Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:7][N:8]([CH3:39])[C:9]1[CH:10]=[C:11]([CH:36]=[CH:37][CH:38]=1)[C:12]([NH:14][C:15]1[CH:16]=[CH:17][C:18]([CH3:35])=[C:19]([NH:21][C:22](=[O:34])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH2:30][CH:31]3[O:33][CH2:32]3)[CH:24]=2)[CH:20]=1)=[O:13]>C(Cl)Cl.CO>[CH3:39][N:8]([CH3:7])[C:9]1[CH:10]=[C:11]([CH:36]=[CH:37][CH:38]=1)[C:12]([NH:14][C:15]1[CH:16]=[CH:17][C:18]([CH3:35])=[C:19]([NH:21][C:22](=[O:34])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH2:30][CH:31]([OH:33])[CH2:32][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:24]=2)[CH:20]=1)=[O:13]
Reactant: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1NC(=O)c1cccc(OCC2CO2)c1
Reactant: C1CCNCC1
Solvent: CO
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1NC(=O)c1cccc(OCC(O)CN2CCCCC2)c1
Yield: 84 %

Procedure:
Piperidine (3 g) was added to a stirred solution of N-[5-(3-dimethylaminobenzamido)-2-methylphenyl]-3-(2,3-epoxypropoxy)benzamide (0.19 g) in a mixture of methylene chloride (3 ml) and methanol (3 ml). The resultant solution was stirred at ambient temperature for 18 hours. The mixture was evaporated and the residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and methanol as eluent. There was thus obtained the title compound (0.19 g); NMR Spectrum: (DMSOd6) 1.6 (m, 6H), 2.18 (s, 3H), 2.92 (m, 12H), 4.02 (m, 2H), 4.22 (m, 1H), 6.9 (m, 1H), 7.2 (m, 4H), 7.29 (t, 1H), 7.43 (t, 1H), 7.57 (m, 3H), 7.8 (d, 1H), 9.92 (br s, 1H), 10.12 (br s, 1H); Mass Spectrum: M+H+ 531.
Reaction SMILES: [C:1]1([S:7]([O-:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].O1CCOCC1.Cl[CH2:18][C:19](=[O:21])[CH3:20]>O>[C:1]1([S:7]([CH2:18][C:19](=[O:21])[CH3:20])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S([O-])c1ccccc1
Reactant: CC(=O)CCl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)CS(=O)(=O)c1ccccc1
Temperature: 50 °C
Yield: 60.3 %

Procedure:
Sodium benzenesulfinate (50 g, 304.6 mmol) was dissolved in water (200 ml). A dioxane solution (200 ml) of chloroacetone (29.6 g, 319.9 mmol) was added and the solution was stirred and heated to 50° C. for 22 hours then cooled to approximately 25° C. The solution was extracted with methylene chloride (2X, 250 ml), the methylene chloride layers were combined and washed with saturated aqueous sodium bicarbonate solution (1X, 250 ml) and water (1X, 250 ml) then the aqueous wash solutions were combined and extracted with methylene chloride (2X, 100 ml). All of the methylene chloride layers were combined and washed with saturated aqueous sodium chloride solution (1X, 150 ml), dried over sodium sulfate, filtered and concentrated in vacuo to a solid. The solid was dissolved in diethyl ether (800 ml) with gentle heating and then the solution was stirred and allowed to cool to room temperature. The solution was slowly cooled to 0° C. with stirring, causing the product to crystallize. The resulting crystals were collected by filtration, washed with cold diethyl ether, and dried in vacuo at 35° C. for 4 hours to yield 36.43 g of (phenylsulfonyl)acetone. The filtrate was concentrated to approximately one-eighth of its volume in vacuo and was gradually cooled below room temperature to induce crystallization, then stirred overnight at room temperature. The resulting crystals were collected by filtration, washed with cold diethyl ether, and dried in vacuo at 35° C. for 8 hours to yield an additional 14 g of the (phenylsulfonyl)acetone: n.m.r. (90 MHz, CDCl3): δ 2.39 (s, 3), 4.17 (s, 2), 7.55-7.95 (m, 5); m.p. 56°-58° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:10][C:9]2[C:8]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][C@@H:12]3[CH3:17])=[N:7][C:6]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=O)[O:26]C4C=CC=CC=4)=[CH:20][CH:19]=3)=[N:5][C:4]=2[CH2:3]1.[CH:34]1([NH2:38])[CH2:37][CH2:36][CH2:35]1>>[CH:34]1([NH:38][C:25]([NH:24][C:21]2[CH:20]=[CH:19][C:18]([C:6]3[N:7]=[C:8]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][C@@H:12]4[CH3:17])[C:9]4[CH2:10][N:2]([CH3:1])[CH2:3][C:4]=4[N:5]=3)=[CH:23][CH:22]=2)=[O:26])[CH2:37][CH2:36][CH2:35]1
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)nc2c1CN(C)C2
Reactant: NC1CCC1
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CCC3)cc2)nc2c1CN(C)C2

Procedure:
Method as described for example 51 using intermediate 10 and cyclobutanamine as starting materials. Purified by prep. LCMS (high pH).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([CH2:22][CH2:23][CH3:24])[NH:17][C:16]2=[O:25])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].S(OC)(O[CH3:30])(=O)=O.[Na]>C(O)(C)C>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([CH2:22][CH2:23][CH3:24])[N:17]([CH3:30])[C:16]2=[O:25])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: COS(=O)(=O)OC
Reactant: CCCc1cc(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(=O)[nH]1
Agent: [Na]
Solvent: CC(C)O
Product: CCCc1cc(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(=O)n1C

Procedure:
using isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-4-propyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate and dimethyl sulphate with sodium isopropylate in isopropanol there is obtained isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-3-methyl-4-propyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate, 1H--NMR (CDCl3, 400 MHz) 7.83 ppm (d, 1H), 7.34 ppm (d, 1H), 5.73 ppm (s, 1H), 5.23 ppm (m, 1H), 3.45 ppm (s, 3H), 2.53 ppm (t, 2H), 1.72 ppm (m, 2H), 1.36 ppm (d, 6H), 1.10 ppm (t, 3H),
Reaction SMILES: [N:1]([C@@H:4]1[C@@H:8]([CH2:9][OH:10])[O:7][C@@H:6]([N:11]2[CH:18]=[CH:17][C:15](=[O:16])[NH:14][C:12]2=[O:13])[CH2:5]1)=[N+:2]=[N-:3].C(OC(=O)C)(=O)C.[Br:26]Br>C(O)(=O)C>[N:1]([C@@H:4]1[C@@H:8]([CH2:9][OH:10])[O:7][C@@H:6]([N:11]2[CH:18]=[C:17]([Br:26])[C:15](=[O:16])[NH:14][C:12]2=[O:13])[CH2:5]1)=[N+:2]=[N-:3]
Reactant: BrBr
Reactant: [N-]=[N+]=N[C@H]1C[C@H](n2ccc(=O)[nH]c2=O)O[C@@H]1CO
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: [N-]=[N+]=N[C@H]1C[C@H](n2cc(Br)c(=O)[nH]c2=O)O[C@@H]1CO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3'-Azido-5-bromo-2',3'-dideoxyuridine was prepared from the known 3'-azido-2',3'-dideoxyuridine (T. A. Krenitsky, et al., J. Med. Chem., 26, 891, (1983)) (0.827 g, 3.3 mMol) by first acetylating the 5'-hydroxyl group with acetic anhydride (15 mL) then by brominating the 5 position by the addition of acetic acid (0.5 mL) and bromine (0.566 g). The red-brown solution was stirred at room temperature for two hours. The reaction was taken to an oil in vacuo and triturated with ethyl ether. The oil was dissolved in methanol ammonia to remove the acetyl group. The desired product was isolated by chromatography on silica gel by elution with CHCl3 :MeOH (95:5 v/v). The yield was 32%; mp=148°-149° C.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.F[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C>O>[N+:21]([C:18]1[CH:19]=[CH:20][C:15]([N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=3)[CH2:6][CH2:5]2)=[CH:16][CH:17]=1)([O-:23])=[O:22]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Oc1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=[N+]([O-])c1ccc(N2CCN(c3ccc(O)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 76 %

Procedure:
A mixture of 91.7 parts of 4-(1-piperazinyl)phenol, 71.0 parts of 1-fluoro-4-nitrobenzene, 60.0 parts of potassium carbonate and 450 parts of N,N-dimethylacetamide was stirred over weekend at room temperature. Water was added and after standing for 5 hours, the product was filtered off. It was purified by column chromatography over silica gel using trichloromethane as eluent. The pure fractions were collected and the eluent was evaporated, yielding 114.4 parts (76%) of 4-[4-(4-nitrophenyl)-1-piperazinyl]phenol; mp. 260.0° C. (intermediate 9).
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])=[NH:4].[C:14](OC(=O)C)(=O)[CH3:15]>C(O)(=O)C>[CH3:14][C:15]1[O:1][N:2]=[C:3]([C:5]2[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=2)[C:8]([OH:10])=[O:9])[N:4]=1
Reactant: CC(=O)OC(C)=O
Reactant: N=C(NO)c1cccc(C(=O)O)c1
Solvent: CC(=O)O
Product: Cc1nc(-c2cccc(C(=O)O)c2)no1
Temperature: 118 °C

Procedure:
A mixture of 614 g (3.41 mol) of 3-(N-hydroxycarbamimidoyl)benzoic acid, 756 ml (8.0 mol) of acetic anhydride and 2 l of acetic acid is heated at a temperature of 118° C. for 14 hours. The reaction mixture is cooled to 6° C. and filtered with suction. The residue is taken up in 2 l of water, filtered off with suction and washed well with water. The residue is recrystallised from ethanol/water: 3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoic acid as colourless crystals; m.p. 225° C.; ESI 205 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([O:13][CH3:14])=[O:12])=[CH:10][C:5]=2[O:4][CH:3]=1.[H][H]>[Pd].CO>[CH3:1][CH:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([O:13][CH3:14])=[O:12])=[CH:10][C:5]=2[O:4][CH2:3]1
Reactant: COC(=O)c1ccc2c(C)coc2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc2c(c1)OCC2C
Yield: 95.1 %

Procedure:
Methyl 3-methylbenzofuran-6-carboxylate (400 mg, 2.1 mmol), palladium on carbon (50 mg, 0.56 mmol), in methanol (10 mL) was charged with hydrogen (0.4 MPa) at room temperature for 12 hours. Then filtered, and the organic layer was concentrated to dryness and the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=10:1) to give the product methyl 3-methyl-2,3-dihydrobenzofuran-6-carboxylate (384 mg, 95%) as white solid. LRMS (M+H+) m/z: calcd 192.21. found 192. 1H NMR (300 MHz, CDCl3) δ 7.54-7.51 (m, 1H), 7.27-7.22 (m, 2H), 4.72-4.66 (m, 1H), 4.10-4.06 (m, 1H), 3.56-3.53 (m, 1H), 1.32 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[N:19]=[C:18]([NH:20][C@H:21]3[CH2:26][CH2:25][C@H:24]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23][CH2:22]3)[N:17]=[C:16]3[C:12]=1[N:13]=[CH:14][N:15]3[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:6][CH2:5]2.[CH3:42][N:43]([CH3:53])[C:44]1[CH:49]=[CH:48][C:47]([N:50]=[C:51]=[O:52])=[CH:46][CH:45]=1.ClCCl>O>[CH3:42][N:43]([CH3:53])[C:44]1[CH:49]=[CH:48][C:47]([NH:50][C:51]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([C:11]2[N:19]=[C:18]([NH:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:28]([O:30][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:29])[CH2:23][CH2:22]4)[N:17]=[C:16]4[C:12]=2[N:13]=[CH:14][N:15]4[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:6][CH2:5]3)=[O:52])=[CH:46][CH:45]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2nc(N3CCc4cc(N)ccc43)c3ncn(C(=O)OC(C)(C)C)c3n2)CC1
Reactant: CN(C)c1ccc(N=C=O)cc1
Solvent: ClCCl
Solvent: O
Product: CN(C)c1ccc(NC(=O)Nc2ccc3c(c2)CCN3c2nc(N[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)nc3c2ncn3C(=O)OC(C)(C)C)cc1
Reaction time: 20 h

Procedure:
80 mg of product obtained in stage 4 of example 41 are mixed with 32.2 mg of 4-dimethylaminophenyl isocyanate and 5 ml of dichloromethane. Stirring is carried out for 20 hours at ambient temperature, 0.5 ml of water is added, and the mixture is evaporated to dryness. Purification is carried out on an Xterra LCMSprep column, eluting with acetonitrile/ammonium hydrogen carbonate buffer, pH 9. 55 mg of expected product are obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([N+:16]([O-])=O)=[N:11][C:12]([Br:15])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.[Fe]>[CH2:1]([O:8][C:9]1[C:10]([NH2:16])=[N:11][C:12]([Br:15])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1nc(Br)ccc1OCc1ccccc1
Agent: [Fe]
Solvent: CC(=O)O
Product: Nc1nc(Br)ccc1OCc1ccccc1
Temperature: 25 °C
Yield: 68.9 %

Procedure:
A mixture of 3-benzyloxy-6-bromo-2-nitropyridine (1.6 g, 5.2 mmol) and iron powder (2.9 g, 51.8 mmol) in acetic acid (25 mL) and IMS (25 mL) was stirred at reflux for 1 hour, then cooled to room temperature and filtered though a pad of celite. The filtrate was concentrated under reduced pressure to give a residue that was partitioned between an aqueous saturated solution of sodium bicarbonate and EtOAc. The organic layer was separated and washed with water and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (Si—PPC, EtOAc:cyclohexane, gradient 0:100 to 40:60) to give 3-Benzyloxy-6-bromopyridin-2-ylamine as a pale yellow solid (1.0 g, 71%). 1H NMR (400 MHz, CHCl3-d): δ 7.41-7.34 (m, 5 H); 6.82 (d, J=8.1 Hz, 1 H); 6.71 (d, J=8.1 Hz, 1 H); 5.04 (s, 2 H); 4.80 (s, 2 H).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N+:11]([O-])([OH:13])=[O:12]>S(=O)(=O)(O)O>[I:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1ccccc1I
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc([N+](=O)[O-])ccc1I
Temperature: 80 °C

Procedure:
2-Iodobenzoic acid (100 g) was dissolved in 400 mL of concentrated sulphuric acid and placed in a 2 liter 3 necked flask. The flask was fitted with reflux condenser, a thermometer and an addition funnel. Fuming nitric acid (400 ml) was added drop by drop. The addition was adjusted in such a way that the temperature was allowed to raise to 80° C. over a period of 2 hours. During the addition, the reaction mixture was stirred vigorously and maintained the temperature at 80° C. for an additional 2 hours. After the completion of the reaction, the reaction mixture was poured slowly into crushed ice (3 Kg). The contents were allowed to settle and were filtered. The yellow precipitate was collected and dried at 30° C. The yield was 90 grams.
Reaction SMILES: C[O-].[Na+].[CH3:4][C:5]([CH3:8])([SH:7])[CH3:6].Br[CH2:10][C:11]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=[CH:17][C:12]=1[C:13]([O:15][CH3:16])=[O:14]>CO>[CH3:4][C:5]([CH3:8])([S:7][CH2:10][C:11]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=[CH:17][C:12]=1[C:13]([O:15][CH3:16])=[O:14])[CH3:6]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1CBr
Reactant: CC(C)(C)S
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cccc([N+](=O)[O-])c1CSC(C)(C)C
Yield: 92 %

Procedure:
To a solution of 34.7 g of sodium methoxide in 600 ml methanol was added 57.9 g of 1,1-dimethylethanethiol below 25°. The resulting solution was stirred one hour before the portionwise addition of 172.7 g of methyl 2-bromomethyl-3-nitrobenzoate. The resulting suspension was refluxed two hours. The mixture was cooled, and the solvent evaporated in vacuo. The residual oil was partitioned between ether and water. The organic solution was washed twice with 2.5% sodium hydroxide solution, twice with water, followed by brine, then dried over magnesium sulfate, filtered and the filtrate concentrated in vacuo to give 164.2 g of crude methyl 2-[(1,1-dimethylethylthio)methyl]-3-nitrobenzoate as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[C:13]2[CH2:17][CH:18]([OH:21])[CH2:19][OH:20])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:25][C:26]1[N:27]=[C:28](/[CH:31]=[CH:32]/[C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=2[F:40])[O:29][CH:30]=1>>[F:40][C:34]1[CH:35]=[C:36]([F:39])[CH:37]=[CH:38][C:33]=1/[CH:32]=[CH:31]/[C:28]1[O:29][CH:30]=[C:26]([CH2:25][O:1][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]3[CH:16]=[CH:15][N:14]=[C:13]3[CH2:17][CH:18]([OH:21])[CH2:19][OH:20])=[CH:4][CH:3]=2)[N:27]=1
Reactant: Fc1ccc(/C=C/c2nc(CCl)co2)c(F)c1
Reactant: OCC(O)Cc1nccn1CCCCc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Product: OCC(O)Cc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(F)cc3F)n2)cc1
Yield: 62.3 %

Procedure:
Using 3-{1-[4-(4-hydroxyphenyl)butyl]-1H-imidazol-2-yl}-1,2-propanediol(204 mg), 65% oily sodium hydride (28 mg) and 4-(chloromethyl)-2-[(E)-2-(2,4-difluorophenyl)ethenyl]-1,3-oxazole (188 mg), the same reaction as Example 2 was carried out to yield the titled compound (223 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13])[C:5]([OH:7])=[O:6].O=S(Cl)Cl.[CH3:19]O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13])[C:5]([O:7][CH3:19])=[O:6]
Reactant: CC(C)Oc1ccc(C(=O)O)cc1Cl
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(OC(C)C)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-chloro-4-[(1-methylethyl)oxy]benzoic acid (1.00 g, 4.66 mmol) in methanol (10.0 mL) was treated with SOCl2 (0.68 mL, 9.32 mmol). After stirring overnight at ambient temperature, the solution was concentrated in vacuo and taken on without purification. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.04 (d, J=2.3 Hz, 1 H) 7.89 (dd, J=8.7, 2.1 Hz, 1 H) 6.93 (d, J=8.6 Hz, 1 H) 4.66 (qq, J=6.1 Hz, 1 H) 3.88 (s, 3 H) 1.41 (d, J=6.1 Hz, 6 H). MS(ES+) m/e 229 [M+H]+.
Reaction SMILES: [C-:1]#[N:2].[K+].[F:4][C:5]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]([F:15])[C:6]=1[CH2:7]Br.C([O-])(O)=O.[Na+]>O.CN(C)C=O>[F:4][C:5]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]([F:15])[C:6]=1[CH2:7][C:1]#[N:2]
Reactant: COc1cc(F)c(CBr)c(F)c1
Reactant: [C-]#N
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(F)c(CC#N)c(F)c1
Reaction time: 0.33 h
Yield: 98.8 %

Procedure:
A solution of KCN (0.88 g, 13 mmol) dissolved in water (2 mL) was added dropwise to a water-bath-cooled solution of 2,6-difluoro-4-methoxybenzyl bromide (2.50 g, 10.5 mmol) in N,N-dimethylformamide (10 mL). The reaction mixture was stirred for 20 min. Water was added (20 mL) and then the reaction mixture was poured into saturated aqueous NaHCO3 solution (20 mL) and extracted with ether (50 mL). The organic phase was washed with water (5×25 mL), dried over MgSO4, and concentrated to give an oil, which crystallized on standing to provide the title compound as a white solid (1.9 g).
Reaction SMILES: CN(C)C=O.[C:6]([O:25][CH2:26][CH:27]([CH2:29][O:30][C:31](=[O:49])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]/[CH:39]=[CH:40]\[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[OH:28])(=[O:24])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[CH2:50]([N:52]([CH2:58][CH3:59])[CH2:53][CH2:54][C:55](O)=[O:56])[CH3:51]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:50]([N:52]([CH2:58][CH3:59])[CH2:53][CH2:54][C:55]([O:28][CH:27]([CH2:29][O:30][C:31](=[O:49])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]/[CH:39]=[CH:40]\[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[CH2:26][O:25][C:6](=[O:24])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:56])[CH3:51]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(O)COC(=O)CCCCCCC/C=C\CCCCCCCC
Reactant: CCN(CC)CCC(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(COC(=O)CCCCCCC/C=C\CCCCCCCC)OC(=O)CCN(CC)CC
Reaction time: 8 h
Yield: 62.2 %

Procedure:
In a solvent mixture of 3 ml N,N-dimethylformamide and 6 ml methylene chloride was dissolved 172 mg (0.277 mmol) of 1,3-dioleoylglycerol followed by addition of 101 mg (0.556 mmol) of N,N-diethyl-β-alanine (hydrochloride), 114 mg (0.553 mmol) of N,N-dicyclohexylcarbodiimide, and 7 mg (0.057 mmol) of 4-dimethylaminopyridine and the mixture was stirred overnight. This reaction mixture was then filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in methylene chloride and washed with water. The washed solution was dried and concentrated and the residue was subjected to column chromatography (silica gel/methylene chloride-methanol) to provide 129 mg (62%) of the title compound.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][CH:12]1[CH:16]2[O:17][CH2:18][CH:19]([OH:20])[CH:15]2[O:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:28][S:29]([O:20][CH:19]1[CH2:18][O:17][CH:16]2[CH:12]([O:11][CH2:10][CH2:9][O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:13][O:14][CH:15]12)(=[O:31])=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: OC1COC2C(OCCOCc3ccccc3)COC12
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC1COC2C(OCCOCc3ccccc3)COC12
Temperature: 0 °C
Reaction time: 8 h
Yield: 94.2 %

Procedure:
To a suspension of 6-(2-(benzyloxy)ethoxy)hexahydrofuro[3,2-b]furan-3-ol (1.50 g, 5.36 mmol) in anhydrous DCM (20 mL) was added N,N-diethylethanamine (1.20 mL, 8.60 mmol) and N,N-dimethylpyridin-4-amine (0.13 g, 1.07 mmol) under the nitrogen atmosphere, and the mixture was cooled down to 0° C. To the mixture was added methanesulfonyl chloride (0.50 mL, 6.50 mmol) at 0° C., and then the mixture was moved to room temperature and stirred overnight. The mixture was diluted with DCM (50 mL), washed with brine (50 mL) and dried over anhydrous Na2SO4, then filtered and concentrated in vacuo. The residue was purified by silica chromatography (EtOAc/PE (v/v)=2/1) to give the title compound as yellow liquid (1.81 g, 94%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[C:10]1(=O)[O:15][C:13](=[O:14])[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]12>O1CCOCC1>[O:14]=[C:13]1[C:12]2[C:11](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:10](=[O:15])[N:1]1[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6]
Reactant: N#Cc1cccc(N)c1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: C1COCCO1
Product: N#Cc1cccc(N2C(=O)c3ccccc3C2=O)c1
Temperature: 0 °C
Yield: 50.8 %

Procedure:
Dissolved 3-aminobenzonitrile (1.5 g, 12.7 mmol) in anhydrous dioxane (42 mL) under N2. Added phthalic anhydride (2.54 g, 17.1 mmol). Affixed Dean-Stark trap and refluxed for 16 h. Cooled to 0° C. and filtered off solid (2-((3-cyanophenyl)carbamoyl)benzoic acid). Concentrated filtrate to afford 3-(1,3-dioxoisoindolin-2-yl)benzonitrile (1.6 g) as a white solid. MS, calc'd=248.06. Obsv'd m/z: 248.91 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:16]([C@H:19]2[C@H:24]([O:25]CC3C=CC=CC=3)[C@@H:23]([O:33]CC3C=CC=CC=3)[C@H:22]([O:41]CC3C=CC=CC=3)[C@@H:21]([CH2:49][O:50]CC3C=CC=CC=3)[S:20]2)=[CH:15][C:3]=1[CH2:4][C:5]1[CH:14]=[CH:13][C:8]2[O:9][CH2:10][CH2:11][O:12][C:7]=2[CH:6]=1.B(Cl)(Cl)Cl>ClCCl>[Cl:1][C:2]1[CH:18]=[CH:17][C:16]([C@H:19]2[C@H:24]([OH:25])[C@@H:23]([OH:33])[C@H:22]([OH:41])[C@@H:21]([CH2:49][OH:50])[S:20]2)=[CH:15][C:3]=1[CH2:4][C:5]1[CH:14]=[CH:13][C:8]2[O:9][CH2:10][CH2:11][O:12][C:7]=2[CH:6]=1
Reactant: Clc1ccc([C@@H]2S[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc2c(c1)OCCO2
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: OC[C@H]1S[C@@H](c2ccc(Cl)c(Cc3ccc4c(c3)OCCO4)c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 11.4 %

Procedure:
6-(2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-thiopyran-2-yl)benzyl)-2,3-dihydrobenzo[b][1,4]dioxine (126, 204 mg, 0.26 mmol) in dichloromethane (5 mL) reacted with BCl3 (1.5 mL) at 0° C. The reaction mixture was stirred at 0° C. for 0.5 h. After quenching the reaction with methanol, solvent was evaporated under a reduced pressure. Purification by reverse phase preparative HPLC (Gilson®, SunFire™ Prep, 5 to 50% acetonitrile in water gradient) provided the title compound (E047, 13 mg, 12% yield) as a white solid.