Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[OH:10].FC(F)(F)C(O)=O.[O:35]1[CH2:40][CH2:39][N:38]([CH2:41][CH2:42][N:43]([CH2:48][C:49]2[CH:50]=[C:51]3[C:55](=[CH:56][CH:57]=2)[C:54](=[O:58])[N:53]([CH2:59][C:60](O)=[O:61])[C:52]3=[O:63])[S:44]([CH3:47])(=[O:46])=[O:45])[CH2:37][CH2:36]1.C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][CH:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[O:10][C:60](=[O:61])[CH2:59][N:53]1[C:52](=[O:63])[C:51]2[C:55](=[CH:56][CH:57]=[C:49]([CH2:48][N:43]([CH2:42][CH2:41][N:38]3[CH2:39][CH2:40][O:35][CH2:36][CH2:37]3)[S:44]([CH3:47])(=[O:46])=[O:45])[CH:50]=2)[C:54]1=[O:58]
Reactant: CS(=O)(=O)N(CCN1CCOCC1)Cc1ccc2c(c1)C(=O)N(CC(=O)O)C2=O
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)N(CCN1CCOCC1)Cc1ccc2c(c1)C(=O)N(CC(=O)OC(Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC3CC3)c1)C2=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 36.4 %

Procedure:
A mixture of (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (0.174 g, 0.415 mmol), 2-(5-((N-(2-morpholinoethyl)methylsulfonamido)methyl)-1,3-dioxoisoindolin-2-yl)acetic acid 2,2,2 trifluoroacetic acid salt (0.224 g, 0.415 mmol), EDC (0.239 g, 1.246 mmol), and DMAP (0.101 g, 0.830 mmol) in DCM (10 ml) was stirred at room temperature for 3 hours. The mixture was diluted with DCM and washed with 0.5N HCl, aqueous 5% NaHCO3 and brine; the organic phase was dried over sodium sulfate; and the solvent removed under vacuum. The crude was purified by filtration through a silica cartridge (DCM:MeOH=98:2); a further purification by flash chromatography on silica gel column (DCM:MeOH=99=1) was performed to afford S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(5-((N-(2-morpholinoethyl)methylsulfonamido)methyl)-1,3-dioxoisoindolin-2-yl)acetoxy)ethyl)pyridine 1-oxide (0.125 g, 0.151 mmol, 36.4% yield, MS/ESI+ 827.03 [MH]+, [αD]=−28.63, c=0.8, DCM). 1H NMR (300 MHz, DMSO-d6) δ ppm 8.44 (s, 2H), 7.70-8.09 (m, 3H), 7.19 (d, 1H), 7.03-7.13 (m, 1H), 6.96 (dd, 1H), 7.08 (t, 1H), 6.02 (dd, 1H), 4.59 (s, 2H), 4.21-4.52 (m, 2H), 3.75-4.03 (m, 2H), 3.44-3.54 (m, 4H), 3.30-3.44 (m, 3H), 3.17-3.23 (m, 1H), 3.12 (s, 3H), 2.37 (t, 2H), 2.16-2.32 (m, 4H), 1.13-1.33 (m, 1H), 0.48-0.72 (m, 2H), 0.16-0.48 (m, 2H)
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]=3[CH:33]=2)[C@@H:14]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[CH2:13][C@H:12]1[C:42](O)=[O:43])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:45][NH:46][CH3:47]>>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]=3[CH:33]=2)[C@@H:14]([C:34]2[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=2)[CH2:13][C@H:12]1[C:42](=[O:43])[N:46]([CH3:47])[CH3:45])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)[C@H](C(=O)O)C[C@@H]3c3ccc(OC)cc3)cc21
Reactant: CNC
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)[C@H](C(=O)N(C)C)C[C@@H]3c3ccc(OC)cc3)cc21

Procedure:
Similar to example 6a, 50.0 mg of (2S,4R,5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidin-1,2-dicarboxylic acid 1-benzyl ester (from example 3b) are allowed to react with dimethylamine to afford the title compound as a yellow oil. Rf=0.04 (dichlormethane-methanol 98:2); Rt=4.85.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:10]([N:13]2[C:18](=[O:19])[CH:17]=[CH:16][NH:15][C:14]2=[O:20])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:21]N(C)C=O>>[Cl:1][C:2]1[CH:12]=[CH:11][C:10]([N:13]2[C:18](=[O:19])[CH:17]=[CH:16][N:15]([CH3:21])[C:14]2=[O:20])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1cc(-n2c(=O)cc[nH]c2=O)ccc1Cl
Product: CCOC(=O)c1cc(-n2c(=O)ccn(C)c2=O)ccc1Cl

Procedure:
using ethyl 2-chloro-5-[3,6-dihydro-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate in dimethylformamide there is obtained ethyl 2-chloro-5-[3,6-dihydro-3-methyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate, m.p. 147°-148° C.,
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20]([C:22](=[O:25])[CH2:23][NH2:24])[CH3:21])[C:14]=3[Cl:26])[C:5]2=[N:4][C:3]=1[CH3:27].N1C=CC=CC=1.[C:34](Cl)(=[O:37])[CH2:35][CH3:36]>C(Cl)Cl>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20]([CH3:21])[C:22](=[O:25])[CH2:23][NH:24][C:34](=[O:37])[CH2:35][CH3:36])[C:14]=3[Cl:26])[C:5]2=[N:4][C:3]=1[CH3:27]
Reactant: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)cccn2c1Br
Reactant: CCC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(=O)NCC(=O)N(C)c1ccc(Cl)c(COc2cccn3c(Br)c(C)nc23)c1Cl
Reaction time: 0.5 h

Procedure:
To a mixture of 3-bromo-8-[2,6-dichloro-3-(N-glycyl-N-methylamino)benzyloxy]-2-methylimidazo[1,2-a]pyridine (100 mg), pyridine (25 mg) and methylene chloride (2 ml) was added propionyl chloride (0.02 ml) at ambient temperature and the mixture was stirred at the same temperature for 30 minutes. The mixture was partitioned between methylene chloride and water, and the organic layer was washed with water, dried over magnesium sulfate and concentrated in vacuo to give 3-bromo-8-[2,6-dichloro-3-[N-methyl-N-(propionylglycyl)amino]benzyloxy]-2-methylimidazo[1,2-a]pyridine (111 mg).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7].[SH:10][C:11]1[C:12]2[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:13]=2[S:14][C:15]=1[C:16]([NH2:18])=[O:17].C([O-])(O)=O.[Na+]>C1COCC1.C(OCC)(=O)C>[NH2:18][C:16]([C:15]1[S:14][C:13]2[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:12]=2[C:11]=1[S:10][CH:4]([CH2:3][CH3:2])[CH2:5][C:6]([O:8][CH3:9])=[O:7])=[O:17]
Reactant: COC(=O)CCCCBr
Reactant: COc1ccc2sc(C(N)=O)c(S)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(CC(=O)OC)Sc1c(C(N)=O)sc2ccc(OC)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
Methyl 5-bromovalerate (144 μL, 1.00 mmol) is added to a room temperature solution of 3-mercapto-5-methoxybenzo[b]thiophene-2-carboxamide (200 mg, 0.84 mmol) in 8 mL of THF followed by NaHCO3 (351 mg, 4.18 mmol) and the reaction mixture is stirred at room temperature overnight. Additional methyl 5-bromovalerate (100 μL) is added and the reaction mixture is stirred at room temperature for 3 days. The reaction mixture is diluted with ethyl acetate and washed with 1N HCl, water, saturated NaHCO3, and brine. The organic layer is dried over MgSO4. Filtration followed by concentration in vacuo and recrystallization from ethyl acetate:hexane gives methyl 3-[[2-(aminocarbonyl)-5-methoxybenzo[b]thien-3-yl]thio]pentanoate in 30% yield; mp=134.5°-135.5° C.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:13]3[S:14][CH:15]=[CH:16][N:17]=3)[CH:10]=2)[N:5]=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:30]>ClCCl>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:13]3[S:14][CH:15]=[CH:16][N:17]=3)[CH:10]=2)[N+:5]([O-:30])=[CH:4][CH:3]=1
Reactant: Clc1ccc(C(c2ccc3nccc(Br)c3c2)c2nccs2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: [O-][n+]1ccc(Br)c2cc(C(c3ccc(Cl)cc3)c3nccs3)ccc21
Reaction time: 3 h

Procedure:
A solution of 2-((4-bromoquinolin-6-yl)(4-chlorophenyl)methyl)thiazole (900 mg, 2.165 mmol, 1 equip) and meta-chloroperoxybenzoic acid (578 mg, 3.247 mmol, 1.5 equip) in dichloromethane (30 mL) was stirred at room temperature for 1 h, at which point additional meta-chloroperoxybenzoic acid (578 mg, 3.247 mmol, 1.5 equip) was added and the solution stirred for an additional 3 h. The reaction mixture was washed with 10% Na2CO3 and the aqueous layer extracted with dichloromethane (2×). The combined organic extracts were washed with water, dried over Na2SO4, and concentrated to yield 4-bromo-6-((4-chlorophenyl)(thiazol-2-yl)methyl)quinoline 1-oxide as a pale yellow semi-solid.
Reaction SMILES: S(=O)(=O)(O)O.[C:6]([OH:13])(=[O:12])/[CH:7]=[CH:8]/[CH:9]=[CH:10]/[CH3:11].[OH-].[K+:15]>[Fe].O>[C:6]([O-:13])(=[O:12])/[CH:7]=[CH:8]/[CH:9]=[CH:10]/[CH3:11].[C:6]([O-:13])(=[O:12])/[CH:7]=[CH:8]/[CH:9]=[CH:10]/[CH3:11].[K+:15].[K+:15]
Reactant: C/C=C/C=C/C(=O)O
Agent: [Fe]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: C/C=C/C=C/C(=O)[O-]
Temperature: 25 °C

Procedure:
25 l of active coal (based on pit coal, granulation: 2-4 mm) which had been freed from iron by sulfuric acid (at 1%) and subsequently neutralized by washing with water, were charged into a tube having a length of 10 m and being equipped with a heating jacket (nominal size: 50 mm) in such a way, that no gas bubbles are formed while charging. At a temperature of from 75°-85° C. a solution prepared at 80° C. of 56 parts by weight of sorbic acid (at 89%), 15.8 parts by weight of potassium hydroxide (scales, at 90%) and of 35.2 parts by weight of water is pumped through this column under a nitrogen atmosphere from the bottom to the top at an hourly rate of 2.5 kg. The purified solution is filtered while still hot and cooled to room temperature within the next 4 hours. The crystallization product is removed by centrifugation and dried in vacuo at 50° C. 1.08 kg of potassium disorbate are obtained per hour, which contains from 0.6-0.7 weight % of potassium sorbate more than the stoichiometric quantity would stand for. The yield is from 98-99%, calculated on the sorbic acid (at 100%). The mother liquor is re-used after dissolution of 22.4 parts by weight of crude sorbic acid and of 5.8 parts by weight of potassium hydroxide in 100 parts by weight of mother liquor.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][C:6]1[S:10][N:9]=[C:8]([N:11]([CH3:13])[CH3:12])[C:7]=1[C:14]#[N:15])=[O:4].S(=O)(=O)(O)[OH:17]>>[CH3:1][NH:2][C:3]([NH:5][C:6]1[S:10][N:9]=[C:8]([N:11]([CH3:12])[CH3:13])[C:7]=1[C:14](=[O:17])[NH2:15])=[O:4]
Reactant: O=S(=O)(O)O
Reactant: CNC(=O)Nc1snc(N(C)C)c1C#N
Product: CNC(=O)Nc1snc(N(C)C)c1C(N)=O
Temperature: 0 °C

Procedure:
A mixture of 11.2 g of 1-methyl-3-(4-cyano-3-(dimethylamino)-5-isothiazolyl)urea and 20 ml of concentrated sulfuric acid was heated at 85°-90° for 11/2 hours. The reaction mixture was poured into 300 ml of ice-water and the solid precipitate was collected by filtration. The solid was washed with water and a small amount of cold ethanol. The nmr spectrum of this solid (m.p. 243°, decomposes) indicated it to be the bisulfate salt of 1-methyl-3-(4-carbamoyl-3-(dimethylamino)-5-isothiazolyl)urea. The water-sulfuric acid filtrate was concentrated under reduced pressure, the concentrate was cooled and a solid precipitate was collected by filtration. This solid was combined with the bisulfate salt described above and was stirred with a saturated solution of sodium bicarbonate. A new solid was collected by filtration and purified by recrystallization from ethanol to give 9.2 g of 1-methyl-3-(4-carbamoyl-3-(dimethylamino)-5-isothiazolyl)urea; m.p. 221°. The nmr spectrum was consistent with the assigned structure.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH:8]=[O:9].[N+:10]([C:13]1[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][C:14]=1[CH2:24]Br)([O-:12])=[O:11]>O1CCCC1>[N+:10]([C:13]1[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][C:14]=1[CH2:24][N:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH:8]=[O:9])([O-:12])=[O:11]
Reactant: CCOC(=O)c1ccc([N+](=O)[O-])c(CBr)c1
Reactant: O=Cc1ccc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc([N+](=O)[O-])c(Cn2cccc2C=O)c1
Temperature: 20 °C
Reaction time: 8 h
Yield: 83.9 %

Procedure:
To a stirred slurry of 2.2 g of sodium hydride (60% in oil, washed with hexane) in tetrahydrofuran is added at 0° C. a solution of 4.5 g of pyrrole-2-carboxaldehyde in 25 ml of tetrahydrofuran. After the addition is complete, a solution of 15 g of ethyl 4-nitro-3-bromomethylbenzoate in 30 ml of dry tetrahydrofuran is slowly added under nitrogen. The reaction mixture is stirred at 20° C. for 8 hours and carefully quenched with water. The reaction mixture is extracted with chloroform which is washed with water, dried with Na2SO4 and concentrated in vacuo to give 12 g of the desired product as a solid; mass spectrum (M+ H)349.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[CH:2]1.Br[C:11]1[CH:12]=[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O.[Cu]>[C:13]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:14]=[CH:15][CH:16]=[C:11]([N:3]2[C:4]3=[N:5][CH:6]=[CH:7][CH:8]=[C:9]3[N:1]=[CH:2]2)[CH:12]=1
Reactant: c1cnc2nc[nH]c2c1
Reactant: Brc1cccc(-c2ccccc2)c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: c1ccc(-c2cccc(-n3cnc4cccnc43)c2)cc1

Procedure:
A mixture of imidazo[4,5-b]pyridine (595 mg, 5 mmol), 3-bromobiphenyl (1.16 g, 5 mmol), potassium carbonate (1.03 g, 7.5 mmol), and copper powder (2.0 g) in N-methylpyrrolidone (10 ml) was heated to 200° under nitrogen for 4 h. After dilution with ethyl acetate the mixture was filtered through celite. Water was added and the phases were separated. After two more extractions with ethyl acetate the combined organic phases were dried and evaporated to give a light brown oil. Column chromatography on silica gel gave the two products as separate fractions with 1-(3biphenylyl)imidazo[4,5-b]pyridine being the more polar one. This product was precipitated as the oxalate. Yield: 100 mg, 0.3 mmol, 5%. mp 174°-176° C. Yield of 3(3-biphenylyl)imidazo[5,4-b]pyridine: 270 mg, 1 mmol, 20%. mp 89°-91° C.
Reaction SMILES: C([O:5][C:6](=[O:38])[CH2:7][N:8]([C:14](=[O:37])[CH:15]([CH3:36])[CH2:16][S:17][C:18](=[O:35])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:32])[C:28](=[CH2:31])[CH2:29][CH3:30])=[C:23]([Cl:33])[C:22]=1[Cl:34])[CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:34][C:22]1[C:23]([Cl:33])=[C:24]([C:27](=[O:32])[C:28](=[CH2:31])[CH2:29][CH3:30])[CH:25]=[CH:26][C:21]=1[O:20][CH2:19][C:18]([S:17][CH2:16][CH:15]([CH3:36])[C:14]([N:8]([CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13]1)[CH2:7][C:6]([OH:38])=[O:5])=[O:37])=[O:35]
Reactant: C=C(CC)C(=O)c1ccc(OCC(=O)SCC(C)C(=O)N(CC(=O)OC(C)(C)C)C2CCCC2)c(Cl)c1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=C(CC)C(=O)c1ccc(OCC(=O)SCC(C)C(=O)N(CC(=O)O)C2CCCC2)c(Cl)c1Cl
Yield: 52 %

Procedure:
To a solution containing 5.2 g (8.7 mmol) of N-[3-[2,3-dichloro-4-(2-methylene-1-oxobutyl)phenoxy]acetylthio-2-methylpropanoyl]-N-cyclopentyl glycine t-butyl ester in 100 ml of methylene chloride was added 9.0 ml (117 mmol) of trifluoroacetic acid. After 12 hours the reaction mixture was carefully concentrated in vacuo and the residue was chromatographed via HPLC [methylene chloride/ether/acetic acid (88/10/2.5)]to afford 2.4 g (52%) of N-[3-[2,3-dichloro-4-(2-methylene-1-oxobutyl) phenoxy] acetylthio-2methylpropanoyl]-N-cyclopentyl glycine as a glass.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[N:8]=[C:7]([NH2:9])[CH:6]=[CH:5][CH:4]=1.[H-].[Na+].Br[C:15]1[C:16]2[N:17]([CH:22]=[CH:23][N:24]=2)[N:18]=[C:19]([Cl:21])[CH:20]=1.O>CN(C=O)C>[Cl:21][C:19]1[CH:20]=[C:15]([NH:9][C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([C:2]([F:1])([F:10])[F:11])[N:8]=2)[C:16]2[N:17]([CH:22]=[CH:23][N:24]=2)[N:18]=1
Reactant: Clc1cc(Br)c2nccn2n1
Reactant: Nc1cccc(C(F)(F)F)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)c1cccc(Nc2cc(Cl)nn3ccnc23)n1
Reaction time: 0.5 h
Yield: 99.1 %

Procedure:
A solution of 6-(trifluoromethyl)pyridin-2-amine (0.668 g, 4.12 mmol) in DMF (5 mL) was added NaH (0.10 g, 4.18 mmol) and stirred for 0.5 h. To the mixture was added 8-bromo-6-chloroimidazo[1,2-b]pyridazine (0.38 g, 1.65 mmol) under N2. The mixture was stirred at room temperature for 16 h then 100 mL of water was added and the precipitate collected by filtration and washed with water to give 6-chloro-N-(6-(trifluoromethyl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (0.513 g, 99%) as a light brown solid. LC-MS: [M+H]+, 314.1, tR=1.738 min.
Reaction SMILES: [Mg].BrCCBr.[CH2:6]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1Br)[CH2:7][CH3:8].C[O:19][B:20]([O:23]C)[O:21]C.Cl>C1COCC1>[CH2:6]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][B:20]([OH:23])[OH:21])[CH2:7][CH3:8]
Reactant: COB(OC)OC
Reactant: CCCOCc1ccccc1Br
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: CCCOCc1ccccc1OB(O)O
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a mixture of magnesium (0.83 g) and THF (30 ml) was added 1,2-dibromoethane (0.1 ml) at room temperature and subsequently was added dropwise a solution of 2-bromobenzyl propyl ether (7.88 g) in THF (40 ml) at 60° C. over a period of 30 minutes, under an argon atmosphere. After the dropwise addition, the resulting mixture was stirred further at 60° C. for 2 hours and was then cooled to −78° C., and a solution of trimethylboric acid (12 ml) in THF (24 ml) was added dropwise. The resulting mixture was stirred at 78° C. for one hour and then at room temperature for 10 hours. To the reaction mixture was added 1 N hydrochloric acid (100 ml), and the resulting mixture was stirred for 30 minutes and was then extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. After concentration under reduced pressure, the precipitated crystals were collected by filtration. The crystals were washed with hexane to obtain 2-propoxymethylphenylboric acid (2.95 g) as colorless crystals.
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.Cl[C:25]1[N:30]=[CH:29][C:28]([Br:31])=[CH:27][N:26]=1>O>[N:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:25]3[N:30]=[CH:29][C:28]([Br:31])=[CH:27][N:26]=3)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: Clc1ncc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1cnc(N2CCC(N3CCCCC3)CC2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.8 %

Procedure:
4-(Piperidin-1-yl)piperidine (342 mg, 2.03 mmols) and cesium carbonate (764 mg, 2.34 mmols) were added to DMF solution (10 ml) of 2-chloro-5-bromopyrimidine (300 mg, 1.56 mmols), and stirred at room temperature for 16 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried with anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified through silica gel column chromatography (C-300, chloroform/methanol=100/3) to obtain the entitled compound (349 mg, 69%).
Reaction SMILES: O[CH:2]([C:15]1[CH:19]=[CH:18][O:17][C:16]=1[Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C1(P([N:41]=[N+:42]=[N-:43])(C2C=CC=CC=2)=O)C=CC=CC=1>>[N:41]([CH:2]([C:15]1[CH:19]=[CH:18][O:17][C:16]=1[Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[N+:42]=[N-:43]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCCCCCCCCCCCC(O)c1ccoc1[Si](CC)(CC)CC
Product: CCCCCCCCCCCCC(N=[N+]=[N-])c1ccoc1[Si](CC)(CC)CC

Procedure:
Reacting 3-(1-hydroxytridecyl)-2-triethylsilylfuran (Compound 20) with diphenylphosphoryl azide and diethyl azidocarboxylate gives 3-(1-azidotridecyl)-2-triethylsilylfuran (Compound 24). Reducing this intermediate with lithium aluminum hydride, followed by acetylation with acetic anhydide gives 3-(1-acetamido tridecyl)-2-triethylsilylfuran (Compound 25). Singlet oxygen oxidation of this amide, under conditions as in Example 1, followed by reduction with sodium borohydride gives 3-(1-acetamidotridecyl)-2(5H)-furanone (Compound 10).
Reaction SMILES: F[B-](F)(F)F.[CH2:6]([N:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[NH:18])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:19][S:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1>>[CH2:6]([N:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[N:18][C:28]([NH:27][C:24]1[CH:25]=[CH:26][C:21]([S:20][CH3:19])=[CH:22][CH:23]=1)=[O:29])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CSc1ccc(N=C=O)cc1
Reactant: N=C1CCCN1Cc1ccccc1
Agent: F[B-](F)(F)F
Product: CSc1ccc(NC(=O)N=C2CCCN2Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The fluoroborate salt of 1-benzyl-2-iminopyrrolidine (6.55 g.; 0.025 mole) is converted to the free base (4.36 g.; 0.025 mole) in the usual manner. After drying over K2CO3, the benzene solution is filtered through diatomaceous earth and 4.13 g. (0.025 mole) of 4-methylthiophenylisocyanate is added. The reaction mixture is stirred at room temperature for 1 hour and then evaporated to dryness in vacuo to give an oil which crystallizes. Recrystallizations from acetone-ether yields the pure product, 1-(1-benzyl-2-pyrrolidylidene)-3-(4 -methylthiophenyl)urea, m.p. = 113°-115° C.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH:11]3[CH2:16][CH2:15][C:14]([C:18]4[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][CH3:28])=[C:20]([F:29])[C:19]=4[F:30])(O)[CH2:13][CH2:12]3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:25]([O:24][C:21]1[CH:22]=[CH:23][C:18]([CH:14]2[CH2:15][CH2:16][C:11]([CH:8]3[CH2:9][CH2:10][C:5]4([O:1][CH2:2][CH2:3][O:4]4)[CH2:6][CH2:7]3)=[CH:12][CH2:13]2)=[C:19]([F:30])[C:20]=1[F:29])[CH2:26][CH2:27][CH3:28]
Reactant: CCCCOc1ccc(C2(O)CCC(C3CCC4(CC3)OCCO4)CC2)c(F)c1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCCOc1ccc(C2CC=C(C3CCC4(CC3)OCCO4)CC2)c(F)c1F
Temperature: 30 °C
Yield: 35.4 %

Procedure:
The compound (22) (22.7 g), p-toluenesulfonic acid (0.68 g) and toluene (200 ml) were mixed and the mixture was heated to reflux for 2 hours, while distilled water was removed. After the reaction mixture had been cooled to 30° C., water (200 ml) and toluene (200 ml) were added to the mixture and mixed with it. The mixture was then allowed to stand until it had separated into two phases of organic and aqueous phases, and the extraction into an organic phase was carried out. The resulting organic phase was separated, and washed successively a saturated aqueous solution of sodium hydrogencarbonate and water, and dried over anhydrous magnesium sulfate. The resulting solution was purified with a fractional operation by means of column chromatography using silica gel as a stationary phase powder and toluene as an eluent, and dried. Palladium on carbon (3.0 g) was added and then the mixture was stirred at room temperature under an atmosphere of hydrogen until hydrogen absorption had ceased. After the completion of the reaction, palladium on carbon was removed and the solvent was distilled off. The resulting residue was purified by recrystallization from a mixed solvent of THF and heptane (THF:heptane=1:9 by volume) to give 8-[4-(4-butoxy-2,3-difluorophenyl)-cyclohexenyl]-1,4-dioxaspiro[4.5]decane (23) (7.7 g). The yield based on the compound (7) was 35.2%.