Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Cl.[C@H]1(C[N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[C:39]([F:43])=[CH:40][CH:41]=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:16][CH2:15]2)[C@@H]2N(CCCC2)CCC1.Cl.Cl.Cl.NC1CCN([CH2:54][CH2:55][N:56]2[CH2:61][CH2:60][CH:59]([OH:62])[CH2:58][CH2:57]2)CC1>>[ClH:1].[ClH:1].[OH:62][CH:59]1[CH2:60][CH2:61][N:56]([CH2:55][CH2:54][N:14]2[CH2:15][CH2:16][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[C:39]([F:43])=[CH:40][CH:41]=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:18][CH2:19]2)[CH2:57][CH2:58]1
Reactant: NC1CCN(CCN2CCC(O)CC2)CC1
Reactant: O=C(NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1)c1cc2c(OCc3coc4cccc(F)c34)cccc2[nH]1
Agent: Cl
Product: O=C(NC1CCN(CCN2CCC(O)CC2)CC1)c1cc2c(OCc3coc4cccc(F)c34)cccc2[nH]1

Procedure:
This compound is synthesized from 4-(4-fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (104, see example 48) and amine 21 analogously to the method described in example 1.
Reaction SMILES: [S:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2].[Cl:16][C:17]1[CH:22]=[C:21]([CH:23]2[CH2:28][CH2:27][C:26]([CH3:30])([CH3:29])[CH2:25][CH2:24]2)[CH:20]=[CH:19][C:18]=1O>N1C=CC=CC=1.C1(C)C=CC=CC=1>[F:5][C:4]([F:7])([F:6])[S:1]([O:8][C:18]1[CH:19]=[CH:20][C:21]([CH:23]2[CH2:24][CH2:25][C:26]([CH3:29])([CH3:30])[CH2:27][CH2:28]2)=[CH:22][C:17]=1[Cl:16])(=[O:3])=[O:2]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CC1(C)CCC(c2ccc(O)c(Cl)c2)CC1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC1(C)CCC(c2ccc(OS(=O)(=O)C(F)(F)F)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
8.2 ml of triflic anhydride are added at 5° C. to 9.7 g of 2-chloro-4-(4,4-dimethylcyclohexyl)phenol (compound IX.1) in 60 ml of pyridine, and the reaction mixture is left at 0° C. for 30 mintues and then stirred at room temperature for 12 hours. The reaction mixture is hydrolysed and then extracted with dichloromethane. The organic phase is dried over magnesium sulphate and the solvents are evaporated off under reduced pressure. The residue obtained is taken up in toluene and the solvents are then evaporated off under reduced pressure. The residue obtained is purified by chromatography on a column of silica gel, eluting with a cyclohexane/ethyl acetate mixture varying from 100/0 to 99/1 (v/v). 15 g of the compound are obtained.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH:11]1([NH:17][C:18]2[CH:25]=[CH:24][C:21]([C:22]#N)=[CH:20][CH:19]=2)[CH2:16][CH2:15][CH:14]=[CH:13][CH2:12]1.C[OH:27]>C1(C)C=CC=CC=1>[CH:11]1([NH:17][C:18]2[CH:25]=[CH:24][C:21]([CH:22]=[O:27])=[CH:20][CH:19]=2)[CH2:16][CH2:15][CH:14]=[CH:13][CH2:12]1
Reactant: N#Cc1ccc(NC2CC=CCC2)cc1
Reactant: CO
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: O=Cc1ccc(NC2CC=CCC2)cc1
Temperature: 0 °C

Procedure:
Di-isobutylaluminum hydride (54 ml., 25% solution in toluene) is added with stirring to a solution of 12.1 g. of 4-(cyclohex-3-enylamino)benzonitrile under a nitrogen atmosphere. After addition is completed, the solution stirred for one hour. A solution of methanol in toluene (50 ml., 1:1) is added over 30 minutes and the mixture is poured into 500 ml. vigorously stirred ice-cold 50% aqueous sulfuric acid. The mixture is filtered and the organic layer separated. The aqueous solution is extracted twice with toluene (100 ml.) and the combined organic layers are washed with acqueous sodium bicarbonate, dried over magnesium sulfate, decolorized with charcoal, filtered and evaporated in vacuo to give a light yellow crystalline solid. The product is recrystallized from dichloromethane/hexane giving colorless needles.
Reaction SMILES: [H-].[K+].[CH2:3]([N:6]([CH:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:8][CH3:9])[CH2:4][CH3:5].Br[CH2:22][C:23]1[C:31]2[N:30]=[CH:29][N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:27]=2[CH:26]=[CH:25][CH:24]=1>C1COCC1>[CH3:37][C:35]([CH3:38])([O:34][C:32]([N:28]1[C:27]2[CH:26]=[CH:25][CH:24]=[C:23]([CH2:22][C:10]([N:6]([CH2:7][CH2:8][CH3:9])[CH2:3][CH2:4][CH3:5])([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:31]=2[N:30]=[CH:29]1)=[O:33])[CH3:36]
Reactant: CC(C)(C)OC(=O)n1cnc2c(CBr)cccc21
Reactant: CCCN(CCC)C(C(=O)OCC)C(=O)OCC
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCN(CCC)C(Cc1cccc2c1ncn2C(=O)OC(C)(C)C)(C(=O)OCC)C(=O)OCC
Reaction time: 0.08 h
Yield: 80.7 %

Procedure:
Potassium hydride (3.3 g of 40% oil suspension, washed with ether to remove oil, 0.03 mol) was added to a stirred solution of diethyl (dipropylamino)-malonate (10.2 g, 0.039 mol) in dry THF (100 mL). After 5 minutes, t-butyl 4-(bromomethyl) -1H-benzimidazole-1-carboxylate (6.22 g, 0.02 mol) was added and the solution was refluxed for 6 hours. The solvent was removed under reduced pressure and the residual oil was partitioned between ethyl acetate and water. After evaporation of the ethyl acetate, the crude product was chromatographed on silica gel using ethyl acetate:hexane as the eluant to give 7.9 g of diethyl {((1,1 -dimethylethoxycarbonyl)-1H-benzimidazole-4-yl)methyl}(dipropyl amino)-propanedioate as an oil.
Reaction SMILES: P(Br)(Br)[Br:2].O[CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]2[O:15][CH2:14][CH2:13][C:12]=2[CH:16]=1>C(Cl)(Cl)(Cl)Cl>[Br:2][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]2[O:15][CH2:14][CH2:13][C:12]=2[CH:16]=1
Reactant: BrP(Br)Br
Reactant: OCCc1ccc2c(c1)CCO2
Solvent: ClC(Cl)(Cl)Cl
Product: BrCCc1ccc2c(c1)CCO2
Temperature: 25 °C

Procedure:
Phosphorus tribromide (0.37 g) was added to a solution of 5-(2-hydroxyethyl)-2,3-dihydrobenzofuran (0.612 g--see Preparation 8) in carbon tetrachloride (3 ml) and the mixture was heated under reflux for 3 hours. On cooling to room temperature, the mixture was partitioned between 10% aqueous sodium carbonate (20 ml) and dichloromethane (20 ml). The layers were separated and the aqueous layer Was extracted with dichloromethane (2×10 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give the title compound as an oil which crystallised on standing, yield 0.584 g, m.p. 60°-62° C.
Reaction SMILES: C1C2C(COC([N:18]=[C:19]=[S:20])=O)C3C(=CC=CC=3)C=2C=CC=1.[CH2:21]([O:23][C:24]([CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25])[CH3:22].C(OCC)C>C(Cl)(Cl)Cl>[CH2:21]([O:23][C:24]([CH:26]1[CH2:31][CH2:30][N:29]([C:19](=[S:20])[NH2:18])[CH2:28][CH2:27]1)=[O:25])[CH3:22]
Reactant: O=C(N=C=S)OCC1c2ccccc2-c2ccccc21
Reactant: CCOC(=O)C1CCNCC1
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: CCOC(=O)C1CCN(C(N)=S)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
9-Fluorenylmethoxycarbonyl isothiocyanate (5.90 g, 21.0 mmol) was dissolved in chloroform (20 ml) and a chloroform (10 ml) solution of piperidine-4-carboxylic acid ethyl ester (3.30 g, 21.0 mmol) was added and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated in vacuo, and the residue obtained by adding diethyl ether was collected by filtration. This was dissolved in N,N-dimethylformamide (20 ml) and piperidine (20 ml) was added and the mixture was stirred at room temperature for 1 hour. After the reaction solution was washed with ethyl acetate and the organic layer was washed with a saturated bline and dried over sodium sulfate, the residue obtained by vacuum concentration was purified by silica gel chromatography (n-hexane:ethyl acetate), and the title compound (4.34 g, 100%) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1I)[NH2:5].C(=O)([O-])[O-].[K+].[K+].[C:16]1(B2OC(C)(C)C(C)(C)O2)[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]=1>C(COC)OC.O>[C:16]1([C:8]2[CH:7]=[CH:6][C:4]([NH2:5])=[CH:3][C:2]=2[F:1])[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]=1
Reactant: CC1(C)OB(C2=CCCCC2)OC1(C)C
Reactant: Nc1ccc(I)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Nc1ccc(C2=CCCCC2)c(F)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 62.8 %

Procedure:
In a pressure tube, a solution of 3-fluoro-4-iodoaniline (2.29 g, 9.66 mmol) and potassium carbonate (1.74 g, 12.58 mmol) in 4:1 dimethoxyethane-water (33 mL) was degassed by nitrogen sparge for 40 minutes, followed by addition of 1-cyclohexenyl boronic acid pinacol ester (2.7 mL, 2.61 g, 12.56 mmol). Then 1,1′-bis(diphenylphosphino)ferrocene palladium (II) chloride dichloromethane complex (237 mg, 0.29 mmol) was added followed by degassing for another 5 minutes. The pressure tube was sealed and warmed at 100° C. for 18 hours. The mixture was cooled and diluted with ethyl acetate, followed by extraction with water and saturated sodium chloride solution. The solution was dried (Na2SO4) and stirred with 3-(mercaptopropyl) silica gel for 1 hour. Concentration in vacuo afforded a brown oil, which was chromatographed over a 340 g silica gel cartridge, eluting with 10-100% ethyl acetate in hexanes. These procedures afforded the title compound (1.16 g, 63%) as a light brown oil. 1H NMR (400 MHz, CDCl3) δ ppm 7.00 (m, 1H), 6.37 (m, 2H), 5.84 (s, 1H), 3.71 (br s, 2H), 2.32 (m, 2H), 2.17 (m, 2H), 1.73 (m, 2H), 1.65 (m, 2H); MS (+DCI) m/z (rel abundance) 192 (100, M+H).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:23])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:16]4[CH:17]=[C:18]([Br:22])[N:19]=[C:20](Br)[C:15]4=[N:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[NH2:24][CH2:25][CH2:26][CH2:27][OH:28].C1(C)C=CC=CC=1>CN(C)C=O>[Br:22][C:18]1[N:19]=[C:20]([NH:24][CH2:25][CH2:26][CH2:27][OH:28])[C:15]2[N:16]([C:12]([C:9]3[CH:10]=[CH:11][C:6]([C:5]([NH:4][CH:1]4[CH2:2][CH2:3]4)=[O:23])=[CH:7][CH:8]=3)=[CH:13][N:14]=2)[CH:17]=1
Reactant: O=C(NC1CC1)c1ccc(-c2cnc3c(Br)nc(Br)cn23)cc1
Reactant: NCCCO
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(NC1CC1)c1ccc(-c2cnc3c(NCCCO)nc(Br)cn23)cc1
Temperature: 40 °C
Reaction time: 6 h
Yield: 92 %

Procedure:
To a solution of 500 mg (1.15 mmol) N-cyclopropyl-4-(6,8-dibromoimidazo[1,2-a]pyrazin-3-yl)benzamide which was prepared according to intermediate example 1b in 15 mL N,N-dimethylformamide were added 261 μL 3-aminopropan-1-ol and the mixture was stirred at 40° C. for 6 hours. Toluene was added and the solvents removed. The residue was purified by chromatography to give 453 mg (92%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH2:15][CH2:14][CH2:13][N:12]([C:17](=[O:29])[CH2:18][N:19]4[C:23]([CH3:24])=[CH:22][C:21]([C:25]([F:28])([F:27])[F:26])=[N:20]4)[C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.I[CH2:31][CH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.[H-].[Na+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[CH2:15][CH2:14][CH2:13][N:12]([C:17](=[O:29])[CH:18]([N:19]4[C:23]([CH3:24])=[CH:22][C:21]([C:25]([F:27])([F:26])[F:28])=[N:20]4)[CH2:31][CH:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)[C:11]=3[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: ICC1CCOCC1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCCc2c1cnn2-c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C(F)(F)F)nn1C(CC1CCOCC1)C(=O)N1CCCc2c1cnn2-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 5.5 %

Procedure:
A mixture of 1-[1-(4-fluorophenyl)-6,7-dihydro-5H-pyrazolo[4,3-b]pyridin-4-yl]-2-[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]ethanone (0.100 g, 0.25 mmol), 4-(iodomethyl)tetrahydro-2H-pyran (0.165 g, 0.75 mmol) and NaH (0.030 g, 0.75 mmol, 60% in mineral oil) in DMF (0.8 mL) was stirred at rt for 1.5 hrs. It was then quenched with sat. NH4Cl. The mixture was partitioned between EtOAc (50 mL) and brine (30 mL). The organic layer was separated, dried over Na2SO4, concentrated in vacuo, and purified by reverse phase HPLC to afford the desired product (0.007 g, 6%). 1H NMR (400 MHz, CDCl3) δ 8.44 (s, 1H), 7.43 (dd, J=8.8, 4.8 Hz, 2H), 7.16 (dd, J=8.8, 8.4 Hz, 2H), 6.31 (s, 1H), 5.54 (m, 1H), 3.95 (m, 2H), 3.78 (m, 1H), 3.47 (m, 1H), 3.34 (m, 2H), 2.75 (m, 2H), 2.30 (s, 3H), 2.20 (m, 3H), 1.88 (m, 3H), 1.40 (m, 3H); MS: (ES) m/z calculated for C25H27F4N5O2 [M+H]+ 506.2, found 506.2.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([CH2:7][CH2:8]O)=[CH:5][CH:6]=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.O.[N:22]1C=C[CH:25]=[CH:24][CH:23]=1>>[CH2:23]([NH:22][CH2:8][CH2:7][C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)[CH2:24][CH3:25]
Reactant: c1ccncc1
Reactant: OCCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Product: CCCNCCc1ccccc1
Temperature: 65 °C
Reaction time: 24 h

Procedure:
25.3 g of phenethanol (available commercially from, e.g., Aldrich Chemical Co.) is added to 41 g of p-toluenesulfonyl chloride in 200 ml of pyridine at 0° C. and allowed to stand for 24 h. Water is added, and the mixture extracted with ethyl acetate. The ethyl acetate extract was washed with 5% HCl, water, and brine, dried over Na2SO4, and evaporated to a residue. The resulting tosyloxyethylbenzene is then stirred with 12.2 g of n-propylamine in 100 ml of DMF at 65° C. for one hour. The solution is diluted with water and acidified with HCl. The mixture is then washed with Et2O, basified with NH4OH, and extracted with ethyl acetate. Evaporation of the solvent (after drying over Na2SO4) produces N-propyl-N-phenethylamine (HNR1R2).
Reaction SMILES: C([NH:4][C:5]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:8]([C:9]([O:11]C)=[O:10])=[C:7]([O:18][CH3:19])[CH:6]=1)(=O)C.[OH-].[Na+]>C(O)C>[NH2:4][C:5]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:8]([C:9]([OH:11])=[O:10])=[C:7]([O:18][CH3:19])[CH:6]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])c(NC(C)=O)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(N)c([N+](=O)[O-])cc1C(=O)O

Procedure:
Prepared analogously to example 3b from methyl 4-acetylamino-2-methoxy-5-nitro-benzoate with NaOH in ethanol.
Reaction SMILES: Cl[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([O:17][CH3:18])[CH:12]=3)[S:7][C:6]=2[C:5]([N+:19]([O-:21])=[O:20])=[CH:4][CH:3]=1.[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][NH2:26]>>[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][NH:26][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([O:17][CH3:18])[CH:12]=3)[S:7][C:6]=2[C:5]([N+:19]([O-:21])=[O:20])=[CH:4][CH:3]=1
Reactant: CN(C)CCN
Reactant: COc1ccc2sc3c([N+](=O)[O-])ccc(Cl)c3c(=O)c2c1
Product: COc1ccc2sc3c([N+](=O)[O-])ccc(NCCN(C)C)c3c(=O)c2c1

Procedure:
1-[[2-(Dimethylamino)ethyl]amino]-7-methoxy-4-nitro-9H-thioxanthen-9-one was prepared similarly from 8.0 g of 1-chloro-7-methoxy-4-nitrothioxanthone and 5.6 g of N,N-dimethylethylenediamine affording 7.2 g, mp 190°-192°.
Reaction SMILES: [H-].[Na+].[CH:3]([O:6][C:7]([N:9]1[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11][CH2:10]1)=[O:8])([CH3:5])[CH3:4].C1COCC1.Cl[C:22]1[C:31]2[C:26](=[C:27]([Cl:32])[CH:28]=[CH:29][CH:30]=2)[N:25]=[CH:24][CH:23]=1>C(Cl)Cl>[CH:3]([O:6][C:7]([N:9]1[CH2:10][CH2:11][CH:12]([O:15][C:22]2[C:31]3[C:26](=[C:27]([Cl:32])[CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH2:13][CH2:14]1)=[O:8])([CH3:5])[CH3:4]
Reactant: CC(C)OC(=O)N1CCC(O)CC1
Reactant: Clc1ccnc2c(Cl)cccc12
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)OC(=O)N1CCC(Oc2ccnc3c(Cl)cccc23)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a 50 mL round-bottomed flask equipped with a N2 inlet septum was placed a stir bar, NaH (60% in mineral oil, 1.1 g, 30 mmol) and 4-hydroxy-piperidine-1-carboxylic acid isopropyl ester (0.93 g, 5 mmol). THF (anhydrous, 20 mL) was added to the mixture. The resulting suspension was stirred about 30 min at room temperature. 4,8-Dichloro-quinoline (1 g, 0.5 mmol) was then added in one portion. The mixture was stirred overnight under N2 at 80° C. and the resulting slurry turned slightly yellowish. The slurry was added CH2Cl2 and filtered. The filtrate was concentrated under vacuum to give the crude product. Purification by column chromatography gave 4-(8-chloro-quinolin-4-yloxy)-piperidine-1-carboxylic acid isopropyl ester as an off-white solid. 1H NMR (CDCl3, 400 MHz) δ 1.26 (d, 6H), 1.97 (m, 2H), 2.05 (m, 2H), 3.58 (m, 2H), 3.73 (m, 2H), 4.82 (m, 1H), 4.94 (m, 1H), 6.81 (d, 1H), 7.42 (t, 1H), 7.84 (d, 1H), 8.16 (d, 1H), 8.87 (d, 1H). Exact mass calculated for C18H21ClN2O3 348.12, found 349.2 (MH+)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH3:14])=[CH:9][C:8]=1[CH2:15][CH2:16][CH2:17][O:18][CH3:19])[CH3:2].[H-].[Na+].[Na+].[I-].Cl[CH2:26][C:27]1[C:28]([CH3:43])=[N:29][C:30]([C:33]2[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=2)=[CH:31][CH:32]=1>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]([CH3:14])[CH2:26][C:27]2[C:28]([CH3:43])=[N:29][C:30]([C:33]3[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=3)=[CH:31][CH:32]=2)=[CH:9][C:8]=1[CH2:15][CH2:16][CH2:17][O:18][CH3:19])[CH3:2]
Reactant: CCOC(=O)COc1ccc(NC)cc1CCCOC
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CCl
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(N(C)Cc2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1CCCOC
Reaction time: 0.5 h

Procedure:
To 0.102 g (0.36 mmol) of the above prepared [2-(3-methoxy-propyl)-4-methylamino-phenoxy]-acetic acid ethyl ester, dissolved in 1.4 ml of abs. DMF, were added successively at 0° C. 0.017 g of NaH (60% in mineral oil, 1.2 eq.), 0.054 g (1 eq.) of NaI and 0.100 g (1 eq.) of 3-chloromethyl-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine (see below 1K]). The reaction was allowed to proceed for 5 Min. at 0° C. and for 0.5 h at ambient temperature. Pouring onto crashed ice/KHSO4, twofold extraction with AcOEt, washing with water and brine, drying over magnesium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/AcOEt=75/25), yielded 0.126 g of the title compound as light yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:27])=[C:8]2[C:15]([Br:16])=[C:14]([Br:17])[N:13]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])[C:9]2=[C:10](Br)[N:11]=1)=[O:5])[CH3:2].[C:28]([Cu])#[N:29]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:27])=[C:8]2[C:15]([Br:16])=[C:14]([Br:17])[N:13]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])[C:9]2=[C:10]([C:28]#[N:29])[N:11]=1)=[O:5])[CH3:2]
Reactant: N#C[Cu]
Reactant: CCOC(=O)c1nc(Br)c2c(c1O)c(Br)c(Br)n2Cc1ccccc1OC
Product: CCOC(=O)c1nc(C#N)c2c(c1O)c(Br)c(Br)n2Cc1ccccc1OC

Procedure:
Prepared in analogy to that of Example 105(a) from 2,3,7-tribromo-1-(2-methoxy-benzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester and CuCN. The title compound, ESI MS (m/z): 508 (M+H)+.
Reaction SMILES: CN(C)[CH:3]=[O:4].[OH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[C:22]([OH:23])=[C:21]([O:24][CH3:25])[C:20]([O:26][CH3:27])=[CH:19][C:18]=1C>O=O>[OH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[C:22](=[O:23])[C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[C:3](=[O:4])[C:18]=1[CH3:19]
Reactant: CN(C)C=O
Reactant: COc1cc(C)c(CCCCCCCCCCO)c(O)c1OC
Agent: O=O
Product: COC1=C(OC)C(=O)C(CCCCCCCCCCO)=C(C)C1=O

Procedure:
To a dimethylformamide solution (100 ml) of 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methylphenol (4.1 g) is added bis(3-methoxysalicylidene)ethylenediiminocobalt(II) (0.2 g) and the mixture is stirred in oxygen streams at atmospheric temperature and pressure for 72 hours. After the reaction has been completed, the solvent is distilled off and the residue is extracted with ether. The ethereal layer is washed with water and dried, and the solvent is distilled off in the conventional manner. The crude crystals thus obtained are recrystallized from ethyl acetate-hexane (1:3). The above procedure yields 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (3.77 g) as orange-yellow needles melting at 52° C.-53° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12]O[C:10]=1[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[F:18][C:19]([F:23])([F:22])[CH2:20][NH2:21]>N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:21]([CH2:20][C:19]([F:23])([F:22])[F:18])[C:10]=1[CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCC(F)(F)F
Reactant: Cc1occc(=O)c1OCc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1c(OCc2ccccc2)c(=O)ccn1CC(F)(F)F
Temperature: 75 °C
Yield: 0.1 %

Procedure:
3-(Benzyloxy)-2-methyl-4H-pyran-4-one (1.00 g, 4.6 mmol) was mixed with trifluoroethylamine hydrochloride (1.35 g, 10.0 mmol) in pyridine (10 mL). The reaction mixture was heated in a sealed flask at 75° C. for 5 hours. The mixture was concentrated and the residue was purified by column chromatography on silica gel with 5% methanol in ethyl acetate as eluant to give 3-(benzyloxy)-2-methyl-1-(2,2,2-trifluoroethyl)pyridin-4(1H)-one (0.82 mg) as beige solid. Yield=60%; 1H NMR (CDCl3, 90 MHz) δ (ppm): 7.02-7.58 (m, 6H), 6.42 (d, J=7.5 Hz, 1H), 5.20 (s, 2H), 4.30 (q, J=8.3 Hz, 2H) and 2.10 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([Cl:8])[CH:3]=1.N12CCN(CC1)CC2.[CH3:17][CH:18]([N:20]=[C:21]=[O:22])[CH3:19]>CN(C)C=O>[Cl:8][C:4]1[CH:3]=[C:2]([NH:1][C:21]([NH:20][CH:18]([CH3:19])[CH3:17])=[O:22])[CH:7]=[CH:6][N:5]=1
Reactant: CC(C)N=C=O
Reactant: Nc1ccnc(Cl)c1
Agent: C1CN2CCN1CC2
Solvent: CN(C)C=O
Product: CC(C)NC(=O)Nc1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2.6 grams (0.0203 mole) of 4-amino-2-chloropyridine, 0.53 gram of (0.005 mole) 1,4-diazabicyclo[2.2.2]octane (DABCO), and 3.9 ml (0.0305 mole) of (1-methylethyl) isocyanate in 20 ml of dry dimethylformamide was stirred at ambient temperature for five days. The dimethylformamide was removed under reduced pressure. The residue was taken up in 20 ml of ethanol and this was removed under reduced pressure. The procedure was repeated a second time using an additional 20 ml of ethanol. The residual oil was dried under reduced pressure at ambient temperature for 16 hours, then under reduced pressure at 60° C. for one hour. The resultant solid was triturated in hot water. The mixture was allowed to cool to ambient temperature then placed in a refrigerator where it stood for 60 hours. The solid was collected by filtration, washed with water and dried under reduced pressure for three hours at 40°-50° C. The yield of N-(2-chloro-4-pyridinyl)-N'-(1-methylethyl)urea was 4.1 grams, m.p. 142°-146.5° C. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]1[CH:17]=[C:16]([C:18]2[NH:19][C:20]([C:23]3[S:24][CH:25]=[CH:26][N:27]=3)=[CH:21][CH:22]=2)[CH:15]=[C:14]([O:28][C@@H:29]([CH3:33])[CH2:30][O:31][CH3:32])[CH:13]=1)[C:5]([OH:7])=O.[C:34]([NH:37][NH2:38])(=[O:36])[CH3:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>ClCCl>[C:34]([NH:37][NH:38][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([O:11][C:12]2[CH:17]=[C:16]([C:18]3[NH:19][C:20]([C:23]4[S:24][CH:25]=[CH:26][N:27]=4)=[CH:21][CH:22]=3)[CH:15]=[C:14]([O:28][C@@H:29]([CH3:33])[CH2:30][O:31][CH3:32])[CH:13]=2)=[C:2]([F:1])[CH:3]=1)(=[O:36])[CH3:35]
Reactant: CC(=O)NN
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)O)cc2F)cc(-c2ccc(-c3nccs3)[nH]2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)NNC(C)=O)cc2F)cc(-c2ccc(-c3nccs3)[nH]2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 117.1 %

Procedure:
3-Fluoro-4-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}benzoic acid (84 mg, 0.179 mmol) synthesized in Example (44a) was dissolved in dichloromethane (5.0 mL), and acetohydrazide (40 mg, 0.540 mmol), HATU (200 mg, 0.526 mmol) and N,N-diisopropylethylamine (0.15 mL, 0.861 mmol) were added, followed by stirring at room temperature overnight under nitrogen atmosphere. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate) to afford the desired compound (110 mg, yield ˜100%) as a white solid.