Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([CH3:16])=[CH:4][C:3]=1[OH:17].[CH2:18](Br)[CH2:19][CH2:20][CH3:21].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:18]([O:17][C:3]1[CH:4]=[C:5]([CH3:16])[C:6]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:7][C:2]=1[CH3:1])[CH2:19][CH2:20][CH3:21]
Reactant: CCCCBr
Reactant: Cc1cc(OCc2ccccc2)c(C)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCOc1cc(C)c(OCc2ccccc2)cc1C
Yield: 78.1 %

Procedure:
A mixture of 13.4 g (59 mmol) of 2,5-dimethyl-4-(phenylmethoxy)phenol (Example K), 9.7 g (1.2×59 mmol) of butyl bromide and 12.2 g (1.5×59 mmol) of anhydrous potassium carbonate in 150 mL of acetonitrile is stirred at reflux for 40 hours. The reaction flask and inorganic residue are washed with acetonitrile and the filtrate is evaporated. Chromatography on a 3.5 cm column containing 175 g of basic alumina (activity grade I) prepared in 2:1 hexane-toluene and elution with the same solvent affords 13.1 g of the title compound; bp 153°-155° C./0.50 mm (mp 185°-195° C).
Reaction SMILES: C(OC(=O)[NH:5][C:6]1[N:15]([CH:16]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)=[C:20]([O:36][CH3:37])[CH:19]=2)[CH3:17])[C:9]2=[N:10][CH:11]=[C:12]([I:14])[CH:13]=[C:8]2[N:7]=1)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(O)C.O>[I:14][C:12]1[CH:13]=[C:8]2[N:7]=[C:6]([NH2:5])[N:15]([CH:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:34])([F:35])[F:33])=[CH:28][CH:27]=4)=[C:20]([O:36][CH3:37])[CH:19]=3)[CH3:17])[C:9]2=[N:10][CH:11]=1
Reactant: CCOC(=O)Nc1nc2cc(I)cnc2n1C(C)c1ccc(OCc2ccc(C(F)(F)F)cc2)c(OC)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COc1cc(C(C)n2c(N)nc3cc(I)cnc32)ccc1OCc1ccc(C(F)(F)F)cc1
Temperature: 160 °C
Reaction time: 1 h
Yield: 88.4 %

Procedure:
To a stirred solution of ethyl(6-iodo-3-(1-(3-methoxy-4-((4-(trifluoromethyl)benzyl)oxy)phenyl)ethyl)-3H-imidazo[4,5-b]pyridin-2-yl)carbamate (1.30 g, 2.03 mmol) in ethanol (8 mL)/water (6 mL) was added potassium phosphate tribasic (1.76 g, 8.12 mmol). The mixture was heated to 160° C. in a microwave reactor. After 1 h, the reaction mixture was diluted with water (100 mL), resulting in a precipitate. The solids were isolated by filtration, washed with water (25 mL), and dried to provide 1.02 g (88%) of 6-iodo-3-(1-(3-methoxy-4-((4-(trifluoromethyl)benzyl)oxy)phenyl)ethyl)-3H-imidazo[4,5-b]pyridin-2-amine as a white solid.
Reaction SMILES: B(Br)(Br)Br.[C:5]([C:7]1[CH:8]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=2)[CH:10]=[CH:11][CH:12]=1)#[N:6]>ClCCl>[C:5]([C:7]1[CH:8]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[CH:10]=[CH:11][CH:12]=1)#[N:6]
Reactant: COc1ccc(-c2cccc(C#N)c2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: N#Cc1cccc(-c2ccc(O)cc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.2 %

Procedure:
A solution of boron tribromide (1.0 M in dichloromethane, 38 ml) was added to a solution of 3'-cyano-4-methoxybiphenyl (4.0 g) in dichloromethane (150 ml) at -78 ° C. After the addition was complete the solution was allowed to warm to room temperature and was stirred for 18 hours. The solution was cooled to 0° C. and then ice (100 g) was added. The organic layer was separated and the aqueous phase extracted with ethyl acetate (3×100 ml). The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the sub-title compound as a cream solid (3.18 g).
Reaction SMILES: [CH3:1][C:2]([N:10]1[CH:14]=[C:13]([NH:15][C:16](=[O:22])[CH:17]([NH2:21])[CH2:18][CH2:19][CH3:20])[N:12]=[CH:11]1)([CH3:9])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.[CH2:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][C:24]1=O>>[CH3:1][C:2]([N:10]1[CH:14]=[C:13]([NH:15][C:16](=[O:22])[CH:17]([NH:21][CH:24]2[CH2:23][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:25]2)[CH2:18][CH2:19][CH3:20])[N:12]=[CH:11]1)([CH3:9])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: O=C1Cc2ccccc2C1
Reactant: CCCC(N)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1
Product: CCCC(NC1Cc2ccccc2C1)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1

Procedure:
2-Amino-pentanoic acid [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide was reacted with 2-indanone to provide the title compound: C13 NMR (100 MHz, CDCl3) 14.2, 19.5, 24.3, 26.6, 26.7, 36.4, 39.9, 40.6, 56.0, 59.0, 61.4, 67.3, 104.8, 124.9, 125.0, 126.7, 126.8, 131.2, 137.4, 141.2, 141.7, 172.2; MS m/z 424.4 (M+1).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([O:20][C@H:21]2[CH2:25][NH:24][C@H:23]([C:26]([NH:28][C@:29]3([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:31][C@H:30]3[CH:32]=[CH2:33])=[O:27])[CH2:22]2)=[N:12][C:13]2[C:18]([N:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.[CH3:39][C:40]1[N:45]=[CH:44][C:43]([C:46]([NH:48][C@@H:49]([CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH:58]=[CH2:59])[C:50](O)=[O:51])=[O:47])=[CH:42][N:41]=1.ON1C(=O)C2C(C3CC2C=C3)C1=O.Cl.CN(C)CCCN=C=NCC.CN(C)CCN>CN(C=O)C>[CH3:39][C:40]1[N:41]=[CH:42][C:43]([C:46]([NH:48][C@@H:49]([CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH:58]=[CH2:59])[C:50]([N:24]2[CH2:25][C@H:21]([O:20][C:11]3[C:10]([C:2]4[S:1][C:5]5[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=5[N:3]=4)=[N:19][C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]=3)[CH2:22][C@H:23]2[C:26]([NH:28][C@:29]2([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:31][C@H:30]2[CH:32]=[CH2:33])=[O:27])=[O:51])=[O:47])=[CH:44][N:45]=1
Reactant: C=CCCCCC[C@H](NC(=O)c1cnc(C)nc1)C(=O)O
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](Oc2nc3ccccc3nc2-c2nc3ccccc3s2)CN1)C(=O)OCC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)CCN
Agent: Cl
Solvent: CN(C)C=O
Product: C=CCCCCC[C@H](NC(=O)c1cnc(C)nc1)C(=O)N1C[C@H](Oc2nc3ccccc3nc2-c2nc3ccccc3s2)C[C@H]1C(=O)N[C@]1(C(=O)OCC)C[C@H]1C=C

Procedure:
(1R,2S)-ethyl 1-((2S,4R)-4-(3-(benzo[d]thiazol-2-yl)quinoxalin-2-yloxy)pyrrolidine-2-carboxamido)-2-vinylcyclopropanecarboxylate, the title compound of Example 42a, N-hydroxy-5-norbornene-2,3-dicarboximide, and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride can be mixed and stirred in DMF for hours, followed by addition of N,N-dimethylethylene diamine. The reaction produces (1R,2S)-ethyl 1-((2S,4R)-1-((S)-2-(2-methylpyrimidine-5-carboxamido)non-8-enoyl)-4-(3-(benzo[d]thiazol-2-yl)quinoxalin-2-yloxy)pyrrolidine-2-carboxamido)-2-vinylcyclopropanecarboxylate, which can be dissolved in isopropyl acetate and extracted with aqueous H3PO4, and then extracted with aqueous K2HPO4. The product can be reacted with di-tert-butyldicarbonate in the presence of dimethylaminopyridine, followed by extraction with a mixture of a citric acid solution and a sodium chloride solution, to produce the title compound of Example 42b.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2([C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH2:27][CH2:28][CH2:29][S:30](Cl)(=[O:32])=[O:31])[CH:24]=4)[CH2:19][CH2:18][N:17]=3)[CH2:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=1>ClCCl>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2([C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH2:27][CH2:28][CH2:29][S:30]([NH:4][CH2:1][CH2:2][CH3:3])(=[O:32])=[O:31])[CH:24]=4)[CH2:19][CH2:18][N:17]=3)[CH2:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=1
Reactant: CCCN
Reactant: O=S(=O)(Cl)CCCOc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)=NCC2
Solvent: ClCCl
Product: CCCNS(=O)(=O)CCCOc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)=NCC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-Propylamine (314 mg, 5.31 mmol) was dissolved in dichloromethane (3 mL) and a solution of 3-({1-[1-(4-chlorophenyl)cyclobutyl]-3,4-dihydroisoquinolin-7-yl}oxy)propane-1-sulfonyl chloride (200 mg, 0.442 mmol) in dichloromethane (2 mL) was added dropwise. After 1 h stirring at room temperature the reaction mixture was diluted with dichloromethane (10 mL) and was washed with aqueous ammonium chloride solution (2×) and water (1×), dried (MgSO4) and concentrated in vacuo. The crude product (265 mg) was used for the next step without purification.
Reaction SMILES: CC1(C)[O:7][C:6](=[O:8])[CH:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:4](=[O:15])O1.[CH3:17][C:18]1([CH3:30])[S:22][C@@H:21]2[C@H:23]([NH2:26])[C:24](=[O:25])[N:20]2[C@H:19]1[C:27]([OH:29])=[O:28]>>[CH3:17][C:18]1([CH3:30])[S:22][C@@H:21]2[C@H:23]([NH:26][C:4]([CH:5]([C:6]([OH:7])=[O:8])[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)=[O:15])[C:24](=[O:25])[N:20]2[C@H:19]1[C:27]([OH:29])=[O:28]
Reactant: CC1(C)OC(=O)C(c2ccccc2)C(=O)O1
Reactant: CC1(C)S[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)O
Product: CC1(C)S[C@@H]2[C@H](NC(=O)C(C(=O)O)c3ccccc3)C(=O)N2[C@H]1C(=O)O

Procedure:
When an equivalent amount of 2.2-tetramethylene-5-phenyl-1.3-dioxane-4.6-dione prepared in the example 3 is substituted for 2.2-dimethyl-5-phenyl-1.3-dioxane-4.6-dione and the reaction with 6-aminopenicillanic acid is carried out as disclosed in the example 1, 6-(α-carboxy-α-phenylacetamido)penicillanic acid (carbenicillin) is obtained.
Reaction SMILES: C(C1N(C2C(F)=CC=CC=2Cl)C(C=O)=C(C)N=1)CCC.[H-].[Na+].C(COC)OC.C(C1N(CC2C(F)=CC=CC=2Cl)C(/C(/C)=C(/C2SC=CC=2)\C(O)=O)=CN=1)CCC.[CH2:58]([C:62]1[N:63]([CH2:79][C:80]2[C:85]([F:86])=[CH:84][CH:83]=[CH:82][C:81]=2[Cl:87])[C:64](/[CH:67]=[C:68](\[CH2:73][C:74]2[S:75][CH:76]=[CH:77][CH:78]=2)/[C:69]([O:71]C)=[O:70])=[CH:65][N:66]=1)[CH2:59][CH2:60][CH3:61]>C(OCC)(=O)C.CCCCCC>[CH2:58]([C:62]1[N:63]([CH2:79][C:80]2[C:85]([F:86])=[CH:84][CH:83]=[CH:82][C:81]=2[Cl:87])[C:64](/[CH:67]=[C:68](\[CH2:73][C:74]2[S:75][CH:76]=[CH:77][CH:78]=2)/[C:69]([OH:71])=[O:70])=[CH:65][N:66]=1)[CH2:59][CH2:60][CH3:61]
Reactant: CCCCc1ncc(/C=C(\Cc2cccs2)C(=O)OC)n1Cc1c(F)cccc1Cl
Agent: CCCCc1nc(C)c(C=O)n1-c1c(F)cccc1Cl
Agent: CCCCc1ncc(/C(C)=C(\C(=O)O)c2cccs2)n1Cc1c(F)cccc1Cl
Agent: [H-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CCCCc1ncc(/C=C(\Cc2cccs2)C(=O)O)n1Cc1c(F)cccc1Cl

Procedure:
The procedure of Example 1, Method A is used. 2-n-Butyl-1-(2-chloro-6-fluorophenyl)-methyl-1H-imidazole-5-carboxaldehyde, trimethyl 3-(2-thienyl)-2-phosphonopropionate, sodium hydride and glyme are held at 60° C. for 1 hour to give, after chromatography over silica gel with 50% of hexane in ethyl acetate, methyl (E)-[2-n-butyl-1-{(2-chloro-6-fluorophenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoate and corresponding cis or (Z)-isomer. The (E)-isomer is hydrolyzed to afford (E)-3-[2-n-butyl-1-{(2-chloro-6-fluorophenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid.
Reaction SMILES: [CH3:1][Mg]I.[F:4][C:5]([F:16])([F:15])[O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=1.[Cl-].[NH4+]>C(OCC)C.O>[F:4][C:5]([F:15])([F:16])[O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]([OH:12])[CH3:1])=[CH:9][CH:8]=1
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Reactant: C[Mg]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCOCC
Product: CC(O)c1ccc(OC(F)(F)F)cc1
Yield: 467.7 %

Procedure:
Methyl magnesium iodide [prepared from magnesium (3.5 g) and methyl iodide (20.5 g)] in diethyl ether (50 ml) was treated with a solution of 4-trifluoromethoxybenzaldehyde [20 g, described by Yagupolskii and Troitskaya, Zhur. Obschii Khim., 30, 3129 (1960)] in diethyl ether (25 ml) at reflux with stirring. After the addition the mixture was heated at reflux for 6 hours. The cooled solution was treated with a solution of ammonium chloride (35 g) in water (100 ml) at 0°-5° C. The organic layer was separated and the aqueous layer was washed with diethyl ether (3×50 ml). The ether solution and washings were combined, washed with water (2×100 ml), dried over sodium sulphate and evaporated to dryness. (+)-1-(4-Trifluoromethoxyphenyl)ethanol (20.3 g) was obtained as a clear colourless oil of sufficient purity for subsequent reaction.
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[C:6]([Cl:11])[C:3]=1[CH:4]=[O:5].C[Mg+].[Br-].[CH2:15](OCCCC)CCC>C1COCC1>[Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[C:6]([Cl:11])[C:3]=1[CH:4]([OH:5])[CH3:15]
Reactant: O=Cc1c(Cl)ccc(Cl)c1Cl
Reactant: CCCCOCCCC
Agent: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(O)c1c(Cl)ccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
General Procedure CC: To a solution of 2,3,6-trichlorobenzaldehyde (1.00 g, 4.77 mmol) in THF (10 mL) was added MeMgBr/butyl ether (1M, 5.72 mL, 5.72 mmol) at 0° C. under nitrogen, the resulting mixture was allowed to warm to rt and stirred overnight. The mixture was quenched with sat. aq. NH4Cl (15 mL) at 0° C., then diluted with Et2O (15 mL), the organic phase was washed with brine (20 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The material was purified by silica gel chromatography using Hexane/EtOAc (80:20) as eluent to give the desired product as a colorless oil. 1H NMR (CDCl3, 400 MHz): δ=1.69 (d, J=6.8 Hz, 3H), 2.97 (br. s., 1H), 5.67 (q, J=6.8 Hz, 1H), 7.30 (d, J=3.0 Hz, 1H), 7.35-7.38 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[N:13]=[CH:14][C:15]3[CH2:21][C:20](=[O:22])[NH:19][C:18]4[CH:23]=[C:24]([C:27](O)=[O:28])[CH:25]=[CH:26][C:17]=4[C:16]=3[N:30]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(OC(=O)NCCNC(C1C=C[C:46]2[C:52]3[N:53]=C(NC4C=CC(OC)=C(OC)C=4)N=CC=3CC(=O)[NH:48][C:47]=2C=1)=O)(C)(C)C>>[NH2:48][CH2:47][CH2:46][CH2:52][NH:53][C:27]([C:24]1[CH:25]=[CH:26][C:17]2[C:16]3[N:30]=[C:12]([NH:11][C:5]4[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:13]=[CH:14][C:15]=3[CH2:21][C:20](=[O:22])[NH:19][C:18]=2[CH:23]=1)=[O:28]
Reactant: COc1ccc(Nc2ncc3c(n2)-c2ccc(C(=O)NCCNC(=O)OC(C)(C)C)cc2NC(=O)C3)cc1OC
Reactant: COc1ccc(Nc2ncc3c(n2)-c2ccc(C(=O)O)cc2NC(=O)C3)cc1OC
Product: COc1ccc(Nc2ncc3c(n2)-c2ccc(C(=O)NCCCN)cc2NC(=O)C3)cc1OC

Procedure:
In a manner similar to that described for Method N, 2-(3,4-dimethoxy-phenylamino)-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepine-9-carboxylic acid (I-53) and tert-butyl 4-aminopropylcarbamate were converted to (2-{[2-(3,4-dimethoxy-phenylamino)-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepine-9-carbonyl]-amino}-ethyl)-carbamic acid tert-butyl ester, which was subsequently deprotected (Method K) to give I-72 (30%): HRMS Calcd. for C24H26N6O4: 463.2093, Found 463.2078.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[C:19]1[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=1)=[O:11].Br[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][N:27]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.CC([O-])(C)C.[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:32][C:29]1[CH:30]=[CH:31][C:26]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[C:19]2[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=2)=[O:11])=[N:27][CH:28]=1
Reactant: Fc1ccc(Br)nc1
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(F)cn2)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone (80 mg, 245 μmol), 2-bromo-5-fluoropyridine (47 mg, 270 μmol), Pd2dba3 (5.0 mg, 4.9 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos; 4.2 mg, 7 μmol), and NaOtBu (35 mg, 368 μmol) in dioxane (2 mL) was purged with argon, and then stirred at 100° C. overnight. The reaction was cooled, filtered through a pad of silica gel and concentrated in vacuo. The crude reaction mixture was purified by reverse-phase preparative HPLC to afford the title compound. MS (ESI) 422 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]([C:10]3[S:11][C:12]4[C:13](=[O:21])[NH:14][C:15]([CH3:20])([CH3:19])[CH2:16][C:17]=4[N:18]=3)[CH2:7][CH2:8][O:9][C:4]=2[CH:3]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.Cl.[CH3:49][N:50]1[CH2:55][CH2:54][CH:53]([C:56](O)=[O:57])[CH2:52][CH2:51]1.CCN(C(C)C)C(C)C>CN(C=O)C.O.CC#N>[CH3:19][C:15]1([CH3:20])[NH:14][C:13](=[O:21])[C:12]2[S:11][C:10]([N:6]3[C:5]4[CH:22]=[CH:23][C:2]([NH:1][C:56]([CH:53]5[CH2:54][CH2:55][N:50]([CH3:49])[CH2:51][CH2:52]5)=[O:57])=[CH:3][C:4]=4[O:9][CH2:8][CH2:7]3)=[N:18][C:17]=2[CH2:16]1
Reactant: CC1(C)Cc2nc(N3CCOc4cc(N)ccc43)sc2C(=O)N1
Reactant: CN1CCC(C(=O)O)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: O
Product: CN1CCC(C(=O)Nc2ccc3c(c2)OCCN3c2nc3c(s2)C(=O)NC(C)(C)C3)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 51.2 %

Procedure:
To a stirred solution of Example 233 (0.049 g, 0.15 mmol), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.111 g, 0.29 mmol) and 1-methylpiperidine-4-carboxylic acid hydrochloride (0.034 g, 0.19 mmol) in DMF (0.5 mL) was added DIPEA (0.06 mL, 0.35 mmol). The reaction mixture was stirred at r.t. for 16 h. MeCN (1 mL) and water (1 mL) were added. The insoluble material was filtered, and the filtrate concentrated in vacuo. Purification by preparative HPLC (Method 6) gave the title compound (0.035 g, 51%) as a yellow solid. δH (CD3OD) 7.91 (1H, d, J 9.0 Hz), 7.37 (1H, d, J 2.3 Hz), 7.11 (1H, dd, J 8.9 and 2.3 Hz), 4.40-4.30 (2H, m), 4.20-4.09 (2H, m), 3.62 (2H, d, J 12.6 Hz), 3.17-3.02 (2H, m), 2.92 (3H, s), 2.89 (2H, s), 2.76-2.60 (1H, m), 2.34-1.91 (4H, m), 1.39 (6H, s). Exchangeable protons were not observed. LCMS (ES+) 456.21 (M+H)+, RT 1.80 minutes (Method 1).
Reaction SMILES: [C:1]([O:4][CH2:5]Cl)(=[O:3])[CH3:2].[I-].[Na+].C(OCI)(=O)C.[N:15]([CH2:18][C:19]1[CH2:20][S:21][C@@H:22]2[CH:29]([NH:30][C:31](=[O:65])[C:32]([C:40]3[N:41]=[C:42]([NH:45][C:46]([C:59]4[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=4)([C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=4)[C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[S:43][CH:44]=3)=[N:33][O:34][C:35]([CH3:39])([O:37][CH3:38])[CH3:36])[C:28](=[O:66])[N:23]2[C:24]=1[C:25]([OH:27])=[O:26])=[N+:16]=[N-:17]>CC(C)=O>[N:15]([CH2:18][C:19]1[CH2:20][S:21][C@@H:22]2[CH:29]([NH:30][C:31](=[O:65])[C:32]([C:40]3[N:41]=[C:42]([NH:45][C:46]([C:53]4[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=4)([C:59]4[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=4)[C:47]4[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=4)[S:43][CH:44]=3)=[N:33][O:34][C:35]([CH3:36])([O:37][CH3:38])[CH3:39])[C:28](=[O:66])[N:23]2[C:24]=1[C:25]([O:27][CH2:5][O:4][C:1](=[O:3])[CH3:2])=[O:26])=[N+:16]=[N-:17]
Reactant: CC(=O)OCCl
Reactant: COC(C)(C)ON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CN=[N+]=[N-])CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: CC(=O)OCI
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(C)(C)ON=C(C(=O)NC1C(=O)N2C(C(=O)OCOC(C)=O)=C(CN=[N+]=[N-])CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1

Procedure:
A mixture of 141 mg of chloromethyl acetate, 225 mg of sodium iodide and 4 ml of acetone was refluxed for 40 minutes and was cooled to obtain a suspension of iodomethyl acetate. Using the procedure of Step B of Example 6, 739 mg of 3-azidomethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-(1-methyl-1-methoxy-ethoxyimino)-acetamido]-ceph-3-eme-4-carboxylic acid and the said suspension were reacted to obtain 698 mg of the syn isomer of acetoxymethyl 3-azidomethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-(1-methyl-1-methoxyethoxyimino)-acetamido]-ceph-3-eme-4-carboxylate.
Reaction SMILES: [CH:1]1([N:4]2[C:9](=[O:10])[C:8]3[C:11](OS(C4C=CC(C)=CC=4)(=O)=O)=[C:12]([CH3:17])[C:13](=[O:16])[N:14]([CH3:15])[C:7]=3[N:6]([C:29]3[CH:34]=[CH:33][C:32]([I:35])=[CH:31][C:30]=3[F:36])[C:5]2=[O:37])[CH2:3][CH2:2]1.[NH2:38][C:39]1[CH:40]=[C:41]([CH:46]=[CH:47][CH:48]=1)[NH:42][C:43](=[O:45])[CH3:44].CN(C)C(=O)C.N1C(C)=CC=CC=1C>CO>[CH:1]1([N:4]2[C:9](=[O:10])[C:8]3[C:11]([NH:38][C:39]4[CH:40]=[C:41]([NH:42][C:43](=[O:45])[CH3:44])[CH:46]=[CH:47][CH:48]=4)=[C:12]([CH3:17])[C:13](=[O:16])[N:14]([CH3:15])[C:7]=3[N:6]([C:29]3[CH:34]=[CH:33][C:32]([I:35])=[CH:31][C:30]=3[F:36])[C:5]2=[O:37])[CH2:2][CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)Oc2c(C)c(=O)n(C)c3c2c(=O)n(C2CC2)c(=O)n3-c2ccc(I)cc2F)cc1
Reactant: CC(=O)Nc1cccc(N)c1
Solvent: CO
Solvent: CC(=O)N(C)C
Solvent: Cc1cccc(C)n1
Product: CC(=O)Nc1cccc(Nc2c(C)c(=O)n(C)c3c2c(=O)n(C2CC2)c(=O)n3-c2ccc(I)cc2F)c1
Temperature: 130 °C
Reaction time: 4 h
Yield: 93.2 %

Procedure:
To p-toluenesulfonic acid 3-cyclopropyl-1-(2-fluoro-4-iodo-phenyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-yl ester 77 (28.0 g) and 3′-aminoacetanilide 57 (13.2 g) were added N,N-dimethylacetamide (84.0 ml) and 2,6-lutidine (15.3 ml), and the mixture was stirred at 130° C. for 4 hrs. After allowing to cool with stirring, methanol (196 ml) was added dropwise, and the mixture was stirred at room temperature. The crystals were collected by filtration and dried to give N-{3-[3-cyclopropyl-1-(2-fluoro-4-iodo-phenyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-ylamino]-phenyl}-acetamide 58 (25.2 g, yield 93%) as colorless crystals.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>>[CH:18]1([N:13]2[C:12]([C:36]3[CH:37]=[CH:38][C:33]([O:32][CH3:31])=[CH:34][CH:35]=3)=[C:11]3[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]3)=[N:14]2)[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(C3CCCC3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2c3c(nn2C2CCCC2)CCNCC3)cc1
Yield: 17 %

Procedure:
The title compound (34.9 mg) was prepared as in Example 177, Steps C and D, using 299.2 mg of 2-cyclopentyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 180, Step A) and 329.2 mg of 4-methoxyphenylboronic acid. MS (ESI): exact mass calculated for C19H25N3O, 311.42; found, m/z 312.3 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.26-7.23 (m, 2H), 7.11-7.08 (m, 2H), 4.51 (m, 1H), 3.87 (s, 3H), 3.43-3.40 (m, 2H), 3.20-3.16 (m, 2H), 2.80-2.76 (m, 2H), 2.02-1.86 (m, 6H), 1.64-1.55 (m, 2H).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH:25][C:26]1[CH:27]=[C:28]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:29]=[CH:30][CH:31]=1.[Cl:38][C:39]1[C:40]([C:49]([F:52])([F:51])[F:50])=[N:41][N:42]([CH2:45][C:46](O)=[O:47])[C:43]=1[CH3:44]>>[Cl:38][C:39]1[C:40]([C:49]([F:51])([F:50])[F:52])=[N:41][N:42]([CH2:45][C:46]([N:35]2[CH2:36][CH2:37][N:32]([C:28]3[CH:29]=[CH:30][CH:31]=[C:26]([OH:25])[CH:27]=3)[CH2:33][CH2:34]2)=[O:47])[C:43]=1[CH3:44]
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Reactant: Oc1cccc(N2CCNCC2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCN(c2cccc(O)c2)CC1

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein 1-(3-Hydroxyphenyl)-piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a solid: 1H NMR (DMSO-d6, 400 MHz) 7.10 (t, 1H), 6.66 (m,2H), 6.45 (d, 1H), 5.39 (s, 2H), 3.74 (m, 4H), 3.33 (br, 2H), 3.24 (br, 2H), 2.19 (s, 3H) ppm; MS (ES) M+H expected=403.1, found 403.0.