Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH2:10][CH2:9][N:8]=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])[C:6]=2[CH:19]=1.[N:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.CN(C)C=O>[F:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:7]1[C:6]2[CH:19]=[C:2]([C:23]3[CH:24]=[CH:25][N:20]=[CH:21][CH:22]=3)[CH:3]=[CH:4][C:5]=2[NH:11][CH2:10][CH2:9][N:8]=1
Reactant: Fc1ccccc1C1=NCCNc2ccc(Br)cc21
Reactant: OB(O)c1ccncc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ccccc1C1=NCCNc2ccc(-c3ccncc3)cc21
Temperature: 150 °C
Yield: 41.4 %

Procedure:
A 5-mL microwave tube was charged with 7-bromo-5-(2-fluorophenyl)-2,3-dihydro-1H-1,4-benzodiazepine (85 mg), 4-pyridylboronic acid (100 mg), dichlorobis(triphenylphosphine)palladium(II) (20 mg), dimethylformamide (3.5 mL) and a saturated solution of sodium carbonate (0.5 mL). The reaction was heated to 150° C. for 360 seconds using microwave irradiation. The reaction was concentrated to dryness and the residue was taken up in water and extracted with ethyl acetate. The organic extracts were combined and dried over magnesium sulfate. The drying agent was filtered and the filtrate was concentrated to an oil. Silica gel purification provided the title compound (5-(2-fluorophenyl)-7-(4-pyridinyl)-2,3-dihydro-1H-1,4-benzodiazepine, 35 mg) as an off-white crystalline solid. H1 NMR (d6-dmso): 8.40 (d, 2H), 7.57 (dd, 1H), 7.44 (t, 2H), 7.25 (m, 3H), 7.18 (m, 1H), 7.12 (m, 1H), 6.99 (br t, 1H), 6.85 (d, 1H), 3.98 (m, 2H), 3.54 (m, 2H). Mass (ES+)=318.2 (100%).
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[CH:2]([CH3:4])[OH:3].[CH2:8](Cl)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CC(C)([O-])C.[Na+]>CN(C)C=O>[CH2:8]([O:3][CH:2]([CH3:4])[C:1]([O:6][CH3:7])=[O:5])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: ClCc1ccccc1
Reactant: COC(=O)C(C)O
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)OCc1ccccc1
Temperature: 30 °C
Reaction time: 6 h

Procedure:
To a pre-cooled solution of racemic methyl lactate (200 g) in dimethyl formamide (400 ml) at 0-10° C., added benzyl chloride (218.8 g). Sodium tertiary butoxide (224.6 g) was added to the reaction mixture at 0-10° C. and stirred for 6 hours at 25-35° C. After completion of the reaction, the reaction mixture was quenched with water and extracted with toluene. The toluene layer was washed with water followed by 10% sodium chloride solution. The obtained toluene layer containing title compound was taken to next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[CH:5][C:4]=1[CH:13](Cl)[C:14]([CH3:19])([N+:16]([O-:18])=[O:17])[CH3:15].C(O)C>[H][H].[C].[Pd]>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[CH:5][C:4]=1[CH2:13][C:14]([CH3:19])([N+:16]([O-:18])=[O:17])[CH3:15]
Reactant: COc1ccc(C(Cl)C(C)(C)[N+](=O)[O-])c(OC)c1OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(CC(C)(C)[N+](=O)[O-])c(OC)c1OC
Yield: 89.1 %

Procedure:
A mixture of 5 g of 1-(2,3,4-trimethoxyphenyl)-1-chloro-2-methyl-2-nitropropane, 2 g of 10% palladium-carbon and 50 ml of ethanol is shaken at room temperature in hydrogen gas atmosphere under atmospheric pressure. After the uptake of hydrogen is completed, insoluble materials are removed by filtration, and the filtrate is evaporated to remove solvent. 3.95 g of 1-(2,3,4-trimethoxyphenyl)-2-methyl-2-nitropropane are thereby obtained as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13](OC)=[C:12]([F:18])[CH:11]=2)[CH:5]=[C:4]([Cl:19])[C:3]=1[N:20]=[CH:21][N:22]([CH3:24])[CH3:23].FC1C=C(C=CC=1)C=O>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:18])[CH:11]=2)[CH:5]=[C:4]([Cl:19])[C:3]=1[N:20]=[CH:21][N:22]([CH3:24])[CH3:23]
Reactant: COc1ccc(C=Nc2cc(Cl)c(N=CN(C)C)c(Cl)c2)cc1F
Agent: O=Cc1cccc(F)c1
Solvent: CCO
Product: CN(C)C=Nc1c(Cl)cc(N=Cc2cccc(F)c2)cc1Cl

Procedure:
A 7.0 g. amount of N'-(4-amino-2,6-dichlorophenyl)-N,N-dimethylformamidine (Example 9) is dissolved in 25 ml. of absolute ethanol then 3.7 g. of m-fluorobenzaldehyde is added and the mixture is refluxed for one hour. The solution is evaporated to an amber syrup which crystallizes. The material is dissolved in 50 ml. of refluxing ether and hexane is added until turbidity results. The crystalline product is collected and washed with hexane. The product is recrystallized from ether/hexane to give 1.4 g. of the product of the Example as hard yellow crystals, m.p. 95°-96° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:17])[CH3:16])=[CH:11][C:10]=1[OH:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:24]1[C:26]([CH3:31])([CH2:27][CH2:28][CH:29]=[CH2:30])[CH2:25]1.C(=O)([O-])[O-].[K+].[K+]>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:16])[CH3:17])=[CH:11][C:10]=1[O:23][CH2:25][C:26]([OH:24])([CH3:31])[CH2:27][CH2:28][CH:29]=[CH2:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCCC1(C)CO1
Reactant: CC(C)(C)CC(C)(C)c1ccc(OCc2ccccc2)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C=CCCC(C)(O)COc1cc(C(C)(C)CC(C)(C)C)ccc1OCc1ccccc1
Temperature: 120 °C
Reaction time: 48 h
Yield: 82.8 %

Procedure:
A mixture of 7.4 g (23.7 mmole) of 2-benzyloxy-5-t-octylphenol, 5.3 g (47.4 mmole) of 1,2-epoxy-2-methyl-5-hexene and 3.27 g (23.7 mmole) of potassium carbonate was heated at 120° C., with stirring, under nitrogen, for 48 hours. The cooled reaction mixture was extracted with ethyl acetate, and the resulting solution was washed with water followed by saturated sodium chloride solution. Evaporation of the washed ethyl acetate solution in vacuo, followed by purification of the residue by column chromatography on silica gel, eluting with 9:1 toluene-ethyl acetate, gave 8.33 g of the title compound as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C:3]=1[CH:4]=[CH:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C:10]2=[O:22].[CH2:23]([O:25][C:26](Cl)=[O:27])[CH3:24]>N1C=CC=CC=1>[CH2:23]([O:25][C:26]([NH:1][C:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C:3]=1[CH:4]=[CH:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C:10]2=[O:22])=[O:27])[CH3:24]
Reactant: C[C@]12CCC(=O)C(N)=C1C=C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)NC1=C2C=C[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]2(C)CCC1=O
Reaction time: 0.5 h

Procedure:
To a stirred solution of 3.0 g of 4-aminoandrosta-4,6-dien-3,17-dione in 15 ml of dry pyridine, cooled to 0° to -5° C., 1.25 ml of ethylchlorocarbonate are added dropwise. The mixture is cooled and stirred for 30 minutes and then, after the temperature is left to rise to 20° C., it is quenched in 100 ml of water. The mixture is extracted several times with ethyl acetate, washed with aqueous sodium chloride solution until neutral and dried. The solvent is then distilled in vacuo to obtaind 3.2 g of crude which is purified by crystallization with warm ethyl acetate to yield 2.95 g of pure title compound,
Reaction SMILES: C([N:8]([CH2:28][C@H:29]([OH:51])[CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([O:38]CC2C=CC=CC=2)=[C:34]([NH:46][S:47]([CH3:50])(=[O:49])=[O:48])[CH:33]=1)[C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:27]=[CH:26][C:18]([O:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)C1C=CC=CC=1>C(O)C.[Pd]>[OH:51][C@H:29]([CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([NH:46][S:47]([CH3:50])(=[O:49])=[O:48])[CH:33]=1)[CH2:28][NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:27]=[CH:26][C:18]([O:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1
Reactant: CCOC(=O)COc1ccc([C@H]2CC[C@H](N(Cc3ccccc3)C[C@H](O)COc3ccc(OCc4ccccc4)c(NS(C)(=O)=O)c3)CC2)cc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)COc1ccc([C@H]2CC[C@H](NC[C@H](O)COc3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1
Reaction time: 7 h

Procedure:
A mixture of ethyl trans-(4-{4-[benzyl((2S)-3-{4-(benzyloxy)-3-[(methylsulfonyl)amino]phenoxy}-2-hydroxypropyl)amino]cyclohexyl}phenoxy)acetate (0.26 mmol) and of 0.25 g of 10% palladium-on-charcoal (50% in water) in ethanol (16 ml) is placed under hydrogen atmosphere and stirred for 7 h. The reaction mixture is filtered through celite. The solvents are evaporated under reduced pressure and ethyl trans-(4-{4-[((2S)-2-hydroxy-3-{4-hydroxy-3-[(methylsulfonyl)amino]phenoxy}propyl)amino]cyclohexyl}-phenoxy)acetate is obtained in the form of a white solid (0.08 g, 54%) after purification on silica gel (eluent: dichloromethane/methanol, 99/1 to 85/15 gradient in 30 min).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.Br[C:17]1[C:18]([NH2:24])=[N:19][CH:20]=[C:21]([Br:23])[N:22]=1.CCN(CC)CC>CS(C)=O>[NH2:24][C:18]1[C:17]([NH:1][CH2:2][CH:3]2[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]2)=[N:22][C:21]([Br:23])=[CH:20][N:19]=1
Reactant: Nc1ncc(Br)nc1Br
Reactant: CC(C)(C)OC(=O)N1CCCC(CN)C1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCC(CNc2nc(Br)cnc2N)C1
Temperature: 130 °C
Reaction time: 8 h
Yield: 25.3 %

Procedure:
tert-butyl 3-(aminomethyl)piperidine-1-carboxylate (4.97 g, 22.40 mmol) was dissolved in DMSO (80 ml), and then 3,5-dibromopyrazine-2-amine (8.5 g, 33.60 mmol) and Et3N (6.3 ml) were added, followed by stirring at 130° C. overnight. After the completion of the reaction, the reaction mixture was extracted with H2O, EA, and brine, followed by drying (Na2SO4), filtration, and concentration under reduced pressure, and the residue was purified by column chromatography (EA:Hex=1:1), to give tert-butyl 3-(((3-amino-6-bromopyrazine-2-yl)amino)methyl)piperidine-1-carboxylate (2.19 g, two steps: 26%).
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[N:3]=1.[CH2:12]([N:14]1[C:22]2[C:17](=[N:18][CH:19]=[CH:20][CH:21]=2)[N:16]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)[C:15]1=[O:30])[CH3:13].[H-].[Na+]>CN(C=O)C.CO>[CH2:12]([N:14]1[C:22]2[C:17](=[N:18][CH:19]=[CH:20][CH:21]=2)[N:16]([C:23]2[CH:24]=[CH:25][C:26]([O:29][C:2]3[N:6]([CH3:7])[C:5]4[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=4[N:3]=3)=[CH:27][CH:28]=2)[C:15]1=[O:30])[CH3:13]
Reactant: CCn1c(=O)n(-c2ccc(O)cc2)c2ncccc21
Reactant: Cn1c(Cl)nc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CCn1c(=O)n(-c2ccc(Oc3nc4ccccc4n3C)cc2)c2ncccc21
Temperature: 150 °C
Yield: 82.1 %

Procedure:
2-Chloro-1-methyl-1H-benzimidazole (500 mg) was added to a solution of 1-ethyl-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (789 mg) and NaH (132 mg) in DMF (10 mL) at room temperature. The mixture was heated at 150° C. for 1 h under microwave irradiation. The reaction mixture was diluted with MeOH and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 0%-50% EtOAc in hexane) to give 1-ethyl-3-{4-[(1-methyl-1H-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (950 mg) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:28][C:29]([C@@H:31]2[CH2:40][C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:33][N:32]2C(OC(C)(C)C)=O)=[O:30])[C:10](=[O:27])[N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]([F:26])([F:25])[F:24])[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[C:48]([OH:54])([C:50]([F:53])([F:52])[F:51])=[O:49]>C(Cl)Cl>[F:51][C:50]([F:53])([F:52])[C:48]([OH:54])=[O:49].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:28][C:29]([C@@H:31]2[CH2:40][C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:33][NH:32]2)=[O:30])[C:10](=[O:27])[N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]([F:25])([F:24])[F:26])[CH2:13][CH2:12]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCC(c2ccccc2C(F)(F)F)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCC(c2ccccc2C(F)(F)F)CC1)[C@@H]1Cc2ccccc2CN1
Reaction time: 0.5 h

Procedure:
The title compound was prepared according to the procedure described in Example 3 (Step b) from tert-butyl 3-[N-((1R)-1-[(4-chlorophenyl)methyl]-2-oxo-2-{4-[2-(trifluoromethyl)-phenyl]piperidyl}ethyl)-carbamoyl](3S)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (Step f) (335 mg, 0.5 mmol) and 50% TFA in CH2Cl2 (20 mL). Purification by reverse phase preparative HPLC [Phenomenex; 5 μm 250×21.2 mm, 5% to 95% CH3CN (0.1% TFA) in H2O (0.1% TFA) over 30 min, then 100% CH3CN (0.1% TFA) for 2 min] provided the title compound (TFA salt) as a white solid (202 mg). MS (ESI, pos. ion) m/z: 570 (M+1); (ESI, neg. ion) m/z: 568 (M−1). Calc'd for C31H31ClF3N3O2: 569.21.
Reaction SMILES: [CH:1]1([NH2:5])[CH2:4][CH2:3][CH2:2]1.[Cl:6][C:7]1[N:12]=[C:11](Cl)[C:10]([N+:14]([O-:16])=[O:15])=[C:9]([Cl:17])[N:8]=1.CCN(C(C)C)C(C)C>CC(O)C>[Cl:6][C:7]1[N:12]=[C:11]([NH:5][CH:1]2[CH2:4][CH2:3][CH2:2]2)[C:10]([N+:14]([O-:16])=[O:15])=[C:9]([Cl:17])[N:8]=1
Reactant: NC1CCC1
Reactant: O=[N+]([O-])c1c(Cl)nc(Cl)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: O=[N+]([O-])c1c(Cl)nc(Cl)nc1NC1CCC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Cyclobutanamine (0.485 mL, 5.68 mmol) in iPrOH (20 mL) was added to a solution of 2,4,6-trichloro-5-nitropyrimidine (1.29 g, 5.65 mmol) in iPrOH (40 mL) at −78° C. dropwise via addition funnel. After complete addition, the mixture was allowed to warm to rt over 30 min, then DIEA (0.940 mL, 5.66 mmol) was added and the mixture stirred at rt for 10 min. The solvent was removed under reduced pressure and dried to give the title compound as a pale yellow oil which was used without purification.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([F:12])=[CH2:11])=[C:5](OCC2C=CC=CC=2)[CH:4]=1.Cl.[Cl-].[Na+].[OH-].[Na+]>CCOCC>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([F:12])=[CH2:11])=[CH:5][CH:4]=1
Reactant: C=C(F)Cc1ccc(OC)cc1OCc1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Product: C=C(F)Cc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
3-(4-Methoxybenzyloxyphenyl)-2-fluoro-1-propene, i.e., the compound of example 5, (30 mg, 0.110 mmole) was treated with saturated methanolic hydrochloric acid and stirred at room temperature for one hour. The solution was then poured onto 50 ml cold saturated sodium chloride, diluted with 20 ml ether and the pH adjusted to pH 10 with cold 0.5N sodium hydroxide. The mixture was washed 3 additional times with 15 ml portions of 0.5N sodium hydroxide, and the combined aqueous layers were then washed with 50 ml ether. The aqueous layers were then acidified with 1.0N hydrochloric acid to pH 1, solid sodium chloride added and the product extracted with ether (3×50 ml), dried(MgSO4) and concentrated under reduced pressure to give 8 mg clear oil (48%).
Reaction SMILES: N([O-])=O.[Na+].CC1(C)N([O])C(C)(C)CCC1.CC(O[Na])=[O:18].[F:21][C:22]([F:42])([CH:25]([F:41])[O:26][C:27]([F:40])([F:39])[C:28]([F:38])([F:37])[C:29]([F:36])([F:35])[O:30][C:31]([F:34])([F:33])[F:32])[CH2:23][OH:24].O=O>C(O)(=O)C>[F:21][C:22]([F:42])([CH:25]([F:41])[O:26][C:27]([F:40])([F:39])[C:28]([F:37])([F:38])[C:29]([F:35])([F:36])[O:30][C:31]([F:32])([F:33])[F:34])[C:23]([OH:18])=[O:24]
Reactant: OCC(F)(F)C(F)OC(F)(F)C(F)(F)C(F)(F)OC(F)(F)F
Reactant: CC(=O)O[Na]
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=N[O-]
Agent: O=O
Solvent: CC(=O)O
Product: O=C(O)C(F)(F)C(F)OC(F)(F)C(F)(F)C(F)(F)OC(F)(F)F
Temperature: 60 °C
Reaction time: 16 h
Yield: 81.2 %

Procedure:
150 mL of acetic acid, 0.91 g sodium nitrite, TEMPO (0.68 g), CH3CO2Na (3.78 g) and 20 g of 2,2,3-trifluoro-3-(1,1,2,2,3,3-hexafluoro-3-trifluoromethoxy-propoxy)-propan-1-ol were placed in a 500 mL glass flask equipped with a reflux condenser, a stirrer and a balloon filled with oxygen which was released into the flask by opening a valve such that the reaction was carried out in an oxygen atmosphere. The mixture was stirred 16 hr at 60° C. Then the mixture was acidified and extracted by diethyl ether (three times). The combined organic phases were washed by water and dried over magnesium sulphate. The solvent was removed at a rotary evaporator and the residue was distilled to give 14.15 g of acid (1.6 mmHg, 58° C.). Yield: 68%.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@H:24]([CH2:27][OH:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[N:31][CH:30]=1>>[OH:28][CH2:27][C@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:33]3[CH:34]=[N:29][CH:30]=[N:31][CH:32]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: OB(O)c1cncnc1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@H](CO)C2)c(Br)c1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@H](CO)C2)c(-c2cncnc2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 75 using (S)-5-bromo-6-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 78.1) and pyrimidin-5-ylboronic acid to afford a white solid. UPLC-MS (condition 1) tR=2.12 min, m/z=460.1-461.1 [M+H]+, m/z=458.2 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.53-1.64 (m, 1H) 1.81-1.90 (m, 1H) 2.20-2.28 (m, 1H) 2.97 (dd, J=10.76, 6.85 Hz, 1H) 3.15-3.40 (m, 5H) 4.61 (t, J=5.14 Hz, 1H) 7.35 (d, J=8.80 Hz, 2H) 7.85 (d, J=9.05 Hz, 2H) 8.09 (d, J=2.20 Hz, 1H) 8.79 (d, J=2.20 Hz, 1H) 8.89 (s, 2H) 9.19 (s, 1H) 10.16 (s, 1H).
Reaction SMILES: Br[C:2]([F:9])([F:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl:10][CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])=[O:13].C(OCC)(=O)C.Cl>O1CCCC1.[Zn].O>[Cl:10][CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])([OH:13])[C:2]([F:9])([F:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: O=C(CCl)c1ccc(Cl)cc1Cl
Reactant: CCOC(=O)C(F)(F)Br
Agent: Cl
Agent: [Zn]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C(F)(F)C(O)(CCl)c1ccc(Cl)cc1Cl
Yield: 52.6 %

Procedure:
In 20 ml of dried tetrahydrofuran was suspended 0.97 g of zinc. To the suspension was dropwise added 3.0 g of ethyl bromodifluoroacetate under reflux. Then, 10 ml of a solution of 2.2 g of 2,2',4'-trichloroacetophenone dissolved in dried tetrahydrofuran was dropwise added under reflux. The resulting mixture was refluxed for 10 minutes. The insolubles were removed by filtration. The solvent was removed by distillation under reduced pressure. To the residue obtained were added 20 ml of ethyl acetate and 20 ml of water. The resulting solution was adjusted to pH 1.0 with 6N hydrochloric acid. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by a column chromatography (eluant: n-hexane/toluene=1/2) to obtain 1.8 g of oily ethyl 4-chloro-3-(2,4-dichlorophenyl)-2,2-difluoro-3-hydroxybutyrate.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(Cl)(=O)C(Cl)=O.CN(C=O)C.[NH2:25][NH2:26]>ClCCl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([NH:25][NH2:26])=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Reactant: NN
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: NNC(=O)Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-nitrophenylacetic acid (2.81 mmol) in dry dichloromethane (10 ML) was treated with a 2N solution of oxalyl chloride (3.0 mL) and DMF (0.02 mL) via syringe, and the reaction stirred at ambient temperature for 1 h. The reaction was concentrated to dryness in vacuo and the crude product was dissolved in dry dichloro-methane (20 mL), treated with anhydrous hydrazine (11.1 mmol) via syringe, and stirred at ambient temperature for 18 h. The resulting suspension was filtered, solids rinsed with dichloromethane, dissolved in MeOH/CH2Cl2, filtered, and filtrate concentrated in vacuo giving the title compound as an orange solid. 1H NMR (DMSO-d6) δ 8.17 (2H, d, J=8.8 Hz,), 7.54 (2H, d, J=8.8 Hz), 3.54 (2H, s).
Reaction SMILES: Br[C:2]1[CH:13]=[C:12]([F:14])[C:11]([F:15])=[CH:10][C:3]=1[CH2:4][N:5]([CH2:8][CH3:9])[CH2:6][CH3:7].C(=O)([O-])[O-].[K+].[K+].O.[NH2:23][C:24]1[N:33]=[C:32]([C:34]([N:36]2[CH2:44][C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH2:37]2)=[O:35])[C:31]2[C:26](=[CH:27][CH:28]=[C:29](B3OC(C)(C)C(C)(C)O3)[CH:30]=2)[N:25]=1>C(O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:23][C:24]1[N:33]=[C:32]([C:34]([N:36]2[CH2:37][C:38]3[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH2:44]2)=[O:35])[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([C:2]3[CH:13]=[C:12]([F:14])[C:11]([F:15])=[CH:10][C:3]=3[CH2:4][N:5]([CH2:8][CH3:9])[CH2:6][CH3:7])[CH:30]=2)[N:25]=1
Reactant: CC1(C)OB(c2ccc3nc(N)nc(C(=O)N4Cc5ccccc5C4)c3c2)OC1(C)C
Reactant: CCN(CC)Cc1cc(F)c(F)cc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCO
Product: CCN(CC)Cc1cc(F)c(F)cc1-c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Temperature: 120 °C

Procedure:
148 mg of (2-bromo-4,5-difluorobenzyl)diethylamine, 170 mg of potassium carbonate, 7 μl of water and 17 mg of [1,1′-bis(diphenylphosphino)ferrocene]-palladium(II) dichloride are added to a solution of 170 mg of [2-amino-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl]-(1,3-dihydroisoindol-2-yl)methanone in 4 ml of ethanol under argon. The mixture is heated at 120° C. for 30 min; the hot mixture is filtered through kieselguhr, and the filtrate is evaporated and purified by chromatography (reversed phase HPLC).
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CC(C)([O-])C.[K+].C(O)(CC)(C)C.C1([B-](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([PH+](C(C)(C)C)C)(C)(C)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:9]1([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCCCCCCBr
Reactant: OB(O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: CCC(C)(C)O
Product: CCCCCCCc1ccccc1
Yield: 89.1 %

Procedure:
A 50-ml four-necked flask was equipped with a stirrer, a thermometer and a reflux condenser. 0.896 g (5 mmol) of n-heptyl bromide, 0.914 g (7.5 mmol) of phenylboronic acid, 0.056 g (0.25 mmol) of palladium (II) acetate, 1.683 g (15 mmol) of potassium tert-butoxide and 25 ml of tert-amyl alcohol were weighed in the flask, followed by stirring. Further, 0.240 g (0.5 mmol) of di-tert-butylmethylphosphonium tetraphenylborate obtained in Example B-1 was weighed in air and added into the flask. The flask was purged with argon, followed by stirring at 25° C. for 24 hours. After the completion of the reaction, 20 ml of saturated sodium chloride solution was added, followed by separation. The organic phase was purified by column chromatography to afford 0.785 g of 1-phenylheptane (yield: 89 mol % based on n-heptyl bromide). The identification of the product was made by mass spectroscopy.