Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[C:7]([F:9])([F:8])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:10][C:11]1[N:16]=[C:15](Cl)[C:14]2[C:18](=[O:32])[N:19]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=3[O:30][CH3:31])[CH2:20][C:13]=2[C:12]=1[F:33].[CH3:34][N:35]1[CH:39]=[C:38](B2OC(C)(C)C(C)(C)O2)[CH:37]=[N:36]1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC>[NH2:1][C@H:2]1[C:7]([F:9])([F:8])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:10][C:11]1[N:16]=[C:15]([C:38]2[CH:37]=[N:36][N:35]([CH3:34])[CH:39]=2)[C:14]2[C:18](=[O:32])[N:19]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=3[O:30][CH3:31])[CH2:20][C:13]=2[C:12]=1[F:33]
Reactant: COc1ccc(CN2Cc3c(F)c(N[C@@H]4CCCC(F)(F)[C@@H]4N)nc(Cl)c3C2=O)c(OC)c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: COCCOC
Product: COc1ccc(CN2Cc3c(F)c(N[C@@H]4CCCC(F)(F)[C@@H]4N)nc(-c4cnn(C)c4)c3C2=O)c(OC)c1
Temperature: 80 °C

Procedure:
A microwave vial was charged with 6-(cis-2-amino-3,3-difluorocyclohexylamino)-4-chloro-2-(2,4-dimethoxybenzyl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one (13.7 mg, 0.028 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (8.82 mg, 0.042 mmol) and bis(triphenylphosphine)palladium chloride (3.97 mg, 5.65 μmol) and placed under an inert environment. DME (283 μL) was added to the mixture and the resulting yellow slurry was degassed for 5 min. Sodium carbonate was added (56.5 μL, 0.113 mmol) and the slurry degassed for an additional 3 min. The vessel was capped and the mixture was heated at 80° C. for 4 h, cooled to ambient temperature, diluted with EtOAc (5 mL), and washed with water (3 mL) and brine (3 mL). The organic layer was collected, dried over sodium sulfate, and concentrated to give the title compound as a dark brown residue which was used in the next step without further purification (21 mg). [M+H] calc'd for C26H29F3N6O3, 531. found, 531.
Reaction SMILES: [C:1]1([CH:7]([OH:17])[CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:19][CH2:20][CH2:21][Cl:22].[H-].[Na+].C1(C)C=CC=CC=1>O>[Cl:22][CH2:21][CH2:20][CH2:19][O:17][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: ClCCCBr
Reactant: OC(CCCc1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: ClCCCOC(CCCc1ccccc1)c1ccccc1

Procedure:
A mixture of 30 g of 1,4-diphenyl-1-butanol, 42 g of 1-bromo-3-chloropropane, 9.5 g of sodium hydride (65%) and 400 ml of toluene was heated under refluxing for 2 hours. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 1-(3-chloropropoxy)-1,4-diphenylbutane.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12](O)=[O:13])=[CH:9][CH:10]=2)[N:5]=[C:4]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:3]12.C1(C)C=CC=CC=1.[F:28][C:29]1[CH:39]=[CH:38][C:32](/[C:33](=[N:36]\[H])/[NH:34]O)=[CH:31][CH:30]=1>O=S(Cl)Cl.N1C=CC=CC=1>[F:28][C:29]1[CH:39]=[CH:38][C:32]([C:33]2[N:36]=[C:12]([C:8]3[CH:7]=[C:6]4[C:11]([C:2](=[O:1])[N:3]5[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:4]5=[N:5]4)=[CH:10][CH:9]=3)[O:13][N:34]=2)=[CH:31][CH:30]=1
Reactant: O=C(O)c1ccc2c(=O)n3c(nc2c1)CCCCCC3
Reactant: [H]/N=C(/NO)c1ccc(F)cc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: O=c1c2ccc(-c3nc(-c4ccc(F)cc4)no3)cc2nc2n1CCCCCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 11.9 %

Procedure:
A solution of 13-oxo-7,8,9,10,11,13-hexahydro-6H-azocino[2,1-b]quinazoline-3-carboxylic acid (75 mg, 0.28 mmol) in SOCl2 (3 mL) was stirred at reflux for 0.5 h. The excess SOCl2 was removed and the residue was diluted with toluene (5 mL). The toluene solution was added dropwise to a solution of (E)-4-fluoro-N-hydroxybenzimidamide (51 mg, 0.33 mmol) in pyridine (2 mL). After stirring at room temperature for 0.5 h, the mixture was heated and kept at 60° C. overnight. The reaction mixture was concentrated and then diluted with water (25 mL). The aqueous mixture was extracted with ethyl acetate (2×25 mL). The combined organic layers were washed with brine and dried over Na2SO4. After concentration, the crude product was purified by column chromatography to give the desired product (13 mg). MS (ESI): 391 (MH+); 1H NMR (300 MHz, CDCl3) δ 8.52 (s, 1H), 8.45-8.42 (d, J=7.68 Hz, 1H), 8.25-8.18 (m, 3H), 7.23-7.20 (t, J=7.8 Hz, 2H), 4.38 (broad, 2H), 3.11-3.09 (m, 2H), 2.03 (broad, 2H), 1.94 (broad, 2H), 1.64 (broad, 2H), 1.48 (broad, 2H).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[F:9][CH:10]([F:17])[C:11]1[CH:15]=[CH:14][N:13]([CH3:16])[N:12]=1.FC(F)C1N(C)N=CC=1.O>CN(C)C=O>[Cl:1][C:15]1[C:11]([CH:10]([F:17])[F:9])=[N:12][N:13]([CH3:16])[CH:14]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cn1ccc(C(F)F)n1
Agent: Cn1nccc1C(F)F
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(Cl)c(C(F)F)n1
Temperature: 60 °C
Reaction time: 12 h
Yield: 88 %

Procedure:
At 0-5° C., a solution of N-chlorosuccinimide (NCS, 12.6 g, 0.09 mol) in dimethyl-formamide (DMF, 70 ml) was added dropwise to a solution of 3-difluoromethyl-N-methylpyrazole (14.9 g, 0.09 mol, 83.7% pure according to GC analysis) comprising, as minor component, 4.1% of 5-difluoromethyl-N-methylpyrazole, based on the total amount of the isomer mixture, in DMF (30 ml). The reaction mixture was then heated at 60° C. and stirred for a further 12 h. With stirring, the reaction mixture was then poured into water (1000 ml) and extracted twice with methyl tert-butyl ether (MTBE, 150 ml). The organic phases were combined, washed with a saturated aqueous solution of NaCl, dried over magnesium sulfate, filtered and then freed from the solvent under reduced pressure. 4-Chloro-3-difluoromethyl-N-methylpyrazole was obtained as an oil (17.6 g; purity: 78.4% according to GC analysis) comprising 3.7% of unreacted 5-difluoromethyl-N-methylpyrazole. This corresponds to a yield of 88%.
Reaction SMILES: [NH2:1][C:2](=[N:28][N+:29]([O-:31])=[O:30])[NH:3][CH2:4][CH2:5][CH2:6][C@H:7]([C:16]([NH:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)=[O:17])[NH:8]C(OC(C)(C)C)=O.[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35]>ClCCl>[NH2:1][C:2](=[N:28][N+:29]([O-:31])=[O:30])[NH:3][CH2:4][CH2:5][CH2:6][C@H:7]([C:16]([NH:18][CH2:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([OH:27])=[CH:25][CH:26]=1)=[O:17])[NH2:8].[F:32][C:33]([F:38])([F:37])[C:34]([O-:36])=[O:35]
Reactant: CC(C)(C)OC(=O)N[C@H](CCCNC(N)=N[N+](=O)[O-])C(=O)NCCc1ccc(O)cc1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=N[N+](=O)[O-])NCCC[C@@H](N)C(=O)NCCc1ccc(O)cc1
Product: O=C([O-])C(F)(F)F
Reaction time: 4 h

Procedure:
To a solution of 0.8 g (1.82 mMol) of (R)-N5 -[amino(nitroimino) methyl]-N2 -(tert.-butoxycarbonyl)-N-[2-(4-hydroxyphenyl)ethyl]-ornithinamide in 20 ml of dichloromethane, externally cooled with crushed ice/ethanol, were added 2.5 ml of trifluoroacetic acid, then the mixture was allowed to come up to ambient temperature and stirred for a further 4 hours at this temperature. The clear solution obtained was evaporated down in a water jet vacuum and combined twice with 10 ml of water and once with 10 ml of toluene and then dried once more. The amorphous (R)-N5 -[amino (nitroimino)-methyl]-N-[2-(4-hydroxyphenyl) ethyl]-ornithinamide-trifluoroacetate obtained (0.61 g, 74% of theory), Rf 0.33 (test conditions as in Example 5d) was further processed without any more purification.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][O:10][CH2:11][CH2:12][N:13]1[CH:21]=[N:20][C:19]2[C:18](=[O:22])[NH:17][C:16]([NH2:23])=[N:15][C:14]1=2)([O:6]CC)=[O:5])[CH3:2].Cl>[OH-].[Na+]>[CH2:1]([O:3][P:4]([CH2:9][O:10][CH2:11][CH2:12][N:13]1[CH:21]=[N:20][C:19]2[C:18](=[O:22])[NH:17][C:16]([NH2:23])=[N:15][C:14]1=2)([OH:6])=[O:5])[CH3:2]
Reactant: CCOP(=O)(COCCn1cnc2c(=O)[nH]c(N)nc21)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCOP(=O)(O)COCCn1cnc2c(=O)[nH]c(N)nc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
9-(2-(diethylphosphonomethoxy)ethyl)guanine (0.198 g, 0.57 mmol) was dissolved in 15 mL of 1N sodium hydroxide solution and the mixture was stirred at room temperature for 1 hour. The solution was then acidified with 10% aqueous hydrochloric acid to pH 1 and concentrated in vacuo. Residual salts were removed by reverse phase column chromatography (C18 adsorbent, elution with water) to provide 0.150 g of 9-(2-(ethylphosphonomethoxy)ethyl)guanine as a white crystalline solid, mp=192.5°-193.5° C.
Reaction SMILES: [C:1]1([CH:7]([CH3:19])[CH2:8][NH:9][C:10]([C:12]2[N:13]=[N:14][C:15](Cl)=[CH:16][CH:17]=2)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:20]1([C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:37])([F:36])[F:35])=[O:27])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[C:1]1([CH:7]([CH3:19])[CH2:8][NH:9][C:10]([C:12]2[N:13]=[N:14][C:15]([N:23]3[CH2:24][CH2:25][N:20]([C:26](=[O:27])[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]([F:37])([F:35])[F:36])[CH2:21][CH2:22]3)=[CH:16][CH:17]=2)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Reactant: CC(CNC(=O)c1ccc(Cl)nn1)c1ccccc1
Product: CC(CNC(=O)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1)c1ccccc1

Procedure:
Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid (2-phenylpropyl)amide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(2-trifluoromethylphenyl)methanone, the title compound was obtained as a white powder (63.2% yield). 1H NMR (500 MHz, CDCl3) δ 7.97, 7.80, 7.68, 7.57, 7.50, 7.30, 7.24, 7.20-7.12, 6.92, 3.98, 3.80, 3.74-3.60, 3.53, 3.28, 3.00, 1.28.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=3)[C:13]([CH2:25][CH2:26][OH:27])=[N:12][C:11]=2[CH:28]([CH3:30])[CH3:29])[CH:5]=[C:6]([Cl:8])[CH:7]=1>C(OCC)(=O)C.[Pt]>[NH2:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][N:14]2[C:10]([S:9][C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)=[C:11]([CH:28]([CH3:30])[CH3:29])[N:12]=[C:13]2[CH2:25][CH2:26][OH:27])=[CH:17][CH:18]=1
Reactant: CC(C)c1nc(CCO)n(Cc2ccc([N+](=O)[O-])cc2)c1Sc1cc(Cl)cc(Cl)c1
Agent: [Pt]
Solvent: CCOC(C)=O
Product: CC(C)c1nc(CCO)n(Cc2ccc(N)cc2)c1Sc1cc(Cl)cc(Cl)c1

Procedure:
In 10 ml of ethyl acetate was dissolved 124 mg (0.26 mmol) of the nitrobenzyl compound (126a), and 120 mg of platinum sulfided carbon was added at room temperature. H2 gas was introduced for 7 hours under stirring, and the mixture was worked up. The reaction mixture was filtered through Celite under reduced pressure, and the filtrate was distilled off. The residue was purified by silica gel column chromatography (ethyl acetate), the resulting oil was treated with ether for crystallization to give Compound I-139 (yield 33%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH2:15][NH2:16])=[C:9]([N:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]3=[O:23])[C:8]=2[CH:24]=1)([O-:3])=[O:2].C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34].O>ClCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:13])([CH3:14])[C:10]([CH2:15][NH:16][S:33]([CH3:32])(=[O:35])=[O:34])=[C:9]([N:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]3=[O:23])[C:8]=2[CH:24]=1)([O-:3])=[O:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)Oc2ccc([N+](=O)[O-])cc2C(n2ccccc2=O)=C1CN
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC1(C)Oc2ccc([N+](=O)[O-])cc2C(n2ccccc2=O)=C1CNS(C)(=O)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 56.5 %

Procedure:
To a solution of 6-nitro-2,2-dimethyl-3-aminomethyl-4-(2-oxo-1,2-dihydropyridin-1-yl)-2H-1-benzopyran (0.43 g, 1.31 mmol) and triethylamine (0.22 ml, 1.58 mmol) in dichloromethane (15 ml) was added methanesulfonylchloride (0.12 ml, 1.55 mol). The solution was stirred at room temperature for four hours, and then water was added. The organic phase was separated and evaporated under reduced pressure. The residue was washed with diethyl ether, affording 0.3 g of 6-nitro-2,2-dimethyl-3-(methanesulfonamido)methyl-4-(2-oxo-1,2-dihydropyridin-1-yl)-2H-1-benzopyran, m.p. 195° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.Cl.[N:16]1([CH2:22][CH2:23][C:24]2[N:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]3=[C:26]([C:33](Cl)=[O:34])[N:25]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>C(Cl)Cl>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:33]([C:26]2[N:25]=[C:24]([CH2:23][CH2:22][N:16]3[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)[N:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=23)=[O:34])[CH:3]=1
Reactant: Nc1cccnc1
Reactant: O=C(Cl)c1nc(CCN2CCOCC2)n2ccccc12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1cccnc1)c1nc(CCN2CCOCC2)n2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.6 %

Procedure:
To a solution of 3-aminopyridine (0.051 g, 0.54 mmol) and triethylamine (0.16 mL, 1.14 mmol) in CH2Cl2 (10 mL) was added 3-(2-morpholin-4-yl-ethyl)-imidazo[1,5-a]pyridine-1-carbonyl chloride hydrochloride (150 mg, 0.45 mmol). The mixture was stirred at ambient temperature for 1 h then washed with sat. aq. NaHCO3 (20 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane (20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica to yield the title compound (50 mg, 32%). 1H NMR (DMSO-d6) δ 10.05 (1H), 9.05 (1H), 8.45 (1H), 8.28 (2H), 8.15 (1H), 7.35 (1H), 7.20 (1H), 6.94 (1H), 3.58 (4H), 3.26 (2H), 2.80 (2H), 2.45 (4H); m/z (M+H)=352.17.
Reaction SMILES: [F:1][C:2]1([F:26])[CH2:8][N:7]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][C:10]=2[N+:15]([O-])=O)[CH2:6][CH2:5][CH:4]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:3]1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:15][C:10]1[CH:11]=[N:12][N:13]([CH3:14])[C:9]=1[N:7]1[CH2:8][C:2]([F:26])([F:1])[CH2:3][CH:4]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])[CH2:5][CH2:6]1
Reactant: Cn1ncc([N+](=O)[O-])c1N1CCC(NC(=O)OC(C)(C)C)CC(F)(F)C1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Cn1ncc(N)c1N1CCC(NC(=O)OC(C)(C)C)CC(F)(F)C1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
To a solution of tert-butyl 6,6-difluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-ylcarbamate (2.5 g, 6.67 mmol) in ethanol (100 mL) and water (10 mL) was added ammonium chloride (3.5 g, 65.0 mmol) and iron powder (3.0 g, 53.7 mmol). The reaction mixture was heated at 100° C. for 2.5 hr, before being cooled down at room temperature, filtered through Celite®, washed with MeOH and the filtrate concentrated under reduced pressure. The residue was dissolved in DCM (200 mL), quenched with a saturated solution of sodium hydrogencarbonate (300 mL) and a 10% solution of sodium sulfite (100 mL) and the mixture stirred for 30 min. The layers were separated and the aqueous layer extracted with DCM (100 mL). The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. Purification via silica gel column chromatography (0-30% EtOAc/isohexane) gave tert-butyl 1-(4-amino-1-methyl-1H-pyrazol-5-yl)-6,6-difluoroazepan-4-ylcarbamate as an orange foam (2.12 g). A solution of PyBOP (1.92 g, 3.70 mmol) and 2-bromo-5-(tert-butoxycarbonyl-amino)thiazole-4-carboxylic acid (795 mg, 2.46 mmol) in DCM (50 mL) was stirred at room temperature for 15 min. tert-Butyl 1-(4-amino-1-methyl-1H-pyrazol-5-yl)-6,6-difluoroazepan-4-ylcarbamate (850 mg, 2.46 mmol) and DIPEA (2.0 mL, 11.4 mmol) were added and the mixture stirred at room temperature for 18 hr. The reaction mixture was diluted with DCM (50 mL) and washed with a saturated solution of sodium hydrogencarbonate (100 mL). The organic layer was passed through a phase separation cartridge and concentrated under reduced pressure. Purification of the residue via silica gel column chromatography (0-100% EtOAc/isohexane) gave tert-butyl 1-(4-(5-(tert-butoxycabonyl-amino)-2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-6,6-difluoroazepan-4-ylcarbamate as a pale yellow foam (1.35 g, 77% over two steps). 1H NMR (400 MHz, CDCl3) δ 10.24 (s, 1H), 8.37 (s, 1H), 7.65 (s, 1H), 4.88 (s, 1H), 4.04 (s, 1H), 3.77 (s, 3H), 3.63-3.43 (m, 2H), 3.38-3.24 (m, 2H), 2.52-2.40 (m, 2H), 2.13-2.05 (m, 1H), 1.99 (s, 1H), 1.53 (s, 9H), 1.43 (s, 9H).
Reaction SMILES: C(O[C:4](=[O:12])[CH2:5][C:6](=[O:11])[C:7]([CH3:10])([CH3:9])[CH3:8])C.[CH:13]1([NH2:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.N(CCO)(CCO)CCO>C1(C)C=CC=CC=1>[CH:13]1([NH:19][C:4](=[O:12])[CH2:5][C:6](=[O:11])[C:7]([CH3:8])([CH3:9])[CH3:10])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: NC1CCCCC1
Reactant: CCOC(=O)CC(=O)C(C)(C)C
Solvent: OCCN(CCO)CCO
Solvent: Cc1ccccc1
Product: CC(C)(C)C(=O)CC(=O)NC1CCCCC1

Procedure:
Ethylpivaloylacetate (172 g.), cyclohexylamine (99 g.), triethanolamine (1 g.) and toluene (200 ml.) are mixed in a distillation flask and heated at reflux under a 6 in. Vigreux distillation column. When the head temperature stabilized at 82° C. distillation was begun at a take off to reflux ratio of 1 to 10. Distillation was continued until a head temperature of 110° C. is obtained. The remainder of the solvent is removed in a vacuum and residue is crystallized by trituation with hexane. A yield of 201 g. of product melting at 69°-70° C. is obtained.
Reaction SMILES: C(OP([CH2:9][C:10]1[N:11]=[CH:12][N:13]([C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=1)(OCC)=O)C.[Li+].CC([N-]C(C)C)C.[CH:42]([CH:44]1[CH2:49][CH2:48][N:47]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH2:46][CH2:45]1)=O>C1COCC1>[C:28]1([C:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:13]2[CH:14]=[C:10]([CH:9]=[CH:42][CH:44]3[CH2:49][CH2:48][N:47]([C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)[CH2:46][CH2:45]3)[N:11]=[CH:12]2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=CC1CCN(c2ccccc2)CC1
Reactant: CCOP(=O)(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)OCC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C(=CC1CCN(c2ccccc2)CC1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
The product from Step D is dissolved in THF and cooled to -78° C. under nitrogen. A solution of LDA in THF is added dropwise. The reaction was stirred at -78° C. for 1 h, then a solution of 4-formyl-1-phenylpiperidine from Step A is added, and the reaction warmed to room temperature overnight. The reaction is quenched with ammonium chloride solution, and extracted with ethyl acetate. The title compound is obtained after chromatography on silica gel.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[CH2:3]1.[C:18](Cl)(=[O:20])[CH3:19]>>[C:18]([N:7]1[C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:10]=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)[CH2:3][C@H:2]1[CH3:1])(=[O:20])[CH3:19]
Reactant: CC(=O)Cl
Reactant: C[C@@H]1CN(c2ccc([N+](=O)[O-])cc2)C[C@H](C)N1
Product: CC(=O)N1[C@H](C)CN(c2ccc([N+](=O)[O-])cc2)C[C@@H]1C

Procedure:
The title compound was prepared from (3R,5S)-3,5-dimethyl-1-(4-nitrophenyl)piperazine (Method 27, 16 g, 68.027 mmol) and acetyl chloride (8.22 ml, 115.65 mmol) by the procedure of Method 26. It was obtained as a solid which was dried in vac oven overnight at 50° C. (20.5 g, 109%, contaminated with solvent). NMR (400 MHz) 1.19 (brd, 6H), 2.08 (s, 3H), 3.21 (brd, 2H), 4.00 (d, 2H), 4.34 (v brs, 2H), 7.08 (d, 2H), 8.06 (d, 2H); m/z 278.
Reaction SMILES: C(Cl)CCl.[C:5]([O:9][C:10](=[O:18])[C:11]([CH3:17])([CH3:16])[CH2:12][C:13]([OH:15])=[O:14])([CH3:8])([CH3:7])[CH3:6].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2([NH:29][C:30](=[O:64])/[CH:31]=[CH:32]/[C@:33]34[CH2:59][C:58](=[O:60])[C:57]([CH:61]([CH3:63])[CH3:62])=[C:34]3[C@@H:35]3[C@@:48]([CH3:51])([CH2:49][CH2:50]4)[C@@:47]4([CH3:52])[C@@H:38]([C@:39]5([CH3:56])[C@@H:44]([CH2:45][CH2:46]4)[C:43]([CH3:54])([CH3:53])[C@@H:42](O)[CH2:41][CH2:40]5)[CH2:37][CH2:36]3)[CH2:28][CH2:27]2)=[CH:22][CH:21]=1>CN(C1C=CN=CC=1)C.ClCCl>[CH3:16][C:11]([CH3:17])([CH2:12][C:13]([O:15][C@H:42]1[CH2:41][CH2:40][C@@:39]2([CH3:56])[C@@H:44]([CH2:45][CH2:46][C@:47]3([CH3:52])[C@@H:38]2[CH2:37][CH2:36][C@H:35]2[C@@:48]3([CH3:51])[CH2:49][CH2:50][C@@:33]3(/[CH:32]=[CH:31]/[C:30]([NH:29][C:26]4([C:23]5[CH:22]=[CH:21][C:20]([Cl:19])=[CH:25][CH:24]=5)[CH2:27][CH2:28]4)=[O:64])[CH2:59][C:58](=[O:60])[C:57]([CH:61]([CH3:63])[CH3:62])=[C:34]32)[C:43]1([CH3:53])[CH3:54])=[O:14])[C:10]([O:9][C:5]([CH3:8])([CH3:6])[CH3:7])=[O:18]
Reactant: CC(C)(C)OC(=O)C(C)(C)CC(=O)O
Reactant: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(/C=C/C(=O)NC2(c3ccc(Cl)cc3)CC2)CC1=O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: 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)NC2(c3ccc(Cl)cc3)CC2)CC1=O
Temperature: 20 °C
Reaction time: 2 h
Yield: 51.1 %

Procedure:
To a solution of DMAP (647 mg, 5.30 mmol), EDC (1016 mg, 5.30 mmol) and 4-tert-butoxy-3,3-dimethyl-4-oxobutanoic acid (663 mg, 3.18 mmol) (11) in Dichloromethane (10 mL) stirred at 20° C. for 30 min was added (E)-N-(1-(4-chlorophenyl)cyclopropyl)-3-((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-9-hydroxy-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-3a-yl)acrylamide (685 mg, 1.060 mmol). The reaction mixture was stirred at 20° C. for 2 h. The mixture was washed with saturated ammonium chloride, water, and saturated NaHCO3, water, and brine. The organic layer was dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by silica gel column eluting with Petrol ether/Ethyl acetate (5:1) to afford the product 1-tert-butyl 4-((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((E)-3-((1-(4-chlorophenyl)cyclopropyl)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 (480 mg, 0.542 mmol, 51.2%) as a light yellow solid.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[C:10]([O:14][C:15](=[O:42])[N:16]([CH:18]1[CH2:23][CH2:22][CH:21]([NH:24][CH2:25][C:26]2[CH:27]=[C:28]([C:34]3[CH:39]=[CH:38][C:37]([C:40]#[N:41])=[CH:36][CH:35]=3)[C:29]([O:32][CH3:33])=[CH:30][CH:31]=2)[CH2:20][CH2:19]1)[CH3:17])([CH3:13])([CH3:12])[CH3:11].[Cl:43][C:44]1[C:45]2[CH:55]=[CH:54][CH:53]=[CH:52][C:46]=2[S:47][C:48]=1[C:49](Cl)=[O:50]>ClCCl>[C:10]([O:14][C:15](=[O:42])[N:16]([CH:18]1[CH2:23][CH2:22][CH:21]([N:24]([C:49]([C:48]2[S:47][C:46]3[CH:52]=[CH:53][CH:54]=[CH:55][C:45]=3[C:44]=2[Cl:43])=[O:50])[CH2:25][C:26]2[CH:27]=[C:28]([C:34]3[CH:39]=[CH:38][C:37]([C:40]#[N:41])=[CH:36][CH:35]=3)[C:29]([O:32][CH3:33])=[CH:30][CH:31]=2)[CH2:20][CH2:19]1)[CH3:17])([CH3:13])([CH3:11])[CH3:12]
Reactant: COc1ccc(CNC2CCC(N(C)C(=O)OC(C)(C)C)CC2)cc1-c1ccc(C#N)cc1
Reactant: O=C(Cl)c1sc2ccccc2c1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CN(C(=O)c2sc3ccccc3c2Cl)C2CCC(N(C)C(=O)OC(C)(C)C)CC2)cc1-c1ccc(C#N)cc1
Yield: 92.8 %

Procedure:
N,N-Diisopropylethylamine (2.1 mL, 12.1 mmol) was added to a solution of amine 5 (2.2 g, 4.9 mmol), 3-chlorobenzo[b]thiophene-2-carbonyl chloride (1.3 g, 5.86 mmol) and anhydrous dichloromethane (22 mL), with stirring under argon. Once all of the starting material had been consumed as monitored by TLC (˜2.5 hours), the mixture was washed with water, saturated aqueous sodium hydrogen carbonate, and brine. The organic layer was dried (MgSO4), and concentrated in vacuo. The yellow residue was then purified by silica-gel chromatography using hexane/ethyl acetate 3:1 to give the title compound 6 (2.93 g, 93%) as a pale yellow solid: