Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:6][CH:7]1[CH:11]2[O:12][C:13](=[O:19])[CH:14]3[CH:15]([C:16](O)=[O:17])[CH:8]1[CH2:9][CH:10]23)(=[O:5])[C:2]([CH3:4])=[CH2:3].C(Cl)(=O)C([Cl:23])=O>C1(C)C=CC=CC=1>[C:1]([O:6][CH:7]1[CH:11]2[O:12][C:13](=[O:19])[CH:14]3[CH:15]([C:16]([Cl:23])=[O:17])[CH:8]1[CH2:9][CH:10]23)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)OC1C2CC3C1OC(=O)C3C2C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Product: C=C(C)C(=O)OC1C2CC3C1OC(=O)C3C2C(=O)Cl
Reaction time: 4 h

Procedure:
Suspended into 135 mL of toluene was 18.0 g of the carboxylic acid (26) obtained in Synthesis Example 1-1-2, and then into the resulting suspension was gradually added 10.3 g of oxalyl chloride at 80° C. After this mixture was stirred for 4 hours, toluene was removed by distillation under reduced pressure to obtain the intended product. The obtained acid chloride was used in the next reaction without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:13][C@H:14]([C:16]([NH:18][CH:19]1[N:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23]2[CH:32]=[CH:33][CH:34]=[CH:35][C:22]=2[N:21]([CH2:36][CH:37]2[CH2:39][CH2:38]2)[C:20]1=[O:40])=[O:17])[CH3:15]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:13][C@H:14]([C:16]([NH:18][CH:19]2[N:25]=[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:23]3[CH:32]=[CH:33][CH:34]=[CH:35][C:22]=3[N:21]([CH2:36][CH:37]3[CH2:39][CH2:38]3)[C:20]2=[O:40])=[O:17])[CH3:15])=[O:12])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](N)C(=O)NC1N=C(c2ccccc2)c2ccccc2N(CC2CC2)C1=O
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NC1N=C(c2ccccc2)c2ccccc2N(CC2CC2)C1=O

Procedure:
Following General Procedure D above using 3,5-difluorophenylacetic acid (Oakwood Products, Inc.) and 3-(L-alaninyl)amino-2,3-dihydro-1-cyclopropylmethyl-5-phenyl-1H-1,4-benzodiazepin-2-one (Example 8-L), the title compound was prepared as a solid (mp.=203-205° C.). The product was purified by slurrying in ether/hexanes.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[C:15]3[S:16][CH:17]=[CH:18][C:14]=3[O:13][N:12]=2)[CH:8]=[CH:9][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[C:25](#[N:27])[CH3:26]>>[N:27]1([CH2:2][CH2:3][O:4][C:5]2[CH:6]=[C:7]([C:11]3[C:15]4[S:16][CH:17]=[CH:18][C:14]=4[O:13][N:12]=3)[CH:8]=[CH:9][CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:10][CH2:9][CH2:26][CH2:25]1
Reactant: BrCCOc1cccc(-c2noc3ccsc23)c1
Reactant: CC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Product: c1cc(OCCN2CCCCCCC2)cc(-c2noc3ccsc23)c1

Procedure:
The title compound is prepared from 3-[3-(2-bromo-ethoxy)-phenyl]-thieno[2,3-d]isoxazole, potassium carbonate, heptamethyleneimine and acetonitrile essentially as described above in example 40. Purity by LC/MS (APCI)=99%, [M+H]+=357.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[BH4-:8].[Na+:9]>>[F:1][C:2]([F:7])([F:6])[C:3]([O:5][BH3-:8])=[O:4].[Na+:9]
Reactant: [BH4-]
Reactant: O=C(O)C(F)(F)F
Agent: [Na+]
Product: [BH3-]OC(=O)C(F)(F)F

Procedure:
Sodium trifluoroacetoxyborohydride was prepared in situ from trifluroacetic acid and sodium borohydride, which means the operation was carried out in a single pot.
Reaction SMILES: Br[CH:2]1[C:10]2[N:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[N:8]=[C:7]([CH3:17])[C:6]=2[C:5](=[O:18])[CH2:4][C:3]1([CH3:20])[CH3:19].C[C:22](C)=[O:23]>CO.[N+]([O-])([O-])=O.[Ag+]>[CH3:22][O:23][CH:2]1[C:10]2[N:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[N:8]=[C:7]([CH3:17])[C:6]=2[C:5](=[O:18])[CH2:4][C:3]1([CH3:20])[CH3:19]
Reactant: CC(C)=O
Reactant: Cc1nn(-c2ccccn2)c2c1C(=O)CC(C)(C)C2Br
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CO
Product: COC1c2c(c(C)nn2-c2ccccn2)C(=O)CC1(C)C
Reaction time: 48 h
Yield: 25 %

Procedure:
A solution of 0.1N silver nitrate in methanol (12 ml, 1.2 mmol) was added to a solution of 7-bromo-1-(2-pyridyl)-3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydroindazole (0.2 g, 0.6 mmol), prepared as described in example 4, in acetone (12 ml). After stirring for about 48 hours, 6 ml of a 0.1N silver nitrate solution in methanol were added. The reaction mixture was stirred for further 72 hours and then filtered. The solvent was evaporated and the residue was chromatographed on silica gel (cyclohexane:ethyl acetate=90:10) to yield the title compound as a colourless solid (0.044 g, 25%): m.p. 86-89° C.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1([C:17]2[NH:21][C:20](=[O:22])[O:19][N:18]=2)[C:11]2([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:10]1)(C)(C)C.[ClH:24].CCOCC>O1CCOCC1>[ClH:24].[NH2:7][CH2:8][C:9]1([C:17]2[NH:21][C:20](=[O:22])[O:19][N:18]=2)[C:11]2([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]2)[CH2:10]1
Reactant: CC(C)(C)OC(=O)NCC1(c2noc(=O)[nH]2)CC12CCCCC2
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: NCC1(c2noc(=O)[nH]2)CC12CCCCC2
Reaction time: 18 h
Yield: 64 %

Procedure:
To a solution of [1-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-spiro[2.5]oct-1-ylmethyl]-carbamic acid tert-butyl ester (4.30 g, 13.3 mmol) in 1,4-dioxane (90 mL) was added 4N HCl in 1,4-dioxane (45 mL). The solution was stirred for 18 hours, ether (200 mL) was added and the precipitate isolated by vacuum filtration. The residue was chromatographed on a wet-packed silica gel column (5.5×30 cm) eluting with 80:20:5 CH2Cl2/MeOH/NH4OH. The appropriate fractions were combined and evaporated under reduced pressure. The solid was stirred with 1N HCl in ether (150 mL). The solid was isolated by vacuum filtration, dried in a vacuum oven at 48° C. to give 2.22 g (64%) of 3-(1-aminomethyl-spiro[2.5]oct-1-yl)-4H-[1,2,4]oxadiazol-5-one hydrochloride as a white solid: mp: 179-181° C. (decomposition); 1H NMR (300 MHz, CD3OD) δ 1.05 (d, J=5.8 Hz, 1H), 1.21 (m, 1H), 1.41 (d, J=5.8 Hz, 1H), 1.4-1.72 (m, 9H), 3.12 (d, J=14 Hz, 1H), 3.54 (d, J=14 Hz, 1H); MS (APCI) m/z 224 [M+H]+. Anal. Calc'd For C11H17N3O2—HCl: C, 50.52; H, 7.01; N, 16.07; Cl, 13.56. Found: C, 50.23; H, 7.05; N, 15.89; Cl, 13.53.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH2:14][CH2:13][NH:12][C:11]3=[O:15])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.Br[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:22]=1[CH:23]([F:25])[F:24].N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH2:14][CH2:13][N:12]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][C:22]=4[CH:23]([F:25])[F:24])[C:11]3=[O:15])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C1NCCN1c1ccc2ncsc2c1
Reactant: FC(F)c1ccncc1Br
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: O=C1N(c2ccc3ncsc3c2)CCN1c1cnccc1C(F)F
Yield: 2 %

Procedure:
Using the same reaction conditions as in Example 14, 1-benzothiazol-6-yl-imidazolidin-2-one (I-84b: 75 mg, 0.3173 mmol) was reacted with 3-bromo-4-difluoromethyl-pyridine (60 mg, 0.2884 mmol), 1,4-dioxane (5 mL), copper iodide (7.5 mg), trans-1,2-diamino cyclohexane (15 mg) and potassium phosphate (122 mg, 0.5769 mmol) to afford the crude product. Purification by column chromatography on silica gel (2% MeOH in CHCl3), followed by preparative HPLC afforded 2 mg of the product (2% yield).
Reaction SMILES: Cl.[Br:2][CH2:3][CH2:4][NH2:5].C(N(CC)CC)C.[CH2:13]([O:20][C:21](Cl)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)Cl>[CH2:13]([O:20][C:21]([NH:5][CH2:4][CH2:3][Br:2])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCCBr
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCBr)OCc1ccccc1
Reaction time: 19 h

Procedure:
To a solution of 2-bromoethylamine hydrochloride (25 g: a product of Tokyo Kasei Kogyo Co., Ltd.) and triethylamine (34 ml) in methylene chloride (450 ml), benzyloxycarbonyl chloride (19 ml) was added dropwise over a period of 20 minutes and the mixture was agitated at room temeprature for 19 hours. The resulting reaction mixture was washed with water, with saturated aqueous sodium bicarbonate solution and with saturated aqueous sodium chloride succeedingly, whereupon the separated organic layer was dried and, then, removed off the solvent by distilling it of under reduced pressure. The residue was cooled with ice and the crystals were collected by filtration and washed with hexane, whereby the above-identified compound was obtained (29.4 g).
Reaction SMILES: FC(F)(F)S([O-])(=O)=O.[Ca+2].FC(F)(F)S([O-])(=O)=O.[C:18]1([S:24]([N:27]2[C:39]3[CH2:38][NH:37][CH2:36][CH2:35][C:34]=3[C:33]3[C:28]2=[CH:29][CH:30]=[CH:31][CH:32]=3)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[O:40]1[CH2:42][CH:41]1[CH:43]1[CH2:52][CH2:51][C:46]2([O:50][CH2:49][CH2:48][O:47]2)[CH2:45][CH2:44]1>O1CCCC1>[C:18]1([S:24]([N:27]2[C:39]3[CH2:38][N:37]([CH2:42][CH:41]([CH:43]4[CH2:52][CH2:51][C:46]5([O:50][CH2:49][CH2:48][O:47]5)[CH2:45][CH2:44]4)[OH:40])[CH2:36][CH2:35][C:34]=3[C:33]3[C:28]2=[CH:29][CH:30]=[CH:31][CH:32]=3)(=[O:26])=[O:25])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: C1COC2(CCC(C3CO3)CC2)O1
Reactant: O=S(=O)(c1ccccc1)n1c2c(c3ccccc31)CCNC2
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Ca+2]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1c2c(c3ccccc31)CCN(CC(O)C1CCC3(CC1)OCCO3)C2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Calcium trifluoromethanesulfonate (1.22 g, 3.60 mmol) was added to a solution of the product from stage 3 (2.51 g, 8.05 mmol) and 8-oxiranyl-1,4-dioxaspiro[4.5]decane (1.34 g, 7.30 mmol) in anhydrous tetrahydrofuran (50 ml) and the mixture was stirred at room temperature for 48 h. The tetrahydrofuran was removed i. vac. The residue was taken up in methylene chloride (40 ml) and the mixture was washed with 25% potassium carbonate solution (2×25 ml). The organic phase was dried with sodium sulfate and concentrated i. vac. The crude product (4.31 g) was purified by flash chromatography with cyclohexane/ethyl acetate (1:2).
Reaction SMILES: [F:1][C:2]1[C:17]([F:18])=[C:16]([F:19])[C:15]([F:20])=[C:14]([F:21])[C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12]C)=[CH:8][CH:7]=1)=[O:5].B(Br)(Br)Br>C(Cl)CCl>[F:1][C:2]1[C:17]([F:18])=[C:16]([F:19])[C:15]([F:20])=[C:14]([F:21])[C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)=[O:5]
Reactant: COc1ccc(C(=O)c2c(F)c(F)c(F)c(F)c2F)cc1
Agent: BrB(Br)Br
Solvent: ClCCCl
Product: O=C(c1ccc(O)cc1)c1c(F)c(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 72.5 %

Procedure:
A solution of 5.6 g of 2,3,4,5,6-pentafluoro-4'-methoxy-benzophenone in 100 ml of ethylene chloride was added dropwise at -7° under argon to a solution of 23.23 g of boron tribromide in 100 ml of ethylene chloride. The reaction mixture was warmed to room temperature and stirred at this temperature for 5 hours. The reaction mixture was poured into 200 ml of ice-cold water and extracted three times with 150 ml of methylene chloride each time. The combined extracts were washed with 200 ml of water and dried over magnesium sulphate. After evaporation of the solvent the residue was chromatographed on 900 g of silica gel with methylene chloride. There were obtained 3.87 g (72%) of 2,3,4,5,6-pentafluoro-4'-hydroxy-benzophenone; m.p. 138°-140°.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[S:9][C:10]([CH:13](O)[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])=[CH:11][N:12]=1)(C)(C)C.C([SiH](CC)CC)C.[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35]>ClCCl>[CH3:22][O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH2:14][CH2:13][C:10]1[S:9][C:8]([NH2:7])=[N:12][CH:11]=1.[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35]
Reactant: COc1ccccc1CC(O)c1cnc(NC(=O)OC(C)(C)C)s1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1CCc1cnc(N)s1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of {5-[1-Hydroxy-2-(2-methoxy-phenyl)-ethyl]-thiazol-2-yl}-carbamic acid tert-butyl ester (28 g, 0.080 mol), triethylsilane (130 g, 1.12 mol) and trifluoroacetic acid (250 g, 2.24 mol) in dichloromethane (500 mL) was stirred at room temperature for 15 hours. The mixture was evaporated to dryness and then stirred in water. The solid was filtered and washed with ether to give 5-[2-(2-Methoxy-phenyl)-ethyl]-thiazol-2-ylamine as a trifluoracetic acid salt (11 g, 0.033 mol, yield 42%). ESI-MS m/z cacl. 234.08. found 235.16 (M+1)+ 1H NMR (CDCl3) δ 8.81 (br, 2H), 7.20 (t, 1H), 7.12 (d, 1H), 6.95 (m, 2H), 6.85 (t, 1H), 3.76 (s, 3H), 2.83 (d, 2H), 2.80 (d, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([F:13])[C:10]([N+:14]([O-])=O)=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]>C(O)(=O)C.C(OCC)(=O)C.[Fe]>[NH2:14][C:10]1[C:11]([F:13])=[CH:12][C:2]([Cl:1])=[C:3]([CH:9]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(F)cc1Cl
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(N)c(F)cc1Cl
Temperature: 40 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
Then, 60 g of iron powder and 500 ml of 10% acetic acid were mixed, and the mixture was heated to 40° C. Separately, 50 g (0.20 mol) of ethyl 2-chloro-4-fluoro-5-nitrobenzoate was dissolved in a mixed solution of 20 ml of acetic acid and 20 ml of ethyl acetate. and added dropwise to the above iron powder-acetic acid mixed solution. Then, the reaction mixture was stirred at 50° C. for 1 hour and filtered though celite. The filtrate was extracted with 100 ml of ethyl acetate. The ethyl acetate layer was washed with aqueous sodium bicarbonate solution and saturated sodium chloride solution, and dried with magnesium sulfate. The solvent was distilled out, and the residue was purified by silica gel chromatography, which afforded to 40 g (0.18 mol) of ethyl 5-amino-2-chloro-4-fluorobenzoate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH:4]([CH2:8][C:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][C:17]([F:20])([F:19])[F:18])[C:5](=O)[CH3:6].[CH2:23]([NH2:29])[C@H:24]1[O:28][CH2:27][CH2:26][CH2:25]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:1][O:2][C:3]([C:4]1[CH:8]=[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][C:17]([F:20])([F:19])[F:18])[N:29]([CH2:23][C@@H:24]2[CH2:25][CH2:26][CH2:27][O:28]2)[C:5]=1[CH3:6])=[O:22]
Reactant: COC(=O)C(CC(=O)c1ccccc1OC(F)(F)F)C(C)=O
Reactant: NC[C@@H]1CCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(=O)c1cc(-c2ccccc2OC(F)(F)F)n(C[C@@H]2CCCO2)c1C
Temperature: 25 °C

Procedure:
To a solution of 250 mg of 3-oxo-2-[2-oxo-2-(2-trifluoromethoxy-phenyl)-ethyl]-butyric acid methyl ester in methanol was added 84 μl of (S)-tetrahydrofurfurylamine and 5 mg of p-toluene sulfonic acid. The reaction mixture was then heated at reflux for 24 hours. After such time the reaction mixture was allowed to cool to room temperature before being concentrated in vacuo and purified by column chromatography to give 171 mg of the title compound; MS (EI) 383.1 (M)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]([OH:10])[CH3:9])[CH:3]=1.[S:11](Cl)([CH3:14])(=[O:13])=[O:12]>CN(C1C=CN=CC=1)C.ClCCl>[CH3:14][S:11]([O:10][CH:8]([C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][N:5]=1)[CH3:9])(=[O:13])=[O:12]
Reactant: CC(O)c1cc(Br)ccn1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(OS(C)(=O)=O)c1cc(Br)ccn1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A stirring solution of the 1-(4-bromopyridin-2-yl)ethanol (3.72 g, 18.41 mmol and DMAP (4.5 g, 36.82 mmol) in 75 mL of dichloromethane was cooled to 0° C. To it was added mesyl chloride (1.71 mL, 22.09 mmol) dropwise. The mixture was stirred at 0° C. for 10 minutes, then warmed to room temperature and stirred for 15 min. The reaction was quenched with 50 mL ice water, the layers were separated, and the aqueous layer was extracted with dichloromethane (50 mL). The organics were combined, washed with water and brine, dried over Na2SO4, and purified by column chromatography (gradient 0 to 45% EtOAc/hexanes) to afford the product. 1H NMR (400 MHz, CDCl3) δ 8.40 (d, J=5.3 Hz, 1H), 7.64 (d, J=1.6 Hz, 1H), 7.45 (dd, J=5.3, 1.8 Hz, 1H), 5.75 (q, J=6.6 Hz, 1H), 3.00 (s, 3H), 1.75 (d, J=6.6 Hz, 3H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([O:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=O)(=[O:9])[CH3:8].[NH2:20][C:21]1[CH:33]=[C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:31]=[CH:30][C:22]=1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].C(=O)([O-])O.[Na+]>C(N(CC)CC)C.C(Cl)Cl.CN(C)C=O>[C:7]([O:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([NH:20][C:21]1[CH:33]=[C:32]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:31]=[CH:30][C:22]=1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:15])(=[O:9])[CH3:8]
Reactant: CC(=O)Oc1ccccc1C(=O)O
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1N
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccccc1C(=O)Nc1cc(-c2ccccc2)ccc1C(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
2.0 mL of methylene chloride, 3.9 μL of N,N-dimethylformamide and 0.094 mL of oxalyl chloride were added to 180 mg of 2-acetoxybenzoic acid at room temperature sequentially and stirred at the same temperature for 1 hour. The reaction mixture was added to a mixed solution of 81 mg of tert-butyl 2-amino-4-phenylbenzoate, 3.0 mL of methylene chloride and 0.67 mL triethylamine, and stirred at room temperature for 1 hour. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, and the organic layer was separated, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane:ethyl acetate=4:1] to obtain tert-butyl 2-(2-acetoxybenzamido)-4-phenylbenzoate.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].N1C=CC=CC=1.[CH3:15][CH:16]([C:22](OCC)=[O:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:22](=[O:23])[CH:16]([CH3:15])[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: Nc1ccccc1F
Reactant: CCOC(=O)C(C)C(=O)OCC
Solvent: c1ccncc1
Product: CCOC(=O)C(C)C(=O)Nc1ccccc1F

Procedure:
Prepared according to general Procedure A using 2-fluoroaniline (17 mL, 180 mmol), pyridine (29 mL, 360 mmol) and diethyl methylmalonate (46 mL, 270 mmol). The crude was purified by column chromatography on silica (using a gradient of hexanes:EtOAc, 1:0 to 4:1 as eluant) to give ethyl 3-(2-fluorophenylamino)-2-methyl-3-oxopropanoate as a light brown solid. Mass Spectrum (ESI) m/e=239.9 (M+1).
Reaction SMILES: [H-].[Na+].[CH:3]12[CH2:8][CH:7]1[C:6](=[O:9])[NH:5][C:4]2=[O:10].I[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].CN(C)C=O>O1CCCC1.ClCCl>[CH2:12]([N:5]1[C:6](=[O:9])[CH:7]2[CH:3]([CH2:8]2)[C:4]1=[O:10])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCI
Reactant: O=C1NC(=O)C2CC12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCCCCN1C(=O)C2CC2C1=O
Reaction time: 0.08 h

Procedure:
Sodium hydride (0.11 g) was added to a solution of 3-azabicyclo[3.1.0]hexane-2,4-dione (0.3 g) in dry tetrahydrofuran (10 ml) under a nitrogen atmosphere at room temperature. The suspension was stirred for 5 minutes and 1-iodoheptane (0.61 g) was then added in one portion to the reaction mixture. After stirring for two hours at room temperature, dimethylformamide (5 ml) was added and the reaction mixture was stirred for a further 16 hours at room temperature. The reaction mixture was diluted with dichloromethane and then partitioned with water (20 ml). The aqueous phase was extracted with dichloromethane (20 ml) and the combined organic extracts were washed with water (2×20 ml), dried (MgSO4) and evaporated in vacuo. The residue was purified by chromatography on silica gel (50 g) using 25-30% ethyl acetate/hexane as eluant to give the title compound as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[C:8]([CH3:14])([CH3:13])[C:7](=[O:15])[C:6]([C:16]([NH:18][CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])=[O:17])=[C:5]2[OH:27]>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[C:8]([CH3:14])([CH3:13])[C:7](=[O:15])[C:6]([C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])=[C:5]2[OH:27]
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cc(Cl)cc(F)c2C(C)(C)C1=O
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)C(=O)C(C(=O)NCC(=O)O)=C(O)c2cc(Cl)cc(F)c21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 112.2 %

Procedure:
1,1-Dimethylethyl N-((6-chloro-8-fluoro-4-hydroxy-1,1-dimethyl-2-oxo-naphthalene-3-yl)carbonyl)glycinate (227 mg, 571 μmol) was dissolved in TFA (2 mL) and stirred at ambient temperature for 30 minutes. The resulting mixture was concentrated, precipitated with hexanes, filtered, washed with hexanes, and dried in a vacuum oven to give the title compound (219 mg, 112% yield) as a white solid. MS (m/z)=342 (M+H)+. Calculated for C15H13ClFNO5 341.05.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=O.C(O)(C)C.Cl.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24]N)=[CH:20][CH:19]=1.C([O-])(O)=O.[Na+]>O>[CH3:16][O:17][C:18]1[CH:19]=[C:20]2[C:21](=[CH:22][CH:23]=1)[NH:24][C:2]1[CH2:3][C:4]3[C:9]([C:1]2=1)=[CH:8][CH:7]=[CH:6][CH:5]=3
Reactant: COc1ccc(NN)cc1
Reactant: O=C1Cc2ccccc2C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: COc1ccc2[nH]c3c(c2c1)-c1ccccc1C3
Temperature: 82 °C
Yield: 96.7 %

Procedure:
8.21 g of 2-indanone (Aldrich, 98%, Mw=132.16, 60.88 mmol), 40 mL of isopropanol, 10.84 g of p-methoxyphenylhydrazin hydrochloride (Aldrich, 98%, Mw=174.63, 60.83 mmol) were charged at room temperature in a 250 mL flask equipped with magnetic stirrer. The slurry was brought to reflux (82° C.), (a black slurry was obtained), and kept at reflux for 1 hour. The dark brown viscous suspension was then cooled to room temperature; 200 mL of water saturated with NaHCO3 were added into the reactor (final pH ca. 7.5-8), the resulting mixture was filtered and the residue washed with plenty of water. The dark green solid on the filter was dried in vacuo at 70° C. for 4 hours (14 g, 98.9% pure by GC, 96.7% yield of pure product).
Reaction SMILES: [CH3:1][O:2][C@:3]([CH3:16])([CH2:12][CH2:13][CH2:14][CH3:15])[C@@H:4]([OH:11])[C:5]#[C:6][Si](C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH3:1][O:2][C@:3]([CH3:16])([CH2:12][CH2:13][CH2:14][CH3:15])[C@@H:4]([OH:11])[C:5]#[CH:6]
Reactant: CCCC[C@@](C)(OC)[C@@H](O)C#C[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#C[C@H](O)[C@@](C)(CCCC)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.3 %

Procedure:
Dissolve (3S,4R)-4-methoxy-4-methyl-1-trimethylsilyl-1-octyn-3-ol (90 mg, 0.37 mmol) in tetrahydrofuran (2 mL) and place under an argon atmosphere. Add, by dropwise addition, tetra-n-butylammonium fluoride (3.7 mL) of a 1M solution in tetrahydrofuran, 3.7 mmol). Stir for 1 hour at room temperature and partition between methylene chloride and water. Separate the organic phase, wash with saturated aqueous sodium chloride and dry (MgSO4). Evaporate the solvent in vacuo and purify by silica gel chromatography (19:1 hexane/ethyl acetate) to give the title compound as a clear thick oil (55 mg, 87%).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[Cl-].[CH3:11][C:12]1[NH:16][C:15]([CH3:17])=[CH:14][NH+:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:11][C:12]1[N:13]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH:14]=[C:15]([CH3:17])[N:16]=1
Reactant: Cc1c[nH+]c(C)[nH]1
Reactant: N#Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cn(-c2ccc(C#N)cc2)c(C)n1
Temperature: 145 °C
Yield: 52.7 %

Procedure:
A mixture of 4-fluorobenzonitrile (3 g, 25 mmol), 2,4-dimethylimidazolium chloride (3 g, 25 mmol) and potassium carbonate (7.2 g, 52 mmol) in dimethylformamide (50 ml) was heated at 145° C. for 16 hours. Most of the solvent was evaporated in vacuo and the residue was partitioned between ethyl acetate and brine. The organic layer was driied (magnesium sulphate) and evaporated a yellow solid. Crystallization from hexane/ether afforded a pale-yellow solid (2.6 g, 57%).