Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([C:28]([NH2:30])=[O:29])=[CH:5][C:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([CH2:15][C@@H:16]([NH2:26])[CH2:17][O:18]CC3C=CC=CC=3)[C:7]=2[N:27]=1.I[Si](C)(C)C.Cl>C(Cl)(Cl)Cl.CO>[NH2:2][C:3]1[C:4]([C:28]([NH2:30])=[O:29])=[CH:5][C:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([CH2:15][C@@H:16]([NH2:26])[CH2:17][OH:18])[C:7]=2[N:27]=1
Reactant: NC(=O)c1cc2c3ccccc3n(C[C@@H](N)COCc3ccccc3)c2nc1N
Agent: C[Si](C)(C)I
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: NC(=O)c1cc2c3ccccc3n(C[C@@H](N)CO)c2nc1N
Temperature: 25 °C
Yield: 50.1 %

Procedure:
To a cooled (0° C.) solution of 2-amino-9-[(2R)-2-amino-3-(benzyloxy)propyl]-9H-pyrido[2,3-b]indole-3-carboxamide (61, 81 mg, 0.160 mmol) in chloroform (2 mL) was added iodotrimethylsilane (140 uL, 0.990 mmol). The reaction was stirred under argon, allowed to warm slowly to room temperature and then stirred an additional 16 h. The reaction mixture was filtered and concentrated in vacuo. The crude mixture was purified by reverse phase HPLC (Phenomenex Luna 15 μm C18, aqueous NH4OAc/CH3CN) to provide the product which was then converted to the hydrochloride salt by stirring with a solution of excess hydrochloric acid in methanol to afford 2-amino-9-[(2R)-2-amino-3-hydroxypropyl]-9H-pyrido[2,3-b]indole-3-carboxamide (65, 24 mg, 45%). NH4OAc standard conditions. DAD Retention time =4.76 min. M+H=300. 1H NMR (300 MHz, MeOD-d4): Δ 8.97 (s, 1H), 8.01 (d, J=7.0 Hz, 1H) 7.67 (d, J=7.4 Hz, 1H), 7.52 (t, J=6.9, 1H), 7.38 (t, J=6.9 Hz, 1H), 4.75-4.69 (m, 2H), 3.96-3.81 (m, 2H), 3.71-3.62 (m, 1H).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][CH:6]([C:9]2[C:10]([F:16])=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=2)[CH2:5][CH2:4]1)[CH3:2].[OH-].[Na+].Cl[CH:20]([F:22])[F:21]>C(O)(C)C>[F:21][CH:20]([F:22])[O:15][C:11]1[C:10]([F:16])=[C:9]([CH:6]2[CH2:7][CH2:8][N:3]([CH2:1][CH3:2])[CH2:4][CH2:5]2)[CH:14]=[CH:13][CH:12]=1
Reactant: CCN1CCC(c2cccc(O)c2F)CC1
Reactant: FC(F)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: CCN1CCC(c2cccc(OC(F)F)c2F)CC1
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-(1-ethylpiperidin-4-yl)-2-fluorophenol (0.43 g, 1.9 mmol) ) in isopropanol (5 ml) and aqueous sodium hydroxide (30%, 5 ml) was added chlorodifluoromethane gas through a liner for 1 min. The mixture was heated to 65° C. and bubbling of chlorodifluoromethane was continued for an additional 30 min. Water (50 ml) was added and the mixture was extracted with ethylacetate (3×50 ml). The combined organic phases was dried (MgSO4), filtered and evaporated to dryness. MS m/z (rel. intensity, 70 eV) 273 (M+, 14), 272 (13), 259 (12), 258 (bp), 84 (13).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.CCO.[OH:29][CH:30]1[CH2:35][CH2:34][N:33]([C:36]2[CH:43]=[CH:42][C:39]([CH:40]=O)=[CH:38][CH:37]=2)[CH2:32][CH2:31]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(OCC)C>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:40]([C:39]3[CH:38]=[CH:37][C:36]([N:33]4[CH2:34][CH2:35][CH:30]([OH:29])[CH2:31][CH2:32]4)=[CH:43][CH:42]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(c1ccccc1)N1CCN(c2c(Br)cnc(N)c2[N+](=O)[O-])CC1
Reactant: O=Cc1ccc(N2CCC(O)CC2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: CC(c1ccccc1)N1CCN(c2c(Br)cnc3[nH]c(-c4ccc(N5CCC(O)CC5)cc4)nc23)CC1
Temperature: 80 °C
Reaction time: 22 h

Procedure:
To a mixture of 5-bromo-3-nitro-4-[4-(1-phenyl-ethyl)-piperazin-1-yl]-pyridin-2-ylamine (0.036 g, 0.09 mmol) and EtOH (4.5 ml) was added 4-(4-hydroxy-piperidin-1-yl)-benzaldehyde (0.025 g, 0.12 mmol) followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.38 ml, 0.38 mmol). The reaction mixture was stirred at 80° C. for 22 h, then allowed to cool to room temperature, and concentrated in vacuo. The residue was absorbed on silica gel, the free-running powder was placed on a 10 g isolute silica column and elution with a gradient of methanol (0 to 5%) in ethyl acetate/dichloromethane (v:v; 1:1) afforded a yellow solid. The title compound was obtained as a white solid after trituration with diethyl ether (0.016 g, 32%); 1H-NMR (500 MHz, DMSO-d6) 1.35 (d, J=6.7 Hz, 3H, CHCH3), 1.45 (m, 2H) and 1.82 (m, 2H) (piperidine CH2), 2.54 (m, 2H), 2.62 (br s, 2H), 2.98 (t, 2H) and 3.70 (m, 3H) (piperazine N—(CH2)2, piperidine CH2 and piperidine CHOH), 3.50 (q, J=6.7 Hz, 1H, CHCH3), 3.67 (br s, 4H, piperazine N(CH2)2), 4.67 (d, J=4.1 Hz, CHOH, exchangeable with D2O), 7.03 (d, J=8.9 Hz, 2H) and 8.00 (d, J=8.8 Hz, 2H) (3,5-C6H4—N and 2,6-C6H4—N), 8.14 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.16 (br s, 1H, imidazo[4,5-b]pyridine N—H); LC (Method B)-MS (ESI, m/z): Rt=3.39 min—561, 563 [(M+H)+, Br isotopic pattern]. ESI-HRMS: Found: 561.1975, calculated for C29H34BrN6O (M+H)+: 561.1977.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.Br[CH2:13][CH2:14][CH2:15][C:16]([F:19])([F:18])[F:17].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:17][C:16]([F:19])([F:18])[CH2:15][CH2:14][CH2:13][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: FC(F)(F)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCCCC(F)(F)F)cc1
Yield: 100 %

Procedure:
First, about 1 mole of methyl 4-hydroxybenzoate and about 1 mole of 4-bromo-1,1,1-trifluorobutane were added to excess acetone which was mixed with potassium carbonate at a temperature of about 40° C. for about 90 minutes to obtain about 1 mole of methyl 4-(4,4,4-trifluorobutoxy)benzoate. About 1 mole of methyl 4-(4,4,4-trifluorobutoxy)benzoate was mixed with about 1 N (normality) of excess sodium hydroxide, and methyl 4-(4,4,4-trifluorobutoxy)benzoate and sodium hydroxide were mixed to perform reflux for about 30 minutes and then neutralized to hydrochloric acid to obtain about 1 mole of 4-(4,4,4-trifluorobutoxy)benzoic acid. About 1 mole of 4-(4,4,4-trifluorobutoxy)benzoic acid was mixed with carbon dichloride and carbonyl diimidazole (CDI). After 4-(4,4,4-trifluorobutoxy)benzoic acid, carbon dichloride, and CDI were reacted at a temperature of about 25° C. for about 2 hours. About 1 mole of 4-hydroxybenzaldehyde was mixed with the above mixture at a temperature of about 25° C. for about 12 hours and, carbon dichloride and water were added to extract about 1 mole of 4-formylphenyl 4-(4,4,4-trifluorobutoxy)benzoate.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[O:5])#[N:2].[O-]CC.[Na+].Br[C:12](=[N:17][NH:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:21][CH2:20]1)[C:13]([F:16])([F:15])[F:14]>CCO>[NH2:2][C:1]1[N:18]([CH:19]2[CH2:20][CH2:21][N:22]([C:25]([O:27][CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[O:26])[CH2:23][CH2:24]2)[N:17]=[C:12]([C:13]([F:16])([F:15])[F:14])[C:3]=1[C:4](=[O:5])[NH2:6]
Reactant: N#CCC(N)=O
Reactant: O=C(OCc1ccccc1)N1CCC(NN=C(Br)C(F)(F)F)CC1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: NC(=O)c1c(C(F)(F)F)nn(C2CCN(C(=O)OCc3ccccc3)CC2)c1N
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 38.5 %

Procedure:
To a stirred solution of 2-Cyanoacetamide (520 mg, 6.19 mmol) in EtOH (8.6 mL) at room temperature was added Sodium ethoxide (21% in EtOH, 1.6 mL, 4.13 mmol). A solution of 111 (842 mg, 2.063 mmol) in EtOH (1.7 mL) was added dropwise and the resulting suspension was allowed to stir for 10 min at room temperature, then for 2 h at 80° C. The solvent was removed and after the usual work-up the crude material was purified via Biotage (10% to 40% EtOAc/Hexane; 25S column) to give 117 (327 mg, 38.5% yield) as an orange solid. LRMS (ESI): calc.411.4; found 412.1 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:29][C:30]([O:32]C)=[O:31])[CH:5]=[CH:6][C:7]=1[S:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:22]([CH2:23][CH2:24][CH3:25])=[C:21]2[C:16]([CH:17]=[C:18]([CH2:27][CH3:28])[C:19](=[O:26])[O:20]2)=[CH:15][CH:14]=1.[OH-].[K+].CO.Cl>CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:29][C:30]([OH:32])=[O:31])[CH:5]=[CH:6][C:7]=1[S:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:22]([CH2:23][CH2:24][CH3:25])=[C:21]2[C:16]([CH:17]=[C:18]([CH2:27][CH3:28])[C:19](=[O:26])[O:20]2)=[CH:15][CH:14]=1
Reactant: CCCc1c(OCCCSc2ccc(CC(=O)OC)cc2Cl)ccc2cc(CC)c(=O)oc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCc1c(OCCCSc2ccc(CC(=O)O)cc2Cl)ccc2cc(CC)c(=O)oc12
Temperature: 30 °C

Procedure:
To a solution of methyl 3-chloro-4-(3-ethyl-8-propyl-7-coumarinoxy)propylthio)phenylacetate (Example 3; 30 mg, 0.0613 mmol) 1.0 mL methanol:water (2:1) was added a 0.5M solution of potassium hydroxide in methanol (0.61 mL, 0.3061 mmol). The mixture was heated to 30° C. for two hours at which time the mixture was acidified to pH=3 with 1M hydrochloric acid. The aqueous solution was extracted with ethyl acetate and the combined organics were dried over magnesium sulfate, filtered, and the crude residue was purified by flash chromatography on silica gel (30% ethyl acetate/hexane/1% acetic acid) which provided the title compound
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[N:11]1[CH2:15][CH:14]([C:16](N2CCCC2)=[O:17])[CH2:13][C:12]1=[O:23])([CH3:4])([CH3:3])[CH3:2].C(C1CCCCC1=[O:34])(C)(C)C>>[C:1]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[N:11]1[C:12](=[O:23])[CH2:13][CH:14]([C:16]([OH:17])=[O:34])[CH2:15]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)C1CCCCC1N1CC(C(=O)N2CCCC2)CC1=O
Reactant: CC(C)(C)C1CCCCC1=O
Product: CC(C)(C)C1CCCCC1N1CC(C(=O)O)CC1=O

Procedure:
1-(2-tert-Butyl-cyclohexyl)-4-(pyrrolidine-1-carbonyl)-pyrrolidin-2-one was similarly prepared as described in Examples I, II, and VI. 2-tert-Butylcyclohexanone (commercially available at Alfa Aesar GmbH & Co. KG) was used to obtain 1-(2-tert-butyl-cyclohexyl)-5-oxo-pyrrolidine-3-carboxylic acid (1 g, 3.74 mmol), which was subsequently used to provide 1-(2-tert-butyl-cyclohexyl)-4-(pyrrolidine-1-carbonyl)-pyrrolidin-2-one (1.1 g, 3.2 mmol).
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[CH2:10][C@H:9]([NH2:11])[CH2:8][CH2:7][C@@H:6]1[N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:13]1=[O:28])(=[O:3])[CH3:2].[CH3:29][C:30]([CH3:32])=O.C([O-])(=O)C.[Na+].C([BH3-])#N.[Na+]>CO>[C:1]([NH:4][C@@H:5]1[CH2:10][C@H:9]([NH:11][CH:30]([CH3:32])[CH3:29])[CH2:8][CH2:7][C@@H:6]1[N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:13]1=[O:28])(=[O:3])[CH3:2]
Reactant: CC(C)=O
Reactant: CC(=O)N[C@@H]1C[C@H](N)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Agent: CC(=O)[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(=O)N[C@@H]1C[C@H](NC(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A stirring solution of benzyl (S)-1-((1S,2R,4R)-2-acetamido-4-aminocyclohexyl)-2-oxopyrrolidin-3-ylcarbamate (˜0.135 mol) in methanol (675 mL) was charged sequentially with acetone (37.8 g, 4 eq), sodium acetate (33.2 g, 3 eq), and sodium cyanoborohydride (16.9 g, 2 eq). The mixture was stirred at room temperature for 6 h and filtered. The filtrate was dissolved in dichloromethane (1 L); this solution was washed with 1N NaOH (1 L). The solids collected in the filtration were dissolved in 1N NaOH (1 L) at 0° C. and then extracted with dichloromethane (1 L). The organic extracts were combined and extracted with aqueous HCl (200 mL 1N HCl+800 mL water). The aqueous phase was basified with sat. NaHCO3 (500 mL) and then 1N NaOH (100 mL) until pH 11. The aqueous phase was extracted with dichloromethane (2 L). The organic extracts were combined, dried (Na2SO4), filtered, and concentrated in vacuo to give benzyl (S)-1-((1S,2R,4R)-2-acetamido-4-(isopropylamino)cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate as an oil. LC/MS found [M+H]+=431.45. 1H-NMR (400 MHz, d4-MeOH): δ 7.3-7.4 (m, 5H), 5.12 (s, 2H), 4.31 (m, 1H), 4.24 (t, J=9.4 Hz, 1H), 4.11 (m, 1H), 3.61 (t, J=9.1 Hz, 1H), 3.52 (q, J=8.6 Hz, 1H), 3.04 (br. s, 1H), 2.96 (sep, J=6.3 Hz, 1H), 2.40 (m, 1H), 2.15 (m, 1H), 1.92 (s, 3H), 1.7-1.9 (m, 5H), 1.65 (m, 1H), 1.12 (app. dd, J=6.3, 1.1 Hz, 6H).
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([O:10]C(=O)C)[C@@H:8]([CH2:14][O:15]C(=O)C)[O:7][C@H:6]1[N:19]1[C:34]2[N:33]=[C:32]([Br:35])[N:31]=[C:23]([NH:24][N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[C:22]=2[N:21]=[CH:20]1)(=O)C>N>[Br:35][C:32]1[N:31]=[C:23]([NH:24][N:25]2[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]2)[C:22]2[N:21]=[CH:20][N:19]([C:34]=2[N:33]=1)[C@@H:6]1[O:7][C@H:8]([CH2:14][OH:15])[C@@H:9]([OH:10])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(NN4CCCCC4)nc(Br)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: N
Product: OC[C@H]1O[C@@H](n2cnc3c(NN4CCCCC4)nc(Br)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The above 2',3',5'-tri-O-acetyl-2-bromo-N-(1-piperidinyl)adenosine was treated with methanolic ammonia (10 ml) (previously saturated at -10° C.) and stirred at room temperature for 16 hours after which time TLC investigation indicated that the starting material was consumed and a new product was present [rf 0.24 (SiO2, ethyl acetate/methanol (90/10)]. The reaction mixture was evaporated and the resultant residue was treated with water (25 ml) and the suspension was extracted with ethyl acetate (2×25 ml). The combined extracts were dried (MgSO4) and coevaporated with dichloromethane; 1H NMR (400 MHz, Me2SO-d6) δ 3.54, 3.65 (2H, ABX, H-5'a and H-5'b), 3.94 (1H, q, H-4'), 4.12 (1H, m, H-3'), 4.50 (1H, m, H-2'), 5.82 (1H, d, H-1'), 8.38 (1H, s, H-8). HPLC retention time 14.25 (gradient elution, 5-25% acetonitrile/0.1M pH 3.3 ammonium sulphate buffer: 214 nm detector).
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26]([NH:28][NH:29][C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=O)=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:47])=CC=1>>[N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26]3[S:47][C:30]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[N:29][N:28]=3)[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C(NNC(=O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1)c1ccccc1
Product: O=C(N1CCOCC1)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nnc(-c3ccccc3)s2)C1

Procedure:
132 mg (0.239 mmol) of the compound from Example 123A and 193 mg (0.478 mmol) of Lawesson reagent were reacted according to the General Method 9. Yield: 40 mg (32% of theory)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:11]=[C:12]([CH3:14])[CH:13]=1)[NH:5][CH2:6][CH2:7][C:8](O)=O.S(=O)(=O)(O)[OH:16]>>[CH3:1][C:2]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:4]2[C:3]=1[CH:8]=[CH:7][C:6](=[O:16])[NH:5]2
Reactant: Cc1cc(C)cc(NCCC(=O)O)c1
Reactant: O=S(=O)(O)O
Product: Cc1cc(C)c2ccc(=O)[nH]c2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
β-(3,5-Dimethylanilino)propionic acid (1.2 g) was added by portions to sulfuric acid (60° C., 12 ml), and the mixture was stirred at the same temperature for 0.5 hr. The reaction mixture was poured into ice water (100 ml) and extracted with chloroform (100 ml). After washing with water, the chloroform layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/benzene=1/5-1/1) to give 750 mg of 5,7-dimethylquinolone as crystals.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:11][C:12]([CH2:15][S:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=4)=[N:13][N:14]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:32])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:11][C:12]([CH2:15][S:16]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=4)=[O:32])=[N:13][N:14]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Fc1cccc(SCc2nnc(-c3ccc4c(c3)CCO4)o2)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: O=S(Cc1nnc(-c2ccc3c(c2)CCO3)o1)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.9 %

Procedure:
To a solution of 2-(2,3-dihydro-1-benzofuran-5-yl)-5-[[(3-fluorophenyl)thio]methyl]-1,3,4-oxadiazole (0.25 g, 0.76 mmol) in acetonitrile (5 mL) was added m-chloroperbenzoic acid (70%, 0.18 g, 0.76 mmol) at 0° C., and the resulting mixture was stirred overnight at room temperature. A saturated aqueous sodium thiosulfate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1-2/1) and recrystallized from hexane/ethyl acetate to give the title compound (0.12 g, yield 46%) as colorless crystals.
Reaction SMILES: [CH2:1]([CH:4]1[N:7]([C:8]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])=P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:6](=[O:38])[CH:5]1[CH3:39])[CH:2]=C.FC(F)(F)C(O)=O>C(OCC)(=O)C>[CH3:39][CH:5]1[C:6](=[O:38])[N:7]2[CH:4]1[CH2:1][CH:2]=[C:8]2[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]
Reactant: C=CCC1C(C)C(=O)N1C(C(=O)OCc1ccccc1)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CC1C(=O)N2C(C(=O)OCc3ccccc3)=CCC12
Reaction time: 0.17 h
Yield: 57.2 %

Procedure:
A solution of 4-allyl-3-methyl-1-(1-benzyloxycarbonyl-1-triphenylphosphoranylidenemethyl)azetidine-2-one (38) (0.29 g) in ethyl acetate (25 ml) was treated with trifluoroacetic acid (0.4 ml) and then cooled to -78°. Ozone was bubbled through the solution until it just became pale blue in colour. The excess ozone was blown off in a stream of argon and an ethyl acetate solution of triphenylphosphine (0.14 g) was then added. After a further 10 minutes the reaction flask was transferred to an ice bath and saturated aqueous sodium bicarbonate (45 ml) was added with vigorous stirring. This was continued for 30 minutes and the ethyl acetate solution was then separated, washed with brine and dried over sodium sulphate. The solution was concentrated and chromatographed on silica gel 60 (<230 mesh) eluting with ethyl acetate/60°-80° petroleum ether mixtures grading from 3:7 to 6:4. This gave the trans-isomer of benzyl 6-methyl-7-oxo-1-azabicyclo[3,2,0]hept-2-ene- 2-carboxylate (39) (0.08 g, 55%); νmax (CHCl3) 3000, 1780, 1725 and 1615 cm-1 ; δppm ((CD3)2CO) 1.34 (3H, d, J 7 Hz, CH3), 2.85 (2H, dd, J 9 and 2 Hz, C4--H2), 3.24 (1H, dq, J 3 and 7 Hz, C6--H), 3.91 (1H, dt, J 3 and 9 Hz, C5--H), 5.20 (2H, s, benzyl CH2), 6.45 (1H, t, J 2 Hz, C3--H) and 7.2-7.5 (5H, m, phenyl); (M+ at m/e 257.1052 C15H15NO3 requires 257.1051).
Reaction SMILES: [C:1]([C:5]1[O:6][C:7](=[O:20])[CH:8]=[C:9]2[C:13]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:12]=3[O:11][C:10]=12)([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:22]([NH:24][CH2:25][CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH3:23].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:28][C:27]([CH3:30])([CH3:29])[CH2:26][CH2:25][N:24]([CH2:22][CH3:23])[C:7](=[O:20])[CH2:8][C:9]1[C:13]2[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:12]=2[O:11][C:10]=1[C:5](=[O:6])[C:1]([CH3:2])([CH3:3])[CH3:4]
Reactant: CCNCCC(C)(C)C
Reactant: COc1ccc2oc3c(C(C)(C)C)oc(=O)cc3c2c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN(CCC(C)(C)C)C(=O)Cc1c(C(=O)C(C)(C)C)oc2ccc(OC)cc12
Temperature: 45 °C

Procedure:
To a mixture containing 21.8 mg 1-tert-butyl-6-methoxy-3H-pyrano[3,4-b][1]benzofuran-3-one from the Step B above and 21.6 mg N-Ethyl-3,3-dimethylbutan-1-amine hydrochloride from the Step A above in 0.75 mL DMF was 26 μL DIEA. The mixture was heated in 45° C. oil bath over night. It was purified directly on RP-HPLC using 65˜85% MeCN gradient. The fractions containing pure product were pooled and lyophilized to give the title compound. LC-MS: 4.38 min. (m/Z=318.2, 402.3, 424.3). Alternative preparation of N-(3,3-dimethylbutyl)-2-[2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]-N-ethylacetamide
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH:14]2[CH2:17][N:16]([C@@H:18]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)[C:19]3[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=3)[C:22]#[N:23])[CH2:15]2)[C:10]([F:13])([CH3:12])[CH3:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[NH2:35][OH:36].C(N(CC)CC)C>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH:14]2[CH2:17][N:16]([C@@H:18]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)[C:19]3[CH:20]=[C:21]([C:22](=[N:35][OH:36])[NH2:23])[CH:24]=[CH:25][CH:26]=3)[CH2:15]2)[C:10]([F:13])([CH3:12])[CH3:11])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC(C)(F)[C@H](c1cc(F)cc(Br)c1)C1CN([C@@H](c2ccc(Cl)cc2)c2cccc(C#N)c2)C1
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(F)[C@H](c1cc(F)cc(Br)c1)C1CN([C@@H](c2ccc(Cl)cc2)c2cccc(C(N)=NO)c2)C1

Procedure:
The mixture of 240 mg (0.45 mmol) of 3-[(S)-{3-[(1S)-1-(3-bromo-5-fluorophenyl)-2-fluoro-2-methylpropyl]azetidin-1-yl}(4-chlorophenyl)methyl]benzonitrile, 47.2 mg (0.68 mmol) of hydroxylamine hydrochloride, 0.124 mL (0.9 mmol) of triethylamine, and 5 mL of ethanol was heated to reflux for 4 h. The solution was concentrated and the residue was poured into 20 mL of CH2Cl2 and 5 mL of aq NaHCO3 (PH>7). The aqueous layer was extracted with two 10 mL portions of CH2Cl2. The combined organic layer was dried over Na2SO4 and concentrated to afford the title compound as a white solid; Mass Spectrum: m/e=562 (M+1, 35Cl), 564 (M+1, 37Cl).
Reaction SMILES: [O:1]1[C:5]2[CH2:6][NH:7][CH2:8][CH2:9][C:4]=2[CH:3]=[C:2]1[C:10]([O:12][CH3:13])=[O:11].[C:14]1([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](O)=[O:26])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N.[OH-].[Na+]>ClCCl>[C:14]1([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([N:7]2[CH2:8][CH2:9][C:4]3[CH:3]=[C:2]([C:10]([O:12][CH3:13])=[O:11])[O:1][C:5]=3[CH2:6]2)=[O:26])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)c1cc2c(o1)CNCC2
Reactant: O=C(O)CCCCCc1ccccc1
Agent: CCOP(=O)(C#N)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc2c(o1)CN(C(=O)CCCCCc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 95 mg (0.52 mmol) of methyl 4,5,6,7-tetrahydrofuro[2,3-c]pyridine-2-carboxylate, 0.12 g (0.63 mmol) of 6-phenylhexanoic acid and 0.15 ml (1.0 mmol) of triethylamine in 30 ml of dichloromethane, 0.10 ml (0.63 mmol) of diethyl cyanophosphonate was added dropwise under ice-cooling, followed by overnight stirring at room temperature. The reaction mixture was poured into aqueous sodium hydroxide and extracted with dichloromethane 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=3/1 to 2/1) to yield the desired product.