Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-:1].[CH2:2]([N+](CC[CH2:17][CH3:18])(CCCC)CCCC)CCC.[Cl:19][C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=1[S:27]([N:30]([C:39]1[C:44]([O:45][CH3:46])=[N:43][C:42](Cl)=[C:41]([Cl:48])[N:40]=1)COCC[Si](C)(C)C)(=[O:29])=[O:28]>COCCOC.C(OCC)(=O)C>[C:44]([O:45][CH2:17][CH3:18])(=[O:1])[CH3:39].[CH3:22][CH2:23][CH2:24][CH:25]([CH3:20])[CH3:2].[Cl:19][C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=1[S:27]([NH:30][C:39]1[C:44]([O:45][CH3:46])=[N:43][C:42]([OH:1])=[C:41]([Cl:48])[N:40]=1)(=[O:29])=[O:28]
Reactant: [OH-]
Reactant: COc1nc(Cl)c(Cl)nc1N(COCC[Si](C)(C)C)S(=O)(=O)c1cccc(Cl)c1Cl
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CCCC(C)C
Product: COc1nc(O)c(Cl)nc1NS(=O)(=O)c1cccc(Cl)c1Cl
Reaction time: 16 h

Procedure:
tetrabutylammonium hydroxide (0.28 g of 40% aqueous solution) was added to a solution of 2,3-dichloro-N-(5,6-dichloro-3-methoxy-2-pyrazinyl)-N-{[2-(trimethylsilyl)ethoxy]methyl}benzenesulfonamide (0.25 g) in 1,2-dimethoxyethane (3.0 mL) at room temperature. After 16 h, the solution was diluted with ethyl acetate (20 mL). The organic solution was washed with aqueous citric acid (10 mL) and brine, dried (MgSO4) and evaporated. Chromatography on silica gel eluting with ethyl acetate/isohexane mixtures gave the title compound containing the SEM group, as a white solid (0.08 g). The solid was dissolved in trifluroacetic acid (2.0 mL) and dichloromethane (2.0 mL) and stirred at room temperature for 1 h. The reaction mixture was concentrated and chromatography on silica gel eluting with ethyl acetate/isohexane mixtures gave the title compound as a white solid (0.027 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([C:9]([OH:11])=[O:10])[N:3]=1.[CH3:12][NH2:13]>O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([OH:11])=[O:10])[C:5]([NH:13][CH3:12])=[CH:6][CH:7]=1
Reactant: O=C(O)c1nc(Cl)ccc1F
Reactant: CN
Solvent: C1COCCO1
Product: CNc1ccc(Cl)nc1C(=O)O
Temperature: 125 °C
Yield: 87 %

Procedure:
A mixture of 2-chloro-5-fluoropyridine-6-carboxylic acid (2.00 g, 11.4 mmol), 41% aq. methylamine solution (8 mL) and 1,4-dioxane (8 mL) was heated at 125° C. under microwave irradiation for 60 min. After cooling, volatile material was distilled off, and the residue was dissolved in water (20 mL) and acidified to pH 3 by addition of 37% aq. hydrochloric acid solution. The precipitate was collected by filtration to produce the title compound (1.85 g, 87%). Light yellow solid, MS (ISP): 185.1 (M−H)−.
Reaction SMILES: [C:1]1([CH:7]=[CH:8][C:9]([O:16][Si](C)(C)C)=[CH:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:21]N1C(=O)CCC1=O>O1CCCC1>[Br:21][CH:10]([C:9](=[O:16])[CH:8]=[CH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)CC=C(C=Cc1ccccc1)O[Si](C)(C)C
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: COC(=O)CC(Br)C(=O)C=Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 44.2 %

Procedure:
A mixture of 4.2 g of the product of Step C, 40 ml of tetrahydrofuran and 2.7 g of N-bromo-succinimide was cooled to 0° C. and stirred for one hour at this temperature, then brought to dryness. The residue was chromatographed on silica, eluting with a hexane--ethyl acetate mixture (8-2) to obtain 1.9 g of the expected product. Thin layer chromatography; Rf=0.28 [eluant: hexane-- ethyl acetate (8-2)].
Reaction SMILES: C[O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[OH:11].I[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(=O)([O-])[O-].[K+].[K+]>>[Br:10][C:8]1[CH:7]=[CH:6][C:5]([O:11][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[C:4]([CH:9]=1)[C:3]([OH:2])=[O:12]
Reactant: CCCCCCCI
Reactant: COC(=O)c1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCCCCOc1ccc(Br)cc1C(=O)O

Procedure:
5-Bromo-2-heptyloxy-benzoic acid was prepared by reacting 5-bromo-2-hydroxy-benzoic acid methyl ester (1.0 g, 4.32 mmol) with iodoheptane (1.46 g, 6.49 mmol) as per general procedure H with potassium carbonate (1.5 g, 10.8 mmol) added. The ester thus obtained was subjected to hydrolysis as per general procedure C to yield the 5-Bromo-2-heptyloxy-benzoic acid (0.950 gm, 70%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]([F:25])([F:24])[F:23])[CH2:3][N:4]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:14].[CH3:26][N:27]1[C:31]([C:32]2[N:36]([CH3:37])[N:35]=[CH:34][CH:33]=2)=[CH:30][C:29]([C:38](O)=[O:39])=[CH:28]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>ClCCl>[O:14]=[C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:12](=[O:13])[N:4]1[CH2:3][C@@H:2]([NH:1][C:38]([C:29]1[CH:30]=[C:31]([C:32]2[N:36]([CH3:37])[N:35]=[CH:34][CH:33]=2)[N:27]([CH3:26])[CH:28]=1)=[O:39])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]([F:25])([F:23])[F:24]
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Reactant: Cn1cc(C(=O)O)cc1-c1ccnn1C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1-c1ccnn1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.9 %

Procedure:
To a solution of 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (200 mg, 0.97 mmol)[prepared according to Preparation 5], 1-methyl-5-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrole-3-carboxylic acid (339 mg, 0.97 mmol) and N,N-diisopropylethylamine (0.85 ml, 4.87 mmol) in dichloromethane (4.873 ml) at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (501 mg, 1.07 mmol) in one portion. The solution was stirred at 25° C. for 1 h and was then dry loaded onto silica and purified via column chromatography (silica, 30-70% EtOAc in hexanes) yielding N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-1-methyl-5-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrole-3-carboxamide (522 mg, 0.93 mmol, 95% yield) as a white foam: LCMS (ES) m/e 536 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]([NH:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.Cl.[CH3:17][O:18][C@H:19]1[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]1.CCN(C(C)C)C(C)C.[Cl-].[Na+]>C(OCC)(=O)C.CN1C(=O)CCC1>[Br:8][C:6]1[N:7]=[C:2]([NH:25][C@H:22]2[CH2:23][CH2:24][C@H:19]([O:18][CH3:17])[CH2:20][CH2:21]2)[C:3]([NH:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:4][CH:5]=1
Reactant: CCOC(=O)CNc1ncc(Br)nc1Br
Reactant: CO[C@H]1CC[C@H](N)CC1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCOC(=O)CNc1ncc(Br)nc1N[C@H]1CC[C@H](OC)CC1
Temperature: 125 °C

Procedure:
Alternatively, ethyl 2-(3,5-dibromopyrazin-2-ylamino)acetate (1 equiv) and trans-4-methoxycyclohexanamine hydrochloride (1.5 equiv), NMP and DIPEA were combined and heated to 125° C. and maintained at that temperature for 18 h. Upon reaction completion, the mixture was cooled to room temperature and transferred to a mixture of ethyl acetate and aqueous sodium chloride. The aqueous layer was removed and the organic layer was washed successively with aqueous sodium chloride and water. The organic layer was concentrated by vacuum distillation to a low volume, cooled to ambient temperature and the solids were collected and dried to give ethyl 2-(5-bromo-3-(trans-4-methoxycyclohexylamino)pyrazin-2-ylamino)acetate. A mixture of ethyl 2-(5-bromo-3-(trans-4-methoxycyclohexylamino)pyrazin-2-ylamino) acetate (1 equiv), water (161 equiv) and 85% phosphoric acid (16.5 equiv) was heated at 80° C. Upon reaction completion, the mixture was cooled to 25° C., filtered and the solids were washed with water. The solids were resuspended in water and the filtration and wash were repeated. The resulting material was dried to give 7-bromo-1-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one. 7-Bromo-1-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (1 equiv), 2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)propan-2-ol (1.08 equiv) and PdCl2(AmPhos)2 (0.0025 equiv) were combined in tetrahydrofuran. The mixture was treated with a solution of potassium carbonate (2.5 equiv) and heated to reflux. After cooling to 40° C., toluene was added, and the layers were separated. The organic layer was washed with potassium dihydrogenphosphate solution and treated with a metal scavenger (SiliaBond® Thiol). The mixture was filtered and distilled with the addition of toluene until the temperature reached 100° C. Upon cooling the resulting solids were collected by filtration and dried. The solid was combined with butylated hydroxyl toluene (BHT) (9×10−4 equiv) in IPA and water (3×:5× vol). The mixture was heated to 65° C. and while maintaining this temperature, water (5× vol) was added. A small amount of the title compound (0.02 equiv) in water was added. The mixture was allowed to stand for 2 h, cooled to room temperature and stirred. The resulting solids were collected by filtration and dried to give 7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one as an off-white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][O:9][CH3:10])[N:5]=[C:4]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[CH:3]=1.[C:22]([C:25]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)([CH3:27])[CH3:26])([OH:24])=[O:23].C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.O.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>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[CH2:13][CH2:12][NH:11][C:4]1[N:5]=[C:6]([CH2:8][O:9][CH3:10])[N:7]=[C:2]([C:30]2[CH:29]=[C:28]([C:25]([CH3:27])([CH3:26])[C:22]([OH:24])=[O:23])[CH:33]=[CH:32][CH:31]=2)[CH:3]=1
Reactant: CC(C)(C(=O)O)c1cccc(B(O)O)c1
Reactant: COCc1nc(Cl)cc(NCCc2ccc(Cl)cc2Cl)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: COCc1nc(NCCc2ccc(Cl)cc2Cl)cc(-c2cccc(C(C)(C)C(=O)O)c2)n1
Temperature: 90 °C
Reaction time: 16 h
Yield: 60 %

Procedure:
Argon is bubbled through a mixture of (6-chloro-2-methoxymethyl-pyrimidin-4-yl)-[2-(2,4-dichloro-phenyl)-ethyl]-amine (200 mg, 0.58 mmol), 3-(1-carboxy-1-methyl-ethyl)-phenyl boronic acid [266 mg, 1.28 mmol, see Example 49(b) step 2], Cs2CO3 (1.56 g, 2.52 mmol), and tetrakis(triphenylphosphine)palladium (0) (69 mg, 0.06 mmol) in ethylene glycol dimethyl ether (4 mL) and water (1 mL), for a period of 10 minutes. The reaction vessel is sealed and heated to 90° C. After stirring for 16 hours the mixture is diluted with water (40 mL) and extracted twice with EtOAc (25 mL). The organic extracts are combined and dried over magnesium sulfate, filtered and evaporated. The residue is subjected to chromatography on silica gel eluting with 40% ethyl acetate:heptane to afford 2-(3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxymethyl-pyrimidin-4-yl}-phenyl)-2-methyl-propionic acid [165 mg, 60%, Example 85] as a solid. LCMS RT=2.59 minutes, MS: 474 (M+H). IC50=2.7 nM
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[CH:10]=[C:11]([C:13]([NH:15][CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[O:14])[N:12]=1.CI.[CH3:31]CN(CC)CC>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)[CH:10]=[C:11]([C:13]([NH:15][CH:16]2[CH2:17][CH2:18][N:19]([CH3:31])[CH2:20][CH2:21]2)=[O:14])[N:12]=1
Reactant: O=C(NC1CCNCC1)c1cn(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)n1
Reactant: CCN(CC)CC
Solvent: CI
Solvent: ClCCl
Product: CN1CCC(NC(=O)c2cn(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)n2)CC1
Temperature: 25 °C
Yield: 27.9 %

Procedure:
To a solution of 2-(2-chlorophenyl)-1-(4-chlorophenyl)-N-(4-piperidinyl)-1H-imidazole-4-carboxamide (Example 37) (80 mg, 0.2 mmol) in CH2Cl2 (6 mL) was added CH3I (28.4 mg, 0.2 mmol) and Et3N (0.031 mL, 0.22 mmol). The reaction mixture was heated at reflux for 5 h, cooled to rt, and washed with brine. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (2M NH3 in methanol:EtOAc=1:10) to afford the product 2-(2-chlorophenyl)-1-(4-chlorophenyl)-N-(1-methyl-4-piperidinyl)-1H-imidazole-4-carboxamide (24 mg, 28% yield): LC-MS m/z 429.1 (MH+), retention time 2.27 min (method 1); Rf=0.31 (EtOAc: 2M NH3 in MeOH=9:1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[CH2:12]([O:15][C:16]([N:18]1[CH2:22][CH2:21][C@@H:20]([NH2:23])[CH2:19]1)=[O:17])[CH:13]=[CH2:14].C(N(CC)CC)C>C(OCC)(=O)C>[CH2:12]([O:15][C:16]([N:18]1[CH2:22][CH2:21][C@@H:20]([NH:23][C:7]2[CH:6]=[CH:5][C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]=2[F:1])[CH2:19]1)=[O:17])[CH:13]=[CH2:14]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: C=CCOC(=O)N1CC[C@@H](N)C1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N1CC[C@@H](Nc2ccc([N+](=O)[O-])cc2F)C1

Procedure:
A solution of 5.01 g of 3,4-difluoro nitrobenzene, 5.1 g (3R)-1-allyloxycarbonyl-3-amino pyrrolidine (30 mmol) and 6,27 ml of triethylamine (31.5 mmol) in 100 ml of ethyl acetate was stirred at reflux. The reaction was monitored by HPLC. The reaction was diluted with ethyl acetate, washed with water and brine, the org. layer dried over Mg sulfate, filtered and evaporated. The residue crystallized from an ether/hexane mixture.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C(N(C(C)C)CC)(C)C.[Cl:25][CH2:26][C:27](Cl)=[O:28]>C(Cl)Cl>[Cl:25][CH2:26][C:27]([NH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:28]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CN
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCCCC1CNC(=O)CCl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 2-(aminomethyl)piperidine-1-carboxylate (2.0 g, 9.3 mmol) and diisopropylethylamine (5 mL) in DCM (30 mL) was added 2-chloroacetyl chloride (1.2 g, 10.6 mmol) dropwise at 0° C. The mixture was stirred at room temperature overnight. Then the mixture was quenched with water (30 mL) and extracted with DCM (5×100 mL). The combined organic layers were dried over Na2SO4. After filtration and concentration, the residue was used directly for the next reaction. MS (ESI): 291, 293 (MH+).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][C@@H:4]1[NH:8][C:9](=[O:20])[C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19].CCN(C(C)C)C(C)C.F[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[N:32]=1>CN1C(=O)CCC1>[CH3:17][O:16][C:15]1[CH:14]=[CH:13][CH:12]=[C:11]([O:18][CH3:19])[C:10]=1[C:9]([NH:8][C@H:4]1[CH2:5][CH2:6][CH2:7][C@@H:3]1[NH:2][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[N:32]=1)=[O:20]
Reactant: Fc1cccc(C(F)(F)F)n1
Reactant: COc1cccc(OC)c1C(=O)N[C@H]1CCC[C@@H]1N
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(OC)c1C(=O)N[C@H]1CCC[C@@H]1Nc1cccc(C(F)(F)F)n1
Reaction time: 0.33 h

Procedure:
To a microwave vial were charged N-[(1S,2S)-2-Aminocyclopentyl]-2,6-dimethoxybenzamide hydrochloride (Intermediate 5; 80 mg, 0.266 mmol) in dry NMP (1 ml). To this was then added DIPEA (138 μl, 0.798 mmol) and 2-fluoro-6-(trifluoromethyl)pyridine (CAS number 94239-04-0; 53 mg, 0.319 mmol). The reaction was subjected to microwave irradiation at 200° C. for 30 minutes and then at 250° C. for 20 minutes. The reaction mixture was directly purified by reverse phase preparative HPLC (eluted with acetonitrile/water containing 0.1% ammonia) to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][C:7]2[NH:8][CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.F[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1>>[Br:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][C:7]2[N:8]([C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2c[nH]c(Cc3ccc(Br)cc3)n2)c(Cl)c1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: O=[N+]([O-])c1ccc(-n2cc(-c3ccc(Cl)cc3Cl)nc2Cc2ccc(Br)cc2)cc1

Procedure:
2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-1H-imidazole (38.2 g, 0.1 mol) was treated as described in general procedure B using 1-fluoro-4-nitrobenzene to give 2-(4-bromo-benzyl)-1-(4-nitro-phenyl)-4-(2,4-dichloro-phenyl)-1H-imidazole.
Reaction SMILES: [F:1][C:2]1[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:20]=[CH:19][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]1)=[O:5].[ClH:27].O1CCOCC1>CO>[ClH:27].[F:1][C:2]1[C:22]([C:23]([F:26])([F:24])[F:25])=[CH:21][CH:20]=[CH:19][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cccc(C(F)(F)F)c2F)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=C(c1cccc(C(F)(F)F)c1F)N1CCNCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of 7.74 g of tert-butyl 4-(2-fluoro-3-(trifluoromethyl)benzoyl)piperazine-1-carboxylate and 10 ml of methanol was added a hydrochloric acid-1,4-dioxane solution (4 M, 20 ml) followed by stirring at room temperature for 4 hours. The reaction mixture was concentrated in vacuo to give the title compound.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=O.[F:10][C:11]([F:16])([F:15])[C:12](O)=[O:13]>>[F:10][C:11]([F:16])([F:15])[C:12]([NH:1][C@@H:2]1[C:7](=[O:8])[O:9][C:4](=[O:6])[CH2:3]1)=[O:13]
Reactant: N[C@@H](CC(=O)O)C(=O)O
Reactant: O=C(O)C(F)(F)F
Product: O=C1C[C@H](NC(=O)C(F)(F)F)C(=O)O1
Temperature: 0 °C
Yield: 75 %

Procedure:
Aspartic acid (100 g: 0.75 mol) is suspended in trifluoroacetic acid (300 ml) and cooled under mechanical agitation in an ice and salt bath; trifluoroacetic acid (300 ml: 2.16 mol) is added drop-wise, adjusting the addition so that the temperature does not rise above 10° C. On completing the addition, the suspension is left for half an hour under vigorous stirring at a temperature below 10° C., after which the temperature is allowed to rise slowly to room temperature. The solution is reacted for 2 hours at 45° C. and for 1 night at room temperature. Extraction is done with acetone (300 ml) and cooling to solubilise the mass which is of very firm consistency and the solution is then concentrated to dryness. The solid obtained is washed twice with 500 cc of n-hexane and then with 1 liter of n-hexane/ethyl ether at a ratio of 4:1, triturating and vacuum filtering. 135 g of product are obtained which can be used as such if the analyses are compliant. The product is crystallised by n-hexane/EtOAc obtaining 119 g of product which is vacuum dried thoroughly at 40° C. Yield 75%.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([NH2:12])=[S:11])=[CH:5][CH:4]=1.Br[CH2:16][C:17](=O)[C:18]([OH:20])=[O:19]>CO>[F:14][C:2]([F:1])([F:13])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]2[S:11][CH:16]=[C:17]([C:18]([OH:20])=[O:19])[N:12]=2)=[CH:7][CH:8]=1
Reactant: NC(=S)Nc1ccc(C(F)(F)F)cc1
Reactant: O=C(O)C(=O)CBr
Solvent: CO
Product: O=C(O)c1csc(Nc2ccc(C(F)(F)F)cc2)n1
Yield: 95.5 %

Procedure:
2-(4-Trifluoromethyl-phenylamino)-thiazole-4-carboxylic acid (275 mg) was prepared according to General Procedure B using (4-trifluoromethyl-phenyl)-thiourea (220 mg) and 3-bromo-2-oxo-propionic acid (200 mg) in methanol (2 mL). The crude product was used in a subsequent step without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5].C([O-])([O-])=O.[K+].[K+].[CH3:13][C:14]([C:16](Cl)=[O:17])=[CH2:15]>CN(C)C=O.CO>[OH:6][CH:3]([CH2:4][OH:5])[CH2:2][NH:1][C:16](=[O:17])[C:14]([CH3:15])=[CH2:13]
Reactant: NCC(O)CO
Reactant: C=C(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: C=C(C)C(=O)NCC(O)CO
Temperature: 0 °C

Procedure:
4.56 g of 3-amino-1,2-propanediol (0.05 mol) were dissolved in 30 ml of dimethylformamide (anhydrous). This solution, and also 13.8 g of K2CO3, were transferred to a 100 ml three-necked flask fitted with dropping funnel and gas inlet and gas outlet pipe. The mixture was cooled to 0° C. in an ice bath. 6.18 ml of methacryl chloride (0.06 mol), dissolved in 30 ml of dimethylformamide, were added dropwise over 30 minutes with moderate stirring and gentle passage of nitrogen. After stirring for a further hour with ice cooling, the mixture was allowed to warm to room temperature and was stirred for a further 30 minutes. The reaction batch was filtered through a fluted filter, and the residue was discarded. The filtrate was concentrated in a rotary evaporator until a viscous oil was produced. This oil was dissolved in 30 ml of methanol and filtered a second time, and the filtrate was again concentrated in a rotary evaporator. The residual amounts of solvent were removed in a high vacuum. The yield was 8.52 g.
Reaction SMILES: BrC1C=C(C)C(C(N2CCC(N3CCCC3)CC2)=O)=C(C)C=1.[CH3:23][C:24]1[C:29]([C:30]([N:32]2[CH2:37][CH2:36][CH:35]([N:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)[CH2:34][CH2:33]2)=[O:31])=[C:28]([CH3:43])[CH:27]=[C:26]([C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([O:50][C:51]([F:54])([F:53])[F:52])[CH:45]=2)[N:25]=1.N1CCC(N2CCC[C@H]2[CH2:66][O:67][C:68](=[O:75])[C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)CC1>>[CH3:23][C:24]1[C:29]([C:30]([N:32]2[CH2:37][CH2:36][CH:35]([N:38]3[CH2:39][CH2:40][CH2:41][C@H:42]3[CH2:66][O:67][C:68](=[O:75])[C:69]3[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=3)[CH2:34][CH2:33]2)=[O:31])=[C:28]([CH3:43])[CH:27]=[C:26]([C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([O:50][C:51]([F:53])([F:54])[F:52])[CH:45]=2)[N:25]=1
Reactant: O=C(OC[C@@H]1CCCN1C1CCNCC1)c1ccccc1
Reactant: Cc1cc(-c2cccc(OC(F)(F)F)c2)nc(C)c1C(=O)N1CCC(N2CCCC2)CC1
Agent: Cc1cc(Br)cc(C)c1C(=O)N1CCC(N2CCCC2)CC1
Product: Cc1cc(-c2cccc(OC(F)(F)F)c2)nc(C)c1C(=O)N1CCC(N2CCC[C@H]2COC(=O)c2ccccc2)CC1

Procedure:
In analogy to the procedures described for intermediate 1 and for intermediate 4B,2,4-dimethyl-6-(3-trifluoromethoxy-phenyl)-nicotinic acid (example 28) was converted into its acid chloride and reacted with benzoic acid (S)-1-piperidin-4-yl-pyrrolidin-2-ylmethyl ester (intermediate 3) to give benzoic acid (S)-1-{1-[2,4-dimethyl-6-(3-trifluoromethoxy-phenyl)-pyridine-3-carbonyl]-piperidin-4-yl}-pyrrolidin-2-ylmethyl ester, which was subsequently saponified to give the title compound as colorless amorphous solid. MS: 478.2 (MH+).
Reaction SMILES: [CH3:1][N:2]1[C@H:14]2[C@H:5]([CH2:6][CH2:7][C:8]3[CH:9]=[CH:10][N:11]=[CH:12][C:13]=32)[CH2:4][CH2:3]1.[I:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].[CH3:27]C(O)=O>>[I-:15].[CH2:26]([N+:11]1[CH:10]=[CH:9][C:8]2[CH2:7][CH2:6][C@@H:5]3[CH2:4][CH2:3][N:2]([CH3:1])[C@@H:14]3[C:13]=2[CH:12]=1)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH3:27]
Reactant: CN1CC[C@H]2CCc3ccncc3[C@H]21
Reactant: CCCCCCCCCCCI
Reactant: CC(=O)O
Product: CCCCCCCCCCCC[n+]1ccc2c(c1)[C@@H]1[C@H](CC2)CCN1C
Product: [I-]
Yield: 66 %

Procedure:
To a stirred solution of cis-1-methyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-h]isoquinoline (120 mg, 0.64 mmol) in AcOH (2 ml) was added 1-iodoundecane (569 mg, 1.92 mmol). The mixture was heated at reflux under nitrogen for 3 days. AcOH was evaporated and the residue was dissolved in CHCl3. The mixture was washed with saturated aqueous NaHCO3, water and brine successively and dried. Evaporation of the solvent followed by titration with ether afforded 205 mg (66%) of cis-8-dodecyl-1-methyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-h]isoquinolin-8-ium iodide (ACDD) as a brown oil. 1H NMR (300 MHz, CDCl3) δ9.08 (1H, s, C9-H), 9.02 (1H, d, J6.3 Hz, C7-H), 7.79 (1H, d, J6.3 Hz, C6-H), 4.90 (2H, m. pyCH2), 3.48 (1H, d, J8.4 Hz, C9b-H), 2.36 (3H, s, NCH3), 1.50-3.10 (9H, m, CH2+CH), 2.00 (2H, m, pyCH2CH2), 1.10-1.40 (18H, m, 9×CH2), 0.85 (3H, t, J6.9 Hz, CH2CH3); 13C NMR (75 MHz, CDCl3) δ161.5, 143.3, 142.5, 138.8, 127.5, 63.1, 61.0, 55.7, 41.0, 35.6, 32.0, 31.9, 30.0, 29.6×2, 29.5, 29.4, 29.3, 29.1, 28.1, 27.3, 26.0, 22.7, 14.1.