Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:11]([CH3:22])[CH2:10]2)=[CH:4][CH:3]=1.CO[C:25]([CH3:27])=[CH2:26].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[CH3:22][C@H:11]1[CH2:10][N:9]([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([NH:1][CH:25]([CH3:27])[CH3:26])=[CH:3][CH:4]=2)[CH2:14][CH2:13][N:12]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]
Reactant: C[C@H]1CN(Cc2ccc(N)cc2)CCN1C(=O)OC(C)(C)C
Reactant: C=C(C)OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)Nc1ccc(CN2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.3 %

Procedure:
To a stirred solution of 1,1-dimethylethyl (2S)-4-[(4-aminophenyl)methyl]-2-methyl-1-piperazinecarboxylate (D2) (0.30 g, 1 mmol) in dry 1,2 DCE (5 mL) was added sequentially 2-methoxypropene (0.141 mL, 1.5 mmol), acetic acid (0.056 mL, 1 mmol) and sodium triacetoxyborohydride (0.313 g, 1.5 mmol). Further 1,2 DCE (5 mL) was added and the reaction mixture was stirred under argon at room temperature for 16 hours. Saturated NaHCO3 (15 mL) was added and reaction mixture stirred for a further 1 hour. The aqueous layer was then extracted with DCM (×3) and the combined organic layers were dried (Na2SO4) and concentrated in vacuo. The crude material was purified by column chromatography eluting with 0-100% ether/petroleum ether to give the title compound (0.265 g). δH (CDCl3, 400 MHz) 7.09 (2H, d), 6.54 (2H, d), 4.16 (1H, br.s), 3.78 (1H, d), 3.61 (1H, sp), 3.49 (1H, s), 3.42 (2H, m), 3.28 (1H, d), 3.08 (1H, td), 2.75 (1H, d), 2.59 (1H, d), 1.95 (1H, dd), 1.94 (1H, m), 1.45 (9H, s), 1.20 (9H, m). MS (AP+): 370.3 (MNa+), 248.3, no molecular ion (MH+) observed.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([N:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21](Cl)=[O:22])[C:12]3=[O:24])[CH:9]=[CH:10][C:2]1=2.[C:25]1(=[O:32])[CH2:30][CH2:29][CH2:28][C:27](=[O:31])[CH2:26]1.C(N(CC)CC)C.CC(C)(O)C#N.[OH-].[Na+]>ClCCl.O>[O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([N:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]([C:26]4[C:27](=[O:31])[CH2:28][CH2:29][CH2:30][C:25]=4[OH:32])=[O:22])[C:12]3=[O:24])[CH:9]=[CH:10][C:2]1=2
Reactant: O=C(Cl)c1nc2ccccc2n(-c2ccc3c(c2)OCCO3)c1=O
Reactant: O=C1CCCC(=O)C1
Agent: CC(C)(O)C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCCC(O)=C1C(=O)c1nc2ccccc2n(-c2ccc3c(c2)OCCO3)c1=O
Reaction time: 3 h
Yield: 40 %

Procedure:
The 1-(2,3-dihydrobenzo[b]1,4-dioxin-6-yl)-2-oxo-1,2-dihy droquinoxaline-3-carbonyl chloride thus obtained was dissolved in dichloromethane (30 mL), and this solution was added dropwise at 0° C. over 5 minutes to a solution prepared by dissolving 4.2 g (37 mmol) of 1,3-cyclohexanedione and 6.2 g (61 mmol) of triethylamine in dichloromethane (30 mL). The reaction solution was returned to room temperature and stirred for 3 hours, and then acetone cyanohydrin (1 mL) and 6.2 g (61 mmol) of triethylamine were added thereto. The mixture was stirred for 12 hours at room temperature. After confirming the completion of the reaction, water (50 mL) was added to the reaction solution, the reaction solution was adjusted to pH 12 using a 10% aqueous solution of sodium hydroxide, and the reaction solution was separated. The aqueous layer was adjusted to pH 1 by adding 6 N hydrochloric acid, and then the aqueous layer was extracted with dichloromethane. The obtained organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue thus obtained was washed with methanol, to obtain 5.2 g (yield: 40%) of 1-(2,3-dihydrobenzo[b]1,4-dioxin-6-yl)-3-(2-hydroxy-6-oxo-1-cyclohexenecarbonyl)-quinoxalin-2(1H)-one as milky white crystals.
Reaction SMILES: COC(C)(C)C.[CH3:7][CH:8]([CH3:20])[C:9]([O:11][CH:12]([O:16][C:17]([CH3:19])=[S:18])[CH:13]([CH3:15])[CH3:14])=[O:10]>O>[CH3:7][CH:8]([CH3:20])[C:9]([O:11][C@@H:12]([O:16][C:17]([CH3:19])=[S:18])[CH:13]([CH3:14])[CH3:15])=[O:10]
Reactant: CC(=S)OC(OC(=O)C(C)C)C(C)C
Solvent: O
Solvent: COC(C)(C)C
Product: CC(=S)O[C@H](OC(=O)C(C)C)C(C)C
Yield: 70 %

Procedure:
A mixture of 990 mL methyl-tert-butylether (MTBE) and 10 mL water was stirred until a clear solution was obtained (ca. 5 hrs). To this solution was added 2-methyl-1-methylthiocarbonyloxypropyl 2-methylpropanoate (2b) (50 g) and PLE/MPEG (50 mg/1 g, 7.5 g). The resulting suspension was stirred at room temperature. The reaction was monitored by 1H-NMR using a chiral solvating agent. After 1H-NMR showed only one enantiomer remained in the reaction mixture (ca. 48 hrs), the reaction was quenched by filtration through a pad of CELITE® 545. The supernatant was washed with water, aqueous sodium bicarbonate (NaHCO3) and brine, and dried over anhydrous sodium sulfate (Na2SO4). After rotary evaporation, the title compound (12) was obtained with 70% yield. The enantiomeric excess of the S-enantiomer was 100% e.e. as determined by chiral HPLC. 1H-NMR (CDCl3): δ 0.96 (d, J=6.8 Hz, 6H), 1.16 (d, J=6.8 Hz, 3H), 1.17 (d, J=6.8 Hz, 3H), 1.98-2.07 (m, 1H), 2.32 (s, 3H), 2.56 (septet, J=7.2 Hz, 1H), 6.67 (d, J=5.6 Hz, 1H) ppm. 1H-NMR with chiral solvating agent (R)-(−)-2,2,2-trifluoro-1-(9-anthryl)ethanol: δ 0.98 (d, J=6.8 Hz, 3H), 0.99 (d, J=6.8 Hz, 3H), 1.19 (d, J=7.2 Hz, 1.5H), 1.19 (d, J=6.8 Hz, 1.5H), 1.20 (d, J=6.8 Hz, 1.5H), 1.20 (d, J=7.2 Hz, 1.5H), 2.01-2.09 (m, 1H), 2.34 1(s, 1.5H), 2.44 (s, 1.5H), 2.59 (septet, J=7.2 Hz, 0.5H), 2.59 (septet, J=6.8 Hz, 0.5H), 6.70 (d, J=5.6 Hz, 0.5H), 6.70 (d, J=5.2 Hz, 0.5H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([Cl:16])[C:3]=1[OH:17].Cl[CH2:19][CH2:20][CH2:21][CH2:22][OH:23]>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([Cl:16])[C:3]=1[O:17][CH2:19][CH2:20][CH2:21][CH2:22][OH:23]
Reactant: Oc1c(Cl)cc(OCc2ccccc2)cc1Cl
Reactant: OCCCCCl
Product: OCCCCOc1c(Cl)cc(OCc2ccccc2)cc1Cl

Procedure:
In a second series of steps, 2,6-dichloro-4-phenylmethoxyphenol (known compound) was reacted under basic conditions with, for example 4-chlorobutan-1-ol, as a means of attaching bridging group B, yielding the corresponding intermediate 4-[2,6-dichloro-4-(phenylmethoxy)phenoxy]butan-1-ol (H). Intermediate (H) was then de-protected by cleavage of the phenylmethyl moiety using hydrogenation under catalytic conditions affording the corresponding phenol intermediate (J), which was in turn reacted with, for example 1,1,1,3-tetrachloropropane under basic conditions, affording the corresponding butanol intermediate (K). Intermediate (K) was then brominated with, for example carbon tetrabromide and triphenylphosphine, providing the corresponding bromobutane intermediate (L). Intermediate (L) was in turn reacted with intermediate (G) under basic conditions, affording a compound of formula I where, for example R8 is trifluoromethyl (Compound 20). Example 3 set forth below, provides a detailed method to how Compound 20 shown in Scheme 3 was prepared.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]#[CH:26])[C:20](=[O:27])[CH2:19]1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:28]([O:32][C:33](=[O:42])[NH:34][C:35]1[CH:40]=[CH:39][N:38]=[CH:37][C:36]=1I)([CH3:31])([CH3:30])[CH3:29].C1CCN2C(=NCCC2)CC1>CN(C=O)C.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:28]([O:32][C:33]([N:34]1[C:35]2[CH:40]=[CH:39][N:38]=[CH:37][C:36]=2[CH:26]=[C:25]1[CH2:24][N:21]1[CH2:22][CH2:23][N:18]([C:16]([O:15][CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:17])[CH2:19][C:20]1=[O:27])=[O:42])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)Nc1ccncc1I
Reactant: C#CCN1CCN(C(=O)OCc2ccccc2)CC1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1c(CN2CCN(C(=O)OCc3ccccc3)CC2=O)cc2cnccc21
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 76.7 %

Procedure:
Pd(PPh3)2Cl2 (0.29 g, 0.41 mmol), CuI (0.05 g, 0.25 mmol) and triethylamine (4.6 mL, 3.29 mmol) is added to a solution of 3-oxo-4-prop-2-ynylpiperazine-1-carboxylic acid benzyl ester (2.24 g, 8.23 mmol) and (3-iodopyridin-4-yl)-carbamic acid tert-butyl ester (2.63 g, 8.23 mmol) in DMF (30 mL) at room temperature. The mixture is heated to 100° C. and stirred for 1.5 hours. The reaction mixture is then cooled to 50° C. and DBU (2.5 mL, 16.5 mmol) is added. After 30 minutes the solution is cooled to room temperature, diluted with ethyl acetate and washed with saturated ammonium chloride, water and brine. The organic layer is dried over MgSO4, filtered and concentrated in vacuo. The resulting solid is purified by column chromatography eluting with a gradient of 2% MeOH/CH2Cl2to 5% MeOH/CH2Cl2to give the product (2.93 g, 6.31 mmol) as a white solid. 1H NMR (CDCl3, 300 MHz) δ8.75 (s, 1H), 8.4 (d, 1H), 7.85 (d, 1H), 7.35 (m, 5H), 6.38 (s, 1H), 5.2 (s, 2H), 5.00 (s, 2H), 4.29 (s, 2H), 3.85 (m, 2H), 3.52 (m, 2H), 1.7 (s, 9H). Ion spray MS, [M+H]+=465.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH3:12])[CH:6]=1)(=[O:4])=[O:3].ClC1C=C(S(C)(=O)=O)C=CC=1O[CH2:17][C:18]1[C:23]([CH3:24])=[CH:22][C:21]([CH:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]2)=[CH:20][N:19]=1>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:17][C:18]2[C:23]([CH3:24])=[CH:22][C:21]([CH:25]3[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]3)=[CH:20][N:19]=2)=[C:7]([CH3:12])[CH:6]=1)(=[O:3])=[O:4]
Reactant: Cc1cc(S(C)(=O)=O)ccc1O
Reactant: Cc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)cnc1COc1ccc(S(C)(=O)=O)cc1Cl
Product: Cc1cc(S(C)(=O)=O)ccc1OCc1ncc(C2CCN(C(=O)OC(C)(C)C)CC2)cc1C
Yield: 30 %

Procedure:
The title compound was prepared from tert-butyl 4-[(2-hydroxymethyl)-3-methylpyridin-5-yl]piperidine-1-carboxylate (Example 80 (3)) (69 mg, 0.225 mmol) and 4-methanesulfonyl-2-methylphenol (48 mg, 0.260 mmol) following a procedure analogous to that in Example 1(3) and (4) as a pale yellow amorphous (37 mg, yield 30%).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH2:6][SH:7])=[O:5].[H-].[Na+].Cl[C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH:17]=[N:18][N:19]=2)[N:16]=1.O>C(O)C>[CH2:2]([O:3][C:4]([CH2:6][S:7][C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH:17]=[N:18][N:19]=2)[N:16]=1)=[O:5])[CH3:1]
Reactant: Clc1ccc2nncn2n1
Reactant: CCOC(=O)CS
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CSc1ccc2nncn2n1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Ethyl thioglycollate, 1.2 g, is dissolved in 30 ml of dry ethanol, to which 400 mg of sodium hydride (60% in an oil) is added under cooling with ice water and the mixture stirred for 10 minutes. Then 1.55 g of 6-chloro-[1,2,4]triazolo[4,3-b]pyridazine is added and stirred at room temperature for 67 hours. The reaction mixture is treated with water and extracted twice with chloroform. The combined extract is washed with saline and dried over anhydrous potassium carbonate. The solvent is evaporated under reduced pressure, and the residue is purified by column chromatogaraphy (on 40 g of silica gel, developed and eluted with ethyl acetate), to give 1.93 g of the desired compound as colorless crystals of m.p. 130°-133° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][C:4]=1[C:13]([F:16])([F:15])[F:14])[CH3:2].[Br:17][C:18]1[C:23]([NH2:24])=[CH:22][C:21]([Cl:25])=[CH:20][N:19]=1>N1C=CC=CC=1>[Br:17][C:18]1[C:23]([NH:24][S:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[C:4]([C:13]([F:16])([F:15])[F:14])[CH:5]=2)(=[O:11])=[O:10])=[CH:22][C:21]([Cl:25])=[CH:20][N:19]=1
Reactant: CCc1ccc(S(=O)(=O)Cl)cc1C(F)(F)F
Reactant: Nc1cc(Cl)cnc1Br
Solvent: c1ccncc1
Product: CCc1ccc(S(=O)(=O)Nc2cc(Cl)cnc2Br)cc1C(F)(F)F

Procedure:
Prepared from 1.04 g (3.82 mmol) of 4-ethyl-3-trifluoromethyl-benzenesulfonyl chloride and 0.87 g (4.20 mmol) of 2-bromo-5-chloro-pyridin-3-ylamine in 3 mL pyridine using procedure x. Yield: 0.45 g of a white solid. LC-MSD, m/z for C14H11BrClF3N2O2S [M+H]+=442.9, 444.9, 446.9
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:9])[CH:5]=[N:6][C:7]=1[Cl:8].C(N(CC)CC)C.[C:17](Cl)(=[O:19])[CH3:18]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:17](=[O:19])[CH3:18])[CH:5]=[N:6][C:7]=1[Cl:8]
Reactant: Nc1cnc(Cl)c(Cl)c1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1cnc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 5,6-dichloropyridin-3-amine (commercially available) and triethyl amine (3 eq) in CH2Cl2 (0.2 M) at 0° C. was added acetyl chloride (2 eq). After stirring at room temperature overnight the reaction mixture was concentrated under vacuum and the resulting crude residue was purified by chromatography (silica gel, 20-50% EtOAc in hexanes) to afford N-(5,6-dichloropyridin-3-yl)acetamide.
Reaction SMILES: O[CH2:2][C:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH:4]=1.S(Cl)(Cl)=O.C(=O)([O-])[O-].[K+].[K+].Cl.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH2:31][CH2:32][NH:33][CH2:34][CH:35]=2)=[CH:26][CH:25]=1>O>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH2:35][CH2:34][N:33]([CH2:2][C:3]3[C:11]4[C:6](=[N:7][CH:8]=[CH:9][CH:10]=4)[O:5][CH:4]=3)[CH2:32][CH:31]=2)=[CH:26][CH:25]=1
Reactant: OCc1coc2ncccc12
Reactant: Clc1ccc(C2=CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: O
Product: Clc1ccc(C2=CCN(Cc3coc4ncccc34)CC2)cc1
Temperature: 25 °C
Yield: 53.5 %

Procedure:
3-Hydroxymethylfuro[2,3-b]pyridine (101.5 mg, 0.681 mmol) was treated with thionyl chloride (2 ml) and the solution stirred at room temperature for an hour. The mixture was concentrated in vacuo, toluene added (5 ml) and evaporated to dryness. The residue was dissolved in anhydrous dimethylformamide (5 ml), potassium carbonate (0.47 g, 3.40 mmol) and 4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (173.3 mg, 0.753 mmol) were added and the mixture stirred at room temperature, under nitrogen, overnight (19 hours). The reaction mixture was poured into water (50 ml) and extracted with ethyl acetate (2×25 ml). The extracts were washed with brine (25 ml), combined, dried (MgSO4) and the residue after evaporation purified by flash chromatography, eluting with 1:1 then 2:1 ethyl acetate/hexane, to afford the title compound (118.3 mg, 54%) as a pale yellow solid. Recrystallisation from ethyl acetate/hexane gave yellow plates, m.p. 115.5°-116.5° C.; (Found: C, 70.06; H, 5.19; N, 8.52. C19H17ClN2O requires C, 70.26; H, 5.28; N, 8.62%); δH (CDCl3) 2.54 (2H, br s, tetrahydropyridinyl CH2), 2.78 (2H, t, J 5.6 Hz, tetrahydropyridinyl CH2), 3.23 (2H, m, tetrahydropyridinyl CH2), 3.78 (2H, s, ArCH2N), 6.06 (1H, t, J 3.5 Hz, tetrahydropyridinyl CH), 7.21-7.32 (5H, m, ArH), 7.68 (1H, s, 2-H), 8.12 (1H, dd, J 7.6, 1.7 Hz, 4-H), 8.34 (1H, dd, J 4.8, 1.7 Hz, 6-H); m/z (ES+) 325/327 (M+1)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([N:16]3[CH2:19][CH:18]([C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[CH2:17]3)=[O:15])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[CH:26]1([CH:31]=O)[CH2:30][CH2:29][CH2:28][CH2:27]1.C(O)(=O)C.C([BH3-])#N>CO>[CH:26]1([CH2:31][N:1]2[CH2:6][CH2:5][CH:4]([C:7]3[CH:8]=[CH:9][C:10]([NH:13][C:14]([N:16]4[CH2:19][CH:18]([C:20]5[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=5)[CH2:17]4)=[O:15])=[CH:11][CH:12]=3)[CH2:3][CH2:2]2)[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: O=C(Nc1ccc(C2CCNCC2)cc1)N1CC(c2cccnc2)C1
Reactant: O=CC1CCCC1
Agent: [BH3-]C#N
Solvent: CO
Solvent: CC(=O)O
Product: O=C(Nc1ccc(C2CCN(CC3CCCC3)CC2)cc1)N1CC(c2cccnc2)C1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
In a 20 mL vial was added N-(4-(piperidin-4-yl)phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide, bistrifluoroacetic acid (67 mg, 0.12 mmol) dissolved in methanol, (2.0 mL) followed by the addition of cyclopentanecarbaldehyde (13 mg, 0.13 mmol) dissolved in methanol (0.45 mL), followed by the addition of acetic acid neat (68 μL, 1.2 mmol). The reaction mixture was shaken for 1 hour at 70° C. After that, MP-cyanoborohydride (272 mg, 2-3 mmol/g) resin was added and the resulting mixture was shaken at 70° C. overnight. The reaction mixture was filtered and concentrated to dryness. The residues were dissolved in 1:1 DMSO/methanol and purified by reverse phase chromoatography. 1H NMR (500 MHz, pyridine/d5-D2O Temp=90° C.) δ ppm 8.55 (dd, J=4.73, 1.68 Hz, 1 H) 8.40-8.48 (m, 1 H) 7.75 (d, J=8.54 Hz, 2 H) 7.56-7.61 (m, 1 H) 7.21 (d, J=8.54 Hz, 2 H) 7.16-7.19 (m, 1 H) 4.46 (t, J=8.24 Hz, 2 H) 4.10 (dd, J=8.09, 5.95 Hz, 2 H) 3.64-3.74 (m, 1 H) 3.28 (d, 2 H) 2.39-2.66 (m, 5 H) 2.02-2.26 (m, 3 H) 1.75-1.88 (m, 4 H) 1.40-1.59 (m, 4 H) 1.20-1.31 (m, 2 H); (ESI) m/z 419 (M+H).
Reaction SMILES: [CH3:1][C:2]1([C:16]([O:18][CH3:19])=[O:17])[CH2:6][C:5](=[O:7])[N:4]([C@@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:9])[CH2:3]1.[CH:20]([N-]C(C)C)(C)[CH3:21].[Li+].C(C1C=CC=CC=1)C.C(I)C>O1CCCC1.CCCCCCC.CN(C)P(=O)(N(C)C)N(C)C>[CH2:20]([CH:6]1[C:5](=[O:7])[N:4]([C@@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:9])[CH2:3][C:2]1([C:16]([O:18][CH3:19])=[O:17])[CH3:1])[CH3:21]
Reactant: COC(=O)C1(C)CC(=O)N([C@H](C)c2ccccc2)C1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: CCC1C(=O)N([C@H](C)c2ccccc2)CC1(C)C(=O)OC
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of the methyl 3-methyl-5-oxo-1-[(R)-1-phenylethyl]pyrrolidin-3-yl-carboxylate (stereoisomer A) produced in Reference Example 31 (19.86 g, 76.0 mmol) and hexamethylphosphoric triamide (30 mL) in tetrahydrofuran (300 mL), a solution of lithium diisopropyl amide in heptane, tetrahydrofuran, and ethylbenzene (1.8M, 63.3 mL, 113.9 mmol) was gradually added in 15 minutes at −78° C. After stirring the mixture at −78° C. for 30 minutes, ethyl iodide (12.2 mL, 152.0 mmol) was added dropwise at the same temperature in 10 minutes. After stirring at −78° C. for 1 hour, the mixture was quenched by adding saturated aqueous solution of ammonium chloride (100 mL). The reaction mixture was extracted with ethyl acetate (300 mL), and the organic layer was washed with water (200 mL×2) and saturated aqueous solution of sodium chloride (200 mL). After drying with anhydrous sodium sulfate, the dessicating agent was removed by filtration, and the solvent was removed by distillation under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane : ethyl acetate, 90:10→85:15→80:20) to obtain 10.63 g of the title compound (a mixture of stereoisomers of position 4, 36.7 mmol, 48%) as a pale yellow oil.
Reaction SMILES: [OH-].[Na+].[NH2:3][S:4]([CH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH3:45])[CH2:12][CH2:13][N:14]([CH3:44])[C@@H:15]1[CH2:22][N:21]2[C:23]3[CH:24]=[C:25]([C:36]([O:38]C)=[O:37])[CH:26]=[CH:27][C:28]=3[C:29]([CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)=[C:20]2[C:19]2[CH:40]=[CH:41][CH:42]=[CH:43][C:18]=2[O:17][CH2:16]1)(=[O:6])=[O:5]>CO>[NH2:3][S:4]([CH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH3:45])[CH2:12][CH2:13][N:14]([CH3:44])[C@@H:15]1[CH2:22][N:21]2[C:23]3[CH:24]=[C:25]([C:36]([OH:38])=[O:37])[CH:26]=[CH:27][C:28]=3[C:29]([CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)=[C:20]2[C:19]2[CH:40]=[CH:41][CH:42]=[CH:43][C:18]=2[O:17][CH2:16]1)(=[O:5])=[O:6]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@@H](N(C)CCN(C)CCCCS(N)(=O)=O)COc1ccccc1-3
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(CCCCS(N)(=O)=O)CCN(C)[C@H]1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)O)cc3n2C1
Temperature: 60 °C
Yield: 37 %

Procedure:
Sodium hydroxide (1N, 5 eq.) was added to a solution of methyl (7R)-7-[{2-[[4-(aminosulfonyl)butyl](methyl)amino]ethyl}(methyl)amino]-1 4-cyclohexyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (0.03 M) in MeOH. The reaction was heated at 60° C. for 1 h prior to introducing further sodium hydroxide (2 N, 5 eq.) and continuing heating for 30 min. The reaction mixture was concentrated in vacuo, redissolved in DMSO and purified by RP-HPLC (WATERS XTERRA column, C18, 5um, 19×100 mm. Mobile phase: MeCN/H2O buffered with 0.1% TFA). Fractions containing the pure compound were combined and freeze dried to afford the title compound (37%) as a white powder. (ES+) m/z 597 (M+H)+.
Reaction SMILES: [ClH:1].[CH3:2][N:3]1[CH2:8][CH2:7][CH:6]([N:9]2[CH2:14][CH2:13][N:12]([S:15]([CH2:18][CH2:19][CH2:20][C@@H:21]3[CH2:25][CH2:24][CH2:23][N:22]3C(OC(C)(C)C)=O)(=[O:17])=[O:16])[CH2:11][CH2:10]2)[CH2:5][CH2:4]1.C(OCC)(=O)C.C(OCC)C>CO>[ClH:1].[CH3:2][N:3]1[CH2:8][CH2:7][CH:6]([N:9]2[CH2:14][CH2:13][N:12]([S:15]([CH2:18][CH2:19][CH2:20][C@@H:21]3[CH2:25][CH2:24][CH2:23][NH:22]3)(=[O:17])=[O:16])[CH2:11][CH2:10]2)[CH2:5][CH2:4]1
Reactant: CN1CCC(N2CCN(S(=O)(=O)CCC[C@@H]3CCCN3C(=O)OC(C)(C)C)CC2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Solvent: CCOC(C)=O
Product: CN1CCC(N2CCN(S(=O)(=O)CCC[C@@H]3CCCN3)CC2)CC1
Reaction time: 1 h

Procedure:
Hydrogen chloride in methanol (5 ml, 1.25 mol/l) was added to (S)-tert-butyl 2-(3-(4-(1-methylpiperidin-4-yl)piperazin-1-ylsulfonyl)propyl)pyrrolidine-1-carboxylate (0.27 g, 0.589 mmol) and the mixture was refluxed. After 1 h ethyl acetate (10 ml) and diethyl ether (20 ml) were added to the suspension, the mixture was stirred in an ice bath for 1 h and the precipitate was filtered out with suction, washed with diethyl ether and dried in vacuo. Yield: 0.22 g (79%)
Reaction SMILES: [O:1]=[C:2]1[O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]([OH:6])=[C:3]1[OH:4].C(=O)([O-])O.[Na+].O.[CH2:19]1[O:21][CH:20]1[CH2:22][OH:23]>CO>[CH2:19]([O:4][C:3]1[C:2]([O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]=1[OH:6])=[O:1])[CH:20]([CH2:22][OH:23])[OH:21]
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Reactant: OCC1CO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C1O[C@H]([C@@H](O)CO)C(O)=C1OCC(O)CO
Temperature: 60 °C
Reaction time: 5 h
Yield: 8.5 %

Procedure:
Under an argon atmosphere, L-ascorbic acid (10.0 g) and sodium hydrogen carbonate (9.54 g) were added to water and the resultant mixture was stirred at room temperature for 30 minutes, then, glycidol (8.41 g) was added thereto. Thereafter, the mixture was heated up to 60° C. and stirred for 5 hours. Thereto, methanol was added and filtration was performed. The filtrate was concentrated under reduced pressure, and 19.0 g of the resultant residue was subjected to silica gel column chromatography. Elution was performed with chloroform/methanol/water(volume ratio:6/4/1), and concentration was performed under reduced pressure to obtain 2-O-glyceryl ascorbic acid (1.21 g).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:7]2[CH2:8][NH:9][CH2:10][CH2:11][N:6]2[N:5]=1)([O-:3])=[O:2].BrC1C=C(NC2C=C3CN([CH:31]4[CH2:34][O:33][CH2:32]4)CCN3N=2)C(=O)N(C)C=1.C([O-])([O-])=O.[K+].[K+].BrCCOC>C(#N)C>[CH3:34][O:33][CH2:32][CH2:31][N:9]1[CH2:10][CH2:11][N:6]2[N:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[C:7]2[CH2:8]1
Reactant: O=[N+]([O-])c1cc2n(n1)CCNC2
Reactant: Cn1cc(Br)cc(Nc2cc3n(n2)CCN(C2COC2)C3)c1=O
Agent: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCCN1CCn2nc([N+](=O)[O-])cc2C1
Temperature: 80 °C

Procedure:
To a solution of 2-nitro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (190 mg, 1.13 mmol) 125i in acetonitrile (10 mL) was added K2CO3 (311.9 mg, 2.26 mmol) and 1-bromo-2-methoxyethane (188.3 mg, 1.36 mmol). The reaction mixture was heated at 80° C. for 17 h under microwave irradiation. Analysis of reaction mixture by LCMS showed complete conversion to the desired product. The mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure to afford 304a as a white solid (230 mg, 90%), which was used in the next step without further purification. MS-ESI: [M+H]+ 227.0