Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][S:11][C@H:12]1[N:15]([CH:16]([C:30]([CH3:32])=C)[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)=[O:18])[C:14](=[O:33])[C@H:13]1[NH:34][C:35](=[O:44])[CH2:36][O:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.[O:45]=[O+][O-]>CO.ClCCl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][S:11][C@H:12]1[N:15]([C:16](=[C:30]([OH:45])[CH3:32])[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)=[O:18])[C:14](=[O:33])[C@H:13]1[NH:34][C:35](=[O:44])[CH2:36][O:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: C=C(C)C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)[C@@H](NC(=O)COc2ccccc2)[C@H]1SSc1nc2ccccc2s1
Reactant: O=[O+][O-]
Solvent: CO
Solvent: ClCCl
Product: CC(O)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)[C@@H](NC(=O)COc2ccccc2)[C@H]1SSc1nc2ccccc2s1
Yield: 95 %

Procedure:
A solution of 4-nitrobenzyl 2-[(3R,4R)-4[(benzothiazol-2-yl)dithio]-3-phenoxyacetamido-2-oxo-azetidin-1-yl]-3-methyl-3-butenoate (XIIIc. 1.52 g 0.00244 mole) in 2:1 methanol/dichloromethane (165 mL), at -78° C., was treated with a stream of dry ozone until a pale blue coloration was reached (10 min). Nitrogen was then bubbled through the solution to discharge the blue color and methyl sulfide (1.5 mL) was added. The solution allowed to reach 0° C. over the course of 2 h. Evaporation of the solvents gave a crude product which was purified by flash-chromatography over silica gel (65% ethyl acetate in hexane) to yield 1.448 g (95%) of the title compound, XIVb, as a white foam.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[C:7]([CH2:15][C:16]2[CH:20]=[CH:19][S:18][C:17]=2[S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:23])=[O:22])=[C:6]1[CH3:30].O1CCCC1.[OH-].[Na+].Cl>CO>[F:14][C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[N:5]([CH2:4][C:3]([OH:31])=[O:2])[C:6]([CH3:30])=[C:7]2[CH2:15][C:16]1[CH:20]=[CH:19][S:18][C:17]=1[S:21]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)(=[O:23])=[O:22]
Reactant: COC(=O)Cn1c(C)c(Cc2ccsc2S(=O)(=O)c2ccccc2)c2cc(F)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(Cc2ccsc2S(=O)(=O)c2ccccc2)c2cc(F)ccc2n1CC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
A mixture of [5-fluoro-3-(2-benzenesulfonylthiophen-3-ylmethyl)-2-methylindol-1-yl]acetic acid methyl ester (0.18 g), tetrahydrofuran (4.0 mL) and methanol (2.0 mL) was treated with 1.0 M aqueous sodium hydroxide solution (2.0 mL), and the resulting mixture was stirred at room temperature for 1 hour. The mixture was acidified by the addition of 1.0 M aqueous hydrochloric acid solution and concentrated to low bulk under reduced pressure. The resulting precipitate was collected by filtration, washed with water and dried to afford the title compound as a white solid (0.16 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].C([N-]C(C)C)(C)C.[Li+].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[C:23](Cl)=[O:24].O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[CH2:8][C:23]([C:22]1[CH:26]=[CH:27][C:28]([O:29][CH3:30])=[C:20]([O:19][CH3:18])[CH:21]=1)=[O:24]
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: Cc1c(Cl)cncc1Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)cc1OC
Temperature: 0 °C
Yield: 50.4 %

Procedure:
A solution of 3,5-dichloro-4-methyl-pyridine (2.06 g, 12.7 mmol) in dry tetrahydrofuran (30 ml) was cooled down to −78° C., then a 1.8 M solution of lithium diisopropylamide in tetrahydrofuran (7.4 ml, 13.3 mmol) was added dropwise under stirring, keeping the temperature below −70° C. The resulting solution was stirred for 30 min., then a solution of 3,4-dimethoxy-benzoyl chloride (2.55 g, 12.7 mmol) in dry tetrahydrofuran (20 ml) was added dropwise, maintaining the temperature below −70° C. After stirring for 15 minutes, ice (20 g) was added, followed by further 500 ml of water. The mixture was extracted with ethyl acetate (2×50 ml), the combined organic layers were dried over sodium sulphate and evaporated under reduced pressure to give an oil that was purified by flash chromatography (Eluent:ethyl acetate/petroleum ether from 10/90 to 30/70 v:v). 2.1 grams (6.4 mmol, 52% yield) of the title compound were obtained as a white solid.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][NH:11][C:12]1([C:23]([NH:25][CH3:26])=[O:24])[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]1.[Cl:27][C:28]1[C:29]([F:49])=[C:30]([NH:34][C:35]2[C:44]3[C:39](=[CH:40][C:41]([O:47][CH3:48])=[C:42]([CH2:45]Cl)[CH:43]=3)[N:38]=[CH:37][N:36]=2)[CH:31]=[CH:32][CH:33]=1>CN(C=O)C>[Cl:27][C:28]1[C:29]([F:49])=[C:30]([NH:34][C:35]2[C:44]3[C:39](=[CH:40][C:41]([O:47][CH3:48])=[C:42]([CH2:45][N:11]([CH3:10])[C:12]4([C:23]([NH:25][CH3:26])=[O:24])[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:13]4)[CH:43]=3)[N:38]=[CH:37][N:36]=2)[CH:31]=[CH:32][CH:33]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CCl
Reactant: CNC(=O)C1(NC)CN(C(=O)OC(C)(C)C)C1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)C1(N(C)Cc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CN(C(=O)OC(C)(C)C)C1
Temperature: 85 °C
Reaction time: 0.08 h
Yield: 40.8 %

Procedure:
Diisopropylethylamine (0.55 ml, 3.10 mmol) was added to a solution of tert-butyl 3-(methylamino)-3-[(methylamino)carbonyl]azetidine-1-carboxylate (301 mg, 1.24 mmol) in DMF (0.5 ml). After 5 minutes of stirring, the reaction mixture became homogeneous and was warmed up to 85° C. N-(3-chloro-2-fluorophenyl)-6-(chloromethyl)-7-methoxyquinazolin-4-amine (400 mg, 1.03 mmol) was added portionwise over 2 hours. The reaction mixture was cooled to room temperature, diluted with DMF (2 ml) and purified by preparative HPLC (standard basic condition) to afford tert-butyl 3-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]-3[(methylamino)carbonyl]azetidine-1-carboxylate (235 mg, 41%) as a white solid. 1H NMR Spectrum: (CDCl3) 1.45 (s, 9H), 2.34 (s, 3H), 2.90 (d, 3H), 3.78 (brs, 2H), 4.01 (s, 3H), 4.10 (d, 2H), 4.25 (brs, 2H), 6.84 (brs, 1H), 7.17 (m, 2H), 7.29 (s, 1H), 7.60 (brs, 1H), 7.78 (brs, 1H), 8.53 (brs, 1H), 8.75 (s, 1H); Mass Spectrum: (M+H)+ 559.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[NH:10][NH2:11].[N:12]1[CH:17]=NC=N[CH:13]=1>CCO>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[N:10]1[CH:17]=[N:12][CH:13]=[N:11]1
Reactant: NNc1cc(F)ccc1Br
Reactant: c1ncncn1
Agent: Cl
Solvent: CCO
Product: Fc1ccc(Br)c(-n2cncn2)c1
Temperature: 90 °C
Yield: 61.3 %

Procedure:
Prepared according to the procedure described in J. Org. Chem., 1956, 21, 1037. A stirred mixture of (2-bromo-5-fluoro-phenyl)-hydrazine hydrochloride (31.9 g, 0.132 mol) and s-triazine (10.7 g, 0.132 mol; Aldrich) in EtOH (250 mL) was heated at 90° C. for 3 h. After cooling, the insoluble material was filtered off and the filtrate was concentrated. The residue was partitioned between CH2Cl2 (200 mL) and water (200 mL), and the aqueous phase was extracted once more with CH2Cl2 and the combined extracts were dried (MgSO4), filtered and concentrated to a red semi-solid which was triturated with hexanes to give 19.6 g of the title compound as an orange solid: HPLC rt=1.68 min. LC/MS m/z 242 (M+H); 1H NMR (CDCl3, 500 MHz) δ ppm 7.02–7.15 (1H, m, 5-CH), 7.29 (1H, dd, J=8.4, 2.9 Hz, 3-CH), 7.68 (1H, dd, J=8.8, 5.5 Hz, 6-CH), 8.10 (1H, s, 8-CH), 8.54 (1H, s, 7-CH); 13C NMR (CDCl3, 125.8 Hz) δ ppm 112.54, 112.57 (d, J=1.5 Hz, 1-C), 115.68, 115.88 (d, J=25 Hz, 3-CH), 118.07, 118.25 (d, J=22 Hz, 5-CH), 135.11, 135.18 (d, J=8.6 Hz, 6-CH), 137.43, 137.52 (d, J=11 Hz, 2-C), 144.4 (7-CH), 152.6 (8-CH), 160.95, 162.94 (d, J=251 Hz, 4-CF); HRMS (ESD) calcd for C8H6FBrN3 (M+H) 241.9727. found 241.9733 (δ 1.6 ppm); UV (MeOH) λmax 275 nm (ε 1.45×103); Anal. calcd for C8H5BrFN3: C, 39.69; H, 2.08; N, 17.36. found C, 39.63; H, 1.83; N, 17.22.
Reaction SMILES: [C:1]([O:9][CH2:10][C:11]1[O:15][N:14]=[C:13]([CH3:16])[CH:12]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(O)=O.C1C(=O)N([Br:28])C(=O)C1>O>[C:1]([O:9][CH2:10][C:11]1[O:15][N:14]=[C:13]([CH3:16])[C:12]=1[Br:28])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(COC(=O)c2ccccc2)on1
Solvent: CC(=O)O
Solvent: O
Product: Cc1noc(COC(=O)c2ccccc2)c1Br
Temperature: 110 °C

Procedure:
To a resealable vial was added (3-methylisoxazol-5-yl)methyl benzoate (907 mg, 4.18 mmol), AcOH (3.5 mL, 61.1 mmol), and NBS (892 mg, 5.01 mmol). The reaction was heated to 110° C. overnight. The reaction was cooled to room temperature and diluted with water. The aqueous was extracted with EtOAc and the combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude residue was purified via Biotage (EtOAc/hex) to afford (4-bromo-3-methylisoxazol-5-yl)methyl benzoate. LC/MS m/z 296 [M+H]+.
Reaction SMILES: [C:1]1([C@@H:7]2[CH:12]=[CH:11][CH2:10][CH2:9][C@@H:8]2[C:13]([OH:15])=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][Si](C=[N+]=[N-])(C)C>CO.C1COCC1>[C:1]1([C@@H:7]2[CH:12]=[CH:11][CH2:10][CH2:9][C@@H:8]2[C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)[C@H]1CCC=C[C@H]1c1ccccc1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)[C@H]1CCC=C[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 900 mg (4.45 mmol) of 1(R)-phenyl-2(S)-carboxy cyclohex-5-ene (See U.S. Pat. No. 5,750,549, Example 158, Step B) in a 4:1 solution of MeOH/THF was added trimethylsilyldiazomethane until a yellow color persisted. After stirring at room temperature for 3 hour the reaction was concentrated in vacuo and the residue was purified by flash chromatography eluting with 0-15% EtOAc in hexanes to afford the ester (300 mg) as a colorless oil. 1H NMR (CDCl3, 500 MHz) δ 7.19-7.30 (m, 5H), 5.98-6.01 (m, 1H), 5.76-5.79 (m, 1H),3.89 (s, 1H),3.50 (s, 3H), 2.95-2.98 (m, 1H), 2.16-2.32 (m, 2H),1.80-1.87 (m, 2H) ppm.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:21][O:22][C:23](=[O:36])[C:24]1[CH:33]=[CH:32][C:31]([CH2:34]Br)=[C:26]([C:27]([O:29][CH3:30])=[O:28])[CH:25]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:21][O:22][C:23](=[O:36])[C:24]1[CH:33]=[CH:32][C:31]([CH2:34][N:9]2[CH:8]([C:3]3[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=3)[CH2:13][CH2:12][CH2:11][CH:10]2[C:14]2[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=2)=[C:26]([C:27]([O:29][CH3:30])=[O:28])[CH:25]=1
Reactant: Cc1cccnc1C1CCCC(c2ncccc2C)N1
Reactant: COC(=O)c1ccc(CBr)c(C(=O)OC)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CN2C(c3ncccc3C)CCCC2c2ncccc2C)c(C(=O)OC)c1
Yield: 100 %

Procedure:
Using General Procedure A: A solution of 3,3″-Dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine (0.402 g, 1.50 mmol), 4-bromomethyl-isophthalic acid dimethyl ester (0.603 g, 2.10 mmol), KI (63 mg, 0.38 mmol), and DIPEA (0.60 mL, 3.44 mmol) in DMF (7.5 mL) was heated at 60 ° C. for 24 hours. Purification of the crude material by column chromatography on silica gel (20:1:1 CH2Cl2—CH3OH—NH4OH) provided 710 mg (99%) of COMPOUND 52 as a white solid. 1H NMR (CDCl3) δ 1.63-1.77 (m, 3H), 2.09 (br s, 1H), 2.34-2.52 (m, 8H), 3.84 (s, 6H), 4.02 (s, 2H), 4.18 (d, 2H, J=11.1 Hz), 6.82 (dd, 2H, J=4.8, 7.5 Hz), 7.14 (d, 2H, J=7.5 Hz), 7.72 (s, 2H), 7.92 (s, 1H), 8.22 (d, 2H, J=4.8 Hz); 13C NMR (CDCl3) δ 19.32, 25.66, 28.30, 50.13, 52.23, 52.36, 67.14, 122.20, 126.83, 128.07, 130.49, 131.08, 131.33, 132.14, 138.08, 146.90, 149.71, 159.50, 166.88, 167.23; ES-MS m/z 474 (M+H). Anal. Calcd. For C28H31N3O4.0.3H2O: C, 70.21; H, 6.65; N, 8.77. Found: C, 70.17; H, 6.60; N, 8.72.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[CH3:19][C:20]([N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)([CH3:23])[CH2:21][NH2:22]>>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][NH:22][CH2:21][C:20]([CH3:23])([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH3:19])=[CH:8][C:6]=2[N:7]=1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CC(C)(CN)N1CCOCC1
Product: CC(C)(CNCc1cc2nc(Cl)nc(N3CCOCC3)c2s1)N1CCOCC1

Procedure:
Following the procedures for 172, 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde and 2-methyl-2-morpholinopropan-1-amine were reacted by reductive amination to give N-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-2-methyl-2-morpholinopropan-1-amine, which was converted to the 2-tributylstannyl intermediate and reacted with 2-methyl-1H-benzo[d]imidazole to give 203. LCMS m/z: 522.2 (MH+)
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][CH:18]([CH:20]4[CH2:25][CH2:24][N:23]([C:26]#[N:27])[CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[F:28][C:29]([F:35])([F:34])[C:30]([NH:32][OH:33])=N>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][CH:18]([CH:20]4[CH2:25][CH2:24][N:23]([C:26]5[O:33][N:32]=[C:30]([C:29]([F:35])([F:34])[F:28])[N:27]=5)[CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: N=C(NO)C(F)(F)F
Reactant: CS(=O)(=O)c1ccc(-c2cc3c(cn2)OC(C2CCN(C#N)CC2)C3)cc1
Product: CS(=O)(=O)c1ccc(-c2cc3c(cn2)OC(C2CCN(c4nc(C(F)(F)F)no4)CC2)C3)cc1

Procedure:
The title compound is prepared from 4-[5-(4-methanesulfonyl-phenyl)-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-piperidine-1-carbonitrile and 2,2,2-trifluoro-N-hydroxy-acetamidine following a procedure analogous to that described in Example 2. LC (method 5): tR=1.32 min; Mass spectrum (ESI+): m/z=495 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:7][O:8][C:9]1[C:10]([CH3:36])=[C:11]([CH3:35])[C:12]2[O:17][C:16]([CH2:19][CH2:20][CH2:21]OS(C3C=CC(C)=CC=3)(=O)=O)([CH3:18])[CH2:15][CH2:14][C:13]=2[C:33]=1[CH3:34].O>C1(C)C=CC=CC=1>[CH3:7][O:8][C:9]1[C:10]([CH3:36])=[C:11]([CH3:35])[C:12]2[O:17][C:16]([CH2:19][CH2:20][CH2:21][N:1]3[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]3)([CH3:18])[CH2:15][CH2:14][C:13]=2[C:33]=1[CH3:34]
Reactant: C1CNCCN1
Reactant: COc1c(C)c(C)c2c(c1C)CCC(C)(CCCOS(=O)(=O)c1ccc(C)cc1)O2
Solvent: O
Solvent: Cc1ccccc1
Product: COc1c(C)c(C)c2c(c1C)CCC(C)(CCCN1CCNCC1)O2
Yield: 91.7 %

Procedure:
To a refluxing solution of 7.2 g (0.085 mol) of piperazine in 50 ml of toluene was added 3.8 g (8.5 mmol) of the 3,4-dihydro-6-methoxy-2-[3-(p-toluenesulfonyloxy)propyl]-2,5,7,8-tetramethyl-2H-benzopyran obtained in the above manner, followed by refluxing for 6 hours. After cooling, the reaction mixture was poured into water and extracted with diethyl ether. The ether layer was dried over anhydrous sodium sulfate and low-boiling substances were distilled off therefrom under reduced pressure and the excess piperazine was then removed by sublimation under reduced pressure. The thus-obtained residue was purified by silica gel column chromatography to give 2.7 g (91.8% yield) of 3,4-dihydro-6-methoxy-2-[3-(piperazin-1-yl)propyl]-2,5,7,8-tetramethyl-2H-benzopyran.
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[I:7][C:8]1[N:15]2[C:11]([S:12][C:13]([S:16][CH3:17])=[N:14]2)=[N:10][CH:9]=1>CO.O>[I:7][C:8]1[N:15]2[C:11]([S:12][C:13]([S:16]([CH3:17])=[O:1])=[N:14]2)=[N:10][CH:9]=1
Reactant: O=S([O-])OO
Reactant: CSc1nn2c(I)cnc2s1
Agent: [K+]
Solvent: O
Solvent: CO
Product: CS(=O)c1nn2c(I)cnc2s1
Reaction time: 1 h

Procedure:
Oxone(r), monopersulfate compound (263.99 mg; 0.43 mmol; 1.00 eq.) was added to a solution of 5-iodo-2-methylsulfanyl-imidazo[2,1-b][1,3,4]thiadiazole (127.60 mg; 0.43 mmol; 1.00 eq.) in MeOH (1.50 ml) and water (1.50 ml) at room temperature. After 1 h, the reaction was finished. Water was added and the reaction was extracted 2 times with dichloromethane. The combined organic extracts were dried over magnesium sulphate, filtered and concentrated to give 106.9 mg of the desired product as a beige solid.
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].FC(F)(F)C(O)=O.[C:15](Cl)(=[O:19])[CH2:16][CH2:17][CH3:18]>C(OCC)C>[C:15]([O:4][CH2:3][C@@H:2]([C:5]([OH:7])=[O:6])[NH2:1])(=[O:19])[CH2:16][CH2:17][CH3:18]
Reactant: CCCC(=O)Cl
Reactant: N[C@@H](CO)C(=O)O
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: CCCC(=O)OC[C@H](N)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
L-Serine (10.5 g, 0.10 mol) was added with stifling to trifluoroacetic acid (70 ml) and the resultant solution was decanted from the insoluble material. Butyryl chloride (13.5 ml, 0.123 mol) was then added to the solution and the mixture was stirred for 1 h at room temperature. Upon the addition of diethyl ether (20 ml), a white solid precipitated which redissolved upon stirring. The reaction vessel was sealed and left to stand overnight in a refrigerator. Further diethyl ether (60 ml) was added to the cold solution with stirring. The resultant fine white precipitate was collected by filtration, washed with diethyl ether, and dried under vacuum to afford 13.4 g (60.0 mmol, 63%) of 2020371, m.p. 165-168° C. (dec.). 1H NMR (300 MHz, d6-DMSO) δ 0.80 (t, J 7 Hz, 3H), 1.46 (m, 2H), 2.24 (m, 2H), 4.21 (br s, 1H), 4.38 (m, 2H), 8.75 (br s, 3H). 13C NMR (75.5 MHz, d6-DMSO) δ 13.5, 18.1, 35.1, 57.7, 62.1, 168.3, 173.0. m/z 176.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:3](CC2C=CC(OC)=CC=2)[CH:4]=[C:5]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]2[CH2:14][CH:15]([CH3:17])[CH3:16].C(O)(C(F)(F)F)=O.C(S(O)(=O)=O)(F)(F)F.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[NH:3][CH:4]=[C:5]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]2[CH2:14][CH:15]([CH3:17])[CH3:16]
Reactant: COc1ccc(Cn2cc3c(c2Cl)c(=O)n(C)c(=O)n3CC(C)C)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(Cl)[nH]cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-chloro-1-isobutyl-6-(4-methoxybenzyl)-3-methyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (14 mg, 0.032 mmol) in CH2Cl2 (0.5 mL) is added TFA (100 μL) and TFMSA (50 μL). The mixture is stirred at r.t. for 2 h, and then carefully basified with saturated NaHCO3 aqueous solution, followed by extractions with CH2Cl2. The combined organic phase is dried over sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give crude product, which is used in the next step without further purification. MS (ESI) m/z 256.1 [M+H]+.
Reaction SMILES: [I:1][CH2:2][C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[O:4].[B-](F)(F)(F)F.CN(C(O[N:33]1[C:38](=[O:39])[CH2:37][CH2:36][C:34]1=[O:35])=[N+](C)C)C.CCN(C(C)C)C(C)C.Cl>C1COCC1>[O:35]=[C:34]1[CH2:36][CH2:37][C:38](=[O:39])[N:33]1[O:18][C:17](=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:3](=[O:4])[CH2:2][I:1]
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Reactant: O=C(O)CCCCCCCCCCCNC(=O)CI
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CI)NCCCCCCCCCCCC(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 12-(2-Iodoacetylamino)dodecanoic acid (460 mg) in THF (10 ml) was added TSTU (415 mg) and DIPEA (0.315 ml). After stirring at room temperature for 2 h, the mixture was pored in to 0.5 N HCl (200 ml) and was extracted with ethyl acetate (2×200 ml). The combined organic layers was washed with 0.1 N HCl and brine, dried with magnesium sulphate and concentrated. The residue was used without further purification. Yield, 99% (575 mg). LC-MS, M/z: 481.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:15])[N:4]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[N:5]([CH3:8])[C:6]=1[CH3:7].[Si:16]([O:23][C@@H:24]([CH3:40])[C@H:25]([C:31]1[O:35][N:34]=[C:33]([C:36](O)=[O:37])[C:32]=1[CH3:39])[O:26][CH2:27][C:28]([CH3:30])=[CH2:29])([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Si:16]([O:23][C@@H:24]([CH3:40])[C@H:25]([C:31]1[O:35][N:34]=[C:33]([C:36]([NH:1][C:2]2[C:3](=[O:15])[N:4]([CH:9]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]3)[N:5]([CH3:8])[C:6]=2[CH3:7])=[O:37])[C:32]=1[CH3:39])[O:26][CH2:27][C:28]([CH3:30])=[CH2:29])([C:19]([CH3:22])([CH3:20])[CH3:21])([CH3:18])[CH3:17]
Reactant: Cc1c(N)c(=O)n(C2CCCCC2)n1C
Reactant: C=C(C)CO[C@@H](c1onc(C(=O)O)c1C)[C@H](C)O[Si](C)(C)C(C)(C)C
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: C=C(C)CO[C@@H](c1onc(C(=O)Nc2c(C)n(C)n(C3CCCCC3)c2=O)c1C)[C@H](C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-Amino-2-cyclohexyl-1,5-dimethyl-1H-pyrazol-3(2H)-one (Intermediate D) (2.63 g, 12.55 mmol) was added portionwise to 5-((1R,2S)-2-((tert-butyldimethylsilyl)oxy)-1-((2-methylallyl)oxy)propyl)-4-methylisoxazole-3-carboxylic acid (4.14 g, ˜70% w/w) in DMF (100 mL) followed by DIPEA (7.8 ml, 44.8 mmol) and HATU (4.8 g, 12.55 mmol). After stirring at room temperature for 18 h the reaction mixture was partitioned between EtOAc and brine. The aqueous phase was extracted with EtOAc and the combined organic extracts were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude material was adsorbed onto silica and purification by chromatography eluting with 50-100% EtOAc in iso-hexane afforded the title compound;
Reaction SMILES: CC(OC(C)=O)=O.NC1C=CC2OC([C:17]3[O:22][C:21](=[O:23])[C:20]([CH3:24])=[C:19]([O:25][CH2:26][O:27][CH3:28])[C:18]=3[CH3:29])=CC=2C=1.[NH4+].[Cl-]>N1C=CC=CC=1>[CH3:24][C:20]1[C:21](=[O:23])[O:22][CH:17]=[C:18]([CH3:29])[C:19]=1[O:25][CH2:26][O:27][CH3:28]
Reactant: COCOc1c(C)c(-c2cc3cc(N)ccc3o2)oc(=O)c1C
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: COCOc1c(C)coc(=O)c1C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Pyridine (400 μl) and Ac2O (15 μl) were added to 6-(5-aminobenzofuran-2-yl)-3,5-dimethyl-4-methoxymethoxy-2H-pyran-2-one (45 mg), and after stirring the mixture at room temperature for 6 hours, an NH4Cl aqueous solution was added and extraction was performed with CH2Cl2. The organic layer was dried, filtered and concentrated, and the residue was purified by silica gel thin-layer chromatography (CH2Cl2) to obtain 6-(5-acetylamino)benzofuran-2-yl)-3,5-dimethyl-4-methoxymethoxy-2H-pyran-2-one.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=1)=O)(C)(C)C.BrC1C=CC(CN2CCC[CH:27]2[CH2:31][O:32][CH2:33]C)=CC=1>>[CH2:31]([O:32][CH2:33][CH:6]1[CH2:10][CH2:11][CH2:12][N:8]1[CH2:9][C:13]1[CH:14]=[CH:15][C:16]([NH2:19])=[CH:17][CH:18]=1)[CH3:27]
Reactant: CCOCC1CCCN1Cc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ccc(N)cc1
Product: CCOCC1CCCN1Cc1ccc(N)cc1
Yield: 47 %

Procedure:
Using the same procedure described for the preparation of 2-(4-Amino-phenyl)-pyrrolidine-1-carboxylic acid tert-butyl ester, the title compound is prepared from 1-(4-Bromo-benzyl)-2-ethoxymethyl-pyrrolidine (using the crude product obtained in the previous step) in 47% yield (two steps, based on crude residue, ˜85%).