Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([F:27])[CH:21]=2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[O:11])=[C:4]([CH3:28])[CH:3]=1.[CH3:29][O:30][C:31]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)=[O:32].N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:29][O:30][C:31](=[O:32])[C:33]1[CH:34]=[CH:35][CH:36]=[C:37]([O:26][C:23]2[CH:24]=[CH:25][C:20]([CH:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=3[CH3:28])[CH2:9][C:10]([C:12]3[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=3)=[O:11])=[CH:21][C:22]=2[F:27])[CH:38]=1
Reactant: COC(=O)c1cccc(B(O)O)c1
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(O)c(F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1cccc(Oc2ccc(C(CC(=O)c3ccc(=O)n(C)c3)c3ccc(Cl)cc3C)cc2F)c1

Procedure:
In analogy to example 222, step 1, 5-[3-(4-chloro-2-methyl-phenyl)-3-(3-fluoro-4-hydroxy-phenyl)-propionyl]-1-methyl-1H-pyridin-2-one (example 324, step 1) was reacted with 3-methoxycarbonylphenylboronic acid in dichloromethane in the presence of copper(II) acetate, pyridine and air to give the title compound as a colourless solid, MS (ESI+): m/z=534.1 [M+H]+.
Reaction SMILES: [CH2:1]1[CH:10]2[N:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4]C[CH:2]1[CH2:11][NH2:12].N1C2C(=CC=CC=2)C(C(Cl)=[O:23])=C1>>[NH:5]1[C:10]2[C:1](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:2]([C:11]([NH2:12])=[O:23])=[CH:4]1
Reactant: NCC1CCN2CCCCC2C1
Reactant: O=C(Cl)c1c[nH]c2ccccc12
Product: NC(=O)c1c[nH]c2ccccc12
Yield: 55 %

Procedure:
eq-Quinolizidin-2-ylmethylamine (D12) was reacted with indole-3-carboxylic acid chloride using the method of Description 1b) to afford N-(eq-quinolizidin-2-ylmethyl) indole-3-carboxamide as a white solid (55%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH:23]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)=[O:24]>>[F:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)=[CH:3][C:2]=1[C:28]1[CH:29]=[CH:30][C:25]([CH:23]=[O:24])=[CH:26][CH:27]=1
Reactant: CC(C)(O)c1ccn2c(-c3ccc(F)c(Cl)c3)cnc2c1F
Reactant: O=Cc1ccc(B(O)O)cc1
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4ccc(C=O)cc4)c3)cnc2c1F
Yield: 83 %

Procedure:
2-[3-(3-Chloro-4-fluorophenyl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]-propan-2-ol and 4-formylbenzeneboronic acid were coupled in the same way as in Example 30 to give 2′-fluoro-5′-[8-fluoro-7-(1-hydroxy-1-methylethyl)imidazo[1,2-α]pyridin-3-yl]biphenyl-4-carbaldehyde as an off-white solid (100 mg, 83%): m/z (ES+) 393 [MH+].
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:9].[N-:10]=[N+:11]=[N-:12].[Na+]>C(#N)C>[N:10]([CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:9])=[N+:11]=[N-:12]
Reactant: Clc1ccccc1CBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC#N
Product: [N-]=[N+]=NCc1ccccc1Cl

Procedure:
A mixture of 1-(bromomethyl)-2-chlorobenzene (5 g, 24.3 mmol) and sodium azide (2.37 g, 36.5 mmol) in acetonitrile (48.7 mL) was refluxed for 3 h under N2 atmosphere. Then, the mixture was filtered and concentrated in vacuo. The residue was diluted in DCM, washed with H2O and brine, dried over Na2SO4 and concentrated in vacuo to afford crude 1-(azidomethyl)-2-chlorobenzene. The residue was used for the next reaction without further purification. A mixture of the above crude residue, 2-cyanoacetamide (1.82 g, 21.7 mmol) and sodium ethanolate (1.47 g, 21.7 mmol) in ethanol (43.3 mL) was refluxed for 3 h under N2 atmosphere. The mixture was concentrated in vacuo, diluted with 4M AcOH aq. and filtered. The residue was washed with H2O and dried in vacuo to afford 5-amino-1-(2-chlorobenzyl)-1H-1,2,3-triazole-4-carboxamide as pale-orange solid (5.10 g, 94% for 2 steps). MS(m/e): 252.1 (MH+).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].Cl[CH2:11][C:12]1[N:13]([C:17]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:14]=[CH:15][N:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH2:11][C:12]1[N:13]([C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:14]=[CH:15][N:16]=1
Reactant: ClCc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Oc1cccc(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Fc1cccc(OCc2nccn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1F
Temperature: 80 °C
Reaction time: 8 h
Yield: 95.2 %

Procedure:
To a stirred solution of 2,3-difluorophenol (109 mg) at room temperature in dimethylformamide DMF (5 ml) under an argon atmosphere were added 2-chloromethyl-1-trityl-1H-imidazole (200 mg) and potassium carbonate (193 mg). The mixture was heated to 80° C. and stirring was continued overnight. The brown suspension was cooled to room temperature, diluted with EtOAc and washed with 1 N NaOH. The aqueous phase was back extracted with EtOAc. The combined organics were washed with H2O and brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (silica gel; gradient:cyclohexane→cyclohexane/EtOAc 55:45) to give 2-(2,3-difluoro-phenoxymethyl)-1-trityl-1H-imidazole (240 mg) as a light yellow gum. MS (ISP): 453.0 ([M+H]+)
Reaction SMILES: [OH:1][CH2:2][C:3](=[C:14]1[S:18][C:17](=[O:19])[NH:16][C:15]1=[O:20])[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.CC(O)C>CC(C)=O>[O:1]=[CH:2][C:3](=[C:14]1[S:18][C:17](=[O:19])[NH:16][C:15]1=[O:20])[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: O=C1NC(=O)C(=C(CO)c2cccc3ccccc23)S1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: CC(C)=O
Product: O=CC(=C1SC(=O)NC1=O)c1cccc2ccccc12
Yield: 98.2 %

Procedure:
To a solution of 5-[2-hydroxy-1-(1-naphthalenyl)ethylidene]-2,4-thiazolidinedione (10.13 g, 35.5 mmol) in acetone (250 mL) at 0° C. was added Jones reagent (8N, 10.26 mL, 82 mmol). After 30 min 2-propanol (10 mL) was added. The reaction mixture was filtered and concentrated in vacuo. The resulting oil was taken up in ether and washed with water (2×). The organic phase was dried over magnesium sulfate, filtered and concentrated to give a foam (9.88 g). Recrystallization (chloroform/ethyl acetate) gave crystals (6.87 g) of the E-isomer. m.p. 184°-185° C.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:21][CH2:20][C@H:19]([C:22](O)=[O:23])[C@@H:18]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C@@H:17]2[C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.ClC(OCC(C)C)=O.C(N(CC)CC)C>C1COCC1>[F:37][C:2]([F:1])([F:38])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:21][CH2:20][C@H:19]([CH2:22][OH:23])[C@@H:18]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C@@H:17]2[C:30]2[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: CCOC(=O)[C@H]1[C@H](c2ccc(F)cc2)[C@@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC[C@@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H]1[C@@H](CO)CC[C@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]1c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68.3 %

Procedure:
To a solution of intermediate carboxylic acid (2.7 g, 4.91 mmol) from Step A in 60 mL THF was added isobutyl chloroformate (0.96 mL, 7.32 mmol) and triethyl amine (1.23 mL, 8.84 mmol). The mixture was stirred at 0° C. for 0.5 hr then at room temperature for 0.5 hr. The white precipitate was filtered and the solid was washed with dry THF. The filtrate was added to a suspension of 1 g NaBH4 in 3 mL water at 0° C. The resulting mixture was stirred at room temperature for 16 hr, quenched with 2 N aq. HCl (20 mL), then diluted with ethyl acetate (50 mL). The organic layer was separated and the aqueous was extracted with ethyl acetate (2×60 mL). The combined organic extract was washed with brine, dried over MgSO4, filtered and the solvent was removed under vacuum. The residue was purified by column chromatography (2:1 hexane:ethyl acetate) to give the title compound (1.8 g). 1H-NMR (CDCl3) δ: 7.71 (1H, s), 7.20 (2H, s), 7.00 (2H, m), 6.85 (2H, m), 4.45 (1H, q, J=6.4 Hz), 3.83 (2H, m), 3.55 (2H, m), 3.35 (1H, m), 2.93 (1H, t, J=11.0 Hz), 2.47 (1H, t, J=11.0Hz), 2.37 (1H, s), 2.33 (1H, m), 1.97 (2H, m), 1.62-1.50 (2H, m), 1.20 (1H, m), 1.33 (3H, d, J=6.4 Hz), 0.90 (3H, t, J=7.1 Hz).
Reaction SMILES: [Na].[Cl:2][C:3]1[C:4]([OH:11])=[N:5][C:6]([F:10])=[C:7]([Cl:9])[CH:8]=1.Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]>C(O)C>[CH2:17]([O:16][C:14](=[O:15])[CH2:13][O:11][C:4]1[C:3]([Cl:2])=[CH:8][C:7]([Cl:9])=[C:6]([F:10])[N:5]=1)[CH3:18]
Reactant: Oc1nc(F)c(Cl)cc1Cl
Reactant: CCOC(=O)CBr
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)COc1nc(F)c(Cl)cc1Cl

Procedure:
A solution was prepared by dissolving 6.9 grams (0.3 mole) of sodium metal in 700 milliliters of 95 percent ethanol. To this solution was added with stirring 54.5 grams (0.3 mole) of 3,5-dichloro-6-fluoro-2-pyridinol. Thereafter 58.5 grams (0.35 mole) of ethyl bromoacetate was added and the mixture refluxed for 5 hours. At the completion of the reaction, the ethanol was distilled off and the residue poured into water. The solid which precipitated was filtered off and taken up in hexane and dried with activated carbon and anhydrous sodium sulfate. The mixture was filtered and the hexane removed and the ethyl-(3,5-dichloro-6-fluoro-2-pyridyloxy) acetate product was recovered by distillation. The product was a white waxy solid which boiled at 135°-170° C. (M.P. 63.5°-64° C.)
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[C:13](=[O:14])[C:12]2[C:7](=[N:8][C:9]([C:15]([F:18])([F:17])[F:16])=[CH:10][CH:11]=2)[N:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]=1[C:25]([O:27][CH3:28])=[O:26].[NH:29]1[CH:33]=[CH:32][N:31]=[C:30]1[C:34]1[CH:42]=[CH:41][C:37]([C:38](O)=[O:39])=[CH:36][CH:35]=1>>[CH3:28][O:27][C:25]([C:5]1[N:6]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:7]2[C:12]([C:13](=[O:14])[C:4]=1[CH2:3][NH:2][C:38](=[O:39])[C:37]1[CH:36]=[CH:35][C:34]([C:30]3[NH:31][CH:32]=[CH:33][N:29]=3)=[CH:42][CH:41]=1)=[CH:11][CH:10]=[C:9]([C:15]([F:16])([F:17])[F:18])[N:8]=2)=[O:26]
Reactant: COC(=O)c1c(CN)c(=O)c2ccc(C(F)(F)F)nc2n1-c1ccccc1
Reactant: O=C(O)c1ccc(-c2ncc[nH]2)cc1
Agent: Cl
Product: COC(=O)c1c(CNC(=O)c2ccc(-c3ncc[nH]3)cc2)c(=O)c2ccc(C(F)(F)F)nc2n1-c1ccccc1

Procedure:
3-{[4-(1H-Imidazol-2-yl)-benzoylamino]-methyl}-4-oxo-1-phenyl-7-trifluoromethyl-1,4-dihydro-[1,8]naphthyridine-2-carboxylic acid methyl ester was prepared starting from intermediate J and 4-(1H-imidazol-2-yl)-benzoic acid. 1H NMR (DMSO-d6) δ ppm 8.90 (d, J=8.1 Hz, 1H) 8.77 (t, J=4.6 Hz, 1H) 7.91-8.00 (m, 3H) 7.83-7.89 (m, 2H) 7.52-7.59 (m, 3H) 7.47 (s, 2H) 7.43 (dd, J=6.7, 2.7 Hz, 2H) 4.46 (d, J=4.8 Hz, 2H) 3.40 (s, 3H). MS calcd. for C28H20F3N5O4 [(M+H)+] 548.1, obsd. 548.1.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:21])[N:4](C2CCCCO2)[N:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl>CO.O>[Cl:1][C:2]1[C:3](=[O:21])[NH:4][N:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=c1c(Cl)c(Oc2ccccc2)cnn1C1CCCCO1
Agent: Cl
Solvent: O
Solvent: CO
Product: O=c1[nH]ncc(Oc2ccccc2)c1Cl
Temperature: 110 °C
Reaction time: 4 h
Yield: 86.4 %

Procedure:
A solution of 4-chloro-5-phenoxy-2-(tetrahydro-pyran-2-yl)-2H-pyridazin-3-one (2.84 g, 9.25 mmol) in methanol (6.17 mL, 1.5M) was treated with a 6N aqueous hydrochloric acid solution (7.71 mL, 1.2M). The reaction solution was heated to 110° C., where it stirred for 4 h and was then allowed to completely cool down to 25° C. The reaction was then diluted with water (200 mL). The resulting white precipitate was collected by filtration, washed with water (2×50 mL), and dried in vacuo to afford 4-chloro-5-phenoxy-2H-pyridazin-3-one (1.78 g, 86%) as a white solid; ES+-HRMS m/e calcd for C10H7N2O2Cl [M+H+] 223.0269, found 223.0269.
Reaction SMILES: C[Al](C)C.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH2:15][CH2:16][C:17]2[CH:18]=[C:19]([NH2:22])[NH:20][N:21]=2)[CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1.[CH2:23]1[CH:28]2[CH2:29][CH2:30][CH2:31][N:27]2[CH2:26][CH2:25][N:24]1[C:32]1[N:37]=[CH:36][C:35]([C:38](OC)=[O:39])=[CH:34][N:33]=1>C1(C)C=CC=CC=1>[CH2:23]1[CH:28]2[CH2:29][CH2:30][CH2:31][N:27]2[CH2:26][CH2:25][N:24]1[C:32]1[N:37]=[CH:36][C:35]([C:38]([NH:22][C:19]2[NH:20][N:21]=[C:17]([CH2:16][CH2:15][C:9]3[CH:8]=[C:7]([O:6][CH3:5])[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=3)[CH:18]=2)=[O:39])=[CH:34][N:33]=1
Reactant: COC(=O)c1cnc(N2CCN3CCCC3C2)nc1
Reactant: COc1cc(CCc2cc(N)[nH]n2)cc(OC)c1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(CCc2cc(NC(=O)c3cnc(N4CCN5CCCC5C4)nc3)[nH]n2)cc(OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 29.6 %

Procedure:
Trimethylaluminium (2M in toluene, 2.55 ml, 5.10 mmol) was added dropwise to a stirred suspension of 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (504 mg, 2.04 mmol) and methyl 2-(3,4,6,7,8,8a-hexahydro-1H-pyrrolo[2,1-c]pyrazin-2-yl)pyrimidine-5-carboxylate (535 mg, 2.04 mmol) in toluene (10.20 ml) at 25° C. The resulting solution was stirred at ambient temperature for 18 h and then at 60° C. for 2 h. The reaction mixture was quenched with methanol (20 mL) and treated with HCl (2N aqueous solution, until a freely stirred solution was obtained). The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH and evaporated to dryness to afford impure product. The impure material was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 0.1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (288 mg, 30%) as a solid.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[F:21][CH2:22][CH2:23][NH:24][CH2:25][CH:26]1[CH2:30][CH2:29][NH:28][CH2:27]1.C1CCN2C(=NCCC2)CC1>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:28]4[CH2:29][CH2:30][CH:26]([CH2:25][NH:24][CH2:23][CH2:22][F:21])[CH2:27]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: FCCNCC1CCNC1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCC(CNCCF)C3)c(F)cc2c1=O
Reaction time: 8 h
Yield: 48.4 %

Procedure:
A suspension of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (200 mg), 3-(2-fluoroethylaminomethyl)pyrrolidine (165 mg) and 1,8-diazabicyclo[5,4,0]-7-undecene (100 mg) in absolute acetonitrile (2 ml) was refluxed for an hour. After cooling, the reaction mixture was concentrated and to the residue was added acetonitrile-ether (1:1, 5 ml). The solution was allowed to stand overnight at 5° C., then the resulting precipitate was collected by filtration and recrystallized from chloroform-methanol-ether to give the title compound (140 mg), mp 134°-138° C.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7].Cl[C:14]1[N:19]=[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]3)=[C:23]([O:33][CH3:34])[CH:22]=2)[CH:17]=[CH:16][CH:15]=1>>[CH3:34][O:33][C:23]1[CH:22]=[C:21]([NH:20][C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([NH:7][C:6]3[CH:8]=[CH:9][CH:10]=[C:4]([O:3][C:2]([F:11])([F:12])[F:1])[CH:5]=3)[N:19]=2)[CH:26]=[CH:25][C:24]=1[N:27]1[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]1
Reactant: COc1cc(Nc2cccc(Cl)n2)ccc1-n1cnc(C)c1
Reactant: Nc1cccc(OC(F)(F)F)c1
Product: COc1cc(Nc2cccc(Nc3cccc(OC(F)(F)F)c3)n2)ccc1-n1cnc(C)c1

Procedure:
Prepared in analogy to example 62 from 3-(trifluoromethoxy)aniline and (6-chloro-pyridin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine. The title compound was obtained as a brownish solid (Yield=3%). MS ISP (m/e): 456.3 (100) [(M+H)+].
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6](/[C:8](=[N:11]\[S@@:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[O:13])/[CH2:9][F:10])[C:5]([F:18])=[C:4]([Si:19]([CH2:24][CH3:25])([CH2:22][CH3:23])[CH2:20][CH3:21])[CH:3]=1.C1COCC1.[Cl-].[C:32]([O:36][C:37](=[O:40])[CH2:38][Zn+])([CH3:35])([CH3:34])[CH3:33]>C([O-])(O)=O.[Na+].O>[Br:1][C:2]1[N:7]=[C:6]([C@:8]([NH:11][S@@:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[O:13])([CH2:9][F:10])[CH2:38][C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:40])[C:5]([F:18])=[C:4]([Si:19]([CH2:20][CH3:21])([CH2:22][CH3:23])[CH2:24][CH3:25])[CH:3]=1
Reactant: CC(C)(C)OC(=O)C[Zn+]
Reactant: CC[Si](CC)(CC)c1cc(Br)nc(/C(CF)=N\[S@](=O)C(C)(C)C)c1F
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC[Si](CC)(CC)c1cc(Br)nc([C@](CF)(CC(=O)OC(C)(C)C)N[S@](=O)C(C)(C)C)c1F
Temperature: 0 °C

Procedure:
To a 1000 mL 3-neck round-bottomed flask equipped with an addition funnel and internal temperature probe was added (R,E)-N-(1-(6-bromo-3-fluoro-4-(triethylsilyl)pyridin-2-yl)-2-fluoroethylidene)-2-methylpropane-2-sulfinamide (43.3 g, 95 mmol) and THF (400 mL). The mixture was cooled to 0° C. and 2-tert-butoxy-2-oxoethylzinc chloride (Rieke Metals; 458 mL, 229 mmol, 0.5 M in diethyl ether) was added dropwise over 1 h keeping the internal temperature under 3° C. After the addition the ice bath was allowed to melt and warm to rt overnight. The reaction mixture was diluted with sat NaHCO3 (200 mL) and water (200 mL) and extracted with EtOAc (3×200 mL). The combined extracts were washed with brine, dried (Na2SO4) and concentrated onto silica. Purification by silica gel chromatography (Gradient: 0.0 to 25% EtOAc/hexane, 1500 g RediSep column) afforded:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH3:13][C:14]1(C)[C:18](C)(C)OB(C(C)=C)O1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1.O>O.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>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:14]([CH3:18])=[CH2:13])=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Reactant: COc1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C=C(C)c1ccc(OC)cc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 52.9 %

Procedure:
To 1-chloro-4-methoxy-2-nitrobenzene (5.03 g, 26.8 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (5.41 g, 32.2 mmol), bis(triphenylphosphine)palladium(II) chloride (1.50 g, 2.15 mmol), and sodium carbonate (3.41 g, 32.2 mmol) was added dioxane/water (4:1, 100 mL:25 mL). The reaction was heated at 80° C. for 5 hours. The reaction was cooled to room temperature overnight. The reaction mixture was diluted with water, extracted with ethyl acetate (3×), dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography using 0-5% ethyl acetate/hexanes as eluent followed by drying in vacuum oven provided the title compound as an orange oil (2.74 g, 53%): 1H NMR (400 MHz, CDCl3) δ 7.37 (d, J=2.7 Hz, 1H), 7.23 (d, J=8.6 Hz, 1H), 7.08 (dd, J=8.5, 2.6 Hz, 1H), 5.24-4.75 (m, 2H), 3.86 (s, 3H), 2.19-1.88 (m, 3H); 13C NMR (101 MHz, CDCl3) δ 158.79, 148.61, 142.53, 131.41, 131.32, 119.24, 115.20, 108.64, 55.84, 23.38; EIMS m/z 193 ([M]+).
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:16])/[CH:7]=[CH:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:2]([CH3:4])[CH3:3].II>C1(C)C=CC=CC=1>[CH2:1]([NH:5][C:6](=[O:16])/[CH:7]=[CH:8]/[CH:9]=[CH:10]/[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:2]([CH3:4])[CH3:3]
Reactant: CCCCC/C=C\C=C\C(=O)NCC(C)C
Agent: II
Solvent: Cc1ccccc1
Product: CCCCC/C=C/C=C/C(=O)NCC(C)C

Procedure:
277 mg of 2E,4Z-decadienoic acid-N-isobutylamide from Example 1 were stirred with 29 mg of iodine in 10 ml of toluene for one hour at room temperature. The mixture was chromatographed on silica gel 60 with the eluent hexane/ethyl acetate 5:1. Yield: 61 mg (>95%, NMR); 1H-NMR (CDCl3; 200 MHz): 7.19 (1H, dd, 14.9 Hz, 9.7 Hz), 6.13 (1H, dd, 15.1 Hz, 9.6 Hz), 6.07 (1H, dd, 15.1 Hz, 6.4 Hz), 5.75 (1H, d 14.9 Hz), 5.50 (1H, bs), 3.17 (2H, dd, 6.9 Hz, 6.1 Hz), 2.14 (2H, dd, 7 Hz, 6.4 Hz), 1.80 (1H, m, 6.7 Hz), 1.42 (2H, m, 7.1 Hz), 1.37-1.22 (4H, m), 0.93 (6H, d, 6.7 Hz), 0.89 (3H, m) ppm.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[Cl:10][CH2:11][CH2:12][C:13](Cl)=[O:14]>C1C=CC=CC=1>[CH3:1][S:2][C:3]1[CH:4]=[C:5]([NH:6][C:13](=[O:14])[CH2:12][CH2:11][Cl:10])[CH:7]=[CH:8][CH:9]=1
Reactant: CSc1cccc(N)c1
Reactant: O=C(Cl)CCCl
Solvent: c1ccccc1
Product: CSc1cccc(NC(=O)CCCl)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3-Methylthioaniline (0.3 mole), β-chloropropionyl chloride (0.35 mole) and benzene (100 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux with stirring for a period of about 3 hours. After this time the reaction mixture is cooled to room temperature and is washed with dilute aqueous sodium bicarbonate, with dilute hydrochloric acid and with water. The washed mixture is then dried over anhydrous magnesium sulfate, filtered and stripped of benzene under reduced pressure to yield the desired product N-(3-methylthiophenyl)-β-chloropropionamide as the residue.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[CH:7][NH:6][C:5](=[O:9])[CH:4]=1.[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:10]([N:6]1[C:5](=[O:9])[CH:4]=[C:3]([NH:2][CH3:1])[N:8]=[CH:7]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrCc1ccccc1
Reactant: CNc1cc(=O)[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CNc1cc(=O)n(Cc2ccccc2)cn1
Yield: 43.6 %

Procedure:
6-(Methylamino)pyrimidin-4(3H)-one (compound 1B) (3 g, 24 mmol, 1 eq), benzyl bromide (5.7 mL, 48 mmol, 2 eq) and potassium carbonate (6.96 g, 50.4 mmol, 2.1 eq) were stirred in ethanol (30 mL) at RT overnight. The solvent was removed in vacuo and the residue purified by silica chromatography to give 2.25 g of the title compound (43%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.64 (d, J=4.29 Hz, 3H) 4.92-5.01 (m, 2H) 6.96 (q, J=4.63 Hz, 1H) 7.22-7.30 (m, 3H) 7.30-7.37 (m, 2H) 8.24 (s, 1H). [M+H] calc'd for C12H13N3O, 216; found, 216.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:12][C@@H:11]([O:13][S:14]([CH3:17])(=[O:16])=[O:15])[C@@H:10]2[C@@H:8]([N:9]2[P:18]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])=[O:19])[CH:7]=1)=[O:5])[CH3:2].[CH3:26][CH2:27][CH:28]([OH:31])[CH2:29][CH3:30].B(F)(F)F.CCOCC>CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[CH2:12][C@@H:11]([O:13][S:14]([CH3:17])(=[O:16])=[O:15])[C@@H:10]([NH:9][P:18]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])=[O:19])[C@H:8]([O:31][CH:28]([CH2:29][CH3:30])[CH2:27][CH3:26])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCC(O)CC
Reactant: CCOC(=O)C1=C[C@H]2[C@@H]([C@H](OS(C)(=O)=O)C1)N2P(=O)(OCC)OCC
Agent: FB(F)F
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](NP(=O)(OCC)OCC)[C@H](OS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1.94 g of 16 and 3-pentanol (20 mL) cooled to 0-5° C. in a 50 mL round-bottom flask equipped with a magnetic stirrer and an argon gas supply was added 736 μl boron trifluoride ethyl etherate. The reaction mixture was stirred for 16 h at RT and the reaction mixture was then diluted with 50 mL of EtOAc and twice extracted with 70 mL of water. The organic phase was separated, dried (Na2SO4, 25 g) filtered and concentrated in a rotary evaporator at 40° C./70-10 mbar to afford 2.18 g of the crude product as a yellow oil. The crude product was purified by SiO2 column chromatography eluting with tert-butyl methyl ether. The combined fractions were evaporated and dried on a rotary evaporator at 40° C./250-10 mbar to afford 1.47 g of 18 as a light yellow solid.