Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)[C:6]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:5]2.[F:24][C:25]([F:37])([F:36])[O:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1>>[CH3:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:7]2[C:8]3[C:4](=[CH:3][C:2]([C:30]4[CH:29]=[CH:28][C:27]([O:26][C:25]([F:24])([F:36])[F:37])=[CH:32][CH:31]=4)=[CH:10][CH:9]=3)[CH:5]=[C:6]2[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:13][CH:14]=1
Reactant: CCOC(=O)c1cc2cc(Br)ccc2n1Cc1ccc(C)cc1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Product: CCOC(=O)c1cc2cc(-c3ccc(OC(F)(F)F)cc3)ccc2n1Cc1ccc(C)cc1

Procedure:
The title compound was prepared from ethyl 5-bromo-1-(4-methylbenzyl)-1H-indole-2-carboxylate and 4-(trifluoromethoxy)phenylboronic acid in substantially the same manner, as described in Step 2 of Example 25. The product was obtained as an off-white solid, m.p. 77-78° C. Mass spectrum (ESI, [M+H]+) m/z 454. 1H NMR (400 MHz, DMSO-d6) δ 8.00 (s, 1H), 7.78 (d, 2H, J=8.70 Hz), 7.67 (d, 1H, J=8.85 Hz), 7.61 (dd, 1H, J=8.70 and 1.68 Hz), 7.44 (s, 1H), 7.42-7.41 (m, 3H), 7.06 (d, 2H, J=7.94 Hz), 6.94 (d, 2H, J=8.09 Hz), 5.83 (s, 2H), 4.29 (q, 2H), 2.21 (s, 3H), and 1.30 ppm (t, 3H). Elemental Analysis for C26H22F3NO3: Calculated: C, 68.87; H, 4.89; N, 3.09. Found: C, 69.00; H, 4.66; N, 3.06.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].[Cl:12][C:13]1[CH:27]=[CH:26][C:16]([O:17][CH:18](Cl)[C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:15][CH:14]=1>CC(C)=O>[Cl:12][C:13]1[CH:27]=[CH:26][C:16]([O:17][CH:18]([N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)[C:19](=[O:24])[C:20]([CH3:22])([CH3:23])[CH3:21])=[CH:15][CH:14]=1
Reactant: CC(C)(C)C(=O)C(Cl)Oc1ccc(Cl)cc1
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)C(=O)C(Oc1ccc(Cl)cc1)n1cncn1
Temperature: 25 °C
Reaction time: 6 h
Yield: 87.1 %

Procedure:
418 g (6.6 mols) of 1,2,4-triazole were dissolved in 3,000 ml of acetone. 934 g (7.2 mols) of anhydrous, powdered potassium carbonate were added to this solution, the suspension was heated to the boil and a solution of 1,565 g (6 mols) of 1-(4-chlorophenoxy)-1-chloro-3,3-dimethyl-butan-2-one in 1,500 ml of acetone was added dropwise in a manner such that the mixture boiled under reflux without heating. After the addition had ended, the mixture was heated under reflux for 15 hours in order to bring the reaction to completion; the resulting precipitate was then filtered off, washed with acetone and discarded. The filtrate was freed from solvent under a waterpump vacuum, the residue was taken up in 3,000 ml of toluene and the toluene solution was washed once with a solution of 100 g of 37% strength hydrochloric acid in 2,000 ml of water. The aqueous phase was separated off and discarded; the organic phase was washed with 5,000 ml of water and, after adding a further 4,000 ml of toluene, was stirred with a solution of 145 g of sodium hydroxide in 3,500 ml of water at room temperature for 6 hours. Thereafter, the organic phase was separated off, washed with water until neutral and freed from solvent under a waterpump vacuum. 1,535 g (87% of theory) of 1-(4-chlorophenoxy)-3,3-dimethyl-1-(1,2,4-triazol-1-yl)-butan-2-one of melting point 75°-76° C. were obtained. ##STR11##
Reaction SMILES: [Cl:1][GeH:2]([Cl:4])[Cl:3].[C:5]([O:15][CH3:16])(=[O:14])[CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[Cl:1][Ge:2]([Cl:4])([Cl:3])[CH:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:6][C:5]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)C=Cc1ccccc1
Reactant: Cl[GeH](Cl)Cl
Product: COC(=O)CC(c1ccccc1)[Ge](Cl)(Cl)Cl
Reaction time: 2 h
Yield: 82.2 %

Procedure:
A mixture of 36.0 g (0.2 mol) of trichlorogermane and 32.4 g (0.2 mol) of methyl cinnamate was stirred for 2 hours and then distilled in vacuum to obtain 56.2 g of a fraction, b.p. 148°. Yield 82.2%.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)[Br:21].O=[CH:26][CH2:27][CH:28]1[CH2:32][CH2:31][CH2:30][N:29]1[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34]>ClCCl>[Br:21][C:20]([Br:24])=[CH:26][CH2:27][CH:28]1[CH2:32][CH2:31][CH2:30][N:29]1[C:33]([O:35][C:36]([CH3:37])([CH3:39])[CH3:38])=[O:34]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)N1CCCC1CC=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC1CC=C(Br)Br
Temperature: -15 °C
Reaction time: 0.33 h

Procedure:
Into a 10 L 3-necked roundbottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of triphenylphosphine (516.6 g, 1.970 mol) in dichloromethane (2,000 ml). The solution was cooled to −15° C. and a solution of carbontetrabromide (327.3 g, 985.8 mmol) in dichloromethane (1,000 ml) was added over a period of 120 minutes. Then a solution of tert-butyl 2-(2-oxoethyl)pyrrolidine-1-carboxylate (105 g, 493 mmol) in dichloromethane (1,000 ml) was added dropwise over a period of 120 minutes. The resulting solution was allowed warm to warm to 0° C., and stir for 20 minutes. The resulting solution was diluted with 4,000 ml of petroleum ether. The mixture was filtered and concentrated. The residue was purified by flash column chromatography (ethylacetate/petroleum ether gradient) to afford tert-butyl 2-(3,3-dibromoprop-2-en-1-yl)pyrrolidine-1-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[C:3]=1[S:14]([NH2:17])(=[O:16])=[O:15].[CH2:18]([N:25]([CH3:41])[C:26]1[CH:27]=[C:28]([NH:33][C:34]2[N:39]=[C:38](Cl)[CH:37]=[CH:36][N:35]=2)[CH:29]=[CH:30][C:31]=1[CH3:32])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>CC(O)C>[CH2:18]([N:25]([CH3:41])[C:26]1[CH:27]=[C:28]([NH:33][C:34]2[N:35]=[C:36]([NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][C:10]([F:11])([F:13])[F:12])[C:3]=3[S:14]([NH2:17])(=[O:16])=[O:15])[CH:37]=[CH:38][N:39]=2)[CH:29]=[CH:30][C:31]=1[CH3:32])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Nc1cccc(OCC(F)(F)F)c1S(N)(=O)=O
Reactant: Cc1ccc(Nc2nccc(Cl)n2)cc1N(C)Cc1ccccc1
Agent: Cl
Solvent: CC(C)O
Product: Cc1ccc(Nc2nccc(Nc3cccc(OCC(F)(F)F)c3S(N)(=O)=O)n2)cc1N(C)Cc1ccccc1

Procedure:
A solution of 2-amino-6-(2,2,2-trifluoro-ethoxy)-benzenesulfonamide (54 mg, 0.2 mmol) and N3-benzyl-N1-(4-chloro-pyrimidin-2-yl)-N3,4-dimethyl-benzene-1,3-diamine (according to step a), 55 mg, 0.163 mmol) in 2-propanol (6 mL) and 1M HCl (0.32 mL) is heated under reflux for 1 h. Solvents are evaporated and the residue is adjusted to pH 8 by the addition of aqueous NH3. Partition between EtOAc and water, washing with 10% brine, drying of the organic phase (Na2SO4), evaporation of solvents, and chromatography (silica gel) of the residue gives 2-{2-[3-(benzyl-methyl-amino)-4-methyl-phenylamino]-pyrimidine-4-ylamino}-6-(2,2,2-trifluoro-ethoxy)-benzenesulfonamide, eluted with EtOAc/hexanes 2:3. 1H-NMR (400 MHz, DMSO-d6): 2.20 (s, CH3C(4″)); 2.43 (s, NCH3); 3.90 (s, NCH2C6H5); 4.90 (q, J=9, OCH2CF3); 6.20 (d, J=5, H—C(5′)); 6.93 and 6.97 (2d, J=9; H—C(5), H—C(5″)); 7.14-7.20, 7.20-7.34, and 7.34-7.4 (3m, NCH2C6H5, H—C(2″), H—C(6″), SO2NH2); 7.45 (t, J=8, H—C(4)); 8.05 (d, J=5, H—C(6′)); 8.12 (db, J=9, H—C(3′)); 9.12 (b, NH); 8.9-10.3 (NH).
Reaction SMILES: C(OC(P(O)(O[C@@H](CCCCNC(OCC1C=CC=CC=1)=O)C([N:24]1[CH2:38][CH2:37][CH2:36][C@H:25]1[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])=O)=O)CC1C=CC=CC=1)(=O)C1C=CC=CC=1.ClCCC(C)(C)C([O-])=O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[NH:24]1[CH2:38][CH2:37][CH2:36][C@H:25]1[C:26]([O:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:27]
Reactant: O=C(NCCCC[C@H](OP(=O)(O)C(Cc1ccccc1)OC(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)OCc1ccccc1
Agent: CC(C)(CCCl)C(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reaction time: 8 h

Procedure:
1-[(S)-2-[[[1-(Benzoyloxy)-2-phenylethyl]hydroxyphosphinyl]oxy]-1-oxo-6-[[(phenylmethoxy)carbonyl]amino]hexyl]-L-proline, phenylmethyl ester from Example 5(d) is suspended in dry dimethylformamide and treated with chloromethylpivalate. After several hours, additional chloromethylpivalate and anhydrous potassium carbonate are added and the resulting mixture is stirred overnight. The mixture is then diluted with ethyl acetate and washed successively with water, 5% potassium bisulfate, saturated sodium bicarbonate, and saturated sodium chloride solution, dried (Na2SO4), and evaporated. The residue is purified by flash chromatography (silica gel) to give 1-[(S)-2-[[[(2,2-dimethyl-1-oxopropoxy)methoxy][1-(benzoyloxy)-2-phenylethyl]phosphinyl]oxy]-1-oxo]-6-[[(phenylmethoxy)carbonyl]amino]hexyl]-L-proline, phenylmethyl ester.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.BrN1C(=[O:18])CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(OCC)(=O)C>[N:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([CH2:1][OH:18])[CH:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1ccc2cccnc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCOC(C)=O
Product: OCc1ccc2cccnc2c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 3 %

Procedure:
To a solution of 7-methylquinoline (2.86 g) in ethyl acetate (100 mL) were added N-bromosuccinimide (3.56 g) and 2,2′-azobis(isobutyronitrile) (197 mg) at room temperature, and the mixture was refluxed for 1.5 hr. The reaction mixture was allowed to cool to room temperature, and washed with water. The obtained organic layer was concentrated under reduced pressure, to the residue were added DME (200 mL), water (100 mL), and silver carbonate (27.6 g), and the mixture was stirred at room temperature for 20 hr. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol), and then purified by NH silica gel column chromatography (ethyl acetate/hexane) to give the title compound (94 mg).
Reaction SMILES: C(O[C:4](=[O:12])/[CH:5]=[C:6](\[NH2:11])/[C:7]([F:10])([F:9])[F:8])C.N1C=CC=CC=1.C([CH:21]([C:25](Cl)=[O:26])[C:22](Cl)=[O:23])C.[CH3:28][C:29](C)([O-:31])C.[K+]>ClCCl.C(O)C>[CH2:29]([O:31][C:25](=[O:26])[C:21]1[C:4]([OH:12])=[CH:5][C:6]([C:7]([F:8])([F:9])[F:10])=[N:11][C:22]=1[OH:23])[CH3:28]
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Reactant: CC(C)(C)[O-]
Reactant: CCC(C(=O)Cl)C(=O)Cl
Agent: [K+]
Solvent: ClCCl
Solvent: CCO
Solvent: c1ccncc1
Product: CCOC(=O)c1c(O)cc(C(F)(F)F)nc1O
Temperature: 5 °C
Reaction time: 3 h

Procedure:
To dissolve 3-Amino-4,4,4-trifluorocrotonic acid ethyl ester (100 g/546 mmol) in dichloromethane (600 mL) was added pyridine (53 mL/660 mmol). Placed under nitrogen and cooled to 5° C. by suspending in an ice-bath. Ethyl malonyl chloride was added dropwise over approx 1 hr such that temperature did not exceed 20° C. Resulting pale brown solution was stirred at 5° C. for 3 hrs then allowed to warm to room temperature overnight to give a dark green solution. Washed with 1M HCl(aq) (200 mL) then saturated NaHCO3(aq) (250 mL). Aqueous washings sequentially re-extracted with further dichloromethane (2×250 mL). Organics combined, dried over Na2SO4, filtered and concentrated to a dark green oil of crude 3-(2-Ethoxycarbonyl-acetylamino)-4,4,4-trifluoro-but-2-enoic acid ethyl ester (175 g). A portion of the crude (120 g) was dissolved in ethanol (300 mL) and placed under nitrogen. Potassium tert-butoxide (54 g/480 mmol) was added in several portions such that temperature did not exceed 60° C. resulting in a purple solution. Heated at 70° C. for 3 hrs. Added ethanol (100 mL) to reduce viscosity and heated at 80° C. for a further hour. Allowed to cool and concentrated in vacuo to a red solid. Dissolved in water (500 mL) and added citric acid (180 g) causing precipitation. Added ethyl acetate (600 mL). Poured into separating funnel and ran off aqueous. The organic layer containing much undissolved solid was filtered to give the title compound (46.5 g) as a white solid. Concentration of the organic filtrate and trituration with methanol afforded 2,4-dihydroxy-6-trifluoromethyl-nicotinic acid ethyl ester (15.3 g) as a white solid.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([NH:16][C:17](=[O:25])OC3C=CC=CC=3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][C:37]=1[O:38][CH2:39][CH2:40][O:41][CH3:42])[N:34]=[CH:33][N:32]=[C:31]2[O:43][C:44]1[CH:45]=[C:46]([CH:48]=[CH:49][CH:50]=1)[NH2:47]>>[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][C:37]=1[O:38][CH2:39][CH2:40][O:41][CH3:42])[N:34]=[CH:33][N:32]=[C:31]2[O:43][C:44]1[CH:45]=[C:46]([NH:47][C:17]([NH:16][C:9]2[CH:10]=[C:11]([C:12]([F:13])([F:14])[F:15])[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)=[O:25])[CH:48]=[CH:49][CH:50]=1
Reactant: O=C(Nc1cc(C(F)(F)F)n(-c2ccccc2)n1)Oc1ccccc1
Reactant: COCCOc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Product: COCCOc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(F)(F)F)n(-c5ccccc5)n4)c3)c2cc1OC
Yield: 58 %

Procedure:
The title compound was prepared as described in Example 169C using phenyl 1-phenyl-5-(trifluoromethyl)-1H-pyrazol-3-ylcarbamate described in Example 169B (0.115 g, 0.33 mmol), 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline from Example 117B (0.112 g, 0.33 mmol), to afford 1-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy]phenyl}-3-[1-phenyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]urea as solid (0.114 g, 58%). 1H NMR (300 MHz, DMSO-d6) δ 9.47 (s, 1H), 8.99 (s, 1H), 8.56 (s, 1H), 7.58 (m, 7H), 7.42 (m, 2H), 7.27 (d, 1H), 7.13 (s, 1H), 6.97 (d, 1H), 4.35 (m, 2H), 4.00 (s, 3H), 3.78 (m, 2H), 3.35 (s, 3H); LC-MS (ESI) m/z 595 (M+H)+.
Reaction SMILES: S1C=CN=C1.C[O:7][C:8](=[O:20])[C:9]1[CH:14]=[CH:13][C:12]([C:15](=O)[CH:16](Br)[F:17])=[CH:11][CH:10]=1.[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([C:28](=[S:30])[NH2:29])[CH2:24][CH2:23]1>>[F:17][C:16]1[S:30][C:28]([N:25]2[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]2)=[N:29][C:15]=1[C:12]1[CH:13]=[CH:14][C:9]([C:8]([OH:7])=[O:20])=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(C(=O)C(F)Br)cc1
Reactant: CN1CCN(C(N)=S)CC1
Agent: c1cscn1
Product: CN1CCN(c2nc(-c3ccc(C(=O)O)cc3)c(F)s2)CC1

Procedure:
The starting material, methyl 4-acetylbenzoate, is commercially available. Bromination at the α-position to the ketone is achieved with bromine in acetic acid to provide the desired 4-(2-bromo-acetyl)-benzoic acid methyl ester. Subsequent treatment of 4-(2-bromo-acetyl)-benzoic acid methyl ester with potassium fluoride in the presence of 18-crown-6 at 90° C., provides 4-(2-fluoro-acetyl)-benzoic acid methyl ester after column chromatography. Repeated bromination at the α-position to the ketone is achieved with bromine in acetic acid to provide the desired 4-(2-bromo-2-fluoro-acetyl)-benzoic acid methyl ester. Formation of the thiazole is typically carried out by heating 4-(2-bromo-2-fluoro-acetyl)-benzoic acid methyl ester with 4-methylpiperazine-1-carbothioamide at 70° C. for 2 hours. On cooling, the desired 4-[5-fluoro-2-(4-methyl-piperazin-1-yl)-thiazol-4-yl]-benzoic acid methyl ester precipitates out. Deprotection of the methyl ester is carried out using a lithium hydroxide solution and the desired acid, 4-[5-fluoro-2-(4-methyl-piperazin-1-yl)-thiazol-4-yl]-benzoic acid is generally obtained in good yield as the dihydrochloride salt on workup with hydrochloric acid.
Reaction SMILES: C(O[CH2:5][C:6]1[C:7]2[N:8]([C:12]([CH3:15])=[CH:13][N:14]=2)[CH:9]=[CH:10][CH:11]=1)(=O)C.[SH:16][C:17]1[NH:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1>Br.C(O)(=O)C>[CH3:15][C:12]1[N:8]2[CH:9]=[CH:10][CH:11]=[C:6]([CH2:5][S:16][C:17]3[NH:21][C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[N:18]=3)[C:7]2=[N:14][CH:13]=1
Reactant: CC(=O)OCc1cccn2c(C)cnc12
Reactant: Sc1nc2ccccc2[nH]1
Agent: Br
Solvent: CC(=O)O
Product: Cc1cnc2c(CSc3nc4ccccc4[nH]3)cccn12
Temperature: 25 °C
Yield: 64.9 %

Procedure:
A mixture of 5.0 g (30 mmole) of 3-(acetoxymethyl)-2-pyridinamine and 4.8 g (35 mmole) of 2-bromopropanal spontaneously heated upon mixing. After cooling, the mixture was partitioned between aqueous potassium carbonate and dichloromethane. The organic phase was separated, washed with water, dried over magnesium sulfate, filtered, and concentrated in vacuo. Chromatography on silica gel (using ethanol-dichloromethane as eluent) yielded 2.3 g of 8-(acetoxymethyl)-3-methylimidazo[1,2-a]pyridine, as confirmed by the nmr and infrared spectra and by elemental analysis. [Calcd. for C11H12N2O2 : C, 64.69; H, 5.92; N, 13.72. Found: C, 63.70; H, 5.85; N, 14.24). A mixture of 2.3 g (11 mmole) of 8-(acetoxymethyl)-3-methylimidazo[1,2-a]pyridine and 1.65 g (11 mmole) of 2-mercaptobenzimidazole in 40 ml of 15% hydrogen bromide in acetic acid was heated on a steam bath. After being cooled to room temperature, the mixture was partitioned between 5% aqueous sodium hydroxide and dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated to an oil. Chromatography yielded 2.1 g of the title compound. Structure assignment was supported by the nmr and infrared spectra.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[CH:18]=O)([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:30]=[C:29]2[C:25]([CH2:26][C:27](=[O:31])[NH:28]2)=[CH:24][CH:23]=1.N1CCCC1>CO>[C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1/[CH:18]=[C:26]1\[C:27](=[O:31])[NH:28][C:29]2[C:25]\1=[CH:24][CH:23]=[C:22]([Cl:21])[CH:30]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCOc1ccc(Cl)cc1C=O
Reactant: O=C1Cc2ccc(Cl)cc2N1
Solvent: CO
Solvent: C1CCNC1
Product: CC(C)(C)OC(=O)NCCOc1ccc(Cl)cc1/C=C1\C(=O)Nc2cc(Cl)ccc21
Yield: 131.9 %

Procedure:
In a manner similar to the method described in Example 1b, [2-(4-Chloro-2-formyl-phenoxy)-ethyl]-carbamic acid tert-butyl ester (8 g, 27 mmol) was reacted with 6-chloro-1,3-dihydro-indol-2-one (4.5 g, 27 mmol) and pyrrolidine (2.1 g, 30 mmol) in methanol (70 mL) to give title compound as a yellow solid (16 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH:29]1[C:33]([S:34](Cl)(=[O:36])=[O:35])=[N:32][CH:31]=[N:30]1>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:10](=[O:13])[N:11]([S:34]([C:33]3[NH:29][N:30]=[CH:31][N:32]=3)(=[O:36])=[O:35])[N:12]=2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ncn[nH]1
Reactant: COc1ccc(Cn2c(-c3ccc(Cl)cc3)n[nH]c2=O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COc1ccc(Cn2c(-c3ccc(Cl)cc3)nn(S(=O)(=O)c3ncn[nH]3)c2=O)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
529 mg (1.68 mmol) of 5-(4-chlorophenyl)-4-(4-methoxybenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one [preparation according to WO 2007/134862 Example 55A] were dissolved in 10 ml of acetonitrile, and 1.09 g (3.35 mmol) of cesium carbonate and 281 mg (1.68 mmol) of 1H-1,2,4-triazole-5-sulfonyl chloride, dissolved in 5 ml of acetonitrile, were added successively. The reaction mixture was stirred at RT for 90 min. For work-up, 10 g of silica gel were added and the solvent was removed under reduced pressure. The crude product, adsorbed on silica gel, was purified by chromatography on silica gel (mobile phase: first ethyl acetate, then dichloromethane/methanol 90:10→80:20). This gave 268 mg (32% of theory) of the target compound.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]([CH3:10])[CH2:6][CH2:7][CH2:8]Cl.[CH3:11][N:12]([CH3:14])[CH3:13]>C(#N)C>[Cl-:1].[Cl-:1].[CH3:11][N+:12]([CH3:14])([CH3:13])[CH2:2][CH2:3][CH2:4][N:5]([CH2:6][CH2:7][CH2:8][N+:5]([CH3:10])([CH3:6])[CH3:4])[CH3:10]
Reactant: CN(CCCCl)CCCCl
Reactant: CN(C)C
Solvent: CC#N
Product: CN(CCC[N+](C)(C)C)CCC[N+](C)(C)C
Product: [Cl-]
Reaction time: 21 h

Procedure:
To this N,N-bis(3-chloropropyl)methylamine is added 166 ml of a 2.06 M solution of trimethylamine in acetonitrile. The resulting mixture is allowed to stand at a temperature of about 25° C. for a period of 21 hours during which time a white solid material crystallizes; the mixture is stirred for an additional 7-hour period, the solid crystalline material is recovered by filtration, washed with a small amount of acetonitrile, then with ether, and finally with hexane, the washings being collected separately. The washed crystalline material is dried in vacuo at 25° C. to give about 6.0 grams of bis(3-trimethylammoniopropyl) methylamine dichloride; the latter is dissolved in isopropanol, an equivalent amount of anhydrous hydrogen chloride is added, and the hydrochloride salt, which precipitates, is recovered by filtration and dried to give substantially pure bis(3-trimethylammoniopropyl)methylamine dichloride hydrochloride; m.p. 251°-253° C.
Reaction SMILES: [OH:1][C:2]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1)([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=1)[C:3]([OH:5])=[O:4].C1N=CN(C(N2C=NC=C2)=O)C=1.[N:34]12[CH2:41][CH2:40][CH:37]([CH2:38][CH2:39]1)[C@@H:36](O)[CH2:35]2>C1COCC1.C(OCC)(=O)C>[N:34]12[CH2:41][CH2:40][CH:37]([CH2:38][CH2:39]1)[C@@H:36]([O:4][C:3](=[O:5])[C:2]([OH:1])([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1)[CH2:35]2
Reactant: O[C@H]1CN2CCC1CC2
Reactant: COc1cccc(C(O)(C(=O)O)c2cccc(OC)c2)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cccc(C(O)(C(=O)O[C@H]2CN3CCC2CC3)c2cccc(OC)c2)c1

Procedure:
To a stirred solution of hydroxy-bis-(3-methoxy-phenyl)-acetic acid (Intermediate J) (1.384 g, 4.8 mmol) in dry THF (20 ml) is added CDI (0.870 g, 5.3 mmol) and the mixture is heated to reflux for 90 minutes. (R)-1-aza-bicyclo[2.2.2]octan-3-ol (0.67 g, 5.3 mmol) is then added. After refluxing for 16 hours, the reaction mixture is diluted with ethyl acetate and washed with water. The organic layer is then extracted with 2M HCl and the aqueous portion is treated with potassium carbonate to basify the solution. The aqueous portion is re-extracted with ethyl acetate. The organic portions are combined, dried over MgSO4 and concentrated in vacuo to yield a crude residue which is purified using C-18 reverse phase column chromatography (eluent: water-acetonitrile), to afford the titled compound.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:26](O)([CH3:29])([CH3:28])[CH3:27].N12CCCN=C1CCCCC2>CN(C=O)C>[C:26]([O:12][C:11]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:1]=[CH:2][CH:3]=[CH:4]2)=[O:13])([CH3:29])([CH3:28])[CH3:27]
Reactant: O=C(O)c1ccc2ncccc2c1
Reactant: CC(C)(C)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccc2ncccc2c1
Temperature: 40 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
To a suspension of 6-quinolinecarboxylic acid (12 g, 69 mmol) in DMF (100 mL) was added 1,1′-Carbonyldiimidazole (11.2 g, 69.3 mmol) and the mixture stirred at 40° C. for 1 hour. tert-Butanol (13 mL, 139 mmol) and 1,8-Diazabicyclo[5.4.0]undec-7-ene (10.4 mL, 69.3 mmol) were added and the mixture was stirred at 80° C. for 4 h. After cooling to room temperature the reaction mixture was quenched with water (400 mL) and extracted with ethyl acetate/heptane (1:3, 2×400 mL). The organic layer was dried over MgSO4 and concentrated to give quinoline-6-carboxylic acid t-butyl ester (14.54 g, 92%). 1H NMR (400 MHz, CDCl3) δ 1.63 (9H, s), 7.42-7.46 (1H, m), 8.10 (1H, d), 8.23 (1H, d), 8.26 (1H, d), 8.50 (1H, d), 8.96-8.98 (1H, m). LCMS: Retention time: 1.42 min. MS (ESI) m/z 230 (M+H)+