Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12](OC(C)(C)C)=O)[CH2:7]1)=[O:5])[CH3:2].[CH:19]([N-]C(C)C)(C)[CH3:20].[Li+].O1CCCC1.BrCCCCl>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]12[CH2:7][N:8]([CH2:9][CH2:10][CH2:11]1)[CH2:12][CH2:20][CH2:19]2)=[O:5])[CH3:2]
Reactant: CC(C)[N-]C(C)C
Reactant: CCOC(=O)C1CCCN(C(=O)OC(C)(C)C)C1
Agent: ClCCCBr
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C12CCCN(CCC1)C2
Temperature: -35 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
A cooled (-50° C.) solution of 1,3-piperidinedicarboxylic acid 1-(1,1-dimethylethyl) 3-ethyl ester (12.9 g, 50 mmol) in anhydrous tetrahydrofuran (60 mL) was treated (via syringe) with 1.15N lithium diisopropylamide/tetrahydorfuran (52 mmol), stirred for one hour at -15°±5° C., cooled (-35° C.), treated with 1-bromo-3-chloropropane (10.2 g, 65 mmol), warmed to room temperature over one hour, and stirred for 30 minutes. Most of the solvent was removed in vacuo, replaced with ether, and the organic solution was washed with saturated sodium bicarbonate (150 mL). The aqueous solution was extracted with ether (2×50 mL), and the combined organic solution was dried (MgSO4), concentrated in vacuo, and passed through a short column of alumina (eluted with methylene chloride). The concentrated filtrate was dissolved in anhydrous methylene chloride (25 mL), cooled (10° C.), and treated dropwise with trifluoroacetic acid (15 mL). The solution was stirred for one hour at room temperature, 15 minutes at 45° C., and concentrated in vacuo. The residue was partitioned between 1.25N sodium carbonate (75 mL) and methylene chloride (100 mL), and the organic layer was separated. The aqueous solution was extracted with methylene chloride (2×50 mL), and the combined organic solution was dried (Na2SO4), concentrated in vacuo, taken up in warm hexane, treated with a little charcoal, and filtered. The filtrate was concentrated in vacuo and the residue was distilled (bp 0.6 83°-85° C.) to give 7.2 g (73%) of the product.
Reaction SMILES: [CH3:1][C:2]1([CH3:40])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:19][C:18](=[O:20])[NH:17][C:16](=[O:21])[CH2:15]3)[CH:11]=[CH:10][C:9]=2[NH:22][C:23]([C:25]2[N:26](COCC[Si](C)(C)C)[CH:27]=[C:28]([C:30]#[N:31])[N:29]=2)=[O:24])=[CH:4][CH2:3]1.CO.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]1([CH3:40])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:15][C:16](=[O:21])[NH:17][C:18](=[O:20])[CH2:19]3)[CH:11]=[CH:10][C:9]=2[NH:22][C:23]([C:25]2[NH:26][CH:27]=[C:28]([C:30]#[N:31])[N:29]=2)=[O:24])=[CH:4][CH2:3]1
Reactant: CC1(C)CC=C(c2cc(C3CC(=O)NC(=O)C3)ccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CC1(C)CC=C(c2cc(C3CC(=O)NC(=O)C3)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Yield: 63.7 %

Procedure:
A solution of 190 mg (0.338 mmol) of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid [2-(4,4-dimethyl-cyclohex-1-enyl)-4-(2,6-dioxo-piperidin-4-yl)-phenyl]-amide (as prepared in the previous step) in CH2Cl2 (10 mL) was treated with MeOH (200 μL) and TFA (3 mL) at RT for 1.5 h. MeOH (30 mL) was added, the mixture was concentrated to half volume, MeOH (15 mL) was added, and the solvents were removed completely in vacuo at <35° C. Silica gel chromatography of the residue with 25-75% EtOAc-hexane afforded 92.9 mg (64%) of the title compound as a white solid: 1H-NMR (CD3OD; 400 MHz): δ 8.22 (d, 1H, J=8.4 Hz), 8.02 (s, 1H), 7.26 (dd, 1H, J=8.4, 2.4 Hz), 7.18 (d, 1H, J=2.4 Hz), 5.79-5.75 (m, 1H), 3.52-3.42 (m, 1H), 2.93-2.76 (m, 4H), 2.37-2.30 (m, 2H), 2.12-2.07 (m, 2H), 1.62 (t, 2H, J=5.6 Hz), 1.10 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C24H25N5O3, 432.2 (M+H). found 432.1.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)[N:3]=1.[F:16][C@@H:17]1[C@@H:21]([CH2:22][OH:23])[O:20][C@@H:19](N2C=CC(=O)NC2=O)[CH2:18]1.[N-]=[N+]=[N-].[K+].[C@@H]1(N2C=C(C)C(=O)NC2=O)O[C@H](CO)[C@@H](O)C1>P([O-])([O-])([O-])=O.[K+].[K+].[K+].CO>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:19]2[O:20][C@H:21]([CH2:22][OH:23])[C@@H:17]([F:16])[CH2:18]2)=[C:4]([O:11][CH2:12][CH:13]2[CH2:14][CH2:15]2)[N:3]=1
Reactant: Nc1nc(OCC2CC2)c2nc[nH]c2n1
Reactant: O=c1ccn([C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]1
Agent: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Nc1nc(OCC2CC2)c2ncn([C@H]3C[C@H](F)[C@@H](CO)O3)c2n1
Temperature: 45 °C
Reaction time: 96 h
Yield: 58.2 %

Procedure:
2-Amino-6-(cyclopropylmethoxy)-9H-purine (0.53 g, 2.6 mmoles) and 2',3'-dideoxy-3'-fluorouridine (0.50 g, 2.2 mmoles) were suspended in 50 ml 10 mM potassium phosphate buffer, pH 7.0, containing 0.04% potassium azide. Purine nucleoside phosphorylase (1120 I.U.) and thymidine phosphorylase (10,000 I.U.) (Krenitsky, et al., Biochemistry, 20, 3615, 1981 and U.S. Pat. No. 4,381,344) immobilized on DEAE cellulose was added to the reaction and the suspension was stirred at 45° C. After 4 days, 182 ml MeOH was added to the reaction. The reaction was applied to a column containing AG1-X2 (OH-- form, 2.5×10 cm) and eluted with MeOH. Fractions containing product were pooled, concentrated, and flash chromatographed on silica gel (2.5×20 cm) with dichloromethane:acetone (9:1). Solvent was removed and lyophilization yielded 0.414 g of 2-amino-6-(cyclopropylmethoxy)-9-(2,3-dideoxy-3-fluoro-β-D-erythro-pentofuranosyl)-9H-purine (57%): mp 80°-81° C.; TLC Rf 0.75 (silica gel, MeCN:15N NH4OH:H2O/85:5:10); [α]D20 -19.0 (c=0.5, DMF); UV λmax (ε×10-3) at pH 7, 247 (9.7); at pH 13, 247 (9.3), 1H NMR (200 MHz, DMSO-d6) δ8.13 (s, 1H, H8), 6.47 (b, 2H, NH2), 6.27 (dd, 1H, H1', J=9.3 Hz, J=5.6 Hz), 5.43 (dd, 1H, H3', J=54 Hz, J=4.2 Hz), 5.24 (t, 1H, OH5', J=5.6 Hz), 4.26 (d, 2H, OCH2, J=7.2 Hz), 4.11-4.27 (m, 1H, H4'), 3.59 (t, 2H, H5' and H5", J=5.2 Hz), and 2.62-3.01 (m, 2H, H2' and H2"), and 1.25-1.35, 0.55-0.64, and 0.35-0.40 (m, 5H, cyclopropyl group); MS (ci) 324 (M+1), 304 (M-F), 206 (MH2 --C5H8FO2).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]([NH:30][C@@H:31]([CH2:34][CH3:35])[CH2:32][OH:33])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCCCCC>C(Cl)Cl.CCOCC>[C:11]([NH:30][C@@H:31]([CH2:34][CH3:35])[CH:32]=[O:33])([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC[C@@H](CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCOCC
Solvent: ClCCl
Product: CC[C@@H](C=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: -45 °C
Reaction time: 1 h

Procedure:
To a stirred solution of DMSO (2.4 mL, 2.8 eq, 33.82 mmol) in DCM (30 mL) under an argon atmosphere at −45° C., was added oxalyl chloride (2 M in DCM, 8.45 mL, 1.40 eq, 16.9 mmol), dropwise. The reaction mixture was stirred at −45° C. for 1 h, after which time a solution of (S)-2-(trityl-amino)-butan-1-ol (4 g, 1 eq, 12.07 mmol) in DCM (30 mL) was added dropwise with stirring. The reaction mixture was stirred at this temperature for 3 h, when TLC (hexane:ether; 80:20) indicated that the reaction had gone to completion. To the reaction mixture was added a solution of TEA (8.4 mL, 5 eq, 60.27 mmol) in DCM (30 mL), and the solution allowed to warm to room temperature over 16 h. The reaction mixture was diluted with more DCM (100 mL) and washed with water (250 mL). The aqueous phase was extracted with DCM (3×50 mL), and the combined organic phase washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was dissolved in ether (30 mL), the solid precipitate removed by filtration and the filtrate was evaporated in vacuo. The residue was dissolved in hexane (50 mL), the solid precipitate removed by filtration and the filtrate was evaporated in vacuo to afford the title compound as a light yellow oil. Yield: 3.64 g (91%). 1H-NMR (d6-DMSO, 250 MHz): δ 0.77 (t, 3H, J=7.42 Hz, —NHCH (CH2CH3)CHO), 1.37-1.59 (m, 2H, —NHCH(CH2CH3)CHO), 2.93 (m, 1H, —NHCH(CH2CH3)CHO), 3.62 (d, 1H, J=5.84 Hz, —NHCH(CH2CH3)CHO), 7.16-7.46 (m, 15H, 3×Ph), 8.77 (d, 1H, J=3.00 Hz, —NHCH(CH2CH3)CHO).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17](Cl)[CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:22][O:23][CH2:24][CH:25]([NH2:28])[CH2:26][CH3:27].ClCCl>CN1CCCC1=O>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:28][CH:25]([CH2:24][O:23][CH3:22])[CH2:26][CH3:27])[CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1cc(Nc2nccc(-c3ccnc(Cl)c3)n2)ccn1
Reactant: CCC(N)COC
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: CCC(COC)Nc1cc(-c2ccnc(Nc3ccnc(Cl)c3)n2)ccn1
Yield: 199 %

Procedure:
300 mg of N,4-bis(2-chloropyridin-4-yl)pyrimidin-2-amine (0.94 mmol), 486 mg of 1-methoxybutan-2-amine (4.71 mmol), were heated at 240° C. for 90 minutes under micro-waves irradiation in 0.6 ml of 1-Methyl-2-pyrrolidinone. After cooling, the reaction mixture was poured into 10 ml of dichloromethane, washed twice with 5 ml of water. After drying over magnesium sulfate, filtration and concentration in vacuo, the crude product was chromatographed on silica (ethyl acetate/heptane) to yield 0.72 g of N-(2-chloropyridin-4-yl)-4-(2-{[1-(methoxymethyl)propyl]amino}pyridin-4-yl)pyrimidin-2-amine (yield=19%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1)[C:6]([CH:24]([OH:27])[CH2:25][CH3:26])=[C:5]2[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C1COCC1.C(OC(C)C)(C)C>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([S:20]([CH3:23])(=[O:21])=[O:22])=[CH:18][CH:19]=1)[C:6]([C:24](=[O:27])[CH2:25][CH3:26])=[C:5]2[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CCC(O)c1c(-c2ccccc2)c2cc(Cl)ccc2c(=O)n1Cc1ccc(S(C)(=O)=O)cc1
Solvent: CC(C)OC(C)C
Solvent: C1CCOC1
Product: CCC(=O)c1c(-c2ccccc2)c2cc(Cl)ccc2c(=O)n1Cc1ccc(S(C)(=O)=O)cc1

Procedure:
In the same manner as in Example 311, the title compound was synthesized using 6-chloro-3-(1-hydroxypropyl)-2-(4-methanesulfonylbenzyl)-4-phenyl-2H-isoquinolin-1-one. Crystals (THF-diisopropyl ether).
Reaction SMILES: [C:1]1([C:7]2([C:17]#[N:18])[CH2:16][CH2:15][C:10]3([O:14][CH2:13][CH2:12][O:11]3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[C:1]1([C:7]2([CH2:17][NH2:18])[CH2:8][CH2:9][C:10]3([O:14][CH2:13][CH2:12][O:11]3)[CH2:15][CH2:16]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CC1(c2ccccc2)CCC2(CC1)OCCO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: NCC1(c2ccccc2)CCC2(CC1)OCCO2
Reaction time: 3 h

Procedure:
A solution of the title compound of step 3 (10.0 g, 41.1 mmol) in dry THF (70 mL) was slowly added to a mixture of LiAlH4 (1.87 g, 49.3 mmol) in dry THF (25 mL) in a protective gas. The mixture was then stirred for 3 h with reflux. After the reaction mixture had cooled, a solution of water (1.87 mL, 104 mmol) diluted with a little THF was added in drops with ice cooling and subsequently stirred for 10 min. 15% aqueous NaOH (1.87 mL, 8.17 mmol) diluted with a little THF was then added in drops and water (5.6 mL) was then added again. The precipitate formed was filtered over diatomaceous earth and the solvent removed in a vacuum. The amine remained as residue.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:17]=[C:16]3[C:11]([CH2:12][CH2:13][CH2:14][C:15]3=O)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:19][C:20]1[CH:21]=[C:22]([CH:31]=[CH:32][CH:33]=1)[O:23][CH2:24][C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:17]=[C:16]3[C:11]([CH2:12][CH2:13][CH2:14][C:15]3=[N:19][C:20]3[CH:21]=[C:22]([CH:31]=[CH:32][CH:33]=3)[O:23][CH2:24][C:25]([O:27][CH:28]([CH3:29])[CH3:30])=[O:26])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCCc2ccc(-c3cccc(F)c3)cc21
Reactant: CC(C)OC(=O)COc1cccc(N)c1
Solvent: Cc1ccccc1
Product: CC(C)OC(=O)COc1cccc(N=C2CCCc3ccc(-c4cccc(F)c4)cc32)c1
Temperature: 120 °C
Reaction time: 16 h
Yield: 8 %

Procedure:
Approximately forty oven dried 3 Å molecular sieves were added to a solution of 7-(3-fluorophenyl)-3,4-dihydronaphthalen-1(2H)-one (174 mg, 0.724 mmol) and isopropyl 2-(3-aminophenoxyl)acetate (644 mg, 3.08 mmol) in toluene (15 mL) at 25° C. The reaction was heated in an 120° C. oil bath and allowed to stir overnight for approximately 16 hours. The reaction was cooled to room temperature and concentrated. The resulting crude residue was purified by combiflash (4 g column, hexanes→100% ethyl acetate/hexanes, gradient) to afford 25 mg (4%) of isopropyl 2-(3-((7-(3-fluorophenyl)-3,4-dihydronaphthalen-1(2H)-ylidene)amino)phenoxy)acetate.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][OH:7].[CH2:8]1[CH2:12][O:11][CH2:10]C1>C(C1OC1)Cl.[OH-].[Na+].CCCC[N+](CCCC)(CCCC)CCCC.[Br-]>[CH2:8]([O:7][CH2:6][C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)[CH:12]1[O:11][CH2:10]1
Reactant: OCc1ccco1
Reactant: C1CCOC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCC1CO1
Product: c1coc(COCC2CO2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
With reference to the chemical reaction formula 7, epichlorohydrin (23.5 mL, 300 mmol), NaOH aqueous solution (22.0 g, 275 mmol) of 50% and TBABr (0.644 g, 2 mmol) as a catalyst are put into a 100 mL round-bottom flask one after another, and intensely magnetic stirred. 2-furanmethanol (9.81 g, 100 mmol) diluted in THF 30 mL is then slowly added by drops into the flask at a room temperature, and then intensely stirred for two hours at a room temperature. Afterwards the reaction liquid is moved to a separatory funnel, into which are added distilled water and EtOAc 200 ml each to wash an organic layer twice and washed with saturated NaCI aqueous solution. After moisture in the funnel is removed by MgSO4, the residue having been filtered and vacuum evaporated is separated to flash chromatography (hexanes:EtOAc=1:1→1:2) to obtain a furfuryl glycidyl ether (13.3 g, 86.3 mmol, 86% of yield) in the form of transparent oil. The data of 1H and 13C-NMR referring to that is as below.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1.[Br:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1>>[Br:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH:1][C:2]2[CH:7]=[CH:6][C:5]([S:8][C:9]3[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=3)=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=2)=[CH:22][CH:21]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: Nc1ccc(Sc2ccc(O)cc2)c([N+](=O)[O-])c1
Product: O=[N+]([O-])c1cc(NCc2ccc(Br)cc2)ccc1Sc1ccc(O)cc1
Yield: 73 %

Procedure:
A solution of the product from Example 84A and 4-Bromobenzaldehyde were reacted according to the procedure from Example 84B substituting 4-Bromobenzaldehyde for the product from Example 84A to provide the crude product which was purified by silica gel chromatography eluting with 2% methanol in methylene chloride to provide the title compound as a yellow solid (0.11 g, 73%).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].C([O-])([O-])=O.[Ca+2]>OCC(CO)O>[OH:8][C:7]1[C@@H:5]([C@@H:3]([OH:4])[CH2:2][OH:1])[O:6][C:11](=[O:12])[C:9]=1[OH:10]
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: OCC(O)CO
Product: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Reaction time: 45 h

Procedure:
3 ml of the seed culture were transferred into 500 ml Erlenmeyer flasks containing 50 ml of the production medium containing 8.0% D-sorbitol, 5.0% baker's yeast, 0.05% glycerol, 0.25% MgSO4.7H2O, 3.0% corn steep liquor, 1.5% CaCO3 and 0.15% antifoam. The cultivation was carried out at 30° C. with 180 rpm for 45 h on a rotary shaker. Then, the concentration of vitamin C produced was measured by HPLC at a wavelength of 264 nm with the system which was composed of a UV detector (TOSOH UV8000; TOSOH Co., Kyobashi 3-2-4, Chuo-ku, Tokyo, Japan), a dualpump (TOSOH CCPE; TOSOH Co.), an integrator (Shimadzu C-R6A; Shimadzu Co., Kuwahara-cho 1, Nishinokyo, Chukyo-ku, Kyoto, Japan) and a column (YMC-Pack polyamine II; YMC, Inc., 3233 Burnt Mill Drive Wilimington, N.C. 28403, USA), As a result, 118.1 mg/L of vitamin C was produced.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[C:18][C:19]([C:22]4[N:23]=[CH:24][N:25](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[CH:26]=4)([OH:21])[CH3:20])[CH:15]=3)[C:10]([CH3:46])=[N:9]2)[CH:5]=[CH:4][N:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[C:18][C:19]([C:22]4[N:23]=[CH:24][NH:25][CH:26]=4)([OH:21])[CH3:20])[CH:15]=3)[C:10]([CH3:46])=[N:9]2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1nn(-c2ccnc(N)n2)c2cc(C#CC(C)(O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nn(-c2ccnc(N)n2)c2cc(C#CC(C)(O)c3c[nH]cn3)ccc12
Reaction time: 0.5 h

Procedure:
To a solution of 4-[1-(2-aminopyrimidin-4-yl)-3-methylindazol-6-yl]-2-[1-(triphenylmethyl)imidazol-4-yl]but-3-yn-2-ol (45 mg, 0.07 mmol) in DCM (2 ml) was added trifluoroacetic acid (0.4 ml). The reaction was allowed to stand at RT for 0.5 hr and then concentrated in vacuo. DCM (5 mL) and saturated aqueous sodium bicarbonate (2 mL) were added and the organics extracted (4×5 mL DCM extractions). The combined extracts were dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography (Isolute, 0-10% methanol gradient in DCM) to surrender the title compound as a pale brown solid: 1H NMR (250 MHz, MeOD) delta 1.92 (3H, s), 2.58 (3H, s), 7.28-7.14 (2H, m), 7.39 (1H, dd, J=8.2, 1.2 Hz), 7.82-7.64 (2H, m), 8.19 (1H, d, J=5.8 Hz), 8.98 (1H, s); LC-MS: m/z=+360.05 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([CH2:12][N:13]2[CH:17]=[C:16]([C:18]3[CH:19]=[N:20][C:21]4[C:26]([CH:27]=3)=[CH:25][C:24]([CH2:28][C:29]3[N:33]5[N:34]=[C:35]([CH3:38])[CH:36]=[CH:37][C:32]5=[N:31][N:30]=3)=[CH:23][CH:22]=4)[CH:15]=[N:14]2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH:8]1[CH2:11][CH:10]([CH2:12][N:13]2[CH:17]=[C:16]([C:18]3[CH:19]=[N:20][C:21]4[C:26]([CH:27]=3)=[CH:25][C:24]([CH2:28][C:29]3[N:33]5[N:34]=[C:35]([CH3:38])[CH:36]=[CH:37][C:32]5=[N:31][N:30]=3)=[CH:23][CH:22]=4)[CH:15]=[N:14]2)[CH2:9]1
Reactant: Cc1ccc2nnc(Cc3ccc4ncc(-c5cnn(CC6CN(C(=O)OC(C)(C)C)C6)c5)cc4c3)n2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2nnc(Cc3ccc4ncc(-c5cnn(CC6CNC6)c5)cc4c3)n2n1
Reaction time: 2 h

Procedure:
To 3-{4-[6-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylmethyl)-quinolin-3-yl]-pyrazol-1-ylmethyl}-azetidine-1-carboxylic acid tert-butyl ester (189 mg) was added 6 mL of TFA:dichloromethane/1:1 solution. The mixture was allowed to sit for 2 hours. The volatiles were removed by rotary evaporation and then Methanol (6 mL) and MP-carbonate (400 mg, 3.18 mmol/g) were added. The resin was filtered and the volatiles were removed in vacuo to obtain a quantitative yield of 3-(1-azetidin-3-ylmethyl-1H-pyrazol-4-yl)-6-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylmethyl)-quinoline. Analytical data presented in Table 2.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[N:6][N:5]=[N:4]1.Br[CH2:9][CH2:10][CH2:11][Cl:12].CO>CN(C=O)C>[Cl:12][CH2:11][CH2:10][CH2:9][N:3]1[CH:7]=[N:6][N:5]=[N:4]1
Reactant: c1nnn[nH]1
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: ClCCCn1cnnn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To anhydrous DMF (25 mL) was added NaH (0.70 g, 17.50 mmol, 60%) in one portion in an ice bath, and the mixture was warmed to rt and stirred at rt for 30 min. Then a solution of 1H-tetrazole (1.00 g, 14.28 mmol) in anhydrous DMF (6 mL) was added dropwise to the mixture cooled in an ice bath. The reaction mixture was then warmed to rt and stirred for 1.5 h followed by dropwise addition of 1-bromo-3-chloropropane (2.35 g, 14.93 mmol) to the mixture. The reaction mixture was stirred further at rt overnight. MeOH (1 mL) was added in one portion, and the mixture was filtered. The filtrate was concentrated in vacuo to give the crude product, which was used for next step without further purification.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([F:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[CH:4]=1.[C:22]1([N:28]2[CH:32]=[C:31]([C:33](O)=[O:34])[CH:30]=[N:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(CC)CC)C>CN(C=O)C>[F:14][C:8]1[CH:7]=[C:6]2[C:11]([C:12](=[O:13])[C:3]([CH2:2][NH:1][C:33]([C:31]3[CH:30]=[N:29][N:28]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:32]=3)=[O:34])=[CH:4][N:5]2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[CH:10][CH:9]=1
Reactant: O=C(O)c1cnn(-c2ccccc2)c1
Reactant: NCc1cn(-c2ccccc2F)c2cc(F)ccc2c1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NCc1cn(-c2ccccc2F)c2cc(F)ccc2c1=O)c1cnn(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.6 %

Procedure:
A mixture of 3-(aminomethyl)-7-fluoro-1-(2-fluorophenyl)quinolin-4(1H)-one (intermediate H) (50 mg, 0.175 mmol), 1-phenyl-1H-pyrazole-4-carboxylic acid (66 mg, 0.349 mmol), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBrOP) (112 mg, 0.24 mmol), triethylamine (53 mg, 0.524 mmol), and DMF (3 mL) was stirred at room temperature overnight. The crude material was purified by flash chromatography (12 g silica gel eluting with 100% hexanes ramped to 70% ethyl acetate in hexanes). The product 1-phenyl-1H-pyrazole-4-carboxylic acid [7-fluoro-1-(2-fluoro-phenyl)-4-oxo-1,4-dihydro-quinolin-3-ylmethyl]-amide (46 mg, 58%) was obtained as an off-white solid. MS calcd. for C22H14ClF2N3O2 [(M+H)+] 426.1, obsd. 426.1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([O:25][CH2:26][C:27]([OH:29])=O)=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[C:9]2[CH2:14][CH2:13][CH2:12][N:10]2[N:11]=1.C(Cl)(=O)C([Cl:33])=O>ClCCl.CN(C)C=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([O:25][CH2:26][C:27]([Cl:33])=[O:29])=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[C:9]2[CH2:14][CH2:13][CH2:12][N:10]2[N:11]=1
Reactant: O=C(O)COc1ccc2c(-c3c(-c4ccccn4)nn4c3CCC4)ccnc2c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)COc1ccc2c(-c3c(-c4ccccn4)nn4c3CCC4)ccnc2c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of [4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-acetic acid (150 mg, 0.39 mmol) in dichloromethane (3 mL) is added oxalyl chloride (490 mg, 3.9 mmol) and 1 drop of N,N-dimethylformamide. The mixture is stirred at room temperature for 5 h, concentrated in vacuo, and residual solvents removed by co-evaporation three times with chloroform to yield [4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-acetyl chloride as a yellow solid. To a solution of [4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-acetyl chloride (50 mg, 0.12 mmol) in dichloromethane at room temperature is added 1-methyl-piperazine (62 mg, 62 mmol) and the mixture stirred for 2.5 h. The mixture is partitioned between dichloromethane and water, the organic portion dried (sodium sulfate), filtered, and concentrated in vacuo. The crude residue is chromatographed on SiO2 (89% dichloromethane 10% methanol 1% concentrated ammonium hydroxide) to yield the title compound, 28 mg (48%), as a light brown solid.