Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH2:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)(=[O:25])=[O:24].[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][CH2:40][NH2:41])[CH:34]=1>>[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([NH:41][CH2:40][CH2:39][C:35]3[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=3)=[O:18])=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH2:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)(=[O:24])=[O:25]
Reactant: Cc1ccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)O)cc3)oc2C)cc1
Reactant: NCCc1cccnc1
Agent: O=C(Cl)C(=O)Cl
Product: Cc1ccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)NCCc4cccnc4)cc3)oc2C)cc1
Yield: 81 %

Procedure:
Method E. Reaction of oxalyl chloride (71.2 μL, 0.82 mmol) and benzoic acid 4 (202 mg, 0.54 mmol) with subsequent reaction with 2-(3-pyridinyl)ethylamine (71 λL, 0.59 mmol) gave benzamide 12 (208 mg, 81%) as a white powder: mp (EtOAc) 207-208° C.; 1H NMR δ 8.68 (t, J=5.6Hz, 1 H, CONH), 8.46 (d, J=1.7Hz, 1 H, H-2′), 8.41 (dd, J=4.7, 1.6Hz, 1 H, H-6′), 7.93 (dd, J=8.6, 2.0Hz, 2 H, H-2, H-6), 7.87 (dd, J=8.6, 2.0Hz, 2 H, H-3, H-5), 7.65-7.69 (m, 3 H, H-4′, H-2″, H-6″), 7.42 (d, J=8.3Hz, 2 H, H-3″, H-5″), 7.31 (ddd, J=7.8, 4.7, 0.7Hz, 1 H, H-5′), 4.62 (s, 2 H, CH2SO2), 3.54 (dt, J=7.0, 5.8 Hz, 2 H, CH2N), 2.89 (t, J=7.1Hz, 2 H, CH2), 2.40 (s, 3 H, CH3), 2.13 (s, 3 H, CH3); 13C NMR δ 165.4, 158.0, 149.9, 149.8, 147.4, 144.5, 136.2, 135.8, 135.6, 134.9, 129.6 (2), 128.7, 128.3 (2), 127.9 (2), 126.0, 125.4 (2), 123.4, 53.0, 40.4, 32.0, 21.0, 9.7; MS m/z 476.6 (MH+, 100%). Anal. calcd for C26H25N3O4S: C, 65.67; H, 5.30; N, 8.84. Found: C, 65.53; H, 5.18; N, 8.75%.
Reaction SMILES: [F:1][CH:2]([F:8])[C:3]([O:5]CC)=O.C[O-].[Na+].CO.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:23])[CH3:22])=[CH:17][CH:16]=1.Cl>C(OCC)C>[F:8][CH:2]([F:1])[C:3](=[O:5])[CH2:22][C:21]([C:18]1[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=1)=[O:23]
Reactant: CC(=O)c1ccc(Cl)cc1
Reactant: CCOC(=O)C(F)F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: O=C(CC(=O)C(F)F)c1ccc(Cl)cc1
Yield: 99.5 %

Procedure:
Ethyl difluoroacetate (24.82 g, 200 mmol) was placed in a 500 mL three-necked round bottom flask, and dissolved in diethyl ether (200 mL). To the stirred solution was added 25% sodium methoxide in methanol (48 mL, 210 mmol) via an addition funnel over a 2 minute period. Next, 4'-chloroacetophenone (25.94 g, 200 mmol) was dissolved in diethyl ether (50 mL), and added to the reaction dropwise over 5 minutes. After stirring overnight (18 hours), 1N HCl (250 mL) and ether (250 mL) were added. The organic layer was collected, washed with brine (250 mL), dried over MgSO4, filtered, and concentrated in vacuo to give 46.3 g of a yellow solid. The solid was recrystallized from methylene chloride and iso-octane to give 31.96 g (69%) of the dione: mp 65°-66.5° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)[N:7]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:6]=2[CH:23]=1.[CH3:24][O:25][C:26](=[O:33])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]Br>>[CH3:24][O:25][C:26](=[O:33])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][O:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)[N:7]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:6]=2[CH:23]=1
Reactant: COC(=O)CCCCCBr
Reactant: Oc1ccc2nc(-c3cccnc3)n(-c3ccc(F)cc3)c2c1
Product: COC(=O)CCCCCOc1ccc2nc(-c3cccnc3)n(-c3ccc(F)cc3)c2c1

Procedure:
6-Hydroxy-1-(4-fluorophenyl)-2-(3-pyridinyl)-1H-benzimidazole was reacted with 6-bromohexanoic acid methyl ester according to general operating instructions 3.
Reaction SMILES: FC(F)(F)C(O)=[O:4].[CH2:8]([N:15]1[CH:20]2[CH2:21][CH2:22][CH:16]1[CH:17]=[C:18]([C:23]1[C:24]([O:31]C(C)(C)C)=[C:25]([CH:28]=[CH:29][CH:30]=1)[C:26]#[N:27])[CH2:19]2)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>S(=O)(=O)(O)O>[CH2:8]([N:15]1[CH:20]2[CH2:21][CH2:22][CH:16]1[CH:17]=[C:18]([C:23]1[C:24]([OH:31])=[C:25]([CH:28]=[CH:29][CH:30]=1)[C:26]([NH2:27])=[O:4])[CH2:19]2)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)Oc1c(C#N)cccc1C1=CC2CCC(C1)N2Cc1ccccc1
Agent: O=S(=O)(O)O
Product: NC(=O)c1cccc(C2=CC3CCC(C2)N3Cc2ccccc2)c1O
Temperature: 65 °C

Procedure:
Trifluoroacetic Acid (50 mL) and sulfuric acid (20 mL) were added to crude 3-(8-benzyl-8-aza-bicyclo[3.2.1]oct-2-en-3-yl)-2-tert-butoxy -benzonitrile (37.53 g, 0.101 mol) and the reaction mixture was heated at 65° C. overnight, poured into ice water and neutralized to pH 7. The aqueous layer was extracted EtOAc (3×) and the solvent was evaporated. The reaction mixture was purified by silica gel chromatography (10 min 7% MeOH:DCM, 10 min 10% MeOH: DCM, ramping to 20% MeOH:DCM over 30 min) to provide the title compound (22.15 g). (m/z): [M+H]+ calcd for C21H22N2O2 335.17; found 335.4
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([NH2:13])=[O:12])=[CH:5][CH:4]=1.[Cl:16][CH2:17][C:18]([CH2:20]Cl)=O.O>C1(C)C=CC=CC=1>[Cl:16][CH2:17][C:18]1[N:13]=[C:11](/[CH:10]=[CH:9]/[C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:14])([F:15])[F:1])=[CH:8][CH:7]=2)[O:12][CH:20]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=O)/C=C/c1ccc(C(F)(F)F)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: FC(F)(F)c1ccc(/C=C/c2nc(CCl)co2)cc1
Yield: 63.1 %

Procedure:
A mixture of (E)-3-(4-trifluoromethylphenyl)-2-propenamide (17.9 g) and 1,3-dichloroacetone (14.8 g) in toluene (83 ml) was refluxed for 9 hours by use of Dean-Stark apparatus. After cooling, the reaction mixture was combined with water, extracted with ethyl acetate, washed with saturated brine, and dried over magnesium sulfate, then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane:ethyl acetate=6:1 to 5:1) to give the titled compound (15.1 g) as colorless needle crystals.
Reaction SMILES: [OH:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[CH3:17][N:18]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:19](Cl)=[O:20].N12CCN(CC1)CC2.O>CN(C)C=O>[CH:11]1([C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([O:1][C:19](=[O:20])[N:18]([CH3:17])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:7][CH:6]=2)=[O:10])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: O=C(Nc1ccc(O)nc1)C1CCCCC1
Agent: C1CN2CCN1CC2
Solvent: CN(C)C=O
Solvent: O
Product: CN(C(=O)Oc1ccc(NC(=O)C2CCCCC2)cn1)c1ccccc1
Yield: 70.7 %

Procedure:
A solution of cyclohexanecarboxylic acid (6-hydroxy-pyridin-3-yl)-amide (0.66 g, 3.00 mmol), N-methyl-N-phenylcarbamoyl chloride (0.51 g, 3.00 mmol) and 1,4-diazabicyclo[2.2.2]octane (0.34 g, 3.00 mmol) in dimethylformamide (20 ml) was stirred at room temperature for 18 hours. Water was added and the precipitates were collected by suction. The solids were dissolved in dichloromethane and the solution was dried over sodium sulphate, filtered and evaporated in vacuo. The residue was crystallised from ethyl acetate:heptane yielding the title compound (0.75 g, 71% yield) as a slightly coloured solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH2:14][CH2:15][NH2:16])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][C:12]#[CH:13].C(N(CC)C(C)C)(C)C.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([C:33](=[O:40])[CH2:34][CH:35]([OH:39])[C:36](O)=[O:37])=[CH:29][CH:28]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([C:33](=[O:40])[CH2:34][CH:35]([OH:39])[C:36]([NH:16][CH2:15][CH2:14][C:6]2[CH:7]=[CH:8][C:9]([O:10][CH2:11][C:12]#[CH:13])=[C:4]([O:3][CH3:2])[CH:5]=2)=[O:37])=[CH:31][CH:32]=1
Reactant: C#CCOc1ccc(CCN)cc1OC
Reactant: O=C(CC(O)C(=O)O)c1ccc(Cl)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C#CCOc1ccc(CCNC(=O)C(O)CC(=O)c2ccc(Cl)cc2)cc1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-(3-Methoxy-4-prop-2-ynyloxy-phenyl)-ethylamine hydrochloride (5.4 g, 22 mmol) and N,N-diisopropylethylamine (11 g, 83 mmol) are dissolved in 70 ml of N,N-dimethylformamide. To this solution 4-(4-chloro-phenyl)-2-hydroxy-4-oxo-butyric acid (4.8 g, 21 mmol) and (benzotriazol-1-yloxy)-tris-(dimethylamino)-phosphonium hexafluorophosphate (10 g, 23 mmol) are added successively. The reaction mixture is stirred for 16 hours at room temperature, subsequently poured on ice-water and extracted several times with ethyl acetate. The combined organic layer is washed with brine, dried over sodium sulfate and evaporated in vacuum. The remaining oil is purified by chromatography on silicagel (ethyl acetate/hexane 6:4) to give 4-(4-chloro-phenyl)-2-hydroxy-N-[2-(3-methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]-4-oxo-butyramide (Compound E1.10).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C.[OH:36][CH:37]1[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]1.O[C:45]1[CH:46]=[CH:47][CH:48]=[C:49]2[C:54]=1[N:53]=[C:52]([NH:55][C:56]1[CH:57]=[C:58]([S:62]([NH2:65])(=[O:64])=[O:63])[CH:59]=[CH:60][CH:61]=1)[N:51]=[CH:50]2>C1COCC1>[CH3:43][N:40]1[CH2:41][CH2:42][CH:37]([O:36][C:45]2[CH:46]=[CH:47][CH:48]=[C:49]3[C:54]=2[N:53]=[C:52]([NH:55][C:56]2[CH:57]=[C:58]([S:62]([NH2:65])(=[O:64])=[O:63])[CH:59]=[CH:60][CH:61]=2)[N:51]=[CH:50]3)[CH2:38][CH2:39]1
Reactant: NS(=O)(=O)c1cccc(Nc2ncc3cccc(O)c3n2)c1
Reactant: CN1CCC(O)CC1
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN1CCC(Oc2cccc3cnc(Nc4cccc(S(N)(=O)=O)c4)nc23)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 24.2 %

Procedure:
To a 0.3M solution of triphenylphosphine (1.5 eq) in THF was added di-tert-butylazodicarboxylate (1.5 eq). The mixture was stirred 15 minutes at ambient temperature. 4-Hydroxy-1-methylpiperidine (4.5 eq) was added. The mixture was stirred 15 minutes at ambient temperature. 3-(8-Hydroxyquinazolin-2-ylamino)benzenesulfonamide (1.0 eq) was added. The mixture was stirred an additional 1 hour. The crude mixture was concentrated, purified by RPHPLC, and lyophilized to give the desired product in 24.2% yield ES/MS m/z 414 (MH+).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.C(N(CC)CC)C.[C:20](OC(=O)C)(=[O:22])[CH3:21]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:20]([O:1][CH:2]1[CH2:3][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:5]1)(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OC1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.2 %

Procedure:
A solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (2.0 g), DMAP (1.55 g) and triethylamine (2.34 g) in DCM (80 mL) was cooled to 0° C. A solution of acetic anhydride (2.35 g) in DCM (20 mL) was added dropwise over 20 minutes and the reaction mixture was stirred at room temperature for 1 hour. The mixture was washed with water and brine, dried (MgSO4) and filtered. The filtrate was concentrated in vacuo and the residue was dissolved in ether and washed with 10% aqueous citric acid solution and brine, dried (MgSO4), filtered. The filtrate was concentrated in vacuo to give tert-butyl 3-acetoxyazetidine-1-carboxylate (2.34 g) as a clear oil.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:16]2[C:7]3=[N:8][C:9](C#N)=[C:10]([C:12]#[N:13])[N:11]=[C:6]3[C:5](=[O:19])[C:4]=2[CH:3]=1.[OH:20]O.ClCCl>CS(C)=O>[Cl:1][C:2]1[CH:18]=[CH:17][C:16]2[C:7]3=[N:8][C:9]([OH:20])=[C:10]([C:12]#[N:13])[N:11]=[C:6]3[C:5](=[O:19])[C:4]=2[CH:3]=1
Reactant: N#Cc1nc2c(nc1C#N)-c1ccc(Cl)cc1C2=O
Reactant: OO
Solvent: ClCCl
Solvent: CS(C)=O
Product: N#Cc1nc2c(nc1O)-c1ccc(Cl)cc1C2=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 70 %

Procedure:
To a suspension of 50 mg (0.19 mmol) 17g and 2.2 mg (5 Mol-%) Na2MoO4 in 2 ml DMSO was added dropwise 82 μl (0.95 mmol) of an aqueous solution of H2O2 (35%). The colour turned to red, and the mixture was stirred for 48 h at room temperature. After addition of 20 mL Dichloromethane, the resulting solution was washed with water and sat. brine (3×5 ml). After drying, filtration and evaporation, the crude product was purified by chromatography (DCM/MeOH 8/2) to yield 35 mg (70%) compound 42 as yellow-orange powder. 1H-NMR (d6-DMSO, 300 MHz): δ (ppm)=7.55 (s, 1H); 7.64 (m, 2H). ESI−MS: calcd for C12H4ClN3O2: 257.64; found: 255.9 (M-H+).
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH3:4][CH:5]([NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([O:21][CH3:22])=[O:20])=[C:14]2[N:13]=[C:12](Cl)[C:11]=1[C:24]1[S:25][CH:26]=[CH:27][C:28]=1[CH3:29])[CH:6]([CH3:8])[CH3:7].O>CO>[CH3:4][CH:5]([NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([O:21][CH3:22])=[O:20])=[C:14]2[N:13]=[C:12]([O:2][CH3:1])[C:11]=1[C:24]1[S:25][CH:26]=[CH:27][C:28]=1[CH3:29])[CH:6]([CH3:8])[CH3:7]
Reactant: C[O-]
Reactant: COC(=O)c1cnn2c(NC(C)C(C)C)c(-c3sccc3C)c(Cl)nc12
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1cnn2c(NC(C)C(C)C)c(-c3sccc3C)c(OC)nc12
Temperature: 22 °C
Reaction time: 16 h

Procedure:
0.17 g (3 mmol) of sodium methoxide was dissolved in 10 ml of methanol, and 0.79 g (2 mmol) of methyl 7-(1,2-dimethylpropylamino)-5-chloro-6-(3-methylthiophen-2-yl)pyrazolo[1,5-α]-pyrimidine-3-carboxylate was added. The mixture was stirred at 22° C. for 16 hours. 10 ml of water were then added, the methanol was distilled off and 10 ml of dichloromethane were added to the residue. The organic phase was separated off, dried over sodium sulphate and concentrated under reduced pressure. This gave 0.35 g of methyl 7-(1,2-dimethylpropylamino)-5-methoxy-6-(3-methylthiophen-2-yl)pyrazolo[1,5-α]pyrimidine-3-carboxylate (logPs=4.60; content according to HPLC: 96%).
Reaction SMILES: O[C@H:2]([C:22]1[CH:31]=[CH:30][C:25]2[C:26](=[O:29])[O:27][CH2:28][C:24]=2[C:23]=1[CH3:32])[CH2:3][N:4]1[CH2:21][CH2:20][C:7]2([C:11](=[O:12])[N:10]([C:13]3[CH2:14][O:15][C:16](=[O:19])[C:17]=3[CH3:18])[CH2:9][CH2:8]2)[CH2:6][CH2:5]1.CS([Cl:37])(=O)=O.C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Cl:37][C@@H:2]([C:22]1[C:23]([CH3:32])=[C:24]2[C:25](=[CH:30][CH:31]=1)[C:26](=[O:29])[O:27][CH2:28]2)[CH2:3][N:4]1[CH2:21][CH2:20][C:7]2([C:11](=[O:12])[N:10]([C:13]3[CH2:14][O:15][C:16](=[O:19])[C:17]=3[CH3:18])[CH2:9][CH2:8]2)[CH2:6][CH2:5]1
Reactant: CC1=C(N2CCC3(CCN(C[C@H](O)c4ccc5c(c4C)COC5=O)CC3)C2=O)COC1=O
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1=C(N2CCC3(CCN(C[C@@H](Cl)c4ccc5c(c4C)COC5=O)CC3)C2=O)COC1=O
Reaction time: 0.33 h

Procedure:
To a solution of 8-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one (Example 7) (1.1 g, 2.5 mmol) and methanesulfonyl chloride (0.584 mL, 7.49 mmol) in DCM (30 mL) was added triethylamine (1.22 mL, 8.74 mmol) and N,N-dimethylpyridin-4-amine (0.031 g, 0.250 mmol) at −10 to −15° C. (ice-NaCl). The mixture was stirred at the same temperature for 20 min, quenched with NH4Cl aqueous. The organic layer was separated, and the aqueous was extracted with DCM (30 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to give product was used in the next step without further purification. LCMS: 459.05 (M+1).
Reaction SMILES: [I-].[K+].[CH2:3]([C@:5]1([OH:37])[CH2:29][C@@H:9]2[CH2:10][CH2:11][CH2:12][C:13]3[C:14](=[CH:15][C:16]4[CH:17]=[N:18][N:19]([C:22]5[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=5)[C:20]=4[CH:21]=3)[C@:8]2([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)[CH2:7][CH2:6]1)[CH3:4].[O:38](C(C)(C)C)O>CC#N>[CH2:3]([C@:5]1([OH:37])[CH2:29][C@@H:9]2[CH2:10][CH2:11][C:12](=[O:38])[C:13]3[C:14](=[CH:15][C:16]4[CH:17]=[N:18][N:19]([C:22]5[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=5)[C:20]=4[CH:21]=3)[C@:8]2([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)[CH2:7][CH2:6]1)[CH3:4]
Reactant: CC(C)(C)OO
Reactant: CC[C@@]1(O)CC[C@@]2(Cc3ccccn3)c3cc4cnn(-c5ccc(F)cc5)c4cc3CCC[C@H]2C1
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CC[C@@]1(O)CC[C@@]2(Cc3ccccn3)c3cc4cnn(-c5ccc(F)cc5)c4cc3C(=O)CC[C@H]2C1
Yield: 6 %

Procedure:
Potassium iodide (1 M solution in water, 0.365 mL, 0.365 mmol) was added to a solution of (3R,4aS,12bS)-3-ethyl-9-(4-fluorophenyl)-12b-(pyridin-2-ylmethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazol-3-ol (13, R1=4-Fluorophenyl, R2=Pyridyin-2-ylmethyl, R3=Ethyl) (0.143 g, 0.305 mmol) and MeCN (3 mL) under air. 2-Hydroperoxy-2-methylpropane (0.717 mL, 5.18 mmol) was added dropwise over about 5 min. The reaction was mixed at rt for about 24 h. The reaction was quenched with sat. aq. sodium sulfite (5 mL) and then a 1:1 solution of sat. aq. NaHCO3/water (5 mL) was added. The solution was extracted with EtOAc (3×5 mL). The combined organics were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified on silica gel (12 g) using a gradient of 50-86% EtOAc in heptane. Product fractions were combined and concentrated under reduced pressure. The residue was further purified by reverse phase HPLC (Atlantis Prep T3 OBD (Waters), 5 μm particle size 19×100 mm) using a gradient of 0-95% MeCN in aqueous NH4OAc (50 mM). The fractions containing product were combined and concentrated under reduced pressure to remove the organic volatiles. The resulting mixture was frozen then lyophilized to give (3R,4aS,12bS)-3-ethyl-9-(4-fluorophenyl)-3-hydroxy-12b-(pyridin-2-ylmethyl)-1,2,3,4,4a,5,6,12b-octahydrobenzo[6,7]cyclohepta[1,2-f]indazol-7(9H)-one (48, R1=4-Fluorophenyl, R2=Pyridin-2-ylmethyl, R3=Ethyl) (0.008 g, 6% yield). LC/MS, method 2, Rt=2.32 min.; MS m/z: 484 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.38 (d, J=4.8 Hz, 1H), 8.30 (d, J=0.9 Hz, 1H), 7.88-7.78 (m, 2H), 7.69 (s, 1H), 7.54 (s, 1H), 7.48-7.41 (m, 2H), 7.35 (td, J=7.6, 1.8 Hz, 1H), 7.10-7.04 (m, 1H), 6.34-6.30 (m, 1H), 3.95 (s, 1H), 3.02-2.86 (m, 3H), 2.74-2.64 (m, 2H), 2.47-2.43 (m, 1H), 2.12-2.03 (m, 1H), 2.02-1.90 (m, 1H), 1.73-1.62 (m, 1H), 1.55-1.46 (m, 2H), 1.39-1.25 (m, 2H), 1.20 (q, J=7.8 Hz, 2H), 0.73 (t, J=7.4 Hz, 3H).
Reaction SMILES: Cl[C:2]1[N:6]2[N:7]=[C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[CH:10][C:5]2=[N:4][N:3]=1.[CH:25]1([NH2:31])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:8]1[C:9]([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)=[CH:10][C:5]2[N:6]([C:2]([NH:31][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[N:3][N:4]=2)[N:7]=1
Reactant: Clc1ccc(-c2cc3nnc(Cl)n3nc2-c2ccccc2Cl)cc1
Reactant: NC1CCCCC1
Product: Clc1ccc(-c2cc3nnc(NC4CCCCC4)n3nc2-c2ccccc2Cl)cc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 41 %

Procedure:
A suspension of 3-chloro-6-(2-chlorophenyl)-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazine (38 mg, 0.1 mmol) in cyclohexylamine (0.5 mL) was stirred at 100° C. for 16 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (30 mL), washed with H2O, saturated aqueous NaCl, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified using a silica gel cartridge (12 g) eluting with a gradient of EtOAc (40-100%) in hexanes to afford 18 mg (41%) of the title compound as a yellow powder. HPLC/MS (method A): retention time=3.58 min, (M+H)+=438.1. 1H NMR (CDCl3, 400 MHz): δ 7.87 (s, 1H), 7.35-7.43 (m, 3H), 7.30-7.33 (m, 1H), 7.20 (d, J=8.56 Hz, 2H), 7.04 (d, J=8.31Hz, 2H), 4.83 (s, 1H), 3.98 (s, 1H), 2.22-2.25 (m, 2H), 1.79 (dd, J=9.78, 3.67 Hz, 2H), 1.63-1.72 (m, 1H), 1.41-1.52 (m, 2H), 1.27-1.39 (m, 2H), 1.21-1.26 (m, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]([CH:17]([NH:21][CH2:22][CH:23]=[CH2:24])[CH2:18][CH2:19][OH:20])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27].CCN(CC)CC>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]([CH:17]([NH:21][CH2:22][CH:23]=[CH2:24])[CH2:18][CH2:19][O:20][S:26]([CH3:25])(=[O:28])=[O:27])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: C=CCNC(CCO)[C@@H]1CCCN(C(=O)OCc2ccccc2)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCNC(CCOS(C)(=O)=O)[C@@H]1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of (R)-3-(1-allylamino-3-hydroxypropyl)piperidine-1-carboxylic acid benzyl ester (0.264 g, 0.794 mmol) in DCM (15 mL) cooled at 0° C. was added successively methanesulfonyl chloride (68 μL, 0.873 mmol) and Et3N (0.133 mL, 0.953 mmol). The mixture was stirred at RT for 1.5 h, and then diluted with DCM, washed with a saturated solution of NaHCO3, followed by water, then dried (Na2SO4) and concentrated in vacuo affording the title compound as a colourless gum (quantitative). LCMS (Method B): RT 2.14 min [M+H]+ 411.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=[CH:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:24]([O:26][C:27](=[O:47])[CH2:28][C:29]1([C:32]2[CH:37]=[CH:36][C:35](B3OC(C)(C)C(C)(C)O3)=[CH:34][CH:33]=2)[CH2:31][CH2:30]1)[CH3:25]>>[CH2:24]([O:26][C:27](=[O:47])[CH2:28][C:29]1([C:32]2[CH:37]=[CH:36][C:35]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]=[CH:15][CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:4][CH:3]=3)=[CH:34][CH:33]=2)[CH2:31][CH2:30]1)[CH3:25]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=CCCc1ccccc1
Reactant: CCOC(=O)CC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)CC1(c2ccc(-c3ccc(-c4onc(C)c4C=CCCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using 5-(4-bromo-phenyl)-3-methyl-4-(4-phenyl-but-1-enyl)-isoxazole and {1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropyl}-acetic acid ethyl ester.