Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]3=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:32]1([S:38](Cl)(=[O:40])=[O:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>ClCCl>[CH3:24][CH:23]([CH3:25])[C@H:18]([N:13]1[CH2:12][C:11]2[C:15](=[CH:16][C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:38]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)(=[O:40])=[O:39])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)[C:14]1=[O:17])[C:19]([O:21][CH3:22])=[O:20]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NS(=O)(=O)c4ccccc4)cc3)cc2C1=O
Reaction time: 0.08 h

Procedure:
To a solution of compound of example 6 (0.250 g, 0.0073 mol) in dichloromethane (5 mL), pyridine (0.174 g, 0.00219 mol) was added and stirred for 5 min. To this reaction mixture, benzene sulfonyl chloride was added and stirred for about 16 h. After completion of the reaction, solvent was evaporated and the crude title compound obtained was directly used for the preparation of compound of example 78.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[N+:8]([C:11]1[CH:18]=[CH:17][C:14]([CH2:15][Br:16])=[CH:13][CH:12]=1)([O-:10])=[O:9]>CC#N.CCOCC>[Br-:16].[N+:8]([C:11]1[CH:18]=[CH:17][C:14]([CH2:15][N:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]2=[NH2+:1])=[CH:13][CH:12]=1)([O-:10])=[O:9]
Reactant: Nc1ccccn1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Solvent: CCOCC
Solvent: CC#N
Product: [Br-]
Product: [NH2+]=c1ccccn1Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 87.9 %

Procedure:
1.04 g (11 mmol) of 2-aminopyridine and 2.39 g (11 mmol) of p-nitrobenzylbromide were dissolved in 20 mL CH3CN. The solution was warmed to reflux for 1 hr then cooled to room temperature, diluted with Et2O, and the solid filtered, washed 4× with Et2O and collected to yield 3 g (88%) of 1-(4-Nitro-benzyl)-1H-pyridin-2-ylidene-ammonium bromide (174) as an off white solid.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[F:10][C:11]1[CH:16]=[C:15]([C:17]2[C:18]([NH2:23])=[N:19][CH:20]=[CH:21][CH:22]=2)[CH:14]=[CH:13][C:12]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>C1COCC1.CCCCCC>[F:10][C:11]1[CH:16]=[C:15]([C:17]2[C:18]3=[N:23][S:6](=[O:8])(=[O:7])[CH2:5][CH2:4][N:19]3[CH:20]=[CH:21][CH:22]=2)[CH:14]=[CH:13][C:12]=1[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Nc1ncccc1-c1ccc(-c2ccccc2)c(F)c1
Reactant: O=S(=O)(Cl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: O=S1(=O)CCN2C=CC=C(c3ccc(-c4ccccc4)c(F)c3)C2=N1
Yield: 54 %

Procedure:
To a suspension of 60% sodium hydride (0.76 g) in THF (20 mL) was added 2-chloroethanesulfonyl chloride (1.85 g) under ice-cooling. The reaction mixture was stirred under ice-cooling for 5 min, and a solution of 3-(2-fluorobiphenyl-4-yl)pyridin-2-amine (1.0 g) in THF (20 mL) was added. The reaction mixture was stirred at room temperature overnight, and water and hexane were added under ice-cooling. The resulting solid was collected by filtration, washed with ethyl acetate, and dried under reduced pressure to give the title compound (0.724 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14]3[N:15]=[C:16]([CH2:19][O:20]C)[N:17]=[CH:18][C:13]=3[CH2:12][CH:11](C)[C:10]2=[O:23])=[CH:4][CH:3]=1.N1C=CC=C[CH:25]=1.I[Si](C)(C)C.CO>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14]3[N:15]=[C:16]([CH2:19][OH:20])[N:17]=[C:18]([CH3:25])[C:13]=3[CH2:12][CH2:11][C:10]2=[O:23])=[CH:4][CH:3]=1
Reactant: COCc1ncc2c(n1)N(Cc1ccc(Br)cc1)C(=O)C(C)C2
Reactant: c1ccncc1
Agent: C[Si](C)(C)I
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1nc(CO)nc2c1CCC(=O)N2Cc1ccc(Br)cc1

Procedure:
To a solution of 8-[(4-bromophenyl)methyl]-6-methyl-2-methoxymethyl-5,8-dihydro-6H-pyrido[2,3-d]pyrimidin-7-one (1.00 g, 2.70 mmol) and pyridine (0.11 g, 1.30 mmol) in CHCl3 (9 mL) was added iodotrimethylsilane (0.77 g, 3.80 mmol). The mixture was heated under reflux for 30 h and MeOH (0.5 mL) was added. The mixture was concentrated, taken up in CH2Cl2, washed with aqueous Na2SO3 and brine, dried (MgSO4), and concentrated. Purification by flash chromatography (5% MeOH/CH2Cl2) gave o.54 g (56%) of product as a colorless foam.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:14]([C:15]#[N:16])=[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:24][CH3:25])[CH:11]=2)[N:6]=1)[CH:2]=[CH2:3].C[N+]1([O-])CC[O:30]CC1.CC(O)(C)C.C1COCC1.[OH2:44]>O.CCOC(C)=O.O=[Os](=O)(=O)=O>[OH:44][CH:2]([CH2:3][OH:30])[CH2:1][O:4][C:5]1[C:14]([C:15]#[N:16])=[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:24][CH3:25])[CH:11]=2)[N:6]=1
Reactant: C=CCOc1nc2ccc(OC)cc2c(-c2cccc(F)c2)c1C#N
Reactant: C[N+]1([O-])CCOCC1
Reactant: O
Agent: O=[Os](=O)(=O)=O
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: COc1ccc2nc(OCC(O)CO)c(C#N)c(-c3cccc(F)c3)c2c1
Reaction time: 18 h

Procedure:
To a solution of 2-(allyloxy)-4-(3-fluorophenyl)-6-methoxyquinoline-3-carbonitrile (140 mg, 0.419 mmol) in 10 mL of tBuOH:THF:water (10:3:1) was added N-methylmorpholine N-oxide (49 mg, 0.42 mmol), followed by a solution of OsO4 (106 mg, 0.42 mmol) in water (ca. 0.5 mL). After stirring for 18 hours, the reaction was diluted with EtOAc, washed with saturated NaHCO3 solution, 10% citric acid solution and brine, and the organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue (144 mg) was subjected to preparative chiral HPLC through a Chiralcel OD column (85% hexanes containing 0.1% diethylamine:EtOH). The first eluting peak was collected and concentrated in vacuo to provide the titled product. 1H-NMR (500 MHz, CDCl3) δ 7.81 (d, J=9.0 Hz, 1H), 7.70 (ddd, J=8.1, 8.1, 5.6 Hz, 1H), 7.44 (dd, J=9.0, 2.9 Hz, 1H), 7.30 (ddd, J=8.6, 2.4, 1.0 Hz, 1H), 7.25 (m, 1H), 7.19 (br d, J=8.6 Hz, 1H), 6.83 (d, J=2.9 Hz, 1H), 4.68-4.76 (m, 2H), 4.19 (m, 1H), 3.84 (dd, J=11.6, 4.1 Hz, 1H), 3.79 (dd, J=11.6, 5.4 Hz, 1H), 3.74 (s, 3H) ppm. HRMS (ES) exact mass calculated for C20H18FN2O4 (M+H+): 369.1245. Found 369.1195.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[CH:8]1[CH2:17][CH2:16][C:15]2[CH:14]=[C:13]([C:18]#[N:19])[CH:12]=[CH:11][C:10]=2[CH2:9]1.[N:20]1[O:21][N:22]=[C:23]2[CH:28]=[C:27]([CH2:29][CH:30]=O)[CH:26]=[CH:25][C:24]=12>>[N:20]1[O:21][N:22]=[C:23]2[CH:28]=[C:27]([CH2:29][CH2:30][N:6]3[CH2:5][CH2:4][N:3]([CH:8]4[CH2:17][CH2:16][C:15]5[CH:14]=[C:13]([C:18]#[N:19])[CH:12]=[CH:11][C:10]=5[CH2:9]4)[C:2](=[O:1])[CH2:7]3)[CH:26]=[CH:25][C:24]=12
Reactant: O=CCc1ccc2nonc2c1
Reactant: N#Cc1ccc2c(c1)CCC(N1CCNCC1=O)C2
Product: N#Cc1ccc2c(c1)CCC(N1CCN(CCc3ccc4nonc4c3)CC1=O)C2

Procedure:
The title compound was prepared from 6-(2-Oxopiperazin-1-yl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile and 2,1,3-benzoxadiazol-5-ylacetaldehyde following essentially the same procedure as Example 6. The product was purified by mass-directed reverse phase HPLC (AcCN-Water with 0.1% TFA). LC-MS (IE, m/z): 402 [M+1]+.
Reaction SMILES: [CH2:1]([C:8]1[CH:16]=[CH:15][C:11](C(O)=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:17]=[C:18]=[O:19].[CH2:20]([CH:22]([NH:25][OH:26])[CH2:23][CH3:24])[CH3:21]>>[OH:26][N:25]([CH:22]([CH2:23][CH3:24])[CH2:20][CH3:21])[C:18]([NH:17][C:11]1[CH:10]=[CH:9][C:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:16][CH:15]=1)=[O:19]
Reactant: CCC(CC)NO
Reactant: O=C(O)c1ccc(Cc2ccccc2)cc1
Reactant: [N-]=C=O
Product: CCC(CC)N(O)C(=O)Nc1ccc(Cc2ccccc2)cc1

Procedure:
Using the method of Compound 76, 4-benzylbenzoic acid (1.93 g, 9 mmole) was converted to the corresponding isocyanate then reacted with N-(1-ethylpropyl)hydroxylamine (1.4 g, 14 mmole) to provide 1.9 g of the desired product as off-white crystals, m.p. 132.5°-134.1° C. Analysis: Calculated for C19H24N2O2 : %C, 73.05; %H, 7.74; %N, 8.97; Found: %C, 72.82; %H, 7.82; %N, 8.79.
Reaction SMILES: [CH2:1]([C:8]([OH:10])=[O:9])[C:2]([CH2:4][C:5]([OH:7])=O)=[O:3].[C:11](OC(=O)C)(=[O:13])[CH3:12]>C1(C)C=CC=CC=1>[C:11]([O:7][C:5]1[CH2:4][C:2](=[O:3])[O:1][C:8](=[O:9])[CH:10]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)CC(=O)CC(=O)O
Solvent: Cc1ccccc1
Product: CC(=O)OC1=CC(=O)OC(=O)C1
Temperature: 35 °C
Reaction time: 24 h
Yield: 54.2 %

Procedure:
Acetone-1,3-dicarboxylic acid (30 g; 205 mmol) was added in portions to acetic anhydride (55 ml; 582 mmol) and the mixture was stirred at 35° C. for 24 h. The reaction mixture was diluted with toluene (200 ml) and kept at 4° C. for 3 h. A precipitate was isolated by filtration, washed with toluene and dried under reduced pressure to furnish 18.91 g (54%) of 2,6-dioxo-3,6-dihydro-2H-pyran-4-yl acetate as a light brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:4]=1B(O)O.C(C1C=CC(B(O)O)=CC=1)(O)=O.Br[C:26]1[CH:27]=[N:28][CH:29]=[C:30]([CH:34]=1)[C:31]([OH:33])=[O:32]>>[Cl:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([C:26]2[CH:27]=[N:28][CH:29]=[C:30]([CH:34]=2)[C:31]([OH:33])=[O:32])[CH:5]=1
Reactant: O=C(O)c1cncc(Br)c1
Reactant: COc1ccc(Cl)cc1B(O)O
Agent: O=C(O)c1ccc(B(O)O)cc1
Product: COc1ccc(Cl)cc1-c1cncc(C(=O)O)c1

Procedure:
Following the procedure of Example 1b), except substituting 2-methoxy-5-chlorophenylboronic acid; for 4-carboxyphenylboronic acid; and substituting 5-bromonicotinic acid; for the compound of 1a), the title compound was prepared. MS (ES) m/z 264 [M+H].
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[CH2:12][CH2:11][C@H:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:9]1[C:19](=[O:43])[CH2:20][NH:21][C:22](=[O:42])[NH:23][C:24]1[CH:25]=[C:26]([CH:30]([CH3:41])[C:31]([O:33]CC2C=CC=CC=2)=[O:32])[CH:27]=[CH:28][CH:29]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO>C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6]([C@@H:8]1[CH2:12][CH2:11][C@H:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:9]1[C:19](=[O:43])[CH2:20][NH:21][C:22](=[O:42])[NH:23][C:24]1[CH:25]=[C:26]([CH:30]([CH3:41])[C:31]([OH:33])=[O:32])[CH:27]=[CH:28][CH:29]=1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C(=O)OCc1ccccc1)c1cccc(NC(=O)NCC(=O)N2[C@@H](c3ccccc3)CC[C@H]2C(=O)OC(C)(C)C)c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C(=O)O)c1cccc(NC(=O)NCC(=O)N2[C@@H](c3ccccc3)CC[C@H]2C(=O)OC(C)(C)C)c1
Yield: 67.2 %

Procedure:
The operation is carried out as in Example 84, but starting from 0.88 g of benzyl 2-{3-{3-[2-((2S,5R)-2-tert-butoxycarbonyl-5-phenyl-1-pyrrolidinyl)-2-oxoethyl]ureido}phenyl}propionate (B form) in solution in 50 cm3 of ethyl acetate and 0.22 g of 10% palladium on charcoal. After treatment, 0.5 g of 2-{3-{3-[2-((2S,5R)-2-tert-butoxycarbonyl-5-phenyl-1-pyrrolidinyl)-2-oxoethyl]ureido}phenyl}propionic acid (B form), melting at 120° C., [α]D20 =+49.8°±0.8° (c=0.53; methanol), is obtained.
Reaction SMILES: Br[C:2]([CH3:12])(C)[C:3]([N:5]([CH3:10])[C:6]([NH:8][CH3:9])=[O:7])=[O:4].[Na+].[C:14]([O:17][CH2:18][C:19]1[CH2:20][S:21][C@@H:22]2[C@H:29]([NH:30][C:31](=[O:40])/[C:32](/[C:35]3[O:36][CH:37]=[CH:38][CH:39]=3)=[N:33]\[OH:34])[C:28](=[O:41])[N:23]2[C:24]=1[C:25]([O-:27])=[O:26])(=[O:16])[CH3:15].[CH3:42]CO>CS(C)=O>[C:14]([O:17][CH2:18][C:19]1[CH2:20][S:21][C@@H:22]2[C@H:29]([NH:30][C:31](=[O:40])/[C:32](=[N:33]\[O:34][CH:12]([CH2:2][C:3]([N:5]([CH3:10])[C:6]([NH:8][CH3:9])=[O:7])=[O:4])[CH3:42])/[C:35]3[O:36][CH:37]=[CH:38][CH:39]=3)[C:28](=[O:41])[N:23]2[C:24]=1[C:25]([OH:27])=[O:26])(=[O:16])[CH3:15]
Reactant: CCO
Reactant: CC(=O)OCC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)/C(=N\O)c3ccco3)[C@H]2SC1
Reactant: CNC(=O)N(C)C(=O)C(C)(C)Br
Agent: [Na+]
Solvent: CS(C)=O
Product: CNC(=O)N(C)C(=O)CC(C)O/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12)c1ccco1
Yield: 73 %

Procedure:
This compound was prepared from 1-(2-bromo-2-methylpropionyl)-1,3-dimethylurea and (6R,7R)-3-acetoxymethyl-7-[Z-2-(fur-2-yl)-2-hydroxyiminoacetamido]-ceph-3-em-4-carboxylic acid sodium salt by the method described in Example 1. Yield 73%, λmax (EtOH) 274 nm (ε12,500), νmax (Nujol) 3300 (NH), 3700-2100 (bonded OH), 1789 (β-lactam), 1730 (CO2H), 1685, 1535 (CONH), τ(DMSO d6) 0.18 (CONH), 2.11, 3.28, 3.31 (furyl), 4.11, (7H), 4.77 (6H), 4.97, 6.29 (3--CH2), 6.29, 6.49 (2--CH2), 6.75 (NMe), 7.28 (NHMe), 7.93 (OAc), 8.41 (CMe2).
Reaction SMILES: [Br-].[Li+].[C:3]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C@@H:12]1[CH2:29][C:28]2[C@H:23]([CH2:24][CH2:25][C:26](=[O:30])[CH:27]=2)[C@@H:22]2[C@@H:13]1[C@H:14]1[C@@:18]([CH2:20][CH2:21]2)([CH3:19])[C:17](=[O:31])[CH2:16][CH2:15]1)(=[O:5])[CH3:4]>C(#N)C.[Cu](Br)Br>[C:3]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C@@H:12]1[CH2:29][C:28]2[CH:27]=[C:26]([OH:30])[CH:25]=[CH:24][C:23]=2[C@@H:22]2[C@@H:13]1[C@H:14]1[C@@:18]([CH2:20][CH2:21]2)([CH3:19])[C:17](=[O:31])[CH2:16][CH2:15]1)(=[O:5])[CH3:4]
Reactant: CC(=O)OCCCCC[C@@H]1CC2=CC(=O)CC[C@@H]2[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@H]12
Agent: Br[Cu]Br
Agent: [Br-]
Agent: [Li+]
Solvent: CC#N
Product: CC(=O)OCCCCC[C@@H]1Cc2cc(O)ccc2[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@H]12
Reaction time: 0.17 h
Yield: 73.8 %

Procedure:
17.8 g of lithium bromide and 92.83 g of copper(II) bromide are added to a solution of 82.3 g of 7α-(5-acetoxypentyl)4-estr-ene-3,17-dione in 936 ml of acetonitrile at a bath temperature of 80° C. After 10 minutes at a bath temperature of 80° C., the reaction solution is cooled, extracted three times with ethyl acetate, washed with water and sodium bicarbonate solution and dried. The residue that is obtained after the concentration by evaporation is chromatographed on silica gel, and 60.4 g of 7α-(5-acetoxypentyl)-3-hydroxy-estra-1,3,5(10)-trien-17-one is obtained as oil.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][C:12]([OH:14])=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].S(Cl)([Cl:17])=O>>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][C:12]([Cl:17])=[O:14])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(CCC(=O)O)CC1
Reactant: O=S(Cl)Cl
Product: CC(=O)N1CCC(CCC(=O)Cl)CC1
Reaction time: 0.08 h

Procedure:
3-(1-Acetyl-4-piperidinyl)propionic acid (4.0 g, 20.0 mmol) was added portionwise to thionyl chloride (2.0 ml) with ice-bath cooling. After the mixture was stirred for 5 minutes, the excess thionyl chloride was distilled off and the residue was washed with hexane to give 3-(1-acetyl-4-piperidinyl)propionyl chloride as light-yellow solid. Aluminum chloride (8.3 g, 62.2 mmol) powders were added in small portions to a mixed solution of the above acid chloride and 5-formyl-5,6,11,12-tetrahydrobenz[bf]azocine (4.0 g, 16.85 mmol), obtained in Example 5, in 1,2-dichloroethane (15 ml) with ice-bath cooling. This mixture was stirred at room temperature for 16 hours, then poured in ice-water, and extracted with-ethyl acetate. The extract was washed with saturated NaCl/H2O and dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate-methanol=20:1) to provide 3-(1-acetyl-4-piperidinyl)-1-(5-formyl-5,6,11,12-tetrahydrodibenz[bf]azocin-8-yl)-1-propanone (6.5 g) as light yellow oil.
Reaction SMILES: CS[C:3](=[NH:8])[NH:4][N+:5]([O-:7])=[O:6].CN([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)C.C(O)C.[C:21]([O:24][CH2:25]C)(=O)C>>[O:24]1[CH2:25][CH2:16][CH:15]([CH2:14][N:13]2[CH2:12][CH2:17][NH:8][C:3]2=[N:4][N+:5]([O-:7])=[O:6])[CH2:21]1
Reactant: CSC(=N)N[N+](=O)[O-]
Reactant: CN(C)c1ccccn1
Reactant: CCOC(C)=O
Solvent: CCO
Product: O=[N+]([O-])N=C1NCCN1CC1CCOC1

Procedure:
The thus obtained crude oily substance was mixed with 3.07 g of S-methyl-N-nitroisothiourea, 0.1 g of dimethylaminopyridine (DMAP) and 30 ml of ethanol, and the mixture was refluxed. After the completion of reaction, ethyl acetate was added, and insolubles were then removed by filtration. The filtrate was concentrated under a reduced pressure to precipitate crystals, and the thus precipitated crystals were then removed by filtration. Next, the filtrate was concentrated under a reduced pressure to obtain an oily substance, and this oily substance was then purified by silica gel column chromatography (1:2 acetone/ethyl acetate) to obtain 1.04 g of 1-[(tetrahydro-3-furanyl)methyl]-2-(nitroimino)imidazolidine as a pale yellow oil.
Reaction SMILES: [CH:1]1([C:7]([C:9]2[N:13]([CH3:14])[C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH3:19].Cl>C(Cl)Cl>[CH:1]1([C:7]([C:9]2[N:13]([CH3:14])[C:12]([S:15]([NH2:19])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N
Reactant: Cn1c(C(=O)C2CCCCC2)ccc1S(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Product: Cn1c(C(=O)C2CCCCC2)ccc1S(N)(=O)=O
Yield: 69 %

Procedure:
Through a solution of compound 25c (1.7 g, 5.88 mmol) in DCM (120 mL) was bubbled NH3 for 30 min at 0° C. with stirring and then was added HCl to adjusted pH to 4-5 and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated to give compound 25d (1.1 g, 69%) as a crude solid.
Reaction SMILES: [CH2:1]1[CH2:6][C@H:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3][C@H:2]1[CH2:10][NH2:11].[C:12]([O:20][CH2:21][O:22][C:23](ON1C(=O)CCC1=O)=[O:24])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CC(OC)(C)C.CC(C)=O.O>[C:12]([O:20][CH2:21][O:22][C:23]([NH:11][CH2:10][C@H:2]1[CH2:3][CH2:4][C@H:5]([C:7]([OH:9])=[O:8])[CH2:6][CH2:1]1)=[O:24])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: O=C(OCOC(=O)c1ccccc1)ON1C(=O)CCC1=O
Solvent: COC(C)(C)C
Solvent: CC(C)=O
Solvent: O
Product: O=C(NC[C@H]1CC[C@H](C(=O)O)CC1)OCOC(=O)c1ccccc1

Procedure:
Following the general nucleophilic carbamoylation procedure, tranexamic acid (472 mg, 3.0 mmol) and 1-[(2,5-dioxopyrrolidinyl)oxycarbonyloxy]methyl benzoate (587 mg, 2.0 mmol) were reacted in the MTBE/acetone/water mixture (16 mL) to yield the title compound 7 (445 mg, 66% yield) a white powder after work-up and mass-guided preparative HPLC purification. 1H NMR (400 MHz, DMSO-d6): δ=0.83-0.95 (br. m, 2H), 1.16-1.39 (br. m, 3H), 1.65-1.72 (br. M, 2H), 1.82-1.91 (br. m, 2H), 2.09 (tt, J=12.4, 3.6 Hz, 1H), 2.81-2.88 (br. m, 2H), 5.88 (s, 2H), 7.50-7.57 (m, 2H), 7.61 (t, J=6.0 Hz, 1H), 7.65-7.70 (m, 1H), 7.93-7.97 (m, 2H), 11.96 (br. s, 1H). MS (ESI) m/z 336.01 (M+H)+; 333.98 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][CH:3]=1.[CH:11]([N:14](CC)C(C)C)(C)[CH3:12].BrCC#N>C(#N)C.C(OCC)(=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH:8][CH2:12][C:11]#[N:14])=[CH:4][CH:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: NCCc1ccc(F)cc1
Agent: N#CCBr
Solvent: CCOC(C)=O
Solvent: CC#N
Product: N#CCNCCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
To a solution of 4-fluorophenethylamine (1.4 g) in acetonitrile (20 mL) was added dropwise N,N-diisopropylethylamine (2.6 mL) and bromoacetonitrile (0.84 mL). After stirring at room temperature for 50 minutes, the solution was diluted with ethyl acetate, the solution was washed with water, then with saturated sodium chloride water. After drying with anhydrous sodium sulfate, the solvent was removed by evaporation to provide the title compound (2.12 g) as a yellow oily substance.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([N+:7]([O-:9])=[O:8])=[CH:5][N:6]=1.C(=O)([O-])[O-].[Na+].[Na+].[Br:16][CH2:17][C:18](Br)=[O:19]>C(OCC)(=O)C>[Br:16][CH2:17][C:18]([NH:1][C:2]1[S:3][C:4]([N+:7]([O-:9])=[O:8])=[CH:5][N:6]=1)=[O:19]
Reactant: Nc1ncc([N+](=O)[O-])s1
Reactant: O=C(Br)CBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(CBr)Nc1ncc([N+](=O)[O-])s1

Procedure:
To a stirred solution of 2-amino-5-nitrothiazole (725.7 mg) in ethyl acetate (50 mL) in the presence of saturated sodium carbonate (10 mL) at 0° C., is added bromoacetyl bromide (434.3 uL), and additional bromoacetyl bromide is added to complete the reaction. The organic layer is separated, washed with 3 N HCl solution, followed by brine and dried over sodium sulfate and concentrated in vacuo to give a brown oil. The crude product is purified by silica gel column chromatography (40% ethyl acetate/hexanes) to give a solid (950 mg). ESI MS m/z 266 (M+H+); 1H NMR (400 MHz, CDCl3) δ 8.26 (s, 1H), 3.98 (s, 2H).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:41])=[N:14][C:15]2[N:16]([N:33]=[C:34]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH:35]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][C@H:30]([OH:32])[CH3:31])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[C:47]([Si:51](Cl)([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)([CH3:50])([CH3:49])[CH3:48].O>CN(C=O)C>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:41])=[N:14][C:15]2[N:16]([N:33]=[C:34]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH:35]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][C@H:30]([O:32][Si:51]([C:47]([CH3:50])([CH3:49])[CH3:48])([C:58]2[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=2)[C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH3:31])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)c1cc2nc(C)c([C@H](OC(C)(C)C)C(=O)OCC)c(N3CCC(C)(OCCCC[C@@H](C)O)CC3)n2n1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2nc(C)c([C@H](OC(C)(C)C)C(=O)OCC)c(N3CCC(C)(OCCCC[C@@H](C)O[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)CC3)n2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.5 %

Procedure:
To a solution of ethyl 6-((S)-1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-7-(4-(((R)-5-hydroxyhexyl)oxy)-4-methylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (800 mg, 1.387 mmol) in DMF (10 mL) at 0° C. was added imidazole (142 mg, 2.081 mmol) followed by tert-butylchlorodiphenylsilane (0.533 mL, 2.081 mmol) and the resulting mixture was stirred at room temp for 16 h. Water (20 mL) was then added and the mixture was extracted with ether (2×25 mL). Ether layer was then washed with brine (25 mL), dried (Na2SO4), filtered and concentrated. The residue was purified via Biotage (0-10% EtOAc/hexane) to afford ethyl 6-((S)-1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-7-(4-(((R)-5-((tert-butyldiphenylsilyl)oxy)hexyl)oxy)-4-methylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (1 g, 1.227 mmol, 88% yield) as viscous liquid. 1H NMR (400 MHz, CDCl3) δ 7.69 (dd, J=8.0, 1.5 Hz, 4H), 7.47-7.28 (m, 6H), 7.01 (s, 1H), 5.82 (br. s., 1H), 4.50-4.38 (m, 2H), 4.31-4.07 (m, 2H), 3.94-3.77 (m, 1H), 3.41-3.24 (m, 3H), 2.61 (s, 3H), 1.88 (br. s., 2H), 1.67 (br. s., 1H), 1.54 (br. s., 1H), 1.51-1.39 (m, 5H), 1.30 (s, 3H), 1.26-1.23 (m, 6H), 1.22 (s, 9H), 1.08 (s, 3H), 1.06 (s, 9H). 4 missing piperidine hydrogens. LCMS (M+H)=816.4.
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]>O.[Pd]>[CH2:11]([OH:12])[C@H:9]([OH:10])[C@H:7]1[O:8][C:2](=[O:1])[C@@H:3]([OH:4])[C@H:5]1[OH:6]
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: [Pd]
Solvent: O
Product: O=C1O[C@H]([C@@H](O)CO)[C@H](O)[C@@H]1O
Reaction time: 60 h

Procedure:
To a solution of L-ascorbic acid in water is added Pd/C (10%). The mixture is subjected to hydrogenation in a Parr hydrogenator at 48 psi, 18° C. for about 2 to 3 days. The reaction mixture is filtered and the filtrate is concentrated in vacuo to afford L-gulonic γ-lactone, after drying at 50° C. in a vacuum oven for about 1 to 3 hours.