Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]([CH3:22])([N:7]1[C:11](=[O:12])[C:10]2[CH:13]=[CH:14][C:15]3[CH:19]=[CH:18][N:17]([CH3:20])[C:16]=3[C:9]=2[C:8]1=[O:21])[C:5]#[N:6])([CH3:3])[CH3:2].S(=O)(=O)(O)[OH:24]>C(Cl)Cl>[CH:1]([C:4]([CH3:22])([N:7]1[C:11](=[O:12])[C:10]2[CH:13]=[CH:14][C:15]3[CH:19]=[CH:18][N:17]([CH3:20])[C:16]=3[C:9]=2[C:8]1=[O:21])[C:5]([NH2:6])=[O:24])([CH3:3])[CH3:2]
Reactant: O=S(=O)(O)O
Reactant: CC(C)C(C)(C#N)N1C(=O)c2ccc3ccn(C)c3c2C1=O
Solvent: ClCCl
Product: CC(C)C(C)(C(N)=O)N1C(=O)c2ccc3ccn(C)c3c2C1=O
Reaction time: 8 h
Yield: 23.2 %

Procedure:
A solution of 6,8-dihydro-α-isopropyl-α,1-dimethyl-6,8-dioxobenzo[2,1-b:3,4-c']dipyrrole-7(1H)acetonitrile (5.30 g, 18.0 mmol) in methylene chloride is added dropwise to concentrated sulfuric acid at 5°-10° C. with rapid stirring. The ice bath is removed and the reaction mixture is stirred overnight at ambient temperatures, poured over crushed ice, diluted with methylene chloride, treated with 50% sodium hydroxide solution with ice bath cooling to pH 3-4 and separated. The aqueous layer is extracted with methylene chloride. The combined organic layers are dried (MgSO4) and concentrated in vacuo to give an orange foam residue, which is recrystallized from methylene chloride to afford the title product as yellow crystals (1.30 g, 23.2%), mp 184°-189° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][C:8]([N:12]3[CH:16]=[C:15]([C:17]([O:19]CC)=[O:18])[CH:14]=[N:13]3)=[N:9]2)=[CH:4][C:3]=1[CH:23]([CH3:25])[CH3:24].[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[N:7][C:8]([N:12]3[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[N:13]3)=[N:9]2)=[CH:4][C:3]=1[CH:23]([CH3:24])[CH3:25]
Reactant: CCOC(=O)c1cnn(-c2nc3cc(F)c(C(C)C)cc3c(=O)[nH]2)c1
Reactant: C1CCNC1
Product: CC(C)c1cc2c(N3CCCC3)nc(-n3cc(C(=O)O)cn3)nc2cc1F

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(7-fluoro-6-isopropyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and pyrrolidine in step E. MS (ESI): predicted mass calcd. for C19H20FN5O2, 369.2
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:11]1([C:17]2[CH:18]=[CH:19][CH:20]=[C:21]3[C:25]=2[NH:24][C:23](=[O:26])[C:22]3=[O:27])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:2]([N:24]1[C:25]2[C:21](=[CH:20][CH:19]=[CH:18][C:17]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:22](=[O:27])[C:23]1=[O:26])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: O=C1Nc2c(cccc2-c2ccccc2)C1=O
Reactant: CCCCCCCCCBr
Product: CCCCCCCCCN1C(=O)C(=O)c2cccc(-c3ccccc3)c21

Procedure:
The title compound was prepared in a manner similar to the process step described in the text from Page 7, line 34 to Page 8, line 5 of WO 94/29272 but using a haloalkane such as 1-bromononane together with 7-phenyl-1H-indole-2,3-dione.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[Br:5][C:6]1[CH:7]=[CH:8][C:9]2[N:15]=[C:14]([NH:16][CH3:17])[CH2:13][N:12]=[C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[C:10]=2[CH:24]=1.C(O)(=O)C>O>[Br:5][C:6]1[CH:7]=[CH:8][C:9]2[N:15]=[C:14]([NH:16][CH2:17][N:1]=[O:3])[CH2:13][N:12]=[C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[C:10]=2[CH:24]=1
Reactant: O=N[O-]
Reactant: CNC1=Nc2ccc(Br)cc2C(c2ccccn2)=NC1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=NCNC1=Nc2ccc(Br)cc2C(c2ccccn2)=NC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4.3 g. (0.0625 mol) of sodium nitrite was added in small portions to a stirred solution of 16.4 g. (0.05 mol) of 7-bromo-2-methylamino-5-(2-pyridyl)-3H-1,4-benzodiazepine in 200 ml. of glacial acetic acid. After addition (15 minutes), the mixture was stirred for 30 minutes at room temperature, diluted with water and extracted with ether. The extracts were washed with saturated sodium bicarbonate solution, dried over sodium sulfate and evaporated, giving crude 7-bromo-2-(N-nitrosomethylamino)-5-(2-pyridyl)-3H-1,4-benzodiazepine as an oil. 2 g. of the remaining oil was chromatographed over 60 g. of silica gel using 10 percent ethanol in methylene chloride. The clean fractions were combined and evaporated. The residue was stirred in isopropanol overnight, whereupon crystalline 7-bromo-2-(N-nitrosomethylamino)-5-(2-pyridyl)-3H-1,4-benzodiazepine separated, m.p. 102°-106°.
Reaction SMILES: [CH3:1][Si:2]([CH2:5][Mg]Cl)([CH3:4])[CH3:3].[O:8]1[CH2:13][CH2:12][CH2:11][O:10][CH:9]1[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[S:21][C:22]3[C:27]([N:28]=2)=[CH:26][CH:25]=[C:24]([C:29]([CH:31]2[CH2:34][CH2:33][CH2:32]2)=[O:30])[N:23]=3)=[C:16]([F:35])[CH:15]=1>C1COCC1>[O:10]1[CH2:11][CH2:12][CH2:13][O:8][CH:9]1[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[S:21][C:22]3[C:27]([N:28]=2)=[CH:26][CH:25]=[C:24]([C:29]([CH:31]2[CH2:32][CH2:33][CH2:34]2)([OH:30])[CH2:5][Si:2]([CH3:3])([CH3:4])[CH3:1])[N:23]=3)=[C:16]([F:35])[CH:15]=1
Reactant: C[Si](C)(C)C[Mg]Cl
Reactant: O=C(c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2n1)C1CCC1
Solvent: C1CCOC1
Product: C[Si](C)(C)CC(O)(c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2n1)C1CCC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Trimethylsilylmethylmagnesium chloride (1.1M solution in THF; 1.12 mL, 1.23 mmol) was added to a solution of (2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)thiazolo[5,4-b]pyridin-5-yl)(cyclobutyl)methanone (327.0 mg, 0.821 mmol) in THF (15 mL) at 25° C., and the resulting solution was stirred at 25° C. for 5 min. Excess Grignard reagent was quenched by the careful addition of sat. aq. NH4Cl (5 mL), water was added to dissolve precipitated salts, and THF was then removed in vacuo. The resulting solution was partitioned between EtOAc (100 mL) and sat. aq. NH4Cl (20 mL), and the organic layer was separated and washed with brine. The organic layer was then dried over sodium sulfate, filtered, and concentrated in vacuo to provide 1-(2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)thiazolo[5,4-b]pyridin-5-yl)-1-cyclobutyl-2-(trimethylsilyl)ethanol as a yellow oil. MS (ESI) m/z: Calculated: 486.2; Observed: 487.1 (M++1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[NH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[N:10]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu]I.C1(C)C=CC=CC=1>[N:9]1[N:10]([C:2]2[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=2)[CH:11]=[C:12]2[C:17]=1[CH:16]=[CH:15][CH:14]=[CH:13]2
Reactant: Oc1ccc(Br)cc1
Reactant: c1ccc2[nH]ncc2c1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Oc1ccc(-n2cc3ccccc3n2)cc1
Temperature: 25 °C
Yield: 19.6 %

Procedure:
4-Bromophenol (2.00 g, 11.6 mmol) was combined with 1H-indazole (1.64 g, 13.9 mmol), copper (I) iodide (110 mg, 0.578 mmol), potassium phosphate (5.15 g, 24.3 mmol), trans-dimethylcyclohexane-1,2-diamine (0.365 mL, 2.31 mmol), and toluene (10 mL). The reaction was refluxed for 21 hours, then cooled to room temperature and partitioned between ethyl acetate and water/ammonium hydroxide. The organic layer was washed with 0.5 N HCl and brine, dried over magnesium sulfate, filtered and concentrated. Purification by column chromatography (0-40% ethyl acetate in heptane) gave 4-(2H-indazol-2-yl)phenol (0.479 g, 20%) as a tan solid. 1H NMR (400 MHz, (CD3)2SO, δ): 9.84 (s, 1H), 8.90 (s, 1H), 7.86 (d, J=8.8 Hz, 2H), 7.74 (d, J=8.4 Hz, 1H), 7.68 (d, J=8.8 Hz, 1H), 7.22-7.33 (m, 1H), 7.03-7.12 (m, 1H), 6.94 (d, J=8.8 Hz, 2H). MS (M+1): 211.2.
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:4]=1[O:5][CH2:6][CH2:7][NH:8]C(=O)OC(C)(C)C)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][CH2:7][CH2:6][O:5][C:4]1[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:3]=1[C:1]#[N:2]
Reactant: CC(C)(C)OC(=O)NCCOc1cc([N+](=O)[O-])ccc1C#N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc([N+](=O)[O-])cc1OCCN
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
To an ice-cold solution of tert-butyl (2-(2-cyano-5-nitrophenoxy)ethyl)carbamate (4 g, 13.02 mmol) in DCM (20 mL) was added TFA (10 mL). The reaction mixture was stirred at rt for 60 min. The solvent was removed under reduced pressure and treated with saturated sodium bicarbonate solution (10 mL) and extracted with ethyl acetate (2×25 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to get 2-(2-aminoethoxy)-4-nitrobenzonitrile (2.4 g, 89%) as a yellow solid. LC-MS (M+H)+=208.0. 1H NMR (400 MHz, CDCl3) δ ppm 7.89 (1H, d, J=8.4 Hz), 7.83 (1H, s), 7.76 (1H, d, J=8.4 Hz), 4.23 (2H, t, J=5.2 Hz), 3.22 (2H, t, J=5.2 Hz).
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]([C:10]([NH:12][C:13]2[C:14]([N:19]3[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[C:20]3=[O:26])=[N:15][N:16]([CH3:18])[CH:17]=2)=[O:11])[CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH2:27]1COCC1>C(OCC)(=O)C.O>[CH3:24][C:21]1([CH3:25])[CH2:22][CH2:23][N:19]([C:14]2[C:13]([NH:12][C:10]([C:8]3[CH:7]=[CH:6][CH:5]=[C:4]([C:1]([OH:3])([CH3:27])[CH3:2])[N:9]=3)=[O:11])=[CH:17][N:16]([CH3:18])[N:15]=2)[C:20]1=[O:26]
Reactant: C1CCOC1
Reactant: CC(=O)c1cccc(C(=O)Nc2cn(C)nc2N2CCC(C)(C)C2=O)n1
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1cc(NC(=O)c2cccc(C(C)(C)O)n2)c(N2CCC(C)(C)C2=O)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of 6-acetyl-N-(3-(3,3-dimethyl-2-oxopyrrolidin-1-yl)-1-methyl-1H-pyrazol-4-yl)pyridine-2-carboxamide (35 mg) and THF (3.0 mL) was added 3M methylmagnesium bromide diethyl ether solution (0.33 mL) at 0° C., and the mixture was stirred at room temperature for 4 hr. The reaction solution was diluted with ethyl acetate, and water was added thereto. The extract was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane), and the obtained solid was washed with diisopropyl ether, and dried under reduced pressure to give the title compound (14 mg).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C@H:17]([OH:19])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:37])[C@@H:15]2[CH2:20][CH2:21][C@H:22]2[O:27][C:26](=[O:28])[CH2:25][C@H:24]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:23]2)=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH:38]([CH:41]([CH:45]([CH3:47])[CH3:46])[C:42](Cl)=[O:43])([CH3:40])[CH3:39]>>[Si:1]([O:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:42](=[O:43])[CH:41]([CH:45]([CH3:47])[CH3:46])[CH:38]([CH3:40])[CH3:39])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:37])[C@@H:15]2[CH2:20][CH2:21][C@H:22]2[O:27][C:26](=[O:28])[CH2:25][C@H:24]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:31])[CH3:32])[CH2:23]2)=[CH:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Reactant: CC(C)C(C(=O)Cl)C(C)C
Product: CC(C)C(C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21)C(C)C
Yield: 16.2 %

Procedure:
A procedure similar to that described in Example 4, above, was followed, but using 1.0 g (1.8 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above] and 888 mg (5.5 mmol) of 2-isopropyl-3-methylbutyryl chloride, to provide 198 mg of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH:8]([CH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[CH2:9][CH2:10][OH:11])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:7][CH:8]([CH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[CH2:9][CH2:10][O:11][S:27]([CH3:26])(=[O:29])=[O:28])=[O:18])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NC(CCO)C1CCOCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC(CCOS(C)(=O)=O)C1CCOCC1
Temperature: 25 °C
Reaction time: 10 h
Yield: 62.4 %

Procedure:
To a solution of [3-hydroxy-1-(tetrahydro-pyran-4-yl)-propyl]-carbamic acid tert-butyl ester (0.200 g, 0.770 mmol) and NEt3 (192 μL, 0.920 mmol) in CH2Cl2 (8 mL) was added MsCl (72 μL, 0.92 mmol) at 0° C. and the mixture was stirred at room temperature for 10 h. The solvent was evaporated to dryness and EtOAC was added. The ethyl acetate layer was washed with aq. NaHCO3, dried (Na2SO4), filtered, and solvent was evaporated under reduced pressure to afford methanesulfonic acid 3-tert-butoxycarbonylamino-3-(tetrahydro-pyran-4-yl)-propyl ester (0.162 g). LC-MS [M+Na] 360.2. The product was sufficiently pure for the next step and used without further purification.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:8]Br)=[N:4][CH:5]=[CH:6][CH:7]=1.[C-:10]#[N:11].[Na+]>O1CCOCC1.O>[Br:1][C:2]1[C:3]([CH2:8][C:10]#[N:11])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: [C-]#N
Reactant: BrCc1ncccc1Br
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: N#CCc1ncccc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 39.9 %

Procedure:
To a stirred solution of the above crude 3-bromo-2-bromomethylpyridine (70 g, 0.28 mol) in dioxane (500 mL) and water (250 mL), was added NaCN (28 g, 0.74 mol) at 0° C. and then stirred at RT for 16 h. The reaction mixture was quenched with 3 Lit of water and extracted with ethylacetate (4×500 mL). The organic layer was washed with water (400 L), brine (250 mL), dried over Na2SO4 and concentrated to give crude product. The crude was purified by column chromatography over silica gel (pet. ether/ethylacetate, 8:2) to give 3-bromopyridine-2-yl-acetonitrile (22 g, 40%). [TLC: Pet. ether/ethylacetate, 7:3, Rf=0.35]
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])O[C:6]2=[O:13].[CH3:16][C:17]([NH2:20])([CH3:19])[CH3:18]>C(O)(=O)C>[C:17]([N:20]1[C:6](=[O:13])[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([C:2]([F:1])([F:15])[F:14])[CH:4]=2)[C:8]1=[O:12])([CH3:19])([CH3:18])[CH3:16]
Reactant: CC(C)(C)N
Reactant: O=C1OC(=O)c2cc(C(F)(F)F)ccc21
Solvent: CC(=O)O
Product: CC(C)(C)N1C(=O)c2ccc(C(F)(F)F)cc2C1=O
Temperature: 100 °C

Procedure:
A suspension of 5-(trifluoromethyl)isobenzofuran-1,3-dione and 2-methylpropan-2-amine in acetic acid was heated at 100° C. overnight, concentrated, diluted with EtOAc, washed with saturated aqueous NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated to give crude 2-tert-butyl-5-(trifluoromethyl)isoindoline-1,3-dione, which was used without purification.
Reaction SMILES: [CH3:1][CH:2]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:3]([C:5]1[CH:6]=[C:7]([OH:12])[CH:8]=[C:9]([CH:11]=1)[OH:10])[CH3:4].O=[C:19]1[CH2:23][CH2:22][S:21][CH:20]1[C:24](OC)=[O:25]>C(O)C>[OH:10][C:9]1[C:8]2[C:19]3[CH2:23][CH2:22][S:21][C:20]=3[C:24](=[O:25])[O:12][C:7]=2[CH:6]=[C:5]([CH:3]([CH:2]([CH3:1])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:4])[CH:11]=1
Reactant: CCCCCC(C)C(C)c1cc(O)cc(O)c1
Reactant: COC(=O)C1SCCC1=O
Solvent: CCO
Product: CCCCCC(C)C(C)c1cc(O)c2c3c(c(=O)oc2c1)SCC3
Reaction time: 72 h

Procedure:
A solution of 2.5 g. (0.011 mole) of 5-(3-methyl-2-octyl)resorcinol and 2.0 g. (0.013 mole) of the methyl 3-oxo-2, 3,4,5-tetrahydrothiophene-2-carboxylate in 50 ml. of absolute ethanol in a three-necked flask equipped with drying tube was cooled in an ice-water bath and saturated with dry hydrogen chloride. The 5-(3-methyl-2-octyl)resorcinol was prepared according to the method of Adams, MacKenzie and Loewe (J. Amer. Chem. Soc. 70, 664-8 (1948)). The reaction mixture was allowed to stand for three days at room temperature, during which time a heavy yellow solid formed. The hydrogen chloride was evaporated, the mixture was concentrated and the solid was filtered and washed with ethanol. The yield of the crude benzopyrone thus obtained was 2.6 g. (59%), m.p. 190°-205°C.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[C:8]2[C:9]([O:11][C:12](=[O:13])[C:7]2=[CH:6][CH:5]=1)=O)([O-])=O.[CH3:15][C:16]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:17]=1[NH2:18].[Sn](Cl)Cl.[OH-].[Na+]>C(O)(=O)C.C(OCC)(=O)C>[NH2:1][C:4]1[CH:14]=[C:8]2[C:7](=[CH:6][CH:5]=1)[C:12](=[O:13])[N:18]([C:17]1[C:19]([CH3:23])=[CH:20][CH:21]=[CH:22][C:16]=1[CH3:15])[C:9]2=[O:11]
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Reactant: Cc1cccc(C)c1N
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1cccc(C)c1N1C(=O)c2ccc(N)cc2C1=O
Temperature: 100 °C
Yield: 67.2 %

Procedure:
A mixture of 5-nitrophthalic anhydride (1.0 g, 5.2 mmol) and 2,6-dimethylaniline (0.65 mL, 5.3 mmol) in acetic acid (50 mL) was heated at 100° C. overnight (14 h). The reaction mixture was cooled, diluted with ethyl acetate and washed with saturated sodium bicarbonate. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The product was dissolved in ethanol (50 mL), tin (II) chloride (1.4 g, 6.2 mmol) was added and the mixture was heated to reflux for 5 h. The reaction mixture was cooled and made basic by adding aqueous 2 N sodium hydroxide. Ethyl acetate was added and the layers were separated. The organic layer was washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to give 5-amino-2-(2,6-dimethylphenyl)isoindoline-1,3-dione (0.93 g, 67%), which was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([NH:15][C:16]2[S:17][C:18](Br)=[CH:19][N:20]=2)=[O:14])=[C:8]([C:22]([CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:23])[CH:7]=1)[CH3:2].[NH:30]1[CH:34]=[CH:33][N:32]=[C:31]1[SH:35]>>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([NH:15][C:16]2[S:17][C:18]([S:35][C:31]3[NH:30][CH:34]=[CH:33][N:32]=3)=[CH:19][N:20]=2)=[O:14])=[C:8]([C:22]([CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:23])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(NC(=O)Nc2ncc(Br)s2)c(C(=O)C2CCCC2)c1
Reactant: Sc1ncc[nH]1
Product: CCOC(=O)Cc1ccc(NC(=O)Nc2ncc(Sc3ncc[nH]3)s2)c(C(=O)C2CCCC2)c1
Yield: 24 %

Procedure:
(3-Cyclopentanecarbonyl-4-{3-[5-(1H-imidazol-2-ylsulfanyl)-thiazol-2-yl]-ureido}-phenyl)acetic acid ethyl ester (120 mg, 24%) was prepared from {4-[3-(5-bromo-thiazol-2-yl)-ureido]-3-cyclopentanecarbonyl-phenyl}-acetic acid ethyl ester (480 mg, 1 mmol) and 1H-imidazole-2-thiol (200 mg, 2 mmol) following the general procedure Q.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].[CH3:8][O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15](OC)=[O:16].C(O)(=O)C>C1COCC1>[CH3:8][O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15](=[O:16])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: COCCCCCC(=O)OC
Reactant: COP(C)(=O)OC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COCCCCCC(=O)CP(=O)(OC)OC
Temperature: -60 °C
Reaction time: 0.5 h

Procedure:
A solution of dimethyl methylphosphonate (8.88 g) in THF (60 ml) was cooled to -60° C. , to which n-butylithium (1.55-M, 46.2 ml) was added dropwise. After addition, the solution was stirred at -60° C. for 30 minutes. A solution of methyl 6-methoxy-caproate (5.65 g) in THF (50 ml) was added dropwise to the resulting solution and held at -60° C. overnight, and at room temperature for 2 hours. After the reaction solution was cooled to 0° C., the reaction was neutralized by addition of acetic acid (4 ml). The crude product obtained after the usual work-up was chromatographed (dichloromethane/methanol (5%)).
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]#[C:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:21]([C:23]3[O:24][CH:25]=[CH:26][C:27]=3[CH3:28])=[O:22])[CH:15]=2)=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][N:3]=1.[OH-].[K+]>CO.O>[NH2:1][C:2]1[C:11]([C:12]#[C:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:21]([C:23]3[O:24][CH:25]=[CH:26][C:27]=3[CH3:28])=[O:22])[CH:15]=2)=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1
Reactant: COC(=O)c1cnc(N)c(C#Cc2cccc(NC(=O)c3occc3C)c2)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cc(C(=O)O)cnc2N)c1
Temperature: 65 °C
Yield: 99.9 %

Procedure:
To a solution of methyl 6-amino-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinate, (1.82 g, 4.85 mmol, 1 eq) in MeOH—H2O (100 mL, 3:1) at RT was added potassium hydroxide (2.72 g, 10 eq) with stirring. The mixture was heated at 65° C. for 2 hours and a brown solution was observed at this time. The reaction mixture was concentrated to remove most of the methanol. The resulting solution was cooled to 0° C. and concentrated HCl was added until the pH was around 3 at which time a white precipitates formed. The solid which had formed was collected by filtration, rinsed with water, and dried to give the title compound as a white solid (1.75 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[CH3:19][S:20]([NH:1][CH2:2][CH2:3][NH:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCNS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.1 %

Procedure:
In a 1000 ml reaction flask, 36.9 g of tert-butyl 2-aminoethylaminoformate and 200 ml of dichloromethane were added. The mixture was stirred by an electromagnetic stirrer, cooled with ice-bath, added with 96 ml of triethylamine, slowly added dropwise with 35.9 g of methylsulfonyl chloride in 200 ml of dichloromethane. The temperature of the mixture was naturally warmed to room temperature and the mixture was conducted overnight. The mixture was added dropwise with ice-water to quench reaction, the organic layer was separated, and the water layer was extracted with dichloromethane. The organic layers were combined, washed sequentially with 5 mol/L dilute hydrochloric acid, saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtrated, and distilled under a reduced pressure to remove the solvent to obtain 28.6 g of brown yellow solid, yield 52.1%.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[N:27](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:26]=[N:25][N:24]=3)=[CH:13][CH:12]=2)[C:8]2[CH:47]=[CH:48][CH:49]=[CH:50][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].Cl>C(Cl)Cl.CO>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[CH:13][CH:12]=2)[C:8]2[CH:47]=[CH:48][CH:49]=[CH:50][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccccc2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CCCCc1nc2ccccc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2 g (3 mmol) of 4'-[(2-n-butyl-benzimidazol-1-yl)-methyl]-2-(1-triphenylmethyl-tetrazol-5-yl)-biphenyl are dissolved in a mixture of 10 ml of methylene chloride and 10 ml of methanol, treated with 10 ml of etherified hydrochloric acid and stirred at ambient temperature for 3 hours. The mixture is rotary evaporated to dryness in vacuum. The residue is dissolved in methanol, rendered alkaline using ammonia and rotary evaporated once again. The crude product is purified over a silica gel column (grain size: 0.063-0.2 mm, eluting agent: methylene chloride/ethanol/ammonia=19:1:0.1). The product is crystallised from ether and dried at 50° C. in vacuum.