Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8](Br)[CH:7]=[CH:6]2.C([Li])CCC.[B:19](OC(C)C)([O:24]C(C)C)[O:20]C(C)C.Cl>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([B:19]([OH:24])[OH:20])[CH:7]=[CH:6]2
Reactant: COc1ccc2cc(Br)ccc2c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc2cc(B(O)O)ccc2c1
Reaction time: 1.5 h

Procedure:
A solution of 6-methoxy-2-bromonaphthalene (25 g) in tetrahydrofuran (300 ml) was cooled at −78° C. under a nitrogen atmosphere. n-Butyllithium (2.66 M solution in hexane) (42 ml) was added dropwise thereto over 1.5 hours, and the solution was stirred for 30 minutes. Triisopropyl borate (26.5 ml) was added dropwise thereto for 30 minutes, then the solution was stirred for 40 minutes while warming from −78° C. to 0° C. 1N hydrochloric acid (200 ml) and ethyl acetate (200 ml) were sequentially added thereto, the solution was stirred, extracted with ethyl acetate, then washed with brine, dried over anhydrous magnesium sulfate, then the solvent was evaporated in vacuo, the resulting solid was washed with a hexane-diethyl ether system to provide the title compound (18 g).
Reaction SMILES: [CH:1]1[C:6]([CH:7]=O)=[CH:5][C:4]2[O:9][CH2:10][O:11][C:3]=2[CH:2]=1.[OH-].[Na+].O.C(O)(=O)C.[CH3:19][C:20]([CH3:22])=[O:21]>>[CH3:19][C:20](/[CH:22]=[CH:7]/[C:6]1[CH:1]=[CH:2][C:3]2[O:11][CH2:10][O:9][C:4]=2[CH:5]=1)=[O:21]
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)/C=C/c1ccc2c(c1)OCO2

Procedure:
A solution of 100 g piperonal in 900 ml acetone was stirred at room temperature with 15 ml of 10% aqueous sodium hydroxide and 30 ml of water. After 3 hours 5 ml of acetic acid was added and the reaction mixture was evaporated. The residue was recrystallized from methanol and dried in vacuo to yield 60 g of piperonalacetone, m.p. 104°-105° C. (EtoAc).
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23](I)[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC[Mg+].[Br-].[CH2:30]([C:32]1[S:33][C:34]([CH2:39][CH3:40])=[CH:35][C:36]=1[CH:37]=[O:38])[CH3:31]>C(Cl)Cl.ClCl>[CH2:30]([C:32]1[S:33][C:34]([CH2:39][CH3:40])=[CH:35][C:36]=1[CH:37]([C:23]1[N:22]=[CH:21][N:20]([C:1]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:24]=1)[OH:38])[CH3:31]
Reactant: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CCc1cc(C=O)c(CC)s1
Agent: CC[Mg+]
Agent: ClCl
Agent: [Br-]
Solvent: ClCCl
Product: CCc1cc(C(O)c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)c(CC)s1
Reaction time: 3 h

Procedure:
To a solution of N-trityl-4-iodo-imidazole (13.5 g, 31 mmol) in dry CH2Cl2 (75 mL) was added EtMgBr (10.0 mL, 3.0M in Et2O) and the solution was stirred for 3 hrs. Then a solution of 2,5-diethylthiophene-3-carboxaldehyde, D6, (5.0 g, 30 mmol) in CH2 Cl2 (20 mL) was added, and the reaction mixture was stirred at room temperature overnight. The reaction was quenched with NH4Cl (aq) and the mixture was transferred to a separatory funnel. The aqueous layer was extracted with a second portion of CH2Cl2. The extracts were combined and washed with a small portion of water, dried (Na2 SO4), and filtered. The solvent was evaporated in vacuo to give a thick syrup which was triturated with Et2O to give a solid which was recrystallized from EtOAc to give (2,5-diethylthien-3-yl)-1-trityl-imidazol-4-yl-methanol, E6. 1H NMR (CDCl3) supported the assigned structure. ##STR52##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[F:23].C(N(CC)CC)C.ClC(Cl)(O[C:35](=[O:41])OC(Cl)(Cl)Cl)Cl.[S:43]1[CH:47]=[CH:46][N:45]=[C:44]1[CH:48]([NH2:50])[CH3:49]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:35]([NH:50][CH:48]([C:44]2[S:43][CH:47]=[CH:46][N:45]=2)[CH3:49])=[O:41])=[CH:18][C:17]=1[F:23]
Reactant: CC(N)c1nccs1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)NC(C)c4nccs4)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.2 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (30 mg) was dissolved in chloroform (1 ml) and triethylamine (0.1 ml) to prepare a solution. A solution of triphosgene (35 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for one hr. Next, a solution of 1-(1,3-thiazol-2-yl)-1-ethylamine (35 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (39 mg, yield 87%).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=CC(S(Cl)(=O)=O)=C[CH:2]=1.[Cl:12][C:13]1[N:18]=[C:17]([C:19]([OH:21])=[O:20])[C:16]([CH3:22])=[CH:15][CH:14]=1.N1C=CC=CC=1.C(=O)([O-])O.[Na+]>C(O)(C)(C)C.O>[Cl:12][C:13]1[N:18]=[C:17]([C:19]([O:21][C:1]([CH3:11])([CH3:6])[CH3:2])=[O:20])[C:16]([CH3:22])=[CH:15][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ccc(Cl)nc1C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Solvent: CC(C)(C)O
Product: Cc1ccc(Cl)nc1C(=O)OC(C)(C)C
Reaction time: 24 h
Yield: 93.1 %

Procedure:
p-Toluenesulfonyl chloride (10.5 g, 55.1 mmol) was added to a solution of 6-chloro-3-methylpyridine-2-carboxylic acid (4.73 g, 27.6 mmol) as a known compound in tert-butyl alcohol (150 ml) and pyridine (21 ml) at room temperature, and the mixture thus obtained was then stirred at the same temperature as above for 24 hours. Thereafter, a solution of sodium hydrogen carbonate (11.6 g, 138 mmol) in water (300 ml) was added to the resulting solution, and the mixed solution was then stirred. Then, the solvent was distilled away from the reaction solution under reduced pressure. While being washed with water, the solid thus generated was collected by filtration, and was then dried to obtain the title compound (5.85 g, yield: 93%).
Reaction SMILES: O[CH2:2][C@@H:3]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:4][O:5][C:6](=[O:8])[CH3:7].[Br:15][C:16]1[C:17](=[O:33])[NH:18][C:19](=[O:32])[N:20]([CH2:23][C:24]2[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=2[F:31])[C:21]=1[CH3:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C>C1COCC1>[Br:15][C:16]1[C:17](=[O:33])[N:18]([CH2:2][C@@H:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][O:5][C:6](=[O:8])[CH3:7])[C:19](=[O:32])[N:20]([CH2:23][C:24]2[C:25]([F:31])=[CH:26][CH:27]=[CH:28][C:29]=2[F:30])[C:21]=1[CH3:22]
Reactant: Cc1c(Br)c(=O)[nH]c(=O)n1Cc1c(F)cccc1F
Reactant: CC(=O)OC[C@@H](CO)c1ccccc1
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)OC[C@@H](Cn1c(=O)c(Br)c(C)n(Cc2c(F)cccc2F)c1=O)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.8 %

Procedure:
A solution of acetic acid 3-hydroxy-2-(R)-phenyl-propyl ester (1.87 g, 9.64 mmol) in THF (50 mL) was treated with 5-bromo-1-(2,6-difluorobenzyl)-6-methyluracil 4d.1 (3.19 g, 9.64 mmol) and triphenylphosphine (3.16 g, 12.1 mmol) at ambient temperature, then di-tert-butylazodicarboxylate (2.77 g, 12.1 mmol) was introduced. The reaction mixture was stirred at ambient temperature for 16 h and volatiles were evaporated. The residue was partitioned between saturated NaHCO3/H2O and EtOAc. The organic layer was dried (sodium sulfate), evaporated, purified by flash chromatography (silica, 33% EtOAc/hexanes) to give compound 8a (4.54 g, 93%). MS (CI) m/z 508.1 and 509.0 (MH+).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[N:32]=[C:19]4[CH:20]=[CH:21][CH:22]=[C:23]([C:24]5[CH:25]=[C:26]([CH2:30]O)[CH:27]=[CH:28][CH:29]=5)[N:18]4[N:17]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.CS([Cl:44])(=O)=O>ClCCl>[Cl:44][CH2:30][C:26]1[CH:25]=[C:24]([C:23]2[N:18]3[N:17]=[C:16]([NH:15][C:12]4[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][N:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)=[CH:10][CH:11]=4)[N:32]=[C:19]3[CH:20]=[CH:21][CH:22]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCc1cccc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: ClCc1cccc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
(3-{2-[4-(2-Pyrrolidin-1-yl-ethoxy)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-5-yl}-phenyl)-methanol (0.35 g, 0.815 mmol) was dissolved in dichloromethane (20 mL). Triethylamine (508 μL, 3.670 mmol) was added and the mixture cooled to 0° C., then methanesulfonyl chloride (252 μL, 3.260 mmol) was added dropwise and the reaction was allowed to warm to room temperature and stirred overnight. A small sample of the desired product was purified by preparatory HPLC. RT: 2.56 min, MI: 448 and 450.18, Method: 2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[CH2:9][N:10]2[CH:14]=[CH:13][CH:12]=[C:11]2[C:15]([O:17][CH2:18]C)=[O:16])=[CH:4][CH:3]=1.[Cl:21][C:22]([Cl:27])([Cl:26])[C:23](Cl)=[O:24].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[CH2:9][N:10]2[CH:14]=[C:13]([C:23](=[O:24])[C:22]([Cl:27])([Cl:26])[Cl:21])[CH:12]=[C:11]2[C:15]([O:17][CH3:18])=[O:16])=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cccn1CC(=O)c1ccc(Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)c1cc(C(=O)C(Cl)(Cl)Cl)cn1CC(=O)c1ccc(Cl)cc1
Yield: 42.5 %

Procedure:
To a solution of ethyl 1-[2-(4-Chlorophenyl)-2-oxoethyl]-1H-pyrrole-2-carboxylate (150 mg, 0.54 mmol) in CH2Cl2 (10 ml) was added trichloroacetyl chloride (120 μL, 1.1 mmol) and aluminium chloride (290 mg, 2.2 mmol). After 16 h the reaction was quenched by the addition of a saturated aqueous solution of NaHCO3 (50 mL) and extracted with CH2Cl2 (3×50 mL). The organic extracts were combined, dried (MgSO4) and concentrated in vacuo to give a residue that was purified using flash chromatography (2× Biotage SP4, 12 g cartridge, 20-100% EtOAc gradient in n-hexanes) to give methyl 1-[2-(4-chlorophenyl)-2-oxoethyl]-4-(trichloroacetyl)-1H-pyrrole-2-carboxylate (97 mg, yield 42%) as a brown solid. 1H NMR (400 MHz, d6-acetone): δ 3.75 (s, 3H), 6.12 (s, 2H), 7.56 (d, 1H, J 2.0 Hz), 7.64-7.68 (m, 2H), 8.10-8.14 (m, 2H), 8.15 (d, 1H, J 2.0 Hz).
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)=[C:7]([NH:22][C:23]([NH:25][C:26]2[C:31]([CH:32]([CH3:34])[CH3:33])=[CH:30][CH:29]=[CH:28][C:27]=2[CH:35]([CH3:37])[CH3:36])=[O:24])[C:6]1=[O:38])[CH2:2][CH2:3][CH3:4].[N:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[CH2:45][CH2:46]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.O>[CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:46][CH2:45][C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][N:39]=3)[CH:16]=2)=[C:7]([NH:22][C:23]([NH:25][C:26]2[C:27]([CH:35]([CH3:37])[CH3:36])=[CH:28][CH:29]=[CH:30][C:31]=2[CH:32]([CH3:33])[CH3:34])=[O:24])[C:6]1=[O:38])[CH2:2][CH2:3][CH3:4]
Reactant: OCCc1ccccn1
Reactant: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cccc2C(C)C)c(-c2cccc(O)c2)c2cccnc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cccc2C(C)C)c(-c2cccc(OCCc3ccccn3)c2)c2cccnc21
Temperature: 25 °C
Reaction time: 40 h
Yield: 12.1 %

Procedure:
To a solution of N-[1-butyl-4-(3-hydroxyphenyl)-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-N'-(2,6-diisopropylphenyl)urea (300 mg, 0.58 mmol), 2-pyridinethanol (71 mg, 0.58 mmol) in THF (5 ml) were added triphenylphosphine (152 mg, 0.58 mmol), and diethyl azodicarboxylate (101 mg, 0.58 mmol), and the mixture was stirred at room temperature for 40 hours. The mixture was poured into water, and extracted with ethyl acetate. The extract was washed with water, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The resultant was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=5:5) and thin layer chromatography to give the title compound (43 mg, 0.07 mmol).
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(N(CC)CC)C.[NH2:19][C:20]1[CH:41]=[CH:40][C:23]([C:24]([N:26]2[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[CH2:30][N:29]3[CH:37]=[CH:38][CH:39]=[C:28]3[CH2:27]2)=[O:25])=[CH:22][CH:21]=1>C(Cl)Cl>[CH:39]1[CH:38]=[CH:37][N:29]2[CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[N:26]([C:24]([C:23]3[CH:22]=[CH:21][C:20]([NH:19][C:4](=[O:5])[C:3]4[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:2]=4[CH3:1])=[CH:41][CH:40]=3)=[O:25])[CH2:27][C:28]=12
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reactant: Cc1cccc(C(=O)Cl)c1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc(C(=O)Nc2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2)c1C
Reaction time: 0.25 h
Yield: 56 %

Procedure:
To a stirred solution of 0.320 g of 2,3-dimethylbenzoyl chloride in 10 ml of methylene chloride is added 0.33 ml of triethylamine. After stirring for 15 minutes, 0.485 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine is added and stirring continued for 5 hours. The reaction mixture is washed with water, 1N HCl, NAHCO3, and brine. The reaction mixture is dried with Na2SO4, filtered and evaporated in vacuo to give a solid which is purified by flash chromatography using 1:1 ethyl acetate-hexane to give 0.39 g of solid, m.p. 168°-170° C.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[C:7]([CH:10]([CH3:21])[CH2:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1)([OH:9])=[O:8].Cl[C:23]1[C:28]([S:29]([N:32]([C:42]([O:44][CH2:45][CH:46]([CH3:48])[CH3:47])=[O:43])[C:33]2[C:38]([O:39][CH3:40])=[N:37][C:36]([CH3:41])=[CH:35][N:34]=2)(=[O:31])=[O:30])=[CH:27][CH:26]=[CH:25][N:24]=1.C(O)C>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH2:45]([O:44][C:42]([N:32]([C:33]1[C:38]([O:39][CH3:40])=[N:37][C:36]([CH3:41])=[CH:35][N:34]=1)[S:29]([C:28]1[C:23]([C:15]2[CH:16]=[CH:17][C:12]([CH2:11][CH:10]([C:7]([OH:9])=[O:8])[CH3:21])=[CH:13][CH:14]=2)=[N:24][CH:25]=[CH:26][CH:27]=1)(=[O:31])=[O:30])=[O:43])[CH:46]([CH3:48])[CH3:47]
Reactant: CC(Cc1ccc(B(O)O)cc1)C(=O)O
Reactant: COc1nc(C)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1cccnc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: COc1nc(C)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1cccnc1-c1ccc(CC(C)C(=O)O)cc1
Temperature: 80 °C
Yield: 39 %

Procedure:
Tetrakis(triphenylphosphine)palladium (0) (500 mg) was added to a deoxygenated solution of sodium carbonate (3.74 g), 4-(2-carboxypropyl)phenyl boronic acid (3.67 g) and 2-chloro-N-(isobutoxycarbonyl)-N-(3-methoxy-5-methyl-pyrazin-2-yl)pyridine-3-sulphonamide (6.1 g) in a mixture of water (30 ml), ethanol (75 ml) and toluene (75 ml). The mixture was stirred and heated under argon at 80° C. for 17 hours and then allowed to cool to ambient temperature. Ice water (5 g) was added and the reaction extracted with ethyl acetate (75 ml). The combined organic layers were extracted with saturated aqueous sodium carbonate solution (2×15 ml) and combined aqueous extracts were acidified to pH 2 with 2M hydrochloric-acid and extracted with ethyl acetate (3×100 ml). The combined organic extracts were dried (MgSO4) and evaporated to low volume affording crystalline material which was filtered and washed with diethyl ether to give N-(isobutoxycarbonyl)-2-(4-(2-carboxypropyl)phenyl)-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (3.11 g); NMR 1H (d6 -DMSO): 0.61 (d, 6 H), 1.09 (d, 3 H), 1.50-1.73 (m, 1 H), 2.55 (partly obscured by DMSO, 3 H), 2.6-2.77 (m, 2 H), 2.72-3.09 (m, 1 H), 2.83 (d, 2 H), 3.96 (s, 3 H), 7.25 (d, 2 H), 7.43 (d, 2 H), 7.78 (dd, 1 H), 8.15 (s, 1 H), 8.83-8.96 (m, 2 H), 12.14 (br s, 1 H); mass spectrum (-ve ESP) 541.1 (M-H )-.
Reaction SMILES: [CH2:1]([NH:10][CH2:11][CH2:12][NH:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:27](Cl)(Cl)=[S:28]>O1CCCC1>[CH2:1]([N:10]1[CH2:11][CH2:12][N:13]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[C:27]1=[S:28])/[CH:2]=[CH:3]/[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: C(=C/c1ccccc1)\CNCCNc1cccnc1
Reactant: S=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: S=C1N(C/C=C/c2ccccc2)CCN1c1cccnc1
Reaction time: 2 h
Yield: 45.7 %

Procedure:
To a solution of 5.37 g of (E)-N-cinnamyl-N'-(3-pyridyl)ethylenediamine dissolved in 100 ml of tetrahydrofuran, 4.5 g of triethylamine was added and the mixture was ice-cooled. To the mixture was added dropwise 20 ml of a tetrahydrofuran solution containing 5.12 g of thiophosgene over 5 minutes, and subsequently the mixture was stirred under ice-cooling for 30 minutes and then at room temperature for 2 hours. The solvent was distilled off, and the residue was dissolved in chloroform, washed with water and dried, followed by distillation of the solvent. The residue was purified by silica gel column chromatorgraphy (solvent: chloroform-methanol=20:1) to give 2.86 g of (E)-1-cinnamyl-3-(3-pyridyl)imidazolidine-2-thione as caramel.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[N:19]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)=[C:20]=[S:21].S(Cl)([Cl:32])=O>C(Cl)(Cl)Cl>[ClH:1].[ClH:32].[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:20]3[S:21][C:23]4[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:22]=4[N:19]=3)[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1ccc(N=C=S)cc1
Reactant: O=S(Cl)Cl
Reactant: NCCCN1CCN(c2ccc(Cl)c(Cl)c2)CC1
Solvent: ClC(Cl)Cl
Product: COc1ccc2nc(NCCCN3CCN(c4ccc(Cl)c(Cl)c4)CC3)sc2c1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
A mixture of 4-(3,4-dichlorophenyl)-1-piperazinepropanamine (0.009 mol), prepared according to the procedure described in Example A.5, and 1-isothiocyanato-4-methoxy-benzene (0.009 mol) in CHCl3 (100 ml) was stirred for one hour at room temperature, then cooled to 0° C. on an ice-bath. Thionylchloride (30 ml) was added dropwise and the resulting reaction mixture was allowed to slowly warm to room temperature. The reaction mixture was stirred for 3 hours at 60° C. The mixture was cooled to room temperature and the resulting precipitate was filtered off, stirred in boiling 2-propanone, filtered off, then dried. This fraction was converted into the free base by addition of aqueous ammonia. The mixture was extracted with CH2Cl2. The separated organic layer was dried, filtered and the solvent evaporated. The residue was crystallized from CH3CN, filtered off, dissolved in 2-propanone and converted into the hydrochloric acid salt (1:2) with HCl/2-propanol. The precipitate was filtered off and dried, yielding 1.6 g (34%) of N-[3-[4-(3,4-dichlorophenyl)-1-piperazinyl]propyl]-6-methoxy-2-benzothiazolamine dihydrochloride (comp. 72).
Reaction SMILES: [O:1]1[C@H:8]([CH2:9][OH:10])[C@@H:6]([OH:7])[C@H:4]([OH:5])[CH:3]=[CH:2]1.[C:11](OCC)(=[O:13])[CH3:12]>C(OC=C)(=O)C>[C:11]([O:10][CH2:9][C@H:8]1[O:1][CH:2]=[CH:3][C@@H:4]([OH:5])[C@@H:6]1[OH:7])(=[O:13])[CH3:12]
Reactant: CCOC(C)=O
Reactant: OC[C@H]1OC=C[C@@H](O)[C@@H]1O
Solvent: C=COC(C)=O
Product: CC(=O)OC[C@H]1OC=C[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
1.022 g (7 mmol) of glucal are taken up in 2 ml of ethyl acetate and 30 ml of vinyl acetate, 400 mg of lipase from Candida cylindracea lipase OF (Meito Sangyo Co. Ltd.) are added, and the mixture is stirred at room temperature overnight. After the reusable enzyme has been separated off, and subsequent chromatography or crystallization, 1.12-1.25 g of 6-O-acetylglucal (85-95% yield) are obtained.
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[CH:16]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.O>CS(C)=O>[CH2:9]([O:8][C:6](=[O:7])[C:5]1[CH:11]=[CH:12][C:2]([NH:22][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:3]([N+:13]([O-:15])=[O:14])[CH:4]=1)[CH3:10]
Reactant: NC1CCCCC1
Reactant: CCOC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1ccc(NC2CCCCC2)c([N+](=O)[O-])c1
Temperature: 60 °C
Reaction time: 5 h
Yield: 100.9 %

Procedure:
Ethyl 4-chloro-3-nitrobenzoate (20.00 g, 87 mmol) was dissolved in DMSO (50 mL) and cyclohexylamine (2.1 equiv. 21 mL, 183 mmol) was added and the mixture stirred at 60° C. for 5 h. After cooling to ambient temperature, the reaction mixture was added drop-wise with vigorous stirring to water (500 mL). After stirring for an additional 15 min, the precipitated solid was collected by filtration, washed with water and dried. The title compound (25.67 g, 100% yield) was obtained as a bright yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[H-].[Na+].[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[S:22](Cl)(=[O:24])=[O:23]>O1CCCC1>[CH3:1][C:2]1([CH3:9])[N:6]([S:22]([C:13]2[CH:14]=[CH:15][C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:12]=2)(=[O:24])=[O:23])[C:5](=[O:7])[N:4]([S:22]([C:13]2[CH:14]=[CH:15][C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:12]=2)(=[O:24])=[O:23])[C:3]1=[O:8]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: CC1(C)NC(=O)NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)C(=O)N(S(=O)(=O)c2ccc3ccccc3c2)C(=O)N1S(=O)(=O)c1ccc2ccccc2c1
Reaction time: 0.5 h
Yield: 22.4 %

Procedure:
5,5-Dimethylimidazolidine-2,4-dione (1.28 g) was dissolved in tetrahydrofuran (20 mL), and sodium hydride (60%, in oil) (0.25 g) was added at 0° C. under ice-cooling. After stirred for 30 minutes, 2-naphthalenesulfonyl chloride (2.38 g) was added at 0° C., and the mixture was stirred at room temperature overnight. After the solvent was distilled off, ethyl acetate (150 mL) was added to the reaction solution, and the solution was washed with 1N hydrochloric acid, an aqueous saturated sodium bicarbonate solution and a saturated brine in turn. After drying over anhydrous magnesium sulfate, the solvent was distilled off. Further purification by silica gel chromatography (hexane:ethyl acetate=2:1) afforded 597 mg of white crystals.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[N:5][N:4]=[N:3]1.C([Li])CCC.[F:13][C:14]1[CH:27]=[CH:26][C:17]([C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:19])=[CH:16][CH:15]=1>C1COCC1.CCCCCC>[F:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([OH:19])[CH2:7][C:6]2[N:2]([CH3:1])[N:3]=[N:4][N:5]=2)=[CH:26][CH:27]=1
Reactant: Cc1nnnn1C
Reactant: O=C(c1ccccc1)c1ccc(F)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cn1nnnc1CC(O)(c1ccccc1)c1ccc(F)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 62.1 %

Procedure:
A solution of 1,5-dimethyltetrazole (29.25 g; 0.298 mole) in dry THF (400 mL) was cooled to -78° C. and treated with n-butyllithium (133 mL of a 2.5M solution in hexane; 0.3325 mole) over 30 minutes. The mixture was stirred at -78° C. for 30 minutes and treated with 4-fluorobenzophenone (50 g; 0.25 mole). The mixture was stirred at -78° C. for 30 minutes and allowed to warm up to 23° C. over 2 hours. The reaction was quenched with 2N HCl (100 mL) and the organic solvent was removed by evaporation. The residue was extracted with CHCl3 (2×100 mL) and the combined organic layers were dried (Na2SO4) and evaporated to afford a brown oil. Purification by chromatography using 20% EtOAc-hexane as eluent afforded the title compound as a white solid (46.3 g; 62%). m.p.=113°- 114° C. (crystallized from EtOAc-hexane). MS (CI): m/e=299 for (M+H)+.