

Procedure:
A small screw cap test tube was charged with 5-Acetyl-thiophene-2-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (prepared below, 100 mg, 0.231 mmol) and THF (2 mL). To the resulting solution was added 5-amino-2-methoxyphenol (35.39 mg, 0.254 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature. Hexanes were added to the reaction mixture. The solid precipitate that formed was washed with ˜1 mL of i-prOH yielding 59% (75 mg, 0.136 mmol) of the title compound.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]([C:16]2[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=2[C:18](O)=[O:19])=[O:15])=[C:6]1[CH3:25])[CH2:2][CH2:3][CH3:4].[CH3:26][N:27]([CH3:37])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([N:34]([CH3:36])[CH3:35])[CH:29]=1.C(OC(=O)C)(=O)C.[OH-].[Na+]>O>[CH3:35][N:34]([CH3:36])[C:30]1[CH:29]=[C:28]([N:27]([CH3:37])[CH3:26])[CH:33]=[CH:32][C:31]=1[C:14]1([C:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]=2[CH3:25])[C:16]2[C:17](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:18](=[O:19])[O:15]1
Reactant: CCCCn1c(C)c(C(=O)c2ccccc2C(=O)O)c2ccccc21
Reactant: CN(C)c1cccc(N(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CCCCn1c(C)c(C2(c3ccc(N(C)C)cc3N(C)C)OC(=O)c3ccccc32)c2ccccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 3.35 g (0.01 mole) of 2-[(1-n-butyl-2-methyl-3-indolyl)carbonyl]benzoic acid, prepared as described in part A above, 1.80 g (0.011 mole) of N,N,N',N'-tetramethyl-m-phenylenediamine and five ml of acetic anhydride was stirred at ambient temperature for a period of approximately 18 hours. The reaction mixture was then poured into a mixture of 40 ml of water, 40 ml of ligroin and 20 ml of 10 percent aqueous sodium hydroxide. The ligroin layer was separated and the white crystals which separated from the solution on standing, were collected by filtration and dried to obtain 3-[2,4-bis(dimethylamino)phenyl]-3-(1-n-butyl-2-methyl-3-indolyl)phthalide (Formula III: R0 =R1 =R2 =R3 =Y1 =H; R=R5 =CH3 ; R4 =N(CH3)2 ; R6 =(CH2)3CH3) which melted at 165°-167° C. A characteristic infrared maximum appeared at 1752 cm-1 (C=O; s). A toluene solution of the product spotted on silica gel developed an intense purple-colored image.
Reaction SMILES: [CH:1]1([O:7][CH2:8][C:9]2[N:14]=[C:13]([S:15][CH3:16])[NH:12][C:11](=O)[CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:20])=O>ClCCl.CN(C)C=O>[Cl:20][C:11]1[CH:10]=[C:9]([CH2:8][O:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[N:14]=[C:13]([S:15][CH3:16])[N:12]=1
Reactant: CSc1nc(COC2CCCCC2)cc(=O)[nH]1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CSc1nc(Cl)cc(COC2CCCCC2)n1

Procedure:
To a mixture of 6-cyclohexyloxymethyl-2-methylsulfanyl-3H-pyrimidin-4-one (20 mg) in dichloromethane (2 mL) and dimethylformamide (catalytic amount) was added thionyl chloride (47 mg). The mixture was heated at reflux for 1.5 h. The solvent was removed under vacuum to give 4-chloro-6-cyclohexyloxymethyl-2-methylsulfanylpyrimidine, which was used in the next reaction without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][O:9][CH2:8][C:7]1=O)=[O:5])[CH3:2].[CH3:13][C@@H:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]([O:3][C:4]([C:6]1[CH2:11][CH2:10][O:9][CH2:8][C:7]=1[NH:21][C@@H:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:13])=[O:5])[CH3:2]
Reactant: C[C@@H](N)c1ccccc1
Reactant: CCOC(=O)C1CCOCC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)C1=C(N[C@H](C)c2ccccc2)COCC1
Yield: 104.2 %

Procedure:
A solution of 3-oxo-tetrahydro-pyran-4-carboxylic acid ethyl ester (3.03 g, 17.6 mmol), R-(+)-α-methylbenzylamine (2.35 g, 19.4 mmol) and p-toluenesulfonic acid hydrate (67 mg, 230 μmol) in benzene (60 mL) was heated at reflux under a Dean-Stark trap for 16 h . The cooled mixture was concentrated in vacuo to provide the product as a yellow oily semisolid (5.05 g), used without further purification. 1H NMR (300 mHz, CDCl3) δ8.97 (bd, J=7.3 Hz, 1H), 7.3-7.2 (m, 5H), 4.41 (m, 1H), 4.30 (d, J=16.1 Hz, 1H), 4.18 (q, J=7.3 Hz, 2H), 3.91 (d, J=16.1 Hz, 1H), 3.64 (m, 2H), 2.34 (m, 2H), 1.48 (d, J=6.5 Hz, 3H), 1.30 (t, J=7.3 Hz, 3H).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:37][O:38][C:39]1[CH:44]=[CH:43][C:42](B(O)O)=[CH:41][N:40]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.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>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:42]2[CH:41]=[N:40][C:39]([O:38][CH3:37])=[CH:44][CH:43]=2)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccc(B(O)O)cn1
Reactant: Cc1ccc(S(=O)(=O)OC(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1ccc(C(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cn1
Yield: 85.5 %

Procedure:
To a mixture of toluene-4-sulfonic acid-1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl ester (prepared as in Example 43, 0.15 g, 0.28 mmol), 2-methoxy-5-pyridineboronic acid (110 mg, 0.72 mmol) and dichlorobis(triphenylphosphine)palladium (II) (21 mg, 0.03 mmol) in dioxane (3 mL) was added an aqueous sodium carbonate solution (2 M, 0.36 mL). The resulting mixture was subjected to microwave irradiation for 2 h at 100° C. The mixture was diluted with ethyl acetate (100 mL), washed with a saturated aqueous sodium bicarbonate solution (2×30 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 30% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-2-[2-cyclopentyl-1-(6-methoxy-pyridin-3-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (110 mg, 83%) as a white solid: LC/MS m/e calcd for C26H25N3O3S [M+H]+ 460.57, observed 460.0.