Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[F:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=1[CH3:22]>>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:21][C:18]2[CH:19]=[CH:20][C:15]([F:14])=[C:16]([CH3:22])[CH:17]=2)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(Cl)c1ccc(F)c([N+](=O)[O-])c1
Reactant: Cc1cc(N)ccc1F
Product: Cc1cc(NC(=O)c2ccc(F)c([N+](=O)[O-])c2)ccc1F

Procedure:
A mixture of the product from Example 86A was reacted with 4-Fluoro-3-methyl-phenylamine to produce 4-Fluoro-N-(4-fluoro-3-methyl-phenyl)-3-nitro-benzamide according to the procedure of Example 86B, which was treated sequentially using the procedures from Examples 86C and 395D to provide the title product.
Reaction SMILES: [O:1]=[C:2]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]2)[CH2:3][CH2:4]Cl.[I-].[Na+].[CH2:19]([CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1CCN2C(=NCCC2)CC1.C(=O)([O-])O.[Na+]>C(O)(C)C>[O:1]=[C:2]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]2)[CH2:3][CH2:4][N:29]1[CH2:30][CH2:31][CH:26]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:27][CH2:28]1
Reactant: O=C1CCc2cc(C(=O)CCCl)ccc2N1
Reactant: c1ccc(CC2CCNCC2)cc1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(C)O
Product: O=C1CCc2cc(C(=O)CCN3CCC(Cc4ccccc4)CC3)ccc2N1
Reaction time: 2 h

Procedure:
2.4 Grams of 6-(1-oxo-3-chloropropyl)-3,4-dihydrocarbostyril and 1.6 g of sodium iodide were mixed in 60 ml of isopropanol and stirred at 40°-50° C. for 2 hours. Then 2.2 g of 4-benzylpiperidine and 3.0 g of DBU were added to the reaction mixture and refluxed by heating for 6 hours. The reaction mixture was poured into 100 ml of 5%-sodium hydrogen-carbonate aqueous solution and stirred at a room temperature for 1 hour. The insoluble matters fromed were collected by filtration washed with water and dried, then recrystallized from ethanol to obtain 1.8 g of 6-[1-oxo-3-(4-benzyl-1-piperidyl)propyl]-3,4-dihydrocarbostyril in light yellow plate-like crystals.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[NH:10][C:11]1[N:12]=[CH:13][C:14]2[CH2:20][NH:19][CH2:18][CH2:17][C:15]=2[N:16]=1.[NH:21]1[C:25]([CH2:26][CH2:27][O:28][CH2:29][C:30](O)=[O:31])=[CH:24][N:23]=[N:22]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=N)C.C(N(CC)CC)C>ClCCl>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[NH:10][C:11]1[N:12]=[CH:13][C:14]2[CH2:20][N:19]([C:30](=[O:31])[CH2:29][O:28][CH2:27][CH2:26][C:25]3[N:21]=[N:22][NH:23][CH:24]=3)[CH2:18][CH2:17][C:15]=2[N:16]=1
Reactant: c1ccc2c(c1)CC(Nc1ncc3c(n1)CCNC3)C2
Reactant: O=C(O)COCCc1cnn[nH]1
Agent: CCN=C=N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(COCCc1c[nH]nn1)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1
Yield: 60.4 %

Procedure:
Add N-indan-2-yl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (4.2 g, 15.8 mmol) to a mixture of 2-[2-(1H-triazol-5-yl)ethoxy]acetic acid (2.7 g, 15.8 mmol), 1-hydroxybenzotriazole (3.20 g, 23.7 mmol), and dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.44 g, 28.4 mmol) in dichloromethane (40 mL) at 25° C. Add triethylamine (4.40 mL, 31.6 mmol) to the reaction mixture and stir for 16 h. Wash with water (2×50 mL) and concentrate the organic layer. Purify by silica gel column chromatography, eluting with ethyl acetate/methanol, to give the title compound (4.0 g, 60%) as a solid. MS (m/z): 420 (M+H).
Reaction SMILES: N[C:2]1[C:3]2[C:4]3[C:5](=[CH:13][N:14]([C@@H:16]4[O:22][C@H:21]([CH2:23][OH:24])[C@@H:19]([OH:20])[C@@:17]4([CH3:25])[OH:18])[N:15]=2)[CH:6]=[CH:7][C:8]=3[C:9](=[O:12])[NH:10][N:11]=1.N([O-])=[O:27].[Na+]>C(O)(=O)C.CC[N+](CC)(CC)CC.[Br-]>[CH3:25][C@@:17]1([OH:18])[C@H:19]([OH:20])[C@@H:21]([CH2:23][OH:24])[O:22][C@H:16]1[N:14]1[CH2:13][C:5]2=[CH:6][CH:7]=[C:8]3[C:9](=[O:12])[NH:10][NH:11][C:2](=[O:27])[C:3](=[C:4]23)[NH:15]1
Reactant: O=N[O-]
Reactant: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1cc2ccc3c(=O)[nH]nc(N)c(n1)c23
Agent: CC[N+](CC)(CC)CC
Agent: [Br-]
Agent: [Na+]
Solvent: CC(=O)O
Product: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1N1Cc2ccc3c(=O)[nH][nH]c(=O)c(c2-3)N1
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.9 %

Procedure:
To a solution 4-amino-2-(2-C-methyl-β-D-ribofuranosyl)-2,6-dihydro-7H-2,3,5,6-tetraazabenzo[cd]azulene-7-one 15.6 (35 mg, 0.1 mmol) in 50% aqueous acetic acid (5 mL) was added sodium nitrite (42 mg, 0.6 mmol) and the mixture stirred at room temperature for 4 hr. The mixture was neutralized with 1M TEAB buffer and purified by reversed phase ion-pairing HPLC on a Phenomenex Luna C18(2) 250×21 mm 10 μM column. 100 mM triethylammonium acetate (TEAA), pH 7 was used as the ion-pairing agent. A gradient of 20% to 55% MeOH over 40 min was applied. The target compound eluted at 26 min followed by two smaller peaks at 29 and 31 min. TEAA was removed by repeated lyophilzation to yield the target compound as a fluffy yellow material (28 mg, 80%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([S:10][CH2:11][C:12]([O:14]C)=[O:13])=[CH:2]1>O1CCCC1.[Li+].[OH-].ClCCl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([S:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:2]1
Reactant: COC(=O)CSc1c[nH]c2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(O)CSc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38 %

Procedure:
Methyl 2-((1H-indol-3-yl)thio)acetate from Step A was dissolved in a mixture of tetrahydrofuran (20 mL) and 2.0 M aqueous LiOH (15 mL), then stirred vigorously at ambient temperature for 30 min. Tetrahydrofuran was removed in vacuo, the aqueous layer neutralized with 1.2 N HCl and extracted with CH2Cl2. The organic layer was dried over magnesium sulfate and the solvent was removed in vacuo to produce an oily residue. Upon diluting the residue in dichloromethane a solid formed which was filtered and dried to yield the desired product (2.00 grams, 9.65 mmol, 38% yield over 2 steps). LCMS>99% at 254 nm, RT=1.02 min, m/z=208 (M+1).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH3:7][O:8][C:9]1[CH:10]=[C:11](CC(O)=O)[CH:12]=[CH:13][CH:14]=1>C(Cl)Cl>[CH3:7][O:8][C:9]1[CH:14]=[C:13]([CH2:1][C:2]([Cl:4])=[O:3])[CH:12]=[CH:11][CH:10]=1
Reactant: COc1cccc(CC(=O)O)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COc1cccc(CC(=O)Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Oxalyl chloride (57.1 g) is added to a stirred solution of 3-methoxyphenylacetic acid (49.85 g) in 300 ml of methylene chloride. The reaction mixture is stirred for 11/2 hr at RT, refluxed overnight, and then evaporated in vacuo. The residual product is used in the next step.
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[O:7][CH2:6][C:5]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:19][C:20]4[CH:25]=[CH:24][C:23]([O:26][C:27]5C=[CH:31][CH:30]=[CH:29][CH:28]=5)=[CH:22][CH:21]=4)[CH:15]=3)[CH:10]=2)([NH2:8])[CH2:4][O:3]1.CC1(C)OCC([N+]([O-])=O)(C2C=CC3C(=CC=C(OC4C=CC(OCCCCC)=CC=4)C=3)C=2)CO1>>[CH3:1][C:2]1([CH3:33])[O:7][CH2:6][C:5]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:19][C:20]4[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:22][CH:21]=4)[CH:15]=3)[CH:10]=2)([NH2:8])[CH2:4][O:3]1
Reactant: CC1(C)OCC(N)(c2ccc3cc(Oc4ccc(Oc5ccccc5)cc4)ccc3c2)CO1
Agent: CCCCCOc1ccc(Oc2ccc3cc(C4([N+](=O)[O-])COC(C)(C)OC4)ccc3c2)cc1
Product: CCCCCOc1ccc(Oc2ccc3cc(C4(N)COC(C)(C)OC4)ccc3c2)cc1
Yield: 87 %

Procedure:
2,2-dimethyl-5-(6-(4-(pentyloxy)phenoxy)naphthalen-2-yl)-1,3-dioxan-5-amine was synthesized as per 2,2-dimethyl-5-(6-(4-phenoxyphenoxy)naphthalen-2-yl)-1,3-dioxan-5-amine (Example 244) in 87% yield using 2,2-dimethyl-5-nitro-5-(6-(4-(pentyloxy)phenoxy)naphthalen-2-yl)-1,3-dioxane as starting material.
Reaction SMILES: [CH3:1][C:2]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:22])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:21])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[CH:3][C:4]([OH:6])=O.[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26][NH2:27]>>[CH3:1][C:2]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:22])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:21])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[CH:3][C:4]([NH:27][CH2:26][CH2:25][N:24]([CH3:28])[CH3:23])=[O:6]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CC(=O)O
Reactant: CN(C)CCN
Product: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CC(=O)NCCN(C)C
Yield: 88 %

Procedure:
The procedure of Example 9 was repeated except that 6.1 g of 3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraenoic acid and 3.3 ml of N,N-dimethylethylene diamine were used as starting materials. 6.5 g (yield 88%) of the title compound was obtained as a pale yellow oil.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[NH:11]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12]1.C(=O)([O-])[O-].[Cs+].[Cs+].N1CCC[C@H]1C(O)=O>CS(C)=O.[Cu]I>[NH:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([N:11]3[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12]3)[CH:10]=2)[CH:6]=[CH:7]1
Reactant: OC1CCNC1
Reactant: Brc1ccc2cc[nH]c2c1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: OC1CCN(c2ccc3cc[nH]c3c2)C1
Temperature: 95 °C
Reaction time: 5.5 h
Yield: 50.1 %

Procedure:
To a pressure tube containing a light orange, homogeneous solution of 6-bromo-1H-indole (1.01 g, 5.15 mmol) in DMSO (8.58 mL) purged with nitrogen were added pyrrolidin-3-ol (4.49 g, 51.5 mmol), cesium carbonate (3.36 g, 10.30 mmol), copper(I) iodide (0.098 g, 0.515 mmol) and (S)-pyrrolidine-2-carboxylic acid (0.652 g, 5.67 mmol). The pressure tube was sealed and stirred at 95° C. for 5.5 hr. The reaction was cooled to room temperature and immersed in an ice-water bath. Ice water (20 mL) was added, and the mixture was stirred for 10 min. It was extracted with EtOAc (4×75 mL), and the organic layers were combined, dried over MgSO4, and concentrated in vacuo to give a residue which was purified by flash chromatography using an ISCO 120 g column eluting with 20-100% EtOAc/hexanes. Appropriate fractions were collected and concentrated in vacuo to give the desired product (0.5215 g, 2.58 mmol, 50.1% yield) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[O:11])=[C:4]([CH3:27])[CH:3]=1.[CH3:28][O:29][C:30]([C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1)=[O:31].N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:28][O:29][C:30](=[O:31])[C:32]1[CH:33]=[CH:34][CH:35]=[C:36]([O:26][C:23]2[CH:22]=[CH:21][C:20]([CH:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=3[CH3:27])[CH2:9][C:10]([C:12]3[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=3)=[O:11])=[CH:25][CH:24]=2)[CH:37]=1
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(O)cc1
Reactant: COC(=O)c1cccc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cccc(Oc2ccc(C(CC(=O)c3ccc(=O)n(C)c3)c3ccc(Cl)cc3C)cc2)c1

Procedure:
In analogy to example 222, step 1, 5-[3-(4-chloro-2-methyl-phenyl)-3-(4-hydroxy-phenyl)-propionyl]-1-methyl-1H-pyridin-2-one (example 346, step 1) was reacted with 3-methoxycarbonylphenylboronic acid in dichloromethane in the presence of copper(II) acetate, pyridine and air to give the title compound as a colourless solid, MS (ESI+): m/z=516.4 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](Cl)[CH:8]=[N:7]2.[CH3:13][O:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[C:19]([O:23][CH3:24])[C:20]=1[O:21][CH3:22].C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:17]1[CH:18]=[C:19]([O:23][CH3:24])[C:20]([O:21][CH3:22])=[C:15]([O:14][CH3:13])[CH:16]=1)[CH:8]=[N:7]2
Reactant: Clc1cnc2cccc(Br)c2n1
Reactant: COc1cc(B(O)O)cc(OC)c1OC
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: [Na+]
Product: COc1cc(-c2cnc3cccc(Br)c3n2)cc(OC)c1OC
Temperature: 105 °C

Procedure:
A microwave tube is charged with 30 mg (0.123 mmol) of 8-Bromo-2-chloro-quinoxaline, 26.4 mg (0.123 mmol) of 3,4,5-trimethoxyphenylboronic acid, 40 mg (0.370 mmol) of Na2CO3 and 4.4 mg (0.0037 mmol) of Pd(PPh3)4. After several cycles of vacuum/purge with argon, 1.5 ml of dry DMF are added. The reaction mixture is then heated tot 105° C. for 15 h. After cooling, the yellow suspension is poured onto de-ionized water and filtered. After drying under H.V. at 50° C., the residue is purified by chromatography (silicagel, hexane:EtOAc=100=>1:1) to afford the title compound as a yellow solid, Rt=1.294 min (Acquity HPLC BEH C18, 2.1×50 mm, 1.7 micron, detection 215 nM, 0.1 min 2% CH3CN in H2O, 2% to 100% CH3CN in H2O in 1.5 min, 0.4 min 100% CH3CN+0.1% TFA, flow rate 1.0 ml/min); MS: 375 (M)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][CH2:10][NH2:11])([CH3:4])([CH3:3])[CH3:2].[CH3:13][C:14]1[C:15]([CH:21]=O)=[N:16][CH:17]=[C:18]([CH3:20])[CH:19]=1.[BH4-].[Na+]>CO>[C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][CH2:21][C:15]1[C:14]([CH3:13])=[CH:19][C:18]([CH3:20])=[CH:17][N:16]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: Cc1cnc(C=O)c(C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cnc(CNCCCNC(=O)OC(C)(C)C)c(C)c1

Procedure:
Using General Procedure B: Reaction of (3-aminopropyl)-carbamic acid tert-butyl ester and 3,5-dimethylpyridine-2-carboxaldehyde in anhydrous MeOH with NaBH4 gave {3-[(3,5-dimethyl-pyridin-2-ylmethyl)-amino]-propyl}-carbamic acid tert-butyl ester as a brown oil.
Reaction SMILES: C(O[C:4]1[C:5](=[O:20])[C:6](=[O:19])[C:7]=1[NH:8][C:9]1[C:17]2[O:16][C:15](=[O:18])[NH:14][C:13]=2[CH:12]=[CH:11][CH:10]=1)C.[CH3:21][C:22]1[O:26][C:25]([CH:27]([NH2:33])[C:28]2([CH3:32])[CH2:31][O:30][CH2:29]2)=[CH:24][CH:23]=1>CO>[CH3:21][C:22]1[O:26][C:25]([CH:27]([NH:33][C:4]2[C:5](=[O:20])[C:6](=[O:19])[C:7]=2[NH:8][C:9]2[C:17]3[O:16][C:15](=[O:18])[NH:14][C:13]=3[CH:12]=[CH:11][CH:10]=2)[C:28]2([CH3:32])[CH2:29][O:30][CH2:31]2)=[CH:24][CH:23]=1
Reactant: CCOc1c(Nc2cccc3[nH]c(=O)oc23)c(=O)c1=O
Reactant: Cc1ccc(C(N)C2(C)COC2)o1
Solvent: CO
Product: Cc1ccc(C(Nc2c(Nc3cccc4[nH]c(=O)oc34)c(=O)c2=O)C2(C)COC2)o1
Temperature: 65 °C
Yield: 45.8 %

Procedure:
A mixture of 0.35 g (1.28 mmol, 1 eq) of 3-ethoxy-4-(2-oxo-2,3-dihydrobenzooxazol-7-ylamino)cyclobut-3-ene-1,2-dione and 0.278 g (1.53 mmol, 1.2 eq) of C-(5-methylfuran-2-yl)-C-(3-methyloxetan-3-yl)methylamine in 6 ml of methanol was heated at 65° C. for 5 hours. The methanol was evaporated off and the residue was chromatographed on silica gel, eluted with 95/5 dichloromethane/methanol. The paste obtained was crystallized from ethyl ether, filtered and dried under vacuum at 40° C. 0.24 g of product was obtained in the form of a beige solid. Yield=46%. HPLC 96.4%, ES+ [410].
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[F:27][C:28]([F:35])([F:34])[CH2:29][CH2:30][C:31](O)=[O:32]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:31](=[O:32])[CH2:30][CH2:29][C:28]([F:35])([F:34])[F:27])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: O=C(O)CCC(F)(F)F
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Agent: Cl
Product: O=C(CCC(F)(F)F)N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1

Procedure:
The title compound, light brown solid (80 mg, 71%), MS (ISP) m/z=451.2 [(M+H)+], mp 192° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 4,4,4-trifluoro-butanoic acid.
Reaction SMILES: C1(COC(=O)[NH:10][CH2:11][CH:12]2[CH2:15][N:14]([CH2:16][CH2:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([O:28][CH3:29])[N:26]=4)[N:21]=[CH:20][C:19]=3[F:30])[CH2:13]2)C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[F:30][C:19]1[CH:20]=[N:21][C:22]2[C:27]([C:18]=1[CH2:17][CH2:16][N:14]1[CH2:13][CH:12]([CH2:11][NH2:10])[CH2:15]1)=[N:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2
Reactant: COc1ccc2ncc(F)c(CCN3CC(CNC(=O)OCc4ccccc4)C3)c2n1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COc1ccc2ncc(F)c(CCN3CC(CN)C3)c2n1
Reaction time: 18 h
Yield: 93.6 %

Procedure:
To a solution of phenylmethyl[(1-{2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-3-azetidinyl)methyl]carbamate (0.44 g, 1.03 mmole) in MeOH (50 mL) was added Pd(OH)2 (100 mg). The reaction contents were placed under a balloon of H2 and stirred for 18 hours. The reaction contents were filtered through Celite® (MeOH) and concentrated under vacuum to give the title compound (0.28 g, 95%) as a light yellow oil: LC-MS (ES) m/e 291 (M+H)+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH:2]1C(O)=O.B.[O:14]1CCC[CH2:15]1.CO>O1CCCC1>[O:1]1[C:5]2[C:6]([CH2:15][OH:14])=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: O=C(O)C1Cc2ccccc2O1
Reactant: C1CCOC1
Agent: B
Solvent: CO
Product: OCc1cccc2c1OCC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2,3-Dihydrobenzofuran carboxylic acid (5.047 g, 30.77 mmol) in tetrahydrofuran at −10° C. was treated dropwise with a solution of 1.0 M borane-tetrahydrofuran (20 mL 20 mmol). The temperature was allowed to warm to room temperature overnight, and was then treated with additional 1.0 M borane-tetrahydrofuran (10 mL 10 mmol), and stirred at room temperature for 2 hours. The mixture was cooled to 5° C., slowly treated with methanol (20 mL), and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated sodium bicarbonate (2×), saturated sodium chloride, dried (sodium sulfate), filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (hexanes:ethyl acetate, 3:2) to provide the title compound. MS (DCI/NH3) M/Z 168 (M+NH4)+; 1H NMR (CDCl3) δ 3.21 (t, 2H), 4.60 (t, 2H), 4.68 (s, 2H), 6.83 (t, 1H), 7.08 (dd, 1H), 7.14 (dd, 1H).
Reaction SMILES: CS(O[CH2:6][C:7]1[N:8]([CH3:26])[C:9](=[O:25])[C:10]2[C:15]([C:16]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:14][C:13]([CH3:23])=[C:12]([CH3:24])[CH:11]=2)(=O)=O.[NH3:27].CO>C1COCC1>[NH2:27][CH2:6][C:7]1[N:8]([CH3:26])[C:9](=[O:25])[C:10]2[C:15]([C:16]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:14][C:13]([CH3:23])=[C:12]([CH3:24])[CH:11]=2
Reactant: Cc1cc2c(-c3ccccc3)c(COS(C)(=O)=O)n(C)c(=O)c2cc1C
Reactant: N
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc2c(-c3ccccc3)c(CN)n(C)c(=O)c2cc1C
Temperature: 140 °C

Procedure:
A mixture of the compound (0.68 g) obtained in Step 1, THF (20 ml) and 15% ammonia/methanol (20 ml) was heated for 20 hours at 140° C. in a sealed tube. The solvent was distilled off. To the residue was added ethyl acetate, and the mixture was washed with an aqueous solution of potassium carbonate and water, successively, then dried (MgSO4). The solvent was distilled off to leave the title compound as colorless crystals (0.37 g),
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH2:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][NH:6]1.C(OC([N:22]1[C:27](=[O:28])[CH:26]2[CH:24]([CH:25]2[C:29]([O-:31])=[O:30])[CH:23]1[C:32]([O-:34])=[O:33])=O)(C)(C)C.O>C(Cl)Cl>[C:29]([CH:25]1[CH:26]([C:27]([CH:5]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8][CH2:7][NH:6]2)=[O:28])[CH:24]1[CH:23]([C:32]([OH:34])=[O:33])[NH2:22])([OH:31])=[O:30]
Reactant: CC(C)(C)OC(=O)N1C(=O)C2C(C(=O)[O-])C2C1C(=O)[O-]
Reactant: c1ccc2c(c1)CCNC2
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: NC(C(=O)O)C1C(C(=O)O)C1C(=O)C1NCCc2ccccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 106.6 %

Procedure:
To a solution of AlCl3 (48.7 mg, 0.36 mmol) in dry CH2Cl2 (1 mL) at 0° C., tetrahydroisoquinoline (88 μl, 0.70 mmol) in CH2Cl2 (1 mL) was added dropwise. The mixture was stirred at room temperature for 10 min, and then ethyl (1SR, 2SR, 5RS, 6RS) 3-tert-butoxycarbonyl-4-oxo-3-azabicyclo[3.1.0]hexane-2,6-dicarboxylate (96 mg, 0.28 mmol) in dry CH2Cl2 (1 mL) was added. After stirring at room temperature for 3 h, a mixture of ice and water was added. The layers were separated and the aqueous phase was extracted with CH2Cl2. The combined organic layers were dried over MgSO4 and the solvent removed under reduced pressure. The residue was purified by flash chromatography (hexane/ethyl acetate 2/1) to give 95 mg of the desired compound (71% yield).
Reaction SMILES: C([O:8][C:9]1[CH:29]=[C:28]([CH2:30][CH3:31])[CH:27]=[CH:26][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][CH2:23][CH3:24])(=[O:20])=[O:19])=[CH:14][C:13]=1[F:25])C1C=CC=CC=1.O1CCCC1>C(O)C>[CH2:30]([C:28]1[CH:27]=[CH:26][C:10]([O:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][CH2:23][CH3:24])(=[O:20])=[O:19])=[CH:14][C:13]=2[F:25])=[C:9]([OH:8])[CH:29]=1)[CH3:31]
Reactant: CCCNS(=O)(=O)c1ccc(Oc2ccc(CC)cc2OCc2ccccc2)c(F)c1
Solvent: C1CCOC1
Solvent: CCO
Product: CCCNS(=O)(=O)c1ccc(Oc2ccc(CC)cc2O)c(F)c1
Yield: 61.9 %

Procedure:
According to the procedure of example 20 (b) except substituting 4-ethyl-2-methoxy-1-[4-nitro-2-(trifluoromethyl) phenoxy]benzene for 4-(2-Benzyloxy-4-ethyl-phenoxy)-3-fluoro-N-propyl-benzenesulfonamide (140 mg; 0.32 mmol) and tetrahydrofurane for ethanol (3 mL), the title compound (70 mg; 62%) was obtained as a clear oil, after purification on preparative TLC (dichloromethane)
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.[CH2:28]([C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][NH2:38])=[CH:32][CH:31]=1)[CH3:29].[C:39]([O:43][C:44]([N:46]1[CH2:51][CH2:50][C:49]([CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=2[F:62])([C:52](O)=[O:53])[CH2:48][CH2:47]1)=[O:45])([CH3:42])([CH3:41])[CH3:40].C(N(CC)CC)C>O1CCCC1.C(OCC)C>[C:39]([O:43][C:44]([N:46]1[CH2:51][CH2:50][C:49]([C:52](=[O:53])[NH:38][CH2:37][CH2:36][C:33]2[CH:34]=[CH:35][C:30]([CH2:28][CH3:29])=[CH:31][CH:32]=2)([CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=2[F:62])[CH2:48][CH2:47]1)=[O:45])([CH3:41])([CH3:42])[CH3:40]
Reactant: CCc1ccc(CCN)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2ccccc2F)(C(=O)O)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCc1ccc(CCNC(=O)C2(Cc3ccccc3F)CCN(C(=O)OC(C)(C)C)CC2)cc1
Yield: 65.7 %

Procedure:
Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.650 g, 1.47 mmol) was added to a solution of 2-(4-ethyl-phenyl)-ethylamine (0.235 mL, 1.47 mmol), 4-(2-fluoro-benzyl)-piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (0.330 g, 0.978 mmol) and triethylamine (0.409 mL, 2.93 mmol) in tetrahydrofuran (5 mL). After 1 hour the mixture was diluted with ethyl ether (20 mL) and washed with saturated aqueous sodium bicarbonate (20 mL) followed by water (2×10 mL). The organic layer was collected, concentrated under reduced pressure and crude product purified by column chromatography to give 0.301 g (65 %) of 4-[2-(4-ethyl-phenyl)-ethylcarbamoyl]-4-(2-fluoro-benzyl)-piperidine-1-carboxylic acid tert-butyl ester. LRMS m/z 469.1 (M+H)+.