Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9](=[O:37])[CH2:10][C:11]1([C:16]([NH:18][CH2:19][CH:20]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=2)[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12]1)C1C=CC=CC=1>CCO.[Pd]>[C:24]([O:23][C:21](=[O:22])[CH:20]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=1)[CH2:19][NH:18][C:16]([C:11]1([CH2:10][C:9]([OH:37])=[O:8])[CH2:12][CH2:13][CH2:14][CH2:15]1)=[O:17])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)C(CNC(=O)C1(CC(=O)OCc2ccccc2)CCCC1)Cc1ccc(Cl)c(Cl)c1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)C(CNC(=O)C1(CC(=O)O)CCCC1)Cc1ccc(Cl)c(Cl)c1
Reaction time: 6.5 h
Yield: 45.1 %

Procedure:
A suspension of tert-butyl 3-(1-(2-(benzyloxy)-2-oxoethyl)cyclopentanecarboxamido)-2-(3,4-dichlorobenzyl)propanoate (81.2 mg, 0.148 mmol) and Pd/C (31.5 mg, 0.015 mmol) in EtOH (1 ml) was allowed to stir under hydrogen atmosphere (1 atm) for 6.5 hr. The reaction mixture was filtered, and the filter cake was washed with MeOH. The combined filtrate was concentrated under reduced pressure. The obtained residue was purified by RP-HPLC (X-Bridge C18, H2O (0.1% NH4OH)/CH3CN) to give 2-(1-(3-tert-butoxy-2-(3,4-dichlorobenzyl)-3-oxopropylcarbamoyl)cyclopentyl)acetic acid (30.6 mg); Retention time=1.30 minutes (condition B); MS (m+1)=458.2; 1H NMR (400 MHz, CDCl3, data for major rotamer) δ ppm 1.37 (s, 9H) 1.70-1.98 (m, 8H) 2.64-2.88 (m, 5H) 3.34-3.53 (m, 2H) 6.53-6.56 (m, 1H) 7.02-7.04 (m, 1H) 7.28 (d, J=2.0 Hz, 1H) 7.36 (d, J=8.0 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([CH2:8][NH:9][C:10]2[C:11]([F:18])=[C:12]([OH:17])[CH:13]=[CH:14][C:15]=2[F:16])[CH:7]=1.C([O-])([O-])=O.[Na+].[Na+].Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([CH2:8][NH:9][C:10]2[C:11]([F:18])=[C:12]([CH:13]=[CH:14][C:15]=2[F:16])[O:17][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:7]=1
Reactant: Oc1ccc(F)c(NCc2cc(Br)ccc2F)c1F
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(F)c(NCc2cc(Br)ccc2F)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.7 %

Procedure:
To a solution of 3-[(5-bromo-2-fluoro-phenyl)methylamino]-2,4-difluoro-phenol (5.26 g, 15.8 mmol, 1.0 eq) in DMF (50 mL) was added Na2CO3 (2.35 g, 22.2 mmol, 1.4 eq). The reaction was stirred at room temperature for 30 min then ethyl bromoacetate (2.91 g, 17.4 mmol, 1.1 eq) was added. The reaction mixture was stirred at room temperature for 1 h then poured into water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography (petroleum ether:EtOAc, 40:1 to 30:1) to give the title compound as a colorless oil (5 g, 75%).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([C:11]([NH2:13])=[O:12])=[C:7]2[C:3]=1[C:4]1[CH2:17][N:16]([C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][CH2:14][C:5]=1[NH:6]2.[CH3:37][C:38]1[C:43](B2OC(C)(C)C(C)(C)O2)=[CH:42][CH:41]=[CH:40][C:39]=1[N:53]1[C:62](=[O:63])[C:61]2[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=2)[N:55]=[CH:54]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.CCOC(C)=O.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>[CH3:37][C:38]1[C:39]([N:53]2[C:62](=[O:63])[C:61]3[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=3)[N:55]=[CH:54]2)=[CH:40][CH:41]=[CH:42][C:43]=1[C:2]1[CH:10]=[CH:9][C:8]([C:11]([NH2:13])=[O:12])=[C:7]2[C:3]=1[C:4]1[CH2:17][N:16]([C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:15][CH2:14][C:5]=1[NH:6]2
Reactant: NC(=O)c1ccc(Br)c2c3c([nH]c12)CCN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C3
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1cnc2ccccc2c1=O
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: Cc1ccccc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1c(-c2ccc(C(N)=O)c3[nH]c4c(c23)CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC4)cccc1-n1cnc2ccccc2c1=O
Temperature: 90 °C
Reaction time: 16 h
Yield: 75.4 %

Procedure:
A mixture of 9-bromo-2-trityl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-6-carboxamide (250 mg, 0.466 mmol), 3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazolin-4(3H)-one (186 mg, 0.513 mmol), and 2 M aqueous sodium carbonate (0.699 mL, 1.398 mmol) in toluene (4 mL) and ethanol (1 mL) was degassed by bubbling with argon for ca. 5-10 min (1 minute with sonication). The mixture was treated with tetrakis(triphenylphosphine)palladium (26.9 mg, 0.023 mmol) and heated at 90° C. under argon. After 16 h, the mixture was cooled to room temperature, diluted with EtOAc and a small amount of water and the layers were separated. The aqueous phase was extracted with EtOAc and the combined organic phases were filtered, dried and concentrated. The residue was subjected to column chromatography on silica gel (40 g), eluting with EtOAc-hexane (gradient from 15:85 to 100:0) to provide the desired product as a light yellow glass (243 mg, 70% yield). LCMS (M+H-trityl)+ m/z 450.2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[CH2:4][CH2:5][S:6][CH:7]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][O:27][C:28]2[CH:33]=[CH:32][C:31]([C:34](=[O:39])[C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=2)=[CH:19][CH:18]=1)[CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[BH4-].[Na+]>CO>[CH3:1][O:2][C:3](=[O:40])[CH2:4][CH2:5][S:6][CH:7]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][O:27][C:28]2[CH:33]=[CH:32][C:31]([CH:34]([OH:39])[C:35]([F:36])([F:37])[F:38])=[CH:30][CH:29]=2)=[CH:19][CH:18]=1)[CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COC(=O)CCSC(CCCc1ccccc1)c1ccc(OCCCOc2ccc(C(=O)C(F)(F)F)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)CCSC(CCCc1ccccc1)c1ccc(OCCCOc2ccc(C(O)C(F)(F)F)cc2)cc1
Yield: 99.7 %

Procedure:
The product from Step 5 of Example 7 (150 mg) was dissolved in 20 mL of MeOH, and treated with 15 mg of NaBH4 at 0° C. After 10 min. the mixture was quenched with 10 mL of sat. NH4Cl, and extracted with 50 mL of EtOAc. The extract was dried over NaSO4 and concentrated to give 150 mg of the title compound.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:16]=[CH:15][C:7]([CH:8]=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=1.[C:17]([O:20][CH2:21][CH2:22]Br)(=[O:19])[CH3:18].O>CN(C)C=O>[C:17]([O:20][CH2:21][CH2:22][O:3][C:4]1[CH:5]=[CH:6][C:7]([CH:8]=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:15][CH:16]=1)(=[O:19])[CH3:18]
Reactant: CCOC(=O)C=Cc1ccc(O)cc1
Reactant: CC(=O)OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C=Cc1ccc(OCCOC(C)=O)cc1
Reaction time: 1 h
Yield: 98.9 %

Procedure:
To a suspension of sodium hydride (60% active, 124 mg) in dimethylformamide (2 ml) at ambient temperature was added ethyl 4-hydroxycinnamate (500 mg) under nitrogen, and the mixture was stirred for 1 hour. 2-Bromoethyl acetate (522 mg) was added to the mixture at same temperature, and the mixture was allowed to stand for 19 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel eluting with chloroform to give ethyl 4-(2-acetoxyethoxy)cinnamate (716 mg) as an oil.
Reaction SMILES: C(Cl)CCl.[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:14][N:15]2[CH2:18][CH:17]([OH:19])[CH2:16]2)=[C:10]([CH:13]=1)[CH2:11][NH2:12].[C:20]([N:27]1[CH2:34][CH2:33][CH2:32][C@H:28]1[C:29](O)=[O:30])([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:14][N:15]2[CH2:16][CH:17]([OH:19])[CH2:18]2)=[C:10]([CH:13]=1)[CH2:11][NH:12][C:29](=[O:30])[C@@H:28]1[CH2:32][CH2:33][CH2:34][N:27]1[C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: NCc1cc(Cl)ccc1CN1CC(O)C1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NCc1cc(Cl)ccc1CN1CC(O)C1
Yield: 9.4 %

Procedure:
EDC (1.51 g, 7.87 mmol) was added to a stirred mixture of 5-chloro-2-[(3-hydroxyazetidin-1-yl)methyl]benzylamine (1.19 g, 5.25 mmol), N-Boc-L-proline (1.13 g, 5.25 mmol) and HOAT (0.36 g, 2.62 mmol) in DMF (9 mL). After 16 h the mixture was concentrated and the residue was partitioned between EtOAc and 10% NaHCO3. The organic layer was washed with water and brine, dried (Na2SO4)and evaporated. The residue was partitioned between EtOAc and 1M citric acid. The aqueous layer was made neutral with NaHCO3 and was extracted into CH2Cl2. The organic layer was evaporated and the residue was purified by chromatography on silica (ammonia saturated CHCl3/MeOH, 95:5) to give N-{5-chloro-2-[(3-hydroxyazetidin-1-yl)methyl]benzyl}-1-(tert-butoxycarbonyl)-L-prolinamide (210 mg) as a glass: MS: 424.5 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][C:15]=2[F:21])=[O:12])[N:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:29]1[C:38]2[C:33](=[CH:34][C:35]([O:41][CH3:42])=[C:36]([O:39][CH3:40])[CH:37]=2)[N:32]=[CH:31][N:30]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([O:20][C:29]3[C:38]4[C:33](=[CH:34][C:35]([O:41][CH3:42])=[C:36]([O:39][CH3:40])[CH:37]=4)[N:32]=[CH:31][N:30]=3)[CH:17]=[CH:16][C:15]=2[F:21])=[O:12])[N:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cc(O)ccc2F)n(-c2ccccc2)n1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2ncnc(Oc3ccc(F)c(NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccccc4)c3)c2cc1OC
Temperature: 35 °C
Reaction time: 15 h
Yield: 5.8 %

Procedure:
To a stirred solution of 1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(2-fluoro-5-hydroxyphenyl)urea (217 mg, 0.59 mmol) and 4-chloro-6,7-dimethoxyquinazoline (132 mg, 0.59 mmol) in DMF (4 mL) at rt, was added potassium carbonate (163 mg, 1.18 mmol). The reaction mixture was stirred at 35° C. for 15 h. The mixture was poured into water, and the resulting brown solid was filtrated, washed with water, and dried to afford the crude product. Purification via reverse-phase preparative HPLC afforded 1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(5-(6,7-dimethoxyquinazolin-4-yloxy)-2-fluorophenyl)urea (19 mg, 6%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ 9.02 (brs, 1H), 8.89 (brs, 1H), 8.57 (s, 1H), 8.16 (m, 1H), 7.53-7.59 (m, 5H), 7.37-7.46 (m, 3H), 7.15 (m, 1H), 6.43 (s, 1H), 4.00 (s, 3H), 3.98 (s, 3H), 1.29 (s, 9H); LC-MS (ESI) m/z 557 (M+H)+.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:11](O)=[O:12])[CH3:10])=O)(C)(C)C.C1CCC(N=C=NC2CCCCC2)CC1.CO[C:31](=[O:42])[C@@H:32]([CH3:41])[NH:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>ClCCl>[CH2:34]([N:33]1[C@H:32]([CH3:41])[C:31](=[O:42])[NH:8][C@@H:9]([CH3:10])[C:11]1=[O:12])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: COC(=O)[C@@H](C)NCc1ccccc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: C[C@@H]1NC(=O)[C@@H](C)N(Cc2ccccc2)C1=O
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A 0.98 g portion of N-tert-butoxycarbonyl-L-alanine was added to 50 ml of 0° C.-cooled dichloromethane solution containing 1.07 g of DCC, and the mixture was stirred for 5 minutes. This solution was mixed with 10 ml of dichloromethane solution containing 1.0 g of N-benzyl-D-alanine methyl ester and stirred at room temperature for 2 days. White precipitate was separated by filtration and washed with diethyl ether and then the filtrate was concentrated. The residue was dried under reduced pressure, dissolved with 30 ml of dichloromethane, cooled to 0° C., mixed with 5 ml of trifluoroacetic acid and then stirred at room temperature for 3 hours. The reaction solution was neutralized with saturated aqueous sodium bicarbonate, extracted with chloroform, dried over anhydrous magnesium sulfate, filtered and then concentrated. The residue was subjected to a silica gel column chromatography and purified with n-hexane-ethyl acetate (1:5, v/v) to obtain 1.0 g of the title compound as a colorless oily substance.
Reaction SMILES: Cl.[NH+]1C=CC=CC=1.[CH3:8][C:9]1[C:13]2[C:14]([O:25]C)=[CH:15][CH:16]=[C:17]([C:18]([C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)=[O:19])[C:12]=2[O:11][CH:10]=1.O.Cl>N1C2C(=CC=CC=2)C=CC=1>[CH3:8][C:9]1[C:13]2[C:14]([OH:25])=[CH:15][CH:16]=[C:17]([C:18]([C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)=[O:19])[C:12]=2[O:11][CH:10]=1
Reactant: COc1ccc(C(=O)c2cccs2)c2occ(C)c12
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: c1ccc2ncccc2c1
Product: Cc1coc2c(C(=O)c3cccs3)ccc(O)c12
Reaction time: 1 h

Procedure:
A solution of freshly prepared pyridinium hydrochloride (4.84 g, 41.9 mmol) and 3-methyl-4-methoxy-7-(2-thienoyl)benzofuran (2.30 g, 8.38 mmol) in quinoline (10 mL) was heated to reflux for 2.5 hours. The mixture was cooled, an additional portion of pyridinium hydrochloride added (2.42 g, 20.9 mmol) and reflux was resumed for one hour. After cooling the reaction mixture was poured into water (200 mL) and acidified with 2N HCl. The resulting mixture was extracted with chloroform (5×50 mL) and the combined organic extracts were washed with water (50 mL), dried (Na2SO4), and concentrated. Chromatographic purification by preparative HPLC using 25% ethyl acetate in hexane as eluant afforded 3-methyl-4-hydroxy-7-(2-thienoyl)benzofuran compound 3 along with recovered starting material. A sample of the desired product was recrystallized from ether/hexane. 1H NMR d 2.45 (3H, s), 6.24 (1H, br s), 6.45 (1H, d, J=8 Hz), 7.17 (1H, dd, J=4 Hz, 4 Hz), 7.37 (1H, s), 7.61 (1H, d, J=8 Hz), 7.67 (1H, d, J=4 Hz), 7.75 (1H, d, J=4 Hz).
Reaction SMILES: C(OC(=O)[N:7]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:34])[NH:22][CH2:23][CH2:24][CH2:25][CH2:26][N:27]([CH2:31][CH2:32][CH3:33])[CH2:28][CH2:29][CH3:30])=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1)(C)(C)C.Cl.O1CCOCC1>CO>[NH:10]1[CH:11]=[CH:12][N:13]=[C:9]1[CH2:8][NH:7][C:14]1[C:17]([CH3:16])=[C:18]([CH:19]=[CH:20][CH:15]=1)[C:21]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][N:27]([CH2:28][CH2:29][CH3:30])[CH2:31][CH2:32][CH3:33])=[O:34]
Reactant: CCCN(CCC)CCCCNC(=O)c1ccc(CN(Cc2ncc[nH]2)C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CCCN(CCC)CCCCNC(=O)c1cccc(NCc2ncc[nH]2)c1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 127 %

Procedure:
The compound (117 mg) obtained in Example 6-2 was dissolved in methanol (1.2 ml) and then added with a 4 mol/l hydrogen chloride/dioxane solution (1.2 ml) and the whole was stirred at room temperature for 5 hours. After completion of the reaction, the solvent was distilled off. Then, the residue was dissolved in water and then purified through solid-phase extraction column (Sep-Pak, tC18, manufactured by Waters Corporation), thereby obtaining a hydrochloride (118 mg) of the subject compound as a white solid.
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C.[NH2:44][CH2:45][C:46]1[CH:51]=[CH:50][C:49]([N:52]2[C:56]([NH:57][C:58]([NH:60][C:61]3[CH:66]=[CH:65][C:64]([O:67][C:68]4[CH:73]=[CH:72][N:71]=[CH:70][CH:69]=4)=[CH:63][CH:62]=3)=[O:59])=[CH:55][C:54]([C:74]([CH3:77])([CH3:76])[CH3:75])=[N:53]2)=[CH:48][CH:47]=1>C1COCC1.C(#N)C>[C:4]([O:3][C:1](=[O:2])[NH:8][CH2:9][C:10](=[O:12])[NH:44][CH2:45][C:46]1[CH:51]=[CH:50][C:49]([N:52]2[C:56]([NH:57][C:58]([NH:60][C:61]3[CH:66]=[CH:65][C:64]([O:67][C:68]4[CH:69]=[CH:70][N:71]=[CH:72][CH:73]=4)=[CH:63][CH:62]=3)=[O:59])=[CH:55][C:54]([C:74]([CH3:77])([CH3:76])[CH3:75])=[N:53]2)=[CH:48][CH:47]=1)([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(Oc3ccncc3)cc2)n(-c2ccc(CN)cc2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCC(=O)NCc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccncc3)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 10.7 %

Procedure:
To a solution of N-Boc-glycine (260 mg, 1.48 mmol), EDCl (283 mg, 148 mmol) and HOBT (200 mg, 1.48 mmol) in THF/acetonitrile (50:50, 5 mL) was added N,N-diisopropylethylamine (380 mg, 2.96 mmol), and the resulting reaction mixture was stirred at room temperature for 1 h. Then, 1-[2-(4-aminomethyl-phenyl)-5-tert-butyl-2H-pyrazol-3-yl]-3-[4-(pyridin-4-yloxy)phenyl]urea (450 mg, 0.99 mmol) was added to the solution and the reaction mixture was stirred at 50° C. for 18 h. The reaction mixture was cooled to room temperature, concentrated at reduced pressure, and the residue was dissolved in EtOAc (20 mL). The solution was washed with water and brine, dried over Na2SO4, and concentrated at reduced pressure. The residue was purified by preparative TLC (50:50 hexanes/EtOAc) to give 65 mg (11%) of the desired product. 1H-NMR (DMSO-d6) δ 8.68 (s, 1H), 8.42 (d, J=6.3 Hz, 2H), 7.98 (s, 1H), 7.82 (b, 1H), 7.61 (d, J=6.9 Hz, 2H), 7.50 (d, J=8.4 Hz, 2H), 7.42 (d, J=8.4 Hz, 2H), 7.08 (d, J=6.6 Hz, 2H), 6.80 (d, J=6.3 Hz, 2H), 6.46 (s, 1H), 4.48 (d, J=6.0 Hz, 2H), 3.78 (d, J=5.7 Hz, 2H), 1.35 (s, 9H), 1.30 (s, 9H); MS LC-MS [M+H]+=614, RT=2.89 min.
Reaction SMILES: [CH2:1]([C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[Br-].[C:15]([CH2:18][CH2:19][CH2:20][CH2:21][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:17])=[O:16]>C1COCC1>[CH2:1]([C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[CH:21][CH2:20][CH2:19][CH2:18][C:15]([OH:17])=[O:16])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: O=C(O)CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCCc1ccc(C=O)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CCCCCc1ccc(C=CCCCC(=O)O)cc1
Yield: 47.8 %

Procedure:
This compound was synthesized from p-pentylbenzaldehyde (3.52 g, 20 mmol, prepared from p-pentylbenzoyl chloride and lithium tri(t-butoxy)aluminum hydride) and 4-carboxybutyltriphenylphosphonium bromide (8.86 g, 20 mmol) in THF (100 mL) by a Wittig reaction. Kugelrohr distillation (bp 147-151° C./0.05 torr) afforded the product (2.49 g, 48%). IR: 3400-2500, 1725 cm-1 ; 1H-NMR: 0.90 (t, 3H), 1.28 (m, 6H), 1.82 (m, 2H), 1.37 (m, 4H), 2.57 (t, 2H), 5.55+6.10 (m, 1H), 6.38 (m, 1H), 7.10 (m, 4H), 10.50 (bs, 1H). Anal. Calcd. for C17H24O2 : C, 78.42, H, 9.29%; Found: C, 78.22, H, 9.27%. Z:E=35:65.
Reaction SMILES: Br[CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([O:5]CC)=[O:4].[CH2:14]([C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19])[CH3:15].C(N(C(C)C)C(C)C)C.O.[OH-].[Li+].[ClH:35]>C(#N)C.O1CCOCC1.O>[ClH:35].[CH2:14]([C:16]1[CH:17]=[C:18]([NH:19][CH:2]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:3]([OH:5])=[O:4])[CH:20]=[CH:21][CH:22]=1)[CH3:15]
Reactant: CCc1cccc(N)c1
Reactant: CCOC(=O)C(Br)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cccc(NC(C(=O)O)c2ccccc2)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
Ethyl 2-bromo-2-phenylacetate (0.29 mL, 1.64 mmol), 3-ethylaniline (0.31 mL, 2.47 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.43 mL, 2.47 mmol) are dissolved in acetonitrile (5 mL) and stirred under MW irradiation at 100° C. for 1 hour (Conversion complete by UPLC/MS-UV). Lithium hydroxide hydrate (207 mg, 4.94 mmol) and water (3 mL) are added and the mixture is stirred at RT for 16 hours. 4M HCl in dioxane is added until pH 1 and the solvents are evaporated. The residue is suspended in water, sonicated, cooled at 0° C. and filtered under suction. The recovered white solid is dried under vacuum at 40° C. overnight (414 mg, 86% yield).
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([CH3:46])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:45])[CH2:12][CH2:13][C@@:14]3([C:30]([N:32]4[CH2:37][CH2:36][C:35]([CH2:43][CH3:44])([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:34][CH2:33]4)=[O:31])[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:48])[CH3:47])(=O)C.C1COCC1.[OH-].[Na+]>CO>[CH2:43]([C:35]1([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:34][CH2:33][N:32]([C:30]([C@:14]23[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]2[C@@H:16]2[C@@:11]([CH3:45])([CH2:12][CH2:13]3)[C@@:10]3([CH3:46])[C@@H:19]([C@:20]4([CH3:23])[C@@H:7]([CH2:8][CH2:9]3)[C:6]([CH3:48])([CH3:47])[C@@H:5]([OH:4])[CH2:22][CH2:21]4)[CH2:18][CH2:17]2)=[O:31])[CH2:37][CH2:36]1)[CH3:44]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)N3CCC(CC)(C(=O)OCC)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(C)=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N3CCC(CC)(C(=O)OCC)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 6 h
Yield: 77.4 %

Procedure:
Ethyl 1-((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-acetoxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carbonyl)-4-ethylpiperidine-4-carboxylate (Example 72, 2.0 g) was taken in MeOH:THF (8:8 ml) and cooled the contents to 0° C. then sodium hydroxide (1.5 g in 4 ml water) was added and the contents were stirred for about 6 hours at room temperature. After completion of the reaction (monitored by TLC), the reaction mixture was evaporated under reduced pressure. The residue was taken in water and extracted with DCM; the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% methanol in DCM as eluent to furnish the title compound (1.45 g) as a white solid. 1H NMR (300 MHz, CDCl3): 0.57-0.97 (m, 19H); 1.18-1.21 (m, 8H); 1.25-1.41 (m, 12H); 1.49-1.62 (m, 10H); 1.65-1.82 (m, 10H); 1.85-1.98 (m, 4H); 2.56-2.69 (m, 2H); 3.29-3.38 (m, 1H); 3.89-3.90 (m, 1H); 4.15-4.18 (m, 2H); 4.56 (s, 1H); 4.71 (s, 1H); MASS: 624 (100%).
Reaction SMILES: Cl.[NH2:2][CH:3]([CH:21]([CH3:23])[CH3:22])[C:4]([C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:9]([OH:16])=[C:8]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:7]=1)=O.[N-:24]=[C:25]=[O:26].[K+].Cl>>[C:12]([C:10]1[CH:11]=[C:6]([C:4]2[NH:24][C:25](=[O:26])[NH:2][C:3]=2[CH:21]([CH3:23])[CH3:22])[CH:7]=[C:8]([C:17]([CH3:20])([CH3:18])[CH3:19])[C:9]=1[OH:16])([CH3:14])([CH3:13])[CH3:15]
Reactant: [N-]=C=O
Reactant: CC(C)C(N)C(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: Cl
Agent: [K+]
Product: CC(C)c1[nH]c(=O)[nH]c1-c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Yield: 21.3 %

Procedure:
By following the same procedure as in Example 6 using 1.7 g of 2-amino-1-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-methyl-1-butanone hydrochloride, 0.8 g of potassium isocyanate, and 1 ml of concentrated hydrochloric acid and recrystallizing the reaction product from aqueous isopropanol, 0.35 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-isopropyl-2-oxo-4-imidazoline was obtained.