Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([NH:7][C@@H:8]([CH3:12])[CH2:9][O:10][CH3:11])=[O:6].[H-].[Na+].CCOC(C)=O>C1COCC1>[CH3:11][O:10][CH2:9][C@H:8]([N:7]1[CH2:2][CH2:3][NH:4][C:5]1=[O:6])[CH3:12]
Reactant: COC[C@H](C)NC(=O)NCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC[C@@H](C)N1CCNC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A −20° C. solution of (S)-1-(2-chloroethyl)-3-(1-methoxypropan-2-yl)urea (393 mg, 2.019 mmol) in THF (10 mL) was treated portion-wise with NaH (60% in mineral oil, 178 mg, 4.44 mmol), warmed to RT and stirred overnight. The mixture was treated with EtOAc, washed with water, then brine, dried over Na2SO4 and concentrated to dryness to afford crude (R)-1-(1-methoxypropan-2-yl)imidazolidin-2-one (100% yield assumed) which was used without further purification. MS (ESI) m/z: 159.1 (M+H+).
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([O:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([C:23](=[O:34])[NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:17]=2)=[C:10]([Cl:35])[CH:9]=1)=[O:6].[OH-].[Na+]>CO.O.[OH-].[K+]>[Cl:14][C:12]1[CH:13]=[C:8]([NH:7][C:5](=[O:6])[CH2:4][C:3]([OH:36])=[O:2])[CH:9]=[C:10]([Cl:35])[C:11]=1[O:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([C:23](=[O:34])[NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:17]=1
Reactant: CCCCCCCCCNC(=O)c1cc(Oc2c(Cl)cc(NC(=O)CC(=O)OC)cc2Cl)ccc1O
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCCCCCCNC(=O)c1cc(Oc2c(Cl)cc(NC(=O)CC(=O)O)cc2Cl)ccc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-[3,5-Dichloro-4-(4-hydroxy-3-nonylcarbamoyl-phenoxy)-phenyl]-malonamic acid methyl ester (78 mg, 0.14 mmol) was dissolved in a mixture of MeOH (2 ml), water (1.5 ml), and 1 M NaOH (0.5 ml, 0.5 mmol). The resulting solution was stirred at RT for 2 h then diluted with 15 ml 0.1 M KOH. The solution was washed with a 1:1 mixture of Et2O and EtOAc (3×10 ml) and the combined organic washings were extracted with 0.1 M KOH (2×10 ml). The combined basic solutions were acidified with concentrated HCl and extracted with EtOAc (3×15 ml) and the combined organic extracts washed with brine. The dried extracts were filtered and concentrated to give the title compound of Step G and Example 3, (64 mg). MS (APCI+) Calc.: 524.1, Found: 525.1 (M+).
Reaction SMILES: Cl.[NH2:2][C:3]1[S:4][CH:5]=[C:6]([CH2:8][Cl:9])[N:7]=1.N1C=CC=CC=1.CN(C)[CH:18]=[O:19].C(OC(=O)C)=O>O>[CH:18]([NH:2][C:3]1[S:4][CH:5]=[C:6]([CH2:8][Cl:9])[N:7]=1)=[O:19]
Reactant: CN(C)C=O
Reactant: Nc1nc(CCl)cs1
Agent: CC(=O)OC=O
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: O=CNc1nc(CCl)cs1

Procedure:
To a mixture of 2-amino-4-chloromethylthiazole hydrochloride (2 g), anhydrous pyridine (3.2 g) and anhydrous N,N-dimethylformamide (10 ml) was slowly added acetic formic anhydride (1.7 g) with stirring at 0° to 5° C. After one hour of stirring, the reaction mixture was poured into cold water and extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid and aqueous sodium chloride solution successively and dried over magnesium sulfate. The solvent was then distilled off and the residue was collected and dried to give 2-formylamino-4-chloromethylthiazole (0.94 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][C:3]=1[C:15]([F:18])([F:17])[F:16].[Li][CH2:20]CCC.CI>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:12])[CH3:13])=[C:4]([CH3:20])[C:3]=1[C:15]([F:16])([F:17])[F:18]
Reactant: CC(C)(C)C(=O)Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: Cc1c(NC(=O)C(C)(C)C)ccc(Cl)c1C(F)(F)F
Temperature: 0 °C
Reaction time: 3 h
Yield: 63.6 %

Procedure:
N-(4-chloro-3-(trifluoromethyl)phenyl)pivalamide (3b) (3 g, 10.7 mmol) was dissolved in dry THF (30 mL), cooled to 0° C., and n-BuLi (15.6 mL, 25.7 mmol) was added. After 3 h, a solution of MeI (0.66 mL, 10.56 mmol) in THF (7 mL) was added to the reaction mixture maintaining the temperature at 0° C. and stirred for further 3 h. and quenched with aqueous NH4Cl solution. The reaction mixture was extracted with EtOAc (3×30 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure to give the crude material which was purified by column chromatography to afford N-(4-chloro-2-methyl-3-(trifluoromethyl)phenyl)pivalamide (3c) (2.0 g, 64%) as off white solid.
Reaction SMILES: C(C1[CH:8]=[CH:7][C:6]([C:9](=[O:25])[C:10]2[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:13]([OH:20])=[C:12]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:11]=2)=[CH:5][CH:4]=1)#N.[OH-:26].[Na+].[CH2:28]([OH:30])[CH3:29]>>[C:28]([C:29]1[CH:8]=[CH:7][C:6]([C:9](=[O:25])[C:10]2[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:13]([OH:20])=[C:12]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:11]=2)=[CH:5][CH:4]=1)([OH:26])=[O:30]
Reactant: CCO
Reactant: [OH-]
Reactant: CC(C)(C)c1cc(C(=O)c2ccc(C#N)cc2)cc(C(C)(C)C)c1O
Agent: [Na+]
Product: CC(C)(C)c1cc(C(=O)c2ccc(C(=O)O)cc2)cc(C(C)(C)C)c1O

Procedure:
A mixture of 3.35 g (0.010 mole) of 4'-cyano-3,5-di(tertiary-butyl)-4-hydroxybenzophenone, 25 ml of 20% aqueous sodium hydroxide solution and 25 ml of ethanol was heated at its reflux temperature for about 16 hours. The solution was extracted and washed twice with dichloromethane. The aqueous portion was poured into cold dilute hydrochloric acid and a white solid precipitated. The solid was collected by filtration and was washed with water. The solid was recrystallized from about 50 ml of ethanol with treatment with decolorizing charcoal to provide white solid 4'-carboxy-3,5-di(tertiary-butyl)-4-hydroxybenzophenone, m.p. 248.5°250.5° C. Analysis: Calculated for C22H26O4 : %C, 74.6; %H, 7.4; Found: %C, 74.7; %H, 7.5.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:7](=[O:14])[NH:6][C:5]2=[O:15].N[CH2:17][C@@H:18]([OH:21])[CH2:19][OH:20].N1C=CN=C1>C(O)CCCC>[NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:7](=[O:14])[N:6]([CH2:17][C@@H:18]([OH:21])[CH2:19][OH:20])[C:5]2=[O:15]
Reactant: NC[C@@H](O)CO
Reactant: Nc1cc2c(cc1[N+](=O)[O-])C(=O)NC2=O
Agent: c1c[nH]cn1
Solvent: CCCCCO
Product: Nc1cc2c(cc1[N+](=O)[O-])C(=O)N(C[C@@H](O)CO)C2=O
Temperature: 25 °C
Yield: 83.2 %

Procedure:
A mixture of 5-amino-6-nitroisoindoline-1,3-dione (2.27 g, 10.98 mmol), (R)-3-aminopropane-1,2-diol (1.0 g, 10.98 mmol), and imidazole (0.75 g, 10.98 mmol) in 100 mL of pentanol was heated to reflux and maintained for 8 h and allowed to cool down to rt. The precipitate was filtered and washed with heptanes and dried to give a yellow crystalline solid (2.57 g, 9.14 mmol, 83%). 1H NMR (500 MHz, DMSO-d6) δ 8.38 (s, 2H), 8.31 (s, 1H), 7.45 (1, 1H), 4.90 (d, J=5.0 Hz, 1H), 4.66 (t, J=5.5 Hz, 1H), 3.82-3.74 (m, 1H), 3.55 (d, J=6.5 Hz, 2H), 3.42-3.18 (m, 2H). ESI MS: m/z 279.8 (M−1).
Reaction SMILES: N1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl.[I:12]I.[C@@H:14]12[O:21][CH2:20][C@@H:18]([O:19]1)[CH:17]=[CH:16][C:15]2=[O:22]>C(OCC)(=O)C>[I:12][C:16]1[C:15](=[O:22])[C@@H:14]2[O:21][CH2:20][C@H:18]([CH:17]=1)[O:19]2
Reactant: II
Reactant: O=C1C=C[C@H]2CO[C@@H]1O2
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=C1C(I)=C[C@H]2CO[C@@H]1O2
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.1 %

Procedure:
150 ml of a dry pyridine-carbon tetrachloride (1:1) solution containing 40 g of iodine, was gradually added at 0° C. to 150 ml of a dry pyridine-carbon tetrachloride (1:1) solution containing 5 g of 1,6-anhydro-3,4-dideoxy-β-D-glycero-hex-3-enopyranos-2-ulose (disclosed in U.S. Pat. No. 3,926,947) under an inert atmosphere of nitrogen gas. The mixture was stirred at room temperature for two hours. Then, disappearance of the starting material was confirmed by thin layer chromatography, and 200 ml of ethyl acetate was added thereto. The mixture was washed twice with 200 ml of a saturated sodium chloride aqueous solution and once with 200 ml of 20% sodium thiosulfate. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained syrup crude product was purified by silica gel column chromatography (ethyl acetate: hexane=1:3) to obtain 6.1 g of the desired product (Intermediate No. 5) as slightly yellow crystals. The NMR analytical data and physical data of this product are as follows.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)[CH:5]=O.N1C=CC=CC=1.Cl.[O:25]([NH2:27])[CH3:26]>O>[CH3:26][O:25][N:27]=[CH:5][C:4]1[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[C:2]([OH:1])[CH:3]=1
Reactant: O=Cc1ccc(OCCN2CCCC2)c(O)c1
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CON=Cc1ccc(OCCN2CCCC2)c(O)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 59.1 %

Procedure:
An amount of 3-hydroxy-4-(2-pyrrolidin-1-yl-ethoxy)-benzaldehyde (150 mg, 0.64 mmol) is added pyridine (3.5 ml) at room temperature, followed by addition of methoxylamine hydrogen chloride (58.2 mg, 0.70 mmol). The mixture is stirred at ambient temperature for 24 h, and 4 mL of water is added. After the solvents were evaporated, the residue is dissolved 8 mL of anhydrous ether, washed successively with 2 mL of aqueous sodium bicarbonate, 2 mL of sodium bisulfite, and 2 mL of brine. Dried over magnesium sulfate, evaporated to give a yellow solid (100 mg). MS (ESI) m/z 265.8 (M+1)
Reaction SMILES: [OH-].[K+].C(O)C.[SH:6][C:7]1[CH:8]=[C:9]([C:17]([OH:19])=[O:18])[C:10]2[O:14][CH:13]([CH3:15])[CH2:12][C:11]=2[CH:16]=1.[CH:20]1([CH2:23]Br)[CH2:22][CH2:21]1>O>[CH:20]1([CH2:23][S:6][C:7]2[CH:8]=[C:9]([C:17]([OH:19])=[O:18])[C:10]3[O:14][CH:13]([CH3:15])[CH2:12][C:11]=3[CH:16]=2)[CH2:22][CH2:21]1
Reactant: CC1Cc2cc(S)cc(C(=O)O)c2O1
Reactant: BrCC1CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC1Cc2cc(SCC3CC3)cc(C(=O)O)c2O1

Procedure:
73 g of potassium hydroxide were dissolved in 84 ml of water in a 2-liter round-bottomed flask and 387 ml of absolute ethanol and 130.5 g of 5-mercapto-2-methyl-2,3-dihydrobenzofuran-7-carboxylic acid were then added. 86 g of cyclopropylmethyl bromide were then quickly poured in and the contents were heated under reflux for 1 hour. After adding water, the contents were filtered and the solution was acidified by adding concentrated hydrochloric acid until a color change of Congo red was observed. The precipitate formed was drained, washed with water and dried at 40° C.
Reaction SMILES: [C:1]1([C:7]2[S:11][C:10]([NH:12][C:13]3[CH:18]=[C:17]([CH2:19]O)[CH:16]=[CH:15][N:14]=3)=[N:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)C=O.P(Cl)(Cl)([Cl:28])=O>C(Cl)Cl>[Cl:28][CH2:19][C:17]1[CH:16]=[CH:15][N:14]=[C:13]([NH:12][C:10]2[S:11][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:8][N:9]=2)[CH:18]=1
Reactant: OCc1ccnc(Nc2ncc(-c3ccccc3)s2)c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: ClCc1ccnc(Nc2ncc(-c3ccccc3)s2)c1

Procedure:
[2-(5-Phenyl-thiazol-2-ylamino)-pyridin-4-yl]-methanol 8-7 (0.500 g, 1.77 mmol) was stirred in anh CH2Cl2 (5 mL) under N2. N,N-Dimethylformamide (0.137 mL, 1.76 mmol, 1 equiv) was added followed by the addition of phosphorous oxychloride (0.165 mL, 1.76 mmol). After 1.5 h the reaction was concentrated and quenched by the addition of saturated NaHCO3 (aq). A precipitate formed which was filtered and washed with water to provide the titled compound. 1H NMR (DMSO-d6) δ 11.49 (bs, 1H), 8.34 (d, 1H, J=5.2 Hz), 7.81 (s, 1H), 7.60 (d, 2H, J=7.7 Hz), 7.39 (t, 2H, J=7.6 Hz), 7.26 (t, 1H, 7.0 Hz), 7.13 (s, 1H), 6.99 (d, 1H, J=5.3 Hz), 4.77 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]([CH:16]([CH3:18])[CH3:17])[C:7]([N:9]3[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]3)=[N:8][C:4]=2[CH:3]=1.[N+:21]([O-])([OH:23])=[O:22].O.[OH-].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][C:5]2[N:6]([CH:16]([CH3:18])[CH3:17])[C:7]([N:9]3[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]3)=[N:8][C:4]=2[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: CC(C)n1c(N2CCN(C)CC2)nc2cc(Cl)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)n1c(N2CCN(C)CC2)nc2cc(Cl)c([N+](=O)[O-])cc21
Temperature: 60 °C
Reaction time: 1 h

Procedure:
5-Chloro-1-isopropyl-2-(4-methyl-1-piperazinyl)benzimidazole (2.7 g) was dissolved in acetic acid (15 ml). To the solution was added fuming nitric acid (3 ml) at 0° C. and then the mixture was stirred at 60° C. for 1 hour. The reaction mixture was poured into water and the mixture was made basic with an aqueous sodium hydroxide solution and extracted with chloroform. The chloroform layer was washed with water and dried over anhydrous magnesium sulfate and then the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography [eluted with chloroform-methanol (10:1, v/v)] to give 5-chloro-1-isopropyl-2-(4-methyl-1-piperazinyl)-6-nitrobenzimidazole (1.8 g). A part of the obtained product was recrystallized from acetonitrile, which showed the following physical properties:
Reaction SMILES: O.[CH:2](/[CH:7]1[CH:11]=[CH:10][CH2:9][C:8]1=[O:12])=[CH:3]/[CH2:4][CH2:5][CH3:6].C(O)(=O)C.[C-:17]#[N:18].[Na+]>C(O)C>[CH:2](/[CH:7]1[CH:11]([C:17]#[N:18])[CH2:10][CH2:9][C:8]1=[O:12])=[CH:3]/[CH2:4][CH2:5][CH3:6]
Reactant: [C-]#N
Reactant: CCC/C=C\C1C=CCC1=O
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: CCC/C=C\C1C(=O)CCC1C#N
Temperature: 35 °C

Procedure:
Into a 500 ml reaction flask equipped with mechanical stir, immersion thermometer, water cool bubble condenser, 150 ml addition funnel and heating mantle is placed 10 grams (0.07 moles) of 2-(2-cis-pentenyl)-3-cyclopenten-1-one prepared according to Example B; (0.07 moles); 4.20 grams of glacial acetic acid (0.07 moles) and 245 ml of 95% aqueous ethanol. The reaction mass is heated to 35° C. and, dropwise with stirring while keeping the temperature between 35° and 37° C., 6.86 grams (0.14 moles) of sodium cyanide (dissolved in 75 ml water) is added. After addition, the reaction mass is stirred at a temperature of 35° C. for a period of 3.5 hours.
Reaction SMILES: [N+:1]([CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([O-:3])=[O:2].C[O:13][CH:14](OC)[CH2:15][CH2:16][CH2:17][CH:18]=O>CCOC(C)=O.CCCCCC>[N+:1](/[C:4](/[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[CH:18]/[CH2:17][CH2:16][CH2:15][CH:14]=[O:13])([O-:3])=[O:2]
Reactant: COC(CCCC=O)OC
Reactant: O=[N+]([O-])CCc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=CCCC/C=C(\Cc1ccccc1)[N+](=O)[O-]
Yield: 39.9 %

Procedure:
Prepared according to the general procedure B from 1-(2-nitroethyl)benzene 112e (24 mmol) and 5,5-dimethoxypentanal 131 (16 mmol) to provide the title compound as yellow oil (1.49 g, 40% yield) after silica gel chromatography (EtOAc/Hexane).
Reaction SMILES: CC1(C)[O:9][C:8](=[O:10])[C:5]2([CH2:7][CH2:6]2)[C:4](=[O:11])O1.[F:13][C:14]([F:23])([F:22])[C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>C(O)C>[O:11]=[C:4]1[CH:5]([C:8]([OH:9])=[O:10])[CH2:7][CH2:6][N:19]1[C:18]1[CH:20]=[CH:21][C:15]([C:14]([F:13])([F:22])[F:23])=[CH:16][CH:17]=1
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Reactant: Nc1ccc(C(F)(F)F)cc1
Solvent: CCO
Product: O=C(O)C1CCN(c2ccc(C(F)(F)F)cc2)C1=O
Yield: 42.7 %

Procedure:
This compound was prepared according to general method 1 starting from 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione (0.500 g, 2.94 mmol) and 4-trifluoromethyl aniline (1.28 mL, 8.82 mmol) in ethanol (3 mL). 2-oxo-1-(4-(trifluoromethyl)phenyl)pyrrolidine-3-carboxylic acid 0.343 g (43%) was obtained as a bright yellow solid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[O:6][CH2:7][CH2:8][N:9]([CH3:12])[C:10]=2[N:11]=1.CC1(C)C(C)(C)OB([C:27]2[CH:28]=[N:29][C:30]([NH2:33])=[N:31][CH:32]=2)O1.C(Cl)Cl.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[CH3:12][N:9]1[CH2:8][CH2:7][O:6][C:5]2[C:4]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:3][C:2]([C:27]3[CH:28]=[N:29][C:30]([NH2:33])=[N:31][CH:32]=3)=[N:11][C:10]1=2
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: CN1CCOc2c1nc(Cl)nc2N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: CN1CCOc2c1nc(-c1cnc(N)nc1)nc2N1CCOCC1
Temperature: 100 °C

Procedure:
A mixture of 2-chloro-8-methyl-4-morpholin-4-yl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine (120 mg, 0.44 mmol), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine (196 mg, 0.88 mmol), PdCl2dppf.DCM (36 mg, 0.04 mmol) and cesium carbonate (573 mg, 1.76 mmol) in dioxane (5 mL) and water (0.5 mL) was degassed and heated at 100° C. for 18 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. The resulting residue was loaded onto an Isolute® SCX-2 cartridge which was washed with methanol and the product eluted with 2M ammonia in methanol. The basic fractions were combined and concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, gradient 0-5% methanol in DCM) then triturated with diethyl ether affording 119 (357 mg, 24%). LCMS: RT=3.04 min, [M+H]+=330. 1H NMR (400 MHz, DMSO): δ 8.94 (2H, s), 6.92 (2H, s), 4.16 (2H, t, J=4.37 Hz), 3.67 (4H, t, J=4.57 Hz), 3.52 (4H, t, J=4.56 Hz), 3.48 (2H, t, J=4.36 Hz), 3.13 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]1[CH2:11][CH:10]1[N:12]=[C:13]=[O:14].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C@H:9]1[CH2:11][C@H:10]1[NH:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=1)=[O:14]
Reactant: O=C=NC1CC1c1c(F)cccc1Cl
Reactant: Nc1ccc(Cl)cn1
Product: O=C(Nc1ccc(Cl)cn1)N[C@@H]1C[C@@H]1c1c(F)cccc1Cl

Procedure:
2-(2-chloro-6-fluorophenyl)cyclopropylisocyanate prepared as described above was condensed with 2-amino-5-chloropyridine according to the method used in Example 7 to provide N-(cis-2-(2-chloro-6-fluorophenyl)-cyclopropyl)-N'-(5-chloropyrid-2-yl)-urea: 1H-NMR (250 MHz, CDCl3): 1.3-1.4 (m, 1H), 1.5-1.6 (m, 1H), 2.0-2.1 (m, 1H), 3.3-3.4 (m, 1H), 6.7-6.8 (m, 1H), 6.9-7.0 (m, 1H), 7.15-7.30 (m, 2H), 7.4-7.5 (m, 1H), 7.7 (m, 1H), 8.8 (s, 1H), 9.1 (s, 1H).
Reaction SMILES: Cl.[NH2:2][CH:3]1[C:25](=[O:26])[N:5]2[C:6]([C:22]([O-:24])=[O:23])=[C:7](/[CH:10]=[CH:11]/[CH2:12][N+:13]3[CH:18]=[CH:17][C:16]([C:19](=[O:21])[NH2:20])=[CH:15][CH:14]=3)[CH2:8][S:9][C@H:4]12.Cl.[CH2:28]([O:31][N:32]=[C:33]([C:37]1[N:41]=[C:40]([NH2:42])[S:39][N:38]=1)[C:34](Cl)=[O:35])[C:29]#[CH:30].C([O-])([O-])=O.[Na+].[Na+].Cl>CC(C)=O>[NH2:42][C:40]1[S:39][N:38]=[C:37]([C:33](=[N:32][O:31][CH2:28][C:29]#[CH:30])[C:34]([NH:2][CH:3]2[C:25](=[O:26])[N:5]3[C:6]([C:22]([O-:24])=[O:23])=[C:7]([CH:10]=[CH:11][CH2:12][N+:13]4[CH:14]=[CH:15][C:16]([C:19](=[O:21])[NH2:20])=[CH:17][CH:18]=4)[CH2:8][S:9][C@H:4]23)=[O:35])[N:41]=1
Reactant: C#CCON=C(C(=O)Cl)c1nsc(N)n1
Reactant: NC(=O)c1cc[n+](C/C=C/C2=C(C(=O)[O-])N3C(=O)C(N)[C@H]3SC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: C#CCON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C=CC[n+]3ccc(C(N)=O)cc3)CS[C@H]12)c1nsc(N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 12 %

Procedure:
To a solution of 86 mg (0.19 mmole) of 7-amino-3-[3-(4-carbamoylpyridinio)-1-(E)-propenyl]-3-cephem-4-carboxylate hydrochloride (XXII-H) in 2 ml of 50% aqueous acetone was added 63 mg of 2-propargyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetyl chloride hydrochloride (from Preparation No. 26). The suspension was maintained at pH 6.5-7.0 with 2N Na2CO3 and then stirred at room temperature for 1 hour. The reaction mixture was acidified to pH 2 with 1N HCl and concentrated in vacuo. The residue was diluted with 30 ml of water, neutralized with NaHCO3 and filtered. The filtrate was transferred on the top of a column which was packed with reverse phase carrier (30 ml) taken from a PrepPAK-500/C18 cartridge (Waters). The column was eluted with water, 5% CH3OH, 10% CH3OH and 20% CH3OH, successively. Fractions containing the product were combined and lyophilized to afford 13 mg (12%) of the title product I-4H. Estimated purity 70%. Mp. 160° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=1N)(=[O:4])=[O:3].[ClH:12].N([O-])=O.[Na+].[S:17](=[O:19])=[O:18]>O.Cl[Cu].CC(O)=O>[CH3:1][S:2]([C:5]1[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=1[S:17]([Cl:12])(=[O:19])=[O:18])(=[O:4])=[O:3]
Reactant: Cl
Reactant: CS(=O)(=O)c1ccccc1N
Reactant: O=S=O
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)Cl
Temperature: 50 °C
Yield: 61 %

Procedure:
2-Methylsulfonylaniline (48 g, 0.28 mole), was added portion-wise with stirring to 365 mL of water, 250 mL of conc. HCl and 60 mL of HOAc. The mixture was cooled to 50° C. and sodium nitrite (22.3 g; 0.32 mole) dissolved in 250 mL water, was added drop-wise with stirring maintaining the temperature between 0-5° C. After complete addition of sodium nitrite, the resulting solution was stirred for 30 minutes at 0-5° C. Sulfur dioxide was bubbled into 200 mL of glacial acetic acid at room temperature for 10 minutes CuCl2·2H2O (11 g; 0.06 mole) and CuCl (3.7 g; 0.037 mole) were added to the HOAc and cooled to 10° C. Sulfur dioxide was bubbled through the suspension for an additional 15 minutes and the diazotized amine was added portionwise with stirring keeping the temperature between 0-5° C. Sulfur dioxide was bubbled in continuously until the diazotized amine was added completely. After the complete addition of the diazotized amine, bubbling of SO2 was stopped and the green suspension was stirred at 0-5° C. for 3 hours. At the end of 3 hours, the suspension was diluted with water (300 mL), filtered and the solid washed three times with 50 mL of water. The product was dried at room temperature in vacuum (30 in. Hg) to give 46 g of 2-methylsulfonylbenzenesulfonyl chloride (61% yield) as a white solid. mp 135-137° C. (lit. 133-135° C.). 1H NMR (CDCl3) δ 8.3-8.6 (m, 2H), 7.87-8.02 (m, 2H), 3.41 (s, 3H). 13C NMR (CDCl3) δ 142.94, 139.24, 136.61, 135.22, 133.58, 132.13, 45.49. CIMS (m/e) 255 (M+H+, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:28]([F:31])([F:30])[F:29])[O:14][N:13]=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:24][CH:23]([C:25]([OH:27])=O)[CH2:22]4)=[CH:17][CH:16]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].[CH3:32][N:33](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)[CH3:34].F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.CNC>CN(C=O)C.C1COCC1>[CH3:32][N:33]([CH3:34])[C:25]([CH:23]1[CH2:24][N:21]([C:18]2[CH:17]=[CH:16][C:15]([C:12]3[CH2:11][C:10]([C:4]4[CH:3]=[C:2]([Cl:1])[C:7]([Cl:8])=[C:6]([Cl:9])[CH:5]=4)([C:28]([F:31])([F:29])[F:30])[O:14][N:13]=3)=[CH:20][CH:19]=2)[CH2:22]1)=[O:27]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)C1CN(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)C(=O)C1CN(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 1-{4-[5-(3,4,5-Trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-phenyl}-azetidine-3-carboxylic acid (Preparation 12, 0.1 g, 0.203 mmol) in DMF (3 mL) was added HATU (0.115 g, 0.304 mmol) HOBt (0.03 g, 0.223 mmol), DIPEA (0.052 g, 0.406 mmol) followed by addition of saturated solution of dimethyl amine in THF (2 mL) at 0° C. and stirred at 0° C. for 3 hours. After complete consumption of starting material, reaction mixture was quenched with water (20 mL), extracted with EtOAc (3×20 mL). Combined organic layer was washed with brine (50 mL), saturated solution of lithium chloride (50 mL), and water (50 mL), dried over sodium sulphate and evaporated in vacuo to get crude. Crude was purified by column chromatography on silica gel (100-200 mesh size). Compound was eluted using 0.6% methanol in DCM to afford white solid (0.050 g, 48%. 1H-NMR (400 MHz, CDCl3) δ: 2.94 (s, 3H), 2.97 (s, 3H), 3.61 (d, 1H, J=17.08 Hz), 3.69-3.77 (m, 1H), 4.02 (d, 1H, J=17.04 Hz), 4.11 (d, 4H, J=7.48 Hz), 6.40 (d, 2H, J=8.72 Hz), 7.46 (d, 2H, J=8.68 Hz), 7.63 (s, 2H); LC-MS (m/z): [M+H] 519.80.