Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:12](=[O:28])[C:13]2[C:18]([C:19]=1[C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)=[CH:17][C:16]([C:25]([OH:27])=O)=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C([N:36]=C=NCCCN(C)C)C.[NH4+].ON1C2C=CC=CC=2N=N1.O>CN(C)C=O>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[N:11]([CH2:29][CH:30]([CH3:31])[CH3:32])[C:12](=[O:28])[C:13]2[C:18]([C:19]=1[C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)=[CH:17][C:16]([C:25]([NH2:36])=[O:27])=[CH:15][CH:14]=2)([CH3:2])([CH3:4])[CH3:3]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2cccs2)c2cc(C(=O)O)ccc2c1=O
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2cccs2)c2cc(C(N)=O)ccc2c1=O
Yield: 94.6 %

Procedure:
A solution of 3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-(2-thienyl)-1,2-dihydro-6-isoquinolinecarboxylic acid (0.59 g, 1.3 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.50 g, 2.6 mmol) and 1-hydroxybenzotriazole ammonium salt (0.40 g, 2.6 mmol) in N,N-dimethylformamide (10 ml) was stirred at room temperature for 2 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting crystals were recrystallized from tetrahydrofuran-diisopropyl ether to give tert-butyl[6-(aminocarbonyl)-2-isobutyl-1-oxo-4-(2-thienyl)-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.56 g, 94.9%) as crystals.
Reaction SMILES: Cl.[CH2:2]([N:9]1[C:17]2[C:16](=[O:18])[NH:15][C:14](N)=[N:13][C:12]=2[N:11]=[CH:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.N([O-])=[O:21].[Na+]>O.C(O)(=O)C>[CH2:2]([N:9]1[C:17]2[C:16](=[O:18])[NH:15][C:14](=[O:21])[NH:13][C:12]=2[N:11]=[CH:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=N[O-]
Reactant: Nc1nc2ncn(Cc3ccccc3)c2c(=O)[nH]1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]c(=O)c2c(ncn2Cc2ccccc2)[nH]1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
35.9 g (0.13 mol) of 7-benzylguanine hydrochloride from stage a) were dissolved in a mixture of 90 ml of water and 807 ml of glacial acetic acid and heated to 100° C. After cooling to 50° C., a solution of 35.88 g (0.52 mol) of sodium nitrite in 90 ml of water was added in one portion. After 16 hours at room temperature, the resulting precipitate was filtered off with suction, washed with water on the suction filter and dried.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][N:24]([C:27](=O)[CH2:28][C@@H:29]([NH:38][C:39]2[CH:44]=[CH:43][C:42]([S:45]([NH2:48])(=[O:47])=[O:46])=[CH:41][C:40]=2[S:49]([C:52]([F:55])([F:54])[F:53])(=[O:51])=[O:50])[CH2:30][S:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:23][CH2:22]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.C1COCC1>C1COCC1.N.CO>[Si:1]([O:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][C@@H:29]([NH:38][C:39]2[CH:44]=[CH:43][C:42]([S:45]([NH2:48])(=[O:46])=[O:47])=[CH:41][C:40]=2[S:49]([C:52]([F:54])([F:53])[F:55])(=[O:50])=[O:51])[CH2:30][S:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:23][CH2:22]1)([C:14]([CH3:15])([CH3:16])[CH3:17])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](OCCN1CCN(C(=O)C[C@H](CSc2ccccc2)Nc2ccc(S(N)(=O)=O)cc2S(=O)(=O)C(F)(F)F)CC1)(c1ccccc1)c1ccccc1
Agent: B
Agent: N
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OCCN1CCN(CC[C@H](CSc2ccccc2)Nc2ccc(S(N)(=O)=O)cc2S(=O)(=O)C(F)(F)F)CC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.5 %

Procedure:
(R)-4-(4-(4-(2-(tert-Butyldiphenylsilyloxy)ethyl)piperazin-1-yl)-4-oxo-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethyl sulfonyl)benzenesulfonamide (INTERMEDIATE 21, 0.98 g, 1.15 mmol) was dissolved in THF (4.6 ml), under a nitrogen atmosphere, and a solution of borane-THF complex (1M in THF; 6.93 ml, 6.93 mmol) was added. The mixture was diluted with NH3 in MeOH (7N, 20 ml) and stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, diluted with EtOAc (75 ml), washed with water (40 ml), and dried (Na2SO4). Evaporation of the volatiles under reduced pressure afforded a concentrate, which was purified by column chromatography (ISCO, 40 g silica gel column, eluting with 0→100% EtOAc/hexanes) to provide the title compound (245 mg, yield: 25%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:17]([NH2:20])(=[O:19])=[O:18])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]1([F:16])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.FC(F)(F)C(O)=O.[CH3:28][N:29]([CH3:34])[CH2:30][C:31](Cl)=[O:32].Cl.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([S:17]([NH2:20])(=[O:19])=[O:18])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]1([F:16])[CH2:15][CH2:14][N:13]([C:31](=[O:32])[CH2:30][N:29]([CH3:34])[CH3:28])[CH2:12][CH2:11]1
Reactant: CN(C)CC(=O)Cl
Reactant: NS(=O)(=O)c1cnc(OCC2(F)CCNCC2)c(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CN(C)CC(=O)N1CCC(F)(COc2ncc(S(N)(=O)=O)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-chloro-6-((4-fluoropiperidin-4-yl)methoxy)pyridine-3-sulfonamide, 2.trifluoroacetic acid (0.131 g), 2-(dimethylamino)acetyl chloride, hydrochloric acid (0.139 g), and sodium carbonate (0.048 g) were combined in a 5-mL vial with N,N-dimethylformamide (3 mL) and stirred overnight at room temperature. Additional sodium carbonate (0.048 g) was added followed by 2-(dimethylamino)acetyl chloride, hydrochloric acid (0.139 g) and stirring was continued over a second night. The reaction mixture was concentrated under high vacuum, slurried in CH2Cl2, filtered, concentrated, chromatographed on amine functionalized silica gel with 0 to 4% methanol in CH2Cl2 as the eluent and dried in a vacuum oven at 80° C.
Reaction SMILES: [N:1]1[CH:7]=[CH:6][C:5](=[O:8])[N:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>C(Cl)Cl>[O:8]=[C:5]1[CH:6]=[CH:7][N:1]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:2][CH:3]=[N:4]1
Reactant: O=c1ccnccn1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1C=CN(C(=O)OCc2ccccc2)CC=N1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4.8 g (42.0 mmol) [1,4]diazepin-5-one are dissolved in 60 ml DCM and at ice bath temperature successively combined with 11.0 ml (83.9 mmol) triethylamine and 6.8 ml (46.2 mmol) benzyl chloroformate. The mixture is heated to RT and kept for three hours at this temperature. Then the mixture is concentrated and combined with water. The aqueous phase is extracted three times with ethyl acetate. The combined organic phases are dried on sodium sulphate, filtered and evaporated down i. vac. The crude product is [purified] by column chromatography on silica gel (eluant DCM/MeOH 95:5→90:10).
Reaction SMILES: CCN=C=NCCCN(C)C.[O:12]1[C:16]2[CH:17]=[C:18]([C:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:30][CH:29]([NH2:31])[CH2:28]4)[CH2:23][CH:22]=3)[CH:19]=[CH:20][C:15]=2[CH2:14][CH2:13]1.[F:32][C:33]([F:48])([F:47])[C:34]1[CH:35]=[C:36]([CH:44]=[CH:45][CH:46]=1)[C:37]([NH:39][CH2:40][C:41](O)=[O:42])=[O:38]>>[O:12]1[C:16]2[CH:17]=[C:18]([CH:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:30][CH:29]([NH:31][C:41]([CH2:40][NH:39][C:37](=[O:38])[C:36]5[CH:44]=[CH:45][CH:46]=[C:34]([C:33]([F:48])([F:32])[F:47])[CH:35]=5)=[O:42])[CH2:28]4)[CH2:23][CH2:22]3)[CH:19]=[CH:20][C:15]=2[CH2:14][CH2:13]1
Reactant: NC1CN(C2CC=C(c3ccc4c(c3)OCC4)CC2)C1
Reactant: O=C(O)CNC(=O)c1cccc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(c3ccc4c(c3)OCC4)CC2)C1

Procedure:
The title compounds were prepared as white solids from the EDCI coupling between the amine (from step D) and (3-trifluoromethyl-benzoylamino)-acetic acid followed by H-Cube hydrogenation using the procedures described in Steps E and F of Example 1.
Reaction SMILES: [C:1]([O:5][P:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23]C)=[O:22])=[CH:16][CH:15]=1)([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>C1COCC1.O>[C:9]([O:8][P:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[CH:16][CH:15]=1)([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])([CH3:10])([CH3:11])[CH3:12]
Reactant: COC(=O)Cc1ccc(OP(=O)(OC(C)(C)C)OC(C)(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OP(=O)(Oc1ccc(CC(=O)O)cc1)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.7 %

Procedure:
To a stirred solution of Intermediate 43B (0.635 g, 1.772 mmol) in THF (12.0 mL) and water (3.00 mL) was added lithium hydroxide (0.122 g, 2.14 mmol). The reaction mixture was stirred at room temperature for 2 hr and then the organics were removed under reduced pressure. The resulting mixture was diluted with 10 mL of pH 4 phosphate solution. The resulting mixture was extracted with EtOAc. The combined EtOAc extracts were washed with brine, dried with anhydrous magnesium sulfate, filtered and concentrated to afford Intermediate 43C (0.462 g, 76%). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.30 (br. s., 1H), 7.25 (d, J=8.4 Hz, 2H), 7.13-7.03 (m, 2H), 3.55 (s, 2H), 1.44 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:17][CH3:18])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH:30]=[C:29]([C:31]#[N:32])[N:28]=[CH:27]2)=[C:22]([O:33][CH3:34])[CH:21]=1.CC(O)=O.[OH-].[Na+]>O1CCOCC1>[CH3:34][O:33][C:22]1[CH:21]=[C:20]([NH:19][C:2]2[N:3]=[C:4]([NH:17][CH3:18])[C:5]3[CH2:10][CH2:9][CH:8]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[C:6]=3[N:7]=2)[CH:25]=[CH:24][C:23]=1[N:26]1[CH:30]=[C:29]([C:31]#[N:32])[N:28]=[CH:27]1
Reactant: CNc1nc(Cl)nc2c1CCC2c1ccccc1
Reactant: COc1cc(N)ccc1-n1cnc(C#N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CNc1nc(Nc2ccc(-n3cnc(C#N)c3)c(OC)c2)nc2c1CCC2c1ccccc1
Reaction time: 8 h
Yield: 22.5 %

Procedure:
To a solution of 2-chloro-N-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (Preparation Ga) (150 mg, 0.578 mmol) in Dioxane (Ratio: 1, Volume: 1013 μl) was added 1-(4-amino-2-methoxyphenyl)-1H-imidazole-4-carbonitrile (Preparation AA) (124 mg, 0.578 mmol), and AcOH (Ratio: 1.000, Volume: 1013 μl). The resulting mixture was brought to 100° C. in a sealed vial and stirred overnight. The mixture was brought to pH 8 by the addition of 1 N aqueous sodium Hydroxide. The resulting mixture was extracted with EtOAc (3×1 mL). The combined extracts were dried over MgSO4, filtered and concentrated in vacuo. Purification by prep HPLC (Waters Sunfire C18, 50×250 mm, acetonitrile/H2O/ammonium acetate) gave 1-(2-methoxy-4-(4-(methylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-ylamino)phenyl)-1H-imidazole-4-carbonitrile (57 mg, 0.130 mmol, 22.56% yield). LC-MS (M+H)+=438.2. 1H NMR (500 MHz, MeOD) δ ppm 8.02-8.08 (2H, m), 7.90-7.94 (1H, m), 7.31 (2H, t, J=7.63 Hz), 7.16-7.24 (4H, m), 6.99 (1H, dd, J=8.55, 2.14 Hz), 4.18 (1H, t, J=8.09 Hz), 3.56 (3H, s), 3.07 (3H, s), 2.76-2.84 (1H, m), 2.59-2.74 (2H, m), 1.98-2.05 (1H, m). The racemic mixture was separated by chiral chromatography to afford the enantiomers Example 204A and 204B.
Reaction SMILES: C[N:2](C)[CH:3]=[C:4]([C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH3:13])[CH:8]=1)[C:5]#[N:6].O.[NH2:16]N>C(O)C>[CH3:13][C:9]1[CH:8]=[C:7]([C:4]2[CH:5]=[N:6][NH:2][C:3]=2[NH2:16])[CH:12]=[CH:11][N:10]=1
Reactant: Cc1cc(C(C#N)=CN(C)C)ccn1
Reactant: NN
Solvent: CCO
Solvent: O
Product: Cc1cc(-c2cn[nH]c2N)ccn1
Yield: 35.8 %

Procedure:
To stirred solution of 3-dimethylamino-2-(2-methyl-pyridin-4-yl)-acrylonitrile (1.8 g, 9.61 mmol) in ethanol (18 ml) was added at room temperature hydrazine monohydrate (1.03 ml, 21.1 mmol), the reaction mixture was heated under reflux conditions for 16 h and evaporated. Purification by column chromatography on silica gel (dichloromethane/methanol/NH4OH 80:10:1) and crystallization from diethyl ether yielded 4-(2-methyl-pyridin-4-yl)-2H-pyrazol-3-ylamine (0.6 g, 36%) as an orange solid. MS (ISP) 175.1 [(M+H)+]; mp 230° C.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)/[C:5](=[N:12]/[S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])/[CH:4]=[C:3]1[S:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].[O-]S(S([O-])=O)=O.[Na+].[Na+]>C1COCC1.C(OCC)(=O)C>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])=[CH:4][C:3]=1[S:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)CSC1=C/C(=N\S(=O)(=O)c2cccs2)c2ccccc2C1=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CSc1cc(NS(=O)(=O)c2cccs2)c2ccccc2c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.2 %

Procedure:
52 mg (E)-ethyl 2-(1-oxo-4-(thiophen-2-ylsulfonylimino)-1,4-dihydronaphthalen-2-ylthio)acetate (8a) was dissolved in 2 ml THF, to which was added 2 ml aqueous solution containing 107 mg Na2S2O4. The resulting biphasic solution was stirred at r.t. for 1 h until it turned pale yellow. The mixture was diluted with ethyl acetate and washed with water and brine. Dried over Na2SO4, the organic solution was filtered and the filtrate was concentrated. The crude product was purified via flash column (EtOAc/Hexane) yielding 25.2 mg (58.7%) title compound, m.p.: 116-118° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[NH2:8].CCOC(C)=O.O.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[O:22]1[CH2:23][CH2:24][N:19]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=2[NH2:8])[CH2:20][CH2:21]1
Reactant: Nc1c(Br)cncc1[N+](=O)[O-]
Reactant: C1COCCN1
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1c(N2CCOCC2)cncc1[N+](=O)[O-]

Procedure:
A solution of 3-bromo-5-nitropyridin-4-amine (XLVI) (1 eq.), in neat morpholine in a sealed tube was heated at 120-140° C. overnight. The solution was poured into a mixture of EtOAc and water. The organic layer was separated. The aqueous layer was extracted with EtOAc. The combined organic layers was washed with brine, dried over MgSO4 and concentrated to get a residue. The crude product was purified on a silica gel column eluting with chloroform:MeOH gradient. The fractions containing product were mixed and concentrated under vacuum. The residue was triturated with hexane to give 3-morpholino-5-nitropyridin-4-amine (LIII).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:12]([S:15][CH2:16][CH:17]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:18](O)=[O:19])(=[O:14])[CH3:13].NC1N=CC=CC=1C(OC)=O>N1C=CC=CC=1>[C:12]([S:15][CH2:16][CH:17]([CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:18]([NH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6])=[O:19])(=[O:14])[CH3:13]
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)O
Reactant: COC(=O)c1ccnc(N)c1
Agent: COC(=O)c1cccnc1N
Solvent: c1ccncc1
Product: COC(=O)c1ccnc(NC(=O)C(CSC(C)=O)Cc2ccccc2)c1

Procedure:
Following the procedure of Example 1, but substituting an equivalent amount of methyl 2-amino-isonicotinate and 2-acetylthiomethyl-3-phenyl-propionic acid respectively for methyl 2-amino-nicotinate and 2-acetylthiomethyl-3-phenyl-propionic acid, using pyridine as reaction solvent, maintaining the reaction mixture at 50°-60° C. for five hours and purifying by chromatography on silica gel column (eluent, petroleum ether/ether 7:3), methyl 2-(2-acetylthiomethyl-3-phenyl-propionamido)-isonicotinate is obtained as an oil which is transformed into the corresponding hydrochloride with an alcoholic solution of hydrogen chloride; m.p. 137°-139° C., from acetone/ether.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([CH2:16][NH2:17])=[N:14][N:15]=3)[N:12]=2)[O:4][N:3]=1.Cl[C:19]1[CH:20]=[CH:21][N:22]=[C:23]2[C:28]=1[N:27]=[CH:26][C:25]([O:29][CH3:30])=[CH:24]2>CC(O)CC>[CH3:30][O:29][C:25]1[CH:24]=[C:23]2[C:28]([C:19]([NH:17][CH2:16][C:13]3[N:11]4[N:12]=[C:7]([C:5]5[O:4][N:3]=[C:2]([CH3:1])[CH:6]=5)[CH:8]=[CH:9][C:10]4=[N:15][N:14]=3)=[CH:20][CH:21]=[N:22]2)=[N:27][CH:26]=1
Reactant: COc1cnc2c(Cl)ccnc2c1
Reactant: Cc1cc(-c2ccc3nnc(CN)n3n2)on1
Solvent: CCC(C)O
Product: COc1cnc2c(NCc3nnc4ccc(-c5cc(C)no5)nn34)ccnc2c1
Temperature: 120 °C
Reaction time: 4 h

Procedure:
To a microwave vial (10-20 mL) was added (6-(3-methylisoxazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methanamine (1.00 g, 4.34 mmol) and 8-chloro-3-methoxy-1,5-naphthyridine (1.10 g, 5.65 mmol) in 2-butanol (12 mL). The suspension was stirred at 120° C. under microwave irradiation for four hours. The mixture was concentrated and taken up in ammonia in methanol (2.0 M) then purified by MPLC chromatography (eluted with 0-10% methanol in dichloromethane) to yield the product as a tan solid. MS m/z=389.0 [M+1]+. Calc'd for C19H16N8O2: 388.1
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH:7]([OH:8])[CH2:6][CH2:5][O:4]1.[H-].[Na+].[CH2:11]([O:18][CH2:19][CH2:20]O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>CN(C=O)C>[CH2:11]([O:18][CH2:19][CH2:20][O:8][CH:7]1[CH2:6][CH2:5][O:4][CH:3]1[O:2][CH3:1])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OCCOCc1ccccc1
Reactant: COC1OCCC1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC1OCCC1OCCOCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 2-methoxy-tetrahydro-furan-3-ol in DMF 200 mL was added sodium hydride in small portions with stirring at 0° C. for 2 hrs, then 2-Benzyloxy-ethanol was added from the dropping funnel over a period of 1 hour, the resulting mixture was stirred at 25° C. for 15 hrs, it was poured into 400 mL water, EtOAC (1 L) were added and separated. The organic layer was washed with sat. NaHCO3 (500 mL), dried over Na2SO4, filtered and concentrated, The residue was purified by column chromatography (PE:EA=5:1) to yield 10 g of 3-(2-Benzyloxy-ethoxy)-2-methoxy-tetrahydro-furan (oil).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]2=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:10]=[CH:11][N:4]2[N:3]=1.CCN(C(C)C)C(C)C.[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33][NH2:34]>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:34][CH2:33][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][N:27]=2)[C:5]2=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:10]=[CH:11][N:4]2[N:3]=1
Reactant: Clc1nc(Cl)c2c(-c3ccccc3)ccn2n1
Reactant: NCc1ccccn1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Clc1nc(NCc2ccccn2)c2c(-c3ccccc3)ccn2n1
Temperature: 25 °C
Reaction time: 14 h
Yield: 35.1 %

Procedure:
2,4-Dichloro-5-phenylpyrrolo[2,1-f][1,2,4]triazine (0.560 g, 2.12 mmol) was dissolved in THF (15 mL) and then DIPEA (1.85 mL, 10.6 mmol) was added followed by the addition of pyridin-2-ylmethanamine (0.688 g, 6.36 mmol). Then the reaction mixture was stirred at room temperature for 14 h. The reaction mixture was concentrated under reduced pressure to remove THF and to this residue water (10 mL) added. The aqueous solution was extracted with CH2Cl2 (25×3 mL) and the organic layer was separated, dried over anhydrous sodium sulfate and was concentrated under reduced pressure. The residue was purified by column chromatography using CombiFlash (REDISEP®, silica gel, 40 g, 20% EtOAc/hexanes) to afford 2-chloro-5-phenyl-N-(pyridin-2-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (0.250 g, 35.1%). LCMS Condition B-39: retention time 2.10 min, [M+1]=336.0.
Reaction SMILES: [CH3:1][C:2]1([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([S:17](=[O:20])(=[O:19])[NH2:18])[CH:12]=2)=[O:9])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl[C:22]1[C:23]2[C:30]([CH3:31])=[CH:29][NH:28][C:24]=2[N:25]=[CH:26][N:27]=1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[CH3:1][C:2]1([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([S:17](=[O:20])(=[O:19])[NH2:18])[CH:12]=2)=[O:9])[CH2:3][CH2:4][N:5]([C:22]2[C:23]3[C:30]([CH3:31])=[CH:29][NH:28][C:24]=3[N:25]=[CH:26][N:27]=2)[CH2:6][CH2:7]1
Reactant: CC1(C(=O)Nc2cccc(S(N)(=O)=O)c2)CCNCC1
Reactant: Cc1c[nH]c2ncnc(Cl)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cc1c[nH]c2ncnc(N3CCC(C)(C(=O)Nc4cccc(S(N)(=O)=O)c4)CC3)c12
Temperature: 105 °C
Yield: 21 %

Procedure:
4-Methyl-N-(3-sulfamoylphenyl)piperidine-4-carboxamide from step B (33 mg, 0.098 mmol), 4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (16 mg, 0.098 mmol), N,N-diisopropylethylamine (51 mg, 0.39 mmol), and isopropanol (1.0 mL) were combined in a pressure rated sealed tube and heated at 105° C. for 18 hours. The mixture was concentrated, and the residue was purified by preparative HPLC to give the title compound in 21% yield.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:20]([CH3:22])[CH3:21])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]1[C:11]([CH2:17][CH2:18][OH:19])([CH2:15][CH3:16])[O:12][CH2:13][CH2:14][C:7]2=1.[C:23]([C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1)#[N:24]>>[C:23]([C:25]1[CH:30]=[C:29]([C:2]2[CH:3]=[C:4]([CH:20]([CH3:21])[CH3:22])[CH:5]=[C:6]3[C:10]=2[NH:9][C:8]2[C:11]([CH2:17][CH2:18][OH:19])([CH2:15][CH3:16])[O:12][CH2:13][CH2:14][C:7]3=2)[CH:28]=[CH:27][CH:26]=1)#[N:24]
Reactant: CCC1(CCO)OCCc2c1[nH]c1c(Br)cc(C(C)C)cc21
Reactant: N#Cc1cccc(B(O)O)c1
Product: CCC1(CCO)OCCc2c1[nH]c1c(-c3cccc(C#N)c3)cc(C(C)C)cc21

Procedure:
The title compound is prepared in a manner analogous to Example 1, except using 2-(8-bromo-1-ethyl-6-isopropyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol and 3-cyanophenylboronic acid in step 1.F.
Reaction SMILES: N1([C:10](=[O:15])[CH:11]=[C:12]([CH3:14])[CH3:13])C2C=CC=CC=2N=N1.[Br:16][C:17]1[CH:18]=[CH:19][C:20]([NH:23][NH2:24])=[N:21][CH:22]=1.CCN(CC)CC>C1COCC1>[Br:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[C:10](=[O:15])[CH2:11][C:12]([CH3:14])([CH3:13])[NH:24]2)=[N:21][CH:22]=1
Reactant: NNc1ccc(Br)cn1
Reactant: CC(C)=CC(=O)n1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1(C)CC(=O)N(c2ccc(Br)cn2)N1
Reaction time: 1.5 h
Yield: 42.6 %

Procedure:
(400 mg, 2.0 mmol) 1-Benzotriazol-1-yl-3-methyl-but-2-en-1-one (Example 1, step 1), (5-bromo-pyridin-2-yl)-hydrazine (410 mg, 2.2 mmol, 1.1 equiv.) and Et3N (1.95 ml, 14.0 mmol, 7 equiv.) were dissolved together in THF (2 ml) and stirred for 90 minutes at reflux temperature. The reaction mixture was cooled and extracted with saturated Na2CO3 solution and two times with ethyl acetate. The organic extracts were extracted with brine, dried over sodium sulfate and evaporated to dryness. The crude product was purified by flash chromatography on a silica gel column eluting with an ethyl acetate:cyclohexane gradient 0:100 to 50:50. The desired 2-(5-bromo-pyridin-2-yl)-5,5-dimethyl-pyrazolidin-3-one (230 mg, 43% yield) was obtained as a yellow oil, MS: m/e=270.2/272.2 (M+H+).
Reaction SMILES: S1[CH:5]=[CH:4][C:3]([C:6]2[S:10][C:9]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)=[N:8][CH:7]=2)=[CH:2]1.[Br:19][C:20]1C=C(CC=O)C=C[CH:25]=1>C(Cl)Cl.CO>[Br:19][C:20]1[CH:2]=[C:3]([C:6]2[S:10][C:9]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)=[N:8][CH:7]=2)[CH:4]=[CH:5][CH:25]=1
Reactant: O=CCc1cccc(Br)c1
Reactant: Oc1ccc(Nc2ncc(-c3ccsc3)s2)cc1
Solvent: ClCCl
Solvent: CO
Product: Oc1ccc(Nc2ncc(-c3cccc(Br)c3)s2)cc1

Procedure:
The title compound is prepared as described in Example 12 (Procedure B) for 4-(5-thiophen-3-yl-thiazol-2-yl-amino)-phenol but starting from (3-bromophenyl)-acetaldehyde. The title compound: ES-MS: 348.9 [M+2]+; single peak at tR=3.92 min (System 2); Rf=0.47 (CH2Cl2/MeOH, 90/10).