Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]2[O:14][N:15]=[C:16]([CH3:17])[C:3]=12.[CH2:18]([NH2:22])[CH2:19][CH2:20][CH3:21]>O>[CH2:18]([NH:22][C:2]1[C:3]2[C:16]([CH3:17])=[N:15][O:14][C:4]=2[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1)[CH2:19][CH2:20][CH3:21]
Reactant: Cc1noc2nc(-c3ccccc3)cc(Cl)c12
Reactant: CCCCN
Solvent: O
Product: CCCCNc1cc(-c2ccccc2)nc2onc(C)c12
Temperature: 25 °C

Procedure:
12.2 g. of 4-chloro-3methyl-6-phenylisoxazolo[5,4-b]-pyridine (0.05 mol.) are added to 150 ml. of n-butylamine. The reaction mixture is heated at 150°-160° for 3 hours in an autoclave and, after cooling to room temperature, is evaported in vacuo. The residue is treated with water, filtered off and dried. 14.1 g. (100%) of N-butyl-3-methyl-6-phenylisoxazolo[5,4-b]pyridin-4-amine are recrystallized from a mixture of ligroin and ethylacetate (3:1), m.p. 126°-127°.
Reaction SMILES: [C@H]1(C[N:12]2[CH2:17][CH2:16][CH:15]([NH:18][C:19]([C:21]3[NH:22][C:23]4[C:28]([CH:29]=3)=[C:27]([O:30][CH2:31][C:32]3[C:36]5[CH:37]=[CH:38][C:39]([O:41][CH3:42])=[CH:40][C:35]=5[O:34][CH:33]=3)[CH:26]=[CH:25][CH:24]=4)=[O:20])[CH2:14][CH2:13]2)[C@@H]2N(CCCC2)CCC1.Cl.Cl.Cl.NC1CCN([CH2:53][CH2:54][N:55]2[CH2:60][CH2:59][CH:58]([OH:61])[CH2:57][CH2:56]2)CC1>>[OH:61][CH:58]1[CH2:59][CH2:60][N:55]([CH2:54][CH2:53][N:12]2[CH2:17][CH2:16][CH:15]([NH:18][C:19]([C:21]3[NH:22][C:23]4[C:28]([CH:29]=3)=[C:27]([O:30][CH2:31][C:32]3[C:36]5[CH:37]=[CH:38][C:39]([O:41][CH3:42])=[CH:40][C:35]=5[O:34][CH:33]=3)[CH:26]=[CH:25][CH:24]=4)=[O:20])[CH2:14][CH2:13]2)[CH2:56][CH2:57]1
Reactant: COc1ccc2c(COc3cccc4[nH]c(C(=O)NC5CCN(C[C@@H]6CCCN7CCCC[C@H]67)CC5)cc34)coc2c1
Reactant: NC1CCN(CCN2CCC(O)CC2)CC1
Agent: Cl
Product: COc1ccc2c(COc3cccc4[nH]c(C(=O)NC5CCN(CCN6CCC(O)CC6)CC5)cc34)coc2c1

Procedure:
This compound is synthesized from 4-(6-methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (120, see example 86) and amine 21 analogously to the method described in example 1.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:11]=1)[O:8][C:7]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[C:6]([CH3:22])[C:5]2=[O:23].C([O-])(=O)C.[Na+].[H][H]>[C].[Pd].C(O)(C)C>[CH3:22][C:6]1[C:5](=[O:23])[C:4]2[C:9](=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:11]=[CH:2][CH:3]=2)[O:8][C:7]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: [H][H]
Reactant: COC(=O)c1cc(Cl)cc2c(=O)c(C)c(-c3ccccc3)oc12
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(C)O
Product: COC(=O)c1cccc2c(=O)c(C)c(-c3ccccc3)oc12
Reaction time: 6 h
Yield: 81.9 %

Procedure:
Into a pressure reactor were placed 1.5 g (4.57 m mole) of methyl 6-chloro-3-methylflavone-8-carboxylate, 1.8 g (14.2 m mole) of sodium acetate, 150 ml of isopropanol and 0.075 g of 5% palladium-carbon. After the atmosphere was replaced with hydrogen gas, reaction was conducted at 70° C. under a pressure of 5.0 kg/cm2G for 6 hours. Thereafter the contents were withdrawn from the reactor and were subjected to filtration while being hot to remove the catalyst. The solvent was recovered from the filtrate to provide 1.1 g (82.1%) of white needle-like crystals which melt at 162.2° to 164.8° C. The crystals were recrystallized from alcohol to obtain a product having a melting point of 166.4° to 168.2° C. The product was found identical in melting point with the compound prepared by the conventional method. When the product of this example and the compound prepared by the conventional method were melted together, the melting point was not lower than that of the product of this example.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15](Cl)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:2].CS(C)=O.[CH2:21]([NH2:29])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:29][CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:2]
Reactant: CCn1ncc2c(Cl)c3ccccc3nc21
Reactant: NCCc1ccccc1
Solvent: CS(C)=O
Solvent: O
Product: CCn1ncc2c(NCCc3ccccc3)c3ccccc3nc21
Temperature: 80 °C
Yield: 79 %

Procedure:
A mixture of 1-ethyl-4-chloro-1H-pyrazolo[3,4-b]quinoline (11.6 g, 0.05 mol), DMSO (20 ml) and phenethylamine (12.1 g, 0.1 mol) is heated at 80° C. overnight. The reaction mixture is poured into water (1 L), and the precipitate that forms is collected by filtration and washed with water. The solid is dissolved in hot ethyl acetate, and then the solution is dried over MgSO4, filtered and evaporated to a small volume. Hexane is added, and then the mixture is cooled in an ice bath, and then the product that crystallizes is collected by filtration, washed with hexane and dried to afford 12.5 g of 1-ethyl-N-(phenylethyl)-1H-pyrazolo[3,4-b]quinoline-4 amine, m.p. 157°-158° C.
Reaction SMILES: C1(C)C=CC=CC=1.CN(C)C.[CH3:12][O:13][CH:14]([CH2:26][O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH2:15][S:16]([CH2:19][CH2:20]OS(C)(=O)=O)(=[O:18])=[O:17]>CCCCCC>[CH:19]([S:16]([CH2:15][CH:14]([O:13][CH3:12])[CH2:26][O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])(=[O:18])=[O:17])=[CH2:20]
Reactant: CCCCCCCCCCCCCCCCCCOCC(CS(=O)(=O)CCOS(C)(=O)=O)OC
Agent: CN(C)C
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: C=CS(=O)(=O)CC(COCCCCCCCCCCCCCCCCCC)OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 73.3 %

Procedure:
Into 10 ml of toluene containing 2 g of trimethylamine is dissolved 1.0 g of 2-mesyloxyethyl 2-methoxy-3-octadecyloxypropyl sulfone and the solution is stirred at room temperature for 6 hours. Then 30 ml of hexane is added to the mixture and precipitates are removed by filtration. The filtrate is concentrated to give 0.6 g of the captioned compound as colorless crystals (m.p.47°-49° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:21])=[C:7]([C:13]3[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[CH:14]=3)[C:8](=[O:12])[NH:9]2)=[CH:4][C:3]=1[I:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[C:54]([O:58][C:59]([N:61]1[CH2:66][CH2:65][CH2:64][CH2:63][CH:62]1[CH2:67][CH2:68]O)=[O:60])([CH3:57])([CH3:56])[CH3:55]>>[C:54]([O:58][C:59]([N:61]1[CH2:66][CH2:65][CH2:64][CH2:63][CH:62]1[CH2:67][CH2:68][O:21][C:6]1[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[C:3]([I:22])[CH:4]=2)[NH:9][C:8](=[O:12])[C:7]=1[C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[CH:14]=1)=[O:60])([CH3:57])([CH3:56])[CH3:55]
Reactant: Cc1cc(C)cc(-c2c(O)c3cc(I)c(Cl)cc3[nH]c2=O)c1
Reactant: CC(C)(C)OC(=O)N1CCCCC1CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c3cc(I)c(Cl)cc3[nH]c2=O)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 2-(2-hydroxyethyl)-piperidine-1-carboxylic acid tert-butyl ester (10 g in 450 mL dry tetrahydrofuran) was added 22.3 g of 7-chloro-3-(3,5-dimethylphenyl)-4-hydroxy-6-iodo-1H-quinolin-2-one followed by 13.7 g of triphenylphosphine and the mixture stirred at room temperature. To this was added 8.2 mL of diethyl azodicarboxylate (DEAD) and stirring was continued for 72 hours. At this time the solvents were removed to a minimum volume in vacuo and the mixture filterd through a silica gel pad to remove the phosphine by-products. The filtrate was concentrated in vacuo to provide the partially purified title compound (17.5 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH2:21][CH2:22][N:23]([CH2:28][C:29]([OH:31])=[O:30])[CH2:24][C:25]([OH:27])=[O:26])[CH2:10][CH2:11][N:12]([CH2:17][C:18]([OH:20])=[O:19])[CH2:13][C:14]([OH:16])=[O:15].C(CON1[C:41](=[O:42])[CH:40]=[CH:39][C:38]1=[O:43])(O)=O>C(=O)(O)[O-].[Na+]>[C:38]1(=[O:43])[N:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH2:21][CH2:22][N:23]([CH2:24][C:25]([OH:27])=[O:26])[CH2:28][C:29]([OH:31])=[O:30])[CH2:10][CH2:11][N:12]([CH2:13][C:14]([OH:16])=[O:15])[CH2:17][C:18]([OH:20])=[O:19])[C:41](=[O:42])[CH:40]=[CH:39]1
Reactant: O=C(O)CON1C(=O)C=CC1=O
Reactant: NCCCCCCCN(CCN(CC(=O)O)CC(=O)O)CCN(CC(=O)O)CC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(O)CN(CCN(CCCCCCCN1C(=O)C=CC1=O)CCN(CC(=O)O)CC(=O)O)CC(=O)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 49.7 %

Procedure:
A solution of [((7-aminoheptyl)imino)bis(ethylenenitrilo)]tetraacetic acid (0.72g, 1.6 mmol) in saturated aqueous sodium bicarbonate (15 ml) was cooled in an ice bath and N-carboxymethoxymaleimide (prepared according to Helv. Chim. Acta, 58, 531 [1975]) (0.25 g, 1.6 mmol) was added in one portion. After stirring 20 minutes the ice bath was removed and stirring was continued for 30 minutes. The solution was brought to ph≈6 with 1N HC1 and concentrated under reduced pressure. The residue was chromatographed on a 2×30 cm column of Bio-Rad AG 1×8 ion exchange resin in the formate form (gradient elution, 0-1M formic acid) to provide 0.61 g of slightly impure product. This material was rechromatographed as above to yield pure [((7-maleimidoheptyl)imino)bis(ethylenenitrilo)]tetraacetic acid (0.42g, 50%).
Reaction SMILES: [C:1]([N:8]([CH2:20][C:21]([CH3:25])([CH3:24])[CH2:22][OH:23])[C:9](=[O:19])[C@H:10]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[NH2:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1([CH:32]([S:39]([O:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)(=[O:41])=[O:40])[CH2:33][CH2:34][S:35](Cl)(=[O:37])=[O:36])C=CC=CC=1>N1C=CC=CC=1.ClCCl.ClCCl>[C:1]([N:8]([CH2:20][C:21]([CH3:25])([CH3:24])[CH2:22][O:23][S:35]([CH2:34][CH2:33][CH2:32][S:39]([O:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)(=[O:41])=[O:40])(=[O:36])=[O:37])[C:9](=[O:19])[C@H:10]([CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[NH2:11])([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2]
Reactant: CC(C)(CO)CN(C(=O)OC(C)(C)C)C(=O)[C@@H](N)Cc1ccccc1
Reactant: O=S(=O)(Cl)CCC(c1ccccc1)S(=O)(=O)Oc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(COS(=O)(=O)CCCS(=O)(=O)Oc1ccccc1)CN(C(=O)OC(C)(C)C)C(=O)[C@@H](N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a stirred solution of 3-(N-Boc-L-phenylalaninamido)-2,2-dimethylpropanol from Step 1 (2 mmol) in a mixture of pyridine/dichloromethane (5 mL:10 mL) was added a solution of phenyl 3-phenoxysulfonyl-1-propanesulfonyl chloride (Example 1 (b)) (2.2 mmol) in dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 15 h, then concentrated and rediluted with ethyl acetate and aqueous hydrochloric acid (1 N). The organic phase was isolated, washed with aqueous hydrochloric acid (1 N) and concentrated. The residual material was purified by silica gel chromatography using hexanes/ethyl acetate (70:30 to 50:50) as eluent to afford 3-phenoxysulfonyl-1-propanesulfonic acid 3-(N-Boc-L-phenylalaninamido)-2,2-dimethylpropyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](Cl)=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH2:16]([NH2:19])[CH2:17][NH2:18]>CN(C=O)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:18][CH2:17][CH2:16][NH2:19])=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cnc2cc(Br)ccc2c1Cl
Reactant: NCCN
Solvent: CN(C)C=O
Product: NCCNc1c([N+](=O)[O-])cnc2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 7-bromo-4-chloro-3-nitroquinoline (143.8 g, 0.5 mol) in 800 mL warm DMF was added to a stirred solution of ethylenediamine in 200 mL DMF at room temperature; the reaction was stirred at room temperature overnight. The reaction was quenched with 2 L water and stirred for an additional hour. Additional water was added, and the mixture was stirred overnight. A precipitate formed and was isolated by filtration and air-dried overnight on the filter funnel to provide N1-(7-bromo-3-nitroquinolin-4-yl)ethane-1,2-diamine as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:22])=[CH:4][C:5]([Cl:21])=[C:6]([CH:20]=1)[O:7][C:8]1[CH:19]=[CH:18][CH:17]=[CH:16][C:9]=1[O:10][CH2:11][C:12]([O:14][CH3:15])=[O:13].Cl[C:24]([O:26][CH3:27])=[O:25].O1CCCC1.Cl>N1C=CC=CC=1>[Cl:21][C:5]1[CH:4]=[C:3]([F:22])[C:2]([NH:1][C:24]([O:26][CH3:27])=[O:25])=[CH:20][C:6]=1[O:7][C:8]1[CH:19]=[CH:18][CH:17]=[CH:16][C:9]=1[O:10][CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)COc1ccccc1Oc1cc(N)c(F)cc1Cl
Reactant: COC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COC(=O)COc1ccccc1Oc1cc(NC(=O)OC)c(F)cc1Cl
Temperature: 25 °C

Procedure:
Into a mixture of methyl [2-(5-amino-2-chloro-4-fluorophenoxy)phenoxy]acetate [Intermediate compound A3-22], methyl chloroformate and tetrahydrofuran is added dropwise pyridine, and the mixture is stirred at room temperature. Dilute hydrochloric acid is added to the reaction solution, and this is extracted with ethyl acetate. The organic layer is washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated to obtain methyl [2-(2-chloro-4-fluoro-5-methoxycarbonylaminophenoxy)phenoxy]acetate [Intermediate compound A9-22].
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH:4]([O:13][C:14]1[C:22]3[N:21]=[C:20]([CH3:23])[NH:19][C:18]=3[CH:17]=[C:16]([C:24]([OH:26])=O)[CH:15]=1)[CH2:5][CH2:6][O:7]2.[CH3:27][NH:28][CH2:29][CH2:30][OH:31]>>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH:4]([O:13][C:14]1[C:22]3[N:21]=[C:20]([CH3:23])[NH:19][C:18]=3[CH:17]=[C:16]([C:24]([N:28]([CH2:29][CH2:30][OH:31])[CH3:27])=[O:26])[CH:15]=1)[CH2:5][CH2:6][O:7]2
Reactant: Cc1nc2c(OC3CCOc4cc(F)cc(F)c43)cc(C(=O)O)cc2[nH]1
Reactant: CNCCO
Product: Cc1nc2c(OC3CCOc4cc(F)cc(F)c43)cc(C(=O)N(C)CCO)cc2[nH]1
Yield: 40 %

Procedure:
The title compound was prepared as a white solid (50 mg, 40% yield for 3 steps) from 4-[(5,7-difluoro-3,4-dihydro-2H-chromen-4-yl)oxy]-2-methyl-1H-benzimidazole-6-carboxylic acid (100 mg, crude, STEP 4 in Example 4) and 2-(methylamino)ethanol (63 mg, 0.83 mmol) by the same manner in STEP 5 of Example 1.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](C1C=CC(S(O[C:22]2[C:23]([O:25][C@H:26]([CH3:32])[C:27]=2[C:28]([O:30][CH3:31])=[O:29])=[O:24])(=O)=O)=CC=1)([O-])=O>C(Cl)Cl>[CH2:1]([NH:8][C:22]1[C:23]([O:25][C@H:26]([CH3:32])[C:27]=1[C:28]([O:30][CH3:31])=[O:29])=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C1=C(OS(=O)(=O)c2ccc([N+](=O)[O-])cc2)C(=O)O[C@@H]1C
Reactant: NCc1ccccc1
Solvent: ClCCl
Product: COC(=O)C1=C(NCc2ccccc2)C(=O)O[C@@H]1C

Procedure:
At 0° C., 25.5 g of benzylamine are added dropwise within a period of 1 hour to a solution of 35.7 g of (R)-2-(4-nitrobenzenesulphonyloxy)-3-methoxycarbonyl-2-penten-4-olide in 250 ml of methylene chloride. The resulting benzylamine-p-nitrobenzenesulphonic acid salt is filtered off, and the filtrate is concentrated by evaporation, filtered over silica gel with toluene, and recrystallised from ether/petroleum ether. [α]D20 =+22° (3% in CHCl3), m.p. 68°-70° C., IR (CH2Cl2) 1752, 1678, 1632 cm-1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)O.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1
Reactant: OC(c1ccncc1)c1c[nH]c2ccc(F)cc12
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1ccc2[nH]cc(Cc3ccncc3)c2c1
Reaction time: 8 h

Procedure:
A suspension of (5-fluoro-1H-indol-3-yl)-pyridin-4-yl-methanol (3.36 g, 13.9 mmol) in methylene chloride is treated with triethylsilane (2.48 ml, 15.5 mmol) followed by trifluoroacetic acid (11.9 ml, 155 mmol) at room temperature, stirred overnight and concentrated in vacuo. The resultant residue is treated with saturated Na2CO3 to pH>9 and extracted with methylene chloride. The combined extracts are washed sequentially with water and brine, dried over Na2SO4 and concentrated in vacuo. This residue is purified by flash chromatography (silica gel, CH2Cl2/MeOH: 95/5) to give the title product as a white solid, 2.5 g (80%) mp 141-142° C. (lit. mp 149° C., Malleron et al, J. Med. Chem. 1993, 36, 1194).
Reaction SMILES: [F:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH3:15][NH:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:22]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29].CCN(C(C)C)C(C)C>C(Cl)Cl>[F:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:5]([C:6]([N:16]([CH3:15])[C:17]2[CH:18]=[N:19][CH:20]=[CH:21][C:22]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(F)c(C(F)(F)F)c1
Reactant: CNc1cnccc1-c1ccccc1C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1-c1ccncc1N(C)C(=O)c1ccc(F)c(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
4-Fluoro-5-trifluoromethylbenzoyl chloride (80 mg, 0.35 mmol, CAS RN 67515-56-4) was added to a solution of methyl-(4-o-tolyl-pyridin-3-yl)-amine (35 mg, 0.18 mmol, example 1, intermediate a) and DIPEA (92 μL, 0.53 mmol) in CH2Cl2 (1 mL). The reaction mixture was stirred overnight and then loaded directly onto a silica gel column and eluted with 50% EtOAc in n-hexane to yield the desired product as a waxy solid (33 mg, 48%) MS (ESI): m/z=388.9 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([O:9][C:10](=[O:11])[C:5]=12)=O)([O-:3])=[O:2].[NH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22]>>[N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([N:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C:10](=[O:11])[C:5]=12)=[O:9])([O-:3])=[O:2]
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Reactant: NCCCCCC(=O)O
Product: O=C(O)CCCCCN1C(=O)c2cccc([N+](=O)[O-])c2C1=O
Yield: 93.1 %

Procedure:
The starting material used in the above example can be prepared as follows: 3.86 g (0.02 mol) of 3-nitrophthalic anhydride and 2.9 g (0.022 mol) of 6-aminocaproic acid are heated under reflux for 8 hours and then evaporated. The solid residue is stirred with water, filtered off with suction and dried for 24 hours at 80° C. 5.7 g (93% of theory) of 6-(3-nitrophthalimidyl)-caproic acid are obtained; melting point 148°-150° C. IR spectrum (CH2Cl2): 1790 and 1725 cm-1 (CO--N--CO); 1550 and 1370 cm-1 (NO2).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([C:10](=[O:12])[CH3:11])[CH:7]=[CH:6][C:5]=1[Cl:13].[Br:15]Br>C(O)(=O)C.Br.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([C:10](=[O:12])[CH2:11][Br:15])[CH:7]=[CH:6][C:5]=1[Cl:13]
Reactant: BrBr
Reactant: COC(=O)c1cc(C(C)=O)ccc1Cl
Agent: Br
Solvent: CC(=O)O
Product: COC(=O)c1cc(C(=O)CBr)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.2 %

Procedure:
To a solution of 5-acetyl-2-chloro-benzoic acid methyl ester (100 mg, 0.47 mmol) in glacial acetic acid (5 mL) was added bromine (0.05 mL, 0.94 mmol). The mixture was stirred at room temperature for 2 h. Hydrobromic acid-acetic acid (2 drops, 30%) was added and the mixture was stirred for 10 minutes. The mixture was concentrated in vacuo to afford the title compound (140 mg).
Reaction SMILES: Cl[C:2]1[C:7]2[C:8]([CH3:11])=[N:9][NH:10][C:6]=2[CH:5]=[N:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[CH2:22][NH2:23]>C(O)CCC>[CH3:12][O:13][C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[CH2:22][NH:23][C:2]1[CH:3]=[N:4][CH:5]=[C:6]2[NH:10][N:9]=[C:8]([CH3:11])[C:7]=12
Reactant: COc1ccc(CN)c(OC)c1
Reactant: Cc1n[nH]c2cncc(Cl)c12
Solvent: CCCCO
Product: COc1ccc(CNc2cncc3[nH]nc(C)c23)c(OC)c1
Yield: 42.3 %

Procedure:
A solution of 4-chloro-3-methyl-1H-pyrazolo[4,3-d]pyridine (330 mg, 1.9 mmol) and 1-(2,4-dimethoxyphenyl)methanamine (0.58 mL, 3.9 mmol) in 1-butanol was heated in the microwave at 150° C. for 40 minutes. Purification via preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) gave the desired product (240 mg, 42%). LCMS for C16H19N4O2 (M+H)+: m/z=299.1; Found: 299.2.
Reaction SMILES: [CH2:1]([O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].Br[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][Br:38].C([O-])([O-])=O.[K+].[K+]>CC(=O)CC>[Br:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][O:25][C:22]1[CH:21]=[CH:20][C:19]([C:16]2[CH:17]=[CH:18][C:13]([O:12][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11])=[CH:14][CH:15]=2)=[CH:24][CH:23]=1
Reactant: C=CCCCCCCCCCOc1ccc(-c2ccc(O)cc2)cc1
Reactant: BrCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=CCCCCCCCCCOc1ccc(-c2ccc(OCCCCCCCCCCCBr)cc2)cc1
Yield: 183.6 %

Procedure:
A mixture of 2.80 g (8.68 mmol) of the compound obtained in Step 1, 8.18 g (26.0 mmol) of 1,11-Dibromo-undecane, 3.66 g ((26.0 mmol) of K2CO3 and 40 mL of dry butanone is refluxed for 24 h, then the reaction mixture is allowed to return to room temperature. The mixture is filtered and the solvent is distilled off under reduced pressure. The resulting crude is purified by column chromatography on silica gel using CH2Cl2 as eluent to give a pure white solid (9.11 g, 41% yield).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[CH3:25][NH:26][C:27]([N:29]1[C:37]2[C:32](=[CH:33][C:34]([O:38][C:39]3[CH:44]=[CH:43][N:42]=[C:41]([NH:45][C:46]([N:48]4[CH2:53][CH2:52][C:51](=O)[CH2:50][CH2:49]4)=[O:47])[CH:40]=3)=[CH:35][CH:36]=2)[CH:31]=[CH:30]1)=[O:28]>ClCCl>[CH3:25][NH:26][C:27]([N:29]1[C:37]2[C:32](=[CH:33][C:34]([O:38][C:39]3[CH:44]=[CH:43][N:42]=[C:41]([NH:45][C:46]([N:48]4[CH2:53][CH2:52][CH:51]([N:1]5[CH2:6][CH2:5][O:4][CH2:3][CH2:2]5)[CH2:50][CH2:49]4)=[O:47])[CH:40]=3)=[CH:35][CH:36]=2)[CH:31]=[CH:30]1)=[O:28]
Reactant: C1COCCN1
Reactant: CNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)N4CCC(=O)CC4)c3)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)N4CCC(N5CCOCC5)CC4)c3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.7 %

Procedure:
Morpholine (228 mg, 1.64 mmol), sodium triacetoxyborohydride (372 mg, 1.76 mmol), and acetic acid (0.134 ml, 2.34 mmol) were added to a dichloromethane (3.5 ml) solution of N1-methyl-5-(2-(4-oxopiperidin-1-ylcarbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide (476 mg) synthesized in Example 40, and stirred overnight at room temperature. The reaction mixture was partitioned between ethyl acetate and water; and the organic layer was dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure; and the residue was purified by silica gel column chromatography (Fuji Silysia NH, ethyl acetate-methanol system). The resultant was washed with a solvent mixture of ether-hexane=1:1; and the solid was filtered off to yield the title compound (110 mg) as crystals.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1([CH3:19])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][C:7]1=[O:18])C.[CH3:21][NH2:22]>C(O)C>[CH3:21][N:22]1[C:7]2([OH:18])[C:6]([CH3:19])([C:15]3[CH:14]=[C:13]([O:16][CH3:17])[CH:12]=[CH:11][C:10]=3[CH2:9][CH2:8]2)[CH2:5][C:4]1=[O:3]
Reactant: CCOC(=O)CC1(C)C(=O)CCc2ccc(OC)cc21
Reactant: CN
Solvent: CCO
Product: COc1ccc2c(c1)C1(C)CC(=O)N(C)C1(O)CC2

Procedure:
A solution of 22.0 g (79.7 mmol) ethyl-7-methoxy-1-methyl-2-oxo-1,2,3,4-tetrahydro-1-naphthaleneacetate (IXb) and 7.5 g (240 mmol) methylamine in 25 ml ethanol was left at room temperature for 24 hr. The crystalline precipitate formed was separated to give 15.5 g (74.5%) Xb, m.p. 182°-186°. From the mother liquor, after evaporation (35°) and treatment with ether, 1.0 g, additional Xb was collected increasing the yield to 79.5%; IR (Nujol), 3300 (OH), 1670 cm-1 (lactam); NMR (CDCl3 -DMSO) δ, 1.48 (s, 3, CH3), 2.82 (s, 3, N-CH3), 3.78 (s, 3, OCH3), 6.6-7.1 (m, 3, ArH).