Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](SC)[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[N:14][C:13]([O:16][CH:17]([CH:19]2[CH2:24][CH2:23][N:22]([C:25]3[O:29][N:28]=[C:27]([CH:30]([CH3:32])[CH3:31])[N:26]=3)[CH2:21][CH2:20]2)[CH3:18])=[CH:12][N:11]=1.O[O:34][S:35]([O-:37])=O.[K+].[CH3:39]C(C)=O>O>[F:1][C:2]1[CH:7]=[C:6]([S:35]([CH3:39])(=[O:37])=[O:34])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[N:14][C:13]([O:16][C@H:17]([CH:19]2[CH2:24][CH2:23][N:22]([C:25]3[O:29][N:28]=[C:27]([CH:30]([CH3:31])[CH3:32])[N:26]=3)[CH2:21][CH2:20]2)[CH3:18])=[CH:12][N:11]=1
Reactant: O=S([O-])OO
Reactant: CC(C)=O
Reactant: CSc1ccc(-c2cnc(OC(C)C3CCN(c4nc(C(C)C)no4)CC3)cn2)c(F)c1
Agent: [K+]
Solvent: O
Product: CC(C)c1noc(N2CCC([C@H](C)Oc3cnc(-c4ccc(S(C)(=O)=O)cc4F)cn3)CC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
A mixture of 2-[2-fluoro-4-(methylthio)phenyl]-5-[(1-{1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}ethyl)oxy]pyrazine (0.33 g, 0.72 mmol) in acetone (25 mL) and water (10 mL) was treated with Oxone® (1.33 g, 2.17 mmol). The reaction mixture was stirred at ambient temperature overnight. Water (60 mL) was added, the mixture was extracted with EtOAc. The combined organic extract was washed with water, brine, and dried over Na2SO4, filtered, and the filtrate was concentrated to a light beige solid, which was purified by chromatography on an ISCO silica gel column using 0 to 55% EtOAc/hexanes to give 2-[2-fluoro-4-(methylsulfonyl)phenyl]-5-[((1S)-1-{1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}ethyl)oxy]pyrazine (0.255 g, 70% ee, 72%) as a white solid. The solid was subjected to chiral separation [column: OJ-H, column mobile phase: 75% CO2: 25% of a 9/1 mixture of MeOH/CHCl3 (2 mL/min), pressure 140 bar, temperature 40° C., 215 nm] to give two (R and S) enantiomers, with the (S)-isomer eluting first. The material was triturated with 9% EtOAc/hexanes to afford the title compound (0.15 g) as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.64 (s, 1H), 8.28 (d, 1H, J=1.2 Hz), 8.22 (t, 1H, J=7.7 Hz), 7.82 (dd, 1H, Ja=8.2 Hz, Jb=1.7 Hz), 7.75 (dd, 1H, Ja=10.3 Hz, Jb=1.7 Hz), 5.25-5.10 (m, 1H), 4.30-4.15 (m, 2H), 3.10-3.00 (m, 5H), 2.87 (septet, 1H, J=6.9 Hz), 2.00-1.80 (m, 3H), 1.55-1.40 (m, 2H), 1.34 (d, 3H, J=6.1 Hz), 1.26 (d, 6H, J=6.8 Hz); LRMS (ESI), m/z 490 (M+H).
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].Cl.[CH2:13]([O:15][C:16](=[O:19])[CH2:17][NH2:18])[CH3:14].N1C=CC=CC=1>ClCCl>[CH2:13]([O:15][C:16](=[O:19])[CH2:17][NH:18][S:1]([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2])[CH3:14]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)CNS(=O)(=O)c1ccc(C)cc1
Reaction time: 8 h
Yield: 96.4 %

Procedure:
Tosyl chloride (14.75 g, 77.37 mmol) was added to a stirring mixture of glycine ethyl ester hydrochloride (9.0 g, 64.48 mmol) and pyridine (11.45 mL, 141.85 mmol) in 100 mL of dichloromethane. After stirring overnight, the mixture was washed with water and dilute NaOH. The combined organics were dried with Na2SO4, filtered, evaporated under reduced pressure to give 16.0 g (96%) of 81, which was used without purification in the next reaction. 1H-NMR (400 MHz, CDCl3): δ 1.18 (t, 3H), 2.42 (s, 3H), 3.76 (d, 2H), 4.08 (q, 2H), 5.22 (m, 1H), 7.30 (d, 2H), 7.75 (d, 2H) ppm. 13C-NMR (100 MHz, CDCl3): δ 13.99, 21.55, 44.19, 61.89, 127.28, 129.76, 136.20, 143.81, 168.87 ppm. □ DEPT (100 MHz, CDCl3): CH3 carbons: 13.99, 21.55; CH2 carbons: 44.19, 61.89; CH carbons: 127.28, 129.76 ppm. LC/MS: 95%, m/z=257.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[N:13]=[C:14]([C:16]1[CH:17]=[CH:18][C:19]2[C:20]3[CH:21]=[CH:22][CH:23]=[C:24]4[C:38]=3[C:28]([C:29]3[C:34]=2[C:33]=1[C:32]([C:35]([OH:37])=[O:36])=[CH:31][CH:30]=3)=[CH:27][CH:26]=[C:25]4Br)[OH:15])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH2:47]([O:53][S:54]([C:57]1[CH:62]=[CH:61][C:60]([CH3:63])=[CH:59][CH:58]=1)(=[O:56])=[O:55])[CH2:48][CH2:49][CH2:50][C:51]#[CH:52]>CN(C)C=O.C(Cl)Cl.C1(P([Pd-4](P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[N:13]=[C:14]([C:16]1[CH:17]=[CH:18][C:19]2[C:20]3[CH:21]=[CH:22][CH:23]=[C:24]4[C:38]=3[C:28]([C:29]3[C:34]=2[C:33]=1[C:32]([C:35]([OH:37])=[O:36])=[CH:31][CH:30]=3)=[CH:27][CH:26]=[C:25]4[C:52]#[C:51][CH2:50][CH2:49][CH2:48][CH2:47][O:53][S:54]([C:57]1[CH:58]=[CH:59][C:60]([CH3:63])=[CH:61][CH:62]=1)(=[O:55])=[O:56])[OH:15])([CH3:3])[CH3:2]
Reactant: C#CCCCCOS(=O)(=O)c1ccc(C)cc1
Reactant: CC(C)c1cccc(C(C)C)c1N=C(O)c1ccc2c3cccc4c(Br)ccc(c5ccc(C(=O)O)c1c52)c43
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCCCC#Cc2ccc3c4ccc(C(=O)O)c5c(C(O)=Nc6c(C(C)C)cccc6C(C)C)ccc(c6cccc2c36)c54)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a degassed mixture of 2.40 g (4.32 mmoles) of N-(2,6-diisopropylphenyl)-9-bromo-perylene-3,4-dicarboxylic acid imide (synthesized according to WO2001016109) and 0.576 g (3.36 mmoles) of Cu(I) iodide in 72 ml dimethylformamide (DMF) and 144 ml methylene chloride were added 2.00 g (1.72 mmoles) of tetrakis(triphenylphosphino)-palladium (0), 2.09 g (2.88 ml, 2.05 mmol) triethylamine and a degassed solution of 1.82 g (7.20 mmol) p-toluensulfonic acid-5-hexinyl ester (synthesized according to (Y. Yang and T. M. Swager, Macromolecules 2006, 39, 2013-2015) in 12 ml methylene chloride. The reaction mixture was stirred for 90 minutes at room temperature, subsequently the solvent was evaporated until dryness and purified on silica gel (solvent: toluene:methylene chloride: 10:1 to 1:1). 2.04 g (65% of the theoretical yield) of a red solid were obtained.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:11][CH2:10][N:9](OCCC2C=CC=CC=2)[CH2:8][CH2:7]1)=[O:5])C>C1COCC1.CO.[OH-].[Na+]>[CH2:31]([O:30][C:27]1[CH:28]=[CH:29][C:24]([S:21]([C:6]2([C:4]([OH:3])=[O:5])[CH2:11][CH2:10][N:9]([CH2:32][CH2:31][O:30][C:27]3[CH:28]=[CH:29][CH:24]=[CH:25][CH:26]=3)[CH2:8][CH2:7]2)(=[O:22])=[O:23])=[CH:25][CH:26]=1)[CH2:32][CH2:33][CH3:34]
Reactant: CCCCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(OCCc3ccccc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(CCOc3ccccc3)CC2)cc1

Procedure:
4-(4-n-Butoxy-benzenesulfonyl)-1-(2-phenoxy-ethyl)-piperidine-4-carboxylic acid was prepared starting from 4-(4-n-butoxy-benzenesulfonyl)-1-(2-phenyl-ethoxy)-piperidine-4- carboxylic acid ethyl ester (2.5 g, 5.76 mmol) dissolved in THF:methanol 3:1 and 10N NaOH (40 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 1.5 g (56%); off white powder, mp 204° C.; MS: 462.5 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)[C:5]#[N:6].[H][H].CCCCCC.C(OCC)(=O)C>[Pd].C(O)C>[OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH2:10])[C:5]#[N:6]
Reactant: N#Cc1ccc([N+](=O)[O-])c(O)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCCCCC
Solvent: CCO
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N)c(O)c1
Reaction time: 1 h

Procedure:
A parr bottle was charged with palladium on activated carbon (5%, 0.204 g). A solution of 3-hydroxy-4-nitrobenzonitrile (1.36 g, 0.00829 mol) in 41 ml of ethanol was added. The reaction mixture was placed under 25 psi of hydrogen gas and shaken for 1 hour. TLC (1:1 hexane:ethyl acetate) shows that no starting material remained. The mixture was filtered through Celite® and evaporated to yield 3-hydroxy-4-aminobenzonitrile, 1.08 g (0.00806 mol, 97%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.CO[CH:23]1[CH2:27][CH2:26][CH:25](OC)O1>ClCCCl>[C:5]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:3][C:2]([N:1]2[CH:23]=[CH:27][CH:26]=[CH:25]2)=[CH:7][CH:6]=1
Reactant: Nc1ccc(-c2ccccc2)cc1
Reactant: COC1CCC(OC)O1
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(-c2ccc(-n3cccc3)cc2)cc1
Temperature: 75 °C
Yield: 61.8 %

Procedure:
To a solution of 4-aminobiphenyl (1.0 g, 5.9 mmol) in 1,2-dichloroethane (20 mL) was added TFA (0.46 ml, 5.9 mmol). To the resultant suspension of the TFA salt was added 2,5-dimethoxy-tetrahydrofuran (0.92 mL, 7.1 mmol). The suspension was heated at 75° C. for 17 hours. The mixture was allowed to cool, partitioned between EtOAc and 1M pH 7 phosphate buffer, and the aqueousueous layer was extracted again with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated to a crude residue, which was purified via flash column chromatography with 10-25% CH2Cl2 /hex gradient eluent. The purified material was triturated with MTBE/hex to give 800 mg (62%) of N-biphenyl-4-yl-1H-pyrrole as an off-white solid, mp190-2° C. 1H NMR: δ 7.65 (d, 2H, J=8.5 Hz), 7.61 (d, 2H, J=7.0 Hz), 7.48-7.43 (m, 4H), 7.36 (t, 1H, J=7.0 Hz), 7.14 (t, 2H, J=2.0 Hz), 6.37 (t, 2H, J=2.0 Hz). Anal. Calculated for C16H13N: C, 87.63; H, 5.98; N, 6.39. Found: C, 87.48; H, 6.01; N, 6.30.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[S:14])[CH:5]=[C:6]([CH3:13])[O:7]2.C(=O)([O-])[O-].[K+].[K+].[CH:21](I)([CH3:23])[CH3:22].[CH3:25]I>O.CC(C)=O>[CH:21]([O:12][C:10]1[CH:9]=[C:8]2[C:3]([C:4](=[S:14])[CH:5]=[C:6]([CH3:13])[O:7]2)=[C:2]([O:1][CH3:25])[CH:11]=1)([CH3:23])[CH3:22]
Reactant: Cc1cc(=S)c2c(O)cc(O)cc2o1
Reactant: CC(C)I
Reactant: CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COc1cc(OC(C)C)cc2oc(C)cc(=S)c12
Yield: 54.6 %

Procedure:
354 mg of 5,7-dihydroxy-2-methylthiochromone (1.58 mmol), 1.09 g of potassium carbonate (7.90 mmol), 0.79 ml isopropyl iodide (7.90 mmol) and 20 ml acetone were refluxed overnight. After addition of 2.95 ml methyl iodide (47.4 mmol), the mixture was further refluxed overnight. Following addition of water, the reaction solution was extracted twice with ethyl acetate, and the organic layer was washed with saturated NaCl water and dried over sodium sulfate anhydride. The solvent was distilled off under reduced pressure, and the crude product was purified by flash column chromatography (hexane: ethyl acetate =1 : 3→1:6), to give 228 mg of 7-isopropoxy-5-methoxy-2-methylthiochromone (52% yield).
Reaction SMILES: Cl.C(OC(=O)[NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([NH:15][C:16](=[O:25])[CH2:17][N:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)[CH2:11][CH2:10]1)(C)(C)C.CCOCC>CO>[NH2:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([NH:15][C:16](=[O:25])[CH2:17][N:18]2[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]2)[CH2:13][CH2:14]1
Reactant: CN1CCN(CC(=O)N[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)CC1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: CN1CCN(CC(=O)N[C@H]2CC[C@H](N)CC2)CC1
Reaction time: 8 h

Procedure:
An aqueous solution of HCl (2 M, 15 mL) was added to a solution of trans-{4-[2-(4-methyl-piperazin-1-yl)-acetylamino]-cyclohexyl}-carbamic acid tert-butyl ester (199 mg, 0.56 mmol) in MeOH (15 mL) at RT, and the resulting mixture was stirred overnight. The reaction mixture was concentrated under reduced pressure to give a solid residue. Et2O was added to this material, and the resulting suspension was sonicated. The ether phase was decanted away, leaving a powdery brown solid which was purified by preparative TLC. The resulting oil was dissolved in the minimum quantity of MeOH, and Et2O was added. A solid precipitated; the liquid phase was decanted away to give, after drying, 75 mg of trans-N-(4-amino-cyclohexyl)-2-(4-methyl-piperazin-1-yl)-acetamide as a fine powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=2)[NH:16][CH:15]=1)[C:6]([O:8][CH3:9])=[O:7].[H-].[Na+].I[CH3:29].Cl>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=2)[N:16]([CH3:29])[CH:15]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: CI
Reactant: COC(=O)c1ccc(Cc2c[nH]c3ccc([N+](=O)[O-])cc23)c(OC)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cc2cn(C)c3ccc([N+](=O)[O-])cc23)c(OC)c1
Reaction time: 0.17 h
Yield: 73.4 %

Procedure:
Methyl 3-methoxy-4-(5-nitroindol-3-yl-methyl)benzoate (C) (0.44 g.) was added to a stirred suspension of oil-free sodium hydride (0.031 g.) in dry tetrahydrofuran (10 ml.), under an atmosphere of nitrogen. The dark-red solution was stirred for 10 minutes, and iodomethane (0.18 g.) was added. The mixture was stirred for 30 minutes, and was poured into 1M hydrochloric acid (30 ml.). The mixture obtained was extracted with ethyl acetate (2×50 ml.). The combined extracts were washed with brine (25 ml.), then dried (MgSO4), and evaporated. The yellow oil obtained was purified by flash chromatography on silica gel (50 ml.), eluting with 50:45:5 v/v/v hexane:dichloromethane:ethyl acetate, to give methyl 3-methoxy-4-(1-methyl-5-nitroindol-3-ylmethyl)benzoate (E) (0.33 g., 72%) as a yellow oil, which was crystallized from dichloromethane/hexane to give a yellow solid, m.p. 144°-146° C.; NMR: 3.81(s,3H, N.CH3), 3.83(s,3H, CO.OCH3), 3.92(s,3H, OCH3), 4.11(s,2H, CH2.Ar), 7.27(d,1H), 7.37(s,1H, H2 -indole), 7.49(m,2H), 7.60(d,1H), 8.01(dd,1H, H6 -indole), 8.50(d,1H, H4 -indole).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(N(CC)CC)C.Cl[C:36]([O:38][CH:39]1[CH:44]([CH:45]([CH3:47])[CH3:46])[CH2:43][CH2:42][CH:41]([CH3:48])[CH2:40]1)=[O:37]>CN(C=O)C>[CH:45]([CH:44]1[CH2:43][CH2:42][CH:41]([CH3:48])[CH2:40][CH:39]1[O:38][C:36]([N:25]1[CH2:26][CH2:27][CH:22]([O:21][C:16]2[C:17]([N+:18]([O-:20])=[O:19])=[C:12]([NH:11][C:8]3[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=3)[N:13]=[CH:14][N:15]=2)[CH2:23][CH2:24]1)=[O:37])([CH3:46])[CH3:47]
Reactant: CC1CCC(C(C)C)C(OC(=O)Cl)C1
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc(OC3CCNCC3)c2[N+](=O)[O-])cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1CCC(C(C)C)C(OC(=O)N2CCC(Oc3ncnc(Nc4ccc(S(C)(=O)=O)cc4)c3[N+](=O)[O-])CC2)C1

Procedure:
Compound A23 was prepared in a similar manner as described above using (4-methanesulfonyl-phenyl)-[5-nitro-6-(piperidin-4-yloxy)-pyrimidin-4-yl]-amine (i.e., Comound A2) (15 mg, 0.035 mmol), triethylamine (501 μl), menthyl chloroformate (10 mg, 0.046 mmol), DMF (0.6 mL), 1H NMR (CDCl3, 400 MHz) δ 0.81 (d, 3H), 0.92 (d, 6H), 1.06 (m, 1H), 1.10 (m, 1H), 1.41 (m, 1H), 1.51 (m, 1H), 1.67 (m,2H), 1.94 (m, 4H), 2.08 (m, 2H), 3.08 (s, 3H), 3.65 (m, 4H), 4.58 (m, 1H), 5.60 (m, 1H), 7.86 (d, 2H), 7.97 (d, 2H), 8.41 (s, 1H), 10.18 (s, 1H). Exact mass calculated for C27H37N5O7S 575.24, found 576.4 (MH+).
Reaction SMILES: [OH:1][CH2:2][C:3](=O)[CH3:4].[O:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[O:12][NH2:13].C(O)(=O)C>N1C=CC=CC=1.CO>[O:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[O:12]/[N:13]=[C:3](\[CH3:4])/[CH2:2][OH:1]
Reactant: NOC1CCCCO1
Reactant: CC(=O)CO
Solvent: CC(=O)O
Solvent: CO
Solvent: c1ccncc1
Product: C/C(CO)=N\OC1CCCCO1
Temperature: 25 °C
Reaction time: 12 h
Yield: 77 %

Procedure:
To a solution of 1-hydroxypropan-2-one (1 g, 13.5 mmol) and O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (1.9 g, 16.2 mmol) in pyridine (7 mL) and methanol (20 mL) was added acetic acid (0.23 mL, 4 mmol) and the resulting mixture was stirred at room temperature for 12 hours. The mixture was then concentrated under reduced pressure and the residue was treated with a saturated solution of NaHCO3 and extracted with ethyl acetate. The organic layer was washed with brine, dried with MgSO4 and concentrated under reduced pressure. The residue was purified by chromatography (EtOAc-Hexanes 2:1) to afford 1.8 g of the title compound. MS (DCI/NH3) m/z 174 (M+H)+.
Reaction SMILES: C([Mg]Cl)(C)C.[C:6]([O:10][C:11](=[O:27])[NH:12][C:13]1([C:19]2[CH:24]=[CH:23][C:22]([C:25]#N)=[CH:21][CH:20]=2)[CH2:16][C:15]([OH:18])([CH3:17])[CH2:14]1)([CH3:9])([CH3:8])[CH3:7].[CH2:28]([Mg]Cl)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C1C[O:40]CC1>>[C:6]([O:10][C:11](=[O:27])[NH:12][C:13]1([C:19]2[CH:24]=[CH:23][C:22]([C:25](=[O:40])[CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:21][CH:20]=2)[CH2:16][C:15]([OH:18])([CH3:17])[CH2:14]1)([CH3:9])([CH3:8])[CH3:7]
Reactant: Cl[Mg]Cc1ccccc1
Reactant: CC1(O)CC(NC(=O)OC(C)(C)C)(c2ccc(C#N)cc2)C1
Reactant: C1CCOC1
Agent: CC(C)[Mg]Cl
Product: CC1(O)CC(NC(=O)OC(C)(C)C)(c2ccc(C(=O)Cc3ccccc3)cc2)C1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of i-PrMgCl (9.65 mL, 19.3 mmol) in THF was added dropwise to a solution of compound 2-2 (5.84 g, 19.3 mmol) in dry THF at −5.deg.C. After stirring for 20 min, a solution of BnMgCl (58 mL, 2M, 116 mmol) in THF was added dropwise to the reaction mixture. After completion of addition, the reaction mixture was stirred for 1 h at 0.deg.C, then warmed slowly to room temperature, and stirred for another 1 h. The reaction was quenched with saturated NH4 Cl solution, extracted with ethyl acetate. Separated and collected the organic layer, and the aqueous solution was washed EA for two times. The combined organic layer was washed with brine, dried and concentrated in vacuo to get the crude product, which was purified by silica chromatography to afford 6.2 g of ketone 2-3.
Reaction SMILES: [C-:1]#[N:2].[K+].[F:4][C:5]1[CH:6]=[CH:7][C:8]([C:13]([F:16])([F:15])[F:14])=[C:9]([CH:12]=1)[CH2:10]Br.O>C(O)C.C(OCC)(=O)C>[F:4][C:5]1[CH:6]=[CH:7][C:8]([C:13]([F:16])([F:15])[F:14])=[C:9]([CH2:10][C:1]#[N:2])[CH:12]=1
Reactant: Fc1ccc(C(F)(F)F)c(CBr)c1
Reactant: [C-]#N
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: N#CCc1cc(F)ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 64 h

Procedure:
1.95 g (30 mmol) of potassium cyanide is added to a solution of 5.14 g (20 mmol) of 5-fluoro-2-trifluoromethylbenzyl bromide in 45 ml of ethanol/8 ml of water, and it is stirred for 64 hours at room temperature. The reaction solution is diluted with ethyl acetate and extracted with saturated sodium bicarbonate solution. The organic phase is washed with water, dried and concentrated by evaporation. The remaining residue is purified by bulb tube distillation and recrystallized. Yield: 3.6 g (89%).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:6]=2[S:12]([NH:15][C:16]2[C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24]3[C:19]([CH:20]4[CH2:30][CH:21]4[CH2:22][O:23]3)=[CH:18][CH:17]=2)(=[O:14])=[O:13])[CH2:2]1.I[CH2:32][CH3:33].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:32]([N:1]1[CH2:4][CH:3]([C:5]2[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:6]=2[S:12]([NH:15][C:16]2[C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24]3[C:19]([CH:20]4[CH2:30][CH:21]4[CH2:22][O:23]3)=[CH:18][CH:17]=2)(=[O:13])=[O:14])[CH2:2]1)[CH3:33]
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2C2CNC2)ccc2c1OCC1CC21
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN1CC(c2cc(F)ccc2S(=O)(=O)Nc2ccc3c(c2C(=O)OC)OCC2CC32)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 22.2 %

Procedure:
A mixture of methyl (1aRS,7bSR)-5-[2-(azetidin-3-yl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 87, 0.216 g), iodoethane (0.078 g) and potassium carbonate (0.138 g) in acetonitrile (5 mL) was stirred at room temperature for 18 hours. The mixture was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM with a gradient of 0-15% to give methyl (1aRS,7bSR)-5-[2-(1-ethylazetidin-3-yl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate (0.051 g).
Reaction SMILES: [CH3:1][C:2]([CH:5]=O)([CH3:4])[CH3:3].[NH2:7][OH:8].O.C1C(=O)N(Cl)C(=O)C1.[C:18]([O:22][CH3:23])(=[O:21])[C:19]#[CH:20]>CN(C=O)C.O>[CH3:23][O:22][C:18]([C:19]1[O:8][N:7]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[CH:20]=1)=[O:21]
Reactant: CC(C)(C)C=O
Reactant: NO
Reactant: C#CC(=O)OC
Agent: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C(C)(C)C)no1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Pivaldehyde (1.10 mL, 10.0 mmol) was dissolved in dry DMF (10 mL), and NH2OH.H2O (0.590 mL of 55 wt % aqueous solution, 10.5 mmol) was added via syringe. The resulting mixture was stirred at room temperature for 4 h, NCS (1.40 g, 10.5 mmol) was added in small portions, and the resulting mixture was stirred at room temperature for 1 h. CuSO4.5H2O (75.0 mg, 0.300 mmol), methyl propiolate (1.07 mL, 12.0 mmol), and H2O (5 mL) were added followed by Cu powder (25.0 mg, 0.393 mmol). The resulting mixture was stirred at room temperature for 16 h and quenched with dilute aqueous NH4OH (2 mL). The aqueous solution was extracted with hexanes (3×30 mL), and then the combined organic extracts were dried over MgSO4 and filtered. The solvent was removed under reduced pressure to yield the title compound as a colorless oil. 1H-NMR (400 MHz, CDCl3) δ: 6.88 (s, 1H), 3.96 (s, 3H), 1.36 (s, 9H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5]C=C[CH:2]=1.[C:7]([Cl:12])(=[O:11])[O:8][CH2:9][CH3:10].C(OCC)(=[O:15])C>CN(C)C1C=CN=CC=1>[ClH:12].[C:7](=[O:11])([O:15][CH2:5][CH2:6][NH:1][CH3:2])[O:8][CH2:9][CH3:10]
Reactant: c1ccncc1
Reactant: CCOC(C)=O
Reactant: CCOC(=O)Cl
Agent: CN(C)c1ccncc1
Product: CCOC(=O)OCCNC
Product: Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of tert-butyl 2-hydroxyethyl (methyl)carbamate (1.75 g) obtained in Reference Example 1 and ethyl acetate (20 mL) were added pyridine (0.97 mL) and 4-dimethylaminopyridine (catalytic amount), and ethyl chlorocarbonate (1.25 mL) was dropwise added. The mixture was stirred overnight at room temperature and ethyl acetate (50 mL) was added. The mixture was washed with water (50 mL), a 5% aqueous citric acid solution (50 mL) and saturated brine (50 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, a 4N hydrogen chloride-ethyl acetate solution (10 mL) was added to the residue. After stirring at room temperature for 2 hrs., diethyl ether (10 mL) was added, and the precipitated solid was collected by filtration. The solid was dried under reduced pressure to give the title compound (1.66 g) as a white solid.
Reaction SMILES: N1C=CC=CC=1.Cl.[CH3:8][NH:9][O:10][CH3:11].[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1>C(Cl)Cl>[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([N:9]([O:10][CH3:11])[CH3:8])=[O:18])=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CNOC
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CON(C)C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Pyridine (27.6 mL, 343 mmol) was added to N,O-dimethylhydroxylamine hydrochloride (16.7 g, 172 mmol) in DCM (400 mL). 4-Chlorobenzoyl chloride (20 mL, 156 mmol) was then added and the mixture was stirred at room temperature for 3 days. Solids were removed by vacuum filtration, washing with DCM. The filtrate was washed with 1 N aqueous HCl followed by water. The organic phase was dried (Na2SO4), filtered, and concentrated, affording the crude title compound as a colorless liquid which was used without purification in the next step.