Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[O:13])[N:3]=1.CCN(C(C)C)C(C)C.[CH3:30][C:31]1[NH:35][N:34]=[C:33]([NH2:36])[CH:32]=1>CN(C=O)C>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]([C:4]2[N:3]=[C:2]([NH:36][C:33]3[CH:32]=[C:31]([CH3:30])[NH:35][N:34]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)=[O:13])=[CH:15][CH:16]=1
Reactant: O=C(c1ccc(F)cc1)c1nc(Cl)c2ccccc2n1
Reactant: Cc1cc(N)n[nH]1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2nc(C(=O)c3ccc(F)cc3)nc3ccccc23)n[nH]1
Temperature: 40 °C
Yield: 29 %

Procedure:
To a solution of (4-chloroquinazolin-2-yl)(4-fluorophenyl)methanone (84 mg, 0.30 mmol) in DMF (3mL) were added DIEA (0.103 mL, 0.6 mmol) and 5-methyl-1H-pyrazol-3-amine (88 mg, 0.9 mmol at rt. The reaction mixture was heated at 40° C. overnight. The reaction was quenched by adding water and the yellow precipitate was collected by filtration and washed with water. The crude product was purified by silica gel chromatography eluting with DCM/MeOH to give (4-fluorophenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methanone (30 mg, 29%). 1H NMR (300 MHz, DMSO-d6) δ 2.19 (s, 3H), 6.54 (s, 1H), 7.40 (m, 2H), 7.68 (t, 1H), 7.9-7.7 (m, 2H), 8.08 (m, 2H), 8.74 (d, 1H), 10.66 (s, 1H), 12.20 (s, 1H);LC-MS (ESI) m/z 348 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:23][O:24][Si](C(C)(C)C)(C)C)=[C:4]([NH:8][CH2:9][C:10]2[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[S:12][C:11]=2[C:19]([O:21]C)=[O:20])[CH:5]=[CH:6][CH:7]=1.[OH-].[Li+].C1COCC1.C(O)C>O>[Br:1][C:2]1[C:3]([CH2:23][OH:24])=[C:4]([NH:8][CH2:9][C:10]2[CH:14]=[C:13]([C:15]([CH3:16])([CH3:17])[CH3:18])[S:12][C:11]=2[C:19]([OH:21])=[O:20])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1sc(C(C)(C)C)cc1CNc1cccc(Br)c1CO[Si](C)(C)C(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)c1cc(CNc2cccc(Br)c2CO)c(C(=O)O)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
A 50-mL single-necked round-bottomed flask equipped with a magnetic stirrer was charged with 114e (1.10 g, 2.09 mmol), lithium hydroxide (201 mg, 8.36 mmol), THF (10 mL), ethanol (10 mL) and water (10 mL). After stirring at room temperature for 2 h, the solvent was removed under reduced pressure and the resulting residue was acidified with 2N hydrochloric acid to pH of 4. The resulting aqueous solution was extracted with ethyl acetate (3×30 mL), and the organic extracts were combined and dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography to afford 114f in 65% yield (540 mg) as a white solid: mp 68-69° C.; 1H NMR (500 MHz, CDCl3) δ 7.03-6.97 (m, 2H), 6.86 (s, 1H), 6.71 (d, 1H, J=8.0 Hz), 4.94 (s, 2H), 4.60 (s, 2H), 1.35 (s, 9H); MS (ESI+) m/z 398.0 (M+H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].N1C=CC=CC=1.O[CH2:23][C:24]([CH3:46])([CH3:45])[O:25][C:26]1[C:27]([CH2:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[C:28]2[C:33](=[CH:34][CH:35]=1)[C:32](=[O:36])[CH2:31][CH2:30][CH2:29]2>ClCCl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][CH2:45][C:24]([CH3:46])([O:25][C:26]1[CH:35]=[CH:34][C:33]2[C:32](=[O:36])[CH2:31][CH2:30][CH2:29][C:28]=2[C:27]=1[CH2:37][CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[CH3:23])(=[O:5])=[O:4]
Reactant: CC(C)(CO)Oc1ccc2c(c1CCc1ccccc1)CCCC2=O
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(COS(=O)(=O)C(F)(F)F)Oc1ccc2c(c1CCc1ccccc1)CCCC2=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 90 %

Procedure:
Trifluoromethanesulfonic anhydride (0.12 mL, 0.74 mmol) was added to a solution of pyridine (0.14 mL, 1.77 mmol) in dichloromethane (0.5 mL). The resulting mixture was added over 15 min to an ice-cooled solution of 6-(2-hydroxy-1,1-dimethylethoxy)-5-(2-phenylethyl)-3,4-dihydro-1(2H)-naphthalenone (100 mg, 0.30 mmol) in dichloromethane (0.5 mL). The resulting mixture was stirred for 15 min and was then quenched by the addition of water (2 mL). The mixture was diluted with 1 M aqueous hydrochloric acid (10 mL) and extracted with ethyl acetate (3×5 mL). The combined extracts were washed with 1 M aqueous hydrochloric acid (10 mL), saturated aqueous copper sulfate (3×5 mL), and was then dried (brine, Na2SO4) and concentrated. The residue was purified by dry-flash column chromatography (SiO2, 5-40% ethyl acetate-hexane) to give 2-methyl-2-{[5-oxo-1-(2-phenylethyl)-5,6,7,8-tetrahydro-2-naphthalenyl]oxy}propyl trifluoromethanesulfonate as a colorless oil, 125 mg, 90% yield. NMR spectrum was consistent with structure. MS EI: M+• 470.1376 (M+• 470.1375).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](I)[CH:5]=[CH:6][C:7]=1[F:8].C[CH2:11][O:12][CH2:13][CH3:14]>[Ni]>[F:1][C:2]1[CH:3]=[C:4]([C:2]2[CH:3]=[CH:14][C:13]([O:12][CH3:11])=[CH:6][CH:7]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCOCC
Reactant: Fc1ccc(I)cc1F
Agent: [Ni]
Product: COc1ccc(-c2ccc(F)c(F)c2)cc1

Procedure:
A p-methoxyphenylmagnesium halide as a Grignard reagent, obtained from a p-halogenoanisole (IV), is reacted with a 3,4-difluoro-1-iodobenzene (V) at a low temperature in the vicinity of 0° C. in an ether solvent in the presence of Ni catalyst to obtain a 3,4-difluoro-4'-methoxybiphenyl (VI), which is then reacted with HBr to obtain (III). These reactions are expressed by the following reaction equations: ##STR6##
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:10]([C:11]([OH:13])=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.OS(O)(=O)=O.[CH3:19]O>>[CH3:19][O:12][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([Br:1])[N:3]=2)[NH:8][CH:9]=1)=[O:13]
Reactant: CO
Reactant: O=C(O)c1c[nH]c2ncc(Br)nc12
Agent: O=S(=O)(O)O
Product: COC(=O)c1c[nH]c2ncc(Br)nc12
Yield: 43 %

Procedure:
To a stirred solution of 2-bromo-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (0.527 g, 2.18 mmol) in 50 ml, of methanol was added H2SO4 (1.5 mL) slowly at room temperature. The reaction mixture was stirred at reflux for 16 h. The solvent was evaporated at 40° C. under reduced pressure then the residue was suspended in 5 mL of water and treated with solid NaHCO3 until pH=7. The solution was extracted with ethyl acetate (90 mL), then the organics were washed with water (20 mL), brine (20 mL) and dried over anhydrous sodium sulfate. The drying agent was removed by filtration and the solvent was evaporated at 40° C. under reduced pressure to give a crude product, which was purified by column chromatography (silica gel, 200-300 mesh, eluting with a mixture of petroleum ether and ethyl acetate (1:1, v/v) to give 2-bromo-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid methyl ester (0.24 g, 43%) as a white solid.
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[CH2:12][O:11][CH2:10][CH2:9][NH:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][C:22]=1[Cl:23])[CH:19]([C:24](Cl)=[O:25])[CH2:18][C:17]2=[O:27]>C(N(CC)CC)C>[ClH:13].[Cl:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][C:22]=1[Cl:23])[CH:19]([C:24]([N:8]1[CH2:9][CH2:10][O:11][CH2:12][CH:7]1[CH2:6][N:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)=[O:25])[CH2:18][C:17]2=[O:27]
Reactant: C1CCN(CC2COCCN2)C1
Reactant: O=C1CC(C(=O)Cl)c2cc(Cl)c(Cl)cc21
Solvent: CCN(CC)CC
Product: Cl
Product: O=C1CC(C(=O)N2CCOCC2CN2CCCC2)c2cc(Cl)c(Cl)cc21
Yield: 80.2 %

Procedure:
The procedure described in Example 24 was repeated, but using 0.88 g of 3-(pyrrolidin-1-ylmethyl)morpholine, 2.0 ml of triethylamine and 1.0 g of 5,6-dichloro-3-oxo-indan-1-carbonyl chloride, to afford 0.66 g of the title compound, melting at 250°-257° C. (dec.).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:5]([O:27][CH3:28])=[CH:6][C:7]2[C:16]3[CH2:15][CH2:14][N:13]([C:17]4[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=4)[C:20](O)=[O:21])[CH2:12][C:11]=3[CH:10]=[N:9][C:8]=2[CH:26]=1.C(N(CC)C(C)C)(C)C.CCCP(=O)=O.[CH:44]([C:47]1[CH:53]=[CH:52][C:50]([NH2:51])=[CH:49][CH:48]=1)([CH3:46])[CH3:45]>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:2][O:3][C:4]1[C:5]([O:27][CH3:28])=[CH:6][C:7]2[C:16]3[CH2:15][CH2:14][N:13]([C:17]4[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=4)[C:20]([NH:51][C:50]4[CH:52]=[CH:53][C:47]([CH:44]([CH3:46])[CH3:45])=[CH:48][CH:49]=4)=[O:21])[CH2:12][C:11]=3[CH:10]=[N:9][C:8]=2[CH:26]=1
Reactant: COc1cc2ncc3c(c2cc1OC)CCN(c1cccc(C(=O)O)c1)C3
Reactant: CC(C)c1ccc(N)cc1
Agent: CCCP(=O)=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc2ncc3c(c2cc1OC)CCN(c1cccc(C(=O)Nc2ccc(C(C)C)cc2)c1)C3
Temperature: 80 °C
Reaction time: 0.13 h
Yield: 12.6 %

Procedure:
To a mixture of 3-(8,9-dimethoxy-1,4-dihydrobenzo[c]-2,7-naphthyridin-3(2H)-yl)benzoic acid hydrochloride (0.38 mmol, 152 mg), N, N-diisopropylethylamine (1.14 mmol, 0.199 mL), and catalytic DMAP in 2.0 mL DMF at rt was added propylphosphonic anhydride solution (50 wt % in EtOAc, 0.494 mmol, 0.293 mL). After 8 min at rt, 4-isopropylaniline (0.57 mmol, 0.081 mL) was added and the reactions continued for 1.8 hours. Then an additional 0.050 mL propylphosphonic anhydride solution and 0.020 mL 4-isopropylaniline was added, the mixture briefly heated to 80° C. 3 times, and then continued at rt for 2 hours. The reaction was quenched into dilute aqueous Na2CO3 solution, extracted into EtOAc, the EtOAc layer washed with H2O, brine, dried with anhydrous Na2SO4 and rotary evaporated. The resulting solid was chromatographed eluting with CHCl3/EtOAc/MeOH and then triturated with EtOAc to give the title compound as a light yellow solid (23 mg, 13%).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:10][C:11]1[N:15]=[CH:14][NH:13][N:12]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[CH3:10][C:11]1[N:15]=[CH:14][N:13]([C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])[N:12]=1
Reactant: Cc1nc[nH]n1
Reactant: O=Cc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1ncn(-c2ccccc2C=O)n1
Temperature: 100 °C
Yield: 9.1 %

Procedure:
To a solution of 2-fluorobenzaldehyde (400 mg, 3.22 mmol) in DMSO (10 mL) are added 3-methyl-1H-1,2,4-triazole (321 mg, 3.87 mmol) and K2CO3 (890 mg, 6.45 mmol) at room temperature. The solution is heated to 100° C. for 2 hours. The solution is cooled down and extracted with H2O (10 mL) and EtOAc (3×10 mL). The combined organic layer is dried (MgSO4), filtered and concentrated. The residue is purified by silica gel chromatography eluting with 50% EtOAc in heptane as the eluent to afford 2-(3-methyl-1,2,4-triazol-1-yl)-benzaldehyde (55 mg, 8%) as a white solid.
Reaction SMILES: [CH:1]1([CH2:6][N:7]2[C:19](=[O:20])[C:18]3[C:17]([O:21][C:22](=[O:29])[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[C:16]4[C:11]([C:12]([CH3:30])=[CH:13][CH:14]=[N:15]4)=[CH:10][C:9]=3[CH2:8]2)[CH2:5][CH:4]=[CH:3][CH2:2]1.[Br:31]N1C(=O)CCC1=O>C(OCC)(=O)C>[Br:31][CH2:30][C:12]1[C:11]2[C:16](=[C:17]([O:21][C:22](=[O:29])[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:18]3[C:19](=[O:20])[N:7]([CH2:6][CH:1]4[CH2:5][CH:4]=[CH:3][CH2:2]4)[CH2:8][C:9]=3[CH:10]=2)[N:15]=[CH:14][CH:13]=1
Reactant: Cc1ccnc2c(OC(=O)c3ccccc3)c3c(cc12)CN(CC1CC=CC1)C3=O
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Product: O=C(Oc1c2c(cc3c(CBr)ccnc13)CN(CC1CC=CC1)C2=O)c1ccccc1

Procedure:
For example, benzoic acid 7-cyclopent-3-enylmethyl-4-methyl-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-9-yl ester A17.12 is reacted with N-bromosuccinimide in refluxing ethyl acetate to afford benzoic acid 4-bromomethyl-7-cyclopent-3-enylmethyl-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-9-yl ester A17.13. This compound is heated to 120° C. with an excess of a trialkyl phosphite to give after deprotection the phenolic phosphonate ester A17.14.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:27]([CH3:31])[CH2:28][CH2:29][CH3:30])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:22]([CH2:23]O)=[CH:21][N:20]=[N:19]4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1.S(Cl)(Cl)=O.[Cl-].[NH:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1>ClCCl.CN(C=O)C>[Cl:1][C:2]1[C:3]([N:27]([CH3:31])[CH2:28][CH2:29][CH3:30])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:22]([CH2:23][N:37]5[CH2:41][CH2:40][CH2:39][CH2:38]5)=[CH:21][N:20]=[N:19]4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1
Reactant: C1CCNC1
Reactant: CCCN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCCN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3nncc3CN3CCCC3)c1)=N2

Procedure:
The title compound was prepared from 8-chloro-7-(methyl-propyl-amino)-4-[3-(5-hydroxymethyl-[1,2,3]triazol-1-yl)-phenyl]-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 29) (220 mg, 0.50 mmol) by reaction with thionylchloride in dichloromethane and subsequent treatment of the corresponding chloride with pyrrolidine in DMF according to the method described in Example 45. Obtained as a yellow foam (63 mg, 26%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:7]=O.[CH3:9][O:10][C:11]1[CH:16]=[C:15]([CH:17]=[O:18])[CH:14]=[CH:13][C:12]=1[OH:19]>C(O)C>[OH:19][C:12]1[C:13]([CH2:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:14][C:15]([CH:17]=[O:18])=[CH:16][C:11]=1[O:10][CH3:9]
Reactant: COc1cc(C=O)ccc1O
Reactant: C1CCNCC1
Reactant: C=O
Solvent: CCO
Product: COc1cc(C=O)cc(CN2CCCCC2)c1O

Procedure:
25.5 g (0.30 mol) of piperidine were added to 24.0 g (0.30 mol) of a 37% aqueous formaldehyde solution in 180 ml of ethanol. Then 30.4 g (0.20 mol) of 4-hydroxy-3-methoxybenzaldehyde (vanillin) were added. The reaction mixture was refluxed for one hour. A solid began to precipitate out as early as during cooling, which was filtered out after complete cooling of the reaction batch and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]([O:17]CC)=[O:16])=[CH:10][C:9]=2[CH3:20])=[O:7])=[CH:4][CH:3]=1.C(I)CC>>[CH2:14]([C:11]1[N:12]([CH3:13])[C:8]([C:6](=[O:7])[C:5]2[CH:21]=[CH:22][C:2]([Cl:1])=[CH:3][CH:4]=2)=[C:9]([CH3:20])[CH:10]=1)[CH3:15].[CH2:11]([CH2:14][C:15]([O-:17])=[O:16])[CH2:10][CH3:9]
Reactant: CCOC(=O)Cc1cc(C)c(C(=O)c2ccc(Cl)cc2)n1C
Solvent: CCCI
Product: CCCCC(=O)[O-]
Product: CCc1cc(C)c(C(=O)c2ccc(Cl)cc2)n1C

Procedure:
The alkylation procedure of Example 77A is performed upon ethyl 5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2-acetate (from Example 84), using an equivalent quantity of n-propyl iodide instead of methyl iodide used in Example 77A to yield ethyl 5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2-(α-n-propyl)acetate.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[S:4][N:3]=1.[C:16]1([C:22]2[N:26]=[C:25]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[S:24][N:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[CH3:1][C:2]1[CH:6]=[C:5]([NH:7][C:8]([N:30]2[CH2:31][CH2:32][N:27]([C:25]3[S:24][N:23]=[C:22]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[N:26]=3)[CH2:28][CH2:29]2)=[O:15])[S:4][N:3]=1
Reactant: Cc1cc(NC(=O)OCC(Cl)(Cl)Cl)sn1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1cc(NC(=O)N2CCN(c3nc(-c4ccccc4)ns3)CC2)sn1
Temperature: 70 °C
Reaction time: 20 h
Yield: 29.5 %

Procedure:
A mixture of 2,2,2-trichloroethyl (3-methylisothiazol-5-yl)carbamate (259 mg, 0.893 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and diisopropylethylamine (0.156 ml, 0.893 mmol) in dimethylsulfoxide (2.7 ml) was stirred at 70° C. for 20 hours. Water was poured into the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:7) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to obtain the desired product (92.7 mg, 29.5%) as a solid.
Reaction SMILES: [CH3:1]C1C=CC(S(O)(=O)=O)=CC=1.[OH:12][CH2:13][CH2:14][O:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=[O:20].[CH3:24][OH:25]>>[CH3:24][O:25][CH:19]([O:20][CH3:1])[C:18]1[CH:17]=[C:16]([CH:23]=[CH:22][CH:21]=1)[O:15][CH2:14][CH2:13][OH:12]
Reactant: CO
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=Cc1cccc(OCCO)c1
Product: COC(OC)c1cccc(OCCO)c1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
p-TsOH (165 mg, 0.87 mmol) was added to a solution of the product obtained in Step 1 (1.45 g, 8.73 mmol) in dry MeOH (60 mL). After being stirred for 23 h at room temperature, more p-TsOH (170 mg, 0.89 mmol) was added. After additional 4 h of stirring, the reaction was quenched by the addition of NaHCO3 (saturated aqueous solution, 70 mL) and H2O (50 mL). The aqueous phase was extracted with EtOAc (3×100 mL). The combined organic phases were washed with brine and dried (MgSO4). Evaporation of the solvents afforded a yellow oil that was used in the next step without purification. Yield 1.59 g (86%). The product contained about 5% of starting material (1H NMR).
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([NH:24][CH2:25][CH3:26])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[N:6][CH:5]=1.Cl.C(O)(C)C.O>CO.[OH-].[Na+]>[CH2:25]([NH:24][C:23]1[C:18]([N:15]2[CH2:14][CH2:13][N:12]([C:10]([C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:27])=[O:2])=[CH:5][N:6]=3)=[O:11])[CH2:17][CH2:16]2)=[N:19][CH:20]=[CH:21][CH:22]=1)[CH3:26]
Reactant: CCNc1cccnc1N1CCN(C(=O)c2ccc(C(=O)OC)cn2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Solvent: CO
Product: CCNc1cccnc1N1CCN(C(=O)c2ccc(C(=O)O)cn2)CC1
Temperature: 20 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
6-[1-[3-(Ethylamino)-2-pyridyl]piperazin-4-yl-carbonyl]nicotinic acid methyl ester (3 g) was dissolved in methanol (18 ml) and with the addition of aqueous 1N-sodium hydroxide (18 ml), the mixture was hydrolyzed at 30° C. for 2 hours. 3N-hydrochloric acid was slowly added to the mixture for neutralization (pH=5˜6), followed by the addition of isopropanol (25 ml) and the slow addition of excess of water to precipitate. After 2-hours stirring at 20° C., the precipitate was filtered, washed with water and dried to give a desired compound of 2.48 g (yield: 86%).
Reaction SMILES: C(O[C:4](=[O:23])[C:5]([N:7]([C:14]1[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=1[CH3:22])C1C=CC=CC=1)=[O:6])C.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[OH:31].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:19]1([CH3:20])[CH:18]=[C:17]([CH3:21])[CH:16]=[C:15]([CH3:22])[C:14]=1[NH:7][C:5](=[O:6])[C:4]([NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[OH:31])=[O:23]
Reactant: Nc1ccccc1O
Reactant: CCOC(=O)C(=O)N(c1ccccc1)c1c(C)cc(C)cc1C
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(NC(=O)C(=O)Nc2ccccc2O)c(C)c1
Yield: 72.5 %

Procedure:
N-(Mesityl)-oxanilic acid ethyl ester (5.23 g, 24.4 mmol, 1 eq) and 2-aminophenol (2.67 g, 24.4 mmol, 1.0 eq) were dissolved in toluene (50 ml), forming a suspension. To this suspension was added triethylamine (6.8 ml, 50 mmol, 2 eq). The suspension was then heated to reflux, causing the solids to dissolve. After heating at reflux overnight, the product precipitated. At this point, ethyl acetate was added until the precipitate redissolved. The solution was then washed with 2 M HCl solution (2×100 ml). The aqueous layer was then washed with ethyl acetate, and the combined organic layers were washed with brine (100 ml), and dried over MgSO4. The solvent was then removed under reduced pressure, leaving a yellowish solid. The yellowish solid was then recrystallized from toluene, producing a product, white crystalline solid (5.26 g, 17.7 mmol, 72.4% yield). 1H NMR (300 MHz, CDCl3) δ 9.69 (s, 1H), 8.84 (s, 1H), 8.11 (s, J=7.7 Hz, 1H), 7.51 (dd, J=8.0, 1.8 Hz, 1H), 7.14 (ddd, J=1.5, 8.1, 7.2 Hz, 1H), 6.92 (m, 3H), 2.30 (s, 3H), 2.22 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 158.2, 157.9, 148.2, 138.2, 134.9, 129.5, 129.4, 127.7, 124.3, 122.2, 121.1, 118.9, 21.2, 18.6. Anal. Calcd for C17H18N2O3: C, 68.44; H, 6.08; N, 9.39. Found: C, 68.50; H, 5.96; N, 9.44.
Reaction SMILES: [CH3:1][NH:2][C:3]([C@@:5]12[CH2:10][C@@H:9]1[C@@H:8]([N:11]1[CH:19]=[N:18][C:17]3[C:12]1=[N:13][C:14]([Cl:48])=[N:15][C:16]=3[NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]#[C:29][CH2:30][CH2:31][CH2:32][C:33]3[N:34]=[N:35][N:36]([C:38]4[CH:43]=[CH:42][C:41]([F:44])=[C:40]([N+:45]([O-])=O)[CH:39]=4)[CH:37]=3)[CH:23]=1)[C@H:7]([OH:49])[C@@H:6]2[OH:50])=[O:4].C(O)(=O)C>C(#N)C.[Zn]>[CH3:1][NH:2][C:3]([C@@:5]12[CH2:10][C@@H:9]1[C@@H:8]([N:11]1[CH:19]=[N:18][C:17]3[C:12]1=[N:13][C:14]([Cl:48])=[N:15][C:16]=3[NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]#[C:29][CH2:30][CH2:31][CH2:32][C:33]3[N:34]=[N:35][N:36]([C:38]4[CH:43]=[CH:42][C:41]([F:44])=[C:40]([NH2:45])[CH:39]=4)[CH:37]=3)[CH:23]=1)[C@H:7]([OH:49])[C@@H:6]2[OH:50])=[O:4]
Reactant: CNC(=O)[C@@]12C[C@@H]1[C@@H](n1cnc3c(NCc4cccc(C#CCCCc5cn(-c6ccc(F)c([N+](=O)[O-])c6)nn5)c4)nc(Cl)nc31)[C@H](O)[C@@H]2O
Agent: [Zn]
Solvent: CC#N
Solvent: CC(=O)O
Product: CNC(=O)[C@@]12C[C@@H]1[C@@H](n1cnc3c(NCc4cccc(C#CCCCc5cn(-c6ccc(F)c(N)c6)nn5)c4)nc(Cl)nc31)[C@H](O)[C@@H]2O
Reaction time: 2 h
Yield: 63.9 %

Procedure:
Zinc dust (3 mg, 0.045 mmol) was added to a solution of compound 203 (5 mg, 0.007 mmol) in acetonitrile (0.5 mL)-acetic acid (0.5 mL) at 0° C. After addition, the reaction mixture was brought to room temperature and stirred for 2 h under the same conditions. The reaction mixture was filtered on a Celite bed, and the filtrate was evaporated under vacuum. The residue was purified on flash silica gel column chromatography (CH2Cl2: MeOH=20:1) to give compound 207 (3 mg, 62%). 1H NMR (CD3OD, 400 MHz) δ 8.65-8.58 (m, 1H),
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[CH:9]1([NH2:12])[CH2:11][CH2:10]1>C1COCC1>[Br:1][C:2]1[CH:3]=[N:4][C:5]([NH:12][CH:9]2[CH2:11][CH2:10]2)=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)cn1
Reactant: NC1CC1
Solvent: C1CCOC1
Product: Brc1cnc(NC2CC2)nc1
Yield: 95.1 %

Procedure:
A solution of 5-bromo-2-chloropyrimidine (3.87 g, 20 mmol) and cyclopropylamine (5.7 g, 0.1 mol) in 20 mL THF was heated at 65° C. for 5 hrs in a sealed tube. The mixture was evaporated in vacuo, to the residue ethanol was added, after filtration, the cake was washed with ethanol to give 4.07 g product as a colorless solid (95.5%). 1H NMR (300 MHz, CDCl3) δ: 8.32 (2 H, s), 5.58 (1 H, brs), 2.72 (1 H, brs), 0.82-0.84 (2 H, m), 0.54 (2 H, brs). LCMS: m/z [M+H]+ 214.0011.
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:3]([OH:5])=[O:4].Cl.[CH3:15]O>>[CH3:15][O:4][C:3](=[O:5])[C@H:2]([OH:1])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[OH:1][C@@H:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:3]([OH:5])=[O:4]
Reactant: CCCCCCCCC(O)C(=O)O
Reactant: CO
Agent: Cl
Product: CCCCCCCC[C@@H](O)C(=O)OC
Product: CCCCCCCC[C@H](O)C(=O)O

Procedure:
An alternate novel method of resolving 2-hydroxydecanoic acid is illustrated in scheme 3. According to this method, racemic 2-hydroxydecanoic acid (VI) is first converted to the racemic methyl ester (X) by reacting it with methanol and hydrochloric acid as described for the analogous reaction in scheme 2 (VIII→IX). The racemic methyl ester (X) is then reacted with Lipase P-30 to form (R)-methyl-2-hydroxydecanoate (IX) and (S)-2-hydroxydecanoic acid (VIII'). This reaction is typically carried out at a temperature from about 5° C. to about 55° C. in water or a water miscible solvent, or at the organic/aqueous interface of a water miscible solvent and an organic cosolvent. Examples of appropriate solvents are dimethylsulfoxide (DMSO)/water, toluene/water, methanol/water, hexane/water and tetrahydrofuran (THF)/water. The preferred temperature is from about 20° C. to about 50° C. and the preferred solvent is water. The pH is generally maintained at about 6.0 to about 8.0.