Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:3][CH2:4][N:5]([CH3:13])[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[C:24](F)[CH:23]=1>>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([C:26]#[N:27])=[C:28]([CH:29]=1)[O:1][CH:2]([CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:3][CH2:4][N:5]([CH3:13])[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: N#Cc1ccc(Cl)cc1F
Reactant: CN(CCC(O)Cc1ccccc1)C(=O)OC(C)(C)C
Product: CN(CCC(Cc1ccccc1)Oc1cc(Cl)ccc1C#N)C(=O)OC(C)(C)C

Procedure:
The title compound was prepared according to the method of Example 3 step (b) but using (3-hydroxy-4-phenylbutyl)methylcarbamic acid, 1,1-dimethylethyl ester, and 4-chloro-2-fluorobenzonitrile.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=1.S(Cl)([Cl:16])=O>C(Cl)(Cl)Cl>[Cl:16][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=1
Reactant: CC(=O)NCc1ccc(CO)cc1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CC(=O)NCc1ccc(CCl)cc1

Procedure:
To a solution of N-(4-hydroxymethylphenylmethyl)acetamide (1.5 g) in chloroform (50 ml) was added thionyl chloride (0.73 ml) and the mixture was refluxed under heating for 1 hr. The solvent was evaporated and the obtained residue was crystallized from ethyl acetate to give the title compound (1.8 g) as pale-yellow crystals.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][C:16](OCC)=[O:17])[CH2:11][CH2:10]1)(=[O:8])[C:2]1C=CC=CC=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>C1(C)C=CC=CC=1.CCCCCC>[C:1]([N:9]1[CH2:10][CH2:11][CH:12]([CH2:15][CH:16]=[O:17])[CH2:13][CH2:14]1)(=[O:8])[CH3:2]
Reactant: CCOC(=O)CC1CCN(C(=O)c2ccccc2)CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CC(=O)N1CCC(CC=O)CC1
Temperature: -75 °C

Procedure:
A solution was prepared containing 5 g. of N-benzoyl-4-(carbethoxymethyl)piperidine in 50 ml of anhydrous toluene. The solution was cooled to about -75° C. under a dry nitrogen atmosphere. 38.3 ml of a 20 percent solution of di-isobutylaluminum hydride in hexane were added slowly with stirring. After the addition had been completed, the reaction mixture was stirred for an additional 3 hours; then 25 ml of 6 N aqueous hydrochloric acid were added. The aqueous layer was separated, washed with methylene chloride, the methylene chloride layer separated and discarded and the aqueous layer neutralized with solid sodium bicarbonate. The resulting amorphous solid was removed by suction filtration and discarded. The filtrate was concentrated in vacuo with gentle heating to a volume of about 50 ml. The resulting solution was saturated with solid sodium chloride and cooled to a temperature in the range 0° - 5° C. with an ice/salt bath. To this solution was added simultaneously with vigorous stirring a solution of 15 g sodium acetate in 15 ml of water and 15 ml of acetic anhydride. After the simultaneous additions had been completed, the reaction mixture was stirred for additional 30 minutes. Excess acid was neutralized with solid sodium carbonate and the resulting aqueous solution extracted with four 75 ml portions of methylene chloride. The methylene chloride extracts were combined and dried and the solvent removed therefrom by evaporation in vacuo. A yield of about 2.31 g of N-acetyl-4-piperidineacetaldehyde boiling in the range 88°-90° C. at 0.03 mm Hg was obtained. The compound had the following physical characteristics.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[CH3:15][C:16]1[N:17]=[C:18]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)[S:19][C:20]=1[CH2:21][C:22]([OH:24])=O.[CH3:35][C:36]1[CH:48]=[CH:47][CH:46]=[CH:45][C:37]=1[O:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41].C(=O)(O)[O-].[Na+]>CS(O)(=O)=O.O>[CH3:35][C:36]1[CH:48]=[C:47]([C:22](=[O:24])[CH2:21][C:20]2[S:19][C:18]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)=[N:17][C:16]=2[CH3:15])[CH:46]=[CH:45][C:37]=1[O:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CC(=O)O
Reactant: CCOC(=O)COc1ccccc1C
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Product: CCOC(=O)COc1ccc(C(=O)Cc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C
Temperature: 60 °C

Procedure:
A well stirred suspension of phosphorus pentoxide (0.92 g) in methane sulfonic acid (6.5 ml) under nitrogen was heated to 60° C. until a clear solution formed. The mixture was then allowed to cool to room temperature prior to addition of {4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}acetic acid (intermediate 14, 0.98 g) and ethyl (2-methylphenoxy)acetate (0.49 ml). The mixture was heated to 60° C. for 90 minutes, after cooling to room temperature the reaction mixture was poured onto iced water (100 ml) and the acidic suspension basified by cautious addition of solid sodium bicarbonate. The product was extracted into ethyl acetate and the combined organic extracts dried (magnesium sulfate) filtered and evaporated. Purification by flash column chromatography using ethyl acetate:cyclohexane (1:9) as eluent gave title compound as a pale yellow solid.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8](Cl)([Cl:10])=[O:9]>CN(C)C=O>[C:1]1([O:7][C:8]([Cl:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)Cl
Reactant: Oc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)Oc1ccccc1

Procedure:
In a device provided with a deep-freezing cooler as described in Example 1 a mixture of 94 g of phenol and 15 g of N,N-dimethyl-formamide was reacted at 80° C within 3 hours with 150 g of phosgene. After the reaction had been completed, the mixture was distilled. About 110g of chloroformic acid phenyl ester were obtained. In the distillation flask, a strongly hygroscopic residue remained wich served as catalyst for the following reaction.
Reaction SMILES: O[CH:2]([C:7]1[O:8][C:9]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:11]=1)[CH2:3][CH2:4][CH2:5]O.CS(Cl)(=O)=O.C([N:31]([CH2:34][CH3:35])CC)C>O1CCCC1.C(OCC)(=O)C>[CH2:34]([N:31]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:7]1[O:8][C:9]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:11]=1)[C:35]1[CH:5]=[CH:4][CH:3]=[CH:2][CH:7]=1
Reactant: CCN(CC)CC
Reactant: OCCCC(O)c1nc(-c2ccccc2)c(-c2ccccc2)o1
Agent: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: c1ccc(CN2CCCC2c2nc(-c3ccccc3)c(-c3ccccc3)o2)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(1,4-dihydroxybutyl)-4,5-diphenyloxazole (1 g) in tetrahydrofuran (10 ml) were added methanesulfonyl chloride (1.6 g) and triethylamine (1.5 ml) at 0° C. The solution was diluted with ethyl acetate and washed with sat. NaHCO3 and brine, dried over MgSO4, and evaporated. The residue was dissolved in benzylamine (10 ml). After being stirred for 2 hours at 80° C., the mixture was partitioned between ether and water. The or-ganic layer was washed with water and brine. The dried solvent was evaporated in vacuo and the residue was purified by chromatography on silica gel to afford 1-benzyl-2-(4,5-diphenyloxazol-2-yl)pyrrolidine (1.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[CH:6]=[C:7]([C:9]3[C:18]([N:19]([CH3:23])[CH:20]([CH3:22])[CH3:21])=[N:17][C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:24]([O:26]C)=[O:25])[CH:15]=4)[N:10]=3)[O:8][C:4]=2[CH:3]=1.[OH-].[Na+].Cl>CO.O>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[CH:6]=[C:7]([C:9]3[C:18]([N:19]([CH3:23])[CH:20]([CH3:22])[CH3:21])=[N:17][C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:24]([OH:26])=[O:25])[CH:15]=4)[N:10]=3)[O:8][C:4]=2[CH:3]=1
Reactant: COC(=O)c1ccc2nc(-c3cc4ccc(Cl)cc4o3)c(N(C)C(C)C)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1cc2ccc(Cl)cc2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.4 %

Procedure:
To a solution of methyl 2-(6-chloro-1-benzofuran-2-yl)-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylate (60 mg, 0.15 mmol) in methanol (20 mL) and water (1 mL) was added sodium hydroxide (16 mg, 0.40 mmol). After stirring overnight at room temperature, the reaction mixture was concentrated under reduced pressure to afford a residue, which was dissolved in water (20 mL), adjusted the pH to 6 with 3N HCl and filtered to give 2-(6-chloro-1-benzofuran-2-yl)-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylic acid as a light yellow solid (25.2 mg, 43%).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9]([C:11]([O:13]CC)=[O:12])=[CH:8][C:7](/[CH:16]=[CH:17]/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:6][C:5]=2[N:4]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:27][CH:26]=2)[N:3]=1.[OH-].[K+].C1COCC1>CC(O)C.O>[CH3:1][C:2]1[C:10]2[C:9]([C:11]([OH:13])=[O:12])=[CH:8][C:7](/[CH:16]=[CH:17]/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:6][C:5]=2[N:4]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([O:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:29][CH:30]=2)[N:3]=1
Reactant: CCOC(=O)c1cc(/C=C/c2ccccc2)nc2c1c(C)nn2Cc1ccc(Oc2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)O
Product: Cc1nn(Cc2ccc(Oc3ccccc3)cc2)c2nc(/C=C/c3ccccc3)cc(C(=O)O)c12
Yield: 88.6 %

Procedure:
A solution of ester 52 (56 mg, 0.11 mmol) and KOH (19 mg, 0.34 mmol) in iPrOH:THF (2 mL/1 mL) was refluxed at 87° C. for 2 h. Reaction mixture was diluted with water (10 mL) and washed with EtOAc (10 mL×2). Aqueous layer was acidified with 1N HCl and extracted with EtOAc (10 mL×2). Combined organic extracts were washed with brine, dried (Na2SO4) and filtered. The solvent was removed under reduced pressure to give the title compound (45 mg, 94%) as a yellow solid. 88% pure by HPLC. 1H NMR (500 MHz, DMSO-d6) δ 13.86 (s, 1H), 7.87 (d, J=16.2 Hz, 1H), 7.81 (s, 1H), 7.74 (d, J=7.8 Hz, 2H), 7.52 (d, J=16.2 Hz, 1H), 7.42 (t, J=7.5 Hz, 2H), 7.37-7.29 (m, 5H), 7.09 (t, J=7.4 Hz, 1H), 6.98-6.92 (m, 4H), 5.64 (s, 2H), 2.58 (s, 3H). 13C NMR (125 MHz, DMSO-d6) δ 167.16, 156.97, 156.47, 155.22, 152.20, 140.74, 136.47, 135.39, 134.92, 133.00, 130.46, 129.90, 129.30, 128.04, 127.87, 123.90, 119.11, 119.02, 116.60, 110.13, 49.41, 16.02. ESI MS: m/z 462.0 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].N1C=CN=C1.O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(OCc2ccccc2)cc1
Reaction time: 8 h

Procedure:
4-Benzyloxyphenol (39 g, 0.19 mole) and tert-butyldimethylsilyl chloride (32.31 g, 0.21 mole) were dissolved in dimethylformamide (200 ml). Imidazole (14.59 g, 0.21 mole) was added in portions and after the addition the reaction mixture was stirred overnight. Water was added and the mixture was extracted with ether. The combined organic layers were washed with water and dried over anhydrous calcium chloride. The solvent was evaporated to yield crystallized product (60.2 g, 0.19 mole, 98%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:23]=[CH:22][C:15]4[N:16]=[C:17](S(C)=O)[S:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1.Cl.[NH2:25][C@@H:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@@H:27]1[OH:32].CCN(C(C)C)C(C)C>CC(N(C)C)=O>[F:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:23]=[CH:22][C:15]4[N:16]=[C:17]([NH:25][C@@H:26]5[CH2:31][CH2:30][CH2:29][CH2:28][C@@H:27]5[OH:32])[S:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1
Reactant: N[C@@H]1CCCC[C@@H]1O
Reactant: CS(=O)c1nc2ccc(Cn3cnc4cc(F)cnc43)cc2s1
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: O[C@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(F)cnc43)cc2s1
Temperature: 110 °C
Yield: 7.5 %

Procedure:
To a suspension of 6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole (1.0 g, 3.0 mmol) and (1S,2R)-2-aminocyclohexanol hydrochloride (916 mg, 6 mmol) in anhydrous DMA (12 mL) was added DIEA (1.6 mL, 9.0 mmol). The mixture was heated in a sealed tube at 110° C. for 12 h. The mixture was cooled to rt and additional (1S,2R)-2-aminocyclohexanol hydrochloride (458 mg, 3 mmol) and DIEA (530 μL, 3 mmol) were added. The mixture was further heated in a sealed tube at 120° C. for 12 h. The mixture was cooled to rt and partitioned between EtOAc (200 mL) and 0.5 M aq K2CO3 (100 mL). The organic layer was separated, washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluting with 5% MeOH in CH2Cl2, then by reverse-phase preparative HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C18 column as the stationary phase to afford (1S,2R)-2-((6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (89 mg, 7%) as a white powder. 1H NMR (500 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.41 (s, 1H), 8.06 (dd, J=2.5, 9.5 Hz, 1H), 7.85 (d, J=7.5 Hz, 1H), 7.66 (s, 1H), 7.29 (d, J=8.0 Hz, 1H), 7.21 (dd, J=1.3, 8.3 Hz, 1H), 5.47 (s, 2H), 4.67 (m, 1H), 3.90 (m, 1H), 3.84 (m, 1H), 1.64-1.74 (m, 2H), 1.43-1.63 (m, 4H), 1.25-1.34 (m, 2H); LCMS (ESI) m/z 398 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:5][C:4](=[O:20])[CH:3]=1.CCN(CC)CC.[CH:28]([C:31]1[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=1[C:33](Cl)=O)([CH3:30])[CH3:29].CC(C)(O)C#N.C([BH3-])#N.[Na+]>C(O)(=O)C.C(#N)C.C(Cl)Cl>[OH:1][C:2]1[CH2:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:5][C:4](=[O:20])[C:3]=1[CH2:33][C:32]1[CH:36]=[CH:37][CH:38]=[CH:39][C:31]=1[CH:28]([CH3:30])[CH3:29]
Reactant: O=C1C=C(O)CC(c2ccccc2)(c2ccccc2)O1
Reactant: CC(C)c1ccccc1C(=O)Cl
Agent: CC(C)(O)C#N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CC#N
Product: CC(C)c1ccccc1CC1=C(O)CC(c2ccccc2)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared as described in General Method 8 using the following: 5,6-dihydro-4-hydroxy-6,6-diphenyl-2H-pyran-2-one (0.300 g, 1.15 mmol), Et3N (0.17 mL, 1.2 mmol), 2-isopropylbenzoyl chloride (1.02 mmol), CH2Cl2 (4.0 mL), acetonitrile (4.0 mL), acetone cyanohydrin (0.05 mL, 0.5 mmol), Et3N (0.35 mL, 2.5 mmol), glacial acetic acid (5.0 mL), sodium cyanoborohydride (0.50 g, 8.5 mmol). Purification was achieved by submitting the final residue to column chromatograpy (SiO2, 100% CH2Cl2 to 1% MeOH in CH2Cl2) to provide a solid (0.128 g, 224-226° C.). 1H NMR (400 MHz, DMSO-d6) δ 11.180 (bs, 1 H), 7.445-7.235 (m, 10 H), 7.109 (d, 1 H, J=7.5 Hz), 6.970 (t, 1 H, J=7.5 Hz), 6.515 (t, 1 H, J=7.5 Hz), 5.841 (d, 1 H, J=7.5 Hz), 3.560 (s, 2 H), 3.463 (s, 2 H), 1.174-1.094 (m, 7 H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C:3]=1[CH3:19].[O:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:29][C:27]=2[NH2:28])[CH2:22][CH2:21]1.Cl.O1CCOCC1>CO>[N:23]1([C:26]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)=[CH:29][C:27]=2[NH:28][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=3)[N:5]=[C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:3]=2[CH3:19])[CH2:24][CH2:25][O:20][CH2:21][CH2:22]1
Reactant: Cc1c(-c2ccccn2)nc2ccc(F)cc2c1Cl
Reactant: Nc1cc(N2CCOCC2)ccc1N1CCOCC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1c(-c2ccccn2)nc2ccc(F)cc2c1Nc1cc(N2CCOCC2)ccc1N1CCOCC1

Procedure:
Prepared according to general Procedure K using 4-chloro-6-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (100 mg, 0.37 mmol), 2,5-dimorpholinoaniline (97 mg, 0.37 mmol) and a 4.0M solution of HCl in dioxane (0.09 mL, 0.37 mmol) in MeOH (1.0 mL) and heating in the microwave for 2 h at 150° C. After purification N-(2,5-di-4-morpholinylphenyl)-6-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinamine was obtained. 1H NMR (500 MHz, chloroform-d) δ ppm 8.67-8.81 (1H, m), 8.19 (1H, dd, J=9.0, 5.4 Hz), 7.83-7.94 (2H, m), 7.42-7.52 (2H, m), 7.39 (1H, ddd, J=7.3, 4.8, 1.6 Hz), 7.17 (1H, s), 7.12 (1H, d, J=8.6 Hz), 6.45 (1H, dd, J=8.7, 2.8 Hz), 5.99 (1H, d, J=2.7 Hz), 3.84-3.98 (4H, m), 3.65-3.79 (4H, m), 3.06 (4H, dd, J=3.4, 2.0 Hz), 2.83-2.95 (4H, m), 2.39 (3H, s). Mass Spectrum (ESI) m/e=500.2 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[C:5]2[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1.[NH:26]1[CH2:29][CH:28]([OH:30])[CH2:27]1>>[F:17][C:14]([F:15])([F:16])[C:13]([C:6]1[C:7]([CH3:12])=[N:8][C:9]2[C:4]([C:5]=1[C:19]1[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=1)=[CH:3][C:2]([N:26]1[CH2:29][CH:28]([OH:30])[CH2:27]1)=[CH:11][CH:10]=2)=[O:18]
Reactant: Cc1nc2ccc(Br)cc2c(-c2ccc(F)cc2)c1C(=O)C(F)(F)F
Reactant: OC1CNC1
Product: Cc1nc2ccc(N3CC(O)C3)cc2c(-c2ccc(F)cc2)c1C(=O)C(F)(F)F
Reaction time: 12 h
Yield: 12 %

Procedure:
The title compound was prepared from 1-[6-Bromo-4-(4-fluoro-phenyl)-2-methyl-quinolin-3-yl]-2,2,2-trifluoro-ethanone [example 24] and azetidin-3-ol according to the procedure of example 25, except that the reaction time was of 12 h. Yield: 12%; MS: m/z=405 (M+H).
Reaction SMILES: N1C2C(=CC=CC=2)C(CC(=O)C(O)=O)=C1.[OH-].[Na+].Cl.C([O-])(=O)C(C)=O.[Na+].N[C@@H](C(O)=O)C.CC1C(O)=C(C=O)C(COP(O)(O)=O)=CN=1.[CH:48]1[CH:53]=[C:52]2[C:54]([CH2:57][C@@:58]([OH:68])([C:65]([OH:67])=[O:66])[CH2:59][C@@H:60]([NH2:64])[C:61]([OH:63])=[O:62])=[CH:55][NH:56][C:51]2=[CH:50][CH:49]=1>O>[CH:48]1[CH:53]=[C:52]2[C:54]([CH2:57][C@@:58]([OH:68])([C:65]([OH:67])=[O:66])[CH2:59][C@H:60]([NH2:64])[C:61]([OH:63])=[O:62])=[CH:55][NH:56][C:51]2=[CH:50][CH:49]=1
Reactant: N[C@H](C[C@@](O)(Cc1c[nH]c2ccccc12)C(=O)O)C(=O)O
Agent: CC(=O)C(=O)[O-]
Agent: C[C@@H](N)C(=O)O
Agent: Cc1ncc(COP(=O)(O)O)c(C=O)c1O
Solvent: O
Product: N[C@@H](C[C@@](O)(Cc1c[nH]c2ccccc12)C(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
5.0 g of indole-3-pyruvic acid was suspended in 100 ml of water, which was dissolved by addition of 2N sodium hydroxide aqueous solution and adjusted to pH 12. Then, the solution was adjusted to pH 9 by addition of 1N hydrochloric acid, and then sodium pyruvate (8.12 g) and the solution of trans-L-hydroxyproline/zinc (II) complex (22 ml) were added. The mixture was stirred at room temperature for 4 hours, and the cross-aldol reaction was performed. To 25 ml of the obtained reaction mixture, D-Ala (1.8 g) and pyridoxal-5′-phosphate (1 mg) were added, and then 0.5 g of BMDAT-expressing E. coli or S243N/A182S mutant BMDAT-expressing E. coli was added in suspension to carry out amination reaction at 33° C. for 24 hours. By HPLC analysis of the reaction mixture with appropriate dilution, it was confirmed to genarate (2R,4R)-monatin or (2R,4S)-monatin as shown in Table 4. Incidentally, the BMDAT-expressing E. coli and S243N/A182S mutant BMDAT-expressing E. coli used for the amination reaction were prepared according to the method described in the following Reference Example.
Reaction SMILES: [Cl:1]NC(=O)CCC(N)=O.CSC.[CH2:13]([O:20][C:21]1[C:26]([CH2:27]O)=[C:25]([CH2:29][CH3:30])[CH:24]=[C:23]([CH3:31])[N:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>ClCCl.[Cl-].[Na+].O>[CH2:13]([O:20][C:21]1[C:26]([CH2:27][Cl:1])=[C:25]([CH2:29][CH3:30])[CH:24]=[C:23]([CH3:31])[N:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NC(=O)CCC(=O)NCl
Reactant: CCc1cc(C)nc(OCc2ccccc2)c1CO
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CSC
Solvent: O
Product: CCc1cc(C)nc(OCc2ccccc2)c1CCl
Temperature: -20 °C
Yield: 22.9 %

Procedure:
To a 0° C. solution of N-chloro succinamide (81.5 mg, 0.598 mmol) in dichloromethane (2.47 mL) was added dimethyl sulfide (48 ul, 0.653 mmol). The reaction mixture was then cooled to −20° C. and a solution of [2-(benzyloxy)-4-ethyl-6-methylpyridin-3-yl]methanol (Cpd DD, 140 mg, 0.554 mmol) in dichloromethane (1 mL) was added drop wise. After 2 hours the reaction mixture was poured into brine (5 mL) then extracted with dichloromethane (10 mL). The organic layer was dried over sodium sulfate, filtered, then concentrated under vacuum. The residue was purified by column chromatography (heptane/EtOAc) to give the title compound (Cpd EE, 35 mg, 23% yield) as a colorless oil. 1H NMR (chloroform-d) δ 7.52 (d, J=7.3 Hz, 2H), 7.29-7.44 (m, 3H), 6.65 (s, 1H), 5.46 (s, 2H), 4.74 (s, 2H), 2.72 (q, J=7.6 Hz, 2H), 2.44 (s, 3H), 1.28 (t, J=7.6 Hz, 3H).
Reaction SMILES: ClC1C=C([C:9](=[O:17])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)C=C(Cl)C=1.Br[C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=1>>[F:26][C:21]1[CH:20]=[C:19]([C:9](=[O:17])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:24]=[C:23]([F:25])[CH:22]=1
Reactant: O=C(Cc1ccccc1)c1cc(Cl)cc(Cl)c1
Reactant: Fc1cc(F)cc(Br)c1
Product: O=C(Cc1ccccc1)c1cc(F)cc(F)c1
Yield: 10.3 %

Procedure:
Prepared following the procedure described in Intermediate 13, starting from 1-bromo-3,5-difluorobenzene, where the crude product was purified by column chromatography (PE:EtOAc=100:1) to afford Intermediate 18 (100 mg, yield 10.3%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([OH:12])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.[Cl:13]N1C(=O)CCC1=O>ClCCl.CN(C=O)C>[Cl:13][C:3]1[C:4]2[C:9](=[CH:8][C:7]([C:10]([OH:12])=[O:11])=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(O)c1ccc2c(Cl)c[nH]c2c1
Reaction time: 3 h
Yield: 80 %

Procedure:
To a solution of indole-6-carboxylic acid (2.45 g, 15.2 mmol) in dichloromethane (100 mL) and DMF (10 mL) was added N-chlorosuccinimide (2 g, 15.2 mmol). After 3 h, the solvent was removed in vacuo and the residue was suspended in dichloromethane, sonicated and filtered to give 2.38 g (80%) of the title compound.
Reaction SMILES: [CH2:1]([N:10]1[C:15](=[O:16])[C:14]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[C:13]([C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)[CH:12]=[N:11]1)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].[BH4-].[Na+]>C(O)C>[OH:3][CH:2]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH2:1][N:10]1[C:15](=[O:16])[C:14]([C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)=[C:13]([C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)[CH:12]=[N:11]1
Reactant: CS(=O)(=O)c1ccc(-c2cnn(CC(=O)c3ccccc3)c(=O)c2-c2ccc(F)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CS(=O)(=O)c1ccc(-c2cnn(CC(O)c3ccccc3)c(=O)c2-c2ccc(F)cc2)cc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 77.5 %

Procedure:
A mixture of the product from Example 46, 2-phenacyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (700 mg, 1.5 mmol), and sodium borohydride (69 mg, 1.8 mmol) in ethanol (200 mL), was stirred at 40° C. for 2 hours. The reaction mixture was then concentrated in vacuo and the residue was partitioned between ethyl acetate and 2 N aqueous hydrochloric acid. The organic layer was washed with brine, dried over MgSO4, and filtered. The filtrate was concentrated in vacuo to provide a pale yellow solid which was crystallized from ethyl acetate/hexanes to provide the title compound as white crystals (yield: 540 mg, 78%). mp 205–207° C. 1H NMR (300 MHz, CDCl3) δ 3.07 (s, 3H), 3.75 (br s, 1H), 4.63–4.47 (m, 2H), 5.33 (dd, J=9 Hz, 3 Hz, 1H), 7.00 (t, J=9 Hz, 2H), 7.20 (dd, J=9 Hz, 3 Hz, 2H), 7.30–7.45 (m, 5H), 7.52 (d, J=9 Hz, 2H), 7.91 (s, 1H), 7.91 (d, J=9 Hz, 2H). MS (DCI/NH3) m/z 465 (M+H)+. Anal. calc. for C25H21FN2O4S: C, 64.64; H, 4.55; N, 6.03. Found: C, 64.34; H, 4.66; N, 5.93.