Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1/[CH:8]=[C:9]1\[C:10](=[O:21])[N:11]([C:18](Cl)=[O:19])[C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[N:22]1([CH2:28][CH:29]([OH:32])[CH2:30][OH:31])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.N1C=CC=CC=1>C1COCC1>[OH:32][CH:29]([CH2:28][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)[CH2:30][O:31][C:18]([N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)/[C:9](=[CH:8]/[C:3]2[NH:4][C:5]([CH3:7])=[CH:6][C:2]=2[CH3:1])/[C:10]1=[O:21])=[O:19]
Reactant: Cc1cc(C)c(/C=C2\C(=O)N(C(=O)Cl)c3ccccc32)[nH]1
Reactant: OCC(O)CN1CCOCC1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cc1cc(C)c(/C=C2\C(=O)N(C(=O)OCC(O)CN3CCOCC3)c3ccccc32)[nH]1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 55 %

Procedure:
A reaction mixture of 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carbonyl chloride (150 mg, 0.5 mmol), 3-morpholin-4-yl-propane-1,2-diol, and pyridine in 3.0 mL of THF was stirred at room temperature for 15 min and filtered. The solid was then washed with ethyl acetate and ether to give 116 mg (55%) of 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid 2-hydroxy-3-morpholin-4-yl-propyl ester as an orange solid. 1HNMR (400 MHz, DMSO-d6) δ 12.06 (s, br, 1H, NH-1′), 10.47 (s, br, 1H, OH), 7.86-7.88 (m, 1H, H-4), 7.79-7.81 (m, 1H, H-7), 7.66 (s, 1H, H-vinyl), 7.19-7.23 (m, 2H, H-5, 6), 6.12 (d, J=2.34 Hz, 1H, H-4′), 4.35-4.45 (m, 3H), 3.75-3.98 (m, 4H), 3.26-3.51 (m, 7H), 2.37 (s, 3H, CH3), and 2.34 (s, 3H, CH3)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH3:15])=[CH:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[N:16]([O-])=O.[Na+].[C:20](#[N:24])[CH2:21][C:22]#[N:23]>>[CH3:15][C@H:9]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][N:16]=[C:21]([C:20]#[N:24])[C:22]#[N:23])=[CH:3][CH:4]=2)=[N:13][NH:12][C:11](=[O:14])[CH2:10]1
Reactant: N#CCC#N
Reactant: Cc1cc(=O)[nH]nc1-c1ccc(N)cc1
Reactant: O=N[O-]
Agent: [Na+]
Product: C[C@@H]1CC(=O)NN=C1c1ccc(NN=C(C#N)C#N)cc1

Procedure:
U.S. Pat. No. 5,569,657 discloses the preparation of levosimendan and its salts. (±)-6-(4-aminophenyl)-5-methylpyridazin-3-(2H)-one is dissolved in 2-propanol on heating. L-tartaric acid is gradually added to the solution and stirred on heating to obtain a clear solution. The solution is cooled slowly to room temperature and then stirred overnight at 200 C to obtain a crystalline product. On filtering, the wet salt is dissolved in water and to it potassium carbonate solution is added with stirring. The free base obtained is filtered, washed with water and dried. The product is further dissolved in dioxane on heating and allowed to cool to room temperature. The contents are filtered and dried under vacuum to obtain (−)-6-(4-aminophenyl)-5-methylpyridazin-3-(2H)-one crystalline solid. The pure (−)-6-(4-aminophenyl)-5-methylpyridazin-3-(2H)-one compound is then treated with sodium nitrite and malononitrile under acidic condition to obtain levosimendan. A disadvantage of the resolution process disclosed is that to obtain a high optical purity (99.5%) of the pyridazinone compound, recrystallisation with dioxane is required. Also the process involves multiple steps and is time consuming.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=1[N:17]1[CH:21]=[N:20][CH:19]=[N:18]1)[C:6]([NH:8][CH2:9][Si:10]([CH3:13])([CH3:12])[CH3:11])=O)#[N:2].C1(C)C=CC=CC=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:38])=CC=1>O>[C:1]([C:3]1[CH:4]=[C:5]([C:6](=[S:38])[NH:8][CH2:9][Si:10]([CH3:13])([CH3:12])[CH3:11])[CH:14]=[CH:15][C:16]=1[N:17]1[CH:21]=[N:20][CH:19]=[N:18]1)#[N:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: C[Si](C)(C)CNC(=O)c1ccc(-n2cncn2)c(C#N)c1
Solvent: Cc1ccccc1
Solvent: O
Product: C[Si](C)(C)CNC(=S)c1ccc(-n2cncn2)c(C#N)c1
Yield: 129.4 %

Procedure:
3-cyano-4-(1H-1,2,4-triazol-1-yl)-N-[(trimethylsilyl)methyl]benzamide (1.1 g) was dissolved with toluene. To the mixture was added Lawesson reagent (1.5 g) and heated to reflux for 5 hours. The reaction mixture was returned to room temperature, water was added thereto, and the aqueous layer was extracted with ethyl acetate. The combined organic layers, were washed with a saturated aqueous sodium hydrogen carbonate solution, subsequently dried over magnesium sulfate. After filtering the reaction mixture, the solvent was distilled off under reduced pressure, and the resulting mixture was purified by silica gel chromatography, to obtain 3-cyano-4-(1H-1,2,4-triazol-1-yl)-N-[(trimethylsilyl)methyl]benzenecarbothioamide (1.5 g).
Reaction SMILES: C[O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[CH:15]=[C:14]([CH2:16][OH:17])[N:13]=[CH:12]2)=[CH:6][CH:5]=1.[H-].[Na+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1.CN(C=O)C>[CH2:21]([O:17][CH2:16][C:14]1[N:13]=[CH:12][N:11]([CH2:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:18])=[CH:5][CH:6]=2)[CH:15]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)c1ccc(Cn2cnc(CO)c2)cc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(Cn2cnc(COCc3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 3.3 %

Procedure:
To a solution of 4-(4-hydroxymethylimidazol-1-yl-methyl)benzoic acid methyl ester of Example A1 (0.4 g, 1.6 mmol) in THF/DMF (6/4) was added portionwise NaH 60% (162 mg, 4 mmol). The reaction mixture was stirred at room temperature for 1.5 h, then benzyl bromide (328 mg, 1.92 mmol) was added and the reaction was stirred overnight. The solvent was removed under reduced pressure, then water (10 ml) was added and the mixture was extracted with CH2Cl2. The aqueous phase was acidified with HCl 1 N to pH=4 and extracted with CH2Cl2. The latest organic phase was dried over MgSO4 and concentrated under vacuum. The crude product was purified by flash chromatography on silica gel (CH2Cl2/MeOH: 95/05) to give a white solid (17 mg).
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:52])[C@@H:24]([NH:25][C:26](=[O:51])[C@@H:27]([C:37]4[CH:42]=[CH:41][C:40](C(OC(C)(C)C)=O)=[CH:39][C:38]=4N)[NH:28][C:29]([N:31]4[CH2:35][C:34](=[O:36])[N:33]=[C-:32]4)=[O:30])[C@H:21]3[S:20][CH2:19][C:18]=2[CH2:53][S:54][C:55]2[N:59]([CH3:60])[N:58]=[N:57][N:56]=2)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[C:62]1([CH3:72])[CH:67]=[CH:66][C:65]([S:68]([OH:71])(=[O:70])=[O:69])=[CH:64][CH:63]=1.CCOCC.C(#[N:80])C>>[C:62]1([CH3:72])[CH:63]=[CH:64][C:65]([S:68]([O-:71])(=[O:69])=[O:70])=[CH:66][CH:67]=1.[C:8]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:52])[C@@H:24]([NH:25][C:26](=[O:51])[C@@H:27]([C:37]4[CH:42]=[CH:41][C:40]([NH2:80])=[CH:39][CH:38]=4)[NH:28][C:29]([N:31]4[CH2:35][C:34](=[O:36])[N:33]=[C-:32]4)=[O:30])[C@H:21]3[S:20][CH2:19][C:18]=2[CH2:53][S:54][C:55]2[N:59]([CH3:60])[N:58]=[N:57][N:56]=2)=[O:16])[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Cn1nnnc1SCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)[C@H](NC(=O)N3[C-]=NC(=O)C3)c3ccc(C(=O)OC(C)(C)C)cc3N)[C@H]2SC1
Reactant: CC#N
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Product: Cn1nnnc1SCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)[C@H](NC(=O)N3[C-]=NC(=O)C3)c3ccc(N)cc3)[C@H]2SC1

Procedure:
5 g of 3-[(1-methyl-1H-tetrazol-5-yl)-thiomethyl]-7β-[(2R)-2-(4-BOC-aminophenyl)-2-(2-imidazolidone-1-carboxamido)-acetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester are stirred at room temperature for 21/2 hours with 2.3 g of p-toluenesulphonic acid monohydrate in 50 ml of acetonitrile. After adding 500 ml of ether, filtering the precipitate with suction, washing with 300 ml of ether and drying in vacuo, 3-[(1-methyl-1H-tetrazol-5-yl)-thiomethyl]-7β-[(2R)-2-(4-aminophenyl)-2-(2-imidazolidone-1-carboxamido)-acetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester p-toluenesulphonate is obtained [α]D20 =-37°±1° (0.758% in CH3OH).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:15]=[CH:16][CH:17]=1)[NH:8][C:9](=[O:14])[CH2:10][C:11](=[O:13])[CH3:12])(=[O:3])[CH3:2].[C:18]1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])([O-])OC.N1C2C(=CC=CC=2)C=CC=1>C1(C)C=CC=CC=1>[C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:15]=[CH:16][CH:17]=1)[NH:8][C:9](=[O:14])/[CH:10]=[C:11](\[O:13][CH3:18])/[CH3:12])(=[O:3])[CH3:2]
Reactant: CC(=O)CC(=O)Nc1cccc(OC(C)=O)c1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: COC([O-])[O-]
Solvent: Cc1ccccc1
Solvent: c1ccc2ncccc2c1
Product: CO/C(C)=C\C(=O)Nc1cccc(OC(C)=O)c1
Temperature: 20 °C
Reaction time: 16 h
Yield: 2038 %

Procedure:
A mixture of 50 g of m-acetoxy-acetylacetanilide, 1 g of p-toluene sulfonic acid and 50 ml of methyl orthoformate was stirred for 16 hours at 20°C. and after the addition of 2 ml of quinoline and 200 ml of toluene, the reaction mixture was heated at 140°C. for 4 hours while distilling off a toluene-methanol azeotrope. The mixture was evaporated to dryness under reduced pressure and the residue was chromatographed over silica gel. The product was eluted with an 8-2 methylene chloride-acetone mixture and was crystallized from isopropyl ether to obtain 29.5 g of m-acetoxy-3-methoxy-crotonanilide melting at 111°C.
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.Br[C:26]1[CH:31]=[CH:30][C:29]([S:32]([N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)(=[O:34])=[O:33])=[CH:28][CH:27]=1>>[F:24][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][C:26]3[CH:31]=[CH:30][C:29]([S:32]([N:35]4[CH2:36][CH2:37][O:38][CH2:39][CH2:40]4)(=[O:33])=[O:34])=[CH:28][CH:27]=3)=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1
Reactant: O=S(=O)(c1ccc(Br)cc1)N1CCOCC1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: O=S(=O)(c1ccc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cc1)N1CCOCC1

Procedure:
The title compound was prepared from 7-Difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (340 mg, 1.0 mmol) and 4-(4-bromo-benzenesulfonyl)-morpholine (example B.26) (276 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (420 mg, 74%). MS (ISP) 563.4 [(M+H)+]; mp 227-228° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH:13]=O.[S:19]1[CH2:25][C:23](=[O:24])[NH:22][C:20]1=[S:21].NCCC(O)=O>C(O)(=O)C>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1/[CH:13]=[C:25]1/[C:23](=[O:24])[NH:22][C:20](=[S:21])[S:19]/1
Reactant: O=C1CSC(=S)N1
Reactant: Cc1ccc(Cl)c(Nc2ccccc2C=O)c1Cl
Agent: NCCC(=O)O
Solvent: CC(=O)O
Product: Cc1ccc(Cl)c(Nc2ccccc2/C=C2\SC(=S)NC2=O)c1Cl

Procedure:
To a room temperature solution of 2-[(2,6-dichloro-3-methylphenyl)amino]benzaldehyde (209 mg, 0.75 mmols) and rhodanine (104 mg, 0.78 mmols) in 15 mL of acetic acid is added β-alanine (48 mg, 0.54 mmols). The solution is heated at reflux for one hour. During this time a thick precipitate forms. The mixture is filtered hot, washing with an additional 5 mL of [[2- [(2,6-dichloro-3-methylphenyl)amino]phenyl]methylene]-2-thioxo-4-thiazolidinone as a fluffy orange solid; mp 274°-276° C. dec.
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][N:18]=2)[CH2:13][CH2:12]1)C(=O)OC(C)(C)C.C([Cl:26])(=O)C>C(O)C>[ClH:26].[ClH:26].[CH3:1][NH:2][CH2:10][CH:11]1[CH2:12][CH2:13][N:14]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][N:18]=2)[CH2:15][CH2:16]1
Reactant: CC(=O)Cl
Reactant: CN(CC1CCN(c2ccncn2)CC1)C(=O)OC(C)(C)C
Solvent: CCO
Product: CNCC1CCN(c2ccncn2)CC1
Product: Cl
Temperature: 40 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
tert-Butyl methyl((1-(pyrimidin-4-yl)piperidin-4-yl)methyl)carbamate (0.718 mmol, 1 eq) was dissolved in ethanol (2.5 ml), and acetyl chloride (3.59 mmol, 5.0 eq) was added while cooling with ice. The reaction mixture was then stirred for 2 hours at 40° C. and then concentrated. The residue was taken up in a small amount of acetone and a solid was precipitated with diethyl ether. The solid was filtered off, washed with diethyl ether and dried. Yield: >99%
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:37])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26](Br)[CH:25]=[C:24](Br)[CH:23]=2)[C:10]=1[CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH3:2].[F:38][C:39]1[CH:44]=[C:43](B(O)O)[CH:42]=[CH:41][N:40]=1>>[CH2:1]([O:3][C:4](=[O:37])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:43]3[CH:42]=[CH:41][N:40]=[C:39]([F:38])[CH:44]=3)[CH:25]=[C:24]([C:43]3[CH:42]=[CH:41][N:40]=[C:39]([F:38])[CH:44]=3)[CH:23]=2)[C:10]=1[CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH3:2]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(Br)c2)c1CCC(=O)OCC
Reactant: OB(O)c1ccnc(F)c1
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(-c3ccnc(F)c3)cc(-c3ccnc(F)c3)c2)c1CCC(=O)OCC
Yield: 66.7 %

Procedure:
A similar procedure as described in Example 1, step 2 was used, starting from 4-{3-[6-(3,5-dibromo-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy}-butyric acid ethyl ester (321 mg, 0.5 mmol) and 2-fluoro-pyridin-4-ylboronic acid (422 mg, 3.0 mmol) to isolate 4-[3-{6-[3,5-bis-(2-fluoro-pyridin-4-yl)-phenoxy]-hexyl}-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (225 mg, 67%) as a colorless oil: ES(+)-HRMS m/e calculated for C39H44F2N2O6 (M+H)+ 675.3240, found 675.3238.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[C:9](Cl)(=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11].C(N(C(C)C)C(C)C)C>C(Cl)Cl.CCOCC>[Br:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1cccc(Br)n1
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1cccc(Br)n1
Temperature: 0 °C
Yield: 69.1 %

Procedure:
To an ice cold solution of 6-bromopyridine-2-amine (7 g, 40.5 mmol) in DCM was added pivaloyl chloride (5.23 mL, 42.48 mmol), N-ethyl-N-isopropylpropan-2-amine (13.6 mL, 82.9 mmol) sequentially. The solution was stirred for an hour then diluted with 50 mL of ether. The mixture was washed with saturated sodium bicarbonate. The organic layer was dried over sodium sulfate, filtered concentrated. The residue was slowly solidified after scratching in ethyl acetate-hexane mixture to afford 7.2 gm (69.2% yield) of the titled compound. LCMS: m/z=257.0 (M+1).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C[C:11]([CH3:22])([C:13](=O)[CH2:14][C:15](=[O:20])[C:16]([CH3:19])(C)C)C.C(=O)([O-])[O-].[Cs+].[Cs+].C[N:30]1C(=O)CCC1>[Cu]Cl>[NH2:5][CH2:4][C:3]1[CH:6]=[CH:7][C:8]([O:20][C:15]2[CH:14]=[CH:13][CH:11]=[CH:22][C:16]=2[C:19]#[N:30])=[CH:9][CH:2]=1
Reactant: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Reactant: CN1CCCC1=O
Reactant: N#Cc1ccccc1Br
Agent: Cl[Cu]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: N#Cc1ccccc1Oc1ccc(CN)cc1
Temperature: 120 °C
Reaction time: 16 h
Yield: 38 %

Procedure:
Mix under argon (4-hydroxybenzyl)-carbamic acid tert-butyl ester (1.5 g, 6.7 mmol), 2-bromobenzonitrile (813 mg, 4.5 mmol), 2,2,6,6-tetramethylheptane-3,5-dione (83 mg, 0.45 mmol), and cesium carbonate (2.2 g, 6.7 mmol) in anhydrous NMP (8.5 mL). Degas the flask and fill with argon. Add copper(I) chloride (223 mg, 2.25 mmol) quickly. Degas the flask, fill with argon and heat at 120° C. for 3 h. Cool to ambient temperature, dilute with EtOAc, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0, 9:1 and 3:1). Evaporate the solvent and dissolve the residue in DCM (100 mL). Add trifluoroacetic acid (20 mL) and stir at ambient temperature for 16 h. Concentrate in vacuo, dissolve the residue in EtOAc and wash with 1N aqueous NaOH. Dry over Na2SO4 and concentrate in vacuo. Purify by SCX chromatography to obtain the title compound (385 mg, 38%). MS (ES+) m/z: 225 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[O:11][C:9]2=[O:10])=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=O.[CH2:25]([NH2:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1(C)C(C)=CC=CC=1>[CH2:25]([N:32]1[CH:20]([C:19]2[CH:22]=[CH:23][CH:24]=[C:17]([O:16][CH3:15])[CH:18]=2)[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)([C:9]([OH:11])=[O:10])[CH2:13][C:12]1=[O:14])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COc1cccc(C=O)c1
Reactant: O=C1CC(c2ccc(Cl)cc2)C(=O)O1
Reactant: NCc1ccccc1
Solvent: Cc1ccccc1C
Product: COc1cccc(C2N(Cc3ccccc3)C(=O)CC2(C(=O)O)c2ccc(Cl)cc2)c1
Temperature: 0 °C

Procedure:
6.3 g (0.03 mole) of (4-chlorophenyl)-succinic anhydride and 6.75 g (0.03 mole) of Schiff base, prepared from 3-methoxybenzaldehyde and benzylamine, according to the general procedure, are refluxed at 140° C. in 90 ml of xylene for 12 hr. After cooling to 0° C. the solid is collected, washed with xylene and ether: 9.15 g (70%) of title compound mp 76°-8° C.
Reaction SMILES: N[C@@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][S:5][CH3:6].N([O-])=O.[Na+].O.[C:15]([O:18]CC)(=[O:17])[CH3:16]>C(O)(=O)C>[C:15]([O:18][C@H:2]([CH2:3][CH2:4][S:5][CH3:6])[C:7]([OH:9])=[O:8])(=[O:17])[CH3:16]
Reactant: CSCC[C@@H](N)C(=O)O
Reactant: CCOC(C)=O
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CSCC[C@@H](OC(C)=O)C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
D-Methionine (14.9 g, 0.10 mol) was stirred in 300 ml of acetic acid. Sodium nitrite (13.8 g, 0.2 mol) was added portionwise over 45 minutes while maintaining the temperature in the range 20°-30° C. After stirring for an additional 90 minutes at room temperature, the resulting yellow solution was stripped in vacuo to solids which were distributed between 300 ml each of water and ethyl acetate. The organic layer was separated, washed with saturated NaCl, dried over MgSO4 and stripped to yield 7.0 g of title product as a yellow oil, used directly in the next step; tlc Rf 0.08 (3:1 hexane:ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[C:9]([OH:12])[CH:8]=[C:7]2[C:3]=1[C:4](=[O:18])[C:5]1([CH2:17][CH2:16][CH2:15][CH2:14]1)[C:6]2=[O:13].Cl[CH2:20][C:21]#[N:22].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.O>[O:13]=[C:6]1[C:7]2[C:3](=[C:2]([Cl:1])[C:10]([CH3:11])=[C:9]([O:12][CH2:20][C:21]#[N:22])[CH:8]=2)[C:4](=[O:18])[C:5]21[CH2:17][CH2:16][CH2:15][CH2:14]2
Reactant: N#CCCl
Reactant: Cc1c(O)cc2c(c1Cl)C(=O)C1(CCCC1)C2=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(OCC#N)cc2c(c1Cl)C(=O)C1(CCCC1)C2=O
Temperature: 65 °C

Procedure:
A stirred mixture of 4'-chloro-5'-methyl-6'-hydroxyspiro(cyclopentane-1,2'-indan)-1' ,3'-dione (9.3 g., 0.035 mole), chloroacetonitrile (2.83 g., 0.0375 mole), potassium carbonate (5.2 g., 0.0375 mole) and potassium iodide (6.2 g., 0.0375 mole) in dimethylformamide (100 ml.) is heated at 65°C. for 21/2 hours, cooled, then poured into water (1.5 1.) affording 10.7 g. of [1' ,3'-dioxo-4'-chloro-5'-methylspiro(cyclopentane-1,2'-indan)-6'-yloxylacetonitrile which melts at 137°-9°C. after recrystallization from ethanol-water.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=2[O:16]CC)[C:10]([OH:12])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)C>O>[C:1]1([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=2[OH:16])[C:10]([OH:12])=[O:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOc1ccc(C(=O)O)cc1-c1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1ccc(O)c(-c2ccccc2)c1
Reaction time: 1 h

Procedure:
A solution of 3-phenyl-4-ethoxybenzoic acid (26.6 g, 0.110 mole) and 550 ml of acetic acid was added to a one-liter, three-necked, round-bottom flask equipped with a 250 ml pressure equalizing dropping funnel, thermometer, cold water condenser, nitrogen inlet adapter and a polytetrafluoroethylene-coated magnetic stir bar. The flask was purged with nitrogen and the solution was brought to reflux. Approximately 125 ml of a 48 weight percent solution of HBr was added dropwise over fifteen minutes to the refluxing solution. The solution was refluxed for 30 hours. Without cooling, the solvent was rotary evaporated off leaving a slurry of a pinkish solid. The slurry was poured into one liter of deionized water and the mixture was stirred for one hour and filtered. The filter cake was dried in an 80° C. vacuum oven for three hours yielding 3-phenyl-4-hydroxybenzoic acid.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1.[NH2:12][C:13]1[N:17]=[C:16]([SH:18])[NH:15][N:14]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][S:18][C:16]2[N:17]=[C:13]([NH2:12])[NH:14][N:15]=2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(OCCBr)cc1
Reactant: Nc1n[nH]c(S)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nc(SCCOc2ccc(Cl)cc2)n[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 96.1 %

Procedure:
A mixture of 1-(2-bromoethoxy)-4-chlorobenzene (2.0 g, 8.49 mmol), 3-amino-5-mercapto-1,2,4-triazole (1.04 g, 8.92 mmol), potassium carbonate (2.34 g, 16.98 mmol), and anhydrous N,N-dimethylformamide (4 mL) was added to a 50 mL RBF with a magnetic stirring bar. The mixture was allowed to stir at ambient temperature for 3 days. Progress of the reaction was monitored by analytical HPLC with UV detection at 215 nm (Rt=6.04 min). The mixture was diluted with 40 mL of water and allowed to stir for 5 min. A precipitate was isolated by filtration, rinsed with 25 mL of water, and allowed to dry under reduced pressure. The solid material was >98% pure by analytical HPLC and afforded the title compound as a white powder (2.21 g, 96% yield). EM (calc.): 270.7; MS (ESI) m/e: 271.0 (M+H)+. 1H NMR (DMSO-d6, 400 MHz) δ ppm: 12.00 (br s, 1H), 7.32 (d, 2H), 7.00 (d, 2H), 6.04 (s, 2H), 4.19 (t, 2H), 3.30 (t, 2H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][C@H:5]([OH:7])[C@@H:4]([CH2:8][OH:9])[CH2:3]1.[Cl:10][C:11]1[CH:16]=[C:15](Cl)[N:14]=[CH:13][N:12]=1.CCN(CC)CC>C(O)(C)C>[Cl:10][C:11]1[N:12]=[CH:13][N:14]=[C:15]([NH:1][C@H:2]2[CH2:6][C@H:5]([OH:7])[C@@H:4]([CH2:8][OH:9])[CH2:3]2)[CH:16]=1
Reactant: N[C@@H]1C[C@H](CO)[C@@H](O)C1
Reactant: Clc1cc(Cl)ncn1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: OC[C@H]1C[C@@H](Nc2cc(Cl)ncn2)C[C@@H]1O
Temperature: 90 °C
Yield: 59.1 %

Procedure:
To a neat mixture of (1S,2R,4R)-4-amino-2-(hydroxymethyl)cyclopentanol (3.00 g, 22.9 mmol) and 4,6-dichloropyrimidine (3.70 g, 24.8 mmol) was added isopropyl alcohol (30.0 mL) and Et3N (8.00 mL, 57.4 mmol) and the resulting mixture was heated to 90° C. for 1 h. The mixture was then cooled to 23° C., filtered and concentrated in vacuo. The residue was purified via silica gel chromatography eluting with a gradient of 5 to 7% MeOH in DCM, and the compound was recrystallized from EtOAc to afford the title compound as a white solid (3.30 g, 59%). LC/MS: Rt=0.84 min, ES+ 244 (AA standard).