Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:11][C:10]=2[C:20]([NH:22][CH2:23][C:24]2[CH:32]=[CH:31][C:27]([C:28]([OH:30])=O)=[CH:26][CH:25]=2)=[O:21])=[CH:5][CH:4]=1.[C:33]1([NH2:40])[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[NH2:39].C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.C(OCC)(=O)C>[NH2:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[NH:40][C:28]([C:27]1[CH:31]=[CH:32][C:24]([CH2:23][NH:22][C:20]([C:10]2[NH:11][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:13][C:9]=2[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[O:21])=[CH:25][CH:26]=1)=[O:30]
Reactant: Nc1ccccc1N
Reactant: COc1ccc(-c2cc(-c3ccccc3)[nH]c2C(=O)NCc2ccc(C(=O)O)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc(-c3ccccc3)[nH]c2C(=O)NCc2ccc(C(=O)Nc3ccccc3N)cc2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 54 %

Procedure:
A solution of 4-[({[3-(4-methoxyphenyl)-5-phenyl-1H-pyrrol-2-yl]carbonyl}amino)methyl]benzoic acid (0.213 g, 0.5 mmol) and phenylenediamine (0.108 g, 1.0 mmol) in DMF (10 ml) was cooled to 0° C. Triethylamine (0.40 ml, 2.87 mol), 1-hydroxybenzotriazole (0.101 g, 0.75 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.144 g, 0.75 mmol) were added subsequently, and the mixture was stirred for 2 h at 0° C., and for an additional 96 h at room temperature. Ethyl acetate (40 ml) was added, and the obtained solution was washed with water (7 ml), Na2S2O3 1N (7 ml, aqueous solution), water (7 ml), NaHCO3 (7 ml, saturated aqueous solution), and NaCl (7 ml, saturated aqueous solution), dried over Na2SO4 and evaporated under reduced pressure, to obtain 0.142 g (0.27 mmol) of N-(4-{[(2-aminophenyl)amino]carbonyl}benzyl)-3-(4-methoxyphenyl)-5-Phenyl-1H-pyrrole-2-carboxamide: Yield 55%; m.p. 142-143° C. (dec); IR 3407, 3296, 1627, 1530, 1493, 1246 cm−1; 1H-NMR (300 MHz, δ ppm, DMSO-d6) 11.54 (s, 1H), 9.61 (s, 1H), 7.95 (d, J=7.8 Hz, 3H), 7.80 (d, J=7.4 Hz, 2H), 7.45-7.38 (m, 6H), 7.26 (t, J=7.3 Hz, 1H), 7.17 (d, J=7.7 Hz, 1H), 6.97 (dt, J=8.0 Hz, J′=1.4 Hz, 1H), 6.90 (d, J=8.7 Hz, 2H), 6.79 (dd, J=7.9 Hz, J′=1.1 Hz, 1H), 6.67 (d, J=2.6 Hz, 1H), 6.60 (dt, J=7.5 Hz, J′=1.0 Hz, 1H), 4.86 (s, 2H), 4.49 (d, J=5.7 Hz, 2H), 3.77 (s, 3H); 13C-NMR (126 MHz, δ ppm, DMSO-d6) 165.0, 161.1, 157.9, 143.0, 142.9, 133.1, 132.9, 131.5, 129.9, 128.6, 127.9, 127.8, 127.7, 127.1, 126.7, 126.6, 126.4, 124.5, 123.3, 122.6, 116.2, 116.1, 113.4, 108.3, 55.0, 42.1.
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]2)=[C:22]([F:34])[C:23]2[O:27][N:26]=[C:25]([C:28](OCC)=[O:29])[C:24]=2[CH:33]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:43][O:44][CH2:45][C:46]([CH2:51][O:52][CH3:53])([NH2:50])[CH2:47][O:48][CH3:49]>>[CH3:49][O:48][CH2:47][C:46]([NH:50][C:28]([C:25]1[C:24]2[CH:33]=[C:20]([CH2:19][OH:18])[C:21]([N:35]3[CH2:36][C@H:37]([CH3:42])[O:38][C@H:39]([CH3:41])[CH2:40]3)=[C:22]([F:34])[C:23]=2[O:27][N:26]=1)=[O:29])([CH2:51][O:52][CH3:53])[CH2:45][O:44][CH3:43]
Reactant: CCOC(=O)c1noc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc12
Reactant: COCC(N)(COC)COC
Product: COCC(COC)(COC)NC(=O)c1noc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO)cc12

Procedure:
Starting materials: ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-6-((2R,6S)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-3-carboxylate (Intermediate 204) and 1,3-dimethoxy-2-(methoxymethyl)propan-2-amine
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:2]1[O:4][CH2:3]1.[CH3:12][O:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([NH:24][CH2:25][CH2:26][NH2:27])=[N:16][CH:15]=1.O>CN(C)C=O>[O:5]([CH2:1][CH:2]([OH:4])[CH2:3][NH:27][CH2:26][CH2:25][NH:24][C:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:14]([O:13][CH3:12])=[CH:15][N:16]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: c1ccc(OCC2CO2)cc1
Reactant: COc1cnc(NCCN)c2ccccc12
Solvent: O
Solvent: CN(C)C=O
Product: COc1cnc(NCCNCC(O)COc2ccccc2)c2ccccc12
Reaction time: 72 h

Procedure:
5.2 g. Phenyl glycidyl ether and 15 g. 4-methoxy-1-(2-aminoethylamino)-isoquinoline are dissolved in dimethylformamide and left to stand for 72 hours at ambient temperature. The reaction mixture is then poured into water, extracted with methylene chloride, dried and purified chromatographically on a silica gel column using, as elution agent, methylene chloride-methanol-triethylamine (8:1:0.05 v/v/v). By evaporation of the pure fractions, there are obtained 5.5 g. (44% of theory) of an oil. By the addition of 1.7 g. fumaric acid to a solution of this oil in ethyl acetate-ethanol, a hydrogen fumarate is precipitated out and this is then recrystallized from isopropyl alcohol. The desired product is obtained in the form of colorless cyrstals; m.p. 152°-153° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:28]2[S:32][C:31]([C:33]3([O:37][CH2:38][O:39][CH3:40])[CH2:36][CH2:35][CH2:34]3)=[N:30][CH:29]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[N:8]([S:18]([C:21]3[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[C:5]2=[N:6][CH:7]=1.[O:41]1[CH2:45][CH2:44][CH:43](O)[CH2:42]1.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>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([C:28]2[S:32][C:31]([C:33]3([O:37][CH2:38][O:39][CH3:40])[CH2:36][CH2:35][CH2:34]3)=[N:30][CH:29]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH:43]4[CH2:44][CH2:45][O:41][CH2:42]4)=[CH:13][CH:12]=3)[N:8]([S:18]([C:21]3[CH:22]=[CH:23][C:24]([CH3:25])=[CH:26][CH:27]=3)(=[O:19])=[O:20])[C:5]2=[N:6][CH:7]=1
Reactant: COCOC1(c2ncc(-c3c(Cl)cnc4c3cc(-c3ccc(O)cc3)n4S(=O)(=O)c3ccc(C)cc3)s2)CCC1
Reactant: OC1CCOC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCOC1(c2ncc(-c3c(Cl)cnc4c3cc(-c3ccc(OC5CCOC5)cc3)n4S(=O)(=O)c3ccc(C)cc3)s2)CCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 4-(5-chloro-4-(2-(1-(methoxymethoxy)cyclobutyl)thiazol-5-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-2-yl)phenol (Example 69A) (60 mg, 0.101 mmol), tetrahydrofuran-3-ol (12 mg, 0.131 mmol), and triphenylphosphine (34.3 mg, 0.131 mmol) in anhydrous tetrahydrofuran (1 mL) was treated with diisopropyl azodicarboxylate (0.025 mL, 0.131 mmol). The reaction was stirred for 16 hours at ambient temperature. The reaction treated with more tetrahydrofuran-3-ol (12 mg, 0.131 mmol), diisopropyl azodicarboxylate (0.025 mL, 0.131 mmol) and triphenylphosphine (34.3 mg, 0.131 mmol), and the reaction was warmed to 70° C. for 5 hours. The reaction was cooled, diluted with ethyl acetate, and washed with water and brine. The organic layer dried with sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with a gradient of 30 to 40% ethyl acetate in hexanes, to give the title compound. MS ESI(+) m/z 666.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:11][S:10][CH2:9][CH2:8][C:6]=2[N:7]=1.CCN(CC)CC.[CH3:20][C@H:21]1[CH2:26][O:25][CH2:24][CH2:23][NH:22]1>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][C@@H:21]2[CH3:20])[C:5]2[CH2:11][S:10][CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: C[C@H]1COCCN1
Reactant: Clc1nc(Cl)c2c(n1)CCSC2
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@H]1COCCN1c1nc(Cl)nc2c1CSCC2
Yield: 58.3 %

Procedure:
To a solution of 2,4-dichloro-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidine (200 mg, 0.9 mmol), and Et3N (182 mg, 1.8 mmol) in DMF (3 mL) at 0° C. was added 3-(S)-methylmorpholine (100 mg, 0.99 mmol). The resultant mixture was stirred at rt overnight. The solvent was removed under vacuum to give a residue which was partitioned between water and ethyl acetate. The organic layer was washed with brine dried and concentrated to give the product which was purified by preparative TLC (petroleum ether/ethyl acetate=2/1) to produce (S)-2-chloro-4-(3-methylmorpholino)-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidine (150 mg, 58%).
Reaction SMILES: [CH3:1][CH:2]([CH3:31])[CH2:3][CH:4]([C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[N:24]=[CH:23]2)=[CH:18][CH:17]=1)[O:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12]C)=[O:11])=[CH:8][CH:7]=1.[OH-].[Na+].Cl>CO.O>[CH3:1][CH:2]([CH3:31])[CH2:3][CH:4]([C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH:26]=[C:25]([C:27]([F:29])([F:28])[F:30])[N:24]=[CH:23]2)=[CH:18][CH:17]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([OH:12])=[O:11])=[CH:14][CH:15]=1
Reactant: COC(=O)c1ccc(OC(CC(C)C)c2ccc(-n3cnc(C(F)(F)F)c3)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)CC(Oc1ccc(C(=O)O)cc1)c1ccc(-n2cnc(C(F)(F)F)c2)cc1
Reaction time: 8 h
Yield: 103.6 %

Procedure:
Methyl 4-(3-methyl-1-(4-(4-(trifluoromethyl)-1H-imidazol-1-yl)phenyl)butoxy)benzoate (65 mg, 0.15 mmol) was dissolved in methanol (1.5 mL) and 1M NaOH (0.75 mL) was added at room temperature. The resulting mixture was stirred overnight. The reaction mixture was diluted with water (10 mL), acidified with 1M HCl (1 mL) and extracted with ethyl acetate (2×10 mL). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated to give (+/−)-4-(3-methyl-1-(4-(4-(trifluoromethyl)-1H-imidazol-1-yl)phenyl)butoxy)benzoic acid (65 mg, 100%) as a gum. 1H NMR (400 MHz, CDCl3, δ): 7.98 (d, J=9 Hz, 2H), 7.88 (s, 1H), 7.59 (d, J=8.5 Hz, 2H), 7.58 (s, 1H), 7.39 (d, J=8.5 Hz, 2H), 6.89 (d, J=8.8 Hz, 2H), 5.33 (dd, J=9, 4.6 Hz, 1H), 2.05 (m, 1H), 1.96-1.83 (m, 1H), 1.67-1.60 (m, 1H), 1.04 (d, J=6.6 Hz, 3H), 0.99 (d, J=6.6 Hz, 3H). MS (M+1): 419.0.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[O:13]1[CH2:17][CH2:16][NH:15][C:14]1=[O:18]>>[O:18]=[C:14]1[N:15]([CH2:2][C:3]2[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=2)[CH2:16][CH2:17][O:13]1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: O=C1NCCO1
Product: COC(=O)c1ccc(CN2CCOC2=O)cc1
Yield: 87.8 %

Procedure:
Using methyl 4-bromomethylbenzoate (1.83 g) and oxazolidin-2-one (0.77 g) and by the reaction and treatment in the same manner as in Preparation Example 42, the title compound (1.65 g) was obtained.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:49]=[CH:50][CH:51]=1)[CH2:6][O:7][C:8]([C@@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16](=[O:48])[C@@H:17]([NH:33][C:34](=[O:47])[C@@H:35]([NH:39][C:40](OC(C)(C)C)=[O:41])[CH:36]([CH3:38])[CH3:37])[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[CH:20]=2)[NH:11]1)=[O:9])=[CH2:2].FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C(N(CC)C(C)C)(C)C.[CH2:73]([O:75][C@H:76]([CH2:82][CH2:83][CH:84]=[CH2:85])[C@@H:77](C)[C:78](O)=O)[CH3:74].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>ClCCl>[CH:1]([C:3]1[CH:4]=[C:5]([CH:49]=[CH:50][CH:51]=1)[CH2:6][O:7][C:8]([C@@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16](=[O:48])[C@@H:17]([NH:33][C:34](=[O:47])[C@@H:35]([NH:39][C:40](=[O:41])[C@H:77]([CH3:78])[C@H:76]([O:75][CH2:73][CH3:74])[CH2:82][CH2:83][CH:84]=[CH2:85])[CH:36]([CH3:38])[CH3:37])[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][Si:26]([C:29]([CH3:32])([CH3:30])[CH3:31])([CH3:28])[CH3:27])[CH:20]=2)[NH:11]1)=[O:9])=[CH2:2]
Reactant: C=Cc1cccc(COC(=O)[C@@H]2CCCN(C(=O)[C@H](Cc3cccc(O[Si](C)(C)C(C)(C)C)c3)NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)N2)c1
Reactant: C=CCC[C@@H](OCC)[C@@H](C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCC[C@@H](OCC)[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H](Cc1cccc(O[Si](C)(C)C(C)(C)C)c1)C(=O)N1CCC[C@@H](C(=O)OCc2cccc(C=C)c2)N1)C(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 60.2 %

Procedure:
A solution of (S)-1-{(S)-2-((S)-2-tert-butoxycarbonylamino-3-methyl-butyrylamino)-3-[3-(tert-butyl-dimethyl-silanyloxy)-phenyl]-propionyl}-hexahydro-pyridazine-3-carboxylic acid 3-vinyl-benzyl ester (300 mg, 0.42 mmol) in anhydrous dichloromethane (9 mL) was treated with trimethylsilyl trifluoromethanesulfonate (114 μL, 0.63 mmol). The reaction mixture was stirred at room temperature for 1.5 hours then N,N-diisopropylethylamine (293 μL, 1.68 mmol) was added. The reaction mixture was evaporated to give the crude amine as a colourless solid. A solution of (2R,3R)-3-ethoxy-2-methyl-hept-6-enoic acid (78 mg, 0.42 mmol) in anhydrous dichloromethane (8 mL) was cooled to 0° C. before adding N,N-diisopropylethylamine (2934, 1.68 mmol) and 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (160 mg, 0.42 mmol). The mixture was stirred at 0° C. for 20 minutes before adding a solution of the crude amine in dichloromethane (8 mL). The reaction mixture was allowed to warm to room temperature and was stirred under a nitrogen atmosphere for 16 hours. The reaction mixture was evaporated and purified by silica gel chromatography using iso-hexanes/ethyl acetate 1:1 to yield the title compound (200 mg, 60%) as a colourless solid. 1H NMR (300 MHz, CDCl3) δ0.17 (s, 6H), 0.88-0.99 (m, 6H), 0.97 (s, 9H), 1.08-1.30 (m, 8H), 1.34-1.60 (m, 3H), 1.61-1.87 (m, 4H), 2.09-2.26 (m, 3H), 2.38-2.55 (m, 2H), 3.39-3.72 (m, 4H), 4.24-4.36 (m, 2H), 4.91-5.19 (m, 4H), 5.30 (d, J=10.9 Hz, 1H), 5.70-5.90 (m, 3H), 6.53-6.84 (m, 6H), 6.97-7.50 (m, 1H), 7.21-7.44 (m, 4H). LCMS (m/z) 791.4 [M+H] Tr=6.01 min.
Reaction SMILES: [CH3:1][CH:2]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[H-].[Na+].[C:17]([O:21][C:22](=[O:32])[NH:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30]Br)=[CH:26][N:25]=1)([CH3:20])([CH3:19])[CH3:18].CCOC(C)=O>CN(C=O)C.CCCCCCC.CCOC(C)=O>[CH2:13]([O:12][C:10](=[O:11])[C:2]([CH2:30][C:27]1[CH:26]=[N:25][C:24]([NH:23][C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:32])=[CH:29][CH:28]=1)([CH3:1])[C:3]([O:5][C:6]([CH3:8])([CH3:9])[CH3:7])=[O:4])[CH3:14]
Reactant: CC(C)(C)OC(=O)Nc1ccc(CBr)cn1
Reactant: CCOC(=O)C(C)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(Cc1ccc(NC(=O)OC(C)(C)C)nc1)C(=O)OC(C)(C)C
Reaction time: 0.33 h
Yield: 61.5 %

Procedure:
A solution of tert-butyl ethyl methylmalonate (457 mg, 2.26 mmol) in DMF (4 mL) was added dropwise to a suspension of NaH (90 mg, 2.26 mmol, 60% in oil) in DMF (4 mL). The reaction mixture was stirred for 20 min. A solution of (5-bromomethyl-pyridin-2-yl)-carbamic acid tert-butyl ester (500 mg, 1.74 mmol) in DMF (2.5 mL) was added and the reaction was stirred for 70 min. EtOAc was added and the mixture was washed with water and brine, dried and concentrated under reduced pressure. Chromathography (Heptane/EtOAc, 3:1→1:3) gave 2-(6-tert-butoxycarbonylamino-pyridin-3-ylmethyl)-2-methyl-malonic acid tert-butyl ester ethyl ester (437 mg, 61% yield).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:39]([OH:41])=O)=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]([N:23]4[CH2:28][CH2:27][CH:26]([N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)[CH2:25][CH2:24]4)=[O:22])=[CH:18][C:17]4[CH:35]=[CH:36][CH:37]=[CH:38][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.C(O)(=O)C.[NH2:55][CH2:56][C:57]([N:59]([CH3:61])[CH3:60])=[O:58].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>C(Cl)Cl>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:39]([NH:55][CH2:56][C:57]([N:59]([CH3:61])[CH3:60])=[O:58])=[O:41])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]([N:23]4[CH2:24][CH2:25][CH:26]([N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)[CH2:27][CH2:28]4)=[O:22])=[CH:18][C:17]4[CH:35]=[CH:36][CH:37]=[CH:38][C:16]=4[C:15]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)N1CCC(N2CCOCC2)CC1)=Cc1ccccc1-3
Reactant: CN(C)C(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)CNC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)N1CCC(N2CCOCC2)CC1)=Cc1ccccc1-3
Temperature: 25 °C
Reaction time: 48 h
Yield: 49.3 %

Procedure:
To a stirred solution of 13-cyclohexyl-6-[[4-(4-morpholinyl)-1-piperidinyl]carbonyl]-7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid (40 mg, 0.07 mmol) in CH2Cl2 (1.5 mL) were added N,N-diisopropylethylamine (60 μL, 0.34 mmol), 2-amino-N,N-dimethylacetamide monoacetate (16 mg, 0.1 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (19 mg, 0.1 mmol), and 1-hydroxybenzotriazole (14 mg, 0.1 mmol). The suspension was allowed to stir at r.t. for 2 days, then diluted with CH2Cl2, filtered through Celite, and chromatographed on silica gel (gradient elution: 0%→10% MeOH in CH2Cl2) to give the title compound as a yellow solid (22 mg, 48% yield). LC/MS (ESI) retention time: 1.66 min, m/z 638 (MH+); 1H NMR (400 MHz, CDCl3) δ 1.29-1.43 (m, 2 H) 1.47-1.59 (m, 1 H) 1.71-1.80 (m, 2 H) 1.87-1.96 (m, 1 H) 2.34-2.35 (m, 1 H) 2.40-2.51 (m, 3 H) 2.60-2.76 (m, 2 H) 2.77-2.89 (m, 1 H) 3.02 (s, 3 H) 3.04 (s, 3 H) 3.66 (s, 4 H) 4.25 (d, J=3.78 Hz, 2 H) 4.39 (s, 1 H) 5.07-5.08 (m, 1 H) 6.61 (s, 1 H) 6.81 (s, 1 H) 7.33-7.49 (m, 5 H) 7.51-7.59 (m, 1 H) 7.86 (d, J=8.56 Hz, 1 H) 8.02 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20](I)=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:22].[CH3:23][Si:24]([C:27]#[CH:28])([CH3:26])[CH3:25].C(N(CC)CC)C>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:28]#[C:27][Si:24]([CH3:26])([CH3:25])[CH3:23])=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:22]
Reactant: Cc1cc(-c2cc(C(F)(F)F)n3ncc(I)c3n2)ccc1Cl
Reactant: C#C[Si](C)(C)C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C#C[Si](C)(C)C)c3n2)ccc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 114.5 %

Procedure:
A mixture of 5-(4-chloro-3-methyl-phenyl)-3-iodo-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (5.85 g, 12.4 mmol), trimethylsilylacetylene (3.33 mL, 24.1 mmol) and triethylamine (3.71 mL, 26.7 mmol) in N,N-dimethylformamide (20 mL) was stirred for 10 min at room temperature while being purged with Argon, then PdCl2(PPh3)2 (94 mg, 1 mol %), PPh3 (35 mg, 1 mol %) and CuI (8 mg, 0.3 mol %) were added. Stirring was continued at 90° C. for 4 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (150 mL), washed with water (2×50 mL) and brine (70 mL), dried (MgSO4) and evaporated to give 5-(4-chloro-3-methyl-phenyl)-7-trifluoromethyl-3-trimethylsilanylethynyl-pyrazolo[1,5-a]pyrimidine (5.79 g, 106%) as an orange solid, which was dissolved in THF (70 mL) and MeOH (70 mL), while stirring at 0° C. potassium carbonate (196 mg, 1.42 mmol) was added and the mixture was stirred at 0° C. for 5 h. The mixture was diluted with ice water (250 mL) and extracted with TBME (3×250 mL). The combined organic layers were washed with brine (300 mL), dried (MgSO4) and evaporated. The crude product was further purified by column chromatography on silica gel (heptane/EtOAc 9:1) followed by trituration with heptane to give 5-(4-chloro-3-methyl-phenyl)-3-ethynyl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (3.22 g, 68%) as an orange solid. MS (EI) 335.0 [(M+H)+]; mp 166° C.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])=[CH:5][N:4]([CH2:15][CH3:16])[N:3]=1.[CH3:17][C:18]1[O:22][C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:20][C:19]=1[CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1>N1C=CC=CC=1>[C:7]([C:6]1[C:2]([NH:1][S:37]([C:34]2[CH:35]=[CH:36][C:31]([O:30][CH2:29][C:19]3[N:20]=[C:21]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[O:22][C:18]=3[CH3:17])=[CH:32][CH:33]=2)(=[O:38])=[O:39])=[N:3][N:4]([CH2:15][CH3:16])[CH:5]=1)(=[O:8])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCn1cc(C(=O)c2ccccc2)c(N)n1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CCn1cc(C(=O)c2ccccc2)c(NS(=O)(=O)c2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of the title A compound, (3-amino-1-ethyl-1H-pyrazol-4-yl)-phenyl-methanone (0.035 g, 0.16 mmol) in pyridine at RT, is added 4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonyl chloride (0.06 g, 0.16 mmol) in pyridine. The solution is stirred at RT for 16 h. The reaction mixture is concentrated, the residue is taken up into ethyl acetate, washed with 1 N HCl, water, saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, filtered and concentrated at reduced pressure. The crude product is chromatographed on silica gel using 50% ethyl acetate in hexanes to yield N-(4-benzoyl-1-ethyl-1H-pyrazol-3-yl)-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonamide as a solid: MS [m/z] 541.1 [M-1]−.
Reaction SMILES: C(O[C:6]1[C:7](=[O:25])[C:8](=[O:24])[C:9]=1[NH:10][CH2:11][C:12]1[O:13][C:14]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:15]=2[CH:16]=1)CCC.[C:26]([NH2:30])([CH3:29])([CH3:28])[CH3:27]>C(O)C>[C:26]([NH:30][C:6]1[C:7](=[O:25])[C:8](=[O:24])[C:9]=1[NH:10][CH2:11][C:12]1[O:13][C:14]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:15]=2[CH:16]=1)([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)N
Reactant: CCCCOc1c(NCc2cc3cc([N+](=O)[O-])ccc3o2)c(=O)c1=O
Solvent: CCO
Product: CC(C)(C)Nc1c(NCc2cc3cc([N+](=O)[O-])ccc3o2)c(=O)c1=O
Temperature: 70 °C
Reaction time: 18 h
Yield: 80.1 %

Procedure:
To 3-butoxy-4-[(5-nitro-benzofuran-2-ylmethyl)amino]-cyclobut-3-ene-1,2-dione (0.25 g, 0.727 mmol), as prepared in Example 8, in ethanol (5 mL) was added tert-butylamine (0.51 mL, 4.85 mmol). The reaction was stirred at 70° C. for 18 hours and then at room temperature for 48 hours. Workup in a manner identical to Example 9 afforded 0.20 g (80%) of 3-tert-butylamino-4-[(5-nitro-benzofuran-2-ylmethyl)-amino]-cyclobut-3-ene-1,2-dione as an off-white solid: mp>300° C.; 1H NMR (DMSO-d6): δ 8.61 (d, 1H), 8.20 (dd, 1H), 7.91 (br t, 1H), 7.81 (d, 1H), 7.59 (br s, 1H), 7.07 (s, 1H), 4.98 (d, 2H), 1.36 (s, 9H). IR (KBr): 3220, 2930, 1800, 1675 cm-1 ; MS (m/z) 344.3 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]([N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[CH2:21][CH2:20][CH2:19][C@H:18]3[CH2:22][OH:23])[CH2:13][CH2:12]2)=[O:10])=[C:4]([CH3:24])[CH:3]=1.[F:25][C:26]([F:38])([F:37])[O:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>>[CH3:24][C:4]1[CH:3]=[C:2]([C:31]2[CH:30]=[CH:29][C:28]([O:27][C:26]([F:25])([F:37])[F:38])=[CH:33][CH:32]=2)[CH:7]=[C:6]([CH3:8])[C:5]=1[C:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[CH2:21][CH2:20][CH2:19][C@H:18]2[CH2:22][OH:23])[CH2:13][CH2:12]1)=[O:10]
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: Cc1cc(Br)cc(C)c1C(=O)N1CCC(N2CCC[C@H]2CO)CC1
Product: Cc1cc(-c2ccc(OC(F)(F)F)cc2)cc(C)c1C(=O)N1CCC(N2CCC[C@H]2CO)CC1

Procedure:
In analogy to the procedure described for example 1, (4-bromo-2,6-dimethyl-phenyl)-[4-((S)-2-hydroxymethyl-pyrrolidin-1-yl)-piperidin-1-yl]-methanone (intermediate 4) was reacted with 4-trifluoromethoxy-phenyl boronic acid to give the title compound as light yellow solid. MS: 477.1 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14](=[O:16])[CH2:13][CH:12]([Si](F)(C)C)[CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[F-].[K+].C(=O)(O)[O-:24].[Na+].OO>CO>[NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14](=[O:16])[CH2:13][CH:12]([OH:24])[CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: O=C([O-])O
Reactant: C[Si](C)(F)C1CC(=O)c2c(nc3ccccc3c2N)C1
Agent: OO
Agent: [F-]
Agent: [K+]
Solvent: CO
Product: Nc1c2c(nc3ccccc13)CC(O)CC2=O
Reaction time: 3 h
Yield: 88.8 %

Procedure:
A solution 9-amino-3,4-dihydro-3-(fluorodimethylsilyl)acridin-1(2H)-one (3.7 g) 1:1-tetrahydrofuran:methanol (70 ml), potassium fluoride (7.45 g), and sodium bicarbonate (10.7 g) was chilled in an ice/water bath, and 30% aqueous hydrogen peroxide (44 ml) was added slowly. Upon completion of the addition, the bath was removed and stirring was continued for 3 hr. The reaction mixture was poured into water (250 ml) and a little diethyl ether was added. The mixture was filtered and the filter cake was washed with water and diethyl ether to give 2.6 g (89%) of product, mp 205° C. (dec).