Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:14][C:15](=[O:27])[O:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][C:20]=2[CH3:26])[CH:6]=[CH:7][C:8]=1[S:9]([CH2:12][CH3:13])(=[O:11])=[O:10])#[N:2].Br[C:29]1C=C(C)C(CCO)=C(C)C=1.C(C1C=C(NC(=O)OC2C=CC=CC=2)C=CC=1S(CC)(=O)=O)#N>>[C:1]([C:3]1[CH:4]=[C:5]([NH:14][C:15](=[O:27])[O:16][CH2:17][CH2:18][C:19]2[C:24]([CH3:29])=[CH:23][C:22]([Br:25])=[CH:21][C:20]=2[CH3:26])[CH:6]=[CH:7][C:8]=1[S:9]([CH2:12][CH3:13])(=[O:10])=[O:11])#[N:2]
Reactant: CCS(=O)(=O)c1ccc(NC(=O)OCCc2ccc(Br)cc2C)cc1C#N
Reactant: Cc1cc(Br)cc(C)c1CCO
Agent: CCS(=O)(=O)c1ccc(NC(=O)Oc2ccccc2)cc1C#N
Product: CCS(=O)(=O)c1ccc(NC(=O)OCCc2c(C)cc(Br)cc2C)cc1C#N
Yield: 59 %

Procedure:
Using a procedure analogous to that used to prepare 31A, 32B (400 mg, 1.75 mmol) was reacted with 25A (579 mg, 1.75 mmol) to give 32C (480 mg, 59%) as a white solid. MS (ESI) m/z 465.1/467.1 (M+H)+.
Reaction SMILES: [CH:1]1[N:5]([CH2:6][O:7][CH2:8][CH2:9][OH:10])[C:4]2[N:11]=[C:12]([NH2:16])[N:13]=[C:14]([OH:15])[C:3]=2[N:2]=1.[C:17]1(=[O:23])[O:22][C:20](=[O:21])[CH2:19][CH2:18]1.C(N(CC)CC)C>CN(C)C=O>[CH:1]1[N:5]([CH2:6][O:7][CH2:8][CH2:9][OH:10])[C:4]2[N:11]=[C:12]([NH2:16])[N:13]=[C:14]([OH:15])[C:3]=2[N:2]=1.[C:17]([O-:22])(=[O:23])[CH2:18][CH2:19][C:20]([O-:7])=[O:21]
Reactant: O=C1CCC(=O)O1
Agent: Nc1nc(O)c2ncn(COCCO)c2n1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C([O-])CCC(=O)[O-]

Procedure:
Acyclovir succinate is prepared by heating a solution of 0.2252 g of acyclovir (1 mmol) (Sigma), 0.200 g of succinic anhydride (2 mmoles) (Aldrich) and 0.14 mL of triethylamine in 15 mL of dry dimethylformamide at 60° C. in an oil bath for 21 hours. The solution was then cooled and the volatile constituents were evaporated in vacuo, and the residue was taken up in 8 mL of ice water and acidified to pH 2 with 2 N HCl. A white precipitate was formed that was collected by filtration, thoroughly washed with ice water and dried in vacuo over P2O5 at 40° C. to yield 0.180 g (54 percent) of the product. The ester was then recrystallized from methanol and characterized by IR and 1H NMR spectroscopy.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]=[CH:5][C:6](=[C:11]([NH:13][CH3:14])[CH3:12])[C:7]([O:9][CH3:10])=[O:8].C[O-].[Na+].[Br:19]N1C(=O)CCC1=O>CO>[CH3:10][O:9][C:7]([C:6]1[CH:5]=[C:4]([Br:19])[C:3](=[O:2])[N:13]([CH3:14])[C:11]=1[CH3:12])=[O:8]
Reactant: CNC(C)=C(C=CC(=O)OC)C(=O)OC
Reactant: O=C1CCC(=O)N1Br
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(Br)c(=O)n(C)c1C
Temperature: 25 °C
Yield: 45.6 %

Procedure:
MeOH (45 mL) was added to a flask containing 4-(1-methylamino-ethylidene)-pent-2-enedioic acid dimethyl ester (0.97 g, 4.55 mmol). NaOMe solution (1.04 mL, 4.55 mmol, 4.375 M in MeOH) and N-bromosuccinimide (0.97 g, 5.46 mmol) were added, and the resulting mixture was refluxed for 1 h. After cooling to r.t., the solvent was evaporated in vacuo. The residue was partitioned between saturated NH4Cl and CH2Cl2. The aqueous layer was extracted with additional CH2Cl2 and the organic layers were combined, dried over MgSO4, and concentrated. The crude product was chromatographed (0-50% EtOAc/hexanes) to give 540 mg of the title compound. MS: (+) m/z 260.22, 262.18 (M+Na, 79/81Br).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:6](Cl)=[O:7].[CH2:15]([N:22]1[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.N1C=CC=CC=1>C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH2:15]([N:22]1[CH2:26][CH2:25][C@H:24]([O:27][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:11]([N+:12]([O-:14])=[O:13])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COc1cc(C(=O)Cl)ccc1[N+](=O)[O-]
Reactant: O[C@H]1CCN(Cc2ccccc2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(C(=O)O[C@H]2CCN(Cc3ccccc3)C2)ccc1[N+](=O)[O-]
Reaction time: 18 h
Yield: 77.6 %

Procedure:
A solution of 3-methoxy -4-nitro-benzoyl chloride (608 mg, 2.82 mmol) in 10 mL of CH2Cl2 was added to stirred solution of 500 mg (2.82 mmol) of (3S)-1-benzyl-pyrrolidin-3-ol and 1 mL of pyridine in 15 mL CH2Cl2 at room temperature. After stirring for 18 h, the reaction mixture was diluted with 20 mL of saturated aqueous NaHCO3, and extracted with CH2Cl2 (2×10 mL). The combined extracts were washed with 20 mL of brine, dried over MgSO4, filtered, and concentrated in vacuo to furnish 780 mg (71%) of the desired ester as a yellow oil, which solidified after drying under high vacuum. The resulting solid was further purified by trituration with 1:1 ether-hexane. 1H-NMR (400 MHz, CDCl3) δ7.83 (d, J =7.83 Hz, 1H), 7.74 (s, 1H), 7.68 (d, J=7.83 Hz, 1H), 7.2-7.4 (m, 5H), 5.44 (br.m, 1H), 4.02 (s, 2H), 3.69 (dd, J=30 Hz, J=13 Hz, 1H), 2.8-3.0 (m, 2H), 2.5-2.6 (m, 1H), 2.3-2.45 (m, 1H), 2.0-2.1 (m, 1H)
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][N:6]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][N:12]=2)=[N:7]1)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2[CH:9]=[CH:10][N:6]([CH2:5][CH:4]=[O:3])[N:7]=2)=[N:12][CH:13]=1
Reactant: CCOC(Cn1ccc(-c2ccc(F)cn2)n1)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: O=CCn1ccc(-c2ccc(F)cn2)n1
Temperature: 35 °C
Reaction time: 6 h

Procedure:
To a solution of 2-[1-(2,2-diethoxyethyl)-1H-pyrazol-3-yl]-5-fluoropyridine obtained in Reference Example 12 (4.0 g, 14.3 mmol) in CHCl3 (72 mL), TFA (6.4 mL, 85.9 mmol) was added, and the resulting mixture was stirred for 6 hours at 35° C. TFA (6.4 mL, 85.9 mmol) was further added thereto, and the mixture was stirred for 3 hours at 35° C. The reaction mixture was allowed to cool to room temperature, then an aqueous solution of NaHCO3 was added to the reaction mixture, followed by extraction with CHCl3. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over MgSO4, and then the drying agent was filtered off. The solvent was distilled off under reduced pressure to obtain [3-(5-fluoropyridin-2-yl)-1H-pyrazol-1-yl]acetaldehyde (colorless oil). To a solution of [3-(5-fluoropyridin-2-yl)-1H-pyrazol-1-yl]acetaldehyde in CHCl3 (36 mL), activated molecular sieve 4 A (29 g) and 2-aminoethanol (1.1 mL, 14.3 mmol) were added, and the resulting mixture was stirred for 48 hours at room temperature. The molecular sieve 4 A was filtered off through Celite®, and then the solvent was distilled off under reduced pressure to obtain a colorless oil. To a solution of the obtained colorless oil (0.10 g, 0.40 mmol) and 2-(2H-1,2,3-triazol-2-yl)benzoic acid (76 mg, 0.40 mmol) in DMF (0.4 mL), DIPEA (0.21 mL, 1.2 mmol) and HATU (0.16 g, 0.48 mmol) were added, and the resulting mixture was stirred for 48 hours at room temperature. The reaction mixture was purified by HPLC to obtain the title compound (40.8 mg) (colorless solid).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.C([O:15][C:16](=[O:19])[CH2:17]Br)(C)(C)C.Cl.FC(F)(F)C(O)=O>[OH-].[Na+].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.ClCCl.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][CH2:17][C:16]([OH:19])=[O:15])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: OCCc1ccc(Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)COCCc1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
2-(4-Chlorophenyl)ethanol (10 g) was stirred in 50 % aqueous sodium hydroxide (70 ml), tetrabutylammoniumbromide (1.4g ) was added and the mixture stirred for 1 hour. t-Butylbromoacetate (28.6 ml) in toluene (140 ml) was added and stirring continued for 18 hours. Water (50 ml) was added and after 2 hours the mixture was cooled in ice and acidified to pH 1 with concentrated hydrochloric acid. The organic layer was separated and the aqueous extracted with ethyl acetate. The combined organic extracts were washed with brine and dried (MgSO4). The solvent was removed in vacuo to give a pale yellow oil This was dissolved in dichoromethane (100 ml) and trifluoroacetic acid (100 ml) added, the mixture was heated at reflux for 1 hour. The volatiles were removed in vacuo and the residue taken up in sodium hydroxide and washed with ethyl acetate. The aqueous layer was then acidified with concentrated hydrochloric acid and extracted with ethyl acetate, this ethyl acetate was washed with water, dried (MgSO4) and the volatiles removed in vacuo to provide the subtitle compound as a buff solid (16.4 g) which was used without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH:8]([S:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=2[F:16])[C:5]([Cl:25])=[CH:4][N:3]=1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>O1CCOCC1>[Cl:25][C:5]1[C:6]([CH:8]([S:17][C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)[C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=2[F:16])=[CH:7][C:2]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[N:3][CH:4]=1
Reactant: C1COCCN1
Reactant: Fc1ccc(F)c(C(Sc2ccc(Cl)cc2)c2cc(Cl)ncc2Cl)c1
Solvent: C1COCCO1
Product: Fc1ccc(F)c(C(Sc2ccc(Cl)cc2)c2cc(N3CCOCC3)ncc2Cl)c1
Temperature: 25 °C
Yield: 89 %

Procedure:
A solution of the 2,5-dichloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridine (100 mg, 0.24 mmol) obtained in Example 342 and morpholine (200 μl) in 1,4-dioxane (1.0 ml) was stirred under nitrogen atmosphere at 100° C. for 2 days. The reaction mixture was cooled to room temperature. After dilution with ethyl acetate (40 ml), the solution was washed with water and brine, dried and concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography (hexane:ethyl acetate=5:1) to yield the title compound (100 mg, 89%) as an oil.
Reaction SMILES: C1N2CN3CN(C2)CN1C3.[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:13]=1[OH:20].FC(F)(F)[C:23](O)=[O:24]>>[F:11][C:12]1[C:13]([OH:20])=[C:14]([O:18][CH3:19])[CH:15]=[CH:16][C:17]=1[CH:23]=[O:24]
Reactant: O=C(O)C(F)(F)F
Reactant: COc1cccc(F)c1O
Agent: C1N2CN3CN1CN(C2)C3
Product: COc1ccc(C=O)c(F)c1O
Reaction time: 0.17 h
Yield: 65 %

Procedure:
To a heated solution (80° C.) of hexamethylenetetramine (2.8 g, 20 mmol) in trifluoroacetic acid (10 mL) was added dropwise over a 50 minutes period 2-fluoro-6-methoxyphenol (1.42 g, 10 mmol) in trifluoroacetic acid (10 mL). The mixture was heated for an additional 1 hour, concentrated and water (50 ml) was added. The solution was stirred for 10 minutes and solid potassium carbonate was added until the solution was neutral. The solid that formed was collected to afford 1.1 g of 2-fluoro-3-hydroxy-4-methoxybenzaldehyde (65%). 1H NMR (500 MHz; DMSO-d6): δ3.90 (s, 3 H); 6.98 (d, J=8.5 Hz, 1 H); 7.31 (t, J=8.5 Hz, 1 H); 9.66 (br, 1 H); 10.02 (s, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6](Br)[CH:5]=1.[CH3:13][C:14]1[CH:15]=[CH:16][C:17]([Sn](CCCC)(CCCC)CCCC)=[N:18][CH:19]=1>C1(C)C=CC=CC=1.CN(C=O)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>[OH:10][C:8]1[CH:9]=[C:4]([CH:5]=[C:6]([C:17]2[CH:16]=[CH:15][C:14]([CH3:13])=[CH:19][N:18]=2)[CH:7]=1)[C:3]([O:2][CH3:1])=[O:12]
Reactant: COC(=O)c1cc(O)cc(Br)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C)cn1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(O)cc(-c2ccc(C)cn2)c1

Procedure:
A mixture of 3-bromo-5-hydroxy-benzoic acid methyl ester (1.47 g, 6.36 mmol), 5-methyl-2-(tributylstannyl)pyridine (3.0 g, 7.85 mmol), tetrakis(triphenylphosphine)-palladium(0) (300 mg, 0.26 mmol) in toluene (20 mL) and DMF (2 mL) was subjected to microwave irradiation at 110° C. for 1 hour. After cooling, the mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography to afford the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH2:11])[CH:6]=[CH:7][CH:8]=1.[Cl:12][CH2:13][C:14](Cl)=[O:15]>C(Cl)Cl>[Cl:12][CH2:13][C:14]([NH:11][CH2:10][CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:15]
Reactant: COc1cccc(CCN)c1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Product: COc1cccc(CCNC(=O)CCl)c1
Temperature: -60 °C
Reaction time: 1 h

Procedure:
The amine, 2-(3-Methoxy-phenyl)-ethylamine, was taken up as a 0.6 M solution in DCM, followed by addition of TEA (2 equiv.). The mixture was then cooled in an IPA/dry ice bath. When the reaction temperature reached −60° C., a solution of chloroacetylchloride in DCM (2.6 M) was added dropwise so as to keep the temperature below −60° C. After complete addition, the reaction was stirred at −60° C. for 1 h. The reaction was then warmed to −20° C. and filtered over GF filter paper to remove some of the TEA —HCl salt. The filtrate was warmed the rest of the way to rt and transferred to a separatory funnel where it was washed with 1 N HCl (2×) and brine. The organic layer was dried over MgSO4 and concentrated to give a dark purple solid. This crude product was directly used in the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[C:6]2[N:11]([CH:12]=1)[CH2:10][C@H:9]([OH:13])[CH2:8][O:7]2)([O-:3])=[O:2].Cl.[Br:15][C:16]1[CH:17]=[N:18][CH:19]=[C:20]([CH2:22]Cl)[CH:21]=1.[H-].[Na+]>CN(C=O)C>[Br:15][C:16]1[CH:21]=[C:20]([CH2:22][O:13][C@@H:9]2[CH2:8][O:7][C:6]3=[N:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][N:11]3[CH2:10]2)[CH:19]=[N:18][CH:17]=1
Reactant: ClCc1cncc(Br)c1
Reactant: O=[N+]([O-])c1cn2c(n1)OC[C@@H](O)C2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cn2c(n1)OC[C@@H](OCc1cncc(Br)c1)C2
Temperature: 25 °C
Reaction time: 16 h
Yield: 30.2 %

Procedure:
A solution of (S)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxa-zin-6-ol (3.63 g, 19.6 mmol) and 3-bromo-5-(chloromethyl)pyridine hydrochloride (4.78 g, 19.6 mmol, 1 eq) in dry DMF (80 mL) was treated with NaH (1.88 g, 47 mmol, 2.4 eq, 60% in mineral oil) at 0-5° C., then stirred at room temperature overnight (16 h), quenched with water (150 mL), and extracted into EtOAc. Chromatography of the crude product on silica gel, eluting with MeOH/CH2Cl2 (1:19), gave the title product (2.10 g, 30%) as white solid. APCI MS m/z 355.7, 357.7 (M+H). 1H NMR (400 MHz, (CD3)2SO) δ 8.64 (d, J=2.3 Hz, 1H), 8.52 (d, J=1.7 Hz, 1H), 8.03 (s, 1H), 7.97 (br t, J=2.1 Hz, 1H), 4.73 (d, J=12.6 Hz, 1H), 4.70-4.65 (m, 2H), 4.48 (d, J=12 Hz, 1H), 4.31-4.20 (m, 3H).
Reaction SMILES: F[CH2:2][C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[C:10]=2[CH3:19])[C:6]2[CH:20]=[C:21]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:22]=[C:23]([B:24]([OH:26])[OH:25])[C:5]=2[N:4]=1.C(#N)C.[OH2:36]>>[OH:36][CH2:2][C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:16])([F:18])[F:17])[C:10]=2[CH3:19])[C:6]2[CH:20]=[C:21]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:22]=[C:23]([B:24]([OH:26])[OH:25])[C:5]=2[N:4]=1
Reactant: Cc1c(Cn2c(CF)nc3c(B(O)O)cc(N4CCOCC4)cc32)cccc1C(F)(F)F
Reactant: O
Solvent: CC#N
Product: Cc1c(Cn2c(CO)nc3c(B(O)O)cc(N4CCOCC4)cc32)cccc1C(F)(F)F
Temperature: 70 °C
Reaction time: 48 h
Yield: 46 %

Procedure:
(2-(fluoromethyl)-1-(2-methyl-3-(trifluoromethyl)benzyl)-6-morpholino-1H-benzo[d]imidazol-4-yl)boronic acid (40 mg, 0.089 mmol) was dissolved in Water+0.1% TFA (2.5 mL) and Acetonitrile+0.1% TFA (2.5 mL) in a 20 mL scintillation vial. The mixture was stirred at 70° C. for 2 days, solution was evaporated and taken up in 50% water/acetonitrile and was purified by reversed phase HPLC eluted with a gradient of acetonitrile (0.1% TFA) and water (0.1% TFA v/v) (20-55%) over 12 minutes. The appropriate fractions were collected and evaporated to yield (2-(hydroxymethyl)-1-(2-methyl-3-(trifluoromethyl)benzyl)-6-morpholino-1H-benzo[d]imidazol-4-yl)boronic acid (18.5 mg, 0.041 mmol, 46.0% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.59 (s, 3H) 3.11-3.21 (m, 4H) 3.75-3.86 (m, 4H) 5.04 (s, 2H) 5.88 (s, 2H) 6.75 (d, 1H) 7.03 (d, J=2.27 Hz, 1H) 7.25 (t, J=7.83 Hz, 1H) 7.65 (d, J=7.83 Hz, 1H) 7.72 (br. s., 1H); LC/MS: MS (ES+) m/e 450 [M+H]+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[CH3:15][C:16]1[C:20]([C:21](Cl)=[O:22])=[C:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:18][N:17]=1.C(N(CC)CC)C.C(OCC)(=O)C>ClCCl>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:21]([C:20]1[C:16]([CH3:15])=[N:17][O:18][C:19]=1[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:22]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: Cc1noc(-c2ccccc2)c1C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1noc(-c2ccccc2)c1C(=O)NCCc1c[nH]c2ccc(Cl)cc12
Yield: 83.8 %

Procedure:
This compound was obtained following Method B starting from 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.0454 g, 0.193 mmol), 3-methyl-5-phenyl-4-isoxazolecarbonyl chloride (0.044 g; 0.193 mmol), and triethylamine (0.068 mL; 0.481 mmol) in dichloromethane (3 mL). Flash chromatography on silica gel eluting with 2 to 20% of ethyl acetate in dichloromethane gave 0.0614 g (84%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-methyl-5-phenylisoxazole-4-carboxamide as a solid.
Reaction SMILES: [Cl-].[CH3:2][NH3+:3].[N:4]1[C:13]2[CH:12]=[CH:11][CH2:10][CH2:9][C:8]=2[CH:7]=[CH:6][CH:5]=1.O.[OH-].[Na+]>CO.[Cl-].[Na+].O.C(OCC)(=O)C.C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH3:2][NH:3][CH:11]1[CH2:12][C:13]2[N:4]=[CH:5][CH:6]=[CH:7][C:8]=2[CH2:9][CH2:10]1
Reactant: C[NH3+]
Reactant: C1=Cc2ncccc2CC1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CNC1CCc2cccnc2C1
Yield: 83.2 %

Procedure:
A solution of methylammonium chloride (1.35 g, 20 mmol) in methanol (2 ml) was added to 5,6-dihydroquinoline (1.31 g, 10 mmol) in methanol (2 ml) and the solution was heated under reflux for 21h, poured onto a mixture of water (25 ml) and brine (25 ml), and basified with 10N-NaOH (25 ml). The mixture was extracted with chloroform (3×25 ml), and the extracts were dried (Na2SO4) and concentrated in vacuo to give an orange oil. Chromatography [alumina; ethyl acetate-toluene (1:4)→ethyl acetate] gave the product (1.35 g) as an oil which was identical to the compound isolated in Example 2.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](B(CC)CC)[CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][C:27]=1[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:30][CH:29]=1)[N:24]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[N:23]=[C:22]2[NH:50][C:51](=[O:55])[CH2:52][CH2:53][CH3:54].C(OCC)(=O)C>O.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>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][C:27]=2[C:28]2[CH:29]=[CH:30][C:31]([O:34][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[CH:32][CH:33]=2)[N:24]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:47])([CH3:48])[CH3:49])[N:23]=[C:22]3[NH:50][C:51](=[O:55])[CH2:52][CH2:53][CH3:54])[CH:2]=1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(-c3ccc(OCc4ccccc4)cc3)c(Br)cc12
Reactant: CCB(CC)c1cccnc1
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: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(-c3ccc(OCc4ccccc4)cc3)c(-c3cccnc3)cc12
Yield: 160.5 %

Procedure:
371 mg of 3-pyridyldiethylborane, 428 mg of sodium carbonate in 30 cm3 of water, and 258 mg of tetrakis(triphenylphosphine)palladium are added to 1 g of N-[5-bromo-6-[4-(phenylmethoxy)phenyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, prepared in Example 63, in 100 cm3 of dioxane, and the mixture is refluxed for 18 hours. 100 cm3 of ethyl acetate and 100 cm of water are added and the reaction medium is filtered through a sinter funnel packed with Celite. The organic phase is separated out after settling of the phases has taken place, washed successively with 75 cm3 of water and with 75 cm3 of saturated sodium chloride solution, dried over magnesium sulphate, filtered and concentrated under reduced pressure (2 kPa; 50° C.) to give 1.6 g of an oil, which is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 3.5 cm), eluting with a cyclohexane/ethyl acetate mixture (70/30 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.) to give 700 mg of N-[5-(3-pyridyl)-6-[4-(phenylmethoxy)phenyl]-1-[[2-(trimethylsilyl)ethoxy]methyl])-1H-indazol-3-yl]butanamide in the form of a yellow oil.
Reaction SMILES: C(OC([NH:11][CH:12]1[C:18](=[O:19])[NH:17][C:16]2[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=2[S:14][CH2:13]1)=O)C1C=CC=CC=1>CO.[C].[Pd]>[NH2:11][CH:12]1[C:18](=[O:19])[NH:17][C:16]2[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=2[S:14][CH2:13]1
Reactant: O=C(NC1CSc2ccccc2NC1=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: NC1CSc2ccccc2NC1=O

Procedure:
1.0 g of 3-benzyloxycarbonylamino-2,3-dihydro-1,5-benzothiazepin-4(5H)-one was dissolved in 20 ml of methanol and then hydrogenated at atmospheric pressure in the presence of 50 mg of 5% palladium-carbon. Thus, there was obtained the desired compound, or 3-amino-2,3-dihydro-1,5-benzothiazepin-4(5H)-one.
Reaction SMILES: [C:1]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:22][O:23][C:24](=[O:37])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32](=[N:34]O)Cl)=[C:28]([Cl:36])[CH:27]=1>CCOCC.CC#N>[C:8]([O:7][C:1]([C:2]1[C:32]([C:29]2[CH:30]=[CH:31][C:26]([CH2:25][C:24]([O:23][CH3:22])=[O:37])=[CH:27][C:28]=2[Cl:36])=[N:34][O:4][C:3]=1[CH3:5])=[O:6])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(=O)CC(=O)OC(C)(C)C
Reactant: COC(=O)Cc1ccc(C(Cl)=NO)c(Cl)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CC#N
Solvent: CCOCC
Product: COC(=O)Cc1ccc(-c2noc(C)c2C(=O)OC(C)(C)C)c(Cl)c1
Temperature: 25 °C

Procedure:
tert-Butyl acetoacetate (5.0 g, 32 mmol) is dissolved in ether (100 mL). Potassium bis(trimethylsilyl)amide (5.7 g, 29 mmol) is added slowly while stirring at room temperature. Then the mixture is concentrated and triturated with hexane. The precipitate is filtered and dried to yield crude potassium enolate 23 (4.6 g, 23 mmol, 81%). Enolate 23 (1.0 g, 5.0 mmol) is dissolved in MeCN (50 mL) and cooled to 0° C. Intermediate 16 (1.1 g, 4.2 mmol) dissolved in MeCN (10 mL) is added dropwise and the solution is stirred at 0° C. for 2 hours. The solvent is evaporated and the remainder is purified by column chromatography using a hexanes/EtOAc gradient to afford 3-(2-chloro-4-methoxycarbonylmethyl-phenyl)-5-methyl-isoxazole-4-carboxylic acid tert-butyl ester 24 as a white solid: 1H-NMR (400 MHz, CDCl3) δ=7.41 (d, J=1.5 Hz, 1H), 7.33 (d, J=7.8 Hz, 1H), 7.25 (dd, J=8.0 Hz, J=1.5 Hz, 1H), 3.69 (s, 3H), 3.65 (s, 2H), 2.73 (s, 3H), 1.28 (s, 9H). MS calculated for C18H21ClNO5 (M+H+) 366.1, found 366.4.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]([CH3:15])[C:12]([OH:14])=[O:13])[CH:7]=[CH:8][C:9]=1[OH:10])([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:11]([CH3:15])[C:12]([OH:14])=[O:13])[CH:7]=[CH:8][C:9]=1[OH:10]
Reactant: CC(C(=O)O)c1ccc(O)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: CC(C(=O)O)c1ccc(O)c(N)c1
Yield: 95.2 %

Procedure:
30 grams of 3-nitro-4-hydroxyphenyl-α-methylacetic acid are dissolved in 500 ml of anhydrous ethanol, 1.5 g of 5% Pd on carbon are added, and hydrogenation is carried out at atmospheric pressure and ambient temperature. The catalyst is filtered off and the filtrate concentrated to a small volume. This is filtered, and crystallised from methanol. 24.5 g of raceme 3-amino-4-hydroxyphenyl-α-methylacetic acid are obtained, with a yield of 95%.