Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:18]=[C:17]3[N:19]([CH:23]4[CH2:28][CH2:27][CH2:26][CH2:25][O:24]4)[N:20]=[C:21]([CH3:22])[C:16]3=[C:15]([CH2:29][N:30]3[CH2:35][C:34]([CH3:37])([CH3:36])[NH:33][CH2:32][C:31]3([CH3:39])[CH3:38])[CH:14]=2)=[CH:9][CH:8]=1.[CH3:40][O:41][CH2:42][C:43](Cl)=[O:44]>C1COCC1>[CH3:40][O:41][CH2:42][C:43]([N:33]1[CH2:32][C:31]([CH3:39])([CH3:38])[N:30]([CH2:29][C:15]2[CH:14]=[C:13]([C:10]3[CH:9]=[CH:8][C:7]([O:6][CH2:5][O:4][CH3:3])=[CH:12][CH:11]=3)[N:18]=[C:17]3[N:19]([CH:23]4[CH2:28][CH2:27][CH2:26][CH2:25][O:24]4)[N:20]=[C:21]([CH3:22])[C:16]=23)[CH2:35][C:34]1([CH3:37])[CH3:36])=[O:44]
Reactant: COCC(=O)Cl
Reactant: COCOc1ccc(-c2cc(CN3CC(C)(C)NCC3(C)C)c3c(C)nn(C4CCCCO4)c3n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCOc1ccc(-c2cc(CN3CC(C)(C)N(C(=O)COC)CC3(C)C)c3c(C)nn(C4CCCCO4)c3n2)cc1
Yield: 102.4 %

Procedure:
To 16 mg sodium hydride (60% in mineral oil) in 2 ml of abs. THF were added 80 mg of 6-(4-methoxymethoxy-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-4-(2,2,5,5-tetramethyl-piperazin-1-ylmethyl)-1H-pyrazolo[3,4-b]pyridine and after 10 min 17 mg of 2-methoxyacetyl chloride were added. After 16 h at rt the reaction was quenched by the addition of water, the layers were separated and the aqueous layer was extracted with ethyl acetate twice. The combined organic layers were dried and concetrated in vacuo. 93 mg of the title compound were obtained.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]1[N:11]2[CH:12]=[C:13]([O:16][C@H:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C@@H:20]([NH2:27])[CH2:19][CH2:18]3)[CH:14]=[CH:15][C:10]2=[N:9][N:8]=1.ClC(Cl)(Cl)C[O:31][C:32](=O)[NH:33][C:34]1[N:35]([C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([S:49][CH2:50][CH2:51][OH:52])[CH:44]=2)[N:36]=[C:37]([C:39]([CH3:42])([CH3:41])[CH3:40])[CH:38]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:39]([C:37]1[CH:38]=[C:34]([NH:33][C:32]([NH:27][C@@H:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:17]([O:16][C:13]3[CH:14]=[CH:15][C:10]4[N:11]([C:7]([C@@H:3]5[CH2:4][CH2:5][CH2:6][N:2]5[CH3:1])=[N:8][N:9]=4)[CH:12]=3)[CH2:18][CH2:19]2)=[O:31])[N:35]([C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([S:49][CH2:50][CH2:51][OH:52])[CH:44]=2)[N:36]=1)([CH3:42])([CH3:40])[CH3:41]
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cccc(SCCO)c2)n1
Reactant: CN1CCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CN1CCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(SCCO)c4)c4ccccc43)cn12
Temperature: 90 °C
Reaction time: 4 h

Procedure:
A mixture of Intermediate 5c (109 mg, 0.3 mmol) and Intermediate 35c (140 mg, 0.3 mmol) in 1,4-dioxane (3 mL) and DIPEA (78 μL, 0.45 mmol) was stirred at 90° C. for 4 h. The cooled mixture was concentrated in vacuo. The residue was purified by FCC, using 0-14% MeOH in DCM, to give the title compound as an off-white powder after freeze-drying (115 mg, 56%). LCMS (Method 5): Rt 3.47 min, m/z 681 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.28 (9H, s), 1.83-2.26 (11H, m), 2.31-2.39 (1H, m), 3.04 (2H, t, J 6.8), 3.09 (1H, m), 3.59 (2H, q, J 6.0), 3.99 (1H, t, J 8.2), 4.78-4.86 (1H, m), 4.95 (1H, t, J 5.6), 5.36-5.41 (1H, m), 6.33 (1H, s), 7.08 (1H, d, J 8.4), 7.24-7.46 (9H, m), 7.75 (1H, d, J 9.6), 8.12 (1H, s), 8.25 (1H, br d).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:10]([OH:13])=[CH:11][N:12]=1)[C:8]#[N:9])([CH3:4])([CH3:3])[CH3:2].[CH3:14]CN(C(C)C)C(C)C.C[Si](C=[N+]=[N-])(C)C>CC#N.CO>[C:1]([C:5]1[CH:6]=[C:7]([C:10]([O:13][CH3:14])=[CH:11][N:12]=1)[C:8]#[N:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(C#N)c(O)cn1
Reactant: CCN(C(C)C)C(C)C
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CC#N
Solvent: CO
Product: COc1cnc(C(C)(C)C)cc1C#N
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.9 %

Procedure:
To a solution of 10.0 g (73.5 mmol) of 2-tert-Butyl-5-hydroxy-isonicotinonitrile ((a) J. Med. Chem. 1981, 24, 115 (b) U.S. Pat. No. 4,123,537) in MeCN/MeOH (9:1, 20 mL) was added iPr2NEt (1.48 mL, 8.52 mmol) followed by (trimethylsilyl)diazomethane (2.0 M in hexane, 4.30 mL, 8.52 mmol). The red solution was stirred 18 h at rt then concentrated. The residue was dissolved in CH2Cl2, washed with saturated NaHCO3, dried over Na2SO4, filtered, and concentrated to provide 2-tert-Butyl-5-methoxy-isonicotinonitrile (1.10 g, 99%) as a pale yellow oil which was utilized without further purification.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:12]([O-:14])=[O:13])[CH:9]=2)[CH2:4]1.C(N(CC)CC)C.[Cl:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=[O:27].O>C(Cl)Cl>[Cl:22][C:23]1[CH:24]=[C:25]([C:26]([NH:2][CH:3]2[CH2:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([N+:12]([O-:14])=[O:13])[CH:9]=3)[CH2:4]2)=[O:27])[CH:29]=[CH:30][CH:31]=1
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: NC1Cc2ccc([N+](=O)[O-])cc2C1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C(NC1Cc2ccc([N+](=O)[O-])cc2C1)c1cccc(Cl)c1

Procedure:
To 2-amino-5-nitroindane hydrochloride (1.5 g, 7.0 mmol) in methylene chloride (50 ml) at 0° C. was added triethylamine (2.1 ml, 15.0 mmol) followed by 3-chlorobenzoyl chloride (1.0 ml, 7.5 mmol). The mixture was dumped immediately into water and the layers separated. The aqueous layer was extracted with methylene chloride (2×20 ml) and the combined extracts washed with water, dried over MgSO4, filtered, and concentrated to an oil which was homogeneous by TLC and used immediately in the next step: M.S. (M+H)+ =317.
Reaction SMILES: [C:1]1(=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9](=[O:17])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:19](O)[CH2:20][OH:21].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[O:18]1[C:1]2([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9](=[O:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]2)[O:21][CH2:20][CH2:19]1
Reactant: O=C1CCCCCCCC(=O)CCCCCCC1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1CCCCCCCC2(CCCCCCC1)OCCO2

Procedure:
To a solution of 44.0 g (175 mmol) of 1,9-cyclohexadecanedione in 125 ml of toluene is added 13.1 g (210 mmol) of ethylene glycol and 500 mg (2.5 mmol) of p-toluenesulphonic acid. The mixture is then heated with a water separator until visible amounts of water are no longer eliminated. Washing with sat. NaHCO3 solution is then carried out, the phases are separated, the organic phase is dried over Na2SO4, filtration is carried out, and the solvent is removed on a rotary evaporator. This gives 57.7 g of a solid comprising 3 components having the following GC content: 1,9-cyclohexadecanedione (33.7%); 1,4-dioxaspiro-[4.15]-eicosan-13-one (52.5%); 1,4,14,17-tetraoxadispiro-[4.7.4.7]-tetracosane (13.2%).
Reaction SMILES: C[Si](C)(C)CC[O:5][C:6](=[O:12])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].C1COCC1.[OH2:20].[OH2:21].[OH2:22].[F-].[CH2:24]([N+:28](CCCC)(CCCC)CCCC)[CH2:25]CC.[OH2:41]>C(#N)C>[OH:12][CH:6]1[O:5][C@H:10]([CH2:11][OH:22])[C@H:9]([OH:21])[C@H:8]([OH:20])[C@H:7]1[NH:28][C:24]([CH3:25])=[O:41]
Reactant: O
Reactant: CCCCCC(=O)OCC[Si](C)(C)C
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC#N
Product: CC(=O)N[C@H]1C(O)O[C@H](CO)[C@H](O)[C@@H]1O

Procedure:
The above compound was prepared as above using (S)-2-amino-6-(E)-hexadec-8-enoylamino)-hexanoic acid 2-trimethylsilanyl-ethyl ester and cleaving the protecting group as follows: After the penultimate step, the resultant 2-trimethylsilanyl-ethyl ester (245 mg, 0.107 mmol, Eq: 1.00) was combined with THF abs, (5 mL) to give a colorless solution. Tetrabutyl-ammonium fluoride trihydrate (168 mg, 0.533 mmol, Eq: 5.00) was added at 0° C. and the reaction was stored in the fridge over night. Pouring onto crushed ice, extraction with ethyl acetate, washing with water, drying over Na2SO4, and evaporation of all solvents yielded a sticky oil. Dissolution in acetonitrile and water and lyophilization afforded eventually 0.120 g of the title compound as white solid, MS (ISP): 112.5 [M+2Na]2+/2.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:47])[N:20]([CH2:39][CH2:40][N:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:47])[N:20]([CH2:39][CH2:40][N:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:28][CH:29]=1)[CH2:14][CH2:15][CH3:16]
Reactant: [NH3+]O
Reactant: CCCCc1nc(C)n(CCN2CCOCC2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(CCN2CCOCC2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 38.5 %

Procedure:
A mixture of hydroxylammonium chloride (2.9 g), sodium hydrogen carbonate (4.77 g) and dimethyl sulfoxide (30 mL) was stirred at 40° C. for 30 min, 4′-{[4-butyl-2-methyl-1-(2-morpholin-4-ylethyl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.34 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.55 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.47 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was adjusted to pH 5 with water and 1 M hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.58 g, 39%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])[CH3:2].I[CH2:12][CH3:13].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:12][CH3:13])[CH3:2]
Reactant: CCI
Reactant: CCOc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOc1ccccc1OCC
Temperature: 80 °C
Reaction time: 30 h

Procedure:
15.0 g of 2-ethoxyphenol, 18.0 ml of iodoethane and 30.0 g of potassium carbonate were suspended in 150 ml dimethylformamide, and the mixture was stirred at 80° C. for 30 hours. Ethyl acetate was added thereto, and the mixture was washed with water for five times and with brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated to give the title compound quantitatively as a red-brown oil.
Reaction SMILES: [OH:1][C:2]([CH3:28])([CH3:27])[CH2:3][N:4]1[CH2:8][C@H:7]([C:9]2[CH:14]=[C:13]([CH3:15])[N:12]([CH2:16][C:17]([OH:19])=O)[C:11](=[O:20])[CH:10]=2)[C@H:6]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:5]1.Cl.Cl.[NH2:31][CH2:32][C:33]1[CH:34]=[C:35]2[C:39](=[N:40][CH:41]=1)[NH:38][CH:37]=[C:36]2[F:42].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.C(Cl)CCl>CN(C=O)C>[OH:1][C:2]([CH3:27])([CH3:28])[CH2:3][N:4]1[CH2:8][C@H:7]([C:9]2[CH:14]=[C:13]([CH3:15])[N:12]([CH2:16][C:17]([NH:31][CH2:32][C:33]3[CH:34]=[C:35]4[C:39](=[N:40][CH:41]=3)[NH:38][CH:37]=[C:36]4[F:42])=[O:19])[C:11](=[O:20])[CH:10]=2)[C@H:6]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:5]1
Reactant: NCc1cnc2[nH]cc(F)c2c1
Reactant: Cc1cc([C@H]2CN(CC(C)(C)O)C[C@H]2c2ccccc2)cc(=O)n1CC(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc([C@H]2CN(CC(C)(C)O)C[C@H]2c2ccccc2)cc(=O)n1CC(=O)NCc1cnc2[nH]cc(F)c2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 4-(1-(2-hydroxy-2-methylpropyl)-cis-3-phenylpyrrolidin-4-yl)-6-methyl-1-carboxymethyl-2-pyridinone from step 8 above (0.23 mmol), 5-aminomethyl-3-fluoro-7-azaindole bis hydrochloride (55 mg, 0.23 mmol), HOBT (35 mg, 0.23 mmol) and DIEA (0.12 mL, 0.69 mmol) in DMF (2 mL) was added EDC (134 mg, 0.46 mmol). The resulting solution was stirred at ambient temperature for 18 h. The solvent was removed in vacuo and the residue was purified by flash column chromatography using a gradient elution of 96:4 to 92:8 CH2Cl2:MeOH as eluant to give the title compound as an amorphous solid (0.1 g, TLC Rf=0.4, 92:8 CH2Cl2:MeOH; HPLC RT=4.71 min, method A).
Reaction SMILES: C(O[C:4](=[NH:20])[C:5]1[CH:10]=[CH:9][C:8]([S:11](=[O:19])(=[O:18])[NH:12][C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[CH:7][CH:6]=1)C.[NH2:21][NH2:22].[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[Cl:32])[CH:27]=O.C(O)(=O)C>C(O)C>[S:14]1[CH:15]=[CH:16][N:17]=[C:13]1[NH:12][S:11]([C:8]1[CH:7]=[CH:6][C:5]([C:4]([NH:21][N:22]=[CH:27][C:26]2[CH:29]=[CH:30][C:31]([Cl:32])=[C:24]([Cl:23])[CH:25]=2)=[NH:20])=[CH:10][CH:9]=1)(=[O:18])=[O:19]
Reactant: NN
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: CCOC(=N)c1ccc(S(=O)(=O)Nc2nccs2)cc1
Solvent: CCO
Solvent: CC(=O)O
Product: N=C(NN=Cc1ccc(Cl)c(Cl)c1)c1ccc(S(=O)(=O)Nc2nccs2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-(thiazol-2-ylsulfamoyl)-benzimidic acid ethyl ester (0.965 mmol) and hydrazine (0.5 mL) was stirred for 10 min. in ethanol (5 mL) at room temperature. The solution was concentrated in vacuo and DMF (5 mL) was added followed by the addition of 3,4-dichloro-benzaldehyde (1.06 mmol). Acetic acid (1 mL) was added and the solution was stirred for 2 h at room temperature. The solution was quenched with sat NaHCO3, extracted with ethyl acetate, washed with brine and dried with MgSO4. The reaction was concentrated in vacuo and that material was purification by column chromatography to yield 4-(thiazol-2-ylsulfamoyl)-N-(3,4-Dichloro-benzylideneamino)-benzamidine (0.39 mmol).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9]Cl)=[N:7][CH:8]=1.[OH:11][N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22].C(N(CC)C(C)C)(C)C>C(#N)C.O>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][O:11][N:12]2[C:16](=[O:17])[C:15]3[C:14](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:13]2=[O:22])=[N:7][CH:8]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: ClCc1ccc(Br)cn1
Agent: Cl
Solvent: CC#N
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1c2ccccc2C(=O)N1OCc1ccc(Br)cn1
Temperature: 65 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
To a mixture of 5-Bromo-2-chloromethyl-pyridine hydrochloride (63.7 g, 0.262 mol) and N-hydroxylphthalimide (64 g, 0.393 mol) in acetonitrile (400 mL) was placed in water bath and added N,N-diisopropylethylamine (182 mL, 1.05 mol) using dropping funnel for 10 min. It was heated at 65° C. for 4 hrs and evaporated off the solvent and extra base. Then, water (100 mL) was added to the reaction mixture and stirred for overnight. The resulting solid was filtered, washed with water (2×50 mL) and acetonitrile (100 mL). The white solid was dried on vacuum pump to provide the title compound (84.2 g, 84%) as a white solid. MS-ESI m/z 334.95 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1Cl.[CH3:12][C@H:13]1[CH2:18][NH:17][CH2:16][C@@H:15]([CH3:19])[NH:14]1.C(N(CC)CC)C>CCO>[Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:17]1[CH2:16][C@H:15]([CH3:19])[NH:14][C@H:13]([CH3:12])[CH2:18]1
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Solvent: CCO
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(c2ccc([N+](=O)[O-])cc2Cl)C[C@H](C)N1

Procedure:
1.0 g (5.21 mmol) of 3,4-dichloronitrobenzene (Fluka, Buchs, Switzerland), 624 mg (5.47 mmol) cis-2,6-dimethylpiperazine (Aldrich, Buchs, Switzerland) and 580 mg (5.73 mmol) triethylamine in 20 ml of EtOH are heated in a microwave oven at 170° C. for 6 h and 180° C. for 2 h. The reaction mixture is evaporated to dryness and then taken in EtOAc. The organic layers is extracted with 1 M aqueous HCl(5×) and the combined aqueous layers are basified with NaHCO3 and extracted with CH2Cl2 (3×), washed with brine, dried over MgSO4, filtered and evaporated to dryness to give the title compound as a yellow solid. ES-MS: 270 (M+H)+; analytical HPLC: tret=2.72 minutes (Grad 1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:13]2([C:19]([O:21][CH3:22])=[O:20])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[H-].[Na+].[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([N:12]([CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:13]2([C:19]([O:21][CH3:22])=[O:20])[CH2:14][CH2:15][N:16]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:17][CH2:18]2)(=[O:11])=[O:10])=[CH:7][CH:8]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)C1(N(Cc2ccccc2)S(=O)(=O)c2ccc(OC)cc2)CCNCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1(N(Cc2ccccc2)S(=O)(=O)c2ccc(OC)cc2)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-[[4-methoxybenzenesulfonyl](benzyl)amino]-4-[carbomethoxy]-piperidine (1.0 g, 2.39 mmol) in dimethylformamide (160 mL) is added sodium hydride (287.0 mg, 7.18 mmol, 60% in oil) at 0° C., followed by benzyl bromide (450.0 mg, 2.63 mmol). The reaction mixture is slowly warmed to room temperature and stirred overnight. The mixture is quenched with water and extracted with ethyl acetate. The combined organic layers are washed with brine, dried (Na2SO4) and the solvent is evaporated to give 4-[[4-methoxybenzenesulfonyl](benzyl)amino]- 1-[benzyl]-4-[carbomethoxy]-piperidine.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[CH3:15][O:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19][NH2:20].[S:25]1[CH:29]=[CH:28][N:27]=[C:26]1[CH:30]=O>>[CH3:15][O:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19][NH:20][C:8]1[CH:7]=[CH:6][C:5]2[C:4]([NH:1][CH2:30][C:26]3[S:25][CH:29]=[CH:28][N:27]=3)=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: COc1ccccc1CN
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Reactant: O=Cc1nccs1
Product: COc1ccccc1CNc1ccc2c(NCc3nccs3)cccc2n1

Procedure:
The title compound, MS: m/e=377.4 (M+H+), was prepared from 5-nitro-2-chloroquinoline, 2-methoxybenzylamine and thiazole-2-carbaldehyde as described in example 26.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.[CH3:12][O-:13].[Na+].O>CO>[F:9][C:8]([F:11])([F:10])[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([O:13][CH3:12])[CH:7]=1
Reactant: FC(F)(F)c1ccnc(Cl)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc(C(F)(F)F)ccn1
Yield: 85.1 %

Procedure:
A solution having 5.05 g (27.8 mmol) of 2-chloro-4-trifluoromethylpyridine and 3.59 g (66.5 mmol) of sodium methoxide dissolved in 40 ml of methanol was stirred under reflux with heating for 4 hours. Water was added to terminate the reaction, followed by extraction with diethyl ether. The organic layer was dried over anhydrous sodium sulfate and subjected to filtration on the pad of a silica gel cake. The solvent was distilled off under reduced pressure to obtain 4.19 g (yield: 85%) of 4-trifluoromethyl-2-methoxypyridine.
Reaction SMILES: C([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([C:13]#[N:14])=[C:6]2[O:15][CH:16]([C:21]([F:24])([F:23])[F:22])[C:17]([F:20])([F:19])[F:18])=O.COC1C=CC(/[CH:39]=[C:40]2/[C:41]([NH:43][C:44]([S:46]/2)=[NH:45])=[O:42])=CC=1OC1CCCC1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[NH2:45][C:44]1[S:46]/[C:40](=[CH:39]\[C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[N:9]=[CH:8][C:7]([C:13]#[N:14])=[C:6]3[O:15][CH:16]([C:17]([F:20])([F:18])[F:19])[C:21]([F:22])([F:23])[F:24])/[C:41](=[O:42])[N:43]=1
Reactant: N#Cc1cnc2ccc(C=O)cc2c1OC(C(F)(F)F)C(F)(F)F
Reactant: COc1ccc(/C=C2\SC(=N)NC2=O)cc1OC1CCCC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: N#Cc1cnc2ccc(/C=C3\SC(N)=NC3=O)cc2c1OC(C(F)(F)F)C(F)(F)F

Procedure:
Similar procedure as described in example 38 was used, starting from 6-formyl-4-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-quinoline-3-carbonitrile (example 45b), pseudothiohydantoin, sodium acetate and acetic acid to give 6-[2-amino-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-4-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-quinoline-3-carbonitrile. LC-MS m/e 447 (MH+).
Reaction SMILES: ClCCl.[F:4][C:5]([F:16])([F:15])[C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9](Cl)=[O:10].C(Cl)(Cl)Cl.[Cl:21][C:22]1[CH:39]=[CH:38][C:25]([CH2:26][N:27]2[CH2:31][CH2:30][CH:29]([CH2:32][NH:33][C:34](=[O:37])[CH2:35][NH2:36])[CH2:28]2)=[CH:24][CH:23]=1>CO>[F:4][C:5]([F:16])([F:15])[C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([NH:36][CH2:35][C:34]([NH:33][CH2:32][CH:29]1[CH2:30][CH2:31][N:27]([CH2:26][C:25]2[CH:38]=[CH:39][C:22]([Cl:21])=[CH:23][CH:24]=2)[CH2:28]1)=[O:37])=[O:10]
Reactant: NCC(=O)NCC1CCN(Cc2ccc(Cl)cc2)C1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: CO
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NCC1CCN(Cc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A dichloromethane (0.2 mL) solution of 3-(trifluoromethyl)benzoyl chloride (0.058 mmol) was added to a mixture of a chloroform (0.2 m-L) solution of 1-(4-chlorobenzyl)-3-[(glycylamino)methyl]pyrrolidine (0.050 mmol) with a dichloromethane (1 mL) solution of a piperidinomethylpolystyrene (60 mg). The resulting reaction mixture was stirred at room temperature for 2.5 hours, and methanol (0.30 mL) was then added. The reaction mixture was loaded onto a Varian™ SCX column and washed with methanol (15 mL). The obtained crude product was eluted with a methanol (5 mL) solution of 2 M NH3 and concentrated to thereby provide 3-[[N-[3-trifluoromethylbenzoyl]glycyl]aminomethyl]-1-(4-chlorobenzyl)pyrrolidine (Compd. No. 1463) (22.4 mg, 99%). The purity was determined by RPLC/MS (97%). ESI/MS m/e 454.2 (M++H, C22H23ClF3N3O2).
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[F-:12].[K+]>[Br-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(#N)C.CCOCC>[F:12][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: [F-]
Reactant: Cc1cc([N+](=O)[O-])cnc1Cl
Agent: [Br-]
Agent: [K+]
Agent: c1ccc([P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CC#N
Product: Cc1cc([N+](=O)[O-])cnc1F
Yield: 61.9 %

Procedure:
2-Chloro-3-methyl-5-nitropyridine (15 g, 86.9 mmol; from Maybridge Chemical Co.), KF (12 g, 258 mmol) and tetraphenylphosphonium bromide (20 g, 47.7 mmol; Aldrich) were combined in 200 mL of acetonitrile and heated at reflux for 4 days. The mixture was diluted with Et2O (500 mL) and filtered, and the filtrate was concentrated. The residue was triturated with hot hexane (4×200 mL), and the hexane solutions were combined and concentrated to afford the title compound as a solid (8.4 g, 60%): 1H NMR (DMSO-d6, 300 MHz) δ2.42 (s, 3H), 8.43 (m, 1H), 8.95 (dd, J=1.6 Hz, 1H); MS (CI/NH3) m/z: 157 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[S:10][C:9]([CH:11]=[C:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:33]2[CH:41]=[CH:40][CH:39]=[C:38]3[C:34]=2[CH:35]=[N:36][NH:37]3)O1>>[NH:37]1[C:38]2[C:34](=[C:33]([C:2]3[N:3]=[C:4]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[C:5]4[S:10][C:9]([CH:11]=[C:12]5[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]5)=[CH:8][C:6]=4[N:7]=3)[CH:41]=[CH:40][CH:39]=2)[CH:35]=[N:36]1
Reactant: CN1CCC(=Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Product: CN1CCC(=Cc2cc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3s2)CC1

Procedure:
2-Chloro-6-(1-methyl-piperidin-4-ylidenemethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine was reacted with 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole in general procedure A. Purification on silica yielded 181. NMR: (CDCl3) 2.37 (3H, s); 2.55 (6H, m); 2.82 (2H, t, J=5.5 Hz); 3.93 (4H, t, J=4.8 Hz); 4.10 (4H, t, J=4.8 Hz); 6.44 (1H, s); 7.33 (1H, s); 7.51 (1H, s); 7.60 (1H, d, J=8.2 Hz); 8.28 (1H, d, J=7.1 Hz); 9.03 (1H, s); 10.25 (br s). M+H (447)