Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][C@H:6]([N:8]([C:13]([C:15]2[C:16]([NH:25][CH2:26][CH2:27][CH2:28][S:29][CH3:30])=[N:17][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[N:19][CH:20]=2)=[O:14])[CH2:9][CH:10]([CH3:12])[CH3:11])[CH2:5][N:4]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:3]1.CC(C)([O-])C.[K+].Cl[CH2:45][CH2:46][CH2:47][N:48]=[C:49]=[O:50]>ClCCCl.C1COCC1.O>[C:21]([C:18]1[N:17]=[C:16]([NH:25][CH2:26][CH2:27][CH2:28][S:29][CH3:30])[C:15]([C:13]([N:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[C@H:6]2[CH2:7][C@@H:2]([N:1]3[CH2:45][CH2:46][CH2:47][NH:48][C:49]3=[O:50])[CH2:3][N:4]([C:31]([O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:32])[CH2:5]2)=[O:14])=[CH:20][N:19]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CSCCCNc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@H]1C[C@@H](N)CN(C(=O)OC(C)(C)C)C1
Reactant: O=C=NCCCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCCl
Solvent: O
Product: CSCCCNc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@H]1C[C@@H](N2CCCNC2=O)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl (3R,5S)-3-amino-5-{[(2-tert-butyl-4-{[3-(methylsulfanyl)propyl]amino}pyrimidin-5-yl)carbonyl](2-methylpropyl)amino}piperidine-1-carboxylate (97 mg) was dissolved in 1,2-dichloroethane (2 ml)-THF (2 ml), chloropropyl isocyanate (25 μl) was added, and the mixture was stirred at room temperature for 1 hr. Potassium tert-butoxide (30 mg) was added and the reaction mixture was stirred at room temperature for 8 hr, and further at 60° C. for 12 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in THF (4 ml), sodium hydride (50% contained, 26 mg) was added under ice-cooling, and the mixture was stirred under ice-cooling for 4 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with ethyl acetate-methanol (100:0-90:10) and concentrated under reduced pressure to give the object compound (103 mg).
Reaction SMILES: O.[OH-].[Li+].C([O:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([B:15]([OH:17])[OH:16])=[C:11]([O:18][CH3:19])[CH:10]=1)=[O:8])C.O.Cl>O1CCOCC1>[C:7]([C:9]1[CH:14]=[CH:13][C:12]([B:15]([OH:17])[OH:16])=[C:11]([O:18][CH3:19])[CH:10]=1)([OH:8])=[O:6]
Reactant: CCOC(=O)c1ccc(B(O)O)c(OC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(C(=O)O)ccc1B(O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.7 %

Procedure:
Lithium hydroxide monohydrate (0.092 g) was added to a mixture of 4-ethoxycarbonyl-2-methoxyphenylboronic acid (0.049 g), water (1 mL) and 1,4-dioxane (1 mL), and the mixture was stirred at room temperature overnight. To the reaction mixture was added 2 mol/L hydrochloric acid (1.09 mL), and the solvent was evaporated under reduced pressure. The residue was washed with water to afford the title compound (0.035 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[NH:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[C:18]([C:28]([O:30]CC)=[O:29])[N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].S([O-])(O)(=O)=O.[K+]>CO>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[NH:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[C:18]([C:28]([OH:30])=[O:29])[N:17]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1nc(N[C@H]2CCCC[C@H]2NC(=O)OC(C)(C)C)c2cc(OC)ccc2n1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2nc(C(=O)O)nc(N[C@H]3CCCC[C@H]3NC(=O)OC(C)(C)C)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.1 %

Procedure:
A solution of 1.70 g of cis-N-tert-butoxycarbonyl-2-(2-ethoxycarbonyl-6-methoxyquinazolin-4-yl)aminocyclohexylamine in 5 mL of methanol was combined with 5 mL of a 1N aqueous solution of sodium hydroxide, and stirred at room temperature for 3 hours. After the pH was adjusted to 5 by addition of a 1N aqueous solution of potassium hydrogen sulfate to the reaction solution, which was then extracted with chloroform and dried. After the solvent was distilled off, the residue was purified by column chromatography on silica gel (chloroform:methanol=10:1) to obtain 1.10 g of the desirable compound.
Reaction SMILES: C([S:4][CH2:5][CH2:6][C@@H:7]([C:19]([NH:21][C@H:22]([C:32]([O:34][CH3:35])=[O:33])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH:30]=[O:31])=[O:20])[NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])(=O)C>CO.C(Cl)Cl>[CH:30]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:23][C@@H:22]([C:32]([O:34][CH3:35])=[O:33])[NH:21][C:19](=[O:20])[C@H:7]([CH2:6][CH2:5][SH:4])[NH:8][C:9]([O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:10])=[O:31]
Reactant: COC(=O)[C@H](Cc1ccccc1C=O)NC(=O)[C@H](CCSC(C)=O)NC(=O)OCc1ccccc1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccccc1C=O)NC(=O)[C@H](CCS)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 104.2 %

Procedure:
A solution of the title compound of step (J) (0.77 g, 1.54 mmol) in MeOH (16 mL) and CH2Cl2 (3 mL) cooled at 0° C. was purged with argon for 20 minutes. To this solution 370 μL of NaOMe (25% w/w in MeOH) was added dropwise. After addition, the mixture was stirred at 0° C. for 15 minutes before being quenched with sat. aqueous NH4Cl (20 mL). The mixture was extracted with EtOAc (200 mL). The separated aqueous phase was back-extracted with EtOAc (50 mL). The combined EtOAc was washed with sat. aqueous NH4Cl, H2O, brine, dried (MgSO4), filtered, concentrated and dried in vacuo to give 0.736 g of the title compound of this step as a white foam which was used in the next reaction step without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][CH:9]2[CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]2)=[CH:3][CH:2]=1.[ClH:20]>C(OCC)C>[ClH:20].[ClH:20].[NH:11]1[CH2:12][CH:9]([O:8][CH2:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CC(OCc2ccncc2)C1
Agent: Cl
Solvent: CCOCC
Product: c1cc(COC2CNC2)ccn1
Reaction time: 1 h
Yield: 65 %

Procedure:
To a solution of tert-butyl 3-(pyridin-4-ylmethoxy)azetidine-1-carboxylate (313 mg, 1.18 mmol; which may be prepared as described in Step 3) in diethyl ether (4 mL) at 0° C. was added HCl 2N in diethyl ether (12 mL). The reaction mixture was stirred for 1 h then mixture was filtered. The resulting solid was rinsed with diethyl ether and collected to give the title compound as a white solid (155 mg, 65%).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:30]O.Cl>CO.O.C(Cl)Cl>[F:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][CH2:18][C@H:10]2[CH2:9][C@H:8]([C:6]3[O:7][NH:30][C:4](=[O:3])[CH:5]=3)[CH2:13][CH2:12][N:11]2[C:14]([O:16][CH3:17])=[O:15])=[CH:21][CH:22]=1
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](CCc2ccc(F)cc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1CCc1ccc(F)cc1
Temperature: -40 °C
Reaction time: 0.25 h
Yield: 82.2 %

Procedure:
Trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(4-fluorophenethyl)piperidine-1-carboxylate (730 mg, 1.92 mmol) (from example 92, step 1) was dissolved in MeOH (7 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (77 mg, 1.92 mmol) dissolved in water (0.700 mL) was added and the mixture was stirred at −40° C. for 15 min. Hydroxylamine (50% by weight in water, 0.118 mL, 1.92 mmol) was added. The resulting solution was stirred at −40° C. for 3 h. The mixture was then transferred into a prewarmed (80° C.) solution of 6 M hydrogen chloride (9.94 mL, 59.64 mmol) and the mixture was stirred at 80° C. for 20 min. DCM and water were added. The phases were separated, the aqueous phase extracted with DCM and the combined organic layers passed through a phase separator and evaporated. The residue was purified by automated flash chromatography on a Biotage® KP-SIL 100 g column. DCM:MeOH:HCOOH=50:1:0.1 over 10 CV was used as mobile phase. Trans-methyl 2-(4-fluorophenethyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (550 mg, 82%) was isolated. 1H NMR (400 MHz, cdcl3) δ 1.01-2.13 (m, 6H), 2.48-2.70 (m, 2H), 2.88-3.08 (m, 2H), 3.70 (s, 3H), 3.98-4.69 (m, 2H), 5.64 (s, 1H), 6.91-7.02 (m, 2H), 7.06-7.21 (m, 2H). MS m/z 349 (M+H)+
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[Cl:7][C:8]1[CH:17]=[CH:16][C:11]2[NH:12][C:13](=O)[O:14][C:10]=2[CH:9]=1.[ClH:18]>ClC1C=CC=CC=1Cl>[Cl:18][C:13]1[O:14][C:10]2[CH:9]=[C:8]([Cl:7])[CH:17]=[CH:16][C:11]=2[N:12]=1
Reactant: Cl
Reactant: O=c1[nH]c2ccc(Cl)cc2o1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: Clc1ccccc1Cl
Product: Clc1ccc2nc(Cl)oc2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 72 %

Procedure:
1 litre of o-dichlorobenzene and 625 g (3 moles) of phosphorus pentachloride are heated to 160° C., then 169.5 g (1 mole) of solid 6-chlorobenzoxazolin-2-one are introduced in small portions over the course of 60 minutes, vigorous evolution of hydrogen chloride occuring for a short time after each portion. The mixture is then stirred for a further 15 minutes at 150°-160° C., and then cooled to 0° C., whereupon the major part of the excess pCl5 crystallises out. The phosphorus pentachloride precipitate is filtered off with suction, Washed with a little cold o-dichlorobenzene, and the filtrate is fractionated under reduced pressure. phosphorus oxychloride distils over first, then o-dichlorobenzene together with the remainder of the excess phosphorus pentachloride, and last, at about 110° C. and 17.3 mbar, 2,6-dichlorobenzoxazole. About 136 g of 2,6-dichlorobenzoxazole of melting point 48-49° C. are obtained. GC purity 99.7%. yield: 72% of theory.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([CH:6]1[CH2:8][CH:7]1[C:9]1[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:16])[CH3:5].C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C>[Cl:15][C:14]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:16])[C:9]=1[C@@H:7]1[CH2:8][C@H:6]1[CH:4]([NH:3][O:2][CH3:1])[CH3:5]
Reactant: CON=C(C)C1CC1c1c(Cl)cccc1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CONC(C)[C@@H]1C[C@H]1c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A solution of 1-[2-(2,6-dichloro-phenyl)-cyclopropyl]-ethanone O-methyl-oxime (300 mg, 1.16 mmol), prepared as described in example P22, in ethanol (2 ml) and acetic acid (1 ml) was treated at ambient temperature with sodium cyanoborohydride (144 mg, 2.32 mmol) added in one portion. The resulting solution was stirred at ambient temperature for 10 hours. The solvent was evaporated under reduced pressure (co-evaporation with toluene twice) and the residue was slurried with 1 M NaOH (15 ml). The aqueous phase was extracted with ether (3×10 ml), washed with brine and dried over anhydrous Na2SO4. After removal of the solvent, the residue was purified by flash chromatography over silica gel (15 g) (eluent: c-hexane/ethyl acetate 3:1). 260 mg (89.0% of theory) of trans-N-{1-[2-(2,6-dichlorophenyl)-cyclopropyl]-ethyl}-O-methyl-hydroxylamine as a mixture of diastereomeres was obtained in form of a clear liquid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]([CH:9]2[CH2:13][CH2:12][CH:11]([NH:14][S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20](Br)[CH:19]=3)(=[O:17])=[O:16])[CH2:10]2)[C:4](=[O:25])[N:3]=1.[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>C(#N)C.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]>[NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]([CH:9]2[CH2:13][CH2:12][CH:11]([NH:14][S:15]([C:18]3[CH:19]=[C:20]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[F:26])[CH:21]=[CH:22][CH:23]=3)(=[O:17])=[O:16])[CH2:10]2)[C:4](=[O:25])[N:3]=1
Reactant: OB(O)c1ccccc1F
Reactant: Nc1nc(=O)n(C2CCC(NS(=O)(=O)c3cccc(Br)c3)C2)cc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: Nc1nc(=O)n(C2CCC(NS(=O)(=O)c3cccc(-c4ccccc4F)c3)C2)cc1F
Reaction time: 0.01 h
Yield: 38.1 %

Procedure:
To a solution of N-[3-(4-amino-5-fluoro-2-oxo-2H-pyrimidin-1-yl)-cyclopentyl]-3-bromo-benzenesulfonamide (66 mg, 0.153 mmol) in acetonitrile (2.5 mL), 2-fluorophenylboronic acid (35 mg, 0.25 mmol), [1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium (20 mg, 0.024 mmol) and 2M Na2CO3 solution (2.5 mL) were added, the mixture was stirred for 30 seconds. The reaction was completed by microwave at 120° C. for ten minutes. The organic phase of the reaction mixture was filtered and purified by a reverse phase preparative HPLC, giving 26 mg (38%) 2′-fluoro-biphenyl-3-sulfonic acid [3-(4-Amino-5-fluoro-2-oxo-2H-pyrimidin-1-yl)-cyclopentyl]-amide (6) as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:24])[CH2:4][N:5]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)(=[O:8])=[O:7].O.[OH-].[Li+]>C1COCC1>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([N:5]([CH2:4][C:3]([OH:24])=[O:2])[S:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)(=[O:7])=[O:8])=[CH:22][CH:21]=1
Reactant: COC(=O)CN(c1ccc(Cl)cc1)S(=O)(=O)c1cccc(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(S(=O)(=O)N(CC(=O)O)c2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of [(4-chlorophenyl)-(3-methoxy-benzenesulfonyl)-amino]-acetic acid methyl ester (1.03 g, 2.7 mmol) in THF (20 mL) was added an aqueous solution (10 mL) of lithium hydroxide monohydrate (168 mg, 4.0 mmol) slowly under ice-cooled condition. The reaction mixture was stirred for 2 h at 25° C. THF was evaporated in vacuo and water was added. The mixture was washed with diethyl ether. The aqueous layer was acidified with 1(N) hydrochloride acid to pH 6, and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with water, dried (Na2SO4), and evaporated under reduced pressure to yield the title compound as pure solid compound, which used as such in the final coupling reaction. Yield: 810 mg (84%).
Reaction SMILES: [CH2:1]([OH:12])[C@H:2]([OH:11])[C@@H:3]([OH:10])[C@H:4]([OH:9])[C:5]([CH:7]=[O:8])=[O:6].C[N+]1C2C(=CC=CC=2)N=C2C=1C=CC=C2.C[O:29]S([O-])(=O)=O>P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[CH2:1]([OH:12])[C@H:2]([OH:11])[C@@H:3]([OH:10])[C@H:4]([OH:9])[C:5]([C:7]([OH:29])=[O:8])=[O:6]
Reactant: O=CC(=O)[C@@H](O)[C@H](O)[C@@H](O)CO
Reactant: COS(=O)(=O)[O-]
Agent: C[n+]1c2ccccc2nc2ccccc21
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: O=C(O)C(=O)[C@@H](O)[C@H](O)[C@@H](O)CO
Reaction time: 1 h

Procedure:
A reaction mixture containing the purified aldehyde dehydrogenase (0.04 mg protein, and prepared according to Example 1), L-sorbosone (4 mg) and phenazine methosulfate (0.2 mg) in 1.0 ml of 0.5M potassium phosphate buffer (pH 7.0) was incubated for 1.0 hour at 25° C. with gentle shaking. As a result, 2-keto-L-gulonic acid was formed at the rate of about 2.3 mg/hour.
Reaction SMILES: [C:1]([O:5]/[N:6]=[CH:7]\[C:8]1[C:9]([C:14](=[O:23])[C:15]2[CH:20]=[C:19]([Br:21])[CH:18]=[CH:17][C:16]=2[OH:22])=[N:10][CH:11]=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].CC(C)=[O:26].OS(O)(=O)=O.O=[Cr](=O)=O.C(OCC)C>CC(C)=O>[C:1]([O:5]/[N:6]=[C:7](\[OH:26])/[C:8]1[CH:13]=[CH:12][CH:11]=[N:10][C:9]=1[C:14](=[O:23])[C:15]1[CH:20]=[C:19]([Br:21])[CH:18]=[CH:17][C:16]=1[OH:22])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)=O
Reactant: CC(C)(C)O/N=C\c1cccnc1C(=O)c1cc(Br)ccc1O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: CC(C)(C)O/N=C(\O)c1cccnc1C(=O)c1cc(Br)ccc1O

Procedure:
To a solution of (Z)-2-(5-bromo-2-hydroxybenzoyl)-3-formylpyridine O-t-butyloxime (500 mg) in acetone (4 ml) was added, at room temperature, Jones reagent (1 ml), and the mixture was stirred for 30 minutes. To the reaction mixture was added diethyl ether. Insolubles then formed were filtered off. To the filtrate was added a small volume of isopropyl alcohol, and the mixture was concentrated. The concentrate was purified by means of a silica gel column chromatography (eluent: diethyl ether) to give (Z)-2-(5-bromo-2-hydroxybenzoyl)nicotinic acid O-t-butyloxime (240 mg (Compound 138).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([CH:20]3[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]3)=[O:19])[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:13][CH2:14][N:15]([C:18]([CH:20]3[CH2:24][CH2:23][NH:22][CH2:21]3)=[O:19])[CH2:16][CH2:17]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)N2CCN(C(=O)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCN(C(=O)C2CCNC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of tert-butyl 3-[(4-{[(3,4-dichlorophenyl)amino]carbonyl}piperazin-1-yl)carbonyl]pyrrolidine-1-carboxylate (3.485 g, 7.39 mmol) in DCM (30 ml) was added TFA (30 ml). The reaction was allowed to stir at ambient temperature for 1 hour. The solvents were then removed in vacuo, residue partitioned between DCM and 2M NaOH, extracted twice and the combined organics dried (Na2SO4), filtered and evaporated to dryness to give the product, N-(3,4-dichlorophenyl)-4-(pyrrolidin-3-ylcarbonyl)piperazine-1-carboxamide, as a pale yellow foam (20.745 g, 7.39 mmol, 100%).
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:10]([CH3:15])=[C:11]([CH:13]=O)[N:12]=2)[CH:9]=1.[CH2:16]1COCC1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:13]([C:11]1[N:12]=[C:7]2[CH:6]=[CH:5][C:4]([I:3])=[CH:9][N:8]2[C:10]=1[CH3:15])=[CH2:16]
Reactant: C1CCOC1
Reactant: Cc1c(C=O)nc2ccc(I)cn12
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [H-]
Product: C=Cc1nc2ccc(I)cn2c1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred suspension of methyltriphenylphosphonium bromide (3.1 g) in THF (20 ml) was added NaH (60% in oil, 336 mg) at 0° C. The reaction mixture was then stirred at room temperature for 16 h. A solution of 6-iodo-3-methylimidazo[1,2-a]pyridine-2-carbaldehyde (500 mg) in THF (10 ml) was added to the reaction mixture at 0° C., and the resulting mixture was stirred at room temperature for 4 h. The reaction mixture was quenched with ice-water (20 ml) and extracted with EtOAc. The extract was washed with brine, dried over Na2SO4, concentrated in vacuo and purified by column chromatography (hexane/EtOAc) to afford the title compound (350 mg) as an off-white solid.
Reaction SMILES: [F:1][C:2]1[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:3]=1[CH2:4][S:5][C:6]1[N:11]=[C:10]([NH:12][S:13]([N:16]2[CH2:19][CH:18]([NH:20]C(=O)OC(C)(C)C)[CH2:17]2)(=[O:15])=[O:14])[CH:9]=[C:8]([O:28][CH3:29])[N:7]=1.C(O)(C(F)(F)F)=O>CO>[NH2:20][CH:18]1[CH2:19][N:16]([S:13]([NH:12][C:10]2[CH:9]=[C:8]([O:28][CH3:29])[N:7]=[C:6]([S:5][CH2:4][C:3]3[CH:30]=[CH:31][CH:32]=[C:33]([F:34])[C:2]=3[F:1])[N:11]=2)(=[O:14])=[O:15])[CH2:17]1
Reactant: COc1cc(NS(=O)(=O)N2CC(NC(=O)OC(C)(C)C)C2)nc(SCc2cccc(F)c2F)n1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(NS(=O)(=O)N2CC(N)C2)nc(SCc2cccc(F)c2F)n1
Reaction time: 2 h

Procedure:
A solution of tert-butyl {1-[({2-[(2,3-difluorobenzyl)thio]-6-methoxypyrimidin-4-yl}amino)sulfonyl]azetidin-3-yl}carbamate (the product of step ii, 0.48 g) and TFA (2 ml) in methanol (6 ml) was stirred at room temperature for 1.5 h then the volatiles evaporated and 7M ammonia in methanol (6 ml) added to the residue. The solution was stirred for 2 h then the volatiles evaporated and the residue purified by column chromatography on silica using a 2-8% mixture of methanol in DCM and then further purified by reverse phase HPLC (gradient 5-95% acetonitrile in 0.1% aqueous ammonium acetate) to afford the title compound as a white solid. Yield: 73 mg
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:5][CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:26][C:27]1[C:36]2[C:31](=[C:32]([CH3:41])[C:33]([S:37](Cl)(=[O:39])=[O:38])=[CH:34][CH:35]=2)[N:30]=[CH:29][CH:28]=1.[NH4+].[Cl-]>C1COCC1>[Cl:26][C:27]1[C:36]2[C:31](=[C:32]([CH3:41])[C:33]([S:37]([N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:15][CH:14]=3)[C:9]3[S:10][CH:11]=[CH:12][N:13]=3)(=[O:38])=[O:39])=[CH:34][CH:35]=2)[N:30]=[CH:29][CH:28]=1
Reactant: COc1ccc(CNc2nccs2)cc1
Reactant: Cc1c(S(=O)(=O)Cl)ccc2c(Cl)ccnc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)ccnc3c2C)cc1
Reaction time: 0.25 h
Yield: 29.4 %

Procedure:
To a flask containing ice cold suspension of N-(4-methoxybenzyl)thiazol-2-amine (557 mg, 2.53 mmol) in THF (9.0 ml) was added lithium bis(trimethylsilyl)amide (1M in THF) (4816 μl, 4.82 mmol) faster than drop wise. The mixture was stirred for 15 mins prior to the drop wise addition of a solution of 4-chloro-8-methylquinoline-7-sulfonyl chloride (665 mg, 2.408 mmol) in THF (6.0 ml, 1.0 ml wash). The solution was allowed to stir for 20 mins (ice melt) providing a brown solution containing primarily product according to LC-MS. The mixture was added to a flask containing sat. aq. NH4Cl and ice. The aqueous mixture was extracted 2× with EtOAc and the combined organics were dried with Na2SO4, filtered, and dried under reduced pressure. The crude material was purified with a 25 g HP silicycle column ramping EtOAc in heptane (0-50%, 10% DCM throughout) affording product, 4-chloro-N-(4-methoxybenzyl)-8-methyl-N-(thiazol-2-yl)quinoline-7-sulfonamide (326 mg, 0.709 mmol, 29.4% yield) as a yellow solid. m/z (ESI) 460.3 (M+H)+.
Reaction SMILES: C([Mg]Br)C.[C:5]([Si:7]([CH3:10])([CH3:9])[CH3:8])#[CH:6].[CH3:11][CH:12]([CH3:21])[C:13]([C:15]1[CH:16]=[N:17][CH:18]=[N:19][CH:20]=1)=[O:14]>O1CCCC1>[OH:14][C:13]([C:15]1[CH:20]=[N:19][CH:18]=[N:17][CH:16]=1)([CH:12]([CH3:21])[CH3:11])[C:6]#[C:5][Si:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)C(=O)c1cncnc1
Reactant: C#C[Si](C)(C)C
Agent: CC[Mg]Br
Solvent: C1CCOC1
Product: CC(C)C(O)(C#C[Si](C)(C)C)c1cncnc1
Reaction time: 0.75 h
Yield: 81.7 %

Procedure:
A solution of ethyl magnesium bromide (33 ml of a solution which was 3M in tetrahydrofuran; 0.1 mol) was added to a stirred, cooled solution of ethynyltrimethylsilane (9.8 g,0.1 mol) in dry tetrahydrofuran (150 ml) under nitrogen. The rate of addition was adjusted so as to maintain the reaction temperature below 30° C. After stirring for 45 minutes, 2-methyl-1-pyrimidin-5-ylpropan-1-one (15 g, 0.1 mol) in dry tetrahydrofuran (30 ml) was slowly added. The mixture was allowed to react for 2.8 hours before quenching with dilute aqueous HCl. Extraction with ethyl acetate, drying (over sodium sulphate) and concentration under reduced pressure gave the title compound as white crystals (20.3 g). The product was further purified by recrystallisation from hexane to give a solid of melting point 116.6° C.