Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[NH:3]1[C:10]2[N:6]([N:7]=[CH:8][CH:9]=2)[CH:5]=[CH:4]1.Br[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].C(OCC)(=O)C>CN(C)C=O.O>[CH2:16]([O:15][C:13]([CH2:12][N:3]1[C:10]2[N:6]([N:7]=[CH:8][CH:9]=2)[CH:5]=[CH:4]1)=[O:14])[CH3:17]
Reactant: CCOC(=O)CBr
Reactant: c1cc2[nH]ccn2n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1ccn2nccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 62% sodium hydride (7.23 g) in N,N-dimethylformamide (70 ml) was added 1H-imidazo[1,2-b]-pyrazole (20 g) by portions under ice-cooling. A solution of ethyl bromoacetate (20.7 ml) in N,N-dimethylformamide (50 ml) was added thereto at the same condition. The mixture was stirred for 2 hours at room temperature. The reaction mixture was poured into a mixture of ethyl acetate (1 l) and water (500 ml). The separated organic layer was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated and the residue was subjected to column chromatography on silica gel using ethyl acetate as an eluent. Fractions containing the object compound were combined and evaporated in vacuo to give 1-ethoxycarbonylmethyl-1H-imidazo[1,2-b]pyrazole (25 g).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([C:20]1[N:24]([CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:23]=[N:22][N:21]=1)[CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:18]=[CH:19][C:10]=1[CH2:9][C@@H:8]([NH2:7])[C:20]1[N:24]([CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:23]=[N:22][N:21]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc2ccccc2c1)c1nnnn1CCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H](Cc1ccc2ccccc2c1)c1nnnn1CCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.8 %

Procedure:
((1R )-2-(2-Naphthyl)-1-(1-phenethyl-1H-tetrazol-5-yl)ethyl)carbamic acid tert-butylester (0.30 g; 0.68 mmol) was dissolved in methylene chloride (20 ml) and trifluoroacetic acid (2 ml) was added. The mixture was stirred for 3 h at RT. The solvent was removed in vacuo and the residue was dissolved in methylene chloride (50 ml) and washed with sodium hydrogencarbonate (10%; 30 ml). The organic phase was dried (Magnesium sulfate) and the solvent removed in vacuo. The residue was chromatographed on silica (2.5×15 cm) using ethyl acetate as eluent to afford 170 mg of (1R)-2-(2-naphthyl)-1-(1-phenethyl-1H-tetrazol-5-yl)ethylamine.
Reaction SMILES: N1(C2C=CC(C(=O)CN3CCCC3C3C=CC=C(OCCCN4CCOCC4)C=3)=CC=2)C=CN=C1.[N:36]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[CH2:48][N:49]4[CH2:69][CH2:68][CH+:67][C:50]4=[C:51]4[C:56]=3[CH:55]=[CH:54][C:53]([O:57][CH2:58][CH2:59][CH2:60][N:61]3[CH2:66][CH2:65][O:64][CH2:63][CH2:62]3)=[CH:52]4)=[CH:43][CH:42]=2)[CH:40]=[CH:39][N:38]=[CH:37]1>>[N:36]1([C:41]2[CH:42]=[CH:43][C:44]([C@H:47]3[C:56]4[C:51](=[CH:52][C:53]([O:57][CH2:58][CH2:59][CH2:60][N:61]5[CH2:62][CH2:63][O:64][CH2:65][CH2:66]5)=[CH:54][CH:55]=4)[C@@H:50]4[CH2:67][CH2:68][CH2:69][N:49]4[CH2:48]3)=[CH:45][CH:46]=2)[CH:40]=[CH:39][N:38]=[CH:37]1.[N:36]1([C:41]2[CH:42]=[CH:43][C:44]([C@H:47]3[C:56]4[C:51](=[CH:52][C:53]([O:57][CH2:58][CH2:59][CH2:60][N:61]5[CH2:62][CH2:63][O:64][CH2:65][CH2:66]5)=[CH:54][CH:55]=4)[C@H:50]4[CH2:67][CH2:68][CH2:69][N:49]4[CH2:48]3)=[CH:45][CH:46]=2)[CH:40]=[CH:39][N:38]=[CH:37]1
Reactant: c1cn(-c2ccc(C3=c4ccc(OCCCN5CCOCC5)cc4=C4[CH+]CCN4C3)cc2)cn1
Agent: O=C(CN1CCCC1c1cccc(OCCCN2CCOCC2)c1)c1ccc(-n2ccnc2)cc1
Product: c1cn(-c2ccc([C@@H]3CN4CCC[C@@H]4c4cc(OCCCN5CCOCC5)ccc43)cc2)cn1
Product: c1cn(-c2ccc([C@@H]3CN4CCC[C@H]4c4cc(OCCCN5CCOCC5)ccc43)cc2)cn1
Yield: 4 %
Yield: 37 %

Procedure:
1-(4-Imidazol-1-yl-phenyl)-2-{2-[3-(3-morpholin-4-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-ethanone. Prepared as described in Example 8, Step 1, on a 3.44 mmol scale, to give 1.77 g (>100%) of crude product. MS: exact mass calcd for C28H34N4O3, 474.3; m/z found, 475.5 [M+H]+. Step 2. 6-(4-Imidazol-1-yl-phenyl)-9-(3-morpholin-4-yl-propoxy)-2,3-dihydro-1H-pyrrolo[2,1-a]isoquinolinylium. Prepared as described in Example 17, Step 2, on a 3.43 mmol scale, to give 1.60 g (95%) of crude product. MS: exact mass calcd for C28H31N4O2+, 455.2; m/z found, 455.5 [M]+. Step 3. Prepared as described in Example 17, Step 3, on a 3.43 mmol scale, to give 579 mg (37%) of 48A and 63 mg (4%) of 48B after column chromatography and HPLC. 48A: Cis-6-(4-Imidazol-1-yl-phenyl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline. MS: exact mass calcd for C26H33N4O2, 458.3; m/z found, 459.5 [M+H]+. 1H NMR (MeOH-d4): 9.52 (s, 1H), 8.10 (s, 1H), 7.79 (m, 3H), 7.57 (d, J=8.4, 2H), 6.93 (d, J=2.4, 1H), 6.82 (dd, J=1.8, 8.4, 1H), 6.71 (d, J=8.4, 1H), 4.92 (t, J=7.2, 1H), 4.61 (dd, J=4.2, 12.0, 1H), 4.12 (t, J=6.0, 2H), 4.05 (d, J=12.0, 2H), 3.92 (m, 1H), 3.82 (t, J=12.0, 2H), 3.69 (dd, J=4.8, 11.7, 1H), 3.57 (d, J=12.6, 2H), 3.51 (t, J=12.0, 1H), 3.45 (m, 1H), 3.39 (t, J=7.8, 2H),3.18 (m, 2H), 2.87 (m, 1H), 2.30 (br m, 5H). 48B: Trans-6-(4-Imidazol-1-yl-phenyl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline
Reaction SMILES: Cl.CN(C)[CH2:4][CH2:5][CH2:6][N:7]=[C:8]=NCC.[NH2:13][CH2:14][CH2:15][O:16][CH2:17][C:18]1[NH:19][C:20]([CH3:40])=[C:21]([C:36]([O:38][CH3:39])=[O:37])[CH:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[Cl:35])[C:23]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25].O.ON1C2C=CC=CC=2N=N1.CN1CC[O:56][CH2:55][CH2:54]1>ClCCl>[Cl:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[CH:22]1[C:21]([C:36]([O:38][CH3:39])=[O:37])=[C:20]([CH3:40])[NH:19][C:18]([CH2:17][O:16][CH2:15][CH2:14][NH:13][C:55]([C:54]2[CH:8]=[N:7][CH:6]=[CH:5][CH:4]=2)=[O:56])=[C:23]1[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCN=C=NCCCN(C)C
Reactant: CN1CCOCC1
Reactant: CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C1=C(COCCNC(=O)c2cccnc2)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Temperature: 0 °C
Yield: 56.3 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.42 g) was added to an ice-cooled solution of 2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (0.41 g), nicetinic acid (0.14 g) and 1-hydroxybenzotriazole hydrate (0.17 g) in dichloromethane (40 ml). The mixture was stirred with ice-cooling for 15 minutes, treated with N-methylmorpholine (0.61 g) and stirred at room temperature for 16 hours. The solution was then diluted with dichloromethane, washed successively with water, 2N hydrochloric acid, water, 10% aqueous sodium carbonate solution, and water, dried (Na2SO4) and evaporated. The residue was chromatographed on silica (t.l.c. grade, Merck Kieselgel 60H (Trade Mark) 8 g) eluting with dichloromethane plus 0-5% methanol. Appropriate fractions were combined and evaporated. The residue was triturated with diethyl ether and the resulting solid collected, washed with diethyl ether and dried to give the title compound (0.29 g), m.p. 81°-84° C. Found: C. 61.01; H, 5.48; N, 8.23. C26H28ClN3O6 requires C, 60.76; H, 5.49; N, 8.18%.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][C:6]([C:15]([F:18])([F:17])[F:16])=[C:7]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:8]=1.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][C:29]2[NH:32][N:33]=[C:34]([C:35](O)=[O:36])[C:28]=2[CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C(N(C(C)C)CC)(C)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[F:2][C:3]1[CH:4]=[CH:5][C:6]([C:15]([F:18])([F:16])[F:17])=[C:7]([CH:9]2[CH2:10][CH2:11][N:12]([C:35]([C:34]3[C:28]4[CH2:27][N:26]([C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])[CH2:31][CH2:30][C:29]=4[NH:32][N:33]=3)=[O:36])[CH2:13][CH2:14]2)[CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(C(=O)O)c2C1
Reactant: Fc1ccc(C(F)(F)F)c(C2CCNCC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCc2[nH]nc(C(=O)N3CCC(c4cc(F)ccc4C(F)(F)F)CC3)c2C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Step A To a solution of 4-(5-fluoro-2-trifluoromethyl)phenylpiperidine hydrochloride (11, 90 mg, 0.32 mmol), 5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (85 mg, 0.32 mmol), and diisopropylethylamine (0.17 mL, 0.96 mmol) in DMF (5.8 mL) was added EDCI (74 mg, 0.38 mmol) and HOBt (52 mg, 0.38 mmol). The resulting solution was stirred at ambient temperature for 24 h. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (3×30 mL). The combined organic extracts were washed with a saturated brine solution (4×20 mL) and concentrated to dryness under reduced pressure. The obtained residue was chromatographed over silica gel (Isco CombiFlash Rf unit, 12 g Redisep column, 0% to 5% MeOH in CH2Cl2 with 0.1% NH4OH in CH2Cl2) to provide tert-butyl 3-(4-(5-fluoro-2-(trifluoromethyl)phenyl) piperidine-1-carbonyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (45) as a white film (120 mg, 80%): 1H NMR (300 MHz, DMSO-d6) δ 12.96 (br s, 1H), 7.76 (dd, J=9.0, 5.7 Hz, 1H), 7.61-7.51 (m, 1H), 7.30-7.18 (m, 1H), 5.34-5.16 (m, 1H), 4.76-4.58 (m, 1H), 4.53-4.38 (m, 2H), 3.65-3.52 (m, 2H), 3.22-3.01 (m, 2H), 2.60-2.43 (m, 3H, overlaps with solvent), 1.83-1.65 (m, 4H), 1.42 (s, 9H); ESI MS m/z 497 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10]([N:12]1[C@@H:16]([CH3:17])[CH2:15][CH2:14][C@H:13]1[C:18]1[NH:22][C:21]2[C:23]3[C:28]([CH:29]=[CH:30][C:20]=2[N:19]=1)=[CH:27][C:26]1[C:31]2[C:36]([CH2:37][O:38][C:25]=1[CH:24]=3)=[CH:35][C:34]([C:39]1[NH:43][C:42]([C@@H:44]3[CH2:48][C@H:47]([CH3:49])[CH2:46][N:45]3C(OC(C)(C)C)=O)=[N:41][CH:40]=1)=[CH:33][CH:32]=2)=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4].CO[C@H:59]([CH3:69])[C@H:60]([NH:64][C:65]([O:67][CH3:68])=[O:66])[C:61]([OH:63])=O.[CH3:70]N(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>Cl.CCO.CN(C=O)C>[CH3:68][O:67][C:65]([NH:64][C@@H:60]([CH:59]([CH3:69])[CH3:70])[C:61]([N:45]1[CH2:46][C@@H:47]([CH3:49])[CH2:48][C@H:44]1[C:42]1[NH:43][C:39]([C:34]2[CH:35]=[C:36]3[CH2:37][O:38][C:25]4[CH:24]=[C:23]5[C:28]([CH:29]=[CH:30][C:20]6[N:19]=[C:18]([C@@H:13]7[CH2:14][CH2:15][C@H:16]([CH3:17])[N:12]7[C:10](=[O:11])[C@@H:6]([NH:5][C:3](=[O:4])[O:2][CH3:1])[CH:7]([CH3:9])[CH3:8])[NH:22][C:21]=65)=[CH:27][C:26]=4[C:31]3=[CH:32][CH:33]=2)=[CH:40][N:41]=1)=[O:63])=[O:66]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COC(=O)N[C@H](C(=O)O)[C@@H](C)OC
Reactant: COC(=O)N[C@H](C(=O)N1[C@@H](C)CC[C@H]1c1nc2ccc3cc4c(cc3c2[nH]1)OCc1cc(-c2cnc([C@@H]3C[C@H](C)CN3C(=O)OC(C)(C)C)[nH]2)ccc1-4)C(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCO
Solvent: CN1CCOCC1
Product: COC(=O)N[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1ncc(-c2ccc3c(c2)COc2cc4c(ccc5nc([C@@H]6CC[C@H](C)N6C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]c54)cc2-3)[nH]1)C(C)C
Reaction time: 3 h
Yield: 30.5 %

Procedure:
tert-butyl (2S,4S)-2-[5-(2-{(2S,5S)-1-[N-(methoxycarbonyl)-L-valyl]-5-methylpyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-methylpyrrolidine-1-carboxylate (20 mg, 0.079 mmol) in 1.25 N HCl in EtOH (2 mL) was heated to 50° C. for 3 h and then concentrated under reduced pressure. The crude residue was treated with (2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid (8 mg, 0.04 mmol), HATU (12 mg, 0.03 mmol) and DMF (0.5 mL), then N-methylmorpholine (0.009 mL, 0.078 mmol) was added dropwise. After 3 h, the mixture was quenched with 1N HCl (0.100 mL) and then purified by HPLC to afford methyl {(2S)-1-[(2S,5S)-2-(9-{2-[(2S,4S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-4-methylpyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate (7.5 mg, 35%).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[CH2:5]1[O:8][CH:6]1[CH3:7].[Cl:9][C:10]([Cl:16])([Cl:15])[CH2:11][CH:12]1[O:14][CH2:13]1.CO>C(O)(C)C>[OH:2][CH2:1][CH2:3][N:4]([CH2:13][CH:12]([OH:14])[CH2:11][C:10]([Cl:16])([Cl:15])[Cl:9])[CH2:5][CH:6]([OH:8])[CH3:7]
Reactant: NCCO
Reactant: CC1CO1
Reactant: ClC(Cl)(Cl)CC1CO1
Solvent: CC(C)O
Solvent: CO
Product: CC(O)CN(CCO)CC(O)CC(Cl)(Cl)Cl

Procedure:
To a solution of 30.6g (0.5 mole) monoethanolamine in 150 ml isopropanol heated to reflux was slowly added 33.8g (0.58 mole) propylene oxide over a period of about one hour. After refluxing the mixture overnight the solvent and unreacted starting material were distilled off, affording a residue weighing 49.1g. To this residue was added 5.7g of the unreacted monoethanolamine distillate. To this mixture was added 90g (0.51 mole) 4,4,4-trichloro-1,2-epoxybutane over a period of 45 minutes. An equivolume amount of methanol was then added and the reaction mixture refluxed overnight. Evaporation of the solvent yielded 140.8g (95.5%) of N-(2-hydroxyethyl)-N-(2-hydroxypropyl)-4,4,4-trichloro-2-hydroxy-1-butylamine, a brown viscous liquid very soluble in methanol but only slightly soluble in water(pH 7-8); hydroxyl number = 564. Analysis: (Calculated) %N 4.79; %Cl, 36.35. (Found) %N, 4.56; %Cl, 36.92.
Reaction SMILES: [NH2:1][C:2]1[C:3](=O)[C:4](=[O:9])[C:5]=1[O:6]CC.Br.[NH2:12][CH2:13][CH2:14][N:15]1[C:19](=[O:20])[NH:18][C:17](=[O:21])[O:16]1.[OH-].[Na+]>C(O)C>[NH2:1][C:2]1[C:5](=[O:6])[C:4](=[O:9])[C:3]=1[NH:12][CH2:13][CH2:14][N:15]1[C:19](=[O:20])[NH:18][C:17](=[O:21])[O:16]1
Reactant: NCCn1oc(=O)[nH]c1=O
Reactant: CCOc1c(N)c(=O)c1=O
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1c(NCCn2oc(=O)[nH]c2=O)c(=O)c1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 3-amino-4-ethoxy-3-cyclobutene-1,2-dione (0.56 g, 4.0 mmol) in ethanol (20 mL) was added to 2-(2-aminoethyl)-1,2,4-oxadiazolidine-3,5-dione hydrobromide (0.90 g, 4.0 mmol) in ethanol (100 mL). The reaction mixture was treated with 1N sodium hydroxide solution (8 mL, 8 mmol) and allowed to stir for 24 hours at room temperature. The resulting precipitate was filtered, dissolved in water and passed through an ion exchange column (AG 50W-X2, 100-200 mesh, H+ form), eluting with water. The eluent was freeze dried yielding the title compound as a cream colored solid, partial hydrate (0.45 g, 45%, mp 225° C. (dec)); IR (KBr, cm-1) 3300, 3140, 1820, 1740, 1720, 1640; MS (+FAB) 242 (MH+); 1H NMR (DMSO, 400 MHz): δ 12.4 (br s, NH), 7.5 (br s, 3 NH), 4.0- 3.5 (m, 4H); 13C NMR (DMSO, 400 MHz): ppm 183.72, 183.63, 170.06, 168.96, 158.17, 152.72, 50.41, 41.68.
Reaction SMILES: P(Br)(Br)[Br:2].[CH3:5][N:6]1[C:10]([CH2:11]O)=[CH:9][C:8]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=2)=[N:7]1>CCOCC>[Br:2][CH2:11][C:10]1[N:6]([CH3:5])[N:7]=[C:8]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=2)[CH:9]=1
Reactant: Cn1nc(-c2ccc(OC(F)(F)F)cc2)cc1CO
Reactant: BrP(Br)Br
Solvent: CCOCC
Product: Cn1nc(-c2ccc(OC(F)(F)F)cc2)cc1CBr
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.3 %

Procedure:
PBr3 (0.15 mL, 1.60 mmol) was added to a solution of alcohol 72 (0.205 g, 0.75 mmol) in Et2O (10 mL) at 0° C. The mixture was stirred at room temperature for 16 h, cooled to 0° C., quenched with ice and diluted with Et2O (100 mL). Chromatography of the organic portion on silica gel (eluting with CH2Cl2) gave 5-(bromomethyl)-1-methyl-3-[4-(trifluoromethoxy)phenyl]-1H-pyrazole (73) (0.212 g, 85%) as a white solid: mp 70-71° C.; 1H NMR (CDCl3) δ 7.76 (d, J=8.9 Hz, 2H), 7.22 (d, J=8.9 Hz, 2H), 6.55 (s, 1H), 4.50 (s, 2H), 3.94 (s, 3H). APCI MS m/z 335, 337 [M+H]+.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[C:23]([C:25]3[CH:34]=[C:33]4[C:28]([CH2:29][CH2:30][NH:31][CH2:32]4)=[CH:27][CH:26]=3)[N:22]=[C:21]([NH2:35])[N:20]=2)[CH2:15][CH2:14]1>>[CH3:12][N:13]1[CH2:14][CH2:15][N:16]([C:19]2[CH:24]=[C:23]([C:25]3[CH:34]=[C:33]4[C:28]([CH2:29][CH2:30][N:31]([C:8](=[O:9])[CH2:7][C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[CH2:32]4)=[CH:27][CH:26]=3)[N:22]=[C:21]([NH2:35])[N:20]=2)[CH2:17][CH2:18]1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Reactant: O=C(Cl)Cc1ccccc1
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)Cc3ccccc3)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared from benzeneacetyl chloride and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt using procedures analogous to those for Example 2. Analytic LCMS (M+H)+: m/z=443.4.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]([CH3:17])[C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:5]=[N:6][CH:7]=1.C(N(CC)CC)C.Cl[CH2:26][CH2:27][S:28](Cl)(=[O:30])=[O:29].[H-].[Na+].[CH2:34]([OH:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(Cl)Cl>[CH2:34]([O:41][CH2:26][CH2:27][S:28]([NH:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]2[N:9]([CH3:17])[C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:3]=1)(=[O:30])=[O:29])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=S(=O)(Cl)CCCl
Reactant: OCc1ccccc1
Reactant: Cn1c(-c2cncc(N)c2)cc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1c(-c2cncc(NS(=O)(=O)CCOCc3ccccc3)c2)cc2ccccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 5-(1-methyl-1H-indol-2-yl)pyridin-3-amine (Example 100, 150 mg, 0.672 mmol) and triethylamine (272 mg, 2.69 mmol) in DCM (6 mL) is added 2-chloroethanesulfonyl chloride (274 mg, 1.68 mmol) in DCM (2 mL) dropwise at 0° C. The mixture is stirred at 0° C. for 1 h. Silica gel (5 g) is added and the mixture is concentrated. After elution, the fractions containing the product are concentrated to give a residue, which is redissolved in benzyl alcohol (20 mL). 60% NaH in mineral oil is added. The mixture is stirred at 70° C. for 1 day. The mixture is then filtered and the filtrate is purified on Xbridge C18 eluting with a 1:9 to 9:1 acetonitrile-water gradient to give 2-(benzyloxy)-N-(5-(1-methyl-1H-indol-2-yl)pyridin-3-yl)ethanesulfonamide. MS (ESI) m/z 422.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH3:21][C:22]1[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=1>>[ClH:1].[CH2:13]([NH:20][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([N:23]2[C:22]([CH3:21])=[CH:26][C:25]([CH3:27])=[N:24]2)[N:11]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCc1ccccc1
Reactant: Cc1cc(C)[nH]n1
Reactant: Clc1nc(Cl)c2ccccc2n1
Product: Cc1cc(C)n(-c2nc(NCc3ccccc3)c3ccccc3n2)n1
Product: Cl

Procedure:
Was prepared according to Method A from 2,4-dichloroquinazoline, benzylamine and 3,5-dimethylpyrazole. Mp. 160.2° C.
Reaction SMILES: [CH:1]1([C:7]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:8]=2[CH:9]=[C:10]2[C:16]4[CH:17]=[C:18]([C:21]([OH:23])=O)[CH:19]=[CH:20][C:15]=4[N:14]4[CH2:24][CH:25]=[N:26][C:13]4=[CH:12][N:11]23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:31][N:32]([CH3:37])[S:33]([NH2:36])(=[O:35])=[O:34].CCN=C=NCCCN(C)C.Cl>CN(C=O)C.CN(C1C=CN=CC=1)C.CS(C)=O.CO>[CH:1]1([C:7]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:8]=2[CH:9]=[C:10]2[C:16]4[CH:17]=[C:18]([C:21]([NH:36][S:33]([N:32]([CH3:37])[CH3:31])(=[O:35])=[O:34])=[O:23])[CH:19]=[CH:20][C:15]=4[N:14]4[CH2:24][CH:25]=[N:26][C:13]4=[CH:12][N:11]23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc2c(c1)-c1cc3c(C4CCCCC4)cccc3n1C=C1N=CCN12
Reactant: CN(C)S(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CO
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: CN(C)S(=O)(=O)NC(=O)c1ccc2c(c1)-c1cc3c(C4CCCCC4)cccc3n1C=C1N=CCN12
Temperature: 60 °C
Reaction time: 2 h
Yield: 17.5 %

Procedure:
To a solution of 10-cyclohexyl-4H-imidazo[1,2-a]indolo[1,2-d][1,4]benzodiazepine-7-carboxylic acid (25 mg, 0.063 mmol) and N,N-dimethylsulfamide (41 mg, 0.33 mmol) in DMF (1.5 mL), was added DMAP (40 mg, 0.33 mmol) and then EDCI-HCl (50 mg, 0.26 mmol). The reaction mixture was stirred at 60° C. for 2 h, cooled to rt, diluted with DMSO and MeOH and purified by prep HPLC (MeOH/H2O with 10 mM TFA buffer) to yield 10-cyclohexyl-N-((dimethylamino)sulfonyl)-4H-imidazo[1,2-a]indolo[1,2-d][1,4]benzodiazepine-7-carboxamide (5.4 mg, 0.011 mmol, 17%) as a bright yellow solid. 1H NMR (500 MHz, CD3OD) δ 1.18-1.56 (m, 4H), 1.74-1.85 (m, 2H), 1.95-2.21 (m, 4H), 2.86-2.98 (m, 1H), 3.04 (s, 6H), 5.19 (d, J=16.1 Hz, 1H), 6.01 (d, J=16.1 Hz, 1H), 7.47 (d, J=2.2 Hz, 1H), 7.66 (dd, J=8.4, 1.5 Hz, 1H), 7.77-7.91 (m, 4H), 7.94 (d, J=1.8 Hz, 1H), 8.01 (d, J=8.4 Hz, 1H), 8.28 (s, 1H). LCMS: m/e 504 (M+H)+, ret time 1.81 min.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:9][CH2:8][C:7](=O)[CH2:6]2)[CH2:3]C1.[C-:11]#[N:12].[Na+].[NH4+:14].[Cl-]>N.CO>[NH2:14][C:7]1([C:11]#[N:12])[CH2:8][CH2:9][N:5]([CH:4]2[CH2:1][CH2:3]2)[CH2:6]1
Reactant: [C-]#N
Reactant: O=C1CCN(CC2CC2)C1
Reactant: [NH4+]
Agent: N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: N#CC1(N)CCN(C2CC2)C1
Reaction time: 2 h

Procedure:
1-Cyclopropylmethyl-pyrrolidin-3-one (6.1 g, 44 mmol, 1.0 equiv), NaCN (2.4 g, 48 mmol, 1.1 equiv) and NH4Cl (2.6 g, 48 mmol, 1.1 equiv) were mixed in 88 mL of 2 M NH3 in MeOH, and the resulting mixture was refluxed for 2 h at which time another 88 mL of 2 M NH3 in MeOH was added followed by another 2 h at reflux. The reaction mixture was cooled, filtered, concentrated, and taken up in 100 mL of CH2Cl2. The mixture was filtered a second time and concentrated to a red oil (5.9 g) which was used without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[C:12]([C:17]([F:20])([F:19])[F:18])[CH:11]=2)[N:3]=1.[Cl:21][C:22]1[N:27]=[CH:26][C:25]([CH2:28][NH2:29])=[CH:24][CH:23]=1>O1CCOCC1.O.C(OCC)(=O)C>[Cl:8][C:6]1[N:7]=[C:2]([NH:29][CH2:28][C:25]2[CH:26]=[N:27][C:22]([Cl:21])=[CH:23][CH:24]=2)[N:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[C:12]([C:17]([F:20])([F:19])[F:18])[CH:11]=2)[N:5]=1
Reactant: Fc1ccc(Nc2nc(Cl)nc(Cl)n2)cc1C(F)(F)F
Reactant: NCc1ccc(Cl)nc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: Fc1ccc(Nc2nc(Cl)nc(NCc3ccc(Cl)nc3)n2)cc1C(F)(F)F
Temperature: 50 °C
Yield: 60 %

Procedure:
To a stirred solution of (4,6-Dichloro-[1,3,5]triazin-2-yl)-(4-fluoro-3-trifluoromethylphenyl)amine (XVII) (2.0 g, 6.11 mmol) in dioxane (5 mL) was added i-Pr2(Et)N (0.832 g, 6.44 mmol) and (6-chloropyridin-3-yl)methylamine (0.912 g, 6.44 mmol), and the mixture heated at 50° C. for 12 h. The mixture was cooled to ambient temperature and diluted with water and ethyl acetate. The organic phase was separated, washed with brine and concentrated under vacuum to give 1 6-chloro-N-(6-chloropyridin-3-ylmethyl)-N′-(4-fluoro-3-trifluoromethylphenyl)-1,3,5-triazine-2,4-diamine (XVIII) (1.60 g (60% yield): 1H NMR (DMSO) δ 8.32 (bs, 1H), 7.98 (bs, 1H), 7.58 (bd, 1H), 7.28 (m, 3H), 7.16 (t, J=9.0 Hz, 1H), 6.60 (bs, 1H), 4.64 (m, 2H); ESI/MS 433 (M+H), 431(M−H).