Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.C1(C)C=CC=CC=1.[S:16]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17]1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(O)C>[S:16]1[CH:20]=[CH:19][C:18]([C:2]2[CH:7]=[C:6]([Br:8])[CH:5]=[N:4][CH:3]=2)=[CH:17]1
Reactant: OB(O)c1ccsc1
Reactant: Brc1cncc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: Brc1cncc(-c2ccsc2)c1
Temperature: 75 °C
Yield: 337.1 %

Procedure:
Under a nitrogen atmosphere, a mixture of 3,5-dibromopyridine (5 g, 21 mmol), distilled water (35 mL), toluene (140 mL), ethyl alcohol (35 mL), 3-thiopheneboronic acid (2.8 g, 22 mmol), sodium carbonate (4.67 g, 44.1 mmol) and tetrakis(triphenylphosphine)palladium (1.22 g, 1.05 mmol) were stirred. This black suspension was heated at 75° C. for 20 h. After cooling to room temperature, the mixture was diluted with distilled water (200 mL) and extracted with ethyl acetate (2×200 mL, then 100 mL). The combined organic phases were dried with MgSO4, filtered and concentrated by rotary evaporation, producing 17 g of a purple oil. Purification by column chromatography on silica gel, using cyclohexane:ethyl acetate (95:5) as eluent, afforded 2.9 g (58%) of white crystals, mp 58° C.
Reaction SMILES: Cl.C([Si](C)(C)[O:7][C@@H:8]1[CH2:12][N:11]=[C:10]([NH:13][CH2:14][CH:15](OCC)OCC)[CH2:9]1)(C)(C)C>O1CCOCC1>[N:13]1[CH:14]=[CH:15][N:11]2[CH2:12][C@@H:8]([OH:7])[CH2:9][C:10]=12
Reactant: CCOC(CNC1=NC[C@@H](O[Si](C)(C)C(C)(C)C)C1)OCC
Agent: Cl
Solvent: C1COCCO1
Product: O[C@H]1Cc2nccn2C1
Temperature: 25 °C
Yield: 71.5 %

Procedure:
An aqueous solution of hydrochloric acid (0.625 M, 1000 mL) was added to a mixture of the compound isolated in Step 3 (207 g, 0.625 mol) in 1,4-dioxane (200 mL). The mixture was refluxed for 2 hours, and then cooled to room temperature, before washing with diethyl ether (3×300 mL). The aqueous layer was basified with sodium carbonate and extracted with dichloromethane (20×500 mL). The combined organic extracts were washed with brine (500 mL) evaporated under reduced pressure to give the title compound as a solid (55.5 gm 71%). 1H NMR (400 MHz, (CD3)2SO): δ 2.45 (m, 1H), 2.90 (m, 1H), 3.60 (m, 1H), 4.00 (m, 1H), 4.75 (m, 1H), 5.40 (m, 1H), 6.75 (m, 1H), 6.95 (m, 1H).
Reaction SMILES: O=[C:2]([CH2:8][CH2:9][C:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].[NH2:18][C:19]1[CH:31]=[CH:30][C:22]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:21][CH:20]=1>C(O)(=O)C>[C:26]([O:25][C:23](=[O:24])[C:22]1[CH:21]=[CH:20][C:19]([N:18]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][CH:8]=[C:2]2[CH2:3][CH2:4][C:5]([OH:7])=[O:6])=[CH:31][CH:30]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: O=C(O)CCC(=O)CCC(=O)c1ccccc1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)c1ccc(-n2c(CCC(=O)O)ccc2-c2ccccc2)cc1
Temperature: 80 °C
Yield: 59 %

Procedure:
To a stirred solution of 4,7-dioxo-7-phenyl-heptanoic acid (3.57 mmol, 1.0 eq.) in acetic acid (10 ml) was added tert-butyl 4-aminobenzoate (1.05 eq., 3.75 mmol). The mixture was heated to 80° C. for 36 hours. The solvent was evaporated in vacuo and the crude residue purified by flash silica-gel chromatography. Gradient elution with ethyl acetate/hexane (0% to 50% ethyl acetate in hexane over 20 minutes) gave the semi-pure product after combination of the appropriate fractions and evaporation of the solvent in vacuo. The tan solid obtained was used without further purification, 59% yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14]3[C:15](=[O:19])[NH:16][N:17]([CH3:18])[C:13]=3[NH:12][C:11]3[CH2:20][O:21][CH2:22][C:23](=[O:24])[C:10]2=3)[CH:5]=[CH:6][C:7]=1[F:8].[C:25](OC(=O)C)(=[O:27])[CH3:26]>>[C:25]([N:16]1[C:15](=[O:19])[C:14]2[CH:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Br:1])[CH:3]=3)[C:10]3[C:23](=[O:24])[CH2:22][O:21][CH2:20][C:11]=3[NH:12][C:13]=2[N:17]1[CH3:18])(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: Cn1[nH]c(=O)c2c1NC1=C(C(=O)COC1)C2c1ccc(F)c(Br)c1
Product: CC(=O)n1c(=O)c2c(n1C)NC1=C(C(=O)COC1)C2c1ccc(F)c(Br)c1

Procedure:
The product from Example 26C (0.1 g) was heated for 15 minutes on a steam bath with 5 mL of acetic anhydride. The reaction mixture was evaporated under reduced pressure and the residue was chromatographed on silica gel eluting with 5% ethanol/methylene chloride to provide 0.035 g of the title compound as the more polar compound. 1H NMR (DMSO-d6) δ 2.12 (s, 3H), 3.55 (s, 3H), 4.0 (m, 2H), 4.56 (q, 2H), 4.89 (s, 1H), 7.15 (m, 1H), 7.22 (t, 1H), 7.35 (dd, 1H), 10.18 (s, 1H); MS (ESI−) m/z 436 (M−H)−; Anal. Calcd for C18H15N3BrFO4: C, 49.58; H, 3.47; N, 9.63. Found: C, 49.31; H, 3.32; N, 9.62.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([Cl:11])[C:3]=1[CH:4]=[O:5].Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:9]=[C:8]([CH:7]=[C:6]([Cl:11])[C:3]=1[CH:4]=[O:5])[O:10][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: O=Cc1c(Cl)cc(O)cc1Cl
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1cc(Cl)c(C=O)c(Cl)c1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A mixture of 2.87 g (15 mmol) A1, 2.76 g (16.5 mmol) ethyl bromoacetate and 2.90 g (21 mmol) potassium carbonate in 50 ml dry acetone were stirred for 3 h at 60° C. After filtration and removal of the solvent the residue was purified by column chromatography on Silica (ethyl acetate/methanol 100:2). Yield: 3.5.5 g (86 %) A2, colorless solid.
Reaction SMILES: Cl.[CH2:2]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][C:14]2[N:15]3[CH:21]=[N:20][CH:19]=[C:16]3[S:17][CH:18]=2)[CH2:11][C@@H:10]([O:22][Si](C(C)(C)C)(C)C)[CH2:9]1)=[O:7])[CH:3]=[CH2:4].C(OCC)(=O)C.C(=O)([O-])O.[Na+]>C(#N)C.O>[CH2:2]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][C:14]2[N:15]3[CH:21]=[N:20][CH:19]=[C:16]3[S:17][CH:18]=2)[CH2:11][C@@H:10]([OH:22])[CH2:9]1)=[O:7])[CH:3]=[CH2:4]
Reactant: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1Cc1csc2cncn12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: C=CCOC(=O)N1C[C@H](O)C[C@H]1Cc1csc2cncn12
Reaction time: 0.5 h

Procedure:
Concentrated hydrochloric acid (0.75 ml) is added dropwise to a solution of 732 mg of (3R,5R)-1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5-(imidazo[5,1-b]thiazol-3-yl)methylpyrrolidine in 15 ml of dry acetonitrile under ice cooling, and the mixture is stirred at that temperature for 30 min. The reaction solution is diluted wit 50 ml of ethyl acetate, water is added thereto, and the mixture is rendered weakly alkaline by addition of a saturated aqueous sodium hydrogencarbonate solution and extracted three times with ethyl acetate. The organic layer is washed once with saturated saline, dried over anhydrous magnesium sulfate, and filtered, and the solvent is removed by evaporation under reduced pressure to give a crude product of (3R,5R)-1-allyloxycarbonyl-3-hydroxy-5-(imidazo[5,1-b]thiazol-3-yl)methylpyrrolidine. Triethylamine (0.41 ml) and 0.23 ml of methanesulfonyl chloride are successively added to a solution of this compound in 3 ml of dichloromethane under an argon stream under ice cooling, and the mixture is stirred at that temperature for 2 hr. Water is added to the reaction solution, and the mixture is extracted three times with dichloromethane. The organic layer is washed twice with saturated saline, dried over anhydrous magnesium sulfate, and filtered, and the solvent is removed by evaporation under reduced pressure to give a crude product which is then purified by column chromatography on silica gel (ethyl acetate) to give 428.2 mg of (3R,5R)-1-allyloxycarbonyl-5-(imidazo[5,1-b]thiazol-3-yl)methyl-3-methanesulfonyloxypyrrolidine as a colorless oil.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([C:10](O)=[O:11])[CH2:3][C:4]([CH3:9])([CH3:8])[C:5](O)=[O:6].[NH2:14]C(N)=O>O>[CH3:1][C:2]1([CH3:13])[CH2:3][C:4]([CH3:9])([CH3:8])[C:5](=[O:6])[NH:14][C:10]1=[O:11]
Reactant: NC(N)=O
Reactant: CC(C)(CC(C)(C)C(=O)O)C(=O)O
Solvent: O
Product: CC1(C)CC(C)(C)C(=O)NC1=O
Temperature: 160 °C
Reaction time: 10 h
Yield: 98.4 %

Procedure:
The mixture of 2.6 g of tetramethylglutaric acid and 8.3 g of urea was stirred for 10 hours at 160° C. Into the reaction mixture was added water at 100° C., and the mixture was cooled to near room temperature. The mixture was extracted with ethyl acetate three times. The organic layers were washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 2.3 g of 3,3,5,5-tetramethylpiperidin-2,6-dione.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[N:4][O:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C1C(=O)N([Br:24])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:24][CH2:1][C:2]1[C:3]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[N:4][O:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1onc(-c2cccs2)c1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1onc(-c2cccs2)c1CBr

Procedure:
Ethyl 4-methyl-3-(thiophen-2-yl)isoxazole-5-carboxylate (3.9 g, 16.5 mmol), NBS (3.5 g, 19.7 mmol), and benzoyl peroxide (0.4 g, 1.65 mmol) were added to 100 mL of carbon tetrachloride and the mixture was refluxed for 16 h. The reaction mixture was filtered and the filtrate was removed in vacuo. The residue, containing both unreacted starting material and the title compound, was used in the next reaction without purification. MS: (+) m/z 316, 318 (M+1, 79Br/81Br).
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10].N1C=CC=CC=1>C(OCC)(=O)C>[CH3:10][C:9]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([I:1])=[CH:3][CH:4]=1)=[O:11]
Reactant: Nc1ccc(I)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.8 %

Procedure:
4-Iodoaniline (11.0 g, 50.4 mmol) was dissolved in 60 mL of ethyl acetate and the solution was added with 10 mL of acetic anhydride (10.8 g, 106 mmol) and 7.8 mL of pyridine (7.65 g, 99.4 mmol), and the mixture was stirred at room temperature for 2 hours with an equipment of a CaCl2 tube. A solvent was evaporated under reduced pressure to obtain 4-iodoacetanilide (yield: 13.0 g, percent yield: 99.0%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[N:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[CH:27]=O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([N:11]2[CH2:12][CH2:13][N:14]([CH2:27][C:18]3[CH:19]=[CH:20][C:21]4[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=4)[N:17]=3)[CH2:15][CH2:16]2)=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(Nc1ccc(F)cc1)N1CCNCC1
Reactant: O=Cc1ccc2ccccc2n1
Product: O=C(Nc1ccc(F)cc1)N1CCN(Cc2ccc3ccccc3n2)CC1

Procedure:
The title compound was prepared from piperazine-1-carboxylic acid (4-fluoro-phenyl)-amide and 2-quinolinecarbaldehyde. 1H NMR (400 MHz, CDCl3): 8.16 (d, J=8.3 Hz, 1H), 8.08 (d, J=8.6 Hz, 1H), 7.82 (d, J=7.6 Hz, 1H), 7.74-6.69 (m, 1H), 7.63 (d, J=8.3 Hz, 1H), 7.56-7.52 (m, 1H), 7.32-7.25 (m, 2H), 6.99-6.94 (m, 2H), 6.38 (s, 1H), 3.88 (s, 2H), 3.52 (t, J=5.1 Hz, 4H), 2.60 (t, J=5.1 Hz, 4H).
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:40])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[S:16][C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)=[N:14][C:13]=2[CH2:27][N:28]2[CH2:33][CH2:32][CH:31]([C:34]([F:37])([F:36])[F:35])[CH2:30][CH2:29]2)=[CH:6][C:5]=1[O:38][CH3:39].N1C=CC=CC=1.[C:47]1([O:53]C(Cl)=O)C=CC=CC=1.O>ClCCl>[CH3:39][O:38][C:5]1[CH:6]=[C:7]([O:10][CH2:11][C:12]2[S:16][C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:19][CH:18]=3)=[N:14][C:13]=2[CH2:27][N:28]2[CH2:33][CH2:32][CH:31]([C:34]([F:37])([F:36])[F:35])[CH2:30][CH2:29]2)[CH:8]=[CH:9][C:4]=1[C:3]1[NH:40][C:47](=[O:53])[O:1][N:2]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CN2CCC(C(F)(F)F)CC2)ccc1C(=N)NO
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: COc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CN2CCC(C(F)(F)F)CC2)ccc1-c1noc(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 150 mg of N-hydroxy-2-methoxy-4-[2-(4-trifluoromethyl-phenyl)-4-(4-trifluoromethyl-piperidin-1-ylmethyl)-thiazol-5-ylmethoxy]-benzamidine in 5 mL of anhydrous dichloromethane at 0° C. were dropwise added 50 μL of pyridine followed by 40 μL of phenylchloroformate. The resulting mixture was stirred at room temperature for 1 h then water and dichloromethane were added. The aqueous layer was separated and extracted with dichloromethane. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. To a solution of the resulting residue in 2.7 mL of acetonitrile was added 60 μL of 1,8-diazabicyclo[5.4.0]undec-7-ene. The mixture was stirred at room temperature overnight. The solvent was removed under vacuo. The resulting residue was taken into tetrahydrofuran/ethyl acetate 50/50, washed with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (gradient from dichloromethane 100 to dichloromethane 90/methanol 10) to give 105 mg of 3-{2-methoxy-4-[2-(4-trifluoromethyl-phenyl)-4-(4-trifluoromethyl-piperidin-1-ylmethyl)-thiazol-5-ylmethoxy]-phenyl}-4H-[1,2,4]oxadiazol-5-one.
Reaction SMILES: COCCOC.Br[C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=[O:12].[CH3:16][C:17]1[C:18](B(O)O)=[CH:19][C:20]2[C:21]([CH3:30])([CH3:29])[CH2:22][CH2:23][C:24]([CH3:28])([CH3:27])[C:25]=2[CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.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>[CH3:16][C:17]1[C:18]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=[O:12])=[CH:19][C:20]2[C:21]([CH3:30])([CH3:29])[CH2:22][CH2:23][C:24]([CH3:28])([CH3:27])[C:25]=2[CH:26]=1
Reactant: Cc1cc2c(cc1B(O)O)C(C)(C)CCC2(C)C
Reactant: O=Cc1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCO
Product: Cc1cc2c(cc1-c1cccc(C=O)c1)C(C)(C)CCC2(C)C
Reaction time: 0.17 h

Procedure:
700 ml of DME, 2.4 g (2 mmol) of tetrakistriphenylphosphinepalladium(0) and 8.44 g (45.6 mmol) of 3-bromobenzaldehyde are introduced into a three-necked flask under a stream of nitrogen and the mixture is stirred for 10 minutes. A solution of 17 g (69.1 mmol) of 3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylboronic acid in 25 ml of ethanol are then added, followed by 46 ml (91 mmol) of potassium carbonate solution (2 M) and the mixture is refluxed for four hours. The reaction medium is cooled and filtered and the solid is washed with bicarbonate solution and then with ethyl acetate. The solid obtained is recrystallized from ethanol and 7 g (50%) of the expected aldehyde are collected, with a melting point of 104-5° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[O:17][C:16]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][S:27][CH2:26][CH2:25]3)=[CH:20][CH:19]=2)=[N:15][N:14]=1.[OH:30]OS([O-])=O.[K+].S(=O)(O)[O-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CO.O>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[O:17][C:16]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][S:27](=[O:30])[CH2:26][CH2:25]3)=[CH:20][CH:19]=2)=[N:15][N:14]=1
Reactant: O=S([O-])OO
Reactant: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(N3CCSCC3)cc2)o1
Agent: O=C([O-])[O-]
Agent: O=S([O-])O
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(N3CCS(=O)CC3)cc2)o1
Temperature: 50 °C
Reaction time: 4 h
Yield: 20.2 %

Procedure:
To a suspension of 4-{4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-thiomorpholine (239 mg, 0.59 mmol) in methanol (2 mL) and water (0.5 mL) was added oxone (545 mg, 0.89 mmol) and stirred for 18 h at 60° C. and for 4 h at 50° C. After the reaction mixture was cooled to ambient temperature further oxone (331 mg, 0.54 mmol) was added and stirred for 18 h at 50° C. It was cooled to ambient temperature and aqueous sodium bisulfite (38%, 1.5 mL) was added and stirred for 15 min. After the addition of aqueous sodium carbonate (saturated, 10 mL) the mixture was extracted with ethyl acetate (20 mL) and washed with aqueous sodium carbonate (saturated, 20 mL). Drying over sodium sulfate and purification by chromatography (SiO2, heptane:ethyl acetate:dichloromethane:methanol=40:50:10:0 to 0:90:0:10) afforded the title compound (50 mg, 20%) as a white solid. MS: m/e=421.1 [M+H]+.
Reaction SMILES: [Cl-].[NH4+].O.[N+:4]([C:7]1[CH:8]=[CH:9][C:10]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[C:11]([CH:14]=1)[C:12]#[N:13])([O-])=O>[Fe].C(O)C>[NH2:4][C:7]1[CH:8]=[CH:9][C:10]([O:15][CH2:16][C:17]([F:18])([F:19])[F:20])=[C:11]([CH:14]=1)[C:12]#[N:13]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1OCC(F)(F)F
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: N#Cc1cc(N)ccc1OCC(F)(F)F
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
Subsequently, ammonium chloride (0.5 g) and iron powder (2.5 g) were added to a mixed solvent of water (40 ml) and ethanol (120 ml), and the mixture was heated to 65° C. Then, 5-nitro-2-(2,2,2-trifluoroethoxy)benzonitrile (80.5 g) was added in parts over 20 min and the mixture was stirred at a refluxing temperature for 30 min. The reaction mixture was ice-cooled and filtrated. The solvent was evaporated under reduced pressure. To the residue was added aqueous sodium hydroxide solution and the mixture was extracted with toluene. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, after which the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue to allow crystallization. The crystals were recrystallized from a mixed solvent of ethyl acetate-n-hexane to give the title compound (70 g), melting point: 98–100° C.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[S:15])[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1.CC[O-].[Na+].Cl.Cl[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([S:15][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[N:3]=1
Reactant: N#Cc1c(-c2ccco2)nc(N)[nH]c1=S
Reactant: ClCc1ccccn1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: N#Cc1c(SCc2ccccn2)nc(N)nc1-c1ccco1
Reaction time: 16 h
Yield: 72 %

Procedure:
To a stirred solution of 200 mg (0.92 mmol) 2-amino-4-furan-2-yl-6-thioxo-1,6-dihydro-pyrimidine-5-carbonitrile in 10 ml ethanol were added 0.69 (1.84 mmol) sodium ethylate solution (2.67M in ethanol) and 117 mg (0.92 mmol) 2-(chloromethyl)pyridine hydrochloride and stirring continued for 16 hours at room temperature. The reaction mixture was then concentrated in vacuo and the residue partitioned between dichloromethane and water. The organic phase was dried over sodium sulfate and concentrated in vacuo. The residue was triturated in ether to afford 205 mg (72%) 2-amino-4-furan-2-yl-6-(pyridin-2-ylmethylsulfanyl)-pyrimidine-5-carbonitrile as a white crystalline solid. ES-MS m/e (%): 310 (M+H+, 100).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:43]=[CH:42][N:41]=[C:40]([CH:44]([CH3:46])[CH3:45])[CH:39]=2)[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:43]=[CH:42][N:41]=[C:40]([CH:44]([CH3:45])[CH3:46])[CH:39]=2)[CH:33]=1)=[O:31])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CC(C)c1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ccn1
Product: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(C(C)C)c3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from [2-amino-5-ethoxy-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J6) (240 mg, 0.75 mmol) and 3-[3-(2-isopropyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K39) (255 mg, 0.75 mmol) according to the general procedure M. Obtained as an off-white solid (340 mg, 77%).
Reaction SMILES: [CH2:1]([PH:8](=[O:10])[OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C[Si](Cl)(C)C.[CH2:23]=[C:24]([CH2:35][CH2:36][C:37]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:38])[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>ClCCl>[CH2:1]([P:8]([CH2:23][CH:24]([C:25]([O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:26])[CH2:35][CH2:36][C:37]([O:39][CH2:40][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)=[O:38])(=[O:9])[OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[PH](O)Cc1ccccc1
Reactant: C=C(CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCC(CP(=O)(O)Cc1ccccc1)C(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 28 %

Procedure:
Benzylphosphinic acid (2.3 g, 15 mmol) in 150 mL of dry dichloromethane was cooled to 0° C. under a nitrogen atmosphere. Triethylamine (6.5 g, 65 mmol) was added followed by trimethylsilyl chloride (5.8 g, 54 mmol) while the reaction temperature was maintained at 0° C. After 30 minutes dibenzyl 2-methylenepentanediote (2) in 20 mL of dichloromethane was added over 5 minutes. The reaction mixture was left to warm to room temperature and stirred overnight. The clear solution was cooled to 0° C. and quenched with 5% hydrochloric acid and with brine, dried (MgSO4) and evaporated to give a clear yellow liquid. Purification by flash chromatography and elution with 1:1 hexane/ethyl acetate containing 10% acetic acid yielded 2.0 g (28%) of benzyl[2,4-di(benzyloxycarbonyl)butyl]phosphinic acid (3, R=CH2Ph, R1+H) as a clear light yellow oil. Rf 0.37 (1:1 Hex./EtOAc, 10% AcOH).
Reaction SMILES: [Cl:1][C:2]([Cl:11])=[CH:3][CH:4]([CH:8]([CH3:10])[CH3:9])[C:5](O)=[O:6].S(Cl)([Cl:14])=O>C1C=CC=CC=1>[Cl:1][C:2]([Cl:11])=[CH:3][CH:4]([CH:8]([CH3:10])[CH3:9])[C:5]([Cl:14])=[O:6]
Reactant: CC(C)C(C=C(Cl)Cl)C(=O)O
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CC(C)C(C=C(Cl)Cl)C(=O)Cl

Procedure:
In 20 ml of dry benzene were dissolved 2.0 g of α-(2,2-dichlorovinyl)isovaleric acid, followed by the addition of 6.0 g of thionyl chloride. The mixture was refluxed overnight. It was then distilled to remove the low-boiling fraction, whereby α-(2,2-dichlorovinyl)isovaleroyl chloride was obtained. This α-(2,2-dichlorovinyl)isovaleroyl chloride was dissolved in 25 ml of dry benzene, followed by the addition of 2.3 g of α-cyano-3-phenoxybenzyl alcohol and, then, 2.4 g of pyridine. The mixture was stirred at room temperature overnight. The resultant reaction mixture was diluted with diethyl ether, washed with water and dilute aqueous hydrogen chloride, dried over anhydrous magnesium sulfate and distilled to remove the low-boiling fraction. Column chromatography was carried out on the residue to obtain 3.2 g of α-cyano-3-phenoxybenzyl α-(2,2-dichlorovinyl)isovalerate (Compound [1]) which was shown to have the properties given below [yield: 78% based on α-(2,2-dichlorovinyl)isovaleric acid].