Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3]/[CH:4]=[CH:5]/[C:6]1[N:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1)[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][CH2:4][CH2:5][C:6]1[N:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1)[CH3:2]
Reactant: CCO/C=C/c1cnc(N)cn1
Agent: [Pd]
Solvent: CCO
Product: CCOCCc1cnc(N)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (E)-5-(2-ethoxyvinyl)pyrazin-2-amine (75 mg, 0.454 mmol) in ethanol (4.54 mL) was added Pd/C (48.3 mg, 0.454 mmol). The reaction mixture was purged by nitrogen for 10 min, and then stirred at room temperature for 2 h under hydrogen balloon. The reaction mixture was then filtered through Celite and washed with methanol and EtOAc, then concentrated. The crude product was used in next step reaction without purification. LCMS (m/z): 168.1 (MH+), 0.33 min.
Reaction SMILES: [C:1]([O:5][C:6](NC(COC(=O)NCCCCCCCCCCCCCCCCCC)CN)=O)(C)(C)C.ClCCCS([NH:42][CH2:43][CH:44](OC)[CH2:45][S:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62])(=O)=O.C1(=O)NC(=O)C2=CC=CC=C12>>[CH2:47]([S:46][CH2:45][CH:44]([CH2:1][O:5][CH3:6])[CH2:43][NH2:42])[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62]
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CN)NC(=O)OC(C)(C)C
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)OC
Agent: O=C1NC(=O)c2ccccc21
Product: CCCCCCCCCCCCCCCCSCC(CN)COC

Procedure:
3-Hexadecylthio-2-methoxymethylpropanol IV k3 is allowed to react and worked up by the same procedure as described in (4). The phthalimide compound m.p. 45° C. The summary of the experimental condition and the physical data of the product are listed in Tables 5 and 6.
Reaction SMILES: [CH:1]1([N:4]2[C:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:7][NH:6][C:5]2=[O:15])[CH2:3][CH2:2]1.Cl[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][N:6]1[CH:7]=[C:8]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:4]([CH:1]2[CH2:3][CH2:2]2)[C:5]1=[O:15])[CH3:22]
Reactant: CCOC(=O)CCl
Reactant: O=c1[nH]cc(-c2ccccc2)n1C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)Cn1cc(-c2ccccc2)n(C2CC2)c1=O

Procedure:
270 mg (1.35 mmol) of 1-cyclopropyl-5-phenyl-1,3-dihydro-2H-imidazol-2-one from Example 119A are dissolved in 5 ml acetonitrile and treated with 165 mg (1.35 mmol) of ethyl chloroacetate and 373 mg (2.70 mmol) of potassium carbonate. The mixture is stirred under reflux for 4 hrs, then a further 165 mg (1.35 mmol) of ethyl chloroacetate are added. After stirring overnight under reflux the reaction mixture is evaporated, the residue is partitioned between dichloromethane and water, the organic phase is separated, and this is dried over sodium sulphate and again concentrated. The crude product is purified by flash chromatography on silica gel (eluent: dichloromethane/methanol firstly 200:1, then 100:1) and thus yields 353 mg (91% of theory) of the target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[NH:7][S:8][C:4]=2[CH:3]=1.[CH2:12]([N:15]=[C:16]=[O:17])[CH2:13][CH3:14]>>[CH2:12]([NH:15][C:16]([N:7]1[C:6](=[O:9])[C:5]2[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][C:4]=2[S:8]1)=[O:17])[CH2:13][CH3:14]
Reactant: O=c1[nH]sc2cc(Cl)ccc12
Reactant: CCCN=C=O
Product: CCCNC(=O)n1sc2cc(Cl)ccc2c1=O

Procedure:
Following the synthetic procedure of 6a as described in Example 1, compound 6u (96% yield) was synthesized from 6-chloro-benzo[d]isothiazol-3-one and n-propyl isocyanate as a white solid. IR(KBr) 3294, 1709, 1635, 1520 cm−1; 1H-NMR (CDCl3) δ1.00 (t, J=7.3 Hz, 3H), 1.61-1.71 (m, 2H), 3.38-3.44 (m, 2H), 7.38 (d, J=8.8 Hz, 1H), 7.58 (s, 1H), 7.93 (d, J=8.8 Hz, 1H), 8.79 (br s, 1H); ESIMS m/e 271 and 273 (M++1, 35Cl and 37Cl).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH2:10][CH:11]([CH3:13])[CH3:12])=[N:5][CH:6]=[CH:7][CH:8]=1.C([O:16][C:17](=[O:29])[CH2:18][CH2:19][C:20]1[CH:25]=[C:24]([F:26])[C:23]([OH:27])=[C:22]([F:28])[CH:21]=1)C>>[F:26][C:24]1[CH:25]=[C:20]([CH2:19][CH2:18][C:17]([OH:29])=[O:16])[CH:21]=[C:22]([F:28])[C:23]=1[O:27][CH2:2][C:3]1[C:4]([S:9][CH2:10][CH:11]([CH3:13])[CH3:12])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)CSc1ncccc1CCl
Reactant: CCOC(=O)CCc1cc(F)c(O)c(F)c1
Product: CC(C)CSc1ncccc1COc1c(F)cc(CCC(=O)O)cc1F
Yield: 60 %

Procedure:
3-Chloromethyl-2-isobutylsulfanyl-pyridine (0.048 g, 0.22 mmol) obtained in Step C of Preparation Example 12 and 3-(3,5-difluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (0.051 g, 0.22 mmol) obtained in Step D of Preparation Example 2 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (60% yield).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:16][C@H:15]([CH3:17])[NH:14][C:13]2=[O:18])[S:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(=O)([O-])[O-].[Cs+].[Cs+].[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1>CC(=O)CC>[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][N:14]2[C@@H:15]([CH3:17])[CH2:16][N:12]([C:4]3[S:5][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:2]([CH3:1])[N:3]=3)[C:13]2=[O:18])=[CH:28][CH:27]=1
Reactant: CCOC(=O)c1sc(N2C[C@H](C)NC2=O)nc1C
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCC(C)=O
Product: CCOC(=O)c1sc(N2C[C@H](C)N(Cc3ccc(F)cc3)C2=O)nc1C
Yield: 87.3 %

Procedure:
To a solution of (S)-ethyl 4-methyl-2-(4-methyl-2-oxoimidazolidin-1-yl)thiazole-5-carboxylate (0.45 g, 1.67 mmol) in 2-butanone (20.0 mL) was added cesium carbonate (1.09 g, 3.34 mmol) and 4-fluorobenzyl bromide (0.40 g, 2.09 mmol). The reaction mixture was refluxed for 16 h, filtered and washed with acetone (150 mL). The filtrate was concentrated in vacuo and the residue was purified by column chromatography eluted with 2-5% methanol in dichloromethane to afford the title compound as a colorless solid (0.55 g, 87%): 1H NMR (300 MHz, CDCl3) δ 7.40-7.35 (m, 2H), 7.21-7.15 (m, 2H), 4.60 (d, J=15.6 Hz, 1H), 4.31 (d, J=15.6 Hz, 1H), 4.26-4.17 (m, 3H), 3.79-3.72 (m, 1H), 3.57 (dd, J=10.3, 6.7 Hz, 1H), 2.52 (s, 3H), 1.27 (t, J=7.1 Hz, 3H), 1.22 (d, J=6.2 Hz, 3H); MS (ES+) m/z 377.9 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[F:8].Br[C:13]1[CH:14]=[CH:15][C:16]([OH:22])=[C:17]([CH:21]=1)[C:18]([OH:20])=[O:19].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:14]=[CH:15][C:16]([OH:22])=[C:17]([C:18]([OH:20])=[O:19])[CH:21]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: OB(O)c1ccc(F)c(Cl)c1
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: [Na+]
Solvent: COCCOC
Product: O=C(O)c1cc(-c2ccc(F)c(Cl)c2)ccc1O
Temperature: 80 °C
Yield: 43.8 %

Procedure:
3-Chloro-4-fluoro-phenylboronic acid (3.2 g, 18.4 mmol), 5-bromo-2-hydroxy-benzoic acid (4.0 g, 18.4 mmol), and Pd (PPh3)4 (1.67 g, 1.84 mmol) were dissolved in 250 mL of DME, a 1 M Na2CO3 solution (46 mL, 46.0 mmol) added and the mixture heated to 80° C. for 20 h. The reaction mixture was filtered, partially evaporated and EtOAc (200 mL) and 1 N HCl (100 mL) added. The organic layer washed with 1N HCl and saturated sodium bicarbonate, dried over sodium sulfate, and evaporated. The crude material was filtered through a silica plug (THF) to give 3′-chloro-4′-fluoro-4-hydroxy-biphenyl-3-carboxylic acid (2.15 g).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[C:8]([CH:12]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:10][CH3:11])=[O:9]>C1C=CC=CC=1>[CH3:11][O:10][C:8]([CH2:12][CH2:6][C:2]1[NH:1][CH:5]=[CH:4][CH:3]=1)=[O:9]
Reactant: O=Cc1ccc[nH]1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: COC(=O)CCc1ccc[nH]1

Procedure:
The 2-(2-methoxycarbonylethyl)pyrrole is prepared as follows: A solution of pyrrole-2-carboxaldehyde (3.9 g, 41 mmol) and (carbomethoxymethylene)-triphenylphosphorane (14 g, 42 mmol) in 160 mL of dry benzene is heated at reflux for 18 hours under a nitrogen atmosphere. After cooling, the reaction mixture is concentrated under vacuum and the resulting oil is purified by silica gel column chromatography, eluting with a mixture of ethyl acetate and hexane (1:9) to give 5.11 g of a mixture of cis- and trans-methyl 2-(2-pyrrolyl)acrylate.
Reaction SMILES: CO[C:3]([C@@H:5]1[CH2:9][C@H:8]([O:10][CH3:11])[C@@H:7]([NH:12][C:13]([C:15]2[S:16][C:17]([Cl:20])=[CH:18][CH:19]=2)=[O:14])[CH2:6]1)=[O:4].[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]2=[O:34])=[CH:24][C:23]=1[F:35]>>[F:35][C:23]1[CH:24]=[C:25]([N:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]2=[O:34])[CH:26]=[CH:27][C:22]=1[NH:21][C:3]([C@H:5]1[CH2:6][C@H:7]([NH:12][C:13]([C:15]2[S:16][C:17]([Cl:20])=[CH:18][CH:19]=2)=[O:14])[C@@H:8]([O:10][CH3:11])[CH2:9]1)=[O:4]
Reactant: COC(=O)[C@H]1C[C@H](NC(=O)c2ccc(Cl)s2)[C@@H](OC)C1
Reactant: Nc1ccc(-n2ccccc2=O)cc1F
Product: CO[C@H]1C[C@@H](C(=O)Nc2ccc(-n3ccccc3=O)cc2F)C[C@@H]1NC(=O)c1ccc(Cl)s1

Procedure:
In analogy to example 1C, (1S,3S,4S)-3-[(5-chloro-thiophene-2-carbonyl)-amino]-4-methoxy-cyclopentanecarboxylic acid methyl ester was reacted with 1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one to give 5-chloro-thiophene-2-carboxylic acid {(1S,2S,4S)-4-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-2-methoxy-cyclopentyl}-amide. Yellow solid. MS: 490.0 ([M+H]+).
Reaction SMILES: [Na].[OH:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7].Br[CH:12]([OH:14])[CH3:13]>C(O)C>[OH:14][CH2:12][CH2:13][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7]
Reactant: O=Cc1cccc(O)c1
Reactant: CC(O)Br
Agent: [Na]
Solvent: CCO
Product: O=Cc1cccc(OCCO)c1

Procedure:
1.42 g of sodium were dissolved in 200 ml of ethanol. 7.5 g of 3-hydroxybenzaldehyde and 10.5 g of bromoethanol were added and the resulting solution was refluxed for 5 hours. The solution was purified by column chromatography (silica, CH2Cl2).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[C:7](O)(=O)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]CC>CN(C=O)C.ClCCl>[C:2]([Cl:4])(=[O:3])[CH2:1][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH3:7]
Reactant: CCCCCCCCCCCCCCCCCCCC(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCCC(=O)Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100.4 %

Procedure:
Oxalyl chloride (2.67 ml, 0.0191 mol) was added drop-wise to a mixture of Arachidic acid (6.0 g, 0.0211 mol) and DMF (4 drops) in dichloromethane (50 ml) at 0° C. After the addition was completed, the reaction mixture was stirred at 0° C. for 30 minutes and then stirred at 25° C. for 1 hour, the reaction mixture was partitioned between dichloromethane and water, and the aqueous layer was extracted with dichloromethane. The combined organic extracts were washed with brine, then dried with sodium sulphate and concentrated in vacuo to provide the desired product (6.35 g, 100% yield) as a solid which was not purified any further.
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:25])=[C:5]([NH:11][C:12](=[O:24])[CH2:13][C:14]23[CH2:23][CH:18]4[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]4)[CH2:15]2)[CH2:21]3)[CH:6]=[C:7]([O:9]C)[CH:8]=1>C(O)(=O)C>[OH:2][C:3]1[C:4]([CH3:25])=[C:5]([NH:11][C:12](=[O:24])[CH2:13][C:14]23[CH2:23][CH:18]4[CH2:17][CH:16]([CH2:22][CH:20]([CH2:19]4)[CH2:21]2)[CH2:15]3)[CH:6]=[C:7]([OH:9])[CH:8]=1
Reactant: COc1cc(NC(=O)CC23CC4CC(CC(C4)C2)C3)c(C)c(OC)c1
Solvent: CC(=O)O
Product: Cc1c(O)cc(O)cc1NC(=O)CC12CC3CC(CC(C3)C1)C2

Procedure:
A solution of dimethoxy ether from Example 43 (2.0 g) in 50% hycdrobromic acid in acetic acid was heated at 100 degrees for 12 hours. The solution was concentrated under vacuum, the residue taken in water and extracted with ethyl acetate. The organic layers were dried over magnesium sulfate, filtered, concentrated under vacuum. The crude material was purified over silica eluting with dichloromethane' ethyl acetateto afford the title compound as a white solid.
Reaction SMILES: C1(N=C=O)C=CC=CC=1.[CH:10]([P:12]([CH3:16])(=[O:15])[O:13][CH3:14])=[CH2:11].C(N(CC)CC)C.[C:24]1([CH2:30][CH2:31][N+:32]([O-])=[O:33])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[CH2:30]([C:31]1[CH2:11][CH:10]([P:12]([CH3:16])(=[O:15])[O:13][CH3:14])[O:33][N:32]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=[N+]([O-])CCc1ccccc1
Reactant: C=CP(C)(=O)OC
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O=C=Nc1ccccc1
Product: COP(C)(=O)C1CC(Cc2ccccc2)=NO1
Yield: 79 %

Procedure:
Preparation is carried out in analogy to Example 23 from 37.1 ml (0.34 mol) of phenyl isocyanate, 22.5 g (0.187 mol) of methyl vinyl(P-methyl)phosphinate, 4 ml of triethylamine and 25.7 g (0.17 mol) of 2-phenylnitroethane in toluene, resulting in 34 g of brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:29])[C:7]=1[NH:8][C:9]([C:11]1[C:19]2[C:18]3[CH:20]=[C:21]([N+:24]([O-])=O)[CH:22]=[CH:23][C:17]=3[O:16][C:15]=2[C:14]([O:27][CH3:28])=[CH:13][CH:12]=1)=[O:10].O.NN>CO.[Ni]>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:29])[C:7]=1[NH:8][C:9]([C:11]1[C:19]2[C:18]3[CH:20]=[C:21]([NH2:24])[CH:22]=[CH:23][C:17]=3[O:16][C:15]=2[C:14]([O:27][CH3:28])=[CH:13][CH:12]=1)=[O:10]
Reactant: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c1oc1ccc([N+](=O)[O-])cc12
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c1oc1ccc(N)cc12
Yield: 79.1 %

Procedure:
To a suspension of N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-nitro dibenzo[b,d]furan-1-carboxamide (example 38) (4.8 gm, 0.011 mol) in methanol (25 ml) was added activated raney nickel (1.44 gm, 30% w/w) and stirred at reflux for 10 min. Hydrazine hydrate (1.117 gm, 0.022 mol) was added dropwise to the above refluxing reaction mixture. The reaction was refluxed for further 30 min. and filtered through celite bed. The filterate was concentrated in vaccuo and the residue was purified using silica gel chromatography using 15% acetone in chlroform as the eluent to afford 3.5 gm of N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-amino-dibenzo[b,d]furan-1-carboxamide as white solid. mp: 249° C. (dec).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].S(Cl)(Cl)=O.[Br:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[NH2:29].C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14](=[O:16])[NH:29][C:23]2[CH:24]=[CH:25][C:26]([F:28])=[CH:27][C:22]=2[Br:21])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: Nc1ccc(F)cc1Br
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccc(F)cc2Br)CC1

Procedure:
Piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (16.5 g, 72.00 mmol) was dissolved in dry methylene chloride (100 mL) and dry pyridine (15 mL). To the reaction mixture was then added thionyl chloride (10.28 g, 86.40 mmol) under nitrogen atmosphere and the reaction mixture was stirred at room temperature for 30 minutes. To the reaction mixture was then added successively, under nitrogen atmosphere, 2-bromo-4-fluoro-phenylamine (15.0 g, 79.00 mmol), dry triethylamine (25.50 g, 252.0 mmol), dry methylene chloride (120 mL), 4-(dimethylamino)pyridine (0.87 g, 7.20 mmol) and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was then partitioned with aqueous 2N HCl and tert-butyl methyl ether. The organic layer was washed with aqueous 2N HCl, aqueous NaHCO3, brine, dried with Na2SO4, filtered and the solvent evaporated in vacuo to yield the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[NH:22][C:21]2[C:16]3[N:17]=[C:18]([CH3:20])[O:19][C:15]=3[C:14]([C:23](O)=[O:24])=[CH:13][C:12]=2[N:11]=1.C(Cl)(=O)C(Cl)=O.[F:32][C:33]([F:43])([F:42])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH2:40][NH2:41].[H-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[NH:22][C:21]2[C:16]3[N:17]=[C:18]([CH3:20])[O:19][C:15]=3[C:14]([C:23]([NH:41][CH2:40][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[C:33]([F:32])([F:42])[F:43])=[O:24])=[CH:13][C:12]=2[N:11]=1
Reactant: NCc1ccccc1C(F)(F)F
Reactant: Cc1nc2c(o1)c(C(=O)O)cc1nc(Nc3c(Cl)cccc3Cl)[nH]c12
Agent: O=C(Cl)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc2c(o1)c(C(=O)NCc1ccccc1C(F)(F)F)cc1nc(Nc3c(Cl)cccc3Cl)[nH]c12
Yield: 38.3 %

Procedure:
The title compound was prepared following the procedure described for Example-177 using 7-[(2,6-dichlorophenyl)amino]-2-methyl-8H-imidazo[4,5-e][1,3]benzoxazole-4-carboxylic acid (Intermediate-55, 0.050 g, 0.132 mmol), oxalyl chloride (0.1 mL), 1-[2-(trifluoromethyl)phenyl]methanamine (0.046 g, 0.262 mmol), THF (5.0 mL) and 60% NaH (0.021 g, 0.525 mmol). The obtained crude product was purified by column chromatography on neutral alumina eluting with 1.5-2.0% MeOH:DCM to afford 0.027 g of the desired product. 1HNMR (DMSO-d6): δ 2.64 (s, 3H), 4.76 (s, 2H), 7.37-7.47 (m, 2H), 7.61-7.63 (m, 5H), 7.75 (d, J=6.9 Hz, 1H), 8.65 (s, 1H), 9.43 (s, 1H), 11.53 (s, 1H); MS [M+H]+: 534.43.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:22])[C:10]2[CH:15]=[CH:14][C:13]([CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])=[C:12]([OH:21])[CH:11]=2)=[CH:4][C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1.I[CH3:30]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:22])[C:10]2[CH:15]=[CH:14][C:13]([CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])=[C:12]([O:21][CH3:30])[CH:11]=2)=[CH:4][C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: CS(=O)(=O)Cc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1O
Reactant: CI
Product: COc1cc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)ccc1CS(C)(=O)=O
Yield: 23.2 %

Procedure:
N-(4-Chloro-3-(pyridin-2-yl)phenyl)-3-hydroxy-4-(methylsulfonylmethyl)benzamide (50 mg, 0.12 mmol) was treated with iodomethane (7.5 μl, 0.12 mmol) via procedure U to yield 12 mg of N-(4-chloro-3-(pyridin-2-yl)phenyl)-3-methoxy-4-(methylsulfonylmethyl)benzamide. MS (Q1) 431 (M)+.
Reaction SMILES: [C:1]([NH:9][C:10]1[S:11][C:12]([C:15]2[CH2:22][S:21][CH:20]3[N:17]([C:18](=[O:32])[CH:19]3[NH:23][C:24](=[O:31])[CH2:25][C:26]3[S:27][CH:28]=[CH:29][CH:30]=3)[C:16]=2[C:33]([O:35]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:34])=[CH:13][N:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)=O>[C:1]([NH:9][C:10]1[S:11][C:12]([C:15]2[CH2:22][S:21][CH:20]3[N:17]([C:18](=[O:32])[CH:19]3[NH:23][C:24](=[O:31])[CH2:25][C:26]3[S:27][CH:28]=[CH:29][CH:30]=3)[C:16]=2[C:33]([OH:35])=[O:34])=[CH:13][N:14]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cnc(NC(=O)c4ccccc4)s3)CSC12
Solvent: O=CO
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)O)=C(c3cnc(NC(=O)c4ccccc4)s3)CSC12
Temperature: 60 °C
Yield: 87.7 %

Procedure:
A solution of 3-(2-benzamido-thiazol-5-yl)-2-benzhydryloxycarbonyl-8-oxo-7-(thien-2-yl-acetamido)-5-thia-1-azabicyclo[4.2.0]oct-2-ene (1.5 g) in a mixture of formic acid (43 cc) and distilled water (8 cc) is heated for 30 minutes at 60° C. and then diluted with distilled water (35 cc). The precipitate is filtered off, washed with 50% strength (by volume) formic acid (2×10 cc) and then with isopropyl ether (3×75 cc) and dried; 3-(2-benzamidothiazol-5-yl)-2-carboxy-8-oxo-7-(thien-2-yl-acetamido)-5-thia-1-azabicyclo[4.2.0]oct-2-ene (1 g) is obtained in the form of a white solid.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O-:23])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Na+].[CH:27]([O:30][C:31]([O:33][CH:34](I)[CH3:35])=[O:32])([CH3:29])[CH3:28]>>[OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O:23][CH:34]([O:33][C:31]([O:30][CH:27]([CH3:29])[CH3:28])=[O:32])[CH3:35])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Reactant: CC(C)OC(=O)OC(C)I
Agent: [Na+]
Product: CC(C)OC(=O)OC(C)OC(=O)C1=C(S/C=C\c2scnc2CO)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Yield: 81.3 %

Procedure:
In the same manner as in Example 81, 137 mg of the title compound was prepared from 133 mg of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate prepared in Example 41 and 110 mg of 1-(isopropyloxycarbonyloxy)ethyl iodide.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C(=O)(O)[O-].[Cs+].[CH2:20](Br)[CH2:21][CH2:22][CH3:23]>C1COCC1.CCOC(C)=O>[CH2:20]([N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=2)[CH2:4][CH2:3][CH2:2]1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCCBr
Reactant: COC(=O)c1ccc2c(c1)NCCC2
Agent: O=C([O-])O
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCN1CCCc2ccc(C(=O)OC)cc21
Temperature: 25 °C
Yield: 67.1 %

Procedure:
To a stirred solution of methyl 1,2,3,4-tetrahydroquinoline-7-carboxylate (180 mg, 0.94 mmol) and cesium bicarbonate (1.5 g, 4.7 mmol) in THF (2 mL) was added n-butyl bromide (1.0 mL, 9.4 mmol), and the reaction mixture was heated at reflux for 48 h. The reaction mixture was cooled to room temperature, and diluted with EtOAc. The organic layer was washed with water, and brine, dried (magnesium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 1:3 ethyl acetate/hexanes) afforded methyl 1-butyl-1,2,3,4-tetrahydroquinoline-7-carboxylate (156 mg): ESI MS m/z 248 [M+H]+.
Reaction SMILES: C(O[C:9]([NH:11][C@H:12]1[CH2:15][N:14]([O:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:13]1=[O:25])=[O:10])C1C=CC=CC=1.[NH2:26][C:27]1[S:28][CH:29]=[C:30](/[C:32](=[N:36]/[O:37][CH3:38])/C(O)=O)[N:31]=1.O.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O.[Pd]>[NH2:26][C:27]1[S:28][CH:29]=[C:30]([C:32](=[N:36][O:37][CH3:38])[C:9]([NH:11][CH:12]2[CH2:15][N:14]([O:16][CH2:17][C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[C:13]2=[O:25])=[O:10])[N:31]=1
Reactant: CC(C)(C)OC(=O)CON1C[C@H](NC(=O)OCc2ccccc2)C1=O
Reactant: CO/N=C(\C(=O)O)c1csc(N)n1
Agent: [Pd]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CON=C(C(=O)NC1CN(OCC(=O)OC(C)(C)C)C1=O)c1csc(N)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(S)-[[3-[(Benzyloxycarbonyl)amino]-2-oxo1-azetidinyl]oxy]acetic acid. 1,1-dimethylethyl ester (1.4 g, 4.0 mmol) was dissolved in 25 ml of dry dimethylformamide and hydrogenated with 1 g of 10% palladium on charcoal as catalyst. After 20 minutes the catalyst was filtered and a mixture of (Z)-2-amino-α-(methoxyimino)-4-thiazoleacetic acid (4.4 mmol). 1-hydroxybenzotriazole hydrate (0.15 g, 1.0 mmol). dicyclohexylcarbodiimide (0.81g. 4.4 mmol) and 30 ml of dry dimethylformamide was added. The mixture was stirred overnight at room temperature. The precipitated dicyclohexyl urea was filtered off and the solvent removed in vacuo. The residue was dissolved in ethyl acetate, washed with 5% NaHCO3 and dried over MgSO4. Filtration and evaporation in vacuo gave the title compound which solidified by stirring with ether/petroleum ether; melting point 120° C. dec.