Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[C:8]([NH:11][C:12]1[S:13][C:14]([S:18](Cl)(=[O:20])=[O:19])=[C:15]([CH3:17])[N:16]=1)(=[O:10])[CH3:9].C(N(CC)CC)C>O1CCOCC1>[OH:4][CH2:3][CH2:2][N:1]([CH2:5][CH2:6][OH:7])[S:18]([C:14]1[S:13][C:12]([NH:11][C:8](=[O:10])[CH3:9])=[N:16][C:15]=1[CH3:17])(=[O:19])=[O:20]
Reactant: CC(=O)Nc1nc(C)c(S(=O)(=O)Cl)s1
Reactant: OCCNCCO
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc(C)c(S(=O)(=O)N(CCO)CCO)s1
Temperature: 25 °C
Reaction time: 17 h
Yield: 58.2 %

Procedure:
To a stirred solution of diethanolamine (1.24 g, 11.8 mmol) in dioxane (20 ml) was added at 0° C. (ice water bath) commercially available 2-acetamido-4-methyl-thiazole-5-sulfonyl chloride (1.0 g, 3.93 mmol) and triethylamine (0.6 ml, 4.32 mmol). The light yellow suspension was stirred at room temperature for 17 h, and evaporated. The crude product was further purified by flash chromatography on silica gel (dichloromethane/MeOH) and subsequent crystallization (dichloromethane/MeOH/hexane) to yield 2-acetamido-4-methyl-thiazole-5-sulfonic acid bis-(2-hydroxy-ethyl)-amide (0.74 g, 58%) as a white solid. MS (ISP) 324.0 [(M+H)+]; mp 204° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([SH:11])[NH:8][C:7]=2[CH:12]=1.[H-].[Na+].[CH2:15]([O:17][C:18](=[O:21])[CH2:19]Br)[CH3:16]>CN(C=O)C>[CH2:15]([O:17][C:18](=[O:21])[CH2:19][S:11][C:9]1[NH:8][C:7]2[CH:12]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[N:10]=1)[CH3:16]
Reactant: COc1ccc2nc(S)[nH]c2c1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CSc1nc2ccc(OC)cc2[nH]1
Yield: 99.3 %

Procedure:
6-Methoxy-1H-benzoimidazole-2-thiol (10.00 g, 55.56 mmol) was dissolved in DMF (300 mL). NaH (2.44 g, 60 w/w % in mineral oil, 61.11 mmol) was added in small portions at room temperature. The resulted mixture was stirred for one h then bromo-acetic acid ethyl ester (10.21 g, 61.11 mmol) was added. After 12 h the mixture was evaporated and the resulted slurry was diluted with HCl (340 mL, 2N) and was stirred for a 0.5 h at room temperature then was filtered, washed with water and n-hexane respectively. The title compound (14.70 g, 99%) was isolated as a pale yellow powder.
Reaction SMILES: ClC1C=CC(C(OC)=O)=C(C=CC(O)=O)C=1.[Cl:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:20]([CH:28]=[CH:29][C:30]([O:32][CH3:33])=[O:31])[CH:19]=1>>[Cl:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:20]([CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH:19]=1
Reactant: COC(=O)C=Cc1cc(Cl)ccc1C(=O)OC
Agent: COC(=O)c1ccc(Cl)cc1C=CC(=O)O
Product: COC(=O)CCc1cc(Cl)ccc1C(=O)OC

Procedure:
The same product is obtained using, instead of methyl 4-chloro-2-(3-hydroxy-3-oxo-1-propenyl)-benzoate, methyl 4-chloro-2-(3-methoxy-3-oxo-1 -propenyl)-benzoate from Example 1.
Reaction SMILES: C([Si](C)(C)[O:6][C@H:7]1[CH2:15][CH2:14][CH2:13][C@@:12]2([CH3:16])[C@H:8]1[CH2:9][CH2:10][C@@H:11]2[C@H:17]([CH3:20])[C:18]#[CH:19])(C)(C)C.F>C1COCC1.[Cl-].[Na+].O>[CH3:16][C@@:12]12[C@@H:11]([C@H:17]([CH3:20])[C:18]#[CH:19])[CH2:10][CH2:9][C@H:8]1[C@@H:7]([OH:6])[CH2:15][CH2:14][CH2:13]2
Reactant: C#C[C@@H](C)[C@H]1CC[C@H]2[C@@H](O[Si](C)(C)C(C)(C)C)CCC[C@]12C
Agent: F
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C#C[C@@H](C)[C@H]1CC[C@H]2[C@@H](O)CCC[C@]12C
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.7 %

Procedure:
Typically, the compound of formula IX, (1R,3aR,4S,7aR)-4-(tert-Butyl-dimethyl-silanyloxy)-7a-methyl-1-[(S)-1-methyl-propynyl]-octahydro-indene (900 mg; 2.81 mmol) was dissolved in THF (35 ml). Hydrofluoric acid (40% aqueous solution; 18 ml) was added and the reaction mixture was stirred at room temperature for three hours. The reaction mixture was then poured on chilled brine, extracted twice with ethyl acetate, washed twice with brine, dried over anhydrous sodium sulfate and the solvent was removed. After flash-chromatography (eluent: hexanes/ethyl-acetate 82/18) the compound [1R,3aR,4S,7aR]-7a-Methyl-1-[(S)-1-methyl-prop-2-ynyl]-octahydro-inden-4-ol (497 mg; yield: 86%) was obtained as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][O:5][C:6]1[N:11]=[CH:10][C:9]([C:12](=[O:21])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:8][N:7]=1.[CH3:23][C:24]1[C:29](O)=[CH:28][CH:27]=[C:26](C)[N:25]=1.CN(C)CCCN=C=NCC>CN(C1C=CN=CC=1)C.ClCCl>[CH3:27][C:26]1[C:1]([O:2][C:3](=[O:22])[CH2:4][O:5][C:6]2[N:11]=[CH:10][C:9]([C:12](=[O:21])[NH:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[CH:8][N:7]=2)=[CH:28][CH:29]=[C:24]([CH3:23])[N:25]=1
Reactant: Cc1ccc(O)c(C)n1
Reactant: COC(=O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(OC(=O)COc2ncc(C(=O)Nc3ccc(F)cc3)cn2)c(C)n1
Reaction time: 1 h
Yield: 31.2 %

Procedure:
A mixture of [5-(4-fluorophenylcarbamoyl)pyrimidin-2-yloxy]acetic acid methyl ester (prepared above, 50 mg, 0.17 mmol), 2,6-dimethyl-pyridin-3-ol (21 mg, 0.17 mmol) and DMAP (41 mg, 0.34 mmol) were slurried in dichloromethane. The solution was treated with (3-dimethylamino-propyl)-ethyl-carbodiimide (EDC) (54 mg, 0.28 mmol). After 1 h, thin layer chromatography indicated complete conversion. The reaction mixture was quenched with 10 mL 1 M HCl(aq) and 30 mL dichloromethane. The phases were partitioned, and the aqueous phase extracted with 5 mL dichloromethane. The organic phases were combined and sequentially washed with 10 mL portions of 0.1 M HCl(aq), saturated. NaHCO3(aq) and brine. The organic layer was dried using Na2SO4, filtered and concentrated. The resulting 31 mg of off-white solid was chromatographed over SiO2 (5% methanol/dichloromethane) to yield 21 mg (31%) of the titled compound. ESI-MS z/z 397 (MH+), 395 (M−H−).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:18]2[C:13](=[C:14]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[Cl:35])[CH:15]=[C:16]([CH:19]3[CH2:28][CH2:27][C:22]4(OCC[O:23]4)[CH2:21][CH2:20]3)[CH:17]=2)[CH2:12][NH:11][C:10]1=[O:36]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:18]2[C:13](=[C:14]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[Cl:35])[CH:15]=[C:16]([CH:19]3[CH2:20][CH2:21][C:22](=[O:23])[CH2:27][CH2:28]3)[CH:17]=2)[CH2:12][NH:11][C:10]1=[O:36]
Reactant: O=C1NCc2c(-c3ccccc3Cl)cc(C3CCC4(CC3)OCCO4)cc2N1c1c(Cl)cccc1Cl
Solvent: CC(C)=O
Product: O=C1CCC(c2cc(-c3ccccc3Cl)c3c(c2)N(c2c(Cl)cccc2Cl)C(=O)NC3)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a suspension of 1-(2,6-Dichlorophenyl)-5-(2-chlorophenyl)-7-(1,4-dioxaspiro(4.5)dec-8-yl)-3,4-dihydro-2(1H)-quinazolinone (248 mg, 0.456 mmol) (INTERMEDIATE 72) in acetone (12 mL) was added Amberlyst-15 (130 mg). The mixture was stirred at RT for 6 hours at which time the reaction mixture became homogeneous. The solution was filtered and the solvent concentrated. The crude material was purified by silica gel chromatography eluting with 1:4 acetone:hexanes followed by 1:3 acetone:hexanes to give 1-(2,6-Dichlorophenyl)-5-(2-chlorophenyl)-7-(1-cyclohexanon-4-yl)-3,4-dihydro-2(1H)-quinazolinone. 1H NMR (CDCl3, 500 MHz): selected data δ 1.78 (m, 2H), 2.14 (m, 2H), 2.4 (m, 4H) 2.86 (m, 1H). MS(ES) 499 (M+H); LC 1: 3.19 min.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Br:15][C:16]1[CH:17]=[C:18]([CH3:28])[C:19]([C:22]2[CH2:23][CH2:24][NH:25][CH2:26][CH:27]=2)=[N:20][CH:21]=1.[O:29]1[CH2:34][CH2:33][C:32](=O)[CH2:31][CH2:30]1.[OH-].[Na+]>O1CCCC1.CCCCCC>[Br:15][C:16]1[CH:17]=[C:18]([CH3:28])[C:19]([C:22]2[CH2:23][CH2:24][N:25]([CH:32]3[CH2:33][CH2:34][O:29][CH2:30][CH2:31]3)[CH2:26][CH:27]=2)=[N:20][CH:21]=1
Reactant: O=C1CCOCC1
Reactant: Cc1cc(Br)cnc1C1=CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(Br)cnc1C1=CCN(C2CCOCC2)CC1
Yield: 44.5 %

Procedure:
Sodium triacetoxyborohydride (5.25 g) was added at room temperature to a solutions of 5-bromo-3-methyl-1′,2′,3′,6′-tetrahydro-2,4′-bipyridine (5.23 g) and tetrahydro-4H-pyran-4-one (2.07 g) in tetrahydrofuran (50 ml) and n-hexane (20 ml), and stirred at the same temperature. After completion of the reaction, 1N aqueous solution of sodium hydroxide was added under ice cooling and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified with silica gel column chromatography (chloroform/methanol) and washed with diethyl ether and n-hexane to give 5-bromo-3-methyl-1′-(tetrahydro-2H-pyran-4-yl)-1′,2′,3′,6′-tetrahydro-2,4′-bipyridine (3.1 g) as a pale yellow solid.
Reaction SMILES: I[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:3]=1.[Cl:28][C:29]1[CH:30]=[N:31][CH:32]=[CH:33][C:34]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.[Pd+2].ClC1C=C[C-](P(C2C=CC=CC=2)C2C=CC=CC=2)C=1Cl.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[Cl:28][C:29]1[CH:30]=[N:31][CH:32]=[CH:33][C:34]=1[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:3]=1
Reactant: OB(O)c1ccncc1Cl
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(I)n2)cc1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: Clc1cc[c-](P(c2ccccc2)c2ccccc2)c1Cl
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3ccncc3Cl)n2)cc1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A mixture of 4-iodo-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (306 mg, 0.642 mmol), 3-chloropyridine-4-boronic acid (101 mg, 0.642 mmol), dichloro 1,1′-bis(diphenylphosphino)ferrocene palladium (II) (52.4 mg, 0.064 mmol) and cesium carbonate (251 mg, 0.770 mmol) in dioxane (6 mL) and water (1 mL) was stirred at 90° C. for 1 h. The mixture was cooled down to room temperature. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2×30 mL). The organic extract was washed with saturated NaCl (10 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as a light-yellow glass. The crude product was purified by silica gel chromatography eluting with 50% EtOAc/hexanes to give the product as a glass. 1H NMR (300 MHz, CDCl3) δ 8.69 (s, 1H); 8.58 (d, J=4.97 Hz, 1H); 7.71 (d, J=4.82 Hz, 1H); 7.10-7.26 (m, 4H); 6.86 (t, J=8.77 Hz, 4H); 4.80 (s, 4H); 3.81 (s, 3H); 3.80 (s, 3H); 2.56 (s, 3H). m/z (ESI, +ve ion) 462.0 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12](=[N:15][NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Br:23])[C:18]=3[O:24]C)[C:11]([CH3:26])=[N:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8].C(O)(=O)C.O.C(=O)(O)[O-].[Na+]>Br>[CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12](=[N:15][NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Br:23])[C:18]=3[OH:24])[C:11]([CH3:26])=[N:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: COc1c(Br)cccc1NN=C1C(=O)N(c2ccc(C)c(C)c2)N=C1C
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC1=NN(c2ccc(C)c(C)c2)C(=O)C1=NNc1cccc(Br)c1O

Procedure:
A solution of 1-(3,4-dimethylphenyl)-3-methyl-4-(3-bromo-2-methoxyphenyl)hydrazono-5-pyrazolone(5 g) prepared as in Example 2, in 48% aqueous hydrobromic acid (200 mL) and glacial acetic acid (50 mL) was stirred and heated under reflux for about 80 hours. The reaction mixture was concentrated under vacuum to obtain a thick residue. Water (40 mL) was added and basified to pH 7-8 using saturated solution of sodium bicarbonate (20 mL). The mixture was filtered to give an orange solid, which was washed with water (25 mL) and dried in an oven at about 55° C. to about 60° C. for about 12 hours. Yield: 3.5 g
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=O)=[CH:5][CH:4]=1.[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:19].[BH4-].[Na+]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18]([N:20]1[CH2:21][CH2:22][N:23]([CH:9]2[C:10]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:11]=3)[CH2:7][CH2:8]2)[CH2:24][CH2:25]1)=[O:19]
Reactant: COc1ccc2c(c1)C(=O)CC2
Reactant: O=C(c1cccs1)N1CCNCC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Product: COc1ccc2c(c1)C(N1CCN(C(=O)c3cccs3)CC1)CC2

Procedure:
The title compound was prepared by the above procedure using 6-methoxy-1-indanone (2.6 g, 13.2 mmol), 1-(2-thienylcarbonyl)piperazine (2.1 g, 13.2 mol), titanium(IV) isopropoxide (5 mL, 15 mmol) and sodium borohydride (2.7 g, 67 mmol) to give 1.5 g of product as the fumarate salt.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([C:12]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]4[CH3:29])=[C:19]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])[CH:18]=3)[O:14][N:13]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].Cl>>[F:1][C:2]1[CH:11]=[C:10]([C:12]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]4[CH3:29])=[C:19]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])[CH:18]=3)[O:14][N:13]=2)[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(-c2noc(-c3ccc(N4CCCCC4C)c(NS(C)(=O)=O)c3)n2)cc1F
Agent: Cl
Product: CC1CCCCN1c1ccc(-c2nc(-c3ccc(C(=O)O)c(F)c3)no2)cc1NS(C)(=O)=O
Reaction time: 18 h
Yield: 80 %

Procedure:
The title compound was prepared following procedure described for example 4, step 2, but starting from methyl 2-fluoro-4-(5-{4-(2-methylpiperidin-1-yl)-3-[(methylsulfonyl)amino]phenyl}-1,2,4-oxadiazol-3-yl)benzoate, obtained in step 1 (280 mg; 0.57 mmol). After 18 h, HCl (573.14 μL; 5 M; 2.87 mmol) was added and the mixture was evaporated to dryness. The solid was triturated in water and filtered to afford the title compound as a light yellow powder (220 mg; 80%). 1H NMR (DMSO-d6, 300 MHz) δ 13.6 (bs, 1H), 8.67, (bs, 1H), 8.20 (d, 2.1 Hz, 1H), 8.08, (t, J=7.9 Hz, 1H), 8 (dd, J=8.1, 1.6 Hz, 1H), 7.95-7.90 (m, 2H), 7.55 (d, J=8.4 Hz, 1H), 3.22 (s, 3H), 3.18-3.12 (m, 1H), 2.92-2.88 (m, 1H), 2.65-2.57 (m, 1H), 1.82-1.68 (m, 4H), 1.53-1.44 (m, 2H), 0.81 (d, J=6 Hz, 3H). LC/MS (Method B): 475.3 (M+H)+. HPLC (Method A) Rt 4.68 min (purity: 97.0%). CHN analysis: [C22H23N4O5SF] Calculated: C, 55.69%; H, 4.89%; N, 11.81%. Found: C, 55.41%; H, 4.76%; N, 11.70%.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[C:11]([CH3:20])=[C:12]([S:16](Cl)(=[O:18])=[O:17])[CH:13]=[CH:14][CH:15]=1>N1C=CC=CC=1>[Cl:9][C:10]1[C:11]([CH3:20])=[C:12]([S:16]([NH:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[N:7]=2)(=[O:18])=[O:17])[CH:13]=[CH:14][CH:15]=1
Reactant: Cc1nccc(N)n1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Solvent: c1ccncc1
Product: Cc1nccc(NS(=O)(=O)c2cccc(Cl)c2C)n1
Temperature: 55 °C
Reaction time: 48 h
Yield: 9.3 %

Procedure:
2-Methyl-pyrimidin-4-ylamine (91 mg, Gabriel, Chem. Ber. 37, 1904, 3641) and 3-chloro-2-methyl-benzenesulfonyl chloride (179 mg) were dissolved in pyridine (5 mL) and the resulting mixture was allowed to stir at 50 to 60° C. for 48 hours. The mixture was then evaporated in vacuo and the residue was dissolved in ethyl acetate. The solution was washed with 1M CuSO4 solution twice, dried over Na2SO4, filtered and evaporated. The residue was purified by flash chromatography (CH2Cl2MeOH/NH3 90:10:0.5) to give the desired product 3-chloro-2-methyl-N-(2-methyl-pyrimidin-4-yl)-benzenesulfonamide as a yellow powder (22 mg). MS (ESI−): 297.1 ([M−H]−).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)(=[O:18])[CH3:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCCl.O.C(O)(=O)C>[C:16]([N:19]1[CH2:24][CH2:23][N:22]([CH2:11][C:10]2[CH:13]=[CH:14][CH:15]=[C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:9]=2)[CH2:21][CH2:20]1)(=[O:18])[CH3:17]
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Reactant: CC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)N1CCN(Cc2cccc(Oc3ccccc3)c2)CC1
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 84.3 %

Procedure:
3-phenoxybenzaldehyde (1.0 g) and 1-acetylpiperazine (739 mg) were dissolved in 1,2-dichloroethane (10 ml) and sodium triacetoxyboro hydride (1.72 g) and acetic acid (300 mg) were added. The atmosphere was replaced with argon and the mixture was stirred at room temperature for 6.5 hours. Water (5 ml) and saturated sodium hydrogen carbonate (20 ml) were added and the aqueous layer was extracted 5 times with chloroform. Organic layers were combined and dried over anhydrous sodium sulfate. Chloroform was removed and the residue was purified by silica gel column chromatography (ethyl adetate-ethyl acetate:methanol=20:1-10:1) to obtain 1.32 g of 1-acetyl-4-((3-phenoxyphenyl)methyl)piperazine. Yield: 84%.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[C:10]([Cl:17])=[CH:9][C:4]=1[C:5]([O:7]C)=[O:6].B(Br)(Br)Br.[OH-].[Na+]>C(Cl)Cl>[C:14]([NH:13][C:11]1[CH:12]=[C:3]([OH:2])[C:4](=[CH:9][C:10]=1[Cl:17])[C:5]([OH:7])=[O:6])(=[O:16])[CH3:15]
Reactant: COC(=O)c1cc(Cl)c(NC(C)=O)cc1OC
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(=O)Nc1cc(O)c(C(=O)O)cc1Cl
Reaction time: 24 h

Procedure:
To a mixture of 16 g of methyl 2-methoxy-4-acetylamino-5-chlorobenzoate in 130 ml of methylene chloride is slowly added 100 ml of a methylene chloride solution of borontribromide (250 g BBr3 per liter) and stirring continued for 24 hours. 1N sodium hydroxide solution is then added until all material is dissolved. The two layers are separated and the aqueous layer is acidified with 1N hydrochloric acid, filtered, washed with water and evaporated to dryness to give 4-acetylamino-5-chlorosalicylic acid which is used directly in the next step.
Reaction SMILES: [CH2:1]([N:5]([CH2:17][CH2:18][CH2:19][CH3:20])[C:6](=O)[N:7]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH2:9][CH2:10][CH3:11])[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)(Cl)=O.[CH2:26]([NH2:30])[CH2:27][CH2:28][CH3:29]>C(#N)C>[CH2:1]([N:5]([CH2:17][CH2:18][CH2:19][CH3:20])[C:6](=[N:30][CH2:26][CH2:27][CH2:28][CH3:29])[N:7]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH2:9][CH2:10][CH3:11])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN
Reactant: CCCCN(CCCC)C(=O)N(CCCC)CCCC
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: CCCCN=C(N(CCCC)CCCC)N(CCCC)CCCC
Temperature: 0 °C
Yield: 82.9 %

Procedure:
A mixture of 56.9 grams (200 mmol.) of tetra-n-butylurea, 32.2 grams (210 mmol.) of phosphorus oxychloride and 75 ml. of acetonitrile was heated at 75° C. in a nitrogen atmosphere for one hour. The mixture was then cooled to 0° C. and 33.6 grams (460 mmol.) of n-butylamine was added over 15 minutes with stirring, whereupon a soft, fluffy precipitate formed. The mixture was warmed to 60° C. for one hour and again cooled to 0° C., quenched with 50 ml. of 25% (by weight) aqueous sodium hydroxide solution and extracted with ether. The ether extracts were dried over magnesium sulfate, filtered and stripped to give a pale yellow oil which, upon distillation, yielded 56.32 grams (83% of theoretical) of penta-n-butylguanidine.
Reaction SMILES: OC[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[NH2:13][CH2:14][C@H:15]([OH:24])[C@@H:16]([OH:23])[C@H:17]([OH:22])[C:18](=[O:21])[CH2:19][OH:20]>>[NH2:13][CH2:14][C@@H:15]([C@H:16]([C@@H:17]([C@@H:18]([CH2:19][OH:20])[OH:21])[OH:22])[OH:23])[OH:24]
Reactant: NC[C@H](O)[C@@H](O)[C@H](O)C(=O)CO
Agent: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Product: NC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reaction time: 16 h

Procedure:
Glucobacter oxydans ssp. suboxydans is cultured, on a 10 l scale, in a fermenter in a medium which contains, per 1 l, 100 g of sorbitol, 20 g of yeast extract and 2 g of KH2PO4 --dissolved in tap water. 5 l of air per minute are blown through the fermenter and the fermenter is stirred at 500 rpm and kept at a temperature of 30° C. After a 16 hour incubation period, the cells are centrifuged off from the culture broth, washed once by suspending in 10 mM KH2PO4 and again centrifuging and then suspended in 300 ml of 10 mM KH2PO4. The cell suspension thus obtained is broken up by passing twice through a French pressure cell under 8 bars. The cell-free extract is introduced into a 1 l conical flask, 1-amino-1-deoxy-D-glucitol (oxalate salt) is added to give a concentration of 10 g/l and the mixture is incubated at 30° C. on a rotary shaker at 280 rpm. After 7 hours it is possible to detect 3.7 g/l of 6-amino-6-deoxy-L-sorbose--corresponding to a 37% conversion--in this extract, with the aid of the saccharase inhibitory activity. The reaction is discontinued at this time and the extract is worked up as indicated in Example 1.
Reaction SMILES: [C:1]([C:3]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24]O)=[CH:20][CH:19]=2)[C:6]2[N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1)#[N:2].C(N(C(C)C)CC)(C)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37].C(C1C=C(C2C=CC=C(CS(C)(=O)=O)C=2)C2N(C3C=CC=CC=3)C=NC=2C=1)#N>ClCCl>[C:1]([C:3]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][S:36]([CH3:35])(=[O:38])=[O:37])=[CH:20][CH:19]=2)[C:6]2[N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1)#[N:2]
Reactant: CS(=O)(=O)Cl
Reactant: N#Cc1cc(-c2ccc(CO)cc2)c2c(c1)ncn2-c1ccccc1
Agent: CS(=O)(=O)Cc1cccc(-c2cc(C#N)cc3ncn(-c4ccccc4)c23)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)Cc1ccc(-c2cc(C#N)cc3ncn(-c4ccccc4)c23)cc1

Procedure:
5-Cyano-7-(4-methanesulphonylmethylphenyl)-1-phenylbenzimidazole was prepared from 5-cyano-7-(4-hydroxymethylphenyl)-1-phenylbenzimidazole (500 mg, 1.54 mmol), diisopropylethylamine (0.82 ml, 4.62 mmol) and methanesulphonyl chloride (0.13 ml, 1.69 mmol) in dichloromethane (10 ml) using the method described for 5-cyano-7-(3-methanesulphonylmethylphenyl)-1-phenylbenzimidazole. The crude solution (approximately 0.14 M of product) was used directly in the next stage.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][OH:4].N1C=CN=C1.[Si:11](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C)C=O.C(OCC)(=O)C>[Si:11]([O:4][CH2:3][CH2:2][CH2:1][OH:5])([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OCCCO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](OCCCO)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 1,3-propanediol (1.25 g, 16.4 mmol) in N,N-dimethylformamide (50 mL) was added imidazole (2.23 g, 32.8 mmol) and tert-butyldiphenylsilyl chloride (4.97 g, 18.1 mmol). The reaction was stirred for 3 days at room temperature, then was diluted with ethyl acetate and was washed with water and brine. Concentration in vacuo afforded the crude product as a thick colorless oil which was used directly in the next step.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[NH:18][C:19](=[O:26])[C:20](=[CH:24][CH:25]=2)[C:21]([OH:23])=[O:22])=[CH:13][CH:12]=1)=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].C(N(CC)CC)C.[C:34](OC(=O)C)(=[O:36])[CH3:35]>CN(C)C=O>[C:34]([NH:1][C@H:2]([C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[NH:18][C:19](=[O:26])[C:20](=[CH:24][CH:25]=2)[C:21]([OH:23])=[O:22])=[CH:13][CH:12]=1)=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6])(=[O:36])[CH3:35]
Reactant: NC(=O)CC[C@H](N)C(=O)Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)N[C@@H](CCC(N)=O)C(=O)Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1
Yield: 80.7 %

Procedure:
A solution of 30.6 g (83 m mol) of 6-[4-(L-glutaminylamino)phenyl]-1,2-dihydro-2-oxonicotinic acid, 56 ml (0.4 mol) of triethylamine, 19 ml (0.2 mol) of acetic anhydride, and 400 ml dimethylformamide is stirred at room temperature for 3 hrs. The reaction solution is evaporated to dryness under reduced pressure and the residue treated with ice and water. The solid is filtered, washed with water, methanol, ether and dried to give 27.6 g of 6-[4-(N-acetyl-L-glutaminylamino)phenyl]-1,2-dihydro-2-oxonicotinic acid; [α]D23 +19° (cl, DMSO). ##EQU45##