Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([Br:24])[CH:23]=3)=[CH:15][N:16]=2)[CH2:11][CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+].CCOC(C)=O>C(Cl)Cl.O>[Br:24][C:22]1[CH:23]=[C:18]([C:14]2[CH:13]=[C:12]3[C:17](=[N:16][CH:15]=2)[NH:8][CH2:9][CH2:10][CH2:11]3)[CH:19]=[N:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCCc2cc(-c3cncc(Br)c3)cnc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Brc1cncc(-c2cnc3c(c2)CCCN3)c1
Reaction time: 21 h

Procedure:
6-(5-Bromo-pyridin-3-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester (260 mg, 0.67 mmol) is dissolved in 3.0 mL of DCM and trifluoroacetic acid (1.0 mL, 12 mmol) is added. The mixture is stirred for 21 hrs. Then saturated aqueous NaHCO3 is used to adjust the pH to about 8 and EtOAc (25 mL) along with 15 mL of water are added. The mixture is stirred for 10 min and the aqueous layer is separated and extracted with EtOAc (2×15 ml). The organic layers are combined and concentrated to give 6-(5-bromo-pyridin-3-yl)-1,2,3,4-tetrahydro-[1,8]naphthyridine which is used in the next step without puification.
Reaction SMILES: [OH:1][C:2]1[C:3]([O:14][CH3:15])=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:16]C1CCCO1.C(Cl)(=O)C(Cl)=O.CO>C([O-])([O-])=O.[Na+].[Na+]>[OH:1][C:2]1[C:3]([O:14][CH3:15])=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:16])=[O:8]
Reactant: COc1cc([N+](=O)[O-])c(C(=O)O)cc1O
Reactant: CC1CCCO1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(O)c(OC)cc1[N+](=O)[O-]
Temperature: 15 °C
Yield: 92 %

Procedure:
5-hydroxy-4-methoxy-2-nitrobenzoic acid (31.9 g, 0.15 mol, 1.0 eq) and 2-methyltetrahydrofuran (200 mL) are charged into a glass reactor under nitrogen. The solution is stirred and jacket temp is set to 20° C. Oxalyl chloride (24 g, 0.19 mol, 1.25 eq) is added at a rate that the internal temperature is below 25° C. The reaction mixture is stirred for 1-2 hour at 20° C., and cooled to 15° C. Then, anhydrous MeOH (60 ml, 1.5 mol, 10 eq) is added over 15 min, and the reaction temperature is maintained below 25° C. during addition. The reaction mixture is stirred for 2-4 hour at 20° C. until HPLC sample shows complete conversion. Na2CO3 aqueous solution (1 M, 100 ml) is added to the reaction mixture. Layers are separated. The upper organic layer is distilled under vacuum to minimum volume. The dark brown residue is stirred in 100 mL mixed solvent of toluene/hexane (v/v, 2:1) to give a suspension. The slurry is filtered. The solid is dried under vacuum to provide the desired product, methyl 5-hydroxy-4-methoxy-2-nitrobenzoate (31.3 g, 92% yield).
Reaction SMILES: [OH:1][S:2]([OH:5])(=[O:4])=[O:3].[CH3:6][N:7]1[C@@H:24]2[CH2:25][C:12]3=[CH:13][CH:14]=[C:15](O)[C:16]4[O:17][C@H:18]5[C:19]([CH2:21][CH2:22][C@@H:23]2[C@:10]5([C:11]=43)[CH2:9][CH2:8]1)=[O:20].C(#N)C.[OH-].[Na+]>CCO>[CH3:6][N:7]1[C@@H:24]2[CH2:25][C:12]3=[CH:13][CH:14]=[C:15]([O:3][S:2]([OH:5])(=[O:1])=[O:4])[C:16]4[O:17][C@H:18]5[C:19]([CH2:21][CH2:22][C@@H:23]2[C@:10]5([C:11]=43)[CH2:9][CH2:8]1)=[O:20]
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)CC[C@H]3[C@H]1C5
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CCO
Product: CN1CC[C@]23c4c5ccc(OS(=O)(=O)O)c4O[C@H]2C(=O)CC[C@H]3[C@H]1C5
Temperature: 81 °C

Procedure:
Morphine base (30.0 g, wet, 75% wt, 78.85 mmol) was dried in a vacuum oven at 90° C. for 3 h. The dried solid was added to a reaction flask, along with water (30 mL) and EtOH (60 mL). The reaction mixture was stirred to form a suspension. The reactor was flushed with nitrogen and the reaction mixture was kept under nitrogen throughout the reaction. The reaction flask was charged with H2SO4 (98%, 7.73 g, 78.85 mmol) and the catalyst (RuCl3.xH2O, 0.20 g). The reaction mixture was heated to reflux (80-82° C.) for 16 h. HPLC analysis indicated that 96.8% (area) hydromorphone was formed. The reaction mixture was cooled down overnight. Acetonitrile (30 mL) was added to the reaction mixture and the mixture was heated at reflux for 1 h. The pH of the reaction mixture was adjusted the pH to 1.6 with 50% NaOH. EtOH (90 mL) was added to the mixture, which as cooled down to 15° C. for 1 h. The mixture was filtered, and the solid was washed with 95% EtOH (2×15 mL). The solid was dried under vacuum at 65° C. for 18 h to give 11.6 g of hydromorphone sulfate as solids (purity>99% area).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[CH3:22][C:23]1([CH3:31])[CH2:27][NH:26][CH:25]([C:28]([NH2:30])=[O:29])[CH2:24]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CS(C)=O>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:26]3[CH2:27][C:23]([CH3:31])([CH3:22])[CH2:24][CH:25]3[C:28]([NH2:30])=[O:29])=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: CC1(C)CNC(C(N)=O)C1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC1(C)CC(C(N)=O)N(C(=O)c2ccc(N3CC(F)(F)C3)c(OCC3CC3)n2)C1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with 4,4-dimethylpyrrolidine-2-carboxamide hydrochloride (Example 90 d) in the presence of TBTU and DIEA. The mixture of enantiomers was separated by chiral HPLC (Reprosil Chiral NR). The (+) enantiomer was isolated as yellow solid; MS (EI): m/e=409.6 [MH+]; αD20 (DMSO)=+19.3°.
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:8]1[C:13]([N+:14]([O-])=O)=[CH:12][CH:11]=[CH:10][C:9]=1[B:17]1[O:21][C:20]([CH3:23])([CH3:22])[C:19]([CH3:25])([CH3:24])[O:18]1)([CH3:4])([CH3:3])[CH3:2]>CCOC(C)=O.[Pd]>[C:1]([SiH2:5][O:6][C:7]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:8]1[C:9]([B:17]2[O:18][C:19]([CH3:24])([CH3:25])[C:20]([CH3:23])([CH3:22])[O:21]2)=[CH:10][CH:11]=[CH:12][C:13]=1[NH2:14])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)[SiH2]OC(c1ccccc1)(c1ccccc1)c1c(B2OC(C)(C)C(C)(C)O2)cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)[SiH2]OC(c1ccccc1)(c1ccccc1)c1c(N)cccc1B1OC(C)(C)C(C)(C)O1
Reaction time: 20 h

Procedure:
The nitro compound Intermediate 26 (10.0 g, 19.32 mmol) was dissolved in 300 ml EtOAc and Pd/C 10% (Pd) (2.0 g) were added. The mixture was hydrogenated at room temperature and normal pressure for 20 hours. The mixture was filtered over Kieselgur (Supelco) and evaporated. The residue was purified by flash chromatography on silica (cyclohexane to cyclohexane/EtOAc 4:1) to afford the compound Intermediate 27 as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11](B(O)O)=[CH:10][C:9]=2[F:17])=[CH:4][N:3]=1.Cl[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[CH:26]=[N:27][C:28]([NH2:31])=[N:29][CH:30]=1>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]3[CH:26]=[N:27][C:28]([NH2:31])=[N:29][CH:30]=3)=[CH:10][C:9]=2[F:17])=[CH:4][N:3]=1
Reactant: Nc1ncc(-c2ccccc2Cl)cn1
Reactant: Nc1ncc(-c2ncc(B(O)O)cc2F)cn1
Product: Nc1ncc(-c2ccccc2-c2cnc(-c3cnc(N)nc3)c(F)c2)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 427 using (6-(2-aminopyrimidin-5-yl)-5-fluoropyridin-3-yl)boronic acid and 5-(2-chlorophenyl)pyrimidin-2-amine. MS (ESI): mass calcd. for C19H14FN7, 359.13; m/z found, 360.1 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.93 (s, 2H), 8.31-8.28 (m, 1H), 8.19 (s, 2H), 7.64 (dd, J=12.0, 1.9, 1H), 7.59-7.51 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=2)[C:10](=[O:12])[CH3:11])=[CH:4][CH:3]=1.CCC(C)[BH-](C(C)CC)C(C)CC.[Li+].[OH-].[Na+].OO>O1CCCC1.C1(C)C=CC=CC=1.CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=2)[CH:10]([OH:12])[CH3:11])=[CH:4][CH:3]=1
Reactant: CC(=O)C(Cc1ccc(Cl)cc1)c1cccc(Br)c1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: OO
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CC(O)C(Cc1ccc(Cl)cc1)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 13 h

Procedure:
To a solution of 4-(4-chlorophenyl)-3-(3-bromophenyl)-2-butanone (1.55 kg, 4.6 mol) in tetrahydrofuran (8.4 L) at −60° C. was added L-selectride (1.0 M in tetrahydrofuran, 5.3 L, 5.3 mol), and the reaction mixture was allowed to slowly warm up to room temperature overnight. The mixture was cooled back to 0° C., and was quenched by slow addition of acetone, aqueous sodium hydroxide (2.5 N, 8.5 L, 21 mol) and 30% hydrogen peroxide (2.1 L, 21 mol). After stirig at room temperature for 13 h, the reaction mixture was diluted with toluene (30 L). The organic layer was separated, washed with water (2×12 L), and concentrated to give the title compound as an oil. 1H NMR (500 MHz, CD3OD): δ 7.40 (s, 1H), 7.30 (d, 1H), 7.28-7.10 (m, 4H), 7.04 (d, 2H), 3.98 (m, 1H), 3.12 (dd, 1H), 2.90 (dd, 1H), 2.80 (m, 1H), 1.08 (d, 3H).
Reaction SMILES: N[C@H:2]([C:8](O)=[O:9])CCCCN.[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([NH:20][C:21]([C@H:23]([N:30]([CH3:55])[C:31]([C@H:33]([NH:45][C:46](=[O:54])/[CH:47]=[CH:48]/[CH2:49][C:50]([NH2:53])([CH3:52])[CH3:51])[CH2:34][C:35]1[CH:44]=[CH:43][C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=1)=[O:32])[CH2:24][C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)=[O:22])[C:17](=[O:19])[NH2:18]>>[C:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([NH:20][C:21]([C@H:23]([N:30]([CH3:55])[C:31]([C@H:33]([NH:45][C:46](=[O:54])/[CH:47]=[CH:48]/[CH2:49][C:50]([NH2:53])([CH3:52])[CH3:51])[CH2:34][C:35]1[CH:44]=[CH:43][C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=1)=[O:32])[CH2:24][C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)=[O:22])[C:17](=[O:19])[NH2:18])(=[O:9])[CH3:2]
Reactant: NCCCC[C@H](N)C(=O)O
Reactant: CN(C(=O)[C@@H](Cc1ccc2ccccc2c1)NC(=O)/C=C/CC(C)(C)N)[C@H](Cc1cccs1)C(=O)N[C@@H](CCCCN)C(N)=O
Product: CC(=O)NCCCC[C@H](NC(=O)[C@@H](Cc1cccs1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)NC(=O)/C=C/CC(C)(C)N)C(N)=O

Procedure:
This compound was prepared by acetylation of the epsilon amino group in the lysine fragment using the general method described above and using the compound prepared in example 22 as starting material.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([CH3:10])[N:3]=1.[S:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[C:13]([S:20]([N:23]=[C:24]=[O:25])(=[O:22])=[O:21])=[CH:12]1>C(#N)C>[CH3:9][O:8][C:6]1[N:5]=[C:4]([CH3:10])[N:3]=[C:2]([NH:1][C:24]([NH:23][S:20]([C:13]2[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[S:11][CH:12]=2)(=[O:21])=[O:22])=[O:25])[N:7]=1
Reactant: O=C=NS(=O)(=O)c1csc2ccccc12
Reactant: COc1nc(C)nc(N)n1
Solvent: CC#N
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)c2csc3ccccc23)n1
Yield: 73.9 %

Procedure:
To 1.4 g of 2-amino-4-methoxy-6-methyl-1,3,5-triazine in 25 ml acetonitrile was added 2.4 g of benzothiophene-3-sulfonyl isocyanate with stirring. After stirring overnight at ambient temperature the mixture was filtered and the precipitate was washed with butyl chloride to yield 2.8 g of a white solid, m.p. 187°-188°. It showed absorption peaks by Nuclear Magnetic Resonance (60 MC) at 2.25 and 3.9 (methyl and methoxy in triazine), at 7-8 (benzo hydrogens) and 8.3 δ (thiophene hydrogen) consistent for the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O.[CH3:17][CH2:18][C:19](=O)[CH2:20][C:21](=[O:24])[CH2:22][CH3:23].[Na]>C(O)C>[Br:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[N:1]=[C:19]([CH2:18][CH3:17])[C:20]([C:21](=[O:24])[CH2:22][CH3:23])=[C:9]2[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1ccc(Br)cc1C(=O)c1ccccc1
Reactant: CCC(=O)CC(=O)CC
Agent: [Na]
Solvent: CCO
Product: CCC(=O)c1c(CC)nc2ccc(Br)cc2c1-c1ccccc1
Yield: 37 %

Procedure:
The title compound was prepared according to the general procedure of method A. The (2-Amino-5-bromo-phenyl)-phenyl-methanone [example A16] (on 0.1-1 g scale) and 3,5-heptanedione (1.5 equiv) and sodium tetrachloroaureate(III) dihydrate (0.025 equiv) were heated in parallel in a Radley carousel under nitrogen in ethanol (10% w/w-solution of (2-Amino-5-bromo-phenyl)-phenyl-methanone) and reacted for 24 h. The reaction mixture was evaporated to dryness and the residue purified by chromatography on silica gel in heptane/ethyl acetate (20:1). Yield: 37%. MS: m/z=368 (M).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][C@H:12]([CH3:14])[O:11][C@H:10]([CH3:15])[CH2:9]2)=[C:6]([CH2:16][OH:17])[N:5]=[C:4]2[C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[N:19][O:20][C:3]=12>ClCCl.[Mn]>[Cl:1][C:2]1[C:7]([N:8]2[CH2:13][C@H:12]([CH3:14])[O:11][C@H:10]([CH3:15])[CH2:9]2)=[C:6]([CH:16]=[O:17])[N:5]=[C:4]2[C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[N:19][O:20][C:3]=12
Reactant: C[C@@H]1CN(c2c(CO)nc3c(-c4ccccn4)noc3c2Cl)C[C@H](C)O1
Agent: [Mn]
Solvent: ClCCl
Product: C[C@@H]1CN(c2c(C=O)nc3c(-c4ccccn4)noc3c2Cl)C[C@H](C)O1
Temperature: 25 °C
Reaction time: 48 h
Yield: 41.3 %

Procedure:
To a stirring solution of (7-chloro-6-((2R,6S)-2,6-dimethylmorpholino)-3-(pyridin-2-yl)isoxazolo[4,5-b]pyridin-5-yl)methanol (Intermediate 201, 0.39 g, 1.04 mmol) in dichloromethane (20 mL) was added Manganese dioxode (0.543 g, 6.24 mmol). The mixture was allowed to stir 2 days at room temperature. The reaction was filtered over Celite®, and the filtrate concentrated under vacuum to give clear oil. The oil was purified on short bed of silica using 20-30% acetone in n-hexane to give 0.16 g (42%) of the title compound as a yellow solid.
Reaction SMILES: [F:1][C:2]1[C:3]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[O:28][CH3:29])=[C:4]2[CH:10]=[C:9]([C:11]3[CH2:16][CH2:15][N:14]([CH2:17][C:18](O)=[O:19])[CH2:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl.[NH:71]1[CH2:76][CH2:75][CH:74]([OH:77])[CH2:73][CH2:72]1>CN(C)C=O.[Cl-].[Na+].O.O>[F:1][C:2]1[C:3]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[O:28][CH3:29])=[C:4]2[CH:10]=[C:9]([C:11]3[CH2:16][CH2:15][N:14]([CH2:17][C:18]([N:71]4[CH2:76][CH2:75][CH:74]([OH:77])[CH2:73][CH2:72]4)=[O:19])[CH2:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: OC1CCNCC1
Reactant: COc1ccc(F)cc1-c1c(F)cnc2[nH]c(C3=CCN(CC(=O)O)CC3)cc12
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(F)cc1-c1c(F)cnc2[nH]c(C3=CCN(CC(=O)N4CCC(O)CC4)CC3)cc12

Procedure:
A mixture of Example 294A (0.085 g, 0.195 mmol), (benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (0.122 g, 0.234 mmol), triethylamine (0.109 mL, 0.780 mmol), and piperidin-4-ol.hydrochloride (0.032 g, 0.234 mmol) in N,N-dimethylformamide (2 mL) was stirred for 3 hours. The mixture was treated with water and brine and extracted with ethyl acetate (twice). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, concentrated, and purified on silica gel using the ISCO Companion eluting with dichloromethane/methanol/ammonium hydroxide (18:1:0.1 to 9:1:0.1) to give the title compound. 1H NMR (400 MHz, Methanol-d4) δ 1.33-1.60 (m, 2H), 1.79-1.94 (m, 2H), 2.56 (bs, 2H), 2.73-2.80 (m, 2H), 3.06-3.18 (m, 1H), 3.27-3.30 (m, 2H), 3.32-3.43 (m, 2H), 3.76 (s, 3H), 3.78-3.98 (m, 2H), 4.03-4.12 (m, 1H), 4.56 (d, J=1.1 Hz, 1H), 6.16 (s, 1H), 6.34-6.40 (m, 1H), 6.99-7.24 (m, 3H), 8.06 (d, J=2.9 Hz, 1H). MS (ESI+) m/z 483.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C:5]([O:22][CH:23]([CH3:25])[CH3:24])=[CH:6][C:7]1[CH:8]=[CH:9][C:10]([O:20][CH3:21])=[C:11]([CH:19]=1)[C:12]([O:14]C(C)(C)C)=[O:13])[CH3:2].FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>ClCCl>[CH2:1]([O:3][C:4](=[O:26])/[C:5](/[O:22][CH:23]([CH3:25])[CH3:24])=[CH:6]/[C:7]1[CH:8]=[CH:9][C:10]([O:20][CH3:21])=[C:11]([CH:19]=1)[C:12]([OH:14])=[O:13])[CH3:2]
Reactant: CCOC(=O)C(=Cc1ccc(OC)c(C(=O)OC(C)(C)C)c1)OC(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCOC(=O)/C(=C/c1ccc(OC)c(C(=O)O)c1)OC(C)C
Yield: 25.6 %

Procedure:
0.3 g of tert-butyl 5-(3-ethoxy-2-isopropoxy-3-oxo-1-propenyl)-2-methoxybenzoate was dissolved in 2.5 ml dichloromethane, and 1.2 ml trifluoroacetic acid was added under ice-cooling, and the mixture was stirred as such under ice-cooling for 2 hours. 30 ml toluene was added to the reaction mixture and the solvent was evapoarated; this procedure was repeated twice. Then, the residue was subjected to silica gel column chromatography, and from fractions eluted with hexane-ethyl acetate (2:1), 65 mg of 5-[(Z)-3-ethoxy-2-isopropoxy-3-oxo-1-propenyl]-2-methoxybenzoic acid was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N+:3]=1[O-:12].OS(O)(=O)=O.[OH-].[Na+].[N+:20]([O-])([OH:22])=[O:21]>>[Br:1][C:2]1[CH:11]=[C:10]([N+:20]([O-:22])=[O:21])[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N+:3]=1[O-:12]
Reactant: [O-][n+]1c(Br)ccc2c1CCCC2
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=[N+]([O-])c1cc(Br)[n+]([O-])c2c1CCCC2
Temperature: 90 °C
Yield: 83 %

Procedure:
With efficient ice bath cooling 2-bromo-5,6,7,8-tetrahydro-quinoline 1-oxide (8.0 g, 35 mmol) (S. Zimmermann et al., J. Am. Chem. Soc., 1991, 113, 183) was treated with conc. H2SO4 (65 ml), followed by conc. HNO3 (10 ml). The resulting mixture was heated to 90° C. for 90 min, cooled and poured on crushed ice (200 g). NaOH (28%) was added to reach pH 7 and the aqueous phase extracted with AcOEt. The organic phase was dried (Na2SO4) and concentrated to yield 7.9 g (83%) of the title compound as a yellow oil. MS: m/e=272 (M+).
Reaction SMILES: [CH3:1][C:2](=[N:4][OH:5])[CH3:3].C([Li])CCC.CO[C:13](=O)[C@@H:14]1[CH2:18][CH2:17][C:16](=[O:19])[NH:15]1.S(=O)(=O)(O)O>C1COCC1.O>[CH3:1][C:2]1[CH:3]=[C:13]([C@H:14]2[NH:15][C:16](=[O:19])[CH2:17][CH2:18]2)[O:5][N:4]=1
Reactant: COC(=O)[C@@H]1CCC(=O)N1
Reactant: CC(C)=NO
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc([C@@H]2CCC(=O)N2)on1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
To a cooled (0°-5° C.) solution of acetone oxime (11.74 g, 160.8 mmol)in THF (200 mL) was slowly added n-butyl lithium (128.6 mL, 2.5M, 321.6 mmol)in hexanes. After being stirred at 0°-5° C. for one hour, a solution of pyroglutamic methyl ester (10.0 g, ~69.9 mmol, the product of step 13a)in THF (50 mL) was added. After stirring for 4 hr, the solution was allowed to slowly warm up to room temperature, and the stirring was continued for 16 hr. Sulfuric acid (35 g, 98%) was slowly added with cooling, followed by the addition of water (35 mL). The resulting mixture was refluxed for one hour. The organic layer was decanted and the slurry was washed with ethyl acetate (5×50 mL). To the mixture was added ethyl acetate (400 mL) and sodium carbonate until basic. Again, the organic layer was decanted and the slurry was washed with ethyl acetate (4×20 mL). The combined organics were then dried over magnesium sulfate. Evaporation of the solvents gave the title product (5.33 g, 46%), which was taken directly to the next step. HPLC (analytical Chiralark AD column) analysis indicated >99.6% ee.
Reaction SMILES: [CH:1]1([NH:5][C:6](=[O:27])[C:7]2[CH:12]=[C:11]([O:13][C:14]3[C:19]([Cl:20])=[CH:18][C:17]([CH2:21][O:22][CH3:23])=[CH:16][C:15]=3[Cl:24])[CH:10]=[CH:9][C:8]=2[O:25][CH3:26])[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:30]I>CN(C)C=O.Cl>[CH:1]1([N:5]([CH3:30])[C:6](=[O:27])[C:7]2[CH:12]=[C:11]([O:13][C:14]3[C:19]([Cl:20])=[CH:18][C:17]([CH2:21][O:22][CH3:23])=[CH:16][C:15]=3[Cl:24])[CH:10]=[CH:9][C:8]=2[O:25][CH3:26])[CH2:4][CH2:3][CH2:2]1
Reactant: COCc1cc(Cl)c(Oc2ccc(OC)c(C(=O)NC3CCC3)c2)c(Cl)c1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCc1cc(Cl)c(Oc2ccc(OC)c(C(=O)N(C)C3CCC3)c2)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.1 %

Procedure:
To a solution of the title compound of Step E (170 mg, 0.41 mmol) in dimethylformamide (4 ml) at 0° C. under nitrogen was added sodium hydride (60% dispersion in mineral oil, 41 mg, 1 mmol). The resulting slurry mixture was stirred at 0° C. for about 30 minutes and gradually became a brownish-yellow solution. To this solution at 0° C. was added methyl iodide (0.13 ml, 2 mmol). The resulting solution was warmed to room temperature and stirred for about 19 hours. The solution was diluted with 1N HCl (30 ml) and extracted with ethyl acetate (3×15 ml). The combined organic extracts were washed with 1N HCl (3×50 ml), brine, dried, filtered, and concentrated. The residue was purified by preparative TLC (50% ethyl acetate in hexanes) to afford the title compound (155 mg). MS (APCI+) Calc: 423.1, found: 424.0 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:12]1([C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: FC(F)(F)c1ccc(Cl)cc1
Reactant: C1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: FC(F)(F)c1ccc(N2CCCCC2)cc1
Reaction time: 48 h
Yield: 23.4 %

Procedure:
The general procedure from Example 1 was followed using 4-chlorobenzotrifluoride (650 mg, 3.6 mmol) and piperidine (258 mg, 3.0 mmol) with Pd2(dba)3 (55 mg, 0.081 mmol) and (Me3C)2PH(O) (21.0 mg, 0.126 mmol) and NaOtBu (432 mg, 4.5 mmol) in 6.0 mL of toluene. After 48 h, the reaction mixture was chromatographed with 5% ethyl acetate/hexane to give 161 mg (23% yield) of 4-piperidinobenzotrifluoride. It was >95% pure by 1H NMR and GC/MS. 1H NMR (500 MHz, CDCl3): δ 7.36 (d, J=8.78 Hz, 2H), 6.82 (d, J=8.79 Hz, 2H), 3.18 (m, 4H), 1.60 (m, 4H), 1.54 (m, 2H) ppm. 13C NMR (125 MHz, CDCl3): d 153.7, 127.6, 126.3, 114.5, 49.2, 25.4, 24.2 ppm. MS: Calculated for C12H14F3N(M+): 229.1. Found: 230.2 (M++H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:14](O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@H:9]([C@H:14]([S:30]([CH3:29])(=[O:32])=[O:31])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H](O)c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](NC(=O)OC(C)(C)C)[C@@H](c1ccccc1)S(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of alcohol 4 (0.94 g, 3.18 mmol) and NEt3 (0.73 g, 7.18 mmol) at 0° C. in Cl2CH2 (10 mL), methanesulfonyl chloride (418 mg, 3.65 mmol) was added. The reaction mixture was allowed to stir at 0° C. for 45 min. It was then quenched with cold dilute HCl, diluted with Cl2CH2 and the organic layer was washed with an aqueous solution of NaHCO3 followed by brine and dried over Na2SO4. The solvent was eliminated in vacuo and the crude mesylate 6 was obtained as a foamy white solid which was used in the next step without further purification. 1H NMR (CDCl3).δ1.417 (s, 9H), 2.910 (s, 3H, CH3 --OMs), 3.705 (s, 3H, CH3O--), 4.853 (dd, J=9.6, 6.6 Hz, 1H, H--C2), 5.173 (bd, J=9.6 Hz, 1H, H--N), 5.893 (d, J=6.6 Hz, 1H, H--C3), 7.389-7.400 (m, 5H); IR (KBR) 3400, 2980, 2950, 1745, 1715, 1520, 1360, 1180 cm-1.