Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[C:7]([OH:13])(=[O:12])[CH2:8][CH2:9][CH:10]=[CH2:11].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C.O>[C:7]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:12])[CH2:8][CH2:9][CH:10]=[CH2:11]
Reactant: BrCc1ccccc1
Reactant: C=CCCC(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A suspension of K2CO3 (4.17 g, 30.2 mmol) and pent-4-enoic acid (3.01 g, 29.2 mmol) in DMF (25 mL) was stirred at room temperature for 5 minutes. Benzyl bromide (3.55 mL, 29.3 mmol) was added from a syringe over 3 minutes, and the resulting white suspension was stirred at room temperature for 23 hours, then diluted with water (150 mL) and extracted with EtOAc (3×50 mL). The combined extract was washed with saturated brine (30 mL) and concentrated under vacuum to leave the title compound. 1H NMR (300 MHz, CD3OD) δ ppm 2.30-2.41 (m, 2H) 2.42-2.50 (m, 2H) 4.96 (dddd, J=10.2, 1.7, 1.4, 1.0 Hz, 1H) 5.03 (dq, J=17.3, 1.6 Hz, 1H) 5.11 (s, 2H) 5.82 (tdd, J=17.0, 10.4, 6.3 Hz, 1H) 7.25-7.38 (m, 5H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:5]=[C:6](N)[C:7]2[C:8]([N:23]=1)=[N:9][C:10]([C:13]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:16]=[CH:15][N:14]=1)=[CH:11][N:12]=2.N([O-])=[O:26].[Na+]>C(O)(=O)C.O>[CH3:1][O:2][CH2:3][C:4]1[CH:5]=[C:6]([OH:26])[C:7]2[C:8]([N:23]=1)=[N:9][C:10]([C:13]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:16]=[CH:15][N:14]=1)=[CH:11][N:12]=2
Reactant: COCc1cc(N)c2ncc(-c3ncccc3C(F)(F)F)nc2n1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COCc1cc(O)c2ncc(-c3ncccc3C(F)(F)F)nc2n1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
6-Methoxymethyl-3-(3-trifluoromethyl-pyridin-2-yl)-pyrido-[2,3-b]pyrazin-8-ylamine (252 mg, 0.751 mmol) is dissolved in a solution of acetic acid (2 mL) and water (5 mL). The mixture is heated to 50° C. and sodium nitrite (362 mg, 5.26 mmol) is added in portions over 1 hour. The solution is warmed to 70° C. and stirred overnight. Water (20 mL) is added and the aqueous mixture is extracted with EtOAc (4×50 mL). The combined organic extracts are washed with brine and dried over Na2SO4. The solvent is removed under reduced pressure. The crude product is chromatographed on silica gel eluting with hexanes/acetone (1:1) to afford the title compound as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]=[C:13]=[O:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:15][C:16]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:17]=1[CH:18]=[C:19]([CH3:27])[N:20]=[C:21]2[CH3:26].CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][NH:12][C:13]([NH:15][C:16]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:17]=2[CH:18]=[C:19]([CH3:27])[N:20]=[C:21]3[CH3:26])=[O:14])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc2c(N)cccc2c(C)n1
Reactant: CC(C)(C)c1ccc(CN=C=O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: Cc1cc2c(NC(=O)NCc3ccc(C(C)(C)C)cc3)cccc2c(C)n1

Procedure:
The product from Example 186A (3.42 mmol) in toluene (12 mL) was treated with 5-amino-1,3-dimethylisoquinoline (245 mg, 1.42 mmol) and DIEA (5 mL). The mixture was heated at 80° for 3 hours, cooled to room tempoerature, and filtered. The precipitate thus obtained was purified by silica gel chromatography (97:3 CH2Cl2:CH3OH to 95:5 CH2Cl2:CH3OH) to provide the title compound. The corresponding hydrochloride salt was prepared by treatment with methanolic HCl. 1H NMR (300 MHz, DMSO-d6) δ 8.55 (s, 1H), 8.21 (d, 1H, J=7.1 Hz), 7.78 (d, 1H, 8.5 Hz), 7.59 (s, 1H), 7.48 (t, 1H, J=8.0 Hz), 7.36-7.40 (m, 2H), 7.27-7.29 (m, 2H), 6.98 (m, 1H), 4.31 (d, 2H, J=5.8 Hz), 2.84 (s, 3H), 1.28 (s, 9H); MS (ESI+) m/z 362 (M+H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[OH:15][C:16]1[CH:20]=[C:19]([CH3:21])[O:18][N:17]=1.C(=O)([O-])O.[Na+].CS(C)=O>O>[CH3:21][C:19]1[O:18][N:17]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])[C:16](=[O:15])[CH:20]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Reactant: Cc1cc(O)no1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(=O)n(-c2ccc(C(F)(F)F)cc2[N+](=O)[O-])o1

Procedure:
226 g of 4-chloro-3-nitrobenzotrifluoride, 129 g of 3-hydroxy-5-methylisoxazole, 336 g of sodium hydrogen carbonate, and 600 ml of dimethylsulfoxide were mixed with each other and reacted at 75° C. for 6 hours. After completion of the reaction, the reaction solution was poured into water, and the crystals which precipitated were purified using a silica gel short column chromatography and recrystallized from water-methanol.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[Cl-].[CH3:12][O:13][C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[CH:16]=[N+:17]([CH3:19])[CH3:18]>>[CH3:12][O:13][C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[CH:16]([N:17]([CH3:18])[CH3:19])[C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]=1[CH3:1]
Reactant: Cc1cc2ccccc2[nH]1
Reactant: COc1ccccc1C=[N+](C)C
Agent: [Cl-]
Product: COc1ccccc1C(c1c(C)[nH]c2ccccc12)N(C)C

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 2-methyl-1H-indole and (2-methoxy-benzylidene)-dimethyl-ammonium chloride.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:20]([NH:22][C@@H:23]([CH2:27][CH2:28][CH2:29][CH3:30])[C:24](O)=[O:25])=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2:38][C:39]1[CH:44]=[CH:43][C:42]([CH2:45][OH:46])=[CH:41][CH:40]=1.C(OC1C=CC2C(=CC=CC=2)N1C(OCC)=O)C>C(Cl)Cl>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:17])[NH:18][C@H:19]([C:20](=[O:21])[NH:22][C@H:23]([C:24](=[O:25])[NH:38][C:39]3[CH:44]=[CH:43][C:42]([CH2:45][OH:46])=[CH:41][CH:40]=3)[CH2:27][CH2:28][CH2:29][CH3:30])[CH2:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CCCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: Nc1ccc(CO)cc1
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: ClCCl
Product: CCCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)Nc1ccc(CO)cc1
Yield: 41.3 %

Procedure:
In a pear-shaped flask, the above synthesized (S)-2-[(S)-2-(9H-fluoren-9-ylmethoxy-carbonylamino)-3-phenyl-propionylamino]-hexanoic acid (10.72 g, 21 mmol, Eq: 1.00), (4-aminophenyl)methanol (2.717 g, 22 mmol, Eq: 1.03), and 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ) (7.994 g, 32 mmol, Eq: 1.50) were dissolved in CH2Cl2 (320 ml) and stirred over night under a balloon of Ar. The mixture was poured onto crashed ice/NH4Cl, extracted 2× with AcOEt, washed with H2O, dried over Na2SO4, and the volume reduced to ˜300 ml. The precipitate was filtered off and dryed to give 5.25 g of the title compound as light-brown solid. MS (ISP): (M+H) 606.3.
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][S:10][C:11](=S)[S:12]C>C(#N)C.C(OCC)C>[CH3:9][S:10][C:11]([N:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[NH2:8])=[S:12]
Reactant: CSC(=S)SC
Reactant: NNc1ccccc1
Solvent: CC#N
Solvent: CCOCC
Product: CSC(=S)N(N)c1ccccc1
Reaction time: 18 h

Procedure:
To a stirred solution of phenylhydrazine (30 mmol, 1 equiv) in dry acetonitrile (20 mL) was added trithiocarbonic acid dimethyl ester (30 mmol, 1 equiv) slowly at ice bath temperature. The mixture was stirred for 18 hours and diluted with diethylether (30 mL). The resulting white solid was filtered and was washed with ether and dried under nitrogen to afford title compound.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].O=[C:15]1[CH2:18][CH:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:16]1.O>O1CCCC1.C(OCC)C>[C:3]([CH:5]=[C:15]1[CH2:18][CH:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:16]1)#[N:4]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CCOC(=O)C1CC(=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)C1CC(=CC#N)C1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a suspension of sodium hydride (60% dispersion in mineral oil, 0.730 g, 18.3 mmol) in tetrahydrofuran (100 mL) at 0° C. was added diethyl cyanomethylphosphonate (3.22 mL, 19.9 mmol), dropwise. The cooling bath was removed and the reaction was allowed to reach room temperature and was stirred at this temperature for 45 minutes. The solution was re-cooled to 0° C. and a solution of ethyl 3-oxocyclobutanecarboxylate (2.36 g, 16.6 mmol) in tetrahydrofuran (50 mL) was introduced dropwise. After stirring for 2 hours, water and ethyl ether were added into the reaction. The layers were separated and the aqueous portion extracted with two further portions of ether. The combined extracts were washed with brine, dried over sodium sulfate, decanted and concentrated. The residue was azeotroped once with toluene to afford product, used without further purification in Step 5.
Reaction SMILES: C(O)(=O)C.[NH2:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:7]=1[SH:16].[OH:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([OH:26])[CH:25]=1)[CH:21]=O.C([O-])(=O)C.[Na+]>O.C(OCC)(=O)C>[F:15][C:12]([F:13])([F:14])[C:10]1[CH:9]=[CH:8][C:7]2[S:16][C:21]([C:20]3[CH:23]=[C:24]([OH:26])[CH:25]=[C:18]([OH:17])[CH:19]=3)=[N:5][C:6]=2[CH:11]=1
Reactant: O=Cc1cc(O)cc(O)c1
Reactant: Nc1cc(C(F)(F)F)ccc1S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: Oc1cc(O)cc(-c2nc3cc(C(F)(F)F)ccc3s2)c1
Yield: 36.9 %

Procedure:
In an acetic acid (0.42 mL) solvent, a mixture including 2-amino-4-(trifluoromethyl)benzenethiol (100 mg, 0.44 mmol), 3,5-dihydroxybenzaldehyde (60 mg, 0.44 mmol), and sodium acetate (107 mg, 1.30 mmol) was refluxed for 6.5 hours. After cooling, the reaction mixture was distributed between ethyl acetate and water, and an organic layer was dried by using MgSO4, filtered, and evaporated under reduced pressure. The residual was purified by silica gel column chromatography using hexane and ethyl acetate (2:1) as a developer to obtain a solid Compound 36 (50.6 mg, 37%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:15])=O>>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([Cl:15])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(F)c(F)cc1Cl
Product: O=C(Cl)c1cc(F)c(F)cc1Cl
Reaction time: 3 h
Yield: 92.9 %

Procedure:
Into a 300 cc glass reactor, 100 g of 2-chloro-4,5-difluorobenzoic acid and 200 g of thionyl chloride were charged and stirred at about 60° to 70° C. for 3 hours. Unreacted thionyl chloride was distilled off, and the residue was subjected to distillation under reduced pressure to obtain 101.8 g of 2-chloro-4,5-difluorobenzoyl chloride. The physical properties of the obtained 2-choloro-4,5-difluorobenzoyl chloride were as follows.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[OH:11].C[N+]1([O-])CCOCC1.C([N+](CCC)(CCC)CCC)CC>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:20])[CH:4]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][C:7]1=[O:11]
Reactant: COC(=O)C(CC1CCCC1O)c1ccc(Cl)c(Cl)c1
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: COC(=O)C(CC1CCCC1=O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
A mixture of 2-(3,4-dichloro-phenyl)-3-(2-hydroxy-cyclopentyl)-propionic acid methyl ester (prepared as in Example 25, 408.5 mg, 1.28 mmol), N-methylmorpholine N-oxide (679 mg, 5.79 mmol), and powdered molecular sieves (1.29 g) in methylene chloride (2.6 mL) at 25° C. was treated with tetrapropylammonium perrhuthenate (45 mg, 0.12 mmol). The resulting mixture was stirred at 25° C. for 2 h. At this time, the reaction was filtered through a pad of celite (ethyl acetate as eluent). The filtrate was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 75/25 hexanes/ethyl acetate) afforded 2-(3,4-dichloro-phenyl)-3-(2-oxo-cyclopentyl)-propionic acid methyl ester (278.2 mg, 68.5%) as a clear oil: EI-HRMS m/e calcd for C15H16Cl2O3 (M+) 314.0476, found 314.0476.
Reaction SMILES: CCN(C(C)C)C(C)C.[Br:10][C:11]1[C:12](Cl)=[N:13][CH:14]=[C:15]([CH:30]=1)[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]([Cl:29])([F:28])[F:27])=[CH:21][CH:20]=1)=[O:17].[NH:32]1[CH2:36][CH2:35][C@H:34]([OH:37])[CH2:33]1>CC(O)C.CCOC(C)=O>[Br:10][C:11]1[C:12]([N:32]2[CH2:36][CH2:35][C@H:34]([OH:37])[CH2:33]2)=[N:13][CH:14]=[C:15]([CH:30]=1)[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]([Cl:29])([F:28])[F:27])=[CH:21][CH:20]=1)=[O:17]
Reactant: O[C@H]1CCNC1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(Br)c1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC[C@H](O)C2)c(Br)c1
Temperature: 140 °C

Procedure:
DIPEA (190 μL, 1.1 mmol) was added to a solution of 5-bromo-6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide (Stage 9.3, 206 mg, 0.5 mmol) and (S)-pyrrolidin-3-ol (52.3 mg, 0.6 mmol) in iPrOH (500 μL) in a vial, which was sealed and heated at 140° C. for 1 h. After cooling at RT, the RM was dissolved in EtOAc, washed with 0.5 M aq. HCl and brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the crude product which was purified by flash chromatography (RediSep® Silica gel column, n-heptane/EtOAc from 20 to 100% EtOAc) to afford the title compound as a white crystalline powder. HPLC (Condition 4) tR=5.59 min, UPLC-MS (Condition 3) tR=1.17 min, m/z=462.0/464.1 [M+H]+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:25])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15](=[O:24])[N:16]([CH3:23])[C:17](=[O:22])[N:18]([CH3:21])[C:19]=2[CH3:20])=[CH:10][CH:9]=1)[NH2:6].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:50][O:51][CH2:52][CH2:53][C:54]1([C:59](O)=[O:60])[CH2:58][CH2:57][CH2:56][CH2:55]1.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[CH3:2][O:3][C:4](=[O:25])[C@H:5]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:15](=[O:24])[N:16]([CH3:23])[C:17](=[O:22])[N:18]([CH3:21])[C:19]=2[CH3:20])=[CH:12][CH:13]=1)[NH:6][C:59]([C:54]1([CH2:53][CH2:52][O:51][CH3:50])[CH2:58][CH2:57][CH2:56][CH2:55]1)=[O:60]
Reactant: COCCC1(C(=O)O)CCCC1
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCC1(C(=O)N[C@@H](Cc2ccc(-c3c(C)n(C)c(=O)n(C)c3=O)cc2)C(=O)OC)CCCC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 71.6 %

Procedure:
To a suspension of 4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine methyl ester hydrochloride salt (0.4 mmol, 173 mg), HBTU (0.5 mmol, 189 mg) and 1-(2-methoxyethyl)cyclopentane carboxylic acid (0.5 mmol, 86 mg) in DMF (2 mL) was added diisopropylethylamine (1.2 mmol, 0.29 mL) at room temperature. After 5 min, everything went into solution and the clear yellow solution was stirred for 24 h at room temperature. The resulting dark-brown solution was diluted with ethyl acetate (30 mL). The ethyl acetate layer was washed successively with 1N hydrochloric acid (2×30 mL), saturated sodium bicarbonate solution (30 mL), and brine solution (30 mL) and was dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the solvent gave the crude product which was purified by silica gel column chromatography using a Biotage (40m) column to afford 139 mg (72% yield) of N-[[1-(2-methoxyethyl)cyclopentyl]carbonyl]-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine methyl ester as an amorphous white solid. FAB-HRMS m/e calcd for C26H35N3O6 (M+H) 486.2604, found 486.2602.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@H:15]([CH2:25][O:26][Si:27]([C:40]([CH3:43])([CH3:42])[CH3:41])([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:14][C@@H:11]([O:12][CH3:13])[C@@H:10]1[OH:44])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Cl:47][C:48]1[CH:55]=[CH:54][C:51]([CH2:52]Cl)=[CH:50][CH:49]=1>>[CH2:1]([O:8][C@H:9]1[C@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@H:15]([CH2:25][O:26][Si:27]([C:40]([CH3:41])([CH3:43])[CH3:42])([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:14][C@@H:11]([O:12][CH3:13])[C@@H:10]1[O:44][CH2:52][C:51]1[CH:54]=[CH:55][C:48]([Cl:47])=[CH:49][CH:50]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: CO[C@@H]1O[C@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1O
Agent: [H-]
Agent: [Na+]
Product: CO[C@@H]1O[C@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccc(Cl)cc1
Yield: 48.3 %

Procedure:
General procedure A using using methyl 3,4-di-O-benzyl-6-O-(tert-butyldiphenylsilyl)-β-D-glucopyranoside (0.124 g, 0.202 mmol), NaH (15 mg, 0.303 mmol, 60% in mineral oil) and 4-chlorobenzylchloride (34.2 mg, 0.212 mmol) and gave 72 mg (48%) of 23 as a colorless oil after purification by flash column chromatography on silica gel (10% EtOAc/Hexanes). [α]24D: +6.9° (c 1.16, CH2Cl2); IR (thin film) 2929, 1492, 1428, 1072 cm−1; 1H-NMR (CDCl3) δ 7.82 (dd, J=1.5, 7.9 Hz, 2H), 7.76 (dd, J=1.2, 7.9 Hz, 2H), 7.49-7.31 (m, 18H), 7.27-7.24 (m, 2H), 4.97-4.88 (m, 4H), 4.76 (d, J=10.7 Hz, 1H), 4.75 (d, J=11.3 Hz, 1H), 4.37 (d, J=7.6 Hz, 1H), 3.99 (s, 2H), 3.83 (dd, J=9.2, 9.5 Hz, 1H), 3.71 (dd, J=9.2, 9.2 Hz, 1H), 3.64 (s, 3H), 3.49 (dd, J=7.9, 8.8 Hz, 1H), 3.41-3.39 (m, 1H), 1.12 (s, 9H); 13C-NMR (CDCl3) δ 138.7, 138.4, 137.4, 136.1, 135.8, 135.0, 133.8, 133.5, 133.3, 129.8, 129.5, 128.7, 128.6, 128.1, 128.0, 127.9, 127.8, 104.6, 84.8, 82.7, 77.9, 76.1, 75.8, 75.4, 74.1, 62.8, 56.9, 27.0, 26.8, 19.5; FAB MS m/z (M)+: calcd 759.2885, obsd 759.2881.
Reaction SMILES: [I-].[K+].C(=O)([O-])[O-].[K+].[K+].[C:9]1([OH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH2:16]([O:18][C:19](=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23]Br)[CH3:17]>CC(C)=O>[CH2:16]([O:18][C:19](=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23][O:15][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:17]
Reactant: Oc1ccccc1
Reactant: CCOC(=O)CCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CCCCOc1ccccc1
Temperature: 60 °C

Procedure:
Dehydrated acetone of 240 ml was put in a 3-necked round-bottom flask, potassium iodide (0.06 mol), potassium carbonate (0.11 mol), and phenol (0.07 mol) were added to stir sufficiently. In this solution, 5-bromo valeric acid ethyl ester (0.06 mol) was dropped in a nitrogen atmosphere and refluxed at 60±5° C. to react for 24 hours. After completion of the reaction, a reaction solution was exsiccated to condensation using an evaporator, and dissolved again in methylene chloride, and water was added to the solution to separate and an organic layer was dehydrated by using magnesium sulfate anhydride followed by exsiccation for condensation using the evaporator. Hot methanol was added to a dried matter (reactant) yielded to dissolve and cooled slowly to precipitate again, resulting in a yield of 5-phenoxy valeric acid ethyl ester (PxVA). At this point, the yield ratio of this ester to 5-bromo valeric acid ethyl ester was 72 mol %.
Reaction SMILES: [CH2:1]([C@H:8]1[C@H:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19]C)=[C:15]([O:21]C)[CH:14]=2)[CH2:11][NH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)[Br:24].Br>C(Cl)Cl>[BrH:24].[CH2:1]([C@H:8]1[C@H:12]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([OH:21])[CH:14]=2)[CH2:11][NH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc([C@@H]2CNC[C@H]2Cc2ccccc2)cc1OC
Reactant: BrB(Br)Br
Agent: Br
Solvent: ClCCl
Product: Oc1ccc([C@@H]2CNC[C@H]2Cc2ccccc2)cc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 16 %

Procedure:
0.37 g (1.24 mmol) of trans-3-benzyl-4-(3,4-dimethoxyphenyl)pyrrolidine was dissolved in methylene chloride, and 10 ml of a solution of 1M boron tribromide in methylene chloride was added to the resultant solution. The solution was stirred at room temperature for 3 hr. The reaction mixture was concentrated in vacuo. Further, methylene chloride was added to the concentrate and methanol (3 ml) was dropwise added thereto. The mixture was again concentrated in vacuo. This procedure was repeated several times, and a precipitated crystal was recovered by filtration to prepare 70 mg of a hydrobromide as an intended product (yield: 16%).
Reaction SMILES: [O:1]=[C:2]([OH:14])[C@H:3]([C@H:5]([C@@H:7]([C@@H:9]([C:11]([OH:13])=[O:12])[OH:10])[OH:8])[OH:6])[OH:4].[Na:15][Na].[OH-].[Na+]>>[Na+:15].[Na+:15].[O:1]=[C:2]([O-:14])[C@H:3]([C@H:5]([C@@H:7]([C@@H:9]([C:11]([O-:13])=[O:12])[OH:10])[OH:8])[OH:6])[OH:4]
Reactant: [Na][Na]
Reactant: O=C(O)[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C([O-])[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)C(=O)[O-]

Procedure:
Isolation of D-mannaric acid as its disodium salt. Prior to titration with sodium hydroxide the solution was stirred at 60° C. for approximately 45 min to promote equilibration between D-mannaric acid acid and lactone species. The isolation procedure was then followed as in Example 1 to give crude mannaric acid disodium salt: 144.4 grams (92% based on pure disodium D-mannarate).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](Cl)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1.[NH2:15][C@@H:16]([C@H:19]([OH:21])[CH3:20])[CH2:17][OH:18].C(N(C(C)C)CC)(C)C.O>CC(N(C)C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:15][C@@H:16]([C@H:19]([OH:21])[CH3:20])[CH2:17][OH:18])=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1
Reactant: C[C@@H](O)[C@H](N)CO
Reactant: NC(=O)c1cnn2cc(Br)cc2c1Cl
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](O)[C@@H](CO)Nc1c(C(N)=O)cnn2cc(Br)cc12
Temperature: 125 °C
Reaction time: 8 h

Procedure:
A mixture of 6-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (686 mg, 2.5 mmol), (2R,3R)-2-aminobutane-1,3-diol (394 mg, 3.75 mmol) and diisopropylethylamine (0.873 mL, 5.00 mmol) in DMA (10 mL) was heated to 125° C. for 3 hr. After cooling to rt, the volatiles were removed under high vacuum to afford a red oil that was treated with ˜25 ml of water. A gummy solid formed and the mixture was stirred at rt overnight. A few crystals of pure title compound from a previous batch were added at the beginning of the stirring. The suspension was filtered and dried to afford a yellow solid that was washed with 25 ml of Et2O:EtOAc, 1:1. Drying afforded 6-bromo-4-(((2R,3R)-1,3-dihydroxybutan-2-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide (670 mg, 1.952 mmol, 78% yield) as a pale yellow solid. 1H NMR (400 MHz, CD3OD) δ 8.13 (s, 1H), 7.62 (d, J=1.8 Hz, 1H), 7.09 (d, J=1.5 Hz, 1H), 4.21 (dd, J=6.4, 2.6 Hz, 1H), 4.15-4.06 (m, 1H), 3.90-3.74 (m, 2H), 1.23 (d, J=6.4 Hz, 3H); (ES+) m/z: 343.1, 345.1 (M+H); LC retention time: 1.957 min (analytical HPLC Method P).
Reaction SMILES: [NH:1]([CH:3]1[C:7]2=[CH:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[N:6]2[CH2:5][CH2:4]1)[OH:2].C[Si]([N:19]=[C:20]=[O:21])(C)C.O>C1COCC1>[CH:3]1([N:1]([OH:2])[C:20]([NH2:19])=[O:21])[C:7]2=[CH:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[N:6]2[CH2:5][CH2:4]1
Reactant: C[Si](C)(C)N=C=O
Reactant: ONC1CCn2c1cc1ccccc12
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)N(O)C1CCn2c1cc1ccccc12
Reaction time: 0.5 h

Procedure:
To a solution of the product from Step 2 (652 mg, 3.47 mmol) in THF (20 mL) at r.t. there was added 85% trimethylsilyl isocyanate (850 mg, 6.28 mmol) and the mixture was stirred for 30 minutes. There was added H2O (5 mL) and after stirring for another 5 minutes the THF was evaporated. The residual aqueous suspension was diluted with H2O and filtered to afford the title compound as a white solid, m.p.: 194° C. (dec).