Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[N:24]=[C:25]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[O:26][C:27]=3[CH3:28])=[CH:17][CH:16]=2)=[C:6]([CH2:8][C:9]([O:11]C)=[O:10])[CH:7]=1.O1CCCC1.[OH-].[Na+].Cl>O.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]3[N:24]=[C:25]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[O:26][C:27]=3[CH3:28])=[CH:19][CH:20]=2)=[C:6]([CH2:8][C:9]([OH:11])=[O:10])[CH:7]=1
Reactant: COC(=O)Cc1cc(Cl)ccc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2ccc(Cl)cc2CC(=O)O)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 95.4 %

Procedure:
To a mixture of methyl 2-[5-chloro-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetate (0.68 g), tetrahydrofuran (2 mL) and methanol (2 mL) was added a 1N aqueous sodium hydroxide solution (2.8 mL) and the mixture was stirred at 50° C. for 1 hr. 1N Hydrochloric acid (3 mL) and water were added to the reaction mixture, and the precipitated solid was collected by filtration, and dried with air to give crystals (0.63 g, 97%) of 2-[5-chloro-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetic acid. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 160-161° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([O:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([CH2:32]O)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C(Cl)Cl.O>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([CH2:32][O:1][C:2]2[CH:3]=[C:4]([O:9][S:10]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)(=[O:12])=[O:11])[CH:5]=[C:6]([CH3:8])[CH:7]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: Cc1cc(O)cc(OS(=O)(=O)c2ccccc2)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1cc(OCC2CCN(C(=O)OC(C)(C)C)CC2)cc(OS(=O)(=O)c2ccccc2)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 84.6 %

Procedure:
To a solution of benzenesulfonic acid 3-hydroxy-5-methylphenyl ester (528 mg, 2.0 mmol), as prepared in the preceding step, N-(tert-butoxycarbonyl)-4-piperidinemethanol (430 mg, 2.0 mmol), as prepared in step f of Example 1, and triphenylphosphine (525 mg, 2.0 mmol) in tetrahydrofuran (20 mL) at 0° C. was added diethyl azodicarboxylate (349 mg, 2.0 mmol). The reaction mixture was stirred at 0° C. for 2 h and at room temperature for 3 h. The reaction mixture was diluted with methylene chloride (200 mL) and water (50 mL). The organic extract was washed sequentially with saturated NaHCO3 (2×50 mL) and brine (2×50 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography (1:2 ethyl acetate:hexane) to give the title compound as a colorless liquid (781 mg, 84%). 1H-NMR (300 MHz, CDCl3) δ 1.24 (m, 2H), 1.47 (s, 9H), 1.76 (m, 2H), 1.88 (m, 1H), 2.24 (s, 3H), 2.73 (t, 2H), 3.66 (d, 2H), 4.12 (m, 2H), 6.32 (s, 1H), 6.58 (s, 1H), 7.54 (t, 2H), 7.67 (t, 1H), 7.86 (d, 2H).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[O:8]1[C:12]2([CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:29]=[C:28]4[C:23]([CH2:24][CH2:25][CH2:26][NH:27]4)=[CH:22][C:21]=3[O:30][CH3:31])[CH2:14][CH2:13]2)[O:11][CH2:10][CH2:9]1>N1C=CC=CC=1>[C:1]([N:27]1[C:28]2[C:23](=[CH:22][C:21]([O:30][CH3:31])=[C:20]([CH2:19][CH2:18][N:15]3[CH2:14][CH2:13][C:12]4([O:11][CH2:10][CH2:9][O:8]4)[CH2:17][CH2:16]3)[CH:29]=2)[CH2:24][CH2:25][CH2:26]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc2c(cc1CCN1CCC3(CC1)OCCO3)NCCC2
Solvent: c1ccncc1
Product: COc1cc2c(cc1CCN1CCC3(CC1)OCCO3)N(C(C)=O)CCC2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
3 ml of acetic anhydride and 3 ml of pyridine were added to 251 mg of 7-(2-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)ethyl)-6-methoxy-1,2,3,4-tetrahydroquinoline, and the obtained mixture was then stirred at room temperature for 90 minutes. The reaction solution was concentrated under a reduced pressure. The residue was diluted with ethyl acetate and then washed with water and a saturated sodium chloride aqueous solution. The organic layer was dried over magnesium sulfate and then concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (hexane-ethyl acetate) and then by silica gel column chromatography (ethyl acetate-methanol), so as to obtain 162 mg of the subject compound.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:12]([C:15]([F:18])([F:17])[F:16])=[N:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:19]([NH:21][CH2:22][CH3:23])[CH3:20]>CN(C)C=O>[CH2:19]([N:21]([CH2:22][CH3:23])[C:2]1[C:3]2[N:4]([C:12]([C:15]([F:18])([F:17])[F:16])=[N:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:20]
Reactant: CCNCC
Reactant: FC(F)(F)c1nnc2c(Cl)nc3ccccc3n12
Solvent: CN(C)C=O
Product: CCN(CC)c1nc2ccccc2n2c(C(F)(F)F)nnc12

Procedure:
A mixture consisting of 700 mg. (0.0025 mole) of 4-chloro-1-trifluoromethyl-[1,2,4]triazolo[4,3-a]quinoxaline (prepared as described above) and 560 mg. (0.0075 mole) of diethylamine (0.8 ml.) in 10 ml. of N,N-dimethylformamide was stirred at room temperature overnight and then poured over ice. The resulting mixture was then filtered and the recovered solid product washed with water and then dissolved in ethyl acetate. The latter organic solution was next washed with saturated brine and dried over anhydrous magnesium sulfate. After removal of the drying agent by means of filtration and the solvent by means of evaporation under reduced pressure, there are ultimately obtained a light yellow solid which after recrystallization from diethyl ether gave pure 4-diethylamino-1-trifluoromethyl-[1,2,4]triazolo[4,3-a]quinoxaline. The yield of the first crop melting at 155°-157° C. amounted to 260 mg. (34%), while the yield of the second crop melting at 153°-156° C. amounted to 170 mg. (22%).
Reaction SMILES: C[O:2][C:3](=[O:21])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15](Br)[CH:14]=2)=[CH:8][C:7]=1[CH3:20].[OH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:30]>>[C:29]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[O:22][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[O:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:2])=[O:21])=[C:7]([CH3:20])[CH:8]=1)(=[O:30])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=C(c1ccccc1)c1ccccc1O
Reactant: COC(=O)CCc1ccc(Oc2cccc(Br)c2)cc1C
Product: Cc1cc(Oc2cccc(Oc3ccccc3C(=O)c3ccccc3)c2)ccc1CCC(=O)O

Procedure:
The title compound is prepared by reacting the compound of 3-[4-(3-bromo-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester with (2-hydroxy-phenyl)-phenyl-methanone as in Example 18 to afford 0.020 g (14%). 1H NMR (400 MHz, CDCl3); HRMS (ES+) m/z mass calculated for C29H24O5 453.1702, found 453.1699.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[C:6]([OH:11])[CH:5]=1)([O-:3])=[O:2].[Br:12][C:13]1[CH:18]=[C:17]([Br:19])[CH:16]=[CH:15][C:14]=1[N:20]=[C:21]=[O:22]>>[OH:11][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:10]=[CH:9][C:7]=1[NH:8][C:21]([NH:20][C:14]1[CH:15]=[CH:16][C:17]([Br:19])=[CH:18][C:13]=1[Br:12])=[O:22]
Reactant: O=C=Nc1ccc(Br)cc1Br
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Product: O=C(Nc1ccc([N+](=O)[O-])cc1O)Nc1ccc(Br)cc1Br
Yield: 39.4 %

Procedure:
The urea was prepared from 4-nitro 2-hydroxy aniline(308 mg, 2 mmol) and 2,4-dibromo phenyl isocyanate(2 mmol) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the title compound(0.34 g, 39%). EI-MS m/z 430(M+H)+
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:17]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(C(C)C)CC)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>>[CH2:25]([N:24]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:14]([CH:11]1[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]1)=[O:16])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(C(=O)N(Cc2ccccc2)Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.7 %

Procedure:
To a stirred mixture of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (J. Med. Chem. 1998, 41, 2492–2502, 3.0 g, 13.1 mmol), dibenzylamine (2.5 mL, 13.1 mmol) and diisopropylethylamine (3.4 mL, 19.7 mmol) in dichrolomethane (150 mL) was added PyBroP (bromo-tris-pyrrolidino-phosophonium hexafluorophosphate) (6.1 g, 15.7 mmol) was added at 0° C. The mixture was stirred at ambient temperature for 18 h and partitioned between dichloromethane and water. After extraction with dichloromethane, the combined organic phase was dried over magnesium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel eluting with hexane/ethyl acetate (6:1) to afford 4.0 g (75%) of the title compound as a colorless amorphous powder.
Reaction SMILES: C[C@@H](N)C1C=CC=CC=1.[O:10]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH2:13][CH2:12][CH:11]1[C:20]([OH:22])=[O:21]>C(O)C>[O:10]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH2:13][CH2:12][C@@H:11]1[C:20]([OH:22])=[O:21]
Reactant: O=C(O)C1CCc2ccccc2O1
Agent: C[C@@H](N)c1ccccc1
Solvent: CCO
Product: O=C(O)[C@H]1CCc2ccccc2O1
Yield: 13.4 %

Procedure:
A solution of (+)-(R)-α-methylbenzylamine (0.37 mol) in ethanol (100 ml) was added to a solution of 3,4-dihydro-2H-1-benzopyran-2-carboxylic acid (0.36 mol) in ethanol (200 ml). The mixture was allowed to crystallize out. The precipitate was filtered off and dried. The residue was crystallized 4 times from ethanol. The precipitate was filtered off and dried. The residue was taken up in water, treated with HCl 10% and extracted with diethyl ether. The organic layer was separated, dried, filtered and the solvent was evaporated, yielding 8.6 g of (−)-(R)-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid (mp. 85.5° C., [α]D20=−6.7° (c=100 mg/10 ml in methanol)) (interm. 1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[C:12]([O:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=2)[CH2:23][CH2:22]1)(=[O:17])[CH2:13][C:14]([CH3:16])=O.[NH2:34]/[C:35](/[CH3:41])=[CH:36]\[C:37]([O:39][CH3:40])=[O:38]>C(O)(C)C>[CH3:16][C:14]1[NH:34][C:35]([CH3:41])=[C:36]([C:37]([O:39][CH3:40])=[O:38])[CH:7]([C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:13]=1[C:12]([O:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=2)[CH2:23][CH2:22]1)=[O:17]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CC(=O)CC(=O)OCCN1CCN(c2cccc(Cl)c2)CC1
Reactant: COC(=O)/C=C(/C)N
Solvent: CC(C)O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN2CCN(c3cccc(Cl)c3)CC2)C1c1cccc([N+](=O)[O-])c1
Yield: 29 %

Procedure:
A mixture of m-nitrobenzaldehyde, 2-[4-(3-chlorophenyl)-1-piperazinyl]ethyl acetoacetate and methyl 3-aminocrotonate was worked up in isopropyl alcohol in the same manner as Example 1 to give 2-[4-(3-chlorophenyl)-1-piperazinyl]ethyl methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate as a light yellow powder, m.p. 65°-68° C. (sintering). Yield 29.0%. IR(Nujol)cm-1 : 3300. NMR(CDCl3) δ: 2.34(3H,s, ##STR29## 2.36(3H,s, ##STR30## 3.63(3H,s,COOCH3), 4.21(2H,t,J=6,--COOCH2CH2 --), 5.12(1H,s,C(4) --H), 5.89(1H,s,NH).
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[N+]=[N-]>CO.[Pd]>[NH2:1][CH2:4][CH2:5][O:6][CH2:7][CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:14])([CH3:13])[CH3:15]
Reactant: CC(C)(C)OC(=O)NCCOCCN=[N+]=[N-]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCOCCN
Reaction time: 24 h
Yield: 84.7 %

Procedure:
A solution of tert-butyl 2-(2-azidoethoxy)ethylcarbamate (47.0 g, 0.204 mol) in MeOH was treated with 4 g of 10% Pd on carbon and shaken under H2 (3 Kg/cm2) for 24 hours. The solution was then filtered through a CELITE pad and concentrated to give 35.3 g of crude tert-butyl 2-(2-aminoethoxy)ethylcarbamate as a colorless liquid that was used without further purification.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[C:5]([C:15]#[N:16])=[C:6]([C:13]#[N:14])[C:7]([Cl:12])=[C:8](Cl)[C:9]=1[Cl:10].[C:17]1([OH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O.CC(C)=O>[Cl:12][C:7]1[C:6]([C:13]#[N:14])=[C:5]([C:15]#[N:16])[C:4]([Cl:3])=[C:9]([Cl:10])[C:8]=1[O:23][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: N#Cc1c(Cl)c(Cl)c(Cl)c(Cl)c1C#N
Reactant: Oc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: N#Cc1c(Cl)c(Cl)c(Oc2ccccc2)c(Cl)c1C#N
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A solution of potassium hydroxide (11.2 parts) in water (22 parts) was added dropwise to a stirred solution of 3,4,5,6-tetra-chloro-1,2-dicyanobenzene (26.6 parts) and phenol (9.4 parts) in acetone (100 parts) at 0° C. The solution was stirred at 60° C. for 2 hours before pouring into water (500 parts). The aqueous mixture was extracted with dichloromethane (3×500 parts). The dichloromethane extracts were washed with water (3×200 parts), dried over anhydrous Na2SO4, filtered and the dichloromethane was removed under reduced pressure to leave a brown solid. The solid was recrystallised from butan-1-ol. 3,5,6-Trichloro-l,2-dicyano-4-phenoxybenzene (17 parts) was obtained as a brown solid, m.p. 147°-150° C.
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14]([NH:16][C@H:17]1[CH2:21][CH2:20][NH:19][C:18]1=[O:22])=[O:15])[N:10]([CH2:23][CH:24]([CH3:26])[CH3:25])[N:9]=[CH:8]2.N[C@H:33]1CCCNC1=O>ClCCl.C(OCC)(=O)C>[F:1][C:2]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14]([NH:16][C@H:17]1[CH2:21][CH2:33][CH2:20][NH:19][C:18]1=[O:22])=[O:15])[N:10]([CH2:23][CH:24]([CH3:25])[CH3:26])[N:9]=[CH:8]2
Reactant: N[C@H]1CCCNC1=O
Reactant: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3F)c(C(=O)N[C@H]3CCNC3=O)cc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3F)c(C(=O)N[C@H]3CCCNC3=O)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.1 %

Procedure:
To a solution of 2,5-dioxopyrrolidin-1-yl-5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylate (prepared according to Example 16; 1.01 g, 2.28 mmol) in dichloromethane (10 mL) was added (S)-3-aminopiperidin-2-one (prepared according to Example 3; 521 mg, 4.56 mmol) and the reaction was allowed to stir overnight at ambient temperature. The reaction mixture was diluted with ethyl acetate and washed with 1M hydrochloric acid, 1M sodium hydroxide, saturated sodium bicarbonate, and saturated sodium chloride. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on a silica gel column, eluting with a gradient of 50-100% acetone/hexanes to yield (S)-5-(2,4-difluorophenoxy)-1-isobutyl-N-(2-oxopiperidin-3-yl)-1H-indazole-6-carboxamide (Ib) (1.00 g, 99%). Mass spec: 443 (M+1). 1H NMR (CDCl3) δ 8.58 (br, 1H), 8.34 (s, 1H), 7.87 (s, 1H), 7.15 (m, 1H), 7.04 (s, 1H), 7.00 (m, 1H), 6.89 (m, 1H), 5.80 (br, 1H), 4.51 (ddd, 1H), 4.22 (d, 2H), 3.38 (m, 2H), 2.70 (m, 1H), 2.36 (m, 2H), 1.99 (m, 2H), 1.70 (m, 1H), 0.93 (d, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[Cl-].[Al+3].[Cl-].[Cl-].COCCOC.CCO.[CH:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[Br:1][C:2]1[CH:3]=[C:4]([C:5]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:6])[CH:8]=[CH:9][CH:10]=1
Reactant: c1ccccc1
Reactant: O=C(Cl)c1cccc(Br)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCO
Solvent: COCCOC
Product: O=C(c1ccccc1)c1cccc(Br)c1
Yield: 92.4 %

Procedure:
1.65 ml (12.50 mmol) 3-Bromobenzoyl chloride was dissolved in 10 ml of dry benzene. This solution was then added cautiously under stirring to a suspension of 2.00 g (15.00 mmol, 1.20 eq.) aluminum chloride in 20 ml dry benzene at 10° C. After the complete addition the resulting mixture was refluxed for 5 h. After quenching the mixture by adding water and conc. hydrochloric acid the aq. layer was extracted with ethyl acetate. The comb. org. fractions were dried over Na2SO4 and evaporated. Column chromatography (hexanes/ether (9+1)) yielded 3.02 g (11.55 mmol, 92.40%) (3-Bromo-phenyl)-phenyl-methanone as a white solid. Rf.(hexanes/ether (9+1))=0.40. 1H-NMR (500 MHz, CDCl3): δ=7.37 (t, 1H, J=7.88 Hz), 7.51 (m, 2H), 7.62 (tt, 1H, J1=7.41 Hz, J2=1.42 Hz), 7.72 (m, 2H), 7.79 (m, 2H), 7.94 (t, 1H, J=1.80 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:13](=[O:14])[C:12]3[CH2:15][CH2:16][CH2:17][CH2:18][C:11]=3[C:10]2=[O:19])=[C:4]([F:20])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:27](Br)[C:28]#[CH:29].O>CN(C)C=O>[Cl:1][C:2]1[C:7]([O:8][CH2:29][C:28]#[CH:27])=[CH:6][C:5]([N:9]2[C:10](=[O:19])[C:11]3[CH2:18][CH2:17][CH2:16][CH2:15][C:12]=3[C:13]2=[O:14])=[C:4]([F:20])[CH:3]=1
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(O)c(Cl)cc1F
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCOc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl
Temperature: 25 °C
Yield: 70.9 %

Procedure:
To a solution of N-(4-chloro-2-fluoro-5-hydroxy-phenyl)-3,4,5,6-tetrahydrophthalimide (1 g) in dimethylformamide (10 ml), there was added anhydrous potassium carbonate (0.34 g) while stirring at room temperature. After stirring for 30 minutes at about 40° C., propargyl bromide (1 g) was added thereto, and the resultant mixture was stirred for 3 hours at 50°-60° C. After being allowed to cool to room temperature, the mixture was poured into water and extracted with ether. The ether layer was washed with water, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography to obtain 0.8 g of N-[4-chloro-2-fluoro-5-(2-propynyloxy)phenyl]-3,4,5,6-tetrahydrophthalimide (Compound No. 3). M.P., 136.4° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:13]([O-:15])=[O:14])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].Cl.Cl[CH2:18][CH2:19][N:20]([CH2:23][CH3:24])[CH2:21][CH3:22]>>[N+:13]([C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:18][CH2:19][N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:12][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8])([O-:15])=[O:14]
Reactant: CCN(CC)CCCl
Reactant: CCOC(=O)c1cc(O)ccc1[N+](=O)[O-]
Agent: Cl
Product: CCOC(=O)c1cc(OCCN(CC)CC)ccc1[N+](=O)[O-]

Procedure:
Prepared analogously to intermediate product Z5a from ethyl 5-hydroxy-2-nitrobenzoate and (2-chloroethyl)-diethyl-amine-hydrochloride
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:21][OH:22])=[C:4]([N:8]2[C:12](=[O:13])[C:11]3[S:14][C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:16][C:10]=3[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[C:29](Cl)(=[O:31])[CH3:30]>C(Cl)Cl>[C:29]([O:22][CH2:21][C:3]1[C:4]([N:8]2[C:12](=[O:13])[C:11]3[S:14][C:15]([C:17]([CH3:19])([CH3:18])[CH3:20])=[CH:16][C:10]=3[CH2:9]2)=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1])(=[O:31])[CH3:30]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)c1cc2c(s1)C(=O)N(c1cccc(Br)c1CO)C2
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCc1c(Br)cccc1N1Cc2cc(C(C)(C)C)sc2C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with 114g (240 mg, 0.633 mmol), pyridine (150 mg, 1.90 mmol) and methylene chloride (10 mL). The solution was cooled to 0° C., and acetyl chloride (75 mg, 0.950 mmol) was added. The cooling bath was then removed, and the reaction mixture was stirred at room temperature for 1 h. After this time, the reaction mixture was partitioned between water (5 mL) and methylene chloride (5 mL), and the layers were separated. The aqueous phase was extracted with methylene chloride (2×10 mL), and the combined organic extracts were washed with saturated aqueous sodium bicarbonate (10 mL), water (10 mL) and brine (10 mL). The organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography to afford 114h in 86% yield (231 mg) as a white solid: mp 172-173° C.; 1H NMR (500 MHz, CDCl3) δ 7.63 (d, 1H, J=8.0 Hz), 7.34-7.21 (m, 2H), 6.87 (s, 1H), 5.21 (s, 2H), 4.64 (s, 2H), 2.05 (s, 3H), 1.42 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:8][C:9]2[C:15]([CH3:16])=[CH:14][C:12]([NH2:13])=[C:11]([CH3:17])[CH:10]=2)[S:5][C:6]=1[Cl:7].COC(OC)OC.[C:25]1([CH3:35])C=CC(S(O)(=O)=O)=CC=1.[CH3:36][NH:37][CH2:38]C>COC(C)(C)C>[Cl:1][C:2]1[N:3]=[C:4]([O:8][C:9]2[C:15]([CH3:16])=[CH:14][C:12]([N:13]=[CH:36][N:37]([CH2:25][CH3:35])[CH3:38])=[C:11]([CH3:17])[CH:10]=2)[S:5][C:6]=1[Cl:7]
Reactant: Cc1cc(Oc2nc(Cl)c(Cl)s2)c(C)cc1N
Reactant: CCNC
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(OC)OC
Solvent: COC(C)(C)C
Product: CCN(C)C=Nc1cc(C)c(Oc2nc(Cl)c(Cl)s2)cc1C
Temperature: 50 °C
Reaction time: 16 h
Yield: 91 %

Procedure:
To a mixture of 2.0 g (6.9 mmol) of 4-[(4,5-dichloro-1,3-thiazol-2-yl)oxy]-2,5-dimethylaniline and 11.3 ml (0.13 mol) of trimethoxymethane 0.12 g (0.7 mmol) of p-toluene sulfonic acid were added. The reaction mixture was refluxed for 16 hrs and concentrated in vacuo. The crude product was solved in 12 ml of toluene and 0.82 g (13.8 mmol) N-methylethanamine were added. The reaction mixture was stirred for 16 hrs at 50° C. The reaction mixture was concentrated in vacuo. Column chromatographie (gradient: petroleum ether->methyl-tert. butyl ether) yielded 2.3 g (6.3 mmol) 91% of N′-{4-[(4,5-dichloro-1,3-thiazol-2-yl)oxy]-2,5-dimethylphenyl}-N-ethyl-N-methylimidoformamide; log P (pH 2.3)=2.04
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:5]=1[CH3:14].[Br:16]N1C(=O)CCC1=O.C(OCC)(=O)C.CCCCCC>C1C=CC=CC=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:12])([F:11])[F:13])[C:5]=1[CH2:14][Br:16]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cccc(C(F)(F)F)c1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: c1ccccc1
Product: COC(=O)c1cccc(C(F)(F)F)c1CBr
Temperature: 25 °C
Reaction time: 48 h
Yield: 80.9 %

Procedure:
To a solution of 2-methyl-3-trifluoromethyl-benzoic acid methyl ester (0.95 g, 4.35 mmol) in benzene (10 mL) was added N-bromosuccinimide (0.77 g, 4.33 g) and benzoyl peroxide (0.052 g, 0.21 mmol) and the resulting mixture heated to reflux for 4 h, cooled and stirred at room temperature for 48 h. The mixture was filtered, the filter cake washed with diethyl ether and the filtrate washed with a 1 N sodium thiosulfate solution (10 mL), brine and dried over magnesium sulfate. The mixture was filtered and evaporated and the residue purified via automated flash chromatography (Analogix, SF25-80 g column, 5->10% ethyl acetate/hexane gradient) to give 2-bromomethyl-3-trifluoromethyl-benzoic acid methyl ester (1.04 g, 3.50 mmol, 81%) as an off white solid; 1H NMR (300 MHz, DMSO-d6) δ ppm 3.72-4.16 (m, 3H), 5.03 (s, 2H), 7.47-8.32 (m, 3H).