Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:24]([NH:26][CH:27]([C:34]([NH:36]N)=[O:35])[CH2:28][C:29]1[S:30][CH:31]=[CH:32][CH:33]=1)=[O:25])[CH2:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CN1CC[O:43]CC1.Cl.N[C@@H:48]([CH3:65])[C@@:49](O)([CH3:63])[C@@H:50]([CH2:61][OH:62])[NH:51][C:52](=[O:60])[CH2:53][CH2:54][CH2:55][CH2:56][CH:57]([CH3:59])[CH3:58]>CN(C)C=O.O1CCOCC1>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:24]([NH:26][CH:27]([C:34]([NH:36][C@@H:55]([CH2:56][CH:57]([CH3:59])[CH3:58])[C@@H:54]([OH:43])[CH2:53][C:52]([NH:51][C@H:50]([CH2:61][OH:62])[C@H:49]([CH2:48][CH3:65])[CH3:63])=[O:60])=[O:35])[CH2:28][C:29]1[S:30][CH:31]=[CH:32][CH:33]=1)=[O:25])[CH2:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCOCC1
Reactant: CC(C)CCCCC(=O)N[C@H](CO)[C@@](C)(O)[C@H](C)N
Reactant: NNC(=O)C(Cc1cccs1)NC(=O)[C@H](Cc1cccc2ccccc12)NC(=O)OCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@@H](CO)NC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)C(Cc1cccs1)NC(=O)[C@H](Cc1cccc2ccccc12)NC(=O)OCc1ccccc1
Temperature: -60 °C
Reaction time: 0.17 h
Yield: 13.2 %

Procedure:
517 mg (1 mmole) of N-benzyloxycarbonyl-3-(1-naphthyl)-L-alanyl-3-(2-thienyl)-DL-alanine hydrazide were dissolved in 10 ml of dimethylformamide, and the solution was cooled down to -60° C. 0.85 ml (3.4 mmole) of 4N hydrogen chloride in dioxane was then added. The temperature of this mixture was elevated to -20° C., and then 0.16 ml (1.19 mmole) of isoamyl nitrile was added and the mixture was stirred for 10 minutes. The reaction product was again cooled down to -60° C., and 0.42 ml (3.82 mmole) of N-methylmorpholine was added for neutralization. Subsequently, 370 mg (1.2 mmole) of 4(S)-amino-3(S)-hydroxy-6-methylheptanoyl-L-isoleucinol hydrochloride were added, and the mixture was stirred for 30 minutes. The reaction product was stirred overnight at 0° C., condensed by evaporation under reduced pressure and purified by thin layer chromatography, using as developing solvent a 99:1 by volume mixture of chloroform and methanol, to yield 100 mg (13.2%) of the title compound melting at 160°-162° C., [α]23 -61.7° (C=0.3, dimethylformamide).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([N:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=4)=[CH:13][C:12]3=[O:29])[CH:7]=[CH:6][C:5]=2[C:4]2[CH2:30][N:31](C(OC(C)(C)C)=O)[CH2:32][CH2:33][C:3]1=2.[ClH:41]>CO.CCOCC>[ClH:41].[ClH:41].[CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([N:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]4[CH:20]=[CH:21][C:22]([C:25]([F:27])([F:26])[F:28])=[CH:23][CH:24]=4)=[CH:13][C:12]3=[O:29])[CH:7]=[CH:6][C:5]=2[C:4]2[CH2:30][NH:31][CH2:32][CH2:33][C:3]1=2
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(C(F)(F)F)cc5)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(C(F)(F)F)cc5)cc4=O)cc31)CNCC2
Reaction time: 3 h
Yield: 38 %

Procedure:
tert-Butyl 5-methyl-7-(2-oxo-4-(4-(trifluoromethyl)benzyloxy)pyridin-1(2H)-yl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (73 mg, 0.13 mmol) was dissolved in MeOH (0.5 mL) and 2 N HCl in Et2O (3 mL) was added. The reaction was allowed to proceed for 3 h. The mixture was concentrated and purified by preparative HPLC. Conversion to the HCl salt (2 N HCl/Et2O) provided the title compound (26 mg, 38%) as a yellow solid: mp 311-315° C.; 1H NMR (500 MHz, CD3OD) δ 7.77 (d, J=8.3 Hz, 2H), 7.71 (d, J=8.2 Hz, 2H), 7.65 (d, J=7.6 Hz, 1H), 7.62 (d, J=8.3 Hz, 1H), 7.50 (s, 1H), 7.09 (dd, J=8.3, 1.8 Hz, 1H), 6.38 (dd, J=7.6, 2.7 Hz, 1H), 6.17 (d, J=2.7 Hz, 1H), 5.33 (s, 2H), 4.51 (s, 2H), 3.77 (s, 3H), 3.71 (t, J=6.2 Hz, 2H), 3.24 (t, J=6.1 Hz, 2H); ESI MS m/z 454 [M+H]+; HPLC (Method B)>99% (AUC), tR=14.2 min.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[S:5].Cl[CH:13]([C:19]([CH3:21])=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15]>C(O)C>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]1[S:5][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:19]([CH3:21])[N:6]=1
Reactant: NC(=S)c1ccc(Cl)cc1Cl
Reactant: CCOC(=O)C(Cl)C(C)=O
Solvent: CCO
Product: CCOC(=O)c1sc(-c2ccc(Cl)cc2Cl)nc1C
Yield: 63.5 %

Procedure:
In ethanol (10 ml), 2,4-dichlorothiobenzamide (378 mg) was dissolved, and ethyl 2-chloroacetoacetate (302 mg) was added thereto. The mixture was heated under reflux for 25 hours. After the mixture was allowed to cool, the precipitated crystal was separated by filtration, washed with water, and dried to give ethyl 2-(2,4-dichlorophenyl)-4-methylthiazole-5-carboxylate (368 mg, 64%).
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[CH:11]1[C:20]2[C:15](=[C:16]([CH:21]([CH3:25])[C:22](O)=[O:23])[CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][N:12]=1.C1C2C(=C(CC(O)=O)C=CC=2)C=CN=1>>[Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH:5][C:22](=[O:23])[CH:21]([C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:15]=1[CH:14]=[CH:13][N:12]=[CH:11]2)[CH3:25]
Reactant: CC(C(=O)O)c1cccc2cnccc12
Reactant: NCc1cccc(Cl)c1Cl
Agent: O=C(O)Cc1cccc2cnccc12
Product: CC(C(=O)NCc1cccc(Cl)c1Cl)c1cccc2cnccc12

Procedure:
The title compound was prepared using the procedure described in Example 222B using 2,3-dichlorobenzylamine and 2-(5-isoquinolinyl)propanoic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS (ESI+) m/z 359 (M+H)+; MS (ESI−) m/z 357 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 1.54 (d, J 7.1, 3H), 4.20 (m, 2H), 4.53 (q, J 7.1, 1H), 7.17 (d, J 7.8, 1H), 7.26 (t, J 7.8, 1H), 7.52 (d, J 8.1, 1H), 7.78 (t, J 7.8, 1H), 7.91 (d, J 6.5, 1H), 8.16 (d, J 8.1, 1H), 8.24 (d, J 6.4, 1H), 8.59 (d, J 6.2, 1H), 8.66 (t, J 5.8, 1H), 9.50 (s, 1H).
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].S(=O)(=O)(O)O.[CH2:13]1[CH:18]2CC3[O:22][C:23](=O)[CH:16]([CH2:17]2)[CH2:15][CH:14]1[CH2:21]3>C1CCCCC1>[C:5]([O:4][CH:1]1[CH:18]2[CH2:17][CH:16]3[CH2:15][CH:14]([CH2:21][CH:2]1[C:23]3=[O:22])[CH2:13]2)(=[O:7])[CH3:6]
Reactant: O=C1OC2CC3CC(C2)CC1C3
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: C1CCCCC1
Product: CC(=O)OC1C2CC3CC(C2)C(=O)C1C3
Reaction time: 6 h

Procedure:
A mixture containing 4-Oxahomoadamantane-5-one (12.5 grams, 75.3 mmol), 40 mL acetic anhydride, and 100 mL cyclohexane was charged to a 250-mL round-bottom flask and heated to reflux with a heating mantle. Concentrated sulfuric acid (0.52 grams, 5.4 mmol) was added dropwise from the top of the condenser with magnetic stirring. After 40 hours of reflux, about 5% of the 4-Oxahomoadamantan-5-one was converted to the products. More concentrated H2SO4 was added (15.8 grams, 158 mmol) in the same fashion. This separated the reaction mixture into a top grayish layer of mostly cyclohexane and a black bottom layer. Refluxing was continued for additional 6 hrs, when GC analysis of the top layer showed that the reaction was complete. After cooling, the reaction mixture was transferred into a separatory funnel and the layers were separated. The dark bottom layer was extracted with 3×50 mL cyclohexane. The combined cyclohexane solutions was washed with 100 mL each of 1N NaOH and saturated brine. GC analysis of the solution showed >99% pure two isomers of 4-Acetoxyadamantanones. After drying over anhydrous Na2SO4, removal of solvent gave 4.03 gram of 4-Acetoxyadamantanone as a yellowish oil. Crushed ice was added to the conc. H2SO4 layer separated from the reaction mixture. The resulting solution was diluted with water to ≈500 mL and extracted with 4×100 mL CH2Cl2. The combined yellow CH2Cl2 solutions was washed with 1N NaOH (2 ×200 mL), water (100 mL), and saturated brine (100 mL). GC analysis of the solution showed that it was predominantly 4-Acetoxyadamantanone with small amounts of 4-Hydroxyadamantanones. Removal of solvent by rotary evaporation gave 7.24 grams of a red oil.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH2:13][CH:14]([NH2:16])[CH3:15].[Cl:17][C:18]1[S:22][C:21]([CH:23]=O)=[CH:20][CH:19]=1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH2:13][CH:14]([NH:16][CH2:23][C:21]1[S:22][C:18]([Cl:17])=[CH:19][CH:20]=1)[CH3:15]
Reactant: O=Cc1ccc(Cl)s1
Reactant: CC(N)COc1ccc2ccccc2c1Cl
Product: CC(COc1ccc2ccccc2c1Cl)NCc1ccc(Cl)s1
Yield: 61 %

Procedure:
Prepared from 1-[(1-chloronaphthalen-2-yl)oxy]propan-2-amine and 5-chlorothiophen-2-carbaldehyde in 61% yield as a slightly white oil.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][CH2:9][NH:10][C:11]([C:13]1[CH:14]=[CH:15][C:16]([N:28]2[CH2:33][CH2:32][N:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH3:40])[CH2:30][CH2:29]2)=[C:17]([NH:19][C:20]([C:22]2[O:23][C:24](Br)=[CH:25][CH:26]=2)=[O:21])[CH:18]=1)=[O:12].C[Si]([C:45]#[CH:46])(C)C.C(N(CC)CC)C>C(#N)C.[Cu]I>[O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][CH2:9][NH:10][C:11]([C:13]1[CH:14]=[CH:15][C:16]([N:28]2[CH2:33][CH2:32][N:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH3:40])[CH2:30][CH2:29]2)=[C:17]([NH:19][C:20]([C:22]2[O:23][C:24]([C:45]#[CH:46])=[CH:25][CH:26]=2)=[O:21])[CH:18]=1)=[O:12]
Reactant: C#C[Si](C)(C)C
Reactant: Cc1ccccc1N1CCN(c2ccc(C(=O)NCCCN3CCCC3=O)cc2NC(=O)c2ccc(Br)o2)CC1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C#Cc1ccc(C(=O)Nc2cc(C(=O)NCCCN3CCCC3=O)ccc2N2CCN(c3ccccc3C)CC2)o1
Temperature: 80 °C
Reaction time: 4 h
Yield: 14.1 %

Procedure:
In a 20 mL scintillation vial, 5-bromo-furan-2-carboxylic acid [5-[3-(2-oxo-pyrrolidin-1-yl)-propylcarbamoyl]-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide (0.1 g, 0.231 mmol) was taken in acetonitrile (5.0 mL). Trimethylsilyl acetylene (0.045 g, 0.462 mmol), CuI (0.009 g, 0.046 mmol), triethylamine (0.116 g, 1.155 mmol) and PdCl2(Ph3P) (0.032 g, 0.046 mmol) were added to this, and the solution was evacuated for 5 min and nitrogen purged and stirred at 80° C. for 4 h. LC-MS indicated the completion of the reaction. It was diluted with acetonitrile and filtered through celite and concentrated. The crude was dissolved in THF and stirred with TBAF (2.0 mL of 2 M solution in THF) at room temperature for 16 h. The reaction was concentrated and dissolved in methanol and purified on preparative HPLC using methanol/water as eluent to give the desired product (0.018 g, 14% yield).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=C[C:14]([C:17]3[C:18](C(OC(C)(C)C)=O)=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]([C:43]([NH:45][CH:46]3[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]3)=[O:44])[CH2:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].F[C:53](F)(F)[C:54]([OH:56])=[O:55]>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[C:53]([C:54]([OH:56])=[O:55])[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]([C:43]([NH:45][CH:46]3[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51]3)=[O:44])[CH2:35][CH2:36][C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(O)C(F)(F)F
Reactant: CCCCc1nc2ccc(N(CCc3ccccc3)C(=O)NC3CCCCC3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Product: CCCCc1nc2ccc(N(CCc3ccccc3)C(=O)NC3CCCCC3)cc2n1Cc1ccc(-c2ccccc2)c(C(=O)O)c1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-(N-cyclohexylaminocarbonyl-N-(2-phenylethyl)-amino)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]([CH3:10])[C:8]3=[N:11][C:12]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[C:13]([CH:14](O)[C:15]([N:17]([CH3:19])[CH3:18])=[O:16])[N:7]3[C:6]=2[CH:27]=1.S(Cl)(Cl)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]([CH3:10])[C:8]3=[N:11][C:12]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[C:13]([CH2:14][C:15]([N:17]([CH3:19])[CH3:18])=[O:16])[N:7]3[C:6]=2[CH:27]=1
Reactant: CN(C)C(=O)C(O)c1c(-c2ccccc2)nc2n(C)c3ccc(Cl)cc3n12
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CN(C)C(=O)Cc1c(-c2ccccc2)nc2n(C)c3ccc(Cl)cc3n12
Reaction time: 6 h
Yield: 94.8 %

Procedure:
16.5 g (0.043 mol) of 6-chloro-α-hydroxy-N,N,9-trimethyl-2-phenyl-9H-imidazo[1,2-a]benzimidazole-3-acetamide are treated with 90 ml of thionyl chloride in 250 ml of dichloromethane. The mixture is stirred for 6 h and allowed to stand overnight. The solvent and excess thionyl chloride are evaporated under reduced pressure. The residue is taken up in toluene and the mixture is again evaporated. The residue is dissolved in 800 ml of dichloromethane and treated with 26.5 g of Rongalite®. The mixture is stirred for 48 h and the insoluble matter is then separated by filtration. The organic phase is washed with sodium bicarbonate and then with water. The solvent is evaporated under reduced pressure and the residue is taken up in pentane. 14.96 g of solid are obtained which are purified by silica gel column chromatography, eluting with a dichloromethane/methanol 95/5 mixture. 8.59 g of product are isolated, of which a sample of 1.4 g is taken and dissolved in dichloromethane. The solution is filtered and the filtrate is concentrated under reduced pressure. The residue is treated with carbon black in methanol, and the product is then recrystallized from an N,N-dimethylformamide/water 2/1 mixture and 0.98 g of solid is obtained. Melting point: 233°-236° C.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH:12]=[N:11][C:10](O)=[N:9][C:8]2=[O:14])=[CH:4][CH:3]=1.[N:17]1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)[C:21]2C=[CH:23][CH:24]=[CH:25][C:20]=2N=N1.N12CCCN=C1CCCCC2.[F:54][C:55]1[CH:64]=[CH:63][C:58]2[NH:59][C:60](=[S:62])[NH:61][C:57]=2[CH:56]=1>C(#N)C>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH:12]=[N:11][C:10]([N:17]3[CH2:23][CH2:24][CH:25]([N:59]4[C:58]5[CH:63]=[CH:64][C:55]([F:54])=[CH:56][C:57]=5[NH:61][C:60]4=[S:62])[CH2:20][CH2:21]3)=[N:9][C:8]2=[O:14])=[CH:4][CH:3]=1
Reactant: O=c1nc(O)ncn1Cc1ccc(Cl)cc1
Reactant: Fc1ccc2[nH]c(=S)[nH]c2c1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=c1nc(N2CCC(n3c(=S)[nH]c4cc(F)ccc43)CC2)ncn1Cc1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 2.1 %

Procedure:
To an acetonitrile solution (1 mL) of 1-(4-chlorobenzyl)-4-hydroxy-1,3,5-triazin-2(1H)-one (20 mg, 0.08 mmol) synthesized in Reference Synthesis Example 10, (benzotriazol-1-yloxy)tripyrrolidino-phosphonium (47 mg, 0.10 mmol) and 1,8-diazabicyclo[5.4.0]undeca-7-ene (15 μL, 0.10 mmol) were added at room temperature and the resultant mixture was stirred for 20 minutes. To the reaction solution, 5-fluoro-1H-benzo[d]imidazole-2(3H)-thione (25 mg, 0.10 mmol) was added and the resultant reaction solution was stirred at 80° C. for 10 minutes. After the completion of the reaction, the reaction solution was concentrated under reduced pressure and the resultant residue was purified by silica gel column chromatography (chloroform/ethyl acetate=1/1 (v/v)) to obtain the title compound (0.8 mg, yield: 2.0%).
Reaction SMILES: [S:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1.C([Li])CCC.CCCCCC.[CH3:21][N:22](C=O)[CH3:23]>C1COCC1>[CH3:21][NH:22][CH2:23][C:2]1[S:1][C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=1
Reactant: CN(C)C=O
Reactant: c1cc2sccc2cn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CNCc1cc2cnccc2s1
Reaction time: 0.08 h
Yield: 41.5 %

Procedure:
A solution of thieno[3,2-c]pyridine (500 mg, 3.70 mmol) in anhydrous THF (10 mL) was stirred under argon and maintained at −78° C. while a solution of 1.6 M n-butyllithium in hexane (2.5 mL, 4.07 mmol) was added dropwise. The resulting wine red solution was stirred for 5 min. then DMF (573 μL, 7.4 mmol) was added. The cooling bath was removed and the reaction mixture was stirred at room temperature for 16 hr. The reaction mixture was treated with 10% aqueous HCl, made alkaline with saturated aqueous NaHCO3 and extracted with CH2Cl2 (2×50 mL) The combined organic fractions were concentrated in vacuo to give an oily residue which was subjected to flash chromatography on silica gel (70% ethyl acetate:hexanes) to give the title compound as a white solid (41.5%): 1H-NMR (300 MHz, DMSO-d6) δ 10.20 (s, 1H), 9.39 (s, 1H), 8.60 (s, 1H), 8.59 (d, J=5.5 Hz, 1H), 8.19 (d, J=5.6 Hz, 1H); MS (ES) m/e 164 (M+H)+.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[C:7]([Li])(C)([CH3:9])[CH3:8].[CH:12]([C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=1)=[O:13].[Cl-].[NH4+]>C1COCC1.CCCCC>[NH:5]1[CH:6]=[C:2]([C:12]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)([OH:13])[CH:7]([CH3:9])[CH3:8])[N:3]=[CH:4]1
Reactant: Brc1c[nH]cn1
Reactant: O=Cc1ccc2ccccc2c1
Reactant: [Li]C(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCC
Product: CC(C)C(O)(c1ccc2ccccc2c1)c1c[nH]cn1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
4-Bromo-1H-imidazole (1.95 g) was dissolved in THF (30 ml), and the solution was cooled to −78° C. To the solution was added a solution of t-butyllithium in pentane (1.7 M; 20 ml). The mixture was stirred at 0° C. for 1.5 h. The mixture was again cooled to −78° C., and a solution of 2-formylnaphthalene (3.32 g) in THF (20 ml) was added. After the temperature was elevated from −78° C. to room temperature, the mixture was stirred at room temperature for 16 h. To the mixture was added an aqueous solution of ammonium chloride, and the mixture was extracted with ethyl acetate. The organic layer was dried and concentrated. The residue was purified by silica gel column chromatography,(eluent, dichloromethane:methanol=10:1). Recrystallization from dichloromethane-methanol gave the titled compound (1.00 g) as a colorless solid.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].C([N:15]1[CH2:24][CH2:23][C:22]2[C:17](=[N:18][C:19]([NH:40][CH2:41][CH:42]([F:44])[F:43])=[C:20]([N:25]3[CH2:30][CH2:29][CH:28]([O:31][C:32]4[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=4[F:39])[CH2:27][CH2:26]3)[N:21]=2)[CH2:16]1)C1C=CC=CC=1>C1COCC1.[OH-].[OH-].[Pd+2]>[F:44][CH:42]([F:43])[CH2:41][NH:40][C:19]1[N:18]=[C:17]2[CH2:16][NH:15][CH2:24][CH2:23][C:22]2=[N:21][C:20]=1[N:25]1[CH2:26][CH2:27][CH:28]([O:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=2[F:39])[CH2:29][CH2:30]1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: Fc1ccc(OC2CCN(c3nc4c(nc3NCC(F)F)CN(Cc3ccccc3)CC4)CC2)c(F)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: Fc1ccc(OC2CCN(c3nc4c(nc3NCC(F)F)CNCC4)CC2)c(F)c1
Reaction time: 1 h

Procedure:
A solution of 6-benzyl-N-(2,2-difluoroethyl)-2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (132.5 mg, 0.210 mmol) in THF (2.1 mL) was treated with Pd(OH)2 (20 wt %, 29.6 mg, 0.042 mmol). Hydrogen gas (balloon) was bubbled through the reaction mixture for 5 min. The vent needle was removed and the reaction was stirred under hydrogen atmosphere for 1 h. The reaction mixture was opened to air and was filtered through a pad of Celite™, eluting with EtOAc and MeOH. The filtrate was concentrated under reduced pressure to give the title compound as a TFA salt (114 mg), which was used without further purification. ESI-MS m/z [M+H]+ 426.5.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10](I)=[N:9]2)=[CH:5][CH:4]=1.[CH3:29][N:30]([CH3:36])[C@H:31]1[CH2:35][CH2:34][NH:33][CH2:32]1.C([O-])([O-])=O.[K+].[K+].N1CCC[C@H]1C(O)=O>CS(C)=O.ClCCl>[NH2:24][C:21]1[CH:22]=[CH:23][C:18]([O:17][C:16]2[CH:15]=[CH:14][N:13]=[C:12]3[N:8]([CH2:7][C:6]4[CH:27]=[CH:28][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[N:9]=[C:10]([N:33]4[CH2:34][CH2:35][C@H:31]([N:30]([CH3:36])[CH3:29])[CH2:32]4)[C:11]=23)=[C:19]([F:25])[CH:20]=1
Reactant: COc1ccc(Cn2nc(I)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Reactant: CN(C)[C@H]1CCNC1
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: COc1ccc(Cn2nc(N3CC[C@H](N(C)C)C3)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Temperature: 90 °C
Yield: 19.9 %

Procedure:
To a stirred solution of 4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorobenzenamine (49 mg, 0.1 mmol) (prepared in Example 7, step B) in 300 μL DMSO at ambient temperature in a capped reaction vial was added (S)—N,N-dimethylpyrrolidin-3-amine (19 uL, 0.15 mmol) followed by K2CO3 (27 mg, 0.2 mmol), Cu(I)I (19 mg, 0.01 mmol) and L-proline (2.3 mg, 0.02 mmol). The mixture was heated 90° C. overnight, then the mixture was cooled to room temperature, diluted to 30 mL with dichloromethane and washed with H2O. The organic layer was dried (MgSO4), filtered and concentrated. The crude product was loaded onto a Biotage 12S column with dichloromethane and eluted with 5/95 MeOH/dichloromethane to provide the product as a tan oil (9.5 mg, 20% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([Cl:8])[CH:3]=1.C([Li])CCC.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([C:24]2[C:36](=[O:37])[N:35]([CH2:38][CH3:39])[C:27]3[N:28]=[C:29](S(C)=O)[N:30]=[CH:31][C:26]=3[CH:25]=2)[CH:19]=[C:20]([O:22][CH3:23])[CH:21]=1.C(OCC)(=O)C.O>C1COCC1>[CH3:23][O:22][C:20]1[CH:19]=[C:18]([C:24]2[C:36](=[O:37])[N:35]([CH2:38][CH3:39])[C:27]3[N:28]=[C:29]([NH:1][C:2]4[CH:7]=[CH:6][N:5]=[C:4]([Cl:8])[CH:3]=4)[N:30]=[CH:31][C:26]=3[CH:25]=2)[CH:17]=[C:16]([O:15][CH3:14])[CH:21]=1
Reactant: Nc1ccnc(Cl)c1
Reactant: CCn1c(=O)c(-c2cc(OC)cc(OC)c2)cc2cnc(S(C)=O)nc21
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCn1c(=O)c(-c2cc(OC)cc(OC)c2)cc2cnc(Nc3ccnc(Cl)c3)nc21
Temperature: -10 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
To a −78° C. solution of 4.1 g (32.1 mmol) of 4-amino-2-chloropyridine in 120 mL of THF was added dropwise 17.5 mL (30.5 mmol) of 1.6 M n-butyllithium in hexanes. The reaction solution was stirred for 15 minutes at which time 3.0 g (8.0 mmol) of the product of Example 7, 6-(3,5-dimethoxy-phenyl)-8-ethyl-2-methanesulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one, was added in small portions as a solid. The reaction mixture was allowed to warm slowly to −10° C. then remain at −10° C. overnight. The reaction mixture was poured into ethyl acetate/water/5 mL 6N HCl. The mixture was shaken and separated. The organic phase was washed with a saturated solution of sodium bicarbonate, twice with water, and brine, then dried over magnesium sulfate, filtered, and concentrated to a volume of about 200 mL. The suspension was stirred overnight and filtered to give a yellow solid. The solid was triturated under 20 mL of 1:9 methanol/chloroform, filtered, and dried to give 1.89 g (54%) of the titled compound.