Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=1.O.O.Cl[Sn]Cl.[OH-].[Na+]>C(O)C>[CH3:1][O:2][C:3](=[O:15])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1
Reactant: COC(=O)C=Cc1ccc([N+](=O)[O-])cc1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COC(=O)C=Cc1ccc(N)cc1
Temperature: 75 °C

Procedure:
A mixture of 3-(4-nitro-phenyl)-acrylic acid methyl ester (72) (39.54 g, 0.191 mol) and SnCl2.2H2O (220 g, 0.98 mol) in anhydrous ethanol (300 ml) was heated at 50° C. for 1 hour and at 75° C. for 1 hour. The reaction mixture was allowed to cool to 10° C., treated with 20% NaOH solution to pH 8–9, and extracted with ethyl acetate (3×200 ml). The organic extract was washed with saturated NaCl (3×150 ml), dried (MgSO4), and evaporated under reduced pressure. Recrystallization from isopropanol (180 ml) afforded pure title compound in a form of yellowish crystals (17.938 g, 53%). 1H NMR (DMSO-d6, HMDSO), δ: 3.64 (3H, s); 5.73 (2H, s); 6.22 (1H, d, J=16.0 Hz); 6.57 (2H, d, J=8.0 Hz); 7.38 (2H, d, J=8.0 Hz); 7.50 (1H, d, J=16.0 Hz).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.C[OH:15]>O>[C:10]([O:9][C:7]([N:1]1[CH2:2][C:3](=[O:15])[S:4][CH2:5][CH2:6]1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCSCC1
Reactant: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCSC(=O)C1
Temperature: 0 °C
Reaction time: 72 h
Yield: 97 %

Procedure:
A mechanically-stirred mixture of tert-butyl thiomorpholine-4-carboxylate (243 g, 1.19 mol), MeOH (1.5 L), and H2O (1.5 L) was cooled to 0° C. Solid NaIO4 (280 g, 1.3 mol) was added in portions over a 2 hour period. For convenience, the suspension was stirred for 3 days at room temperature. The solids were filtered, washing with MeOH (3×500 mL). The filtrate was concentrated. Residual water was saturated with solid NaCl, and the aqueous phase was extracted with EtOAc (4×200 mL). The combined organic phases were dried (MgSO4), filtered, and concentrated to obtain the product (255 g, 97%).
Reaction SMILES: [C:1]([Si:5]([CH3:22])([CH3:21])[O:6][C@@H:7]1[CH2:12][C@@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][NH:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32]>C1COCC1>[CH2:34]([O:33][C:31]([N:9]1[CH2:10][C@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:12][C@@H:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:22])[CH3:21])[CH2:8]1)=[O:32])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CNC[C@H](O[Si](C)(C)C(C)(C)C)C1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Yield: 92.3 %

Procedure:
To a solution of 0.50 g (1.4 mmol) (3R,5R)-3,5-bis-(tert-butyl-dimethyl-silanyloxy)-piperidine and 0.15 g (1.5 mmol) triethylamine in 30 ml of THF was added dropwise a solution of 0.26 g (1.5 mmol) benzyl chloroformate in 2 ml of THF at 0° C. After completed addition, the mixture was allowed to warm to room temperature during 30 min. Quenching with a saturated aqueous solution of sodium hydrogencarbonate was followed by extraction with three portions of dichloromethane. The combined organic extracts were washed with brine and dried over sodium sulfate. Flash chromatography gave 0.62 g (90%) of the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:10]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[N:11][C:12]3[C:17]([N:18]=2)=[CH:16][C:15]([C:19]([O:21]C)=[O:20])=[CH:14][CH:13]=3)[C@@H:5]([CH3:30])[CH2:4]1)[CH3:2].[OH-].[Na+].O>CO>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:10]([C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)=[N:11][C:12]3[C:17]([N:18]=2)=[CH:16][C:15]([C:19]([OH:21])=[O:20])=[CH:14][CH:13]=3)[C@@H:5]([CH3:30])[CH2:4]1)[CH3:2]
Reactant: CCN1CCN(c2nc3cc(C(=O)OC)ccc3nc2-c2ccc(F)cc2)[C@@H](C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCN1CCN(c2nc3cc(C(=O)O)ccc3nc2-c2ccc(F)cc2)[C@@H](C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.8 %

Procedure:
To a solution of (S)-methyl 3-(4-ethyl-2-methylpiperazin-1-yl)-2-(4-fluorophenyl)quinoxaline-6-carboxylate (80 mg, crude) in methanol (30 mL) was added sodium hydroxide (31.0 mg, 0.78 mmol) and water (1 mL), and the reaction was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo, dissolved in water (30 mL), and adjusted to pH 5 with HCl (3N) to give the precipitate, which was purified by Prep-HPLC with the following conditions [(Agilent 1200 prep HPLC): Column, SunFire Prep C18, 19*50 mm 5 um; mobile phase, water with 0.05% NH3.H2O and CH3CN (10% CH3CN up to 45% in 10 min); Detector, UV 220 nm] to afford (S)-3-(4-ethyl-2-methylpiperazin-1-yl)-2-(4-fluorophenyl)quinoxaline-6-carboxylic acid (40 mg, 52.0%).
Reaction SMILES: [F:1][CH:2]([F:19])[C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[CH:11][CH:10]=2)[CH:6]=[CH:5][N:4]=1.[N:20]1[CH:25]=[CH:24][N:23]=[CH:22][C:21]=1[C:26]1[CH:27]=[CH:28][C:29]([NH2:32])=[N:30][CH:31]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C>[F:19][CH:2]([F:1])[C:3]1[CH:8]=[C:7]([C:9]2[CH:10]=[CH:11][C:12]([CH2:15][C:16]([NH:32][C:29]3[CH:28]=[CH:27][C:26]([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][N:20]=4)=[CH:31][N:30]=3)=[O:18])=[CH:13][CH:14]=2)[CH:6]=[CH:5][N:4]=1
Reactant: Nc1ccc(-c2cnccn2)cn1
Reactant: O=C(O)Cc1ccc(-c2ccnc(C(F)F)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(-c2ccnc(C(F)F)c2)cc1)Nc1ccc(-c2cnccn2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(4-(2-(difluoromethyl)pyridin-4-yl)phenyl)acetic acid 203-5 (70 mg, 0.27 mmol), 5-(pyrazin-2-yl)pyridin-2-amine (55 mg, 0.32 mmol), N,N-diisopropylethylamine (139 μL, 0.80 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (152 mg, 0.40 mmol) in DMF (2 mL) was stirred at room temperature overnight. The solvent was removed by rotary evaporation. The crude product was purified by reverse phase HPLC to give 2-(4-(2-(difluoromethyl)pyridin-4-yl)phenyl)-N-(5-(pyrazin-2-yl)pyridin-2-yl)acetamide 203. MS m/z 418.2 (M+1); 1H NMR 400 MHz (CDCl3) δ 8.99(d, 1H), 8.90(dd, 1H), 8.70(d, 1H), 8.63(dd, 1H), 8.53(d, 1H), 8.40-8.33(m, 2H), 8.30(s, 1H), 7.84(s, 1H), 7.70-7.68(m, 2H), 7.62-7.60(m, 1H), 7.50-7.49(m, 2H), 6.70(t, 1H), 3.87(s, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][O:10][CH3:11])=[CH:4][N:3]=1.[F:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C)C=O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:12][C:13]1[CH:18]=[C:17]([C:2]2[CH:7]=[CH:6][C:5]([O:8][CH2:9][O:10][CH3:11])=[CH:4][N:3]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: COCOc1ccc(Cl)nc1
Reactant: OB(O)c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1ccc(-c2cccc(F)c2)nc1
Reaction time: 0.5 h
Yield: 81.9 %

Procedure:
200 mg (1.0 eq) of the obtained 2-chloro-5-(methoxymethoxy)pyridine was dissolved in N,N-dimethylformamide/H2O=5:1 (16 mL), 193 mg (1.2 eq) of (3-fluorophenyl)boronic acid, 48 mg (3 mol %) of Pd(PPh3)4 and 586 mg (4.0 eq) of Na2CO3 were added. After reacting with microwave reactor at 120° C. for 30 minutes, N,N-dimethylformamide was removed by concentrating under reduced pressure. After extracting with ethyl acetate, the extract was treated with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography (developing solvent, hexane:ethyl acetate=9:1) to obtain 220 mg of 2-(3-fluorophenyl)-5-(methoxymethoxy)pyridine.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([NH:10][S:11](/[CH:14]=[CH:15]/[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=1.[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]Br.O>C1COCC1>[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][N:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([Cl:3])[CH:5]=1)[S:11](/[CH:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=1)(=[O:13])=[O:12]
Reactant: O=S(=O)(/C=C/c1cccc(Cl)c1)Nc1cccc(Cl)c1
Reactant: Clc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=S(=O)(/C=C/c1cccc(Cl)c1)N(Cc1cccc(Cl)c1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
To a well-stirred suspension of NaH (23.2 mg, 0.92 mmol, 5.6 eq.) in 4 mL of THF, a THF solution (1.5 mL) of compound 2 (53.9 mg, 0.16 mmol, 1 eq.) was added and the mixture was stirred for 1 hour at room temperature. Afterwards, the reaction mixture was cooled at 0° C. and a THF solution (1.5 mL) of 3-chlorobenzylbromide (52.2 mg, 0.25 mmol, 1.5 eq.) was added. After the reaction mixture was stirred at room temperature for 22 h, water was added and the product was extracted three times from the aqueous phase with EtOAc. The resulting organic phase was washed with brine, dried under Na2SO4 and the solvent evaporated. After the product was purified from the crude by flash column chromatography (15% EtOAc/hexanes), compound ef-rs-03-075 (26.1 mg, 0.06 mmol) was obtained in a 35% yield. 1H NMR (400 MHz, CDCl3) δ 7.46 (s, ArH, 1H), 7.42 (dt, J=7.6, 1.7 Hz, ArH, 1H), 7.36 (m, ArH, 3H), 7.23 (m, ArH, 6H), 7.14 (m, ArH, 2H), 6.78 (d, J=15.4 Hz, C═CH, 1H), 4.76 (s, CH2, 2H). 13C NMR (100 MHz, CDCl3, δ): 141.55 (CH), 140.00 (C), 137.62 (C), 135.26 (C), 134.81 (C), 134.51 (C), 134.14 (C), 131.04 (CH), 130.45 (CH), 130.24 (CH), 129.92 (CH), 128.91 (CH), 128.56 (CH), 128.49 (CH), 128.27 (CH), 127.97 (CH), 127.03 (CH), 126.59 (CH), 126.55 (CH), 124.48 (CH), 54.36 (CH2).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:8][C:9]=1[NH:10][CH:11]([CH3:14])[CH2:12]O)=[O:4].C(OC([N+](C(OCC)=O)=[N-])=O)C.C1(P([N:47]=[N+:48]=[N-:49])(C2C=CC=CC=2)=O)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:8][C:9]=1[NH:10][CH:11]([CH3:14])[CH2:12][N:47]=[N+:48]=[N-:49])=[O:4]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1sc(-c2ccccc2)cc1NC(C)CO
Agent: CCOC(=O)[N+](=[N-])C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COC(=O)c1sc(-c2ccccc2)cc1NC(C)CN=[N+]=[N-]

Procedure:
A mixture of 3-(2-Hydroxy-1-methyl-ethylamino)-5-phenyl-thiophene-2-carboxylic acid methyl ester (213 mg, 0.257 mmol), diethyldiazodicarboxylate (250 μL, 1.59 mmol, 2 eq), diphenylphosphoryl azide (343 μL, 1.59 mmol, 2 eq) and triphenyl phosphine (417 mg, 1.59 mmol, 2 eq) was stirred at 21° until all starting alcohol was consumed. The reaction was evaporated to dryness and the crude residue purified on biotage with 5% EtOAc/hexane followed by 100% toluene as eluent. 3-(2-Azido-1-methyl-ethylamino)-5-phenyl-thiophene-2-carboxylic acid methyl ester was isolated as a solid (181 mg, 78%); 1H NMR (300 MHz, CDCl3) 1.33 (d, J=6.6 Hz, 3H), 3.38-3.46 (m, 2H), 3.78-3.81 (m, 1H), 6.82 (s, 1H), 7.36-7.41 (m, 3H), 7.60-7.62 (m, 2H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([NH:12][CH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1)=[O:11].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[Cl:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40]Br)=[CH:38][CH:37]=1>O>[Cl:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40][N:1]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=[C:2]2[C:10]([NH:12][CH2:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=2)=[O:11])=[CH:38][CH:37]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: COC(=O)c1ccc(CNC(=O)c2nc3ccccc3[nH]2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(CNC(=O)c2nc3ccccc3n2Cc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 83.4 %

Procedure:
To a mixture of methyl 4-{[(1H-benzimidazol-2-ylcarbonyl)amino]methyl}benzoate (230 mg), potassium carbonate (257 mg), and DMF (4.6 mL) was added p-chlorobenzylbromide (191 mg), followed by stirring at room temperature for 2.5 days. To the reaction mixture was added water (30 mL), followed by extraction with ethyl acetate (30 mL). The organic layer was sequentially washed with saturated aqueous sodium bicarbonate and saturated brine, and dried over anhydrous magnesium sulfate. After filtration and concentration, the obtained residue was washed with methanol (2 mL) to obtain methyl 4-[({[1-(4-chlorobenzyl)-1H-benzimidazol-2-yl]carbonyl}amino)methyl]benzoate (269 mg) as a white solid.
Reaction SMILES: C([O:4][C:5](=[O:49])[CH:6]([NH:15][C:16]([O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][O:26][C:27]([N:29]2[C:35]3[CH:36]=[C:37]([O:42][CH3:43])[C:38]([O:40][CH3:41])=[CH:39][C:34]=3[C:33](=[O:44])[N:32]3[CH2:45][CH2:46][CH2:47][C@H:31]3[C@@H:30]2[OH:48])=[O:28])=[CH:21][CH:20]=1)=[O:17])[CH2:7][CH2:8][C:9]([O:11]CC=C)=[O:10])C=C.N1CCCC1>C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:41][O:40][C:38]1[C:37]([O:42][CH3:43])=[CH:36][C:35]2[N:29]([C:27]([O:26][CH2:25][C:22]3[CH:21]=[CH:20][C:19]([O:18][C:16]([NH:15][CH:6]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[C:5]([OH:49])=[O:4])=[O:17])=[CH:24][CH:23]=3)=[O:28])[C@@H:30]([OH:48])[C@@H:31]3[CH2:47][CH2:46][CH2:45][N:32]3[C:33](=[O:44])[C:34]=2[CH:39]=1
Reactant: C=CCOC(=O)CCC(NC(=O)Oc1ccc(COC(=O)N2c3cc(OC)c(OC)cc3C(=O)N3CCC[C@H]3[C@@H]2O)cc1)C(=O)OCC=C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNC1
Solvent: ClCCl
Product: COc1cc2c(cc1OC)N(C(=O)OCc1ccc(OC(=O)NC(CCC(=O)O)C(=O)O)cc1)[C@@H](O)[C@@H]1CCCN1C2=O
Yield: 80.5 %

Procedure:
A solution of the diallyl ester 45 (0.596 g, 0.95 mmol, 1 eq), Pd(PPh3)4 (0.055 g, 0.047 mmol, 0.05 eq) and pyrrolidine (0.34 g, 0.39 mL, 4.7 mmol, 5 eq) in anhydrous CH2Cl2 (18 mL) was stirred at room temperature for 1 h and the solvent removed in vacuo. The residue was washed with EtOAc (3×15 mL), dissolved in MeOH (15 mL) and passed down an IRC 50, weakly acidic, ion exchange column, eluting with MeOH (80 mL). The solvent was removed in vacuo to give the product as a white foam (0.46 g, 88%). 1H NMR (d6 DMSO) δ 7.95 (d, J=6.25 Hz, 1H), 7.33 (d, J=8 Hz, 2H), 7.10 (m, 3H) 6.73 (s, 1H), 5. 49 (d, J=9.2 Hz, 1H), 5.2 (d, J=12.5 Hz, 1H), 4.89 (d, J=12.75 Hz, 1H), 4.00 (m, 1H), 3.80 (m, 7H), 3.45 (m, 4H) 2.30 (t, J=7.5 Hz, 2H), 1.95 (m, 5H). MS (ES+) 602.2.
Reaction SMILES: [C:1](Cl)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]C.C[C:22]1(C)[O:29][C:27](=[O:28])[CH2:26][C:24](=[O:25])O1.N1C=CC=CC=1>C(Cl)Cl>[O:25]=[C:24]([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])[CH2:26][C:27]([O:29][CH3:22])=[O:28]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCC(=O)CC(=O)OC

Procedure:
270 ml of stearoyl chloride were added dropwise at a maximum of 150° C. to a solution of 117 g of Meldrum's acid and 131 ml of pyridine in 1.5 l of methylene chloride. After stirring the reaction mixture was washed with 4N hydrochloric acid, the aqueous phase was back-extracted with methylene chloride and the methylene chloride phase was dried and concentrated. The residue was taken up in methanol and stirred under reflux. After cooling the separated crystals were filtered off, dissolved in methylene chloride and chromatographed on silica gel with methylene chloride. There were obtained 175 g of methyl 3-oxoeicosanoate, m.p. 52°-54° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([Mg]Br)[CH:5]=[CH:6][CH:7]=1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>C1COCC1>[C:10]([O:14][C:15]([N:17]1[CH2:18][CH2:19][C:20]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[CH:7]=2)([OH:23])[CH2:21][CH2:22]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Cc1cccc([Mg]Br)c1
Solvent: C1CCOC1
Product: Cc1cccc(C2(O)CCN(C(=O)OC(C)(C)C)CC2)c1
Reaction time: 0.5 h

Procedure:
To a solution of 3-methylphenyl magnesium bromide (58 ml of a 1M solution in THF, 58.0 mmol) at 0° C. was added a solution of N-t-butoxycarbonyl piperidin-4-one (10.0 g, 53 mmol) in THF (30 ml) dropwise over 20 min, and the reaction stirred under argon for a further 30 min. The reaction was quenched by addition of sat NH4Cl solution (100 ml), and diluted with EtOAc. The organic extracts were dried, (MgSO4) and the solvent evaporated in vacuo to afford the title compound of sufficient purity to be used in the next step.
Reaction SMILES: [F:1][B-](F)(F)F.N#[O+].[CH3:8][O:9][C:10](=[O:29])[CH:11]([C:18]1[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[C:20](N)[CH:19]=1)[CH2:12][CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.ClC1C=CC=CC=1Cl>C(Cl)Cl>[CH3:8][O:9][C:10](=[O:29])[CH:11]([C:18]1[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[C:20]([F:1])[CH:19]=1)[CH2:12][CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)c(N)c1
Reactant: F[B-](F)(F)F
Agent: N#[O+]
Solvent: Clc1ccccc1Cl
Solvent: ClCCl
Product: COC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)c(F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A slurry of nitrosonium tetrafluoroborate (215 mg, 1.84 mmol) in methylene chloride (6 mL) was cooled to 0° C. and then treated dropwise with a solution of 2-(3-amino-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid methyl ester (500 mg, 1.54 mmol) in a small amount of methylene chloride. The resulting reaction mixture was stirred at 0° C. for 1 h. The reaction mixture was then allowed to warm to 25° C. and was treated with 1,2-dichlorobenzene (6 mL). The resulting reaction mixture was heated at 100° C. for 1 h, during which time, the methylene chloride was distilled off. After 1 h at 100° C., the reaction mixture was allowed to cool to 25° C. The crude reaction mixture was directly purified by flash chromatography (Merck Silica gel 60, 230–400 mesh, 9/1 hexanes/ethyl acetate to elute 1,2-dichlorobenzene then 2/1 hexanes/ethyl acetate) to afford impure 3-cyclopentyl-2-(3-fluoro-4-methanesulfonyl-phenyl)-propionic acid methyl ester as a yellow oil. Repurification by flash chromatography (Merck Silica gel 60, 230–400 mesh, 3/1 hexanes/ethyl acetate) afforded pure 3-cyclopentyl-2-(3-fluoro-4-methanesulfonyl-phenyl)-propionic acid methyl ester (214 mg, 42%) as a pale yellow oil which solidified upon sitting at 25° C. to a pale yellow solid: mp 66–68° C.; EI-HRMS m/e calcd for C16H21FO4S (M+) 328.1144, found 328.1148.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([C:13]#[C:14]C(O)=O)=[CH:8]2>N1C2C(=CC=CC=2)C=CC=1.O>[C:13]([C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[CH:12][C:3]=2[O:2][CH3:1])[CH:8]=1)#[CH:14]
Reactant: COc1cccc2cc(C#CC(=O)O)ccc12
Solvent: O
Solvent: c1ccc2ncccc2c1
Product: C#Cc1ccc2c(OC)cccc2c1

Procedure:
5-methoxynaphth-2-ylpropiolic acid (5.85) is heated at 120-124° for 5 hours in quinoline. The reaction product is diluted with water and washed thoroughly with dilute hydrochloric acid. This is followed by washing with sodium bicarbonate (10%). The material is passed through a short aluminum (H+) column, eluted with N-hexane to give a fraction free of carbonyl absorption (I.R.). Removal of solvent gives 2-ethynyl-5-methoxynaphthalene.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[CH:9]([NH2:12])([CH3:11])[CH3:10]>C1COCC1.C(O)C>[N:6]1[CH:7]=[CH:8][C:3]([CH2:2][NH:12][CH:9]([CH3:11])[CH3:10])=[CH:4][CH:5]=1
Reactant: CC(C)N
Reactant: BrCc1ccncc1
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)NCc1ccncc1
Reaction time: 24 h

Procedure:
4-Bromomethylpyridine (1 g) was suspended in THF:ethanol (5:1) and cooled to 0–5° C. Isopropylamine (1.01 ml) was added and the resultant mixture allowed to reach room temperature. After 24 h, the mixture was concentrated under reduced pressure and the residue purified using SPE (silica, eluting with DCM:methanol 1:1, 3:7, 1:4 and methanol) to give an impure sample of the title compound. Further purification using SPE (silica, eluting with DCM, ethyl acetate, acetonitrile, methanol) gave the title compound (0.25 g) as a white solid.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.[CH2:11]([SH:14])[CH2:12][SH:13]>C(Cl)(Cl)Cl>[CH3:2][C:3]1[CH:4]=[C:5]([CH:6]2[S:14][CH2:11][CH2:12][S:13]2)[CH:8]=[CH:9][CH:10]=1
Reactant: SCCS
Reactant: Cc1cccc(C=O)c1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: Cc1cccc(C2SCCS2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
Anhydrous HCl was bubbled rapidly for about 5 minutes through a solution of 46.87 gm (0.39 moles) of 3-methylbenzaldehyde and 44.92 gm (0.477 moles) of 1,2-ethanedithiol in 300 ml of CHCl3. During the addition of HCl, there was a slight exotherm with a rise in temperature to about 60° C. After completion of the addition of HCl, the reaction was stirred for 1 hour at room temperature, washed twice with 100 ml portions of water, dried with MgSO4, and fractionated to give 54.55 gm (0.278 moles) of a clear, colorless liquid (71% yield) b.p. 108°-110° C. (0.2 mm/Hg). Elemental analysis for C10H12S2 :
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([NH:8][C:9](=[O:15])[C:10](=[O:14])[NH:11]2)=[CH:6][C:5]=1[S:16](Cl)(=[O:18])=[O:17])([O-:3])=[O:2].[NH4+:20].C(O)(=O)C>O>[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([NH:8][C:9](=[O:15])[C:10](=[O:14])[NH:11]2)=[CH:6][C:5]=1[S:16]([NH2:20])(=[O:18])=[O:17])([O-:3])=[O:2]
Reactant: O=c1[nH]c2cc([N+](=O)[O-])c(S(=O)(=O)Cl)cc2[nH]c1=O
Reactant: [NH4+]
Solvent: CC(=O)O
Solvent: O
Product: NS(=O)(=O)c1cc2[nH]c(=O)c(=O)[nH]c2cc1[N+](=O)[O-]
Reaction time: 3 h
Yield: 17 %

Procedure:
A mixture of 4.58 g (0.015 mole) of 1,2,3,4-tetrahydro-7-nitro-2,3-dioxo-6-quinoxalinesulfonyl chloride and 30 ml of 25% ammonium hydroxyde is stirred at a temperature between 5° C. and 10° C. for 3 hours and then allowed to stand for 16 hours. To the mixture 6 ml of acetic acid and 40 ml of water are added, the separated crystals are filtered off, washed with water and acetone, dried and dissolved in a slight amount of hot dimethyl sulfoxide. The product is precipitated from this solution with 2-propanol. Thus 1.40 g (17%) of 1,2,3,4-tetrahydro-7-nitro-2,3-dioxo-6-quinoxaline sulfonamide are obtained, m.p.: >330° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:6]2=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=[C:5]2[O:4][CH2:3]1.Cl[C:14]1[N:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=1>CN(C)C=O>[CH3:1][C:2]1([CH3:12])[C:6]2[C:7]([O:11][C:14]3[N:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1
Reactant: CC1(C)COc2cccc(O)c21
Reactant: O=[N+]([O-])c1cnc(Cl)nc1
Solvent: CN(C)C=O
Product: CC1(C)COc2cccc(Oc3ncc([N+](=O)[O-])cn3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.2 %

Procedure:
To a solution of 3,3-dimethyl-2,3-dihydro-1-benzofuran-4-ol (Intermediate 50, 724 mg) in dry N,N-Dimethylformamide (40 mL) potassium carbonate and 2-chloro-5-nitropyrimidine (774 mg, 4.85 mmol) were added. The reaction mixture was stirred at room temperature overnight. The reaction was quenched with water (40 ml) and extracted with ethyl acetate (3×40 ml). The combined organic layers were washed with brine (2×50 ml), separated, dried over sodium sulphate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using a column SNAP 50 g and cyclohexane/ethyl acetate as eluents from 100/0 to 70/30 to afford the title compound (1.257 g) as a yellow oil.