Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8](Br)[O:7][C:6]=1[CH3:11])=[O:4].[CH3:12][O:13][C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[CH:16][C:15]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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>[CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([C:15]2[CH:16]=[CH:17][CH:18]=[C:19]([N+:20]([O-:22])=[O:21])[C:14]=2[O:13][CH3:12])[O:7][C:6]=1[CH3:11])=[O:4]
Reactant: COC(=O)c1cc(Br)oc1C
Reactant: COc1c(B2OC(C)(C)C(C)(C)O2)cccc1[N+](=O)[O-]
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: [Na+]
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2cccc([N+](=O)[O-])c2OC)oc1C
Temperature: 100 °C
Yield: 75.4 %

Procedure:
5-Bromo-2-methyl-furan-3-carboxylic acid methyl ester 53a (0.65 g, 3.0 mmol) and 2-(2-methoxy-3-nitro-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 6a (1.0 g, 3.58 mmol) were dissolved in 1,4-dioxane (15 mL) followed by addition of tetrakis(triphenylphosphine)palladium (173 mg, 0.15 mmol) and sodium carbonate (636 mg, 6.0 mmol). The reaction mixture was heated to reflux at 100° C. for 3 hours. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was cooled and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound 5-(2-methoxy-3-nitro-phenyl)-2-methyl-furan-3-carboxylic acid methyl ester 53b (659 mg, yield 75%) as a white solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:38][CH3:39])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[C:34]([F:37])[C:35]=2[CH3:36])[C:30](O)=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].[CH3:40][N:41](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.CN>CN(C=O)C.C1COCC1>[CH2:1]([N:3]([CH2:38][CH3:39])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[C:34]([F:37])[C:35]=2[CH3:36])[C:30]([NH:41][CH3:40])=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=3[F:25])[C:12]=2[N:13]=1)[CH3:2]
Reactant: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)cc(F)c2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCN(CC)CCCNc1nc(-c2cc(C(=O)NC)cc(F)c2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.6 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-5-fluoro-4-methylbenzoic acid (30 mg, 0.055 mmol) in DMF (0.5 mL) were added HBTU (25 mg, 0.066 mmol), triethylamine (15.5 uL, 0.11 mmol) and methylamine (41.5 uL, 0.0825 mmol, 2M soln in THF). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (9.6 mg, 31.5%). LC-MS m/z 553 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:44])[C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]3[N:24]=[CH:25][C:26]4[N:32]([CH3:33])[C:31](=[O:34])[C:30]([F:36])([F:35])[CH2:29][N:28]([CH:37]5[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]5)[C:27]=4[N:43]=3)=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:37]1([N:28]2[CH2:29][C:30]([F:35])([F:36])[C:31](=[O:34])[N:32]([CH3:33])[C:26]3[CH:25]=[N:24][C:23]([NH:22][C:19]4[CH:20]=[CH:21][C:16]([C:15]([NH:14][CH:11]5[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]5)=[O:44])=[CH:17][CH:18]=4)=[N:43][C:27]2=3)[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCCC2)c2nc(Nc3ccc(C(=O)NC4CCN(C(=O)OC(C)(C)C)CC4)cc3)ncc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1C(=O)C(F)(F)CN(C2CCCCC2)c2nc(Nc3ccc(C(=O)NC4CCNCC4)cc3)ncc21
Reaction time: 1 h
Yield: 80.5 %

Procedure:
A mixture of 0.095 g (0.15 mmole) of 4-[4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-benzoylamino]-piperidine-1-carboxylic acid tert-butyl ester (I-259) 1 mL of trifluoroacetic acid and 5 mL of dichloromethane was stirred for 1 hour and then concentrated under reduced pressure. The residue was taken up in 30 mL of ethyl acetate, washed twice with 30 mL of saturated aqueous sodium bicarbonate and then brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was triturated with ether, to give 0.062 g of 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-piperidin-4-yl-benzamide (I-260).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[NH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:16]([F:24])[CH:15]=1.[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31](O)=[O:32]>N1C=CC=CC=1>[F:24][C:16]1[CH:15]=[C:14]([NH:13][C:31]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=2)=[O:32])[CH:23]=[CH:22][C:17]=1[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)c1ccc(N)cc1F
Reactant: O=C(O)c1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(NC(=O)c2ccccn2)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride was added to a pyridine (500 ml) solution of 18.9 g of methyl 4-amino-2-fluorobenzoate and 16.5 g of picolinic acid, and stirred at room temperature for 2 hours. The solvent was evaporated away under reduced pressure, 600 ml of ethyl acetate was added to the residue, the organic layer was washed with aqueous 0.25 N hydrochloric acid solution, aqueous 0.25 N sodium hydroxide solution and saturated saline water, dried, concentrated under reduced pressure, solidified from a mixed solvent of hexane/ethyl acetate, and the solid was taken out through filtration. This was dried under reduced pressure to obtain 28.3 g of the entitled compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([C:12]2[CH:17]=[CH:16][C:15]([C@H:18]([NH:20][C:21]([C:23]3([NH2:27])[CH2:26][O:25][CH2:24]3)=[O:22])[CH3:19])=[C:14]([F:28])[CH:13]=2)=[CH:7][CH:8]=[CH:9][C:10]=1[Cl:11])=[O:4].[O:29]1[C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=[N:30]1>>[CH3:1][O:2][C:3]([C:5]1[C:6]([C:12]2[CH:17]=[CH:16][C:15]([C@H:18]([NH:20][C:21]([C:23]3([NH:27][C:34]([C:33]4[O:29][N:30]=[CH:31][CH:32]=4)=[O:35])[CH2:24][O:25][CH2:26]3)=[O:22])[CH3:19])=[C:14]([F:28])[CH:13]=2)=[CH:7][CH:8]=[CH:9][C:10]=1[Cl:11])=[O:4]
Reactant: COC(=O)c1c(Cl)cccc1-c1ccc([C@@H](C)NC(=O)C2(N)COC2)c(F)c1
Reactant: O=C(O)c1ccno1
Product: COC(=O)c1c(Cl)cccc1-c1ccc([C@@H](C)NC(=O)C2(NC(=O)c3ccno3)COC2)c(F)c1

Procedure:
The title compound was prepared in analogy to example 1 using intermediate 4 instead of intermediate 1 and isoxazole-5-carboxylic acid instead of 3-fluoro-5-(trifluoromethyl)benzoic acid and was obtained as white solid. MS: 502.1 [M+H]+.
Reaction SMILES: [H-].[Na+].[C:3]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N:15]3[C:19](=[O:20])[C:18]([CH3:22])([CH3:21])[NH:17][C:16]3=[O:23])[CH:13]=2)[C:8]([CH3:25])([CH3:24])[CH2:7]1)(=[O:5])[CH3:4].[Cl:26][C:27]1[CH:32]=[C:31]([CH2:33]Cl)[CH:30]=[CH:29][N:28]=1>CN(C)C=O.O>[C:3]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N:15]3[C:19](=[O:20])[C:18]([CH3:22])([CH3:21])[N:17]([CH2:33][C:31]4[CH:30]=[CH:29][N:28]=[C:27]([Cl:26])[CH:32]=4)[C:16]3=[O:23])[CH:13]=2)[C:8]([CH3:25])([CH3:24])[CH2:7]1)(=[O:5])[CH3:4]
Reactant: ClCc1ccnc(Cl)c1
Reactant: CC(=O)N1CC(C)(C)c2ccc(N3C(=O)NC(C)(C)C3=O)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)N1CC(C)(C)c2ccc(N3C(=O)N(Cc4ccnc(Cl)c4)C(C)(C)C3=O)cc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.6 %

Procedure:
To 949 mg of sodium hydride are added dropwise, under argon, 5 mL of dimethylformamide, followed by addition of a solution of 6.8 g of 3-(1-acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-5,5-dimethylimidazolidine-2,4-dione obtained in stage g) below in 40 mL of dimethylformamide. The solution obtained is stirred for 1.5 hours at 25° C., followed by addition of 5.24 g of 2-chloro-4-chloromethylpyridine obtained in stage b) below. The reaction mixture is stirred at room temperature for 15 hours and diluted with 300 mL of water, and the solid formed is filtered off, washed with three times 20 mL of water and with twice 20 mL of diethyl ether and dried to give 8.8 g of 3-(1-acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-1-[(2-chloropyridin-4-yl)methyl]-5,5-dimethylimidazolidine-2,4-dione in the form of a beige-coloured solid, the characteristics of which are as follows:
Reaction SMILES: [CH3:1][CH:2]([CH3:12])[CH2:3][CH2:4][C@@H:5]([CH2:9][CH:10]=[CH2:11])[C:6](O)=[O:7].Cl.[CH3:14][NH:15][O:16][CH3:17].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>ClCCl>[CH3:17][O:16][N:15]([CH3:14])[C:6](=[O:7])[C@@H:5]([CH2:4][CH2:3][CH:2]([CH3:12])[CH3:1])[CH2:9][CH:10]=[CH2:11]
Reactant: CNOC
Reactant: C=CC[C@H](CCC(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C=CC[C@H](CCC(C)C)C(=O)N(C)OC

Procedure:
A solution of Example 8D (4.54 g, 26.7 mmol), N,O-dimethyl hydroxylamine hydrochloride (5.6 g, 57 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.19 g, 27 mmol), 1-hydroxybenzotriazole (4.12 g, 30.5 mmol), and N-methylmorpholine (7.0 mL, 64 mmol) in dichloromethane (270 mL) at room temperature was stirred for 4 hours, diluted with dichloromethane, washed sequentially with aqueous NaHCO3, brine, 10% KHSO4, and brine, dried (MgSO4), filtered, and concentrated. Flash column chromatography (silica gel, 10% ethyl acetate/hexanes) provided the desired product. MS (ESI(+)) m/e 214 (M+H)+.
Reaction SMILES: [I:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([CH:10]([OH:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1.[C@:19]12([CH3:31])[C:25]([CH3:27])([CH3:26])[CH:22]([CH2:23][CH2:24]1)[CH2:21][CH:20]2[C:28](Cl)=[O:29]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C@:19]12([CH3:31])[C:25]([CH3:26])([CH3:27])[CH:22]([CH2:23][CH2:24]1)[CH2:21][CH:20]2[C:28]([O:15][CH:10]([C:5]1[CH:6]=[C:7]([O:8][CH3:9])[C:2]([I:1])=[CH:3][C:4]=1[N+:16]([O-:18])=[O:17])[C:11]([CH3:14])([CH3:13])[CH3:12])=[O:29]
Reactant: CC1(C)C2CC[C@@]1(C)C(C(=O)Cl)C2
Reactant: COc1cc(C(O)C(C)(C)C)c([N+](=O)[O-])cc1I
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1cc(C(OC(=O)C2CC3CC[C@]2(C)C3(C)C)C(C)(C)C)c([N+](=O)[O-])cc1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.1 %

Procedure:
To a solution of racemic (R/S)-1-(4-iodo-5-methoxy-2-nitrophenyl)-2,2-dimethyl-1-propanol (395 mg, 1.1 mmol) and DMAP (263 mg, 2.16 mmol) in anhydrous CH2Cl2 (5.0 mL), (1S)-camphanic chloride (Corrie et al., 1992, which is incorporated by reference) (350 mg, 1.62 mmol) was added, and the mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction mixture was diluted with CH2Cl2 (50 mL) and washed with saturated NaHCO3 solution (50 mL). The organic phase was dried over Na2SO4, concentrated in vacuo, and the residue was purified by silica gel column chromatography to yield (R/S)-1-(4-iodo-5-methoxy-2-nitrophenyl)-2,2-dimethyl-1-propyl(1S)-camphanate (490 mg, 80%, 1:1 mixture of diastereomers).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:29])[CH:9]=P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:4][C:3]=1[CH3:30].[Cl:31][C:32]1[CH:33]=[C:34]([C:39](=O)[C:40]([F:43])([F:42])[F:41])[CH:35]=[C:36]([Cl:38])[CH:37]=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:29])[CH:9]=[C:39]([C:34]2[CH:35]=[C:36]([Cl:38])[CH:37]=[C:32]([Cl:31])[CH:33]=2)[C:40]([F:43])([F:42])[F:41])=[CH:4][C:3]=1[CH3:30]
Reactant: Cc1cc(C(=O)C=P(c2ccccc2)(c2ccccc2)c2ccccc2)ccc1Br
Reactant: O=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Solvent: Cc1ccccc1
Product: Cc1cc(C(=O)C=C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1Br
Yield: 86.8 %

Procedure:
473 mg of 1-(4-Bromo-3-methyl-phenyl)-2-(triphenylphosphanylidene)-ethanone (Va) was refluxed with 243 mg of 1-(3,5-Dichloro-phenyl)-2,2,2-trifluoro-ethanone (VIa) (Journal of Physical Organic Chemistry (1989), 2(4), 363-6) in 3 ml of toluene for 3 hours. The solvent was then evaporated, and the residue was triturated with the mixture hexane:ethyl acetate 20:1. The solid that separated was filtered off and the filtrate after evaporation was purified on silica gel (40 g, hexane:acetate 10:1) giving 380 mg (86%) of 1-(4-Bromo-3-methyl-phenyl)-3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-but-2-en-1-one (IVa) as a yellow oil which solidified on standing (mixture of E and Z isomers). 1H-NMR (CDCl3, δ in ppm): 2.41 (s) and 2.46 (s) (total of 3H), 6.80-7.80 (m, total of 7H).
Reaction SMILES: C[O:2][C:3]1[C:8]2[NH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:7]=2[C:6]([C:18]([OH:20])=[O:19])=[CH:5][CH:4]=1.OS(O)(=O)=O.[CH3:26]O>>[CH3:26][O:20][C:18]([C:6]1[C:7]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:9][C:8]=2[C:3]([OH:2])=[CH:4][CH:5]=1)=[O:19]
Reactant: CO
Reactant: COc1ccc(C(=O)O)c2nc(-c3ccccc3)[nH]c12
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(O)c2[nH]c(-c3ccccc3)nc12
Temperature: 25 °C
Yield: 83 %

Procedure:
7-methoxy-2-phenyl-1H-benzoimidazole-4-carboxylic acid (2.00 g, 7.46 mmol) obtained in step 4 was dissolved in 30 ml of methanol, H2SO4 (2.00 ml, 37.28 mmol) was added dropwise thereto and refluxed for 15 hours. The resulting solution was cooled to room temperature, concentrated under a reduced pressure to remove methanol, and the residue was neutralized with NaHCO3. Then, the neutralized residue was extracted with ethyl acetate and concentrated under a reduced pressure to obtain a residue which purified by recrystallization from CHCl3/MeOH/hexane to obtain the title compound (1.7 g, 5.89 mmol) in a yield of 83%.
Reaction SMILES: O[C:2]1([C:12]#[C:13][C:14]([CH3:18])=[CH:15][CH2:16][OH:17])[C:7]([CH3:9])([CH3:8])[CH2:6][C:5](=[O:10])[CH:4]=[C:3]1[CH3:11].[OH-].[Na+]>C(O)CC.O.[Zn]>[OH:17][CH2:16][CH2:15][C:14]([CH3:18])=[C:13]=[CH:12][CH:2]1[C:7]([CH3:8])([CH3:9])[CH2:6][C:5](=[O:10])[CH:4]=[C:3]1[CH3:11]
Reactant: CC(C#CC1(O)C(C)=CC(=O)CC1(C)C)=CCO
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: O
Solvent: CCCO
Product: CC(=C=CC1C(C)=CC(=O)CC1(C)C)CCO
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 73.6 %

Procedure:
10 g (40 mmol) of 4-hydroxy-4-(5-hydroxy-3-methyl-3-penten-1-ynyl)-3,5,5-trimethyl-2-cyclohexen-1-one (prepared in accordance with Example 1) were dissolved in 200 ml of n-propanol/water (1:1, v/v) under argon in a 500 ml multi-necked flask provided with stirrer, thermometer, dropping funnel and gasification headpiece and treated with 20.9 g (0.32 g-atoms) of zinc powder. Thereupon, 120 ml (0.12 mol) of 1N sodium hydroxide solution were added dropwise thereto in 5 minutes at room temperature while stirring and the mixture was stirred for a further 1 hour. The resulting mixture was then worked-up in a manner analogous to that described in Example 1 and there were obtained 9.2 g of crude product. The purification on silica gel in a manner analogous to that described in Example 1 gave 6.9 g (74.3%) of 4-(5-hydroxy-3-methyl-1,2-pentadienyl)-3,5,5-trimethyl-2-cyclohexen-1-one in the form of an oil. The structure of this compound was characterized unequivocally by microanalysis, NMR, IR and MS spectra.
Reaction SMILES: C(C1N=C(N2CCOCC2)C2N=NN(CC3C=CC(OC)=CC=3)C=2N=1)(C)(C)C.[C:29]([C:33]1[N:34]=[C:35](Cl)[C:36]2[N:41]=[N:40][N:39]([CH2:42][C:43]3[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=3)[C:37]=2[N:38]=1)([CH3:32])([CH3:31])[CH3:30].Cl.[F:53][C:54]1([F:61])[C:58]([F:60])([F:59])[CH2:57][NH:56][CH2:55]1>>[C:29]([C:33]1[N:34]=[C:35]([N:56]2[CH2:57][C:58]([F:60])([F:59])[C:54]([F:61])([F:53])[CH2:55]2)[C:36]2[N:41]=[N:40][N:39]([CH2:42][C:43]3[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=3)[C:37]=2[N:38]=1)([CH3:32])([CH3:31])[CH3:30]
Reactant: FC1(F)CNCC1(F)F
Reactant: COc1ccc(Cn2nnc3c(Cl)nc(C(C)(C)C)nc32)cc1
Agent: COc1ccc(Cn2nnc3c(N4CCOCC4)nc(C(C)(C)C)nc32)cc1
Agent: Cl
Product: COc1ccc(Cn2nnc3c(N4CC(F)(F)C(F)(F)C4)nc(C(C)(C)C)nc32)cc1

Procedure:
In analogy to the procedure described for the synthesis of 4-(5-tert-butyl-3-(4-methoxybenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)morpholine (example 58, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(4-methoxybenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3,3,4,4-tetrafluoropyrrolidine hydrochloride and used without further purification in the consecutive step.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14](I)[CH:13]=2)=[O:10])=[CH:4][C:3]=1[O:19][CH3:20].[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCCC1.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>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:13]=2)=[O:10])=[CH:4][C:3]=1[O:19][CH3:20]
Reactant: OB(O)c1ccccc1
Reactant: COc1cc(CC(=O)Nc2cccc(I)c2)ccc1O
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: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(CC(=O)Nc2cccc(-c3ccccc3)c2)ccc1O
Yield: 82.8 %

Procedure:
Intermediate 1 (500 mg), phenylboronic acid (300 mg), tetrakis(triphenylphosphine)palladium (0) (150 mg) are dissolved in tetrahydrofuran (20 ml), and thereto are added cesium carbonate (850 mg) and water (10 ml). The mixture is heated under reflux for 18 hours under argon atmosphere. The reaction solution is extracted with ethyl acetate, and the organic layer is dried over sodium sulfate, and the solvent is evaporated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: gradient from 0% to 100% hexane/ethyl acetate) to give the desired compound (360 mg).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1)=[O:3].OCC(C1C=CC=CC=1)=O.[N:21]1[CH:26]=[CH:25][C:24]([CH:27]=O)=[CH:23][CH:22]=1.[OH-].[Na+]>>[NH2:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH:1]=[CH:27][C:24]2[CH:25]=[CH:26][N:21]=[CH:22][CH:23]=2)=[CH:5][CH:6]=1
Reactant: O=Cc1ccncc1
Reactant: CC(=O)c1ccc(N)cc1
Agent: O=C(CO)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: Nc1ccc(C(=O)C=Cc2ccncc2)cc1
Yield: 98.2 %

Procedure:
The procedure is as in Example 11, starting from 1.35 g of 4-aminoacetophenone (instead of 24 g of 2-hydroxyacetophenone) and 2.14 g of pyridine-4-carbaldehyde instead of 21 g and using a 2.5 N aqueous sodium hydroxide solution instead of an 11 N solution. 2.2 g of 1-(4-aminophenyl) 3-(4-pyridyl) 2-propene-1-one which melts at 207° C. are obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:8][CH2:7][CH:6]=[CH:5][CH2:4][O:3]1.C(=O)([O-])[O-:11].[Na+].[Na+].C(#N)C.OO>CO.[Cl-].[Na+].O>[CH3:1][C:2]1([CH3:9])[O:8][CH2:7][CH:6]2[CH:5]([O:11]2)[CH2:4][O:3]1
Reactant: O=C([O-])[O-]
Reactant: CC1(C)OCC=CCO1
Agent: OO
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: CO
Product: CC1(C)OCC2OC2CO1
Reaction time: 5 h
Yield: 98.6 %

Procedure:
To a stirred solution of 2,2-dimethyl-4,7-dihydro-1,3-dioxepin (151.4 g, 1.18 mole) in methanol (500 ml) was added anhydrous sodium carbonate (85 g), followed by acetonitrile (150 ml). This suspension was treated with aqueous hydrogen peroxide (30%; 315 ml, 2.78 mole) dropwise at such a rate that the temperature was maintained at 40°. After 5 hr. at 40°, the reaction mixture was poured into brine (1.5 l) and the solution was extracted with n-butanol. The organic layer was washed with brine, dried, and, then, freed of the solvent in vacuo. Vacuum distillation of the residue yielded the product (III) as a colorless liquid (114 g) (67% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH2:7][CH:6]=[CH:5]2.C(=O)(O)[O-:13].[Na+].C1C=C(Cl)C=C(C(OO)=O)C=1>ClCCl.C1C=C(Cl)C=C(C(OO)=O)C=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([CH2:8][CH2:7][C@H:6]3[O:13][C@H:5]32)=[CH:10][CH:11]=1
Reactant: O=C([O-])O
Reactant: Brc1ccc2c(c1)C=CCC2
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: Brc1ccc2c(c1)[C@@H]1O[C@@H]1CC2
Temperature: 2.5 °C
Reaction time: 1.5 h
Yield: 98 %

Procedure:
To a solution of 6-bromo-1,2-dihydronaphthalene (250 g, 1.20 mol) in dichloromethane (3.75 L) add saturated aqueous sodium bicarbonate (1250 mL) and cool to 0-5° C. Add MCPBA (77%, 275 g, 1.23 mol, 1.03 eq) in portions. Stir the mixture mechanically at 0-5° C. for 1.5 hr. and allow to warm to room temperature. Stir at room temperature for approximately 1.5 hr. and add additional MCPBA (77%, 15.0 g, 67 mmol, 0.05 eq) at room temperature and stir for approximately one hour. Dilute the mixture with dichloromethane (3750 mL) and separate the layers. Wash the organic layer with saturated aqueous sodium bicarbonate (3 L). Mix a 10% aqueous sodium bisulfate solution (3750 mL) with aqueous saturated sodium bicarbonate (1250 mL) to prepare a solution with a final pH of approximately 7. Add this solution to the dichloromethane layer and stir at room temperature for about 10 min. Separate the layers, wash the organic layer with saturated aqueous sodium bicarbonate (3 L) and brine (3 L). Concentrate in vacuo to obtain the title compound as an oil (263 g, 98%). GC/MS m/z (79Br/81Br) 224/226 [M+].
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:13]([OH:15])=[O:14])=[N:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1.[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.CO.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:10]1([CH2:9][O:8][C:7]2[N:6]=[C:5]([C:13]([OH:15])=[O:14])[CH:4]=[CH:3][C:2]=2[N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:12][CH2:11]1
Reactant: C1CCNC1
Reactant: O=C(O)c1ccc(Br)c(OCC2CC2)n1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CO
Product: O=C(O)c1ccc(N2CCCC2)c(OCC2CC2)n1
Temperature: 95 °C
Yield: 49.6 %

Procedure:
A mixture of 5-bromo-6-(cyclopropylmethoxy)-pyridine-2-carboxylic acid (Example 9 d, 600 mg, 2 mmol), pyrrolidine (CAN 123-75-1, 1.57 g 22 mmol), tris(dibenzylidene-acetone)dipalladium (CAN 52409-22-0, 202 mg 0.2 mmol), rac-BINAP (CAN 76189-55-4, 275 mg, 0.4 mmol) and Cs2CO3 (2.88 mg 9 mmol) in toluene (50 mL) was heated to 95° C. for 20 h in a nitrogen atmosphere. Then the mixture was diluted with methanol (30 mL), filtered and the filtrate was evaporated to dryness. The residue was purified by column chromatography (silica gel, 5 g, eluting with 10% ethyl acetate in petroleum ether) to obtain the product as a white solid (0.26 g 45%), MS (LC/MS): 263.1 [M+H]+.