Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:23]=[C:14]3[CH2:15][N:16]([CH:19]4[CH2:22][O:21][CH2:20]4)[CH2:17][CH2:18][N:13]3[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:24]([O:27][CH2:28][C:29]1[C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][CH:32]=[CH:31][C:30]=1[N:44]1[CH2:56][CH2:55][N:47]2[C:48]3[CH2:49][CH2:50][CH2:51][CH2:52][C:53]=3[CH:54]=[C:46]2[C:45]1=[O:57])(=[O:26])[CH3:25].CC([O-])=O.[Na+]>CC#N.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:24]([O:27][CH2:28][C:29]1[C:30]([N:44]2[CH2:56][CH2:55][N:47]3[C:48]4[CH2:49][CH2:50][CH2:51][CH2:52][C:53]=4[CH:54]=[C:46]3[C:45]2=[O:57])=[CH:31][CH:32]=[CH:33][C:34]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:23]=[C:14]3[CH2:15][N:16]([CH:19]4[CH2:22][O:21][CH2:20]4)[CH2:17][CH2:18][N:13]3[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: Cn1cc(Br)cc(Nc2cc3n(n2)CCN(C2COC2)C3)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Product: CC(=O)OCc1c(-c2cc(Nc3cc4n(n3)CCN(C3COC3)C4)c(=O)n(C)c2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Temperature: 110 °C
Yield: 44.8 %

Procedure:
A sealed tube was charged with the mixture of 5-bromo-1-methyl-3-(5-(oxetan-3-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)pyridin-2(1H)-one 252a (265 mg, 0.7 mmol),2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate 114a (320 mg, 0.7 mmol), Pd(dppf)Cl2 (56 mg, 0.07 mmol), K3PO4.3H2O(367 mg, 1.4 mmol), and NaOAc (113 mg, 1.4 mmol) in CH3CN (20 mL). The system was evacuated and refilled with N2. The reaction mixture was heated at 110° C. for 2 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by flash column chromatography eluting with 30:1 methylene chloride/methanol to afford 319a as a yellow solid (200 mg, 38%). MS: [M+H]+ 638.
Reaction SMILES: C(O[C:4]([C:6]1[O:10][N:9]=[C:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)[N:7]=1)=[O:5])C.[CH2:21]([NH:23][CH2:24][CH3:25])[CH3:22]>>[CH2:21]([N:23]([CH2:24][CH3:25])[C:4]([C:6]1[O:10][N:9]=[C:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)[N:7]=1)=[O:5])[CH3:22]
Reactant: CCOC(=O)c1nc(-c2cccc3ccccc23)no1
Reactant: CCNCC
Product: CCN(CC)C(=O)c1nc(-c2cccc3ccccc23)no1

Procedure:
5-Ethoxycarbonyl-3-α-naphthyl-1,2,4-oxadiazole (30.9 g.) was heated under reflux in an excess of diethylamine (35.6g.) for 1.5 hr. The mixture was cooled and evaporated under reduced pressure to give a solid which was recrystallised from methanol yielding title compound (29.3 g.), m.p. 101.5°-102.5°, λmax. (EtOH) 302 nm. (ε 9,700), νmax. (CHBr3) 1662 cm.-1 (CONEt2).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[C:13](=[O:14])[C:12]([CH3:15])=[C:11]([CH3:16])[C:10](=[O:17])[C:9]=2[CH3:18])[CH:2]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].[C:27]([Si:31](Cl)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([CH3:30])([CH3:29])[CH3:28].N1C=CN=C1>ClCCl.O>[Si:31]([O:17][C:10]1[C:9]([CH3:18])=[C:8]([CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[C:13]([OH:14])=[C:12]([CH3:15])[C:11]=1[CH3:16])([C:27]([CH3:30])([CH3:29])[CH3:28])([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CC1=C(C)C(=O)C(Cc2cccnc2)=C(C)C1=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: Cc1c(C)c(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(C)c(Cc2cccnc2)c1O
Reaction time: 1 h

Procedure:
6-(3-Pyridylmethyl)-2,3,5-trimethyl-1,4-benzoquinone (241 mg, 1 mmol) was dissolved in dichloromethane (5 ml). The solution was stirred for 1 hour with a solution containing sodium hydrosulfite (400 mg, 2.3 mmol) in water (5 ml). The dichloromethane layer was separated, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in dichloromethane (5 ml), and tert-butylchlorodiphenylsilane (550 mg, 2 mmol) was added. Then imidazole (136 mg, 2 mmol) was added under a stream of nitrogen. The reaction mixture was stirred at 43° C. for 16 hours and washed with water (5 ml). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain crude 4-tert-butyldiphenylsilyloxy-6-(3-pyridylmethyl)-2,3,5-trimethylphenol. This crude product was dissolved in dichloromethane (10 ml), and methyl 1-O-trichloroacetimidoyl-2,3,4-tri-O-acetyl-α-D-glucopyranosiduronate (1 g, 2.1 mmol) was added. Boron trifluoride diethyl ether (0.2 ml) was added under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. Then water (10 ml) containing sodium bicarbonate (1 g) was added, and the mixture was stirred for 5 minutes. The dichloromethane layer was separated and concentrated under reduced pressure. To the residue were added tetrahydrofuran (15 ml), methanol (10 ml) and 1N sodium hydroxide solution (20 ml), and the mixture was allowed to react at room temperature for 40 hours and concentrated under reduced pressure. The residue was extracted with ether, and the aqueous layer was subjected to Sephadex (trade mark) LH-20 column chromatography and eluted with water. The desired fraction was lyophilized to obtain the desired compound (210 mg) as white powder.
Reaction SMILES: [C:1]([C:9]1[C:10]2[CH:21]=[CH:20][CH:19]=[CH:18][C:11]=2[S:12][C:13]=1[NH:14]C(=O)C)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[NH2:14][C:13]1[S:12][C:11]2[CH:18]=[CH:19][CH:20]=[CH:21][C:10]=2[C:9]=1[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:8]
Reactant: CC(=O)Nc1sc2ccccc2c1C(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1sc2ccccc2c1C(=O)c1ccccc1
Temperature: 85 °C
Yield: 28.5 %

Procedure:
To a stirred solution of 0.26 g (0.90 mmol) N-(3-benzoyl-benzo[b]thiophen-2-yl)-acetamide in 20 ml ethanol was added 1 ml aqueous sodium hydroxide (1 M). The mixture was heated at 85° C. for 1 hour and then poured onto water and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. Flash chromatography (heptane/ethyl acetate 6:1) afforded 65 mg (25%) (2-amino-benzo[b]thiophen-3-yl)-phenyl-methanone as an orange solid. ES-MS m/e (%): 254 (M+H+, 100).
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1=[CH:7][N:8]([C:23]([CH3:26])([CH3:25])[CH3:24])[S:9]/[C:10]/1=[N:11]\[C:12](=[O:22])[C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[O:20][CH3:21])=[N+]=[N-]>CCO.[Pd]>[NH2:1][CH2:4][CH2:5][C:6]1=[CH:7][N:8]([C:23]([CH3:26])([CH3:25])[CH3:24])[S:9]/[C:10]/1=[N:11]\[C:12](=[O:22])[C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[O:20][CH3:21]
Reactant: COc1ccc(Cl)cc1C(=O)/N=c1\sn(C(C)(C)C)cc1CCN=[N+]=[N-]
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(Cl)cc1C(=O)/N=c1\sn(C(C)(C)C)cc1CCN
Yield: 90.6 %

Procedure:
The product from Example 14 (70 mg, 0.18 mmol) in EtOH (10 mL) was treated with Pd/C (10 mg) under a hydrogen balloon for 3 hrs. The Pd/C was filtered off and washed with EtOH. The filtrate was concentrated to afford 60 mg (91%) of the title compound. 1H NMR (500 MHz, CDCl3) δ ppm 1.68 (s, 9 H) 3.08 (dd, J=5.80, 4.88 Hz, 2 H) 3.27 (dd, J=5.19 Hz, 2 H) 3.92 (s, 3 H) 6.94 (d, J=8.85 Hz, 1 H) 7.37 (dd, J=8.85, 2.75 Hz, 1 H) 7.97 (d, J=2.75 Hz, 1 H) 8.03 (s, 1 H); MS (DCI/NH4+) m/z 368 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[C:6]([NH:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[N+:28]([O-:30])=[O:29])(=[O:21])=[O:20])[CH:5]=1.[C:32](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:15])[CH3:16])=[O:12])=[C:6]([N:18]([CH3:32])[S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[N+:28]([O-:30])=[O:29])(=[O:21])=[O:20])[CH:5]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ccc(NC(=O)OC(C)(C)C)c(NS(=O)(=O)c2ccccc2[N+](=O)[O-])c1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NC(=O)OC(C)(C)C)c(N(C)S(=O)(=O)c2ccccc2[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
After dissolving 4-tert-butoxycarbonylamino-3-(2-nitro-benzenesulfonylamino)-benzoic acid methyl ester (1.23 g, 2.73 mmol) in dimethylformamide (10 ml), potassium carbonate (1.13 g, 8.16 mmol) and methyl iodide (0.254 ml, 4.09 mmol) were added in an ice bath, and the mixture was stirred at room temperature for 2 hours. Water (100 ml) was added to the reaction mixture, and extraction was performed with ethyl acetate (40 ml×4 times). The obtained organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the crystallized residue was dried to obtain 4-tert-butoxycarbonylamino-3-[methyl-(2-nitro-benzenesulfonyl)-amino]-benzoic acid methyl ester. The compound was identified by LC-MS.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:12])[C:5]([NH2:11])=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].N[C:14](N)=[O:15]>>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]2[NH:11][C:14](=[O:15])[NH:12][C:4]=2[CH:3]=1
Reactant: NC(N)=O
Reactant: Nc1cc(Cl)c([N+](=O)[O-])cc1N
Product: O=c1[nH]c2cc(Cl)c([N+](=O)[O-])cc2[nH]1

Procedure:
A mixture of 14 g (0.074 mol) of 4-chloro-5-nitro-1,2-benzenediamine and of 13.44 g (0.226 mol) of urea is heated at 180° C. for 4 hours. The reaction mixture is cooled and evaporated to dryness. The residue is taken up in methanol and evaporated again. The residue is triturated in ether and a solid is obtained which is filtered. The product is used as is in the subsequent stages.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=2[Cl:19])(=[O:11])=[O:10])=[C:4]([F:20])[CH:3]=1.Cl[C:22]1[C:27]([C:28]2[CH:33]=[CH:32][N:31]=[CH:30][N:29]=2)=[CH:26][CH:25]=[CH:24][N:23]=1.N(CC)(CC)CC.FC(C(O)=O)(F)F>C(Cl)Cl.CO>[Cl:19][C:13]1[C:14]([Cl:18])=[CH:15][CH:16]=[CH:17][C:12]=1[S:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:22]2[C:27]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][N:29]=3)=[CH:26][CH:25]=[CH:24][N:23]=2)=[CH:3][C:4]=1[F:20])(=[O:11])=[O:10]
Reactant: Clc1ncccc1-c1ccncn1
Reactant: Nc1ccc(NS(=O)(=O)c2cccc(Cl)c2Cl)c(F)c1
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1ccc(Nc2ncccc2-c2ccncn2)cc1F)c1cccc(Cl)c1Cl
Temperature: 100 °C

Procedure:
To N-(4-amino-2-fluorophenyl)-2,3-dichlorobenzenesulfonamide (0.150 g, 0.45 mmol) and 4-(2-chloropyridin-3-yl)pyrimidine (0.086 g, 0.45 mmol) was added NEt3.TFA. The mixture was heated at 100° C. CH2Cl2/MeOH was added, producing a yellow precipitate, which was filtered. Trituration with a further portion of CH2Cl2/MeOH, followed by filtration, afforded 2,3-dichloro-N-(2-fluoro-4-(3-(pyrimidin-4-yl)pyridin-2-ylamino)phenyl)benzenesulfonamide as an orange solid. MS m/z=491 [M+H]+. Calc'd for C21H14Cl2FN5O2S: 490.35.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH2:8].CCN(CC)CC.Cl[C:17](=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][C:17](=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: Nc1cnccc1Cl
Reactant: CCOC(=O)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=O)Nc1cnccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-chloropyridin-3-amine (R-1) (5 g, 38.9 mmol) in THF (100 mL) was added Et3N (4.72 g, 6.5 mL, 46.7 mmol), followed by ethyl 2-chloro-2-oxoacetate (5.84 g, 4.78 mL, 42.8 mmol) in THF (5 mL) dropwise at 0° C. The resulting mixture was stirred at room temperature for 1 h, and then concentrated in vacuo. The resulting residue was dissolved in EtOAc, and washed with aqueous saturated NaHCO3. The organic layer was separated, dried over Na2SO4, and concentrated to give the title compound, which was used for the next step without further purification. MS (m/z): 229 (M+1)+.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[CH2:3][CH2:4][NH:5][C:6]1[N:7]=[N+:8]([O-:21])[C:9]2[CH:15]=[C:14]3[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:13]3=[CH:12][C:10]=2[N:11]=1.C[OH:24]>>[O-:21][N+:8]1[C:9]2[CH:15]=[C:14]3[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:13]3=[CH:12][C:10]=2[N+:11]([O-:24])=[C:6]([NH:5][CH2:4][CH2:3][N:2]([CH3:22])[CH3:1])[N:7]=1
Reactant: CN(C)CCNc1nc2cc3c(cc2[n+]([O-])n1)CCCCC3
Reactant: CO
Product: CN(C)CCNc1n[n+]([O-])c2cc3c(cc2[n+]1[O-])CCCCC3

Procedure:
H2O2 (70%, 0.31 mL, ca. 6.2 mmol) was added dropwise to a stirred solution of TFAA (0.9 mL, 6.2 mmol) in DCM (10 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. and added to a stirred solution of 1-oxide 188 (186 mg, 0.6 mmol) and TFA (0.24 mL, 3.1 mmol) in DCM (10 mL) at 0° C. The solution was stirred at 20° C. for 16 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with CHCl3 (4×50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give (i) starting material 188 (43 mg, 23%) and (ii) 1,4-dioxide 189 (82 mg, 42%) as a red solid: mp (MeOH) 131-133° C.; 1H NMR δ 8.03 (s, 1H, H-11), 7.99 (s, 1H, H-5), 7.36 (br s, 1H, NH), 3.63 (br t, J=6.0 Hz, 2H, CH2N), 2.98-3.03 (m, 2H, CH2), 2.91-2.95 (m, 2H, CH2), 2.60 (br t, J=6.0 Hz, 2H, CH2N), 2.30 [s, 6H, N(CH3)2], 1.82-1.89 (m, 2H, H-8), 1.68-1.76 (m, 4H, H-7, H-9); 13C NMR δ 154.4, 149.7, 144.7, 137.1, 128.7, 119.8, 115.9, 57.5, 45.2 (2), 38.9, 37.0, 36.2, 31.8, 28.4, 28.2. Anal. calcd for C16H23N5O2.¼CH3OH: C, 60.0; H, 7.4; N, 21.5. Found: C, 59.9; H, 7.0; N, 21.5%.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([F:20])[CH:5]=[C:6]2[C:11]=1[N:10]([C@@H:12]1[CH2:14][C@@H:13]1[F:15])[CH:9]=[C:8]([C:16]([OH:18])=[O:17])[C:7]2=[O:19].[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH2:32][C@H:31]2[CH2:35][NH:36][CH2:37][C@@H:30]12)=[O:28])([CH3:25])([CH3:24])[CH3:23].C(N(CC)CC)C>C(#N)C>[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH2:32][C@@H:31]2[C@H:30]1[CH2:37][N:36]([C:3]1[C:2]([Cl:1])=[C:11]3[C:6]([C:7](=[O:19])[C:8]([C:16]([OH:18])=[O:17])=[CH:9][N:10]3[C@@H:12]3[CH2:14][C@@H:13]3[F:15])=[CH:5][C:4]=1[F:20])[CH2:35]2)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]2CNC[C@H]21
Reactant: O=C(O)c1cn([C@@H]2C[C@@H]2F)c2c(Cl)c(F)c(F)cc2c1=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC[C@H]2CN(c3c(F)cc4c(=O)c(C(=O)O)cn([C@@H]5C[C@@H]5F)c4c3Cl)C[C@H]21
Yield: 55.9 %

Procedure:
In 20 ml of acetonitrile were dissolved 344 mg of 8-chloro-6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 490 mg of (S,S)-1-t-butoxycarbonyloctahydropyrrolo[3.4-b]pyridine (also termed "(S,S)-2-t-butoxycarbonyl-2,8-azabicyclo[4.3.0]nonane"), and 1 ml of triethylamine, and the solution was heated under reflux for 5 hours. After completion of the reaction, the solvent was removed under reduced pressure. To a residue was added 30 ml of water, followed by extracting with chloroform (30 ml×4). The combined organic layer was washed with 100 ml of a 10% citric acid aqueous solution and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and a residue was recrystallized from acetonitrile to yield 317 mg of the titled compound.
Reaction SMILES: [CH3:1][CH:2]([C:15]1([O:21][CH2:20]1)[C:16]([O:18]C)=[S:17])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[O-]CC.[Na+].O>C(O)C>[CH3:1][CH:2]([C:15]1([O:21][CH2:20]1)[C:16]([OH:18])=[S:17])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCC(C)C1(C(=S)OC)CO1
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCCC(C)C1(C(O)=S)CO1
Reaction time: 0.25 h

Procedure:
A solution of 3.15 g (0.01 mole) of methyl 2-tetradecylthioglycidate in 50 ml of absolute ethanol is added dropwise to a cooled (0°-5° C.) solution of sodium ethoxide (0.25 g sodium in 12 ml absolute ethanol). The mixture is stirred for 15 minutes while maintaining the temperature below 20° C. and 0.19 g of water is added. Stirring is continued overnight (about 15 hours) at room temperature. The resulting suspension is filtered and the precipitate washed with ether, dried and then stirred for several hours in dilute HCl. The acidic suspension is extracted with ether and the ether layer dried (Na2SO4) and evaporated in vacuo giving the product, 2-tetradecylthioglycidic acid, in good yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[CH:38]=[CH:37][C:15]([O:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])=[CH:19][C:18]=3[CH2:31][NH:32][S:33]([CH3:36])(=[O:35])=[O:34])=[CH:14][CH:13]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[CH:13]=[CH:14][C:15]([O:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][C:24]([OH:26])=[O:25])=[CH:19][C:18]=3[CH2:31][NH:32][S:33]([CH3:36])(=[O:35])=[O:34])=[CH:37][CH:38]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)Cc1ccc(Oc2ccc(C(=O)Nc3ccc(Cl)c(Cl)c3)cc2)c(CNS(C)(=O)=O)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)NCc1cc(CC(=O)O)ccc1Oc1ccc(C(=O)Nc2ccc(Cl)c(Cl)c2)cc1
Reaction time: 1 h
Yield: 75.4 %

Procedure:
The product of step E (22 mg, 0.038 mmol) was diluted with methylene chloride (1 mL) followed by the addition of TFA (1 mL). After stirring for 1 hour, the reaction was concentrated, diluted with ether, sonicated and concentrated to yield 2-(4-(4-((3,4-dichlorophenyl)carbamoyl)phenoxy)-3-(methylsulfonamidomethyl)phenyl)acetic acid (15 mg, 75% yield) as a white solid. 1H NMR (400 MHz, CDCl3/CD3OD) 7.92 (m, 1H), 7.90 (d, 2H), 7.59 (m, 1H), 7.42 (m, 2H), 7.25 (m, 1H), 7.10 (d, 2H), 6.90 (d, 1H), 4.28 (s, 2H), 3.62 (s, 2H), 2.85 (s, 3H).
Reaction SMILES: CN1CCCC1=O.[C:8]([NH:12][C:13]1[C:22]([F:23])=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15](F)[N:14]=1)([CH3:11])([CH3:10])[CH3:9].[CH3:25][C:26]([NH2:33])([CH3:32])[CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29]>C(Cl)(Cl)Cl>[C:8]([NH:12][C:13]1[C:22]([F:23])=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([NH:33][C:26]([CH3:32])([CH3:25])[CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])[N:14]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: COC(=O)c1cc(F)c(NC(C)(C)C)nc1F
Reactant: CC(C)(C)CC(C)(C)N
Solvent: ClC(Cl)Cl
Solvent: CN1CCCC1=O
Product: COC(=O)c1cc(F)c(NC(C)(C)C)nc1NC(C)(C)CC(C)(C)C
Temperature: 140 °C
Reaction time: 16 h
Yield: 82.1 %

Procedure:
To 7 ml N-methylpyrrolidone were added 2.44 g of methyl 6-t-butylamino-2,5-difluoronicotinate and 4.0 g of 1,1,3,3-tetramethylbutylamine, and the mixture was stirred at 140° C. for 16 hours and allowed to cool. After adding 50 ml of chloroform, the mixture was washed three times with 300 ml of distilled water. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The brown oily residue was subjected to column chromatography (silica gel, 40 g; eluent: chloroform:n-hexane, 1:1) to obtain 2.90 g of the title compound as a colorless oily residue.
Reaction SMILES: [CH:1]1[C:14]2C(=CC3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9]C=3)C=[CH:3][CH:2]=1>C/C=C/CCCCCC>[CH3:3][CH:2]=[CH:1][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH3:9]
Reactant: c1ccc2cc3ccccc3cc2c1
Agent: C/C=C/CCCCCC
Product: CC=CCCCCCC

Procedure:
To obtain an olefin further enriched in trans-2-nonene, 8.9 g (91 mmoles) of Olefin Product 1 treated with 12.6 g (70 mmoles) of the anthracene, as described above, to form a Diels-Alder adduct with the 2-nonene. By distillation, as above, 3.3 g (33 mmoles) of Unreacted Olefins 3 was separated from the crude nonene-anthracene mixture. The remaining nonene-anthracene adduct was thermally dissociated, as described above, and 3.7 g (37 mmoles) of Olefin Product 3 recovered. Olefin Product 3 was further enriched in trans-2-nonene. Olefin Product 3 contained 97.2% trans-2-nonene compared with 75.6% in the original feedstock and 91.9% in Olefin Product 1.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[CH3:7][C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1>>[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([C:2]2[S:3][CH:4]=[CH:5][CH:6]=2)=[CH:10][CH:9]=1
Reactant: Brc1cccs1
Reactant: Cc1ccc(B(O)O)cc1
Product: Cc1ccc(-c2cccs2)cc1

Procedure:
2-Bromothiophene and 4-methylphenylboronic acid were treated in a manner similar to Reference Example 20-(1) to give the target compound.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:10]([N:12]1[CH2:30][CH2:29][CH2:28][C@H:13]1[C:14]([NH:16][CH2:17][C:18]([N:20]1[CH2:27][CH2:26][CH2:25][C@H:21]1[C:22]([OH:24])=[O:23])=[O:19])=[O:15])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].CCOCC>Cl.O1CCOCC1>[NH2:1][C@H:2]([C:10]([N:12]1[CH2:30][CH2:29][CH2:28][C@H:13]1[C:14]([NH:16][CH2:17][C:18]([N:20]1[CH2:27][CH2:26][CH2:25][C@H:21]1[C:22]([OH:24])=[O:23])=[O:19])=[O:15])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=N)N)C(=O)N1CCC[C@H]1C(=O)NCC(=O)N1CCC[C@H]1C(=O)O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: N=C(N)NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(=O)N1CCC[C@H]1C(=O)O
Reaction time: 0.75 h

Procedure:
4.23 g (5.8 mmol) of Boc-Arg-Pro-Gly-Pro-OH were suspended in 10 ml of 2N hydrochloric acid in dioxane and incubated at room temperature for 45 min. Then, dry ether was added, and the precipitate was washed by decantation with dry ether. It was reprecipitated with ether from absolute methanol. The resulting precipitate was dissolved in 7.5 ml of 30% ethanol and applied to Amberlyst A-21 (AcO− form) column for acetate/hydrochloride salt exchange. Peptide was eluted with 200 ml of 30% ethanol, evaporated to dryness under vacuum and precipitated with absolute ether from methanol.
Reaction SMILES: [C:1](Cl)(=O)C.[Br:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14](=[O:18])[C:15]([OH:17])=[O:16])=[C:8]([F:19])[CH:7]=1>CO>[CH3:1][O:16][C:15](=[O:17])[C:14](=[O:18])[CH:13]=[CH:12][C:9]1[CH:10]=[CH:11][C:6]([Br:5])=[CH:7][C:8]=1[F:19]
Reactant: CC(=O)Cl
Reactant: O=C(O)C(=O)C=Cc1ccc(Br)cc1F
Solvent: CO
Product: COC(=O)C(=O)C=Cc1ccc(Br)cc1F
Yield: 81.5 %

Procedure:
Acetyl chloride (4.8 mL, 68.5 mmol) was slowly added at 0° C. to methanol (28.0 mL) under stirring. A solution of 4-(4-bromo-2-fluoro-phenyl)-2-oxo-3-butenoic acid (5.5 g, 20.1 mmol) prepared in Step 1 in methanol (5.0 mL) was added to the reaction mixture at room temperature. The reaction mixture was stirred at room temperature for 1 hour, additionally at 80° C. for 16 hours, and then filtered at room temperature to give 4.7 g of the titled compound as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][CH:7]=[C:6]([C:13](O)=[O:14])[C:5]2=[O:16].S(Cl)([Cl:19])=O>>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][CH:7]=[C:6]([C:13]([Cl:19])=[O:14])[C:5]2=[O:16]
Reactant: O=C(O)c1coc2cc(O)c(O)cc2c1=O
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1coc2cc(O)c(O)cc2c1=O
Yield: 93.4 %

Procedure:
A mixture of 6,7-dihydroxychromone-3-carboxylic acid (9.0 g, 4 mmol) and thionyl chloride (150 ml) was refluxed for 45 minutes and the thionyl chloride was evaporated. After the addition of benzene, the mixture was evaporated again to dryness and the residue was triturated with n-hexane to afford the desired compound (9.1 g, 93.4%).