Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[CH:14][O:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11].O.C[N+]1([O-])CC[O:22]CC1>C(Cl)(Cl)(Cl)Cl>[CH:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[CH:14][O:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[O:22]
Reactant: COC=C(C(=O)OC)c1ccccc1CBr
Reactant: C[N+]1([O-])CCOCC1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: COC=C(C(=O)OC)c1ccccc1C=O
Yield: 67.2 %

Procedure:
35.5 g (0.125 mol) of methyl alpha-(2-bromomethylphenyl)-β-methoxyacrylate are dissolved in 500 ml of CCl4. 43.4 g (0.321 mol) of methylmorpholine N-oxide monohydrate are added, and the mixture is refluxed for 20 hours. The solid is filtered of f and the CCl4 phase is washed with water, with 2 N hydrochloric acid and again with water, dried and concentrated. 18.5 g (67%) of product are obtained as a reddish brown oil.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[OH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=1>>[F:20][C:17]([F:18])([F:19])[C:14]1[CH:15]=[CH:16][C:11]([O:10][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)=[N:12][CH:13]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Oc1ccc(C(F)(F)F)cn1
Product: O=Cc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1

Procedure:
4-(5-Trifluoromethyl-pyridin-2-yloxy)-benzaldehyde was prepared from 4-fluorobenzaldehyde (2.48 g, 20 mmol) and 2-hydroxy-5-trifluoromethylpyridine (3.29 g, 20 mmol) following general procedure B. (4.62 g)
Reaction SMILES: [CH2:1]([C:11]1[S:15][C:14]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C([Li])CCC.CN([CH:29]=[O:30])C.[Cl-].[NH4+]>CCCCCC.C1COCC1>[CH2:1]([C:11]1[S:15][C:14]([C:16]2[S:17][C:18]([CH:29]=[O:30])=[CH:19][CH:20]=2)=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCc1ccc(-c2cccs2)s1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCc1ccc(-c2ccc(C=O)s2)s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
5-Decyl-2,2′-bithiophene (39.0 g, 0.127 mol) prepared above and THF (300 ml) were placed in a 1000-ml three-necked flask equipped with a 200-ml dropping funnel and a reflux tube. The solution was cooled in an ice bath to 0° C., and a solution (80 ml) of n-butyllithium (1.6 M) in n-hexane was added dropwise to the cooled solution over a period of about one hr. After the completion of the dropwise addition, the mixture was stirred for about one hr. DMF (13.9 g, 0.191 mol) was added dropwise thereto at 0° C. over a period of about one hr. After the completion of the dropwise addition, the reaction temperature was raised to room temperature, and, at that temperature, the mixture was stirred overnight. After the completion of the reaction, a 1 N ammonium chloride solution (200 ml) was added, and the organic layer was extracted with diethyl ether, was dried over sodium sulfate, and was applied to column chromatography (CH2Cl2:hexane=1:1) to give an objective compound 5-decyl-5′-formyl-2,2′-bithiophene as a yellow solid (37.2 g, yield 87.60%). An NMR spectrum of the compound thus obtained was measured at room temperature with an NMR spectrometer (model JNM-LA400W, manufactured by Japan Electric Optical Laboratory). 1H-NMR (CDCl3, TMS/ppm): 0.88 (t, 3H, J=6.83 Hz), 1.26 (m, 14H), 1.69 (m, 2H), 2.81 (t, 2H, J=7.32 Hz), 6.74 (d, 1H, J=3.90 Hz), 7.16 (d, 1H, J=3.90 Hz), 7.18 (d, 1H, J=3.90 Hz), 7.64 (d, 1H, J=3.90 Hz), 9.84 (s, 1H).
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[C:23]([C:27]1[CH:51]=[CH:50][C:30]([CH2:31][N:32]2[CH2:36][CH2:35][N:34]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([NH:44][S:45]([CH3:48])(=[O:47])=[O:46])=[CH:40][CH:39]=3)[C:33]2=O)=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24].C1(C)C=CC=CC=1>O>[C:23]([C:27]1[CH:51]=[CH:50][C:30]([CH2:31][N:32]2[CH2:36][CH2:35][N:34]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([NH:44][S:45]([CH3:48])(=[O:47])=[O:46])=[CH:40][CH:39]=3)[C:33]2=[S:10])=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)c1ccc(CN2CCN(Cc3ccc(NS(C)(=O)=O)cc3)C2=O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(CN2CCN(Cc3ccc(NS(C)(=O)=O)cc3)C2=S)cc1
Reaction time: 8 h
Yield: 79.9 %

Procedure:
Lawesson's reagent (2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetan-2,4-disulfide) (640 mg, 1.58 mmol) was added to a solution of N-{4-[3-(4-tert-butylbenzyl)-2-oxoimidazolidin-1-ylmethyl]phenyl}methanesulfonamide (4) (1008 mg, 2.63 mmol) in abs. toluene (30 mL). The reaction mixture was heated to the boil over a period of 5 h. The reaction mixture was then stirred overnight. Water (40 mL) was added and the mixture was extracted with chloroform (3×30 mL). The combined organic phases were washed with H2O (2×20 mL), dried over Na2SO4, and the solvent was removed in vacuo. Following purification of the residue by means of column chromatography (SiO2 (150 g); 1000 mL cyclohexane/EtOAc 4:1), the desired product N-{4-[3-(4-tert-butylbenzyl)-2-thioxoimidazolidinylmethyl]phenyl}methanesulfonamide (1) (545 mg, 52% of theory) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.[OH-].[K+].[Cl:13][C:14]1[CH:19]=[C:18](Cl)[N:17]=[C:16]([CH3:21])[N:15]=1>CN(C=O)C.C(OCC)(=O)C>[Cl:13][C:14]1[CH:19]=[C:18]([O:8][CH2:7][C:6]2[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:17]=[C:16]([CH3:21])[N:15]=1
Reactant: COc1ccc(CO)cc1
Reactant: Cc1nc(Cl)cc(Cl)n1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(COc2cc(Cl)nc(C)n2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
4-Methoxybenzyl alcohol (1.66 g, 12 mmol) was dissolved in DMF (20 mL). Potassium hydroxide (2.31 g, 36 mmol, 87%) was added and stirred at room temperature for 10 min followed by cooling to 0° C. 4,6-dichloro-2-methylpyrimidine (2.15 g, 13.2 mmol) was dissolved in DMF (4 mL) and added to the solution drop-wise. The internal temperature was controlled under 2° C. The reaction solution was kept at 0° C. for 2 h, then allowed to warm slowly to 16° C. over 1 hr. The reaction was diluted with ethyl acetate (50 mL), washed with brine (50 mL×2), dried over MgSO4, filtered and concentrated i. vac. The crude mixture was purified by chromatography on silica gel (eluting 7.7% ethyl acetate/hexane) to yield the titled compound as a colorless oil. LC-MS (M+1): 265.51, (M+23): 287.52.
Reaction SMILES: C([Mg]Cl)=C.[Cl:5][CH2:6][CH2:7][CH2:8][Si:9]([CH3:12])(C)Cl.O1C[CH2:16][CH2:15][CH2:14]1>>[Cl:5][CH2:6][CH2:7][CH2:8][SiH2:9][CH:12]=[C:15]([CH3:16])[CH3:14]
Reactant: C1CCOC1
Reactant: C[Si](C)(Cl)CCCCl
Agent: C=C[Mg]Cl
Product: CC(C)=C[SiH2]CCCCl
Reaction time: 2 h
Yield: 92 %

Procedure:
A flask equipped with a stirrer, reflux condenser, dropping funnel and thermometer was charged with 500 mL (0.73 mol) a tetrahydrofuran solution of 1.46M vinylmagnesium chloride, to which 119.8 g (0.7 mol) of chloropropyldimethylchlorosilane was added dropwise over 2 hours at an internal temperature of 25-50° C. The reaction solution was stirred for 2 hours. A salt formed was removed by filtration. By subsequent distillation, the target compound, chloropropyldimethylvinylsilane was collected as a fraction having a boiling point of 82° C./5 kPa in an amount of 104.4 g (yield 92%).
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[N:9][C:10]([OH:13])=[N:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C1(C)C=CC=CC=1.[CH2:21]([O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>N1C=CC=CC=1>[CH2:21]([O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32]([O:13][C:10]2[N:11]=[CH:12][C:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:8][N:9]=2)=[O:33])=[CH:30][CH:29]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCOc1ccc(C(=O)Cl)cc1
Reactant: CCCCCCc1cnc(O)nc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCCCCCOc1ccc(C(=O)Oc2ncc(CCCCCC)cn2)cc1
Yield: 57.2 %

Procedure:
This 5-hexylpyrimidin-2-ol (1.8 g, 10 mmol) was dissolved in pyridine (2 ml), followed by adding dropwise to the solution, a toluene solution (30 ml) of p-hexyloxybenzoyl chloride (2.4 g, 10 mmol), stirring at 50° C. for 4 hours, further adding toluene (50 ml) to the reaction mixture to carry out extraction, washing the toluene layer twice with 6N-HCl aqueous solution (30 ml), further washing 5 times with 2N-NaOH aqueous solution (40 ml), washing with pure water until the aqueous layer became pH 7, drying the toluene layer over anhydrous Na2SO4 and distilling off toluene to obtain raw crystals (3.1 g) (yield 81%), which were then purified by activated alumina chromatography (solvent: toluene) and recrystallized from ethanol to obtain 5-hexylpyrimidin-2-yl p-hexyloxybenzoate (2.2 g) (yield 58%). This compound exhibited liquid crystallinity and as to their phase transition points, C-N point was 28.4° C. and N-I point was 35° C.
Reaction SMILES: C(OC([N:11]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][CH:13]([CH2:21][O:22][CH2:23][CH:24]=[CH2:25])[CH2:12]1)=O)C1C=CC=CC=1.CO>C(Cl)Cl>[CH2:23]([O:22][CH2:21][CH:13]1[CH2:12][NH:11][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[O:14]1)[CH:24]=[CH2:25]
Reactant: C=CCOCC1CN(C(=O)OCc2ccccc2)c2ccccc2O1
Solvent: CO
Solvent: ClCCl
Product: C=CCOCC1CNc2ccccc2O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.8 ml of iododtrimethylsilane is added to a solution of 1.37 g of N-benzyloxycarbonyl-2(R,S)allyloxymethyl-3,4-dihydro-2H-1,4-benzoxazine in 25 ml of methylene chloride under argon. The reaction mixture is stirred at room temperature for 2 h, 10 ml of methanol are then added and the mixture is concentrated. The residue is extracted twice with 50 ml of a 10:1 mixture of hexane and diethyl ether and then dissolved in ethyl acetate, and the solution is washed with a 1N sodium carbonate solution and saturated sodium chloride solution. The crude product is purified by means of FC (100 g of silica gel, mobile phase D). This gives the pure title compound: Rf (D)=0.17.
Reaction SMILES: [C:1]1([C:7](=[O:22])[C:8]([S:20][CH3:21])=[CH:9][CH:10]=[C:11]([N:17]([CH3:19])[CH3:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[B-](F)(F)F.C[NH2+]C.[CH3:31][CH2:32][O-].[Na+]>C(O)C>[CH3:19][N:17]([CH3:18])[C:11](=[CH:10][CH:9]=[C:8]([S:20][CH3:21])[C:7]([C:1]1[CH:2]=[CH:3][C:4]([C:32]2[CH:31]=[CH:3][CH:2]=[CH:1][CH:6]=2)=[CH:5][CH:6]=1)=[O:22])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C(=CC=C(SC)C(=O)c1ccccc1)N(C)C
Reactant: CC[O-]
Agent: C[NH2+]C
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=CC=C(SC)C(=O)c1ccc(-c2ccccc2)cc1)N(C)C

Procedure:
The procedure is as in Example 4 for the preparation of ethyl 6-phenyl-6-oxo-5-methylthio-2-dimethylamino-2,4-hexadienoate, starting with N-(3-dimethylamino)-3-ethoxycarbonylpropenylidene)-N-methylmethanaminium tetrafluoroborate (6 g), a 2M ethanolic solution of sodium ethylate (10.5 cc) and α-methylthio-4-phenylacetophenone (5.1 g) in ethanol (150 cc). After purification by chromatography on a silica column with a mixture of cyclohexane and ethyl acetate (50:50 by volume) as eluent, ethyl 2-dimethylamino-6-(4-biphenylyl)-5-methylthio-6-oxo-2,4-hexadienoate (2.8 g) is obtained in the form of an orange-coloured oil, and is used in the crude state in the subsequent syntheses.
Reaction SMILES: [CH3:1][O:2][C:3]([NH2:5])=[NH:4].Cl.[Br:7][C:8]1[CH:9]=[C:10]2NC(=O)O[C:12](=[O:13])[C:11]2=[CH:18][CH:19]=1.[O-]CC.[Na+].O>CN(C=O)C>[Br:7][C:8]1[CH:9]=[C:10]2[C:11]([C:12](=[O:13])[NH:4][C:3]([O:2][CH3:1])=[N:5]2)=[CH:18][CH:19]=1
Reactant: COC(=N)N
Reactant: O=c1[nH]c2cc(Br)ccc2c(=O)o1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1nc2cc(Br)ccc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.6 %

Procedure:
A solution of o-methylisourea hydrochloride (1.256 g, 11.36 mmol) and 4-bromoisatoic anhydride (2.500 g, 10.33 mmol) in 10 mL DMF was treated with sodium ethoxide (1.476 g, 21.69 mmol) and was allowed to stir at room temperature overnight. LC/MS showed mostly product, so the reaction mixture was poured into water and the resulting solid was filtered and dried yielding 7-bromo-2-methoxyquinazolin-4(3H)-one (2.57 g, 10.08 mmol, 98% yield) with impurities. (M+H)+=255.0.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH:37]1[CH2:43][CH2:42][CH2:41][C@H:38]1[CH2:39][OH:40].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:37]3[CH2:43][CH2:42][CH2:41][C@H:38]3[CH2:39][OH:40])=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: Cc1cc(F)ccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: OC[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(F)ccc1-c1cc(N2CCC[C@H]2CO)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 180 °C
Yield: 79.3 %

Procedure:
A mixture of 0.20 g (0.38 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide, 0.23 g (2.3 mmol) L-prolinol and 0.15 g (1.1 mmol) potassium carbonate in 0.5 ml dimethyl sulfoxide was heated at 180° C. under microwave irradiation for 30 min. in a sealed tube. After cooling to room temperature the reaction mixture was diluted with water and extracted with three portions of tert-butyl methyl ether. The combined organic extracts were washed with water and brine, dried over sodium sulfate and concentrated in vacuo. Flash column chromatography gave 0.18 g (78%) of the title compound as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:14]([Cl:20])=[CH:13][N:12]=1.O>C1(C)C(C)=CC=CC=1.CC1C=CC(CC)=CN=1>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:11]2[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:14]([Cl:20])=[CH:13][N:12]=2)=[CH:4][CH:3]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1cc(Cl)cnc1Cl
Agent: CCc1ccc(C)nc1
Solvent: O
Solvent: Cc1ccccc1C
Product: O=[N+]([O-])c1cc(Cl)cnc1NCc1ccc(Cl)cc1
Yield: 87 %

Procedure:
A solution of 20.9 g of 4-chlorobenzylamine and 15.7 g of 2,5-dichloro-3-nitropyridine in 250 ml of xylene and 20 ml of 2-methyl-5-ethylpyridine is refluxed for 30 hours. After cooling, water is added to the reaction mixture, the resulting mixture is then extracted with ethyl acetate and the organic phase is washed with a dilute solution of hydrochloric acid and dried over magnesium sulfate. The solvent is evaporated off under vacuum and the residue obtained crystallizes from isopropyl ether to give 21.1 g of 2-(4-chlorophenylmethylamino)-3-nitro-5-chloropyridine in the form of crystals melting at 120° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=O)=[CH:4][CH:3]=1.[C:17]1(=O)[CH2:21][CH2:20][CH2:19][CH2:18]1.O>C1COCC1.[Zn].Cl[Ti](Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(O)cc1)c1ccc(Br)cc1
Reactant: O=C1CCCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: O
Solvent: C1CCOC1
Product: Oc1ccc(C(=C2CCCC2)c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.8 %

Procedure:
To a stirred suspension of zinc powder (0.71 g, 10.9 mmoL) in anhydrous THF (15 mL) was slowly added, via syringe, TiCl4 (0.58 mL, 1.0 g, 5.3 mmoL) at RT under a nitrogen atmosphere. The stirred reaction mixture was heated at reflux under a nitrogen atmosphere for 2.5 h. To the refluxing reaction mixture was added a solution of (4-bromophenyl)(4-hydroxyphenyl)methanone (2) (0.408 g, 1.47 mmol) and cyclopentanone (0.38 mL, 0.36 g, 4.3 mmol) in THF (15 mL) and heating continued an additional 2 h. The reaction mixture was allowed to cool to room temperature and water (10 mL) slowly added. The reaction mixture was then filtered through a pad of Celite and the Celite pad washed with EtOAc. The filtrate was transferred to a separatory funnel and the organic layer was separated. The organic phase washed with brine, dried (MgSO4), filtered, and the filtrate concentrated in vacuo to give the crude product. The crude product was purified by flash chromatography on silica gel with hexanes:EtOAc (100:0 to 60:40) to give 0.391 g (81%) of compound 3 as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 1.59 (m, 4 H), 2.27 (m, 4 H), 6.66 (d, J=8.5 Hz, 2 H), 6.89 (d, J=8.4 Hz, 2 H), 7.04 (d, J=8.4 Hz, 2 H), 7.45 (d, J=8.4 Hz, 2 H), 9.32 (s, 1 H). HRMS (EI) Calcd for C18H17BrO: 328.0463 (M+). Found: 328.0469.
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([NH:17][C:18]1[S:19][C:20]2[CH:26]=[C:25]([O:27][S:28]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)(=[O:30])=[O:29])[CH:24]=[CH:23][C:21]=2[N:22]=1)=[O:16])=[O:7])(C)(C)C.NC1SC2C=C(OS(C3C=CC(F)=CC=3)(=O)=O)C=CC=2N=1.C(C(CCCCCN)C(O)=O)([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=O>>[C:62]([O:61][CH:9]([N:8]=[C:6]=[O:7])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([NH:17][C:18]1[S:19][C:20]2[CH:26]=[C:25]([O:27][S:28]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)(=[O:29])=[O:30])[CH:24]=[CH:23][C:21]=2[N:22]=1)=[O:16])([CH3:65])([CH3:64])[CH3:63]
Reactant: CC(C)(C)OC(=O)C(CCCCCN)C(=O)O
Reactant: CC(C)(C)OC(=O)NCCCCCCC(=O)Nc1nc2ccc(OS(=O)(=O)c3ccc(F)cc3)cc2s1
Agent: Nc1nc2ccc(OS(=O)(=O)c3ccc(F)cc3)cc2s1
Product: CC(C)(C)OC(CCCCCC(=O)Nc1nc2ccc(OS(=O)(=O)c3ccc(F)cc3)cc2s1)N=C=O

Procedure:
According to the method of intermediate 46, 4-fluorobenzenesulfonic acid 2-(7-tert-butoxycarbonylaminoheptanoylamino)benzothiazol-6-yl ester is prepared via the action of 4-fluorobenzenesulfonic acid 2-aminobenzothiazol-6-yl ester (intermediate 16, brevetbenzothiazole_V2) with BOC-7-amino-heptanoic acid to give 0.164 g of product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([S:13][CH3:14])=[C:11]([C:15]([O:17]C(C)(C)C)=[O:16])[N:10]=[C:9]2[C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([S:13][CH3:14])=[C:11]([C:15]([OH:17])=[O:16])[N:10]=[C:9]2[C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])=[CH:4][CH:3]=1
Reactant: CSc1c(C(=O)OC(C)(C)C)nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSc1c(C(=O)O)nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(Cl)cc1
Yield: 98 %

Procedure:
To a magnetically stirred solution of tert-butyl 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-methylsulfanyl-1H-imidazole-4-carboxylate (4.00 g, 8.53 mmol) in CH2Cl2 (60 ml) was added excess TFA (8.40 ml, 0.111 mol). The solution was reacted at room temperature for 16 hours and subsequently concentrated in vacuo. Water was added and the formed precipitate was collected by filtration and subsequently dried to give 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-methylsulfanyl-1H-imidazole-4-carboxylic acid in 98% yield, mp ˜100° C. (decomposition); 1H-NMR (400 MHz, CDCl3) δ 2.41 (s, 3H), 3.60 (br s, 1H), 7.08 (br d, J˜8 Hz, 2H), 7.26 (dd, J=8 and 2 Hz, 1H), 7.30 (d, J=8 Hz, 1H), 7.35 (d, J=2 Hz, 1H), 7.37 (br d, J˜8 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:18][OH:19])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[C:13]([F:15])[C:12]([F:16])=[C:11]([F:17])[CH:10]=1.[H-].[Na+].Cl[C:23]1[CH:24]=[C:25]2[N:32]([CH3:33])[CH2:31][CH2:30][N:26]2[C:27](=[O:29])[N:28]=1>C1COCC1.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[C:11]([F:17])[C:12]([F:16])=[C:13]([F:15])[CH:14]=1)[CH2:18][O:19][C:23]1[CH:24]=[C:25]2[N:32]([CH3:33])[CH2:31][CH2:30][N:26]2[C:27](=[O:29])[N:28]=1
Reactant: OCc1ccc(Oc2cc(F)c(F)c(F)c2)c(F)c1
Reactant: CN1CCn2c1cc(Cl)nc2=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CN1CCn2c1cc(OCc1ccc(Oc3cc(F)c(F)c(F)c3)c(F)c1)nc2=O

Procedure:
Prepared in a manner similar to that described for E1 using (3-fluoro-4-(3,4,5-trifluorophenoxy)phenyl)methanol in THF (6 mL), sodium hydride (0.013 g, 0.323 mmol) and 7-chloro-1-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (0.040 g, 0.216 mmol) in DMF (1 mL).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:15])=[C:9]([N+]([O-])=O)[CH:10]=2)[N:5]=[CH:4][N:3]=1.NC1C=C(F)C=CC=1C(O)=[O:20].C(N)=N.C(O)(=O)C>COCCO>[F:15][C:8]1[CH:7]=[C:6]2[C:11]([C:2](=[O:20])[NH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: Nc1cc(F)ccc1C(=O)O
Reactant: O=[N+]([O-])c1cc2c(Cl)ncnc2cc1F
Agent: N=CN
Solvent: CC(=O)O
Solvent: COCCO
Product: O=c1[nH]cnc2cc(F)ccc12

Procedure:
4-Chloro-7-fluoro-6-nitroquinazoline (7) can be prepared by methods similar to those described in J.Med. Chem. 1996, 39, 918-928. Generally, 2-amino-4-fluoro-benzoic acid (1) can be reacted with formamidine (2) and acetic acid (3) in the presence of 2-methoxyethanol to provide 7-Fluoro-3H-quinazolin-4-one (4). The 7-fluoro-3H-quinazolin-4-one (4) can be nitrated to 7-fluoro-6-nitro-3H-quinazolin-4-one (5), which can be treated with thionyl chloride to yield 4-chloro-6-nitro-7-fluoro-3H-quinazoline (6). The 4-chloro-quinazoline compound (6) can be combined with a desirably substituted aniline, represented above by 4-fluoro-3-chloro-aniline, in the presence of a tertiary amine and isopropanol to provide the 4-anilino-6-nitro-7-fluoro-quinazoline (7).
Reaction SMILES: [NH:1]1[C:7]2=[C:8]3[C:13](=[N:14][C:15]4=[CH:16][CH:17]=[CH:18][C:5](=[C:6]24)[O:4][CH2:3][C:2]1=[O:19])[CH2:12][CH2:11][CH2:10][CH2:9]3.[CH3:20]C(C)([O-])C.[K+].IC>O1CCCC1>[CH3:20][N:1]1[C:7]2=[C:8]3[C:13](=[N:14][C:15]4=[CH:16][CH:17]=[CH:18][C:5](=[C:6]24)[O:4][CH2:3][C:2]1=[O:19])[CH2:12][CH2:11][CH2:10][CH2:9]3
Reactant: CC(C)(C)[O-]
Reactant: O=C1COc2cccc3nc4c(c(c23)N1)CCCC4
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: CN1C(=O)COc2cccc3nc4c(c1c23)CCCC4
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82.2 %

Procedure:
To a suspension of 1,3,9,10,11,12-hexahydro-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one (4.0 g) in dry tetrahydrofuran (120 ml) was added potassium tert-butoxide (1.94 g). The mixture was stirred at room temperature for 15 mins, iodomethane (1.08 ml) was added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated, saturated potassium carbonate solution (150 ml) was added, and mixture was extracted twice with 150 ml portions of ethyl acetate. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered, concentrated. Trituration with diethyl ether/pentane gave 3.47 g (82%) of product. Recrystallization from methanol gave the analytical sample, mp 176.5°-177.5° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[CH:7]=[CH:6]2.[CH3:19][S:20]([C:23]1[CH:24]=[CH:25][C:26]([O:32][C@@H:33]([CH3:38])[C:34]([F:37])([F:36])[F:35])=[C:27]([CH:31]=1)[C:28](O)=[O:29])(=[O:22])=[O:21].C(OCC)(=O)C>C(#N)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([N:13]1[CH2:14][CH2:15][N:16]([C:28]([C:27]3[CH:31]=[C:23]([S:20]([CH3:19])(=[O:21])=[O:22])[CH:24]=[CH:25][C:26]=3[O:32][C@@H:33]([CH3:38])[C:34]([F:36])([F:37])[F:35])=[O:29])[CH2:17][CH2:18]1)[CH:7]=[CH:6]2
Reactant: Clc1ccc2nc(N3CCNCC3)ccc2c1
Reactant: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ccc3cc(Cl)ccc3n2)CC1)C(F)(F)F

Procedure:
Prepared in analogy to example 1.1 b) from 6-chloro-2-piperazin-1-yl-quinoline hydrochloride (Example 1.20b) and 5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid (Example 2.7) in acetonitrile. Chromatography (SiO2; ethyl acetate) yields the title compound as a colorless solid.