Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[C:2]1([CH2:8][CH:9]2[CH:14]3[C:15]([CH2:17][CH3:18])=[CH:16][CH:11]([CH:12]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:13]3)[N:10]2[CH3:24])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd].C(O)C>[ClH:1].[C:2]1([CH2:8][CH:9]2[CH:14]3[CH:15]([CH2:17][CH3:18])[CH2:16][CH:11]([CH:12]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:13]3)[N:10]2[CH3:24])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1CC2C(CC)=CC1N(C)C2Cc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C1CC2C(CC)CC1N(C)C2Cc1ccccc1
Temperature: 50 °C
Yield: 72.9 %

Procedure:
A mixture of ethyl 3-(phenylmethyl)-8-ethyl-2-methyl-2-azabicyclo[2.2.2]oct-7-ene-6-carboxylate hydrochloride (23.2 g, 0.067 mol), ethanol (300 mL) and 10% palladium on carbon (1.0 g) was placed on a Parr hydrogenator at approximately 50 psi and was heated to 50° C. for 3 hours and 20 minutes. The catalyst was removed by filtration and the filtrate was concentrated in vacuo. The residue was dissolved in hot ethanol and cooled on an ice-bath. The precipitate which formed was collected by filtration and dried at 40° C. in vacuo to afford 17.2 g (73%) of ethyl 3-(phenylmethyl)-8-ethyl-2-methyl-2-azabicyclo[2.2.2]octane-6-carboxylate hydrochloride, m.p. 226°-227° C.
Reaction SMILES: [F:1][C:2]1[C:3]([C:14]([F:17])([F:16])[F:15])=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:18][Si](C)(C)Cl>CO>[CH3:18][O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([F:1])[C:3]([C:14]([F:15])([F:16])[F:17])=[CH:4][C:5]=1[N+:11]([O-:13])=[O:12]
Reactant: C[Si](C)(C)Cl
Reactant: O=C(O)c1cc(F)c(C(F)(F)F)cc1[N+](=O)[O-]
Solvent: CO
Product: COC(=O)c1cc(F)c(C(F)(F)F)cc1[N+](=O)[O-]

Procedure:
A solution of 6.2 g (24.5 mmole) of 5-fluoro-2-nitro-4-trifluoromethyl-benzoic acid in 250 ml of methanol is treated with 9.28 ml (73.5 mmole) of trimethylchlorosilane and heated to reflux for six days during which every evening additional 9.28 ml of trimethylchlorosilane are added. The cooled solution is evaporated in vacuo and distributed between dichloro-methane and water. The combined organic phases are extracted twice with 50 ml of a 0.5 M sodium hydroxide solution and with 50 ml brine. After drying over sodium sulfate, filtering and evaporation the crystalline residue is recrystallized from acetone/petrolether to give 5-fluoro-2-nitro-4-trifluoromethyl-benzoic acid methyl ester of m.p. 66-68° C.
Reaction SMILES: [N+:1]([CH:4]([CH:10]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH:14]=[CH:13][C:12]2[CH:21]=[CH:22][CH:23]=[CH:24][C:11]1=2)[C:5]([O:7][CH2:8][CH3:9])=[O:6])([O-])=O.O.[ClH:26]>C(O)C.[Pd]>[ClH:26].[NH2:1][CH:4]([CH:10]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH2:14][CH2:13][C:12]2[CH:21]=[CH:22][CH:23]=[CH:24][C:11]1=2)[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C(C1c2ccccc2C=Cc2ccccc21)[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(N)C1c2ccccc2CCc2ccccc21

Procedure:
Ethyl α-nitro-5H-dibenzo[a,d]cycloheptene-5-acetate (13 g, 40 mmol) (Example 4, Step A) is dissolved in 150 mL of ethanol, 40 mL of water, and 3.5 mL of concentrated hydrochloric acid and hydrogenated with 2.0 g of 20% palladium on carbon (52 psi, 30 hours). The filtered solution is stripped and a white solid washed with diethyl ether, dried at 50° C./2 mm Hg. The crude product is used as is in the next step.
Reaction SMILES: [H-].[Na+].[C:3]12([C:13]3[CH:14]=[C:15]([OH:21])[CH:16]=[CH:17][C:18]=3[O:19][CH3:20])[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2.[CH3:22][N:23]([CH3:27])[C:24](Cl)=[S:25].O>CN(C=O)C>[CH3:22][N:23]([CH3:27])[C:24](=[S:25])[O:21][C:15]1[CH:16]=[CH:17][C:18]([O:19][CH3:20])=[C:13]([C:3]23[CH2:4][CH:5]4[CH2:11][CH:9]([CH2:8][CH:7]([CH2:6]4)[CH2:12]2)[CH2:10]3)[CH:14]=1
Reactant: CN(C)C(=S)Cl
Reactant: COc1ccc(O)cc1C12CC3CC(CC(C3)C1)C2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(OC(=S)N(C)C)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 0 °C

Procedure:
600 mg (20 mmol) of sodium hydride (80% in oil) and 50 ml of DMF were introduced into a round-bottomed flask under a stream of nitrogen. The mixture was cooled to 0° C. and a solution of 5.5 g (20 mmol) of 3-(1-adamantyl)-4-methoxyphenol in 100 ml of DMF was added dropwise, tand he mixture was stirred until the evolution of gas had ceased. A solution of 3.3 g (26 mmol) of dimethylthiocarbamoyl chloride in 50 ml of DMF was then added thereto and the mixture was stirred for eight hours at room temperature. The reaction medium was poured into water and extracted with ethyl acetate. The organic phase was separated out after settling had taken place, washed with water, dried over magnesium sulfate and evaporated. The residue obtained was purified by chromatography on a column of silica, eluted with a mixture of dichloromethane and hexane (70/30). After evaporation of the solvents, 3.1 g (46%) of the expected compound having a melting point of 162°-4° C., were recovered.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][O:14]C(=O)C)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>Cl>[C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][OH:14])[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)OCc1cccc(-c2ccccc2)n1
Agent: Cl
Product: OCc1cccc(-c2ccccc2)n1
Yield: 81 %

Procedure:
4.5 g of 2-phenyl-6-(acetoxymethyl)-pyridine (20 mmol) was treated with an aqueous HCl solution (15%, 10 ml) and the mixture was heated at reflux temperature while stirring. After 30 minutes the reaction mixture was concentrated with the aid of an oil pump (10 mm) at 40° C., CH3CN was added, and the mixture was evaporated to dryness in vacuo and yielded 2-phenyl-6-(hydroxymethyl)-pyridine (3.0 g, 80%) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[NH:16][C:15](=O)[N:14]([CH3:18])[C:13](=[N:19][C:20]3[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=3[CH3:28])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].P(Cl)(Cl)([Cl:31])=O>>[Cl:31][C:15]1[N:14]([CH3:18])[C:13](=[N:19][C:20]2[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=2[CH3:28])[CH:12]=[C:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:16]=1
Reactant: COc1ccc(-c2cc(=Nc3c(C)cc(C)cc3C)n(C)c(=O)[nH]2)cc1OC
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc(-c2cc(=Nc3c(C)cc(C)cc3C)n(C)c(Cl)n2)cc1OC

Procedure:
To 3,4-dihydro-6-(3,4-dimethoxyphenyl)-3-methyl-4-(2,4,6-trimethylphenylimino)-2-(1H)pyrimidone (5.0 g) was added phosphorus oxychloride (50 ml). The mixture was refluxed for 7 hours and evaporated under reduced pressure. The resulting syrup was triturated in a mixture of ice and water, neutralized with aqueous sodium bicarbonate and extracted with chloroform. The extract was dried and evaporated under reduced pressure. The residue was chromatographed on silica gel using chloroform to give 2-chloro-3,4-dihydro-6-(3,4-dimethoxyphenyl)-3-methyl-4-(2,4,6-trimethylphenylimino)pyrimidine (3.26 g).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][C:7]2([C:10]([O:12]C(C)(C)C)=[O:11])[CH2:9][CH2:8]2)=[C:4]([F:19])[C:3]=1[NH:20][C:21](=[O:36])[C@H:22]([C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[C@@H:23]([CH3:28])[C:24]([F:27])([F:26])[F:25].C(O)(C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][C:7]2([C:10]([OH:12])=[O:11])[CH2:9][CH2:8]2)=[C:4]([F:19])[C:3]=1[NH:20][C:21](=[O:36])[C@H:22]([C:29]1[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=1)[C@@H:23]([CH3:28])[C:24]([F:27])([F:26])[F:25]
Reactant: C[C@H]([C@H](C(=O)Nc1c(Cl)ccc(CC2(C(=O)OC(C)(C)C)CC2)c1F)c1ccc(Cl)cc1)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H]([C@H](C(=O)Nc1c(Cl)ccc(CC2(C(=O)O)CC2)c1F)c1ccc(Cl)cc1)C(F)(F)F
Reaction time: 1 h

Procedure:
22.0 mg (0.040 mmol) of tert-butyl 1-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}-2-fluorobenzyl)cyclopropanecarboxylate were dissolved in 0.19 ml of dichloromethane, and 0.5 ml of TFA was added at RT. After 1 h at RT, the reaction mixture was concentrated under reduced pressure and the residue was dried under high vacuum overnight. This gave 17.8 mg (82.2% of theory) of the target compound.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1.[CH2:15]([NH:22][C:23]([C:25]1[S:29][C:28]([NH2:30])=[N:27][C:26]=1[CH3:31])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([NH:22][C:23]([C:25]1[S:29][C:28]([NH:30][C:8](=[O:9])[C:7]2[CH:11]=[CH:12][C:4]([O:3][C:2]([F:14])([F:13])[F:1])=[CH:5][CH:6]=2)=[N:27][C:26]=1[CH3:31])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Product: Cc1nc(NC(=O)c2ccc(OC(F)(F)F)cc2)sc1C(=O)NCc1ccccc1
Yield: 20 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use 4-trifluoromethoxybenzoyl chloride in place of benzoyl chloride to react with 2-amino-4-methylthiazole-5-carboxylic acid benzylamide, the title compound was obtained as a white solid in 20% yield; m.p. 168-170° C.; 1H NMR (CDCl3, 300 MHz) δ 7.98 (d, J=8.8 Hz, 2H), 7.41-7.23 (m, 7H), 5.97 (t, J=5.6 Hz, 1H), 4.58 (d, J=5.6 Hz, 2H), 2.49 (s, 3H); MS (ES+) m/z 436.1 (M+1).
Reaction SMILES: C(N(C(C)C)/[CH:5]=[C:6](\[F:9])/[CH:7]=O)(C)C.NC1C(C(ON2C3C=CC=CC=3N=N2)=O)=C2N=CC(CC#N)=CN2N=1.[NH2:38][C:39]1[C:43]([C:44]([NH:46][C:47]2[CH:48]=[N:49][CH:50]=[CH:51][C:52]=2[N:53]2[CH2:58][CH2:57][N:56]([CH3:59])[CH2:55][CH2:54]2)=[O:45])=[C:42]([NH2:60])[NH:41][N:40]=1.O>CS(C)=O>[NH2:60][C:42]1[C:43]([C:44]([NH:46][C:47]2[CH:48]=[N:49][CH:50]=[CH:51][C:52]=2[N:53]2[CH2:58][CH2:57][N:56]([CH3:59])[CH2:55][CH2:54]2)=[O:45])=[C:39]2[N:38]=[CH:5][C:6]([F:9])=[CH:7][N:40]2[N:41]=1
Reactant: CC(C)N(/C=C(\F)C=O)C(C)C
Reactant: CN1CCN(c2ccncc2NC(=O)c2c(N)n[nH]c2N)CC1
Agent: N#CCc1cnc2c(C(=O)On3nnc4ccccc43)c(N)nn2c1
Solvent: CS(C)=O
Solvent: O
Product: CN1CCN(c2ccncc2NC(=O)c2c(N)nn3cc(F)cnc23)CC1
Temperature: 140 °C
Reaction time: 0.42 h

Procedure:
A mixture of (Z)-3-(diisopropylamino)-2-fluoro-prop-2-enal (Tetrahedron Letters (1992), 33(3), 357-60) (22.81 mg, 0.1317 mmol), 4-methylbenzenesulfonic acid (Water (1)) (30.05 mg, 0.1580 mmol), 3,5-diamino-N-[4-(4-methylpiperazin-1-yl)-3-pyridyl]-1H-pyrazole-4-carboxamide (50 mg, 0.1580 mmol) in DMSO (1 mL)/H2O (0.5 mL) was stirred at 140° C. for 25 min. The crude mixture was purified by Fractionlynx HPLC. The aqueous fractions were combined and lyophilised to yield 2-amino-6-fluoro-N-(4-(4-methylpiperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. (10 mg, 21%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:9]([C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])[N:8]=[C:7]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])[O:6]1.[CH3:29][C:30]([CH3:32])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C.C([O-])([O-])=O.[Na+].[Na+]>[F:22][C:16]1[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=1[C:7]1[O:6][C:5]([CH2:4][CH2:3][CH2:2][NH:1][CH:30]([CH3:32])[CH3:29])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:9]([C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])[N:8]=1
Reactant: CC(C)=O
Reactant: CC(C)C(=O)N1N=C(c2cc(F)ccc2F)OC1(CCCN)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)NCCCC1(c2ccccc2)OC(c2cc(F)ccc2F)=NN1C(=O)C(C)C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 24.8 %

Procedure:
To a solution of 1-[2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-[1,3,4]oxadiazol-3-yl]-2-methylpropan-1-one (12 mg, 0.031 mmol) in acetonitrile (0.5 mL) was added acetone (60 μL, 0.082 mmol) and sodium triacetoxyborohydride (10 mg, 0.045 mmol). After stirring at room temperature for 45 minutes, more sodium triacetoxyborohydride (10 mg, 0.045 mmol) was added. The mixture stirred at room temperature for 5 hours. The reaction mixture was diluted with 10% Na2CO3 (30 mL) and extracted with ethyl acetate (3×30 mL). The combined organics were washed with brine (45 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (40% to 100% ethyl acetate in hexanes with 2% triethylamine) to provide the final product (3.3 mg, 25%). MS ESI (+) m/z 430 (M+1) detected; 1H NMR (400 MHz, CDCl3) δ 7.56 (m, 2H), 7.50 (m, 1H), 7.36 (m, 3H), 7.15 (m, 2H), 3.36 (m, 1H), 3.01 (m, 1H), 2.78 (m, 1H), 2.67 (m, 2H), 2.53 (m, 1H), 1.66 (m, 2H), 1.20 (d, 3H, J=7 Hz), 1.14 (d, 3H, J=6 Hz), 1.04 (d, 6H, J=6 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([S:13][CH2:14][C:15]([OH:17])=O)[S:11][CH:12]=2)=[CH:4][CH:3]=1.[C:18]([NH2:22])([CH3:21])([CH3:20])[CH3:19]>>[C:18]([NH:22][C:15](=[O:17])[CH2:14][S:13][C:10]1[S:11][CH:12]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[N:9]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: O=C(O)CSc1nc(-c2ccc(F)cc2)cs1
Reactant: CC(C)(C)N
Product: CC(C)(C)NC(=O)CSc1nc(-c2ccc(F)cc2)cs1

Procedure:
The title compound was prepared analogously as described in Example 30(d) from 100 mg (0.37 mmol) of [4-(4-fluoro-phenyl)-thiazol-2-ylsulfanyl]-acetic acid and 54.3 mg (0.74 mmol) of tert-butylamine. Yield: 31 mg.
Reaction SMILES: [CH3:1][N:2]1[C:6]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16]([O:18]C)=[O:17])=[CH:8]2)=[CH:5][N:4]=[CH:3]1.C[Si](C)(C)[O-].[K+]>C1COCC1>[CH3:1][N:2]1[C:6]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16]([OH:18])=[O:17])=[CH:8]2)=[CH:5][N:4]=[CH:3]1
Reactant: COC(=O)c1cn(-c2cncn2C)c2ccccc12
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cn1cncc1-n1cc(C(=O)O)c2ccccc21
Reaction time: 8 h

Procedure:
A solution of methyl 1-(1-methyl-1H-imidazol-5-yl)-1H-indole-3-carboxylate (40 mg, 0.157 mmol) in THF (1567 μl) was treated with potassium trimethylsilanolate (223 mg, 1.567 mmol) in one portion at RT and the resulting reaction mixture stirred overnight. ISCO purification (10% MeOH/DCM) afforded the title compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Si:9]([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)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:6]([Br:8])[CH:7]=1.CC1(C)C(C)(C)OB([C:36]2[CH:53]=[CH:52][C:51]3[C:50]4[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=4)[C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[C:38]=3[CH:37]=2)O1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.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>[Br:8][C:6]1[CH:5]=[C:4]([Si:9]([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)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:3]=[C:2]([C:47]2[CH:48]=[CH:49][C:50]3[C:51]4[C:38](=[CH:37][CH:36]=[CH:53][CH:52]=4)[C:39]4[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=4)[C:45]=3[CH:46]=2)[CH:7]=1
Reactant: CC1(C)OB(c2ccc3c4ccccc4c4ccccc4c3c2)OC1(C)C
Reactant: Brc1cc(Br)cc([Si](c2ccccc2)(c2ccccc2)c2ccccc2)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: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: Brc1cc(-c2ccc3c4ccccc4c4ccccc4c3c2)cc([Si](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Yield: 52.5 %

Procedure:
A solution of (3,5-dibromophenyl)triphenylsilane (2.20 g, 4.45 mmol), 4,4,5,5-tetramethyl-2-(triphenylen-2-yl)-1,3,2-dioxaborolane (3.15 g, 8.90 mmol), Pd(PPh3)4 (0.051 g, 0.045 mmol) and K2CO3 (1.23 g, 8.90 mmol) in toluene (100 mL) and water (20 mL) was refluxed under nitrogen overnight. After cooling to room temperature, the organic phase was isolated, filtered through a short plug of Celite® and the solvent was evaporated. The residue was purified by column chromatography on silica gel with hexane/DCM (7/3, v/v) as eluent followed by recrystallization from the same solvent to yield (3-bromo-5-(triphenylen-2-yl)phenyl)triphenylsilane (1.50 g, 52%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[H][H]>C(O)(C)C.[Pd]>[OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][CH2:9][CH2:8][C:7]2=[O:12]
Reactant: [H][H]
Reactant: Oc1cccc2c(O)cccc12
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: O=C1CCCc2c(O)cccc21
Temperature: 25 °C
Yield: 59.3 %

Procedure:
To a mixture of 1,5-dihydroxynaphthalene (25.0 g, 156 mmol) in isopropanol (150 mL) and an aqueous (40 mL) solution of sodium hydroxide (6.3 g, 157 mmol) was added 10% palladium on carbon (3.9 g) at room temperature. The reaction mixture was put under 100 psi hydrogen in a Parr autoclave (from Parr Instrument Company) at 80° C. for 20 hours. After being cooled to room temperature, the reaction mixture was filtered through a pad of Celite® (a diatomite filter from World Minerals Inc.), and then washed with isopropanol (200 mL). The combined filtrates were treated with charcoal at 50° C. for 1 hour, and then were filtered through a pad of Celite® (diatomite filter). Isopropanol was removed, and the resulting solution was adjusted to a pH of about 2 by the slow addition of concentrated hydrochloric acid, during which a solid precipitate appeared. The solid was collected, and washed with water (100 mL×2), and then dried under high vacuum at 50° C. to give 5-hydroxy-3,4-dihydro-2H-naphthalen-1-one (15.0 g, 60%) as a dark brown solid, which was used in the next step without further purification. MS cald. (calculated) for C10H10O2 162, obsd. (observed) 163 [(M+H)+].
Reaction SMILES: C1C2C(COC(=O)[NH:17][C@H:18]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:19][CH2:20][C:21](=[O:42])[NH:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])C3C(=CC=CC=3)C=2C=CC=1.[OH-].N>O1CCOCC1>[NH2:17][C@H:18]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:19][CH2:20][C:21](=[O:42])[NH:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][NH:34][C:35](=[O:41])[O:36][C:37]([CH3:38])([CH3:39])[CH3:40]
Reactant: CC(C)(C)OC(=O)NCCOCCOCCOCCNC(=O)CC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C
Agent: N
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCCOCCOCCOCCNC(=O)CC[C@H](N)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.4 %

Procedure:
To (S)-tert-butyl 1-(9H-fluoren-9-yl)-24,24-dimethyl-3,8,22-trioxo-2,12,15,18,23-pentaoxa-4,9,21-triazapentacosane-5-carboxylate (1.18 g, 1.69 mmol), in 1,4-dioxane (45 mL) chilled to 0° C. concentrated ammonia hydroxide (9.5 mL, 133 mmol) was added dropwise over 15 minutes. The reaction was stirred at 0° C. for 2 hours and then at ambient temperature for 16 hours. After this time, the reaction was dry loaded onto silica and purified by silica gel column chromatography eluting with methylene chloride to 3:17 methanol/methylene chloride to afford (S)-tert-butyl 21-amino-2,2-dimethyl-4,18-dioxo-3,8,11,14-tetraoxa-5,17-diazadocosan-22-oate (802 mg, 99%) as an off-white solid: 1H NMR (300 MHz, CDCl3) δ 6.92 (bs, 1H), 5.14 (bs, 3H), 3.90-3.85 (m, 1H), 3.80-3.54 (m, 9H), 3.49-3.45 (m, 2H), 3.34-3.29 (m, 2H), 3.23-3.15 (m, 3H), 2.61-2.41 (m, 2H), 2.33-2.23 (m, 1H), 2.15-2.03 (m, 1H), 1.48 (s, 9H), 1.46 (s, 9H); ESI MS m/z=478 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[NH:8][C:9](=[O:18])[N:10]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]=2[CH:5]=[C:4]([CH3:19])[N:3]=1.C([O-])(=O)C.[Na+].[Br:25]Br>C(O)(=O)C.O>[NH2:1][C:2]1[C:7]2[NH:8][C:9](=[O:18])[N:10]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]=2[C:5]([Br:25])=[C:4]([CH3:19])[N:3]=1
Reactant: Cc1cc2c([nH]c(=O)n2Cc2ccccc2)c(N)n1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1nc(N)c2[nH]c(=O)n(Cc3ccccc3)c2c1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Amino-1-benzyl-6-methyl-1,3-dihydro-imidazo[4,5-c]pyridin-2-one (20 mg, 0.08 mmol) was suspended in 5 mL of acetic acid then sodium acetate (5 mg, 0.08 mmol) was added followed by bromine (4□L, 0.08 mmol) dropwise. The mixture was stirred at room temperature for 30 minutes. The mixture was diluted in water (50 mL) and extracted with ethyl acetate (50 mL), the organic layer was separated, dried over magnesium sulfate and the solvent was removed in vacuo. The residue was purified by column chromatography on silica gel using 10% of methanol in ethyl acetate to give 15 mg of the title compound as a brown solid.
Reaction SMILES: [CH3:1][C:2]([CH3:58])([CH2:10][C:11]([O:13][C@H:14]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@@H:16]([CH2:17][CH2:18][C@:19]3([CH3:55])[C@@H:28]2[CH2:27][CH2:26][C@H:25]2[C@@:20]3([CH3:54])[CH2:21][CH2:22][C@@:23]3(/[CH:40]=[CH:41]/[C:42]([NH:44][C@@H:45]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=4[Cl:53])[CH3:46])=[O:43])[CH2:35][C:34](=[O:36])[C:33]([CH:37]([CH3:39])[CH3:38])=[C:24]32)[C:15]1([CH3:57])[CH3:56])=[O:12])[C:3]([O:5]C(C)(C)C)=[O:4].C(O)(C(F)(F)F)=O>ClCCl>[Cl:53][C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=1[C@H:45]([NH:44][C:42](=[O:43])/[CH:41]=[CH:40]/[C@:23]12[CH2:35][C:34](=[O:36])[C:33]([CH:37]([CH3:39])[CH3:38])=[C:24]1[C@@H:25]1[C@@:20]([CH3:54])([CH2:21][CH2:22]2)[C@@:19]2([CH3:55])[C@@H:28]([C@:29]3([CH3:32])[C@@H:16]([CH2:17][CH2:18]2)[C:15]([CH3:56])([CH3:57])[C@@H:14]([O:13][C:11](=[O:12])[CH2:10][C:2]([CH3:1])([CH3:58])[C:3]([OH:5])=[O:4])[CH2:31][CH2:30]3)[CH2:27][CH2:26]1)[CH3:46]
Reactant: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)OC(C)(C)C)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(/C=C/C(=O)N[C@H](C)c2ccccc2Cl)CC1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(/C=C/C(=O)N[C@H](C)c2ccccc2Cl)CC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
To a solution of 1-tert-butyl 4-((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((E)-3-(((R)-1-(2-chlorophenyl)ethyl)amino)-3-oxoprop-1-en-1-yl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) 2,2-dimethylsuccinate (200 mg, 0.101 mmol) in dichloromethane (6 mL) stirred at room temp was added TFA (3 ml, 38.9 mmol). The reaction mixture was stirred at 25° C. for 2 h. The product was extracted with DCM (20 mL*2) and the combined organic phase was washed with H2O (20 mL*2) and brine (30 mL), dried. Then, the solvent was removed under reduced pressure. The residue was purified by preparative-HPLC to give the title compound (70 mg, 0.092 mmol, 91%) was collected as white solid. 1H NMR (400 MHz, METHANOL-d4) δ=8.69 (d, J=7.3 Hz, 1H), 7.50-7.17 (m, 4H), 6.83 (d, J=16.1 Hz, 1H), 6.03 (d, J=15.8 Hz, 1H), 5.52-5.35 (m, 1H), 4.50 (dd, J=5.1, 11.2 Hz, 1H), 3.32-3.26 (m, 1H), 3.00-2.80 (m, 1H), 2.73-2.49 (m, 2H), 2.35-0.77 (m, 50H); LC/MS: m/z calculated 761.4. Found 762.3 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:22]#[N:23])=[C:11]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[S:12][C:13]=1[CH:14]=O.C(O)CCC.[NH2:29][CH2:30][CH:31]([NH2:33])[CH3:32].II.C(=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:22]#[N:23])=[C:11]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[S:12][C:13]=1[C:14]1[NH:29][CH2:30][CH:31]([CH3:32])[N:33]=1
Reactant: N#Cc1c(N2CCOCC2)sc(C=O)c1-c1ccc(Cl)cc1Cl
Reactant: CC(N)CN
Agent: II
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: CC1CNC(c2sc(N3CCOCC3)c(C#N)c2-c2ccc(Cl)cc2Cl)=N1
Reaction time: 0.5 h
Yield: 31.8 %

Procedure:
To 4-(2,4-dichlorophenyl)-5-formyl-2-morpholin-4-ylthiophene-3-carbonitrile (52.0 mg, 0.000142 mol) in tent-butyl alcohol (0.75 g, 0.010 mol) was added 1,2-diaminopropane (12.9 mg, 0.000174 mol) and the mixture was stirred for 30 min. Iodine (51 mg, 0.00020 mol) and potassium carbonate (65.7 mg, 0.000475 mol) was added the mixture was stirred at 70° C. for 3 hr. The reaction mixture was quenched by saturated sodium bicarbonate solution and brine. The organic layer was collected and purified by column chromatography to afford 4-(2,4-dichlorophenyl)-5-(4-methyl-4,5-dihydro-1H-imidazol-2-yl)-2-morpholinothiophene-3-carbonitrile (19 mg, 32%). LCMS: (FA) ES+ 421. 1H NMR (400 MHz, d1-chloroform) δ: 7.60 (s, 1H), 7.50-7.40 (m, 1H), 7.40-7.30 (m, 1H), 4.20-4.05 (m, 1H), 3.90-3.75 (m, 5H), 3.60-3.70 (m, 4H), 3.38-3.20 (m, 1H), 1.25 (s, 3H).