Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([CH:13]=[CH:14][CH3:15])[C@@H:10]([OH:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([CH2:13][CH2:14][CH3:15])[C@@H:10]([OH:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC=C[C@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1O
Agent: [Pd]
Solvent: CCO
Product: CCC[C@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1O
Reaction time: 3 h
Yield: 102.7 %

Procedure:
The synthesis of this compound follows the same general route outlined in scheme 5 [see Preparative Example 2.01]. To a suspension of ethyltriphenylphosphonium bromide (2.9 g, 6.93 mmol) in dry THF (15 mL) under argon at 0° C. was added 1.6 M BuLi in THF (4 mL, 6.40 mmol) and the deep red solution left stirring without cooling for 10 min. After re-cooling to 0° C., the aldehyde 46 (580 mg, 2.69 mmol) in THF (10 mL) was added and the mixture stirred at r.t. for 12 h. The reaction was then quenched with water (1 mL) and extracted with dichloromethane (100 mL). The organic phase was washed with sat. aq. NaHCO3 (15 mL) then water (15 mL), dried over MgSO4) and concentrated in vacuo. The residue was subjected to chromatography to afforded (3R,4S)-N-tert-butoxycarbonyl-3-hydroxy-4-propenyl-pyrrolidine (50) as a light yellow syrup (165 mg, 27%). To a solution of intermediate 50 (165 mg, 0.73 mmol) in ethanol (10 mL) was added 10% Pd/C (60 mg) and the suspension was stirred under an atmosphere of hydrogen for 3 h. After filtration, the solvent was removed in vacuo to give (3R,4S)-N-tert-butoxycarbonyl-3-hydroxy-4-propyl-pyrrolidine (51) as a syrup (172 mg, 102%). 1H NMR (300 MHz, CDCl3): δ ppm: 3.98-3.96 (m, 1H), 3.61-3.57 (m, 3H), 3.22-3.18 (m, 1H), 3.10-3.01 (m, 1H), 2.03 (m, 1H), 1.45 (s, 9H), 1.41-1.31 (m, 2H), 1.24-1.12 (m, 1H), 0.94-0.89 (m, 3H). 13C NMR (300 MHz, CDCl3): δ ppm (note that some peaks are doubled due to slow conversion of rotamers): 155.20, 79.69, (75.53, 74.76), (53.10, 52.80), (49.94, 49.38), (46.19, 45.67), 34.04, 28.83, 21.27, 14.47. To a solution of intermediate 51 (172 mg, 0.75 mmol) in methanol (10 mL) was added 12N (conc.) HCl (4 mL) and the solution stirred at 40° C. for 30 min. After removal of the solvent in vacuo and azeotroping with toluene, the crude title compound (3R,4S)-3-hydroxy-4-propyl-pyrrolidine hydrochloride (52) was obtained as a syrup (138 mg, 0.83 mmol, 111%). 1H NMR (300 MHz, MeOH-d4): δ ppm: 4.20-4.16 (m, 1H), 3.59-3.52 (m, 1H), 3.44-3.39 (m, 1H), 3.19-3.14 (m, 1H), 3.05-2.99 (m, 1H), 2.23-2.17 (m, 1H), 1.55-1.28 (m, 4H), 0.98-0.94 (m, 3H). 13C NMR (300 MHz, MeOH-d4): δ ppm: 75.65, 52.82, 50.30, 47.45, 34.69, 22.30, 14.78.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH:11]([CH3:15])[C:12]([OH:14])=O)[CH:4]=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.C(Cl)(=O)C(Cl)=O.[F:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[C:37]3[CH2:36][CH2:35][CH2:34][NH:33][C:32]=3[CH:31]=[N:30]2)=[CH:25][CH:24]=1.N1C=CC=CC=1>ClCCl.O.CN(C)C=O>[F:22][C:23]1[CH:24]=[CH:25][C:26]([N:29]2[C:37]3[CH2:36][CH2:35][CH2:34][N:33]([C:12](=[O:14])[CH:11]([N:3]4[CH:4]=[C:5]([C:7]([F:8])([F:9])[F:10])[N:6]=[C:2]4[CH3:1])[CH3:15])[C:32]=3[CH:31]=[N:30]2)=[CH:27][CH:28]=1
Reactant: Cc1nc(C(F)(F)F)cn1C(C)C(=O)O
Reactant: Fc1ccc(-n2ncc3c2CCCN3)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(C(F)(F)F)cn1C(C)C(=O)N1CCCc2c1cnn2-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.9 %

Procedure:
2-[2-Methyl-4-(trifluoromethyl)imidazol-1-yl]propanoic acid (151 mg, 0.679 mmol) was dissolved in dichloromethane (2 mL) at room temperature. Oxalyl chloride (120 μL, 1.38 mmol) and a catalytic amount of dimethylformamide (1 μL) was added and the reaction was stirred at room temperature for 2 h. Solvent was removed under reduced pressure and the acid chloride was dried under vacuum. The crude acid chloride was dissolved in dichloromethane (2.1 mL). To a portion of this solution (0.7 mL, 0.22 mmol) was added 1-(4-fluorophenyl)-4,5,6,7-tetrahydropyrazolo[4,3-b]pyridine (41.5 mg, 0.191 mmol) and pyridine (55 μL, 0.68 mmol) at room temperature and the reaction mixture was stirred for 2 h. Water was added and the layers were separated. The aqueous layer was extracted twice more with dichloromethane. The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (SiO2, 40-100% ethyl acetate in hexanes with 0.1% aqueous ammonium hydroxide) to afford the desired product as a white solid (70.1 mg, 0.166 mmol, 87%). 1H NMR (400 MHz, CDCl3) δ 8.44 (s, 1H), 7.45 (ddd, J=9.2, 4.8, 2.0 Hz, 2H), 7.17 (dt, J=9.2, 2.0 Hz, 2H), 5.21 (q, J=6.8 Hz, 1H), 3.75 (ddd, J=12, 7.2, 3.2 Hz, 1H), 3.51 (ddd, J=12, 8.0, 3.2 Hz, 1H), 2.84 (t, J=6.6 Hz, 2H), 2.47 (s, 3H), 1.96-2.09 (m, 2H), 1.72 (d, J=6.4 Hz, 3H); MS: (ES) m/z calculated for C20H19N5OF4 [M+H]+ 422, found 422.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:25](=[O:26])[CH2:24][C:23]([CH3:28])([CH3:27])[O:22][C:11]3=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[CH:4][CH:3]=1.C=O.N1CCC[CH2:32]1.[BH4-].[Na+]>CCO.CCOC(C)=O.CO.C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]3[CH:25]([OH:26])[CH:24]([CH3:32])[C:23]([CH3:28])([CH3:27])[O:22][C:11]3=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[CH:6][CH:7]=1
Reactant: CC1(C)CC(=O)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2O1
Reactant: C1CCNC1
Agent: C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CO
Product: CC1C(O)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2OC1(C)C
Temperature: 65 °C

Procedure:
To the product of Example 1 (500 mg, 1.155 mmol) was added paraformaldehyde (347 mL, 11.6 mmol) and pyrrolidine (0.243 mL, 2.94 mmol) in EtOH (10 mL)/THF (3 mL). The reaction vessel was sealed and heated to 65° C. for 4.5 h. The reaction was cooled and diluted with EtOAc and washed with brine. The solution was dried (Na2SO4) and concentrated. The residue was dissolved in THF (8 mL) and MeOH (1 mL) and NaBH4 (87 mg, 2.31 mmol) was added. After 25 min the reaction was diluted with EtOAc and washed with 2 M aq HCl and brine. The concentrated residue was purified by flash chromatography on silica gel gradient eluted with 0-60% EtOAc in hexane affording the title compound. (LC-2) HPLC/MS: 448.2 (M+1), 450.2 (M+3); Rt=4.23 min.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].CC1(C)C(C)(C)OB([C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)O1.[C:23]([O:27][C:28]([N:30]1[CH2:33][CH:32]([CH2:34][NH:35][C:36]2[N:41]=[C:40](Cl)[N:39]=[C:38]([N:43]3[CH2:48][CH2:47][O:46][CH2:45][CH2:44]3)[N:37]=2)[CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(COC)OC>[C:23]([O:27][C:28]([N:30]1[CH2:33][CH:32]([CH2:34][NH:35][C:36]2[N:41]=[C:40]([C:15]3[CH:16]=[CH:17][C:18]([NH2:21])=[CH:19][CH:20]=3)[N:39]=[C:38]([N:43]3[CH2:48][CH2:47][O:46][CH2:45][CH2:44]3)[N:37]=2)[CH2:31]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CC(CNc2nc(Cl)nc(N3CCOCC3)n2)C1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CC(CNc2nc(-c3ccc(N)cc3)nc(N3CCOCC3)n2)C1
Temperature: 140 °C
Yield: 53.2 %

Procedure:
To a microwave processing tube was added dimethoxyethane (15 mL), aqueous Na2CO3 (2 molar)(4 mL, 8 mmol, 2 eq), (Ph3P)4Pd (317 mg, 0.55 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (1.81 g, 8.30 mmol, 1.5 eq) and 3-[(4-Chloro-6-morpholin-4-yl-[1,3,5]triazin-2-ylamino)-methyl]-azetidine-1-carboxylic acid tert-butyl ester (1.3 g, 5.53 mmol) and the vessel was sealed. The mixture was heated to 140° C. for 60 minutes. The solvents were removed and the crude compound was purified by silica gel chromatography using CH2Cl2/Ethyl acetate (10:1) and later CH2Cl2/MeOH/NH3 (15:1:0.1) to give the product as a off-white solid (1.3 g, 53% yield).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([NH:11][C:12]([C:14]2[CH:15]=[CH:16][C:17]3[O:22][CH2:21][CH2:20][N:19]([S:23]([C:26]4[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=4[CH3:33])(=[O:25])=[O:24])[C:18]=3[CH:34]=2)=[O:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].F[C:36]1C=CC(C)=C(S(Cl)(=O)=O)[CH:41]=1>>[CH2:36]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([NH:11][C:12]([C:14]2[CH:15]=[CH:16][C:17]3[O:22][CH2:21][CH2:20][N:19]([S:23]([C:26]4[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=4[CH3:33])(=[O:25])=[O:24])[C:18]=3[CH:34]=2)=[O:13])=[CH:10][C:2]=1[F:1])[CH3:41]
Reactant: Cc1ccc(F)cc1S(=O)(=O)Cl
Reactant: Cc1ccc(F)cc1S(=O)(=O)N1CCOc2ccc(C(=O)Nc3ccc(C(=O)O)c(F)c3)cc21
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(F)ccc2C)CCO3)cc1F

Procedure:
2-Fluoro-4-{[4-(5-fluoro-2-methyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoic acid, MS (ISP): m/e=487.1 (M−H), was prepared as described for example 21, steps 1 to 8. Step 7 was performed using 5-fluoro-2-methyl-benzenesulfonyl chloride and yielded 2-fluoro-4-{[4-(5-fluoro-2-methyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoic acid ethyl ester, which was hydrolyzed in step 8.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[CH2:47]([O:54][C:55]1[CH:81]=[CH:80][C:79](Br)=[CH:78][C:56]=1[C:57]([NH:59][C:60]1[CH:69]=[C:68]([C:70]2[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=2)[C:67]([O:76][CH3:77])=[CH:66][C:61]=1[C:62]([O:64][CH3:65])=[O:63])=[O:58])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH2:47]([O:54][C:55]1[CH:81]=[CH:80][C:79]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:78][C:56]=1[C:57]([NH:59][C:60]1[CH:69]=[C:68]([C:70]2[CH:71]=[CH:72][CH:73]=[CH:74][CH:75]=2)[C:67]([O:76][CH3:77])=[CH:66][C:61]=1[C:62]([O:64][CH3:65])=[O:63])=[O:58])[C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1
Reactant: COC(=O)c1cc(OC)c(-c2ccccc2)cc1NC(=O)c1cc(Br)ccc1OCc1ccccc1
Reactant: C1CCNCC1
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(OC)c(-c2ccccc2)cc1NC(=O)c1cc(N2CCCCC2)ccc1OCc1ccccc1
Temperature: 25 °C

Procedure:
Piperidine (0.012 mL), cesium carbonate (0.054 g), tris(dibenzylideneacetone)dipalladium(0) (2.3 mg), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (5.9 mg), and palladium(II) acetate (1.1 mg) were added to a toluene (2.0 mL) solution of methyl 2-(2-(benzyloxy)-5-bromobenzamido)-5-methoxy-4-phenylbenzoate (0.045 g), followed by heating to reflux under a nitrogen atmosphere for 2 hours and 20 minutes. The reaction mixture was cooled to room temperature, and ethyl acetate and water were added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 95-85% hexane/ethyl acetate] to obtain 0.034 g of methyl 2-(2-(benzyloxy)-5-(piperidin-1-yl)benzamido)-5-methoxy-4-phenylbenzoate as a yellow solid.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:15])[CH:6]=[CH:7][C:8]=1[O:9]C.B(I)(I)I.C(=O)(O)[O-].[Na+].Cl>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:15])[CH:6]=[CH:7][C:8]=1[OH:9]
Reactant: COc1ccc(CCNC(=O)C2CCCCC2)cc1OC
Agent: Cl
Agent: IB(I)I
Agent: O=C([O-])O
Solvent: ClCCl
Product: O=C(NCCc1ccc(O)c(O)c1)C1CCCCC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Dissolve 2.0 g. of the product of Step A carboxylate in 15 ml. of methylene chloride and cool the solution to about -78°C. Add 2.5 g. of boron triiodide and allow the reaction mixture to warm up to about 0°C with vigorous stirring. Stir the reaction mixture at about 0°C overnight, then add about 10 ml. saturated sodium bicarbonate solution. Acidify the mixture with 2N hydrochloric acid and extract with ethyl acetate. Decolorize the extract with aqueous sodium thiosulfate, then wash the extract successively with 2N hydrochloric acid solution, saturated sodium bicarbonate solution, and water. Dry the extract over anhydrous sodium sulfate and evaporate to a residue. Crystallize the residue from a toluene-ethanol mixture to obtain the title product 124°C - 126°C.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4]1[C:9]([OH:10])=[C:8]([C:11]([CH3:13])=[O:12])[CH:7]=[CH:6][C:5]=1[OH:14].[C:15](OC)(=O)[C:16]([O:18][CH3:19])=[O:17].C[O-].[Na+].C(O)(=O)C>CN(C)C=O>[OH:14][C:5]1[CH:6]=[CH:7][C:8]2[C:11](=[O:12])[CH:13]=[C:15]([C:16]([O:18][CH3:19])=[O:17])[O:10][C:9]=2[C:4]=1[CH2:3][CH2:2][CH3:1]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: COC(=O)C(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCCc1c(O)ccc2c(=O)cc(C(=O)OC)oc12
Reaction time: 4 h
Yield: 66.7 %

Procedure:
To a solution of 99.7 g (0.513 mole) of 2,4-dihydroxy-3-propylacetophenone and 72.7 g (0.77 mole) of dimethyl oxalate in 1 liter of dry dimethylformamide was added in portions 97 g (1.8 mmole) of sodium methoxide. After stirring for 4 hours, 1.8 l of acetic acid was added and stirring was continued for 4 days. The reaction mixture was heated in a steam bath for four hours and evaporated to dryness. Water was added to the residue and the mixture was heated to boiling. A solid was filtered off and recrystallized from ethanol to give 89.8 g of the title compound, mp. 222°-224°. Structure assignment was supported by nmr and infrared spectra.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[N:12]([CH2:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[C@H:11]([C:20]([F:23])([F:22])[F:21])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1.Cl.[C@H:25]12[CH2:31][C@H:28]([NH:29][CH2:30]1)[CH2:27][O:26]2.C(N(CC)CC)C>>[CH3:16][C:15]([CH3:18])([CH3:17])[C:14](=[O:19])[CH2:13][N:12]1[C:4]2=[N:3][C:2]([N:29]3[CH2:30][C@@H:25]4[CH2:31][C@H:28]3[CH2:27][O:26]4)=[CH:7][C:6](=[O:8])[N:5]2[CH2:9][CH2:10][C@H:11]1[C:20]([F:23])([F:22])[F:21]
Reactant: CC(C)(C)C(=O)CN1c2nc(Cl)cc(=O)n2CC[C@H]1C(F)(F)F
Reactant: C1O[C@@H]2CN[C@H]1C2
Agent: Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)CN1c2nc(N3C[C@@H]4C[C@H]3CO4)cc(=O)n2CC[C@H]1C(F)(F)F

Procedure:
180 mg (0.511 mmol) of (8S)-2-chloro-9-(3,3-dimethyl-2-oxobutyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, 76.32 mg (0.563 mmol) of (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride and 179 μl (1.28 mmol) of triethylamine were used in the reaction. After purification by chromatography on silica gel (eluent A/B: DCM/MeOH, gradient A/B: t 0 min 0% B, t 15 min 4% B, t 18 min 4% B, t 33 min 10% B), 130 mg of (8S)-9-(3,3-dimethyl-2-oxobutyl)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one were obtained, corresponding to the following characteristics:
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:42])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:41])[CH2:12][CH2:13][C@@:14]3([CH2:31][CH2:32][NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:26][C:25](=[O:27])[C:24]([CH:28]([CH3:30])[CH3:29])=[C:15]32)[C:6]1([CH3:44])[CH3:43])(=O)C.[OH-].[Na+].O.CCOC(C)=O>CO.C1COCC1>[OH:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:42])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:41])[CH2:12][CH2:13][C@@:14]3([CH2:31][CH2:32][NH:33][C:34](=[O:35])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:26][C:25](=[O:27])[C:24]([CH:28]([CH3:30])[CH3:29])=[C:15]32)[C:6]1([CH3:43])[CH3:44]
Reactant: CC(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@@H]4C5=C(C(C)C)C(=O)C[C@]5(CCNC(=O)OC(C)(C)C)CC[C@@]4(C)[C@]3(C)CC[C@H]2C1(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: 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(CCNC(=O)OC(C)(C)C)CC1=O
Yield: 83 %

Procedure:
A solution of (3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((tert-butoxycarbonyl)amino)ethyl)-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 acetate (35) (5.8 g, 9.48 mmol), NaOH (11.37 g, 284 mmol) in methanol (4 mL), THF (6 mL), and Water (2 mL) was stirred at room temperature for 1 h. EtOAc was added and the reaction mixture was washed with water. The organic layer was separated, washed with water and brine, and dried (Na2SO4). Removal of the solvent provide tert-butyl (2-((3aR,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)ethyl)carbamate (36) (5.4 g, 7.87 mmol, 83% yield) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ=4.53-4.36 (m, 1H), 3.30-2.94 (m, 4H), 2.94-2.67 (m, 2H), 2.28 (d, J=18.8 Hz, 1H), 2.11-0.55 (m, 50H); LC/MS: m/z calculated 569.4. found 592.3 (M+Na)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:26])[C:10]([C:16]1[CH:23]=[C:22]([CH3:24])[C:19]([C:20]#[N:21])=[C:18]([CH3:25])[CH:17]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[Cl:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][C:33]=1[C:34]([O:36][CH3:37])=[O:35]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.N1C=CC=CC=1>[CH3:37][O:36][C:34](=[O:35])[C:33]1[CH:32]=[CH:31][C:30]([O:8][C:6]2[CH:5]=[CH:4][C:3]([CH:9]([CH3:26])[C:10]([C:16]3[CH:17]=[C:18]([CH3:25])[C:19]([C:20]#[N:21])=[C:22]([CH3:24])[CH:23]=3)([OH:15])[C:11]([F:14])([F:12])[F:13])=[C:2]([Cl:1])[CH:7]=2)=[CH:29][C:28]=1[Cl:27]
Reactant: Cc1cc(C(O)(C(C)c2ccc(O)cc2Cl)C(F)(F)F)cc(C)c1C#N
Reactant: COC(=O)c1ccc(B(O)O)cc1Cl
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Product: COC(=O)c1ccc(Oc2ccc(C(C)C(O)(c3cc(C)c(C#N)c(C)c3)C(F)(F)F)c(Cl)c2)cc1Cl

Procedure:
In analogy to Example 5, 4-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-2,6-dimethyl-benzonitrile (Example 141, step 5) was reacted with 3-chloro-4-methoxycarbonylphenylboronic acid, copper-(II)-acetate and pyridine to give the title compound as a colorless solid. MS (m/e, ISP neg. ion)=550.1 [M−H+].
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][C:5]2=[C:4]([Cl:11])[CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[N:17][CH:18]=1.C([O-])([O-])=O.[Cs+].[Cs+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.CCO>[Cl:11][C:4]1[CH:3]=[C:2]([C:15]2[CH:16]=[N:17][CH:18]=[C:13]([Cl:12])[CH:14]=2)[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][C:5]=12
Reactant: Clc1cc(Cl)c2c(n1)CCC2
Reactant: OB(O)c1cncc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: Clc1cncc(-c2cc(Cl)c3c(n2)CCC3)c1
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 30.1 %

Procedure:
A 25-mL round bottom flask was charged with 2,4-dichloro-6,7-dihydro-5H-cyclopenta[b]pyridine (0.300 g, 1.59 mmol), 5-chloro3-pyridinyl boronic acid (0.301 g, 1.91 mmol), tetrakis(triphenylphosphine)palladium(0) (0.092 g, 0.08 mmol), and Cs2CO3 (1.56 g, 4.78 mmol). Toluene (8 ml), EtOH (2 ml) and water (4 ml) were added. The resulting mixture was stirred under Ar at 90° C. for 2.5 h. After this time, the mixture was cooled to rt, filtered through celite, and the filtrate concentrated under reduced pressure. The residue was purified by chromatography on silica using hexane/ethyl acetate (10:0 to 0:10) as eluent to afford the title compound (0.127 g, 30%) as a white solid. MW=265.14. 1H NMR (CDCl3, 500 MHz) δ 8.99 (d, J=2.0 Hz, 1H), 8.59 (d, J=2.5 Hz, 1H), 8.30 (t, J=2.5 Hz, 1H), 7.50 (s, 1H), 3.15 (t, J=7.5 Hz, 2H), 3.05 (t, J=7.5 Hz, 2H), 2.21 (quin, J=7.5 Hz, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](Cl)=[O:29]>ClCCl>[C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:28](=[O:29])[C:27]2[CH:31]=[CH:32][CH:33]=[C:25]([C:24]([F:23])([F:34])[F:35])[CH:26]=2)[CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC1CCCNC1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC1CCCN(C(=O)c2cccc(C(F)(F)F)c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.1 %

Procedure:
To a solution of the tert-butyl(piperidin-3-ylmethyl)carbamate (429 mg) in 10 ml dichloromethane was added triethylamine (558 μl) followed by 417 mg of 3-(trifluoromethyl)benzoyl chloride. The mixture was stirred at room temperature for 1 h, and then concentrated in vacuo. The residue was filtered through a plug of silica gel (eluting with ethyl acetate) to provide tert-butyl({1-[3-(trifluoromethyl)benzoyl]piperidin-3-yl}methyl)carbamate (665 mg, 86%). To a solution of this in 10 ml of dichloromethane was added trifluoroacetic acid (10 ml). The mixture was stirred at 60° C. for 1 h, and then concentrated in vacuo. The residue was diluted with 30 ml of ethyl acetate and basified by slow and cautious addition of 30 ml of a saturated aqueous solution of sodium bicarbonate. The aqueous layer was separated and extracted once with 30 ml of ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to provide the title compound (401 mg, 82%). Mass spectrum (ESI) 287.3 (M+1).
Reaction SMILES: Cl.[NH2:2][CH:3]([CH3:18])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=1)=O.[CH:19]([N:22]=[C:23]=[O:24])([CH3:21])[CH3:20].C(N(CC)CC)C.FC(F)(F)C(O)=O>CC(C)=O>[CH:12]1([C:9]2[CH:10]=[CH:11][C:6]([C:4]3[N:22]([CH:19]([CH3:21])[CH3:20])[C:23](=[O:24])[NH:2][C:3]=3[CH3:18])=[CH:7][CH:8]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CC(C)N=C=O
Reactant: CC(N)C(=O)c1ccc(C2CCCCC2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)=O
Product: Cc1[nH]c(=O)n(C(C)C)c1-c1ccc(C2CCCCC2)cc1
Reaction time: 1 h

Procedure:
2-Amino-4'-cyclohexylpropiophenone hydrochloride (477 mg, 1.78 mmol) was suspended in acetone (30 ml) under ice-cooling, and isopropyl isocyanate (198 mg, 2.33 mmol) was added thereto. Triethylamine (533 mg, 5.28 mmol) was added, and the mixture was stirred for one hour under ice-cooling. After addition of trifluoroacetic acid (2 ml), the mixture was stirred for 2 days at room temperature. The solvent was removed by evaporation in vacuo, and the residue was extracted with dichloromethane. The extract was washed successively with water and saturated aqueous sodium chloride, and dried over magnesium sulfate. Evaporation of the solvent provided a crude product, which was purified by column chromatography (chloroform/ ethanol=50/1 (v/v)) and recrystalization (ethanol-chloroform) to give the title compound. Yield: 351 mg (66%), m.p. 274° C.