Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[O:12]1[C:16]2([CH2:21][CH2:20][CH:19](O)[CH2:18][CH2:17]2)[O:15][CH2:14][CH2:13]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([CH:19]3[CH2:20][CH2:21][C:16]4([O:15][CH2:14][CH2:13][O:12]4)[CH2:17][CH2:18]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: OC1CCC2(CC1)OCCO2
Reactant: Clc1ncnc2[nH]cc(I)c12
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1ncnc2c1c(I)cn2C1CCC2(CC1)OCCO2
Reaction time: 20 h
Yield: 200.8 %

Procedure:
To a solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (25.0 g, 0.09 mol), 1,4-dioxaspiro[4.5]decan-8-ol (35.8 g, 0.0267 mol) and triphenylphosphine (46.7 g, 0.178 mol) in THF (1.2 L) was added diethylazodicarboxylate (30.9 g, 0.178 mol) under nitrogen. The solution was stirred for 20 hr and the majority of solvent was then evaporated (250 mL remaining). EtOAc (450 mL) was then added and the resulting solid was filtered, washed with EtOAc (2×50 mL) and dried in vacuo to give 4-chloro-7-(1,4-dioxaspiro[4.5]dec-8-yl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (22.5 g, 60%) as a cream solid. 1H NMR (d6 DMSO, 400 MHz) 8.64(1H, s), 8.10(1H, s), 4.74(1H, m), 3.90(4H, m), 2.12(2H, m), 1.91(2H, m), 1,71-1.83(4H, m). Rf in 1:4 EtOAc:heptane=0.12.
Reaction SMILES: [N:1]1[C:11]2[CH2:10][CH2:9][CH2:8][C:7](=O)[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].CO>O1CCCC1>[N:1]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCCc2ncccc2N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: c1cnc2c(c1)NCCCC2
Yield: 70.9 %

Procedure:
A mixture of 1.56 g of 5,7,8,9-tetrahydro-6H-pyrido[3,2-b]azepine-6-one, 3.31 g of lithium aluminum hydride in 40 ml of tetrahydrofuran is refluxed for 4 hours. The mixture is cooled (0° C.) and 25 ml of methanol is added dropwise. The mixture is filtered through diatomaceous earth, the filter cake washed with tetrahydrofuran and the filtrate concentrated to dryness under vacuum. Water (50 ml) is added to the residue and the mixture extracted with diethyl ether. The extract is dried (Na2SO4) and filtered through a thin pad of hydrous magnesium silicate (pad washed with) diethyl ether. The filtrate is concentrated under vacuum to give 1.01 g of crystals, m.p. 70°-71° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[C:8]([CH3:10])[CH:9]=1)=[O:4].[Br:18]Br>C(Cl)(Cl)Cl.[Cl-].[Zn+2].[Cl-]>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)=[C:8]([CH3:10])[C:9]=1[Br:18])=[O:4]
Reactant: COC(=O)c1cc(C)c(-c2ccc(Cl)cc2)s1
Reactant: BrBr
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClC(Cl)Cl
Product: COC(=O)c1sc(-c2ccc(Cl)cc2)c(C)c1Br
Temperature: 62.5 °C
Reaction time: 1.5 h
Yield: 42.53 %

Procedure:
To a stirred solution of methyl-5-(4-chlorophenyl)-4-methylthiophene-2-carboxylate (prepared according to the procedure reported in WO 2007092751, 4.0 g, 15.0 mmol) in chloroform (50 ml) at 25° C. was added zinc chloride (2.06 g, 15.0 mmol) followed by the addition of bromine (2.64 g, 0.85 ml, 16.5 mmol) in a dropwise manner under a nitrogen atmosphere. The resulting mixture was stirred at 60-65° C. for 1.5 hr. The progress of the reaction was monitored by TLC. The reaction mixture was cooled to 0° C. and quenched with water (30 ml). The resulting organic layer was washed with 10% aqueous sodium bicarbonate solution (2×50 ml) and dried over anhydrous Na2SO4. The solvent in the organic layer was evaporated under reduced pressure to obtain a crude product, which was then purified by column chromatography over silica gel (100-200 mesh) using 3% ethyl acetate in hexanes as an eluent to obtain the title compound (2.2 g, 42.53%);
Reaction SMILES: C(O[C:4](=[O:35])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12]1[C:17]([Cl:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]2[CH:34]=[CH:33][C:23]3[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][O:31][CH3:32])[CH2:27][CH2:28][C:22]=3[CH:21]=2)[N:13]=1)C.[CH:36]1([CH2:39][NH2:40])[CH2:38][CH2:37]1>>[Cl:18][C:17]1[C:12]([NH:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([NH:40][CH2:39][CH:36]2[CH2:38][CH2:37]2)=[O:35])=[N:13][C:14]([NH:19][C:20]2[CH:34]=[CH:33][C:23]3[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][O:31][CH3:32])[CH2:27][CH2:28][C:22]=3[CH:21]=2)=[N:15][CH:16]=1
Reactant: CCOC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCN(CCOC)CC3)ncc1Cl
Reactant: NCC1CC1
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(Nc4ccccc4C(=O)NCC4CC4)n3)cc2CC1

Procedure:
2-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-N-cyclopropylmethyl-benzamide was prepared from 2-{5-chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-benzoic acid ethyl ester and cyclopropylmethylamine in an analogous manner to Example 1396. Product isolated as a tan solid (30 mg, 47%). m.p.=173-175° C.; LCMS (m/e) 521 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 11.02 (s, 1H), 8.66 (d, 1H, J=8.4 Hz), 8.09 (s, 1H), 7.54 (d, 1H, J=7.6 Hz), 7.49-7.40 (m, 1H), 7.35 (s, 1H), 7.24 (d, 1H, J=8.0 Hz), 7.16-7.04 (m, 2H), 7.03 (d, 1H, J=8.0 Hz), 6.40-6.30 (m, 1H), 3.56 (t, 2H, J=5.6 Hz), 3.39 (s, 3H), 3.37-3.30 (m, 2H), 2.98-2.83 (m, 4H), 2.82-2.67 (m, 6H), 1.14-1.01 (m, 1H), 0.64-0.55 (m, 2H), 0.35-0.27 (m, 2H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([N:13]1[CH:17]=[CH:16]N=C1)=[S:12].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1CCN>CN(C)C=O>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:16][CH2:17][NH:13][C:11]([NH:10][C:2]1[S:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1)=[S:12]
Reactant: COc1ccccc1CCN
Reactant: S=C(Nc1nc2ccccc2s1)n1ccnc1
Solvent: CN(C)C=O
Product: COc1ccccc1CCNC(=S)Nc1nc2ccccc2s1
Temperature: 25 °C
Yield: 65.5 %

Procedure:
A solution of 1-[(2-benzothiazolyl)-thiocarbamoyl] imidazole (1.04 g, 4 mmol) and 2-(2-methoxyphenyl)ethylamine (0.62 g, 4 mmol) in dimethylformamide (15 mL) was stirred at 100° C. for 1 h, the reaction was cooled to room temperature and the solvent removed in vacuo. The residue was crystallized from ethyl acetate to provide 0.9 g (66%) of the title product:
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:25])[CH2:12][CH2:11][CH2:10][C:9]2[CH:8]=[C:7]([C:13]3[N:14]=[C:15]([N:18]4[CH2:23][CH2:22][CH:21]([NH2:24])[CH2:20][CH2:19]4)[S:16][CH:17]=3)[CH:6]=[CH:5][C:4]1=2.CC1(C)[O:31][C@@H:30]([CH:32]=O)[CH2:29][O:28]1.Cl.CO.Cl>>[CH3:2][C:3]1([CH3:25])[CH2:12][CH2:11][CH2:10][C:9]2[CH:8]=[C:7]([C:13]3[N:14]=[C:15]([N:18]4[CH2:23][CH2:22][CH:21]([NH:24][CH2:32][C@H:30]([OH:31])[CH2:29][OH:28])[CH2:20][CH2:19]4)[S:16][CH:17]=3)[CH:6]=[CH:5][C:4]1=2
Reactant: CC1(C)OC[C@H](C=O)O1
Reactant: CC1(C)CCCc2cc(-c3csc(N4CCC(N)CC4)n3)ccc21
Agent: Cl
Solvent: CO
Product: CC1(C)CCCc2cc(-c3csc(N4CCC(NC[C@H](O)CO)CC4)n3)ccc21

Procedure:
The preparation was carried out as already described above starting from 100 mg (0.27 mmol) of 1-[4-(5,5-dimethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperidin-4-ylamine hydrochloride and 34 mg (0.27 mmol) of (R)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde. The protecting group was cleaved off as described by means of a 1.25 N HCl/methanol solution. The product was converted into the hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.[CH2:10]([O:17][C:18](Cl)=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CCOC(C)=O>[CH2:10]([O:17][C:18](=[O:19])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1cc(N)ccc1O
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1cc(NC(=O)OCc2ccccc2)ccc1O

Procedure:
4-Amino-2-methyl-phenol (717 mg, 5.8 mmol) and benzyloxycarbonyl chloride (1.09 g, 6.4 mmol) are stirred in a suspension of AcOEt/concentrated Na2CO3 solution (50 mL/50 mL) for 7 h. The organic phase is concentrated under reduced pressure and flash chromatographed (silica gel, 3.8×66 cm, AcOEt/hexane=1:3): M+H=257.9; HPLC (System 1): 5.43 min.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:4]=1[NH:11][NH2:12].[CH3:13][CH2:14][C:15](=O)[CH2:16][C:17](=O)[CH2:18][CH3:19].C(N(CC)CC)C>C(O)C>[CH2:14]([C:15]1[CH:16]=[C:17]([CH2:18][CH3:19])[N:11]([C:4]2[C:3]([CH3:2])=[CH:8][C:7]([CH3:9])=[CH:6][C:5]=2[CH3:10])[N:12]=1)[CH3:13]
Reactant: CCC(=O)CC(=O)CC
Reactant: Cc1cc(C)c(NN)c(C)c1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCc1cc(CC)n(-c2c(C)cc(C)cc2C)n1
Yield: 95 %

Procedure:
A solution of 7.46 g (0.04 mol) of 2,4,6-trimethylphenylhydrazine hydrochloride, 5.12 g (0.40 mol) of 3,5-heptanedione and 4.18 mL (0.60 mol) of triethylamine in 100 mL of absolute ethanol was refluxed overnight. The solvent was evaporated from the cooled reaction mixture and the residues were partitioned between water and ethyl acetate. The organic extracts were dried with brine and magnesium sulfate, and the solvent was evaporated to give the desired product in 95% yield. This compound was used in the subsequent reaction without further purification 1H-NMR (CDCl3): 11 (3H, t, J=7),1.24 (3H, t, J=7),1.90 (6H, s), 2.22 (2H, q, J-7), 2.28 (3H, 5.96 (1H, s), 6.86 (2H, s).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N+:6]([O-])[CH:7]=[C:8]([N+:11]([O-])=O)[CH:9]=2)[S:4][C:3]=1[S:15]([C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([C:25]#[N:26])[CH:19]=1)(=[O:17])=[O:16].C(Cl)(Cl)Cl>C(O)(=O)C.[Fe]>[NH2:11][C:8]1[CH:9]=[C:10]2[C:2]([Br:1])=[C:3]([S:15]([C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([C:25]#[N:26])[CH:19]=3)(=[O:16])=[O:17])[S:4][C:5]2=[N:6][CH:7]=1
Reactant: N#Cc1cc(F)cc(S(=O)(=O)c2sc3c(cc([N+](=O)[O-])c[n+]3[O-])c2Br)c1
Agent: [Fe]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: N#Cc1cc(F)cc(S(=O)(=O)c2sc3ncc(N)cc3c2Br)c1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
3-Bromo-2-(3-cyano-5-fluoro-benzenesulfonyl)-5-nitro-thieno[2,3-b]pyridin-N-oxide (1.0 g, 2.18 mmol) was suspended in acetic acid (12 ml) and Fe powder was added (0.73 g, 13 mmol). The reaction mixture was stirred at 60-70° C. for 60 minutes. Chloroform (45 ml) was added and after filtration through celite the filtrate was evaporated, the crude residue was treated with methanol (3 ml). The product was filtered, washed with methanol. It was obtained (0.69 g, 76.7%) as a yellow powder. LC-MS: (M+H)+ 413.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1F)[N:8]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[F:20])[CH:7]=[C:6]([C:21]([OH:23])=[O:22])[C:5]2=[O:24].Cl.Cl.[NH2:27][CH2:28][CH:29]1[C:33](=[N:34][O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:32][NH:31][CH2:30]1.N12CCCN=C1CCCCC2>C(#N)C>[NH2:27][CH2:28][CH:29]1[C:33](=[N:34][O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:32][N:31]([C:11]2[N:10]=[C:9]3[C:4]([C:5](=[O:24])[C:6]([C:21]([OH:23])=[O:22])=[CH:7][N:8]3[C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[F:20])=[CH:3][C:2]=2[F:1])[CH2:30]1
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2nc(F)c(F)cc2c1=O
Reactant: CC(C)(C)ON=C1CNCC1CN
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(C)(C)ON=C1CN(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3-c2ccc(F)cc2F)CC1CN
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80.6 %

Procedure:
168 mg (0.5 mmole) of 6,7-difluoro-1-(2,4-difluorophenyl)-4-oxo-1,4-dihydro-naphthyridine-3-carboxylic acid and 143 mg (0.55 mmole) of 3-aminomethyl-4-t-butyloxyiminopyrrolidine dihydrochloride were suspended in 3 ml of dry acetonitrile. Then, 230 mg (1.5 mmole) of 1,8-diazabicyclo[5.4.0]undec-7-ene was added thereto, and the reaction mixture was stirred for 15 minutes at room temperature and then treated according to the same manner as Example 89 to obtain 203 mg (Yield: 81%) of the title compound.
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.C(O)=O.[CH2:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][CH2:14][CH2:13][NH:12]1>C(OCC)(=O)C>[CH:5]([N:12]1[CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:11]1)=[O:7]
Reactant: CC(=O)OC(C)=O
Reactant: c1ccc2c(c1)CCCNC2
Solvent: O=CO
Solvent: CCOC(C)=O
Product: O=CN1CCCc2ccccc2C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Acetic anhydride (20 ml) was added dropwise to formic acid (60 ml) at room temperature and after the mixture was stirred for 30 minutes, a solution of 2,3,4,5-tetrahydro 1H-2-benzazepine (10.71 g, 72.75 mmol) in ethyl acetate (5 ml) was added dropwise at room temperature. This mixture was stirred for 3 hours, after which it was diluted with ice-water and extracted with ethyl acetate. The extract was washed successively with water, aqueous solution of potassium carbonate (K2CO3), and saturated NaCl/H2O and dried over MgSO4. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel column chromatography (eluent: ethyl acetate) to provide the title compound (11.35 g) as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][C:6]([CH3:13])=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)CC)C.[OH:21][C@H:22]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:23]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:24]>C(Cl)Cl>[Cl:1][C:2]1[N:11]=[C:10]([N:28]2[CH2:27][CH2:26][N:25]([C:23](=[O:24])[C@H:22]([OH:21])[CH2:31][CH:32]([CH3:33])[CH3:34])[CH2:30][CH2:29]2)[C:9]2[C:4](=[CH:5][C:6]([CH3:13])=[CH:7][CH:8]=2)[N:3]=1
Reactant: CC(C)C[C@@H](O)C(=O)N1CCNCC1
Reactant: Cc1ccc2c(Cl)nc(Cl)nc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc2c(N3CCN(C(=O)[C@H](O)CC(C)C)CC3)nc(Cl)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 183 %

Procedure:
To a solution of 2,4-dichloro-7-methylquinazoline (2.09 g, 9.83 mmol) in CH2Cl2 (10 mL) at 0° C. was added triethylamine (2.74 mL, 19.66 mmol), followed by the addition of (R)-2-hydroxy-4-methyl-1-(piperazin-1-yl)pentan-1-one (1.97 g, 9.83 mmol). The reaction mixture was warmed to room temperature and stirred overnight. The mixture was then quenched with water and extracted twice with CH2Cl2. The combined organic extracts were dried over MgSO4, filtered, and concentrated to obtain (R)-1-(4-(2-chloro-7-methylquinazolin-4-yl)piperazin-1-yl)-2-hydroxy-4-methylpentan-1-one (6.78 g, 95%). LC/MS: m/z 377.5 (M+H)+ at 2.61 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([CH3:11])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24])[N:6]2[CH2:12][CH2:13][S:14]([CH3:17])(=[O:16])=[O:15].[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(N(CC)CC)C>C(O)C>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:5]1[N:6]([CH2:12][CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:7]2[C:3]([N:4]=1)=[C:2]([N:29]1[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]1)[N:10]=[C:9]([CH3:11])[N:8]=2
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3Cl)n(CCS(C)(=O)=O)c2n1
Reactant: CN1CCNCC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1nc(N2CCN(C)CC2)c2nc(-c3ccccc3Cl)n(CCS(C)(=O)=O)c2n1
Yield: 76.4 %

Procedure:
Heat a solution of 6-chloro-8-(2-chlorophenyl)-2-methyl-9-(2-methylsulfonylethyl)purine (0.3 g, 0.0007 mol), N-methylpiperazine (0.08 g, 0.0008 mol) and triethylamine (0.08 g, 0.0008 mol) in ethanol (15 mL) at 90° C. for 16 h. Cool and concentrate the reaction mixture under reduced pressure. Dissolve the residue in dry dichloromethane and wash with saturated sodium bicarbonate solution, water, and brine. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate to give a residue. Purify the residue on a silica gel column using dichloromethane:methanol (96:4) as eluent to afford a 8-(2-chlorophenyl)-6-(4-methylpiperazin-1-yl)-2-methyl-9-(2-methylsulfonylethyl)purine (0.24 g). ES/MS m/z 449 (M+1).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([N:13]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)[CH:6]=[CH:7][C:8]=2[OH:12])[CH2:3]1.C(N(CC)CC)C.[CH2:27]([O:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=1)[CH2:28][CH2:29][CH3:30]>CN(C)C=O>[OH:12][C:8]1[CH:7]=[CH:6][C:5]([N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[C:4]2[C:9]=1[CH2:10][CH2:11][C@@H:2]([NH:1][C:36](=[O:37])[C:35]1[CH:34]=[CH:33][C:32]([O:31][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:40][CH:39]=1)[CH2:3]2
Reactant: CN1CCN(c2ccc(O)c3c2C[C@H](N)CC3)CC1
Reactant: CCCCOc1ccc(C(=O)Cl)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCOc1ccc(C(=O)N[C@@H]2CCc3c(O)ccc(N4CCN(C)CC4)c3C2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To an ice-cooled solution of (R)-2-amino-5-hydroxy-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (100 mg, 0.38 mmol) and triethylamine (79 μL, 0.57 mmol) in N,N-dimethylformamide (30 mL) was 4-butoxybenzoyl chloride in N,N-dimethylformamide (5 mL) added dropwise. After the addition the reaction was stirred at ambient temperature for 15 min. The solvent was evaporated in vacuo and the residue was purified on a silica gel column using chloroform/methanol/concentrated ammonium hydroxide (95:5:0.5) as the eluent. Yield: 73 mg (44%) as an amorphous solid: mp 125° C. (decomp.); [α]21D−20° (c=0.25, chloroform); EIMS (70 eV) m/z (relative intensity) 437 (16, M+).
Reaction SMILES: [CH2:1]([C:8]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])([CH2:30][OH:31])[CH2:9][O:10][CH2:11][C:12]1[CH:13]=[C:14]([C:26]([O:28]C)=[O:27])[CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]#[N:25])[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-]>C1COCC1.O>[CH2:1]([C:8]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])([CH2:30][OH:31])[CH2:9][O:10][CH2:11][C:12]1[CH:13]=[C:14]([C:26]([OH:28])=[O:27])[CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]#[N:25])[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(COCC(CO)(Cc2ccccc2)NC(=O)OC(C)(C)C)cc(-c2ccccc2C#N)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(CO)(COCc1cc(C(=O)O)cc(-c2ccccc2C#N)c1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 60.4 %

Procedure:
To a solution of crude methyl 5-({2-benzyl-2-[(tert-butoxycarbonyl)-amino]-3-hydroxypropoxy}methyl)-2′-cyano-1,1′-biphenyl-3-carboxylate from step A (442 mg, 0.83 mmol) in 4 mL THF was added 1 N LiOH (1.25 mL, 1.25 mmol) and the reaction mixture was stirred at room temperature for 1.5 h. 1 N LiOH (1.25 mL, 1.25 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water, extracted with CH2Cl2 (3×), dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography (90 g silica, 0->85% (0.5% HOAc in EtOAc)/hexanes) to provide 259 mg of 5-({2-benzyl-2-[(tert-butoxycarbonyl)amino]-3-hydroxypropoxy}methyl)-2′-cyano-1,1′-biphenyl-3-carboxylic acid as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.21 (s, 1H), 8.13 (s, 1H), 7.84 (s, 1H), 7.81 (d, J=7.7 Hz, 1H), 7.70 (t, J=7.3 Hz, 1H), 7.57 (d, J=7.7 Hz, 1H), 7.51 (t, J=7.3 Hz, 1H), 7.30-7.16 (m, 5H), 4.98 (s, 1H), 4.69 (A of AB, d, J=12.0 Hz, 1H), 4.65 (B of AB, d, J=12.0 Hz, 1H), 3.77 (A of AB, d, J=12.0 Hz, 1H), 3.69 (B of AB, d, J=12.0 Hz, 1H), 3.59 (A of AB, d, J=9.3 Hz, 1H), 3.69 (B of AB, d, J=9.3 Hz, 1H), 3.17 (A of AB, d, J=13.8 Hz, 1H), 2.93 (B of AB, d, J=13.8 Hz, 1H), 1.44 (s, 9H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:8])([F:7])[CH2:5][OH:6].[F:9][C:10]1[C:11]([C:17]#[N:18])=[N:12][CH:13]=[C:14](F)[CH:15]=1.O>CN(C)P(=O)(N(C)C)N(C)C>[F:9][C:10]1[C:11]([C:17]#[N:18])=[N:12][CH:13]=[C:14]([O:6][CH2:5][C:4]([F:8])([F:7])[F:3])[CH:15]=1
Reactant: N#Cc1ncc(F)cc1F
Reactant: OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: N#Cc1ncc(OCC(F)(F)F)cc1F
Reaction time: 1 h
Yield: 50.6 %

Procedure:
60% sodium hydride (0.219 g, 5.71 mmol) was added to a solution of 2,2,2-trifluoroethanol (0.257 ml, 3.57 mmol) in N,N,N′,N′,N″,N″-hexamethylphosphoric triamide (6 ml) at 0 oC and stirred for 1 hour. Then 3,5-difluoropicolinonitrile (1.0 g, 7.1 mmol) in N,N,N′,N′,N″,N″-hexamethylphosphoric triamide (4 mL) was added to the reaction mixture and stirred at room temperature for 20 hours. Then 2,2,2-trifluoroethanol (0.257 ml, 3.57 mmol) and 60% sodium hydride (0.22 g, 5.7 mmol) were added to the reaction mixture and stirred at room temperature for 3 hours. After reaction, the mixture was poured into water, and the aqueous phase was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (6:1-4:1) to give 398 mg (25% yield) of the title compound as a oily solution:
Reaction SMILES: [CH3:1]O.[Cl:3][C:4]1[CH:5]=[C:6]([CH2:11][C:12]([OH:14])=[O:13])[CH:7]=[CH:8][C:9]=1[Cl:10].S(=O)(=O)(O)O>ClCCCl>[Cl:3][C:4]1[CH:5]=[C:6]([CH2:11][C:12]([O:14][CH3:1])=[O:13])[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: CO
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Agent: O=S(=O)(O)O
Solvent: ClCCCl
Product: COC(=O)Cc1ccc(Cl)c(Cl)c1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 98 %

Procedure:
Methanol (59 mL, 3.0 equivalent amounts) was added to a 1,2-dichloroethane (400 mL) solution of 2-(3,4-dichlorophenyl)acetic acid (100 g, 0.488 mol). The solution was heated to 50° C., and then concentrated sulfuric acid (10 mL) was dropwise added over a period of 15 minutes, followed by stirring at 50° C. for 1.5 hours. The reaction solution was cooled to room temperature, followed by liquid separation to remove a sulfuric acid layer, and the obtained organic layer was sequentially washed with water, a saturated sodium hydrogencarbonate aqueous solution and a saturated salt solution, and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the solvent was distilled off to give the desired product as a colorless oil (105 g, yield: 98%).
Reaction SMILES: O=P(Cl)(Cl)Cl.CN(C=O)C.[CH3:11][CH:12]1[CH2:18][CH2:17][N:16]2[C:19](=[O:31])[C:20]3[C:25]4[CH2:26][CH2:27][CH2:28][C:29](=[O:30])[C:24]=4[S:23][C:21]=3[N:22]=[C:15]2[CH2:14][CH2:13]1.[CH:32](Cl)(Cl)[Cl:33]>>[Cl:33][C:32]1[C:24]2[S:23][C:21]3[N:22]=[C:15]4[CH2:14][CH2:13][CH:12]([CH3:11])[CH2:18][CH2:17][N:16]4[C:19](=[O:31])[C:20]=3[C:25]=2[CH2:26][CH2:27][C:28]=1[CH:29]=[O:30]
Reactant: ClC(Cl)Cl
Reactant: CC1CCc2nc3sc4c(c3c(=O)n2CC1)CCCC4=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CC1CCc2nc3sc4c(c3c(=O)n2CC1)CCC(C=O)=C4Cl
Temperature: 50 °C
Reaction time: 8 h

Procedure:
POCl3 (2.91 mmol) was added dropwise into DMF (3.02 mmol) in CHCl3 (2 ml) at 0° C. After 30 minutes compound 17 (0.36 mmol) in CHCl3 (6 ml) was added slowly dropwise. The reaction mixture was allowed to reach room temperature and stirred overnight after which the reaction mixture was heated to 50° C. for 12 hours. The reaction mixture was cooled to room temperature and quenched with saturated NaOAc, extracted with CH2Cl2, washed with brine and water, and dried over Na2SO4. After filtration the solvent was evaporated. The product was purified by flash chromatography using CH2Cl2-EtOAc 9:1 as an eluent.