Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[CH3:19][C:20]([NH2:23])([CH3:22])[CH3:21]>>[C:20]([NH:23][C:10]([C:7]1[CH:6]=[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C:4]([CH:1]2[CH2:2][CH2:3]2)=[CH:9][N:8]=1)=[O:12])([CH3:22])([CH3:21])[CH3:19]
Reactant: CC(C)(C)N
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2CC2)cn1
Product: CC(C)(C)NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1

Procedure:
The title compound was synthesized in analogy to Example 63b, using 5-Cyclopropyl-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 48c) and 2-methylpropan-2-amine (CAN 75-64-9) as starting materials and isolated (12.5 mg, 17%) as colorless oil; MS (ESI, m/z): 317.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([C:12]#[N:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5](/[CH:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[N:6][NH:7]2.[OH2:22]>S(=O)(=O)(O)O>[CH3:1][O:2][C:3]1[C:11]([C:12]([NH2:13])=[O:22])=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5](/[CH:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[N:6][NH:7]2
Reactant: O
Reactant: COc1c(C#N)ccc2[nH]nc(/C=C/c3ccccc3)c12
Agent: O=S(=O)(O)O
Product: COc1c(C(N)=O)ccc2[nH]nc(/C=C/c3ccccc3)c12
Temperature: 110 °C
Reaction time: 0.25 h

Procedure:
35 mg of 4-methoxy-3-(E)-styryl-1H-indazole-5-carbonitrile was dissolved in a mixed solvent 2 mL concentrated sulfuric acid/1 mL water, and stirred at 110° C. for 1 hour and 15 minutes. After cooling the reaction mixture on ice, water was slowly poured under ice cooling, and the precipitated crystals were collected by filtration, and washed with water. After drying under reduced pressure, 22 mg of the title compound was obtained as brown crude crystals.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[C:12]2[CH:11]=[N:10][CH:9]=[CH:8][C:7]=2[C:6]([NH2:13])=[CH:5][CH:4]=1.[F:16][C:17]([F:29])([F:28])[C:18]1[CH:27]=[CH:26][C:21]([CH2:22][N:23]=[C:24]=[O:25])=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[F:15][C:2]([F:1])([F:14])[C:3]1[CH:4]=[CH:5][C:6]([NH:13][C:24]([NH:23][CH2:22][C:21]2[CH:20]=[CH:19][C:18]([C:17]([F:16])([F:29])[F:28])=[CH:27][CH:26]=2)=[O:25])=[C:7]2[C:12]=1[CH:11]=[N:10][CH:9]=[CH:8]2
Reactant: Nc1ccc(C(F)(F)F)c2cnccc12
Reactant: O=C=NCc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=C(NCc1ccc(C(F)(F)F)cc1)Nc1ccc(C(F)(F)F)c2cnccc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 34 %

Procedure:
To a solution of 8-(trifluoromethyl)isoquinolin-5-amine (Description 93; 150 mg, 0.708 mmol) in CDCl3 (10 ml) was added [4-(trifiuoromethyl)benzyl]isocyanate (Description 58) [0.506M soln in DCM; 1.403 ml, 0.71 mmol) and the resulting mixture heated at reflux overnight. NMR analysis showed a deficit of the [4-(trifluoromethyl)benzyl]isocyanate in comparison to remaining 8-(trifluoromethyl)isoquinolin-5-amine so a further portion of [4-(trifluoromethyl)benzyl]isocyanate [0.506M solution in DCM] (1.403 ml; 0.71 mmol) was added and refluxing continued for 2 days. The cooled reaction mixture was evaporated to dryness and purified by column chromatography on silica elution with 1% MeOH in DCM+0.5% NH4OH. NMR showed the product was the bis acylated urea. This material was dissolved in methanol (5 ml) and K2CO3 (500 mg, 3.6 mmol) added and the mixture stirred at room temperature for 2.5 hours. The mixture was filtered and the residue purified by preparative TLC eluting with 10% MeOH in DCM+0.5% NH4OH to give the title compound (100 mg, 34%) as a white solid. m/z (ES+) 414 (M+H)+.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](/[CH:11]=[CH:12]/[CH2:13][CH2:14]C2C3C(=CC=CC=3)C=N2)=[CH:3][N:2]=1.O.[NH2:25]N>C(O)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](/[CH:11]=[CH:12]/[CH2:13][CH2:14][NH2:25])=[CH:3][N:2]=1
Reactant: C1=NC(CC/C=C/c2cncc3ccccc23)c2ccccc21
Reactant: NN
Solvent: CCO
Solvent: O
Product: NCC/C=C/c1cncc2ccccc12

Procedure:
To a refluxing solution of 1.75 g of (E)-1-[4-(4-isoquinolinyl)-3-butenyl]-1H-isoindole-1,3-(2H-dione in 80 mL of ethanol was added 1.1 mL of hydrazine hydrate and the reaction was stirred at reflux for 17 hours. The solvent was removed in vacuo and the residue was triturated with chloroform. The extract was concentrated to yield 1 g of (E)-4-(4-isoquinolinyl)-3-buten-1-amine as an oil.
Reaction SMILES: [CH2:1]([CH:3]([CH2:7][CH3:8])[C:4]([OH:6])=O)[CH3:2].N=C=N.C1C=CC2N(O)N=NC=2C=1.[CH3:22][O:23][C:24](=[O:46])[CH:25]([N:32]1[CH2:37][CH2:36][N:35]([C:38]2[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][C:39]=2[F:45])[CH2:34][CH2:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-]>C(Cl)Cl>[CH3:22][O:23][C:24](=[O:46])[CH:25]([N:32]1[CH2:33][CH2:34][N:35]([C:38]2[CH:43]=[CH:42][C:41]([NH:44][C:4](=[O:6])[CH:3]([CH2:1][CH3:2])[CH2:7][CH3:8])=[CH:40][C:39]=2[F:45])[CH2:36][CH2:37]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COC(=O)C(c1ccccc1)N1CCN(c2ccc(N)cc2F)CC1
Reactant: CCC(CC)C(=O)O
Agent: N=C=N
Agent: O=C([O-])[O-]
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCC(CC)C(=O)Nc1ccc(N2CCN(C(C(=O)OC)c3ccccc3)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 55.9 %

Procedure:
A mixture of 2-ethylbutyric acid (32 μL, 0.22 mmol), polymer-supported carbodiimide (240 mg, 0.29 mmol), and HOBt (33 mg, 0.25 mmol) in DCM (5 mL) was stirred at rt for 15 min. A solution of [4-(4-amino-2-fluoro-phenyl)-piperazin-1-yl]-phenyl-acetic acid methyl ester (50 mg, 0.15 mmol) in DCM (1 mL) was added and the mixture was stirred for 16 h. Polymer-bound tetraalkylammonium carbonate (PB-carbonate; 250 mg, 0.77 mmol) was added and the mixture was stirred for 2 h. The resins were removed by filtration and the filtrate was concentrated to give an oil, which was purified by PTLC to give a peach solid (37 mg, 57%). MS (ESI): mass calcd. for C25H32FN3O3, 441.54; m/z found, 442.5 [M+H]+. 1H NMR (CDCl3): 7.46-7.44 (m, 3H), 7.36-7.33 (m, 3H), 7.19-7.12 (m, 1H), 7.00 (br s, 1H), 6.87 (t, J=9.0, 1H), 4.06 (s, 1H), 3.70 (s, 3H), 3.09-3.08 (m, 4H), 2.64-2.62 (m, 4H), 2.02-1.95 (m, 1H), 1.70-1.67 (m, 2H), 1.56-1.53 (m, 2H), 0.94 (t, J=7.4, 6H).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]([C:23]2[N:27]([CH2:28][CH2:29][CH2:30][CH3:31])[N:26]=[N:25][N:24]=2)=[CH:11][C:10]=1[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38](O)=[O:39])[CH:33]=1)C1C=CC=CC=1.[CH3:41][CH:42]([NH2:46])[CH2:43][O:44][CH3:45]>>[CH3:45][O:44][CH2:43][CH:42]([NH:46][C:38]([C:34]1[CH:33]=[C:32]([C:10]2[CH:11]=[C:12]([C:23]3[N:27]([CH2:28][CH2:29][CH2:30][CH3:31])[N:26]=[N:25][N:24]=3)[C:13]([OH:15])=[CH:14][C:9]=2[OH:8])[CH:37]=[CH:36][CH:35]=1)=[O:39])[CH3:41]
Reactant: COCC(C)N
Reactant: CCCCn1nnnc1-c1cc(-c2cccc(C(=O)O)c2)c(OCc2ccccc2)cc1OCc1ccccc1
Product: CCCCn1nnnc1-c1cc(-c2cccc(C(=O)NC(C)COC)c2)c(O)cc1O

Procedure:
This product was synthesized using 2′,4′-bis-benzyloxy-5′-(1-butyl-1H-tetrazol-5-yl)-biphenyl-3-carboxylic acid and 2-methoxyisopropylamine as described in general procedure D. LCMS: 426 [M+H].
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]=O)[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:14]([NH:22][CH2:23][C:24]([OH:26])=[O:25])(=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])(=O)C.[Na+]>C(OC(=O)C)(=O)C.CCOC(C)=O>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8](/[CH:12]=[C:23]2\[N:22]=[C:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[O:26][C:24]\2=[O:25])[C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C(O)CNC(=O)c1ccccc1
Reactant: COC(=O)c1c(F)cccc1C=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1c(F)cccc1/C=C1\N=C(c2ccccc2)OC1=O

Procedure:
This step was performed in five separate batches. For each batch, a solution of methyl 2-fluoro-6-formylbenzoate (3 g, 16.5 mmol), 2-benzamidoacetic acid (3.6, 20 mmol) and sodium acetate (1.62 g, 19.7 mmol) in acetic anhydride (30 mL) was heated at 100° C. in a microwave reactor (100 W, 150 psi) under nitrogen atmosphere for 2 hours. The reaction mixtures were diluted with EtOAc (100 mL) and washed with saturated aqueous Na2CO3. The combined organic layers were concentrated in vacuo to give the title compound as a brown solid, which was used without further purification (15 g). ESI-MS m/z [M+H]+ 326.2.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[CH:13][N:14]=[C:15]([O:17][CH3:18])[CH:16]=[C:11]2[C:10]([CH:19]=[O:20])=[C:9]1[CH:21]([CH3:23])[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-:24]Cl=O.[Na+]>CC(O)(C)C.CC(=CC)C.O>[CH2:1]([N:8]1[C:12]2=[CH:13][N:14]=[C:15]([O:17][CH3:18])[CH:16]=[C:11]2[C:10]([C:19]([OH:24])=[O:20])=[C:9]1[CH:21]([CH3:23])[CH3:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2c(C=O)c(C(C)C)n(Cc3ccccc3)c2cn1
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: COc1cc2c(C(=O)O)c(C(C)C)n(Cc3ccccc3)c2cn1
Temperature: 25 °C

Procedure:
To a solution of 1-benzyl-2-isopropyl-5-methoxy-1H-pyrrolo[2,3-c]pyridine-3-carbaldehyde (Compound 7, 20 mg, 0.065 mmol) in t-BuOH (1.5 ml) and 2-methyl-2-butene (1 ml) was added a solution of NaH2PO4 (94 mg, 0.78 mmol) and NaClO2 (80%, 73 mg, 0.65 mmol) in H2O (1.5 ml). The mixture was stirred at room temperature and additional 2-methyl-2-butene and a solution of NaH2PO4 and NaClO2 in H2O were added at the above ratio every 6-16 h until the progress of the reaction was satisfactory. The reaction mixture was extracted with EtOAc (×3) and the combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by preparative thin layer chromatography (PTLC) on silica gel (50% EtOAc-hexanes) to yield the title compound.
Reaction SMILES: Cl[S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH2:21][CH2:20][CH2:19]2>>[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[N:22]([S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3])[CH2:21][CH2:20][CH2:19]2
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc2c(c1)CCCN2
Product: COc1ccc2c(c1)CCCN2S(=O)(=O)c1ccc(C(=O)O)cc1

Procedure:
4-(chlorosulfonyl)benzoic acid (500 mg, 2.27 mmol) was treated with 6-methoxy-1,2,3,4-tetrahydroquinoline (1.0 g, 6.13 mmol) using method A to give 4-(6-methoxy-3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid as an off-white solid. Yield: 358 mg (46%). 1H-NMR: 8.04 (d, J=8.5 Hz, 2H), 7.64 (d, J=8.5 Hz, 2H), 7.52 (d, J=9.0 Hz, 1H), 6.81 (dd, J=9.0, 3.0 Hz, 1H), 6.65 (d, J=3.0 Hz, 1H), 3.75-3.70 (m, 5H), 2.29 (t, J=7.0 Hz, 2H), 1.53-1.45 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:17][C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[C:10](=[O:18])[CH:9]=2)=[CH:4][CH:3]=1.[CH3:19][C:20](OC(C)=O)=[O:21].O>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:20]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:17][C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[C:10](=[O:18])[CH:9]=2)=[CH:6][CH:7]=1)(=[O:21])[CH3:19]
Reactant: O=c1cc(-c2ccc(O)cc2)oc2ncccc12
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(-c2cc(=O)c3cccnc3o2)cc1
Yield: 52.7 %

Procedure:
In a 50 mL round-bottomed flask fitted with condenser and magnetic stirrer were placed 2-(4-hydroxy-phenyl)-pyrano[2,3-b]pyridin-4-one (1.5 g, 6.27 mmol), Ac2O (700 mg, 6.89 mmol) and a catalytic amount of DMAP (50 mg) in pyridine (10 mL) and the reaction mixture was stirred for 16 h at rt. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer washed with water, dried and concentrated to give a 2-(4-acetoxyphenyl)-pyrano[2,3-b]pyridin-4-one (930 mg, 53%).
Reaction SMILES: [Si]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)(O)[CH:14]([C:19]3[CH:24]=[CH:23][C:22]([O:25][Si](C(C)(C)C)(C)C)=[CH:21][CH:20]=3)[CH2:15][O:16]2)=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.CC1C=CC(S(O)(=O)=O)=CC=1.C(O)C>CO>[OH:25][C:22]1[CH:21]=[CH:20][C:19]([C:14]2[CH2:15][O:16][C:17]3[C:12]([C:13]=2[C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)=[CH:11][CH:10]=[C:9]([OH:8])[CH:18]=3)=[CH:24][CH:23]=1
Reactant: COc1ccc(C2(O)c3ccc(O[Si](C)(C)C(C)(C)C)cc3OCC2c2ccc(O[Si](C)(C)C(C)(C)C)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: CO
Product: COc1ccc(C2=C(c3ccc(O)cc3)COc3cc(O)ccc32)cc1
Reaction time: 8 h

Procedure:
7-(tert-Butyldimethylsilyloxy)-3-(4-(tert-butyldimethylsilyloxy)phenyl)-4-(4-methoxyphenyl)chroman-4-ol (42 g), pTsOH (435 g), boiling chips and 2.5 L of ethanol were combined in a 2-neck 5 L round bottom flask with condenser attached. The reaction was heated at reflux for 3 hours. The solvent was concentrated in vacuo to ˜100 ml before being poured into chilled, stirred water (700 ml). The mixture was then extracted with ethyl acetate, the combined organic layers washed with water (3×2 L), brine (1×500 ml), dried over anhydrous magnesium sulphate and filtered and solvent removed in vacuo to give red/brown oil. The oil was dissolved in methanol (˜100 ml) and put in freezer overnight.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[CH:25]=[C:26]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([F:36])[CH:29]=1)[CH3:27]>CN(C=O)C.[Cu]I>[F:36][C:30]1[CH:29]=[C:28](/[C:26](/[CH3:27])=[CH:25]/[N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:15][CH2:14][C:5]2=3)[CH:33]=[CH:32][C:31]=1[O:34][CH3:35]
Reactant: COc1ccc(C(C)=CBr)cc1F
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(/C(C)=C/n2c3c(c4cc(C)ccc42)CN(C)CC3)cc1F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (68 mg, 0.34 mmol) was dissolved in DMF (3 mL). Copper (I) iodide (6.5 mg, 0.034 mmol) L-proline (7.8 mg, 0.068 mmol) and potassium phosphate (144 mg, 0.68 mmol) were added and the reaction mixture was stirred for 10 min. at RT. 4-(1-Bromoprop-1-en-2-yl)-2-fluoro-1-methoxybenzene (100 mg, 0.408 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated overnight at 80° C. (prolonged heating in some cases was required). DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh). 1H NMR (CD3OD, HCl salt) δ (ppm): 7.42 (m, 2H), 7.30 (s, 1H), 7.18 (d, 1H), 7.10 (m, 2H), 7.0 (s, 1H), 4.75 (m, 1H), 4.40 (m, 1H), 3.95 (s, 3H), 3.85 (m, 1H), 3.60 (m, 1H), 3.20 (m, 2H), 3.10 (s, 3H), 2.42 (s, 3H), 1.90 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])/[C:5](/O)=[CH:6]/[C:7]1[C:12]([N+:13]([O-])=O)=[CH:11][N:10]=[C:9]([N:16]2[CH2:21][CH2:20][N:19]([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH2:18][CH2:17]2)[CH:8]=1)[CH3:2]>C(O)(=O)C.[Fe]>[CH2:1]([O:3][C:4]([C:5]1[NH:13][C:12]2=[CH:11][N:10]=[C:9]([N:16]3[CH2:21][CH2:20][N:19]([CH:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)[CH2:18][CH2:17]3)[CH:8]=[C:7]2[CH:6]=1)=[O:28])[CH3:2]
Reactant: CCOC(=O)/C(O)=C/c1cc(N2CCN(C3CCCC3)CC2)ncc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: CCOC(=O)c1cc2cc(N3CCN(C4CCCC4)CC3)ncc2[nH]1

Procedure:
(Z)-3-[2-(4-Cyclopentyl-piperazin-1-yl)-5-nitro-pyridin-4-yl]-2-hydroxy-acrylic acid ethyl ester was reacted with 0.47 g iron powder in 40 mL acetic acid for 6 h at 80° C. After evaporation of all volatiles the residue was taken up in water and extracted with DCM. The combined organic layers were dried with MgSO4 and evaporated to dryness. Purification on silica eluting with a gradient mixture of n-heptan/ethyl acetate/0.1% NEt3 yielded after evaporation of the product fractions 0.65 g (23% from 2-chloro-4-methyl-5-nitropyridine) of the title compound as light brown solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:19])[NH:12][C:11]([CH2:20][O:21][CH2:22][C:23]#[N:24])=[C:10]1[C:25]([O:27][CH2:28][CH3:29])=[O:26].C([Sn]([N:43]=[N+:44]=[N-:45])(CCCC)CCCC)CCC>O1CCOCC1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:19])[NH:12][C:11]([CH2:20][O:21][CH2:22][C:23]2[NH:45][N:44]=[N:43][N:24]=2)=[C:10]1[C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: CCOC(=O)C1=C(COCC#N)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Solvent: C1COCCO1
Product: CCOC(=O)C1=C(COCc2nnn[nH]2)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Yield: 81.2 %

Procedure:
A solution of [4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridin-2-yl]methoxyacetonitrile (3.52 g) and tri-n-butyltin azide (3.00 g) in dioxane (100 ml) was heated under reflux for 21.5 hours and then evaporated. The residual oil was taken up in diethyl ether (200 ml) and dry hydrogen chloride was bubbled through the stirred solution in a slow stream for 50 minutes. The resulting precipitate was collected, washed with diethyl ether and dried to give the title compound (3.14 g), m.p. 112°-114° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:21])[CH3:20])=[CH:15][CH:14]=1>>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:9]=[CH:10][CH:11]=[C:2]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19](=[O:21])[CH3:20])=[CH:15][CH:14]=2)[CH:3]=1
Reactant: COC(=O)c1cccc(Br)c1
Reactant: CC(=O)c1ccc(N)cc1
Product: COC(=O)c1cccc(Nc2ccc(C(C)=O)cc2)c1

Procedure:
Reaction of methyl 3-bromobenzoate with 4′-aminoacetophenone according to general procedure A provided methyl ester of 6 as a white solid (84% yield). 1H NMR (CDCl3, 500 MHz): δ=7.89 (d, J=8.7 Hz, 2H), 7.85 (s, 1H), 7.73 (m, 1H), 7.36-7.42 (m, 2H), 7.03 (d, J=8.5 Hz, 2H), 6.31 (s, 1H), 3.92 (s, 3H), 2.55 (s, 3H). 13C NMR (CDCl3, 125 MHz): δ=196.7, 167.0, 147.9, 141.3, 131.8, 130.9, 129.9, 129.8, 124.6, 124.2, 121.2, 115.1, 52.5, 26.4.
Reaction SMILES: [CH2:1]([C@@H:8]([NH:25][CH3:26])[CH2:9][N:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[O:23][CH3:24])[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:34][C:35]1([C:41](Cl)=[O:42])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>ClCCl>[CH2:1]([C@@H:8]([N:25]([CH3:26])[C:41]([C:35]1([CH3:34])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)=[O:42])[CH2:9][N:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[O:23][CH3:24])[CH2:12][CH2:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN[C@H](Cc1ccccc1)CN1CCC(c2cc(F)ccc2OC)CC1
Reactant: CC1(C(=O)Cl)CCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(F)cc1C1CCN(C[C@@H](Cc2ccccc2)N(C)C(=O)C2(C)CCCCC2)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
Under a N2 atmosphere, a solution of {(1R)-1-benzyl-2-[4-(5-fluoro-2-methoxy-phenyl)-piperidin-1-yl]-ethyl}-methyl-amine (0.12 g. 0.33 mmole) and triethylamine (0.10 mL, 0.74 mmole) in dichloromethane (10 mL) was cooled to 0° C. To the solution, 1-methyl-1-cyclohexanecarboxylic acid chloride (93 mg, 0.58 mmole) in a minimal amount of dichloromethane was added. The resulting mixture was stirred at 0° C. overnight. The solvent was evaporated and the residue dissolved in EtOAc (50 mL) and water (50 mL). The layers were separated, the organics washed with water (2×50 mL) and brine and dried over Na2SO4, filtered and concentrated. Flash chromatography (elution with 1:3 EtOAc-hexane) gave 0.14 g (88% yield) of 1-methyl-cyclohexanecarboxylic acid {(1R)-1-benzyl-2-[4-(5-fluoro-2-methoxy-phenyl)-piperidin-1-yl]-ethyl}-methylamide. An ethanolic solution of the product was heated to gentle reflux and 1 equivalent of fumaric acid in hot ethyl alcohol solution was added to afford the fumarate salt of the titled compound as a white solid. m.p. 160-165° C.
Reaction SMILES: [CH3:1][C:2]([CH3:19])=[C:3]([N:8]1[C@H:11]([CH2:12][CH:13]=[CH2:14])[C@@H:10]([CH:15]([OH:17])[CH3:16])[C:9]1=[O:18])[C:4]([O:6][CH3:7])=[O:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:39](O)=[O:40].N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C(OCC)(=O)C>[CH3:19][C:2]([CH3:1])=[C:3]([N:8]1[C@H:11]([CH2:12][CH:13]=[CH2:14])[C@@H:10]([C@H:15]([O:17][CH:39]=[O:40])[CH3:16])[C:9]1=[O:18])[C:4]([O:6][CH3:7])=[O:5]
Reactant: C=CC[C@@H]1[C@@H](C(C)O)C(=O)N1C(C(=O)OC)=C(C)C
Reactant: O=CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CC[C@@H]1[C@@H]([C@@H](C)OC=O)C(=O)N1C(C(=O)OC)=C(C)C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A 1:3 mixture of methyl 3-methyl-2-[(3S,4R)-3-[(1RS)-1-hydroxyethyl]-2-oxo-4-allylazetidin-1-yl]but-2-enoate (55 mg) was dissolved in tetrahydrofuran (2 ml) and triphenylphosphine (135 mg) and formic acid (19.4 μl) were added to the mixture. This mixture was cooled to 0° C. and a solution of diethyl azodicarboxylate (81 μl) in tetrahydrofuran (1 ml) was added. After stirring at the same temperature overnight, the mixture was diluted with ethyl acetate (30 ml), washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel (5 g) eluting with hexane and ethyl acetate (10:1-2:1) to give 25 mg of methyl 3-methyl-2-[(3S,4R)-3-[(1R)-1-formyloxyethyl]-2-oxo-4-allylazetidin-1-yl]-but-2-enoate.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH:9][CH3:10].[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:17][CH2:10][CH:9]=[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC=C(c1ccccc1)c1ccccc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1ccccc1C(=CCBr)c1ccccc1
Yield: 75.3 %

Procedure:
To a solution of 1-(2-methylphenyl)-1-phenyl-1-propene (9.0 g, 43 mmol) in carbon tetrachloride (40 ml), N-bromosuccinimide (7.7 g, 43 mmol) and benzoylperoxide (0.1 g) were added. The reaction mixture was heated at reflux temperature for 18 h. The cooled reaction mixture was filtered through silica gel and the solvent evaporated in vacuo to give 9.3 g (76%) of 3-bromo-1-(2-methylphenyl)-1-phenyl-1-propene.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH:5]=[C:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)[CH3:2].[H][H]>[Pd].CO>[CH2:1]([O:3][C:4](=[O:12])[CH2:5][CH:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C=C1CCOCC1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CC1CCOCC1
Yield: 91.3 %

Procedure:
A mixture of (tetrahydro-pyran-4-ylidene)-acetic acid ethyl ester (27 g, 159 mmol) and 10% palladium on activated carbon (3 g) in methanol (300 mL) was stirred at 25° C. under 30 psi of hydrogen for 20 h. The catalyst was filtered off, washed with ethyl acetate and concentrated in vacuo to afford (tetrahydro-pyran-4-yl)-acetic acid ethyl ester (25 g, 91%) as a colorless oil which was used in the next step without purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].[CH:17]([C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=1)=[O:18].Cl>O1CCCC1.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:17]([OH:18])[C:19]1[CH:20]=[CH:21][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:27][CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccccc1OCc1ccccc1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(C(O)c2ccccc2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.1 %

Procedure:
A Grignard reagent was prepared from 1-benzyloxy-2-bromobenzene (5.3 g), magnesium (0.49 g) and tetrahydrofuran (160 mL). The obtained Grignard reagent was added to a solution of methyl 4-formylbenzoate (3.3 g) in tetrahydrofuran (60 mL), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture were added water and dilute hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on aminopropyl silica gel (eluent: hexane/ethyl acetate=4/1) to give methyl 4-[(2-benzyloxyphenyl)hydroxymethyl]benzoate (2.6 g).