Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:15][C:16]([C:19]3[C:20]([NH2:26])=[N:21][CH:22]=[C:23](Br)[CH:24]=3)=[N:17][N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[C:33]1([CH3:42])[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:15][C:16]([C:19]3[C:20]([NH2:26])=[N:21][CH:22]=[C:23]([C:36]4[CH:37]=[CH:38][C:33]([CH3:42])=[CH:34][CH:35]=4)[CH:24]=3)=[N:17][N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nnc(-c3cc(Br)cnc3N)o2)CC1
Reactant: Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(-c2cnc(N)c(-c3nnc(C4CCN(C(=O)OC(C)(C)C)CC4)o3)c2)cc1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
To a solution of 4-[5-(2-amino-5-bromo-pyridin-3-yl)-[1,3,4]oxadiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (500 mg, 1.179 mmol) in dioxane (20 mL) and water (10 mL) were added K2CO3 (488 mg, 3.537 mmol) and 4-tolyl boronic acid (179 mg, 1.297 mmol) in a sealed tube. The reaction mixture was degassed with N2 for 20 min, then Pd(PPh3)4 (136 mg, 0.118 mmol) was added to the reaction mixture at RT, The reaction mixture temperature was raised to 100° C., stirred for 18 h at 100° C. The reaction mixture was diluted with water (30 mL) extracted with ethyl acetate (3×30 mL) and organic layer was washed with brine, dried the organic layer over anhydrous sodium sulphate and concentrated under reduced pressure to affords the crude product. Crude was purified by column chromatography using 100-200 mesh silica gel compound eluted with 35% ethyl acetate in petroleum ether to afford the title compound as a white solid.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[N:19]=[CH:18][C:17]([CH2:20][N:21]2[CH2:26][CH2:25][S:24][CH2:23][CH2:22]2)=[CH:16][CH:15]=1.[B:27](OC(C)C)([O:32]C(C)C)[O:28]C(C)C>C1COCC1>[F:13][C:14]1[C:15]([B:27]([OH:32])[OH:28])=[CH:16][C:17]([CH2:20][N:21]2[CH2:26][CH2:25][S:24][CH2:23][CH2:22]2)=[CH:18][N:19]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Fc1ccc(CN2CCSCC2)cn1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: OB(O)c1cc(CN2CCSCC2)cnc1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
A solution of diisopropylamine (0.767 mL, 5.43 mmol) in 2 mL of THF at −40° C. was treated with n-butyllithium (3.4 ml of 1.6 M solution in hexanes, 5.43 mmol) and stirred at this temperature for 30 min. The solution was cooled to −78° C. and treated dropwise via cannula with a solution of 4-((6-fluoropyridin-3-yl)methyl)thiomorpholine (922 mg, 4.34 mmol) in THF (2+2 mL) over 10 min. The brown mixture was stirred at −78° C. for 90 min and then treated dropwise via syringe with a solution of triisopropyl borate (1.49 mL, 6.51 mmol) in THF (1 mL). The mixture was stirred at −78° C. for 30 min. The cooling bath was removed, and the reaction mixture was allowed to warm up to RT. The mixture was quenched with 1.0N NaOH (5 mL) and stirred for an additional 30 min. The mixture was transferred to a separatory funnel and extracted with 5 mL of ether. The ether layer was discarded, and the aqueous layer was carefully acidified with 2.5N aqueous HCl until acidic (pH 4 about 5) and the resulting cloudy mixture was diluted with EtOAc (50 mL). The separated aqueous layer was extracted with EtOAc (2×15 mL) and the combined organic extracts were washed with brine, dried (Na2SO4), filtered, and concentrated to give 2-fluoro-5-(thiomorpholinomethyl)pyridin-3-ylboronic acid (790 mg, 3.08 mmol, 71.0% yield) as an off-white crystalline solid. 1H NMR (400 MHz, d4-MeOH) δ 8.11 (1H, d, J=2.5 Hz); 8.00 (1H, dd, J=8.0, 2.5 Hz); 3.75 (2H, s.); 2.91 (4H, m); 2.73 (4H, br. s.). m/z (ESI, +ve ion) 257 (M+H)+.
Reaction SMILES: [CH:1]12[CH2:6][CH:5]1[CH2:4][N:3]([C:7]1[N:12]=[C:11]([NH:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([Cl:23])[CH:16]=3)[C:10]([C:24]([OH:26])=O)=[CH:9][N:8]=1)[CH2:2]2.[CH3:27][C:28]1[N:29]=[CH:30][C:31]([CH2:34][NH2:35])=[N:32][CH:33]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[CH:1]12[CH2:6][CH:5]1[CH2:4][N:3]([C:7]1[N:12]=[C:11]([NH:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([Cl:23])[CH:16]=3)[C:10]([C:24]([NH:35][CH2:34][C:31]3[CH:30]=[N:29][C:28]([CH3:27])=[CH:33][N:32]=3)=[O:26])=[CH:9][N:8]=1)[CH2:2]2
Reactant: COc1ccc(CNc2nc(N3CC4CC4C3)ncc2C(=O)O)cc1Cl
Reactant: Cc1cnc(CN)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(CNc2nc(N3CC4CC4C3)ncc2C(=O)NCc2cnc(C)cn2)cc1Cl
Reaction time: 18 h
Yield: 40.5 %

Procedure:
In THF (50 mL) were dissolved 2-(3-azabicyclo[3.1.0]hexan-3-yl)-4-((3-chloro-4-methoxybenzyl)amino)pyrimidine-5-carboxylic acid (202 mg, 0.54 mmol), (5-methylpyrazine-2-yl)methylamine (79 mg, 0.64 mmol) and triethylamine (0.2 mL). The solution was cooled in an ice bath and HATU (266 mg, 0.70 mmol) was then added. The reaction was conducted at ambient temperature for 18 h. The reaction mixture was concentrated, followed by addition of water and extraction with ethyl acetate. The organic phase was dried, concentrated, and purified by silica gel column chromatography (DCM/methanol=50/1) to give 2-(3-azabicyclo[3.1.0]hexan-3-yl)-4-((3-chloro-4-methoxybenzyl)amino)-N-((5-methylpyrazine-2-yl)methyl)pyrimidine-5-formamide (105 mg, 40% yield).
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].OCC([C@H]([C@@H]([C@H](CO)O)O)O)=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(CO)[C@@H](O)[C@H](O)[C@@H](O)CO
Product: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O

Procedure:
A series of resting cell reactions (0.5 ml reaction mixture in 5 ml reaction tube) was carried out with 2% D-sorbitol or with 2% L-sorbose, and all reaction mixtures further contained 0.3% NaCl, 1% CaCO3 and cells at a final concentration of 5 absorbance units at 600 nanometers (OD600). After 20 h incubation time, G. oxydans DSM 17078 produced 270 mg/l or 670 mg/l of Vitamin C, respectively from 2% D-sorbitol or 2% L-sorbose, respectively. In comparison, strain G. oxydans DSM 17078-dSMS 05 produced 1540 mg/l or 1990 mg/l of Vitamin C, respectively.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([CH:14]([O:22][C:23]2[C:31]3[N:30]=[C:29]([CH2:32][CH3:33])[NH:28][C:27]=3[CH:26]=[CH:25][CH:24]=2)CC2C=CC=CN=2)[C:8]=1[Cl:34])[CH3:6])=[O:4].[CH3:35][NH:36][C:37]([N:39]1[CH2:44][CH2:43][N:42]([CH2:45][CH2:46][C:47]([OH:49])=O)[CH2:41][CH2:40]1)=[O:38].ClC1C(COC2C3N=C(OC)N([CH2:70][C:71]4[CH:76]=[CH:75][CH:74]=[CH:73][N:72]=4)C=3C=CC=2)=C(Cl)C=CC=1N(C)C(=O)CNC(=O)CCC1C=CC(C(NCCOC)=O)=CC=1>>[Cl:34][C:8]1[C:9]([CH2:14][O:22][C:23]2[C:31]3[N:30]=[C:29]([CH2:32][CH3:33])[N:28]([CH2:70][C:71]4[CH:76]=[CH:75][CH:74]=[CH:73][N:72]=4)[C:27]=3[CH:26]=[CH:25][CH:24]=2)=[C:10]([Cl:13])[CH:11]=[CH:12][C:7]=1[N:5]([CH3:6])[C:3](=[O:4])[CH2:2][NH:1][C:47](=[O:49])[CH2:46][CH2:45][N:42]1[CH2:41][CH2:40][N:39]([C:37]([NH:36][CH3:35])=[O:38])[CH2:44][CH2:43]1
Reactant: CCc1nc2c(OC(Cc3ccccn3)c3c(Cl)ccc(N(C)C(=O)CN)c3Cl)cccc2[nH]1
Reactant: CNC(=O)N1CCN(CCC(=O)O)CC1
Reactant: COCCNC(=O)c1ccc(CCC(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc4c3nc(OC)n4Cc3ccccn3)c2Cl)cc1
Product: CCc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)CCN4CCN(C(=O)NC)CC4)c3Cl)cccc2n1Cc1ccccn1

Procedure:
2-Amino-N-[2,4-dichloro-3-(2-ethyl-1-pyridin-2-ylmethyl-1H-benzoimidazol-4-yloxymethyl)-phenyl]-N-methyl-acetamide and 3-(4-(methylcarbamoyl)piperazin-1-yl)propanoic acid were coupled as described for compound 1 above to give 19. MS (APCI) 694 (M+), 1HNMR (400 MHz, MeOD) δ 2.12 (t, 3H), 2.49 (t, 2H), 2.71 (m, 4H), 2.89 (s, 3H), 2.89 (m, 2H), 2.93 (q, 2H), 3.2 (s, 3H), 3.31 (m, 4H), 3.46-3.84 (dd, 3H), 5.55 (m, 4H), 6.93-8.51 (m, 9Har), LCMS 695 (M+1); C34H38Cl2N8O4+1.73 H2O; Calculated: C, 56.69; H, 5.98; N, 15.56. Found: C, 56.69; H, 6.18; N, 15.81.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[O-]CC.[Na+].CS(C)=O.[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[Cl:1][C:2]1[C:7]([O:8][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: ClCc1ccccc1
Reactant: Oc1cccnc1Cl
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CS(C)=O
Product: Clc1ncccc1OCc1ccccc1

Procedure:
2-Chloro-3-hydroxypyridine (9.47 g; 0.073 moles) was added to a solution of sodium ethoxide in ethanol (from sodium, 1.67 g; 0.073 g. atom). Sufficient dimethyl sulphoxide was added to dissolve all of the solid, and ethanol was removed in vacuo. To the resulting solution was added benzyl chloride (9.3 g; 0.073 moles) with cooling and stirring, and the reaction mixture was left to stir under reflux for 6 hours. Unreacted benzyl chloride, and solvent, were evaporated off under vacuum on a boiling water bath, and the residue was treated with water to precipitate out an oil which was extracted with chloroform, washed with N sodium hydroxide solution and dried over anhydrous magnesium sulfate. After removing the solvent, 2-chloro-3-benzyloxypyridine was obtained as a solid (11.63 g, mp 36°-8°).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].[F:11][C:12]([F:21])([F:20])[C:13]1[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][N:14]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:19][C:17]1[CH:16]=[CH:15][N:14]=[C:13]([C:12]([F:21])([F:11])[F:20])[CH:18]=1)[CH:5]=[O:6]
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: Oc1ccnc(C(F)(F)F)c1
Product: O=Cc1ccc(Oc2ccnc(C(F)(F)F)c2)c(F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 3,4-difluorobenzaldehyde and 2-(trifluoromethyl)pyridin-4-ol.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.[F:11][C:12]1[CH:13]=[CH:14][C:15]2[N:19]=[C:18]([CH:20]([NH2:22])[CH3:21])[N:17]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[C:16]=2[CH:30]=1.CCN(C(C)C)C(C)C>C(O)CCC>[F:11][C:12]1[CH:13]=[CH:14][C:15]2[N:19]=[C:18]([CH:20]([NH:22][C:2]3[N:10]=[CH:9][N:8]=[C:7]4[C:3]=3[N:4]=[CH:5][NH:6]4)[CH3:21])[N:17]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[C:16]=2[CH:30]=1
Reactant: Clc1ncnc2nc[nH]c12
Reactant: CC(N)c1nc2ccc(F)cc2n1-c1cccc(F)c1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1-c1cccc(F)c1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
To a microwave vessel was added 6-chloropurine (0.113 g, 0.732 mmol), 1-(6-fluoro-1-(3-fluorophenyl)-1H-benzo[d]imidazol-2-yl)ethanamine (Prepared in Example 22, 0.200 g, 0.732 mmol), and DIEA (0.256 mL, 1.46 mmol) in n-butanol (3.66 mL). The solution was stirred at 120° C. for 3 h, filtered and the resulting precipitate was washed with EtOAc:hexane (1:4) to give an off-white solid. The solid was purified by column chromatography on a silica gel column using 10 to 90% gradient of DCM:MeOH:NH4OH (90:10:1) in DCM as eluent to give an off-white solid. This material was triturated in EtOAc:hexane (1:3) and the suspension was filtered to give N-(1-(6-fluoro-1-(3-fluorophenyl)-1H-benzo[d]imidazol-2-yl)ethyl)-9H-purin-6-amine as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.60 (d, J=6.65 Hz, 3H) 5.57 (br. s., 1H) 6.94 (dd, J=8.90, 2.25 Hz, 1H) 7.11 (td, J=9.39, 2.35 Hz, 1H) 7.29 (t, J=7.04 Hz, 1H) 7.40-7.47 (m, 1H) 7.47-7.63 (m, 2H) 7.70 (dd, J=8.80, 4.89 Hz, 1H) 7.94 (s, 1H) 8.07 (s, 1H) 8.12 (s, 1H) 12.78 (br. s., 1H); LC-MS (ESI) m/z 392.1 [M+H]+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH:21]1[CH2:25][NH:24][C:23](=[O:26])[CH2:22]1.N(C(OCC)=O)=NC(OCC)=O.[C:39]([OH:42])(=[S:41])[CH3:40]>O1CCCC1>[C:39]([S:41][CH:21]1[CH2:25][NH:24][C:23](=[O:26])[CH2:22]1)(=[O:42])[CH3:40]
Reactant: O=C1CC(O)CN1
Reactant: CC(O)=S
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)SC1CNC(=O)C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
20-(1) 15.6 g of triphenylphosphine were added to a suspension of 3 g of 4-hydroxy-2-pyrrolidinone in 200 ml of tetrahydrofuran, and then the mixture was stirred at room temperature for 5 minutes, after which it was cooled to -20° C. A solution of 9.3 ml of diethyl azodicarboxylate in 9 ml of tetrahydrofuran was added dropwise, whilst cooling at -12° C. to -20° C., to the previous solution. The mixture was then stirred at 0°-5° C. for 5 minutes, after which it was again cooled to -20° C. 4.2 ml of thioacetic acid were then added dropwise to the mixture, whilst cooling at -18° C. to -20° C. The mixture was then warmed to 0-5° C. and stirred at that temperature for 2 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure. The residue was purified first by column chromatography through silica gel, eluted with a 10:1 by volume mixture of ethyl acetate and methanol, and then by column chromatography through silica gel, eluted with a 2:1 by volume mixture of acetonitrile and benzene, to give 2.45 g of 4-acetylthio-2-pyrrolidinone as colorless crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=O)[CH:14]=[CH:15][NH:16]2)=[CH:11][C:10]=1[CH2:20][CH2:21][CH2:22][CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:26].CN(C)C1C=CC=CC=1>>[ClH:26].[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([Cl:26])=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[CH2:20][CH2:21][CH2:22][CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCc1cc2c(=O)cc[nH]c2cc1OCc1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: CCCCc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Product: Cl
Temperature: 60 °C
Yield: 98.9 %

Procedure:
A suspension of 900 mg (2.93 mmol) of 7-benzyloxy-6-butyl-1H-quinolin-4-one in 1.44 ml of POCl3 (15.8 mmol) was treated with 0.074 ml of N,N-dimethylaniline and heated at 60° C. for 3 h with stirring. The reaction mixture was then poured into ice water and stirred for 0.5 h. The solid which precipitated was filtered off by suction washed with water and dried in a high vacuum to give 1.05 g (99%) of 7-benzyloxy-6-butyl-4-chloro-quinoline hydrochloride as light gray solid. ISP mass spectrum, m/e: XX (M+1 calculated for C20H20ClNO: 325.84).
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4][CH3:5].[N:6]1[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.C(Br)(CC)C>C1COCC1>[CH:3]([CH:14]1[C:15]2[N:6]=[CH:7][CH:8]=[CH:9][C:10]=2[CH2:11][CH2:12][CH2:13]1)([CH2:4][CH3:5])[CH3:2]
Reactant: c1cnc2c(c1)CCCC2
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCC(C)Br
Product: CCC(C)C1CCCc2cccnc21
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 89 %

Procedure:
A solution of BuLi (6.8 ml, 1.6 M in hexane) was added dropwise to a cold (−78° C.) solution of 5,6,7,8-tetrahydroquinoline (1.33 g, 10 mmol) in THF (20 ml). The mixture was stirred for 10 min at −78° C. and sec-butyl bromide (1.51 g, 11 mmol) was added dropwise. The mixture was allowed to warm up to room temperature during 1 h, was then carefully quenched with water and extracted with MTBE (3×50 ml). The combined organic phases were washed with water and brine, dried (MgSO4) and concentrated in vacuo. The brown residue was distilled bulb-to-bulb to yield 1.69 g (89%) of the title compound as a colorless oil. This is a general synthetic procedure and the other compounds exemplified were made according to this procedure, duly modified to employ the appropriate alkyl halide alkylating agent in order to add the correct alkyl group at the 8-position.
Reaction SMILES: [C:1]([NH:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([F:25])=[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:16]([C:17]#[N:18])=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].OO.S([O-])([O-])(=[O:32])=S.[Na+].[Na+]>CO.O.C(OCC)(=O)C>[F:25][C:14]1[N:11]2[CH2:12][CH2:13][N:8]([C:6]([NH:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][C:10]2=[C:16]([C:17]([NH2:18])=[O:32])[C:15]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=S([O-])([O-])=S
Reactant: CC(C)(C)NC(=O)N1CCn2c(F)c(-c3ccccc3)c(C#N)c2C1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)NC(=O)N1CCn2c(F)c(-c3ccccc3)c(C(N)=O)c2C1
Temperature: 60 °C
Reaction time: 2 h
Yield: 15.8 %

Procedure:
To a solution of 0.360 g (1.06 mmol) of N-tert-butyl-6-fluoro-8-cyano-7-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxamide in 4.2 ml of methanol is added 0.1 ml (1.1 mmol) of aqueous 35% sodium hydroxide solution and then 0.28 ml (3.2 mmol) of 35-volumes aqueous hydrogen peroxide solution. After stirring for 2 hours at 60° C., a further 0.05 ml (0.5 mmol) of 35-volumes aqueous hydrogen peroxide solution is added and the mixture is stirred for 16 hours at 60° C. After cooling, 0.25 g of sodium thiosulfate dissolved in 0.5 ml of water is added and the heterogeneous mixture is diluted with 75 ml of ethyl acetate. The organic phase is separated out, washed twice with 25 ml of water and then with 25 ml of saturated aqueous sodium chloride solution, after which it is dried over sodium sulfate. The solvent is evaporated off under reduced pressure to give a yellow oil, which is purified by chromatography on a column of silica gel, eluting with a mixture of 2 to 6% methanol in dichloromethane, to give 0.06 g of 6-fluoro-7-phenyl-N2-(tert-butyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2,8(1H)-dicarboxamide in the form of a solid after triturating in diisopropyl ether, filtering off and drying.
Reaction SMILES: C([O:8][C:9]1[C:10](=[N:29][OH:30])[N:11]([CH3:28])[CH:12]=[N:13][C:14]=1[C:15]1[O:16][C:17]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[N:18][N:19]=1)C1C=CC=CC=1.[H][H]>[Pd]>[F:27][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][C:17]2[O:16][C:15]([C:14]3[N:13]=[CH:12][N:11]([CH3:28])[C:10](=[N:29][OH:30])[C:9]=3[OH:8])=[N:19][N:18]=2)=[CH:26][CH:25]=1
Reactant: Cn1cnc(-c2nnc(Cc3ccc(F)cc3)o2)c(OCc2ccccc2)c1=NO
Reactant: [H][H]
Agent: [Pd]
Product: Cn1cnc(-c2nnc(Cc3ccc(F)cc3)o2)c(O)c1=NO
Yield: 68 %

Procedure:
5-Benzyloxy-6-[5-(4-fluoro-benzyl)-[1,3,4]oxadiazol-2-yl]-3-methyl-3H-pyrimidin-4-one oxime was hydrogenated at 1 atmosphere of hydrogen in the presence of equal weight of 10% Pd/C to give 68% yield of 6-[5-(4-fluoro-benzyl)-[1,3,4]oxadiazol-2-yl]-5-hydroxy-3-methyl-3H-pyrimidin-4-one oxime (COTI-HIV-1DOxime or, also referred to as COTI-HIV-1). Results are summarized below.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([SH:11])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C[O-].[Na+].C(NC1C=CC(S)=CC=1)(=O)C.[Na].[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30](Cl)[N:29]=1>CS(C)=O>[Cl:27][C:28]1[N:29]=[C:30]([S:11][C:8]2[CH:9]=[CH:10][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=2)[CH:31]=[CH:32][CH:33]=1
Reactant: Clc1cccc(Cl)n1
Reactant: CC(=O)Nc1ccc(S)cc1
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CS(C)=O
Product: CC(=O)Nc1ccc(Sc2cccc(Cl)n2)cc1
Temperature: 100 °C

Procedure:
4-Acetamidothiophenol (16.8 grams; 0.1 mole) was mixed with a solution of sodium methylate (prepared by mixing sodium metal (2.3 grams; 0.1 mole) in 90 ml. of methanol) and the resulting sodium 4-acetamidothiophenol solution added over a period of about one hour to a well-stirred solution of 2,6-dichloropyridine (14.8 grams; 0.1 mole) in 100 ml. of dimethylsulfoxide. The reaction mixture was distilled during the addition and the reaction temperature maintained at about 100° C. for this period and for a period of about two hours thereafter. The reaction mixture was then poured into 350 ml. of water and the resulting product precipitate recovered by filtration, washed several times and taken up in 300 ml. of hot benzene and dried and treated with Norite. About 350 ml. of hexane was added to precipitate the product from the benzene solvent which was recovered by filtration. As a result of such operations, the desired N-(4-((6-chloro-2-pyridinyl)thio)phenyl)acetamide compound was recovered as a crystalline solid which was found to have carbon, hydrogen, nitrogen, chlorine and sulfur contents of 56.2, 4.3, 9.9, 11.4 and 11.63 percent, respectively, as compared with the theoretical contents of 56.0, 3.96, 10.05, 12.7 and 11.45, respectively, calculated for the named structure.
Reaction SMILES: [CH3:1][Mg]Br.[F:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][C:6]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCCC1>[F:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]([OH:10])[CH3:1])=[CH:7][C:6]=1[O:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: C[Mg]Br
Reactant: O=Cc1ccc(F)c(Oc2ccccc2)c1
Solvent: C1CCOC1
Product: CC(O)c1ccc(F)c(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 103.3 %

Procedure:
A stirred solution of 34 ml (0.10 mole) of methylmagnesium bromide (3.0 M in diethyl ether) in 100 ml of tetrahydrofuran was cooled to 0° C., and 22.0 grams (0.10 mole) of 4-fluoro-3-phenoxybenzaldehyde was slowly added during a 30 minute period. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature at which it was stirred for two hours. At the end of this time the reaction was quenched with aqueous 10% hydrochloric acid, and the reaction mixture was extracted with two 100 ml portions of diethyl ether. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 24.0 grams of 1-(4-fluoro-3-phenoxyphenyl)ethanol. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[O:9]1[CH:14]=[CH:13][CH2:12][CH2:11][CH2:10]1>C(Cl)Cl.C1(C)C(S(O)(=O)=O)=CC=CC=1>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14][O:9]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(I)cc1
Reactant: C1=COCCC1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: ClCCl
Product: Ic1ccc(OC2CCCCO2)cc1
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 92.1 %

Procedure:
To a stirred solution of 4-iodophenol (11.0 g, 50 mmol) in CH2Cl2 (50 ml) cooled with an ice bath, dihydropyran (5.0 g, 60 mmol) was added dropwise over 10 min at 0° C. to 5° C. After the solution became clear, toluenesulfonic acid (TsOH′ 10 mg) was added. The solution was stirred at 20° C. for 15 min. Then it was quenched by addition of NaHCO3 (1 g) and 3 drops of water, and after stirring for 5 min at 20° C., the solvent was removed in vacuo and the residue was purified by column chromatography on silica gel with petroleum ether as eluent to give 14.0 g (92%) of 1 as colorless crystal; mp 66° C.; δH(CDCl3, 300 MHz): 7.55 (d, J=8.3, 2H, Ar—H), 6.83 (d, J=8.4, 2H, Ar—H), 5.37 (t, J=3.1, 1H, OCHO), 3.86 (m, 1H, THP), 3.59 (m, 1H, THP), 1.87˜1.58 (m, 6H, THP).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4]Cl.[N-:11]=[N+:12]=[N-:13].[Na+].O.C1CCCCC1>CS(C)=O>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4][N:11]=[N+:12]=[N-:13]
Reactant: Fc1cccc(F)c1CCl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: C1CCCCC1
Product: [N-]=[N+]=NCc1c(F)cccc1F
Temperature: 22.5 °C
Reaction time: 4 h
Yield: 100.9 %

Procedure:
A solution of 0.200 g (1.23 mmol) of 2,6-difluorobenzyl chloride in 0.5 mL of DMSO was added dropwise to a mixture of 0.090 g (1.23 mmol) of NaN3 in 2 mL of DMSO at 20-25° C. The reaction was left stirring at 20-25° C. during 4 h. until showing completion by TLC. The crude was treated with 1.6 mL of water and 1.6 mL of cyclohexane and the organic phase was vacuum distilled to obtain 0.210 g (97%) of 2,6-difluorobenzyl azide as yellowish oil