Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][CH2:11][CH2:12][OH:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>COCCOC>[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20]([O:13][CH2:12][CH2:11][O:10][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1ccc(S(=O)(=O)OCCOCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.3 %

Procedure:
An example is disclosed in U.S. patent application Ser. No. 269,205. To a slurry of sodium hydride (0.4 g,17 mmol) in 20 ml ethylene glycol dimethyl ether cooled with an ice bath under an atmosphere of nitrogen, a solution of 2-benzyloxyethanol (2.1 ml, 15 mmol) and p-toluene sulfonyl chloride (2.9 g,15 mmol) in ethylene glycol dimethyl ether was added dropwise. When the addition was complete, the ice bath was removed and the solution stirred at room temperature for 18 hours. After dilution with diethyl ether, the resulting slurry was filtered through anhydrous magnesium sulfate and concentrated under vacuum to yield 3.6 g of crude 2-benzyloxyethyl p-toluenesulfonate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].[Br:13][C:14]1[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[S:22](Cl)(=[O:24])=[O:23])=[CH:16][CH:15]=1>>[Br:13][C:14]1[CH:15]=[CH:16][C:17](/[CH:20]=[CH:21]/[S:22]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=2[S:9]([NH2:12])(=[O:10])=[O:11])(=[O:24])=[O:23])=[CH:18][CH:19]=1
Reactant: O=S(=O)(Cl)/C=C/c1ccc(Br)cc1
Reactant: Cc1ccc(N)c(S(N)(=O)=O)c1
Product: Cc1ccc(NS(=O)(=O)/C=C/c2ccc(Br)cc2)c(S(N)(=O)=O)c1
Yield: 96 %

Procedure:
The title compound was synthesized as described for Example 178 in 96% yield, starting from 2-amino-5-methylbenzenesulfonamide and (E)-2-(4-bromophenyl)ethenesulfonyl chloride (US20040186134 A1). Purification by column chromatography using a gradient of 10-50% ethyl acetate in heptane as the eluent.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7](=[O:23])[CH:8]([NH:13][C:14](=O)[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.O>CN(C)C=O>[Cl:1][C:2]1[S:6][C:5]([C:7]2[O:23][C:14]([C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)=[N:13][C:8]=2[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1
Reactant: COC(=O)C(NC(=O)c1ccc(F)cc1)C(=O)c1ccc(Cl)s1
Solvent: CN(C)C=O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1nc(-c2ccc(F)cc2)oc1-c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 72 h
Yield: 40.7 %

Procedure:
To a solution of methyl 3-(5-chlorothiophen-2-yl)-2-(4-fluorobenzoylamino)-3-oxopropionate (7.25 g) in N,N-dimethyl-formamide (80 ml) was added dropwise phosphorus oxychloride (5.7 ml) under ice-cooling, and the mixture was then stirred at room temperature for 3 days. After cooling, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (solvent: hexane:ethyl acetate=100:1), and then, triturated with diethyl ether-hexane to obtain methyl 5-(5-chloro-thiophen-2-yl)-2-(4-fluorophenyl)oxazol-4-carboxylate (2.8 g) as colorless powder.
Reaction SMILES: S(=O)(=O)(O)O.Cl.[CH2:7]([N:14]1[CH2:19][CH2:18][C:17]([C:21]#N)([OH:20])[CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(=O)([O-])[OH:24].[Na+].[CH2:28]([OH:30])[CH3:29]>>[CH2:7]([N:14]1[CH2:19][CH2:18][C:17]([C:21]([O:30][CH2:28][CH3:29])=[O:24])([OH:20])[CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: N#CC1(O)CCN(Cc2ccccc2)CC1
Reactant: O=C([O-])O
Reactant: CCO
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)C1(O)CCN(Cc2ccccc2)CC1
Temperature: 130 °C

Procedure:
Conc. sulfuric acid (12 ml) was added to an ethanol solution (50 ml) of 1-benzyl-4-cyano-4-hydroxypiperidine hydrochloride (10 g) and the resulting mixture was heated at 130° C. for 24 hours in a sealed tube. After concentration of the reaction mixture, ice water was added to the concentrate. The resulting mixture was added with an aqueous solution of sodium hydrogencarbonate. After adjusting the thus-obtained solution to pH 7.0, it was extracted with diethyl ether. The extract was washed with brine and then added with anhydrous sodium sulfate to dry the same. The solvent was distilled off to obtain the intended product (9.7 g).
Reaction SMILES: Br[C:2]1[O:6][CH:5]=[C:4]([C:7]([OH:9])=[O:8])[CH:3]=1.[CH2:10]([OH:28])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]/[CH:18]=[CH:19]\[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].[H-].[Na+].CC1C=CC(C)=CC=1>O.C(O)(=O)C>[CH2:10]([O:28][C:2]1[O:6][CH:5]=[C:4]([C:7]([OH:9])=[O:8])[CH:3]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]/[CH:18]=[CH:19]\[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: O=C(O)c1coc(Br)c1
Reactant: CCCCCCCC/C=C\CCCCCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccc(C)cc1
Solvent: CC(=O)O
Solvent: O
Product: CCCCCCCC/C=C\CCCCCCCCOc1cc(C(=O)O)co1
Reaction time: 48 h

Procedure:
A mixture of 57.2 g (0.300 mole) of 5-bromo-3-furoic acid, 121.0 g (0.45 mole) of cis-9-octadecenol, 18.0 g (0.750 mole) of sodium hydride and 2 liters of p-xylene are heated to reflux with stirring for 48 hours. The mixture is allowed to cool, then is acidified with acetic acid, and diluted with 2 liters of water. The organic layer is separated, dried, evaporated to dryness, and the residue is recrystallized from hexane to give 5-(cis-9-octadecen-1-yloxy)-3-furoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:15]C)=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][C:13]=2N)[CH:7]=1.C1COCC1.O>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:15][C:13]3[CH:12]=[CH:11][N:10]=[CH:9][C:8]=3[C:6]=2[CH:7]=1
Reactant: COc1ccc(Cl)cc1-c1cnccc1N
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: Clc1ccc2oc3ccncc3c2c1
Temperature: 25 °C

Procedure:
3-(5-chloro-2-methoxyphenyl)pyridin-4-amine (2 g, 8.5 mmol) was dissolved in 25 mL of acetic acid and 10 mL of THF at −10° C. To the solution t-butyl nitrile (2 ml, 17 mmol) was dropwisely added. The mixture was warmed to room temperature overnight. Water was added to the reaction mixture and was extracted by dichloromethane, the organic layer was then dried by MgSO4 and concentrated. The residue was then purified by column chromatography using THF:hexane (1:3, v/v) as the eluent. 0.8 g (46%) of product was collected as the product.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:23][C@@H:24]([C:37]1[N:41]2[C:42]3[S:56][C:55]([CH2:57][CH3:58])=[CH:54][C:43]=3[C:44]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=3[Cl:53])=[N:45][CH2:46][C:40]2=[N:39][N:38]=1)[CH2:25][CH2:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28].[Cl:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=1[N:66]=[C:67]=[O:68].C(N(CC)CC)C.O>CN(C=O)C>[Cl:53][C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=1[C:44]1[C:43]2[CH:54]=[C:55]([CH2:57][CH3:58])[S:56][C:42]=2[N:41]2[C:37]([C@H:24]([NH:23][C:67]([NH:66][C:61]3[CH:62]=[CH:63][CH:64]=[CH:65][C:60]=3[Cl:59])=[O:68])[CH2:25][CH2:26][C:27]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[O:28])=[N:38][N:39]=[C:40]2[CH2:46][N:45]=1
Reactant: O=C=Nc1ccccc1Cl
Reactant: CCc1cc2c(s1)-n1c(nnc1[C@H](N)CCC(=O)OCc1ccccc1)CN=C2c1ccccc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCc1cc2c(s1)-n1c(nnc1[C@@H](CCC(=O)OCc1ccccc1)NC(=O)Nc1ccccc1Cl)CN=C2c1ccccc1Cl

Procedure:
Benzyl (R)-4-amino-4-(4-(2-chlorophenyl)-2-ethyl-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepin-9-yl)butanoate di-p-toluenesulfonate (3.0 g) and 2-chlorophenyl isocyanate (0.46 ml) were dissolved in DMF (30 ml). Triethylamine (1.46 ml) was added and the mixture was stirred and water was added to the reaction mixture. The mixture was washed with an aqueous citric acid solution, saturated brine, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography using ethyl acetate as an eluent to give 2.02 g of benzyl (R)-4-(4-(2-chlorophenyl)-2-ethyl-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepin-9-yl)-4-(3-(2-chlorophenyl)ureido)butanoate.
Reaction SMILES: C[NH:2][CH2:3][C:4]([OH:6])=[O:5].[C:7]([C:10]1[C:11](=[O:20])[O:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)([OH:9])=O.[CH2:21](Cl)Cl>CN(C1C=CN=CC=1)C>[CH3:21][O:6][C:4](=[O:5])[CH2:3][NH:2][C:7]([C:10]1[C:11](=[O:20])[O:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:9]
Reactant: CNCC(=O)O
Reactant: ClCCl
Reactant: O=C(O)c1cc2ccccc2oc1=O
Agent: CN(C)c1ccncc1
Product: COC(=O)CNC(=O)c1cc2ccccc2oc1=O
Reaction time: 0.5 h

Procedure:
To a round bottom flask containing methyl-glycine (89 mg, 1.00 mmol), 3-carboxy coumarine, anh. DCM (25 ml), under Ar, N′-(3 Dimethylaminopropil)-N-ethyl-carbodiimid hydrochlorid (EDC) (479 mg, 2.50 mmol) and DMAP (489 mg, 4.00 mmol) were added at room temperature. The resulting mixture was stirred for 1 h 30 min (total conversion was observed by TLC). Then, DCM (20 ml) was added and the solution was washed successively with aq. NaHCO3 (10 ml, sat) and brine (10 ml). The organic phase was dried (Na2SO4), filtered and concentrated. The resulting orange solid obtained was purified by flash LC (silica gel, grad hex:EtOAc 1:1 to 2:1) to give the title compound (445 mg, quant) as a colourless oil. Rf=0.08 (Hex/EtOAc 1:1).
Reaction SMILES: C1([C:7]([C:11]2[N:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:8][CH:9]=O)C=CC=CC=1.[CH3:17][C:18]1[CH:30]=[CH:29][C:21]([CH2:22][N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:20][CH:19]=1.[C:31]([OH:36])(=[O:35])[C:32]([OH:34])=[O:33]>O1CCCC1.C(OCC)(=O)C.C(C(C)=O)C>[C:31]([OH:36])(=[O:35])[C:32]([OH:34])=[O:33].[CH3:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:22][N:23]2[CH2:28][CH2:27][N:26]([C:14]3[CH2:15][N:16]([C:32]4[CH:31]=[CH:9][CH:8]=[CH:7][CH:11]=4)[C:11]4[N:12]([CH:9]=[CH:8][CH:7]=4)[CH:13]=3)[CH2:25][CH2:24]2)=[CH:29][CH:30]=1
Reactant: O=CC=C(c1ccccc1)c1ncccn1
Reactant: Cc1ccc(CN2CCNCC2)cc1
Agent: O=C(O)C(=O)O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCC(C)=O
Product: Cc1ccc(CN2CCN(C3=Cn4cccc4N(c4ccccc4)C3)CC2)cc1
Temperature: 65 °C
Yield: 94.9 %

Procedure:
A solution of 3-phenyl-3-(2-pyrimidinyl)propenal (1.25 g) in tetrahydrofuran (125 cc) is added to 4-(4-methylbenzyl)piperazine (11.2 g). The solution is stirred and heated to a temperature in the region of 65° C. for 3 hours. After being coiled to a temperature in the region of 20° C., the reaction mixture is concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. The residue obtained is dissolved in ethyl acetate (10 cc) and the solution obtained is poured onto silica (25 g) contained in a column 1.5 cm in diameter. Elution is performed with a mixture (750 cc) of ethyl acetate and cyclohexane (50:50 by volume); the corresponding eluates are discarded. Elution is then performed with the same mixture (300 cc) and the corresponding eluate is concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. The oil obtained is dissolved in methyl ethyl ketone (20 cc). Oxalic acid (120 mg) dissolved in methyl ethyl ketone (20 cc) is added and the mixture is stirred for approximately 15 minutes at a temperature in the region of 20° C. The precipitate formed is separated by filtration and then recrystallized in boiling isopropyl alcohol (50 cc). 3-[4-(4-Methylbenzyl)-1-piperazinyl]-1-phenylpyrrolo[1,2-a]pyrimidine oxalate (300 mg), m.p. 205° C., is thereby obtained.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[N:4][N:5]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:9][C:8](Cl)=[N:7][C:6]=12.C(=O)([O-])[O-].[K+].[K+].O.[NH2:32][NH2:33].[CH2:34](O)[CH3:35]>>[Br:1][C:2]1[C:3]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[N:4][N:5]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:9][C:8]([NH:32][N:33]=[CH:23][C:18]3[CH:3]=[CH:2][CH:6]=[C:34]([CH3:35])[CH:19]=3)=[N:7][C:6]=12
Reactant: Cc1ccc(-c2nn3c(N4CCOCC4)cc(Cl)nc3c2Br)cc1
Reactant: NN
Reactant: CCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1ccc(-c2nn3c(N4CCOCC4)cc(NN=Cc4cccc(C)c4)nc3c2Br)cc1
Temperature: 150 °C
Reaction time: 0.17 h

Procedure:
There was suspended, in ethanol (2 mL), 3-bromo-5-chloro-2-(4-methyl-phenyl)-7-morpholin-4-yl-pyrazolo[1,5-a]-pyrimidine (21.7 mg, 0.0532 mM) and then potassium carbonate (9.2 mg, 0.067 mM) and hydrazine monohydrate (13.0 μL, 0.268 mM) were added to the resulting suspension. This suspension was stirred at 150° C. for 10 minutes under the irradiation with microwaves, diluted with a saturated aqueous common salt solution and then extracted with ethyl acetate. The extracts thus obtained were combined, dried over anhydrous sodium sulfate and the solvent was then distilled off. The resulting residue was suspended in ethanol (2 mL), then acetic acid (5.0 μL, 0.087 mM) and 3-methyl-benzaldehyde (13.0 μL, 0.106 mM) were added to the suspension and the resulting mixture was stirred at room temperature for 2 hours. This reaction mixture was filtered and then the resulting solid was purified by the NH-silica gel column chromatography (methylene chloride) to thus give the title compound (6.3 mg, overall yield of these two steps: 23%).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[C:13]1[CH:14]=[CH:15][C:16]2[O:20][C:19]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[C:18]([C:28](=[O:31])[NH:29][CH3:30])[C:17]=2[CH:32]=1)(=O)=O.[NH:35]1[C:43]2[C:38](=[C:39](B(O)O)[CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36]1.O1CCOCC1>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.O>[F:27][C:24]1[CH:23]=[CH:22][C:21]([C:19]2[O:20][C:16]3[CH:15]=[CH:14][C:13]([C:39]4[CH:40]=[CH:41][CH:42]=[C:43]5[C:38]=4[CH:37]=[CH:36][NH:35]5)=[CH:32][C:17]=3[C:18]=2[C:28]([NH:29][CH3:30])=[O:31])=[CH:26][CH:25]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(OS(=O)(=O)C(F)(F)F)cc12
Reactant: OB(O)c1cccc2[nH]ccc12
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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc4[nH]ccc34)cc12
Temperature: 90 °C
Yield: 47.8 %

Procedure:
Cesium carbonate (176 mg, 0.539 mmol) was added to Pd(Ph3P)4 (20.77 mg, 0.018 mmol), 2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl trifluoromethanesulfonate (150 mg, 0.359 mmol), 1H-indol-4-ylboronic acid (87 mg, 0.539 mmol). Dioxane (3 mL) and water (600 μL) was added at rt. The reaction was degassed 3× and then heated to 90° C. overnight. It was allowed to cool. The mixture was diluted with ethyl acetate and washed with sat NaHCO3, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated and purified on silica gel (Biotage, EtOAc/hexanes gradient, fraction collection at λ=254 nm) to give the titled compound (66 mg, 46%). 1H NMR (500 MHz, DMSO-d6) δ ppm 11.28 (1H, br. s.), 8.48-8.57 (1H, m), 7.98-8.07 (2H, m), 7.86 (1H, br. s.), 7.79 (1H, d, J=8.24 Hz), 7.69 (1H, d, J=7.93 Hz), 7.37-7.47 (4H, m), 7.21 (1H, t, J=7.63 Hz), 7.14 (1H, d, J=7.02 Hz), 6.60 (1H, br. s.), 2.84 (3H, d, J=4.27 Hz). LC-MS retention time: 1.53 min; m/z (MH+): 385. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode. Additional HPLC method: Solvent A=5% CH3CN/95% H2O/0.1% TFA, Solvent B=95% CH3CN/5% H2O/0.1% TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 μm, Rt=13.46 min, purity=99%; Column: Waters Xbridge Phenyl column 4.6×150 mm, 3.5 μm, Rt=12.27 min, purity=97%.
Reaction SMILES: [K].[OH:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][OH:7].Br[C:12]1[CH:13]=[C:14]([O:18][CH3:19])[CH:15]=[CH:16][CH:17]=1>CN1C(=O)CCC1.O.[Cu]Cl>[CH3:19][O:18][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][OH:7]
Reactant: COc1cccc(Br)c1
Reactant: OCc1cccc(O)c1
Agent: Cl[Cu]
Agent: [K]
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1cccc(Oc2cccc(CO)c2)c1
Temperature: 170 °C
Yield: 52.1 %

Procedure:
To a solution of the potassium salt of 3-hydroxybenzyl alcohol (8.1 g, 50 mmol) in N-methyl pyrolidinone (20 ml) were added 3-bromoanisole (11.22 g, 60 mmol), copper (I) chloride (0.1 g, 1 mmol) and p-hydroxyquinoline (0.1 g, 1 mmol) and the reaction was heated to 170° C. for fifty hours. The reaction was cooled to room temperature, diluted with water (150 ml) and extracted with ether (5×50 ml). The combined extracts were dried (MgSO4) and evaporated. The residue was purified by flash chromatography (eluting with 10% ethyl acetate/60°-80° petrol) to afford 3-(3-methoxyphenoxy)benzyl alcohol as a pale oil 6.0 g (52%); a (CDCl3) 3.80 (3H, s, OCH3), 4.64 (2H, s, CH2OH), 6.54-6.70 (3H, m, ArH), 6.88-7.10 (3H, m, ArH), 7.18-7.36 (2H, m, ArH).
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([CH2:8][N:9]2[CH:13]=[N:12][N:11]=[N:10]2)=[CH:6][CH:5]=1)([O-])=O.C(O)C>[C].[Pd].O1CCCC1>[NH2:1][C:4]1[CH:15]=[CH:14][C:7]([CH2:8][N:9]2[CH:13]=[N:12][N:11]=[N:10]2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Cn2cnnn2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1ccc(Cn2cnnn2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 71 %

Procedure:
A mixture of 1-(4-nitrobenzyl)-1H-tetrazole (5 g), 10% palladium carbon (500 mg), ethanol (100 ml) and tetrahydrofuran (100 ml) was stirred under a hydrogen atmosphere at room temperature for 4 hrs. Palladium carbon was removed from the reaction mixture by filtration, and the filtrate was concentrated. Recrystallization of the residue from ethyl acetate-hexane gave 1-(4-aminobenzyl)-1H-tetrazole (3.03 g, 71%) as yellow prism crystals. melting point: 138-140° C.
Reaction SMILES: [C:1]1([C@@H:7]2[NH:11][C@H:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19]([O:23][C:24]([NH:26][CH2:27][C:28](O)=[O:29])=[O:25])([CH3:22])([CH3:21])[CH3:20].C1(N=C=NC2CCCCC2)CCCCC1.CO>C(#N)C>[C:19]([O:23][C:24]([NH:26][CH2:27][C:28]([N:11]1[C@@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9][C@H:10]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:29])=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)[C@@H]1CC[C@H](c2ccccc2)N1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CO
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCC(=O)N1[C@@H](c2ccccc2)CC[C@H]1C(=O)OC(C)(C)C
Yield: 80.3 %

Procedure:
tert-Butyl (2S,5R)-1-(2-tert-butoxycarbonylaminoacetyl)-5-phenylprolinate may be obtained as per Example 2 B, but starting from a solution containing 8 g of tert-butyl (2S,5R)-5-phenylprolinate, 5.7 g of 2-tert-butoxycarbonylaminoacetic acid and 6.7 g of N,N'-dicyclohexylcarbodiimide in 75 cm3 of anhydrous acetonitrile. 10.5 g of tert-butyl (2S,5R)-1-(2-tert-butoxycarbonylaminoacetyl)-5-phenylprolinate, melting at 136° C., [α]D20 +19.1°±0.8° (C=0.64; methanol), are thus obtained.
Reaction SMILES: [C:1]([NH2:4])(=[S:3])[CH3:2].Cl[CH:6]([C:12]([C:14]([F:17])([F:16])[F:15])=O)[C:7]([O:9]CC)=[O:8].C(N(CC)CC)C.[OH-].[Na+].Cl>O.C(#N)C>[CH3:2][C:1]1[S:3][C:6]([C:7]([OH:9])=[O:8])=[C:12]([C:14]([F:17])([F:16])[F:15])[N:4]=1
Reactant: CCOC(=O)C(Cl)C(=O)C(F)(F)F
Reactant: CC(N)=S
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1nc(C(F)(F)F)c(C(=O)O)s1
Temperature: 25 °C
Reaction time: 2.3 h
Yield: 75.4 %

Procedure:
To a 22 L flask fitted with a mechanical stirrer, thermocouple, and a reflux condenser, was charged thioacetamide (500.6 g, 6.66 mol) and acetonitrile (4 L). This resulted in an endothermic dissolution. To this solution was added ethyl 2-chloro-4,4,4-trifluoroacetoacetate (1105 g, 5.06 mol) over a period of 40 minutes. A slight exotherm occurred which raised the temperature to 55.820 C. The reaction mixture was stirred for 2.3 hours at room temperature during which time a yellow solid precipitated. Then triethylamine (1380 g, 13.64 mol) was added slowly. The reaction temperature rose to about 52° C. The contents were gently refluxed for one hour (internal temperature 75.8° C). After cooling to 46° C., a 40% sodium hydroxide solution (prepared from 1304 g 50% NaOH and 326 mL water, 16.3 mol) was added over 10 minutes. An exotherm to 53.6° C. was noted. The mixture was placed under a vacuum of 95 mm and the solvent distilled from the reaction until only water (of saponification) is present in the distillate. To the remaining reaction mixture was added 2 L water and 1.5 kg ice. Then concentrated HCl (1500 mL, 18 mol) was added over a 15 minute period to bring the pH to less than 2. Another 2 L water and 2 kg ice were added, and the product was filtered, washed on the filter with 12 L water, and dried in a vacuum oven to obtain 2-methyl-4-(trifluoromethyl)thiazole-5-carboxylic acid, 825 g as a beige solid, a 75.4% yield at 97.6% purity.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH:3]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:4][CH2:5][OH:6].[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.Cl>N1C=CC=CC=1>[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21]([O:6][CH2:5][CH2:4][CH:3]([C:2]([F:13])([F:14])[F:1])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: CCCCCCC(CCO)C(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCC(CCOS(=O)(=O)c1ccc(C)cc1)C(F)(F)F
Reaction time: 2 h
Yield: 6488.1 %

Procedure:
3.08 mg of 3-trifluoromethyl-1-nonanol was dissolved in 453 mg of pyridine, and the solution was cooled with ice, followed by addition of 276 mg of p-toluenesulfonic chloride, stirring for 2 hours under cooling with ice and stirring overnight at room temperature. After the reaction, the product was acidified with 2N-hydrochloric acid and extracted with diethyl ether. The resultant diethyl ether solution was washed with water and dried with magnesium sulfate, and the solvent was distilled off. The crude product was purified by thin layer chromatography with benzene as the developer to obtain 345 mg (yield: 65%) of 3-trifluoromethylnonyl p-toluenesulfonate, which showed: [α]D28 +1.63 (c 5.04, CHCl3).