Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]([CH3:20])[C:5]2[C:6](=[O:19])[NH:7][C:8]3[C:13]([N:14]=2)=[CH:12][C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:10][CH:9]=3)[CH2:3][CH2:2]1.N1C=CC=CC=1.[O:27](S(C(F)(F)F)(=O)=O)[S:28]([C:31]([F:34])([F:33])[F:32])(=O)=[O:29]>ClCCl>[CH:1]1([N:4]([CH3:20])[C:5]2[C:6]([O:19][S:28]([C:31]([F:34])([F:33])[F:32])(=[O:29])=[O:27])=[N:7][C:8]3[C:13]([N:14]=2)=[CH:12][C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:10][CH:9]=3)[CH2:2][CH2:3]1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1ccc2[nH]c(=O)c(N(C)C3CC3)nc2c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N(C)C3CC3)nc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 3-(cyclopropyl(methyl)amino)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (120 mg, 0.44 mmol) in dichloromethane (10 mL) was added pyridine (135 mg, 1.71 mmol) and Tf2O (230 mg, 0.82 mmol) under nitrogen atmosphere. After stirring overnight at room temperature, the reaction was quenched by the addition water/ice (50 mL), extracted with dichloromethane (2×10 mL), dried over anhydrous magnesium sulfate and concentrated under vacuum to give methyl 3-(cyclopropyl(methyl)amino)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate as red oil (130 mg, crude).
Reaction SMILES: [CH2:1]([C:8]1([C:13]2[CH:14]=[C:15]([CH:27]=[CH:28][CH:29]=2)[CH2:16][NH:17][S:18]([C:21]2[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=2)(=[O:20])=[O:19])[CH2:12][CH2:11][NH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:30]=O>CO.[Pd]>[CH2:1]([C:8]1([C:13]2[CH:14]=[C:15]([CH:27]=[CH:28][CH:29]=2)[CH2:16][NH:17][S:18]([C:21]2[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=2)(=[O:20])=[O:19])[CH2:12][CH2:11][N:10]([CH3:30])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=O
Reactant: Cn1cc(S(=O)(=O)NCc2cccc(C3(Cc4ccccc4)CCNC3)c2)cn1
Agent: [Pd]
Solvent: CO
Product: CN1CCC(Cc2ccccc2)(c2cccc(CNS(=O)(=O)c3cnn(C)c3)c2)C1
Yield: 37.1 %

Procedure:
To a solution of 1-methyl-1H-pyrazole-4-sulfonic acid 3-(3-benzyl-pyrrolidin-3-yl)benzylamide (example 67, 108 mg, 0.26 mmol) and formaldehyde (37% in water, 0.2 ml, 2.6 mmol) in methanol (10 ml) was added palladium on charcoal (10%, 10 mg). Hydrogenation was performed at room temperature over night. The mixture was filtered and the solvent evaporated. The residue was diluted with dichloromethane, extracted with water, dried over Na2CO3. The solvent was evaporated to give 41 mg of product. Re-extraction of the aqueous layer afforded further 38 mg of product as a clear oil.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH:4]=[C:5]([CH:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:11]([F:21])[CH:10]=2)[CH3:8])[N:6]=1.[CH:22]([O-])([O-])OCC.[BH4-].[Na+]>C(O)C>[F:21][C:11]1[CH:10]=[C:9]([CH:7]([C:5]2[N:6]=[C:2]([NH:1][CH3:22])[O:3][CH:4]=2)[CH3:8])[CH:14]=[CH:13][C:12]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCOC([O-])[O-]
Reactant: CC(c1ccc(-c2ccccc2)c(F)c1)c1coc(N)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CNc1nc(C(C)c2ccc(-c3ccccc3)c(F)c2)co1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
A mixture of 2-amino-4-(1-(2-fluoro-4-biphenylyl)ethyl)oxazole (1.66 g, 5.88 mmol) and ethyl orthoformate (20 ml) was refluxed for 5 hr and the reaction mixture was evaporated under reduced pressure to a residue. To the residue in ethanol (50 ml) was added sodium borohydride (0.27 g, 7.14 mmol) under cooling, then the mixture was stirred at room temperature for 2 hr. After evaporation, the residue was extracted with ethyl acetate and the extracts were washed with water, dried and then evaporated under reduced pressure to a residue, which was chromatographed and recrystallized to afford 4-(1-(2-fluoro-4-biphenylyl)ethyl)-2-methylaminooxazole (0.66 g, 40% yield): mp 133.5°-135.0° C.
Reaction SMILES: [F:1][C:2]([C:12]([F:15])([F:14])[F:13])([C:8]([F:11])([F:10])[F:9])[CH2:3][CH:4](I)[CH2:5][OH:6].C([SnH](CCCC)CCCC)CCC>>[F:1][C:2]([C:12]([F:13])([F:14])[F:15])([C:8]([F:9])([F:11])[F:10])[CH2:3][CH2:4][CH2:5][OH:6]
Reactant: OCC(I)CC(F)(C(F)(F)F)C(F)(F)F
Agent: CCCC[SnH](CCCC)CCCC
Product: OCCCC(F)(C(F)(F)F)C(F)(F)F
Reaction time: 2 h

Procedure:
In accordance with scheme (9) above, a 500 mL two neck round bottom flask can be equipped with a thermocouple, agitator, and heating mantle. About 212.1 g (0.599 mole) 4,5,5,5-tetrafluoro-4(trifluoromethyl)-2-iodopentan-1-ol (212.1 g, 0.599 mole) can be added to the flask and heated to about 60° C. to 70° C. From a 100 mL pressure equalized addition funnel, about 196.4 g (0.675 mole) tributyltin hydride can be added drop-wise over a 4 hour period followed by 2 hours of continued heating and stirring. The RF-intermediate 4,5,5,5-tetrafluoro-4(trifluoromethyl)pentan-1-ol, can be obtained through vacuum distillation and verified by gas chromatography/mass spectrometry (m/z 228 (M+), 211 (M+-OH), 159 (M+-CF3)).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([O:11][CH3:12])=[CH:5][C:4]=1[N+:13]([O-])=O.[C-]#[Si+].[OH-].[Na+]>Cl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([O:11][CH3:12])=[CH:5][C:4]=1[NH2:13]
Reactant: COc1cc(OC)c([N+](=O)[O-])cc1OC
Agent: Cl
Agent: [C-]#[Si+]
Agent: [Na+]
Product: COc1cc(OC)c(OC)cc1N

Procedure:
Into a 500 cm3 flask, provided with a cooling device, were added successively 21.3 g (0.1 mole) of 2,4,5-trimethoxy nitrobenzene, 80 g of chemically pure stannous chloride for mirror making, 100 cm3 of a hydrochloric acid solution (d=1.18) and carborundum. The mixture was brought to boiling under reflux for 1 h. After cooling, a caustic soda solution was added until the precipitate disolved. The solution obtained was extracted with methylene chloride. The organic extracts were dried over sodium sulfate then evaporated under reduced pressure. The residue obtained was crystallized in ethanol.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([CH3:41])=[C:14]([C:18]2[C:30]3[C:29]4[C:24](=[CH:25][C:26]([O:31][CH2:32][CH2:33][O:34][CH3:35])=[CH:27][CH:28]=4)[NH:23][C:22]=3[C:21]([C:36]([O:38]CC)=[O:37])=[N:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+]>O1CCCC1.CO.O>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([CH3:41])=[C:14]([C:18]2[C:30]3[C:29]4[C:24](=[CH:25][C:26]([O:31][CH2:32][CH2:33][O:34][CH3:35])=[CH:27][CH:28]=4)[NH:23][C:22]=3[C:21]([C:36]([OH:38])=[O:37])=[N:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ncc(-c2cccc(NC(=O)OCc3ccccc3)c2C)c2c1[nH]c1cc(OCCOC)ccc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COCCOc1ccc2c(c1)[nH]c1c(C(=O)O)ncc(-c3cccc(NC(=O)OCc4ccccc4)c3C)c12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 83.5 %

Procedure:
To a solution of ethyl 4-(3-(benzyloxycarbonylamino)-2-methylphenyl)-7-(2-methoxyethoxy)-9H-pyrido[3,4-b]indole-1-carboxylate (0.299 g, 0.540 mmol) in tetrahydrofuran (15 mL) and methanol (5 mL) at room temperature was added a solution of lithium hydroxide hydrate (0.091 g, 2.160 mmol) in water (2 mL). The resulting mixture was stirred at room temperature for 1.5 hr, and then concentrated under vacuum to almost dryness. To the residue was added water (8 mL), and the mixture was neutralized with 1N HCl to pH 4-5. The insoluble product (0.237 g, 0.451 mmol, 83% yield) was collected as a beige solid by suction filtration and dried over Drierite under vacuum.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:27]3[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17]C(=O)OC(C)(C)C)=[C:13]([O:25][CH3:26])[CH:12]=3)[C:3]=12.FC(F)(F)C(O)=O>ClCCl>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:27]3[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([O:25][CH3:26])[CH:12]=3)[C:3]=12
Reactant: COc1cc(-c2nn(-c3ccc([N+](=O)[O-])cc3)c3ncnc(N)c23)ccc1NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(-c2nn(-c3ccc([N+](=O)[O-])cc3)c3ncnc(N)c23)ccc1N
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 93.8 %

Procedure:
A suspension of tert-butyl N-(4-{4-amino-1-[4-nitrophenyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)carbamate (0.386 g, 0.808 mmol) in dichloromethane (8 mL) at 0° C. was treated with trifluoroacetic acid (1.6 mL). The reaction mixture stirred for 20 min at 0° C., then ice bath was removed to stir at room temperature under a nitrogen atmosphere. The reaction mixture was stirred for 18 h. Solvent was removed under reduced pressure. Dichloromethane (15 mL) and sodium hydroxide 1N solution were added to the oil residue. The precipitate formed was filtered and dried over night on the lyophilizer to give 0.286 g (94%) of 4-amino-3-(4-amino-3-methoxyphenyl)-1-[4-nitrophenyl]-1H-pyrazolo[3,4-d]pyrimidine. 1H NMR (DMSO-d6, 400 MHz) δ 8.7826-8.759 (m, 2H), 8.4892-8.4296 (m, 3H), 7.1861-7.1338 (m, 2H), 6.8320-6.8121 (d, 1H, J=7.96 Hz), 5.2225 (s, 2H), 3.8672 (s, 3H); LCMS (Perkin Elmer, Pecosphere C18 column, 3 um particle size, 33×4.6 mm; 100% 50 mM ammonium Acetate in Water to 100% Acetonitrile over 5 min, 3.0 to 3.5 mil/min) tR=3.48 min M+ 377.6.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([C:15]3[CH:24]=[CH:23][C:18]([O:19][CH2:20][CH2:21][NH2:22])=[CH:17][CH:16]=3)[N:13]=[C:12]([C:25]([F:28])([F:27])[F:26])[CH:11]=2)=[CH:6][CH:5]=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>ClCCl.C(N(CC)CC)C>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:14]([C:15]3[CH:24]=[CH:23][C:18]([O:19][CH2:20][CH2:21][NH:22][S:30]([CH3:29])(=[O:32])=[O:31])=[CH:17][CH:16]=3)[N:13]=[C:12]([C:25]([F:28])([F:26])[F:27])[CH:11]=2)=[CH:8][CH:9]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(OCCN)cc2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(OCCNS(C)(=O)=O)cc2)cc1

Procedure:
To a solution of 2-{4-[5-(4-methoxyphenyl)-3-(trifluoromethyl)-1-H-pyrazol-1-yl]phenoxy}ethanamine hydrochloride obtained by Example 96 (100 mg) in dichloromethane (5 ml) and triethylamine (0.1 ml) was added dropwise methanesulfonyl chloride (38 μl) at room temperature.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:22]([O-])=O)=[CH:4][C:5]([O:10][CH2:11][C:12]2[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[C:14]([F:20])[C:13]=2[F:21])=[C:6]([O:8][CH3:9])[CH:7]=1.O1CCCC1.[BH4-].[Na+].C(=O)([O-])O.[Na+]>[Ni](Br)Br.CO>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH2:11][C:12]2[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[C:14]([F:20])[C:13]=2[F:21])=[CH:4][C:3]=1[NH2:22]
Reactant: COc1cc(Cl)c([N+](=O)[O-])cc1OCc1c(OC)ccc(F)c1F
Agent: Br[Ni]Br
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(Cl)c(N)cc1OCc1c(OC)ccc(F)c1F
Yield: 90.1 %

Procedure:
To a mixture of 5-chloro-2-(2,3-difluoro-6-methoxybenzyloxy)-4-nitroanisole (9.41 g), nickel(II) bromide (0.29 g), tetrahydrofuran (100 mL) and methanol (100 mL) was added sodium borohydride (2.97 g) under ice-cooling, and the mixture was stirred under ice-cooling for 30 minutes, and then stirred at room temperature for 30 minutes. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine twice, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=4/1-3/2) to give the title compound (7.77 g).
Reaction SMILES: [H-].[Na+].[C:3]([N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[F:16][C:17]1[CH:24]=[CH:23][CH:22]=[C:21](F)[C:18]=1[C:19]#[N:20]>CN(C=O)C>[C:6]([O:5][C:3]([N:10]1[CH2:11][CH2:12][N:13]([C:21]2[CH:22]=[CH:23][CH:24]=[C:17]([F:16])[C:18]=2[C:19]#[N:20])[CH2:14][CH2:15]1)=[O:4])([CH3:9])([CH3:8])[CH3:7]
Reactant: N#Cc1c(F)cccc1F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(F)c2C#N)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.4 %

Procedure:
In a round bottom flask, sodium hydride (60%) (2.40 g; 60 mmol) was suspended in DMF (25 mL) and cooled in an ice water bath under nitrogen. 1-Boc-piperazine (9.53 g; 50.6 mmol) was added in small portions to the reaction mixture at 0° C. over 30 minutes. The mixture was allowed to stir at room temperature for 3 hours and the recooled to 0° C. 2,6-Difluorobenzonitrile (8.57 g; 60 mmol) was added to the reaction mixture in DMF (10 mL) over 45 minutes. The mixture was stirred at room temperature for 16 hours. The reaction mixture was poured in ice water (250 mL) and stirred. The solid was collected by vacuum filtration and washed with water. And then dried under vacuum to yield the title compound (11.65 g; 75% yield).
Reaction SMILES: C(C1CC1CC(Cl)=O)CCCC.C1(C(Cl)=O)CCCCC1.[C:22]([NH:26][CH2:27][C:28]([C:30]1[CH:35]=[CH:34][C:33]([O:36][C:37](=[O:47])[CH2:38][CH:39]2[CH2:41][CH:40]2[CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[C:32]([O:48][C:49](=[O:59])[CH2:50][CH:51]2[CH2:53][CH:52]2[CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])[CH:31]=1)=[O:29])([CH3:25])([CH3:24])[CH3:23]>>[CH2:54]([CH:52]1[CH2:53][CH:51]1[CH2:50][C:49]([O:48][C:32]1[CH:31]=[C:30]([CH:35]=[CH:34][C:33]=1[O:36][C:37](=[O:47])[CH2:38][CH:39]1[CH2:41][CH:40]1[CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH:28]([OH:29])[CH2:27][NH:26][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:59])[CH2:55][CH2:56][CH2:57][CH3:58]
Reactant: CCCCCC1CC1CC(=O)Oc1ccc(C(=O)CNC(C)(C)C)cc1OC(=O)CC1CC1CCCCC
Agent: CCCCCC1CC1CC(=O)Cl
Agent: O=C(Cl)C1CCCCC1
Product: CCCCCC1CC1CC(=O)Oc1ccc(C(O)CNC(C)(C)C)cc1OC(=O)CC1CC1CCCCC

Procedure:
When 2-amylcyclopropaneacetyl chloride is substituted for the cyclohexanecarbonyl chloride in the procedure described in Example 15A above, the acylation product obtained is 3,4-bis(2-amylcyclopropaneacetoxy)phenyl tert-butylaminomethyl ketone; and when this product is catalytically hydrogenated using the procedure described in Example 15B above, there is obtained 3,4-bis(2-amylcyclopropaneacetoxy)-alpha-(tert-butylaminomethyl)benzyl alcohol.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[N:17]=[C:18]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[O:19][C:20]=3[C:21]([F:24])([F:23])[F:22])=[O:15])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.F[C:32]1[CH:40]=[CH:39][C:35]([C:36]([OH:38])=[O:37])=[CH:34][N:33]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[C:25]1([C:18]2[O:19][C:20]([C:21]([F:22])([F:23])[F:24])=[C:16]([C:14]([NH:13][C:10]3[CH:9]=[CH:8][C:7]([CH:4]4[CH2:5][CH2:6][N:1]([C:32]5[CH:40]=[CH:39][C:35]([C:36]([OH:38])=[O:37])=[CH:34][N:33]=5)[CH2:2][CH2:3]4)=[CH:12][CH:11]=3)=[O:15])[N:17]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(O)c1ccc(F)nc1
Reactant: O=C(Nc1ccc(C2CCNCC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(O)c1ccc(N2CCC(c3ccc(NC(=O)c4nc(-c5ccccc5)oc4C(F)(F)F)cc3)CC2)nc1
Temperature: 135 °C
Yield: 15.1 %

Procedure:
A mixture of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-piperidin-4-yl-phenyl)-amide (208 mg, 0.5 mmol) and 6-fluoronicotinic acid (72 mg, 0.5 mmol) in DMSO (2 L) containing potassium carbonate (135 mg, 1 mmol) was heated in a microwave at 135° C. for 35 minutes. The mixture was extracted with ethyl acetate and 0.1N hydrochloric acid. The organic layer was washed with water and brine. Solvents were evaporated and the residue was purified through ISCO column chromatography (silica gel, ethyl acetate in hexanes, 10% to 100% linear gradient). The collected fractions were concentrated and the white crystalline material was filtered to give 4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carboxylic acid (40.5 mg). LC-MS for C28H23F3N4O4 (m/e) calcd 536, obsd 537 (M+H). 1H-NMR is consistent with the desired structure.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[CH:6][C:7]=1[F:8].BrBr.C(=O)([O-])[O-:13].[Ca+2]>O>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[F:8])[CH:9]=[O:13]
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(F)c(F)c1
Agent: BrBr
Agent: [Ca+2]
Solvent: O
Product: O=Cc1ccc(F)c(F)c1
Reaction time: 2 h

Procedure:
In a 250 ml three-necked flask equipped with a magnetic stirrer, thermometer, condenser, and dropping funnel is placed 25.6 g (0.2 mol) of 3,4-difluorotoluene. The liquid is heated to 105° and illuminated as 67 g (0.42 mol) of bromine is added slowly. The temperature is kept between 105°-110° C. while the first half of the bromine is added over a period of one hour. The rest of the bromine is added over approx. a 2 hour period, and the temperature is raised to 150° and kept there for 5 minutes. The reaction mixture is cooled and transferred to a 1 liter 3-necked flask with a motor driven stirrer and condenser. 120 ml H2O and 90 g of calcium carbonate are added, and the mixture is refluxed for 20 h with good stirring. The reaction mixture is steam distilled until no further oil is collected. The oil is taken up in methylene chloride and dried over MgSO4. Evaporation of the solvent yields 3,4-difluorobenzaldehyde which is used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:9])[C:5]([NH2:8])=[N:6][CH:7]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[Cl-].[C:45]([O:49][C:50](=[O:53])[CH2:51][Zn+])([CH3:48])([CH3:47])[CH3:46]>C1COCC1.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]>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([CH2:51][C:50]([O:49][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:53])=[CH:3][C:4]=1[F:9]
Reactant: Nc1ncc(Br)cc1F
Reactant: CC(C)(C)OC(=O)C[Zn+]
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Cc1cnc(N)c(F)c1
Temperature: 65 °C

Procedure:
To 5-bromo-3-fluoropyridin-2-amine (300 mg, 2.0 mmol) in THF (10 mL) was added Pd2(dba)3 (94 mg, 0.10 mmol) and X—PHOS (98 mg, 0.20 mmol), followed by 2-(tert-butoxy)-2-oxoethylzinc chloride solution (10.6 mL, 0.5 M, 5.3 mmol). The reaction mixture was heated at 65° C. over night. The reaction mixture was quenched with NH4Cl, and the aqueous layer was extracted with EtOAc. The organic extracts were washed with brine, dried, and evaporated to give the crude product, which was purified by column chromatography (0-100% EtOAc/hexanes) to give title compound: LC/MS: [(M+1-56)]+=171.5;
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]=O)[CH:9]=2)=[CH:6][C:5]([CH2:16][N:17]([CH3:30])[C:18]([C:20]2[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=2)[C:23]([O:25][CH3:26])=[O:24])=[O:19])=[CH:4][CH:3]=1.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:35]3[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]3)[CH:9]=2)=[CH:6][C:5]([CH2:16][N:17]([CH3:30])[C:18]([C:20]2[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=2)[C:23]([O:25][CH3:26])=[O:24])=[O:19])=[CH:4][CH:3]=1
Reactant: CN1CCNCC1
Reactant: COC(=O)c1cccc(C(=O)N(C)Cc2ccc(F)c(-c3cccc(C=O)c3)c2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1cccc(C(=O)N(C)Cc2ccc(F)c(-c3cccc(CN4CCN(C)CC4)c3)c2)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 92.9 %

Procedure:
To a solution of methyl 3-{[[(6-fluoro-3′-formyl-3-biphenylyl)methyl](methyl)amino]carbonyl}benzoate (0.18 g, 0.444 mmol) in DCM (4.4 mL) was added 1-methylpiperazine (0.0542 mL, 0.488 mmol), and NaBH(OAc)3 (0.141 g, 0.666 mmol). The mixture was stirred at room temperature for 17 h and then the reaction was quenched with H2O (˜1 mL). The organic layer was separated, dried over Na2SO4 and purified by CombiFlash chromatograph to afford the title compound 0.202 g (93%). LC-MS m/z 490 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:18][CH2:19][OH:20])[CH:10]=[C:11]([C:13]([O:15]CC)=[O:14])[N:12]=2)=[C:4](F)[CH:3]=1.[OH-].[K+].Cl.C[N+](CCCC)(CCCC)CCCC>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[N:9]([CH:10]=[C:11]([C:13]([OH:15])=[O:14])[N:12]=3)[CH2:18][CH2:19][O:20][C:4]=2[CH:3]=1
Reactant: CCOC(=O)c1cn(CCO)c(-c2ccc(Br)cc2F)n1
Agent: CCCC[N+](C)(CCCC)CCCC
Agent: Cl
Agent: [K+]
Product: O=C(O)c1cn2c(n1)-c1ccc(Br)cc1OCC2

Procedure:
Ethyl 2-(4-bromo-2-fluorophenyl)-1-(2-hydroxyethyl)-1H-imidazole-4-carboxylate 27, potassium hydroxide and methyl tributylammonium hydrochloride were reacted at 65° C., cooled, and concentrated. The mixture was dissolved in ethanol and water to crystallize 28.
Reaction SMILES: O[CH:2]([CH3:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].C[OH:13]>[Pt]=O>[OH:13][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[CH:3]([OH:4])[CH2:2][CH3:11]
Reactant: CO
Reactant: CC(O)C(=O)c1ccccc1
Agent: O=[Pt]
Product: CCC(O)c1ccccc1O
Reaction time: 1 h

Procedure:
A mixture of platinum oxide (302 mg) in methanol (30 mL) is stirred under a hydrogen atmosphere (balloon) for 1 hr and then treated with 2-hydroxypropiophenone (2.00 g). The mixture is stirred under hydrogen for 4 hrs, the catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure to give an oily residue which is chromatographed on silica gel (230-400 mesh, 200 ), eluting with a gradient of ethyl acetate/hexane (5/95-20/80). Pooling of fractions with an Rf =0.41 by TLC (ethyl acetate/hexane, 25/75) and removal of solvent under reduced pressure gives the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C@H:4]([OH:13])[C@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[NH2:6].Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:14])[C@H:4]([OH:13])[C@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[NH:6][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)[C@H](O)[C@@H](N)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](O)[C@@H](NC(=O)OCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (2R,3S)-β-phenyl isoserine methyl ester (2) (Preparation No. 1, 2 mM) in pyridine containing a small amount of DMAP is cooled in an ice bath and treated with benzyl chloroformate (0.8 ml). After stirring at room temperature overnight, the reaction is diluted with ethyl acetate, washed with 5% aqueous sodium bisulfate, dried and evaporated. The product is obtained pure by silica gel chromatography in ethyl acetate-hexane mixtures. Mp 120-121° C. NMR(CDCl3, TMS): δ 3.26 (m, 1H); 3.79 (s, 3H); 4.47 (m, 1H); 5.06 (m, 2H); 5.27 (d, 1H); 5.75 (m, 1H); 7.20-7.50 (m, 10 H).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.Cl.CN(C)[CH2:14][CH2:15]CN=C=NCC.C(O)C>ClCCl.CN(C)C1C=CN=CC=1>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:14][CH3:15])=[O:7])=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(I)nc1
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)c1ccc(I)nc1
Temperature: 50 °C

Procedure:
To a suspension of 23.38 g (94.2 mmol) of 6-iodonicotinic acid in 100 ml of dichloromethane was added a solution of 19.86 g (103.6 mmol) of 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride in 250 ml of dichloromethane. To this suspension was added 12.40 g (15.8 ml, 269.3 mmol) of ethanol (95%) and 1.15 g (9.4 mmol) of 4-dimethylaminopyridine. The resulting solution mixture was then heated at 50° C. in an oil bath for 24.5 hours, concentrated in vacuo, partitioned between 200 ml of water and 250 ml of ethyl ether, and the layers were separated. The aqueous phase was washed with 2×150 ml portions of ethyl ether. All organic phases were combined, washed once with 75 ml of brine solution, dried over MgSO4, filtered and concentrated in vacuo to a yellow solid. Purification by flash chromatography (silica, 10% ethyl acetate in hexane) yielded the title compound as a white solid.