Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C=O.N.[O:4]([C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14]Cl)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[O:19](C1C=C(C=CC=1)C(Cl)Cl)C1C=CC=CC=1>C(O)(=O)C>[O:4]([C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH:14]=[O:19])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: ClC(Cl)c1cccc(Oc2ccccc2)c1
Reactant: ClCc1cccc(Oc2ccccc2)c1
Agent: C=O
Agent: N
Solvent: CC(=O)O
Product: O=Cc1cccc(Oc2ccccc2)c1
Reaction time: 3 h

Procedure:
A solution of formalin (40%, 150 ml) was cooled to 10° C and then treated with aqueous ammonia solution (35%, 75 ml) over 15 minutes. A mixture of 3-phenoxybenzyl chloride and 3-phenoxybenzal chloride containing 70% monochloride chloride and 30% dichloride mixture (50 g) was added and the mixture stirred under a nitrogen blanket for 3 hours. The mixture was then acidified with acetic acid (150 ml), stirred for a further 3 hours in the cold, and then refluxed for 4 hours. After cooling, the reaction mixture was extracted with toluene (100 ml) and the extract washed neutral with sodium bicarbonate solution. The toluene solution of crude 3-phenoxybenzaldehyde was diluted with an equal quantity of ethanol and then stirred with a saturated aqueous solution of sodium bisulphite. The resulting bisulphite adduct was filtered off and washed with toluene. After vacuum drying, this gave 63.0 g of purified 3-phenoxybenzaldehyde bisulphite compound which on treatment with dilute mineral acid yielded the pure 3-phenoxybenzaldehyde. Yield based on chloride mixture was 95%.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=O)=[C:6](Cl)[N:5]=[C:4]([CH3:11])[N:3]=1.[NH2:12][NH2:13]>>[Cl:1][C:2]1[N:3]=[C:4]([CH3:11])[N:5]=[C:6]2[NH:12][N:13]=[CH:8][C:7]=12
Reactant: Cc1nc(Cl)c(C=O)c(Cl)n1
Reactant: NN
Product: Cc1nc(Cl)c2cn[nH]c2n1
Reaction time: 0.25 h
Yield: 5.86 %

Procedure:
The resulting solution of 4,6-dichloro-2-methylpyrimidine-5-carbaldehyde was treated dropwise with a solution of anhydrous hydrazine (1101 μL, 35071 μmol) at −78° C. The mixture was stirred for 15 min, and then the cooling bath was removed and the mixture stirred at RT for 1 h. The mixture was concentrated and partitioned between water (110 mL) and EtOAc (110 mL). The organic layer was washed with saturated aqueous NaHCO3 (100 mL), separated, dried (MgSO4), treated with activated charcoal and filtered through a plug of silica, washing with EtOAc. The filtrate was concentrated and purified by flash chromatography on silica eluting with 5% acetone/DCM to 25% EtOAc/hexane. The residue was suspended in DCM (3 mL), cooled in a freezer, and filtered to give 4-chloro-6-methyl-1H-pyrazolo[3,4-d]pyrimidine (330 mg, 5.86% yield) as a tan solid. 1H NMR (400 MHz, d6-DMSO) δ 14.25 (bs, 1H); 8.35 (s, 1H); 2.68 (s, 3H).
Reaction SMILES: [H-].[Na+].C(OCC)(=O)C(OCC)=O.[F:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH:24]=O>C1COCC1>[Cl:20][C:21]1[CH:22]=[C:23]([CH:24]=[C:14]([F:13])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:26]=[CH:27][C:28]=1[Cl:29]
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)CF
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(=O)C(=O)OCC
Product: CCOC(=O)C(F)=Cc1ccc(Cl)c(Cl)c1

Procedure:
A mixture of sodium hydride (0.33 g), diethyl oxalate (1.83 g), ethyl fluoroacetate (1.33 g) and anhydrous THF (10 ml) was heated under reflux for 4 hours whereupon 3,4-dichlorobenzaldehyde (2.18 g) (ex.Aldrich) in THF was added. After 18 hours at room temperature the reaction mixture was partitioned between water and ether and worked up in conventional fashion. Purification by chromatography (silica, 80:20 hexane/ether) gave (Z) ethyl 3-(3,4-dichlorophenyl)-2-fluoroprop-2-enoate (2.1 g.
Reaction SMILES: [OH-].[Li+].C([O:5][C:6]([C:8]1[C:17]2[C:12](=[C:13]([O:20][CH3:21])[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=2)[C:11]([CH2:22][N:23]2[C:31](=[O:32])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]2=[O:33])=[N:10][CH:9]=1)=[O:7])C.Cl>C1COCC1>[O:33]=[C:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:31](=[O:32])[N:23]1[CH2:22][C:11]1[C:12]2[C:17](=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=2[O:20][CH3:21])[C:8]([C:6]([OH:7])=[O:5])=[CH:9][N:10]=1
Reactant: CCOC(=O)c1cnc(CN2C(=O)c3ccccc3C2=O)c2c(OC)cc(OC)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(OC)c2c(CN3C(=O)c4ccccc4C3=O)ncc(C(=O)O)c2c1
Reaction time: 16 h
Yield: 68.9 %

Procedure:
Lithium hydroxide (1N, 100 mL) was added to a solution of Example 1A (19.6 g, 46.6 mmol) in THF (50 mL), and the reaction was stirred for 16 h. The solution was acidified to pH=3 with 1N HCl. The resulting solid was collected by filtration and dried under vacuum to give 12.6 g (69%) of the title compound. H1-NMR (DMSO-d6): δ 8.90 (s, 1H), 8.58 (t, 1H, J=4.8 Hz), 8.01 (d, 1H, J=2.0 Hz), 7.73 (d, 1H, J=3.6 Hz), 7.66 (d, 1H, J=3.6 Hz), 7.58 (t, 1H, J=3.6 Hz), 7.52 (t, 1H, J=3.6 Hz), 5.10 (d, 2H, J=4.8 Hz), 4.02 (s, 3H), 3.91 (s, 3H). MS (ES) (M+H) calc'd for C21H16N2O6, 393; found 393.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][C:9](=[O:13])[NH:10]2)=[CH:6][C:5]=1[OH:14])(=O)[CH3:2].[N:15]1C=CC=CC=1>CN(C=O)C>[CH3:2][C:1]1[C:4]2[CH:12]=[C:11]3[NH:10][C:9](=[O:13])[CH2:8][C:7]3=[CH:6][C:5]=2[O:14][N:15]=1
Reactant: c1ccncc1
Reactant: CC(=O)c1cc2c(cc1O)CC(=O)N2
Solvent: CN(C)C=O
Product: Cc1noc2cc3c(cc12)NC(=O)C3
Yield: 11.9 %

Procedure:
The procedure described in Example 33d was followed with the oxime acetate obtained in step c (2.75 g, 10.97 mmol) and pyridine (8.9 mL, 109.7 mmol) in DMF (110 m). After concentration in vacuo, the residue was purified by silica gel flash chromatography (2% MeOH--CH2Cl,) to give the title compound (0.245 g, 12%) as a pastel yellow solid.
Reaction SMILES: [C:1]([NH:5][CH2:6][CH:7]([OH:43])[CH2:8][O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14](=[O:42])[CH:15]=[C:16]([C:20]3[CH:25]=[C:24]([O:26]CC4C=CC=CC=4)[CH:23]=[C:22]([O:34]CC4C=CC=CC=4)[CH:21]=3)[O:17]2)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([NH:5][CH2:6][CH:7]([OH:43])[CH2:8][O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14](=[O:42])[CH:15]=[C:16]([C:20]3[CH:21]=[C:22]([OH:34])[CH:23]=[C:24]([OH:26])[CH:25]=3)[O:17]2)=[CH:12][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NCC(O)COc1ccc2c(=O)cc(-c3cc(OCc4ccccc4)cc(OCc4ccccc4)c3)oc2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)NCC(O)COc1ccc2c(=O)cc(-c3cc(O)cc(O)c3)oc2c1

Procedure:
To a suspension of 7-(3-tert-butylamino-2-hydroxy-propoxy)-3′,5′-dibenzyloxy-flavone, 34 (1.0 g, 1.73 mmol) in dry methanol (60 mL) was added 40 mg 10% Pd/C. The reaction mixture was shaken in Parr hydrogenation assembly under hydrogen gas atmosphere at 60 lbs for 4 h after replacement of the air by nitrogen. The Pd/C was filtered and methanol evaporated on rotavapor under reduced pressure to provide 48. Yield 660 mg (96%); mp 153° C. (decomposes); MS (FAB) 400 (M++1); IR (KBr) 3401, 1618; 1H NMR (200 MHz, DMSO-d6) δ 7.98 (d, J=8.8 Hz, 1IH), 7.30 (s, 1H), 7.13 (d, J=8.8 Hz, 1H), 6.90 (d, J=1.2 Hz, 2H), 6.7 (s, 1H), 6.52 (s, 1H), 4.27-4.23 (m, 3H), 3.18-2.99 (m, 2H), 1.32 (s, 9H). Analysis Calcd for C22H25NO6: C, 66.15; H, 6.31; N, 3.51. Found: C, 66.19; H, 6.47; N, 3.43.
Reaction SMILES: [OH:1][C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.Cl[CH:29]([OH:31])[CH3:30].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[OH:31][CH2:29][CH2:30][O:1][C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: COc1ccc2nc(-c3ccc(NC(=O)c4ccc(O)cc4)cc3)sc2c1
Reactant: CC(O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2nc(-c3ccc(NC(=O)c4ccc(OCCO)cc4)cc3)sc2c1
Temperature: 25 °C
Yield: 76.3 %

Procedure:
A mixture of 4-hydroxy-N-[4-(6-methoxybenzothiazol-2-yl)-phenyl]-benzamide (0.20 g, 0.53 mmol), chloroethanol (0.064 g, 0.80 mmol) and potassium carbonate (0.26 g, 1.86 mmol) was heated at 100° C. in dry DMF (10 ml) for 18 h. On cooling to room temperature, water (30 ml) was added and the reaction mixture was extracted with EtOAc (7×40 ml). The combined organic extracts were washed with brine (80 ml) and dried (Na2SO4). The solvent was removed under reduced pressure to give the title compound (0.17 g, 76%) as a colourless solid.
Reaction SMILES: [CH3:1][C@H:2]([O:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[C:12]([O:24][CH3:25])[N:13]2[CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]2)=[C:9]([NH2:26])[N:8]=1)[CH2:3][CH2:4][CH3:5].I[CH2:28][CH3:29].C(N(CC)CC)C>CN(C=O)C>[CH2:28]([N:20]1[CH2:21][CH2:22][CH2:23][CH:18]([CH2:17][CH2:16][N:13]2[C:12]([O:24][CH3:25])=[N:11][C:10]3[C:14]2=[N:15][C:7]([O:6][C@@H:2]([CH3:1])[CH2:3][CH2:4][CH3:5])=[N:8][C:9]=3[NH2:26])[CH2:19]1)[CH3:29]
Reactant: CCI
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCC3CCCNC3)c2n1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCC3CCCN(CC)C3)c2n1

Procedure:
A solution of 2-{[(1S)-1-methylbutyl]oxy}-8-(methyloxy)-9-[2-(3-piperidinyl)ethyl]-9H-purin-6-amine (45 mg, 0.124 mmol), iodoethane (0.012 ml, 0.149 mmol) and triethylamine (0.035 mL, 0.248 mmol) in DMF (3 ml) was heated at 50° C. for 18 hours.
Reaction SMILES: [C:1]1(=[N:11]O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[OH2:13]>>[NH:11]1[C:6](=[O:13])[CH2:7][CH2:8][CH2:9][C:10]2[CH:5]=[CH:4][CH:3]=[CH:2][C:1]1=2
Reactant: ON=C1CCCc2ccccc21
Reactant: O
Product: O=C1CCCc2ccccc2N1
Temperature: 120 °C

Procedure:
To 3,4-dihydro-2H-naphthalen-1-one oxime (5 g, 31 mmol), PPA (50 g) was added and the mixture was heated at 120° C. for 4.5 hrs. While hot the mixture was quenced in a slurry of ice and water and vigorously stirred until a precipitate formed. The precipitate was filtered and rinsed with water to yield 1,3,4,5-tetrahydrobenzo[b]azepin-2-one (3.1 g). MS [M+H]+: 162.0; tR=1.76 min. (method 1)
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:9][C:6]2([CH2:8][CH2:7]2)[CH2:5][N:4]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].CC1(C)N([O])C(C)(C)CCC1.CC(C(O)=O)CN>C(Cl)Cl>[CH:2]([C@@H:3]1[CH2:9][C:6]2([CH2:7][CH2:8]2)[CH2:5][N:4]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:1]
Reactant: CC(C)(C)OC(=O)N1CC2(CC2)C[C@H]1CO
Agent: CC(CN)C(=O)O
Agent: CC1(C)CCCC(C)(C)N1[O]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC2(CC2)C[C@H]1C=O
Reaction time: 2 h

Procedure:
To (S)-tert-butyl 6-(hydroxymethyl)-5-azaspiro[2.4]heptane-5-carboxylate (Intermediate 59, 2.2 g, 9.7 mmol) dissolved in 10 ml of DCM, TEMPO (306 mg, 1.9 mmol) and BAIB (3.43 mg, 10.6 mmol) were added. After 2 hours at 25° C., the reaction is diluted with DCM (150 ml), washed with an aqueous solution of Na2S2O3 then with water, dried (Na2SO4) and evaporated to obtain a crude that was purified by silica gel chromatography (petroleum ether to petroleum ether/ethylacetate 95/5). (S)-tert-butyl 6-formyl-5-azaspiro[2.4]heptane-5-carboxylate was obtained as light yellow solid (1.8 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[CH:14][CH:13]=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([N:18]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:15]2[CH:16]=[CH:17][C:12]([O:11][CH3:10])=[CH:13][CH:14]=2)=[CH:3][CH:4]=1
Reactant: COc1ccc(Br)cc1
Reactant: COc1ccc(Nc2ccc(OC)cc2)cc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COc1ccc(N(c2ccc(OC)cc2)c2ccc(OC)cc2)cc1
Reaction time: 1 h
Yield: 95.7 %

Procedure:
The above general procedure was followed using 4-bromoanisole (187 mg, 1.00 mmol) and di(4-methoxyphenyl)amine (229 mg, 1.00 mmol) with 1 mol % Pd(dba)2 and 0.8 mol % tri-t-butylphosphine in 1.5 mL of toluene. After one hour, the reaction mixture was adsorbed onto silica gel and chromatographed with 5% ethyl acetate/hexanes to give 321 mg (96%) of tri(4-methoxyphenyl)amine as a white solid. 1H NMR (500 MHz, C6D6) δ 7.08 (d, J=10 Hz, 6 H), 6.73 (d, J=10 Hz, 6H), 3.31 (s, 9H). 13C NMR (125 MHz, C6D6) δ 155.7, 142.6, 125.3, 115.0, 55.0.
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[CH:8]1[CH2:12][N:11]([CH:13]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:10](=[O:20])[C:9]1([CH3:22])[CH3:21])(C)(C)C>Cl.CO>[CH:13]1([N:11]2[CH2:12][CH:8]([CH2:7][OH:6])[C:9]([CH3:21])([CH3:22])[C:10]2=[O:20])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: CC(C)(C)[SiH2]OC(C)(C)C1CN(C2CCCCCC2)C(=O)C1(C)C
Agent: Cl
Solvent: CO
Product: CC1(C)C(=O)N(C2CCCCCC2)CC1CO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Two drops of 12M HCl was added to a solution of Example 1D (75 mg, 0.21 mmoles) in methanol (1.25 mL) and stirred for one hour at room temperature. The solvent was evaporated in vacuo to provide the title compound as a colorless oil.
Reaction SMILES: [F:1][C:2]1[C:3]([S:35][CH3:36])=[C:4]([F:34])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[C:13]([F:24])[CH:12]=3)=[CH:8][C:7](=[O:25])[C:6]=2[C:26]=1[NH:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30].ClC1C=CC=C(C(OO)=[O:45])C=1.S([O-])(O)=O.[Na+]>ClCCl>[F:1][C:2]1[C:3]([S:35]([CH3:36])=[O:45])=[C:4]([F:34])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[C:13]([F:24])[CH:12]=3)=[CH:8][C:7](=[O:25])[C:6]=2[C:26]=1[NH:27][C:28](=[O:33])[C:29]([CH3:30])([CH3:32])[CH3:31]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1c(F)c(NC(=O)C(C)(C)C)c2c(=O)cc(-c3ccc(NC(=O)C(C)(C)C)c(F)c3)oc2c1F
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)c1c(F)c(NC(=O)C(C)(C)C)c2c(=O)cc(-c3ccc(NC(=O)C(C)(C)C)c(F)c3)oc2c1F
Yield: 95.6 %

Procedure:
204 mg (0.392mmol) of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-7-methylthio-5-pivaloyiamino-4H-1-benzopyran-4-one obtained in Example 85 (2) was dissolved in 5 mL of dichloromethane, 86 mg (0.39 mmol) of m-chloroperbenzoic acid was added under ice-cooling and the mixture was stirred at the same temperature for2 hours. An aqueous solution of sodium hydrogensulfite was added to the reaction solution and the mixture was extracted once with chloroform. The organic layer was washed once with an aqueous solution of sodium bicarbonate, once with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=100:1) to give 200 mg of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-7-methylsulfinyl-5-pivaloylamino-4H-1-benzopyran-4-one (yield: 95%).
Reaction SMILES: C[O:2][C:3](=[O:18])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[C:7]([O:13][C:14]([F:17])([F:16])[F:15])[CH:6]=1.C1COCC1.CO.O[Li].O>O>[C:11]([C:8]1[CH:9]=[CH:10][C:5]([CH2:4][C:3]([OH:18])=[O:2])=[CH:6][C:7]=1[O:13][C:14]([F:15])([F:17])[F:16])#[N:12]
Reactant: COC(=O)Cc1ccc(C#N)c(OC(F)(F)F)c1
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1ccc(CC(=O)O)cc1OC(F)(F)F

Procedure:
To a solution of methyl(4-cyano-3-trifluoromethoxyphenyl)acetate (2.15 g, 8.3 mmol) in 1:1 THF:MeOH (10 mL each) was added LiOH—H2O (0.42 g, 10.0 mmol) in water (30 mL). The reaction mixture was stirred at room temperature for 12 hours at which time the starting ester was consumed by TLC (25% ethyl acetate/hexanes). The mixture was concentrated in vacuo and acidified to pH<3 by dropwise addition of 12N HCl. The acidified solution was then extracted with ethyl acetate, dried over sodium sulfate and concentrated in vacuo to yield the crude title product. LC-MS (IE, m/z): 246 [M+1]+. 1H-NMR (500 MHz, CDCl3) δ ppm 3.81 (s, 2H), 7.39 (d, J=7.5 Hz, 1H), 7.40 (s, 1H), 7.75 (d, J=7.5 Hz, 1H).
Reaction SMILES: [CH3:1][CH:2]([O:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[C:10]([C:16]([OH:18])=O)[NH:11]2)[CH:3]([CH3:5])[CH3:4].Cl.Cl.Cl.[N:22]1([CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][CH:34]([NH2:37])[CH2:33][CH2:32]2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[N:22]1([CH2:29][CH2:30][N:31]2[CH2:32][CH2:33][CH:34]([NH:37][C:16]([C:10]3[NH:11][C:12]4[C:8]([CH:9]=3)=[C:7]([O:6][CH:2]([CH3:1])[CH:3]([CH3:4])[CH3:5])[CH:15]=[CH:14][CH:13]=4)=[O:18])[CH2:35][CH2:36]2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: NC1CCN(CCN2CCCCCC2)CC1
Reactant: CC(C)C(C)Oc1cccc2[nH]c(C(=O)O)cc12
Agent: Cl
Product: CC(C)C(C)Oc1cccc2[nH]c(C(=O)NC3CCN(CCN4CCCCCC4)CC3)cc12

Procedure:
This compound is synthesized analogously to Example 1 from 4-(1,2-Dimethyl-propoxy)-1H-indole-2-carboxylic acid 88 (preparation see below) and amine 5.
Reaction SMILES: [CH3:1][C:2]1[S:9][C:8]2[CH:7]=[C:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[NH:5][C:4]=2[CH:3]=1.[Br:15]N1C(=O)CCC1=O.O>O1CCCC1>[Br:15][C:7]1[C:8]2[S:9][C:2]([CH3:1])=[CH:3][C:4]=2[NH:5][C:6]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)c1cc2sc(C)cc2[nH]1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1[nH]c2cc(C)sc2c1Br
Reaction time: 1 h
Yield: 69.7 %

Procedure:
To a solution of ethyl 2-methyl-4H-thieno[3,2-b]pyrrole-5-carboxylate (1.0 g) in tetrahydrofuran (10 mL) was added N-Bromosuccinimide (0.94 g) under ice-cooling, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture was added water and the resulting mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=97/3−76/24) to give the title compound (0.96 g).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].Cl.Cl.[NH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH:15]1[C:20]([OH:22])=[O:21].[C:23]([O-:26])([O-])=[O:24].[Na+].[Na+].Cl>O>[CH2:5]([O:4][C:2]([N:14]1[CH2:19][CH2:18][N:17]([C:23]([O:26][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:24])[CH2:16][CH:15]1[C:20]([OH:22])=[O:21])=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)C1CNCCN1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)C1CN(C(=O)OCc2ccccc2)CCN1C(=O)OCc1ccccc1
Temperature: 0 °C

Procedure:
Benzyl chloroformate (3.1 mL, 22 mmol, Aldrich) was added dropwise over a period of 5 min to a mixture of piperazine-2-carboxylic acid dihydrochloride (2.03 g, 10 mmol, Aldrich) and Na2CO3 (4.24 g, 40 mmol) in water (10 mL) with stirring at 0° C. The mixture was stirred at 0° C. for 1 h, 2N HCl (10 mL) was added and the mixture was extracted with EtOAc (3×40 mL). The combined organic extracts were washed with water (10 mL) and brine (20 mL), dried over Na2SO4, and filtered. The filtrate was evaporated in vacuo to give the title compound as a gum, which was used for the next step without additional purification. MS (ESI, pos. ion) m/e: 399 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH:5]([CH3:9])[C:6]([O-:8])=O)[CH3:2].[C:11]([O:15][C:16](=[O:22])[C@@H:17]1[CH2:21][CH2:20][CH2:19][NH:18]1)([CH3:14])([CH3:13])[CH3:12].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[C:11]([O:15][C:16](=[O:22])[C@@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1[C:6](=[O:8])[CH:5]([C:4]([O:3][CH2:1][CH3:2])=[O:10])[CH3:9])([CH3:14])([CH3:12])[CH3:13]
Reactant: CCOC(=O)C(C)C(=O)[O-]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCOC(=O)C(C)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Temperature: 0 °C

Procedure:
Monoethylmethylmalonate [prepared according to the procedure of Organic Syntheses, 37, 34 (1957)] (2.92 g.) and L-proline tert.-butyl ester (3.42 g.) are dissolved in dichloromethane (80 ml.). The solution is chilled with stirring in an ice bath. Dicyclohexylcarbodiimide (4.12 g.) is added and the mixture is stirred 15 minutes in the ice bath and 16 hours at room temperature. The precipitate is filtered off and the filtrate concentrated to dryness in vacuo. The residue is dissolved in ethyl acetate and washed with 5% aqueous potassium bisulfate, water, saturated sodium bicarbonate and water. The organic phase is dried over magnesium sulfate and concentrated to dryness in vacuo to obtain 1-(2-ethoxycarbonylpropanoyl)-L-proline tert.-butyl ester, yield 5.9 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1.C(O[O:14][C:15]([CH3:18])(C)C)(C)(C)C.[C]=O.[CH2:21]([OH:23])C>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:21]([O:14][CH2:15][CH3:18])=[O:23])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(Cl)c1
Reactant: CC(C)(C)OOC(C)(C)C
Reactant: CCO
Agent: [C]=O
Product: CCOC(=O)Cc1cccc(Cl)c1
Temperature: 120 °C
Reaction time: 16 h
Yield: 82.7 %

Procedure:
m-Chlorotoluene (1.89 g), ethanol (46 mg), di-tert-butyl peroxide (73 mg, 1 equivalent), and Pd(Xantphos)Cl2 (3.8 mg, 1 mol %) were added into a reaction kettle, into which 10 atm carbon monoxide was introduced. The reaction was heated to 120° C., and stirred at this constant temperature for 16 h. After the reaction was completed, carbon monoxide was discharged, and 82 mg ethyl m-chlorophenylacetate was obtained by column chromatography, in a yield of 83%. 1HNMR (400 MHz, CDCl3) δ 1.24 (t, J=7.2 Hz, 3H), 3.58 (s, 2H), 4.13 (q, J=7.2 Hz, 2H), 7.15-7.18 (m, 1H), 7.24-7.26 (m, 1H), 7.29 (s, 1H); 13CNMR (100 MHz, CDCl3) δ 14.2, 40.9, 61.1, 127.3, 127.5, 129.5, 129.8, 134.3, 135.9, 170.9; HRMS (ESI) calcd. for C10H11ClNaO2 [M+Na]: 221.0340. found: 221.0342. The ethyl m-chlorophenylacetate obtained was dissolved in 1,4-dioxane. 6 N sodium hydroxide solution was added, and the reaction was heated to 60° C. After 2 h of reaction, the pH value was adjusted to 1 by adding 2 N hydrochloric acid. After removing the organic solvent under reduced pressure, 64 mg product m-chlorophenylacetic acid was obtained by extraction with ethyl acetate, and the yield of hydrolysis was 91%.
Reaction SMILES: [C:1]1(=[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=N)[NH:12]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=N)[NH:2]1.[CH3:21][C:22]1[CH2:26][C:25](=[O:27])[N:24]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([OH:36])=[O:35])[CH:29]=2)[N:23]=1.[C:37]([OH:40])(=[O:39])[CH3:38]>CN1C(=O)CCC1>[CH3:21][C:22]1[C:26](=[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:1](=[C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13](=[C:26]4[C:25](=[O:27])[N:24]([C:28]5[CH:29]=[CH:30][CH:31]=[C:38]([C:37]([OH:40])=[O:39])[CH:33]=5)[N:23]=[C:22]4[CH3:21])[NH:12]3)[NH:2]2)[C:25](=[O:27])[N:24]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([OH:36])=[O:35])[CH:29]=2)[N:23]=1
Reactant: CC(=O)O
Reactant: CC1=NN(c2cccc(C(=O)O)c2)C(=O)C1
Reactant: N=C1NC(=C2NC(=N)c3ccccc32)c2ccccc21
Solvent: CN1CCCC1=O
Product: CC1=NN(c2cccc(C(=O)O)c2)C(=O)C1=c1[nH]c(=c2[nH]c(=C3C(=O)N(c4cccc(C(=O)O)c4)N=C3C)c3ccccc23)c2ccccc12
Temperature: 25 °C

Procedure:
10.0 g of [1,1′]biisoindolylidene-3,3′-diimine and 25.3 g of 3-methyl-1-(3-carboxyphenyl)-2-pyrazolin-5-one are stirred in a mixture of 160 ml of NMP and 40 ml of glacial acetic acid at reflux for 5 hours. After cooling to room temperature the suspension is filtered and the filter product is washed with ethanol and then water and dried at 60° C. This gives 21.7 g (85%) of a brownish black powder of a compound of the following formula
Reaction SMILES: [C:1]1(=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.Br.[NH2:8][CH:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:20])[C:15]=2[OH:19])[C:10]1=[O:21]>C(O)C>[C:1]1(=[N:8][CH:9]2[CH2:18][CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:20])[C:15]=3[OH:19])[C:10]2=[O:21])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCC1
Reactant: NC1CCc2c(ccc(O)c2O)C1=O
Agent: Br
Solvent: CCO
Product: O=C1c2ccc(O)c(O)c2CCC1N=C1CCCC1

Procedure:
In a mixture of 20 volume parts of cyclopentanone and 100 volume parts of ethanol is dissolved 1 part of 2-amino-5,6-dihydroxy-3,4-dihydro-1(2H)-naphthalenone hydrobromide to produce 2-cyclopentylideneamino-5,6-dihydroxy-3,4-dihydro-1(2H)-naphthalenone. The resulting mixture is subjected to catalytic reduction with 0.1 part of platinum dioxide and 0.39 part of anhydrous sodium acetate at ordinary temperature and pressure.