Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[C:13]([CH:14]=2)=[N:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])=[CH:17][CH:16]=2)[CH:10]=3)[CH2:3][CH2:2]1.[CH:32]([N-]C(C)C)(C)C.[Li+].CI.O>C1COCC1>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[C:13]([CH:14]=2)=[N:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][Si:22]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:29]([CH3:31])[CH3:30])=[CH:17][CH:16]=2)[C:10]=3[CH3:32])[CH2:2][CH2:3]1
Reactant: CC(C)[Si](Oc1ccc(-n2cc3ccc(OCC4CC4)cc3n2)cc1)(C(C)C)C(C)C
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: CI
Solvent: C1CCOC1
Product: Cc1c2ccc(OCC3CC3)cc2nn1-c1ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc1
Reaction time: 0.5 h

Procedure:
To a solution of 6-(cyclopropylmethoxy)-2-(4-{[tris(1-methylethyl)silyl]oxy}phenyl)-2H-indazole (218 mg) in THF (5 mL) was added dropwise a THF solution (1.11 M, 0.59 mL) of lithium diisopropylamide at −78° C. under an argon atmosphere, and the mixture was stirred for 30 min. To the reaction mixture was added methyl iodide (142 mg) at −78° C., and the mixture was stirred for 1.5 hr. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as a colorless oil (159 mg).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:9]=[CH:8][S:7][CH:6]=1)=[O:4].[C:10]1([CH:16]([N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[C:17]([O:19][C@@H:20]2[CH:25]3[CH2:26][CH2:27][N:22]([CH2:23][CH2:24]3)[CH2:21]2)=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CCOCC>C(OCC)(=O)C.C(#N)C>[Br-:1].[O:4]=[C:3]([C:5]1[CH:9]=[CH:8][S:7][CH:6]=1)[CH2:2][N+:22]12[CH2:23][CH2:24][CH:25]([CH2:26][CH2:27]1)[C@@H:20]([O:19][C:17](=[O:18])[CH:16]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[N:28]1[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1)[CH2:21]2
Reactant: O=C(CBr)c1ccsc1
Reactant: O=C(O[C@H]1CN2CCC1CC2)C(c1ccccc1)N1CCCCC1
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C(c1ccccc1)N1CCCCC1)C2)c1ccsc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 75 %

Procedure:
2-Bromo-1-(thiophen-3-yl)ethanone (54.9 mg, 0.27 mmol) was added to a solution of (R)-quinuclidin-3-yl 2-phenyl-2-(piperidin-1-yl)acetate (80 mg, 0.24 mmol) in ethyl acetate (1.2 ml) and acetonitrile (1.2 ml). The reaction was stirred at room temperature for 24 h (UPLC-MS: complete conversion). The solvents were evaporated and the residue was purified first by flash chromatography (DCM/MeOH=92/8) and then by trituration with Et2O to obtain compound (3R)-1-(2-oxo-2-(thiophen-3-yl)ethyl)-3-(2-phenyl-2-(piperidin-1-yl)acetoxy)-1-azoniabicyclo[2.2.2]octane bromide (96 mg, 73.9% yield) as a white solid.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH2:17])[C:15](=[O:18])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2].CC(OC[C:24]1[CH2:33]S[C@@H]2[C@H](N)C(=O)N2[C:25]=1[C:34]([OH:36])=[O:35])=O.C[C:38](OCC1CS[C@@H]2[C@H](NC(CCC[C@@H](N)C(O)=O)=O)C(=O)N2C=1C(O)=O)=[O:39]>>[CH3:2][C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:16]([NH:17][C:38]([CH2:33][CH2:24][CH2:25][C:34]([OH:36])=[O:35])=[O:39])[C:15](=[O:18])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])=[O:3]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)CCC[C@@H](N)C(=O)O)[C@H]2SC1
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)CCCC(=O)O)[C@H]2SC1

Procedure:
3-Acetoxymethyl 7-amino-3-cephem-4-carboxylic acid (7-aminocephalosporanic acid, 7-ACA) is the starting material for the synthesis of many semi-synthetic cephalosporin antibiotics. 7-ACA can be generated from cephalosporin C (a readily available fermentation product) by a two-step enzymatic process (Scheme 1), using first a D-amino acid oxidase in conjunction with oxidative decarboxylation to produce glutaryl 7-ACA (Step A), and then using a glutaryl 7-ACA acylase to remove the glutaryl group to produce 7-ACA (Step B).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:17][CH2:18][C:19](Br)([CH3:21])[CH3:20])=[C:14]([OH:16])[CH:15]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-:24].[K+].[K+]>CN(C=O)C.Cl>[C:1]1([S:7]([C:10]2[CH:11]=[CH:12][C:13]3[NH:17][C:18](=[O:24])[C:19]([CH3:21])([CH3:20])[O:16][C:14]=3[CH:15]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(Br)CNc1ccc(S(=O)(=O)c2ccccc2)cc1O
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)Oc2cc(S(=O)(=O)c3ccccc3)ccc2NC1=O
Temperature: 80 °C
Reaction time: 2 h

Procedure:
The crude 5-benzenesulfonyl-2-(2-bromo-2-methyl-propylamino)-phenol from step 1 was dissolved in 10 mL DMF and potassium carbonate (0.565 g., 4.096 mmol) was added. The reaction mixture was heated to 80° C. with stirring for 2 hours, then cooled to room temperature and poured onto 100 g of ice in 150 mL 10% aqueous hydrogen chloride. The resulting solid was filtered and dried under vacuum for 18 hours to give 0.570 g (1.79 mmol) of 7-benzenesulfonyl-2,2-dimethyl-4H-benzo[1,4]oxazin-3-one. MS: 316 (M−H)−.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])O.[Na+].Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>CN(C)C=O>[CH2:21]([N:11]1[CH2:12][CH2:13][C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=2)([CH3:14])[CH2:9][CH2:10]1)[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCBr
Reactant: CC1(c2cccc(O)c2)CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCN1CCC(C)(c2cccc(O)c2)CC1
Temperature: 100 °C
Yield: 89.4 %

Procedure:
To 4-(3-hydroxyphenyl)-4-methylpiperidine (776 mg, 4.06 mmol) in N,N-dimethylformamide (5 ml) was added sodium hydrogen carbonate (341 mg, 4.06 mmol) and 1-bromohexane (0.57 ml, 4.06 mmol). The reaction mixture was heated at 100° C. for 4 h and then allowed to cool to room temperature. The solution was poured onto water (20 ml) and extracted with diethyl ether (3×10 ml). The combined extracts were washed with water (20 ml), dried (MgSO4) and concentrated in vacuo to give the title compound as a clear oil (1.0 g, 90%).
Reaction SMILES: [Li+].[OH-].[CH3:3][C:4]1[CH:5]=[C:6]([CH2:11][C:12]([NH:14][C@@H:15]([CH2:20][C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][CH:22]=2)[C:16]([O:18]C)=[O:17])=[O:13])[CH:7]=[C:8]([CH3:10])[CH:9]=1.O>CO>[CH3:10][C:8]1[CH:7]=[C:6]([CH2:11][C:12]([NH:14][C@@H:15]([CH2:20][C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][CH:22]=2)[C:16]([OH:18])=[O:17])=[O:13])[CH:5]=[C:4]([CH3:3])[CH:9]=1
Reactant: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)Cc1cc(C)cc(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(C)cc(CC(=O)N[C@@H](Cc2c[nH]c3ccccc23)C(=O)O)c1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 93 %

Procedure:
DMAP (122.2 mg, 0.5 mmol) and DIC (N,N-diisopropylcarbodiimide) (235 μl, 1.5 mmol) were added to a solution of tryptophan methyl ester (255 mg, 1.0 mmol) and 3,5-dimethylphenylacetic acid (164 mg, 1.0 mmol) in dry DCM (11 ml). After 17 h at room temperature the solvent was removed under reduced pressure and the crude product was purified by flash chromatography (DCM containing 1% EtOH) to afford (S)-methyl 2-(2-(3,5-dimethylphenyl)acetamido)-3-(1H-indol-3-yl)propanoate. An aqueous solution of LiOH (1N, 4.5 ml, 4.5 mmol) was added to a solution of (S)-methyl 2-(2-(3,5-dimethylphenyl)acetamido)-3-(1H-indol-3-yl)propanoate (365 mg, 1 mmol) in methanol (24.5 ml) and the reaction mixture was stirred at room temperature for 4.5 h. Then water was added and methanol was removed under reduced pressure. The aqueous residue was washed with DCM (5×20 ml), treated with HCl 2N to obtain a pH 4 and extracted with DCM (3×25 ml). The organic phases were dried with anhydrous Na2SO4 and the solvent was removed under reduced pressure to afford (S)-2-(2-(3,5-dimethylphenyl)acetamido)-3-(1H-indol-3-yl)propionic acid (93% c.y.).
Reaction SMILES: [CH3:1][Si:2]([CH3:15])([CH3:14])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[C:10]([C:12]#[N:13])[N:9]=[CH:8]1.C[Si](C)(C)CCOCN1C(C#N)=CN=C1.[Br:31]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:31][C:8]1[N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:15])([CH3:14])[CH3:1])[CH:11]=[C:10]([C:12]#[N:13])[N:9]=1
Reactant: C[Si](C)(C)CCOCn1cnc(C#N)c1
Reactant: O=C1CCC(=O)N1Br
Agent: C[Si](C)(C)CCOCn1cncc1C#N
Solvent: ClC(Cl)(Cl)Cl
Product: C[Si](C)(C)CCOCn1cc(C#N)nc1Br
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A 22-L, four-neck, round-bottom flask equipped with a mechanical stirrer, a temperature probe, and a condenser with a nitrogen inlet was charged with a mixture of 1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-4-carbonitrile and 3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazole-4-carbonitrile [600 g, 2.69 mol, as prepared in the previous step) and carbon tetrachloride (1.8 L). Agitation was initiated and the mixture was heated to 60° C. At this point N-bromosuccinimide (502 g, 2.82 mol) was added in several portions over 30 min, which resulted in an exotherm to 74° C. The reaction was allowed to cool to 60° C. and further stirred at 60° C. for 1 h. The reaction was allowed to cool slowly to ambient temperature and the resulting slurry was filtered and the filtrate washed with satd NaHCO3 solution (4.0 L). The organics were passed through a plug of silica gel (8×15 cm, silica gel; 600 g) using 2:1 heptane/ethyl acetate (6.0 L) as eluent. The fractions containing the product (based on TLC analysis) were combined and concentrated under reduced pressure to give a crystalline light yellow solid, which was then filtered and washed with heptane (500 mL) to give the title compound as a crystalline white solid [593 g, 73%). The 1H and 13C NMR spectra were consistent with the assigned structure and showed no evidence of the minor regioisomer.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:32]=[CH:31][C:22]([C:23]([CH2:25][CH2:26][C:27]([O:29]C)=[O:28])=[O:24])=[CH:21][CH:20]=1.[OH-].[K+].C(O)C.Cl>O>[F:1][C:2]([F:33])([F:34])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:32]=[CH:31][C:22]([C:23]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[O:24])=[CH:21][CH:20]=1
Reactant: COC(=O)CCC(=O)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CCC(=O)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1
Temperature: 25 °C

Procedure:
A solution of 5.4 g. of methyl 3-{4-[15-(trifluoromethyl)pentadecylamino]benzoyl}propionate is stirred with 5.4 g. of potassium hydroxide in 100 ml. of 95% ethanol for 3 hours at reflux. The reaction mixture is cooled, diluted with 50 ml. of ethanol and 100 ml. of water, and neutralized with hydrochloric acid. The solution is cooled to room temperature and filtered. The white solid is washed with 50% aqueous ethanol and dried. The product is recrystallized from ethanol to yield 3-{4-[15-(trifluoromethyl)pentadecylamino]benzoyl}propionic acid as a white crystalline solid.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([C:22]([F:25])([F:24])[F:23])=[C:16]2[C:21]=1[N:20]=[CH:19][CH:18]=[CH:17]2)(=[O:10])=[O:9].CC(O)=O>C1COCC1>[F:25][C:22]([F:24])([F:23])[C:15]1[CH:14]=[C:13]2[C:12](=[C:21]3[C:16]=1[CH:17]=[CH:18][CH:19]=[N:20]3)[NH:11][S:8](=[O:10])(=[O:9])[C:3]1[C:2]2=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Nc1ccccc1S(=O)(=O)Nc1ccc(C(F)(F)F)c2cccnc12
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=S1(=O)Nc2c(cc(C(F)(F)F)c3cccnc23)-c2ccccc21
Yield: 12.2 %

Procedure:
In a similar fashion using route 16 general procedure 61, 2-amino-N-(5-trifluoromethyl-quinolin-8-yl)-benzenesulfonamide (Intermediate 281) (230 mg, 0.63 mmol), t-butyl nitrile (111 mg, 0.94 mmol) and AcOH:THF (2.3 ml: 2.3 ml) gave the title compound (27 mg, 12%) after purification by column chromatography with DCM/MeOH (99.7:0.3) as the eluent.
Reaction SMILES: B(O)(O)O.[OH:5]O.S(=O)(=O)(O)O.[F:12][C:13]1[CH:14]=[C:15]([N+:23]([O-:25])=[O:24])[C:16]([OH:22])=[C:17](C(=O)C)[CH:18]=1>O1CCCC1.O>[F:12][C:13]1[CH:18]=[C:17]([OH:5])[C:16]([OH:22])=[C:15]([N+:23]([O-:25])=[O:24])[CH:14]=1
Reactant: CC(=O)c1cc(F)cc([N+](=O)[O-])c1O
Reactant: OO
Agent: O=S(=O)(O)O
Agent: OB(O)O
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(F)cc(O)c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
Boric acid (20.45 g, 330.7 mmol), and hydrogen peroxide (35%, 36.8 mL) in tetrahydrofuran (150 ml) was treated with concentrated sulfuric acid (15 ml) and the mixture was stirred at rt for 30 min. 1-(5-Fluoro-2-hydroxy-3-nitrophenyl)ethanone (15 g, 75.4 mmol) in tetrahydrofuran (45 ml) was added and reaction heated for 48 h at 75° C. The reaction mixture was cooled to rt, diluted with water and extracted with DCM (3×500 ml). The combined organic phases were dried on magnesium sulphate, evaporated and the residue was subjected to column chromatography on silica gel using a 20%-80% EtOAc: 40-60 petroleum ether gradient to provide the desired compound (6.55 g, 50%), a 5:1 mixture of desired product and 1-(5-fluoro-2-hydroxy-3-nitrophenyl)ethanone (4 g) and recovered 1-(5-fluoro-2-hydroxy-3-nitrophenyl)ethanone (1.5 g).
Reaction SMILES: [NH2:1][C@H:2]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:3][N:4]1[C:9](=[O:10])[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=2[F:19])=[C:7]([CH3:20])[N:6]([CH2:21][C:22]2[C:27]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:25]=[CH:24][C:23]=2[F:32])[C:5]1=[O:33].C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:47][CH2:48][CH2:49][N:50]1[C:54](=[O:55])[C:53]2=[CH:56][CH:57]=[CH:58][CH:59]=[C:52]2[C:51]1=[O:60].C(OCC)(=O)C>CN(C=O)C>[C:51]1(=[O:60])[N:50]([CH2:49][CH2:48][CH2:47][NH:1][C@H:2]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:3][N:4]2[C:9](=[O:10])[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=3[F:19])=[C:7]([CH3:20])[N:6]([CH2:21][C:22]3[C:27]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:25]=[CH:24][C:23]=3[F:32])[C:5]2=[O:33])[C:54](=[O:55])[C:53]2=[CH:56][CH:57]=[CH:58][CH:59]=[C:52]12
Reactant: COc1cccc(-c2c(C)n(Cc3c(F)cccc3S(C)(=O)=O)c(=O)n(C[C@H](N)c3ccccc3)c2=O)c1F
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cccc(-c2c(C)n(Cc3c(F)cccc3S(C)(=O)=O)c(=O)n(C[C@H](NCCCN3C(=O)c4ccccc4C3=O)c3ccccc3)c2=O)c1F
Temperature: 80 °C
Yield: 68.1 %

Procedure:
To a solution of compound 6d (4.0 g, 7.2 mmol) in anhydrous DMF (8 mL) was added sodium carbonate (0.76 g, 7.2 mmmol) and N-(3-bromopropyl)phthalimide (2.4 g, 9.0 mmmol). The reaction mixture was heated to 80° C. under nitrogen for 4 hr. The reaction mixture was cooled and partitioned between dichloromethane and water. The organic layer was washed with saturated aqueous sodium bicarbonate solution and brine, dried with sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel, eluting with dichloromethane, 50% ethyl acetate in hexane and then ethyl acetate to yield 6e as a pale yellow solid (3.6 g, 4.9 mmol, 67%). MS (CI) m/z 743.1 (M+H+), tR=2.539 min. (method 4). 1H NMR (CDCl3): δ 1.62–1.70 (m, 2H), 2.26 (s, 1.5H), 2.27 (s, 1.5H), 2.29–2.33 (m, 1H), 2.40–2.48 (m, 1H), 3.51 (s, 1.5H), 3.52 (s, 1.5H), 3.54–3.74 (m, 2H), 3.90 (s, 1.5H), 3.91 (s, 1.5H), 3.93–4.26 (m, 3H), 5.60 (brs, 2H), 6.80–6.89 (m, 1H), 6.99 (dd, 1H), 7.11–7.36 (m, 8H), 7.42–7.49 (m, 1H), 7.71–7.75 (m, 2H), 7.84–7.89 (m, 1H), 7.95 (d, J=8.4 Hz, 1H).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:15]1[CH2:19][C@H:18]([OH:20])[CH2:17][C@H:16]1[C:21]([OH:24])([CH3:23])[CH3:22])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>ClCCl>[CH2:8]([N:15]1[CH2:19][C@H:18]([O:20][S:26]([CH3:25])(=[O:28])=[O:27])[CH2:17][C@H:16]1[C:21]([OH:24])([CH3:22])[CH3:23])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(O)[C@@H]1C[C@@H](O)CN1Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of triethylamine (4.32 ml) and (2S,4R)-1-benzyl-2-(1-hydroxy-1-methylethyl)-4-hydroxypyrrolidine (4.87 g) in dichloromethane (50 ml) was added methanesulfonyl chloride (2.4 ml) at 0° C. After stirring at room temperature for 4 hours, the mixture was quenched with water and extracted with ethyl acetate (×2). The combined extracts were washed with brine, dried over magnesium sulfate, evaporated under reduced pressure, and purified with column chromatography (silica gel, 500 ml, methanol:dichloromethane=4:96) to give (2S,4R)-1-benzyl-2-(1-hydroxy-1-methylethyl)-4-(methanesulfonyloxy)pyrrolidine (3.34 g) as a pale yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:17]([OH:19])=O)[CH:14]=2)[C@@H:9]1[CH:20]([CH3:22])[CH3:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:23]([S:25]([C:28]1[CH:33]=[CH:32][C:31]([CH2:34][NH2:35])=[CH:30][CH:29]=1)(=[O:27])=[O:26])[CH3:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH2:23]([S:25]([C:28]1[CH:33]=[CH:32][C:31]([CH2:34][NH:35][C:17]([C:13]2[CH:14]=[C:15]3[CH2:16][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[C@@H:9]([CH:20]([CH3:21])[CH3:22])[C:10]3=[N:11][CH:12]=2)=[O:19])=[CH:30][CH:29]=1)(=[O:27])=[O:26])[CH3:24]
Reactant: CC(C)[C@H]1c2ncc(C(=O)O)cc2CN1C(=O)OC(C)(C)C
Reactant: CCS(=O)(=O)c1ccc(CN)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCS(=O)(=O)c1ccc(CNC(=O)c2cnc3c(c2)CN(C(=O)OC(C)(C)C)[C@H]3C(C)C)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 71.5 %

Procedure:
To a solution of (S)-6-(tert-butoxycarbonyl)-7-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxylic acid (83.3 mg, 281 μmol) and (4-(ethylsulfonyl)phenyl)methanamine (67.1 mg, 337 μmol) in DMF (2 mL) at rt was added HATU (160 mg, 421 μmol) and diisopropylethylamine (97.8 μL, 561 μmol). The mixture was stirred at rt for 15 h, at which point it was quenched with saturated aqueous ammonium chloride solution (15 mL). EtOAc (25 mL) was added, then the phases were separated. The organic layer was washed with brine (15 mL), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with 50% EtOAc in hexanes, gradient to 100%) to afford 98.0 mg tert-butyl(S)-3-((4-(ethylsulfonyl)benzyl)carbamoyl)-7-isopropyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate, (15), (77%). LC-MS tR=0.92 min in 1 min chromatography, MS (ESI) m/z 488.5 [M+H]+. 1H NMR (CD3OD, 400 MHz, mixture of rotamers): δ 8.94 (d, J=2.0 Hz, 1H), 8.16 (d, J=12.0 Hz, 1H), 7.89 (dd, J=2.0 Hz, 8.4 Hz, 2H), 7.64 (d, J=8.8 Hz, 2H), 4.96 (m, 1H), 4.83 (m, 1H), 4.70 (s, 2H), 4.59 (m, 1H), 3.20 (q, J=7.2 Hz, 2H), 2.56-2.42 (m, 1H), 1.48 (s, 9H), 1.20 (t, J=7.2 Hz, 3H), 1.06 (d, J=7.2 Hz, 1.5H), 1.02 (d, J=6.8 Hz, 1.5H), 0.80 (d, J=6.8 Hz, 1.5H), 0.74 (d, J=6.8 Hz, 1.5H).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[O:6][CH:7]([CH2:15][CH3:16])[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=O.[NH2:20][CH2:21][CH2:22][CH2:23][OH:24].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[OH:24][CH2:23][CH2:22][CH2:21][NH:20][CH2:1][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[O:6][CH:7]([CH2:15][CH3:16])[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: CCC(Oc1cccc(C=O)c1)C(=O)OC(C)(C)C
Reactant: NCCCO
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CCC(Oc1cccc(CNCCCO)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 31.9 %

Procedure:
tert-Butyl 2-(3-formylphenoxy)butyrate (105.1 mg, 0.42 mmol) was dissolved in chloroform (10 ml) at room temperature, and thereto were added 3-amino-1-propanol (0.04 ml, 0.47 mmol), sodium triacetoxyborohydride (134.6 mg, 0.63 mmol) and acetic acid (0.03 ml, 0.51 mmol) in sequential order at the same temperature, and then stirred at room temperature for 24 hours. The reaction mixture was added to a saturated aqueous sodium hydrogencarbonate solution and thereafter extracted by chloroform, to obtain an organic layer. The extracted organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressured. The resultant substance was purified by silica gel column chromatography (chloroform/methanol=10/1), whereby the target compound was obtained as a colorless oil (43.3 mg, 33.3%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH3:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>C1COCC1.CCOC(C)=O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([N:13]2[CH2:14][CH2:15][N:10]([CH3:9])[CH2:11][CH2:12]2)=[N:3][CH:4]=1
Reactant: Fc1ccc(Br)cn1
Reactant: CN1CCNCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN1CCN(c2ccc(Br)cn2)CC1
Yield: 64.2 %

Procedure:
Heat 2-fluoro-5-bromopyridine (2.15 g, 12.22 mmol) with 1-methyl-piperazine (3.4 mL, 30.54 mmol) in THF (10 mL) in a microwave reactor at 120° C. for 45 min. Dilute with EtOAc (60 mL), then wash with NaHCO3 (2×30 mL) and brine (20 mL). Dry with Na2SO4, filter, and concentrate to give 2.01 g (64%) of the title compound. MS/ES m/z (79Br) 256 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:24])=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][C:9]([CH:12]1[CH2:17][CH2:16][N:15]([C:18](=[O:21])[CH2:19][CH3:20])[CH2:14][CH2:13]1)=[C:8]([CH3:22])[C:7]2=[O:23].C(N(C(C)C)CC)(C)C.Cl[CH2:35][O:36][CH3:37].O>ClCCl>[Br:1][C:2]1[C:3]([O:24][CH2:35][O:36][CH3:37])=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][C:9]([CH:12]1[CH2:17][CH2:16][N:15]([C:18](=[O:21])[CH2:19][CH3:20])[CH2:14][CH2:13]1)=[C:8]([CH3:22])[C:7]2=[O:23]
Reactant: CCC(=O)N1CCC(c2oc3c(Br)c(O)ccc3c(=O)c2C)CC1
Reactant: COCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CCC(=O)N1CCC(c2oc3c(Br)c(OCOC)ccc3c(=O)c2C)CC1
Reaction time: 1 h
Yield: 42.1 %

Procedure:
To a solution of 8-bromo-7-hydroxy-3-methyl-2-(1-propanoylpiperidin-4-yl)-4H-chromen-4-one (3.82 mol) obtained in Example 32 in dichloromethane (25 mL), diisopropylethylamine (1.32 mL, 7.66 mmol) and chloro(methoxy)methane (345 μL, 4.59 mmol) were added under cooling with ice, and the mixture was stirred for 1 hour under cooling with ice and then at room temperature for 2 hours. Water was added to the reaction solution, followed by extraction with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (dichloromethane/methanol=98/2) to obtain 847 mg of 8-bromo-7-(methoxymethoxy)-3-methyl-2-(1-propanoylpiperidin-4-yl)-4H-chromen-4-one (yield: 51%). Subsequently, 2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (181 μL, 0.953 mmol), potassium carbonate (167 mg, 1.21 mmol), and a palladium chloride-dppf complex (40.7 mg) were added to a mixed solution of the obtained compound (104 mg, 0.24 mmol) in N,N-dimethylformamide (2 mL) and water (0.2 mL), and the mixture was stirred at 90° C. for 14 hours under the nitrogen atmosphere. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=50/50→0/100) and then further purified by HPLC to obtain 38 mg of the title compound (yield: 40%) as an oil.