Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F-:1].[Cs+].Cl[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:13].Cl>CS(C)=O>[F:1][C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:13]
Reactant: [F-]
Reactant: Cc1cccc([N+](=O)[O-])c1Cl
Agent: Cl
Agent: [Cs+]
Solvent: CS(C)=O
Product: Cc1cccc([N+](=O)[O-])c1F
Temperature: 140 °C
Reaction time: 10 h
Yield: 81.9 %

Procedure:
Cesium fluoride (97.5 g, 642 mmol) was added under nitrogen atmosphere to a solution of 2-chloro-1-methyl-3-nitrobenzene (73.4 g, 428 mmol) in DMSO (185 mL), and the mixture was stirred at 140° C. for 10 hours. The reaction mixture was then poured into 0.5N hydrochloric acid and extracted twice with ethyl acetate. The organic extract was washed with saturated saline and dried over magnesium sulfate. A crude product was obtained by vacuum concentration, and then purified by reduced-pressure distillation (boiling point: 118° C. to 122° C./15 mm Hg) to yield the title compound (54.4 g, 82%) as a yellow oil.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.CCCC[Sn]([C:27]1[N:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(CCCC)CCCC>C1(C)C=CC=CC=1.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>[Cl:13][C:10]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([C:31]2[CH:30]=[CH:29][CH:28]=[CH:27][N:32]=2)[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2ncccc2c1Cl
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccn2)nc2ncccc2c1Cl
Temperature: 25 °C

Procedure:
The Stille coupled product was prepared according to Procedure E using 2,4-dichloro-3-methyl-1,8-naphthyridine (540 mg, 2.53 mmol), 2-(1,1,1-tributylstannyl)pyridine (933 μL, 2.53 mmol), Pd(PPh3)4 in toluene (10 mL) and heating at reflux for 14 h. The reaction was allowed to cool to rt and evaporated in vacuo. The resulting residue was triturated with hexanes and the solid was dried under vacuum to give 4-chloro-3-methyl-2-(pyridin-2-yl)-1,8-naphthyridine. 1H NMR (400 MHz, CDCl3) δ ppm 9.14 (1H, dd, J=4.3, 2.0 Hz), 8.72 (1H, ddd, J=4.9, 1.8, 1.0 Hz), 8.65 (1H, dd, J=8.3, 1.9 Hz), 8.09 (1H, dt, J=8.0, 1.1 Hz), 7.90 (1H, td, J=7.7, 1.8 Hz), 7.60 (1H, dd, J=8.3, 4.2 Hz), 7.40 (1H, ddd, J=7.6, 4.8, 1.3 Hz), 2.75 (3H, s)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:33][CH2:34]C=CCCC)[CH2:10][N:11]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])[C:12]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[C:16]([C:24]#[N:25])[C:15]=2[CH2:26][CH3:27])=[O:13])[CH:5]=[CH:6][C:7]=1[Cl:8].C1C[O:43]CC1.[O-]S([O-])(=S)=O.[Na+].[Na+]>O=[Os](=O)(=O)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:33][CH:34]=[O:43])[CH2:10][N:11]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])[C:12]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[C:16]([C:24]#[N:25])[C:15]=2[CH2:26][CH3:27])=[O:13])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCCC=CCCC(CN(CCC(=O)O)C(=O)c1c(CC)c(C#N)cc2ccccc12)c1ccc(Cl)c(Cl)c1
Reactant: C1CCOC1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Product: CCc1c(C#N)cc2ccccc2c1C(=O)N(CCC(=O)O)CC(CC=O)c1ccc(Cl)c(Cl)c1
Reaction time: 18 h

Procedure:
To a stirred slurry of N-[2-(3,4-dichlorophenyl)-4-pentenylbutyl]-N-[(carboxymethyl)methyl]-3-cyano-2-ethyl-1-naphthamide (0.51 g) and NaIO4 (0.47 g) in 100 mL 1:1 THF:H2O was slowly added 0.32 mL OsO4 solution (4% w/w in H2O). Mixture was stirred for 18 h, 10 mL sat'd Na2S2O3(aq) was added, THF was evaporated, and aqueous residue was extracted with DCM. Extracts were dried over Na2SO4, filtered, and concentrated. This gave 0.64 g of N-[2-(3,4-dichlorophenyl)-4-oxobutyl]-N-[(carboxymethyl)methyl]-3-cyano-1-naphthamide after purification by chromatography (100:1, DCM:MeOH); MS: m/z 511 (M+); 1H NMR (CDCl3) δ 9.53 (s), 8.25 (s), 7.79 (d), 7.70-7.20 (m), 6.89 (d), 6.73 (d), 6.48 (dd), 4.58-4.20 (m), 3.88 (s), 3.84 (s), 3.60-3.21 (m), 3.18-2.82 (m), 2.65-2.32 (m), 1.33 (t).
Reaction SMILES: [Cl:1][C:2]([Cl:33])([Cl:32])[CH2:3][O:4][C:5]([NH:7][C:8]1[C:9]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)=[N:10][O:11][N:12]=1)=[O:6].O[CH:35]([CH2:40][CH:41]([CH3:43])[CH3:42])[C:36]([O:38][CH3:39])=[O:37].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>CN(C=O)C.O>[C:28]([O:27][C:25]([N:22]1[CH2:21][CH2:20][N:19]([C:16]2[CH:17]=[CH:18][C:13]([C:9]3[C:8]([N:7]([C:5]([O:4][CH2:3][C:2]([Cl:32])([Cl:1])[Cl:33])=[O:6])[C@H:35]([C:36]([O:38][CH3:39])=[O:37])[CH2:40][CH:41]([CH3:43])[CH3:42])=[N:12][O:11][N:10]=3)=[CH:14][CH:15]=2)[CH2:24][CH2:23]1)=[O:26])([CH3:30])([CH3:29])[CH3:31]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3nonc3NC(=O)OCC(Cl)(Cl)Cl)cc2)CC1
Reactant: COC(=O)C(O)CC(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CC(C)C)N(C(=O)OCC(Cl)(Cl)Cl)c1nonc1-c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To tert-butyl 4-[4-(4-{[(2,2,2-trichloroethoxy)carbonyl]amino}-1,2,5-oxadiazol-3-yl)phenyl]piperazine-1-carboxylate (485 mg, 0.932 mmol), methyl 2-hydroxy-4-methylpentanoate (275 mg, 1.87 mmol) and triphenyl phosphine (490 mg, 1.87 mmol) in dry DMF (15 mL) at 0° C. under dry nitrogen was added diisopropyl azodicarboxylate (0.375 mL, 1.87 mmol) dropwise over ½ hour and the reaction mixture stirred overnight at rt. The reaction was poured into water and the product extracted with Et2O (2×), dried over Na2SO4, concentrated in vacuo and purified by flash chromatography over silica gel (EtOAc/Hex, 2/8) to afford methyl N-(4-{4-[4-(tert-butoxycarbonyl)piperazin-1-yl]phenyl}-1,2,5-oxadiazol-3-yl)-N-[(2,2,2-trichloroethoxy)carbonyl]leucinate.
Reaction SMILES: [NH:1]1[C:14]2[CH:13]=[N:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[O:4][CH2:3][CH2:2]1.[Br:15][C:16]1[CH:17]=[C:18]([CH:22]=[C:23]([Br:27])[C:24]=1[O:25][CH3:26])[C:19](Cl)=[O:20].C(N(CC)CC)C.Cl>ClCCl>[Br:15][C:16]1[CH:17]=[C:18]([C:19]([N:1]2[C:14]3[CH:13]=[N:12][C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:5]=3[O:4][CH2:3][CH2:2]2)=[O:20])[CH:22]=[C:23]([Br:27])[C:24]=1[O:25][CH3:26]
Reactant: COc1c(Br)cc(C(=O)Cl)cc1Br
Reactant: c1ccc2c3c(cnc2c1)NCCO3
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1c(Br)cc(C(=O)N2CCOc3c2cnc2ccccc32)cc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.5 %

Procedure:
In a 10 ml flask, 2,3-dihydro-1H-4-oxa-1,9-diaza-phenanthrene (50 mg, 0.269 mmol) and 3,5-dibromo-4-methoxy-benzoyl chloride (88 mg, 0.269 mmol) were dissolved in dichloromethane. Triethylamine (0.51 ml, 3.7 mmol) was added thereto and then stirred at room temperature for 3 hours. After neutralizing with 1N hydrochloric acid solution, the mixture was extracted with dichloromethane, and the combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on amine silica eluting with a solvent of dichloromethane:methanol=20:1. The fractions containing the product were collected and evaporated to obtain the target compound as yellow solid (110 mg, 86%).
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([N+:14]([O-])=O)=[CH:11][CH:12]=2)[CH:7]=[C:6]1[C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)=[O:18].C([O-])=O.[NH4+]>C(OCC)(=O)C.C(O)C.[Pd]>[NH2:14][C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[N:5]([CH2:4][C:3]1[CH:27]=[CH:28][C:29]([F:31])=[CH:30][C:2]=1[F:1])[C:6]([C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)=[O:18])=[CH:7]2
Reactant: O=C(Nc1ccc(F)cc1)c1cc2cc([N+](=O)[O-])ccc2n1Cc1ccc(F)cc1F
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ccc2c(c1)cc(C(=O)Nc1ccc(F)cc1)n2Cc1ccc(F)cc1F

Procedure:
485 mg (1.14 mmol) of 1-(2,4-difluorobenzyl)-N-(4-fluorophenyl)-5-nitro-1H-indole-2-carboxamide from Example XXIV are initially charged in ethyl acetate and ethanol. 287 mg (4.56 mmol) of ammonium formate and 49 mg of palladium on activated carbon (10%) are added. The mixture is heated to reflux, and at 50° C. gas evolves. To bring the reaction to completion, the same amounts of ammonium formate and palladium as above are added. After a further 3 hours at reflux, the mixture is cooled and filtered off through kieselguhr, which is washed with 500 ml of ethanol. The solvent is removed under reduced pressure and the residue is dried.
Reaction SMILES: [I-].[NH2:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][N+:9]([CH3:13])=[CH:10]2)=[CH:5][CH:4]=1.[CH3:14][Mg]Cl.O>O1CCCC1>[NH2:2][C:3]1[CH:12]=[C:11]2[CH:6]([CH2:7][CH2:8][N:9]([CH3:13])[CH:10]2[CH3:14])[CH2:5][CH:4]=1
Reactant: C[Mg]Cl
Reactant: C[N+]1=Cc2cc(N)ccc2CC1
Agent: [I-]
Solvent: O
Solvent: C1CCOC1
Product: CC1C2=CC(N)=CCC2CCN1C
Temperature: -78 °C
Reaction time: 18 h
Yield: 98 %

Procedure:
(±) 7-Amino-2-methyl-3,4-dihydroisoquinolinium iodide (0.50 g, 1.7 mmol) was suspended in anhydrous tetrahydrofuran (50 ml) and cooled to −78° C. The cooled solution was treated with methyl magnesium chloride (2.14 ml of a 3M solution in THF, 6.96 mmol), added as a single portion. The reaction was allowed to reach 25° C. over 18 h before being poured into water (50 ml). The organic solvent was removed in vacuo and the organic product extracted into dichloromethane. Drying over magnesium sulfate and evaporation in vacuo furnished the title compound as a pale yellow oil (0.3 g, 98%). For ease of handling the product was converted into a monohydrochloride.
Reaction SMILES: C([Li])(CC)C.[F:6][C:7]1[CH:8]=[C:9]([N:13]2[Si](C)(C)CC[Si]2(C)C)[CH:10]=[CH:11][CH:12]=1.[C:22]1([CH:28]([N:35]2[CH2:38][C:37](=[O:39])[CH2:36]2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>C1CCCCC1.C1COCC1>[NH2:13][C:9]1[CH:10]=[CH:11][C:12]([C:37]2([OH:39])[CH2:38][N:35]([CH:28]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:36]2)=[C:7]([F:6])[CH:8]=1
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: C[Si]1(C)CC[Si](C)(C)N1c1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: Nc1ccc(C2(O)CN(C(c3ccccc3)c3ccccc3)C2)c(F)c1
Reaction time: 2 h

Procedure:
Sec. butyllithium (22.5 mL of a 1.3M solution in cyclohexane, 29.5 mmol) was added dropwise to a stirred solution of 1-(3-fluorophenyl)-2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane (Example 20, Step 1) (6.0 g, 23.7 mmol) at −78° C. under nitrogen in dry THF (75 mL). After 2 hr a solution of 1-(1,1-diphenylmethyl)azetidin-3-one (5.6 g, 23.6 mmol) in dry THF (60 mL) was added dropwise and stirring continued at −78° for 2 hr, when the cooling bath was removed. After reaching room temperature, a solution of saturated ammonium chloride (75 mL) was added followed by water (200 mL). The mixture was extracted with ether (500 mL), washed with brine (100 mL), dried over magnesium sulfate, filtered and evaporated. The residue was dissolved in methanol (150 mL) and anhydrous potassium carbonate (6.0 g, 43.5 mmol) added and then stirred overnight. The suspension was filtered and the filtrate evaporated. The residue was partitioned between ether (500 mL) and water (200 mL). The water was extracted with additional ether (200 mL) and the combined ether extracts washed with brine (100 mL), dried over magnesium sulfate, filtered and evaporated to afford an orange foam. Chromatography over silica gel (150 g, 40-60 μm) eluting with 25-50% ethyl acetate-hexane gave the title compound as a pale yellow foam. 1H NMR δ (CDCl3): 2.62, 3.53, 3.78, 4.41, 6.36, 6.41, 7.03, 7.14-7.30, 7.39-7.47.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:18]([OH:20])=O)[C:5]2[C:10]([I:11])=[N:9][N:8]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[C:6]=2[N:7]=1.[C:21]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O1CCCC1.CN(C)C(=O)C>[C:24]([O:23][C:21]([N:28]1[CH2:33][CH2:32][N:31]([C:18]([C:4]2[C:5]3[C:10]([I:11])=[N:9][N:8]([CH:12]4[CH2:17][CH2:16][CH2:15][CH2:14][O:13]4)[C:6]=3[N:7]=[C:2]([Cl:1])[CH:3]=2)=[O:20])[CH2:30][CH2:29]1)=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)c1cc(Cl)nc2c1c(I)nn2C1CCCCO1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc(Cl)nc3c2c(I)nn3C2CCCCO2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 99.2 %

Procedure:
To a solution of 6-chloro-3-iodo-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (17 g, 42 mmol) in a mixture of tetrahydrofuran (250 mL) and N,N-dimethylacetamide (40 mL) were added 1-boc-piperazine (8.6 g, 46 mmol), 1-hydroxybenzotriazole (0.56 g, 4.2 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (8.03 g, 42 mmol). The reaction mixture was stirred at room temperature for 20 hours and then the THF was evaporated under vacuum. An aqueous solution of bicarbonate (200 mL) was then added and the mixture stirred for 1 hour. The precipitate was filtered, washed with water, and then dried to afford the title compound as a yellow solid (24 g, 100%).
Reaction SMILES: C[O:2][C:3]1[C:12]2[C@@H:11]3[CH2:13][C:14](=[O:17])[CH2:15][CH2:16][C@H:10]3[C:9]([CH3:19])([CH3:18])[O:8][C:7]=2[CH:6]=[C:5]([C:20]([CH3:28])([CH3:27])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:4]=1.B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[C:12]2[C@@H:11]3[CH2:13][C:14](=[O:17])[CH2:15][CH2:16][C@H:10]3[C:9]([CH3:18])([CH3:19])[O:8][C:7]=2[CH:6]=[C:5]([C:20]([CH3:27])([CH3:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:4]=1
Reactant: CCCCCCC(C)(C)c1cc(OC)c2c(c1)OC(C)(C)[C@@H]1CCC(=O)C[C@@H]21
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCCCCC(C)(C)c1cc(O)c2c(c1)OC(C)(C)[C@@H]1CCC(=O)C[C@@H]21

Procedure:
A solution of dl-trans-1-methoxy-3-(1,1-dimethylheptyl)-6,6-dimethyl-6,6a,7,8,10,10a-hexahydro-9H-dibenzo[b,d]pyran-9-one (prepared as described in Example 1) and boron tribromide in dichloromethane is stirred for about eight hours at about 40° C. The reaction mixture is then washed with water, dried, and the solvent is removed by evaporation under reduced pressure to give dl-trans-1-hydroxy-3-(1,1-dimethylheptyl)-6,6-dimethyl-6,6a,7,8,10,10a-hexahydro-9H-dibenzo[b,d]pyran-9-one. This compound is known as nabilone and is especially useful in the treatment of nausea in humans.
Reaction SMILES: C[O:2][C:3](=[O:24])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:15]2[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:14]=2[O:13][C:12]1=[O:23].[OH-].[Na+]>>[N+:20]([C:17]1[CH:18]=[CH:19][C:14]2[O:13][C:12](=[O:23])[N:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:24])=[O:2])[C:15]=2[CH:16]=1)([O-:22])=[O:21]
Reactant: COC(=O)CCCCCCCn1c(=O)oc2ccc([N+](=O)[O-])cc21
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCCCCCn1c(=O)oc2ccc([N+](=O)[O-])cc21

Procedure:
The product is produced as described in example 22 from 18.3 g. of 8-(5-nitro-2-oxo-benzoxazolin-3-yl)-caprylic acid methyl ester and 2.4 g. of NaOH. Eluant in chromatographic purification: chloroform.
Reaction SMILES: [C:1]1([NH2:15])[N:2]=[C:3]([NH2:14])[N:4]=[C:5]2[C:10]=1[C:9]1[CH:11]=[CH:12][NH:13][C:8]=1[CH:7]=[CH:6]2.[H-].[Na+].Cl[C:19]1[S:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1>CN(C)C=O>[S:20]1[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=[C:19]1[N:13]1[C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[C:1]([NH2:15])[N:2]=[C:3]([NH2:14])[N:4]=3)[C:9]=2[CH:11]=[CH:12]1
Reactant: Nc1nc(N)c2c(ccc3[nH]ccc32)n1
Reactant: Clc1nc2ccccc2s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1nc(N)c2c(ccc3c2ccn3-c2nc3ccccc3s2)n1
Reaction time: 11 h

Procedure:
To 3.98 g. 7H-pyrrolo[3,2-f]quinazoline-1,3-diamine dissolved in 250 ml. dry dimethylformamide are added, with stirring under nitrogen, 1.15 g. ca. 50% sodium hydride-mineral oil dispersion. After stirring for 1.5 hours, 3.90 g. 2-chlorobenzothiazole are added and the mixture is heated at 95° for 3 hours. An additional 1.29 g. 2-chlorobenzothiazole are added and heating at 95° is continued for 11 hours. A third portion of 2-chlorobenzothiazole (1.29 g.) is added and heating at 95° is continued for 8 hours. The reaction mixture is processed as in Example 69 and the crude product is recrystallized (twice) from dimethylformamide and is thoroughly dried to yield 2.30 g. title compound, m.p. 326° (dec).
Reaction SMILES: [OH-:1].[Na+].[NH2:3][C:4]1[CH:22]=[CH:21][C:7]([C:8]([C:10]2[N:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]3=[C:12]([C:19]#[N:20])[N:11]=2)=[O:9])=[CH:6][C:5]=1[O:23][CH3:24]>C(O)C>[NH2:3][C:4]1[CH:22]=[CH:21][C:7]([C:8]([C:10]2[N:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]3=[C:12]([C:19]([NH2:20])=[O:1])[N:11]=2)=[O:9])=[CH:6][C:5]=1[O:23][CH3:24]
Reactant: [OH-]
Reactant: COc1cc(C(=O)c2nc(C#N)c3ccccn23)ccc1N
Agent: [Na+]
Solvent: CCO
Product: COc1cc(C(=O)c2nc(C(N)=O)c3ccccn23)ccc1N
Yield: 58.8 %

Procedure:
4.4 ml (26.4 mmol) of 6N aqueous sodium hydroxide solution are added to 0.5 g (1.7 mmol) of 3-(4-amino-3-methoxybenzoyl)imidazo[1,5-a]pyridine-1-carbonitrile obtained in example 85 in 50 ml of ethanol under a nitrogen atmosphere. After heating at reflux for 2 hours, the reaction medium is concentrated under reduced pressure. The residue obtained is washed with water, with acetone and with ethyl ether and then dried. 0.447 g of a yellow solid is collected. The product is salified by addition of a 1N solution of hydrochloric acid in ethyl ether. 0.310 g of a yellow solid is obtained. Melting point: 241° C.; 1H NMR (d6-DMSO): 3.89 (3H, s), 6.74 (1H, d), 7.24-7.27 (1H, m), 7.45-7.49 (1H, m), 7.88 (1H, s), 8.33 (1H, d), 8.42 (1H, d), 9.65 (1H, d)
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.C(N1C(=O)[C:23]([CH3:26])=[C:22]([CH3:27])[N:21]=[C:20]1[C@H:28]([N:32]([CH2:42][CH2:43][N:44]1C(=O)C2C(=CC=CC=2)C1=O)[C:33](=O)[C:34]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=1)[CH:29]([CH3:31])[CH3:30])C1C=CC=CC=1.O.NN>C(O)C>[CH2:4]([N:5]1[C:1](=[O:11])[C:23]([CH3:26])=[C:22]([CH3:27])[N:21]=[C:20]1[C@H:28]([N:32]1[CH2:42][CH2:43][N:44]=[C:33]1[C:34]1[CH:35]=[CH:36][C:37]([CH3:40])=[CH:38][CH:39]=1)[CH:29]([CH3:31])[CH3:30])[C:3]1[CH:2]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1ccc(C(=O)N(CCN2C(=O)c3ccccc3C2=O)[C@@H](c2nc(C)c(C)c(=O)n2Cc2ccccc2)C(C)C)cc1
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1ccc(C2=NCCN2[C@@H](c2nc(C)c(C)c(=O)n2Cc2ccccc2)C(C)C)cc1
Temperature: 120 °C

Procedure:
The phthalimide protected amine, N-[(R)-1-(1-benzyl-4,5-dimethyl-6-oxo-1,6-dihydro-pyrimidin-2-yl)-2-methyl-propyl]-N-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-4-methyl-benzamide, (0.075 g, 0.13 mMol) was treated with hydrazine monohydrate (0.013 ml, 0.26 mMol) in ethanol (1 mL at 70° C. for 12 h. The reaction was filtered, concentrated under vacuum and dissolved in toluene (1 mL) and heated to 120° C. for 20 h. The reaction was concentrated under vacuum, taken up in CH3CN and purified by reverse phase HPLC (YMC, ODS-A, 20 min, 5–90% gradient, CH3CN : H2O, 0.1% TFA) The fractions were collected and evaporated to give the title compound as a clear oil. (0.016 g): MS (ES) m/e 429.4 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH2:17][C:18]1[CH:30]=[C:29]([CH2:31][CH2:32][CH2:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:28]=[CH:27][C:19]=1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>C(Cl)Cl>[C:8]([NH:17][C:18]1[CH:30]=[C:29]([CH2:31][CH2:32][CH2:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:28]=[CH:27][C:19]=1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)c1ccc(CCCCc2ccccc2)cc1N
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(CCCCc2ccccc2)cc1NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
0.34 mL of triethylamine and 0.15 mL of benzoyl chloride were added to 4 mL of methylene chloride solution containing 0.40 g tert-butyl 2-amino-4-(4-phenylbutyl)benzoate while ice-cooled sequentially and stirred at room temperature for 19 hours. The solvent was evaporated under reduced pressure, and the obtained residue was purified with silica gel column chromatography [eluent; hexane:ethyl acetate=20:1]to obtain 0.50 g of tert-butyl 2-(benzamido)-4-(4-phenylbutyl)benzoate as white solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([NH:17][C:18](=[O:38])[C:19]2[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([O:27][CH2:28][CH2:29][O:30]CC3C=CC=CC=3)[CH:20]=2)([CH3:16])[CH3:15])[N:5]=[C:4]([CH3:39])[C:3]=1[C:40]([OH:42])=[O:41]>CCO.CCOC(C)=O.[Pd]>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([NH:17][C:18](=[O:38])[C:19]2[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([O:27][CH2:28][CH2:29][OH:30])[CH:20]=2)([CH3:15])[CH3:16])[N:5]=[C:4]([CH3:39])[C:3]=1[C:40]([OH:42])=[O:41]
Reactant: COc1cc(OCCOCc2ccccc2)cc(C(=O)NC(C)(C)COc2cccc3nc(C)c(C(=O)O)c(N)c23)c1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cc(OCCO)cc(C(=O)NC(C)(C)COc2cccc3nc(C)c(C(=O)O)c(N)c23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.9 %

Procedure:
To a solution of 4-amino-5-(2-(3-(2-(benzyloxy)ethoxy)-5-methoxybenzamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylic acid (Example 38a, 237 mg, 0.5 mmol) in EtOH/EtOAc (1:1, 20 mL) was added 10% Pd/C (wet, 50 mg). The suspension was then stirred under an atmosphere of hydrogen at room temperature overnight. The Pd/C was filtered off, and the filtrate was concentrated. The residue was purified by HPLC (eluent: 10-100% MeOH in H2O) to give the title compound as an off-white solid (152 mg, 63%). 1H NR (400 MHz, DMSO-d6) δ 1.49 (s, 6H), 2.75 (s, 3H), 3.68 (t, J=5.2 Hz, 2H), 3.73 (s, 3H), 3.99 (t, J=5.2 Hz, 1H), 4.47 (s, 2H), 6.57 (s, 1H), 6.88 (s, 1H), 6.96 (s, 1H), 7.06 (d, J=7.6 Hz, 1H), 7.28 (d, J=8 Hz, 1H), 7.67 (t, J=8 Hz, 1H), 8.14 (s, 1H). MS 484 (MH+).
Reaction SMILES: [O:1]=[C:2]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:16](O)=[O:17])[C:10]=2[NH:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.ON1C2C=CC=CC=2N=N1.[Br:29][CH2:30][CH2:31][CH2:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([NH2:40])=[CH:36][CH:35]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C=O)C>[Br:29][CH2:30][CH2:31][CH2:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([NH:40][C:16]([C:11]2[C:10]3[NH:9][C:8]4[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=4)[C:2](=[O:1])[C:15]=3[CH:14]=[CH:13][CH:12]=2)=[O:17])=[CH:36][CH:35]=1
Reactant: Nc1ccc(OCCCBr)cc1
Reactant: O=C(O)c1cccc2c(=O)c3ccccc3[nH]c12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(OCCCBr)cc1)c1cccc2c(=O)c3ccccc3[nH]c12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 9,10-dihydro-9-oxo-4-acridinecarboxylic acid (1.5 g) and 1-hydroxybenzotriazole (1.1 g) in DMF (50 ml) was stirred at room temperature for 10 min. The product of part (ii) above (1.5 g) was then added followed by dicyclohexylcarbodiimide (1.3 g), and the mixture was stirred at room temperature for 16 h and then filtered. The filtrate was concentrated in vacuo, treated with water and extracted with dichloromethane. The combined, dried organic extracts were concentrated to give the title compound (0.5 g) which was recrystallised from acetonitrile, MP 126°.