Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[CH:25][CH:24]=[CH:23]2)([F:19])[C:3]([N:5]1[N:6]=[C:7]([C:13]2[CH:14]=[N:15][N:16]([CH3:18])[CH:17]=2)[CH:8]=[CH:9]/[C:10]/1=[N:11]\[NH2:12])=O.COCC(O)C.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>O>[F:1][C:2]([F:19])([C:3]1[N:5]2[N:6]=[C:7]([C:13]3[CH:14]=[N:15][N:16]([CH3:18])[CH:17]=3)[CH:8]=[CH:9][C:10]2=[N:11][N:12]=1)[C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[CH:25][CH:24]=[CH:23]2
Reactant: Cn1cc(-c2cc/c(=N\N)n(C(=O)C(F)(F)c3ccc4ncccc4c3)n2)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: COCC(C)O
Product: Cn1cc(-c2ccc3nnc(C(F)(F)c4ccc5ncccc5c4)n3n2)cn1
Temperature: 105 °C
Reaction time: 1 h

Procedure:
The crude 6-{1,1-difluoro-2-[(6E)-6-hydrazono-3-(1-methyl-1H-pyrazol-4-yl)pyridazin-1(6H)-yl]-2-oxoethyl}quinoline from step 3 above (3.67 mmol) was brought in a reaction balloon under argon. 36 mL of 1-methoxy-2-propanol was added and the mixture was stirred at 105° C. for 1 h. Then the reaction mixture was brought to gentle reflux for one additional hour (108° C.). The reaction mixture was allowed to cool to room temperature and poured out in a solution of 10 g of sodium carbonate in 100 mL of water. 100 mL toluene was added and the layers were separated. The water layer was extracted with toluene (100 mL). The combined organic layers were washed with water and evaporated, yielding 700 mg of compound (I) (1.86 mmol; 51%).
Reaction SMILES: [CH2:1]([N:8]([CH:12]1[CH2:14][CH2:13]1)[C:9]([Cl:11])=[O:10])[C:2]1[CH:7]=[CH:6]C=[CH:4][CH:3]=1.C1(NCC2CC[O:23]CC2)CC1.C(NCC1CC1)C1C=CC=CC=1>C(Cl)Cl.CO>[CH:12]1([N:8]([CH2:1][CH:2]2[CH2:7][CH2:6][O:23][CH2:4][CH2:3]2)[C:9]([Cl:11])=[O:10])[CH2:14][CH2:13]1
Reactant: C1CC(CNC2CC2)CCO1
Reactant: O=C(Cl)N(Cc1ccccc1)C1CC1
Agent: c1ccc(CNCC2CC2)cc1
Solvent: CO
Solvent: ClCCl
Product: O=C(Cl)N(CC1CCOCC1)C1CC1

Procedure:
The title compound is prepared analogously as described for benzyl-cyclopropyl-carbamoyl chloride starting from cyclopropyl-(tetrahydro-pyran-4-ylmethyl)-amine (prepared analogously as described for benzyl-cyclopropylmethyl-amine). TLC, Rf (CH2Cl2/MeOH 95:5)=0.9.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[N:14]=[C:13](/[CH:15]=[C:16]3/[C:17](=[O:22])[NH:18][C:19](=[O:21])[NH:20]/3)[CH:12]=[CH:11][N:10]=2)[CH2:5][CH2:4]1.[S:23]1[CH:27]=[CH:26][C:25]([C:28]2[N:33]=[C:32]([CH:34]=O)[CH:31]=[CH:30][CH:29]=2)=[CH:24]1.C(N(C(C)C)CC)(C)C.[Na]>C(Cl)Cl.CS(C)=O>[S:23]1[CH:27]=[CH:26][C:25]([C:28]2[N:33]=[C:32]([CH2:34][NH:1][CH2:2][CH:3]3[CH2:4][CH2:5][N:6]([C:9]4[N:14]=[C:13](/[CH:15]=[C:16]5/[C:17](=[O:22])[NH:18][C:19](=[O:21])[NH:20]/5)[CH:12]=[CH:11][N:10]=4)[CH2:7][CH2:8]3)[CH:31]=[CH:30][CH:29]=2)=[CH:24]1
Reactant: NCC1CCN(c2nccc(/C=C3\NC(=O)NC3=O)n2)CC1
Reactant: O=Cc1cccc(-c2ccsc2)n1
Agent: [Na]
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C1NC(=O)/C(=C/c2ccnc(N3CCC(CNCc4cccc(-c5ccsc5)n4)CC3)n2)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.8 %

Procedure:
A 2 dram round bottomed vial was charged with (Z)-5-((2-(4-(aminomethyl)piperidin-1-yl)pyrimidin-4-yl)methylene)imidazolidine-2,4-dione (17 mg, 0.056 mmol), 6-(thiophen-3-yl)picolinaldehyde (10.64 mg, 0.056 mmol, 1 equiv.), diisopropylethylamine (0.1 mL, 0.573 mmol, 10 equiv.), and DMSO (1 mL). The reaction mixture was shaken for 1 h at room temperature then treated with sodium triacetoxyhydroborate (23.83 mg, 0.112 mmol, 2 equiv.) and DCM (0.5 mL). The reaction mixture was shaken overnight. The sample was then filtered through a 0.45 micron syringe filter. The DMSO solution was purified using reverse phase HPLC (MS-triggered fraction collection) with an acetonitrile/water gradient and trifluoroacetic acid as the modifier. The pure fractions were then concentrated under reduced pressure (Genevac HT-4) to provide the desired product (9.8 mg, 26.7 mg theoretical, 36%). LC-MS m/z 476 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:34])[C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([NH:11][C:12]2[C:16]3[CH:17]=[C:18]([N+:21]([O-])=O)[CH:19]=[CH:20][C:15]=3[O:14][C:13]=2[C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][N:28]=2)=[O:25])=[O:10])[CH2:5][CH2:4]1.[Sn](Cl)Cl.O.[OH-].[Na+]>C(O)C.O1CCCC1>[NH2:21][C:18]1[CH:19]=[CH:20][C:15]2[O:14][C:13]([C:24]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][N:28]=3)=[O:25])=[C:12]([NH:11][C:9]([C@H:6]3[CH2:7][CH2:8][C@H:3]([N:2]([CH3:1])[CH3:34])[CH2:4][CH2:5]3)=[O:10])[C:16]=2[CH:17]=1
Reactant: CN(C)[C@H]1CC[C@H](C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3ccc([N+](=O)[O-])cc23)CC1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CN(C)[C@H]1CC[C@H](C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3ccc(N)cc23)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trans-3-[4-(dimethylamino)cyclohexylcarbonylamino]-5-nitro-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (3.00 g) obtained in Example 18 is suspended in ethanol (100 ml), and thereto are added tin(II) chloride (anhydrous) (7.02 g) and water (1.0 ml). The mixture is heated under reflux for 7 hours, and allowed to stand for cooling. To the reaction solution are added 10% aqueous sodium hydroxide solution (30 ml) and tetrahydrofuran (200 ml), and the mixture is stirred at room temperature for one hour. The insoluble materials are filtered on celite, and the filtrate is concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/1, then chloroform/ethyl acetate=1/1). The resulting residue is suspended in ethyl acetate/n-hexane, and the precipitates are collected by filtration and dried to give trans-5-amino-3-[4-(dimethylamino)cyclohexylcarbonylamino]-N-(5-chloropyridin-2-yl)-benzofuran-2-carboxamide (1.43 g). This product (35 mg) is dissolved in ethanol, and treated with 4N hydrogen chloride/ethyl acetate to give the title compound (43 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=2[Cl:19])=O)[C:5]([Cl:8])=[N:6][CH:7]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:21]>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:9]([Cl:21])=[N:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=2[Cl:19])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: O=C(Nc1cccc(Cl)c1Cl)c1cc(Br)cnc1Cl
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: ClC(=Nc1cccc(Cl)c1Cl)c1cc(Br)cnc1Cl
Reaction time: 1.5 h
Yield: 96.7 %

Procedure:
To a slurry of 5-bromo-2-chloro-N-(2,3-dichlorophenyl)pyridine-3-carboxamide (0.75 g, 1.97 mmol) in benzene was added phosphorous pentachloride (0.5 g, 2.365 mmol) and the mixture heated to reflux. After 1.5 hours, the resulting solution was concentrated to provide 0.76 g of N-((5-bromo-2-chloropyridin-3-yl)chloromethylene)-2,3-dichlorobenzenamine as an off white solid. This material was used directly in the next reaction as is.
Reaction SMILES: Cl[CH:2]([CH3:30])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]3[CH:16]=[CH:17][C:18]([C:20]([NH:22][CH2:23][C:24]4[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=4)=[O:21])=[CH:19][C:14]=3[N:13]=[CH:12]2)=[CH:7][CH:6]=1.[F:31][C:32]([F:42])([F:41])[O:33][C:34]1[CH:35]=[C:36]([OH:40])[CH:37]=[CH:38][CH:39]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>C(#N)C.O>[N:26]1[CH:27]=[CH:28][CH:29]=[C:24]([CH2:23][NH:22][C:20]([C:18]2[CH:17]=[CH:16][C:15]3[N:11]([C:8]4[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][CH2:30][O:40][C:36]5[CH:37]=[CH:38][CH:39]=[C:34]([O:33][C:32]([F:31])([F:41])[F:42])[CH:35]=5)=[CH:6][CH:7]=4)[CH:12]=[N:13][C:14]=3[CH:19]=2)=[O:21])[CH:25]=1
Reactant: CC(Cl)COc1ccc(-n2cnc3cc(C(=O)NCc4cccnc4)ccc32)cc1
Reactant: Oc1cccc(OC(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: CN(C)C=O
Product: O=C(NCc1cccnc1)c1ccc2c(c1)ncn2-c1ccc(OCCCOc2cccc(OC(F)(F)F)c2)cc1

Procedure:
1-[4-(2-Chloropropoxy)phenyl]-N-pyridin-3-ylmethyl-1H-benzimidazole-5-carboxamide (prepared as described above using 1-(4-hydroxyphenyl)-N-pyridin-3-ylmethyl-1H-benzimidazole-5-carboxamide as phenol and 1-bromo-3-chloropropane as alkylating agent) (100 mg, 0.24 mmol), 3-trifluoromethoxyphenol (42 mg, 31 μL 0.24 mmol) and potassium carbonate (36 mg, 0.26 mmol) were suspended in acetonitrile (2 mL), DMF (1 mL), and water (0.5 mL) and the mixture stirred at 60° C. for 18 h. The reaction mixture was then concentrated in vacuo and purified by reverse-phase preparative HPLC to give N-pyridin-3-ylmethyl-1-(4-{3-[3-(trifluoromethoxy) phenoxy]propoxy}phenyl)-1H-benzimidazole-5-carboxamide. 1H NMR (CDCl3, 400 MHz): δ 8.66 (d, J=2.0 Hz, 1H), 8.56 (dd, J=4.8, 1.2 Hz, 1H), 8.34 (d, J=1.6 Hz, 1H), 8.05 (s, 1H), 7.90 (dd, J=8.4, 1.6 Hz, 1H), 7.78 (ddd, J=8.0, 2.0, 2.0 Hz, 1H), 7.48 (d, J=8.0 Hz, 1H), 7.43-7.37 (m, 2H), 7.34-7.28 (m, 2H), 7.20-7.08 (m, 3H), 6.90-6.78 (m, 3H), 4.75 (d, J=5.6 Hz, 2H), 4.27 (t, J=6.0 Hz, 2H), 4.22 (t, J=6.0 Hz, 2H), 2.35 (quin, J=6.0 Hz, 2H); MS (ES+): m/z 563 [MH+]
Reaction SMILES: I[C:2]1C=CC(O)=CC=1.C(=O)([O-])[O-].[K+].[K+].[I:15][C:16]1[CH:32]=[CH:31][C:19]([O:20][CH:21]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH3:22])=[CH:18][CH:17]=1>CN(C=O)C>[I:15][C:16]1[CH:32]=[CH:31][C:19]([O:20][CH:21]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:2])[CH3:22])=[CH:18][CH:17]=1
Reactant: Oc1ccc(I)cc1
Reactant: CCCCCCCCC(C)Oc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCC(C)Oc1ccc(I)cc1
Temperature: 84 °C
Reaction time: 13 h
Yield: 31 %

Procedure:
The above product (31.3 g, 136.7 mmol) was reacted with 4-iodophenol (30.1 g, 136.8 mmol), and potassium carbonate (18.9 g, 136.7 mmol) in DMF (270 ml) at 80° C. as for 2-(4-iodophenoxy)decane. After stirring for 13 hrs, the reaction was analyzed by 1H NMR indicating that the reaction was about 66% complete. The temperature of the oil was increased 84° C. After an additional 34 hrs, 1H NMR spectral analysis indicated that the reaction was complete. The reaction was processed as for 2-(4-iodophenoxy)-decane except at 2 times the volume to give a light yellow oil. This product was further purified by flash column chromatography (silica, hexanes) to give 2-(4-iodophenoxy)-undecane (16.1 g, 31%) as a clear oil.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:9]1[CH:11]([CH:12]([OH:23])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:10]1>O1CCOCC1>[CH2:1]([NH:8][CH2:10][CH:11]([OH:9])[CH:12]([OH:23])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCCCCCC(O)C1CO1
Reactant: NCc1ccccc1
Solvent: C1COCCO1
Product: CCCCCCCCCCC(O)C(O)CNCc1ccccc1
Reaction time: 12 h
Yield: 71.8 %

Procedure:
A 500-ml flask equipped with a stirrer was charged with 107 g (1 mol) of benzylamine, to which a solution of 5.2 g (71 mmol) of 1,2-epoxy-3-tridecanol in 170 ml of dioxane was added dropwise over 2 hours. After completion of the dropping, a reaction was conducted further for 12 hours at 80° C. Dioxane and excess benzylamine were distilled off under reduced pressure. The resultant residue was recrystallized from hexane, thereby obtaining 16.4 g (yield: 72%) of the title compound (IIh-1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:17])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[C:18]([C:22]1[CH:23]=[C:24]([CH2:33][CH2:34][C:35](O)=[O:36])[CH:25]=[C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])[C:27]=1[OH:28])([CH3:21])([CH3:20])[CH3:19].C1(C)C(C)=CC=CC=1>CCCC[O-].CCCC[O-].CCCC[O-].CCCC[O-].[Ti+4].O>[C:29]([C:26]1[CH:25]=[C:24]([CH2:33][CH2:34][C:35]([O:1][CH2:2][CH2:3][NH:4][C:5](=[O:17])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:36])[CH:23]=[C:22]([C:18]([CH3:20])([CH3:19])[CH3:21])[C:27]=1[OH:28])([CH3:32])([CH3:30])[CH3:31]
Reactant: CCCCCCCCCCCC(=O)NCCO
Reactant: CC(C)(C)c1cc(CCC(=O)O)cc(C(C)(C)C)c1O
Agent: [Ti+4]
Agent: CCCC[O-]
Solvent: Cc1ccccc1C
Solvent: O
Product: CCCCCCCCCCCC(=O)NCCOC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: -10 °C

Procedure:
A mixture of 13.9 g (0.055 mole) N-(2-hydroxyethyl)lauramide, 13.9 g (0.05 mole) 3(3,5-di-tert-butyl-4-hydroxyphenyl)propionic acid, 0.5 g Tyzor TBT catalyst and 100 ml xylene was refluxed until evolution of water ceased (3 hours). The xylene was removed by vacuum stripping. The residue was taken up in acetonitrile. White crystals separated upon cooling at about -10° C. The acetonitrile was decanted and the recrystallization was repeated. The last traces of acetonitrile were removed under vacuum, and the title product thus obtained was a yellow oil at room temperature.
Reaction SMILES: [CH3:1][C:2]1=[C:3]([CH3:9])[C:4]([O:6][C:7]1=O)=[O:5].[F:10][C:11]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:12]=1[NH2:13].O>CN(C)C1C=CN=CC=1.CC1C=CC=CC=1C>[F:10][C:11]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:12]=1[N:13]1[C:7](=[O:6])[C:2]([CH3:1])=[C:3]([CH3:9])[C:4]1=[O:5]
Reactant: Nc1ccc(Cl)cc1F
Reactant: CC1=C(C)C(=O)OC1=O
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1C
Solvent: O
Product: CC1=C(C)C(=O)N(c2ccc(Cl)cc2F)C1=O

Procedure:
A mixture of 126 g (1.0 mol) of dimethylmaleic anhydride, 145.5 g (1.0 mol) of 2-fluoro-4-chloroaniline and 2 g of 4-dimethylaminopyridine is heated under reflux in 800 ml of o-xylene for 16 hours using a water separator. The whole is then evaporated to dryness in vacuo and the residue is dissolved in a 1:1 mixture of ethyl acetate:ether and washed with each of 1N hydrochloric acid, 1N sodium hydroxide solution and water. Afer drying over sodium sulphate and evaporating off the solvent, the residue (227.5 g) is recrystallised from methanol. In this manner there are obtained 211.1 g (84% of the theoretical yield) of the title product in the form of colourless crystals which melt at 96°-97°.
Reaction SMILES: Cl.[OH:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][C:4]=1[O:11][CH3:12].[OH2:13].[C:14](=[O:17])([O-])O.[Na+].Cl>O1CCOCC1>[OH:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:8][C:14](=[O:17])[CH2:7][C:6]2[CH:9]=[CH:10][C:3]([OH:13])=[C:4]([OH:11])[CH:5]=2)=[CH:5][C:4]=1[O:11][CH3:12]
Reactant: O=C([O-])O
Reactant: COc1cc(CN)ccc1O
Reactant: O
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1cc(CNC(=O)Cc2ccc(O)c(O)c2)ccc1O
Temperature: 80 °C
Reaction time: 1 h

Procedure:
N-Succinimidyl 3,4-bis(methoxycarbonyloxy)-phenylacetate (500 mg, 1.76 mmol) and 4-hydroxy-3-methoxybenzylamine hydrochloride were dissolved in 20 ml of 1,4-dioxane and 20 ml of water under nitrogen, and sodium hydrogencarbonate (148 mg, 1.76 mmol) was added. The mixture was heated at 80° C. for 2 h, treated with further sodium hydrogen carbonate (325 mg, 3.87 mmol), stirred for a further 1 h at 80° C. and left to cool. The orange-red mixture was acidified using hydrochloric acid (5%) and extracted with ethyl acetate. The organic phase was washed with saturated NaCl solution, dried over Na2SO4 and filtered, and the filtrate was evaporated under reduced pressure. The residue was purified by chromatography on silica gel using the eluent ethyl acetate. Yield of N-(4-hydroxy-3-methoxybenzyl)-3,4-dihydroxyphenylacetamide 340 mg (63% of theory).
Reaction SMILES: [NH2:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.CN(C)CCC(N[C@]12CC[C@@H](C(C)=C)[C@@H]1[C@@H]1[C@@](C)(CC2)[C@@]2(C)[C@@H]([C@]3(C)[C@@H](CC2)C(C)(C)C(C2C=CC(C(O)=O)=CC=2)=CC3)CC1)=O.[CH:87]1([NH:93][C:94](=[O:98])[C:95](O)=[O:96])[CH2:92][CH2:91][CH2:90][CH2:89][CH2:88]1>>[CH:87]1([NH:93][C:94](=[O:98])[C:95]([NH:1][C@:2]23[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]2[C@@H:4]2[C@@:17]([CH3:20])([CH2:18][CH2:19]3)[C@@:16]3([CH3:21])[C@@H:7]([C@:8]4([CH3:34])[C@@H:13]([CH2:14][CH2:15]3)[C:12]([CH3:22])([CH3:23])[C:11]([C:24]3[CH:33]=[CH:32][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=3)=[CH:10][CH2:9]4)[CH2:6][CH2:5]2)=[O:96])[CH2:92][CH2:91][CH2:90][CH2:89][CH2:88]1
Reactant: O=C(O)C(=O)NC1CCCCC1
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: C=C(C)[C@@H]1CC[C@]2(NC(=O)CCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NC(=O)C(=O)NC3CCCCC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 40 %

Procedure:
The title compound was prepared in 40% yield from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-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)benzoate following the same procedure as described for the preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-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)benzoic acid, except 2-(cyclohexylamino)-2-oxoacetic acid was used instead of 3-(dimethylamino)propionic acid hydrochloride in Step 1. LCMS: m/e 681.7 (M−H)−, 2.42 min (method 9). 1H NMR (500 MHz, CHLOROFORM-d) δ=8.03 (d, J=8.5 Hz, 2H), 7.61 (s, 1H), 7.52 (d, J=8.5 Hz, 1H), 7.25 (d, J=8.2 Hz, 2H), 6.51 (br. s., 1H), 5.33 (d, J=4.6 Hz, 1H), 4.79 (d, J=1.2 Hz, 1H), 4.67 (s, 1H), 3.83-3.72 (m, 1H), 2.62-2.54 (m, 2H), 2.50 (dd, J=8.5, 11.6 Hz, 1H), 2.14 (dd, J=6.3, 17.2 Hz, 1H), 2.00-1.89 (m, 3H), 1.86-1.75 (m, 4H), 1.71-1.62 (m, 2H), 1.61-1.36 (m, 13H), 1.35-1.20 (m, 5H), 1.18-1.11 (m, 2H), 1.08 (s, 3H), 1.05-1.02 (m, 3H), 1.00 (s, 3H), 0.96 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH2:9](Br)[CH:10]=[CH2:11].C(=O)([O-])[O-].[K+].[K+].CC(C)=O>O>[CH2:11]([O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH:10]=[CH2:9]
Reactant: C=CCBr
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: C=CCOc1ccc(F)cc1
Temperature: 25 °C

Procedure:
A mixture of 336.3 parts of 4-fluorophenol, 417.5 parts of allyl bromide, 420 parts of potassium carbonate and 480 parts of acetone is stirred and refluxed for 8 hours. After cooling to room temperature, 2250 parts of water are added. The aqueous layer is separated and extracted twice with ether. The combined extracts are washed successively twice with sodium hydroxide solution 10% and twice with sodium chloride solution, dried over potassium carbonate, filtered and evaporated. The oily residue is distilled in vacuo, yielding 381.8 parts of 4-allyloxy-fluorobenzene; bp. 93° C at 23 mm. pressure; nD20 : 1.4950; d2020 : 1.070.
Reaction SMILES: [F:1][C:2]1([F:18])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[C:5]([CH:14]([CH3:16])[CH3:15])(O)[CH:4]([OH:17])[CH2:3]1.C1COCC1.[Si](OC1CC(F)(F)C2C(=CC=C(F)C=2)C1=O)(C(C)(C)C)(C)C.F>N1C=CC=CC=1>[F:18][C:2]1([F:1])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[C@H:5]([CH:14]([CH3:16])[CH3:15])[C:4](=[O:17])[CH2:3]1
Reactant: CC(C)C1(O)c2ccc(F)cc2C(F)(F)CC1O
Agent: CC(C)(C)[Si](C)(C)OC1CC(F)(F)c2cc(F)ccc2C1=O
Agent: F
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(C)[C@@H]1C(=O)CC(F)(F)c2cc(F)ccc21
Temperature: 25 °C
Yield: 69 %

Procedure:
4,4,6-Trifluoro-1-isopropyl-1,2,3,4-tetrahydronaphthalene-1,2-diol (62): A THF solution (8 mL) of 2-((tert-butyldimethylsilyl)oxy)-4,4,6-trifluoro-3,4-dihydronaphthalen-1(2H)-one 54 (0.585 g, 1.77 mmol) was cooled to 0° C. and a solution of hydrogen fluoride in pyridine (70%, 200 μL) was added dropwise. The reaction was allowed to warm to ambient temperature over 12 h at which point the reaction was quenched with an aqueous solution of saturated sodium bicarbonate, volatiles were removed and the mixture was re-dissolved in ethyl acetate. The aqueous phase was extracted with ethyl acetate (3×), dried over sodium sulfate, filtered and concentrated to give an orange oil. The desired product, 4,4,6-trifluoro-2-hydroxy-3,4-dihydronaphthalen-1(2H)-one, was purified with a gradient heptanes/ethyl acetate eluent system on silica gel by a ISCO companion system to give the desired product as a colorless oil (0.263 g, 1.22 mmol, 69% yield). 1H NMR (400 MHz, CDCl3) δ: 8.14 (dd, J=8, 4 Hz, 1H), 7.48 (dt, J=8, 4 Hz, 1H), 7.36 (m, 1H), 4.67 (ddd, J=12, 8, 4 Hz, 1H), 3.66 (s, 1H), 3.17 (m, 1H), 2.54 (m, 1H).
Reaction SMILES: C[Mg]Cl.[CH3:4][C:5]([OH:8])([CH3:7])[CH3:6].[Cl:9][C:10]1[N:15]=[N:14]C(C(OC)=O)=[CH:12][CH:11]=1.Cl>CC1OCCC1.CCOC(C)=O.C1(C)C=CC=CC=1>[Cl:9][C:10]1[N:15]=[N:14][C:4]([C:5]([OH:8])([CH3:7])[CH3:6])=[CH:12][CH:11]=1
Reactant: CC(C)(C)O
Reactant: COC(=O)c1ccc(Cl)nn1
Agent: C[Mg]Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC1CCCO1
Solvent: Cc1ccccc1
Product: CC(C)(O)c1ccc(Cl)nn1
Temperature: -20 °C

Procedure:
To a solution of MeTHF (2.5 mL) and toluene (10 mL) was added MeMgCl (3.0 M, 9.7 mL) and stirred at −20° C. under N2 atmosphere followed by the addition of t-BuOH (0.5 mL, 5.79 mmol) in MeTHF (7 mL) dropwise. The solution was allowed to stir for 30 min and warmed to 3° C. and cooled backed down to −20° C. followed by the addition of the methyl 6-chloropyridazine-3-carboxylate (1.0 g, 5.79 mmol) in portions. The solution quickly turned dark violet and stirred at 0° C. for 30 min. The solution was then poured into a flask containing 1 N HCl at −5° C. and diluted with EtOAc followed by stirring for 10 min. The layers were separated and the organic layers were washed with sat. NaHCO3 and brine. The acidic aqueous layer was neutralized with sat. NaHCO3 and extracted with EtOAc. The organic layers were combined and concentrated under rotary evaporation. Column chromatography Hex to 100% EtOAc provided the title compound.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[C:25]([O:29][C:30]([NH:32][C:33]1([C:48](O)=[O:49])[CH2:38][CH2:37][N:36]([C:39]2[C:40]3[CH:47]=[CH:46][NH:45][C:41]=3[N:42]=[CH:43][N:44]=2)[CH2:35][CH2:34]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C(N(C(C)C)C(C)C)C.[Cl:60][C:61]1[CH:66]=[CH:65][C:64]([CH:67]([NH2:72])[CH2:68][CH2:69][O:70][CH3:71])=[CH:63][CH:62]=1>CN1C(=O)CCC1.CCOC(C)=O>[Cl:60][C:61]1[CH:62]=[CH:63][C:64]([CH:67]([NH:72][C:48]([C:33]2([NH:32][C:30](=[O:31])[O:29][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:34][CH2:35][N:36]([C:39]3[C:40]4[CH:47]=[CH:46][NH:45][C:41]=4[N:42]=[CH:43][N:44]=3)[CH2:37][CH2:38]2)=[O:49])[CH2:68][CH2:69][O:70][CH3:71])=[CH:65][CH:66]=1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
Reactant: COCCC(N)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCC(NC(=O)C1(NC(=O)OC(C)(C)C)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 68.4 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (55.2 mg, 0.15 mmol) was added to 4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 1) (50 mg, 0.14 mmol) and N-ethyldiisopropylamine (0.029 mL, 0.17 mmol) in NMP (5 mL). The resulting solution was stirred at 50° C. for 10 minutes then cooled to ambient temperature. 1-(4-Chlorophenyl)-3-methoxypropan-1-amine (Intermediate 100) (27.6 mg, 0.14 mmol) was added as a solution in NMP (2 mL). The resulting mixture was stirred at 22° C. for 16 hours. The reaction mixture was diluted with EtOAc (75 mL) and washed sequentially with water (6×75 mL), and saturated brine (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 1 to 4% (10:1 MeOH/conc. NH3 (aq)) in DCM. Pure fractions were evaporated to dryness to afford tert-butyl 4-(1-(4-chlorophenyl)-3-methoxypropylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (52.0 mg, 69.2%) as a white solid.