Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][C:8]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21])(=O)=O.[F:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:27][C:28]1[CH:33]=[CH:32][C:31]([C:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:9][C:8]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:30][CH:29]=1
Reactant: CCOC(=O)C1=C(OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)C1
Reactant: OB(O)c1ccc(F)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)C1=C(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)C1
Temperature: 80 °C
Yield: 87.9 %

Procedure:
A vigorously stirred suspension of the product of step C (1.00 g, 2.48 mmol), 4-fluorophenylboronic acid (0.382 g, 2.73 mmol) and [1,1′-bis(diphenylphosphino)-ferrocene)dichloropalladium(II) (0.102 g, 0.124 mmol) in toluene/ethanol (3:2; 24.0 mL) was degassed via three vacuum/nitrogen ingress cycles and then heated to approximately 80° C. Aqueous 2 M sodium carbonate (3.10 mL, 6.20 mmol) was added dropwise via syringe and the resulting mixture maintained at reflux overnight. After cooling to ambient temperature, the reaction mixture was diluted with ethyl acetate and filtered through celite®. The filtrate was poured into water and extracted three times with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. Purification of the residue by medium pressure liquid chromatography on silica gel (gradient elution; 0–15% ethyl acetate/hexanes as eluent) afforded the title compound as a colorless oil (0.762 g).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:9]=[C:8]([F:10])[CH:7]=[C:6](F)[N:5]=1.[CH2:12]([OH:19])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>>[NH2:3][C:4]1[N:9]=[C:8]([F:10])[CH:7]=[C:6]([O:19][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[N:5]=1
Reactant: CCCCCCCO
Reactant: Nc1nc(F)cc(F)n1
Agent: [H-]
Agent: [Na+]
Product: CCCCCCCOc1cc(F)nc(N)n1
Reaction time: 2.5 h

Procedure:
A solution of 1.14 g (0.038 mol) of 80% sodium hydride (suspension in linseed oil) in 30 ml of n-heptanol was added to a stirred mixture of 5 g (0.038 mol) of 2-amino-4,6-difluoropyrimidine in 70 ml of n-heptanol at 20° to 25° C. within 5 minutes. After 2.5 hours working up was carried out as in Example 6. 6.3 g (73% of theory) of the title compound of melting point 30°-32° C. were obtained in this way.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:13])[C:5]2[O:9][C:8]([F:11])([F:10])[O:7][C:6]=2[CH:12]=1.C(O[B:18]1[O:22][C:21]([CH3:24])([CH3:23])[C:20]([CH3:26])([CH3:25])[O:19]1)(C)C.[NH4+].[Cl-].Cl>O1CCCC1.C(OCC)(=O)C.[Na+].[Cl-]>[CH3:25][C:20]1([CH3:26])[C:21]([CH3:24])([CH3:23])[O:22][B:18]([C:2]2[CH:3]=[C:4]([F:13])[C:5]3[O:9][C:8]([F:11])([F:10])[O:7][C:6]=3[CH:12]=2)[O:19]1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: Fc1cc(Br)cc2c1OC(F)(F)O2
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(C)OB(c2cc(F)c3c(c2)OC(F)(F)O3)OC1(C)C
Temperature: -2.5 °C
Reaction time: 0.5 h

Procedure:
6-Bromo-2,2,4-trifluorobenzo[d][1,3]dioxole (2.0 g, 7.8 mmol) was dissolved in dry tetrahydrofuran (10 mL), cooled to −5 to 0° C. and treated in portions with isopropylmagnesium lithium chloride complex (1.3 M; 6.3 mL, 8.2 mmol). The cooling bath was removed and the mixture was stirred for 30 min. 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.6 g, 8.4 mmol) was added, the mixture was stirred for 1 h and then treated with saturated NH4Cl (5 mL). The mixture was diluted with ethyl acetate (40 mL) and saturated NaCl (10 mL) and the pH was adjusted to 2 by addition of HCl. The organic phase was washed with saturated NaCl (5 mL), dried (Na2SO4) and evaporated to give the title compound which was used without further purification (2 g, 85%): 1H NMR (400 MHz, CDCl3) δ 7.36 (d, J=9.8 Hz, 1H), 7.29 (d, J=6.5 Hz, 1H), 1.33 (s, 12H); 19F NMR (376 MHz, CDCl3) δ −49.79, −136.26; EIMS m/z 302.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](OCC)=[O:9])[CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cccc(Br)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cccc(Br)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The ester from Step 2 was dissolved in THF (1.2 L), the solution cooled to 0° C., and under a N2 atmosphere, there was slowly added LiAlH4 (20 g) over 1 h. After a further 30 min., the mixture was quenched carefully with sat'd aqueous NH4Cl (250 mL). The granular salts were filtered off, washed with EtOAc, and the filtrate was dried over MgSO4, and evaporated to afford the title alcohol (85 g) as an oil.
Reaction SMILES: [CH:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11](B(O)O)[CH:12]=2)[NH:7][C:6](=[O:17])[CH2:5]1)([CH3:3])[CH3:2].Br[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Cl:26])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.C(O)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>[Cl:26][C:21]1[CH:20]=[C:19]([C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6](=[O:17])[CH2:5][N:4]3[CH:1]([CH3:3])[CH3:2])[CH:24]=[CH:23][C:22]=1[F:25]
Reactant: Fc1ccc(Br)cc1Cl
Reactant: CC(C)N1CC(=O)Nc2ccc(B(O)O)cc21
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: COCCOC
Solvent: CCO
Product: CC(C)N1CC(=O)Nc2ccc(-c3ccc(F)c(Cl)c3)cc21
Temperature: 25 °C

Procedure:
A mixture of (3,4-dihydro-4-isopropyl-2-oxoquinoxalin-6-yl)boronic acid (2.4 g, 10 mmol), 4-bromo-2-chlorofluorobenzene (2 g, 10 mmol), potassium carbonate (4 g, 30 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.46 g, 0.4 mmol) in dimethoxyethane (100 ml), ethanol (25 ml) and water (25 mol) was heated to reflux for 6 hrs. After cooling to room temperature the mixture was diluted with water and extracted with ethyl acetate (3×). The combined organic layers were washed with water, then brine, dried (MgSO4) and evaporated to obtain crude product (2.9 g, 91%). Recrystallization from EtOAc/hexane afforded the title compound, mp 208-213° C.: 1H-NMR (DMSO-d6) δ 1.16 (d, J=6.59 Hz, 6H), 3.56 (s, 2H), 4.22 (septet, J=6.59 Hz, 1H), 6.86 (d, J=7.91 Hz, 1H), 6.96 (dd, J=7.91, 1.76 Hz, 1H), 7.01 (d, J=1.76 Hz, 1H), 7.43 (t, J=9.01 Hz, 1H), 7.61 (m, H), 7.82 (dd, J=7.14, 2.31 Hz, 1H), 10.47 (s, 1H). MS (EI) m/z 318 [M]++1 chlorine.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24][CH2:23][C:22]3[N:21]4[C:16]([CH2:17][CH2:18][CH2:19][CH2:20]4)=[CH:15][C:14]=3[C:13]2=[O:25])=[CH:10][C:9]([F:26])=[CH:8][C:7]=1Br)(=[O:3])[CH3:2].[CH2:28]([C@H:30]1[CH2:35][N:34]([CH:36]2[CH2:39][O:38][CH2:37]2)[CH2:33][CH2:32][N:31]1[C:40]1[CH:41]=[CH:42][C:43]([NH:46][C:47]2[C:48](=[O:63])[N:49]([CH3:62])[CH:50]=[C:51](B3OC(C)(C)C(C)(C)O3)[CH:52]=2)=[N:44][CH:45]=1)[CH3:29].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C.O>[C:1]([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24][CH2:23][C:22]3[N:21]4[C:16]([CH2:17][CH2:18][CH2:19][CH2:20]4)=[CH:15][C:14]=3[C:13]2=[O:25])=[CH:10][C:9]([F:26])=[CH:8][C:7]=1[C:51]1[CH:52]=[C:47]([NH:46][C:43]2[CH:42]=[CH:41][C:40]([N:31]3[CH2:32][CH2:33][N:34]([CH:36]4[CH2:37][O:38][CH2:39]4)[CH2:35][CH:30]3[CH2:28][CH3:29])=[CH:45][N:44]=2)[C:48](=[O:63])[N:49]([CH3:62])[CH:50]=1)(=[O:3])[CH3:2]
Reactant: CC[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(B3OC(C)(C)C(C)(C)O3)cn(C)c2=O)nc1
Reactant: CC(=O)OCc1c(Br)cc(F)cc1N1CCc2c(cc3n2CCCC3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CCC1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3cc(F)cc(N4CCc5c(cc6n5CCCC6)C4=O)c3COC(C)=O)cn(C)c2=O)nc1
Temperature: 100 °C
Yield: 53.7 %

Procedure:
A 100-mL single-neck round-bottomed flask was charged with 2-bromo-4-fluoro-6-(1-oxo-3,4,6,7,8,9-hexahydropyrido[3,4-b]indolizin-2(1H)-yl)benzyl acetate 101h (120 mg, 0.27 mmol), (S)-3-(5-(2-ethyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one 122a (158.4 mg, 0.32 mmol), Pd(dppf)Cl2 (24.5 mg, 0.03 mmol), K3PO4 (114.5 mg, 0.54 mmol), sodium acetate.trihydrate (73.4 mg, 0.54 mmol), water (0.5 mL), and acetonitrile (20 mL). The system was evacuated and refilled with N2. The reaction mixture was heated at 100° C. for 2 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with 25:1 dichloromethane/methanol to afford 123a (105 mg, 53%) as a yellow brown solid. MS: [M+H]+ 724.3.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:9]=[CH:10][C:11]2[O:15][CH:14]([CH:16]3[CH2:21][CH2:20][N:19](C(=O)C(F)(F)F)[CH2:18][CH2:17]3)[CH2:13][C:12]=2[CH:28]=1.CO.O>[Cl-].[Na+].O>[Br:7][C:8]1[CH:9]=[CH:10][C:11]2[O:15][CH:14]([CH:16]3[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]3)[CH2:13][C:12]=2[CH:28]=1
Reactant: O=C(N1CCC(C2Cc3cc(Br)ccc3O2)CC1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Brc1ccc2c(c1)CC(C1CCNCC1)O2
Temperature: 25 °C

Procedure:
Potassium carbonate (10.17 g) is added to an ice-cooled mixture of 1-[4-(5-bromo-2,3-dihydro-benzofuran-2-yl)-piperidin-1-yl]-2,2,2-trifluoro-ethanone (4.64 g), methanol (120 mL), and water (30 mL). The reaction mixture is stirred over night at room temperature. Brine (150 mL) is added and the mixture is extracted with dichloromethane. The combined organic phases are dried over MgSO4 and concentrated in vacuo. The crude product is used for the next step without further purification. LC (method 2): tR=1.05 min; Mass spectrum (ESI+): m/z=282, 284 [M+H]+.
Reaction SMILES: [CH2:1]([Zn]CC)C.FC(F)(F)C(O)=O.[CH:13]1([C:19]([O:21][CH3:22])=[O:20])[CH2:18][CH2:17][CH:16]=[CH:15][CH2:14]1>ClCCl>[CH:15]12[CH2:1][CH:16]1[CH2:17][CH2:18][CH:13]([C:19]([O:21][CH3:22])=[O:20])[CH2:14]2
Reactant: COC(=O)C1CC=CCC1
Reactant: CC[Zn]CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1CCC2CC2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
To a solution of diethyl zinc (1.0 M in hexanes, 35 mL, 35.00 mmol) in anhydrous dichloromethane (34 mL) was added trifluoroacetic acid (3.99 g, 35.0 mmol) in 17.2 mL anhydrous dichloromethane at 0° C. The reaction mixture was stirred at the same temperature for 1 hour, and then added a solution of diidomethane (9.37 g, 35.00 mmol) in anhydrous dichloromethane (17 mL) at 0° C. The reaction mixture was further stirred at the same temperature for another 1 hour. To this mixture was added a solution of methyl cyclohex-3-enecarboxylate (2.45 g, 17.50 mmol) in anhydrous dichloromethane 17 mL) at 0° C. The resulting mixture was warmed to ambient temperature and further stirred for 4 hours. The mixture was quenched with a saturated solution of ammonium chloride (50 mL) and separated the organic layer. The aqueous layer was extracted with dichloromethane (15 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to dryness. The residue was purified by column chromatography with ethyl acetate in hexanes (30%) to afford the title compound as yellow oil (2.56 g, 95%): 1H NMR (300 MHz, CDCl3) δ 3.64 (s, 3H), 2.31-1.92 (m, 3H), 1.84-1.65 (m, 2H), 1.54 (t, J=12.9 Hz, 1H), 1.19-1.04 (m, 1H), 0.93-0.86 (m, 2H), 0.63-0.55 (m, 1H), 0.05-0.00 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]#N)[CH:7]=1)[CH3:2].C(O)=[O:16]>[Al].[Ni]>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]=[O:16])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(C#N)c1
Reactant: O=CO
Agent: [Ni]
Agent: [Al]
Product: CCOC(=O)Cc1cccc(C=O)c1
Temperature: 100 °C

Procedure:
To a solution of (3-cyano-phenyl)-acetic acid ethyl ester (4.8 g, 25.4 mmol) in 75% aqueous formic acid was added nickel-aluminum alloy (4.6 g). The mixture was heated at reflux (100° C.) for 2.25 h. The reaction mixture was cooled and was filtered through Celite with the aid of boiling EtOH. The filtrate was diluted with H2O and the product was extracted into CHCl3 (3×). The organic solution was stirred with saturated NaHCO3 solution until a pH of 8 was attained. The organic solution was dried over MgSO4, filtered, and concentrated. The product was purified by flash chromatography (5:1 hexanes/EtOAc) to afford the title compound (3.33 g). 1H NMR (400 MHz, CDCl3) δ7.76-7.79 (m, 2H), 7.47-7.57 (m, 2H), 4.15 (q, 2H), 3.69 (s, 2H), 1.25 (t, 3H); MS 193 (M+1).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[C:5]([NH:9][NH2:10])[CH:6]=[CH:7][CH:8]=1.[O:17]1[CH:21]=[CH:20][CH2:19][CH2:18]1>O.C1COCC1>[Cl:2][C:3]1[C:4]([O:11][CH2:12][C:13]([F:15])([F:14])[F:16])=[C:5]([NH:9][N:10]=[CH:21][CH2:20][CH2:19][CH2:18][OH:17])[CH:6]=[CH:7][CH:8]=1
Reactant: C1=COCC1
Reactant: NNc1cccc(Cl)c1OCC(F)(F)F
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: OCCCC=NNc1cccc(Cl)c1OCC(F)(F)F
Reaction time: 3 h

Procedure:
The 3-chloro-2-(2,2,2-trifluoroethoxy)phenylhydrazine hydrochloride (13.3 g, 48 mmol) was dissolved in H2O (133 mL) and THF (133 mL). Dihydrofuran (3.75 mL, 48 mmol) was added in one portion, and the reaction mixture was stirred for 3 hours. After this time, the organic layer was separated and the aqueous layer extracted with Et2O (250 mL). The combined organic layers were washed with brine (250 mL), dried (MgSO4), and concentrated to afford 14 g (98%) of a 3:1 mixture of E:Z isomers of 4-[3-chloro-2-(2,2,2-trifluoroethoxy)phenylhydrazono]-1-butanol as an orange oil which was used without further purification.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:24])[CH2:6][CH2:7][C:8]2([CH2:20][CH2:21][CH2:22][CH3:23])[C:16]=1[C:15]1[C:10](=[C:11]([Cl:19])[C:12]([O:17]C)=[CH:13][CH:14]=1)[CH2:9]2)(=[O:3])[CH3:2].Cl.N1C=CC=CC=1>>[C:1]([C:4]1[C:5](=[O:24])[CH2:6][CH2:7][C:8]2([CH2:20][CH2:21][CH2:22][CH3:23])[C:16]=1[C:15]1[C:10](=[C:11]([Cl:19])[C:12]([OH:17])=[CH:13][CH:14]=1)[CH2:9]2)(=[O:3])[CH3:2]
Reactant: CCCCC12CCC(=O)C(C(C)=O)=C1c1ccc(OC)c(Cl)c1C2
Agent: Cl
Solvent: c1ccncc1
Product: CCCCC12CCC(=O)C(C(C)=O)=C1c1ccc(O)c(Cl)c1C2
Temperature: 200 °C

Procedure:
A mixture of 4-acetyl-9a-butyl-8-chloro-7-methoxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one (54 mg) and pyridine hydrochloride (3.5 g) was heated in an oil bath at 200° C. for one hour. After cooling to room temperature, the mixture was partitioned between EtOAc (50 mL) and water (50 mL). The organic phase was washed with brine (20 mL), dried over MgSO4, filtered, and evaporated under vacuum to an oil (32 mg). The crude product was purified by preparative layer chromatography on a 0.1×20×20 cm silica gel GF plate, developing with 5% MeOH in CH2Cl2. The product band was eluted with 10% MeOH in CH2Cl2, the eluant evaporated under vacuum, and the residue lyophilized from benzene to afford 4-acetyl-9a-butyl-8-chloro-7-hydroxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one as an amorphous solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([NH:13][NH:14][C:15](=O)[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[O:23][C:24]([C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=4)=[CH:25][N:26]=3)[CH:17]=2)=[O:12])=[CH:6][CH:5]=1>O>[CH3:1][O:2][C:3](=[O:36])[C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]2[O:12][C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]4[O:23][C:24]([C:27]5[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=5)=[CH:25][N:26]=4)[CH:17]=3)=[N:14][N:13]=2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(CC(=O)NNC(=O)c2cccc(-c3ncc(-c4ccc(OC)cc4)o3)c2)cc1
Solvent: O
Product: COC(=O)c1ccc(Cc2nnc(-c3cccc(-c4ncc(-c5ccc(OC)cc5)o4)c3)o2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.8 %

Procedure:
0.24 g (0.49 mmol) of 4-[2-(N′-{3-[5-(4-Methoxy-phenyl)-oxazol-2-yl]-benzoyl}-hydrazino)-2-oxo-ethyl]-benzoic acid methyl ester from Preparation 8 was dissolved in about 10 mL of poly phosphoric acid. The mixture was stirred at 90–100° C. for 1 hour before allowing to cool to room temperature. Water was added and the product was extracted with 1:1:1 EtOAC/THF/Et2O (2×). The extracts were combined and washed with saturated aqueous NaCl solution then dried MgSO4. Slurried solid product in hot EtOAc and filtered. Dried in vacuum oven overnight at 70° C. to obtain 0.13 g (57%) desired product.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][OH:25])=[CH:19][CH:18]=3)[N:13]=2)=[CH:9][C:8]=1[CH3:26])[CH2:4][CH3:5])[CH3:2].CCN(C(C)C)C(C)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>C1COCC1.C(Cl)Cl>[CH2:1]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][O:25][S:37]([CH3:36])(=[O:39])=[O:38])=[CH:21][CH:22]=3)[N:13]=2)=[CH:9][C:8]=1[CH3:26])[CH2:4][CH3:5])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCN(CC)Cc1sc(-c2nc(-c3ccc(CCO)cc3)no2)cc1C
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCN(CC)Cc1sc(-c2nc(-c3ccc(CCOS(C)(=O)=O)cc3)no2)cc1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 134.5 %

Procedure:
To a cooled (0° C.) solution of 2-{4-[5-(5-diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-ethanol (196 mg, 488 μmol) and DIPEA (84 mg, 732 μmol) in THF (5 mL), methanesulfonyl chloride (126 mg, 976 μmol) is added as a solution in THF (2.5 mL). The reaction mixture is stirred at 0° C. for 1 h, then at rt for 1 h. The mixture is diluted with DCM (100 mL) and washed with brine (3×50 mL). The organic extract is dried over MgSO4, filtered, concentrated and dried to give crude methanesulfonic acid 2-{4-[5-(5-diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-ethyl ester (295 mg); LC-MS: tR=0.59 min; [M+1]+=449.71. b) A solution of methanesulfonic acid 2-{4-[5-(5-diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-ethyl ester (295 mg, 658 μmol) in 7 N NH3 in methanol (10 mL) is stirred in a sealed vessel at 80° C. for 16 h. The reaction mixture is concentrated and dried to give the title compound (255 mg) as a pale yellow oil; LC-MS: tR=0.64 min; [M+1]+=370.97.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[I-].[CH2:46]([N+:50]1[N:54]=[C:53]([CH3:55])[S:52][C:51]=1[CH3:56])[CH2:47][CH2:48][CH3:49]>>[CH2:46]([N:50]1[N:54]=[C:53]([CH3:55])[S:52]/[C:51]/1=[CH:56]\[C:7]([C:6]1[CH:10]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[CH3:11])=[O:9])[CH2:47][CH2:48][CH3:49]
Reactant: Cc1ccc(F)cc1C(=O)O
Reactant: CCCC[n+]1nc(C)sc1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN1N=C(C)S/C1=C\C(=O)c1cc(F)ccc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 5-fluoro-2-methylbenzoic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (76 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (51 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (49 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.90 (t, 3 H) 1.68-1.76 (m, 2 H) 2.34 (s, 3 H) 2.48 (s, 3 H) 4.16 (t, 2 H) 6.26 (s, 1 H) 7.10-7.16 (m, 1 H) 7.23-7.32 (m, 2 H); MS (ESI) m/z 307 (M+H)+.
Reaction SMILES: [C:1]1([C@H:11]([NH:13][CH2:14][CH:15]2[CH:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:19][CH2:18][NH:17][CH2:16]2)[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[Cl:34][C:35]1[CH:36]=[C:37]([CH:42]=[CH:43][C:44]=1[NH:45][C:46](OC1C=CC([N+]([O-])=O)=CC=1)=[O:47])[C:38]([O:40][CH3:41])=[O:39]>C1COCC1>[Cl:34][C:35]1[CH:36]=[C:37]([CH:42]=[CH:43][C:44]=1[NH:45][C:46]([N:17]1[CH2:18][CH2:19][CH:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]([CH2:14][NH:13][C@@H:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[CH3:12])[CH2:16]1)=[O:47])[C:38]([O:40][CH3:41])=[O:39]
Reactant: C[C@@H](NCC1CNCCC1c1ccccc1)c1cccc2ccccc12
Reactant: COC(=O)c1ccc(NC(=O)Oc2ccc([N+](=O)[O-])cc2)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(NC(=O)N2CCC(c3ccccc3)C(CN[C@H](C)c3cccc4ccccc34)C2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 217 mg of the crude product of (1R)-1-(1-naphthyl)-N-[(4-phenylpiperidin-3-yl)methyl]ethaneamine and 0.175 mL of triethylamine in 4.0 mL of THF was added 243 mg of methyl 3-chloro-4-{[(4-nitrophenoxy)carbonyl]amino}benzoate. After stirring at room temperature overnight, the reaction mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 214 mg of methyl 3-chloro-4-({[3-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpiperidin-1-yl]carbonyl}amino)benzoate.
Reaction SMILES: [H-].[Na+].[C:3]1([CH:10]=[CH:9][C:7]([OH:8])=[CH:6][CH:5]=1)[OH:4].I[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].Cl>CN(C)C=O.O1CCCC1>[CH2:27]([O:4][C:3]1[CH:10]=[CH:9][C:7]([OH:8])=[CH:6][CH:5]=1)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12]
Reactant: Oc1ccc(O)cc1
Reactant: CCCCCCCCCCCCCCCCI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCOc1ccc(O)cc1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To a suspension of 28.99 g of 60% sodium hydride in 350 ml of N,N-dimethylformamide, cooled to 0° C. and under argon is added 60 g of hydroquinone in 450 ml of N,N-dimethylformamide with stirring over 40 minutes. After an additional 30 minutes, 450 ml of tetrahydrofuran is added followed by 192 g of 1-iodohexadecane over one hour. The mixture is stirred at room temperature for 3 hours. The reaction mixture is poured into dilute hydrochloric acid and extracted with chloroform. The organic layer is washed with water, dried and evaporated to give the desired product as an oil.
Reaction SMILES: C[O:2][C:3](=[O:24])[C@@H:4]1[CH2:8][C@@H:7]([O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])[CH2:6][N:5]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].[OH-].[Na+]>CO.O>[C:20]([O:19][C:17]([N:5]1[CH2:6][C@H:7]([O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:11])[CH3:12])[CH2:8][C@H:4]1[C:3]([OH:24])=[O:2])=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: COC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 6 h
Yield: 89.5 %

Procedure:
(2S,4R)-N-tert-Butoxycarbonyl-4-tert-butyldimethylsiloxyproline methyl ester (5.9 g, 16.5 mmol) was dissolved in methanol (45 ml) and water (11 ml). Then, 2.5N aqueous sodium hydroxide (6.6 ml, 16.5 mmol) was added thereto. The mixture was stirred at room temperature for 6 h, and then the organic solvent was distilled off. The aqueous layer was washed with ethyl acetate, then adjusted to pH 2.5 with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and concentrated in vacuo to obtain crude (2S,4R)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxyproline (5.1 g). ##STR384##