Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C@H:2]1[C@H:7]([OH:8])[C:6]2[CH:9]=[C:10]([C:13]#[N:14])[CH:11]=[CH:12][C:5]=2[O:4][C:3]1([CH3:16])[CH3:15].C(Cl)CCl.[C:21]([S:24][CH2:25][C@H:26]([CH3:30])[C:27](Cl)=[O:28])(=[O:23])[CH3:22]>N1C=CC=CC=1>[Br:1][C@H:2]1[C@H:7]([O:8][C:27](=[O:28])[C@H:26]([CH3:30])[CH2:25][S:24][C:21](=[O:23])[CH3:22])[C:6]2[CH:9]=[C:10]([C:13]#[N:14])[CH:11]=[CH:12][C:5]=2[O:4][C:3]1([CH3:16])[CH3:15]
Reactant: CC(=O)SC[C@H](C)C(=O)Cl
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](O)[C@@H]1Br
Solvent: ClCCCl
Solvent: c1ccncc1
Product: CC(=O)SC[C@@H](C)C(=O)O[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1Br
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.4 %

Procedure:
To a mixture of 94 g of (±)-trans-3-bromo-6-cyano-3,4-dihydro-2,2-dimethyl-4-hydroxy-2H-1-benzopyran, 800 ml of ethylene chloride and 32.4 ml of pyridine was added 66 g of (S)-(-)-3-acetylthio-2-methylpropionyl chloride under ice-cooling over 5 minutes and stirred for 1.5 hours under room temperature. The reaction mixture was washed with diluted hydrochloric acid once and 10% aqueous sodium chloride solution twice. The organic layer was separated, dried over magnesium sulfate and concentrated under reduced pressure to give 139.8 g of (±)-trans-3-bromo-6-cyano-3,4-dihydro-2,2-dimethyl-4-[(S)-(-)-3-acetylthio-2-methylpropionyloxy]-2H-1-benzopyran as a light yellow oily substance.
Reaction SMILES: N1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=N1.[Br:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1.[CH:18](=[O:22])CCC.C(NC=O)=C>C1(C)C=CC=CC=1.CCOC(C)=O.O.CC1C=CC(S(O)(=O)=O)=CC=1>[Br:10][C:11]1[CH:17]=[C:16]2[C:14](=[CH:13][CH:12]=1)[NH:15][C@@H:6]([CH2:7][CH2:8][CH3:9])[CH2:5][C@H:4]2[NH:3][CH:18]=[O:22]
Reactant: Nc1ccc(Br)cc1
Reactant: c1ccc2[nH]nnc2c1
Reactant: CCCC=O
Agent: C=CNC=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: CCC[C@H]1C[C@@H](NC=O)c2cc(Br)ccc2N1
Temperature: 0 °C
Reaction time: 16 h
Yield: 29.9 %

Procedure:
To a suspension of 1H-1,2,3-benzotriazole (3.46 g, 29.1 mmol) in toluene (38 mL) was added 4-bromoaniline (5.09 g, 29.1 mmol) in toluene (4.7 mL) and the reaction mixture was bubbled with Argon gas then cooled to 0° C. Butanal (2.88 mL, 32 mmol) in toluene (4.7 mL) was added dropwise and the resulting mixture was allowed to warm to room temperature and stirred for 16 h before being treated with ethenylformamide (2.03 mL, 29.1 mmol), 4-methylbenzenesulfonic acid monohydrate (55.3 mg, 0.29 mmol). The resulting mixture was stirred at 72° C. for 3 h then cooled to room temperature and diluted with AcOEt (50 mL). The organic phase was washed with a 1M NaOH aqueous solution (20 mL), water (50 mL) then brine (50 mL), dried over MgSO4 and concentrated in vacuovacuo. The residue was recrystallised from petroleum/Et2O (1:10, 3×30 mL) to give [(cis)-6-bromo-2-propyl-1,2,3,4-tetrahydro-4-quinolinyl]formamide (2.59 g, 29%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([NH:18][C:19]3([C:27]4[CH:28]=[N:29][N:30](C5CCCCO5)[CH:31]=4)[CH2:24][O:23]C(C)(C)[O:21][CH2:20]3)=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.[ClH:43].O1CCOCC1>CO.O>[ClH:43].[F:42][C:38]1[CH:39]=[CH:40][CH:41]=[C:2]([F:1])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([NH:18][C:19]([C:27]3[CH:31]=[N:30][NH:29][CH:28]=3)([CH2:20][OH:21])[CH2:24][OH:23])=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NC1(c2cnn(C3CCCCO3)c2)COC(C)(C)OC1
Agent: Cl
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NC(CO)(CO)c1cn[nH]c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 75 mg of 8-[(2,6-difluorobenzyl)oxy]-N-{2,2-dimethyl-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]-1,3-dioxan-5-yl}-2-methylimidazo[1,2-a]pyridine-3-carboxamide in 0.4 ml of methanol and 0.4 ml of water was added 1.6 ml of a 4 M hydrogen chloride/1,4-dioxane solution, followed by stirring at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure to obtain 74 mg of 8-[(2,6-difluorobenzyl)oxy]-N-[1,3-dihydroxy-2-(1H-pyrazol-4-yl)propan-2-yl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide hydrochloride.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[OH:13][C:14]([CH3:53])([CH3:52])[CH:15]([CH3:51])[O:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=4)=[CH:33][CH:32]=3)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]3[N:48]=[CH:49][N:50]=[C:24]23)[CH2:19][CH2:18]1>O.C(OCC)(=O)C>[OH:13][C:14]([CH3:52])([CH3:53])[CH:15]([CH3:51])[O:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=4[C:43]4[NH:3][C:4](=[O:7])[O:5][N:44]=4)=[CH:33][CH:32]=3)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]3[N:48]=[CH:49][N:50]=[C:24]23)[CH2:19][CH2:18]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OC(C)C(C)(C)O)CC2)c2ncnn12
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OC(C)C(C)(C)O)CC2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.36 g), sodium hydrogen carbonate (0.58 g) and dimethyl sulfoxide (3 mL) was stirred at 40° C. for 30 min, 4′-({4-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.19 g) was added, and the mixture was stirred at 90° C. for 15 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (2 mL). N,N′-Carbonyldiimidazole (0.070 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.065 mL) were added, and the mixture was stirred at room temperature for 1 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was acidified with 1 M hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.12 g, 58%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O-:12])=[O:11])=[CH:4][C:3]=1[O:13][CH3:14].[K+].CN(C=O)C.Br[CH2:22][CH2:23][CH2:24][CH2:25][O:26][N+:27]([O-:29])=[O:28]>C(Cl)Cl>[N+:27]([O:26][CH2:25][CH2:24][CH2:23][CH2:22][O:11][C:10](=[O:12])/[CH:9]=[CH:8]/[C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([O:13][CH3:14])[CH:4]=1)([O-:29])=[O:28]
Reactant: COc1cc(/C=C/C(=O)[O-])ccc1O
Reactant: O=[N+]([O-])OCCCCBr
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(/C=C/C(=O)OCCCCO[N+](=O)[O-])ccc1O
Temperature: 40 °C
Yield: 70 %

Procedure:
A mixture of potassium (E)-3-(4-hydroxy-3-methoxyphenyl)-2-propenoate (2.07 g; 9 mmol), obtained in the previous step, DMF (8.3 g), KI (0.5 g) and a 20% w/w solution (82.5 g) of 4-bromobutylnitrate (16.5 g; 16.7 mmol) in CH2Cl2 is heated under stirring to 40° C. and kept at this temperature under stirring for 136 h. After work up, (E)-3-(4-hydroxy-3-methoxyphenyl)-2-propenoic acid 4-(nitrooxy)butyl ester was obtained in 70% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:18]([F:21])([F:20])[F:19])=[CH:11][C:12]=2[S:13][C:14]([F:17])([F:16])[F:15])=[CH:4][CH:3]=1.OO.C(OCC)(=[O:26])C.[OH2:30]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:18]([F:21])([F:19])[F:20])=[CH:11][C:12]=2[S:13]([C:14]([F:16])([F:17])[F:15])(=[O:26])=[O:30])=[CH:4][CH:3]=1
Reactant: O
Reactant: CCOC(C)=O
Reactant: FC(F)(F)Sc1cc(C(F)(F)F)[nH]c1-c1ccc(Cl)cc1
Agent: OO
Solvent: CC(=O)O
Product: O=S(=O)(c1cc(C(F)(F)F)[nH]c1-c1ccc(Cl)cc1)C(F)(F)F
Temperature: 95 °C

Procedure:
A solution of 2-(p-chlorophenyl)-5-(trifluoromethyl)-3-[(trifluoromethyl)thio]pyrrole (1.5 g, 4.3 mmol) in acetic acid is treated with hydrogen peroxide (1.5 mL, 30%, 13 mmol), stirred at 95° C. for several hours, treated with additional hydrogen peroxide (1 mL), stirred at 90° C. for four hours, cooled to room temperature, stirred for 48 hours, treated with additional hydrogen peroxide (1 mL), stirred for several hours at reflux, cooled and diluted with an ethyl acetate/water mixture. The organic phase is separated, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain an oil. Crystallization of the oil from petroleum ether gives a white semi-solid which is chromatographed using silica gel and a 1:9 ethyl acetate/hexanes solution to obtain the title product as a white solid (mp 167°-169° C.) which is identified by 1HNMR, 19FNMR and 13CNMR spectral analyses.
Reaction SMILES: ClCCCl.Cl.[NH2:6][C:7]12[CH2:14][CH:13]3[CH2:15][CH:9]([CH2:10][CH:11]1[CH2:12]3)[CH2:8]2.C(N(CC)CC)C.Cl.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]([C:42]2[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=2)[C:33]2[CH:34]=[N:35][CH:36]=[CH:37][C:38]=2[C:39](Cl)=[O:40])=[CH:28][CH:27]=1>O>[CH:9]12[CH2:15][CH:13]3[CH2:12][CH:11]([CH2:10]1)[C:7]([NH:6][C:39]([C:38]1[CH:37]=[CH:36][N:35]=[CH:34][C:33]=1[CH:32]([C:29]1[CH:30]=[CH:31][C:26]([O:25][CH3:24])=[CH:27][CH:28]=1)[C:42]1[CH:43]=[CH:44][C:45]([O:48][CH3:49])=[CH:46][CH:47]=1)=[O:40])([CH2:14]3)[CH2:8]2
Reactant: COc1ccc(C(c2ccc(OC)cc2)c2cnccc2C(=O)Cl)cc1
Reactant: NC12CC3CC(CC1C3)C2
Agent: Cl
Solvent: O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(c2ccc(OC)cc2)c2cnccc2C(=O)NC23CC4CC(CC2C4)C3)cc1
Reaction time: 7 h
Yield: 46.5 %

Procedure:
To 10 ml of 1,2-dichloroethane solution containing 2 g of 3-aminotricyclo[3.3.1.03,7 ]nonane hydrochloride and 10 ml of triethylamine was added 4.64 g of Compound c at room temperature. Then the mixture was stirred for 7 hours, followed by addition of water thereto to separate the organic layer. The aqueous layer was extracted with chloroform, then combined with the organic layer, washed with a saturated sodium chloride and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, 2.5 g of the desired compound was obtained as a solid.
Reaction SMILES: O=[CH:2][CH2:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14].Cl.[CH3:16][O:17][NH2:18].C(=O)([O-])[O-].[Na+].[Na+].O>C(O)C>[CH3:16][O:17][N:18]=[CH:2][CH2:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14]
Reactant: CON
Reactant: O=CCN1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CON=CCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 45.1 %

Procedure:
0.560 g (2.96 mmol) of N-(2-oxoethyl)phthalimide was dissolved in 20 ml of ethanol and to the solution was added 0.330 g (3.95 mmol) of O-methylhydroxylamine hydrochloride. To this suspension was added 10 ml of 0.35M aqueous sodium carbonate solution, followed by being stirred at room temperature for 3 days. The reaction mixture was poured into 100 ml of water and extracted with chloroform (20 ml×3), and the combined organic layer was dried over magnesium sulfate. Chloroform was distilled off and the residual solids were washed with petroleum ether to give 0.291 g (yield 45%) of the titled compound as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8](CC3C=CC(OC)=CC=3)[N:9]=[CH:10][C:3]=12.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][N:9]=[CH:10][C:3]=12
Reactant: COc1ccc(Cn2ncc3c(Cl)ccnc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccnc2[nH]ncc12
Temperature: 75 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
4-chloro-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine (1.506 g, 5.502 mmol) was dissolved in neat TFA (8.478 ml, 110.0 mmol) and the reaction mixture was stirred at 75° C. for 2 hours. The reaction mixture was concentrated to a dark yellow oil and MeOH was added to give a thick white precipitate that was filtered and washed with MeOH. The filtrate, which contained the desired product, was concentrated to a yellow oil that was dried in vacuo overnight to yield a yellow waxy solid. The crude solid was partitioned between EtOAc and saturated NaHCO3. The phases were separated, and the aqueous layer was re-extracted with EtOAc (1×). The combined organic phases were dried over Na2SO4, filtered and concentrated to yield the desired product (0.845 g, 100%) as a yellow solid. LRMS (APCI pos) m/e 154, 156 (M+, Cl pattern).
Reaction SMILES: [Br:1][C:2]1[CH2:6][CH:5]([C:7]([O:9]CC)=O)[O:4][N:3]=1.[NH3:12]>CO>[Br:1][C:2]1[CH2:6][CH:5]([C:7]([NH2:12])=[O:9])[O:4][N:3]=1
Reactant: CCOC(=O)C1CC(Br)=NO1
Reactant: N
Solvent: CO
Product: NC(=O)C1CC(Br)=NO1

Procedure:
A mixture of ethyl 3-bromo-4,5-dihydroisoxazole-5-carboxylate (6.2 g, 28 mmol) and a solution of 2M ammonia in MeOH (56 mL) was stirred at room temperature for 1-2 h. Volatile materials were removed in vacuo to give the crude title compound as a white solid.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](=O)[CH2:7][C:8]1[O:13]C(C)(C)O[C:10](=[O:16])[CH:9]=1)(=[O:3])[CH3:2].[NH2:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([NH2:24])=[O:23].CS(O)(=O)=O>O1CCOCC1>[C:1]([O:4][CH2:5][C:6]1[N:18]([C:19]2[CH:27]=[CH:26][CH:25]=[C:21]([C:22]([NH2:24])=[O:23])[CH:20]=2)[C:10](=[O:16])[CH:9]=[C:8]([OH:13])[CH:7]=1)(=[O:3])[CH3:2]
Reactant: NC(=O)c1cccc(N)c1
Reactant: CC(=O)OCC(=O)CC1=CC(=O)OC(C)(C)O1
Agent: CS(=O)(=O)O
Solvent: C1COCCO1
Product: CC(=O)OCc1cc(O)cc(=O)n1-c1cccc(C(N)=O)c1
Temperature: 70 °C

Procedure:
3-(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-2 oxopropyl acetate (4.00 g, 16.52 mmol) was dissolved in 1,4-dioxane (160 mL) and 3-aminobenzamide (1.73 g, 12.71 mmol) was added. The reaction was heated to reflux for 1 hour then cooled to 70° C. Methanesulfonic acid (1.22 g, 12.71 mmol) was added and the reaction brought back to reflux for 1 hour. The reaction was cooled to room temperature, concentrated and used as crude product for the next step.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:22])[CH2:4][C@@H:5]1[CH2:10][C:9]([CH3:12])([CH3:11])[CH2:8][CH2:7][C@H:6]1[O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].[C:23]([O:27][C:28](SC1C=C(C)C=C(C)N=1)=[O:29])([CH3:26])([CH3:25])[CH3:24].C(N(CC)CC)C.O>CO>[C:23]([O:27][C:28]([NH:1][CH2:2][CH:3]([OH:22])[CH2:4][C@@H:5]1[CH2:10][C:9]([CH3:12])([CH3:11])[CH2:8][CH2:7][C@H:6]1[O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: CCCCCCCCO[C@@H]1CCC(C)(C)C[C@H]1CC(O)CN
Reactant: Cc1cc(C)nc(SC(=O)OC(C)(C)C)c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CO
Product: CCCCCCCCO[C@@H]1CCC(C)(C)C[C@H]1CC(O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.4 %

Procedure:
A mixture of 3-amino-1-[(1S*,2R*)-5,5-dimethyl-2-octyloxycyclohexyl]-2-propanol (50 mg), S-t-butyloxycarbonyl-4,6-dimethyl-2-mercaptopyridine (46 mg) and triethylamine (20 ml) in methanol (1.5 ml) was stirred at room temperature for 2 hrs. Water was added to a reaction mixture and the mixture was partitioned between water and ether. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. Purification of the residue by silica gel chromatography (using n-hexane:ethylacetate=5:1 as an eluent) gave 3-[(tert-butoxycarbonyl)amino]-1-[(1S*,2R*)-5,5-dimethyl-2-octyloxycyclohexyl]-2-propanol (55 mg, y. 83%); EI-MS: m/z 395 (M+ -H2O).
Reaction SMILES: [CH2:1]([S:5][CH2:6][CH2:7][C:8](=[O:30])[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH2:18][CH:19]([O:22][C:23](=[O:29])[CH2:24][NH:25][C:26](=[O:28])[CH3:27])[O:20][CH3:21])[CH:11]=1)[CH2:2][CH2:3][CH3:4].C[I:32].[CH3:33]COCC>CN(C)C=O>[I-:32].[C:26]([NH:25][CH2:24][C:23]([O:22][CH:19]([O:20][CH3:21])[CH2:18][CH2:17][O:16][C:12]1[CH:11]=[C:10]([NH:9][C:8]([CH2:7][CH2:6][S+:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH3:33])=[O:30])[CH:15]=[CH:14][CH:13]=1)=[O:29])(=[O:28])[CH3:27]
Reactant: CCOCC
Reactant: CCCCSCCC(=O)Nc1cccc(OCCC(OC)OC(=O)CNC(C)=O)c1
Reactant: CI
Solvent: CN(C)C=O
Product: CCCC[S+](C)CCC(=O)Nc1cccc(OCCC(OC)OC(=O)CNC(C)=O)c1
Product: [I-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 89.3 %

Procedure:
Dissolved in 4 ml of dimethylformamide was 4.41 g of 2-{3-(2-acetylaminoacetoxy-3-methoxypropoxy)phenylcarbamoyl}ethyl butyl sulfide. Thereto was added 5.00 g of methyl iodide and the mixture was stirred at room temperature for 24 hours. Ether was added to the reaction mixture and the insoluble solid was separated. The solid was purified with ethanol-ether, giving 5.20 g of 2-{3-(2-acetylaminoacetoxy-3-methoxypropoxy)phenyl carbamoyl}ethylbutylmethylsulfonium iodide (Compound 63) in 89.3% yield.
Reaction SMILES: N1C(Cl)=NC(Cl)=NC=1[Cl:3].CN(C)C=O.[Br:15][C:16]1[C:17]([O:27][CH3:28])=[C:18]([CH:24](O)[CH3:25])[CH:19]=[C:20]([Cl:23])[C:21]=1[CH3:22]>C(Cl)Cl>[Br:15][C:16]1[C:21]([CH3:22])=[C:20]([Cl:23])[CH:19]=[C:18]([CH:24]([Cl:3])[CH3:25])[C:17]=1[O:27][CH3:28]
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: COc1c(C(C)O)cc(Cl)c(C)c1Br
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1c(C(C)Cl)cc(Cl)c(C)c1Br
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of cyanuric chloride (1.7 g, 9.2 mmol) and N,N-dimethylformamide (710 μL, 9.2 mmol) was stirred at room temperature for 10 minutes and then a solution of 1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethanol (1.72 g, 6.15 mmol) in methylene chloride (34 mL) was added and the reaction was stirred at room temperature overnight. The mixture was diluted with methylene chloride, washed with sat. NaHCO3, water, brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography, eluting with 0 to 10% EtOAc in hexanes.
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[N:3]1[CH:11]1[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]1.[ClH:24].O1CCOCC1>CO>[ClH:24].[ClH:24].[NH:14]1[CH2:13][CH2:12][CH:11]([N:3]2[C:4]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[NH:10][C:2]2=[O:1])[CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=c1[nH]c2ncccc2n1C1CCNCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87 %

Procedure:
tert-Butyl 4-(2-oxo-2,3-dihydroimidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate (5.97 g, 18.75 mmol) was dissolved in methanol (180 ml). 4M Hydrogen chloride in 1,4-dioxane (50 ml, 200 mmol) was added to the mixture. Reaction stirred at room temperature for 18 hours. Solids were filtered off and washed with methanol. Solids were collected and dried in vacuo. Title compound was obtained as white solid in 87% yield. MS (M+H)+=219.1.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)[CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:13]=[C:8]2[N:7]=[C:6]1[CH3:18].[Cl:28]N1C(=O)CCC1=O.ClCCl>C(O)(=O)C>[Cl:1][C:2]1[CH:22]=[C:21]([C:23]2[S:24][C:25]([Cl:28])=[CH:26][CH:27]=2)[CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:13]=[C:8]2[N:7]=[C:6]1[CH3:18]
Reactant: COC(=O)c1ccc2nc(C)n(Cc3ccc(-c4cccs4)cc3Cl)c2n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)c1ccc2nc(C)n(Cc3ccc(-c4ccc(Cl)s4)cc3Cl)c2n1
Reaction time: 8 h
Yield: 95.5 %

Procedure:
To a suspension of methyl 3-[2-chloro-4-(thiophen-2-yl)benzyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (50 mg, 0.126 mmol) in acetic acid (1 ml) was added N-chlorosuccinimide (19 mg, 0.138 mmol) at room temperature. Thirty minutes later, dichloromethane (0.5 ml) was added to the reaction mixture to give a clear transparent solution. Four hours later, N-chlorosuccinimide (19 mg, 0.138 mmol) was further added. The reaction mixture was left standing overnight and concentrated. The residue was purified by p-TLC (chloroform/methanol=40/1) to give the object compound (52 mg, 95.7%) as a colorless oil.
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([CH3:3])[CH3:2].B(O)(O)O.C1(C)C(C)=CC=CC=1.C([O:25][C:26](=[O:35])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32](O)=[O:33])C>C(OCC)(=O)C.O>[CH:1]([N:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:32](=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][C:26]([OH:35])=[O:25])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CCCCCC(=O)O
Reactant: CC(C)Nc1ccccc1
Agent: OB(O)O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Solvent: O
Product: CC(C)N(C(=O)CCCCCC(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
A dried, 200 mL, 3-necked, round-bottomed flask was equipped with a Teflon-coated magnetic bar and a vacuum jacketed Dean-Stark trap which was topped with a reflux condenser fitted with a Nitrogen inlet. The reaction vessel was charged with N-isopropyl-N-phenylamine (8.11 g, 60 mmol), boric acid (0.93 g, 15 mmol,), and xylene (88 mL). To the stirred reaction mixture was added 7-ethoxy-7-oxoheptanoic acid (11.29 g, 60 mmol) in one portion. The reaction was heated to reflux using a heating mantle. The azeotroped water began to separate and was collected in the Dean-Stark trap. After 16 hours of reflux, water was collected, and the reaction was allowed to cool to ambient temperature reaction. The reaction mixture was diluted with ethyl acetate (100 mL), and was washed with an aqueous 2N solution of HCl (50 mL), and followed with a saturated solution of sodium bicarbonate (60 mL). The majority of the organic solvent was removed in vacuum. To residue was added a 2 N aqueous solution of sodium hydroxide (60 mL). The mixture was heated at 60° C. for 4 hours. Upon cooling to room temperature, the mixture was washed 60 mL of ethyl acetate. After being carefully separated from the organic layer, the aqueous phase was subjected to evaporation to remove any residual ethyl acetate. Ice was added to the aqueous solution, followed by an aqueous solution of HCl (2N, 60 mL) leading to the precipitation of a white solid. Stirring was continued for an additional 30 minutes before the precipitate was collected with a sintered funnel. The collected white solid was successfully washed with water and hexane before it was in vacuo at room temperature for 12 h to afford 7.49 g (45%) of 7-[isopropyl(phenyl)amino]-7-oxoheptanoic acid as a white solid. HPLC: single peak at 4.83 min.; Mp: 62-63° C. 1H NMR (DMSO-d6,) δ: 0.95-0.97 (d, 6H), 1.08-1.10 (m, 2H), 1.34-1.40 (m, 4H), 1.76-1.79 (m, 2H), 2.09-2.13 (m, 2H), 4.81-4.85 (m, 1H), 7.18-7.20 (m, 2H), 7.44-7.46 (m, 3H). Mass (M+1): 278. Anal. Calc'd for C16H23NO3: C, 69.29; H, 8.36; N5.05. Found: C, 69.06; H, 8.45; N, 4.99.
Reaction SMILES: Cl[C:2]([C@@H:4]1[CH2:9][CH2:8][CH2:7][N:6]([C:10]([O:12][CH2:13][CH:14]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:11])[CH2:5]1)=[O:3].[CH3:27][Si](C=[N+]=[N-])(C)C.C1COCC1.CC#N.[BrH:42]>C1COCC1.CC#N>[Br:42][CH2:27][C:2]([C@@H:4]1[CH2:9][CH2:8][CH2:7][N:6]([C:10]([O:12][CH2:13][CH:14]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:11])[CH2:5]1)=[O:3]
Reactant: O=C(Cl)[C@@H]1CCCN(C(=O)OCC2c3ccccc3-c3ccccc32)C1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Br
Solvent: C1CCOC1
Solvent: CC#N
Product: O=C(CBr)[C@@H]1CCCN(C(=O)OCC2c3ccccc3-c3ccccc32)C1
Temperature: 0 °C
Reaction time: 4 h
Yield: 91.3 %

Procedure:
(R)-(9H-fluoren-9-yl)methyl 3-(chlorocarbonyl)piperidine-1-carboxylate (4.21 g, 11.4 mmol, prepared using W from (R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)piperidine-3-carboxylic acid [Fluka]) was dissolved in a mixture of THF and MeCN (1:1, 16 mL) and added to a solution of trimethylsilyldiazomethane (2 M in Et2O, 22.8 mL, 45.5 mmol) and THF/MeCN (1:1, 16 mL) at about 0° C. The resulting mixture was stirred at about 0° C. for about 4 h followed by the drop-wise addition of HBr (48% aqueous solution, 6.2 mL, 114 mmol). The organic solvents were removed and the precipitate was collected by filtration and dried in air to give (R)-(9H-fluoren-9-yl)methyl 3-(2-bromoacetyl)piperidine-1-carboxylate (4.46 g, 92%): LC/MS (Table 2, Method a) Rt=2.59 min; MS m/z: 428/430 (M+H)+.