Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([O:16][CH3:17])[CH:8]=2)=[O:5])[CH2:3][CH2:2]1.[N+:18]([O-])([OH:20])=[O:19]>C(OC(=O)C)(=O)C.C(O)(=O)C>[CH:1]1([C:4]([NH:6][C:7]2[C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([O:16][CH3:17])[CH:8]=2)=[O:5])[CH2:3][CH2:2]1
Reactant: COc1cc(NC(=O)C2CC2)ccc1C(=O)O
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: COc1cc(NC(=O)C2CC2)c([N+](=O)[O-])cc1C(=O)O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A 780 mg portion of 4-cyclopropylcarbonylamino-2-methoxybenzoic acid was dissolved in 10 ml of acetic anhydride and 0.5 ml of acetic acid, and 790 μl of concentrated nitric acid was slowly added to the above solution under ice-cooling, followed by 2 hours of stirring. The reaction solution was poured into ice water, and the thus formed precipitate was collected by filtration and dried under a reduced pressure to give 713 mg of 4-cyclopropylcarbonylamino-2-methoxy-5-nitrobenzoic acid.
Reaction SMILES: [Si:1]([O:8][C:9]1[C:10]([F:16])=[C:11](O)[CH:12]=[CH:13][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([Li])(CC)C.[C:22](=[O:24])=[O:23].C(OCC)C.O>C1COCC1>[Si:1]([O:8][C:9]1[C:10]([F:16])=[C:11]([CH:12]=[CH:13][CH:14]=1)[C:22]([OH:24])=[O:23])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=C=O
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(O)c1F
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C(=O)O)c1F
Temperature: -70 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
A solution of 3-tert-butyldimethylsilyloxy-2-fluorophenol (10.59 g, 46.8 mmol) in THF (150 ml) cooled to -70° C. was added dropwise over 5 min. sec-butyllithium (42 ml, 1.12M in cyclohexane). The reaction mixture was stirred ad -70° C. for 1 h and then poured into a slurry of dry-ice/diethyl ether. Water (200 ml) was added cautiously and the organic layer separated and discarded. The aqueous layer was acidified to pH 2 with concentrated HCl and extracted with ethyl acetate (3×100 ml). The combined organic extracts were dried (MgSO4) and evaporated to afford title compound (7.90 g, 70%) as a white solid.
Reaction SMILES: [PH:1](=[O:4])([OH:3])[OH:2].[CH:5]([C:8]([CH:36]([CH3:38])[CH3:37])([F:35])/[CH:9]=[CH:10]/[C:11]1[N:15]=[CH:14][N:13]([C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:12]=1)([CH3:7])[CH3:6]>C(O)(C)C.[Pd]>[PH:1](=[O:2])([OH:4])[OH:3].[CH:36]([C:8]([CH:5]([CH3:7])[CH3:6])([F:35])[CH2:9][CH2:10][C:11]1[N:15]=[CH:14][N:13]([C:16]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:12]=1)([CH3:37])[CH3:38]
Reactant: CC(C)C(F)(/C=C/c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1)C(C)C
Agent: [Pd]
Agent: O=[PH](O)O
Solvent: CC(C)O
Product: CC(C)C(F)(CCc1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1)C(C)C
Yield: 38.6 %

Procedure:
Diisopropyl E-1-fluoro-3(1-trityl-1,2,4-triazol-3-yl)prop-2-ene phosphonate (0.62 g, prepared as described in Example 19), was hydrogenated in dry isopropanol (10 ml) over 10% palladium on carbon (0.20 g) over a period of five days. The solution was filtered through Hyflo Super-Cel and evaporated under reduced pressure. The residue was chromatographed on silica, using ethyl acetate then ethyl acetate-ethanol (9:1) as eluant, to give diisopropyl 1-fluoro-3(1-trityl-1,2,4-triazol-3-yl)propane phosphonate (0.24 g) as a colourless gum. NMR (CDCl3): δ 1.3(12H,m), 2.3(2H,m), 3.0(2H,m), 4.7(2H,m and 1H,m), 7.05-7.4(15H,m), 7.85(1H,s). The structure was confirmed by 13C and 31P NMR. M/S: MH+ 536. Other fractions gave detritylated material (0.18 g), also as a clear gum.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[C:9]1([CH2:15][CH2:16]CO)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1(C)C=CC=CC=1>[C:1]([O:7][CH2:8][CH2:16][CH2:15][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4]
Reactant: OCCCc1ccccc1
Reactant: COC(=O)CC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)OCCCc1ccccc1
Temperature: 110 °C
Yield: 97 %

Procedure:
A mixture of 1 equivalent of methyl acetoacetate, 1 equivalent of 3-phenylpropyl alcohol and 100 mg of sulfated tin oxide catalyst in 20 ml of toluene was heated to 110° C. in a two necked round bottom flask provided with a distillation condenser to remove methanol. The reaction was monitored by thin layer chromatography (TLC). After completion of the reaction (about 6 hours), the catalyst was filtered and the filtrate was concentrated and chromatographed on a silica gel column (95% petroleum ether and 5% ethyl acetate) to afford 3-phenylpropyl acetoacetate as a viscous colorless liquid in 97% yield.
Reaction SMILES: [C:1]([CH2:9][C:10]#[N:11])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+:12].[OH-]>>[NH2:12]/[C:1](/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[CH:9]\[C:10]#[N:11]
Reactant: [NH4+]
Reactant: N#CCC(=O)c1ccccc1
Agent: [OH-]
Product: N#C/C=C(\N)c1ccccc1
Reaction time: 20 h
Yield: 18.8 %

Procedure:
A mixture of benzoylacetonitrile (510 mg, 3.51 mmol) and conc. NH4OH (4 mL, 56.0 mmol) in a sealed tube was stirred at 80 C for 20 h. After cooling, solids precipitated out, which were collected by filtration, dried on vacuum to give (Z)-3-amino-3-phenylacrylonitrile (95 mg).
Reaction SMILES: [C:1]1(=[O:26])[N:5]([CH2:6][CH:7](O)[CH2:8][N:9]2[C:13](=[O:14])[C:12]3=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]3[C:10]2=[O:19])[C:4](=[O:21])[C:3]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:2]12.CC(C)=[O:29].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[C:1]1(=[O:26])[N:5]([CH2:6][CH2:7][C:8]([N:9]2[C:13](=[O:14])[C:12]3=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]3[C:10]2=[O:19])=[O:29])[C:4](=[O:21])[C:3]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:2]12
Reactant: O=C1c2ccccc2C(=O)N1CC(O)CN1C(=O)c2ccccc2C1=O
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: O=C1c2ccccc2C(=O)N1CCC(=O)N1C(=O)c2ccccc2C1=O

Procedure:
To a solution of 1,3-diphthalimido-2-hydroxypropane (1.00 g., 2,86 mmol) in 80 mL of acetone was added Jones reagent (chromium trioxide and sulfuric acid) until an orange color persisted. The excess oxidant was removed by the addition of 2-isopropanol until a green color was obtained and the solvents were evaporated under reduced pressure. The residue was partitioned between methylene chloride and water and the layers were separated. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure to give 1,3-diphthalimido-3-oxopropane.
Reaction SMILES: CO[C:3]([CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]3([CH3:19])[O:18]CCO3)[CH:12]=2)[N:7]([CH2:20][CH3:21])[C:6]1=[O:22])=[O:4].[NH2:23][C:24]1[CH:25]=[C:26]([CH:37]=[CH:38][CH:39]=1)[C:27]([NH:29][C:30]1[CH:35]=[CH:34][C:33]([I:36])=[CH:32][CH:31]=1)=[O:28]>>[I:36][C:33]1[CH:34]=[CH:35][C:30]([NH:29][C:27]([C:26]2[CH:25]=[C:24]([NH:23][C:3]([CH:5]3[C:13]4[C:8](=[CH:9][CH:10]=[C:11]([C:14](=[O:18])[CH3:19])[CH:12]=4)[N:7]([CH2:20][CH3:21])[C:6]3=[O:22])=[O:4])[CH:39]=[CH:38][CH:37]=2)=[O:28])=[CH:31][CH:32]=1
Reactant: CCN1C(=O)C(C(=O)OC)c2cc(C3(C)OCCO3)ccc21
Reactant: Nc1cccc(C(=O)Nc2ccc(I)cc2)c1
Product: CCN1C(=O)C(C(=O)Nc2cccc(C(=O)Nc3ccc(I)cc3)c2)c2cc(C(C)=O)ccc21

Procedure:
Prepared as in Example 1 from 1-ethyl-5-(2-methyl-[1,3]dioxolan-2-yl)-2-oxo-2,3-dihydro-1H-indole-3-carboxylic acid methyl ester and 3-amino-N-(4-iodo-phenyl)-benzamide. mp 205-210° C. Calculated for C26H22IN3O4 : C 55.04; H 3.91; N 7.41; found C 55.13; H 4.04; N 7.12.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[C:3]=1[C:4]([NH:6][C:7]1[S:18][C:10]2[C:11]([CH3:17])([CH3:16])[O:12][C:13]([CH3:15])([CH3:14])[C:9]=2[C:8]=1[C:19]([OH:21])=O)=[O:5].[CH2:30]([NH2:33])[CH2:31][CH3:32]>>[F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:28])([F:29])[F:27])[C:3]=1[C:4]([NH:6][C:7]1[S:18][C:10]2[C:11]([CH3:17])([CH3:16])[O:12][C:13]([CH3:14])([CH3:15])[C:9]=2[C:8]=1[C:19]([NH:33][CH2:30][CH2:31][CH3:32])=[O:21])=[O:5]
Reactant: CC1(C)OC(C)(C)c2c1sc(NC(=O)c1c(F)cccc1C(F)(F)F)c2C(=O)O
Reactant: CCCN
Product: CCCNC(=O)c1c(NC(=O)c2c(F)cccc2C(F)(F)F)sc2c1C(C)(C)OC2(C)C

Procedure:
The title compound was prepared from the product of Example 45A and propylamine using the procedure described in Example 2B. 1H NMR (DMSO-d6, 300 MHz) δ 0.85 (t, J=7.3 Hz, 3H), 1.42-1.49 (m, 2H), 1.44 (s, 6H), 1.48 (s, 6H), 3.08-3.14 (m, 2H), 7.67-7.8 (m, 3H), 8.05 (t, J=5.4 Hz, 1H), 11.54 (br s, 1H). MS (ESI+) m/z 473 (M+H)+. Anal. calcd. for C22H24F4N2O3S: C, 55.92; H, 5.12; N, 5.93. Found: C, 55.39; H, 4.65; N, 5.69.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]2)=[C:4]([O:14][CH3:15])[CH:3]=1.[Cl:16][C:17]1[CH:29]=[CH:28][C:20]([CH2:21][N:22]2[CH:26]=[CH:25][C:24]([NH2:27])=[N:23]2)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:29]=[CH:28][C:20]([CH2:21][N:22]2[CH:26]=[CH:25][C:24]([NH:27][C:2]3[CH:7]=[CH:6][C:5]([N:8]4[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]4)=[C:4]([O:14][CH3:15])[CH:3]=3)=[N:23]2)=[CH:19][CH:18]=1
Reactant: Nc1ccn(Cc2ccc(Cl)cc2)n1
Reactant: COc1cc(Br)ccc1-n1cnc(C)c1
Product: COc1cc(Nc2ccn(Cc3ccc(Cl)cc3)n2)ccc1-n1cnc(C)c1

Procedure:
Prepared in analogy to example 43 starting with 1-(4-bromo-2-methoxy-phenyl)-4-methyl-1H-imidazole and 1-(4-chloro-benzyl)-1H-pyrazol-3-yl amine. The title compound was obtained as a yellow liquid (Yield=41%). MS ISP (m/e): 394.1 (100) [(M+H)+].
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:36]=[CH:37][CH:38]=1)[CH2:8][N:9]1[CH2:13][CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]2([CH2:24][CH2:23][N:22](C(OCC3C=CC=CC=3)=O)[CH2:21][CH2:20]2)[C:10]1=[O:35])=[O:4]>Cl.O1CCOCC1>[O:35]=[C:10]1[C:11]2([CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:13][N:9]1[CH2:8][C:7]1[CH:6]=[C:5]([CH:38]=[CH:37][CH:36]=1)[C:3]([O:2][CH3:1])=[O:4]
Reactant: COC(=O)c1cccc(CN2CC(c3ccccc3)C3(CCN(C(=O)OCc4ccccc4)CC3)C2=O)c1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1cccc(CN2CC(c3ccccc3)C3(CCNCC3)C2=O)c1
Yield: 105.7 %

Procedure:
A solution of benzyl 2-(3-(methoxycarbonyl)benzyl)-1-oxo-4-phenyl-2,8-diazaspiro[4.5]decane-8-carboxylate (1.335 g, 2.79 mmol, 1 equiv) in 4M hydrogen chloride solution in dioxane was stirred at ambient temperature for 3 h. The mixture was concentrated in vacuo to afford the hydrogen chloride salt of the title compound as a cream powder (1.116 g, 97%); 1H NMR (400 MHz, DMSO-d6): δ 1.11-1.18 (m, 1H); 1.71-1.83 (m, 2H); 1.93-1.97 (m, 1H); 3.38-3.42 (m, 1H); 3.45-3.49 (m, 3H); 3.55-3.59 (m, 2H); 3.65-3.72 (m, 1H); 3.69-3.71 (m, 1H); 3.86 (s, 3H); 4.57 (d, 2H, J=4 Hz); 7.19-7.21 (m, 2H); 7.25-7.33 (m, 3H); 7.53-7.60 (m, 2H); 7.89-7.92 (m, 2H); 8.61 (bs, 1H); 9.07 (bs, 1H); MS for C23H26N2O3 m/z 379.2 (M+H)+.
Reaction SMILES: CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[C:20]1(=[N:30]O)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22][CH2:21]1.[OH-:32].[Na+]>>[NH:30]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:29]=2[CH2:28][CH2:27][CH2:26][C:25]1=[O:32]
Reactant: [OH-]
Reactant: ON=C1CCCc2ccccc21
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Product: O=C1CCCc2ccccc2N1
Temperature: 90 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
To 10 L of methanesulfonic acid in a 22 L 3-neck flask equipped with an overhead stirrer, a temperature probe, nitrogen inlet and reflux condenser was added 2.6 Kg (18.61 mol) of phosphorus pentoxide. An additional 1.6 L of methansulfonic acid was used to wash all the phosphorus pentoxide into the vessel. The mixture was heated at 90° C. for 2.5 hours then cooled to 50° C. using an ice bath and treated with 2.00 Kg (12.41 mol) of 1-tetralone oxime in several portions over 15 minutes. The mixture was heated at 63° C. for 10 minutes then slowly heated to 80° C. and kept at 80° C. for 3 hours. The reaction mixture was pumped into 70 L of ice then treated slowly with 11.25 L of 50% aqueous sodium hydroxide over 90 minutes at such a rate so as to maintain the temperature below 28° C. The mixture was filtered and 4 L of the filtrate was used to rinse the vessel. The wet cake (pink) was washed with 8 L of water then suction dried for 45 minutes then transferred to two trays and dried under vacuum at 40° C. for 2 days to give 1.9 Kg (11.79 mol, 95%) of product, 1H NMR (250 MHz, CDCl3): 2.24 (m, 2H), 2.38 (t, 6 Hz, 2H), 2.82 (t, 6 Hz, 2H), 7.03 (d, 8 Hz, 1H), 7.13 (m, 1H), 7.24 (m, 2H), 8.63 (br s, 1H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:8]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:7][CH2:6]2.[CH3:25][S:26](Cl)(=[O:28])=[O:27].C1COCC1>O>[CH3:25][S:26]([O:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:8]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:7][CH2:6]2)(=[O:28])=[O:27]
Reactant: CCOC(=O)C1c2ccc(CO)cc2CCN1C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C1c2ccc(COS(C)(=O)=O)cc2CCN1C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 104.2 %

Procedure:
To a mixture of 1-ethyl 2-tert-butyl 6-(hydroxymethyl)-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate (390 mg, 1.16 mmol), methanesulfonyl chloride (0.135 mL, 1.74 mmol) and THF (10 mL) was added TEA (0.243 mL, 1.74 mmol) at 0° C., and the mixture was stirred for 1 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give 1-ethyl 2-tert-butyl 6-(((methylsulfonyl)oxy)methyl)-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate (500 mg, 1.209 mmol, 104%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:15]=3)[CH:9]=2)[N:4](C(OC(C)(C)C)=O)[N:3]=1.[N:30]([CH2:33][CH2:34][CH3:35])=[C:31]=[O:32].[N-]=C=O.O>N1C=CC=CC=1>[CH2:16]([N:14]1[CH:15]=[C:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[NH:4][N:3]=[C:2]3[NH:1][C:31]([NH:30][CH2:33][CH2:34][CH3:35])=[O:32])[N:12]=[N:13]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)n1nc(N)c2cc(-c3cn(Cc4ccccc4)nn3)ccc21
Reactant: CCCN=C=O
Agent: [N-]=C=O
Solvent: c1ccncc1
Solvent: O
Product: CCCNC(=O)Nc1n[nH]c2ccc(-c3cn(Cc4ccccc4)nn3)cc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of Example 64A (75 mg, 0.19 mmol) in pyridine (2 mL) was added 1-isocyanatopropane (16 mg, 0.19 mmol) and the reaction mixture was stirred at ambient temperature for about 3 hours. Additional isocyanate (0.1 mL) was added and the mixture was heated at about 80° C. for about 16 hours. The reaction mixture was cooled to ambient temperature and water (5 mL) was added. The resulting precipitate was collected by filtration then treated with hydrochloric acid (4 N solution in dioxane, 3 mL) and stirred at room temperature for about 4.5 hours. Diethyl ether (5 mL) was added and the precipitate collected by filtration. The crude material was purified by reverse-phase HPLC using acetonitrile/water (0.05 M ammonium acetate) gradient elution method to afford the title compound as the acetate salt. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.34 (s, 1H), 8.50 (s, 1H), 8.42 (s, 1H), 7.80 (d, J=8.7 Hz, 1H), 7.38 (d, J=8.7 Hz, 1H), 7.31-7.48 (m, 5H), 5.65 (s, 2H), 3.18 (dd, J=6.6, 12.7 Hz, 2H), 1.51 (dd, J=7.1, 14.3 Hz, 2H), 0.91 (t, J=7.3 Hz, 3H). MS (ESI+) m/z 376 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:20])([S:16]([OH:19])(=[O:18])=[O:17])[C:3]([F:15])([F:14])[C:4]([F:13])([F:12])[C:5]([F:11])([F:10])[S:6](O)(=[O:8])=[O:7].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[F:11][C:5]1([F:10])[S:6](=[O:7])(=[O:8])[O:17][S:16](=[O:19])(=[O:18])[C:2]([F:20])([F:1])[C:3]([F:15])([F:14])[C:4]1([F:12])[F:13]
Reactant: O=S(=O)(O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)S(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: O=S1(=O)OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C1(F)F

Procedure:
Perfluorobutane-1,4-bis-sulphonic acid (11.0 g, ˜30 mmol) was mixed with P2O5 (40 g, ˜10 eq) and sand. The mixture was heated to 140–180° C. and distilled under reduced pressure with dry-ice cooling collector to afford crude product (5.12 g). Redistilation gives pure perfluorobutane-1,4-bis-sulphonic acid anhydride.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:28]=[CH:27][C:7]([CH2:8][N:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10]2)=[CH:6][CH:5]=1.Cl[CH2:30][C:31]1[N:32]=[C:33]([C:36]2[S:37][CH:38]=[CH:39][CH:40]=2)[S:34][CH:35]=1.O>CN(C)C=O>[C:14]1([C:12]2[C:11]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10][N:9]([CH2:8][C:7]3[CH:27]=[CH:28][C:4]([O:3][CH2:30][C:31]4[N:32]=[C:33]([C:36]5[S:37][CH:38]=[CH:39][CH:40]=5)[S:34][CH:35]=4)=[CH:5][CH:6]=3)[CH:13]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: ClCc1csc(-c2cccs2)n1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)cc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3csc(-c4cccs4)n3)cc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 74.4 %

Procedure:
Sodium hydride (60%, oily, 60.0 mg) was added to a solution of ethyl 3-[1-(4-hydroxybenzyl)-4-phenyl-3-pyrrolyl]propionate (524 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 15 minutes. 4-Chloromethyl-2-(2-thienyl)thiazole (324 mg) was added to the mixture, which was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[4-phenyl-1-[4-[2-(2-thienyl)-4-thiazolylmethoxy]benzyl]-3-pyrrolyl]propionate (590 mg, yield: 74%) was obtained as an oily substance from the fraction eluted with ethyl acetate-hexane (1:3, volume ratio).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([C:14]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])[CH2:16][CH2:15]2)[S:12][CH:13]=1.[Li+].CCC[CH2-].[C:30](Cl)(=[O:32])[CH3:31].O>C1COCC1.CCCCC>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([C:14]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])[CH2:15][CH2:16]2)[S:12][C:13]=1[C:30](=[O:32])[CH3:31]
Reactant: COc1ccccc1C1(c2nc(-c3ccc(Cl)cc3Cl)cs2)CC1
Reactant: CC(=O)Cl
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: CCCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1ccccc1C1(c2nc(-c3ccc(Cl)cc3Cl)c(C(C)=O)s2)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
4-(2,4-Dichloro-phenyl)-2-[1-(2-methoxy-phenyl)-cyclopropyl]-thiazole (30 mg, 0.079 mmol) was dissolved in 1 mL of dry THF and the solution was cooled to −78° C. N-butyllithium (0.044 mL, 0.088 mmol) was added dropwise as a commercial 2M solution in pentane and the reaction stirred for 30 min at −78° C. Acetylchloride (0.056 mL, 0.79 mmol) was added as a neat liquid and the reaction warmed to room temperature with stirring over 1h. Water (1 volume equivalent relative to THF) was added and the THF removed in vacuo. The crude material was then dissolved in 1:1 methanol/DMSO (2 volume equivalents relative to THF) and the desired product purified by reversed phase HPLC/MS using an acetonitrile/water gradient and C18 stationary phase. Yield: 4.4 mg (14%). [MH]+ 418.2, 420.2.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12].[Cl:13]N1C(=O)CCC1=O.O>CN(C)C=O>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]([Cl:13])=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12]
Reactant: Nc1cccc2c1CCCC2=O
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(Cl)c2c1CCCC2=O
Reaction time: 60 h

Procedure:
A solution of 5-amino-1-tetralone (Itoh, K. Chem. Pharm. Bull. (1984), 32, 130-151) (0.50 g, 3.1 mmol) in dimethylformamide (15 mL) was treated with N-chlorosuccinimide (0.49 g, 3.7 mmol), stirred for 60 hours, treated with water and extracted with ether (4×30 mL). The combined ether extracts were washed with brine, dried (Na2SO4) and concentrated. Purification of the residue on silica gel with ethyl acetate:hexanes 1:1 provided the desired product.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:20]([NH2:23])([CH3:22])[CH3:21].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][C:17](=[O:19])[NH:23][CH:20]([CH3:22])[CH3:21])=[CH:14][CH:15]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCc1ccc(CC(=O)O)cc1
Reactant: CC(C)N
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)NC(=O)Cc1ccc(CNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.7 %

Procedure:
Combine [4-(tert-butoxycarbonylaminomethyl)-phenyl]-acetic acid (400 mg, 1.5 mmol), isopropylamine (0.14 mL, 1.65 mmol), EDC (345 mg, 1.8 mmol), HOBt (243 mg, 1.8 mmol), triethylamine (0.63 mL, 4.5 mmol) and DMAP (18.3 mg, 0.15 mmol) in anhydrous DCM (15 mL). Stir at room temperature for 1 day under nitrogen. Concentrate in vacuo and purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (1:1) to obtain the desired intermediate as a white solid (426 mg, 92%). MS (ES+) m/z: 324 (M+NH4+)+.
Reaction SMILES: [Cl:1][CH:2]([Cl:15])[CH:3]([C:5]1[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=[CH:7][C:6]=1[OH:14])[OH:4].[Cl:16][C:17]([Cl:22])([Cl:21])[CH:18](O)O.S(=O)(=O)(O)O>>[Cl:1][CH:2]([Cl:15])[CH:3]1[C:5]2[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=[CH:7][C:6]=2[O:14][CH:18]([C:17]([Cl:22])([Cl:21])[Cl:16])[O:4]1
Reactant: O=C(O)c1ccc(O)c(C(O)C(Cl)Cl)c1
Reactant: OC(O)C(Cl)(Cl)Cl
Agent: O=S(=O)(O)O
Product: O=C(O)c1ccc2c(c1)C(C(Cl)Cl)OC(C(Cl)(Cl)Cl)O2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 2,2-dichloro-1-(2-hydroxy-5-carboxyphenyl)ethanol (1.25 g.), chloral hydrate (1.0 g.) and concentrated sulphuric acid (12.5 ml.) was stirred at room temperature for 3 days. The reaction mixture was poured onto ice, and the product was filtered off, washed with water, dried and crystallised from aqueous acetic acid to give 4-dichloromethyl-2-trichloromethylbenzo[1,3]dioxin-6-carboxylic acid, m.p. 209° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:24]=[C:13]3[C:14]4[C:19]([CH2:20][CH2:21][N:12]3[C:11](=[O:25])[N:10]=2)=[CH:18][C:17]([O:22][CH3:23])=[CH:16][CH:15]=4)[CH:5]=[CH:6][CH:7]=1.[CH:26]1([C:31](Cl)=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH3:23][O:22][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[C:13]1=[CH:24][C:9]([NH:8][C:4]3[CH:3]=[C:2]([NH:1][C:31]([CH:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)=[O:32])[CH:7]=[CH:6][CH:5]=3)=[N:10][C:11](=[O:25])[N:12]1[CH2:21][CH2:20]2
Reactant: COc1ccc2c(c1)CCn1c-2cc(Nc2cccc(N)c2)nc1=O
Reactant: O=C(Cl)C1CCCC1
Product: COc1ccc2c(c1)CCn1c-2cc(Nc2cccc(NC(=O)C3CCCC3)c2)nc1=O

Procedure:
The title compound was prepared from 2-(3-amino-phenylamino)-9-methoxy-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one (6) and cyclopentanecarbonyl chloride according the method described in Example 28 c. 1H-NMR (400 MHz, d6-DMSO) δ 9.92 (s, 1H), 9.66 (br, 1H), 7.91 (s, 1H), 7.69 (d, 1H), 7.57 (br, 1H), 7.28-7.20 (2H), 7.05-6.97 (2H), 6.40 (s, 1H), 3.98 (t, 2H), 3.84 (s, 3H), 2.97 (t, 2H), 2.80 (m, 1H) and 1.92-1.50 (8H); MS (ESI) (M+H)+ 431.