Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:13][C:14]4[CH2:20][CH:19]([O:21][CH2:22][C:23](N5CCOCC5)=[O:24])[CH2:18][CH2:17][C:15]=4[N:16]=3)=[CH:8][C:7]=2[F:31])[CH2:3][CH2:2]1.[CH3:32][Mg]Br.[Cl-].[NH4+]>C1COCC1>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:13][C:14]4[CH2:20][CH:19]([O:21][CH2:22][CH:23]([OH:24])[CH3:32])[CH2:18][CH2:17][C:15]=4[N:16]=3)=[CH:8][C:7]=2[F:31])[CH2:2][CH2:3]1
Reactant: C[Mg]Br
Reactant: O=C(COC1CCc2nc(-c3ccc(OCC4CC4)c(F)c3)oc2C1)N1CCOCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)COC1CCc2nc(-c3ccc(OCC4CC4)c(F)c3)oc2C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-((2-(4-(cyclopropylmethoxy)-3-fluorophenyl)-4,5,6,7-tetrahydro-1,3-benzoxazol-6-yl)oxy)-1-(morpholin-4-yl)ethanone (1.68 g) in THF (25 mL) was added methylmagnesium bromide (1 M THF solution, 5.85 mL). To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To the obtained residue in a mixed solvent of THF (10 mL)-methanol (10 mL) was added sodium tetrahydroborate (148 mg), and the mixture was stirred at room temperature for 10 min. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (920 mg).
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[O:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=3)[N:8]=2)[N:3]=1.C([O-])([O-])=O.[K+].[K+].[Na+].[I-].Cl[CH2:32][C:33]1[S:37][C:36]([Cl:38])=[N:35][CH:34]=1>C1COCC1>[Cl:38][C:36]1[S:37][C:33]([CH2:32][N:6]2[C:2]([CH3:1])=[N:3][C:4]([C:7]3[O:11][N:10]=[C:9]([C:12]4[CH:13]=[CH:14][C:15]([O:18][C:19]([F:22])([F:20])[F:21])=[CH:16][CH:17]=4)[N:8]=3)=[N:5]2)=[CH:34][N:35]=1
Reactant: ClCc1cnc(Cl)s1
Reactant: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)n[nH]1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1cnc(Cl)s1
Temperature: 25 °C
Reaction time: 72 h
Yield: 54.2 %

Procedure:
To a suspension of 5-(5-methyl-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole (31 mg, 0.1 mmol) in THF (1 mL), K2CO3 (28 mg, 0.2 mmol), NaI (22 mg, 0.15 mmol), and 5-(chloromethyl)-2-chlorothiazole (25 mg, 0.15 mmol) were added at RT. The mixture was stirred at RT for 3 days. The resulting crude product was filtered and purified by a silica gel column with (EtOAc/Hexane 16% to 100% EtOAc) to give 5-(1-((2-chlorothiazol-5-yl)methyl)-5-methyl-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole as a white solid (24 mg, 55%). MS (ES+) C16H10F3N6ClO2S requires: 442, 444. found: 443, 445 [M+H]+; 1H NMR (600 MHz, CDCl3) δ 8.28 (d, J=8.9 Hz, 2H), 7.60 (s, 1H), 7.35 (d, J=8.2 Hz, 2H), 5.57 (s, 2H), 2.65 (s, 3H).
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.Br[CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11]>>[SH:7][C:4]1[S:3][C:2]([S:1][CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:6][N:5]=1
Reactant: Sc1nnc(S)s1
Reactant: CCOC(=O)C(C)Br
Product: CCOC(=O)C(C)Sc1nnc(S)s1
Yield: 76 %

Procedure:
By following the same procedure as Reference Example 6 using 7.5 g of 2,5-dimercapto-1,3,4-thiadiazole and 5.8 g of ethyl 2-bromopropionate as the starting materials, 6.1 g of ethyl 2-[(5-mercapto-1,3,4-thiadiazol-2-yl)thio]propionate was obtained as an oily product.
Reaction SMILES: C[O:2][C:3](=[O:28])[C@H:4]([CH2:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=1)[NH:5][C:6](=[O:14])[C:7](=[N:12][OH:13])[CH2:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+]>C(O)C>[OH:13][N:12]=[C:7]([CH2:8][CH:9]([CH3:11])[CH3:10])[C:6]([NH:5][C@H:4]([C:3]([OH:28])=[O:2])[CH2:15][C:16]1[CH:17]=[C:18]([O:26][CH3:27])[C:19]([O:24][CH3:25])=[C:20]([O:22][CH3:23])[CH:21]=1)=[O:14]
Reactant: COC(=O)[C@H](Cc1cc(OC)c(OC)c(OC)c1)NC(=O)C(CC(C)C)=NO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(C[C@H](NC(=O)C(CC(C)C)=NO)C(=O)O)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 13 h
Yield: 100.3 %

Procedure:
To an ethanol solution (500 ml) of 31.98 g of N-(2-hydroxyimino-4-methylpentanoyl)-(3,4,5-trimethoxy)phenylalanine methyl ester was added 180 ml of 1N-sodium hydroxide aqueous solution, and the mixture was stirred at room temperature for 13 hours. After the removal of the solvent by distillation, the residue was acidified by adding with a hydrochloric acid, then was extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous solution saturated with sodium chloride and was dried with magnesium sulfate. By removal of the solvent by distillation, 30.93 g of N-(2-hydroxyimino-4-methylpentanoyl)-(3,4,5-trimethoxy)phenylalanine was obtained.
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[CH2:11][CH2:12][C:13](O)=O.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[SH:23]>[OH-].[Na+]>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[CH2:11][CH2:12][C:13]1[S:23][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=1
Reactant: O=C(O)CCc1cnc2ccccc2n1
Reactant: Nc1ccccc1S
Agent: [Na+]
Agent: [OH-]
Product: c1ccc2nc(CCc3nc4ccccc4s3)cnc2c1
Temperature: 120 °C
Reaction time: 0.17 h

Procedure:
A mixture of 3-(quinoxalin-2-yl)propanoic acid (530 mg, 2.6 mmol) and 2-aminobenzenethiol (390 mg, 3.12 mmol) in PPA (7 g) was heated to 120° C. and stirred for 10 minutes. The reaction mixture was cooled and aqueous NaOH (20 mL) was added. The mixture was extracted with DCM (2×20 mL). The combined organic layers were dried over sodium sulfate, filtered, concentrated and then purified by prep-TLC to give 2-(2-(quinoxalin-2-yl)ethyl)benzo[d]thiazole as a yellow solid. (38 mg). MS (ESI) m/z 318 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[C:13]=3[CH:14]=2)[C@H:9]([N:26]([CH2:31][C:32]2[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[C:34]([C:42]([F:45])([F:44])[F:43])[CH:33]=2)[C:27]([O:29][CH3:30])=[O:28])[CH2:8][C@@H:7]1[CH3:46])=[O:5])[CH3:2].Cl>O1CCOCC1>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]3[CH2:18][CH2:17][NH:16][C:13]=3[CH:14]=2)[C@H:9]([N:26]([CH2:31][C:32]2[CH:33]=[C:34]([C:42]([F:43])([F:44])[F:45])[CH:35]=[C:36]([C:38]([F:41])([F:39])[F:40])[CH:37]=2)[C:27]([O:29][CH3:30])=[O:28])[CH2:8][C@@H:7]1[CH3:46])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2cc3c(cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1C)CCN3C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)N1c2cc3c(cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1C)CCN3
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.9 %

Procedure:
To an ice-cold solution of cis-5-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-7-methyl-2,3,6,7-tetrahydro-5H-pyrrolo[3,2-g]quinoline-1,8-dicarboxylic acid 1-tert-butyl ester 8-ethyl ester (Example 11) (200 mg) in 10 ml anhydrous dioxane was added 4M HCl in dioxane (15 ml) and the resulting solution was stirred for 18 h at room temperature. The solution was concentrated in vacuo. The residue was diluted with dichloromethane and washed twice with a saturated sodium bicarbonate solution. The organic phase was dried (MgSO4), filtered and concentrated. The crude product was chromatographed (50% ethyl acetate:hexane) to afford the title product (100 mg). MS m/z 559.3 (M+); 1H NMR (CDCl3) δ1.1 (d, 3H), 3.0 (t, 2H), 3.6 (t, 2H), 3.8 (s, 3H), 6.6 (s, 1H), 6.9 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2([C:19]([NH2:21])=[O:20])[CH2:18][CH2:17]2)[C:5]([Cl:22])=[CH:4][N:3]=1>CCN(C(C)C)C(C)C.CO.[Pt]=O>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2([C:19]([NH2:21])=[O:20])[CH2:17][CH2:18]2)[C:5]([Cl:22])=[CH:4][N:3]=1
Reactant: NC(=O)C1(c2ccccc2C#Cc2nc(Cl)ncc2Cl)CC1
Agent: O=[Pt]
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)C1(c2ccccc2CCc2nc(Cl)ncc2Cl)CC1
Reaction time: 58 h

Procedure:
A suspension of 1-(2-((2,5-dichloropyrimidin-4-yl)ethynyl)phenyl)cyclopropanecarboxamide (A13) (0.536 g, 1.61 mmol) and platinum oxide (0.110 g, 0.484 mmol) in DIPEA (16 mL) and MeOH (3 mL) was stirred under a hydrogen atmosphere for 58 hours. The resulting mixture was filtered through a pad of Celite and the filtrate concentrated in vacuo. The residue was diluted with water and EtOAc and filtered through a pad of Celite. The filtrate was extracted with EtOAc (2×20 mL) and the combined organic fractions were washed with water (3×20 mL), brine, dried (magnesium sulfate), filtered and concentrated in vacuo. The residue was adsorbed onto silica gel and purified by column chromatography (CombiFlash Rf, 24 g SiO2 Cartridge, 30-60% EtOAc in cyclohexane) to give the title compound A14 as a white solid (375 mg, 69%); 1H NMR (300 MHz, CDCl3) δ 8.52 (s, 1H), 7.43 (d, J=7.2 Hz, 1H), 7.28-7.31 (m, 3H), 5.37 (d, J=17 Hz, 2H), 3.27 (brs, 4H), 1.76 (brs, 2H), 1.16 (brs, 2H). LCMS-B: rt 5.30 min; m/z 337 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1([CH2:7][O:8][CH3:9])[CH2:6][O:5][CH2:4]1.[Br:10][C:11]1[C:16]([OH:17])=[C:15]([O:18][CH3:19])[C:14]([O:20][CH3:21])=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Br:10][C:11]1[C:16]([O:17][CH2:2][C:3]2([CH2:7][O:8][CH3:9])[CH2:6][O:5][CH2:4]2)=[C:15]([O:18][CH3:19])[C:14]([O:20][CH3:21])=[CH:13][CH:12]=1
Reactant: COc1ccc(Br)c(O)c1OC
Reactant: COCC1(CBr)COC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCC1(COc2c(Br)ccc(OC)c2OC)COC1
Temperature: 100 °C

Procedure:
3-(bromomethyl)-3-(methoxymethyl)oxetane (0.35 g, 0.18 mmol) preparation described in example 24) and 6-bromo-2,3-dimethoxyphenol (0.21 g, 0.9 mmol) (preparation described in Preparation 1) were dissolved in DMF (8 mL). K2CO3 (0.31 g, 2.2 mmol) was added. The suspension was heated in a microwave oven at 100° C. for 10 min. H2O was added and the mixture was extracted with EtOAc (×2). The combined organic phases were washed with brine, dried (Na2SO4), filtered and concentrated. Purification by flash chromatography (Heptane:EtOAc 100:0->75:25) yielded 3-(6-Bromo-2,3-dimethoxy-phenoxymethyl)-3-methoxymethyl-oxetane as an oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[C:3]=1[O:15][CH2:16][O:17][CH3:18].C(=O)([O-])[O-].[Cs+].[Cs+].O.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[C:36]3[C:40](=[CH:41][CH:42]=2)[C:39](=[O:43])[O:38][CH2:37]3)O1>CN(C)C=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:12]1([CH2:11][O:10][C:4]2[C:3]([O:15][CH2:16][O:17][CH3:18])=[C:2]([C:34]3[CH:35]=[C:36]4[C:40](=[CH:41][CH:42]=3)[C:39](=[O:43])[O:38][CH2:37]4)[CH:7]=[CH:6][C:5]=2[O:8][CH3:9])[CH2:14][CH2:13]1
Reactant: COCOc1c(Br)ccc(OC)c1OCC1CC1
Reactant: CC1(C)OB(c2ccc3c(c2)COC3=O)OC1(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1c(-c2ccc3c(c2)COC3=O)ccc(OC)c1OCC1CC1
Temperature: 80 °C
Yield: 51.4 %

Procedure:
A stirring solution of 1-bromo-3-(cyclopropylmethoxy)-4-methoxy-2-(methoxymethoxy)benzene (3 g, 9.46 mmol) in dimethylformamide (50 mL) was purged with argon for 1 h, to this cesium carbonate (9.23 g, 28.39 mmol), water (3 mL), tetrakis(triphenylphosphine) palladium(0) (546 mg, 0.472 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isobenzofuran-1(3H)-one (2.96 g, 11.47 mmol) were added and the resultant reaction mixture was heated to 80° C. for 5 h. The reaction mixture was cooled to RT, filtered and the filtrate was diluted with water and extracted with ethyl acetate (3×). The combined ethyl acetate layers were washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. Purification of the residue by column chromatography (silica gel, 0-20% ethyl acetate in pet ether) afforded 5-(3-(Cyclopropylmethoxy)-4-methoxy-2-(methoxymethoxy)phenyl)isobenzofuran-1(3H)-one as a solid (1.8 g, 51%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:13]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:12]=[N:11]1.[C-:27]#[N:28].[Na+]>>[C:27]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:13]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:12]=[N:11]1)#[N:28]
Reactant: [C-]#N
Reactant: BrCCCCCCCCn1nnc(-c2ccccc2)c1-c1ccccc1
Agent: [Na+]
Product: N#CCCCCCCCCn1nnc(-c2ccccc2)c1-c1ccccc1
Yield: 74.4 %

Procedure:
1-(8-Bromooctyl)-4,5-diphenyltriazole (ex. example 60a) (1.8 g) was reacted with sodium cyanide in a method similar to Example 60b). Work-up and recrystallisation from dichloromethane and hexane gave 1-(8-cyanooctyl)-4,5-diphenyltriazole (1.16 g, 74.4%) as a white solid, m.p. 77-8° C. Found: C, 77.03; H, 7.25; N, 15.35%; C23H26N4 requires: C, 77.06; H, 7.31; N, 15.63%.
Reaction SMILES: C(Cl)(Cl)Cl.[Cl:5][C:6]1[CH:27]=[CH:26][CH:25]=[CH:24][C:7]=1[C:8]([C:10]1[C:15](OS(C(F)(F)F)(=O)=O)=[CH:14][CH:13]=[CH:12][N:11]=1)=[O:9].[F:28][C:29]([F:66])([F:65])[C:30]1[CH:31]=[C:32]([CH:58]=[C:59]([C:61]([F:64])([F:63])[F:62])[CH:60]=1)[CH2:33][N:34]1[C:38]([C:39]2[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=2)=[C:37]([Sn](CCCC)(CCCC)CCCC)[N:36]=[N:35]1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].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>[F:64][C:61]([F:62])([F:63])[C:59]1[CH:58]=[C:32]([CH:31]=[C:30]([C:29]([F:28])([F:65])[F:66])[CH:60]=1)[CH2:33][N:34]1[C:38]([C:39]2[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=2)=[C:37]([C:15]2[C:10]([C:8]([C:7]3[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=3[Cl:5])=[O:9])=[N:11][CH:12]=[CH:13][CH:14]=2)[N:36]=[N:35]1
Reactant: O=C(c1ccccc1Cl)c1ncccc1OS(=O)(=O)C(F)(F)F
Reactant: CCCC[Sn](CCCC)(CCCC)c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1ccncc1
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(c1ccccc1Cl)c1ncccc1-c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1ccncc1
Temperature: 120 °C
Yield: 10.8 %

Procedure:
Add Pd2(dba)3.CHCl3 (42 mg, 0.04 mmol) to a degassed solution of trifluoro-methanesulfonic acid 2-(2-chloro-benzoyl)-pyridin-3-yl ester (149 mg, 0.41 mmol) and 4-[3-(3,5-bis-trifluoromethyl-benzyl)-5-tributylstannanyl-3H-[1,2,3]triazol-4-yl]-pyridine (296 mg, 0.45 mmol) in toluene (2 mL). Seal the mixture under N2 and heat at 120° C. for 2 hours. Add Pd(PPh3)4 (94 mg, 0.08 mmol), seal and heat at 120° C. for another 48 hours. Concentrate, dissolve in ACN, wash with hexanes (×3), dry over MgSO4 and concentrate. Purify the residue by flash chromatography on silica gel eluting with 0-10% ACN/Et2O to afford the title compound (26 mg, 11%) as tan solid. MS(IS) 588 (M+1). TLC: Rf=0.33 (10% ACN/Et2O).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[S:9][C:10]([CH2:13][NH:14][CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:11][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:19][O:20][C:21](=[O:38])[C@H:22]([CH2:33][C:34]([O:36][CH3:37])=[O:35])[NH:23][C:24](OC1C=CC=CC=1)=[O:25].C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:19][O:20][C:21](=[O:38])[C@H:22]([CH2:33][C:34]([O:36][CH3:37])=[O:35])[NH:23][C:24]([N:14]([CH2:13][C:10]1[S:9][C:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:12][CH:11]=1)[CH2:15][CH:16]([CH3:18])[CH3:17])=[O:25]
Reactant: COC(=O)C[C@H](NC(=O)Oc1ccccc1)C(=O)OC
Reactant: CC(C)CNCc1ccc(C(=O)OC(C)(C)C)s1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C[C@H](NC(=O)N(Cc1ccc(C(=O)OC(C)(C)C)s1)CC(C)C)C(=O)OC
Temperature: 60 °C
Reaction time: 2 h

Procedure:
The compound (1.1 g, 4.1 mmol) obtained in step 1 and the compound (1.2 g, 4.1 mmol) obtained in step 2 were dissolved in acetonitrile (40 ml), N,N-diisopropylethylamine (0.71 mL, 4.1 mmol) was added, and the mixture was stirred at 60° C. for 2 hours. The solvent was evaporated under reduced pressure, ethyl acetate was added, and the mixture was washed with water and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH2:9])[N:3]=1.[CH:10]1([NH2:15])[CH2:14][CH2:13][CH2:12][CH2:11]1>CO>[Cl:8][C:6]1[N:5]=[C:4]([NH2:9])[N:3]=[C:2]([NH:15][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:7]=1
Reactant: NC1CCCC1
Reactant: Nc1nc(Cl)cc(Cl)n1
Solvent: CO
Product: Nc1nc(Cl)cc(NC2CCCC2)n1
Temperature: 50 °C
Reaction time: 16 h
Yield: 93.3 %

Procedure:
In a 25 mL sealable tube under argon were combined 4,6-dichloro-2-pyrimidinamine (0.50 g, 3.05 mmol), cyclopentylamine (0.75 mL, 7.62 mmol) and CH3OH (10 mL). The vial was sealed and the reaction mixture was stirred for 16 hours at 50° C. The reaction was concentrated, and the resulting oil was partitioned between EtOAc and water. The organic layer was separated, dried (MgSO4), filtered and concentrated to afford the title compound (605 mg, 93%) as an orange oil. LC-MS (ES) m/z=213 [M+H]+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].Cl.CN1CCOCC1.[N:23]1[CH:28]=[CH:27][N:26]=[CH:25][C:24]=1[C:29]([NH:31][C@H:32]([C:40](O)=[O:41])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:30].C1(N=C=NC2CCCCC2)CCCCC1.C1C=CC2N(O)N=NC=2C=1>C1COCC1>[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH:6][C:40](=[O:41])[C@H:32]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[NH:31][C:29]([C:24]1[CH:25]=[N:26][CH:27]=[CH:28][N:23]=1)=[O:30]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)c1cnccn1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)c1cnccn1
Reaction time: 2 h
Yield: 95.2 %

Procedure:
L-phenylalanine methyl ester hydrochloride (0.8 g, 3.69 mmol) was dissolved with 20 ml of THF, then the hydrochloric acid was neutralized with NMM (0.49 ml, 4.43 mmol), cooled with an ice bath for later use. N-Pyrazineformyl-L-phenylalanine (1.0 g, 3.69 mmol) of Preparation example 3 was added to another reaction flask, dissolved with 20 ml of THF, and cooled with an ice water bath, dicyclohexylcarbodiimide (DCC) (0.76 g, 3.69 mmol), HOBt (0.60 g, 4.42 mmol) were added at 0° C. and reacted for 40 min at 0° C., then the solution of L-phenylalanine methyl ester hydrochloride in THF prepared, cooled and neutralized according to the above was added, the reaction was monitored by TLC and completed after 2 h, insoluble DCU was removed by filtration, to the filtrate was added 80 ml of ethyl acetate, washed with 5% sodium bicarbonate solution, 10% citric acid solution, 5% sodium bicarbonate solution, saturated salt solution (2×20 ml) successively. The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, and evaporated the solvent under reduced pressure, 1.52 g of white solid was obtained with a yield of 95.6%, m.p.: 111˜113° C. 1H-NMR (CDCl3, 300 MHz): δ 3.04 (—CH2, m, 2H), 3.18 (—CH2, d, 2H), 3.69 (—CH3, s, 3H), 4.82 (—CH, m, 2H), 6.36 (—CONH, d, 1H), 6.92˜7.30 (-Ph, m, 10H), 8.26 (—CONH, d, 1H), 8.54 (-Pyz, d, 1H), 8.76 (-Pyz, d, 1H), 9.33 (-Pyz, s, 1H).
Reaction SMILES: [Br:1]/[CH:2]=[C:3]1\[CH2:4][CH2:5][CH2:6][C@@:7]2([CH3:15])[C@H:11]\1[CH2:10][CH2:9][C@@H:8]2[C:12](=[O:14])[CH3:13].C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+].[OH-].[Na+].OO>O1CCCC1.CO>[Br:1]/[CH:2]=[C:3]1\[CH2:4][CH2:5][CH2:6][C@@:7]2([CH3:15])[C@H:11]\1[CH2:10][CH2:9][C@@H:8]2[C@H:12]([OH:14])[CH3:13]
Reactant: CC(=O)[C@H]1CC[C@H]2/C(=C/Br)CCC[C@]12C
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: OO
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H](O)[C@H]1CC[C@H]2/C(=C/Br)CCC[C@]12C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 95.5 %

Procedure:
Under a nitrogen atmosphere, a solution of 1-{(E,3S,3aS,7aR)-7-(bromomethylene)-octahydro-3a-methyl-1H-indene-3-yl}ethanone (Compound 11: 302.7 mg, 1.116 mmol) in tetrahydrofuran (10 ml) was cooled to −20° C., and lithium tri-sec-butylborohydride (1.02 M in tetrahydrofuran, 1.64 ml, 1.674 mmol) was added dropwise thereto over 15 minutes. After stirring the reaction mixture at the same temperature for 1 hour, methanol (0.75 ml), 3 M aqueous sodium hydroxide solution (1.75 ml) and hydrogen peroxide solution (34.5%, 1.55 ml) were added thereto, and the resulting mixture was stirred in the ice bath for 30 minutes. The resulting mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated brine (15 ml), dried over sodium sulfate, and evaporated under reduced pressure. The obtained crude product was purified by flash column chromatography to obtain (R)-1-{(E,3S,3aS,7aR)-7-(bromomethylene)-octahydro-3a-methyl-1H-indene-3-yl}ethanol (291.1 mg, 95.4%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5]([C:8]#[N:9])=[CH:4][N:3]=1.C(Cl)Cl.N1C=CC=CC=1.[C:19]1([O:25][C:26](Cl)=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1.O>[C:19]1([O:25][C:26](=[O:27])[NH:1][C:2]2[CH:7]=[N:6][C:5]([C:8]#[N:9])=[CH:4][N:3]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: N#Cc1cnc(N)cn1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: N#Cc1cnc(NC(=O)Oc2ccccc2)cn1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 58 %

Procedure:
2-Amino 5-cyano pyrazine (0.25 g, 2.08 mmol) was dissolved in THF and DCM (3:1, 40 mL) and pyridine (0.49 g, 6.2 mmol) was added. The mixture was stirred for 15 minutes. Phenylchloroformate (0.97 g, 6.2 mmol) was added and the reaction mixture was heated at 50° C. for 2 hours. The reaction mixture was cooled to RT and DCM (40 mL) and water (25 mL) were added. The separated organic layer was washed with water (2×25 mL), brine (25 mL), dried (Na2SO4) and the solvents evaporated under reduced pressure. The product was purified by column chromatography on neutral silica gel using 15-20% EtOAc in hexane to give the title compound (0.29 g, 54%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1(=[O:15])[O:10][C:8](=[O:9])[C:7]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:6]12.[C:16]1([O:22][CH3:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(=S)=S>[CH3:23][O:22][C:16]1[CH:21]=[CH:20][C:19]([C:8]([C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[C:5]([OH:10])=[O:15])=[O:9])=[CH:18][CH:17]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: COc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: COc1ccc(C(=O)c2ccccc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Anhydrous aluminum chloride (140 g) was added at ambient temperature to a vigorously stirred mixture of 148 g of phthalic anhydride, 250 ml anisole, and 250 ml carbon disulfide. After 2.5 hours, the solution was hydrolyzed with ice water and the organic solvents were removed by steam distillation. A gray solid which precipitated when the residual solution cooled to room temperature was separated from the liquid by decantation and dissolved in ca. 1 L chloroform. Rotary evaporation of the chloroform left 107 g (42%) of white solid which was recrystallized from acetic acid/water: mp. 142°-144.5° C. (lit.* mp. 122°-123.5° C.). IR (KBr): 1686, 1660 (two different carbonyls), 1550-1600, 1420-1370, 1280, 1255, 1170, 1150, 1015, 850, 800, 755 cm-1.