Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:11]=[C:10]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:9]=2)=[CH:4][CH:3]=1.N[C:32]1C=CC(C2C=C(C3C=CC=CC=3)N=C(OCCCCC(C)(C)C(OC)=O)C=2)=CC=1.CNC1C=CC(C2C=C(C3C=CC=CC=3)N=C(OCCCCC(C)(C)C(OC)=O)C=2)=CC=1>>[CH3:32][NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:11]=[C:10]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)C(C)(C)CCCCOc1cc(-c2ccc(N)cc2)cc(-c2ccccc2)n1
Reactant: CCOC(=O)CCCCCOc1cc(-c2ccc(N)cc2)cc(-c2ccccc2)n1
Agent: CNc1ccc(-c2cc(OCCCCC(C)(C)C(=O)OC)nc(-c3ccccc3)c2)cc1
Product: CCOC(=O)CCCCCOc1cc(-c2ccc(NC)cc2)cc(-c2ccccc2)n1

Procedure:
When the procedure of Example 16 is followed and ethyl 6-{[4-(4-aminophenyl)-6-phenyl-2-pyridyl]oxy}hexanoate is replaced with methyl 6-{[4-(4-aminophenyl)-6-phenyl-2-pyridyl]oxy}-2,2-dimethylhexanoate then the compound prepared is methyl 6-{[4-(4-methylaminophenyl)-6-phenyl-2-pyridyl]oxy}-2,2-dimethylhexanoate. (m.p.=77° C.)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[C:5]([NH2:17])=[CH:4][N:3]=1.[N:18]([O-])=O.[Na+].[OH-].[Na+]>Cl>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:17]=[N:18][N:8]([C:9]3[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=3)[C:6]=2[N:7]=1
Reactant: O=N[O-]
Reactant: COc1ccc(Nc2nc(Cl)ncc2N)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(-n2nnc3cnc(Cl)nc32)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 1.51 g (6.02 mmol) 2-chloro-N4-(4-methoxy-phenyl)-pyrimidine-4,5-diamine in 75 ml 37% aqueous hydrochloric acid is treated with 852 mg (12.4 mmol) sodium nitrite. The mixture is stirred for 16 hours at room temperature. Aqueous sodium hydroxide is added to the reaction mixture to reach a neutral pH-value. Then the mixture is extracted with dichloromethane. The organic phase is dried over sodium sulfate and evaporated giving 5-chloro-3-(4-methoxy-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine as brown solid; HPLC/MS (A): 1.89 min, [M+H] 262;
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]1[N:13]=[C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)[C:11]([CH:25]=[O:26])=[CH:10][N:9]=1.[CH2:27]([Li])[CH2:28][CH2:29][CH3:30].C(=O)([O-])O.[Na+]>OC[C@@H]1CCCN1C1N=C(NCC2C=CC(OC)=C(Cl)C=2)C(C(=O)C)=CN=1.CCCCCC>[OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]1[N:13]=[C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)[C:11]([C@@H:25]([OH:26])[CH2:27][CH2:28][CH2:29][CH3:30])=[CH:10][N:9]=1
Reactant: [Li]CCCC
Reactant: COc1ccc(CNc2nc(N3CCC[C@H]3CO)ncc2C=O)cc1Cl
Agent: COc1ccc(CNc2nc(N3CCC[C@H]3CO)ncc2C(C)=O)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Product: CCCC[C@H](O)c1cnc(N2CCCC2CO)nc1NCc1ccc(OC)c(Cl)c1

Procedure:
A solution of (S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-formylpyrimidine (10.0 mg) in tetrahydro-furan (1.0 ml) obtained in Example 2 (3) is treated with a 1.6M solution of n-butyl lithium in hexane (83 μl) at −78° C. for 3 minutes, and thereto is added an aqueous sodium hydrogen carbonate solution. The reaction mixture is extracted with ethyl acetate to give (S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-(1-hydroxypentyl)pyrimidine (13.7 mg) as oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[CH3:18][Li].O>O1CCCC1>[CH3:18][C:7]1[C:2]([CH3:1])=[CH:3][N:4]=[C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([F:17])([F:15])[F:16])=[CH:12][CH:13]=2)[N:6]=1
Reactant: [Li]C
Reactant: Cc1cnc(-c2ccc(C(F)(F)F)cc2)nc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1cnc(-c2ccc(C(F)(F)F)cc2)nc1C
Temperature: -30 °C
Reaction time: 1.5 h
Yield: 94.1 %

Procedure:
The title compound of Step A (9.0 g, 38 mmol) was dissolved in 50 mL of tetrahydrofuran and treated with methyl lithium (1.4 M in ether, 34 mL, 47 mmol) at a temperature of −70° C. The reaction mixture exothermed to −35° C. The mixture was stirred at −30° C. for 1.5 h and then treated with 1 mL of water and dichlorodicyanoquinone (9.44 g, 42 mmol). The mixture was stirred at 25° C. for 30 minutes and then partitioned twice between 100 mL of water and 100 mL of dichloromethane. The combined organics were washed with brine and dried over magnesium sulfate. The residue after evaporation was subjected to silica gel chromatography using hexanes/ethyl acetate (95:5) as eluent to give 9.02 g of the title compound of Step B as a white solid melting at 128-131° C. 1H NMR (CDCl3): δ2.31 (s, 3H), 2.56 (s, 3H), 7.71 (d, 2H), 8.49 (d, 2H), 8.53 (s, 1H).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[O:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11]([N+:15]([O-])=O)=[C:10]([Cl:18])[CH:9]=1)([CH3:3])[CH3:2].O.O.[Sn](Cl)Cl.C([O-])(O)=O.[Na+]>O1CCOCC1.Cl>[CH:1]([C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[O:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11]([NH2:15])=[C:10]([Cl:18])[CH:9]=1)([CH3:3])[CH3:2]
Reactant: Cc1cc([N+](=O)[O-])c(Cl)cc1Oc1cccc(C(C)C)c1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(N)c(Cl)cc1Oc1cccc(C(C)C)c1
Temperature: 25 °C
Yield: 95.7 %

Procedure:
A solution of 3.80 g (12.5 mmol) of 4-(3-isopropylphenoxy)-2-chloro-5-methylnitrobenzene in 60 ml of dioxane and 60 ml of hydrochloric acid is admixed with 8.41 g (37.2 mmol) of tin(II) chloride dihydrate at room temperature and the mixture is then refluxed for 2 h. It is cooled to room temperature, neutralized with NaHCO3 and extracted repeatedly with dichloromethane, and the extracts are dried over Na2SO4 and filtered, and the solvent is removed under reduced pressure (3.47 g, 94.5% purity, 95.7% yield, log P (pH 2.3)=4.68).
Reaction SMILES: CN1C2C=C3C(=O)COC3=CC=2CC1=O.[C:16]1([N:22]2[C:30]3[CH:29]=[C:28]4[C:31](=[O:34])[CH2:32][O:33][C:27]4=[CH:26][C:25]=3[CH2:24][C:23]2=[O:35])C=CC=C[CH:17]=1.C(N1C2C=C3C(=O)COC3=CC=2CC1=O)CC.C(N1C2C=C3C(=O)COC3=CC=2CC1=O)(C)C>>[CH2:16]([N:22]1[C:30]2[CH:29]=[C:28]3[C:31](=[O:34])[CH2:32][O:33][C:27]3=[CH:26][C:25]=2[CH2:24][C:23]1=[O:35])[CH3:17]
Reactant: O=C1COc2cc3c(cc21)N(c1ccccc1)C(=O)C3
Agent: CC(C)N1C(=O)Cc2cc3c(cc21)C(=O)CO3
Agent: CCCN1C(=O)Cc2cc3c(cc21)C(=O)CO3
Agent: CN1C(=O)Cc2cc3c(cc21)C(=O)CO3
Product: CCN1C(=O)Cc2cc3c(cc21)C(=O)CO3

Procedure:
Starting with the requisite 1-substituted-5-hydroxyoxindole and following the procedures of Preparation B, 5-methyl-3,6-dioxo-2,3,6,7-tetrahydrofuro[2,3-f]indole, 5-phenyl-3.6-dioxo-2,3,6,7-tetrahydrofuro[2,3-f]indole, 5-n-propyl-3,6-dioxo-2,3,6,7-tetrahydro-furo[2,3-f]indole and 5-i-propyl-3,6-dioxo-2,3,6,7-tetrahydro-furo[2,3-f]indole are prepared.
Reaction SMILES: C1(C)C=CC(S([N:10]2[CH2:30][CH2:29][N:28](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:27][CH2:26][N:25](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:24][CH2:23][N:22](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:21][CH2:20][N:19](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:18][CH2:17][N:16](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:15][CH2:14][N:13](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:12][CH2:11]2)(=O)=O)=CC=1.OS(O)(=O)=O.C(O)C>C(OCC)C>[NH:10]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26][NH:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20][NH:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1
Reactant: Cc1ccc(S(=O)(=O)N2CCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CC2)cc1
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: CCOCC
Product: C1CNCCNCCNCCNCCNCCNCCN1
Temperature: 100 °C
Reaction time: 96 h
Yield: 8.2 %

Procedure:
A mixture of 1,4,7,10,13,16,19-hepta(p-toluenesulfonyl)-1,4,7,10,13,16,19-heptaazacycloheneicosane (28.3 g, 0.0205 mole) and concentrated H2SO4 (85 ml) was heated at 100° C. with stirring under a dry argon atmosphere for 4 days. To the resulting solution, ethanol (170 mL) was added dropwise with stirring at 0° C., followed by ethyl ether (430 ml). The solid was filtered and dried in vacuo over P2O5. The solid was then dissolved in H2O (75 ml) and the pH of the solution was adjusted to 10 with 10N NaOH. Insoluble impurities were removed by filtration and the solution was extracted with 6×CHCl3. The extracts were combined, dried (Na2SO4) and the solvent removed in vacuo to give a yellow oil which crystallized on standing. The aqueous layer was taken to dryness in vacuo and the resulting brown oily solid was extracted with hot THF (2×500 ml). The THF extracts were filtered and combined with the yellow solid obtained above. Insoluble impurities were removed by filtration and the solvent was removed in vacuo to give a yellow crystalline solid. The crude solid was crystallized from CHCl3 -acetonitrile to give 505 mg (8% yield) of the product as colorless needles: mp 163°-5° C.; 1H NMR (CDCl3) δ 2.99 (s, 28H), 4.00 (br s, 7H); Exact mass (M+H)+ : calcd., 302.3032; Found: 302.3097 (C14H36N7).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([NH:12][CH:13]1[N:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]2[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=2[NH:15][C:14]1=[O:30])=[O:11].Cl.C([N:51]1[CH:55]=[C:54]([CH2:56]Cl)[N:53]=[CH:52]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[H-].[Na+].Cl>O.C(OCC)(=O)C.C(O)(=O)C.CN(C)C=O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([NH:12][CH:13]1[N:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]2[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=2[N:15]([CH2:56][C:54]2[N:53]=[CH:52][NH:51][CH:55]=2)[C:14]1=[O:30])=[O:11]
Reactant: O=C(NC1N=C(c2ccccc2)c2ccccc2NC1=O)c1cc2ccccc2[nH]1
Reactant: ClCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NC1N=C(c2ccccc2)c2ccccc2N(Cc2c[nH]cn2)C1=O)c1cc2ccccc2[nH]1
Temperature: 0 °C
Yield: 32.3 %

Procedure:
To a mixture of-(3RS)-1,3-dihydro-3-(2-indolylcarbonylamino)-5-phenyl-2H-1,4-benzodiazepine-2-one (800 mg), 1-trityl-4-chloromethylimidazole hydrochloride (790 mg) and N,N-dimethylformamide (16 ml) was added sodium hydride (62% suspension in mineral oil, 168 mg) under stirring and cooling at 0 ° C. in an ice-bath. The mixture was stirred for 30 minutes at 0° to 5 ° C. and heated at 70° to 80° C. for 3.0 hours. To the cooled reaction mixture were added acetic acid (2.0 ml) and 6N hydrochloric acid (5 ml). The mixture was stirred for 1.0 hour at 60° C. The cooled reaction mixture was poured into a mixture of ethyl acetate (100 ml) and water (100 ml) under stirring. The organic layer was separated, washed with water three times, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel with an eluent of a mixture of chloroform and methanol (20:1) to give (3RS)-1,3-dihydro-3-(2-indolylcarbonylamino )-1-(4-imidazolylmethyl)-5-phenyl-2H-1,4-benzodiazepine-2-one (306.0 mg).
Reaction SMILES: C(Cl)CCl.[NH:5]([C:7]1[C:8]2[N:9]([CH:17]=[CH:18][CH:19]=2)[C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH2:6].[C:20]([CH:27]([CH:31]([NH2:39])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[Cl:38])C(O)=O)(OC(C)(C)C)=[O:21].C(=O)(O)[O-].[Na+].C(O)(C(F)(F)F)=O.C1(OC)C=CC=CC=1>CN(C1C=CN=CC=1)C.C(OCC)(=O)C.O>[CH:17]1[N:9]2[C:10]3[C:15]([N:16]=[C:7]([NH:5][NH:6][C:20](=[O:21])[CH2:27][CH:31]([NH2:39])[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[Cl:38])[C:8]2=[CH:19][CH:18]=1)=[CH:14][CH:13]=[CH:12][CH:11]=3
Reactant: CC(C)(C)OC(=O)C(C(=O)O)C(N)c1ccccc1Cl
Reactant: NNc1nc2ccccc2n2cccc12
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COc1ccccc1
Solvent: ClCCCl
Solvent: O
Product: NC(CC(=O)NNc1nc2ccccc2n2cccc12)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of EDC (94 mg, 0.49 mmol) and DMAP (cat.) in ethyl acetate (15 mL), 4-hydrazinopyrrolo[1,2-a]quinoxaline 14a (77 mg, 0.39 mmol) and Boc-3-amino-3-(2-chlorophenyl)propionic acid (78 mg, 0.39 mmol) were added, portion wise over 15 minutes period. The resulting mixture was stirred at room temperature for 24 h, then shaken with sodium bicarbonate saturated solution and water. Evaporation of the dried extract gave a residue which was purified by crystallization and used for the subsequent hydrolytic step without further characterization. The solid obtained was added to a stirred mixture of TFA (2 mL) and anisole (2 mL) at 0° C. The reaction mixture was allowed to reach to room temperature and stirred for an additional 50 minutes. Evaporation of the volatiles by azeotropization with toluene (3×3 mL) gave the title compound as a solid.
Reaction SMILES: [CH2:1]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[C:11]([F:18])[CH:12]=[CH:13][CH:14]=2)[CH:9]1[C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].C(O)(=O)C>O1CCCC1>[CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[C:11]([F:18])[CH:12]=[CH:13][CH:14]=2)[CH:9]1[C:19]1[CH:20]=[CH:21][C:22]([C:25]([F:28])([F:26])[F:27])=[CH:23][CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1cccc2c1C(c1ccc(C(F)(F)F)cc1)N(Cc1ccccc1)C=C2
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Fc1cccc2c1C(c1ccc(C(F)(F)F)cc1)N(Cc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A 250-mL round-bottomed flask containing a solution of 2-benzyl-8-fluoro-1-(4-(trifluoromethyl)phenyl)-1,2-dihydroisoquinoline (1.0 g, 2.6 mmol) in anhydrous tetrahydrofuran (20 mL) was treated with sodium borohydride (0.3 g, 8.4 mmol) at RT. After 20 min, acetic acid (3.3 mL) was added and the reaction was stirred at RT for 2.5 h. The reaction mixture was concentrated and the resulting residue was taken up in ethyl acetate (150 mL), water (25 mL), 1N sodium hydroxide, and brine (35 mL). The ethyl acetate layer was separated, dried over anhydrous sodium sulfate, and concentrated to yield the crude product. The crude product was purified by silica gel chromatography (20-30% EtOAc in hexanes) to give 2-benzyl-8-fluoro-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline as a colorless oil. MS (ESI, pos. ion) m/z: 386 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:7](=[O:8])[C:6]([CH3:9])=[C:5]([CH3:10])[C:4](=[O:11])[C:3]=1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21](O)=[O:22])=[CH:15][CH:14]=1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[CH3:1][C:2]1[C:7](=[O:8])[C:6]([CH3:9])=[C:5]([CH3:10])[C:4](=[O:11])[C:3]=1[CH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:22])=[CH:17][CH:18]=1
Reactant: CC1=C(C)C(=O)C(Cc2ccc(CCC(=O)O)cc2)=C(C)C1=O
Reactant: C1COCCN1
Product: CC1=C(C)C(=O)C(Cc2ccc(CCC(=O)N3CCOCC3)cc2)=C(C)C1=O
Yield: 68.8 %

Procedure:
3-[4-(3,5,6-trimethyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionic acid (25 mg, 0.08 mmol) and morpholine (0.010 ml, 0.12 mmol) were used, and a method similar to that described in Example 46 was employed to obtain the title compound (21 mg, 0.055 mmol, yield 69%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][S:10]([N:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])[C:5]([Cl:8])=[N:6][CH:7]=1.F[C:17]1[C:22]([C:23]2[N:28]=[C:27]([CH3:29])[N:26]=[C:25]([NH2:30])[N:24]=2)=[CH:21][C:20]([O:31][CH3:32])=[CH:19][N:18]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[NH4+].[Cl-]>CN(C=O)C>[NH2:30][C:25]1[N:26]=[C:27]([CH3:29])[N:28]=[C:23]([C:22]2[C:17]([NH:1][C:2]3[CH:3]=[C:4]([NH:9][S:10]([N:13]([CH3:15])[CH3:14])(=[O:11])=[O:12])[C:5]([Cl:8])=[N:6][CH:7]=3)=[N:18][CH:19]=[C:20]([O:31][CH3:32])[CH:21]=2)[N:24]=1
Reactant: COc1cnc(F)c(-c2nc(C)nc(N)n2)c1
Reactant: CN(C)S(=O)(=O)Nc1cc(N)cnc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COc1cnc(Nc2cnc(Cl)c(NS(=O)(=O)N(C)C)c2)c(-c2nc(C)nc(N)n2)c1
Reaction time: 0.75 h
Yield: 20.4 %

Procedure:
To a stirred solution of N′-(5-amino-2-chloro-3-pyridinyl)-N,N-dimethylsulfamide (Example 384, Step 2, 0.0697 g, 0.278 mmol) and 4-(2-fluoro-5-methoxypyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (Example 330, Step 5, 0.0595 g, 0.253 mmol) in DMF (1 mL) in 5 mL microwave vial, NaHMDS (Aldrich, 1 M in THF, 1.02 mL, 1.02 mmol) was added dropwise at 0° C. The dark red solution was stirred at that temperature for 45 min. Sat'd NH4Cl (0.2 mL) was added to quench the reaction. The reaction mixture was poured into sat'd NH4Cl (20 mL) and the mixture was stirred for 5 min. The resulting brown precitipate was collected and the crude product was purified by preparative HPLC using a Phenomenex, Gemni 5 micron C18 100×30 mm column (1% to 90% CH3CN w/0.1% TFA/H2O w/0.1% TFA in 10 min). The corresponding fractions were collected and concentrated in vacuo. The residue was collected and washed with water and small amount of MeOH to afford N′-(5-((3-(4-amino-6-methyl-1,3,5-triazin-2-yl)-5-methoxy-2-pyridinyl)amino)-2-chloro-3-pyridinyl)-N,N-dimethylsulfamide (0.0240 g, 20% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.00 (br. s., 1H) 9.53 (br. s., 1H) 8.77 (br. s., 1H) 8.52 (br. s., 1H) 8.35-8.46 (m, 1H) 8.19 (br. s., 1H) 7.71-8.03 (m, 2H) 3.86 (br. s., 3H) 2.79 (br. s., 6H) 2.46 (br. s., 3H). m/z (ESI, positive ion) m/z: 466.0 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][NH:5][C:6](N1CCN(C2C=CC(F)=CC=2)CC1)=[O:7].C(N1C=CN=C1)(N1C=CN=C1)=O.CN(CCN)C.[Cl:40][C:41]1[CH:42]=[C:43]([N:48]2[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]2)[CH:44]=[CH:45][C:46]=1[Cl:47]>O1CCCC1>[Cl:40][C:41]1[CH:42]=[C:43]([N:48]2[CH2:53][CH2:52][N:51]([C:6]([NH:5][CH2:4][CH2:3][N:2]([CH3:21])[CH3:1])=[O:7])[CH2:50][CH2:49]2)[CH:44]=[CH:45][C:46]=1[Cl:47]
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Reactant: CN(C)CCNC(=O)N1CCN(c2ccc(F)cc2)CC1
Agent: CN(C)CCN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CN(C)CCNC(=O)N1CCN(c2ccc(Cl)c(Cl)c2)CC1

Procedure:
This compound was prepared according to the procedure used to synthesize the compound of Example 11. A mixture of 2.5 g (0.025 mole) of 1,1'-carbonyldiimidazole, 1.4 g (0.015 mole) of unsym-dimethylethylenediamine and 3.6 g (0.015 mole) of 1-(3,4-dichlorophenyl)piperazine in a total of 100 ml of tetrahydrofuran gave an oil which solidified when triturated with cyclohexane. White solid, the title compound, in the amount of 4.0 g (75%) was collected, m.p. 80°-83° C.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:23]=[C:22]3[C:14]([C:15]4[CH2:16][CH2:17][C:18]5[CH:27]=[C:26]([C:28]([OH:30])=O)[CH:25]=[CH:24][C:19]=5[C:20]=4[NH:21]3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH3:31][N:32](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN.O1CCCC1>CN(C=O)C.C(OCC)(=O)C>[CH3:31][NH:32][C:28]([C:26]1[CH:25]=[CH:24][C:19]2[C:20]3[NH:21][C:22]4[C:14]([C:15]=3[CH2:16][CH2:17][C:18]=2[CH:27]=1)=[CH:13][CH:12]=[C:11]([C:8]1[CH:7]=[CH:6][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[CH:10][CH:9]=1)[CH:23]=4)=[O:30]
Reactant: CCCCc1ccc(-c2ccc3c4c([nH]c3c2)-c2ccc(C(=O)O)cc2CC4)cc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCc1ccc(-c2ccc3c4c([nH]c3c2)-c2ccc(C(=O)NC)cc2CC4)cc1
Reaction time: 8 h

Procedure:
A sample of 9-(4-Butyl-phenyl)-5,11-dihydro-6H-benzo[a]carbazole-3-carboxylic acid (116.2 mg, 41 μmol) is dissolved in DMF (1 mL) and treated with HATU (16.3 mg, 41 μmol) and a solution of methylamine (2M) in tetrahydrofuran (0.1 mL, 100 μmol). After stirring overnight, the reaction is diluted with ethyl acetate and extracted with water twice. The organics are dried over MgSO4 and the solvent is removed. The resulting residue is purified by mass triggered HPLC to afford the title material as a white solid after lyophilisation. LC/MS calculated for [M+H]+ C28H29N2O: 409.5, found: 409.1
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[C@@H:6]([CH2:14][CH3:15])[N:5]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:4]=2[N:3]=1.Cl.[NH2:22][C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1>C(O)(C)C.O1CCOCC1>[CH:16]1([N:5]2[C:4]3[N:3]=[C:2]([N:26]4[CH:27]=[CH:28][C:23](=[NH:22])[CH:24]=[CH:25]4)[N:11]=[CH:10][C:9]=3[N:8]([CH3:12])[C:7](=[O:13])[C@H:6]2[CH2:14][CH3:15])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Cl)nc2N1C1CCCC1
Reactant: Nc1ccncc1
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: CC[C@@H]1C(=O)N(C)c2cnc(-n3ccc(=N)cc3)nc2N1C1CCCC1
Temperature: 160 °C

Procedure:
To a solution of the Intermediate B (400 mg, 1.36 mmol) in 5 mL of isopropanol in a microwave vial, 4N HCl in dioxane (0.43 mL) and 4-aminopyridine (320 mg, 2 eq) were added and the vial was heated in a microwave oven at 160° C. for 1 hour. Solvent was removed under reduced pressure and the resulting yellow solid was purified by reversed phase HPLC to give the title compound. 1H NMR (CDCl3) δ: 9.62 (bs, 1H), 8.91 (d, J=7.7 Hz, 2H), 7.81 (s, 1H), 7.37 (d, J=7.8 Hz, 2H), 4.44-4.36 (m, 2H), 3.41 (s, 3H), 2.08-1.71 (m, 10H), 0.89 (t, J=7.5 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.Cl.[NH2:12][OH:13].C(N(CC)CC)C>CO>[NH2:1][C:2]1[C:3](/[C:9](=[N:12]\[OH:13])/[NH2:10])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1
Reactant: NO
Reactant: N#Cc1nc(Br)cnc1N
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: N/C(=N/O)c1nc(Br)cnc1N
Temperature: 0 °C
Reaction time: 48 h
Yield: 98.4 %

Procedure:
3-amino-6-bromo-pyrazine-2-carbonitrile (4.5958 g, 23.09 mmol) was dissolved in MeOH (91.92 mL), cooled to 0° C. and treated with hydroxylamine hydrochloride (1.605 g, 23.09 mmol) and triethylamine (2.336 g, 3.218 mL, 23.09 mmol). The reaction was allowed to warm to ambient temperature, stirred for 48 hours and then evaporated to dryness. Methanol (a minimum amount) was added, the mixture sonicated, filtered and washed with MeOH to give the product as a brown solid 5.27 g, 98% Yield). 1H NMR (400.0 MHz, DMSO) d 5.88 (s, 2H), 7.64 (br s, 2H), 8.14 (s, 1H) and 10.38 (s, 1H) ppm; MS (ES+) 233.75
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:12][Si](C=[N+]=[N-])(C)C.O>CO.C1(C)C=CC=CC=1>[NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: Nc1cc(F)ccc1C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(F)cc1N
Temperature: 0 °C
Reaction time: 2 h
Yield: 95.3 %

Procedure:
2-Amino-4-fluorobenzoic acid (10.0 g, 64.5 mmol) was dissolved in methanol (50 mL) and toluene (150 mL). (Trimethylsilyl)diazomethane (2M in diethyl ether, 48.3 mL, 96.7 mmol) was added over 10 minutes at RT. Stirring was continued for 2 h at RT. Water (300 mL) was added to the mixture and the volatiles were removed in vacuo. The remaining aqueous phase was cooled to 0° C. for 30 minutes and the formed precipitate was collected by filtration, washed with water and dried to give pure title compound (10.4 g, 95%).