Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6](=O)[N:7](C)[C@H:8]([C:10](=[O:35])[NH:11][C@H:12]([C:16]([N:18]1[C:22]2=[N:23][CH:24]=[CH:25][CH:26]=[C:21]2[CH2:20][C@H:19]1[CH2:27][NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:17])[CH:13]([CH3:15])[CH3:14])[CH3:9])(C)(C)C.[ClH:38]>O1CCOCC1>[ClH:38].[CH3:6][NH:7][C@@H:8]([CH3:9])[C:10]([NH:11][C@H:12]([C:16]([N:18]1[C:22]2=[N:23][CH:24]=[CH:25][CH:26]=[C:21]2[CH2:20][C@H:19]1[CH2:27][NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:35]
Reactant: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1c2ncccc2C[C@H]1CNc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: CN[C@@H](C)C(=O)N[C@H](C(=O)N1c2ncccc2C[C@H]1CNc1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of methyl-{(S)-1-[(S)-2-methyl-1-((S)-2-phenylaminomethyl-2,3-dihydro-pyrrolo[2,3-b]pyridine-1-carbonyl)-propylcarbamoyl]-ethyl}-carbamic acid tert-butyl ester (25 mg, 0.05 mmol) in 1,4-dioxane (0.5 mL) was added 4 M HCl in dioxane (0.5 mL) dropwise at 0° C. The reaction mixture was stirred at rt for 3 h then concentrated in vacuo to obtain (S)-2-methylamino-N—[(S)-2-methyl-1-((S)-2-phenylaminomethyl-2,3-dihydro-pyrrolo[2,3-b]pyridine-1-carbonyl)-propyl]-propionamide hydrochloride (18 mg), m/z=410.4 (M+H).
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[OH:22][C:23]1[CH:24]=[C:25]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:34]2[CH2:33][CH2:32][N:31]([C:25]3[CH:26]=[CH:27][C:28]([O:29][CH3:30])=[C:23]([OH:22])[CH:24]=3)[CH2:36][CH2:35]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: COc1ccc(N2CCNCC2)cc1O
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Product: CCc1cc(NC(=O)N2CCN(c3ccc(OC)c(O)c3)CC2)c(OC)nc1C

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(3-hydroxy-4-methoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound. yield: 59% Example 53
Reaction SMILES: FC(F)(F)C(O)=O.C([O:15][C:16]1[CH:35]=[CH:34][C:19]([CH2:20][NH:21][C:22]([C:24]2[CH:25]=[C:26]3[C:31](=[CH:32][CH:33]=2)[N:30]=[CH:29][CH:28]=[CH:27]3)=[O:23])=[CH:18][CH:17]=1)C1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C1(SC)C=CC=CC=1>[OH:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:20][NH:21][C:22]([C:24]2[CH:25]=[C:26]3[C:31](=[CH:32][CH:33]=2)[N:30]=[CH:29][CH:28]=[CH:27]3)=[O:23])=[CH:34][CH:35]=1
Reactant: O=C(NCc1ccc(OCc2ccccc2)cc1)c1ccc2ncccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CSc1ccccc1
Product: O=C(NCc1ccc(O)cc1)c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 21.5 %

Procedure:
Trifluoroacetic acid (5 mL) and thioanisole (3 drops) were added to quinoline-6-carboxylic acid 4-benzyloxybenzylamide (2.67 g, 7.25 mmol) synthesized in Example E-8, the solution was stirred at room temperature for 14 hours, followed by stirring at 50° C. for 4 hours, lastly, and the solution was stirred at 70° C. for 3 hours. The reaction solution was allowed to room temperature, then, was neutralized with an aqueous solution of saturated sodium bicarbonate, extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The solvent was evaporated, the residue was purified by NH silica gel column chromatography (ethyl acetate), and the title compound (433 mg, 22%) was obtained as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:10][C@@H:11]2[CH2:16][CH2:15][C@H:14]([C:17]([NH:19][CH:20]([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[F:23][C:24]1[CH:34]=[CH:33][C:27]([C:28]([N:30]=[C:31]=S)=[O:29])=[CH:26][CH:25]=1.C(Cl)CCl.CCN(C(C)C)C(C)C>C1COCC1>[F:23][C:24]1[CH:25]=[CH:26][C:27]([C:28](/[N:30]=[C:31]2/[N:10]([C@H:11]3[CH2:12][CH2:13][C@@H:14]([C:17](=[O:18])[NH:19][CH:20]([CH3:22])[CH3:21])[CH2:15][CH2:16]3)[C:3]3[CH:4]=[C:5]([O:8][CH3:9])[N:6]=[CH:7][C:2]=3[NH:1]/2)=[O:29])=[CH:33][CH:34]=1
Reactant: COc1cc(N[C@H]2CC[C@@H](C(=O)NC(C)C)CC2)c(N)cn1
Reactant: O=C(N=C=S)c1ccc(F)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COc1cc2c(cn1)[nH]/c(=N\C(=O)c1ccc(F)cc1)n2[C@H]1CC[C@@H](C(=O)NC(C)C)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a 0° C. cooled solution of cis-4-(5-amino-2-methoxypyridin-4-ylamino)-N-isopropylcyclohexanecarboxamide (211 mg, 0.689 mmol) in 1 mL THF, was added a suspension of 4-fluorobenzoyl isothiocyanate (250 mg, 1.377 mmol) in THF (3.4 mL). The resulting reaction mixture was stirred at 0° C. for 15 minutes. The ice bath was removed, and the mixture was stirred for 15 minutes at RT. To the mixture were added EDC (396 mg, 2.066 mmol) and DIPEA (0.433 mL, 2.479 mmol), and the flask was heated at 60° C. for 1 hour. The resulting mixture was allowed to cool to RT, and the solvents were removed. The residue was dissolved in 10% IPA in DCM and was washed with water and brine. The organic layer was dried over Na2SO4 and filtered. The mixture was purified via flash chromatography using a linear gradient of 0% to 5% of 1% NH4OH in MeOH in DCM. The title compound was collected as an off-white solid. The solid was partitioned with 10% IPA/EtOAc and was washed with 1 mL:2 mL saturated aqueous NH4Cl/water, and brine. The organic layer was dried over Na2SO4, filtered and the solvents were removed to afford the title compound as an off-white solid (212 mg, 68%). M/Z calc'd for C24H28FN5O3: 453.51. found 454 [M+H].
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[CH:5]=[CH:6][CH:7]=[C:8]3[C:14](=[O:15])[NH:13][CH2:12][CH2:11][C:10]=1[C:9]=23.C([Sn](CCCC)(CCCC)[C:21]#[C:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)CCC.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>CN(C=O)C.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:23]1([C:22]#[C:21][C:2]2[NH:3][C:4]3[CH:5]=[CH:6][CH:7]=[C:8]4[C:14](=[O:15])[NH:13][CH2:12][CH2:11][C:10]=2[C:9]=34)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCCC[Sn](C#Cc1ccccc1)(CCCC)CCCC
Reactant: O=C1NCCc2c(Br)[nH]c3cccc1c23
Agent: [Pd]
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C1NCCc2c(C#Cc3ccccc3)[nH]c3cccc1c23
Temperature: 60 °C
Yield: 55.2 %

Procedure:
Tricyclic bromide 11 (58.6 mg, 0.22 mmol) in DMF (1 mL) was degassed and treated with tributyl(phenylethynyl)tin (95.2 mg, 0.24 mmol) and tetrakis(triphenylphosphine) palladium(0) (13 mg, 2 mol %). One crystal of 2,6-di-t-butyl-4-methyl phenol was added, and the solution was heated at 60° C. for 10 h. Starting material was still present, so the solution was heated at 100° C. for an additional 2 h. The reaction mixture was cooled to ambient temperature and diluted with water (2 mL) and extracted with EtOAc (5 mL×3). The organic solution was washed with water and brine, dried (Na2SO4), filtered, and concentrated. The crude product was purified by radial chromatography (2 mm SiO2; 3% MeOH in CH2Cl2) to yield 17 as a white solid (34.8 mg, 55%). mp 255-256° C. (dec); 1H NMR (DMSO-d6) δ 11.86 (s, 1H), 8.17 (m, 1H), 7.75 (d, 1H, J=7.6 Hz), 7.63 (m, 3H), 7.51 (m, 3H), 7.33 (t, 1H, J=7.6 Hz), 3.50 (m, 2H), 3.09 (m, 2H); HRMS (FAB, M+H) Calcd for C19H14N2O+H: 287.1184, Found: 287.1192; Anal. (C19H14N2O.0.6 H2O) C, H, N.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1C=C[C:7]([C:8](O)=O)=[CH:6][CH:5]=1.CCCC([O:20][CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1Br)=[O:23])CC.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:3]([O:2][C:27]1[CH:26]=[CH:25][C:24]([C:22](=[O:23])[CH2:21][OH:20])=[CH:29][CH:28]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCC(CC)OCC(=O)c1ccccc1Br
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCOc1ccc(C(=O)CO)cc1
Temperature: 60 °C
Reaction time: 10 h
Yield: 45 %

Procedure:
To a solution of terephthalic acid monomethyl ester (1.0 g, 5.6 mmol) and 4-hexyloxy-2′-bromoacetophenone (synthesized by following (2.0 g, 6.7 mmol) in DMF (10 mL) was added K2CO3 (0.77 g, 5.6 mmol) and heated at 60° C. After 10 h, the reaction mixture was cooled to room temperature and poured into water. The product was extracted using EtOAc, washed with brine, dried and concentrated. The crude residue was purified by combiflash to afford 1.0 g (45%) product. 1H NMR (500 MHz, CDCl3): δ 0.94 (t, 3H, J=7.0 Hz), 1.36-1.39 (m, 4H), 1.48-1.58 (m, 2H), 1.81-1.85 (m, 2H), 3.99 (s, 3H), 4.07 (t, 2H, J=6.5 Hz), 5.58 (s, 2H), 6.99 (d, 2H, J=9.0 Hz), 7.92 (d, 2H, J=9.0 Hz), 8.16 (d, 2H, J=9.0), 8.122 (d, 2H, J=9.0 Hz).
Reaction SMILES: [I-].[Li+].CO[C:5]([C:7]1(C)[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])[CH2:12][C:11]2[CH:22]=[C:23]([C:26]([F:29])([F:28])[F:27])[CH:24]=[CH:25][C:10]=2[NH:9][C:8]1=[O:30])=O>N1C=CC=CC=1.C(OCC)(=O)C>[CH3:21][O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH:13]1[CH2:12][C:11]2[CH:22]=[C:23]([C:26]([F:27])([F:28])[F:29])[CH:24]=[CH:25][C:10]=2[NH:9][C:8](=[O:30])[CH:7]1[CH3:5]
Reactant: COC(=O)C1(C)C(=O)Nc2ccc(C(F)(F)F)cc2CC1c1ccccc1OC
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COc1ccccc1C1Cc2cc(C(F)(F)F)ccc2NC(=O)C1C
Reaction time: 8.5 h
Yield: 100 %

Procedure:
Lithium iodide (5.26 g; 39.3 mmole) was added to 1,3,4,5-tetrahydro-3-(methoxycarbonyl)-4-(methoxyphenyl)-3-methyl-7-(trifluoromethyl)-2H-1-benzazepin-2-one (4.00 g; 9.82 mmole) in pyridine (40 ml) (five drops of water were added) and the mixture was refluxed with stirring for 8.5 hours. The solution was dissolved in ethyl acetate and washed with 1N hydrochloric acid (three times). The organic layer was dried (magnesium sulfate) and concentrated giving 3.43 g of the title compound as a solid.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH:25]([O:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[CH:32]=O)([CH3:27])[CH3:26]>C(Cl)Cl.CCCCCC.[Zn]>[Br:2][C:1]([Br:5])=[CH:32][C:31]1[CH:34]=[CH:35][C:36]([O:37][CH3:38])=[C:29]([O:28][CH:25]([CH3:27])[CH3:26])[CH:30]=1
Reactant: COc1ccc(C=O)cc1OC(C)C
Reactant: BrC(Br)(Br)Br
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: ClCCl
Product: COc1ccc(C=C(Br)Br)cc1OC(C)C
Temperature: 0 °C
Reaction time: 22 h
Yield: 99.8 %

Procedure:
Carbon tetrabromide (51.3 g, 154.7 mmol) was added portion-wise to a magnetically stirred mixture of zinc dust (10.1 g, 154.5 mmol) and PPh3 (40.5 g, 154.4 mmol) in CH2Cl2 (350 mL) maintained at 0° C. on an ice-salt bath. The resulting suspension was allowed to warm to room temperature and then stirred for a further 22 h. After this time the reaction mixture was re-cooled to 0° C. and isovanillin isopropyl ether (15.0 g, 77.3 mmol) was added dropwise over 2 min. The resulting mixture was allowed to stir at room temperature for 1 h then diluted with hexane (200 mL) and filtered through a No. 3 porosity sintered-glass funnel. The filtrate was concentrated on to silica gel (400-200 mesh, 30 g) and the resulting solid added to the top of a flash chromatography column (20 cm long×10 cm wide) which was subjected to gradient elution with 2:1, 1:1 then 1:2 hexane/CH2Cl2. Concentration of the appropriate fractions (Rf 0.5 in 1:1 hexane/CH2Cl2) afforded the title compound (27.0 g, 99%) as white crystalline masses, m.p. 67-69° C. νmax (KBr) 3009, 2975, 2929, 1597, 1572, 1508, 1463, 1441, 1429, 1373, 1301, 1276, 1260, 1233, 1144, 1110 and 999 cm−1. 1H n.m.r. δ 7.38 (s, 1H), 7.24 (d, J=2.1 Hz, 1H), 7.08 (dd, J=8.4 and 2.1 Hz, 1H), 6.84 (d, J=8.4 Hz, 1H), 4.53 (septet, J=6.0 Hz, 1H), 3.86 (s, 3H), 1.38 (d, J=6.0 Hz, 6H). 13C n.m.r. δ 150.5 (C), 146.7 (C), 136.4 (C), 127.7 (C), 122.1 (CH), 115.3 (CH), 111.3 (CH), 87.0 (C), 71.4 (CH), 55.8 (CH3), 22.0 (2×CH3). Mass spectrum m/z 352 (20) 350 (40) 348 (22) (M+·), 310 (50) 308 (100) 306 (50) [(M-C3H6)+·], 295 (30), 293 (61) 291 (33) [(M-C3H6—CH3+·)+]. Anal. Calcd for C12H14Br2O2 C, 41.2; H, 4.0; Br, 45.7. Found: C, 41.1; H, 3.7: Br, 45.3%.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.[CH3:10][CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][N:12]1[C:21]1[CH:26]=[C:25]([CH2:27][CH2:28][CH3:29])[N:24]=[C:23]([Cl:30])[N:22]=1>CN(C)C=O>[ClH:30].[CH3:9][C:4]1[CH:3]=[C:2]([F:1])[CH:8]=[CH:7][C:5]=1[NH:6][C:23]1[N:22]=[C:21]([N:12]2[CH2:13][CH2:14][C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:11]2[CH3:10])[CH:26]=[C:25]([CH2:27][CH2:28][CH3:29])[N:24]=1
Reactant: Cc1cc(F)ccc1N
Reactant: CCCc1cc(N2CCc3ccccc3C2C)nc(Cl)n1
Solvent: CN(C)C=O
Product: CCCc1cc(N2CCc3ccccc3C2C)nc(Nc2ccc(F)cc2C)n1
Product: Cl
Yield: 28.2 %

Procedure:
After 4-fluoro-2-methylaniline(0.35 ml, 3.15 mmol) was added to a mixture solution of 4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)-6-propyl-2-chloropyrimidine(0.5 g, 1.66 mmol) and dimethylformamide(5 ml), 0.2 g of the titled compound was obtained in accordance with the same procedure as in Step 2 of Example 1.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.C(O)(=O)[CH2:12][C:13]([OH:15])=[O:14].N1CCCCC1>N1C=CC=CC=1>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[CH:12][C:13]([OH:15])=[O:14]
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1ccc(F)cc1F
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1ccc(F)cc1F
Temperature: 100 °C
Reaction time: 2 h
Yield: 73.3 %

Procedure:
2,4-Difluoro-benzaldehyde (10.0 g, 70.4 mmol), malonic acid (16.5 g, 158.3 mmol), and piperidine (5.8 mL, 58.4 mmol) were added to pyridine (42.7 mL). The reaction mixture was stirred at 100° C. for 2 hours, concentrated under reduced pressure, and then distilled water was added thereto. The mixture was filtered and then the resulting solid was dried under reduced pressure to give 9.5 g of the titled compound as a yellow solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8]O.C(N(C(C)C)CC)(C)C.CS(Cl)(=O)=[O:21].C([NH:27][C@:28]1([C:45](NC(C)(C)C)=[O:46])[C@@H:32]([CH2:33][CH2:34][CH2:35][B:36]2[O:40]C(C)(C)C(C)(C)[O:37]2)[CH2:31][NH:30][CH2:29]1)(=O)C>C(#N)C>[NH2:27][C@:28]1([C:45]([OH:46])=[O:21])[C@@H:32]([CH2:33][CH2:34][CH2:35][B:36]([OH:37])[OH:40])[CH2:31][N:30]([CH2:8][CH:3]2[CH2:4][CH2:5][CH2:6][CH2:7][N:2]2[CH3:1])[CH2:29]1
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)N[C@@]1(C(=O)NC(C)(C)C)CNC[C@@H]1CCCB1OC(C)(C)C(C)(C)O1
Reactant: CN1CCCCC1CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CN1CCCCC1CN1C[C@H](CCCB(O)O)[C@](N)(C(=O)O)C1
Temperature: 60 °C
Reaction time: 3 h
Yield: 74 %

Procedure:
A cooled (0° C.) solution of 1-methylpiperidine-2-methanol (97 mg, 0.75 mmol) and diisopropylethylamine (0.31 mL, 1.75 mmol) in anhydrous acetonitrile (12 mL) under nitrogen was treated with methanesulfonyl chloride (86 mg, 0.75 mmol), stirred 3 h, and treated with (3R,4S)-3-acetamido-N-tert-butyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl)pyrrolidine-3-carboxamide (Example 8, step 4) (198 mg, 0.5 mmol) and heated to 60° C. for 15 h. The reaction mixture was concentrated, deprotected and isolated using the method described for example 8, step 5 to afford (3R,4S)-3-amino-4-(3-boronopropyl)-1-((1-methylpiperidin-2-yl)methyl)pyrrolidine-3-carboxylic acid (121 mg, 55%) as a white foam. NMR (D2O) δ 3.60-4.00 (m, 4 H), 3.15-3.55 (m, 3 H), 2.90 (m, 2 H), 2.67 (s, 3 H), 2.50-2.80 (m, 2 H), 2.00-2.30 (m, 1 H), 1.45-1.95 (m, 5 H), 1.10-1.40 (m, 3 H), 0.63-0.73 (m, 2 H). MS (m+1): 328.1; MS (m−H2O+1): 310.1.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:8]([CH:9]2[CH2:11][CH2:10]2)[C:7]2[C:12]([C:16]([NH:18][CH3:19])=[O:17])=[CH:13][CH:14]=[CH:15][C:6]=2[N:5]=1)[CH3:3].Cl[C:21]1[N:26]=[CH:25][N:24]=[C:23]([NH2:27])[C:22]=1[I:28].CCN(C(C)C)C(C)C>C(O)CCC>[NH2:27][C:23]1[N:24]=[CH:25][N:26]=[C:21]([NH:1][C@H:2]([C:4]2[N:8]([CH:9]3[CH2:10][CH2:11]3)[C:7]3[C:12]([C:16]([NH:18][CH3:19])=[O:17])=[CH:13][CH:14]=[CH:15][C:6]=3[N:5]=2)[CH3:3])[C:22]=1[I:28]
Reactant: CNC(=O)c1cccc2nc([C@H](C)N)n(C3CC3)c12
Reactant: Nc1ncnc(Cl)c1I
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CNC(=O)c1cccc2nc([C@H](C)Nc3ncnc(N)c3I)n(C3CC3)c12
Temperature: 120 °C
Reaction time: 18 h

Procedure:
A mixture of (S)-2-(1-aminoethyl)-1-cyclopropyl-N-methyl-1H-benzo[d]imidazole-7-carboxamide (Prepared in Example 20, 190 mg, 0.74 mmol), 6-chloro-5-iodopyrimidin-4-amine (188 mg, 0.736 mmol) and 1,1′-dimethyltriethylamine (256 μL, 1.47 mmol) in n-butanol (2 mL) was stirred at 120° C. After 18 h, the mixture was cooled to rt and concentrated under reduced pressure. The residue was purified by column chromatography on a silica gel column using 0 to 10% gradient of MeOH in DCM-EtOAc (1:1) as eluent to give (S)-2-(1-(6-amino-5-iodopyrimidin-4-ylamino)ethyl)-1-cyclopropyl-N-methyl-1H-benzo-[d]imidazole-7-carboxamide: 1H NMR (400 MHz, DMSO-d6) δ 8.46-8.40 (m, 1H), 7.87 (s, 1H), 7.67 (d, J=8 Hz, 1H), 7.24 (d, J=8 Hz, 1H), 7.20 (dd, J=8, 8 Hz, 1H), 6.46 (m, 1H), 6.37 (d, J=8 Hz, 1H), 5.82-5.75 (m, 1H), 2.84 (d, J=4 Hz, 3H), 1.60 (d, J=8 Hz, 3H), 1.14-1.04 (m, 2H), 0.93-0.90 (m, 1H), 0.85-0.76 (m, 1H); LC-MS (ESI) m/z 478.0 [M+H]+.
Reaction SMILES: CC([NH:5][S:6]([C:9]1[CH:13]=[CH:12][N:11]([CH3:14])[C:10]=1[S:15][CH3:16])(=[O:8])=[O:7])(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:14][N:11]1[CH:12]=[CH:13][C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[C:10]1[S:15][CH3:16]
Reactant: CSc1c(S(=O)(=O)NC(C)(C)C)ccn1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CSc1c(S(N)(=O)=O)ccn1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.6 %

Procedure:
To a solution of 4.63 g (17.66 mmol) N-(1,1-dimethylethyl)-1-methyl-2-(methylthio)-1H-pyrrole-3-sulfonamide in 50 mL of methylene chloride was added 50 mL of trifiuoroacetic acid (TFA) under a nitrogen atmosphere. The orange reaction mixture was stirred at room temperature overnight ca. 16 hours. The reaction mixture was concentrated to a tan solid. Diethyl ether was added to the tan solid and was removed by evaporation to remove residual TFA. The solid was suspended in diethyl ether and filtered giving 2.9 g of the title compound as a solid, m.p. 135°-137° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=O)[CH:6]=[CH:7][CH:8]=1.[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([N+:30]([O-:32])=[O:31])[C:28]=1[OH:29])[CH:24]=O)[CH3:19].[NH2:33][C:34]([NH2:36])=[O:35].Cl>C(O)C>[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([CH:24]2[C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)=[C:10]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[NH:36][C:34](=[O:35])[NH:33]2)[CH:26]=[C:27]([N+:30]([O-:32])=[O:31])[C:28]=1[OH:29])[CH3:19]
Reactant: NC(N)=O
Reactant: COc1cccc(CC(=O)c2cccnc2)c1
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Agent: Cl
Solvent: CCO
Product: CCOc1cc(C2NC(=O)NC(c3cccnc3)=C2c2cccc(OC)c2)cc([N+](=O)[O-])c1O
Yield: 25 %

Procedure:
To a solution of 2-(3-methoxyphenyl)-1-(pyridin-3-yl)ethanone (Intermediate 69) (60 mg, 0.26 mmol), 3-ethoxy-4-hydroxy-5-nitro-benzaldehyde (55.8 mg, 0.26 mmol) and urea (46.8 mg, 0.78 mmol) in 3 mL of ethanol was added 0.2 mL of concentrated HCl. The mixture was refluxed for 2 days. After the solvent was removed, the residue was purified by reverse-phase preparatory HPLC (26-53% acetonitrile+0.1% trifluoroacetic acid in water+0.1% trifluoroacetic acid, over 15 min.) to give Compound 134 (30 mg, yield 24.6%). 1H NMR (CD3OD 400 MHz): δ 8.75 (s, 1H), 8.55 (d, J=8.0 Hz, 1H), 8.01 (dd, J1=6.0 Hz, J2=8.4 Hz, 1H), 7.60 (d, J=2.0 Hz, 1H), 7.08 (m, 2H), 6.75 (dd, J1=2.4 Hz, J2=8.4 Hz, 1H), 6.55 (s, 1H), 6.49 (d, J=3.6 Hz, 1H), 5.53 (s, 1H), 4.02 (m, 2H), 3.64 (s, 3H); 1.39 (t, J=6.8 Hz, 3H); MS (ESI): m/z 463.1 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:4][C:5]2[O:9][C:8](=[O:10])[CH2:7][C:6]=2[CH:11]=1.[H-].C([Al+]CC(C)C)C(C)C.S(=O)(=O)(O)O>O1CCCC1.C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:4][C:5]2[O:9][CH:8]([OH:10])[CH2:7][C:6]=2[CH:11]=1
Reactant: O=C1Cc2cc(Cl)c(N3CCCCC3)cc2O1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)(O)O
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: OC1Cc2cc(Cl)c(N3CCCCC3)cc2O1
Reaction time: 0.5 h

Procedure:
A solution of 251 mg (1.00 mmole) of 5-chloro-6-(piperidin-1-yl)-benzofuran-2(3H)-one in 5 ml of absolute tetrahydrofuran is cooled to -78° under a nitrogen atmosphere, 0.84 ml (1.00 mmole) of a 20% diisobutyl aluminium hydride solution in toluene is added and the whole is stirred for 30 minutes at -78°. 2 ml of 2N sulphuric acid are then added and the whole is stirred for 15 minutes at -40°. The reaction mixture is diluted with water and extracted with methylene chloride. The organic phases are washed with water, combined, dried over sodium sulphate and concentrated in a vacuum rotary evaporator. 5-chloro-2-hydroxy-6-(piperidin-1-yl)-2,3-dihydrobenzofuran is obtained in the form of an oil which is used for the following reactions without purification. Rf [silica gel, chloroform/ethyl acetate (3:1)]=0.48.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)N=N[C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.[C:27]1(C)C=CC(C)=C[CH:28]=1.C12CC(C=C1)C=C2.O>C(OCC)(=O)C.CCCCCC>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]2[CH:27]=[CH:28][C:10]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[N:9][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)=[CH:15][CH:16]=1
Reactant: Cc1ccc(C)cc1
Reactant: Brc1ccc(-c2nnc(-c3ccncc3)nc2-c2ccc(Br)cc2)cc1
Agent: C1=CC2C=CC1C2
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCCCCC
Product: Brc1ccc(-c2ccc(-c3ccncc3)nc2-c2ccc(Br)cc2)cc1
Temperature: 140 °C
Reaction time: 14 h

Procedure:
Into a 100 mL three-neck flask, 2.2 g (4.7 mmol) of 5,6-bis(4-bromophenyl)-3-(4-pyridyl)-1,2,4-triazine, 45 mL of para-xylene, 2.5 mL (23 mmol) of 2,5-Norbornadiene were put, and the solution was stirred at 140° C. for 14 hours under a nitrogen stream. After a certain time, water was added to the solution, and an aqueous layer was extracted with chloroform. The obtained extract was washed with a saturated saline together with the organic layer and then dried over magnesium sulfate. The obtained mixture was subjected to gravity filtration, and the obtained filtrate was concentrated to give a solid. The obtained solid was refined with silica gel column chromatography (hexane:ethyl acetate=2:1), so that 1.7 g of a target substance, yellow powder was obtained in a yield of 78%.
Reaction SMILES: C([C:4]1[N:9]=[N:8][C:7]2[C:10]3[CH:16]=[CH:15][C:14]([CH3:17])=[N:13][C:11]=3[S:12][C:6]=2[C:5]=1[OH:18])(O)=O>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1.CCCCCC>[OH:18][C:5]1[C:6]2[S:12][C:11]3[N:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:10]=3[C:7]=2[N:8]=[N:9][CH:4]=1
Reactant: Cc1ccc2c(n1)sc1c(O)c(C(=O)O)nnc12
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: CCCCCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1ccc2c(n1)sc1c(O)cnnc12
Temperature: 225 °C
Reaction time: 0.5 h
Yield: 66.5 %

Procedure:
A mixture of 2.4 g (0.009 mol) of 3-carboxy-4-hydroxy-7-methylpyrido[3',2':4,5]-thieno[3,2-C]pyridazine in 70 ml of Dowtherm-A was stirred at 225° C. for 30 minutes. It was cooled, diluted with hexane and filtered. The crude product was crystallized by 5% NaOH/HOAC giving 1.3 g (65%) of 4-hydroxy-7-methylpyrido[3',2':4,5]thieno[3,2-C]pyridazine, m.p.>300° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]#[N:10])=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1.[C:17]1([OH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([O:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]([C:9]#[N:10])=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1
Reactant: Oc1ccccc1
Reactant: N#Cc1c(Cl)nc(N)nc1-c1ccccc1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(Oc2ccccc2)nc(N)nc1-c1ccccc1

Procedure:
From 2-amino-4-chloro-6-phenyl-pyrimidine-5-carbonitrile, phenol and DBU in DME. EI-MS m/e (%): 288 (M+, 100), 287 ([M—H]+, 60).