Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([N:17]3[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[C:24](Cl)=[O:25])=[CH:18]3)(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH:5]=[N:4]1.[NH2:27][OH:28]>>[OH:28][NH:27][C:24](=[O:25])/[CH:23]=[CH:22]/[C:19]1[CH:20]=[CH:21][N:17]([S:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]3[CH:5]=[N:4][N:3]([CH3:2])[CH:7]=3)=[CH:9][CH:10]=2)(=[O:16])=[O:15])[CH:18]=1
Reactant: NO
Reactant: Cn1cc(-c2ccc(S(=O)(=O)n3ccc(/C=C/C(=O)Cl)c3)cc2)cn1
Agent: Cl
Product: Cn1cc(-c2ccc(S(=O)(=O)n3ccc(/C=C/C(=O)NO)c3)cc2)cn1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The above prepared solution of (E)-3-{1-[4-(1-Methyl-1H-pyrazol-4-yl)-benzenesulfonyl]-1H-pyrrol-3-yl}-acryloyl chloride hydrochloride was added to an aqueous hydroxylamine solution (50%, 105 mL, 1.78 mol) at 10-20° C. over a period of 20 min. After stirring for 90 min, the suspension was filtered and dried. The crude product (48.4 g) was suspended in a mixture of isopropanol (480 mL) and water (480 mL) and stirred at reflux for 1 h. After cooling to room temperature, the suspension was filtered and dried. The title compound was obtained as beige solid (28.1 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[O:11])O[C:8](=[O:12])[NH:7][C:6]=2[CH:13]=1.[C:14]([CH2:16]C(OCC)=O)#[N:15].C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[CH:13]=[C:6]2[C:5]([C:10]([OH:11])=[C:16]([C:14]#[N:15])[C:8](=[O:12])[NH:7]2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]c2cc(F)ccc2c(=O)o1
Reactant: CCOC(=O)CC#N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#Cc1c(O)c2ccc(F)cc2[nH]c1=O

Procedure:
A mixture of 7-fluoro-1H-benzo[d][1,3]oxazine-2,4-dione (515 mg, 2.8 mmol) (commercially available through AstaTech™, Inc.), ethyl 2-cyanoacetate (303 μL, 2.8 mmol), and triethylamine (793 μL, 5.7 mmol) in DMF (1.4 mL) was stirred at 120° C. for 6 h. The reaction mixture was then concentrated. Upon addition of 1M HCl a precipitate formed, which was isolated by filtration and dried under vacuum, affording 7-fluoro-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbonitrile. Mass Spectrum (ESI) m/e=205 (M+1).
Reaction SMILES: [C:1](=[O:26])([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[O:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)[CH:4]=1.[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[C:1](=[O:26])([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[O:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:16][CH:15]=2)[CH:4]=1
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)Oc1cc(-c2ccc(Br)cc2)nn1-c1ccccn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Oc1cc(-c2ccc(-c3ccccc3)cc2)nn1-c1ccccn1
Temperature: 100 °C
Yield: 90.5 %

Procedure:
1 mmol of 3-(4-bromophenyl)-1-(pyridin-2-yl)-1H-pyrazol-5-yl tert-butyl carbonate (21) prepared in Example B-2 was charged in a 50 mL round-bottom flask and dissolved in 1,4-dioxane (10 mL), and phenylboronic acid (2.5 equivalents, manufactured by Aldrich) and K3PO4 (3 equivalents) were added thereto. Thereafter, PdCl2(dppf) (0.08 equivalents, manufactured by Aldrich) and dppf (1,1′-bis(diphenylphosphino)ferrocene, 0.04 equivalents, manufactured by Aldrich) were added thereto, followed by heating at 100° C. for 10 minutes. After the solid was filtered through Celite, the organic layer was concentrated under reduced pressure, dissolved in ethyl acetate and then washed with water. The organic layer was dried over anhydrous MgSO4 and concentrated. The resulting residue was purified by column chromatography (n-hexane:EA (ethyl acetate)=5:1 (v/v)) to afford the title compound.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.O.[NH4+].[Cl-].[NH4+].[OH-].[CH3:16][N:17](C=O)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].[C-]#N.[C-]#N.[Zn+2]>[NH:8]1[C:4]2[N:5]=[CH:6][CH:7]=[C:2]([C:16]#[N:17])[C:3]=2[CH:10]=[CH:9]1
Reactant: CN(C)C=O
Reactant: Ic1ccnc2[nH]ccc12
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: N#Cc1ccnc2[nH]ccc12
Temperature: 90 °C
Reaction time: 20 h
Yield: 74 %

Procedure:
To a solution of (4.7 g, 19.3 mmol) of 4-Iodo-1H-pyrrolo[2,3-b]pyridine in degassed DMF (25 mL) was added Pd2(dba)3 (10 mg), dppf (15 mg), degassed H2O (2 mL) and Zn(CN)2 (1.4 g, 11.6 mmol). The mixture was stirred at 90° C. under nitrogen for 20 hr, then cooled to 70° C. and 75 mL of a 4:1:4 mixture of saturated NH4Cl: NH4OH: H2O was added. The mixture was stirred at 5° C. for 20 min. and the resulting precipitate filtered off, washed with 75 mL 4:1:5 mixture of saturated NH4Cl: NH4OH: H2O, 500 mL H2O and 100 mL toluene, then dried in vacuo to give 2.06 g (74%) 1H-Pyrrolo[2,3-b]pyridine-4-carbonitrile. MS (ES+): 143 [MH+]. 1H NMR (DMSO-d6, 400 MHz): δ 6.65 (d, 1H, J=3.2), 7.56 (d, 1H, J=4.8 Hz), 7.84 (d, 1H, J=4.0 Hz), 8.40 (d, 1H, J=4.8 Hz).
Reaction SMILES: Cl.[C:2]1([CH3:10])[CH:7]=[CH:6][C:5]([NH:8]N)=[CH:4][CH:3]=1.Cl.[CH:12]12[NH:20][CH:16]([CH2:17][CH2:18][CH2:19]1)[CH2:15][C:14](=O)[CH2:13]2.S(=O)(=O)(O)O>O1CCOCC1>[CH3:10][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:8][C:14]1[CH2:13][CH:12]3[NH:20][CH:16]([C:15]2=1)[CH2:17][CH2:18][CH2:19]3
Reactant: Cc1ccc(NN)cc1
Reactant: O=C1CC2CCCC(C1)N2
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: Cc1ccc2[nH]c3c(c2c1)C1CCCC(C3)N1
Temperature: 80 °C

Procedure:
In a 100 mL round-bottom flask were combined p-tolylhydrazine hydrochloride (1.80 g, 11.4 mmol; Alfa Aesar), 9-azabicyclo[3.3.1]nonan-3-one hydrochloride (2.0 g, 11.4 mmol; Accela ChemBio), and concentrated sulfuric acid (5 mL) in dioxane (50 mL). The reaction mixture was heated to 80° C. for 2.5 hours, then cooled to room temperature. The solvent was decanted, and the residue was dissolved in water (20 mL) and basified with solid potassium carbonate to pH ˜12. This solution was extracted with dichloromethane (3×50 mL), and the combined organic phases were dried over magnesium sulfate. After removing the solvent under vacuum, the residue was purified by silica gel chromatography (CH2Cl2/CH3OH, 3:1) to afford the title compound: 1H NMR (300 MHz, CDCl3) δ ppm 1.39-1.50 (m, 2H), 1.75 (d, J=14 Hz, 2H), 1.91-2.07 (m, 2H), 2.38 (s, 3H), 2.72 (d, J=17 Hz, 1H), 3.27-3.39 (m, 1H), 3.70 (t, J=5 Hz, 1H), 4.55 (t, J=3 Hz, 1H), 6.88 (dd, J=8, 1 Hz, 1H), 7.14 (s, 1H), 7.18 (d, J=8 Hz, 1H); MS (DCI/NH3) m/z 227 (M+H)+.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[Si:11]([O:18][C@H:19]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:20](OCC)=[O:21])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].O1CCCC1.O>CCCCCC>[Si:11]([O:18][C@H:19]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH:20]=[O:21])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: CCOC(=O)[C@H](O[Si](C)(C)C(C)(C)C)c1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CC(C)(C)[Si](C)(C)O[C@@H](C=O)c1ccccc1
Temperature: -40 °C
Reaction time: 4 h

Procedure:
20 ml of a 1M hexane solution of diisobutylaluminum hydride were added dropwise at -65° C. and in an atmosphere of nitrogen to a solution of 5.9 g of ethyl (R)-α-(t-butyldimethylsilyloxy)-α-phenylacetate (prepared as described in Preparation 23) in 300 ml of dry hexane, and the resulting mixture was stirred at -40° C. for 4 hours. At the end of this time, 10 ml of a tetrahydrofuran solution containing 1 ml of water was added dropwise to the reaction mixture at -40° C., and then the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was then filtered using a Celite (trade mark) filter aid, and the filtrate was concentrated by evaporation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 1:60 by volume mixture of ethyl acetate and hexane as the eluent, to give the title compound having an Rf=0.64 (thin layer chromatography over silica gel, using a 1:50 by volume mixture of ethyl acetate and hexane).
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13]CC)=O)[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[S:4][C@H:3]1[C:20]1[S:21][CH:22]=[CH:23][CH:24]=1.[NH3:25]>CO>[NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([NH2:25])=[O:13])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[S:4][C@H:3]1[C:20]1[S:21][CH:22]=[CH:23][CH:24]=1
Reactant: N
Reactant: CCOC(=O)CN1C(=O)[C@@H](N)[C@H](c2cccs2)Sc2ccccc21
Solvent: CO
Product: NC(=O)CN1C(=O)[C@@H](N)[C@H](c2cccs2)Sc2ccccc21
Reaction time: 24 h

Procedure:
In 300 ml of methanol is dissolved 8 g of ethyl trans-3-amino-4-oxo-2-(2-thienyl)-2,3,4,5-tetrahydro-1,5 -benzothiazepine-5-acetate, and ammonia gas is under ice-cooling blown into the solution until being saturated with ammonia gas. The reaction temperature is slowly elevated to room temperature, and the mixture is left standing for one day. Thereafter, the reaction mixture is concentrated under reduced pressure. Isopropyl alcohol is added to the obtained residue to crystallize. The crystals are collected by filtration to give 7 g of trans-3 amino-4-oxo-2-(2-thienyl)-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetamide, m.p. 207°-210° C. (decomposition).
Reaction SMILES: N[C@H](C([NH:12][C@H:13]([C:19]([N:21]1[CH2:35][CH2:34][CH2:33][C@H:22]1[C:23]([N:25]1[CH2:32][CH2:31][CH2:30][C@H:26]1[C:27]([OH:29])=[O:28])=[O:24])=[O:20])[CH2:14][CH2:15][CH2:16][CH2:17][NH2:18])=O)CCCNC(=N)N.[NH2:36][C@H:37](C(N[C@H](C(N1CCC[C@H]1C(N1CCC[C@H]1C(O)=O)=O)=O)CCCNC(=N)N)=O)CCCCN>>[NH2:12][C@H:13]([C:19]([NH:21][C@H:22]([C:23]([N:25]1[CH2:32][CH2:31][CH2:30][C@H:26]1[C:27]([OH:29])=[O:28])=[O:24])[CH2:33][CH2:34][CH2:35][CH2:37][NH2:36])=[O:20])[CH2:14][CH2:15][CH2:16][CH2:17][NH2:18]
Reactant: N=C(N)NCCC[C@H](NC(=O)[C@@H](N)CCCCN)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)O
Reactant: N=C(N)NCCC[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)O
Product: NCCCC[C@H](NC(=O)[C@@H](N)CCCCN)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
Arg-Lys-Pro-Pro; or Lys-Arg-Pro-Pro,
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([NH:22][C:23]4[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=4)=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:9][N:8]([CH:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[C:4]=2[N:5]=[CH:6][N:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:61](O)(=[O:68])[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1>CN(C=O)C>[NH2:1][C:2]1[C:3]2[C:10]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([NH:22][C:23]4[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=4)=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:9][N:8]([CH:31]3[CH2:32][CH2:33][N:34]([C:61](=[O:68])[C:62]4[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=4)[CH2:35][CH2:36]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=C(O)c1ccccc1
Reactant: Nc1ncnc2c1c(C(=O)c1cccc(NC(=O)Nc3cc(Cl)cc(Cl)c3)c1)cn2C1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(C(=O)c1cccc(NC(=O)Nc3cc(Cl)cc(Cl)c3)c1)cn2C1CCN(C(=O)c2ccccc2)CC1
Yield: 14.2 %

Procedure:
A solution of 1-[3-(4-Amino-7-piperidin-4-yl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-3-(3,5-dichloro-phenyl)-urea (100 mg, 0.19 mmol), HATU (73 mg, 0.19 mmol), and benzoic acid (24 mg, 0.19 mmol) in DMF (5 mL) was stirred for 12 hours at room temperature The reaction mixture concentrated in vacuo. Purification by reverse phase preparative HPLC (HPLC method 2) provided the title compound as a white solid (17 mg, 14%). MS: 629.5 (MH+); HPLC Rf: 2.5 min. (HPLC method 2); HPLC purity: 100%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:27]([CH3:31])[CH2:28][CH2:29][CH3:30])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:22]([CH2:23]O)=[N:21][CH:20]=[N:19]4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1.S(Cl)(Cl)=O.[Cl-].[CH:37]1([NH2:40])[CH2:39][CH2:38]1>ClCCl.CN(C=O)C>[Cl:1][C:2]1[C:3]([N:27]([CH3:31])[CH2:28][CH2:29][CH3:30])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:22]([CH2:23][NH:40][CH:37]5[CH2:39][CH2:38]5)=[N:21][CH:20]=[N:19]4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1
Reactant: NC1CC1
Reactant: CCCN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3ncnc3CO)c1)=N2
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CCCN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3ncnc3CNC3CC3)c1)=N2

Procedure:
The title compound was prepared from 8-chloro-7-(methyl-propyl-amino)-4-[3-(5-hydroxymethyl-[1,2,4]triazol-1-yl)-phenyl]-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 162) (220 mg, 0.50 mmol) by reaction with thionylchloride in dichloromethane and subsequent treatment of the corresponding chloride with cyclopropylamine in DMF according to the method described in Example 45. Obtained as a light yellow solid (95 mg, 40%).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]([F:15])[C:5]2[N:6]([CH:10]([CH3:12])[CH3:11])[C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.[CH3:16][O:17][C:18]([C@@H:20]1[O:22][CH2:21]1)=[O:19].FC(F)(F)S([O-])(=O)=O.[Li+]>C(#N)C>[F:15][C:13]1[C:5]2[N:6]([CH:10]([CH3:12])[CH3:11])[C:7](=[O:9])[O:8][C:4]=2[CH:3]=[C:2]([NH:1][CH2:21][C@@H:20]([OH:22])[C:18]([O:17][CH3:16])=[O:19])[CH:14]=1
Reactant: COC(=O)[C@H]1CO1
Reactant: CC(C)n1c(=O)oc2cc(N)cc(F)c21
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Li+]
Solvent: CC#N
Product: COC(=O)[C@H](O)CNc1cc(F)c2c(c1)oc(=O)n2C(C)C

Procedure:
Prepared from 6-amino-4-fluoro-3-isopropyl-1,3-benzoxazol-2(3H)-one (Step 2, 0.77 g, 3.66 mmol), methyl (2R)-glycidate (0.374 g, 3.66 mmol) and lithium trifluoromethanesulfonate (0.57 g, 3.66 mmol) in acetonitrile (10 ml) according to the method of EXAMPLE 86, Step 8 (0.89 g, 78%); MS for C14H17FN2O5 m/z 313 (M+H)+.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:14]=[N:15][N:16]([CH3:18])[CH:17]=3)=[CH:9][C:8]=2[Cl:19])=[N:5][N:6]=1.[CH3:20][N:21]1[CH2:28][C@@H:27]2[C@@H:23]([CH2:24][NH:25][CH2:26]2)[CH2:22]1>CN1C(=O)CCC1.C(Cl)Cl>[Cl:19][C:8]1[CH:9]=[C:10]([C:13]2[CH:14]=[N:15][N:16]([CH3:18])[CH:17]=2)[CH:11]=[CH:12][C:7]=1[C:4]1[S:3][C:2]([N:25]2[CH2:26][C@@H:27]3[C@@H:23]([CH2:22][N:21]([CH3:20])[CH2:28]3)[CH2:24]2)=[N:6][N:5]=1
Reactant: Cn1cc(-c2ccc(-c3nnc(Br)s3)c(Cl)c2)cn1
Reactant: CN1C[C@H]2CNC[C@H]2C1
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: CN1C[C@@H]2CN(c3nnc(-c4ccc(-c5cnn(C)c5)cc4Cl)s3)C[C@@H]2C1
Temperature: 120 °C
Reaction time: 16 h
Yield: 12.7 %

Procedure:
A stirred suspension of 2-bromo-5-(2-chloro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-1,3,4-thiadiazole (70 mg, 0.197 mmol) and (3aR,6aS)-2-methyloctahydropyrrolo[3,4-c]pyrrole (75 mg, 0.590 mmol) in NMP (0.5 mL) was heated to 120° C. and the resulting solution was stirred for 16 hours. The reaction mixture was diluted with DCM (20 mL) and washed with saturated NaHCO3(aq) (20 mL). The organic phase was separated and the aqueous phase was re-extracted with DCM (20 mL). The combined organic phases were concentrated in vacuo to afford the crude product as a dark brown oily residue. The crude material was purified by mass directed preparative HPLC under acidic conditions (TFA modified) and the product containing fractions were loaded onto a 1 g SCX cartridge (pre-wet with MeOH). The cartridge was washed with MeOH (15 mL) then flushed with 7M NH3 in MeOH (10 mL). The MeOH/NH3 was removed in vacuo to afford the title compound as a light brown solid (10 mg, 13% yield). LC-MS: Rt 0.79 min; MS m/z 401.4 [M+H]+ [Method D]. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.32 (s, 1H), 7.99-8.03 (m, 2H), 7.84 (d, J=2.02 Hz, 1H), 7.65-7.69 (m, 1H), 3.88 (s, 3H), 3.70 (dd, J=10.61, 8.08 Hz, 2H), 3.36 (dd, J=10.61, 3.03 Hz, 2H), 2.99 (br. s., 2H), 2.55 (br. s., 4H), 2.25 (s, 3H). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.21 (d, J=8.08 Hz, 1H), 7.81 (s, 1H), 7.69 (s, 1H), 7.57 (d, J=2.02 Hz, 1H), 7.46 (dd, J=8.34, 1.77 Hz, 1H), 3.99 (s, 3H), 3.79 (dd, J=9.85, 7.83 Hz, 2H), 3.53 (d, J=11.12 Hz, 2H), 3.12 (br. s., 2H), 2.76 (br. s., 2H), 2.58 (d, J=8.08 Hz, 2H), 2.41 (br. s., 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:36]=[C:37]([NH:39][C:40]2[NH:41][CH2:42][CH:43]([OH:46])[CH2:44][N:45]=2)[CH:38]=1)[C:5]([NH:7][CH2:8][C:9]([NH:11][C@H:12]([C:19]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([C:29]([OH:35])([CH3:34])[C:30]([F:33])([F:32])[F:31])[CH:20]=1)[CH2:13][C:14]([O:16]CC)=[O:15])=[O:10])=[O:6].O.[OH-].[Li+].ClCCl>C(#N)C.O.O>[OH:1][C:2]1[CH:3]=[C:4]([CH:36]=[C:37]([NH:39][C:40]2[NH:45][CH2:44][CH:43]([OH:46])[CH2:42][N:41]=2)[CH:38]=1)[C:5]([NH:7][CH2:8][C:9]([NH:11][C@H:12]([C:19]1[CH:24]=[C:23]([C:25]([F:27])([F:28])[F:26])[CH:22]=[C:21]([C:29]([OH:35])([CH3:34])[C:30]([F:31])([F:32])[F:33])[CH:20]=1)[CH2:13][C:14]([OH:16])=[O:15])=[O:10])=[O:6]
Reactant: CCOC(=O)C[C@H](NC(=O)CNC(=O)c1cc(O)cc(NC2=NCC(O)CN2)c1)c1cc(C(F)(F)F)cc(C(C)(O)C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Solvent: ClCCl
Solvent: O
Product: CC(O)(c1cc([C@H](CC(=O)O)NC(=O)CNC(=O)c2cc(O)cc(NC3=NCC(O)CN3)c2)cc(C(F)(F)F)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of (3S)-ethyl 3-(2-(3-hydroxy-5-((5-hydroxy-1,4,5,6-tetrahydropyrimidin-2-yl)amino)benzamido) acetamido)-3-(3-(1,1,1-trifluoro-2-hydroxypropan-2-yl)-5-(trifluoromethyl)phenyl)propanoate (from step 2 above) (˜708 mmol, crude residue) in a mixture of acetonitrile/water (1:1) (6 mL) was added lithium hydroxide mono hydrate (150 mg, 3.575 mmol) and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated in vacuo to afford a yellow-orange viscous residue. The residue was dissolved in water (25 mL) and stirred with dichloromethane (50 mL) to remove the urea. The aqueous layer was neutralized with TFA (1 mL in 3 mL ACN) and evaporated in vacuo to afford a pale viscous residue. The crude residue was purified by reverse-phase preparative HPLC on a Biotage 40+M (100 g) C18HS column and a gradient 10-60% acetonitrile in water containing 0.05% TFA to give the desired product, after lyophilzation, as a colorless lyophilized powder (287.8 mg). LC-MS analysis of the solid shows the desired product's mass: m/z 636 (M+H); Calcd for C26H27F6N5O7: 635.51
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:22])[CH:3]=1.[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>CN1CCCC1=O>[CH3:22][C:4]1[CH:3]=[C:2]([N:27]2[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]2)[C:11]2[C:6](=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)=[CH:9][CH:10]=2)[N:5]=1
Reactant: Cc1cc(Cl)c2ccc(COc3ccc(C#N)cc3)cc2n1
Reactant: CN1CCNCC1
Solvent: CN1CCCC1=O
Product: Cc1cc(N2CCN(C)CC2)c2ccc(COc3ccc(C#N)cc3)cc2n1
Yield: 67.1 %

Procedure:
A solution of 4-(4-chloro-2-methyl-quinolin-7-ylmethoxy)-benzonitrile (100 mg, 0.32 mmol) and 1-methylpiperazine (81 mg, 0.81 mmol) in 1-methylpyrrolidin-2-one (1.5 mL) was stirred at 100° C. for 24 h. After cooling the reaciton mixture was partitioned between sat. aq. sodium hydrogencarbonate solution and dichloromethane, the organic layer was separated, washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2, dichloromethane/methanol 19:1) yielded the title compound (80 mg, 66%). Light yellow oil, ISP-MS: m/e=373.5 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21]Cl)[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:26]([NH:28][CH2:29][CH3:30])[CH3:27]>CN(C)C=O>[Br:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21][N:28]([CH2:29][CH3:30])[CH2:26][CH3:27])[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCNCC
Reactant: O=C1c2c(Br)cccc2-n2cnc(-c3noc(CCl)n3)c2[C@@H]2CCN12
Solvent: CN(C)C=O
Product: CCN(CC)Cc1nc(-c2ncn3c2[C@@H]2CCN2C(=O)c2c(Br)cccc2-3)no1
Yield: 83.1 %

Procedure:
1.26 g (3 mmol) of (S)-8-bromo-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one were stirred at room temperature for 5 hours with 0.44 g (6 mmol) of diethylamine and 10 ml of N,N-dimethylformamide. By evaporation of the reaction mixture and chromatography of the residue on silica gel while eluting with methylene chloride/methanol 19/1 there were obtained 1.14 g (82%) of (S)-8-bromo-1-(5-diethylaminomethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one, which was converted into the hydrochloride of m.p. 206°-209°.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[C:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)=[CH:21][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18](O)=[O:19])[CH:8]=1)=[O:5].[NH2:32][CH2:33][C:34]([CH3:37])([OH:36])[CH3:35].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[C:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)=[CH:21][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18]([NH:32][CH2:33][C:34]([OH:36])([CH3:37])[CH3:35])=[O:19])[CH:8]=1)=[O:5]
Reactant: CC(C)(O)CN
Reactant: O=C(O)c1cc(NC(=O)c2cc(-c3ccccn3)c(Cl)cc2Cl)n(-c2ccccc2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(O)CNC(=O)c1cc(NC(=O)c2cc(-c3ccccn3)c(Cl)cc2Cl)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 36.4 %

Procedure:
To a solution of 5-(2,4-dichloro-5-(pyridin-2-yl)benzamido)-1-phenyl-1H-pyrazole-3-carboxylic acid (Example 111, 150 mg, 0.33 mmol) and 1-amino-2-methylpropan-2-ol (50 mg, 0.66 mmol) in DMF (2 mL) was added DIPEA (0.11 mL, 0.66 mmol, 2 eq) and HATU (188 mg, 0.50 mmol). The reaction was stirred at room temperature for 18 hours. The reaction was partitioned between saturated aqueous sodium carbonate solution (50 mL) and EtOAc (50 mL). The organic layer was collected, washed with brine, dried over magnesium sulphate and concentrated in vacuo. The residue was triturated with acetonitrile to afford the title compound (63 mg, 36%).
Reaction SMILES: [Na].Cl.[NH2:3]O.[O:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:7]([CH2:14][C:15](Cl)=[N:16][OH:17])=[N:6]1>C(O)C>[O:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:7]([CH2:14][C:15](=[N:16][OH:17])[NH2:3])=[N:6]1
Reactant: NO
Reactant: ON=C(Cl)Cc1noc2ccccc12
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: NC(Cc1noc2ccccc12)=NO
Yield: 45.4 %

Procedure:
In ethanol (10 ml) was dissolved metal sodium (0.4 g) and thereto was further added hydroxylamine hydrochloride (0.8 g). To the solution was added a solution of 1,2-benzisoxazole-3-acetohydroximic chloride (5.0 g) in ethanol (40 ml) under ice-cooling and the mixture was stirred for hour. The mixture was distilled under a reduced pressure to remove the solvent. To the residue was added chloroform and the insoluble substance was filtered off, and the filtrate was subjected to silica gel column chromatography and eluted with 5 % methanol-chloroform. The resulting precipitated crystallines were separated by filtration and recrystallized from ethanol to give the desired compound (1.0 g). m.p. 161° to 163°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH3:13][NH:14][CH3:15]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:14]([CH3:15])[CH3:13])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CNC
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)N(C)C)cc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To an ice-cooled solution of 4-methoxybenzenesulfonyl chloride (25 g) in tetrahydrofuran (25 ml) was added dimethylamine (50% solution in water, 25 ml). After addition was complete, the mixture was stirred at 50° C. for 30 minutes. The reaction mixture was concentrated to give 4-methoxy-N,N-dimethylbenzenesulfonamide (38 g).