Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[O:12]C)=[CH:4][C:3]=1[O:14][CH:15]1[CH2:20][CH2:19][C:18]([CH:25]([NH2:28])[CH2:26][CH3:27])([C:21]([F:24])([F:23])[F:22])[CH2:17][CH2:16]1.CC(O)C.Cl>O>[NH2:28][CH:25]([C:18]1([C:21]([F:23])([F:24])[F:22])[CH2:17][CH2:16][CH:15]([O:14][C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][C:2]=2[Cl:1])[C:9](=[O:12])[NH:8][CH:7]=[CH:6]3)[CH2:20][CH2:19]1)[CH2:26][CH3:27]
Reactant: CCC(N)C1(C(F)(F)F)CCC(Oc2cc3ccnc(OC)c3cc2Cl)CC1
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: CCC(N)C1(C(F)(F)F)CCC(Oc2cc3cc[nH]c(=O)c3cc2Cl)CC1
Yield: 0.1 %

Procedure:
160 mg (336 mmol) of 1-[4-(7-Chloro-1-methoxy-isoquinolin-6-yloxy)-1-trifluoromethyl-cyclohexyl]-propylamine (76) were dissolved using 2 ml of 2-propanol and 2 ml of a 1N aqueous solution of HCl. The mixture was treated for 1 h at 100° C. under microwave irradiation. Afterwards, the mixture was diluted using 50 ml of water and lyophilized to yield 154 mg of the desired product. Rt=0.66 min (Method P). Detected mass: 403.2 (M+H+).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH2:17][CH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:24][CH3:25])=O)C.[CH2:26]([N:28]=[C:29]=[O:30])[CH3:27]>>[CH2:26]([N:28]1[C:4](=[O:3])[C:6]2[CH:7]=[N:8][C:9]3[C:10]([O:24][CH3:25])=[CH:11][CH:12]=[CH:13][C:14]=3[C:15]=2[N:16]([CH2:17][CH:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[C:29]1=[O:30])[CH3:27]
Reactant: CCN=C=O
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NCC1CCOCC1
Product: CCn1c(=O)c2cnc3c(OC)cccc3c2n(CC2CCOCC2)c1=O
Yield: 51.4 %

Procedure:
4-Chloro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (265 mg, 1.0 mmol) was treated with C-(tetrahydro-pyran-4-yl)-methylamine (1.5 mmol) following general procedure B to afford 8-methoxy-4-[(tetrahydro-pyran-4-ylmethyl)-amino]-quinoline-3-carboxylic acid ethyl ester (324 mg). 3-Ethyl-7-methoxy-1-(tetrahydro-pyran-4-ylmethyl)-1H-pyrimido[5,4-c]quinoline-2,4-dione (19 mg) was prepared from 8-methoxy-4-[(tetrahydro-pyran-4-ylmethyl)-amino]-quinoline-3-carboxylic acid ethyl ester (0.10 mmol) and ethyl isocyanate (0.4 mmol) following general procedure C. LCMS: m/z 370 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[C:5]2[C:6]([C@@H:10]3[CH2:12][C@H:11]3[CH2:13][NH2:14])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.C(N(CC)CC)C.[CH:23]1([C:26](Cl)=[O:27])[CH2:25][CH2:24]1>O1CCCC1.C(=O)([O-])O.[Na+]>[CH3:1][C:2]1[CH:15]=[C:5]2[C:6]([C@@H:10]3[CH2:12][C@H:11]3[CH2:13][NH:14][C:26]([CH:23]3[CH2:25][CH2:24]3)=[O:27])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: O=C(Cl)C1CC1
Reactant: Cc1cc2c([C@@H]3C[C@H]3CN)cccn2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc2c([C@@H]3C[C@H]3CNC(=O)C3CC3)cccn2n1
Yield: 65 %

Procedure:
To a solution of trans-1-[2-(2-methylpyrazolo[1,5-a]pyridin-4-yl)cyclopropyl]methanamine (100 mg, 0.497 mmol) and triethylamine (83.2 μL, 0.596 mmol) in tetrahydrofuran (5 mL) was added cyclopropanecarbonyl chloride (49.6 μL, 0.547 mmol) under ice-cooling, and the mixture was stirred under ice-cooling for 10 min. The reaction solution was diluted with saturated aqueous sodium hydrogen carbonate solution. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=35/65→90/10) to give the title compound (87.0 mg, yield 65%).
Reaction SMILES: [CH2:1]([NH:8][C@H:9]1[C@H:15]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[O:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)(=O)C.Cl>>[ClH:22].[CH2:1]([NH:8][C@H:9]1[C@H:15]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[O:14][CH2:13][CH2:12][NH:11][CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](NCc2ccccc2)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: Clc1ccc([C@@H]2OCCNC[C@H]2NCc2ccccc2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.2 %

Procedure:
To tert-butyl (6R,7S)-6-(benzylamino)-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (80 mg) was added 4.0 M hydrogen chloride-ethyl acetate solution (4 mL), and the mixture was stirred at room temperature for 1 hr. The residue obtained by concentration under reduced pressure was washed with diethyl ether to give the title compound (20 mg).
Reaction SMILES: [OH:1][C@H:2]([CH3:35])[C:3]([N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[C:16]3[CH:17]=[CH:18][NH:19][C:15]=3[N:14]3[N:20]=[CH:21][C:22]([C:23]4[CH:24]=[N:25][C:26]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)=[CH:27][CH:28]=4)=[C:13]3[N:12]=2)[CH2:7][CH2:6]1)=[O:4].[OH:36][C@H](CO)C(O)=O>>[OH:1][C@H:2]([CH2:35][OH:36])[C:3]([N:5]1[CH2:6][CH2:7][CH:8]([C:11]2[C:16]3[CH:17]=[CH:18][NH:19][C:15]=3[N:14]3[N:20]=[CH:21][C:22]([C:23]4[CH:24]=[N:25][C:26]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)=[CH:27][CH:28]=4)=[C:13]3[N:12]=2)[CH2:9][CH2:10]1)=[O:4]
Reactant: C[C@@H](O)C(=O)N1CCC(c2nc3c(-c4ccc(-c5ccccc5)nc4)cnn3c3[nH]ccc23)CC1
Reactant: O=C(O)[C@H](O)CO
Product: O=C([C@H](O)CO)N1CCC(c2nc3c(-c4ccc(-c5ccccc5)nc4)cnn3c3[nH]ccc23)CC1

Procedure:
The title compound was prepared in a similar way to compound 25, except that (R)-2,3-dihydroxypropanoic acid was used in place of D-lactic acid in Step C. LC/MS (10 min method) RT: 2.63 min, [M+]=482.21, [M+H]=483.21
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][CH:12]([C:15]([OH:17])=O)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[F:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][CH:24]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClCCl>[C:1]([N:9]1[CH2:10][CH2:11][CH:12]([C:15](=[O:17])[C:26]2[CH:25]=[CH:24][C:23]([F:22])=[CH:28][C:27]=2[F:29])[CH2:13][CH2:14]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1CCN(C(=O)c2ccccc2)CC1
Reactant: Fc1cccc(F)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(c1ccc(F)cc1F)C1CCN(C(=O)c2ccccc2)CC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
To a solution of 1-benzoylpiperidine-4-carboxylic acid (66 g, 285 mmol) in dichloromethane (160 mL) was added thionyl chloride (26 mL, 388 mmol). After stirring at 60° C. for 1 h, the mixture was added portionwise to a stirred suspension of 2,4-difluorobenzene (45 g, 397 mmol) and anhydrous aluminum chloride (88 g, 666 mmol) in dichloromethane (245 mL), and the reaction mixture was refluxed for 5 h. The reaction mixture was poured into a mixture of ice and concentrated hydrochloric acid and extracted with chloroform. The organic layer was dried over sodium sulfate and the solvent was evaporated under reduced pressure. Recrystallization from hexane gave 1-benzoyl-4-(2,4-difluorobenzoyl)piperidine (46 g, 50%) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:7])=[N:5][N:6]=1.[BH4-].[Na+].O.[CH3:11][CH:12](O)[CH3:13]>CC(C)=O>[CH3:7][C:4]1[S:3][C:2]([NH:1][CH:12]([CH3:13])[CH3:11])=[N:6][N:5]=1
Reactant: CC(C)O
Reactant: Cc1nnc(N)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1nnc(NC(C)C)s1

Procedure:
2-Amino-5-methyl-1,3,4-thiadiazole (23 g, 0.2 mole) in IPA (700 ml) and acetone (100 ml) was treated with sodium borohydride (20 g) in portions with stirring and cooling. The reaction mixture was then stirred and heated to reflux for 31/2 hours. The solution was then poured into water (3 L) and extracted with ether (× 3). The ethereal solution was dried, filtered and evaporated to give the title compound as a cream solid. m.p. 145° C.
Reaction SMILES: [CH3:1][N:2]([CH:4]=[N:5][C:6]1[NH:7][C:8](=O)[C:9]2[NH:10][CH:11]=[N:12][C:13]=2[N:14]=1)[CH3:3].CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:27])=O.C(=O)([O-])O.[Na+]>>[CH3:1][N:2]([CH:4]=[N:5][C:6]1[N:14]=[C:13]2[C:9]([NH:10][CH:11]=[N:12]2)=[C:8]([Cl:27])[N:7]=1)[CH3:3]
Reactant: CN(C)C=Nc1nc2nc[nH]c2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)c1ccccc1
Product: CN(C)C=Nc1nc(Cl)c2[nH]cnc2n1
Temperature: 80 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
20.6 g (0.1 mol) of N-dimethylaminomethyleneguanine obtained in Example 15, and 12.1 g (0.1 mol) of N,N-dimethylaniline were added to 38.3 g (0.25 mol) of phosphorus oxychloride, followed by stirring at 80° C. for 2 hours. After cooling, the reaction mixture was added to 500 ml of ice water, and then neutralized with 126.0 g (1.5 mol) of sodium hydrogen carbonate. The precipitating crystal was collected by filtration and then washed with 50 ml of water, subsequently with 50 ml of methanol to yield 18.0 g (0.08 mol) of a crystal of 2-dimethylaminomethyleneamino-6-chloropurine (yield 80% ). Comparative Example (method disclosed in Japanese Patent Laid-Open No. 227583/1986)
Reaction SMILES: [C:1]([C:7]1[CH:8]=[C:9]([O:13][CH2:14][C@@H:15]2[CH2:19][CH2:18][CH2:17][N:16]2[CH3:20])[CH:10]=[N:11][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH3:6]>CO.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[CH:1]([C:7]1[CH:8]=[C:9]([O:13][CH2:14][C@@H:15]2[CH2:19][CH2:18][CH2:17][N:16]2[CH3:20])[CH:10]=[N:11][CH:12]=1)=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCC#Cc1cncc(OC[C@@H]2CCCN2C)c1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CO
Product: CCCCC=Cc1cncc(OC[C@@H]2CCCN2C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
To a solution of 5-(1-hexynyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)-pyridine (from Example 4a, 100 mg, 0.37 mmol) in MeOH (3.0 mL) was added Lindlar's catalyst (10 mg). The mixture was stirred at room temperature overnight. The solvent was removed, and the residue was chromatographed on a silica gel column, eluting with NH4OH/MeOH/EtOAc 0:1:9 and 1:10:90 to afford a light yellowish oil (98 mg, 98%). MS (CI/NH3) m/z 277 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ 0.88 (t, J=4.8 Hz, 3H), 1.23-1.37 (m, 6 H), 1.53-1.62 (m, 2H), 1.70-2.08 (m, 4H), 2.26-2.36 (m, 1H), 2.48 (s, 3H), 2.56 (t, J=7.7 Hz, 2H), 2.58-2.71 (m, 1H), 3.07-3.14 (m, 1H), 3.88-4.05 (m, 2H), 7.03 (dd, J=3.0 Hz, J=J=2.1 Hz, 1H), 8.06 (d, J=2.1 Hz, 1H), 8.13 (d, J=3.0 Hz, 1H).
Reaction SMILES: [C:1]1([CH:7]([N:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][C:10]2=[O:22])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]1([CH:7]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][C:10]2=[O:22])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(c1ccccc1)N1CCN(C(=O)OC(C)(C)C)CC1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(c1ccccc1)N1CCNCC1=O
Yield: 68.3 %

Procedure:
Prepared in the same manner as that described in Example 5, Step 2, using 1-(1-phenylethyl)-4-(tert-butyloxycarbonyl)piperazin-2-one (673 mg, 2.2 mmol), trifluoroacetic acid (4 mL) and CH2Cl2 (40 mL). The crude product was chromatographed on silica gel, eluting with CH2Cl2 :MeOH (90:10), to afford the amine (307 mg, 68%) as a colourless oil. 1H NMR (250 MHz, CDCl3) δ1.53 (3H, d, J=7.2 Hz), 2.75-2.94 (2H, m), 2.98-3.07 (1H, m), 3.12-3.21 (1H, m), 3.62 (2H, s), 6.13 (1H, q, J=7.2 Hz), 7.24-7.39 (5H, m).
Reaction SMILES: [NH2:1][C@H:2]([CH3:18])[C:3]([NH:5][C@H:6]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]1)=[O:4].[N+:19]([C:22]1[CH:52]=[CH:51][C:25]([CH2:26][O:27][C:28]([N:30]=[C:31]([NH:37][C:38](=[O:50])[O:39][CH2:40][C:41]2[CH:46]=[CH:45][C:44]([N+:47]([O-:49])=[O:48])=[CH:43][CH:42]=2)N2C=CC=N2)=[O:29])=[CH:24][CH:23]=1)([O-:21])=[O:20]>O1CCCC1>[N+:19]([C:22]1[CH:23]=[CH:24][C:25]([CH2:26][O:27][C:28]([N:30]=[C:31]([NH:37][C:38]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][C:44]([N+:47]([O-:49])=[O:48])=[CH:43][CH:42]=2)=[O:50])[NH:1][C@H:2]([CH3:18])[C:3]([NH:5][C@H:6]2[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]2)=[O:4])=[O:29])=[CH:51][CH:52]=1)([O-:21])=[O:20]
Reactant: C[C@@H](N)C(=O)N[C@H]1CCN(C(=O)OC(C)(C)C)C1
Reactant: O=C(N=C(NC(=O)OCc1ccc([N+](=O)[O-])cc1)n1cccn1)OCc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Product: C[C@@H](NC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)NC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)N[C@H]1CCN(C(=O)OC(C)(C)C)C1
Yield: 100.6 %

Procedure:
To a solution of tert-butyl (3S)-3-[(2R)-2-amino-2-methylacetylamino]-1-pyrrolidinecarboxylate (448 mg) in anhydrous tetrahydrofuran (20 ml), 4-nitrobenzyl [(4-nitrobenzyloxy)carbonylimino-pyrazol-1-ylmethyl]carbamate (776 mg) was added under ice cooling. The resulting mixture was treated in a similar manner to that described in Referential Example 16-(1), whereby the title compound (1.096 g) was obtained as an amorphous substance.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11](OS(C)(=O)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:19]=[N+:20]=[N-:21].[Na+].O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:19]=[N+:20]=[N-:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(N=[N+]=[N-])CC1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester and sodium azide in DMF was stirred at 60° C. overnight. The mixture was poured into water and the resulting mixture was extracted with EtOAc. The organic phase was separated and washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo to give the desired product as a pale yellow oil, which was used without further purification. 1H NMR (CDCl3): δ 7.9 (2H, d), 7.12 (2H, d), 4.79 (2H, d), 3.05 (3H, s), 2.58 9 (1H, t).
Reaction SMILES: C[CH:2]([CH:6]1[C:10]2=[C:11]([S:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[C:12]3[C:13](Br)=[CH:14][C:15]([F:18])=[CH:16][C:17]=3[N:9]2[CH2:8][CH2:7]1)[C:3]([O-:5])=[O:4].[N:28]1[C:37]2[C:32](=[CH:33][C:34](B(O)O)=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1>>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([S:20][C:11]2[C:12]3[C:13]([C:34]4[CH:33]=[C:32]5[C:37](=[CH:36][CH:35]=4)[N:28]=[CH:29][CH:30]=[CH:31]5)=[CH:14][C:15]([F:18])=[CH:16][C:17]=3[N:9]3[CH2:8][CH2:7][CH:6]([CH2:2][C:3]([OH:5])=[O:4])[C:10]=23)=[CH:22][CH:23]=1
Reactant: OB(O)c1ccc2ncccc2c1
Reactant: CC(C(=O)[O-])C1CCn2c1c(Sc1ccc(Cl)cc1)c1c(Br)cc(F)cc12
Product: O=C(O)CC1CCn2c1c(Sc1ccc(Cl)cc1)c1c(-c3ccc4ncccc4c3)cc(F)cc12

Procedure:
Starting from (+/−)-methyl[8-bromo-9-[(4-chlorophenyl)sulfanyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate (Example 7, Step 9) and quinolin-6-ylboronic acid, the title compound was synthesized following the procedures described in Example 108.
Reaction SMILES: [BH4-].[Na+].[I-].[CH3:4][N+:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[O:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[CH:15]=1>O.CO>[CH3:4][N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[C:11]1[O:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[CH:15]=1
Reactant: C[n+]1ccccc1-c1cc2ccccc2o1
Agent: [BH4-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CN1CCCCC1c1cc2ccccc2o1
Temperature: 25 °C

Procedure:
6.15 g of sodium borohydride dissolved in 50 ml of water is added dropwise in the course of 30 minutes, with stirring and ice-water cooling, to a solution of 18.2 g of 1-methyl-2-(2-benzofuranyl)-pyridinium-iodide in 150 ml of methanol. Stirring is maintained for 1 hour at room temperature, and the light-yellow solution then poured into 1000 ml of water. The precipitating oil is extracted with chloroform; the chloroform extracts are dried over anhydrous sodium sulphate, and the solvent distilled off in vacuo. The oily residue is taken up in a little methylene chloride, and chromatographed through 150 g of aluminum oxide (2% water). The methylene chloride eluates yield after concentration by evaporation 13.2 g of 1-methyl-2-(2-benzofuranyl)-1,4,5,6-tetrahydropyridine in the form of light-yellow oil. This is dissoled in 130 ml of ethyl acetate and, after the addition of 1 g of palladium-charcoal catalyst (10%), hydrogenated at room temperature. After absorption of 935 ml of hydrogen in the course of 19 hours, hydrogenation ceases. The catalyst is filtered off, the filtrate concentrated in vacuo, and the residue distilled in high vacuum to obtain 1-methyl-2-(2-benzofuranyl)-piperidine as colourless oil, B.P. 93°-97° (0.02 Torr). The hydrochloride is obtained as colourless crystals, M.P. 188°-189°, by dissolving the distilled base in the fivefold amount of acetone, and neutralising the solution with a 2 N solution of hydrogen chloride in ethyl acetate.
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.[Br:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1>C(OCC)C>[CH2:1]([CH:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:18])[C:15]([NH:24][C:23]2[CH:25]=[CH:26][C:20]([Br:19])=[CH:21][CH:22]=2)=[O:17])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccccc2)CC1
Reactant: Nc1ccc(Br)cc1
Solvent: CCOCC
Product: O=C(Nc1ccc(Br)cc1)C(=O)N1CCC(Cc2ccccc2)CC1

Procedure:
The title compound is prepared from (4-benzyl-piperidin-1-yl)-oxo-acetic acid (Example 5b) and 4-bromo-aniline (Aldrich) according to the method described in Example 1c. Melting Point: 131-132° C. (diethylether)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:28]=[CH:27][C:15]4[N:16]=[C:17]([NH:19][C@@H:20]5[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]5[OH:26])[S:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1.[N:29]1[CH:34]=[CH:33][CH:32]=[C:31](B(O)O)[CH:30]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC>[N:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:2]2[CH:3]=[C:4]3[N:10]=[CH:9][N:8]([CH2:11][C:12]4[CH:28]=[CH:27][C:15]5[N:16]=[C:17]([NH:19][C@@H:20]6[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]6[OH:26])[S:18][C:14]=5[CH:13]=4)[C:5]3=[N:6][CH:7]=2)[CH:30]=1
Reactant: OB(O)c1cccnc1
Reactant: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(Br)cnc43)cc2s1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(-c5cccnc5)cnc43)cc2s1
Temperature: 100 °C
Yield: 31.3 %

Procedure:
A stirred mixture of (1R,2R)-2-((6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (80 mg, 0.175 mmol) from Example 29, pyridine-3-ylboronic acid (43 mg, 0.350 mmol), 2M aq Na2CO3 (400 μL, 0.40 mmol), and anhydrous DME (1.5 mL) was degassed under argon for 15 min. Bis(triphenylphosphine)palladium (II) dichloride (12 mg, 0.0171 mmol) was added and the reaction vessel was sealed and the mixture was heated at 100° C. for 15 h. After cooling to rt, the mixture was purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HOAc) and CH3CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRs diphenyl column as the stationary phase to afford (1R,2R)-2-((6-((6-(pyridin-3-yl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (25 mg, 31%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.99 (br s, 1H), 8.66-8.77 (m, 2H), 8.60 (br s, 1H), 8.46 (s, 1H), 8.19 (d, J=7.9 Hz, 1H), 8.00 (d, J=7.3 Hz, 1H), 7.69 (s, 1H), 7.52 (dd, J=4.7, 7.7 Hz, 1H), 7.21-7.34 (m, 2H), 5.53 (s, 2H), 4.77 (br s, 1H), 3.51 (m, 1H), 3.35 (m, 1H), 2.03 (m, 1H), 1.87 (m, 1H), 1.56-1.66 (m, 2H), 1.11-1.34 (m, 4H). LCMS (ESI) m/z 457 (M+H)+.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][CH:19]([CH2:21][C:22]([OH:24])=O)[N:20]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.O[NH:26][C:27]([CH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1)=[NH:28].O>CN(C)C=O>[CH:1]1([NH:6][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21][C:22]4[O:24][N:28]=[C:27]([CH:29]5[CH2:33][CH2:32][CH2:31][CH2:30]5)[N:26]=4)[N:20]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)CC1CSC(c2cc3cccc(NC4CCCC4)c3[nH]2)=N1
Reactant: N=C(NO)C1CCCC1
Solvent: O
Solvent: CN(C)C=O
Product: c1cc(NC2CCCC2)c2[nH]c(C3=N[C@H](Cc4nc(C5CCCC5)no4)CS3)cc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
[(7-Cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]acetic acid (140 mg, 0.41 mmol) prepared in Example 75 was dissolved in N,N-dimethylformamide (5 mL). 1,1′-Dicarbonyldiimidazole (73 mg, 0.45 mmol) was added thereto, and the mixture was stirred for 30 min at room temperature. N-hydroxy-cyclopentanecarboxamidine (260 mg, 2.03 mmol) was added thereto, and the mixture was stirred for 5 h at 80° C. After completion of the reaction, water was added. The reaction mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and the residue was purified by column chromatography to give the title compound (100 mg, Yield 56%).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[CH:25]=[CH:24][C:9]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[O:22][N:21]=[C:20]([CH3:23])[CH:19]=2)=[CH:8][CH:7]=1.[O:26]=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O>>[O:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[O:22][N:21]=[C:20]([CH2:23][OH:26])[CH:19]=2)=[CH:24][CH:25]=1
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: Cc1cc(CCCCCCCOc2ccc(C3=NCCO3)cc2)on1
Product: OCc1cc(CCCCCCCOc2ccc(C3=NCCO3)cc2)on1
Reaction time: 24 h

Procedure:
5-{7-[4-(4,5-Dihydro-2-oxazolyl)phenoxy]heptyl}-3-methylisoxazole (Example 1c) (1 g) was added to each of three 10-liter fermentation tanks containing a culture of Aspergillus niger (A1) in soy-dextrose medium. After 24 hours, thin layer chromatography showed essentially complete conversion to a more polar product. The total fermentation brews were extracted with two volumes each of dichloromethane. These were combined and concentrated in vacuo. The concentrate was washed with 0.05N sodium hydroxide and with water, leaving an oily material upon removal of remaining solvent. Several crystallizations from ethyl acetate and from acetone yielded 330 mg of 5-{7-[4-(4,5-dihydro-2-oxazolyl)phenoxy]heptyl}-3-isoxazolemethanol, colorless needles, m.p. 122°-124° C. The structure was established by nmr, ir and uv spectra.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:21])[N:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20])[C:6]([CH2:12]Cl)=[N:7]2.[N:22]1[C:30]([NH2:31])=[C:29]2[C:25]([N:26]=[CH:27][NH:28]2)=[N:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:31][C:30]1[N:22]=[CH:23][N:24]=[C:25]2[C:29]=1[N:28]=[CH:27][N:26]2[CH2:12][C:6]1[N:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[C:4](=[O:21])[C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[Cl:1])[N:7]=1
Reactant: Nc1ncnc2nc[nH]c12
Reactant: Cc1ccccc1-n1c(CCl)nc2cccc(Cl)c2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccccc1-n1c(Cn2cnc3c(N)ncnc32)nc2cccc(Cl)c2c1=O
Yield: 38.6 %

Procedure:
Prepared according to Procedure C using 2j (200 mg, 0.626 mmol), adenine (93 mg, 0.689 mmol), K2CO3 (95 mg, 0.689 mmol), and DMF (3 mL). The crude product was chromatographed in MeOH/CH2Cl2 to provide 101 mg of an off-white solid (39%), mp 262.0-266.5° C. 1H NMR (DMSO-d6) δ: 8.08 (s, 1H); 8.07 (s, 1H); 7.70 (t, J=8.0 Hz, 1H); 7.58 (dd, J=0.6, 7.9 Hz, 1H); 7.43-7.57 (m, 4H); 7.36 (dd, J=0.7, 8.0 Hz, 1H); 7.26 (br s, 2H); 5.12 (d, J=18 Hz, 1H); 4.78 (d, J=18 Hz, 1H); 2.20 (s, 3H). 13C NMR (DMSO-d6) ppm: 158.7, 156.2, 152.9, 152.7, 150.0, 149.4, 142.1, 136.1, 135.1, 135.0, 133.2, 131.8, 130.3, 130.1, 128.9, 128.1, 127.2, 118.5, 117.9, 44.9, 17.4. MS (ES): m/z 418.1 (M+). Anal. calcd. for C21H16ClN7O.0.1H2O.0.05KCl: C, 59.57; H, 3.86; Cl, 8.79; N, 23.16. Found: C, 59.65; H, 3.80; Cl, 8.70; N, 22.80.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([Cl:12])[C:5]2[O:9][C:8](=O)[NH:7][C:6]=2[CH:11]=1.[Cl:13]C1C=CC2NC(=O)OC=2C=1>C1(C)C=CC=CC=1>[Cl:13][C:8]1[O:9][C:5]2[C:4]([Cl:12])=[CH:3][C:2]([Cl:1])=[CH:11][C:6]=2[N:7]=1
Reactant: O=c1[nH]c2ccc(Cl)cc2o1
Reactant: O=c1[nH]c2cc(Cl)cc(Cl)c2o1
Solvent: Cc1ccccc1
Product: Clc1cc(Cl)c2oc(Cl)nc2c1
Yield: 68 %

Procedure:
In analogy to Example 1, 204 g of 5,7-dichlorobenzoxazolin-2-one, in place of 6-Chlorobenzoxazolin-2-one, are reacted. 2,5,7-Trichlorobenzoxazole of melting point 140° -142° C. is obtained in a yield of 68% of theory by recrystallisation, from toluene or ligroin, of the residue remaining after distilling out the o-dichlorobenzene.