Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH:26]1[CH2:31][C:30]([CH3:33])([CH3:32])[NH:29][C:28]([CH3:35])([CH3:34])[CH2:27]1)[CH2:3][NH:4][C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH:13]([CH:15]2[CH2:20][C:19]([CH3:22])([CH3:21])[NH:18][C:17]([CH3:24])([CH3:23])[CH2:16]2)[OH:14])[N:8]=[C:7](Cl)[N:6]=1.[NH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][NH2:43]>C1(C)C(C)=CC=CC=1>[OH:1][CH:2]([CH:26]1[CH2:31][C:30]([CH3:33])([CH3:32])[NH:29][C:28]([CH3:35])([CH3:34])[CH2:27]1)[CH2:3][NH:4][C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH:13]([CH:15]2[CH2:20][C:19]([CH3:22])([CH3:21])[NH:18][C:17]([CH3:24])([CH3:23])[CH2:16]2)[OH:14])[N:8]=[C:7]([NH:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][NH:43][C:7]2[N:8]=[C:9]([NH:11][CH2:12][CH:13]([CH:15]3[CH2:20][C:19]([CH3:22])([CH3:21])[NH:18][C:17]([CH3:23])([CH3:24])[CH2:16]3)[OH:14])[N:10]=[C:5]([NH:4][CH2:3][CH:2]([CH:26]3[CH2:27][C:28]([CH3:35])([CH3:34])[NH:29][C:30]([CH3:33])([CH3:32])[CH2:31]3)[OH:1])[N:6]=2)[N:6]=1
Reactant: CC1(C)CC(C(O)CNc2nc(Cl)nc(NCC(O)C3CC(C)(C)NC(C)(C)C3)n2)CC(C)(C)N1
Reactant: NCCCCCCN
Solvent: Cc1ccccc1C
Product: CC1(C)CC(C(O)CNc2nc(NCCCCCCNc3nc(NCC(O)C4CC(C)(C)NC(C)(C)C4)nc(NCC(O)C4CC(C)(C)NC(C)(C)C4)n3)nc(NCC(O)C3CC(C)(C)NC(C)(C)C3)n2)CC(C)(C)N1

Procedure:
2,4-Bis{2-hydroxy-N-(2,2,6,6-tetramethyl-4-piperidyl)ethylamino}-6-chloro-1,3,5-triazine (20.5 g) and hexamethylenediamine (2.0 g) were dissolved in xylene (700 ml), and the mixture was refluxed for 12 hours. The xylene was distilled off from the reaction mixture, and the residue was put into aqueous ammonia, extracted with chloroform and dried over anhydrous magnesium sulfate. The residue obtained by removing the chloroform was chromatographed through silica gel (eluent=ethyl acetate:triethylamine:ethanol=5:1:5), giving the desired product as white crystals with a melting point of 165°-168° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:15][NH2:16])[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH:17]([C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=1)=O.O1CCCC1>C(O)C>[C:1]([C:5]1[CH:6]=[C:7]([NH:15][N:16]=[CH:17][C:19]2[CH:20]=[CH:21][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:27][CH:28]=2)[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NN)cc(C(C)(C)C)c1
Reactant: COC(=O)c1ccc(C=O)cc1
Solvent: CCO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C=NNc2cc(C(C)(C)C)cc(C(C)(C)C)c2)cc1
Yield: 58.2 %

Procedure:
3.5g (15 mmoles) of 3,5-di-t-butylphenylhydrazine and 2.6g (15 mmoles) of methyl 4-formylbenzoate were stirred for 1 hour under reflux in 150ml of a 1:1 mixture of tetrahydrofuran and ethanol. After evaporation of the solvent the residue was digested with ethanol at the boil and then cooled, filtered off in vacuo and rinsed with ethanol. After drying in vacuo at ambient temperature, there were obtained 3.2g of the above compound, m.p. 215°-220° C.
Reaction SMILES: [C:1](Cl)(=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[Al+3].[Cl-].[Cl-].[Cl-].[OH:16][C:17]1[C:25]2[O:24][CH:23]=[C:22]([CH3:26])[C:21]=2[CH:20]=[C:19]([CH3:27])[C:18]=1[CH3:28]>ClCCCl>[OH:16][C:17]1[C:25]2[O:24][C:23]([C:1](=[O:10])[C:2]3[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=3)=[C:22]([CH3:26])[C:21]=2[CH:20]=[C:19]([CH3:27])[C:18]=1[CH3:28]
Reactant: Cc1cc2c(C)coc2c(O)c1C
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COc1ccc(C(=O)c2oc3c(O)c(C)c(C)cc3c2C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 189.3 %

Procedure:
To p-anisoyl chloride (205 g) in 1,2-dichloroethane (2 L), cooled to 0° C., was added AlCl3 (240 g). The reaction mixture was warmed to room temperature and a solution of 7-hydroxy-3,5,6-trimethylbenzofuran (51 g) in 1,2-dichloroethane (400 mL) was added dropwise. The reaction was stirred for 51/2 h then quenched with H2O (2 L). The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined extracts were washed with 25% NH4OAc buffer, dried (Na2SO4) and filtered on silica gel to give 170 g of crude material which was used as such in the next step.
Reaction SMILES: C([O:8][C:9](=[O:37])[CH2:10][NH:11][C:12]([C:14]1[N:15]=[C:16]([C:32](=[O:36])[N:33]([CH3:35])[CH3:34])[C:17]2[C:22]([C:23]=1[O:24]CC1C=CC=CC=1)=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:13])C1C=CC=CC=1.CCOC(C)=O>[Pd].CO>[CH3:34][N:33]([CH3:35])[C:32]([C:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:23]([OH:24])=[C:14]([C:12]([NH:11][CH2:10][C:9]([OH:37])=[O:8])=[O:13])[N:15]=1)=[O:36]
Reactant: CN(C)C(=O)c1nc(C(=O)NCC(=O)OCc2ccccc2)c(OCc2ccccc2)c2ccccc12
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CN(C)C(=O)c1nc(C(=O)NCC(=O)O)c(O)c2ccccc12
Reaction time: 18 h
Yield: 91.5 %

Procedure:
A mixture of [(4-Benzyloxy-1-dimethylcarbamoyl-isoquinoline-3-carbonyl)-amino]-acetic acid benzyl ester (209 mg, 0.42 mmol), Pd/C (100 mg, 10 wt % Pd), EtOAc (10 ml) and MeOH (50 ml) was stirred under a H2-atmosphere at ambient pressure and temperature for 18 h. Then the mixture was filtered through a pad of celite. Celite and filter cake were washed thoroughly with EtOAc and the combined organic phases were concentrated in vacuo to give the title compound as a brown solid (122 mg); MS-(−)-ion: M−1=316.1.
Reaction SMILES: [C:1]1([C:7](=O)[CH2:8][CH:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10](=O)[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[CH:23][CH:22]=1>C(O)(=O)C>[CH3:11][C:10]1[N:20]([C:21]2[CH:22]=[CH:23][C:24]([CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[CH:25][CH:26]=2)[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:8][C:9]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ccc(CCCC(=O)O)cc1
Reactant: CC(=O)C(CC(=O)c1ccccc1)c1ccccc1
Solvent: CC(=O)O
Product: Cc1c(-c2ccccc2)cc(-c2ccccc2)n1-c1ccc(CCCC(=O)O)cc1
Reaction time: 6 h

Procedure:
A soln of 1,3-diphenyl-pentane-1,4-dione (104 mg; 0.412 mmol) and 4-(4-amino-phenyl)-butyric acid (89 mg; 0.497 mmol) in acetic acid (2 mL) was heated at 120° C. After 6 h, the reaction was concentrated on a rotary evaporator. Ethyl acetate (5 mL) was added and this washed with H2O (1×2 mL) and satd NaCl (1×3 mL). The organic portion was dried (MgSO4) and filtered through silica with an EtOAc wash. Crude product was adsorbed onto silica (0.3 g) then purified by MPLC (12 g of silica using a 0→50% EtOAc in hexanes gradient). Pure product was obtained as a white solid (115 mg; 71%). 1H NMR (CDCl3) d 7.54-7.49 (m, 2H), 7.44-7.38 (m, 2H), 7.26-7.07 (m, 10H), 6.56 (s, 1H), 2.72 (t, J=7.6 Hz, 2H), 2.40 (t, J=7.4 Hz, 2H), 2.25 (s, 3H), 2.00 (m, 2H); LC-MS (ESI−) 394 ([M−H]−).
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([C:12]3[N:17]=[CH:16][C:15]([S:18]([NH:21][C@@H:22]([CH3:27])[C:23]([F:26])([F:25])[F:24])(=[O:20])=[O:19])=[CH:14][CH:13]=3)[NH:9]2)=[CH:5][C:4]=1[F:28])[CH3:2].ClS([N:33]=[C:34]=O)(=O)=O>CN(C=O)C.C(#N)C>[C:34]([C:7]1[C:6]2[C:10](=[CH:11][C:3]([CH2:1][CH3:2])=[C:4]([F:28])[CH:5]=2)[NH:9][C:8]=1[C:12]1[N:17]=[CH:16][C:15]([S:18]([NH:21][C@@H:22]([CH3:27])[C:23]([F:25])([F:26])[F:24])(=[O:19])=[O:20])=[CH:14][CH:13]=1)#[N:33]
Reactant: CCc1cc2[nH]c(-c3ccc(S(=O)(=O)N[C@@H](C)C(F)(F)F)cn3)cc2cc1F
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCc1cc2[nH]c(-c3ccc(S(=O)(=O)N[C@@H](C)C(F)(F)F)cn3)c(C#N)c2cc1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of (S)-6-(6-ethyl-5-fluoro-1H-indol-2-yl)-N-(1,1,1-trifluoropropan-2-yl)pyridine-3-sulfonamide (0.22 g, 0.53 mmol) in a mixture of DMF (0.5 mL) and acetonitrile (0.5 mL) was added chlorosulfonyl isocyanate dropwise at −50° C. The reaction mixture was kept stirring at 0° C. for 0.5 hr and then quenched with ice, following by pouring into water. After 0.5 hr stirring at room temperature, the resulting solid was collected by filtration and washed with water, hexane and CH2Cl2. After air drying, (S)-6-(3-cyano-6-ethyl-5-fluoro-1H-indol-2-yl)-N-(1,1,1-trifluoropropan-2-yl)pyridine-3-sulfonamide was obtained and used in the next step without further purification.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7](Cl)=[CH:8][N:9]=1)(=[O:3])[CH3:2].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([SH:19])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([NH:4][C:5]1[S:6][C:7]([S:19][C:16]2[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)=[CH:8][N:9]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(S)cc1
Reactant: CC(=O)Nc1ncc(Cl)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(Sc2cnc(NC(C)=O)s2)cc1
Temperature: 120 °C
Yield: 78.7 %

Procedure:
A mixture of 2-acetylamino-5-chlorothiazole (1.76 g), 4-methoxythiophenol (1.5 g) and potassium carbonate (2.0 g) in N,N-dimethylformamide (30 ml) was heated at 120° C. for 3.5 hours with stirring. The reaction mixture was poured into ice water and the precipitates were collected by filtration to give solid. The solid was recrystallized from ethanol to give 2-acetylamino-5-(4-methoxyphenylthio)thiazole (2.2 g, Yield: 78.6%).
Reaction SMILES: [OH:1][C:2]1[C:7]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[C:14]([CH3:16])[C:13]([O:17][CH3:18])=[C:12]([CH3:19])[CH:11]=2)=[C:6]([OH:21])[N:5]=[C:4]([S-:22])[N:3]=1.[Na+].[OH-].[Na+].I[CH3:27].Cl>O.CN1CCCC1=O>[OH:21][C:6]1[C:7]([NH:8][C:9](=[O:20])[C:10]2[CH:11]=[C:12]([CH3:19])[C:13]([O:17][CH3:18])=[C:14]([CH3:16])[CH:15]=2)=[C:2]([OH:1])[N:3]=[C:4]([S:22][CH3:27])[N:5]=1
Reactant: CI
Reactant: COc1c(C)cc(C(=O)Nc2c(O)nc([S-])nc2O)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1c(C)cc(C(=O)Nc2c(O)nc(SC)nc2O)cc1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
19.1 g of sodium 4,6-dihydroxy-5-(4-methoxy-3,5-dimethylbenzoylamino)pyrimidine-2-thiolate in 190 ml of water and 80 ml of N-methylpyrrolidin-2-one were cooled to 0° C. With cooling, 5.9 g of sodium hydroxide were added, after which the mixture was stirred at 0° C. for 30 min. A solution of 3.7 ml of iodomethane in 4.3 ml of N-methylpyrrolidin-2-one was then added. After the reaction had ended (2 h), the mixture was acidified with concentrated hydrochloric acid. The precipitate obtained was filtered off with suction, washed with water and dried under reduced pressure. This gave 10.1 g of the title compound.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:8][C:7]([CH2:15][CH2:16][CH:17]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:8][C:7]([CH2:15][CH2:16][CH2:17][N:29]2[CH2:28][CH2:27][N:26]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[F:19])[CH2:31][CH2:30]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1ccccc1N1CCNCC1
Reactant: CC(C)(C)n1nc(CCC=O)cc1-c1cccs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)n1nc(CCCN2CCN(c3ccccc3F)CC2)cc1-c1cccs1

Procedure:
77 mg (73%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)propanal (50 mg, 0.191 mmol), 1-(2-fluorophenyl)piperazine (34 mg, 0.191 mmol), DIPEA (0.050 mL, 0.287 mmol) and NaBH(OAc)3 (121 mg, 0.573 mmol).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:30])[NH:4][C:5]2[C:10]([N:11]=1)=[C:9]([O:12][C:13]1[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)[N:16]=[C:15](Cl)[N:14]=1)[CH:8]=[CH:7][CH:6]=2.[NH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[NH2:1][C:2]1[C:3](=[O:30])[NH:4][C:5]2[C:10]([N:11]=1)=[C:9]([O:12][C:13]1[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)[N:16]=[C:15]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[N:14]=1)[CH:8]=[CH:7][CH:6]=2
Reactant: Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)nc(Cl)n3)cccc2[nH]c1=O
Reactant: C1CNCCN1
Product: Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)nc(N4CCNCC4)n3)cccc2[nH]c1=O

Procedure:
The reaction of 3-amino-5-(2-chloro-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)quinoxalin-2(1H)-one (180 mg, 1.0 mmol, Example 106(a)) with piperazine (71 mg, 2.0 mmol, Aldrich) under the conditions of Example 34 afforded the title compound as an amorphous solid. MS (ESI, pos. ion) m/z: 484 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([CH3:14])[N:6]=[C:5]([C:15]2[CH:16]=[N:17][C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=2)[CH:4]=1.C1C(=O)N([Br:32])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)(Cl)Cl>[Br:32][CH2:14][C:7]1[N:6]=[C:5]([C:15]2[CH:16]=[N:17][C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=2)[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)c1c(OC)cc(-c2cnc(OC)c(OC)c2)nc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1c(OC)cc(-c2cnc(OC)c(OC)c2)nc1CBr
Temperature: 65 °C
Reaction time: 24 h

Procedure:
As shown in step 9-iv of Scheme 9, Compound 2032 (200 mg, 0.628 mmol) and NBS (112 mg, 0.63 mmol) were added to 15 mL of CCl4 and the solution purged with nitrogen for 5 minutes. Benzoyl peroxide (20 mole %) was added and the reaction mixture heated at 65° C. under nitrogen for 16 hours. An additional equivalent of NBS and 0.3 equivalents of benzoyl peroxide were added and heating continued for an additional hour. Potassium carbonate (1.0 g) was added as an acid scavenger and heating continued for an additional 24 hours. The reaction mixture was cooled and filtered through a cotton plug and the volatiles removed under reduced pressure. The residue was taken up in DCM and passed through a plug of silica gel, which was eluted with additional DCM. Elution with EtOAc recovered crude product, which was further purified by silica gel chromatography (DCM—1:1 EtOAc/DCM to give ethyl 6-(bromomethyl)-4,5′,6′-trimethoxy-2,3′-bipyridine-5-carboxylate (Compound 2033, 87 mg of white solid: ESMS (M+1) 397/399.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]([CH2:19][CH:20]=O)[N:13]([CH3:18])[C:14](=[O:17])[C:15]=2[OH:16])=[O:9])=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].[C:29]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C([BH3-])#N.[Na+]>CO>[C:29]([N:37]1[CH2:42][CH2:41][N:40]([CH2:20][CH2:19][C:12]2[N:13]([CH3:18])[C:14](=[O:17])[C:15]([OH:16])=[C:10]([C:8]([NH:7][CH2:6][C:5]3[CH:22]=[CH:23][C:2]([F:1])=[CH:3][CH:4]=3)=[O:9])[N:11]=2)[CH2:39][CH2:38]1)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(c1ccccc1)N1CCNCC1
Reactant: Cn1c(CC=O)nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O
Agent: CC(=O)[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Cn1c(CCN2CCN(C(=O)c3ccccc3)CC2)nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Step 2 was dissolved in MeOH and treated with sodium acetate (1.6 eq.), 1-benzoylpiperazine (2 eq.), and sodium cyanoborohydride (1.43 eq.). The mixture was left stirring at room temperature-for 1 hour. The reaction mixture was concentrated and the title compound was obtained by RP-HPLC purification (C18, eluting with water and acetonitrile containing 0.1% TFA).
Reaction SMILES: [Li+].[OH-].C[O:4][C:5](=[O:45])[CH:6]([N:18]1[CH2:23][CH2:22][N:21]([C:24](=[O:42])[CH:25]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH:20]([CH2:43][CH3:44])[CH2:19]1)[CH2:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=1.Cl>C1COCC1.O>[C:38]([O:37][C:35]([NH:34][CH:25]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)[C:24]([N:21]1[CH2:22][CH2:23][N:18]([CH:6]([CH2:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=2)[C:5]([OH:45])=[O:4])[CH2:19][CH:20]1[CH2:43][CH3:44])=[O:42])=[O:36])([CH3:39])([CH3:40])[CH3:41]
Reactant: CCC1CN(C(Cc2ccc3ccccc3c2)C(=O)OC)CCN1C(=O)C(Cc1ccc(F)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCC1CN(C(Cc2ccc3ccccc3c2)C(=O)O)CCN1C(=O)C(Cc1ccc(F)cc1)NC(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 98 %

Procedure:
LiOH (0.61 g, 25.5 mmol) is added to a cold solution of 2-{4-[2-tert-butoxycarbonylamino-3-(4-fluorophenyl)-propionyl]-3-ethyl-piperazin-1-yl}-3-naphthalen-2-yl-propionic acid methyl ester, 35, (3.5 g, 5.9 mmol) in THF/H2O (2:1, 36 mL). The reaction mixture is stirred overnight. The reaction mixture is cooled in a ice bath and the pH is adjusted to 3 with 1M HCl. The aqueous layer is extracted with EtOAc (3×100 mL) and dried over Na2SO4. The organic layers are combined and concentrated in vacuo to afford 3.4 g (98% yield) of the desired product.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:32][CH2:33][CH2:34][C:35]1[CH:43]=[CH:42][CH:41]=[C:40]2[C:36]=1[CH2:37][C:38](=[O:44])[NH:39]2.[CH:45]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1O)([CH3:47])[CH3:46]>O1CCCC1>[CH:45]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[O:32][CH2:33][CH2:34][C:35]1[CH:43]=[CH:42][CH:41]=[C:40]2[C:36]=1[CH2:37][C:38](=[O:44])[NH:39]2)([CH3:47])[CH3:46]
Reactant: CC(C)c1ccccc1O
Reactant: O=C1Cc2c(CCO)cccc2N1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)c1ccccc1OCCc1cccc2c1CC(=O)N2
Reaction time: 0.25 h
Yield: 8.8 %

Procedure:
Diethyl azodicarboxylate (1.58 mL, 10 mmol) was added to a solution of triphenylphosphine (2.62 g, 10 mmol) in tetrahydrofuran (20 mL) under nitrogen atmosphere. The mixture was stirred for 15 minutes. To it was then added 4-(2-hydroxy-ethyl)-1,3-dihydro-indol-2-one (1.77 g, 10 mmol) followed by 2-isopropylphenol (1.36 mL, 10 mmol). The mixture was stirred at room temperature for 18 hours and the solvent was evaporated. The residue was chromatographed on silica gel eluting with ethyl acetate: hexane 2:8 to give 0.26 g (9%) of 4-[2-(2-isopropyl-phenoxy)-ethyl]-1,3-dihydro-indol-2-one as a light yellow solid.
Reaction SMILES: C([NH:4][C:5]1[CH:23]=[CH:22][C:8]([O:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14]([NH2:19])=[C:13]3[C:20]#[N:21])=[CH:7][CH:6]=1)(=O)C.O.Cl.C([O-])(O)=O.[Na+]>CO>[NH2:4][C:5]1[CH:23]=[CH:22][C:8]([O:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14]([NH2:19])=[C:13]3[C:20]#[N:21])=[CH:7][CH:6]=1
Reactant: CC(=O)Nc1ccc(Oc2ccc3[nH]c(N)c(C#N)c3c2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: N#Cc1c(N)[nH]c2ccc(Oc3ccc(N)cc3)cc12
Yield: 95 %

Procedure:
A suspension of 5-(4-acetylaminophenoxy)-2-amino-1H-indole-3-carbonitrile (Example 14)(306 mg; 1 mmol) in MeOH (10 ml) was treated with water (2 ml) and conc. HCl (1 ml) and the mixture heated under reflux for 30 hours. After cooling the mixture was poured into sat. aqueous NaHCO3 and extracted with EtOAc. The organic phase was washed with brine and dried over MgSO4. The residue was purified by flash chromatography eluting with increasingly polar mixtures of EtOAc/hexanes (80 to 100% EtOAc) to give 5-(4-aminophenoxy)-2-amino-1H-indole-3-carbonitrile as a pale beige solid (251 mg).
Reaction SMILES: [NH:1]1[CH:5]([C:6]([OH:8])=[O:7])[CH2:4][CH2:3][C:2]1=[O:9].[CH2:10](O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].S(=O)(=O)(O)O.C([O-])(O)=O.[Na+]>C1C=CC=CC=1>[CH2:10]([O:7][C:6]([CH:5]1[NH:1][C:2](=[O:9])[CH2:3][CH2:4]1)=[O:8])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: O=C1CCC(C(=O)O)N1
Reactant: CCCCCCCO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: c1ccccc1
Product: CCCCCCCOC(=O)C1CCC(=O)N1
Temperature: 25 °C
Yield: 65.1 %

Procedure:
A 200-ml eggplant-shaped flask equipped with a condenser and a mechanical stirrer was charged with 6.5 g (0.05 mole) of 2-pyrrolidone-5-carboxylic acid, 23.2 g (0.20 mole) of n-heptyl alcohol, a catalytic amount of concentrated sulfuric acid and 40 ml of benzene and the mixture was refluxed for 3.5 hours. The reaction mixture was cooled to room temperature and poured into saturated aqueous NaHCO3, followed by extraction with benzene. Washing, drying, solvent removal and distillation under reduced pressure as performed in the conventional manner gave 7.4 g of yellow 2-pyrrolidone-5-carboxylic acid n-heptyl ester. Boiling point: 186°-188° C./3 mm Hg.
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:29])=[C:4]([CH2:24][O:25][C:26](=[O:28])[CH3:27])[C:5]([I:23])=[C:6]([C:21]=1[I:22])[C:7]([NH:9][CH2:10][CH:11]([O:17][C:18](=[O:20])[CH3:19])[CH2:12][O:13][C:14](=[O:16])[CH3:15])=[O:8].[C:30]([O:33][CH2:34][C:35]([CH2:44][O:45][C:46](=[O:48])[CH3:47])([CH2:39][O:40][C:41](=[O:43])[CH3:42])[C:36](Cl)=[O:37])(=[O:32])[CH3:31].C(=O)([O-])O.[Na+]>CC(N(C)C)=O>[C:41]([O:40][CH2:39][C:35]([CH2:44][O:45][C:46](=[O:48])[CH3:47])([CH2:34][O:33][C:30](=[O:32])[CH3:31])[C:36]([NH:1][C:2]1[C:3]([I:29])=[C:4]([CH2:24][O:25][C:26](=[O:28])[CH3:27])[C:5]([I:23])=[C:6]([C:21]=1[I:22])[C:7]([NH:9][CH2:10][CH:11]([O:17][C:18](=[O:20])[CH3:19])[CH2:12][O:13][C:14](=[O:16])[CH3:15])=[O:8])=[O:37])(=[O:43])[CH3:42]
Reactant: CC(=O)OCC(COC(C)=O)(COC(C)=O)C(=O)Cl
Reactant: CC(=O)OCc1c(I)c(N)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(=O)OCc1c(I)c(NC(=O)C(COC(C)=O)(COC(C)=O)COC(C)=O)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I
Temperature: 60 °C
Reaction time: 120 h

Procedure:
5-Amino-3-acetoxymethyl-N-(2,3-diacetoxypropyl)-2,4,6-triiodobenzamide (1.05 g, 1.43 mmol) was dissolved in dimethylacetamide (2 ml) and added to trisacetoxymethylacetyl chloride (2.17 g, 7.4 mmol). The mixture was stirred at 60° C. for 5 days, and after cooling the mixture was added to an aqueous solution of sodium hydrogen carbonate (60 ml, 2%). The precipitate formed was filtered off and dissolved in chloroform (90 ml). The organic phase was washed with water (4×40 ml), dried (Na2SO4), and the solvent evaporated. A semisolid residue (1.16 g) was left, which according to MS analysis consisted of the two compounds: 5-(3-Acetoxy-2,2-diacetoxymethyl-propionylamino)-3-acetoxymethyl-N-(2,3-diacetoxypropyl)-2,4,6-triiodobenzamide with MS (ESP, m/e): 1002 ([M]+, 100%) and 5-acetamido-3-acetoxymethyl-N-(2,3-diacetoxypropyl)-2,4,6-triiodobenzamide with
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]2[C:12]([CH:16]=1)=[N:13][O:14][N:15]=2)(=O)=O.[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>CN(C=O)C>[N:15]1[O:14][N:13]=[C:12]2[CH:16]=[C:8]([CH2:7][CH2:6][N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[CH:9]=[CH:10][C:11]=12
Reactant: C1CNCCN1
Reactant: CS(=O)(=O)OCCc1ccc2nonc2c1
Solvent: CN(C)C=O
Product: c1cc2nonc2cc1CCN1CCNCC1
Yield: 96.9 %

Procedure:
5-[2-(Methanesulfonyloxy)ethyl]benzofurazan (242 mg, 1 mmol) and piperazine (0.86 g, 10 mmol) in DMF (9 ml) were stirred together at room temperature for 19 hours. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel eluting with CH2Cl2 /CH3OH/NH3 (Aq.); 90:10:1 to give the piperazine as a yellow solid (225 mg, 97%).