Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([Cl:8])[CH:3]=1.[Li+].CC([N-]C(C)C)C.Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C1COCC1>[CH2:21]([O:20][C:18](=[O:19])[C:3]1[C:2]([Br:1])=[CH:7][CH:6]=[N:5][C:4]=1[Cl:8])[CH3:22]
Reactant: CCOC(=O)Cl
Reactant: Clc1cc(Br)ccn1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c(Br)ccnc1Cl
Temperature: -78 °C
Reaction time: 0.58 h

Procedure:
To a solution of 4-bromo-2-chloropyridine (21.2 mmol) in 60 mL THF was added dropwise 11.7 mL of a solution of LDA (2M in THF) at −78° C. After stirring at −78° C. for 35 min, a solution of ethyl chloroformate (20.7 mmol) in 5 mL THF was added and the mixture was stirred at −78° C. for 2 h. The reaction was quenched with sat. aq. NaHCO3 solution and extracted with EtOAc (3×). The combined organic layers were dried over MgSO4 and concentrated in vacuo. Purification by (KP-SIL™ from Biotage) using Hept to Hept/EtOAc (8/2) gives the desired product as brown oil;
Reaction SMILES: [F:1][C@@H:2]1[C@@H:6]([CH2:7][OH:8])[O:5][C@@H:4]([N:9]2[C:19]3[N:18]=[C:16]([NH2:17])[NH:15][C:13](=[O:14])[C:12]=3[N:11]=[CH:10]2)[CH2:3]1.C1C=CC2N(O)N=NC=2C=1.[C:30]([NH:40][C@H:41]([C:45]([O:47][CH:48]([CH2:58][O:59][C:60](=[O:76])[C@H:61]([CH:73]([CH3:75])[CH3:74])[NH:62][C:63]([O:65][CH2:66][C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)=[O:64])[CH2:49][O:50][C:51](=[O:57])[CH2:52][CH2:53][C:54](O)=[O:55])=[O:46])[CH:42]([CH3:44])[CH3:43])([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.CN(C=O)C>[F:1][C@@H:2]1[C@@H:6]([CH2:7][O:8][C:54](=[O:55])[CH2:53][CH2:52][C:51]([O:50][CH2:49][CH:48]([O:47][C:45](=[O:46])[C@H:41]([CH:42]([CH3:44])[CH3:43])[NH:40][C:30]([O:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[O:31])[CH2:58][O:59][C:60](=[O:76])[C@H:61]([CH:73]([CH3:75])[CH3:74])[NH:62][C:63]([O:65][CH2:66][C:67]2[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=2)=[O:64])=[O:57])[O:5][C@@H:4]([N:9]2[C:19]3[N:18]=[C:16]([NH2:17])[NH:15][C:13](=[O:14])[C:12]=3[N:11]=[CH:10]2)[CH2:3]1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(COC(=O)CCC(=O)O)OC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Reactant: Nc1nc2c(ncn2[C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(COC(=O)CCC(=O)OC[C@H]1O[C@@H](n2cnc3c(=O)[nH]c(N)nc32)C[C@@H]1F)OC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 2′,3′-dideoxy-3′-fluoroguanosine (0.538 g, 2 mmole), HOBT (0.327 g, 2.42 mmole), DMAP(29.3 mg, 0.24 mmole) and succinic acid 2,3-bis-(N-CBZ-L-valyloxy)-1-propyl ester (1.6 g, 2.42 mmole) was coevaporated two times with DMF and reduced to about 50 ml. DCC (0.536 g, 2.6 mmole) was added and the mixture was stirred 72 hours at room temperature. The mixture was filtered and the solution was evaporated under reduced pressure. 100 ml of ethyl acetate was added and the organic phase washed twice with 5% acetic acid, 5% sodium hydrogen carbonate and water. The organic phase was dried with sodium sulfate and evaporated under reduced pressure. The product was isolated by silica gel column chromatography. Yield: 0.65 g.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:20]([CH2:23][C@H:24]1[O:28][C:27](=[O:29])[N:26]([C:30]2[CH:35]=[CH:34][C:33]([S:36]([CH3:38])=[O:37])=[C:32]([F:39])[CH:31]=2)[CH2:25]1)=[N+]=[N-].O>O1CCCC1>[NH2:20][CH2:23][C@@H:24]1[O:28][C:27](=[O:29])[N:26]([C:30]2[CH:35]=[CH:34][C:33]([S:36]([CH3:38])=[O:37])=[C:32]([F:39])[CH:31]=2)[CH2:25]1
Reactant: CS(=O)c1ccc(N2C[C@@H](CN=[N+]=[N-])OC2=O)cc1F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)c1ccc(N2C[C@H](CN)OC2=O)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.9 %

Procedure:
A mixture of triphenylphosphine (0.092 g, 0.352 mmol) and 5-(S)-azidomethyl-3-[4′-methylsulfinyl-3′-fluorophenyl]oxazolidine-2-one (0.100 g, 0.335 mmol) in tetrahydrofuran (2 ml) was stirred at r.t. for 4 h. Water (0.1 ml, 5.36 mmol) was added, and the mixture heated at 40° C. overnight. Solvent was evaporated under vacuum and the residue purified by PTLC (10% methanol in DCM) to give product as a white solid (0.082 g, 86%). MS (m/z): [M+H]+=273.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[O:12]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[O:15][CH2:14][CH2:13]1.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([C:20]1[CH:19]=[CH:18][C:17]2[O:12][CH2:13][CH2:14][O:15][C:16]=2[CH:21]=1)=[O:5]
Reactant: O=C(Cl)c1cc(I)ccc1Br
Reactant: c1ccc2c(c1)OCCO2
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(c1ccc2c(c1)OCCO2)c1cc(I)ccc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.5 %

Procedure:
To a stirred solution of 2-bromo-5-iodo-benzoyl chloride (−158 g, 457 mmol) in DCM (1500 ml) was added benzo(1,4)-dioxane (65.8 ml, 549 mmol) at 0° C. To this reaction mixture, aluminum chloride (195.4 g, 1465 mmol) was added in portions. After stirring for overnight at room temperature, reaction mixture was poured into crushed ice. This was extracted with dichloromethane (1000 ml×2). Dichloromethane layer was washed with water (1000 ml), saturated aqueous sodium bicarbonate solution (1000 ml×2), brine (1000 ml), dried over sodium sulfate, and concentrated. The solid product was triturated with hexanes. The product was dried under vacuum to give 180 g of (2-bromo-5-iodo-phenyl)-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-methanone.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]#[N:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH3:13]I.[Cl-].[NH4+]>C1COCC1>[CH3:13][C:8]1([C:11]#[N:12])[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1
Reactant: N#CC1CCC2(CC1)OCCO2
Reactant: CI
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(C#N)CCC2(CC1)OCCO2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 101.4 %

Procedure:
A 1.6M solution of Butyllithium in THF (14.6 mL, 23.3 mmol) was slowly added over 10 min to a solution of diisopropylamine (3.54 mL, 25.15 mmol) in 11 mL of anhydrous THF at −40° C. under nitrogen. The resulting mixture was stirred for 30 min at −40° C. and the solution of lithium diisopropylamide obtained was transferred dropwise over 15 min to a 0° C. solution of 1,4-Dioxa-spiro[4.5]decane-8-carbonitrile (3.00 g, 17.9 mmol) in 25 of anhydrous THF. The reaction mixture was stirred 15 min at 0° C. and methyl iodide (3.35 mL, 53.8 mmol) was added dropwise over 15 min. The resulting mixture was stirred 30 min at 0° C. then, 30 min at room temperature. A portion of 20 mL of saturated aqueous ammonium chloride was added. It was extracted with ether (3×150 mL). The organic portions were combined, dried over anhydrous Na2SO4 and concentrated. Drying under vacuum for 30 min afforded the desired 8-methyl-1,4-dioxa-spiro[4.5]decane-8-carbonitrile as a yellow solid (3.29 g, 101%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([NH:13][C:14]2[C:15]3[N:16]([CH:27]=[CH:28][N:29]=3)[N:17]=[C:18]([C:20]3[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=3)[CH:19]=2)[CH:10]=[CH:9][CH:8]=1.C([O-])([O-])=O.[K+].[K+].CS(O[CH2:41][CH2:42][N:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1)(=O)=O.O>CN(C=O)C>[CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([NH:13][C:14]2[C:15]3[N:16]([CH:27]=[CH:28][N:29]=3)[N:17]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:41][CH2:42][N:43]4[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]4)[CH:21]=3)[CH:19]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: CS(=O)(=O)OCCN1CCCCC1
Reactant: CC1CCCN1c1cccc(Nc2cc(-c3cccc(O)c3)nn3ccnc23)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1CCCN1c1cccc(Nc2cc(-c3cccc(OCCN4CCCCC4)c3)nn3ccnc23)n1
Temperature: 50 °C
Yield: 40.2 %

Procedure:
To a mixture of 3-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)phenol (40 mg, 0.1 mmol) and K2CO3 (28 mg, 0.2 mmol) in DMF (5 mL) was added 2-(piperidin-1-yl)ethyl methanesulfonate (25 mg, 0.12 mmol). The mixture was heated at 50° C. for 16 h. After cooling, the mixture was poured into water and extracted with EtOAc (8 mL 3). The combined organic layers were washed with brine, then dried over MgSO4. After filtration and concentration, the residue was purified by chromatography (silica gel, EtOAc) to give N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)-6-(3-(2-(piperidin-1-yl)ethoxy)phenyl)imidazo[1,2-b]pyridazin-8-amine (20 mg, 40%). 1H NMR (300 MHz, CDCl3): δ 8.67 (s, 1H), 8.08 (s, 1H), 7.93 (s, 1H), 7.60-7.53 (m, 3H), 7.45-7.37 (m, 2H), 7.05-7.01 (m, 1H), 6.23 (d, 1H, J=7.5 Hz), 6.04 (d, 1H, J=8.4 Hz), 4.31-4.21 (m, 3H), 3.71-3.65 (m, 1H), 3.54-3.48 (m, 1H), 2.85 (t, 2H, J=6.0 Hz), 2.57 (brs, 4 h), 2.17-2.04 (m, 3H), 1.76-1.62 (m, 5H), 1.48 (brs, 2H), 1.26 (d, 3H, J=6.6 Hz). LC/MS: 498 [M+H]+, tR=1.15 min. HPLC: 99.14% at 214 nm, 99.51% at 254 nm, tR=3.97 min.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=S)[NH:10][NH2:11].Cl[CH:14]([C:20]([CH3:22])=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16].Cl.O>C(O)C.CC(C)=O.CO>[CH3:22][C:20]1[NH:11][N:10]=[C:9]([NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: Cc1ccccc1NC(=S)NN
Reactant: CCOC(=O)C(Cl)C(C)=O
Agent: Cl
Solvent: CCO
Solvent: CO
Solvent: O
Product: CCOC(=O)c1c(Nc2ccccc2C)n[nH]c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A stirred slurry of 4-(2-methylphenyl)-3-thiosemicarbazide, 15.3 g (0.08 mole), in 100 mL of absolute ethanol was treated under nitrogen atmosphere with ethyl 2-chloroacetoacetate, 13.61 g (0.08 mole). After stirring for 1 hr the slurry had turned from white to yellow with most of the material going into solution. The reaction mixture was treated with 50 mL of 2N ethanolic hydrogen chloride and stirred for 18 hr., after which the reaction mixture was heated at reflux for 2 hours. A clear orange solution was decanted from some residual material. The hot solution was filtered through a sintered glass filter and the filtrate concentrated in vacuo to give a yellow solid residue. This residue was dissolved in 500 mL of acetone and 50 mL methanol. After filtering, the volume of the filtrate was concentrated to 125 mL under nitrogen atmosphere. The product was allowed to crystallize at ~7-10° C. for ~72 hr. Some sulfur crystals separated and were removed by filtration. The filtrate was again concentrated in vacuo to a solid. The solid was dissolved in hot acetone and upon cooling at ~7-10° C., long needle-like crystals formed and redissolved on warming to room temperature. The solution was treated with water and overnight gave pale, yellow needle-like crystals which, after drying, weighed 15 g, mp 156°-160° C. After 3 recrystallizations from benzene/ligroin a fine white crystalline solid was obtained (8.6 g, mp 160°-161° C.).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].C[N:14]1[CH2:19][CH2:18]N[CH2:16][CH2:15]1>C(O)C>[N+:10]([C:7]1[CH:8]=[CH:9][C:2]([N:14]([CH2:19][CH3:18])[CH2:15][CH3:16])=[C:3]([CH:6]=1)[C:4]#[N:5])([O-:12])=[O:11]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: CN1CCNCC1
Solvent: CCO
Product: CCN(CC)c1ccc([N+](=O)[O-])cc1C#N
Reaction time: 1 h
Yield: 70.5 %

Procedure:
2-Chloro-5-nitrobenzonitrile (15 g) and methylpiperazine (9.8 g) were added to ethanol (100 ml) and the mixture was stirred at a refluxing temperature for 1 h. The solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue to allow crystallization. The crystals were recrystallized from hydrous ethanol to give 5-nitro-2-diethylaminobenzonitrile (12.7 g), melting point: 83–85° C.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[SH:11][C:12]1[S:13][CH:14]=[C:15]([C:17]2[CH2:18][C@H:19]([CH3:29])[N:20]([C:23]([O:25][CH2:26][CH:27]=[CH2:28])=[O:24])[CH2:21][CH:22]=2)[N:16]=1.O(P(OC1C=CC=CC=1)O[C:39]1[C@H:45]([CH3:46])[C@H:44]2[N:41]([C:42](=[O:54])[C@@H:43]2[C@H:47]([O:49][Si:50]([CH3:53])([CH3:52])[CH3:51])[CH3:48])[C:40]=1[C:55]([O:57][CH2:58][CH:59]=[CH2:60])=[O:56])C1C=CC=CC=1.C(#N)C>C1COCC1>[CH2:26]([O:25][C:23]([N:20]1[CH2:21][CH:22]=[C:17]([C:15]2[N:16]=[C:12]([S:11][C:39]3[C@H:45]([CH3:46])[C@H:44]4[N:41]([C:42](=[O:54])[C@@H:43]4[C@H:47]([O:49][Si:50]([CH3:51])([CH3:52])[CH3:53])[CH3:48])[C:40]=3[C:55]([O:57][CH2:58][CH:59]=[CH2:60])=[O:56])[S:13][CH:14]=2)[CH2:18][C@@H:19]1[CH3:29])=[O:24])[CH:27]=[CH2:28]
Reactant: C=CCOC(=O)N1CC=C(c2csc(S)n2)C[C@@H]1C
Reactant: C=CCOC(=O)C1=C(OP(Oc2ccccc2)Oc2ccccc2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C)C(=O)N12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CC#N
Solvent: C1CCOC1
Product: C=CCOC(=O)C1=C(Sc2nc(C3=CCN(C(=O)OCC=C)[C@@H](C)C3)cs2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C)C(=O)N12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 47 %

Procedure:
A solution of lithium hexamethyldisilazide in THF (1M, 0.30 ml, 0.30 mmol) was added at 0–5° C. to a solution of allyl (2S)-4-(2-mercapto-1,3-thiazol-4-yl)-2-methyl-3,6-dihydro-1(2 H)-pyridinecarboxylate (89 mg, 0.30 mmol) in THF (2.0 ml) and the mixture was stirred for 10 minutes. To the reaction solution was added at 0° C. a solution of allyl (4R,5R,6S)-3-[(diphenoxyphosphino)oxy]-4-methyl-7-oxo-6-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate in acetonitrile (30%, 1.2 g, 0.60 mmol) and the solution was allowed to stand in a refrigerator for 16 hours. To the reaction solution was added ice water and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After removal of the solvent in vacuo, the residue was purified with silica gel chromatography (hexane/ethyl acetate: 1/4→1/3) to give allyl (4R,5S,6S)-3-[(4-{(2S)-1-[(allyloxy)carbonyl]-2-methyl-1,2,3,6-tetrahydro-4-pyridinyl}-1,3-thiazol-2-yl)sulfanyl]-4-methyl-7-oxo-6-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (87 mg, 47%).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([O:17][C:18]([F:21])([F:20])[F:19])[CH:10]=1.[C:22]([O:25][CH2:26][C:27](Cl)=[O:28])(=[O:24])[CH3:23]>C(Cl)Cl>[C:22]([O:25][CH2:26][C:27]([NH:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([O:17][C:18]([F:19])([F:20])[F:21])[CH:10]=1)=[O:28])(=[O:24])[CH3:23]
Reactant: N#Cc1ccc(N)cc1OC(F)(F)F
Reactant: CC(=O)OCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCC(=O)Nc1ccc(C#N)c(OC(F)(F)F)c1
Reaction time: 0.25 h
Yield: 83.2 %

Procedure:
Triethylamine (6.5 g, 64.2 mmol) was added to a stirred solution of 4-amino-2-[(trifluoromethyl)oxy]benzonitrile (Intermediate 51, 6.5 g, 32.2 mmol) in DCM (100 mL) at 0° C. and the mixture was stirred for 15 min. Chloro-2-oxoethyl acetate (5.2 g, 38.1 mmol) was added at 0° C. and stirring was continued for 4 hr at room temperature. The reaction mixture was diluted with DCM and washed with ice-water, saturated aq. NaHCO3 solution and brine solution, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude product. This was purified by column chromatography (100-200 mesh silica gel), eluting with 30% EtOAc/pet ether to give the title compound (8.10 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]([O:12][CH3:13])=[O:11])[S:7][C:8]=1[CH3:9])([O-:3])=[O:2].[CH2:14]([O:21][C:22]1[CH:29]=[C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:27]=[CH:26][C:23]=1[CH:24]=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.N1CCCC1>C(O)C>[CH2:14]([O:21][C:22]1[CH:29]=[C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:27]=[CH:26][C:23]=1/[CH:24]=[CH:9]/[C:8]1[S:7][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:5][C:4]=1[N+:1]([O-:3])=[O:2])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Reactant: COC(=O)c1cc([N+](=O)[O-])c(C)s1
Solvent: CCO
Solvent: C1CCNC1
Product: COC(=O)c1cc([N+](=O)[O-])c(/C=C/c2ccc(OCc3ccccc3)cc2OCc2ccccc2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.3 %

Procedure:
To a solution of methyl 4-nitro-5-methylthiophene-2-carboxylate (1.50 g, 7.46 mmol) in ethanol (7.5 ml) were added 2,4-bisbenzyloxybenzaldehyde (2.49 g, 7.83 mmol) and pyrrolidine (0.65 ml, 7.83 mmol). After stirring for 1 hr with heating under reflux, the reaction mixture was allowed to cool to room temperature. The precipitated solid was collected by filtration. The solid was washed with ethanol (3 ml×3), and dried under reduced pressure to give methyl (E)-5-[2-(2,4-bisbenzyloxyphenyl)vinyl]-4-nitrothiophene-2-carboxylate (3.08 g, yield 82%).
Reaction SMILES: C(O[CH2:5][C:6]([CH3:27])=[CH:7][CH:8]=[C:9]([CH3:26])[CH:10]=[CH:11][CH:12]=[C:13]([CH3:25])[CH:14]=[CH:15][C:16]1[C:21]([CH3:23])([CH3:22])[CH2:20][CH2:19][CH2:18][C:17]=1[CH3:24])(=O)C.[S-:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[Na+]>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C.C(OCC)C>[C:29]1([S:28][CH2:5][C:6]([CH3:27])=[CH:7][CH:8]=[C:9]([CH3:26])[CH:10]=[CH:11][CH:12]=[C:13]([CH3:25])[CH:14]=[CH:15][C:16]2[C:21]([CH3:22])([CH3:23])[CH2:20][CH2:19][CH2:18][C:17]=2[CH3:24])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: [S-]c1ccccc1
Reactant: CC(=O)OCC(C)=CC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C=CC1=C(C)CCCC1(C)C)=CC=CC(C)=CC=C(C)CSc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1.85 g (5 mmol) of 2,5,9-trimethyl-11-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8,10-undecapentaenyl acetate in 25 ml of anhydrous THF and 8 ml of HMPA is added in portions 0.68 g (5.2 mmol) of sodium thiophenoxide. The resulting mixture is stirred at room temperature for 18 hours and then taken up in 250 ml of diethyl ether. The solution is washed with saturated aqueous NH4Cl and water, dried and evaporated in vacuo to give an oil. Purification on a silica gel dry column gives the desired product.
Reaction SMILES: [Na][Na].C(CN1C(S)=NN=N1)(O)=O.N(CC1C=CC=CC=1CC(NC1C(=O)N2C(C(O)=O)=C(COC(=O)C)CS[C@H]12)=O)=[N+]=[N-].[N:44]([CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[CH2:54][C:55]([NH:57][CH:58]1[C:79](=[O:80])[N:60]2[C:61]([C:76]([OH:78])=[O:77])=[C:62]([CH:65]([S:70][C:71]3[NH:75][N:74]=[N:73][N:72]=3)[CH2:66][C:67]([OH:69])=[O:68])[CH2:63][S:64][C@H:59]12)=[O:56])=[N+]=[N-].C(=O)(O)[O-].[Na+].[H][H]>[Ni].O>[NH2:44][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[CH2:54][C:55]([NH:57][CH:58]1[C:79](=[O:80])[N:60]2[C:61]([C:76]([OH:78])=[O:77])=[C:62]([CH:65]([S:70][C:71]3[NH:72][N:73]=[N:74][N:75]=3)[CH2:66][C:67]([OH:69])=[O:68])[CH2:63][S:64][C@H:59]12)=[O:56]
Reactant: [H][H]
Reactant: [N-]=[N+]=NCc1ccccc1CC(=O)NC1C(=O)N2C(C(=O)O)=C(C(CC(=O)O)Sc3nnn[nH]3)CS[C@H]12
Agent: [Ni]
Agent: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3ccccc3CN=[N+]=[N-])[C@H]2SC1
Agent: O=C(O)Cn1nnnc1S
Solvent: O
Product: NCc1ccccc1CC(=O)NC1C(=O)N2C(C(=O)O)=C(C(CC(=O)O)Sc3nnn[nH]3)CS[C@H]12
Temperature: 0 °C

Procedure:
The aqueous filtrate from the above nucleophilic displacement with disodium salt of 1-carboxymethyl-5-mercaptotetrazole on 4.4 g. of 7-(2-azidomethylphenylacetamido)-3-acetoxymethyl-3-cephem-4-carboxylic acid in 100 ml. of water (or an aqueous solution of II that was adjusted to pH 7 with sodium bicarbonate) was placed in a hydrogenating bottle along with 4 g. of Raney nickel (washed until neutral with water) and shaken for one-half hour at room temperature and 50 psi of hydrogen (Paar hydrogenator). After the catalyst was filtered off, 50 ml. of ethyl acetate was added. The two-layer solution was cooled to 0° C. and then adjusted to pH 2.4 to 3 with 6N hydrochloric acid. The crude 7-(2-aminomethylphenylacetamido)-3-(1-carboxymethyltetrazol-5-ylthiomethyl-3-cephem-4-carboxylic acid that was suspended in the two layer solution was collected by filtration, washed once with 30 ml. of water and once with 30 ml. of ethyl acetate and was dried in vacuum to constant weight. The yield was 3.3 g. or 63.6% of theoretical (estimated by 1c to be 95% pure). A sample was purified and was found to be identical in every way to an authentic sample.
Reaction SMILES: [CH2:1]([S:7][C:8]1[N:16]=[CH:15][N:14]=[C:13]2[C:9]=1[N:10]=[CH:11][NH:12]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[F:17][C@@H:18]1[C@@H:22]([CH2:23][OH:24])[O:21][C@@H:20](N2C=CC(=O)NC2=O)[CH2:19]1.[N-]=[N+]=[N-].[K+].[C@@H]1(N2C=C(C)C(=O)NC2=O)O[C@H](CO)[C@@H](O)C1>P([O-])([O-])([O-])=O.[K+].[K+].[K+].CO>[F:17][C@@H:18]1[C@@H:22]([CH2:23][OH:24])[O:21][C@@H:20]([N:12]2[CH:11]=[N:10][C:9]3[C:13]2=[N:14][CH:15]=[N:16][C:8]=3[S:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:19]1
Reactant: O=c1ccn([C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]1
Reactant: CCCCCCSc1ncnc2[nH]cnc12
Agent: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCCCCCSc1ncnc2c1ncn2[C@H]1C[C@H](F)[C@@H](CO)O1
Temperature: 45 °C
Reaction time: 168 h
Yield: 59.8 %

Procedure:
6-Hexylthio-9H-purine (0.59 g, 2.5 mmoles) (Alfred Bader Division of Aldrich Chemical Company) and 2',3'-dideoxy-3'-fluorouridine (0.70 g, 3.0 mmoles) were suspended in 50 ml 10 mM potassium phosphate buffer, pH 7.0, containing 0.04% potassium azide. Purine nucleoside phosphorylase (1120 I.U.) and thymidine phosphorylase (10,000 I.U.) (Krenitsky, et al., Biochemistry, 20, 3615, 1981 and U.S. Pat. No. 4,381,344) immobilized on DEAE cellulose was added to the reaction and the suspension was stirred at 45° C. After 7 days, 193 ml MeOH was added to the reaction. The reaction was applied to a column containing AG1-X2 (OH-- form, 2.5×10 cm) and eluted with MeOH. Fractions containing product were pooled, concentrated, and flash chromatographed on silica gel (2.5×20 cm) with dichloromethane:acetone (95:5). Solvent was removed and lyophilization yielded 0.53 g of 9-(2,3-dideoxy-3-fluoro-β-D-erythro-pentofuranosyl)-6-hexylthio-9H -purine (59%): mp 46°-49° C.; TLC Rf 0.75 (silica gel, MeCN:15N NH4OH:H2O/85:5:10); [α]D20 -17.8 (c=0.5, DMF); UV λmax (ε×10-3) at pH 7, 293 (20.4); at pH 13, 293 (20.4); 1NMR (200 MHz, DMSO-d6) δ8.75 and 8.69 (2s, 2H, H2 and 8), 6.50 (dd, 1H, H1', J=8.9 Hz), J=5.8 Hz), 5.49 (dd, 1H, H3', J=53.2 Hz), J=4.4 Hz), 5.23 (t, 1H, OH5', J=5.4 Hz), 4.18-4.38 (m, 1H, H4'), 3.63 (t, 2H, H5' and H5", J=5.2 Hz), 3.34 (t, 2H, sCH2, J=7.2 Hz), 2.54-3.00 (m, 2H, H2' and H2"), 1.62-1.74, 1.23-1.44, and 0.81-0.88 (m, 11H); MS (ci) 355 (M+1), 335 (M-F), 237 (MH2 --C5H8FO2).
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[C:5]1([N:15]=[C:16]=[O:17])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1>O>[C:5]1([NH:15][C:16]([O:3][CH2:2][CH2:1][OH:4])=[O:17])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1
Reactant: O=C=Nc1cccc2ccccc12
Reactant: OCCO
Solvent: O
Product: O=C(Nc1cccc2ccccc12)OCCO
Reaction time: 3 h

Procedure:
Ethylene glycol (3.0 g) was mixed with α-naphthyl isocyanate (8.5 g), and reaction was allowed to proceed at room temperature for 3 hours, then at 50° C. for 2 hours. The reaction mixture was poured into water, which was subjected to extraction with chloroform. The extract was concentrated and subjected to purification by means of a silica gel chromatography(silica gel 400 g, developing solvent:hexane-ethyl acetate, 1:2→1:3).