Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]3[CH:18]=[C:19]4[C@:24]([C:26]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=5)=[O:27])([CH2:25][C:16]=3[CH:15]=[N:14]2)[CH2:23][N:22]([S:34]([C:37]2[CH:42]=[CH:41][C:40](F)=[CH:39][CH:38]=2)(=[O:36])=[O:35])[CH2:21][CH2:20]4)=[CH:9][CH:8]=1>CN1CCCC1>[F:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[C:17]3[CH:18]=[C:19]4[C@:24]([C:26]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=5)=[O:27])([CH2:25][C:16]=3[CH:15]=[N:14]2)[CH2:23][N:22]([S:34]([C:37]2[CH:38]=[CH:39][C:40]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:41][CH:42]=2)(=[O:35])=[O:36])[CH2:21][CH2:20]4)=[CH:11][CH:12]=1
Reactant: C1CCNC1
Reactant: O=C(c1ccccn1)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(F)cc1)C2
Agent: CN1CCCC1
Product: O=C(c1ccccn1)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(N3CCCC3)cc1)C2
Yield: 34.1 %

Procedure:
A solution of pyrrolidine (0.065 mL, 0.783 mmol) and (R)-(1-(4-fluorophenyl)-6-((4-fluorophenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone (183 mg, 0.261 mmol) in N-methylpyrrolidine (2 mL) was stirred in a sealed vial at 100° C. for 22 hours. The cooled reaction mixture was then purified directly by preparative HPLC (Waters, Acidic (0.1% Formic acid), Waters X-Select Prep-C18, 5 μm, 19×50 mm column, 5-95% acetonitrile in water) to afford (R)-(1-(4-fluorophenyl)-6-((4-(pyrrolidin-1-yl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone as an off-white solid (52 mg). LCMS (Method F, ES-API): RT 2.78 min, m+H=584.3; 1H NMR (400 MHz, CDCl3): δ 8.63-8.62 (1H, m), 7.89 (1H, dt, J=8.0, 1.2 Hz), 7.81 (1H, td, J=7.5, 1.8 Hz), 7.51-7.47 (2H, m), 7.46-7.41 (3H, m), 7.28 (1H, s), 7.18-7.12 (2H, m), 6.48-6.45 (3H, m), 5.41 (1H, dd, J=12.2, 2.1 Hz), 4.31 (1H, d, J=16.9 Hz), 3.80-3.76 (1H, m), 3.33-3.30 (4H, m), 2.88 (1H, d, J=16.9 Hz), 2.85-2.76 (1H, m), 2.61 (1H, d, J=12.1 Hz), 2.45-2.35 (2H, m), 2.07-2.01 (4H, m).
Reaction SMILES: COC1C=CC(C2[O:14][CH2:13][C:12]([CH2:30][O:31][C:32]([C:41]([F:44])([F:43])[F:42])([C:37]([F:40])([F:39])[F:38])[C:33]([F:36])([F:35])[F:34])([CH2:15][O:16][C:17]([C:26]([F:29])([F:28])[F:27])([C:22]([F:25])([F:24])[F:23])[C:18]([F:21])([F:20])[F:19])[CH2:11][O:10]2)=CC=1.C1(OC)C=CC=CC=1.[Al](Cl)(Cl)Cl>ClCCl>[F:19][C:18]([F:20])([F:21])[C:17]([C:26]([F:27])([F:28])[F:29])([C:22]([F:23])([F:24])[F:25])[O:16][CH2:15][C:12]([CH2:30][O:31][C:32]([C:33]([F:35])([F:36])[F:34])([C:37]([F:38])([F:39])[F:40])[C:41]([F:44])([F:43])[F:42])([CH2:11][OH:10])[CH2:13][OH:14]
Reactant: COc1ccc(C2OCC(COC(C(F)(F)F)(C(F)(F)F)C(F)(F)F)(COC(C(F)(F)F)(C(F)(F)F)C(F)(F)F)CO2)cc1
Agent: Cl[Al](Cl)Cl
Solvent: COc1ccccc1
Solvent: ClCCl
Product: OCC(CO)(COC(C(F)(F)F)(C(F)(F)F)C(F)(F)F)COC(C(F)(F)F)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
To a stirred mixture of compound 8 (33.1 g, 48.0 mmol) and anisole (20.7 g, 192.0 mmol) in dichloromethane (200 mL) at 0° C. was slowly added powdered aluminum chloride anhydrous (19.5 g, 144.0 mmol). After the addition, the reaction mixture was allowed to warm to room temperature and stirred for additional 30 minutes. The reaction mixture was quenched by slowly addition of 1N HCl (100 mL) and the resulted mixture was extracted with ether (100 mL, 3 times). The combined organic layer was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (n-hexane/ethyl acetate=8/1) to give compound 9 as a clear oil (27.4 g, 99%). 1H NMR (400 MHz, CD3OD) δ 3.63 (s, 4H), 4.14 (s, 4H); 19F NMR (376 MHz, CD3OD) δ −71.14 (s); 13C NMR (100.7 MHz, CD3OD) δ 47.8, 60.4, 69.1, 80.9 (m), 121.8 (q, J=292.6 Hz); MS (CI) m/z 573 (M++1, 100); HRMS (CI) Calcd for C13H11F18O4: 573.0374, Found: 573.0374.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:31]2[S:35][C:34]([C:36]3([O:40][CH2:41][O:42][CH3:43])[CH2:39][CH2:38][CH2:37]3)=[N:33][CH:32]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][CH:17]([OH:20])CO)[CH:15]=3)[N:8]([S:21]([C:24]3[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[C:5]2=[N:6][CH:7]=1.O1CCCC1.I([O-])(=O)(=O)=O.[Na+]>O>[Cl:1][C:2]1[C:3]([C:31]2[S:35][C:34]([C:36]3([O:40][CH2:41][O:42][CH3:43])[CH2:37][CH2:38][CH2:39]3)=[N:33][CH:32]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][CH:17]=[O:20])[CH:15]=3)[N:8]([S:21]([C:24]3[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[C:5]2=[N:6][CH:7]=1
Reactant: COCOC1(c2ncc(-c3c(Cl)cnc4c3cc(-c3cnn(CC(O)CO)c3)n4S(=O)(=O)c3ccc(C)cc3)s2)CCC1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: COCOC1(c2ncc(-c3c(Cl)cnc4c3cc(-c3cnn(CC=O)c3)n4S(=O)(=O)c3ccc(C)cc3)s2)CCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ambient solution of 3-(4-(5-chloro-4-(2-(1-(methoxymethoxy)cyclobutyl)thiazol-5-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-pyrazol-1-yl)propane-1,2-diol (Example 14B) (1.28 g, 1.987 mmol) in a solvent mixture of tetrahydrofuran (14.90 mL) and water (4.97 mL) was added solid sodium periodate (0.638 g, 2.98 mmol) in a single portion. The reaction was stirred at room temperature for 1 hour and was then quenched by the addition of 10% aqueous sodium thiosulfate solution (10 mL) and ethyl acetate (15 mL). The layers were separated, and the aqueous layer was extracted with additional ethyl acetate (2×15 mL). The combined organics were washed once with 10% aqueous sodium thiosulfate solution (10 mL), dried with anhydrous sodium sulfate, filtered and concentrated to give the title compound, which was used in the next step without further purification. MS ESI(−) m/z 610.2 [M−H]−.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C@@H:6]([NH:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[CH:7]([CH3:9])[CH3:8])C.[CH3:22][NH2:23]>>[CH3:22][NH:23][C:4](=[O:3])[CH2:5][C@@H:6]([NH:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[CH:7]([CH3:9])[CH3:8]
Reactant: CN
Reactant: CCOC(=O)C[C@@H](NC(=O)OCc1ccccc1)C(C)C
Product: CNC(=O)C[C@@H](NC(=O)OCc1ccccc1)C(C)C
Reaction time: 48 h

Procedure:
2.23 g of 3(R)-benzyloxycarbonylamino-4-methylpentanoic acid ethyl ester and 50 ml of 33% methylamine (in ethanol) are left to stand for 48 hours at room temperature. The reaction mixture is concentrated by evaporation and the residue is crystallised from ethyl acetate. The title compound is obtained: Rf (dichloromethane/methanol=95:5)=0.24; m.p. 190°-191° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.C(Cl)(Cl)Cl.C(=O)=O.[Si:18]([O:35][C:36]1[CH:53]=[CH:52][C:51]2[C@@H:50]3[C@H:41]([C@H:42]4[C@@:46]([CH2:48][CH:49]3[OH:54])([CH3:47])[CH:45]3[O:55][CH2:56][CH2:57][O:58][CH:44]3[CH2:43]4)[CH2:40][CH2:39][C:38]=2[CH:37]=1)([C:31]([CH3:34])([CH3:33])[CH3:32])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>ClCCl>[Si:18]([O:35][C:36]1[CH:53]=[CH:52][C:51]2[C@@H:50]3[C@H:41]([C@H:42]4[C@@:46]([CH2:48][C:49]3=[O:54])([CH3:47])[CH:45]3[O:55][CH2:56][CH2:57][O:58][CH:44]3[CH2:43]4)[CH2:40][CH2:39][C:38]=2[CH:37]=1)([C:31]([CH3:34])([CH3:33])[CH3:32])([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)[Si](Oc1ccc2c(c1)CC[C@@H]1[C@@H]2C(O)C[C@]2(C)C3OCCOC3C[C@@H]12)(c1ccccc1)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C=O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CS(C)=O
Product: CC(C)(C)[Si](Oc1ccc2c(c1)CC[C@@H]1[C@@H]2C(=O)C[C@]2(C)C3OCCOC3C[C@@H]12)(c1ccccc1)c1ccccc1
Reaction time: 0.17 h
Yield: 83.8 %

Procedure:
To a stirred solution of 1.5 mL (16.5 mmol) of oxalyl chloride in 15 mL of freshly distilled dichloromethane was added dropwise 2.35 mL (33.0 mmol) of dimethyl sulfoxide at −65° C. (chloroform/dry ice bath) under argon atmosphere. After 10 minutes, a solution of 6.2 gm (10.9 mmol) of 3-tert-butyldiphenylsilyloxy-17-ethylenedioxyestra-1,3,5(10)-11-ol 38 in 15 mL of dichloromethane was added dropwise, and the reaction mixture was stirred for 40 minutes at the same temperature. Then, a 12 mL (87.3 mmol) of triethylamine was added at −65° C., slowly allowed to attain room temperature, washed with saturated NH4Cl solution, water, brine, and dried (Na2SO4). Evaporation of the solvent furnished a gum, which was chromatographed (15% ethyl acetate/hexanes) to afford 5.18 g (84%) the product 39.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:27])[C:13]([CH3:26])([CH3:25])[CH:14]([CH2:23][CH3:24])[NH:15][C:16](OC(C)(C)C)=[O:17])[CH2:8][CH2:7]1)[CH3:2].C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O.[N:44]1([C:50]([C:52]2[CH:60]=[CH:59][C:55](C(O)=O)=[CH:54][CH:53]=2)=[NH:51])[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1.C1C=CC2N(O)N=NC=2C=1>C(N(CC)CC)C>[N:44]1([C:50]([C:52]2[CH:53]=[CH:54][C:55]([C:16]([NH:15][CH:14]([CH2:23][CH3:24])[C:13]([CH3:25])([CH3:26])[C:12]([N:9]3[CH2:10][CH2:11][CH:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:28])[CH2:7][CH2:8]3)=[O:27])=[O:17])=[CH:59][CH:60]=2)=[NH:51])[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1
Reactant: CCOC(=O)CC1CCN(C(=O)C(C)(C)C(CC)NC(=O)OC(C)(C)C)CC1
Reactant: N=C(c1ccc(C(=O)O)cc1)N1CCOCC1
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)CC1CCN(C(=O)C(C)(C)C(CC)NC(=O)c2ccc(C(=N)N3CCOCC3)cc2)CC1
Reaction time: 1 h
Yield: 22.1 %

Procedure:
To the obtained N-(N-Boc-βethyl-α,α-dimethyl-β-alanyl)-4-piperidineacetic acid ethyl ester (0.38 g, 0.95 mmol) were added anisole (0.3 ml) and TFA (10 ml) and the mixture was stirred for 1 hour under cooling with ice. After the TFA was distilled off at room temperature, the residue was washed with hexane 3 times and dissolved in DMF (20 ml) under cooling with ice. After the resulting solution was neutralized with triethylamine, 4-(4-morpholinoimidoyl)benzoic acid (0.25 g, 1.05 mmol), HOBT (0.14 g, 1.05 mmol) and WSDC (0.22 g, 1.14 mmol) were added thereto and the mixture was stirred overnight. After the solvent was distilled off, the residue was dissolved in ethyl acetate, washed sequentially with a 5% aqueous solution of citric acid, a 5% aqueous solution of sodium hydrogencarbonate and saturated saline 3 times each, and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was applied to a silica gel column (2.1 φ×20 cm) and eluted with a mixed solution (chloroform:ethanol=30:1). The desired fractions were collected and the solvents were distilled off to yield a powder of the titled compound (108 mg, 22%).
Reaction SMILES: [ClH:1].[C:2](=[NH:12])(OCC)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:13]([NH2:16])[CH:14]=[CH2:15]>CO>[ClH:1].[CH2:13]([NH:16][C:2](=[NH:12])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[CH:14]=[CH2:15]
Reactant: C=CCN
Reactant: CCOC(=N)c1ccccc1
Agent: Cl
Solvent: CO
Product: C=CCNC(=N)c1ccccc1
Reaction time: 48 h

Procedure:
To a solution of ethyl benzimidate hydrochloride (20 g) in methanol at 0° C. was added allyl amine. The resulting solution was allowed to stand for 2 days at 5° C. before it was evaporated to yield a solid which was collected and washed with ether to give N-allyl benzamidine hydrochloride (21.5 g) as a white solid; 300 MHz NMR: 10.1 (s,1), 9.68 (s,1), 9.29 (s,1), 7.72 (s,5), 5.92 (m,1), 5.35 (d,2), 5.26 (d,2), 4.14 (s,2).
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[CH2:7]([O:10][C@@H:11]1[CH2:15][O:14][C@@H:13]2[C@H:16]([O:19][C:20]3[N:21]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[C:22]4[C:23]([N:41]=3)=[N:24][C:25]([C:29]3[CH:34]=[CH:33][C:32]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)=[CH:31][CH:30]=3)=[C:26]([Cl:28])[CH:27]=4)[CH2:17][O:18][C@H:12]12)[CH:8]=C.C[OH:51].C(Cl)Cl>C(#N)C.O.CCOC(C)=O.O.[Ru](Cl)(Cl)Cl>[Cl:28][C:26]1[CH:27]=[C:22]2[N:21]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:48])([CH3:47])[CH3:49])[C:20]([O:19][C@H:16]3[C@H:13]4[O:14][CH2:15][C@@H:11]([O:10][CH2:7][CH:8]=[O:51])[C@H:12]4[O:18][CH2:17]3)=[N:41][C:23]2=[N:24][C:25]=1[C:29]1[CH:30]=[CH:31][C:32]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)=[CH:33][CH:34]=1
Reactant: CO
Reactant: C=CCO[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc2n1COCC[Si](C)(C)C
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3OCC=O)nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Sodium periodate (53.4 mg, 0.250 mmol) was added to a stirred suspension of 2-[[2-[[(3R,3aR,6R,6aR)-3-allyloxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy]-6-chloro-5-(4-phenylphenyl)imidazo[4,5-b]pyridin-1-yl]methoxy]ethyl-trimethyl-silane (68.9 mg, 0.111 mmol) and ruthenium(III) chloride hydrate (1.9 mg, 8.43 μmol) in acetonitrile (0.95 ml) and water (0.16 ml). The reaction mixture was stirred at room temperature for 4 h. Additional sodium periodate (31.8 mg, 0.149 mmol) was added and the reaction mixture was stirred for 2 h at room temperature, then in the refrigerator overnight. The reaction mixture was allowed to warm to room temperature before being partitioned between EtOAc (40 ml) and saturated aqueous sodium thiosulfate (30 ml). An inseparable emulsion formed, which was filtered through a pad of Celite™. The biphasic filtrate was re-partitioned and the aqueous layer was extracted with EtOAc (2×20 ml). The organic layers were combined, washed with brine (1×15 ml), dried over MgSO4, filtered, and evaporated under reduced pressure to give a colorless residue. The residue was dissolved in EtOAc and loaded onto two 500 micron 20 cm×20 cm silica gel plates, which were developed using 10% MeOH/DCM. The silica containing the desired product band was collected and eluted with 10% MeOH/DCM (80 ml). The solvent was evaporated under reduced pressure and the resulting residue was lyophilized from ethanol and benzene to give the title compound as a white solid. LC-MS: calculated for C32H36ClN3O6Si 621.21 observed m/e: 622.31 (M+H)+ (Rt 1.34/2 min)
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>CC#N>[C:10]([O:9][C:7]([N:4]1[CH2:5][CH2:6][CH:2]([NH:1][S:22]([CH3:21])(=[O:24])=[O:23])[CH2:3]1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCC(N)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(NS(C)(=O)=O)C1
Reaction time: 2.5 h

Procedure:
To a solution of (+/−)-3-amino-1N-BOC-pyrrolidine (0.5 g) in MeCN (10 mL) was added triethylamine (0.41 mL) then methanesulfonyl chloride (0.22 mL). The mixture was stirred for 2.5 h. An aqueous work-up followed by purification on silica gave 3-methanesulfonylamino-pyrrolidine-1-carboxylic acid tert-butyl ester (0.49 g).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH2:5]([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2([CH:17]=[C:18]([F:21])[CH2:19][OH:20])[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)[CH3:6].C1C=CC=CC=1>N1C=CC=CC=1>[C:1]([O:20][CH2:19][C:18]([F:21])=[CH:17][C:14]1([C:11]2[CH:12]=[CH:13][C:8]([O:7][CH2:5][CH3:6])=[CH:9][CH:10]=2)[CH2:16][CH2:15]1)(=[O:3])[CH3:2]
Reactant: CCOc1ccc(C2(C=C(F)CO)CC2)cc1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CCOc1ccc(C2(C=C(F)COC(C)=O)CC2)cc1
Yield: 99 %

Procedure:
The method of Example 17 was repeated using acetyl chloride (2 ml), 1-(4-ethoxyphenyl)-1-(2-fluoro-3-hydroxyprop-1-enyl)cyclopropane (Example 10) (0.99 g), benzene (50 ml) and pyridine (0.38 ml) to yield the title compound (1.16 g, 99%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:17]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]=O)[CH:18]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1CN1CCN(C2C=CC=CC=2)CC1>>[C:17]1([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:14]2[CH2:13][CH2:12][N:11]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:16][CH2:15]2)[CH:18]=1
Reactant: O=Cc1cccc(-c2ccccc2)c1
Reactant: COc1ccc(N2CCNCC2)cc1OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: c1ccc(-c2ccccc2CN2CCN(c3ccccc3)CC2)cc1
Product: COc1ccc(N2CCN(Cc3cccc(-c4ccccc4)c3)CC2)cc1OC

Procedure:
166.8 mg of the target compound (0.43 mmol, 78.0%) was obtained using 1-(3,4-dimethoxyphenyl)piperazine (244.5 mg, 1.10 mmol), biphenyl-3-carbaldehyde (100 mg, 0.55 mmol) and NaBH(OAc)3 (355 mg, 1.65 mmol) according to the synthesis method of Compound 1.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([Br:10])[N+:7]([O-])=[C:6]([Br:12])[CH:5]=1)([O-])=O.[OH-].[Na+]>[Fe].C(O)(=O)C>[NH2:1][C:4]1[CH:9]=[C:8]([Br:10])[N:7]=[C:6]([Br:12])[CH:5]=1
Reactant: O=[N+]([O-])c1cc(Br)[n+]([O-])c(Br)c1
Agent: [Fe]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Nc1cc(Br)nc(Br)c1
Temperature: 100 °C

Procedure:
A mixture of 4-nitro-2,6-dibromopyridine-N-oxide (1.2 g), iron powder (1.2 g) and acetic acid (15 ml) were stirred and heated to 100° C. for 1 hour. Upon cooling the mixture was basified with 3 molar sodium hydroxide and continuously extracted with ether. Removal of the ether under reduced pressure left a white crystalline product of 4-amino-2,6-dibromopyridine (1.0 g, 99%), m.p. 212-214° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[NH2:20][C:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]2)=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2)CC1
Yield: 70.3 %

Procedure:
A suspension of 4-(N-tert-butyloxycarbonyl-N'-piperazinyl)-1-nitrobenzene (3.09 g) in ethanol (70 ml) was hydrogenated at 30 psi for 15 min, in the presence of a palladium on carbon catalyst (0.35 g, 11% (w/w)). The catalyst was filtered off and the residue evaporated in vacuo. The resultant oil was azeotroped with toluene (2×20 ml) followed by petrol (60/80) (20 ml) to afford the aniline (1.96 g). 1H NMR (360 MHz, CDCl3) δ 1.48 (9H, s), 2.96-2.98 (4H, m), 3.56-3.59 (4H, m), 6.65 (2H, d, J=8.7), 6.81 (2H, d, J=8.7 Hz). MS (CI, NH3) 278 (M+1).
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]1[CH2:7][CH:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[C:11]([O:18][CH3:19])[CH:10]=2)[CH2:5]1>O1CCOCC1.[Pd]>[F:1][CH2:2][CH2:3][N:4]1[CH2:7][CH:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([O:18][CH3:19])[CH:10]=2)[CH2:5]1
Reactant: COc1cc(NC2CN(CCF)C2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1COCCO1
Product: COc1cc(NC2CN(CCF)C2)ccc1N
Yield: 68 %

Procedure:
A solution of 1-(2-fluoroethyl)-N-(3-methoxy-4-nitrophenyl)azetidin-3-amine (2.6 g) and Pd/C (1 g) in 1,4-dioxane (50 mL) was hydrogenated for 4 hours at room temperature. The reaction mixture was filtered through diatomaceous earth, washing with MeOH. The filtrate was concentrated and purified by column chromatography (DCM/MeOH=50/1 as elution) to provide the title compound (1.57 g, yield 68%, M+H+=240.2).
Reaction SMILES: C([O:3][C:4](=[O:14])[CH:5]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)[CH2:6][CH3:7])C>Cl>[N:10]1[CH:11]=[CH:12][CH:13]=[C:8]([CH:5]([CH2:6][CH3:7])[C:4]([OH:14])=[O:3])[CH:9]=1
Reactant: CCOC(=O)C(CC)c1cccnc1
Agent: Cl
Product: CCC(C(=O)O)c1cccnc1
Yield: 50 %

Procedure:
A mixture of 2-Pyridin-3-yl-butyric acid ethyl ester (8 g, 0.04 mol) and a 20% aqueous solution of hydrochloric acid (50 mL) was heated to reflux for 3 hours. The solvent evaporated to dryness to yield the desired product (5 g, 0.02 mol, 50%), ESI-MS m/z calc. 165.1. found 166.5 (M+1)+ 1H NMR (DMSO-d6): δ 8.86 (s, 1H), 8.80 (d, 1H, J=5.6 Hz), 8.47 (d, 1H, J=8.0 Hz), 7.97 (dd, 1H, J=5.6, 8.0 Hz), 3.83 (t, 1H, J=8.0 Hz), 2.07-2.04 (m, 1H), 1.82-1.80 (m, 1H), 0.80 (t, 3H, J=7.6 Hz).
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][S:14][CH2:15][CH2:16][C@@H:17]([C:31]([N:33]1[C@H:42]([C:43]([O:45]CC)=[O:44])[CH2:41][C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34]1)=[O:32])[NH:18][CH:19]([C:28]([OH:30])=[O:29])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=O)C1C=CC=CC=1.Br>C(O)(=O)C>[NH2:11][CH2:12][CH2:13][S:14][CH2:15][CH2:16][C@@H:17]([C:31]([N:33]1[C@H:42]([C:43]([OH:45])=[O:44])[CH2:41][C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34]1)=[O:32])[NH:18][CH:19]([C:28]([OH:30])=[O:29])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)[C@@H]1Cc2ccccc2CN1C(=O)[C@H](CCSCCNC(=O)OCc1ccccc1)NC(CCc1ccccc1)C(=O)O
Agent: Br
Solvent: CC(=O)O
Product: NCCSCC[C@H](NC(CCc1ccccc1)C(=O)O)C(=O)N1Cc2ccccc2C[C@H]1C(=O)O
Yield: 25 %

Procedure:
Compound 3 was then hydrolyzed with 30% hydrogen bromide in glacial acetic acid. After purification over LH-20 with methanol, 0.054 g. (25%) of N-[S-(2-aminoethyl)-N-(1-carboxy-3-phenylpropyl)-L-homocysteinyl]-1,2,3,4-tetrahydroisoquinoline-3-(S)-carboxylic acid was obtained; a white solid after freeze drying; nmr (CO3OD): δ2.1-2.25 (m, 4H, aromatic CH2CH2 --, --SCH2CH2CH<), 2.7-2.9 (m, 8H, aromatic CH2CH2 --, aromatic CH2CH<--CH2S--CH2 --), 3.0-3.25 (m, 2H, --SCH2CH2NH2), 3.32 (S, 2H, aromatic CH2N<), 3.5-3.8 (m, 1H, NCHRCO2 --), 7.2.-7.3 (m, 4H, aromatic), ms: M+ 463.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[C:23]([C:25]1[N:26]([CH3:30])[CH:27]=[CH:28][N:29]=1)=[O:24]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[C:23]([C:25]2[N:26]([CH3:30])[CH:27]=[CH:28][N:29]=2)=[O:24])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Cn1ccnc1C(=O)c1cc(Cl)ccc1N
Product: Cn1ccnc1C(=O)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
The title compound was prepared using 4-t-butyl-benzenesulfonyl chloride and (2-Amino-5-chloro-phenyl)-(1-methyl-1H-imidazol-2-yl)-methanone following the general procedure described for the preparation of N-aryl-benzenesulfonamides. MS: m/z 452.1 (M++1).
Reaction SMILES: [C:1]([O-:7])([O-])([O:3][CH2:4][CH3:5])[CH3:2].[CH:8]1([C:14]#[C:15][CH2:16]O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.C(O)(=O)CC>>[CH:8]1([CH:14]=[C:15]=[CH:16][CH2:2][C:1]([O:3][CH2:4][CH3:5])=[O:7])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: OCC#CC1CCCCC1
Reactant: CCOC(C)([O-])[O-]
Solvent: CCC(=O)O
Product: CCOC(=O)CC=C=CC1CCCCC1
Temperature: 132.5 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
A mixture of 66 g of ethyl ortho-acetate, 25 g of cyclohexylethynylcarbinol and 2.5 g of propionic acid was agitated at 130 to 135°C. for 8 hours while distilling off ethanol. The resulting liquid mixture was directly subjected to distillation under reduced pressure and a fraction boiling at 107° to 108°C. under 5 mm Hg was collected. Ethyl 5-cyclohexyl-3,4-pentadienoate was obtained in a yield of 93%.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[Br:1][C:2]1[C:3]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Reactant: C1COCCN1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCOCC2)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 6.1 using 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 6.2) and morpholine to afford an off-white solid. UPLC-MS (Condition 3) tR=1.20 min, m/z=445.9 [M+H]+, m/z=443.9 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 3.37-3.46 (m, 4H) 3.69-3.81 (m, 4H) 7.39 (d, J=8.78 Hz, 2H) 7.86 (d, J=9.16 Hz, 2H) 8.47 (d, J=2.13 Hz, 1H) 8.80 (d, J=2.13 Hz, 1H) 10.44 (s, 1H).