Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:10])(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].CN1CCOCC1.[NH2:18][CH2:19][CH:20]1[CH2:22][CH2:21]1.C(N=C=NCCCN(C)C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[NH2:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([NH:18][CH2:19][CH:20]1[CH2:22][CH2:21]1)=[O:10]
Reactant: NCC1CC1
Reactant: Nc1ccccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Nc1ccccc1C(=O)NCC1CC1
Yield: 72 %

Procedure:
A 100 ml, round bottom flask was charged with anthranilic acid (500 mg, 3.65 mmol), added DMF (15 mL) under nitrogen atmosphere and stirring. Then, added N-methylmorpholine (1 mL, 9.12 mmol), aminomethylcyclopropane (311 mg, 4.38 mmol), N-ethyl-N′-dimethylaminopropylcarbodiimide (EDCI) (840 mg, 4.38 mmol) and HOBt (670 mg, 4.38 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with water and extracted with diethyl ether (50 mL×2). The organic extracts were combined, washed with brine, dried over MgSO4, filtered and concentrated to afford amorphous colorless 2-amino-N-(cyclopropylmethyl)benzamide (500 mg, 72% yield), which was checked by NMR and used for next step without further purification. 1H-NMR (Bruker 300 MHz, DMSO-d6) δ 0.20-1.01 (m, 4H), 1.01-1.04 (m, 1H), 3.06-3.11 (m, 2H), 6.37-8.21 (m, 7H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12]1.[Cl-].[NH4+].CC(C)=O.S([O-])([O-])(=O)=O.[Na+].[Na+]>[Zn].CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12]1
Reactant: O=[N+]([O-])c1ccc(N2CCc3ccccc3C2)c(Cl)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: Nc1ccc(N2CCc3ccccc3C2)c(Cl)c1
Temperature: 0 °C
Yield: 96.6 %

Procedure:
A mixture of 2-(2-chloro-4-nitro-phenyl)-1,2,3,4-tetrahydro-isoquinoline (1.4 g, 4.8 mmol), saturated aqueous ammonium chloride (5 mL), and acetone (20 mL) was cooled in an ice bath. Solid zinc powder (3.2 g, 48 mmol) was added in portions over 10 min with stirring. The ice bath was allowed to expire and the mixture was stirred for 16 h. EtOAc (200 mL) was then added, followed by anhydrous sodium sulfate (20 g). The mixture was stirred for 15 min, then filtered through a pad of silica gel, eluting with EtOAc. The resulting clear solution was concentrated to afford the titled compound (1.2 g, 96%). 1H NMR (500 MHz, CDCl3): 7.20-7.11 (m, 3H), 7.11-7.04 (m, 1H), 6.95 (d, J=8.5 Hz, 1H), 6.78 (d, J=2.7 Hz, 1H), 6.56 (dd, J=8.5, 2.7 Hz, 1H), 4.17 (s, 2H), 3.55 (s, 2H), 3.27 (t, J=5.8 Hz, 2H), 3.00 (t, J=5.8 Hz, 2H).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[C:33]([N+:38]([O-:40])=[O:39])[CH:34]=[CH:35][CH:36]=5)[CH:31]=[CH:30][C:29]4=[O:41])[CH2:22][CH2:21]3)C(=O)OC(C)(C)C)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[ClH:42].O1CCOCC1>O1CCOCC1>[ClH:42].[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][NH:12][CH:20]3[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[C:33]([N+:38]([O-:40])=[O:39])[CH:34]=[CH:35][CH:36]=5)[CH:31]=[CH:30][C:29]4=[O:41])[CH2:24][CH2:25]3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)ccc3c([N+](=O)[O-])cccc32)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=c1ccc2c([N+](=O)[O-])cccc2n1CCN1CCC(NCc2ccc3c(c2)OCCO3)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 80 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(5-nitro-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 3 mL of 1,4-dioxane and 1 mL of 4.0 mol/L hydrogen chloride/1,4-dioxane were added, and stirred at room temperature overnight. The resulting solid was filtered to give 23 mg of 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-5-nitroquinolin-2(1H)-one hydrochloride as a yellow solid.
Reaction SMILES: [NH2:1][CH:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:3]1([N:8]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1.[CH3:29][C:30]1[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[C:31]=1[C:32](Cl)=[O:33].C(N(CC)CC)C>C(Cl)Cl>[C:10]1([CH2:9][N:8]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:3]2([CH:2]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[NH:1][C:32](=[O:33])[C:31]3[C:35]([CH3:39])=[CH:36][CH:37]=[CH:38][C:30]=3[CH3:29])[CH2:7][CH2:6][CH2:5][CH2:4]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NC(c1ccccc1)C1(N(Cc2ccccc2)Cc2ccccc2)CCCC1
Reactant: Cc1cccc(C)c1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc(C)c1C(=O)NC(c1ccccc1)C1(N(Cc2ccccc2)Cc2ccccc2)CCCC1
Yield: 80 %

Procedure:
The title compound (2.51 g; 80%) was prepared from (±)-{1-[amino(phenyl)methyl]cyclopentyl}bis(phenylmethyl)amine D33 (2.31 g; 6.23 mmol), 2,6-dimethyl benzoyl chloride (1.15 g; 6.85 mmol), triethylamine (1.73 ml; 12.5 mmol) in DCM (70 ml) in a similar manner to that described in E13. 1H NMR (CDCl3) δ: 1.40-2.05 (8H, m), 2.28 (6H, s), 3.68 (4H, s), 5.37 (1H, d), 6.78 (1H, m), 6.95-7.36 (16H, m), 7.45 (2H, m); Mass Spectrum (Electrospray LC/MS), API+: Found 503 (MH+). C35H38N2O requires 502. Ret. time 3.77 min.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:8])[C:5]([CH3:7])=[CH2:6])O.C1(C=CC(O)=CC=1)O.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>O>[N:17]1([CH2:1][NH:3][C:4](=[O:8])[C:5]([CH3:7])=[CH2:6])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: C=C(C)C(=O)NCO
Reactant: C1COCCN1
Agent: Oc1ccc(O)cc1
Solvent: O
Product: C=C(C)C(=O)NCN1CCOCC1

Procedure:
In a 300 cc capacity round bottom flask equipped with a stirrer were put 57.5 g (0.5 mole) of N-methylolmethacrylamide and 50 cc of water and, as a polymerization inhibitor, 500 mg of hydroquinone. On the other hand, 43 g (0.5 mole) of morpholine were gradually added thereto while stirring. Afterwards, the contents were stirred for 1 hour at 50°-60°C. Finally, the reaction mixture was concentrated and then was recrystallized from ethyl acetate. m.p.; 78.0°C. Yield: 48.3 g (52.5%).
Reaction SMILES: [I-].[CH:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([CH3:4])[CH3:3].C([Li])CCC.[CH3:29][C:30]([CH2:37][O:38][C:39]1[CH:44]=[CH:43][C:42]([CH:45]=O)=[CH:41][C:40]=1[O:47][CH3:48])=[CH:31][C:32]([O:34][CH2:35][CH3:36])=[O:33].CCOCC>O1CCCC1.O>[CH3:29][C:30]([CH2:37][O:38][C:39]1[CH:44]=[CH:43][C:42]([CH:45]=[C:2]([CH3:4])[CH3:3])=[CH:41][C:40]=1[O:47][CH3:48])=[CH:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]
Reactant: CCOC(=O)C=C(C)COc1ccc(C=O)cc1OC
Reactant: CC(C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)C=C(C)COc1ccc(C=C(C)C)cc1OC

Procedure:
Vanillin (3.43 g, 22.5 mmol) in 10 ml of DMF is added portionwise, at 0°, to sodium hydride (21.5 g, 23.6 mmol) in ml of DMF. The mixture is stirred for 10 min. and then ethyl 4-bromo-3-methyl-2-butenoate (4.87 g, 23.5 mmol) in 3 ml of DMF is added. After 3 hours, the reaction mixture is poured into ether and 5% sodium hydroxide solution. The aqueous layer is extracted with ether, and the organic layers are combined and washed with 5% sodium hydroxide, with water and with brine and dried. Solvent is removed in vacuo and the crude product is chromatographed to give ethyl 3-methyl-4-(4-formyl-2-methoxyphenoxy)-2-butenoate. To isopropyltriphenylphosphonium iodide (2.26 g, 5.23 mmol) in 15 ml of tetrahydrofuran (THF) is added n-butyllithium (1.6 M; 3.10 ml, 5.0 mmol) at -5°. The mixture is cooled to -60°, and ethyl 3-methyl-4-(4-formyl-2-methoxyphenoxy)-2-butenoate (0.70 g, 2.51 mmol) in 10 ml of THF is added. After 45 min. the reaction mixture is poured into ether and water, and the aqueous phase is extracted with ether. The combined ether layers are washed with water and with brine and dried. Solvent is removed in vacuo, and the crude product is triturated with hexane and the hexane-soluble fraction is purified by prep. TLC to give ethyl 3-methyl-4-[2-methoxy-4-(2-methyl-1-propenyl)phenoxy]-2-butenoate, MS m/e 304 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[OH:10].[CH2:11]([O:13][C:14](=[O:17])[CH:15]=O)[CH3:12].CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[Cl:9][C:5]1[C:6]([Cl:8])=[CH:7][C:2]([NH:1][CH2:15][C:14]([O:13][CH2:11][CH3:12])=[O:17])=[C:3]([OH:10])[CH:4]=1
Reactant: CCOC(=O)C=O
Reactant: Nc1cc(Cl)c(Cl)cc1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)CNc1cc(Cl)c(Cl)cc1O
Reaction time: 1 h
Yield: 80.4 %

Procedure:
To a solution of 2-amino-4,5-dichlorophenol (2.0 g, 11.3 mmol) and ethyl-2-oxoacetate (2.26 g, 12.42 mmol) in DCM (50 mL) at room temperature, AcOH (1 mL) was added and the resulting mixture was stirred for 1 h. To this mixture, NaBH(OAc)3 (7.2 g, 33.9 mmol) was added and then stirred for 16 h. The mixture was concentrated in vacuo and the residue was suspended in DCM. The mixture was filtered through a pad of Celite and the filtrate was washed with brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate=10:1) to afford the desired product (2.4 g, 81% yield) as a solid.
Reaction SMILES: C1OCCOCCOCCOCCOCCOC1.COC(CP(=O)(OCC(F)(F)F)OCC(F)(F)F)=O.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[ClH:48].[CH2:49]([N:56]1[CH2:68][C@@H:67]2[C@H:58]([C:59](=[O:72])[N:60]3[CH2:71][CH2:70][CH2:69][C:62]4[CH:63]=[CH:64][CH:65]=[C:66]2[C:61]3=4)[CH2:57]1)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>O1CCCC1.C1(C)C=CC=CC=1>[ClH:48].[CH2:49]([N:56]1[CH2:68][C@H:67]2[C@H:58]([C:59](=[O:72])[N:60]3[CH2:71][CH2:70][CH2:69][C:62]4[CH:63]=[CH:64][CH:65]=[C:66]2[C:61]3=4)[CH2:57]1)[C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1
Reactant: O=C1[C@@H]2CN(Cc3ccccc3)C[C@H]2c2cccc3c2N1CCC3
Agent: C1COCCOCCOCCOCCOCCO1
Agent: COC(=O)CP(=O)(OCC(F)(F)F)OCC(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C1[C@@H]2CN(Cc3ccccc3)C[C@@H]2c2cccc3c2N1CCC3
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
To a solution of 18-crown-6 (7.6 g, 28.7 mmol) in 100 mL of tetrahydrofuran at −78° C. was added bis(2,2,2-trifluoroethyl) (methoxycarbonylmethyl)phosphonate (2.0 g, 6.31 mmol). Potassium bis(trimethylsilyl)amide (12.6 mL of a 0.5M solution in toluene, 6.31 mmol) was added dropwise over 15 min and the mixture was stirred an additional 30 min at −78° C. Then there was added tert-butyl 8-formyl-3,4-dihydro-1(2H)-quinolinecarboxylate from EXAMPLE 1, Part B (1.5 g, 5.74 mmol) in 10 mL of tetrahydrofuran and the resulting cloudy mixture was stirred −78° C. for 1 h. The reaction was quenched with saturated aqueous ammonium chloride, diluted with ethyl acetate, washed with brine, dried (MgSO4), filtered through a pad of silica gel and concentrated in vacuo. The residue was purified by flash chromatography (elution with 6:1 hexane/ethyl acetate) to afford 1.7 g (93%) of the title compound as a solid. 1H NMR (CDCl3): δ 7.42-7.36 (m, 1H), 7.12-7.08 (m, 2H), 7.02 (d, 1H, J=12.4 Hz), 5.89 (d, 1H, J=12.0 Hz), 4.37-4.22 (broad m, 1H), 4.14 (q, 2H, J=7.3 Hz), 3.10-2.98 (broad s, 1H), 2.79-2.70 (m, 2H), 2.18-2.05 (broad m, 1H), 1.95-1.88 (broad s, 1H), 1.42 (broad s, 9H), 1.28 (t, 3H, J=7.2 Hz).
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11]C[N:9]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:8]2=[O:19])=[C:4]([Cl:22])[CH:3]=1.[OH:23][CH:24]1[CH2:28][CH2:27][NH:26][CH2:25]1.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O.[Cu]I>[Cl:22][C:4]1[CH:3]=[C:2]([N:26]2[CH2:27][CH2:28][CH:24]([OH:23])[CH2:25]2)[CH:21]=[CH:20][C:5]=1[CH2:6][CH:7]1[CH2:12][CH2:11][N:9]([CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]2)[C:8]1=[O:19]
Reactant: OC1CCNC1
Reactant: O=C1C(Cc2ccc(Br)cc2Cl)CCCN1C1CCCCC1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=C1C(Cc2ccc(N3CCC(O)C3)cc2Cl)CCN1C1CCCCC1
Yield: 19.2 %

Procedure:
Dissolve 3-(4-bromo-2-chloro-benzyl)-1-cyclohexyl-piperidin-2-one (Example 55) (0.2 g, 0.54 mmol), rac-3-hydroxy-pyrrolidine (0.053 mL, 0.64 mmol), copper (I) iodide (10.5 mg, 0.05 mmol), in dimethylacetamide (1 mL) with potassium carbonate (0.13 g, 0.95 mmol), and heat at 90° C. 48 h. Evaporate and purify the residue by chromatography on silica gel (eluting 10% to 100% ethyl acetate in hexane) to give the desired product (39 mg, 19%). MS (ES+) m/z=377 (M+H)+.
Reaction SMILES: O[CH:2]([C:4]1[CH:17]=[CH:16][C:7]2[CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[S:10][C:6]=2[CH:5]=1)[CH3:3].C1(P([N:32]=[N+:33]=[N-:34])(C2C=CC=CC=2)=O)C=CC=CC=1.C1CCN2C(=NCCC2)CC1.[N-]=[N+]=[N-]>C1(C)C=CC=CC=1>[N:32]([CH:2]([C:4]1[CH:17]=[CH:16][C:7]2[CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[S:10][C:6]=2[CH:5]=1)[CH3:3])=[N+:33]=[N-:34]
Reactant: CCOC(=O)c1cc2ccc(C(C)O)cc2s1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: [N-]=[N+]=[N-]
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1cc2ccc(C(C)N=[N+]=[N-])cc2s1
Reaction time: 24 h
Yield: 79.8 %

Procedure:
To a solution of ethyl 6-(1-hydroxyethyl)-1-benzothiophene-2-carboxylate (2.0 g, 8.06 mmol) in toluene (30 mL) was added diphenylphosphorylazide (2.64 g, 9.58 mmol), then DBU (1.31 mL, 8.79 mmol) dropwise. After 24 h, added more azide (0.5 mL) and DBU (0.3 mL) to the thick solution. After an additional 24 h, the reaction mixture was concentrated and purified via column chromatography yielding the desired product (1.77 g, 80.4% over two steps). 1H NMR (CDCl3, 600 MHz) δ 8.03 (d, J=0.9 Hz, 1H), 7.87 (d, J=8.2 Hz, 1H), 7.81 (m, 1H), 7.36 (dd, J=8.2, 0.9 Hz, 1H), 4.75 (q, J=6.8 Hz, 1H), 4.40 (q, J=7.3 Hz, 2H), 1.58 (d, J=6.8 Hz, 3H), 1.41 (t, J=7.3 Hz, 3H). MS: cal'd 276 (MH+), exp 276 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:15]([O:16][CH3:17])=[CH:14][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][CH2:12][OH:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2([CH2:32][C:33]([NH2:35])=[O:34])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:22]([Cl:36])=[CH:21][N:20]=1>>[Cl:36][C:22]1[C:23]([NH:25][C:26]2([CH2:32][C:33]([NH2:35])=[O:34])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[N:24][C:19]([NH:1][C:2]2[C:15]([O:16][CH3:17])=[CH:14][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][CH2:12][OH:13])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:20][CH:21]=1
Reactant: COc1cc2c(cc1N)CCN(CCO)CC2
Reactant: NC(=O)CC1(Nc2nc(Cl)ncc2Cl)CCCCC1
Product: COc1cc2c(cc1Nc1ncc(Cl)c(NC3(CC(N)=O)CCCCC3)n1)CCN(CCO)CC2

Procedure:
The title compound was prepared from 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-ethanol and 2-[1-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-acetamide in an analogous manner to Example 61e. Product isolated as a pale yellow foam (0.064 g, 24%). MP: 84-96° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 7.93 (s, 1H), 7.89 (s, 1H), 7.18 (s, 1H), 6.66 (s, 1H), 5.44 (br s, 1H), 5.26 (s, 1H), 5.11 (br s, 1H), 3.86 (s, 3H), 3.66-3.61 (m, 2H), 2.93 (m, 6H), 2.73-2.64 (m, 6H), 2.37-2.29 (m, 2H), 1.72-1.29 (m, 9H). MS: 503.17 (MH)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](/[CH:7]=[CH:8]/[C:9]2[C:17]3[C:12](=[CH:13][C:14]([C@H:18]4[C@@:20]5([C:28]6[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=6)[NH:22][C:21]5=[O:29])[CH2:19]4)=[CH:15][CH:16]=3)[N:11](COCC[Si](C)(C)C)[N:10]=2)=[CH:3][CH:2]=1.B(F)(F)F.CCOCC>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][C:4](/[CH:7]=[CH:8]/[C:9]2[C:17]3[C:12](=[CH:13][C:14]([C@H:18]4[C@@:20]5([C:28]6[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=6)[NH:22][C:21]5=[O:29])[CH2:19]4)=[CH:15][CH:16]=3)[NH:11][N:10]=2)=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)CCOCn1nc(/C=C/c2ccncc2)c2ccc([C@@H]3C[C@@]34C(=O)Nc3ccccc34)cc21
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: O=C1Nc2ccccc2[C@]12C[C@H]2c1ccc2c(/C=C/c3ccncc3)n[nH]c2c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 93.8 %

Procedure:
A dry-round bottom was charged with (1R*,2S*)-(E)-2-(3-(2-(pyridin-4-yl)vinyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indolin]-2′-one (320 mg, 0.62 mmol), and CH2Cl2 (15 mL) under an atmosphere of N2. Boron trifluoride etherate (1 mL) was added dropwise and the reaction was stirred for 2 h. Methylene chloride was removed in vacuo, and then 5 mL of a 2:1 mixture of EtOH/2M HCl was added and the reaction heated to 50° C. for 2 h. The reaction was cooled with an ice-bath and neutralized with NH4OH to pH˜8, the EtOH was removed and the resulting precipitate was collected. The product was purified by silica gel chromatography (85:15 CH2Cl2/MeOH) to give the title compound as a yellow solid (220 mg, 90%). 1H NMR (400 MHz, DMSO-d6) δ 13.31 (s, 1H), 10.63 (s, 1H), 8.57-8.50 (m, 2H), 8.10 (d, J=8.1 Hz, 1H), 7.80 (d, 1H, J=16.6 Hz), 7.75-7.70 (m, 2H), 7.50-7.42 (m, 2H), 7.09-6.99 (m, 2H), 6.85 (d, 1H, J=7.6 Hz), 6.53 (t, 1H, J=7.5 Hz), 6.01 (d, 1H, J=7.8 Hz) 3.23-3.19 (m, 1H), 2.35-2.31 (m, 1H), 2.02-1.98 (m, 1H); MS ESI 379.2 [M+H]+, calcd for [C24H18N4O+H]+ 379.4.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C@@H:10]([OH:37])[CH2:11][C@@H:12]([NH:26][C:27](=[O:36])[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=[CH:16][CH:15]=1)=O)(C)(C)C.Cl>C1COCC1>[NH2:8][C@@H:9]([CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C@@H:10]([OH:37])[CH2:11][C@@H:12]([NH:26][C:27](=[O:36])[O:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccc(-c2ccccn2)cc1)NC(=O)OCc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccc(-c2ccccn2)cc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution containing the product from Example 1C (0.088 g, 0.15 mmol) in a mixture of THF (2 mL) and aqueous HCl (0.26 mL, 4 N) was stirred at 25° C. for 16 hours, then heated at 60° C. for 2 hours, cooled and concentrated. The residue was treated with ethanol and concentrated several times to give the title compound as the hydrochloride salt, which was used without further purification.
Reaction SMILES: [Na].C(O)C.[F:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:20]3[C:15](=[CH:16][C:17]4[C@@:25]5([CH2:31][C:32]6C=CC=CN=6)[CH2:26][CH2:27][C:28](=[O:30])[CH2:29][C@H:24]5[CH2:23][CH2:22][CH2:21][C:18]=4[CH:19]=3)[CH:14]=[N:13]2)=[CH:8][CH:7]=1.FC1C=CC(N2[C:53]3[C:48](=[CH:49][C:50]4[C@]5(CC6C=CC=CN=6)CCC(=O)C[C@@H]5CCC[C:51]=4[CH:52]=3)[CH:47]=N2)=CC=1.C(=O)C1C=CC=CC=1>C1COCC1>[CH:47](=[C:27]1/[CH2:26][C:25]2([CH2:31][CH3:32])[C:17]3=[CH:16][C:15]4[CH:14]=[N:13][N:12]([C:9]5[CH:8]=[CH:7][C:6]([F:5])=[CH:11][CH:10]=5)[C:20]=4[CH:19]=[C:18]3[CH2:21][CH2:22][CH2:23][CH:24]2[CH2:29][C:28]/1=[O:30])/[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: O=C1CC[C@]2(Cc3ccccn3)c3cc4cnn(-c5ccc(F)cc5)c4cc3CCC[C@@H]2C1
Reactant: O=C1CC[C@@]2(Cc3ccccn3)c3cc4cnn(-c5ccc(F)cc5)c4cc3CCC[C@H]2C1
Agent: [Na]
Solvent: C1CCOC1
Solvent: O=Cc1ccccc1
Solvent: CCO
Product: CCC12C/C(=C\c3ccccc3)C(=O)CC1CCCc1cc3c(cnn3-c3ccc(F)cc3)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.9 %

Procedure:
Sodium (0.092 g, 4.0 mmol) was added to ethanol (20 mL) and mixed at rt until the sodium was completely consumed. A solution of rac-(4aS,12bR)-12b-ethyl-9-(4-fluorophenyl)-1,4,4a,5,6,7,9,12b-octahydrobenzo[6,7]cyclohepta[1,2-f]indazol-3 (2H)-one (10, R1=4-Fluorophenyl, R2=Ethyl) (1.00 g, 2.66 mmol) in THF (10 mL) was added in one portion. Benzaldehyde (0.310 g, 2.92 mmol) was added and the reaction mixture was stirred at rt for about 3 h. The organic volatiles were removed under reduced pressure. The residue was partitioned between EtOAc (70 mL) and water (50 mL). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified on silica gel (40 g) using a gradient of 5-18% EtOAc in heptane. The product fractions were combined and concentrated under reduced pressure to give rac-(4aS,12bR,E)-2-benzylidene-12b-ethyl-9-(4-fluorophenyl)-1,4,4a,5,6,7,9,12b-octahydrobenzo[6,7]cyclohepta[1,2-f]indazol-3(2H)-one (53, R1=4-Fluorophenyl, R2=Ethyl) (1.00 g, 81% yield); LC/MS, method 3, Rt=3.11 min.; MS m/z: 465 (M+H)+. 1H NMR (400 MHz, DMSO) δ 7.98-7.96 (m, 1H), 7.80-7.73 (m, 2H), 7.73-7.67 (m, 2H), 7.62-7.55 (m, 3H), 7.53-7.46 (m, 2H), 7.44-7.35 (m, 2H), 6.99 (s, 1H), 3.72-3.62 (m, 1H), 3.27-3.15 (m, 1H), 3.01-2.91 (m, 1H), 2.90-2.81 (m, 1H), 2.58-2.52 (m, 1H), 2.48-2.37 (m, 1H), 2.36-2.25 (m, 1H), 2.25-2.14 (m, 1H), 2.11-1.97 (m, 1H), 1.87-1.45 (m, 4H), 0.65 (t, J=7.3 Hz, 3H).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]1([S:17]([C:20]([CH3:32])([CH3:31])[CH2:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][CH2:27][CH:26]([OH:30])[CH2:25]2)(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>ClCCl>[C:11]1([S:17]([C:20]([CH3:32])([CH3:31])[CH2:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][CH2:27][C:26](=[O:30])[CH2:25]2)(=[O:18])=[O:19])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)(CCCN1CCCC(O)C1)S(=O)(=O)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(CCCN1CCCC(=O)C1)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78.7 %

Procedure:
Dimethylsulphoxide (1.2 ml, 16.6 mmol) was added to a solution of oxalyl chloride (1.5 ml, 16.6 mmol) in dichloromethane (200 ml) at −78° C. and stirred for 15 minutes. 1-(4-Benzenesulfonyl-4-methylpentyl)-3-hydroxypiperidine (3.5 g, 11.0 mmol) in dichloromethane (50 ml) was added and the reaction stirred at −20° C. for 15 minutes. Triethylamine (4.6 ml, 33 mmol) was added and the reaction stirred for 90 minutes, warming slowly to room temperature. The mixture was diluted with dichloromethane and washed with water. The organic layer was dried (MgSO4) and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with 5% methanol/dichloromethane to give the title compound (2.8 g, 80%).