Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[CH:14][NH:15]3)=[CH:11][CH:10]=2)[C:5]([F:18])=[CH:4][N:3]=1.[CH3:19][NH:20][C:21]([C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH2:26])=[O:22]>>[F:18][C:5]1[C:6]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[CH:14][NH:15]3)=[CH:11][CH:10]=2)=[N:7][C:2]([NH:26][C:25]2[CH:27]=[CH:28][CH:29]=[C:23]([C:21]([NH:20][CH3:19])=[O:22])[CH:24]=2)=[N:3][CH:4]=1
Reactant: CNC(=O)c1cccc(N)c1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2cc[nH]c2c1
Product: CNC(=O)c1cccc(Nc2ncc(F)c(Nc3ccc4cc[nH]c4c3)n2)c1

Procedure:
In like manner to the preparation of 5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N4-[(1H)indol-6-yl]-4-pyrimidineamine and 3-[(N-methylamino)carbonyl]aniline were reacted to provide 5-fluoro-N4-[(1H)indol-6-yl]-N2-[3-[(N-methylamino)carbonyl]phenyl]-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 7.99 (t, 1H, J=1.8 Hz), 7.89 (d, 1H, J=3.6 Hz), 7.78–7.76 (m, 1H), 7.70 (ddd, 1H, J=1.2, 2.4, and 8.4 Hz), 7.50 (d, 1H, J=9.0 Hz), 7.31 (td, 1H, J=1.2 and 7.5 Hz), 7.23–7.17 (m, 3H), 6.43 (dd, 1H, J=1.2 and 3.6 Hz), 2.73 (s, 3H); 19F NMR (282 MHz, CD3OD): −47513; LCMS: purity: 99%; MS (m/e): 377(MH+).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]#[N:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.N>CO.[Ni]>[NH2:12][CH2:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:1]=[CH:2][CH:3]=[CH:4]2
Reactant: N#Cc1ccc2ncccc2c1
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCc1ccc2ncccc2c1
Yield: 77.9 %

Procedure:
Combine 6-quinolinecarbonitrile (1.0 g, 6.49 mmol), Raney® 3201 nickel (slurry in water, 0.2 g), 2N ammonia in methanol (20 mL) and hydrogenate at 50 psi for 1 h. Filter the reaction mixture through a pad of Celite®, remove the solvent and purify by SCX chromatography to obtain the title compound as a yellow oil (0.8 g, 78%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([OH:16])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>O1CCCC1>[N:29]1([C:14]([C@@H:10]2[CH2:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]2)=[O:16])[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: C1CCNC1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)O)C1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)N2CCCC2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.3 %

Procedure:
To a solution of (R)-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (50.64 g, 220.9 mmol) in anhydrous tetrahydrofuran (552 mL) at 2° C. was added 1,1′-carbonyldiimidazole (77.59 g, 460 mmol). The mixture was stirred at room temperature for 2 h, cooled to 10° C. and then pyrrolidine (74 mL, 890 mmol) was added slowly. The reaction mixture was stirred at room temperature for 18 h. The solvent was removed under reduced pressure and water (200 mL) was added to the residue. The mixture was extracted with ethyl acetate (2×). The combined organics were washed with aqueous hydrochloric acid (200 mL×4, 1N) and with a saturated aqueous solution of sodium bicarbonate (200 mL×2). The organics were dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford (R)-tert-butyl 3-(pyrrolidine-1-carbonyl)piperidine-1-carboxylate as a white solid (58.82 g). The compound was used for the next step without further purification. 1H NMR (400 MHz, CD3OD) δ 1.39-1.54 (m, 10H) 1.59-1.65 (m, 1H) 1.67 (d, 1H) 1.69-1.77 (m, 1H) 1.80-2.05 (m, 5H) 2.58 (tt, 1H) 2.77 (br s, 1H) 3.33-3.46 (m, 2H) 3.51-3.66 (m, 2H) 3.98-4.12 (m, 2H); MS (AP+) (M+H) 283.3.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[CH3:27])[C:5]([NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([N:18]2[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19]2)[CH:9]=1)=[O:6].C(N(CC)C(C)C)C.[C:36]([C:38]1[N:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:41]2=[N:40][CH:39]=1)#[CH:37]>CN(C=O)C.[Cu]I>[N:40]1[CH:39]=[C:38]([C:36]#[C:37][C:2]2[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=2[CH3:27])[C:5]([NH:7][C:8]2[CH:13]=[C:12]([C:14]([F:16])([F:17])[F:15])[CH:11]=[C:10]([N:18]3[CH2:22][CH:21]([CH3:23])[N:20]=[CH:19]3)[CH:9]=2)=[O:6])[N:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=12
Reactant: C#Cc1cnc2ccccn12
Reactant: Cc1cn(-c2cc(NC(=O)c3ccc(C)c(I)c3)cc(C(F)(F)F)c2)cn1
Agent: [Cu]I
Agent: CCN(CC)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)Nc2cc(N3C=NC(C)C3)cc(C(F)(F)F)c2)cc1C#Cc1cnc2ccccn12
Temperature: 25 °C
Reaction time: 28 h

Procedure:
To a solution of 3-iodo-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)benzamide (0.11 g, 0.22 mmol.) in DMF (1 mL) in a sealed tube was added Pd[(PPh3)4] (0.013 g, 0.011 mmol), CuI (3 mg, 0.016 mmol), diethylisopropylamine (0.057 mL, 0.33 mmol.), followed by 3-ethynylimidazo[1,2-a]pyridine (0.040 g, 0.28 mmol.). The mixture was purged with argon for 15 minutes, sealed and stirred at rt for 28 h. The solvent was concentrated and the residue was taken up in methylene chloride (50 mL). The organic layer was washed with water, dried (Na2SO4) and evaporated to leave a brown residue which was purified by combiflash (hexane/ethyl acetate/methanol) to yield the desired material: MS (M+H)+ 500.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].F[C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[F:23][C:21]1[CH:20]=[CH:19][C:18]([N+:24]([O-:26])=[O:25])=[C:17]([CH:22]=1)[NH:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: CCOC(=O)c1c(N)sc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1c(Nc2cc(F)ccc2[N+](=O)[O-])sc2ccccc12
Temperature: 50 °C
Reaction time: 1.17 h
Yield: 44.9 %

Procedure:
Ethyl 2-aminobenzo[b]thiophene-3-carboxylate (69.3 g) and 2,4-difluoronitrobenzene (50 g) were dissolved in dimethyl sulfoxide (550 ml) and heated to 50° C. Thereto was added potassium carbonate (63 g) and the mixture was stirred at 100° C. for 70 min. After cooling, the reaction mixture was allowed to cool to 70° C. and poured into water (2.5 L). The reaction mixture was allowed to stand still, and filtered. The filtrated orange crystals were washed with ethyl acetate to give ethyl 2-(5-fluoro-2-nitroanilino)benzo[b]thiophene-3-carboxylate (50.7 g).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:11])[NH:6]2.[CH2:12]([O:14][C:15](=[O:21])[CH:16](Br)[CH:17]([CH3:19])[CH3:18])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:12]([O:14][C:15](=[O:21])[CH:16]([O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:11])[NH:6]2)[CH:17]([CH3:19])[CH3:18])[CH3:13]
Reactant: Cc1cc2c(O)cccc2[nH]1
Reactant: CCOC(=O)C(Br)C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(Oc1cccc2[nH]c(C)cc12)C(C)C

Procedure:
A mixture of 4-hydroxy-2-methylindole (1) (1.5 g, 0.010 mole), 2-bromo-3-methyl-butyric acid ethyl ester (2.2 g, 0.010 mole) and potassium carbonate (excess) in acetone (50 mL) was refluxed for 3 days. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by column chromatography (20:1 Hex:EtOAc) to afford intermediate 2. Yield: 1.88 g, 71%
Reaction SMILES: [H-].[Na+].[Si:3]([O:10][CH2:11][C@H:12]1[O:17][C@:16]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH3:36])=[CH:30][CH:29]=3)[CH:21]=2)([O:18][CH3:19])[C@H:15]([OH:37])[C@@H:14]([OH:38])[C@@H:13]1[OH:39])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].[CH2:40](Br)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>O1CCCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:6]([Si:3]([CH3:5])([CH3:4])[O:10][CH2:11][C@@H:12]1[C@@H:13]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C@H:14]([O:38][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@@H:15]([O:37][CH2:16][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@@:16]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH3:36])=[CH:30][CH:29]=3)[CH:21]=2)([O:18][CH3:19])[O:17]1)([CH3:9])([CH3:7])[CH3:8]
Reactant: CCOc1ccc(Cc2cc([C@]3(OC)O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1
Reactant: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Product: CCOc1ccc(Cc2cc([C@]3(OC)O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.9 %

Procedure:
To a suspension of sodium hydride (65.4 g, 1.627 mol, 60% dispersion in Mineral oil) in anhydrous tetrahydrofuran (100 mL) was added dropwise a solution of (2S,3R,4S,5S,6R)-6-[(tert-butyl (dimethyl)silyl)oxymethyl]-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-2-methoxy-tetrahydropyran-3,4,5-triol 1e (150 g, 0.271 mol) in anhydrous tetrahydrofuran (800 mL) at 0° C. The mixture was stirred at 0° C. for 1 hour and then allowed to warm up to room temperature. After benzyl bromide (113 mL, 951.84 mmol) and tetrabutylammonium iodide (3.91 g, 10.6 mmol) were added in turn, the mixture was stirred at 40° C. for 12 hours and cooled to 0° C., and then quenched with 50 mL of water. Most of the solvent was removed in vacuo. To the residue was added 200 mL of water. The resulting mixture was extracted with ethyl acetate (150 mL×3). The combined organic layers were washed with saturated aqueous sodium chloride (200 mL×2), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=20/1 to give the title compound 1f as yellow oil (97 g, 43.5%). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CDCl3) δ (ppm): 7.46 (m, 1H), 7.35 (m, 12H), 7.20 (m, 3H), 7.04 (m, 4H), 6.74 (m, 2H), 4.90 (m, 3H), 4.72 (d, 1H), 4.50 (d, 1H), 4.15 (t, 1H), 4.05 (d, 1H), 3.97 (m, 3H), 3.80 (m, 3H), 3.75 (m, 1H), 3.65 (m, 1H), 3.29 (d, 1H), 3.05 (s, 3H), 1.38 (t, 3H), 0.90 (s, 9H), 0.11 (s, 3H), 0.08 (s, 3H).
Reaction SMILES: [CH2:1]([Si:3]([CH2:21][CH3:22])([CH2:19][CH3:20])[O:4][CH:5]([CH2:9][CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:6][CH:7]=C)[CH3:2].C[N+]1([O-])CC[O:27]CC1.O.I([O-])(=O)(=O)=O.[Na+]>O1CCCC1.[Os](=O)(=O)(=O)=O>[CH2:1]([Si:3]([CH2:21][CH3:22])([CH2:19][CH3:20])[O:4][CH:5]([CH2:9][CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:6][CH:7]=[O:27])[CH3:2]
Reactant: C=CCC(CCOCc1ccccc1)O[Si](CC)(CC)CC
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)OC(CC=O)CCOCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 10.0 g (31.2 mmol) of 4-Triethylsilyloxy-6-benzyloxy-1-hexene in 310 mL of tetrahydrofuran at 0° C. were added 4.38 g (37.4 mmol) of 4-methylmorpholine N-oxide, 6.24 mL (1.248 mmol) of osmium tetroxide (0.2M in benzene) and 45 mL of water and stirred overnight at room temperature. To the mixture at 0° C. were added 185 mL of water and 20.02 g (93.6 mmol) of sodium periodate and stirred at room temperature for 1 hour, followed by partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated for the next reaction. 1H NMR (CDCl3): δ 9.79 (t, J=2.4 Hz, 1H, CH═O), 7.35-7.31 (m, 5H, ArH), 4.51 (d, J=12.0 Hz, 1H, ArCH2O), 4.46 (d, J=12.0 Hz, 1H, ArCH2O), 4.40 (p, J=6.0 Hz, 1H, CH—O), 3.55 (m, 2H, CH2—O), 2.56 (m, 2H, CH2C═O), 1.85 (m, 2H, CH2), 0.94 (t, J=8.1 Hz, 9H, TES CH3), 0.59 (q,J=8.1 Hz, 6H, TES CH2). 13CNMR (CDCl3): δ 201.94, 138.14, 128.31, 127.60, 127.55, 72.99, 66.31, 65.49, 51.14, 37.71, 6.84, 4.88.
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][C:4]([CH2:11][NH2:12])([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1.[C:13]([O:18][CH:19]([O:21][C:22](OC1CC(=O)NC1=O)=[O:23])[CH3:20])(=[O:17])[CH:14]([CH3:16])[CH3:15]>O.C(#N)C.C(OC)(C)(C)C>[C:13]([O:18][CH:19]([O:21][C:22]([NH:12][CH2:11][C:4]1([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2][CH2:1][CH2:6][CH2:5]1)=[O:23])[CH3:20])(=[O:17])[CH:14]([CH3:16])[CH3:15]
Reactant: NCC1(CC(=O)O)CCCCC1
Reactant: CC(OC(=O)OC1CC(=O)NC1=O)OC(=O)C(C)C
Solvent: COC(C)(C)C
Solvent: CC#N
Solvent: O
Product: CC(OC(=O)NCC1(CC(=O)O)CCCCC1)OC(=O)C(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 101.2 %

Procedure:
To a solution of gabapentin (6.8 g, 0.04 mole) in water (40 mL) is added a solution of [(1-isobutanoyloxyethoxy)carbonyloxy]succinimide (10 g, 0.036 mol) in acetonitrile (40 mL) over a period of 30 minutes. The reaction is stirred at ambient temperature for 3 hours. The reaction mixture is diluted with methyl tert-butyl ether (200 mL), washed with water (2×100 mL) and brine (50 mL). The organic phase is separated, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford the title compound as a white solid (12 g, quantitative).
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1.C(=O)([O-])[O-].[Na+].[Na+].[Br:22][C:23]1[N:24]=[N:25][C:26](Br)=[CH:27][CH:28]=1>CN(C)C=O>[Br:22][C:23]1[N:24]=[N:25][C:26]([N:13]2[CH2:14][CH2:15][N:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([CH3:3])[CH:5]=3)[CH2:11][CH2:12]2)=[CH:27][CH:28]=1
Reactant: Cc1cccc(N2CCNCC2)c1
Reactant: Brc1ccc(Br)nn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(N2CCN(c3ccc(Br)nn3)CC2)c1
Temperature: 65 °C
Reaction time: 1 h
Yield: 61.5 %

Procedure:
A mixture of 5 parts of 1-(3-methylphenyl)piperazine dihydrochloride, 10.6 parts of sodium carbonate and 180 parts of N,N-dimethylformamide was stirred for 1 hour at 65° C. Then there were added 7.2 parts of 3,6-dibromopyridazine and the whole was stirred overnight at about 65° C. The reaction mixture was poured into ice water. The product was filtered off and dissolved in dichloromethane. The solution was washed twice with water, dried, filtered and evaporated. The residue was crystallized from ethanol. The product was filtered off and dried, yielding 4.1 parts (61.5%) of 3-bromo-6-[4-(3-methylphenyl)-1-piperazinyl]pyridazine; mp. 145.7° C. (compound 136).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[CH:12]=[CH:11][N:10](C(OCC2C=CC=CC=2)=O)[C@@H:9]([CH2:23][CH2:24][C:25]([NH:27][CH2:28][NH:29][S:30]([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=2)(=[O:32])=[O:31])=[NH:26])[C:8]1=[O:40])=[O:5])[CH3:2].Cl>C(O)C.[OH-].[OH-].[Pd+2]>[CH2:1]([O:3][C:4](=[O:5])[CH2:6][N:7]1[CH2:12][CH2:11][NH:10][C@@H:9]([CH2:23][CH2:24][C:25]([NH:27][CH2:28][NH:29][S:30]([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=2)(=[O:31])=[O:32])=[NH:26])[C:8]1=[O:40])[CH3:2]
Reactant: CCOC(=O)CN1C=CN(C(=O)OCc2ccccc2)[C@@H](CCC(=N)NCNS(=O)(=O)c2ccc(C)cc2)C1=O
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)CN1CCN[C@@H](CCC(=N)NCNS(=O)(=O)c2ccc(C)cc2)C1=O
Reaction time: 5 h

Procedure:
A solution of the compound of Example 9 (0.43 mmol) in absolute ethanol (10 mL) was treated with Pd(OH)2 (46 mg, 0.086 mmol) and concentrated HCl (1 mL). The mixture was hydrogenated in a PARR shaker at 40 p.s.i. for 5 h. The mixture was filtered through Celite to remove the catalyst and the filtrate was evaporated under reduced pressure to give the title compound.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:18])[C:15]([OH:17])=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C:20]1[S:21][C:22]2[CH:28]=[C:27]([NH2:29])[CH:26]=[CH:25][C:23]=2[N:24]=1>>[NH2:19][C:20]1[S:21][C:22]2[CH:28]=[C:27]([NH:29][C:15](=[O:17])[C:14]([N:11]3[CH2:10][CH2:9][CH:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH2:13][CH2:12]3)=[O:18])[CH:26]=[CH:25][C:23]=2[N:24]=1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccccc2)CC1
Reactant: Nc1ccc2nc(N)sc2c1
Product: Nc1nc2ccc(NC(=O)C(=O)N3CCC(Cc4ccccc4)CC3)cc2s1

Procedure:
The title compound is prepared from (4-benzyl-piperidin-1-yl)-oxo-acetic acid (Example 5b) and 2,6-diamino-benzthiazole [Arch. Pharm., 13, 48. (1935)] according to the method described in Example 2. The filtered crystals are purified by column chromatography using Kieselgel 60 (Merck) as adsorbent and toluene:methanol=4:1 as eluent. Melting Point: 203° C. (isopropanol)
Reaction SMILES: [C:1]([OH:5])([CH3:4])([CH3:3])[CH3:2].[CH3:6][O:7][C:8]1([C:17]2[O:27][C:20]3=[C:21]([O:25][CH3:26])[N:22]=[CH:23][CH:24]=[C:19]3[CH:18]=2)[CH2:13][CH2:12][N:11]([C:14](O)=[O:15])[CH2:10][CH2:9]1.[H-].[Na+].IC>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:14]([N:11]1[CH2:10][CH2:9][C:8]([O:7][CH3:6])([C:17]2[O:27][C:20]3=[C:21]([O:25][CH3:26])[N:22]=[CH:23][CH:24]=[C:19]3[CH:18]=2)[CH2:13][CH2:12]1)=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)O
Reactant: COc1nccc2cc(C3(OC)CCN(C(=O)O)CC3)oc12
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CI
Product: COc1nccc2cc(C3(OC)CCN(C(=O)OC(C)(C)C)CC3)oc12
Reaction time: 0.5 h
Yield: 124.5 %

Procedure:
A solution of 4-methoxy-4-(7-methoxyfuro[2,3-c]pyridin-2-yl)piperidine carboxylic acid tert-butyl alcohol (8.59 g) in dry N,N-dimethylformamide (100 ml) was stirred at room temperature under an atmosphere of dry nitrogen. Sodium hydride (60% in oil, 1.18 g) was added portionwise and stirring continued for 30 minutes. Iodomethane (3.07 ml) was added and stirring continued for 80 minutes. The mixture was diluted with ethyl acetate (300 ml) and washed with water (4×100 ml) and brine (1×100 ml). The organic extract was dried over magnesium sulphate, filtered and the solvent removed in vacuo to give the title compound (10.19 g) as a pale yellow liquid.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[O:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11](OS(C(F)(F)F)(=O)=O)[C:5]=2[C:4](=[O:20])[O:3]1.C([Sn](CCCC)(CCCC)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)CCC.[Cl-].[Li+].CN(C)C=O>O1CCOCC1.O>[CH3:1][C:2]1([CH3:21])[O:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[C:5]=2[C:4](=[O:20])[O:3]1
Reactant: CC1(C)OC(=O)c2c(cccc2OS(=O)(=O)C(F)(F)F)O1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: O
Product: CC1(C)OC(=O)c2c(cccc2-c2ccccn2)O1
Reaction time: 8 h

Procedure:
6.0 g (18.4 mmol) of 2,2-dimethyl-5-trifluoromethylsulfonyloxy-4H-(1,3)benzodioxin-4-one, 7.0 g (19.0 mmol) of 2-tributylstannylpyridine, 2.3 g (55.2 mmol) of lithium chloride and 420 mg (0.36 mmol) of tetrakistriphenylphosphinepalladium0 are dissolved in 60 ml of dioxane and 90 ml of dimethylformamide and the mixture is refluxed for 1.5 h (reaction temperature about 120° C.). It is stirred into 1.4 l of water at 0° C. and extracted with methyl tert-butyl ether, and the extract is washed with water and sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The residue is taken up in 60 ml of ethyl acetate, 8 g of potassium fluoride are added and the mixture is stirred overnight. The solid is filtered off and subsequently washed with plenty of ethyl acetate, and the filtrate is concentrated in vacuo. The crude product is purified by chromatography on silica gel 60 using hexane/ethyl acetate. Yield: 2.39 g (51%). Melting point: 142° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:18][CH3:19])[C:9]=1OS(C(F)(F)F)(=O)=O)[CH:5]=[O:6].CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].CC#N>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:18][CH3:19])[CH:9]=1)[CH:5]=[O:6]
Reactant: COc1cc(C=O)cc(Cl)c1OS(=O)(=O)C(F)(F)F
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Product: COc1cc(Cl)cc(C=O)c1
Temperature: 90 °C
Yield: 89 %

Procedure:
Triflate 5 (9 g, 28 mmol), palladium(II) acetate (120 mg, 0.5 mmol), 1,1'-bis(diphenylphosphino)ferrocene (620 mg, 1 mmol) and hplc grade CH3CN (10 ml) were mixed well in a teflon-lined stainless steel bomb. After adding freshly made, pulverized proton sponge formate2 (7.84 g, 30 mmol), the bomb was sealed and heated at 90° C. for 4 h. The cooled reaction was then filtered to remove proton sponge crystals, partitioned between EtOAc and 3N HCl. washed once each with dilute brine and dilute NaHCO3, dried over Na2SO4, and evaporated. Silica gel chromatography (15% EtOAc/hexanes) yielded 4.25 g (88.5%) of chloromethoxybenzaldehyde 6, mp 45° C.
Reaction SMILES: ClC12[O:8]C1CCC(Cl)(F)C2.[CH:11]([C:13]1(O)[C:18]([Cl:20])([Cl:19])[CH2:17][CH2:16][CH2:15][C:14]1([Cl:22])Cl)=[CH2:12].[OH-].[Na+]>O>[Cl:22][C:14]12[O:8][CH:15]1[CH2:16][CH2:17][C:18]([Cl:20])([Cl:19])[CH:13]2[CH:11]=[CH2:12]
Reactant: C=CC1(O)C(Cl)(Cl)CCCC1(Cl)Cl
Reactant: FC1(Cl)CCC2OC2(Cl)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=CC1C(Cl)(Cl)CCC2OC21Cl
Reaction time: 0.25 h
Yield: 90 %

Procedure:
The same procedure was employed as for the preparation of 2e in Example 17: it was performed with 1.14 g (4.32 mmol) of pure alcohol 1k, 12 cm3 of distilled water and 0.5 g (12.5 mmol) of sodium hydroxide; reaction time was 1 h 15 min; ether extraction (4×25 cm3); the crude product was employed as such (crude yld=90.5%) or purified by flash chromatography on silica (eluent: ether/petroleum ether=3/97): 0.88 g of epoxide 2i were obtained, that was a 90% yield (macrobore GC purity>98.6%) MW: 227.519; 1H NMR: 6.75-6.30 (m, 1H); 5.80-5.45 (m, 2H); 3.00-1.25 (m, 6H). 13C NMR: 126.1 (C7); 123.1 (C8); 88.35 (C3); 85.5 (C1); 70.0 (C2); 39.75 (C4); 32.4 (C6); 18.3 (C5). IR in cm-1 (film): 1080-940-875-785-735.
Reaction SMILES: [C:1]1([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)CCC(O)=O>>[OH:13][C@@H:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C(=O)c1ccccc1
Agent: O=C(O)CCC(=O)O
Product: CCOC(=O)[C@@H](O)c1ccccc1
Yield: 87 %

Procedure:
Ethyl phenylglyoxylate acid (0.5 g) was asymmetrically reduced in the same manner as in Example 19, except that 1.33 g (11.2 mmol) of succinic acid was used in place of benzoic acid, giving 0.44 g of ethyl (S)-(+)-2-hydroxy-2-phenylacetate, having a specific rotation [α]D18 of +19.4° (cl. 18, CHCl3). The synthesis yield was 87% and the optical yield was 15% e.e. (see Reference 7).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:19][CH2:18][CH2:17][C:16]([C:20]([O:22]CC)=[O:21])=[CH:15][C:14]=3[CH:25]=2)=[CH:6][CH:5]=1.[OH-].[Na+]>O1CCCC1CCO>[F:27][C:2]([F:1])([F:26])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:19][CH2:18][CH2:17][C:16]([C:20]([OH:22])=[O:21])=[CH:15][C:14]=3[CH:25]=2)=[CH:6][CH:5]=1
Reactant: CCOC(=O)C1=Cc2cc(-c3ccc(OC(F)(F)F)cc3)ccc2OCC1
Agent: OCCC1CCCO1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C1=Cc2cc(-c3ccc(OC(F)(F)F)cc3)ccc2OCC1
Reaction time: 120 h
Yield: 94 %

Procedure:
To a solution of ethyl 7-(4-trifluoromethoxyphenyl)-2,3-dihydro-1-benzoxepine-4-carboxylate (323.9 mg) in tetrahydrofuran-ethanol (5-5 ml) was added 1N sodium hydroxide (2.0 ml) at room temperature, and the mixture was stirred for 5 days and concentrated under reduced pressure. To the residue 1N hydrochloric acid (5 ml) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated. The resulting crystal was collected by filtration to give 7-(4-trifluoromethoxyphenyl)-2,3-dihydro-1-benzoxepine-4-carboxylic acid (282 mg) as colorless crystals.
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:12][CH2:11][C@@H:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH2:9]1.[CH2:21]([CH:29]1[CH2:31][O:30]1)[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[OH:30][C@H:29]([CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:31][N:8]1[CH2:12][CH2:11][C@@H:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH2:9]1
Reactant: c1ccc(CCC2CO2)cc1
Reactant: Oc1ccc(S[C@@H]2CCNC2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Oc1ccc(S[C@@H]2CCN(C[C@H](O)CCc3ccccc3)C2)cc1

Procedure:
The title compound, MS: m/e=344.4 (M+H+) was prepared from (R)-4-(pyrrolidin-3-yl-sulfanyl)-phenol trifluoro-acetic acid and (RS)-2-phenethyl-oxirane.