Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[N:2]([C:18]1[C:23]([C:24]#[N:25])=[CH:22][C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=1)[C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]([C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)=[O:12])[CH2:7][CH2:6]1)=S.[Cl-:30].[NH4+:31]>C(N)=O>[CH3:27][O:26][C:21]1[CH:22]=[C:23]2[C:24]([NH2:25])=[N:31][C:3]([N:5]3[CH2:6][CH2:7][N:8]([C:11]([C:13]4[O:14][CH:15]=[CH:16][CH:17]=4)=[O:12])[CH2:9][CH2:10]3)=[N:2][C:18]2=[CH:19][C:20]=1[O:28][CH3:29].[ClH:30]
Reactant: [Cl-]
Reactant: COc1cc(C#N)c(N(C)C(=S)N2CCN(C(=O)c3ccco3)CC2)cc1OC
Reactant: [NH4+]
Solvent: NC=O
Product: COc1cc2nc(N3CCN(C(=O)c4ccco4)CC3)nc(N)c2cc1OC
Product: Cl
Temperature: 120 °C

Procedure:
275 g (0.66 moles) of methyl-N-(3,4-dimethoxy-6-cyanophenyl)-[4-(2-furoyl)-1-piperazinyl]thioformamidate is dissolved in 3000 ml of formamide, and 1375 g (25.7 moles) of ammonium chloride is added while stirring. Thereafter, the reaction mixture is heated for 15-20 hours at 120° C., while stirring and also feeding nitrogen gas in order to remove the methane thiol produced (can be absorbed into a sodium hypochlorite solution). The prazosine hydrochloride produced gradually crystallizes out from the reaction mixture. After the reaction has ceased, 3-4 kg of ice is added to the mixture. The product is filtered, washed with cold water and acetone, and dried. Yield 254-259 g (93-95%). Purity 99.5% (HPLC). The product is crystallized out from about 10 liters of a mixture of water and ethanol (15:50). Yield 232-235 g (85-86%). Purity 99.7-99.8% (HPLC). The IR, NMR and mass spectra of the product are identical to the corresponding spectra of prazosine hydrochloride produced by methods previously described in the literature.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][C:6]1[C:11]([Cl:12])=[CH:10][N:9]=[C:8]([N:13]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:14][C:15]([F:23])([F:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[C:7]=1[F:31])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:38]>ClCCCl.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][C:6]1[C:11]([Cl:12])=[CH:10][N:9]=[C:8]([N:13]([C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[CH2:14][C:15]([F:23])([F:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N+:17]=2[O-:38])[C:7]=1[F:31])[CH3:2]
Reactant: CCOC(=O)Cc1c(Cl)cnc(N(CC(F)(F)c2ccccn2)C(=O)OC(C)(C)C)c1F
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1c(Cl)cnc(N(CC(F)(F)c2cccc[n+]2[O-])C(=O)OC(C)(C)C)c1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 0.8 g (1.7 mmol) ethyl(2-{(tert-butoxycarbonyl)[2,2-difluoro-2-(2-pyridinyl)ethyl]amino}-5-chloro-3-fluoro-4-pyridinyl)acetate 1-6 in 3 mL 1,2-dichloroethane was added 0.44 g (1.8 mmol, 70% by weight) m-chloroperoxybenzoic acid. The reaction mixture was stirred at room temperature 16 h, heated to 60° C. 2 h, cooled, diluted with 300 mL EtOAc, washed with 200 mL 0.1M NaOH, and 200 mL brine. Dried over Na2SO4, filtered, and concentrated. Purification by automated flash chromatography (40 g silica cartridge, linear gradient 1-10% MeOH/CH2Cl2 over 25 min, 40 mL/min flow rate) followed by repurification of the mixed fractions by traditional silica gel chromatography (2×15 cm silica gel, linear gradient 2-5% MeOH/CH2Cl2) afforded ethyl(2-{(tert-butoxycarbonyl)[2,2-difluoro-2-(1-oxido-2-pyridinyl)ethyl]amino}-5-chloro-3-fluoro-4-pyridinyl)acetate 1-7. 1H NMR (400 mHz, CDCl3) δ8.20 (s, 1H); 8.18 (br d, 1H, J=5 Hz); 7.57 (br dd, 1H, J=7.7 and 2 Hz); 7.31 (br m, 2H); 5.0 (br m, 2H); 4.19 (q, 2H, J=7.14 Hz); 3.82 (s, 2H); 1.28 (s, 9H); 1.25 (t, 3H, J=7.14 Hz). Mass spectrum (electrospray) M+H=490.1
Reaction SMILES: [C:1]([O-:4])(=O)[CH3:2].[Na+].[Br:6][C:7]1[CH:8]=[C:9]([CH2:14]C(O)=O)[CH:10]=[CH:11][C:12]=1[OH:13].[OH-].[Na+].Cl>C(OC(=O)C)(=O)C>[Br:6][C:7]1[CH:8]=[C:9]([CH2:14][C:1]([CH3:2])=[O:4])[CH:10]=[CH:11][C:12]=1[OH:13]
Reactant: CC(=O)[O-]
Reactant: O=C(O)Cc1ccc(O)c(Br)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Cc1ccc(O)c(Br)c1
Temperature: 25 °C
Yield: 78.6 %

Procedure:
Sodium acetate (50.5 g) was added to a solution of 3-bromo-4-hydroxyphenylacetic acid (28.5 g) in acetic anhydride (100 ml) and the mixture was refluxed with heating for 21 hours. After cooling to room temperature, 20% aqueous solution of sodium hydroxide was added to the reaction mixture to adjust to pH 11. The mixture was refluxed with heating for one hour. After cooling to room temperature, 10% aqueous solution of hydrochloric acid was added to the reaction mixture to adjust to pH 6. The mixture was extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous solution of sodium bicarbonate, and saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-n-hexane) to obtain 1-(3-bromo-4-hydroxyphenyl) acetone (22.2 g).
Reaction SMILES: [Mg].[CH2:2](Br)[CH:3]=[CH2:4].[CH3:6][C:7]1([CH3:16])[CH2:12][CH2:11][CH2:10][C:9]([CH3:14])([CH3:13])[C:8]1=[O:15].Cl>O.C(OCC)C>[CH2:4]([C:8]1([OH:15])[C:9]([CH3:14])([CH3:13])[CH2:10][CH2:11][CH2:12][C:7]1([CH3:16])[CH3:6])[CH:3]=[CH2:2]
Reactant: C=CCBr
Reactant: CC1(C)CCCC(C)(C)C1=O
Agent: Cl
Agent: [Mg]
Solvent: O
Solvent: CCOCC
Product: C=CCC1(O)C(C)(C)CCCC1(C)C
Temperature: 25 °C
Yield: 68 %

Procedure:
Magnesium (11.5 g, 0.48 moles) and dried diethyl ether (300 ml) were added, in this order, to one liter four-necked flask equipped with a mechanical stirrer, a dropping funnel, a thermometer, a reflux condenser and a nitrogen gas inlet tube and stirred at room temperature. While stirring at room temperature, a mixed solution of allyl bromide (57.7 g, 0.48 moles)/dried diethyl ether (100 ml) was dropped to the mixture in 2 hours. The resulting mixture was heated under reflux for 30 minutes. Into the mixture was dropped a mixed solution of 2,2,6,6-tetramethylcyclohexanone (49 g, 0.32 moles)/dried diethyl ether (100 ml) in about 40 minutes while stirring under heating and refluxing conditions. The mixture was further stirred for 2 hours under refluxing conditions. The resultant reaction mixture was poured into iced water, followed by adding a 1N hydrochloric acid aqueous solution to render the mixture weakly acidic and separating it into two layers. The organic layer was washed with a saturated sodium bicarbonate aqueous solution (50 ml) and then with water (50 ml) three times. The organic layer was dried over anhydrous magnesium sulfate and separated by filtration, followed by concentration and fractionation to obtain 42.7 g (yield 68%) of the captioned compound. This compound was a colorless transparent liquid having a woody, green, earthy and patchuli oil-like odor.
Reaction SMILES: Cl.[O:2]([CH2:9][CH2:10][O:11][C:12]([C:14]1[CH:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[C:22]2[C:21](=[O:31])[CH2:20][N:19](CC3C=CC=CC=3)[CH2:18][C:17]=2[NH:16][C:15]=1[CH3:39])=[O:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CO.Cl.[H][H]>[Pd].O>[O:2]([CH2:9][CH2:10][O:11][C:12]([C:14]1[CH:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[C:22]2[C:21](=[O:31])[CH2:20][NH:19][CH2:18][C:17]=2[NH:16][C:15]=1[CH3:39])=[O:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC1=C(C(=O)OCCOc2ccccc2)C(c2ccccc2C)C2=C(CN(Cc3ccccc3)CC2=O)N1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CO
Product: CC1=C(C(=O)OCCOc2ccccc2)C(c2ccccc2C)C2=C(CNCC2=O)N1

Procedure:
The hydrochloride from above (21.5 g), 500 ml of methanol, 5 ml of concentrated hydrochloric acid, 15 ml of water and 0.6 g of 10% palladium on carbon were shaken with hydrogen (50 psig initial pressure) for 20 hours. The catalyst was separated and the solution was evaporated to dryness in vacuo. The residue was slurried with diethyl ether and filtered. The solid was triturated with refluxing ethanol, filtered and dried to obtain 12 g of the title compound as the hydrochloride, m.p. 238°-240° C. dec.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:10])[CH:8]=2)[CH:3]=[CH:2]1.[O:11]1[CH2:15][CH2:14][CH:13](O)[CH2:12]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.N1C2C(=CC=CC=2)C=C1>ClCCl>[O:11]1[CH2:15][CH2:14][CH:13]([O:10][C:7]2[CH:8]=[C:9]3[C:4]([CH:3]=[CH:2][NH:1]3)=[CH:5][CH:6]=2)[CH2:12]1
Reactant: OC1CCOC1
Reactant: Oc1ccc2cc[nH]c2c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc2[nH]ccc2c1
Solvent: ClCCl
Product: c1cc2ccc(OC3CCOC3)cc2[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of 1H-indol-6-ol (2.00 g, 15.02 mmol), tetrahydrofuran-3-ol (1.46 mL, 18.0 mmol), and triphenylphosphine (4.33 g, 16.52 mmol) in dichloromethane (80 mL) at 0° C. was added diisopropyl diazene-1,2-dicarboxylate (3.49 mL, 18.03 mmol) over 10 min. The mixture was stirred at room temperature for 16 hr. The starting indole and desired product were detected in a ratio of 3:2. The dark mixture was diluted with CH2Cl2 (80 mL), washed with 1N NaOH (50 mL), water (50 mL), and brine (50 mL). The organic solution was dried over anhydrous MgSO4. The desired product (0.642 g, 3.16 mmol, 21.03% yield) was isolated as viscous oil by ISCO (300 g silica gel, solid loading, 10-50% ethyl acetate/hexane).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]([CH3:17])([OH:16])[CH3:15])=[CH:9][CH:8]=[C:7]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:6]=2.[C:26]([O:29][CH2:30][C:31]([Cl:33])=[O:32])(=[O:28])[CH3:27]>C(#N)C>[ClH:33].[C:26]([O:29][CH2:30][C:31]([NH:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]([OH:16])([CH3:17])[CH3:15])=[CH:9][CH:8]=[C:7]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:6]=2)=[O:32])(=[O:28])[CH3:27]
Reactant: CC(=O)OCC(=O)Cl
Reactant: CC(C)(O)CNc1c(N)cnc2cc(OCc3ccccc3)ccc12
Solvent: CC#N
Product: CC(=O)OCC(=O)Nc1cnc2cc(OCc3ccccc3)ccc2c1NCC(C)(C)O
Product: Cl
Temperature: 40 °C
Yield: 91.4 %

Procedure:
Under a nitrogen atmosphere, a mixture of 1-{[3-amino-7-(benzyloxy)quinolin-4-yl]amino}-2-methylpropan-2-ol (45.0 g, 0.133 mol) and acetonitrile (180 mL) was heated to 40° C. Acetoxyacetyl chloride (21.8 g, 0.160 mol) was added to the resulting gray suspension over a period of 15 minutes while maintaining the temperature at 55±5° C. during the addition. Following the addition, a precipitate formed, and the reaction was heated at 55° C. for 15 minutes. The reaction mixture was then cooled to ˜0° C., and the product was isolated by filtration, washed sequentially with a small amount of acetonitrile and acetone, and dried under vacuum at 50° C. to provide 57.6 g of 2-({7-benzyloxy-4-[(2-hydroxy-2-methylpropyl)amino]quinolin-3-yl}amino)-2-oxoethyl acetate hydrochloride.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].[CH2:14]([NH2:16])[CH3:15].C([O-])([O-])=O.[Na+].[Na+].O>C(OCC)(=O)C.C(Cl)Cl>[CH2:14]([NH:16][S:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11])[CH3:15]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: CCN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: CCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Yield: 161.2 %

Procedure:
A solution of 2-nitrobenzenesulfonyl chloride (140 g, 361 mmol) in ethyl acetate (250 mL) was added dropwise at room temperature to a mixture of 70% aqueous ethylamine (50 mL, 630 mmol), ethyl acetate (100 mL), Na2CO3 (67 g, 632 mmol), and water (250 mL). The reaction mixture was stirred for 4 h (TLC monitoring, CH2Cl2). The organic layer was separated, washed with water, with a solution of citric acid, dried with Na2SO4, and evaporated. The residue solidified into a white crystalline mass. The latter was triturated with hexane, filtered off, and dried to give 134 g (92%) of the product.
Reaction SMILES: C([N:3]([CH2:6][CH3:7])CC)C.[C:8]([NH:15][C@H:16]([C:21]([OH:23])=O)[CH2:17][CH2:18][S:19][CH3:20])([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].ClC(OCC)=O.CC1[CH2:36][CH:35](N)[CH:34]([CH:38]([CH3:40])[CH3:39])[CH2:33][CH2:32]1>C1COCC1>[C:6]1([NH:3][C:21](=[O:23])[C@H:16]([CH2:17][CH2:18][S:19][CH3:20])[NH:15][C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])([CH3:7])[CH2:36][CH2:35][CH:34]([CH:38]([CH3:40])[CH3:39])[CH2:33][CH2:32]1
Reactant: CC1CCC(C(C)C)C(N)C1
Reactant: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Product: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)NC1(C)CCC(C(C)C)CC1
Temperature: -12 °C
Reaction time: 0.33 h

Procedure:
0.45 mol of triethylamine is added to 0.45 mol of N-BOC-L-methionine in 1 l of THF at 0° C. The mixture is cooled to -12° C., and 0.45 mol of ethyl chloroformate is added dropwise. Stirring at -12° C. is continued for 20 minutes, and 0.45 mol of L-menthylamine is added dropwise. Stirring at 0° C. is continued for 45 minutes, and the mixture is then allowed to warm to room temperature.
Reaction SMILES: [CH2:1]([N:8]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:9]([CH:13]([OH:21])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:10]([OH:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].F[C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=1[N+:39]([O-:41])=[O:40].Cl>CN(C)C=O>[CH2:22]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:9]([CH:13]([O:21][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=1[N+:39]([O-:41])=[O:40])[CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:10]([OH:12])=[O:11])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Reactant: O=C(O)C(C(O)Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)C(C(Cc1ccccc1)Oc1ccc(F)cc1[N+](=O)[O-])N(Cc1ccccc1)Cc1ccccc1
Reaction time: 2 h

Procedure:
4.20 g (11.2 mmol) racemic (2R,3R and 2S,3S)-2-dibenzylamino-3-hydroxy-4-phenyl-butyric acid in 14 ml dimethylformamide were added at 0° C. to 1.04 g (23.7 mmol) sodium hydride (55%) in 2.5 ml dimethylformamide. The suspension was stirred for 2 hours and then 2.69 ml (24.6 mmol) 2.5-difluoro-nitrobenzene in 3.5 ml dimethylformamide were added. After stirring overnight at 0° C. the mixture was poured on ice/water. The pH was adjusted to 1 by adding aqueous hydrochloric acid. Extraction with ethylacetate and chromatography on silicagel with dichloromethane/methanol (100:0 to 95:5) yielded 4.02 g (70%) racemic (2R,3R and 2S,3S)-2-dibenzylamino-3-(4-fluoro-2-nitro-phenoxy)-4-phenyl-butyric acid as yellow oil, 1H-NMR (ppm, CDCl3): 2.55–2.63 (m, 1H); 3.54–3.69 (m, 2H); 3.61, 3.66, 3.92, 3.97 (AB, 4H); 4.73–4.80 (m, 1H); 6.14–6.19 (m, 1H); 6.79–6.84 (m,1H); 7.01–7.03 (m, 2H); 7.14–7.16 (m, 3H); 7.2–7.4 (m,11H).
Reaction SMILES: [C:1]([BH3-])#[N:2].[Na+].[CH3:5][O:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C@H:22]([CH3:29])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[C:17](N)[CH:16]=2)=[CH:11][CH:10]=1)=[O:8].C=O.[CH3:33][C@H](OC1C=CC(O)=C(N(C)C)C=1)CCCCCC>C(#N)C.C(O)(=O)C>[CH3:5][O:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C@H:22]([CH3:29])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[C:17]([N:2]([CH3:1])[CH3:33])[CH:16]=2)=[CH:11][CH:10]=1)=[O:8]
Reactant: CCCCCC[C@@H](C)Oc1ccc(-c2ccc(C(=O)OC)cc2)cc1N
Reactant: [BH3-]C#N
Reactant: CCCCCC[C@H](C)Oc1ccc(O)c(N(C)C)c1
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CCCCCC[C@@H](C)Oc1ccc(-c2ccc(C(=O)OC)cc2)cc1N(C)C
Yield: 78 %

Procedure:
Sodium cyanoborohydride (202 mg, 3.20 mmol), compound 62 (380 mg, 1.07 mmol), glacial acetic acid (2×0.09 ml), and aqueous formaldehyde (1.28 ml, 16.0 mmol) in 35 ml acetonitrile were reacted according to the procedure for compound 57. Evaporation of solvent yielded 321 mg (78%) of a white solid. The crude product was used without purification. ##STR48##
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.O.O.[Sn](Cl)Cl.C(OCC)(=O)C.[BH4-].[Na+]>CC(O)(C)C>[Cl:11][C:4]1[N:3]=[C:2]([NH2:1])[C:7]([NH2:8])=[CH:6][CH:5]=1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1ccc(Cl)nc1N
Temperature: 60 °C
Reaction time: 1 h
Yield: 65.5 %

Procedure:
A mixture of 12.0 g of 2-amino-6-chloro-3-nitro-pyridine, 78.0 g of tin(II) chloride dihydrate and 360 ml of a 9:1 by volume mixture of ethyl acetate and 2-methyl-2-propanol was stirred at 60° C. for 1 hour, after which 1.32 g of sodium borohydride were added at 60° C., and the mixture was stirred for 3 hours at the same temperature. At the end of this time, the reaction mixture was freed from the solvent by distillation under reduced pressure. The resulting residue was diluted with water and neutralized by adding an aqueous solution of potassium carbonate, after which it was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The residue thus obtained was crystallized by trituration with a mixture of ethyl acetate and hexane, to give 6.50 g of title compound, melting at 120-122° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4](Cl)[N:3]=1.C([CH:11]([NH2:14])[CH2:12][CH3:13])C.[CH3:15][CH2:16]O>>[CH2:4]([N:3]1[CH:2]=[CH:7][N:6]=[C:12]([CH2:13][CH2:16][CH3:15])[CH:11]1[NH2:14])[CH3:5]
Reactant: CCO
Reactant: CCC(N)CC
Reactant: Clc1cncc(Cl)n1
Product: CCCC1=NC=CN(CC)C1N

Procedure:
A solution of 2,6-dichloropyrazine (2.2 g) and 1-ethylpropylamine (5 mL) in EtOH (10 mL) is heated at 140° C. in a Teflon-sealed tube. The resulting solution is concentrated in vacuo, diluted by water, and extracted twice with hexane-ethyl ether. Combined extracts are dried (sodium sulfate), filtered, concentrated in vacuo, and the residue is filtered through a short pad of silica gel. The filtrate is concentrated to give 6-chloro-[N-(1-ethyl(propyl]pyrazine-2-amine as brownish oil that solidifies on standing (3.0 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:7]([O:9][CH3:10])=[O:8].[O:19]=[C:20]1[CH2:23][CH:22]([C:24](O)=[O:25])[CH2:21]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:7]([O:9][CH3:10])=[O:8].[C:15]([O:14][C:12]([NH:11][C@@H:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:24]([CH:22]1[CH2:23][C:20](=[O:19])[CH2:21]1)=[O:25])[C:7]([O:9][CH3:10])=[O:8])=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: O=C1CC(C(=O)O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: COC(=O)[C@H](CCCCN)NC(=O)OC(C)(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CCCCNC(=O)C1CC(=O)C1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 1M stock solution of (S)-methyl 6-amino-2-(tert-butoxycarbonylamino)hexanoate in 20 mL DMF was prepared, and used. A 2 mL aliquot of the (S)-methyl 6-amino-2-(tert-butoxycarbonylamino)hexanoate stock solution, 3-oxocyclobutanecarboxylic acid (2) (Parkway *BX-102, 283 mg), HATU (800 mg), DIEA (1.0 mL) and 8 mL DMF were combined in a 40 mL glass vial, and stirred at ambient temperature overnight. The LC-MS analysis revealed a complete reaction. The reaction mixture was diluted with EtOAc, washed successively with water, sat aq. NaCl, dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified by silica gel flash chromatography (hexanes/EtOAc), affording (S)-methyl 2-(tert-butoxycarbonylamino)-6-(3-oxocyclobutanecarboxamido)hexanoate (TU3000-140) as a clear viscous oil. MS (ESI+): calcd. 379.18. found 379.20 (MNa+), calcd. 257.15. found 257.20((M-Boc)H+). H-NMR (400 MHz, DMSO-d6):1.245 (4H, m), 1.371 (9H, s), 1.579 (2H, m), 3.065 (3H, m), 3.135 (4H, m), 3.608 (3H, s), 3.895 (1H, m), 7.209 (1 h, d, J=8.0 Hz), 8.123 (1H, t, J=5.4 Hz). C-NMR (100 MHz, DMSO-d6): 22.850, 27.185, 28.111, 28.551, 30.209, 38.276, 50.859, 51.639, 53.412, 53.529, 78.137, 155.507, 172.992, 173.167, 205.576.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].N12CCCN=C1CCCCC2.ON1C2C=CC=CC=2N=N1.[S:44]1[CH:48]=[CH:47][CH:46]=[C:45]1[CH2:49][C:50](O)=[O:51]>C(#N)C>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:50](=[O:51])[CH2:49][C:45]3[S:44][CH:48]=[CH:47][CH:46]=3)[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: O=C(O)Cc1cccs1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C(Cc1cccs1)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.17 h
Yield: 77.3 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.2 mmol) in acetonitrile (60 mL), was added 1,8-diazabicyclo[5,4,0]undec-7-ene (0.8 g, 5.4 mmol). After stirring for 10 minutes, 1-hydroxybenzotriazole (0.4 g, 2.6 mmol) and 2-thiopheneacetic acid (0.3 g, 2.4 mmol) were added, followed by 1-(3-dimethylaminopropyo)-3-ethylcarbodiimide hydrochloride (0.6 g, 3.2 mmol). The mixture was stirred at room temperature overnight and was concentrated in vacuo. The residue was dissolved in CH2Cl2 (80 mL) and washed with water (3×40 mL) and brine (40 mL), and dried over MgSO4. Solvent was removed in vacuo, and the residue was purified by ISCO silica gel flash chromatography (Eluent: EtOAc: CH2Cl2 3:7) to afford N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-2-thiophen-2-yl-acetamide (0.7 g, 78%) as a white solid: mp 171-173° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=2.24 min. (99%); 1H NMR (DMSO-d6) δ 2.02-2.09 (m, 1H), 2.51-2.63 (m, 2H), 2.84-2.96 (m, 1H), 3.77 (s, 2H), 4.72 (d, J=5.9 Hz, 2H), 5.12-5.18 (dd, J=5.3 and 12.7 Hz, 1H), 6.95-6.97 (m, 2H), 7.35-7.38 (m, 1H), 7.65-7.69 (m, 1H), 7.78-7.84 (m, 2H), 8.70 (t, J=5.9 Hz, 1H), 11.13 (s, 1H); 13C NMR (DMSO-d6) δ 21.95, 30.90, 36.35, 37.87, 48.84, 121.91, 124.90, 126.22, 126.60, 127.13, 131.52, 133.21, 134.68, 137.33, 138.97, 166.89, 167.42, 169.61, 169.78, 172.73; Anal. Calcd. for C20H17N3O5S: C, 58.39; H, 4.16; N, 10.21; S, 7.79. Found: C, 58.41; H, 4.01; N, 10.07; S, 7.62.
Reaction SMILES: [I-].[CH:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([CH3:4])[CH3:3].C([Li])CCC.[Br:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH:40]=O>O1CCCC1.CCCCCC>[Br:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH:40]=[C:2]([CH3:4])[CH3:3]
Reactant: O=CCCCCCCCCCCBr
Reactant: CC(C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)=CCCCCCCCCCCBr
Temperature: -40 °C

Procedure:
Isopropyltriphenylphosphonium iodide (6 g, 14 mmoles) was suspended in tetrahydrofuran (120 ml), stirred at -40° C. and treated with n-butyllithium (14 mmoles) dissolved in hexane (2.5M). The mixture was stirred at -40° C. for 15 minutes, cooled to -75° C. and treated with a solution of 1-bromo-11-oxoundecane (2.8 g, 11.5 mmoles) in tetrahydrofuran (30 ml). The mixture was stirred at -75° C. for 15 minutes, allowed to warm to 25° C. and concentrated in vacuo. The residue was triturated with hexane, filtered and the filtrate concentrated in vacuo. The residue was chromatographed on silica gel eluted with hexane to afford 1-bromo-12-methyl-11-tridecene.