Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([S:13][CH3:14])=[C:11]([C:15]([OH:17])=O)[N:10]=[C:9]2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)[C:46]2[CH:47]=[CH:48][CH:49]=C[C:45]=2[N:44]=[N:43]1.NN1CCCCC1>CC#N.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([S:13][CH3:14])=[C:11]([C:15]([NH:43][N:44]3[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]3)=[O:17])[N:10]=[C:9]2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])=[CH:4][CH:3]=1
Reactant: CSc1c(C(=O)O)nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(Cl)cc1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NN1CCCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: O
Product: CSc1c(C(=O)NN2CCCCC2)nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(Cl)cc1
Reaction time: 40 h
Yield: 72 %

Procedure:
To a magnetically stirred suspension of 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-methylsulfanyl-1H-imidazole-4-carboxylic acid (1.72 g, 4.16 mmol) in anhydrous CH3CN (45 ml) was successively added N,N-diisopropylethylamine (Hunig's base) (1.60 ml, 9.20 mmol), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU) (1.89 g, 4.99 mmol) and 1-aminopiperidine (0.54 ml, 5.01 mmol). After stirring for 40 h, water was added and the resulting mixture was extracted with dichloromethane. The dichloromethane layer was successively twice washed with an 1N HCl solution and water, dried over MgSO4, filtered and concentrated to give a crude oil. This oil was further purified by flash chromatography (silicagel, EtOAc) and triturated with diethyl ether to give 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-methylsulfanyl-N-(piperidin-1-yl)-1H-imidazole-4-carboxamide in 72% yield, mp 170° C. (dec);
Reaction SMILES: [F:1][C:2]1([C:18](F)=[O:19])[C:7]([F:9])([F:8])[C:6]([F:11])([F:10])[C:5]([F:13])([F:12])[C:4]([F:15])([F:14])[C:3]1([F:17])[F:16].C(N(CC)CC)C.[Br:28][C:29]1[CH:35]=[C:34]([N+:36]([O-:38])=[O:37])[CH:33]=[CH:32][C:30]=1[NH2:31].NC1C=CC=CC=1>C(OCC)C>[Br:28][C:29]1[CH:35]=[C:34]([N+:36]([O-:38])=[O:37])[CH:33]=[CH:32][C:30]=1[NH:31][C:18]([C:2]1([F:1])[C:3]([F:16])([F:17])[C:4]([F:14])([F:15])[C:5]([F:13])([F:12])[C:6]([F:11])([F:10])[C:7]1([F:9])[F:8])=[O:19]
Reactant: Nc1ccc([N+](=O)[O-])cc1Br
Reactant: O=C(F)C1(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C1(F)F
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: Nc1ccccc1
Product: O=C(Nc1ccc([N+](=O)[O-])cc1Br)C1(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C1(F)F
Reaction time: 2 h

Procedure:
1,2,2,3,3,4,4,5,5,6,6-Undecafluorocyclohexanecarbonyl fluoride estimated to be of 60% purity (10.9 grams; 0.02 mole) and triethylamine (2 grams; 0.02 mole) were placed in 25 ml of diethyl ether. 2-Bromo-4-nitroaniline (11.35 grams; 0.02 mole) in 75 ml of diethyl ether was added dropwise at ambient temperature of about 25° C. The reaction mixture was then stirred for 11/2 hours. TLC showed no remaining aniline starting material. The reaction mixture was washed with water three times and with dilute sodium bicarbonate solution once, and thereafter dried. The solvent was then removed by evaporation. The product residue was chromatographed on silica gel HPLC with ethyl acetate:hexane 1:5, which yielded 14.5 grams of product containing occluded solvent. It was recrystallized from hexane and air dried, yielding 5.0 grams (48%) of purified product melting at 98°-101° C. An additional 1 gram was obtained from the mother liquor for a total yield of 57%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11][OH:12])[CH:6]=[CH:7][CH:8]=1.CCN(CC)CC.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11][O:12][S:21]([CH3:20])(=[O:23])=[O:22])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(CCCO)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: COc1cccc(CCCOS(C)(=O)=O)c1

Procedure:
In a manner analogous to the preparation of Example 83(a), 3-(3-methoxy-phenyl)-propan-1-ol (0.83 g, 5.00 mmol), Et3N (1.40 mL, 10.0 mmol) and MsCl (0.46 mL, 6.00 mmol) gave the desired compound as a light brown oil. 1H NMR (300 MHz, CDCl3) δ2.04-2.09 (m, 2H), 2.69-2.74 (t, 2H) 2.99 (s, 3H), 3.82 (s, 3H), 4.22-4.26 (t, 2H), 6.70-6.80 (m, 3H), 7.16-7.19 (m, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:3]=1.[C:24]1([CH:30]2[CH2:35][CH2:34][CH2:33][NH:32][CH2:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>O1CCCC1.C(=O)([O-])O>[CH3:8][C:6]1[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:3]=[C:2]([N:32]2[CH2:33][CH2:34][CH2:35][CH:30]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:31]2)[N:7]=1
Reactant: c1ccc(C2CCCNC2)cc1
Reactant: CCCC(C(=O)OC)c1c(C)nc(Cl)nc1-c1ccc(C)cc1
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCC(C(=O)OC)c1c(C)nc(N2CCCC(c3ccccc3)C2)nc1-c1ccc(C)cc1
Temperature: 110 °C
Yield: 32.9 %

Procedure:
A mixture of methyl 2-(2-chloro-4-methyl-6-p-tolylpyrimidin-5-yl)pentanoate (0.104 g; 0.312 mmol), 3-phenylpiperidine (0.151 g; 0.937 mmol) and triethylamine (0.220 mL; 1.56 mmol) in tetrahydrofuran (2 mL) was heated to 110° C. in a sealed tube for 5 h. The reaction mixture was diluted with a saturated solution of hydrogen carbonate and extracted twice with ethyl acetate. The organic layers were washed with brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (2-15%) in heptane furnished 0.047 g (33%) of the title compound as a colorless oil.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][N:6]([CH2:15][C:16]2[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:7][C:8]2[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:2]1.CCN(C(C)C)C(C)C.[C:32](Cl)(Cl)=[O:33].[NH2:36][OH:37].Cl.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[OH:37][NH:36][C:32]([N:1]1[CH2:4][CH:3]([CH2:5][N:6]([CH2:7][C:8]2[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:15][C:16]2[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:2]1)=[O:33]
Reactant: NO
Reactant: Cc1cccnc1CN(Cc1ncccc1C)CC1CNC1
Reactant: O=C(Cl)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: Cc1cccnc1CN(Cc1ncccc1C)CC1CN(C(=O)NO)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 38 %

Procedure:
To a 0° C. solution of azetidin-3-ylmethyl-bis(3-methyl-pyridin-2-ylmethyl)-amine from above (134 mg, 0.452 mmol) in toluene (5 mL) and DIPEA (0.20 mL, 0.90 mmol) was added phosgene solution in toluene (20 wt %, 0.247 mL, 0.543 mmol). The reaction mixture was warmed to room temperature and was stirred for 1.5 hours. The volatiles were removed under reduced pressure and the remaining yellow solid was dissolved in DMF (5 mL). DIPEA (1 mL) and NH2OH.HCl (180 mg, 2.56 mmol) were added and the mixture was stirred for 17 hours at room temperature. Saturated NaHCO3 (15 mL) was added and the mixture was extracted with CH2Cl2 (3×30 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated. The crude material was purified by radial chromatography (10:1:0.2 CH2Cl2:MeOH:NH4OH) on silica gel to provide COMPOUND 330 (61 mg, 38%) as a white solid. 1H NMR (MeOH-d4) δ 2.14 (s, 6H), 2.69-2.72 (m, 2H), 2.82-2.85 (m, 1H), 3.25-3.31 (m, 2H), 3.73 (s, 4H), 3.93 (dd, 2H, J=8.4, 8.4 Hz), 7.26 (dd, 2H, J=4.5, 7.5 Hz), 7.59 (d, 2H, J=7.5 Hz), 8.29 (d, 2H, J=4.5 Hz); 13C NMR (DMSO-d6) δ 18.5, 29.3, 55.3, 60.3, 60.6, 124.9, 136.0, 140.8, 146.9, 157.8, 164.2; ES-MS m/z 378 (M+Na). Anal. Calcd. for C19H25N5O2.0.6H2O.0.9 CH2Cl2: C, 53.99; H, 6.37; N, 15.82. Found: C, 54.27; H, 6.33; N, 16.10.
Reaction SMILES: [OH:1][C@H:2]1[C@@H:6]2[CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10][N:5]2[CH2:4][CH2:3]1.Cl[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][N:20]=1.CC(C)([O-])C.[K+]>O1CCCC1>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([O:1][CH:2]2[CH:6]3[CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10][N:5]3[CH2:4][CH2:3]2)=[N:20][CH:21]=1
Reactant: Clc1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CCN2CC[C@@H](O)[C@@H]2C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN2CCC(Oc3ccc(Cl)cn3)C2C1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
(8R*,8aS*)-tert-Butyl 8-hydroxyhexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate (Example 35D, 0.969 g, 4.0 mmol) and 2,5-dichloropyridine (0.651 g, 4.40 mmol) were treated with potassium tert-butoxide (0.987 g, 8.80 mmol) in dry tetrahydrofuran (5 mL). The mixture was heated to 80° C. and stirred for 16 hours. After the mixture cooled to room temperature, the mixture was purified via HPLC (Gilson®, Xbridge™ 30×100 mm column, eluted with pH=10 aqueous ammonium bicarbonate-ammonium hydroxide/methanol, UV=222 nm) to give the tert-butoxycarbonyl protected product, tert-butyl 8-(5-chloropyridin-2-yloxy)hexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate. This tert-butoxycarbonyl compound was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (2 mL) was added. The reaction mixture was stirred at room temperature for 3 hours. The mixture was concentrated and then purified via HPLC (Gilson®, Xbridge™ 30×100 mm column, eluted with pH=10 aqueous ammonium bicarbonate-ammonium hydroxide/methanol, UV=220 nm) to give the title compound. 1H NMR (300 MHz, methanol-d4) δ ppm 1.72-1.86 (m, 1H), 2.08-2.22 (m, 3H), 2.31-2.45 (m, 1H), 2.69-2.80 (m, 2H), 2.87-2.98 (m, 1H), 2.99-3.21 (m, 3H), 5.51 (ddd, 1H, J=7, 4, 2 Hz), 6.77 (d, 1H, J=9 Hz), 7.65 (dd, 1H, J=8, 2 Hz), 8.07 (d, 1H, J=2 Hz); MS (DCI) m/z 254 (M+H)+.
Reaction SMILES: [C:1]([C:9]1[CH:25]=[CH:24][CH:23]=[CH:22][C:10]=1[C:11]([N:13]1[CH2:18][CH2:17][C:16]2[O:19][CH:20]=[CH:21][C:15]=2[CH2:14]1)=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][NH:27][CH3:28].[CH2:29]=O>C(O)(=O)C>[CH3:26][N:27]([CH2:29][C:20]1[O:19][C:16]2[CH2:17][CH2:18][N:13]([C:11](=[O:12])[C:10]3[CH:22]=[CH:23][CH:24]=[CH:25][C:9]=3[C:1](=[O:8])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:14][C:15]=2[CH:21]=1)[CH3:28]
Reactant: CNC
Reactant: C=O
Reactant: O=C(c1ccccc1)c1ccccc1C(=O)N1CCc2occc2C1
Solvent: CC(=O)O
Product: CN(C)Cc1cc2c(o1)CCN(C(=O)c1ccccc1C(=O)c1ccccc1)C2
Temperature: 100 °C
Reaction time: 0.75 h

Procedure:
To a solution of 0.140 g (0.422 mmol) of 5-(2-benzoylbenzoyl)-4,5,6,7-tetrahydrofuro[3,2-c]pyridine in 20 ml of acetic acid, 0.060 ml (0.63 mmol) of 50% aqueous dimethylamine and 0.052 ml (0.63 mmol) of 37% aqueous formaldehyde were added, followed by stirring at 100° C. for 45 minutes. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with aqueous sodium hydroxide and extracted with dichloromethane 3 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform to chloroform/methanol=25/1) to yield the desired product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH2:8]([Cl:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CC(C)=O>[Cl-:15].[CH2:8]([N+:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: ClCc1ccccc1
Reactant: Cc1ccncc1
Solvent: CC(C)=O
Product: Cc1cc[n+](Cc2ccccc2)cc1
Product: [Cl-]
Temperature: 50 °C
Reaction time: 18 h
Yield: 64.5 %

Procedure:
To a stirred solution of 4-methylpyridine (26 mL/0.268 mol) in 70 mL of acetone was added 31 mL (0.268 mol) of benzylchloride. The resulting mixture was stirred at 50° C. for 18 hours. After cooling to room temperature, the reaction was filtered, washed with acetone and dried under reduced pressure affording 38 g of the title compound. The filtrate was concentrated under reduced pressure producing an additional 5.6 grams of the title compound (74% combined yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[Mg].[CH2:13]([O:20][C:21]([N:23]1[CH2:28][CH2:27][C:26](=[O:29])[CH2:25][CH2:24]1)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CCOCC>[CH2:13]([O:20][C:21]([N:23]1[CH2:28][CH2:27][C:26]([OH:29])([C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=2)[CH2:25][CH2:24]1)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: FC(F)(F)c1ccc(Br)cc1
Agent: [Mg]
Solvent: CCOCC
Product: O=C(OCc1ccccc1)N1CCC(O)(c2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C

Procedure:
4-Bromobenzotrifluoride (6.05 mL, 43.21 mmol) dissolved in ether (5 mL) was added dropwise over 10 minutes to magnesium turnings (1.25 g, 51.42 mmol). The mixture became mildly exothermic and turned red-brown while the Grignard reagent formed during 1.5 hours of stirring. The mixture was chilled with ice and 1-benzyloxycarbonyl-4-piperidone (10.0 g, 42.87 mmol dissolved in 50 mL of ether) was added dropwise over 10 minutes to the reaction. The reaction was allowed to warm to room temperature and stirred overnight. The mixture was quenched with saturated ammonium chloride and the phases were separated. The aqueous layer was further extracted with ether. The combined organic phase was washed with water and brine, dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography on silica gel (3×6 inches, 30% ethyl acetate/hexane) to give 1-benzyloxycarbonyl4-hydroxy-4-(4-trifluoromethylphenyl)piperidine as an orange oily product which solidified on standing (12.48 g, 77%). The material was suitable for use in the next step. A sample recrystallized from ether/hexane had mp 102°-102.5° C. Analysis calculated for C20H20F3NO3 : C, 63.32; H, 5.31; N, 3.69. Found: C, 63.25; H, 5.27; N, 3.71.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:13]([NH:15][CH:16]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C:17]([F:20])([F:19])[F:18])=[O:14])[N:8]2[CH2:11][CH3:12])=[CH:4][C:3]=1[C:31]([NH:33][C:34]1([C:37]#[N:38])[CH2:36][CH2:35]1)=[O:32].ClS([N:43]=[C:44]=O)(=O)=O.CN(C)C=O>C(#N)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:44]#[N:43])=[C:7]([C:13]([NH:15][CH:16]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:28])[F:29])[CH:22]=3)[C:17]([F:18])([F:20])[F:19])=[O:14])[N:8]2[CH2:11][CH3:12])=[CH:4][C:3]=1[C:31]([NH:33][C:34]1([C:37]#[N:38])[CH2:35][CH2:36]1)=[O:32]
Reactant: CCn1c(C(=O)NC(c2cccc(C(F)(F)F)c2)C(F)(F)F)cc2cc(C(=O)NC3(C#N)CC3)c(Cl)cc21
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCn1c(C(=O)NC(c2cccc(C(F)(F)F)c2)C(F)(F)F)c(C#N)c2cc(C(=O)NC3(C#N)CC3)c(Cl)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 5.7 %

Procedure:
6-Chloro-N5-(1-cyanocyclopropyl)-1-ethyl-N2-{2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}-1H-indole-2,5-dicarboxamide (0.100 g, 0.18 mmol) is initially charged in dry acetonitrile (2 ml) under argon and cooled to 0° C., and chlorosulphonyl isocyanate (0.028 g, 0.19 mmol) is added dropwise. After 30 min, N,N-dimethylformamide (0.015 g, 0.19 mmol) is added and the mixture is stirred at 0° C. for a further 30 min and at room temperature overnight. Then the mixture is cooled again to 0° C. and chlorosulphonyl isocyanate (0.028 g, 0.19 mmol) is added dropwise, N,N-dimethylformamide (0.015 g, 0.19 mmol) is added after 30 min, and the mixture is stirred at room temperature for a further 48 h. The reaction mixture is then concentrated under reduced pressure, and the residue is admixed with sodium hydrogencarbonate and extracted with dichloromethane. The organic phase is dried with sodium sulphate, filtered and concentrated under reduced pressure. The residue is purified by means of preparative HPLC (Kromasil100, C18 250×20; eluent: acetonitrile in water, gradient: 10-100%) to obtain 0.006 g (5% of theory) of 6-chloro-3-cyano-N5-(1-cyanocyclopropyl)-1-ethyl-N2-{2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}-1H-indole-2,5-dicarboxamide.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([CH2:32][CH3:33])=[CH:28][CH:27]=2)=[CH:4][C:5]([C@H:14]2[C@H:19]([OH:20])[C@@H:18]([OH:21])[C@H:17]([OH:22])[C@@H:16]([CH2:23][OH:24])[O:15]2)=[C:6]([CH:13]=1)[CH2:7][O:8][CH2:9][C:10](=[O:12])[CH3:11].[BH4-].[Na+].CO>C1COCC1>[Cl:1][C:2]1[C:3]([CH2:25][C:26]2[CH:27]=[CH:28][C:29]([CH2:32][CH3:33])=[CH:30][CH:31]=2)=[CH:4][C:5]([C@H:14]2[C@H:19]([OH:20])[C@@H:18]([OH:21])[C@H:17]([OH:22])[C@@H:16]([CH2:23][OH:24])[O:15]2)=[C:6]([CH2:7][O:8][CH2:9][CH:10]([OH:12])[CH3:11])[CH:13]=1
Reactant: CCc1ccc(Cc2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c(COCC(C)=O)cc2Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1ccc(Cc2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c(COCC(C)O)cc2Cl)cc1
Temperature: 25 °C
Yield: 67.5 %

Procedure:
To a solution of 1-(5-chloro-4-(4-ethylbenzyl)-2-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)benzyloxy)propan-2-one (compound K) (3.7 mg, 0.0077 mmol) in dry THF (0.5 mL) was added NaBH4 (1.76 mg, 0.0045 mmol) with stirring under argon at room temperature. After the mixture was stirred for 20 min, anhydrous methanol was added dropwise, and the resulting mixture was stirred at 20° C. for 2 h, then quenched by addition of sat. NH4Cl. The mixture was extracted with EtOAc and the combined organic layers were washed with water, brine, dried over Na2SO4, filtered and concentrated to provide the crude product, which was purified by preparative TLC to yield 2.5 mg of the product. 1H-NMR (CD3OD, 300 MHz) δ 7.45 (s, 1H), 7.43 (s, 1H), 7.08 (s, 4H), 4.75-4.56 (m, 1H), 4.47 (dd, J=9.3 Hz, 3.3 Hz, 1H), 4.10 (d, J=14.8 Hz, 1H), 4.05 (d, J=14.8 Hz, 1H), 3.93-3.83 (m, 2H), 3.68-3.66 (m, 1H), 3.47-3.37 (m, 6H), 2.60 (q, J=7.8 Hz, 2H), 1.21 (t, J=7.8 Hz, 3H), 1.15 (d, J=7.8 Hz, 3H); LC-MS (m/z) 481 [(M+1)+], 525 [(M+45)−].
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=1.C(Cl)(Cl)[Cl:29].C(=O)([O-])[O-].[Na+].[Na+].[C:38](Cl)([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39]>O>[C:38]([N:18]([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Br:1])[C:19]1[CH:20]=[CH:21][C:22]([C:23]([Cl:29])=[O:25])=[CH:26][CH:27]=1)([O:40][CH2:41][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)=[O:39]
Reactant: O=C(O)c1ccc(NCCCCCCCCCCCCCCCCBr)cc1
Reactant: ClC(Cl)Cl
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(Cl)c1ccc(N(CCCCCCCCCCCCCCCCBr)C(=O)OCc2ccccc2)cc1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
To 15 g. 4-(16-bromohexadecylamino)benzoic acid in 200 ml. warm chloroform is added 15 g. sodium carbonate in 150 ml. water. To the vigorously stirred solution is added 10 g. carbobenzyloxy chloride. After 2 hours stirring at 40° C., the layers are separated, washed three times with 1 N hydrochloric acid dried, and evaporated to an oil. The oil is dissolved in 300 ml. toluene, treated with 15 ml. thionyl chloride and the solution is refluxed for 5 hours. The solvents are evaporated and the residue is dissolved three times in toluene, evaporating each time to yield a viscous, orange oil.
Reaction SMILES: Cl.[CH2:2]([N:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[CH2:9][NH:10]C(=O)C1C(OC)=CC=C([Cl:20])C=1OC)[CH3:3].[Br:24][C:25]1[C:26]([O:37][CH3:38])=[C:27]([C:31]([O:35][CH3:36])=[C:32]([Br:34])[CH:33]=1)[C:28]([OH:30])=O.NCC1CCCN1CC>S(Cl)(Cl)=O>[ClH:20].[CH2:2]([N:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[CH2:9][NH:10][C:28](=[O:30])[C:27]1[C:31]([O:35][CH3:36])=[C:32]([Br:34])[CH:33]=[C:25]([Br:24])[C:26]=1[O:37][CH3:38])[CH3:3]
Reactant: COc1c(Br)cc(Br)c(OC)c1C(=O)O
Reactant: CCN1CCCC1CNC(=O)c1c(OC)ccc(Cl)c1OC
Agent: CCN1CCCC1CN
Agent: Cl
Solvent: O=S(Cl)Cl
Product: CCN1CCCC1CNC(=O)c1c(OC)c(Br)cc(Br)c1OC

Procedure:
Using the same method as for compound of Example 8 this compound is prepared from 20.4 g (0.06 mol) of 3,5-dibromo-2,6-dimethoxybenzoic acid, 50 ml of thionyl chloride and 7.7 g (0.06 mol) of 2-(aminomethyl)-1-ethylpyrrolidine. The obtained product is recrystallized from ethanol-ethyl ether. Yield: 20.2 g, m.p. 164°-65° C. The free base is precipitated from the water solution of the hydrochloric salt by the addition of sodium hydroxide, m.p. 133°-134° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=O.[NH:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[C:21]1[C:25]([NH2:26])=[CH:24][NH:23][N:22]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[NH:14]1[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:12]=[C:13]1[C:21]1[C:25]([NH:26][C:4](=[O:6])[C:3]2[C:7]([F:11])=[CH:8][CH:9]=[CH:10][C:2]=2[F:1])=[CH:24][NH:23][N:22]=1
Reactant: Nc1c[nH]nc1-c1nc2ccccc2[nH]1
Reactant: O=C(O)c1c(F)cccc1F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: O
Product: O=C(Nc1c[nH]nc1-c1nc2ccccc2[nH]1)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 23.6 %

Procedure:
A mixture of 2,6-difluorobenzoic acid (43 mg, 0.28 mmol), 3-(1H-benzimidazol-2-yl)-1H-pyrazol-4-ylamine (50 mg, 0.25 mmol), EDC (58 mg, 0.30 mmol) and HOBt (40.5 mg, 0.30 mmol) in DMF (10 ml) was stirred at ambient temperature for 24 h. The mixture was reduced in vacuo, water (30 ml) added and the resultant solid collected by filtration, dried in the vacuum oven and purified by flash column chromatography [SiO2, EtOAc-petrol (1:2, 1:1, 3:1)] affording N-[3-(1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-2,6-difluoro-benzamide (20 mg, 24%). (LC/MS: Rt 3.29, [M+H]+ 339.64).
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5](=[O:15])[C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=1[OH:14].COC(C)(C)C>CCCCCCC.O>[CH3:3][O:4][C:5](=[O:15])[C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]([Br:1])[C:7]=1[OH:14]
Reactant: COC(=O)c1cc(OC)ccc1O
Reactant: BrBr
Solvent: CCCCCCC
Solvent: COC(C)(C)C
Solvent: O
Product: COC(=O)c1cc(OC)cc(Br)c1O
Reaction time: 0.62 h
Yield: 82.5 %

Procedure:
In the course of from 30 to 45 minutes, at 20°, with stirring, 43.9 g of bromine are added dropwise to a solution of 45.9 g of 2-hydroxy-5-methoxy-benzoic acid methyl ester in 125 ml of heptane. The reaction mixture is then stirred for a further 3 to 4 hours, then diluted with 110 ml of water and stirred for a further one hour and then 295 ml of heptane and 46 ml of tert-butyl methyl ether are added thereto. The mixture is then heated to from 50° to 55° and the aqueous phase is separated off. The organic phase is extracted twice with 114 ml of water each time and cooled to -20°. The crystals which precipitate are filtered off and dried under a high vacuum. 3-Bromo-2-hydroxy-5-methoxy-benzoic acid methyl ester is thus obtained; yield 82.5% of the theoretical yield.