Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19](=O)[CH3:20])[N:14]=1)[CH3:12].[C:22]([C:26]1[CH:27]=[C:28]([CH:30]=[C:31]([C:33]([CH3:36])([CH3:35])[CH3:34])[CH:32]=1)[NH2:29])([CH3:25])([CH3:24])[CH3:23]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19](=[N:29][C:28]2[CH:30]=[C:31]([C:33]([CH3:35])([CH3:34])[CH3:36])[CH:32]=[C:26]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:27]=2)[CH3:20])[N:14]=1)[CH3:12]
Reactant: CC(C)(C)c1cc(N)cc(C(C)(C)C)c1
Reactant: CC(=O)c1cccc(C(C)=Nc2c(C)cc(C)cc2C)n1
Solvent: Cc1ccccc1
Product: CC(=Nc1cc(C(C)(C)C)cc(C(C)(C)C)c1)c1cccc(C(C)=Nc2c(C)cc(C)cc2C)n1
Reaction time: 48 h

Procedure:
2-[1-(2,4,6-trimethylphenylimino)ethyl]-6-acetylpyridine (1.3 g, 4.64 mmol), prepared according to the method disclosed in WO02/28805, and 3,5-di-tert-butylaniline (1 g, 4.87 mmol) were dissolved in 100 ml of toluene. To this solution, 4 Å molecular sieves were added. After standing for 2 days the mixture was filtered. The solvent was removed in vacuo. The residue was washed with methanol and crystallised from ethanol. Yield 1.1 g (51%) of 2-[1-(2,4,6-trimethylphenylimino)ethyl]-6-[1-(3,5-di-tert-butylphenylimino)ethyl]pyridine.
Reaction SMILES: [CH2:1]([N:3]([CH2:26][CH3:27])[C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:7][CH:6]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:34](Br)[CH:35]=[CH2:36]>C(#N)C.O>[CH2:26]([N:3]([CH2:1][CH3:2])[C:4](=[O:25])[C:5]1[CH:6]=[CH:7][C:8]([N:11]([CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:12]2[CH2:17][CH2:16][N:15]([CH2:36][CH:35]=[CH2:34])[CH2:14][CH2:13]2)=[CH:9][CH:10]=1)[CH3:27]
Reactant: C=CCBr
Reactant: CCN(CC)C(=O)c1ccc(N(Cc2ccccc2)C2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: C=CCN1CCC(N(Cc2ccccc2)c2ccc(C(=O)N(CC)CC)cc2)CC1
Reaction time: 144 h
Yield: 39.7 %

Procedure:
To a solution of N,N-diethyl-4-[benzyl(piperidin-4-yl)amino]benzamide (Compound 8) (0.25 g, 0.684 mmole) in 10 mL of acetonitrile was added potassium carbonate (0.10 g, 0.752 mmole) and allyl bromide (0.08 g, 0.684 mmol). The reaction mixture was stirred for six days under Argon and then was diluted with water (50 mL). This solution was extracted three times with dichloromethane (50 mL). The organic extracts were combined, washed with sodium carbonate solution, dried (Na2SO4), and concentrated to provide a yellow foam. This material was purified on a flash silica gel column (5% methanol-chloroform to 10% methanol-chloroform) to provide 0.11 g (40%) of N,N-diethyl-4-[benzyl(1-allylpiperidin-4-yl)amino]benzamide as a colorless oil. MS (ES), m/z 406 (MH+). 300 MHz 1H NMR (CDCl3) δ1.17 (t, J=7.0 Hz, 6H), 1.68-1.90 (m, 4H), 2.06 (br t, J=10.6 Hz, 2H), 2.91-3.08 (m, 4H), 3.31-3.52 (m, 4H), 3.75-3.92 (br m, 1H), 4.52 (s, 2H), 5.09-5.25 (m, 2H), 5.75-5.95 (m, 1H), 6.65 (d, J=8.7 Hz, 2H), 7.15-7.38 (m, 7H).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:8])[C:4]([F:7])([F:6])[F:5].[N+]([C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1)([O-])=O>CS(C)=O.[Cl-].[Na+].O>[F:5][C:4]([F:7])([F:6])[CH2:3][O:8][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1
Reactant: OCC(F)(F)F
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=Cc1ccc(OCC(F)(F)F)cc1
Reaction time: 0.33 h
Yield: 43.4 %

Procedure:
To a stirred suspension of sodium hydride (60% dispersion in mineral oil, 0.87 g, 21.8 mmol) in DMSO (20 ml) was added trifluoroethanol (3.97 g, 39.7 mmol) at 10-15° C. under an atmosphere of argon. The reaction mixture was stirred at this temperature for 20 min then 4-nitrobenzaldehyde (3.0 g, 19.85 mmol) was added in one portion. The reaction mixture was stirred at 10-15° C. for 3 h then at room temperature for 60 h. Brine (100 ml) was added cautiously to the reaction mixture followed by extraction with Et2O (3×70 ml). The combined organic extracts were washed with water, dried (MgSO4) and the solvent removed under reduced pressure to give an oil which was purified by flash chromatography (3:1 Hexane/EtOAc) to give a yellow oil which solidified on standing at room temperature to give the title compound (1.76 g, 43%) as a yellow solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH2:9])(=[O:8])=[O:7].[Cl:10][C:11]1[CH:12]=[C:13]([N:18]=[C:19]=[O:20])[CH:14]=[CH:15][C:16]=1[Cl:17].[OH-].[Na+].Cl>CC(C)=O>[Cl:10][C:11]1[CH:12]=[C:13]([NH:18][C:19]([NH:9][S:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)(=[O:8])=[O:7])=[O:20])[CH:14]=[CH:15][C:16]=1[Cl:17]
Reactant: NS(=O)(=O)c1cccs1
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: O=C(Nc1ccc(Cl)c(Cl)c1)NS(=O)(=O)c1cccs1
Yield: 39 %

Procedure:
2-Thiophenesulfonamide (1.55 g, 9.5 mmole) was combined with 3,4-dichlorophenyl isocyanate (1.79 g, 9.5 mmole), 1N NaOH (9.5 ml) and acetone (25 ml) followed by 1N HCl (9.5 ml) using the method of Example 4B to give the named product (1.3 g).
Reaction SMILES: [CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:32](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:31]=[N:30][N:29]=3)=[CH:18][CH:17]=2)[C:13](=[O:52])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C@H:53]3[O:65][N:56]4[CH2:57][CH2:58][C:59]5[C:64]([C@@H:55]4[CH2:54]3)=[CH:63][CH:62]=[CH:61][CH:60]=5)[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]>CO.O1CCCC1>[CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[NH:29][N:30]=[N:31][N:32]=3)=[CH:20][CH:21]=2)[C:13](=[O:52])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C@H:53]3[O:65][N:56]4[CH2:57][CH2:58][C:59]5[C:64]([C@@H:55]4[CH2:54]3)=[CH:63][CH:62]=[CH:61][CH:60]=5)[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc([C@@H]3C[C@H]4c5ccccc5CCN4O3)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CO
Product: CCCCc1nc2ccc([C@@H]3C[C@H]4c5ccccc5CCN4O3)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 85.5 %

Procedure:
A solution of 0.134 g of Cis-2-butyl-6-(1,5,6,10b-tetrahydro-2H-isoxazolo[3,2-a]isoquinolin-2-yl)-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone in 2.5 ml of methanol and 0.5 ml of tetrahydrofuran is heated at reflux for 18 hours. The volatiles are evaporated in vacuo to a residue which is purified by column chromatography on silica gel by elution with 99:1 chloroform-methanol to give 0.082 g of the desired product as a solid. FAB mass spec 610 (M+H).
Reaction SMILES: [CH2:1]([CH:7]([CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH2:8][C:9]1[S:13][C:12]([C:14]2[C:25]3[S:24][CH:23]=[CH:22][C:21]=3[C:20]([C:26]3[S:27][C:28]([CH2:31][CH:32]([CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[CH:29][CH:30]=3)=[C:19]3[C:15]=2[CH:16]=[CH:17][S:18]3)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C1COCC1.C([Li])CCC.[CH3:65][Sn:66](Cl)([CH3:68])[CH3:67]>CCCCCC>[CH2:41]([CH:32]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:31][C:28]1[S:27][C:26]([C:20]2[C:19]3[S:18][C:17]([Sn:66]([CH3:68])([CH3:67])[CH3:65])=[CH:16][C:15]=3[C:14]([C:12]3[S:13][C:9]([CH2:8][CH:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])=[CH:10][CH:11]=3)=[C:25]3[C:21]=2[CH:22]=[C:23]([Sn:66]([CH3:68])([CH3:67])[CH3:65])[S:24]3)=[CH:30][CH:29]=1)[CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]
Reactant: CCCCCCCCC(CCCCCC)Cc1ccc(-c2c3ccsc3c(-c3ccc(CC(CCCCCC)CCCCCCCC)s3)c3ccsc23)s1
Reactant: C[Sn](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCCCCC(CCCCCC)Cc1ccc(-c2c3cc([Sn](C)(C)C)sc3c(-c3ccc(CC(CCCCCC)CCCCCCCC)s3)c3cc([Sn](C)(C)C)sc23)s1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
4,8-Bis-[5-(2-hexyl-decyl)-thiophen-2-yl]-1,5-dithia-s-indacene (2.06 g, 2.56 mmol) was added into a 200-mL flask. The system was vacuumed and backfilled with argon 3 times before 80 mL of anhydrous THF was injected. n-Butyl lithium (2.5 M in hexane, 2.3 mL, 5.6 mmol) was added after the mixture was cooled to −78° C. The mixture was stirred at −78° C. for 30 minutes and then at room temperature for one more hour. The system was cooled down to −78° C. again before trimethyltin chloride (0.5 g, 2.5 mmol) was added in portions. Stirring was continued overnight at room temperature. Hexane (200 mL) was added and the organic layer was washed with 150 mL of water. The aqueous layer was extracted with 100 mL of hexane twice. The combined organic layer was dried over anhydrous Na2SO4. Removal of the solvent under vacuum yielded a yellow liquid (2.2 g, 76.0% yield) as the final product after drying in vacuo overnight. 1H NMR (CDCl3, 500 MHz): δ 7.57 (s, 2H), δ 7.21 (d, 2H, J=3.0 Hz), δ 6.78 (d, 2H, J=3.5 Hz), δ 2.76 (d, 4H, J=6.5 Hz), δ 1.62 (s, 2H), δ 1.26˜1.19 (m, 48H), δ 0.76 (m, 12H), δ 0.29 (m, 18H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[C@H:7]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)[NH2:8])([CH3:4])([CH3:3])[CH3:2].[C:18](ON1C(=O)CCC1=O)([O:20][CH2:21][CH:22]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19]>O1CCOCC1.O>[C:1]([O:5][C:6](=[O:17])[C@@H:7]([NH:8][C:18]([O:20][CH2:21][CH:22]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=2[C:29]2[C:34]1=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:19])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(O)cc1
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.1 %

Procedure:
A solution of -tyrosine t-butyl ester (Bachem, 20.0 g, 84.3 mmol) and FMOC-OSu (Bachem, 24.68 g, 71.2 mmol) was dissolved in 400 mL of dioxane and 400 mL of water. The pH of the resulting solution was adjusted to pH=9 and the solution stirred overnight at room temperature. The reaction mixture was concentrated to ½ volume and treated with concentrated HCl until the pH=5. The resulting solution was extracted with ethyl acetate (5×150 mL), the combined organic extracts were dried with MgSO4 and concentrated. The residue was crystallized from hot heptane/EtOAc. The solid that formed was collected by filtration and air dried to give the title compound (28.5 g, 87%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([OH:13])([CH2:11][CH3:12])[CH2:9][CH3:10])=[CH:6][CH:5]=[CH:4][N:3]=1.[OH-].[Na+].[CH3:16]I>CN(C=O)C>[CH2:9]([C:8]([C:7]1[C:2]([CH3:1])=[N:3][CH:4]=[CH:5][CH:6]=1)([O:13][CH3:16])[CH2:11][CH3:12])[CH3:10]
Reactant: CI
Reactant: CCC(O)(CC)c1cccnc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCC(CC)(OC)c1cccnc1C
Reaction time: 6 h
Yield: 36.7 %

Procedure:
A solution of 3-(2-methyl-pyridin-3-yl)-pentan-3-ol (0.444 g, 2.48 mmol) and NaOH (0.125 g, 5.2 mmol) in DMF (—mL) was stirred for 16 h. MeI (0.55 g, 3.9 mmol) was added. The mixture was stirred for 6 h, and the solvent was removed by evaporation under vacuum. Brine (25 mL) was added, and the aqueous mixture was extracted with CH2Cl2 (4×25 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration the solvent was removed by evaporation under vacuum, and the residue was purified by flash chromatography on a silica gel column (1:1 Et2O/CH2Cl2), affording 3-(1-ethyl-1-methoxy-propyl)-2-methyl-pyridine (0.176 g, 37%). 1H NMR (CDCl3) δ 0.73 (t, 6H, J=7.5 Hz), 1.87-2.04 (m, 4H), 2.77 (s, 3H), 3.01 (s, 3H), 7.09 (dd, 1H, J=8.1, 4.8 Hz), 7.56 (dd, 1H, J=8.1, 1.5 Hz), 8.40 (dd, 1H, J=4.8, 1.5 Hz).
Reaction SMILES: C([O:3][C:4](=[O:29])[C:5](=[O:28])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14](=[O:27])[N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)=[CH:8][CH:7]=1)C.C(=O)([O-])[O-].[Na+].[Na+]>CO.O>[O:27]=[C:14]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:17][CH2:16]1)[CH2:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([C:5](=[O:28])[C:4]([OH:29])=[O:3])=[CH:7][CH:8]=1
Reactant: CCOC(=O)C(=O)c1ccc(OCC(=O)N2CCN(c3ccccc3)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(O)C(=O)c1ccc(OCC(=O)N2CCN(c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 46.1 %

Procedure:
4-[2-Oxo-2-(4-phenyl-1-piperazinyl)ethoxy]-alpha-oxobenzeneacetic acid ethyl ester (0.7 g) in methanol (40 mL) was treated with sodium carbonate (0.24 g) in water (6 mL), and the mixture was stirred at room temperature for 1.25 hours. After the methanol was evaporated under reduced pressure, water was added and the solution was acidified with 3N hydrochloric acid, then the aqueous layer was extracted with a dichloromethane-tetrahydrofuran mixture (1:1). The organic layer was dried (MgSO4), evaporated, and the residue was crystallized from acetone to furnish 0.3 g of 4-[2-oxo-2-(4-phenyl-1-piperazinyl)ethoxy]-alpha-oxobenzeneacetic acid, mp 188°-192 ° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Br:10])=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[Cl:11][C:12]1[N:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](Cl)=[O:15]>C(Cl)Cl.N1C=CC=CC=1>[Br:10][C:3]1[C:2]([NH:1][C:14]([C:13]2[C:12]([Cl:11])=[N:20][CH:19]=[CH:18][CH:17]=2)=[O:15])=[CH:7][CH:6]=[C:5]([O:8][CH3:9])[N:4]=1
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: COc1ccc(N)c(Br)n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(NC(=O)c2cccnc2Cl)c(Br)n1
Reaction time: 0.33 h
Yield: 95.7 %

Procedure:
To a solution of 3-amino-2-bromo-6-methoxypyridine (2.7 g) in methylene chloride (20 ml) and pyridine (1 ml) was added 2-chloronicotinoyl chloride (2.2 g), and the resulting mixture was stirred 20 min. The mixture was then diluted with methylene chloride (100 ml), washed with water (100 ml), dried (anhydrous magnesium sulfate), and concentrated. The semisolid residue was saturated with hexane, filtered, and dried to give 4.1 g of product suitable for use in the next reaction.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([B:21]2[O:29][C:26]([CH3:28])([CH3:27])[C:23]([CH3:25])([CH3:24])[O:22]2)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CCOC(C)=O>CN(C=O)C>[CH3:27][C:26]1([CH3:28])[C:23]([CH3:24])([CH3:25])[O:22][B:21]([C:18]2[CH:17]=[CH:16][C:15]([CH2:14][O:12][C:10]3[CH:9]=[CH:8][C:6]4[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]=4[CH:11]=3)=[CH:20][CH:19]=2)[O:29]1
Reactant: CC1(C)OB(c2ccc(CBr)cc2)OC1(C)C
Reactant: N#Cc1nc2ccc(O)cc2s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)OB(c2ccc(COc3ccc4nc(C#N)sc4c3)cc2)OC1(C)C
Temperature: 60 °C
Reaction time: 0.79 h
Yield: 82.1 %

Procedure:
2-Cyano-6-hydroxybenzothiazole (300 mg, 1.7 mmol) and 4-(bromomethyl)benzeneboronic acid pinacol ester (505.7 mg, 1.7 mmol) were dissolved in 30 mL dry DMF prior to the addition of cesium carbonate (610.25 mg, 1.87 mmol). The mixture was stirred at 60° C. for 45-50 minutes before it was allowed to cool to room temperature. 100 mL EtOAc was added to the reaction mixture, and the organic phase was washed three times with deionized water (DI H2O). The aqueous layers were combined and washed three times with EtOAc. All of the organic layers were combined, washed twice with brine, dried over sodium sulfate, and concentrated. The crude material was purified on a silica column (90:10 hexanes:ethyl acetate, dry loaded) to give 547.4 mg (82%) of the pure product. 1H NMR (400 MHz, CDCl3): δ 1.36 (1H, s), 5.21 (2H, s), 7.32 (1H, d, J=8.8 Hz), 7.40 (1H, s), 7.45 (2H, d, J=7.6 Hz), 7.86 (2H, d, J=7.2 Hz), 8.09 (1H, d, J=9.2 Hz). LRESI-MS: calculated for [C21H22BN2O3S]+393.1. found 393.1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([C:24]([O:26]C)=[O:25])=[C:12]2[C:28]1[S:29][CH:30]=[CH:31][CH:32]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+].Cl>CO.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([C:24]([OH:26])=[O:25])=[C:12]2[C:28]1[S:29][CH:30]=[CH:31][CH:32]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1c(-c2cccs2)c2cc(OCc3ccccc3)ccc2c(=O)n1CC(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)Cn1c(C(=O)O)c(-c2cccs2)c2cc(OCc3ccccc3)ccc2c1=O
Yield: 87.7 %

Procedure:
To a suspension of methyl 6-(benzyloxy)-2-isobutyl-1-oxo-4-(2-thienyl)-1,2-dihydro-3-isoquinolinecarboxylate (2.01 g, 4.5 mmol) in methanol (30 ml) was added a solution of lithium hydroxide monohydrate (0.57 g, 13.5 mmol) in water (10 ml). The resulting mixture was refluxed under heating for 48 h. The reaction mixture was poured into water, acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting crystals were recrystallized from ethyl acetate-n-hexane to give 6-(benzyloxy)-2-isobutyl-1-oxo-4-(2-thienyl)-1,2-dihydro-3-isoquinolinecarboxylic acid (1.71 g, 87.7%) as crystals.
Reaction SMILES: [OH:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH3:15])[C:6]=2[N:5]=[C:4]([CH3:16])[C:3]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18].CCN(CC)CC.[O:29](S(C(F)(F)F)(=O)=O)[S:30]([C:33]([F:36])([F:35])[F:34])(=O)=[O:31]>ClCCl>[CH3:16][C:4]1[C:3]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:2]([O:1][S:30]([C:33]([F:36])([F:35])[F:34])(=[O:31])=[O:29])[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH3:15])[C:6]=2[N:5]=1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)c1c(C)nc2c(c1O)c1ccccc1n2C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(C)nc2c(c1OS(=O)(=O)C(F)(F)F)c1ccccc1n2C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 93.2 %

Procedure:
An ice cold mixture of ethyl 4-hydroxy-2,9-dimethyl-9H-pyrido[2,3-b]indole-3-carboxylate (210 mg, 0.739 mmol) in dichloromethane (DCM) (3.5 mL) was treated with Et3N (0.154 mL, 1.108 mmol) and Tf2O (0.137 mL, 0.812 mmol), and then stirred at 0° C. for 90 min. The mixture was concentrated and purified with column chromatography (0-100% DCM/Hexane) to afford ethyl 2,9-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)-9H-pyrido[2,3-b]indole-3-carboxylate (286.8 mg, 0.689 mmol, 93% yield) as white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.23 (d, J=7.9 Hz, 1 H), 7.65-7.57 (m, 1 H), 7.49 (d, J=8.2 Hz, 1 H), 7.42-7.34 (m, 1 H), 4.46 (q, J=7.1 Hz, 2 H), 3.98 (s, 3 H), 2.88 (s, 3 H), 1.45 (t, 3 H); LCMS (m/z) ES+=417 (M+1).
Reaction SMILES: C([BH3-])#N.[Na+].[CH2:5]([O:8][C:9]([C:11]1[N:12]([NH2:16])[CH:13]=[CH:14][CH:15]=1)=[O:10])[CH:6]=[CH2:7].[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1.C(O)(=O)C>CO>[CH2:5]([O:8][C:9]([C:11]1[N:12]([NH:16][CH2:22][C:21]2[CH:24]=[CH:25][C:18]([F:17])=[CH:19][CH:20]=2)[CH:13]=[CH:14][CH:15]=1)=[O:10])[CH:6]=[CH2:7]
Reactant: O=Cc1ccc(F)cc1
Reactant: C=CCOC(=O)c1cccn1N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: C=CCOC(=O)c1cccn1NCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 37.4 %

Procedure:
Sodium cyanoborohydride (2.29 g, 36.4 mmol) was added to a solution of 1-amino-1H-pyrrole-2-carboxylic acid allyl ester (Example 1b, 3.03 g, 18.2 mmol), 4-fluorobenzaldehyde (1.96 mL, 18.3 mmol) and acetic acid (6 mL), in methanol (120 mL) at 25° C. The reaction mixture was stirred at 25° C. for 18 h, and then was concentrated in vacuo to a volume of about 30 mL. The remaining liquid was partitioned between half-saturated aqueous sodium bicarbonate solution (150 mL) and a 1:1 mixture of ethyl acetate and hexanes (2×200 mL). The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by flash column chromatography (Merck silica gel 60, 40-63 μm, 0→40% ethyl acetate in hexanes) afforded the desired product, 1-(4-fluoro-benzylamino)-1H-pyrrole-2-carboxylic acid allyl ester (1.87 g, 6.8 mmol, 37% yield) as a clear liquid. 1H NMR (400 MHz, CDCl3) δ: 4.08 (2H, d, J=5.4 Hz), 4.75-4.77 (1H, m), 5.27-5.30 (1H, m), 5.37-5.41 (1H, m), 5.95-5.97 (1H, m), 5.98-6.05 (1H, m), 6.58-6.61 (1H, m), 6.75-6.76 (1H, m), 6.89-6.91 (1H, m), 6.97-7.01 (2H, m), 7.22-7.25 (2H, m).
Reaction SMILES: S(=O)(O)[O-].[Na+].[CH3:6][C@@H:7]1[CH:12]=[CH:11][CH2:10][CH2:9][C@H:8]1[CH:13]=[O:14].[C-:15]#[N:16].[K+]>O.C(O)C>[CH3:6][C@@H:7]1[CH:12]=[CH:11][CH2:10][CH2:9][C@H:8]1[CH:13]([OH:14])[C:15]#[N:16]
Reactant: C[C@@H]1C=CCC[C@H]1C=O
Reactant: [C-]#N
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C[C@@H]1C=CCC[C@H]1C(O)C#N
Temperature: 15 °C
Reaction time: 0.5 h

Procedure:
Sodium bisulfite (10.4 g., 0.1 mole) was dissolved in 50 ml. H2O. Absolute ethanol (50 ml.) and trans-2-methyl-3-cyclohexene-1-carbaldehyde (85%, 8.6 g., 0.07 mole) were added and the mixture heated in an oil bath at 63°-65° C. for 1.5 hours, then cooled to 15° C. in an ice-water bath. KCN (13 g., 0.2 mole) in 50 ml. H2O was added at 15°-18° C. The reaction mixture was stirred at room temperature 0.5 hour and extracted with 150 ml. ether. The ether was back-washed with 75 ml. H2O and concentrated in vacuo to yield title product as an oil, 5.5 g. Based on pnmr, the product contained 85% trans isomer (doublet at 4.6 ppm, J=4) and 15% cis isomer (doublets at 4.2 and 4.35, J=2).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]([CH3:15])([N:7]1[CH:11]=[C:10]([N+:12]([O-])=O)[N:9]=[CH:8]1)[CH3:6].[F:17][C:18]1[CH:19]=[C:20]2[C:25](=[C:26]([F:28])[CH:27]=1)[CH2:24][CH:23]([NH:29][CH:30]([CH2:34][CH2:35][CH3:36])[C:31](O)=[O:32])[CH2:22][CH2:21]2>>[CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]([N:7]1[CH:11]=[C:10]([NH:12][C:31](=[O:32])[CH:30]([NH:29][CH:23]2[CH2:22][CH2:21][C:20]3[C:25](=[C:26]([F:28])[CH:27]=[C:18]([F:17])[CH:19]=3)[CH2:24]2)[CH2:34][CH2:35][CH3:36])[N:9]=[CH:8]1)([CH3:15])[CH3:6]
Reactant: COC(=O)CC(C)(C)n1cnc([N+](=O)[O-])c1
Reactant: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)O
Product: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)Nc1cn(C(C)(C)CC(=O)OC)cn1

Procedure:
3-Methyl-3-(4-nitro-imidazol-1-yl)-butyric acid methyl ester was reduced and coupled with 2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid to afford the title compound; MS 463.5 m/z (M+1).
Reaction SMILES: [C:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH:2]=1.[CH:7](O)([CH3:9])[CH3:8].CC(C)=O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH:7]([O:6][CH:1]1[CH2:5][CH2:4][CH:3]=[CH:2]1)([CH3:9])[CH3:8]
Reactant: OC1=CCCC1
Reactant: CC(C)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Solvent: CC(C)=O
Solvent: O
Product: CC(C)OC1C=CCC1
Temperature: 40 °C
Reaction time: 4 h
Yield: 6 %

Procedure:
1-Cyclopentenol (0.30 g), isopropanol (0.40 g), and an aqueous solution of 0.020 g of tetrabutylammonium hydrogen sulfate in 0.25 g of water were mixed, and the two-phase system was stirred vigorously at 40° C. for 4 hours. Acetone was then added to homogenize the mixture, and it was analyzed by gas chromatography. Peaks corresponding to about a 6% yield of 2-cyclopentenyl isopropyl ether and about a 12% yield of 2-cyclopentenol were observed along with a concomitant peak for the co-product acetic acid. No bis-(2-cyclopentenyl) ether was formed.