Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9](O)[CH3:10])=[CH:4][N:3]=1.P(Cl)(Cl)([Cl:14])=O.C(N(C(C)C)CC)(C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9]([Cl:14])[CH3:10])=[CH:4][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(O)c1cnc(Cl)nc1Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CC(Cl)c1cnc(Cl)nc1Cl
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of (±)-1-(2,4-dichloro-pyrimidin-5-yl)-ethanol (1.27 g, 6.60 mmol) (from Example 1a supra) in phosphorus oxychloride (5.0 mL, 53.11 mmol) (Aldrich), at 0° C., was added diisopropylethyl-amine (2.60 mL, 14.78 mmol) (Aldrich). The reaction was stirred at 0° C. for 5 minutes, at ambient temperature for 15 minutes and then at 115° C. for 3 hours. The reaction was cooled to room temperature, diluted with toluene (10 mL) and the mixture was then poured into ice (15 g). After stirring for 10 minutes, the layers were separated and the aqueous extract was back washed with toluene. The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by flash chromatography (Biotage, 40M, 10:90 to 15:85 ethyl acetate-hexanes gradient) gave (±)-2,4-dichloro-5-(1-chloroethyl)-pyrimidine as an oil. (Yield 1.233 g; 88.3%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([F:22])=[C:11]3[N:20]=[CH:19][N:18]([CH3:21])[C:12]3=[N:13][C:14]=2[C:15](O)=[O:16])=[C:4]([F:23])[CH:3]=1.C1C=CC2N(O)[N:31]=[N:30]C=2C=1.CCN=C=NCCCN(C)C.NN>CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([F:22])=[C:11]3[N:20]=[CH:19][N:18]([CH3:21])[C:12]3=[N:13][C:14]=2[C:15]([NH:30][NH2:31])=[O:16])=[C:4]([F:23])[CH:3]=1
Reactant: On1nnc2ccccc21
Reactant: Cn1cnc2c(F)c(Nc3ccc(Br)cc3F)c(C(=O)O)nc21
Agent: CCN=C=NCCCN(C)C
Agent: NN
Solvent: CCOC(C)=O
Product: Cn1cnc2c(F)c(Nc3ccc(Br)cc3F)c(C(=O)NN)nc21
Reaction time: 1 h

Procedure:
To a solution of 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (1.00 equivalent) and HOBt (3.00 equivalents) is added EDCI (3.00 equivalents) at room temperature. After stirring for 1 hour, hydrazine (3.00 equivalents) and TEA (3.00 equivalents) are added. The reaction mixture is stirred for 1 hour and diluted with EtOAc. The resulting mixture is washed with saturated aqueous NH4Cl, brine, saturated aqueous NaHCO3, and brine. The organic layer is dried over MgSO4, filtered, and concentrated in vacuo to give the crude material that is used directly without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]([C:14]([F:17])([F:16])[F:15])[CH:8]=2)=[CH:3][CH:2]=1.I[CH2:19][CH2:20][CH3:21]>>[CH2:19]([N:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]([C:14]([F:15])([F:16])[F:17])[CH:8]=2)[CH2:3][CH2:2]1)[CH2:20][CH3:21]
Reactant: Nc1ccc(-c2ccncc2)cc1C(F)(F)F
Reactant: CCCI
Product: CCCN1CC=C(c2ccc(N)c(C(F)(F)F)c2)CC1
Temperature: 100 °C

Procedure:
4-Pyridin-4-yl-2-trifluoromethyl-phenylamine (270 mg) was dissolved in 1-iodo-propane (2 ml) and heated to 100° C. for 2 h. Then the voilatiles were evaporated and the residue redissolved in abs EtOH (20 ml) and NaBH4 (800 mg) was added portions wise at −20° C. The mixture was then allowed to reach r.t. and stirred over night. To the mixture was added 10% Na2CO3 solution (20 ml). The aqueous layer was extracted with CH2Cl2 and the combined organic phases were dried (MgSO4), filtered and evaporated to dryness. The crude product was purified by flash chromatography (MeOH: CH2Cl2 (1:9 (v/v)). Collection of the fractions containing pure product and evaporation of the solvent afforded pure 4-(1-Propyl-1,2,3,6-tetrahydro-pyridine-4-yl)-2-trifluoromethyl-phenylamine (200 mg). MS m/z (rel. intensity, 70 eV)) 284 (M+, 53), 255 (bp), 144 (40), 127 (39), 70 (39). Rf 0.28 (MeOH)
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:26]([NH2:28])=[O:27])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:14][C@@H:15]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH3:16])[C:6]=2[N:25]=1.[CH2:29](N1C2C(=CC=CC=2)C2C=C(C(N)=O)C(NC)=NC1=2)C>>[NH2:28][C:26]([C:3]1[C:2]([NH:1][CH3:29])=[N:25][C:6]2[N:7]([CH2:14][C@@H:15]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])[CH3:16])[C:8]3[C:13]([C:5]=2[CH:4]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3)=[O:27]
Reactant: CCn1c2ccccc2c2cc(C(N)=O)c(NC)nc21
Reactant: C[C@@H](Cn1c2ccccc2c2cc(C(N)=O)c(N)nc21)NC(=O)OC(C)(C)C
Product: CNc1nc2c(cc1C(N)=O)c1ccccc1n2C[C@H](C)NC(=O)OC(C)(C)C
Yield: 89 %

Procedure:
tert-butyl {(1S)-2-[2-amino-3-(aminocarbonyl)-9H-pyrido[2,3-b]indol-9-yl]-1-methylethyl}carbamate (xvi-b, 20 mg, 0.052 mmol) was alkylated according to procedure detailed in the preparation of 48, to afford tert-butyl {(1S)-2-[3-(aminocarbonyl)-2-(methylamino)-9H-pyrido[2,3-b]indol-9-yl]-1-methylethyl}carbamate (xxxii-a, 20 mg, 89%). NH4OAc QC conditions. M+H=398.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[O:9]1[CH2:14][CH2:13][C:12](=[CH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:11][CH2:10]1>CS(C)=O>[CH:15]1([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:12]2([CH2:13][CH2:14][O:9][CH2:10][CH2:11]2)[CH2:4]1
Reactant: C[S+](C)(C)=O
Reactant: CCOC(=O)C=C1CCOCC1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)C1CC12CCOCC2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
51.93 g of sodium hydride (60% dispersion in oil) is taken up in 1100 ml of dry dimethyl sulphoxide under argon. 272 g of trimethylsulphoxonium iodide are added in portions over 20 minutes at room temperature, and the reaction mixture is then stirred at room temperature for 1.5 hours. 170.00 g of ethyl (tetrahydropyran-4-ylidene)acetate [130312-00-4] are added dropwise, and the reaction mixture is stirred at room temperature for 18 hours. The mixture is poured into ice and extracted with tert-butyl methyl ether. The combined organic extracts are washed with brine, dried with sodium sulphate and evaporated. The title compound is obtained as a colourless oil from the residue by vacuum distillation (68-70° C., 0.09 mbar). Rt=3.49 (Gradient I).
Reaction SMILES: C([O:4][C:5]1[CH:14]=[C:13]([NH:15][C:16](=[O:18])[CH3:17])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])C=C.[C:19]1(C)[CH:24]=CC=C[CH:20]=1>>[CH2:24]([C:14]1[C:13]([NH:15][C:16](=[O:18])[CH3:17])=[CH:12][CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]=1[OH:4])[CH:19]=[CH2:20]
Reactant: C=CCOc1cc(NC(C)=O)ccc1C(=O)OC
Reactant: Cc1ccccc1
Product: C=CCc1c(NC(C)=O)ccc(C(=O)OC)c1O
Temperature: 25 °C

Procedure:
A solution of 5 g (20.1 mmol) of the allyl ether from Example 19 in 20 ml of toluene is heated at 200° C. in a sealed tube for 24 hours. After cooling to room temperature a precipitate begins forming and the reaction mixture is cooled further to 0° C. The precipitate is filtered off and allowed to air dry, giving methyl 3-allyl-4-acetylaminosalicylate which can be used directly in the next step.
Reaction SMILES: F[C:2]1[CH:3]=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[CH3:22][NH:23][C:24]([CH3:27])([CH3:26])[CH3:25]>>[C:24]([N:23]([CH3:22])[C:2]1[CH:3]=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2)([CH3:27])([CH3:26])[CH3:25]
Reactant: O=C1NCCc2[nH]c(-c3cccc4ncc(F)nc34)cc21
Reactant: CNC(C)(C)C
Product: CN(c1cnc2cccc(-c3cc4c([nH]3)CCNC4=O)c2n1)C(C)(C)C
Temperature: 120 °C
Yield: 72 %

Procedure:
Prepared similarly to that described in Example 210 using 2-(3-fluoroquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 210i; 73 mg, 0.259 mmol) and N,2-dimethylpropan-2-amine (93 μl, 0.776 mmol, Fluka) and heating at 120° C. for 7 h. Purification by silica gel (100% DCM to 4% MeOH/DCM) provided 2-(3-(tert-butyl(methyl)amino)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (72% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.56 (s, 9H) 2.87 (t, J=6.94 Hz, 2H) 3.26 (s, 3H) 3.44 (td, J=6.80, 2.45 Hz, 2H) 6.95 (br. s., 1H) 7.07 (d, J=2.35 Hz, 1 H) 7.44 (t, J=7.82 Hz, 1H) 7.70 (dd, J=8.02, 1.17 Hz, 1H) 7.90 (dd, J=7.43, 1.37 Hz, 1H) 8.75 (s, 1H) 11.78 (br. s., 1H). MS (ESI, pos. ion) m/z: 350.1 (M+1).
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[O:9]2)=[C:4](I)[C:3]=1[OH:19].[C:20]([CH:22]1[CH2:27][CH2:26][CH:25]([CH2:28][CH2:29][CH3:30])[CH2:24][CH2:23]1)#[CH:21].Cl>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[O:9]2)=[C:4]([C:21]#[C:20][CH:22]2[CH2:27][CH2:26][CH:25]([CH2:28][CH2:29][CH3:30])[CH2:24][CH2:23]2)[C:3]=1[OH:19]
Reactant: C#CC1CCC(CCC)CC1
Reactant: CCCCCC1CCc2c(I)c(O)c(F)c(F)c2O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: CCN(CC)CC
Product: CCCCCC1CCc2c(C#CC3CCC(CCC)CC3)c(O)c(F)c(F)c2O1
Temperature: 0 °C

Procedure:
8.0 g (20.9 mmol) of 7,8-difluoro-5-iodo-2-pentylchroman-6-ol are stirred at 50° C. for 19 h together with 4.72 g (31.4 mmol) of 1-ethynyl-4-propylcyclohexane in the presence of 441 mg (0.63 mmol) of bis(triphenylphosphine)palladium(II) chloride and 120 mg (0.63 mmol) of copper(I) iodide in 90 ml of triethylamine. After cooling, the batch is added to ice/water and acidified using hydrochloric acid. The mixture is extracted a number of times with MTBE, and the combined extracts are washed with water and sat. sodium chloride soln. The solution is dried using sodium sulfate and concentrated to dryness. The residue is purified by column chromatography (SiO2, 1-chlorobutane). The phenol obtained is used directly for the following reaction.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[S:8][C:9](Br)=[C:10]([C:12]([O:14][CH2:15][CH:16]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:13])[CH:11]=2)=[CH:4][C:3]=1[C:28]([O:30][CH2:31][CH:32]([CH2:39][CH2:40][CH2:41][CH3:42])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[O:29].C([Sn](CCCC)(CCCC)[C:48]1[S:49][CH:50]=[CH:51][CH:52]=1)CCC>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.CN(C=O)C>[S:6]1[CH:2]=[CH:3][CH:4]=[C:5]1[C:2]1[S:6][C:5]([C:7]2[S:8][C:9]([C:50]3[S:49][CH:48]=[CH:52][CH:51]=3)=[C:10]([C:12]([O:14][CH2:15][CH:16]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:13])[CH:11]=2)=[CH:4][C:3]=1[C:28]([O:30][CH2:31][CH:32]([CH2:39][CH2:40][CH2:41][CH3:42])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[O:29]
Reactant: CCCCCCC(CCCC)COC(=O)c1cc(-c2cc(C(=O)OCC(CCCC)CCCCCC)c(Br)s2)sc1Br
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCCCCCC(CCCC)COC(=O)c1cc(-c2cc(C(=O)OCC(CCCC)CCCCCC)c(-c3cccs3)s2)sc1-c1cccs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the mixture of bis(2-butyl-1-octyl) 5,5′-dibromo-2,2′-bithiophene-4,4′-dicarboxylate (1.00 g, 1.34 mmol) and 2-tributylstannylthiophene (1.50 g, 4 mmol) was added Pd(PPh3)4 (46 mg, 0.04 mmol), and anhydrous DMF (15 ml). The mixture was placed under vacuum and flushed with argon several times and was put on a microwave reactor with a setting of 160° C. for 60 min. The reaction mixture was cooled to room temperature and the solvent was removed. The residue was washed with methanol to remove traces of DMF. After drying, the liquid was dissolved in hexane and purified twice by column chromatography on silica gel using a mixture of hexane/ethyl acetate (9/1) (Rf=0.5). A light yellow liquid was obtained. Yield: 1.01 g (100%).
Reaction SMILES: [CH2:1]([N:4]=[C:5]=[O:6])[CH2:2][CH3:3].[CH2:7]([NH2:10])[CH2:8][CH3:9]>>[CH2:1]([NH:4][C:5]([NH:10][CH2:7][CH2:8][CH3:9])=[O:6])[CH2:2][CH3:3]
Reactant: CCCN=C=O
Reactant: CCCN
Product: CCCNC(=O)NCCC
Yield: 98.4 %

Procedure:
1700 g. (98.4%) of product was prepared according to the method of Hayes et al., J. Agr. Food Chem. 17, 1077 (1969) from n-propylisocyanate (1020 g. 12 mole) and n-propylamine (708 g., 4.75 mole).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[C:7]([OH:15])[C:5]=2[CH:6]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:23][CH:24]([CH3:26])[CH3:25].O>CN(C=O)C>[CH3:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[C:7]([O:15][CH2:23][CH:24]([CH3:26])[CH3:25])[C:5]=2[CH:6]=1
Reactant: CC(C)CI
Reactant: COC(=O)c1cc(O)c2cc(C)oc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(OCC(C)C)c2cc(C)oc2c1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
2-Methyl-4-hydroxy-6-methoxycarbonylbenzofuran (Method 12; 412 mg, assumed 1.0 mmol) was stirred in anhydrous DMF (10 ml) and the solution treated sequentially with potassium carbonate (690 mg, 5 mmol, 5 eq) and 1-iodo-2-methylpropane (442 mg, 276 μl, 2.4 mmol, 2.4 eq). The reaction mixture was stirred at 90° C. for 3 hours, then cooled and poured into water; the resulting mixture was extracted twice with ethyl acetate, the extracts dried (MgSO4) and evaporated in vacuo to yield a brown oil. This was chromatographed (50 g Bondelut, eluting with hexane containing ethyl acetate, 0-100%) to give the title compound as a clear oil contaminated with ca 15% of the corresponding iso-butyl ester. NMR: 1.02 (d, 6H), 2.06 (sept, 1H), 2.45 (s, 3H), 3.84 (s, 3H), 3.91 (d, 2H), 6.66 (s, 1H), 7.24 (s, 1H), 7.66 (s, 1H); the spectrum also contained signals consistent with isobutyl ester, ca 15 mol %.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].[CH2:8]([N:15]1[C:23]2[C:18](=[CH:19][C:20]([NH:24][C:25]3[C:26]4[CH:34]=[C:33](Cl)[N:32]=[CH:31][C:27]=4[N:28]=[CH:29][N:30]=3)=[CH:21][CH:22]=2)[CH:17]=[N:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CS(C)=O>[CH2:8]([N:15]1[C:23]2[C:18](=[CH:19][C:20]([NH:24][C:25]3[C:26]4[CH:34]=[C:33]([N:1]5[CH:5]=[CH:4][N:3]=[CH:2]5)[N:32]=[CH:31][C:27]=4[N:28]=[CH:29][N:30]=3)=[CH:21][CH:22]=2)[CH:17]=[N:16]1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Clc1cc2c(Nc3ccc4c(cnn4Cc4ccccc4)c3)ncnc2cn1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: c1ccc(Cn2ncc3cc(Nc4ncnc5cnc(-n6ccnc6)cc45)ccc32)cc1
Temperature: 120 °C
Reaction time: 168 h

Procedure:
Imidazole (0.8 g) in dry DMSO was treated with sodium hydride (60%, 0.47 g) and (1-Benzyl-1H-indazol-5-yl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine in a reacti-vial and heated at 120° C. After 7 days, the mixture was poured onto water and extracted with ethyl acetate. Purification using a Bond Elute™ cartridge gave the title compound as a brown solid after trituration from water; δH [2H6]DMSO 10.28(1H,s), 9.25(1H,s), 8.90(1H,s), 8.78(1H,s), 8.67(1H,s), 8.40(1H,s), 8.30(1H,s), 8.10(1H,s), 7.88(2H,m), 7.40(5H,m), 5.70(2H,s); m/z (M+) 419.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]([O:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:5]=1)([O-])=O.CO.[H][H]>[Pd].C(OCC)(=O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][CH2:10][OH:11])=[CH:12][CH:13]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(OCCO)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1ccc(OCCO)cc1
Yield: 97.3 %

Procedure:
A mixture of 2-(4-nitro-phenoxy)-ethanol (1.0 g, 5.5 mmol), 10% palladium on carbon (110 mg), methanol (40 ml), and ethyl acetate (20 ml) was treated with hydrogen gas (50 psi) on a Parr shaker for 1 hour. The mixture was filtered through a pad of celite under suction and the filtrate was concentrated under reduced pressure to give 2-(4-amino-phenoxy)-ethanol (820 mg, 99% yield). 1H NMR (DMSO-d6) δ 3.61-3.64 (m, 2H, CH2), 3.80 (t, 2H, J=5.0 Hz CH2), 4.57 (br s, 2H, NH2), 4.74 (t, 1H, J=5.6 Hz, OH), 6.47 (d, 2H, J=8.7 Hz, Ar), 6.62 (d, 2H, J=8.8 Hz, Ar).
Reaction SMILES: FC1C=C(C=C(C(F)(F)F)C=1)[C:5]([N:7]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[O:22][CH3:23])C)=O.[Cl:31][C:32]1[CH:33]=[C:34]([CH:38]=[C:39]([O:41][CH3:42])[N:40]=1)[C:35]([OH:37])=O>>[Cl:31][C:32]1[CH:33]=[C:34]([CH:38]=[C:39]([O:41][CH3:42])[N:40]=1)[C:35]([N:7]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[O:22][CH3:23])[CH3:5])=[O:37]
Reactant: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(F)cc(C(F)(F)F)c1
Reactant: COc1cc(C(=O)O)cc(Cl)n1
Product: COc1cc(C(=O)N(C)c2cnccc2-c2ccc(F)cc2OC)cc(Cl)n1

Procedure:
The title compound was prepared in analogy to example 90, from [4-(4-fluoro-2-methoxy-phenyl)-pyridin-3-yl]-methyl-amine (example 129, intermediate) and 2-chloro-6-methoxy-isonicotinic acid (CAS RN 15855-06-8). Colorless solid (21%). MS (ESI): m/z=402.10 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([OH:23])=O)[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[CH3:56][NH:57][CH2:58][C:59]1[CH:71]=[CH:70][C:62]([CH2:63][N:64]2[CH2:68][CH2:67][CH:66]([OH:69])[CH2:65]2)=[CH:61][CH:60]=1>C(Cl)Cl>[OH:69][CH:66]1[CH2:67][CH2:68][N:64]([CH2:63][C:62]2[CH:70]=[CH:71][C:59]([CH2:58][N:57]([CH3:56])[C:21]([C:18]3[CH:17]=[C:16]([CH2:15][N:13]([S:10]([C:6]4[C:7]([CH3:9])=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=4[CH3:24])(=[O:11])=[O:12])[CH3:14])[O:20][CH:19]=3)=[O:23])=[CH:60][CH:61]=2)[CH2:65]1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Reactant: CNCc1ccc(CN2CCC(O)C2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)N(C)Cc3ccc(CN4CCC(O)C4)cc3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure BH using 5-{[(4-methoxy-2,6-dimethyl-benzenesulfonyl)-methyl-amino]-methyl}-furan-3-carboxylic acid (35 mg, 0.10 mmol), EDCI (27 mg, 0.14 mmol), HOBt (20 mg, 0.15 mmol), DIPEA (0.03 mL, 0.20 mmol), 1-(4-methylaminomethyl-benzyl)-pyrrolidin-3-ol hydrochloride (30 mg, 0.10 mmol) and DCM (10 mL).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([NH2:9])[C:6]([N+:10]([O-:12])=[O:11])=[CH:5][CH:4]=1.[I:13]N1C(=O)CCC1=O>C(O)(=O)C>[I:13][C:4]1[CH:5]=[C:6]([N+:10]([O-:12])=[O:11])[C:7]([NH2:9])=[N:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc([N+](=O)[O-])c(N)n1
Reactant: O=C1CCC(=O)N1I
Solvent: CC(=O)O
Product: COc1nc(N)c([N+](=O)[O-])cc1I
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
A suspension of 6-methoxy-3-nitro-2-pyridineamine (14.6 g, 86.4 mmol) and N-iodosuccinimide (29.2 g, 130 mmol) in acetic acid (280 ml) was stirred at room temperature for 21 hours and 30 minutes. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate and 0.5N sodium hydroxide. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and a saturated brine solution, dried over anhydrous sodium sulfate, and concentrated. The residue was suspended in hexane, and a resulted precipitate was filtered and washed with hexane, thereby yielding the title compound (25.2 g, 85.5 mmol, 98.9%) as a yellow solid.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[C:6]([CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]3[N:24]=[C:23]([CH2:25][O:26][C:27]4[CH:40]=[CH:39][C:30]([CH2:31][CH:32]5[S:36][C:35](=[O:37])[NH:34][C:33]5=[O:38])=[CH:29][CH:28]=4)[N:22]([CH3:41])[C:21]=3[CH:42]=2)[CH:7]=[CH:8][C:9]=1[C:10]([CH3:13])([CH3:12])[CH3:11].[F:43][C:44]([F:55])([F:54])[C:45]1[CH:50]=[CH:49][C:48]([N:51]=[C:52]=[O:53])=[CH:47][CH:46]=1.C(N(CC)CC)C>CN(C)C=O>[C:10]([C:9]1[CH:8]=[CH:7][C:6]([CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]3[N:24]=[C:23]([CH2:25][O:26][C:27]4[CH:40]=[CH:39][C:30]([CH2:31][CH:32]5[S:36][C:35](=[O:37])[NH:34][C:33]5=[O:38])=[CH:29][CH:28]=4)[N:22]([CH3:41])[C:21]=3[CH:42]=2)=[CH:5][C:4]=1[NH:3][C:52]([NH:51][C:48]1[CH:47]=[CH:46][C:45]([C:44]([F:43])([F:54])[F:55])=[CH:50][CH:49]=1)=[O:53])([CH3:13])([CH3:12])[CH3:11]
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(OCCc3ccc(C(C)(C)C)c(N)c3)cc21
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(OCCc3ccc(C(C)(C)C)c(NC(=O)Nc4ccc(C(F)(F)F)cc4)c3)cc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 50.8 %

Procedure:
A mixture of 5-[4-[6-[2-(3-amino-4-t-butylphenyl)ethoxy]-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione dihydrochloride (0.40 g), α,α,α-trifluoro-p-tolyl isocyanate (0.13 g), triethylamine (0.13 g) and anhydrous N,N-dimethylformamide (8 ml) was stirred at room temperature for 24 hours and then at 60° C. for 2.5 hours. The reaction mixture was concentrated and partitioned between ethyl acetate and water. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then concentrated. The residue was purified by preparative reverse phase high performance liquid chromatography using acetonitrile:water=57:43 containing triethylamine (2%) and acetic acid (2%) as the eluant to afford the title compound (0.24 g, mp 165-167° C.).
Reaction SMILES: CO[C:3]([C:5]1[CH:10]=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4].C[Si]([C:15]([F:18])([F:17])[F:16])(C)C.[F-].[Cs+]>C(COC)OC>[F:16][C:15]([F:18])([F:17])[C:3]([C:5]1[CH:10]=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: COC(=O)c1cnccn1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Product: O=C(c1cnccn1)C(F)(F)F

Procedure:
Pyrazine carboxylate methyl ester (7 g) was dissolved in dimethoxy ethane (monoglyme) (20 mL) and treated at room temperature with trimethylsilyltrifluoro-methane (10 mL; 1.44 eq) and caesium fluoride (0.77 g; 0.1 eq) that had been freshly dried at for 10 minutes under vacuum while being heated with a heat gun. After 18 hours at room temperature the reaction mixture was concentrated under reduced pressure at room temperature, and the residue was dissolved in tetrahydrofuran (50 mL) and acetic acid (20 mL) and treated with tert-butylammonium fluoride (50 mL; 1M THF solution) for 3 hours at room temperature. The reaction was diluted with ethyl acetate, and washed with dilute aqueous sodium bicarbonate solution (3 times), brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to an oil. Trituration of the oil with dichloromethane/hexane gave 2,2,2-trifluoro-1-(pyrazin-2-yl)ethanone (18) as a brown solid (2.9 g).
Reaction SMILES: [OH:1][C:2]1[C:11]([CH2:12][CH2:13][C:14]([CH3:16])=[CH2:15])=[C:10]([O:17][CH3:18])[CH:9]=[C:8](/[CH:19]=[CH:20]/[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:27]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[CH3:27][O:1][C:2]1[C:11]([CH2:12][CH2:13][C:14]([CH3:16])=[CH2:15])=[C:10]([O:17][CH3:18])[CH:9]=[C:8](/[CH:19]=[CH:20]/[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: C=C(C)CCc1c(OC)cc(/C=C/c2ccccc2)c(C(=O)OC)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: C=C(C)CCc1c(OC)cc(/C=C/c2ccccc2)c(C(=O)OC)c1OC
Yield: 89.9 %

Procedure:
Dissolve compound 8 (1.2 g, 3.4 mmol) in DMF (20 ml), add anhydrous K2CO3 (0.7 g, 5.1 mmol), MeI (0.96 g, 6.8 mmol), react at 60° C. for 2h. After completion of the reaction, cool the mixture, filter and evaporate the DMF from filtrate under reduced pressure, feed the redissolved residue solution to a silica gel column, evaporate the solvent in the eluent to obtain a colorless oil (1.12 g, 90%). 1H NMR (400 MHz, DMSO-d6): 1.62 (s, 3H), 1.71 (s, 3H), 3.23 (d, J=6.4 Hz, 2H), 3.68 (s, 3H), 3.86 (s, 3H), 3.90 (s, 3H), 5.10 (t, J=6.4 Hz, 1H), 6.98 (d, J=16.0 Hz, 1H), 7.18 (s, 1H), 7.28 (t, J=7.2 Hz, 1H), 7.30 (d, J=16.0 Hz, 1H), 7.38 (t, J=7.2 Hz, 2H), 7.53 (d, J=7.2 Hz, 2H).