Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:18]2[CH:22]=[C:21](B3OC(C)(C)C(C)(C)O3)[CH:20]=[N:19]2)[CH2:7][N:6]([C:8]2[N:9]=[CH:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[N:12][CH:13]=2)[CH2:5]1)#[N:2].Br[C:33]1[CH:38]=[CH:37][N:36]=[C:35]2[NH:39][CH:40]=[CH:41][C:34]=12.C(=O)(O)[O-].[Na+].O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[C:1]([CH2:3][C:4]1([N:18]2[CH:22]=[C:21]([C:33]3[CH:38]=[CH:37][N:36]=[C:35]4[NH:39][CH:40]=[CH:41][C:34]=34)[CH:20]=[N:19]2)[CH2:7][N:6]([C:8]2[N:9]=[CH:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[N:12][CH:13]=2)[CH2:5]1)#[N:2]
Reactant: COC(=O)c1cnc(N2CC(CC#N)(n3cc(B4OC(C)(C)C(C)(C)O4)cn3)C2)cn1
Reactant: Brc1ccnc2[nH]ccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cnc(N2CC(CC#N)(n3cc(-c4ccnc5[nH]ccc45)cn3)C2)cn1
Temperature: 85 °C
Reaction time: 3 h
Yield: 54.8 %

Procedure:
A mixture of methyl 5-{3-(cyanomethyl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]azetidin-1-yl}pyrazine-2-carboxylate (0.28 g, 0.66 mmol), 4-bromo-1H-pyrrolo[2,3-b]pyridine (0.14 g, 0.72 mmol), tetrakis(triphenylphosphine)palladium(0) (0.04 g, 0.03 mmol) and sodium bicarbonate (0.28 g, 3.3 mmol) in a solution of water (0.5 mL) and 1,4-dioxane (1 mL) was degassed for a while and sealed. The mixture was stirred at 85° C. for 3 h. After cooling the mixture was diluted with ethyl acetate. The organic solution was washed with water and brine, dried over Na2SO4. After filtration the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with methanol in methylene chloride (0-5%) to afford the desired product (0.15 g). LCMS (M+H)+: m/z=415.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([F:31])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]([CH3:19])[CH3:18])=[C:13]([F:20])[CH:12]=3)=[CH:8][C:7](=[O:21])[C:6]=2[C:22]=1[NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][OH:30].[H-].[Na+].I[CH3:35]>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([F:31])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]([CH3:18])[CH3:19])=[C:13]([F:20])[CH:12]=3)=[CH:8][C:7](=[O:21])[C:6]=2[C:22]=1[NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH3:35]
Reactant: CN(C)c1ccc(-c2cc(=O)c3c(NCCCCCCO)c(F)cc(F)c3o2)cc1F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCCCCCNc1c(F)cc(F)c2oc(-c3ccc(N(C)C)c(F)c3)cc(=O)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
500 mg (1.15 mmol) of Compound 60 obtained in Example 60 was dissolved in 20 ml of tetrahydrofuran under argon atmosphere, 92 mg of sodium hydride (60% oil dispersion) and 0.14 ml of iodomethane were added under ice-cooling and the mixture was stirred at room temperature for 1 hour. Thereafter, 0.22 ml of iodomethane was added and the mixture was heated at reflux for 3.5 hours. Additional 0.36 ml of iodomethane was added and the mixture was heated at reflux for 1 hour. The solvent was distilled off under reduced pressure, an aqueous saturated solution of ammonium chloride was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (chloroform:acetone=40:1), followed by recrystallization from n-hexane/ethyl acetate to give 300 mg (58%) of Compound 61.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:17]=2[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][N:22]=2)=[O:19])[CH2:10][CH2:9]1)(OC(C)(C)C)=O>FC(F)(F)C(O)=O>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([NH:20][C:18](=[O:19])[C:17]2[CH:28]=[C:29]([F:32])[CH:30]=[CH:31][C:16]=2[NH:15][CH2:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[N:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2ccc(F)cc2C(=O)Nc2ccc(Cl)cn2)CC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(Cl)cn1)c1cc(F)ccc1NCC1CCNCC1
Reaction time: 24 h
Yield: 84 %

Procedure:
A solution of 2-(1-Boc-piperidin-4-ylmethylamino)-N-(5-chloropyridin-2-yl)-5-fluorobenzamide from above (5.8 g, 12 mmol) in trifluoroacetic acid (125 mL) was heated at 70° C. for 2 h, then at room temperature for 24 h. The solvent was removed in vacuo; then the residue was directly applied to a silica gel column. Elution with dichloromethane-2 M ammonia in methanol (9:1) afforded 3.8 g (84%) of the title compound as a yellow solid.
Reaction SMILES: Cl[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14]C)=[O:13])=[CH:7][CH:6]=2.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1>>[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[C:3]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=3)=[CH:26][CH:25]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Cl)nc2c1
Product: COc1ccc(-c2nc3cc(C(=O)O)ccc3nc2-c2ccccc2)cc1
Yield: 41.3 %

Procedure:
The product was obtained via a Suzuki coupling reaction using the method previously shown in Example 20, Step 3, with methyl 3-chloro-2-phenylquinoxaline-6-carboxylate (50 mg, 0.17 mmol, 1.00 equiv) and 4-methoxyphenylboronic acid (38 mg, 0.25 mmol, 1.50 equiv) as reactants. Purification via Prep-TLC (silica gel) yielded 25 mg (42%) of 3-(4-methoxyphenyl)-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.
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:13]=[CH:14][CH:15]=[C:16]3[C:21]=2[C:19](=[O:20])[O:18][CH:17]3[O:22]C)[N:4]=1.Cl>O1CCCC1>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([O:11][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:21]=2[C:19](=[O:20])[O:18][CH:17]3[OH:22])[N:6]=1
Reactant: COc1cc(OC)nc(Oc2cccc3c2C(=O)OC3OC)n1
Agent: Cl
Solvent: C1CCOC1
Product: COc1cc(OC)nc(Oc2cccc3c2C(=O)OC3O)n1

Procedure:
15.2 g of 7-[(4,6-dimethoxy-pyrimidin-2-yl)oxy]-3-methoxyphthalide (see Example 8) are heated at reflux temperature in a 1:1 mixture of tetrahydrofuran and hydrochloric acid for 3 hours. Concentration is then carried out under reduced pressure and the resulting crystals are filtered off and washed with water to yield pure 7-[(4,6-dimethoxy-pyrimidin-2-yl)oxy]-3-hydroxy-phthalide, m.p. 143°-145° C.; IR (KBr): 1770 cm-1 ; 1H-NMR (CDCl3): 6.60 ppm (s, 1H).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.Br[C:12]1[CH:17]=CC=C[C:13]=1[OH:18].CC(=O)OCC>CN(C=O)C.O>[Br:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH2:17][CH:12]1[CH2:13][O:18]1
Reactant: Oc1ccccc1Br
Reactant: Oc1cccc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Brc1cccc(OCC2CO2)c1
Reaction time: 0.08 h
Yield: 113.3 %

Procedure:
To a solution of NaH (416.2 mg, 17.34 mmol) in DMF (10 mL) was added 3-bromophenol (1.0 g, 5.78 mmol) at 9° C. and stirred for 5 minutes. To this mixture was added 2-bromophenol (1.2 g, 8.67 mmol) at 9° C. The reaction mixture was stirred for a further 16 h at 9° C. TLC (PE: EA=5:1) showed that the reaction was completed. The mixture was treated with water (50 mL) and extracted with EA (2×20 mL). The organic layer was washed with NaHCO3, brine (30 mL) then dried over Na2SO4 and concentrated to give 2-((3-bromophenoxy)methyl) oxirane (1.5 g, crude) as colorless oil which was used in next step without further purification. LCMS (m/z): 229.1/230.1 [M+H]+/[M+2H]+
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][C:9](=[O:43])[CH2:10][C:11]1[CH:42]=[CH:41][CH:40]=[CH:39][C:12]=1[CH2:13][CH2:14][C:15]1[C:20]([CH3:21])=[CH:19][N:18]=[C:17]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([CH:29]([NH:31]C(=O)OC(C)(C)C)[CH3:30])=[CH:25][CH:24]=2)[N:16]=1>C(Cl)Cl>[NH2:31][CH:29]([C:26]1[CH:27]=[CH:28][C:23]([NH:22][C:17]2[N:16]=[C:15]([CH2:14][CH2:13][C:12]3[CH:39]=[CH:40][CH:41]=[CH:42][C:11]=3[CH2:10][C:9]([NH2:8])=[O:43])[C:20]([CH3:21])=[CH:19][N:18]=2)=[CH:24][CH:25]=1)[CH3:30]
Reactant: Cc1cnc(Nc2ccc(C(C)NC(=O)OC(C)(C)C)cc2)nc1CCc1ccccc1CC(N)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cnc(Nc2ccc(C(C)N)cc2)nc1CCc1ccccc1CC(N)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.8 %

Procedure:
TFA (1 mL) was added to a solution of tert-butyl (1-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-methylpyrimidin-2-yl)amino)phenyl)ethyl)carbamate (A132) (0.099 g, 0.20 mmol) in DCM (5 mL) and the resulting mixture stirred at room temperature for 3 hours. The volatiles were evaporated under reduced pressure then 2 M aqueous K2CO3 solution (10 mL) and water (15 mL) were added to the residue. The resulting suspension was sonicated for 1 minute, filtered and the filter cake dried to give the title compound 34 as a light tan solid (77 mg, 97%); 1H NMR (300 MHz, d6-DMSO) δ 9.26 (s, 1H), 8.15 (s, 1H), 7.67 (d, J=8.6 Hz, 2H), 7.42 (s, 1H), 7.23 (d, J=8.6 Hz, 2H), 7.14-7.23 (m, 4H), 6.92 (s, 1H), 3.92 (d, J=6.4 Hz, 1H), 3.50 (s, 2H), 3.32 (brs, 2H), 3.02-3.07 (m, 2H), 2.88-2.90 (m, 2H), 2.06 (s, 3H), 1.23 (d, J=6.5 Hz, 3H). LCMS-B: rt 4.691 min; m/z 390 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:16])([CH3:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][C:3]=1[N+:17]([O-])=O.[H][H]>[Pd].C(OCC)(=O)C>[NH2:17][C:3]1[CH:4]=[C:5]([C:8]([CH3:15])([CH3:16])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: CCOC(=O)CC(C)(C)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(C)(C)c1ccc(Cl)c(N)c1

Procedure:
40 mg of palladium on carbon (10%) were added to a solution of 213 mg (0.75 mmol) of ethyl 3-(4-chloro-3-nitrophenyl)-3-methylbutanoate in 10 ml of ethyl acetate. The reaction mixture was hydrogenated at RT using a hydrogen pressure of 1 bar overnight. The mixture was then filtered through celite, and the filtrate was concentrated. This gave 166 mg (87% of theory) of the target compound as a yellowish oil.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:10]([NH:12][C@H:13]([C:21]([N:23]1[CH2:97][CH2:96][CH2:95][C@H:24]1[C:25]([NH:27][C@H:28]([C:36]([NH:38][C@H:39]([C:46]([NH:48][C@H:49]([C@H:54]([CH2:56][C:57]([NH:59][C@H:60]([C:65]([NH:67][C@H:68]([C:75]([NH:77][C@H:78]([C:91]([O:93][CH3:94])=[O:92])[CH2:79][CH2:80][CH2:81][CH2:82][NH:83][C:84]([O:86][C:87]([CH3:90])([CH3:89])[CH3:88])=[O:85])=[O:76])[CH2:69][C:70]1[N:74]=[CH:73][NH:72][CH:71]=1)=[O:66])[C@H:61]([CH2:63][CH3:64])[CH3:62])=[O:58])[OH:55])[CH2:50][CH:51]([CH3:53])[CH3:52])=[O:47])[CH2:40][C:41]1[N:45]=[CH:44][NH:43][CH:42]=1)=[O:37])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:26])=[O:22])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:20])[NH2:19])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].[H][H]>CO>[NH2:1][C@H:2]([C:10]([NH:12][C@H:13]([C:21]([N:23]1[CH2:97][CH2:96][CH2:95][C@H:24]1[C:25]([NH:27][C@H:28]([C:36]([NH:38][C@H:39]([C:46]([NH:48][C@H:49]([C@H:54]([CH2:56][C:57]([NH:59][C@H:60]([C:65]([NH:67][C@H:68]([C:75]([NH:77][C@H:78]([C:91]([O:93][CH3:94])=[O:92])[CH2:79][CH2:80][CH2:81][CH2:82][NH:83][C:84]([O:86][C:87]([CH3:88])([CH3:89])[CH3:90])=[O:85])=[O:76])[CH2:69][C:70]1[N:74]=[CH:73][NH:72][CH:71]=1)=[O:66])[C@H:61]([CH2:63][CH3:64])[CH3:62])=[O:58])[OH:55])[CH2:50][CH:51]([CH3:52])[CH3:53])=[O:47])[CH2:40][C:41]1[N:45]=[CH:44][NH:43][CH:42]=1)=[O:37])[CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:26])=[O:22])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:19])[NH2:20])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9]
Reactant: [H][H]
Reactant: CC[C@H](C)[C@H](NC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CCCNC(=N)N)NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)OC
Solvent: CO
Product: CC[C@H](C)[C@H](NC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H](N)CCCNC(=N)N)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)OC

Procedure:
145 mg of Z-Arg-Arg-Pro-Phe-His-Sta-Ile-His-Lys(Boc)-OMe (Example 4) are dissolved in 2.5 ml of 95% strength MeOH and, after the addition of 15 mg of Pd-on-carbon, hydrogenated by passing hydrogen through and stirring with a small magnetic rod until the starting material has disappeared completely (according to thin layer chromatography monitoring). The whole is filtered, the filtrate is concentrated to dryness, dissolved in 3 ml of H2O and lyophilised, yielding H-Arg-Arg-Pro-Phe-His-Sta-Ile-His-Lys(Boc)-OMe; Rf (D)=0.32; Rf (M)=0.25; Rf (N)=0.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]2[O:15][CH2:14][CH2:13][O:12][C:11]=12)[C:6]([OH:8])=O.Cl.[CH2:17]([O:19][CH2:20][CH2:21][N:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[C:23]1[NH:31][CH:32]1[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][C:40]2([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH2:44][CH2:43][NH:42][CH2:41]2)[CH2:34][CH2:33]1)[CH3:18]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]2[O:15][CH2:14][CH2:13][O:12][C:11]=12)[C:6]([N:42]1[CH2:43][CH2:44][C:40]([CH2:39][CH2:38][N:35]2[CH2:36][CH2:37][CH:32]([NH:31][C:23]3[N:22]([CH2:21][CH2:20][O:19][CH2:17][CH3:18])[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[N:24]=3)[CH2:33][CH2:34]2)([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH2:41]1)=[O:8]
Reactant: COc1cc(C(=O)O)cc2c1OCCO2
Reactant: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Agent: Cl
Product: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(OC)c5c(c4)OCCO5)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 59.1 using 3-methoxy-4,5-ethylenedioxybenzoic acid and 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) to give the title compound.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:13][C:14]([O:16]CC)=[O:15]>>[OH:11][CH:10]([CH2:9][CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:13][C:14]([OH:16])=[O:15]
Reactant: CCOC(=O)CBr
Reactant: O=CCCOc1ccccc1
Product: O=C(O)CC(O)CCOc1ccccc1

Procedure:
Hollow magnetic microcapsules 21 were obtained under the same conditions as in Example 88 except that the purified enzyme solution (1) used in Example 88 was replaced by the purified enzyme solution (3) of recombinant PHA synthetic enzyme and (R)-3-hydroxybutyryl CoA was replaced by (R,S)-3-hydroxy-5-phenoxyvaleryl CoA (prepared by hydrolyzing 3-hydroxy-5-phenoxy valerate obtained through a Reformatsky reaction with zinc using 3-phenoxypropanal and ethyl bromoacetate as raw materials, which were synthesized according to a procedure described in J. Org. Chem., 55, 1490-1492, 1990, to produce 3-hydroxy-5-phenoxy valeric acid and then following a procedure described in Eur. J. Biochem., 250, 432-439, 1997). An ultrasonic contrast agent employing the hollow magnetic microcapsules 21 is referred to as an ultrasonic contrast agent 21.
Reaction SMILES: [CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:21]([CH2:31][OH:32])[C:20]([CH3:33])=[C:19]1[CH3:34])[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3].C([O:38]N([C@H]1CN(C(OC(C)(C)C)=O)[C@H](C(O)=O)C=C1C)S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)C=C>>[CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[C@H:21]([C:31]([OH:38])=[O:32])[C:20]([CH3:33])=[C:19]1[CH3:34])[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3]
Reactant: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](CO)C(C)=C1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](C(=O)O)C=C1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Product: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](C(=O)O)C(C)=C1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]

Procedure:
The title compound was prepared from (2S,5R)-tert-butyl 5-(N-(allyloxy)-2-nitrophenylsulfonamido)-2-(hydroxymethyl)-3,4-dimethyl-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 193, 1.68 g, 3.38 mmol) following the procedure described for Intermediate 19. The workup yielded organics that were dried over magnesium sulfate, filtered and concentrated crude material to afford a light orange foam (1.48 g, 86%).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C@H:3]([N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:13]1)[C:4]1[CH:5]=[N:6][C:7]([NH:10][NH2:11])=[CH:8][CH:9]=1.[F:27][C:28]1[CH:29]=[C:30]2[C:35](=[C:36]([O:38][C@H:39]([CH3:43])[CH2:40][O:41][CH3:42])[CH:37]=1)[N:34]=[C:33]([CH:44]=O)[CH:32]=[CH:31]2.C(O)C.C(O)(=O)C.C(O)(=O)C.I(C1C=CC=CC=1)=O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[F:26][C:2]([F:25])([F:1])[C@H:3]([N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:23])[CH3:21])[CH2:13]1)[C:4]1[CH:9]=[CH:8][C:7]2[N:6]([C:44]([C:33]3[CH:32]=[CH:31][C:30]4[C:35](=[C:36]([O:38][C@H:39]([CH3:43])[CH2:40][O:41][CH3:42])[CH:37]=[C:28]([F:27])[CH:29]=4)[N:34]=3)=[N:11][N:10]=2)[CH:5]=1
Reactant: COC[C@@H](C)Oc1cc(F)cc2ccc(C=O)nc12
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN([C@H](c2ccc(NN)nc2)C(F)(F)F)C1
Agent: O=C([O-])O
Agent: O=Ic1ccccc1
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COC[C@@H](C)Oc1cc(F)cc2ccc(-c3nnc4ccc([C@@H](N5CC[C@H](NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)nc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 45.1 %

Procedure:
A solution of tert-butyl (S)-1-((R)-2,2,2-trifluoro-1-(6-hydrazinylpyridin-3-yl)ethyl)pyrrolidin-3-ylcarbamate (0.16 g, 0.43 mmol) and (R)-6-fluoro-8-(1-methoxypropan-2-yloxy)quinoline-2-carbaldehyde (0.11 g, 0.43 mmol) in ethanol (2.2 mL, 0.43 mmol) was allowed to stir at ambient temperature for 12 hours. The solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (2.2 mL) and iodosobenzene diacetate (0.15 g, 0.47 mmol) was added. The reaction mixture was stirred at ambient temperature for 1 hour. Ethyl acetate (20 mL) and saturated sodium bicarbonate (10 mL) were added. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography on C18 (0-100% acetonitrile/water) to give the title compound (0.12 g, 44%).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][O:5][C:6]1[CH:15]=[C:14]([C:16]([O:18]CC2C=CC=CC=2Cl)=[O:17])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH3:27])[CH:12]=2)[N:7]=1.[OH-].[Na+].CO.Cl>C1COCC1.O>[Cl:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][O:5][C:6]1[CH:15]=[C:14]([C:16]([OH:18])=[O:17])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH3:27])[CH:12]=2)[N:7]=1
Reactant: Cc1ccc2nc(OCc3ccccc3Cl)cc(C(=O)OCc3ccccc3Cl)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc2nc(OCc3ccccc3Cl)cc(C(=O)O)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.8 %

Procedure:
To 2-(2-chlorobenzyloxy)-4-(2-chlorobenzyloxycarbonyl)-6-methylquinoline (Method 11; 0.980 g, 2.173 mmol) in THF (100 ml) was added a solution of sodium hydroxide (261 mg, 6.519 mmol) in water (2.6 ml) followed by water (60 ml) and methanol (10 ml). The reaction mixture was stirred at ambient temperature for 2 hrs 30 min and then adjusted to pH 4–5 with 1M HCl. It was then concentrated in vacuo and the resulting solid filtered, washed with water, and dried to give the title compound as a colourless solid (0.704 g, 99%). NMR: 2.45 (3H, s), 5.60 (2H, s), 7.35 (3H, m), 7.50 (1H, m), 7.55 (1H, dd), 7.65 (1H, m), 7.75 (1H, d), 8.30 (1H, s); m/z 328 (M+H)+, 326 (M−H)−.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH2:10][CH2:11][CH:12]2[C:17]#[N:18])=[O:7].[OH2:19]>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH2:10][CH2:11][CH:12]2[C:17]([NH2:18])=[O:19])=[O:7]
Reactant: N#CC1CCc2c(C(=O)c3cccs3)cccc21
Reactant: O
Product: NC(=O)C1CCc2c(C(=O)c3cccs3)cccc21
Temperature: 80 °C

Procedure:
To 2.5 g of 4-(2-thienylcarbonyl)-1-indancarbonitrile is added 50 g of polyphosphoric acid and, with occasional stirring, the mixture is heated at 80° C. for 2.5 hours. The polyphosphoric acid is decomposed by the addition of water, followed by extraction with ethyl acetate. The extract is washed with water and dried. The solvent is distilled off under reduced pressure and the residue obtained is recrystallized from ethyl acetate. By the above procedure is obtained 4-(2-thienylcarbonyl)-1-indancarboxamide as crystals melting at 164°-166° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:30][CH3:31])[N:14]([CH2:15][C:16]3([OH:29])[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]3)[C:10]=2[C:9]2[N:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[ClH:32]>C(O)C>[ClH:32].[ClH:32].[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:30][CH3:31])[N:14]([CH2:15][C:16]3([OH:29])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:10]=2[C:9]2[N:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CCc1nc2c(N)nc3cccnc3c2n1CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCO
Product: CCc1nc2c(N)nc3cccnc3c2n1CC1(O)CCNCC1
Temperature: 50 °C

Procedure:
Under a nitrogen atmosphere a mixture of tert-butyl 4-[(4-amino-2-ethyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]-4-hydroxypiperidine-1-carboxylate (6.00 g), aqueous hydrochloric acid (14 mL of 6M), and ethanol (56 mL) was heated at 50° C. overnight. The reaction mixture was concentrated under reduced pressure. The residue was concentrated from methanol 3 times, triturated with acetonitrile, isolated by filtration, washed with acetonitrile, and then dried under high vacuum to provide 5.55 g of 4-[(4-amino-2-ethyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]piperidin-4-ol dihydrochloride as a tan powder.
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH:4]1[C:5]([C:26]([F:29])([F:28])[F:27])=[CH:6][C:7]([Cl:25])=[C:8]([N:11]2[N:15]=[C:14]([C:16]#[N:17])[C:13]([S+:18]([O-:23])[C:19]([F:22])([F:21])[F:20])=[C:12]2[NH2:24])[C:9]=1[Cl:10].C=O>CO>[C:16]([C:14]1[C:13]([S:18]([C:19]([F:22])([F:20])[F:21])=[O:23])=[C:12]([NH:24][CH2:1][OH:2])[N:11]([C:8]2[C:7]([Cl:25])=[CH:6][C:5]([C:26]([F:27])([F:29])[F:28])=[CH:4][C:9]=2[Cl:10])[N:15]=1)#[N:17]
Reactant: C[O-]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1[S+]([O-])C(F)(F)F
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(NCO)c1S(=O)C(F)(F)F

Procedure:
5 equivalent of a sodium methylate (30% solution in methanol) was rapidly added to a suspension of 0.437 g of Fipronil and 1.4 equivalent of paraformaldehyde in 3 mL of methanol to provide the 3-Cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-hydroxymethylamino-4-trifluoromethylsulfinylpyrazole (Compound V) after 3 hour at 20° C. and 1 hour at 60° C. Then 1 equivalent of sodium borohydride was added to the medium which provide after classical extraction and chromatography separation the 3-Cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-methylamino-4-trifluoromethylsulfinylpyrazole (Compound I).