Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]([C:6]([NH:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[O:7])=[C:4]([CH3:16])[CH:3]=1.C([Li])CCC.CN(C)[CH:24]=[O:25].Cl>O1CCCC1.O>[CH:24]([C:2]1[CH:15]=[CH:14][C:5]([C:6]([NH:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[O:7])=[C:4]([CH3:16])[CH:3]=1)=[O:25]
Reactant: Cc1cc(Br)ccc1C(=O)NCC(F)(F)F
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C=O)ccc1C(=O)NCC(F)(F)F

Procedure:
In a solution of 1.00 g of 4-bromo-2-methyl-N-(2,2,2-trifluoroethyl)benzoic acid amide in 15 ml of tetrahydrofuran under nitrogen atmosphere, 4.7 ml of n-butyl lithium (1.58M hexane solution) was added dropwise at −70° C. with stirring, and then 0.4 ml of N,N-dimethylformamide were added dropwise. After stirring at the same temperature for 30 minutes, 10 ml of 1N hydrochloric acid and then 30 ml of water were added, and extracted with ethyl acetate (30 ml×2). The organic phase was dehydrated with saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 0.80 g of the aimed product as pale yellow crystal.
Reaction SMILES: C(O[CH:5]([C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:26])[N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[CH:16][CH:15]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH3:13])(=O)C.C([O-])=O.[NH4+]>CO.[Pd]>[CH2:24]([N:21]([CH2:22][CH3:23])[C:20]([C:17]1[CH:18]=[CH:19][C:14]([CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[O:12][CH3:13])=[CH:15][CH:16]=1)=[O:26])[CH3:25]
Reactant: CCN(CC)C(=O)c1ccc(C(OC(C)=O)c2ccccc2OC)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CCN(CC)C(=O)c1ccc(Cc2ccccc2OC)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
The obtained 1-(4-diethylcarbamoylphenyl)-1-(2-methoxyphenyl)methyl acetate was dissolved in methanol (280 ml), added with 10% palladium/carbon (7 g) and ammonium formate (28.44 g) under argon atmosphere and stirred at 60° C. for 2 hours. After insoluble matters were removed by filtration, the solvent was evaporated under reduced pressure to obtain 2-(4-diethylcarbamoylbenzyl)anisole.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:8]O)=[N:4][CH:5]=[CH:6][CH:7]=1.S(Cl)([Cl:12])=O.C(=O)(O)[O-].[Na+]>ClCCl.[Cl-].[Na+].O>[Cl:12][CH2:8][C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ncccc1F
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Fc1cccnc1CCl
Temperature: 0 °C
Yield: 80.5 %

Procedure:
Dissolve (3-fluoro-pyridin-2-yl)-methanol (215 mg, 1.69 mmol) in dichloromethane (10 mL) and cool to 0° C. Add thionyl chloride (160 μL, 2.20 mmol) and stir the reaction for one hour. Add dichloromethane (50 mL) and stir the reaction with saturated aqueous sodium bicarbonate (2×40 mL) and brine (2×40 mL). Separate and dry the organic portion over magnesium sulfate, filter, and concentrate under reduced pressure to provide 198 mg (80%) of product, which is used without further purification. MS: m/z 146, 148 [C6H5ClFN+1]+; 1H NMR (300 MHz, CDCl3): δ 8.41-8.44 (m, 1H), 7.41-7.47 (m, 1H), 7.28-7.34 (m, 1H), 4.75 (d, J=2.0 Hz, 2H); 19F NMR (282 MHz, CDCl3): δ-123.8.
Reaction SMILES: N(C(OCC1C=CC=CC=1)=O)[C@H](C(O)=O)C.[NH2:17][C@H:18]([C:26]([O:28][CH3:29])=[O:27])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl.C1C=CC2N(O)N=NC=2C=1.N(C(OCC1C=CC=CC=1)=O)[C@H](C(N[C@H](C(OC)=O)CC1C=CC=CC=1)=O)C.[NH:69]([C:78]([O:80][C:81]([CH3:84])([CH3:83])[CH3:82])=[O:79])[C@H:70]([C:75](O)=[O:76])[C@H:71]([CH2:73][CH3:74])[CH3:72]>C1COCC1.CN(C=O)C>[NH:69]([C:78]([O:80][C:81]([CH3:83])([CH3:82])[CH3:84])=[O:79])[C@H:70]([C:75]([NH:17][C@H:18]([C:26]([O:28][CH3:29])=[O:27])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:76])[C@H:71]([CH2:73][CH3:74])[CH3:72]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)NC(=O)OCc1ccccc1
Agent: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC
Yield: 85 %

Procedure:
Having shown the removability of 1 and its derivatives from organic solvents, we next demonstrate its effectiveness as a peptide coupling reagent and general dehydrating agent. Coupling CBZ-Ala (10) and Phe-OMe.HCl in THF with HOBT and 1 afforded CBZ-Ala-Phe-OMe (21) in 84% yield. Using DMF as the solvent, the yield increased to 93%. The more hindered coupling of BOC-Ile (26) and Phe-OMe.HCl with HOBT and 1 produced yields of 82% and 85% of BOC-Ile-Phe-OMe (26) in THF and DMF, respectively. In all cases there was no racemization, as would be expected from N-carbamate-protected amino acids. The 1/HOBT mediated C-terminus coupling of CBZ-Ala-Phe (11) with Gly-OBn.TsOH in DMF produced CBZ-Ala-Phe-Gly-OBn (27) in which the Phe was racemized to the extent of 0.68% after 4 h and 1.3% after 20 h, consistent with similar experiments using DCC and EDC. The same coupling carried out in the presence of 50 mol % of anhydrous CuCl2 gave racemization-free 27, even after reactions were allowed to proceed for 20 h at room temperature. These results were also in agreement with literature data. (Miyazawa et al., Int. J. Peptide & Protein Res., 39, p. 237 (1992); Miyazawa et al., Int. J. Peptide & Protein Res., 39, p. 308 (1992).) In each case, all residual 1 and urea by-products 3 were easily removed from the reaction mixtures with a simple acid wash.
Reaction SMILES: F[C:2]1[C:3]([CH3:15])=[C:4]([CH:8]=[CH:9][C:10]=1[S:11]([CH3:14])(=[O:13])=[O:12])[C:5]([OH:7])=[O:6].[CH2:16]([O:18][CH:19]([O:22][CH2:23][CH3:24])[CH2:20][NH2:21])[CH3:17].OS(O)(=O)=O>>[CH2:16]([O:18][CH:19]([O:22][CH2:23][CH3:24])[CH2:20][NH:21][C:2]1[C:3]([CH3:15])=[C:4]([CH:8]=[CH:9][C:10]=1[S:11]([CH3:14])(=[O:13])=[O:12])[C:5]([OH:7])=[O:6])[CH3:17]
Reactant: CCOC(CN)OCC
Reactant: Cc1c(C(=O)O)ccc(S(C)(=O)=O)c1F
Agent: O=S(=O)(O)O
Product: CCOC(CNc1c(S(C)(=O)=O)ccc(C(=O)O)c1C)OCC
Temperature: 120 °C
Reaction time: 48 h

Procedure:
5.1 g (22 mmol) of 3-fluoro-2-methyl-4-(methylsulfonyl)benzoic acid were dissolved in 30 ml (218 mmol) of aminoacetaldehyde diethyl acetal. The mixture was heated at 120° C. with stirring for 2 days, cooled to RT, acidified with 10% strength H2SO4 and extracted twice with ethyl acetate. The combined organic phases were dried over MgSO4, and the solvent was removed under reduced pressure. This gave 4.0 g of a yellow oil of a purity of 91%.
Reaction SMILES: Br[C:2]1[N:3]([CH2:13][C:14]2[S:18][C:17]([CH2:19][CH3:20])=[CH:16][CH:15]=2)[C:4]2[N:5]=[C:6]([NH2:12])[NH:7][C:8](=[O:11])[C:9]=2[N:10]=1.[NH2:21]N.COCCO>O>[NH2:21][C:2]1[N:3]([CH2:13][C:14]2[S:18][C:17]([CH2:19][CH3:20])=[CH:16][CH:15]=2)[C:4]2[N:5]=[C:6]([NH2:12])[NH:7][C:8](=[O:11])[C:9]=2[N:10]=1
Reactant: NN
Reactant: CCc1ccc(Cn2c(Br)nc3c(=O)[nH]c(N)nc32)s1
Solvent: O
Solvent: COCCO
Product: CCc1ccc(Cn2c(N)nc3c(=O)[nH]c(N)nc32)s1
Reaction time: 48 h

Procedure:
A mixture of 8-bromo-9-(5-ethyl-2-thenyl)guanine (6.5 g; 18.3 mmol) and 60% aqueous hydrazine (200 ml) was heated to reflux under nitrogen atmosphere for 20 hours. 2-Methoxyethanol (50 ml) was added and the refluxing continued for an additional 48 hours in the open air. The orange-brown solution was cooled, diluted with water (150 ml) and allowed to crystallize in the refrigerator overnight. The crude product thus obtained was converted to the hydrochloride salt by recrystallizing from boiling isopropanol and 1N HCl. Yield, 0.49 g; mp 215°-218° C., dec.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([CH:6]=[CH:7][S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:14][CH2:15][CH2:16][C:17]1[CH:31]=[CH:30][C:20]([O:21][C:22]([CH3:29])([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:19][CH:18]=1>>[Cl:1][C:2]1[CH:13]=[CH:12][C:5]([CH:6]=[CH:7][S:8]([NH:14][CH2:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:21][C:22]([CH3:28])([CH3:29])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:30][CH:31]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)C=Cc1ccc(Cl)cc1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCN)cc1
Product: CCOC(=O)C(C)(C)Oc1ccc(CCNS(=O)(=O)C=Cc2ccc(Cl)cc2)cc1

Procedure:
From p-chlorostyrenesulphonyl chloride and ethyl 2-[4-(2-aminoethyl)-phenoxy]-2-methylpropionate; colourless oil, nD20 =1.5625;
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Br[CH2:9][CH2:10][CH2:11][OH:12]>C1(C)C=CC=CC=1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:9][CH2:10][CH2:11][OH:12])[CH2:4][CH2:3]1
Reactant: CN1CCNCC1
Reactant: OCCCBr
Solvent: Cc1ccccc1
Product: CN1CCN(CCCO)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
1-Methylpiperazine (6.99 mL, 63 mol) was dissolved in toluene (30 mL). 3-Bromopropanol (2.62 mL, 30 mmol) was slowly and the mixture was stirred overnight at r.t. After heating to 80° C. for 2 h and cooling to r.t., the mixture was filtered and the filter cake was thoroughly washed with toluene. After removal of the solvent, the residue was subjected to distillation (b.p., 180° C./2 mbar) to obtain a colourless oil (4.08 g, 25.8 mmol, 86%). 1H NNR (CDCl3): δ=1.70 (Ψ-quint, J≈5.8 Hz, 2 H), 2.26 (s, 3 H), 2.35-2.6 (m, 8 H), 2.60 (Ψ-t, J=5.8 Hz, 2 H), 3.77 (Ψ-t, J=5.3 Hz, 2 H), 4.09 (s, br., 1 H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH2:11][CH2:10][CH2:9][CH:8]=2)[CH2:3][CH2:2]1.P(O)(O)O>>[CH:7]1([N:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)[CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: C1=C(N2CCOCC2)CCC1
Agent: OP(O)O
Product: C1CCC(N2CCOCC2)C1
Yield: 72 %

Procedure:
1-Morpholinocyclopentene (30 g; 0.2 mole) was mixed with phosphorous acid (16.4 g; 0.2 mole) and heated with stirring. As the temperature reached 70° an exothermic process took place taking the internal temperature to 105°. The viscosity of the reaction mixture increased as the reaction proceeded. After maintaining at 100°-105° for 30 mins. the reaction mixture was diluted and basified. Extraction with chloroform yielded N-cyclopentylmorpholine (72%). The product was characterized by 13C and 1H nmr spectra. ##STR16##
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Cl:14][C:15]1[N:20]=[C:19](Cl)[CH:18]=[CH:17][N:16]=1>C1COCC1>[Cl:14][C:15]1[N:20]=[C:19]([N:11]2[CH:10]=[CH:9][N:8]=[C:7]2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:18]=[CH:17][N:16]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: c1ccc(-c2ncc[nH]2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1nccc(-n2ccnc2-c2ccccc2)n1
Temperature: 50 °C

Procedure:
To a solution of 2-phenylimidazole (1-2, 484 mg, 3.36 mmol) in dry THF (15 mL) was added NaH (130 mg, 60% dispersion in mineral oil, 3.36 mmol) at room temperature. After gas evolution had ceased, 2,4-dichloropyrimidine (3-1, 0.5 g, 3.36 mmol) was added. The mixture was heated to 50° C. After 18 hours the mixture was cooled to room temperature, quenched with saturated NH4Cl, and extracted with EtOAc (3×). The combined organic layers were dried (MgSO4), filtered, and concentrated. Flash column chromatography (50% EtOAc/hexanes) gave 2-chloro-4-(2-phenyl-1H-imidazol-1-yl)pyrimidine as a gum. 1H-NMR (300 MHz, CDCl3) δ 8.40 (d, J=5.38 Hz, 1H), 7.80 (s, 1H), 7.45 (m, 5H), 7.25 (s, 1H), 6.68 (d, J=5.38 Hz, 1H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][N:30]([CH3:46])[C:31]([C@H:33]1[CH2:38][CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34]1)=[O:32]>C(Cl)Cl>[C:3]([OH:5])([C:2]([F:7])([F:6])[F:1])=[O:4].[CH3:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][N:30]([CH3:46])[C:31]([C@H:33]1[CH2:38][CH2:37][CH2:36][NH:35][CH2:34]1)=[O:32]
Reactant: COCCOCCOCCOCCOCCOCCOCCN(C)C(=O)[C@H]1CCCN(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCOCCOCCOCCOCCOCCOCCN(C)C(=O)[C@H]1CCCNC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Trifluoroacetic acid (2 mL) was added to a solution of (S)-tert-butyl 3-(2,5,8,11,14,17,20-heptaoxadocosan-22-yl(methyl)carbamoyl)piperidine-1-carboxylate (720 mg) in DCM (2 mL) and stirred at RT for 30 minutes. The solvents were removed under vacuum to give a TFA salt of (S)—N-(2,5,8,11,14,17,20-heptaoxadocosan-22-yl)-N-methylpiperidine-3-carboxamide (760 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.C([Li])CCC.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][C:26](=[O:29])[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>C1COCC1>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][C:26]([OH:29])([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:10]=2[NH:9][CH:8]=[CH:7]3)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Brc1cccc2cc[nH]c12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2cccc3cc[nH]c23)CC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 80.6 %

Procedure:
To a solution of 7-bromoindole (400 mg, 2.04 mmol) in THF (20 mL) under an argon atmosphere and cooled to −78° C. was added n-butyllithium (3.1 mL, 2.0M, 6.1 mmol) dropwise. The reaction was stirred at −78° C. for 15 minutes then warmed to 5° C. and maintained for 30 minutes. The reaction was cooled back to −78° C. and 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (813 mg, 4.08 mmol) was added dropwise in THF (5 mL). The reaction was allowed to come to room temperature and stirred for 1 h. The reaction was quenched with water (15 mL) and extracted with EtOAc (3×20 mL). The combined acetate layers were washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo and chromatographed on silica eluting with 20% acetone in hexanes to afford 4-hydroxy-4-(1H-indol-7-yl)-piperidine-1-carboxylic acid tert-butyl ester as a white foam (520 mg).
Reaction SMILES: [CH3:1][N:2]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[N:11][C:12]2[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)[CH3:3].[NH2:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][N:28]1[C:36]2[C:35]([CH3:37])=[C:34]([CH3:38])[N:33]=[C:32]([NH2:39])[C:31]=2[N:30]=[C:29]1[CH3:40]>>[NH2:39][C:32]1[C:31]2[N:30]=[C:29]([CH3:40])[N:28]([CH2:27][CH2:26][O:25][CH2:24][CH2:23][NH:22][S:18]([C:15]3[CH:16]=[CH:17][C:12]([N:11]=[N:10][C:7]4[CH:8]=[CH:9][C:4]([N:2]([CH3:3])[CH3:1])=[CH:5][CH:6]=4)=[CH:13][CH:14]=3)(=[O:20])=[O:19])[C:36]=2[C:35]([CH3:37])=[C:34]([CH3:38])[N:33]=1
Reactant: Cc1nc(N)c2nc(C)n(CCOCCN)c2c1C
Reactant: CN(C)c1ccc(N=Nc2ccc(S(=O)(=O)Cl)cc2)cc1
Product: Cc1nc(N)c2nc(C)n(CCOCCNS(=O)(=O)c3ccc(N=Nc4ccc(N(C)C)cc4)cc3)c2c1C

Procedure:
Using the method of Examples 34–50, 4-dimethylaminoazobenzene-4′-sulfonyl chloride was reacted with 1-[2-(2-aminoethoxy)ethyl]-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-4-amine to provide the desired compound. The product was purified using Method A. The observed accurate mass was 551.2551.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([O:14][C:15]([CH3:20])([CH3:19])[C:16]([OH:18])=[O:17])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1.[CH3:21][C:22]1[O:26][C:25]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:29][CH:28]=2)=[N:24][C:23]=1[CH2:39][CH2:40]OS(C1C=CC(C)=CC=1)(=O)=O>CCO>[C:30]1([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:31]=[CH:32][C:27]([C:25]2[O:26][C:22]([CH3:21])=[C:23]([CH2:39][CH2:40][O:1][C:2]3[CH:3]=[CH:4][C:5]([O:14][C:15]([CH3:20])([CH3:19])[C:16]([OH:18])=[O:17])=[C:6]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[CH:7]=3)[N:24]=2)=[CH:28][CH:29]=1
Reactant: CC(C)(Oc1ccc(O)cc1-c1ccccc1)C(=O)O
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)cc1
Solvent: CCO
Product: Cc1oc(-c2ccc(-c3ccccc3)cc2)nc1CCOc1ccc(OC(C)(C)C(=O)O)c(-c2ccccc2)c1
Temperature: 67.5 °C

Procedure:
A mixture of 2-(5-hydroxy-biphenyl-2-yloxy)-2-methyl-propionic acid (80 mg, 0.26 mmol), toluene-4-sulfonic acid 2-(5-methyl-2-biphenyl-4-yl-oxazol-4-yl)ethyl ester (0.22 mmol) (see Ex. 1, part F), and 1,5,7-triazobicyclo[4.4.0]dec-5-ene bound to polystyrene (200 mg, 2.6 mmol/g resin, Fluka) was diluted with absolute EtOH (2 mL) and was heated at 65-70° C. for 20 h. The warm mixture was filtered through a cotton plug, and the resin was washed with EtOH (2 mL). The combined filtrates were treated with aqueous 5N NaOH (0.3 mL), heated at 55° C. for 1.5 h, cooled to ambient temperature, and concentrated in vacuo. The residue was treated with ice water (1 mL) and acidified with 5N aqueous HCl (0.5 mL). The mixture with CH2Cl2 (1 mL) was transferred to a ChemElute cartridge (3 g) and eluted with CH2Cl2. The eluent was concentrated to crude product which was purified by mass guided HPLC to afford a white foam. 1H NMR (400 MHz, CDCl3) δ1.26 (s, 6H), 2.44 (s, 3H), 3.10 (t, 2H, J=5.9 Hz), 4.28 (t, 2H, J=6.1 Hz), 6.81 (dd, 1H, J=2.9, 8.8 Hz), 6.86 (d, 1H, J=2.9 Hz), 7.01 (d, 1H, J=8.8 Hz), 7.30-7.48 (m, 8H), 7.63 (d, 2H, J=7.3 Hz), 7.70 (d, 2H, J=8.3 Hz), 8.11 (d, 2H, J=8.3 Hz); MS (ES) m/e [M−1].
Reaction SMILES: [CH2:1]([OH:11])[C:2]1[CH:10]=[CH:9][C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.[C:12](OCC)(=[O:14])[CH3:13]>>[C:12]([O:11][CH2:1][C:2]1[CH:10]=[CH:9][C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1)(=[O:14])[CH3:13]
Reactant: COc1cc(CO)ccc1O
Reactant: CCOC(C)=O
Product: COc1cc(COC(C)=O)ccc1O
Temperature: 65 °C
Reaction time: 69 h
Yield: 89 %

Procedure:
Vanillyl alcohol (5) (10.3 g, 66.8 mmol) was dissolved in ethyl acetate (160 ml) at room temperature, Novozym 435 (2.00 g) was added, and the mixture was stirred at 65° C. for 69 hours. Then, the reaction mixture was cooled to room temperature, the enzyme was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (gradient; ethyl acetate:n-hexane=19:81→40:60) to give 4-acetoxymethyl-2-methoxyphenol (6) (11.8 g, 59.8 mmol, yield 89%) as a colorless solid.
Reaction SMILES: [F:1][C:2]1[C:3]([C:34]([F:37])([F:36])[F:35])=[C:4]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[C:25]4[CH2:24][CH2:23][N:22]([CH2:26][C:27]([O:29]C(C)(C)C)=[O:28])[CH2:21][C:20]=4[NH:19][N:18]=3)=[O:16])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].C(O)(C(F)(F)F)=O>>[F:1][C:2]1[C:3]([C:34]([F:35])([F:36])[F:37])=[C:4]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[C:25]4[CH2:24][CH2:23][N:22]([CH2:26][C:27]([OH:29])=[O:28])[CH2:21][C:20]=4[NH:19][N:18]=3)=[O:16])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(C)OC(=O)CN1CCc2c(C(=O)N3CCC(c4ccc(F)c(F)c4C(F)(F)F)CC3)n[nH]c2C1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CN1CCc2c(C(=O)N3CCC(c4ccc(F)c(F)c4C(F)(F)F)CC3)n[nH]c2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
A solution tert-butyl 2-(3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)acetate (53 mg, 0.10 mmol) in anhydrous CH2C12 (3 mL) was treated with TFA (3 mL) and stirred under an atmosphere of N2 at room temperature for 8 h. After this time, the mixture was concentrated to dryness under reduced pressure and solvent exchanged with CH2Cl2 (10 mL). The residue was diluted in anhydrous CH2Cl2 (10 mL), treated with MP-carbonate (0.50 g) and stirred at room temperature for 15 min. After this time, the solution was filtered and the resin washed with CH2C1 (2×10 mL). The filtrate was concentrated to dryness under reduced pressure to provide 2-(3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)acetic acid as an off-white solid (40 mg, 85%): mp 151-153° C.; 1H NMR (500 MHz, DMSO-d6) δ 13.29 (br s, 0.25H), 12.89 (br s, 0.75H), 7.56-7.55 (m, 1H), 7.51-7.50 (m, 1H), 4.87-4.86 (m, 1H), 4.66-4.64 (m, 1H), 4.04-4.02 (m, 2H), 3.76-3.72 (m, 2H), 3.34-3.32 (m, 2H, partially merged with H2O peak), 3.15-3.11 (m, 4H), 2.76-2.74 (m, 2H), 1.76-1.70 (m; 4H); ESI MS m/z 473 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.N1C=CC=CC=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[CH3:1][N:2]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)[S:20]([CH3:19])(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: CNc1ccc(C(=O)OC)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(N(C)S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
500 mg of methyl 4-(methylamino)benzoate was cooled to 0° C. in DCM with 270 μL of Pyridine before 260 μL Methanesulfonyl Chloride was added dropwise. Reaction was allowed to warm to room temperature and stir overnight. Solvent was concentrated and the crude material was dissolved in Ethyl Acetate and extracted with 0.1N NaOH solution twice. Crude material was dried over Magnesium Sulfate, filtered and concentrated to give methyl 4-(N-methylmethylsulfonamido)benzoate. 698 mg of methyl 4-(N-methylmethylsulfonamido)benzoate was hydrolyzed via Procedure M to give 4-(N-methylmethylsulfonamido)benzoic acid. 100 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-(N-methylmethylsulfonamido)benzoic acid via Procedure G. The crude product was purified by reverse phase HPLC to yield pure N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(N-methylmethylsulfonamido)benzamide. MS (Q1) 416.3 (M)+.
Reaction SMILES: [C@H:1]1([OH:8])[CH2:6][CH2:5][CH2:4][C@@H:3]([OH:7])[CH2:2]1.CC(C)([O-])C.[K+].Br[CH2:16][C:17]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:18]=1[C:19]([O:21][CH3:22])=[O:20].CC1C=CC=C(C)C=1C(OC)=O>C(COC)OC.C(OC)(C)(C)C.O>[OH:7][C@@H:3]1[CH2:4][CH2:5][CH2:6][C@H:1]([O:8][CH2:16][C:17]2[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:18]=2[C:19]([O:21][CH3:22])=[O:20])[CH2:2]1
Reactant: O[C@@H]1CCC[C@H](O)C1
Reactant: COC(=O)c1c(C)cccc1CBr
Agent: CC(C)(C)[O-]
Agent: COC(=O)c1c(C)cccc1C
Agent: [K+]
Solvent: COCCOC
Solvent: O
Solvent: COC(C)(C)C
Product: COC(=O)c1c(C)cccc1CO[C@H]1CCC[C@@H](O)C1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 14.2 %

Procedure:
5 g (42.8 mmol) of cis-1,3-cyclohexanediol were dissolved in 50 ml of dimethoxyethane (DME), admixed at 20–23° C. with 3.36 g (30 mmol) of potassium tert-butoxide (KOtBu) and stirred. After about 30 minutes, the mixture is cooled to 5° C. and 3.7 g (approx. 50%) of methyl 2-bromomethyl-6-methylbenzoate, which may be prepared, for example, by methanolyzing the acid bromide (2-bromomethyl-6-methylbenzoyl bromide) or by brominating methyl 2,6-dimethylbenzoate, are added dropwise. The mixture is stirred at 5–10° C. for 1 h and then at 20–23° C. overnight. Water and methyl tert-butyl ether (MTBE) are added, the mixture is stirred vigorously, the phases are separated, the aqueous phase is washed once more with MTBE and the combined organic phases are concentrated under reduced pressure. The residue is chromatographed on silica gel (1:1 ethyl acetate/n-heptane). 600 mg of the desired compound are obtained as a light yellow oil, 1H NMR (CDCl3), δ =1.27 (m, 1H), 1.45 (m, 1H), 1.55 (m, 1H), 1.74 (m, 1H), 1.83 (m, 1H), 2.05 (m, 1H), 2.34 (s, 3H), 3.47 (m, 1H), 3.72 (m, 1H), 3.91 (s, 3H), 4.58 (dd, 2H), 7.15 (d, 1H), 7.20 (d, 2H), 7.27 (m, 1H).
Reaction SMILES: Br[CH2:2][C:3](=[O:12])[C:4]([CH3:11])([S:6][C:7]([F:10])([F:9])[F:8])[CH3:5].[NH:13]1[CH:17]=[N:16][CH:15]=[N:14]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:5][C:4]([S:6][C:7]([F:10])([F:9])[F:8])([CH3:11])[C:3](=[O:12])[CH2:2][N:13]1[CH:17]=[N:16][CH:15]=[N:14]1
Reactant: c1nc[nH]n1
Reactant: CC(C)(SC(F)(F)F)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(SC(F)(F)F)C(=O)Cn1cncn1
Yield: 61.2 %

Procedure:
26.5 g (0.1 mol) of 1-bromo-3-methyl-3-trifluoromethylthio-butan-2-one were added dropwise to a mixture of 8.3 g (0.12 mol) of 1,2,4-triazole and 28 g (0.2 mol) of potassium carbonate in 150 ml of acetone at room temperature. The mixture was subsequently stirred under reflux for 1 hour, the inorganic salts were filtered off and the filtrate was concentrated. The residue was taken up in methylene chloride, washed with water, dried over sodium sulphate and distilled. 15.5 g (62% of theory) of 3-methyl-1-(1,2,4-triazol-1-yl)-3-trifluoromethylmercaptobutan-2-one of boiling point 91° C./0.5 mm Hg and of melting point ~45° C. were obtained.