Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([F:10])[C:3]=1[CH2:11][C:12]([OH:14])=O.C(Cl)(=O)C(Cl)=O.[NH2:21][C:22]1[CH:63]=[CH:62][C:25]([C:26]([N:28]([CH2:54][C:55]([O:57]C(C)(C)C)=[O:56])[CH2:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3[N:40]=[C:39]([C:41]4[CH:46]=[CH:45][C:44]([C:47]5[CH:52]=[CH:51][C:50]([CH3:53])=[CH:49][CH:48]=5)=[CH:43][CH:42]=4)[O:38][N:37]=3)=[CH:32][CH:31]=2)=[O:27])=[CH:24][CH:23]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.CN(C=O)C>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([F:10])[C:3]=1[CH2:11][C:12]([NH:21][C:22]1[CH:63]=[CH:62][C:25]([C:26]([N:28]([CH2:54][C:55]([OH:57])=[O:56])[CH2:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3[N:40]=[C:39]([C:41]4[CH:46]=[CH:45][C:44]([C:47]5[CH:52]=[CH:51][C:50]([CH3:53])=[CH:49][CH:48]=5)=[CH:43][CH:42]=4)[O:38][N:37]=3)=[CH:32][CH:31]=2)=[O:27])=[CH:24][CH:23]=1)=[O:14]
Reactant: COc1ccc(F)c(CC(=O)O)c1F
Reactant: Cc1ccc(-c2ccc(-c3nc(-c4ccc(CN(CC(=O)OC(C)(C)C)C(=O)c5ccc(N)cc5)cc4)no3)cc2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(F)c(CC(=O)Nc2ccc(C(=O)N(CC(=O)O)Cc3ccc(-c4noc(-c5ccc(-c6ccc(C)cc6)cc5)n4)cc3)cc2)c1F
Reaction time: 2 h
Yield: 57 %

Procedure:
Prepared using General Procedures 7 and 8: To a stirred suspension of 2-(2,6-difluoro-3-methoxyphenyl)acetic acid in DCM (1.5 mL) and DMF (10 μL) was added oxalyl chloride (9.71 μL, 0.111 mmol). After 1 h a solution of tert-butyl 2-(4-amino-N-(4-(5-(4′-methyl-[1,1′-biphenyl]-4-yl)-1,2,4-oxadiazol-3-yl)benzyl)benzamido)acetate INT-59 (50 mg, 0.074 mmol) and TEA (25.8 μL, 0.185 mmol) in DCM (1 mL) was added. After 18 h TFA (1 mL) was added and reaction stirred for 2 h. The solvent was removed from the reaction mixture and the residue purified by preparative HPLC to afford 30 mg (57%) of 2-(4-(2-(2,6-difluoro-3-methoxyphenyl)acetamido)-N-(4-(5-(4′-methyl-[1,1′-biphenyl]-4-yl)-1,2,4-oxadiazol-3-yl)benzyl)benzamido)acetic acid 441. LCMS-ESI (m/z) calculated for C46H32F2N4O6: 702; found 703 [M+H]+, tR=8.75 min (Method 9). 1H NMR (400 MHz, DMSO) δ 12.79 (s, 1H), 10.26 (s, 1H), 8.31-8.22 (m, 2H), 8.12-8.06 (m, 2H), 8.02-7.92 (m, 2H), 7.74-7.69 (m, 2H), 7.69-7.56 (m, 2H), 7.54-7.45 (m, 1H), 7.42-7.29 (m, 4H), 7.23-7.09 (m, 2H), 6.80-6.66 (m, 1H), 4.76 (s, 1H), 4.67 (s, 1H), 4.04 (s, 1H), 3.97 (s, 1H), 2.92-2.81 (m, 5H), 2.38(s, 3H).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[OH2:11].[OH-:12].[Na+]>CC(C)=O>[CH:1]([C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:4][C:5](=[O:12])[CH3:6])=[CH:4][CH:3]=1)=[CH:1][C:2](=[O:11])[CH3:3]
Reactant: O
Reactant: [OH-]
Reactant: O=Cc1ccc(C=O)cc1
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(=O)C=Cc1ccc(C=CC(C)=O)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 76 %

Procedure:
Terephthalaldehyde (10 g) was dissolved in acetone (200 ml) and the solution was added dropwise with stirring into a mixture of water (2.5 1), ice (1.5 kg) and 10 percent aqueous sodium hydroxide solution (20 ml). The mixture was stirred at room temperature for 3 days and then the yellow solid was removed by filtration. The crude product was taken up into ethyl acetate (1 1) and dried over sodium sulfate. Removal of the drying agent by filtration and evaporation of the filtrate gave 1,4-bis(but-1-ene-3-one-1-yl)benzene (12.2 g, 76%) as a yellow solid, mp 155° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH:10]=O)[CH:3]=[CH:2]1.[CH3:12][NH2:13].[BH4-].[Na+].O>CO>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH2:10][NH:13][CH3:12])[CH:3]=[CH:2]1
Reactant: CN
Reactant: O=Cc1cccc2cc[nH]c12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CNCc1cccc2cc[nH]c12
Reaction time: 3 h
Yield: 88.9 %

Procedure:
Indole-7-carbaldehyde (500 mg, 3.4 mmol) was dissolved in anhydrous methanol (10 mL). Methylamine (5.1 mL of 2M solution in methanol, 9.55 mmol) was added and the reaction was stirred for 3 hr. The solution was concentrated to a yellow oil and then dissolved into anhydrous methanol (10 mL). Sodium borohydride (131 mg, 3.45 mmol) was added and the mixture was stirred overnight. Water (1 mL) was added and the solution was concentrated. Sodium hydroxide (5 mL, 1N) was added and the indole was extracted with ethyl acetate (3×20 mL), dried over MgSO4 and concentrated to afford the title compound as a yellow oil (484 mg, 92%). 1H NMR (300 MHz, CDCl3) δ 7.54 (s, 1H), 7.29-7.17 (m, 2H), 7.04 (d, J=3.1 Hz, 1H), 6.44 (d, J=3.1 Hz, 1H), 3.84 (s, 2H), 2.46 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[C:14]([CH3:16])[C:13]2[C:4](=[CH:5][C:6]3[C:11]([N:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1.C(N(CC)CC)C.[CH3:24][CH2:25][O:26][P:27](Cl)([O:29][CH2:30][CH3:31])=[O:28].C(OCC)(=O)C>C1(C)C=CC=CC=1>[P:27]([O:1][C:2]1[CH:15]=[C:14]([CH3:16])[C:13]2[C:4](=[CH:5][C:6]3[C:11]([N:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1)([O:29][CH2:30][CH3:31])([O:26][CH2:25][CH3:24])=[O:28].[P:27]([O-:29])([O-:28])([O:1][C:2]1[CH:15]=[C:14]([CH3:16])[C:13]2[C:4](=[CH:5][C:6]3[C:11]([N:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1)=[O:26]
Reactant: CCOP(=O)(Cl)OCC
Reactant: Cc1cc(O)cc2cc3ccccc3nc12
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOP(=O)(OCC)Oc1cc(C)c2nc3ccccc3cc2c1
Product: Cc1cc(OP(=O)([O-])[O-])cc2cc3ccccc3nc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Hydroxy-4-methylacridine (0.01 mole), triethylamine (0.01 mole) tetrahydrofuran (25 ml) and toluene (25 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The mixture is cooled to a temperature of about 0° C. and O,O-diethyl chloridophosphate (0.01 mole) dissolved in toluene (25 ml) is added with stirring over a period of about 30 minutes. After the addition is completed the reaction mixture is allowed to warm to room temperature and stirring is continued for a period of about 16 hours. After this time the reaction mixture is filtered to remove triethylamine hydrochloride. The filtrate is then washed with water, dried over anhydrous magnesium sulfate and stripped of solvents leaving a residue. This residue is subjected to flash chromatography using ethyl acetate as the eluant to yield the desired product O,O-diethyl (O-(4-methylacridin-2-yl) phosphate.
Reaction SMILES: Cl.[O:2]([NH2:4])[CH3:3].[C:5]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)(=O)[CH3:6].C(=O)([O-])[O-].[K+].[K+]>CO.O>[CH3:3][O:2][N:4]=[C:5]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)[CH3:6]
Reactant: CON
Reactant: CC(=O)c1cccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CON=C(C)c1cccnc1

Procedure:
6.85 g of methoxylamine hydrochloride is added to 10 g of 3-acetyl pyridine in 50 cm3 of methanol and the whole is heated to reflux for 3 hours. The solvent is eliminated under reduced pressure, the residue is taken up in water, alkanlized with potassium carbonate and extracted with ethyl acetate. After evaporating, 11 g of the expected product is recovered. (b.p.: 115°-118° C. under 18 mm Hg).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:23]=[CH:22][C:12]([C:13]([C:15]2[N:19]=[C:18]([CH2:20]Cl)[O:17][N:16]=2)=[O:14])=[CH:11][CH:10]=1.[C:24]1([SH:30])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CCOCC.CC(C)=O>[Cl:8][C:9]1[CH:23]=[CH:22][C:12]([C:13]([C:15]2[N:19]=[C:18]([CH2:20][S:30][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:17][N:16]=2)=[O:14])=[CH:11][CH:10]=1
Reactant: O=C(c1ccc(Cl)cc1)c1noc(CCl)n1
Reactant: Sc1ccccc1
Solvent: CCOCC
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: O=C(c1ccc(Cl)cc1)c1noc(CSc2ccccc2)n1
Reaction time: 1 h

Procedure:
A solution of 8.1 ml of triethylamine in 30 ml Et2O was added to a solution of 7.5 g of 3-(4-chlorobenzoyl)-5-chloromethyl-1,2,4-oxadiazole and 3.0 ml of thiophenol in 20 ml of acetone and 80 ml of Et2O at room temperature. This mixture was stirred for one hour. The reaction mixture was diluted with Et2O, washed with 5% HCl (2×) and brine, and dried over MgSO4. Concentration gave 9.0 g of an oil. Purification by high pressure liquid chromatography with 70% CH2CL2 /hexane as an eluent yielded 6.0 g (62%) of an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[CH2:4][CH2:5][CH2:6]Br.[CH2:9]([CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[CH2:10][CH2:11][CH3:12].C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl.CO>CC#N>[CH3:1][O:2][C:3](=[O:8])[CH2:4][CH2:5][CH2:6][N:16]1[CH2:17][CH2:18][CH:13]([CH2:9][CH2:10][CH2:11][CH3:12])[CH2:14][CH2:15]1
Reactant: COC(=O)CCCBr
Reactant: CCCCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Solvent: CO
Product: CCCCC1CCN(CCCC(=O)OC)CC1
Temperature: 25 °C
Yield: 74 %

Procedure:
To a 25 mL reaction flask was added 4-bromo-butyric acid methyl ester (2.04 g, 11.2 mmol), compound 3 (1.51 g, 10.8 mmol) and potassium carbonate (1.63 g, 11.8 mmol) suspended in CH3CN (10 mL). The reaction mixture was stirred over-night at rt followed by filtration and evaporation to dryness. Addition of H2O (50 mL) was followed by extraction with ethyl acetate (3×100 mL). The combined organic phases were dried (MgSO4) and evaporated to dryness, to produce 2.84 g of crude 23. The crude product was subjected to CC [eluent:CH2Cl2:MeOH (99:1)] to give pure 23 (1.93 g, 75%). LC-MS [M+H]+ 241 (cald. 241.2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[S:6][C:7]=1[N+:8]([O-])=O.[Cl-].[NH4+]>CCO.O.[Fe]>[NH2:8][C:7]1[S:6][C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: CCOC(=O)c1cc(OC)c([N+](=O)[O-])s1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc(OC)c(N)s1
Temperature: 50 °C

Procedure:
A mixture of ethyl 4-methoxy-5-nitrothiophene-2-carboxylate (Int. 68) (300 mg, 1.297 mmol) (prepared as described in Step 4 hereabove reported), and ammonium chloride (139 mg, 2.59 mmol) in EtOH/water=2/1 (18 ml) was heated at 50° C. until complete dissolution. Iron powder (435 mg, 7.78 mmol) was added, and the reaction was heated at 80° C. for 2 hours. The mixture was filtered and the filtrate was concentrated under vacuum; the residue was portioned between brine and EtOAc and the organic phase was dried over sodium sulfate. The solvent was removed to afford ethyl 5-amino-4-methoxythiophene-2-carboxylate (Int. 69) in a mixture with approximately 30% of corresponding methyl ester (261 mg, 1.297 mmol, MS/ESI+201.9 [MH]+). This intermediate was used as such in the following step.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][N:4]=[C:5]([NH2:24])[NH:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18](=[N:21][C:22]#[N:23])SC)[N:11]=1.[CH3:27][NH2:28]>C(O)C>[F:1][C:2]([F:26])([F:25])[CH2:3][N:4]=[C:5]([NH2:24])[NH:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([NH:21][C:22]#[N:23])=[N:28][CH3:27])[N:11]=1
Reactant: CN
Reactant: CSC(=NC#N)NCCCCCc1csc(NC(N)=NCC(F)(F)F)n1
Solvent: CCO
Product: CN=C(NC#N)NCCCCCc1csc(NC(N)=NCC(F)(F)F)n1
Reaction time: 8 h

Procedure:
To 2-[2-(2,2,2-trifluoroethyl)guanidino]-4-[5-(3-cyano-2-methylisothioureido)pentyl]thiazole (0.25 g.) in ethanol (1 ml.) was added ethanolic methylamine (33% w/v, 30 ml.). The mixture was allowed to stand overnight at room temperature and then evaporated to dryness to give 2-[2-(2,2,2-trifluoroethyl)guanidino]-4-[5-(3-cyano-2-methylguanidino)pentyl]thiazole. The n.m.r. spectrum in d6 dimethylsulphoxide containing tetramethylsilane as internal standard (δ=0) included the following resonances (δ):1.5 (multiplet, 6H); 2.7 (doublet, 3H); 3.1 (multiplet, 2H); 4.1 (multiplet, 2H); 6.4 (singlet, 1H).
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:28])([F:27])[O:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[O:21][C:20](=[O:23])[C:19]([C:24]([OH:26])=O)=[CH:18]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:53]1([S:59]([C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][C:63]=2[C:68]2[CH:73]=[CH:72][CH:71]=[C:70]([NH2:74])[CH:69]=2)(=[O:61])=[O:60])[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1>CN(C=O)C>[N:53]1([S:59]([C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][C:63]=2[C:68]2[CH:73]=[CH:72][CH:71]=[C:70]([NH:74][C:24]([C:19]3[C:20](=[O:23])[O:21][C:22]4[C:17]([CH:18]=3)=[CH:16][CH:15]=[CH:14][C:13]=4[O:12][C:11]([F:10])([F:28])[F:27])=[O:26])[CH:69]=2)(=[O:61])=[O:60])[CH2:54][CH2:55][O:56][CH2:57][CH2:58]1
Reactant: O=C(O)c1cc2cccc(OC(F)(F)F)c2oc1=O
Reactant: Nc1cccc(-c2ccccc2S(=O)(=O)N2CCOCC2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(-c2ccccc2S(=O)(=O)N2CCOCC2)c1)c1cc2cccc(OC(F)(F)F)c2oc1=O
Temperature: 25 °C
Yield: 51.8 %

Procedure:
DIEA (0.009 mL, 0.052 mmol) was added to 8-trifluoromethoxy-3-carboxy-coumarin (0.013 g, 0.047 mmol) and HATU (0.020 g, 0.052 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 2′-(Morpholine-4-sulfonyl)-biphenyl-3-ylamine (0.015 g, 0.047 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected were collected and the solvent removed under vacuum to give 0.014 g of product in 50% yield: LCMS (ESI) m/z 591 (MH+).
Reaction SMILES: [S:1]1[C:5]2[C:6]([C:10](Cl)=[O:11])=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[C:13]1([C:19]2([CH2:22][OH:23])[CH2:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[S:1]1[C:5]2[C:6]([C:10]([O:23][CH2:22][C:19]3([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH2:20][CH2:21]3)=[O:11])=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: OCC1(c2ccccc2)CC1
Reactant: O=C(Cl)c1cccc2nnsc12
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCC1(c2ccccc2)CC1)c1cccc2nnsc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 6.7 g of benzo-1,2,3-thiadiazole-7-carboxylic acid chloride in 33 ml of dichloromethane is added dropwise at a maximum of 15° C., with cooling, to a solution of 5.0 g of 1-phenylcyclopropanemethanol, 6.1 ml of triethylamine and 200 mg of 4-dimethylaminopyridine in 50 ml of dichloromethane. The mixture is stirred overnight at room temperature until the reaction is complete, dichloromethane and ice-water are added, the aqueous phase is extracted with dichloromethane, and the organic phase is washed with water and NaCl solution, dried over Na2SO4 and concentrated by evaporation. The residue is purified on silica gel (hexane-ethyl acetate 1:1) and the product obtained is recrystallised from diethyl ether/hexane. 7.5 g of crystals having a melting point of 55°-57° C. are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][C:11](Br)=[C:12](OC)[CH:13]=2)[N:8]([CH:18]2[CH2:20][CH2:19]2)[C:7]=1[CH3:21])=[O:5])[CH3:2].[CH3:22][C:23]1[CH:24]=[C:25]([OH:38])[CH:26]=[CH:27][C:28]=1B1OC(C)(C)C(C)(C)O1.[C:39](=O)([O-])[O-].[Na+].[Na+].Cl>C(O)C.CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([C:28]3[CH:27]=[CH:26][C:25]([OH:38])=[CH:24][C:23]=3[CH3:22])=[C:12]([CH3:39])[CH:13]=2)[N:8]([CH:18]2[CH2:20][CH2:19]2)[C:7]=1[CH3:21])=[O:5])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(O)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: CCOC(=O)c1c(C)n(C2CC2)c2cc(Br)c(OC)cc12
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)n(C2CC2)c2cc(-c3ccc(O)cc3C)c(C)cc12
Temperature: 85 °C
Yield: 50.9 %

Procedure:
A mixture of 6-bromo-1-cyclopropyl-5-methoxy-2-methyl-1H-indole-3-carboxylic acid ethyl ester (355 mg, 1.01 mmol), 3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (472 mg, 2.20 mmol), tetrakis(triphenylphosphene)palladium (87 mg, 0.075 mmol), aqueous sodium carbonate (2 M, 3.0 mL, 6.00 mmol), DMF (5.9 mL) and ethanol (5.9 mL) is heated under nitrogen at 85° C. for 4 h. The mixture is acidified with 1 N HCl and extracted with ethyl acetate. The ethyl acetate layers are combined and washed with water and brine and dried over MgSO4. The residue is purified via flash chromatography eluting with THF-heptane (25→40%) to afford the title compound (187 mg, 49%) as a white solid. ES/MS m/e 380.0 (M+1).
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[C:10]([O:14][C:15](=[O:29])[NH:16][C@H:17]([C:22]([N:24]1[CH2:27][CH:26](O)[CH2:25]1)=[O:23])[C@@H:18]([CH3:21])[CH2:19][CH3:20])([CH3:13])([CH3:12])[CH3:11]>ClCCl.C(OCC)(=O)C>[C:10]([O:14][C:15](=[O:29])[NH:16][C@H:17]([C:22]([N:24]1[CH2:27][CH:26]([F:7])[CH2:25]1)=[O:23])[C@@H:18]([CH3:21])[CH2:19][CH3:20])([CH3:13])([CH3:12])[CH3:11]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC(O)C1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC(F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.8 %

Procedure:
To a cooled (−78° C.) solution of diethylaminosulfur trifluoride (0.46 mL, 3.5 mmol) in dichloromethane (6 mL), was added dropwise a solution of [(1S,2S)-1-(3-hydroxy-azetidine-1-carbonyl)-2-methyl-butyl]-carbamic acid tert-butyl ester (1.0 g, 3.5 mmol) in dichloromethane (4 mL). The mixture was warmed to room temperature, stirred overnight, then diluted with ethyl acetate and poured into ice/water. The layers were separated, and the organic phase washed with water and brine, dried over magnesium sulfate and concentrated. The product was purified by flash-chromatography (ethyl acetate) and isolated as an oil (250 mg, 25%).
Reaction SMILES: [C:1]([Cl:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Fe](Cl)(Cl)Cl.C1C=CC=CC=1>[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:9]
Reactant: O=C(Cl)c1ccccc1
Agent: Cl[Fe](Cl)Cl
Solvent: c1ccccc1
Product: Cl
Product: O=C(c1ccccc1)c1ccccc1

Procedure:
In the presence of catalytic amounts of iron (III) chloride, and under the appropriate conditions of temperature and pressure, benzoyl chloride and benzene react to form benzophenone and hydrochloric acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][CH:9]2[C:11](N2C3CC4C(C)(C)C3(CC4)CS2(=O)=O)=[O:12])=[CH:4][CH:3]=1.[OH2:27].[OH-].[Li+].O>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[CH2:10][C@H:9]2[C:11]([OH:12])=[O:27])=[CH:6][CH:7]=1
Reactant: O
Reactant: CC1(C)C2CCC13CS(=O)(=O)N(C(=O)C1CC1c1ccc(F)cc1)C3C2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)[C@@H]1C[C@H]1c1ccc(F)cc1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
A suspension of the product from step b) (3.74 g) and lithium hydroxide monohydrate (4.11 g) in tetrahydrofuran (100 ml)/water (3 ml) was stirred at 50° C. for 24 hours. The reaction mixture was concentrated in vacuo, and the residue dissolved in water (100 ml), acidified with 2N HCl and extracted into dichloromethane (3×75 ml). The organics were dried and concentrated. Purification (SiO2, isohexane:diethylether 2:1 as eluant) gave the subtitle compound as a colourless solid (1.78 g).
Reaction SMILES: Br[CH:2]([CH3:13])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12])=O.[CH:14]1([CH:17]([NH:24][C:25]([NH2:27])=[S:26])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:16][CH2:15]1.[H-].[Na+].Br[CH2:31][CH2:32][O:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][O:35]1>CN(C)C=O.C(OCC)(=O)C.O>[Cl:12][C:6]1[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]=1[C:3]1[N:27]=[C:25]([NH:24][CH:17]([CH:14]2[CH2:16][CH2:15]2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[S:26][C:2]=1[CH3:13].[Cl:12][C:6]1[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]=1[C:3]1[N:27]=[C:25]([N:24]([CH:17]([CH:14]2[CH2:15][CH2:16]2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:31][CH2:32][O:33][CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][O:35]2)[S:26][C:2]=1[CH3:13]
Reactant: CC(Br)C(=O)c1ccc(Cl)cc1Cl
Reactant: NC(=S)NC(c1ccccc1)C1CC1
Reactant: BrCCOC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1sc(N(CCOC2CCCCO2)C(c2ccccc2)C2CC2)nc1-c1ccc(Cl)cc1Cl
Product: Cc1sc(NC(c2ccccc2)C2CC2)nc1-c1ccc(Cl)cc1Cl
Temperature: 5 °C
Reaction time: 1 h

Procedure:
4-(2,4-Dichlorophenyl)-5-methyl-2-[N-(α-cyclopropylbenzyl)amino]thiazole was prepared from 2-bromo-1-(2,4-dichlorophenyl)-1-propanone (Compound 1) and N-(α-cyclopropylbenzyl)thiourea (Compound 74) according to the process described in Example 1, Step A. 4 g of this compound is dissolved in 60 ml of anhydrous dimethylformamide and the solution is cooled to 5° C., followed by portionwise addition of 493 mg of sodium hydride. After stirring for one hour at room temperature, 3.14 g of 1-bromo-2-(2- tetrahydropyranyloxy) ethane dissolved in 30 ml of dimethylformamide are added dropwise thereto. The mixture is left stirring for 3 hours. After addition of water and extraction with ethyl acetate, the organic phase is washed with water, dried over anhydrous sodium sulphate and evaporated to dryness. The residue is purified on a column of silica, using a mixture of cyclohexane and ethyl acetate (1:1 v/v) as eluent. The expected product is thus obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[OH:12].O(CC)[C:14]([S-])=[S:15].[K+].C(O)C>O>[SH:15][C:14]1[O:12][C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=2[N:1]=1
Reactant: Nc1cc(C(F)(F)F)ccc1O
Reactant: CCOC(=S)[S-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: FC(F)(F)c1ccc2oc(S)nc2c1
Yield: 31.9 %

Procedure:
A mixture of 2-amino-4-trifluoromethylphenol (8.85 g, 0.05 mole), potassium ethyl xanthate (8.8 g, 0.055 mole) and ethanol was heated under gentle reflux for a period of 24 hours. After cooling, the mixture was filtered and the filtrate was distilled under reduced pressure to remove the solvent and to give an orange solid. The solid was dissolved in water, the aqueous solution extracted with ethyl acetate and the organic phase evaporated to give a red wolid. The solid was triturated with boiling petroleum ether (bp 100°-120° C.) and the insoluble material collected by filtration to give the title compound (3.5 g).
Reaction SMILES: [Br:1][CH2:2][CH2:3]Br.[N+:5]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)([O-:7])=[O:6].[OH-].[Na+]>C(O)C>[N+:5]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:3][CH2:2][Br:1])=[CH:10][CH:9]=1)([O-:7])=[O:6]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: BrCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=[N+]([O-])c1ccc(OCCBr)cc1
Yield: 50.8 %

Procedure:
1,2-Dibromoethane (24.4 g, 0.13 mol) and 4-nitrophenol (6 g, 0.044 mol) were dissolved in ethyl alcohol (60 ml) and sodium hydroxide (2 g) was added to the solution. The reaction mixture was refluxed for 24 h and thereafter concentrated under vacuum, followed by column chromatography using a 3:1 solvent system of n-hexane and ethyl acetate as an eluent to yield the end compound 1-(4-nitrophenoxy) -2-bromoethane (5.5 g).