Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].[CH2:6]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][C:10]=1[C:19]1[NH:24][C:23](=[O:25])[N:22]2[C:26]([CH3:32])=[N:27][C:28]([CH2:29][CH2:30][CH3:31])=[C:21]2[N:20]=1)[CH3:7]>ClCCl>[CH2:6]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:5][CH2:4][CH2:3][O:2][CH3:1])(=[O:17])=[O:16])=[CH:11][C:10]=1[C:19]1[NH:24][C:23](=[O:25])[N:22]2[C:26]([CH3:32])=[N:27][C:28]([CH2:29][CH2:30][CH3:31])=[C:21]2[N:20]=1)[CH3:7]
Reactant: COCCN
Reactant: CCCc1nc(C)n2c(=O)[nH]c(-c3cc(S(=O)(=O)Cl)ccc3OCC)nc12
Solvent: ClCCl
Product: CCCc1nc(C)n2c(=O)[nH]c(-c3cc(S(=O)(=O)NCCOC)ccc3OCC)nc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
55 mg (0.73 mmol) of 2-methoxyethylamine are added to a solution of 100 mg (0.24 mmol) of 4-ethoxy-3-(6-methyl-4-oxo-8-propyl-3,4-dihydro-imidazo[1,5-α][1,3,5]triazin-2-yl)-benzenesulfonyl chloride (example VI) in 5 ml of dichloromethane and the reaction mixture is stirred at room temperature for 2 hours. After chromatographic purification (dichloromethane/methanol=95:5) and stirring up with diethyl ether, 64 mg (57%) of 4-ethoxy-N-(2-methoxy-ethyl)-3-(6-methyl-4-oxo-8-propyl-3,4-dihydro-imidazo[1,5-α][1,3,5]triazin-2-yl)-benzenesulfonamide are obtained.
Reaction SMILES: Cl.Cl.[CH2:3]([N:10]([CH3:32])[CH2:11][C@H:12]1[CH2:17][N:16]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH:19]=2)[CH2:15][CH2:14][NH:13]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:40](Cl)(=[O:42])[CH3:41].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:3]([N:10]([CH2:11][C@H:12]1[CH2:17][N:16]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH:19]=2)[CH2:15][CH2:14][N:13]1[C:40](=[O:42])[CH3:41])[CH3:32])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(=O)Cl
Reactant: COc1ccc(N2CCN[C@@H](CN(C)Cc3ccccc3)C2)cc1OC1CCCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(N2CCN(C(C)=O)[C@@H](CN(C)Cc3ccccc3)C2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
A solution of (S)—N-benzyl-1-(4-(3-(cyclopentyloxy)-4-methoxyphenyl)piperazin-2-yl)-N-methylmethanamine dihydrochloride, (Example 42, Compound 130) (96.5 mg, 0.20 mmol) in CH2Cl2 (2 mL) at 0-5 C was treated with triethylamine (84 ul, 0.60 mmol) followed by acetyl chloride (22 uL, 0.30 mmol). The reaction mixture was allowed to warm to room temperature and stir 1 h. After this time the reaction mixture was treated with a saturated aqueous solution of NaHCO3 (1 mL). The organic portion was then dried over MgSO4, filtered, and evaporated to afford quenched with evaporated and the residue purified by silica gel flash chromatography with 100% EtOAc then 5% MeOH/EtOAc as eluant to afford product as an oil (65 mg, 72%). LC/MS (Method B) 2.57 min, [M+1]+ 452. Potency class ND.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5](=[CH:8][C:9]2[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=2)[O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=2)[CH2:4][CH2:3]1.[C:26]1([C:32]2[N:33]=[CH:34][C:35]([NH:38][C:39](=O)[O:40]C3C=CC=CC=3)=[N:36][CH:37]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(C(C)C)CC)(C)C>CS(C)=O>[C:26]1([C:32]2[N:33]=[CH:34][C:35]([NH:38][C:39]([N:2]3[CH2:7][CH2:6][C:5](=[CH:8][C:9]4[CH:25]=[CH:24][CH:23]=[C:11]([O:12][C:13]5[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][N:14]=5)[CH:10]=4)[CH2:4][CH2:3]3)=[O:40])=[N:36][CH:37]=2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C(Nc1cnc(-c2ccccc2)cn1)Oc1ccccc1
Reactant: FC(F)(F)c1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cnc(-c2ccccc2)cn1)N1CCC(=Cc2cccc(Oc3ccc(C(F)(F)F)cn3)c2)CC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 37.6 %

Procedure:
A solution of 2-(3-piperidin-4-ylidenemethyl-phenoxy)-5-trifluoromethyl-pyridine hydrochloride (0.371 g, 1.00 mmol) (from Example 1, Step 5) and phenyl 5-phenylpyrazin-2-ylcarbamate (0.291 g, 1.00 mmol) in DMSO (2.5 mL) was treated with diisopropylethylamine (0.155 g, 1.2 mmol) and heated to 60° C. After 3 h, the reaction mixture was partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted again with ethyl acetate. The combined organic layers were washed with brine and dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (10% of the 1N NH3 in MeOH, in dichloromethane) to afford the title compound (200 mg, 37%) as white crystals after trituration in diethyl ether. MS (APCI 10V) AP+ 532.25; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.34 (t, J=5.46 Hz, 2H) 2.46 (t, J=5.46 Hz, 2H) 3.46 (t, J=5.46 Hz, 2H) 3.50 (t, J=5.46 Hz, 2H) 6.37 (s, 1H) 6.69 (d, J=8.77 Hz, 1H) 7.01-7.03 (m, 2H) 7.10 (d, J=7.81 Hz, 1H) 7.19 (d, J=8.59, Hz, 1H) 7.35-7.39 (m, 2H) 7.43-7.47 (m, 2H) 8.02 (dd, J=7.03 Hz, 1.95 Hz, 2H) 8.17 (dd, J=8.78 Hz, 2.15 Hz, 1H) 8.53 (d, J=2.5 Hz, 1H) 8.85 (s, 1H) 9.04 (s, 1H) 9.63 (s, 1H).
Reaction SMILES: ClC1C=CC(C(=O)[CH2:7][CH:8]([CH3:11])[CH:9]=O)=CC=1.S(C1[CH:25]=[CH:24][C:22]([NH2:23])=CC=1)(=O)(=O)N>>[CH2:7]([N:23]([CH:22]=[CH:24][CH3:25])[CH2:9][CH:8]([CH3:7])[CH3:11])[CH:8]([CH3:11])[CH3:9]
Reactant: CC(C=O)CC(=O)c1ccc(Cl)cc1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Product: CC=CN(CC(C)C)CC(C)C

Procedure:
Following a procedure similar to that described in Example 64(iii), but using 2-(4-chlorophenacyl) propionaldehyde [prepared as described in step (ii) above] and 4-sulfamoylaniline as starting materials, the title compound was obtained as a pale brown powder (yield 35%), melting at 196-198° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[N:10]=[C:11]([N:20]3[CH2:26][CH2:25][C:24](=[O:27])[NH:23][CH2:22][CH2:21]3)[C:12]3[CH2:17][S:16](=[O:19])(=[O:18])[CH2:15][C:13]=3[N:14]=2)=[C:4]([F:28])[CH:3]=1.S(=O)(=O)(O)[OH:30]>>[ClH:1].[ClH:1].[NH2:23][CH2:22][CH2:21][N:20]([C:11]1[C:12]2[CH2:17][S:16](=[O:19])(=[O:18])[CH2:15][C:13]=2[N:14]=[C:9]([C:5]2[CH:6]=[C:7]([F:8])[C:2]([Cl:1])=[CH:3][C:4]=2[F:28])[N:10]=1)[CH2:26][CH2:25][C:24]([OH:27])=[O:30]
Reactant: O=S(=O)(O)O
Reactant: O=C1CCN(c2nc(-c3cc(F)c(Cl)cc3F)nc3c2CS(=O)(=O)C3)CCN1
Product: Cl
Product: NCCN(CCC(=O)O)c1nc(-c2cc(F)c(Cl)cc2F)nc2c1CS(=O)(=O)C2
Temperature: 100 °C
Reaction time: 27 h

Procedure:
A mixture of 321 mg of 1-[2-(4-chloro-2,5-difluorophenyl)-6,6-dioxido-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl]-1,4-diazepan-5-one and 10 ml of 5% sulfuric acid was stirred at 100° C. for 27 hours. After the solvent was distilled off under reduced pressure, 10 ml of dioxane, 10 ml of saturated aqueous sodium bicarbonate solution, and 0.18 g of DIBOC (tert-butoxycarbonyl anhydride) were added in turn to the residue obtained, and the mixture was stirred at ambient temperature for 1 hour. Precipitate was filtered, and the filtrate was evaporated under reduced pressure. The residue was dissolved in chloroform, washed with 5% aqueous citric acid solution and then water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and 4M HCl-dioxane solution was added to the residue, the resultant solution was stirred, and then the solvent was distilled off under reduced pressure. To the residue was added saturated aqueous sodium bicarbonate solution, the aqueous solution was washed with chloroform, added 5% aqueous citric acid, and extracted with chloroform. The organic extract was washed with water, and the solvent was distilled off under reduced pressure. The residue was dissolved in THF, here was added 4M HCl-dioxane solution, precipitate was collected by filtration to yield 92 mg of N-(2-aminoethyl)-N-[2-(4-chloro-2,5-difluorophenyl)-6,6-dioxido-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl]-β-alanine dihydrochloride as colorless solid.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:15]([NH:17][C@@H:18]([C:25]([NH2:27])=[O:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH2:11][C:12](=[O:14])[OH:13])=[O:8])[CH2:3][CH2:4][CH2:5][CH3:6].Cl.[NH:29]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[C@H:30]([C:41](ON1C(=O)CCC1=O)=[O:42])[CH2:31][C:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[NH:34][CH:33]=1.C(N(CC)CC)C>CN(C=O)C>[NH:29]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[C@H:30]([C:41]([NH:1][C@H:2]([C:7]([NH:9][C@H:10]([C:15]([NH:17][C@@H:18]([C:25]([NH2:27])=[O:26])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16])[CH2:11][C:12](=[O:13])[OH:14])=[O:8])[CH2:3][CH2:4][CH2:5][CH3:6])=[O:42])[CH2:31][C:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[NH:34][CH:33]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)ON1C(=O)CCC1=O
Reactant: CCCC[C@H](N)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](C(N)=O)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCC[C@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](C(N)=O)c1ccccc1
Yield: 97.5 %

Procedure:
1.57 g (3.78 mmoles of H-Nle-Asp-D-Phg-NH2.HCl are reacted with 1.52 g (3.78 mmoles) of BOC-Trp-OSu in 50 ml of DMF in the presence of 1.06 ml (7.6 mmoles) of triethylamine. Next day the reaction mixture is evaporated in vacuo, the residue is admixed with water, and the suspension is filtered. 2.45 g (97.5%) of BOC-Trp-Nle-Asp-D-Phg-NH2 are obtained; m.p.: 217° C. (decomposition), Rf5 :0.35, [α]D -32.7° (c: 1.0, in dimethyl formamide).
Reaction SMILES: C(O)(=O)C.[CH:5]([NH:8][C:9]1[N:14]=[CH:13][CH:12]=[CH:11][N:10]=1)([CH3:7])[CH3:6].[Br:15]N1C(=O)CCC1=O>O>[CH:5]([NH:8][C:9]1[N:14]=[CH:13][C:12]([Br:15])=[CH:11][N:10]=1)([CH3:7])[CH3:6]
Reactant: CC(C)Nc1ncccn1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Solvent: O
Product: CC(C)Nc1ncc(Br)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
75 ml of acetic acid, 13.7 g (0.1 mole) of 2-isopropylamino-pyrimidine and 17.8 g (0.1 mole) of N-bromosuccinimide are poured into a 1 liter reaction vessel. The reaction mixture is stirred for 1 hour at room temperature and then poured into iced water. The resultant precipitate is filtered off, washed with water and dried. 20 g (yield 92%) of the title compound was obtained as a white powder melting at 90° C. Elemental analysis showed that the compound had the expected empirical formula of C7H10N3Br.
Reaction SMILES: CCC(N[C:7]1[C:8]([N+]([O-])=O)=[CH:9][C:10](C)=[C:11](C)[C:12]=1[N+:13]([O-])=O)CC.CCCN(C1C([N+:34]([O-:36])=[O:35])=C(N)C(C(F)(F)F)=CC=1[N+]([O-])=O)CCC.CCCN(C1C([N+]([O-])=O)=CC(C(F)(F)F)=CC=1[N+:58]([O-:60])=[O:59])CCC>>[N+:34]([N:13]([N+:58]([O-:60])=[O:59])[C:12]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)([O-:36])=[O:35]
Reactant: CCC(CC)Nc1c([N+](=O)[O-])cc(C)c(C)c1[N+](=O)[O-]
Reactant: CCCN(CCC)c1c([N+](=O)[O-])cc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: CCCN(CCC)c1c([N+](=O)[O-])cc(C(F)(F)F)c(N)c1[N+](=O)[O-]
Product: O=[N+]([O-])N(c1ccccc1)[N+](=O)[O-]

Procedure:
pendimethalin, prodiamine, and trifluralin.
Reaction SMILES: C([O:4][C@H:5]1[C@H:10]([O:11]C(=O)C)[C@@H:9]([CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]3[C:32](=[O:33])[C:31]4[C:30]5[C:25](=[CH:26][C:27]([Br:34])=[CH:28][CH:29]=5)[NH:24][C:23]=4[C:22]([CH3:36])([CH3:35])[C:21]=3[CH:37]=2)[O:8][C@H:7]([O:38][CH3:39])[C@@H:6]1[O:40]C(=O)C)(=O)C.N>CO>[Br:34][C:27]1[CH:26]=[C:25]2[C:30]([C:31]3[C:32](=[O:33])[C:20]4[CH:19]=[CH:18][C:17]([O:16][CH2:15][C@@H:9]5[C@@H:10]([OH:11])[C@H:5]([OH:4])[C@@H:6]([OH:40])[C@@H:7]([O:38][CH3:39])[O:8]5)=[CH:37][C:21]=4[C:22]([CH3:36])([CH3:35])[C:23]=3[NH:24]2)=[CH:29][CH:28]=1
Reactant: CO[C@H]1O[C@H](COc2ccc3c(c2)C(C)(C)c2[nH]c4cc(Br)ccc4c2C3=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Agent: N
Solvent: CO
Product: CO[C@H]1O[C@H](COc2ccc3c(c2)C(C)(C)c2[nH]c4cc(Br)ccc4c2C3=O)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 21 h
Yield: 93.5 %

Procedure:
Under nitrogen atmosphere, to acetic acid (2S,3R,4S,5R,6R)-4,5-diacetoxy-6-(3-bromo-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-8-yl oxymethyl)-2-methoxy-tetrahydro-pyran-3-yl ester (Compound T12-1, 34.0 mg, 51.63 μmol), methanol solution (2.50 mL, 2 M) of ammonia was added, and the mixture was stirred at room temperature for 21 hr. The reaction solution was concentrated under reduced pressure, and the resulting resides were washed with diethyl ether to obtain the target compound (25.7 mg, 94%).
Reaction SMILES: C([Li])CCCCC.I[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[C:20]([CH:21]([CH3:23])[CH3:22])=[CH:19][C:18]([CH:24]([CH3:26])[CH3:25])=[CH:17][C:16]=1[CH:27]([CH3:29])[CH3:28].[P:30](Cl)([O:34]CC)[O:31][CH2:32][CH3:33].Cl>C1COCC1>[CH:21]([C:20]1[CH:19]=[C:18]([CH:24]([CH3:25])[CH3:26])[CH:17]=[C:16]([CH:27]([CH3:29])[CH3:28])[C:15]=1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[PH:30](=[O:34])[O:31][CH2:32][CH3:33])([CH3:22])[CH3:23]
Reactant: CCOP(Cl)OCC
Reactant: CC(C)c1cc(C(C)C)c(-c2ccccc2I)c(C(C)C)c1
Agent: Cl
Agent: [Li]CCCCCC
Solvent: C1CCOC1
Product: CCO[PH](=O)c1ccccc1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Temperature: -60 °C
Reaction time: 0.42 h
Yield: 94 %

Procedure:
A 1-L 3-neck round-bottom flask was fitted with an addition funnel and the atmosphere was purged with nitrogen. Anhydrous, degassed THF (170 mL) was added to the 1-L flask and cooled to −60° C. (internal temperature). The addition funnel was charged with hexyllithium (2.38 M in hexanes, 57 mL, 135 mmol, 2.0 equiv). The hexyllithium was transferred into the cold THF over 20 min, maintaining the temperature below −40° C. The solution was re-cooled to −60° C. (internal temperature). A solution of 2′-iodo-2,4,6-triisopropylbiphenyl (27.5 g, 67.7 mmol, 1.0 equiv) in 170 mL of anhydrous, degassed THF was transferred, via cannula, drop wise to the n-hexyllithium solution. This was done over 25 min while maintaining the temperature below −40° C. After addition, the reaction mixture was allowed to stir at −60° C. for 30 min. Diethyl chlorophosphite (19.62 mL, 135 mmol, 2.0 equiv) was added to the reaction mixture, over 10 min while maintaining the temperature below −40° C. After addition of diethyl chlorophosphite, the reaction was allowed to proceed at −60° C. for an additional 30 min. Aqueous hydrochloric acid (1 M, 338 mL, 338 mmol) was added at −60° C. The flask was removed from the cold bath and the reaction was allowed to warm to 22° C. The resultant solution was diluted with heptane (340 mL) and transferred to a separatory funnel The layers were separated and the organic layer was assayed for product by quantitative HPLC (94% yield). The organic layer was concentrated under reduced pressure to give an oil which was used in the next reaction without further purification.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[C:9]([CH3:11])[C:8]([CH3:12])=[CH:7][C:5]=2[N:6]=1.[Cl-].[CH2:14]([O:21][C:22]([C@@H:24]1[CH2:29][CH2:28][CH2:27][CH2:26][NH2+:25]1)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH3:12][C:8]1[C:9]([CH3:11])=[CH:10][C:4]2[O:3][C:2]([N:25]3[CH2:26][CH2:27][CH2:28][CH2:29][C@H:24]3[C:22]([O:21][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:23])=[N:6][C:5]=2[CH:7]=1
Reactant: Cc1cc2nc(Cl)oc2cc1C
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCC[NH2+]1
Agent: [Cl-]
Product: Cc1cc2nc(N3CCCC[C@H]3C(=O)OCc3ccccc3)oc2cc1C

Procedure:
The title compound was prepared by a similar method to Preparation 2 from 2-chloro-5,6-dimethyl-1,3-benzoxazole [see J.Med. Chem. (1972), 15, 523-9] and (2S)-2-[(benzyloxy)carbonyl]piperidine [see EP 530167 A1 930303]. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 100:0 changing to 80:20, by volume, hexane:ethyl acetate to afford benzyl (2S)-1-[5,6-dimethyl-1,3-benzoxazol-2-yl]-2-piperidinecarboxylate as a yellow coloured solid.
Reaction SMILES: [O:1]1[CH2:20][CH:2]1[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:14]3[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=3[O:12][N:11]=2)[CH2:6][CH2:5]1.[F:21][C:22]1[CH:36]=[CH:35][C:25]2[C:26]([CH:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[N:27][O:28][C:24]=2[CH:23]=1.[ClH:37]>C(O)(C)C.C(O)C>[ClH:37].[ClH:37].[F:19][C:17]1[CH:16]=[CH:15][C:14]2[C:10]([CH:7]3[CH2:8][CH2:9][N:4]([CH2:3][CH:2]([OH:1])[CH2:20][N:32]4[CH2:31][CH2:30][CH:29]([C:26]5[C:25]6[CH:35]=[CH:36][C:22]([F:21])=[CH:23][C:24]=6[O:28][N:27]=5)[CH2:34][CH2:33]4)[CH2:5][CH2:6]3)=[N:11][O:12][C:13]=2[CH:18]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: Fc1ccc2c(C3CCN(CC4CO4)CC3)noc2c1
Agent: Cl
Solvent: CC(C)O
Solvent: CCO
Product: OC(CN1CCC(c2noc3cc(F)ccc23)CC1)CN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 65 °C
Reaction time: 16 h

Procedure:
A stirred mixture of 1-(2,3-epoxypropyl)-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (1.19 g, 4.3 mmol) and 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (0.95 g, 4.3 mmol) in isopropyl alcohol (50 ml) was heated at reflux for 1 hour, then stirred at 65° C. for 16 hours. The solvent was removed on a rotary evaporator. The solid residues were purified by flash chromatography over a silica gel column (SiO2, 35 g: eluted with methylene chloride, DCM, and CH3OH in DCM). The product thus obtained, weighed 2.55 g. This material was dissolved in ethanol and was treated with a solution of HCl (1M in ether). The salt collected weighed 2.35 g, m.p. >270° C. dec.
Reaction SMILES: Cl.[OH:2][CH:3]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4]1.Cl[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].C(N(CC)CC)C>O1CCOCC1.O>[CH2:13]([O:12][C:10]([N:5]1[CH2:6][CH2:7][CH2:8][CH:3]([OH:2])[CH2:4]1)=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OC1CCCNC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CCCC(O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-hydroxypiperidine hydrochloride (20.0 g, 0.145 mol) in dioxane (500 ml) and water (500 ml) was added benzyl chloroformate (24.88 ml, 0.17 mol) and triethylamine (101 ml, 0.73 mol). The mixture was stirred at room temperature overnight. The reaction mixture was extracted with ether and the organic layer was washed with brine, dried over magnesium sulfate and concentrated. The crude product was purified through chromatography on silica gel (eluent: 1:1 ethyl acetate/hexane) and the title compound was obtained as a pale yellow viscous oil (20.7 g, 88 mmol, yield 61%).
Reaction SMILES: Cl.[NH2:2][OH:3].[S:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[S:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][C@@H:15]([CH2:18][CH2:19][C:20](=O)[C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[C:28]([O:31][CH3:32])[CH:29]=3)[N:24]=[CH:23][CH:22]=2)[C@@H:14]([C:34]([O:36][CH3:37])=[O:35])[CH2:13]1>N1C=CC=CC=1.O>[S:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[S:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][C@@H:15]([CH2:18][CH2:19][C:20](=[N:2][OH:3])[C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[C:28]([O:31][CH3:32])[CH:29]=3)[N:24]=[CH:23][CH:22]=2)[C@@H:14]([C:34]([O:36][CH3:37])=[O:35])[CH2:13]1
Reactant: NO
Reactant: COC(=O)[C@H]1CN(CCSc2cccs2)CC[C@H]1CCC(=O)c1ccnc2ccc(OC)cc12
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)[C@H]1CN(CCSc2cccs2)CC[C@H]1CCC(=NO)c1ccnc2ccc(OC)cc12
Temperature: 20 °C
Reaction time: 1 h
Yield: 7.6 %

Procedure:
0.32 g of hydroxylamine hydrochloride is added, with stirring and under an inert atmosphere, to a mixture of 1.27 g of methyl (3R,4R)-1-[2-(thien-2-ylthio)ethyl]-4-[3-oxo-3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-carboxylate in 13 cm3 of pyridine at a temperature in the region of 20° C. The mixture is stirred for 1 hour at a temperature in the region of 20° C. The resulting reaction mixture is diluted with 130 cm3 of distilled water and the mixture thus obtained is extracted with 50 cm3 of ethyl acetate and then two times with 30 cm3 of ethyl acetate. The combined organic phases are washed two times with 50 cm3 of distilled water, dried over magnesium sulfate and then concentrated to dryness under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residue is purified by chromatography under a pressure of 50 kPa of nitrogen on a column of silica gel (particle size 20-45μ; weight of silica 160 g, diameter of the column 3.5 cm), elution being carried out with a mixture of ethyl acetate and cyclohexane (90/10 by volume). Fractions 20 to 22 are combined and then concentrated to dryness under the above conditions. 0.1 g of methyl (3R,4R)-1-[2-(thien-2-ylthio)ethyl]-4-[3-hydroxyimino-3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-carboxylate is obtained.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[CH:9]([CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:18][CH2:17]1)[CH2:8][CH2:7]2.CI.[CH3:30]CN(CC)CC.Cl>C1COCC1>[ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[C:9]([CH3:30])([CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:18][CH2:17]1)[CH2:8][CH2:7]2
Reactant: COc1ccc2c(c1)CCC(CN1CCC(c3ccccc3)CC1)C2=O
Reactant: CCN(CC)CC
Agent: Cl
Solvent: CI
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CCC(C)(CN1CCC(c3ccccc3)CC1)C2=O
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
To a solution of the title compound of Example 1 (379 mg, 1.084 mmol, free base) in THF (10 mL) at -78° C. under nitrogen with stirring was added a solution of KN(SiMe3)2 (0.5 M in toluene, 2.39 mL, 1.19 mmol). The reaction mixture was stirred at -78° C. for 5 minutes followed by the addition of methyl iodide (0.223 mL, 3.58 mmol). The mixture was stirred at -78° C. for another 15 minutes, then kept at -16° C. for 0.5 hours followed by the addition of Et3N (0.832 mL, 5.96 mmol). The mixture was quenched with saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated to afford a thick gummy residue. This was converted to its hydrochloride by treatment with hydrochloric to afford the title compound as a white solid, mp 185-186° C.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[C:4]([CH:13]=O)=[CH:3]1.C(O)(=O)[CH2:16][C:17]([OH:19])=[O:18]>N1C=CC=CC=1.N1CCCCC1>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[C:4](/[CH:13]=[CH:16]/[C:17]([OH:19])=[O:18])=[CH:3]1
Reactant: O=C(O)CC(=O)O
Reactant: Cn1cc(C=O)c(=O)c2ccccc21
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: Cn1cc(/C=C/C(=O)O)c(=O)c2ccccc21

Procedure:
A mixture of 1-methyl-3-formyl-4(1H)-quinolone (5.61 g) and malonic acid (4.5 g) in pyridine (45 ml) with 3 drops piperidine was heated on a steam-bath for two hours. The pyridine was removed in vacuo and the solid residue washed with water and dried. Recrystallisation from DMF/H2O gave the title compound. NMR confirmed the structure as pure trans-isomer, m.p. 248°-250° (with decomposition).
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH3:9])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[C:10]([O:14][CH3:15])(=[O:13])[CH:11]=[CH2:12]>C1CCN2C(=NCCC2)CC1.C1CCCCC1>[CH3:15][O:14][C:10](=[O:13])[CH2:11][CH2:12][C:3]([C:4]([O:6][CH3:7])=[O:5])([C:2](=[O:1])[CH2:8][CH3:9])[CH2:2][CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: C=CC(=O)OC
Reactant: CCC(=O)CC(=O)OC
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCCCC1
Product: CCC(=O)C(CCC(=O)OC)(CCC(=O)OC)C(=O)OC
Temperature: 60 °C
Reaction time: 2 h
Yield: 129 %

Procedure:
39.9 g (0.31 mol) of methyl 3-oxo-pentanoate and 1.9 g (0.012 mol) of DBU were mixed at room temperature in a three necked round bottom flask, equipped with a dropping funnel and a reflux condenser. 66.4 g (0.77 mol) of methyl acrylate was slowly added drop by drop. After the exothermal behavior has leveled off, the reaction mixture was stirred at 60° C. for an additional two hours. Cyclohexane was added and the mixture was washed with diluted hydrochloric acid and was subsequently washed with distilled water until the aqueous layer showed a neutral reaction. The organic layer was dried over sodium sulfate, the solvent was removed, and the addition product was isolated by fractional distillation in a vacuum. 21.4 g (0.20 mol) of 4-(methoxycarbonyl)-4-(1-oxopropyl)-heptanedioic acid 1,7-dimethyl ester was obtained (yield: 64%; boiling temperature: 130° C. at 0.02 mbar; colorless).