Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].C[S+](C)(C)=O.[H-].[Na+].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C@H:17]([N:19]2[C:23](=[O:24])[CH2:22][C@@H:21]([CH:25]=[O:26])[CH2:20]2)[CH3:18])=[CH:13][CH:12]=1.[CH3:27]COC(C)=O>CS(C)=O>[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C@H:17]([N:19]2[CH2:20][C@H:21]([CH:25]3[CH2:27][O:26]3)[CH2:22][C:23]2=[O:24])[CH3:18])=[CH:13][CH:12]=1
Reactant: COc1ccc([C@@H](C)N2C[C@H](C=O)CC2=O)cc1
Reactant: CCOC(C)=O
Agent: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Solvent: CS(C)=O
Product: COc1ccc([C@@H](C)N2C[C@H](C3CO3)CC2=O)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To suspension of trimethylsulfoxonium iodide (579 mg, 2.63 mmol) in DMSO (5 mL) was added NaH (60%, 116 mg, 2.89 mmol), and the reaction was stirred for 30 minutes. A solution of (R)-1-((R)-1-(4-methoxyphenyl)ethyl)-5-oxopyrrolidine-3-carbaldehyde 1.07 (650 mg, 2.63 mmol) in DMSO (5 mL) was added and the reaction was stirred for 30 minutes at 0° C. The reaction was poured into ice water (20 mL) and EtOAc (20 mL) was added. The aqueous layer was extracted with EtOAc (3×25 mL), and the combined organics were dried (MgSO4), filtered and concentrated. Flash chromatography (50→100% EtOAc in hexanes) provided (4R)-1-((R)-1-(4-methoxyphenyl)ethyl)-4-(oxiran-2-yl)pyrrolidin-2-one 1.13.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[S:10])=[CH:4][CH:3]=1.[CH2:11]([NH:15][CH2:16][C:17](O)=[O:18])[CH2:12][CH2:13][CH3:14].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:11]([N:15]1[CH2:16][C:17](=[O:18])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:9]1=[S:10])[CH2:12][CH2:13][CH3:14]
Reactant: CCCCNCC(=O)O
Reactant: Fc1ccc(N=C=S)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCN1CC(=O)N(c2ccc(F)cc2)C1=S
Yield: 44.1 %

Procedure:
The title compound was prepared by the procedure described in Example 54 using 7.7 g of 4-fluorophenyl-isothiocyanate, 12.0 g of N-butyl glycine, 15.0 g of triethyl amine, and 250 mL of chloroform. Crystallization from ethanol afforded the title compound (5.9 g) as an off-white solid, m.p. 92°-93° C. Anal. Calcd. for. C13H15F N2O S: C, 58.62; H, 5.68; N, 10.52. Found: C, 58.23; H, 5.65; N, 10.56. Mass spectrum (EI, M.+) m/z 266.
Reaction SMILES: Br[CH2:2][C:3]([CH3:6])([CH3:5])[CH3:4].[Mg].FC(F)(F)S(O[C:14]1[CH:19]=[C:18]([O:20][Si:21]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])[CH:17]=[CH:16][C:15]=1[C:31]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:32]=1[F:39])(=O)=O.[Cl-].[NH4+]>C(OCC)C.CC(C1C=CC=C(C(C)C)C=1N1[C-]=[N+](C2C(C(C)C)=CC=CC=2C(C)C)CC1)C.C1COCC1>[F:39][C:32]1[CH:33]=[CH:34][C:35]([O:37][CH3:38])=[CH:36][C:31]=1[C:15]1[CH:14]=[CH:19][C:18]([O:20][Si:21]([CH:22]([CH3:24])[CH3:23])([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:27])[CH3:26])=[CH:17][C:16]=1[CH2:2][C:3]([CH3:6])([CH3:5])[CH3:4]
Reactant: COc1ccc(F)c(-c2ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc2OS(=O)(=O)C(F)(F)F)c1
Reactant: CC(C)(C)CBr
Agent: CC(C)c1cccc(C(C)C)c1N1[C-]=[N+](c2c(C(C)C)cccc2C(C)C)CC1
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(F)c(-c2ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc2CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under an argon atmosphere, a solution of 1-bromo-2,2-dimethylpropane (23.2 mL) in diethyl ether (250 mL) was added dropwise to magnesium (4.92 g) at a slow refluxing rate, and the reaction mixture was heated under reflux further for 30 min. Under an argon atmosphere, to a solution of 2′-fluoro-5′-methoxy-4-((triisopropylsilyl)oxy)-[1,1′-biphenyl]-2-yl trifluoromethanesulfonate (19.2 g) and a PEPPSI™-SIPr catalyst (trade name) (1.26 g) in THF (200 mL) was added the solution prepared above, and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound as a crude oil. This compound was used for the next step without further purification.
Reaction SMILES: N1(CC2C=CC(N)=CC=2)CCOCC1.[N+:15]([C:18]1[CH:31]=[CH:30][C:21]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)=[CH:20][CH:19]=1)([O-])=O>>[N:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:23][O:22][C:21]1[CH:30]=[CH:31][C:18]([NH2:15])=[CH:19][CH:20]=1
Reactant: O=[N+]([O-])c1ccc(OCc2ccccn2)cc1
Agent: Nc1ccc(CN2CCOCC2)cc1
Product: Nc1ccc(OCc2ccccn2)cc1
Yield: 100 %

Procedure:
Using the procedure described for the preparation of 4-Morpholin-4-ylmethyl-phenylamine, 1.16 g (100%) of white crystals is obtained from 1.5 g (5.55 mmol) of ′2-[(4-nitrophenoxy)methyl]pyridine; mp 50-51° C. MS (ESI) m/z 201.1 (M+1)+.
Reaction SMILES: C([O:3][C:4]([C@@:6]1([NH:11][C:12]([C@@H:14]2[CH2:18][C@@H:17]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[C:22]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:21]=3)[CH2:16][N:15]2[C:38](=[O:47])[NH:39][C@H:40]([CH:45]=O)[C:41]([CH3:44])([CH3:43])[CH3:42])=[O:13])[CH2:8][C@H:7]1[CH:9]=[CH2:10])=[O:5])C.C(OC(C1(N)CC1(C([C@@H]1C[C@@H](OC2C3C(=CC(OC)=CC=3)N=C(C3C=CC=CC=3)C=2)CN1C(=O)NC(CN[C@H]1C2C(=CC=CC=2)C[C@H]1O)C(C)(C)C)=O)C=C)=O)C.[NH2:105][CH:106]([CH:111]1[CH2:116][CH2:115][CH2:114][CH2:113][CH2:112]1)[C:107]([NH:109][CH3:110])=[O:108]>>[CH:111]1([C@H:106]([NH:105][CH2:45][CH:40]([NH:39][C:38]([N:15]2[CH2:16][C@H:17]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[C:22]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:21]=3)[CH2:18][C@H:14]2[C:12]([NH:11][C@:6]2([C:4]([OH:3])=[O:5])[CH2:8][C@H:7]2[CH:9]=[CH2:10])=[O:13])=[O:47])[C:41]([CH3:44])([CH3:42])[CH3:43])[C:107](=[O:108])[NH:109][CH3:110])[CH2:116][CH2:115][CH2:114][CH2:113][CH2:112]1
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1C(=O)N[C@H](C=O)C(C)(C)C)C(=O)OCC
Reactant: CNC(=O)C(N)C1CCCCC1
Agent: C=CC1(C(=O)[C@@H]2C[C@@H](Oc3cc(-c4ccccc4)nc4cc(OC)ccc34)CN2C(=O)NC(CN[C@H]2c3ccccc3C[C@H]2O)C(C)(C)C)CC1(N)C(=O)OCC
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1C(=O)NC(CN[C@H](C(=O)NC)C1CCCCC1)C(C)(C)C)C(=O)O

Procedure:
Treatment of compound 85 as described for the preparation of 86 but with the use of 2-amino-2-cyclohexyl-N-methyl-acetamide (17 mg) instead of (1S,2R)-1-aminoindan-2-ol followed by hydrolysis of the ethyl ester as described in example 87 provided the title product. Purity by HPLC>95%. M+H+769.5
Reaction SMILES: [CH2:1]([O:4][CH:5]([CH3:8])[CH2:6][OH:7])[CH2:2][CH3:3].[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1.[OH-].[Na+].Cl>C1C=CC=CC=1>[CH2:1]([O:4][CH:5]([CH3:8])[CH2:6][O:7][S:15]([C:12]1[CH:13]=[CH:14][C:9]([CH3:19])=[CH:10][CH:11]=1)(=[O:17])=[O:16])[CH2:2][CH3:3]
Reactant: CCCOC(C)CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: CCCOC(C)COS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 41.6 %

Procedure:
4.75 g of 2-propoxypropanol, 5.39 g of p-toluenesulfonyl chloride, 2,24 g and 10 ml of benzene were placed in a 50 ml-reaction vessel and stirred in a nitrogen gas stream for 22 hours at room temperature. Thereafter, 8.6 ml of heated conc. NaOH solution was added to the reaction mixture, followed by stirring for 5 minutes. The reaction liquid was poured into 200 ml of cooled 10%-hydrochloric acid solution and extracted with hexane to obtain 3.2 g of 2-propoxypropyl-p-toluenesulfonate (tosylate).
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][CH3:13])[CH:8]=[CH:7]2.[CH3:15][O-:16].[Na+]>CO.O.[Cl-].[Na+].O>[Br:1][C:2]1[C:3]([O:16][CH3:15])=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][CH3:13])[CH:8]=[CH:7]2
Reactant: COc1ccc2ncc(F)c(Br)c2n1
Reactant: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc2ncc(OC)c(Br)c2n1
Temperature: 50 °C
Yield: 95 %

Procedure:
8-Bromo-7-fluoro-2-(methoxy)-1,5-naphthyridine (for a synthesis see WO2004058144, example 53(g) (11.215 g, 43.64 mmol) was stirred in methanol (100 mL) at rt under argon and a solution of sodium methoxide in methanol (94 ml of a ca. 25% solution, 10 eq.) was added. The mixture was heated at 50° C. for 1 h. The mixture was allowed to cool to rt, then was diluted with water (500 ml) and brine (500 ml), and extracted with DCM (2×300 ml). The DCM extracts were combined, dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure to give 8-bromo-2,7-bis(methoxy)-1,5-naphthyridine as a cream solid (11.21 g, 95%).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[Br:7][C:8]1[C:14]([O:15][CH2:16][CH3:17])=[CH:13][C:11]([NH2:12])=[C:10]([F:18])[CH:9]=1.N1C=CC=CC=1>C(Cl)Cl>[Br:7][C:8]1[C:14]([O:15][CH2:16][CH3:17])=[CH:13][C:11]([NH:12][C:2](=[O:3])[O:4][CH2:5][CH3:6])=[C:10]([F:18])[CH:9]=1
Reactant: CCOc1cc(N)c(F)cc1Br
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)Nc1cc(OCC)c(Br)cc1F
Temperature: 10 °C
Reaction time: 3 h
Yield: 96.3 %

Procedure:
Ethyl chloroformate (2.15 g) was added dropwise to a solution of 4-bromo-5-ethoxy-2-fluoroaniline (4.21 g) and pyridine (2.84 g) in methylene chloride (36 ml) at 0° C., and the mixture was stirred at 10° C. for 3 hours. After the reaction, this was extracted with methylene chloride, then washed with diluted hydrochloric acid and an aqueous sodium hydrogencarbonate solution, and dried over anhydrous magnesium sulfate. Then, methylene chloride was distilled off, and the resulting crude crystals were crystallized from a mixed solvent of ethyl acetate and n-hexane (1:5 v/v) to obtain the objective ethyl N-(4-bromo-5-ethoxy-2-fluorophenyl)carbamate (5.30 g).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:23])=[CH:4][N:3]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:31]=[C:32]([OH:36])[CH:33]=[CH:34][CH:35]=2)[CH:25]=1>>[Cl:23][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:36][C:32]2[CH:33]=[CH:34][CH:35]=[C:30]([C:26]3[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=3)[CH:31]=2)=[N:3][CH:4]=1
Reactant: Oc1cccc(-c2cccnc2)c1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Cl)cc1
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Oc2cccc(-c3cccnc3)c2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 45 from methyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 48) and 3-pyridin-3-ylphenol (J. Med. Chem. 1981, 24, 1475): 1H-NMR (CDCl3) δ 8.86 (1H, d, J=1.8 Hz), 8.63 (1H, dd, J=4.8, 1.5 Hz), 8.57 (1H, d, J=2.6 Hz), 8.17–8.15 (2H, m), 8.02–7.99 (2H, m), 7.90–7.86 (1H, m), 7.62–7.36 (6H, m), 7.22–7.18 (1H, m), 5.45–5.34 (1H, m), 3.89 (3H, s), 1.61 (3H, d, J=6.9 Hz); MS (ESI) m/z 488 (M+H)+, 486 (M−H)−.
Reaction SMILES: CN(C)C=O.[F:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1F)[N:13]1[CH:18]([CH3:20])[S:19][C:12]1=[C:11]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:10]2=[O:26].Cl.Cl.[N:29]1[CH:34]=[CH:33][CH:32]=[N:31][C:30]=1[N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.C1CCN2C(=NCCC2)CC1>O>[F:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[N:38]1[CH2:39][CH2:40][N:35]([C:30]3[N:29]=[CH:34][CH:33]=[CH:32][N:31]=3)[CH2:36][CH2:37]1)[N:13]1[CH:18]([CH3:20])[S:19][C:12]1=[C:11]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:10]2=[O:26]
Reactant: CCOC(=O)c1c2n(c3cc(F)c(F)cc3c1=O)C(C)S2
Reactant: c1cnc(N2CCNCC2)nc1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c2n(c3cc(N4CCN(c5ncccn5)CC4)c(F)cc3c1=O)C(C)S2
Temperature: 25 °C
Reaction time: 120 h
Yield: 96 %

Procedure:
To 16 ml of N,N-dimethylformamide were added 2.0 g (0.0064 mole) of ethyl 6,7-difluoro-1-methyl-4-oxo-1H,4H-[1,3]-thiazeto[3,2-a]quinoline-3-carboxylate, 3.0 g (0.0129 mole) of 1-(2-pyrimidinyl)piperazine dihydrochloride and 3.9 g (0.0256 mole) of 1,8-diazabicyclo[5.4.0]-7-undecene, and the mixture was stirred at room temperature for 5 days. The reaction mixture was added to water, and crystals precipitated were collected by filtration, washed with water and dried to obtain 2.8 g of ethyl 6-fluoro-1-methyl-4-oxo-7-[4-(2-pyrimidinyl)piperazin-1-yl]-1H,4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate as pale yellow powder.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1>>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=2)=[CH:14][CH:13]=1
Reactant: O=C(O)c1cccc(Br)n1
Reactant: OB(O)c1ccc(F)cc1
Product: O=C(O)c1cccc(-c2ccc(F)cc2)n1

Procedure:
6-Bromo-pyridine-2-carboxylic acid (1 g, 4.95 mmol) was coupled 4-fluoro-phenylboronic acid (693 mg, 4.95 mmol) acid using Method F to give the title compound.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5](=[CH:8][C:9]2[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=2)[O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=2)[CH2:4][CH2:3]1.[CH3:26][C:27]1[N:32]=[CH:31][C:30]([NH:33][C:34](=O)[O:35]C2C=CC=CC=2)=[CH:29][CH:28]=1.NC1C=NC(C)=CC=1>>[CH3:26][C:27]1[N:32]=[CH:31][C:30]([NH:33][C:34]([N:2]2[CH2:7][CH2:6][C:5](=[CH:8][C:9]3[CH:25]=[CH:24][CH:23]=[C:11]([O:12][C:13]4[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][N:14]=4)[CH:10]=3)[CH2:4][CH2:3]2)=[O:35])=[CH:29][CH:28]=1
Reactant: Cc1ccc(NC(=O)Oc2ccccc2)cn1
Reactant: FC(F)(F)c1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1
Agent: Cc1ccc(N)cn1
Agent: Cl
Product: Cc1ccc(NC(=O)N2CCC(=Cc3cccc(Oc4ccc(C(F)(F)F)cn4)c3)CC2)cn1

Procedure:
Following the procedure in Example 1, Step 6, 2-(3-piperidin-4-ylidenemethyl-phenoxy)-5-trifluoromethyl-pyridine hydrochloride (150 mg, 0.40 mmol, from Example 1, Step 5) and phenyl 6-methylpyridin-3-ylcarbamate (92 mg, 0.40 mmol, prepared according to the procedure described in Synthesis, 1997, 1189-1194 from 3-amino-6-methylpyridine, 3B Medical Systems, Inc.) were used to provide the title compound (184 mg). MS (APCI 10V) AP+ 469.3, AP− 467.2, 448.2; 1H NMR (400 MHz, CD3OD) δ ppm 2.41-2.44 (m, 2H) 2.46 (s, 3H) 2.58 (td, J=5.80, 0.83 Hz, 2H) 3.51-3.57 (m, 2H) 3.60-3.67 (m, 2H) 6.45 (s, 1H) 6.97-7.05 (m, 2H) 7.09-7.17 (m, 2H) 7.20 (d, J=8.50 Hz, 1H) 7.40 (td, J=7.70, 0.78 Hz, 1H) 7.77 (dd, J=8.37, 2.52 Hz, 1H) 8.08 (ddd, J=8.71, 2.56, 0.50 Hz, 1H) 8.42 (d, J=0.54 Hz, 1H) 8.43 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[C:10](=[O:11])[CH2:9][NH:8][S:7]1(=[O:13])=[O:12].[C:20]([O:24][C:25](=[O:36])[NH:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34]O)=[CH:30][CH:29]=1)([CH3:23])([CH3:22])[CH3:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:20]([O:24][C:25](=[O:36])[NH:26][CH2:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:34][N:8]2[CH2:9][C:10](=[O:11])[N:6]([CH2:5][C:4]3[CH:14]=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:3]=3[O:2][CH3:1])[S:7]2(=[O:13])=[O:12])=[CH:32][CH:33]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: COc1ccc(CN2C(=O)CNS2(=O)=O)c(OC)c1
Reactant: CC(C)(C)OC(=O)NCc1ccc(CO)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)CN(Cc3ccc(CNC(=O)OC(C)(C)C)cc3)S2(=O)=O)c(OC)c1
Reaction time: 0.17 h

Procedure:
A solution of the title B compound in Example 9, 2-(2,4-dimethoxybenzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (742 mg, 2.59 mmol) and (4-hydroxymethyl-benzyl)-carbamic acid t-butyl ester (738 mg, 3.11 mmol) in THF (15 mL) is treated with triphenylphosphine (1.36 g, 5.18 mmol). The mixture is stirred for 10 min and diethyl azodicarboxylate (902 mg, 5.18 mmol) is added dropwise over 1 min. The mixture is stirred for 72 h. The solvent is evaporated and the residue is chromatographed on silica gel using 1% MeOH/CH2Cl2 as the eluent to afford {4-[5-(2,4-dimethoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-benzyl}-carbamic acid t-butyl ester as a white solid: [M+NH4]+=523.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4](/[CH:7]=[CH:8]/[C:9]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:10])=[CH:5][CH:6]=1.[CH:17](=[O:20])[CH2:18][CH3:19].C(N(CC)CC)C>[Br-].C([N+]1C(C)=C(CCO)SC=1)C.C(O)C>[C:11]1([C:9](=[O:10])[CH2:8][CH:7]([C:4]2[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=2)[C:17](=[O:20])[CH2:18][CH3:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCC=O
Reactant: O=C(/C=C/c1ccccc1)c1ccccc1
Agent: CC[n+]1csc(CCO)c1C
Agent: [Br-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCC(=O)C(CC(=O)c1ccccc1)c1ccccc1
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
A mixture of (E)-1,3-diphenyl-propenone (1.042 g; 5.00 mmol), propionaldehyde (0.40 mL; 5.6 mmol), 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide (126 mg; 0.500 mmol) and triethyl-amine (0.42 mL; 3.0 mmol) in absolute ethanol (3.0 mL) was degassed then heated at 70° C. for 25 h. After an additional 1.5 h at 80° C., the organic volatiles were removed on a rotary evaporator. EtOAc (25 mL) was added and the solution washed with water (3×5 mL) and satd NaCl (2×5 mL); then dried (MgSO4), filtered through silica and washed through with EtOAc. Crude product was adsorbed onto silica (2.0 g) then purified by MPLC (40 g of silica using a 0→20% EtOAc in hexanes gradient). Pure product was obtained as a clear, pale tan liquid (760 mg; 57%). 1H NMR (CDCl3) δ 7.96 (m, 2H), 7.56 (m, 1H), 7.45 (m, 2H), 7.38-7.26 (m, 5H), 4.43 (dd, J=3.4, 10.2 Hz, 1H), 4.05 (dd, J=10.4, 18.0 Hz, 1H), 3.14 (dd, J=3.8, 18.2 Hz, 1H), 2.65 (m, 1H), 2.53 (m, 1H), 1.02 (t(app), J=7.2 Hz, 3H).
Reaction SMILES: Cl.[C:2]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)OCC[O:16]1)(=[O:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]>O1CCCC1>[C:2]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15](=[O:16])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)(=[O:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCC(=O)OCCCCC1(c2ccccc2)OCCO1
Agent: Cl
Solvent: C1CCOC1
Product: CCCCCCC(=O)OCCCCC(=O)c1ccccc1
Temperature: 40 °C
Yield: 72.6 %

Procedure:
2.32 ml of a 1N solution of HCl were added to a solution of 4.37 g (13.0 mmol) of 4-(2-phenyl-1,3-dioxolan-2-yl)butyl heptanoate obtained under d) in 18 ml of THF (tetrahydrofuran). The reaction mixture was heated to 40° C. for 24 h, cooled down to room temperature, extracted with ethyl acetate (2×) and washed with a sat. solution of NaCl (3×). The organic phase was dried (Na2SO4) and concentrated. Column chromatography (SiO2, heptane/ether 8:2) afforded 2.74 g (73%) of a colourless oil, which crystallises at 4° C.
Reaction SMILES: [H-].[Na+].[C:3]([O:10][CH3:11])(=[O:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6].Br[CH:13]([CH2:22][CH2:23][CH2:24][CH3:25])[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15]>CS(C)=O>[CH3:8][O:7][C:5](=[O:6])[CH:4]([CH:13]([C:14](=[O:15])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:22][CH2:23][CH2:24][CH3:25])[C:3]([O:10][CH3:11])=[O:9]
Reactant: CCCCC(Br)C(=O)c1ccccc1
Reactant: COC(=O)CC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCCC(C(=O)c1ccccc1)C(C(=O)OC)C(=O)OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Small portions of NaH (60%, 7.92 g, 198 mmol) are added to a solution of dimethyl malonate (22.6 ml, 198 mmol) in DMSO (100 mL) at 0° C. The ice bath is removed and the mixture stirred at room temperature for 2 hours. The solution is rechilled to 0° C. and a solution of 2-bromo-1-phenyl-hexan-1-one (2–1) (16.8 g, 66 mmol) in DMSO (50 mL) is added slowly. The ice bath is removed and the mixture stirred overnight. Water (500 mL) is added and the mixture is extracted with EtOAc (4×150 mL). The combined extracts are washed with brine (300 mL), dried (Na2SO4), and evaporated, to provide the product as a light yellow oil. LC-MS (M+1) 307. 1H NMR (δ, CDCl3) 7.98–8.02 (m, 2H), 7.46–7.60 (m, 3H), 4.18–4.28 (m, 1H), 4.03–4.12 (m, 1H), 3.80 (s, 3H), 3.6.1 (s, 3H), 1.55–1.63 (m, 2H), 1.02–1.20 (m, 4H), 0.76 (t, J=0.72 Hz, 3H).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[C:8]2[C:18]([CH2:22]O)=[CH:19][CH:20]=[CH:21][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].S(Cl)([Cl:26])=O>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[C:8]2[C:18]([CH2:22][Cl:26])=[CH:19][CH:20]=[CH:21][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=S(Cl)Cl
Reactant: CCCCc1nc2cccc(CO)c2n1Cc1ccccc1Cl
Solvent: ClCCl
Product: CCCCc1nc2cccc(CCl)c2n1Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 2-n-butyl-1-(2-chlorophenyl)methyl-7-hydroxymethyl-1H-benzimidazole (1.01 g, 2.76 mmol) in methylene chloride (50 mL) was added thionyl chloride (0.61 mL). The resulting solution was stirred at ambient temperature for one hour, the solvent was evaporated, the residue triturated with toluene and then petroleum ether, and the white crystals (1.06 g) of 2-n-butyl-7-chloromethyl-1-(2-chlorophenyl)methyl-1H-benzimidazole were isolated and washed well with ether to give the title compound as the hydrochloride salt; mp 180°-184° C.
Reaction SMILES: N#[C-].N[C:4]1[CH:12]=[CH:11][C:7]([C:8](N)=N)=[CH:6][CH:5]=1.Cl.[S:14](=O)(=[O:17])([OH:16])[OH:15].B(F)(F)F.CCOCC>O.C(O)(C)C.O1CCCC1.O1CCOCC1.C(O)C.CO>[C:7]1([CH3:8])[C:6]([S:14]([OH:17])(=[O:16])=[O:15])=[CH:5][CH:4]=[CH:12][CH:11]=1
Reactant: N=C(N)c1ccc(N)cc1
Reactant: O=S(=O)(O)O
Agent: Cl
Agent: FB(F)F
Agent: [C-]#N
Solvent: C1CCOC1
Solvent: CC(C)O
Solvent: CO
Product: Cc1ccccc1S(=O)(=O)O

Procedure:
The reaction of a substituted benzaldehyde of the formula II, an isonitrile of the formula RNC and a 4-aminobenzamidine of the formula III is advantageously carried out in a solvent (e.g. methanol, isopropanol, ethanol, dioxane, or tetrahydrofuran), or in a solvent mixture (e.g. tetrahydrofuran and water or isopropanol and water), advantageously by using an inorganic acid (e.g. hydrochloric acid, sulphuric acid or boron trifluoride etherate), or an organic acid (e.g. toluenesulphonic acid), or in acidic ion exchanger (e.g. Amberlyst K10) as catalyst, at a temperature between 0° C. and 100° C., giving compounds of the formula I. The reaction of a substituted aldehyde of the formula II, of an isonitrile of the formula R1NC and 4-aminobenzonitrile under similar reaction conditions leads to compounds of the formula IV in which Q is hydrogen.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]2[CH:13]=[C:14]([CH:16]=[O:17])[S:15][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]2[CH:13]=[C:14]([CH2:16][OH:17])[S:15][C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cc2ccc(OCc3ccccc3)cc2s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cc2ccc(OCc3ccccc3)cc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.8 %

Procedure:
To a solution of 6-benzyloxy-benzothiophene-2-carbaldehyde (described by Nomura Y., WO 9635688 A1, 6.50 g, 24.20 mmol) in THF (50 ml) was added dropwise to a −30° C. cooled suspension of LiAlH4 (0.85 g, 22.26 mmol). After warming up to room temperature the mixture was stirred overnight, cooled to −10° C., hydrolyzed with ice water, extracted with dichloromethane, dried over Na2SO4, filtered and concentrated under vacuum to give the crude product. Flash chromatography on silica gel (toluene/ethyl acetate: 7/3) yielded a limpid oil (4.50 g, 69%).