Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:9])[CH2:5][CH:4]([C:6]([OH:8])=[O:7])[CH2:3]1.[CH3:10][C:11](O)([CH3:13])[CH3:12].C1(N=C=NC2CCCCC2)CCCCC1.CCCCC>C(Cl)Cl.CN(C)C1C=CN=CC=1>[F:1][C:2]1([F:9])[CH2:5][CH:4]([C:6]([O:8][C:11]([CH3:13])([CH3:12])[CH3:10])=[O:7])[CH2:3]1
Reactant: CC(C)(C)O
Reactant: O=C(O)C1CC(F)(F)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCCCC
Product: CC(C)(C)OC(=O)C1CC(F)(F)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 63.9 %

Procedure:
3,3-difluorocyclobutanecarboxylic acid (1.0 g, 7.3 mmol) was dissolved in DCM (10 mL) and cooled in an ice bath. To the solution was added N,N-dimethylpyridin-4-amine (92 mg, 0.735 mmol) portionwise followed by 2-methylpropan-2-ol (1.1 g, 14.7 mmol) in one portion. A 1M solution of N,N′-dicyclohexylcarbodiimide in DCM (8.1 mL, 8.1 mmol) was added dropwise keeping the temperature below 10° C. The resulting slurry was warmed up to room temperature and stirred for 18 hours. The solid was removed by filtration and the filtrate was washed with 2N aqueous HCl solution (2×15 mL), water (2×15 mL), and then saturated aqueous NaHCO3 solution (2×15 mL). The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo to give 1.49 g of a crude product as a mixture of white solid and yellow oil. To the mixture was added pentane (30 mL) and the mixture as then filtered through a silica gel pad eluting with pentane to give the title compound (896 mg, 63%) as colourless oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[N:20]=1)[C:5]([NH:7][CH2:8][C:9]1[C:10](=[O:17])[NH:11][C:12]([CH3:16])=[CH:13][C:14]=1[CH3:15])=[O:6].B(O)O.[C:30]([O-:33])([O-])=O.[Na+].[Na+].O1[CH2:41][CH2:40]OCC1.O>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>[CH3:15][C:14]1[CH:13]=[C:12]([CH3:16])[NH:11][C:10](=[O:17])[C:9]=1[CH2:8][NH:7][C:5](=[O:6])[C:4]1[CH:18]=[C:19]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[N:20]=[C:2]([C:41]2[CH:40]=[CH:5][C:4]([CH:30]=[O:33])=[CH:3][CH:2]=2)[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: C1COCCO1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc(N3CCCCC3)c2)c(=O)[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: OBO
Agent: [Na+]
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(C=O)cc3)nc(N3CCCCC3)c2)c(=O)[nH]1
Temperature: 100 °C
Yield: 71 %

Procedure:
To a stirred solution of 2-chloro-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-(piperidin-1-yl)isonicotinamide (0.6 g, 1.6 mmol), boronic acid (0.263 g, 1.76 mmol) in dioxane/water mixture (15 mL+5 mL), Na2CO3 (0.61 g, 5.76 mmol) was added and reaction mass purged for 15 min with argon. Then Pd(PPh3)4 (0.184 g, 0.16 mmol) was added and argon was purged again for 10 min. Reaction mass was heated at 100° C. for 3 h. On completion, reaction mass filtered through celite and celite bed washed with ethyl acetate. Combined filtrates were dried over Na2SO4 and solvent removed under reduced pressure to afford crude material which was purified by column over silica gel to obtain N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-formylphenyl)-6-(piperidin-1-yl)isonicotinamide (0.5 g, 71%).
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]([O:6][C:7]2[CH:31]=[CH:30][C:10]([C:11]([NH:13][CH:14]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=3)[C:15]([OH:17])=O)=[O:12])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[NH2:34][CH2:35][CH2:36][OH:37]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:31]=[CH:30][C:10]([C:11]([NH:13][CH:14]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([O:25][C:26]([F:27])([F:29])[F:28])=[CH:23][CH:24]=3)[C:15]([NH:34][CH2:35][CH2:36][OH:37])=[O:17])=[O:12])=[CH:9][CH:8]=2)=[CH:32][CH:33]=1
Reactant: O=C(NC(Cc1ccc(OC(F)(F)F)cc1)C(=O)O)c1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: NCCO
Product: O=C(NC(Cc1ccc(OC(F)(F)F)cc1)C(=O)NCCO)c1ccc(Oc2ccc(Cl)cc2)cc1
Yield: 82.6 %

Procedure:
A reaction similar to that described in Example 32 (32c) was conducted using 2-{[4-(4-chlorophenoxy)benzoyl]amino}-3-[4-(trifluoromethoxy)phenyl]propanoic acid (467 mg, 0.973 mmol) prepared in Example 48 (48a) and 2-aminoethanol (106 μL, 1.75 mmol) to give 420 mg of the title compound (white powder, yield: 83%).
Reaction SMILES: [CH2:1]([OH:12])[C@H:2]1[O:8][C:6](=[O:7])[C@H:5]([OH:9])[C@@H:4]([OH:10])[C@@H:3]1[OH:11].[OH-:13].[Na+].O=O>O>[O:7]=[C:6]([OH:8])[C@@H:5]([C@H:4]([C@@H:3]([C@@H:2]([CH2:1][OH:12])[OH:13])[OH:11])[OH:10])[OH:9]
Reactant: [OH-]
Reactant: O=C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: O=O
Agent: [Na+]
Solvent: O
Product: O=C(O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reaction time: 0.17 h

Procedure:
50.0 g of gluconolactone is dissolved in 950 ml demineralised water. The pH is adjusted to 6.0 with 25 g of a 45% w/w sodium hydroxide solution. The solution is heated to 55° C. under nitrogen, until no more oxygen is detected. 6.35 g of the prepared Pb/Pt/C catalyst (ratio Pt/Pb 5/2) is added and the suspension is stirred at 1300 rpm for another 10 minutes under nitrogen. The reaction is started by switching from nitrogen to oxygen (maximum 10% oxygen in the mixture). The reaction is continued without further pH control. The reaction is stopped after 2.5 hours reaction time.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH2:4].C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC.[CH3:47][S:48]([N:51]=[C:52]=[O:53])(=[O:50])=[O:49]>C1C=CC=CC=1.C(N(CC)CC)C>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH:4][C:52]([NH:51][S:48]([CH3:47])(=[O:50])=[O:49])=[O:53]
Reactant: Nc1c(Cl)cccc1Cl
Reactant: CS(=O)(=O)N=C=O
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CS(=O)(=O)NC(=O)Nc1c(Cl)cccc1Cl
Reaction time: 72 h

Procedure:
A solution was prepared containing 3.2 g (0.02 mole) of 2,6-dichloroaniline in 30 ml benzene, and one drop each of triethylamine and dibutyltin dilaurate. A second solution of 2.4 g (0.02 mole) of methanesulfonylisocyanate in 6 ml of benzene was added to the first solution. The temperature of the reaction mixture was allowed to rise to 35° C. The mixture was then allowed to stand for three days.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([N:12]1[CH2:17][CH2:16][CH:15]([NH2:18])[CH2:14][CH2:13]1)(=[O:11])=[O:10].[C:19](N1C=CN=C1)([N:21]1[CH:25]=[CH:24][N:23]=[CH:22]1)=[O:20]>CN(C)C=O>[CH3:8][S:9]([N:12]1[CH2:13][CH2:14][CH:15]([NH:18][C:19]([N:21]2[CH:25]=[CH:24][N:23]=[CH:22]2)=[O:20])[CH2:16][CH2:17]1)(=[O:11])=[O:10]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CS(=O)(=O)N1CCC(N)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CS(=O)(=O)N1CCC(NC(=O)n2ccnc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.5 %

Procedure:
To a mixture of 1-methanesulfonyl-piperidin-4-ylamine; compound with trifluoro-acetic acid (229.4 mg, 0.785 mmol, US20060014708) in N,N-dimethyl formamide (4.0 mL) was added TEA (101 mg, 1.004 mmol) and 1,1′-carbonyldiimidazole (Aldrich, 134 mg, 0.826 mmol). After it was stirred at rt for 2 hrs, the solvent was removed and the reaction mixture was extracted with EtOAc, and washed with water (2×), and saturated NaCl. The organic phase was separated, dried over Na2SO4, filtered and concentrated to give imidazole-1-carboxylic acid (1-methanesulfonyl-piperidin-4-yl)-amide (150.7 mg, 70.5%) which was used without further purification.
Reaction SMILES: Cl.Cl.Cl[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:7]1.[CH2:18]([O:25][C:26]1[CH:34]=[C:30]([C:31]([NH2:33])=[O:32])[C:29]([NH2:35])=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)CC>[CH2:18]([O:25][C:26]1[CH:27]=[CH:28][C:29]([NH:35][CH2:4][CH2:5][N:6]2[CH2:11][CH2:10][N:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:8][CH2:7]2)=[C:30]([CH:34]=1)[C:31]([NH2:33])=[O:32])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: NC(=O)c1cc(OCc2ccccc2)ccc1N
Reactant: ClCCN1CCN(c2ccccc2)CC1
Agent: Cl
Solvent: CCCO
Product: NC(=O)c1cc(OCc2ccccc2)ccc1NCCN1CCN(c2ccccc2)CC1
Yield: 29.5 %

Procedure:
1-(2-Chloroethyl)-4-phenylpiperazine dihydrochloride (3.3 g) was converted to the base and added to 1.2 g 5-Benzyloxyanthranilamide in 125 ml propanol. The solution was refluxed 3 hours, cooled, filtered, and the filtrate concentrated to dryness. The residue was chromatographed on alumina to give 0.63 g product.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][N:3]=1.[OH-].[K+].[C:11]([N:18]1[CH2:23][CH2:22][CH2:21][CH:20]([CH2:24]Br)[CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].O>CS(C)=O>[Br:8][C:6]1[CH:5]=[CH:4][N:3]([CH2:24][CH:20]2[CH2:21][CH2:22][CH2:23][N:18]([C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])[CH2:19]2)[C:2](=[O:1])[CH:7]=1
Reactant: Oc1cc(Br)ccn1
Reactant: CC(C)(C)OC(=O)N1CCCC(CBr)C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCCC(Cn2ccc(Br)cc2=O)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70.9 %

Procedure:
To a solution of 2-hydroxy-4-bromopyridine (0.10 g, 0.57 mmol) in DMSO (1.50 mL) was added KOH (0.095 g, 1.70 mmol) and the resulting reaction mixture was stirred for 10 min at room temperature followed by addition of 1-Boc-3-bromomethylpiperidine (0.16 g, 0.57 mmol). The reaction mixture was then stirred at 45° C. for 16 h. After the completion of reaction (TLC monitoring), water was added to the reaction and extracted with EtOAc (3×25 mL). The combined organics was washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified over silica gel (100-200 M, 1% MeOH-DCM) to obtain the desired product (0.15 g, 95%). MS: 371.10 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:17][C:18](=[O:30])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:20]=2[O:26][CH:27]([CH3:29])[CH3:28])[CH2:14][C:13]2[C:8](=[CH:9][C:10]([CH3:16])=[C:11]([CH3:15])[CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[CH:27]([O:26][C:20]1[C:21]([CH3:25])=[CH:22][CH:23]=[CH:24][C:19]=1[C:18]([NH:17][C:6]1([C:4]([OH:5])=[O:3])[CH2:7][C:8]2[C:13](=[CH:12][C:11]([CH3:15])=[C:10]([CH3:16])[CH:9]=2)[CH2:14]1)=[O:30])([CH3:29])[CH3:28]
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2OC(C)C)Cc2cc(C)c(C)cc2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cc2c(cc1C)CC(NC(=O)c1cccc(C)c1OC(C)C)(C(=O)O)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.6 %

Procedure:
The mixture of 2-(2-isopropoxy-3-methyl-benzoylamino)-5,6-dimethyl-indan-2-carboxylic acid ethyl ester (90) (440 mg, 1.07 mmol) and KOH (1 g, 18 mmol) is dissolved in EtOH (8 mL) and water (1 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (30 mL) and acidified with conc. HCl until no more precipitate formed. The precipitate is filtered to give the pure product (91) as a pale brown solid (374 mg, 92%).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([NH2:7])=[N:4][N:3]=1.[C:8]([CH:11]1[CH2:15][CH2:14][O:13][C:12]1=O)(=O)[CH3:9].Cl.P(Cl)(Cl)([Cl:20])=O>O.CC1C=CC=CC=1>[Cl:20][CH2:14][CH2:15][C:11]1[C:12](=[O:13])[N:4]2[N:3]=[C:2]([CH3:1])[S:6][C:5]2=[N:7][C:8]=1[CH3:9]
Reactant: CC(=O)C1CCOC1=O
Reactant: Cc1nnc(N)s1
Reactant: O=P(Cl)(Cl)Cl
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1nn2c(=O)c(CCCl)c(C)nc2s1
Temperature: 25 °C

Procedure:
A mixture of 58 parts of 5-methyl-1,3,4-thiadiazol-2-amine, 76 parts of 3-acetyl-4,5-dihydro-2(3H)-furanone, 1.2 parts of hydrochloric acid solution 12N and 540 parts of methylbenzene was stirred and refluxed for 2 hours using a water-separator. After cooling to room temperature, there were added dropwise 340 parts of phosphoryl chloride at 20°-40° C. (cooling was necessary to keep that temperature). The whole was gradually heated to reflux: at 95° C. Hydrogen chloride gas evolution was started. Then 100 parts of the mixture were distilled off and the residue was stirred and refluxed for 2 hours. After cooling, the reaction mixture was evaporated and the residue was poured into an ice/ammonium hydroxide mixture while stirring. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified three times by column-chromatography over silica gel using each time a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2,2'-oxybispropane, yielding 11.8 parts of 6-(2-chloroethyl)-2,7-dimethyl-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one; mp. 118° C. (int. 14).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.Cl.[F:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[C:23]1[CH:28]=[C:27]([N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)[N:26]=[C:25]([NH2:36])[N:24]=1)[CH2:19][NH:18][CH2:17][CH2:16]2.C(N(CC)CC)C>C(#N)C>[NH2:36][C:25]1[N:24]=[C:23]([C:22]2[CH:21]=[C:20]3[C:15]([CH2:16][CH2:17][N:18]([C:9]([NH:8][C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)=[O:10])[CH2:19]3)=[CH:14][C:13]=2[F:12])[CH:28]=[C:27]([N:29]2[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]2)[N:26]=1
Reactant: CN1CCN(c2cc(-c3cc4c(cc3F)CCNC4)nc(N)n2)CC1
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN1CCN(c2cc(-c3cc4c(cc3F)CCN(C(=O)Nc3ccc(Cl)cc3)C4)nc(N)n2)CC1
Reaction time: 0.5 h

Procedure:
1-Chloro-4-isocyanatobenzene (4.1 mg, 0.026 mmol) was added to a mixture of 4-(6-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine HCl salt (10 mg, 0.02 mmol) and triethylamine (15 uL, 0.11 mmol) in acetonitrile (0.3 mL). After 30 min., the mixture was purified by RP-LCMS (pH=10) to afford the desired products. Analytic LCMS (M+H)+: m/z=496.1/498.1.
Reaction SMILES: CO.C(=O)([O-])[O-].[K+].[K+].[NH2:9][C:10]([CH2:15][O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH:11][C:12](=[S:14])[NH2:13].II>CCOCC.O>[NH2:13][C:12]1[S:14][N:9]=[C:10]([CH2:15][O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:11]=1
Reactant: NC(=S)C=C(N)COCc1ccccc1
Agent: II
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CO
Solvent: O
Product: Nc1cc(COCc2ccccc2)ns1

Procedure:
In a stream of argon, 182 ml of dry methanol, 191 ml of dry ether and 38.5 g (0.279 mole) of potassium carbonate were added to 31.0 g (0.140 mole) of 3-amino-4-benzyloxy-2-butenethioamide obtained in Referential Example 4, and under heating and reflux, a solution of 26.6 g (0.209 mole) of iodine in dry ether 191 ml was added droopwise to the mixture. Then, the mixture was refluxed for 1.5 hours, and 130 ml of dry ether containing 17.7 g (0.140 mole) of iodine was added dropwise under reflux. After cooling, water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with water, an aqueous solution of sodium thiosulfate and a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The resulting 5-amino-3-benzyloxymethyl isothiazole was subjected to silica gel column chromatography, and the column was eluted with chloroform/methanol (500/2) to give 25.5 g (83.0%) of a brown oily substance.
Reaction SMILES: CC(C)=[O:3].O[S:6]([OH:9])(=O)=O.O=[Cr](=O)=O.S(=O)(=O)(O)O.[OH:19][CH2:20][CH2:21][CH:22]1[CH:28]=[CH:27][N:26]([C:29](=[O:51])[C:30]2[CH:35]=[CH:34][C:33]([NH:36][C:37](=[O:50])[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[CH:32][CH:31]=2)[C:25]2[CH:52]=[CH:53][CH:54]=[CH:55][C:24]=2S1.O>CC(C)=O>[C:20]([CH2:21][CH:22]1[CH:28]=[CH:27][N:26]([C:29](=[O:51])[C:30]2[CH:35]=[CH:34][C:33]([NH:36][C:37](=[O:50])[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[CH:32][CH:31]=2)[C:25]2[CH:52]=[CH:53][CH:54]=[CH:55][C:24]=2[S:6]1=[O:9])([OH:3])=[O:19]
Reactant: O=S(=O)(O)O
Reactant: CC(C)=O
Reactant: O=C(Nc1ccc(C(=O)N2C=CC(CCO)Sc3ccccc32)cc1)c1ccccc1-c1ccccc1
Agent: O=[Cr](=O)=O
Solvent: O
Product: O=C(O)CC1C=CN(C(=O)c2ccc(NC(=O)c3ccccc3-c3ccccc3)cc2)c2ccccc2S1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Excess Jones reagent (5.0 ml) prepared by a slow addition of concentrated sulfuric acid (150 ml) to a cold solution (0-5° C.) of CrO3 (180 g, 1.8M) in ice water (1.21) and stirred for one hour at 0° C., was slowly added to a cold mixture of Compound 17 as prepared in Example 3 (4.0 g, 7.8 mM) in acetone (60 ml). The resulting mixture was stirred at room temperature overnight. Water (100 ml) was then slowly added and the volatile solvents removed in vacuo. The aqueous mixture was extracted with ethyl acetate (2×100 ml). The combined EtOAc extracts were dried (MgSO4), filtered and evaporated in vacuo to give a crude product. Purification by flash column chromatography (EM silica gel 60; 10% EtOAc in CH2Cl2) gave the desired product as a white solid. m/z (MH+) 539.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]([N:5]1[CH2:9][CH:8]2[CH2:10][C:11]([NH2:14])([CH3:13])[CH2:12][CH:7]2[CH2:6]1)=[O:4].Cl[CH2:17][C:18]([N:20]1[CH2:24][C@@H:23]([F:25])[CH2:22][C@H:21]1[C:26]#[N:27])=[O:19].C(=O)([O-])[O-].[K+].[K+]>ClCCl.CN(C)C=O>[C:26]([C@@H:21]1[CH2:22][C@H:23]([F:25])[CH2:24][N:20]1[C:18](=[O:19])[CH2:17][NH:14][C:11]1([CH3:13])[CH2:12][CH:7]2[CH2:6][N:5]([C:3]([N:2]([CH3:1])[CH3:15])=[O:4])[CH2:9][CH:8]2[CH2:10]1)#[N:27]
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CCl
Reactant: CN(C)C(=O)N1CC2CC(C)(N)CC2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(C)C(=O)N1CC2CC(C)(NCC(=O)N3C[C@@H](F)C[C@H]3C#N)CC2C1
Yield: 57.7 %

Procedure:
5-Amino-5-methyl-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid dimethylamide 12f (130 mg, 0.616 mmol), (2S,4S)-1-(2-chloroacetyl)-4-fluoropyrrolidine-2-carbonitrile 13g (117.4 mg, 0.616 mmol) and potassium carbonate (85 mg, 0.616 mmol) were dissolved in the solvent mixture of 2 mL of dichloromethane and 2 mL of N,N-dimethylformamide with stirring under nitrogen atmosphere. The reaction mixture was reacted overnight at room temperature. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was concentrated under reduced pressure to remove N,N-dimethylformamide and dichloromethane. The resulting residue was purified by silica gel column chromatography to obtain 5-[2-((2S,4S)-2-cyano-4-fluoro-pyrrolidin-1-yl)-2-oxo-ethylamino]-N,N,5-trimethyl-hexahydro-cyclopenta[c]pyrrole-2(1H)-carboxamide 13h (0.13 g, yield 58%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1.[I:11]I>C(O)C.S([O-])([O-])(=O)=O.[Ag+2]>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([I:11])=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2cn[nH]c2c1
Reactant: II
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: Clc1ccc2c(I)n[nH]c2c1
Reaction time: 2 h

Procedure:
A solution of 6-chloroindazole (1-3, 5.24 g, 34.3 mmol) in ethanol (500 mL) was reacted at the ambient temperature with iodine (8.72 g, 34.3 mmol) in the presence of silver sulfate (10.7 g, 34.3 mmol). After 2 h stirring at the same temperature, all the precipitates were removed by filtration and the filtrate solution was concentrated in vacuo. Trituation with dichloromethane and hexanes gave the desired product as an orange solid (1-4); 1H NMR (400 MHz, DMSO-d6) δ 13.62 (bs, 1H), 7.66 (d, 1H, J=1.6 Hz), 7.46 (d, 1H, J=8.5 Hz), 7.21 (dd, 1H, J=8.6, 1.6 Hz).
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O.CO.[NH2:19][C:20]1[N:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]=O.[O-]S(S([O-])=O)=O.[Na+].[Na+]>CS(C)=O.ClCCl>[C:11]1([N:10]2[C:5]3=[N:6][CH:7]=[CH:8][CH:9]=[C:4]3[N:1]=[C:22]2[C:21]2[C:20]([NH2:19])=[N:27][CH:26]=[CH:25][CH:24]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=[N+]([O-])c1cccnc1Nc1ccccc1
Reactant: Nc1ncccc1C=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CO
Product: Nc1ncccc1-c1nc2cccnc2n1-c1ccccc1
Temperature: 100 °C

Procedure:
3-Nitro-N-phenylpyridin-2-amine (structure 3 as shown in Scheme 1) was dissolved in dimethylsulfoxide (8 mL/mmol) and methanol (1.5 mL/mmol) in a round bottom flask. 2-aminonicotinaldehyde 4 (1.1 eq.) and Na2S2O4 (85%, 2.5 eq.) were added. The reaction mixture was heated at 100° C. for 15 to 36 hours. After cooling to room temperature the reaction mixture was diluted with dichloromethane (20 mL/mmol) and washed with water and brine. The organic phase was separated and dried over Na2SO4. After filtration the solvent was removed under reduced pressure. The crude product was purified by silica gel chromatography (dichloromethane/methanol; 0-20% methanol over 60 min) to give a yellow to brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:11][CH2:12][C:13]2([OH:18])[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:8][C:9]=1[NH2:10])=[O:4].CO[CH:21]([N:24]([CH3:26])[CH3:25])OC>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:11][CH2:12][C:13]2([OH:18])[CH2:14][CH2:15][CH2:16][CH2:17]2)=[CH:8][C:9]=1[N:10]=[CH:21][N:24]([CH3:26])[CH3:25])=[O:4]
Reactant: COC(OC)N(C)C
Reactant: COC(=O)c1sc(CCC2(O)CCCC2)cc1N
Product: COC(=O)c1sc(CCC2(O)CCCC2)cc1N=CN(C)C

Procedure:
3-Amino-5-[2-(1-hydroxycyclopentyl)ethyl]thiophene-2-carboxylic acid methyl ester and dimethoxymethyldimethylamine were reacted by method B. The product with the molecular weight of 324.45 (C16H24N2O3S) was obtained in this way; MS (ESI): 325 (M+H+).
Reaction SMILES: [CH3:1][CH2:2][C:3]1([CH2:12][CH3:13])[C:9](=[O:10])[N:8]=[C:7]([O-:11])[NH:6][C:4]1=[O:5].[Na+].[CH2:15]([O:27][CH2:28]Cl)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>CN(C)C=O>[CH2:15]([O:27][CH2:28][N:8]1[C:9](=[O:10])[C:3]([CH2:12][CH3:13])([CH2:2][CH3:1])[C:4](=[O:5])[N:6]([CH2:28][O:27][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:7]1=[O:11])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCC1(CC)C(=O)N=C([O-])NC1=O
Reactant: CCCCCCCCCCCCOCCl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCOCN1C(=O)N(COCCCCCCCCCCCC)C(=O)C(CC)(CC)C1=O
Temperature: 110 °C
Reaction time: 8 h

Procedure:
Sodium barbital (4.0 g.) was suspended in 50 ml of dimethylformamide. To the suspension was added, over a period of 5 minutes, chloromethyl n-dodecyl ether (10 g.). The suspension was heated at 110° C. for a period of 1 hour and then allowed to stand overnight without heating. The suspension was poured into 500 ml of ice water and the resulting aqueous emulsion was extracted with ethyl acetate. The ethyl acetate solution was dried and the ethyl acetate was evaporated under reduced pressure to yield an oil, which was purified by column chromatography using silica gel (70-325 mesh). Elution with benzene provided 1,3-di-n-dodecyloxymethyl-5,5-diethyl barbituric acid.