Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:62][CH3:63])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:41]5[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][N:48]6[CH2:53][CH2:52][N:51](C(OC(C)(C)C)=O)[C@@H:50]([CH3:61])[CH2:49]6)[CH:42]=5)[CH:36]=[C:37]([O:39][CH3:40])[CH:38]=4)=[O:30])[CH:26]=[CH:27][CH:28]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:62][CH3:63])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:41]5[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][N:48]6[CH2:53][CH2:52][NH:51][C@@H:50]([CH3:61])[CH2:49]6)[CH:42]=5)[CH:36]=[C:37]([O:39][CH3:40])[CH:38]=4)=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(OC)cc(-c3cccc(CN4CCN(C(=O)OC(C)(C)C)[C@@H](C)C4)c3)c2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(OC)cc(-c3cccc(CN4CCN[C@@H](C)C4)c3)c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.2 %

Procedure:
237(b) A mixture of 1,1-dimethylethyl (2S)-4-{[3′-{[({3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]phenyl}-carbonyl)amino]-methyl}-5′-(methyloxy)-3-biphenylyl]methyl}-2-methyl-1-piperazinecarboxylate (130 mg, 0.19 mmol) in 25% TFA in DCM (3 mL) was stirred at RT for 2 h. It was purified by preparative hplc (NH2OH condition), eluting with 10 to 90% CH3CN in water. The fractions were dried under GeneVac to give a solid. It was purified further using a Gilson HPLC (with 0.1% TFA condition) and eluting with 10 to 90% CH3CN in water. Fractions containing compound were combined and then converted to its free base with saturated NaHCO3. The organic layer was dried over sodium sulfate, filtered and then concentrated to give N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(5-(methyloxy)-3′-{[(3S)-3-methyl-1-piperazinyl]methyl}-3-biphenylyl)methyl]-1,3-benzenedicarboxamide as a white solid (58 mg, 50%). LC-MS m/z 759 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][C:7](C)=[C:8]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=2)[CH:9]=1)=[O:4].Cl[C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>>[C:15]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:14]=[CH:13][C:12]([O:11][CH2:10][C:8]2[CH:9]=[C:5]([C:3]([OH:2])=[O:4])[O:6][CH:7]=2)=[CH:17][CH:16]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: COC(=O)c1cc(COc2ccc(I)cc2)c(C)o1
Product: O=C(O)c1cc(COc2ccc(-c3ccccc3)cc2)co1

Procedure:
Compound (77) was prepared from compound (20) and (4-chloro-phenyl)-boronic acid by adapting the procedure of Example 5(b). LC/MS System B; Rt=1.93 mins, m/z (ES−)=341 and 343 (M−H for C19H15ClO4).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[C:9](=O)[NH:10][CH:11]=[C:12]([C:15]([NH2:17])=O)[C:13]=3[S:14][C:4]=2[CH:3]=1.O=P(Cl)(Cl)[Cl:21].C([O-])(O)=O.[Na+]>CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[C:9]([Cl:21])=[N:10][CH:11]=[C:12]([C:15]#[N:17])[C:13]=3[S:14][C:4]=2[CH:3]=1
Reactant: NC(=O)c1c[nH]c(=O)c2c1sc1cc(Br)ccc12
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: N#Cc1cnc(Cl)c2c1sc1cc(Br)ccc12

Procedure:
A mixture of 7-bromo-1-oxo-1,2-dihydro[1]benzothieno[3,2-c]pyridine-4-carboxamide and POCl3 (29 equiv) was heated to refluxed for 8 h. The mixture was poured onto ice, neutralized with NaHCO3, filtered, washed with H2O and dried to give a yellow solid. The crude product was heated to reflux with 20% EtOAc in hexanes, cooled and filtered to give the title compound.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=1B1OC(C)(C)C(C)(C)O1.CCN(C(C)C)C(C)C>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=1[C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1
Reactant: CC1(C)OB(c2c(F)cccc2F)OC1(C)C
Reactant: CCOC(=O)c1csc(Br)n1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1csc(-c2c(F)cccc2F)n1
Temperature: 120 °C
Reaction time: 3 h
Yield: 75.3 %

Procedure:
To a screw-cap vial equipped with a magnetic stir bar, ethyl 2-bromo-1,3-thiazole-4-carboxylate (Ark Pharm, 2.026 g, 8.582 mmol) was added followed by 2-(2,6-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Combi-Blocks, 2.47 g, 10.3 mmol) and bis(tri-tert-butylphosphine)palladium (781.8 mg, 1.530 mmol). The vial was sealed with a PTFE-lined septum, and was then evacuated and backfilled with nitrogen three times. 1,4-Dioxane (10.0 mL) was added via syringe, followed by DIPEA (2.41 g, 18.6 mmol) and deoxygenated water (0.60 mL). The reaction mixture was stirred at 120° C. for 3 h. After cooling to room temperature, the mixture was filtered through a silica gel plug (eluted with EtOAc). The filtrate was concentrated under reduced pressure, and the residue was purified by chromatography on silica gel (0-100% EtOAc in hexanes) to give the title compound as a pale yellow oil (1.739 g, 75%). LCMS calc. for C12H10F2NO2S (M+H)+: m/z=270.0. found 270.0.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].[CH2:10](Cl)[CH:11]=[CH2:12]>C(O)(C)C.[OH-].[Na+].C(OCC)C>[CH2:12]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([CH3:9])[CH:4]=1)[CH:11]=[CH2:10]
Reactant: Cc1cc(O)ccc1Br
Reactant: C=CCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CC(C)O
Product: C=CCOc1ccc(Br)c(C)c1
Temperature: 70 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
To a dark yellow solution of 4-bromo-3-methyl-phenol (4.68 g, 25 mmol) in isopropanol (60 mL) and 3 N aq. NaOH (20 mL), allylchloride (8.18 g, 107 mmol) is added. The mixture is stirred at 70° C. for 3 h before it is cooled to rt, diluted with diethyl ether and washed with 1 N aq. NaOH solution (275 mL) and 1 M aq. HCl solution (70 mL) followed by brine (70 mL). The org. extract is dried over MgSO4, filtered, concentrated and dried to give crude 4-allyloxy-1-bromo-2-methyl-benzene (5.67 g) as a yellow oil; LC-MS: tR=0.59 min; [M+1]+=not detectable; 1H NMR (CDCl3): δ 2.38 (s, 3H), 4.52 (dt, J=5.3, 1.5 Hz, 2H), 5.29-5.34 (m, 1H), 5.39-5.46 (m, 1H), 6.00-6.11 (m, 1H), 6.65 (dd, J=8.8, 3.0 Hz, 1H), 6.83 (d, J=3.0 Hz, 1H), 7.41 (d, J=8.5 Hz, 1H).
Reaction SMILES: [CH:1]([NH:4][CH2:5][C:6]([OH:8])=O)([CH3:3])[CH3:2].[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([CH3:19])=[C:14]([N:16]=[C:17]=[S:18])[CH:15]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([CH3:19])=[C:14]([N:16]2[C:6](=[O:8])[CH2:5][N:4]([CH:1]([CH3:2])[CH3:3])[C:17]2=[S:18])[CH:15]=1
Reactant: CC(C)NCC(=O)O
Reactant: Cc1ccc(Cl)cc1N=C=S
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1ccc(Cl)cc1N1C(=O)CN(C(C)C)C1=S
Yield: 54.7 %

Procedure:
A mixture of the crude N-isopropyl glycine (21.2 g), 5-chloro-2-methylphenylisothiocyanate (18.3 g), triethyl amine (21.0 g) and chloroform (300 mL) was heated at reflux for 4 hours. The solvent was evaporated. The residue was dissolved in ethyl acetate (400 mL) and water (300 mL). The organic phase was washed with 2N HCl (2×300 mL), then with water. The organic phase was dried over anhydrous magnesium sulfate and evaporated to dryness. Crystallization from ethanol afforded the title compound (15.4 g) as a peach solid, m.p. 142°-144° C. Anal. Calcd. for. C13H15Cl N2O S: C, 55.21; H, 5.35; N, 9.91. Found: C, 55.07; H, 5.20; N, 9.82. Mass spectrum (+FAB, [M+H]+) m/z 283/285.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:19]=[O:20])=[C:9]([O:11]S(C(F)(F)F)(=O)=O)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1C=CC(C=O)=C(O)C=1)(C)(C)C.[BH4-].[Na+]>CO.O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:19][OH:20])=[C:9]([OH:11])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(C=O)c(OS(=O)(=O)C(F)(F)F)c1
Agent: CC(C)(C)c1ccc(C=O)c(O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)c1ccc(CO)c(O)c1
Reaction time: 1 h

Procedure:
A stirred, cooled (ice-bath) solution of a 1:1 mixture of trifluoro-methanesulfonic acid 5-tert-butyl-2-formyl-phenyl ester and 4-tert-butyl-2-hydroxy-benzaldehyde (Intermediate 105, 0.47 g) in methanol (8 mL) was treated with sodium borohydride (0.1 g, 2.64 mmol). After 1 h, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to a residue that was subjected to flash column chromatography on silica gel (230-400 mesh) to afford the title product (0.3 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]([OH:13])=O)=[N:9][CH:10]=1)=[O:4].C1N=CN(C(N2C=NC=C2)=O)C=1.[Cl:26][C:27]1[CH:28]=[C:29]([CH:31]=[C:32]([Cl:37])[C:33]=1[O:34][CH2:35][CH3:36])[NH2:30].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:26][C:27]1[CH:28]=[C:29]([NH:30][C:11]([C:8]2[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:10][N:9]=2)=[O:13])[CH:31]=[C:32]([Cl:37])[C:33]=1[O:34][CH2:35][CH3:36]
Reactant: COC(=O)c1ccc(C(=O)O)nc1
Reactant: CCOc1c(Cl)cc(N)cc1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1c(Cl)cc(NC(=O)c2ccc(C(=O)OC)cn2)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.1 %

Procedure:
5-(Methoxycarbonyl)-2-pyridine carboxylic acid (50 mg, 276 μmol) was dissolved in DMF (2 mL) and treated with CDI (60 mg, 370 μmol). The reaction mixture was stirred at RT for 2 h. 3,5-Dichloro-4-ethoxyaniline (2) (57 mg, 276 μmol) and DIPEA (96 μL, 552 μmol) were added sequentially and the reaction mixture was stirred at RT overnight, then at 70° C. for 19 h. The reaction mixture was partitioned between EtOAc and aqueous HCl (1 M). The organic layer was washed successively with water and brine, and then dried over MgSO4, filtered and concentrated in vacuo. The residue was crystallised from methanol to afford methyl 6-(3,5-dichloro-4-ethoxyphenylcarbamoyl)nicotinate (3) (46 mg, 45%) as a white solid: m/z 369 [M+H]+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 11.12 (1H, s), 9.18 (1H, dd), 8.55 (1H, dd), 8.29 (1H, dd), 8.13 (2H, s), 4.06 (2H, q), 3.94 (3H, s), 1.37 (3H, t).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH2:7]([O:14][C:15]1[CH:20]=[C:19](F)[CH:18]=[CH:17][C:16]=1[N+:22]([O-:24])=[O:23])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:25]1([OH:31])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>CN(C=O)C>[CH2:7]([O:14][C:15]1[CH:20]=[C:19]([O:31][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:18]=[CH:17][C:16]=1[N+:22]([O-:24])=[O:23])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1OCc1ccccc1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ccccc2)cc1OCc1ccccc1
Temperature: 100 °C
Reaction time: 48 h

Procedure:
To a suspension of K2CO3 (0.654 g, 4.74 mmol) in DMF (6 mL) is added 2-benzyloxy-4-fluoro-1-nitrobenzene (0.90 g, 3.64 mmol), followed by phenol (0.343 g, 3.64 mmol). The mixture is stirred at 100° C. for 48 h. The mixture is allowed to cool to ambient temperature, then poured into water and extracted into EtOAc. The organic phase is washed with water (2×), saturated NaCl (1×), and dried over Na2SO4. The solvent is removed under reduced pressure to afford 2-benzyloxy-4-phenoxy-1-nitrobenzene as a pale-yellow solid: mp=96-98° C.; 1H NMR (CDCl3) δ 7.87 (d, J=9.09 Hz, 1H), 7.36-7.23 (m, 7H), 7.20-7.15 (m, 1H), 6.95 (dd, J=8.59, 1.01 Hz, 1H), 6.58 (d, J=2.27 Hz, 1H), 6.46-6.43 (m, 1H), 5.08 (s, 2H).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[CH:14]=[C:15]([C:18]([NH:20][NH2:21])=[O:19])[CH:16]=[CH:17][C:12]=3[N:11]=[CH:10]2)=[CH:5][CH:4]=1.[F:22][C:23]([F:36])([F:35])[C:24]1[CH:25]=[C:26]([CH2:30][CH2:31][C:32](O)=O)[CH:27]=[CH:28][CH:29]=1>>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[CH:14]=[C:15]([C:18]4[O:19][C:32]([CH2:31][CH2:30][C:26]5[CH:27]=[CH:28][CH:29]=[C:24]([C:23]([F:22])([F:35])[F:36])[CH:25]=5)=[N:21][N:20]=4)[CH:16]=[CH:17][C:12]=3[N:11]=[CH:10]2)=[CH:5][CH:4]=1
Reactant: O=C(O)CCc1cccc(C(F)(F)F)c1
Reactant: CSc1ccc(-n2cnc3ccc(C(=O)NN)cc32)cc1
Product: CSc1ccc(-n2cnc3ccc(-c4nnc(CCc5cccc(C(F)(F)F)c5)o4)cc32)cc1
Yield: 70 %

Procedure:
In the same manner as in Example 14 and using 1-[4-(methylthio)phenyl]-1H-benzimidazole-6-carbohydrazide instead of 1H-benzotriazole-5-carbohydrazide and using 3-[3-(trifluoromethyl)phenyl]propionic acid instead of 3-(3-cyanophenyl)propionic acid, the title compound (yield 70%) was obtained as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:16]3[C:11]([CH:12]=[N:13][C:14]([NH:17][C:18]4[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=4)=[N:15]3)=[C:10]([CH3:30])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:31][C:32]1[CH:33]=[C:34]([CH:36]=[CH:37][C:38]=1[N:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1)[NH2:35].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>O1CCOCC1>[Cl:31][C:32]1[CH:33]=[C:34]([NH:35][C:2]2[CH:3]=[C:4]([C:8]3[N:16]4[C:11]([CH:12]=[N:13][C:14]([NH:17][C:18]5[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=5)=[N:15]4)=[C:10]([CH3:30])[N:9]=3)[CH:5]=[CH:6][CH:7]=2)[CH:36]=[CH:37][C:38]=1[N:39]1[CH2:40][CH2:41][O:42][CH2:43][CH2:44]1
Reactant: COc1cc(Nc2ncc3c(C)nc(-c4cccc(Br)c4)n3n2)cc(OC)c1OC
Reactant: Nc1ccc(N2CCOCC2)c(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: C1COCCO1
Product: COc1cc(Nc2ncc3c(C)nc(-c4cccc(Nc5ccc(N6CCOCC6)c(Cl)c5)c4)n3n2)cc(OC)c1OC
Temperature: 130 °C
Yield: 39.1 %

Procedure:
To a mixture of 7-(3-bromophenyl)-5-methyl-N-(3,4,5-trimethoxyphenyl)imidazo[5,1-f][1,2,4]triazin-2-amine (Example 9) (40 mg, 0.085 mmol), 3-chloro-4-morpholin-4-ylaniline (21.7 mg, 0.102 mmol), (S)-(−)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl ((S)-BINAP) (15.9 mg, 0.026 mmol), Tris(dibenzylidineacetone)dipalladium (0) (7.8 mg, 0.008 mmol) and sodium t-butoxide (11.4 mg, 0.12 mmol) was added 1,4-dioxane (1.5 mL). In a sealed reaction vessel, the mixture was heated with microwave radiation at 130° C. for 30 minutes. After cooling to room temperature, removed solvent under reduced pressure and diluted residue in DMSO (1.0 mL). Filtered and injected (2×0.5 mL) on an Agilent reverse phase prep LC subjected to a gradient elution using acetonitrile (0.1% Formic acid):water (0.1% Formic acid) (10:90 to 90:10). Combined appropriate fractions and removed solvent under reduced pressure. Added methanol, dichloromethane and silica gel (100 mg) followed by evaporation of the volatiles under reduced pressure. The pre-adsorbed solids were loaded into a solid loading cartridge and subjected to a gradient elution using ethyl acetate:hexanes (30:70) to ethyl acetate:hexanes (90:10) using a RediSep silica gel cartridge (4.2 g; ISCO). The appropriate fractions were combined and concentrated under reduced pressure to give 7-{3-[(3-chloro-4-morpholin-4-ylphenyl)amino]phenyl}-5-methyl-N-(3,4,5-trimethoxyphenyl)imidazo[5,1-f][1,2,4]triazin-2-amine (0.020 g) as a yellow solid. 1H NMR (CDCl3): δ8.79 (s, 1H), 8.09 (dd, J=2.0, 1.9 Hz, 1H), 8.01-7.98 (m, 1H), 7.33 (dd, J=8.0, 7.9 Hz, 1H), 7.18 (d, J=2.6 Hz, 1H), 7.15 (ddd, J=8.2, 2.3, 0.9 Hz, 1H), 7.02 (dd, J=8.6, 2.5 Hz, 1H), 6.95-6.93 (m, 3H), 6.90 (s, 1H), 5.95 (s, 1H), 3.88-3.86 (m, 4H), 3.84 (s, 9H), 3.01-2.98 (m, 4H) 2.60 (s, 3H). MS m/z 602 (M+1).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].[C:6]([C:8]1[CH:34]=[CH:33][C:11]([C:12]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([CH3:32])=[C:19]([NH:21][C:22](=[O:31])[C:23]3[CH:28]=[CH:27][C:26]([CH2:29]Cl)=[CH:25][CH:24]=3)[CH:20]=2)=[O:13])=[CH:10][CH:9]=1)#[N:7].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:6]([C:8]1[CH:9]=[CH:10][C:11]([C:12]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([CH3:32])=[C:19]([NH:21][C:22](=[O:31])[C:23]3[CH:28]=[CH:27][C:26]([CH2:29][NH:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:25][CH:24]=3)[CH:20]=2)=[O:13])=[CH:33][CH:34]=1)#[N:7]
Reactant: COCCN
Reactant: Cc1ccc(NC(=O)c2ccc(C#N)cc2)cc1NC(=O)c1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COCCNCc1ccc(C(=O)Nc2cc(NC(=O)c3ccc(C#N)cc3)ccc2C)cc1
Temperature: 55 °C
Reaction time: 96 h
Yield: 59 %

Procedure:
2-Methoxyethylamine (0.019 ml) was added to a stirred solution of N-[5-(4-cyanobenzamido)-2-methylphenyl]-4-(chloromethyl)benzamide (0.060 g) and potassium carbonate (0.041 g) in acetone (5 ml) and the reaction mixture was heated to 55° C. overnight. Further portions of 2-methoxyethylamine and potassium carbonate (same quantities as before) were added and the reaction mixture was stirred at 55° C. for a further 4 days. The reaction mixture was evaporated and the residue was triturated with water. The resultant solid-was isolated and dried under vacuum at 55° C. to give the title compound as a solid (0.039 g, 59%); NMR Spectrum: (CDCl3) 2.27 (s, 3H), 2.83 (m, 2H), 3.37 (m, 4H), 3.56 (t, 2H), 3.91 (s, 2H), 7.19 (d, 1H), 7.49 (d, 2H), 7.77 (m, 7H), 7.95 (d, 2H), 8.13 (s, 1H), 8.3 (s, 1H); Mass Spectrum: M−H− 441.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:4]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[C:5]([N:7]([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])=[O:6].[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33][N:34]=[C:35]=[O:36].CCN(C(C)C)C(C)C.C(O)C(N)(CO)CO>C(Cl)Cl>[CH:11]([N:7]([CH:8]([CH3:9])[CH3:10])[C:5]([CH:4]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[CH:3]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH2:2][NH:1][C:35]([NH:34][CH2:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[F:26])=[O:36])=[O:6])([CH3:13])[CH3:12]
Reactant: CC(C)N(C(=O)C(c1cccnc1)C(CN)c1ccccc1)C(C)C
Reactant: O=C=NCc1ccccc1F
Agent: NC(CO)(CO)CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)N(C(=O)C(c1cccnc1)C(CNC(=O)NCc1ccccc1F)c1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 4-amino-N,N-diisopropyl-3-phenyl-2-(pyridin-3-yl)butanamide (0.030 g, 0.09 mmol) in dry DCM (2 mL) was added 1-fluoro-2-(isocyanatomethyl)benzene (0.028 g, 0.18 mmol), and DIPEA (0.023 mL, 0.135 mmol). The reaction mixture was agitated for 15 h at room temperature before adding PS-trisamine (0.022 g, 0.09 mmol) and agitating for 1 h at room temperature. The crude product was then filtered to remove the solid phase and concentrated. Purification of enantiomers by ChiralPak AD (n-hexanes/EtOH, 85:15) yielded (−)-1-(3-(diisopropylcarbamoyl)-2-phenyl-3-(pyridin-3-yl)propyl)-3-(2-fluorobenzyl)urea as a foamy, off-white solid. Analytical LCMS: single peak (214 nm), 2.523 min. 1H NMR (CDCl3, 300 MHz) δ 8.26 (d, J=4.5 Hz, 1H), 8.03 (s, 1H), 7.38-7.42 (m, 2H), 7.19-7.25 (m, 1H), 6.99-7.13 (m, 6H), 6.91-6.93 (m, 2H), 4.54-4.59 (m, 1.37 (d, J=6.9 Hz, 3H), 1.26 (d, J=6.9 Hz, 3H), 1.19 (d, J=6.9 Hz, 3H), 0.60 (d, J=6.3 Hz, 3H); HRMS m/z 491.2841 (C29H35FN4O2+H requires 491.2817).
Reaction SMILES: [C:1]([CH2:4][CH2:5][NH:6][C:7]([C@:9]12[CH2:43][CH2:42][C@@H:41]([C:44]([CH3:46])=[CH2:45])[C@@H:10]1[C@@H:11]1[C@@:24]([CH3:27])([CH2:25][CH2:26]2)[C@@:23]2([CH3:28])[C@@H:14]([C@:15]3([CH3:40])[C@@H:20]([CH2:21][CH2:22]2)[C:19]([CH3:30])([CH3:29])[C:18]([C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][CH:32]=2)=[CH:17][CH2:16]3)[CH2:13][CH2:12]1)=[O:8])([OH:3])=[O:2].C(N/C(=N/C(C)C)/O[CH2:53][CH2:54][Si:55]([CH3:58])([CH3:57])[CH3:56])(C)C>C1COCC1.CCOC(C)=O>[CH3:27][C@:24]12[C@@:23]3([CH3:28])[C@@H:14]([C@:15]4([CH3:40])[C@@H:20]([CH2:21][CH2:22]3)[C:19]([CH3:30])([CH3:29])[C:18]([C:31]3[CH:32]=[CH:33][C:34]([C:35]([O:37][CH2:53][CH2:54][Si:55]([CH3:58])([CH3:57])[CH3:56])=[O:36])=[CH:38][CH:39]=3)=[CH:17][CH2:16]4)[CH2:13][CH2:12][C@@H:11]1[C@H:10]1[C@H:41]([C:44]([CH3:46])=[CH2:45])[CH2:42][CH2:43][C@:9]1([C:7](=[O:8])[NH:6][CH2:5][CH2:4][C:1](=[O:3])[O:2][CH2:53][CH2:54][Si:55]([CH3:56])([CH3:57])[CH3:58])[CH2:26][CH2:25]2
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCC(=O)O)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: CC(C)/N=C(/NC(C)C)OCC[Si](C)(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCC(=O)OCC[Si](C)(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OCC[Si](C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reaction time: 16 h
Yield: 88.3 %

Procedure:
A mixture of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-carboxyethylcarbamoyl)-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 (35 mg, 0.056 mmol) and (Z)-2-(trimethylsilyl)ethyl N,N′-diisopropylcarbamimidate (27.2 mg, 0.111 mmol) was refluxed in THF (1 mL) for 4 h. Then the mixture was placed at room temperature for 16 h. TLC showed no starting material and a new less polar product Rf=0.4 in 10% AcOEt/Hex. The solvent was removed in vacuo. The residue was dissolved in methylene chloride and purified in silica gel (0-10% AcOEt/Hex) to afford 2-(trimethylsilyl)ethyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(3-oxo-3-(2-(trimethylsilyl)ethoxy)propylcarbamoyl)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (43 mg, 0.049 mmol, 89% yield) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.93 (d, J=8.28 Hz, 2H), 7.20 (d, J=8.03 Hz, 2H), 6.24 (t, J=6.02 Hz, 1H), 5.30 (d, J=4.77 Hz, 1H), 4.76 (d, J=1.51 Hz, 1H), 4.61 (s, 1H), 4.49-4.37 (m, 2H), 4.28-4.17 (m, 2H), 3.65-3.52 (m, 1H), 3.52-3.39 (m, 1H), 3.15 (td, J=10.85, 3.64 Hz, 1H), 2.63-2.43 (m, 3H), 2.11 (dd, J=17.19, 6.40 Hz, 1H), 2.02-1.90 (m, 2H), 1.80-1.04 (m, 22H), 1.70 (s, 3H), 1.01 (s, 3H), 1.00 (s, 3H), 0.98 (s, 3H), 0.93 (s, 6H), 0.10 (s, 9H), 0.06 (s, 9H).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(S)CCC.C[CH:14]1[CH2:20][C:19](C)(C)[CH2:18][C:16](=[O:17])[CH2:15]1.Cl.[OH-].[Na+]>O>[CH:20]1[CH:19]=[C:18]([C:3]2[CH:4]=[CH:5][CH:6]=[C:1]([OH:7])[CH:2]=2)[C:16]([OH:17])=[CH:15][CH:14]=1
Reactant: CC1CC(=O)CC(C)(C)C1
Reactant: Oc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCS
Solvent: O
Product: Oc1cccc(-c2ccccc2O)c1
Temperature: 30 °C
Reaction time: 70 h

Procedure:
564 (6 mol) of phenol, 10.8 g (0.12 mol) of butanethiol and 140 g (1 mol) of dihydroisophorone (3,3,5-trimethylcyclohexan-1-one) are introduced into a stirring apparatus equipped with a stirrer, thermometer, reflux condenser and gas inlet pipe at 30° C. At this temperature 44 g of 37% HCl are added. The reaction mixture is stirred for about 70 h at 28°-30° C. When 95% of the ketone has been converted (examined by GC) 2 l of water are added to the reaction mixture and a pH value of 6 is adjusted by adding a 45% NaOH solution. The reaction mixture is stirred for one hour at 80° C. and then cooled to 25° C. The aqueous phase is decanted off and the remaining residue is washed with water at 80° C. The resulting crude product is filtered off and hot-extracted twice with n-hexane and twice with toluene and then filtered at 30 ° C.