Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](O)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[Br-:13].[Br-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CC#N>[Br:13][C:6]1[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=[CH:8][CH:7]=1
Reactant: Oc1ccnc2cc(Cl)ccc12
Reactant: [Br-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: Clc1ccc2c(Br)ccnc2c1
Temperature: 25 °C

Procedure:
A suspension of 7-chloroquinolin-4-ol (10.0 g, 55.7 mmol) and triphenylphosphine dibromide (35.3 g, 83.6 mmol) in CH3CN (370 mL) was refluxed for 16 hours then cooled to room temperature. The resulting precipitate was collected by vacuum filtration and washed with CH3CN (2×70 mL). The precipitate was then partitioned between CH2Cl2 (300 mL) and 1 M NaOH (aq) (300 mL). The aqueous phase was extracted with CH2Cl2 (100 mL). The combined organics were dried over Na2SO4, filtered, and concentrated to afford the title compound as a white solid: 1H NMR (500 MHz, CDCl3): δ 8.67 (d, J=4.7 Hz, 1H); 8.14 (d, J=9.0 Hz, 1H); 8.11 (d, J=2.1 Hz, 1H); 7.70 (d, J=4.7 Hz, 1H); 7.60 (dd, J=9.0, 2.1 Hz, 1H); LC4 1.86 min. (M+H)=244.
Reaction SMILES: [NH2:1][C@H:2]([CH2:10][OH:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[H][H].[CH3:14][C:15]([CH3:17])=O>C(O)C.[Pt]=O>[CH:15]([NH:1][C@H:2]([CH2:10][OH:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)([CH3:17])[CH3:14]
Reactant: [H][H]
Reactant: CC(C)=O
Reactant: N[C@H](CO)Cc1ccccc1
Agent: O=[Pt]
Solvent: CCO
Product: CC(C)N[C@H](CO)Cc1ccccc1

Procedure:
L-phenylalaninol (31.3 g) was dissolved in a mixture of acetone (23 ml) and ethanol (120 ml). The solution was shaken in an atmosphere of hydrogen in the presence of platinum oxide (0.1 g) until the calculated amount of hydrogen was absorbed. The catalyst was filtered off and the filtrate was concentrated to dryness under reduced pressure to give N-isopropyl-L-phenylalaninol (40 g), mp 65°-66° C., [α]D -5.4°.
Reaction SMILES: Cl.C(OC([N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[N:16]([CH3:31])[CH:17]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[C:22]([C:27]([F:30])([F:29])[F:28])[CH:21]=3)[N:19]=2)[CH2:11][CH2:10]1)=O)(C)(C)C.Cl[C:33]1[N:38]=[CH:37][N:36]=[C:35]2[NH:39][N:40]=[CH:41][C:34]=12.C(N(CC)CC)C>ClCCl>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C:18]2[NH:19][CH:15]([CH:12]3[CH2:11][CH2:10][N:9]([C:33]4[N:38]=[CH:37][N:36]=[C:35]5[NH:39][N:40]=[CH:41][C:34]=45)[CH2:14][CH2:13]3)[N:16]([CH3:31])[CH:17]=2)=[CH:21][C:22]=1[C:27]([F:29])([F:28])[F:30]
Reactant: Clc1ncnc2[nH]ncc12
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1C=C(c2ccc(F)c(C(F)(F)F)c2)NC1C1CCN(c2ncnc3[nH]ncc23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
Add hydrogen chloride (4.00 equiv; 81.41 mmoles; 20.35 mL) to a solution of 4-[4-(4-Fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (8.7 g; 1.00 equiv; 20.35 mmoles) in dichloromethane (101.77 mL), at room temperature. Stir the solution at room temperature for 1 hour. Remove the solvent under reduced pressure, and dissolve the crude in isopropyl alcohol (101.77 mL). Add 4-chloro-1H-pyrazolo[3,4-d]pyrimidine (1.65 equiv; 33.58 mmoles; 5.19 g) and triethylamine (10 equiv; 203.54 mmoles; 28.37 mL). Stir the mixture at reflux for 1 hour. Remove the solvent under reduced pressure and triturate the crude in water overnight. Filter the solid and triturated in hot acetonitrile, filter and dry in vacuo. 4-{4-[5-(4-Fluoro-3-trifluoromethyl-phenyl)-3-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine (8.42 g; 18.86 mmoles; 92.66% yield) is obtained as a light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH2:12][F:13])[C:8](=[O:14])[C:7]2=O>O.NN>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH2:12][F:13])[C:8](=[O:14])[CH2:7]2
Reactant: O=C1C(=O)N(CCF)c2c(F)cccc21
Agent: NN
Solvent: O
Product: O=C1Cc2cccc(F)c2N1CCF
Temperature: 0 °C

Procedure:
7-Fluoro-1-(2-fluoro-ethyl)-1H-indole-2,3-dione (1.04 g, 4.92 mmol) is heated with neat hydrazine hydrate (10 ml) at 130° C. for 20 minutes. The mixture is cooled, diluted with ice water and extracted with ethyl acetate. The extract is washed with brine, dried (Na2SO4), and evaporated to give the title compound as a brown solid. HPLC r.t. 4.36 min; MS for C10H9F2NO m/z 198.1 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]([C:13]3[O:14][C:15]4[C:21]([C:22]([NH2:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:16]=4[N:17]=3)[CH:10]=[CH:11][CH:12]=2)[CH:2]=1.[H][H].Cl>CO.O.[Pt](=O)=O>[NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]2[CH:8]=[C:9]([C:13]3[O:14][C:15]4[C:21]([C:22]([NH2:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:16]=4[N:17]=3)[CH:10]=[CH:11][CH:12]=2)[CH2:2]1
Reactant: [H][H]
Reactant: NC(=O)c1cccc2nc(-c3cccc(-c4cccnc4)c3)oc12
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Solvent: O
Product: NC(=O)c1cccc2nc(-c3cccc(C4CCCNC4)c3)oc12
Yield: 9.8 %

Procedure:
A solution of 2-(3-(Pyridin-3-yl)phenyl)benzo[d]oxazole-7-carboxamide (110 mg, 0.35 mmol) and platinum (IV) oxide monohydrate (55 mg) in methanol (20 mL) was purged with 20 atm of hydrogen at 50° C. for 24 h. Then the mixture was filtered and adjusted to pH=9. The solvent was removed in vacuum. The crude was purified by chromatography (dichlormethane/methanol=9:1) to give the solid. The solid was acidified by hydrochloride acid and wash with ethyl acetate. The solvent was removed in vacuum. 11 mg of 2-(3-(piperidin-3-yl)phenyl)benzo[d]oxazole-7-carboxamide was obtained, yield: 10%. 1H-NMR (400 MHz, CD3OD) δ 1.93-1.97 (m, 2H), 2.12-2.14 (m, 2H), 3.07-3.27 (m, 3H), 3.51 (t, 2H), 7.53 (t, 1H); 7.60-7.63 (m, 2H), 7.91 (d, J=6.4 Hz, 1H); 7.94 (d, J=6.4 Hz, 1H); 8.26-8.29 (d, J=3.2 Hz, 1H). LC-MS (ESI) m/z: 321 (M+1)+.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH:18]3[CH:22]([CH2:23][C:24]4[CH:25]=[C:26]([CH:32]=[CH:33][CH:34]=4)[O:27][CH2:28][C:29]([OH:31])=[O:30])[CH2:21][CH2:20][NH:19]3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:35](Cl)(=[O:37])[CH3:36].[OH-].[Na+]>C1COCC1.O>[C:1]1([C:7]2[N:8]=[C:9]([CH:18]3[CH:22]([CH2:23][C:24]4[CH:25]=[C:26]([CH:32]=[CH:33][CH:34]=4)[O:27][CH2:28][C:29]([OH:31])=[O:30])[CH2:21][CH2:20][N:19]3[C:35](=[O:37])[CH3:36])[O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)COc1cccc(CC2CCNC2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reactant: CC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)N1CCC(Cc2cccc(OCC(=O)O)c2)C1c1nc(-c2ccccc2)c(-c2ccccc2)o1

Procedure:
To a solution of [3-[[2-(4,5-diphenyloxazol-2-yl)pyrrolidin-3-yl]methyl]phenoxy]acetic acid (140 mg) in a mixture of THF (10 ml) and water (10 ml) was added acetyl chloride (1.0 ml) dropwise at 0° C. keeping pH 8-9 with 1N NaOH solution. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with water, 1N-HCl and brine. The dried solvent was evaporated in vacuo and the residue was purified by trituration with hexane to afford [3-[[2-(4,5-diphenyloxazol-2-yl)-1-acetylpyrrolidin-3-yl]methyl]phenoxy]acetic acid (150 mg).
Reaction SMILES: [Na].[NH2:2][C:3]([NH2:5])=[S:4].[C:6]([CH2:11][C:12](OCC)=[O:13])(=O)[CH2:7][CH2:8][CH3:9]>CO>[SH:4][C:3]1[N:5]=[C:12]([OH:13])[CH:11]=[C:6]([CH2:7][CH2:8][CH3:9])[N:2]=1
Reactant: NC(N)=S
Reactant: CCCC(=O)CC(=O)OCC
Agent: [Na]
Solvent: CO
Product: CCCc1cc(O)nc(S)n1
Temperature: 25 °C

Procedure:
Sodium (4.6 g) was added by portions at 0° C. to methanol (150 mL). The mixture was stirred at room temperature until dissolution. After cooling at 0° C., thiourea (11.0 g) was added by portions and the mixture was stirred until dissolution. Ethyl butyrylacetate (15.8 g) in methanol (200 mL) was added dropwise at 0° C. over 30 minutes. The mixture was refluxed for 9 h, then concentrated under reduced pressure. The residue was dissolved in water. After acidification with acetic acid until pH=6 and stirring for 1 h, the mixture was filtered. The precipitate was successively washed with water and isopropanol, then dried under reduced pressure to afford 2-mercapto-6-propyl-pyrimidin-4-ol (14.1) as white crystals (mp=220° C.).
Reaction SMILES: C([S@]([NH:7][C@:8]([C:20]1[CH:21]=[N:22][C:23]([N:26]2[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]2)=[N:24][CH:25]=1)([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[C:9]([F:12])([F:11])[F:10])=O)(C)(C)C.CO>Cl.O1CCOCC1>[F:12][C:9]([F:10])([F:11])[C@:8]([C:13]1[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=1)([C:20]1[CH:21]=[N:22][C:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[N:24][CH:25]=1)[NH2:7]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc([C@@](N[S@](=O)C(C)(C)C)(c3ccc(F)cc3)C(F)(F)F)cn2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: N[C@@](c1ccc(F)cc1)(c1cnc(N2CCNCC2)nc1)C(F)(F)F
Yield: 99.1 %

Procedure:
tert-Butyl 4-(5-((S)-1-(((R)-tert-butylsulfinyl)amino)-2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)pyrimidin-2-yl)piperazine-1-carboxylate (302 mg, 0.540 mmol) was stirred in 4 M HCl in 1,4-dioxane (3 mL)/MeOH (3 mL) at room temperature for 1 hour. The solvent was removed in vacuo and the residue was partitioned between saturated NaHCO3 and EtOAc. The organic phase was extracted a second time with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give (S)-2,2,2-trifluoro-1-(4-fluorophenyl)-1-(2-(piperazin-1-yl)pyrimidin-5-yl)ethanamine (190 mg, 0.535 mmol, 99% yield) with ˜88% e.e. Further purification by chiral SFC gave (S)-2,2,2-trifluoro-1-(4-fluorophenyl)-1-(2-(piperazin-1-yl)pyrimidin-5-yl)ethanamine (123.7 mg, 0.348 mmol, 71.2% yield) with ˜99% e.e.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C:8]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[N:13]3)=[O:9])[CH:7]=1.[CH2:21]([S:24](Cl)(=[O:26])=[O:25])[CH2:22][CH3:23]>C(Cl)Cl>[F:20][C:5]1[CH:4]=[CH:3][C:2]([N:1]([S:24]([CH2:21][CH2:22][CH3:23])(=[O:26])=[O:25])[S:24]([CH2:21][CH2:22][CH3:23])(=[O:26])=[O:25])=[CH:7][C:6]=1[C:8]([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[CH:15][CH:14]=[N:13]2)=[O:9]
Reactant: CCCS(=O)(=O)Cl
Reactant: Nc1ccc(F)c(C(=O)c2ccc3nccnc3c2)c1
Solvent: ClCCl
Product: CCCS(=O)(=O)N(c1ccc(F)c(C(=O)c2ccc3nccnc3c2)c1)S(=O)(=O)CCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.8 %

Procedure:
To a solution of (5-amino-2-fluorophenyl)(quinoxalin-6-yl)methanone (50 mg, 0.187 mmol, 1.0 eq.) in DCM (10 mL) were added TEA (0.26 mL, 1.87 mmol, 10.0 eq.) and propane-1-sulfonyl chloride (133 mg, 0.935 mmol, 5.0 eq.). The resulting mixture was stirred at rt for 1 h, then washed with water and extracted with DCM (20 mL×3). The combined organic layers were dried over Na2SO4, filtered and concentrated. The resulting residue was purified by flash column chromatography (PE/EA=2/1, v/v) to afford N-(4-fluoro-3-(quinoxaline-6-carbonyl)phenyl)-N-(propylsulfonyl)propane-1-sulfonamide (50 mg, 56.8%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7]1([N:11]2[CH2:17][CH2:16][C:15]3[CH:18]=[C:19]([OH:22])[CH:20]=[CH:21][C:14]=3[CH2:13][CH2:12]2)[CH2:10][CH2:9][CH2:8]1.[F:23][C:24]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:25]=1[CH2:26]Br.[I-].[K+]>CC(=O)CC>[CH:7]1([N:11]2[CH2:17][CH2:16][C:15]3[CH:18]=[C:19]([O:22][CH2:26][C:25]4[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:24]=4[F:23])[CH:20]=[CH:21][C:14]=3[CH2:13][CH2:12]2)[CH2:10][CH2:9][CH2:8]1
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: Oc1ccc2c(c1)CCN(C1CCC1)CC2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Fc1ccc(COc2ccc3c(c2)CCN(C2CCC2)CC3)c(F)c1

Procedure:
Potassium carbonate (778 mg, 5.6 mmol) was added to a stirred solution of 3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) (868 mg, 4.0 mmol), 2,4-difluorobenzyl bromide (0.25 ml, 2.1 mmol) and potassium iodide (25 mg) in butanone (9 ml). The reaction mixture was stirred at reflux for 18 hours, cooled, filtered and concentrated in vacuo. The crude residue was dissolved with ethyl acetate and washed with water and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Purification of the resulting residue by column chromatography eluting with a mixture of 0.880 ammonia:ethanol:dichloromethane (0.25:2.25:97.5 then 1:9:10) afforded the title compound (E79); MS (ES+) m/e 344 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([C:18]([C:20]2[CH:21]=[N:22][C:23]([C:26](=[O:28])[NH2:27])=[CH:24][CH:25]=2)=[O:19])[C:12]=1[F:29])[CH2:9][CH3:10])(C)(C)C.Cl.CCOC(C)=O>>[NH2:7][C@@H:8]([C:11]1[C:12]([F:29])=[C:13]([C:14]([Cl:17])=[CH:15][CH:16]=1)[C:18]([C:20]1[CH:25]=[CH:24][C:23]([C:26]([NH2:27])=[O:28])=[N:22][CH:21]=1)=[O:19])[CH2:9][CH3:10]
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)c1ccc(Cl)c(C(=O)c2ccc(C(N)=O)nc2)c1F
Agent: Cl
Solvent: CCOC(C)=O
Product: CC[C@@H](N)c1ccc(Cl)c(C(=O)c2ccc(C(N)=O)nc2)c1F
Reaction time: 1 h
Yield: 54.3 %

Procedure:
To a solution of 5-[3-((R)-1-tert-Butoxycarbonylamino-propyl)-6-chloro-2-fluoro-benzoyl]-pyridine-2-carboxylic acid (Example 19)) in dichloromethane (8 ml) was added ammonium chloride (0.057 g, 0.65 mmol), DIPEA (0.137 mL, 0.78 mmol) and then HATU (0.06 g, 0.156 mmol) and the reaction stirred for 1 h. Further HATU totalling (0.12 g, 0.312 mmol) added. The reaction performed on a further (57 mg), both reactions combined and diluted with dichloromethane washed with water. The organic extract was dried (Na2SO4), filtered and concentrated. Purified by Prep HPLC to give {(R)-1-[3-(6-Carbamoyl-pyridine-3-carbonyl)-4-chloro-2-fluoro-phenyl]-propyl}-carbamic acid tert-butyl ester (0.042 g) MS: [M+H] 436 {(R)-1-[3-(6-Carbamoyl-pyridine-3-carbonyl)-4-chloro-2-fluoro-phenyl]-propyl}-carbamic acid tert-butyl ester (0.042 g, 0.137 mmol) treated with saturated HCl/EtOAc stirred at ambient for 1 hour, precipitate filtered and washed with ether to give 5-[3-((R)-1-amino-propyl)-6-chloro-2-fluoro-benzoyl]-pyridine-2-carboxylic acid amide (0.025 g).
Reaction SMILES: C([Li])CCC.C(NC1CCCCC1)(C)C.[CH:16]1([CH2:19][C:20]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:21])[CH2:18][CH2:17]1.[F:27][C:28]1[CH:42]=[CH:41][C:31]([C:32]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)=[O:33])=[CH:30][CH:29]=1>O1CCCC1>[CH:16]1([CH:19]([C:32]([C:31]2[CH:41]=[CH:42][C:28]([F:27])=[CH:29][CH:30]=2)([C:34]2[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=2)[OH:33])[C:20]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:21])[CH2:17][CH2:18]1
Reactant: CCCCOC(=O)CC1CC1
Reactant: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: CC(C)NC1CCCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCOC(=O)C(C1CC1)C(O)(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 53.4 %

Procedure:
Butyl lithium (5 mL of 2M solution, 10 mmol) was added to a solution of N-isopropylcyclohexylamine(1.4 g, 10 mmol) in 20 mL of tetrahydrofuran at -10° C. After stirring for 30 minutes and cooling to -70° C., butyl cyclopropaneacetate (1.5 g 10 mmol) was added. After stirring for an additional 30 minutes, 4,4'-difluorobenzophenone (1.1 g, 5 mmol) was added and the mixture stirred for 6 hours at -70° C. The mixture was quenched with 2N hydrochloric acid and extracted with diethyl ether. The extracts were dried and concentrated in vacuo. The residue was purified by chromatography on silica eluting with 0.75% ethyl acetate in hexane to give 1.0 g of the title compound; m.p. =77°-80° C.
Reaction SMILES: [CH2:1]([N:8](C)[CH2:9][C:10]1([CH3:36])[CH2:14][C:13]2[C:15]([CH3:35])=[C:16]([N:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=4)[CH2:23][CH2:22]3)[C:17]([CH3:20])=[C:18]([CH3:19])[C:12]=2[O:11]1)C1C=CC=CC=1>[C].[Pd].C(OCC)(=O)C>[CH3:34][O:33][C:30]1[CH:29]=[CH:28][C:27]([N:24]2[CH2:23][CH2:22][N:21]([C:16]3[C:17]([CH3:20])=[C:18]([CH3:19])[C:12]4[O:11][C:10]([CH2:9][NH:8][CH3:1])([CH3:36])[CH2:14][C:13]=4[C:15]=3[CH3:35])[CH2:26][CH2:25]2)=[CH:32][CH:31]=1
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)CC(C)(CN(C)Cc3ccccc3)O4)CC2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CNCC1(C)Cc2c(C)c(N3CCN(c4ccc(OC)cc4)CC3)c(C)c(C)c2O1
Temperature: 25 °C
Reaction time: 15 h
Yield: 32.1 %

Procedure:
To the ethyl acetate (6 mL) solution of N-benzyl-1-{5-[4-(4-methoxyphenyl)piperazin-1-yl]-2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran-2-yl}-N-methylmethaneamine (190 mg, 0.380 mmol) synthesized in Example 103, 10%-palladium carbon (comprising 50% moisture, 70 mg) was added, and then the mixture was stirred at room temperature for 15 hours under hydrogen atmosphere. The reaction mixture was filtered to remove the palladium carbon, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel chromatography (hexane-ethyl acetate 95:5-50:50), and recrystallized from ethyl acetate-hexane to obtain the title compound 50 mg (yield 32%). Melting point was 107 to 113° C. (ethyl acetate-hexane).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C@H:8]([C:18]([N:20]1[CH2:24][CH2:23][C@H:22]([F:25])[CH2:21]1)=[O:19])[C@H:9]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[CH3:10])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Rh]>[C:1]([O:5][C:6](=[O:26])[NH:7][C@H:8]([C:18]([N:20]1[CH2:24][CH2:23][C@H:22]([F:25])[CH2:21]1)=[O:19])[C@H:9]([CH:11]1[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]1)[CH3:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: [H][H]
Reactant: C[C@@H](c1ccc(O)cc1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC[C@H](F)C1
Agent: [Rh]
Solvent: CO
Product: C[C@@H](C1CCC(O)CC1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC[C@H](F)C1
Reaction time: 24 h

Procedure:
The material from Step B (0.022 g, 0.060 mmol) was hydrogenated at 50 psi hydrogen in the presence of 5% rhodium on alumina (22 mg) in methanol (5 mL) using a Parr shaker. After 24 h, the reaction mixture was filtered by passage through a syringe filter. Concentration of the filtrate in vacuo afforded the title compound as a mixture of cis and trans isomers containing a small amount of the fully reduced cyclohexane. LC/MS 395.3 (M+Na)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[C:7]([Cl:12])[C:3]=1[C:4](Cl)=[O:5].[H-].[Na+].[Br:15][C:16]1[CH:21]=[C:20]([NH2:22])[CH:19]=[CH:18][N:17]=1>CN(C=O)C.C(OCC)(=O)C>[Br:15][C:16]1[CH:21]=[C:20]([NH:22][C:4](=[O:5])[C:3]2[C:2]([Cl:1])=[CH:10][C:9]([I:11])=[CH:8][C:7]=2[Cl:12])[CH:19]=[CH:18][N:17]=1
Reactant: Nc1ccnc(Br)c1
Reactant: O=C(Cl)c1c(Cl)cc(I)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Nc1ccnc(Br)c1)c1c(Cl)cc(I)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 40.4 %

Procedure:
To a cooled (0° C.) solution of 2,6-dichloro-4-iodobenzoyl chloride (70 mg, 0.21 mmol) in DMF (2 mL) was added NaH (17 mg, 0.42 mmol). The mixture was stirred for 10 minutes and then 2-bromopyridin-4-amine (40 mg, 0.23 mmol) was added. The resulting mixture was slowly warmed to 25° C., diluted with ethyl acetate (10 mL), quenched with water (1 mL), washed with saturated Na2CO3 and water, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica-gel chromatography (Pet Ether/EtOAc=20:1 to 3:1) to afford N-(2-bromopyridin-4-yl)-2,6-dichloro-4-iodobenzamide (40 mg, 40% yield). LCMS (ESI) m/z: 470.9 [M+H+].
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[C:28]([O:32][C:33]([N:35]([C:81]([O:83][C:84]([CH3:87])([CH3:86])[CH3:85])=[O:82])[C:36]1[C:45]2[C:40](=[CH:41][C:42]([NH:46][CH:47]([C:51]3[CH:56]=[CH:55][C:54]([C@@H:57]([CH3:79])[CH2:58][O:59][C:60](=[O:78])[NH:61][C:62]4[CH:67]=[C:66]([CH2:68][NH:69][CH3:70])[C:65]([O:71][C@@H:72]([CH3:76])[CH2:73][O:74][CH3:75])=[C:64]([F:77])[CH:63]=4)=[C:53]([CH3:80])[CH:52]=3)[C:48](O)=[O:49])=[CH:43][CH:44]=2)[CH:39]=[CH:38][N:37]=1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>CN(C)C1C=CN=CC=1.C(Cl)Cl.CN(C=O)C>[C:28]([O:32][C:33]([N:35]([C:36]1[C:45]2[C:40](=[CH:41][C:42]([NH:46][CH:47]3[C:48](=[O:49])[N:69]([CH3:70])[CH2:68][C:66]4[CH:67]=[C:62]([CH:63]=[C:64]([F:77])[C:65]=4[O:71][C@@H:72]([CH3:76])[CH2:73][O:74][CH3:75])[NH:61][C:60](=[O:78])[O:59][CH2:58][C@H:57]([CH3:79])[C:54]4[C:53]([CH3:80])=[CH:52][C:51]3=[CH:56][CH:55]=4)=[CH:43][CH:44]=2)[CH:39]=[CH:38][N:37]=1)[C:81](=[O:82])[O:83][C:84]([CH3:87])([CH3:86])[CH3:85])=[O:34])([CH3:31])([CH3:30])[CH3:29]
Reactant: CNCc1cc(NC(=O)OC[C@H](C)c2ccc(C(Nc3ccc4c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc4c3)C(=O)O)cc2C)cc(F)c1O[C@@H](C)COC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC[C@H](C)Oc1c(F)cc2cc1CN(C)C(=O)C(Nc1ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c1)c1ccc(c(C)c1)[C@@H](C)COC(=O)N2
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.9 %

Procedure:
To a solution of BOP (196 mg, 0.444 mmol), 4-dimethylaminopyridine (136 mg, 1.109 mmol) in CH2Cl2 (40 mL), was added a solution of 37E (185 mg, 0.222 mmol) in DMF (10 mL) via a syringe pump over 6 h. The reaction mixture was stirred at rt for 16 h, then concentrated and purified by prep HPLC to give 37F (150 mg, 0.184 mmol, 83% yield) as a yellow solid. MS (ESI) m/z: 816.2 (M+H)+.
Reaction SMILES: [BrH:1].C([CH:9]1[NH:17][CH2:16][CH2:15][C:14]2[CH2:13][NH:12][CH2:11][C:10]1=2)C1C=CC=CC=1.[H][H]>C(O)(=O)C.[Pd]>[BrH:1].[BrH:1].[C:10]12[CH2:11][NH:12][CH2:13][C:14]=1[CH2:15][CH2:16][NH:17][CH2:9]2
Reactant: [H][H]
Reactant: c1ccc(CC2NCCC3=C2CNC3)cc1
Agent: [Pd]
Agent: Br
Solvent: CC(=O)O
Product: C1CC2=C(CN1)CNC2
Reaction time: 7 h
Yield: 73 %

Procedure:
0.7 g of N3 -(benzyl)-3,8-diazabicyclo[4.3.0]non-1(6)-ene hydrobromide, prepared in Preparation 10, was dissolved in 20 ml of 5% aqueous acetic acid solution. 0.5 g of 10% palladium chracoal in this solution was suspended and the reaction mixture was refluxed under the hydrogen stream for 7 hours. The solid was filtered off. The filtrate was concentrated under reduced pressure and dissolved in 10 ml of 48% bromic acid. By concentrating the solution under reduced pressure again, 0.5 g of the title compound was obtained (yield 73%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:31])=[CH:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23]CC3C=CC=CC=3)=[CH:15][CH:14]=2)[N:8]=1.C([O-])=O.[NH4+].C([O-])=O>[Pd].C(O)C>[CH3:1][C:2]1[NH:3][C:4]([CH3:31])=[CH:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([OH:23])=[CH:15][CH:14]=2)[N:8]=1
Reactant: Cc1cc(-c2cccc(-c3ccc(OCc4ccccc4)c4ccccc34)n2)c(C)[nH]1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: Cc1cc(-c2cccc(-c3ccc(O)c4ccccc34)n2)c(C)[nH]1

Procedure:
To a 125 mL round-bottomed flask equipped with condenser and N2 inlet were added 1.53 g (3.795 mmol) 2-(2,5-dimethylpyrrolyl)-6-(4-benzyloxy-1-naphthyl)-pyridine, 1.20 g (18.975 mmol) ammonium formate, 100 mg 10% palladium-on-carbon, and 30 mL ethanol. The reaction was refluxed 4 hours, with additional catalyst and formate added at 2 and 3 hours, then cooled and filtered through Celite with ethanol and methylene chloride. The filtrate was evaporated and the residue taken up in ethyl acetate/aqueous sodium bicarbonate solution. The organic layer was washed with brine, dried over sodium sulfate, and evaporated to a light brown solid, 1.21 g (˜100%).
Reaction SMILES: C[O:2][C:3]1[C:8]([O:9]C)=[CH:7][C:6]2[C:11]3[CH2:16][CH2:15][N:14]([CH2:17][C:18](=[O:20])[CH3:19])[CH2:13][C:12]=3[C:21](=[O:23])[O:22][C:5]=2[CH:4]=1.[BrH:24]>>[BrH:24].[OH:2][C:3]1[C:8]([OH:9])=[CH:7][C:6]2[C:11]3[CH2:16][CH2:15][N:14]([CH2:17][C:18](=[O:20])[CH3:19])[CH2:13][C:12]=3[C:21](=[O:23])[O:22][C:5]=2[CH:4]=1
Reactant: COc1cc2oc(=O)c3c(c2cc1OC)CCN(CC(C)=O)C3
Agent: Br
Product: CC(=O)CN1CCc2c(c(=O)oc3cc(O)c(O)cc23)C1

Procedure:
A solution of 1,2,3,4-tetrahydro-8,9-dimethoxy-3-(2-oxopropyl)-5H-[1]benzopyrano[3,4-c]pyridin-5-one (5.0 g, 0.016 moles) in 40 ml of 48% aqueous hydrobromic acid is stirred at reflux for 16 hours. The mixture is cooled, and the precipitated product is filtered and washed several times with cold acetone. The product (5.7 g, mp 280° C. dec.) is used as an intermediate without additional purification.