Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][CH:5]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:9]=1)[C:6]#[CH:7].I[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[O:31][C:32]([CH3:35])=[N:33][N:34]=2)[CH:25]=1>C(N(CC)CC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH3:1][O:2][C:3](=[O:22])[CH2:4][CH:5]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:9]=1)[C:6]#[C:7][C:28]1[CH:29]=[CH:24][CH:25]=[C:26]([C:30]2[O:31][C:32]([CH3:35])=[N:33][N:34]=2)[CH:27]=1
Reactant: Cc1nnc(-c2cccc(I)c2)o1
Reactant: C#CC(CC(=O)OC)c1ccc(OC)c(OC2CCCC2)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COC(=O)CC(C#Cc1cccc(-c2nnc(C)o2)c1)c1ccc(OC)c(OC2CCCC2)c1
Temperature: 80 °C
Yield: 82.5 %

Procedure:
To a solution of the compound from Example 7 (0.15 g, 0.5 mmol) and 1-iodo-3-(5-methyl-[1,3,4]oxadiazol-2-yl)benzene (0.14 g, 0.5 mmol) in triethylamine (5 mL) under an argon atmosphere was added trace tetrakis(triphenylphosphine)palladium(0) and trace copper(I) iodide. The mixture was heated at 80° C. for 0.2 h, was cooled to room temperature and was concentrated in vacuo. Purification by flash chromatography (silica gel, 50% EtOAc/hexane) provided the titled compound as a yellow oil (0.19 g, 80%). Anal. (C27H28N2O5· 0·375 H2O) calcd: C, 69.40; H, 6.20; N, 6.00. found: C, 69.23; H, 6.13;N,5.69.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:8]1[CH2:15][O:14][S:11](=[O:13])(=[O:12])[CH2:10][CH2:9]1>O1CCOCC1>[CH:1]1([NH:7][CH2:15][CH2:8][CH2:9][CH2:10][S:11]([OH:14])(=[O:13])=[O:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S1(=O)CCCCO1
Reactant: NC1CCCCC1
Solvent: C1COCCO1
Product: O=S(=O)(O)CCCCNC1CCCCC1
Temperature: 25 °C
Yield: 52 %

Procedure:
To a solution of cyclohexylamine (2.0 g, 20.2 mmol) in 1,4-dioxane (13 mL) was added 1,4-butane sultone (2.61 g, 19.2 mmol). The solution was heated to reflux for 2 hours. The reaction was cooled to room temperature. The solid was collected by filtration, washed with acetone (2×20 mL) and dried in vacuo. Yield: 52%. 1H NMR (D2O, 500 MHz) δ ppm 2.95 (m, 3H), 2.81 (m, 2H), 1.92 (m, 2H), 1.67 (m, 6H), 1.52 (m, 1H), 1.18 (m, 4H), 1.02 (m, 1H). 13C (D2O, 125 MHz) δ ppm 57.32, 50.31, 44.01, 29.02, 24.84, 24.68, 24.07, 24.55. ES-MS 236 (M+1).
Reaction SMILES: C(O)(C(F)(F)F)=O.CC(C)(OC([N:14](C(OC(C)(C)C)=O)[C:15]1[C:20]([C:21]2[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=2)=[C:19]([O:27][C:28]2[C:33]([F:34])=[CH:32][C:31]([NH:35][C:36]([C:38]3[C:39](=[O:54])[N:40]([C:47]4[CH:52]=[CH:51][C:50]([F:53])=[CH:49][CH:48]=4)[CH:41]=[CH:42][C:43]=3[O:44][CH2:45][CH3:46])=[O:37])=[C:30]([F:55])[CH:29]=2)[CH:18]=[CH:17][N:16]=1)=O)C>C(Cl)Cl>[NH2:14][C:15]1[C:20]([C:21]2[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=2)=[C:19]([O:27][C:28]2[C:33]([F:34])=[CH:32][C:31]([NH:35][C:36]([C:38]3[C:39](=[O:54])[N:40]([C:47]4[CH:48]=[CH:49][C:50]([F:53])=[CH:51][CH:52]=4)[CH:41]=[CH:42][C:43]=3[O:44][CH2:45][CH3:46])=[O:37])=[C:30]([F:55])[CH:29]=2)[CH:18]=[CH:17][N:16]=1
Reactant: CCOc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Nc1cc(F)c(Oc2ccnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c2-c2cnn(C)c2)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Nc1cc(F)c(Oc2ccnc(N)c2-c2cnn(C)c2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
TFA (1 mL) was added to a solution of N-(4-(2-[bis[(1,1-dimethylethoxy)carbonyl]amino]-3-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)-2,5-difluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (0.17 g, 0.22 mmol) in CH2Cl2 (3 mL) and the mixture was stirred at RT for 1 h. The solvent was removed and the residue was partitioned between satd NaHCO3 solution (30 mL) and EtOAc (30 mL). The aqueous layer was extracted with EtOAc (25 mL) and the combined organics were washed with brine, dried (Na2SO4) and concentrated under reduced pressure to afford N-(4-(2-amino-3-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)-2,5-difluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (120 mg, 95% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.12 (s, 1H), 8.24 (t, J=9.8 Hz, 1H), 7.91 (d, J=7.8 Hz, 1H), 7.87 (s, 1H), 7.74 (d, J=5.8 Hz, 1H), 7.58 (s, 1H), 7.47 (m, 2H), 7.36 (t, J=8.7 Hz, 3H), 6.54 (d, J=7.9 Hz, 1H), 5.98 (d, J=5.8 Hz, 1H), 5.69 (s, 2H), 4.27 (q, J=7.0 Hz, 2H), 3.85 (s, 3H), 1.32 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 577.2 (M+H+).
Reaction SMILES: C[O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]([CH3:15])[CH:12]=[N:13][CH:14]=2)=[CH:6][CH:5]=1.[OH-].[Li+].O1CCCC1.O>CO>[CH3:15][N:11]1[C:10]([C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:16])=[O:2])=[CH:5][CH:6]=2)=[CH:14][N:13]=[CH:12]1
Reactant: COC(=O)c1ccc(-c2cncn2C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cn1cncc1-c1ccc(C(=O)O)cc1
Yield: 119678 %

Procedure:
4-(3-Methyl-3H-imidazol-4-yl)-benzoic acid methyl ester was prepared using the procedure similar to that outlined by Pivsa-Art, S.,; Satoh, T., Kawamura, Y., Miura, M., Nomura, M. Bull. Chem. Soc. Jpn. 71, 1998, 467. In a flask was dried Cs2CO3 (3.29 g, 12 mmol) in vacuo at 150° C. for 1.5 hr. After cooling to ambient temperature, N-methylimidazole (0.5 mL, 6 mmol), methyl-4-iodo-benzoate (3.29 g, 12 mmmol), Pd(OAc)2 (0.14 g, 0.6 mmol), PPh3 (4.09 g, 12 mmol), and 20 mL dimethylformamide. The mixture was stirred under nitrogen at 140° C. for 24 hrs and an additional 16 hrs at ambient temperature. The mixture was poured onto 10% aqueous NaOH and extracted with CH2Cl2, dried over Na2SO4. Purification by chromatography (5% MeOH/CHCl3) gave 0.50 g (37%) of 4-(3-methyl-3H-imidazol-4-yl)-benzoic acid methyl ester. A solution of 4-(3-methyl-3H-imidazol-4-yl)-benzoic acid methyl ester (216 mg, 1 mmol), lithium hydroxide (44.0 mg, 1 mmol), tetrahydrofuran (0.6 mL), water (0.6 mL), and methanol (0.6 mL) was stirred at ambient temperature under nitrogen for 24 hrs. The mixture was concentrated in vacuo and then lyophilized to give 242 g of crude material which was taken on without further purification for preparation of compound 42 of Table 1.
Reaction SMILES: [F:1][C:2]1[C:3]([N+:16]([O-])=O)=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([CH2:12][CH:13]([CH3:15])[CH3:14])=[CH:5]2.O>C1COCC1.[Ni]>[F:1][C:2]1[CH:11]=[CH:10][C:9]2[CH:8]=[N:7][C:6]([CH2:12][CH:13]([CH3:14])[CH3:15])=[CH:5][C:4]=2[C:3]=1[NH2:16]
Reactant: CC(C)Cc1cc2c([N+](=O)[O-])c(F)ccc2cn1
Agent: [Ni]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Cc1cc2c(N)c(F)ccc2cn1
Temperature: 25 °C
Reaction time: 1.67 h
Yield: 102.3 %

Procedure:
A solution of Example 139B (2.39 g, 9.63 mmol) in THF (50 mL) was added to a Ra—Ni 2800, water slurry (2.390 g, 40.7 mmol) in a 250 mL pressure bottle and stirred for 100 min at 30 psi and ambient temperature. The mixture was filtered through a nylon membrane and then concentrated under reduced pressure to provide the title compound (2.15 g, 100% yield), which was used without further purification. (ESI) m/z 219.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15](CC3C=CC(OC)=CC=3)[C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[F:30][C:31]1[C:36](B(O)O)=[CH:35][C:34]([CH3:40])=[CH:33][N:32]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[F:30][C:31]1[C:36]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([S:12]([NH:15][C:16]4[S:17][CH:18]=[CH:19][N:20]=4)(=[O:13])=[O:14])=[CH:9][CH:10]=3)[CH:5]=[CH:4][N:3]=2)=[CH:35][C:34]([CH3:40])=[CH:33][N:32]=1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)nccc3c2)cc1
Reactant: Cc1cnc(F)c(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cnc(F)c(-c2nccc3cc(S(=O)(=O)Nc4nccs4)ccc23)c1

Procedure:
To a microwave vial charged with 1-chloro-N-(4-methoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (Intermediate JJJ; 500 mg, 1.121 mmol), 2-fluoro-5-picoline-3-boronic acid (136 μl, 1.121 mmol), potassium carbonate (775 mg, 5.61 mmol) and Pd(Ph3P)4 (130 mg, 0.112 mmol) was added Dioxane (5606 μl) and Water (1869 μl) and irradiated at 100° C. for 30 mins affording ˜75% conversion to desired product as the primary species. Additional boronic acid (80 mg) and Pd(PPh3)4 (65 mg) was added and the mixture irradiated an additional 30 mins at 110° C. affording complete conversion to desired product. The organics were decanted, rinsed with EtOAc and the combined organics were dried under reduced pressure. The crude material was dissolved in DCM (3 ml) and TFA (1 ml) was added and the mixture stirred at room temperature for 2 hrs affording complete PMB cleavage. The crude material was purified with a 25 g Interchim column (25 μm spherical) ramping EtOAc in heptane (0-100%, then isocratic at 100% EtOAc, where product elutes, 10% DCM throughout) affording 1-(2-fluoro-5-methylpyridin-3-yl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide as a light yellow solid (377 mg, 0.941 mmol, 84% yield). 1H NMR (400 MHz, DMSO-d6) δ=12.89 (br. s., 1H), 8.74 (d, J=5.7 Hz, 1H), 8.60 (d, J=1.7 Hz, 1H), 8.26 (s, 1H), 8.21 (d, J=5.6 Hz, 1H), 8.02 (dd, J=2.3, 9.3 Hz, 1H), 7.97-7.91 (m, 1H), 7.91-7.85 (m, 1H), 7.28 (d, J=4.6 Hz, 1H), 6.87 (d, J=4.6 Hz, 1H), 2.40 (s, 3H). m/z (ESI) 401.2 (M+H)+
Reaction SMILES: [CH:1]([C:4]([CH3:14])([N:7]1[C:11](=[O:12])[CH:10]=[CH:9][C:8]1=[O:13])[C:5]#[N:6])([CH3:3])[CH3:2].S(=O)(=O)(O)[OH:16].[Cl-].[Na+].C(OCC)(=O)C>C(Cl)Cl>[CH:1]([C:4]([CH3:14])([N:7]1[C:11](=[O:12])[CH:10]=[CH:9][C:8]1=[O:13])[C:5]([NH2:6])=[O:16])([CH3:3])[CH3:2]
Reactant: CC(C)C(C)(C#N)N1C(=O)C=CC1=O
Reactant: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)C(C)(C(N)=O)N1C(=O)C=CC1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 72 %

Procedure:
A solution of α-isopropyl-α-methyl-2,5-dioxo-3-pyrroline-1-acetonitrile (2.0 g, 0.104 mol) in methylene chloride (30 ml) is added in a fine stream to concentrated sulfuric acid at room temperature. After stirring overnight at room temperature for 16 hours the mixture is poured onto ice, containing sodium chloride and ethyl acetate. The organic layer is washed with aqueous sodium bicarbonate, brine and dried. Evaporation after washing with ether-pentane gives a solid (72%), mp 138.5°-140° C. Anal. calcd. for C10H14N2O3 : C, 57.13; H, 6.71; N, 13.33. Found: C, 56.89; H, 6.64; N, 13.16.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[N:6]=[CH:5][N:4]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:24]([CH2:29][C@H:30]([OH:35])[C:31]([F:34])([F:33])[F:32])[C:25](=[O:28])[NH:26][N:27]=2)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:24]([CH2:29][C@H:30]([OH:35])[C:31]([F:33])([F:34])[F:32])[C:25](=[O:28])[N:26]([CH2:2][C:3]3[CH:8]=[C:7]([C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[Cl:15])[N:6]=[CH:5][N:4]=3)[N:27]=2)=[CH:19][CH:18]=1
Reactant: Clc1ccccc1-c1cc(CBr)ncn1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Product: O=c1n(Cc2cc(-c3ccccc3Cl)ncn2)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F

Procedure:
Analogously to the preparation of the compound in Example 94, 27 mg (0.10 mmol) of the compound from Example 83A and 32 mg (0.11 mmol) of the compound from Example 5A were reacted with one another. This gave 29 mg (54% of theory) of the target compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[C:26]([CH3:28])[N:25]=[C:24]([C:29]([C:31]2[CH:41]=[C:40]([CH3:42])[C:34]3[N:35]([CH3:39])[C:36](=[O:38])[O:37][C:33]=3[CH:32]=2)=[O:30])[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:39][N:35]1[C:34]2[C:40]([CH3:42])=[CH:41][C:31]([C:29]([C:24]3[N:25]=[C:26]([CH3:28])[N:27]=[C:22]([N:17]4[CH2:18][CH2:19][CH:14]([N:10]5[CH2:9][CH2:8][C:7]6[CH:20]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=6[NH:12][C:11]5=[O:13])[CH2:15][CH2:16]4)[CH:23]=3)=[O:30])=[CH:32][C:33]=2[O:37][C:36]1=[O:38]
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: Cc1nc(Cl)cc(C(=O)c2cc(C)c3c(c2)oc(=O)n3C)n1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(C)c5c(c4)oc(=O)n5C)nc(C)n3)CC1)C(=O)N2

Procedure:
83 mg (0.30 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 95 mg (0.30 mmol) 6-(6-chloro-2-methyl-pyrimidine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one and 0.11 mL (0.60 mmol) DIPEA were stirred overnight in 3 mL DMF at RT. Then the reaction mixture was purified by preparative HPLC-MS. The fractions containing the product were combined and the organic solvent was evaporated down i. vac. The residue was neutralised with 4N aqueous sodium hydroxide solution, the precipitate formed was suction filtered, washed with water and dried i. vac.
Reaction SMILES: [B:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:6][CH:5]=1)([OH:3])[OH:2].C(=O)(O)[O-].[K+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C>[CH2:22]([O:13][C:12]([CH2:11][CH2:10][CH2:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([B:1]([OH:3])[OH:2])=[CH:16][CH:15]=1)=[O:14])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)CCCOc1ccc(B(O)O)cc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(CCCOc1ccc(B(O)O)cc1)OCc1ccccc1
Yield: 30.8 %

Procedure:
A solution of 1A (200 mg, 0.89 mmol), potassium bicarbonate (313 mg, 3.1 mmol), and benzyl bromide (0.163 mL, 1.4 mmol) in DMF (2 mL) was heated at 60° C. for 8 h. The reaction mixture was concentrated in vacuo and the residue was partitioned between EtOAc and hydrochloric acid (1 N). The aqueous layer was extracted with EtOAc (2×) and then the combined organics were washed with water (3×) and brine, dried (MgSO4), and concentrated in vacuo. The residue was purified by flash chromatography (30 to 100% EtOAc in hexane) to afford 1B (86 mg, 28%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 2.08 (m, 2H), 2.56 (t, J=7.0 Hz, 2H), 4.00 (m, 2H), 5.12 (s, 2H), 6.84 (2×d, 2H), 7.32 (m, 5H), 7.7-7.5 (2×d, 2H).
Reaction SMILES: [C:1]([N:3]=[C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)OC)#[N:2].[CH3:13][O:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>CO>[C:1]([NH:3][C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)=[N:19][C:18]1[CH:20]=[CH:21][C:15]([O:14][CH3:13])=[CH:16][CH:17]=1)#[N:2]
Reactant: COc1ccc(N)cc1
Reactant: COC(=NC#N)c1ccccn1
Solvent: CO
Product: COc1ccc(N=C(NC#N)c2ccccn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.5 %

Procedure:
Methyl N-cyano-2-pyridinecarboximidate (0.50 g, 3.1 mmol) was dissolved in methanol (10 ml), 4-methoxyaniline (0.36 g, 3.4 mmol) was added, and the resulting mixture was stirred at room temperature for 30 minutes. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue thus obtained was crystallized from dichloromethane-diethyl ether to give the title compound (0.74 g, 2.9 mmol, yield: 94%) as colorless needles.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:10]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:17][C:18](=[O:21])[NH:19][OH:20])[CH:8]=[CH:9]2)[C:3]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29]>>[NH2:1][C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:10]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:17][C:18](=[O:21])[NH:19][O:20][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:8]=[CH:9]2)[C:3]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)Cl
Reactant: CCOC(=O)c1c2ccc(CC(=O)NO)ccc-2c(C(=O)OCC)c1N
Product: CCOC(=O)ONC(=O)Cc1ccc2c(C(=O)OCC)c(N)c(C(=O)OCC)c-2cc1
Yield: 47 %

Procedure:
In an analogous manner to that described in Example 12, from diethyl 2-amino-6-[(hydroxycarbamoyl)-methyl]-azulene-1,3-dicarboxylate and ethyl chloroformate the title compound is obtained in 47% yield as an oil.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:6]=2[N:7]=1.[NH2:35][C:36]1[CH:37]=[C:38]2[C:43](=[CH:44][CH:45]=1)[N:42]([CH3:46])[C:41](=[O:47])[CH2:40][CH2:39]2.C[Si](Cl)(C)C>C(O)CCC>[F:34][C:31]1[CH:30]=[CH:29][C:28]([NH:27][C:4]2[C:5]3[C:10]([C:11]4[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=4)=[CH:9][NH:8][C:6]=3[N:7]=[C:2]([NH:35][C:36]3[CH:37]=[C:38]4[C:43](=[CH:44][CH:45]=3)[N:42]([CH3:46])[C:41](=[O:47])[CH2:40][CH2:39]4)[N:3]=2)=[CH:33][CH:32]=1
Reactant: CN1C(=O)CCc2cc(N)ccc21
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccncc3)c3c(Nc4ccc(F)cc4)nc(Cl)nc32)cc1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: CN1C(=O)CCc2cc(Nc3nc(Nc4ccc(F)cc4)c4c(-c5ccncc5)c[nH]c4n3)ccc21

Procedure:
A solution of 2-chloro-N-(4-fluorophenyl)-5-(pyridin-4-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (31 mg, 0.062 mmol), 6-amino-1-methyl-3,4-dihydroquinolin-2(1H)-one (25 mg, 0.14 mmol) and trimethylsilyl chloride (0.100 mL, 0.790 mmol) in nBuOH (1 mL) was stirred at 135° C. for 20 h. It was concentrated in vacuo. The residue was purified by HPLC to give the titled compound. MS 480.5 (M+H); UV 204.7, 281.7, 314.3 nm.
Reaction SMILES: [Cl:1][C:2]1[C:11](B(O)O)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH4+].[Cl-].[OH2:17].OO>CCOCC>[Cl:1][C:2]1[C:11]([OH:17])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O
Reactant: OB(O)c1cc2ccccc2nc1Cl
Agent: OO
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: Oc1cc2ccccc2nc1Cl
Reaction time: 16 h
Yield: 89 %

Procedure:
A suspension of 2-chloroquinoline-3-boronic acid (15 g, 72.3 mmol) and NH4Cl (7.16 g, 134 mmol) in Et2O:H2O (600 mL) was treated dropwise with aqueous H2O2 (30%, 62 mL, 709 mmol). The mixture was stirred for 16 h. Then, the precipitate was filtered, washed with water and Et2O, and dried at 60° C. over P2O5 to afford the title compound (11.5 g, 89%). LCMS (ES+) m/z 180 (M+H)+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:9](=[O:16])[NH:8][C:7]2=[O:17].I[CH:19]([CH3:21])[CH3:20].O>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:9](=[O:16])[N:8]([CH:19]([CH3:21])[CH3:20])[C:7]2=[O:17]
Reactant: CC(C)I
Reactant: O=C1NC(=O)c2cc([N+](=O)[O-])c(Cl)cc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)N1C(=O)c2cc(Cl)c([N+](=O)[O-])cc2C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
NaH (5.30 g, 0.132 mol) was added in portions to a solution of 5-chloro-6-nitroisoindoline-1,3-dione (20.0 g, 88.27 mmol) in 100 mL of anhydrous DMF at 0° C. under argon. The reaction mixture was then stirred at rt for 3 h. 2-Iodopropane (15.0 g, 106 mol) was added dropwise via a syringe at rt under argon. The resulted mixture was stirred for 6 h at rt, hydrolyzed by adding 200 mL of water. The precipitate was isolated, washed with water and dried under vacuum. The solid was purified by column chromatography (silica-gel, CH2Cl2/Acetone=19/1 v/v) to give a solid product.
Reaction SMILES: [NH2:1][C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1)=[CH:3][C:4]([O:6][CH3:7])=[O:5].[C:17]1([C:23](=O)[CH:24]=[CH:25][CH3:26])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)CCC>[CH3:26][C:25]1[CH:24]=[C:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:1]=[C:2]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=2)[C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)C=C(N)c1cccc([N+](=O)[O-])c1
Reactant: CC=CC(=O)c1ccccc1
Solvent: CCCCO
Product: COC(=O)c1c(C)cc(-c2ccccc2)nc1-c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 5.8 %

Procedure:
A mixture of methyl 3-amino-3-(3-nitrophenyl)-acrylate (45 g) and 1-phenyl-2-buten-1-one (44 g) in n-butanol (450 ml) was refluxed for 4 hours. After allowing to cool at ambient temperature, the reaction mixture was evaporated in vacuo. The residue was subjected to a column chromatography on silica gel (500 g) eluting with benzene. The fractions containing the object compound were combined and concentrated under reduced pressure to give methyl 4-methyl-2-(3-nitrophenyl)-6-phenyl-3-pyridinecarboxylate (4.10 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH2:9][N+:10]([O-])=O>CO.[Ni]>[NH2:10][CH2:9][CH:8]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: CS(=O)(=O)NC(C[N+](=O)[O-])c1ccccc1Cl
Agent: [Ni]
Solvent: CO
Product: CS(=O)(=O)NC(CN)c1ccccc1Cl

Procedure:
A solution of 221 mg (0.79 mmol) of the compound of Example 26A in 45 ml of methanol was hydrogenated in a continuous-flow hydrogenation apparatus fitted with a Raney-nickel cartridge (H-Cube from Thales Nano, Budapest, Model HC-2-SS) at a flow rate of 1 ml/min, a temperature of 45° C. and at standard pressure. After the reaction had ended, the solution was freed from the methanol on a rotary evaporator and the residue was dried briefly under high vacuum. This gave 186 mg (94% of theory) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([O:17]C)=O)=[C:10]3[CH2:9][C:8](=[O:19])[N:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:6]=2[CH:26]=1.[CH3:27][N-:28][CH3:29]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([N:28]([CH3:29])[CH3:27])=[O:17])=[C:10]3[CH2:9][C:8](=[O:19])[N:7]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:6]=2[CH:26]=1
Reactant: COC(=O)c1ncn2c1CC(=O)N(c1ccccc1)c1cc(Cl)ccc1-2
Reactant: C[N-]C
Product: CN(C)C(=O)c1ncn2c1CC(=O)N(c1ccccc1)c1cc(Cl)ccc1-2

Procedure:
As described in previous example, 8-chloro-4,6-dihydro-6-phenyl-5-oxo-5H-imidazo[1,5-a] [1,5]benzodiazepine-3-carboxylic acid, methyl ester was converted to the dimethylamide, mp. 255°-257°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][C:10](=O)[CH2:9][CH2:8]2.[CH3:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][CH:10]([N:18]1[CH2:19][CH2:20][N:15]([CH3:14])[CH2:16][CH2:17]1)[CH2:9][CH2:8]2
Reactant: COc1cccc2c1CC(=O)CC2
Reactant: CN1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1cccc2c1CC(N1CCN(C)CC1)CC2
Reaction time: 0.5 h
Yield: 161.3 %

Procedure:
1.76 g (10 mmol) of 8-methoxy-2-tetralone, 3.00 g (30 mmol) of N-methylpiperazine and 1.80 g (30 mmol) of glacial acetic acid were refluxed in 30 ml of methanol for 4 hours. 1.30 g (20 mmol) of sodium cyanoborohydride were then added, and the mixture was refluxed for a further hour. The reaction mixture was substantially concentrated in a rotary evaporator, taken up in tert.-butyl methyl ether, and stirred vigorously for 30 minutes in 20% strength sodium hydroxide solution. The aqueous phase was extracted carefully with tert.-butyl methyl ether. Washing the combined organic phases with water and saturated sodium chloride solution, drying over potassium carbonate, and concentrating in a rotary evaporator yielded the crude product as an oil (2.9 g). This crude product was combined with that obtained from a batch of equal size (this reaction was carried out in the presence of 3A molecular sieve, otherwise the same) and chromatographed on silica gel (toluene/methanol 4:1). 4.20 g of the title compound were obtained in this fashion as a brownish oil (80%).