Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]([OH:24])[CH2:10][CH:11]=[CH:12][CH2:13][Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[B-](F)(F)(F)[F:26].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.CCCCCC.CCOCC>C(#N)C>[F:26][CH:11]1[CH2:10][CH:9]([CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:24][CH:12]1[CH2:13][Si:14]([CH:21]([CH3:23])[CH3:22])([CH:15]([CH3:16])[CH3:17])[CH:18]([CH3:20])[CH3:19]
Reactant: CC(C)[Si](CC=CCC(O)CCc1ccccc1)(C(C)C)C(C)C
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CCCCCC
Solvent: CC#N
Solvent: CCOCC
Product: CC(C)[Si](CC1OC(CCc2ccccc2)CC1F)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.1 %

Procedure:
A solution of 1-phenyl-7-(triisopropylsilyl)hept-5-en-3-ol (149 mg, 0.43 mmol, 1 eq) in acetonitrile (5 mL) was treated with Selectfluor (152 mg, 0.43 mmol, 1 eq) and stirred at room temperature under an atmosphere of argon for 18 h. The acetonitrile was removed under reduced pressure and the reaction was quenched with saturated aqueous sodium hydrogen carbonate (5 mL). It was then extracted with ether (3×10 mL), dried over MgSO4, filtered and the solvent removed under reduced pressure to give a pale yellow oil. Column chromatography (hexane:ether, 9:1) gave {[3-fluoro-5-(2-phenylethyl)tetrahydrofuran-2-yl]methyl}(triisopropyl)silane as a colourless oil (157 mg, 66% yield). For the major diastereomer depicted on the left hand side in the pair of formulae above: 1H NMR (400 MHz, CDCl3) δ 0.92-1.00 (dd, 1H, CH2Si, J=14.4, 5.6 Hz), 1.08-1.10 (m, 21H, SiCHCH3), 1.19-1.26 (m, 1H, CH2Si) 1.66-1.89 (m, 2H, PhCH2CH2), 1.93-2.02 (m, 1H, CH2CHF), 2.26-2.43 (m, 1H, CH2CHF), 2.60-2.83 (m, 2H, PhCH2), 3.70-3.81 (m, 1H, PhCH2CH2CHO), 4.06-4.17 (dddd, 1H, OCHCHF, J=27.6, 8.4, 5.6, 2.8 Hz), 4.83-4.98 (m, 1H, CHF); 13C NMR (100 MHz, CDCl3) δ 8.21-8.26 (CH2Si), 11.4 (Si(CH(CH3)2)3), 18.9 (Si(CH(CH3)2)3), 32.5 (PhCH2), 38.0 (PhCH2CH2), 39.2-39.4 (d, CH2CHF, J=21 Hz), 76.1 (PhCH2CH2CHO), 78.6-78.8 (d, CHFCHO, J=20 Hz), 94.6-96.5 (d, CHF, J=182), 125.7 (Ph), 125.8 (Ph), 128.3 (Ph), 128.4 (Ph), 142.1 (Ph); 19F NMR (376.5 MHz, CDCl3) δ −191.5 For the major diastereomer depicted on the right hand side in the pair of formulae above: 1H NMR (400 MHz, CDCl3) δ 0.92-1.00 (dd, 1H, CH2Si, J=14.4, 5.6 Hz), 1.08-1.10 (m, 21H, SiCHCH3 ), 1.19-1.26 (m, 1H, CH2Si) 1.66-1.89 (m, 2H, PhCH2CH2), 1.93-2.02 (m, 1H, CH2CHF), 2.26-2.43 (m, 1H, CH2CHF), 2.60-2.83 (m, 2H, PhCH2), 3.70-3.81 (m, 1H, PhCH2CH2CHO), 4.20-4.27 (m, 1H, OCHCHF), 4.78-4.93 (m, 1H, CHF); 13C NMR (100 MHz, CDCl3) δ 8.75-8.82 (CH2Si), 11.4 (Si(CH(CH3)2)3), 18.9 (Si(CH(CH3)2)3), 32.7 (PhCH2), 38.2 (PhCH2CH2), 39.6-39.9 (d, CH2CHF, J=21 Hz), 77.2 (PhCH2CH2CHO), 80.1-80.3 (d, CHFCHO, J=21 Hz), 94.0-94.5 (d, CHF, J=183), 125.8 (Ph), 128.3 (Ph), 128.4 (Ph), 128.5 (Ph), 142.1 (Ph); 19F NMR (376.5 MHz, CDCl3) δ −185.5; IR (v, cm−1) 3027 (Ar—H), 1496 (Ar), 1464 (Ar), 1384 (Ar), 1096 (C—O—C), 699 (Si—C); MS (GCT, CI+) m/z 226.2 [M+NH4]+ HRMS required for C22H41FNOSi: 382.2941, found 382.2935.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C[Al](C)C.[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=1[N:19]1[C:24]2[N:25]=[C:26]([NH:37][CH2:38][C:39](OC)=[O:40])[N:27]=[C:28]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=3[CH3:36])[C:23]=2[CH:22]=[CH:21][C:20]1=[O:43]>ClCCl.CCOC(C)=O>[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=1[N:19]1[C:24]2[N:25]=[C:26]([NH:37][CH2:38][C:39]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:40])[N:27]=[C:28]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=3[CH3:36])[C:23]=2[CH:22]=[CH:21][C:20]1=[O:43]
Reactant: COC(=O)CNc1nc(-c2ccc(F)cc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: C1COCCN1
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1cc(F)ccc1-c1nc(NCC(=O)N2CCOCC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reaction time: 16 h
Yield: 31.2 %

Procedure:
Under Ar, a soln of morpholine (58 mg, 0.66 mmol) and trimethylaluminum (2M in toluene) (0.33 mL, 0.66 mmol) in dichloromethane was stirred for 10 min. A soln of the product of Example 190 (100 mg, 0.22 mmol) in dichloromethane (2 mL) was added. The resulting mixture was stirred for 16 h, diluted with EtOAc and washed with H2O to give the crude material. Purification by Flash chromatography on silica gel, eluting with EtOAc/hexane/triethylamine (70/30/2, v/v/v), followed by recrystallization from dichloromethane and hexane, gave the desired product (35 mg, 31%). LC-MS: 510.10 (MH+, m/z), 1.96 (Rt, min).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:45][CH3:46])=[C:10]([CH2:19][NH:20][C:21](=[O:44])[CH2:22][CH2:23][CH2:24][C:25]([NH:27][CH2:28][C:29]3[CH:30]=[C:31]([C:36]4[CH:41]=[CH:40][CH:39]=[C:38]([CH:42]=O)[CH:37]=4)[C:32]([F:35])=[CH:33][CH:34]=3)=[O:26])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[CH3:47][CH:48]1[CH2:53][NH:52][CH2:51][CH:50]([CH3:54])[NH:49]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CS(C)=O.[Cl-].[Cl-].[Zn+2]>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:45][CH3:46])=[C:10]([CH2:19][NH:20][C:21](=[O:44])[CH2:22][CH2:23][CH2:24][C:25]([NH:27][CH2:28][C:29]3[CH:30]=[C:31]([C:36]4[CH:41]=[CH:40][CH:39]=[C:38]([CH2:42][N:52]5[CH2:51][CH:50]([CH3:54])[NH:49][CH:48]([CH3:47])[CH2:53]5)[CH:37]=4)[C:32]([F:35])=[CH:33][CH:34]=3)=[O:26])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CCCC(=O)NCc1ccc(F)c(-c2cccc(C=O)c2)c1
Reactant: CC1CNCC(C)N1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CCCC(=O)NCc1ccc(F)c(-c2cccc(CN3CC(C)NC(C)C3)c2)c1

Procedure:
N-{[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(6-fluoro-3′-formyl-3-biphenylyl)methyl]pentanediamide (47.0 mg, 0.076 mmol) was diluted in DMSO (1.0 mL) and dispensed into a 1 dram vial containing 2,6-dimethylpiperazine (0.76 mmol), ZnCl2 (0.032 mmol, 4.2 mg), NaB(OAc)3H (0.76 mmol, 180 mg) and fitted with a magnetic stir bar, for 12 h. The material was purified via reverse phase HPLC using a Gilson and the desired product collected. The desired product was dissolved in dichloromethane (1 mL) and washed through 2 g SPE-amine columns (EtOAc:MeOH=4:1, 5 mL) to afford the title compound. LC-MS m/z 727 (M+H)+, 1.09 min (ret time).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[C:17]([Cl:19])[C:5]([CH2:6][C:7]2[CH:8]=[C:9]([CH:14]([CH3:16])[CH3:15])[C:10](=[O:13])[NH:11][N:12]=2)=[C:4]([Cl:20])[CH:3]=1.[C:21]1(=O)[O:26][C:24](=[O:25])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]12>C(O)(=O)C>[Cl:19][C:17]1[CH:18]=[C:2]([N:1]2[C:24](=[O:25])[C:23]3[C:22](=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:21]2=[O:26])[CH:3]=[C:4]([Cl:20])[C:5]=1[CH2:6][C:7]1[CH:8]=[C:9]([CH:14]([CH3:15])[CH3:16])[C:10](=[O:13])[NH:11][N:12]=1
Reactant: CC(C)c1cc(Cc2c(Cl)cc(N)cc2Cl)n[nH]c1=O
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CC(=O)O
Product: CC(C)c1cc(Cc2c(Cl)cc(N3C(=O)c4ccccc4C3=O)cc2Cl)n[nH]c1=O
Temperature: 130 °C
Yield: 60.8 %

Procedure:
A solution of 6-(4-amino-2,6-dichloro-benzyl)-4-isopropyl-2H-pyridazin-3-one (910 mg, 2.90 mmol) in glacial acetic acid (12 mL) was treated with phthalic anhydride (430 mg, 2.9 mmol). The reaction was then heated to 130° C. for 3.5 h. At this time, the reaction was poured onto water (200 mL) and extracted into ethyl acetate (300 mL). The organics were then washed with water, dried with magnesium sulfate, filtered and concentrated under vacuum. The resulting orange solid was slurried in cold acetonitrile, collected by filtration, washed with cold acetonitrile and dried under vacuum to afford 2-[3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-ylmethyl)-phenyl]-isoindole-1,3-dione (92) (780 mg, 61%) as a light, tan solid; ES(+)-LRMS for C22H17Cl2N3O3 (M+H)+ at m/z=442. Exact Mass=441.0647; Molecular Weight=442.3051
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH2:11][O:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[C:9]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:22]([C:29]1[O:33][C:32]([NH2:34])=[N:31][N:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC.C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:22]([C:29]1[O:33][C:32]([NH:34][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][C:9]([S:18]([CH3:21])(=[O:20])=[O:19])=[C:10]([CH2:11][O:12][CH2:13][C:14]([F:17])([F:16])[F:15])[C:2]=2[Cl:1])=[N:31][N:30]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Nc1nnc(Cc2ccccc2)o1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1COCC(F)(F)F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(=O)Nc2nnc(Cc3ccccc3)o2)c(Cl)c1COCC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
90 mg (0.26 mmol) of 2-chloro-4-(methylsulfonyl)-3-[(2,2,2-trifluoroethoxy)methyl]benzoic acid and 45 mg (0.26 mmol) of 5-benzyl-1,3,4-oxadiazol-2-amine are dissolved at room temperature (RT) in 8 ml of CH2Cl2. Then 248 mg (0.398 mmol) of 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (50% solution in THF) are added, the mixture is stirred at RT for one hour and then 0.181 ml (1.3 mmol) of triethylamine, 6 mg (0.052 mmol) of 4-dimethylaminopyridine are added. Then the mixture is stirred at RT for 20 h and washed twice with 4 ml each time of water, dried over Na2SO4 and concentrated. The residue is purified by column chromatography (prep. HPLC; acetonitrile/water). Yield 70 mg (45%).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([OH:9])=[C:4]([O:10][CH3:11])[CH:3]=1.C(N(CC)C(C)C)(C)C.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].CN(C1C=CC=CN=1)C.[SiH4]>C(Cl)Cl>[C:24]([Si:21]([O:9][C:5]1[CH:6]=[C:7]([F:8])[C:2]([F:1])=[CH:3][C:4]=1[O:10][CH3:11])([CH3:23])[CH3:22])([CH3:27])([CH3:26])[CH3:25]
Reactant: COc1cc(F)c(F)cc1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccccn1
Agent: [SiH4]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(F)c(F)cc1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 4,5-difluoro-2-methoxy-phenol (3.75 g, 23.42 mmol, Example 264) in methylene chloride (60 mL) cooled to 0° C. were added N,N-diisopropylethylamine (4.895 mL, 28.10 mmol), tert-butyldimethylsilyl chloride (4.367 g, 28.10 mmol, Aldrich), and dimethylaminopyridine (286 mg, 2.342 mmol, Aldrich). At the end of addition, the ice bath was removed and the reaction mixture was stirred at room temperature for 90 minutes. Water (30 mL) was added and the layers were separated. The aqueous layer was extracted with methylene chloride (20 mL). The combined organic layers were washed with brine and dried over anhydrous magnesium sulfate. The solids were filtered off and the filtrate was concentrated in vacuo. Purification of the crude residue by flash chromatography (Biotage system, 60 Å silica gel, eluting with 3% ethyl acetate in hexanes) yielded tert-butyl-(4,5-difluoro-2-methoxy-phenoxy)-dimethyl. silane as a clear oil (5.22 g, 81%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2].P([O-])([O-])([O-])=[O:10].[K+].[K+].[K+]>CO>[C:1]([NH2:2])(=[O:10])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1
Reactant: N#Cc1cccnc1
Reactant: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CO
Product: NC(=O)c1cccnc1
Reaction time: 0.17 h

Procedure:
3-Cyanopyridine was added at different concentrations (3.1-800 mM; 0.500 ml) to a solution comprising nitrile hydratase solution (0.0697 μmol/min; 0.025 ml) and 15 potassium phosphate buffer (0.1 M; pH 7.0; 0.475 ml). The reaction mixture was incubated at 20° C. for 10 min. The reaction was stopped by adding methanol and the amount of nicotinamide produced was determined by means of HPLC according to Example 1.
Reaction SMILES: O=O.[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([F:12])[F:11])=[CH:6][CH:5]=1.[Br:13]N1C(=O)CCC1=O>ClC(Cl)(Cl)Cl>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([Br:13])([F:12])[F:11])=[CH:6][CH:5]=1
Reactant: FC(F)c1ccc(Br)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=O
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)(Br)c1ccc(Br)cc1
Temperature: 25 °C
Yield: 93.1 %

Procedure:
With exclusion of oxygen, a solution of 14.0 g (67.63 mmol) of 1-bromo-4-(difluoromethyl)benzene [CAS 51776-71-7] and 25.3 g (142 mmol) of N-bromosuccinimide (NBS) in 190 ml of tetrachloromethane is irradiated with a sun lamp. During this, the solvent reaches its boiling point. It is irradiated under reflux for 24 hours. The mixture is then allowed to cool to room temperature and precipitated succinimide is filtered off. The filtrate is again mixed with 25 g of NBS and irradiated once more with exclusion of oxygen under reflux for 24 hours. Cooling is followed by filtration again, and the filtrate is concentrated to dryness. 18 g of an orange-colored oil are obtained as crude product, which is purified further by vacuum distillation at 13 mmHg. 12.7 g (44.4 mmol, 66% yield) of a colorless oil are obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[K+].Cl[C:14]1[N:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[N:15]=1.O>CS(C)=O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:14]2[N:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[N:15]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Cc1cc(C)nc(Cl)n1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(C)nc(Oc2ccc([N+](=O)[O-])cc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.5 %

Procedure:
27.8 g (0.2 mole) of 4-nitro-phenol were dissolved in 100 ml of dimethylsulphoxide. After addition of 11.2 g (0.2 mole) of powdered potassium hydroxide, the mixture was stirred at room temperature for 30 minutes and 28.5 g (0.2 mole) of 2-chloro-4,6-dimethyl-pyrimidine were then added. The mixture was heated at 120° C. for 6 hours and then cooled, stirred with one liter of water and filtered off with suction. The crystals filtered off with suction were dried in air. 38 g (77.5% of theory) of 2-(4-nitrophenoxy)-4,6-dimethyl-pyrimidine were obtained.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:9])=[CH:5][C:6](=[O:8])[CH:7]=1>C(O)C.[Pd]>[CH3:1][C@@H:2]1[CH2:7][C:6](=[O:8])[CH2:5][C@H:4]([CH3:9])[O:3]1
Reactant: Cc1cc(=O)cc(C)o1
Agent: [Pd]
Solvent: CCO
Product: C[C@@H]1CC(=O)C[C@H](C)O1

Procedure:
A solution of 2,6-dimethyl-4H-pyran-4-one (2 g, 16.1 mmol) in 20 ml ethanol was stirred over 10% Pd/C (0.2 g) under hydrogen (15 psi) for 16 hours at ambient temperature. TLC showed two spots; one was desired product and second one was side product in a 1:1 ratio. GCMS M+128 for product, and M+130 for side product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:20])([F:19])[F:18])[C:5]([NH2:8])=[N:6][CH:7]=1.[C:21]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)([OH:23])=[O:22].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([C:27]2[CH:28]=[CH:29][C:24]([C:21]([OH:23])=[O:22])=[CH:25][CH:26]=2)=[CH:3][C:4]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]([F:20])([F:19])[F:18]
Reactant: Nc1ncc(Br)cc1OCc1ccccc1C(F)(F)F
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncc(-c2ccc(C(=O)O)cc2)cc1OCc1ccccc1C(F)(F)F
Temperature: 87 °C
Reaction time: 0.5 h
Yield: 69.4 %

Procedure:
5-Bromo-3-(2-trifluoromethyl-benzyloxy)-pyridin-2-ylamine (5.80 g, 16.7 mmol), 4-carboxybenzeneboronic acid (3.05 g, 18.4 mmol), tetrakis(triphenylphosphine)-palladium(0) (0.62 g, 0.6 mmol), potassium carbonate (8.10 g, 58 mmol), dimethylformamide (47 mL) and water (23 mL) were charged to a 250 mL three neck round bottom flask equipped with a thermometer, a reflux condenser and magnetic stirring. The mixture was purged with nitrogen and gradually heated from 81 to 93° C. over a period of 4 hr. Thin layer chromatography (ethyl acetate:hexane:acetic acid 4:6:0.5) showed product at Rf 0.6 and a few small impurities. The mixture was cooled to 45° C. The solids were collected by vacuum filtration, washed with 10 mL of ethanol:water 1:1 and discarded. The filtrate was diluted with 300 mL of water and 4 mL of 9 N potassium hydroxide solution (to pH 12–13), cooled in an ice bath and stirred for 30 minutes with 3 g of Celite and 3 g of Norit. The solids were collected by vacuum filtration through a pad of Celite and washed with 10 mL of water. The solids were discarded. The filtrate was cooled in an ice bath and acidified to pH 7.3 with acetic acid using a pH meter. The solids were collected by vacuum filtration, washed with 20 mL of ethanol:water 1:1 and dried under vacuum to give 4.5 g (69% yield) of 4-[6-amino-5-(2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-benzoic acid as a brown solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:21])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=O)=[CH:13][CH:12]=1.[NH:22]1[CH2:26][CH2:25][CH2:24][C@H:23]1[CH2:27][O:28][C:29]1[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][C:30]=1[C:39]([O:41][CH3:42])=[O:40].CCN(CC)CC>CN(C=O)C.CCOC(C)=O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:21])[NH:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:17][C:18]([N:22]2[CH2:26][CH2:25][CH2:24][CH:23]2[CH2:27][O:28][C:29]2[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][C:30]=2[C:39]([O:41][CH3:42])=[O:40])=[O:20])=[CH:15][CH:16]=1
Reactant: COC(=O)c1ccc(OC[C@@H]2CCCN2)c(C(=O)OC)c1
Reactant: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OCC2CCCN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)cc2)c(C(=O)OC)c1
Reaction time: 8 h
Yield: 54.8 %

Procedure:
To a stirred solution of pentafluorophenyl ester of 4-[N′-(2-methylphenyl)ureido]phenylacetic acid (2.32 g, 5.15 mmol), dimethyl (S)-4-(2-pyrrolidinylmethoxy)isophthalate (1.51 g, 5.15 mmol) in DMF (20 mL) was added Et3N (1.0 mL, 6.65 mmol), and the mixture was stirred overnight. The resulting mixture was diluted with EtOAc. The solution was washed with brine, dried over MgSO4, and evaporated off in vacuo. The residue was purified by column chromatography on silica-gel with CHCl3—MeOH (10:1, v/v) as eluent to give 1.58 g (55%) dimethyl 4-[1-[4-[N′-(2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinylmethoxy]isophthalate as a yellow crystalline solid. 1H-NMR (CDCl3) δ1.87-2.25 (m, total 7 H), 3.50-3.65 (m, 4 H), 3.85 (s, 3 H), 3.89 (s, 3 H), 4.18-4.31 (m, 2 H), 4.44 (m, 1 H), 6.95-8.45 (m, total 13 H).
Reaction SMILES: [CH:1]1([C:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:9]2[N:13]=[CH:12][N:11]([CH2:14][CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[N:10]=2)[OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][N:38]2[C:46](=[O:47])[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:39]2=[O:48])=[CH:32][CH:31]=1.C(N(CC)CC)C>C(#N)C>[CH:21]1([C@@:7]([OH:8])([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:9]2[N:13]=[CH:12][N:11]([CH2:14][CH:15]3[CH2:20][CH2:19][N:18]([CH2:28][CH2:29][C:30]4[CH:31]=[CH:32][C:33]([CH2:36][CH2:37][N:38]5[C:46](=[O:47])[C:45]6[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=6)[C:39]5=[O:48])=[CH:34][CH:35]=4)[CH2:17][CH2:16]3)[N:10]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: OC(c1ccccc1)(c1ncn(CC2CCNCC2)n1)C1CCCCC1
Reactant: O=C1c2ccccc2C(=O)N1CCc1ccc(CCBr)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1CCc1ccc(CCN2CCC(Cn3cnc([C@](O)(c4ccccc4)C4CCCCC4)n3)CC2)cc1
Temperature: 90 °C
Reaction time: 48 h
Yield: 28 %

Procedure:
Cyclohexyl-phenyl-(1-piperidin-4-ylmethyl-1H-[1,2,4]triazol-3-yl)-methanol (Preparation 4, 8.2 g, 2.98 mmol), 2-{2-[4-(2-Bromo-ethyl)-phenyl]-ethyl}-isoindole-1,3-dione (Preparation 11, 7.56 g, 21.1 mmol), and triethylamine (13.3 ml, 95.9 mmol) were dissolved in acetonitrile (100 ml). After stirring at 90° C. for 48 hours the solvent was removed in vacuo, and the residue partitioned between dichloromethane (200 ml) and water (200 mL). The organic layer was separated, dried over magnesium sulphate, filtered and the solvent removed in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol:880 ammonia (98:2:0.2, by volume) and the resulting material then triturated in tert-butyl methyl ether to furnish title compound as a clear solid in 28% yield, 3.4 g.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]2[C:5]([O:6][C:7]3[CH:8]=[C:9](F)[C:10]([F:17])=[CH:11][C:12]=3[C:13]2=[O:16])=[CH:4][CH:3]=1.[F:19][C:20]([F:24])([F:23])[CH2:21][OH:22].[H-].[Na+].O>CN(C=O)C>[Br:1][C:2]1[CH:15]=[C:14]2[C:5]([O:6][C:7]3[CH:8]=[C:9]([O:22][CH2:21][C:20]([F:24])([F:23])[F:19])[C:10]([F:17])=[CH:11][C:12]=3[C:13]2=[O:16])=[CH:4][CH:3]=1
Reactant: OCC(F)(F)F
Reactant: O=c1c2cc(Br)ccc2oc2cc(F)c(F)cc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2cc(Br)ccc2oc2cc(OCC(F)(F)F)c(F)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.8 %

Procedure:
To a solution of 7-bromo-2,3-difluoro-9H-xanthen-9-one (3.1 g, 9.97 mmol) and 2,2,2-trifluoroethanol (1.445 mL, 19.93 mmol) in DMF (33 mL) at 0° C. was added sodium hydride (0.598 g, 14.95 mmol) slowly in portions. After addition, the mixture was stirred at RT for overnight. Then, H2O (100 mL) was added slowly and the mixture was extracted with EtOAc (1×100 mL). The organic layer was collected, dried over MgSO4, and concentrated. The residue was then washed with hexane (1×100 mL) to give 2.76 g of 7-bromo-2-fluoro-3-(2,2,2-trifluoroethoxy)-9H-xanthen-9-one as a light yellow solid. MS (ESI, positive ion) m/z: 390.9, 392.9 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([NH:12][C@@H:13]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[C:14]([NH:16][CH2:17][C:18]([OH:20])=O)=[O:15])=[O:11])=[CH:4][CH:3]=1.Cl.Cl.[F:30][C:31]([F:41])([F:40])[CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]([NH:12][C@@H:13]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[C:14](=[O:15])[NH:16][CH2:17][C:18](=[O:20])[N:37]2[CH2:36][CH2:35][N:34]([CH2:33][CH2:32][C:31]([F:40])([F:41])[F:30])[CH2:39][CH2:38]2)=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(O)CNC(=O)[C@H](Cc1ccccn1)NC(=O)/C=C/c1ccc(Cl)cc1
Reactant: FC(F)(F)CCN1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(/C=C/c1ccc(Cl)cc1)N[C@@H](Cc1ccccn1)C(=O)NCC(=O)N1CCN(CCC(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.1 %

Procedure:
To a mixture of [[(2S)-2-[[(2E)-3-(4-chlorophenyl)-2propenoyl]amino]-3-(2-pyridyl)propanoyl]amino]acetic acid (38.8 g), 1-(3,3,3-trifluoropropyl)piperazine dihydrochloride (25.5 g), 1-hydroxybenzotriazole (14.9 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (21.1 g) in N,N-dimethylformamide (250 ml) was added dropwise N,N-diisopropylethylamine (38.3 ml) at 10° C. over 50 minutes. The mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was poured into ice-cold saturated aqueous sodium hydrogencarbonate solution (750 ml). The mixture was extracted three times with ethyl acetate (total 2500 ml) and washed successively with water (500 ml×3) and brine (200 ml). The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluent; 12% methanol in ethyl acetate) to give the title compound (37.0 g) as a white amorphous solid, which was recrystallized from ethyl acetate.