Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH:3]([O:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=2)[N:8]=1)([CH3:5])[CH3:4].[CH3:25][O:26][CH2:27][CH2:28]Br>CN(C=O)C>[CH:3]([O:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:28][CH2:27][O:26][CH3:25])=[CH:14][CH:15]=2)[CH:10]=[C:9]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=2)[N:8]=1)([CH3:5])[CH3:4]
Reactant: Cc1cc(Nc2cc3cc(O)ccc3c(OC(C)C)n2)n[nH]1
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOc1ccc2c(OC(C)C)nc(Nc3cc(C)[nH]n3)cc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 8.5 %

Procedure:
NaH (6 mg) was added to 1-Isopropoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-6-ol (50 mg) in DMF (2 ml) and stirred at room temperature for 30 minutes. Then 2-bromoethyl methyl ether (23 mg) was added and stirred at room temperature overnight. The mixture was sent to preparative LC-MS and 5 mg of [1-Isopropoxy-6-(2-methoxy-ethoxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine was produced. LC-MS m/e 357(MH+).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[C:8]1[CH:9]=[C:10]([C:13]2[N:14]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=3[F:33])[C:15](=[O:24])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:23])[O:11][CH:12]=1.[CH2:34]([S:36][C:37]1[CH:38]=[C:39](B2OC(C)(C)C(C)(C)O2)[CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1)[CH3:35].O>C1COCC1.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]>[Cl:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:16]=1[C:15](=[O:24])[N:14]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[F:33])[C:13]([C:10]1[O:11][CH:12]=[C:8]([C:39]3[CH:40]=[C:41]([C:43]([F:45])([F:44])[F:46])[CH:42]=[C:37]([S:36][CH2:34][CH3:35])[CH:38]=3)[CH:9]=1)=[CH:22]2
Reactant: CCSc1cc(B2OC(C)(C)C(C)(C)O2)cc(C(F)(F)F)c1
Reactant: O=c1c2c(Cl)cccc2cc(-c2cc(Br)co2)n1Cc1ccc(F)cc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: CCSc1cc(-c2coc(-c3cc4cccc(Cl)c4c(=O)n3Cc3ccc(F)cc3F)c2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 42.2 %

Procedure:
Potassium carbonate (62 mg, 0.45 mmol), 3-(4-bromofuran-2-yl)-8-chloro-2-(2,4-difluorobenzyl)-2H-isoquinolin-1-one (61 mg, 0.14 mmol), and 2-(3-ethylsulfanyl-5-trifluoromethylphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (59 mg, 0.18 mmol) were combined in a mixture of THF (3 mL), and H2O (1 mL). The resulting biphasic mixture was sparged with nitrogen for 10 minutes. Dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (12 mg, 15 μmol) was then added to afford a dark red-brown solution. After stirring at ambient temperature for 16 hours, HPLC analysis of the reaction showed a later eluting peak present as well as a quantity of the starting 3-(4-bromo-furan-2-yl)-8-chloro-2-(2,4-difluorobenzyl)-2H-isoquinolin-1-one remaining. An additional portion of the Pd catalyst was added and the reaction was then heated in an oil bath held at 60° C. After stirring for 150 minutes at 60° C., HPLC analysis showed the starting 3-(4-bromo-furan-2-yl)-8-chloro-2-(2,4-difluorobenzyl)-2H-isoquinolin-1-one to be consumed. The reaction was allowed to cool to ambient temperature, then diluted with Et2O (50 mL), and H2O (20 mL). The layers were separated and the aqueous layer was extracted with Et2O (3×5 mL). The combined ether layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under educed pressure to afford a brown film. The crude product was purified by silica gel column chromatography by adsorbing the material onto silica gel from a CH2Cl2 solution, loading the resulting solid onto the column and eluting with a gradient from 0% to 12% EtOAc/Hexane. The broad peak that was observed to elute from the column was concentrated under reduced pressure to afford 8-chloro-2-(2,4-difluorobenzyl)-3-[4-(3-ethylsulfanyl-5-trifluoromethylphenyl)furan-2-yl]-2H-isoquinolin-1-one (34 mg, 43% yield) as a clear film. 1H-NMR (400 MHz, CDCl3): δ 7.79 (1H, d, J=0.8 Hz), 7.56-7.53 (2H, m), 7.49-7.41 (4H, m), 7.12-7.04 (1H, m), 6.81-6.71 (4H, m), 5.39 (2H, s), 3.02 (2H, q, J=7.3 Hz), 1.37 (3H, t, J=7.3 Hz).
Reaction SMILES: O.Br.[NH2:3][CH2:4][C:5]([NH:7][N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13](=[O:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20])=[O:6].N[CH2:23][C:24](NN1C=CC=C1C(=O)C1C=CC=CC=1F)=[O:25].Br.N1C=CC=CC=1.C(OC(=O)C)(=O)C>CN(C)C=O.C(Cl)Cl.O>[C:24]([NH:3][CH2:4][C:5]([NH:7][N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13](=[O:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20])=[O:6])(=[O:25])[CH3:23]
Reactant: NCC(=O)Nn1cccc1C(=O)c1ccccc1F
Agent: Br
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)NCC(=O)Nn1cccc1C(=O)c1ccccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-amino-N-[2-(2-fluorobenzoyl)-1H-pyrrol-1-yl]acetamide hydrobromide hemihydrate (2.09 g) in 10 ml of anhydrous dimethylformamide and 40 ml of anhydrous DCM were added pyridine (1.89 g) and acetic anhydride (1.22 g). The reaction mixture was stirred at room temperature for 1 hour, subsequently diluted with water and extracted with DCM. The combined organic layers were washed with 5% hydrochloric acid and water, dried over magnesium sulfate and evaporated in vacuo. The residual oil was recrystallized from DCM/ethyl ether affording the product as crystals (1.58 g), m.p. 146°-147° C.
Reaction SMILES: [CH:1]([C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1)=[O:2]>C(O)C.CCN(C(C)C)C(C)C.[Pd]>[OH:2][CH2:1][C:3]1[CH:13]=[CH:12][C:6]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(C=CC(=O)O)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)CCc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.6 %

Procedure:
A mixture of 4-formyl cinnamic acid (2.82 g, 16.0 mmol) and Pd/C (350 mg, 10% Pd) in ethanol (120 mL) and DIPEA (3 mL) is stirred at rt for 2 h under 1.0 bar H2. The reaction mixture is filtered and the filtrate is evaporated to give 3-(4-hydroxymethyl-phenyl)-propionic acid (2.18 g) as a colourless oil; LC-MS: tR=0.62 min.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12](=[O:23])(=[O:22])[NH:13][C:14]3([CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[C:15]=2[CH3:16])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Br:24]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:24][CH2:16][C:15]1[C:14]2([CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[NH:13][S:12](=[O:23])(=[O:22])[C:11]=1[C:8]1[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1=C(c2ccc(S(C)(=O)=O)cc2)S(=O)(=O)NC12CCCCC2
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CS(=O)(=O)c1ccc(C2=C(CBr)C3(CCCCC3)NS2(=O)=O)cc1
Yield: 67.6 %

Procedure:
3-(4-methanesulfonyl-phenyl)-4-methyl-2-thia-1-azaspiro[4.5]dec-3-ene 2,2-dioxide (4.5 g, 12.6 mmol) and N-bromo succinimide (2.5 g, 14 mmol) were stirred in 200 ml CCl4 with a catalytic amount of benzoyl peroxide for 4 hours at 85° C. Then the solvent was evaporated and the residue disolved in dichloromethane, washed with water and NaHCO3 solution, dried (Na2SO4) and evaporated. The solid product was recrystallized from ethanol to yield 4-bromomethyl-3-(4-methanesulfonyl-phenyl)-2-thia-1-aza-spiro[4.5]dec-3-ene 2,2-dioxide (3.7 g, 68%). This product was dissolved in ethanol (20 ml), ethylamine (70% solution in water, 20 ml) was added, the mixture was left at room temperature for 3 hours and evaporated. The residue was dissolved in CH2Cl2, washed with water and extracted with 2 M HCl. After addition of NaOH and extraction with CH2Cl2 the organic layer was dried (Na2SO4) and evaporated. Chromatography on silica (eluent CH2Cl2/EtOH 95:5) yielded 1.50 g (66%) N-ethyl-N-[3-(4-methanesulfonyl-phenyl)-2,2-dioxo-2-thia-1-aza-spiro[4.5]dec-3-en-4-ylmethyl]-amine, shown below. 1H-NMR (CDCl3) δ 8.01 (d, 2H), 7.83 (d, 2 H), 4.81 (s, 1 H), 3.45 (s, 2 H), 3.09 (s, 3 H), 2.54 (q, 2 H), 2.02-1.15 (m, 10 H), 0.96 (t, 3 H).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[S:4][C:3]=1[C:14]([OH:16])=O.Cl.Cl.[N:19]1([CH:24]([C:26]2[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][NH2:34])=[CH:28][CH:27]=2)[CH3:25])[CH2:23][CH2:22][CH2:21][CH2:20]1.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC>C(OCC)(=O)C.CN(C=O)C>[NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=2)[S:4][C:3]=1[C:14]([NH:34][CH2:33][CH2:32][C:29]1[CH:28]=[CH:27][C:26]([CH:24]([N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH3:25])=[CH:31][CH:30]=1)=[O:16]
Reactant: CC(c1ccc(CCN)cc1)N1CCCC1
Reactant: Nc1cc(-c2ccc(F)cc2)sc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(c1ccc(CCNC(=O)c2sc(-c3ccc(F)cc3)cc2N)cc1)N1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.4 %

Procedure:
To a mixture of 3-amino-5-(4-fluorophenyl)thiophene-2-carboxylic acid (0.20 g), 2-[4-(1-pyrrolidin-1-ylethyl)phenyl]ethanamine dihydrochloride (0.22 g), 1-hydroxybenzotriazole (0.16 g), N,N-diisopropylethylamine (0.30 ml) and DMF (3.0 ml) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.15 g), and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (hexane:ethyl acetate=9:1 (volume ratio)→1:2 (volume ratio)) using NH-silica gel to give 3-amino-5-(4-fluorophenyl)-N-{2-[4-(1-pyrrolidin-1-ylethyl)phenyl]ethyl}thiophene-2-carboxamide (0.15 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]3[CH:14]=[CH:15][S:16][C:11]3=[C:10](O)[CH:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[N:13]=[C:12]2[CH:14]=[CH:15][S:16][C:11]=12
Reactant: Oc1cc(-c2ccc(F)cc2)nc2ccsc12
Reactant: O=P(Cl)(Cl)Cl
Product: Fc1ccc(-c2cc(Cl)c3sccc3n2)cc1
Yield: 88 %

Procedure:
A solution of 5-(4-fluorophenyl)-thieno[3,2-b]pyridin-7-ol (1.6 g) in phosphorus oxychloride (50 mL) is refluxed for 3 hours. After the excess amount of phosphorus oxychloride is removed under vacuum, the residue is treated with ethyl acetate (20 mL), and NaOH (2N, 20 mL). The mixture is extracted with ethyl acetate (3×20 mL). The combinded organic layers are washed with brine and dried over MgSO4. Evaporation of the solvent affords 7-chloro-5-(4-fluorophenyl)thieno[3,2-b]pyridine (1.5 g, 88% yield) as a white solid, m.p. 119-121°C.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][N:8]=[C:7]([C:11]3[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=3[F:18])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:19]C.Cl.N1C=CC=CC=1>>[Cl:1][C:2]1[C:10]2[O:9][N:8]=[C:7]([C:11]3[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=3[F:18])[C:6]=2[CH:5]=[CH:4][C:3]=1[OH:19]
Reactant: COc1ccc2c(-c3cc(F)ccc3F)noc2c1Cl
Agent: Cl
Solvent: c1ccncc1
Product: Oc1ccc2c(-c3cc(F)ccc3F)noc2c1Cl
Temperature: 200 °C

Procedure:
A mixture of 10 g of 7-chloro-3-(2,5-difluorophenyl)-6-methoxy-1,2-benzisoxazole and 40 g of pyridine HCl is heated at 200° C. for 45 minutes. The hot mixture is poured into vigorously stirred ice water and a product precipitates out. The product is filtered and dried giving 7-chloro-3-(2,5-difluorophenyl)-6-hydroxy-1,2-benzisoxazole, mp 256°-257° C.
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][C:11]=2[F:24])[C:5]([CH2:25][CH2:26][CH2:27][CH3:28])=[N:4][C:3]=1[CH3:29].[F:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.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]>[CH2:25]([C:5]1[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][C:11]=2[F:24])[C:7](=[O:8])[C:2]([C:34]2[CH:35]=[CH:36][C:31]([F:30])=[CH:32][CH:33]=2)=[C:3]([CH3:29])[N:4]=1)[CH2:26][CH2:27][CH3:28]
Reactant: CCCCc1nc(C)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1F
Reactant: OB(O)c1ccc(F)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCCCc1nc(C)c(-c2ccc(F)cc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1F
Temperature: 90 °C
Reaction time: 12 h
Yield: 98.7 %

Procedure:
To a solution of 4′-[(5-bromo-2-butyl-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl]-3′-fluorobiphenyl-2-carbonitrile (0.5 g) and 4-fluorophenylboronic acid (0.23 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 (0.51 g, 98%) as a colorless solid.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:3]1[CH3:15].[H-].[Na+].Cl[C:19]1[N:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][N:20]=1>C1COCC1.O>[CH3:15][C@H:3]1[C@H:2]([O:1][C:19]2[N:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][N:20]=2)[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: FC(F)(F)c1cnc(Cl)nc1
Reactant: C[C@H]1[C@H](O)CCCN1C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H]1[C@H](Oc2ncc(C(F)(F)F)cn2)CCCN1C(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 72.3 %

Procedure:
To (2S,3R)-tert-butyl 3-hydroxy-2-methylpiperidine-1-carboxylate (670 mg, prepared according to J. Org. Chem. 2008, 73, 2898) in THF (15 mL) at 0° C. was added NaH (60 wt %, 188 mg). After 15 min, 2-chloro-5-(trifluoromethyl)pyrimidine (570 mg) was added and the reaction allowed to proceed at rt overnight. The reaction was diluted with H2O and extracted with DCM. The organic layers were dried (MgSO4). Purification via silica gel chromatography (0-40% EtOAc in heptane) gave the title compound (813 mg, 72%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.[C:12](=O)([O:18]C(C)(C)C)[O:13][C:14]([CH3:17])([CH3:16])[CH3:15].CCCCC>C1COCC1.CN(C)C1C=CN=CC=1>[C:14]([O:13][C:12]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1)=[O:18])([CH3:17])([CH3:16])[CH3:15]
Reactant: CCOC(=O)c1csc(N)n1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CCCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1csc(NC(=O)OC(C)(C)C)n1
Temperature: 50 °C
Reaction time: 4 h
Yield: 66.4 %

Procedure:
Ethyl 2-aminothiazole-4-carboxylate (55; 10.0 g, 58.1 mmol) was taken up in 150 mL of anhydrous THF along with di-tert-butyl carbonate (BOC2O, 12.67 g, 58.1 mmol) along with 10 mg of 4-(dimethyl)aminopyridine (DMAP). The reaction mixture was stirred at 50° C. for 4 h and then at room temperature for 18 h. It was then concentrated under reduced pressure to obtain a thick oil. Pentane was added and the resulting crystalline materials were collected by filtration and dried to afford 10.5 g of ethyl 2-(tert-butoxycarbonylamino)thiazole-4-carboxylate 56. This material 56 (10.5 g, 38.5 mmol) was dissolved in 300 mL of anhydrous THF and cooled in Dry Ice-acetonitrile bath. A solution of 1 M Super Hydride™ in THF (85 mL) was then added over a period of 10 min. The resulting reaction mixture was stirred at −45° C. for 2 h. Another portion of 1 M Super Hydride™ in THF (35 mL) was then added and the reaction mixture was stirred for an additional 2 h at −45° C. The reaction was quenched at −45° C. by the addition of 50 mL of brine. Upon warming to room temperature, the reaction mixture was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by chromatography to afford 6.39 g of tert-butyl 4-(hydroxymethyl)thiazol-2-ylcarbamate 57 (72%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[C:16]([NH2:18])=O)[CH:8]([CH3:10])[CH3:9].O.[OH-].[Na+]>O1CCCC1>[CH2:7]([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[CH2:16][NH2:18])[CH:8]([CH3:10])[CH3:9]
Reactant: CC(C)CN1CCC[C@@H]1C(N)=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CN1CCC[C@@H]1CN
Reaction time: 0.17 h

Procedure:
Lithium aluminum hydride [1.0mol soln. in tetrahydrofuran] (11.52 ml, 11.52 mmol) was added to a solution of (2R)-1-isobutyl-2-pyrrolidinecarboxamide (1.3 g, 7.68 mmol) [see preparation 59] in tetrahydrofuran (5 ml) @0° C. The reaction mixture was stirred for 10 mins and then heated to reflux for 6 hrs. Water (0.5 ml) was added to the cooled mixture followed by sodium hydroxide (1.5 ml) and water (1.5 ml). Tetrahydrofuran (10 ml) was added and the mixture was stirred at room temperature for 1 hr. The aluminum salts were removed by filtration and washed well with diethyl ether. The filtrate was then evaporated under reduced pressure to afford the title compound as a white solid, 705 mg, (58%).
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:12]=[N:13][C:14]4[C:19]([CH:20]=3)=[CH:18][CH:17]=[CH:16][CH:15]=4)=[C:6]2[N:5]=[C:4]([C:21]2[CH2:26][CH2:25][N:24]([C:27]([C:29]3[S:30][CH:31]=[CH:32][CH:33]=3)=[O:28])[CH2:23][CH:22]=2)[C:3]=1Br.[Cl:35]C1C(C2CCNCC=2)=NC2N(N=CC=2C2C=NC3C(C=2)=CC=CC=3)C=1N.BrC1C(C2CCNCC=2)=NC2N(N=CC=2C2C=NC3C(C=2)=CC=CC=3)C=1N>>[NH2:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:12]=[N:13][C:14]4[C:19]([CH:20]=3)=[CH:18][CH:17]=[CH:16][CH:15]=4)=[C:6]2[N:5]=[C:4]([C:21]2[CH2:26][CH2:25][N:24]([C:27]([C:29]3[S:30][CH:31]=[CH:32][CH:33]=3)=[O:28])[CH2:23][CH:22]=2)[C:3]=1[Cl:35]
Reactant: Nc1c(Cl)c(C2=CCNCC2)nc2c(-c3cnc4ccccc4c3)cnn12
Reactant: Nc1c(Br)c(C2=CCN(C(=O)c3cccs3)CC2)nc2c(-c3cnc4ccccc4c3)cnn12
Agent: Nc1c(Br)c(C2=CCNCC2)nc2c(-c3cnc4ccccc4c3)cnn12
Product: Nc1c(Cl)c(C2=CCN(C(=O)c3cccs3)CC2)nc2c(-c3cnc4ccccc4c3)cnn12

Procedure:
(4-(7-amino-6-chloro-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-5,6-dihydropyridin-1(2H)-yl)(thiophen-2-yl)methanone was synthesized in a manner similar to the synthesis of (4-(7-amino-6-bromo-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-5,6-dihydropyridin-1(2H)-yl)(thiophen-2-yl)methanone, but with 6-chloro-3-(quinolin-3-yl)-5-(1,2,3,6-tetrahydropyridin-4-yl)pyrazolo[1,5-a]pyrimidin-7-amine substituted for 6-bromo-3-(quinolin-3-yl)-5-(1,2,3,6-tetrahydropyridin-4-yl)pyrazolo[1,5-a]pyrimidin-7-amine. The reaction mixture was purified via reverse-phase preparatory HPLC to yield (4-(7-amino-6-chloro-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-5,6-dihydropyridin-1(2H)-yl)(thiophen-2-yl)methanone as yellow solid. (m+H=487.17, retention time=3.73 min)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:36][C@H:37]([OH:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][C:24]([O:26]CC)=[O:25])=[C:19]([O:29][CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[CH:18]=2)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>C(O)C>[C:1]([O:5][C:6]([N:8]([CH2:36][C@H:37]([OH:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][C:24]([OH:26])=[O:25])=[C:19]([O:29][CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[CH:18]=2)=[CH:15][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)Cc1ccc(-c2ccc(CCN(C[C@H](O)c3ccccc3)C(=O)OC(C)(C)C)cc2)cc1OC1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N(CCc1ccc(-c2ccc(CC(=O)O)c(OC3CCCCC3)c2)cc1)C[C@H](O)c1ccccc1
Reaction time: 8 h
Yield: 85.4 %

Procedure:
To a solution of ethyl [4′-[2-[(tert-butoxycarbonyl)-[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]-3-cyclohexyloxy-4-biphenylyl]acetate (441 mg) in ethanol (4.4 ml) was added 1N sodium hydroxide (1.83 ml) at room temperature, and the mixture was stirred at the same temperature for 8 hours. To the resulting mixture was added 1N hydrochloric acid (1.83 ml), and ethanol was removed by evaporation under reduced pressure. To the aqueous mixture was added ethyl acetate and water. After separation, the organic layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform/methanol=100:1 to 20:1) to give [4′-[2-[(tert-butoxycarbonyl)[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]-3-cyclohexyloxy-4-biphenylyl]-acetic acid (359 mg).
Reaction SMILES: [O-]CC.[Na+].[CH2:5]([C:9]([NH2:11])=[O:10])[C:6]([NH2:8])=[NH:7].Cl.Br[CH:14]([CH3:24])[C:15]([C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=1)=O>C(O)C>[NH2:7][C:6]1[NH:8][C:15]([C:17]2[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=2)=[C:14]([CH3:24])[C:5]=1[C:9]([NH2:11])=[O:10]
Reactant: N=C(N)CC(N)=O
Reactant: CC(Br)C(=O)c1ccc(Br)cc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1c(-c2ccc(Br)cc2)[nH]c(N)c1C(N)=O
Reaction time: 0.5 h
Yield: 4.1 %

Procedure:
Under ice-cooling, sodium ethoxide (1.4 g, 20 mmol) was added to a suspension of malonamamidine hydrochloride (2.8 g, 20 mmol) in dehydrated ethanol (80 mL), and the mixture was stirred for 30 minutes. Moreover, 2,4′-dibromopropiophenone (2.9 g, 10 mmol) was added thereto, and the whole was stirred overnight at room temperature. After the reaction mixture was concentrated in vacuo, the residue was purified by silica gel column chromatography to give the title reference compound (0.12 g) as a white solid (Yield 4%).
Reaction SMILES: C([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][Br:22])[C:13](=[O:23])[N:12]([CH3:24])[C:11]=2[N:10]=[CH:9]1)C1C=CC=CC=1.[H][H]>CO.[OH-].[OH-].[Pd+2]>[Br:22][CH2:21][CH2:20][CH2:19][CH2:18][N:14]1[C:15](=[O:17])[C:16]2[NH:8][CH:9]=[N:10][C:11]=2[N:12]([CH3:24])[C:13]1=[O:23]
Reactant: [H][H]
Reactant: Cn1c(=O)n(CCCCBr)c(=O)c2c1ncn2Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: Cn1c(=O)n(CCCCBr)c(=O)c2[nH]cnc21
Yield: 89.7 %

Procedure:
A solution of 2.1 g (0.005 mole) of 95% 7-benzyl-1-(4-brombutyl)-3-methylxanthine in 50 mL methanol and 0.21 g of 20% palladium hydroxide on carbon is hydrated at 40° until cessation of hydrogen absorption (˜1.5 hours). The catalyst is filtered out and washed with hot methanol, then the filtrate is evaporated, yielding 1.35 g of 1-(4-brombutyl)-3-methylxanthine (VI, where R═H, R1=Me, n=4).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([O:10][CH3:11])[N:3]=1.C1N2CCN(CC2)C1.C(=O)([O-])[O-:21].[K+].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O>[CH3:11][O:10][C:4]1[N:3]=[C:2]([OH:21])[CH:7]=[C:6]([O:8][CH3:9])[N:5]=1
Reactant: COc1cc(Cl)nc(OC)n1
Reactant: O=C([O-])[O-]
Agent: C1CN2CCN1CC2
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: O
Product: COc1cc(O)nc(OC)n1
Yield: 34.3 %

Procedure:
A suspension of 4-chloro-2,6-dimethoxy-pyrimidine (4.9 g, 28 mmol), DABCO (6.4 g, 57 mmol) and potassium carbonate (13.8 g, 100 mmol) was refluxed in water (150 ml) for one hour. The mixture was cooled acidified with 5% citric acid and extracted three times with ethyl acetate and three times with DCM with about 105 THF and 10% MeOH. The combined organic phases were dried and evaporated which gave the title compound (1.5 g, 34%), (M+H)+1 157.