Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH:3]([O:11][CH3:12])[C:4]1[O:8][C:7]([CH2:9][OH:10])=[CH:6][CH:5]=1.[OH-].[Na+].[CH2:15]([CH:17]1[O:19][CH2:18]1)Cl>C(C(C)=O)C>[CH3:1][O:2][CH:3]([O:11][CH3:12])[C:4]1[O:8][C:7]([CH2:9][O:10][CH2:15][CH:17]2[O:19][CH2:18]2)=[CH:6][CH:5]=1
Reactant: ClCC1CO1
Reactant: COC(OC)c1ccc(CO)o1
Agent: [Na+]
Agent: [OH-]
Solvent: CCC(C)=O
Product: COC(OC)c1ccc(COCC2CO2)o1
Reaction time: 0.5 h

Procedure:
5-Glycidoxymethyl furfuraldehyde dimethyl acetal was prepared by adding a total of 6.0 g (0.035 mole) of 5-hydroxymethyl furfuraldehyde dimethyl acetal (HMFA) to 1.54 g sodium hydroxide (0.038 mole) in a 100 ml round bottom flask equipped with magnetic stir bar, reflux condenser, and nitrogen inlet. After stirring for 30 min., 3.89 g (0.042 mole) of epichlorohydrin in 50 ml. of methyl ethyl ketone was added quickly, and the reaction mixture was allowed to reflux overnight under an inert (nitrogen) atmosphere. The mixture was then cooled, filtered, and the solvent removed under vacuum. The resulting oil was mixed with 250 ml of toluene and the toluene was distilled off at atmospheric pressure to remove any residual epichlorohydrin. The sample was freed of toluene by subjecting it to high vacuum overnight.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][C:8](=[O:10])[CH3:9])=[N:4][N:3]=1.Br[CH2:12][CH2:13]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][C:2]1[O:6][C:5]([C:7]2([C:8](=[O:10])[CH3:9])[CH2:13][CH2:12]2)=[N:4][N:3]=1
Reactant: CC(=O)Cc1nnc(C)o1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)C1(c2nnc(C)o2)CC1
Temperature: 60 °C
Reaction time: 16 h
Yield: 20.5 %

Procedure:
A mixture of 1-(5-methyl-[1,3,4]oxadiazol-2-yl)-propan-2-one (312 mg, 2.2 mmol), 1,2-dibromo-ethane (0.25 mL, 2.85 mmol), and potassium carbonate (770 mg, 5.6 mmol) in acetone (5 mL) was stirred at 60° C. for 16 h. Insoluble material was filtered off and the filtrate was diluted with ethyl acetate (30 mL). The solution was washed with water and brine, dried over sodium sulfate, and evaporated under reduced pressure. The residual material was purified by chromatography on silica gel using heptane/0-100% ethyl acetate as eluent to afford the title compound (75 mg, 20%) as pale-yellow oil.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:8]=[CH:9][CH:10]=2)[C:5]([CH3:19])=[N:4][C:3]=1[C:20](OC)=[O:21].[NH2:24][CH2:25][C:26]([OH:28])=[O:27].C[O-].[Na+]>CO>[OH:1][C:2]1[C:11]2[C:6](=[C:7]([O:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:8]=[CH:9][CH:10]=2)[C:5]([CH3:19])=[N:4][C:3]=1[C:20]([NH:24][CH2:25][C:26]([OH:28])=[O:27])=[O:21]
Reactant: COC(=O)c1nc(C)c2c(Oc3ccccc3)cccc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1nc(C(=O)NCC(=O)O)c(O)c2cccc(Oc3ccccc3)c12
Temperature: 110 °C

Procedure:
A pressure glass reaction flask which included top threads for a screw cap lid can be fitted with a magnetic stirrer, charged with 4e, glycine (about 3 molar equivalents), methanol, and a sodium methoxide solution (with 1.2 molar eqivalents NaOCH3) and sealed. The reaction can then be heated to 110° C. for at least 6 h during which time the reaction forms a yellow suspension. The reaction can then be cooled to 20-25° C. and evaluated by HPLC. The reaction can be continued until less than 1% 4e remains as determined by HPLC, filtered, washed with methanol, dried under vacuum, dissolved in water and extracted with ethyl acetate to remove impurities to below 0.1%. The ethyl acetate can be removed and an acetic acid solution (with 3 molar eqivalents acetic acid) can be added over one hour. The suspension can be stirred at room temperature for at least 3 hours, filtered, and the solid washed with water (3×), cold acetone (5-10° C., 2×) and evaluated for impurities by HPLC. If acetone removable impurities are present, the flask can be charged with acetone and refluxed for at least 8 h, slowly cooled to 5-10° C., stirred for at least 2-3 h, filtered, washed with cold acetone (5-10° C., 3×) and dried under vacuum to obtain 2-(4-hydroxy-1-methyl-8-phenoxyisoquinoline-3-carboxamido)acetic acid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)([CH2:14]OS(C)(=O)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:26]=[N+:27]=[N-:28].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)([CH2:14][N:26]=[N+:27]=[N-:28])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)(C2CCCCC2)CC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CN=[N+]=[N-])(C2CCCCC2)CC1
Temperature: 100 °C
Yield: 76 %

Procedure:
To a solution of 4-cyclohexyl-4-methanesulfonyloxymethyl-piperidine-1-carboxylic acid tert-butyl ester, 4, (2.42 g, 6.73 mmol) in DMF (25 mL) is added sodium azide (1.32 g, 20.2 mmol) and the mixture is heated and stirred at 100° C. over night. The reaction is cooled and then quenched with water. The resulting solution is extracted with EtOAc (30 mL), dried, filtered and concentrated in vacuo to afford the crude product as a brown oil which is purified via chromatography on silica gel eluting with hexane/EtOAc 3:1 to afford the desired product in 76% yield (1.91 g) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][NH:14][CH2:15][CH2:16][C:11]=3[N:10]([CH2:17][CH:18]([OH:34])[CH2:19][N:20]3[CH2:25][CH2:24][N:23]([C:26]4[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=4[C:28]#[N:29])[CH2:22][CH2:21]3)[N:9]=2)=[CH:4][C:3]=1[CH3:35].Cl[C:37](=[O:42])[C:38]([O:40][CH3:41])=[O:39].CO.C(Cl)Cl>C(Cl)Cl>[CH3:41][O:40][C:38](=[O:39])[C:37]([N:14]1[CH2:15][CH2:16][C:11]2[N:10]([CH2:17][CH:18]([OH:34])[CH2:19][N:20]3[CH2:25][CH2:24][N:23]([C:26]4[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=4[C:28]#[N:29])[CH2:22][CH2:21]3)[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH3:35])[CH:4]=3)[C:12]=2[CH2:13]1)=[O:42]
Reactant: COC(=O)C(=O)Cl
Reactant: Cc1cc(-c2nn(CC(O)CN3CCN(c4ccccc4C#N)CC3)c3c2CNCC3)ccc1Cl
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C(=O)N1CCc2c(c(-c3ccc(Cl)c(C)c3)nn2CC(O)CN2CCN(c3ccccc3C#N)CC2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.3 %

Procedure:
2-(4-{3-[3-(4-Chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperazin-1-yl)-benzonitrile (58 mg, 0.118 mmol) was dissolved in CH2Cl2 (0.59 mL) and treated with methyl chlorooxoacetate (16 mg, 0.129 mmol). The reaction mixture was allowed to stir for 18 h at room temperature. Column chromatography (silica, 2-10% MeOH/CH2Cl2) gave (3-(4-chloro-3-methyl-phenyl)-1-{3-[4-(2-cyano-phenyl)-piperazin-1-yl]-2-hydroxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-oxo-acetic acid methyl ester (54 mg, 79%) as a white solid. MS (electrospray): m/z 577.3 (577.2, calculated for C30H33ClN6O4, [M+H]+). 1H NMR (400 MHz, CDCl3): 7.32-7.62 (m, 5H), 7.14 (t, J=7.6 Hz, 1H), 7.05 (d, J=8.2 Hz, 1H), 4.59-4.80 (m, 3H), 4.12-4.28 (m, 2H), 3.92 (s, 3H), 3.78-3.86 (m, 2H), 3.44-3.60 (m, 5H), 3.15-3.40 (m, 4H), 2.83-3.05 (m, 2H), 2.41 (s, 3H).
Reaction SMILES: CS([O:5][C:6]1[CH:7]=[C:8]([O:20][C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][N:22]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]([O:17]CC)=[O:16])=[CH:11]2)(=O)=O.[OH-].[K+]>O1CCCC1.C(O)C.O>[OH:5][C:6]1[CH:7]=[C:8]([O:20][C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][N:22]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]([OH:17])=[O:16])=[CH:11]2
Reactant: CCOC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)cn3)cc(OS(C)(=O)=O)c2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(Oc2cc(O)c3[nH]c(C(=O)O)cc3c2)nc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 93.2 %

Procedure:
Ethyl 7-[(methylsulfonyl)oxy]-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indole-2-carboxylate (11.74 g) was suspended in a mixture of tetrahydrofuran (300 mL) and ethanol (150 mL). A solution of potassium hydroxide (85%, 6.8 g) in water (100 mL) was added to the mixture at 0° C. The mixture was allowed to warm to room temperature and stirred for 12 h. The mixture was concentrated and 1M hydrochloric acid (130 mL) was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. The residual solid was washed with diethyl ether to give the title compound (8.39 g, 93%) as a brown solid. MS 349 (MH+).
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH:10]2[CH2:15][CH2:14][CH:13]([OH:16])[CH:12]=[CH:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[H-].[Na+].[I-].[K+].[CH2:21]([C@H:26]1[CH2:31][CH2:30][C@H:29]([CH2:32]Br)[CH2:28][CH2:27]1)[CH2:22][CH2:23][CH2:24][CH3:25]>C1COCC1.O>[CH2:1]([C@H:4]1[CH2:5][CH2:6][C@H:7]([CH:10]2[CH:15]=[CH:14][CH:13]([O:16][CH2:32][C@H:29]3[CH2:30][CH2:31][C@H:26]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:27][CH2:28]3)[CH2:12][CH2:11]2)[CH2:8][CH2:9]1)[CH2:2][CH3:3]
Reactant: CCC[C@H]1CC[C@H](C2C=CC(O)CC2)CC1
Reactant: CCCCC[C@H]1CC[C@H](CBr)CC1
Agent: [H-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCC[C@H]1CC[C@H](COC2C=CC([C@H]3CC[C@H](CCC)CC3)CC2)CC1

Procedure:
Under a nitrogen atmosphere, 2.4 g of 4-(trans-4-propylcyclohexyl)-2-cyclohexene-1-ol (r-1) was dissolved into 50 mL of THF, 0.52 g of 60% sodium hydride was added under ice-cooling, and the resultant mixture was stirred at room temperature for 1 hour. Thereto, 2.3 g of potassium iodide and 3.2 g of (trans-4-pentylcyclohexyl)bromomethane (r-2) dissolved in 30 mL of THF were added, and the resultant mixture was stirred under heating reflux for 8 hours. The resultant reaction mixture was poured into water, and subjected to extraction with toluene. Combined organic layers were washed with saturated brine, and then dried over anhydrous magnesium sulfate. A solvent was evaporated under reduced pressure, and a residue was purified by silica gel column chromatography (eluate:heptane:toluene=1:1 (in a volume ratio)), and further purified by recrystallization from a mixed solvent of heptane:Solmix A-11 (registered tradename; Japan Alcohol Trading Co., Ltd.)=1:2 (in a volume ratio), and thus 0.15 g of 6-(trans-4-propylcyclohexyl)-3-(trans-4-pentylcyclohexyl)methoxy cyclohexene [compound (1-3-1-18) was obtained.
Reaction SMILES: [F:1][CH:2]([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1.[Br:12]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[F:1][CH:2]([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][Br:12])=[CH:6][CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(OC(F)F)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)Oc1ccc(CBr)cc1
Reaction time: 8 h
Yield: 62.6 %

Procedure:
270 g of 4-difluoromethoxytoluene in 800 ml of CCl4 were initially introduced and 300 g of N-bromo-succinimide were added. After adding a pinch of azobisisobutyronitrile, the mixture was heated to the reflux temperature. After 8hours, it was cooled, the insoluble succinimide was filtered off and the residue on the filter was washed with CCl4. The carbon tetrachloride was distilled off from the reaction solution and the crude product was purified by fractional distillation. 250 g of 4-difluoromethoxy-benzyl bromide were obtained. Boiling point=82°-5° C./0.4 mm Hg; nD20 =1.5200.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]([NH:12][NH2:13])=[N:4][N:3]=1.C([O-])(=O)C.[Na+].[N:19]#[C:20]Br>CO>[NH2:19][C:20]1[N:4]2[N:3]=[C:2]([Cl:1])[C:11]3[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=3[C:5]2=[N:12][N:13]=1
Reactant: NNc1nnc(Cl)c2c1CCCC2
Reactant: N#CBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: Nc1nnc2c3c(c(Cl)nn12)CCCC3
Reaction time: 0.5 h

Procedure:
A 46.88 gm (0.236 mole) quantity of 1-chloro-4-hydrazino5,6,7,8-tetrahydrophthalazine was added to 450 ml of methanol. A 40.8 gm quantity of sodium acetate and 25.0 gm of cyanogen bromide was added and the mixture was stirred on a warm plate for 30 minutes. Yellow crystals appeared immediately. The mixture was allowed to sit for 3 days. The resulting solid was filtered, washed with ether, and dried, yielding 44.85 gm of 3-amino-6-chloro-7,8,9,10-tetrahydro-1,2,4-triazolo[3,4-a]phthalazine; mp 224-225° C. (ethanol).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH2:7][OH:8])=[N:4][N:3]=1.CN(C=O)C.N1C=CN=C1.[CH3:19][CH:20]([Si:22](Cl)([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])[CH3:21]>CCOC(C)=O>[Br:1][C:2]1[S:6][C:5]([CH2:7][O:8][Si:22]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:21])[CH3:19])=[N:4][N:3]=1
Reactant: OCc1nnc(Br)s1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)[Si](OCc1nnc(Br)s1)(C(C)C)C(C)C
Reaction time: 5 h
Yield: 98.1 %

Procedure:
A 500 mL (one neck) round-bottom flask with a stir bar, septum and needle inlet was charged with (5-bromo-[1,3,4]thiadiazol-2-yl)-methanol (25 g, 128 mmol), DMF (250 mL), imidazole (17.9 g, 263 mmol, 2 equiv.) and TIPSCl (30.0 g, 155 mmol, 1.2 equiv.). The solution was stirred for 5 hours and diluted with EtOAc. The solution was washed with HCl (1N, 2×) and brine. The organic layer was dried over Na2SO4 and concentrated. The crude product was purified by silica gel chromatography (0-10% EtOAc/Hex) to provide 2-bromo-5-triisoproylsilanyloxymethyl-[1,3,4]thiadiazole (44.1 g, 98%).
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[CH:12]=[C:13]([CH3:33])[CH:14]2[Si:19]([CH:22]1[C:30]2[C:25](=[C:26](Br)[CH:27]=[CH:28][CH:29]=2)[CH:24]=[C:23]1[CH3:32])([CH3:21])[CH3:20]>C1COCC1.[Cl-].[Cl-].[Zn+2].CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:1]1([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH:12]=[C:13]([CH3:33])[CH:14]3[Si:19]([CH:22]2[C:30]3[C:25](=[C:26]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH:27]=[CH:28][CH:29]=3)[CH:24]=[C:23]2[CH3:32])([CH3:21])[CH3:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC1=Cc2c(Br)cccc2C1[Si](C)(C)C1C(C)=Cc2c(Br)cccc21
Reactant: Br[Mg]c1ccccc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: CC1=Cc2c(-c3ccccc3)cccc2C1[Si](C)(C)C1C(C)=Cc2c(-c3ccccc3)cccc21
Reaction time: 1 h

Procedure:
In an argon atmosphere, to a solution of 15 mL of THF with 29.0 ml of 0.5 M ZnCl2 (14.5 mmol) in THF 13.0 ml of 1.0 M phenylmagnesium bromide (13.0 mmol) in THF was added at ambient temperature. This mixture was stirred for 1 hour, and, then, 10.0 ml of 0.02 M Pd(PtBu3)2 (0.20 mmol, 4 mol. %) in THF and 2.37 g (5.0 mmol) of 1 were added. The resulting mixture was stirred for 5 hours at reflux. The product was isolated by flash chromatography on Silica Gel 60 (40-63 μm, d 30 mm, l 100 mm; eluent: hexanes). Yield 2.27 g (97%) of white solid of ca. 1 to 1 mixture of rac- and meso-compounds.
Reaction SMILES: C([O:4][NH:5][C:6]([CH:8]1[CH2:13][CH2:12][CH:11]([O:14][CH3:15])[CH2:10][N:9]1[S:16]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:21][CH:20]=1)(=[O:18])=[O:17])=[O:7])C=C.C([O-])=O.C([NH+](CC)CC)C.C(#N)C>O>[OH:4][NH:5][C:6]([CH:8]1[CH2:13][CH2:12][CH:11]([O:14][CH3:15])[CH2:10][N:9]1[S:16]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:21][CH:20]=1)(=[O:18])=[O:17])=[O:7]
Reactant: C=CCONC(=O)C1CCC(OC)CN1S(=O)(=O)c1ccc(OCc2ccccc2)cc1
Agent: CC[NH+](CC)CC
Agent: O=C[O-]
Solvent: O
Solvent: CC#N
Product: COC1CCC(C(=O)NO)N(S(=O)(=O)c2ccc(OCc3ccccc3)cc2)C1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 29.7 %

Procedure:
To a solution of 1-(4-benzyloxy-benzenesulfonyl)-5-methoxy-piperidine-2-carboxylic acid allyloxy-amide (0.090 g, 0.20 mmol), triethylammonium formate (0.28 mL of a 3M solution in water, 0.83 mmol) and acetonitrile (1.1 mL) was added tetrakistriphenylphosphine palladium. After stirring for 15 min at 80° C., the mixture was cooled to room temperature and concentrated in vacuo. The residue was diluted with ether and extracted 2× into 1 M NaOH. The combined aqueous layers were washed 2× with ether, acidified with 1M HCl and extracted 3× with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered and concentrated. Purification of the residue by silica gel chromatography eluting with ethyl acetate afforded 0.025 g of 1-(4-benzyloxy-benzenesulfonyl)-5-methoxy-piperidine-2-carboxylic acid hydroxyamide as a yellow solid after trituration from CH2Cl2-hexane:
Reaction SMILES: [C:1]([C:5]1[C:6]([O:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])=[N:7][NH:8][C:9]=1[CH2:10][OH:11])([CH3:4])([CH3:3])[CH3:2].OCC1NN=C(OCC2N(C)N=CN=2)C=1C1C=CC=CC=1>>[C:1]([C:5]1[C:6]([O:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])=[N:7][NH:8][C:9]=1[CH:10]=[O:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Oc2n[nH]c(CO)c2C(C)(C)C)cc1
Agent: Cn1ncnc1COc1n[nH]c(CO)c1-c1ccccc1
Product: Cc1ccc(S(=O)(=O)Oc2n[nH]c(C=O)c2C(C)(C)C)cc1

Procedure:
This compound was prepared by the procedure described in Example 1, step d) using the product from Example 21, step c) instead of 5-hydroxymethyl-3-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)-4-phenylpyrazole. Data for the title compound: 1H NMR (400 MHz, DMSO) δ 1.33+1.39 (9H, s+s) (tautomers present), 2.44 (3H, m), 6.55 (0.6H, m) (proton due to presence of aldehyde hydrate), 7.49-7.53 (2H, m), 7.79-7.98 (2H, m), 10.03 (0.2H, s) (tautomers present), 13.68 (0.2H, s); MS (ES+) m/e 323 [MH]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.CN(P(N(C)C)(N(C)C)=O)C.[H-].[Na+].[NH:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[C:23]1[C:31]1[C:32]([NH2:38])=[N:33][CH:34]=[C:35](Br)[N:36]=1>CCOC(C)=O>[NH:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[C:23]1[C:31]1[C:32]([NH2:38])=[N:33][CH:34]=[C:35]([S:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[N:36]=1
Reactant: Fc1cccc(S)c1
Reactant: Nc1ncc(Br)nc1-c1nc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Nc1ncc(Sc2cccc(F)c2)nc1-c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 11 %

Procedure:
3-Fluorobenzenethiol (70.49 mg, 46.47 μL, 0.55 mmol) was added to HMPA (1 mL) followed by the addition of sodium hydride (60% dispersion in mineral oil) (24 mg, 0.6 mmol). The reaction mixture was stirred at ambient temperature for 10 minutes then 3-(1H-Benzimidazol-2-yl)-5-bromo-pyrazin-2-amine (80 mg, 0.27 mmol) was added and reaction heated at 110° C. under microwave conditions for 45 minutes. The reaction mixture was cooled to ambient temperature and diluted with EtOAc. The organic layer was washed with water (×2), saturated aqueous NaHCO3 (×1) and brine. (×1), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 mM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected and freeze-dried to give the title compound as a yellow solid (10 mg, 11% Yield). 1H NMR (400.0 MHz, CDCl3) δ 76.95-7.0 (1H, m), 7.03-7.06 (1H, m), 7.1-7.13 (1H, m), 7.3-7.4 (2H, m), 7.50-7.55 (1H, m), 7.8-7.85 (1H, m), 8.22 (1H, s) and 10.2 (1H, br s) ppm; MS (ES+) 338.1.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:18])[C:15]([OH:17])=[O:16])=[CH:10][CH:9]=1)=[O:6].C(=O)([O-])[O-].[K+].[K+].C(OC(=O)C)C.C(OC(C)C)(C)C>CN(C)C=O>[O:6]=[C:5]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([CH3:18])[C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)[CH2:2][CH2:3][O:4]1
Reactant: CC(C(=O)O)c1ccc(NC(=O)OCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CC(C)OC(C)C
Product: CC(C(=O)O)c1ccc(N2CCOC2=O)cc1
Yield: 80.4 %

Procedure:
0.5 g (1.85 mmol) of 2-(4-{[(2-chloroethoxy)carbonyl]amino}phenyl)propanoic acid were dissolved in 10 ml of N,N-dimethylformamide and 0.45 g (3.7 mmol) of potassium carbonate were added. After 48 hours the solvent was evaporated under vacuum, the residue redissolved with dichloromethane and washed with hydrochloric acid 0.5 N. The organic layer was dried over sodium sulphate and evaporated. 0.35 g (80% yield) of the title compound crystallized from a mixture ethylacetate-diisopropylether.
Reaction SMILES: [OH-].[K+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH2:20])=S)=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.O.O.C([O-])(=O)C.[Pb+2].C([O-])(=O)C>O>[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]#[N:20])=[CH:13][CH:12]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: NC(=S)Nc1ccc(OCc2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: N#CNc1ccc(OCc2ccccc2)cc1

Procedure:
A hot solution of potassium hydroxide (25.2 g) in water (70 ml) was added to N-(4-benzyloxyphenyl)thiourea (11.34 g) suspended in boiling water (80 ml). A hot solution of lead acetate trihydrate (71.5 g) in water (80 ml) was added and the mixture heated under reflux for an hour and filtered whilst hot. The filtrate was cooled, acidified to pH 7 with acetic acid and extracted with dichloromethane to give 4-benzyloxyphenylcyanamide as a white solid which was purified by flash chromatography (as described by Still et al in J Org Chem, 1978, 43, 2923-2925) over silica using hexane and chloroform as eluant to give 4-benzyloxyphenylcyanamide (m.p. 105° C.).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:9][CH2:8][C@H:7]([OH:10])[CH2:6]1)(=[O:3])[CH3:2].[CH3:11][S:12](Cl)(=[O:14])=[O:13].C(N(CC)CC)C>COC(C)(C)C>[CH3:11][S:12]([O:10][C@@H:7]1[CH2:8][CH2:9][C@H:5]([O:4][C:1](=[O:3])[CH3:2])[CH2:6]1)(=[O:14])=[O:13]
Reactant: CC(=O)O[C@@H]1CC[C@H](O)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: COC(C)(C)C
Product: CC(=O)O[C@H]1CC[C@@H](OS(C)(=O)=O)C1
Temperature: -8 °C
Yield: 95.8 %

Procedure:
Dissolve (1S,3R)-cis-3-acetoxy-cyclopentanol (9.75 g, 67.6 mmol, prepared in example 23) in tert-butyl methyl ether (80 mL, anhydrous) and cool to -8° C. with stirring. Add methanesulfonyl chloride (5.7 mL, 73.6 mmol, mesyl chloride) over 5 minutes, followed by dropwise addition of triethylamine (11.4 mL, 81.2 mL), over about 30 minutes, maintaining the temperature below -2° C. The ice bath is then removed and the mixture is stirred for 2 hours. The mixture is poured into a water/brine mixture (50 mL/50 mL). The layers are separated and the aqueous layer extracted with tert-butyl methyl ether (100 mL). The organic layer and extract is combined, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide the title compound (14.4 g) as a yellow oil; 1H NMR (CDCl3) δ 8 5.1 (m, 2 H), 3.02 (s, 3 H), 2.41 (m, 1 H), 2.05 (s, 3 H), 2.0 (m, 5 H).
Reaction SMILES: S(Cl)([Cl:3])=O.[Br:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[CH2:13][C:14]([OH:16])=O>C(Cl)Cl>[Br:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[CH2:13][C:14]([Cl:3])=[O:16]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)Cc1ccc(F)cc1Br
Solvent: ClCCl
Product: O=C(Cl)Cc1ccc(F)cc1Br

Procedure:
Add thionyl chloride (1.5 g, 12.6 mmol) to a solution of (2-bromo-4-fluoro-phenyl)-acetic acid (0.3 g, 1.26 mmol) in DCM (3 mL). Reflux the mixture for 2 h. Remove the solvent and excess thionyl chloride under reduced pressure to give the intermediate (2-bromo-4-fluorophenyl)-acetyl chloride. Dissolve the residue in DCM (3 mL) and add to a stirred solution of ethanolamine (0.15 mL, 2.52 mmol) in DCM (3 mL) at 0° C. Stir the mixture overnight. Dilute with DCM and wash with saturated NaHCO3, water, and aqueous saturated sodium chloride. Dry over sodium sulfate. Concentrate the solution in vacuo to give the title compound as a white solid (300 mg, 86%). MS (ES) m/z 276 [M+1]+.