Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClCCl.CC1(C)C(C)(C)OB([C:12]2[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][C:20]#[N:21])=[N:16][CH:17]=2)O1.[Cl:23][CH:24]([Cl:40])[C:25]([NH:27][C@H:28]([CH2:38][F:39])[C@H:29]([OH:37])[C:30]1[CH:35]=[CH:34][C:33](I)=[CH:32][CH:31]=1)=[O:26].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Cl:23][CH:24]([Cl:40])[C:25]([NH:27][C@H:28]([CH2:38][F:39])[C@@H:29]([C:30]1[CH:31]=[CH:32][C:33]([C:12]2[CH:17]=[N:16][C:15]([CH2:18][CH2:19][C:20]#[N:21])=[CH:14][CH:13]=2)=[CH:34][CH:35]=1)[OH:37])=[O:26]
Reactant: CC1(C)OB(c2ccc(CCC#N)nc2)OC1(C)C
Reactant: O=C(N[C@H](CF)[C@H](O)c1ccc(I)cc1)C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#CCCc1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)cn1
Temperature: 60 °C

Procedure:
[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II),complex with dichloromethane (1:1) (30.2 mg, 0.037 mmol) is added to a degassed mixture of the product of step 1, Example 21 along with 2,2-dichloro-N-[(1S,2R)-1-(fluoromethyl)-2-hydroxy-2-(4-iodophenyl)ethyl]acetamide (150 mg, 0.369 mmol), and cesium carbonate (482 mg, 1.48 mmol) in N,N-dimethylformamide (2.76 mL) at room temperature. The reaction mixture is heated at 60° C. for 4 hours. After cooling to room temperature the reaction mixture is concentrated under high vacuum, and the residue slurried in ethyl acetate. The slurry is filtered through solka floc washing the cake with ethyl acetate. The combined filtrates were concentrated and the brown residue purified by chromatography on silica gel eluting with a gradient of 50-80% ethyl acetate in hexanes to afford the title compound (72.5 mg): 1H NMR (300 MHz, DMSO-d6) δ 2.92-2.97 (m, 2H), 3.08-3.13 (m, 2H), 4.23-4.28 (m, 1.5 H), 4.41-4.46 (m, 0.5H), 4.54-4.58 (m, 0.5H), 4.69-4.74 (m, 0.5H), 4.89-4.92 (m, 1H), 5.98 (d, 1H), 6.53 (s, 1H), 7.42-7.49 (m, 3H), 7.79 (d, 2H), 8.03-8.06 (dd, 1H), 8.62 (d, 1H), 8.83-8.84 (m, 1H). MS (ESI+) m/z of 410.0/412.0 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:21]([O-])=O)=[CH:5][C:6]2[CH:12]([CH3:13])[CH2:11][N:10]([C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])[CH2:9][CH2:8][C:7]=2[N:20]=1>CCO.[Pd]>[CH3:1][O:2][C:3]1[C:4]([NH2:21])=[CH:5][C:6]2[CH:12]([CH3:13])[CH2:11][N:10]([C:14](=[O:19])[C:15]([F:18])([F:16])[F:17])[CH2:9][CH2:8][C:7]=2[N:20]=1
Reactant: COc1nc2c(cc1[N+](=O)[O-])C(C)CN(C(=O)C(F)(F)F)CC2
Agent: [Pd]
Solvent: CCO
Product: COc1nc2c(cc1N)C(C)CN(C(=O)C(F)(F)F)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.2 %

Procedure:
The nitro group of 2-methoxy-5-methyl-3-nitro-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine (40.0 mg, 120 μmol) of was reduced with 10% Pd/C in EtOH (5 ml) under H2 (1 attn). After 2 h of stirring at room temperature, the reaction mixture was filtered through a pad of Celite and rinsed with MeOH. 2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-amine (35 mg, 96%) was obtained after removal of solvent. MS (ESI) m/z 304. Removal of the trifluoroacetyl group was carried out as described above and gave 21.0 mg (88%) of 2-methoxy-5-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-amine. 1H-NMR (CDCl3) δ 6.72 (s, 1H), 3.93 (s, 3H), 3.20-2.80 (m, 6H), 2.74 (dd, 1H), 2.76 (1H), 1.28 (d, 3 H) ppm.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=1[C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:11].Cl[C:26]1[N:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=1>>[F:18][C:14]1[C:13]([C:19]2[N:20]=[CH:21][CH:22]=[CH:23][N:24]=2)=[C:12]([C:10]([N:4]2[CH2:5][CH2:6][CH2:7][C@@H:8]([CH3:9])[C@H:3]2[CH2:2][NH:1][C:26]2[N:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=2)=[O:11])[CH:17]=[CH:16][CH:15]=1
Reactant: C[C@@H]1CCCN(C(=O)c2cccc(F)c2-c2ncccn2)[C@@H]1CN
Reactant: Clc1cnc(Cl)nc1
Product: C[C@@H]1CCCN(C(=O)c2cccc(F)c2-c2ncccn2)[C@@H]1CNc1ncc(Cl)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(3-fluoro-2-(pyrimidin-2-yl)phenyl)methanone and 2,5-dichloropyrimidine. ESI-MS (m/z): 441 [M+1]+.
Reaction SMILES: C(O)C.C(O)(=O)C.C[O:9][C:10](=O)[CH:11]([CH3:27])[CH2:12][N:13]([C:19]1[C:24]([NH2:25])=[CH:23][N:22]=[C:21]([Cl:26])[N:20]=1)[CH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>CCOCC>[Cl:26][C:21]1[N:22]=[CH:23][C:24]2[NH:25][C:10](=[O:9])[CH:11]([CH3:27])[CH2:12][N:13]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[C:19]=2[N:20]=1
Reactant: COC(=O)C(C)CN(c1nc(Cl)ncc1N)C1CCCC1
Solvent: CCO
Solvent: CCOCC
Solvent: CC(=O)O
Product: CC1CN(C2CCCC2)c2nc(Cl)ncc2NC1=O
Yield: 65.5 %

Procedure:
A mixture of 1500 mL of ethanol, 25 mL of acetic acid and 35.2 g of the (rac)-3-[(5-amino-2-chloro-pyrimidin-4-yl)-cyclopentyl-amino]-2-methyl-propanoic acid methyl ester (V-1) prepared in the previous step was heated at reflux overnight, and then concentrated under reduced pressure. The residue was taken up in dichloromethane and washed successively with 10% sodium bicarbonate solution, and then water and dried over anhydrous sodium sulfate. The mixture was filtered and then concentrated under reduced pressure to give 31 g of the crude product. Trituration of the residue with ether, provided 20.7 g of (rac)-2-chloro-9-cyclopentyl-7-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[C:9]1([C:15]#[CH:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O1CCCC1>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I.C(N(CC)CC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:16]#[C:15][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: C#Cc1ccccc1
Reactant: Brc1ccc(I)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Brc1ccc(C#Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 58.3 %

Procedure:
28.3 g (0.10 mol) of p-bromoiodobenzene, 10.2 g (0.10 mol) of phenylacetylene, 701 mg (1 mmol) of bis(triphenylphosphine)palladium(II)dichloride, and 190 mg (1 mmol) of copper (I) iodide were placed in a 1000-mL three-neck flask, and nitrogen substitution was carried out. Then, 350 mL of tetrahydrofuran and 18 mL of triethylamine were added thereto, and the mixture was stirred at room temperature for 12 hours. After the reaction, the reaction mixture was washed with a 3% hydrochloric acid aqueous solution, and the aqueous phase was extracted with ethyl acetate. The extracted solution combined with the organic phase was washed with brine and dried with magnesium sulfate. The mixture was filtered through celite, florisil, and alumina, and a solid obtained by the concentration of the filtrate was recrystallized with hexane to give 15 g of a solid that was the target substrate in the yield of 58%.
Reaction SMILES: Cl.[NH2:2][C:3]([CH3:8])([CH3:7])[CH:4]=[N:5][OH:6].ClCl.[OH-].[Na+].Cl.[SH:14][CH2:15][C:16](OCC)=[O:17]>O>[N:5](=[C:4]1[C:3]([CH3:8])([CH3:7])[NH:2][C:16](=[O:17])[CH2:15][S:14]1)[OH:6]
Reactant: CC(C)(N)C=NO
Reactant: CCOC(=O)CS
Agent: Cl
Agent: ClCl
Agent: [Na+]
Solvent: O
Product: CC1(C)NC(=O)CSC1=NO
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 13.6 %

Procedure:
A solution of 41 g α-aminoisobutyraldoxime hydrochloride and 150 ml. of water was charged into a stirred flask and cooled to 0° C. Chlorine was added to the solution at 0° C until 22 g. had been taken up. The reaction mixture was stirred at 0° C for 30 minutes after the chlorine addition. Sodium hydroxide (6 g in 40 ml water) was added with stirring to neutralize the hydrochloric acid, after which a solution of 36 g of ethyl mercaptoacetate and 12 g of sodium hydroxide in 40 ml of water was added rapidly at 5° to 10° C. The mixture was warmed to 25° C and stirred overnight. The solid product was filtered, washed with water then dried at room temperature, to yield 7 g of 2-oximino-3,3-dimethyltetrahydro-1,4-thiazin-5-one, m.p. 234°-236° C. An nmr spectrum and m.p. comparison showed the product to be identical with that from Example II.
Reaction SMILES: C(O)(=O)C.[CH:5]([NH2:7])=[NH:6].[F:8][C:9]1[CH:26]=[CH:25][C:12]([C:13]([NH:15][CH:16]([C:21](OC)=[O:22])[C:17](OC)=[O:18])=[O:14])=[CH:11][CH:10]=1.[Na]>C(O)C>[OH:22][C:21]1[C:16]([NH:15][C:13](=[O:14])[C:12]2[CH:25]=[CH:26][C:9]([F:8])=[CH:10][CH:11]=2)=[C:17]([OH:18])[N:7]=[CH:5][N:6]=1
Reactant: COC(=O)C(NC(=O)c1ccc(F)cc1)C(=O)OC
Reactant: N=CN
Agent: [Na]
Solvent: CCO
Solvent: CC(=O)O
Product: O=C(Nc1c(O)ncnc1O)c1ccc(F)cc1
Yield: 64.9 %

Procedure:
Formamidine acetate (0.46 g, 4.46 mmol) and dimethyl 2-(4-fluorobenzamido)malonate (1.0 g, 3.71 mmol) were added to a solution of sodium (0.17 g, 7.43 mmol) in ethanol (37 ml). The reaction mixture was refluxed for 3 hours. After cooling down, the precipitate was filtered off and washed with ethanol. The product was dissolved in a minimal volume of water and acidified to pH 4-5 with 5M HCl. The precipitate was collected, washed with water and dried to yield the title compound as a white solid (0.60 g, 64%).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]([O:33][CH2:34][C:35](N(OC)C)=[O:36])[CH2:11][N:12]1[C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]#[N:28])[CH:22]=2)=[C:19]2[C:14]([N:15]([CH3:32])[C:16](=[O:31])[N:17]([CH3:30])[C:18]2=[O:29])=[CH:13]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:42]1[S:43][CH:44]=[C:45]([Cl:47])[N:46]=1>>[Si:1]([O:8][CH2:9][CH:10]([O:33][CH2:34][C:35]([C:42]1[S:43][CH:44]=[C:45]([Cl:47])[N:46]=1)=[O:36])[CH2:11][N:12]1[C:20]([C:21]2[CH:22]=[C:23]([CH:24]=[CH:25][CH:26]=2)[C:27]#[N:28])=[C:19]2[C:14]([N:15]([CH3:32])[C:16](=[O:31])[N:17]([CH3:30])[C:18]2=[O:29])=[CH:13]1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: Clc1csc(Br)n1
Reactant: CON(C)C(=O)COC(CO[Si](C)(C)C(C)(C)C)Cn1cc2c(c1-c1cccc(C#N)c1)c(=O)n(C)c(=O)n2C
Product: Cn1c(=O)c2c(-c3cccc(C#N)c3)n(CC(CO[Si](C)(C)C(C)(C)C)OCC(=O)c3nc(Cl)cs3)cc2n(C)c1=O

Procedure:
The title compound was prepared from 2-((1-((tert-butyldimethylsilyl)oxy)-3-(5-(3-cyanophenyl)-1,3-dimethyl-2,4-dioxo-3,4-dihydro-1H-pyrrolo[3,4-d]pyrimidin-6(2H)-yl)propan-2-yl)oxy)-N-methoxy-N-methylacetamide and 2-bromo-4-chlorothiazole analogously to Example 13, step 3;
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH3:7])[CH:3]1[O:5][CH2:4]1.[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH2:15]>>[CH2:14]([NH:15][CH2:4][CH:3]([OH:5])[CH:2]([CH3:1])[CH2:6][CH3:7])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:8][CH2:4][CH:3]([OH:5])[CH:2]([CH3:1])[CH2:6][CH3:7]
Reactant: CCC(C)C1CO1
Reactant: NCCCCCCN
Product: CCC(C)C(O)CNCCCCCCNCC(O)C(C)CC

Procedure:
Condensation of 3-methyl-1-pentene oxide and hexamethylenediamine affords N,N'-(1,6-hexylene)-bis[2-hydroxy-3-methylpentylamine] (I: R = CH3CH2 (CH3)C, R' = H, X = (CH2)6, Z = H).
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[C:12]3[CH:13]=[CH:14][C:15]([OH:17])=[CH:16][C:11]=3[N:10]=[CH:9]2)C=CC=CC=1.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)N2C3C=C(O)C=CC=3N=C2)C=CC=CC=1.F[C:60]1[CH:67]=[CH:66][C:63]([CH:64]=[O:65])=[CH:62][C:61]=1[O:68][CH3:69].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.O>[NH:8]1[C:12]2[CH:13]=[CH:14][C:15]([O:17][C:60]3[CH:67]=[CH:66][C:63]([CH:64]=[O:65])=[CH:62][C:61]=3[O:68][CH3:69])=[CH:16][C:11]=2[N:10]=[CH:9]1
Reactant: Oc1ccc2c(c1)ncn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1cc(C=O)ccc1F
Agent: O=C([O-])[O-]
Agent: Oc1ccc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2c1
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C=O)ccc1Oc1ccc2[nH]cnc2c1
Reaction time: 96 h

Procedure:
A mixture of 1-(triphenylmethyl)-1H-benzimidazol-5-ol and 1-(triphenylmethyl)-1H-benzimidazol-6-ol (750 mg, 2.0 mmol), 4-fluoro-3-(methyloxy)benzaldehyde (461 mg, 3.0 mmol) and cesium carbonate (972 mg, 3.0 mmol) were heated in dimethylformamide at 80 degrees centigrade for 2 hours. The reaction was diluted with water and extracted twice with ethyl acetate. The organic layers were washed with brine, dried over MgSO4, concentrated and dried under vacuum for approximately 18 hours. The residue was dissolved in 15 mL of tetrahydrofuran and stirred with 5 mL or 4N HCl in dioxane for 4 days. The reaction was concentrated and purified by preparative HPLC. Pure fractions were diluted with 1N NaOH to make basic and then extracted twice with ethyl acetate. The organic layers were dried over MgSO4 and concentrated to give 4-(1H-benzimidazol-5-yloxy)-3-(methyloxy)benzaldehyde. (M+1) 269.0, 1.34 min (LC/MS method B)
Reaction SMILES: Cl.[F:2][C:3]([P:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])([F:11])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1.[N:20]1([C:29]2[O:30][C:31]([CH2:41][CH2:42][C:43](O)=[O:44])=[C:32]([C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=3)[N:33]=2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[CH:21]1.ON1C2N=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.Cl>CN(C)C=O>[N:20]1([C:29]2[O:30][C:31]([CH2:41][CH2:42][C:43]([NH:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([P:12]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])=[O:19])([F:2])[F:11])=[CH:5][CH:6]=3)=[O:44])=[C:32]([C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=3)[N:33]=2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[CH:21]1
Reactant: CCOP(=O)(OCC)C(F)(F)c1ccc(N)cc1
Reactant: O=C(O)CCc1oc(-n2cnc3ccccc32)nc1-c1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Product: CCOP(=O)(OCC)C(F)(F)c1ccc(NC(=O)CCc2oc(-n3cnc4ccccc43)nc2-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.2 %

Procedure:
A mixture of the obtained hydrochloride (100 mg), 3-{3-[2-(1H-benzoimidazol-1-yl)-4-(4-chlorophenyl)-5-oxazolyl]propionic acid (30 mg), 1-hydroxy-7-aza-1H-1,2,3-benzotriazole (22 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (29 mg) and N,N-dimethylformamide (0.5 ml) was stirred overnight at room temperature. To the reaction mixture was added 0.1N aqueous hydrochloric acid solution (1 ml) and the reaction mixture was extracted with ethyl acetate (2 ml). The organic layer was concentrated, introduced into preparative HPLC and purified to give 3-[2-(1H-benzoimidazol-1-yl)-4-(4-chlorophenyl)-5-oxazolyl]-N-{4-[(diethylphosphono)(difluoro)methyl]phenyl}propionamide (51.4 mg, yield 50%). Recrystallization from ethyl acetate-isopropyl ether gave yellow prism crystals. melting point: 155–156° C.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:30])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH:25]5[CH2:29][NH:28][CH2:27][CH2:26]5)[CH:20]=4)[N:15]=[CH:14]3)[CH:7]=2)[CH2:3][CH2:2]1.IC.[C:33](=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O.C(OCC)(=O)C>[CH:1]1([NH:4][C:5](=[O:30])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH:25]5[CH2:26][CH2:27][N:28]([CH3:33])[CH2:29]5)[CH:20]=4)[N:15]=[CH:14]3)[CH:7]=2)[CH2:2][CH2:3]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(OC3CCNC3)cc2c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(OC3CCN(C)C3)cc2c1=O
Yield: 39.7 %

Procedure:
N-Cyclopropyl-4-methyl-3-[4-oxo-6-(pyrrolidin-4-yloxy)quinazolin-3(4H)-yl]benzamide (0.18 g), iodomethane (0.031 ml) and potassium carbonate (0.246 g) were stirred in DMA (1 ml) for 18 hours at room temperature. The reaction mixture was diluted with ethyl acetate and the organic phase was washed with water and concentrated. The residue was dissolved in ethyl acetate (2 ml) and triturated with iso-hexane and the resulting solid was filtered and dried under vacuum at 40° C. There was thus obtained the title compound (0.074 g); NMR Spectrum: (DMSOd6) 0.55 (m, 2H), 0.67 (m, 2H), 1.80 (m, 1H), 2.08 (m, 4H), 2.30 (m, 4H), 2.80 (m, 4H), 5.06 (s, 1H), 7.49 (m, 3H), 7.71 (d, 1H), 7.81 (s, 1H), 7.89 (d, 1H), 8.16 (s, 1H), 8.41 (s, 1H); Mass Spectrum: M+H+ 419.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13](=O)[CH3:14])[CH:5]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1.[CH3:16][C:17]([S@:20]([NH2:22])=[O:21])([CH3:19])[CH3:18]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]([NH:22][S@@:20]([C:17]([CH3:19])([CH3:18])[CH3:16])=[O:21])[CH3:14])[CH:5]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1cc(Cl)cc(OC(F)(F)F)c1
Product: CC(N[S@](=O)C(C)(C)C)c1cc(Cl)cc(OC(F)(F)F)c1
Yield: 48 %

Procedure:
The title compound is prepared in 48% yield (416 mg, a white solid) from 1-(3-chloro-5-(trifluoromethoxy)phenyl)ethanone (600 mg, 2.51 mmol, Step-2) and (R)-2-methylpropane-2-sulfinamide (457 mg, 3.77 mmol) by the similar manner in Step-4 of Amine-1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[O:8][C:9]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[C:10]([C:11](=[O:14])[NH:12][CH3:13])[C:5]2=[CH:4][C:3]=1[C:22]1[CH:23]=[C:24]([CH:32]=[CH:33][CH:34]=1)[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].[CH3:35]/[C:36](/[B-](F)(F)F)=[CH:37]\[CH3:38].[K+].C1(P(C2CCCCC2)C2C(C3C(OC)=CC=CC=3OC)=CC(S([O-])(=O)=O)=CC=2)CCCCC1.[Na+].C(=O)([O-])[O-].[Cs+].[Cs+]>C(O[Pd]OC(=O)C)(=O)C>[CH3:35]/[C:36](/[C:2]1[N:7]=[C:6]2[O:8][C:9]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[C:10]([C:11](=[O:14])[NH:12][CH3:13])[C:5]2=[CH:4][C:3]=1[C:22]1[CH:23]=[C:24]([CH:32]=[CH:33][CH:34]=1)[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:37]\[CH3:38]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(Cl)c(-c3cccc(C(=O)OC(C)(C)C)c3)cc12
Reactant: C/C=C(\C)[B-](F)(F)F
Agent: CC(=O)O[Pd]OC(C)=O
Agent: COc1cccc(OC)c1-c1cc(S(=O)(=O)[O-])ccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C([O-])[O-]
Product: C/C=C(\C)c1nc2oc(-c3ccc(F)cc3)c(C(=O)NC)c2cc1-c1cccc(C(=O)OC(C)(C)C)c1
Temperature: 80 °C
Yield: 45.4 %

Procedure:
tert-butyl 3-(6-chloro-2-(4-fluorophenyl)-3-(methylcarbamoyl)furo[2,3-b]pyridin-5-yl)benzoate (250 mg, 0.520 mmol), potassium (Z)-but-2-en-2-yltrifluoroborate (100 mg, 0.617 mmol), sodium 6-(dicyclohexylphosphino)-2′,6′-dimethoxy-[1,1′-biphenyl]-3-sulfonate (107 mg, 0.208 mmol), diacetoxypalladium (23.3 mg, 0.104 mmol), cesium carbonate (254 mg, 0.780 mmol) were combined dry, degassed with N2 and then taken up in DMF (4.7 ml) and water (0.47 ml) and heated to 80° C. for 1 h. The reaction was then concentrated to dryness azeotroping with toluene and the crude mixture was adsorbed onto Celite and was purified on silica gel (Biotage, EtOAc/hexanes gradient, fraction collection at λ=254 nm) give the expected product (E)-tert-butyl 3-(6-(but-2-en-2-yl)-2-(4-fluorophenyl)-3-(methylcarbamoyl)furo[2,3-b]pyridin-5-yl)benzoate (118 mg, 0.236 mmol, 45% yield) consistent by LCMS and NMR. LC-MS retention time: 2.22 min; m/z (MH+): 501. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 3u C18 2.0×30 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 1 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% acetonitrile/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% acetonitrile/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode. 1H NMR (400 MHz, DMSO-d6) δ 8.51-8.43 (m, 1H), 8.10-8.04 (m, 2H), 8.01 (s, 1H), 7.96-7.93 (m, 1H), 7.91-7.87 (m, 1H), 7.68-7.64 (m, 1H), 7.60-7.54 (m, 1H), 7.45-7.37 (m, 2H), 5.44-5.37 (m, 1H), 2.83 (d, J=4.5 Hz, 3H), 1.87-1.82 (m, 3H), 1.59-1.52 (m, 12H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]=[C:9]2[CH3:33])=[CH:4][CH:3]=1.Br[CH:35]1[CH2:38][CH2:37][CH2:36]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C)C=O.O>[CH:35]1([O:1][C:2]2[CH:3]=[CH:4][C:5]([N:8]3[C:13](=[O:14])[C:12]([CH2:15][C:16]4[CH:21]=[CH:20][C:19]([C:22]5[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=5)=[CH:18][CH:17]=4)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]=[C:9]3[CH3:33])=[CH:6][CH:7]=2)[CH2:38][CH2:37][CH2:36]1
Reactant: BrC1CCC1
Reactant: CCCc1nc(C)n(-c2ccc(O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1nc(C)n(-c2ccc(OC3CCC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
To a solution of 4′-{[1-(4-hydroxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.0 g) and bromocyclobutane (1.1 mL) in N,N-dimethylformamide (10 mL) was added cesium carbonate (1.5 g), and the mixture was stirred at 80° C. for 5 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (1.02 g, 91%).
Reaction SMILES: Br[CH:2]([PH3+])[CH2:3][CH:4]([CH3:11])[CH2:5][CH2:6][CH2:7][CH:8]([CH3:10])[CH3:9].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:23]([Si:27]([CH3:46])([CH3:45])[O:28][C:29]1[C:30]([CH3:44])=[C:31]2[C:36](=[C:37]([CH3:40])[C:38]=1[CH3:39])[O:35][C:34]([CH3:43])([CH:41]=O)[CH2:33][CH2:32]2)([CH3:26])([CH3:25])[CH3:24]>C1COCC1>[C:23]([Si:27]([O:28][C:29]1[C:30]([CH3:44])=[C:31]2[C:36](=[C:37]([CH3:40])[C:38]=1[CH3:39])[O:35][C:34]([CH:41]=[CH:2][CH2:3][CH:4]([CH3:11])[CH2:5][CH2:6][CH2:7][CH:8]([CH3:10])[CH3:9])([CH3:43])[CH2:33][CH2:32]2)([CH3:46])[CH3:45])([CH3:24])([CH3:26])[CH3:25]
Reactant: Cc1c(C)c2c(c(C)c1O[Si](C)(C)C(C)(C)C)CCC(C)(C=O)O2
Reactant: CC(C)CCCC(C)CC([PH3+])Br
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(C)c2c(c(C)c1O[Si](C)(C)C(C)(C)C)CCC(C)(C=CCC(C)CCCC(C)C)O2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a suspension of 1-bromo-3,7-dimethyl octanyl phosphonium (1.05 mmol) in 20 mL of anhydrous THF at 0° C. was added 1.05 mL of 1 M lithium bis(trimethysilyl)amide in THF. The mixture was stirred at 0° C. for 30 min, and compound iii (1 mmol) in 10 mL of THF was slowly added over a period of 1 h. After being stirred at room temperature for 1 h, the solution was concentrated, diluted with 20 mL of ethyl acetate, and washed, in tandem, with H2O and brine. The residue was purified by flash silica gel chromatography to afford t-butyl-[2-(4,8-dimethyl-non-1-enyl)-2,5,7,8-tetramethyl-chroman-6-yloxy]-dimethylsilane (iv) as colorless oil in 80% yield. 1H NMR (300 MHz, CDCl3) δ 0.11 (s, 6H), 0.86-0.95 (m, 6H), 1.04 (s, 9H), 1.39 (s, 1H), 1.49-1.56 (m, 1H), 1.76-1.86 (m, 1H), 2.01-2.06 (m, 2H), 2.11 (s, 3H), 2.17 (s, 6H), 2.25-2.32 (m, 1H), 2.62 (t, J=6.60 Hz, 2H), 5.30-5.44 (m, 2H).
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1>CO.Cl.O1CCOCC1>[F:1][C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Fc1cccc(-c2nn(C3CCCCO3)c3cnc(-c4cccnc4)cc23)n1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Fc1cccc(-c2n[nH]c3cnc(-c4cccnc4)cc23)n1
Reaction time: 8 h
Yield: 101.9 %

Procedure:
To a mixture of 120 mg (0.32 mmol) of 3-(6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine from Example 10 in 3 ml of methanol, 12 ml of 4N HCl in dioxane was added. The mixture was stirred for 8 hours and concentrated in vacuum. The residue was triturated with ethyl ether. The solid material was filtered out, washed with ethyl ether and dried. The above solid was dispersed in 30 ml of saturated aqueous sodium bicarbonate and the suspension was stirred for 1 hour. The solid base was collected, washed with water and dried in high vacuum for 24 hours to yield 95 mg of 131 (90%). ESI MS m/z 292.1 (M+1). 1H NMR (400 MHz, DMSO): 9.32-9.21 (m, 1H), 8.81 (s, 1H), 8.61 (dd, J=4.7, 1.4 Hz, 1H), 8.42 (d, J=8.0 Hz, 1H), 8.21-8.06 (m, 1H), 7.55 (dd, J=7.9, 4.7 Hz, 1H), 7.18 (d, J=7.7 Hz, 1H), 6.53 (s, 1H), 6.28 (s, 1H)