Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:18][CH:17]2[CH2:19][CH:10]([C:11]3[CH:12]=[C:13]([NH:21][CH2:22][CH:23]([CH3:25])[CH3:24])[C:14]([NH2:20])=[CH:15][C:16]=32)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.C(Cl)Cl.[CH3:31][CH2:32]O>>[C:1]([O:5][C:6]([N:8]1[CH2:18][CH:17]2[CH2:19][CH:10]([C:11]3[CH:12]=[C:13]4[C:14](=[CH:15][C:16]=32)[N:20]=[C:31]([CH3:32])[N:21]4[CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCO
Reactant: CC(C)CNc1cc2c(cc1N)C1CC2CN(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: CO
Product: Cc1nc2cc3c(cc2n1CC(C)C)C1CC3CN(C(=O)OC(C)(C)C)C1

Procedure:
4-Amino-5-isobutylamino-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene-10-carboxylic acid tert-butyl ester (250 mg, 0.74 mmol) from Example 19B was dissolved in EtOH (10 mL) and HOAC (3 mL) and treated with 1-ethoxyethylenemalononitrile (118 mg, 0.87 mmol). The reaction proceeded as in Example 18C (18 h) and was worked up similarly to provide product (TLC 3% MeOH/CH2Cl2 (NH3) Rf0.57).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11]O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.O=S(Cl)[Cl:15]>C1C=CC=CC=1>[Cl:15][CH2:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:1]=[CH:2][CH:3]=[CH:4]2
Reactant: OCc1ccc2ncccc2c1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: ClCc1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Quinolin-6-yl-methanol (7.7 g, 48 mmol) was dissolved in benzene (3 mL) and SOCl2 (20 mL) was added at 0° C. The mixture was stirred at RT for 1 h, then heated to reflux and stirred an additional 1 h. The mixture was cooled to RT and the solid was filtered to give the 6-chloromethyl-quinoline.
Reaction SMILES: C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O.[C:12]([O:20][C@@H:21]1[C@H:27]([O:28][C:29](=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@@H:26]([O:37][C:38](=[O:45])[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C@H:25]([CH3:46])[O:24][CH:22]1[OH:23])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CCOCC>C(Cl)Cl>[C:12]([O:20][C@@H:21]1[C@H:27]([O:28][C:29](=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@@H:26]([O:37][C:38](=[O:45])[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C@H:25]([CH3:46])[O:24][C:22]1=[O:23])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C[C@@H]1OC(O)[C@H](OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: C[C@@H]1OC(=O)[C@H](OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.9 %

Procedure:
PCC (30 g, 0.139 mmol) and well-dried 4 Å molecular shives (25 g) are added into a flask under N2 current. Dry CH2Cl2 (250 ml) is added to the flask and the flask is stirred for 1 hour at a room temperature and cooled to 0° C. The compound (VI) (16 g, 33.6 mmol) dissolved in dry CH2Cl2 (250 ml) is added to and stirred 4 hours at a room temperature. The reaction is finished with adding cool Et2O (200 ml) and filtered by silica gel. The solvent is vacuum concentrated, and then the compound (VII) (13.54 g, 85%) is isolated using flash column chromatography (toluene/EtOAc, 10:1, v/v).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[O:9][C:4]=2[CH:3]=1.[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([F:25])[C:23]=1F)[CH:19]=[O:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:11][C:8]1([CH3:10])[O:7][C:6](=[O:12])[C:5]2[CH:13]=[CH:14][C:2]([O:1][C:23]3[C:16]([F:15])=[CH:17][C:18]([CH:19]=[O:20])=[CH:21][C:22]=3[F:25])=[CH:3][C:4]=2[O:9]1
Reactant: O=Cc1cc(F)c(F)c(F)c1
Reactant: CC1(C)OC(=O)c2ccc(O)cc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)OC(=O)c2ccc(Oc3c(F)cc(C=O)cc3F)cc2O1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
7-Hydroxy-2,2-dimethyl-benzo[1,3]dioxin-4-one (I-1a: 12.9 g) and 3,4,5-trifluorobenzaldehyde (5.0 g) and potassium carbonate (27.6 g) were combined in dimethylformamide (100 mL) and stirred as the reaction mixture was heated to 80° C. After 24 hours, the reaction mixture was cooled to ambient temperature, combined with water, and extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered, and evaporated. The residue was purified by column chromatography on silica gel eluting with 5-10% ethyl acetate in heptane to give the title compound (I-1b-2).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([Br:15])[C:9]=1[CH:16]=[N:17][NH:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([OH:24])=[O:23].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C=O)C>[Br:7][C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([Br:15])[C:9]=1[CH:16]=[N:17][NH:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([O:24][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:23]
Reactant: Cc1cc(Br)c(C=NNc2cccc(C(=O)O)c2)c(Br)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Br)c(C=NNc2cccc(C(=O)OCc3ccccc3)c2)c(Br)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 103.5 %

Procedure:
Potassium carbonate (7.41 g, 53.61 mmol) was added to a solution of 3-{2-[(2,6-dibromo-4-methylphenyl)methylidene]hydrazino}benzoic acid (19.4 g, 44.65 mmol) in dry DMF (200 mL). Benzyl bromide (5.42 mL, 45.6 mmol) was then added and the mixture stirred at room temperature for 15 hours and then partitioned between ethyl acetate (500 mL) and water (500 mL). The organic phase was separated, combined with a second ethyl acetate extract (300 mL), washed successively with water (4×500 mL) and brine (300 mL), dried over anhydrous sodium sulphate, evaporated and further dried under vacuum to give the title compound (23.2 g).
Reaction SMILES: CC([Mg]Cl)C.Br[C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([S:16]([F:21])([F:20])([F:19])([F:18])[F:17])[CH:15]=1)[C:10]([OH:12])=[O:11].CN([CH:25]=[O:26])C.Cl>C(OCC)C.C1COCC1>[CH:25]([C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([S:16]([F:21])([F:20])([F:19])([F:18])[F:17])[CH:15]=1)[C:10]([OH:12])=[O:11])=[O:26]
Reactant: CN(C)C=O
Reactant: O=C(O)c1cc(Br)cc(S(F)(F)(F)(F)F)c1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=Cc1cc(C(=O)O)cc(S(F)(F)(F)(F)F)c1

Procedure:
With ice bath cooling, 11.5 ml (23 mmol) of a 2 M solution of 2-propylmagnesium chloride in diethyl ether were added dropwise to a solution of 3.0 g (9.17 mmol) of the compound of Example 15A in 1.6 ml of abs. THF. After the addition had ended, stirring was continued without cooling for another 30 min 1.76 ml (22.9 mmol) of DMF were added with ice bath cooling, and the mixture was stirred without cooling for a further 30 min. 20 ml of 1 M hydrochloric acid were then added, and the mixture was extracted with 100 ml of ethyl acetate. The organic phase was washed with 1 M hydrochloric acid and saturated sodium chloride solution, dried over sodium sulphate, filtered and concentrated to dryness on a rotary evaporator. The residue was suspended in 50 ml of dichloromethane/pentane (1:1) and the solid was filtered off and dried. Any contaminations present were removed by preparative HPLC (Method 22). This gave 780 mg (31% of theory) of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([F:15])=[CH:13][C:12]([CH:16]2[CH2:18][CH:17]2[C:19]([OH:21])=[O:20])=[CH:11][C:10]=1[F:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23](C1COC(=O)N1)C1C=CC=CC=1>C1COCC1>[CH3:23][O:20][C:19]([CH:17]1[CH2:18][CH:16]1[C:12]1[CH:11]=[C:10]([F:22])[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:14]([F:15])[CH:13]=1)=[O:21]
Reactant: O=C(O)C1CC1c1cc(F)c(OCc2ccccc2)c(F)c1
Reactant: O=C1NC(Cc2ccccc2)CO1
Solvent: C1CCOC1
Product: COC(=O)C1CC1c1cc(F)c(OCc2ccccc2)c(F)c1
Yield: 75 %

Procedure:
Mixture (41 mg) of 2-(4-benzyloxy-3,5-difluoro-phenyl)-cyclopropane carboxylic acid obtained in Step A and 4-benzyloxazolidine-2-on was dissolved in THF (2 mL), and CH2N2 (0.25M in Et2O, 1 mL, 0.158 mmol) was added thereto. The mixture was reacted at room temperature for 1 hour, and then the reactant was concentrated under reduced pressure. The residue was purified by column chromatography (eluent, EtOAc/Hex=1/2) to obtain the title compound (22.7 mg, two-step yield 75%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][N:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[N:26]=[C:25]1[CH2:33][NH:34][CH2:35][CH2:36][CH:37]([CH3:39])[CH3:38]>ClCCl>[Cl:1][C:2]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:3]=1[C:4]([N:34]([CH2:33][C:25]1[N:24]([CH2:23][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[O:16][CH3:15])[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[N:26]=1)[CH2:35][CH2:36][CH:37]([CH3:39])[CH3:38])=[O:5]
Reactant: COc1ccccc1Cn1c(CNCCC(C)C)nc2ccccc21
Reactant: COc1ccc(C(=O)Cl)c(Cl)c1OC
Solvent: ClCCl
Product: COc1ccccc1Cn1c(CN(CCC(C)C)C(=O)c2ccc(OC)c(OC)c2Cl)nc2ccccc21
Yield: 95 %

Procedure:
A solution of 5.4 mmole 1-{[2-(chloromethyl)-benzimidazolyl]methyl}-2-methoxybenzene in 20 mL of dryacetonitrile is treated with 10 mL of isoamylamine for 16 hours at room temperature. The solvent is removed in vacuo and the residue is partitioned between 30 mL of ethyl acetate and 10 mL of 1 N NaOH. The ethyl acetate layer is dried over anhydrous Na2SO4 and solvent removed in vacuo to afford 1.7 g 97% ({1-[(2-methoxyphenyl)methyl]benzimidazol-2-yl}methyl)(3-methylbutyl) amine. 2-Chloro-3,4-dimethoxybenzoylchloride (1.5 equ.) is treated with 1.0 equivalent of ({1-[(2-methoxyphenyl)methyl]benzimidazol-2-yl}methyl)(3-methylbutyl) amine in dichloromethane at room temperature for 1 hour. The reaction is quenched with 1 N NaOH and partitioned between dichloromethane and water. The organic layer is dried with Na2SO4 and the solvent removed in vacuo. The residue is chromatographed (SiO2) with ethyl acetate to afford 95% of (2-chloro-3,4-dimethoxyphenyl)-N-({1-[(2-methoxyphenyl)methyl]benzimidazol-2-yl}methyl)-N-(3-methylbutyl)carboxamide (Compound 1). Mass Spec M+ 537.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][C:12]1[NH:16][C:15]([C:17]2[C:21]([NH:22][C:23](=[O:32])[C:24]3[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=3[F:31])=[CH:20][N:19](C3CCCCO3)[N:18]=2)=[N:14][C:13]=1C(O)=O)=O)(C)(C)C.C1(OC)C=CC=CC=1.C1(C)C=CC=CC=1.[C:57]([OH:63])(C(F)(F)F)=[O:58]>>[NH2:8][CH2:9][CH2:10][CH2:11][C:12]1[NH:16][C:15]([C:17]2[C:21]([NH:22][C:23](=[O:32])[C:24]3[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=3[F:31])=[CH:20][NH:19][N:18]=2)([C:57]([OH:63])=[O:58])[NH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)NCCCc1[nH]c(-c2nn(C3CCCCO3)cc2NC(=O)c2c(F)cccc2F)nc1C(=O)O
Reactant: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: Cc1ccccc1
Product: NCCCC1=CNC(C(=O)O)(c2n[nH]cc2NC(=O)c2c(F)cccc2F)N1
Yield: 99 %

Procedure:
A solution of 5-(tert-butoxycarbonylamino-propyl)-2-[4-(2,6-difluoro benzoylamino)-1-(tetrahydro-pyran-2-yl)-1H-pyrazol-3-yl]-1H-imidazole-4-carboxylic acid (300 mg, 0.52 mmoles) and anisole (114 μl, 1.04 mmoles) in TFA (3 ml) was heated at 100° C. (80 W) in a CEM discover microwave synthesizer for 10 minutes. Toluene (10 ml) was added and the solvent removed in vacuo to give 5-(3-amino-propyl)-2-[4-(2,6-difluoro-benzoylamino)-1H-pyrazol-3-yl]-1H-imidazole carboxylic acid as a yellow/brown solid (200 mg, 99%). (LC/MS: Rt 1.58, {M+H]+ 391.00).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][NH:11][C:12]([N:14]([CH2:18][CH2:19]O)[CH2:15][CH2:16]O)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:23])=O>ClCCl>[CH2:1]([O:8][CH2:9][CH2:10][N:11]1[CH2:19][CH2:18][N:14]([CH2:15][CH2:16][Cl:23])[C:12]1=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NCCOCc1ccccc1)N(CCO)CCO
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C1N(CCCl)CCN1CCOCc1ccccc1

Procedure:
To 3-benzyloxypropionic acid (129.6 g) in ether (310 ml) and N,N-dimethylformamide (4 ml) was added thionyl chloride (155 ml). The solution was refluxed for 2 hours, and solvents and excess thionyl chloride were removed by evaporation in vacuo. Yield 132 g of 3-Benzyloxypropionic acid chloride as an oil. To an ice cooled solution of the thus prepared acid chloride (132 g) in acetone (450 ml) was added a cold solution of sodium azide (48.5 g) in water (200 ml) at 5° C. After additional stirring at 5° C. for 30 minutes, the mixture was poured into water and toluene, and the aqueous phase was extracted twice with toluene. The combined organic phases were washed with brine. After drying (magnesium sulfate) the solution was heated slowly to 85° C. on a steam bath until evolution of nitrogen ceased. The solvent was removed in vacuo leaving 108.4 g of 2-benzyloxyethylisocyanate as an oil. A mixture of 2-benzyloxy-ethylisocyanate (10 g) and diethanolamine (5.72 g) in dichloromethane (60 ml) was refluxed for 2.5 hours. After cooling to room temperature, the solution was washed with brine. Drying (magnesium sulfate) and evaporation of the solvent yielded 11.4 g of N-(2-benzyloxyethyl)-N',N'-di-(2-hydroxyethyl)-urea as an oil. A solution of the urea derivative (11.4 g) in dichloromethane (55 ml) was cooled to 5° C., and thionyl chloride (8.3 ml) was added at a temperature below 10° C. After the addition the mixture was refluxed for 1 hour and then left over night at room temperature. The solution was washed with cold sodium hydrogen carbonate solution and saturated sodium chloride solution, dried over magnesium sulfate and evaporated in vacuo. The residue was dissolved in 1,1,1-trichloroethane and refluxed for 3 hours. After cooling the solution was washed with sodium hydrogen carbonate solution, dried over magnesium sulfate and evaporated in vacuo, yielding 6.6 g of the title compound 22a as an oil.
Reaction SMILES: [CH3:1][C:2](=[N:4][OH:5])[CH3:3].CC(C)([O-])C.[K+].[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH:27]([O:31][CH2:32][CH3:33])[O:28][CH2:29][CH3:30])=[O:20])=[C:15](F)[CH:14]=1>O1CCCC1.O>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH:27]([O:28][CH2:29][CH3:30])[O:31][CH2:32][CH3:33])=[O:20])=[C:17]([O:5][N:4]=[C:2]([CH3:3])[CH3:1])[CH:18]=1
Reactant: CC(C)=NO
Reactant: CCOC(OCC)c1ccccc1C(=O)c1ccc(Br)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(OCC)c1ccccc1C(=O)c1ccc(Br)cc1ON=C(C)C
Temperature: 20 °C
Reaction time: 0.33 h
Yield: 96 %

Procedure:
To a mechanically stirred solution of acetone oxime (20.33 g) in tetrahydrofuran (500 mL) under nitrogen was added a solution of 1M potassium tert-butoxide in tetrahydrofuran (325 mL) while cooling in an ice water bath. The thick white suspension was stirred at 20° C. for 20 min then a solution of (4-bromo-2-fluorophenyl)(2-(diethoxymethyl)phenyl)methanone (Compound 2a) (118 g) in tetrahydrofuran (400 mL) was added over 20 min and the resulting pale orange suspension stirred at room temperature for 1 h then refluxed for 2 h. The reaction mixture was diluted with water (680 mL) and extracted into ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate and evaporated to give the title compound (116 g).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30]C(=O)C)[C@@H:22]([O:23]C(=O)C)[C@H:17]([O:18]C(=O)C)[C@H:12]1[O:13]C(=O)C.[O:34]1[CH:38]=[CH:37][C:36]2[CH:39]=[C:40]([C:43](Cl)=O)[CH:41]=[CH:42][C:35]1=2>>[O:34]1[CH:38]=[CH:37][C:36]2[CH:39]=[C:40]([CH2:43][C:4]3[C:3]4[C:7](=[CH:8][CH:9]=[CH:10][C:2]=4[Br:1])[N:6]([C@@H:11]4[O:28][C@H:27]([CH2:29][OH:30])[C@@H:22]([OH:23])[C@H:17]([OH:18])[C@H:12]4[OH:13])[CH:5]=3)[CH:41]=[CH:42][C:35]1=2
Reactant: O=C(Cl)c1ccc2occc2c1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ccc3c(Br)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: OC[C@H]1O[C@@H](n2cc(Cc3ccc4occc4c3)c3c(Br)cccc32)[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
The titled compound was prepared from 4-bromo-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)indole obtained in Example 22-(1) and benzo[b]furan-5-carbonyl chloride in a manner similar to Example 27 as a colorless powder. APCI-Mass m/Z 488/490 (M+H). 1H-NMR (DMSO-d6) δ 3.23 (td, J=9.1, 5.5 Hz, 1H), 3.37-3.47 (m, 3H), 3.61-3.69 (m, 2H), 4.39 (s, 2H), 4.53 (t, J=5.5 Hz, 1H), 5.09 (d, J=5.3 Hz, 1H), 5.15 (d, J=5.0 Hz, 1H), 5.22 (d, J=5.9 Hz, 1H), 5.40 (d, J=9.2 Hz, 1H), 6.87 (d, J=1.4 Hz, 1H), 7.04 (t, J=7.9 Hz, 1H), 7.21 (m, 2H), 7.25 (s, 1H), 7.43 (s, 1H), 7.49 (d, J=8.5 Hz, 1H), 7.60 (d, J=8.2 Hz, 1H), 7.93 (d, J=2.1 Hz, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:45])[C:3](=[O:44])[CH2:4][NH:5][C@:6]12[CH2:40][CH2:39][C@@H:38]([C:41]([CH3:43])=[CH2:42])[C@@H:7]1[C@@H:8]1[C@@:21]([CH3:24])([CH2:22][CH2:23]2)[C@@:20]2([CH3:25])[C@@H:11]([C@:12]3([CH3:37])[C@@H:17]([CH2:18][CH2:19]2)[C:16]([CH3:27])([CH3:26])[C:15]([C:28]2[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=2)=[CH:14][CH2:13]3)[CH2:10][CH2:9]1.Cl[CH2:47][C:48](N1CCCC1)=O>>[CH3:24][C@:21]12[C@@:20]3([CH3:25])[C@@H:11]([C@:12]4([CH3:37])[C@@H:17]([CH2:18][CH2:19]3)[C:16]([CH3:27])([CH3:26])[C:15]([C:28]3[CH:29]=[CH:30][C:31]([C:32]([OH:34])=[O:33])=[CH:35][CH:36]=3)=[CH:14][CH2:13]4)[CH2:10][CH2:9][C@@H:8]1[C@H:7]1[C@H:38]([C:41]([CH3:43])=[CH2:42])[CH2:39][CH2:40][C@:6]1([NH:5][CH2:4][C:3](=[O:44])[N:2]1[CH2:1][CH2:48][CH2:47][CH2:45]1)[CH2:23][CH2:22]2
Reactant: C=C(C)[C@@H]1CC[C@]2(NCC(=O)N(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
Reactant: O=C(CCl)N1CCCC1
Product: C=C(C)[C@@H]1CC[C@]2(NCC(=O)N3CCCC3)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

Procedure:
The title compound was prepared following the method described above for the synthesis of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(dimethylamino)-2-oxoethylamino)-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 using 2-chloro-1-(pyrrolidin-1-yl)ethanone as the alkylating reagent in Step 1. The product was isolated as a white solid (19 mg, 46%). LCMS: m/e 641.46 (M+H)+, 2.55 min (method 10). 1H NMR (500 MHz, Acetic acid d4) δ ppm 8.04 (d, J=8.24 Hz, 2H), 7.30 (d, J=8.24 Hz, 2H), 5.38 (d, J=4.58 Hz, 1H), 4.89 (s, 1H), 4.76 (s, 1H), 4.43 (d, J=16.48 Hz, 1H), 3.99 (d, J=16.17 Hz, 1H), 3.73-3.42 (m, 4H), 3.15-2.86 (m, 1H), 2.41-1.19 (m, 26H), 1.79 (s, 3H), 1.28 (s, 3H), 1.14 (s, 3H), 1.10 (s, 3H), 1.03 (s, 3H), 1.00 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:40])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[N:14]([CH2:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][O:29][CH2:30][C:31]5[CH:36]=[CH:35][CH:34]=[C:33]([N+:37]([O-])=O)[CH:32]=5)=[CH:22][CH:21]=4)[CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1>CCOC(C)=O.CCO.O=[Pt]=O>[NH2:37][C:33]1[CH:32]=[C:31]([CH:36]=[CH:35][CH:34]=1)[CH2:30][O:29][CH2:28][CH2:27][O:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][CH2:18][N:14]2[CH2:13][C@@H:12]([C:10]3[CH:9]=[CH:8][C:6]4[O:7][C:2]([CH3:40])([CH3:1])[O:3][CH2:4][C:5]=4[CH:11]=3)[O:16][C:15]2=[O:17])=[CH:25][CH:24]=1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCc4ccc(OCCOCc5cccc([N+](=O)[O-])c5)cc4)C(=O)O3)ccc2O1
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC1(C)OCc2cc([C@@H]3CN(CCc4ccc(OCCOCc5cccc(N)c5)cc4)C(=O)O3)ccc2O1
Reaction time: 3 h
Yield: 86.2 %

Procedure:
(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-3-[2-(4-{2-[(3-nitrobenzyl)oxy]ethoxy}phenyl)ethyl]-1,3-oxazolidin-2-one (1.22 g) in EtOAc (20 mL) and EtOH (15 mL) was hydrogenated over PtO2 (122 mg) at room temperature and atmospheric pressure for 3 h. The catalyst was then removed by filtration over Celite, washed with EtOAc and concentrated in vacuo to give the title compound (994 mg). LCMS RT=3.23 min.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:15][CH:14]3[NH:16][CH:11]([CH2:12][CH2:13]3)[CH2:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[F:24][C:25]([F:39])([F:38])[C:26]([NH:28][CH2:29][CH2:30][CH2:31][CH2:32]OS(C)(=O)=O)=[O:27]>O1CCCC1.C(=O)(O)[O-].[Na+]>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:10][CH:11]3[N:16]([CH2:32][CH2:31][CH2:30][CH2:29][NH:28][C:26](=[O:27])[C:25]([F:24])([F:38])[F:39])[CH:14]([CH2:13][CH2:12]3)[CH2:15]2)=[CH:5][CH:4]=1
Reactant: Clc1ccc(N2CC3CCC(C2)N3)cc1
Reactant: CS(=O)(=O)OCCCCNC(=O)C(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NCCCCN1C2CCC1CN(c1ccc(Cl)cc1)C2)C(F)(F)F
Yield: 39 %

Procedure:
3-(4-Chloro-phenyl)-3,8-diaza-bicyclo[3.2.1] octane hydrochloride salt (1.5 g, 5.79 mmol), triethylamine (1.77 mL, 12.73 mmol) and methanesulfonic acid 4-(2,2,2-trifluoro-acetylamino)-butyl ester (2.29 g, 8.68 mmol) were combined in tetrahydrofuran (25 mL). The resulting white heterogeneous reaction was heated at reflux for 24 hours. The mixture was cooled diluted with saturated sodium bicarbonate (200 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (200 mL), dried with magnesium sulfate and concentrated to a light brown oil. Silica gel flash chromatography using 5% methanol/ chloroform as eluent yielded N-{4-[3-(4-Chloro-phenyl)-3,8-diaza-bicyclo[3.2.1]oct-8-yl]-butyl}-2,2,2-trifluoro-acetamide (0.88 9, 39%) as an off-white solid which had the following properties: Mp. 83-85° C., 1H NMR CDCl3 δ: 7.77 (brd s, 1H), 7.16 (d, J=9.1 Hz, 2H), 6.68 (d, J=9.1 Hz, 2H), 3.44-3.35 (m, 4H), 3.29 (d, J=9.6 Hz, 2H), 3.02 (d, J=9.6 Hz, 2H), 2.51 (t, J=6.2 Hz, 2H), 2.10-1.90 (m, 2H), 1.83-1.76 (m, 2H), 1.73-1.57 (m, 6H).
Reaction SMILES: [CH3:1][C:2]([CH3:56])([CH2:10][C:11]([O:13][C@H:14]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@@H:16]([CH2:17][CH2:18][C@:19]3([CH3:53])[C@@H:28]2[CH2:27][CH2:26][C@H:25]2[C@@:20]3([CH3:52])[CH2:21][CH2:22][C@@:23]3(/[CH:40]=[CH:41]/[C:42]([NH:44][CH2:45][CH:46]4[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]4)=[O:43])[CH2:35][C:34](=[O:36])[C:33]([CH:37]([CH3:39])[CH3:38])=[C:24]32)[C:15]1([CH3:55])[CH3:54])=[O:12])[C:3]([O:5]C(C)(C)C)=[O:4].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:46]1([CH2:45][NH:44][C:42](=[O:43])/[CH:41]=[CH:40]/[C@:23]23[CH2:35][C:34](=[O:36])[C:33]([CH:37]([CH3:38])[CH3:39])=[C:24]2[C@@H:25]2[C@@:20]([CH3:52])([CH2:21][CH2:22]3)[C@@:19]3([CH3:53])[C@@H:28]([C@:29]4([CH3:32])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:54])([CH3:55])[C@@H:14]([O:13][C:11](=[O:12])[CH2:10][C:2]([CH3:1])([CH3:56])[C:3]([OH:5])=[O:4])[CH2:31][CH2:30]4)[CH2:27][CH2:26]2)[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1
Reactant: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)OC(C)(C)C)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(/C=C/C(=O)NCC2CCCCC2)CC1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(/C=C/C(=O)NCC2CCCCC2)CC1=O
Temperature: 30 °C
Reaction time: 2 h
Yield: 29.6 %

Procedure:
To a solution of 1-tert-butyl 4-((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((E)-3-((cyclohexylmethyl)amino)-3-oxoprop-1-en-1-yl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) 2,2-dimethylsuccinate (200 mg, 0.258 mmol) in DCM (10 mL) stirred at room temp was added TFA (5 mL, 64.9 mmol). The reaction mixture was stirred at 30° C. for 2 h. The product was evaporated to dryness and then diluted with 200 mL DCM. The organic phase was washed with saturated NaHCO3, water and brine. The organics were dried and concentrated under reduced pressure to afford crude product, which was purified by preparative-HPLC to afford the title compound (55 mg, 29%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ=12.18 (br. s., 1H), 7.93 (t, J=5.8 Hz, 1H), 6.60 (d, J=15.8 Hz, 1H), 5.89 (d, J=15.8 Hz, 1H), 4.39 (dd, J=4.6, 11.2 Hz, 1H), 3.27-3.12 (m, 1H), 3.03-2.87 (m, 2H), 2.73 (dd, J=3.5, 11.8 Hz, 1H), 2.24-1.99 (m, 3H), 1.96-0.70 (m, 57H); LC/MS: m/z calculated 719.5. Found 720.5 (M+1)+.