Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:16])[C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([C:12]#[N:13])[C:8]([C:14]#[N:15])=[CH:7][CH:6]=2.Cl[CH2:18][C:19]1[N:23]=[C:22]([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[CH:25]=2)[O:21][N:20]=1>>[F:16][CH:2]([F:1])[C:3]1[N:4]([CH2:18][C:19]2[N:23]=[C:22]([C:24]3[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[CH:25]=3)[O:21][N:20]=2)[C:5]2[C:10]([CH:11]=1)=[C:9]([C:12]#[N:13])[C:8]([C:14]#[N:15])=[CH:7][CH:6]=2
Reactant: Fc1cc(F)cc(-c2nc(CCl)no2)c1
Reactant: N#Cc1ccc2[nH]c(C(F)F)cc2c1C#N
Product: N#Cc1ccc2c(cc(C(F)F)n2Cc2noc(-c3cc(F)cc(F)c3)n2)c1C#N

Procedure:
Synthesized as described in Example 23 from 2-(difluoromethyl)-1H-indole-4,5-dicarbonitrile and 3-(chloromethyl)-5-(3,5-difluorophenyl)-1,2,4-oxadiazole: MS (ES) m/z 412 (M+1).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[C:7]([N+:14]([O-])=O)[CH:6]=1)[CH:2]=[CH2:3].[O:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][C:26]([NH:29][C:30]([C:32]3[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=3)=[O:31])=[CH:25][CH:24]=2)[CH2:19][CH2:18]1>>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]2[N:11]=[C:36]([C:35]3[CH:34]=[CH:33][C:32]([C:30]([NH:29][C:26]4[CH:25]=[CH:24][C:23]([N:20]5[CH2:19][CH2:18][O:17][CH2:22][CH2:21]5)=[CH:28][CH:27]=4)=[O:31])=[CH:39][CH:38]=3)[NH:14][C:7]=2[CH:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Reactant: O=Cc1ccc(C(=O)Nc2ccc(N3CCOCC3)cc2)cc1
Product: C=CCOc1ccc2nc(-c3ccc(C(=O)Nc4ccc(N5CCOCC5)cc4)cc3)[nH]c2c1

Procedure:
Compound 632 was prepared according to the procedure similar to that described in Scheme III from 1-allyloxy-3,4-dinitrobenzene and 4-(4-(4-morpholinophenyl)aminocarbonylbenzaldehyde. [M+H]+ calcd for C27H26N4O3: 455.21; found: 455.00.
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][CH2:2]1.Cl.C(N(CC)CC)C.Cl[S:14]([C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[NH:26][CH3:27])[C:20]([OH:22])=[O:21])(=[O:16])=[O:15]>C(OCC)(=O)C>[N:1]1([S:14]([C:17]2[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=2[NH:26][CH3:27])[C:20]([OH:22])=[O:21])(=[O:16])=[O:15])[CH2:4][CH2:3][CH2:2]1
Reactant: CNc1ccc(C(=O)O)cc1S(=O)(=O)Cl
Reactant: C1CNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CNc1ccc(C(=O)O)cc1S(=O)(=O)N1CCC1
Reaction time: 4 h
Yield: 60 %

Procedure:
Azetidine Ae (HCl salt) (0.2 g, 2 mmol) was dissolved in ethyl acetate (8 mL). Triethylamine (0.3 mL, 2 mmol) and 3-(chlorosulfonyl)-4-(methylamino)benzoic acid (1.2, 0.1 g, 0.5 mmol) were added. The reaction was left to stir for 4 hours, then extracted with 0.5 M HCl, washed with water and brine, and dried over magnesium sulfate. The ethyl acetate was evaporated and 3-(azetidin-1-ylsulfonyl)-4-(methylamino)-benzoic acid (1.3.Ae) was obtained (0.08 g, 60% yield). MS analysis (m−1)=269.
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:8][CH:7]=1.O.[CH3:20]O>>[CH3:20][O:17][C:16](=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12][C:9]1[CH:8]=[CH:7][C:6]([F:5])=[CH:11][CH:10]=1
Reactant: CO
Reactant: O=C(O)CCCCc1ccc(F)cc1
Solvent: O=S(Cl)Cl
Solvent: O
Product: COC(=O)CCCCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75 %

Procedure:
Thionylchloride (288 μl, 3.98 mmol) was added dropwise to a solution of 5-(4-fluoro-phenyl)-pentanoic acid (520 mg, 2.65 mmol) in methanol (11 ml) at −15° C. The reaction mixture was then stirred at room temperature for 1.5 h. Water was added and the mixture was extracted 3 times with diethylether. The combined extracts were washed with water and brine, dried (Na2SO4) and evaporated. The remaining residue was purified by column chromatography (silica gel, ethyl acetate/heptane 5:95 to 12:88) to obtain 5-(4-fluoro-phenyl)-pentanoic acid methyl ester (420 mg, 2 mmol; 75%) as colorless liquid. MS: m/e 211.0 [M+H+].
Reaction SMILES: [CH3:1][C:2]1[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([N:10]1[C:19]2[C:14](=[C:15](B3OC(C)(C)C(C)(C)O3)[CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1)=[O:9].Br[C:35]1[CH:40]=[CH:39][N:38]=[C:37]([C:41]([O:43][CH3:44])=[O:42])[CH:36]=1.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][C:2]1[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([N:10]1[C:19]2[C:14](=[C:15]([C:35]3[CH:40]=[CH:39][N:38]=[C:37]([C:41]([O:43][CH3:44])=[O:42])[CH:36]=3)[CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1)=[O:9]
Reactant: Cc1cccc(OCCCC(=O)N2CCCc3c(B4OC(C)(C)C(C)(C)O4)cccc32)c1C
Reactant: COC(=O)c1cc(Br)ccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2cccc3c2CCCN3C(=O)CCCOc2cccc(C)c2C)ccn1
Temperature: 90 °C
Reaction time: 16 h
Yield: 85.8 %

Procedure:
To a degassed solution of 4-(2,3-dimethylphenoxy)-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-1(2H)-yl)butan-1-one (0.020 g, 0.045 mmol), methyl 4-bromopicolinate (0.019 g, 0.089 mmol) and potassium carbonate (0.018 g, 0.134 mmol) in dioxane (0.50 mL)/water (0.20 mL) was added tetrakis(triphenylphosphine)palladium (2.57 mg, 2.225 μmol). Upon completion of addition, the vial was purged with argon, sealed, and stirred at 90° C. for 16 h. After cooling to room temperature, the mixture was extracted with EtOAc. The combined organic layer was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography (0-100% ethyl acetate:hexanes) to afford the title compound (17.7 mg, 87% yield) as a clear colorless oil. LCMS, [M+H]+=459.1.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[N:4]=1.[CH3:10][C:11]([C:14]1[CH:15]=[C:16]([S:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]2[S:31][CH2:32][C:33](N(C)CCC2C=CC=CN=2)=[O:34])[CH:17]=[C:18]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:19]=1)([CH3:13])[CH3:12]>>[CH3:23][C:20]([C:18]1[CH:17]=[C:16]([S:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]2[S:31][CH2:32][C:33]([NH:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[N:4]=2)=[O:34])[CH:15]=[C:14]([C:11]([CH3:10])([CH3:12])[CH3:13])[CH:19]=1)([CH3:21])[CH3:22]
Reactant: Cc1cccc(CN)n1
Reactant: CN(CCc1ccccn1)C(=O)CS[C@@H]1CCCC[C@H]1Sc1cc(C(C)(C)C)cc(C(C)(C)C)c1
Product: Cc1cccc(CNC(=O)CS[C@@H]2CCCC[C@H]2Sc2cc(C(C)(C)C)cc(C(C)(C)C)c2)n1

Procedure:
Substituting 2-aminomethyl-6-methylpyridine for the 2-(2-methylaminoethyl)pyridine of Example 16, and following the procedure described therein, gives trans-2-[[2-[[3,5-bis(1,1-dimethylethyl)phenyl]thio]cyclohexyl]thio]-N-[(6-methylpyridine-2-yl)methyl]acetamide. ##STR99##
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[N:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][C:25]=1[C:34](O)=[O:35]>>[CH3:23][C:13]1[S:14][C:15]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[C:11]([C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:34]([C:25]2[CH:26]=[CH:27][C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:24]=2)=[O:35])=[O:10])[N:12]=1
Reactant: O=C(O)c1ccc2ccccc2n1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2ccc3ccccc3n2)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with Quinoline-2-carboxylic acid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]([CH3:8])[C:5]([CH2:17][CH2:18][CH3:19])([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)[CH2:4][CH2:3]1>C(O)(=O)C>[CH3:1][N:2]1[CH2:7][CH:6]([CH3:8])[C:5]([CH2:17][CH2:18][CH3:19])([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)[CH:4]=[CH:3]1
Reactant: CCCC1(c2cccc(OC)c2)CCN(C)CC1C
Solvent: CC(=O)O
Product: CCCC1(c2cccc(OC)c2)C=CN(C)CC1C

Procedure:
Following the procedure set forth in Example 1, 43 g. of 1,5-dimethyl-4-n-propyl-4-(3-methoxyphenyl)-piperidine was reacted with 276 g. of mercuric acetate in 717 ml. of five percent aqueous acetic acid to provide, after purification by distillation, 30.2 g. of 1,5-dimethyl-4-n-propyl-4-(3-methoxyphenyl)-1,4,5,6-tetrahydropyridine. B.P. 126°-138° C. at 0.15 torr.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH3:6].I[C:8]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=1[NH2:10]>C(N(CC)CC)C.[Cu](I)I>[C:1]([C:8]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=1[NH2:10])#[C:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: C#CCCCC
Reactant: Nc1ccccc1I
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: CCCCC#Cc1ccccc1N
Temperature: 25 °C
Reaction time: 15 h

Procedure:
32 mg of copper iodide and 140 mg of bistriphenyl phosphine palladium chloride and 2.3 ml of 1-hexyne were added to a solution of 4.4 g of 2-iodo aniline in 100 ml of triethylamine and the mixture was stirred for 15 hours at ambient temperature, then evaporated to dryness. The residue was taken up in ether and the insoluble part was filtered out, washed with ether and the ethereal fractions were evaporated to dryness. The residue was chromatographed on silica (eluant:hexane-ethyl acetate (9-1)) to obtain 3.27 of the desired product.
Reaction SMILES: [NH2:1][C:2]1[O:3][N:4]=[C:5]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]2[CH3:14].[CH2:15](I)[CH2:16][CH3:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:12][N:8]1[C:9](=[O:11])[C:10]2=[C:2]([NH:1][CH2:15][CH2:16][CH3:17])[O:3][N:4]=[C:5]2[N:6]([CH3:14])[C:7]1=[O:13]
Reactant: CCCI
Reactant: Cn1c(=O)c2c(N)onc2n(C)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCNc1onc2c1c(=O)n(C)c(=O)n2C
Temperature: 100 °C
Reaction time: 3 h
Yield: 30.4 %

Procedure:
A mixture of 0.588 g of 3-amino-5,7-dimethyl-isoxazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione, 15 ml of dimethylformamide, 2.5 g of propyl iodide and 1.0 g of potassium carbonate was stirred at 100° C. for 3 hours. From the reaction solution was removed the solvent under reduced pressure. To the residue was added water, which was subjected to extraction with chloroform. The chloroform layer was taken and dried over anhydrous sodium sulfate, from which was removed the solvent. The resultant residue was chromatographed on a column of silica gel (30 g), and the column was eluted with chloroform:acetone:formic acid (20:1:0.1). From the elute was recovered the desired compound, which was recrystallized from isopropyl ether-acetone to give 0.217 g of colorless prisms, melting point: 164°-166° C.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[NH:25]([C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30]([NH2:32])=[O:31])N>>[CH3:23][S:20]([C:16]1[CH:15]=[C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:25]([C:27]4[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=4)[C:30]([NH2:32])=[O:31])[N:2]=[CH:3][CH:4]=3)=[N:8]2)[CH:19]=[CH:18][CH:17]=1)(=[O:22])=[O:21]
Reactant: NNc1cccc(C(N)=O)c1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(C)(=O)=O)c2)ccc1=O
Product: CS(=O)(=O)c1cccc(-n2ccc(=O)c(-c3ccnn3-c3cccc(C(N)=O)c3)n2)c1

Procedure:
Reaction of 3-((E)-3-dimethylamino-acryloyl)-1-(3-methansulfonyl-phenyl)-1H-pyridazin-4-one (A-7) and 3-hydrazino-benzamide according to example 43 gave the desired product. MS: M=436.7 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[OH:14])/[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:22]1[CH2:26][CH2:25][NH:24][C:23]1=[O:27]>CS(C)=O.O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[O:14][CH:22]2[CH2:26][CH2:25][NH:24][C:23]2=[O:27])/[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1
Reactant: CCOC(=O)/C(=N\O)c1csc(N)n1
Reactant: O=C1NCCC1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)/C(=N\OC1CCNC1=O)c1csc(N)n1
Reaction time: 0.33 h
Yield: 86 %

Procedure:
10.9 g of ethyl (Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetate are dissolved in 25 ml of dimethylsulfoxide, and a solution of 14 g of anhydrous potassium carbonate in 13 ml of water is added thereto at a temperature of 15° to 20° C. The mixture is stirred at the same temperature for 20 minutes. 10 g of 3-bromo-2-pyrrolidone are added to said mixture at room temperature, and the mixture is stirred at the same temperature for 1.5 hours. 120 ml of water are added to the reaction mixture, and the aqueous mixture is stirred with ice-cooling. Crystalline precipitates are collected by filtration, and the crystals are washed with water and then dried at 40° C. 13 g of ethyl (Z)-2-(2-aminothiazol-4-yl)-2-[(2-pyrrolidon-3yl)oxyimino]acetate are obtained. The physico-chemical properties of this product are identical sith those of the product obtained in Example 2-(3).
Reaction SMILES: [NH3:1].Cl[S:3]([C:6]1[CH:7]=[C:8]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4].ClCCl>C(#N)C>[NH2:1][S:3]([C:6]1[CH:7]=[C:8]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4]
Reactant: N
Reactant: COC(=O)Cc1cccc(S(=O)(=O)Cl)c1
Solvent: ClCCl
Solvent: CC#N
Product: COC(=O)Cc1cccc(S(N)(=O)=O)c1
Temperature: 22 °C
Reaction time: 2 h

Procedure:
0.880 Ammonia (0.027 ml) was added to a stirred solution of methyl [3-(chlorosulfonyl)phenyl]acetate (0.35 g) in a 1:1 mixture of dichloromethane and acetonitrile (1.75 ml), and the mixture was stirred at 22° C. for 2 h. The mixture was allowed to stand for a further 18 h, and the solvent was evaporated in vacuo. The residue was re-dissolved in dichloromethane and applied to a silica gel cartridge (10 g Varian Bond Elut, pre-conditioned with dichloromethane). The cartridge was eluted with dichloromethane, chloroform, ether, ethyl acetate, acetone, acetonitrile and methanol (1 column volume each), the fractions containing the product evaporated in vacuo, and the residue passed down a 5 g silica gel cartridge which was prepared and eluted in an identical manner. The product containing fractions were evaporated in vacuo to give a residue which was further purified using mass-directed preparative HPLC, to give the title compound as a colourless gum (0.018 g).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:23])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15](=[O:22])[N:16]([CH3:21])[CH:17]=[C:18]([Cl:20])[CH:19]=2)=[CH:10][CH:9]=1)[NH2:6].[Cl:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[C:26]=1[C:27](O)=[O:28].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:2][O:3][C:4](=[O:23])[C@H:5]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:15](=[O:22])[N:16]([CH3:21])[CH:17]=[C:18]([Cl:20])[CH:19]=2)=[CH:12][CH:13]=1)[NH:6][C:27]([C:26]1[C:30]([CH3:34])=[CH:31][CH:32]=[CH:33][C:25]=1[Cl:24])=[O:28]
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2cc(Cl)cn(C)c2=O)cc1
Reactant: Cc1cccc(Cl)c1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(-c2cc(Cl)cn(C)c2=O)cc1)NC(=O)c1c(C)cccc1Cl
Yield: 45.6 %

Procedure:
A solution of 4-(5-chloro-1-methyl-2-oxo-3-pyridinyl)-L-phenylalanine methyl ester hydrochloride (89.5 mg, 0.25 mmol), 2-chloro-6-methylbenzoic acid (47 mg, 0.28 mmol), DIEA (175 μL, 1.0 mmol) and HBTU (133 mg, 0.35 mmol) in DMF (3 mL) was stirred at room temperature for 4 hr. The mixture was concentrated, the residue was dissolved in ethyl acetate (15 mL), was washed with 0.5 N HCl (1×5 mL), sat. NaHCO3 (1×5 mL), brine (1×5 mL) and was dried (MgSO4). The residue obtained upon evaporation was chromatographed on 25 g of silica gel, eluting with 3:1 ethyl acetate:hexane to give N-[(2-chloro-6-methylphenyl)carbonyl]-4-(5-chloro-1-methyl-2-oxo-3-pyridinyl)-L-phenylalanine methyl ester (54 mg). LR(+)LSIMS: m/z 962 (2M+NH4), 945 (2M+H), 490 (M+NH4), 473 (M+H (2 Cl)).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:10]=1[SH:16].Br[CH2:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[C:21]#[N:22]>CN(C=O)C.O>[Br:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH3:7])=[C:10]([S:16][CH2:18][C:19]2[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=2[C:21]#[N:22])[CH:11]=1
Reactant: N#Cc1ccccc1CBr
Reactant: COc1ccc(Br)cc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Br)cc1SCc1ccccc1C#N
Temperature: 22 °C
Reaction time: 0.25 h
Yield: 64.9 %

Procedure:
As depicted in Scheme 6, 162 mg (1.18 mmol) of anhydrous K2CO3 was added to a solution of 104 mg (0.470 mmol) of 2-methoxy-5-bromo-thiophenol in 5 mL of DMF, stirred for 15 minutes at 22° C. and 103 mg (0.520 mmol) of 2-bromomethyl-benzonitrile was added, then the reaction was capped and heated to 40° C. for 12 hours. The mixture was subsequently diluted with 5 mL of water, extracted with ethyl acetate (2×10 mL), and the organic extracts washed with water (3×10 mL), brine (2×10 mL), and dried (Na2SO4). The solvent was evaporated and the product was purified on silica gel (eluting with 9:1 of hexane/ethyl acetate) to afford 102 mg of the product as a colorless oil.
Reaction SMILES: [CH3:1][C@:2]1([CH2:23][CH2:24][CH2:25][C:26]([F:29])([F:28])[F:27])[O:19][C:18](=[O:20])[C:17]2[N:21]=[C:14]([S:15][CH:16]=2)[S:13][CH2:12][CH2:11][N:10]2[C@H:6]([CH2:7][O:8][C:9]2=[O:22])[CH:5]=[CH:4][CH2:3]1.[O:30]1CCCC1>CO>[O:22]=[C:9]1[N:10]([CH2:11][CH2:12][S:13][C:14]2[S:15][CH:16]=[C:17]([C:18]([OH:19])=[O:20])[N:21]=2)[C@@H:6](/[CH:5]=[CH:4]/[CH2:3][C@@:2]([OH:30])([CH3:1])[CH2:23][CH2:24][CH2:25][C:26]([F:27])([F:29])[F:28])[CH2:7][O:8]1
Reactant: C[C@@]1(CCCC(F)(F)F)CC=C[C@H]2COC(=O)N2CCSc2nc(cs2)C(=O)O1
Reactant: C1CCOC1
Solvent: CO
Product: C[C@](O)(C/C=C/[C@H]1COC(=O)N1CCSc1nc(C(=O)O)cs1)CCCC(F)(F)F

Procedure:
By the same procedure as the reaction of Example 8 using the compound 64-1 (Less polar) instead of the compound 7 and using a mixture of tetrahydrofuran and methanol instead of methanol, the title compound having the following physical data was obtained.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][S:10][C:11]2[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[C:19]([SH:21])#N.N>ClC1C=CC=CC=1Cl>[C:1]1([CH2:7][CH2:8][CH2:9][S:10][C:11]2[CH:12]=[CH:13][C:14]([N:15]=[C:19]=[S:21])=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CS
Reactant: Nc1ccc(SCCCc2ccccc2)cc1
Agent: Cl
Agent: N
Solvent: Clc1ccccc1Cl
Product: S=C=Nc1ccc(SCCCc2ccccc2)cc1

Procedure:
6.4 g of the 4-(3'-phenyl-propylthio)-aniline obtained under (b) is dissolved in 50 ml of 1,2-dichlorobenzene, and the solution is saturated at room temperature, with stirring, with anhydrous hydrogen chloride. There is subsequently added 2.5 g of ammonium rhodanide, and the whole is heated, with the continuous introduction of hydrogen chloride, for 6 hours at 130° to 140°. The undissolved constituents are filtered off, and the filtrate is chromatographed through silica gel with 1,2-dichlorobenzene as the eluant. There is obtained pure 4-(3'-phenyl-propylthio)-phenyl-isothiocyanate having a refractive index of nD25 = 1.6672 (= Compound No. 1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:10])=[O:9])=[CH:6][C:5]=1[Cl:13].CO[C:17](OC)([N:19]([CH3:21])[CH3:20])[CH3:18]>>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:12]=[CH:11][C:7]([C:8]([N:10]=[C:17]([N:19]([CH3:21])[CH3:20])[CH3:18])=[O:9])=[CH:6][C:5]=1[Cl:13]
Reactant: COC(=O)c1ccc(C(N)=O)cc1Cl
Reactant: COC(C)(OC)N(C)C
Product: COC(=O)c1ccc(C(=O)N=C(C)N(C)C)cc1Cl
Temperature: 90 °C

Procedure:
A mixture of 2-chloro-terephthalamic acid methyl ester of Step A (1.02 g, 4.8 mmol) and N,N-dimethylacetamide dimethyl acetal (3.5 mL, 23.9 mmol) was heated at 90° C. for 30 minutes under nitrogen. The solution was cooled, and excess reagent was removed under high vacuum to provide a brown oil which was used as such in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[O:9][CH3:10].[C:11](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:12]>ClCCl>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]=[C:11]=[S:12])=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: COc1cc(N)ccc1Br
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Solvent: ClCCl
Product: COc1cc(N=C=S)ccc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.3 %

Procedure:
Step P (1): To a solution of 4-bromo-3-methoxyaniline (0.500 g, 2.48 mmol) in dichloromethane (10 mL) was added 1,1′-thiocarbonyldipyridin-2(1H)-one (0.575 g, 2.48 mmol). The resulting mixture was stirred at rt for 3 h. The crude reaction mixture was loaded onto silica gel and purified using silica gel chromatography (3-60% EtOAc/hexanes, linear gradient) to afford 1-bromo-4-isothiocyanato-2-methoxybenzene (0.48 g, 75% yield) as an off white solid. LC-MS (M+H)+ 244.0. 1H NMR (400 MHz, methanol-d4) δ ppm 7.53 (d, J=8.56 Hz, 1 H) 6.94 (d, J=2.27 Hz, 1 H) 6.79 (dd, J=8.56, 2.27 Hz, 1 H) 3.86 (s, 3 H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[C:13]([O:15][CH2:16][O:17][CH3:18])=[CH:12][CH:11]=[CH:10]2.[H-].[Na+].[CH3:21]I.O>CN(C)C=O>[CH3:18][O:17][CH2:16][O:15][C:13]1[C:14]2[C:9](=[CH:8][CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3][CH2:2][O:1][CH3:21])[CH:10]=[CH:11][CH:12]=1
Reactant: CI
Reactant: COCOc1cccc2cccc(CCCO)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCCc1cccc2cccc(OCOC)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5.1 g of 8-(3-hydroxypropyl)-1-methoxymethoxy naphthalene was dissolved in 40 ml of N,N-dimethyl formamide, to which 1.4 g of 55% sodium hydride was added under ice cooling. Then, 1.93 ml of methyl iodide was added and stirred at a room temperature for 2 hours. After adding water to the reaction solution and extracting with ethyl acetate, the organic layer was washed with water and then with a saturated aqueous solution of sodium chloride successively and then dried over magnesium sulfate. After distilling off the solvent, when it was purified on silica gel column chromatography (10% ethyl acetate-hexane), 5.3 g of the above-captioned compound was obtained as a colorless oily product.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:19][CH2:18][CH:17]([CH2:20][NH:21][C:22](=[O:39])[CH2:23][S:24][C:25]2[N:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=3)=[CH:27][N:26]=2)[CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[NH:15]1[CH2:19][CH2:18][CH:17]([CH2:20][NH:21][C:22](=[O:39])[CH2:23][S:24][C:25]2[N:26]=[CH:27][C:28]([C:31]3[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=3)=[CH:29][N:30]=2)[CH2:16]1
Reactant: COc1ccc(-c2cnc(SCC(=O)NCC3CCN(C(=O)OC(C)(C)C)C3)nc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(-c2cnc(SCC(=O)NCC3CCNC3)nc2)cc1
Reaction time: 0.5 h

Procedure:
Neat anhydrous trifluoroacetic acid (3 mL) was added to a solution of N-(1-tert-butoxycarbonylpyrrolidin-3-(RS)-ylmethyl)-2-[5-(4-methoxyphenyl)pyrimidin-2-ylthio]-acetamide (0.60 g, 1.3 mmol) in methylene chloride (20 mL) at room temperature. Gas evolution was apparent immediately upon addition of the acid. After 30 min., the reaction mixture was concentrated using a Teflon dryvac system, and was then further concentrated under high vacuum to give N-(pyrrolidin-3-(RS)-ylmethyl)-2-[5-(4-methoxyphenyl)pyrimidin-2-ylthio]acetamide which was dissolved in 10 mL dichloroethane (0.13 mmol/mL).