Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:27][CH2:26][CH:25]([C:28]3[O:32][N:31]=[C:30]([CH:33]([CH3:35])[CH3:34])[N:29]=3)[CH2:24][CH2:23]2)=[C:4]([C@H:10]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8].[F:36][C:37]1[CH:62]=[CH:61][C:40]([CH2:41][CH2:42][O:43][C:44]2[CH:49]=[CH:48][C:47](B3OC(=O)CN(C)CC(=O)O3)=[CH:46][CH:45]=2)=[CH:39][CH:38]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.CCOC(C)=O.C(O[Pd]OC(=O)C)(=O)C>[C:18]([O:17][C@@H:10]([C:4]1[C:5]([CH3:9])=[N:6][C:7]([CH3:8])=[C:2]([C:47]2[CH:46]=[CH:45][C:44]([O:43][CH2:42][CH2:41][C:40]3[CH:39]=[CH:38][C:37]([F:36])=[CH:62][CH:61]=3)=[CH:49][CH:48]=2)[C:3]=1[N:22]1[CH2:27][CH2:26][CH:25]([C:28]2[O:32][N:31]=[C:30]([CH:33]([CH3:35])[CH3:34])[N:29]=2)[CH2:24][CH2:23]1)[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])([CH3:20])([CH3:21])[CH3:19]
Reactant: CN1CC(=O)OB(c2ccc(OCCc3ccc(F)cc3)cc2)OC(=O)C1
Reactant: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)OC(C)C)c(N2CCC(c3nc(C(C)C)no3)CC2)c1Br
Agent: CC(=O)O[Pd]OC(C)=O
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)OC(C)C)c(N2CCC(c3nc(C(C)C)no3)CC2)c1-c1ccc(OCCc2ccc(F)cc2)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 18.4 %

Procedure:
The diacetoxypalladium (6.11 mg, 0.027 mmol) was added to a nitrogen purged and degassed solution of (S)-isopropyl 2-(5-bromo-4-(4-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate (150 mg, 0.272 mmol), 2-(4-(4-fluorophenethoxy)phenyl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione (111 mg, 0.299 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxy-biphenyl (22.30 mg, 0.054 mmol), and potassium phosphate tribasic (432 mg, 2.040 mmol) in dioxane (4.5 mL) and water (0.9 mL) and stirred in a screw-capped pressure vessel for 4 h at 80° C. The reaction was allowed to cool, diluted with EtOAc, and the organic layer was washed with brine and dried (Na2SO4). The crude product was charged (DCM) to a 24 g ISCO silica gel cartridge and gradient elution (5-85% EtOAc/hexanes) using an Isolera chromatography station gave (S)-isopropyl 2-(tert-butoxy)-2-(5-(4-(4-fluorophenethoxy)phenyl)-4-(4-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetate 34.3 mg (18.4%) as a mixture of diastereomers. 1H NMR (500 MHz, DMSO-d6) δ 7.41-7.39 (m, 2H), 7.24-7.22 (m, 1H), 7.17-7.13 (m, 2H), 7.03 (br. s, 2H), 6.96-6.94/6.87-6.86/6.80-6.78 (series m, 1H), 5.98 (br. s, 1H), 4.95 (br. s, 1H), 4.24 (t, J=6.2 Hz, 2H), 3.99-3.96 (m, 1H), 3.08 (t, J=6.2 Hz, 2H), 3.02-2.98 (m, 1H), 2.77-2.70 (m, 1H), 2.64-2.58 (m, 1H), 2.46 (s, 3H), 2.31-2.28 (m, 1H), 2.05 (s, 3H), 2.01-1.99 (m, 1H), 1.92-1.88 (m, 1H), 1.80 (br. s, 1H), 1.62-1.47 (m, 2H), 1.23-1.17 (m, 12H), 1.14 (s, 9H). UPLC (M+H)=687.5.
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([O:15][CH:16]([CH3:18])[CH3:17])=[C:11]([CH:14]=2)[C:12]#[N:13])=[N:4][CH:3]=1.[C:19]([Si:23]([CH3:44])([CH3:43])[O:24][CH:25]1[C:33]2[C:28](=[C:29](B3OC(C)(C)C(C)(C)O3)[CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26]1)([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+]>CC(O)C(O)C.O>[Si:23]([O:24][CH:25]1[C:33]2[C:28](=[C:29]([C:2]3[O:6][C:5]([C:7]4[CH:8]=[CH:9][C:10]([O:15][CH:16]([CH3:18])[CH3:17])=[C:11]([CH:14]=4)[C:12]#[N:13])=[N:4][CH:3]=3)[CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26]1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:44])[CH3:43]
Reactant: CC(C)Oc1ccc(-c2ncc(Br)o2)cc1C#N
Reactant: CC1(C)OB(c2cccc3c2CCC3O[Si](C)(C)C(C)(C)C)OC1(C)C
Agent: CC(O)C(C)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(C)Oc1ccc(-c2ncc(-c3cccc4c3CCC4O[Si](C)(C)C(C)(C)C)o2)cc1C#N
Temperature: 0 °C
Yield: 94 %

Procedure:
Prepared using General Procedure 13. A 20 mL microwave vial was charged with 5-(5-bromooxazol-2-yl)-2-isopropoxybenzonitrile INT-32 (200 mg, 0.65 mmol), tert-butyldimethyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)silane INT-30 (243 mg, 0.65 mmol), potassium carbonate (269 mg, 1.95 mmol) and a 3:1 mixture of dimethylethylene glycol/H2O (10 mL). The reaction mixture was degassed by bubbling N2 gas through the stirring solution for 10 min. Pd(PPh3)4 was added and the solution degassed for additional 2 min. The vial was subjected to microwave irradiation at 100° C. for 40 min. The vial was cooled to 0° C. and the resulting solid obtained was collected by filtration, washed with ice water, and dried to afford 290 mg (94%) of 5-(5-(1-(tert-butyldimethylsilyloxy)-2,3-dihydro-1H-inden-4-yl) oxazol-2-yl)-2-isopropoxybenzonitrile INT-33 as a light yellow solid. LCMS-ESI (m/z) calculated for C28H34N2O3Si: 474.7; found 475.2 [M+H]+, tR=5.90 min (Method 1). 1H NMR (400 MHz, CDCl3) δ 8.16-7.96 (m, 2H), 7.57-7.42 (m, 1H), 7.24-7.12 (m, 3H), 6.90 (t, J=10.4 Hz, 1H), 5.14 (t, J=7.0 Hz, 1H), 4.57 (dt, J=12.3, 6.1 Hz, 1H), 3.04 (ddd, J=16.1, 9.1, 3.1 Hz, 1H), 2.78 (dt, J=16.1, 8.1 Hz, 1H), 2.43-2.24 (m, 1H), 1.84 (ddd, J=15.8, 12.8, 8.9 Hz, 1H), 1.27 (t, J=5.8 Hz, 6H), 0.86-0.61 (m, 9H), 0.06-−0.14 (m, 6H).
Reaction SMILES: FC(F)(F)C(O)=O.[BH4-].[Na+].[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[CH:18](O)[C:19]1[C:20]2[CH:28]=[C:27]([C:29]([O:31][CH3:32])=[O:30])[CH:26]=[CH:25][C:21]=2[O:22][C:23]=1[CH3:24].[OH-].[Na+]>C(Cl)Cl>[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[CH2:18][C:19]1[C:20]2[CH:28]=[C:27]([C:29]([O:31][CH3:32])=[O:30])[CH:26]=[CH:25][C:21]=2[O:22][C:23]=1[CH3:24]
Reactant: COC(=O)c1ccc2oc(C)c(C(O)c3ccc(Cl)cc3Cl)c2c1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc2oc(C)c(Cc3ccc(Cl)cc3Cl)c2c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Trifluoroacetic acid (50 ml) was ice-cooled and sodium borohydride (873 mg, 23.1 mmol) was gradually added over 20 min under a nitrogen atmosphere at 5-7° C. Thereto was dropwise added a solution of 3-((2,4-dichlorophenyl)-hydroxymethyl)-5-(methoxycarbonyl)-2-methylbenzo[b]furan in methylene chloride over 20 min, and the mixture was stirred at room temperature for 45 min. After the completion of the reaction, the reaction mixture was poured into ice water and a 25% aqueous sodium hydroxide solution was added to make an alkali solution. The solution was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The crystalline residue was purified by silica gel column chromatography to give the objective compound (0.58 g, 72% in 2 steps) as colorless crystals.
Reaction SMILES: C[NH:2][C:3](=[O:15])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-])=O)[CH:7]=1.[CH2:16]([SiH](CC)CC)C>CO.[Pd]>[NH2:12][C:8]1[CH:7]=[C:6]([CH2:5][CH:4]([CH3:16])[C:3]([NH2:2])=[O:15])[CH:11]=[CH:10][CH:9]=1
Reactant: CC[SiH](CC)CC
Reactant: CNC(=O)C=Cc1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: CC(Cc1cccc(N)c1)C(N)=O
Yield: 72.3 %

Procedure:
To a stirred solution of N-methyl-3-(3-nitrophenyl)acrylamide (4 g, 19.40 mmol) and Pd—C (10%, 200 mg) in MeOH (30.0 ml) was added triethylsilane (31 ml, 194 mmol) dropwise at room temperature over a period of 1 hr. Reaction progress was monitored by TLC. After completion of reaction, reaction mixture was filtered through celite bed. The filtrate was concentrated under vacuum to give the title compound (2.5 gm).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.Br[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[OH:1][CH:2]1[CH:7]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:23][CH2:24][CH2:25][O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:12][CH:13]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)C(O)C1
Reactant: BrCCCOc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOc3ccccc3)cc2)C(O)C1

Procedure:
Analogously to Method I, 0.750 g of tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate and 0.692 g of (3-bromopropoxy)benzene are reacted. The title compound is obtained as a slightly yellowish oil. Rf=0.24 (1:2 EtOAc-heptane); Rt=5.13.
Reaction SMILES: [CH3:1][N:2]([C@@H:10]([CH2:29][CH:30]([CH3:32])[CH3:31])[CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]2[C:25]3[C:20](=[CH:21][N:22]=[CH:23][CH:24]=3)[C:19](=[O:26])[N:18]([CH3:27])[C:17]=2[CH:28]=1)C(=O)OC(C)(C)C.Cl.CCOCC>ClCCl>[CH3:27][N:18]1[C:17]2[CH:28]=[C:13]([O:12][CH2:11][C@@H:10]([NH:2][CH3:1])[CH2:29][CH:30]([CH3:32])[CH3:31])[CH:14]=[CH:15][C:16]=2[C:25]2[C:20](=[CH:21][N:22]=[CH:23][CH:24]=2)[C:19]1=[O:26]
Reactant: CC(C)C[C@@H](COc1ccc2c3ccncc3c(=O)n(C)c2c1)N(C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CN[C@H](COc1ccc2c3ccncc3c(=O)n(C)c2c1)CC(C)C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 32.1 %

Procedure:
To the solution of (S)-tert-butyl methyl(4-methyl-1-((6-methyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)pentan-2-yl)carbamate (180 mg, 0.078 mmol) in dichloromethane (4 mL) cooled to 0° C. was added HCl in ether (4 mL, 4.00 mmol) slowly over a period of 1 min. The reaction mixture was stirred at 0° C. for 5 min then warmed to room temperature and stirred for 4 h. The volatiles were then removed under reduced pressure. The residue was purified via reverse phase HPLC (0.1% TFA in water:acetonitrile) to afford (S)-6-methyl-8-((4-methyl-2-(methylamino)pentyl)oxy)benzo[c][2,7]naphthyridin-5(6H)-one (15 mg, 0.025 mmol, 32% yield) as a yellow solid. LC/MS (ESI) m/e 340.2, [(M+H)+, calcd for C20H26N3O2, 340.2]; LC/MS retention time (method I): tR=1.6 min. HPLC retention time (method A): tR=7.59 min; HPLC retention time (method B): tR=8.08 min. 1H NMR (400 MHz, METHANOL-d4) δ ppm 9.54 (s, 1H), 8.83 (d, J=5.8 Hz, 1H), 8.53 (d, J=8.8 Hz, 1H), 8.46 (d, J=6.0 Hz, 1H), 7.27-7.16 (m, 2H), 4.57 (dd, J=11.3, 3.0 Hz, 1H), 4.44 (dd, J=11.3, 5.3 Hz, 1H), 3.84 (s, 3H), 3.78-3.68 (m, 1H), 2.84 (s, 3H), 1.95-1.78 (m, 2H), 1.75-1.61 (m, 1H), 1.08 (d, J=6.5 Hz, 6H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:7]2[CH2:16][CH2:17][CH2:18][O:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1.[CH3:30][N:31]1[C:35]([CH3:36])=[C:34](B2OC(C)(C)C(C)(C)O2)[C:33]([CH3:46])=[N:32]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.C(O[Pd]OC(=O)C)(=O)C>[C:20]1([O:19][CH2:18][CH2:17][CH2:16][C:7]2[C:6]3[C:10](=[C:2]([C:34]4[C:33]([CH3:46])=[N:32][N:31]([CH3:30])[C:35]=4[CH3:36])[CH:3]=[CH:4][CH:5]=3)[NH:9][C:8]=2[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)c1[nH]c2c(Br)cccc2c1CCCOc1cccc2ccccc12
Reactant: Cc1nn(C)c(C)c1B1OC(C)(C)C(C)(C)O1
Agent: CC(=O)O[Pd]OC(C)=O
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1[nH]c2c(-c3c(C)nn(C)c3C)cccc2c1CCCOc1cccc2ccccc12
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To a mixture of ethyl 7-bromo-3-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylate (EXAMPLE 1C) (1.605 g) and 1,3,5-trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.838 g) in toluene (25 ml) was added diacetoxypalladium (0.080 g), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (0.291 g), and K3PO4 (2.259 g). The resulting mixture was stirred at 110° C. overnight. Silica gel (25 g) was added and the mixture was carefully dried on house vacumn overnight. The gel powder was loaded onto a flash column and eluted with 0-50% ethyl acetate in dichloromethane to provide the title compound.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8](=[O:20])[CH:9]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:11]2)=[CH:6][CH:5]=1.[CH2:21]([CH:23]1[O:25][CH2:24]1)Cl>O>[O:25]1[CH2:24][CH:23]1[CH2:21][O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8](=[O:20])[CH:9]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:11]2)=[CH:6][CH:5]=1
Reactant: ClCC1CO1
Reactant: O=c1cc(-c2ccccc2)oc2cc(O)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=c1cc(-c2ccccc2)oc2cc(OCC3CO3)ccc12

Procedure:
To a solution of 82.2 g (2.06 mol) of sodium hydroxide in 585 ml of water were added 3.7 liters of issopropanol and then 490 g (2.06 mol) of 7-hydroxyflavone. To the above mixture were then added 1645 ml (20.5 mol) of epichlorohydrin and the mixture was heated at 70° for 2 hr with stirring. The hot reaction mixture was filtered to remove a solid dimeric by-product. The filtrate was concentrated under reduced pressure (water aspirator) at 50° to 60°. The semisolid residue was treated with 4.4 liters of refluxing isopropanol and more of the dimer from the hot mixture. The clear filtrate on cooling yielded a solid. This was filtered, washed with 600 ml of isopropanol and air dried; yield 434.3 g (72%) of a tan-colored product, m.p. 123°-130° (a pure sample of the title compound melts at 133°-135°.)
Reaction SMILES: FC1(C(O)=O)CC[C:5](=[CH:8][C:9]2[C:10]([CH3:50])([CH3:49])[C@H:11]3[C@:24]([CH3:27])([CH2:25][CH:26]=2)[C@@H:23]2[C@:14]([CH3:48])([C@@:15]4([CH3:47])[C@H:20]([CH2:21][CH2:22]2)[C@H:19]2[C@H:28]([C:31]([CH3:33])=[CH2:32])[CH2:29][CH2:30][C@:18]2([NH:34][CH2:35][CH2:36][N:37]2[CH2:42][CH2:41][CH:40]([S:43]([CH3:46])(=[O:45])=[O:44])[CH2:39][CH2:38]2)[CH2:17][CH2:16]4)[CH2:13][CH2:12]3)CC1.[C:54]([O:60][CH3:61])(=[O:59])/[CH:55]=[CH:56]/C=C>>[CH3:47][C@:15]12[C@@:14]3([CH3:48])[C@@H:23]([C@:24]4([CH3:27])[C@@H:11]([CH2:12][CH2:13]3)[C:10]([CH3:50])([CH3:49])[C:9]([CH:8]=[CH:5][CH:56]=[CH:55][C:54]([O:60][CH3:61])=[O:59])=[CH:26][CH2:25]4)[CH2:22][CH2:21][C@@H:20]1[C@H:19]1[C@H:28]([C:31]([CH3:33])=[CH2:32])[CH2:29][CH2:30][C@:18]1([NH:34][CH2:35][CH2:36][N:37]1[CH2:38][CH2:39][CH:40]([S:43]([CH3:46])(=[O:44])=[O:45])[CH2:41][CH2:42]1)[CH2:17][CH2:16]2
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCC(S(C)(=O)=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C=C6CCC(F)(C(=O)O)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: C=C/C=C/C(=O)OC
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCC(S(C)(=O)=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C=CC=CC(=O)OC)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the procedure described in step 1 of the preparation of 1-fluoro-4-(((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(4-(methylsulfonyl)piperidin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)methylene)cyclohexanecarboxylic acid using (1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(4-(methylsulfonyl)piperidin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yltrifluoromethanesulfonate and (E)-methyl penta-2,4-dienoate as the reactants. The crude material was used in next step without purification. MS: m/e 709.5 (M+H)+, 2.55 min (method 5).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:5](=[O:6])[CH2:4][CH:3]1[NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].[BH4-].[Na+]>CO>[OH:6][CH:5]1[CH2:4][CH:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:12])([CH3:11])[CH3:13])[C:2]1([CH3:15])[CH3:1]
Reactant: CC(C)(C)OC(=O)NC1CC(=O)C1(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CC(O)C1(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a solution of tert-butyl (2,2-dimethyl-3-oxocyclobutyl)carbamate (1.0 equiv.) in MeOH (0.1 M) was added sodium borohydride (1.0 equiv.) in small portions at 0° C. After addition, the mixture was stirred at room temperature for 2 h, then the mixture was quenched with acetone. The solvent was removed under vacuum, the residue was passed through a short silica gel column chromatography (40% ethyl acetate in petroleum ether) to afford the crude title product (85% yield), which was used for the next step without further purification. MS (ESI) m/z 216.2 [M+H]+.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:12]([C:13]([OH:15])=[O:14])[C:11]=1[OH:19]>CC#N.O>[Br:1][C:17]1[CH:18]=[C:10]([Cl:9])[C:11]([OH:19])=[C:12]([CH:16]=1)[C:13]([OH:15])=[O:14]
Reactant: O=C(O)c1cccc(Cl)c1O
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: O
Product: O=C(O)c1cc(Br)cc(Cl)c1O
Reaction time: 1 h
Yield: 93.9 %

Procedure:
N-Bromosuccinimide (2.38 g, 13.38 mmol) was added to a solution of 3-chlorosalicylic acid (2.1 g, 12.16 mmol) in CH3CN (10 mL) solution and stirred for 1 h, reaction mixture was diluted with water (25 mL), solids were filtered and washed with water and dried to get 5-Bromo-3-chloro-2-hydroxy-benzoic acid (2.87 g).
Reaction SMILES: CN(C=O)C.[CH2:6]([N:10]1[C:14](=[O:15])[C:13](O)=[C:12]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)[S:11]1(=[O:25])=[O:24])[CH2:7][CH2:8][CH3:9].C(Cl)(=O)C([Cl:29])=O>C(Cl)Cl>[CH2:6]([N:10]1[C:14](=[O:15])[C:13]([Cl:29])=[C:12]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)[S:11]1(=[O:25])=[O:24])[CH2:7][CH2:8][CH3:9]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCN1C(=O)C(O)=C(c2cccc(Cl)c2)S1(=O)=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCN1C(=O)C(Cl)=C(c2cccc(Cl)c2)S1(=O)=O
Yield: 92.7 %

Procedure:
Dry DMF (0.17 mL, 2.21 mmol) was added to a solution of 2-butyl-5-(3-chlorophenyl)-4-hydroxyisothiazol-3(2H)-one 1,1-dioxide (697 mg, 2.21 mmol) in dry DCM (15 mL) at rt and under an atmosphere of nitrogen. Oxalyl chloride (0.37 mL, 4.41 mmol) was added dropwise and the mixture was heated to reflux for 2.5 h. The reaction mixture was evaporated to dryness. The residue was dissolved in EtOAc and it was washed with several portions of water, dried with MgSO4, and evaporated to give the title compound (685 mg, 84%) as a brown oil which was used without further purification; 1H NMR (500 MHz, CDCl3): δ 7.96 (t, 1H), 7.84-7.88 (m, 1H), 7.57-7.61 (m, 1H), 7.50-7.55 (t, 1H), 3.79 (t, 2H), 1.80-1.87 (m, 2H), 1.39-1.51 (m, 2H), 1.00 (t, 3H); 13C NMR (125 MHz, CDCl3): δ 161.5, 155.9, 142.4, 135.8, 132.8, 131.0, 129.0, 127.3, 125.1, 41.0, 30.4, 20.1, 13.7.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:12]=[C:11]([C:13](=[O:32])[NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2/[CH:21]=[CH:22]/[C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[NH:25][N:24]=2)[N:10]([CH3:33])[CH:9]=1)(C)(C)C.[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38]>C(Cl)Cl>[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38].[NH2:7][C:8]1[CH:12]=[C:11]([C:13]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2/[CH:21]=[CH:22]/[C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[NH:25][N:24]=2)=[O:32])[N:10]([CH3:33])[CH:9]=1
Reactant: Cn1cc(NC(=O)OC(C)(C)C)cc1C(=O)Nc1ccccc1/C=C/c1n[nH]c2ccccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1cc(N)cc1C(=O)Nc1ccccc1/C=C/c1n[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 96 %

Procedure:
(E)-(5-{2-[2-(1H-indazol-3-yl)vinyl]phenylcarbamoyl}-1-methyl-1H-pyrrol-3-yl) carbamic acid tert-butyl ester (15 mg, 0.033 mmol) was dissolved in methylene chloride (1.0 mL) and trifluoroacetic acid (100 μL) was added thereto followed by stirring at room temperature for 5 hours. Then, the mixture was concentrated and dried to obtain Compound 76 (11.3 mg, 96%).
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([CH2:12][C:13]([OH:15])=O)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[Cl:17][C:18]1[CH:19]=[C:20]([CH:29]=[CH:30][C:31]=1[Cl:32])[CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23]1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>ClCCl>[Cl:17][C:18]1[CH:19]=[C:20]([CH:29]=[CH:30][C:31]=1[Cl:32])[CH2:21][N:22]1[CH2:23][CH2:24][CH:25]([NH:28][C:13](=[O:15])[CH2:12][C:10]2[NH:9][N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:11]=2)[CH2:26][CH2:27]1
Reactant: NC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Reactant: O=C(O)Cc1nc(-c2ccccc2)n[nH]1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Cc1nc(-c2ccccc2)n[nH]1)NC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Reaction time: 1 h
Yield: 70.9 %

Procedure:
(3-Phenyl-1H-1,2,4-triazol-5-yl)acetic acid (0.020 g) and N,N′-carbonyl diimidazole (0.016 g) in dichloromethane was stirred under nitrogen for 3 minutes. 1-(3,4-Dichlorobenzyl)-4-piperidinamine hydrochloride (0.031 g) and triethylamine (0.036 g) was then added and allowed to stir for 1 hour under nitrogen. Saturated sodium hydrogen carbonate was added to the reaction with the resulting solution being extracted three times with dichloromethane. The pooled organic phases were washed once with water, once with brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to a white solid. This was purified by RPHPLC (75%-5%, 0.1% ammonium acetate/acetonitrile). Saturated sodium hydrogen carbonate was added to the pooled collected fractions with the resulting solution being extracted three times with dichloromethane. The pooled organic phases were washed once with water, once with brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to leave N-[1-(3,4-dichlorobenzyl)-4-piperidinyl]-2-(3-phenyl-1H-1,2,4-triazol-5-yl)acetamide(0.031 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[SH:9].CS(O[CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)(=O)=O.C([O-])([O-])=O.[K+].[K+].O>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: Fc1ccc(S)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(Sc2ccc(F)cc2F)CC1
Temperature: 80 °C
Yield: 100 %

Procedure:
A mixture of 2,4-difluorobenzenethiol (0.810 mL, 7.15 mmol), tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (1.816 g, 6.5 mmol), and K2CO3 (1.348 g, 9.75 mmol) in ACN (16.25 mL) was heated at 80° C. overnight. The reaction mixture was poured into water and extracted twice with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford tert-butyl 4-((2,4-difluorophenyl)thio)piperidine-1-carboxylate (2.141 g) as a yellow oil, which was carried forward without purification.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C:5]1[CH:10]=[C:9]([S:11][CH3:12])[CH:8]=[C:7]([NH2:13])[CH:6]=1.CCN(CC)CC.[Cl:22][CH2:23][CH2:24][CH2:25][C:26](Cl)=[O:27]>C(Cl)Cl.CCOC(C)=O>[CH3:2][O:3][C:4](=[O:14])[C:5]1[CH:10]=[C:9]([S:11][CH3:12])[CH:8]=[C:7]([NH:13][C:26](=[O:27])[CH2:25][CH2:24][CH2:23][Cl:22])[CH:6]=1
Reactant: COC(=O)c1cc(N)cc(SC)c1
Reactant: O=C(Cl)CCCCl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc(NC(=O)CCCCl)cc(SC)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 103.1 %

Procedure:
To a solution of 3-amino-5-methylsulfanyl-benzoic acid methyl ester hydrochloride (D62) (0.13 g, 0.556 mmol, 1 equiv) in dry CH2Cl2 (2 ml) at 0° C. was added NEt3 (193 ml, 1.39 mmol, 2.5 equiv) then 4-chlorobutyryl chloride (69 ml, 0.612 mmol, 1.1 equiv), dropwise, over 2 min. The resulting solution was stirred at 0° C. for 15 min then at room temperature for 30 min. The solution was then diluted with AcOEt, washed sequentially with 2N aqueous HCl solution, saturated aqueous NaHCO3 solution and brine, dried over Na2SO4 and concentrated in vacuo to give 3-(4-chloro-butanoylamino)-5-methylsulfanyl-benzoic acid methyl ester (D64) (173 mg, 103%) as pale yellow crystals. [M+H]+=302.0, RT=3.20 min