Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([C:13]([C@@H:15]3[C@@H:20]([C:21]([O:23]C)=O)[CH2:19][C@H:18]([S:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:17][N:16]3[C:32]([O:34][CH3:35])=[O:33])=[O:14])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCCC1.[OH:41][NH2:42].C[O-].[Na+].Cl>CO>[OH:41][NH:42][C:21]([C@H:20]1[CH2:19][C@H:18]([S:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:17][N:16]([C:32]([O:34][CH3:35])=[O:33])[C@@H:15]1[C:13]([N:10]1[CH2:9][CH2:8][N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:11]1)=[O:14])=[O:23]
Reactant: COC(=O)[C@H]1C[C@H](Sc2ccccc2)CN(C(=O)OC)[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)N1C[C@@H](Sc2ccccc2)C[C@H](C(=O)NO)[C@H]1C(=O)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
To the reaction mixture of dimethyl (2S,3S,5S)-2-[(4-phenylpiperazin-1-yl)carbonyl]-5-(phenylthio)piperidine-1,3-dicarboxylate (51 mg, 0.00010 mol) in tetrahydrofuran (0.50 mL, 0.0062 mol) was added 1.640 M of N-hydroxyamine in methanol (1.25 mL) made from the corresponding salt and sodium methoxide. After stirred at rt for 1 h, the mixture was acidified with 1N HCl. The resultant mixture was applied directly on RP-HPLC to afford the product as a TFA salt (39 mg, 63%). MS (ESI): (M+H)+=499.1.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:7][N:8]1[C:12]([C:13](=[O:36])[NH:14][C:15]2[N:20]=[C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:18]3[CH:27]=[C:28]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[N:29]=[C:17]3[CH:16]=2)=[C:11]([C:37]([OH:39])=O)[CH:10]=[N:9]1>>[N:21]1([C:19]2[N:18]3[CH:27]=[C:28]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:29]=[C:17]3[CH:16]=[C:15]([NH:14][C:13]([C:12]3[N:8]([CH3:7])[N:9]=[CH:10][C:11]=3[C:37]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:39])=[O:36])[N:20]=2)[CH2:22][CH2:23][O:24][CH2:25][CH2:26]1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1cc2nc(-c3ccccc3)cn2c(N2CCOCC2)n1
Reactant: C1COCCN1
Product: Cn1ncc(C(=O)N2CCOCC2)c1C(=O)Nc1cc2nc(-c3ccccc3)cn2c(N2CCOCC2)n1

Procedure:
The title compound was prepared in analogy to Example 13, Step 2, using morpholine and 1-methyl-5-(5-morpholin-4-yl-2-phenyl-imidazo[1,2-c]pyrimidin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid. MS (m/e)=517.2 [M+H+].
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:5][N:4]=1.Cl>>[N:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:6]1[CH:7]=[CH:8][C:3](=[O:2])[NH:4][CH:5]=1
Reactant: COc1ccc(-c2ccccn2)cn1
Agent: Cl
Product: O=c1ccc(-c2ccccn2)c[nH]1
Yield: 37 %

Procedure:
A mixture of 2-methoxy-5-pyridin-2-yl-pyridine (550 g) and a 4 mol/L aquesous solution of hydrochloric acid (2.4 L) was heated under reflux for 3 hours. After cooling the reaction solution, and washed with tert-butylmethyl ether (2.2 L). To the aqueous layer was added 8 mol/L aqueous solution of sodium hydroxide (1.1 L) under cooling with ice-water, and then the mixture was washed twice with tert-butylmethyl ether (2.2 L). Then, it was adjusted to pH 8 with concentrated hydrochloric acid (310 ml) and 8 mol/L aqueous solution of sodium hydroxide (100 ml), followed by partitioning between 1-butanol (4.5 L) and brine (1.8 L). The aqueous layer was extracted again with 1-butanol (4.5 L), and the combined organic layer was evaporated at 45-50° C. To the resulting residue was added tert-butylmethyl ether (2.2 L), to give crystals. The resulting crystals were collected by filtration under reduced pressure and air-dried at 60° C. Then, water (1.6 L) was added thereto to dissolve under heating. Then the mixture was water-cooled, and recrystallized. The resulting crystals were collected by filtration under reduced pressure and air-dried at 60° C., to give 188 g (66%) of the title compound as grayish white crystals.
Reaction SMILES: [CH:1]1([C:7]([C:9]2[O:17][C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[C:10]=2[CH3:18])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=1.C(=O)([O-])O.[Na+].C([BH3-])#N.[Na+]>O1CCCC1.[Ti](Cl)(Cl)(Cl)Cl.C(O)(=O)C.C(Cl)Cl.C(N(CC)CC)C>[CH:1]1([CH:7]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:28][CH:29]=2)[C:9]2[O:17][C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[C:10]=2[CH3:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: Cc1c(C(=O)C2CCCCC2)oc2cccnc12
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(NC(c2oc3cccnc3c2C)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
To a mixture of cyclohexyl(3-methylfuro[3,2-b]pyridin-2-yl)methanone (1.08 g) synthesized above, methyl 4-aminobenzoate (738 mg), triethylamine (4.95 mL) and methylene chloride (20 mL) was added titanium (IV) chloride (584 μL), and the mixture was stirred under argon atmosphere overnight at room temperature. Saturated aqueous sodium hydrogen carbonate solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a dark brown oil. To a solution (20 mL) of the obtained oil in tetrahydrofuran were added acetic acid (1.27 mL) and sodium cyanoborohydride (558 mg), and the mixture was stirred at room temperature for 1 hr. Saturated aqueous sodium hydrogen carbonate solution was added to quench the reaction, tetrahydrofuran was evaporated in an evaporator, and the residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50% ethyl acetate/hexane) to give the title object compound (789 mg, 47%) as a pale-brown solid.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][CH:12]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[NH:13][N:14]=2)=[CH:6][CH:5]=1.II>CC(C)=O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([S:11][S:11][C:10]([C:7]2[CH:8]=[CH:9][C:4]([Cl:3])=[CH:5][CH:6]=2)=[N:14][N:13]=[CH:12][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[N:14][N:13]=[CH:12][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:6][CH:5]=1
Reactant: Clc1ccc(C2=NNC(c3cccnc3)S2)cc1
Agent: II
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: Clc1ccc(C(=NN=Cc2cccnc2)SSC(=NN=Cc2cccnc2)c2ccc(Cl)cc2)cc1
Reaction time: 0.08 h

Procedure:
3.6 g of powdered potassium hydroxide are added to a solution, cooled to 0° C., of 15 g of the 2-(4-chlorophenyl)-5-(pyrid-3-yl)-4,5-dihydro-1,3,4-thiadiazole prepared according to Example 1a) in 80 ml of acetone. After stirring for ca. 5 minutes at 0°-5° C., 6.9 g of iodine are added in portions and the exothermic reaction is kept at about 0°-5° C. by cooling with ice. The batch is subsequently stirred for 4 hours at ca. 0° C. The precipitated product is isolated by filtration and washed with a small amount of acetone. The crude product is taken up in a 1:3 mixture of tetrahyrofuran/ethyl acetate and the solution is washed once with water and twice with a saturated solution of sodium chloride, dried over sodium sulfate and concentrated by evaporation. The title compound of formula ##STR20## so obtained has a melting point of 143°-145° C. (compound 21).
Reaction SMILES: C(S([C:10]1[C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:14]([N:20]2[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]2)[N:13]=[C:12]([N:27]2[CH2:32][CH2:31][N:30]3[CH:33]=[CH:34][N:35]=[C:29]3[CH2:28]2)[N:11]=1)=O)C1C=CC=CC=1.[Cl:36][C:37]1[CH:38]=[C:39]([CH:42]=[CH:43][C:44]=1[O:45][CH3:46])[CH2:40][NH2:41].C(N(CC)CC)C>CN(C)C(=O)C>[Cl:36][C:37]1[CH:38]=[C:39]([CH:42]=[CH:43][C:44]=1[O:45][CH3:46])[CH2:40][NH:41][C:10]1[C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:14]([N:20]2[CH2:21][CH2:22][CH:23]([OH:26])[CH2:24][CH2:25]2)[N:13]=[C:12]([N:27]2[CH2:32][CH2:31][N:30]3[CH:33]=[CH:34][N:35]=[C:29]3[CH2:28]2)[N:11]=1
Reactant: COc1ccc(CN)cc1Cl
Reactant: COC(=O)c1c(N2CCC(O)CC2)nc(N2CCn3ccnc3C2)nc1S(=O)Cc1ccccc1
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: COC(=O)c1c(NCc2ccc(OC)c(Cl)c2)nc(N2CCn3ccnc3C2)nc1N1CCC(O)CC1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
A mixture of 4-benzylsulfinyl-5-methoxycarbonyl-6-(4-hydroxypiperidin-1-yl)-2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)pyrimidine (prepared in the above (6)) 83 mg, 3-chloro-4-methoxybenzylamine 86 mg, triethylamine 51 mg and N,N-dimethylacetoamide 3 ml is stirred at 110° C. for 1 hour. The reaction mixture is diluted with ice water and extracted with ethyl acetate. The organic layer is washed, dried and concentrated in vacuo. The residue is separated with silica gel chromatography (solvent; ethyl acetate→ethyl acetate:methanol=15:1→10:1) and crystallized from a mixture of methanol, ethyl acetate and isopropyl ether to give 4-(3-chloro-4-methoxybenzylamino)-5-methoxycarbonyl-6-(4-hydroxypiperidin-1-yl)-2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)pyrimidine as a colorless crystalline powder 43 mg. mp 192–194° C.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH3:20])=[CH:10][CH:11]=2)[C:6]([OH:21])=[C:5]([C:22](OCCCC)=[O:23])[N:4]=1)#[N:2].OC(C(F)(F)F)=O.[NH2:36][CH2:37][C:38]([CH3:43])([CH3:42])[C:39]([OH:41])=[O:40].C[O-].[Na+]>CCO>[C:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH3:20])=[CH:10][CH:11]=2)[C:6]([OH:21])=[C:5]([C:22]([NH:36][CH2:37][C:38]([CH3:43])([CH3:42])[C:39]([OH:41])=[O:40])=[O:23])[N:4]=1)#[N:2]
Reactant: CCCCOC(=O)c1nc(C#N)c2ccc(Oc3ccccc3C)cc2c1O
Reactant: CC(C)(CN)C(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: Cc1ccccc1Oc1ccc2c(C#N)nc(C(=O)NCC(C)(C)C(=O)O)c(O)c2c1

Procedure:
Butyl 1-cyano-4-hydroxy-6-(o-tolyloxy)isoquinoline-3-carboxylate (11 mg, 0.03 mmol), 3-amino-2,2-dimethyl-propionic acid TFA salt (27.1 mg, 0.12 mmol) and NaOMe (12.3 mg, 0.23 mmol) in EtOH (3 mL) were heated at 150° C. in a microwave for 90 minutes. The solvent was removed in vacuo and the residue was dissolved in H2O (15 mL) and EtOAc (15 mL). To the stirred mixture was added 1 N hydrochloric acid until pH was 1. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified by flash chromatography (0-25% MeOH/CH2Cl2) to give the title compound in 7 mg. MS: (−) m/z 417.94 (M−1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][CH2:31][C:32](O)=[O:33])[C:25]=1[CH3:35])(=[O:12])=[O:11].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:60]1([CH2:65][C@@H:66]2[CH2:71][CH2:70][CH2:69][NH:68][CH2:67]2)[CH2:64][CH2:63][CH2:62][CH2:61]1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][CH2:31][C:32](=[O:33])[N:68]2[CH2:69][CH2:70][CH2:71][C@@H:66]([CH2:65][N:60]3[CH2:61][CH2:62][CH2:63][CH2:64]3)[CH2:67]2)[C:25]=1[CH3:35])(=[O:11])=[O:12]
Reactant: C1CNC[C@H](CN2CCCC2)C1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CCC(=O)N1CCC[C@@H](CN2CCCC2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-{5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-propionic acid (267 mg), HATU (1.2 eq.), (R)-3-pyrrolidin-1-ylmethyl-piperidine (2×) in DMF (2.5 mL) was stirred at rt for 2 hours. The reaction was concentrated, diluted with DCM, washed with water (2×), sodium carbonate (2×), dried and concentrated. The residue was purified on a silica gel column to give 145 mg of the titled compound as a yellow solid.
Reaction SMILES: [C:1]1([C:14]([O:16][CH3:17])=[O:15])[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:18]1([S:24]([N:27]2[C:39]3[C:38](Br)=[CH:37][CH:36]=[CH:35][C:34]=3[C:33]3[C:28]2=[CH:29][CH:30]=[CH:31][CH:32]=3)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.[Cu]I>[C:18]1([S:24]([N:27]2[C:39]3[C:38]([N:12]4[C:13]5[C:1]([C:14]([O:16][CH3:17])=[O:15])=[CH:2][CH:3]=[CH:4][C:5]=5[C:6]5[C:11]4=[CH:10][CH:9]=[CH:8][CH:7]=5)=[CH:37][CH:36]=[CH:35][C:34]=3[C:33]3[C:28]2=[CH:29][CH:30]=[CH:31][CH:32]=3)(=[O:25])=[O:26])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=S(=O)(c1ccccc1)n1c2ccccc2c2cccc(Br)c21
Reactant: COC(=O)c1cccc2c1[nH]c1ccccc12
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1cccc2c3ccccc3n(-c3cccc4c5ccccc5n(S(=O)(=O)c5ccccc5)c34)c12

Procedure:
8.0 g (42.2 mmol) of copper(I) iodide, 11.7 ml (97.5 mmol) of trans-cyclo-hexanediamine are added to a well-stirred suspension of 26.3 g (117 mmol) of methyl 9H-carbazole-1-carboxylate, 45.2 g (117 mmol) of 9-benzenesulfonyl-1-bromo-9H-carbazole and 416.4 g (1961 mmol) of potassium phosphate in 1170 ml of dioxane, and the mixture is subsequently heated under reflux for 16 h. After cooling, the precipitated solid is filtered off with suction, washed three times with 50 ml of toluene, three times with 50 ml of ethanol:water (1:1, v:v) and three times with 100 ml of ethanol. Yield: 43 g (81 mmol), 70% of theory.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:40])=[C:14]([C:35](OCC)=[O:36])[C:15](=[O:34])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]([CH3:33])[C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:41][CH2:42][CH2:43][OH:44]>CCO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:40])=[C:14]([C:35]([NH:41][CH2:42][CH2:43][OH:44])=[O:36])[C:15](=[O:34])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]([CH3:33])[C:23](=[O:24])[O:25][CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: NCCO
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN(C)C(=O)OCc2ccccc2)c1=O
Solvent: CCO
Product: CN(CCCn1c(=O)c(C(=O)NCCO)c(O)c2ncc(Cc3ccc(F)cc3)cc21)C(=O)OCc1ccccc1
Temperature: 125 °C

Procedure:
A mixture of ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-[3-(methyl{[(phenylmethyl)oxy]carbonyl}amino)propyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (20 mg, 0.036 mmol) and 2-aminoethanol (13 μL, 0.22 mmol) were combined in EtOH (2 mL) and heated for 15 min. at 125° C. in a microwave vessel. Additional 2-aminoethanol (50 μL, 0.84 mmol) was added and the reaction was heated at 150° C. for 20 min. The mixture was evaporated in vacuo and partitioned between CH2Cl2 and 1N NaHSO4. After separating the layers, the aqueous phase was back-extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, evaporated in vacuo and triturated with Et2O to provide the product as a white solid: 1H NMR (d6-DMSO) δ 10.37 (1H, b), 8.54 (1H, s), 7.93-8.03 (1H, m), 7.17-7.40 (7H, m), 7.11 (2H, t, J=9 Hz), 4.89-5.09 (3H, m), 4.12-4.22 (4H, m), 3.52-3.58 (2H, m), 3.40-3.45 (2H, m), 3.29 (3H, s), 2.81-2.88 (2H, m), 1.78 (b, 2H); ES+ MS: 563 (M+H+).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]#[CH:5].[F:6][C:7]1[C:8](I)=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])/[C:10]/2=[CH:17]\[C:18]1[NH:22][CH:21]=[N:20][C:19]=1[CH3:23]>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.CN(C=O)C.CCN(CC)CC>[F:6][C:7]1[C:8]([C:5]#[C:4][CH2:3][NH:2][CH3:1])=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])/[C:10]/2=[CH:17]\[C:18]1[NH:22][CH:21]=[N:20][C:19]=1[CH3:23]
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Reactant: C#CCNC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNCC#Cc1c(F)ccc2c1/C(=C/c1[nH]cnc1C)C(=O)N2

Procedure:
Using Method C above, N-methyl propargyl amine (23.3 mg, 0.34 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (50 mg, 0.135 mmol) (Starting Material 3 supra) using (Ph3P)4Pd (15.6 mg) and Cul (3 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 80° C. for 8 h to give (Z)-1,3-dihydro-5-fluoro-4-[3-(N-methylamino)-1-propynyl]-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one. (Yield 17 mg, 41%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][S:9]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][NH2:19])[CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:20][C:21]1[N:26]=[C:25](Cl)[C:24]([CH3:28])=[CH:23][N:22]=1>>[Cl:20][C:21]1[N:26]=[C:25]([NH:19][CH2:18][CH:15]2[CH2:14][CH2:13][N:12]([S:9]([CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:10])=[O:11])[CH2:17][CH2:16]2)[C:24]([CH3:28])=[CH:23][N:22]=1
Reactant: NCC1CCN(S(=O)(=O)CCc2ccccc2)CC1
Reactant: Cc1cnc(Cl)nc1Cl
Product: Cc1cnc(Cl)nc1NCC1CCN(S(=O)(=O)CCc2ccccc2)CC1

Procedure:
EXAMPLE 91 was prepared from C-[1-(2-phenyl-ethanesulfonyl)-piperidin-4-yl]-methylamine and 2,4-dichloro-5-methyl-pyrimidine: MS (m+1)=410.
Reaction SMILES: [NH2:1][CH:2]1[C:13](=[O:14])[N:4]2[C:5]([C:10]([OH:12])=[O:11])=[C:6]([Cl:9])[CH2:7][S:8][C@H:3]12.[S:15]([CH:19]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:20](Cl)=[O:21])([OH:18])(=[O:17])=[O:16].CC(C)=O.C(=O)(O)[O-].[Na+]>O>[S:15]([CH:19]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:20]([NH:1][CH:2]1[C:13](=[O:14])[N:4]2[C:5]([C:10]([OH:12])=[O:11])=[C:6]([Cl:9])[CH2:7][S:8][C@H:3]12)=[O:21])([OH:18])(=[O:17])=[O:16]
Reactant: NC1C(=O)N2C(C(=O)O)=C(Cl)CS[C@H]12
Reactant: O=C(Cl)C(c1ccccc1)S(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)C1=C(Cl)CS[C@@H]2C(NC(=O)C(c3ccccc3)S(=O)(=O)O)C(=O)N12

Procedure:
The α-sulfo-acylamido-3-halo-cephem compounds of the Formula I wherein Q is a sulfo group (--SO3H) are prepared by following the acylation procedures employed for the preparation of α-sulfobenzylpenicillins described by U.S. Patent No. 3,660,379 and in the J. Med. Chem., 15 (11), 11-5 (1972); ibid, p. 1108. For example, 7-amino-3-chloro-3-cephem-4-carboxylic acid is reacted with α-sulfophenylacetyl chloride in a mixture acetone and water containing an excess of sodium bicarbonate to yield 7-(α-sulfophenylacetamido)-3-chloro-3-cephem-4-carboxylic acid. Examples of α-sulfoacylamido-3-halo-cephems of the present invention are,
Reaction SMILES: Cl[C:2]([F:21])([F:20])[C:3](Cl)([F:18])[O:4][C:5]([Cl:17])([Cl:16])[C:6]([F:15])([F:14])[C:7](Cl)([F:12])[C:8](Cl)([F:10])[F:9]>[Zn].CN(C)C=O>[C:8](=[C:7]([C:6]([C:5]([O:4][C:3](=[C:2]([F:20])[F:21])[F:18])([Cl:16])[Cl:17])([F:15])[F:14])[F:12])([F:10])[F:9]
Reactant: FC(F)(Cl)C(F)(Cl)OC(Cl)(Cl)C(F)(F)C(F)(Cl)C(F)(F)Cl
Agent: [Zn]
Solvent: CN(C)C=O
Product: FC(F)=C(F)OC(Cl)(Cl)C(F)(F)C(F)=C(F)F
Yield: 61.4 %

Procedure:
Into a 500 ml four-necked flask equipped with a stirrer, a reflux condenser and a dropping funnel, 115 g (1.77 mol) of zinc was introduced, and 200 ml of dimethylformamide was introduced thereinto in an atmosphere of an inert gas. Then, the pressure in the system was reduced to 3 kPa, and the internal temperature was adjusted to from 50 to 55° C., and 100 g (0.22 mol) of CF2ClCFClCF2CCl2OCFClCF2Cl was dropwise added thereto gradually by the dropping funnel, and the resulting product was quickly taken out by distillation during the reaction. Then, the crude product was purified to obtain 42 g (yield 62%) of pure CF2═CFCF2CCl2OCF═CF2 (4,4-dichloro-1,1,2,5,5,6,7,7-octafluoro-3-oxa-1,6-heptadiene). Hereinafter this compound will be referred to as a monomer A.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:16])[C:7]2=[C:17]([S:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[NH:27][CH2:28][CH2:29][N:30]([CH3:32])[CH3:31])[CH:18]=[CH:19][N:6]2[N:5]=1)[CH3:3].[NH2:33][C:34]1[C:39]([C:40]#[N:41])=[C:38](Cl)[N:37]=[CH:36][N:35]=1.CCN(C(C)C)C(C)C>C(O)(C)(C)C>[NH2:33][C:34]1[C:39]([C:40]#[N:41])=[C:38]([NH:1][C@H:2]([C:4]2[N:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:8](=[O:16])[C:7]3=[C:17]([S:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[NH:27][CH2:28][CH2:29][N:30]([CH3:31])[CH3:32])[CH:18]=[CH:19][N:6]3[N:5]=2)[CH3:3])[N:37]=[CH:36][N:35]=1
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: C[C@H](N)c1nn2ccc(Sc3ccccc3NCCN(C)C)c2c(=O)n1-c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nn2ccc(Sc3ccccc3NCCN(C)C)c2c(=O)n1-c1ccccc1
Yield: 2.9 %

Procedure:
(S)-2-(1-Aminoethyl)-5-((2-((2-(dimethylamino)ethyl)amino)phenyl)thio)-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (267 mg, 0.54 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (123 mg, 0.81 mmol) and DIEA (280 μl, 1.61 mmol) in 10 ml of tert-BuOH were stirred overnight at 80° C. After evaporation of the solvent under reduced pressure, the residue was purified using SP1® Purification System (0% to 20%, DCM-MeOH) to obtain 9 mg of the title compound as a solid. Purity 99%.
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5]([NH:7][C:8]1[NH:12][C:11]2[CH:13]=[CH:14][C:15]([S:17](Cl)(=O)=O)=[CH:16][C:10]=2[N:9]=1)=[O:6].COC(NC1N[C:29]2C=CC(S)=[CH:34][C:28]=2N=1)=O>[Fe]>[CH3:3][O:4][C:5]([NH:7][C:8]1[NH:12][C:11]2[CH:13]=[CH:14][C:15]([S:17][CH2:29][CH2:28][CH3:34])=[CH:16][C:10]=2[N:9]=1)=[O:6]
Reactant: COC(=O)Nc1nc2cc(S)ccc2[nH]1
Reactant: COC(=O)Nc1nc2cc(S(=O)(=O)Cl)ccc2[nH]1
Agent: [Fe]
Agent: Cl
Product: CCCSc1ccc2[nH]c(NC(=O)OC)nc2c1

Procedure:
Into 100 ml. of a 10% aqueous hydrochloric acid solution 10.8 g. (0.033 moles) of 2-[(methoxycarbonyl)amino]-1H-benzimidazole-5-sulfonic acid chloride hydrochloride and 10 g. of Fe powder are added at room temperature. The mixture is stirred at 70° to 80° C. for 5 hours, whereupon the precipitated 2-[(methoxycarbonyl)amino]-1H-benzimidazole-5-thiol is filtered off and converted into 2-[(methoxycarbonyl)amino]-5-propylthio-1H-benzimidazole as described in Example 10. The product melts at 208° to 210° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH3:11][S:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][C:16]2[CH:17]=[CH:18][C:13]([S:12][CH3:11])=[CH:14][CH:15]=2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: CSc1ccc(O)cc1
Reactant: O=Cc1cc(Cl)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CSc1ccc(Oc2ccc(Cl)cc2C=O)cc1
Yield: 98.1 %

Procedure:
In a manner similar to the method described in Example 50a, 5-chloro-2-fluoro-benzaldehyde (2 g, 12.8 mmol) (Beta Pharma) was reacted with 4-(methylthio)phenol (1.97 g, 14 mmol) (Aldrich) and K2CO3 in N,N-dimethylacetamide to give 5-chloro-2-(4-methylsulfanyl-phenoxy)-benzaldehyde as a brown oil (Yield 3.5 g, 98%).