Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[C:5](Cl)=[N:6][OH:7])[CH3:2].[F:10][C:11]([F:21])([F:20])[C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[CH2:17])=[CH:14][CH:13]=1.C(N(CC)CC)C>O1CCCC1>[F:10][C:11]([F:20])([F:21])[C:12]1[CH:13]=[CH:14][C:15]([CH:16]2[O:7][N:6]=[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:9])[CH2:17]2)=[CH:18][CH:19]=1
Reactant: C=Cc1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)C(Cl)=NO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C1=NOC(c2ccc(C(F)(F)F)cc2)C1
Reaction time: 16 h
Yield: 88.3 %

Procedure:
To a stirred mixture of 2-chloro-2-hydroxyiminoacetic acid ethyl ester (2.11 g, 13.52 mmol) and 4-trifluoromethystyrene (2.0 g, 11.27 mmol) in anhydrous tetrahydrofuran (15 ml) was added dropwise a solution of triethylamine (3.0 ml, 21.52 mmol) in tetrahydrofuran (5 ml) at room temperature. The resulting reaction mixture was stirred at an atmosphere of nitrogen for 16 hours, filtered, partitioned between water and ethyl acetate (2×50 ml), washed with saturated aqueous sodium bicarbonate, 30% aqueous ammonium chloride, brine, dried over sodium sulfate, and concentrated to afford a pale yellow solid, which was purified by chromatography (2:8 EtOAc:Hexane) to afford ethyl 5-(4-(trifluoromethyl)phenyl)-4,5-dihydroisoxazole-3-carboxylate (2.86 g, M+1=288.2)
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]1[CH:15]=[C:14]([OH:16])[CH:13]=[CH:12][C:9]=1[CH:10]=[O:11].Br[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:24][CH:23]=1>CN(C=O)C.O>[C:25]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:24]=[CH:23][C:22]([O:21][CH2:20][CH2:19][CH2:18][O:16][C:14]2[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[C:8]([F:7])[CH:15]=2)=[CH:27][CH:26]=1
Reactant: BrCCCOc1ccc(-c2ccccc2)cc1
Reactant: O=Cc1ccc(O)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(OCCCOc2ccc(-c3ccccc3)cc2)cc1F
Reaction time: 0.5 h
Yield: 87.6 %

Procedure:
Potassium tert-butoxide (0.217 g, 1.93 mmol) was added to a solution of 2-fluoro-4-hydroxy-benzaldehyde (0.246 g, 1.76 mmol) in anhydrous DMF (5 mL) at 0° C., and the mixture was stirred for 30 min. 4-(3-Bromo-propoxy)-biphenyl (0.564 g, 1.93 mmol, Example 132, Step D) was added, and the mixture stirred at room temperature for 24 hours. The reaction mixture was diluted with water and extracted with EtOAc (5×15 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (silica gel, hexanes/ethyl acetate 4:1) to give 4-[3-(biphenyl-4-yloxy)-propoxy]-2-fluoro-benzaldehyde as a white solid (540 mg, 88%). 1H NMR (200 MHz, CDCl3): δ 10.19 (s, 1H), 7.80 (t, 1H, J=8.4); 7.55–7.48 (m, 4H); 7.42–7.27 (m, 3H); 6.99–6.93 (m, 2H); 6.78 (dd, 1H, J=8.8, 2.6); 6.64 (dd, 1H, J=12.4, 2.2); 4.27–4.15 (m, 4H); 2.30 (qn, 2H, J=5.9)ppm.
Reaction SMILES: [CH3:1]C1C=CC(C2C=NN(C)C=2)=C(C=1)C(OC)=O.Br[C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[N:25]=[C:24]([NH:29][CH2:30][C@@H:31]1[C@H:36]([CH3:37])[CH2:35][CH2:34][CH2:33][N:32]1[C:38]([C:40]1[CH:45]=[C:44]([CH3:46])[CH:43]=[CH:42][C:41]=1[N:47]1[N:51]=[CH:50][CH:49]=[N:48]1)=[O:39])[N:23]=[CH:22]2.CB1OB(C)OB(C)O1>>[CH3:37][C@@H:36]1[CH2:35][CH2:34][CH2:33][N:32]([C:38]([C:40]2[CH:45]=[C:44]([CH3:46])[CH:43]=[CH:42][C:41]=2[N:47]2[N:51]=[CH:50][CH:49]=[N:48]2)=[O:39])[C@@H:31]1[CH2:30][NH:29][C:24]1[N:23]=[CH:22][C:21]2[C:26](=[CH:27][CH:28]=[C:19]([CH3:1])[CH:20]=2)[N:25]=1
Reactant: COC(=O)c1cc(C)ccc1-c1cnn(C)c1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncc3cc(Br)ccc3n2)c1
Agent: CB1OB(C)OB(C)O1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncc3cc(C)ccc3n2)c1

Procedure:
The title compound was prepared following the same general protocol as described for methyl 5-methyl-2-(1-methyl-1H-pyrazol-4-yl)benzoate in Example A1, using ((2S,3R)-2-(((6-bromoquinazolin-2-yl)amino)methyl)-3-methylpiperidin-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone (synthesized in Example A122) and 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane. ESI-MS (m/z): 456 [M+1]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([O:13]C)=[O:12])=[C:8]([CH3:15])[C:7]=2[CH:16]=1)#[N:2].O1CCCC1.O.O.[OH-].[Li+]>CO>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([OH:13])=[O:12])=[C:8]([CH3:15])[C:7]=2[CH:16]=1)#[N:2]
Reactant: COC(=O)c1oc2ccc(C#N)cc2c1C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)oc2ccc(C#N)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.2 %

Procedure:
To a mixture of methyl 5-cyano-3-methyl-1-benzofuran-2-carboxylate (4.20 g) synthesized above, tetrahydrofuran (80 mL), water (20 mL) and methanol (20 mL) was added lithium hydroxide monohydrate (1.64 g), and the mixture was stirred overnight at room temperature, and concentrated under reduced pressure. 1N Hydrochloric acid was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was washed with diisopropyl ether to give the title object compound (3.58 g, 91%) as a pale-brown solid.
Reaction SMILES: N[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[N:30]1([C:36](Cl)=[O:37])[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.[N:39]1C=CC=CC=1>>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH2:20][CH2:21][CH2:22][O:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][CH:31]3[CH2:32][O:33][CH2:34][CH2:35][N:30]3[C:36]([NH2:39])=[O:37])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: NCCCCn1c(CCCOc2ccccc2)nc2c(N)nc3ccccc3c21
Reactant: c1ccncc1
Reactant: O=C(Cl)N1CCOCC1
Product: NC(=O)N1CCOCC1CCCCn1c(CCCOc2ccccc2)nc2c(N)nc3ccccc3c21

Procedure:
Using the general method of Example 143 except that pyridine was used in place of chloroform, 1-(4-aminobutyl)-2-(3-phenoxypropyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.25 g, 3.2 mmol) was reacted with 4-morpholinecarbonyl chloride (0.41 mL, 3.5 mmol) to provide 0.50 g of N-(4-[4-amino-2-(3-phenoxypropyl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl morpholine-4-carboxamide as a light brown solid, m.p. 71.5-72.1° C. Analysis: Calculated for C28H34N6O3. 0.5H2O: %C, 65.73; %H, 6.90; %N, 16.43; Found; %C, 65.43; %H, 6.90; %N, 16.29.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13]([CH:14]=O)=[C:9]3[N:8]=[C:7]([NH:16][C:17]([CH:19]3[CH2:21][CH2:20]3)=[O:18])[CH:6]=2)[CH2:3][CH2:2]1.[NH:22]1[CH2:28][C:26](=[O:27])[NH:25][C:23]1=[O:24].N1CCCCC1>C(O)C>[CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13](/[CH:14]=[C:28]4\[NH:22][C:23](=[O:24])[NH:25][C:26]\4=[O:27])=[C:9]3[N:8]=[C:7]([NH:16][C:17]([CH:19]3[CH2:20][CH2:21]3)=[O:18])[CH:6]=2)[CH2:3][CH2:2]1
Reactant: O=Cc1cnn2c(NC3CC3)cc(NC(=O)C3CC3)nc12
Reactant: O=C1CNC(=O)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1NC(=O)/C(=C/c2cnn3c(NC4CC4)cc(NC(=O)C4CC4)nc23)N1
Temperature: 80 °C
Yield: 14.7 %

Procedure:
To N-(7-(cyclopropylamino)-3-formylpyrazolo[1,5-a]pyrimidin-5-yl) cyclopropanecarboxamide (74 mg, 0.26 mmol) in 1.0 mL ethanol was added hydantoin (26 mg, 0.26 mmol) and piperidine (24 ul). The reaction was heated at 80° C. for two hours. The reaction mixture was cooled to room temperature, concentrated and diluted with MeOH. The product was purified by prep HPLC to yield 14 mg (20% yield) (Z)-N-(7-(cyclopropylamino)-3-((2,5-dioxoimidazolidin-4-ylidene)methyl)pyrazolo[1,5-a]pyrimidin-5-yl)cyclopropanecarboxamide. LCMS (M+1=368)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:28])[C:9]2[CH:27]=[CH:26][C:12]3[N:13]([CH3:25])[C:14]([NH:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=4)=[N:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[NH2:29][C:30]1[CH:31]=[CH:32][C:33]([CH3:40])=[C:34]([S:36]([NH2:39])(=[O:38])=[O:37])[CH:35]=1>>[ClH:1].[CH3:40][C:33]1[CH:32]=[CH:31][C:30]([NH:29][C:2]2[N:7]=[C:6]([N:8]([CH3:28])[C:9]3[CH:27]=[CH:26][C:12]4[N:13]([CH3:25])[C:14]([NH:16][CH2:17][C:18]5[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=5)=[N:15][C:11]=4[CH:10]=3)[CH:5]=[CH:4][N:3]=2)=[CH:35][C:34]=1[S:36]([NH2:39])(=[O:38])=[O:37]
Reactant: Cc1ccc(CNc2nc3cc(N(C)c4ccnc(Cl)n4)ccc3n2C)cc1
Reactant: Cc1ccc(N)cc1S(N)(=O)=O
Product: Cc1ccc(CNc2nc3cc(N(C)c4ccnc(Nc5ccc(C)c(S(N)(=O)=O)c5)n4)ccc3n2C)cc1
Product: Cl

Procedure:
The title compound was prepared following the procedure of example one with N5-(2-Chloro-pyrimidin-4-yl)-1,N5-dimethyl-N2-(4-methyl-benzyl)-1H-benzoimidazole-2,5-diamine (98 mg, 0.25 mmol) and 5-amino-2-methyl-benzenesulfonamide (46 mg, 0.25 mmol) as a white solid (127 mg, 88%). 1H NMR (300 MHz, d6-DMSO+NaHCO3) δ 9.34 (s, 1H), 8.62 (s, 1H), 7.70-7.76 (m, 2H), 7.50 (br s, 1H), 7.09-7.30 (m, 9H), 6.85 (d, J=8.1 Hz, 1H), 5.60 (d, J=5.7 Hz, 1H), 4.55 (d, J=5.4 Hz, 1H), 3.58 (s, 3H), 3.44 (s, 3H), 2.50 (s, 3H), 2.26 (s, 3H). MS (ESI) m/z=543 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=[O:3].[OH:5][C:6]1C=[CH:10][C:9](CC(O)=O)=[CH:8][CH:7]=1.[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1.P(Cl)(Cl)(Cl)(Cl)Cl>C1(C)C=C(C)C=C(C)C=1.C(C(CC)=O)C>[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH:21][C:6]([CH2:7][C:8]2[CH:1]=[C:2]([OH:3])[CH:4]=[CH:10][CH:9]=2)=[O:5])=[CH:19][CH:18]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CC(C)=O
Reactant: O=C(O)Cc1ccc(O)cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1cc(C)cc(C)c1
Solvent: CCC(=O)CC
Product: O=C(Cc1cccc(O)c1)Nc1ccc(Cl)cc1
Reaction time: 2 h
Yield: 90 %

Procedure:
FIG. 6b presents a similar reaction scheme to FIG. 6a, except that 3- rather than 4-hydroxyphenylacetic acid (HPAA) is used as the precursor material so that the final compound has a meta rather than a para substitution. In addition, rather than reacting with acetone (dimethyl ketone) a diethyl ketone is used to position ethyl, rather than methyl, moieties in the group substituted on one of the phenyl rings. By example, 1.5 g (10 mmol) 3-HPAA and 2.6 g (20 mmol) 4-chloroaniline in 20 ml of mesitylene was heated to reflux. Then 0.33 g (2.55 mmol) PCl5 was then slowly added to the above refluxing solution and the refluxing was continued for two hours. The reaction mixture was then cooled and then worked up as described above to yield 2.2 g (90% yield) of 3-[((4-chloroanilino)carbonyl)methyl]phenol. As described above, chloroform (0.8 ml) was added to a stirred and ice-cooled mixture of 1.23 grams of 3-[((4-chloroanilino)carbonyl)methyl]phenol and 1.6 g NaOH in 15 ml of acetone. The reaction mixture was allowed to warm to room temperature and stirring continued for an additional 10 hours. The usual work-up yielded 2-[3-(((4-chloroanilino)carbonyl)methyl)]phenoxy!-2-methylpropionic acid as a low temperature melting sticky solid (C,H,Cl,N analysis yielded (C18H18ClNO4); NMR δPPM: 1.42 (6H, s, CH3), 3.61 (2H, s, benzylic CH2), and 6.6-7.75 (8H, m, aromatic H)). However, rather than using acetone as the reaction solvent, diethylketone can be used in the same manner as described above to yield the butanoic acid (as opposed to propanoic acid) structure shown in FIG. 6b.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:28])([F:27])[O:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[O:21][C:20](=[O:23])[C:19]([C:24]([OH:26])=O)=[CH:18]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:53][C:54]1[CH:55]=[C:56]([C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=2[NH:66][C:67](=[O:69])[CH3:68])[CH:57]=[CH:58][CH:59]=1>CN(C=O)C>[C:67]([NH:66][C:61]1[CH:62]=[CH:63][CH:64]=[CH:65][C:60]=1[C:56]1[CH:57]=[CH:58][CH:59]=[C:54]([NH:53][C:24]([C:19]2[C:20](=[O:23])[O:21][C:22]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][C:13]=3[O:12][C:11]([F:10])([F:28])[F:27])=[O:26])[CH:55]=1)(=[O:69])[CH3:68]
Reactant: CC(=O)Nc1ccccc1-c1cccc(N)c1
Reactant: O=C(O)c1cc2cccc(OC(F)(F)F)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccccc1-c1cccc(NC(=O)c2cc3cccc(OC(F)(F)F)c3oc2=O)c1
Temperature: 25 °C
Yield: 25.1 %

Procedure:
DIEA (0.013 mL, 0.073 mmol) was added to 8-trifluoromethoxy-3-carboxy-coumarin (0.018 g, 0.066 mmol) and HATU (0.028 g, 0.073 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, N-(3′-Amino-biphenyl-2-yl)-acetamide (0.015 g, 0.066 mmol) was added and allowed to react overnight and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.008 g of product in 26% yield: LCMS (ESI) m/z 483 (MH+).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)=[C:6]([Cl:13])[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[S:20]1[CH:24]=[C:23]([C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)[N:22]=[N:21]1>CN(C=O)C>[Cl:13][C:6]1[C:7]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)=[C:2]([O:31][C:28]2[CH:27]=[CH:26][C:25]([C:23]3[N:22]=[N:21][S:20][CH:24]=3)=[CH:30][CH:29]=2)[N:3]=[CH:4][N:5]=1
Reactant: Oc1ccc(-c2csnn2)cc1
Reactant: Clc1ncnc(Cl)c1C1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1ncnc(Oc2ccc(-c3csnn3)cc2)c1C1OCCO1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 4,6-dichloro-5-[1,3]dioxolan-2-yl-pyrimidine (100.0 mg, 0.45 mmol) and added Potassium Carbonate (80.62 mg, 0.45 mmol) in DMF (5 mL) cooled to 0° C. was added a solution of 4-[1,2,3]-thiadiazol-4-yl-phenol (DMF) drop wise. The resulting mixture was stirred at room temperature for 30 minutes to give 4-chloro-5-[1,3]dioxolan-2-yl-6-(4-[1,2,3]thiadiazol-4-yl-phenoxy)-pyrimidine. LCMS (ESI) for C15H11ClN4O3S: m/z 362.9 (M+H+, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([CH2:11][C:12](=O)[CH3:13])[N:4]=1.[C:15]1([NH:21]N)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(OCC)(=O)C.O>C1(C)C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:21][C:12]=2[CH3:13])[N:4]=1
Reactant: COc1cc(OC)nc(CC(C)=O)n1
Reactant: NNc1ccccc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc(OC)nc(-c2c(C)[nH]c3ccccc23)n1
Yield: 62 %

Procedure:
In 10 ml of toluene were dissolved 1.61 g (8.2 m moles) of 1-(4,6-dimethoxypyrimidine-2-yl)-2-propanone and 1.08 g (10 m moles) of phenylhydrazine. Thereto was added 1.36 g (10 m moles) of zinc chloride, followed by refluxing for 1 hour. The reaction mixture was allowed to cool, and ethyl acetate and water were added to dissolve the whole reaction mixture. The oily layer was washed with water, separated and dried over Glauber's salt. The resulting oily layer was concentrated under reduced pressure to obtain an orange solid. The solid was recrystallized from methanol to obtain 1.37 g (5.1 m moles) of 3-(4,6-dimethoxypyrimidine-2-yl)-2-methylindole. Yield: 62% Melting point: 182 to 184° C.
Reaction SMILES: [C:1](OC)([O:5][CH3:6])([O:3]C)[CH3:2].[CH3:9][C:10]([CH3:14])=[CH:11][CH2:12]O>P(=O)(O)(O)O.CO>[CH3:9][C:10]([CH3:14])([CH:11]=[CH2:12])[CH2:2][C:1]([O:5][CH3:6])=[O:3]
Reactant: CC(C)=CCO
Reactant: COC(C)(OC)OC
Agent: O=P(O)(O)O
Solvent: CO
Product: C=CC(C)(C)CC(=O)OC
Temperature: 110 °C
Yield: 63 %

Procedure:
A mixture of trimethyl orthoacetate (120 g; 1 mole) and orthophosphoric acid (1.5 g; 0.015 mole) was placed in a flask equipped with a stirrer and a 10 cm fractionating column packed with Fenske rings and the mixture was heated, with stirring, to a temperature of 110° C. 3-Methylbut-2-enol (21.5 g; 0.25 mole) was added to the hot reaction mixture over a period of 4 minutes and the methanol formed was collected by distillation over a period of 30 minutes. The excess trimethyl orthoacetate was then distilled from the reaction mixture over a period of 90 minutes. The product was then distilled to give methyl 3,3-dimethylpent-4-enoate (22.4 g; 63.2%), bp 70° C. at 60 mm Hg.
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[Mg].II.[NH2:11][C:12]1[N:16]([C:17]2[CH:18]=[C:19]([CH:26]=[CH:27][C:28]=2[CH3:29])[C:20]([NH:22][CH:23]2[CH2:25][CH2:24]2)=[O:21])[CH:15]=[N:14][C:13]=1[C:30]#N.C1C[O:35]CC1>>[NH2:11][C:12]1[N:16]([C:17]2[CH:18]=[C:19]([CH:26]=[CH:27][C:28]=2[CH3:29])[C:20]([NH:22][CH:23]2[CH2:25][CH2:24]2)=[O:21])[CH:15]=[N:14][C:13]=1[C:30]([CH:2]1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1)=[O:35]
Reactant: C1CCOC1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc(C#N)c1N
Reactant: BrC1CCOCC1
Agent: II
Agent: [Mg]
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc(C(=O)C2CCOCC2)c1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30 %

Procedure:
A solution of 4-bromo-tetrahydro-pyran (0.82 g, 5 mmol) in dry THF (10 mL) was added dropwise to the suspension of magnesium (132 mg, 5.5 mmol) and iodine (25 mg) in dry THF (20 mL) at 50° C. under N2. The mixture was stirred for 30 min after addition at 50° C., then cooled to room temperature. Then a THF (10 mL) solution of 3-(5-amino-4-cyano-imidazol-1-yl)-N-cyclopropyl-4-methyl-benzamide (90 mg, 0.32 mmol) was added to the reaction mixture and it was stirred at room temperature for 3 h then quenched with HCl (2N) and stirred at room temperature overnight. The pH of the solution was adjusted pH ˜8 with saturated aqueous K2CO3 was and it was extracted with EtOAc. The organic layer was washed by water and brine, dried over Na2SO4, and concentrated. The crude product was purified by column chromatography on silical gel (EtOAc˜EtOAc:MeOH:Et3N=100:10:1), and the product was obtained as a beige solid (35 mg, 30%). HPLC (4 minute gradient) tR=3.05 min; MS m/z 369.18 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([NH:9][C@@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]2[NH:16]C(=O)OC(C)(C)C)=[CH:5][C:4]=1[NH:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[C:27]([CH3:33])[N:26]=1)#[N:2].FC(F)(F)C(O)=O>ClCCl>[NH2:16][C@H:11]1[CH2:12][CH2:13][CH2:14][CH2:15][C@H:10]1[NH:9][C:6]1[CH:5]=[C:4]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[C:27]([CH3:33])[N:26]=2)[C:3]([C:1]#[N:2])=[N:8][CH:7]=1
Reactant: Cc1nc(Nc2cc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)cnc2C#N)ccc1C#N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc(Nc2cc(N[C@@H]3CCCC[C@@H]3N)cnc2C#N)ccc1C#N
Reaction time: 16 h

Procedure:
To a solution of tert-butyl [(1S,2R)-2-({6-cyano-5-[(5-cyano-6-methylpyridin-2-yl)amino]pyridin-3-yl}amino)cyclohexyl]carbamate (58 mg, 0.13 mmol) in dichloromethane (1.3 mL) was added trifluoroacetic acid (1.0 mL, 13 mmol) at room temperature. After 16 hours, the reaction mixture was concentrated under reduced pressure to afford 5-{[(1R,2S)-2-aminocyclohexyl]amino}-3-[(5-cyano-6-methylpyridin-2-yl)amino]pyridine-2-carbonitrile. The material was used in the next step without further purification. MS ESI calc'd for C19H22N7 [M+H]+ 348. found 348.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][C:8](=[O:26])[C:9]1[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:10]=1[O:18][C:19]1[CH:20]=[C:21]([Cl:25])[CH:22]=[N:23][CH:24]=1>CO.[Ni]>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][C:8](=[O:26])[C:9]1[CH:14]=[C:13]([NH2:15])[CH:12]=[CH:11][C:10]=1[O:18][C:19]1[CH:20]=[C:21]([Cl:25])[CH:22]=[N:23][CH:24]=1
Reactant: O=C(NCc1ccco1)c1cc([N+](=O)[O-])ccc1Oc1cncc(Cl)c1
Agent: [Ni]
Solvent: CO
Product: Nc1ccc(Oc2cncc(Cl)c2)c(C(=O)NCc2ccco2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.6 %

Procedure:
To a 0.08M solution of N-(2-furanylmethyl) 5-nitro-2-(3-chloro-5-pyridyloxy)benzamide (3.7 g, 10 mmol, prepared in Example 35.2) in MeOH was added a 50% aqueous slurry of Raney nickel (˜6 mL). Hydrogen was then bubbled through the resulting solution for one minute. The resulting mixture was stirred at ambient temperature under one atmosphere of hydrogen for 16 hr. The crude reaction mixture was filtered through a pad of Celite® and the filter cake was washed 3× with MEOH. NOTE: Raney nickel is pyrophoric and should always be kept wet with solvent during the filtration. The Raney nickel can be quenched by adding 6M aqueous HCl. The filtrate was concentrated in the presence of benzene to azeotropically remove water. The residue was purified by chromatography (1-3% MeOH in CH2Cl2) to yield 2.6 g (76%) of N-(2-furanylmethyl) 5-amino-2-(3chloro-5-pyridyloxy)benzamide as a pale brown solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([N:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][NH:22][CH3:23])[CH2:16][CH2:15]2)=[N:10][CH:11]=[CH:12][N:13]=1.C(N(CC)CC)C.[CH3:31][N:32]1[CH:36]=[C:35]([S:37]([Cl:40])(=[O:39])=[O:38])[N:34]=[C:33]1[CH3:41]>ClCCl>[ClH:40].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([N:14]2[CH2:15][CH2:16][N:17]([CH2:20][CH2:21][N:22]([CH3:23])[S:37]([C:35]3[N:34]=[C:33]([CH3:41])[N:32]([CH3:31])[CH:36]=3)(=[O:39])=[O:38])[CH2:18][CH2:19]2)=[N:10][CH:11]=[CH:12][N:13]=1
Reactant: Cc1nc(S(=O)(=O)Cl)cn1C
Reactant: CNCCN1CCN(c2nccnc2-c2ccccc2F)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc(S(=O)(=O)N(C)CCN2CCN(c3nccnc3-c3ccccc3F)CC2)cn1C
Product: Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 73.3 %

Procedure:
Dissolve {2-[3′-(2-fluoro-phenyl)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-yl]-ethyl}-methyl-amine (0.059 g, 0.190 mmol) in dichloromethane (5 mL). Add triethylamine (29 μL, 0.209 mmol) followed by 1,2-dimethyl-1H-imidazole-4-sulfonyl chloride (0.041 g, 0.209 mmol) and stir at ambient temperature for 72 hr. Concentrate under reduced pressure and purify (silica gel chromatography, eluting with 20:80 to 0:100 hexanes:ethyl acetate, then 10:90 methanol:ethyl acetate, then 20:80 methanol:ethyl acetate) to give the free base of the title compound (71 mg, 79%).
Reaction SMILES: Br[C:2]1[C:3]([O:18][CH2:19][C:20]2[N:21]([CH3:25])[N:22]=[CH:23][N:24]=2)=[N:4][N:5]2[C:10]=1[CH:9]=[N:8][N:7]=[C:6]2[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17].[F:26][C:27]([F:38])([F:37])[C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>O1CCOCC1>[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:6]1[N:5]2[N:4]=[C:3]([O:18][CH2:19][C:20]3[N:21]([CH3:25])[N:22]=[CH:23][N:24]=3)[C:2]([C:32]3[CH:31]=[CH:30][CH:29]=[C:28]([C:27]([F:38])([F:37])[F:26])[CH:33]=3)=[C:10]2[CH:9]=[N:8][N:7]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: Cn1ncnc1COc1nn2c(-c3ccccc3F)nncc2c1Br
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Cn1ncnc1COc1nn2c(-c3ccccc3F)nncc2c1-c1cccc(C(F)(F)F)c1
Temperature: 90 °C
Yield: 80.5 %

Procedure:
A mixture of 3-bromo-7-(2-fluorophenyl)-2-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)pyrazolo[1,5-d][1,2,4]triazine (60.2 mg, 0.149 mmol), 3-trifluoromethylbenzeneboronic acid (42.3 mg, 0.223 mmol) and cesium carbonate (96.9 mg, 0.297 mmol) in anhydrous 1,4-dioxane (5 ml) was degassed using three freeze-pump-thaw cycles. Tris(dibenzylideneacetone)palladium(0) (13.8 mg, 0.0151 mmol) and a 0.1 M solution of tri-tert-butylphosphine in 1,4-dioxane (0.357 ml, 0.357 mmol) was added, and the mixture was further degassed with two more freeze-pump-thaw cycles before heating at 90° C. under nitrogen for 17 h. The mixture was filtered through glass fibre paper, washing well with ethyl acetate (25 ml). The filtrate was washed with saturated aqueous NaCl (10 ml), and the aqueous layer was further extracted with ethyl acetate (25 ml). The combined organic extracts were dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica gel, 2% MeOH/CH2Cl2) to give 56.3 mg (81%) of the title compound as a yellow solid: mp=152-155° C. (EtOAc-isohexane); 1H NMR (360 MHz, CDCl3) δ 3.79 (3H, s), 5.58 (2H, s), 7.31 (1H, m), 7.41 (1H, td, J=7.6 and 0.9 Hz), 7.63-7.68 (3H, m), 7.80 (1H, m), 7.85-7.86 (2H, m), 7.93 (1H, s), 9.44 (1H, s); MS (ES+) m/e 470 [MH]+. Anal. Found C, 56.22; H, 3.35; N, 20.59%. C22H15F4N7O requires C, 56.29; H, 3.22; N, 20.89%.