Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:2]=[C:3]2[N:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=13)[S:6][C:5]([C:13]([OH:15])=O)=[CH:4]2.ON1C(=O)CCC1=O.Cl.C(N=C=NCCCN(C)C)C.[C:36]([O:40][C:41]([N:43]1[CH2:48][CH2:47][C:46](=[CH:49][CH2:50][NH2:51])[CH2:45][CH2:44]1)=[O:42])([CH3:39])([CH3:38])[CH3:37].C(=O)([O-])O.[Na+]>C(#N)C.C(N(CC)CC)C>[C:36]([O:40][C:41]([N:43]1[CH2:48][CH2:47][C:46](=[CH:49][CH2:50][NH:51][C:13]([C:5]2[S:6][C:7]3[N:12]4[C:3](=[CH:2][N:1]=[C:11]4[CH:10]=[CH:9][CH:8]=3)[CH:4]=2)=[O:15])[CH2:45][CH2:44]1)=[O:42])([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)OC(=O)N1CCC(=CCN)CC1
Reactant: O=C(O)C1=Cc2cnc3cccc(n23)S1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(=CCNC(=O)C2=Cc3cnc4cccc(n34)S2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
While 1.56 g (7.17 mM) of 5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid and 0.83 g (7.17 mM) of N-hydroxysuccinimide were stirred together in 50 ml of acetonitrile, 1.51 g (7.89 mM) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added and the mixture was stirred at room temperature for 2 hours. To this reaction mixture was added 1.50 ml (10.8 mM) of triethylamine as well as a solution of the above crude 2-[1-(tert-butoxycarbonyl)piperidin-4-ylidene]ethylamine in 20 ml of acetonitrile and the mixture was stirred at room temperature for 2 hours. This reaction mixture was poured in aqueous solution of sodium hydrogen carbonate and extracted with 3 portions of ethyl acetate. The organic layers were pooled and dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate to ethyl acetate-methanol=9/1) to provide crude N-[2-(1-(tert-butoxycarbonyl)piperidin-4-ylidene]ethyl]-5-thia-1,8b-diazaacenaphthylene-4-carboxamide. To this crude N-[2-(1-(tert-butoxycarbonyl)piperidin-4-ylidene)ethyl]-5-thia-1,8b-diazaacenaphthylene-4-carboxamide was added 4 ml of concentrated hydrochloric acid and the mixture was stirred at room temperature for 0.5 hour. After addition of ethanol, the mixture was stirred and the resulting precipitate was recovered and rinsed serially with ethanol and diethyl ether to provide the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]([OH:30])[CH2:26][N:27]([CH3:29])[CH3:28])=[CH:21][CH:20]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:18][C:19]1[CH:20]=[CH:21][C:22]([CH:25]([OH:30])[CH2:26][N:27]([CH3:28])[CH3:29])=[CH:23][CH:24]=1
Reactant: CN(C)CC(O)c1ccc(N)cc1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Product: CN(C)CC(O)c1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)cc1
Yield: 53.5 %

Procedure:
Following general procedure C, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (240 mg, 0.770 mmol) was reacted with 1-(4-aminophenyl)-2-(dimethylamino)ethanol (139 mg, 0.770 mmol) to afford the desired product (187 mg, 53%) as a yellow solid: ESI MS m/z 454 [C23H24BrN3O2+H]+.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][CH2:10][CH2:11][CH2:12][N:13]([C@H:29]1[CH2:34][CH2:33][C@H:32]([CH3:35])[CH2:31][CH2:30]1)[C:14](=[O:28])[NH:15][C:16]1[S:17][C:18]([S:21][C:22]([CH3:27])([CH3:26])[C:23]([OH:25])=[O:24])=[CH:19][N:20]=1.C(OC(=O)C(SC1SC(N)=NC=1)(C)C)C.[Cl:51]C1C=CC=CC=1S>>[Cl:51][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][CH2:10][CH2:11][CH2:12][N:13]([C@H:29]1[CH2:34][CH2:33][C@H:32]([CH3:35])[CH2:31][CH2:30]1)[C:14](=[O:28])[NH:15][C:16]1[S:17][C:18]([S:21][C:22]([CH3:27])([CH3:26])[C:23]([OH:25])=[O:24])=[CH:19][N:20]=1
Reactant: COc1ccccc1SCCCN(C(=O)Nc1ncc(SC(C)(C)C(=O)O)s1)[C@H]1CC[C@H](C)CC1
Reactant: Sc1ccccc1Cl
Agent: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Product: CC(C)(Sc1cnc(NC(=O)N(CCCSc2ccccc2Cl)[C@H]2CC[C@H](C)CC2)s1)C(=O)O

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis 2-{2-[3-[3-(2-methoxy-phenylsulfanyl)-propyl]-3-(trans-4-methyl -cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2-methyl-propionic acid using 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester and 2-chloro-thiophenol.
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=[O:4].[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=O)[C@@H:17]([NH:34][C:35](=[O:44])[O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]2[S:29](=[O:31])(=[O:30])[NH:28][C:27](=[O:32])[CH2:26]2)=[C:21]([CH3:33])[CH:20]=1.C(O)(=O)C>>[C:3]([OH:5])(=[O:4])[CH3:2].[NH:15]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:16]1[C@@H:17]([NH:34][C:35](=[O:44])[O:36][CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]2[S:29](=[O:30])(=[O:31])[NH:28][C:27](=[O:32])[CH2:26]2)=[C:21]([CH3:33])[CH:20]=1
Reactant: Cc1cc(C[C@H](NC(=O)OCc2ccccc2)C(=O)Nc2ccccc2N)ccc1C1CC(=O)NS1(=O)=O
Reactant: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: Cc1cc(C[C@H](NC(=O)OCc2ccccc2)c2nc3ccccc3[nH]2)ccc1C1CC(=O)NS1(=O)=O

Procedure:
A solution of benzyl (1S)-2-[(2-aminophenyl)amino]-1-[4-(1,1-dioxido-3-oxoisothiazolidin-5-yl)-3-methylbenzyl]-2-oxoethylcarbamate trifluoroacetate (1.20 g, 1.84 mmol) and acetic acid (40.0 mL, 704 mmol) was stirred at 40° C. for 2 h. The solvent was removed in vacuo. The crude product was used in the next step without purification. MF=C27H26N4O5S; LCMS found for C27H27N4O5S (M+H)+: m/z=519.
Reaction SMILES: [CH3:1][Si:2]([CH3:13])([CH3:12])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1.N#C[Br:16].CCOC(C)=O>C(#N)C>[Br:16][C:8]1[N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:13])([CH3:12])[CH3:1])[CH:11]=[CH:10][N:9]=1
Reactant: N#CBr
Reactant: C[Si](C)(C)CCOCn1ccnc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1ccnc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.5 %

Procedure:
To a solution of 107 (100 mg, 0.50 mmol) in acetonitrile (1 mL) at room temperature was added cyanogen bromide (107 mg, 1.0 mmol) and the mixture was allowed to stir at room temperature for 3 h, concentrated to dryness and partitioned between EtOAc and water. The organic phase was collected, dried over anhydrous sodium sulfate and concentrated to dryness. The residue was purified by column chromatography (eluents EtOAc/hexane 25:75, then EtOAc), to afford the title compound 108 (45 mg, 32% yield) as a colorless oil. MS (m/z) 277.0/279.0 (M+H).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:14]([CH2:17][CH2:18][CH2:19][CH3:20])[C:15]#[N:16])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:21][CH2:22]Br.[OH-].[Na+].O>CS(C)=O>[C:15]([C:14]([C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:9]=1)([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:22][Br:21])#[N:16]
Reactant: CCCCC(C#N)c1cccc(Oc2ccccc2)c1
Reactant: BrCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCCCC(C#N)(CBr)c1cccc(Oc2ccccc2)c1
Reaction time: 1 h
Yield: 88.1 %

Procedure:
To a solution of 10 g (0.038 mole) of 2-(3-phenoxyphenyl)hexanenitrile, 6.6 g (0.038 mole) of dibromomethane in 50 ml of dimethyl sulfoxide is added 3.2 g (0.04 mole) of 50% sodium hydroxide solution dropwise. The reaction mixture is stirred at 60° for one hour, poured into water and extracted with ether. The combined ether extracts are washed with water and dried over MgSO4. Solvent is evaporated to give 12 g of product.
Reaction SMILES: C(OC(=O)[CH2:7][CH2:8][C:9]1[C:14](C)=[CH:13][C:12]([C:16](=[NH:19])[NH:17][OH:18])=[CH:11][C:10]=1C)(C)(C)C.C(C1C=CC(C#N)=CC=1)=C>>[OH:18][NH:17][C:16](=[NH:19])[C:12]1[CH:13]=[CH:14][C:9]([CH:8]=[CH2:7])=[CH:10][CH:11]=1
Reactant: Cc1cc(C(=N)NO)cc(C)c1CCC(=O)OC(C)(C)C
Agent: C=Cc1ccc(C#N)cc1
Product: C=Cc1ccc(C(=N)NO)cc1

Procedure:
The title compound is prepared in analogy to 3-[4-(N-hydroxycarbamimidoyl)-2,6-dimethyl-phenyl]-propionic acid tert-butyl ester (step g) starting from 4-vinyl-benzonitrile; LC-MS: tR=0.66*min, [M+1]+=162.92.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=3)[C:6]=2[CH:16]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:28](B(O)O)=[CH:27][CH:26]=[N:25]2)=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[C:28]([C:2]3[CH:3]=[CH:4][C:5]4[N:9]=[CH:8][N:7]([C:10]5[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=5)[C:6]=4[CH:16]=3)=[CH:27][CH:26]=[N:25]2)=[CH:22][CH:23]=1
Reactant: OB(O)c1ccnn1-c1ccc(F)cc1
Reactant: Brc1ccc2ncn(-c3ccncc3)c2c1
Product: Fc1ccc(-n2nccc2-c2ccc3ncn(-c4ccncc4)c3c2)cc1

Procedure:
The title compound, off-white solid (62 mg, 48%), MS (ISP) m/z=356.4 [(M+H)+], mp 199° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-pyridin-4-yl-1H-benzoimidazole (intermediate L) (100 mg, 365 μmol) and 1-(4-fluoro-phenyl)-1H-pyrazol-5-ylboronic acid (intermediate A) (90.2 mg, 438 μmol).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH2:8]([C:10]([CH2:15][OH:16])([CH2:13][OH:14])[CH2:11][CH3:12])[OH:9]>>[CH3:11][C:10]([CH2:13][CH:3]1[C:4](=[O:5])[O:6][C:1](=[O:7])[CH2:2]1)=[CH2:8].[CH2:8]([C:10]([CH2:15][OH:16])([CH2:13][OH:14])[CH2:11][CH3:12])[OH:9]
Reactant: O=C1C=CC(=O)O1
Agent: CCC(CO)(CO)CO
Product: C=C(C)CC1CC(=O)OC1=O

Procedure:
Example 9 is again repeated. After reaction of maleic anhydride, a portion of 1153 g is taken from the reaction mixture and 796 g of a solution containing 318 g of a trimethylolpropane polyisobutenylsuccinate (formed by reaction of polyisobutenylsuccinic anhydride with trimethylolpropane in a molar ratio "anhydride/trimethylolpropane" of 0.5) are added thereto. The reaction mixture is then heated to 160° C. for 7 hours.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]([CH:12]([CH3:14])[CH3:13])[C:6]2=O.C1COCC1.CO.[BH4-].[Na+]>O>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5]([CH:12]([CH3:14])[CH3:13])=[CH:6]2
Reactant: CC(C)C1Cc2c(Br)cccc2C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)C1=Cc2cccc(Br)c2C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 73.4 g (0.29 mol) of 4-bromo-2-isopropylindan-1-one in 530 ml of a mixture of THF-methanol (2:1, vol.), 22.0 g (0.58 mol) of NaBH4 was added in small portions while vigorously stirring for 2 h at 0° C. This mixture was stirred for 12 h at room temperature and then added to 600 ml of cold water. The organic layer was separated, the aqueous layer was extracted with 3×300 ml of methyl-tert-butyl ether. The combined organic fractions were dried over K2CO3 and then evaporated to dryness. The residue was dissolved in 1500 ml of toluene, and 2.0 g of p-TosOH was added. The resulting solution was refluxed for 2 h using a Dean-Stark trap to remove the water formed, and then it was passed through a short Silica Gel 60 column (40-63 um, d 100 mm, l 80 mm, eluent: hexanes). This column was additionally washed with 250 ml of toluene. The combined organic fractions were evaporated to dryness. The product was isolated by vacuum distillation (bp 128-132° C./4 mm Hg). Yield 57.8 g (84%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[O:9]1[CH2:11][CH:10]1[CH2:12][N:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14]1>CCO>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][CH2:11][CH:10]([OH:9])[CH2:12][N:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14]2)[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Br)c1
Reactant: c1ccc2c(c1)CCN(CC1CO1)C2
Solvent: CCO
Product: OC(CNc1cccc(Br)c1)CN1CCc2ccccc2C1
Temperature: 80 °C
Reaction time: 16 h
Yield: 19 %

Procedure:
To a stirred mixture of 3-bromoaniline (300 mg, 1.75 mmol) in EtOH (10 mL) was added 2-(oxiran-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline (331 mg, 1.75 mmol). The mixture was stirred at 80° C. for 16 hours. The reaction mixture was concentrated. The residue was purified by prep-TLC to afford the desired compound (120 mg). LCMS (m/z): 361.1/362.1 [M+H]+/[M+2H]+
Reaction SMILES: [ClH:1].[OH:2][C:3]1([CH3:17])[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[NH:9]C(=O)OC(C)(C)C>O1CCOCC1>[ClH:1].[NH2:9][CH:4]1[CH2:5][CH2:6][CH2:7][CH2:8][C:3]1([CH3:17])[OH:2]
Reactant: CC(C)(C)OC(=O)NC1CCCCC1(C)O
Agent: Cl
Solvent: C1COCCO1
Product: CC1(O)CCCCC1N
Reaction time: 4 h

Procedure:
4M Hydrochloric acid in dioxan (40 ml, 160 mmol) was added to a solution of the less polar diastereoisomer of tert-butyl 2-hydroxy-2-methylcyclohexylcarbamate (875 mg, 3.82 mmol) in dioxan (5 ml). The mixture was stirred for 4 h then the solvent was removed under reduced pressure and the residue dried in vacuo to afford a single diastereoisomer of 2-amino-1-methylcyclohexanol hydrochloride (656 mg) as a white solid.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[OH-].[Na+].[CH2:17]([O:20][C:21](Cl)=[O:22])[CH:18]=[CH2:19]>O.O1CCOCC1>[CH2:17]([O:20][C:21]([NH:1][C@@H:2]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]#[N:14])=[CH:11][CH:12]=1)[C:3]([OH:5])=[O:4])=[O:22])[CH:18]=[CH2:19]
Reactant: N#Cc1ccc(C[C@H](N)C(=O)O)cc1
Reactant: C=CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: C=CCOC(=O)N[C@@H](Cc1ccc(C#N)cc1)C(=O)O
Yield: 51.1 %

Procedure:
A suspension of 50 g (0.221 mol) of (S)-2-amino-3-(4-cyanophenyl)propionic acid in 150 ml of water was adjusted to pH=8 with 1N NaOH. 26.6 g (0.221 mol) of allylchloroformate in 225 ml of dioxane were slowly added at 0 to 5° C. (pH kept at 8 by addition of 1N NaOH). After completion of the reaction (thin layer chromatography (TLC) control) the mixture was extracted with DCM and the aqueous layer was acidified to pH=2 with KHSO4. The precipitate was dissolved in DCM, dried (Na2SO4), and evaporated. The residue was recrystallized from ether/petroleum benzene to give 31 g (51%) of the title compound. MS=275.1 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([N:12]=O)[CH2:7][CH:6]([C:14]1[CH:15]=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=1)[CH2:5]2.[Cl-].[NH4+].O.[CH3:24][C:25]([CH3:27])=O>[Zn]>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([N:12]=[C:25]([CH3:27])[CH3:24])[CH2:7][CH:6]([C:14]1[CH:15]=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=1)[CH2:5]2
Reactant: Cc1ccc2c(c1)CC(c1ccc(C)nc1)CN2N=O
Reactant: CC(C)=O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Product: CC(C)=NN1CC(c2ccc(C)nc2)Cc2cc(C)ccc21
Temperature: 15 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To a stirred solution of 6-methyl-3-(6-methylpyridin-3-yl)-1-nitroso-1,2,3,4-tetrahydroquinoline (0.28 g, 0.00104 mol) in acetone (15 mL) was added saturated ammonium chloride solution (0.8 mL) and water (0.8 mL) at RT. The resulting brown colored reaction mixture was cooled to 15° C. Zinc dust (0.954 g, 0.0146 mol) was added portionwise at the same temperature. After the addition, the reaction mixture was stirred for 1 h at RT. After completion of reaction (monitored by TLC), solvent was removed under reduced pressure and the residue extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and the solvent removed under reduced pressure to obtain product as a brown colored oil (0.28 g, 91% yield).
Reaction SMILES: [CH3:1][C:2]1[C:12](=[O:13])[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:4](=[O:5])[CH:3]=1.Cl>[Zn]>[OH:13][C:12]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]([OH:5])=[CH:3][C:2]=1[CH3:1]
Reactant: CC1=CC(=O)c2ccccc2C1=O
Agent: Cl
Agent: [Zn]
Product: Cc1cc(O)c2ccccc2c1O

Procedure:
First, vitamin K3 is reduced with a suitable reducing agent (e.g., zinc and hydrochloric acid) to form 1,4-dihydroxy-2-methylnaphthalene (III), which then is mono-acylated with an acylation reagent (e.g., benzoyl chloride) in the presence of a deacidification agent (e.g., pyridine), and, optionally, further benzylated with a benzylation reagent (e.g., benzyl bromide) and treated with an acid or a base (deacylation). Position 4 has thus undergone O-acylation or O-benzylation, providing 4-O-acyl-2-methylnaphthol or 4-O-benzyl-3-methylnaphthol (IV). Then, this is reacted with epichlorohydrin (chloromethyloxirane) in the presence of a deacidification agent to form 4-acyloxy-2-methyl-1-(2,3-epoxypropane)naphthol or 4-benzyloxy-3-methyl-1-(2,3-epoxypropane)naphthol (V), which in turn is reacted with a pyridylpiperazine, a pyrimidylpiperazine or a B1B2-substituted phenylpiperazine to form 1-(2-methyl-4-acyloxynaphthoxy)-3-[4-(2-pyridyl)-1-piperazinyl]-propan-2-ol, 1-(2-methyl-4-acyloxynaphthoxy)-3-[4-(2,6-pyrimidyl)-1-piperazinyl]propan-2-ol, or 1-(2-methyl-4-acyloxynaphthoxy)-3-[4-(B1B2-substituted phenyl)-1-piperazinyl]propan-2-ol or 1-(3-methyl-4-benzyloxynaphthoxy)-3-[4-(substitute moiety respectively corresponding to those aforementioned)-1-piperazinyl]propan-2-ol (VI), the protecting acyl or benzyl group at position 4 of which then is cleaved with a base or by catalytic reduction to give the present compound (I).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([NH:13][C:14]2[NH:15][C:16]3[C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)=[O:12])[N:2]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:59]1[C:63]2[CH2:64][CH2:65][CH2:66][CH2:67][C:62]=2[N:61]=[C:60]1[NH2:68]>CN(C=O)C>[NH:59]1[C:63]2[CH2:64][CH2:65][CH2:66][CH2:67][C:62]=2[N:61]=[C:60]1[NH:68][C:23]([C:22]1[C:16]2[N:15]=[C:14]([NH:13][C:11]([C:3]3[N:2]=[CH:1][C:10]4[C:5]([CH:4]=3)=[CH:6][CH:7]=[CH:8][CH:9]=4)=[O:12])[NH:18][C:17]=2[CH:19]=[CH:20][CH:21]=1)=[O:25]
Reactant: O=C(Nc1nc2cccc(C(=O)O)c2[nH]1)c1cc2ccccc2cn1
Reactant: Nc1nc2c([nH]1)CCCC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1nc2c(C(=O)Nc3nc4c([nH]3)CCCC4)cccc2[nH]1)c1cc2ccccc2cn1
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 13 %

Procedure:
To a solution of 70 mg (0.2 mmol) of 2-[(isoquinoline-3-carbonyl)-amino]-3H-benzoimidazole-4-carboxylic acid in DMF (2 mL) was added 100 mg (0.26 mmol) of HBTU and DIEA (0.3 mL). The mixture was stirred for 5 min, then 100 mg (0.7 mmol) of (4,5,6,7-tetrahydro-1H-benzoimidazol-2-ylamine was added. The resulting reaction mixture was heated at 80° C. for 1.5 h. After usual workup, the residue was purified by column chromatography eluting with DCM/EtOAc (v/v=1:1) to afford 12 mg (13%) of isoquinoline-3-carboxylic acid [4-(4,5,6,7-tetrahydro-1H-benzoimidazol-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-amide. LCMS: 452 (M+1)+.
Reaction SMILES: BrN1C(=O)CCC1=O.[S-:9][C:10]#[N:11].[K+].[F:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17]>CO>[F:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[S:9][C:10]#[N:11])[NH2:17]
Reactant: Nc1cccc(F)c1
Reactant: N#C[S-]
Agent: O=C1CCC(=O)N1Br
Agent: [K+]
Solvent: CO
Product: N#CSc1ccc(N)cc1F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
N-Bromosuccinimide (1.76 g, 9.89 mmol) and potassium thiocyanate (1.75 g, 18.0 mmol) in methanol (30 ml) were stirred for 15 minutes at room temperature. The reaction mixture was cooled to 0° C., and 3-fluoroaniline (1.00 g, 9.0 mmol) was added dropwise. The mixture was stirred at 0° C. for 2 h. Solvent was removed under vacuum, and the residue was washed with dichloromethane. The mixture was filtered to remove succinimide by-product, and the solution was washed with water, brine, and dried (MgSO4). Solvent was removed under vacuum to afford the desired product as a colorless oil. Yield 1.45 g (96%).
Reaction SMILES: [C:1]([NH:5][C:6]([NH:8][C:9]1[C:13]([CH:14]([CH3:16])[CH3:15])=[CH:12][S:11][C:10]=1[CH:17]([CH3:19])[CH3:18])=S)([CH3:4])([CH3:3])[CH3:2].[I-].ClC1C=CC=C[N+]=1C.C(N(CC)CC)C>C(#N)C>[C:1]([N:5]=[C:6]=[N:8][C:9]1[C:13]([CH:14]([CH3:15])[CH3:16])=[CH:12][S:11][C:10]=1[CH:17]([CH3:19])[CH3:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)c1csc(C(C)C)c1NC(=S)NC(C)(C)C
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)c1csc(C(C)C)c1N=C=NC(C)(C)C
Reaction time: 2 h

Procedure:
2.50 g of the 1-tert.-butyl-3-(2,4-diisopropyl-3-thienyl)thiourea obtained according to Example 2 and 2.60 g of 2-chloro-1-methylpyridinium iodide are introduced into 25 ml of acetonitrile and, at room temperature, a solution of 1.90 g of triethylamine in 12 ml of acetonitrile is added. The reaction mixture is then stirred for 2 hours at approximately +45° C. After evaporation of the solvent, the residue is taken up in hexane/water. The separated organic phase is dried over magnesium sulfate and the solvent is removed in vacuo. The crude product is purified by column chromatography on silica gel (eluant: ethyl acetate/hexane-1:20). The title compound of formula ##STR13## is obtained in the form of a colourless oil, nD23 =1.5249 (compound No. 4.01).
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:8]=1[CH2:9][C:10]1(C(OC)=O)[CH2:14][CH2:13][CH2:12][C:11]1=[O:15]>C(O)(=O)C>[F:6][C:7]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:8]=1[CH2:9][CH:10]1[CH2:14][CH2:13][CH2:12][C:11]1=[O:15]
Reactant: COC(=O)C1(Cc2ccc(F)cc2F)CCCC1=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: O=C1CCCC1Cc1ccc(F)cc1F

Procedure:
To a stirred solution of glacial acetic acid (100 ml) and an aqueous solution of sulfuric acid (12.5%, 30 ml), there was added methyl 1-(2,4-difluorobenzyl)-2-oxocyclopentanecarboxylate (5.14 g, 21.6 mmol). The mixture was refluxed in a stream of argon for 5 h.
Reaction SMILES: CC([O-])(C)C.[K+].[CH2:7]([N:14]([CH2:22]C(OCC)=O)[CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl>C1(C)C=CC=CC=1>[CH2:7]([N:14]1[CH2:15][CH2:16][CH2:17][CH2:18][C:19](=[O:21])[CH2:22]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)CN(CCCCC(=O)O)Cc1ccccc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C1CCCCN(Cc2ccccc2)C1
Temperature: 25 °C
Yield: 40.9 %

Procedure:
A suspension of potassium tert-butylate (336 mg) in toluene (2.5 ml) is refluxed for 10 min. Then 5-(benzyl-ethoxycarbonylmethyl-amino)-pentanoic acid (695 mg) in toluene (1 ml) is slowly added to the suspension and when the addition is complete the mixture is refluxed for another 1.5 hours. After cooling to room temperature 25% hydrochloric acid (1 ml) is added. The organic phase is separated off and washed with 25% hydrochloric acid (4×1 ml). The combined hydrochloric-acid aqueous phases are then refluxed for 5 hours. After cooling to room temperature the solution is made alkaline (pH 11) with 2N caustic soda solution and extraction is carried out with ethyl acetate. The combined organic phases are concentrated by evaporation after drying over sodium sulphate. The obtained residue produces, after chromatography using silica gel (ethyl acetate/heptane 1:5) the desired title compound (197 mg) in a yield of 45% (Bull. Chem. Soc. Jpn. 1956, 29, 631-632; DE2206385).