Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1N2C3N(C=C4C=CC(C(N)=O)=CN4C=3)C=CC2=CC=C1.N1CCCC[C@H]1CCN.[F:31][C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=1[CH2:39][NH:40][C:41]([C:43]1[C:44](=[O:70])[C:45]([O:62]CC2C=CC=CC=2)=[C:46]2[C:59](=[O:60])[N:50]3[CH2:51][CH2:52][C@@H:53]4[CH2:58][CH2:57][CH2:56][CH2:55][N:54]4[C@@H:49]3[CH2:48][N:47]2[CH:61]=1)=[O:42]>>[F:31][C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=1[CH2:39][NH:40][C:41]([C:43]1[C:44](=[O:70])[C:45]([OH:62])=[C:46]2[C:59](=[O:60])[N:50]3[CH2:51][CH2:52][C@@H:53]4[CH2:58][CH2:57][CH2:56][CH2:55][N:54]4[C@@H:49]3[CH2:48][N:47]2[CH:61]=1)=[O:42]
Reactant: O=C(NCc1ccc(F)cc1F)c1cn2c(c(OCc3ccccc3)c1=O)C(=O)N1CC[C@@H]3CCCCN3[C@@H]1C2
Agent: NC(=O)C1=CN2C=C3N(C=CC4=CC=CCN43)C=C2C=C1
Agent: NCC[C@@H]1CCCCN1
Product: O=C(NCc1ccc(F)cc1F)c1cn2c(c(O)c1=O)C(=O)N1CC[C@@H]3CCCCN3[C@@H]1C2
Yield: 107.3 %

Procedure:
(4S,12aS)—N-[(2,4-Difluorophenyl)methyl]-9-hydroxy-8,10-dioxo-2,3,4,4a,5,6,8,10,14,14a-decahydro, 1H-pyrido[1,2-c]pyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-11-carboxamide. In a manner similar to that described in example Z-35, from {2-[(2S)-2-piperidinyl]ethyl}amine (28 mg, 0.218 mmol) and 16a (30 mg, 0.0638 mmol) was prepared (4aS,14aS)—N-[(2,4-difluorophenyl)methyl]-8,10-dioxo-9-[(phenylmethyl)oxy]-2,3,4,4a,5,6,8,10,14,14a-decahydro-1H-pyrido[1,2-c]pyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-11-carboxamide (29 mg, 82%). This material was deprotected in a second step similar to that described in example Z-37 to give the title compound as a white solid (26 mg, quantitative). 1H NMR (CDCl3) δ 12.44 (br s, 1H), 10.48 (s, 1H), 8.26 (s, 1H), 7.35 (m, 1H), 6.80 (m, 2H), 4.68-4.57 (m, 2H), 4.38 (m, 1H), 4.20 (m, 1H), 3.93 (s, 1H), 3.63-3.39 (m, 2H), 2.91 (m, 2H), 2.29 (br s, 1H), 2.02 (m, 1H), 1.69-1.45 (m, 4H), 1.30-1.24 (m, 2H), 1.12 (br s, 1H); ES+ MS: 459 (M+1).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:10][CH2:11][C:12]1[N:13]([CH2:25][C:26]2([OH:39])[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]2)[C:14]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=[CH:16][C:15]=2[N:24]=1)[CH3:9].[OH-].[Na+]>ClCCl.O>[CH2:8]([O:10][CH2:11][C:12]1[N:13]([CH2:25][C:26]2([OH:39])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[C:14]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=[CH:16][C:15]=2[N:24]=1)[CH3:9]
Reactant: CCOCc1nc2cnc3ccccc3c2n1CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOCc1nc2cnc3ccccc3c2n1CC1(O)CCNCC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Under a nitrogen atmosphere a mixture of trifluoroacetic acid (40 mL) and dichloromethane (200 mL) was chilled in an ice bath. A solution of tert-butyl 4-[(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]-4-hydroxypiperidine-1-carboxylate (20 g, Example 4 Parts A through E) in dichloromethane (200 mL) was slowly added. The reaction mixture was allowed to warm to ambient temperature, stirred for 6 hours, and then concentrated under reduced pressure to provide a dark amber oil. The oil was dissolved in water (200 mL), the pH was adjusted to 13 with 50% sodium hydroxide, and the mixture was extracted with dichloromethane. The combined extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 15.2 g of 4-[(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]piperidin-4-ol as a tan frothy solid.
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=2[N+:19]([O-])=O)=[N:6][CH:7]=1.[NH4+].[Cl-].CCOC(C)=O>C1COCC1.O.[Fe]>[NH2:19][C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][C:9]=1[NH:8][C:5]1[CH:4]=[N:3][C:2]([Br:1])=[CH:7][N:6]=1)[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)c1ccc(Nc2cnc(Br)cn2)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Nc2cnc(Br)cn2)c(N)c1
Temperature: 65 °C
Yield: 74.1 %

Procedure:
Into a 250 mL 3-necked roundbottom flask, was placed a solution of methyl 4-(5-bromopyrazin-2-ylamino)-3-nitrobenzoate (x) (5.0 g, 14.2 mmol) in THF (75 mL). This was followed by the addition of a solution of NH4Cl (3.8 g, 71 mmol) in H2O (25 mL). To the above was added Fe (4.0 g, 71 mmol) in several batches, while warming to a temperature of 65° C. The resulting solution was allowed to react for 3 hours at 65° C. The reaction progress was monitored by TLC (EtOAc/PE=1:2). Undissolved material was removed by filtration. The filtrate was extracted three times with 200 mL of EtOAc and the organic layers were combined and dried (Na2SO4). After removal of the solvent, the residue was separated by silica gel chromatography eluting with a mixture of PE/EtOAc (starting at 10:1 and proceeding through 5:1, 3:1, and 2:1, v/v) to afford the product methyl 3-amino-4-(5-bromopyrazin-2-ylamino)benzoate (xi) (3.4 g, yield 74%) as a yellow solid.
Reaction SMILES: [NH2:1][C@@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.C(N(CC)C(C)C)(C)C.[CH2:34]([S:36](Cl)(=[O:38])=[O:37])[CH3:35]>C1COCC1>[CH2:34]([S:36]([NH:1][C@@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:38])=[O:37])[CH3:35]
Reactant: CCS(=O)(=O)Cl
Reactant: N[C@H](Cc1ccccc1)C(=O)O
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCS(=O)(=O)N[C@H](Cc1ccccc1)C(=O)O
Temperature: -78 °C
Reaction time: 12 h
Yield: 79 %

Procedure:
To a stirring suspension of D-phenylalanine (50 g, 300 mmol) in THF (400 mL) was added N,O-bis(trimethylsilyl) acetamide (92 g, 450 mmol). After stirring for 12 h, the solution was cooled to −78° C. and N,N-diisopropylethylamine (58 mL, 330 mmol) was added. To this solution was slowly added ethanesulfonyl chloride (31 mL, 330 mmol) and the cold bath was removed. After stirring for 20 h, the solvents were removed in vacuo and the residue was partitioned between saturated aqueous NaHCO3 and ethyl acetate. The aqueous phase was washed with diethyl ether, acidified with solid citric acid and extracted twice with ethyl acetate. The combined ethyl acetate extracts were washed with brine, dried with MgSO4, filtered and concentrated in vacuo to give 61 g (79%) of a thick colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].Cl[CH2:13][CH:14]1[CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>>[CH:14]1([CH2:13][O:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=2[O:10][CH3:11])[CH:5]=[O:6])[CH2:16][CH2:15]1
Reactant: COc1ccc(C=O)cc1O
Reactant: ClCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(C=O)cc1OCC1CC1
Temperature: 80 °C
Yield: 78.5 %

Procedure:
A vigorously stirred mixture of 3-hydroxy-4-methoxybenzaldehyde (20 g, 131 mmol), chloromethylcyclopropane (18.2 mL, 197 mmol) and powdered potassium carbonate (27.3 g, 197 mol) in dimethylflormamide (400 mL) was heated under an argon atmosphere at 80° C. for 9 h. The mixture was allowed to cool and was filtered through Celite. The filtrate was concentrated under reduced pressure, the residue was extracted twice with ethyl acetate, the organic extract was washed five times with saturated aqueous sodium carbonate and was dried (sodium sulfate). The solvent was removed in vacuo to provide an off-white solid (21.2 g, 78%): m.p. 67°-69° C.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH:6]([OH:23])[CH:7]([N:18]1[CH2:21][CH2:20][C:19]1=[O:22])[C:8]([O:10]CC1C=CC=CC=1)=[O:9])=[N+]=[N-]>[Pd].C(O)C.O>[NH2:1][CH2:4][CH2:5][CH:6]([OH:23])[CH:7]([N:18]1[CH2:21][CH2:20][C:19]1=[O:22])[C:8]([OH:10])=[O:9]
Reactant: [N-]=[N+]=NCCC(O)C(C(=O)OCc1ccccc1)N1CCC1=O
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: NCCC(O)C(C(=O)O)N1CCC1=O
Yield: 6 %

Procedure:
The fast moving diastereoisomer of benzyl 5-azido-3-hydroxy-2-(2-oxoazetidin-1-yl)valerate (0.76 g, 23.9 mmol) was hydrogenated over 5% palladium on carbon catalyst in ethanol (20 ml) and water (5 ml) for one hour. The catalyst was filtered off and the filtrate evaporated. The residual gum was triturated with ether to yield, after filtration the title compound as a pale yellow solid (456 mg, 97%). The yellow coloured impurity was removed by trituration with ethyl acetate. The title compound (400 mg) was further purified by column chromatography on silica gel (Merck Art. 9385) using water/ethanol (15:85) as eluant to yield the title compound (290 mg) as a white solid containing 1/7 molar equivalent of ethanol. δH (D2O, 400 MHz) 1.16 (t, CH3CH2OH), 1.84 (2H, m), 3.00 (2H, t, J 3.9 Hz), 3.15 (2H, m), 3.50 (1H, m), 3.58 (1H, m), 3.63 (q, CH3CH2OH), 4.07 (1H, d, J 5.4 Hz), 4.19 (1H, m), δC (D2O, 100 HMz), 31.66, 36.12, 37.61, 40.99, 63.19, 69.54, 174.79, and 174.97. Recrystallisation of a sample from aqueous methanol gave white prisms m.p. 130°-135°. νmax (KBr) 3349, 1723, 1653, 1611, 1390, 918 and 769. (Found: C, 43.93; H, 7.40; N, 12.49%. C8H14N2O4.H2O requires C, 43.63; H, 7.32; N, 12.72)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1.[CH3:12][S:13][C:14](=[N:17][C:18]#[N:19])SC>>[C:18]([NH:17][C:14](=[N:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)[S:13][CH3:12])#[N:19]
Reactant: CSC(=NC#N)SC
Reactant: NCCSCc1ccccn1
Product: CSC(=NCCSCc1ccccn1)NC#N

Procedure:
The reaction of 2-((2-aminoethyl)thiomethyl)pyridine with dimethylcyanodithioimidocarbonate by a method similar to that described in Example (3d) afforded N-cyano-N'-[2-(2-pyridylmethylthio)ethyl]-S-methylisothiourea, m.p. 85°-88°. (from isopropyl alcohol-ether)
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].BrCC1C=CC=C(C#N)C=1.[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]2([C:27]3=[CH:28][C:29]4[O:33][CH2:32][O:31][C:30]=4[CH:34]=[C:26]3[O:25][CH2:24]2)[C:16]1=[O:35]>>[O:35]=[C:16]1[C:17]2([C:27]3=[CH:28][C:29]4[O:33][CH2:32][O:31][C:30]=4[CH:34]=[C:26]3[O:25][CH2:24]2)[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:15]1[CH2:2][C:3]#[N:4]
Reactant: N#CCCl
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Agent: N#Cc1cccc(CBr)c1
Product: N#CCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 7 and making non-critical variations using chloroacetonitrile to replace α-bromo-m-tolunitrile, and spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, (2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetonitrile was obtained (61%) as a colorless solid: mp 170-172° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.38 (dt, J=7.7, 1.2 Hz, 1H), 7.26 (d, J=7.7 Hz, 1H), 7.20 (d, J=7.3 Hz, 1H), 7.11 (dt, J=7.7, 1.1 Hz, 1H), 6.66 (s, 1H), 6.21 (s, 1H), 5.89 (d, J=1.5 Hz, 2H), 4.94 (ABq, 2H), 4.73 (ABq, 2H); 13C NMR (75 MHz, DMSO-d6) δ 176.8, 155.8, 148.9, 142.2, 141.0, 131.9, 129.4, 124.3, 124.3, 119.8, 116.0, 109.7, 103.5, 101.9, 93.8, 80.1, 57.8, 28.8; MS (ES+) m/z 321.3 (M+1).
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].BrCC1CCCCO1.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]2([C:25]3=[CH:26][C:27]4[O:31][CH2:30][O:29][C:28]=4[CH:32]=[C:24]3[O:23][CH2:22]2)[C:14]1=[O:33]>>[O:33]=[C:14]1[C:15]2([C:25]3=[CH:26][C:27]4[O:31][CH2:30][O:29][C:28]=4[CH:32]=[C:24]3[O:23][CH2:22]2)[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:13]1[CH2:2][C:3]#[N:4]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Reactant: N#CCCl
Agent: BrCC1CCCCO1
Product: N#CCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using chloroacetonitrile to replace 2-(bromomethyl)tetrahydro-2H-pyran, and spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1H)-one, (2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetonitrile was obtained (61%) as a colorless solid: mp 170-172° C.; 1H NMR (300 MHz, DMSO-d6) δ7.38 (dt, J=7.7, 1.2 Hz, 1H), 7.26 (d, J=7.7 Hz, 1H), 7.20 (d, J=7.3 Hz, 1H), 7.11 (dt, J=7.7, 1.1 Hz, 1H), 6.66 (s, 1H), 6.21 (s, 1H), 5.89 (d, J=1.5 Hz, 2H), 4.94 (ABq, J=17.9 Hz, 2H), 4.73 (ABq, J=9.5 Hz, 2H); 13C NMR (75 MHz, DMSO-d6) δ176.8, 155.8, 148.9, 142.232, 141.0, 131.9, 129.4, 124.3, 124.3, 119.8, 116.0, 109.7, 103.5, 101.9, 93.8, 80.1, 57.8, 28.8; MS (ES+) m/z 321.3 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([O:14]C)=[CH:10][C:8]=2[CH:9]=1)=[O:4].B(Br)(Br)Br.S(Cl)(Cl)=O.O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:8]=2[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc2cc(OC)ccc2o1
Agent: BrB(Br)Br
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1cc2cc(O)ccc2o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.3 %

Procedure:
A solution of 5-methoxybenzofuran-2-carboxylic acid methyl ester (5.15 g, 25 mmol) in anhydrous methylene chloride (15 ml) was cooled to −40° under nitrogen atmosphere. Boron tribromide in CH2Cl2 (27 ml of 1.0 M) was added over 1 h using a syringe pump. The reaction mixture was allowed to warm to room temperature. After 16 h, the reaction mixture was cooled in an ice bath and quenched with MeOH (15 ml). The reaction mixture was poured into brine (100 ml) and extracted with EtOAc. The organic extracts were dried over anhydrous MgSO4, and the solvent was removed on rotary evaporator. The residue was triturated with hexane and the yellow solid was filtered and dissolved in anhydrous MeOH (30 ml). The solution was cooled in an ice bath and thionyl chloride (1.9 ml, 26 mmol) was added dropwise. After 72 h, water (100 ml) was added and solid was collected. Purification of the crude product on a 300 cm3 silica gel in a 5×15 cm plug using EtOAc provided 5-hydroxy-benzofuran-2-carboxylic acid methyl ester (4.53 g).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CN(C)C=O.[Br:12][C:13]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:23][CH2:24][C:25]([OH:27])=O>ClCCl>[Br:12][C:13]1[C:18]([C:19]([F:20])([F:21])[F:22])=[CH:17][CH:16]=[C:15]2[C:14]=1[CH2:23][CH2:24][C:25]2=[O:27]
Reactant: O=C(O)CCc1cccc(C(F)(F)F)c1Br
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C1CCc2c1ccc(C(F)(F)F)c2Br
Temperature: 25 °C

Procedure:
Oxalyl chloride (6.8 mL) and N,N-dimethylformamide (0.1 mL) are added to a solution of 3-(2-bromo-3-trifluoromethyl-phenyl)-propionic acid (15.7 g) in dichloromethane (150 mL) at room temperature. The solution is stirred at reflux temperature for 2 h and then concentrated. Trifluoromethane-sulfonic acid (60 ml) is added to the residue, and the resulting mixture is stirred at 55° C. for 4 h. After cooling to room temperature, the mixture is poured into ice-cold water, and the resulting mixture is stirred for 5 min. The precipitate formed is separated by filtration, washed with water, and dissolved in ethyl acetate. The solution is washed with aqueous NaHCO3 solution, dried (Na2SO4), and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 90:10→80:20) to afford the title compound. LC (method 4): tR=1.04 min.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][C@H:7]2[CH2:11][O:10][C:9](=[O:12])[NH:8]2)=[CH:4][CH:3]=1.[N:15]([O-])=O.[Na+].[OH-].[Na+]>O.Cl>[NH:1]([C:2]1[CH:14]=[CH:13][C:5]([CH2:6][C@H:7]2[CH2:11][O:10][C:9](=[O:12])[NH:8]2)=[CH:4][CH:3]=1)[NH2:15]
Reactant: Nc1ccc(C[C@H]2COC(=O)N2)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NNc1ccc(C[C@H]2COC(=O)N2)cc1

Procedure:
A mixture of (S)-4-(4-aminobenzyl)-1,3-oxazolidin-2-one (100 gms) and concentrated hydrochloric acid (250 ml) in water (500 ml) was treated with an 50% aqueous solution of sodium nitrite (46 gms) at −5 to 10° C. Upon completion of the reaction, as monitored by TLC, the reaction mass was further treated with stannous chloride dihydrate (420 gms) dissolved in concentrated hydrochloric acid (500 ml) and water (544 ml) at −15 to 10° C. When the reaction was complete, as monitored by HPLC, the pH of the reaction mass was adjusted in the range of 2.0 to 6.0 by adding aqueous sodium hydroxide solution. The reaction mass was cooled and filtered to separate the solid. The aqueous layer was extracted with dichloromethane and further made alkaline in the pH range of 6.0 to 10.0 with aqueous sodium hydroxide. The mixture was cooled and filtered to give solid (S)-4-(4-hydrazinobenzyl)-1,3-oxazolidin-2-one (III), which was then suspended in isopropanol (420 ml) and converted to the hydrochloride salt by treatment with hydrogen chloride at reflux temperature to yield the hydrochloride salt of (S)-4-(4-hydrazinobenzyl)-1,3-oxazolidin-2-one (IIIa).
Reaction SMILES: [C:1]([NH:8][C:9]1([C:12](O)=[O:13])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].CN1CCNCC1[Al+]C1CNCCN1C.CCOCC>O1CCCC1>[C:1]([NH:8][C:9]1([CH:12]=[O:13])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC1
Agent: CN1CCNCC1[Al+]C1CNCCN1C
Agent: [H-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1(C=O)CC1
Temperature: 0 °C

Procedure:
N-Boc-1-amino-1-cyclopropanecarboxylic acid is dissolved in tetrahydrofuran and stirred at 0° C. under argon. Bis(N-methylpiperazinyl)aluminum hydride is added and the reaction mixture is heated to reflux overnight. Ether is then added, and the excess hydride is quenched with saturated NaCl. The aqueous phase is separated and extracted with ether. The combined organic phase are washed with 2M NaOH, 2M HCl and saturated NaCl. The solution is dried over Na2SO4 and evaporated to yield N-Boc-1-amino-1-cyclopropanecarboxaldehyde.
Reaction SMILES: [N+:1]([CH3:4])([O-:3])=[O:2].[OH-].[K+].C([C:9]([O:11][CH2:12][CH3:13])=[O:10])#N.C([O-])=O.Cl>CS(C)=O>[N+:1]([CH2:4][C:9]([O:11][CH2:12][CH3:13])=[O:10])([O-:3])=[O:2]
Reactant: C[N+](=O)[O-]
Reactant: CCOC(=O)C#N
Agent: Cl
Agent: O=C[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)C[N+](=O)[O-]
Yield: 68 %

Procedure:
To a 100 ml three necked round bottom flask, equipped with a liquid addition funnel, a solid addition funnel and a condenser topped with a nitrogen inlet, was added 20 ml of dimethylsulfoxide and 1.08 g (0.0178 mole) nitromethane. 0.1 g (0.00178 mole) potassium hydroxide followed by 1 ml of a 20% solution of ethyl cyanoformate in (0.0021 mle) dimethylsulfoxide. The solution was stirred for a short period and the addition of each reactant (base and formate) was repeated nine times. The resultant solution remained homogeneous throughout the addition process, was stirred at ambient temperature for one hour and then acidified to pH of 4 with conc. hydrochloric acid. The product was extracted with ethyl acetate and dried with anhydrous magnesium sulfate. The magnesium sulfate was filtered off and solvent evaporated to give ethyl nitroacetate in 68% yield.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C1(C)C=CC=CC=1>[C:1]1([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Sc1ccccc1
Solvent: Cc1ccccc1
Product: c1ccc(Sc2ccccc2)cc1

Procedure:
A mixture of bis(dineophyl-orthotrifluoromethylphenyltin)oxide (6.0 g, 5.6 mmol) prepared in Example 6, thiophenol (1.2 g, 11.2 mmol) and toluene (40 g) was treated with the procedure described in Example 7. The product was recrystallized from n-hexane to obtain 5.2 g of dineophylorthotrifluoromethylphenyltin phenylsulfide as a white solid.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13](=[O:28])[C:14]2[CH:19]=[CH:18][C:17]([O:20]CC3C=CC=CC=3)=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C1CCCCC1>[OH-].[OH-].[Pd+2].C(O)C>[CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13](=[O:28])[C:14]2[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1ccc(OC(=O)c2ccc(OCc3ccccc3)cc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCCCC1
Product: CCCCCc1ccc(OC(=O)c2ccc(O)cc2)cc1
Yield: 93.2 %

Procedure:
15.6 g (41.5 mmol) of 4-benzyloxy-benzoic acid 4-pentyl-phenyl ester, 25 mL of cyclohexane and 0.78 g of palladium hydroxide/carbon were added to 100 mL of dehydrated ethanol and refluxed for 10 hours in the presence of argon. The resulting reaction mixture was filtered and the filtrate was concentrated. The residue was recrystallized from toluene to obtain 11.0 g of a white solid.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]([OH:8])=O.[NH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C[Si](C)(C)N[Si](C)(C)C>C(Cl)(Cl)Cl>[O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]([N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)=[O:8]
Reactant: O=C(O)C1CCCO1
Reactant: C1CNCCN1
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: ClC(Cl)Cl
Product: O=C(C1CCCO1)N1CCNCC1
Temperature: 110 °C
Reaction time: 5 h
Yield: 92.8 %

Procedure:
In a 100 ml round-bottom flask, tetrahydrofuran-2-carboxylic acid (3.48 grams, 30 mmole), piperazine (5.16 grams, 60 mmole) and 1,1,1,3,3,3-hexamethyldisilazane (4.83 grams, 30 mmole) were added, stirred under a nitrogen atmosphere and heated to 110° C. After 5 hours, the completion of the reaction was detected by thin-layer chromatography (TLC). After cooling to room temperature, the product was dissolved in chloroform, washed with a sodium hydrogen carbonate solution once and with water once. The organic layer was dried with anhydrous sodium sulfate, filtered, and applied suction to obtain 5.13 grams of Compound 3.
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][CH2:4][OH:5].[CH3:7][C:8]([CH3:12])=[CH:9][CH:10]=O>>[CH3:7][C:8](=[CH:9][CH2:10][CH2:1][C:2](=[CH:3][CH:4]=[O:5])[CH3:6])[CH3:12]
Reactant: CC(C)=CC=O
Reactant: CC(C)=CCO
Product: CC(C)=CCCC(C)=CC=O

Procedure:
100 parts of 3-methyl-2 -buten-1-ol and 50 parts of 3,3-dimethylacrolein are heated for ninety minutes at 200°C and a pressure of 40 atmospheres in a rocking autoclave having a capacity of 250 parts by volume. The reaction product is worked up by distillation. 12.5 parts of citral is obtained having a boiling point of 104°C at 12 mm. The yield (based on 3,3-dimethylacrolein) is 53% of theory at a conversion of 26%.
Reaction SMILES: [C:1]1(=[O:15])[N:5]([CH2:6][C:7](=[O:9])[CH3:8])[C:4](=[O:10])[C:3]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:2]12.NC(N)=O.[Br:20]Br>CO>[Br:20][CH2:8][C:7](=[O:9])[CH2:6][N:5]1[C:4](=[O:10])[C:3]2[C:2](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:1]1=[O:15]
Reactant: CC(=O)CN1C(=O)c2ccccc2C1=O
Reactant: BrBr
Agent: NC(N)=O
Solvent: CO
Product: O=C(CBr)CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 2.8 %

Procedure:
To a solution of phthalimidoacetone (4.04 g, 19.9 mmol) in methanol (100 mL) was added urea (1.19 g, 19.9 mmol) and bromine (3.18 g, 19.9 mmol) and the resulting solution was stirred at room temperature overnight. The reaction was concentrated in vacuo and the residue taken up in DCM (150 mL) and water (50 mL). The layers were separated and the organic layer was dried, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (EA/hexanes=0/100→50/50) to give 159 mg (3% yield) of the title compound. 1H NMR (300 MHz, CDCl3) δ: 7.90-7.86 (m, 2H), 7.79-7.73 (m, 2H), 4.78 (s, 2H), 4.01 (s, 2H).
Reaction SMILES: [O:1]=[CH: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].[O:13]=O>[Pd]>[O:1]=[C:2]([OH:13])[C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: O=O
Agent: [Pd]
Product: O=C(O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reaction time: 2.5 h

Procedure:
By using 27.0 g of the thus prepared catalyst (0.1% by weight based on glucose, calculated as palladium metal), an aqueous solution of glucose was oxidized at a temperature of 30° ± 3° C and a pH of 10.0 in the same manner as described in Example 1 except that air was used instead of the oxygen gas used in Example 1. The reaction was completed in 2.5 hours and a colorless transparent liquid was obtained. The content of gluconic acid in the solid obtained by concentration of the liquid was 98.0 wt.% and the saccharide residual ratio was 1.2 wt.%.