Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH:5]=[CH:6][C:7]=1[NH:8][CH3:9].CN(C=O)C.OOS([O-])=O.[K+].[CH:26](=O)[C:27]1[CH:32]=[CH:31][CH:30]=[N:29][CH:28]=1>O>[CH3:9][N:8]1[C:7]2[CH:6]=[CH:5][C:4]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:3][C:2]=2[N:1]=[C:26]1[C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=Cc1cccnc1
Reactant: CNc1ccc(NS(C)(=O)=O)cc1N
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(-c2cccnc2)nc2cc(NS(C)(=O)=O)ccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of N-(3-amino-4-(methyl amino) phenyl) methane sulfonamide (0.3 g, 0.0013 mol) in the mixture of DMF (10 ml) and water (2 ml) was added OXONE® (1.02 g, 0.0016 mol) and followed by nicotinaldehyde (0.16 g, 0.0015 mol) was added portion wise with constant stirring. The reaction mixture was allowed to stir at room temperature for 3 h. The reaction mixture was concentrated on a high vacuo pump and diluted with cold water (10 ml) and extracted with ethyl acetate (3×15 ml). The combined organic layers were washed with brine dried over Na2SO4 and concentrated in vacuo and purified by column chromatography on silica gel to afford the desired product N-[1-methyl-2-(pyridin-3-yl)-1H-benzimidazol-5-yl]methanesulfonamide (363) as a brown solid. 1H NMR (400 MHz, DMSO-d6), δ: 9.53 (bs, 1H), 9.04 (s, 1H), 8.75-8.77 (d, J=4.0 Hz, 1H), 8.28-8.26 (d, J=8.0 Hz, 1H), 7.68-7.57 (m, 3H), 7.24-7.21 (d, J=8.4 Hz, 1H), 3.89 (s, 3H), 2.91 (s, 3H). LCMS (ES) m/e MS (M+1=244), Purity 95.64%.
Reaction SMILES: [C:1]([NH2:20])([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.O=[CH:22][CH2:23][C:24]1([C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]1.ClCCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O>[C:1]([NH:20][CH2:22][CH2:23][C:24]1([C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:35])([CH3:36])[CH3:34])=[O:31])[CH2:25]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C1(CC=O)CCCN(C(=O)OC(C)(C)C)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: CCOC(=O)C1(CCNC(c2ccccc2)(c2ccccc2)c2ccccc2)CCCN(C(=O)OC(C)(C)C)C1
Reaction time: 8 h

Procedure:
Tritylamine (180 mg, 0.00068 mol) was added to a solution of 1-tert-butyl 3-ethyl 3-(2-oxoethyl)piperidine-1,3-dicarboxylate (0.170 g, 0.000568 mol, this was prepared by using procedures analogous to that described for the synthesis of example 1, steps 1-2) in 1,2-dichloroethane (4.0 mL, 0.051 mol) and followed by sodium triacetoxyborohydride (0.36 g, 0.0017 mol) and the mixture was stirred overnight. The mixture was poured into pre-cooled water, and extracted with ethyl acetate. The organic layer was separated, dried (NaSO4), and concentrated in-vacuo. The product was purified by CombiFlash eluting with hexane/EtOAc (max EtOAc 20%). LC-MS: 543.3 (M+H)+; 243.2.
Reaction SMILES: [Cl:1][C:2]([Cl:9])([Cl:8])[C:3]([N:5]=[C:6]=O)=[O:4].[O:10]=[C:11]1[C:16]2[CH:17]=[C:18]3[C:23](=[C:24]([CH2:25][CH2:26][CH3:27])[C:15]=2[O:14][C:13]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:12]1)[NH:22][C:21]([C:28]([O:30][CH3:31])=[O:29])=[CH:20]C3=O>ClCCl>[CH3:31][O:30][C:28]([C:21]1[CH:20]=[C:6]([NH:5][C:3](=[O:4])[C:2]([Cl:9])([Cl:8])[Cl:1])[C:18]2[C:23](=[C:24]([CH2:25][CH2:26][CH3:27])[C:15]3[O:14][C:13]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:12][C:11](=[O:10])[C:16]=3[CH:17]=2)[N:22]=1)=[O:29]
Reactant: CCCc1c2[nH]c(C(=O)OC)cc(=O)c2cc2c(=O)cc(C(=O)OCC)oc12
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCCc1c2nc(C(=O)OC)cc(NC(=O)C(Cl)(Cl)Cl)c2cc2c(=O)cc(C(=O)OCC)oc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Trichloroacetyl isocyanate (1.18 ml, 10 mmol) was added to a solution of ethyl 6,9-dihydro-4,6-dioxo-8-methoxycarbonyl-10-propyl-4H-pyrano[3,2-g]quinoline-2-carboxylate (3.85 g, 10 mmol) in dichloromethane (20 ml) at room temperature. The solution was then agitated gently for 24 hours at room temperature and then the solvent removed by distillation in vacuo. Trituration of the resulting solid with ether gave the sub-title compound as yellow cubes, 4.25 g (80%), mp 167°-169° C.
Reaction SMILES: CS(O[CH2:6][CH:7]1[C:11]2[C:12]([CH3:26])=[C:13]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]([CH3:17])=[C:15]([CH3:16])[C:10]=2[O:9][C:8]1([CH3:28])[CH3:27])(=O)=O.[NH:29]1[CH2:35][CH2:34][CH2:33][C@H:30]1[CH2:31][OH:32]>>[CH2:19]([O:18][C:13]1[C:14]([CH3:17])=[C:15]([CH3:16])[C:10]2[O:9][C:8]([CH3:28])([CH3:27])[CH:7]([CH2:6][N:29]3[CH2:35][CH2:34][CH2:33][C@H:30]3[CH2:31][OH:32])[C:11]=2[C:12]=1[CH3:26])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Cc1c(C)c2c(c(C)c1OCc1ccccc1)C(COS(C)(=O)=O)C(C)(C)O2
Reactant: OC[C@@H]1CCCN1
Product: Cc1c(C)c2c(c(C)c1OCc1ccccc1)C(CN1CCC[C@H]1CO)C(C)(C)O2
Yield: 66.3 %

Procedure:
The title compound (1 g, 66%) was prepared as a pale yellow solid from (3RS)-5-benzyloxy-2,3-dihydro-2,2,4,6,7-pentamethylbenzofuran-3-ylmethyl methanesulfonate (1.49 g) and L-prolinol (1.5 g) by an analogous procedure to that described in preparation 1, mp 99°-101° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:12][N:11]([C:13]([C:15]3[CH:16]=[CH:17][C:18]([CH3:40])=[C:19]([C:21]4[N:22]=[C:23]([CH:27]5[CH2:32][CH2:31][N:30]([C:33]([O:35]C(C)(C)C)=O)[CH2:29][CH2:28]5)[NH:24][C:25]=4[CH3:26])[CH:20]=3)=[O:14])[CH2:10]2)=[CH:5][CH:4]=1)#[N:2].F[C:42](F)(F)C(O)=O.CC1C=CC(C(N2CC(C3C=CC(C#N)=CC=3)C2)=O)=CC=1C1NC(C2CCNCC2)=NC=1C.C(OC(=O)C)(=O)C.C(N(CC)CC)C>C(Cl)Cl>[C:33]([N:30]1[CH2:31][CH2:32][CH:27]([C:23]2[NH:22][C:21]([C:19]3[CH:20]=[C:15]([CH:16]=[CH:17][C:18]=3[CH3:40])[C:13]([N:11]3[CH2:10][CH:9]([C:6]4[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=4)[CH2:12]3)=[O:14])=[C:25]([CH3:26])[N:24]=2)[CH2:28][CH2:29]1)(=[O:35])[CH3:42]
Reactant: Cc1ccc(C(=O)N2CC(c3ccc(C#N)cc3)C2)cc1-c1nc(C2CCN(C(=O)OC(C)(C)C)CC2)[nH]c1C
Reactant: O=C(O)C(F)(F)F
Agent: Cc1ccc(C(=O)N2CC(c3ccc(C#N)cc3)C2)cc1-c1[nH]c(C2CCNCC2)nc1C
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)N1CCC(c2nc(C)c(-c3cc(C(=O)N4CC(c5ccc(C#N)cc5)C4)ccc3C)[nH]2)CC1
Reaction time: 1.5 h

Procedure:
To a solution of tert-butyl 4-(4-(5-(3-(4-cyanophenyl)azetidine-1-carbonyl)-2-methylphenyl)-5-methyl-1H-imidazol-2-yl)piperidine-1-carboxylate (compound 182.3, 475 mg, 0.88 mmol) in 20 mL DCM, was added trifluoroacetic acid (4 mL). The reaction was stirred for 1.5 hours, concentrated under reduced pressure and neutralized with 10 mL Na2CO3 (1M) to obtain a crude product after lyophilization. A mixture of 4-(1-(4-methyl-3-(4-methyl-2-(piperidin-4-yl)-1H-imidazol-5-yl)benzoyl)azetidin-3-yl)benzonitrile (252 mg, 0.57 mmol), acetic anhydride (71 μL, 0.75 mmol) and triethylamine (120 μL, 0.86 mmol) was stirred at room temperature for 16 hours. The reaction was concentrated under reduced pressure, then diluted with saturated NaH2PO4 (20 mL) and extracted with EtOAc (3×20 mL). The organic phase was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by preparative TLC with 10% methanol in dichloromethane and lyophilized to give 235 mg (80%-2 steps) of the title compound as a white solid. m/z (ES+) 482 (M+H)+.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.II.[CH2:22]([O:29][N:30]1[C:36](=[O:37])[N:35]2[CH2:38][C@H:31]1[CH2:32][CH2:33][C@H:34]2[C:39]([NH:41][NH:42][C:43]([C@H:45]1[CH2:49][CH2:48][C@@H:47]([NH:50][C:51](=[O:57])[O:52][C:53]([CH3:56])([CH3:55])[CH3:54])[CH2:46]1)=[O:44])=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH2:22]([O:29][N:30]1[C:36](=[O:37])[N:35]2[CH2:38][C@H:31]1[CH2:32][CH2:33][C@H:34]2[C:39]1[O:44][C:43]([C@H:45]2[CH2:49][CH2:48][C@@H:47]([NH:50][C:51](=[O:57])[O:52][C:53]([CH3:56])([CH3:54])[CH3:55])[CH2:46]2)=[N:42][N:41]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](C(=O)NNC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)C1
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](c2nnc([C@@H]3CC[C@@H]4CN3C(=O)N4OCc3ccccc3)o2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.7 %

Procedure:
To a 0° C. solution of PPh3 (2.2 g 8.4 mmol) in dry DCM (20 mL) was added I2(2.1 g, 8.4 mmol). After I2 was dissolved, TEA (2.4 mL, 16.8 mmol) was added quickly at rt. The reaction mixture was stirred for 15 min. tert-Butyl (1R,3S)-3-(2-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbonyl)hydrazinecarbonyl)cyclopentylcarbamate (2.1 g, 4.2 mmol) was added. The reaction mixture was stirred at rt for 1 h. The reaction mixture was concentrated and the residue was purified by silica gel column (gradient elution 0˜50% EtOAc/petroleum ether) to afford the crude tert-butyl (1R,3S)-3-(5-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octan-2-yl)-1,3,4-oxadiazol-2-yl)cyclopentylcarbamate (˜1.7 g) as a white solid. ESI-MS (EI+, m/z): 484.1.
Reaction SMILES: [SH:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.F[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N+:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[S:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1)([O-:17])=[O:16]
Reactant: Sc1ncccn1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1Sc1ncccn1
Yield: 83.1 %

Procedure:
A mixture of 2 mercaptopyrimidine (2.00 g, 17.8 mmol), 1-fluoro-2-nitrobenzene (2.50 g, 17.8 mmol) and potassium carbonate (2.46 g, 17.8 mmol) in DMF (15 mL) was stirred under reflux for 2 h. After removal of DMF, the residue was dissolved in DCM and washed with NaOH (5%, 3×20 mL) and brine. The organic layer was dried (MgSO4), filtered and evaporated to give 2-(2-nitro-phenylsulfanyl)-pyrimidine (3.45 g, 83%) as a yellow solid which was used in the next step without further purification. LC/MS (APCI) tr=3.66 min, m/z 379.28 (39), 233.98 (M++H, 100). HPLC tr=2.22 min (99.67%) 1H NMR (270 MHz, CDCl3) δ 7.03 (1H, t, J=4.7 Hz, Pyrimidine-H), 7.51-7.64 (2H, m, ArH), 7.80 (1H, dd, J=7.7, 1.5 Hz, ArH), 8.03 (1H, dd, J=7.7, 2.0 Hz, ArH) and 8.48 (2H, d, J=4.7 Hz, Pyrimidine-H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[CH2:9][S:8][CH2:7]1.I[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]I.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[CH2:9][C:13]2([CH2:17][CH2:16][CH2:15][CH2:14]2)[S:8][CH2:7]1
Reactant: ICCCCCI
Reactant: O=C1CSCN1CCCCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1CC2(CCCC2)SCN1CCCCBr
Temperature: -65 °C
Reaction time: 0.5 h
Yield: 63.8 %

Procedure:
To a solution of 3-(4-bromobutyl)-4-thiazolidinone (25 g) in THF (350 ml) cooled to -60° C. was added 1,5-diiodopentane (100 g), and the resultant slurry was cooled to -65° C. A solution of lithium bis(trimethylsilyl)amide (0.220 mole) in hexanes (220 ml) was added dropwise, during which the internal temperature was maintained at or below -55° C. The addition was complete within 30 minutes. The mixture was stirred for additional 15 minutes at the same temperature and thereafter warmed to 0° C. with the aid of an ice bath. The mixture was stirred for additional 20 minutes and thereafter quenched with 500 ml of 0.5N HCl solution. The resultant mixture was placed under vacuum to remove some of the THF and thereafter extracted with ether (350 ml, 2×250 ml). The combined extracts were washed successively with water (400 ml) and brine (400 ml), dried with Na2SO4 and concentrated to a liquid. The liquid was chromatographed (2 silica gel columns) using 20-60% ethyl acetate/hexane as an eluent to obtain about 20.5 g of solid product.
Reaction SMILES: [C:1]([CH2:4][C:5]1[N:6]=[C:7]([S:10][C:11]([CH3:16])([CH3:15])[C:12]([OH:14])=[O:13])[S:8][CH:9]=1)([OH:3])=O.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl.O1CCO[CH2:26][CH2:25]1>CN(C)C=O>[CH2:22]([NH:17][C:1](=[O:3])[CH2:4][C:5]1[N:6]=[C:7]([S:10][C:11]([CH3:16])([CH3:15])[C:12]([OH:14])=[O:13])[S:8][CH:9]=1)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:25][CH3:26]
Reactant: c1ccncc1
Reactant: C1COCCO1
Reactant: CC(C)(Sc1nc(CC(=O)O)cs1)C(=O)O
Agent: Cl
Solvent: CN(C)C=O
Product: CCCCCCCNC(=O)Cc1csc(SC(C)(C)C(=O)O)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 2-{[4-(carboxymethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid resin (5.0 g) synthesized in Example 461-4 in dimethylformamide (20 mL) were added pyridine (1.2 ml) and 4 mol/L-hydrochloric acid-dioxane solution (2.3 ml) and the mixture was gently stirred at room temperature for 30 min. The resin was collected by filtration, and washed three times with dimethylformamide. To the resin were added dimethylformamide (20 mL), pyridine (0.75 ml) and 2-chloro-1,3-dimethylimidazolinium chloride (1.6 g), and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added heptylamine (1.4 ml), and the mixture was stirred at room temperature overnight. The resin was collected by filtration from the mixture, successively washed three times with dimethylformamide, once with water and methanol, three times with tetrahydrofuran, once with methanol, and finally three times with dichloromethane, and vacuum dried to give the title pale-yellow resin (5.2 g).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([O:15][C:16](=[O:18])[CH3:17])[CH2:12][CH:13]=[CH2:14])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]>CCO.O=[Pt]=O>[C:16]([O:15][CH:11]([C:8]1[CH:7]=[CH:6][C:5]([O:4][C:1](=[O:3])[CH3:2])=[CH:10][CH:9]=1)[CH2:12][CH2:13][CH3:14])(=[O:18])[CH3:17]
Reactant: C=CCC(OC(C)=O)c1ccc(OC(C)=O)cc1
Agent: O=[Pt]=O
Solvent: CCO
Product: CCCC(OC(C)=O)c1ccc(OC(C)=O)cc1

Procedure:
1.0 g (4 mmol) diacetate 9 is dissolved in 19 ml EtOH and hydrogentated over 50 mg PtO2. The catalyst is removed by filtration over Celite and the solvent is evaporated. Flash chromatography of the crude product gave 0.92 g (91% by weight) of compound 15 in the form of a yellowish oil having the following 1NMR (CDCl3) values: 0.92 (t, J=7.0, CH3); 1.15-1.45 (m, 2H, CH2); 1.62-2.00 (m, 2H, CH2); 2.05 (s, CH3); 2.30 (s, CH3); 5.74 (t, J=7.0, CH); 7.06 (d, J=9.0, 2 aromatic H). 7.34 (d, J=9.0, 2 aromatic H). MS: 250 (2, [M+]), 208 (19), 165 (32), 123 (68), 43 (100).
Reaction SMILES: [Mg].[Cl:2][CH2:3][C:4]1[CH:5]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:8][CH:9]=1.[CH3:14][N:15]([CH:17]([C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)[CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C:19]1=[O:24])[CH3:16].[Cl-].[NH4+]>CCOCC>[ClH:2].[CH3:16][N:15]([CH:17]([C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)[CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C:19]1([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=1)[OH:24])[CH3:14]
Reactant: FC(F)(F)c1cccc(CCl)c1
Reactant: CN(C)C(c1cccs1)C1CCCCC1=O
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CN(C)C(c1cccs1)C1CCCCC1(O)Cc1cccc(C(F)(F)F)c1
Product: Cl
Temperature: 25 °C
Yield: 8.6 %

Procedure:
0.31 g (12.6 mmole) of magnesium turnings was stirred in 10 ml of ether of analysis purity. 2.46 g (12.6 mmole) of 3-chloromethylbenzotrifluoride dissolved in 10 ml of ether were added dropwise so that the reaction mixture boiled gently. After completion of the addition the reaction mixture was stirred for a further hour at RT. 2.50 g (10.5 mmole) of the 2-(dimethylaminothiophen-2-ylmethyl)cyclohexanone prepared according to stage 1 were dissolved in 10 ml of ether, added dropwise to the Grignard reagent while cooling in an ice bath, and stirred for 15 hours at RT. The reaction mixture was worked up by adding 15 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT with 20 ml of ether each time. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 3.33 g of crude base (79.6% of theory) were obtained, from which a hydrochloride was precipitated according to Example 1 (3rd stage) with chlorotrimethylsilane/water in 2-butanone. The base was freed from the hydrochloride with 20 ml of water and 5 ml of ammonia solution (25 vol. %), extracted three times with 20 ml of ether each time, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 0.63 g of crude base (15.0% of theory) was obtained, from which 0.39 g of 2-[dimethylaminothiophen-2-ylmethyl]-1(3-trifluoromethylbenzyl)cyclohexanol, hydrochloride (8.5% of theory) was obtained according to the procedure described in Example 1 (3rd Stage) with chlorotrimethylsilane/water in 2-butanone. The hydrochloride decomposes on heating above 98° C.
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6](I)[CH:5]=[CH:4][N:3]=1.[CH2:11]([O:13][C:14]([Sn](CCCC)(CCCC)CCCC)=[CH2:15])[CH3:12].[F-].[K+]>O1CCOCC1.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>[CH2:14]([O:13][C:11]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([F:1])[C:7]=1[CH:8]=[O:9])=[CH2:12])[CH3:15]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: O=Cc1c(I)ccnc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: C1COCCO1
Product: C=C(OCC)c1ccnc(F)c1C=O

Procedure:
There are mixed in succession 8 g (31.9 mmol) of 2-fluoro-4-iodo-3-pyridinecarbaldehyde (described in J.O.C, 1993, 58, pp. 7832), 12.7 g (35.96 mmol) of 1-ethoxyvinyltributyltin and 740 mg of tetrakis(triphenylphosphine)palladium (2% molar) in 280 ml of dioxane. The reaction mixture is heated at reflux until the starting material has disappeared completely. After returning to room temperature a solution of potassium fluoride is added to the reaction mixture. Vigorous stirring is maintained for 10 minutes in order to cause precipitation of the tributyltin fluoride, which is filtered off. The filtrate is plunged into a sodium chloride solution. The aqueous phase is extracted 3 times with dichloromethane and then the organic phases are combined, dried over magnesium sulphate, concentrated and purified by chromatography over a silica column, using a dichloromethane/cyclohexane mixture (95/5) as eluant to yield the expected product.
Reaction SMILES: [N:1]([O-])=O.[Na+].Cl.[S:6]([OH:16])(=[O:15])([C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1)=O.[Cl:17][C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=1[OH:25].[OH-].[Na+]>O>[Cl:24][C:23]1[C:18]([Cl:17])=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=1[N:1]=[N:14][C:11]1[CH:10]=[CH:9][C:8](=[S:6](=[O:15])=[O:16])[CH2:13][CH:12]=1
Reactant: Oc1cccc(Cl)c1Cl
Reactant: O=N[O-]
Reactant: Nc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=S(=O)=C1C=CC(N=Nc2ccc(O)c(Cl)c2Cl)=CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.4 %

Procedure:
At 0 to 5° C., a solution of 7.6 g (0.11 mol) of NaNO2 in 12 ml of H2O is added dropwise to 50 ml of aqueous HCl (15%) and 18.1 g (0.105 mol) of sulphanilic acid in a 100 ml two-neck flask fitted with internal thermometer and magnetic stirrer. After 1 hour, this diazonium salt suspension is added at 5 to 10° C. to a solution of 16.3 g (0.1 mol) of 2,3-dichlorophenol and 20 g (0.5 mol) of NaOH in 200 ml of H2O. The mixture is allowed to warm to room temperature, stirred for a further 4 hours and neutralized with aqueous HCl, and the precipitated solid is filtered off with suction using a suction filter. Recrystallization from 200 ml of toluene and 20 ml of methanol affords 26.3 g (83.5% of theory) of pure (2,3-dichloro-4-hydroxyphenyl)-4-sulphonylphenyldiazene.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[CH:5]=[C:4]([C:15]([F:18])([F:17])[F:16])[N:3]=1.[NH:19]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[N:21]=[CH:20]1>>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:5]=[C:4]([C:15]([F:18])([F:17])[F:16])[N:3]=[C:2]([N:19]3[CH:23]=[C:22]([C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)[N:21]=[CH:20]3)[N:7]=2)=[CH:9][CH:10]=1
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc(Cl)n1
Reactant: c1cc(-c2c[nH]cn2)ccn1
Product: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc(-n2cnc(-c3ccncc3)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-(4-chloro-phenyl)-6-trifluoromethyl-pyrimidine (example A.1) (0.15 g, 0.5 mmol) and 4-(1H-imidazol-4-yl)-pyridine [CAS-No. 51746-87-3] (0.073 g, 0.5 mmol) according to the general procedure IVa. Obtained as a light red solid (0.15 g, 76%). MS (ISP) 402.3 [(M+H)+]; mp 269° C.
Reaction SMILES: [N+:1]([C:4]1[CH:28]=[CH:27][C:7]([O:8][CH2:9][CH2:10][N:11]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=2)[CH:12]([CH3:14])[CH3:13])=[C:6]([N:29]2[CH:33]=[CH:32][CH:31]=[CH:30]2)[CH:5]=1)([O-])=O.[H][H].[CH3:36][S:37]([Cl:40])(=[O:39])=[O:38].O>C(OCC)(=O)C.CO.[Pd]>[ClH:40].[CH3:36][S:37]([NH:1][C:4]1[CH:28]=[CH:27][C:7]([O:8][CH2:9][CH2:10][N:11]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=2)[CH:12]([CH3:14])[CH3:13])=[C:6]([N:29]2[CH:33]=[CH:32][CH:31]=[CH:30]2)[CH:5]=1)(=[O:39])=[O:38]
Reactant: [H][H]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(CCN(CCOc2ccc([N+](=O)[O-])cc2-n2cccc2)C(C)C)cc1OC
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: COc1ccc(CCN(CCOc2ccc(NS(C)(=O)=O)cc2-n2cccc2)C(C)C)cc1OC
Product: Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 26.3 %

Procedure:
1-[4-Nitro-2-(1H-pyrrol-1-yl)phenoxy]-2-[N-(3,4-dimethoxyphenethyl)-N-isopropylamino]ethane (0.9 g, 1.98 mmol) was dissolved in 50 ml of a 1:1 solvent system of ethyl acetate and methanol; following 10% Pd/C (0.4 g), the solution was stirred at room temperature for 1 h as hydrogen gas was introduced. Thereafter, the reaction solution was filtered through Celite and the solvent was evaporated; the resulting residue (0.7 g) was dissolved in pyridine (20 ml) and, thereafter, the solution was cooled to 0° C. and methanesulfonyl chloride (0.19 ml, 2.5 mmol) was slowly added dropwise and the mixture was stirred at room temperature for 2 h; thereafter, water was added and extraction was conducted with ethyl acetate. The extracted organic layer was dried with magnesium sulfate and the solvent was evaporated; the resulting residue was purified by being subjected to column chromatography on silica gel using a 7:3:1 solvent system of cyclohexane, ethyl acetate and methanol as an eluent. The fractions containing the product were collected and the solvent was evaporated; the residue was dissolved in methanol (10 ml); after cooling to 0° C., a solution of 1N HCl (0.15 ml) saturated with ethyl ether was added and the mixture was stirred for 20 min to effect evaporation and thereby yield the titled compound 1-[4-methanesulfonamido-2-(1H-pyrrol-1-yl)phenoxy]-2-[N-(3,4-dimethoxyphenethyl)-N-isopropylamino]ethane hydrochloride (0.28 g).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]([OH:12])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:20]1[CH2:25][CH2:24][CH2:23][CH:22]=[CH:21]1.O>CN(C=O)C>[CH:20]1[CH2:25][CH2:24][CH2:23][CH:22]([O:12][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:11][C:6]=2[C:7]([O:9][CH3:10])=[O:8])[CH:21]=1
Reactant: COC(=O)c1cc(Cl)ccc1O
Reactant: BrC1C=CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(Cl)ccc1OC1C=CCCC1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A mixture of 18.6 g of methyl 5-chlorosalicylate, 28 g of K2CO3 and 20 g of 3-bromocyclohexene in 200 ml of DMF is stirred at 90° C. overnight. The mixture is then Poured into water, extracted with ethyl acetate, washed with water, dried over magnesium sulfate and evaporated to dryness to obtain crude product. This is purified by flash chromatography using hexane as the eluent to give pure methyl 2-(cyclohexen-3-yloxy)-5-chlorobenzoate as the first fraction which is used directly in the next step.