Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]2[S:9](=[O:10])[CH:8]=[N:7][C:6]=2[CH:11]=1.C(N(CC)CC)C.[C:22](Cl)(=[O:24])[CH3:23]>CC(C)=O>[C:22]([N:7]1[C:6]2[CH:11]=[C:2]([CH3:1])[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]=2[S:9](=[O:10])[CH2:8]1)(=[O:24])[CH3:23]
Reactant: Cc1cc2c(c([N+](=O)[O-])c1)S(=O)C=N2
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC(=O)N1CS(=O)c2c1cc(C)cc2[N+](=O)[O-]
Yield: 82.6 %

Procedure:
6.3 g (0.03 mol) of 5-methyl-7-nitro-benzothiazolone and 3.3 g (0.03 mol) of triethylamine are dissolved in 150 ml of acetone. 2.35 g (0.03 mol) of acetyl chloride are allowed to run in slowly dropwise, with stirring, at an internal temperature of 5°-10° C. The reaction mixture is stirred at room temperature for a further 3 hours and then poured onto ice. 6.3 g (83 % of theory) of 3-acetyl-5-methyl-7-nitro-benzothiazolone are obtained in the form of creamcolored flakes of melting point 141° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17](O)=[O:18])=[N:11][CH:10]=2)=[CH:5][CH:4]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[C:45]([O:49][C:50]([NH:52][NH2:53])=[O:51])([CH3:48])([CH3:47])[CH3:46]>CN(C)C=O.O>[C:45]([O:49][C:50]([NH:52][NH:53][C:17](=[O:18])[C:16]1[CH:20]=[CH:21][CH:22]=[C:14]([C:12]2[O:13][C:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)=[CH:10][N:11]=2)[CH:15]=1)=[O:51])([CH3:48])([CH3:47])[CH3:46]
Reactant: COc1ccc(-c2cnc(-c3cccc(C(=O)O)c3)o2)cc1
Reactant: CC(C)(C)OC(=O)NN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2cnc(-c3cccc(C(=O)NNC(=O)OC(C)(C)C)c3)o2)cc1
Reaction time: 48 h
Yield: 78.2 %

Procedure:
1.5 g (5.0 mmol) of 3-[5-(4-Methoxy-phenyl)-oxazol-2-yl]-benzoic acid from Preparation 4, 1.3 g (6.6 mmol) EDAC.HCl, 0.89 g (6.6 mmol) HOBT, and 0.87 g (6.6 mmol) hydrazinecarboxylic acid tert-butyl ester was dissolved in 20 mL of dimethylformamide. Stirring was continued 48 hours at room temperature. Water (60 mL) was added, and the product was extracted with 1:1 THF/EtOAc (2×). Combined the organic extracts and washed with saturated aqueous NaCl solution (3×), dried (MgSO4). Dried in a vacuum oven overnight at 70° C. to provide 1.6 g (82%) of desired product. MS: m/z (APCI, AP+) 410 [M−]+
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]([CH2:13][C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:15]=2[Br:24])[NH:8][C:9](=[O:12])[C:10]=1[OH:11])=O.[CH3:25][NH2:26]>C1COCC1>[CH3:25][NH:26][C:3]([C:5]1[N:6]=[C:7]([CH2:13][C:14]2[CH:19]=[C:18]([C:20]([F:21])([F:22])[F:23])[CH:17]=[CH:16][C:15]=2[Br:24])[NH:8][C:9](=[O:12])[C:10]=1[OH:11])=[O:2]
Reactant: CN
Reactant: COC(=O)c1nc(Cc2cc(C(F)(F)F)ccc2Br)[nH]c(=O)c1O
Solvent: C1CCOC1
Product: CNC(=O)c1nc(Cc2cc(C(F)(F)F)ccc2Br)[nH]c(=O)c1O
Yield: 53 %

Procedure:
The compound was prepared according to the same procedure as in Example 21 using 2-(2-bromo-5-trifluoromethyl-benzyl)-5-hydroxy-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid methyl ester (0.080 g; 0.197 mmol) and 2M methylamine solution in THF (1 ml). This provided the title product as an off-white solid (0.043 g; 53%). LCMS: m/z=427 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5]2[N:6]([CH:8]=[CH:9][CH:10]=2)[N:7]=1.[N:12]([S:15]([C:18]1[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=1[C:20]([O:22][CH3:23])=[O:21])(=[O:17])=[O:16])=[C:13]=[O:14]>ClCCl>[CH3:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5]2[N:6]([C:8]([C:13]([NH:12][S:15]([C:18]3[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=3[C:20]([O:22][CH3:23])=[O:21])(=[O:17])=[O:16])=[O:14])=[CH:9][CH:10]=2)[N:7]=1
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Reactant: Cc1cc(C)c2cccn2n1
Solvent: ClCCl
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)c1ccc2c(C)cc(C)nn12
Temperature: 25 °C
Yield: 11.5 %

Procedure:
To a solution of 0.40 g (2.7 mmol) of 2,4-dimethylpyrrolo[1,2-b]pyridazine in 15 mL of dichloromethane at -78° C. was added, by syringe pump over a period 70 min, a solution of 0.62 g (2.7 mmol) of methyl 2-(isocyanatosulfonyl)benzoate. The reaction mixture was allowed to warm to room temperature. The residue was purified by flash chromatography to give 0.12 g of a white solid, m.p. 200°-202° C.
Reaction SMILES: [CH3:1][C:2]1([CH2:6]O)[CH2:5][O:4][CH2:3]1.[OH-].[Na+].[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.O>C(Cl)Cl>[CH3:1][C:2]1([CH2:6][S:16]([C:13]2[CH:14]=[CH:15][C:10]([CH3:20])=[CH:11][CH:12]=2)(=[O:18])=[O:17])[CH2:5][O:4][CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1(CO)COC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(S(=O)(=O)CC2(C)COC2)cc1
Temperature: 0 °C

Procedure:
3-methyl-3-oxetanemethanol (100 g, 0.98 mol) was dissolved in 250 mL methylene chloride, and a 35% solution of sodium hydroxide (143.60 g, 1.08 mol)was added, and the reaction was cooled to 0° C. A solution of p-toluenesulfonyl chloride was added (186.67 g, 0.98 mol) in 375 mL methylene chloride was added over 1 hour. A white precipitate formed immediately. The reaction was stirred for 10 additional hours. 1000 mL of water was added. The dichloromethane solution layer was then removed, and dried with sodium sulfate, and the solvent was removed. Yield: 217.77 grams of 3-methyl-3-tosylmethyloxetane as white crystals, 87%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C@H:8]3[N:19]([CH3:20])[CH2:18][CH2:17][C@@:14]4([C:15]=2[CH:16]=1)[C@@:9]3([O:22][CH3:23])[CH:10]=[CH:11][C:12](=[O:21])[CH2:13]4.[H][H].O.C(=O)(O)[O-].[K+]>C(O)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C@H:8]3[N:19]([CH3:20])[CH2:18][CH2:17][C@@:14]4([C:15]=2[CH:16]=1)[C@@:9]3([O:22][CH3:23])[CH2:10][CH2:11][C:12](=[O:21])[CH2:13]4
Reactant: [H][H]
Reactant: COc1ccc2c(c1)[C@]13CCN(C)[C@H](C2)[C@]1(OC)C=CC(=O)C3
Agent: [Pd]
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc2c(c1)[C@]13CCN(C)[C@H](C2)[C@]1(OC)CCC(=O)C3

Procedure:
A solution of 7,8-didehydro-3,14-dimethoxy-17-methylmorphinan-6-one (3) (4.30 g, 13.72 mmol) in acetic acid (80 ml) was hydrogenated over 1.72 g of Pd/C (10%) at 3 atmospheres pressure until the hydrogen uptake was complete. The mixture was filtered through Celite and the solution concentrated under reduced pressure to give a clear oil. This oil was treated with water (100 ml) and potassium bicarbonate was added until the solution became basic. The mixture was extracted with methylene chloride (3×100 ml) whereupon the organic layer was separated, dried over MgSO4 and filtered. The filtrate was concentrated under vacuum to give 4.19 g (97% theory) of the desired product as a colorless solid (m.p. 152°-156° C.).
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]([O:12][CH3:13])=[O:11].[H-].[Na+].[Cl:16][C:17]1[CH:18]=[C:19]([S:24](Cl)(=[O:26])=[O:25])[CH:20]=[CH:21][C:22]=1[Cl:23]>CN(C=O)C>[Cl:16][C:17]1[CH:18]=[C:19]([S:24]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[C:2]2[C:10]([O:12][CH3:13])=[O:11])(=[O:25])=[O:26])[CH:20]=[CH:21][C:22]=1[Cl:23]
Reactant: COC(=O)c1cc2ccccc2[nH]1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2ccccc2n1S(=O)(=O)c1ccc(Cl)c(Cl)c1
Reaction time: 1 h
Yield: 51 %

Procedure:
Methyl indole-2-carboxylate (0.15 g) was dissolved in DMF and sodium hydride (41 mg) was added in a single portion. The reaction was stirred for 1 hour, then 3,4-dichlorobenzenesulphonyl chloride (0.25 g) was added in a single portion. Stirring was continued for a further 2 hours and then the reaction was quenched by the addition of water. The reaction mixture was partitioned between water and ethyl acetate. Combined organic extracts were dried (MgSO4) and concentrated in vacuo and the residue purified by column chromatography using isohexane-5% ethyl acetate as eluent to give the desired end product as a solid (51%). NMR δ (CDCl3) 3.96 (s, 3H), 7.22-8.20 (m, 8H); M/z (+) 384 (MH+), 352, 175.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[CH2:3][NH:4][S:5](Cl)(=[O:7])=[O:6].[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:22]([CH3:23])[N:21]=[C:20]([C:24]3[CH:25]=[C:26]([C:30]([NH2:33])([CH3:32])[CH3:31])[CH:27]=[CH:28][CH:29]=3)[CH:19]=2)=[CH:14][CH:13]=1.CCN(CC)CC>C(Cl)Cl>[F:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[N:22]([CH3:23])[N:21]=[C:20]([C:24]3[CH:25]=[C:26]([C:30]([NH:33][S:5]([NH:4][CH2:3][C:2]([F:10])([F:9])[F:1])(=[O:7])=[O:6])([CH3:31])[CH3:32])[CH:27]=[CH:28][CH:29]=3)[CH:19]=2)=[CH:16][CH:17]=1
Reactant: Cn1nc(-c2cccc(C(C)(C)N)c2)cc1-c1ccc(F)cc1
Reactant: O=S(=O)(Cl)NCC(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1nc(-c2cccc(C(C)(C)NS(=O)(=O)NCC(F)(F)F)c2)cc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 5.3 %

Procedure:
2,2,2-Trifluoroethylsulfamoyl chloride (53 mg, 0.3 mmol) was added dropwise to a stirred solution of the amine from Step 4 (50 mg, 0.2 mmol) and Et3N (37 μL, 0.3 mmol) in CH2Cl2 (2 m]L) at RT under N2. The mixture was stirred at RT overnight and then diluted with CH2Cl2 (25 mL), washed with NaHCO3 solution (20 m L), dried (MgSO4) and concentrated under reduced pressure. The crude product was purified by column chromatography on silica eluting with 20% EtOAc/iso-hexane to yield the title sulfamide (5 mg, 6%). 1H NMR (CDCl3, 500 MHz) δ 8.02 (1H, s), 7.69 (1H, d, J=6.6 Hz), 7.45-7.42 (4H, m), 7.18 (2H, t, J=8.6 Hz), 6.58 (1H, s), 4.70 (1H, s), 4.30-4.27 (1H, m), 3.90 (3H, s), 3.57-3.53 (2H, m), 1.80 (6H, s). MS (ES+) C21H22F4N4O2S requires: 470, found: 471 (M+H+, 100%).
Reaction SMILES: Cl.[NH2:2][CH:3]([C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([CH:23]([CH3:25])[CH3:24])=[N:21][N:22]=2)[N:19]=1)[C:4]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[F:13])=O.[O-:26][C:27]#[N:28].[K+]>CN(C=O)C>[F:13][C:7]1[CH:8]=[C:9]([F:12])[CH:10]=[CH:11][C:6]=1[C:4]1[NH:28][C:27](=[O:26])[NH:2][C:3]=1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([CH:23]([CH3:25])[CH3:24])=[N:21][N:22]=2)[N:19]=1
Reactant: CC(C)c1nnc2ccc(C(N)C(=O)c3ccc(F)cc3F)nn12
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)c1nnc2ccc(-c3[nH]c(=O)[nH]c3-c3ccc(F)cc3F)nn12
Temperature: 110 °C
Reaction time: 2 h
Yield: 7.9 %

Procedure:
To a solution of 2-amino-1-(2,4-difluorophenyl)-2-(3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone hydrochloride (1.18 g, 3.21 mmol) in DMF (10 mL) was added potassium cyanate (0.65 g, 8.0 mmol). The reaction mixture was stirred at about 110° C. for about 2 h. The temperature was reduced to about 80° C. and stirring continued for about 15 h. The solvent was removed under reduced pressure. The crude material was purified by RP-HPLC (Table 1, Method f). The appropriate fractions were combined and solvent removed under reduced pressure. The sample was dissolved in DCM (20 mL) and washed with saturated NaHCO3 solution (3×10 mL). The organic layer was dried over MgSO4, filtered, and solvent removed under reduced pressure to afford a solid that was dried under vacuum to give the title compound (0.09 g, 8%): LC/MS (Table 1, Method a) Rt=2.25 min; MS m/z: 357.1 (M+H)+.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:9]([C:11]1[CH:19]=[C:15]([C:16]([OH:18])=[O:17])[C:14]([OH:20])=[CH:13][CH:12]=1)=[O:10].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH2:1]([O:20][C:14]1[CH:13]=[CH:12][C:11]([CH:9]=[O:10])=[CH:19][C:15]=1[C:16]([O:18][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)c(C(=O)O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2ccccc2)c(C(=O)OCc2ccccc2)c1
Reaction time: 72 h

Procedure:
Benzyl bromide (25.6 mL, 0.22 mol, 2.5 eq) was added dropwise to a stirred solution of 5-formylsalicylic acid (10 g, 0.06 mol, 1 eq) and cesium carbonate (84.2 g, 0.26 mol, 3 eq) in N,N-dimethylformamide (150 mL). The reaction mixture was stirred for 3 days and concentrated in vacuo. The residue was dissolved in ethyl acetate (200 mL) and the organic solution washed with water (200 mL) and brine (4×200 mL), then dried over sodium sulfate and evaporated in vacuo. This gave a gummy solid which was recrystallized from ethyl acetate and petroleum ether to give a cream coloured powder (16.1 g, 77%). RF (petroleum ether:ethyl acetate 1:1) 0.73. 1H NMR (CDCl3) δ9.91 (s, 1H, O═C—H), 5.38 (s, 2H, CH2Ph), 5.28 (s, 2H, CH2Ph).
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[N:11][C:12](Cl)=[C:13]([NH:18][CH:19]([CH3:21])[CH3:20])[N:14]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([CH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)(=[O:33])=[O:32].CC(C)([O-])C.[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[N:11][C:12]([N:37]3[CH2:36][CH2:35][CH:34]([S:31]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[F:24])(=[O:33])=[O:32])[CH2:39][CH2:38]3)=[C:13]([NH:18][CH:19]([CH3:21])[CH3:20])[N:14]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)Nc1nc2c(nc1Cl)CN(Cc1ccccc1)CC2
Reactant: O=S(=O)(c1ccccc1F)C1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(C)Nc1nc2c(nc1N1CCC(S(=O)(=O)c3ccccc3F)CC1)CN(Cc1ccccc1)CC2
Temperature: 90 °C
Yield: 51.5 %

Procedure:
A suspension of 6-benzyl-3-chloro-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine (117.2 mg, 0.370 mmol) and 4-((2-fluorophenyl)sulfonyl)piperidine hydrochloride (124 mg, 0.444 mmol) in toluene (1.85 mL) was treated with sodium tert-butoxide (107 mg, 1.110 mmol), BINAP (34.6 mg, 0.055 mmol), and Pd2(dba)3 (16.9 mg, 0.018 mmol). Nitrogen gas (balloon) was bubbled through the reaction mixture for 5 min. The reaction mixture was then sealed and heated at 90° C. for 18 h. The reaction mixture was opened to air and concentrated under reduced pressure. The residue was taken up in DMF/MeOH, filtered through a 0.45 μm syringe filter, and purified by HPLC Method A to give the title compound (99.7 mg, 42.3%). ESI-MS m/z [M+H]+ 523.90.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH2:3]1.O[CH:18]=[C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][C:20]1=[O:28]>>[CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([NH:16][CH:18]=[C:19]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[NH:21][C:20]3=[O:28])=[CH:14][CH:15]=2)[CH2:3]1
Reactant: O=C1Nc2ccccc2C1=CO
Reactant: CN1CCCC(COc2ccc(N)cc2)C1
Product: CN1CCCC(COc2ccc(NC=C3C(=O)Nc4ccccc43)cc2)C1
Yield: 81.2 %

Procedure:
In a manner similar to that described in Example 231, 4-(1-methyl-piperidin-3-ylmethoxy)-phenylamine (656 mg, 1.2 equiv.) and 3-hydroxymethylene-1,3-dihydro-indol-2-one (400 mg, 2.48 mmol, 1 equiv.) are reacted to give the named compound as a yellow solid (732 mg, 81%).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=3)[N:9]=2)[NH:4][CH:3]=1.[C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)#[CH:24].C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C)C=O>[C:25]1([C:23]#[C:24][C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=4)[N:9]=3)[NH:4][CH:3]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: C#Cc1ccccc1
Reactant: COc1cc(-c2cnc3[nH]cc(I)c3n2)cc(OC)c1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(-c2cnc3[nH]cc(C#Cc4ccccc4)c3n2)cc(OC)c1OC
Temperature: 70 °C
Yield: 90.8 %

Procedure:
7-Iodo-2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine (500 mg, 1.22 mmol), PdCl2(PPh3)2 (43 mg, 0.061 mmol), and cuprous iodide (6 mg, 0.031 mmol) were added to a 20 ml microwave vial. The vial was capped and purged with nitrogen. Ethynyl benzene (0.4 ml, 3.6 mmol), triethylamine (5 ml) and N,N-dimethylformamide (5 ml) were added through the septum and the vial was purged again with nitrogen. The mixture was heated in a microwave reactor at 70° C. for 30 minutes. The crude mixture was diluted with ethyl acetate and washed with dilute hydrochloric acid and water/brine. The organic layer was filtered through celite and concentrated. The residue was triturated with a mixture of ethyl acetate and hexanes and filtered, washed with hexanes, and dried to give 427 mg of 7-phenylethynyl-2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine. MS: (M+H)+=386.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:7][CH:8]=1.[Cl:17][C:18]1[N:19]=[N:20][C:21](Cl)=[C:22]([CH3:25])[C:23]=1[CH3:24].C(N(CC)CC)C>CN1C(=O)CCC1>[Cl:17][C:18]1[N:19]=[N:20][C:21]([N:12]2[CH2:11][CH2:10][N:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:15])[F:16])=[CH:8][N:7]=3)[CH2:14][CH2:13]2)=[C:22]([CH3:25])[C:23]=1[CH3:24]
Reactant: Cc1c(Cl)nnc(Cl)c1C
Reactant: FC(F)(F)c1ccc(N2CCNCC2)nc1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: Cc1c(Cl)nnc(N2CCN(c3ccc(C(F)(F)F)cn3)CC2)c1C
Yield: 82 %

Procedure:
1-(5-Trifluoromethyl-pyridin-2-yl)-piperazine (10 g, 43.3 mmol) is combined with 3,6-dichloro-4,5-dimethyl-pyridazine (14.4 g, 84.3 mmol), triethylamine (8.25 mL), and NMP (40 mL). The reaction mixture is irradiated to a temperature of 180° C. for 25 min, and then concentrated in vacuo. The residue is purified by flash chromatography on silica gel (0-8% MeOH/CH2Cl2) to afford the title compound (13.2 g, 82%).
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([N:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH2:14][CH:13]([C:27](O)=[O:28])[CH2:12]2)=[O:10])[CH2:5][CH2:4]1)#[N:2].O[N:31]=[C:32]([NH2:39])[CH2:33][C:34]1([CH2:37][OH:38])[CH2:36][CH2:35]1>>[OH:38][CH2:37][C:34]1([CH2:33][C:32]2[N:39]=[C:27]([CH:13]3[CH2:14][CH:15]([C:17]4[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][CH:18]=4)[CH2:16][N:11]([C:9]([N:6]4[CH2:5][CH2:4][CH:3]([C:1]#[N:2])[CH2:8][CH2:7]4)=[O:10])[CH2:12]3)[O:28][N:31]=2)[CH2:36][CH2:35]1
Reactant: NC(CC1(CO)CC1)=NO
Reactant: N#CC1CCN(C(=O)N2CC(C(=O)O)CC(c3ccc(C(F)(F)F)cc3)C2)CC1
Product: N#CC1CCN(C(=O)N2CC(c3ccc(C(F)(F)F)cc3)CC(c3nc(CC4(CO)CC4)no3)C2)CC1

Procedure:
100 mg (0.24 mmol) of the compound from Example 100A and 61 mg (0.37 mmol) of the compound from Example 67A were reacted according to the General Method 2. Yield: 70 mg (56% of theory)
Reaction SMILES: F[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.Cl.[O:24]1[CH2:27][CH:26]([NH2:28])[CH2:25]1.CCN(C(C)C)C(C)C>>[CH3:22][C:3]1[C:2]([NH:28][CH:26]2[CH2:27][O:24][CH2:25]2)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:12]2[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=2)[N:4]=1
Reactant: NC1COC1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC1COC1
Temperature: 100 °C
Yield: 66 %

Procedure:
Prepared similarly to that described in Example 131 using 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 41 mg, 0.138 mmol), oxetan-3-amine hydrochloride (30.3 mg, 0.277 mmol, Frontier Scientific), and DIPEA (121 μl, 0.692 mmol), heating at 100° C. for 30 min. Purification by silica gel (100% DCM to 8% MeOH/DCM) provided 2-(2-methyl-3-(oxetan-3-ylamino)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (66% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.60 (s, 3H) 2.92 (t, J=6.85 Hz, 2H) 3.45 (td, J=6.85, 2.35 Hz, 2H) 4.74 (t, J=6.16 Hz, 2H) 4.98 (t, J=6.16 Hz, 2H) 5.04-5.15 (m, 1H) 6.98 (br. s., 1H) 7.10 (d, J=2.15 Hz, 1H) 7.37 (t, J=7.73 Hz, 1H) 7.60 (dd, J=8.02, 1.17 Hz, 1H) 7.70 (d, J=4.69 Hz, 1H) 7.85 (dd, J=7.63, 1.17 Hz, 1H) 11.80 (br. s., 1H). MS (ESI, pos. ion) m/z: 350.1 (M+1).
Reaction SMILES: O[C:2]1[C:6](=[O:7])[N:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH:4]([CH3:13])[C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].Cl.[NH2:20][OH:21]>N1C=CC=CC=1>[OH:21][N:20]=[C:2]1[C:6](=[O:7])[N:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH:4]([CH3:13])[CH:3]1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: NO
Reactant: CCCCCN1C(=O)C(O)=C(C(=O)OCC)C1C
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCN1C(=O)C(=NO)C(C(=O)OCC)C1C
Reaction time: 120 h
Yield: 59.5 %

Procedure:
To the title compound of Example J (21.6 g, 0.085 mol) in pyridine (150 ml) was added hydroxylamine hydrochloride (10.6 g, 0.17 mol) and the solution was stirred for 5 days. The solvent was removed in vacuo to give an orange oil which as chromatographed on silica gel eluting with 2% EtOH/CH2Cl2 to give the title compound (13.67 g, 59%) as an oil. Calculated C13H22N2O4 1/2H2O: C, 55.90; H, 8.30; N, 10.02 Found: C, 55.99; H, 8.38; N, 10.00. MS calcd for C13H22N2O4 270, found 270.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH2:14][C:13](=[O:15])[NH:12][C:11]3[CH:16]=[C:17]([C:20]([NH:22][CH2:23][C:24]#[CH:25])=[O:21])[CH:18]=[CH:19][C:10]=3[N:9]=2)[CH:5]=[CH:4][N:3]=1.[C:26](C1C=C(C2CC(=O)NC3C=C(C(NCC#C)=O)C=CC=3N=2)C=CN=1)#[N:27].C(C1C=C(C2CC(=O)NC3C=C(B(O)O)C=CC=3N=2)C=CC=1)#N.C(C1C=C(C2CC(=O)NC3C=C(C(=N)N)C=CC=3N=2)C=CC=1)#N.C(C1C=C(C2CC(=O)NC3C=C(C(=N)NC(=O)C)C=CC=3N=2)C=CC=1)#N.O=C1NC2C=C(C(N)=O)C=CC=2N=C(C2C=CN=NC=2)C1.O=C1NC2C=C(C(NCCC)=O)C=CC=2N=C(C2C=CN=NC=2)C1.C(NC(C1C=CC2N=C(C3C=CN=NC=3)CC(=O)NC=2C=1)=O)C=C>>[C:26]([C:2]1[CH:7]=[C:6]([C:8]2[CH2:14][C:13](=[O:15])[NH:12][C:11]3[CH:16]=[C:17]([C:20]([NH:22][CH2:23][CH2:24][CH3:25])=[O:21])[CH:18]=[CH:19][C:10]=3[N:9]=2)[CH:5]=[CH:4][N:3]=1)#[N:27]
Reactant: C#CCNC(=O)c1ccc2c(c1)NC(=O)CC(c1ccnc(C#N)c1)=N2
Reactant: C#CCNC(=O)c1ccc2c(c1)NC(=O)CC(c1ccnc(Cl)c1)=N2
Agent: C=CCNC(=O)c1ccc2c(c1)NC(=O)CC(c1ccnnc1)=N2
Agent: CC(=O)NC(=N)c1ccc2c(c1)NC(=O)CC(c1cccc(C#N)c1)=N2
Agent: CCCNC(=O)c1ccc2c(c1)NC(=O)CC(c1ccnnc1)=N2
Product: CCCNC(=O)c1ccc2c(c1)NC(=O)CC(c1ccnc(C#N)c1)=N2

Procedure:
4-(2-Chloropyridin-4-yl)-2-oxo-N-(prop-2-yn-1-yl)-2,3-dihydro-1H-benzo[b][1,4]diazepine-8-carboxamide (Compound 69); 4-(2-Cyanopyridin-4-yl)-2-oxo-N-(prop-2-yn-1-yl)-2,3-dihydro-1H-benzo[b][1,4]diazepine-8-carboxamide (Compound 70); (4-(3-Cyanophenyl)-2-oxo-2,3-dihydro-1H-benzo[b][1,4]diazepin-8-yl)boronic acid (Compound 71); 4-(3-Cyanophenyl)-2-oxo-2,3-dihydro-1H-benzo[b][1,4]diazepine-8-carboximidamide (Compound 72); N-((4-(3-Cyanophenyl)-2-oxo-2,3-dihydro-1H-benzo[b][1,4]diazepin-8-yl)(imino)methyl)-acetamide (Compound 73); 2-Oxo-4-(pyridazin-4-yl)-2,3-dihydro-1H-benzo[b][1,4]diazepine-8-carboxamide (Compound 74); 2-oxo-N-propyl-4-(pyridazin-4-yl)-2,3-dihydro-1H-benzo[b][1,4]diazepine-8-carboxamide (Compound 75); N-Allyl-2-oxo-4-(pyridazin-4-yl)-2,3-dihydro-1H-benzo[b][1,4]diazepine-8-carboxamide (Compound 76).