Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([OH:20])[CH2:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(#N)C.C(=O)(O)[O-].[Na+].Cl[O-].[Na+]>C(OC)(C)(C)C>[CH2:1]([O:8][CH2:9][C:10](=[O:20])[CH2:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC(COCc1ccccc1)COCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-]Cl
Solvent: CC#N
Solvent: COC(C)(C)C
Product: O=C(COCc1ccccc1)COCc1ccccc1
Temperature: 1.100000023841858 °C
Reaction time: 0.08 h
Yield: 92.5 %

Procedure:
1,3-dibenzyloxy-2-propanol(100.0 g, 367 mmol), acetonitrile (1352 mL) and 2,2,6,6-tetramethyl-1-piperidinyloxy free radical (5.74 g, 36.7 mmol) were placed in a 5,000-mL four-necked flask equipped with a mechanical stirrer and a thermometer under a nitrogen stream, and the mixture was stirred for 5 minutes. Then, 3% aqueous sodium bicarbonate solution (1,028 g, 367 mmol) was added and the mixture was cooled to 1.1° C. using an ice bath. 11.9% aqueous sodium hypochlorite solution (when 10% aqueous sodium hypochlorite solution on the market was titrated, the accurate concentration was 11.9%) (276 g, 441 mmol) was added to the mixture over a period of more than 2 hours while keeping the temperature of the mixture at 5° C. or less (the reaction was a little exothermic), and the mixture was stirred at from 0.5° C. to 2.0° C. for 1 hour. Methyl t-butyl ether (2,700 mL) was added to the reaction mixture, the mixture was stirred for 20 minutes while keeping the temperature at 10° C. or less and allowed to stand for 10 minutes, and the resulting two layers were separated (the water layer weighed 1, 289 g and its pH was 8). The obtained organic layer was washed with 10% aqueous sodium sulfite solution (330 g), 5% saline (200 g) and 20% saline (200 g) in this order. The resulting solution (3,130 g) was analyzed by high performance liquid chromatography and as a result 91.8 g (yield 93%) of the captioned 1,3-dibenzyloxypropanone was obtained.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:13]2[CH2:17][NH:16][C:15](=[O:18])[CH2:14]2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12].[C:19]1([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>CN(C)C=O>[CH3:12][O:11][C:10]1[CH:9]=[CH:8][C:7]([CH:13]2[CH2:17][NH:16][C:15](=[O:18])[CH2:14]2)=[CH:6][C:5]=1[O:4][CH2:3][CH2:2][N:28]1[CH2:29][CH2:30][N:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:26][CH2:27]1
Reactant: COc1ccc(C2CNC(=O)C2)cc1OCCCl
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(C2CNC(=O)C2)cc1OCCN1CCN(c2ccccc2)CC1
Yield: 15.2 %

Procedure:
20 mmol of 4-[3-(2-chloroethoxy)-4-methoxyphenyl]-2-pyrrolidone is dissolved in 50 ml. of dimethylformamide. After adding 22 mmol of 1-phenylpiperazine (95% strength) and 20 mmol of triethylamine, the reaction mixture is heated for 6 hours to 100 ° C. After the reaction has ceased, the solvent is withdrawn at 40° under a high vacuum. The residue is taken up in 50 ml. of ethyl acetate, washed with semisaturated sodium chloride solution, and the solvent, after drying over sodium sulfate, is distilled off under vacuum, thus obtaining in a 15.2% yield 4-{4-methoxy-3-[2-(4-phenylpiperazin-1-yl)ethoxy]-phenyl}-2-pyrrolidone, m.p. 140°-141°. The dihydrochloride, m.p. 219°-221°, is precipitated from ethereal hydrochloric acid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[OH:13])C.[H-].[Na+].[CH2:16](I)[CH3:17]>CN(C=O)C>[CH2:16]([O:13][C:5]1[CH:6]=[C:7]([N+:10]([O-:12])=[O:11])[CH:8]=[CH:9][C:4]=1[O:3][CH3:1])[CH3:17]
Reactant: CCOc1ccc([N+](=O)[O-])cc1O
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1cc([N+](=O)[O-])ccc1OC
Reaction time: 0.5 h
Yield: 84.2 %

Procedure:
Under an inert atmosphere at 0° C., add a solution of 10 g (59 mmol) of 2-ethoxy-5-nitrophenol dissolved in 125 ml of DMF, on a solution of 2.6 g (65 mmol) of 60% NaH in oil dissolved in 125 ml of DMF. After 30 minutes at room temperature, add dropwise 5.2 ml (65 mmol) of EtI at 0° C. Allow to stand at room temperature for 12 hours. Add 1.5 l of a water-ice mixture. Filter the precipitate and wash three times with 100 ml of water then once with 100 ml of pentane. One obtains 9.8 g of the abovenamed product in the form of a white powder. Yield: 93%. 1H-NMR (CDCl3, 300 MHz): d 1.52 (t, 3H, —CH3), 3.98 (s, 3H, OCH3), 4.20 (q, 2H, OCH2), 6.91 (d, 1H Ar), 7.75 (d, 1H Ar), 7.91 (dd,1H Ar).
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7]1[N:11]2[C:12](=[O:24])[C@H:13]([C@H:14]([O:16][Si](C(C)(C)C)(C)C)[CH3:15])[C@H:10]2[C@@H:9]([CH3:25])[C:8]=1[S:26][C@H:27]1[CH2:31][NH:30][C:29](=[S:32])[CH2:28]1)=[O:6])[CH:2]=[CH2:3].F.[NH4+].P([O-])([O-])([O-])=O>CN(C)C=O>[CH2:1]([O:4][C:5]([C:7]1[N:11]2[C:12](=[O:24])[C@H:13]([C@H:14]([OH:16])[CH3:15])[C@H:10]2[C@@H:9]([CH3:25])[C:8]=1[S:26][C@H:27]1[CH2:31][NH:30][C:29](=[S:32])[CH2:28]1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)C1=C(S[C@H]2CNC(=S)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N12
Agent: F
Agent: O=P([O-])([O-])[O-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: C=CCOC(=O)C1=C(S[C@H]2CNC(=S)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Temperature: 25 °C
Reaction time: 72 h
Yield: 85.3 %

Procedure:
A mixture of (1R,5S,6S)-2-[(4R)-pyrrolidine-2-thion-4-ylthio ]-6-[(1R)-1-t-butyldimethylsilyloxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid allyl ester (1.00 g), dimethylformamide (10 ml) and ammonium hydrogenfluoride (459 mg) is stirred at room temperature for three days. To the reaction solution is added a phosphate buffer (pH 7.0), and the mixture is extracted with ethyl acetate. The organic layer is washed with a phosphate buffer, and the both of the phosphate buffer layers are combined, and extracted with ethyl acetate. The organic layers are combined, washed, dried and concentrated under reduced pressure. The resulting residue is crystallized from a mixture of ethyl acetate and n-hexane (2:1) to give (1R,5S,6S)-2-[(4R)-pyrrolidine-2-thion-4-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid allyl ester (657 mg). The filtrate of the above crystallization is concentrated under reduced pressure, and the residue is purified by silica gel flash column chromatography (solvent; chloroform:ethanol=30:1), and further crystallized from a mixture of ethyl acetate and n-hexane (2:1) to give (1R,5S,6S)-2-[(4R)-pyrrolidine-2-thion-4-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid allyl ester (24 mg).
Reaction SMILES: [CH:1]1([N:6]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:7]([C:9]2[CH:28]=[CH:27][C:12]3[N:13]([CH3:26])[C:14]([CH2:16][NH:17][C:18]4[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=4)=[N:15][C:11]=3[CH:10]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:36].C(=O)([O-])[O-].[NH4+:41].[NH4+]>C(O)C>[ClH:36].[CH:1]1([N:6]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:7]([C:9]2[CH:28]=[CH:27][C:12]3[N:13]([CH3:26])[C:14]([CH2:16][NH:17][C:18]4[CH:23]=[CH:22][C:21]([C:24](=[NH:41])[NH2:25])=[CH:20][CH:19]=4)=[N:15][C:11]=3[CH:10]=2)=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C#N)cc1)n2C)C1CCCC1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)C1CCCC1
Yield: 60 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-cyclopentyl-N-(2-ethoxycarbonylethyl)amide and ethanolic hydrochloric acid, ethanol, and ammonium carbonate. Yield: 60% of theory, C27H34N6O3 (490.6); EKA mass spectrum: (M+H)+=491.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:15]=[CH:14][C:8]2[S:9][C:10]([CH2:12]Br)=[CH:11][C:7]=2[CH:6]=1)=[O:4].[NH:16]1[CH:20]=[CH:19][N:18]=[CH:17]1.C(=O)(O)[O-].[Na+]>CC(C)=O>[CH3:1][O:2][C:3]([C:5]1[CH:15]=[CH:14][C:8]2[S:9][C:10]([CH2:12][C:17]3[NH:16][CH:20]=[CH:19][N:18]=3)=[CH:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: c1c[nH]cn1
Reactant: COC(=O)c1ccc2sc(CBr)cc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc2sc(Cc3ncc[nH]3)cc2c1
Yield: 49.6 %

Procedure:
A mixture of 2-bromomethylbenzo[b]thiophene-5-carboxylic acid methyl ester (1.71 g), imidazole (4.08 g) and sodium bicarbonate (0.55 g) in acetone (50 ml) was heated under reflux for 3 hours and then evaporated. The residue was partitioned between ethyl acetate and water. The organic layer was washed with water, dried (Na2SO4) and evaporated to give a solid which was chromatographed on silica gel. Elution with chloroform gave first a small amount of starting material followed by product. Evaporation of the product containing fractions gave a solid which was crystallised from ethyl acetate/petrol (b.p. 60°-80°) to give 2-(1-imidazolylmethyl)benzo[b]thiophene-5-carboxylic acid methyl ester (0.81 g), m.p. 127°-128°.
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.[CH3:9][C:10]([CH3:15])([CH2:13]O)[CH2:11][OH:12].C(Cl)Cl.[OH-].[Na+]>C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[CH3:9][C:10]1([CH3:15])[CH2:11][O:12][C:3]2([CH2:4][CH2:5][CH2:6][C:1](=[O:8])[CH2:2]2)[O:7][CH2:13]1
Reactant: CC(C)(CO)CO
Reactant: O=C1CCCC(=O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC1(C)COC2(CCCC(=O)C2)OC1
Temperature: 25 °C
Yield: 43.6 %

Procedure:
448.5 g 1,3-cyclohexanedione, 416 g 2,2-dimethyl-1,3-propanediol and 12 g p-toluenesulfonic acid were introduced into 3,000 ml methylene chloride and the mixture was heated under reflux for 24 hours using a water separator. When the reaction had ended the mixture was cooled to room temperature and 2,000 ml 32% sodium hydroxide solution were added. The phases were separated and the organic phase was washed first with sodium bicarbonate solution (44.4 g sodium bicarbonate solution/850 ml water) and then with 350 ml water. The organic phase was dried over sodium sulfate and the solvent was then evaporated in vacuo. 345 g (50% of theory) 3,3-dimethyl-1,5-dioxa-spiro[5.5]undecan-8-one were obtained in this way.
Reaction SMILES: [CH2:1]=C.[Cl:3][C:4]([Cl:10])(Cl)[P:5]([Cl:8])([Cl:7])=[O:6].[CH2:11]([Cl:13])Cl>[Ag]>[Cl:3][C:4]([Cl:10])([P:5]([Cl:8])([Cl:7])=[O:6])[CH2:1][CH2:11][Cl:13]
Reactant: ClCCl
Reactant: O=P(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: C=C
Agent: [Ag]
Product: O=P(Cl)(Cl)C(Cl)(Cl)CCCl

Procedure:
5.6 g (0.2 mole) ethylene, 23.6 g (0.1 mole) trichloromethane phosphonic dichloride, 162 mg (1 mmole) anhydrous ferric chloride and 366 mg (1 mmole) dibenzpinacol were heated in a 100 ml silver-lined autoclave in 40 ml dry methylene chloride at 120° during 14 hours. During this time the pressure fell from 500 to 220 psi. After cooling, the reaction product was extracted three times with ice-cold 1N aqueous hydrochloric acid after take-up in methylene chloride and dried on calcium chloride. Evaporation at atmospheric pressure at 50° left an oil which was distilled in vacuo, yielding 13.7 g 1,1,3-trichloropropane-1-phosphonic dichloride, bp/4: 105° -106°. Quantitative half-hydrolysis gave 13.4% chloride ion. Calc.: 13.4%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][NH:7][C:6]2=O.[Cl:14]CCCl.P(Cl)(Cl)(Cl)(Cl)Cl>C(Cl)Cl>[Cl:14][C:6]1[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: COc1ccc2nc[nH]c(=O)c2c1
Reactant: ClCCCl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc2ncnc(Cl)c2c1
Reaction time: 1.11 h
Yield: 75 %

Procedure:
To 0.852 mmoles of 6-methoxy-3H-quinazolin-4-one in 0.4M soln of DCE, add 1.022 mmoles of PCl5. Microwave at 150° C. for 4000 secs. Work-up: The reaction mixture was diluted with CH2Cl2 and washed with water and brine. The organic layer was separated dried over MgSO4, filtered and excess solvent was removed on rotavap to yield the title compound in 75% yield. The compound was used for the next step without further purification. LC-MS: m/z=195 (M++1)
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[C@H:7]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])([CH3:4])([CH3:3])[CH3:2].[N+](=[CH2:24])=[N-]>CO>[C:1]([O:5][C:6](=[O:21])[C@H:7]([CH2:16][CH2:17][C:18]([O:20][CH3:24])=[O:19])[NH:8][C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)O)C(=O)OC(C)(C)C
Solvent: CO
Product: COC(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
2.3 g of N-tert.butyloxycarbonyl-L-glutamic acid 1-tert.-butyl ester (7.58 mmol) are dissolved in 80 ml of methanol and a freshly prepared diazomethane solution (23 mmol of Diazald®) is added dropwise at room temperature. After one hour, the solvent is removed under vacuum. The compound is purified using chromatography on silica gel. (column: 18.5*4 cm, DCM/MeOH=99/1, Rf=0.99).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:18])[O:5][C:6]2[CH:13]=[C:12]([O:14][C:15](=[O:17])[CH3:16])[CH:11]=[CH:10][C:7]=2[C:8]=1[OH:9].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]1[C:4](=[O:18])[O:5][C:6]2[CH:13]=[C:12]([O:14][C:15](=[O:17])[CH3:16])[CH:11]=[CH:10][C:7]=2[C:8]=1[O:9][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: COc1c(O)c2ccc(OC(C)=O)cc2oc1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1c(OCc2ccccc2)c2ccc(OC(C)=O)cc2oc1=O
Reaction time: 2 h
Yield: 37 %

Procedure:
To a mixture of 8.11 g of 3-methoxy-4-hydroxy-7-acetoxy-2H-l-benzopyran-2-one (27.8 mmol) and 5.71 g of benzyl bromide (33.4mmol) in 50 ml of DMF was added 4.61 g of sodium carbonate (33.4 mmol) under argon atmosphere, then the mixture was stirred at 50° for 2 hours. The solid in the reaction mixture was filtered off, the filtrate was poured into 200 ml of water and extracted with 500 ml of benzene. The organic layler was concentrated in vacuo after drying over magnesium sulfate to give oily residue. The residue was purified on silica gel column chromatography (eluent: benzene/ethyl acetate=7/3) to give 3.50 g of the title compound. (yield=33%)
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[SH:13].[CH2:14](OC(OCC)OCC)C>S(=O)(=O)(O)O.C(O)C>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[CH:5][C:4]2[S:13][CH:14]=[N:2][C:3]=2[CH:8]=1
Reactant: CCOC(OCC)OCC
Reactant: Nc1cc(C(F)(F)F)ccc1S
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CCO
Product: FC(F)(F)c1ccc2scnc2c1
Temperature: 180 °C
Yield: 84.2 %

Procedure:
A mixture of 5.1 g (22.2 mmol) of 2-amino-4-(trifluoromethyl) benzenethiol hydrochloride, 5.5 mL (33.3 mmol) of triethylorthoformate, and 2 drops of sulfuric acid was slowly heated to 180° C. over 1 h. The ethanol formed was allowed to escape via a short path distillation still. The reaction mixture was cooled to room temperature and the residue was dissolved in ethyl acetate, washed with saturated sodium bicarbonate, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography with ethyl acetate:hexane (1:9) to afford 3.8 g (86%) of 5-(trifluoromethyl)-1,3-benzothiazole as a solid. 1H-NMR (400 MHz, DMSO-d6): δ 9.58 (s, 1H), 8.44–8.42 (m, 2H), 7.80 (d, 1H).
Reaction SMILES: [N+](C1C=CC(N(C[C:15]2[C:16](=[O:42])[C:17]3[C:22]([C:23](=[O:41])[C:24]=2CCCCCCCCCCCCCCCC)=[CH:21][CH:20]=[CH:19][CH:18]=3)C(Cl)=O)=CC=1)([O-])=O.ClCCl>N1C=CC=CC=1.C(OCC)(=O)C>[CH:19]1[CH:20]=[CH:21][C:22]2[C:23](=[O:41])[CH:24]=[CH:15][C:16](=[O:42])[C:17]=2[CH:18]=1
Reactant: CCCCCCCCCCCCCCCCC1=C(CN(C(=O)Cl)c2ccc([N+](=O)[O-])cc2)C(=O)c2ccccc2C1=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C1C=CC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
N-4-Nitrophenyl-N-(3-hexadecyl-1,4-naphthoquinonylmethyl)carbamoyl chloride (6.72 g, 11.3 mmol) was dissolved in 10 ml dry pyridine, using a minimum quantity of dichloromethane to aid in dissolution. The dye (as the methylsulfamoyl form) ##STR8## (4.2 g, 4.72 mmol) was then added and the resulting solution was stirred at room temperature overnight. The mixture was then diluted with ethyl acetate, extracted with 2N hydrochloric acid, dried with anhydrous magnesium sulfate, and filtered. The ethyl acetate was removed in vacuo and the residue was dissolved in 20 percent ethyl acetate in toluene. This solution was passed through a short column of silica gel, eluting first with 20 percent ethyl acetate in toluene to remove some impurities, then with 30 percent ethyl acetate in toluene. This second elutant was concentrated under reduced pressure to yield the crude product (60 percent).
Reaction SMILES: CC1C(OC2C=C(CC(O)=O)C=C(C(F)(F)F)C=2)=NC=C([S:8](C2C=CC=CC=2)(=O)=O)C=1.[Cl:32][C:33]1[CH:34]=[C:35]([CH2:40][C:41]([OH:43])=[O:42])[CH:36]=[C:37](O)[CH:38]=1>>[Cl:32][C:33]1[CH:34]=[C:35]([CH2:40][C:41]([OH:43])=[O:42])[CH:36]=[C:37]([SH:8])[CH:38]=1
Reactant: O=C(O)Cc1cc(O)cc(Cl)c1
Reactant: Cc1cc(S(=O)(=O)c2ccccc2)cnc1Oc1cc(CC(=O)O)cc(C(F)(F)F)c1
Product: O=C(O)Cc1cc(S)cc(Cl)c1

Procedure:
The subtitle compound was prepared as described in example 58 steps (i) to (iii) but instead using the product from example 18 step (iv).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]([NH:14][C:15](=[O:17])[CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8](Br)[CH:7]=1.[P:19]([O-:26])([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22].CN1CCOCC1>C1(C)C=CC=CC=1.CC#N.[NH4+].[Cl-]>[CH3:1][O:2][C:3](=[O:18])[CH:4]([NH:14][C:15](=[O:17])[CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([P:19]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])=[O:26])[CH:7]=1
Reactant: CCOP([O-])OCC
Reactant: COC(=O)C(Cc1ccc(O)c(Br)c1)NC(C)=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC#N
Solvent: Cc1ccccc1
Solvent: CN1CCOCC1
Product: CCOP(=O)(OCC)c1cc(CC(NC(C)=O)C(=O)OC)ccc1O
Temperature: 100 °C
Reaction time: 48 h

Procedure:
To 2-Acetylamino-3-(3-bromo-4-hydroxy-phenyl)-propionic acid methyl ester (3 g, 9 mmol), diethyl phosphite (1.6 ml, 11 mmol) and 4-methylmorpholine (1.5 mL, 13.5 mmol) in toluene (10 mL) and MeCN (10 mL) was added Pd(Ph3)4 (0.5 g, 0.45 mmol). The mixture was allowed to stir for two days at 100° C. It was then diluted with saturated NH4Cl and extracted with EtOAc. The organic layer was dried over magnesium sulfate, concentrated , and chromatographed over silica gel (5% MeOH/CHCl3) to an oil. MS [M+H]+ 374 and [M−H]− 372.
Reaction SMILES: [N+:1]([CH:4]([CH:7]=O)[CH:5]=O)([O-:3])=[O:2].CS[C:11](=[NH:13])[NH2:12].[CH3:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>O>[CH3:14][N:15]1[CH2:20][CH2:19][N:18]([C:11]2[N:13]=[CH:7][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][N:12]=2)[CH2:17][CH2:16]1
Reactant: CSC(=N)N
Reactant: O=CC(C=O)[N+](=O)[O-]
Reactant: CN1CCNCC1
Solvent: O
Product: CN1CCN(c2ncc([N+](=O)[O-])cn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
2-Nitro-malonaldehyde (1.57 g, 10 mmol) is dissolved in water (15 mL), followed by addition of 2-methyl-isothiourea (1.56 g, 5.6 mmol) and N-methylpiperazine (1.92 mL, 17.3 mL). After stirring at room temperature overnight, it is filtered and washed with water and hexane to yield 1.38 g (62%) of 2-(4-methyl-piperazin-1-yl)-5-nitro-pyrimidine as a white solid. MS (ESI) m/z 224.3 (M+H)+1. [Heterocycles. 1977, 6(12), 1999-2004].
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[F:15][C:16]([F:30])([F:29])[O:17][C:18]1[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=1)[CH:21]=[CH:22][C:23](O)=O>>[CH2:12]([N:4]1[C:3](=[O:14])[C:2]2[NH:1][C:23](/[CH:22]=[CH:21]/[C:20]3[CH:26]=[CH:27][CH:28]=[C:18]([O:17][C:16]([F:15])([F:29])[F:30])[CH:19]=3)=[N:8][C:7]=2[N:6]([CH2:9][CH3:10])[C:5]1=[O:11])[CH3:13]
Reactant: O=C(O)C=Cc1cccc(OC(F)(F)F)c1
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Product: CCn1c(=O)c2[nH]c(/C=C/c3cccc(OC(F)(F)F)c3)nc2n(CC)c1=O
Yield: 59.8 %

Procedure:
Substantially the same procedure as in Reference Example 70 was repeated using 1.00 g (5.05 mmol) of 5,6-diamino-1,3-diethyluracil and 1.29 g (5.56 mmol) of 3-trifluoromethoxy-cinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane/water to give 1.19 g (yield 60%) of Compound 143 as white needles.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][C@H:3]1[CH2:16][O:17][CH3:18].[F:19][C:20]([F:35])([F:34])[C:21]1[CH:22]=[C:23]([CH:31]=[CH:32][CH:33]=1)[C:24]([NH:26][CH2:27][C:28](O)=[O:29])=[O:25].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(#N)C.C(OCC)(=O)C>[CH3:18][O:17][CH2:16][C@H:3]1[C@@H:2]([NH:1][C:28](=[O:29])[CH2:27][NH:26][C:24](=[O:25])[C:23]2[CH:31]=[CH:32][CH:33]=[C:21]([C:20]([F:19])([F:35])[F:34])[CH:22]=2)[CH2:7][CH2:6][C@@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])[CH2:4]1
Reactant: COC[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1N
Reactant: O=C(O)CNC(=O)c1cccc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1NC(=O)CNC(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2.75 h
Yield: 60.4 %

Procedure:
A solution of tert-butyl (1R,3R,4S)-4-amino-3-(methoxymethyl)cyclohexylcarbamate (45 mg, assumed 0.163 mmol) in acetonitrile (1.5 mL) was treated sequentially with 2-(3-(trifluoromethyl)benzamido)acetic acid (43 mg, 0.174 mmol, see PCT WO 0250019), diisopropylethylamine (61 μL, 0.348 mmol) and TBTU (62 mg, 0.192 mmol). The mixture was stirred at rt for 2.75 h, then was diluted with ethyl acetate, washed sequentially with 1.0 M aqueous HCl, saturated aqueous NaHCO3, water and brine, dried over Na2SO4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with 1:3 v/v hexane-ethyl acetate, to provide tert-butyl (1R,3R,4S)-3-(methoxymethyl)-4-(2-(3-(trifluoromethyl)benzamido)acetamido)cyclohexylcarbamate as a white solid (48 mg). MS found: (M+H)+=488.3.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].Br[CH:6]([C:12](=O)[CH:13]([CH3:15])[CH3:14])[C:7]([O:9][CH2:10][CH3:11])=[O:8]>C(O)C>[NH2:1][C:2]1[S:3][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:12]([CH:13]([CH3:15])[CH3:14])[N:4]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)C(Br)C(=O)C(C)C
Solvent: CCO
Product: CCOC(=O)c1sc(N)nc1C(C)C
Yield: 40.6 %

Procedure:
A solution of thiourea (1.1 g) in ethanol (10 mL) was brought to reflux. Ethyl 2-bromo-4-methyl-3-oxopentanoate (3.0 g) was then added and the reaction mixture refluxed further for 1 h. The reaction was complete (by TLC) and was concentrated in vacuum. Flash chromatography (100% DCM→90:10 DCM:MeOH) afforded the product (1.1 g).
Reaction SMILES: [C:1](Cl)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8](Cl)=[O:9].[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CCN(C(C)C)C(C)C.Cl.C1C[O:34]CC1>CCOC(C)=O>[CH2:13]([NH:20][C:1](=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:34])=[O:9])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C1CCOC1
Reactant: NCc1ccccc1
Reactant: O=C(Cl)CCCCCCC(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C(O)CCCCCCC(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of suberoyl chloride (1.00 mL, 5.55 mmol) in THF (40 mL) at 0° C. was added a solution of benzylamine (0.61 mL, 5.55 mmol) and DIEA (1.45 mL, 8.33 mmol) in THF (10 mL) dropwise. The mixture was allowed to warm to ambient temperature and stirred for 1 h. Then, HCl (10 mL, 1 N) was added and the mixture stirred for 0.5 h. The contents were diluted with EtOAc (30 mL) and the layers separated. The aqueous portion was extracted with EtOAc (3×10 mL), the organics combined, washed with brine (5 mL), and dried over MgSO4. Filtration and concentration under reduced pressure left 49 as an off-white solid. 1H-NMR (300 MHz, DMSO-d6) δ 11.98 (br s, 1H), 9.80 (t, 1H), 7.32 (m, 2H), 7.23 (m, 3H), 4.25 (d, 2H), 2.19 (t, 2H), 2.12 (t, 2H), 1.50 (m, 4H), 1.25 (m, 4H).