Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([NH2:7])=[O:6])[CH2:3][CH2:2]1.Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].C(=O)([O-])[O-].[K+].[K+]>>[CH2:25]([N:1]1[CH2:9][CH2:8][CH:4]([C:5]([NH2:7])=[O:6])[CH2:3][CH2:2]1)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH3:11]
Reactant: CCCCCCCCCCCCCCCBr
Reactant: NC(=O)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCCCCCCCCCCCCN1CCC(C(N)=O)CC1
Yield: 85.2 %

Procedure:
Prepared from isonipecotamide (2.0 g, 15.6 mmol), 1-bromopentadecane (4.5 g, 15.6 mmol) and potassium carbonate (2.16 g, 15.6 mmol) according to procedure used for Example 8 (Step A) to give 4.5 g of the title compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=[O:9])[CH:3]=1.OS(O)(=O)=O.[CH3:16]O>>[OH:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([O:10][CH3:16])=[O:9])[CH:3]=1
Reactant: CO
Reactant: O=C(O)c1cc(O)ccn1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(O)ccn1

Procedure:
A mixture of commercially available 4-hydroxypicolinic acid (3.000 g; 21.56 mmol) and concentrated H2SO4 (0.6 ml) in anh. MeOH (40 ml) was refluxed, under nitrogen, for 22 h. MeOH was removed under reduced pressure, and the residue was basified by addition of a solution of 10% aq. NaHCO3. The mixture was then extracted with DCM (3×), and the mixed organic layers were dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure affording methyl 4-hydroxypicolinate as a beige solid. LC-MS (conditions A): tR=0.18 min.; [M+H]+: 154.11 g/mol.
Reaction SMILES: F[C:2]1[C:7](F)=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:15][NH:14][C:13](=[O:16])[C@H:12]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:11][CH2:10]1.[H][H]>C(O)(=O)C.[Pt]=O>[CH:3]1([C@H:9]2[CH2:15][NH:14][C:13](=[O:16])[C@H:12]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH2:11][CH2:10]2)[CH2:2][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)CNC1=O
Agent: O=[Pt]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](C2CCCCC2)CNC1=O
Reaction time: 72 h
Yield: 49.7 %

Procedure:
Platinum oxide (300 mg, 1.32 mmol) was added to a solution of tert-butyl (3R,6S)-6-(2,3-difluorophenyl)-2-oxoazepan-3-ylcarbamate (463 mg, 1.36 mmol) in glacial acetic acid (15 mL) and the mixture hydrogenated under 50 psi hydrogen in a Parr apparatus. After 3 d, the mixture was concentrated. Saturated aqueous sodium bicarbonate was added, and the mixture was extracted with dichloromethane (3×). The combined organic extracts were washed with brine, dried with magnesium sulfate, filtered, and concentrated. Purification by silica gel chromatography (hexanes→55% ethyl acetate/hexanes) gave the title compound (210 mg). MS 311.2 (M+1).
Reaction SMILES: Br[CH2:2]/[C:3](/[C:11]1([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:13][CH2:12]1)=[C:4](/[F:10])\[C:5]([O:7]CC)=O.C(=O)([O-])O.[Na+].[C:24]1([C@@H:30]([NH2:32])[CH3:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(O)C>[CH2:17]([O:16][C:14]([C:11]1([C:3]2[CH2:2][N:32]([C@H:30]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH3:31])[C:5](=[O:7])[C:4]=2[F:10])[CH2:12][CH2:13]1)=[O:15])[CH3:18]
Reactant: C[C@H](N)c1ccccc1
Reactant: CCOC(=O)/C(F)=C(\CBr)C1(C(=O)OCC)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1(C2=C(F)C(=O)N([C@@H](C)c3ccccc3)C2)CC1
Temperature: 25 °C
Yield: 81.4 %

Procedure:
To a solution of (E)-ethyl 4-bromo-3-(1-ethoxycarbonylcyclopropyl)-2-fluoro-2-butenoate (143 mmol) in ethanol (1000 ml) was added sodium hydrogencarbonate (30.08 g, 358 mmol). After adding dropwise 1-(S)-phenylethylamine (20.31 ml, 158 mmol) thereinto at room temperature, the mixture was heated under reflux for 3 hours. Then the liquid reaction mixture was cooled and filtered through celite. The filtrate was concentrated under reduced pressure and the residue was subjected to flash silica gel column chromatography (eluent:n-hexane:ethyl acetate=2:1) to obtain 36.95 g (81.2%) of the-title compound as an oily substance.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:11])([F:10])[C:5]1[CH:9]=[CH:8][NH:7][N:6]=1.[N:12]1[C:17]2[NH:18][C:19]3[CH:44]=[CH:43][CH:42]=[CH:41][C:20]=3[N:21]([C:23]([C:25]3[CH:30]=[CH:29][C:28](N4C=CC(C)=N4)=[CH:27][C:26]=3[C:37]([F:40])([F:39])[F:38])=[O:24])[CH2:22][C:16]=2[CH:15]=[CH:14][CH:13]=1>CCCCCC>[N:12]1[C:17]2[NH:18][C:19]3[CH:44]=[CH:43][CH:42]=[CH:41][C:20]=3[N:21]([C:23]([C:25]3[CH:30]=[CH:29][C:28]([N:7]4[CH:8]=[CH:9][C:5]([C:4]([F:11])([F:10])[F:3])=[N:6]4)=[CH:27][C:26]=3[C:37]([F:39])([F:40])[F:38])=[O:24])[CH2:22][C:16]=2[CH:15]=[CH:14][CH:13]=1
Reactant: FC(F)(F)c1cc[nH]n1
Reactant: Cc1ccn(-c2ccc(C(=O)N3Cc4cccnc4Nc4ccccc43)c(C(F)(F)F)c2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Product: O=C(c1ccc(-n2ccc(C(F)(F)F)n2)cc1C(F)(F)F)N1Cc2cccnc2Nc2ccccc21
Yield: 58.4 %

Procedure:
Sodium hydride (60% suspension in oil, 0.17 g, 4.25 mmol) was washed with hexane, dried under nitrogen and resuspended in dry dimethylformamide (10 mL). 3-trifluoromethyl pyrazole (0.34 g, 2.5 mmol ) was added in one portion. After the gas evolution subsided stirring was continued at room temperature. The (5,11-dihydro-pyrido [2,3-b][1,5]benzodiazepin-6-yl)- (4-fluoro-2-trifluoromethyl-phenyl)methanone of Example 4, Step B (0.75 g, 1.94 mmol) was added in one portion and the mixture was placed in an oil bath (preheated at 130° C.) overnight. After cooling, the mixture was partitioned between water and ethyl acetate. The organic extracts were dried over sodium sulfate, and evaporated to dryness in vacuo. The residue was crystallized from ethanol to yield the title compound (0.57 g, 57.3%) as an off-white solid, m.p. 127-129° C.
Reaction SMILES: Cl.[CH3:2][N:3](C)[OH:4].[CH2:6](N(CC)CC)C.Cl.[Cl:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([C:21](Cl)=[O:22])[CH:16]=1>C1COCC1.C(#N)C>[Cl:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([C:21]([N:3]([O:4][CH3:6])[CH3:2])=[O:22])[CH:16]=1
Reactant: CN(C)O
Reactant: O=C(Cl)c1cc(Cl)ccn1
Reactant: CCN(CC)CC
Agent: Cl
Solvent: C1CCOC1
Solvent: CC#N
Product: CON(C)C(=O)c1cc(Cl)ccn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 97.9 %

Procedure:
To a mixture of dimethylhydroxylamine HCl (510 mg, 5.18 mmol) and triethylamine (2.16 mL, 15.5 mmol) in anhydrous THF (9.41 mL) and acetonitrile (2.35 mL) was added 4-chloropyridine-2-carbonyl chloride hydrochloride (1.00 g, 4.71 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 2 h then at RT for 16 h. The solvent was removed under reduced pressure and partitioned between EtOAc and water. The organic layer was washed with H2O and brine, dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by MPLC (biotage) eluted with 30% EtOAc/Hex to afford 925 mg (98%) of 4-chloro-N-methoxy-N-methylpyridine-2-carboxamide as an orange oil: TLC (50% EtOAc/Hex), Rf=0.31.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]1([C:14]2[CH:18]=[C:17]([CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([CH2:26][NH:27]C(=O)OC(C)(C)C)[CH2:22][CH2:21]3)[O:16][N:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>ClCCl>[C:8]1([C:14]2[CH:18]=[C:17]([CH2:19][N:20]3[CH2:21][CH2:22][CH:23]([CH2:26][NH2:27])[CH2:24][CH2:25]3)[O:16][N:15]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)NCC1CCN(Cc2cc(-c3ccccc3)no2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCC1CCN(Cc2cc(-c3ccccc3)no2)CC1
Reaction time: 8 h
Yield: 83 %

Procedure:
Trifluoroacetic acid (2.1 mL) was added to a room temperature solution of the compound prepared in Example 8 (0.99 g) in dichloromethane (10 mL). The reaction was stirred overnight and then concentrated. The crude residue was azeotroped with a solution of hexane and toluene, diluted with ethyl acetate and washed with an aqueous 10% sodium carbonate solution. The organics were dried over anhydrous magnesium sulfate and concentrated to obtain the title compound (0.60 g) having the following physical data.
Reaction SMILES: C[O:2][C:3](=[O:38])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:28][N:29]5[CH2:34][CH2:33][N:32]6[CH:35]=[CH:36][N:37]=[C:31]6[CH2:30]5)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.COC(=O)C[C@H]1C2C=CC(O[C@H]3C4C(=C(CBr)C(C(F)(F)F)=CC=4)CC3)=CC=2OC1.N1C=CN2CCNCC=12>>[N:37]1[CH:36]=[CH:35][N:32]2[CH2:33][CH2:34][N:29]([CH2:28][C:19]3[C:20]([C:24]([F:25])([F:27])[F:26])=[CH:21][CH:22]=[C:23]4[C:18]=3[CH2:17][CH2:16][C@H:15]4[O:14][C:12]3[CH:11]=[CH:10][C:9]4[C@H:5]([CH2:4][C:3]([OH:38])=[O:2])[CH2:6][O:7][C:8]=4[CH:13]=3)[CH2:30][C:31]=12
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4CN3CCn4ccnc4C3)ccc21
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4CBr)ccc21
Agent: c1cn2c(n1)CNCC2
Product: O=C(O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4CN3CCn4ccnc4C3)ccc21

Procedure:
The methyl ester of the title compound, {(S)-6-[(R)-4-(5,6-dihydro-8H-imidazo[1,2-a]pyrazin-7-ylmethyl)-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester, is prepared from {(S)-6-[(R)-4-bromomethyl-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 5,6,7,8-tetrahydro-imidazo[1,2-a]pyrazine following a procedure analogous to that described for Intermediate 42. The crude product is directly submitted to the saponification conditions described for Example 1 to give the title compound upon chromatography on reversed phase (HPLC; acetonitrile/water). LC (method 6): tR=0.76 min; Mass spectrum (ESI+): m/z=514 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[C:6]([C:12](=O)[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:3]=1[C:4]#[N:5].C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[Br:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)[C:3]=1[C:4]#[N:5]
Reactant: COc1ccc(C(=O)c2ccc(F)cc2)c(C#N)c1Br
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Cc2ccc(F)cc2)c(C#N)c1Br
Temperature: 25 °C
Reaction time: 20 h
Yield: 94 %

Procedure:
To a solution of I-123 (0.15 g, 0.45 mmol) in trifluoroacetic acid (1.0 mL) was added triethylsilane (0.55 g, 4.5 mmol). The reaction mixture was stirred at room temperature for 20 h, then concentrated under vacuum to afford I-124 (0.14 g, 94% yield) as white solid.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[CH3:27][C:28]([CH3:34])([CH3:33])[CH2:29][C:30](O)=[O:31]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:30](=[O:31])[CH2:29][C:28]([CH3:34])([CH3:33])[CH3:27])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: CC(C)(C)CC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Agent: Cl
Product: CC(C)(C)CC(=O)N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1

Procedure:
The title compound, off-white solid (83 mg, 78%), MS (ISP) m/z=425.3 [(M+H)+], mp 174° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 3,3-dimethyl-butyric acid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].N1C=CC=CC=1.[CH2:15]([C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1)[CH3:16]>C1C=CC=CC=1>[CH2:15]([C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[OH:8])=[O:22])=[CH:19][CH:18]=1)[CH3:16]
Reactant: Nc1ccccc1O
Reactant: CCc1ccc(C(=O)Cl)cc1
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCc1ccc(C(=O)Nc2ccccc2O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 8.2 gm. of o-aminophenol in 70 cc. of dry pyridine is added a solution of p-ethylbenzoyl chloride (prepared from 10 gm. of p-ethylbenzoic acid and thionyl chloride) in 20 cc. of benzene. An exothermic reaction occurs and the reaction mixture is stirred overnight at ambient temperature. The mixture is concentrated in vacuo and taken up between a 1:1 mixture of benzene and ether and 2.5 N hydrochloric acid. The organic layer is washed with saturated sodium bicarboxate, water, then dried and concentrated. Recrystallization from benzene-hexane gives 4-ethyl-2'-hydroxybenzanilide, m.p. 103°-105° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:21](O)=[O:22])[NH:3]1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]([NH2:38])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:27][CH:26]=1>>[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([CH:31]([NH:38][C:21]([C@H:11]2[CH2:10][CH2:9][C@H:8]3[C@H:7]4[C@H:16]([CH2:15][CH2:14][C@:12]23[CH3:13])[C@:17]2([CH3:20])[C:4]([NH:3][C:2](=[O:1])[CH2:19][CH2:18]2)=[CH:5][CH2:6]4)=[O:22])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:29][CH:30]=1
Reactant: NC(c1ccccc1)c1ccc(Cl)cc1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4NC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)O
Product: C[C@]12CC[C@H]3[C@@H](CC=C4NC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Yield: 78 %

Procedure:
The title compound was prepared in a yield of 78% in a similar manner to that described in Example 2 by reacting 3-oxo-4-azaandrost-5-ene-17β-carboxylic acid and α-(4-chlorophenyl)benzylamine.
Reaction SMILES: CO[CH:3](OC)[CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[C:9]([F:16])[CH:8]=1.[S-:19][C:20]#[N:21].[K+].Cl>C(O)C.O>[F:16][C:9]1[CH:8]=[C:7]([CH:12]=[C:11]([F:13])[C:10]=1[O:14][CH3:15])[CH2:6][N:5]1[CH:4]=[CH:3][N:21]=[C:20]1[SH:19]
Reactant: N#C[S-]
Reactant: COc1c(F)cc(CNCC(OC)OC)cc1F
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: COc1c(F)cc(Cn2ccnc2S)cc1F
Yield: 45.8 %

Procedure:
To a solution of N-(3,5-difluoro-4-methoxybenzyl)-aminoacetaldehyde dimethyl acetal (4.94 g, 0.0189 mole) in ethyl alcohol (30 ml) was added potassium thiocyanate (2.10 g, 0.0216 mole) in water (48 ml) followed by 12 N hydrochloric acid (4 ml), and the reaction mixture was heated under reflux for 3.5 hours. The solvent was partially removed under reduced pressure, the mixture was cooled in ice, and the product was filtered. The product was recrystallized from ethyl alcohol - hexane to give 1-(3,5-difluoro-4-methoxybenzyl)-2-mercaptoimidazole as a solid melting at 160-161° (2.22 g, 46%).
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:30]=[CH:29][C:21]([CH:22]=[CH:23][C:24]([O:26]CC)=[O:25])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[OH-].[Na+].O.C(O)C>C(O)(=O)C>[CH2:1]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([CH:22]=[CH:23][C:24]([OH:26])=[O:25])=[CH:29][CH:30]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C=CC(=O)OCC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CCCCCCCCCCCCCCCCNc1ccc(C=CC(=O)O)cc1

Procedure:
A mixture of ethyl p-aminocinnamate, one equivalent of 1-bromohexadecene, one equivalent of anhydrous potassium carbonate in hexamethylphosphoramide is heated for 20 hours at 60° C. The mixture is then cooled, diluted with water and extracted with ether. The combined ether extracts are dried, filtered and evaporated to provide ethyl 4-hexadecylaminocinnamate. The ester is hydrolyzed with sodium hydroxide in a 1:1 water:ethanol solution at steam bath temperature for 10 hours. The hot solution is then acidified with acetic acid, cooled, filtered and the precipitate is washed with water. Recrystallization from chloroform yields 4-hexadecylaminocinnamic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[OH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:11][C:10]=1[C:25](OCC)=[O:26]>C1(C)C=CC=CC=1>[OH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:11][C:10]=1[C:25]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)=[O:26]
Reactant: CCOC(=O)C1=C(O)c2ccccc2N(c2ccccc2)C1
Reactant: Nc1ccccn1
Solvent: Cc1ccccc1
Product: O=C(Nc1ccccn1)C1=C(O)c2ccccc2N(c2ccccc2)C1
Yield: 75.8 %

Procedure:
A solution of 2.8 g of 2-aminopyridine and 4.2 g of 1,2-dihydro-4-hydroxy-1-phenyl-3-quinolinecarboxylic acid, ethyl ester in 190 ml of toluene was refluxed for 16 hours in a soxhlet apparatus containing 10 g of 4 Å molecular sieves. Evaporation of the volatiles afforded a residue which was purified by means of high pressure liquid chromatography (silica gel: 1:1 ethyl acetate-hexane as the eluent) to yield 3.7 g (73%) of 1,2-dihydro-4-hydroxy-1-phenyl-N-(2-pyridyl)-3-quinolinecarboxamide, m.p. 145° C. (dec).
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12]([C:17]4[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][C:18]=4[O:27][CH3:28])=[N:11][C:10]=3[N:9]([CH2:29][CH3:30])[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:31][N:32]1[CH2:38][CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[CH:1]1([C:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12]([C:17]4[CH:22]=[CH:21][C:20]([S:23]([N:35]5[CH2:36][CH2:37][CH2:38][N:32]([CH3:31])[CH2:33][CH2:34]5)(=[O:25])=[O:24])=[CH:19][C:18]=4[O:27][CH3:28])=[N:11][C:10]=3[N:9]([CH2:29][CH3:30])[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCn1nc(C2CCCCC2)c2c(=O)[nH]c(-c3ccc(S(=O)(=O)Cl)cc3OC)nc21
Reactant: CN1CCCNCC1
Product: CCn1nc(C2CCCCC2)c2c(=O)[nH]c(-c3ccc(S(=O)(=O)N4CCCN(C)CC4)cc3OC)nc21
Yield: 74 %

Procedure:
The same reaction procedure as in Example 49 was performed, except that the compound obtained in Example 206 was used in place of the compound obtained in Example 48, and N-methyl-1,4-diazacycloheptane was used in place of N-methylpiperazine. In this manner, 129 mg (74%) of the captioned compound was obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][OH:8].C(N(CC)CC)C.[S:16](Cl)(Cl)(=[O:18])=[O:17]>ClCCl>[S:16]1(=[O:18])(=[O:17])[N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]2[CH2:7][O:8]1
Reactant: O=S(=O)(Cl)Cl
Reactant: OCC1CCCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S1(=O)OCC2CCCCN21
Reaction time: 18 h
Yield: 38.6 %

Procedure:
To a −78° C. hazy solution under a nitrogen atmosphere of racemic 2-piperidinemethanol (0.576 g, 5.00 mmol) and triethylamine (1.42 mL, 10.0 mmol) in anhydrous dichloromethane (30 mL) was added a solution of sulfuryl chloride (0.41 mL, 5.06 mmol) in anhydrous dichloromethane (30 mL) and the reaction was stirred for around 18 h from −78° C. to ambient temperature. The clear, yellow solution was washed with 1.0N HCl (2×25 mL) and brine (25 mL), dried over Na2SO4, concentrated in vacuo to a dark yellow oil, and purified by flash column chromatography (silica gel, ether) to afford the title product as a clear yellow oil (0.342 g, 39%). The proton NMR was identical to the desired product in procedure A, step 2.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[N:16][C:17]#[N:18])OC2C=CC=CC=2)[CH:2]=1.[Cl:19][C:20]1[CH:21]=[C:22]([C:26]2([NH2:30])[CH2:29][CH2:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1.CN1CCOCC1>O1CCOCC1>[Cl:19][C:20]1[CH:21]=[C:22]([C:26]2([NH:30][C:8](=[N:16][C:17]#[N:18])[NH:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH2:29][CH2:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1
Reactant: NC1(c2cccc(Cl)c2)CCC1
Reactant: N#CN=C(Nc1cccnc1)Oc1ccccc1
Solvent: C1COCCO1
Solvent: CN1CCOCC1
Product: N#CN=C(Nc1cccnc1)NC1(c2cccc(Cl)c2)CCC1
Reaction time: 1 h
Yield: 46 %

Procedure:
A stirred mixture of N-(3-pyridyl)-N'-cyano-O-phenylisourea (see, Example 5 for procedure) (2.62 g, 0.0110 mol), the product from Step 4 (2.00 g, 0.0110 mol), N-methylmorpholine (3.00 ml, 0.275 mol) and 1,4-dioxane (40 ml) was refluxed, under nitrogen for 4 hours and kept ambient temperature for 1 hour. The product which had precipitated from the mixture was collected by filtration, washed with tert-butyl methyl ether and crystallized from CH3CN to give 1.65 g (46%) of the titled product, m.p. 201°-202° C.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:3].C=O.F[C:14](F)(F)C([O-])=O.C[NH2+]C1C=CC=CC=1.C(OCC)C>C1COCC1>[OH:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH:1]=[CH2:14])=[CH:5][CH:6]=1
Reactant: O=C([O-])C(F)(F)F
Reactant: CC(=O)c1ccc(O)cc1
Agent: C=O
Agent: C[NH2+]c1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CC(=O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 40.8 %

Procedure:
The mixture of 4-hydroxyacetophenone (2.719 g, 20 mmol), paraformaldehyde (2.702 g, 90 mmol) and N-methylanilinium trifluoroacetate (6.603 g, 30 mmol) in 20 mL of anhydrous THF was refluxed for 3.5 h and cooled to room temperature. To the red solution was added 60 mL of diethyl ether and the mixture was vigorously stirred for 15 min. The resultant yellow solution was decanted and residual brown-red sticky mud was repeatedly extracted with 50 mL portions of diethyl ether until it turned into yellow solid. The combined organic extracts were washed with half saturated sodium bicarbonate solution (2×) and the aqueous wash was extracted with ether (2×). The combined organic layers were dried over anhydrous sodium sulfate prior to concentration. Flash chromatography on silica gel with 5:1 hexanes/ethyl acetate as the eluent afforded product 27 (1.21 g, 41%) as a pale yellow solid. 1H NMR (400 MHz, CDCl3): δ 5.89 (dd, J=1.8, 10.6 Hz, 1H), 5.91 (s, 1H), 6.43 (dd, J=1.6, 16.9 Hz, 1H), 6.92 (d, J=8.4 Hz, 2H), 7.17 (dd, J=10.6, 17.2 Hz, 1H), 7.93 (d, J=8.4 Hz, 2H).
Reaction SMILES: Br[CH2:2][C:3]#[N:4].C(N(C(C)C)C(C)C)C.[CH3:14][S:15][C:16](=[O:30])[CH2:17][CH2:18][C@H:19]([NH:23][C:24](=[O:29])[CH2:25][CH2:26][CH:27]=[CH2:28])[C:20]([OH:22])=[O:21].[Cl-].[NH4+]>CS(C)=O>[CH3:14][S:15][C:16](=[O:30])[CH2:17][CH2:18][C@H:19]([NH:23][C:24](=[O:29])[CH2:25][CH2:26][CH:27]=[CH2:28])[C:20]([O:22][CH2:2][C:3]#[N:4])=[O:21]
Reactant: N#CCBr
Reactant: C=CCCC(=O)N[C@@H](CCC(=O)SC)C(=O)O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: C=CCCC(=O)N[C@@H](CCC(=O)SC)C(=O)OCC#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
2-Bromoacetonitrile (3.60 ml, 52.0 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.297 ml, 2.86 mmol) were added to a solution of (S)-5-(methylthio)-5-oxo-2-(pent-4-enamido)pentanoic acid (Compound 1f-IIA) (673 mg, 2.60 mmol) in DMSO (5.5 ml), and the mixture was stirred at room temperature for 30 minutes. A saturated aqueous ammonium chloride solution (3 ml) was added to the reaction mixture, after which the mixture was extracted with ethyl acetate and the organic layer was washed with water. The organic extract was then dried over magnesium sulfate. Following concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0→30/70) to afford (S)-cyanomethyl 5-(methylthio)-5-oxo-2-(pent-4-enamido)pentanoate (Compound 1g-IIA) (772 mg, 100%).