Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]([CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)(=O)[CH3:12].CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[C:1]1([C@@H:7]2[CH2:9][C@H:8]2[NH:10][CH:11]([CH:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:18][CH2:19]2)[CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: N[C@@H]1C[C@H]1c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC(N[C@@H]1C[C@H]1c1ccccc1)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of [trans-2-phenylcyclopropyl]amine (116 mg, 0.871 mmol), 1,1-dimethylethyl 4-acetyl-1-piperidinecarboxylate (110 mg, 0.484 mmol) and AcOH (1 μL, 0.017 mmol) in Chloroform (10 mL) was stirred at room temperature for 18 hours. Sodium triacetoxyborohydride (196 mg, 0.925 mmol) was added and stirring continued for 18 hours. Upon completion, saturated NaHCO3 was added to the reaction mixture and the mixture was extracted with CHCl3 (2×50 mL). The organics were combined, dried over Na2SO4 and concentrated. The residue was adsorbed onto silica and purified via column chromatography on the Isco Companion (gradient 0-100% 80:20:2 [CHCl3/MeOH/NH4OH]/CHCl3; 12 g column) to yield the desired product. This was further purified via reverse phase column chromatography on Gilson (C18 column: 0.1% Formic acid H2O/CH3CN, 95-5%) to obtain pure the pure title compound (67 mg, 22% yield) as a colorless oil: LC-MS (ES) m/z=345 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10](I)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].[CH3:16][O:17][C:18]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:19]=1[NH2:20].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([NH:20][C:19]2[CH:21]=[C:22]([O:25][CH3:26])[CH:23]=[CH:24][C:18]=2[O:17][CH3:16])[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COc1ccc(OC)c(N)c1
Reactant: COC(=O)c1cccc(I)c1C(=O)OC
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COC(=O)c1cccc(Nc2cc(OC)ccc2OC)c1C(=O)OC
Yield: 68 %

Procedure:
A mixture of 3-iodophthalic acid dimethyl ester (1.0 g, 3.1 mmol), 2,5-dimethoxyaniline (0.48 g, 3.1 mmol), Pd2(dba)3 (0.13 g, 0.14 mmol), rac-BINAP (0.058 g, 0.093 mmol), and cesium carbonate (1.4 g, 4.3 mmol), in 6 mL toluene was heated to reflux under nitrogen for 24 hours. The reaction mixture was cooled, diluted with CH2Cl2 (10 mL), and filtered through Celite, and the filter was washed with additional CH2Cl2 (30 mL). The filtrate was evaporated, and the residue was chromatographed using a hexanes-ethyl acetate gradient, eluting 0.73 g of the product at 80:20 hexanes-ethyl acetate, in 68% yield: 1H NMR (CDCl3) δ 3.74 (s, 3H), 3.85 (s, 3H), 3.88 (s, 3H), 3.89 (s, 3H), 6.48 (dd, J=8.8 Hz, J=2.9 Hz, 1H), 6.83 (d, J=8.8 Hz, 1H), 6.87 (d, J=2.9 Hz, 1H), 7.19 (dd, J=7.7 Hz, J=0.9 Hz, 1H), 7.34 (t, J=7.9 Hz, 1H), 7.55 (dd, J=8.5 Hz, J=0.9 Hz, 1H), 7.95 (br, 1H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:17]([CH2:18][CH2:19][C@:3]12[CH3:4])[C:16]1[CH:15]=[CH:14][C:13]([O:20]C)=[CH:12][C:11]=1[CH2:10][C@H:9]3[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH:31]([CH2:37][CH2:38][CH2:39][C:40]([F:46])([F:45])[C:41]([F:44])([F:43])[F:42])[C:32]([O:34][CH2:35][CH3:36])=[O:33].[Br-].[Br-].[Br-].B.O>ClCCl>[OH:20][C:13]1[CH:14]=[CH:15][C:16]2[C@@H:17]3[C@H:8]([C@H:5]4[C@@:3]([CH2:19][CH2:18]3)([CH3:4])[C@@H:2]([OH:1])[CH2:7][CH2:6]4)[C@H:9]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH:31]([CH2:37][CH2:38][CH2:39][C:40]([F:45])([F:46])[C:41]([F:42])([F:43])[F:44])[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:10][C:11]=2[CH:12]=1
Reactant: CCOC(=O)C(CCCCCCCCC[C@@H]1Cc2cc(OC)ccc2[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12)CCCC(F)(F)C(F)(F)F
Agent: B
Agent: [Br-]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C(CCCCCCCCC[C@@H]1Cc2cc(O)ccc2[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12)CCCC(F)(F)C(F)(F)F
Temperature: 0 °C
Reaction time: 3 h
Yield: 71.9 %

Procedure:
Ethyl 11-[17β-hydroxy-3-methoxyestra-1,3,5(10)-trien-7α-yl]-2-(4,4,5,5,5-pentafluoropentyl)undecanoate (946 mg, 1.43 mmol) was dissolved in dichloromethane (18 ml). To this solution, a 1M solution of borane tribromide in dichloromethane (4.3 ml, 4.3 mmol) was added dropwise at −78° C. The reaction mixture was warmed slowly and stirred for 3 hours at 0° C. Water was added to stop the reaction and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and then filtered. After concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=2/1) to give ethyl 11-[3,17β-dihydroxyestra-1,3,5(10)-trien-7α-yl]-2-(4,4,5,5,5-pentafluoropentyl)undecanoate (663 mg, Yield 72%).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][NH:11]3)=[CH:4][C:3]=2[O:2]1.Cl[C:24]1[N:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)=[CH:26][N:25]=1>C1(C)C=CC=CC=1.C1CCN2C(=NCCC2)CC1>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][N:11]3[C:24]3[N:25]=[CH:26][C:27]([C:30]4[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=4)=[CH:28][N:29]=3)=[CH:4][C:3]=2[O:2]1
Reactant: c1ccc2c3c([nH]c2c1)C(c1ccc2c(c1)OCO2)NCC3
Reactant: Cc1ccc(-c2cnc(Cl)nc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ccc(-c2cnc(N3CCc4c([nH]c5ccccc45)C3c3ccc4c(c3)OCO4)nc2)cc1

Procedure:
Following the same procedure as outlined in Example 12, 1-(3,4-methylenedioxyphenyl)-2,3,4,9-tetrahydro-1H-β-carboline (2.19 g, 7.5 mmol) (prepared according to the process as disclosed in WO97/43287, Intermediate 7, page 24) and 2-chloro-5-(4-methylphenyl)pyrimidine (1.03 g, 5 mmol) in toluene (50 mL, anhydrous) and DBU (0.9 mL) were reacted to yield the product as a white solid.
Reaction SMILES: [OH:1][C@@H:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[N:16]=[C:15]([C:17]4[O:21][N:20]=[C:19]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[C:18]=4[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=3)=[CH:9][CH:10]=2)[O:5][CH2:4][C@@H:3]1[NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36].[C:40]([OH:46])([C:42]([F:45])([F:44])[F:43])=[O:41]>C(Cl)Cl>[C:35]([O:34][C:33](=[O:39])[NH:32][C@H:3]1[C@@H:2]([OH:1])[C:11]2[C:6](=[CH:7][C:8]([C:12]3[N:16]=[C:15]([C:17]4[O:21][N:20]=[C:19]([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=5)[C:18]=4[C:28]([F:29])([F:30])[F:31])[O:14][N:13]=3)=[CH:9][CH:10]=2)[O:5][CH2:4]1)([CH3:38])([CH3:36])[CH3:37].[C:40]([OH:46])([C:42]([F:45])([F:44])[F:43])=[O:41]
Reactant: CC(C)(C)OC(=O)N[C@H]1COc2cc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)ccc2[C@H]1O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N[C@@H]1COc2cc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)ccc2[C@@H]1O

Procedure:
tert-Butyl (3S,4R)-4-hydroxy-7-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)chroman-3-ylcarbamate (500 mg) was dissolved in 30% TFA solution in DCM (3673 μl). After 2 h the reaction mixture was concentrated to give (3R,4S)-tert-butyl-4-hydroxy-7-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)chroman-3-ylcarbamate, TFA salt (quant.): LCMS=445.0 [M+H]+; 1H NMR and HPLC as in Ex. 1.
Reaction SMILES: C(OC([NH:11][C@@H:12]([CH2:20][NH:21][C:22](=[O:35])[C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:25][CH:24]=1)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=O)C1C=CC=CC=1.C(O)(=O)C.[H][H]>CO.[Pd]>[C:16]([O:15][C:13](=[O:14])[C@@H:12]([NH2:11])[CH2:20][NH:21][C:22](=[O:35])[C:23]1[CH:24]=[CH:25][C:26]([CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:27][CH:28]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: [H][H]
Reactant: COC(=O)CCc1ccc(C(=O)NC[C@H](NC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)cc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)CCc1ccc(C(=O)NC[C@H](N)C(=O)OC(C)(C)C)cc1

Procedure:
6.88 g (14.2 mmol) of tert-butyl (2S)-2-benzyloxycarbonylamino-3-(4-(2-methoxycarbonyl-ethyl)-benzoylamino)propionate was dissolved in 200 ml of methanol and 852 mg (14.2 mmol) of acetic acid was added. The mixture was hydrogenated for 7 hours at room temperature over Pd/C (5% strength) at 1 bar of hydrogen. The mixture was filtered and the solvent was removed in vacuo. The residue was washed with n-heptane and dried in vacuo. Yield 6.9 g. MS (ES+): m/e=351.2 (M+H+).
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([NH:8][CH:9]([CH:27]([CH3:29])[CH3:28])[C:10]([NH:12][C@@H:13]([CH3:26])[C:14]([NH:16][C@@H:17]([CH3:25])[C:18]([O:20]C(C)(C)C)=[O:19])=[O:15])=[O:11])=[N:5][CH:4]=1)=[O:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]([C:3]1[S:7][C:6]([NH:8][CH:9]([CH:27]([CH3:29])[CH3:28])[C:10]([NH:12][C@@H:13]([CH3:26])[C:14]([NH:16][C@@H:17]([CH3:25])[C:18]([OH:20])=[O:19])=[O:15])=[O:11])=[N:5][CH:4]=1)=[O:2]
Reactant: CC(C)C(Nc1ncc(C=O)s1)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C(Nc1ncc(C=O)s1)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)O
Yield: 145.2 %

Procedure:
Following the procedure as described in Example 11, except using material from Example 26 (213 mg, 0.499 mmol), CH2Cl2 (75 mL) and TFA (25 mL, 324 mmol), 268.4 mg (quantitative yield) of the title compound is obtained as a white solid as a mono TFA salt. LC/MS (Condition A): ret. T=2.15 min, (M+H)+ 371.14.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[C:16]1([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.P(C(C)(C)C)(C(C)(C)C)C(C)(C)C>C1(C)C=CC=CC=1>[C:23]1([N:22]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:2]2[CH:7]=[CH:6][C:5]([C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:9])=[CH:4][CH:3]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: O=C(c1ccccc1)c1ccc(Br)cc1
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Product: O=C(c1ccccc1)c1ccc(N(c2ccccc2)c2ccccc2)cc1
Reaction time: 24 h
Yield: 83.5 %

Procedure:
(4-bromophenyl)(phenyl)methanone (5.0 g, 19.2 mmol) and diphenylamine (4.2 g, 25.0 mmol) were dissolved in 150 mL of toluene under a nitrogen atmosphere, and then tris(benzylidene acetone dipalladium) (0.4 g, 0.4 mmol) was added thereto under nitrogen. Also, P(t-Bu)3 (0.8 g, 3.8 mmol) was added to the reaction mixture solution, followed by addition of NaOBut (5.5 g, 57.7 mmol). The reaction mixture solution was refluxed and stirred for 24 hours. After the reaction was over, the reaction mixture solution was filtered through a thin silica pad at a high temperature to thereby remove palladium. The filtrate was concentrated, and passed through a silica gel column by using hexane-dichloromethane 7:3 as an eluant. After the solvent was removed, the residue material was dried in vacuum to thereby obtain a white solid (5.6 g, yield: 84%).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH2:12][C@H:13]([CH2:17][OH:18])[CH:14]([CH3:16])[CH3:15].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:5]([O:4][C:2]([NH:12][C@H:13]([CH2:17][OH:18])[CH:14]([CH3:16])[CH3:15])=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)[C@H](N)CO
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)[C@@H](CO)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.5 %

Procedure:
Benzyl chloroformate (91.0 g, 95% purity) was added dropwise over a period of 1 h to a precooled (0° C.) solution of L-valinol (50.0 g) and triethylamine (60.0 g) in chloroform (1500 ml). The reaction mixture was stirred for 1 h at 0° C. and then allowed to warm to,room temperature over 2 h. After the reaction mixture was evaporated, ethyl acetate (1500 ml) was added to the residue and the organic solution was washed (1N NaOH, brine), dried (MgSO4), and evaporated. The residue was purified by flash chromatography, using a stepwise gradient elution of ether:hexane (1:5) followed by ether, to give the alcohol (91.4 g) as a white waxy solid; TLC, Rf =0.23, hexane:ethanol (50:50).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:12]3[C@@H:21]4[C@@H:16]([C:17]5[CH:25]=[CH:24][C:23]([C:26](O)=[O:27])=[CH:22][C:18]=5[CH2:19][CH2:20]4)[CH2:15][CH2:14][CH2:13]3)=[O:11])=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:12]3[C@@H:21]4[C@@H:16]([C:17]5[CH:25]=[CH:24][C:23]([C:26]([N:29]6[CH2:33][CH2:32][CH2:31][CH2:30]6)=[O:27])=[CH:22][C:18]=5[CH2:19][CH2:20]4)[CH2:15][CH2:14][CH2:13]3)=[O:11])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: C1CCNC1
Reactant: O=C(O)c1ccc2c(c1)CC[C@H]1[C@@H]2CCCN1C(=O)c1ccc2[nH]cnc2c1
Product: O=C(c1ccc2c(c1)CC[C@H]1[C@@H]2CCCN1C(=O)c1ccc2[nH]cnc2c1)N1CCCC1
Yield: 57 %

Procedure:
The title compound is prepared from cis-4-(1H-benzoimidazole-5-carbonyl)-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline-8-carboxylic acid and pyrrolidine following a procedure analogous to that described in Example 1. Yield: 57% of theory; LC (method 1): tR=2.27 min; Mass spectrum (ESI+): m/z=429 [M+H]+.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:12]([C:13]3[CH:18]=[C:17]([O:19][CH3:20])[N:16]=[N:15][C:14]=3OC)=[CH:11][N:10]=[C:9]([NH2:23])[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1COCC1.[H-].[Na+]>CO.C(Cl)Cl>[CH:1]1([N:6]2[C:14]3[N:15]=[N:16][C:17]([O:19][CH3:20])=[CH:18][C:13]=3[C:12]3[CH:11]=[N:10][C:9]([NH2:23])=[N:8][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(-c2cnc(N)nc2NC2CCCC2)c(OC)nn1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc2c3cnc(N)nc3n(C3CCCC3)c2nn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94.9 %

Procedure:
To a 35 mL microwave reaction vessel were placed with compound 316 (200 mg, 0.63 mmol) followed by THF and sodium hydride, (60% in mineral oil, 0.063 g, 1.6 mmol). The resulting mixture was stirred at room temperature for 10 min to allow gas release. Then the vessel was subjected to microwave reaction condition (60 min at 150° C.). The crude mixture was subjected to combi-flash column chromatography (methanol/DCM) to give compound 317 (0.17 g) as a light yellow solid (contaminated with mineral oil). 1H NMR (500 MHz, DMSO-d6) δ ppm 8.97 (1 H, s), 7.57 (1 H, s), 7.28 (2 H, s), 5.28 (1 H, quin, J=8.7 Hz), 4.02 (3 H, s), 2.38-2.46 (2 H, m), 1.89-2.10 (4 H, m), 1.62-1.78 (2 H, m). LCMS-ESI (POS), M/Z, M+1: Found 285.1.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][NH:9][CH2:10][C:11]2[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][N:12]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.Br[CH2:19][C:20]1[C:21]([CH2:25][N:26]2[C:34](=[O:35])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]2=[O:36])=[CH:22][S:23][CH:24]=1.CCN(C(C)C)C(C)C>CC#N>[CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:19][C:20]2[C:21]([CH2:25][N:26]3[C:34](=[O:35])[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:27]3=[O:36])=[CH:22][S:23][CH:24]=2)[CH2:10][C:11]2[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][N:12]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1cscc1CBr
Reactant: Cc1cccnc1CNCc1ncccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1cccnc1CN(Cc1cscc1CN1C(=O)c2ccccc2C1=O)Cc1ncccc1C

Procedure:
Using General Procedure A: Reaction of bis-(3-methyl-pyridin-2-ylmethyl)-amine, 2-(4-Bromomethyl-thiophen-3-ylmethyl)-isoindole-1,3-dione, and DIPEA in CH3CN gave 2-(4-{[bis-(3-methyl-pyridin-2-ylmethyl)-amino]-methyl}-thiophen-3-ylmethyl)-isoindole-1,3-dione as a white foam. Deprotection with H2NNH2H2O using General Procedure E gave the free base as a pale yellow solid. Conversion to the HBr salt gave COMPOUND 396 as a beige solid. 1H NMR (D2O) δ 2.43 (s, 6H), 3.88 (s, 2H), 3.99 (s, 2H), 4.31 (s, 4H), 7.29 (d, 1H, J=3 Hz), 7.48 (d, 1H, J=3 Hz), 7.79 (dd, 2H, J=6.0, 7.8 Hz), 8.31 (d, 2H, J=7.8 Hz), 8.55 (d, 2H, J=6.0 Hz); 13C NMR (D2O) δ 17.39, 36.42, 53.37, 54.95, 126.10, 127.73, 128.48, 132.21, 134.97, 137.81, 139.23, 148.51, 150.64; ES-MS m/z 353 (M+H). Anal. Calcd. for C20H24N4S.3.2HBr.5H2O: C, 37.63; H, 4.77; N, 8.78; S, 5.02; Br, 40.05. Found: C, 37.52; H, 4.62; N, 8.68; S, 4.95; Br, 40.21.
Reaction SMILES: [C:1]([C:5]1[CH:18]=[C:17]2[C:19]3=[C:20]4[C:10]([CH:11]=[CH:12][CH:13]=[C:14]4[CH:15]=[CH:16]2)=[CH:9][CH:8]=[C:7]3[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CO.[Br-:23].[Br-].[Br-].C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.O>ClCCl.[Br-].[Br-].[Br-].C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1>[Br:23][C:13]1[C:14]2[C:20]3=[C:19]4[C:17](=[CH:16][CH:15]=2)[CH:18]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=[C:7]4[CH:8]=[CH:9][C:10]3=[CH:11][CH:12]=1
Reactant: CC(C)(C)c1cc2ccc3cccc4ccc(c1)c2c34
Reactant: [Br-]
Agent: C[N+](C)(C)Cc1ccccc1
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)c1cc2ccc3ccc(Br)c4ccc(c1)c2c34
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 161.5 %

Procedure:
Next, a mixed solution of 45.0 g (content: 83%) of 2-t-butylpyrene, 660 ml of dichloromethane and 220 ml of methanol was cooled to 0° C. under an argon gas stream and then 56.4 g of benzyltrimethylammonium tribromide dissolved in 100 ml of dichloromethane was added dropwise. This mixed solution was stirred at room temperature for 2.5 hours and 5.64 g of benzyltrimethylammonium tribromide was added, followed by stirring for 1.5 hours. After the organic layer was isolated by pouring 250 ml of water into this mixed solution, the aqueous layer was extracted twice with 250 ml of dichloromethane. The combined organic layer was washed with 300 ml of water, dried over magnesium sulfate and then evaporated. To the resulting solid, 300 ml of methanol was added, followed by stirring and further filtration. To the resulting solid, 200 ml of hexane was added, and then the resulting solution was stirred, filtered and vacuum-dried to obtain 44.5 g of 1-bromo-7-t-butylpyrene.
Reaction SMILES: [CH3:1][C:2]1[O:16][C:5]2[CH:6]=[CH:7][C:8]3[O:9][CH2:10][C@H:11]([CH2:14][OH:15])[O:12][C:13]=3[C:4]=2[CH:3]=1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>N1C=CC=CC=1>[CH3:27][C:17]1[CH:22]=[CH:21][C:20]([S:23]([O:15][CH2:14][CH:11]2[CH2:10][O:9][C:8]3[CH:7]=[CH:6][C:5]4[O:16][C:2]([CH3:1])=[CH:3][C:4]=4[C:13]=3[O:12]2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cc2c3c(ccc2o1)OC[C@H](CO)O3
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccc4oc(C)cc4c3O2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 0.20 g (0.90 mmole) of [(2S)-8-methyl-2,3-dihydrofuro[3,2-f][1,4]benzodioxin-2-yl]methanol in 5.0 mL of pyridine was added 1.0 g (5.2 mmole) of p-toluenesulfonyl chloride. The mixture was stirred at room temperature under nitrogen for 15 hours. The solvent was then removed in vacuum and replaced with 200 mL of methylene chloride. The solution was washed with 100 mL portions of 2 N aqueous HCl, saturated aqueous sodium bicarbonate and saturated brine, dried over magnesium sulfate, filtered and concentrated in vacuum to a brown residue. The residue was column chromatographed on silica gel with 1:1 methylene chloride/hexane as eluant and the product fractions combined and concentrated in vacuum to give 0.28 g of the (R)-enantiomer of the title compound as a pale yellow oil. 1H-NMR (CDCl3): doublet 7.79 δ (2H); doublet 7.30 δ (2H); doublet 6.86 δ (1H); doublet 6.68 δ (1H); singlet 6.29 δ (1H); multiplet 4.48 δ (1H); multiplet 4.26 δ (3H); doublet of doublets 4.06 δ (1H); singlet 2.43 δ (3H); singlet 2.41 δ (3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH:7]([OH:9])[CH3:8])[CH2:3][CH2:2]1.[O:10](C(OC(C)(C)C)=O)[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=O.CCN(CC)CC>ClCCCl>[OH:9][CH:7]([CH:4]1[CH2:5][CH2:6][N:1]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:10])[CH2:2][CH2:3]1)[CH3:8]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CC(O)C1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.9 %

Procedure:
(±)-1-(4-Piperidinyl)ethanol (see reference: WO 9725992A, 12.44 g, 65.7 mmol) in 1,2-dichloroethane (500 mL) was stirred at room temperature and BOC2O (14.36 g, 65.8 mmol) was added followed by Et3N (19 mL, 136 mmol). The stirred mixture was heated at gentle reflux for 15 min and then allowed to cool to room temperature and stirred overnight. The solution was washed twice with 10% citric acid, once with 10% Na2CO3, dried over MgSO4, filtered and concentrated to afford (±)-1,1-dimethylethyl 4-(1-hydroxyethyl)-1-piperidinecarboxylate (14 g, 93% yield) as a light amber oil. 1H NMR (400 MHz, DMSO-d6): δ 4.35 (d, 1H, J=4.8 Hz), 3.92 (m, 2H), 3.32 (m, 1H), 2.59 (m, 2H), 1.68 (m, 1H), 1.47 (m, 1H), 1.34 (s, 9H), 1.25 (m, 1H), 1.08-0.88 (m, 2H), 0.97 (d, 3H, J=6.4 Hz).
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)=[O:2].C(=O)([O-])[O-].[Na+].[Na+].[CH3:15][O:16][CH2:17][CH2:18]Br>CO>[CH:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:18][CH2:17][O:16][CH3:15])[CH2:5][CH2:4]1)=[O:2]
Reactant: O=CN1CCNCC1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: COCCN1CCN(C=O)CC1
Temperature: 25 °C
Yield: 102.2 %

Procedure:
To a solution of 37.1 g of N-formylpiperazine and 37.1 g of anhydrous sodium carbonate in 50 mL of methanol was added dropwise 53.15 g of methoxyethyl bromide, and the mixture was refluxed for 3.5 hours. After cooling to room temperature, insolubles were filtered out and the filtrate was concentrated. To the residue was added water and chloroform. After separating the organic layer, the aqueous layer was extracted with chloroform. The combined organic layer was dried over anhydrous magnesium sulfate and concentrated to give 57.2 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C@@H:4]2[CH2:5][C:6]3[C:10]([C@H:3]12)=[C:9]([CH3:11])[S:8][C:7]=3[C:12](=[O:14])[CH3:13].[Br-:16].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>C(Cl)Cl.CO.C([O-])(O)=O.[Na+].O>[Br:16][CH2:13][C:12]([C:7]1[S:8][C:9]([CH3:11])=[C:10]2[C:6]=1[CH2:5][C@H:4]1[C:2]([CH3:15])([CH3:1])[C@H:3]12)=[O:14]
Reactant: CC(=O)c1sc(C)c2c1C[C@@H]1[C@H]2C1(C)C
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: Cc1sc(C(=O)CBr)c2c1[C@H]1[C@@H](C2)C1(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.8 %

Procedure:
To a solution of (1aS,5aR)-1-(1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-ethanone (275 mg, 1.25 mmol) in DCM (7 mL) and methanol (3.5 mL) is added phenyltrimethyl-ammoniumbromid-dibromid (570 mg, 1.5 mmol) and the reaction mixture is stirred at rt for 30 min. Another portion of phenyltrimethyl-ammoniumbromid-dibromid (600 mg, 1.6 mmol) is added and stirring is continued for 1 h before the mixture is diluted with sat. aq. NaHCO3 (5 mL) and water (25 mL) and extracted twice with DCM (2×20 mL). The organic extracts are dried over Na2SO4 and evaporated to give crude 2-bromo-1-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-ethanone (250 mg) as a brownish oil; LC-MS: tR=1.06 min, [M+3]+=300.99.