Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:14])[C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[C:6](Cl)[CH:5]=2.[CH:15](=O)[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([C:16]1[O:1][C:2]2[C:3](=[O:14])[C:4]3[C:9]([C:10](=[O:12])[C:11]=2[CH:15]=1)=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[OH:1][C:2]1[C:3](=[O:14])[C:4]2[C:9]([C:10](=[O:12])[C:11]=1[CH:15]=[CH:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: O=CCCc1ccccc1
Reactant: O=C1C=C(O)C(=O)c2cc(Cl)ccc21
Product: O=C1C(O)=C(C=CCc2ccccc2)C(=O)c2ccccc21
Product: O=C1c2ccccc2C(=O)c2oc(Cc3ccccc3)cc21

Procedure:
The intermediate product 2-hydroxy-3-(3-phenyl-1-n-propenyl)-1,4-naphthoquinone 1-2 (R1=H, R4=C6H5) was prepared according to the procedure described in example 3 by using 2-hydroxy-1,4-naphthoquinone 1-1 (R1=H) and hydrocinnamaldehyde as starting material. 2-benzyl-4H,9H-naphtho[2,3-b]furan-4,9-dione 1-3 (R1=H, R4=C6H5) was obtained from 10 gram (0.035 mol) of 1-2 (R1=H, R4=C6H5) by using the procedure described in example 4 to afford yellow crystals; 50% yield. 2-benzyl-4H,9H-naphtho[2,3-b]furan-4,9-dione 1-3 (R1=H, R4=C6H5), 1H NMR (in CDCl3) δ 4.14 (s, 2H), 6.56 (s, 1H), 7.27-7.38 (m, 5H), 7.70-7.77 (m, 2H), 8.14-8.22 (m, 2H);
Reaction SMILES: FC1C=C(F)C=CC=1NC1C=CC(C(C2C=C(N3C=C(CCO)N=N3)C=CC=2C)=O)=C(C)C=1.Br[C:35]1[CH:40]=[CH:39][C:38]([C:41]([C:43]2[CH:48]=[C:47]([N:49]3[CH:53]=[C:52]([CH2:54][CH2:55][OH:56])[N:51]=[N:50]3)[CH:46]=[CH:45][C:44]=2[CH3:57])=[O:42])=[C:37]([CH3:58])[CH:36]=1.[Cl:59][C:60]1[C:61]([CH3:67])=[C:62]([NH2:66])[CH:63]=[CH:64][CH:65]=1>>[Cl:59][C:60]1[C:61]([CH3:67])=[C:62]([NH:66][C:35]2[CH:40]=[CH:39][C:38]([C:41]([C:43]3[CH:48]=[C:47]([N:49]4[CH:53]=[C:52]([CH2:54][CH2:55][OH:56])[N:51]=[N:50]4)[CH:46]=[CH:45][C:44]=3[CH3:57])=[O:42])=[C:37]([CH3:58])[CH:36]=2)[CH:63]=[CH:64][CH:65]=1
Reactant: Cc1cc(Br)ccc1C(=O)c1cc(-n2cc(CCO)nn2)ccc1C
Reactant: Cc1c(N)cccc1Cl
Agent: Cc1cc(Nc2ccc(F)cc2F)ccc1C(=O)c1cc(-n2cc(CCO)nn2)ccc1C
Product: Cc1cc(Nc2cccc(Cl)c2C)ccc1C(=O)c1cc(-n2cc(CCO)nn2)ccc1C

Procedure:
The reaction was carried out similarly as described in the preparation of compound 148, using compound 452 (0.13 mmol) and 3-chloro-2-methyl-phenylamine (0.13 mmol). The crude product was purified by continuous gradient flash chromatography using MeOH/DCM/petroleum ether (40-60) 0:50:50, 0:100:0 and 5:95:0 as the eluent to afford the title compound as yellow solid. 13C NMR (CDCl3) δ 197.0, 148.6, 146.3, 143.5, 142.5, 139.9, 137.0, 135.7, 135.5, 134.6, 132.2, 130.9, 127.5, 127.1, 126.0, 122.4, 121.3, 119.9, 119.9, 117.8, 111.1, 61.6, 28.7, 22.3, 19.5, 15.0
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])[CH:9]=[N:8][CH:7]=[C:6]2[CH2:15][C:16]([OH:18])=[O:17].[CH3:19][NH:20][CH2:21][CH2:22][CH2:23][N:24]1[CH2:33][CH2:32][C:31]2[C:26](=[CH:27][C:28]([O:36][CH3:37])=[C:29]([O:34][CH3:35])[CH:30]=2)[C:25]1=[O:38]>CN(C)C=O>[OH2:2].[CH3:19][N:20]([C:16](=[O:18])[CH2:15][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:9]=[N:8][CH:7]=1)[CH2:21][CH2:22][CH2:23][N:24]1[CH2:33][CH2:32][C:31]2[C:26](=[CH:27][C:28]([O:36][CH3:37])=[C:29]([O:34][CH3:35])[CH:30]=2)[C:25]1=[O:38].[CH3:19][N:20]([CH2:21][CH2:22][CH2:23][N:24]1[CH2:33][CH2:32][C:31]2[C:26](=[CH:27][C:28]([O:36][CH3:37])=[C:29]([O:34][CH3:35])[CH:30]=2)[C:25]1=[O:38])[C:16](=[O:17])[CH2:15][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:9]=[N:8][CH:7]=1
Reactant: CNCCCN1CCc2cc(OC)c(OC)cc2C1=O
Reactant: COc1cc2cncc(CC(=O)O)c2cc1OC
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OC)C(=O)N(CCCN(C)C(=O)Cc1cncc3cc(OC)c(OC)cc13)CC2
Product: O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3.2 g (20 mmol) of N,N'-carbonyl-diimidazole are added to a solution of 4.9 g (17 mmol) of 6,7-dimethoxy-isoquinolin-4-yl-acetic acid in 100 ml of dimethylformamide. After about 30 minutes 4.8 g (17 mmol) of 2-(3-methylamino-propyl)-6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline are added and the mixture is stirred for 2 hours at ambient temperature. The solvent is evaporated off in vacuo and the residue remaining is dissolved in a mixture of 2 molar sodium hydroxide solution and methylene chloride. The organic phase is washed with water, dried over magnesium sulphate and evaporated down in vacuo.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][S:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=3)[N:14]=2)=[CH:9][CH:8]=1.[O:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[C:34]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)=[O:35].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C1COCC1.C(Cl)Cl>[O:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[C:34]([N:36]1[CH2:37][CH2:38][N:39]([C:24]([C:23]2[CH:22]=[CH:21][C:20]([NH:19][C:15]3[N:14]=[C:13]([C:10]4[CH:9]=[CH:8][C:7]([S:6][CH2:5][CH2:4][CH2:3][CH2:2][OH:1])=[CH:12][CH:11]=4)[CH:18]=[CH:17][N:16]=3)=[CH:28][CH:27]=2)=[O:25])[CH2:40][CH2:41]1)=[O:35]
Reactant: O=C(O)c1ccc(Nc2nccc(-c3ccc(SCCCCO)cc3)n2)cc1
Reactant: O=C(c1ccco1)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(c1ccc(Nc2nccc(-c3ccc(SCCCCO)cc3)n2)cc1)N1CCN(C(=O)c2ccco2)CC1
Reaction time: 12 h
Yield: 8.8 %

Procedure:
4-{4-[4-(4-Hydroxybutylsulfanyl)phenyl]pyrimidin-2-ylamino}benzoic acid (0.34 g, 0.86 mmol) was dissolved in THF (5 mL). To this solution was added 1-furoylpiperazine (0.170 g), EDCI (0.180 g), and HOBt (0.127 g). The mixture was stirred 12 h. The mixture was then diluted with CH2Cl2 (20 mL) and washed with 2% NaOH (aq, 30 mL), water (30 mL), and then brine (30 mL). The organic layer was dried (Na2SO4), filtered, and concentrated. The crude solid was subjected to preparatory HPLC (30-80 acetonitrile/water gradient, 20 min). The desired fractions were concentrated to remove most of the acetonitrile, and then the aqueous mixture was extracted with CH2Cl2/2% NaOH (aq). The organic layer was dried (Na2SO4), filtered, and concentrated to afford [4-(Furan-2-carbonyl)-piperazin-1-yl]-(4-{4-[4-(4-hydroxybutylsulfanyl)phenyl]pyrimidin-2-ylamino}phenyl)methanone (0.042 g, 9%): HPLC Retention Time; 10.07 min. (Method B) M+H=558.3.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][O:14][CH2:15][C:16]1[S:49][C:19]2[N:20]([CH2:34][C:35]3[CH:40]=[CH:39][C:38]([C:41]4[C:42]([C:47]#[N:48])=[CH:43][CH:44]=[CH:45][CH:46]=4)=[CH:37][CH:36]=3)[C:21](=[O:33])[N:22]([CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:23](=[O:24])[C:18]=2[CH:17]=1>C(OCC)(=O)C>[CH3:13][O:14][CH2:15][C:16]1[S:49][C:19]2[N:20]([CH2:34][C:35]3[CH:36]=[CH:37][C:38]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=4[C:47]4[NH:3][C:4](=[O:7])[O:5][N:48]=4)=[CH:39][CH:40]=3)[C:21](=[O:33])[N:22]([CH2:25][CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:23](=[O:24])[C:18]=2[CH:17]=1
Reactant: COCc1cc2c(=O)n(CCc3ccccc3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COCc1cc2c(=O)n(CCc3ccccc3)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 66.5 %

Procedure:
A mixture of hydroxylammonium chloride (0.40 g), sodium hydrogencarbonate (0.58 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[6-(methoxymethyl)-2,4-dioxo-3-(2-phenylethyl)-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile (0.35 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.17 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.16 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed successively with saturated aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as pale-yellow crystals (0.26 g, 67%).
Reaction SMILES: [C:1]([C:3]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:4]=1[O:5][CH2:6][CH:7]1[O:9][CH2:8]1)#[N:2].C(C1C(C)=CC=CC=1O)#N.C(C1OC1)[Cl:26].[C:30]([NH2:34])([CH3:33])([CH3:32])[CH3:31]>[OH-].[Na+].CO>[ClH:26].[C:1]([C:3]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:4]=1[O:5][CH2:6][CH:7]([OH:9])[CH2:8][NH:34][C:30]([CH3:33])([CH3:32])[CH3:31])#[N:2]
Reactant: ClCC1CO1
Reactant: CC(C)(C)N
Reactant: Cc1cccc(OCC2CO2)c1C#N
Agent: Cc1cccc(O)c1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cccc(OCC(O)CNC(C)(C)C)c1C#N
Product: Cl

Procedure:
1-(2-cyano-3-methyl-phenoxy)-2,3-epoxy propane, prepared from 17 gm (0.128 mol) of 2-cyano-3-methylphenol and 12.2 gm (0.132 mol) of epichlorohydrin in 125 ml of 1 N NaOH, was dissolved as a dark, impure viscous oil in 200 ml of methanol, and 29 ml of tert.-butylamine were added thereto. After refluxing the mixture for 2 hours, the solvent was distilled off under vacuum, and the brown residue was extracted with dilute HCl. The clear solution was filtered over charcoal and was made alkaline with NaOH. The precipitating base was taken up in ether and the organic phase was separated and was washed repeatedly with water and dried over MgSO4. After concentration up to weight constancy, 4.5 gm of a base remained and this was dissolved in a small amount of ethanol. The hydrochloride salt was precipitated by an addition of ethereal HCl and was isolated as a solid product. It was recrystallized from acetonitrile with an addition of ether followed by a second recrystallization from ethanol with an addition of ether to obtain 1-(2-cyano-3-methyl-phenoxy)-2-hydroxy-3-tert.-butylamino propane hydrochloride having a melting point of 178° - 180°C. Using this same procedure, there was obtained 1-(2-cyanomethyl-3-methyl-phenoxy)-2-hydroxy-3-tert.-butylamino-propane hydrochloride.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:18]=[CH:19][C:20]=1[OH:21])[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].I[CH:29]([CH3:31])[CH3:30]>C(C(C)=O)C>[C:1]([C:5]1[CH:6]=[C:7]([CH:18]=[CH:19][C:20]=1[O:21][CH:29]([CH3:31])[CH3:30])[C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)I
Reactant: CC(C)(C)c1cc(C(=O)OCc2ccccc2)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)Oc1ccc(C(=O)OCc2ccccc2)cc1C(C)(C)C

Procedure:
5.7 g (0.02 mol) of benzyl 3-tert-butyl-4-hydroxybenzoate, 7 g (0.05 mol) of finely ground potassium carbonate, 4 ml (0.04 mol) of 2-iodopropane and 100 ml of methyl ethyl ketone are introduced under nitrogen into a three-necked flask. The mixture is heated to reflux for 24 h, the inorganic matter is filtered off and the filtrate is evaporated. The residue is taken up with ethyl ether and water and the organic phase is separated after settling has taken place, dried over magnesium sulphate and evaporated.
Reaction SMILES: [C:1]([O:11][CH3:12])(=[O:10])[C:2]1[C:3](=[CH:5][CH:6]=[C:7]([CH:9]=1)[OH:8])[OH:4].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>S1(CCCC1)(=O)=O>[CH2:19]([O:8][C:7]1[CH:9]=[C:2]([C:1]([O:11][CH3:12])=[O:10])[C:3]([OH:4])=[CH:5][CH:6]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: ClCc1ccccc1
Reactant: COC(=O)c1cc(O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=S1(=O)CCCC1
Product: COC(=O)c1cc(OCc2ccccc2)ccc1O
Temperature: 100 °C
Yield: 41.5 %

Procedure:
A mixture of methyl gentisate (16.8 g) and anhydrous potassium carbonate (7.0 g) in dry sulpholane (150 ml) was treated, with stirring, with benzyl chloride (12.7 g), and the mixture was stirred and heated at 100° C. for 4 hours. The mixture was then poured into water (800 ml) and the separated solid was filtered off and recrystallized from ethanol (with the aid of charcoal) to give methyl 5-benzyloxysalicylate (10.7 g), m.p. 108°-112° C. This ester (9.2 g) was heated at 150° C. for 3 hours with a mixture of anhydrous potassium carbonate (2.5 g) and benzyl chloride (4.52 g) in dry sulpholane (100 ml) and the mixture was then cooled and poured into a mixture of ice and water (700 ml), and the mixture was extracted with diethyl ether (2 × 300 ml). The ether extracts were combined and evaporated, the residual oil was triturated with water (100 ml), the oil was separated and the aqueous layer was extracted with diethyl ether (25 ml). The combined oil and extracts were washed with brine, dried over magnesium sulphate and evaporated to give crude methyl 2,5-dibenzyloxybenzoate (12.7 g). This ester (12.4 g) was heated at reflux with aqueous sodium hydroxide solution (2N; 400 ml) for 2 hours and allowed to cool. The separated sodium salt was filtered off and ground with hydrochloric acid (6N; 100 ml), the mixture was heated at reflux for 5 minutes and then cooled. The solid which separated was filtered off, washed with water and dried to give 2,5-dibenzyloxybenzoic acid (8.2 g), m.p. 107°-108.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])[CH:3]=1.[C:15](Cl)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[C:16]1([C:15]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:6][C:5]2[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][C:4]=2[C:9](=[O:14])[C:10]([F:12])([F:13])[F:11])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Nc1ccc(Cl)cc1C(=O)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(c1cc(Cl)ccc1NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 14 h
Yield: 77.1 %

Procedure:
4-Chloro-2-trifluoroacetylaniline (22.4 g, 100 mmol), trityl chloride (30.0 g, 107 mmol), triethylamine (11.6 g, 115 mmol) and DMAP (0.5 g, 4 mmol) were dissolved in DMF (50 mL) and held 14 h at 60° C. The resulting slurry was cooled to room temperature, diluted with 20 mL water and filtered to give 35.9 g (77%) of title compound. An analytical sample was obtained by recrystallization from acetonitrile: mp 165-167° C.; 1H NMR (CDCl3) δ 10.4 (brs, 1H), 7.71 (brt, J=2 Hz, 1H), 7.3 (brs, 15 H), 6.9 (dd, J=2, 8 Hz, 1H), 6.27 (d, J=8 Hz, 1H) 13C NMR (75 MHz, CDCl3) δ 180.5, 151.2, 144.1, 135.7, 130.7, 130.6, 129.2, 128.9, 128.7, 128.6, 128.5, 128.2, 128.0, 127.7, 127.5, 122.9, 120.3, 119.3, 119.1, 115.2, 112.3, 111.3, 71.9; 19F NMR (282 MHz, CDCL3) δ -69.5.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[C:15]([O:20][CH2:21][CH3:22])(=[O:19])[C@H:16]([CH3:18])O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.O>[CH2:21]([O:20][C:15](=[O:19])[C@@H:16]([CH3:18])[O:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])[CH3:22]
Reactant: COC(=O)c1ccc(O)c([N+](=O)[O-])c1
Reactant: CCOC(=O)[C@H](C)O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](C)Oc1ccc(C(=O)OC)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of methyl 4-hydroxy-3-nitrobenzoate (5.0 g) and ethyl L-lactate (2.9 ml) in tetrahydrofuran (120 ml) was added triphenylphosphine (10 g), and the mixture was stirred at room temperature for 10 minutes. To the mixture was added under ice-cooling diisopropyl azodicarboxylate (20 ml), and the mixture was stirred at 60° C. for 4 hours. The reaction solution was cooled to room temperature, and water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1) to give the title compound (9.5 g).
Reaction SMILES: [Br:1][C:2]1C=C[S:4][C:3]=1C(O)=O.Cl.C(N=C=N[CH2:16][CH2:17][CH2:18][N:19](C)C)C.O.[OH:23]N1C2C=CC=CC=2N=N1.O>CN(C=O)C>[Br:1][C:2]1[CH:16]=[C:17]([C:18]([NH2:19])=[O:23])[S:4][CH:3]=1
Reactant: On1nnc2ccccc21
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1sccc1Br
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1cc(Br)cs1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
A solution of 4 bromo-thiophene-2-carboxylic acid (2.0 g, 9.66 mmol), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (2.04 g, 10.63 mmol) and 1-hydroxybenzotriazole hydrate (1.44 g, 10.63 mmol) in DMF (20 mL) is stirred at room temperature for 2 hours. The reaction mixture is then cooled to 0° C. and aq. NE3 (1 mL, 17.3 mmol) is added. The mixture is stirred at room temperature for an additional 5 hours, then water is added to the reaction mixture and the resultant precipitate is collected by filtration and washed with 1M NaOH, H2O and petroleum ether. The title compound is isolated as a white solid (1.56 g, 78%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.[Li]CCCC.[O:14]1[CH2:17][C:16](=[O:18])[CH2:15]1.[NH4+].[Cl-]>C1COCC1.O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:16]2([OH:18])[CH2:17][O:14][CH2:15]2)=[CH:3][CH:4]=1
Reactant: O=C1COC1
Reactant: Brc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: OC1(c2ccc(Br)cc2)COC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
1,4-Dibromobenzene (2 g, 8.48 mmol) was taken up in THF (35 mL) and cooled to −78° C. before adding n-BuLi (3.39 mL, 8.48 mmol) dropwise. After stirring at −78° C. for 30 minutes, oxetan-3-one (0.611 g, 8.48 mmol) was added and the reaction was warmed to room temperature for 1 hour at which time water and saturated NH4Cl were added and the products were extracted into EtOAc (2×). The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. Purification of the residue by flash silica gel column chromatography (6-50% EtOAc-hexanes) gave the title compound as a white solid.
Reaction SMILES: C([Li])CCC.CCCCCC.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21].[Br:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]Br>O1CCCC1>[Br:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([O:13][CH3:12])[C:15]=1[O:20][CH3:21]
Reactant: BrCCCCCCBr
Reactant: COc1ccccc1OC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cccc(CCCCCCBr)c1OC
Yield: 32 %

Procedure:
A solution of 1.55M butyl lithium in hexane (195 mL, 0.3 mol) was added dropwise over 30 minutes to a stirred solution of 1,2-dimethoxybenzene (41.4 g, 0.3 mol) in 700 mL of anhydrous tetrahydrofuran at room temperature under argon. The reaction mixture was stirred and heated at 40° for 4 hours and then cooled to -70°. A solution of 46 mL (0.3 mol) of 1,6-dibromohexane in 250 mL of anhydrous tetrahydrofuran was added dropwise over 30 minutes. The cooling bath was removed and the reaction mixture was stirred for 1 hour and then heated at 40° for 4 hours. Most of the solvent was removed, 90 mL of 3NHCl was added and the product was extracted with hexane. The extract was washed with sodium bicarbonate solution, dried and concentrated under reduced pressure to yield an oil. Distillation gave 1-(6-bromohexyl)-2,3-dimethoxybenzene as a yellow oil (29 g, 32% yield, b.p. 125°-140°/0.15 mm).
Reaction SMILES: FC(F)(F)C(O)=O.[OH:8][CH2:9][C:10]1([CH2:23][C:24]([CH3:26])=[CH2:25])[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]1>ClCCl>[CH3:25][C:24]1([CH3:26])[CH2:23][C:10]2([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH2:9][O:8]1
Reactant: C=C(C)CC1(CO)CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CC2(CCNCC2)CO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.9 %

Procedure:
Trifluoroacetic acid (20 mL) was added to a solution of 1-(1,1-dimethylethyl) 4-(hydroxymethyl)-4-(2-methyl-2-propenyl)-1-piperidinecarboxylate (Description 90, 1.14 g, 4.2 mmol) in dichloromethane (4 mL) and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure and water (40 mL) was added. The pH was adjusted to 12 with aqueous sodium hydroxide (4M) and the mixture was extracted with ethyl acetate (4×40 mL). The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was dissolved in ethanol (10 mL) and ethereal hydrogen chloride (1M, 10 mL) was added. The solvent was evaporated under reduced pressure and the residue was triturated with ethyl acetate (15 mL). The solid was collected and dried in vacuo to give the title compound as a colorless solid (483 mg, 56%). m/z (ES+) 170 (M+1).
Reaction SMILES: [C:1]1([C:7]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][O:18][CH:19]([O:26]C)[CH2:20][CH2:21][C:22](OC)=O.C([O-])(=O)C.[NH4+:32].[OH-].[NH4+:34]>C(O)(=O)C.O>[CH3:17][O:18][C:19](=[O:26])[CH2:20][CH2:21][C:22]1[NH:32][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:34]=1
Reactant: [NH4+]
Reactant: COC(=O)CCC(OC)OC
Reactant: O=C(C(=O)c1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)CCc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1

Procedure:
A solution of 1 g of benzil, 1.01 g of methyl 4,4-dimethoxybutyrate and 2.87 g of ammonium acetate in 23 mL of acetic acid was refluxed for 5 h. The mixture was poured into water, basified with a 25% aq. ammonium hydroxide solution and extracted with DCM. The organic phase was dried over anh. Na2SO4 and concentrated in vacuo. The resulting crude material was purified by CC using heptane/EtOAc from 85/15 to 0/100 as eluant to yield 633 mg of 3-(4,5-diphenyl-1H-imidazol-2-yl)-propionic acid methyl ester as a yellowish solid.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[N:2]1.Cl[CH2:12][C:13]1[C:14]([CH3:19])=[N:15][O:16][C:17]=1[CH3:18].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.Cl>[CH3:19][C:14]1[C:13]([CH2:12][N:1]2[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[N:2]2)=[C:17]([CH3:18])[O:16][N:15]=1
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: Cc1noc(C)c1CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn(Cc2c(C)noc2C)c1
Temperature: 25 °C
Yield: 80.2 %

Procedure:
Ethyl 1H-pyrazole-4-carboxylate (4.2 g, 30 mmol), 4-(chloromethyl)-3,5-dimethylisoxazole (5.1 g, 35 mmol), and cesium carbonate (9.8 g, 30 mmol), in DMF (50 mL), were stirred at 80° C. for 12 hours. The reaction was cooled to ambient temperature, diluted with 0.1 N HCl (150 mL) and extracted with ethyl acetate (3×, 75 mL). The combined organic extracts were dried over sodium sulfate and concentrated on the rotovap. The solid product was triturated with ethyl acetate/hexanes(1/9) and collected by filtration to afford ethyl 1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazole-4-carboxylate (6 g, 80%) as a white solid. 1H NMR (CDCl3, 400 MHz): δ1.34 (t, J=7.2 Hz, 3H), 2.19 (s, 3H), 2.43 (s, 3H), 4.29 (q, J=7.2 Hz, 2H), 5.06 (s, 2H), 7.77 (s, 1H), 7.91 (s, 1H).