Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:2]([C:6]([OH:8])=[O:7])[C@@H:3]([CH3:5])[OH:4].Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19]>CCOC(C)=O>[CH2:17]([O:7][C:6](=[O:8])[C@H:2]([C@@H:3]([CH3:5])[OH:4])[NH:1][C:9]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19]
Reactant: O=C(CBr)c1ccccc1
Reactant: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: CCOC(C)=O
Product: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)OCC(=O)c1ccccc1
Temperature: 20 °C
Reaction time: 48 h
Yield: 84.8 %

Procedure:
To a stirred suspension of Boc-Thr-OH (21.91 g, 0.1 mol) in EtOAc (200 ml) at 0° C., TEA (14 ml, 0.1 mol) and bromoacetophenone (19.0 g, 0.1 mol) were added. The reaction mixture was allowed to warm to 20° C., stirred for 2 days and then diluted with EtOAc (500 ml). After washing successively with aq HCl (200 ml, 0.1 N), H2O (100 ml), aq NaHCO3 (200 ml, 1 N) and brine (200 ml), drying (Na2SO4), filtered and concentrated in vacuo, the residue was triturated with Et2O and filtered. The resulting solid was dried in the dark to yield D3 (28.6 g, 85%). Rf=0.55 (hex-EtOAc 1:1, silica); M.p.=114.2° C.; [α]D22−29.4 (c 2, EtOAc).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([N:5]([CH2:12][P:13]([O:17]Cl)([O:15]Cl)=[O:14])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:4].[CH3:21][OH:22].C(N(CC)CC)C.[CH:30]([NH2:33])([CH3:32])[CH3:31]>CCOCC>[F:1][C:2]([F:20])([F:19])[C:3]([N:5]([CH:12]([O:22][CH3:21])[P:13]([OH:17])([O:15][NH:33][CH:30]([CH3:32])[CH3:31])=[O:14])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:4]
Reactant: CC(C)N
Reactant: CO
Reactant: CCOC(=O)CN(CP(=O)(OCl)OCl)C(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(=O)CN(C(=O)C(F)(F)F)C(OC)P(=O)(O)ONC(C)C
Reaction time: 2 h
Yield: 64.2 %

Procedure:
A solution of ethyl N-trifluoroacetyl-N-(dichlorophosphonomethyl)glycinate (8.25 g, 0.025 mole) in 150 ml. of ether was cooled to 0° C. and treated with a solution of methanol (1.01 ml, 0.025 mole) and triethylamine (3.49 ml, 0.025 mole) in 25 ml. of ether. The solution was stirred for two hours, then filtered and the filtrate was cooled and treated with isopropylamine (4.25 ml. 0.05 mole) in 100 ml. of ether. After stirring for 16 hours, the mixture was filtered and the filtrate was washed with water, dried over sodium sulfate and concentrated in vacuo to yield ethyl N-trifluoroacetyl-N-(methoxy(isopropylamino)phosphonomethyl)glycinate (6.1 g) as a yellow oil, ND =1.4335.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[C:22]3[O:21][CH2:20][O:19][C:18]=3[CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:23].O1CCOCC1.C(OC(C)C)(C)C>ClCCl>[ClH:23].[O:19]1[C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([C:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=3)[C:22]=2[O:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cccc3c2OCO3)CC1
Agent: Cl
Solvent: CC(C)OC(C)C
Solvent: C1COCCO1
Solvent: ClCCl
Product: C1=C(c2cccc3c2OCO3)CCNC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 85 %

Procedure:
In a 50 mL flask, 4-Benzo[1,3]dioxol-4-yl-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.22 g, 4.02 mmol was combined with dichloromethane (20 ml) to give a colorless solution. Hydrochloric acid solution, 4M in dioxane (10.1 ml, 40.2 mmol) was added and the reaction mixture was stirred for 4 hours at room temperature. 15 ml of diisoproylether were added and the mixture was stirred for 5 min at 0° C. The precipitate was collected by filtration, washed with 2 ml of diisopropylether and dried to yield the title compound as a white solid (0.820 grs, 85%). MS (ISP) m/z=204.2[(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:9]([O:11]C)=[O:10])=[C:4]([F:18])[CH:3]=1.CO.[OH-].[Na+].Cl>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17]2)[C:9]([OH:11])=[O:10])=[C:4]([F:18])[CH:3]=1
Reactant: COC(=O)C(c1ccc(Cl)cc1F)C1CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(c1ccc(Cl)cc1F)C1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7.55 g (27.9 mmol) of methyl (4-chloro-2-fluorophenyl)(cyclopentyl)acetate were dissolved in 32 ml each of THF, methanol and water, and 11.15 g (287.9 mmol) of sodium hydroxide were added with ice cooling. The reaction mixture was stirred at RT overnight and then diluted with water and adjusted to pH 2 with 1 N hydrochloric acid. The aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulphate and concentrated under reduced pressure. The solid that remained was triturated with water, filtered off with suction and dried thoroughly under reduced pressure. This gave 6.96 g of the target compound (97.2% of theory).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]([CH3:26])([CH3:25])[CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[C:8]1[CH2:21][O:22][CH2:23][CH3:24].C(N(CC)CC)C.[C:34](Cl)(=[O:36])[CH3:35]>C(Cl)Cl>[NH2:20][C:11]1[C:10]2[N:9]=[C:8]([CH2:21][O:22][CH2:23][CH3:24])[N:7]([CH2:6][C:5]([CH3:25])([O:4][CH2:3][CH2:2][NH:1][C:34](=[O:36])[CH3:35])[CH3:26])[C:19]=2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)OCCN
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)OCCNC(C)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.1 %

Procedure:
1-(2-(2-Aminoethoxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine (32 mg, 89.5 μmol) was combined with DCM (1.0 mL) to give a colorless solution. To this solution was added triethylamine (25.0 μL, 179 μmol) and acetyl chloride (7.00 μL, 98.5 μmol) and the reaction mixture was stirred 18 hours at room temperature. After concentrating the mixture in vacuo the residue was purified by flash chromatography (silica gel-NH2, 0% to 10% methanol in DCM) to give the title compound (19 mg, 53%) as white foam; LC-MS (UV peak area, ESI) 97%, 400.2348 (MH+).
Reaction SMILES: [NH:1]([N:41]=[N+:42]=[N-:43])[C@H:2]([C:10]([NH:12][C@H:13]([C:29]([NH:31][C@H:32]([C:37]([O:39]C)=O)[CH2:33][CH:34]([CH3:36])[CH3:35])=[O:30])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.[NH2:45][NH2:46]>CO>[NH:1]([N:41]=[N+:42]=[N-:43])[C@H:2]([C:10]([NH:12][C@H:13]([C:29]([NH:31][C@H:32]([C:37]([NH:45][NH2:46])=[O:39])[CH2:33][CH:34]([CH3:36])[CH3:35])=[O:30])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])=[CH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: NN
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1ccc(NC(=O)OC(C)(C)C)cc1)NC(=O)[C@H](Cc1ccccc1)NN=[N+]=[N-]
Solvent: O
Solvent: CO
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccc(NC(=O)OC(C)(C)C)cc1)NC(=O)[C@H](Cc1ccccc1)NN=[N+]=[N-])C(=O)NN
Reaction time: 8 h

Procedure:
N3-Phe-Phe(4-NHBoc)-Leu-OMe (160 mg, 276 μmol) was dissolved in MeOH and hydrazine hydrate (800 μl, 16.6 mmol, 60 equiv.) was added and the mixture was stirred overnight. Co-evaporation with toluene (3×) yielded the title compound which was used without further purification. LC/MS: Rt 7.54 minutes (linear gradient 10->90% MeCN+0.1% TFA, 15 minutes), (ESI-MS (m/z): 581.13. 1H NMR (400 MHz, CD3OD): δ ppm 7.40-7.17 (m, 7H), 7.02 (d, J=8.5 Hz, 2H), 4.61 (t, J=7.0 Hz, 1H), 4.35 (t, J=7.3 Hz, 1H), 4.13 (dd, J=8.6, 4.8 Hz, 1H), 3.15 (dd, J=14.0, 4.7 Hz, 1H), 3.00-2.81 (m, 3H), 1.60-1.45 (m, 3H), 1.51 (s, 9H), 0.93 (d, J=6.0 Hz, 3H), 0.89 (d, J=5.9 Hz, 3H).
Reaction SMILES: O.[P:2]([Cl:6])(Cl)([Cl:4])=[O:3].[CH2:7]([OH:12])[CH2:8][CH2:9][CH2:10][CH3:11]>C(Cl)(Cl)(Cl)Cl>[P:2]([Cl:6])([Cl:4])(=[O:3])[O:12][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCCO
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CCCCCOP(=O)(Cl)Cl
Reaction time: 18 h
Yield: 102.9 %

Procedure:
To a tap water cooled solution of 79 g of phosphorous oxychloride in 200 ml of carbon tetrachloride is added dropwise with stirring a solution of 50 g of 1-pentanol in 125 ml of carbon tetrachloride. The temperature rises to 30° C. and stirring is continued for 18 hours. The solvent is evaporated and the syrup evaporated with toluene several times. The residue is distilled from a Kugelrohr still to give 108.7 g of the desired product as a colorless oil, B.P. 85°-90° C./0.3 mm.
Reaction SMILES: C([Mg]Br)C.C1COCC1.Br[C:11]1[N:18]2[C:14]([S:15][CH:16]=[CH:17]2)=[CH:13][N:12]=1.[CH2:19]([O:22][C:23]([N:25]1[C@H:29]([CH:30]=[O:31])[CH2:28][C@@H:27]([O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[CH2:26]1)=[O:24])[CH:20]=[CH2:21].[Cl-].[NH4+]>C1COCC1>[CH2:19]([O:22][C:23]([N:25]1[CH:29]([CH:30]([OH:31])[C:11]2[N:18]3[C:14]([S:15][CH:16]=[CH:17]3)=[CH:13][N:12]=2)[CH2:28][CH:27]([O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:34])[CH3:35])[CH2:26]1)=[O:24])[CH:20]=[CH2:21]
Reactant: Brc1ncc2sccn12
Reactant: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C=O
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CCOC(=O)N1CC(O[Si](C)(C)C(C)(C)C)CC1C(O)c1ncc2sccn12
Temperature: -3 °C
Reaction time: 0.08 h

Procedure:
A 0.99 M ethylmagnesium bromide/THF solution (15.2 ml) is diluted with 60 ml of anhydrous THF. A solution of 3.046 g of 5-bromoimidazo[5,1-b]thiazole in 60 ml of anhydrous THF is added dropwise to the diluted solution in an argon atmosphere over a period of 15 min (4 to 8° C.), and the mixture is stirred in this state for 5 min. The mixture is then cooled to −3° C. over a period of 10 min. Thereafter, a solution of 4.702 g of (3R,5S)-1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5-formylpyrrolidine in 60 ml of anhydrous THF is added dropwise thereto over a period of 20 min (−3 to −1° C.). The mixture is stirred in this state at −1 to +1° C. for 80 min. An aqueous semi-saturated ammonium chloride solution (180 ml) is added thereto, and the mixture is extracted twice with 360 ml of ethyl acetate. The organic layer is dried over magnesium sulfate and filtered, and the solvent is removed by evaporation under reduced pressure to give a yellow oil which is then purified by flash column chromatography on silica gel (n-hexane:ethyl acetate=1:1 to 1:2) to give 4.934 g of 3R,5S)-1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5-[1-hydroxy-1-(imidazo[5,1-b]thiazol-5-yl)methyl]pyrrolidine (stereoisomer A, a high polar component) as a colorless amorphous material and 605.5 mg of (3R,5S)-1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5-[1-hydroxy-1-(imidazo[5,1-b]thiazol-5-yl)methyl]pyrrolidine(stereoisomer B, a low polar component) as a slightly yellow, high viscous material.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]#[N:19])=[CH:13][CH:12]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH:25]=O>>[CH3:20][O:21][C:22]1[CH:23]=[C:24](/[CH:25]=[C:17](/[C:14]2[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][OH:1])=[CH:16][CH:15]=2)\[C:18]#[N:19])[CH:27]=[CH:28][C:29]=1[O:30][CH3:31]
Reactant: COc1ccc(C=O)cc1OC
Reactant: N#CCc1ccc(OCCCCCCCCO)cc1
Product: COc1ccc(/C=C(\C#N)c2ccc(OCCCCCCCCO)cc2)cc1OC
Yield: 65 %

Procedure:
(2Z)-3-(3,4-dimethoxyphenyl)-2-{4-[(8-hydroxyoctyl)oxy]phenyl}prop-2-enenitrile is prepared starting from {4-[(8-hydroxyoctyl)oxy]phenyl}acetonitrile and commercial 3,4-dimethoxybenzaldehyde according the same procedure following for example 1 in 65% yield. This material proves chromatographically homogenous and displays spectral characteristics consistent with its assigned structure.
Reaction SMILES: CN(C1C=CC=CN=1)C.[C:10](OC(OC(C)(C)C)=O)(OC(C)(C)C)=[O:11].[CH3:25][O:26][C:27]([C:29]1([NH2:35])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)=[O:28].C(N(CC)CC)C.[CH2:43]([OH:49])[C:44]1[O:48][CH:47]=[CH:46][CH:45]=1>C1(C)C=CC=CC=1>[CH3:25][O:26][C:27]([C:29]1([NH:35][C:10]([O:49][CH2:43][C:44]2[O:48][CH:47]=[CH:46][CH:45]=2)=[O:11])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]1)=[O:28]
Reactant: COC(=O)C1(N)CCCCC1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: OCc1ccco1
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)C1(NC(=O)OCc2ccco2)CCCCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88.1 %

Procedure:
3.67 g (30 mmol) of dimethylaminopyridine was added to a solution of 65.48 g (0.3 mol) of di-t-butyl dicarbonate in 300 ml of anhydrous toluene, and the mixture was stirred at room temperature for 15 minutes. A solution of 47.17 g (0.3 mol) of 1-aminocyclohexanecarboxylic acid methyl ester in 100 ml of anhydrous toluene was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. Further, after 60.71 g (0.6 mol) of triethylamine and 44.1 g (0.45 mol) of furfuryl alcohol were added, the mixture was heated under reflux for 3 hours. The reaction solution was returned to room temperature and concentrated under reduced pressure. The obtained residue was crushed in a mortar and stirred in a mixture solution of 5 ml of hydrochloric acid and 3 L of water for 18 hours. The obtained crystal was collected by filtration to obtain 74.37 g (88%) of the title compound.
Reaction SMILES: Br.[O:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](SCC1C=CC=CC=1)=[NH:8].[NH2:17][C:18]1[CH:19]=[CH:20][C:21]2[N:26]([CH2:27][CH2:28][N:29]([CH3:37])[C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:25][CH2:24][S:23][C:22]=2[CH:38]=1>CCO>[O:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[NH:8])[NH:17][C:18]1[CH:19]=[CH:20][C:21]2[N:26]([CH2:27][CH2:28][N:29]([CH3:37])[C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:34])[CH3:35])[CH2:25][CH2:24][S:23][C:22]=2[CH:38]=1
Reactant: CN(CCN1CCSc2cc(N)ccc21)C(=O)OC(C)(C)C
Reactant: N=C(SCc1ccccc1)c1ccco1
Agent: Br
Solvent: CCO
Product: CN(CCN1CCSc2cc(NC(=N)c3ccco3)ccc21)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.5 %

Procedure:
Benzyl furan-2-carbimidothioate hydrobromide (1.199 g, 4.02 mmol) was added to a mixture of tert-butyl 2-(7-amino-2H-benzo[b][1,4]thiazin-4(3H)-yl)ethyl(methyl)carbamate (0.763 g, 2.361 mmol) in EtOH (20 mL). The mixture was stirred under room temperature overnight. The mixture was quenched with saturated sodium bicarbonate solution (50 mL), diluted with water (50 mL), and extracted with CH2Cl2 (2×50 mL). The organic phase was washed with brine (50 mL) and dried (Na2SO4). The crude material was subject to flash chromatography on silica gel (2.5-5% (2M NH3 in MeOH):CH2Cl2). The collected fractions were concentrated to give a white foam (0.88 g, 90%). 1H NMR (CDCl3) δ 7.85 (s, 1H), 7.44 (s, 1H), 6.74-6.69 (m, 1H), 6.62 (d, J=7.5 Hz, 1H), 4.72 (brs, 2H), 3.64-3.60 (m, 2H), 3.41 (s, 4H), 3.04-3.01 (m, 2H), 2.92 (s, 3H), 1.45 (s, 9H); ESI-MS (m/z, %): 419, 417 (MH+, 100).
Reaction SMILES: [H-].[Na+].[CH2:3]([NH:5][C:6]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]#[N:25])=[CH:14][CH:13]=2)[C:9]2[C:26]([C:30]([O:32][CH3:33])=[O:31])=[CH:27][CH:28]=[CH:29][C:8]=2[N:7]=1)[CH3:4].[CH3:34]I.O>CN(C=O)C>[CH2:3]([N:5]([CH3:34])[C:6]1[N:10]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]#[N:25])=[CH:16][CH:17]=2)[C:9]2[C:26]([C:30]([O:32][CH3:33])=[O:31])=[CH:27][CH:28]=[CH:29][C:8]=2[N:7]=1)[CH3:4]
Reactant: CCNc1nc2cccc(C(=O)OC)c2n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(C)c1nc2cccc(C(=O)OC)c2n1Cc1ccc(-c2ccccc2C#N)cc1
Yield: 82 %

Procedure:
A mixture of sodium hydride (60% dispersion in mineral oil, 0.13 g) in DMF (5 ml) was stirred under ice-cooling for 5 min. and methyl 2-ethylamino-1-[(2′-cyanobiphenyl-4-yl)methyl]benzimidazole-7-carboxylate (0.95 g) was added to the mixture, followed by stirring for 10 min. To the mixture was added methyl iodide (0.2 ml) and the mixture was stirred for 20 min. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The extract was washed with water, dried and evaporated to dryness. The residue was purified by column chromatography on silica gel to give crude cristals, which were recrystallized from ethyl acetate-hexane to afford colorless needles (0.88 g, 82%), m.p. 66-69° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=C(C=CC=1)C=CC(O)=O.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[S:20](Cl)(Cl)=O>N1C=CC=CC=1>[Cl:1][C:2]1[C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([Cl:13])[C:15]=2[S:20][CH:3]=1
Reactant: Clc1ccccc1
Reactant: O=C(O)C=Cc1cccc(Cl)c1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Product: Clc1csc2c(Cl)cccc12

Procedure:
A stirred mixture of 0.2 mole of 3-chlorocinnamic acid in a solution containing 200 ml. of chlorobenzene, 75 ml. of thionyl chloride and 2.0 ml of pyridine was heated at reflux for 72 hours and filtered while hot to remove insoluble material. The filtrate was concentrated to remove the solvent and the solid residue was recrystallized from toluene to give 3,7-dichlorobenzo[b]thiophene-;b 2-carbonyl chloride, m.p. 100°-102° C.
Reaction SMILES: [NH:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3].C(O[C@@H:14]1[C:18]([F:20])([CH3:19])[C@@:17]([O:22][C:23](=[O:25])[CH3:24])([CH3:21])[CH:16]([CH2:26][O:27][C:28](=[O:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:15]1)(=O)C.Cl[Sn](Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>C(#N)C>[C:28]([O:27][CH2:26][C@@H:16]1[C:17]([O:22][C:23](=[O:25])[CH3:24])([CH3:21])[C@:18]([F:20])([CH3:19])[CH:14]([N:1]2[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]2=[O:3])[O:15]1)(=[O:35])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Reactant: CC(=O)O[C@H]1OC(COC(=O)c2ccccc2)[C@@](C)(OC(C)=O)C1(C)F
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)OC1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cc(C)c(=O)[nH]c2=O)[C@]1(C)F
Yield: 34 %

Procedure:
To a stirred solution of thymine (about 0.68 g, 5.43 mmol) in acetonitrile (about 15 ml) was added compound N,O-Bis-trimethylsilylacetamide (7.90 ml, 32.6 mmol) at room temperature and refluxed for about 2 hours. To this added (2R,4R)-5-(benzoyloxymethyl)-3-fluoro-3,4-dimethyltetrahydrofuran-2,4-diyl diacetate (about 1.00 g, 2.71 mmol) in acetonitrile (about 15 ml) drop wise at about 0° C. and SnCl4 (about 0.47 ml, 4.00 mmol) then refluxed for about 15 hours. Completion of the reaction monitored by thin-layer chromatography, neutralized the reaction mixture with saturated sodium bicarbonate, aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine and dried over sodium sulphate. Concentrated under reduced pressure and purified by silica gel column chromatography using 3% methanol in dichloromethane as eluent furnished title compound (0.40 g) as a colorless solid. Yield: 34%; 1H NMR (300 MHz, CDCl3): δ 8.07 (s, 1H), 8.05-8.04 (m, 2H), 7.60-7.58 (m, 1H), 7.49-7.44 (m, 2H), 7.15-7.13 (m, 1H), 6.38 (d, 1H, J=23.1 Hz), 4.74-4.65 (m, 2H), 4.49-4.41 (m, 1H), 2.12 (s, 3H), 1.94 (d, 3H, J=0.9 Hz), 1.83 (d, 3H, J=2.4 Hz), 1.48 (d, 3H, J=23.4 Hz); ES Mass: [M+1] 435 (30%), [M+Na] 457 (100%); IR cm−: 3432, 2926, 1753, 1692, 1602, 1547, 1384, 1276, 1115, 954, 833; HPLC:. 92%.
Reaction SMILES: [OH-:1].[K+:2].[CH:3]([CH:9]1[CH2:14][C:13](=[O:15])[O:12][C:10]1=[O:11])=[CH:4][CH2:5][CH2:6][CH2:7][CH3:8]>C(O)CO>[K+:2].[K+:2].[CH:3]([CH:9]([CH2:14][C:13]([O-:12])=[O:15])[C:10]([O-:1])=[O:11])=[CH:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCC=CC1CC(=O)OC1=O
Reactant: [OH-]
Agent: [K+]
Solvent: OCCO
Product: CCCCC=CC(CC(=O)[O-])C(=O)[O-]
Temperature: 100 °C
Reaction time: 2 h

Procedure:
Into a glass flask there were charged 16 grams of potasium hydroxide, 41.5 grams of ethyleneglycol and 25.5 grams of hexenyl succinic anhydride. The mixture was stirred for two hours at 100° C. Yield: 78.9 grams=98.0% of theoretical. The catalyst solution thus obtained is hygroscopic.
Reaction SMILES: [Li]CCCC.CN([CH:9]=[O:10])C.[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH3:26])=[CH:21][C:20]=1Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1>[CH2:11]([O:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][CH3:26])=[CH:23][C:24]=1[CH:9]=[O:10])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCc1ccc(OCc2ccccc2)c(Br)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1ccc(OCc2ccccc2)c(C=O)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
n-BuLi (7.56 mL, 18.9 mmol, 2.5M in hexanes) followed by DMF (5.5 mL) were added to a cooled −78° C. solution of 1-benzyloxy-2-bromo-4-ethyl-benzene (5 g, 17.2 mmol) in THF (40 mL). The reaction was stirred at −78° C. for 1 hr and then warmed up to rt. After 2 hrs the reaction was quenched with 1N HCl and extracted with EtOAc. The organic layers were washed with brine, dried over Na2SO4 and concentrated to a yellow oil. Purification by flash column chromatography (0% to 5% EtOAc in hexanes) gave the title compound as a clear oil (3.6 g, 87%). 1H NMR (400 MHz, CDCl3): δ 1.22 (t, J=7.8 Hz, 3 H), 2.62 (q, J=7.8 Hz, 2 H), 5.17 (s, 2 H), 6.97 (d, J=8.6 Hz, 1 H), 7.33–7.45 (m, 6 H), 7.69 (s, 1 H), 10.54 (s, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH2:4].[N+]([C:13]1[CH:18]=CC(O)=C[CH:14]=1)([O-])=O.OCC(CO)O.S(=O)(=O)(O)O>O>[Br:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[C:5]2[C:3]=1[N:4]=[CH:18][CH:13]=[CH:14]2
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: Nc1cc(F)ccc1Br
Agent: O=S(=O)(O)O
Solvent: O
Solvent: OCC(O)CO
Product: Fc1ccc(Br)c2ncccc12

Procedure:
Alternatively, 8-bromo-5-fluoroquinoline was prepared by adding a warm mixture containing 2-bromo-5-fluoroaniline (100 g, 1.0 eq), 4-nitrophenol (40 g, 0.54 eq), and glycerol (97 g, 2.0 eq) over 1.5 hours to sulfuric acid (267 ml) and water (114 mL) at 140-150° C. The initial mixture showed 37.8% 4-nitrophenol by relative HPLC area %. Samples showed 4.7% 4-nitrophenol immediately after adding 50% of mixed starting materials and 5.0% immediately after adding all of the materials. The yield upon workup was 87.5%, with total impurities 0.29%. Addition of less (0.46 eq, 34 g) 4-nitrophenol also successfully produced the intermediate of interest at acceptable yield.
Reaction SMILES: [CH:1]([NH:4][C:5]1[N:10]=[CH:9][C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][N:6]=1)([CH3:3])[CH3:2].S(OC)(O[CH3:19])(=O)=O>O1CCCC1>[OH-:12].[CH3:19][N+:10]1[CH:9]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:7]=[N:6][C:5]=1[NH:4][CH:1]([CH3:3])[CH3:2]
Reactant: COC(=O)c1cnc(NC(C)C)nc1
Reactant: COS(=O)(=O)OC
Solvent: C1CCOC1
Product: COC(=O)c1cnc(NC(C)C)[n+](C)c1
Product: [OH-]
Yield: 233.8 %

Procedure:
A mixture of 27.45 g (0.140 mol) of 2-isopropylamino-5-methoxycarbonylpyrimidine and 56 ml (2 eq; 0.59 mol) of dimethyl sulfate in 440 ml of anhydrous tetrahydrofuran is refluxed for 24 hours. The reaction medium is extracted with ethyl acetate and water. Purification on silica gel (eluent: 95 CH2Cl2 [sic]/5% MeOH/saturation with gaseous NH3) of the oil resulting from the evaporation of the aqueous phases gives 37.2 g of 1-methyl-2-isopropylamino-5-methoxycarbonylpyrimidinium hydroxide (yield: 82%).