Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC1C=C(C(F)(F)F)C=C(F)[C:3]=1[OH:13].[N+:14]([C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=1Cl)([O-:16])=[O:15].C[O-].[Na+]>>[N+:14]([C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=1[O:13][CH3:3])([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Reactant: Nc1cc(C(F)(F)F)cc(F)c1O
Agent: C[O-]
Agent: [Na+]
Product: COc1ccc(C(F)(F)F)cc1[N+](=O)[O-]

Procedure:
The 2-amino-4-trifluoromethylphenols (XI) required for the reaction sequence just described may be prepared by conventional methods. Thus, 2-amino-6-fluoro-4-trifluoromethylphenol may be prepared from 2-nitro-4-trifluoromethylchlorobenzene by reacting the latter with sodium methoxide to give 2-nitro-4-trifluoromethylanisole, and reducing this compound to 2-amino-4-trifluoromethylanisole. The latter compound may be diazotised and converted to its fluoborate salt and heated to give 2-fluoro-4-trifluoromethylanisole. This may then be nitrated to form 2-fluoro-6-nitro-4-trifluoromethylanisole, which is then reduced to give 2-amino-6-fluoro-4-trifluoromethylanisole. Finally the latter compound is heated with a demethylating agent, for example an excess of pyridine hydrochloride to give 2-amino-6-fluoro-4-trifluoromethylphenol.
Reaction SMILES: [C:1]([NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[CH:20][C:21]([N:24]4[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]4)=[N:22][CH:23]=3)=[C:14]([F:37])[CH:13]=2)[CH2:7]1)(=[O:3])[CH3:2]>C(Cl)Cl.FC(F)(F)C(O)=O>[F:37][C:14]1[CH:13]=[C:12]([N:8]2[CH2:7][C@H:6]([CH2:5][NH:4][C:1](=[O:3])[CH3:2])[O:10][C:9]2=[O:11])[CH:17]=[CH:16][C:15]=1[C:18]1[CH:23]=[N:22][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(-c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)nc3)c(F)c2)C(=O)O1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(-c3ccc(N4CCNCC4)nc3)c(F)c2)C(=O)O1
Yield: 97.5 %

Procedure:
A solution of tert-butyl 4-[5-(4-{(5S)-5-[(acetylamino)methyl]-2-oxo-1,3-oxazolidin-3-yl}-2-fluorophenyl)-2-pyridinyl]-1-piperazinecarboxylate (0.191 g, 0.372 mmol) in DCM (10 mL) and trifluoroacetic acid (10 mL) was stirred at room temperature for 3 h. The solvent was removed in vacuo and the residue was partitioned between EtOAc and 1 M NaOH solution. The organic layer was dried and evaporated to give the titled compound (0.150 g, 98%) as a colourless foam. APCI MS m/z 414 (M+H). 1H NMR (400 MHz, DMSO-d6) δ 8.30 (s, 1H), 8.22 (t, J=5.8 Hz, 1H), 7.72 (bdt, J=9.0, 2.1 Hz, 1H), 7.52-7.60 (m, 2H), 7.38 (dd, J=8.6, 2.1 Hz, 1H), 6.89 (d, J=9.0 Hz, 1H), 4.72-4.80 (m, 1H), 4.16 (t, J=9.0 Hz, 1H), 3.78 (dd, J=9.1, 6.7 Hz, 1H), 3.41-3.51 (m, 6H), 2.80-2.85 (m, 4H), 1.84 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][N:10]1[C:18]2[C:17](Cl)=[N:16][CH:15]=[N:14][C:13]=2[CH:12]=[CH:11]1)([CH3:4])([CH3:3])[CH3:2].[CH3:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[O:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=1)[NH2:25].C(O)(C)C>C(OCC)(=O)C>[CH3:21][C:22]1[CH:23]=[C:24]([NH:25][C:17]2[C:18]3[N:10]([CH2:9][CH2:8][NH:7][C:6](=[O:20])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH:11]=[CH:12][C:13]=3[N:14]=[CH:15][N:16]=2)[CH:26]=[CH:27][C:28]=1[O:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:37])([F:38])[F:39])[CH:31]=1
Reactant: CC(C)(C)OC(=O)NCCn1ccc2ncnc(Cl)c21
Reactant: Cc1cc(N)ccc1Oc1cccc(C(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: Cc1cc(Nc2ncnc3ccn(CCNC(=O)OC(C)(C)C)c23)ccc1Oc1cccc(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
A mixture of tert-butyl[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]carbamate (297 mg), 3-methyl-4-[3-(trifluoromethyl)phenoxy]aniline (401 mg) and isopropyl alcohol (2.97 mL) was stirred at 80° C. for 16 hrs. The reaction mixture was diluted with ethyl acetate (80 mL), and washed with aqueous sodium hydrogen carbonate (30 mL). The organic layer was separated, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10→0/100) to give the title compound (528 mg) as a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C@@H:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]2[C:14]([OH:16])=[O:15])=[O:7])=[CH:4][CH:3]=1.[CH3:19][Si:20]([CH3:25])([CH3:24])[CH2:21][CH2:22]O.CCN=C=NCCCN(C)C.O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C@@H:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]2[C:14]([O:16][CH2:22][CH2:21][Si:20]([CH3:25])([CH3:24])[CH3:19])=[O:15])=[O:7])=[CH:17][CH:18]=1
Reactant: C[Si](C)(C)CCO
Reactant: O=C(O)[C@@H]1CCCC[C@H]1C(=O)c1ccc(Br)cc1
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: ClCCl
Product: C[Si](C)(C)CCOC(=O)[C@@H]1CCCC[C@H]1C(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 36.9 %

Procedure:
To a solution of trans-2-(4-bromobenzoyl)cyclohexanecarboxylic acid (5.0 g, 16.07 mmol) in DCM (80 mL) was added 2-(trimethylsilyl)ethanol (2.1 g, 17.68 mmol), N,N′-dimethylamino-pyridine (98 mg, 0.80 mmol), and EDCI (4.0 g, 20.89 mmol). The resulting reaction mixture was stirred at rt for 2 days. Water was added, and the mixture was diluted with DCM. The aqueous layer was separated and extracted with DCM. The combined organic phases were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Silica gel chromatography (Biotage cartridge), eluting with 10% EtOAc in hexane gave trans-(trimethylsilyl)ethyl 2-(4-bromobenzoyl)cyclohexanecarboxylate (2.44 g, 37%). 1H NMR (400 MHz, CD2Cl2) δ −0.01 (s, 9H), 0.85 (m, 2H), 1.45 (m, 3H), 1.73 (m, 2H), 1.90 (m, 2H), 2.18 (m, 1H), 2.71 (m, 1H), 3.80 (m, 1H), 4.05 (m, 2H), 7.58 (d, 2H), 7.70 (d, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)[N:5]=[N:4][C:3]=1[NH2:24].[Cl:25][C:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:27]=1[S:36](Cl)(=[O:38])=[O:37]>>[Cl:25][C:26]1[CH:31]=[C:30]([C:32]([F:34])([F:33])[F:35])[CH:29]=[CH:28][C:27]=1[S:36]([NH:24][C:3]1[N:4]=[N:5][C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([N:18]3[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]3)(=[O:16])=[O:17])=[CH:11][CH:10]=2)=[CH:7][C:2]=1[CH3:1])(=[O:38])=[O:37]
Reactant: Cc1cc(Sc2ccc(S(=O)(=O)N3CCCCC3)cc2)nnc1N
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1Cl
Product: Cc1cc(Sc2ccc(S(=O)(=O)N3CCCCC3)cc2)nnc1NS(=O)(=O)c1ccc(C(F)(F)F)cc1Cl

Procedure:
Can be prepared from 4-methyl-6-[4-(piperidine-1-sulfonyl) -phenylsulfanyl]-pyridazin-3-ylamine and 2-chloro-4-trifluoromethylbenzenesulfonyl chloride. 1H NMR (CDCl3) 8.30 (1H, d) 7.75 (2H, m) 7.70(1H, s) 7.6(3H, m) 7.05(1H, s) 3.0 (4H, m) 2.1 (3H, s) 1.6(4H, m) 1.40(2H, m) LCMS Polarity/Scan type: Negative Q1 Scan. M.wt. 605 (—H), 607 (—H). Retention time 7.39 minutes. HPLC MS8 Retention time 5.36 minutes.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]([NH2:16])[CH3:15])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:18][C:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26]Br.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([CH:14]([N:16]2[CH2:26][C:21]3[C:20](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:19]2=[O:18])[CH3:15])=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(N)c1ccc(Oc2ccccc2)cc1
Reactant: COC(=O)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(c1ccc(Oc2ccccc2)cc1)N1Cc2ccccc2C1=O
Reaction time: 16 h
Yield: 44.3 %

Procedure:
A mixture of 1-(4-phenoxyphenyl)ethylamine (213 mg, 1 mmol), 2-bromomethyl-benzoic acid methyl ester (250 mg, 1.1 mmol), and K2CO3 (1 g, 7.2 mmol) in toluene (10 mL) was heated at reflux with stirring for 16 h. Workup and silica gel column chromatography using a gradient of hexanes to 30% ethyl acetate in hexanes afforded 2-[1-(4-phenoxyphenyl)-ethyl]-2,3-dihydroisoindol-1-one (146 mg, 44%). GC/MS gave: m/z (rel.int.) 329 (M+, 46), 314 (100), 196 (8) and 77 (8). 1H NMR (300 MHz, CDCl3): δ 1.68 (d, 3H), 4.03 (d, 1H), 4.34 (d, 1H), 5.80 (q, 1H), 6.98 (br t, 4H), 7.10 (t, 1H), 7.49 (dt, 2H), 7.33 (br m, 5H), 7.88 (dd, 1H).
Reaction SMILES: N1C=CC=CC=1.[Cl:7][C:8]1[C:14]([CH3:15])=[CH:13][CH:12]=[C:11]([Cl:16])[C:9]=1[NH2:10].[C:17]([NH:20][C:21]1[NH:25][N:24]=[C:23]([S:26](Cl)(=[O:28])=[O:27])[N:22]=1)(=[O:19])[CH3:18].[OH-].[Na+]>C(Cl)Cl>[Cl:7][C:8]1[C:14]([CH3:15])=[CH:13][CH:12]=[C:11]([Cl:16])[C:9]=1[NH:10][S:26]([C:23]1[N:22]=[C:21]([NH:20][C:17](=[O:19])[CH3:18])[NH:25][N:24]=1)(=[O:27])=[O:28]
Reactant: CC(=O)Nc1nc(S(=O)(=O)Cl)n[nH]1
Reactant: Cc1ccc(Cl)c(N)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1nc(S(=O)(=O)Nc2c(Cl)ccc(C)c2Cl)n[nH]1
Reaction time: 3.5 h
Yield: 60 %

Procedure:
A 250 ml, 1-necked flask equipped with a magnetic stirrer and filled with nitrogen gas was charged with 15 ml of dry pyridine and 8.8 g (0.05 mole) of 2,6-dichloro-3-methylaniline. To the stirred solution was added 11.3 g (0.05 mole) of crude 5-acetylamino-3-chlorosulfonyl-1,2,4-triazole over 10-30 minutes. The resulting dark green mixture, which had a mild exotherm during the addition, was heated to 100°-105° C. with stirring for 3-4 hours. It was then dispersed between a mixture of methylene chloride and dilute aqueous sodium hydroxide and the organic layer was removed. Acidification of the aqueous phase and filtraton and drying of the precipitate that formed gave the title sulfonamide as a tan solid melting at 284° (dec.). The yield was 60 percent of theory. A sample of this compound which was recrystallized from a mixture of methanol and water was a pale ivory powder melting at 285°-285.5° C. (dec.) and had the following elemental analysis:
Reaction SMILES: O.C1(C)C=CC(C([C@](C(O)=O)(O)[C@](C(C2C=CC(C)=CC=2)=O)(O)C(O)=O)=O)=CC=1.[CH2:30]([N:33]1[C:37]([CH2:38][S@@:39]([C:41]2[CH:47]=[CH:46][C:44]([NH2:45])=[CH:43][CH:42]=2)=[O:40])=[CH:36][N:35]=[CH:34]1)[CH2:31][CH3:32]>C(OCC)(=O)C>[CH2:30]([N:33]1[C:37]([CH2:38][S:39]([C:41]2[CH:42]=[CH:43][C:44]([NH2:45])=[CH:46][CH:47]=2)=[O:40])=[CH:36][N:35]=[CH:34]1)[CH2:31][CH3:32]
Reactant: CCCn1cncc1C[S@](=O)c1ccc(N)cc1
Agent: Cc1ccc(C(=O)[C@@](O)(C(=O)O)[C@](O)(C(=O)O)C(=O)c2ccc(C)cc2)cc1
Solvent: O
Solvent: CCOC(C)=O
Product: CCCn1cncc1CS(=O)c1ccc(N)cc1

Procedure:
(S)-4-(((1-propylimidazol-5-yl)methyl)sulfinyl)aniline di-p-toluoyl-D-tartrate monohydrate (479 mg) was dissolved in ethyl acetate (5 ml) and 1 N hydrochloric acid (2.44 ml), followed by separation. To the aqueous layer was added an aqueous 25% potassium carbonate solution (2.44 ml), followed by extraction with 2-propanol-ethyl acetate (1:4) twice. The organic layers were combined, washed with saturated brine and dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. To the resulting residue was added tetrahydrofuran, and then the solvent was again distilled off under reduced pressure-to give (S)-(4-(((1-propylimidazol-5-yl)methyl)sulfinyl)aniline. Then, to a solution of 3-[4-(2-butoxyethoxy)phenyl]-10-isobutyl-7,8,9,10-tetrahydropyrido[2,3-b]azocine-6-carboxylic acid (250 mg) in dichloromethane (10 ml) were added a drop of DMF, and then oxalyl chloride (0.063 ml) at 0° C. The mixture was returned to room temperature and stirred for 30 minutes under a nitrogen atmosphere, and then the resulting solution was added dropwise to a solution of (S)-4-(((1-propylimidazol-5-yl)methyl)sulfinyl)aniline and pyridine (1.16 ml) in tetrahydrofuran (10 ml) at 0° C. under a nitrogen atmosphere. The mixture was returned to room temperature and stirred overnight. Then, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water twice and saturated brine once, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the residue was separated and purified by basic silica gel column chromatography (ethyl acetate→methanol:ethyl acetate=3:100) to give (S)-3-[4-(2-butoxyethoxy)phenyl]-10-isobutyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]-7,8,9,10-tetrahydropyrido[2,3-b]azocine-6-carboxamide (294 mg) (Compound 1) as a yellow amorphous material.
Reaction SMILES: Br.[N+:2]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[N:9]([CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[C:8]2=[O:22])([O-:4])=[O:3].Cl[C:24]1[C:33]2[C:28](=[CH:29][C:30]([O:36][CH3:37])=[C:31]([O:34][CH3:35])[CH:32]=2)[N:27]=[CH:26][N:25]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:35][O:34][C:31]1[CH:32]=[C:33]2[C:28](=[CH:29][C:30]=1[O:36][CH3:37])[N:27]=[CH:26][N:25]=[C:24]2[N:19]1[CH2:18][CH2:17][CH:16]([N:9]2[C:8](=[O:22])[C:7]3[C:12](=[CH:13][CH:14]=[C:5]([N+:2]([O-:4])=[O:3])[CH:6]=3)[NH:11][C:10]2=[O:15])[CH2:21][CH2:20]1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: O=c1[nH]c2ccc([N+](=O)[O-])cc2c(=O)n1C1CCNCC1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2ncnc(N3CCC(n4c(=O)[nH]c5ccc([N+](=O)[O-])cc5c4=O)CC3)c2cc1OC
Temperature: 80 °C

Procedure:
In 150 ml of DMF was dissolved 3.0 g (8.09 mmol) of 1,2,3,4-tetrahydro-6-nitro-2, 4-dioxo-3-(4-piperidinyl)quinazoline hydrobromide, and 1.7 g (8.09 mmol) of 4-chloro6,7-dimethoxyquinazoline and 1.1 g (24 mmol) of potassium carbonate were added to the solution, followed by heating at 80° C. for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with an aqueous solution of sodium chloride and dried. After the solvent was distilled off, ethanol and ether were added to the residue. The precipitated crystals were collected by filtration and washed with ether to give 3.28 g (yield: 8=%) of Compound 24 as white crystals 1H-HMR (DMSO-d6) δ (ppm) 12.01 (s, 1H, NH), 8.67 (d, 1H, J=2.5 Hz), 8.55 (s, 1H), 8.45 (dd, 1H, J=9.0, 2.5 Hz), 7.34 (d, 1H, J=9.0 Hz), 7.23 (s, 1H), 7.15 (s, 1H), 5.09-5.04 (m, 1H), 4.37-4.32 (br.-d, 2H), 3.95 (s, 3H), 3.93 (s, 3H), 3.27-3.23 (br.-t, 2H), 2.87-2.78 (m, 2H), 1.81-1.77 (br.-d, 2H).
Reaction SMILES: Cl.[CH3:2][O:3][NH:4][CH3:5].[Cl:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1>[OH-].[Na+].ClCCl>[Cl:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([N:4]([CH3:5])[O:3][CH3:2])=[O:12])=[CH:9][CH:8]=1
Reactant: CNOC
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 95 %

Procedure:
To a solution 11.38 gm (116.7 mMol) N-methoxy-N-methyl amine hydrochloride in 700 mL 1N sodium hydroxide was added a solution of 18.56 gm (106.04 mMol) 4-chlorobenzoyl chloride in 200 mL dichloromethane and the mixture was stirred at ambient temperature. After 18 hours the phases were separated and the remaining aqueous was extracted well with dichloromethane. All organic phases are combined, dried over sodium sulfate and concentrated under reduced pressure to give 27.9 gm (95%) of the title compound as a clear oil.
Reaction SMILES: [O:1]=[C:2]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=1)[CH2:3][C:4]([O:6]CC)=[O:5].C[O-].[Na+].CO[CH:25]=[CH:26][C:27](=O)[CH3:28].[OH-].[Na+]>CCO.O>[CH3:25][C:26]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:17])([F:18])[F:19])[CH:11]=2)[C:2](=[O:1])[C:3]([C:4]([OH:6])=[O:5])=[CH:28][CH:27]=1
Reactant: CCOC(=O)CC(=O)Nc1cccc(C(F)(F)F)c1
Reactant: COC=CC(C)=O
Agent: C[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccc(C(=O)O)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.7 %

Procedure:
To a solution of ethyl 3-oxo-3-{[3-(trifluoromethyl)phenyl]amino}propanoate (19.2 g, 70 mmol) and sodium methoxide (7.6 g, 140 mmol) in EtOH (250 ml) was added 4-methoxybut-3-en-2-one (90%) (7.72 g, 77 mmol). After the addition, the reaction mixture was refluxed for 2 h and then cooled. Water (50 ml) and 2M NaOH were added and the mixture was stirred at room temperature overnight. The organic solvents were removed and the reaction mixture was extracted (washed) with EtOAc. The water phases were acidified with hydrochloric acid to pH 3-4, an orange coloured precipitate appeared and was filtered off, washed with water and dried. Recrystallisation twice from heptane/EtOAc (4:1) afforded the title compound (12 g, 58%) as a white powder.
Reaction SMILES: [CH2:1]([NH:4][CH:5]1[CH2:13][CH2:12][C:8]2[N:9]=[CH:10][S:11][C:7]=2[CH2:6]1)[CH2:2][CH3:3].[O:14]=[C:15]([N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:23][CH2:22]1)[CH2:16][CH2:17][CH2:18][CH:19]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:27]1([N:24]2[CH2:25][CH2:26][N:21]([C:15](=[O:14])[CH2:16][CH2:17][CH2:18][CH2:19][N:4]([CH2:1][CH2:2][CH3:3])[CH:5]3[CH2:13][CH2:12][C:8]4[N:9]=[CH:10][S:11][C:7]=4[CH2:6]3)[CH2:22][CH2:23]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCCNC1CCc2ncsc2C1
Reactant: O=CCCCC(=O)N1CCN(c2ccccc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCCN(CCCCC(=O)N1CCN(c2ccccc2)CC1)C1CCc2ncsc2C1
Reaction time: 8 h
Yield: 67 %

Procedure:
A solution of 395 mg (2 mmol) propyl-(4,5,6,7-tetrahydro-benzothiazol-6-yl)-amine and 781 mg (3 mmol) 5-oxo-5-(4-phenylpiperazin-1-yl)pentanal in 1,2-dichloroethane (20 mL) is stirred for about 30 minutes. Then 0.75 g (3 mmol) of sodium triacetoxyborohydride is added and the mixture is stirred overnight. After hydrolysation with 30 mL of 1N aqueous NaOH solution the organic phase is separated, dried over sodium sulfate and concentrated in vacuum. The crude product obtained is purified via column chromatography on silica gel.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:24]=[C:23]3[C:19]([CH2:20][N:21]([C@@H:26]([CH:31]([CH3:33])[CH3:32])[C:27]([O:29][CH3:30])=[O:28])[C:22]3=[O:25])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1.[O:59](C1C=CC=CC=1C(Cl)=O)[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1>>[CH3:32][CH:31]([CH3:33])[C@H:26]([N:21]1[CH2:20][C:19]2[C:23](=[CH:24][C:16]([C:13]3[CH:12]=[CH:11][C:10]([NH:9][C:1](=[O:8])[C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=4[O:59][C:60]4[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=4)=[CH:15][CH:14]=3)=[CH:17][CH:18]=2)[C:22]1=[O:25])[C:27]([O:29][CH3:30])=[O:28]
Reactant: O=C(Cl)c1ccccc1Oc1ccccc1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4Oc4ccccc4)cc3)cc2C1=O
Yield: 92 %

Procedure:
The compound of example 151 was prepared analogous to compound of example 97 by reaction of compound of example 6 with 2-phenoxy benzoyl chloride.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:13])=[C:4]([CH:8]=[C:9]([F:12])[C:10]=1[F:11])[C:5]([OH:7])=[O:6].[N+:14]([O-])([OH:16])=[O:15]>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:3]([F:13])=[C:4]([C:8]([N+:14]([O-:16])=[O:15])=[C:9]([F:12])[C:10]=1[F:11])[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1cc(F)c(F)c(Cl)c1F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C(O)c1c(F)c(Cl)c(F)c(F)c1[N+](=O)[O-]
Temperature: 60 °C

Procedure:
To a solution of 42.1 g (200 mmol) of 3-chloro-2,4,5-trifluorobenzoic acid (E.P.O. No. 0 183 129) in 100 ml of sulfuric acid was added concentrated nitric acid (50 ml) dropwise such that the reaction temperature stayed below 40° C. The reaction mixture was heated at 60° C. for 18 hours, then poured cautiously onto 500 g of ice water. The aqueous solution was extracted with ether, and the ether extracts were washed with water, dried over magnesium sulfate, and concentrated to give 26.5 g of 3-chloro-2,4,5-trifluoro-6-nitrobenzoic acid.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[CH3:24][O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[C:28]([CH3:35])[CH:27]=1>>[CH3:24][O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH:1][CH2:2][C@H:3]2[N:8]([C:9]([C:11]3[N:12]=[C:13]([CH3:23])[S:14][C:15]=3[C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)=[O:10])[CH2:7][C@H:6]3[C@@H:4]2[CH2:5]3)=[O:31])=[C:28]([CH3:35])[CH:27]=1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Reactant: COc1ccc(C(=O)O)c(C)c1
Product: COc1ccc(C(=O)NC[C@@H]2[C@H]3C[C@H]3CN2C(=O)c2nc(C)sc2-c2cccc(C)c2)c(C)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 4-Methoxy-2-methyl-benzoic acid. LC-MS (basic): tR=0.90 min; [M+H]+=476.2.
Reaction SMILES: Cl.[OH:2][C@H:3]1[CH2:13][N:6]2[C:7](=[O:12])[CH2:8][CH2:9][NH:10][CH2:11][C@@H:5]2[CH2:4]1.Br[C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][N:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>CS(C)=O>[OH:2][C@H:3]1[CH2:13][N:6]2[C:7](=[O:12])[CH2:8][CH2:9][N:10]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][N:16]=3)[CH2:11][C@@H:5]2[CH2:4]1
Reactant: O=C1CCNC[C@@H]2C[C@@H](O)CN12
Reactant: FC(F)(F)c1ccc(Br)nc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C1CCN(c2ccc(C(F)(F)F)cn2)C[C@@H]2C[C@@H](O)CN12
Temperature: 100 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
A mixture of (8R,9aS)-8-hydroxyoctahydro-5H-pyrrolo[1,2-a][1,4]diazepin-5-one hydrochloride (90 mg, 0.435 mmol, Part A), 2-bromo-5-(trifluoromethyl)pyridine (148 mg, 0.635 mmol) and sodium carbonate (138 mg, 1.306 mmol) in dimethyl sulfoxide (0.4 mL) was stirred at 100° C. overnight. The mixture was purified by chromatography on silica gel (ethyl acetate/methanol=15:1) to give 135 mg (98% yield) of the titled compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.77 (m, 1H), 2.09 (m, 1 H), 2.50-2.66 (m, 2 H), 3.08 (m, 1 H), 3.35 (m, 2 H), 3.50 (m, 1 H), 3.98 (m, 2H), 4.20 (m, 1H), 4.44 (m, 1H), 4.55 (m, 1H), 4.88 (br s, 1H), 7.01 (d, J=8 Hz, 1 H), 7.81 (d, J=8 Hz, 1 H), 8.43 (s, 1H); MS (ESI) m/z 316.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[NH2:11][CH:12]1[C:16](=[O:17])[N:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:14][CH:13]1[C:23]([O:25][CH2:26][CH3:27])=[O:24]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C@H:12]2[C:16](=[O:17])[N:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:14][C@H:13]2[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CCCCCN1CC(C(=O)OCC)C(N)C1=O
Solvent: ClCCl
Product: CCCCCN1C[C@@H](C(=O)OCC)[C@@H](NC(=O)Nc2ccc(Cl)cc2)C1=O
Reaction time: 18 h
Yield: 72.3 %

Procedure:
To a solution of 4-chlorophenyl isocyanate (113 mg, 0.734 mmol) in CH2Cl2 (1 ml) was added the aminopyrrolidinone of Example R (178 mg, 0.734 mmol) in CH2Cl2 (1ml). After stirring for 18 h, the solvent was removed in vacuo and the resulting mixture was chromatographed on silica gel (5% EtOH/CH2Cl2) to give the title compound (210 mg, 72%). 'H NMR (300 MHz, CDCl3) δ7.99 (1H, s), 7.42 (2H, d), 7.24 (2H, t), 6.21 (1H, d), 4.92 (1H, q), 4.21 (1H, m), 4.11 (1H, m), 3.55 (2H, q), 3 32 (2H, m), 1.55 (2H, q), 1.29 (4H, m), 1.21 (2H, t), 0.89 (3H, t).