Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[NH:6][CH:7]=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].C[O-].[Na+].[Cl:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16]Br>CO>[CH2:1]([C:5]1[N:6]([CH2:16][C:15]2[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=2[Cl:13])[CH:7]=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Clc1ccccc1CBr
Reactant: CCCCc1ncc[nH]1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCc1nccn1Cc1ccccc1Cl
Temperature: 50 °C
Reaction time: 1 h
Yield: 61.3 %

Procedure:
2-n-Butylimidazole (9.7 g, 0.078 mol) was dissolved in methanol (50 mL) and added dropwise to a solution of sodium methoxide [from sodium hydride (2.31 g, 0.0934 mol) in methanol(250 mL)]. After one hour, the solution was evaporated to dryness, and the sodium salt was taken up in dry dimethylformamide (150 mL), and 2-chlorobenzyl bromide (16.3 g, 0.079 mol) was added. The mixture was heated at 50° C. for 17 hours under argon, poured onto ice water, and the product was extracted into ethyl acetate. The extract was washed, dried, and concentrated to give 18.5 g of crude product which was flash chromatographed over silica gel with 2:1 hexane/ethyl acetate to provide 11.9 g (61%) of 2-n- butyl-1-(2-chlorophenyl)methyl-1H-imidazole as an oil. Thin layer chromatography on silica gel with 4:1 hexane/ethyl acetate gave an Rf value of 0.59.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[NH:10][C:11]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)=[N:12][N:13]=2)=[CH:4][C:3]=1[C:21]([F:24])([F:23])[F:22].C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:32]1([NH2:39])[CH:37]=[CH:36][N:35]=[C:34]([NH2:38])[NH:33]1>O1CCOCC1.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[NH:10][C:11]([C:14]3[CH:15]=[CH:16][C:17]([O:20][C:36]4[N:35]=[C:34]([NH2:38])[N:33]=[C:32]([NH2:39])[CH:37]=4)=[CH:18][CH:19]=3)=[N:12][N:13]=2)=[CH:4][C:3]=1[C:21]([F:22])([F:23])[F:24]
Reactant: Oc1ccc(-c2nnc(Nc3ccc(Cl)c(C(F)(F)F)c3)[nH]2)cc1
Reactant: NC1=NC=CC(N)(Cl)N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: C1COCCO1
Product: Nc1cc(Oc2ccc(-c3nnc(Nc4ccc(Cl)c(C(F)(F)F)c4)[nH]3)cc2)nc(N)n1
Temperature: 80 °C
Yield: 46.3 %

Procedure:
4-[5-(4-chloro-3-trifluoromethyl-phenylamino)-4H[1,2,4]triazol-3-yl]-phenol (1.3 g, 3.66 mmol) was dissolved in 18 mL of anhydrous dioxane in a 10-20 md microwave vial (Personal Chemistry). Solid Cs2CO3 (1.19 g, 3.66 mmol, 1.0 eq) was added and the reaction mixture was stirred with heating at 80° C. for 10 min, then 4-chloro-2,4-diaminopyrimidine (0.530 g, 3.66 mmol) was added. The vial was capped and microwaved at 200° C. for 25 min. Then the reaction mixture was diluted with ca. 10 mL of MeOH, transferred into a round-bottom flask and concentrated in vacuo to ca. 20 mL. The resulting reddish solution was loaded on a short pad of silica gel and eluted first with 100% ethyl acetate to remove the unreacted starting material and then with 20% MeOH in EtOAc to elute the product. The product was further purified by ISCO system (80 g pre-packed column, 40 min method, 0% to 10% MeOH gradient in ethyl acetate). Solvent was removed in vacuo to give the title product as an off-white solid (0.785 g). Yield 46.3%.
Reaction SMILES: CO.[C:3]1([NH:9][C:10]2[O:11][C:12]3[CH:18]=[C:17]([CH2:19][C:20]([O:22]C)=[O:21])[CH:16]=[CH:15][C:13]=3[N:14]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[Na+]>O1CCCC1>[C:3]1([NH:9][C:10]2[O:11][C:12]3[CH:18]=[C:17]([CH2:19][C:20]([OH:22])=[O:21])[CH:16]=[CH:15][C:13]=3[N:14]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)Cc1ccc2nc(Nc3ccccc3)oc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)Cc1ccc2nc(Nc3ccccc3)oc2c1
Temperature: 25 °C
Yield: 79.6 %

Procedure:
In tetrahydrofuran (which will hereinafter be abbreviated as “THF”) (2 ml) and methanol (2 ml) was dissolved methyl 2-phenylaminobenzoxazol-6-acetate (460 mg, 1.63 mmol), followed by the addition of 1N NaOH (3.3 ml) under stirring at room temperature. After further stirring overnight at room temperature, the reaction mixture was concentrated into a small volume. The concentrate was acidified with acetic acid. The crystals thus obtained were collected by filtration, washed with water and then dried, whereby 2-phenylaminobenzoxazol-6-acetic acid (348 mg, 80%) was obtained as a pale yellow solid.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][NH2+:19][CH2:18]3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:10])(=[O:9])[N:8]=1.C1COCC1.C([O-])(O)=O.[Na+].[CH:33]1([C:38](Cl)=[O:39])[CH2:37][CH2:36][CH2:35][CH2:34]1>O>[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:38]([CH:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)=[O:39])[CH2:18]3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:9])(=[O:10])[N:8]=1
Reactant: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCC[NH2+]C3)c21
Reactant: O=C(Cl)C1CCCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCN(C(=O)C4CCCC4)C3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.1 %

Procedure:
To a solution of (S)-3-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidinium hydrochloride (Example 2a, 528 mg, 1.52 mmol) in H2O:THF (20 mL, 2:1), was added NaHCO3 (640 mg, 7.60 mmol). Upon complete dissolution of the NaHCO3, cyclopentanecarbonyl chloride (945 uL, 7.60 mmol) was added dropwise. The reaction was stirred at room temperature overnight. The precipitate was collected by vacuum filtration and purified by preparative HPLC (10-90% acetonitrile in water). The pure fractions were combined, concentrated then dissolved in a solution of NaHCO3 (250 mg in 10 mL water). After complete dissolution, the mixture was cooled in an ice bath and neutralized with 1N HCl. The resulting white solid was collected by vacuum filtration to provide the desired product (322 mg, 52%) as a white solid. 1H NMR (DMSO-d6, 400 MHz, 80° C.): 1.43 (m, 2H), 1.51-1.80 (m, 10H), 1.90 (m, 1H), 2.09 (m, 1H), 2.96 (m, 2H), 4.01 (br m, 2H), 4.12 (d, J=6.4 Hz, 2H), 6.67 (d, J=7.8 Hz, 1H), 6.77 (d, J=8.3 Hz, 1H), 7.46 (t, J=8.3 Hz, 1H), 7.92 (br s, 2H), 10.70 (br s, 1H). MS=407 (MH+).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[N:15]=[C:16]([N:19]2[CH2:22][CH:21](OS(C)(=O)=O)[CH2:20]2)[S:17][CH:18]=1)=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:28]([O-:31])(=[S:30])[CH3:29].[K+]>CN(C)C=O>[C:28]([S:30][CH:21]1[CH2:20][N:19]([C:16]2[S:17][CH:18]=[C:14]([C:12](=[O:13])[NH:11][CH2:10][CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3])[N:15]=2)[CH2:22]1)(=[O:31])[CH3:29]
Reactant: CC([O-])=S
Reactant: CC(C)(C)[Si](C)(C)OCCNC(=O)c1csc(N2CC(OS(C)(=O)=O)C2)n1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC1CN(c2nc(C(=O)NCCO[Si](C)(C)C(C)(C)C)cs2)C1
Temperature: 80 °C
Reaction time: 4 h
Yield: 64.3 %

Procedure:
To a solution of 1-{4-[2-(t-butyldimethylsilyloxy)ethylcarbamoyl]-1,3-thiazol-2-yl}-3-methanesulfonyloxyazetidine (647.1 mg, 1.49 mmol) (obtained as described in Reference Example 33(5)) in dimethylformamide (32.0 ml) was added potassium thioacetate (1.28 mg, 8.9 mmol) at room temperature. The mixture was stirred in an oil bath (80° C.) for 4 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The obtained organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane:ethyl acetate (3:2) as the eluant to afford 3-acetylthio-1-{4-[2-(t-butyldimethylsilyloxy)ethylcarbamoyl]-1,3-thiazol-2-yl}azetidine (398.2 mg, yield 65%) as a pale brown solid.
Reaction SMILES: [CH2:1]([C:8]1[C:13](=[O:14])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][C:11]2=[N:10][C:9]=1[CH:19](O)[CH:20]([CH3:22])[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]1(=[O:34])[NH:28][C:27](=[O:29])[C:26]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:25]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[CH2:1]([C:8]1[C:13](=[O:14])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][C:11]2=[N:10][C:9]=1[CH:19]([N:28]1[C:24](=[O:34])[C:25]2[C:26](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:27]1=[O:29])[CH:20]([CH3:22])[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)C(O)c1nc2n(c(=O)c1Cc1ccccc1)CCCC2
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)C(c1nc2n(c(=O)c1Cc1ccccc1)CCCC2)N1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Yield: 44 %

Procedure:
A previous batch of the product from Step 8 (18) was combined with the above and 150 mg (0.48 mmol) of this crude material was dissolved in 3 ml of dry tetrahydrofuran then cooled to 0° C. Phthalimide 212 mg (1.4 mmol) was added to the cold solution followed by triphenylphosphine 189 mg (0.72 mmol) then DIAD 140 μl (0.72 mmol). The reaction mixture was stirred under nitrogen and allowed to warm to room temperature overnight. The solvent was evaporated and the solid redissolved in ethyl acetate then washed with saturated NaHCO3 and brine. The organic layer was then dried over MgSO4 and the solvent was removed in vacuo resulting in 700 mg of crude material that was purified by flash chromatography to give 95 mg (0.22 mmol, 44%) of 2-[1-(3-benzyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-2-yl)-2-methylpropyl]-1H-isoindole-1,3(2H)-dione (19) as a white solid.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.[C:16]1([CH2:22][C:23](Cl)=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH3:8][C@H:6]1[N:7]([C:23](=[O:24])[CH2:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@@H:2]([CH3:1])[CH2:3][N:4]([C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[CH2:5]1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1
Reactant: O=C(Cl)Cc1ccccc1
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1C(=O)Cc1ccccc1

Procedure:
Prepared by the method of example 67 part (a) using (3R,5S)-3,5-dimethyl-1-piperazinecarboxylic acid, 1,1-dimethylethyl ester and phenyl acetyl chloride to give the sub-title compound.
Reaction SMILES: [K+].[C:2]([C:4]1[N:5]=[C:6]([C:17]([O-:19])=O)[N:7]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[CH:8]=1)#[N:3].CCN(C(C)C)C(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:53]([O:57][C:58]([N:60]1[CH2:65][CH2:64][CH:63]([C:66]2[CH:71]=[CH:70][C:69]([NH2:72])=[C:68]([C:73]3[CH2:78][CH2:77][CH2:76][CH2:75][CH:74]=3)[N:67]=2)[CH2:62][CH2:61]1)=[O:59])([CH3:56])([CH3:55])[CH3:54]>C(Cl)Cl.CCOC(C)=O>[C:53]([O:57][C:58]([N:60]1[CH2:65][CH2:64][CH:63]([C:66]2[CH:71]=[CH:70][C:69]([NH:72][C:17]([C:6]3[N:7]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:14])([CH3:15])[CH3:16])[CH:8]=[C:4]([C:2]#[N:3])[N:5]=3)=[O:19])=[C:68]([C:73]3[CH2:78][CH2:77][CH2:76][CH2:75][CH:74]=3)[N:67]=2)[CH2:62][CH2:61]1)=[O:59])([CH3:56])([CH3:54])[CH3:55]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)c(C3=CCCCC3)n2)CC1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(NC(=O)c3nc(C#N)cn3COCC[Si](C)(C)C)c(C3=CCCCC3)n2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 42.3 %

Procedure:
To a solution of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate potassium salt (296 mg, 0.970 mmol) (as prepared in Example 3, step (d)) in 8 mL DCM was added DIEA (291 μL, 1.72 mmol) and PyBroP (512 mg, 1.10 mmol), and the reaction was stirred at 25° C. for 15 min. A solution of 5-amino-6-cyclohex-1-enyl-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester (233 mg, 0.65 mmol) (as prepared in the previous step) in 4 mL DCM was added and the reaction stirred overnight at 25° C. The reaction was diluted with EtOAc (25 mL) and washed with NaHCO3 (1×25 mL) and brine (25 mL) and the organic layer was dried over Na2SO4 and then concentrated. The residue was purified by flash chomatography (silica gel, 5% MeOH—CHCl3) to afford 167 mg (40%) of the title compound as a white solid. Mass Spectrum (ESI, m/z): Calcd. for C32H46N6O4Si, 607.3 (M+H), found 607.3.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[H-].[Na+].[Br:19][CH2:20][CH2:21][CH2:22]Br>CN(C)C=O>[Br-:19].[CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[C:5]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:6]3[CH2:22][CH2:21][CH2:20][N+:7]3=2)[CH:3]=1
Reactant: BrCCCBr
Reactant: Cc1ccc2[nH]nc(-c3ccccc3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c(-c1ccccc1)n1[n+]2CCC1
Product: [Br-]
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 56 %

Procedure:
To a solution of 5-methyl-3-phenylindazole (10.4 g) in dimethylformamide (60 ml), 50% sodium hydride (2.5 g) was added and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was then added dropwise to dimethylformamide (20 ml) containing 1,3-dibromopropane (25 g) while cooling with ice, and the resulting mixture was stirred at room temperature for 30 minutes. The mixture was extracted with xylene (120 ml), and the extract was washed with water, dried over anhydrous sodium sulfate and heated at reflux for 2 hours. The resulting precipitate was recovered by filtration, and washed with acetone to give 9.2 g of 2,3-dihydro-7-methyl-9-phenyl-1H-pyrazolo[1,2-a]indazolium bromide. After recrystallization from isobutanol, the product had a melting point of 237° to 241° C. (decomposition).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([C:10]#[C:11][C:12]2[N:13]=[C:14]([CH3:17])[NH:15][CH:16]=2)[CH:7]=[CH:6][N:5]=1.Br.Br[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1.O>C1COCC1>[N:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH2:20][N:15]1[CH:16]=[C:12]([C:11]#[C:10][C:8]2[CH:7]=[CH:6][N:5]=[C:4]([CH3:3])[CH:9]=2)[N:13]=[C:14]1[CH3:17]
Reactant: BrCc1ccccn1
Reactant: Cc1cc(C#Cc2c[nH]c(C)n2)ccn1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C#Cc2cn(Cc3ccccn3)c(C)n2)ccn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (69 mg, 55%, 1.59 mmol) was suspended in 2 mL dry THF. A solution of 2-methyl-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine (95 mg, 0.48 mmol) in 8 mL dry THF was added and the reaction mixture was stirred at room temperature for 30 min. 2-(Bromomethyl)pyridine hydrobromide (162 mg, 0.63 mmol) was added and stirring was continued overnight. The reaction mixture was poured into 70 mL water and extracted three times with ethyl acetate (70 mL each). The combined organic extracts were dried with sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (dichloromethane/methanol 100:0→90:10 gradient) and a mixture of two regioisomers was obtained. This mixture could be separated by crystallization from diethylether and the desired compound was obtained as a white solid (35 mg, 25%), MS: m/e=289.1 (M+H30).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]2[C:15]([O:16][CH2:17][CH3:18])=[CH:14][N:13]=[C:12]([O:19]C)[CH:11]=2)[CH:3]=1.Br.[NH+]1C=CC=CC=1>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]2[C:15]([O:16][CH2:17][CH3:18])=[CH:14][NH:13][C:12](=[O:19])[CH:11]=2)[CH:3]=1
Reactant: CCOc1cnc(OC)cc1-c1cc(Cl)ccc1C#N
Agent: Br
Agent: c1cc[nH+]cc1
Product: CCOc1c[nH]c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
135 mg (0.44 mmol) of 4-chloro-2-(5-ethoxy-2-methoxypyridin-4-yl)benzonitrile and pyridinium hydrobromide were reacted according to General Method 3A. Yield: 134 mg (purity 76%, 83% of theory)
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][C:4]=1[NH:12][C:13]1[N:18]=[C:17]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:16]=[CH:15][N:14]=1.[H][H]>C(O)C.[Ni]>[NH2:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][OH:1])=[C:4]([NH:12][C:13]2[N:18]=[C:17]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[CH:16]=[CH:15][N:14]=2)[CH:5]=1
Reactant: O=[N+]([O-])c1ccc(CO)c(Nc2nccc(-c3cccnc3)n2)c1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: Nc1ccc(CO)c(Nc2nccc(-c3cccnc3)n2)c1

Procedure:
A solution of N-(2-hydroxymethyl-5-nitro-phenyl)-4-(3-pyridinyl)-2-pyrimidinamine (0.23 g, 0.71 mmol) in ethanol (230 mL) is hydrogenated at atmospheric pressure over Raney nickel (0.2 g) at 25° C.. The calculated amount of hydrogen is taken up in 13 h. The mixture is then filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by column chromatography on silica gel, eluent 25% aqueous ammonia-ethanol-dichloromethane (1:9:90), to give the title compound as a yellow crystalline solid, m.p. 213-215° C.
Reaction SMILES: C(OC([NH:8][C:9]1[S:13][N:12]=[C:11](/[C:14](=[N:45]/[O:46][C:47]([C:50]([O:52]C(C)(C)C)=[O:51])([CH3:49])[CH3:48])/[C:15]([NH:17][C@@H:18]2[C:43](=[O:44])[N:20]3[C:21]([C:27]([O:29]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:28])=[C:22]([CH2:25]Cl)[CH2:23][S:24][C@H:19]23)=[O:16])[N:10]=1)=O)(C)(C)C.[I-].[Na+].[NH2:59][C:60]1[N:64]([CH3:65])[N:63]=[CH:62][C:61]=1[NH:66][C:67]([NH:69][CH2:70][CH2:71][CH2:72][NH:73]C(OC(C)(C)C)=O)=[O:68].C(OCC)(=O)C>CN(C)C=O.O>[NH2:8][C:9]1[S:13][N:12]=[C:11](/[C:14](=[N:45]/[O:46][C:47]([C:50]([OH:52])=[O:51])([CH3:48])[CH3:49])/[C:15]([NH:17][C@@H:18]2[C:43](=[O:44])[N:20]3[C:21]([C:27]([O-:29])=[O:28])=[C:22]([CH2:25][N+:63]4[N:64]([CH3:65])[C:60]([NH2:59])=[C:61]([NH:66][C:67]([NH:69][CH2:70][CH2:71][CH2:72][NH2:73])=[O:68])[CH:62]=4)[CH2:23][S:24][C@H:19]23)=[O:16])[N:10]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CCl)CS[C@H]23)ns1
Reactant: Cn1ncc(NC(=O)NCCCNC(=O)OC(C)(C)C)c1N
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(N)c(NC(=O)NCCCN)c[n+]1CC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)/C(=N\OC(C)(C)C(=O)O)c3nsc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 6.4 %

Procedure:
To a solution of benzhydryl 7β-[(Z)-2-(5-tert-butoxycarbonylamino-1,2,4-thiadiazol-3-yl)-2-(1-tert-butoxycarbonyl-1-methylethoxyimino)acetamido]-3-chloromethyl-3-cephem-4-carboxylate (1.0 g) in N,N-dimethylformamide (2.0 ml) was added sodium iodide (199 mg), and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added 5-amino-4-(3-{3-[(tert-butoxycarbonyl)amino]propy}ureido)-1-methylpyrazole (415 mg) and the whole mixture was stirred at 32° C. for 24 hours. To the resulting reaction mixture were added ethyl acetate (50 ml) and water (50 ml). The aqueous layer was separated, and the organic layer was washed with 10% aqueous sodium trifluoroacetate solution and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to about 5 ml in vacuo. The concentrate was poured into diisopropyl ether (100 ml), and the resulting precipitate was collected by filtration and dried in vacuo. To a solution of the resulting solid in methylene chloride (3.6 ml) were added anisole (1.2 ml) and trifluoroacetic acid (2.4 ml). The resulting solution was stirred at room temperature for 4 hours and poured into diisopropyl ether (100 ml). The resulting precipitate was collected by filtration and dried in vacuo to give a crude product (939 mg), which was purified by preparative HPLC utilizing ODS column. The eluate containing a desired product was concentrated to about 30 ml in vacuo. The concentrate was adjusted to about pH 3 with concentrated hydrochloric acid and chromatographed on Diaion® HP-20 (Mitsubishi Chemical Corporation) eluting with 30% aqueous 2-propanol. The eluate was concentrated to about 30 ml in vacuo and lyophilized to give 7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-{3-amino-4-[3-(3-aminopropyl)ureido]-2-methyl-1-pyrazolio}methyl-3-cephem-4-carboxylate (53 mg) as an amorphous solid.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](O)([CH:10]([CH3:12])[CH3:11])[CH3:9])=[CH:4][CH:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1.[C:25]1([OH:31])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:28]2[CH:29]=[CH:30][C:25]([OH:31])=[CH:26][CH:27]=2)([CH3:9])[CH:10]([CH3:12])[CH3:11])=[CH:4][CH:3]=1
Reactant: CC(C)C(C)(O)c1ccc(I)cc1
Reactant: Oc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(C)C(C)(c1ccc(O)cc1)c1ccc(I)cc1
Temperature: 25 °C

Procedure:
A mixture of 5a (56.0 g, 193 mmol), p-TSA (36.0 g, 193 mmol) and phenol (25.0 g, 251 mmol) was heated to 95 for 1 h. After cooling to room temperature, the reaction mixture was partitioned between DCM and water. The separated organic phase was washed with water, three times with saturated aqueous sodium bicarbonate, brine, dried (MgSO4) and concentrated in vacuo to afford the title compound 5b. This was used without further purification in the subsequent step.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[O:6][C:7]1[N:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=O.[CH3:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[NH:28][CH2:27][CH2:26][CH2:25]2>>[CH3:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[N:28]([C:9]([C:8]1[C:7]([O:6][C:5]3[CH:16]=[CH:17][CH:18]=[C:3]([C:2]([F:1])([F:20])[F:19])[CH:4]=3)=[N:15][CH:14]=[CH:13][CH:12]=1)=[O:11])[CH2:27][CH2:26][CH2:25]2
Reactant: O=C(O)c1cccnc1Oc1cccc(C(F)(F)F)c1
Reactant: Cc1ccc2c(c1)CCCN2
Product: Cc1ccc2c(c1)CCCN2C(=O)c1cccnc1Oc1cccc(C(F)(F)F)c1

Procedure:
The title compound was prepared from 2-(3-trifluoromethyl-phenoxy)-nicotinic acid in analogy to Example 1, Step 2, by replacing 1,2,3,4-tetrahydro-quinoline with 6-methyl-1,2,3,4-tetrahydro-quinoline ([CAS RN 91-61-2]). MS (ISP): 413.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.Cl[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[N:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: COc1ccc(CCl)cc1
Reactant: Clc1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c(Cl)nc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a round bottomed flask was added 2-chloro-1H-benzo[d]imidazole (1.000 g, 6.55 mmol), 1-(chloromethyl)-4-methoxybenzene (1.540 g, 9.83 mmol), and potassium carbonate (1.359 g, 9.83 mmol) in DMF (21.85 mL) to stir overnight. Reaction was allowed to cool to room temperature. The reaction mixture was diluted with water and extracted with DCM. The organic extract was washed with water, brine, dried with magnesium sulfate, filtered, and concentrated to provide 2-Chloro-1-(4-methoxybenzyl)-1H-benzo[d]imidazole. MS (ESI, pos. ion) m/z: 273.2 (M+1).