Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=O.[CH2:3]([SH:7])[CH2:4][CH2:5][CH3:6].CO.[OH-].[Na+]>O>[CH2:3]([S:7][S:7][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:4][CH2:5][CH3:6]
Reactant: CCCCS
Agent: O=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCSSCCCC
Reaction time: 1 h

Procedure:
This example illustrates the invention and shows that when the reaction liquid is circulated through a restricted area (aspirator) such that a more intimate contact with oxygen is made, the rate of reaction (rate of mercaptan conversion) is greatly increased. A 10-gallon glass-lined reactor, equipped with a Scott oxygen analyzer, reflux condenser, stirrer, thermocouple and circulating inlet tube as shown in FIG. 1 was charged with 38 pounds (0.42 pound moles) of n-butyl mercaptan, 17.2 pounds (0.432 pound moles) of methyl alcohol and 0.91 pounds (0.023 pound moles) of sodium hydroxide. The reactor was sealed and pressured with nitrogen to 220 psig. The stirrer was started and the liquid externally circulated at 1.5-2 gallons per minute using a Lawrence can pump by first passage through a heat exchanger and then being passed through an Ametex water jet exhauster (aspirator) having a 1.27 cm (0.50 in.) opening on the circulated side and a 0.635 cm (0.25 in.) opening on the suction side. The liquid was then returned to the vapor phase of the reactor. Oxygen was then added such that entry was made through the aspirator (see FIG. 1). The system was pressured to about 280 psig with the additional oxygen and the amount of oxygen present in the vapor phase of the reactor monitored by a Scott analyzer and maintained at about 20 mole percent. The reaction temperature immediately began to slowly rise such that after about 1 hour the temperature in the liquid phase of the reactor was about 60° C. (140° F.). The temperature was maintained between about 49° C.-60° C. (120° F.-140° F.) throughout the run. After 1 hour analysis indicated the reaction was 65 percent complete and after 2 hours the reaction was complete as determined by GLC. The product was separated and dried as previously described to give 33.3 pounds (88.6 mole percent yield) of essentially pure di-n-butyl disulfide. A comparison of the rates of reaction carried out by the closed system (Example I) and the circulating-intimate mixing system (Example II) is shown in Table I and FIG. 2. When another run employing the method described in Example II was carried out wherein the separated oil was distilled rather than air dried at 100° C.-120° C., the yield of di-n-butyl disulfide was increased giving 35 pounds (93.1 mole percent) of product.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[OH:6][C:7]1[CH:8]=[CH:9][C:10]([CH3:17])=[C:11]2[C:15]=1[C:14](=[O:16])[CH2:13][CH2:12]2>C(Cl)(Cl)(Cl)Cl>[OH:6][C:7]1[C:8]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:9][C:10]([CH3:17])=[C:11]2[C:15]=1[C:14](=[O:16])[CH2:13][CH2:12]2
Reactant: Cc1ccc(O)c2c1CCC2=O
Reactant: O=S(=O)(O)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(S(=O)(=O)Cl)c(O)c2c1CCC2=O
Temperature: 0 °C

Procedure:
Into a solution of 90 ml of chlorosulfonic acid in 150 ml of carbon tetrachloride was added 30 g of 7-hydroxy-4-methyl-1-indanone gradually under an ice-cooling condition. The carbon tetrachloride layer was removed by separation, and one liter of ice-water was added into the residual layer then the mixture was stirred vigorously. The solid matter precipitated was collected by filtration, then washed with water to obtain 8.7 g of 7-hydroxy-6-chlorosulfonyl-4-methyl-1-indanone. This product was added, without purified, to a solution consisting of 31.4 g of stannous chloride dihydrate and 100 ml of concentrated hydrochloric acid, and the mixture was stirred at a room temperature for 4 hours. The reaction mixture was poured into 500 ml of ice-water, the crystals precipitated were collected by filtration, washed with water, dried to obtain 7.86 g of 7-hydroxy-6-mercapto-4-methyl-1-indanone. Next, this product was suspended, without purified, in 100 ml of methanol, then to this suspension was added 3.9 ml of methyl iodide and a solution of 5.1 g of sodium bicarbonate in 20 ml of water, the whole mixture was stirred at a room temperature for 1 hour. The mixture was concentrated under a reduced pressure to remove the solvent to dryness. The residue was purified by means of a silica gel column chromatography (eluent: chloroform) and recrystallized from ethanol to obtain 1.52 g of 7-hydroxy-4-methyl-6-methylthio-1-indanone.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([C@@H:14]([NH:22][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[NH:12][CH:13]=2)=[CH:5][CH:4]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].[CH2:37](I)[CH3:38]>CN(C=O)C.O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([C@@H:14]([NH:22][C:23](=[O:30])[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:12]([CH2:37][CH3:38])[CH:13]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(-c2c[nH]c([C@H](Cc3ccccc3)NC(=O)c3ccccc3)n2)cc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1cc(-c2ccc(C#N)cc2)nc1[C@H](Cc1ccccc1)NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
The compound of Example 182 Part A (60 mg, 0.15 mmol) was dissolved in DMF (2.5 mL) and potassium carbonate (32 mg, 0.23 mmol) was added followed by ethyl iodide (0.015 mL, 0.19 mmol), and the resulting mixture was stirred overnight at room temperature. The reaction mixture was diluted with water and extracted with EtOAc (3×). The combined extracts were washed with water and brine, then dried over Na2SO4, filtered and evaporated. The residue was chromatographed on silica gel to provide the product (48 mg, 76%). 1H NMR (400 MHz, DMSO-D6) δ 1.17 (t, J=7.25 Hz, 3H) 3.34-3.48 (m, 2H) 3.89-4.05 (m, 2H) 5.46 (d, J=7.03 Hz, 1H) 7.14 (d, J=7.03 Hz, 1H) 7.21 (t, J=7.47 Hz, 2H) 7.31 (d, J=7.47 Hz, 2H) 7.41 (t, J=7.25 Hz, 2H) 7.48 (d, J=7.03 Hz, 1H) 7.76-7.84 (m, 3H) 7.88 (s, 1H) 7.94 (d, J=8.79 Hz, 2H) 9.08 (d, J=8.35 Hz, 1H). m/z 421.2 (M+H)+.
Reaction SMILES: I[C:2]1[N:3]=[C:4]([NH2:22])[C:5]2[N:6]=[C:7]([NH:20][CH3:21])[N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].[CH2:23]=[CH:24][CH2:25][CH2:26][CH2:27][CH3:28]>>[CH:23](/[C:2]1[N:3]=[C:4]([NH2:22])[C:5]2[N:6]=[C:7]([NH:20][CH3:21])[N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11])=[CH:24]\[CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: C=CCCCC
Reactant: CNc1nc2c(N)nc(I)nc2n1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Product: CCCC/C=C/c1nc(N)c2nc(NC)n([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Reaction time: 0.58 h

Procedure:
The reaction was performed with 2-iodo-8-methylaminoadenosine (7, 520 mg, 1.23 mmol) and (E)-1-borocatechol)-1-hexene (3.70 mmol). The mixture was purified by column chromatography (20% MeOH in CH2Cl2). Yield 42 mg (1.11 mmol, 9%), mp 161–166÷C; Rƒ 0.60 (20% MeOH in CH2Cl2); 1H NMR (MeOD-d4) δ 6.91–6.83 (m, 1H, ═CHCH2), 6.29 (d, 1H, J=15.44 Hz, ═CH), 5.98 (d, 1H, J=7.55 Hz, H-1′), 4.81–4.74 (m, 1H, H-2′), 4.29 (t, 1H, J=5.49 Hz, H-3′), 4.13 (m, 1H, H-4′), 3.82–3.79 (m, 2H, H-5′), 2.97 (m, 3H, NHCH3), 2.29–2.22 (m, 2H, ═CHCH2), 1.52–1.36 (m, 4H, CH2CH2), 0.94 (t, 3H, J=6.52 Hz, CH3); MS m/z 379 (M+H)+; HPLC, System A: 20–100% CH3CN in H2O in 35 min., retention time=6.15 min.; System B: 30–100% CH3OH in H2O in 40 min., retention time=18.67 min.
Reaction SMILES: C(Cl)Cl.[NH3:4].[CH:5]1[CH:10]=[C:9]2C(C(O)(O)[C:14](=[O:15])[C:8]2=[CH:7][CH:6]=1)=O>CO>[C:14]([NH2:4])(=[O:15])[C:8]1[CH:9]=[CH:10][CH:5]=[CH:6][CH:7]=1
Reactant: N
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Solvent: ClCCl
Solvent: CO
Product: NC(=O)c1ccccc1

Procedure:
RF 0.8 in 100:30:5/CH2Cl2:MeOH: 880 Ammonia, visualised with ninhydrin.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH2:16]([C:23]1[N:28]=[N:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([OH:35])=[C:31]([F:36])[CH:30]=2)=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1.CCOC(C)=O>[CH2:16]([C:23]1[N:28]=[N:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([O:35][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][CH:3]=3)=[C:31]([F:36])[CH:30]=2)=[CH:25][CH:24]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Oc1ccc(-c2ccc(Cc3ccccc3)nn2)cc1F
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc2nccc(Oc3ccc(-c4ccc(Cc5ccccc5)nn4)cc3F)c2cc1OC
Temperature: 180 °C

Procedure:
A mixture of 4-Chloro-6,7-dimethoxy-quinoline (0.19 g, 0.85 mmol), 4-(6-benzyl-pyridazin-3-yl)-2-fluoro-phenol (Step 3, 0.2 g, 0.71 mmol) and DMAP (0.1 g, 0.85 mmol) in 6 mL of toluene was heated in a microwave (Personal Chemistry, Emrys Optimizer) at 180° C. for 2 h. The mixture was cooled to RT and diluted with 60 mL of EtOAc. The solution was washed with 20 mL of brine 2×, dried over Na2SO4 and concentrated in vacuo. The residue was further purified with silica gel column chromatography (50% to 100% EtOAc in hexanes) to provide title compound as a white solid. MS (ESI pos. ion) m/z: 487.3 (M+H). Calc'd Exact Mass for C28H22FN3O3: 467.49.
Reaction SMILES: FC1C=CC([C:8]2[C:9]([NH2:37])=[N:10][CH:11]=[N:12][C:13]=2[N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[N:21]([CH3:36])[CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=CC=1.[C:38]([C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][C:41]=1[F:49])#[N:39]>>[NH2:37][C:9]1[C:8]([C:43]2[CH:44]=[CH:45][C:40]([C:38]#[N:39])=[C:41]([F:49])[CH:42]=2)=[C:13]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[N:21]([CH3:36])[CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:34])([F:33])[F:35])[CH:26]=4)[N:24]=3)[CH2:16][CH2:15]2)[N:12]=[CH:11][N:10]=1
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccc(F)cc2)CC1
Reactant: N#Cc1ccc(B(O)O)cc1F
Product: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccc(C#N)c(F)c2)CC1

Procedure:
The title compound was prepared in an analogous manner as 5-(4-Fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine using 4-cyano-3-fluorophenylboronic acid instead of 4-fluorophenylboronic acid. LC-MS: (M+1=540, obsd.=540).
Reaction SMILES: Cl.[F:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)=[N:8][O:9][C:5]=2[CH:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35](=[O:37])[CH3:36])=[C:31]([CH3:38])[CH:30]=1>CN(C)C=O.C(#N)C>[F:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]3[CH2:11][CH2:12][N:13]([CH2:25][CH2:26][CH2:27][O:28][C:29]4[CH:34]=[CH:33][C:32]([C:35](=[O:37])[CH3:36])=[C:31]([CH3:38])[CH:30]=4)[CH2:14][CH2:15]3)=[N:8][O:9][C:5]=2[CH:4]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: CC(=O)c1ccc(OCCCBr)cc1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: CC(=O)c1ccc(OCCCN2CCC(c3noc4cc(F)ccc34)CC2)cc1C
Temperature: 120 °C
Yield: 39.8 %

Procedure:
A stirred mixture of 6-fluoro-3(4-piperidinyl)-1,2 benzisoxazole hydrochloride (5.5 g, 21.6 mmol), K2CO3 (3.5 g), 1-[4-(3bromopropoxy)-2-methylphenyl]-ethanone (4.83 g, 17.8 mmol) in dimethylformamide (25 ml) and acetonitrile (75 ml) was heated at 120° C. for 5 hours. At the end of the reaction, the solvent was removed and the residue was extracted into dichloromethane (300 ml) and the solution was washed with water and brine. The organic solution was dried and evaporated to a crude oil. The purification was done by flash chromatography over a silica gel column (80 g, eluted with dichloromethane, 1 1; 1% methanol: dichloromethane, 1.2 1; 2% methanol:dichloromethane, 1.2 1). The purest fractions were combined and afforded 2.91 g of solid. Recrystallization from dichloromethane and ethanol gave 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxyl-2-methylphenyl]ethanone as off-white crystals: 2.42 g, m.p.=113°-114° C.
Reaction SMILES: [C:1]1([CH:7]([N:14]2[CH2:17][CH:16]([OH:18])[CH2:15]2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19]([CH:21]1[O:23][CH2:22]1)Cl>CS(C)=O.[OH-].[Na+]>[C:1]1([CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:14]2[CH2:17][CH:16]([O:18][CH2:19][CH:21]3[O:23][CH2:22]3)[CH2:15]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: ClCC1CO1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: c1ccc(C(c2ccccc2)N2CC(OCC3CO3)C2)cc1
Reaction time: 72 h

Procedure:
37.5 g of diphenylmethylazetidin-3-ol are dissolved at room temperature in a mixture of 250 ml of dimethyl sulphoxide and 150 ml of 5% strength sodium hydroxide solution, 65 ml of epichlorohydrin are added and the mixture is allowed to stand for 3 days at room temperature. The reaction mixture is extracted using 300 ml of methylene chloride, and the organic phase is dried over sodium sulphate and evaporated. The crude product is distilled in vacuo.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[N:28]=[C:27](F)[CH:26]=[CH:25][C:9]=2[C:10]([NH:12][C:13]2[CH:22]=[C:21]3[C:16]([CH2:17][CH2:18][C:19](=[O:24])[N:20]3[CH3:23])=[CH:15][CH:14]=2)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH:1]1([NH:7][C:8]2[N:28]=[C:27]([N:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[CH:26]=[CH:25][C:9]=2[C:10]([NH:12][C:13]2[CH:22]=[C:21]3[C:16]([CH2:17][CH2:18][C:19](=[O:24])[N:20]3[CH3:23])=[CH:15][CH:14]=2)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: CN1C(=O)CCc2ccc(NC(=O)c3ccc(F)nc3NC3CCCCC3)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1C(=O)CCc2ccc(NC(=O)c3ccc(N4CCCCC4)nc3NC3CCCCC3)cc21
Temperature: 60 °C
Reaction time: 18 h
Yield: 79 %

Procedure:
A mixture of 2-(cyclohexylamino)-6-fluoro-N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)nicotinamide (150 mg), piperidine (64 mg), potassium carbonate (63 mg) and DMF was stirred at 60° C. for 18 hours. Then, water was added, followed by extraction with ethyl acetate. After drying the organic layer with magnesium sulfate, the solution was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (basic silica gel, hexane:ethyl acetate, 2:1 to 1:1) to obtain 2-(cyclohexylamino)-N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)-6-piperidin-1-ylnicotinamide (138 mg) as a solid.
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].[H-].[Na+].Cl[CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[N:14]([CH3:27])[N:15]=[C:16]2[C:25]=1[C:24]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:18]=[C:17]2[NH2:26].[I-].[Na+]>CN(C=O)C>[NH2:26][C:17]1[C:16]2=[N:15][N:14]([CH3:27])[C:13]([CH2:12][CH2:11][CH2:10][CH2:9][NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[C:25]2[C:24]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N:18]=1
Reactant: Cn1nc2c(N)nc3ccccc3c2c1CCCCCl
Reactant: CS(N)(=O)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1nc2c(N)nc3ccccc3c2c1CCCCNS(C)(=O)=O
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 38.4 %

Procedure:
Methanesulfonamide (1.5 g, 16.5 mmol) was added to a suspension of sodium hydride (60% dispersion in mineral oil, 0.660 g, 16.5 mmol) in DMF (10 mL); the reaction was stirred for five minutes. 1-(4-Chlorobutyl)-2-methyl-2H-pyrazolo[3,4-c]quinolin-4-amine (0.952 g, 3.3 mmol) in DMF (1 mL) and sodium iodide (123 mg, 0.825 mmol) were sequentially added. The reaction was heated at 80° C. for four hours, allowed to cool to ambient temperature, and poured into ice water (70 mL). The resulting mixture was extracted with dichloromethane (6×50 mL), and the combined extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified twice by chromatography using a HORIZON HPFC system (40+M cartridge, eluting with 0-30% CMA in chloroform first and 5-10% methanol in dichloromethane second) followed by recrystallization from acetonitrile to provide 440 mg of N-[4-(4-amino-2-methyl-2H-pyrazolo[3,4-c]quinolin-1-yl)butyl]methanesulfonamide as light tan crystals, mp 188-189° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[CH:22]([NH:23][C:24](=[O:71])[C:25]([C:46]3[N:47]=[C:48]([NH:51][C:52]([C:65]4[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=4)([C:59]4[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=4)[C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=4)[S:49][CH:50]=3)=[N:26][O:27][CH:28]([C:30]([O:32][CH:33]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:31])[CH3:29])[C:21](=[O:72])[N:7]2[C:8]=1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)=[O:10].[I-:73].[Na+]>CC(C)=O>[I:73][CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[CH:22]([NH:23][C:24](=[O:71])[C:25]([C:46]3[N:47]=[C:48]([NH:51][C:52]([C:65]4[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=4)([C:59]4[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=4)[C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=4)[S:49][CH:50]=3)=[N:26][O:27][CH:28]([C:30]([O:32][CH:33]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:31])[CH3:29])[C:21](=[O:72])[N:7]2[C:8]=1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)=[O:10]
Reactant: COc1ccc(COC(=O)C2=C(CCl)CS[C@@H]3C(NC(=O)C(=NOC(C)C(=O)OC(c4ccccc4)c4ccccc4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1ccc(COC(=O)C2=C(CI)CS[C@@H]3C(NC(=O)C(=NOC(C)C(=O)OC(c4ccccc4)c4ccccc4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1

Procedure:
280 mg (0.28 mmol) of p-methoxybenzyl 3-chloromethyl-7-{(2-tritylamino-4-thiazolyl)-2-(1-diphenylmethoxycarbonyl-ethoxyimino)acetamido}-ceph-3-em-4-carboxylate-syn isomer was dissolved in 3 ml of acetone, and 1.0 ml of acetone solution containing 60 mg (0.4 mmol) of sodium iodide was added to the resulting solution at room temperature and reacted for 40 minutes. After the reaction, the solvent was distilled out, and methylene chloride was added to the resulting residue, the insoluble materials were filtered off, and the remaining filtrate was concentrated under reduced pressure, to obtain p-methoxybenzyl 3-iodomethyl-7- {2-(2-tritylamino-4-thiazolyl)-2-(1-diphenylmethoxycarbonyl-ethoxyimino)acetamido}-ceph-3-em- 4-carboxylate-syn isomer. To this was added 52 mg (0.34 mmol) of 1-(2-fluoroethyl)-4-pyridothione, and the resulting mixture was dissolved in 3 ml of chloroform and reacted for 1 hour at room temperature. After the reaction, the chloroform was distilled out under reduced pressure, and the residue was purified by silicagel-chromatography (chloroform/ethanol=10/1) and dissolved in 0.8 ml of anisol, and then, 4.0 ml of trifluoroacetic acid was added thereto, while cooled with ice, and reacted for 1 hour. After the reaction, isopropylether was added to the reaction solution to form a precipitate. After dried, 190 mg of a powder was obtained. To this was added 1 ml of water and the pH value of the resulting solution was adjusted to 7.8 with sodium hydrogencarbonate, and the solution was purified with HP-20 resin (methanol/H2O=1/4) to obtain 110 mg of the above-entitled compound.
Reaction SMILES: [CH2:1]([N:4]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:5][CH2:6][CH2:7][N:8]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:9]/[CH:10]=[CH:11]/[CH2:12][N:13]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:14][CH2:15][CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:2]=[CH2:3].[H-].[Na+].[CH3:48]I>CN(C=O)C>[CH2:1]([N:4]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:5][CH2:6][CH2:7][N:8]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:9]/[CH:10]=[CH:11]/[CH2:12][N:13]([C:25]([O:27][C:28]([CH3:31])([CH3:29])[CH3:30])=[O:26])[CH2:14][CH2:15][CH2:16][N:17]([CH3:48])[C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH:2]=[CH2:3]
Reactant: CI
Reactant: C=CCN(CCCN(C/C=C/CN(CCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCN(CCCN(C/C=C/CN(CCCN(C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C

Procedure:
To a solution of 0.6 g (0.936 mmol) of (E)-1-allyl-1,5,10,14-tetra-BOC-1,5,10,14-tetraazatetradec-7-ene (see Example 2a) in 8 ml of DMF there are added, with stirring, 0.075 g (1.875 mmol) of sodium hydride dispersion (approx. 60%) and, after 5 min., 0.117 ml (1.875 mmol) of methyl iodide. The reaction mixture is stirred for 15 h at room temperature; a further 0.075 g (1.875 mmol) of sodium hydride dispersion (approx. 60% ) and 0.117 ml (1.875 mmol) of methyl iodide are added, and the mixture is stirred for a further 96 h at 20° C. and is then concentrated by evaporation in vacuo. Working up analogously to Example 1a, but using ethyl acetate-hexane (1:2) in the flash chromatography, yields the title compound, Rf value=0.36 (silica gel/ethyl acetate:hexane (2:3)).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([NH:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][N:12]=2)[CH:3]=1.[CH2:20]([O:29][CH2:30][CH2:31][CH2:32][NH2:33])[CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][CH2:27][NH2:28]>CCOC(C)=O>[NH2:33][CH2:32][CH2:31][CH2:30][O:29][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][CH2:27][NH:28][C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([NH:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][N:12]=2)[CH:3]=1
Reactant: CSc1nc(Cl)cc(Nc2ccc(C(=O)O)cn2)n1
Reactant: NCCCOCCCCOCCCN
Solvent: CCOC(C)=O
Product: CSc1nc(NCCCOCCCCOCCCN)cc(Nc2ccc(C(=O)O)cn2)n1
Temperature: 100 °C
Yield: 9.1 %

Procedure:
A mixture of 6-(6-chloro-2-(methylthio)pyrimidin-4-ylamino)nicotinic acid (280 mg) and 3,3′-(butane-1,4-diylbis(oxy))dipropan-1-amine (1928 mg) was heated at 100° C. for 16 hours. After cooling to room etmperature, the mixture was diluted with EtOAc (200 mL), washed with H2O (100 mL), brine (100 mL), and dried over MgSO4 and concentrated. The residue was purified by preparative HPLC to give 6-(6-(3-(4-(3-aminopropoxy)butoxy)propylamino)-2-(methylthio)pyrimidin-4-ylamino)nicotinic acid (40 mg).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[Br:10][C:11]1[CH:12]=[C:13]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:32][CH3:33])=[C:25]([O:28][CH2:29][CH2:30]Br)[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:14]=[CH:15][CH:16]=1.[OH:34][C@@H:35]([CH3:46])[CH2:36][NH:37][CH2:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40]>C(#N)C>[Br:10][C:11]1[CH:12]=[C:13]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:32][CH3:33])=[C:25]([O:28][CH2:29][CH2:30][N:37]([CH2:38][C:39]([O:41][C:42]([CH3:43])([CH3:45])[CH3:44])=[O:40])[CH2:36][C@@H:35]([OH:34])[CH3:46])[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: C[C@H](O)CNCC(=O)OC(C)(C)C
Reactant: COc1cc2ncnc(Nc3cccc(Br)c3)c2cc1OCCBr
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Nc3cccc(Br)c3)c2cc1OCCN(CC(=O)OC(C)(C)C)C[C@H](C)O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
0.25 ml of diisopropylethylamine are added to 650 mg of 4-[(3-bromo-phenyl)amino]-6-(2-bromoethoxy)-7-methoxy-quinazoline and 1.10 g of tert.butyl (S)-(2-hydroxy-propylamino)-acetate in 15 ml of acetonitrile. The reaction mixture is stirred overnight at 50° C. Since no reaction can be detected, the reaction mixture is concentrated by evaporation, combined with 20 ml of N,N-dimethylformamide and stirred for eight hours at 60° C. Then the temperature is increased to 80° C. After another eight hours the reaction is complete. The reaction mixture is concentrated by evaporation and chromatographed over a silica gel column with ethyl acetate as eluant. The desired product is obtained as a white solid.