Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][C@@H:6]([OH:8])[C@H:5]([CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:3]1.O[C@@H](C)CC(OC1(C)CCC(C(C)C)CC1)=O>>[CH:2]1([CH3:1])[CH2:3][CH2:4][CH:5]([CH:9]([CH3:10])[CH3:11])[CH:6]([OH:8])[CH2:7]1
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Agent: CC(C)C1CCC(C)(OC(=O)C[C@H](C)O)CC1
Product: CC1CCC(C(C)C)C(O)C1

Procedure:
A sensate composition was prepared by mixing l-menthol and the (3S)-l-menthyl 3-hydroxybutyrate obtained in Example 1 at a ratio of 95:5 (weight ratio). Oral sensory evaluation was carried out by preparing 1,000 ml of a 20 ppm aqueous solution of the thus obtained sensate composition, and the oral sensory evaluation was carried out also on a 20 ppm aqueous solution of l-menthol alone as a comparison.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:8]([OH:10])=O)=[C:5]([CH3:7])[N:6]=1.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[CH2:32]([NH2:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C)C=O.CN1CCCC1=O>[CH2:32]([NH:39][C:8]([C:4]1[S:3][C:2]([Br:1])=[N:6][C:5]=1[CH3:7])=[O:10])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: Cc1nc(Br)sc1C(=O)O
Reactant: NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCCC1=O
Product: Cc1nc(Br)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture consisting of 2-bromo-4-methylthiazole-5-carboxylic acid (Sigma-Aldrich, 1.0 g), 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide (EDC, 1.3 g), 1-hydroxybenzotriazole (0.613 g), N-methyl-2-pyrrolidinone (0.48 mL) in N,N-dimethylformamide was added a mixture consisting of benzylamine (0.54 mL) in N,N-dimethylformamide (5 mL). The reaction mixture was stirred overnight at room temperature and was subsequently partitioned between ethyl acetate (200 mL) and water (200 mL). The layers were separated and the organic phase was further washed twice with water (2×200 mL) and brine solution (150 mL), was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure afforded the title intermediate as a crude yellow oil (1.847 g; major spot Rf 0.45 with 3:1 v/v hexanes-ethyl acetate solvent system) that solidified on standing at room temperature; MS (ESI−) m/z 311.
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[OH-].[NH4+:10].[OH-].[Na+]>O>[C:1]([O-:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[NH4+:10]
Reactant: O=C(O)/C=C/C(=O)O
Agent: [NH4+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C([O-])/C=C/C(=O)O
Reaction time: 0.25 h

Procedure:
Following the examples of U.S. Pat. No. 4,839,461, a slurry of 11.6 g (0.1 mole) fumaric acid was dissolved in 30 ml water was mixed with 13 g of 30% aqueous solution of ammonium hydroxide (0.11 mol NH3). Carefully warming the slurry to boiling gave a clear solution. This solution was boiled to dryness over a period of 15 minutes to give a white crystalline solid. The solid was tumbled under nitrogen at 100 Torr, at 145°-150° C. for 8 hours to give an off-white glasslike solid weighing 13.2 g. This solid was dissolved in 40 g of an aqueous solution containing 4.0 g of sodium hydroxide to form a pale yellow solution, pH 8.5, containing 25% solids.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[H-].[Na+].Br[C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Br:19])[CH:18]=1.O>CN(C)C=O.C(OCC)(=O)C>[Br:19][C:17]1[CH:16]=[N:15][CH:14]=[C:13]([O:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:18]=1
Reactant: COc1ccc(O)cc1
Reactant: Brc1cncc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(Oc2cncc(Br)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.8 %

Procedure:
Under an argon atmosphere, a solution of 4-methoxyphenol (15.7 g, 0.126 mol) in dimethylformamide (50 mL) was added slowly to a stirred suspension sodium hydride (3.6 g of a 80% suspension in mineral oil, 0.125 mol) in dimethylformamide (100 mL) at 3-7° C. The ice-bath was removed and the resulting mixture was stirred for 2 h at room temperature. A solution of 3,5-dibromopyridine (20 g, 0.083 mol) in dimethylformamide (120 mL) was added to the mixture, which was then heated to 100° C. for 36 h, then cooled to room temperature and poured into a mixture of water (500 mL) and ethyl acetate (500 mL). The aqueous phase was separated and extracted with ethyl acetate (2×100 mL). The combined organic phases were washed with water (3×100 mL) and then brine (100 mL), then dried (MgSO4), filtered and concentrated by rotary evaporation to give 22.5 g of an orange oil, which was purified by column chromatography, with cyclohexane/ethyl acetate (95/5, v/v) as eluant. Selected fractions containing the product were concentrated via rotary evaporation to give 18.8 g (81%) of a colorless oil.
Reaction SMILES: Br[C:2]1[S:3][C:4]([S:17]([N:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]2)(=[O:19])=[O:18])=[CH:5][C:6]=1[C:7]1[S:11][C:10]([NH:12][C:13](=[O:15])[CH3:14])=[N:9][C:8]=1[CH3:16].C([Li])CCC>>[CH3:16][C:8]1[N:9]=[C:10]([NH:12][C:13](=[O:15])[CH3:14])[S:11][C:7]=1[C:6]1[CH:5]=[C:4]([S:17]([N:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]2)(=[O:19])=[O:18])[S:3][CH:2]=1
Reactant: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)N3CCN(C)CC3)sc2Br)s1
Agent: [Li]CCCC
Product: CC(=O)Nc1nc(C)c(-c2csc(S(=O)(=O)N3CCN(C)CC3)c2)s1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
N-{5-[2-Bromo-5-(4-methyl-piperazine-1-sulfonyl)-thiophen-3-yl]-4-methyl-thiazol-2-yl}-acetamide obtained in Step I as described above (400 mg; 0.83 mmol; 1 eq), is dissolved in anhydrous TBF (50 ml). The reaction mixture is cooled down to −70° C. and put under nitrogen. n-Butyllithium (4.2 ml; 1.6 M; 6.67 mmol; 8 eq) is added dropwise. After 1 hour the reaction is complete and quenched with water. Solvents are evaporated and the crude product is dissolved in EtOAc. The resulting organic phase is washed with water (2 times), brine and dried over MgSO4. After evaporation of the solvents, the resulting product is precipitated in an ether/DCM mixture, affording Compound (29) as a white-off solid (125 mg; 37%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11].S(Cl)(Cl)=O.[CH3:16]O>>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:16])=[O:7])=[CH:4][C:3]=1[CH3:11]
Reactant: CO
Reactant: Cc1cc(C(=O)O)ccc1F
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(F)c(C)c1
Temperature: 35 °C
Reaction time: 7 h
Yield: 85 %

Procedure:
To a solution of 4-fluoro-3-methyl-benzoic acid (27.4 g, 178.0 mmol) in methanol (200 mL) was slowly added thionyl chloride (17.8 mL, 243.3 mmol). The solution was stirred at 35° C. for 7 hours. The solution was allowed to cool to room temperature and concentrated in vacuo to an oil. This oil was dissolved in EtOAc (75 mL) and washed sequentially with saturated aqueous sodium bicarbonate solution (2×75 mL) and brine solution (1×75 mL). The organic layer was separated and dried over sodium sulfate, filtered and concentrated in vacuo to provide methyl 4-fluoro-3-methyl-benzoate (25.4 g, 85%) as a red oil. ESI-MS m/z calc. 168.0. found 169.2 (M+1)+; Retention time: 1.48 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 7.92-7.88 (m, 1H), 7.88-7.83 (m, 1H), 7.04 (t, J=8.9 Hz, 1H), 3.90 (s, 3H), 2.31 (d, J=2.0 Hz, 3H).
Reaction SMILES: [Li+].CC(O[Al-](OC(C)(C)C)OC(C)(C)C)(C)C.[C:18]1([C:27](OCC)=[O:28])([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:21][CH2:20][CH2:19]1.OS([O-])(=O)=O.[K+]>C1COCC1.C(OCC)(=O)C>[CH2:25]([O:24][C:22]([C:18]1([CH2:27][OH:28])[CH2:21][CH2:20][CH2:19]1)=[O:23])[CH3:26]
Reactant: CCOC(=O)C1(C(=O)OCC)CCC1
Agent: CC(C)(C)O[Al-](OC(C)(C)C)OC(C)(C)C
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(CO)CCC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 63.2 %

Procedure:
A solution of lithium aluminum-tri-tert-butoxyhydride 1.0M in THF (100.0 mL, 100.0 mmol) is added at −78° C. to a solution of diethyl 1,1-cyclobutanedicarboxylate (10.0 g, 50.0 mmol) in anhydrous THF (50.0 mL). After stirring the reaction mixture at room temperature for 14 h, 10% aq. KHSO4 solution is added and the reaction mixture diluted with ethyl acetate. After separating the two phases, the organic phase is washed with water and brine and dried over anhydrous Na2SO4. Filtration and removal of the solvent under reduced pressure affords 5.0 g of 1-hydroxymethyl-cyclobutanecarboxylic acid ethyl ester that is used in the next step without further purification. Yield: 63%; m/z 159 [M+H].
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:5](=[O:6])[C:4]([CH3:8])([CH3:7])[C:3]1=[O:9]>[Ni].O>[CH3:7][C:4]1([CH3:8])[CH:5]([OH:6])[C:2]([CH3:10])([CH3:1])[CH:3]1[OH:9]
Reactant: CC1(C)C(=O)C(C)(C)C1=O
Agent: [Ni]
Solvent: O
Product: CC1(C)C(O)C(C)(C)C1O
Temperature: 100 °C
Reaction time: 5 h

Procedure:
A 300 mL Autoclave Engineers autoclave was charged with 25 grams of 2,2,4,4-tetramethylcyclobutane-1,3-dione, 87.50 grams Isopar™ G, 12.50 grams of water, and approximately 8 grams of washed raney nickel catalyst. The autoclave was pressure purged three times with nitrogen and three times with hydrogen, and the pressure was increased to 3.5 MPa (500 psig) with hydrogen. The autoclave was heated to 100° C. with stirring at approximately 1400 rpm and held for 5 hours at 3.5 MPa (500 psig). Analysis of the product by gas chromatography indicated that complete conversion of the 2,2,4,4-tetramethylcyclobutane-1,3-dione was obtained with 97.3% selectivity to 2,2,4,4-tetramethycyclobutane-1,3-diol with a cis:trans ratio of 0.6:1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[CH3:14][CH:15]([O:17][C:18](=[O:43])[NH:19][C@H:20]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27](B3OC(C)(C)C(C)(C)O3)[CH:28]=2)[N:23]([C:39](=[O:41])[CH3:40])[C@@H:22]([CH3:42])[CH2:21]1)[CH3:16].C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[C:39]([N:23]1[C:24]2[C:29](=[CH:28][C:27]([C:2]3[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=3)=[CH:26][CH:25]=2)[C@H:20]([NH:19][C:18]([O:17][CH:15]([CH3:16])[CH3:14])=[O:43])[CH2:21][C@@H:22]1[CH3:42])(=[O:41])[CH3:40]
Reactant: CCOC(=O)Cc1ccc(Br)cc1
Reactant: CC(=O)N1c2ccc(B3OC(C)(C)C(C)(C)O3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)Cc1ccc(-c2ccc3c(c2)[C@H](NC(=O)OC(C)C)C[C@H](C)N3C(C)=O)cc1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 59.7 %

Procedure:
A flask was charged with ethyl (4-bromophenyl)acetate (0.174 mL, 1.000 mmol), 1-methylethyl[(2S,4R)-1-acetyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation, see Intermediate 52) (416 mg, 1 mmol), potassium carbonate (415 mg, 3.00 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (73.2 mg, 0.100 mmol) then filled with 1,4-dioxane (6 mL) and water (2 mL) and flushed with nitrogen. The resulting mixture was stirred under microwave irradiation at 120° C. for 30 min then cooled to room temperature. Most of the 1,4-dioxane was removed in vacuo and the residue was partitioned between AcOEt and water. The layers were separated and the aqueous phase was extracted with AcOEt. The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by SP4 on a 25 G silica cartridge (gradient: 5 to 25% of (10% MeOH in DCM) in DCM) gave ethyl {4-[(2S,4R)-1-acetyl-2-methyl-4-({[(1-methylethyl)oxy]carbonyl}amino)-1,2,3,4-tetrahydro-6-quinolinyl]phenyl}acetate (270 mg, 0.597 mmol, 59.7% yield).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=2)[CH:8]=1.CN(C)[CH:21]=[O:22]>C1COCC1>[CH3:18][O:17][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH:21]=[O:22])[CH:16]=[CH:15]2
Reactant: CN(C)C=O
Reactant: COc1ccc2cc(Br)ccc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc2cc(C=O)ccc2c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 75.2 %

Procedure:
To a solution of butyllithium (50.6 ml of a 2.5M solution in hexanes, 126.5 mmol) in THF (200 mL) at -78° C., was added 2-bromo-6-methoxynaphthalene (15.00 g, 63.3 mmol) portionwise. Upon completion of addition, the mixture was stirred for 30 min at -78° C. N,N-Dimethylformamide (6.94 g, 94.95 mmol) was added dropwise. The cooling bath was withdrawn and the reaction allowed to warm to ambient temperature. It was then quenched with saturated aqueous NH4Cl (200 mL) and the THF was stripped off in vacuo. The aqueous residue was extracted with ethyl acetate (3×200 mL). The organics were combined, dried over MgSO4 and concentrated. The resulting residue was chromatographed (silica gel; 1:4 ether, hexanes) to afford 8.86 g (75%) of 6-methoxy-2-naphthalenecarboxaldehyde as a pale yellow solid.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=2)[CH:8]=1.CN([CH:22]=[O:23])C.Cl>CCCCCC.C1COCC1>[CH:22]([C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=2)[CH:8]=1)=[O:23]
Reactant: COc1ccc2cc(Br)ccc2c1
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc2cc(C=O)ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
n-BuLi in hexane (1.59M, 125 ml) was added dropwise to a solution of 2-bromo-6-methoxynaphthalene (42.27 g) in THF (600 ml) at −78° C. and was stirred at −78+ C. for 30 minutes. To the mixture was added DMF (28 ml), and the whole was allowed to warm to room temperature. The reaction mixture was acidified with HCl and extracted with ethyl acetate. The extract was dried and concentrated to give the titled compound (32.31 g) as a colorless solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([OH:25])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].C(N(CC)CC)C>ClCCl>[CH:11](=[O:25])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCCCCCCO
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCC=O
Temperature: 15 °C

Procedure:
A solution of oxalylchloride (8.0 mL, 88.0 mmol, 2.2 eq.) in abs. dichloromethane (200 mL) was treated with DMSO (13.6 mL, 192 mmol, 4.8 eq.) at −60° C. After 3 min the reaction mixture was warmed to approx. 15° C. Then a solution of tetradecan-1-ol (8.56 g, 40.0 mmol) in dry dichloromethane (40 mL) and after further 3 min triethylamine (28 mL, 200 mmol, 5.0 eq.) were added. Then the reaction mixture was slowly warmed to 5° C. and quenched by addition of water (200 mL). The phases were separated and the aqueous phase was extracted with dichloromethane (3×100 mL). The combined organic phases were washed with brine (1×200 mL) and dried over MgSO4. The solvent was removed under reduced pressure and the product was isolated as a white solid, which was used in the next reaction without purification. Yield: 10.4 g (100%), purity: 98% (GC).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8]C(=O)C(C)(C)C)[C:5]([I:15])=[CH:4][CH:3]=1>Cl.CO>[Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([I:15])=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)Nc1nc(Cl)ccc1I
Agent: Cl
Solvent: CO
Product: Nc1nc(Cl)ccc1I
Temperature: 110 °C
Yield: 97.2 %

Procedure:
N-(6-Chloro-3-iodopyridin-2-yl)-2,2-dimethylpropionamide (33 g, 97 mmol) is dissolved in 1N HCl (300 mL) in the presence of catalytic amount of methanol (0.5 mL) at 0° C. The reaction mixture is heated at 110° C. for 5 h. After cooling, the reaction mixture is extracted with ethyl acetate (2×250 mL). The organic layers are separated and the solvent is evaporated to afford the title compound as a viscous liquid (24 g, 97%) which is used in the next step without purification.
Reaction SMILES: [C:1]1([C:7](=[O:11])[C:8](=[O:10])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:12]Br>ClCCCl>[Br:12][CH2:9][C:8](=[O:10])[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:11]
Reactant: BrBr
Reactant: CC(=O)C(=O)c1ccccc1
Solvent: ClCCCl
Product: O=C(CBr)C(=O)c1ccccc1
Reaction time: 1.25 h
Yield: 121.9 %

Procedure:
To a solution of 1-phenyl-propane-1,2-dione (1.72 g, 0.0116 mol) in DCE (5 mL) was added Br2 (1.87 g, 0.0169 mol). The reaction mixture was stirred for 75 min. and the volatiles were removed to yield 3.21 g of 3-bromo-1-phenyl-propane-1,2-dione. The crude bromoketone (0.1046 mol) was combined at room temperature with 3-(1-cyclopentyl-thioureido)-propionic acid tert-butyl ester (7.00 g, 0.031 mol) in NMP (50 mL) following general procedure B. The reaction was purified by silica gel chromatography (gradient, hexane→8% EtOAc-hexane) to yield 3-[(4-Benzoyl-thiazol-2-yl)-cyclopentyl-amino]-propionic acid tert-butyl ester (4.0 g).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:21][C:22]1[N:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.CO.C(Cl)Cl>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:21][C:22]1[N:27]=[CH:26][C:25]([S:28]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(Cl)nc2)CC1
Temperature: 0 °C
Yield: 84.7 %

Procedure:
To a stirred ice-cooled solution of tert-butyl 1-piperazinecarboxylate (0.88 g, 4.7 mmol), triethylamine (1.3 mL, 9.4 mmol), and 4-dimethylaminopyridine (0.0058 g, 0.047 mmol) in DCM (10 mL) was added 6-chloropyridine-3-sulfonyl chloride (1.0 g, 4.7 mmol) in one portion. The resulting mixture was stirred at 0° C. and gradually warmed up to ambient temperature for 1.5 h. Upon workup, the mixture was directly subjected to combi-flash column chromatography (methanol/DCM) to give compound 360 (1.44 g, 84% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8]O)=[CH:6][CH:5]=[CH:4][N:3]=1.S(Cl)([Cl:12])=O>C(Cl)Cl>[Cl:1][C:2]1[C:7]([CH2:8][Cl:12])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: OCc1cccnc1Cl
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: ClCc1cccnc1Cl
Temperature: 10 °C

Procedure:
To a 500 mL, round-bottom, 3-necked flask equipped with dropping funnel and magnetic stirrer and set for reflux was prepared a solution of 2-chloro-3-(hydroxymethyl)-pyridine (25.0 g, 174 mmol) in DCM (250 mL) under positive nitrogen atmosphere. The solution was cooled to 10° C. and thionyl chloride (31.0 g) was added dropwise over 25 minutes (exothermic). The reaction was then heated to reflux for 90 minutes, at which point the reaction was deemed complete by HPLC. The reaction mixture was cooled below boiling point and the equipment set for distillation. A total of 110 mL of DCM was initially removed and replenished with fresh DCM (110 mL), followed by another 80 mL of DCM before cooling the solution to 5-10° C. The acidic mixture was treated with a saturated solution of sodium bicarbonate (3 volumes) to pH 10. The lower organic phase was separated and the aqueous phase extracted with DCM (2 volumes). The organic phases were gathered, dried on sodium sulfate, filtered and concentrated in vacuo to afford the title compound as a pale yellow oil in excellent purity and yield (24.8 g, 88%). δH (d6-DMSO, 300 MHz) 8.45 (1H, dd), 8.10 (1H, dd), 7.50 (1H, dd), 4.85 (2H, s). LCMS (ES)+RT 3.00 min, m/e 162.1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12].C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]([CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[S:11]([C:14]1[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=1)(=[O:13])=[O:12]
Reactant: CCOC(=O)CCCBr
Reactant: COC(=O)c1ccccc1NS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCN(c1ccccc1C(=O)OC)S(=O)(=O)c1ccc(C)cc1
Temperature: 80 °C
Yield: 72 %

Procedure:
2-(Toluene-4-sulfonylamino)-benzoic acid methyl ester from Example E5.1 (100 g) was dissolved in DMF (250 ml). Potassium carbonate (125 g) and ethyl 4-bromobutanoate (60 g) were added and the mixture was heated at 80° C. for 18 h. The mixture was cooled to room temperature, filtered and reduced in vacuo. The residue was partitioned between chloroform and 1M HCl solution. The aqueous layer was extracted with chloroform. The organic layers were combined, washed with brine, dried, filtered and concentrated in vacuo. The material was crystallised from EtOAc/hexane and dried in a vacuum oven at 60° C. for 3 hours to yield the title compound (98.6 g, 72%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][C:4]=1[OH:11].C([O-])([O-])=O.[K+].[K+].[Cl:18][CH2:19][CH2:20][CH2:21]Br>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:6]=[CH:5][C:4]=1[O:11][CH2:21][CH2:20][CH2:19][Cl:18])[C:9]#[N:10]
Reactant: ClCCCBr
Reactant: COc1cc(C#N)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C#N)ccc1OCCCCl
Temperature: 37 °C
Yield: 103 %

Procedure:
2-methoxy-4-cyano-phenol (0.25 g, 1.67 mmol) and anhydrous DMF (2.00 mL) were added into a round bottom flask. The solution was stirred and cooled in a water bath. Several batches of anhydrous K2CO3 (0.347 g, 2.50 mmol) were added to the solution and the mixture was stirred at 20° C. to react for 1 h. 1-chloro-3-bromopropane (0.23 ml, 2.14 mmol) was added, and the mixture was stirred at room temperature (25° C.) to react overnight. The mixture was heated to 37° C. to react for 6 h and then poured into a mixture of ice/H2O (25 mL). After stirring for 10 min, a precipitate was formed. Filtered, washed with H2O, and air-dried to yield white solid product (0.388 g) with a recovery rate of 90%.