Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:9]=1)[CH2:3][OH:4].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl.C(OCC)C>[CH3:1][C:2]([CH3:21])([CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:9]=1)[CH:3]=[O:4]
Reactant: CC(C)(CO)COCc1cccc(Oc2ccccc2)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C=O)COCc1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Yield: 48.3 %

Procedure:
A solution of 2,2-dimethyl-3-(3-phenoxybenzyloxy)-propan-1-ol (15 g) in dry dichloromethane (50 cm3) was added dropwise to a stirred suspension of pyridinium chlorochromate (18.75 g) in dichloromethane (100 cm3) whilst the reaction temperature was maintained within the range 0°-5° C. When the addition was complete, the mixture was allowed to warm to the ambient temperature (ca. 25° C.) over a period of 2 hours. After the reaction mixture had been diluted with diethyl ether, the ethereal layer was decanted and filtered through celite. The solvent was removed by evaporation and the residual oil purified by column chromatography using a silica gel column and eluting with dichloromethane as eluent, to yield 2,2-dimethyl-3-(3-phenoxybenzyloxy)propane-1-al (7.2 g) as an orange oil.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][C:9]2([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:5]=[CH:4][CH:3]=1.[C:27]([N:31]1[C:35]([NH2:36])=[CH:34][CH:33]=[N:32]1)([CH3:30])([CH3:29])[CH3:28].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1>[C:27]([N:31]1[C:35]([NH:36][C:2]2[N:7]=[C:6]([CH2:8][C:9]3([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]3)[CH:5]=[CH:4][CH:3]=2)=[CH:34][CH:33]=[N:32]1)([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)n1nccc1N
Reactant: CCOC(=O)C1(Cc2cccc(Br)n2)CCN(C(=O)OC(C)(C)C)CC1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)C1(Cc2cccc(Nc3ccnn3C(C)(C)C)n2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
A mixture of 1.33 g of 1-tert-butyl 4-ethyl 4-((6-bromopyridin-2-yl)methyl)piperidine-1,4-dicarboxylate, 650 mg of 1-tert-butyl-1H-pyrazol-5-amine (WO2007/126126, page 72, Reference 1), 360 mg of 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene, 322 mg of tris(dibenzylideneacetone)dipalladium(0)-chloroform complex, 1.98 g of potassium phosphate and 30 ml of 1,4-dioxane was stirred at 100° C. for 4 hours, followed by cooling down to room temperature. An insoluble matter was filtered off using Celite and washed with ethyl acetate. The resulting ethyl acetate solution was concentrated in vacuo. The resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate=20/1−3/2) to give the title compound as a pale brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH:9]1([CH2:15]C2C=CC=CC=2O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:15][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: Oc1ccccc1CC1CCCCC1
Reactant: Oc1ccc(Br)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Brc1ccc(OCC2CCCCC2)cc1
Yield: 54.6 %

Procedure:
To a solution of 4-bromophenol (6.0 g, 34.7 mmol), cyclohexylmethylphenol (4.3 ml, 34.7 mmol) and triphenylphosphine (9.1 g, 34.7 mmol) in tetrahydrofuran (100 ml) was added slowly a 40% solution of diethyl azodicarboxylate in toluene (15.1 ml, 34.7 mmol) in portions at 0° C. with stirring, and then the resulting mixture was stirred at room temperature for 3 hours. After stirring, the reaction mixture was evaporated in vacuo, and hexane was added to the residue. After filtration, the filtrate was evaporated in vacuo once again, and the residue was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:20) as the eluent to afford 1-bromo-4-(cyclohexylmethoxy)benzene (5.1 g, yield: 54%).
Reaction SMILES: Cl.[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][N:3]=1.[CH2:12]([C:14]([C:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]=1)=[O:15])[CH3:13].O>C(O)C>[CH3:13][CH:12]1[CH:2]2[N:3]([CH2:4][CH2:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=32)[CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21][CH:16]2[C:14]1=[O:15]
Reactant: C1=NCCc2ccccc21
Reactant: CCC(=O)C1=CCCCC1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC1C(=O)C2CCCCC2N2CCc3ccccc3C12

Procedure:
A mixture of 16.75 g (0.1 mole) of 3,4-dihydroisoquinoline hydrochloride and 28.0 g of (0.2 mole) of 1-cyclohexen-1-yl ethyl ketone in 28 ml of ethanol is refluxed for 52 hours then poured into 300 ml of water and extracted with ether. The aqueous layer is separated and made basic by slowly adding ammonium hydroxide solution with stirring. Stirring is continued until a solid is formed after which the liquid is decanted. The solid is washed with water, dissolved in methylene chloride, dried over sodium sulfate and concentrated to an oil. The oil is dissolved in refluxing hexane, filtered, concentrated and cooled to give a solid which is recrystallized from hexane-benzene to give 2,3,4,4a,6,7,11b,12,13,13a-decahydro-12-methyl-1H-dibenzo[a,f]quinolizin-13-one, M.P. 144.5°-147.5°C.
Reaction SMILES: [H-].[Na+].[C:3]([N:13]1[CH2:18][CH2:17][CH:16]([N:19]2[CH2:23][CH2:22][NH:21][C:20]2=[O:24])[CH2:15][CH2:14]1)([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[O:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[O:31][CH2:32][CH2:33]Br>CN(C)C=O>[C:3]([N:13]1[CH2:14][CH2:15][CH:16]([N:19]2[CH2:23][CH2:22][N:21]([CH2:33][CH2:32][O:31][CH:26]3[CH2:27][CH2:28][CH2:29][CH2:30][O:25]3)[C:20]2=[O:24])[CH2:17][CH2:18]1)([O:5][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:4]
Reactant: O=C(OCc1ccccc1)N1CCC(N2CCNC2=O)CC1
Reactant: BrCCOC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)N1CCC(N2CCN(CCOC3CCCCO3)C2=O)CC1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A mixture of 1.35 g of sodium hydride in 70 ml of dimethylformamide and 14.2 g of 1-(1-carbobenzoxy-4-piperidyl)-imidazolidin-2-one is stirred at 80° C. for 4 hours. A solution of 11.7 g of 2-bromoethyl 2-tetrahydro-pyranyl ether in 30 ml of absolute dimethylformamide is then added dropwise in the course of 15 minutes. The mixture is stirred for a further 4 hours at 80° C. and is then evaporated under reduced pressure. The residue is freed from dimethylformamide which is still adhering, by treatment with toluene. The reaction product is dissolved in ethyl acetate, the solution is washed twice with, in each case, 50 ml of water and the ethyl acetate phase is dried over sodium sulphate and evaporated. The residual oil is chromatographed on 1.5 g of silica gel using a mixture of chloroform/methyl alcohol (95:5) as the eluant mixture. In this way, 1-(1-carbobenzoxy-4-piperidyl)-3-[2-(2-tetrahydropyranyloxy)-ethyl]-imidazolidin-2-one is obtained in the form of a slightly yellowish oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[NH:12][CH:13]=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])=[C:4]([C:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=2)[CH:3]=1.C([Mg]Cl)(C)C.[CH3:29][C:30]1([CH3:33])[CH2:32][O:31]1.B(F)(F)F.CCOCC.[Li]C(C)(C)C>C1COCC1>[C:18]1([C:4]2[CH:3]=[C:2]([CH2:29][C:30]([OH:31])([CH3:33])[CH3:32])[CH:7]=[CH:6][C:5]=2[NH:8][C:9]([C:11]2[NH:12][CH:13]=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=1
Reactant: N#Cc1c[nH]c(C(=O)Nc2ccc(Br)cc2C2=CCCCC2)n1
Reactant: CC1(C)CO1
Agent: CC(C)[Mg]Cl
Agent: FB(F)F
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(O)Cc1ccc(NC(=O)c2nc(C#N)c[nH]2)c(C2=CCCCC2)c1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 15.2 %

Procedure:
To a solution of 4-cyano-1H-imidazole-2-carboxylic acid (4-bromo-2-cyclohex-1-enyl-phenyl)-amide (prepared in Example 11, step (g)) (0.10 g, 0.27 mmol) in 1.5 mL of THF at −40° C. was added 0.15 mL of i-PrMgCl (0.30 mmol, 2 M solution in THF) and the solution was stirred at this temperature for 15 min. The mixture was then cooled to −78° C. and 2,2-dimethyl-oxirane (0.12 mL, 1.3 mmol) was added followed by boron trifluoride etherate (0.044 mL, 0.35 mmol) and t-BuLi (0.41 mL, 0.69 mmol, 1.7 M solution in pentane). After stirring for 30 min at −78° C. the mixture was quenched with satd NH4Cl (10 mL), extracted with EtOAc (2×10 mL) and the organic layer was dried over Na2SO4 and concentrated. The title compound was eluted from a 20-g SPE column with 50% EtOAc/hexanes to give 0.015 g (15%) of a white solid: 1H-NMR (DMSO-d6, 400 MHz): δ 14.25 (s, 1H), 9.71 (s, 1H), 8.33 (s, 1H), 7.84 (d, J=8.2 Hz, 1H), 7.14 (dd, J=8.2, 1.9 Hz, 1H), 7.06 (d, J=1.9 Hz, 1H), 5.74 (s, 1H), 4.63 (t, J=5.2 Hz, 1H), 3.61 (m, 2H), 2.70 (t, J=7.0 Hz, 2H), 2.23-2.11 (m, 4H), 1.76-1.62 (m, 4H). Mass spectrum (ESI, m/z): Calcd. for C21H24N4O2, 365.2 (M+H), found 365.1.
Reaction SMILES: Cl[C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:13]([O-:15])=[O:14])[CH:8]=2)[N:3]=1.[Na].[CH3:17][OH:18]>>[Cl:12][C:11]1[C:2]([O:18][CH3:17])=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][C:7]([N+:13]([O-:15])=[O:14])=[CH:6][CH:5]=2
Reactant: O=[N+]([O-])c1ccc2nc(Cl)c(Cl)nc2c1
Reactant: CO
Agent: [Na]
Product: COc1nc2ccc([N+](=O)[O-])cc2nc1Cl
Temperature: 50 °C
Yield: 58 %

Procedure:
A slurry of 6.1 g (25 mmol) of 2,3-dichloro-6-nitroquinoxaline in 70 ml of dry methanol was heated to 50° C and treated dropwise over 5 h with 0.7 g (30 mmol) of sodium dissolved in 70 ml of dry methanol. The mixture was stirred over night at 50° C., cooled and filtered. The resulting precipitate was washed with cold ethanol and water and finally chromatographed on silica gel with toluene to give 3.5 g (58%) of the title compound; m.p. 155-158° C.; 1H-NMR (DMSO-d6): δ4.17 (s, 3H, CH3), 8.05 (d,J=9 Hz, 1H, H-8), 8.48 (dd, J7-8 =9 Hz, J7-5 =2 Hz, 1H, H-7), 8.73 (d, J=2 Hz, 1H, H-5).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[CH:7]=1.F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:19]=1[F:27].C(=O)([O-])[O-].[Cs+].[Cs+].O>CS(C)=O>[F:27][C:19]1[CH:20]=[C:21]([N+:24]([O-:26])=[O:25])[CH:22]=[CH:23][C:18]=1[O:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:15][CH2:16]3)=[O:13])[N:10]=2)[CH:7]=1
Reactant: O=C(Nc1cn2cc(O)ccc2n1)C1CC1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(Nc1cn2cc(Oc3ccc([N+](=O)[O-])cc3F)ccc2n1)C1CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 94.6 %

Procedure:
To a solution of N-(6-hydroxyimidazo[1,2-a]pyridin-2-yl)cyclopropanecarboxamide (30 g, 138 mmol) and 1,2-difluoro-4-nitrobenzene (24.2 g, 152 mmol) in dimethyl sulfoxide (180 mL) was added cesium carbonate (58.5 g, 180 mmol), and the mixture was stirred at room temperature for 5 hr under an argon atmosphere. Water (1080 mL) was added to the reaction mixture, and the mixture was stirred for 20 min. The precipitate was collected by filtration and washed with water and ethyl acetate. After air drying for one day, the mixture was dried under reduced pressure at 100° C. for 5 hr to give the title compound (46.5 g, 95%) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1>CN(C)C=O.C(O)C>[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH:28][CH2:19][C@@H:17]([OH:18])[CH2:16][O:15][C:12]2[CH:11]=[CH:10][C:9]([C:6]3[C:5]4[CH:20]=[CH:21][C:2]([F:1])=[CH:3][C:4]=4[O:8][N:7]=3)=[CH:14][CH:13]=2)=[CH:25][CH:24]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Solvent: CN(C)C=O
Solvent: CCO
Product: O[C@H](CNCc1ccc(Cl)cc1)COc1ccc(-c2noc3cc(F)ccc23)cc1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 4-chlorobenzylamine in ethanol, essentially as described above in Example 70. Purity by LC/MS=<100%, [M+H]+=427.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:12]2[CH:18]=[CH:17][C:16](=[O:19])[N:15]([CH2:20][CH2:21][CH2:22][C:23]([N:25]3[CH2:32][CH2:31][C:28]4([CH2:30][CH2:29]4)[C@H:27]([OH:33])[CH2:26]3)=[O:24])[CH2:14][C@H:13]2[CH3:34])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].C(O)(=O)C>CO.O=[Pt]=O.O=[Pt]=O.[H][H]>[Cl:1][C:2]1[CH:3]=[C:4]([N:12]2[CH2:18][CH2:17][C:16](=[O:19])[N:15]([CH2:20][CH2:21][CH2:22][C:23]([N:25]3[CH2:32][CH2:31][C:28]4([CH2:29][CH2:30]4)[C@H:27]([OH:33])[CH2:26]3)=[O:24])[CH2:14][C@H:13]2[CH3:34])[CH:5]=[CH:6][C:7]=1[C:8]([F:10])([F:9])[F:11]
Reactant: [H][H]
Reactant: C[C@@H]1CN(CCCC(=O)N2CCC3(CC3)[C@H](O)C2)C(=O)C=CN1c1ccc(C(F)(F)F)c(Cl)c1
Agent: O=[Pt]=O
Solvent: CO
Solvent: CC(=O)O
Product: C[C@@H]1CN(CCCC(=O)N2CCC3(CC3)[C@H](O)C2)C(=O)CCN1c1ccc(C(F)(F)F)c(Cl)c1
Reaction time: 48 h
Yield: 113.6 %

Procedure:
A solution of 0.066 g (0.1 mmol) of (R)-1-(3-chloro-4-trifluoromethyl-phenyl)-4-[4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-4-oxo-butyl]-2-methyl-1,2,3,4-tetrahydro-[1,4]diazepin-5-one (61% ds) (example 65) in 2 ml MeOH was treated with 0.007 g of PtO2 and was stirred over H2-atmosphere for 2 days. After filtration and evaporation, the crude compound was again hydrogenated in 2 ml of MeOH and 0.007 ml (0.1 mmol) of acetic acid with 0.007 g of PtO2/H2 over night. After filtration and evaporation, the residue was reevaporated (3 times) with toluene and the solvent was removed under vacuum to give 0.057 g (86%) of the titled compound as white foam. MS: 502.21 (MH+, Cl).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([OH:11])=O)[CH:2]=1.C(OC(Cl)=O)C.[CH2:18]([N:25]1[CH2:30][CH2:29][CH:28]([O:31][CH2:32][CH2:33][CH2:34][NH2:35])[CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([N:25]1[CH2:26][CH2:27][CH:28]([O:31][CH2:32][CH2:33][CH2:34][NH:35][C:9](=[O:11])[CH:8]=[CH:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH2:29][CH2:30]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: NCCCOC1CCN(Cc2ccccc2)CC1
Reactant: O=C(O)C=Cc1cccnc1
Agent: CCOC(=O)Cl
Product: O=C(C=Cc1cccnc1)NCCCOC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.4 g (16.2 mmol) 3-(3-pyridyl)-acrylic acid and 2.3 g (16.2 mmol) TEA were suspended in 50 ml abs. tolueneand a solution of 1.5 ml (15.5 mmol) chloroformic ethyl ester in 20 ml abs. tolueneis added dropwise under moisture exclusion and gentle cooling. This yellow suspension is stirred two hours at RT and then a solution of 3.5 g (14.1 mmol) 3-(1-benzylpiperidine-4-yloxy)-propylamine in 20 ml abs. tolueneis added dropwise. The mixture is stirred at RT and subsequently extracted by shaking in the heat three times with 10 ml water, 2M sodium hydroxide solution and again with water, respectively. The organic phase is concentrated under vacuum and the orange colored, oily residue is chromatographically purified twice over silica gel with CHCl3/CH3OH/NH4OH (90/9/1 and 95/5/0 to 90/10/0) and crystallized twice from 10 ml acetic acid ethyl ester. Colorless crystals with a MP of 100-102° C. were recovered; yield: 1.9 g (35%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[C:16]([F:18])[C:15]([C:19]([F:22])([F:21])[F:20])=[C:14]([Cl:23])[CH:13]=2)=[CH:7][C:3]=1[C:4](Cl)=[O:5].[OH-].[NH4+:25].O>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[C:16]([F:18])[C:15]([C:19]([F:22])([F:21])[F:20])=[C:14]([Cl:23])[CH:13]=2)=[CH:7][C:3]=1[C:4]([NH2:25])=[O:5]
Reactant: O=C(Cl)c1cc(Oc2cc(F)c(C(F)(F)F)c(Cl)c2)ccc1Br
Reactant: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: NC(=O)c1cc(Oc2cc(F)c(C(F)(F)F)c(Cl)c2)ccc1Br
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-bromo-5-[(2-chloro-α,α,α,6-tetrafluoro-p-tolyl)oxy]benzoyl chloride (16 g, 0.036 mol) in methylene chloride is cooled to 0° C., treated dropwise with 9.2 mL of a 30% ammonium hydroxide solution (0.071 mol), stirred at 0° C. for 30 minutes, stirred at room temperature overnight and poured into water. The aqueous mixture is extracted with methylene chloride. The organic extracts are combined, washed sequentially with saturated sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give the title product as a white solid, mp 115°-116° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][S:5][CH:6]([CH3:15])[CH2:7][C:8]([O:10]C(C)(C)C)=[O:9].FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3](=[O:16])[CH2:4][S:5][CH:6]([CH3:15])[CH2:7][C:8]([OH:10])=[O:9]
Reactant: COC(=O)CSC(C)CC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CSC(C)CC(=O)O
Yield: 85 %

Procedure:
1.5 g (6.0 mmol) of t-butyl 3-[(2-methoxy-2-oxoethyl)thio]butanoate (product of step 1) was stirred at room temperature with 10 mL of dichloromethane and 5 mL of trifluoroacetic acid for 6 hours, followed by distillation under reduced pressure. After addition of 40 mL of ethylacetoacetate 40 mL and washing with water, an organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and then the residue was purified by column chromatography to give 1 g (5.1 mmol) of the title compound in a yield of 85%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:16]([F:19])([F:18])[F:17])=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH2:11][CH2:12][CH2:13][OH:14])[NH:7][C:6]=2[CH:15]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:26][Si:27]([CH2:30][CH2:31][O:32][CH2:33]Cl)([CH3:29])[CH3:28]>CN(C=O)C>[Cl:1][C:2]1[C:3]([C:16]([F:17])([F:19])[F:18])=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH2:11][CH2:12][CH2:13][OH:14])[N:7]([CH2:33][O:32][CH2:31][CH2:30][Si:27]([CH3:29])([CH3:28])[CH3:26])[C:6]=2[CH:15]=1
Reactant: OCCCCc1nc2cc(C(F)(F)F)c(Cl)cc2[nH]1
Reactant: C[Si](C)(C)CCOCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1c(CCCCO)nc2cc(C(F)(F)F)c(Cl)cc21
Reaction time: 1 h
Yield: 58.3 %

Procedure:
4-[6-chloro-5-(trifluoromethyl)-1H-1,3-benzodiazol-2-yl]butan-1-ol (5.88 g, 20.09 mmol) was dissolved in DMF (50 ml) and anhydrous potassium carbonate (3.47 g, 25.11 mmol) was added at r.t. under N2 and the reaction stirred for 1 hr. SEM-Cl (3.92 ml, 22.10 mmol) was added and the reaction stirred for 3 hrs. The reaction mixture was concentrated in vacuo, EtOAc (150 ml) was added and the mixture was washed with 50% sat. brine solution (3×200 ml). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product. The product was purified by silica flash column chromatography eluting with MeOH:DCM (1:99-6:94) to give the product as a light orange oil (4.95 g, 58%): MS (ESI+) for C18H26ClF3N2O2Si m/z 424.40 [M+H]+; LC purity 81% (ret. time, 2.41 min); 1H NMR (500 MHz, CHLOROFORM-d) δ ppm −0.11-0.01 (9H, m), 0.66-1.12 (2H, m), 1.60-1.87 (2H, m), 2.07 (2H, td, J=7.33, 2.05 Hz), 2.91-3.21 (2H, m), 3.43-3.61 (2H, m), 3.70 (2H, d, J=4.10 Hz), 5.49 (2H, d, J=17.81 Hz), 7.45-8.15 (2H, m)
Reaction SMILES: Cl.[O:2]([CH2:6][CH2:7][NH2:8])[N+:3]([O-:5])=[O:4].C[O-].[Na+].[NH2:12][C:13]1[CH:14]=[C:15]([C:19](=[N:24][C:25]#[N:26])OCCC)[CH:16]=[N:17][CH:18]=1>CN(C=O)C.CO>[NH2:12][C:13]1[CH:14]=[C:15]([C:19](=[N:8][CH2:7][CH2:6][O:2][N+:3]([O-:5])=[O:4])[NH:24][C:25]#[N:26])[CH:16]=[N:17][CH:18]=1
Reactant: CCCOC(=NC#N)c1cncc(N)c1
Reactant: NCCO[N+](=O)[O-]
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: N#CNC(=NCCO[N+](=O)[O-])c1cncc(N)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.8 %

Procedure:
To a solution of 2-nitroxyethylamine hydrochloride (140 mg, 0.98 mmol) in DMF (1 ml) was added sodium methoxide (42 mg, 0.78 mmol) followed by a solution of propyl 5-amino-N-cyano-3-pyridinecarboximidate (100 mg, 0.49 mmol) in methanol (1 ml) described in Example 6 of Experimental Example 1, and the mixture was stirred at room temperature for 3 hours. After the reaction was completed, the reaction mixture was evaporated under reduced pressure. The residue was suspended in water and extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography with a mixed solvent of methanol and chloroform as an eluent to give the title compound (77 mg, yield 63%) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:7]2[Cl:17].C([O:20][CH:21]=[C:22]([C:28]([CH3:30])=[O:29])[C:23](OCC)=O)C.C1(OC2C=CC=CC=2)C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:28]([CH:22]1[C:21](=[O:20])[C:3]2[C:2](=[C:11]3[C:6](=[CH:5][CH:4]=2)[C:7]([Cl:17])=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:9]=[N:10]3)[N:1]=[CH:23]1)(=[O:29])[CH3:30]
Reactant: CCOC=C(C(C)=O)C(=O)OCC
Reactant: CCOC(=O)c1cnc2c(N)cccc2c1Cl
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1cnc2c3c(ccc2c1Cl)C(=O)C(C(C)=O)C=N3
Temperature: 90 °C
Yield: 29 %

Procedure:
A mixture of 8-amino-4-chloro-3-ethoxycarbonylquinoline (0.3 g) and ethyl 2-ethoxymethyleneacetoacetate (Annalen, 1897, 297, 16, 0.25 g) was heated at 90° C. for 2.5 hours. The mixture was cooled to ambient temperature and the resulting solid added to diphenyl ether at reflux. The mixture was refluxed for 45 minutes, and cooled to 60° C. The mixture was diluted with carbon tetrachloride (50 ml) and cooled to ambient temperature with stirring. The mixture was filtered and the solid so obtained purified by flash chromatography on silica using increasingly polar mixtures of methanol and chloroform. The product so obtained was recrystallised from methanol to give 3-acetyl-7-chloro-8-ethoxycarbonyl-4-oxo-3,4-dihydro-1,10-phenanthroline in 29% yield, mp 288-290° C.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[N:10][C:5]2=[CH:4][CH:3]=1.[CH3:11][Si:12]([CH3:16])([CH3:15])[C:13]#[CH:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C1COCC1.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>[CH3:11][Si:12]([C:13]#[C:14][C:3]1[CH:4]=[C:5]2[N:10]=[CH:9][NH:8][C:6]2=[N:7][CH:2]=1)([CH3:16])[CH3:15]
Reactant: C#C[Si](C)(C)C
Reactant: Brc1ccc2nc[nH]c2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1cnc2[nH]cnc2c1

Procedure:
The title compound is synthesized according to general procedure GP2 starting from 1.2 g (6.1 mmol) 5-bromo-3H-imidazo[4,5-b]pyridine and 1.2 mL (8.4 mmol) 1-trimethylsilyl-ethyne using 34 mg (0.18 mmol) CuI, 159 mg (0.61 mmol) triphenylphosphine, 128 mg (0.18 mmol) PdCl2(PPh3)2 and 10.1 mL (72.7 mmol) triethylamine in 10 mL dry THF. The formed precipitate is filtered off and the product is purified by RP-HPLC using an ACN/H2O gradient. Yield: 606 mg (46%).