Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:12]([CH2:16][CH3:17])[N:13]=[CH:14][CH:15]=3)=[CH:9][N:8]([CH2:18][O:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[C:5]2=[N:6][CH:7]=1.[NH2:26][C:27]1[CH:37]=[CH:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][C:28]=1[C:29]([N:31]([CH3:33])[CH3:32])=[O:30].ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.C(#N)C>[NH2:26][C:27]1[CH:37]=[CH:36][C:35]([C:2]2[CH:3]=[C:4]3[C:10]([C:11]4[N:12]([CH2:16][CH3:17])[N:13]=[CH:14][CH:15]=4)=[CH:9][N:8]([CH2:18][O:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[C:5]3=[N:6][CH:7]=2)=[CH:34][C:28]=1[C:29](=[O:30])[N:31]([CH3:32])[CH3:33]
Reactant: CCn1nccc1-c1cn(COC(=O)C(C)(C)C)c2ncc(Br)cc12
Reactant: CN(C)C(=O)c1cc(B2OC(C)(C)C(C)(C)O2)ccc1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CC#N
Product: CCn1nccc1-c1cn(COC(=O)C(C)(C)C)c2ncc(-c3ccc(N)c(C(=O)N(C)C)c3)cc12

Procedure:
2,2-dimethyl-propionic acid 5-bromo-3-(2-ethyl-2H-pyrazol-3-yl)-pyrrolo[2,3-b]pyridin-1-ylmethyl ester, 2-amino-N,N-dimethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide, [1,1′-bis(diphenylphosphino)-ferrocene]dichloro-palladium(II) complex with dichloromethane, acetonitrile, 1M aqueous sodium carbonate solution, and tetrahydrofuran were combined in a microwave vial. The tube was placed in a microwave reactor and irradiated to 120° C. for 20 minutes. The reaction mixture was concentrated in vacuo and the residue partitioned between dichloromethane and water. The organic layer was dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography (0 to 100% [10% methanol in ethyl acetate] in hexanes) to give 2,2-dimethyl-propionic acid 5-(4-amino-3-dimethylcarbamoyl-phenyl)-3-(2-ethyl-2H-pyrazol-3-yl)-pyrrolo[2,3-b]pyridin-1-ylmethyl ester. MS: m/z 489.3 (M+H+).
Reaction SMILES: C([NH:4][C:5]([CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH2:8][OH:9])[CH2:6][OH:7])(=O)C.[OH-].[Na+].Cl>CO>[NH2:4][C:5]([CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)([CH2:8][OH:9])[CH2:6][OH:7]
Reactant: CC(=O)NC(CO)(CO)CCCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NC(CO)(CO)CCCc1ccccc1
Temperature: 0 °C
Yield: 50 %

Procedure:
2-Acetamido-2-(3-phenylpropyl)-1,3-propanediol (600 mg) was dissolved in 25 ml of methanol and 11.9 ml of a 1N aqueous sodium hydroxide solution was added thereto. The mixture was refluxed under heating for 6 hours. The mixture was poured into 30 ml of ice water and neutralized with dilute hydrochloric acid. The solvent was distilled away. Chloroform was added to the residue for extraction and the chloroform layer was washed and dried. The solvent was distilled away and the residue was purified by column chromatography (chloroform:methanol=9:1-4:1) to give 250 mg of 2-amino-2-(3-phenylpropyl)-1,3-propanediol as a pale yellow, oily substance.
Reaction SMILES: Cl.[CH:2]([C:4]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[N:6]([C:15](OC(C)(C)C)=O)[N:5]=1)=[O:3].[CH2:22]1CCN2C(=NCCC2)C[CH2:23]1.ICCC>O1CCOCC1.CN(C=O)C>[CH3:14][O:13][C:9]1[CH:8]=[C:7]2[C:12]([C:4]([CH:2]=[O:3])=[N:5][N:6]2[CH2:15][CH2:22][CH3:23])=[CH:11][CH:10]=1
Reactant: COc1ccc2c(C=O)nn(C(=O)OC(C)(C)C)c2c1
Reactant: C1CCC2=NCCCN2CC1
Agent: Cl
Solvent: CCCI
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CCCn1nc(C=O)c2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.6 %

Procedure:
A solution of 2 M HCl in dioxane (0.47 mL, 0.94 mmol) was added to a stirred, room temperature mixture of tert-butyl 3-formyl-6-methoxy-1H-indazole-1-carboxylate (50 mg, 0.18 mmol) in dioxane (1 mL) and the mixture was stirred at room temperature for 8 hours. It was concentrated and dried under vacuum. To the residue in DMF (1.0 mL), DBU (0.08 mL, 0.54 mmol) was added and the reaction mixture was stirred for 30 minutes. Then 1-iodopropane (0.09 mL, 0.90 mmol) was added and the solution was stirred for 16 hours at room temperature. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate (20 mL) and saturated sodium bicarbonate (5 mL), washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (25 mg, 63% crude yield).
Reaction SMILES: [NH2:1][OH:2].[F:3][C:4]([F:23])([F:22])[C:5]1[N:9]2[N:10]=[C:11]([N:14]3[CH2:19][CH2:18][CH:17]([C:20]#[N:21])[CH2:16][CH2:15]3)[CH:12]=[CH:13][C:8]2=[N:7][N:6]=1>C(O)C>[OH:2][NH:1][C:20]([CH:17]1[CH2:18][CH2:19][N:14]([C:11]2[CH:12]=[CH:13][C:8]3[N:9]([C:5]([C:4]([F:23])([F:3])[F:22])=[N:6][N:7]=3)[N:10]=2)[CH2:15][CH2:16]1)=[NH:21]
Reactant: N#CC1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Reactant: NO
Solvent: CCO
Product: N=C(NO)C1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.6 %

Procedure:
Hydroxylamine (50% w/v aqueous solution) (0.669 mL, 10.13 mmol) was added to a stirred suspension of 1-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidine-4-carbonitrile (2.5 g, 8.44 mmol) in ethanol (16.88 mL) and the suspension was stirred at ambient temperature. Additional hydroxylamine (50% w/v aqueous solution) (3 mL) was added and stirring was continued for 18 hours. The mixture was then heated for 1 hour. The precipitate was collected by filtration, washed with EtOH and ether and dried under vacuum to afford N-hydroxy-1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidine-4-carboximidamide (2.380 g, 86%) as a colourless crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[C:7]1(=[O:13])[O:12][C:10](=[O:11])[CH2:9][CH2:8]1>>[Cl:1][C:2]1[S:3][C:4]([C:7](=[O:13])[CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)O1
Reactant: Clc1cccs1
Product: O=C(O)CCC(=O)c1ccc(Cl)s1
Yield: 74 %

Procedure:
As described for Example 1, 0.3 mole of 2-chlorothiophene is reacted with succinic anhydride to give 4-(5-chloro-2-thienyl)-4-ketobutyric acid (74%), m.p. 121°-123° C. The preceding compound is coupled to L-proline to give 1-[3-(5-chloro-2-thenoyl)propionyl]-L-proline (94%) as crystals, m.p. 131°-133° C. The above compound is reacted with bromine in acetic acid to give 1-[3-bromo-3-(5-chloro-2-thenoyl)propionyl]-L-proline as a glass. As for Example 1, reaction of the preceding compound with sodium thioacetate in ethanol gives the desired product (84%) as a glass.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[C:14]2[C:10]=1[C:11]([CH3:24])=[CH:12][N:13]2C(OC)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].C(Cl)(Cl)Cl>CO.O>[CH2:1]([O:8][C:9]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[C:14]2[C:10]=1[C:11]([CH3:24])=[CH:12][NH:13]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)n1cc(C)c2c(OCc3ccccc3)c(OC)ccc21
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1ccc2[nH]cc(C)c2c1OCc1ccccc1
Yield: 98.7 %

Procedure:
The 4-benzyloxy-5-methoxy-1-methoxycarbonyl-3-methylindole (5.3 g) was dissolved in methanol (60 ml). A solution of potassium hydroxide (40.0 g) in water (60 ml) was added to the solution, and the mixture was heated under reflux for 2 hours. The reaction mixture was poured into water, and chloroform extraction was conducted. The extract was washed with saturated saline and dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (Wako Gel C-200, 100 g). Elution with chloroform gave 4-benzyloxy-5-methoxy-3-methylindole (4.3 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[H-].[Na+].F[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1>CN(C)C=O.Cl[Cu]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Oc1ccccc1F
Agent: Cl[Cu]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ccccc2F)cc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 36.7 %

Procedure:
Into a 100 mL 3-necked round-bottom flask, was placed a solution of 2-fluorophenol (2.6 g, 23.19 mmol, 1.00 equiv) in N,N-dimethylformamide (30 mL) and CuCl (2.2 g, 2.41 equiv). This was followed by the addition of sodium hydride (1.34 g, 55.83 mmol, 0.86 equiv) in portions and then 1-fluoro-4-nitrobenzene (2.8 g, 19.84 mmol, 0.67 equiv). The resulting solution was stirred for 5 h at 100° C. in an oil bath and the resulting solution was diluted with water/ice. The aqueous mixture was extracted with ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was loaded onto a silica gel column and elution with ethyl acetate/petroleum ether (1:100) gave 1.7 g (31%) of 1-(2-fluorophenoxy)-4-nitrobenzene as a light yellow solid.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH2:11][OH:12])[CH2:3][CH2:2]1.C(Cl)Cl.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>O>[CH3:23][S:24]([O:12][CH2:11][CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[O:1][CH2:2][CH2:3]1)(=[O:26])=[O:25]
Reactant: OCC1CCOc2ccccc21
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC1CCOc2ccccc21
Reaction time: 2 h

Procedure:
To chroman-4-ylmethanol (15.0 g), methylene chloride (80 ml) and triethylamine (12.9 ml) was added dropwise methanesulfonyl chloride (6.85 ml) under ice-cooling, and the mixture was stirred for 2 hr. The reaction mixture was poured into water, and the mixture was extracted with methylene chloride. The extract was washed with water and saturated brine, dried over magnesium sulfate, and concentrated to give chroman-4-ylmethyl methanesulfonate.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[O:12][C@@H:11]([N:23]2[C:33]3[N:32]=[C:30]([NH2:31])[NH:29][C:27](=[O:28])[C:26]=3[N:25]=[CH:24]2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C[Si](Cl)(C)C.ClC([O:42][C:43]1C=CC=CC=1)=O.[NH3:49]>N1C=CC=CC=1>[Si:1]([O:8][C@@H:9]1[C@@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:20])([CH3:21])[CH3:22])([CH3:17])[CH3:18])[O:12][C@@H:11]([N:23]2[C:33]3[N:32]=[C:30]([NH:31][C:43](=[O:42])[NH2:49])[NH:29][C:27](=[O:28])[C:26]=3[N:25]=[CH:24]2)[CH2:10]1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(=O)[nH]c(N)nc32)C[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: O=C(Cl)Oc1ccccc1
Reactant: N
Agent: C[Si](C)(C)Cl
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(=O)[nH]c(NC(N)=O)nc32)C[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.5 %

Procedure:
3′,5′-Bis-O-(tert-butyldimethylsilyl)deoxyguanosine (2.8 g, 5.83 mmol) was azeotroped with anhydrous pyridine three times and then dissolved in anhydrous pyridine (60 mL), and trimethylsilyl chloride (1.11 mL, 8.75 mmol) was added thereto. The mixture was stirred at room temperature for 1 hour, and then phenyl chloroformate (1.10 mL, 8.75 mmol) was added thereto. The resulting mixture was stirred at room temperature for 4 hours, and 28% aqueous ammonia (4.1 mL, 29.1 mmol) was added thereto. The resulting mixture was stirred at room temperature for 2 hours. The reaction solution was extracted with ethyl acetate (250 mL)/water (200 mL) once and then with ethyl acetate (250 mL)/brine (150 mL) twice. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (25 g) with methanol/6% to 30% chloroform to give 3′,5′-bis-O-(tert-butyldimethylsilyl)-2-N-carbamoyldeoxyguanosine (2.12 g, 68%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][N+:4]=1[O-])[CH3:2].[CH3:14][N:15](C)C(Cl)=O.C(N(CC)CC)C.C[Si](C#N)(C)C>C(#N)C>[C:14]([C:5]1[CH:6]=[C:7]([CH:8]=[C:3]([CH2:1][CH3:2])[N:4]=1)[C:9]([O:11][CH3:12])=[O:10])#[N:15]
Reactant: CN(C)C(=O)Cl
Reactant: CCc1cc(C(=O)OC)cc[n+]1[O-]
Agent: C[Si](C)(C)C#N
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCc1cc(C(=O)OC)cc(C#N)n1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
Under N2, 2-ethyl-4-(methoxycarbonyl)pyridine 1-oxide (0.165 g, 911 μmol, Eq: 1.00) was dissolved in Acetonitrile (4 ml). Dimethylcarbamylchlorid (108 mg, 92.1 μl, 1.00 mmol, Eq: 1.1), triethylamine (175 mg, 239 μl, 1.73 mmol, Eq: 1.9) and Trimethylsilylcyanid (280 mg, 355 μl, 2.82 mmol, Eq: 3.10) were added and the RM was stirred at 90° C. overnight. The RM became an orange solution. Control with TLC: the reaction was finished. At RT, the RM was partitioned between water and EtOAc. The organic phase was dried over MgSO4; filtered; concentrated in vacuo: 350 mg; NMR: T205185. The crude material was purified by flash chromatography (silica gel, 20 g, 5% to 50% EtOAc in heptane). Light yellow oil.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([OH:16])[C:8](=[CH:13][C:14]=1[Cl:15])[C:9]([O:11][CH3:12])=[O:10])(=[O:3])[CH3:2].Br[CH:18]1[CH2:23][CH2:22][CH2:21][CH:20]=[CH:19]1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>O>[CH:18]1[CH2:23][CH2:22][CH2:21][CH:20]([O:16][C:7]2[CH:6]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[C:14]([Cl:15])=[CH:13][C:8]=2[C:9]([O:11][CH3:12])=[O:10])[CH:19]=1
Reactant: COC(=O)c1cc(Cl)c(NC(C)=O)cc1O
Reactant: BrC1C=CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(Cl)c(NC(C)=O)cc1OC1C=CCCC1
Temperature: 110 °C

Procedure:
A mixture of 2.5 g methyl 4-acetylamino-5-chlorosalicylate, 2 g of 3-bromocyclohexene, 2 g K2CO3 and 30 ml DMF are combined and heated at 110° C. overnight. The reaction mixture is then poured into water, filtered, dried and then extracted into ether. The ether solution is treated with charcoal, filtered and evaporated to dryness to obtain methyl 2-(cyclo-hexen-3-yloxy)-4-acetylamino-5-chlorobenzoate. This is then purified by recrystallization from ether/hexane. (M.P. 100°-102° C.)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:18]#N)[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH-:20].[K+].[OH2:22].Cl>C(O)CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:18]([OH:22])=[O:20])[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O
Reactant: [OH-]
Reactant: N#CC1(c2ccc(F)cc2)CCC2(CC1)OCCO2
Agent: Cl
Agent: [K+]
Solvent: OCCO
Product: O=C(O)C1(c2ccc(F)cc2)CCC2(CC1)OCCO2
Temperature: 25 °C

Procedure:
30.1 g of 8-(4-Fluoro-phenyl)-1,4-dioxa-spiro[4.5]decane-8-carbonitrile (74) were dissolved in 91 mL of ethylene glycol. 19.4 g of powdered potassium hydroxide were added and the mixture was heated to reflux until conversion was complete. The mixture was allowed to cool down to room temperature and poured into 300 mL of water. The pH was adjusted to 4 by addition of 2N HCl and the aqueous layer was extracted With ethyl acetate. The organic layer was extracted with brine, dried over magnesium sulfate and evaporated to dryness to give 29.85 g of the desired product. Rt=1.81 min (Method B). Detected mass: 281.2 (M+H+).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([OH:19])([C:15]([F:18])([F:17])[F:16])[C:11]([F:14])([F:13])[F:12])=[CH:6][CH:5]=1)[CH3:2].Cl[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)[O:25][C:26]=1[CH3:27]>CN(C=O)C>[CH2:1]([N:3]([CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)[O:25][C:26]=1[CH3:27])[C:4]1[CH:5]=[CH:6][C:7]([C:10]([OH:19])([C:11]([F:13])([F:14])[F:12])[C:15]([F:16])([F:18])[F:17])=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCNc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Reactant: Cc1oc(-c2cccc(C(F)(F)F)c2)nc1CCl
Solvent: CN(C)C=O
Product: CCN(Cc1nc(-c2cccc(C(F)(F)F)c2)oc1C)c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Yield: 49.4 %

Procedure:
A solution of 100 mg (0.35 mmol) of 2-(4-ethylamino-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol and 96 mg (0.35 mmol) of 4-chloromethyl-5-methyl-2-(3-trifluoromethyl-phenyl)-oxazole (example 22.1) in 0.5 mL of DMF was stirred overnight at 80° C. After distribution of the crude mixture between a saturated aqueous solution of NH4Cl and Et2O, the combined organic phases were dried over Na2SO4 and the solvent was evaporated. Column chromatography on silica gel with toluene/EtOAc gave 91 mg (53%) of 2-(4-{ethyl-[5-methyl-2-(3-trifluoromethyl-phenyl)-oxazol-4-ylmethyl]-amino}-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol, yellow solid, MS: 527 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:6]2=[N:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]([NH:15][CH2:16][CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][C:20]3=O)=[C:5]2[CH2:4][O:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O1CCCC1>O1CCCC1>[CH3:1][C:2]1([CH3:25])[C:6]2=[N:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]([NH:15][CH2:16][CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[C:5]2[CH2:4][O:3]1
Reactant: CC1(C)OCc2c1nc1ccccc1c2NCCCN1CCCC1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)OCc2c1nc1ccccc1c2NCCCN1CCCC1

Procedure:
A solution of 1,3-dihydro-3,3-dimethyl-9-[[3-(2-oxo-1-pyrrolidinyl)propyl]amino]-furo[3,4-b]quinoline (9.5 g, described in Example 36) in tetrahydrofuran (150 ml) is slowly added to a mixture of lithium aluminum hydride (9.5 g) in tetrahydrofuran (600 ml). The mixture is heated at reflux for 3 hours and cooled. A solution of water-tetrahydrofuran (1:1) is added dropwise and the mixture is filtered. The filtrate is evaporated and a mixture of water-chloroform is added to the residue. The organic phase is separated, dried and evaporated. The residue is subjected to chromatography on a column of alumina (activity II) using acetone-benzene (3:7) as eluant. Evaporation of the eluates and crystallization of the residual oil gives the title compound, mp 70°-75° C. Treatment of the title compound with a solution of hydrogen chloride in ether gives the hydrochloride salt of the title compound, mp 170°-175° C.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[NH2:6][C:7]1[C:20]2[C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:22])[C:11]=2[C:10]([NH2:23])=[C:9]([Cl:24])[C:8]=1[Cl:25].B(O)(O)O.S(=O)(=O)(O)O>>[C:1]([CH2:2][CH2:3][NH:23][C:10]1[C:11]2[C:12](=[O:22])[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:19](=[O:21])[C:20]=2[C:7]([NH:6][CH2:3][CH2:2][C:1]([OH:5])=[O:4])=[C:8]([Cl:25])[C:9]=1[Cl:24])([OH:5])=[O:4]
Reactant: C=CC(=O)O
Reactant: Nc1c(Cl)c(Cl)c(N)c2c1C(=O)c1ccccc1C2=O
Agent: O=S(=O)(O)O
Agent: OB(O)O
Product: O=C(O)CCNc1c(Cl)c(Cl)c(NCCC(=O)O)c2c1C(=O)c1ccccc1C2=O
Reaction time: 60 h
Yield: 93 %

Procedure:
20 Parts of acrylic acid are gradually added to a mixture of 15.8 parts of 1,4-diamino-2,3-dichloroanthraquinone, 3.1 parts of boric acid and 100 parts of 100% sulphuric acid at 25°-30° C, and the mixture is then stirred for 60 hours at 25°-30°. The reaction mixture is then processed as described in Example 1 to give 21 parts (93%) of 1,4-bis(β-carboxyethylamino)-2,3-dichloroanthraquinone.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:31])[C:13]([CH3:30])([CH3:29])[CH:14]([CH2:27][CH3:28])[NH:15][C:16](=[O:26])[C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][C:18]=2[F:25])[CH2:8][CH2:7]1)[CH3:2].[OH:33][CH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][CH:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:31])[C:13]([CH3:30])([CH3:29])[CH:14]([CH2:27][CH3:28])[NH:15][C:16](=[O:26])[C:17]2[CH:22]=[CH:21][C:20]([C:23]([N:37]3[CH2:38][CH2:39][CH:34]([OH:33])[CH2:35][CH2:36]3)=[NH:24])=[CH:19][C:18]=2[F:25])[CH2:10][CH2:11]1)[CH3:2]
Reactant: OC1CCNCC1
Reactant: CCOC(=O)CC1CCN(C(=O)C(C)(C)C(CC)NC(=O)c2ccc(C#N)cc2F)CC1
Product: CCOC(=O)CC1CCN(C(=O)C(C)(C)C(CC)NC(=O)c2ccc(C(=N)N3CCC(O)CC3)cc2F)CC1
Yield: 26 %

Procedure:
The same procedure as in Example 45 was performed with ethyl-N-(N-(4-cyano-2-fluorobenzoyl)-β-ethyl-α,α-dimethyl-β-alanyl)-4-piperidineacetate (1.4 g, 3.1 mmol) by using 4-hydroxypiperidine (3.1 g) as an amine to yield the titled compound (440 mg, 26%).
Reaction SMILES: [CH2:1]1[N:6]2[CH2:7][N:8]3[CH2:10][N:4]([CH2:5]2)[CH2:3][N:2]1[CH2:9]3.[Br:11][CH2:12][C:13]([C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)=[O:14]>C(Cl)(Cl)Cl>[Br-:11].[O:14]=[C:13]([C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)[CH2:12][N+:2]12[CH2:9][N:8]3[CH2:10][N:4]([CH2:5][N:6]([CH2:7]3)[CH2:1]1)[CH2:3]2
Reactant: C1N2CN3CN1CN(C2)C3
Reactant: O=C(CBr)c1cccs1
Solvent: ClC(Cl)Cl
Product: O=C(C[N+]12CN3CN(CN(C3)C1)C2)c1cccs1
Product: [Br-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.3 %

Procedure:
To a stirred mixture of 58.0 g (0.410 mole) of hexamethylenetetramine in 900 ml of chloroform was added 77.0 g (0.380 mole) of 2-bromo-1-thien-2-ylethanone. The mixture was stirred at room temperature for approximately 18 hours. A precipitate formed and was collected by filtration. The filter cake was washed with methylene chloride and was dried to yield 122.4 g of 1-(2-oxo-2-thien-2-ylethyl)-3,5,7-triaza-1-azoniatricyclo[3,3,1,13,7 ]decane bromide.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:15]([C:17]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=1B(O)O)=[O:16]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:18]2[C:17]([CH:15]=[O:16])=[CH:22][C:21]([O:23][CH3:24])=[CH:20][CH:19]=2)=[CH:3][CH:4]=1
Reactant: Brc1ccc(Br)cc1
Reactant: COc1ccc(B(O)O)c(C=O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(-c2ccc(Br)cc2)c(C=O)c1
Temperature: 90 °C
Yield: 56 %

Procedure:
A solution of 1,4-dibromobenzene (5.11 g, 21.67 mmol), potassium carbonate (6.91 g, 50.0 mmol) and 2-formyl-4-methoxyphenylboronic acid (3 g, 16.67 mmol) in DME (75 mL) and water (15 mL) (in a pressure vessel) was sparged with nitrogen for 15 min. Pd(Ph3P)4 (0.578 g, 0.500 mmol) was added and then the reaction was heated to 90° C. overnight. The reaction was cooled to r.t. and evaporated on rotovap. The residue was diluted with EtOAc and washed with water then brine, dried over MgSO4, filtered and evaporated to give the crude material. The crude material was purified by flash chromatography on the Biotage (5-15% EtOAc:Hex) to give 4′-bromo-4-methoxybiphenyl-2-carbaldehyde (2.72 g, 9.34 mmol, 56% yield) as a white solid. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 3.91 (s, 3H) 7.18-7.26 (m, 3H) 7.34 (d, J=824 Hz, 1H) 7.52 (d, J=2.75 Hz, 1H) 7.54-7.70 (m, 2H) 9.94 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][CH:9]=[C:10]([C:16]([O:18]CC)=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[CH:6][CH:7]=1>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([C:16](=[O:18])[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][NH:8]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=CNc1cccc(Br)c1)C(=O)OCC
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1c[nH]c2cc(Br)ccc2c1=O
Temperature: 250 °C
Yield: 69.4 %

Procedure:
Dowtherm (50 mL) was taken in double neck round bottom flask (100 mL) and heated to 250° C. in sand bath. At this temperature diethyl {[(3-bromophenyl)amino]methylidene}propanedioate (Intermediate 32, 10.0 g, 29.2 mmol) was added and the reaction temperature was maintained for another 1 h at 250° C. After completion of the reaction, the reaction mixture was cooled to room temperature, a white solid was collected by filtration and dried to yield 6.0 g (69.3%) ethyl 7-bromo-4-oxo-1,4-dihydroquinoline-3-carboxylate.