Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[Si](C)(C)C.[O:6]=[C:7]1[N:12]2[CH:13]=[C:14]([C:17]([OH:19])=[O:18])[CH:15]=[CH:16][C:11]2=[N:10][C:9]2[CH2:20][S:21][CH2:22][C:8]1=2.[Cl:23]N1C(=O)CCC1=O>N1C=CC=CC=1.O>[Cl:23][C:20]1[S:21][CH:22]=[C:8]2[C:7](=[O:6])[N:12]3[CH:13]=[C:14]([C:17]([OH:19])=[O:18])[CH:15]=[CH:16][C:11]3=[N:10][C:9]=12
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C(O)c1ccc2nc3c(c(=O)n2c1)CSC3
Agent: C[Si](C)(C)Cl
Solvent: c1ccncc1
Solvent: O
Product: O=C(O)c1ccc2nc3c(Cl)scc3c(=O)n2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Chlorotrimethylsilane (0.4 ml, 0.03 mol) is added to a cooled (ice bath) solution of 3,10-dihydro-10-oxo-1H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carboxylic acid (0.75 g., 0.03 mol) in pyridine (5 ml) under nitrogen. The mixture is stirred at ice bath temperature for one hour and then allowed to warm to room temperature. N-Chlorosuccinimide (0.8 g., 0.06 mol) is added and the mixture is heated at 95° C. for 20 minutes. The mixture is cooled, diluted with water (3 ml) and stirred for 15 minutes. The precipitate is filtered off, dried and recrystallized from ethanol to give the product (0.5 g.), mp 285° C. (dec).
Reaction SMILES: C[O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([C:10]#[N:11])[N:7]=[C:6]([NH:12][C@H:13]([CH2:15][CH3:16])[CH3:14])[CH:5]=1.[OH-].[Na+].Cl>CO>[C@@H:13]([NH:12][C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([C:10]#[N:11])[N:7]=1)[C:3]([OH:17])=[O:2])([CH2:15][CH3:16])[CH3:14]
Reactant: CC[C@H](C)Nc1cc(C(=O)OC)cc(C#N)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC[C@H](C)Nc1cc(C(=O)O)cc(C#N)n1

Procedure:
Dissolve (S)-2-sec-butylamino-6-cyano-isonicotinic acid methyl ester (250 mg, 0.93 mmol) in methanol (3 mL). Slowly add 2 N NaOH (1.5 mL) and stir overnight at room temperature. Acidify to about pH=6 with 5 N HCl and concentrate. Dilute with ethyl acetate (20 mL) and wash the organic layer with saturated aqueous sodium chloride, dry (magnesium sulfate) and concentrate to give the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[F:11][C:12]([F:16])([F:15])[CH2:13][NH2:14].C(N(CC)C(C)C)(C)C>CN1CCCC1=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:14][CH2:13][C:12]([F:16])([F:15])[F:11])=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: NCC(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1ccc(NCC(F)(F)F)nc1
Temperature: 200 °C
Yield: 43.1 %

Procedure:
A mixture of 2-chloro-5-nitro-pyridine (500 mg, 3.15 mmol), 2,2,2-trifluoro-ethylamine (940 mg, 9.45 mmol) and N,N-diisopropylethylamine (1.64 mL, 9.45 mmol) in 1-methyl-pyrrolidin-2-one (10 mL) in a sealed tube was heated by microwave at 200° C. for 10 minutes. The reaction mixture was evaporated to dryness and purified by silica gel chromatography (Isco 120 g column, 40% ethyl acetate/hexanes) to give (5-nitro-pyridin-2-yl)-(2,2,2-trifluoro-ethyl)-amine (300 mg, 43%) as a yellow solid. LCMS calcd for C7H6F3N3O2 (m/e) 221, obsd 222 (M+H). The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: B(Cl)(Cl)Cl.C([O:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:24][CH2:23][C:22]([O:29][CH3:30])([C:25]([F:28])([F:27])[F:26])[CH2:21][CH2:20]2)=[CH:15][CH:14]=1)C1C=CC=CC=1.C(=O)([O-])O.[Na+]>ClCCl>[CH3:30][O:29][C:22]1([C:25]([F:28])([F:26])[F:27])[CH2:23][CH2:24][N:19]([C:16]2[CH:17]=[CH:18][C:13]([OH:12])=[CH:14][CH:15]=2)[CH2:20][CH2:21]1
Reactant: COC1(C(F)(F)F)CCN(c2ccc(OCc3ccccc3)cc2)CC1
Agent: ClB(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC1(C(F)(F)F)CCN(c2ccc(O)cc2)CC1
Reaction time: 0.33 h
Yield: 96.3 %

Procedure:
Boron trichloride (1 M dichloromethane solution, 2.3 ml) was added to a solution (50 ml) of 1-(4-benzyloxyphenyl)-4-methoxy-4-trifluoromethylpiperidine (0.7 g) in dichloromethane (50 ml) at 0° C. and stirred for 20 minutes. A sodium hydrogen carbonate aqueous solution was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with water and dried over sodium sulfate. The result was concentrated under reduced pressure, and the residue was washed with diethylether and then dried to afford the title compound as a pale yellow powder (508 mg).
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[CH3:5][S:6]([O:9][C:10]1[CH:20]=[CH:19][CH:18]=[C:12]2[C:13]([O:15][C:16](=[O:17])[C:11]=12)=[O:14])(=[O:8])=[O:7]>C(#N)C>[CH:1]([NH:4][C:16](=[O:17])[C:11]1[C:12](=[CH:18][CH:19]=[CH:20][C:10]=1[O:9][S:6]([CH3:5])(=[O:8])=[O:7])[C:13]([OH:15])=[O:14])([CH3:3])[CH3:2]
Reactant: CC(C)N
Reactant: CS(=O)(=O)Oc1cccc2c1C(=O)OC2=O
Solvent: CC#N
Product: CC(C)NC(=O)c1c(OS(C)(=O)=O)cccc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
Isopropylamine (0.78 g) was added to an acetonitrile solution (10 mL) of 3-methanesulfonyloxyphthalic anhydride (1.60 g) under ice cooling and the mixture was further stirred at room temperature for 8 hours. After finishing the reaction, the solvent and the excess of isopropylamine were distilled off under reduced pressure and the obtained crude product was washed with a small amount of acetonitrile to obtain N-isopropyl-3-methanesulfonyloxyphthalamic acid (1.80 g) having the melting point of 56–59° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:16][C:17]2[N:22]=[C:21]([C:23](=[O:25])[CH3:24])[CH:20]=[C:19]([CH2:26][O:27][CH2:28][C:29]([F:32])([F:31])[F:30])[N:18]=2)[CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[C:13]([CH3:15])[N:12]=[N:11][CH:10]=1.[CH3:33][Mg]Br.[Cl-].[NH4+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:16][C:17]2[N:22]=[C:21]([C:23]([OH:25])([CH3:33])[CH3:24])[CH:20]=[C:19]([CH2:26][O:27][CH2:28][C:29]([F:30])([F:32])[F:31])[N:18]=2)[CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[C:13]([CH3:15])[N:12]=[N:11][CH:10]=1
Reactant: C[Mg]Br
Reactant: COc1cc(Nc2nc(COCC(F)(F)F)cc(C(C)=O)n2)ccc1-c1cnnc(C)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cc(Nc2nc(COCC(F)(F)F)cc(C(C)(C)O)n2)ccc1-c1cnnc(C)c1
Reaction time: 0.08 h

Procedure:
1-(2-(3-Methoxy-4-(6-methylpyridazin-4-yl)phenylamino)-6-((2,2,2-trifluoroethoxy)methyl)-pyrimidin-4-yl)ethanone (60 mg, 0.13 mmol) was dissolved in THF (5 mL) and was added slowly to a solution of methylmagnesium bromide (3 M in THF, 0.358 mL, 1.07 mmol) in THF (5 mL). The mixture was stirred for 5 min. The mixture was cooled on an ice bath and ammonium chloride (sat, aq, 5 mL) was added. The mixture was stirred for 5 min. The mixture was extracted with EtOAc (×2). The solvents were evaporated and the residue was purified by column chromatography on silica eluting with a gradient of MeOH in DCM to give the title compound as a solid, 42 mg (68%).
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:38])([CH3:37])[O:6][C@@H:7]1[C@H:11]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[C@@H:10]([CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[O:9][C@H:8]1[N:29]1[CH:36]=[CH:35][C:33](=[O:34])[NH:32][C:30]1=[O:31])([CH3:4])[CH3:3].[C:39]1([C:45]2[CH:50]=[CH:49][C:48]([C:51](Cl)=[O:52])=[CH:47][CH:46]=2)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[C:39]1([C:45]2[CH:50]=[CH:49][C:48]([C:51]([C:35]3[C:33](=[O:34])[NH:32][C:30](=[O:31])[N:29]([CH:36]=3)[C@@H:8]3[O:9][C@H:10]([CH2:20][O:21][Si:22]([C:25]([CH3:26])([CH3:27])[CH3:28])([CH3:23])[CH3:24])[C@@H:11]([O:12][Si:13]([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:14])[CH3:15])[C@H:7]3[O:6][Si:5]([C:2]([CH3:1])([CH3:3])[CH3:4])([CH3:38])[CH3:37])=[O:52])=[CH:47][CH:46]=2)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cc(C(=O)c3ccc(-c4ccccc4)cc3)c(=O)[nH]c2=O)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C

Procedure:
5-((4-Phenyl)phenylcarbonyl)-2',3',5'-tris-O-((1,1-dimethylethyl)dimethylsilyl)uridine was prepared from 2',3',5'-tris-O-((1,1-dimethylethyl)dimethylsilyl)uridine according to the method of Example 1 step (i) (using (4-phenyl)phenylcarbonyl chloride instead of benzophenone) as a colourless foam.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[C:15](O)(=O)[CH2:16][OH:17]>>[CH2:12]([N:4]1[C:3](=[O:14])[C:2]2[NH:1][C:15]([CH2:16][OH:17])=[N:8][C:7]=2[N:6]([CH2:9][CH3:10])[C:5]1=[O:11])[CH3:13]
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Reactant: O=C(O)CO
Product: CCn1c(=O)c2[nH]c(CO)nc2n(CC)c1=O
Yield: 59.3 %

Procedure:
Substantially the same procedure as in Reference Example 1 was repeated using 5.0 g (25.2 mmol) of 5,6-diamino-1,3-diethyluracil [J. Am. Chem. Soc., 75, 114 (1953)] and 8.4 g (111 mmol) of glycolic acid. The resulting crude crystals were recrystallized from methanol to give 3.56 g (yield 60%) of Compound d as white needles.
Reaction SMILES: Cl.[NH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([NH2:14])=[O:13])[C:3]([NH2:5])=[NH:4].Cl.Cl.[NH2:17][CH2:18][CH2:19][CH2:20][NH:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:31])[CH:28](O)[OH:29].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O>[NH2:17][CH2:18][CH2:19][CH2:20][NH:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:31])[CH:28]([NH:14][C:12](=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][NH:2][C:3]([NH2:5])=[NH:4])[OH:29]
Reactant: NCCCNCCCCNC(=O)C(O)O
Reactant: N=C(N)NCCCCCCC(N)=O
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Product: N=C(N)NCCCCCCC(=O)NC(O)C(=O)NCCCCNCCCN
Temperature: 60 °C

Procedure:
A mixture of 10.0 g (45.0 m moles) of 7-guanidinoheptanamide hydrochloride, 13.1 g (45.0 moles) of N-[4-(3-aminopropyl)aminobutyl]-2,2-dihydroxyethanamide dihydrochloride, and 3.2 g (15 m moles) of citric acid in water (100 ml) was evaporated to dryness to give a syrup which contained 1.0 g of water. The resulting syrup was heated at 60° C. for 8 hours.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:28])[N:4]([CH2:14][C:15]([NH:17][CH:18]([CH:25]([CH3:27])[CH3:26])[C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])=[O:16])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.ClS([N:33]=[C:34]=[O:35])(=O)=O.C(=O)(O)[O-].[Na+]>O1CCCC1.C(OCC)(=O)C>[O:28]=[C:3]1[C:2]([NH:1][C:34]([NH2:33])=[O:35])=[CH:7][CH:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:4]1[CH2:14][C:15]([NH:17][CH:18]([CH:25]([CH3:26])[CH3:27])[C:19](=[O:24])[C:20]([F:22])([F:23])[F:21])=[O:16]
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ccc(N)c1=O)C(=O)C(F)(F)F
Reactant: O=C=NS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ccc(NC(N)=O)c1=O)C(=O)C(F)(F)F
Reaction time: 0.17 h
Yield: 69.1 %

Procedure:
To a solution of 2-(3-amino-2-oxo-6-phenyl-1,2-dihydro-1-pyridyl)-N-(3,3,3-trifluoro-1-isopropyl-2-oxopropyl)acetamide (0.30 g) in tetrahydrofuran (5 mL), cooled to 0° C., was added, dropwise, chlorosulfonyl isocyanate (0.12 g). The reaction mixture was stirred for 10 min, neutralized with saturated aqueous sodium bicarbonate solution (1 mL), diluted with ethyl acetate (10 mL), and the organic phase washed (water, brine), dried (MgSO4) and evaporated. Purification by chromatography, using an eluant of methylene chloride:methanol (30:1), followed by overnight vacuum-drying (50° C. at 27 Pa), yielded the title product as a white solid (0.23 g); mp 227°-230° C. (dec); TLC: Rf =0.16, dichloromethane:methanol (20:1); 300 MHz NMR: 0.88 (2d,6), 2.15 (m,1), 4.50 (q,2), 4.65 (d,1), 6.18 (d,1), 6.40 (broad s,2), 7.40 (m,5), 8.08 (d,1), 8.35 (s,1), 8.75 (d,1); IR(KBr): 3470 (broad), 3360, 2980, 1760, 1700, 1535, 1490, 1210, 1160, 1020 cm-1 ; MS: m/z=439(M+1).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([C:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH3:17])[CH2:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1.Cl>[Pd].C(O)C>[CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH3:17])[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCCN1CC=C(c2cccc(SC)c2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCCN1CCC(c2cccc(SC)c2)CC1
Reaction time: 1 h

Procedure:
4-(3-Methylsulfanyl-phenyl)-1-propyl-1,2,3,6-tetrahydropyridine (2) (290 mg, 1.17 mmol) was brought in a Parr-flask with 10 mL of ethanol (100%) in a nitrogen atmosphere. 100 mg of Pd/C and 0.5 mL of HCl (37%) were added. The flask was attached to a Parr reduction apparatus and H2 gas was added to a pressure of 3 Bar. It was left shaking for 1 h. Then, the mixture was filtered over celite, put back in the flask and another 100 mg of Pd/C and 1 ml of HCl (37%) was added before attaching the flask to the Parr apparatus again and starting another session of 75 min this time. This procedure was repeated another 3 times, with session durations of 105 min, 1 night and 2 h. Eventually, the mixture was filtered, the solvent evaporated in vacuo on a rotavapor. 10 mL of NaHCO3 10% was added (pH 8). Then 30 mL of water and 40 mL of diethyl ether were added and shaken. The aqueous layer was extracted three times with diethyl ether. The combined organic layers were washed with brine, dried on MgSO4, filtered and the solvent was evaporated on a rotavapor. The slightly yellow oil was taken up in CH2Cl2 and purified by gradient column chromatography (Al2O3, CH2Cl2, CH2Cl2:MeOH 10:1). Fractions 9-20 contained the desired product. The fractions were collected and the solvent was evaporated in under reduced pressure. Yield: 335 mg (115%). The reaction was followed on thin layer chromatography (SiO2 flushed with NH3, CH2Cl2:MeOH 20:1 and Al2O3, CH2CL2:MeOH 40:1). 1H-NMR (CDCl3, 300 MHz): δ 7.2 (m), 3.1 (t), 2.5 (s), 2.4 (m), 2.0 (m), 1.8 (m), 1.6 (m), 1.2 (m), 0.9 (m) ppm; 13C-NMR (CDCl3, 300 MHz): δ 145.673, 136.767, 127.345, 126.882, 126.722, 125.372, 124.576, 123.650, 123.430, 122.793, 122.216, 120.479, 59.631, 52.841, 41.333, 31.888, 26.630, 18.680, 14.287, 10.577 ppm; GCMS (EI): m/z 249 (M+), 220 (M−29); GC (100-320° C., 10° C./min): 4.7, 9.9 min.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:16])=[C:9]([C:11](OCC)=[O:12])[N:10]=2)[CH:7]=1.[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:16])=[C:9]([CH2:11][OH:12])[N:10]=2)[CH:7]=1
Reactant: CCOC(=O)c1nc2ccc(I)cn2c1C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: Cc1c(CO)nc2ccc(I)cn12
Reaction time: 4 h
Yield: 63 %

Procedure:
To a stirred solution of ethyl 6-iodo-3-methylimidazo[1,2-a]pyridine-2-carboxylate (2.0 g) in DCM (20 ml) was added diisobutylaluminum hydride (1.76 M solution in toluene, 7.72 ml) at −19° C. The resultant mixture was stirred at the same temperature for 3 h and then at room temperature for 4 h. The reaction mixture was then quenched with MeOH and water at −40° C. The reaction mixture was acidified with few drops of 5 M HCl and poured into saturated NaHCO3. The mixture was extracted with EtOAc, and the extract was washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (1.1 g) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:22]([Cl:23])=[CH:21][C:5]([NH:6][C:7]2[S:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8]=2[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:4]([N+:24]([O-])=O)[CH:3]=1.[H][H]>[C].[Pd].C(OCC)(=O)C>[NH2:24][C:4]1[CH:3]=[C:2]([Cl:1])[C:22]([Cl:23])=[CH:21][C:5]=1[NH:6][C:7]1[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[C:8]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: [H][H]
Reactant: CCOC(=O)c1c(Nc2cc(Cl)c(Cl)cc2[N+](=O)[O-])sc2ccccc12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(Nc2cc(Cl)c(Cl)cc2N)sc2ccccc12

Procedure:
In the same manner as in Starting Material Synthesis Example 19 and using ethyl 2-(4,5-dichloro-2-nitroanilino)benzo[b]thiophene-3-carboxylate, ethyl acetate, 10% palladium-carbon and hydrogen (60 atm kg/cm2), ethyl 2-(2-amino-4,5-dichloroanilino)benzo[b]thiophene-3-carboxylate is obtained.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl-].[Mg+2].[Cl-].[CH2:24]([O:26][C:27](=[O:32])[CH2:28]C([O-])=O)[CH3:25]>O1CCCC1.O>[O:8]=[C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH2:28][C:27]([O:26][CH2:24][CH3:25])=[O:32]
Reactant: O=C(O)c1cccs1
Reactant: CCOC(=O)CC(=O)[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CC(=O)c1cccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.1 %

Procedure:
To a suspension of 2-thiophenecarboxylic acid (6.48 g, 50.57 mmol) in tetrahydrofurane (100 ml) at 5. was added 1,1′-Carbonyldiimidazole (8.61 g, 53.09 mmol) by portions. The mixture was allowed to warm to room temperature, and the stirring was continued for 1 hour. The reaction mixture was added into a suspension mixture of magnesium chloride (4.86 g, 51.07 mmol) and pottasium 3-ethoxy-3-oxopropanoate (12.91 g, 75.85 mmol) in tetrahydrofurane (50 ml). After being stirred at 50. for 2 hours and at room temperature overnight, the reaction mixture was poured into water, and then extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica-gel (ethyl acetate/hexane, 15/85) to give ethyl 3-oxo-3-(2-thienyl)propanoate (7.83 g, 78% yield) as a yellow oil.
Reaction SMILES: C[N:2]1[CH2:7][CH2:6][CH:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[CH:11]=2)[CH2:4][CH2:3]1.[C:19](O)(=O)C>[Fe]>[CH3:19][CH:9]([O:8][CH:5]1[CH2:4][CH2:3][NH:2][CH2:7][CH2:6]1)[C:10]1[CH:11]=[C:12]([NH2:16])[CH:13]=[CH:14][CH:15]=1
Reactant: CN1CCC(OCc2cccc([N+](=O)[O-])c2)CC1
Reactant: CC(=O)O
Agent: [Fe]
Product: CC(OC1CCNCC1)c1cccc(N)c1
Temperature: 120 °C

Procedure:
A 500 mL 4-necked flask with mechanical stirrer, N2 inlet and reflux condenser is charged with 9.3 g (37.2 mmol) 1-methyl-4-(3-nitro-benzyloxy)-piperidine and 150 mL of acetic acid. Under efficient stirring 13.14 g (223 mmol) of iron powder is added and the mixture heated in an oil bath. At around 90 to 100° C. an exothermic reaction starts. The heating is interrupted for about 15 min until the exothermic reaction ceases and then the mixture is re-immersed into the oil bath and heated for 1 h at 120° C. The mixture is transferred to a round-bottomed flask and the solvent removed under reduced pressure. The residue is taken up in 1N HCl and washed with ethyl acetate (3×200 mL). The aqueous phase is treated with sodium carbonate until PH 9-10. The voluminous precipitate is removed by filtration through Celite and the solid washed extensively with ethyl acetate. The aqueous filtrate and the ethyl acetate washings are separated and the aqueous phase extracted with ethyl acetate. The organic phase is washed with brine, dried with sodium sulfate and evaporated. According to the H-NMR the residue is composed of a 1:1 mixture of the desired aniline and the corresponding acetanilide. The mixture is therefore dissolved in 50 mL of ethanol and treated with 50 mL of 2N NaOH. The resulting mixture is heated 20 h under reflux. After cooling the ethanol is distilled off and the remaining aqueous phase extracted with dichloromethane (2×150 mL). The organic phases are washed with brine, dried with potassium carbonate and evaporated. 3-(1-Methyl-piperidin-4-yloxymethyl)-phenylamine is obtained as a brown viscous oil and used without further purification. HPLC: 7.54 (System X2); [M+H]+221.0.
Reaction SMILES: COC(=O)[CH2:4][N:5]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:6][CH:7]([NH:9][C:10](OC(C)(C)C)=[O:11])[CH3:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:17]([N:5]1[CH2:6][C@H:7]([CH3:8])[NH:9][C:10](=[O:11])[CH2:4]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)CN(Cc1ccccc1)CC(C)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]1CN(Cc2ccccc2)CC(=O)N1

Procedure:
Ester (2) was stirred in a 50:50 solution of TFA:CH2Cl2 for 1 hour. The solvent was then removed, and the residue was redissolved in methylene chloride and washed with a saturated solution of Na2CO3. The organic layer was then separated and dried over MgSO4 giving desired piperazine compound (3) as a white solid (87%).
Reaction SMILES: [CH2:1]([C@@H:8]1[C@@H:16]([O:17][CH2:18][C:19]([CH3:21])=[CH2:20])[C@H:15]([CH3:22])[O:14][C:13](=[O:23])[C@@H:12]([N:24]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:11][O:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CCOC(C)=O.[Pd]>[CH2:1]([C@@H:8]1[C@@H:16]([O:17][CH2:18][CH:19]([CH3:21])[CH3:20])[C@H:15]([CH3:22])[O:14][C:13](=[O:23])[C@@H:12]([N:24]([C:25]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:31])[C:32](=[O:33])[O:34][C:35]([CH3:36])([CH3:37])[CH3:38])[CH2:11][O:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: C=C(C)CO[C@@H]1[C@@H](Cc2ccccc2)COC[C@H](N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)O[C@H]1C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)CO[C@@H]1[C@@H](Cc2ccccc2)COC[C@H](N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)O[C@H]1C
Reaction time: 8 h
Yield: 98.8 %

Procedure:
To a solution of tert-butyl N-[(3S,7S,8R,9S)-7-benzyl-9-methyl-8-(2-methylallyloxy)-2-oxo-1,5-dioxonan-3-yl]-N-tert-butoxycarbonylcarbamate (3.65 g, 6.84 mmol, 1.00 equiv) in EtOAc (68 ml) was added Pd/C (10%; 0.364 g, 0.342 mmol, 0.0500 equiv). The atmosphere was replaced with hydrogen (1 atm, balloon) and the mixture was stirred vigorously overnight. The reaction was filtered through a plug of Celite® and the plug was then flushed with EtOAc (100 mL). The filtrate was concentrated to give tert-butyl N-[(3S,7S,8R,9S)-7-benzyl-8-isobutoxy-9-methyl-2-oxo-1,5-dioxonan-3-yl]-N-tert-butoxycarbonylcarbamate (3.62 g, 99%) as a white, crystalline solid: IR (ATR) 2987, 2933, 2914, 2876, 1749, 1723, 1413, 1391, 1367, 1317, 1271, 1257, 1238, 1229, 1196, 1147, 1097, 1084, 1065, 1058, 854, 744 cm−1; 1H NMR (400 MHz, CDCl3) δ 3.33-3.27 (m, 1H), 3.40-3.33 (m, 1H), 1.92-1.79 (m, 1H), 7.35-7.22 (m, 2H), 7.22-7.11 (m, 3H), 5.11 (dd, J=8.5, 6.4 Hz, 1H), 4.88 (dq, J=9.0, 6.3 Hz, 1H), 3.46-3.40 (m, 1H), 4.07 (dd, J=11.8, 6.4 Hz, 1H), 3.84 (dd, J=11.8, 8.6 Hz, 1H), 3.52 (d, J=10.6 Hz, 1H), 3.18-3.08 (m, 2H), 2.35 (s, 1H), 1.98 (s, 1H), 1.48 (s, 21H), 0.94 (d, J=6.7 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 169.98, 152.62, 140.12, 129.25, 128.32, 125.99, 84.52, 82.99, 78.82, 75.39, 70.96, 57.47, 47.05, 34.98, 29.16, 27.92, 19.49, 18.95; HRMS-ESI (m/z) [M−H]− calc'd for C29H44NO8; 534.3072. found, 534.3069.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([S:14][C:15]2[CH:16]=[CH:17][C:18]3[O:27][CH2:26][CH2:25][N:24]4[C:20](=[N:21][C:22]([C:28]5[N:29]([CH:33]([CH3:35])[CH3:34])[N:30]=[CH:31][N:32]=5)=[CH:23]4)[C:19]=3[CH:36]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:33]([N:29]1[C:28]([C:22]2[N:21]=[C:20]3[N:24]([CH2:25][CH2:26][O:27][C:18]4[CH:17]=[CH:16][C:15]([S:14][CH:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)=[CH:36][C:19]=43)[CH:23]=2)=[N:32][CH:31]=[N:30]1)([CH3:35])[CH3:34]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(SC3CCN(C(=O)OC(C)(C)C)CC3)ccc1OCC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(SC3CCNCC3)ccc1OCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.4 %

Procedure:
An ice-cooled solution of 4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-9-ylsulfanyl]piperidine-1-carboxylic acid tertbutyl ester (0.722 g) in DCM (10 mL) was treated with TFA (2 mL) and stirred at RT for 2 h. Volatiles were removed under reduced pressure and the resulting residue was purified by column chromatography (C18, gradient 20-50% MeOH in 0.5% TFA/H2O) and then loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product eluted with 0.5M NH3/MeOH affording 2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-9-(piperidin-4-ylsulfanyl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene (0.368 g). LCMS: RT 2.08/2.14 min [M+H]+ 411.2