Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[N:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])[C:5]2=[N:6][CH:7]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>C(#N)C.[Cl-].[Na+].O>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[O:19][CH3:18])=[N:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])[C:5]2=[N:6][CH:7]=1
Reactant: COCCOCn1nc(I)c2cc(Br)cnc21
Reactant: COc1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: COCCOCn1nc(-c2ccccc2OC)c2cc(Br)cnc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 45.5 %

Procedure:
A mixture of 5-bromo-3-iodo-1-(2-methoxy-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridine (180 mg, 0.44 mmol), 1,1′-bis(diphenylphosphino)ferrocenepalladium(II)-dichloride dichlormethane adduct (18 mg, 25 μmol) and 2-methoxyphenylboronic acid (82 mg, 0.51 mmol) in acetonitrile (3 mL) and 2 M aqueous solution of sodium carbonate (3 ml) in a sealed vial was stirred at 60° C. for 2 h. The crude mixture was distributed between ethyl acetate and brine. The aqueous phase was extracted with ethyl acetate (3×) and the combined organic phases were dried over sodium sulfate, filtered and concentrated. The crude was then purified by flash silica gel chromatography using a gradient of ethyl acetate in hexanes to afford 5-bromo-1-(2-methoxy-ethoxymethyl)-3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridine (80 mg, 0.2 mmol, 46% yield) as a yellow oil. 1H-NMR (500 MHz, d6-DMSO) δ 8.70 (d, 1H), 8.40 (d, 1H), 7.62 (dd, 1H), 7.49 (ddd, 1H), 7.22 (d, 1H), 7.09 (dt, 1H), 5.85 (s, 2H), 3.85 (s, 3H), 3.68-3.70 (m, 2H), 3.39-3.41 (m, 2H), 3.18 (s, 3H). MS: m/z 316, 318 [MH+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:13]=2[C:14]([O:16]C)=[O:15])[N:4]=1.[OH-].[Na+].O>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:13]=2[C:14]([OH:16])=[O:15])[N:4]=1
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1Oc1nc(OC)cc(OC)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cc(OC)nc(Oc2cc([N+](=O)[O-])ccc2C(=O)O)n1
Yield: 78.3 %

Procedure:
To a suspension in ethanol (20 ml) of methyl 2-(4,6-dimethoxypyrimidin-2-yl)oxy-4-nitrobenzoate (2.4 g), an equimolar amount of an aqueous sodium hydroxide solution (20 ml) was added, and the mixture was reacted at room temperature for 12 hours under stirring. The reaction mixture was poured into water, and extracted with ethyl ether, and non-reacted starting materials were removed. Then, the aqueous phase was acidified with a 10% hydrochloric acid aqueous solution. This was extracted with ethyl ether. The extract was washed with water and dried, and then the solvent was distilled off under reduced pressure to obtain 1.8 g of a yellow crystal. This crystal was further washed with a mixture of hexane and isopropyl ether to obtain the above identified compound as a yellow crystal (1.7 g). (Melting point: 93°-96° C.).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)[C:10]([C:18]2[N:19]=[C:20]3[C:26]([C:27]([NH:29][CH:30]([CH3:32])[CH3:31])=[O:28])=[CH:25][N:24](COCC[Si](C)(C)C)[C:21]3=[N:22][CH:23]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C(N)CN>ClCCl>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)[C:10]([C:18]2[N:19]=[C:20]3[C:26]([C:27]([NH:29][CH:30]([CH3:32])[CH3:31])=[O:28])=[CH:25][NH:24][C:21]3=[N:22][CH:23]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(Cc4ccccc4)c4cc(Cl)ccc34)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: NCCN
Solvent: ClCCl
Product: CC(C)NC(=O)c1c[nH]c2ncc(-c3nn(Cc4ccccc4)c4cc(Cl)ccc34)nc12
Reaction time: 4 h
Yield: 115.9 %

Procedure:
2-(1-Benzyl-6-chloro-1H-indazol-3-yl)-N-isopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (87 mg, 151 μmol) was dissolved in dichloromethane (25 mL) and to this was added trifluoroacetic acid (1.72 g, 1.17 mL, 15.1 mmol). The mixture was stirred for 4 h then concentrated in vacuo. The residue was diluted in dichloromethane and re-concentrated again, then suspended in dichloromethane and ethylenediamine (682 mg, 0.766 mL, 11.3 mmol) added. The mixture was stirred for 15 h then concentrated in vacuo. The residue was triturated with water and the solid collected by filtration and dried. The solid was adsorbed onto silica gel and purified by chromatography (silica, SiliCycle 25 g cartridge, 0-5% methanol in dichloromethane, 15 min gradient) to give 2-(1-benzyl-6-chloro-1H-indazol-3-yl)-N-isopropyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (78 mg, 175 μmol, quantitative) as a pale yellow powder. MS (M−H)−=443; 1H NMR (DMSO-d6) δ: 12.84 (br. s., 1H), 9.05-9.13 (m, 1H), 8.37-8.50 (m, 2H), 8.08 (d, J=1.1 Hz, 1H), 8.01 (d, J=7.6 Hz, 1H), 7.23-7.38 (m, 6H), 5.79 (s, 2H), 4.20 (dq, J=13.6, 6.7 Hz, 1H), 1.30 (d, J=6.4 Hz, 6H).
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[S:11]1[CH:15]=[C:14]([C@@H:16]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:17]([O:19][C@@H:20]2[CH:25]3[CH2:26][CH2:27][N:22]([CH2:23][CH2:24]3)[CH2:21]2)=[O:18])[C:13]2[CH:35]=[CH:36][CH:37]=[CH:38][C:12]1=2>CC#N>[Cl-:1].[S:11]1[CH:15]=[C:14]([C@@H:16]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:17]([O:19][C@@H:20]2[CH:25]3[CH2:26][CH2:27][N+:22]([CH2:2][C:3](=[O:4])[C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)([CH2:23][CH2:24]3)[CH2:21]2)=[O:18])[C:13]2[CH:35]=[CH:36][CH:37]=[CH:38][C:12]1=2
Reactant: O=C(CCl)c1ccccc1
Reactant: O=C(O[C@H]1CN2CCC1CC2)[C@H](Nc1ccccc1)c1csc2ccccc12
Solvent: CC#N
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)[C@H](Nc1ccccc1)c1csc3ccccc13)C2)c1ccccc1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
2-Chloro-1-phenylethanone (98 mg, 0.64 mmol) was added to a solution of (R)—((R)-quinuclidin-3-yl) 2-(benzo[b]thiophen-3-yl)-2-(phenylamino)acetate (diastereomer 1 of C19) (250 mg, 0.64 mmol) in CH3CN (3 ml). The reaction mixture was stirred at r.t. overnight, and then the solvent was evaporated and the residue was triturated with Et2O. The crude was purified by preparative HPLC (Eluent: CH3CN/H2O), to obtain (R)-3-((R)-2-(benzo[b]thiophen-3-yl)-2-(phenylamino)acetoxy)-1-(2-oxo-2-phenylethyl)-1-azoniabicyclo[2.2.2]octane chloride (210 mg, 60.3% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](Br)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Mg].[CH3:13][C:14]1([CH3:21])[CH2:18][C:17](=[O:19])[O:16][C:15]1=[O:20].[Cl-].[NH4+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:17](=[O:19])[CH2:18][C:14]([CH3:21])([CH3:13])[C:15]([OH:20])=[O:16])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(Br)cc1OC
Reactant: CC1(C)CC(=O)OC1=O
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)CC(C)(C)C(=O)O)cc1OC
Temperature: 25 °C

Procedure:
Under an atmosphere of dry nitrogen a grignard solution, prepared from 43.4 g 3,4-dimethoxybromobenzene and 6.1 g magnesium in 200 ml of tetrahydrofuran, is added dropwise to a solution of 20.5 g 3,3-dimethyl-dihydro-furan-2,5-dione in 200 ml of tetrahydrofuran cooled in an ice-bath. The reaction mixture is stirred for an additional hour at RT. 100 ml of a 20% ammonium chloride solution is added and the water layer is extracted twice with 75 ml of ethyl acetate. The combined organic layers are washed twice with 100 ml of half saturated brine and extracted with 3×100 ml 1 M sodium hydroxide solution. The aqueous layers are washed with 75 ml of ethyl acetate, acidified with concentrated hydrochloric acid and extracted 3 times with 100 ml of dichloromethane. The organic layers are dried over magnesium sulfate, filtered and concentrated in vacuo. The oily residue is crystallized from ethyl acetate/petroleum ether (60-80° C.). M. p. 114-116° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([OH:17])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:19][NH:20][O:21][CH3:22].CN1CCOCC1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([C:15](=[O:17])[N:20]([O:21][CH3:22])[CH3:19])[CH2:13][CH2:14]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CON(C)C(=O)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 20 g (82.2 mmol) trans-4-tert-Butoxycarbonylamino-cyclohexanecarboxylic acid in 1.2 l CH2Cl2 was treated with 12.83 g (131.5 mmol) N,O-dimethyl-hydroxylamine hydrochloride, 10.85 ml (98.6 mmol) N-methylmorpholine and at 0° C. with 18.91 g (98.64 mmol) EDCI and 12.62 g (82.2 mmol) HOBT. The reaction mixture was stirred 2 h at room temperature and extracted with aqueous 10% KHSO4/Et2O (3×). The organic phases were washed with aqueous saturated NaHCO3, 10% NaCl and dried over Na2SO4 to yield 24.25 g (quantitative) trans-[4-(Methoxy-methyl-carbamoyl)-cyclohexyl]-carbamic acid tert-butyl ester, mp: 130-140° C., slowly dec.; MS: 287 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]O.C(Br)(Br)(Br)[Br:15].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][Br:15]
Reactant: BrC(Br)(Br)Br
Reactant: COC(=O)CCCCCCCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)CCCCCCCCBr
Temperature: 4 °C
Reaction time: 10 h

Procedure:
A solution of methyl-9-hydroxy-nonanoate (1.1 g, 5.85 mmol, 1.0 equiv) in CH2Cl2 (30 mL, 0.2 M) at 0° C. was treated successively with CBr4 (2.5 g, 7.54 mmol, 1.3 equiv) and PPh3 (2.15 g, 8.19 mmol, 1.4 equiv) and the reaction mixture was stirred at 4° C. for 10 h. The reaction mixture was then concenctrated under reduced pressure and washed repeatedly with Et2O (8×10 mL washes). The Et2O washes were combined and concentrated under reduced pressure. Chromatography (SiO2, 5 cm×15 cm, hexanes) afforded the intermediate as a clear, colorless oil (1.02 g, 1.47 g theorectical, 69.5%): 1H NMR (CDCl3, 250 MHz) d 3.64 (s, 3H, C(O)OCH3), 3.38 (t, 2H, J=6.8 Hz, CH2Br), 2.29 (t, 2H, J=7.4 Hz CH2C(O)OCH3), 1.83 (p, 2H, CH2CH2Br), 1.63 (m, 2H, CH2CH2C(O)OCH3) 1.47-1.28 (m, 8H, alkyl protons).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]3[NH:38][N:37]=[N:36][N:35]=3)[CH2:24][CH:23]2[OH:39])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11].C(N(CC)CC)C>CS(C)=O.C(OCC)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]3[NH:38][N:37]=[N:36][N:35]=3)[CH2:24][C:23]2=[O:39])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11]
Reactant: O=C(NC1(C(=O)NC2CCN(c3ccccc3-c3nnn[nH]3)CC2O)CCCCC1)c1cc2ccccc2o1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C(NC1(C(=O)NC2CCN(c3ccccc3-c3nnn[nH]3)CC2=O)CCCCC1)c1cc2ccccc2o1
Temperature: 0 °C
Reaction time: 2 h
Yield: 43.1 %

Procedure:
To the solution of 4-[N-[1-[N-(benzofuran-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-1-[2-(1H-tetrazol-5-yl)phenyl]piperidin-3-ol (120 mg, 0.22 mmol) obtained in Step 2 in 5 ml of dimethyl sulfoxide (DMSO), was added 0.093 ml of triethylamine (0.66 mmol). The reaction mixture was cooled to 0° C. Pyridine-SO3 complex (103 mg, 0.66 mmol) was added to the reaction mixture, which was then stirred for about 2 hours at room temperature. The reaction mixture was diluted with 100 ml of ethyl acetate, washed with brine. The resulting organic layer was dried on sodium sulfate. The resulting residue was purified with column chromatography to give 50 mg of the titled compound.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[C:20]3[C:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[O:33][CH3:34])=[N:25][N:24](COCC[Si](C)(C)C)[C:21]3=[N:22][CH:23]=2)=[CH:14][C:10]=1[C:11]([OH:13])=[O:12])=O)(C)(C)C.Cl(O)(=O)(=O)=O.SCC(O)=O>C(O)(=O)C.O>[NH2:8][C:9]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[C:20]3[C:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[O:33][CH3:34])=[N:25][NH:24][C:21]3=[N:22][CH:23]=2)=[CH:14][C:10]=1[C:11]([OH:13])=[O:12]
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3ccc(NC(=O)OC(C)(C)C)c(C(=O)O)c3)cc12
Agent: O=C(O)CS
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)O
Solvent: O
Product: COc1ccccc1-c1n[nH]c2ncc(-c3ccc(N)c(C(=O)O)c3)cc12
Temperature: 80 °C
Reaction time: 24 h
Yield: 82.4 %

Procedure:
200 mg (0.34 mmol) of 2-tert-butoxycarbonylamino-5-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-benzoic acid were dissolved in 5 mL of glacial acetic acid. 500 μL of 70% perchloric acid was added and the mixture left at ambient temperature for 24 h. 3 mL of water and 300 μL of mercaptoacetic acid was added and the mixture heated to 80° C. for 20 h. The resulting mixture was cooled to room temperature and diluted with 50 mL of water. The resulting precipitate was filtered off and dried by suction to afford 101 mg (0.28 mmol, 82%) of 2-amino-5-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-benzoic acid as a red-brown solid. MS: m/z 361.1 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)=[O:9])=[CH:4][C:3]=1[C:21](=[O:29])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=1.Cl[C:31](=[O:38])[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].O>C(Cl)Cl>[CH2:36]([O:35][C:33](=[O:34])[CH2:32][C:31](=[O:38])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)=[O:9])=[CH:4][C:3]=1[C:21](=[O:29])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=1)[CH3:37]
Reactant: CCOC(=O)CC(=O)Cl
Reactant: Nc1ccc(C(=O)c2nc(-c3ccccc3)cs2)cc1C(=O)c1cccc(Cl)c1
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)CC(=O)Nc1ccc(C(=O)c2nc(-c3ccccc3)cs2)cc1C(=O)c1cccc(Cl)c1
Reaction time: 0.5 h

Procedure:
A mixture of intermediate (16) (0.048 mol) in DCM (200 ml) was cooled on an ice bath. 3-chloro-3-oxo-propanoic acid, ethyl ester (0.105 mol) was added dropwise. The mixture was stirred at a low temperature for 30 min, then stirred and refluxed for 1 hour and poured out into water. The organic layer was separated, washed with K2CO3 10%, dried (MgSO4), filtered and the solvent was evaporated till dryness. The product was used without further purification, yielding (quant.) N-[2-(3-chlorobenzoyl)-4-[(4-phenyl-2-thiazolyl)carbonyl]phenyl]-3-oxo-β-alanine ethyl ester (intermediate 17).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[N:6]=[C:5]([CH3:9])[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:3]1.[CH2:16]([Mg]Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(Cl)C1C=CC=CC=1.[Mg]>C(OCC)C>[CH2:16]([C:5]1([CH3:9])[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:3][N:2]([CH3:1])[C:7](=[O:8])[NH:6]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1nc(=O)n(C)nc1-c1ccccc1
Reactant: Cl[Mg]Cc1ccccc1
Agent: [Mg]
Solvent: ClCc1ccccc1
Solvent: CCOCC
Product: CN1N=C(c2ccccc2)C(C)(Cc2ccccc2)NC1=O

Procedure:
2,5-Dimethyl-6-phenyl-1,2,4-triazin-3(2H)-one (3.2 g) was added to a stirred solution of benzylmagnesium chloride prepared from benzyl chloride (9.99 g) and magnesium turnings (1.92 g) in diethyl ether (48 ml) at room temperature. The reaction mixture was treated in a similar manner to that of Example 30 to give 5-benzyl-2,5-dimethyl-6-phenyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (2.6 g), m.p. 174.2°~175.3° C. recrystallized from a mixture of chloroform and diisopropyl ether).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]#[C:18][CH2:19][CH2:20][CH2:21]OS(C)(=O)=O)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:27][NH:28][CH3:29]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]#[C:18][CH2:19][CH2:20][CH2:21][N:28]([CH3:29])[CH3:27])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CNC
Reactant: CS(=O)(=O)OCCCC#Cc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Product: CN(C)CCCC#Cc1ccc2c(-c3ccc(Br)cc3)nsc2c1

Procedure:
In analogy to example 16.1, Methanesulfonic acid 5-[3-(4-bromo-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl ester and Dimethylamine were converted to yield {5-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl}-dimethyl-amine as off-white semisolid, MS: 399 (MH+, 1Br).
Reaction SMILES: [B-](F)(F)(F)F.[CH3:6][CH2:7][O+](CC)CC.[CH3:13][C:14]1[CH:15]=[CH:16][C:17]([O:23][CH2:24][CH2:25][CH3:26])=[C:18]([CH:22]=1)[C:19]([NH2:21])=[O:20]>C(Cl)Cl>[CH3:13][C:14]1[CH:15]=[CH:16][C:17]([O:23][CH2:24][CH2:25][CH3:26])=[C:18]([CH:22]=1)[C:19](=[NH:21])[O:20][CH2:6][CH3:7]
Reactant: CCCOc1ccc(C)cc1C(N)=O
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CCCOc1ccc(C)cc1C(=N)OCC
Reaction time: 8 h

Procedure:
A solution of triethyloxonium borofluoride (34 g.) in anhydrous methylene chloride (90 ml.) was added during 5 minutes to a solution of crude 5-methyl-2-propoxybenzamide (34.5 g.) in anhydrous methylene chloride (300 ml.), and the solution was left to stand at room temperature overnight. The solution was concentrated to about 150 ml. and then diluted with anhydrous diethyl ether (500 ml.). The precipitated solid was filtered off and washed with anhydrous diethyl ether to give crude ethyl 5-methyl-2-propoxybenzimidate borofluoride (47 g.), m.p. 148°-150° C.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([N+:20]([O-:22])=[O:21])[C:6]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=3)=[CH:8][C:7]=2[CH:19]=1.N1C(=O)CC[C@H]1C(O)=O.Cl>>[OH:17][C:14]1[CH:13]=[CH:12][C:11]([C:9]2[O:10][C:6]3[C:5]([N+:20]([O-:22])=[O:21])=[CH:4][C:3]([OH:2])=[CH:19][C:7]=3[CH:8]=2)=[CH:16][CH:15]=1
Reactant: COc1ccc(-c2cc3cc(OC)cc([N+](=O)[O-])c3o2)cc1
Agent: Cl
Agent: O=C1CC[C@@H](C(=O)O)N1
Product: O=[N+]([O-])c1cc(O)cc2cc(-c3ccc(O)cc3)oc12
Temperature: 200 °C
Yield: 47.3 %

Procedure:
A mixture of 98 (0.56 g) and Pyr-HCl and heated at 200° C. for 1 h (while occasionally adding more Pyr-HCl). The reaction was allowed to cool and then partitioned between 2 N HCl aq and EtOAc. A small amount of MeOH was added to facilitate the dissolution process. The organic layer was washed with saturated NaHCO3 aq, brine, and dried over MgSO4. Filtration, concentration and trituration of the pdt with CH2Cl2 yielded 0.44 g of the desired pdt which contained some inorganic impurities. The material was then chromatographeid on silica gel (MeOH/CH2Cl2 1:19 to MeOH/CH2Cl2 1:9) to yield 0.24 g of 99: Mp=236–2372° C.; 1H NMR (DMSO-d6) δ 10.06 (br s, 1 H), 7.73 (d, 2 H, J=8.3 Hz), 7.46 (dd, 1 H, J=2.4 Hz, 0.7 Hz), 7.38 (dd, 1 H, J=2.3 Hz, 0.7 Hz), 7.28 (s, 1 H), 6.93 (d, 2 H, J=8.3 Hz); MS 270 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:30]([O:31][CH3:32])=[CH:29][C:6]2[CH2:7][C:8](=[O:28])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:27])[CH2:16][CH2:17][C:18]3[CH:23]=[C:22]([Cl:24])[C:21]([NH2:25])=[C:20]([Cl:26])[CH:19]=3)[CH:10]=[CH:11][C:5]=2[CH:4]=1.[H][H]>C(O)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[C:30]([O:31][CH3:32])=[CH:29][C:6]2[CH2:7][C:8](=[O:28])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:27])[CH2:16][CH2:17][C:18]3[CH:23]=[C:22]([Cl:24])[C:21]([NH2:25])=[C:20]([Cl:26])[CH:19]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)CCc1cc(Cl)c(N)c(Cl)c1)C=C2
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)CCc1cc(Cl)c(N)c(Cl)c1)CC2

Procedure:
This compound was prepared analogous to Example 4 from 1-[7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-on-3-yl]-3-[N-methyl-N-(2-{4-amino-3,5-dichloro-phenyl}-ethyl)-amino]-propane and hydrogen in the presence of palladium-on-charcoal in glacial acetic acid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7](Br)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[B:19](OC)([O:22]C)[O:20]C.Cl>C1COCC1>[C:1]([C:5]1[CH:6]=[C:7]([B:19]([OH:22])[OH:20])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(Br)cc1C(C)(C)C
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(B(O)O)cc1C(C)(C)C
Reaction time: 2 h

Procedure:
4 g (16.5 mmol) of 3-tert-butyl-4-methoxybromobenzene and 50 ml of THF are introduced into a three-necked flask under a stream of nitrogen. 7.9 ml (19.8 mmol) of n-butyllithium (2.5 M in hexane) are added dropwise at −78° C., the mixture is stirred for 15 minutes at this temperature, 5.6 ml (49.5 mmol) of trimethyl borate are added and the mixture is stirred for 2 hours. 20 ml of hydrochloric acid (1 N) are added at −50° C. and the mixture is allowed to return to room temperature. The reaction medium is extracted with ethyl ether and the organic phase is separated out after settling has taken place, dried over magnesium sulphate and evaporated. 3.79 g (100%) of the expected boronic acid are collected, which is used in its present state for the rest of the synthesis.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:19]2[S:20][C:21](Br)=[CH:22][CH:23]=2)[N:9]([C:11]2[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:18])[CH:10]=1)=[O:5])[CH3:2].[CH3:25][S:26]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)(=[O:28])=[O:27].C([O-])([O-])=O.[K+].[K+].O>COCCOC>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:19]2[S:20][C:21]([C:33]3[CH:32]=[CH:31][CH:30]=[C:29]([S:26]([CH3:25])(=[O:28])=[O:27])[CH:34]=3)=[CH:22][CH:23]=2)[N:9]([C:11]2[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:18])[CH:10]=1)=[O:5])[CH3:2]
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: CCOC(=O)c1cn(-c2c(Cl)cccc2Cl)c(-c2ccc(Br)s2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)c1cn(-c2c(Cl)cccc2Cl)c(-c2ccc(-c3cccc(S(C)(=O)=O)c3)s2)n1
Temperature: 80 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
A mixture of 2-(5-bromothiophen-2-yl)-1-(2,6-dichlorophenyl)-1H-imidazole-4-carboxylic acid ethyl ester (335 mg, 0.75 mmol), 3-methanesulfonyl-phenylboronic acid (180 mg, 0.90 mmol), K2CO3 (0.32 g, 2.3 mmol), Cl2Pd(dppf)DCM (30 mg, 5 mol %) and H2O (0.4 mL) in DME (4 mL) was sparged with Argon for 5 min and then heated at 80° C. as a sealed flask. After 2 h the reaction mixture was allowed to cool to ambient temperature, filtered (Celite™) and the filter agent rinsed with EtOAc. The combined filtrates were concentrated under reduced pressure and purified by chromatography (silica, EtOAc/Hex, 30:70 to 80:20) to give the title compound (313 mg, 80%) as a pale yellow solid, which was used in the next step without further purification. 1H-NMR (DCM-d2): δ 8.08 (m, 1H), 7.82 (m, 2H), 7.64 (s, 1H), 7.51-7.62 (m, 4H), 7.24 (d, 1H), 6.72 (d, 1H), 438 (q, 2H), 3.05 (s, 3H), 1.40 (t, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH3:11][C@@H:12]([CH2:15][CH3:16])[CH2:13]O.S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[CH3:11][CH:12]([CH2:15][CH3:16])[CH2:13][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: CC[C@H](C)CO
Reactant: O=C(O)c1ccc(O)cc1
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CCC(C)COC(=O)c1ccc(O)cc1
Yield: 88.1 %

Procedure:
0.29 mole (40.0 g) of 4-hydroxybenzoic acid and 0.35 mole (30.9 g) of (S)-(-)-2-methylbutanol were refluxed for 20 hours in 150 ml of toluene in the presence of 1 ml of conc. sulfuric acid. The reaction solution was concentrated, and then purified by column chromatography to obtain 53.2 g of 4-hydroxybenzoic acid 2-methylbutyl ester [[α]D23 =+4.95° (CHCl3)]. (yield: 88%)