Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[C:15](=[O:33])[N:16]([CH3:32])[C:17](=[O:31])[N:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=4)[C:19]=3[CH3:20])=[C:12]([S:34]([OH:37])(=O)=[O:35])[CH:11]=[N:10]2)=[CH:5][CH:4]=1)#[N:2].P(Cl)(Cl)(Cl)=O.C(C1C=CC(N2C(C3C(=O)N(C)C(=O)N(C4C=CC=C(C(F)(F)F)C=4)C=3C)=C(S(Cl)(=O)=O)C=N2)=CC=1)#[N:44].O.N>C(#N)C.C(OCC)(=O)C.O.N1C=CC=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[C:15](=[O:33])[N:16]([CH3:32])[C:17](=[O:31])[N:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=4)[C:19]=3[CH3:20])=[C:12]([S:34]([NH2:44])(=[O:37])=[O:35])[CH:11]=[N:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: Cc1c(-c2c(S(=O)(=O)Cl)cnn2-c2ccc(C#N)cc2)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: Cc1c(-c2c(S(=O)(=O)O)cnn2-c2ccc(C#N)cc2)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Agent: N
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CC#N
Product: Cc1c(-c2c(S(N)(=O)=O)cnn2-c2ccc(C#N)cc2)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
To a suspension of (+)-1-(4-cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-sulfonic acid (prepared in Example 196) (2.67 g) in acetonitrile (20 ml) were added pyridine (0.81 ml) and phosphorus oxychloride (1.87 ml) and the resulting mixture was stirred at room temperature for forty five minutes. Without an isolation of the formed 1-(4-cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-sulfonyl chloride, the reaction solution was added dropwise to ammonia water (28%, 20 ml) that cooled to 0° C. and the resulting mixture was stirred for ten minutes. To the reaction solution were added water (40 ml) and ethyl acetate (40 ml×2) such that the intended products were extracted into an organic layer. The organic layer washed with 4% ammonia water (20 ml), saturated saline (8 ml), 1N hydrochloric acid (20 ml×2) and saturated saline (20 ml), dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford (+)-1-(4-cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-sulfonamide (2.33 g). UPLC/MS 531 (M+H)/0.87 min. (measurement condition 9)
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH2:24]([O:26][C:27]1[CH:32]=[C:31](B(O)O)[CH:30]=[CH:29][N:28]=1)[CH3:25]>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:31]5[CH:30]=[CH:29][N:28]=[C:27]([O:26][CH2:24][CH3:25])[CH:32]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: CCOc1cc(B(O)O)ccn1
Product: CCOc1cc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)ccn1

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.107 mmol) and 2-ethoxy-4-pyridinylboronic acid (Combi-Blocks, San Diego, USA, 22.4 mg, 0.134 mmol) to give the title compound as a white solid. (HPLC: tR 2.45 min (Method A); M+H=415 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.99 (s, 1H), 8.24-8.16 (m, 2H), 8.14-8.07 (m, 1H), 8.02-7.94 (m, 1H), 7.66-7.59 (m, 1H), 7.09-7.02 (m, 1H), 6.87-6.80 (m, 1H), 4.32 (q, 2H), 3.94 (s, 3H), 3.57 (s, 3H), 1.96 (s, 3H), 1.34 (t, 3H))
Reaction SMILES: ClC1N=C(Cl)N=C(Cl)N=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([NH2:26])=O)=[CH:20][CH:19]=2)=[CH:14][CH:13]=1.O.C(Cl)Cl>CN(C=O)C>[C:24]([C:21]1[CH:20]=[CH:19][C:18]([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH3:10])=[CH:13][CH:14]=2)=[CH:23][CH:22]=1)#[N:26]
Reactant: COc1ccc(-c2ccc(C(N)=O)cc2)cc1
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: COc1ccc(-c2ccc(C#N)cc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 72.7 %

Procedure:
A fine suspension of 44.2 g (0.24 mol) of 2,4,6-trichloro-1,3,5-triazine in 190 ml of DMF is added to a suspension of 20 g (0.09 mol) of 4'-methoxy-4-biphenyl carboxamide in 370 ml of DMF and is left under agitation for 20 hours. A mixture of 300 ml water and 200 g crushed ice is added to the reaction medium and extraction is carried out with methylene chloride (3×100 ml). The combined organic extracts are washed with water (2×200 ml), dried over magnesium sulphate, and the solvent is eliminated by distillation under reduced pressure. The dry extract is taken up in 80 ml ethanol and agitation is carried out for 15 minutes, followed by crystallization by the addition of 200 ml of heptane, cooling down to ambient temperature under agitation, drying and washing with heptane. After drying, 13.7 g of 4-cyano-4'-methoxy biphenyl is obtained in the form of a beige powder (yield: 72.5%).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:11]([NH:13][C:14]1[CH:22]=[C:21]2[C:17]([CH:18]=[CH:19][N:20]2[CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:16][CH:15]=1)=[O:12].Br[CH2:32][CH2:33]Br>CCCC[N+](CCCC)(CCCC)CCCC.[Br-].[OH-].[Na+].O>[Cl:1][C:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]2[CH2:32][CH2:33][N:13]([C:14]3[CH:22]=[C:21]4[C:17]([CH:18]=[CH:19][N:20]4[CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:16][CH:15]=3)[C:11](=[O:12])[C:3]=12
Reactant: BrCCBr
Reactant: CC(C)(C)OC(=O)Cn1ccc2ccc(NC(=O)c3[nH]c4ccccc4c3Cl)cc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Product: CC(C)(C)OC(=O)Cn1ccc2ccc(N3CCn4c(c(Cl)c5ccccc54)C3=O)cc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 78 %

Procedure:
tert-Butyl 2-(6-(3-chloro-1H-indole-2-carboxamido)-1H-indol-1-yl)acetate (1.41 mmol, 1.0 equiv.) and TBAB (1.41 mmol, 1.0 equiv.) were dissolved in 1 N NaOH (12 ml); 1,2-dibromoethane (14.18 mmol, 10.0 equiv.) was added, and the mixture was stirred for 12 h at 25° C. The reaction mixture was diluted with water (50 ml) and extracted with ethyl acetate (100 ml). The organic phase was washed with sat. NaCl solution (50 ml), dried over Na2SO4 and concentrated under reduced pressure, and the desired product was obtained by purification by column chromatography. Yield: 78%
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:34])[NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:35]([O:37]CC)=[O:36].[OH-].[Na+].C1COCC1.Cl>C(OCC)(=O)C.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:34])[NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29][C:30]([F:31])([F:33])[F:32])=[CH:25][CH:24]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:35]([OH:37])=[O:36]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(SC(F)(F)F)cc4)cc3)c(Cl)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(NCCc1ccc(SC(F)(F)F)cc1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Yield: 84.1 %

Procedure:
ethyl 6-chloro-7-(4-(4-(trifluoromethylthio)phenethylcarbamoyl)phenoxy)chroman-4-carboxylate (73.3 mg, 0.126 mmol) was reacted with 1.0 molar sodium hydroxide (506 μL, 0.506 mmol) in a 3:1 THF:Ethanol solution (0.05 M). After 2 hours the reaction was diluted with ethyl acetate, neutralized with 1.0 molar hydrochloric acid (531 μL, 0.531 mmol) and partitioned between saturated aqueous sodium chloride. The organic layer was dried with sodium sulfate, filtered, concentrated, and dried under high vacuum to provide the title compound (58.7 mg, 0.106 mmol, 84.2% yield) as a solid.
Reaction SMILES: [CH2:1]1[CH2:9][O:8][CH:4]([CH2:5][CH2:6]Cl)[CH:3]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH2:14][CH2:13]3)[O:2]1.[I-].[Na+].[NH:23]1[CH:27]=[N:26][CH:25]=[N:24]1.C1CCN2C(=NCCC2)CC1>CN(C)C=O>[CH2:1]1[CH2:9][O:8][CH:4]([CH2:5][CH2:6][N:23]2[CH:27]=[N:26][CH:25]=[N:24]2)[CH:3]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH2:14][CH2:13]3)[O:2]1
Reactant: c1nc[nH]n1
Reactant: O=C1CCc2cc(C3OCCOC3CCCl)ccc2N1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: O=C1CCc2cc(C3OCCOC3CCn3cncn3)ccc2N1
Temperature: 80 °C

Procedure:
10.5 Grams (35.5 mM) of 6-(1-ethylenedioxy-4-chlorobutyl)-3,4-dihydrocarbostyril was dissolved in 10.6 g (71 mM) of dimethylformamide, to this solution was added 10.6 g (71 mM) of sodium iodide, 5.4 g (78.1 mM) of 1H-1,2,4-triazol and 6.5 ml (46.2 mM) of DBU, and the whole mixture was heated at 80° C. for 7 hours with stirring. The reaction mixture was concentrated by removing the solvent by evaporation under reduced pressure, the residue was extracted with chloroform. The chloroform extract was washed with water, dried with anhydrous magnesium sulfate, then concentrated. The resulting residue was purified by means of a silica gel column chromatography (eluent: chloroform:methanol=40:1), and recrystallized from ethanol-n-hexane to yield 8.0 g of 6-[1-ethylenedioxy-4-(1H-1,2,4-triazol-1-yl)butyl]-3,4-dihydrocarbostyril. Next, to a solution of 1 g (3.0 mM) of 6-[1-ethylenedioxy-4-(1H-1,2,4-triazol-1yl)butyl] -3,4-dihydrocarbostyril with 10 ml of DMF was added 3 ml of 5%-hydrochloric acid and stirred for 2 hours at room temperature. After concentration by removal of the solvent, the residue was extracted with chloroform:methanol=3:1. The extract was washed with water, dried with an anhydrous magnesium sulfate, then concentrated by removal of the solvent. The resulting residue was recrystallized from chloroform-ethanol to yield 6-[4-(1H-1,2,4-triazol-1-yl)butyryl]-3,4-dihydrocarbostyril. Colorless needle-like crystals. Melting point: 194.0°- 195.0° C.
Reaction SMILES: [C:1]1([Si:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([Cl:9])Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:16]([Mg]Cl)([CH3:18])[CH3:17]>C1COCC1>[C:10]1([Si:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([CH:16]([CH3:18])[CH3:17])[Cl:9])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cl[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)[Si](Cl)(c1ccccc1)c1ccccc1

Procedure:
Into 200 ml of dry THF was dissolved 160 g (0.63 mole) of diphenyldichlorosilane. To this was added dropwise 450 ml (0.90 mole) of a 2.0 M solution of isopropylmagnesium chloride in THF at a room temperature over 20 minutes. A mildly ethothermic reaction was observed. After the conclusion of the dropwise addition, the reaction mixture was refluxed for 3 days. The formed salt and the solvent were removed from the reaction mixture. The residue was distilled under a reduced pressure to give 130 g of a colorless clear liquid (b.p. 116° to 118° C./0.22 Torr).
Reaction SMILES: [C:1]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=[CH:9][CH:10]([OH:12])[CH3:11])[CH3:8].[H][H]>[Pd].C(O)C>[C:1]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([CH2:9][CH:10]([OH:12])[CH3:11])[CH3:8]
Reactant: [H][H]
Reactant: CC(=CC(C)O)c1ccccc1-c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(O)CC(C)c1ccccc1-c1ccccc1

Procedure:
To a pressure vessel, mixture of 0.675 g. of 2-(p-biphenylyl)-2-penten-4-ol (obtainable by Example 1) and 0.5 g. 10% palladium on carbon in 175 ml. of ethanol, is added hydrogen at about 2 at. pressure via low pressure hydrogenation. The catalyst is then removed, and the solution is evaporated to give a colorless oil which solidifies on standing to give solid 2-(p-biphenylyl)-pentan-4-ol, m.p. 53° C., which may also be designated 4-(p-biphenylyl)-pentan-2-ol.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([C:17]2([C:23]([O:25][CH3:26])=[O:24])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)(=[O:16])=[O:15])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N([CH2:32][CH3:33])CC)C>>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([S:14]([C:17]2([C:23]([O:25][CH3:26])=[O:24])[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][C:33]3[CH:32]=[CH:4][CH:3]=[CH:2][CH:7]=3)=[O:24])[CH2:19][CH2:18]2)(=[O:16])=[O:15])=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C1(S(=O)(=O)c2ccc(Oc3ccccc3)cc2)CCNCC1
Reactant: CCN(CC)CC
Product: COC(=O)C1(S(=O)(=O)c2ccc(Oc3ccccc3)cc2)CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 1 h

Procedure:
1-Benzyl 4-methyl 4-((4-phenoxyphenyl)sulfonyl)piperidine-1,4-dicarboxylate was synthesized as shown in FIG. 10. A 100 ml RBF equipped with magnetic stir bar was charged with 1.1 g (2.67 mmole) 4-methyl 4-((4-phenoxyphenyl)sulfonyl)piperidine-4-carboxylate 0.73 g (2.94 mmole) Cbz-OSu, 0.8 g (8.01 mmole) triethylamine. LCMS after 1 hour showed complete reaction with M+H=510 g/mol. The reaction was partitioned between EA and satd. aq. sodium bicarbonate. The organics were washed with 10 aq. KHSO4, dried and concentrated to thick syrup that turned into white dry foam upon high vacuum drying. The product was dried overnight to afford 1.29 g (95% yield) of the Cbz ester that was used in Step 2.
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].[CH2:6]([C:10]1([CH2:23][OH:24])[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1)[CH2:7][CH:8]=[CH2:9].O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:6]([C:10]1([CH2:23][O:24][S:1]([CH3:4])(=[O:3])=[O:2])[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:14][CH2:15]1)[CH2:7][CH:8]=[CH2:9]
Reactant: CS(=O)(=O)Cl
Reactant: C=CCCC1(CO)CCN(C(=O)OC(C)(C)C)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: C=CCCC1(COS(C)(=O)=O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.6 %

Procedure:
Ms-Cl (5.59 mL, 71.7 mmol) was added dropwise at 0° C. to a stirred solution of tert-butyl 4-(but-3-en-1-yl)-4-(hydroxymethyl)piperidine-1-carboxylate (16.1 g, 59.8 mmol) TEA (16.66 mL, 120 mmol) and DMAP (0.365 g, 2.99 mmol) in CH2Cl2 (300 mL) and the mixture was stirred at room temp for 2 h. Water was then added and the mixture was extracted with methylene chloride (100 mL), dried (Na2SO4), filtered and concentrated. The residue was purified by Biotage (0-40% Hex/EtOAc) to afford tert-butyl 4-(but-3-en-1-yl)-4-(((methylsulfonyl)oxy)methyl)piperidine-1-carboxylate (18 g, 51.8 mmol, 87% yield) as colorless oil. 1H NMR (500 MHz, CDCl3) δ 5.88-5.75 (m, 1H), 5.11-4.90 (m, 2H), 4.09 (s, 2H), 3.58-3.44 (m, 2H), 3.40-3.32 (m, 2H), 3.05 (s, 3H), 2.07-2.02 (m, 2H), 1.59-1.54 (m, 2H), 1.53-1.49 (m, 4H), 1.48 (s, 9H).
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([C:6]([N:15]([CH:25]3[CH2:27][CH2:26]3)[CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[N:7][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[N:9]2)=[N:4][CH:3]=1.C[C:29]([N:31](C)C)=O>[C-]#N.[Zn+2].[C-]#N.[Zn].CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH:25]1([N:15]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[C:6]2[C:5]3=[N:4][CH:3]=[C:2]([C:29]#[N:31])[N:10]3[N:9]=[C:8]([S:11]([CH3:14])(=[O:13])=[O:12])[N:7]=2)[CH2:27][CH2:26]1
Reactant: CC(=O)N(C)C
Reactant: COc1ccc(CN(c2nc(S(C)(=O)=O)nn3c(Br)cnc23)C2CC2)cc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [C-]#N
Agent: [Zn+2]
Product: COc1ccc(CN(c2nc(S(C)(=O)=O)nn3c(C#N)cnc23)C2CC2)cc1
Temperature: 100 °C

Procedure:
In a round-bottom flask, a mixture of 7-bromo-N-cyclopropyl-N-(4-methoxybenzyl)-2-(methylsulfonyl)imidazo[2,1-f][1,2,4]triazin-4-amine (0.115 g, 0.254 mmol), zinc cyanide (0.021 g, 0.178 mmol), and zinc powder (4.99 mg, 0.076 mmol) in DMA (30 mL) was degassed by evacuating with vacuum and back filling with nitrogen. The mixture was treated with bis(tri-t-butylphosphine)palladium (0) (0.026 g, 0.051 mmol), degassed again as described above, and the reaction was heated at 100° C. for 4 hours. The reaction mixture was filtered and the filtrate diluted with ethyl acetate, washed with water, brine, dried with sodium sulfate and concentrated in vacuo. The crude product mixture was purified via ISCO (0-15% of methanol/dichloromethane in 20 minutes, 40 g silica column) to give the pure product 4-(cyclopropyl(4-methoxybenzyl)amino)-2-(methylsulfonyl)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (75 mg).
Reaction SMILES: [Br:1][CH:2]1[C:7]([CH2:8][Br:9])=[C:6]([C:10]([O:12]C(C)(C)C)=[O:11])[N:5]2[C:17](=[O:22])[CH:18]([NH:19][CH:20]=[O:21])[C@H:4]2[S:3]1=[O:23]>FC(F)(F)C(O)=O>[Br:1][CH:2]1[C:7]([CH2:8][Br:9])=[C:6]([C:10]([OH:12])=[O:11])[N:5]2[C:17](=[O:22])[CH:18]([NH:19][CH:20]=[O:21])[C@H:4]2[S:3]1=[O:23]
Reactant: CC(C)(C)OC(=O)C1=C(CBr)C(Br)S(=O)[C@@H]2C(NC=O)C(=O)N12
Solvent: O=C(O)C(F)(F)F
Product: O=CNC1C(=O)N2C(C(=O)O)=C(CBr)C(Br)S(=O)[C@H]12
Yield: 108.6 %

Procedure:
10 g of t-butyl 2-bromo-3-bromomethyl-7-formamido-3-cephem-4-carboxylate-1-oxide in 40 ml of trifluoroacetic acid were stirred for 15 minutes at room temperature and the solvent was removed by evaporation under vacuo. 25 ml of dichloromethane were added to the residue and evaporation to dryness was repeated. A 1:1 mixture of heptane and ether was added to the residue whereafter the slightly yellow crystals were vacuum filtered and were washed with the same solvent mixture to obtain 9.57 g of 2-bromo-3-bromomethyl-7-formamido-3-cephem-4-carboxylic acid-1-oxide having the following characteristics:
Reaction SMILES: [Br:1][CH2:2][CH2:3]Br.[N:5]1([C:11]2[CH:12]=[CH:13][C:14]([N+:18]([O-:20])=[O:19])=[C:15]([OH:17])[CH:16]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.C(=O)([O-])[O-].[K+].[K+].C1(O)C=CC=CC=1.BrC(Br)C>C(#N)C.C(OCC)(=O)C>[Br:1][CH2:2][CH2:3][O:17][C:15]1[CH:16]=[C:11]([N:5]2[CH2:6][CH2:7][O:8][CH2:9][CH2:10]2)[CH:12]=[CH:13][C:14]=1[N+:18]([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1ccc(N2CCOCC2)cc1O
Reactant: BrCCBr
Agent: CC(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Oc1ccccc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(N2CCOCC2)cc1OCCBr
Temperature: 25 °C
Reaction time: 72 h
Yield: 38.2 %

Procedure:
1,2-Dibromoethane (1.50 mL, 17.4 mmol) was added to 5-Morpholin-4-yl-2-nitro-phenol (0.792 g, 3.53 mmol) and Potassium carbonate (1.71 g, 12.4 mmol) in Acetonitrile (40 mL) and the reaction was stirred under an atmosphere of Nitrogen at room temperature for 72 h (no change by HPLC), then was brought to reflux. After 4d, 1H-NMR indicated that the assumed starting material my LCMS was in actuality the 2:1 phenol-dibromoethane adduct. The reaction was cooled, diluted with ethyl acetate and filtered, conc. onto 5 g Celite. Chromatography (ISCO, 40 g, 0-40% EtOAc:Hex) afforded 4-[3-(2-Bromo-ethoxy)-4-nitro-phenyl]-morpholine (447 mg, 38%) as a colorless oil. 1H-NMR (CDCl3): 7.99 (d, 1H, J=8.8 Hz), 6.48 (m, 1H), 6.36 (d, 1H, J=1.5 Hz), 4.39 (t, 2H, J=6.8 Hz), 3.85 (t, 4H, J=4.8 Hz), 3.71 (t, 2H, J=6.8 Hz), 3.34 (t, 4H, J=4.8 Hz).
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][O:6]S(C2C=CC(C)=CC=2)(=O)=O)[CH2:3][CH2:2]1.O[C:18]1[CH:23]=[CH:22][N:21]([C:24]2[S:25][C:26]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:27]([CH3:29])[N:28]=2)[C:20](=[O:35])[CH:19]=1>>[CH:1]1([CH2:4][CH2:5][O:6][C:18]2[CH:23]=[CH:22][N:21]([C:24]3[S:25][C:26]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:27]([CH3:29])[N:28]=3)[C:20](=[O:35])[CH:19]=2)[CH2:2][CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)OCCC2CC2)cc1
Reactant: CCOC(=O)c1sc(-n2ccc(O)cc2=O)nc1C
Product: CCOC(=O)c1sc(-n2ccc(OCCC3CC3)cc2=O)nc1C
Yield: 35 %

Procedure:
Following the procedure as described in Example 15, making variations only as required to use 2-cyclopropylethyl-4-methylbenzenesulfonate in place of (bromomethyl)cyclopropane to react with ethyl 2-(4-hydroxy-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylate, the title compound was obtained as a colorless solid in 35% yield: mp 188-190° C. (hexane/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 8.67 (dd, J=8.1, 1.1 Hz, 1H), 6.17-6.13 (m, 1H), 6.00-5.99 (m, 1H), 4.35-4.27 (m, 2H), 4.04 (t, J=6.6 Hz, 2H), 2.68 (s, 3H), 1.68 (q, J=6.6 Hz, 2H), 1.35 (dt, J=7.1, 1.3 Hz, 3H), 0.90-0.68 (m, 1H), 0.52-0.44 (m, 2H), 0.14-0.09 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 167.8, 162.9, 162.2, 156.6, 155.6, 131.3, 119.7, 104.1, 96.7, 69.1, 60.9, 33.6, 17.3, 14.3, 7.5, 4.2; MS (ES+) m/z 349.2 (M+1).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[C:8](=[O:17])[C:7]1=[O:18].FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>>[O:17]=[C:8]1[C:7](=[O:18])[NH:6][CH2:11][CH2:10][N:9]1[CH2:12][C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)CN1CCN(Cc2ccc(OC)cc2OC)C(=O)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: COC(=O)CN1CCNC(=O)C1=O
Temperature: 25 °C
Yield: 77.4 %

Procedure:
A mixture of 10.5 g of methyl [4-(2,4-dimethoxybenzyl)-2,3-dioxopiperazin-1-yl]acetate, 42 ml of trifluoroacetic acid and 21 ml of anisole was refluxed for 4 hours. The reaction mixture was cooled to room temperature and then distilled under reduced pressure to remove the solvent. The resulting residue was purified by a silica gel column chromatography (eluent; chloroform: methanol=6:1) to obtain 4.5 g of methyl (2,3-dioxopiperazin-1-yl)acetate as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:14])=[CH:4][C:5]([CH:8]([OH:13])[C:9]([F:12])([F:11])[F:10])=[N:6][CH:7]=1.ClCCl.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=[O:20].S([O-])([O-])(=O)=S.[Na+].[Na+]>>[Br:1][C:2]1[C:3]([CH3:14])=[CH:4][C:5]([C:8]([OH:20])([OH:13])[C:9]([F:10])([F:11])[F:12])=[N:6][CH:7]=1
Reactant: Cc1cc(C(O)C(F)(F)F)ncc1Br
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(C(O)(O)C(F)(F)F)ncc1Br
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 1-(5-bromo-4-methylpyridin-2-yl)-2,2,2-trifluoro-ethanol (345 mg; 1.2775 mmol) in dichloromethane (10 mL; 156.0 mmol) was added Dess-Martin periodinane (0.7313 g; 1.672 mmol). The reaction mixture was stirred at room temperature for 5 hours. 20 mL of a 10% aqueous solution of sodium thiosulfate was added and the reaction stirred for an additional 10 minutes. The reaction mixture was washed with 2 M aqueous sodium carbonate, dried over MgSO4, filtered, and concentrated. The crude product was carried forward without purification. LCMS (ESI): M+H=286.0; 1H NMR (400 MHz, DMSO) δ 8.70 (s, 1H), 7.72 (s, 1H), 7.59 (s, 2H), 2.43 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[C:18]([NH2:20])=[O:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=1>C(#N)C.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]([F:31])([F:32])[F:33])=[CH:25][CH:24]=2)[C@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[C:18]([NH2:20])=[O:19])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Reactant: NC(=O)[C@@H]1CCCC[C@@H]1NS(=O)(=O)c1ccc(Cl)cc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: NC(=O)[C@@H]1CCCC[C@@H]1N(Cc1ccc(OC(F)(F)F)cc1)S(=O)(=O)c1ccc(Cl)cc1
Yield: 66.3 %

Procedure:
cis-2-(4-Chloro-benzenesulfonylamino)-cyclohexanecarboxylic acid amide (200 mg, 0.63 mmol), CsCO3 (250 mg, 0.76 mmol), and 1-bromomethyl-4-trifluoromethoxy-benzene (155 mg, 0.69 mmol) was stirred in acetonitrile (15 mL) at room temperature for 18 h. The reaction was then diluted with EtOAc (150 mL) and washed with H2O, brine, dried over Na2SO4 and concentrated to give a crude white wax. Further purification by flash chromatography (silica gel, 0.5%–1% MeOH/CHCl3) afforded the titled compound (205 mg) as a white solid in 67% yield: 1H NMR (DMSO-d6) δ 7.75 (d, 2 H, J=8.0 Hz), 7.59 (d, 2 H, J=8.0 Hz), 7.36 (m, 3 H), 7.21 (d, 2 H, J=8.0 Hz), 6.69 (s br, 1 H), 4.58 (AB2, 2 H, Δv=17, Jab=64 Hz), 3.89 (m, 1 H), 2.79 (s, 1 H), 2.44 (m, 1 H), 1.78 (m, 1 H), 1.66 (m, 2 H), 1.31 (m, 3 H), 0.98 (m, 1 H); MS m/e 491.03 (M+H)+.