Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:9][CH2:10][C:11]1[S:12][CH:13]=[C:14](/[CH:16]=[CH:17]/[C:18]2[C:19]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH2:38][C:39]4[N:40]=[C:41]([C:45]5[CH:50]=[CH:49][C:48]([CH2:51][C:52]([O:54]CC)=[O:53])=[CH:47][CH:46]=5)[O:42][C:43]=4[CH3:44])=[C:33]([O:57][CH3:58])[CH:32]=3)=[N:20][N:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:22]=2)[N:15]=1)(=O)C1C=CC=CC=1.O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[OH:9][CH2:10][C:11]1[S:12][CH:13]=[C:14](/[CH:16]=[CH:17]/[C:18]2[C:19]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH2:38][C:39]4[N:40]=[C:41]([C:45]5[CH:46]=[CH:47][C:48]([CH2:51][C:52]([OH:54])=[O:53])=[CH:49][CH:50]=5)[O:42][C:43]=4[CH3:44])=[C:33]([O:57][CH3:58])[CH:32]=3)=[N:20][N:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:22]=2)[N:15]=1
Reactant: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C/c4csc(COC(=O)c5ccccc5)n4)cc3OC)c(C)o2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: COc1cc(COc2nn(-c3ccccc3)cc2/C=C/c2csc(CO)n2)ccc1OCc1nc(-c2ccc(CC(=O)O)cc2)oc1C
Temperature: 50 °C
Reaction time: 20 h
Yield: 95.9 %

Procedure:
To a mixture of {4-[(E)-2-(3-{[4-({2-[4-(2-ethoxy-2-oxoethyl)phenyl]-5-methyl-1,3-oxazol-4-yl}methoxy)-3-methoxybenzyl]oxy}-1-phenyl-1H-pyrazol-4-yl)ethenyl]-1,3-thiazol-2-yl}methyl benzoate (0.5 g), tetrahydrofuran (6 mL) and ethanol (3 mL) was added 1N aqueous sodium hydroxide solution (3 mL), and the mixture was stirred at 50° C. for 20 hrs. To the reaction mixture were added 1N hydrochloric acid (3 mL) and water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give (4-{4-[(4-{[(4-{(E)-2-[2-(hydroxymethyl)-1,3-thiazol-4-yl]ethenyl}-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl)acetic acid as crystals (0.4 g, yield 90%). Recrystallization twice from tetrahydrofuran-hexane gave colorless prism crystals. melting point: 204-205° C.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl.Cl[CH2:9][CH2:10][N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([Cl:24])[CH:18]=1>CN(C=O)C.CCOC(C)=O>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:19]([Cl:24])[CH:18]=1
Reactant: ClCCN1CCCC1
Reactant: Oc1ccc(Br)cc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Clc1cc(Br)ccc1OCCN1CCCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
415 mg (3.00 mmol) K2CO3 and 170 mg (1.00 mmol) N-(2-chloroethyl)-pyrrolidine-hydrochloride is added to a solution of 207 mg (1.00 mmol) 4-bromo-2-chloro-phenol in 5 mL DMF and the mixture is stirred for 24 h at RT. The reaction mixture is diluted with 50 mL EtOAc, extracted once with 30 mL water and twice with 30 mL semisaturated NaHCO3 solution. The organic phase is dried over MgSO4 and the solvent is eliminated i.vac. Further purification is carried out by column chromatography on silica gel (gradient: DCM to DCM/MeOH 9:1).
Reaction SMILES: [Br:1][C:2]1[C:12]2[CH2:11][CH2:10][NH:9][CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]2[N:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[O:15][C:3]=12.[Cl:20][CH2:21][CH2:22][CH2:23][CH2:24][S:25][C:26]1[N:27]([CH3:42])[C:28]([C:31]2[CH:40]=[CH:39][CH:38]=[C:37]3[C:32]=2[CH:33]=[CH:34][C:35]([CH3:41])=[N:36]3)=[N:29][N:30]=1>>[ClH:20].[Br:1][C:2]1[C:12]2[CH2:11][CH2:10][N:9]([CH2:21][CH2:22][CH2:23][CH2:24][S:25][C:26]3[N:27]([CH3:42])[C:28]([C:31]4[CH:40]=[CH:39][CH:38]=[C:37]5[C:32]=4[CH:33]=[CH:34][C:35]([CH3:41])=[N:36]5)=[N:29][N:30]=3)[CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]2[N:13]=[C:14]([C:16]([F:19])([F:17])[F:18])[O:15][C:3]=12
Reactant: FC(F)(F)c1nc2cc3c(c(Br)c2o1)CCNCC3
Reactant: Cc1ccc2c(-c3nnc(SCCCCCl)n3C)cccc2n1
Product: Cc1ccc2c(-c3nnc(SCCCCN4CCc5cc6nc(C(F)(F)F)oc6c(Br)c5CC4)n3C)cccc2n1
Product: Cl

Procedure:
The title compound was prepared in analogy to General Procedure 1 from 10-Bromo-2-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-[1,3]oxazolo[4,5-h][3]benzazepine (120 mg) and 5-{5-[(4-chlorobutyl)thio]-4-methyl-4H-1,2,4-triazol-3-yl}-2-methylquinoline (177 mg) and was obtained as a colourless slightly hygroscopic solid (66 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][C:7]([C:9]1[O:10][C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[CH:13]=1)=O)=[O:5])[CH3:2].[BH4-].[Na+].C(O)(=O)C>C(O)C.O.[Pd]>[O:10]1[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[CH:13]=[C:9]1[CH2:7][CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCOC(=O)CC(=O)c1cc2ccccc2o1
Agent: [Pd]
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)CCc1cc2ccccc2o1
Reaction time: 2 h

Procedure:
232 g of compound 3 are dissolved in 500 ml of ethanol. Cool in ice-bath and add 100 g of sodium borohydride in 500 ml of water. Stir for 2 hours. Add acetic acid until the sodium borohydride has been neutralized. Cool the solution in ice-bath under an atmosphere of nitrogen and add 10 g of 10% Pd/C catalyst. Stir under a hydrogen atmosphere at 15PSI until the reaction is complete, as judged by TLC. Filter through celite and evaporate organic solvents. Extract with ethyl acetate. Dry over sodium sulfate. Filter. Evaporate solvent.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([O:9][CH3:10])[CH:3]=1.C(N(CC)CC)C.[C:18](Cl)(=[O:20])[CH3:19]>ClCCl>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:18](=[O:20])[CH3:19])=[C:4]([O:9][CH3:10])[CH:3]=1
Reactant: COc1cc(F)ccc1N
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(F)ccc1NC(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-fluoro-2-(methyloxy)aniline (Heterocycles 1992, 34, 2301-2311) (5.6 g, 40 mmol) and triethylamine (6.9 ml, 50 mmol) in dichloromethane (200 ml) at 0° C. was treated with acetyl chloride (2.85 ml, 40 mmol). After stirring at room temperature for 1 hour the solution was washed with 2N hydrochloric acid. The organic phase was separated, washed with water and brine then dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica gel (1:5 to 1:2 ethyl acetate in dichloromethane) to afford the title compound. MS (ES+) m/e 184 [M+H]+.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:8])[CH2:4][C:5](Cl)=[O:6].[CH3:9][OH:10].S(Cl)(Cl)=O.S(OC)(O[CH3:18])=O>C(Cl)Cl>[CH3:9][O:10][C:5](=[O:6])/[CH:4]=[C:3](/[O:8][CH3:18])\[CH2:2][Cl:1]
Reactant: COS(=O)OC
Reactant: O=C(Cl)CC(=O)CCl
Reactant: CO
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COC(=O)/C=C(\CCl)OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
206.6 g (0.47 mol) of a 35 percent mixture of 4-chloroacetoacetyl chloride in methylene chloride was cooled to -10° C. Under nitrogen, 102.4 g (3.2 mol) of methanol was added in 30 minutes and then 83.3 g (0.7 mol) of thionyl chloride was added in 30 minutes (formation of dimethyl sulfite). The temperature was raised to room temperature and the solution was stirred for 3 hours at 20° to 25° C. The excess methanol and methylene chloride were then distilled off at reduced pressure. The residue (raw 4-chloro-3,3-dimethoxybutanoic acid methyl ester) was mixed with 0.21 g of methanesulfonic acid and warmed to 125° to 130° C. at a pressure of 100 mbars. Thus, the formed methanol and the excess dimethyl sulfite was distilled off. The residue (raw 4-chloro-3-methoxy-but-2E-enoic acid methyl ester) was taken up in 110.2 g (120 ml) of toluene and the organic phase was washed with 69.8 g of aqueous 16 percent HCl for 30 minutes, with 32.1 g of an aqueous 10 percent sodium chloride solution for 10 minutes, with 134 g of aqueous 10 percent NaOH for 75 minutes and finally with 32.1 g of an aqueous 10 percent sodium chloride solution for 10 minutes. The toluene was then evaporated off and the residue was distilled at a pressure of 20 mbars and a temperature of 95° to 97° C. 4-chloro-3-methoxybut-2E-enoic acid methyl ester was obtained in a yield of 61.7 g (80 percent) in a purity of 99.5 percent (GC).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][CH:6]=[CH:5]1.S(=O)(=O)(O)O.N1C=CC=C1.[C:19](Cl)(=[O:21])[CH3:20].C(OC(=O)C)(=O)C>C(O)(=O)C>[C:19]([O:1][CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][CH:6]=[CH:5]1)(=[O:21])[CH3:20]
Reactant: OCCn1cccc1
Reactant: CC(=O)Cl
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Solvent: c1cc[nH]c1
Solvent: CC(=O)O
Product: CC(=O)OCCn1cccc1

Procedure:
Once the 1-(2-hydroxyethyl)pyrrole is obtained, it is esterified by any suitable means known in the art. For example, acetic acid is reacted with the 1-(2-hydroxyethyl)pyrrole in the presence of a strong acid such as sulfuric acid, and the reaction mixture is heated sufficiently to distill off the water that is formed as a result of the reaction. Preferably however, the pyrrole is reacted with acetyl chloride or acetic anhydride in a suitable solvent wherein there is a molar excess of the acetyl chloride or acetic anhydride. This reaction takes place at room temperature and will be completed in a relatively short period of time, with only an hour or two at the most being required for the reaction to reach completion. The 1-(2-acetoxyethyl)pyrrole is then isolated and purified by any means known in the art, such as extraction with a suitable organic solvent and removal of the solvent, to yield the desired compound represented by Formula (3).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6](F)[C:3]=1[C:4]#[N:5].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].C(=O)(O)O.[NH2:29][C:30]([NH2:32])=[NH:31]>CN(C)C(=O)C.CN(C)C=O>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:2]2[CH:9]=[CH:8][CH:7]=[C:6]3[C:3]=2[C:4]([NH2:5])=[N:31][C:30]([NH2:32])=[N:29]3)=[CH:14][CH:13]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: N#Cc1c(F)cccc1F
Reactant: N=C(N)N
Agent: O=C(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Product: Nc1nc(N)c2c(Oc3ccc(Cl)cc3)cccc2n1
Temperature: 50 °C
Reaction time: 10 h
Yield: 66.5 %

Procedure:
10.0 g (71.89 mmol) of 2,6-difluorobenzonitrile, 10.17 g (79.08 mmol) of 4-chlorophenol and 19.87 g (143.78 mmol) of potassium carbonate were added into 300 ml of N,N-dimethylformamide, and stirred at 50° C. for 10 h to complete the reaction. The reaction mixture was evaporated to dryness, diluted with 200 ml water and extracted with 400 ml ethyl acetate. The organic layer was dried with anhydrous sodium sulfate and evaporated to dryness. The residue was passed through column chromatography to provide an intermediate. The intermediate and 17.41 g (143.78 mmol) of guanidine carbonate were heated to 140° C. in 300 ml of N,N-dimethylacetamide and reacted for 8 h to complete the reaction. The reaction mixture was evaporated to dryness, diluted with 200 ml of water and extracted with 400 ml of dichloromethane. The organic layer was dried with anhydrous sodium sulfate and evaporated to dryness. The residue was passed through column chromatography to provide 13.7 g of compound Yhhu-0968 with a total yield of 67% in the two steps).
Reaction SMILES: FC(F)(F)[O:3][C:4]1C=CC(N2C=NC(C3C=CC(C(CC)CC(N=[N+]=[N-])=O)=CC=3)=N2)=C[CH:5]=1.[N:32]([CH2:35][CH:36]([C:39]1[CH:44]=[CH:43][C:42]([C:45]2[N:49]=[CH:48][N:47]([C:50]3[CH:55]=[CH:54][C:53]([O:56][C:57]([F:60])([F:59])[F:58])=[CH:52][CH:51]=3)[N:46]=2)=[CH:41][CH:40]=1)[CH2:37][CH3:38])=[C:33]=[O:34].[CH:61]([C:64]1[CH:69]=[CH:68][C:67]([O:70][CH3:71])=[CH:66][C:65]=1[NH:72][C:73]([NH2:75])=[S:74])([CH3:63])[CH3:62]>>[CH:61]([C:64]1[CH:69]=[CH:68][C:67]([O:70][CH3:71])=[CH:66][C:65]=1[N:72]1[C:4](=[O:3])[CH2:5][S:74]/[C:73]/1=[N:75]\[C:33]([NH:32][CH2:35][CH:36]([C:39]1[CH:40]=[CH:41][C:42]([C:45]2[N:49]=[CH:48][N:47]([C:50]3[CH:51]=[CH:52][C:53]([O:56][C:57]([F:59])([F:58])[F:60])=[CH:54][CH:55]=3)[N:46]=2)=[CH:43][CH:44]=1)[CH2:37][CH3:38])=[O:34])([CH3:63])[CH3:62]
Reactant: CCC(CC(=O)N=[N+]=[N-])c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: COc1ccc(C(C)C)c(NC(N)=S)c1
Reactant: CCC(CN=C=O)c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Product: CCC(CNC(=O)/N=C1\SCC(=O)N1c1cc(OC)ccc1C(C)C)c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1

Procedure:
The title compound was prepared from 3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)pentanoyl azide/3-(4-(1-isocyanatobutan-2-yl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (C42a) and 1-(2-isopropyl-5-methoxyphenyl)thiourea (CA40) and isolated as a brown foam (0.091 g, 47%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:11]([CH3:21])([CH3:20])[O:10][C:9]2=[O:22])[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.Cl[C:33]1[CH:38]=[CH:37][N:36]=[CH:35][C:34]=1[N+:39]([O-:41])=[O:40]>C(#N)C>[F:19][C:16]1[CH:15]=[CH:14][C:13]([C@H:12]2[C:11]([CH3:20])([CH3:21])[O:10][C:9](=[O:22])[N:8]2[CH:5]2[CH2:4][CH2:3][CH:2]([NH:1][C:33]3[CH:38]=[CH:37][N:36]=[CH:35][C:34]=3[N+:39]([O-:41])=[O:40])[CH2:7][CH2:6]2)=[CH:18][CH:17]=1
Reactant: CC1(C)OC(=O)N(C2CCC(N)CC2)[C@H]1c1ccc(F)cc1
Reactant: O=[N+]([O-])c1cnccc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC1(C)OC(=O)N(C2CCC(Nc3ccncc3[N+](=O)[O-])CC2)[C@H]1c1ccc(F)cc1
Temperature: 80 °C

Procedure:
To a vial charged with (S)-3-(4-aminocyclohexyl)-4-(4-fluorophenyl)-5,5-dimethyloxazolidin-2-one (0.320 g, 1.044 mmol) were added ACN (3.48 mL), DIEA (0.365 mL, 2.089 mmol) and 4-chloro-3-nitropyridine (commercially available from Sigma-Aldrich, Milwaukee, Wis.) (0.166 g, 1.044 mmol) respectively. The vial was sealed and heated at 80° C. for 2 hours leading to ˜90% conversion to the desired product with starting amine present. Additional chloropyridine (0.2 eq) and DIEA (0.2 eq) were added, and the mixture was heated at 80° C. for an additional 15 hours. The dark mixture was dried under reduced pressure and purified with a 25 g HP spherical silica column ramping DCM:MeOH (90:10) in DCM from 0-50%, then isocratic at 50% (detection at 215 nm) leading to isolation of (S)-4-(4-fluorophenyl)-5,5-dimethyl-3-(4-((3-nitropyridin-4-yl)amino)cyclohexyl)oxazolidin-2-one (0.286 g, 0.668 mmol, 63.9% yield) as an orange/brown oil and as a mixture of cis/trans isomers. m/z (ESI) 429.0 (M+H)+.
Reaction SMILES: CO/N=C(/C1OCCON=1)\C1C=CC=CC=1O.[C:18]([O:27][CH3:28])(=[O:26])[C:19]1[C:20](=[CH:22][CH:23]=[CH:24][CH:25]=1)[OH:21].Cl[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].C(=O)([O-])[O-].[K+].[K+]>>[CH2:34]([O:33][C:31](=[O:32])[CH2:30][O:21][C:20]1[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=1[C:18]([O:27][CH3:28])=[O:26])[CH3:35]
Reactant: COC(=O)c1ccccc1O
Reactant: CCOC(=O)CCl
Agent: CO/N=C(/C1=NOCCO1)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)COc1ccccc1C(=O)OC

Procedure:
Another synthesis of (E)-(5,6-dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanone O-methyl oxime (13) is illustrated in Scheme 2B. According to the synthesis, methyl salicylate reacts with ethyl chloroacetate in the presence of potassium carbonate to give methyl 2-(2-ethoxy-2-oxoethoxy)benzoate (6). Hydrolysis of methyl 2-(2-ethoxy-2-oxoethoxy)benzoate (6) followed by a consecutive cyclization of 2-(carboxymethoxy)benzoic acid (7) with acetic anhydride in the presence of sodium acetate gives benzofuran-3-yl acetate (8) which is converted to benzofuran-3(2H)-one (9) by methanolysis. Treatment of benzofuran-3(2H)-one (9) with O-methylhydroxylamine and sodium acetate affords benzofuran-3(2H)-one O-methyl oxime (10) which is oxidized with tert-butyl nitrate in hydrochloric acid to yield exclusively or predominantly (3E)-benzofuran-2,3-dione O3-methyl dioxime (11A). In the presence of potassium hydroxide and 2-haloethanol, the (3E)-benzofuran-2,3-dione O3-methyl dioxime (11A) may form (3E)-benzofuran-2,3-dione O2-(2-hydroxyethyl) O3-methyl dioxime (12A), which may undergo potassium hydroxide-catalyzed cyclization to provide (E)-(5,6-dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanone O-methyl oxime (13).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=1[NH2:8].[N+:17]([C:20]1[CH:21]=[C:22]([CH:28]=[CH:29][CH:30]=1)[CH:23]=[CH:24][C:25](O)=O)([O-:19])=[O:18]>>[N+:17]([C:20]1[CH:21]=[C:22]([CH:28]=[CH:29][CH:30]=1)/[CH:23]=[CH:24]/[C:25]1[NH:1][C:2]2[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=2[N:8]=1)([O-:19])=[O:18]
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Reactant: O=C(O)C=Cc1cccc([N+](=O)[O-])c1
Product: CCCn1c(=O)c2[nH]c(/C=C/c3cccc([N+](=O)[O-])c3)nc2n(CCC)c1=O
Yield: 56.9 %

Procedure:
Substantially the same procedure as in Reference Example 1 was repeated using 4.0 g (17.7 mmol) of 5,6-diamino-1,3-dipropyluracil and 3.8 g (19.5 mmol) of 3-nitrocinnamic acid. Then, the resultant crude crystals were recrystallized from toluene to give 3.86 g (yield 57%) of Compound 34 as pale yellow needles.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([CH3:23])([O:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1)[CH3:11])=O)(C)(C)C.C1(OC)C=CC=CC=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:8][CH2:9][C:10]([CH3:23])([O:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1)[CH3:11]
Reactant: COC(=O)c1ccc(OC(C)(C)CNC(=O)OC(C)(C)C)cc1
Solvent: COc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(OC(C)(C)CN)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 116.7 %

Procedure:
A mixture of methyl 4-(1-tert-butoxycarbonylamino-2-methyl-2-propoxy)benzoate (460 mg, 1.42 mmol) and anisole (0.155 mL, 1.42 mmol) in CH2Cl2(15 mL) and TFA (3 mL) was stirred for 3 hr at room temp. The mixture was evaporated off. The residue was dissolved in CH2Cl2 (30 mL) and made basic by the addition of 0.5 N NaOH. The CH2Cl2 layer was separated, dried over Na2SO4, and evaporated. The residue was chromatographed on silica-gel with CH2Cl2 as eluent to give 370 mg (100%) methyl 4-(1-amino-2-methyl-2-propoxy)benzoate as a gum. 1H-NMR (CDCl3) δ 1.34 (s, 6H), 2.87 (s, 2H), 3.90 (s, 3H), 7.10 (d, J=8.8 Hz, 2H), 7.97 (d, J=8.8 Hz, 2H).
Reaction SMILES: Br[C:2]1[C:3]2[S:17][CH:16]=[CH:15][C:4]=2[N:5]=[C:6]([C:8]2[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=2)[N:7]=1.C([Sn](CCCC)(CCCC)[C:23]1[S:27][CH:26]=[N:25][CH:24]=1)CCC>CC(N(C)C)=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>[S:27]1[C:23]([C:2]2[C:3]3[S:17][CH:16]=[CH:15][C:4]=3[N:5]=[C:6]([C:8]3[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=3)[N:7]=2)=[CH:24][N:25]=[CH:26]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncs1
Reactant: Oc1cccc(-c2nc(Br)c3sccc3n2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)N(C)C
Product: Oc1cccc(-c2nc(-c3cncs3)c3sccc3n2)c1
Temperature: 150 °C
Yield: 14.4 %

Procedure:
A suspension of 3-(4-bromo-thieno[3,2-d]pyrimidin-2-yl)-phenol (150 mg, 0.49 mmol), 5-tributylstannanyl-thiazole (275 mg, 0.735 mmol), and Pd(PPh3)4 (28 mg, 0.0245 mmol) in anhydrous DMA (4 ml) was heated in a microwave at 150° C. for 15 mins. The reaction was extracted into ethyl acetate, washing with brine and water before drying the organic layer over MgSO4. The crude material was purified by flash column chromatography using 1:1 ethyl acetate/petrol as the eluent. The resulting solid was triturated with dichloromethane to give the title compound as an off-white solid (22 mg, 14%).
Reaction SMILES: [OH:1][CH:2]([CH2:16][CH3:17])[CH2:3][CH2:4][CH2:5][CH2:6][CH:7]1[CH2:14][CH2:13][CH:12]2[CH:8]1[CH2:9][C:10](=[O:15])[CH2:11]2.[C:18](O)(=[O:20])[CH3:19]>>[C:18]([O:1][CH:2]([CH2:16][CH3:17])[CH2:3][CH2:4][CH2:5][CH2:6][CH:7]1[CH2:14][CH2:13][CH:12]2[CH:8]1[CH2:9][C:10](=[O:15])[CH2:11]2)(=[O:20])[CH3:19]
Reactant: CCC(O)CCCCC1CCC2CC(=O)CC12
Reactant: CC(=O)O
Product: CCC(CCCCC1CCC2CC(=O)CC12)OC(C)=O
Temperature: 70 °C
Reaction time: 4 h

Procedure:
The starting material from Example 3, 2-(5-hydroxyhept-1-yl)bicyclo[3.3.0]octan-7-one {hexahydro-4-(5-hydroxyheptyl)-2(1H)-pentalenone} (2.5 g, 10.5 mmoles) is diluted with glacial acetic acid (10 ml) and stirred in a 70° C. water bath for 4 hours. The reaction is cooled to room temperature and partitioned between ether (50 ml) and water (50 ml). The ether layer is separated and the aqueous phase extracted with ether (2×50 ml). The organic layers are combined, neutralized with a solution of saturated sodium bicarbonate, and dried over anhydrous sodium sulfate. The solvent is removed under vacuum leaving a clear yellow oil. The crude product is chromatographed on silica gel and subsequently kugelrohred under vacuum leaving a clear, colorless oil (2.1 g, 7.4 mmoles).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH2:9].[C:10]([Cu])#[N:11]>CN1C(=O)CCC1>[NH2:9][C:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[C:10]#[N:11]
Reactant: N#C[Cu]
Reactant: Cc1ccc(N)c(Br)c1
Solvent: CN1CCCC1=O
Product: Cc1ccc(N)c(C#N)c1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 59.7 %

Procedure:
Combine 2-bromo-4-methyl-phenylamine (8.00 g, 43.0 mmol), CuCN (4.62 g, 51.6 mmol), and NMP (30.0 ml) and stir at reflux. After 75 minutes, cool to ambient temperature, pour the mixture onto ice chips and stir for 1 hour. Remove the resulting precipitate by vacuum filtration. Dissolve the precipitate in NH4OH and extract with dichloromethane. Combine, wash (brine), dry (sodium sulfate), and reduce the extracts to residue. Purify the residue on silica gel using dichloromethane/hexanes (75:25) to give 3.39 g (60%) of an orange solid: mass spectrum (ion spray): m/z=133.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([F:23])[CH:17]=1.ClC(Cl)(O[C:28](=[O:34])OC(Cl)(Cl)Cl)Cl.Cl.[F:37][CH2:38][CH2:39][CH2:40][CH2:41][NH2:42].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.ClCCl.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:28]([NH:42][CH2:41][CH2:40][CH2:39][CH2:38][F:37])=[O:34])=[C:18]([F:23])[CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NCCCCF
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc(NC(=O)NCCCCF)c(F)c3)c2cc1OC
Yield: 58.3 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (100 mg) was dissolved in toluene (6 ml) and triethylamine (1.0 ml) with heating, and a solution of triphosgene (104 mg) in dichloromethane (1.0 ml) was then added to the solution. The mixture was heated under reflux for 5 min. Next, 4-fluorobutylamine hydrochloride (55 mg) was added to the reaction solution, and the mixture was heated under reflux for additional 2 hr. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, followed by extraction with chloroform. The chloroform layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by chromatography on silica gel by development with chloroform/acetone (2/1) to give 80 mg (yield 55%) of the title compound.