Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].O.[C:13]1(C)C=CC(S(O)(=O)=O)=C[CH:14]=1>C(O)C>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH2:13][CH3:14])=[O:10]
Reactant: O=C(O)Cc1ccccc1O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Product: CCOC(=O)Cc1ccccc1O

Procedure:
The stirred solution of 2-(2-Hydroxyphenyl)acetic acid (10 g, 65.7 mmol) and p-Toluenesulfonic acid monohydrate (1.40 g, 7.3 mmol) in abs ethanol (100 ml) was refluxed for 4 hours or until all the starting material is consumed. The reaction mixture was concentrated, diluted with ethyl acetate and washed with 1M HCl and brine. The organic layer was dried over Na2SO4, filtered, concentrated, and purified by flash chromatography on a silica gel column (hex:ethyl acetate 2:1) to give the title compound.
Reaction SMILES: [C:1]([NH2:7])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH2:8]([N:10]([CH2:19][CH3:20])[C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1)[CH3:9]>>[CH2:8]([N:10]([CH2:19][CH3:20])[C:11]1[CH:18]=[CH:17][C:14]([CH:15]([NH:7][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])[NH:7][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])=[CH:13][CH:12]=1)[CH3:9]
Reactant: CC(C)(C)C(N)=O
Reactant: CCN(CC)c1ccc(C=O)cc1
Product: CCN(CC)c1ccc(C(NC(=O)C(C)(C)C)NC(=O)C(C)(C)C)cc1
Yield: 77 %

Procedure:
Compound 51 was prepared from pivalamide and 4-(diethylamino)benzaldehyde using method 1. Yield: 77%. 1H NMR (400 MHz, DMSO) δ 7.70 (d, J=8.8 Hz, 2H), 7.03 (d, J=8.8 Hz, 2H), 6.62 (d, J=8.8 Hz, 2H), 6.52 (t, J=8.4 Hz, 1H), 3.30-3.33 (m, 4H), 1.12 (s, 18H), 1.05-1.08 (m, 6H). LC-MS (ESI): m/z 262.2 (M+H)+. HRMS (ESI) for C21H36N3O2 (MH+): calcd, 362.2802. found 362.2795.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)[CH2:5][C:6]([OH:8])=O.[NH2:17][C:18](=[N:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[S:19][CH3:20].CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[CH3:1][O:2][N:3]=[C:4]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)[CH2:5][C:6]([NH:17][C:18](=[N:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])[S:19][CH3:20])=[O:8]
Reactant: CSC(N)=NC(=O)OC(C)(C)C
Reactant: CON=C(CC(=O)O)c1ccc(OC)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON=C(CC(=O)NC(=NC(=O)OC(C)(C)C)SC)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 88.6 %

Procedure:
A mixture of 3-(methoxyimino)-3-(4-methoxyphenyl)propanoic acid (223 mg), tert-butyl amino(methylthio)methylenecarbamate (190 mg), EDAC.HCl (384 mg), DMAP (122 mg) and triethylamine (0.56 mL) in dichloromethane (3 mL) was stirred at room temperature for 12 h. The crude reaction mixture was purified directly by preparative TLC eluting with 35% ethyl acetate/75% hexanes to give the title compound as a yellowish oil (350 mg). HPLC retention time: 2.42 min (method A). MS (ESI) (M+Na)+ 418.18.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:20]=[CH:19][C:7]([NH:8][C:9](=[O:18])[CH2:10][N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[CH:6][C:5]=1[N+:21]([O-])=O)[CH3:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH2:35]([N:42]1[C:46](=[O:47])[C:45](=[C:48]2[N:52]([CH3:53])[C:51]3[CH:54]=[CH:55][CH:56]=[CH:57][C:50]=3[S:49]2)[S:44][CH2+:43]1SC)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH2:35]([N:42]1[C:46](=[O:47])[C:45](=[C:48]2[N:52]([CH3:53])[C:51]3[CH:54]=[CH:55][CH:56]=[CH:57][C:50]=3[S:49]2)[S:44][C:43]1=[N:21][C:5]1[CH:6]=[C:7]([NH:8][C:9](=[O:18])[CH2:10][N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[CH:19]=[CH:20][C:4]=1[NH:3][CH2:1][CH3:2])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: CCNc1ccc(NC(=O)CN2CCN(C)CC2)cc1[N+](=O)[O-]
Reactant: CS[CH2+]1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CCNc1ccc(NC(=O)CN2CCN(C)CC2)cc1N=C1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1

Procedure:
In a manner similar to Example 30, intermediate 4′-ethylamino-2-(4-methylpiperazin-1-yl)-3′-nitroacetanilide was hydrogenated and then condensed with 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazolium p-toluene sulfonate to afford the title compound. MS(ESI): 628(MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Si:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:6]([Br:8])[CH:7]=1.CC1(C)C(C)(C)OB([C:36]2[CH:53]=[CH:52][C:51]3[C:50]4[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=4)[C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[C:38]=3[CH:37]=2)O1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.O.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>[Br:8][C:6]1[CH:5]=[C:4]([Si:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:3]=[C:2]([C:47]2[CH:48]=[CH:49][C:50]3[C:51]4[C:38](=[CH:37][CH:36]=[CH:53][CH:52]=4)[C:39]4[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=4)[C:45]=3[CH:46]=2)[CH:7]=1
Reactant: Brc1cc(Br)cc([Si](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: CC1(C)OB(c2ccc3c4ccccc4c4ccccc4c3c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: Brc1cc(-c2ccc3c4ccccc4c4ccccc4c3c2)cc([Si](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Yield: 52.5 %

Procedure:
A solution of (3,5-dibromophenyl)triphenylsilane (2.20 g, 4.45 mmol), 4,4,5,5-tetramethyl-2-(triphenylen-2-yl)-1,3,2-dioxaborolane (3.15 g, 8.90 mmol), Pd(PPh3)4 (0.051 g, 0.045 mmol) and K2CO3 (1.23 g, 8.90 mmol) in toluene (100 mL) and water (20 mL) was refluxed under nitrogen overnight. After cooling to room temperature, the organic phase was isolated, filtered through a short plug of Celite® and the solvent was evaporated. The residue was purified by column chromatography on silica gel with hexane/DCM (7/3, v/v) as eluent followed by recrystallization from the same solvent to yield (3-bromo-5-(triphenylen-2-yl)phenyl)triphenylsilane (1.50 g, 52%) as a white solid.
Reaction SMILES: C[Sn](C)(C)[C:3]1[CH:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][N:4]=1.Br[C:14]1[O:18][C:17]([C:19]2[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=2)[C:22]#[N:23])=[CH:16][CH:15]=1>C1(C)C=CC=CC=1.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>[C:9]([C:6]1[CH:7]=[CH:8][C:3]([C:14]2[O:18][C:17]([C:19]3[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=3)[C:22]#[N:23])=[CH:16][CH:15]=2)=[N:4][CH:5]=1)#[N:10]
Reactant: N#Cc1cccc(-c2ccc(Br)o2)c1
Reactant: C[Sn](C)(C)c1ccc(C#N)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: N#Cc1ccc(-c2ccc(-c3cccc(C#N)c3)o2)nc1
Temperature: 110 °C
Reaction time: 15 h
Yield: 23 %

Procedure:
In a similar fashion, Pd(PPh3)4 (10 mg, 0.009 mmol) was added to a solution of 2-trimethylstannyl-5-cyano-pyridine (22.7 mg, 0.085-mmol) and 3-(5-bromofuran-2-yl)-benzonitrile (31 mg, 0.125 mmol) in toluene (1 mL) under argon. The resulting solution was stirred at 110° C. for 15 h. After cooling to room temperature, the solvent was removed in vacuo. Chromatography (5 g silica gel SPE tube, 50% chloroform in hexane to 20% ethyl acetate in 1:1 chloroform:hexane) followed by triturating with 50% dichloromethane in hexane afforded 5.3 mg (23%) of 3-(5-(5-cyano-2-pyridyl)-2-furyl)-benzonitrile (91% pure by GC/MS, contaminated by 9% dimer). 1H-NMR (CDCl3), δ (ppm): 8.85 (s, 1H), 7.87–8.05 (m, 5H), 7.52–7.63 (m, 3H), 7.36 (d, 1H), 6.95 (d, 1H), dimer impurity caused peak intensity to increase in region 8.00, 7.92, 7.49–7.57, plus 2 peaks additional peaks exactly overlapping with pure dimer @ δ (ppm): 6.87 (d) & 6.80 d).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][C:7]2([OH:13])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[Cl:16][CH2:17][C:18](N1CC(=O)N(C2C=CC=C(Cl)C=2C)C1)=[O:19]>>[Cl:16][CH2:17][C:18]([N:10]1[CH2:9][CH2:8][C:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:15][CH:14]=2)([OH:13])[CH2:12][CH2:11]1)=[O:19]
Reactant: Cc1c(Cl)cccc1N1CN(C(=O)CCl)CC1=O
Reactant: OC1(Cc2ccc(F)cc2)CCNCC1
Product: O=C(CCl)N1CCC(O)(Cc2ccc(F)cc2)CC1

Procedure:
2-Chloro-1-[4-(4-fluoro-benzyl)-4-hydroxy-piperidin-1-yl]-ethanone was prepared from 4-(4-fluorobenzyl)piperidin-4-ol according to the procedure described for Compound 76 in Example 40.
Reaction SMILES: [C:1]([C:3]1[CH:24]=[CH:23][C:6]([C:7]([NH:9][CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]([CH3:16])([CH3:15])[C:12](O)=[O:13])=[O:8])=[CH:5][CH:4]=1)#[N:2].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH2:61]([O:68][C:69](=[O:77])[CH2:70][CH:71]1[CH2:76][CH2:75][NH:74][CH2:73][CH2:72]1)[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1>C(Cl)Cl>[CH2:61]([O:68][C:69](=[O:77])[CH2:70][CH:71]1[CH2:72][CH2:73][N:74]([C:12](=[O:13])[C:11]([CH3:15])([CH3:16])[CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[NH:9][C:7](=[O:8])[C:6]2[CH:23]=[CH:24][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:75][CH2:76]1)[C:62]1[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=1
Reactant: O=C(CC1CCNCC1)OCc1ccccc1
Reactant: CC(C)(C(=O)O)C(NC(=O)c1ccc(C#N)cc1)c1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C(=O)N1CCC(CC(=O)OCc2ccccc2)CC1)C(NC(=O)c1ccc(C#N)cc1)c1ccccc1
Reaction time: 0.5 h
Yield: 69.6 %

Procedure:
N-4-Cyanobenzoyl-β-phenyl-α,α-dimethyl-β-alanine (0.5 g, 1.55 mmol) was dissolved in methylene chloride (30 ml). To the resulting solution, BOP reagent (0.89 g, 4.03 mmol) and diisopropylethyl-amine (DIEA) (1.67 ml, 9.3 mmol) were added under cooling with ice and the mixture was stirred for 30 minutes. To the reaction mixture was added 4-piperidineacetic acid benzyl ester (1.08 g, 4.65 mmol) and the resulting mixture was stirred overnight. After the solvent was distilled off, the residue was dissolved in ethyl acetate, washed sequentially with a 5% aqueous solution of citric acid, a 5% aqueous solution of sodium bicarbonate and a saturated aqueous solution of NaCl 3 times each and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was applied to a silica gel column (2.2×20 cm) and eluted with a mixed solution (hexane:ethyl acetate=3:1). The desired fractions were collected and the solvents were distilled off to yield an oil of N-4-cyanobenzoyl-β-phenyl-α,α-dimethyl-β-alanyl-4-piperidineacetic acid benzyl ester (0.58 g, 69.6%).
Reaction SMILES: [OH:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[S:4][C:3]=1[C:11]([O:13][CH3:14])=[O:12].S(OC)(O[CH3:19])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:19][O:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[S:4][C:3]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COS(=O)(=O)OC
Reactant: COC(=O)c1sc2ncccc2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1sc2ncccc2c1OC

Procedure:
995 mg of 3-hydroxy-2-methoxycarbonylthieno[2,3-b]pyridine (4.76 mmol, 1 eg.) is reflux heated for 4 hrs with 0.54 ml of dimethyl sulfate (5.71 mmol, 1.2 eq.) in 30 ml of acetone in the presence of 987 mg of potassium carbonate (7.14 mmol, 1.5 eq.). The insoluble is filtered, washed with acetone and vacuum evaporated.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[C:5]([N:7]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[O:22][CH3:23])[CH3:8])=[O:6].[CH3:31][N:32]([CH3:49])[S:33](C1C=C(C=C(C(F)(F)F)C=1)C(O)=O)(=[O:35])=[O:34]>>[CH3:31][N:32]([CH3:49])[S:33]([C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([C:27]([F:29])([F:30])[F:28])[CH:26]=1)[C:5]([N:7]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[O:22][CH3:23])[CH3:8])=[O:6])(=[O:35])=[O:34]
Reactant: CN(C)S(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Reactant: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(F)cc(C(F)(F)F)c1
Product: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(S(=O)(=O)N(C)C)c1

Procedure:
The title compound was prepared in analogy to example 90, from [4-(4-fluoro-2-methoxy-phenyl)-pyridin-3-yl]-methyl-amine (example 129, intermediate) and 3-dimethylsulfamoyl-5-trifluoromethyl-benzoic acid (Buttpark Ltd.) after a reaction time of 65 hours. The compound was purified by silica gel chromatography on a 50 g column using a MPLC system eluting with EtOAc. Light brown foam (19%). MS (ESI): m/z=512.13 [M+H]+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]1[NH:13][C:12]2[C:11](=[O:14])[N:10]([CH2:15][CH2:16][CH2:17][CH2:18][C@H:19]([OH:21])[CH3:20])[C:9](=[O:22])[N:8]([CH3:23])[C:7]=2[N:6]=1.C(N(CC)CC)C.[C:31](OC(=O)C)(=[O:33])[CH3:32]>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[C:31]([O:21][C@H:19]([CH3:20])[CH2:18][CH2:17][CH2:16][CH2:15][N:10]1[C:11](=[O:14])[C:12]2[NH:13][C:5]([NH:4][CH2:3][CH2:2][Cl:1])=[N:6][C:7]=2[N:8]([CH3:23])[C:9]1=[O:22])(=[O:33])[CH3:32]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@@H](O)CCCCn1c(=O)c2[nH]c(NCCCl)nc2n(C)c1=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(=O)O[C@H](C)CCCCn1c(=O)c2[nH]c(NCCCl)nc2n(C)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.1 %

Procedure:
To a stirring mixture of (R)-8-(2-chloroethylamino)-1-(5-hydroxyhexyl)-3-methylxanthine (2.2 g, 6.4 mmol), triethylamine (1.94 g, 19.2 mmol) and 4-dimethylaminopyridine (0.39 g, 3.2 mmol) in chloroform (50 ml) at 0-5° C. was added acetic anhydride (1.30 g, 12.8 mmol). The mixture was warmed to room temperature, stirred overnight, and concentrated under reduced pressure. The residue was purified by column chromatography eluting with ethylacetate-methanol (7:1) to provide (R)-1-(5-acetoxyhexyl)-8-(2-chloroethylamino)-3-methylxanthine (2.2 g, 89% yield) as a white powder.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:6]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:8]=1.C(Br)(Br)(Br)[Br:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl.C(Cl)(Cl)Cl>[CH2:17]([O:16][C:14]([C:5]1[CH:4]=[C:3]([CH2:2][Br:20])[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=1)=[O:15])[CH3:18]
Reactant: CCOC(=O)c1cc(CO)cc(C(=O)OCC)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cc(CBr)cc(C(=O)OCC)c1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of diethyl 5-(hydroxymethyl)benzene-1,3-dioate (3.5 g, 0.014 mol) and carbon tetrabromide (5.0 g, 0.015 mol) in 30 mL CH2Cl2, cooled to 0° C., was added dropwise a solution of triphenylphosphine (3.9 g, 0.015 mol) in 20 mL CH2Cl2. The reaction was stirred at 0° C. for 1.5 h, diluted with CHCl3, and washed with water and brine. Drying, solvent evaporation and flash chromatography (silica gel, 0-30% EtOAc/hexanes) gave diethyl-5-(bromomethyl)benzene-1,3-dioate. 1H NMR (400 MHz, CDCl3) δ 8.61 (s, 1H), 8.25 (app d, J=1.6 Hz, 2H), 4.55 (s, 2H), 4.42 (q, J=7.1 Hz, 4H), 1.42 (t, J=7.1 Hz, 6H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C@H:4]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)[NH:5][C:6]([C:8]1([CH2:13][CH2:14][O:15][CH3:16])[CH2:12][CH2:11][CH2:10][CH2:9]1)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:37])=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:27])[C@H:4]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)[NH:5][C:6]([C:8]1([CH2:13][CH2:14][O:15][CH3:16])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[S:37]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COCCC1(C(=O)N[C@@H](Cc2ccc([N+](=O)[O-])cc2)C(=O)OC)CCCC1
Solvent: Cc1ccccc1
Product: COCCC1(C(=S)N[C@@H](Cc2ccc([N+](=O)[O-])cc2)C(=O)OC)CCCC1
Reaction time: 18 h
Yield: 98.6 %

Procedure:
To a solution of [[1-(2-methoxyethyl)cyclopentyl]carbonyl]-4-nitro-L-phenylalanine methyl ester (4.30 g, 11.4 mmol) in toluene (20 mL) was added Lawesson's reagent (2.60 g, 6.27 mmol). The resultant mixture was warmed to 50° C. and stirred for 18 h. The reaction mixture was filtered through a sintered glass funnel and the filtrate was concentrated in vacuo. The residue was by flash column chromatography over silica gel (hexane-ethyl acetate, 9:1 then 8:1) to afford N-[[1-(2-methoxyethyl)cyclopentyl]thioxomethyl]-4-nitro-L-phenylalanine methyl ester (2.44 g, 54%; 70% based on recovered starting material) as a light yellow oil. HR MS: Obs. mass, 395.1639. Calcd. mass, 395.1640 (M+H).
Reaction SMILES: [I-:1].F[C:3]1[CH:12]=[CH:11][C:10]2[N:9]3[C:13]4[CH:22]=[CH:21][C:20]5[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=5[N+:14]=4[CH:23]=[C:8]3[CH:7]=[CH:6][C:5]=2[CH:4]=1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>CN(C)C=O>[I-:1].[N:24]1([C:3]2[CH:12]=[CH:11][C:10]3[N:9]4[C:13]5[CH:22]=[CH:21][C:20]6[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=6[N+:14]=5[CH:23]=[C:8]4[CH:7]=[CH:6][C:5]=3[CH:4]=2)[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1
Reactant: C1COCCN1
Reactant: Fc1ccc2c(ccc3c[n+]4c5ccccc5ccc4n32)c1
Agent: [I-]
Solvent: CN(C)C=O
Product: c1ccc2c(c1)ccc1n3c(ccc4cc(N5CCOCC5)ccc43)c[n+]21

Procedure:
A mixture of 1.04 g. of 10-fluoroimidazo[1,2-a:3,4-a']diquinolin-15-ium iodide, 3.0 ml. of morpholine and 40 ml. of dimethylformamide is heated at gentle reflux for 40 hours, treated with 1.5 g. of sodium iodide and evaporated at reduced pressure to give 10-(4-morpholinyl)imidazo[1,2-a:3,4-a']diquinolin-15-ium iodide; m.p. >300° C. after two crystallizations from aqueous methanol.
Reaction SMILES: C(=O)(O)[O-].[Na+:5].[OH-].[Na+].[CH3:8][C@@:9]1([CH2:22][N:23]2[N:27]=[N:26][CH:25]=[CH:24]2)[S:13](=[O:15])(=[O:14])[C@@H:12]2[CH2:16][C:17](=[O:18])[N:11]2[C@H:10]1[C:19]([OH:21])=[O:20]>>[CH3:8][C@@:9]1([CH2:22][N:23]2[N:27]=[N:26][CH:25]=[CH:24]2)[S:13](=[O:14])(=[O:15])[C@@H:12]2[CH2:16][C:17](=[O:18])[N:11]2[C@H:10]1[C:19]([O-:21])=[O:20].[Na+:5]
Reactant: C[C@]1(Cn2ccnn2)[C@H](C(=O)O)N2C(=O)C[C@H]2S1(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Product: C[C@]1(Cn2ccnn2)[C@H](C(=O)[O-])N2C(=O)C[C@H]2S1(=O)=O

Procedure:
In one embodiment of the unit dosage form container, the tazobactam in the second solution is tazobactam acid, and wherein the tazobactam acid in the second solution is lyophilized in the presence of sodium bicarbonate or sodium hydroxide, thereby forming lyophilized tazobactam sodium in the second lyophilized tazobactam solution. A pharmaceutical composition can include ceftolozane sulfate and tazobactam in an amount providing 1,000 mg of ceftolozane active per 500 mg of tazobactam active, and 0.03% to 0.15% by HPLC of a compound of formula (III) detectable at a retention time relative to ceftolozane of 1.22 by high performance liquid chromatography using a Develosil column ODS-UG-5; 5 micrometers; 250×4.6 mm, a mobile phase of sodium perchlorate buffer solution (pH 2.5)/CH3CN 90:10 (v/v) at a 1.0 mL/min flow rate and oven temperature of 45° C. Optionally, the pharmaceutical composition can further include 125 mg to 500 mg of sodium chloride per 1,000 mg of ceftolozane active, and L-arginine. The tazobactam in the composition can be tazobactam sodium.
Reaction SMILES: [N+:1]([C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[OH:13])([O-:3])=[O:2].Cl[CH2:15][CH2:16][O:17][CH2:18][CH3:19]>>[CH2:16]([O:17][CH2:18][CH2:19][O:13][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([N+:10]([O-:12])=[O:11])[C:4]=1[N+:1]([O-:3])=[O:2])[CH3:15]
Reactant: O=[N+]([O-])c1cccc(O)c1[N+](=O)[O-]
Reactant: CCOCCCl
Product: CCOCCOc1cccc([N+](=O)[O-])c1[N+](=O)[O-]

Procedure:
1-(2-Ethoxy-ethoxy)-2,3-dinitro-benzene was prepared by a procedure according to example 108 (i) starting from 500 mg (2.72 mmol) 2,3-dinitro-phenol and 0.72 mL (6.52 mmol) 1-chloro-2-ethoxy-ethane. Yield: 450 mg MS (ES+): m/e=257.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:21][C:22]2[CH:26]=[C:25]([CH:27]3[CH2:29][CH2:28]3)[NH:24][N:23]=2)=[N:4][C:5]([C:8]2[S:12][C:11]([S:13]([NH:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])=[O:14])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[CH3:30][C:31](OC(C)=O)=[O:32]>C1COCC1.O>[C:31]([N:24]1[C:25]([CH:27]2[CH2:28][CH2:29]2)=[CH:26][C:22]([NH:21][C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]([C:8]3[S:12][C:11]([S:13]([NH:16][C:17]([CH3:19])([CH3:20])[CH3:18])(=[O:14])=[O:15])=[CH:10][CH:9]=3)[N:4]=2)=[N:23]1)(=[O:32])[CH3:30]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2ncc(Br)c(Nc3cc(C4CC4)[nH]n3)n2)s1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)n1nc(Nc2nc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)ncc2Br)cc1C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.4 %

Procedure:
To 5-(5-bromo-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)-N-tert-butylthiophene-2-sulfonamide (1.6 g, 3.21 mmol, 1.0 eq) in THF/H2O (30 mL/15 mL), Ac2O (0.64 g, 6.42 mmol, 2.0 eq) was added dropwise. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was filtered to afford compound 5-(4-(1-acetyl-5-cyclopropyl-1H-pyrazol-3-ylamino)-5-bromopyrimidin-2-yl)-N-tert butylthiophene-2-sulfonamide (1.6 g, 92%). LC-MS (m/z)=539 [M+H]+
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([CH3:11])=[N:8][CH:7]=1)=[O:5])[CH3:2].[Br:12]N1C(=O)CCC1=O>C(OCC)(=O)C>[Br:12][CH2:11][C:9]1[S:10][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7][N:8]=1
Reactant: CCOC(=O)c1cnc(C)s1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc(CBr)s1

Procedure:
2-Methyl-5-thiazolecarboxylic acid ethyl ester (3.9 g) (J. Am. Chem. Soc. 1982, 104, 4461), N-bromosuccinimide (4.1 g) and catalytic azoisobutyronitrile in ethyl acetate (150 ml) was heated at reflux and under a 500 W halogen lamp for 16 hours. The solution was washed with water, dried (MgSO4) and evaporated. Purification was by chromatography eluting with 50% ethyl acetate in isohexane. Yield 1.5 g.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[C:19](=[O:20])[CH:18]=[C:17]([CH3:21])[N:16]=[C:15]2[CH3:22])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:30][C:31]#[CH:32]>CC#N>[F:1][C:2]1[CH:3]=[C:4]([N:14]2[C:19](=[O:20])[CH:18]=[C:17]([CH3:21])[N:16]=[C:15]2[CH3:22])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:9][CH2:10][N:11]([CH2:32][C:31]#[CH:30])[CH2:12][CH2:13]1
Reactant: Cc1cc(=O)n(-c2ccc(N3CCNCC3)c(F)c2)c(C)n1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C#CCN1CCN(c2ccc(-n3c(C)nc(C)cc3=O)cc2F)CC1
Temperature: 25 °C
Reaction time: 36 h
Yield: 44.1 %

Procedure:
To a suspension of 3-(3-fluoro-4-(piperazin-1-yl)phenyl)-2,6-dimethylpyrimidin-4(3H)-one (0.30 g, 1.00 mmol) and K2CO3 (0.69 g, 5.00 mmol) in CH3CN (15 mL) was added 3-bromoprop-1-yne (0.12 g, 1.01 mmol) and the mixture was stirred at rt for 36 h. The mixture was then filtered, and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:1) to give the title compound as a white solid (0.15 g, 44%). The compound was characterized by the following spectroscopic data: