Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:6][C:7]([C:10]([NH:12][CH:13]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:14]([OH:16])=O)=[O:11])=[N:8][CH:9]=2)[CH2:3][CH2:2]1.Cl.[CH3:28][NH:29][CH3:30]>>[CH:1]1([C:4]2[C:5]([O:21][CH2:22][C:23]([F:24])([F:25])[F:26])=[CH:6][C:7]([C:10]([NH:12][CH:13]([C:17]([CH3:19])([CH3:18])[CH3:20])[C:14]([N:29]([CH3:30])[CH3:28])=[O:16])=[O:11])=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: CNC
Reactant: CC(C)(C)C(NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1)C(=O)O
Agent: Cl
Product: CN(C)C(=O)C(NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1)C(C)(C)C

Procedure:
The title compound was synthesized in analogy to Example 112e, using 2-[[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridine-2-carbonyl]amino]-3,3-dimethyl-butanoic acid (Example 194b) and dimethylamine hydrochloride as starting materials and isolated (24 mg, 46%); MS (ESI, m/z): 402.6 (M+H+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][C:12]([NH:14][CH3:15])=O)[CH:3]=[CH:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH:10]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:11][CH2:12][NH:14][CH3:15])[CH:3]=[CH:2]1
Reactant: CNC(=O)CC(c1ccccc1)c1cccc2cc[nH]c12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNCCC(c1ccccc1)c1cccc2cc[nH]c12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 64.9 %

Procedure:
To a stirring solution of 3-(1H-indol-7-yl)-N-methyl-3-phenyl-propionamide XIX (296 mg, 1.06 mmol) in THF (8 ml) was added a suspension of LiAlH4 (165 mg, 4.24 mmol) in THF (6 ml) at room temperature. The mixture was refluxed for 5 hours, cooled to room temperature, and quenched by slow addition of freshly ground Na2SO4.10H2O (4 g). The resulting mixture was stirred at room temperature for 45 minutes, and the solid was filtered and washed with EtOAc. The filtrate was concentrated and purified via flash chromatography (DCM/MeOH) affording [3-(1H-Indol-7-yl)-3-phenyl-propyl]-methyl-amine XX (182 mg, 65% yield). The free amine (100 mg) was dissolved in Et2O (15 ml) and cooled to 0° C. To the resulting solution was added HCl (1 M in Et2O, 568 μl), and the precipitate was filtered and dried in vacuo to afford the hydrochloride salt. (62 mg, 36% yield). MS (M+H)=265.
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[N:5]=[CH:6][C:7]=1[OH:8].C(N(CC)CC)C>CO.[Pd]>[OH:8][C:7]1[CH:6]=[N:5][N:4]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[C:3](=[O:15])[CH:2]=1
Reactant: O=c1c(Cl)c(O)cnn1C1CCCCO1
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: O=c1cc(O)cnn1C1CCCCO1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 14.3 g (62.0 mmol) 4-chloro-5-hydroxy-2-(tetrahydro-pyran-2-yl)-2H-pyridazin-3-one in 200 mL MeOH and 8.71 mL (62.0 mmol) triethylamine is added 5.00 g 10% Pd/C. The reaction mixture is stirred under a hydrogen atmosphere of 1700 hPa at RT for 16 h. The catalyst is removed by filtration and the solvent is evaporated. 200 mL water is added to the residue, the precipitate is collected, washed with water and dried (fraction A, 7.80 g). The aqueous phase is concentrated and the residue is directly added to a reverse HPLC for purification (Waters xbridge; water (0.15% NH4OH)/acetonitril 95:5 to 10:90) to afford fraction B (4.2 g) which is combined with fraction A.
Reaction SMILES: [CH3:1][N:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][N:5]=1)[NH2:3].[CH3:14][C:15]1[N:19]([CH2:20][C:21]([N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[S:30][CH:31]=[C:32]([CH:34]=O)[N:33]=3)[CH2:25][CH2:24]2)=[O:22])[N:18]=[C:17]([C:36]([F:39])([F:38])[F:37])[CH:16]=1>C(O)C>[CH3:1][N:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:11])[F:12])=[CH:6][N:5]=1)[N:3]=[CH:34][C:32]1[N:33]=[C:29]([CH:26]2[CH2:25][CH2:24][N:23]([C:21](=[O:22])[CH2:20][N:19]3[C:15]([CH3:14])=[CH:16][C:17]([C:36]([F:37])([F:39])[F:38])=[N:18]3)[CH2:28][CH2:27]2)[S:30][CH:31]=1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C=O)cs2)CC1
Reactant: CN(N)c1ccc(C(F)(F)F)cn1
Solvent: CCO
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C=NN(C)c3ccc(C(F)(F)F)cn3)cs2)CC1
Reaction time: 24 h

Procedure:
At room temperature, 2-(1-methylhydrazinyl)-5-(trifluoromethyl)pyridine (58 mg) is added to a solution of 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carbaldehyde (100 mg) in ethanol. The reaction mixture is stirred for 24 hours, and the solvent is then removed under reduced pressure. The residue is purified by column chromatography (silica gel, ethyl acetate:hexane 0%-100% elution gradient). This gives 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carbaldehyde methyl[5-(trifluoromethyl)pyridin-2-yl]hydrazone (79 mg, 56%), (log P(pH2.7)=4.23).
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:16])=[CH:4][C:5]2[C:6]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11][C:7]=3[NH:8][C:9]=2[CH:10]=1>C(O)(C(F)(F)F)=O.CO>[Cl:1][C:2]1[C:3]([Cl:16])=[CH:4][C:5]2[C@@H:6]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11][C@@H:7]3[NH:8][C:9]=2[CH:10]=1
Reactant: Clc1cc2[nH]c3c(c2cc1Cl)CCNCC3
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Clc1cc2c(cc1Cl)[C@@H]1CCNCC[C@@H]1N2
Reaction time: 2.5 h
Yield: 34 %

Procedure:
A solution of 8,9-dichloro-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.40 g, 1.6 mmol) in TFA (4.0 mL) was cooled to 0° C., then a freshly prepared solution of Na(CN)BH3 (0.49 g, 7.8 mmol) in MeOH (1.5 mL) was added dropwise. The ice bath was removed after the addition was complete. After 2.5 h, the reaction was diluted with H2O, made basic with 50% aqueous NaOH, and extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, decanted, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography and prep HPLC to give 0.14 g (36%) of the title compound as pale orange solid. 1H NMR (d-CHCl3) δ 7.00, 6.58, 4.22, 3.81, 3.58, 3.14-2.98, 2.79, 2.07-1.87; IR (drift) 3201, 3170, 3149, 3031, 2927, 2852, 2838, 2750, 1608, 1483, 1450, 1365, 1273, 832, 660 cm−1; HRMS (FAB) calcd for C12H14Cl2N2+H 257.0612, found 257.0614.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:19]([CH:20]([CH3:22])[CH3:21])=[CH:18][C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([S:16][CH3:17])[CH:11]=2)=[O:9])=[C:6]([N:23]2[C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[N:26][N:25]=[C:24]2[CH2:34]O)[CH:5]=1)[CH3:2].[C:36]1(=[O:46])[NH:40][C:39](=[O:41])[C:38]2=[CH:42][CH:43]=[CH:44][CH:45]=[C:37]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:3][C:4]1[C:19]([CH:20]([CH3:21])[CH3:22])=[CH:18][C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([S:16][CH3:17])[CH:11]=2)=[O:9])=[C:6]([N:23]2[C:27]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[N:26][N:25]=[C:24]2[CH2:34][N:40]2[C:36](=[O:46])[C:37]3=[CH:45][CH:44]=[CH:43][CH:42]=[C:38]3[C:39]2=[O:41])[CH:5]=1)[CH3:2]
Reactant: CCOc1cc(-n2c(CO)nnc2-c2ccccc2)c(C(=O)c2cccc(SC)c2)cc1C(C)C
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOc1cc(-n2c(CN3C(=O)c4ccccc4C3=O)nnc2-c2ccccc2)c(C(=O)c2cccc(SC)c2)cc1C(C)C

Procedure:
In the manner given in Example 3, a mixture of 4-ethoxy-5-isopropyl-3'-methylthio-2-[3-(hydroxymethyl)-5-phenyl-4H-1,2,4-triazol-4-yl]benzophenone, phthalimide and triphenylphosphine in tetrahydrofuran was treated with diethyl azodicarboxylate to give 4-ethoxy-5-isopropyl-3'-methylthio-2-[3-(phthalimidomethyl)-5-phenyl-4H-1,2,4-triazol-4-yl]benzophenone.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:9][CH:8]=1)(C)C.[OH-].[K+]>C(O)(C)C>[C:13]([C:10]1[CH:9]=[CH:8][C:7]([C:6]#[CH:5])=[CH:12][CH:11]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)c1ccc(C#C[Si](C)(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: C#Cc1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 6.5 h

Procedure:
To a stirred solution of 1.44 g (6.23 mmol) of trimethylsilyl (4-tert-butyl) phenylethyne (Compound 23) in 5 ml of isopropanol was added 10 ml of 1N aqueous KOH and the mixture then stirred at room temperature for 6.5 hours. The isopropanol was removed under vacuum and the residue extracted with ether. The ether extract was washed with dilute HCl until the washings were acidic. The ether solution was then successively washed with water, saturated NaCl and NaHCO3 solutions and then dried (MgSO4). Solvent was then removed in-vacuo to give the title compound as a colorless oil. PMR (CDCl3): δ1.34 (9H, s), 3.05 (1H, s), 7.37 (2H, d, J~8.2 Hz), 7.46 (2H, d, J~8.2 Hz).
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH:8]([CH3:10])[CH3:9])[C:4]([O:6][CH3:7])=[O:5].[C:11](=[O:14])(O)[O-:12].[Na+]>C1COCC1.CO>[C:8]([O:12][C:11]([NH:2][C@H:3]([CH:8]([CH3:10])[CH3:9])[C:4]([O:6][CH3:7])=[O:5])=[O:14])([CH3:10])([CH3:9])[CH3:3]
Reactant: O=C([O-])O
Reactant: COC(=O)[C@H](N)C(C)C
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)[C@H](NC(=O)OC(C)(C)C)C(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 190.8 %

Procedure:
(R)-methyl 2-amino-3-methylbutanoate hydrochloride (4.0 g, 23.86 mmol) was dissolved in THF (60 mL) and methanol (15 mL). The colorless solution was chilled to 0° C., followed by the addition of sodium bicarbonate (6.01 g, 71.6 mmol) in one portion, immediately followed by addition of solid BOC-anhydride (7.81 g, 35.8 mmol). The reaction mixture was allowed to warm to ambient temperature and left stirring overnight, quenched with 200 mL water, and extracted twice with 200 mL MTBE. The organic phase was washed with 200 mL saturated NaHCO3 solution and 200 mL brine, dried over Na2SO4, filtered, and concentrated. The residue was chromatographed on a Grace Reveleris 120 g column, eluted with 0-30% EtOAc in Hexanes (35 mL/min) to obtain the title compound (5.265 g, 22.76 mmol, 95% yield) as a colorless oil. MS (DCI+) m/z 249.2 (M+NH4); 1H NMR (300 MHz, DMSO-d6) δ 7.15 (d, J=8.1, 1H), 3.83 (dd, J=8.0, 6.8, 1H), 3.62 (s, 3H), 2.06-1.91 (m, 1H), 1.38 (s, 9H), 0.86 (dd, J=6.8, 3.2, 6H).
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@H:8]([NH2:9])[CH2:7][CH2:6][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:4]1.ClC(Cl)Cl.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=[O:27]>C(N(CC)CC)C>[CH3:1][O:2][C@H:3]1[C@H:8]([NH:9][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][CH:31]=[C:23]([C:22]([F:21])([F:32])[F:33])[CH:24]=2)[CH2:7][CH2:6][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:4]1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: CO[C@@H]1CN(Cc2ccccc2)CC[C@H]1N
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CO[C@@H]1CN(Cc2ccccc2)CC[C@H]1NC(=O)c1cccc(C(F)(F)F)c1
Reaction time: 20 h
Yield: 80.9 %

Procedure:
To a stirred solution of 10 parts of trans-3-methoxy-1-(phenylmethyl)-4-piperidinamine and 5.95 parts of N,N-diethylethanamine in 75 parts of trichloromethane was added dropwise a solution of 10.4 parts of 3-(trifluoromethyl)benzoyl chloride in 15 parts of N,N-diethylethanamine while cooling in an ice bath. Upon completion, stirring was continued for 20 hours at room temperature. The mixture was washed twice with a sodium hydroxide solution 5% and once with water and then dried, filtered and evaporated in vacuo. After crystallization of the residue from 27 parts of methylbenzene, the product was filtered off, washed with 45 parts of methylbenzene and dried, yielding 14.4 parts (80.9%) of trans-N-[3-methoxy-1-(phenylmethyl)-4-piperidinyl]-3-(trifluoromethyl)benzamide; mp. 135.2° C. (interm. 8).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([NH2:14])[S:11][N:10]=2)=[CH:5][CH:4]=1.C[Al](C)C.[CH3:19][C@@H:20]1[CH2:22][C@H:21]1[C:23](OCC1C=CC=CC=1)=[O:24].N#N>ClCCl.CC(OC)(C)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:13]=[C:12]([NH:14][C:23]([C@@H:21]3[CH2:22][C@H:20]3[CH3:19])=[O:24])[S:11][N:10]=2)=[CH:7][CH:8]=1
Reactant: C[C@@H]1C[C@H]1C(=O)OCc1ccccc1
Reactant: COc1ccc(-c2cc(N)sn2)cc1
Agent: C[Al](C)C
Agent: N#N
Solvent: COC(C)(C)C
Solvent: ClCCl
Product: COc1ccc(-c2cc(NC(=O)[C@@H]3C[C@H]3C)sn2)cc1
Temperature: 2.5 °C
Reaction time: 0.08 h
Yield: 74.5 %

Procedure:
To a stirred suspension of 3-(4-methoxyphenyl)isothiazol-5-ylamine (5.0 g, 24.3 mmol) in anhydrous dichloromethane (230 mL), cooled to 0-5° C., is added trimethylaluminum (2.0 M in toluene, 12.1 mL, 24.2 mmol) by syringe. The solution is stirred 5 min, and benzyl (R,R)-2-methylcyclopropanecarboxylate (4.6 g, 24.21 mmol) is added with the aid of anhydrous dichloromethane (10 mL). The mixture is then warmed to 40-45° C. with N2 flow (needle bleed valve) to slowly remove solvent. After 2 h, most of the dichloromethane has been removed, and the internal temperature rises to about 50° C. The solution is stirred further for 3 h, cooled, and quenched cautiously with dropwise addition of water followed by 0.1 N HCl under a good N2 stream. The resulting residue is then partitioned between ethyl acetate (400 mL) and 0.1 N HCl (400 mL). The organic layer is dried over potassium carbonate, filtered, and evaporated to a low volume. The resulting suspension is diluted with hexanes and the solid filtered to afford 5.9 g of crude product which is re-suspended in MTBE (100 mL), warmed to mild reflux for 1 h, and cooled to room temperature. After standing 1 h, the solid was filtered and dried (20 mm Hg, 40° C.) to afford (R,R)—N-[3-(4-methoxyphenyl)isothiazol-5-yl]-2-methyl-cyclopropanecarboxamide (5.2 g, 75%). 1H NMR (DMSO-d6) 7.86 (d, J=8.8 Hz, 2H), 7.20 (s, 1H), 7.00 (d, J=8.8 Hz, 2H), 3.78 (s, 3H), 1.62 (m, 1H), 1.34 (m, 1H), 1.10 (d, J=6.0 Hz, 3H), 1.09 (m, 1H), 0.80 (m, 1H); ES-MS m/e 289 (m+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:11](=[O:13])[CH3:12])[CH:5]=[C:6]([F:10])[C:7]=1[S:8][CH3:9].[Br:14]Br.O>Br.C(O)(=O)C>[Br:14][CH2:12][C:11]([C:4]1[CH:3]=[C:2]([F:1])[C:7]([S:8][CH3:9])=[C:6]([F:10])[CH:5]=1)=[O:13]
Reactant: CSc1c(F)cc(C(C)=O)cc1F
Reactant: BrBr
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: CSc1c(F)cc(C(=O)CBr)cc1F
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 85.4 %

Procedure:
To a solution of 1-[3,5-difluoro-4-(methylthio)-phenyl]ethanone (prepared in Step 1 of Example 1) (6.2 g, 30 mmol) in 30% HBr in acetic acid (10 mL) was added bromine (4.8 g, 30 mmol) dropwise, and the reaction mixture stirred at room temperature for 45 minutes. The mixture was treated with water and extracted with ethyl acetate (1×250 mL, 1×100 mL). The combined extracts were washed with dilute sodium chloride solution, dried with magnesium sulfate, and concentrated. To the residue was added hexanes (100 mL) and the mixture concentrated. The residue was dissolved in 30% HBr in acetic acid (10 mL) and treated with bromine (0.80 g, 5.0 mmol). After stirring at room temperature for 30 minutes, the mixture was treated with water and extracted with dichloromethane (1×200 mL, 1×100 mL). The combined extracts were washed with water, dried with magnesium sulfate and concentrated. To the residue was added hexanes (100 mL), and the mixture concentrated. Purification of the product by silica gel chromatography using 10% ethyl acetate in hexanes gave 2-bromo-1-[3,5-difluoro-4-(methylthio)-phenyl]ethanone as an orange solid (7.2 g, 86%), MP 30.5-33.2° C. 1H NMR (CDCl3/400 MHz) 7.46-7.50 (m, 2H), 4.33 (s,2H), 2.57(t,3H, J=1.1). ESHRMS m/z 278.9260 (M−H+, Calcd 278.9291). Anal. Calcd for C9H7BrF2OS: C, 38.45; H, 2.52; Found: C, 38.19; H, 2.34.
Reaction SMILES: [N:1]1([C:6]([C:8]2[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:18]1[CH:23]=[CH:22][C:21]([C:24]2[O:25][C:26]([CH3:37])=[C:27]([CH2:29][CH2:30][N:31]3[CH2:35][CH2:34][CH2:33][C@H:32]3[CH3:36])[N:28]=2)=[CH:20][CH:19]=1>>[CH3:37][C:26]1[O:25][C:24]([C:21]2[CH:22]=[CH:23][C:18]([C:11]3[CH:12]=[CH:13][C:8]([C:6]([N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[O:7])=[CH:9][CH:10]=3)=[CH:19][CH:20]=2)=[N:28][C:27]=1[CH2:29][CH2:30][N:31]1[CH2:35][CH2:34][CH2:33][C@H:32]1[CH3:36]
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCC[C@H]1C
Reactant: O=C(c1ccc(B(O)O)cc1)N1CCCC1
Product: Cc1oc(-c2ccc(-c3ccc(C(=O)N4CCCC4)cc3)cc2)nc1CCN1CCC[C@H]1C

Procedure:
The title compound is prepared in a manner substantially analogous to example 133 starting from 4-pyrrolidine-1-carbonyl phenyl boronic acid (314 mg, 1.43 mmol) and 2-(4-Bromo-phenyl)-5-methyl-4-[2-((R)-2-methyl-pyrrolidin-1-yl)-ethyl]-oxazole (100 mg, 0.287 mmol) to give 55 mg (43%). MS (m/e) 444.4 (M+1)
Reaction SMILES: N#N.C(OC([NH:10][C@H:11]([C:15]([NH:17][CH:18]([C:20]1[O:21][C:22]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][C:23]=2[CH:24]=1)[CH3:19])=[O:16])[CH:12]([CH3:14])[CH3:13])=O)(C)(C)C.[ClH:32]>O1CCCC1>[ClH:32].[N+:29]([C:26]1[CH:27]=[CH:28][C:22]2[O:21][C:20]([CH:18]([NH:17][C:15](=[O:16])[C@H:11]([CH:12]([CH3:13])[CH3:14])[NH2:10])[CH3:19])=[CH:24][C:23]=2[CH:25]=1)([O-:31])=[O:30]
Reactant: CC(NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)c1cc2cc([N+](=O)[O-])ccc2o1
Agent: Cl
Agent: N#N
Solvent: C1CCOC1
Product: CC(NC(=O)[C@@H](N)C(C)C)c1cc2cc([N+](=O)[O-])ccc2o1

Procedure:
5.0 g of N2 -tert-butoxycarbonyl-N1 -[1-(5-nitro-2-benzofuranyl)ethyl]-L-valinamide was dissolved in 100 ml of tetrahydrofuran, and placed in a flow of hydrogen chloride gas for 1 hour at room temperature. The reaction mixture was then concentrated under reduced pressure, and the residual crude crystals obtained were washed with acetone to yield 3.6 g of the desired product (melting point: 211°-216° C.).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([C:13]1[CH:18]=[C:17]([F:19])[C:16]([F:20])=[C:15]([F:21])[CH:14]=1)[N:8]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:7][CH2:6]2.C(Cl)Cl>CO.C(Cl)Cl>[C:22]1([N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([OH:2])[CH:4]=3)[CH:9]2[C:13]2[CH:18]=[C:17]([F:19])[C:16]([F:20])=[C:15]([F:21])[CH:14]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COc1ccc2c(c1)CCN(c1ccccc1)C2c1cc(F)c(F)c(F)c1
Solvent: CO
Solvent: ClCCl
Product: Oc1ccc2c(c1)CCN(c1ccccc1)C2c1cc(F)c(F)c(F)c1

Procedure:
The title compound was prepared by analogy to Example 48 except that 6-methoxy-2-phenyl-1-(3,4,5-trifluoro-phenyl)-1,2,3,4-tetrahydroisoquinoline was used instead of 6-methoxy-1-(4-methoxy-phenyl)-2-phenyl-1,2,3,4-tetrahydroisoquinoline, and neat CH2Cl2 to 10% MeOH/CH2Cl2 was used as eluent for flash chromatography purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH3:12].[Br-].[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Zn+]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:12][O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][N:14]=1
Reactant: COc1cc([N+](=O)[O-])ccc1Br
Reactant: [Zn+]c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: COc1cc([N+](=O)[O-])ccc1-c1ccccn1

Procedure:
A solution of 2-bromo-5-nitroanisole (5.8 g, 25 mmol) in THF (50 mL) was treated with 2-pyridyl-zinc bromide (50 mL of a 0.5M solution in THF, 25 mmol) and Pd(PPh3)4 (1.44 g, 1.25 mmol). The reaction mixture was degassed by bubbling argon through the solution for min and was subsequently heated to reflux for 12 h while under an atmosphere of argon. The cooled reaction mixture was concentrated and purified by flash column chromatography on silica gel eluting with EtOAc:hexanes (1:19 to 2:3) to afford the desired 2-(2-methoxy-4-nitrophenyl)pyridine.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([N:12]2[CH2:17][CH2:16][C@@H:15]([NH:18][CH3:19])[C@H:14]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[CH2:13]2)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Cl:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([OH:35])=O)=[CH:31][C:30]=1[C:38]([F:41])([F:40])[F:39]>>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([C:10]([N:12]2[CH2:17][CH2:16][C@@H:15]([N:18]([CH3:19])[C:33](=[O:35])[C:32]3[CH:36]=[CH:37][C:29]([Cl:28])=[C:30]([C:38]([F:41])([F:40])[F:39])[CH:31]=3)[C@H:14]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[CH2:13]2)=[O:11])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CN[C@@H]1CCN(C(=O)C2CCN(C(C)=O)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Reactant: O=C(O)c1ccc(Cl)c(C(F)(F)F)c1
Product: CC(=O)N1CCC(C(=O)N2CC[C@@H](N(C)C(=O)c3ccc(Cl)c(C(F)(F)F)c3)[C@H](c3ccc(Cl)c(Cl)c3)C2)CC1

Procedure:
Using the compound obtained in Example 78 and 4-chloro-3-trifluoromethylbenzoic acid, and by the reaction and purification in the same manner as in Example 3, the title compound was obtained.
Reaction SMILES: O.[Na+].[Cl-].[CH3:4][O:5][C:6](=[O:25])[CH:7]([CH:12]([C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:13][CH2:14][CH2:15][CH3:16])C(OC)=O>CS(C)=O>[CH3:4][O:5][C:6](=[O:25])[CH2:7][CH:12]([C:17](=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCC(C(=O)c1ccccc1)C(C(=O)OC)C(=O)OC
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCCC(CC(=O)OC)C(=O)c1ccccc1
Temperature: 150 °C

Procedure:
Water (3 ml, 166 mmol) and NaCl (5.3 g, 90.2 mmol) are added to a solution of 2-(1-benzoyl-pentyl)-malonic acid dimethyl ester (25.0 g, 81.7 mmol) in DMSO (150 mL). The mixture is heated at 150° C. for 6 hours. Water (450 mL) is added and the mixture is extracted with EtOAc (4×150 mL). The combined extracts are washed with brine (300 mL), dried (Na2SO4), and evaporated, to provides 3-Benzoyl-heptanoic acid methyl ester as a light yellow oil. LC-MS (M+1) 249. This compound without further purification is used directly to the next step.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=O)(C)(C)C.[F:15][C:16]([F:33])([F:32])[O:17][C:18]1[CH:31]=[CH:30][C:21]([O:22][C:23]2[CH:28]=[CH:27][C:26](O)=[CH:25][CH:24]=2)=[CH:20][CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[ClH:67]>C1COCC1.O1CCOCC1>[ClH:67].[F:15][C:16]([F:32])([F:33])[O:17][C:18]1[CH:31]=[CH:30][C:21]([O:22][C:23]2[CH:28]=[CH:27][C:26]([O:14][CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[CH:25][CH:24]=2)=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Oc1ccc(Oc2ccc(OC(F)(F)F)cc2)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: FC(F)(F)Oc1ccc(Oc2ccc(OC3CCNCC3)cc2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 14 %

Procedure:
To a solution of t-butyl-4-hydroxy-1-piperidinecarboxylate (0.40 g, 1.99 mmol) in anhydrous THF (8 mL) was added 4-(4-Trifluoromethoxy-phenoxy)-phenol (0.58 g, 2.65 mmol) and triphenylphosphine (0.63 g, 2.40 mmol). The resulting mixture was cooled to 0° C. Diisopropylazodicarboxylate (0.47 mL, 2.43 mmol) was added portionwise over a ten minute period. The reaction mixture was warmed to ambient temperature for an hour and then heated to 60° C. for 48 h. The solvent was removed in vacuo. The crude residue was purified by silica gel flash chromatography using hexane/EtOAc (gradient system) to give a yellow oil. To the oil was added 4 M HCl in dioxane (7 mL). The resulting mixture was stirred at ambient temperature 2 h. The solvent was removed under reduced pressure to obtain crude product. The residue was triturated with ether to afford the title compound (98 mg, 14%); 1H NMR (400 MHz, DMSO-d6); δ 1.85 (m, 2H), 2.10 (m, 2H), 3.06 (m, 2H), 3.23 (m, 2H), 4.61 (m, 1H), 7.02 (d, J=8.8 Hz, 2H), 7.06 (s, 3H), 7.35 (d, J=8.8 Hz, 2H), 8.92 (br s, 2H); MS (m/z) 354.4 (M+1); LC (97.5%).