Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:14]#[CH:15])[CH:8]=2)[S:3]1.I[C:17]1[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=1.C(Cl)Cl>C(N(CC)CC)C>[CH2:24]([O:23][C:21](=[O:22])[C:20]1[CH:26]=[CH:27][C:17]([C:15]#[C:14][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[S:3][CH:2]([CH3:1])[CH2:11][C:10]3([CH3:12])[CH3:13])=[CH:18][CH:19]=1)[CH3:25]
Reactant: C#Cc1ccc2c(c1)C(C)(C)CC(C)S2
Reactant: CCOC(=O)c1ccc(I)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CC(C)S3)cc1
Temperature: 55 °C
Reaction time: 72 h

Procedure:
A solution of 55 mg (0.26 mmol) of 2,4,4-trimethyl-6-ethynyl-thiochroman (Compound 55) and 70.5 mg (0.26 mmol) of ethyl 4-iodo benzoate (29) in 1.5 ml of distilled triethylamine was placed in a heavy walled tube. Argon was bubbled through the mixture for 20 minutes under slightly reduced pressure. To the mixture was added 18 mg (0.051 mmol) of bis triphenylphosphine palladium (II) chloride and 9.7 mg (0.051 mmol) of cuprous iodide. The tube was then sealed and the mixture was stirred at 55 degrees C. for 72 hours. The mixture was then cooled to room temperature. The reaction mixture was diluted wth CH2Cl2 and treated with a small amount of silica. The solvent was then removed in-vacuo and the residue was subjected to flash chromatography (silica; 1.5% EtOAc/Hexanes) to give the title compound as a white crystalline solid. PMR(CdCl3): 1.25 (3H, s), 1.35 (3H, d, J=6.6 Hz), 1.37-1.44 (6H, m), 1.75 (1H, t, J=13 Hz), 1.88 (1H, dd, J=13 Hz, 3.5 Hz), 3.40-3.50 (1H, m), 4.38 (2H, q, J=7Hz), 7.17 (1H, dd, J=8.1 Hz, 1.8 Hz), 7.26 (1H, d, J=1.5 Hz), 7.33 (1H, J=8.1 Hz), 7.55 (2H, d, J=8.4 Hz, 8.01 (2H, d, J=8.4 Hz).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]3[CH:18]=[CH:17][S:16][CH:15]=3)[CH:12]=2)[CH:7]=[N:6]1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+].[CH3:27][NH:28][CH3:29]>C(#N)C.ClCCl>[CH3:27][N:28]([CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]3[CH:18]=[CH:17][S:16][CH:15]=3)[CH:12]=2)[CH:7]=[N:6]1)[CH3:29]
Reactant: CNC
Reactant: ClCCCn1ncc2ccc(-c3ccsc3)cc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: CN(C)CCCn1ncc2ccc(-c3ccsc3)cc21
Temperature: 25 °C
Yield: 95.3 %

Procedure:
A mixture of 1-(3-chloropropyl)-6-(3-thienyl)-1H-indazole (27.8 mg, 0.10 mmol), potassium iodide (155 mg, 1 mmol), potassium carbonate (130 mg, 1 mmol), and dimethylamine (2M in THF, 0.5 mL, 1 mmol) in acetonitrile (0.5 mL) was heated at reflux overnight. After cooling to room temperature, the mixture was diluted with dichloromethane (5 mL) and filtered through a small plug of alumina to remove the solids, rinsing with dichloromethane (10 mL). After removal of the solvent in vacuo, flash chromatography (silica gel, 2.5-5% 2M methanolic ammonia in dichloromethane) yielded 1-(3-(N,N-dimethylamino)propyl)-6-(3-thienyl)-1H-indazole (27.2 mg, 95%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[NH:11][CH2:12][C:13]([NH2:15])=[O:14])=[CH:4][CH:3]=1.[F:16][C:17]([F:28])([F:27])[C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>CC#N.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>[F:16][C:17]([F:28])([F:27])[C:18]1[CH:23]=[C:22]([C:2]2[CH:7]=[CH:6][C:5]([C@@H:8]3[CH2:10][C@H:9]3[NH:11][CH2:12][C:13]([NH2:15])=[O:14])=[CH:4][CH:3]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: NC(=O)CN[C@@H]1C[C@H]1c1ccc(Br)cc1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
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: [K+]
Solvent: O
Solvent: CC#N
Product: NC(=O)CN[C@@H]1C[C@H]1c1ccc(-c2cccc(C(F)(F)F)c2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 80.8 %

Procedure:
A solution of 2-((trans)-2-(4-bromophenyl)cyclopropylamino)acetamide (100 mg, 0.37 mmol, 1 equiv), 3-trifluoro methyl benzene boronic acid (84 mg, 0.44 mmol 1.2 equiv), K2CO3 (152 mg, 1.11 mmol, 3 equiv) in CH3CN+H2O (4:1) (2 mL) was degassed for 30 min with Argon gas, then Pd(PPh3)4 (0.1 equiv) was added and the reaction mixture was heated at reflux temp. for 2 h. After completion, the reaction mixture was poured into ice water (10 mL), extracted with EtOAc (2×10 mL). The combined extracts were washed with water (10 mL), brine (10 mL), dried over anhydrous Na2SO4, filtered and evaporated. The crude residue was purified by prep HPLC to give 2-((trans)-2-(3′-(trifluoromethyl)biphenyl-4-yl)cyclopropylamino)acetamide (100 mg, 80% yield) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].[Cl:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]2[N:21]([S:40]([C:43]3[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=3)(=[O:42])=[O:41])[C:22]([C:24]3[C:28]4=[N:29][C:30]([O:35][CH3:36])=[C:31]([O:33][CH3:34])[CH:32]=[C:27]4[N:26]([CH2:37][CH2:38]I)[CH:25]=3)=[CH:23][C:16]=12>CC#N>[Cl:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]2[N:21]([S:40]([C:43]3[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=3)(=[O:42])=[O:41])[C:22]([C:24]3[C:28]4=[N:29][C:30]([O:35][CH3:36])=[C:31]([O:33][CH3:34])[CH:32]=[C:27]4[N:26]([CH2:37][CH2:38][N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)[CH:25]=3)=[CH:23][C:16]=12
Reactant: CN1CCNCC1
Reactant: COc1cc2c(nc1OC)c(-c1cc3c(Cl)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc2c(nc1OC)c(-c1cc3c(Cl)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2CCN1CCN(C)CC1
Temperature: 60 °C
Yield: 167.9 %

Procedure:
Add 1-methylpiperazine (3.5 equiv., 35.2 mg, 39.1 μmol, 0.352 mmol) and K2CO3 (13.8 mg, 0.10 mmol) to bisazaindole 32 (64 mg, 0.10 mmol) in CH3CN (6.0 mL). After heating at 60° C. for 48 h, the reaction medium is concentrated under vacuum and the residue of raw product is submitted to flash chromatography on SiO2 (MeOH at 2-4%/CH2Cl2/heptane) to give 35 (40 mg, 64.3%) as a white solid: 1H NMR (CDCl3) δ 8.23 (d, 1H, J=5.4 Hz), 7.68 (d, 2H, J=8.1 Hz), 7.61 (s, 1H), 7.10 (m, 5H), 4.25 (t, 2H, J=6.6 Hz), 4.01 (s, 3H), 3.97 (s, 3H), 2.83 (t, 2H, J=6.9 Hz), 2.57-2.46 (m broad, 8H), 2.28 (s, 3H), TLC (MeOH at 10%/CH2Cl2, 0.25% of NH3) Rf=0.45, m/z obs.=609.04 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:14]([SH:17])([CH3:16])[CH3:15])[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[Na+].Br[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CC#N>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C:14]([CH3:16])([S:17][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH3:15])[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)S
Reactant: BrCCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)SCCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 45 %

Procedure:
To a CH3CN (50 mL) solution containing methyl (2R)-2-[(tert-butoxycarbonyl)amino]-3-mercapto-3-methylbutanoate (as described above) (1.26 g, 4.78 mmol, 1.0 eq) was added sodium tert-butoxide (597 mg, 6.21 mmol, 1.3 eq). The resulting pale yellow mixture was allowed to stir at RT for 10 min at which time (2-bromoethyl)benzene (718 μL, 5.26 mmol, 1.1 eq) was added. The resulting solution was allowed to stir at RT for 18 hr. The reaction was then quenched with a sat NH4Cl solution, poured into H2O, and extracted (2×) with EtOAc. Combined extracts were dried over MgSO4 and concentrated in vacuo. Purified via flash chromatography using 5:1 hexanes/EtOAc as the mobile phase. Isolated 761 mg (2.07 mmol, 45% yield).
Reaction SMILES: [CH:1]([S:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:8](O)=[O:9])([CH3:3])[CH3:2].CN(C)C=O.S(Cl)([Cl:23])=O>C1(C)C=CC=CC=1>[CH:1]([S:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:8]([Cl:23])=[O:9])([CH3:3])[CH3:2]
Reactant: COc1ccc(C(=O)O)cc1SC(C)C
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Cl)cc1SC(C)C
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A solution of 3-isopropylthio-4-methoxybenzoic acid (2.5 g; that is prepared as described in Reference Example 49) in toluene (25 mL) and dimethylformamide (0.2 mL) is treated with thionyl chloride (2.5 mL) and the solution is stirred at 60° C. for 3 hours. The solution is concentrated, treated with toluene (10 mL) and again evaporated to dryness, to give 3-isopropylthio-4-methoxybenzoyl chloride (2.7 g), in the form of a light brown oil.
Reaction SMILES: C([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][C@@H:13]([C:15](=[O:19])[N:16]([CH3:18])[CH3:17])[CH2:12][CH2:11][C@@H:10]1[NH:20][C:21]([C:23]1[NH:24][C:25]2[C:30]([CH:31]=1)=[C:29]([F:32])[CH:28]=[C:27]([Cl:33])[CH:26]=2)=[O:22])=O)(C)(C)C.[ClH:34].[CH3:35][N:36]1[CH2:41][CH2:40][C:39]2[N:42]=[C:43](C([O-])=O)[S:44][C:38]=2[CH2:37]1.[Li+]>O1CCOCC1>[ClH:33].[Cl:34][C:28]1[C:29]([F:32])=[C:30]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23]([C:21]([NH:20][C@H:10]1[CH2:11][CH2:12][C@H:13]([C:15](=[O:19])[N:16]([CH3:18])[CH3:17])[CH2:14][C@H:9]1[NH:8][C:6]([C:43]1[S:44][C:38]3[CH2:37][N:36]([CH3:35])[CH2:41][CH2:40][C:39]=3[N:42]=1)=[O:5])=[O:22])=[CH:31]2
Reactant: CN1CCc2nc(C(=O)[O-])sc2C1
Reactant: CN(C)C(=O)[C@H]1CC[C@H](NC(=O)c2cc3c(F)cc(Cl)cc3[nH]2)[C@H](NC(=O)OC(C)(C)C)C1
Agent: Cl
Agent: [Li+]
Solvent: C1COCCO1
Product: CN1CCc2nc(C(=O)N[C@@H]3C[C@@H](C(=O)N(C)C)CC[C@@H]3NC(=O)c3cc4c(F)c(Cl)ccc4[nH]3)sc2C1

Procedure:
(1S,2R,4S)-N2-(tert-Butoxycarbonyl)-N1-[(6-chloro-4-fluoroindol-2-yl)carbonyl]-4-(N,N-dimethylcarbamoyl)-1,2-cyclohexanediamine was treated with a 4N dioxane solution of hydrochloric acid and then condensed with lithium 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate in a similar manner to Example 118 to obtain the title compound.
Reaction SMILES: [C:1]([N:4]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:8]([CH2:16][OH:17])[C:7](=[O:18])[CH2:6][O:5]1)(=[O:3])[CH3:2].[O:19]1CC[CH2:21][CH2:20]1.C(Cl)(=O)C>C(N(CC)CC)C>[C:1]([N:4]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:8]([CH2:16][O:17][C:20](=[O:19])[CH3:21])[C:7](=[O:18])[CH2:6][O:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1OCC(=O)N(CO)C1c1ccccc1
Reactant: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CC(=O)Cl
Product: CC(=O)OCN1C(=O)CON(C(C)=O)C1c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
To a solution of 1.0 g. (4 mmoles) of 2-acetyl-3-phenyl-4-hydroxymethyl-tetrahydro-1,2,4-oxadiazin-5-one in 10 ml. of dry tetrahydrofurane 0.72 ml. of dry triethyl amine are added. The solution is cooled to 0° C. and 0.36 ml. (0.40 g., 5 mmoles) of acetyl chloride are added dropwise at this temperature. The mixture is stirred at room temperature for two hours, the precipitated triethyl amine hydrochloride is filtered off and the filtrate is evaporated to dryness. The residue is dissolved in 10 ml. of ethyl acetate, the solution is shaken with 3 ml. of a 1 N aqueous sodium hydrocarbonate solution, 3 ml. of a 1 N aqueous hydrochloric acid solution and finally with two 3-ml. portions of water, whereupon it is dried with anhydrous sodium sulfate and evaporated to dryness. The residue is recrystallized from a mixture of 3 ml. of diethyl ether and 6 ml. of n-hexane. 0.90 g. (77%) of 2-acetyl- 3-phenyl-4-acetoxymethyl-tetrahydro-1,2,4-oxadiazin-5-one are obtained, melting at 75° C. to 76° C. RfA =0.7.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:14]3[C:9]([O:10][CH2:11][CH2:12][CH2:13]3)=[C:8]([CH:15]=O)[C:7]=2[N:17]=1.C([O-])(=O)C.[NH4+].[N+:23]([CH3:26])([O-:25])=[O:24]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:14]3[C:9]([O:10][CH2:11][CH2:12][CH2:13]3)=[C:8]([CH:15]=[CH:26][N+:23]([O-:25])=[O:24])[C:7]=2[N:17]=1
Reactant: COc1ccc2c(n1)c(C=O)c1n2CCCO1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: COc1ccc2c(n1)c(C=C[N+](=O)[O-])c1n2CCCO1

Procedure:
300 mg (1.29 mmol) of the compound obtained in Step G dissolved in 15 ml of nitromethane are heated at 120° C. for 4 hours in the presence of 250 mg (3.23 mmol) of ammonium acetate. After returning to room temperature and evaporation to dryness, the reaction mixture is diluted in dichloromethane and washed with water. After drying over magnesium sulphate, evaporation of the organic phase yields the title compound in the form of a yellow solid.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][N:4]=[C:5]([NH2:18])[NH:6][C:7]1[N:11]=[CH:10][N:9]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[N:17])[N:8]=1.N.S(=O)(=O)(O)[OH:23]>>[F:20][C:2]([F:1])([F:19])[CH2:3][N:4]=[C:5]([NH2:18])[NH:6][C:7]1[N:11]=[CH:10][N:9]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]([NH2:17])=[O:23])[N:8]=1
Reactant: N#CCCCCn1cnc(NC(N)=NCC(F)(F)F)n1
Reactant: O=S(=O)(O)O
Agent: N
Product: NC(=O)CCCCn1cnc(NC(N)=NCC(F)(F)F)n1
Yield: 54 %

Procedure:
A solution of 5-[3-(2-[2,2,2-trifluoroethyl]guanidino)-1,2,4-triazol-1-yl]valeronitrile (0.15 g.) in concentrated sulphuric acid (3 ml.) was stirred for 1.5 hours at room temperature then poured onto ice and basified with concentrated aqueous ammonia. Extraction with EtOAc gave 0.12 g. of a white solid which was triturated with ether to give 5-[3-(2-[2,2,2-trifluoroethyl]guanidino)-1,2,4-triazol-1-yl]valeramide (0.085 g., 54%), m.p. 162°-164°.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=1[NH2:8].[Br:17][C:18]1[CH:19]=[C:20]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[CH:21]=[CH:22][C:23](O)=O>>[Br:17][C:18]1[CH:19]=[C:20]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])/[CH:21]=[CH:22]/[C:23]1[NH:1][C:2]2[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=2[N:8]=1
Reactant: COc1cc(C=CC(=O)O)cc(Br)c1OC
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Product: CCCn1c(=O)c2[nH]c(/C=C/c3cc(Br)c(OC)c(OC)c3)nc2n(CCC)c1=O
Yield: 66.6 %

Procedure:
Substantially the same procedure as in Reference Example 1 was repeated using 1.5 g (6.64 mmol) of 5,6-diamino-1,3-dipropyluracil and 2.10 g (7.31 mmol) of 3-bromo-4,5-dimethoxycinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane/water to give 2.11 g (yield 67%) of Compound 60 as white needles.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:18](=[O:23])N(OC)C)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][Mg]Br.[Cl-].[NH4+]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:18](=[O:23])[CH3:24])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1ccc2c(c1)CCN(C(=O)OC(C)(C)C)C2
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)c1ccc2c(c1)CCN(C(=O)OC(C)(C)C)C2
Temperature: -5 °C
Reaction time: 1.5 h

Procedure:
To 2.30 g (7.18 mmol) 6-(methoxy-methyl-carbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (preparation 29a) in 50 mL THF is added under an argon atmosphere at 0° C. 7.18 mL (21.5 mmol; 3 M solution in diethylether) methylmagnesium bromide. The reaction mixture is stirred 1.5 h at −5° C. and is then transferred into a saturated aqueous ammonium chloride solution. The aqueous phase is extracted three times with tert-butylmethylether, dried over MgSO4, filtered and the solvent is evaporated. The residue is purified by silica gel column chromatography with PE/EtOAc (8:2) as eluent.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]([CH:24]=[O:25])=[C:11]([C:26]3[CH2:27][CH2:28][O:29][CH2:30][CH:31]=3)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:33]1[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[C:35]([F:43])[CH:34]=1>C(OCC)C>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:19])([CH3:20])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:22])[CH3:23])[C:12]([C@H:24]([C:33]3[CH:38]=[CH:37][C:36]([C:39]([F:41])([F:42])[F:40])=[C:35]([F:43])[CH:34]=3)[OH:25])=[C:11]([C:26]3[CH2:27][CH2:28][O:29][CH2:30][CH:31]=3)[C:10]1=2)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: Fc1cc(Br)ccc1C(F)(F)F
Reactant: CC(C)c1nc2c(c(C3=CCOCC3)c1C=O)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Solvent: CCOCC
Product: CC(C)c1nc2c(c(C3=CCOCC3)c1[C@@H](O)c1ccc(C(F)(F)F)c(F)c1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2

Procedure:
Obtained by starting from (S)-5-(tert-butyldimethylsilyloxy)-4-(3,6-dihydro-2H-pyran-4-yl)-2-isopropyl-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-3-carbaldehyde and 4-bromo-2-fluoro-1-(trifluoromethyl)benzene. Diethylether is used instead of toluene.
Reaction SMILES: Cl.C[O:3][C:4](=O)[CH2:5][NH2:6].[OH-].[Na+].CO[C:12](=[NH:16])[CH2:13][CH2:14][CH3:15]>CO>[CH2:13]([C:12]1[NH:16][C:4](=[O:3])[CH2:5][N:6]=1)[CH2:14][CH3:15]
Reactant: CCCC(=N)OC
Reactant: COC(=O)CN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC1=NCC(=O)N1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
17.39 g (138 mmol) of glycine methyl ester hydrochloride was added to a solution of sodium hydroxide (5.56 g, 139 mmol) in methanol (55 ml) at 0° C. After 15 minutes, 14.50 g (content 96.3 percent, 138 mmol) of butanimidic acid methyl ester was instilled in the white suspension for 8 minutes. The mixture was stirred for 3 hours at room temperature and then concentrated by evaporation on a Rotavapor. The residue was mixed with CH2Cl2 (250 ml) and the resultant suspension was filtered. The filtrate was concentrated by evaporation on a Rotavapor, again mixed with CH2Cl2 (250 ml) and filtered again. After removal of the solvent, the title compound was obtained (15.13 g, content>95 percent according to 1H-NMR, 83 percent yield). Other data concerning the product was:
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:25][N:26]([CH3:35])[C:27]1[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:31]([C:30]3[CH:33]=[CH:34][C:27]([N:26]([CH3:35])[CH3:25])=[CH:28][CH:29]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3ccncc3)CC2)c1[N+](=O)[O-]
Reactant: CN(C)c1ccc(C=O)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CN(C)c1ccc(-c2nc3c(N4CCN(Cc5ccncc5)CC4)c(Br)cnc3[nH]2)cc1
Temperature: 70 °C

Procedure:
To a mixture of 5-bromo-3-nitro-4-(4-(pyridin-4-ylmethyl)piperazin-1-yl)pyridin-2-amine (0.043 g, 0.11 mmol), ethanol (4 ml), and 4-dimethylaminobenzaldehyde (0.021 g, 0.14 mmol) was added a freshly prepared aqueous solution of Na2S2O4 (1M; 0.44 ml, 0.44 mmol). The reaction mixture was heated at 70° C. for 5 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was absorbed on silica gel and the free running powder was placed on a 10 g isolute silica column which was eluted with 1 to 4% methanol in ethyl acetate/dichloromethane (v/v; 1:1). The title compound was obtained as a yellow solid after trituration with diethyl ether (0.013 g, 24%); 1H-NMR (500 MHz, DMSO-d6) 2.63 (br s, 4H, piperazine N(CH2)2), 3.00 (s, 6H, N(CH3)2), 3.66 (br s, 4H, piperazine N(CH2)2), 3.62 (s, 2H, NCH2), 6.81 (d, J=9.04 Hz, 2H) and 8.01 (d, J=8.81 Hz, 2H) (3,5-C6H4NMe2 and 2,6-C6H4—NMe2), 7.40 (d, J=5.86 Hz, 2H), and 8.54 (d, J=4.42 Hz, 2H) (pyrid-4-yl protons), 8.15 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.14 (s, 1H, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH:13]1([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1>[CH2:21]([O:20][C:18]([C:13]1([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:19])[CH3:22]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)C1CCCC1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C1(Cc2ccccc2)CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.2 %

Procedure:
A solution of diisopropylamine (1.0 mL, 7.7 mmol) in 20 mL of dry THF was cooled to −78° C. in a dry ice-acetone bath under argon. n-Butyl lithium in hexanes (2.5 M, 3.6 mL, 7.7 mmol) was added all at once and the mixture was stirred for 0.5 hour and transferred to a precooled (−30° C.) solution of 1.0 g (7.0 mmol) of ethyl cyclopentane carboxylate in 10 mL of THF. After a further 45 min, benzyl bromide (0.92 mL, 7.7 mmol) was added and the mixture was allowed to warm to room temperature over night. The resulting mixture was concentrated, and the residue was taken up in 70 mL of ether, washed with water, 1 N HCl, water, saturated brine and was dried (MgSO4). The residue obtained after filtration and evaporation was purified by flash chromatography over 100 g of silica gel, eluting with 3% ethyl acetate-hexane to give 1-benzylcyclopentane carboxylic acid ethyl ester (0.80 g, 45%) as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]([CH2:8]P(=O)(OCC)OCC)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:27]=[CH:26][C:23](/[CH:24]=[CH:8]/[C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:18][CH:17]=2)=[CH:22][CH:21]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CCOP(=O)(Cc1ccc([N+](=O)[O-])cc1)OCC
Product: O=[N+]([O-])c1ccc(/C=C/c2ccc(Cl)cc2)cc1

Procedure:
In an analogous manner to that described in Example 36a), the reaction of diethyl (4-nitrobenzyl)phosphonate with 4-chlorobenzaldehyde yields the (E)-1-chloro-4-[2-(4-nitrophenyl)ethenyl]-benzene as an yellow crystalline solid; MS: m/e=259 (M)+.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:19]=1[O:20][CH3:21])[N:16]=[CH:15][CH:14]=[C:13]2[O:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([C:32]2[C:33](=[O:46])[N:34]([C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)[C:35](=[O:38])[NH:36][N:37]=2)=[O:31])=[CH:25][C:24]=1[F:47].[CH2:48](Br)[C:49]#[CH:50].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[OH:3][C:2]([C:4]([F:7])([F:6])[F:5])=[O:1].[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:19]=1[O:20][CH3:21])[N:16]=[CH:15][CH:14]=[C:13]2[O:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([C:32]2[C:33](=[O:46])[N:34]([C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)[C:35](=[O:38])[N:36]([CH2:50][C:49]#[CH:48])[N:37]=2)=[O:31])=[CH:25][C:24]=1[F:47]
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)c4n[nH]c(=O)n(-c5ccc(F)cc5)c4=O)cc3F)c2cc1OC
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: C#CCn1nc(C(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)c(F)c2)c(=O)n(-c2ccc(F)cc2)c1=O
Yield: 21.8 %

Procedure:
A mixture of example 107 (25 mg, 0.046 mmol), propargyl bromide (10 uL, 0.1 mmol), and potassium carbonate (10 mg, 0.07 mmol) in N,N-dimethylformamide (1 mL) was stirred at rt 18 h. The mixture was filtered, solvent was removed and the product was purified by reverse phase HPLC to give an off-white solid (7 mg, 30%). LCMS m/z=586 (M+1); 1H NMR (DMSO) δ: 10.99 (s, 1H), 8.71 (d, 1H, J=6.1 Hz), 8.0 (dd, 1H, J=2.3, 12.7 Hz), 7.68 (s, 1H), 7.65-7.58 (m, 2H), 7.4 (s, 1H), 7.37-7.35 (m, 4H), 6.84 (d, 1H, J=5.8 Hz), 4.88 (d, 2H, J=2.3 Hz), 4.01 (2 s, 6H), 3.53 (s, 3H).