Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:8])[CH2:4][CH:5]([CH3:7])[CH3:6].[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]Br>>[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:8][CH2:3][CH2:4][CH:5]([CH3:7])[CH3:6]
Reactant: BrCCCCCCBr
Reactant: CC(C)CCO
Agent: [H-]
Agent: [Na+]
Product: CC(C)CCOCCCCCCBr
Reaction time: 2 h

Procedure:
4.8 g (0.11 mol) of 55 % sodium hydride dispersion are added at 20°-40°C over the course of 1 hour, to 74 g (1.0 mol) of isopentyl alcohol. After stirring for 2 hours at 20°-25°C, 24.4 g (0.10 mol) of 1,6-dibromohexane are added dropwise over the course of 15 minutes. The mixture is stirred at 60°C for 16 hours, then filtered and the filtrate is taken up in ether. The ether solution is extracted with saturated sodium chloride slution, dried with sodium sulphate and evaporated at 40°C/18 mm Hg. After chromatography of the residue on silica gel with hexane/ethyl acetate (99:1) and subsequent distillation (B.P. 85°-87°/1 mm), 1-bromo-6-isopentyloxy-hexane is obtained as a slightly yellow clear liquid.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH2:8][CH2:9][C:10]([OH:12])=O)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC)=O.[CH2:28]([O:30][C:31]1[CH:40]=[CH:39][CH:38]=[CH:37][C:32]=1[O:33][CH2:34][CH2:35][NH2:36])[CH3:29]>O1CCCC1>[CH2:28]([O:30][C:31]1[CH:40]=[CH:39][CH:38]=[CH:37][C:32]=1[O:33][CH2:34][CH2:35][NH:36][C:10](=[O:12])[CH2:9][CH2:8][C:6](=[O:7])[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:14][CH:13]=1)[CH3:29]
Reactant: O=C(O)CCC(=O)c1ccc(F)cc1
Reactant: CCOc1ccccc1OCCN
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOc1ccccc1OCCNC(=O)CCC(=O)c1ccc(F)cc1
Reaction time: 4 h

Procedure:
To a stirred solution of 10.4 g of 3-(4-fluorobenzoyl)propionic acid and 6.0 g of triethylamine in 120 ml of tetrahydrofuran was added dropwise 6.0 g of ethyl chloroformate at a temperature below 0° C. After stirring was continued for half an hour, to the mixture was added a solution of 9.6 g of 2-(2-ethoxyphenoxy)ethylamine in 10 ml of tetrahydrofuran. Further stirring was continued at room temperature for 4 hours. The reaction mixture was filtered and the filtrate was concentrated to a residue under reduced pressure. The residue was recrystallized from benzene-hexane to give N-[2-(2-ethoxyphenoxy)ethyl]-3-(4-fluorobenzoyl)-propionamide melting at 98° - 100° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br.BrC[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=1[C:26]([C:28]1[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:30][CH:29]=1)=[O:27]>CC(C)=O.C(OCC)(=O)C>[CH:34]([C:31]1[CH:30]=[CH:29][C:28]([C:26]([C:19]2[CH:20]=[C:21]([O:24][CH3:25])[CH:22]=[CH:23][C:18]=2[NH:17][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[O:27])=[CH:33][CH:32]=1)([CH3:36])[CH3:35]
Reactant: BrCCc1ccccn1
Reactant: COc1ccc(N)c(C(=O)c2ccc(C(C)C)cc2)c1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COc1ccc(NCc2ccccn2)c(C(=O)c2ccc(C(C)C)cc2)c1
Temperature: 90 °C
Reaction time: 48 h

Procedure:
410 mg (2.97 mmol) potassium carbonate and 150 mg (0.59 mmol) 2-bromoethylpyridine hydrobromide are added to a solution of 160 mg (0.59 mmol) (2-amino-5-methoxy-phenyl)-(4-isopropyl-phenyl)-methanone in 3 ml acetone. The reaction mixture is stirred for 2 days at 90° C., diluted with ethyl acetate and extracted with brine. The organic layer is dried and evaporated. After chromatography (hexane/ethyl acetate) the product is obtained as yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH2:11][CH2:12][O:13][P:14]([CH2:19][N:20]1[CH:23](SC)[CH:22]([N:26]=[N+:27]=[N-:28])[C:21]1=[O:29])([O:16][CH2:17][CH3:18])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:30]Cl>C(Cl)Cl>[CH2:1]([O:8][C:9]([CH2:11][CH2:12][O:13][P:14]([CH2:19][N:20]1[CH:23]([Cl:30])[CH:22]([N:26]=[N+:27]=[N-:28])[C:21]1=[O:29])([O:16][CH2:17][CH3:18])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCl
Reactant: CCOP(=O)(CN1C(=O)C(N=[N+]=[N-])C1SC)OCCC(=O)OCc1ccccc1
Solvent: ClCCl
Product: CCOP(=O)(CN1C(=O)C(N=[N+]=[N-])C1Cl)OCCC(=O)OCc1ccccc1
Reaction time: 0.17 h

Procedure:
The product of Step E can also be prepared by dissolving 1-(benzyloxycarbonyldiethylphosphono)methyl-3-azido-4-(methylthio)-2-azetidinone (0.44 g.) in methylene chloride (10 ml.) and treating with chlorine (0.110 g.) in methylene chloride (2.0 ml.). The mixture is allowed to stand for 10 minutes at room temperature. The solvent is removed under reduced pressure to afford the 1-(benzyloxycarbonyldiethylphosphono)methyl-3-azido-4-chloro-2-azetidinone as described in Step E. ##STR32##
Reaction SMILES: [C:1]1([CH3:31])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH2:19][N:20]4C(=O)C5=CC=CC=C5C4=O)[CH:16]=3)[CH2:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.O.NN.O>CO>[C:1]1([CH3:31])[CH:2]=[CH:3][C:4]([S:7]([N:10]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH2:19][NH2:20])[CH:16]=3)[CH2:11]2)(=[O:9])=[O:8])=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)N2Cc3ccc(CN4C(=O)c5ccccc5C4=O)cc3C2)cc1
Agent: NN
Solvent: CO
Solvent: O
Product: Cc1ccc(S(=O)(=O)N2Cc3ccc(CN)cc3C2)cc1
Yield: 99.3 %

Procedure:
21.6 g of 2-(p-toluenesulfonyl)-5-phthalimidomethylisoindoline and 5 ml of hydrazine hydrate was dissolved in 300 ml of methanol and the solution was heated under reflux for 2 hours. After reaction mixture was allowed to cool, 50 ml of water was added to it. The mixture was concentrated to a half volume under reduced pressure. To the residue 500 ml of 10% aqueous sodium hydroxide and 1 liter of chloroform were added and the whole mixture was thoroughly shaken. The chloroform layer was separated and washed with 5% aqueous sodium hydroxide and then with water. After removing the solvent by evaporation, the residue was recrystallized from ether to give 15.0 g of 2-(p-toluenesulfonyl)-5-aminomethylisoindoline.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].BrCC.[Mg].O=C1[O:14][C:13](=O)[C:12]2([CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]2)[N:11]1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[Cl-].[NH4+]>O1CCCC1>[O:14]=[C:13]([C:12]1([NH:11][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]1)[CH2:1][CH3:2]
Reactant: CC[Mg]Br
Reactant: CCOC(=O)N1CCC2(CC1)C(=O)OC(=O)N2c1ccccc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCBr
Product: CCOC(=O)N1CCC(Nc2ccccc2)(C(=O)CC)CC1
Reaction time: 1 h

Procedure:
A Grignard-complex, ethyl magnesium bromide, is prepared in the conventional manner, starting from 10.57 parts of 1-bromoethane and 2.14 parts of magnesium in 27 parts of dry tetrahydrofuran. This complex is added dropwise to a warm suspension of 25.7 parts of ethyl 2,4-dioxo-1-phenyl-3-oxa-1,8-diazaspiro[4,5]decane-8-carboxylate in 213 parts of dry tetrahydrofuran: exothermic reaction. Upon completion, stirring is continued for 1 hour at room temperature. After cooling, the reaction mixture is decomposed by dropwise addition of an ammonium chloride solution. The layers are separated and the aqueous phase is extracted with 1,1'-oxybisethane. The combined organic phases are washed with water, dried, filtered and evaporated. The residue is purified by column-chromatography over silicagel using a mixture of trichloromethane and 3% of methanol as eluent. The pure fractions are collected and the eluent is evaporated, yielding ethyl 4-(1-oxopropyl)-4-(phenylamino)-1-piperidinecarboxylate as a residue.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[CH:20][C:19]=1[N+:27]([O-:29])=[O:28]>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:25]([NH:24][C:21]2[CH:22]=[CH:23][C:18]([F:17])=[C:19]([N+:27]([O-:29])=[O:28])[CH:20]=2)=[O:26])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: O=C=Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc(F)c([N+](=O)[O-])c2)cc1-c1c(Br)cnn1C
Yield: 69.2 %

Procedure:
3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.037 g, 0.13 mmol) was treated with 4-fluoro-3-nitrophenyl isocyanate (0.025 g, 0.14 mmol, 1.05 equiv.) in CH2Cl2 (1 mL), in a similar manner as described in Example 1.2 to afford Compound 16 (0.042 g, 0.09 mmol, 69%) as a yellow solid. LCMS m/z (%)=464 (M+H79Br, 100), 466 (M+H81Br, 96). 1H NMR (400 MHz, acetone-d6) δ: 8.55 (s, 1H), 8.44-8.50 (m, 1H), 8.29 (s, 1H), 7.77-7.83 (s, 1H), 7.70 (dd, J=2.7, 9.0 Hz, 1H), 7.49 (s, 1H), 7.37-7.46 (m, 2H), 7.16 (d, J=8.9 Hz, 1H), 3.83 (s, 3H), 3.69 (s, 3H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][CH:8]1[CH2:13][CH:12]([CH3:14])[CH2:11][NH:10][CH2:9]1.CN(C)C=O.[CH2:20](Cl)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([N:10]1[CH2:11][C@@H:12]([CH3:14])[CH2:13][C@H:8]([CH3:7])[CH2:9]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC1CNCC(C)C1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@H]1C[C@H](C)CN(Cc2ccccc2)C1
Reaction time: 15 h
Yield: 14.8 %

Procedure:
A suspension of potassium carbonate (83 g) in a mixture of benzyl chloride (37 g), 3,5-dimethylpiperidine (30 g of acommercial mixture of cis and trans isomers) and N,N-dimethylformamide (200 mL) is stirred for 15 h at a temperature close to 60° C. The mixture is filtered, concentrated under reduced pressure and diluted in ethyl acetate. The organic phase is washed with water, dried over magnesium sulphate, concentrated under reduced pressure and purified by chromatography over silica gel with a mixture diethyl oxide/ligroin/triethylamine 20/80/1 as eluent to give 8 g of trans-1-benzyl-3,5-dimethylpiperidine as a colourless oil used without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:19][S:20][C:21]2[NH:25][C:24]3[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=3[N:22]=2)=[N:4][CH:5]=[CH:6][C:7]=1[S:8][CH2:9][CH2:10][NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl[CH2:31][C:32]([O:34][CH3:35])=[O:33].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][C:2]1[C:3]([CH2:19][S:20][C:21]2[NH:22][C:23]3[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=3[N:25]=2)=[N:4][CH:5]=[CH:6][C:7]=1[S:8][CH2:9][CH2:10][N:11]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:31][C:32]([O:34][CH3:35])=[O:33]
Reactant: COC(=O)CCl
Reactant: Cc1c(SCCNCc2ccccc2)ccnc1CSc1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CN(CCSc1ccnc(CSc2nc3ccccc3[nH]2)c1C)Cc1ccccc1

Procedure:
2-((3-Methyl-4-(2-benzylaminoethylthio)pyridin-2-yl)-methylthio)-1H-benzimidazole (2 g) was dissolved in dimethylformamide and reacted with methyl chloroacetate (0.45 ml) in the presence of potassium carbonate (0.71 g) at 50°-60° C. After the completion of the reaction, the dimethylformamide was distilled away and the residue was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled away to give an oily product. The oily product was purified by column chromatography to give 2-((3-methyl-4-(2-(N-benzyl-N-methoxycarbonylmethylamino)ethylthio)-2-pyridyl)methylthio)-1H-benzimidazole.
Reaction SMILES: [CH2:1]([CH:3]([CH2:9][CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[Br:11][CH2:12][CH2:13][CH2:14][CH2:15]Br>>[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][C:3]([CH2:9][CH3:10])([CH2:1][CH3:2])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: BrCCCCBr
Reactant: CCOC(=O)C(CC)CC
Product: CCOC(=O)C(CC)(CC)CCCCBr

Procedure:
Using ethyl 2-ethylbutyrate and 1,4-dibromobutane, the title compound was produced in the same manner as in Reference Example 6.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][C:16](=[O:30])[C:17]3[CH:22]=[C:21]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[CH:20]=[C:19]([F:29])[CH:18]=3)[CH:12]=[CH:11][C:10]=2[CH3:31])[CH:5]=[CH:4][N:3]=1.[O:32]1[CH:36]=[CH:35][CH:34]=[C:33]1[CH2:37][OH:38].CC(C)([O-])C.[K+]>>[F:29][C:19]1[CH:18]=[C:17]([CH:22]=[C:21]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH:20]=1)[C:16]([NH:15][C:13]1[CH:12]=[CH:11][C:10]([CH3:31])=[C:9]([CH:14]=1)[NH:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([O:38][CH2:37][C:33]2[O:32][CH:36]=[CH:35][CH:34]=2)[N:7]=1)=[O:30]
Reactant: OCc1ccco1
Reactant: Cc1ccc(NC(=O)c2cc(F)cc(N3CCOCC3)c2)cc1Nc1ccnc(Cl)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: Cc1ccc(NC(=O)c2cc(F)cc(N3CCOCC3)c2)cc1Nc1ccnc(OCc2ccco2)n1
Temperature: 100 °C
Yield: 82.9 %

Procedure:
A mixture of 2-chloro-4-[5-(3-fluoro-5-morpholinobenzamido)-2-methylanilino]pyrimidine (0.18 g), approximately one equivalent of 2-furylmethanol (0.043 g) and potassium tert-butoxide (1M in tert-butanol, 0.88 ml) was stirred and heated to 100° C. for 2 hours. The mixture was partitioned between methylene chloride and water and the organic phase was washed with brine, dried over sodium sulphate and evaporated. The residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and methanol as eluent followed by increasingly polar mixtures of methylene chloride and methanol containing 1% aqueous ammonium hydroxide solution. There was thus obtained the title compound as a solid (0.17 g); NMR Spectrum: (DMSOd6) 2.17 (s, 3H), 3.2 (m, 4H), 3.73 (m, 4H), 5.01 (s, 2H), 6.29 (d, 1H), 6.42 (m, 2H), 6.97 (m, 1H), 7.1 (m, 1H), 7.24 (m, 2H), 7.49 (d, 1H), 7.63 (s, 1H), 7.87 (s, 1H), 8.03 (d, 1H), 9.03 (s, 1H), 10.14 (s, 1H); Mass Spectrum: M+H+ 504.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][C:13](=[O:16])[NH:14][CH:15]=2)=[CH:6][CH:5]=1>CN(C=O)C.CO.[Pd]>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[CH2:11][NH:12][C:13](=[O:16])[NH:14][CH2:15]2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(-c2cnc(=O)[nH]c2)cc1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)c1ccc(C2CNC(=O)NC2)cc1
Reaction time: 3 h
Yield: 54.5 %

Procedure:
To a solution of 4-(2-oxo-pyrimidin-5-yl)-benzoic acid methyl ester (761 mg, 3.3 mmol, reference example 19c) in DMF (20 mL) and methanol (5 mL) was added Pd on carbon (250 mg, 10% w/w). The resulting mixtured was stirred under an atmosphere of hydrogen gas for 3 h. This mixture is purged with nitrogen gas then filtered through celite. The filtrate is concentrated and the residue purified by flash chromatography (eluting with 5% methanol in dichloromethane) to give the title compound (421 mg) as a white solid. 1H NMR (CD3OD) ? 3.28 (m, 1H), 3.47 (d, J=7 Hz, 4H), 3.90 (s, 3H), 7.44 (d, J=8 Hz, 2H), 7.90 (d, J=8 Hz, 2H).
Reaction SMILES: CON(C)[C:4]([CH:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)=[O:5].[CH2:13]1COCC1.C[Mg]Br>O.CCOC(C)=O>[C:4]([CH:6]1[CH2:7][CH2:8][O:9][CH2:10][CH2:11]1)(=[O:5])[CH3:13]
Reactant: C1CCOC1
Reactant: CON(C)C(=O)C1CCOCC1
Agent: C[Mg]Br
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)C1CCOCC1
Reaction time: 6 h
Yield: 81 %

Procedure:
A flask was charged with N-methoxy-N-methyltetrahydro-2H-pyran-4-carboxamide 2 (11.7 g, 67.5 mmol) and THF (350 mL). The resulting mixture was immersed in a cooling bath at −60° C., and methylmagnesium bromide (3.0 M in ether, 33.8 mL, 101.4 mmol) was added via syringe over ˜8 min. The temperature of the bath was allowed to rise to 0° C. over 6 h. At that time, the reaction was diluted with water and EtOAc and stirred vigorously for 10 min. The phases were separated, and the aqueous layer was extracted with EtOAc. The organic portions were combined, washed with brine, dried over MgSO4, filtered, and concentrated. The crude residue was subjected to column chromatography (120 g silica, 80 mL/min, 0% to 100% EtOAc/hexanes) to give 4-acetyltetrahydro-4H-pyran 3 (7.05 g, 55.0 mmol, 81%). 1H NMR (400 MHz, CDCl3) for 3: δ 3.95 (ddd, J=11.6, 4.4, 2.8 Hz, 2 H), 3.38 (dt, Jd=2.8 Hz, Jt=11.6 Hz, 2 H), 2.50 (m, 1 H), 2.12 (s, 3 H), 1.75 (m, 2 H), 1.65 (m, 2 H). LCMS for 3 (conditions D): tR=0.83 min, m/e=129.4 (M+H, base).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH2:41]([O:48][C:49]1[CH:50]=[C:51]2[C:56](=[CH:57][CH:58]=1)[CH:55]=[C:54]([C:59]1[N:64]=[C:63]([NH:65][C:66]3[CH:71]=[CH:70][C:69]([NH2:72])=[CH:68][CH:67]=3)[N:62]3[N:73]=[CH:74][CH:75]=[C:61]3[CH:60]=1)[CH:53]=[CH:52]2)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>CN(C=O)C.C(N(CC)CC)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:14](=[O:16])[NH:72][C:69]2[CH:70]=[CH:71][C:66]([NH:65][C:63]3[N:62]4[N:73]=[CH:74][CH:75]=[C:61]4[CH:60]=[C:59]([C:54]4[CH:53]=[CH:52][C:51]5[C:56](=[CH:57][CH:58]=[C:49]([O:48][CH2:41][C:42]6[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=6)[CH:50]=5)[CH:55]=4)[N:64]=3)=[CH:67][CH:68]=2)=[CH:17][CH:18]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1ccc(Nc2nc(-c3ccc4cc(OCc5ccccc5)ccc4c3)cc3ccnn23)cc1
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCc1ccc(C(=O)Nc2ccc(Nc3nc(-c4ccc5cc(OCc6ccccc6)ccc5c4)cc4ccnn34)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.2 %

Procedure:
To a solution of 4-(tert-butoxycarbonylamino-methyl)-benzoic acid (251 mg) and N-hydroxy-benzotriazole (HOBt)(153 mg) in DMF (10 ml) are added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC)(575 mg) and triethylamine (0.416 ml). The mixture is stirred for 0.5 h at ambient temperature. To this solution is added N-[5-(6-benzyloxy-naphthalen-2-yl)-pyrazolo[1,5-c]pyrimidin-7-yl]-benzene-1,4-diamine (compound B2)(0.38 g). After completion of the reaction the mixture is evaporated at high vacuum and the residue is treated with methanol. The resulting solid is filtered and dried. A colorless solid (0.523 g) is obtained in 91% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][N:8]=[C:7](O)[C:6]=2[CH:11]=1.N1C=CC=CC=1.P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:7]1[C:6]2[CH:11]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:9][N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1noc2ccc(Cl)cc12
Solvent: c1ccncc1
Product: Clc1ccc2onc(Cl)c2c1
Temperature: 25 °C
Yield: 92 %

Procedure:
To a suspension of 5-chloro-3-hydroxy-1,2-benzisoxazole (100 g) in phosphorus oxychloride (80 ml) was added pyridine (48 ml) dropwise over 1 hours with stirring at room temperature, and the mixture was then refluxed for 5 hours. The reaction mixture was added to ice water (500 ml) and extracted with ethyl acetate and the combined extracts were dried over anhydrous magnesium sulphate. The solvent was evaporated under reduced pressure and the title compound (102 g, 92%) was obtained by recrystallizng the residue from petroleum ether as a colorless needle.
Reaction SMILES: [C:1]1([C:7]2[N:8]([CH2:12][C:13]3[CH:14]=[C:15]([C:19]4[CH:23]=[C:22]([CH2:24][CH:25]([CH3:27])[CH3:26])[S:21][C:20]=4[S:28]([NH:31]C(C)(C)C)(=[O:30])=[O:29])[CH:16]=[CH:17][CH:18]=3)[CH:9]=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B(Cl)(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+].Cl[C:47]([O:49][CH2:50][CH2:51][CH2:52][CH3:53])=[O:48]>C(Cl)Cl.O>[CH2:50]([O:49][C:47]([NH:31][S:28]([C:20]1[S:21][C:22]([CH2:24][CH:25]([CH3:27])[CH3:26])=[CH:23][C:19]=1[C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([CH2:12][N:8]2[CH:9]=[CH:10][N:11]=[C:7]2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:14]=1)(=[O:29])=[O:30])=[O:48])[CH2:51][CH2:52][CH3:53]
Reactant: CCCCOC(=O)Cl
Reactant: CC(C)Cc1cc(-c2cccc(Cn3ccnc3-c3ccccc3)c2)c(S(=O)(=O)NC(C)(C)C)s1
Agent: ClB(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCCCOC(=O)NS(=O)(=O)c1sc(CC(C)C)cc1-c1cccc(Cn2ccnc2-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To a solution of 3-[3-(2-phenylimidazol-1-ylmethyl)phenyl]-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide (31.2 mg, 0.0615 mmol; see step (a)) in CH2Cl2 (1 mL) was added BCl3 (0.2 mL, 1.0 M in hexane) and the reaction mixture was stirred for 1 h at ambient temperature. The reaction mixture was concentrated in vacuo. Water (5 mL) was added to the residue and this was then extracted with EtOAc. The combined organic phase was washed with water and brine, dried (over anhydrous MgSO4) and concentrated in vacuo. To the crude product dissolved in CH2Cl2 (5 mL) was added Na2CO3 (29.3 mg, 0.277 mmol), water (2 mL) and butyl chloroformate (15.6 μL, 0.123 mmol), and the reaction mixture was stirred for 11 h at ambient temperature. The reaction mixture was diluted with CH2Cl2 (30 mL) and washed with citric acid (10% aq), brine and water, dried (over anhydrous MgSO4), concentrated in vacuo, and the residue purified by flash chromatography using MeOH:CH2Cl2 (5:95) as eluent to give the title compound as a white solid in 87% yield, over two steps, (29.4 mg, 0.0533 mmol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[CH:16]=[C:17]([C:21]([OH:23])=O)[N:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.[OH:25][C:26]([CH3:30])([CH3:29])[CH2:27][NH2:28]>>[OH:25][C:26]([CH3:30])([CH3:29])[CH2:27][NH:28][C:21]([C:17]1[N:18]([CH3:20])[N:19]=[C:15](/[CH:14]=[CH:13]/[C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[N:9][O:10][C:11]=2[CH3:24])[CH:16]=1)=[O:23]
Reactant: CC(C)(O)CN
Reactant: Cc1onc(-c2ccc(F)cc2)c1/C=C/c1cc(C(=O)O)n(C)n1
Product: Cc1onc(-c2ccc(F)cc2)c1/C=C/c1cc(C(=O)NCC(C)(C)O)n(C)n1
Yield: 28 %

Procedure:
As described for example 122, 5-{(E)-2-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-vinyl}-2-methyl-2H-pyrazole-3-carboxylic acid was converted, using 2-hydroxy-2-methylpropylamine instead of isopropylamine, to the title compound (9.4 mg, 28%) which was obtained as a white solid. MS: m/e=399.2 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH:15]2[CH2:17][CH2:16]2)[C:12]=1[O:13][CH3:14])[C:6]([O:8]C)=[O:7])#[N:2].O.[OH-].[Li+]>O1CCCC1.O>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH:15]2[CH2:16][CH2:17]2)[C:12]=1[O:13][CH3:14])[C:6]([OH:8])=[O:7])#[N:2]
Reactant: COC(=O)c1cc(C#N)c(OC)c(C2CC2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1c(C#N)cc(C(=O)O)cc1C1CC1
Reaction time: 20 h
Yield: 85.4 %

Procedure:
Methyl 3-cyano-5-cyclopropyl-4-methoxybenzoate (491 mg) was dissolved in tetrahydrofuran (7.5 mL) and water (2.5 mL), and lithium hydroxide monohydrate (359 mg) was added to the solution, and then the mixture was stirred at mom temperature for 20 hours. The organic solvent was distilled off under reduced pressure and the aqueous layer was washed with n-hexane. To the aqueous layer, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate under acidic conditions. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (394 mg) as a pale brown crystal.
Reaction SMILES: CO[CH:3](OC)[CH2:4][NH:5][C:6](=[O:18])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1.C(O)(=O)C>Cl>[CH3:15][O:14][C:11]1[C:10]([O:16][CH3:17])=[CH:9][C:8]2[CH2:7][C:6](=[O:18])[NH:5][CH:4]=[CH:3][C:13]=2[CH:12]=1
Reactant: COc1ccc(CC(=O)NCC(OC)OC)cc1OC
Agent: Cl
Solvent: CC(=O)O
Product: COc1cc2c(cc1OC)CC(=O)NC=C2
Reaction time: 17 h

Procedure:
A solution of N-(2,2-dimethoxyethyl)-3,4-dimethoxyphenylacetamide (600.6 g) in concentrated hydrochloric acid (3 liters) is mixed with acetic acid (3 liters). After standing for 17 hours at ambient temperature the mixture is poured onto ice. The precipitated crystals are suction filtered, washed with water until neutral and dried.