Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:14]#N)[C:10]([O:12][CH3:13])=[O:11])=[C:5]([N+:16]([O-:18])=[O:17])[CH:4]=1.[CH3:19][OH:20].C1(C)C=CC=CC=1.Cl.[OH2:29]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:14]([O:20][CH3:19])=[O:29])[C:10]([O:12][CH3:13])=[O:11])=[C:5]([N+:16]([O-:18])=[O:17])[CH:4]=1
Reactant: CO
Reactant: O
Reactant: COC(=O)C(C#N)c1ccc(OC)cc1[N+](=O)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Product: COC(=O)C(C(=O)OC)c1ccc(OC)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 86 %

Procedure:
A 80 mL Fischer-Porter® bottle (Fischer-Porter Co., Warminster, Pa.) equipped with a gas pressure head and a magnetic stirring bar was charged with methyl 4-methoxy-2-nitrophenyl-α-cyano-acetate from Example 10 (5.0 g, 0.020 mol), methanol (3 mL), toluene (50 mL), sealed, and then charged with HCl gas (55 psig). After stirring for 4 hours at ambient temperature, the apparatus was vented and water (50 mL) was added. The toluene layer was separated and evaporated to dryness under vacuum to afford 5.1 g of dimethyl 4-methoxy-2-nitrophenylmalonate as a tan colored solid (1H-NMR). By HPLC area % analysis (254 nm), the solid was 95% dimethyl 4-methoxy-2-nitrophenylmalonate and 5% methyl 4-methoxy-2-nitrophenyl-α-carbamido-acetate. Isolated yield: 86% on methyl 4-methoxy-2-nitrophenyl-α-cyanoacetate.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[NH:9][CH:8]=[C:7]([CH2:10][CH2:11]O)[C:5]=2[CH:6]=1.S(Cl)(C)(=O)=O.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.[OH-].[Na+]>C(Cl)Cl.O.CCN(CC)CC>[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([CH2:11][CH2:10][C:7]2[C:5]3[C:4](=[CH:3][CH:2]=[CH:1][CH:6]=3)[NH:9][CH:8]=2)[CH2:21][CH2:20]1
Reactant: CN1CCNCC1
Reactant: OCCc1c[nH]c2ccccc12
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCN(CCc2c[nH]c3ccccc23)CC1
Temperature: 40 °C
Reaction time: 3 h
Yield: 55.7 %

Procedure:
Tryptophol (0.500 g, 3.10 mmol) and Et3N (1 mL) were dissolved in DCM (2 mL) and then mesyl chloride (0.24 mL, 3.102 mmol) was added dropwise at RT. The reaction was stirred for 3 h and then volatiles were removed in vacuo. The crude mesylate was taken up in DCM (3 mL) and to it was added 1-methylpiperazine (1.72 mL, 15.5 mmol) and Et3N (1 mL). The reaction was heated to 40° C. and stirred overnight. After completion, the reaction mixture was poured into cold water, the pH was adjusted to 10 with 1 N NaOH and the organic products were extracted with DCM (3×15 mL). The combined organic extracts were washed with brine (15 mL), dried with Na2SO4, filtered and concentrated in vacuo. Automated column chromatography method 2 was used to isolate the title compound (0.42 g, 56%). 1H NMR (400 MHz, CDCl3): δ 7.54 (d, J=7.8 Hz, 1H), 7.34 (d, J=8.1 Hz, 1H), 7.10 (t, J=7.1 Hz, 1H), 7.03 (t, J=7.3 Hz, 1H), 6.98 (s, 1H), 2.87 (t, J=7.8 Hz, 2H), 2.58 (t, J=5.9 Hz, 2H), 2.38 (br, 8H), 2.17 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 136.7, 127.4, 121.8, 121.0, 118.3, 118.0, 112.4, 111.0, 58.9, 54.1, 52.2, 44.6, 22.2. ESI-HRMS: calc. for C15H21N3: [M+H]+=244.1808 m/z, found: [M+H]+=244.1797 m/z.
Reaction SMILES: CN(C)C(=O)C.Br[C:8]1[CH:9]=[C:10]([CH2:16][C:17]#[N:18])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[OH:19][CH:20]([CH3:27])[C:21](=[CH2:26])[C:22]([O:24][CH3:25])=[O:23].C1(NC2CCCCC2)CCCCC1>O.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CCOC(C)=O>[C:17]([CH2:16][C:10]1[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:8]([CH:9]=1)[CH2:26][CH:21]([C:20](=[O:19])[CH3:27])[C:22]([O:24][CH3:25])=[O:23])#[N:18]
Reactant: COc1ccc(CC#N)cc1Br
Reactant: C=C(C(=O)OC)C(C)O
Agent: C1CCC(NC2CCCCC2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)C(Cc1cc(CC#N)ccc1OC)C(C)=O
Temperature: 80 °C

Procedure:
N,N-dimethylacetamide (200 mL) was added to Pd-118 (1.009 g) and tetrabutylammonium chloride hydrate (0.916 g), followed by 2-(3-bromo-4-methoxyphenyl)acetonitrile (7 g). Methyl 3-hydroxy-2-methylenebutyrate (5.64 mL) and dicyclohexylamine (9.25 mL) were added and the solution was heated at 80° C. for 3 days. The reaction mixture was diluted with EtOAc (200 mL) and extracted with water. The organic phase was dried, filtered and evaporated under reduced pressure. The crude product was purified by chromatography to afford the subtitle compound as an orange oil, 5.01 g.
Reaction SMILES: C[O-].[Na+].CC1C=CC(S([CH2:14][N+:15]#[C-:16])(=O)=O)=CC=1.[NH2:17][C:18]1[C:23]2=[C:24]([C:29]3[CH:34]=[CH:33][C:32]([NH:35][C:36]([NH:38][C:39]4[CH:44]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:42]=[CH:41][N:40]=4)=[O:37])=[C:31]([F:49])[CH:30]=3)[C:25]([CH:27]=[O:28])=[CH:26][N:22]2[N:21]=[CH:20][N:19]=1>CCOC(C)=O.CO.C1COCC1>[NH2:17][C:18]1[C:23]2=[C:24]([C:29]3[CH:34]=[CH:33][C:32]([NH:35][C:36]([NH:38][C:39]4[CH:44]=[C:43]([C:45]([F:47])([F:46])[F:48])[CH:42]=[CH:41][N:40]=4)=[O:37])=[C:31]([F:49])[CH:30]=3)[C:25]([C:27]3[O:28][CH:16]=[N:15][CH:14]=3)=[CH:26][N:22]2[N:21]=[CH:20][N:19]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: Nc1ncnn2cc(C=O)c(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccn4)c(F)c3)c12
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1ncnn2cc(-c3cnco3)c(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccn4)c(F)c3)c12
Temperature: 60 °C
Reaction time: 0.08 h
Yield: 32.5 %

Procedure:
To a solution of THF (10 mL) and MeOH (10 mL) cooled in an ice/water bath was added 0.5 M sodium methoxide in MeOH (0.96 mL, 0.48 mmol) followed by TosMIC (93 mg, 0.48 mmol). The solution was allowed to stir for 5 min and then N-[4-(4-amino-6-formylpyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-fluorophenyl]-N′-[4-(trifluoromethyl)pyridin-2-yl]urea (73 mg, 0.16 mmol) was added. The solution was heated to 60° C. for 17 h. The reaction mixture was allowed to cool and was transferred to a separatory funnel, diluted with EtOAc (20 mL), washed with aq saturated NaHCO3 (20 mL) and H2O (20 mL). The aqueous layer was back extracted with EtOAc (2×20 mL). The combined organic layers were dried (MgSO4), filtered, evaporated in vacuo and purified by flash chromatography 5:4:1 v/v/v DCM/EtOAc/MeOH the resulting purified fractions were combined and evaporated providing 26 mg of the title compound as a white solid (0.052 mmol, yield 33%). 1H-NMR (DMSO-d6) δ 10.18 (s, 1H), 10.16 to 10.12 (br s, 1H), 8.55 to 8.54 (d, J=5.4 Hz, 1H), 8.35 to 8.31 (t, J=8.3 Hz, 1H), 8.30 (s, 1H), 8.10 (s, 1H), 8.01 (s, 1H), 7.91 (s, 1H), 7.39 to 7.36 (m, 2H), 7.23 to 7.21 (d, J=10.4 Hz, 1H), 6.63 (s, 1H); MS [M+H]+=499.0; LCMS RT=2.85 min.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][OH:8].[Si:9](Cl)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].N1C=CN=C1>CN(C)C=O>[Si:9]([O:8][CH2:7][CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCc1cccs1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCc1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
2-(2-Thienyl)ethanol (2.6 g) was dissolved in N,N-dimethylformamide (20 ml), followed by the addition of t-butyldimethylsilyl chloride (3.667 g) and imidazole (1.634 g) and the mixture was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The resulting organic layer was washed with water, dried (over MgSO4) and evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane system), to give the title compound as a colorless oil (4.87 g, yield; 100%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)=[N:9][CH:10]=1)=O.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][N:18]=1>C(#N)C>[I:23][C:20]1[CH:21]=[CH:22][C:17]2[N:18]([CH:2]=[C:3]([C:5]3[CH:6]=[CH:7][C:8]([N:11]4[CH:15]=[N:14][CH:13]=[N:12]4)=[N:9][CH:10]=3)[N:16]=2)[CH:19]=1
Reactant: O=C(CBr)c1ccc(-n2cncn2)nc1
Reactant: Nc1ccc(I)cn1
Solvent: CC#N
Product: Ic1ccc2nc(-c3ccc(-n4cncn4)nc3)cn2c1
Temperature: 100 °C
Yield: 70.7 %

Procedure:
657 mg (corresponding to 2.46 mmol) of 5-(2-bromoacetyl)-2-(1H-1,2,4-triazole-1-yl)pyridine and 541 mg (corresponding to 2.46 mmol) of 2-amino-5-iodopyridine were dissolved in 5.0 mL of acetonitrile. The resulting solution was heated under reflux for 1.5 hours in an oil bath at 100° C. After the completion of the reaction, the reaction solution was cooled down to room temperature, and precipitates were filtered. The precipitates were washed with acetonitrile and dried under reduced pressure. The resulting crude crystals were suspended in a mixed solution of 2 mL of water and 2 mL of methanol. Then, about 1 mL of a saturated sodium hydrogencarbonate solution was added thereto, and the mixture was sonicated for 10 minutes using an ultrasonic washing machine. Precipitates were filtered and recovered from the resulting mixture, sufficiently washed with water, and dried under reduced pressure, to obtain 675 mg (corresponding to 1.74 mmol) of 6-iodo-2-[2-(1H-1,2,4-triazole-1-yl)pyridine-5-yl]imidazo[1,2-a]pyridine (FIG. 4, step 3).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][C:7]1([C:21]([O:23]C(C)(C)C)=O)[CH2:11][C:10](=[O:12])[N:9]([C:13]2[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:20])[CH2:8]1.C(C1NC=CN=1)(C1NC=CN=1)=O.C(N(C(C)C)CC)(C)C.[F:49][C:50]([F:63])([F:62])[C:51]1[CH:52]=[C:53]([CH:55]=[C:56]([C:58]([F:61])([F:60])[F:59])[CH:57]=1)[NH2:54]>Cl.O1CCOCC1.C(OCC)(=O)C>[NH:3]1[CH:4]=[CH:5][N:1]=[C:2]1[CH2:6][C:7]1([C:21]([NH:54][C:53]2[CH:55]=[C:56]([C:58]([F:59])([F:60])[F:61])[CH:57]=[C:51]([C:50]([F:49])([F:62])[F:63])[CH:52]=2)=[O:23])[CH2:11][C:10](=[O:12])[N:9]([C:13]2[C:14]([CH3:20])=[CH:15][CH:16]=[CH:17][C:18]=2[CH3:19])[CH2:8]1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Cc1cccc(C)c1N1CC(Cc2ncc[nH]2)(C(=O)OC(C)(C)C)CC1=O
Agent: Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(C)c1N1CC(Cc2ncc[nH]2)(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 42 %

Procedure:
tert-Butyl 3-((1H-imidazol-2-yl)methyl)-1-(2,6-dimethylphenyl)-5-oxopyrrolidine-3-carboxylate prepared in Step b above (460 mg, 1.2 mmol) was dissolved in 4 mL of 4 M HCl in dioxane and heated at 60° C. for 2 h. The solvent was evaporated to dryness and the residue suspended in THF (5 mL) was treated with carbonyl diimidazole (201 mg, 1.2 mmol) and diisopropylethyl amine (626 μL, 3.6 mmol) and heated at 40° C. for 1 h. The warm reaction mixture was treated with 3,5-bis(trifluoromethyl)aniline (550 mg, 2.4 mmol) and heating was continued for another 2 h. After cooling to room temperature the reaction mixture was diluted with 25 mL ethyl acetate and washed with water. The organic phase was dried, solvent evaporated and the residue was purified by flash chromatography (SiO2, 0-15% MeOH/DCM) to afford 260 mg of 3-((1H-imidazol-2-yl)methyl)-N-(3,5-bis(trifluoromethyl)phenyl)-1-(2,6-dimethylphenyl)-5-oxopyrrolidine-3-carboxamide (42% yield). 1H NMR (400 MHz, CDCl3) δ 2.14 (s, 3H), 2.19 (s, 3H), 2.52 (d, 1H, J=17 Hz), 3.28 (d, 1H, J=17 Hz), 3.38-3.42 (m, 3H), 3.59 (d, 1H, J=10.6 Hz), 4.20 (d, 1H, J=10.6 Hz), 1.60 (bs, 2H), 7.00-7.20 (m, 3H), 7.57 (s, 1H), 8.18 (s, 2H). LC-MS: Rt (retention time)=2.57 min, MS: (ES) m/z 525 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:34]=[CH:33][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[N:13](CC4C=CC(OC)=CC=4)[N:14]=[C:15]([NH:16][CH:17]4[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]4)[C:8]=23)=[C:4]([F:35])[CH:3]=1.[F:36][C:37]1[CH:42]=[CH:41][C:40]([N:43]2[CH:48]=[CH:47][CH:46]=[C:45]([C:49](O)=[O:50])[C:44]2=[O:52])=[CH:39][CH:38]=1.O=C1C(C(OC)=O)=CC=CO1.FC1C=CC(N)=CC=1>>[F:35][C:4]1[CH:3]=[C:2]([NH:1][C:49]([C:45]2[C:44](=[O:52])[N:43]([C:40]3[CH:39]=[CH:38][C:37]([F:36])=[CH:42][CH:41]=3)[CH:48]=[CH:47][CH:46]=2)=[O:50])[CH:34]=[CH:33][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[NH:13][N:14]=[C:15]([NH:16][CH:17]3[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]3)[C:8]=12
Reactant: COc1ccc(Cn2nc(NC3CCN(C)CC3)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Reactant: O=C(O)c1cccn(-c2ccc(F)cc2)c1=O
Agent: COC(=O)c1cccoc1=O
Agent: Nc1ccc(F)cc1
Product: CN1CCC(Nc2n[nH]c3nccc(Oc4ccc(NC(=O)c5cccn(-c6ccc(F)cc6)c5=O)cc4F)c23)CC1
Yield: 73 %

Procedure:
Prepared by a 2-step process from 4-(4-amino-2-fluorophenoxy)-1-(4-methoxybenzyl)-N-(1-methylpiperidin-4-yl)-1H-pyrazolo[3,4-b]pyridin-3-amine (prepared in Example 101, step A) and 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (prepared from methyl 2-oxo-2H-pyran-3-carboxylate with 4-fluoroaniline and followed by hydrolysis using the methods described in US Publication No. 2005/0239820) according to the procedure of Example 101. The crude was rinsed with Et2O to afford 14 mg (73%) of the desired product. LRMS (ESI pos) m/e 572.0 (M+1). 1H-NMR (400 MHz, CD3OD/CDCl3) δ 8.72 (d, 1H), 8.24 (d, 1H), 8.02 (dd, 1H), 8.02 (dd, 1H), 7.87 (d, 1H), 7.47 (m, 2H), 7.41 (m, 1H), 7.38 (m, 3H), 6.72 (m, 1H), 6.12 (d, 1H), 3.70 (m, 1H), 2.88 (d, 2H), 2.35 (s, 3H), 2.24 (m, 1H), 2.21 (m, 2H), 1.62 (m, 2H); 19F NMR (376 MHz, CD3OD/CDCl3) δ −112.6, −128.0.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[N:2]1.Br[CH2:14][CH2:15][N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[O:26]=[C:17]1[C:18]2[C:19](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20](=[O:21])[N:16]1[CH2:15][CH2:14][N:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[N:2]1
Reactant: CC(C)(C)OC(=O)c1cc[nH]n1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccn(CCN2C(=O)c3ccccc3C2=O)n1
Reaction time: 12 h
Yield: 32.2 %

Procedure:
To a solution of 2.31 g of tert-butyl 1H-pyrazole-3-carboxylate and 6.98 g of N-(2-bromoethyl)phthalimide in DMF (65 mL) was added 8.95 g of cesium carbonate at room temperature, followed by stirring for 12 hours. The reaction solution was diluted with water, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: chloroform-hexane) to obtain 1.51 g of tert-butyl 1-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-1H-pyrazole-3-carboxylate as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[C:4]([C:24]([F:27])([F:26])[F:25])[CH:3]=1.Cl[CH2:29][CH2:30][CH2:31][S:32](Cl)(=[O:34])=[O:33]>>[CH3:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:1]3[CH2:29][CH2:30][CH2:31][S:32]3(=[O:34])=[O:33])=[CH:3][C:4]=2[C:24]([F:27])([F:26])[F:25])=[O:9])[CH2:11][CH2:12]1
Reactant: O=S(=O)(Cl)CCCCl
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(N)cc3C(F)(F)F)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3C(F)(F)F)CC2)c(C)c1

Procedure:
Using (4-amino-2-trifluoromethylphenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (850 mg) described in Preparation Example 149 and 3-chloropropane-1-sulfonyl chloride (0.37 mL) and by the reaction and treatment in the same manner as in Example 78, the title compound (544 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][C:15](=[N:18][O:19][CH:20]2[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]2)[CH2:14][CH2:13]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:23]1[CH2:24][CH2:25][CH:20]([O:19][N:18]=[C:15]2[CH2:16][CH2:17][N:12]([C:3]3[CH:4]=[CH:5][C:6]([S:8]([CH3:11])(=[O:9])=[O:10])=[CH:7][C:2]=3[F:1])[CH2:13][CH2:14]2)[CH2:21][CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCC(ON=C2CCN(c3ccc(S(C)(=O)=O)cc3F)CC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(N2CCC(=NOC3CCNCC3)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.5 %

Procedure:
To a solution of 1-1 (1.88 g, 4 mmol) in 30 mL of DCM, was added TFA (3 mL, 40 mmol) and the reaction mixture was stirred at room temperature for 3 h. It was quenched with saturated NaHCO3, extracted with DCM 3 times, dried and concentrated to give 1.37 g (3.7 mmol) of 63a.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([SH:9])[CH3:8].Cl[C:11]1[N:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=1>C(COC)OC>[CH2:7]([S:9][C:11]1[N:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=1)[CH3:8]
Reactant: CCS
Reactant: FC(F)(F)c1cnc(Cl)nc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Product: CCSc1ncc(C(F)(F)F)cn1
Temperature: 0 °C

Procedure:
Potassium tert-butoxide (8.9 mmol) was added to an ice-cooled solution of ethanethiol (8.9 mmol) in dimethoxyethane (40 ml) and the mixture stirred at room temperature for 10 min before 2-chloro-5-trifluoromethylpyrimidine (8.9 mmol) in dimethoxyethane (10 ml) was added. The resultant mixture was stirred at room temperature for 2 h and at 80° C. for 30 mins. The solvent was then removed at reduced pressure and the residue distilled; yield 1.40 g (76%), b.p. 110°-112° C./40 mmHg. 1H NMR (CDCl3): δ 1.41 and 3.21 (Et), 8.65 (H-4 and H-6).
Reaction SMILES: [C:1]1([NH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F-].[Cs+].[CH3:15][O:16][CH2:17]C1COC(=O)O1>CN(C)C=O>[C:1]1([N:7]2[CH2:12][CH:11]([CH2:15][O:16][CH3:17])[O:10][C:8]2=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COCC1COC(=O)O1
Reactant: CCOC(=O)Nc1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Product: COCC1CN(c2ccccc2)C(=O)O1
Temperature: 140 °C
Reaction time: 50 h
Yield: 68 %

Procedure:
Phenylurethane (15.0 g, 90.9 mmol) was dissolved in N,N-dimethylformamide (40 mL), and thereto were added cesium fluoride (1.15 g, 7.57 mmol) and 4-methoxymethyl-1,3-dioxolan-2-one (10.0 g, 75.7 mol), in order. The mixture was stirred for 50 hours at 140° C. under an atmosphere of argon. After filtering off the insoluble materials, the filtrate was condensed in vacuo, and the residue was purified by silica gel chromatography to give the subject 3-phenyl-5-methoxymethyloxazolidin-2-one (12.8 g, yield 81.6%).
Reaction SMILES: [CH3:1][C@H:2]([NH2:12])[CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[C:13](O)(=[O:22])[C@H:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[OH:15].C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1>CN(C)C=O.CO>[OH:15][CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:13]([NH:12][CH:2]([CH3:1])[CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:22]
Reactant: O=C(O)[C@@H](O)c1ccccc1
Reactant: C[C@H](N)CCCc1cccnc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CO
Product: CC(CCCc1cccnc1)NC(=O)C(O)c1ccccc1

Procedure:
Under the conditions outlined in Example 14a, 76.2 g of the amine was reacted with 74.2 g of (S)-mandelic acid in the presence of 105.2 g of 1,3-dicyclohexylcarbodiimide and 78.4 g of 1-hydroxybenzotriazole in 1 L of dimethylformamide. A similar workup furnished 109 g of [S-(S*,S*)]-alpha-hydroxy-N-[1-methyl-4-(3-pyridinyl)butyl]benzeneacetamide, mp 143°-145° C., [α]D25 +27.8° (c, 1.0, MeOH).
Reaction SMILES: [NH2:1][C:2]1[C:12]([CH3:13])=[C:11]([N+:14]([O-:16])=[O:15])[CH:10]=[C:9]([CH2:17][CH3:18])[C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].Cl[C:20]([O:22][C:23](Cl)(Cl)Cl)=[O:21].[CH2:27](O)C.C(N(CC)CC)C>O1CCCC1>[CH2:17]([C:9]1[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:2]([NH:1][C:20]([O:22][CH2:23][CH3:27])=[O:21])[C:12]([CH3:13])=[C:11]([N+:14]([O-:16])=[O:15])[CH:10]=1)[CH3:18]
Reactant: CCO
Reactant: CCOC(=O)c1c(CC)cc([N+](=O)[O-])c(C)c1N
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)Nc1c(C)c([N+](=O)[O-])cc(CC)c1C(=O)OCC
Reaction time: 2 h

Procedure:
A solution of ethyl 2-amino-3-methyl-6-ethyl-4-nitro-benzoate (70 mg, 0.000277 mol) in anhydrous tetrahydrofuran (5 ml) was added slowly to a solution of trichloromethyl chloroformate (43 mg) in tetrahydrofuran (5 ml). The solution was stirred for 2 hrs. at room temperature and then added slowly to a solution of ethanol (1 ml), triethylamine (0.05 ml) in tetrahydrofuran (5 ml). The resulting mixture was sitirred for 2 hrs. and evaporated to dryness. The residue was partitioned between ethyl acetate and water. The organic layer was dried over magnesium sulphate and evaporated to dryness. This material was purified by thick layer plate chromatography to yield ethyl 6-ethyl-3-methyl-2-ethoxycarbonylamino-4-nitrobenzoate. Yield: 35 mg, IR (CHCl3): 3420, 1730, 1530, 1500 cm-1. H-NMR: 1.10-1.50 (overlapping peaks [3t], 9H, CH3CH2, CH3CH2O, CH3CH2O), 2.31 (s, 3H, CH3), 2.70 (q, 2H, CH3CH2Ar), 4.20 (q, 2H, CH2O), 4.40, (q, 2H, CH2O), 6.60 (br.s, 1H, NH), 7.69 (s, 1H, ArH).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](O)=[CH:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1.Cl.[NH2:18][OH:19].[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[N:18][OH:19])[CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NO
Reactant: OC(=Cc1ccncn1)c1cccc(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: ON=C(Cc1ccncn1)c1cccc(Cl)c1
Yield: 67.8 %

Procedure:
To a suspension of 1-(3-chlorophenyl)-2-(4-pyrimidinyl)ethenol (9.0 g, 38.7 mmol) in methanol (100 mL) was added hydroxylamine hydrochloride (11.5 g, 165 mmol) and sodium hydroxide (60 mL, 2.8 M in water, 166 mmol). The reaction mixture was refluxed 4 hours. After cooling, the excess methanol was removed in vacuo. Ice water (˜300 mL) was added to the resultant mixture and the ice was allowed to melt. The aqueous mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over magnesium sulfate. Filtration and concentration followed by flash chromatography (3:1 to 2:1 hexanes:ethyl acetate) provided 1-(3-chlorophenyl)-2-(4-pyrimidinyl)ethanone oxime (6.5 g, 68%) as a white solid. Rf 0.14 (3:1 hexanes:ethyl acetate): 1H NMR (CDCl3) δ 9.50 (br, 1H), 9.18 (s, 1H), 8.61 (d, 1H), 7.78 (s, 1H), 7.58 (d, 1H), 7.38–7.25 (m, 3H), 4.38 (s, 2H); MS m/z 248 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].OS(O)(=O)=O.[CH3:19]O>>[CH3:19][O:12][C:11](=[O:13])[CH2:10][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([OH:1])[CH:3]=1
Reactant: CO
Reactant: COc1ccc(CC(=O)O)cc1O
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(OC)c(O)c1
Yield: 90 %

Procedure:
To a stirred solution of 3-hydroxy-4-methoxyphenyl acetic acid (24.8 g, 136 mmol) in 200 mL of MeOH was added 1 mL of H2SO4 and the reaction mixture was heated at reflux overnight. The methanol was removed by evaporation in vacuo and the residue was poured into saturated NaHCO3 solution and extracted with EtOAc (3×150 mL). Combined organic extracts were then washed with brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo to yield 23.9 g (90% yield) of 3-hydroxy-4-methoxyphenyl acetic acid methyl ester as a yellow oil.
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH2:12][CH2:13][CH:14]=O)=[CH:10][C:9]([CH:16]([CH3:18])[CH3:17])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19]1([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:19]1([N:25]2[CH2:30][CH2:29][N:28]([CH2:14][CH2:13][CH2:12][C:11]3[N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:8]=[C:9]([CH:16]([CH3:18])[CH3:17])[CH:10]=3)[CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)c1cc(CCC=O)n(-c2ccccc2)n1
Reactant: c1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1cc(CCCN2CCN(c3ccccc3)CC2)n(-c2ccccc2)n1

Procedure:
36 mg (86%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-3-isopropyl-1H-pyrazol-5-yl)propanal (26 mg, 0.108 mmol), 1-phenylpiperazine (0.016 mL, 0.108 mmol), DIPEA (0.028 mL, 0.162 mmol) and NaBH(OAc)3 (69 mg, 0.325 mmol).