Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][CH2:14][C:15]3[S:16][C:17]([C:21]([OH:23])=O)=[C:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[N:6][CH:7]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:56][CH:57]1[CH2:62][CH2:61][O:60][CH2:59][CH2:58]1>CN(C=O)C>[O:60]1[CH2:61][CH2:62][CH:57]([NH:56][C:21]([C:17]2[S:16][C:15]([CH2:14][CH2:13][C:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=4)=[N:9][O:10][C:11]=3[CH3:24])=[N:19][C:18]=2[CH3:20])=[O:23])[CH2:58][CH2:59]1
Reactant: Cc1nc(CCc2c(-c3ccc(F)cn3)noc2C)sc1C(=O)O
Reactant: NC1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(CCc2c(-c3ccc(F)cn3)noc2C)sc1C(=O)NC1CCOCC1
Reaction time: 1 h
Yield: 94.1 %

Procedure:
To a solution of 2-{2-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-ethyl}-4-methyl-thiazole-5-carboxylic acid (69 mg, 0.20 mmol) in DMF (1.2 mL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (71 mg, 0.22 mmol), N,N-diisopropyl ethyl amine (171 μL, 1.00 mmol) and 4-aminotetrahydropyran (22 mg, 0.22 mmol). The resulting reaction mixture was stirred for 1 h and then evaporated. Purification by chromatography (silica, heptane:ethyl acetate 4:1 to 0:1) afforded the title compound (81 mg, 94%) as an off white solid. MS: m/e=431.2 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([OH:18])[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:28][N:29]([CH3:33])[CH2:30][CH2:31]Cl>CN(C)C=O.ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([O:18][CH2:31][CH2:30][N:29]([CH3:33])[CH3:28])[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1
Reactant: N#Cc1cc(O)cc(-c2nc(-c3ccccn3)no2)c1
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(C)CCOc1cc(C#N)cc(-c2nc(-c3ccccn3)no2)c1
Yield: 53 %

Procedure:
A mixture of 3-(2-pyridyl)-5-(3-cyano-5-hydroxyphenyl)-1,2,4-oxadiazole (30 mg, 0.11 mmol), potassium carbonate (374 mg, 2.7 mmol) and 2-dimethylaminoethyl chloride hydrochloride. (46 mg, 0.32 mmol) in N,N-dimethylformamide (1 mL) were heated in a sealed vial at 150° C. for 5 minutes. The reaction was cooled, diluted with dichloromethane, washed with water (3×) and saturated brine, filtered and concentrated. Silica gel chromatography using a gradient of 1% methanol in dichloromethane to 5% methanol in dichloromethane afforded 24 mg (53%) of 3-(2-pyridyl)-5-(3-cyano-5-(2-dimethylaminoethoxy)phenyl)-1,2,4-oxadiazole: 1H NMR (CDCl3): δ −8.86 (d, 1H), 8.23 (d, 1H), 8.15 (s, 1H), 8.04 (s, 1H), 7.91 (t, 1H), 7.49 (m, 1H), 7.43 (s, 1H), 4.20 (t, 2H), 2.80 (t, 2H), 2.37 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([C:14]3[C:15](=[O:26])[C:16]4[C:21]([C:22](=[O:25])[C:23]=3Cl)=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH-:27].[Na+]>CO.O>[CH:18]1[CH:19]=[CH:20][C:21]2[C:22]([C:23]([OH:27])=[C:14]([C@@H:11]3[CH2:10][CH2:9][C@@H:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[CH2:13][CH2:12]3)[C:15](=[O:26])[C:16]=2[CH:17]=1)=[O:25]
Reactant: O=C1C(Cl)=C([C@H]2CC[C@H](c3ccc(Cl)cc3)CC2)C(=O)c2ccccc21
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C1C(O)=C([C@H]2CC[C@H](c3ccc(Cl)cc3)CC2)C(=O)c2ccccc21
Temperature: 2.5 °C

Procedure:
6.0 g of trans-2-[4-(4-chlorophenyl)cyclohexyl]-3-chloro-1,4-naphthoquinone (trans-isomer of Formula IV) as obtained in Example 3 was suspended in 120 ml methanol. 6.0 g sodium hydroxide dissolved in 60 ml water was added drop-wise to the suspension under heating over a period of 20 minutes. Further, it was refluxed for 45 minutes and cooled to 0-5° C. and filtered. The filtrate was acidified with 50% aqueous hydrochloric acid to precipitate the product. The precipitated product was filtered, and recrystallized from acetonitrile to obtain 4 g (70% yield) atovaquone.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:24][C:25]([N:27]2[CH2:31][CH2:30][N:29](N3CCCCC3)[C:28]2=[O:38])=[O:26])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[N:19]=[CH:20][N:21]([CH3:23])[CH:22]=3)[S:17][C:10]=12.[CH:39]1(N2CCNC2=O)[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>>[CH:39]1([N:29]2[CH2:30][CH2:31][N:27]([C:25]([NH:24][C:4]3[CH:5]=[CH:6][C:7]([O:8][C:9]4[CH:14]=[CH:13][N:12]=[C:11]5[CH:15]=[C:16]([C:18]6[N:19]=[CH:20][N:21]([CH3:23])[CH:22]=6)[S:17][C:10]=45)=[C:2]([F:1])[CH:3]=3)=[O:26])[C:28]2=[O:38])[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1
Reactant: Cn1cnc(-c2cc3nccc(Oc4ccc(NC(=O)N5CCN(N6CCCCC6)C5=O)cc4F)c3s2)c1
Reactant: O=C1NCCN1C1CCCCC1
Product: Cn1cnc(-c2cc3nccc(Oc4ccc(NC(=O)N5CCN(C6CCCCC6)C5=O)cc4F)c3s2)c1
Yield: 68 %

Procedure:
Following the procedure described above for the compound 276 (example 113) but replacing 1-(piperidin-1-yl)imidazolidin-2-one (278) by 1-cyclohexylimidazolidin-2-one (281), the title compound 279 was obtained in 68% yield. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.69 (s, 1H), 8.44 (dd, J=5.5 Hz, 1H), 7.86 (s, 1H), 7.79 (dd, J=2.5 Hz, J=13 Hz, 1H), 7.72 (s, 1H), 7.68 (s, 1H), 7.46 (t, J=8.9 Hz, 1H), 7.35 (d, J=5.5 Hz, 1H), 6.58 (d, J=5.5 Hz, 1H), 3.8 (dd, J=7.6 Hz, J=8.0 Hz, 2H), 3.73 (s, 3H), 3.7-3.6 (m, 1H), 3.44 (dd, J=7.2 Hz, J=8.0 Hz, 2H), 1.79-1.60 (m, 5H), 1.47-1.41 (m, 2H), 1.36-1.29 (m, 2H), 1.7 (m, 1H). MS (m/z): (M+1) 535.2.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:12])[C:9]#[C:10][CH3:11])=[CH:4][CH:3]=1.Br[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1.OCC1SC(B(O)O)=CC=1>>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([C:14]2[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=2)=[CH:3][CH:4]=1)(=[O:12])[C:9]#[C:10][CH3:11]
Reactant: CC#CC(=O)c1ccc(Br)cc1
Reactant: O=Cc1ccc(Br)cc1
Agent: OCc1ccc(B(O)O)s1
Product: CC#CC(=O)c1ccc(-c2ccc(C=O)cc2)cc1
Yield: 58 %

Procedure:
When the product of Step A and 4-carbaldehyde-boronic acid were substituted for 4-bromobenzaldehyde and 5-(hydroxymethyl)thiophen-2-ylboronic acid, respectively, in Example 22, Step A, the similar procedure afforded the title compound in 58% yield, as a creamy gum. 1H-NMR (CDCl3) 10.07 (s, 1H); 8.23 (d, 2H, J=8.4 Hz); 7.98 (d, 2H, J=8.4 Hz); 7.78 (d, 2H, J=8.24 Hz); 7.72 (d, 2H, J=8.54 Hz); 2.18 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]([OH:10])=O)[CH:4]=[N:3]1.S(Cl)(Cl)=O.[NH2:15][C:16]1[CH:17]=[C:18]([CH:31]=[CH:32][CH:33]=1)[C:19]([C:21]1[CH:29]=[C:28]2[C:24]([CH2:25][C:26](=[O:30])[NH:27]2)=[CH:23][CH:22]=1)=[O:20]>C1COCC1>[O:30]=[C:26]1[CH2:25][C:24]2[C:28](=[CH:29][C:21]([C:19]([C:18]3[CH:17]=[C:16]([NH:15][C:8]([C:5]4[CH:4]=[N:3][N:2]([CH3:1])[C:6]=4[CH3:7])=[O:10])[CH:33]=[CH:32][CH:31]=3)=[O:20])=[CH:22][CH:23]=2)[NH:27]1
Reactant: Cc1c(C(=O)O)cnn1C
Reactant: Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: Cc1c(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4)c2)cnn1C
Temperature: 79 °C
Reaction time: 3 h
Yield: 45.6 %

Procedure:
A dry flask was charged with 1,5-Dimethyl-1H-pyrazole-4-carboxylic acid (0.144 g, 1.03 mmol) and thionyl chloride (5 mL) and allowed to stir at 79° C. for 3 h. The thionyl chloride was then removed by concentration in vacuo. The crude acid chloride was cooled to room temperature, and then dissolved in THF (101 mL). 6-(3-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 40, 0.260 g, 1.03 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux overnight. The reaction mixture was then allowed to cool to room temperature and filtered. The solid residue was washed with 0° C. THF and collected to afford the 1,5-Dimethyl-1H-pyrazole-4-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide as a solid (0.177 g, 0.47 mmol, 46%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1.C1C(=O)N([Br:26])C(=O)C1>C1COCC1>[Br:26][C:5]1[N:1]=[C:2]([CH:6]2[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:11]2)[NH:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncc[nH]2)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2nc(Br)c[nH]2)CC1

Procedure:
A solution of tert-butyl 4-(1H-imidazol-2-yl)piperidine-1-carboxylate (20.04 g, 79.74 mmol) in THF (450 mL) was cooled to −46 C (bath) before the flask was charged with NBS (14.27 g) in equal portions (10-min apart). LCMS data indicated complete reaction after 15 min, so the contents were concentrated to a yellow, solid foam that was further dried under vacuum overnight. The crude material (monobromide:dibromide=40:27) was purified by chromatography to give pure white solid (8.08 g, 24.47 mmol, 31%) as the title compound.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([S:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]([CH2:22][NH2:23])[CH2:17][CH2:16][CH2:15]3)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[O-:24][C:25]#[N:26].[K+]>O>[F:2][C:3]1[CH:4]=[C:5]([S:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C@H:18]([CH2:22][NH:23][C:25]([NH2:26])=[O:24])[CH2:17][CH2:16][CH2:15]3)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1
Reactant: NCC1CCCc2cc(S(=O)(=O)c3cccc(F)c3)ccc21
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: NC(=O)NC[C@@H]1CCCc2cc(S(=O)(=O)c3cccc(F)c3)ccc21
Temperature: 60 °C
Yield: 79.8 %

Procedure:
C-[6-(3-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-methylamine hydrochloride (0.5 gms, 1.41 mmole) and potassium cyanate (0.137 g, 1.69 mmol) added to to 30 mL stirring water, and the mixture was heated to 60° C. for five minutes. The reaction mixture was then cooled to room temperature, and the resulting white precipitate was collected by filtration, washed with cold water, and dried under vacuum to give 0.408 g of (R)-[6-(3-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-urea, M+H=363.
Reaction SMILES: [CH2:1]([O:7][N:8]=[C:9]([C:15](=O)[CH2:16]Cl)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH2:19][C:20]([NH2:22])=[S:21].C(O)C>O>[NH2:22][C:20]1[S:21][CH:16]=[C:15]([C:9](=[N:8][O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:19]=1
Reactant: NC(N)=S
Reactant: CCCCCCON=C(C(=O)CCl)C(=O)OCC
Solvent: O
Solvent: CCO
Product: CCCCCCON=C(C(=O)OCC)c1csc(N)n1
Yield: 49 %

Procedure:
Ethyl 2-n-hexyloxyimino-4-chloro-3-oxobutyrate (syn isomer, 55.6 g,), thiourea (15.2 g.), sodium acetate 3-hydrate (27.2 g.), ethanol (280 ml.) and water (140 ml.) were treated in a similar manner to that of Example F-(3) to give ethyl 2-(2-aminothiazol-4-yl)-2-n-hexyloxyiminoacetate (syn isomer, 29.3 g.), mp 77° to 78° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([O:16][CH3:17])=O)[CH:12]=2)[C:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[C:6]1[C:24]1[NH:25][CH:26]=[CH:27][CH:28]=1.[H-].[Na+].[OH2:31]>CN(C)C=O>[CH:18]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:14]([O:16][CH3:17])=[O:31])=[CH:12][C:13]=3[N:5]3[CH2:4][CH2:3][CH2:2][N:25]4[CH:26]=[CH:27][CH:28]=[C:24]4[C:6]=23)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccc[nH]3)n(CCCCl)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCCn1cccc1-3
Reaction time: 1 h
Yield: 77 %

Procedure:
To a solution of methyl 1-(3-chloropropyl)-3-cyclohexyl-2-(1H-pyrrol-2-yl)-1H-indole-6-carboxylate (130 mg, 0.326 mmol) in N,N-dimethylformamide (4 ml) was added sodium hydride (17 mg, 0.424 mmol) under ice-cooling, and the mixture was stirred for 1 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography (hexane:ethyl acetate=4:1) to give methyl 13-cyclohexyl-6,7-dihydro-5H-pyrrolo[2′,1′:3,4][1,4]diazepino[1,2-a]indole-10-carboxylate (91 mg, yield 77%).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([CH3:17])=[N:13][C:14]=2[CH3:16])[C:9](=O)[CH2:8][CH:7]1[CH2:19][CH3:20])=[O:5])[CH3:2].[NH2:21][OH:22].Cl.N1C=CC=CC=1>>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([CH3:17])=[N:13][C:14]=2[CH3:16])[C:9](=[N:21][OH:22])[CH2:8][CH:7]1[CH2:19][CH3:20])=[O:5])[CH3:2]
Reactant: NO
Reactant: CCOC(=O)N1c2c(cc(C)nc2C)C(=O)CC1CC
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)N1c2c(cc(C)nc2C)C(=NO)CC1CC

Procedure:
This compound can be prepared by reacting an ethanolic solution of 2-ethyl-6,8-dimethyl-4-oxo-3,4-dihydro-2H-[1,7]naphthyridine-1-carboxylic acid ethyl ester, with NH2OH.HCl (2-3 eqv) and pyridine (1-3 eqv), typically at reflux temperature for about 2 to about 6 h, followed by a typical workup procedure.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([N:14]1[CH:19]2[CH2:20][CH2:21][CH:15]1[CH2:16][C:17](=O)[CH2:18]2)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.S([CH2:33][N+:34]#[C-])(C1C=CC(C)=CC=1)(=O)=O.C(O)C>C(COC)OC>[C:33]([CH:17]1[CH2:16][CH:15]2[N:14]([CH2:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:19]([CH2:20][CH2:21]2)[CH2:18]1)#[N:34]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=C1CC2CCC(C1)N2Cc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Solvent: COCCOC
Product: N#CC1CC2CCC(C1)N2Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 41.4 %

Procedure:
Potassium t-butoxide (2.5 g) was added portion wise to a stirred mixture of 8-benzyl-8-azabicyclo[3.2.1]octan-3-one (2.0 g), tosylmethyl isocyanide (2.36 g) and ethanol (2 ml) in dimethoxyethane (50 ml) at 0° C. under nitrogen. The mixture was stirred at 0° C. for 0.5 hours and then overnight at room temperature. The mixture was then filtered and the solid residue washed with dimethoxyethane. The combined filtrates were evaporated under reduced pressure and chromatographed [SiO2; hexane:ethyl acetate (80:20)] to give 3-cyano-8-benzyl-8-azabicyclo[3.2.1]octane (0.87 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:12])[C:9]([OH:11])=O)[CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[O:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[CH2:24][NH2:25]>>[F:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:12])[C:9]([NH:25][CH2:24][C:20]2[O:19][CH:23]=[CH:22][CH:21]=2)=[O:11])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCc1ccco1
Reactant: CC(C(=O)O)c1ccc(-c2ccccc2)c(F)c1
Product: CC(C(=O)NCc1ccco1)c1ccc(-c2ccccc2)c(F)c1
Yield: 75 %

Procedure:
Prepared in a similar manner to Example 3 from 2-(2-fluorobiphenyl-4-yl)propanoic acid and furan-2-ylmethanamine. Yield: 75%. 1H NMR (500 MHz, CDCl3): δ 1.55-1.56 (d, 3H), 3.56-3.58 (m, 1H), 4.35-4.40 (dd, 1H, J1=5.3 Hz, J2=15.5 Hz), 4.45-4.49 (dd, 1H, J1=5.7 Hz, J2=15.6 Hz), 5.72 (s br, 1H), 6.16 (d, 1H, J=2.7 Hz), 6.39 (m, 1H), 7.10-7.15 (m, 2H), 7.25-7.45 (m, 5H), 7.54 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:15](=O)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.[CH2:19]1COCC1.C[Mg]Br>>[Br:1][C:2]1[CH:3]=[C:4]2[C:15](=[CH2:19])[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1
Reactant: C1CCOC1
Reactant: COc1ccc2oc3ncc(Br)cc3c(=O)c2c1
Agent: C[Mg]Br
Product: C=C1c2cc(OC)ccc2Oc2ncc(Br)cc21
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of 3-bromo-7-methoxy-5H-chromeno[2,3-b]pyridin-5-one (4.50 g, 14.7 mmol) in THF (294 ml, 14.7 mmol) at 5° C. was added methylmagnesium bromide (1 M in butyl ether) (36.8 ml, 36.8 mmol). The reaction was removed from the ice bath and stirred for an additional 1 hour. TLC showed complete conversion to a lower Rf material. The reaction mixture was quenched with saturated ammonium chloride (250 mL) and to it DCM (100 mL) was added. The mixture was stirred vigorously for 30 minutes before being poured into a separatory funnel containing 300 mL of DCM. The layers were separated and the aqueous layer was extracted with DCM 2×100 mL. The combined organic layers were washed with brine, dried over Na2SO4 and filtered. TLC revealed tertiary alcohol and no olefin. The organics were concentrated under reduced pressure at 60° C. Flask was maintained at 60° C. on the rotovap for 1 hour at which point TLC and NMR show clean conversion to 3-bromo-7-methoxy-5-methylene-5H-chromeno[2,3-b]pyridine. MS m/z=304.2 [M+H]+. Calc'd for C14H11BrNO2: 304.0.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][CH:5]=[C:4]2[O:8][CH2:9][CH2:10][CH2:11][C:3]=12.C(N(CC)C(C)C)(C)C.[CH3:21][O:22][C:23]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:24]=1[CH2:25][NH2:26]>C(O)(C)C>[CH3:21][O:22][C:23]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:24]=1[CH2:25][NH:26][C:2]1[N:7]=[N:6][CH:5]=[C:4]2[O:8][CH2:9][CH2:10][CH2:11][C:3]=12
Reactant: COc1ccc(CN)c(OC)c1
Reactant: Clc1nncc2c1CCCO2
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: COc1ccc(CNc2nncc3c2CCCO3)c(OC)c1
Temperature: 115 °C
Reaction time: 18 h
Yield: 60 %

Procedure:
A mixture of 5-chloro-3,4-dihydro-2H-pyrano[2,3-d]pyridazine (150 mg, 0.879 mmol), N,N-diisopropylethylamine (0.154 mL, 114 mg, 0.879 mmol), and 2,4-dimethoxybenzylamine (294 mg, 1.76 mmol) in isopropanol (2 mL) was heated in a sealed tube 18 hours at 115° C. and then 4.5 hours at 145° C. before addition of excess 2,4-dimethoxybenzylamine (about 2 g, 12 mmol). The reaction was stirred at 145° C. for 18 hours. After cooling to room temperature, isopropanol was removed in vacuo. The crude was then treated with diethyl ether (30 mL). A tan solid was removed by filtration. The filtrate was washed twice with small amounts of saturated aqueous ammonium chloride. The organic layer was dried over sodium sulfate, filtered, and concentrated down. The crude was purified by silica gel chromatography with a 0 to 10% methanol/dichloromethane gradient to afford the title compound (159 mg) as an amber foamy oil. MS (ESI) [m/e, (M)+]=301.8. 1H NMR (400 MHz, chloroform-d) δ ppm 8.22 (s, 1H), 7.35 (d, J=8.08 Hz, 1H), 6.36-6.56 (m, 2H), 4.73 (d, J=5.56 Hz, 2H), 4.37-4.56 (m, 1H), 4.11-4.24 (m, 2H), 3.86 (s, 3H), 3.81 (s, 3H), 2.27-2.31 (m, 2H), 2.04-2.11 (m, 2H).
Reaction SMILES: C(O[CH:4]=[C:5]([C:11]#[N:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.Cl.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][NH2:22])=[CH:17][CH:16]=1.C(Cl)(Cl)Cl>C(O)C>[NH2:12][C:11]1[N:21]([C:18]2[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=2)[N:22]=[CH:4][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: NNc1ccc(Cl)cc1
Reactant: CCOC=C(C#N)C(=O)OCC
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2ccc(Cl)cc2)c1N
Temperature: 25 °C
Yield: 47.8 %

Procedure:
A solution of ethyl ethoxymethylenecyanoacetate (3 g, 17.7 mmol) and 4-chlorophenylhydrazine hydrochloride (3.33 g, 18.6 mmol) in ethanol (60 mL) was refluxed for 2 days, following the procedure described in Schmidt, P. et al. Helv.Chim.Acta, 1959, 349. The reaction mixture was then allowed to cool to room temperature, whereupon a precipitate was formed. Cold CHCl3 was added, the precipitate was filtered and washed with more CHCl3. The filtrate and the washings were evaporated to dryness, precipitated with ether, filtered and dried to give ethyl 5-amino-1-(4-chlorophenyl)-1H-pyrazole-4-carboxylate (2.25 g, 48%) as a white solid: mp 150°-156° C.; 1H NMR (80 MHz, CDCl3) δ (TMS) 7.77 (s, 1H, pyrazole), 7.48 (s, 4H, arom), 4.30 (q, J=7, 2H, OCH2), 1.36 (t, J=7, 3H, OCH2CH3). Analysis calculated for C12H12ClN3O2 : C 54.25; H 4.55; N 15.81. Found: C 54.77; H 4.49; N 15.65.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]([NH:13][C:14]([C:16]1[C:20]2=[N:21][C:22]([C:25]3[C:33]4[C:28](=[CH:29][C:30]([F:34])=[CH:31][CH:32]=4)[N:27]([CH2:35][CH2:36][CH:37]([OH:39])[CH3:38])[N:26]=3)=[CH:23][N:24]=[C:19]2[N:18](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:17]=1)=[O:15])([CH3:12])[CH3:11])(C(C)(C)C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:34][C:30]1[CH:29]=[C:28]2[C:33]([C:25]([C:22]3[N:21]=[C:20]4[C:16]([C:14]([NH:13][C:10]([CH3:11])([CH3:12])[CH2:9][OH:8])=[O:15])=[CH:17][NH:18][C:19]4=[N:24][CH:23]=3)=[N:26][N:27]2[CH2:35][CH2:36][CH:37]([OH:39])[CH3:38])=[CH:32][CH:31]=1
Reactant: CC(O)CCn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)CO[Si](C)(C)C(C)(C)C)cn3C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccc(F)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(O)CCn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(C)CO)c3n2)c2ccc(F)cc21
Reaction time: 1 h
Yield: 45 %

Procedure:
To a stirred solution of N-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-2-(6-fluoro-1-(3-hydroxybutyl)-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide in dichloromethane (2 mL) was added drop-wise trifluoroacetic acid (1 mL) at room temperature and the reaction mixture was stirred for 1 hour. The solvent was removed under reduced pressure. The residue was dissolved in dichloromethane and washed with NaHCO3 (aqueous), The organic layer was concentrated, and the residue was purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; the gradient conditions are: 36% acetonitrile/64% water (0.1% trifluoroacetic acid, v/v) initially, and then proceed to 42% acetonitrile/58% water (0.1% trifluoroacetic acid, v/v) in a linear fashion after just 9 min.) to give 2-(6-fluoro-1-(3-hydroxybutyl)-1H-indazol-3-yl)-N-(1-hydroxy-2-methylpropan-2-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (10 mg, 45% over three steps) as a white solid. LCMS: (M+H)+=441; 1H NMR (300 MHz, CD3OD): δ 9.15 (s, 1H), 8.58 (dd, 1H, J1=9. Hz, J2=5.4 Hz), 8.29 (s, 1H), 7.42 (d, 1H, J=7.8 Hz), 7.10 (d, 1H, J=7.2 Hz), 4.62-4.56 (m, 2H), 3.82 (s, 2H), 3.76 (brs, 1H), 2.19-2.13 (m, 2H), 2.04-1.99 (m, 2H), 1.55 (s, 6H), 1.22 (d, 3H, J=6.3 Hz).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[CH2:3][O:4][P:5]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([O:21][CH3:22])[CH:15]=1)(=[O:12])[O:6][CH2:7][C:8]([F:11])([F:10])[F:9].Cl[C:26]1[N:31]=[C:30]([NH:32][C:33]2[CH:42]=[CH:41][CH:40]=[CH:39][C:34]=2[C:35]([NH:37][CH3:38])=[O:36])[C:29]([C:43]([F:46])([F:45])[F:44])=[CH:28][N:27]=1>>[F:24][C:2]([F:1])([F:23])[CH2:3][O:4][P:5]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:26]2[N:31]=[C:30]([NH:32][C:33]3[CH:42]=[CH:41][CH:40]=[CH:39][C:34]=3[C:35](=[O:36])[NH:37][CH3:38])[C:29]([C:43]([F:46])([F:44])[F:45])=[CH:28][N:27]=2)=[C:16]([O:21][CH3:22])[CH:15]=1)(=[O:12])[O:6][CH2:7][C:8]([F:9])([F:10])[F:11]
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1C(F)(F)F
Reactant: COc1cc(CP(=O)(OCC(F)(F)F)OCC(F)(F)F)ccc1N
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc(CP(=O)(OCC(F)(F)F)OCC(F)(F)F)cc2OC)ncc1C(F)(F)F

Procedure:
The title compound was prepared according to the procedure for Example 102 bis(2,2,2-trifluoroethyl)(4-amino-3-methoxybenzyl)phosphonate (Compound 114A, 38 mg, 0.1 mmol) and 2-(2-chloro-5-(trifluoromethyl)pyrimidin-4-ylamino)-N-methylbenzamide (33 mg, 0.1 mmol). The reaction mixture was concentrated in vacuo and the residue was purified by HPLC to afford the title compound. 1H-NMR (DMSO-d6, 400 MHz): δ=2.73 (s, 3 H), 3.52 (d, J=21.6 Hz, 2 H), 3.73 (s, 3 H), 4.60-4.65 (m, 4 H), 6.81 (d, J=7.6 Hz, 1 H), 6.98 (s, 1 H), 7.05 (t, J=7.6 Hz, 1 H), 7.34 (t, J=7.2 Hz, 1 H), 7.57 (d, J=8.0 Hz, 1 H), 7.65 (dd, J=1.2, 7.6 Hz, 1 H), 8.34 (s, 1 H), 8.38 (s, 1 H), 8.68 (d, J=4.4 Hz, 1 H), 8.71 (s, 1 H), 11.42 (s, 1 H). MS (ES+): m/z 676.05 [MH+]; HPLC: tR=3.69 min (ZQ3, polar—5 min).