Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:17][C:18]3[N:23]=[C:22]([C:24](O)=[O:25])[CH:21]=[CH:20][CH:19]=3)=[C:8]([C:12]3[CH:16]=[CH:15][S:14][CH:13]=3)[NH:9]2)=[CH:5][CH:4]=1.[CH3:27][S:28]([NH2:31])(=[O:30])=[O:29].Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[CH3:27][S:28]([NH:31][C:24]([C:22]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:17][C:7]2[C:6]3[C:10](=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[NH:9][C:8]=2[C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)[N:23]=1)=[O:25])(=[O:30])=[O:29]
Reactant: COc1ccc2c(Cc3cccc(C(=O)O)n3)c(-c3ccsc3)[nH]c2c1
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc2c(Cc3cccc(C(=O)NS(C)(=O)=O)n3)c(-c3ccsc3)[nH]c2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 39.7 %

Procedure:
Under an argon atmosphere, to a suspension of 6-(6-methoxy-2-thiophen-3-yl-1H-indol-3-ylmethyl)pyridine-2-carboxylic acid (45.5 mg) in dichloromethane (0.6 mL) were added methane sulfonamide (11.9 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (23.9 mg), and 4-dimethylaminopyridine (15.3 mg), and this mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated under reduced pressure. To the residue was added 10% aqueous citric acid solution, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine successively, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. To the residue was added ethanol, and this suspension was heated to reflux for 45 minutes to give a solution. This solution was left to be cooled. The precipitate was collected by filtration and dried under reduced pressure to obtain the title compound (21.9 mg). 1H-NMR (DMSO-d6) δ ppm: 3.38 (3H, s), 3.77 (3H, s), 4.47 (2H, s), 6.65 (1H, dd, J=2.3, 8.6 Hz), 6.85 (1H, d, J=2.3 Hz), 7.27-7.35 (1H, m), 7.42 (1H, d, J=8.6 Hz), 7.56 (1H, dd, J=1.3, 5.0 Hz), 7.67 (1H, dd, J=3.0, 5.0 Hz), 7.81-7.91 (3H, m), 11.17 (1H, s), 11.42-11.66 (1H, br).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7]1([CH2:13][C@@H:14]([NH:30][CH3:31])[CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])[CH2:18][CH2:17]2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[CH3:32][C:33]1([C:39]([Cl:41])=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>ClCCl.O>[CH:7]1([CH2:13][C@@H:14]([N:30]([CH3:31])[C:39]([C:33]2([CH3:32])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)=[O:40])[CH2:15][N:16]2[CH2:17][CH2:18][CH:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])[CH2:20][CH2:21]2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1.[ClH:41]
Reactant: CC1(C(=O)Cl)CCCCC1
Reactant: CN[C@H](CC1CCCCC1)CN1CCC(c2ccccc2OC)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: COc1ccccc1C1CCN(C[C@@H](CC2CCCCC2)N(C)C(=O)C2(C)CCCCC2)CC1
Product: Cl
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of 0.08 g of potassium carbonate (0.58 mmol) in 1 ml. of water 1o was added a solution of 0.18 g of {(1R)-1-cyclohexylmethyl-2-[4-(2-methoxyphenyl)-piperidin-1-yl]-ethyl}-methyl-amine (0.58 mmol) in 10 mL of dichloromethane. The resulting mixture was cooled to 0° C. and 0.093 g of 1-methyl -cyclohexanecarboxylic acid chloride (0.58 mmol) was added. The reaction was allowed to stir overnight at 0° C., and was then diluted with 5 mL of water and 20 mL of dichloromethane and the phases separated. The aqueous phase was extracted with three additional portions of dichloromethane, and the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to yield the crude product, which was purified by flash chromatography on silica gel (dichloromethane/methanol) and converted to the hydrochloride.0.75 hydrate salt of the title compound with isopropanolic HCl to yield 0.220 g (75%) of white solid; mp=169-171° C.; MS(+)ESI m/z=469 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].CS(O[CH:14]1[CH2:18][CH2:17][N:16]([CH:19]2[CH2:21][CH2:20]2)[CH2:15]1)(=O)=O>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH:14]1[CH2:18][CH2:17][N:16]([CH:19]2[CH2:21][CH2:20]2)[CH2:15]1
Reactant: Oc1ccccc1Br
Reactant: CS(=O)(=O)OC1CCN(C2CC2)C1
Product: Brc1ccccc1OC1CCN(C2CC2)C1

Procedure:
The title compound was prepared from 2-bromophenol and 1-cyclopropylpyrrolidin-3-yl methanesulphonate in a similar manner to Example 134 (b) except that the compound was purified by cation exchange chromatography eluting with ammonia/methanol mixtures.
Reaction SMILES: Br[CH:2]1[C:7]([CH3:9])([CH3:8])[O:6][C:5]2[CH:10]=[CH:11][C:12]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])=[CH:13][C:4]=2[CH:3]1O.[NH3:24].C([OH:27])C>>[NH2:24][CH:3]1[CH:2]([OH:27])[C:7]([CH3:8])([CH3:9])[O:6][C:5]2[CH:10]=[CH:11][C:12]([S:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)(=[O:16])=[O:15])=[CH:13][C:4]1=2
Reactant: N
Reactant: CC1(C)Oc2ccc(S(=O)(=O)c3ccccc3)cc2C(O)C1Br
Reactant: CCO
Product: CC1(C)Oc2ccc(S(=O)(=O)c3ccccc3)cc2C(N)C1O

Procedure:
A solution of 3-bromo-3,4-dihydro-2,2-dimethyl-6-phenylsulfonyl-2H-benzo[b]pyran-4-ol in ethanol is shaken under a pressure of 8 bar of NH3 at 50° in an autoclave for 8 hours. The mixture is cooled and then evaporated to dryness and recrystallized from ethyl acetate. 4-Amino-3,4-dihydro-2,2-dimethyl-6-phenylsulfonyl-2H-benzo[b]pyran-3-ol of melting point: 160°-163°C. is obtained and is immediately subjected to acylation with 4-chlorobutyryl chloride. For this purpose, the substance is dissolved together with the acid chloride in CH2Cl2 and stirred in a two-phase mixture with 2N sodium hydroxide solution at room temperature for 24 hours. The usual working up results in 4-(4-chlorobutyrylamino)-3,4-di-hydro-2,2-dimethyl-6-phenylsulfonyl-2H-benzo[b]pyran-4-ol of melting point 155°-157° C. Cyclization to give the title compound is carried out by dissolving the substance in tetrahydrofuran, addition of a stoichiometric amount of 80% NaH suspension in oil and stirring the mixture at room temperature for 24 hours. The final product is identical to the product obtained by process b). Melting point: 200°-201° C. If 4-amino-3,4-dihydro-2,2-dimethyl-6-phenylsulfonyl-2H-benzo[b]pyran-3-ol is subjected to racemate resolution, it is possible to obtain from its (+) enantiomer the pure (+) enantiomer from Example 5a with the data indicated there.
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12]C)=[O:11])=[CH:8][N:7]=1)(=[O:4])=[O:3].[OH-].[Li+]>O1CCCC1.CO.O>[CH3:1][S:2]([CH2:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([OH:12])=[O:11])=[CH:8][N:7]=1)(=[O:4])=[O:3]
Reactant: COC(=O)c1ccc(CS(C)(=O)=O)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CS(=O)(=O)Cc1ccc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
To a stirred solution of methyl 6-[(methylsulfonyl)methyl]nicotinate (800 mg) in 1:1.1 tetrahydrofuran/methanol/water (30 mL) was added lithium hydroxide (440 mg). The mixture was stirred at room temperature for 1 h, and concentrated under reduced pressure. The residue was partitioned between water (10 mL) and chloroform (10 mL). The aqueous layer was acidified to pH 4 with 1 N hydrochloric acid and extracted with 3:1 chloroform/2-propanol (3×30 mL). The combined organic layers were dried (sodium sulfate), filtered, and concentrated under reduced pressure to provide 700 mg of the title compound: 1H NMR (300 MHz, CD3OD) δ 9.07, 8.33, 7.65, 4.77, 3.06.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][N:6]([C@@H:8]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:9]2[CH:14]=[CH:13][C:12]([C:15]#[C:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4][N:3]1[CH2:29][C:30]([O:32]C(C)(C)C)=[O:31].O.[OH-].[Li+]>C1COCC1.CO.O>[CH3:1][C@@H:2]1[CH2:7][N:6]([C@@H:8]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:9]2[CH:10]=[CH:11][C:12]([C:15]#[C:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:13][CH:14]=2)[CH2:5][CH2:4][N:3]1[CH2:29][C:30]([OH:32])=[O:31]
Reactant: C[C@@H]1CN([C@@H](c2ccccc2)c2ccc(C#Cc3ccccc3)cc2)CCN1CC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@H]1CN([C@@H](c2ccccc2)c2ccc(C#Cc3ccccc3)cc2)CCN1CC(=O)O
Reaction time: 8 h
Yield: 84.9 %

Procedure:
To a solution of tert-butyl 2-((R)-2-methyl-4-((S)-phenyl(4-(2-phenylethynyl)phenyl)-methyl)piperazin-1-yl)acetate (320 mg, 0.666 mmol) in THF/MeOH/H2O=5:5:1 (5.5 mL) was added lithium hydroxide monohydrate (279 mg, 6.658 mmol) and the resulting solution was stirred overnight. The solvent was evaporated to dryness under high vacuum and the residue was diluted with water, adjusted pH=5, extracted with DCM, dried over Na2SO4, filtered and evaporated to dryness. The residue was loaded onto flash column (SiO2, DCM to DCM/MeOH=100:5 to 100:10 to 100:15 to 100:20) to give 2-((R)-2-methyl-4-((S)-phenyl(4-(2-phenylethynyl)phenyl)methyl)piperazin-1-yl)acetic acid (240 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[C:6]3[C:7]([CH3:15])([CH3:14])[CH2:8][CH2:9][NH:10][C:11]=3[CH2:12][CH2:13][C:4]=2[CH:3]=1.C(N(CC)CC)C.[C:25](Br)(=[O:27])[CH3:26]>C(Cl)Cl>[C:25]([N:10]1[C:11]2[CH2:12][CH2:13][C:4]3[CH:3]=[C:2]([Cl:1])[CH:17]=[CH:16][C:5]=3[C:6]=2[C:7]([CH3:14])([CH3:15])[CH2:8][CH2:9]1)(=[O:27])[CH3:26]
Reactant: CC(=O)Br
Reactant: CC1(C)CCNC2=C1c1ccc(Cl)cc1CC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCC(C)(C)C2=C1CCc1cc(Cl)ccc12
Reaction time: 1 h

Procedure:
10.6 g (0.043 mol) of 8-chloro-1,1-dimethyl-1,2,3,4,5,6-hexahydrobenzo[f]quinoline and 6.6 ml (0.047 mol) of triethylamine are dissolved in 100 ml of methylene chloride and 3.5 ml (0.047 mol) of acetyl bromide dissolved in 20 ml of methylene chloride are added dropwise thereto at 0°. After stirring for 1 hour, the mixture is extracted with methylene chloride/water, dried with magnesium sulfate and the solvent is distilled in a vacuum. Recrystallization from methylene chloride/hexane gives 4-acetyl-8-chloro-1,1-dimethyl-1,2,3,4,5,6-hexahydrobenzo[f]quinoline as white crystals with melting point 126°-127°.
Reaction SMILES: [C:1]([O:5][C:6]1C=CC(C2C=CC=C(F)C=2F)=CC=1)(=O)C=C.[F:20][C:21]1[CH:26]=[C:25]([Br:27])[CH:24]=[CH:23][C:22]=1[OH:28].C1C(O)=CC=C(Br)C=1>>[Br:27][C:25]1[CH:24]=[CH:23][C:22]([O:28][CH2:1][O:5][CH3:6])=[C:21]([F:20])[CH:26]=1
Reactant: Oc1ccc(Br)cc1F
Reactant: C=CC(=O)Oc1ccc(-c2cccc(F)c2F)cc1
Agent: Oc1ccc(Br)cc1
Product: COCOc1ccc(Br)cc1F
Yield: 86.4 %

Procedure:
The same procedure as in the synthesis (a) of Example 1 was repeated except that 43.9 g of 2-fluoro-4-bromophenol were used instead of 40 g of p-bromophenol to give 46.7 g (Y., 86.4%) of methoxymethy 4-bromo-2-fluorophenyl ether. GC; 97.2% b.p.; 118°-120° C./14 mmHg
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([OH:24])[CH:12]=[C:13]([Cl:23])[C:14]=1[O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si:25](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl.O>[Si:1]([O:8][C:9]1[CH:10]=[C:11]([O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[CH:12]=[C:13]([Cl:23])[C:14]=1[O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(O)cc(Cl)c1O[Si](C)(C)C(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1cc(Cl)c(O[Si](C)(C)C(C)(C)C)c(O[Si](C)(C)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 82.5 %

Procedure:
To a mixture of 1.028 g (2.65 mmol) of 3,4-bis-(t-butyldimethylsilyloxy)-5-chlorophenol, 0.600 g (4.00 mmol) of t-butyldimethylsilyl chloride, and 0.048 g (0.40 mmol) of 4-dimethylaminopyridine in 10 mL of dichloromethane under argon at 25° C. was added 1.30 mL (9.26 mmol) of triethylamine. After stirring at 25° C. for 10 h, the mixture was diluted with 30 mL of water and extracted three times with diethyl ether (50 mL each). The combined extracts were washed with 30 mL of brine, dried (MgSO4), concentrated, and column chromatographed on silica gel using a gradient mixture of hexane and diethyl ether as eluent to give 1.100 g (83% yield) of 14. 1H NMR (CDCl3) d 6.49 (d, J=2.8 Hz, 1H, Ar, C4-H), 6.30 (d, J=2.8 Hz, 1H, C6-H), 1.04˜0.97 (broad s, 27H, t-Bu), 0.18 (s, 6H, Me), 0.175 (s, 12H, Me); 13C NMR (CDCl3) d 149.3 (s), 148.6 (s), 138.6 (s), 126.8 (s), 114.6 (d), 112.1 (d), 26.3 (q, t-Bu), 25.9 (q, t-Bu), 18.9 (s), 8.8 (s), −3.5 (q, 2C, Me), −3.4 (q, 2C, Me), −4.3 (q, 2C, Me). Anal. Calcd for C24H47ClO3Si3: C, 57.27; H, 9.41. Found: C, 57.37; H, 9.55.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH:9][CH3:10])[N:4]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:18]([O:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=1)=[S:19]>CC(C)=O>[CH3:1][O:2][C:3]1[N:4]=[C:5]([N:9]([CH3:10])[C:18](=[S:19])[O:20][C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: S=C(Cl)Oc1ccc2ccccc2c1
Reactant: CNc1cccc(OC)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cccc(N(C)C(=S)Oc2ccc3ccccc3c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.9 %

Procedure:
To the mixture of 1.38 g of 2-methoxy-6-methylaminopyridine, which is one of the compounds of this invention, and the same amount of anhydrous potassium carbonate in 20 ml of acetone, 2.23 g of O-2-naphthyl chlorothioformate dissolved in 20 ml of acetone was added under stirring at room temperature. After 30 minutes, the reaction mixture was extracted with benzene, washed with water, dried and recrystallized to give 2.75 g of O-2-naphthyl N-(6-methoxy-2-pyridyl)-N-methylthiocarbamate.
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C:13]=3[CH:19]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(OOS([O-])(=O)=O)([O-])(=O)=[O:21].[K+].[K+].CC#N.O>O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[CH:1]1([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]3[C:18](=[O:21])[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=3[CH:19]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: c1cc2c(cc1OCC1CCCCC1)CCCCC2
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=C1CCCCc2cc(OCC3CCCCC3)ccc21

Procedure:
A mixture of 2-cyclohexylmethoxy-6,7,8,9-tetrahydro-5H-benzocycloheptene (0.50 g, 1.94 mmol), potassium persulfate (1.57 g, 5.82 mmol), copper(II) sulfate pentahydrate (0.48 g, 1.94 mmol) and CH3CN/H2O (1:1, 13 mL) were heated at reflux for 45 min. After cooling the mixture was diluted with water and extracted with EtOAc. The combined extracts were washed with water, dried over magnesium sulfate, concentrated, and chomatographed over silica gel (20% EtOAc/hexane) to a white solid (0.46 g, 87%). MS [M+H]+ 273, m.p. 86-88° C.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].C(N(CC)CC)C.[C:14]([C:16]1[S:20][C:19]2[CH:21]=[CH:22][C:23](I)=[CH:24][C:18]=2[CH:17]=1)#[N:15].O>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:6][O:5][C:1](=[O:4])[CH:2]=[CH:3][C:23]1[CH:22]=[CH:21][C:19]2[S:20][C:16]([C:14]#[N:15])=[CH:17][C:18]=2[CH:24]=1
Reactant: C=CC(=O)OC
Reactant: N#Cc1cc2cc(I)ccc2s1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)C=Cc1ccc2sc(C#N)cc2c1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
Methyl acrylate (2 g), triethylamine (2.35 g) and palladium acetate (0.05 g) was added to 2-cyano-5-iodobenzo[b]thiophene (4.8 g) in DMF (25 ml) and the mixture was stirred under argon at 90° C. for 30 minutes. The mixture was allowed to cool and then added to water (50 ml). The solid which precipitated was collected by filtration and dissolved in chloroform. Activated charcoal was added and the mixture filtered and the filtrate dried (MgSO4). Solvent was removed by evaporation to give methyl3-(2-cyanobenzo[b]thiophen-5-yl)acrylate (2.5 g); NMR (d6 -DMSO): 3.75 (s, 3H), 6.7 (d, 1H), 7.8 (d, 1H), 8.0 (dd, 1H), 8.2 (d, 1H), 8.3 (d, 1H), 8.85 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:12]([CH3:14])[CH3:13])[C:9]([NH2:11])=[O:10])=[CH:4][CH:3]=1.F[B-](F)(F)F.[CH3:20][O+](C)C.CCOCC.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH:12]([CH3:14])[CH3:13])[C:9](=[NH:11])[O:10][CH3:20])=[CH:6][CH:7]=1
Reactant: C[O+](C)C
Reactant: CC(C)C(C(N)=O)c1ccc(Cl)cc1
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=N)C(c1ccc(Cl)cc1)C(C)C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
to a mixture of 2.32 g (11 mmol) of 2-(4-chlorophenyl)-3-methylbutyramide in methylene chloride is added, at room temperature, 1.78 g (12 mmol) of trimethyloxonium tetrafluoroborate. After stirring overnight under nitrogen, the resulting solution is poured onto an ice-cold mixture of ether, and aqueous sodium bicarbonate. The aqueous layer is discarded, and the ethereal layer is washed with cold water and dried over sodium sulfate. Filtration and concentration in vacuo affords methyl 2-(4-chlorophenyl)-3-methylbutanimidate.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:8]23[CH2:16][N:15]([C:17]4[N:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=4)[CH2:14][CH:13]2[CH2:12][S:11][C:10]([NH:24]C(=O)C2C=CC=CC=2)=[N:9]3)[S:6][CH:7]=1)#[N:2].N1C=CC=CC=1.Cl.CON>C(O)C>[NH2:24][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:14][N:15]([C:17]3[N:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=3)[CH2:16][C@:8]2([C:5]2[S:6][CH:7]=[C:3]([C:1]#[N:2])[CH:4]=2)[N:9]=1
Reactant: N#Cc1csc(C23CN(c4ncc(F)cn4)CC2CSC(NC(=O)c2ccccc2)=N3)c1
Agent: CON
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: N#Cc1csc([C@]23CN(c4ncc(F)cn4)C[C@H]2CSC(N)=N3)c1
Temperature: 25 °C

Procedure:
Racemic N-[7a-(4-cyano-2-thienyl)-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide (1.01 g, 2.17 mmol), pyridine (2.64 mL, 32.6 mmol), and O-methylhydroxylamine hydrochloride (1.82 g, 21.7 mmol) in ethanol (250 mL) are stirred at 60° C. for 24 hours. The mixture is cooled to ambient temperature and concentrated. The mixture is diluted with water and extracted with DCM followed by 3:1 chloroform:isopropyl alcohol. The organic layers are combined, dried over sodium sulfate, filtered, and concentrated. The crude product is purified over silica gel using a gradient of hexane:ethyl acetate (1:0 to 0:1, over 30 min) The product is chirally separated by SFC (Column: Chiralpak AS-H 2.1×15 cm; 5μ; eluent: 30% methyl alcohol with 0.2% isopropylamine) in CO2; flow: 70 mL/minute at 225 nm). The first eluting isomer is the title compound (99% ee). Analysis column: Chiralpak AS-H 4.6×150 mm; eluent: 30% methyl alcohol with 0.2% isopropylamine) in CO2; flow: 5.0 mL/min at UV 225 nm, RT=1.08 minutes). ES/MS (m/e): 361 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].F[C:27]1[CH:34]=[CH:33][C:30]([CH:31]=[O:32])=[CH:29][CH:28]=1.Cl>CN(C)C(=O)C.O>[CH:31]([C:30]1[CH:33]=[CH:34][C:27]([O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8](=[CH:12][C:13]3[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=3)[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=2)=[CH:28][CH:29]=1)=[O:32]
Reactant: O=Cc1ccc(F)cc1
Reactant: Cc1ccc(C=C(C(=O)O)c2ccc(O)cc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1ccc(C=C(C(=O)O)c2ccc(Oc3ccc(C=O)cc3)cc2)cc1
Temperature: 190 °C
Reaction time: 16 h
Yield: 79 %

Procedure:
To a solution of 38 (7.27 g, 28.6 mmol) and potassium carbonate (8.68 g, 62.9 mmol) in 200 mL N,N-dimethylacetamide was added 4-fluorobenzaldehyde (3.9 mL, 36.4 mmol). The reaction mixture was heated to 190° C. for 1.5 h under argon then cooled to room temperature. The addition of 5% HCl in water to pH 1 resulted in the product separating out as oil. Approximately 50 mL ethyl acetate was added to the mixture which is allowed to stir 16 h. The solid was collected and recrystallized out of toluene, rinsed with hexane and dried under vacuum to yield a white powder (8.1 g, 79.0%). 1H NMR (400 MHz, DMSO-d6) δ 12.71 (s, 1H), 9.94 (s, 1H), 7.97 (d, J=8.8 Hz, 2H), 7.76 (s, 1H), 7.25 (d, J=8.4 Hz, 2H), 7.18 (d, J=6.8 Hz, 2H), 7.16 (d, J=6.4 Hz, 2H), 7.07 (d, J=8.0 Hz, 2H), 6.98 (d, J=8.4 Hz, 2H), 2.25 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([O:13][Si](C(C)(C)C)(C)C)=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].[F-].[NH4+]>CO>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(O[Si](C)(C)C(C)(C)C)ccc1OC
Agent: [F-]
Agent: [NH4+]
Solvent: CO
Product: COC(=O)c1cc(O)ccc1OC
Reaction time: 1 h

Procedure:
Combine methyl 2-methoxy-5-(t-butyldimethylsilyloxy)benzoate (11.1 g. 37.4 mmol) and ammonium fluoride (6.94 g, 0.187 mmol) in methanol (150 mL). Heat to reflux. After 1 hour, evaporate in vacuo to give a residue. Partition the residue between ethyl acetate and water, separate the layers, extract the organic layer with water and then brine. Dry the organic layer over MgSO4, filter, and evaporate in uacuo to give methyl 2-methoxy-5-hydroxybenzoate: mp; 110-112° C. Rf=0.27 (silica gel, 5% ethyl acetate/hexane).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([C:23]([OH:25])=O)=[CH:21][N:22]=2)[CH:19]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[F:59][C:60]1[CH:66]=[CH:65][C:63]([NH2:64])=[CH:62][CH:61]=1>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([C:23]([NH:64][C:63]3[CH:65]=[CH:66][C:60]([F:59])=[CH:61][CH:62]=3)=[O:25])=[CH:21][N:22]=2)[CH:19]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=C(O)c1cnc2ccc(N3CCCC3c3cc(F)ccc3F)cn12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(F)cc1)c1cnc2ccc(N3CCCC3c3cc(F)ccc3F)cn12
Reaction time: 0.17 h
Yield: 9.4 %

Procedure:
To a stirred solution of 6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-a]pyridine-3-carboxylic acid (Int-15) (0.15 g, 0.44 mmol) in dry DMF (1.5 ml) was added HATU (0.215 g, 0.57 mmol), DIPEA (0.084 g, 0.65 mmol) under N2 atm at RT and stirred for 10 min, then added 4-fluoroaniline (0.053 g, 0.48 mmol) and stirred for 16 h at RT. After completion of reaction, quenched with ice water and solid was filter. Solid thus obtained was dried under high vacuum to afford 6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(4-fluorophenyl)imidazo[1,2-a]pyridine-3-carboxamide (0.018 g, 9.7% Yield) MS (ESI): m/z 437.1 (M+H); 1H NMR (300 MHz, CDCl3) δ 10.07 (1H, s), 8.72-8.71 (1H, d J=3 Hz), 8.41 (1H, s), 7.74-7.71 (2H, m), 7.59-7.57 (1H, d J=6 Hz), 7.35-7.28 (1H, m), 7.23-7.12 (3H, m), 7.00-6.94 (2H, m), 5.02-5.00 (1H, d), 3.80-3.77 (1H, t), 2.05-1.89 (3H, m).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11](Cl)=[O:12].Cl.[CH:15]12[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][C:17]([NH2:26])([CH2:18][CH2:19]3)[CH2:16]1)[CH2:23]2.N1C=CC=CC=1>O>[CH:15]12[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][C:17]([NH:26][C:11]([C:2]4[CH:3]=[N:4][C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[N:1]=4)=[O:12])([CH2:18][CH2:19]3)[CH2:16]1)[CH2:23]2
Reactant: O=C(Cl)c1cnc2ccccc2n1
Reactant: NC12CCC3CC(CC(C3)C1)C2
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: O=C(NC12CCC3CC(CC(C3)C1)C2)c1cnc2ccccc2n1
Yield: 57 %

Procedure:
Prepared from 2-quinoxaloyl chloride (135 mg, 0.70 mmol), tricyclo[4.3.1.1(3,8)]undec-3-ylamine hydrochloride (100 mg, 0.60 mmol), pyridine (5 mL), and water (50 mL) yielding 110 mg (57%) of (168):