Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:32])([C:28]([F:31])([F:30])[F:29])[C:3]([F:27])([F:26])[C:4]([F:25])([F:24])[O:5][C:6]([F:23])([F:22])[C:7]([F:21])([F:20])[O:8][C:9]([F:19])([F:18])[CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]Br.[CH2:33]([O:39][C:40]1[CH:41]=[N:42][C:43]([C:46]2[CH:51]=[CH:50][C:49]([OH:52])=[CH:48][CH:47]=2)=[N:44][CH:45]=1)[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38].C(=O)([O-])[O-].[K+].[K+].C(#N)C>O.C1(C)C=CC=CC=1>[CH2:33]([O:39][C:40]1[CH:45]=[N:44][C:43]([C:46]2[CH:47]=[CH:48][C:49]([O:52][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][O:11][CH2:10][C:9]([O:8][C:7]([F:21])([F:20])[C:6]([F:23])([F:22])[O:5][C:4]([F:25])([F:24])[C:3]([F:27])([F:26])[C:2]([F:32])([F:1])[C:28]([F:31])([F:30])[F:29])([F:19])[F:18])=[CH:50][CH:51]=2)=[N:42][CH:41]=1)[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: FC(F)(COCCCCCBr)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CCCCCCOc1cnc(-c2ccc(O)cc2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC#N
Product: CCCCCCOc1cnc(-c2ccc(OCCCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2)nc1

Procedure:
A 500 mL flask was charged with 5-(2-(2 -(nonafluorobutoxy)tetrafluoroethoxy)-2,2 -difluoroethoxy)-l-bromopentane (18.6 g, 32 mmol; prepared from 1,5-dibromopentane and 2-(2 -(nonafluorobutoxy)tetrafluoroethoxy)-2,2 -difluoroethanol), 5-hexyloxy-2-(4 -hydroxyphenyl)pyrimidine (8.0 g, 29.4 mmol), potassium carbonate (5.4 g, 39 mmol), and acetonitrile (200 mL), and the resulting mixture was stirred and refluxed overnight under nitrogen. Toluene (150 mL) and water (150 mL) were added to the refluxed mixture. The resulting toluene layer was collected and residual water removed by distillation using a Dean-Stark apparatus. The toluene layer was then filtered through a pad of silica gel and the toluene removed under reduced pressure. The crude product was further purified by distillation using a Kugelrohr apparatus (b.p. 210°- 25° C. at 0.3 torr)
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:12]([OH:14])=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.N1([C:27](=O)[C:26]2N(C)C=N[C:21]=2N(C)C1=O)C.C1(C)CCC(C(C)C)C(O)C1>O>[CH:26]([O:13][C:12](=[O:14])[C@H:3]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[CH:9][CH:10]=1)[NH2:2])([CH3:27])[CH3:21]
Reactant: Cn1c(=O)c2c(ncn2C)n(C)c1=O
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: CC1CCC(C(C)C)C(O)C1
Agent: Cl
Solvent: O
Product: CC(C)OC(=O)[C@@H](N)Cc1ccc(O)cc1

Procedure:
HCl (70 g) and tyrosine (7 g) were dissolved in water (1 L). Caffeine (50 g) and menthol (10 g) were added into the mixture and the mixture was stirred for a few minutes. The mixture was filled into either spray bottles or roll-on bottles.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].C(N(CC)C(C)C)(C)C.[C:14]([Si:18](Cl)([CH3:20])[CH3:19])([CH3:17])([CH3:16])[CH3:15].O>ClCCl>[Si:18]([O:4][CH2:3][CH2:2][NH2:1])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:20])[CH3:19]
Reactant: NCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCN
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.4 %

Procedure:
To a stirred solution of 2-amino-ethanol (55 g, 900.46 mmol) in dichloromethane (1000 mL) were added N,N-diisopropylethylamine (220 mL, 1260.64 mmol) and tert-butyl-chloro-dimethyl-silane (135.7 g, 900.46 mmol) at 0° C. followed by stirring for 16 h at room temperature. After completion of the reaction, water (500 mL) was added and the resulting mixture extracted with dichloromethane. The separated organic part was washed with water (2×100 mL) and brine (100 mL) and dried and concentrated to get 2-(tert-butyl-dimethylsilanyloxy)-ethylamine (8c) (157 g, 99.44%) as a light yellow oil.
Reaction SMILES: C([NH:4][CH:5]([C:10]([OH:12])=[O:11])[CH2:6][CH2:7][S:8][CH3:9])(=O)C>P([O-])([O-])([O-])=O.[Co](Cl)Cl>[NH2:4][C@H:5]([C:10]([OH:12])=[O:11])[CH2:6][CH2:7][S:8][CH3:9]
Reactant: CSCCC(NC(C)=O)C(=O)O
Agent: Cl[Co]Cl
Agent: O=P([O-])([O-])[O-]
Product: CSCC[C@H](N)C(=O)O

Procedure:
To test the bound aminoacylase activity, 100 mg of the charged carrier were carefully shaken for 2 minutes at room temperature in 3 ml of 0.1 molar phosphate buffer solution (pH 7.6) containing 10 mg/ml of N-acetyl-D,L-methionine and 0.36 mg of cobalt chloride (CoCl2 ·6 H2O). The amount of L-methionine formed was then found by reaction with L-aminoacid-oxidase and determination of the resulting hydrogen peroxide with peroxidase by UV-spectrophotometric measurement of o-dianisidine (in the oxidized, ie. quinoid, form) (Methods in Enzymology, Vol. II).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([O:17]C)=[O:16])=[CH:11][C:10]=1[CH3:19].[OH-].[Na+]>CCO.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([OH:17])=[O:16])=[CH:11][C:10]=1[CH3:19]
Reactant: COC(=O)c1ccc(-c2ccccc2OC)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccccc1-c1ccc(C(=O)O)cc1C
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To solution of methyl 2′-methoxy-2-methylbiphenyl-4-carboxylate, prepared in Step 1 (2 g; 7.80 mmol; 1 eq.) in EtOH (60 mL), was added at RT an aqueous solution of sodium hydroxide (4.68 mL; 5 M; 23.41 mmol; 3 eq.). The reaction mixture was stirred at 60° C. for one hour. The reaction mixture was concentrated under vacuum to give an orange solid. It was taken up in water (400 mL) and the aqueous phase was washed twice with EtOAc (200 mL). Aqueous phase was acidified with concentrated HCl (2 mL) to pH 2. Then it was concentrated under vacuum until a precipitate was formed. (⅕ of volume). The suspension was filtered off and dried under vacuum to afford the title compound as a brown solid. 1H NMR: (DMSO-d6, 300 MHz) δ 12.89 (s, 1H), 7.86 (s, 1H), 7.82-7.79 (dd, J=7.99 Hz, J=1.23 Hz, 1H), 7.46-7.40 (m, 1H), 7.26-7.23 (d, J=7.68 Hz, 1H), 7.16-7.04 (m, 3H), 3.75 (s, 3H), 2.13 (s, 3H). LC/MS (Method A): 240.9 (M−H)−. HPLC (Method A) Rt 4.05 min (Purity: 98.5%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([CH3:8])[CH:7]=1.[Br:10]N1C(=O)CCC1=O.C(OOCC1C=CC=CC=1)C1C=CC=CC=1.C1(=O)NC(=O)CC1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([CH2:8][Br:10])[CH:7]=1
Reactant: Cc1cc(Br)ccc1F
Reactant: O=C1CCC(=O)N1Br
Agent: O=C1CCC(=O)N1
Agent: c1ccc(COOCc2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(Br)cc1CBr
Temperature: 79 °C

Procedure:
5-bromo-2-fluorotoluene (5.00 g, 26.5 mmol), N-bromosuccinimide (5.18 g, 29.1 mmol), benzyl peroxide (0.205 g, 0.850 mmol) and carbon tetrachloride (50 mL) were loaded to a r.b. flask and set to reflux (79° C.) for 2 h. Once cooled the succinimide was filtered off and carbon tetrachloride removed via a dry ice-acetone cooled rotary evaporator. The residues were dissolved in dichloromethane (100 mL) and washed with distilled H2O (50 mL×3) and brine (50 mL). Dried over MgSO4 and solvent removed in vacuo to yield the title compound as a colourless liquid yellow (6.80 g, 96%),
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[NH:4][CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[H-].[Na+].[CH2:14]([O:16][CH2:17]Cl)[CH3:15]>O1CCCC1.C(OCC)(=O)C.CCCCCC>[CH2:14]([O:16][CH2:17][N:4]1[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:3]1[C:2]([F:1])([F:10])[F:11])[CH3:15]
Reactant: N#Cc1cc[nH]c1C(F)(F)F
Reactant: CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOCn1ccc(C#N)c1C(F)(F)F
Reaction time: 0.33 h

Procedure:
A stirred solution of 2-trifluoromethyl-3-cyanopyrrole (1.0 g, 6.2 mmol) in dry tetrahydrofuran is treated with NaH (0.30 g, 7.5 mmol) as a 60% dispersion in mineral oil, under nitrogen, at room temperature. After 20 minutes, the reaction mixture is treated dropwise with a solution of chloromethyl ethyl ether (0.77 g, 8.1 mmol) in dry tetrahydrofuran, stirred vigorously for 3 hours and treated with a mixture of 1N HCI and ethyl acetate. The phases are separated and the organic phase is washed with brine, dried over Mg SO4 and concentrated in vacuo to afford a residue. Flash chromatography of the residue using silica gel and 3.5:1 hexane: ethyl acetate yields the title compound as a pale yellow oil, 0.83 g (61%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH2:6][OH:7]>C(O)(=O)C.O>[CH3:14][O:13][C:9]1[CH:8]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:10]=1[O:11][CH3:12])[CH:6]=[O:7]
Reactant: COc1cc(CO)cc(OC)c1OC
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(C=O)cc(OC)c1OC

Procedure:
To this oxydation mixture, g 19.8 of 3,4,5-trimethoxy benzyl alcohol dissolved in 160 ml of glacial acetic acid are very slowly added under continuous stirring. The mixture is kept reacting during 30' after the end of the addition and is then cooled, diluted with water and extracted with CHCl3 (3 fractions of 200 ml each).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:13].O>C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:7][CH3:13])=[CH:4][CH:3]=1
Reactant: CI
Reactant: OCc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In THF (200 ml) was dissolved 4-bromobenzyl alcohol (19.8 g), and to the solution was added under ice-cooling 65% sodium hydride (3.6 g). The mixture was stirred at room temperature for 30 minutes, and to the mixture was added dropwise under ice-cooling iodomethane (8.0 ml). The mixture was stirred at room temperature for 2 hours. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=12/1) to give 1-bromo-4-(methoxymethyl)benzene (14.8 g). In THF (10 ml) was dissolved 1-bromo-4-(methoxymethyl)benzene (12.8 g), and to the mixture was added dropwise at−78° C. 1.6M n-butyllithium/hexane (42.4 ml). The mixture was stirred for 1 hour, and to the mixture was added dropwise a solution of trimethyl borate (19.2 g) in THF (38.4 ml). The mixture was stirred for30 minutes and warmed to room temperature. To the mixture was added 5% sulfuric acid (124 ml), and the mixture was stirred for 15 minutes. The reaction mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was washed with hexane/isopropylether to give 4-(methoxymethyl)phenyl borate (6.3 g).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][C:19]2([OH:32])[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]2)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].Cl>C(O)C>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][C:19]2([OH:32])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2]
Reactant: CCOCc1nc2cnc3ccccc3c2n1CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCO
Product: CCOCc1nc2cnc3ccccc3c2n1CC1(O)CCNCC1
Temperature: 25 °C
Yield: 60.6 %

Procedure:
To a solution of tert-butyl 4-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}-4-hydroxypiperidine-1-carboxylate (prepared as described in Part E of Example 4, 14.94 g, 33.91 mmol) in ethanol (170 mL) was added a solution of HCl in ethanol (2.7 M, 31 mL, 84.7 mmol). The solution was heated at reflux for 1 h, during which time a precipitate formed. The mixture was allowed to cool to rt and the volatiles were removed under reduced pressure. To the residue was added water (400 mL) followed by 50% aqueous NaOH until the pH=10. The solution was extracted with dichloromethane (3×100 mL). The aqueous layer was treated with 50% aqueous NaOH until the pH=12, then was extracted with dichloromethane (2×100 mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting solid was triturated with hot ethyl acetate and the remaining solid was isolated by filtration to afford 4-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}piperidin-4-ol (7.0 g, 61%) as an off-white powder.
Reaction SMILES: B(F)(F)F.[C:5]([N:7]1[C:13]2C=[CH:15][CH:16]=[CH:17][C:12]=2C([N+]([O-])=O)=[CH:10][C:9]2[CH:21]=[CH:22][CH:23]=[CH:24][C:8]1=2)#[N:6].[OH2:25].[C:26]([OH:29])(=O)[CH3:27]>ClC1C=CC=CC=1.[Fe]>[C:5]([N:7]1[C:13]2[CH:12]=[CH:17][CH:16]=[CH:15][C:27]=2[C:26](=[O:29])[CH2:10][C:9]2[CH:21]=[CH:22][CH:23]=[CH:24][C:8]1=2)(=[O:25])[NH2:6]
Reactant: O
Reactant: N#CN1c2ccccc2C=C([N+](=O)[O-])c2ccccc21
Reactant: CC(=O)O
Agent: [Fe]
Agent: FB(F)F
Solvent: Clc1ccccc1
Product: NC(=O)N1c2ccccc2CC(=O)c2ccccc21
Reaction time: 0.17 h

Procedure:
50 ml of a solution of 15% by weight of BF3 in acetic acid are added rapidly to a suspension of 26.3 g (0.1 mole) of 5-cyano-10-nitro-5H-dibenz[b,f]azepine in a mixture of 260 ml of chlorobenzene and 130 ml of acetic acid and, while heating gently, a clear yellow solution is obtained. The reaction mixture is stirred for 10 minutes and then 40 g of iron powder are added in one portion. While stirring well, 100 ml of water are added dropwise in the course of 30 minutes, the temperature increasing to 65°. By external heating the temperature is maintained at 60°-65° for two hours, and the inorganic material is filtered off and washed with chlorobenzene and acetic acid. After separating the chlorobenzene phase, this is washed with water until crystallisation of the product begins. The product is concentrated in vacuo and the residue is taken up in 100 ml of methanol. After suction-filtering and washing with a little methanol, 5-carbamoyl-10-oxo-10,11-dihydro-5H-dibenz[b,f]azepine is obtained, which according to the IR spectrum is identical to authentic material.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[N:5]=[CH:4][C:3]=1[NH-:12].ClC1C2C(=CC=CC=2)[N:17]=[CH:16]C=1[NH-].NO>>[NH:17]1[C:2]2[C:11]3[N:10]=[CH:9][CH:8]=[CH:7][C:6]=3[N:5]=[CH:4][C:3]=2[N:12]=[CH:16]1
Reactant: [NH-]c1cnc2ccccc2c1Cl
Reactant: [NH-]c1cnc2cccnc2c1Cl
Agent: NO
Product: c1cnc2c(c1)ncc1nc[nH]c12

Procedure:
In step (1) of Reaction Scheme VII, an N-(4-chloro[1,5]naphthyridin-3-yl)amide or N-(4-chloroquinolin-3-yl)amide of Formula XXXII is reacted with a hydroxylamine of the Formula Boc-CH2—X—CH2—ONH2 and cyclized to provide a 1H-imidazo[4,5-c][1,5]naphthyridine or a 1H-imidazo[4,5-c]quinoline of Formula LX. The reaction can be carried out using the method described in step (3) of Reaction Scheme I. Hydroxylamines of the Formula Boc-CH2—X—CH2—ONH2 can be prepared by conventional methods.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[NH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1.C(N(C(C)C)C(C)C)C>C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: BrCc1ccc(Br)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Brc1ccc(CN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 12.5 g (50 mmol) 4-bromobenzylbromide is slowly added dropwise to a solution of 4.52 mL (55 mmol) pyrrolidine and 10.3 mL (60 mmol) ethyldiisopropylamine in 100 mL THF and stirred overnight at RT. The precipitate is filtered off and the solvent is eliminated i.vac. The product is obtained as a light-brown liquid which is further reacted without purification.
Reaction SMILES: [CH:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10](Cl)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].C([C@H]1CC[C@H](C(O)=O)CC1)(C)C.[NH2:25][C@@H:26]([C:34]([OH:36])=[O:35])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O.CC(C)=O>[CH3:2][CH:1]([CH3:3])[C@@H:4]1[CH2:9][CH2:8][C@@H:7]([C:10]([NH:25][C@H:26]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:34]([OH:36])=[O:35])=[O:11])[CH2:6][CH2:5]1
Reactant: CC(C)[C@H]1CC[C@H](C(=O)Cl)CC1
Reactant: N[C@H](Cc1ccccc1)C(=O)O
Agent: CC(C)[C@H]1CC[C@H](C(=O)O)CC1
Solvent: CC(C)=O
Solvent: O
Product: CC(C)[C@H]1CC[C@H](C(=O)N[C@H](Cc2ccccc2)C(=O)O)CC1

Procedure:
U.S. Pat. No. 7,208,622 describes a process in which trans-4-isopropylcyclohexane carbonyl chloride (i.e. a derivative of trans-4-isopropylcyclohexane carboxylic acid) is reacted with D-phenylalanine in the presence of a caustic solution followed by acidification in a mixture of water and acetone and crystallization at 58-72° C. which results in Form H of nateglinide.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:13][CH2:12][C@:11]([CH:17]([CH3:19])[CH3:18])([C:14]([OH:16])=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[F:22][C:23]([F:37])([F:36])[C:24]1[CH:29]=[CH:28][N:27]=[C:26]([C:30]2[CH2:31][CH2:32][NH:33][CH2:34][CH:35]=2)[CH:25]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[CH:17]([C@:11]1([C:14]([N:33]2[CH2:34][CH:35]=[C:30]([C:26]3[CH:25]=[C:24]([C:23]([F:37])([F:22])[F:36])[CH:29]=[CH:28][N:27]=3)[CH2:31][CH2:32]2)=[O:16])[CH2:12][CH2:13][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10]1)([CH3:19])[CH3:18]
Reactant: CC(C)[C@]1(C(=O)O)CC[C@@H](NC(=O)OC(C)(C)C)C1
Reactant: FC(F)(F)c1ccnc(C2=CCNCC2)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[C@]1(C(=O)N2CC=C(c3cc(C(F)(F)F)ccn3)CC2)CC[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1S,3R)-3-[(tert-butoxycarbonyl)amino]-1-isopropylcyclopentanecarboxylic acid (0.288 g, 1.06 mmol) and 4-(trifluoromethyl)-1′,2′,3′,6′-tetrahydro-2,4′-bipyridine dihydrochloride (0.320 g, 1.06 mmol) in dry methylene chloride (11.5 mL) was added triethylamine (0.592 mL, 4.25 mmol) followed by benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.517 g, 1.17 mmol). After being stirred at room temperature overnight, the brown reaction mixture was washed with NaHCO3 and brine, dried (MgSO4), filtered, and concentrated. The residue was purified by column chromatography on silica gel (30:70 EtOAc/hexanes) to provide a light yellow solid product: 265 mg (52%). LC-MS calculated for C25H34F3N3O3: (M+H) 482; found 382.2 (M-Boc+1).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]#[CH:12])[CH:8]=[C:7]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:6]=1[O:17][CH3:18])([CH3:4])([CH3:3])[CH3:2].C(O[C:23]1[CH:28]=[CH:27][C:26](I)=[C:25]([CH3:30])[C:24]=1[F:31])(=O)C.C(N(CC)CC)C.[C:39]([O:42][CH2:43]C)(=[O:41])C>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:43][O:42][C:39](=[O:41])[CH2:30][C:25]1[CH:26]=[CH:27][C:28]([C:12]#[C:11][C:9]2[CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:6]([O:17][CH3:18])=[C:7]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:8]=2)=[CH:23][C:24]=1[F:31]
Reactant: CCOC(C)=O
Reactant: C#Cc1cc(C(C)(C)C)c(OC)c(C(C)(C)C)c1
Reactant: CC(=O)Oc1ccc(I)c(C)c1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(C#Cc2cc(C(C)(C)C)c(OC)c(C(C)(C)C)c2)cc1F
Yield: 89 %

Procedure:
Following General Procedure F and using 1,3-di-tert-butyl-5-ethynyl-2-methoxy-benzene (Intermediate 169, 0.087 g, 0.33 mmol), methyl-2-fluoro-4-iodo phenyl acetate (Reagent H, 0.088 g, 0.30 mmol), triethyl amine (5 mL), anhydrous tetrahydrofliran (10 mL), copper(I)iodide (0.02 g, 0.1 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.06 g, 0.085 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 10% ethyl acetate in hexane as the eluent, the title compound (0.122 g, 89%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][CH:7]=1.[CH:21]1([NH:24][S:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]Cl)(=[O:27])=[O:26])[CH2:23][CH2:22]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH:21]1([NH:24][S:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][N:12]2[CH2:11][CH2:10][N:9]([CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:14][CH2:13]2)(=[O:27])=[O:26])[CH2:23][CH2:22]1
Reactant: Clc1cccc(C(c2ccccc2)N2CCNCC2)c1
Reactant: O=S(=O)(CCCCCCCl)NC1CC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=S(=O)(CCCCCCN1CCN(C(c2ccccc2)c2cccc(Cl)c2)CC1)NC1CC1
Yield: 9 %

Procedure:
1-[(3-Chlorophenyl)phenylmethyl]piperazine (543.7 mg, 1.90 mmol) and N-cyclopropyl-6-chlorohexanesulfonamide (500 mg, 2.09 mmol) were refluxed in toluene (15 ml) for 4 hours in the presence of triethylamine (211 mg, 2.09 mmol). The reaction mixture was washed with water, and the organic layer was dried over anhydrous magnesium sulfate. Subsequently, the solvent was removed by evaporation in vacuo. The resulting crude product was purified by column chromatography on silica gel with chloroform-methanol (20:1), to give N-cyclopropyl-6-[4-[(3-chlorophenyl)phenylmethyl]-1-piperazinyl]hexanesulfonamide (84.1 mg) as an oil (yield based on 1-[(3-chlorophenyl)phenylmethyl]piperazine: 9.0%).
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][CH2:4][O:5][C:6]([CH2:8][C:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=O)=[O:7].Cl[CH2:18][C:19](=O)[CH3:20]>>[CH3:1][N:2]1[CH:18]=[C:19]([CH3:20])[C:8]([C:6]([O:5][CH2:4][CH3:3])=[O:7])=[C:9]1[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CC(=O)CCl
Reactant: CCOC(=O)CC(=O)CC(=O)OCC
Reactant: CN
Product: CCOC(=O)Cc1c(C(=O)OCC)c(C)cn1C
Reaction time: 2 h

Procedure:
To a solution of 500 ml. of 25% aqueous methylamine is added 93 g. (0.46 mole) of diethyl acetone-dicarboxylate. To the mixture is added 72 g. (0.782 mole) of chloroacetone over a 10-minute period. The temperature is kept below 60° C. by external cooling. After 2 hours, the mixture is poured into ice-hydrochloric acid. The solid is collected by filtration, washed with water and air dried. It is recrystallized from hexane to give ethyl 1,4-dimethyl-3-ethoxycarbonylpyrrole-2-acetate as a white solid, m.p. 71-72° C. Anal. Calcd. for C13H19NO4 : C, 61.64; H, 7.56; N, 5.53%. Found: C, 61.64; H, 7.64; N, 5.71%.
Reaction SMILES: [F:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([OH:11])=[C:4]([CH3:12])[CH:3]=1.[C:13]([O-])([O-])=O.[K+].[K+].CI>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([O:11][CH3:13])=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(F)c([N+](=O)[O-])cc1O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc([N+](=O)[O-])c(F)cc1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.9 %

Procedure:
4-Fluoro-2-methyl-5-nitrophenol (D16) (0.85 mmol, 145 mg) in dimethylformamide (5 mL) under argon was treated with K2CO3 (0.85 mmol, 117 mg, 1 eq) then methyl iodide (1.7 mmol, 242 mg, 2 eq). The mixture was allowed to stir at room temperature for 1.5 h, concentrated under reduced pressure, treated with 10% Na2CO3 aqueous solution and extracted 3 times with ethyl acetate. Organics were combined, dried on MgSO4 and concentrated under reduced pressure to give the title compound as a bright yellow solid (0.79 mmol, 146 mg, 93% yield). Rt=2.84 min.