Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[C:7](=O)[O:6]C1=O)(=O)[CH3:2].O.[NH4+:19].[OH-]>>[CH3:15][O:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:6])[NH:19][C:1]([CH3:2])=[CH:4]2
Reactant: [NH4+]
Reactant: COc1ccc2c(c1)C(C(C)=O)C(=O)OC2=O
Agent: [OH-]
Solvent: O
Product: COc1ccc2c(=O)[nH]c(C)cc2c1
Temperature: 100 °C

Procedure:
A suspension of 4-acetyl-6-methoxy-isochroman-1,3-dione (10 g, 43 mmol) in NH4OH (60 ml) in a pressure vessel is heated for 2 h at 100° C. After cooling, the reaction mixture is poured into water. The white solid is filtered, washed with water, and dried to give 6.7 g of 6-methoxy-3-methyl-2H-isoquinolin-1-one. 1H NMR (CDCl3) 11.0 (br s, 1H), 8.28 (d, 1H), 6.98 (d, 1H), 6.81 (s, 1H), 6.23 (s, 1H), 3.89 (s, 3H), 2.37 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][P:5]([OH:7])[OH:6].[O:8]1[CH2:22][CH:9]1[CH2:10][N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21]>C[Si](C)(C)N[Si](C)(C)C.Cl.[I-].[Zn+2].[I-]>[NH2:1][CH2:2][CH2:3][CH2:4][P:5]([CH2:22][CH:9]([OH:8])[CH2:10][N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21])(=[O:7])[OH:6]
Reactant: NCCCP(O)O
Reactant: O=C1c2ccccc2C(=O)N1CC1CO1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Agent: [I-]
Product: NCCCP(=O)(O)CC(O)CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 2.46 g of 3-aminopropylphosphonous acid in 20 ml of hexamethyldisilazane is heated to reflux under an inert atmosphere for 24 hours after which a clear solution results. The excess hexamethyldisilazane is removed by distillation at atmospheric pressure under a slight positive pressure of inert gas to afford a colourless oil. The oil is cooled to circa 66° and treated with 0.64 g of anhydrous zinc iodide and 4.62 g of N-(2,3-epoxypropyl)phthalimide. An exothermic reaction occurs. The reaction mixture is refluxed for 6 hours after which time thin layer chromatography indicates the reaction to be complete. The reaction mixture is filtered and the filtrate evaporated to dryness in vacuo at 40°. The residue is dissolved in water and stirred at room temperature for 1 hour and the water removed in vacuo to give an oily solid. This is dissolved in 25 ml of 2.0M aqueous hydrochloric acid and washed with dichloromethane and ether. Removal of the water at 40° in vacuo affords a brown solid which is purified by ion-exchange chromatography on DOWEX® 50 W×8 (14-40 mesh) to give 3-aminopropyl(2-hydroxy-3-phthalimido-propyl)phosphinic acid, m.p. 268°-71°, as a white solid.
Reaction SMILES: ClCCCS([N:8]([CH2:37][CH:38]([CH3:40])[CH3:39])[NH:9][C:10](=[O:36])[C@@H:11]([C@@H](C(=O)NOC1CCCCO1)C/C=C/C1C=CC=CC=1)[CH2:12][CH:13]([CH3:15])[CH3:14])(=O)=O.[I-].[Na+].C(NCC)C>C(C(C)=O)C.C(OCC)(=O)C>[CH2:37]([NH:8][NH:9][C:10](=[O:36])[CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[CH:38]([CH3:40])[CH3:39]
Reactant: CC(C)C[C@@H](C(=O)NN(CC(C)C)S(=O)(=O)CCCCl)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Agent: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: CCNCC
Solvent: CCOC(C)=O
Product: CC(C)CCC(=O)NNCC(C)C
Temperature: 80 °C
Reaction time: 48 h

Procedure:
A solution of 0.60 g of (E)-2′-(3-chloropropylsulphonyl)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-4-methylvalerohydrazide in 10 ml of methyl ethyl ketone was treated with 0.18 g of sodium iodide and 1.04 ml of diethylamine. The mixture was heated at 80° C. for 4 hours and then at 60° C. for 48 hours. The mixture was diluted with ethyl acetate, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulphate and evaporated. The residue was purified by column chromatography on silica gel using methanol/dichloromethane (1:9) for the elution to give 0.16 g of (E)-2′-[3-(diethylamino)propylsulphonyl]-2(R) -[1(S)-(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-4-methylvalerohydrazide in the form of a gum.
Reaction SMILES: [CH3:1][N:2]([CH3:36])[C:3](=[O:35])[CH2:4][C:5]1[C:32]([F:33])=[CH:31][C:8]([O:9][CH2:10][CH2:11][C@@H:12]2[CH2:14][C@@H:13]2[CH:15]2[CH2:20][CH2:19][N:18](C(OCC3C=CC=CC=3)=O)[CH2:17][CH2:16]2)=[C:7]([F:34])[CH:6]=1.[H][H]>CO.[Pd]>[F:33][C:32]1[CH:31]=[C:8]([O:9][CH2:10][CH2:11][C@@H:12]2[CH2:14][C@@H:13]2[CH:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]2)[C:7]([F:34])=[CH:6][C:5]=1[CH2:4][C:3]([N:2]([CH3:36])[CH3:1])=[O:35]
Reactant: [H][H]
Reactant: CN(C)C(=O)Cc1cc(F)c(OCC[C@@H]2C[C@@H]2C2CCN(C(=O)OCc3ccccc3)CC2)cc1F
Agent: [Pd]
Solvent: CO
Product: CN(C)C(=O)Cc1cc(F)c(OCC[C@@H]2C[C@@H]2C2CCNCC2)cc1F
Yield: 96.8 %

Procedure:
To a solution of benzyl 4-[(1R,2S)-2-(2-{4-[2-(dimethylamino)-2-oxoethyl]-2,5-difluorophenoxy}ethyl)cyclopropyl]piperidine-1-carboxylate (226 mg, 0.451 mmol) in 2 ml anhydrous methanol at RT was added 10% Palladium on carbon (25.0 mg, 0.211 mmol). The reaction was stirred with hydrogen balloon for 2 hours. It was filtered by Celite, and the filtrate was concentrated to give the title compound (160 mg, 97%). LC/MS (m/z): 368.4 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:5]([N+:18]([O-])=O)=[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:3]=1.[NH:27]1[CH:31]=[CH:30][N:29]=[CH:28]1>C(Cl)(Cl)Cl>[NH2:18][C:5]1[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:3][C:2]([N:27]2[CH:31]=[CH:30][N:29]=[CH:28]2)=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:6]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: c1c[nH]cn1
Reactant: CCOC(=O)c1c(Cl)nc(-c2ccccc2)c([N+](=O)[O-])c1C(=O)OCC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1c(-n2ccnc2)nc(-c2ccccc2)c(N)c1C(=O)OCC
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.8 %

Procedure:
A mixture of 0.379 g of 2-chloro-3,4-diethoxycarbonyl-5-nitro-6-phenylpyridine, 0.21 g of imidazole and 15 ml of chloroform was heated under reflux for 8 hours. After the reaction mixture was concentrated, the residue was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over sodium sulfate. After the solvent was distilled off, 5 ml of acetic acid and 0.5 g of reduced iron were added to the residue, and the mixture was stirred at room temperature for 4 hours. After an aqueous solution of sodium hydrogencarbonate was added for neutralization, extraction with ethyl acetate was conducted. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over sodium sulfate, followed by filtration with a small amount of silica gel. The filtrate was concentrated under reduced pressure, to give 0.342 g of the title compound as a yellow oily substance.
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:11](=[CH:12][NH:13][N:14]=2)[CH:10]=[C:9]([CH3:16])[C:8]=1[NH:17][C:18]([C:20]1[N:21]([C:27]2[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][N:28]=2)[N:22]=[C:23]([O:25][CH3:26])[CH:24]=1)=[O:19])=[O:6])([CH3:3])[CH3:2].[CH2:34]([O:36][C:37](=[O:43])[CH2:38][S:39][C:40](Cl)=[O:41])[CH3:35].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:34]([O:36][C:37](=[O:43])[CH2:38][S:39][C:40]([N:13]1[CH:12]=[C:11]2[C:15]([C:7]([C:5](=[O:6])[NH:4][CH:1]([CH3:3])[CH3:2])=[C:8]([NH:17][C:18]([C:20]3[N:21]([C:27]4[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][N:28]=4)[N:22]=[C:23]([O:25][CH3:26])[CH:24]=3)=[O:19])[C:9]([CH3:16])=[CH:10]2)=[N:14]1)=[O:41])[CH3:35]
Reactant: COc1cc(C(=O)Nc2c(C)cc3c[nH]nc3c2C(=O)NC(C)C)n(-c2ncccc2Cl)n1
Reactant: CCOC(=O)CSC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)CSC(=O)n1cc2cc(C)c(NC(=O)c3cc(OC)nn3-c3ncccc3Cl)c(C(=O)NC(C)C)c2n1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
In a vial, 6-{[2-(3-chloro-pyridin-2-yl)-5-methoxy-2H-pyrazole-3-carbonyl]-amino}-5-methyl-2H-indazole-7-carboxylic acid isopropyl amide (0.200 g, 0.427 mmol) was suspended in chloroform (1 ml), then a solution of (chlorocarbonylthio)-acetic acid ethyl ester (0.086 g, 0.471 mmol) in chloroform (1 ml) was added, followed by triethylamine (0.065 ml). The reaction mixture became a clear solution that was stirred for 1 hour at a temperature of 20° C. The reaction mixture was concentrated and the residue was purified by flash chromatography over silica gel using a 50% ethyl acetate-50% cyclohexane mixture. The desired compound was isolated as a yellow solid showing the physical properties reported in the corresponding table (P.41.).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9](B2OC(C)(C)C(C)(C)O2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].I[C:23]1[N:27]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[N:26]=[CH:25][C:24]=1[CH3:36].C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]([C:23]2[N:27]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[N:26]=[CH:25][C:24]=2[CH3:36])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(C)cc1C
Reactant: Cc1cnn(COCC[Si](C)(C)C)c1I
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: COC(=O)c1cc(-c2c(C)cnn2COCC[Si](C)(C)C)c(C)cc1C
Temperature: 90 °C
Yield: 85.9 %

Procedure:
Methyl 2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 160.1, 2.7 g, 9.32 mmol), 5-iodo-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (compound 250.2, 3.15 g, 9.32 mmol), K2CO3 (6.42 g, 46.6 mmol) and PdCl2(dppf).CH2Cl2 (0.76 g, 0.93 mmol) were added to a round bottom flask. The flask was purged with argon, then dioxane (50 mL) and water (20 mL) were added and the mixture was heated at 90° C. for 16 hours. The mixture was cooled to room temperature and then partitioned between EtOAc (300 mL) and water (50 mL). The organic layer was washed with brine (50 mL), dried (MgSO4) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexanes:EtOAc, 10:11 to yield the title compound as a light brown oil (3.0 g, 86%). m/z (ES+) 375(M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[N:13]3[CH2:14][CH2:15][CH2:16][C@@:17]([C:28]([OH:31])([CH3:30])[CH3:29])([O:18][C:19]4[CH:24]=[C:23]([F:25])[C:22]([F:26])=[C:21]([F:27])[CH:20]=4)[C:12]3=[N:11][N:10]=2)[CH:6]=[CH:5][C:4]=1[N:32]1[CH:36]=[C:35]([CH3:37])[N:34]=[CH:33]1.[C:38](O)(=[O:47])[C:39]1[C:40](=[CH:42][CH:43]=[C:44]([CH:46]=1)[OH:45])[OH:41].CCCCCCC>C(O)C>[C:38]([O:31][C:28]([C@@:17]1([O:18][C:19]2[CH:24]=[C:23]([F:25])[C:22]([F:26])=[C:21]([F:27])[CH:20]=2)[CH2:16][CH2:15][CH2:14][N:13]2[C:9]([C:7]3[CH:6]=[CH:5][C:4]([N:32]4[CH:36]=[C:35]([CH3:37])[N:34]=[CH:33]4)=[C:3]([O:2][CH3:1])[N:8]=3)=[N:10][N:11]=[C:12]12)([CH3:30])[CH3:29])(=[O:47])[C:39]1[C:40](=[CH:42][CH:43]=[C:44]([CH:46]=1)[OH:45])[OH:41]
Reactant: COc1nc(-c2nnc3n2CCC[C@]3(Oc2cc(F)c(F)c(F)c2)C(C)(C)O)ccc1-n1cnc(C)c1
Reactant: O=C(O)c1cc(O)ccc1O
Solvent: CCCCCCC
Solvent: CCO
Product: COc1nc(-c2nnc3n2CCC[C@]3(Oc2cc(F)c(F)c(F)c2)C(C)(C)OC(=O)c2cc(O)ccc2O)ccc1-n1cnc(C)c1
Reaction time: 3 h
Yield: 69.6 %

Procedure:
To a mixture of 2-{(8R)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-8-(3,4,5-trifluorophenoxy)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridin-8-yl}propan-2-ol (0.50 g) in ethanol (1.5 ml) was added a mixture of gentisic acid (150 mg) in ethanol (1 mL) at room temperature. To the reaction mixture was added IPE/heptane at room temperature, and the mixture was stirred for 3 hr. The crystals were collected by filtration and dried to give the title compound (0.44 g).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:14][C:15]1[CH:16]=[CH:17][C:18]([OH:23])=[C:19]([CH:22]=1)[CH:20]=O>>[F:14][C:15]1[CH:16]=[CH:17][C:18]([OH:23])=[C:19]([CH:22]=1)[CH2:20][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Reactant: O=Cc1cc(F)ccc1O
Product: O=c1cc(N2CCN(Cc3cc(F)ccc3O)CC2)nc[nH]1

Procedure:
6-[4-(5-Fluoro-2-hydroxy-benzyl)-piperazin-1-yl]-3H -pyrimidin-4-one was prepared using Procedure B from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 5-fluoro-2-hydroxybenzaldehyde (available from Aldrich). 1H NMR (400 MHz, DMSO-d6) δ 2.45-2.48 (m, 4H), 3.43-3.49 (m, 4H), 3.57 (s, 2H), 5.28 (s, 1H), 6.73-6.80 (m, 1H), 6.89-6.94 (m, 1H), 6.99-7.02 (m, 1H), 7.89 (s, 1H), 9.90 (br s, 1H), 11.64 (br s, 1H). Mass spectrum (ES) MH+=305.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:25][CH3:26])=[CH:4][C:5](F)=[C:6]([CH:23]=1)[C:7]([C:9](=[CH:15][NH:16][C@H:17]([CH2:21][OH:22])[CH:18]([CH3:20])[CH3:19])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:8].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>CN(C=O)C.[Cl-].[Na+].O>[Br:1][C:2]1[CH:23]=[C:6]2[C:5](=[CH:4][C:3]=1[O:25][CH3:26])[N:16]([C@H:17]([CH2:21][OH:22])[CH:18]([CH3:20])[CH3:19])[CH:15]=[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:7]2=[O:8]
Reactant: CCOC(=O)C(=CN[C@H](CO)C(C)C)C(=O)c1cc(Br)c(OC)cc1F
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn([C@H](CO)C(C)C)c2cc(OC)c(Br)cc2c1=O
Temperature: 45 °C
Reaction time: 8 h
Yield: 93.6 %

Procedure:
Ethyl 2-(5-Bromo-2-fluoro-4-methoxybenzoyl)-3-((S)-1-hydroxymethyl-2-methylpropylamino)acrylate (19.5 g) was dissolved in DMF (50 mL), and potassium carbonate (8.32 g) was added. After stirring at 45° C. for 8 hr, the completion of the reaction was confirmed by HPLC. Toluene (100 mL) and 5% brine (100 mL) were added to the reaction mixture, and after stirring, the toluene layer was separated. The toluene layer was washed 3 times with 10% brine (100 mL). After washing, toluene was evaporated under reduced pressure. Toluene (50 mL) was added to the concentrate residue, and the mixture was concentrated again under reduced pressure. The obtained crude ethyl 6-bromo-7-methoxy-1-((S)-1-hydroxymethyl-2-methylpropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (17.4 g) was directly used in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[C:11]([O:15][CH3:16])[CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([C:17](OC)=[O:18])=[CH:8]2.[H-].COCCO[Al+]OCCOC.[Na+].[H-].N1CCOCC1.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[C:11]([O:15][CH3:16])[CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([CH:17]=[O:18])=[CH:8]2
Reactant: COC(=O)c1ccc2c(OC)c(OC)c(OC)cc2c1
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCN1
Solvent: Cc1ccccc1
Product: COc1cc2cc(C=O)ccc2c(OC)c1OC
Reaction time: 0.5 h

Procedure:
Methyl 5,6,7-trimethoxynaphthalene-2-carboxylate (C. L. Chen, F. D. Hostettler, Tetrahedron, 1969, 25, 3223) was reduced to the aldehyde in the following manner. Sodium bis(2-methoxyethoxy)aluminium hydride in toluene (5.6 ml, 20 mmol, 70% solution) was chilled to -20° C. under nitrogen in 20 ml of dry toluene and then 1.74 ml (20 mmol) of morpholine in 5 ml of toluene was added dropwise to it. The reaction was allowed to stir at -5° for 30 minutes, after which it was rechilled to -20° and added slowly to a solution of methyl 5,6,7-trimethoxynaphthalene-2-carboxylate (2.76 g, 10 mmol) in 20 ml of toluene at -20°. The reaction was stirred for 30 minutes at -10°, then rechilled to -20°, basified with 20 ml (40 mmol) of 2N sodium hydroxide, and extracted with three times 25 ml of toluene. The combined toluene layers were washed with 50 ml of 1N hydrochloric acid, then with 50 ml of 0.5M sodium bicarbonate, and finally with 50 ml of water, and dried over magnesium sulfate, filtered and evaporated to give 2.55 g (52% crude yield) of the title compound. This was purified on a silica gel column eluting with hexane:ethyl acetate/12:1 to give 2.15 g (44%) of the product, m.p. 96°-98°. Anal. Calcd. for C14H14O4 : C, 68.28; H, 5.73. Found: C, 68.16; H, 5.78.
Reaction SMILES: [I:1]I.[OH-].[Na+].[C:5]([S:9]([CH2:12][C@@H:13]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:14]([NH:16][C@@H:17]([CH2:36][C:37]1[N:38]=[CH:39][NH:40][CH:41]=1)[C:18]([NH:20][C@@H:21]([CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[C@@H:22]([OH:28])[C@H:23]([CH:25]1[CH2:27][CH2:26]1)[OH:24])=[O:19])=[O:15])(=[O:11])=[O:10])([CH3:8])([CH3:7])[CH3:6]>CO.O>[C:5]([S:9]([CH2:12][C@@H:13]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:14]([NH:16][C@@H:17]([CH2:36][C:37]1[N:38]=[CH:39][NH:40][C:41]=1[I:1])[C:18]([NH:20][C@@H:21]([CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[C@@H:22]([OH:28])[C@H:23]([CH:25]1[CH2:26][CH2:27]1)[OH:24])=[O:19])=[O:15])(=[O:11])=[O:10])([CH3:8])([CH3:6])[CH3:7]
Reactant: II
Reactant: CC(C)(C)S(=O)(=O)C[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)S(=O)(=O)C[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1nc[nH]c1I)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1
Reaction time: 0.08 h

Procedure:
10.4 ml (2.08 mmol) of a 0.2N methanolic iodine solution and 2.4 ml (0.48 mmol) of 0.2N sodium hydroxide solution are simultaneously added dropwise at 0° while stirring to a mixture of 630 mg (1 mmol) of (S)-α-[(S)-α-[(tert-butylsulphonyl)methyl]hydrocinnamamido]-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]imidazole-4-propionamide and 20 ml (4 mmol) of 0.2N sodium hydroxide solution in 20 ml of methanol. The colourless reaction mixture is stirred at 0° for 5 minutes and thereafter at room temperature for 2.5 hours. Subsequently, the mixture is diluted with 25 ml of water and extracted twice with 80 ml of ethyl acetate each time. The combined organic extracts are washed with saturated sodium chloride solution, dried over sodium sulphate and evaporated under reduced pressure. For purification, the residue (750 mg) is chromatographed using a 15:1 mixture of methylene chloride and methanol as the eluent. There are obtained 504 mg of (S)-α-[(S)-α-[(tert-butylsulphonyl)methyl]hydrocinnamamido]-N-[(1S,2R, 3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-5-iodoimidazole-4-propionamide, MS: 757 (M+H)+, and 38 mg of (S)-α-[(S)-α-[(tert-butylsulphonyl)methyl]hydrocinnamamido]-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-2,5-diiodoimidazole-4-propionamide, MS: 883 (M+H)+, each as a colourless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]#[N:11])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[Cl:20][C:21]([CH2:23]Cl)=[CH2:22].[NH4+]=[S:26]>CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:23][C:21]([Cl:20])=[CH2:22])[C:10]([NH2:11])=[S:26])=[CH:5][CH:4]=1
Reactant: C=C(Cl)CCl
Reactant: COc1ccc(NC#N)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C(Cl)CN(C(N)=S)c1ccc(OC)cc1
Temperature: 50 °C
Yield: 94 %

Procedure:
N-(4-methoxyphenyl)cyanamide (2.22 g) was dissolved in DMF (11.10 g), to which powdered potassium carbonate (3.11 g) and potassium iodide (0.26 g) were added at room temperature with stirring. Further, 2,3-dichloro-1-propene (2.00 g) was added dropwise at room temperature with stirring. The mixture was heated to 50° C. and stirred at the same temperature for 1.5 hours. After cooling to room temperature, ammonium sulfide solution, yellow (8.00 g) having an S content of 6% was added drop-wise to the reaction n-mixture at room temperature with stirring. The mixture was heated to 50° C. and stirred at the same temperature for 3 hours. After cooling to room temperature, water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with water. The solvent was removed by distillation under reduced pressure, which afforded 3.63 g of N-(4methoxyphenyl)-N-(2-chloro-2-propenyl)thiourea as a dark red solid (94% yield in appearance). The percentage area of liquid chromatography was 94%.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[CH3:9][C:10]1[CH:11]=[CH:12][C:13](=[O:16])[NH:14][CH:15]=1>>[CH3:9][C:10]1[CH:11]=[CH:12][C:13](=[O:16])[N:14]([C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=2)[CH:15]=1
Reactant: Cc1ccc(=O)[nH]c1
Reactant: Cc1ccc(I)cc1
Product: Cc1ccc(-n2cc(C)ccc2=O)cc1
Yield: 89 %

Procedure:
The reaction of p-iodotoluene with 5-methyl-2-(1H)-pyridone by the reaction of Example 1, affords 5-Methyl-1-p-tolyl-2-(1H)-pyridone in 89% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:17]2[C:12]([CH:13]=[N:14][C:15](OS(C(F)(F)F)(=O)=O)=[N:16]2)=[CH:11][CH:10]=1.[CH3:26][C:27]1[O:28][C:29]2[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][C:30]=2[N:31]=1.Cl.C(N(CC)C(C)C)(C)C.COCC(O)C>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:17]2[C:12]([CH:13]=[N:14][C:15]([NH:36][C:33]3[CH:34]=[CH:35][C:29]4[O:28][C:27]([CH3:26])=[N:31][C:30]=4[CH:32]=3)=[N:16]2)=[CH:11][CH:10]=1
Reactant: Cc1nc2cc(N)ccc2o1
Reactant: COc1ccccc1-c1ccc2cnc(OS(=O)(=O)C(F)(F)F)nn12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: COCC(C)O
Product: COc1ccccc1-c1ccc2cnc(Nc3ccc4oc(C)nc4c3)nn12

Procedure:
The Title compound was prepared in the following manner: A mixture of Trifluoro-methanesulfonic acid 7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl ester (100 mg, 0.3 mmol), 2-Methyl-benzoxazol-5-ylamine; hydrochloride (100 mg, 0.5 mmol), N,N-Diisopropylethylamine (2 mL, 10 mmol), and 1-Methoxy-2-propanol (0.3 mL, 3 mmol) were heated at 80° C. overnight. The reaction was concentrated, filtered and placed onto the Gilson. The pure fractions were lyophilized to give a yellow solid (30 mg, 20%). LCMS (E/I+) 372 (M+H). NMR 1H (DMSO-d6)-9.5 (s, 1H), 9.0 (s, 1H), 8.2 (s, 1H), 7.78 (d, 1H, J=7.80 Hz), 7.45-7.54 (m, 3H), 7.23 (d, 1H, J=8.26), 7.12 (t, 1H, J=7.51 Hz), 6.92-6.96 (m, 2H), 3.84 (s, 3H), 2.58 (s, 3H).