Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:8]([CH2:9][CH3:10])=[N:7][C:6]2[N:11]([CH2:14][CH3:15])[N:12]=[CH:13][C:5]=2[C:4]=1[NH:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.CC(OC([N:30]1[CH2:35][CH2:34][N:33]([CH2:36][C:37]2[CH:38]=[C:39]([C:43]3[C:48]([F:49])=[CH:47][CH:46]=[C:45]([CH2:50][NH:51][S:52]([C:55]4[CH:56]=[C:57]([CH:61]=[CH:62][CH:63]=4)[C:58](O)=[O:59])(=[O:54])=[O:53])[CH:44]=3)[CH:40]=[CH:41][CH:42]=2)[CH2:32][CH2:31]1)=O)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl>[CH2:14]([N:11]1[C:6]2=[N:7][C:8]([CH2:9][CH3:10])=[C:3]([CH2:2][NH:1][C:58](=[O:59])[C:57]3[CH:61]=[CH:62][CH:63]=[C:55]([S:52]([NH:51][CH2:50][C:45]4[CH:44]=[C:43]([C:39]5[CH:40]=[CH:41][CH:42]=[C:37]([CH2:36][N:33]6[CH2:34][CH2:35][NH:30][CH2:31][CH2:32]6)[CH:38]=5)[C:48]([F:49])=[CH:47][CH:46]=4)(=[O:54])=[O:53])[CH:56]=3)[C:4]([NH:16][CH:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[C:5]2[CH:13]=[N:12]1)[CH3:15]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(-c3cc(CNS(=O)(=O)c4cccc(C(=O)O)c4)ccc3F)c2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(S(=O)(=O)NCc2ccc(F)c(-c3cccc(CN4CCNCC4)c3)c2)c1
Temperature: 25 °C
Reaction time: 21 h
Yield: 32.7 %

Procedure:
To a solution of 5-(aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine-4-amine (0.0195 g, 0.0641 mmol) in DCM (0.64 mL) was added 3-{[({3′-[(4-{[(1,1-dimethyl ethyl)oxy]carbonyl}-1-piperazinyl)methyl]-6-fluoro-3-biphenylyl}methyl)amino]sulfonyl}benzoic acid (0.0374 g, 0.0641 mmol), HBTU (0.0365 g, 0.0962 mmol), Et3N (0.018 mL, 0.128 mmol). The result mixture was stirred at room temperature for 21 h before it was concentrated and purified using a Gilson HPLC (w/TFA). The HPLC fraction was concentrated on a GeneVac EZ-2 evaporator at 45° C. (de-Boc completed during evaporation), basified with an amine cartridge to afford 0.0161 g (33%) of the title compound. LC-MS m/z 769 (M+H)+; 1H-NMR (400 MHz, MeOD) δ ppm 1.41 (t, J=7.30 Hz, 3 H) 1.49 (t, J=7.05 Hz, 3 H) 1.86 (q, J=9.90 Hz, 2 H) 2.09 (d, J=12.34 Hz, 2 H) 3.17 (q, J=7.39 Hz, 2 H) 3.46-3.59 (m, J=12.59 Hz, 8 H) 3.67 (t, J=11.33 Hz, 2 H) 4.04 (d, J=11.83 Hz, 2 H) 4.16 (s, 2 H) 4.30-4.39 (m, 1 H) 4.41 (s, 2 H) 4.48 (q, J=6.88 Hz, 2 H) 4.70 (s, 2 H) 7.04 (t, J=9.44 Hz, 1 H) 7.18-7.27 (m, 1 H) 7.34 (d, J=7.05 Hz, 1 H) 7.50-7.58 (m, 3 H) 7.60-7.68 (m, 2 H) 7.98 (d, J=7.55 Hz, 1 H) 8.08 (d, J=7.81 Hz, 1 H) 8.30 (d, J=13.60 Hz, 2 H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@@H:4]([CH2:5][CH2:6][C@:7]3([CH3:31])[C@@H:16]2[CH2:15][CH2:14][C@H:13]2[C@@:8]3([CH3:30])[CH2:9][CH2:10][C@@:11]3([C:27]([OH:29])=[O:28])[CH2:23][CH2:22][C@@H:21]([C:24]([CH3:26])=[CH2:25])[C@@H:12]32)[C:3]1([CH3:33])[CH3:32]>C(OCC)(=O)C.CO.[Pd]>[OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@@H:4]([CH2:5][CH2:6][C@:7]3([CH3:31])[C@@H:16]2[CH2:15][CH2:14][C@H:13]2[C@@:8]3([CH3:30])[CH2:9][CH2:10][C@@:11]3([C:27]([OH:29])=[O:28])[CH2:23][CH2:22][C@@H:21]([CH:24]([CH3:26])[CH3:25])[C@@H:12]32)[C:3]1([CH3:32])[CH3:33]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reaction time: 18 h

Procedure:
A mixture of (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-hydroxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carboxylic acid (4 g, 8.76 mmol) and 10% Pd/C (1.398 g, 1.314 mmol) in ethyl acetate (80 mL) and MeOH (30 mL) was connected to Parr Shaker and shaked for 18 h under 45 psi at room temperature. LCMS indicated the formation of desired product. The reaction mixture was filtered through celite and the filtrates were concentrated under reduced pressure to give the title compound as white solid (3 g, 75%). LCMS: m/e 457.27 (M−H)−, 2.40 min (method 1).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][C:11]#[N:12])=[CH:5][CH:4]=1.[NH2:15][NH2:16]>CCO>[CH3:14][N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([NH2:12])[NH:15][N:16]=2)=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(C(=O)CC#N)cc1
Reactant: NN
Solvent: CCO
Product: CN(C)c1ccc(-c2cc(N)[nH]n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
3-(4-Dimethylamino-phenyl)-3-oxo-propionitrile (3.262 gms.) is then suspended in 100 mL of anhydrous EtOH. This suspension is treated with 1.09 mL of anhydrous hydrazine, and subsequently is heated to refluxing temperature for 2 h. The reaction mixture is cooled to room temperature and stored in a −20° C. freezer overnight to yield a white crystalline precipitate. This precipitate is filtered and the filtrate is concentrated in vacuo. The residue from the evaporation is triturated with ethyl acetate to give additional precipitate. The combined precipitates are again triturated with ethyl acetate for 45 min. due to the presence of starting material in the initial precipitate. The solid material is collected by filtration providing the 5-(4-dimethylamino-phenyl)-2H-pyrazol-3-ylamine in the amount of 0.86 gms. (37% yield).
Reaction SMILES: [C:1]([NH:4][C:5](C1SC=CC=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1C)[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2]>[Ni].CC(C)=O>[C:1]([NH:4][CH:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)NC(C(=O)O)(c1cccs1)c1ccccc1C
Agent: [Ni]
Solvent: CC(C)=O
Product: CC(=O)NC(C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 67 %

Procedure:
Two (2.0) cc of Raney nickel (WII) was suspended in 15 ml of acetone, and refluxed for 7 minutes. Cooling the suspension to room temperature, 315 mg of α-acetylamino-α-tolylthiophenylacetic acid was added, followed by 5.5 hours' stirring at room temperature. The insoluble matter was separated by filtration, and washed with ethanol. The filtrate and washing were combined and concentrated under reduced pressure. The residue was crystallized from an ether-n-hexane system. Thus 141 mg of α-acetylaminophenylacetic acid was obtained. The yield was 73%.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[O:7][CH2:8][CH2:9][OH:10].[H-].[Na+].Br[C:19]1[N:27]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[C:26]2[C:25](=[O:36])[N:24]([CH2:37][CH2:38][CH2:39][O:40][CH:41]3[CH2:46][CH2:45][CH2:44][CH2:43][O:42]3)[C:23](=[O:47])[N:22]([CH3:48])[C:21]=2[N:20]=1>C1COCC1>[CH3:48][N:22]1[C:21]2[N:20]=[C:19]([O:10][CH2:9][CH2:8][O:7][C:6]3[CH:11]=[CH:12][CH:13]=[C:4]([O:3][C:2]([F:14])([F:15])[F:1])[CH:5]=3)[N:27]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:33])[CH3:34])[C:26]=2[C:25](=[O:36])[N:24]([CH2:37][CH2:38][CH2:39][O:40][CH:41]2[CH2:46][CH2:45][CH2:44][CH2:43][O:42]2)[C:23]1=[O:47]
Reactant: OCCOc1cccc(OC(F)(F)F)c1
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c1nc(Br)n2COCC[Si](C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c1nc(OCCOc1cccc(OC(F)(F)F)c1)n2COCC[Si](C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(3-(trifluoromethoxy)phenoxy)ethanol (0.64 g, 2.9 mmol, intermediate 5) in THF (15 mL) was added sodium hydride (0.23 g, 9.67 mmol) at 0° C. it was stirred at 0° C. for 30 min, then 8-bromo-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione (1.0 g, 1.93 mmol, intermediate 16 step 1) was added. The mixture was stirred 16 h. The reaction was quenched with aq. ammonium chloride (2 mL) at 0° C.; then it was partitioned between ethyl acetate and water. The organic phases were combined, dried over sodium sulfate, filtered and concentrated to give a crude product which was used without purification. LCMS retention time 2.144; LCMS MH+-THP 575.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:5]([CH2:24][CH2:25][CH2:26][CH3:27])=[N:4][C:3]=1[CH:28]1[CH2:30][CH2:29]1.[CH2:31]([O:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)[CH3:32].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:24]([C:5]1[N:6]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:14][CH:15]=2)[C:7](=[O:8])[C:2]([C:37]2[CH:38]=[CH:39][C:34]([O:33][CH2:31][CH3:32])=[CH:35][CH:36]=2)=[C:3]([CH:28]2[CH2:29][CH2:30]2)[N:4]=1)[CH2:25][CH2:26][CH3:27]
Reactant: CCCCc1nc(C2CC2)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CCOc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCCCc1nc(C2CC2)c(-c2ccc(OCC)cc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 90 °C
Reaction time: 12 h
Yield: 69.8 %

Procedure:
To a solution of 4′-[(5-bromo-2-butyl-4-cyclopropyl-6-oxopyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (0.5 g) and 4-ethoxyphenylboronic acid (0.27 g) in 1,4-dioxane (10 mL) were added 2 M aqueous cesium carbonate solution (2 mL) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.05 g), and the mixture was stirred at 90° C. for 12 hr under an argon atmosphere. The reaction mixture was diluted with ethyl acetate, and the insoluble material was filtered off through celite. The filtrate was washed successively with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (0.38 g, 70%) as a colorless solid.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([CH:8]=O)=[CH:5][CH:4]=1)[CH3:2].[CH2:10]([NH:17][C:18]([C:20]1[S:24][C:23]([N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C:26]2=[O:31])=[N:22][C:21]=1[CH3:32])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([NH:17][C:18]([C:20]1[S:24][C:23]([N:25]2[CH2:30][CH2:29][CH2:28][C:27](=[CH:8][C:6]3[S:7][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=3)[C:26]2=[O:31])=[N:22][C:21]=1[CH3:32])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCc1ccc(C=O)s1
Reactant: Cc1nc(N2CCCCC2=O)sc1C(=O)NCc1ccccc1
Product: CCc1ccc(C=C2CCCN(c3nc(C)c(C(=O)NCc4ccccc4)s3)C2=O)s1
Yield: 14 %

Procedure:
Following the procedure as described in Example 10, making variations as required to use 5-ethylthiophene-2-carbaldehyde in place of benzaldehyde to react with N-benzyl-4-methyl-2-(2-oxopiperidin-1-yl)thiazole-5-carboxamide, the title compound was obtained as a white solid in 14% yield: mp 171-172° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 8.05 (s, 1H), 7.42-7.22 (m, 5H), 7.16 (d, J=3.7 Hz, 1H), 6.83 (dd, J=0.7, 3.7 Hz, 1H), 5.98 (t, J=5.5 Hz, 1H), 4.57 (d, J=5.5 Hz, 2H), 4.32-4.25 (m, 2H), 2.93-2.81 (m, 4H), 2.65 (s, 3H), 2.15-2.02 (m, 2H), 1.32 (t, J=7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 164.8, 162.7, 157.5, 153.7, 152.4, 137.9, 136.4, 133.6, 132.9, 128.8, 127.9, 127.6, 124.5, 122.7, 119.5, 46.9, 44.1, 25.9, 23.8, 21.9, 17.4, 15.7; MS (ES+) m/z 452.1 (M+1).
Reaction SMILES: C(N(CC)CC)C.CS(Cl)(=O)=O.C(C(C(C(O)=O)O)O)(O)=O.[CH2:23]([O:25][C:26]([C@@H:28]1[CH2:33][CH2:32][CH2:31][NH:30][CH2:29]1)=[O:27])[CH3:24].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CC(C)=O.O>[CH2:23]([O:25][C:26]([CH:28]1[CH2:33][CH2:32][CH2:31][NH:30][CH2:29]1)=[O:27])[CH3:24]
Reactant: CCOC(=O)[C@@H]1CCCNC1
Agent: CS(=O)(=O)Cl
Agent: O=C(O)C(O)C(O)C(=O)O
Agent: O=C([O-])[O-]
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C1CCCNC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The above alcohol (5.4 g, 0.02 mol) was dissolved in toluene (160 ml) and triethylamine (7 ml) was added. Methanesulfonyl chloride (2.5 ml, 0.032 mol) was added dropwise and when addition was complete the reaction mixture was stirred for 2 h. Water was added and the phases were separated. The organic phase was dried (MgSO4) and the solvent evaporated in vacuo affording a residue which was dissolved in acetone (85 ml). To this solution (R)-3-piperidinecarboxylic acid ethyl ester tartrate (9.0 g, 0.03 mol) and potassium carbonate (7.0 g, 0.051 mol) were added and the mixture was heated at reflux temperature for 16 h. After cooling to room temperature and filtration on filter aid (celite) the solvent was removed by evaporation. The residue was dissolved in diethyl ether (100 ml) and extracted with a 5% tartaric acid solution (3×125 ml). The combined aqueous extracts were washed with diethyl ether and pH was adjusted to 7-8 with a potassium carbonate solution. The neutralised aqueous mixture was extracted with ethyl acetate (4×200 ml). The combined ethyl acetate extracts were washed with water, brine and dried (MgSO4). The solvent was evaporated in vacuo affording 2.6 g (32%) of 1-(4-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-1-butyl!-3-piperidinecarboxylic acid ethyl ester, obtained as an oil. The residue was purified further by column chromatography on silica gel (65 g) using a mixture of dichloromethane and methanol (99.2:0.8) as eluent. Rf : 0.20 (SiO2 ; n-heptane/ethyl acetate=1:1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[N:6][C:7]=1[Cl:8]>O=[Mn]=O.C(Cl)Cl.CCCCCC>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[O:10])[CH:5]=[N:6][C:7]=1[Cl:8]
Reactant: OCc1cnc(Cl)c(Cl)c1
Agent: O=[Mn]=O
Solvent: CCCCCC
Solvent: ClCCl
Product: O=Cc1cnc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (5,6-dichloro-pyridin-3-yl)-methanol (1.78 g, 10 mmol, TCI-US) and MnO2 (17.39 g, 200 mmol, Aldrich) in 1:1 CH2Cl2/hexane (10 ml) was stirred at room temperature for 1 h. The catalyst was filtered and washed with 50% EtOAc/hexane. The filtrate was evaporated and the residue dried in vacuo to give the title compound product, which was used in the next step without additional purification. MS (ESI, pos. ion) m/z: 176 (M+1).
Reaction SMILES: CC1(C)[O:6][C@H:5]([CH2:7][O:8][NH:9][C:10]([C:12]2[CH:13]=[CH:14][C:15]3[N:16]([CH:27]=[N:28][CH:29]=3)[C:17]=2[NH:18][C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=2[F:26])=[O:11])[CH2:4][O:3]1.CCN(CC)CC.C(#N)C.O>CO.ClCCl>[OH:6][C@H:5]([CH2:4][OH:3])[CH2:7][O:8][NH:9][C:10]([C:12]1[CH:13]=[CH:14][C:15]2[N:16]([CH:27]=[N:28][CH:29]=2)[C:17]=1[NH:18][C:19]1[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=1[F:26])=[O:11]
Reactant: CC1(C)OC[C@@H](CONC(=O)c2ccc3cncn3c2Nc2ccc(I)cc2F)O1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(NOC[C@H](O)CO)c1ccc2cncn2c1Nc1ccc(I)cc1F
Yield: 22.8 %

Procedure:
A solution of 5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid ((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-amide (364 mg, 0.7 mmol) in methanol (0.5 ml) and dichloromethane (0.5 ml) was loaded onto an SCX-2 cartridge. The cartridge was flushed with methanol and the desired product was eluted using a 2M solution of ammonia in methanol. The appropriate fractions were combined and concentrated under reduced pressure and the residue was azeotroped with dichloromethane. Purification of the resultant residue by flash chromatography (Si-PPC, gradient 0% to 10%, methanol in dichloromethane) followed by preparative HPLC (Gemini 5 micron C6-Phenyl 250×21.20 mm column, 20 mmol Et3N per liter solvent, gradient acetonitrile/water, 5 to 98%, ramp time 25 minutes) afforded the title compound as a yellow solid (77.6 mg, 23%). LCMS (method A): RT=5.13 min, [M+H]+=487. 1H NMR (DMSO-d6): 8.01 (1H, s), 7.58 (1H, dd, J=10.68, 1.92 Hz), 7.42 (1H, s), 7.38 (1H, d, J=9.34 Hz), 7.30 (1H, dd, J=8.43, 1.82 Hz), 6.91 (1H, d, J=9.32 Hz), 6.32 (1H, t, J=8.68 Hz), 3.72-3.67 (1H, m), 3.60-3.51 (2H, m), 3.30 (2H, d, J=4.94 Hz).
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C:8]1=[O:13])C.FC(F)(F)C(O)=O.CCOC(C)=O.[O-][Mn](=O)(=O)=O.[K+]>C(Cl)Cl>[O:13]=[C:8]1[CH2:9][CH2:10][CH2:11][CH2:12][N:7]1[CH2:6][CH2:5][CH:4]=[O:3]
Reactant: CCOC(CCN1CCCCC1=O)OCC
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=CCCN1CCCCC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1-[3,3-bis(ethyloxy)propyl]-2-piperidinone (1.52 g, 6.61 mmol) in CH2Cl2 (100 mL) under nitrogen was treated with trifluoroacetic acid (TFA) (1.5 mL, 19.5 mmol) and stirred at ambient temperature for 1 h. After adding an additional 1.5 mL of TFA and monitoring by TLC (EtOAc, KMnO4 stain) for complete consumption of starting materials the reaction mixture was partitioned between CH2Cl2 and 1:1 Sat. NaHCO3:water (150 mL) solution. Extracted the aqueous with CH2Cl2 two additional times before combining the organics, washing them with brine, drying over MgSO4, filtering, and concentrating in vacuo to provide the desired product as a clear oil: 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.78-1.91 (m, 4 H), 2.67 (t, J=6.11 Hz, 2 H), 2.85 (td, J=6.42, 0.91 Hz, 2 H), 3.50 (t, J=5.48 Hz, 2 H), 3.71 (t, J=6.32 Hz, 2 H), 9.53-9.58 (m, 1 H); ES+ MS: 156 (M+H+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1.Cl[C:20]1[N:25]=[C:24]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[N:23]=[C:22]([N:32]2[C:36]3[CH:37]=[CH:38][CH:39]=[C:40]([O:41][CH3:42])[C:35]=3[N:34]=[C:33]2[CH:43]([F:45])[F:44])[N:21]=1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[F:45][CH:43]([F:44])[C:33]1[N:32]([C:22]2[N:23]=[C:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[N:25]=[C:20]([N:5]([CH2:4][CH2:3][CH2:2][OH:1])[CH:6]3[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]3)[N:21]=2)[C:36]2[CH:37]=[CH:38][CH:39]=[C:40]([O:41][CH3:42])[C:35]=2[N:34]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(NCCCO)C1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N(CCCO)C2CCCN(C(=O)OC(C)(C)C)C2)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 89.6 %

Procedure:
A mixture of tert-butyl 3-[(3-hydroxypropyl)amino]-1-piperidinecarboxylate (516 mg, 2.00 mmol), 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole (610 mg, 1.54 mmol), and DIPEA (1.5 mL, excess) in DMF (20 mL) was stirred at room temperature for 2 days. The reaction mixture was diluted with water and extracted with CH2Cl2 (3×30 mL). The combined extracts were washed with water, dried over Na2SO4, and concentrated. Chromatography of the residue on SiO2 eluting with a gradient of CH2Cl2/EtOAc (0-40%) gave tert-butyl 3-[[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl](3-hydroxypropyl)-amino]-1-piperidinecarboxylate (854 mg, 90%): mp (CH2Cl2/hexanes) 109-191° C.; 1H NMR (DMSO-d6) (rotamers) δ 8.00 and 7.88 (2d, J=8.3, 8.4 Hz, 1H), 7.79 and 7.63 (2t, JHF=53.0 Hz, 1H), 7.40-7.33 (m, 1H), 6.94 (dd, J=8.0, 4.13 Hz, 1H), 4.60-4.48 and 4.29 (m, 2H), 3.98 and 3.97 (2s, 3H), 3.97-3.48 (m, 16H), 2.93-2.88 and 2.66-2.64 (2m, 2H), 1.99-1.69 (m, 3H), 1.52-1.17 (m, 10H); Anal. Calcd. for C29H40F2N8O5: C, 56.3; H, 6.5; N, 18.1. Found: C, 56.4; H, 6.4; N, 18.1%.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([Cl:12])[C:5]2[N:10]([CH3:11])[N:9]=[CH:8][C:6]=2[N:7]=1.[CH3:13]N1C2C(=O)NC(=O)NC=2C(C)=N1>>[Cl:1][C:2]1[N:3]=[C:4]([Cl:12])[C:5]2[N:10]([CH3:11])[N:9]=[C:8]([CH3:13])[C:6]=2[N:7]=1
Reactant: Cc1nn(C)c2c(=O)[nH]c(=O)[nH]c12
Reactant: Cn1ncc2nc(Cl)nc(Cl)c21
Product: Cc1nn(C)c2c(Cl)nc(Cl)nc12

Procedure:
This compound was prepared in an analogous fashion to 5,7-dichloro-1-methyl-1H-pyrazolo[4,3-d]pyrimidine, using 1,3-dimethyl-1H-pyrazolo[4,3-d]-pyrimidine-5,7(4H,6H)-dione as the starting material. 1H NMR (CDCl3, 400 MHz) δ ppm 4.32 (s, 3H), 2.60 (s, 3H); LC-MS m/z (method B2)=217.2/219.2 [M+H]+, RT=1.688 min.
Reaction SMILES: Cl[C:2]1[C:3]([C:9]#[N:10])=[N:4][C:5]([Cl:8])=[CH:6][N:7]=1.[C:11]1([CH:18]=[CH:17][C:15]([OH:16])=[CH:14][CH:13]=1)[OH:12].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.O.C(OCC)(=O)C>[Cl:8][C:5]1[N:4]=[C:3]([C:9]#[N:10])[C:2]([O:12][C:11]2[CH:18]=[CH:17][C:15]([OH:16])=[CH:14][CH:13]=2)=[N:7][CH:6]=1
Reactant: Oc1ccc(O)cc1
Reactant: N#Cc1nc(Cl)cnc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1nc(Cl)cnc1Oc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.3 %

Procedure:
In 10 mL of dimethylformamide was dissolved 1.0 g of 3,6-dichloro-2-pyrazinecarbonitrile. After adding 0.7 g of hydroquinone and 1.74 g of potassium carbonate, the mixture thus obtained was stirred at room temperature for 30 minutes. The reaction mixture was poured into a mixture of 10 mL of ethyl acetate and 30 mL of water, pH was adjusted to 7 with 2 mol/L hydrochloric acid, and the organic layer was separated. The organic layer thus obtained was washed successively with water and saturated aqueous solution of sodium chloride and dried on anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography [eluent: n-hexane:ethyl acetate=3:1] to obtain 1.0 g of 6-chloro-3-(4-hydroxyphenoxy)-2-pyrazinecarbonitrile as a yellow-colored solid product.
Reaction SMILES: [CH:1]1([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11]C)[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[Cl-].[NH4+]>C(Cl)Cl>[CH:1]1([C:5]2[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: COc1cccc(C2CCC2)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: Oc1cccc(C2CCC2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
To a suspension of 1-cyclobutyl-3-methoxy-benzene (155 mg, 0.95 mmol) in CH2Cl2 (2 mL) was added dropwise 1.0M-BBr2 (1.05 mL, 1.05 mmol) at 0° C. The mixture was stirred for 1 hour at 0° C., treated with saturated ammonium chloride, and then extracted with CH2Cl2. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by column chromatography to give 3-cyclobutyl-phenol (100 mg, 71%).
Reaction SMILES: [F:1][CH2:2][CH2:3][CH2:4]O.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[N:28]1[C:29]2[N:30]([C:41]3[CH:47]=[CH:46][CH:45]=[CH:44][C:42]=3[N:43]=2)[CH:31]=[CH:32][C:33]=1[C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[N:28]1[C:29]2[N:30]([C:41]3[CH:47]=[CH:46][CH:45]=[CH:44][C:42]=3[N:43]=2)[CH:31]=[CH:32][C:33]=1[C:34]1[CH:35]=[CH:36][C:37]([NH:38][CH2:4][CH2:3][CH2:2][F:1])=[CH:39][CH:40]=1
Reactant: OCCCF
Reactant: Nc1ccc(-c2ccn3c(n2)nc2ccccc23)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: FCCCNc1ccc(-c2ccn3c(n2)nc2ccccc23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.2 %

Procedure:
To 3-fluoropropan-1-ol (4 mg, 0.05 mmol) in 0.5 mL DCM was added Dess-Martin reagent (42 mg, 0.1 mmol). The mixture was stirred at rt for 1 h and filtered directly into a mixture of 4-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)aniline (4 mg, 0.015 mmol) and NaBH(OAc)3 (43 mg, 0.2 mmol) with stirring. After vigorously stirred for 5 min, reaction was quenched by adding 0.5 M NaOH (2 mL). The mixture was extracted with EtOAc (3×10 mL) and the organic phase was dried over MgSO4 and concentrated. The crude product was purified by HPLC to afford 4-(Benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)-N-(3-fluoropropyl)aniline as a yellow solid (2.7 mg, 33%). 1H NMR (400 MHz, CDCl3): δ 8.76 (d, J=7.2 Hz, 1H), 7.88 (m, 4H), 7.55 (d, J=7.2 Hz, 1H), 7.53 (m, 1H), 7.40 (m, 1H), 6.47 (d, J=9.2 Hz, 1H), 4.68 (t, J=5.2 Hz, 1H), 4.56 (t, J=5.2 Hz, 1H), 3.34 (t, J=6.8 Hz, 2H), 2.09 (m, 1H), 2.02 (m, 1H); MS (ESI): 321 (M+H+).