Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([OH:8])[CH2:5][CH:6]=[CH2:7].Br[CH2:10][CH:11]=[CH2:12]>CN(C)C=O>[CH2:12]([O:8][CH:4]([CH3:3])[CH2:5][CH:6]=[CH2:7])[CH:11]=[CH2:10]
Reactant: C=CCC(C)O
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOC(C)CC=C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 61.3 %

Procedure:
A 500-mL four neck round-bottom flask was purged and maintained with an inert atmosphere of nitrogen, then a suspension of sodium hydride (14.0 g, 350 mmol, 2.01 equiv, 60%) in N,N-dimethylformamide (100 mL) was added. The mixture was cooled to 0° C., then a solution of pent-4-en-2-ol (15.0 g, 174 mmol, 1.00 equiv) in N,N-dimethylformamide (100 mL) was added drop-wise and the mixture was stirred for 20 min at 0° C. The mixture was cooled to −20° C. and a solution of 3-bromoprop-1-ene (20.9 g, 172 mmol, 0.99 equiv) in N,N-dimethylformamide (100 mL) was added. The resulting mixture was allowed to warm to room temperature and stirred overnight, then carefully quenched with H2O (500 mL). The aqueous was extracted with ethyl acetate (4×100 mL) and the combined organics was washed with brine (2×200 mL), dried (Na2SO4), filtered and concentrated in vacuo to obtain the title compound as a yellow oil (13.3 g, 61%).
Reaction SMILES: [CH3:1][C:2]([C@H:18]1[C@@H:21]([CH2:22][CH:23]=[O:24])[NH:20][C:19]1=[O:25])([O:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)=[O:6])[CH3:3].CC(C)=[O:28].OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C>CC(C)=O>[CH3:3][C:2]([C@@H:18]1[C:19](=[O:25])[NH:20][C@@H:21]1[CH2:22][C:23]([OH:28])=[O:24])([O:4][C:5]([O:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=1)=[O:6])[CH3:1]
Reactant: CC(C)(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@@H]1C(=O)N[C@@H]1CC=O
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: CC(C)(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@@H]1C(=O)N[C@@H]1CC(=O)O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of (3R,4R)-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-4-(2-oxoethyl)azetidin-2-one (9 mg) in acetone (1 ml) was added 2 N Jones reagent (60 μl) at 0° C. and the mixture was stirred at 0° C. for 30 minutes. After addition of isopropyl alcohol (100 μl), the mixture was evaporated in vacuo. The residue was taken up in chloroform (20 ml) and washed with brine. The aqueous layer was extracted with chloroform (5 ml). The combined organic layers were washed with aqueous saturated sodium chloride, dried over magnesium sulfate, and evaporated to give {(2R,3R)-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-4-oxo-azetidin-2-yl}acetic acid (7 mg).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH2:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:10][O:11][C:12]([C:14]1[CH:15]=[C:16]([CH3:36])[C:17]2[O:23][C:22]3[C:24]([Cl:32])=[CH:25][C:26]([NH:28][CH2:29][CH2:30]Cl)=[CH:27][C:21]=3[CH2:20][S:19](=[O:34])(=[O:33])[C:18]=2[CH:35]=1)=[O:13].O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[CH3:10][O:11][C:12]([C:14]1[CH:15]=[C:16]([CH3:36])[C:17]2[O:23][C:22]3[C:24]([Cl:32])=[CH:25][C:26]([NH:28][CH2:29][CH2:30][NH:9][CH2:8][CH2:7][N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[CH:27][C:21]=3[CH2:20][S:19](=[O:33])(=[O:34])[C:18]=2[CH:35]=1)=[O:13]
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCCl)cc(Cl)c1O2
Reactant: NCCN1CCOCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCNCCN3CCOCC3)cc(Cl)c1O2
Temperature: 120 °C
Reaction time: 3 h

Procedure:
2-Morpholin-4-yl-ethylamine (0.18 mL, 1.44 mmol) and tetrabutylammonium iodide (0.075 g, 0.2 mmol) were sequentially added with stirring to a solution of the carboxylic acid of Example 56k (0.5 g, 1.2 mmol) in dry DMF (1 mL). The reaction mixture was then stirred at 120° C. for 3 h in an atmosphere of nitrogen. It was treated with cold water and the solid that precipitated was filtered, washed with water, and dried. The solid was treated with a methanolic HCl solution (10 mL), and refluxed at 70° C. for 3 h. The reaction mixture was concentrated and treated with an aqueous sodium bicarbonate solution. The solid that precipitated was filtered, washed with water, dried and purified using flash chromatography (silica gel, 2% methanol/chloroform) to obtain the title compound. Yield: 0.150 g, (24.19%); 1H NMR (DMSO-d6): δ 2.40 (t, 4H, 2CH2), 2.50-2.60 (m, 4H, 2CH2), 3.10 (m, 4H, 2CH2), 3.15-3.20 (m, 4H, 2CH2), 3.90 (s, 3H, OCH3), 4.50 (t, 1H, NH), 5.15 (s, 2H, CH2), 6.10 (t, 1H, NH), 6.7 (s, 2H, 2Ar), 8.10 (s, 1H, Ar), 8.25 (s, 1H, Ar); MS: m/e (EI+) 524 (M+).
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:34])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25](=[O:32])(=[O:31])[N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[CH:21][CH:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:33])[CH:14]=2)[CH:9]=1.C1COCC1.O>CCCCCC>[Cl:33][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:7][C:6]([OH:34])=[O:5])[C:17]([CH3:18])=[C:16]2[C:19]1[CH:24]=[CH:23][C:22]([S:25](=[O:31])(=[O:32])[N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[CH:21][CH:20]=1
Reactant: CCN(CC)S(=O)(=O)c1ccc(-c2c(C)c(CC(=O)OC)cc3ccc(Cl)cc23)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCN(CC)S(=O)(=O)c1ccc(-c2c(C)c(CC(=O)O)cc3ccc(Cl)cc23)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.2 %

Procedure:
Lithium hydroxide monohydrate (0.015 g, 0.34 mmol) was added to a stirred solution of [6-chloro-4-(4-diethylsulfamoyl-phenyl)-3-methyl-naphthalen-2-yl]-acetic acid methyl ester (0.040 g, 0.09 mmol) in a 3:1 mixture of THF—H2O mixture (5 mL). The reaction mixture was stirred for 16 hours at room temperature. The reaction mixture was concentrated to remove THF, and the crude material was diluted with water, acidified [pH˜2] with a 6 N aqueous solution of hydrochloric acid. The mixture was extracted twice with ethyl acetate. The collected organic layers were washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. Trituration with hexane gave [6-chloro-4-(4-diethylsulfamoyl-phenyl)-3-methyl-naphthalen-2-yl]-acetic acid (0.037 g, 95%) as a solid. 1H NMR (DMSO-d6) δ: 12.49 (br. s, 1H), 7.98 (d, J=8.3 Hz, 3H), 7.91 (s, 1H), 7.49 (d, J=8.3 Hz, 3H), 7.00 (s, 1H), 3.86 (s, 2H), 3.28 (s, 4H), 2.07 (s, 3H), 1.08 (t, J=7.1 Hz, 6H). MS calcd. for C23H25ClNO4S [(M+H)+] 446, obsd. 446.4.
Reaction SMILES: [ClH:1].CCOC(C)=O.C(OC(=O)[NH:14][C:15]1[C:20]([C:21]2([OH:33])[CH2:26][CH2:25][CH:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:23][CH2:22]2)=[CH:19][CH:18]=[CH:17][N:16]=1)(C)(C)C>>[ClH:1].[NH2:14][C:15]1[C:20]([C:21]2([OH:33])[CH2:26][CH2:25][CH:24]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:23][CH2:22]2)=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: CC(C)(C)OC(=O)Nc1ncccc1C1(O)CCC(c2ccccc2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: Nc1ncccc1C1(O)CCC(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4N HCl-EtOAc (5 mL) was added to tert-butyl[3-(1-hydroxy-4-phenylcyclohexyl)pyridin-2-yl]carbamate (450 mg) and the mixture was stirred at room temperature overnight. The resulted precipitates were collected and dried in vacuo to give 1-(2-aminopyridin-3-yl)-4-phenylcyclohexanol hydrochloride.
Reaction SMILES: [C:1](Cl)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]C.C[C:22]1(C)[O:29][C:27](=[O:28])[CH2:26][C:24](=[O:25])O1.N1C=CC=CC=1>C(Cl)Cl>[O:25]=[C:24]([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])[CH2:26][C:27]([O:29][CH3:22])=[O:28]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCC(=O)CC(=O)OC

Procedure:
270 ml of stearoyl chloride were added dropwise at a maximum of 150° C. to a solution of 117 g of Meldrum's acid and 131 ml of pyridine in 1.51 of methylene chloride. After stirring the reaction mixture was washed with 4N hydrochloric acid, the aqueous phase was back-extracted with methylene chloride and the methylene chloride phase was dried and concentrated. The residue was taken up in methanol and stirred under reflux. After cooling the separated crystals were filtered off, dissolved in methylene chloride and chromatographed on silica gel with methylene chloride. There were obtained 175 g of methyl 3-oxoeicosanoate, m.p. 52°-54° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]([OH:11])=O)=[CH:5][N:4]=1.CCN(C(C)C)C(C)C.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.Cl.Cl.[F:40][C:41]1[C:42]([C@H:47]([C:49]2[CH:54]=[CH:53][C:52]([C:55]([F:58])([F:57])[F:56])=[CH:51][CH:50]=2)[NH2:48])=[N:43][CH:44]=[CH:45][CH:46]=1>C1(C)C=CC=CC=1>[F:40][C:41]1[C:42]([C@H:47]([C:49]2[CH:54]=[CH:53][C:52]([C:55]([F:57])([F:58])[F:56])=[CH:51][CH:50]=2)[NH:48][C:9]([C:6]2[CH:7]=[N:8][C:3]([O:2][CH3:1])=[N:4][CH:5]=2)=[O:11])=[N:43][CH:44]=[CH:45][CH:46]=1
Reactant: N[C@@H](c1ccc(C(F)(F)F)cc1)c1ncccc1F
Reactant: COc1ncc(C(=O)O)cn1
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ncc(C(=O)N[C@@H](c2ccc(C(F)(F)F)cc2)c2ncccc2F)cn1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of 2-methoxypyrimidine-5-carboxylic acid (80 mg, 0.519 mmol), DIPEA (0.25 mL, 1.435 mmol) in toluene (3 mL) was added DPPA (0.19 mL, 0.882 mmol). The reaction was stirred at 80° C. for 2 hours. (S)-(3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methanamine dihydrochloride (167 mg, 0.487 mmol) was then added as a solid in one portion. After 24 hours, the reaction was concentrated in vacuo and the residue was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (12 g), eluting with 0% to 80% EtOAc in hexane, to provide the title compound as an off-white solid. 1H NMR (DMSO-d6, 400 MHz) δ ppm 9.02 (d, J=4.7 Hz, 1H), 8.97 (d, J=8.6 Hz, 1H), 8.30 (d, J=7.8 Hz, 1H), 7.63-7.77 (m, 3H), 7.54 (d, J=8.2 Hz, 2H), 7.39 (s, 1H), 7.01 (s, 1H), 6.66 (d, J=8.6 Hz, 1H), 3.93 (s, 3H) MS (ESI pos. ion) m/z: 407.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[C:6]([OH:11])[C:3]=1[CH:4]=O.Cl.[NH2:13][OH:14].[OH-].[Na+]>CCO.O>[Cl:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[C:6]([OH:11])[C:3]=1/[CH:4]=[N:13]/[OH:14]
Reactant: O=Cc1c(O)ccc(O)c1Cl
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O/N=C/c1c(O)ccc(O)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 125.9 %

Procedure:
A mixture of 7A (25.0 g, 144.87 mmol), hydroxylamine hydrochloride (12.08 g, 173.84 mmol, 1.2 eq) and NaOH (8.69 g, 217.3 mmol, 1.5 eq) in EtOH (200 mL) and H2O (100 mL) was stirred at room temperature overnight. TLC monitored the reaction. After the reaction completed, the mixture was extracted with ethyl acetate and concentrated to give a yellow solid 7B (34.2 g, 100% yield).
Reaction SMILES: CO[C:3](=[O:14])[C:4]1[C:9]([Cl:10])=[CH:8][C:7]([Br:11])=[CH:6][C:5]=1[CH2:12]Br.[F:15][C:16]([F:26])([F:25])[C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[Br:11][C:7]1[CH:6]=[C:5]2[C:4](=[C:9]([Cl:10])[CH:8]=1)[C:3](=[O:14])[N:22]([CH2:21][C:20]1[CH:19]=[CH:18][C:17]([C:16]([F:15])([F:25])[F:26])=[CH:24][CH:23]=1)[CH2:12]2
Reactant: COC(=O)c1c(Cl)cc(Br)cc1CBr
Reactant: NCc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C1c2c(Cl)cc(Br)cc2CN1Cc1ccc(C(F)(F)F)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 34.2 %

Procedure:
A mixture of 4-bromo-2-bromomethyl-6-chloro-benzoic acid methyl ester (1.4 g, 4.0 mmol), 4-trifluoromethyl-benzylamine (0.770 mL, 5.4 mmol), and K2CO3 (1.1 g, 8.0 mmol) in toluene (10 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 5-bromo-7-chloro-2-(4-trifluoromethyl-benzyl)-2,3-dihydro-isoindol-1-one (0.553 g, 35%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.23 (s, 2H), 4.83 (s, 2H), 7.28-7.64 (m, 6H). GC-MS: m/z 405 (M+1)+, 336 (M−68)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:5][C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12]CC)=[O:11])=[CH:8][CH:7]=1.[OH-].[Li+]>C1COCC1.CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:5][C:6]1[CH:16]=[CH:15][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1
Reactant: CCOC(=O)c1ccc(Cc2ccc(Cl)c(Cl)c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(Cc2ccc(Cl)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 73 %

Procedure:
To a solution of ethyl 4-(3,4-dichlorobenzyl)benzoate (Preparation 170, 240 mg, 0.78 mmol) in THF/MeOH/water (4:3:2, 7.2 mL) was added lithium hydroxide (65 mg, 1.56 mmol) and the mixture was stirred at room temperature for 4 hours. The solvent was evaporated in vacuo and the residue acidified with 1M hydrochloric acid solution. The crude product was extracted with chloroform/methanol, and the extract dried over Na2SO4 and the solvent evaporated in vacuo to give the title compound as a white solid (160 mg, 73%)
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:10][C:11]1[C:12](Cl)=[N:13][CH:14]=[C:15]([CH3:17])[CH:16]=1.O>CC(N(C)C)=O>[Br:10][C:11]1[C:12]([O:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[N:13][CH:14]=[C:15]([CH3:17])[CH:16]=1
Reactant: Oc1ccccc1
Reactant: Cc1cnc(Cl)c(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1cnc(Oc2ccccc2)c(Br)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 40.8 %

Procedure:
Sodium hydride dispersion in oil (˜70%, 0.68 g) was added in portions to a well stirred solution of phenol (1.33 g, 14 mmol) in DMA (100 mL). After stirring the mixture for 1 h at 50° C. 3-bromo-2-chloro-5-methyl-pyridine (2.68 g, 13 mmol) was added and stirring continued for 28 h at 100° C. The cooled mixture was poured into water and extracted with diethyl ether. Organic phases were pooled, dried with Na2SO4 and the solvent was evaporated. The residue was purified by column chromatography on silica (n-heptane/ethyl acetate 8:1) to yield 1.4 g of the title compound as a colorless oil, 1H NMR (CDCl3): δ=2.27 (s, 3H), 7.12 (d, 2H), 7.19 (t, 1H), 7.39 (t, 2H), 7.76 (s, 1H), 7.88 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].[CH2:11]([O:13][C:14](=[O:17])[CH2:15]Br)[CH3:12].C([O-])([O-])=O.[K+].[K+].[CH3:24][CH2:25][O:26][C:27]([CH3:29])=[O:28]>>[CH2:11]([O:13][C:14](=[O:17])[CH2:15][O:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[O:1][CH2:29][C:27]([O:26][CH2:25][CH3:24])=[O:28])[CH3:12]
Reactant: O=Cc1ccc(O)c(O)c1
Reactant: CCOC(=O)CBr
Reactant: CCOC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)COc1ccc(C=O)cc1OCC(=O)OCC

Procedure:
3,4-Dihydroxy-benzaldehyde was treated with 2-bromo-acetic acid ethyl ester in the presence of K2CO3 and processed as described in the synthesis of example 20a. The crude product was purified using flash chromatography (silica gel, 30-50% EtOAc in PE 60-80° C.). Yield, 87%; mp, 56° C. (EtOAc-PE 60-80° C.); MS (EI): 310 (M+), 237, 163, 149; analysis: C15H18O7, 0.5H2O requires C, 56.37; H, 5.95; found: C, 56.72; H, 5.79%.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:12][C:13]([NH:15][C@@H:16]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH2:30][C:31](=[O:39])[NH:32][C:33]2[NH:34][CH2:35][CH2:36][CH2:37][N:38]=2)=[CH:23][CH:22]=1)[C:17]([OH:19])=[O:18])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:40](O)[CH3:41]>>[ClH:3].[CH2:5]([O:12][C:13]([NH:15][C@@H:16]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH2:30][C:31](=[O:39])[NH:32][C:33]2[NH:38][CH2:37][CH2:36][CH2:35][N:34]=2)=[CH:23][CH:22]=1)[C:17]([O:19][CH2:40][CH3:41])=[O:18])=[O:14])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C(CCCOc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)O)cc1)NC1=NCCCN1
Reactant: O=S(Cl)Cl
Reactant: CCO
Product: CCOC(=O)[C@H](Cc1ccc(OCCCC(=O)NC2=NCCCN2)cc1)NC(=O)OCc1ccccc1
Product: Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
0.14 ml (1.15 eq.) of thionyl chloride were added at −10° C. to 5 ml of ethanol and stirred for 10 min at this temperature. Then 1 g (1.66 mmol) of the compound of Example 1 were added as a suspension in 10 ml of ethanol. Under stirring, the mixture was warmed to room temperature and stirred for further 5 hours. The solution which had meanwhile become clear, was evaporated in vacuo, the residue was dissolved in water and, after filtration, subjected to lyophilization. Yield: 0.85 g of a colourless, amorphous solid. MS (ES+): m/e=511 (M+H+, 100%).
Reaction SMILES: [CH3:1][C:2]1[C:7]2[CH2:8][CH2:9][CH:10]([C:14]([OH:16])=O)[CH2:11][C:12](=[O:13])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.Cl.[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:26]=1[CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C(N(CC)CC)C>C(Cl)Cl.O>[CH3:1][C:2]1[C:7]2[CH2:8][CH2:9][CH:10]([C:14]([N:35]3[CH2:34][CH2:33][CH:32]([C:26]4[C:25]([Cl:24])=[CH:30][CH:29]=[CH:28][C:27]=4[Cl:31])[CH2:37][CH2:36]3)=[O:16])[CH2:11][C:12](=[O:13])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2c1CCC(C(=O)O)CC2=O
Reactant: Clc1cccc(Cl)c1C1CCNCC1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1cccc2c1CCC(C(=O)N1CCC(c3c(Cl)cccc3Cl)CC1)CC2=O
Temperature: 25 °C
Yield: 71 %

Procedure:
1 g (4.58 mmol) of (±)-1-methyl-5-oxo-6,7,8,9-tetrahydro-5H-benzocycloheptene-7-carboxylic acid was dissolved in 40 mL of dry CH2Cl2 and 1.2 mL (13.74 mmol) of oxalyl chloride were added dropwise at 0° C. under a nitrogen atmosphere. The solution was allowed to warm to room temperature overnight, then the solvent and the excess oxalyl chloride were removed in vacuo. The resulting acyl chloride was dissolved in 20 mL of dry CH2Cl2 and added to a solution of 1.22 g (4.58 mmol) of 4-(2,6-dichloro-phenyl)-piperidine hydrochloride and 1.91 mL (13.74 mmol) of triethylamine in 30 mL of dry CH2Cl2 at 0° C. The reaction mire was allowed to warm to room temperature overnight, water was added, the organic phase was collected, washed with 1 N HCl solution and dried. The solvent was removed in vacuo and the resulting crude product was purified by flash chromatography, eluting with a mixture Et2O/Hexane 8:2 respectively, yielding 1.4 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C[N:12]1[C:16](=[O:17])CCC1>>[NH:1]1[C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[NH:6][C:16]1=[O:17].[NH2:12][C:4]([NH2:6])=[O:5]
Reactant: CN1CCCC1=O
Reactant: NC(=O)c1ccccc1N
Product: NC(N)=O
Product: O=c1[nH]c(=O)c2ccccc2[nH]1

Procedure:
Amino-benzamide (6) can be cyclized to provide quinazoline-2,4-dione (7) upon treatment with urea in solvent such as NMP. Compound (7) can be treated with N,N-diethylaniline and POCl3 to give 2,4-dichloroquinazoline (8), which, when treated with NH3 in a solvent such as MeOH provides compound (9). Compound (9) can be reacted with t-butyl nitrite in THF to provide compound (10) which, when coupled with an appropriate amine NH2Q, e.g., in NMP, affords compounds of Formula (I).
Reaction SMILES: FC(F)(F)S([O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])(=O)=O.[Cl:16][C:17]1[C:22]([C:23]([N:25]2[CH2:29][CH:28]([N:30]3[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]3)[CH:27](O)[CH2:26]2)=[O:24])=[CH:21][C:20]([C:38]#[N:39])=[CH:19][C:18]=1[NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44].N1C=CN=C1>CN(C=O)C.C(OCC)(=O)C>[Si:7]([O:6][CH:27]1[CH:28]([N:30]2[CH2:31][CH2:32][N:33]([CH3:36])[CH2:34][CH2:35]2)[CH2:29][N:25]([C:23]([C:22]2[C:17]([Cl:16])=[C:18]([NH:40][C:41](=[O:47])[O:42][C:43]([CH3:44])([CH3:45])[CH3:46])[CH:19]=[C:20]([C:38]#[N:39])[CH:21]=2)=[O:24])[CH2:26]1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CN1CCN(C2CN(C(=O)c3cc(C#N)cc(NC(=O)OC(C)(C)C)c3Cl)CC2O)CC1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1CCN(C2CN(C(=O)c3cc(C#N)cc(NC(=O)OC(C)(C)C)c3Cl)CC2O[Si](C)(C)C(C)(C)C)CC1
Temperature: 25 °C
Yield: 81.1 %

Procedure:
tert-Butyldimethylsilyl trifluoromethanesulfonate (0.240 mL, 1.026 mmol) was added to a solution of (+/−)-tert-butyl (2-chloro-5-cyano-3-(3-hydroxy-4-(4-methylpiperazin-1-yl)pyrrolidine-1-carbonyl)phenyl)carbamate (119 mg, 0.256 mmol) and imidazole (69.8 mg, 1.026 mmol) in DMF (3 mL) and the reaction solution was stirred at room temperature over the weekend. The reaction mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo, the crude product was purified by flash chromatography on silica gel using an automated ISCO system (40 g column, eluting with 1-6% methanol/dichloromethane). (+/−)-tert-butyl (3-(3-((tert-butyldimethylsilyl)oxy)-4-(4-methylpiperazin-1-yl)pyrrolidine-1-carbonyl)-2-chloro-5-cyanophenyl)carbamate (120 mg) was obtained as a colorless oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][N:18]([C:21]2[C:29]3[CH:28]=[CH:27][S:26][C:25]=3[CH:24]=[CH:23][CH:22]=2)[CH2:17][CH2:16]1)(=O)C.O>CO>[S:26]1[CH:27]=[CH:28][C:29]2[C:21]([N:18]3[CH2:17][CH2:16][N:15]([CH2:14][CH2:13][CH2:12][CH2:11][OH:10])[CH2:20][CH2:19]3)=[CH:22][CH:23]=[CH:24][C:25]1=2
Reactant: CC(=O)OCCCCN1CCN(c2cccc3sccc23)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: OCCCCN1CCN(c2cccc3sccc23)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.3 %

Procedure:
Potassium carbonate (3.87 g, 28 mmol) was added to a solution of 7.76 g (23.3 mmol) of 4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butyl acetate in 90% methanol solution (150 ml). The solution mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, which was then extracted with dichloromethane. The extraction solution was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (n-hexane:ethyl acetate=2:1→1:1), and concentrated under reduced pressure to obtain 4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butan-1-ol (6.65 g) as colorless oil.
Reaction SMILES: C(OC([N:6]1[CH2:12][CH2:11][C:10]2[C:13]([Br:21])=[C:14]([CH2:16][C:17]([F:20])([F:19])[F:18])[S:15][C:9]=2[CH2:8][CH2:7]1)=O)C.[Si](I)(C)(C)C>C(Cl)(Cl)Cl>[Br:21][C:13]1[C:10]2[CH2:11][CH2:12][NH:6][CH2:7][CH2:8][C:9]=2[S:15][C:14]=1[CH2:16][C:17]([F:19])([F:18])[F:20]
Reactant: CCOC(=O)N1CCc2sc(CC(F)(F)F)c(Br)c2CC1
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Product: FC(F)(F)Cc1sc2c(c1Br)CCNCC2
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
The product of step (b) (0.18 mmol) was dissolved in CHCl3 (3 mL) and treated with TMSI (1 mmol, 200 μL). After heating for ½ hour at 70° C., another 200 μL of TMSI was added and heating was continued for ½ hour. The reaction was cooled and carefully quenched with 0.5 mL each of EtOH and water. The reaction was diluted with 1 M NaOH (3 mL) and the product was extracted into DCM (2×5 mL). The organic extracts were concentrated and the residue was purified by preparative HPLC-MS. 1H NMR (CD3OD) δ 3.75 (q, J=10.5 Hz, 2H), 3.43-3.34 (m, 4H), 3.26 (t, J=5.4 Hz, 2H), 3.16 (t, J=5.4 Hz, 2H), 3.16 (t, J=5.4 Hz, 2H); MS: ESI (positive): 316, 314 (M+H).
Reaction SMILES: [ClH:1].[C:2]1([CH:8]([N:10]2[C:14]([CH2:15]O)=[CH:13][N:12]=[CH:11]2)[CH3:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:19])=O>CC(O)C>[ClH:19].[Cl:1][CH2:15][C:14]1[N:10]([CH:8]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH3:9])[CH:11]=[N:12][CH:13]=1
Reactant: O=S(Cl)Cl
Reactant: CC(c1ccccc1)n1cncc1CO
Agent: Cl
Solvent: CC(C)O
Product: CC(c1ccccc1)n1cncc1CCl

Procedure:
3 Parts of 1-(1-phenylethyl)-1H-imidazole-5-methanol monohydrochloride were added portionwise to 16 parts of thionyl chloride (exothermic reaction with evolution of SO2 /HCl). After the addition was complete, the whole was stirred and refluxed for 30 minutes. After cooling there were added 40 parts of 2-propanol, whereupon a solid was precipitated. It was filtered off and recrystallized from a mixture of 60 parts of 2-propanol and 60 parts of 2,2'-oxybispropane, yielding 1.5 parts of 5-(chloromethyl)-1-(1-phenylethyl)-1H-imidazole monohydrochloride; mp. 173.5°-175° C. (dec.) (compound 8.49).