Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH:4]=[C:5]1[CH2:10][CH:9]=[CH:8][C:7](=[CH:11][N:12]([CH3:14])[CH3:13])[CH:6]1Br)[CH3:3].C([Li])CCC.[Cl-].[CH3:22][In+:23][CH3:24]>CCCCCC>[CH3:1][N:2]([CH:4]=[C:5]1[CH2:10][CH:9]=[CH:8][C:7](=[CH:11][N:12]([CH3:14])[CH3:13])[CH:6]1[In:23]([CH3:24])[CH3:22])[CH3:3]
Reactant: CN(C)C=C1C=CCC(=CN(C)C)C1Br
Reactant: C[In+]C
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CN(C)C=C1C=CCC(=CN(C)C)C1[In](C)C

Procedure:
2.71 g (10.0 mmol) of 2,6-bis(dimethylaminomethylene)phenyl bromide in 40 ml of hexane, 6.3 ml of n-butyllithium (10.0 mmol; 1.6 mol/l in hexane) and 1.8 g (10.0 mmol) of dimethylindium chloride in 20 ml of hexane are reacted analogously to Example 1 to give [2,6-bis(di-methylaminomethylene)phenyl] dimethylindium, which is obtained in the form of colorless crystals, m.p. 53° C., by cooling a concentrated hexane solution to -30° C.
Reaction SMILES: C(=O)=O.CCO.[CH2:7]([N:14]1[C:18]2[CH:19]=[CH:20][C:21]([C:23](=[O:26])[CH2:24][CH3:25])=[CH:22][C:17]=2[O:16][C:15]1=[O:27])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.I[CH:29]([CH2:34][CH2:35][CH3:36])[C:30]([O:32][CH3:33])=[O:31].Cl>C1COCC1>[CH2:7]([N:14]1[C:18]2[CH:19]=[CH:20][C:21]([C:23](=[O:26])[CH:24]([CH:29]([CH2:34][CH2:35][CH3:36])[C:30]([O:32][CH3:33])=[O:31])[CH3:25])=[CH:22][C:17]=2[O:16][C:15]1=[O:27])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCC(=O)c1ccc2c(c1)oc(=O)n2Cc1ccccc1
Reactant: CCCC(I)C(=O)OC
Agent: Cl
Agent: O=C=O
Solvent: CCO
Solvent: C1CCOC1
Product: CCCC(C(=O)OC)C(C)C(=O)c1ccc2c(c1)oc(=O)n2Cc1ccccc1
Temperature: -2 °C
Reaction time: 0.5 h

Procedure:
200 mL (0.5 mol/l in toluene, 100 mmol) bis-(trimethylsilyl)-potassium amide in 1.50 L THF are placed under protective gas and cooled to −60° C. with dry ice/EtOH. 20 g (71 mmol) of 3-benzyl-6-propionyl-3H-benzoxazol-2-one dissolved in 500 mL THF are slowly added dropwise. The reaction mixture is stirred for 30 min at −2° C. and then cooled to −60° C. again. 20 g (83 mmol) methyl 2-iodo-pentanoate are added and the mixture is stirred for 45 min at −60° C. Then the reaction mixture is combined with 500 mL of 2M HCl and extracted at RT with diethyl ether. The organic phase is washed with saline solution, suction filtered through cellulose and the solv. is eliminated i.V. The residue is purified through silica gel (DCM/MeOH)
Reaction SMILES: Cl.[NH2:2][CH:3]1[C:25](=[O:26])[N:5]2[C:6]([C:22]([OH:24])=[O:23])=[C:7](/[CH:10]=[CH:11]/[CH2:12][N+:13]3[CH:18]=[CH:17][C:16]([C:19](=[O:21])[NH2:20])=[CH:15][CH:14]=3)[CH2:8][S:9][C@H:4]12.C([O-])(O)=O.[Na+].N1([CH2:41][O:42][N:43]=[C:44]([C:48]2[N:52]=[C:51]([NH2:53])[S:50][N:49]=2)[C:45]([O-])=[O:46])C2C=CC=CC=2N=N1.Cl>CN(C=O)C.CC(C)=O>[NH2:53][C:51]1[S:50][N:49]=[C:48]([C:44](=[N:43][O:42][CH3:41])[C:45]([NH:2][CH:3]2[C:25](=[O:26])[N:5]3[C:6]([C:22]([O-:24])=[O:23])=[C:7]([CH:10]=[CH:11][CH2:12][N+:13]4[CH:14]=[CH:15][C:16]([C:19](=[O:21])[NH2:20])=[CH:17][CH:18]=4)[CH2:8][S:9][C@H:4]23)=[O:46])[N:52]=1
Reactant: Nc1nc(C(=NOCn2nnc3ccccc32)C(=O)[O-])ns1
Reactant: NC(=O)c1cc[n+](C/C=C/C2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C=CC[n+]3ccc(C(N)=O)cc3)CS[C@H]12)c1nsc(N)n1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a mixture of 7-amino-3-[3-(4-carbamoylpyridinio)-1-(E)-propenyl]-3-cephem-4-carboxylic acid hydrochloride (XXII-H, 397 mg, 1 mmole) and NaHCO3 (168 mg, 2 mmoles) in aqueous DMF (water, 3.5 ml and DMF, 7.5 ml) was added benzotriazol-1-yl-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetate (479 mg, 1.5 mmoles) (from Preparation No. 28). The mixture was stirred at room temperature for 3.5 hours. The reaction mixture was adjusted to pH 3-4 with 3N HCl and diluted with 200 ml of acetone to give a precipitate, which was collected by filtration. The crude product was dissolved in a small volume of aqueous THF and the solution was adjusted to pH 6.8 with NaHCO3, treated with decolorizing carbon, concentrated to ca. 1 ml and seeded with a few pieces of crystalline I-1H. After stirring overnight, the crystalline precipitate was collected by filtration to afford the title compound I-1H (zwitterion form). Yield 83 mg (16%). Mp. >185° C. (dec.). Physico-chemical data of this product were identical to those of the compound in Example 10.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1/C(=N\O)/C.P(Cl)(Cl)(Cl)=O.C(=O)([O-])O.[Na+].[C:23](#[N:25])[CH3:24]>CC(N(C)C)=O>[CH3:24][C:23]1[O:1][C:2]2[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=2[N:25]=1
Reactant: C/C(=N/O)c1ccc(O)cc1O
Reactant: CC#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC(=O)N(C)C
Product: Cc1nc2ccc(O)cc2o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
To a cooled (5° C.) solution of (1Z)-1-(2,4-dihydroxyphenyl)ethanone oxime (9.7 g, 57.7 mmol) in acetonitrile (65 mL) and dimethylacetamide (11 mL) was added phosphorus oxychloride (5.6 mL, 60.3 mmol) drop wise. The temperature was not allowed to exceed 10° C. during the addition. After 1 hrs stirring at room temperature the yellow slurry was poured on a mixture of sodium hydrogen carbonate and ice. The resulting precipitate was filtered off and dried yielding 6.3 g (73%) the titled compound.
Reaction SMILES: FC(F)(F)C(O[C:6](=[O:11])[C:7](F)(F)F)=O.[Br:14][C:15]1C(C)=[N+:17]([O-])[CH:18]=[CH:19][CH:20]=1>C(Cl)Cl.C(OCC)(=O)C>[Br:14][C:15]1[C:7]([CH2:6][OH:11])=[N:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1c(Br)ccc[n+]1[O-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: OCc1ncccc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.3 %

Procedure:
Trifluoroacetic anhydride (0.52 mL, 3.6 mmol) was added to a solution of 3-bromo-2-methylpyridine 1-oxide (140 mg, 0.72 mmol) in methylene chloride (2 mL) and the mixture was stirred for 16 hours at room temperature. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with saturated aqueous sodium bicarbonate solution (20 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 4 g, ISCO, 0-75% ethyl acetate in heptane) to afford the title compound as a yellow oil (110 mg, 75%). 1H NMR (400 MHz, DMSO) δ 8.56 (d, J=4.7 Hz, 1H), 8.10 (dd, J=8.0, 1.1 Hz, 1H), 7.32 (dd, J=8.0, 4.7 Hz, 1H), 4.64 (s, 2H); OH peak not observed.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][N:7]=[C:6]([S:10][CH2:11][C:12](=O)[CH3:13])[CH:5]=1.Cl.[Cl:17][C:18]1[CH:19]=[C:20]([NH:24]N)[CH:21]=[CH:22][CH:23]=1>>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][N:7]=[C:6]([S:10][C:11]2[C:21]3[C:20](=[CH:19][C:18]([Cl:17])=[CH:23][CH:22]=3)[NH:24][C:12]=2[CH3:13])[CH:5]=1
Reactant: COC(=O)c1ccnc(SCC(C)=O)c1
Reactant: NNc1cccc(Cl)c1
Agent: Cl
Product: COC(=O)c1ccnc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: 2-(2-oxo-propylsulfanyl)-isonicotinic acid methyl ester and (3-chloro-phenyl)-hydrazine hydrochloride.
Reaction SMILES: C([O:3][C:4](=[O:45])[CH2:5][C@@H:6]([CH2:34][CH2:35][C:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[NH:38][CH:37]=1)[NH:7][C:8](=[O:33])[CH2:9][N:10]([C:14](=[O:32])[CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][N:21]=[C:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:19]=1[NH2:31])[CH:11]1[CH2:13][CH2:12]1)C.[OH-].[Na+]>CCO.CCOC(C)=O>[C:24]([C:20]1[C:19]([NH2:31])=[C:18]([CH2:17][CH2:16][CH2:15][C:14]([N:10]([CH:11]2[CH2:13][CH2:12]2)[CH2:9][C:8]([NH:7][C@H:6]([CH2:34][CH2:35][C:36]2[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[NH:38][CH:37]=2)[CH2:5][C:4]([OH:45])=[O:3])=[O:33])=[O:32])[CH:23]=[CH:22][N:21]=1)([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25]
Reactant: CCOC(=O)C[C@@H](CCc1c[nH]c2ccccc12)NC(=O)CN(C(=O)CCCc1ccnc(C(=O)OC(C)(C)C)c1N)C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1nccc(CCCC(=O)N(CC(=O)N[C@H](CCc2c[nH]c3ccccc23)CC(=O)O)C2CC2)c1N

Procedure:
Ester 8-1 (223 mg, 0.36 mmol) was dissolved in 4 mL EtOH, then 1 N NaOH (0.90 mL, 0.90 mmol) was added. After a few hours the reaction was diluted with EtOAc, extracted with water and the pH of the aq. phase was adjusted to 1 with 10% KHSO4. The aqueous layer was extracted with EtOAc (2×), the combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated, providing 8-2 as an oil.
Reaction SMILES: [O:1]([CH2:9][CH:10]1[CH2:13][CH:12]([OH:14])[CH2:11]1)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[O:15]1[CH:20]=[CH:19][CH2:18][CH2:17][CH2:16]1>ClCCl.C1(C)C(S(O)(=O)=O)=CC=CC=1>[C:5]([Si:2]([CH3:4])([CH3:3])[O:1][CH2:9][CH:10]1[CH2:11][CH:12]([O:14][CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][O:15]2)[CH2:13]1)([CH3:8])([CH3:7])[CH3:6]
Reactant: C1=COCCC1
Reactant: CC(C)(C)[Si](C)(C)OCC1CC(O)C1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC1CC(OC2CCCCO2)C1
Yield: 79.9 %

Procedure:
3-(tert-Butyl dimethylsilanoxymethyl)-cyclobutanol (1.46 g) in dry dichloromethane was treated with dihydropyran (1.7 g) and toluenesulphonic acid (0.01 g) for 3 hours. The reaction mixture was diluted with dichloromethane, the organic extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate in cyclohexane (0 to 1:9 by volume) to give the title compound (1.62 g).
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[C:18]([NH2:19])=[C:17]([OH:20])[C:16]([Cl:21])=[CH:15][C:14]=2[F:22])[C:3]1=[O:23].[C:24](Cl)(=O)[CH:25]([CH3:27])[CH3:26].C(N(CC)CC)C.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C(C)=CC=CC=1>[CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[C:18]3[N:19]=[C:24]([CH:25]([CH3:27])[CH3:26])[O:20][C:17]=3[C:16]([Cl:21])=[CH:15][C:14]=2[F:22])[C:3]1=[O:23]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c(O)c2N)c1=O
Reactant: CC(C)C(=O)Cl
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1C
Solvent: CCN(CC)CC
Product: CC(C)c1nc2c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc(Cl)c2o1
Yield: 36.1 %

Procedure:
This compound was prepared in the manner of Step C of Example 1, using 0.52 gram (0.0015 mole) of 1-methyl-6-trifluoromethyl-3-(6-amino4-chloro-2-fluoro-5-hydroxyphenyl)-2,4(1H,3H)-pyrimidinedione, 0.18 gram (0.0017 mole) of isobutyryl chloride, 0.24 gram (0.0017 mole) of triethylamine, and 0.09 gram (0.0004 mole) of pyridinium p-toluenesulfonate in 50 mL of xylene, yielding 0.22 gram of Compound 28. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [OH:1][CH:2]1[CH:6]=[CH:5][C:4](=O)[CH:3]1[CH2:8][CH2:9][CH2:10][S:11][CH2:12][C:13]([O:15]CC)=[O:14].S(=O)(=O)(O)[OH:19].[Cl-].[Na+]>>[C:13]([CH2:12][S:11][CH2:10][CH2:9][CH2:8][C:3]1[C:2](=[O:1])[CH2:6][CH:5]([OH:19])[CH:4]=1)([OH:15])=[O:14]
Reactant: O=S(=O)(O)O
Reactant: CCOC(=O)CSCCCC1C(=O)C=CC1O
Agent: [Cl-]
Agent: [Na+]
Product: O=C(O)CSCCCC1=CC(O)CC1=O

Procedure:
The solution, containing crude 3-hydroxy-2[3-(carbethoxymethylthio)propyl]cyclopent-4-en-1-one, is cooled and treated during 10 minutes with 75 ml of sulfuric acid (d=1.84) with stirring. The stirred solution is refluxed for 16 hours, cooled, saturated with sodium chloride, and extracted with ethyl acetate. The extract is washed with brine, dried over magnesium sulfate, and concentrated. The residue is subjected to chromatography on silica gel with chloroform progressively enriched in ether, ether, and ether progressively enriched in acetone to afford the subject compound as an oil.
Reaction SMILES: OS(O)(=O)=O.[N+:6]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][N:10]=1)([O-:8])=[O:7]>CC(O)(C)C.CCOC(C)=O>[C:17]([N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]([N+:6]([O-:8])=[O:7])=[N:10]1)([CH3:12])([CH3:9])[CH3:16]
Reactant: O=[N+]([O-])c1n[nH]c2ccccc12
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Product: CC(C)(C)n1nc([N+](=O)[O-])c2ccccc21
Temperature: 25 °C
Yield: 147.7 %

Procedure:
Cone. H2SO4 (2 mL) was added to a suspension of 3-nitro-1 H-indazole (3.4 g, 21 mmol) in 2-methyl-propan-2-ol (30 mL) and the resulting mixture was heated to 180° C. in a steel bomb. The reaction mixture was cooled to RT and diluted with EtOAc. The organic phase was washed with brine, dried (MgSO4) and concentrated to give 1-tert-butyl-3-nitro-1 H-indazole (3.4 g, 76%). 1H NMR (400 MHz, DMSO-d6): δ 8.18-8.15 (m, 2 H), 7.59-7.49 (m, 2 H), 1.76 (s, 9 H).
Reaction SMILES: [H-].[Na+].Cl.[NH2:4][C:5]1[C:20]([Cl:21])=[CH:19][C:8]([C:9]([NH:11][CH2:12][CH2:13][N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[O:10])=[C:7]([OH:22])[CH:6]=1.Cl[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:26]>CN(C=O)C>[NH2:4][C:5]1[C:20]([Cl:21])=[CH:19][C:8]([C:9]([NH:11][CH2:12][CH2:13][N:14]([CH2:15][CH3:16])[CH2:17][CH3:18])=[O:10])=[C:7]([O:22][CH2:24][C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:26])[CH:6]=1
Reactant: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1O
Reactant: O=C(CCl)c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OCC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 50.1 %

Procedure:
To a stirred suspension of sodium hydride (320 mg of 60%, 8 mmoles, washed with n-pentane) in DMF (15 ml) was added 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-hydroxybenzamide hydrochloride (1.289 g, 4 mmoles) and the mixture stirred for 20 minutes followed by addition of chloroacetophenone (619 mg, 4 mmoles). The mixture was stirred 4 hours, poured into ice-cold water (50 ml) whereupon a solid separated out. This was isolated by filtration, dried and recrystallized from methanol to give 810 mg (50%) of the title compound as white solid mp 153°-4°. The NMR spectrum (90 MHz) in CDCl3 gave the following resonances: δ 8.64 (bs, 1H); 8.2 (s, 1H); 8 (m, 2H); 7.6 (m, 3H); 6.22 (s, 1H); 5.36 (s, 2H); 4.4 (s, 2H); 3.52 (m, 2H); 2.64 (m, 6H); 1.01 (m, 6H).
Reaction SMILES: O.NN.[CH3:4][O:5][C:6]1[CH:7]=[C:8](/[CH:16]=[CH:17]/[CH:18]=[CH:19]/[C:20]([N:22]2[CH2:27][CH2:26][N:25]([C:28](=[O:45])/[CH:29]=[CH:30]/[CH:31]=[CH:32]/[C:33]3[CH:38]=[C:37]([O:39][CH3:40])[C:36]([O:41][CH3:42])=[C:35]([O:43][CH3:44])[CH:34]=3)[CH2:24][CH:23]2[CH2:46][N:47]2C(=O)C3=CC=CC=C3C2=O)=[O:21])[CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13]>CO>[NH2:47][CH2:46][CH:23]1[CH2:24][N:25]([C:28](=[O:45])/[CH:29]=[CH:30]/[CH:31]=[CH:32]/[C:33]2[CH:38]=[C:37]([O:39][CH3:40])[C:36]([O:41][CH3:42])=[C:35]([O:43][CH3:44])[CH:34]=2)[CH2:26][CH2:27][N:22]1[C:20](=[O:21])/[CH:19]=[CH:18]/[CH:17]=[CH:16]/[C:8]1[CH:7]=[C:6]([O:5][CH3:4])[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=1
Reactant: COc1cc(/C=C/C=C/C(=O)N2CCN(C(=O)/C=C/C=C/c3cc(OC)c(OC)c(OC)c3)C(CN3C(=O)c4ccccc4C3=O)C2)cc(OC)c1OC
Agent: NN
Solvent: CO
Solvent: O
Product: COc1cc(/C=C/C=C/C(=O)N2CCN(C(=O)/C=C/C=C/c3cc(OC)c(OC)c(OC)c3)C(CN)C2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 17 h
Yield: 65.8 %

Procedure:
A solution of 1.3 ml (26 mmol) of hydrazine hydrate in methanol (2 ml) was added to a suspension of 430 mg (0.58 mmol) of N-[1,4-bis[5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoyl]-2-piperazinylmethyl]phthalimide synthesized by the process described in Example 48 in methanol (8 ml), and the mixture was stirred for 17 hours at room temperature. The reaction mixture was concentrated under reduced pressure, and the resultant residue was extracted with chloroform. An organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resultant crude oil was purified by column chromatography on silica gel to obtain 232 mg (yield: 65%) of 2-aminomethyl-1,4-bis[5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoyl]piperazine as a pale yellow amorphous powder.
Reaction SMILES: [Cl:1][C:2]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:3]=1[C:4]([S:7][CH2:8]Cl)([CH3:6])[CH3:5].[P:15]([S-:21])(=[S:20])([O:18][CH3:19])[O:16][CH3:17].[Na+]>>[P:15]([S:21][CH2:8][S:7][C:4]([CH3:6])([CH3:5])[C:3]1[CH:10]=[CH:11][CH:12]=[C:13]([Cl:14])[C:2]=1[Cl:1])(=[S:20])([O:18][CH3:19])[O:16][CH3:17]
Reactant: CC(C)(SCCl)c1cccc(Cl)c1Cl
Reactant: COP(=S)([S-])OC
Agent: [Na+]
Product: COP(=S)(OC)SCSC(C)(C)c1cccc(Cl)c1Cl

Procedure:
Using chloromethyl 2,3-dichloro-α,α-dimethylbenzyl sulfide (prepared from 2,3-dichloro-α,α-dimethyl-α-toluenethiol obtained as in Example 1 from 2,3-dichloro-α,α-dimethylbenzyl alcohol) and stirring vigorously for 2 hours at 50° C. with a 10% excess of 50% aqueous sodium O,O-dimethyl phosphorodithioate solution gives a crude product which is purified as in Example 6 to give the pure, desired product as a colorless oil.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[N+:18]([CH:21]=[C:22]1[NH:27][CH2:26][CH2:25][CH2:24][S:23]1)([O-:20])=[O:19]>ClCCl>[C:1]1([CH2:7][C:8]([N:27]2[CH2:26][CH2:25][CH2:24][S:23][C:22]2=[CH:21][N+:18]([O-:20])=[O:19])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: O=[N+]([O-])C=C1NCCCS1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cc1ccccc1)N1CCCSC1=C[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of phenylacetyl chloride (4.8 g) in dry dichloromethane (30 ml) at -20° C. was added triethylamine (5.2 ml) over a period of 20 minutes, followed by 2-(nitromethylene)-tetrahydro-2H-1,3-thiazine (3.2 g) in dry dichloromethane (30 ml) over a period of 20 minutes. The reaction mixture was allowed to warm to ambient temperature with stirring over a period of 30 minutes and was then worked up in a similar manner to that described in Example 1 to yield the required product as a white crystalline solid m.p. 121°-122° C.
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]([CH2:20][CH3:21])[C:7]([CH2:9][CH2:10][C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)=O)=[N:8][C:4]=2[CH:3]=1.BrBr.[CH:26]([NH2:28])=[S:27].C(N)=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=S>O1CCOCC1>[Br:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]([CH2:20][CH3:21])[C:7]([CH2:9][C:10]3[S:27][CH:26]=[N:28][C:11]=3[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: NC=S
Reactant: CCn1c(CCC(=O)c2cccc(F)c2)nc2cc(Br)ccc21
Agent: BrBr
Agent: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: NC=O
Solvent: C1COCCO1
Product: CCn1c(Cc2scnc2-c2cccc(F)c2)nc2cc(Br)ccc21

Procedure:
A mixture of 3-(5-bromo-1-ethyl-1H-benzoimidazol-2-yl)-1-(3-fluoro-phenyl)-propan-1-one (0.2 g, 0.53 mmol) and bromine (0.1 g, 0.62 mmol) is refluxed in 1,4-dioxane for 2 hours. Thioformamide (freshly made from formamide and P2S5 in 1,4-dioxane) (1.3 mmol) are added to the solution. The mixture is refluxed overnight. The solvent is removed and NaHCO3 (aq.) (15 mL) and DCM (40 mL) are added to the residue. The organic layer is separated and the aqueous layer is extracted with DCM (2×30 mL). The combined organic layers are dried and solvent removed. The crude is purified by PTLC (5% methanol in DCM) to give 5-bromo-1-ethyl-2-[4-(3-fluoro-phenyl)-thiazol-5-ylmethyl]-1H-benzoimidazole. 1H NMR (CDCl3) δ 8.78 (s, 1H), 7.91 (s, 1H), 7.38-7.48 (m, 4H), 7.11-7.19 (m, 2H), 4.59 (s, 2H), 3.90 (q, 2H), 1.12 (t, 3H).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C[O:8][C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[CH2:19][N:18]([CH2:21][CH:22]1[O:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[O:24][CH2:23]1)[CH2:17][CH2:16]2)=O.O>C1COCC1>[O:27]1[C:26]2[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=2[O:24][CH2:23][CH:22]1[CH2:21][N:18]1[CH2:17][CH2:16][C:15]2[C:20](=[C:11]([CH2:9][OH:8])[CH:12]=[CH:13][CH:14]=2)[CH2:19]1
Reactant: COC(=O)c1cccc2c1CN(CC1COc3ccccc3O1)CC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1cccc2c1CN(CC1COc3ccccc3O1)CC2
Temperature: 80 °C

Procedure:
To a suspension of LiAlH4 (0.20 g, 5.44 mmol) in dry THF (10 ml) was added 2-(2,3-dihydrobenzo-[1,4]dioxin-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-8-carboxylic acid methyl ester (0.18 g, 0.54 mmol). The reaction mixture was heated under microwaves at 80° C. for 10 min. Water (10 ml) was slowly added under cooling followed by extraction with EtOAc (3×5 ml). The combined organic phases were dried (Na2SO4), filtered and the filtrate was evaporated to give the title compound, which was purified by column chromatography (EtOAc/heptane, 50:50).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)[CH:10]=[C:9]([C:23]([F:26])([F:25])[F:24])[N:8]=2)[CH:6]=1.[NH2:27][C:28]1[N:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][N:29]=1>>[F:24][C:23]([F:26])([F:25])[C:9]1[CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[N:12]=[C:7]([N:5]2[CH:6]=[C:2]([C:31]3[CH:30]=[N:29][C:28]([NH2:27])=[N:33][CH:32]=3)[N:3]=[CH:4]2)[N:8]=1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: FC(F)(F)c1cccc(-c2cc(C(F)(F)F)nc(-n3cnc(Br)c3)n2)c1
Product: Nc1ncc(-c2cn(-c3nc(-c4cccc(C(F)(F)F)c4)cc(C(F)(F)F)n3)cn2)cn1

Procedure:
The title compound was prepared from 2-(4-bromo-imidazol-1-yl)-4-(3-trifluoromethylphenyl)-6-trifluoromethyl-pyrimidine (example E.57) (0.22 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.13 g, 0.6 mmol) according to the general procedure VI. Obtained as a yellow solid (0.106 g, 47%). MS (ISP) 452.0 [(M+H)+]; mp 223° C.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:13]=[C:12]([N:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[CH3:15])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.C([O-])([O-])=O.[Cs+].[Cs+].[NH2:30][CH2:31][CH2:32][CH2:33][OH:34].CCOC(C)=O>CN(C=O)C>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([N:14]([CH3:15])[C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([CH2:3][NH:30][CH2:31][CH2:32][CH2:33][OH:34])[N:13]=2)=[CH:17][CH:18]=1
Reactant: COc1ccc(N(C)c2nc(CCl)nc3ccccc23)cc1
Reactant: NCCCO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(N(C)c2nc(CNCCCO)nc3ccccc23)cc1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
A mixture of (2-chloromethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine hydrochloride (100 mg, 0.286 mmol), Cs2CO3 (201 mg, 0.617 mmol) and 3-amino-propan-1-ol (44 μL, 0.58 mmol) in DMF (1 mL) was heated at 80° C. After 18 h, EtOAc (12 mL) was added and this was washed with water (2×2 mL) and satd NaCl (2×2 mL). The soln was dried (MgSO4), filtered through a plug of silica with a wash of 100:10:1 chloroform:methanol:concd NH4OH then purified by preparative TLC (SiO2/200:10:1 chloroform:2-propanol:concd NH4OH). A band was removed from this preparative TLC plate and further purified by preparative TLC (SiO2/100:10:1 chloroform:methanol:concd NH4OH) yielding the title compound as a yellow oil. The bis(hydrochloride) salt was formed by adding then evaporating a soln of HCl in i-PrOH, giving an off-white solid. 1H NMR (DMSO-d6) δ 7.84 (m, 1H), 7.78 (m, 1H), 7.35 (m, 2H), 7.25 (m, 1H), 7.09 (m, 2H), 6.90 (m, 1H), 4.91 (t(br), 2H), 3.82 (s, 3H), 3.68 (s, 3H), 3.56 (t, J=6.2 Hz, 2H), 3.24 (m, 2H), 1.91 (m, 2H); LC-MS (ESI+; 353 ([M+H]+)).