Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH:6]=[CH:5]2.CS(O)(=O)=O.[C:18](O)(=[O:20])C.C(O)(=O)C.I(C1C=CC=CC=1)=O>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH:6]=[C:5]2[O:20][CH3:18]
Reactant: O=c1[nH]ccc2cc(Br)ccc12
Reactant: CC(=O)O
Agent: CS(=O)(=O)O
Agent: O=Ic1ccccc1
Solvent: CO
Product: COc1c[nH]c(=O)c2ccc(Br)cc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A round bottom flask was charged with 6-bromo-2h-isoquinolin-1-one (1.0 g, 4.46 mmol), methanol (8 mL), and methanesulfonic acid (0.290 ml, 4.46 mmol) and the flask was cooled to 0° C. In a separate flask, iodosobenzene diacetate (1.581 g, 4.91 mmol) was dissolved in methanol (8 mL) and added to the reaction. The reaction was warmed to room temperature and stirred for one hour, then heated to 50° C. and stirred overnight. The reaction was concentrated and triturated with isopropanol. The solution was stirred for 10 minutes, then filtered. The solids were washed with isopropanol and vacuum dried to afford 6-bromo-4-methoxyisoquinolin-1(2H)-one as a tan solid. (ESI) 254.1 (M+H
Reaction SMILES: [OH:1][C@H:2]1[C@H:9]2[C@H:5]([N:6]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N+:20]([O-:22])=[O:21])(=[O:13])=[O:12])[C:7](=[O:10])[O:8]2)[CH2:4][CH2:3]1.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])(=O)=O>C(Cl)Cl>[Si:37]([O:1][C@H:2]1[C@H:9]2[C@H:5]([N:6]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N+:20]([O-:22])=[O:21])(=[O:13])=[O:12])[C:7](=[O:10])[O:8]2)[CH2:4][CH2:3]1)([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: O=C1O[C@H]2[C@H](O)CC[C@H]2N1S(=O)(=O)c1ccccc1[N+](=O)[O-]
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@@H]2[C@H]1OC(=O)N2S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of (3aR*,6R*,6aR*)-6-hydroxy-3-((2-nitrophenyl)sulfonyl)hexahydro-2H-cyclo-penta[d]oxazol-2-one (1.2 g, 3.66 mmol) and 2,6-lutidine (0.851 mL, 7.31 mmol) in CH2Cl2 (25 mL) was added dropwise at 0° C. the tert-butyldimethylsilyl trifluoromethanesulfonate (1.091 mL, 4.75 mmol). The reaction mixture was stirred for 1 h at 0° C. followed by 2 h at RT. The reaction mixture was diluted with CH2Cl2 and washed with 20% aqueous NaH2PO4 solution and H2O, dried over MgSO4, filtered and concentrated. The title compound was obtained after crystallization from EtOAc/heptane as white solid (1.5 g, 88%): TLC (heptane/EtOAc 1:1) Rf=0.54; tR=1.58 min (UPLC 1), tR=1.43 min (LC-MS 3); ESI-MS: 460 [M+NH4]+ (LC-MS 3).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:29])[C:9]2[CH:28]=[CH:27][C:12]3[N:13]([CH3:26])[C:14]([NH:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)=[N:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:30][S:31]([CH2:34][C:35]1[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=1)(=[O:33])=[O:32]>>[ClH:1].[CH3:30][S:31]([CH2:34][C:35]1[CH:41]=[CH:40][C:38]([NH:39][C:2]2[N:7]=[C:6]([N:8]([CH3:29])[C:9]3[CH:28]=[CH:27][C:12]4[N:13]([CH3:26])[C:14]([NH:16][CH2:17][C:18]5[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=5)=[N:15][C:11]=4[CH:10]=3)[CH:5]=[CH:4][N:3]=2)=[CH:37][CH:36]=1)(=[O:32])=[O:33]
Reactant: COc1ccc(CNc2nc3cc(N(C)c4ccnc(Cl)n4)ccc3n2C)cc1
Reactant: CS(=O)(=O)Cc1ccc(N)cc1
Product: COc1ccc(CNc2nc3cc(N(C)c4ccnc(Nc5ccc(CS(C)(=O)=O)cc5)n4)ccc3n2C)cc1
Product: Cl

Procedure:
The title compound was prepared following the procedure of example two with N5-(2-chloro-pyrimidin-4-yl)-N2-(4-methoxy-benzyl)-1,N5-dimethyl-1H-benzoimidazole-2,5-diamine (82 mg, 0.20 mmol) and 4-[(methylsulfonyl)methyl]aniline (37 mg, 0.20 mmol) as a white solid (86 mg, 72%). 1H NMR (300 MHz, d6-DMSO) δ 9.21 (s, 1H), 7.76-7.81 (m, 3H), 7.29-7.34 (m, 3H), 7.21-7.25 (m, 3H), 7.09 (d, J=1.8 Hz, 1H), 6.82-6.90 (M, 3H), 5.64 (d, J=6.0 Hz, 1H), 4.52 (d, J=5.7 Hz, 2H), 4.35 (s, 2H), 3.72 (s, 3H), 3.56 (s, 3H), 3.43 (s, 3H), 2.85 (s, 3H). MS (ESI) m/z=558 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:11]3[CH:12]=[CH:13][C:14]([F:16])=[CH:15][C:10]=3[O:9][N:8]=2)[CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][CH2:25][N:26]1[C:35](=[O:36])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=[C:27]1[CH3:37]>C(#N)C>[F:16][C:14]1[CH:13]=[CH:12][C:11]2[C:7]([CH:4]3[CH2:3][CH2:2][N:1]([CH2:24][CH2:25][N:26]4[C:35](=[O:36])[C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[NH:28][CH:27]4[CH3:37])[CH2:6][CH2:5]3)=[N:8][O:9][C:10]=2[CH:15]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: Cc1nc2ccccc2c(=O)n1CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1Nc2ccccc2C(=O)N1CCN1CCC(c2noc3cc(F)ccc23)CC1

Procedure:
A stirred mixture of 3-(4-piperidinyl)-6-fluorobenzisoxazole (4 g, 18.2 mmol), K2CO3 (3.76 g, 27.2 mmol) and 3-(2-chloroethyl)-2-methyl-3H-4-quinazolinone (6.0 g; 27 mmol) in acetonitrile (300 ml) was heated at reflux for 16 hours. The reaction was complete as judged by TLC. The solids were filtered and the solvent was evaporated. The residue was purified over a flash chromatography column (SiO2, 75 gm, eluted with dichloromethane and MeOH in dichloromethane). The pure product thus obtained weighed 6.5 gm. Recrystallization from ethanol yielded white crystals, 3.94 gm (53%), m.p. 164°-165° C. This material appeared pure by TLC over silica gel plates.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][CH:11]3[NH:14][CH2:15][CH2:16][CH:10]3[CH2:9]2)=[CH:6][C:5]([C:17]#[N:18])=[CH:4][C:3]=1[NH:19][C:20]1[N:25]=[C:24]([N:26]([CH:36]2[CH2:38][CH2:37]2)CC2C=CC(OC)=CC=2)[C:23]2=[N:39][CH:40]=[C:41]([C:42]#[N:43])[N:22]2[N:21]=1.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O.ClC(Cl)C>>[Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][CH:11]3[NH:14][CH2:15][CH2:16][CH:10]3[CH2:9]2)=[CH:6][C:5]([C:17]#[N:18])=[CH:4][C:3]=1[NH:19][C:20]1[N:25]=[C:24]([NH:26][CH:36]2[CH2:37][CH2:38]2)[C:23]2=[N:39][CH:40]=[C:41]([C:42]#[N:43])[N:22]2[N:21]=1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCC5NCCC5C4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(Cl)Cl
Product: N#Cc1cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c(Cl)c(N2CCC3NCCC3C2)c1
Yield: 89 %

Procedure:
A solution of 2-((2-chloro-5-cyano-3-(hexahydro-1H-pyrrolo[3,2-c]pyridin-5(6H)-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (58 mg, 0.097 mmol), anisole (0.043 ml, 0.390 mmol) and 25% TFA in dichloroethane (2 ml, 6.49 mmol) was heated at 35° C. overnight. Solvent was evaporated in vacuo and the crude was dissolved in acetonitrile (1 ml) and neutralized with 2N ammonia in methanol (1 ml). The crude product was purified by flash chromatography on silica gel using an automated ISCO system (24 g gold column, eluting with 1-12% 2 N ammonia in methanol/dichloromethane). 2-((2-chloro-5-cyano-3-(hexahydro-1H-pyrrolo[3,2-c]pyridin-5(6H)-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (41 mg) was obtained as a white solid.
Reaction SMILES: [CH3:1][CH:2]1[N:9]2[CH:10]=[N:11][C:12]3[CH:13]([CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])[C:14](=[O:16])[CH:15]=[C:7]([C:8]=32)[NH:6][CH2:5][CH2:4][C:3]1=[O:25].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][CH:2]1[N:9]2[CH:10]=[N:11][C:12]3[CH:13]([CH2:17][C:18]([OH:20])=[O:19])[C:14](=[O:16])[CH:15]=[C:7]([C:8]=32)[NH:6][CH2:5][CH2:4][C:3]1=[O:25]
Reactant: CC1C(=O)CCNC2=CC(=O)C(CC(=O)OC(C)(C)C)c3ncn1c32
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1C(=O)CCNC2=CC(=O)C(CC(=O)O)c3ncn1c32
Reaction time: 2 h

Procedure:
To a solution of tert-butyl (8-methyl-2,7-dioxo-5,6,7,8-tetrahydro-4H-imidazo[1,5,4-fg][1,6]benzodiazocin-1(2H)-yl)acetate from Step A (45 mg, 0.13 mmol) in CH2Cl2 (6 mL) was added TFA (2 mL). After 2 h, the mixture was concentrated under reduced pressure to give the title compound. MS: m/z=290 (M+1).
Reaction SMILES: [ClH:1].[O:2](CCCNC(C)(C)CC1C=CC(OC)=CC=1)[C:3]1C=CC=C[CH:4]=1.Cl.[OH:26][C@H:27]([CH2:42][O:43][C:44]1[CH:49]=[CH:48][C:47](C(C)(C)C)=[CH:46][CH:45]=1)[CH2:28][NH:29][C:30]([CH3:41])([CH3:40])[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1.Cl.OC(COC1C=CC=CC=1C)CNC(C)(C)CC1C=CC(OC)=CC=1>>[ClH:1].[OH:26][CH:27]([CH2:42][O:43][C:44]1[CH:49]=[CH:48][C:47]([O:2][CH2:3][CH3:4])=[CH:46][CH:45]=1)[CH2:28][NH:29][C:30]([CH3:41])([CH3:40])[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1
Reactant: COc1ccc(CC(C)(C)NCCCOc2ccccc2)cc1
Reactant: COc1ccc(CC(C)(C)NC[C@H](O)COc2ccc(C(C)(C)C)cc2)cc1
Agent: COc1ccc(CC(C)(C)NCC(O)COc2ccccc2C)cc1
Agent: Cl
Product: CCOc1ccc(OCC(O)CNC(C)(C)Cc2ccc(OC)cc2)cc1

Procedure:
GC/EI-MS, m/z (rel. int.) 358 (M−15, 0.1), 253 (17), 252 (100), 163 (6), 121 (21), 114 (8), 108 (8).
Reaction SMILES: [N+](=[CH:3][C:4]([O:6][CH:7]([C:12]([Cl:15])([Cl:14])[Cl:13])[CH:8]=[C:9]([CH3:11])[CH3:10])=[O:5])=[N-]>O1CCOCC1.CCOCC.CC(CC(C)=O)=O.CC(CC(C)=O)=O.[Cu]>[Cl:13][C:12]([Cl:15])([Cl:14])[CH:7]1[CH:8]2[CH:3]([C:9]2([CH3:11])[CH3:10])[C:4](=[O:5])[O:6]1
Reactant: CC(C)=CC(OC(=O)C=[N+]=[N-])C(Cl)(Cl)Cl
Agent: [Cu]
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: CC(=O)CC(C)=O
Product: CC1(C)C2C(=O)OC(C(Cl)(Cl)Cl)C21
Yield: 56.5 %

Procedure:
To a refluxing solution of cupric acetylacetonate (0.07 g, 0.27 mole) in 70 ml of dioxane was added drop-dropwise over a 31/2 hour period, under an argon atmosphere, a solution of (±)-3-methyl-1-trichloromethyl-2-butenyl diazoacetate (1.09 g, 0.004 moles) and cupric acetylacetonate (0.007 g, 0.027 mmole) in 10 ml of dioxane. The reaction mixture was then heated under reflux for one hour and evaporated to dryness, yielding a residue which was dissolved in ether. The ethereal solution was washed successively with two portions of aqueous 1N hydrochloric acid, two portions of aqueous sodium bicarbonate, and twice with saturated aqueous sodium chloride. After drying the solution over magnesium sulfate, the ether was evaporated to afford a pale yellow oil, which was purified by column chromatography on a silica gel column using a 9/1 mixture of n-hexane/ethyl acetate as the eluent, to give (±)-4-trichloromethyl-6,6-dimethyl-2-oxo-3-oxabicyclo[3.1.0]hexane (0.55 g, 53% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[C:4]([O:12][CH3:13])[C:3]=1[NH2:14].C(N([CH2:20][CH3:21])CC)C.[CH2:22]([O:29][CH2:30][C:31](Cl)=[O:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>ClCCl>[CH2:22]([O:29][CH2:30][C:31]([NH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[C:4]([O:12][CH3:13])[C:3]=1[NH:14][C:5](=[O:10])[CH2:6][O:8][CH2:9][C:21]1[CH:20]=[CH:4][CH:3]=[CH:2][CH:7]=1)=[O:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCN(CC)CC
Reactant: O=C(Cl)COCc1ccccc1
Reactant: COc1cc(N)c(N)c(OC)c1OC
Solvent: ClCCl
Product: COc1cc(NC(=O)COCc2ccccc2)c(NC(=O)COCc2ccccc2)c(OC)c1OC
Reaction time: 4 h

Procedure:
1,2-Diamino-3,4,5-trimethoxybenzene (675 mg) and triethylamine (1.4 mL) were dissolved in dry dichloromethane (25 mL), benzyloxyacetyl chloride (1.34 mL) was added to the solution under ice cooling, and the mixture was stirred for 4 hours as it is. The reaction mixture was extracted with chloroform, and the resultant organic layer was washed with diluted hydrochloric acid, an aqueous solution of potassium carbonate, water and saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane=2:3 to 1:1) to obtain the title compound.
Reaction SMILES: C([N:8]1[C:12]([CH2:13][CH:14]2[C:20](=[O:21])[N:19]([CH2:22][C:23]([N:25]([CH:34]([CH3:36])[CH3:35])[C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)=[O:24])[C:18]3[CH:37]=[CH:38][CH:39]=[CH:40][C:17]=3[N:16]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:15]2=[O:47])=[CH:11][C:10]([CH3:48])=[N:9]1)C1C=CC=CC=1>C(O)=O.C(O)C.[Pd]>[CH:34]([N:25]([C:26]1[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=1)[C:23](=[O:24])[CH2:22][N:19]1[C:20](=[O:21])[CH:14]([CH2:13][C:12]2[NH:8][N:9]=[C:10]([CH3:48])[CH:11]=2)[C:15](=[O:47])[N:16]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:17]2[CH:40]=[CH:39][CH:38]=[CH:37][C:18]1=2)([CH3:35])[CH3:36]
Reactant: COc1ccc(N(C(=O)CN2C(=O)C(Cc3cc(C)nn3Cc3ccccc3)C(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Agent: [Pd]
Solvent: CCO
Solvent: O=CO
Product: COc1ccc(N(C(=O)CN2C(=O)C(Cc3cc(C)n[nH]3)C(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Temperature: 25 °C
Yield: 67.7 %

Procedure:
To a stirring solution of 194 mg (0.30 mmol) of 2-[3-(2-Benzyl-5-methyl-2H-pyrazol-3ylmethyl)-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl]-N-isopropyl-N-(4-methoxy-phenyl)-acetamide, prepared as in Example 54, in 10 mL of 5% formic acid (v/v) in absolute ethanol is added 190 mg of 10% palladium on carbon. The resulting mixture is heated to reflux for 2 h, then cooled to RT and filtered through a pad of Celite to remove the catalyst. The filtrate is concentrated, then poured into 50 mL of EtOAc and washed successively with 1N NaOH (1×50 mL) and H2O (1×50 mL). The organic layer is separated, dried (MgSO4), and the solvents removed in vacuo. Purification by silica gel MPLC using EtOAc/chloroform 8/1 as eluent afforded 112 mg of the title compound as a white solid: mp 156°-159° C.; 1H NMR (CDCl3, 400 MHz) δ7.38-7.18 (m, 9H), 7.14 (d, 1H, J=8.7), 7.06 (t, 1H, J=7.3), 6.96 (m, 2H), 6.86 (d, 1H, J=7.6), 5.81 (s, 1H), 5.02 (m, 1H), 4.18 (dd, 2H, J=16.5, 86.1), 3.83 (s, 3H), 3.59 (t, 1H, J=6.8), 3.32 (ddd, 2H, J=7.5, 15.2, 34.3), 2.19 (s, 3H), 1.08 (m, 6H); low resolution MS (FAB)m/e 552 (MH+), 551 (M+), 387; Anal. (C32H33N5O4) Calcd. C, 69.67; H, 6.03; N, 12.70 Found C, 69.61; H, 6.11; N, 12.44.
Reaction SMILES: [Li+].[OH-].[CH2:3]([C@H:7]1[CH2:11][CH2:10][N:9]([C@@H:12]([CH2:17][CH:18]=[CH2:19])[C:13]([O:15]C)=[O:14])[C:8]1=[O:20])[CH2:4][CH2:5][CH3:6].Cl>O.C1COCC1>[CH2:3]([C@H:7]1[CH2:11][CH2:10][N:9]([C@@H:12]([CH2:17][CH:18]=[CH2:19])[C:13]([OH:15])=[O:14])[C:8]1=[O:20])[CH2:4][CH2:5][CH3:6]
Reactant: C=CC[C@@H](C(=O)OC)N1CC[C@H](CCCC)C1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C=CC[C@@H](C(=O)O)N1CC[C@H](CCCC)C1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 79.2 %

Procedure:
Step B (5): A solution of LiOH (2 M, 69 mg, 2.9 mmol) in 1.4 mL of H2O was added to diastereomer A, (S)-methyl 2-((S)-3-butyl-2-oxopyrrolidin-1-yl)pent-4-enoate, (242 mg, 0.96 mmol) from Step B (4) in THF (1.4 mL). The reaction mixture was stirred at room temperature for 3 days. The mixture was poured into 1 N HCl and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO4 and concentrated in vacuo to give 182 mg of (S)-2-((S)-3-butyl-2-oxopyrrolidin-1-yl)pent-4-enoic acid as colorless oil: LC-MS (M+H)+=240.2; 1H NMR (500 MHz, CDCl3) δ 5.60-5.82 (m, 1H), 5.03-5.21 (m, 2H), 4.74 (dd, J=10.68, 4.88 Hz, 1H), 3.38-3.48 (m, 1H), 3.29-3.38 (m, 1H), 2.70-2.81 (m, 1H), 2.51-2.62 (m, 1H), 2.36-2.49 (m, 1H), 2.11-2.25 (m, 1H), 1.79-1.91 (m, 1H), 1.66-1.79 (m, 1H), 1.23-1.43 (m, 5H), 0.80-0.96 (m, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[Cl:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=1[NH:53][CH:54]1[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]1>CN(C=O)C.O>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]([N:57]1[CH2:56][CH2:55][CH:54]([NH:53][C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=2[Cl:46])[CH2:59][CH2:58]1)=[O:12])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: Clc1ccccc1NC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCC(=O)N1CCC(Nc2ccccc2Cl)CC1
Reaction time: 8 h
Yield: 97.8 %

Procedure:
To a stirred mixture of glycine (30 g, 0.3996 mole) in 1N aqueous NaOH (39.96 g, 0.999 mole) was added tert-butanol (270 mL). The mixture was cooled to 0° C. and di-tert-butyl dicarbonate (96.42 g, 0.4395 mole) was added dropwise. The mixture was stirred at ambient temperature for 5 hours. The reaction mixture was then concentrated under reduced pressure and the resulting residue was acidified with citric acid. The product was extracted with ethyl acetate. the organic layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to afford 49 g (70%) of tert-butoxycarbonylamino-acetic acid. 1H NMR (DMSO-d6): δ 12.8-12.0 (bs, 1H), 7.1 (t, 1H), 3.6 (d, 2H), 1.4 (s 9H). To a stirred solution of tert-butoxycarbonylamino-acetic acid (0.2 g, 0.00114 mol) in DMF (5 mL) was added DIPEA (0.59 g, 0.00457 mol), HOBt (0.193 g, 0.001427 mol) and EDCI.HCl (0.274 g, 0.00143 mol) at ambient temperature. After 5 minutes (2-chloro-phenyl)-piperidin-4-yl-amine dihydrochloride (0.283 g, 0.00114 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water. The resulting precipitate was isolated by filtration and purified by column chromatography using basic aluminium oxide (60% ethyl acetate in hexane) to afford 0.41 g (98%) of {2-[4-(2-chloro-phenylamino)-piperidin-1-yl]-2-oxo-ethyl}-carbamic acid tert-butyl ester. LCMS: 368.18 (M+1)+, 93.53%. A solution of {2-[4-(2-chloro-phenylamino)-piperidin-1-yl]-2-oxo-ethyl}-carbamic acid tert-butyl ester (0.41 g, 0.00111 mole) in methanol (10 mL) was added dioxane.HCl (5 mL) and the resulting mixture was stirred at ambient temperature for 10 minutes. The mixture was then concentrated under reduced and the resulting residue was washed with ether to afford 0.34 g (98%) of 2-amino-1-[4-(2-chloro-phenylamino)-piperidin-1-yl]-ethanone hydrochloride. LCMS: 268.11 (M+1)+, 84.63%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH2:37](I)[CH3:38]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([O:30][CH2:37][CH3:38])=[CH:28][CH:29]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(O)cc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc(Cn2c(C(=O)OC)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1

Procedure:
To a mixture of 6-bromo-2-(4-hydroxybenzyl)-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (200 mg), potassium carbonate (89 mg) and DMF (4.0 ml) was added ethyl iodide (41 μl) at room temperature with stirring, and the mixture was stirred at room temperature for 12 hrs. The reaction mixture was concentrated, and the residue was partitioned between ethyl acetate and water. The organic layer was dried over magnesium sulfate and concentrated. The residue was purified by medium pressure preparative LC (hexane/ethyl acetate=9/1-1/1) to give the title compound (110 mg) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.CN(C=O)C.[Br:17][CH2:18][C:19](Br)=[O:20]>O1CCOCC1>[Br:17][CH2:18][C:19]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)=[O:20]
Reactant: COC(=O)c1ccc(N)cc1
Reactant: O=C(Br)CBr
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NC(=O)CBr)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 76.1 %

Procedure:
A solution of methyl 4-aminobenzoate (5.0 g, 33 mmol) in a mixture of anhydrous DMF (30 mL) and anhydrous dioxane (30 mL) in a 250 mL 3-necked round-bottomed flask equipped with a constant addition funnel (60 mL) was cooled to 0° C. using an ice-bath. Bromoacetyl bromide (6.66 g, 2.9 mL, 33 mmol) was added dropwise, keeping the internal temperature between 0° to 5° C. over a 1/2 h period. After the addition the bromoacetyl bromide was completed, the solution was warmed to rt, stirred overnight, and then the solution was slowly poured into 500 mL of ice-water, causing a solid to precipitate. The precipitate was filtered, washed with water, and then dried in a vacuum dessicator overnight to afford 6.83 g (76%) of the title compound as a pale brown solid; mp 153°-155° C.: 1H NMR (DMSO-d6) δ10.72 (s, 1H), 7.93 (d, J=8.8, 3H), 7.72 (d, J=8.8, 2H), 4.07 (s, 2H), 3.82 (s, 3H) 13C NMR (DMSO-d6) δ165.69, 165.36, 124.91, 130.26, 124.49, 118.64, 51.92, 30.25; MS (EI, m/z) 271 (M+ ).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][C:11]=1[CH2:20][OH:21].[H-].[Na+].[CH2:24](I)[CH3:25]>CN(C=O)C.CCOC(C)=O>[CH2:24]([O:21][CH2:20][C:11]1[CH:12]=[C:13]([C:16]([O:18][CH3:19])=[O:17])[CH:14]=[CH:15][C:10]=1[C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[F:1])[CH3:25]
Reactant: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(CO)c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOCc1cc(C(=O)OC)ccc1-c1cc(OC)ccc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 79 %

Procedure:
To a solution of 66.63A (0.200 g, 0.689 mmol) in DMF (5 mL), was added NaH (0.0198 g, 0.827 mmol). The reaction was stirred at room temperature for 10 minutes. Ethyl iodide was then added and the reaction was stirred at room temperatures for 1 hour. The mixture was diluted with EtOAc, washed with water and brine, and dried over anhydrous Na2SO4. After removing solvent, the residue was purified by flash chromatography (silica gel, 1:1 EtOAc/hexane) and gave 67.23A in 79% yield. MS ESI (pos.) m/e: 336 (M+18)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](I)[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].CN(C)C=O.[O:19]1[C@@:36]2([CH3:37])[C@@H:20]1[CH2:21][C@@H:22]1[C:27]([C:28]([OH:30])=[O:29])=[CH:26][O:25][C@@H:24]([O:31][C:32](=[O:35])[NH:33][CH3:34])[C@H:23]12>CCCCCC.C(OCC)(=O)C>[CH2:7]([O:30][C:28]([C:27]1[C@H:22]2[CH2:21][C@@H:20]3[O:19][C@:36]3([CH3:37])[C@@H:23]2[C@H:24]([O:31][C:32](=[O:35])[NH:33][CH3:34])[O:25][CH:26]=1)=[O:29])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CNC(=O)O[C@@H]1OC=C(C(=O)O)[C@H]2C[C@@H]3O[C@]3(C)[C@H]12
Reactant: CCCCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCCOC(=O)C1=CO[C@@H](OC(=O)NC)[C@@H]2[C@@H]1C[C@@H]1O[C@]21C
Temperature: 70 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
124 mg of potassium carbonate and 0.10 ml of n-hexyliodide were added to a dimethylformamide solution containing 200 mg of (1S,4aS,6S,7R,7aR)-6,7-epoxy-1,4a,5,6,7,7a-hexahydro-7-methyl-1-(methylcarbamoyloxy) cyclopenta [c]-pyrane-4-carboxylic acid described in Example 1 followed by heating and stirring for 1 hour at 70° C. The reaction mixture was then extracted with ethyl acetate. After washing the organic phase with dilute hydrochloric acid, saturated aqueous sodium bicarbonate, and brine, it was dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel chromatography to obtain a colorless oil from the hexane-ethyl acetate eluate in the form of (1S,4aS,6S,7R,7aR)-6,7-epoxy-1,4a,5,6,7,7a-hexahydro-7-methyl-1-(methylcarbamoyloxy) cyclopenta [c]-pyrane-4-carboxylic acid n-hexylester (210 mg, yield: 80%). The physicochemical properties of this compound are described in Table 1, Compound No. 5.