Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13](O)=[O:14])[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C1COCC1.[H-].CN1CCN([Al+]N2CCN(C)CC2)CC1.C(OCC)C>O>[NH:1]([C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[CH:13]=[O:14])[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH:4]=[O:5]
Reactant: O=C(O)c1ccccc1Nc1ccccc1C(=O)O
Agent: CN1CCN([Al+]N2CCN(C)CC2)CC1
Agent: [H-]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1ccccc1Nc1ccccc1C=O
Temperature: -20 °C
Reaction time: 24 h
Yield: 33.4 %

Procedure:
To a 500-ml reactor thoroughly dried and purged with argon, 2.3 g (8.94 mmol) of 2,2′-iminodibenzoic acid and 50 ml of THF were introduced, and they were cooled to −20° C. At that temperature, 90 ml of a THF solution (0.3 M) of bis(1-methylpiperazine-4-yl)aluminum hydride was dropwise added with stirring. Then, the temperature of the system was raised, and the reaction was conducted for 24 hours under reflux. The reaction solution was allowed to stand for cooling to room temperature. To the solution, 100 ml of diethyl ether was added, and 150 ml of water was further added slowly with ice cooling. The oil layer obtained by phase separation was concentrated and subjected to isolation by means of silica gel column chromatography to obtain 673 mg of 2,2′-iminodibenzaldehyde. To a 100-ml reactor thoroughly dried and purged with argon, 650 mg (2.89 mmol) of the 2,2′-iminodibenzaldehyde, 699 mg (5.77 mmol) of 2,6-dimethylaniline, 50 ml of dehydrated methanol and 0.2 ml of acetic acid were introduced, and they were reacted at room temperature for 12 hours. From the reaction solution, the solvent was distilled off, and the remainder was subjected to isolation by means of silica gel column chromatography to obtain 237 mg (yield: 6.1%) of a compound represented by the following formula (L6).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH3:8][N:9]1[C:17]2[C:16](=[O:18])[NH:15][C:14]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=3)=[N:13][C:12]=2[C:11]([CH2:30][CH2:31][CH3:32])=[N:10]1>C(O)C>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([S:26]([C:23]2[CH:24]=[CH:25][C:20]([CH2:19][C:14]3[NH:15][C:16](=[O:18])[C:17]4[N:9]([CH3:8])[N:10]=[C:11]([CH2:30][CH2:31][CH3:32])[C:12]=4[N:13]=3)=[CH:21][CH:22]=2)(=[O:27])=[O:28])[CH2:4][CH2:3]1
Reactant: CN1CCNCC1
Reactant: CCCc1nn(C)c2c(=O)[nH]c(Cc3ccc(S(=O)(=O)Cl)cc3)nc12
Solvent: CCO
Product: CCCc1nn(C)c2c(=O)[nH]c(Cc3ccc(S(=O)(=O)N4CCN(C)CC4)cc3)nc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N-methyl piperazine (1.28 ml, 0.0115 mol) was added to a solution of 4-[(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)methyl]-1-benzenesulfonyl chloride (1.35 g, 0.0035 mol) in ethanol (20 ml) and the reaction stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure and the residue partitioned between dichloromethane (50 ml) and water (20 ml). The aqueous phase was extracted with further dichloromethane (50 ml), the combined organic extracts dried (MgSO4), filtered, and evaporated under reduced pressure.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9]O[C:7]=2[CH2:6][CH2:5][CH2:4][CH2:3]1.C([O-])(=O)C.[NH4+:21]>CN(C)C=O>[O:1]=[C:2]1[C:11]2[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][NH:21][C:7]=2[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CCOC(=O)c1coc2c1C(=O)CCCC2
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c[nH]c2c1C(=O)CCCC2
Temperature: 115 °C
Yield: 50.7 %

Procedure:
A mixture of ethyl 4-oxo-5,6,7,8-tetrahydro-4H-cyclohepta[b]furan-3-carboxylate (3.48 g, 15.7 mmol) and ammonium acetate (2.41 g, 31.3 mmol) in N,N-dimethylformamide (25 mL) was heated at 115° C. for 6 hours. The mixture was concentrated in vacuo, ice water was added, then extracted 2× with dichloromethane. The combined organic layers were washed with saturated aqueous sodium bicarbonate then brine, dried over sodium sulfate, filtered through a small pad of Silica gel (1:19 methyl alcohol/dichloromethane), and the filtrate concentrated in vacuo to give ethyl 4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxylate (1.76 g). A solution of this ester in aqueous 5N sodium hydroxide (30 mL) and ethyl alcohol (6 mL) was heated at reflux for 1 hour, then cooled in an ice bath. The mixture was acidified with hydrochloric acid, and the precipitate collected, rinsed with water followed by diethyl ether and allowed to dry to give 4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxylic acid (1.17 g). m.p. 225°-227° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[CH:11][C:12]([O:14][CH2:15][CH2:16][N:17]3[CH:21]=[CH:20][N:19]=[CH:18]3)=[CH:13][C:7]=2[CH:6]=1)=[O:4].[ClH:22]>>[OH2:2].[ClH:22].[N:17]1([CH2:16][CH2:15][O:14][C:12]2[CH:11]=[CH:10][C:8]3[S:9][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=3[CH:13]=2)[CH:21]=[CH:20][N:19]=[CH:18]1.[N:17]1([CH2:16][CH2:15][O:14][C:12]2[CH:11]=[CH:10][C:8]3[S:9][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=3[CH:13]=2)[CH:21]=[CH:20][N:19]=[CH:18]1.[ClH:22]
Reactant: COC(=O)c1cc2cc(OCCn3ccnc3)ccc2s1
Agent: Cl
Product: O
Product: O=C(O)c1cc2cc(OCCn3ccnc3)ccc2s1

Procedure:
A mixture of 5-[2-(1-imidazolyl)ethoxy]benzo[b]thiophene-2-carboxylic acid methyl ester (0.35 g.) and concentrated hydrochloric acid (5 ml.) was heated on a steam bath for 5 hours and then evaporated. The residue was crystallized twice from ethanol/ether to give 5-[2-(1-imidazolyl)ethoxy]benzo[b]-thiophene-2-carboxylic acid hydrochloride hemihydrate (0.23 g.), m.p. 255°-258° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:5][C:6]=1[CH:7]=[O:8].CS(O[CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH3:25])(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C.O>[Cl:1][C:2]1[N:3]=[C:4]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:5]([CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH3:25])[C:6]=1[CH:7]=[O:8]
Reactant: COCCCCOS(C)(=O)=O
Reactant: O=Cc1[nH]c(-c2ccccc2)nc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COCCCCn1c(-c2ccccc2)nc(Cl)c1C=O
Temperature: 90 °C
Reaction time: 7 h
Yield: 99.1 %

Procedure:
To a solution of 4-chloro-2-phenyl-1H-imidazole-5-carbaldehyde (500 mg) and 4-methoxybutyl methanesulfonate (660 mg) in N,N-dimethylacetamide (10 ml) was added cesium carbonate (2.4 g); and the mixture was stirred at 90° C. for 7 hr. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (5:95-3:7) was concentrated under reduced pressure to give the object product (702 mg).
Reaction SMILES: I[C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(N(CC)CC)C.[C:17]([N:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[C:29]#[CH:30])([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>CN(C=O)C.Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:17]([N:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[C:29]1[O:9][C:3]2[C:2](=[N:7][C:6]([CH3:8])=[CH:5][CH:4]=2)[CH:30]=1)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]
Reactant: C#C[C@@H]1CCCN1C(=O)OC(C)(C)C
Reactant: Cc1ccc(O)c(I)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc2oc([C@@H]3CCCN3C(=O)OC(C)(C)C)cc2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 3.10 g (13.2 mmol) sample of 6-iodo-2-picoline-5-ol (Aldrich Chem. Co.) was dissolved in 5 mL of DMF, and (Ph3P)2PdCl2 (0.38 g, 0.50 mmol), CuI (0.377 g, 1.98 mmol) and triethylamine (1.80 mL, 13.2 mmol) were added. The mixture was stirred under N2 at room temperature for 1 hour, then 2.15 g (11 mmol) of 1-BOC-2-(S)-ethynylpyrrolidine, from Example 1c above, dissolved in 1 mL of DMF, was added carefully. The reaction was stirred at 60° C. for 16 hours, then cooled to room temperature. The reaction mixture was diluted with 2 N HCl and extracted with ether. The aqueous layer was adjusted to pH 10 with K2CO3, then extracted with CH2Cl2. The extract was washed with 20% NaOH, brine, dried over MgSO4, and the solvent was removed. The residue was repeatedly dissolved in toluene and distilled to azeotropically remove the DMF. The residue was chromatographed on silica gel, eluting with 100:0 to 50:50 hexane:EtOAc to give 521 mg of title compound: 1H NMR (CDCl3, 300 MHz) δ 1.33 and 1.47 (2 s, 9H), 1.90-2.30 (m, 4H), 2.63 (s, 3H), 3.45-3.65 (m, 2H), 4.95 and 5.10 (2 s, 1H), 5.58 (s, 1H), 7.02 (d, 1H), 7.55 (d, 1H); MS m/z: 303 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([OH:19])[CH:17]=[CH:18][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[C@H:10]([CH2:24][C:25](O)=[O:26])[N:9]=2)=[CH:4][CH:3]=1.Cl.[CH2:29]([NH2:31])[CH3:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([OH:19])[CH:17]=[CH:18][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[C@H:10]([CH2:24][C:25]([NH:31][CH2:29][CH3:30])=[O:26])[N:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1nnc2n1-c1ccc(O)cc1C(c1ccc(Cl)cc1)=N[C@H]2CC(=O)O
Reactant: CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(O)ccc2-n2c(C)nnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.8 %

Procedure:
Intermediate 22 (383 mg, 1.00 mmol), ethylamine hydrochloride (163 mg, 2.0 mmol), HATU (457 mg, 1.20 mmol) and DIPEA (0.349 mL, 2.0 mmol) were dissolved in DMF (2 mL) and stirred at RT overnight. More ethylamine hydrochloride (163 mg, 2.0 mmol) and DIPEA (0.349 mL, 2.0 mmol) were added and the reaction stirred for a further 2 h. The reaction mixture was diluted with EtOAc (20 mL) and washed with saturated aqueous sodium bicarbonate solution (10 mL), water and brine. The organic phase was dried and evaporated under vacuum. Purification of the residue by flash chromatography on silica gel (DCM-methanol 10 to 20% gradient) gave the title compound as an off-white solid (200 mg, 0.488 mmol, 49% yield). LC/MS (M(35Cl)+H)+ 410, (M(37Cl)+H)+ 412; RT 0.76 min (using LC/MS apparatus c)).
Reaction SMILES: [N:1]1([C:6]2[CH:23]=[CH:22][C:9]([C:10]([C:12]3[C:17]([C:18](OC)=[O:19])=[CH:16][CH:15]=[CH:14][N:13]=3)=O)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.O.[NH2:25][NH2:26]>CCO>[N:1]1([C:6]2[CH:23]=[CH:22][C:9]([C:10]3[C:12]4[N:13]=[CH:14][CH:15]=[CH:16][C:17]=4[C:18](=[O:19])[NH:25][N:26]=3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: NN
Reactant: COC(=O)c1cccnc1C(=O)c1ccc(-n2ccnc2)cc1
Solvent: O
Solvent: CCO
Product: O=c1[nH]nc(-c2ccc(-n3ccnc3)cc2)c2ncccc12

Procedure:
A suspension of 2-[4-(1H-imidazol-1-yl)benzoyl]-3-carbomethoxypyridine (0.94 g, 3.06 mmol) in 50 mL of EtOH is treated with 0.36 g (7.17 mmol) of hydrazine monohydrate. The mixture is heated to reflux for 1 day, then allowed to cool and filtered to give crude product. Crystallization from DMF gives 8-[4-(1H-imidazol-1-yl)phenyl]-5-oxo-5,6-dihydropyrido[3,2-d]-pyridazine as white crystals. M.P. 376°-378° C.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.[CH2:9]([NH:16][C:17](=[O:24])[C@H:18]([C@H:20]([CH2:22][CH3:23])[CH3:21])[NH2:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[O:25]([C:32]1[CH:33]=[C:34]([C:38](=[O:41])[CH2:39]Cl)[CH:35]=[CH:36][CH:37]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O(C1C=C(C=CC=1)C(O)=O)C1C=CC=CC=1>>[O:25]([C:32]1[CH:33]=[C:34]([C:38](=[O:41])[CH2:39][N:1]2[CH2:8][CH2:7][CH2:6][C@H:2]2[C:3]([N:16]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:17](=[O:24])[C@H:18]([C@H:20]([CH2:22][CH3:23])[CH3:21])[NH2:19])=[O:5])[CH:35]=[CH:36][CH:37]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC[C@H](C)[C@H](N)C(=O)NCc1ccccc1
Reactant: O=C(CCl)c1cccc(Oc2ccccc2)c1
Reactant: O=C(O)[C@@H]1CCCN1
Agent: O=C(O)c1cccc(Oc2ccccc2)c1
Product: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)c1cccc(Oc2ccccc2)c1

Procedure:
Using the procedure described in Example 5, treatment of L-proline-L-isoleucine benzylamide (200 mg, 0.63 mmol) with 3'-phenoxy-2-chloroacetophenone (233 mg, 0.95 mmol, 1.5 eq; prepared from 3-phenoxybenzoic acid by the method described in Example 1) provided 80 mg of L-isoleucine, N-[1-(2-(3-phenoxyphenyl)-2-oxoethyl)-L-prolyl] benzylamide as a foam.
Reaction SMILES: C.Cl[C:3]1[CH:8]=[C:7]([NH:9][CH2:10][CH2:11][O:12][CH3:13])[C:6]([N+:14]([O-:16])=[O:15])=[C:5]([NH:17][CH2:18][CH2:19][O:20][CH3:21])[CH:4]=1.C(O)=O>C(N(CC)CC)C.O.[Pd]>[CH3:21][O:20][CH2:19][CH2:18][NH:17][C:5]1[CH:4]=[CH:3][CH:8]=[C:7]([NH:9][CH2:10][CH2:11][O:12][CH3:13])[C:6]=1[N+:14]([O-:16])=[O:15]
Reactant: COCCNc1cc(Cl)cc(NCCOC)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: O=CO
Solvent: O
Solvent: CCN(CC)CC
Product: COCCNc1cccc(NCCOC)c1[N+](=O)[O-]

Procedure:
0.4 g of palladium at a concentration of 10% on active charcoal is added to 0.084 mole (25.5 g) of 4-chloro-2-(β-methoxyethyl)amino-6-(β-methoxyethyl)aminonitrobenzene in 33.4 ml of triethylamine, after which 7 ml of formic acid are added dropwise. At the end of the additions, the reaction mixture is heated for 1 hour 30 minutes, under reflux. The reaction mixture is diluted with 100 ml of 96° alcohol and 100 ml of water. The expected product precipitates. After filtration, the expected product containing the catalyst is dissolved in 90 ml of isopropyl alcohol. The catalyst is removed by hot filtration. The expected product crystallizes.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:18]([OH:20])=[O:19])[C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=3)=[CH:7][C:6]=2[CH:17]=1.Cl.[CH3:22][CH2:23]O>>[CH2:22]([O:19][C:18]([C:4]1[C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=3)=[CH:7][C:6]=2[CH:17]=[C:2]([OH:1])[CH:3]=1)=[O:20])[CH3:23]
Reactant: CCO
Reactant: O=C(O)c1cc(O)cc2cc(-c3ccc(O)cc3)oc12
Agent: Cl
Product: CCOC(=O)c1cc(O)cc2cc(-c3ccc(O)cc3)oc12
Yield: 92 %

Procedure:
A solution of carboxylic acid 24 (3.5 g, 13 mmol) in HCl/EtOH(100 ml) was refluxed for 2 hr. The reaction was then cooled, concentrated and the product was dissolved in EtOAc, washed with sat NaHCO3, dried over MgSO4, and concentrated to give a solid. The solid was triturated with CH2Cl2 filtered to give the desired product (3.5 g, 92%); Mp=221–223° C.; 1NMR (DMSO-d6) δ 9.90 (s, 1 H), 9.55(s, 1 H), 7.73 (d, 2 H, J=8.5 Hz), 7.23 (d, 1 H, J=2.1 Hz), 7.17 (d. 1 H, J=2.5 Hz), 7.12 (s, 1 H), 6.88 (d, 2 H, J=8.5 Hz), 4.43–4.35 (m, 2 H), 1.41 (t, 3 H, J=7.0 Hz); MS 297 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([CH3:11])[C:5]([N+:12]([O-])=O)=[C:4]([CH3:15])[N:3]=1.CS(O)(=O)=O.[H][H]>[Pd].C.CO>[NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([CH3:11])[C:5]([NH2:12])=[C:4]([CH3:15])[N:3]=1
Reactant: Cc1nc(N)c([N+](=O)[O-])c(C)c1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Agent: CS(=O)(=O)O
Solvent: CO
Product: Cc1nc(N)c(N)c(C)c1N

Procedure:
A 500 ml Parr Bottle was charged with 2-amino-4,6-dimethyl-3,5-dinitropyridine (21.2 g, 0.10 mole), 200 ml methanol, methanesulfonic acid (19.2 g, 0.20 mole), and 20. g 5% Pd/charcoal catalyst. The mixture was subjected to hydrogenation at ambient temperature with an initial hydrogen pressure of 5.7 psig. When no further uptake of hydrogen was observed, the mixture was filtered free of catalyst under a nitrogen atmosphere, and methanol removed under vacuum. The bismethanesulfonate salt of 2,3,5-triamino-4,6-dimethylpyridine so obtained was purified by slurrying with dry isopropyl alcohol, filtering under nitrogen, and vacuum drying over P2O5 at 80° - 90° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.Cl[C:24](Cl)([O:26][C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[CH3:35][N:36]([CH3:44])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]CO.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:27](=[O:33])[O:26][CH2:24][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][N:36]([CH3:44])[CH3:35])=[CH:18][CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CN(C)CCCCCCO
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)OCCCCCCN(C)C)cc3)c2cc1OC
Yield: 39.3 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (77 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 6-(dimethylamino)-1-hexanol (38 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, and the extract was washed with water and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (31 mg, yield 34%).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[N:18]=[C:17]([N:19]([CH2:22]C)[CH2:20]C)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH2:4][CH2:3]1.[Br:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH:32]=O)=[C:27]([O:34][C:35]([F:38])([F:37])[F:36])[CH:26]=1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[ClH:57]>C(Cl)Cl.CCOC(C)=O>[ClH:57].[ClH:57].[Br:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][NH:1][C@@H:2]2[CH2:3][CH2:4][C@H:5]([NH:8][C:9]3[N:18]=[C:17]([N:19]([CH3:20])[CH3:22])[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]=3)[CH2:6][CH2:7]2)=[C:27]([O:34][C:35]([F:36])([F:37])[F:38])[CH:26]=1
Reactant: CCN(CC)c1nc(N[C@H]2CC[C@@H](N)CC2)nc2ccccc12
Reactant: O=CCc1ccc(Br)cc1OC(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN(C)c1nc(N[C@H]2CC[C@@H](NCCc3ccc(Br)cc3OC(F)(F)F)CC2)nc2ccccc12
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
To a suspension of cis-N2-(4-amino-cyclohexyl)-N4,N4-dimethyl-quinazoline-2,4-diamine obtained in step C of example 9 (300 mg, 1.05 mmol) in CH2Cl2 (3 mL) were added (4-bromo-2-trifluoromethoxy-phenyl)-acetaldehyde (357 mg, 1.26 mmol), AcOH (76 mg, 1.26 mmol), and NaBH(OAc)3 (334 mg, 1.57 mmol). The reaction mixture was stirred at ambient temperature for 4.5 hr. The reaction was quenched with saturated aqueous NaHCO3 The aqueous layer was extracted with CHCl3 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated, and purified by flash chromatography (NH-silica gel, 50% EtOAc in hexane) to give a pale yellow solid. To a solution of above solid in EtOAc (0.8 mL) was added 4 M hydrogen chloride in EtOAc (0.25 mL). The mixture was stirred at ambient temperature for 30 min and concentrated. A solution of the residue in Et2O (2 mL) was stirred at ambient tempareture for 30 min. The precipitate was collected by filtration, washed with Et2O, and dried under reduced pressure to give cis-N2-{4-[2-(4-bromo-2-trifluoromethoxy-phenyl)-ethylamino]-cyclohexyl}-N4,N4-dimethyl-quinazoline-2,4-diamine dihydrochloride (161 mg, 25%) as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[CH2:13]([NH:20][C:21](=[O:24])[CH2:22]Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O>[CH2:13]([NH:20][C:21](=[O:24])[CH2:22][N:10]1[CH2:9][CH2:8][N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:12][CH2:11]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(CCl)NCc1ccccc1
Reactant: c1ccc(N2CCNCC2)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CN1CCN(c2ccccn2)CC1)NCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 34.4 %

Procedure:
A mixture of 1-pyridin-2-ylpiperazine (24 mg, 0.15 mmol, Aldrich), N-benzyl-2-chloroacetamide (37 mg, 0.20 mmol, Maybridge) and sodium carbonate (50 mg) in N,N-dimethylformamide/water (2:1, 2 mL) was shaken at room temperature for 18 hours. The resulting mixture was decanted, concentrated under reduced pressure and the residue purified by preparative HPLC to provide 16 mg (32%) of the desired product. 1H NMR (500 MHz, DMSO-d6) δ 2.58 (m, 4H), 3.05 (s, 2H), 3.52 (m, 4H), 4.35 (d, J=5 Hz, 2H), 6.63 (t, J=5 Hz, 1H), 6.82 (d, J=6 Hz, 1H), 7.28 (m, 5H), 7.55 (t, J=6 Hz, 1H), 8.12 (t, J=5 Hz, 1H), 8.35 (s, 1H); MS (ESI/APCI+) m/e 311 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:26][C:27]2[CH:39]=[CH:38][C:30]([C:31]([O:33]C(C)(C)C)=[O:32])=[CH:29][CH:28]=2)[C:7](/[CH:10]=[C:11]2\[N:12]([CH2:22][CH2:23][CH2:24][CH3:25])[C:13](=[O:21])[N:14]([CH2:17][CH2:18][CH2:19][CH3:20])[C:15]\2=[O:16])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]>C(Cl)Cl.FC(F)(F)C(O)=O>[CH2:1]([C:5]1[N:6]([CH2:26][C:27]2[CH:39]=[CH:38][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=2)[C:7](/[CH:10]=[C:11]2\[N:12]([CH2:22][CH2:23][CH2:24][CH3:25])[C:13](=[O:21])[N:14]([CH2:17][CH2:18][CH2:19][CH3:20])[C:15]\2=[O:16])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(/C=C2/C(=O)N(CCCC)C(=O)N2CCCC)n1Cc1ccc(C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1ncc(/C=C2/C(=O)N(CCCC)C(=O)N2CCCC)n1Cc1ccc(C(=O)O)cc1
Reaction time: 3 h

Procedure:
1,1-dimethylethyl Z-4-[[2-butyl-5-[(1,3-dibutyl-2,5-dioxo-4-imidazolidinylidene)methyl]-1H-imidazol-1-yl]methyl]benzoate (0.88 g, 1.64 mmol) was dissolved in methylene chloride (16 mL) and trifluoroacetic acid (16 mL). After stirring for 3 hours the reaction mixture was evaporated in vacuo. Dilute NaHCO3 was added to adjust the pH to 6 and extracted with ethyl acetate. This extract was dried over MgSO4 and then evaporated in vacuo and purified via chromatography (eluant methanol in chloroform).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[CH3:10][S:11](Cl)(=[O:13])=[O:12]>ClCCl.N1C=CC=CC=1>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][S:11]([CH3:10])(=[O:13])=[O:12])=[C:4]([F:9])[CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(Br)cc1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Procedure MM: To a stirring solution of 4-bromo-2-fluoroaniline (1.0 mmol) in 3:1 dichloromethane/pyridine, add methanesulfonyl chloride (1.5 mmol) and stir at room temperature for 18 hours. After this time, wash the reaction with 1N hydrochloric acid while extracting with dichloromethane. Purify the title compound via radial chromatography eluting with ethyl acetate and hexane.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N:12]2[CH2:17][C@@H:16]([CH3:18])[NH:15][CH2:14][C@H:13]2[CH3:19])=[N:4][N:3]=1.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C.C(N(CC)C(C)C)(C)C.C(OCC)(=O)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N:12]2[C@H:13]([CH3:19])[CH2:14][N:15]([C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:27])[C@H:16]([CH3:18])[CH2:17]2)=[N:4][N:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C[C@@H]1CN(c2nnc(Cl)c3ccccc23)[C@H](C)CN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H]1CN(c2nnc(Cl)c3ccccc23)[C@H](C)CN1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-chloro-4-((2R,5R)-2,5-dimethylpiperazin-1-yl)phthalazine (245 mg, 0.885 mmol) was dissolved in DMF (3.5 mL) and N,N-diisopropylethylamine (0.70 mL). Benzoyl chloride (0.118 mL, 1.02 mmol) was added and the mixture stirred at rt for 16 hours. The reaction was taken up in ethyl acetate (80 mL) and washed with aqueous K2CO3 (10%), water, and saturated sodium chloride. The organics were dried (MgSO4) and evaporated to give a yellow oil. Chromatography over silica gel with a gradient of hexanes/0-40% ethyl acetate gave an off-white foam. MS (M+H)+=381.8