Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[C@@H:12]([CH:13]([CH3:15])[CH3:14])[CH2:11][O:10][C:9]2=[O:16])[CH:5]=[CH:4][N:3]=1.[F:17][C:18]1[CH:19]=[C:20]([CH:24]([NH2:26])[CH3:25])[CH:21]=[CH:22][CH:23]=1>CS(C)=O.CCOC(C)=O>[F:17][C:18]1[CH:19]=[C:20]([C@H:24]([NH:26][C:2]2[N:7]=[C:6]([N:8]3[C@@H:12]([CH:13]([CH3:15])[CH3:14])[CH2:11][O:10][C:9]3=[O:16])[CH:5]=[CH:4][N:3]=2)[CH3:25])[CH:21]=[CH:22][CH:23]=1.[F:17][C:18]1[CH:19]=[C:20]([C@@H:24]([NH:26][C:2]2[N:7]=[C:6]([N:8]3[C@@H:12]([CH:13]([CH3:15])[CH3:14])[CH2:11][O:10][C:9]3=[O:16])[CH:5]=[CH:4][N:3]=2)[CH3:25])[CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)[C@H]1COC(=O)N1c1ccnc(Cl)n1
Reactant: CC(N)c1cccc(F)c1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)[C@H]1COC(=O)N1c1ccnc(N[C@@H](C)c2cccc(F)c2)n1
Product: CC(C)[C@H]1COC(=O)N1c1ccnc(N[C@H](C)c2cccc(F)c2)n1

Procedure:
A solution of (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one (106 mg, 0.439 mmol) and 1-(3-fluorophenyl)ethanamine (196 mg, 1.41 mmol, 3.21 equiv) in DMSO (1 mL) was heated at 110° C. for 1½ h. The reaction mixture was diluted with EtOAc (8 mL) and washed with water (30 mL). After separation, the aqueous phase was extracted with EtOAc (3×8 mL). Combined organics were dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane 10 to 50%) provided (S)-3-(2-((R)-1-(3-fluorophenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one and (S)-3-(2-((S)-1-(3-fluorophenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([CH2:9][CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:7][CH:8]=1)([OH:3])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.CCN(CC)CC.Cl.Cl.[NH2:44][CH2:45][CH2:46][CH2:47][NH:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][N:50]=1>C(Cl)Cl>[C:17]1([CH:10]([CH2:9][C:6]2[O:7][CH:8]=[C:4]([C:1]([NH:44][CH2:45][CH2:46][CH2:47][NH:48][C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][N:50]=3)=[O:3])[N:5]=2)[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCCCNc1ccccn1
Reactant: CCOC(=O)CC(Cc1nc(C(=O)O)co1)c1ccccc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CC(Cc1nc(C(=O)NCCCNc2ccccn2)co1)c1ccccc1
Reaction time: 2 h
Yield: 90.9 %

Procedure:
To a solution of ethyl (±)-4-(4-carboxy-1,3-oxazol-2-yl)-3-phenylbutanoate (100 mg, 0.33 mmole) in CH2Cl2 (2 mL) was added 1,1′-carbonyldiimidazole (80 mg, 0.49 mmole). After 2 hr, Et3N (0.14 mL, 0.98 mmole) and 2-[(3-amino-1-propyl)amino]pyridine dihydrochloride (110 mg, 0.49 mmole) were added. After 4 h, the mixture was concentrated under reduced pressure. The residue was chromatographed on silica gel (75% EtOAc/hexanes) to give the title compound (131 mg, 91%) as a yellow oil: MS (ES) m/e 437 (M+H)+.
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=[O:4].[C:8]1(C)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>ClC1C=CC=CC=1>[CH3:11][C:10]1[CH:9]=[CH:8][CH:13]=[CH:12][C:2]=1[C:3]([OH:5])=[O:4]
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1ccccc1
Solvent: Clc1ccccc1
Product: Cc1ccccc1C(=O)O
Reaction time: 0.25 h

Procedure:
Trifluoroacetic acid (5 mL) was added to RhCl3.nH2O (10 mg). To this suspension (the Rh complex was insoluble), K2S2O8 (1.40 g) was added, and the mixture was stirred in air for 15 minutes. After toluene (5 mL) was added, the mixture was stirred under CO for 24 hours, and then analyzed by GC-MS, in a usual manner (see above), with chlorobenzene as an internal standard. No toluic acid formed. When the rhodium chloride-catalyzed reaction was run for 61 hours under similar conditions, about 185 mg of p-toluic acid formed (TON=38).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[NH:16][C:15]([CH3:18])([CH3:17])[CH2:14][S:13]1.[CH3:19][C:20](=[CH2:23])[CH2:21][Br:22]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[NH:16][C:15]([CH3:18])([CH3:17])[CH2:14][S:13]1.[BrH:22].[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[N:16]([CH2:21][C:20]([CH3:23])=[CH2:19])[C:15]([CH3:18])([CH3:17])[CH2:14][S:13]1
Reactant: C=C(C)CBr
Agent: Cc1cc([N+](=O)[O-])ccc1N=C1NC(C)(C)CS1
Solvent: Cc1ccccc1
Product: Br
Product: C=C(C)CN1C(=Nc2ccc([N+](=O)[O-])cc2C)SCC1(C)C
Reaction time: 3 h
Yield: 379.7 %

Procedure:
2-(2-methyl-4-nitrophenylimino)-4,4-dimethyl-1,3-thiazolidine was prepared in a manner analogous to that described in Method C1a. To a suspension of 2-(2-methyl-4-nitrophenylimino)-4,4-dimethyl-1,3-thiazolidine (1.5 mmol) in toluene (10 mL) was added 2-methylprop-2-en-1-yl bromide (4.5 mmol) and the reaction mixture was heated at the reflux temp. for 3 h at which time the reaction was judged complete by TLC. The resulting precipitate was filtered at 50 ° C. The collected solids were washed with toluene (20 mL) and CH2Cl2 (20 mL) to yield 2-(2-methyl-4-nitrophenylimino)-3-(2-methyl-prop-2-enyl)-4,4-dimethyl-1,3-thiazolidine HBr salt (1.14 g, 77%): mp 229° C.
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][C:7]2[O:11][C:10]([NH:12][C:13]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]4[CH2:26][CH2:25][CH:24]([CH2:27][C:28]([O:30]CC)=[O:29])[CH2:23][CH2:22]4)=[CH:17][CH:16]=3)=[O:14])=[N:9][N:8]=2)=[CH:4][CH:3]=1.O.[OH-].[Li+]>O1CCCC1.CO.O>[F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][C:7]2[O:11][C:10]([NH:12][C:13]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]4[CH2:22][CH2:23][CH:24]([CH2:27][C:28]([OH:30])=[O:29])[CH2:25][CH2:26]4)=[CH:17][CH:16]=3)=[O:14])=[N:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC1CCC(c2ccc(C(=O)Nc3nnc(Cc4ccc(F)cc4)o3)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CC1CCC(c2ccc(C(=O)Nc3nnc(Cc4ccc(F)cc4)o3)cc2)CC1
Temperature: 4 °C
Reaction time: 4 h
Yield: 54.4 %

Procedure:
0.1 g of ethyl (4-{4-[5-(4-fluorobenzyl)[1,3,4]oxadiazol-2-ylcarbamoyl]phenyl}cyclohexyl)acetate (0.21 mmol, 1 eq.) and 0.036 g of lithium hydroxide hydrate (0.86 mmol, 4 eq.) are dissolved in 4 mL of a 2/1/1 mixture of tetrahydrofuran/methanol/water cooled to 4° C. using an ice bath. The reaction medium is stirred for 4 hours at room temperature. The solvents are evaporated off and an aqueous solution of SO2 is added. The solid obtained is filtered off, washed with water and dried to give 0.05 g of (4-{4-[5-(4-fluorobenzyl)[1.3.4]oxadiazol-2-ylcarbamoyl]phenyl}cyclohexyl)acetic acid.
Reaction SMILES: C([O:5][NH:6][C:7](=[O:34])[CH:8]([NH:19][S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]#[C:32][CH3:33])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]#[CH:18])=[CH:11][CH:10]=1)(C)(C)C>C(O)(C(F)(F)F)=O>[CH2:30]([O:29][C:26]1[CH:25]=[CH:24][C:23]([S:20]([NH:19][CH:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]#[CH:18])=[CH:11][CH:10]=2)[C:7]([NH:6][OH:5])=[O:34])(=[O:22])=[O:21])=[CH:28][CH:27]=1)[C:31]#[C:32][CH3:33]
Reactant: C#CCOc1ccc(C(NS(=O)(=O)c2ccc(OCC#CC)cc2)C(=O)NOC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: C#CCOc1ccc(C(NS(=O)(=O)c2ccc(OCC#CC)cc2)C(=O)NO)cc1
Yield: 17 %

Procedure:
The 75 mg (0.154 mmol) sample of ′N-(tert-butoxy)-2-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-2-[4-(2-propynyloxy)phenyl]acetamide was stirred in neat TFA at room temperature for 72 h. TFA was removed in vacuo. The residue was chromatographed on prep. TLC eluting with 1% HOAc in 10% MeOH/CH2Cl2 to provide 11.1 mg (17%) of 2-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-2-[4-(2-propynyloxy)phenyl]acetamide as a white solid was obtained. High Resolution Mass Spec 429.11155 (M+H)+; Calc'd for C21H21N2O6S 429.11149.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[OH:10].[C:11](Cl)(=O)[CH2:12][CH3:13].C([N:18](CC)CC)C.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C=CC=C(C)C=1>[NH2:18][C:7]1[C:2]2[N:1]=[C:11]([CH2:12][CH3:13])[O:10][C:3]=2[C:4]([Cl:9])=[CH:5][C:6]=1[F:8]
Reactant: Nc1cc(F)cc(Cl)c1O
Reactant: CCC(=O)Cl
Reactant: CCN(CC)CC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1cccc(C)c1
Product: CCc1nc2c(N)c(F)cc(Cl)c2o1
Temperature: 25 °C
Yield: 71.5 %

Procedure:
2-Amino-6-chloro-4-fluorophenol (3 g) was dissolved in m-xylene (150 ml) containing propionyl chloride (2.05 g), triethylamine (2.24 g) and pyridinium p-toluenesulfonate (2.8 g). The mixture was refluxed under N2 for 4 hours, then cooled to room temperature and passed through a silica gel column eluted with a mixture of hexane and ether (5:1) to yield the title compound as a pale-brown solid (2.85 g). 1H-NMR (CDCl3, 300 MHz): 1.45(3H, t, J=7.6 Hz), 2.98(2H, q, J=7.6 Hz), 7.07(1 H, dd, J=2.3 Hz, 9.2 Hz), 7.27(1 H, dd, J=2.4 Hz, 8.1 Hz) ppm.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([C:19]3[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=3)[CH2:17][CH3:18])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:37][O:38][C:39](=[O:43])[CH2:40][CH2:41][NH2:42].CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:37][O:38][C:39](=[O:43])[CH2:40][CH2:41][NH:42][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][C:19]([CH:16]([O:15][C:12]2[CH:11]=[CH:10][C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:28])[F:29])=[CH:8][CH:7]=3)=[CH:14][CH:13]=2)[CH2:17][CH3:18])=[CH:20][CH:21]=1
Reactant: CCC(Oc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)c1ccc(C(=O)O)cc1
Reactant: COC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(Oc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)c1ccc(C(=O)NCCC(=O)OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.1 %

Procedure:
To a mixture of 4-[1-(4′-Trifluoromethyl-biphenyl-4-yloxy)-propyl]-benzoic acid (270 mg, 0.68 mmol) in methylene chloride (7 mL) are added triethyl amine (0.28 mL, 2.03 mmol), DMAP (5.0 mg), 3-amino-propionic acid methyl ester (141 mg, 1.01. mmol) and EDCI (389 mg, 2.03 mmol) at room temperature. The reaction mixture is stirred at room temperature overnight, loaded on silica gel, eluted with eluted with hexanes with a gradient from 0% of ethyl acetate to 100% of ethyl acetate giving 3-{4-[1-(4′-trifluoromethyl-biphenyl-4-yloxy)-propyl]-benzoylamino}-propionic acid methyl ester (215 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.[CH3:16][N:17]([CH3:32])[CH2:18][CH2:19][CH2:20][NH:21][CH2:22][C:23]([CH3:31])=[CH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.Cl>>[CH3:32][N:17]([CH3:16])[CH2:18][CH2:19][CH2:20][N:21]([CH2:22][C:23]([CH3:31])=[CH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:6](=[O:8])[C:5]1[CH:9]=[C:10]([O:14][CH3:15])[C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cc(C(=O)O)cc(OC)c1OC
Reactant: CC(=Cc1ccccc1)CNCCCN(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Product: COc1cc(C(=O)N(CCCN(C)C)CC(C)=Cc2ccccc2)cc(OC)c1OC
Yield: 13 %

Procedure:
Experimental condition analogous to Example 13 were used with 3,4,5-trimethoxy benzoic acid, 0.65 g (3 mmol), and N,N-Dimethyl-N′-(2-methyl-3-phenyl-ally)-propane-1,3-diamine, 0.6 g (2.5 mmol) and O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate 1.5 g (5 mmol) to give 130 mg of a white solid as a HCl salt. Yield: 13%.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:23])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15](=[O:22])[N:16]([CH3:21])[CH:17]=[C:18]([Br:20])[CH:19]=2)=[CH:10][CH:9]=1)[NH2:6].[Br:24][C:25]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:26]=1[C:27](O)=[O:28].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:2][O:3][C:4](=[O:23])[C@H:5]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:15](=[O:22])[N:16]([CH3:21])[CH:17]=[C:18]([Br:20])[CH:19]=2)=[CH:12][CH:13]=1)[NH:6][C:27]([C:26]1[CH:30]=[C:31]([O:34][CH3:35])[CH:32]=[CH:33][C:25]=1[Br:24])=[O:28]
Reactant: COc1ccc(Br)c(C(=O)O)c1
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2cc(Br)cn(C)c2=O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1ccc(-c2cc(Br)cn(C)c2=O)cc1)NC(=O)c1cc(OC)ccc1Br
Yield: 74.9 %

Procedure:
A solution of 4-(5-bromo-1-methyl-2-oxo-3-pyridinyl)-L-phenylalanine methyl ester hydrochloride (120 mg, 0.30 mmol), 2-bromo-5-methoxybenzoic acid (82 mg, 0.36 mmol), DIEA (260 μL, 1.5 mmol) and HBTU (157 mg, 0.41 mmol) in DMF (4 mL) was stirred at room temperature for 18 hr. The mixture was concentrated, the residue was dissolved in ethyl acetate (15 mL), was washed with 0.5 N HCl (1×5 mL), sat. NaHCO3 (1×5 mL), brine (1×5 mL) and was dried (MgSO4). The residue obtained upon evaporation (180 mg) was chromatographed on 25 g of silica gel, eluting with 3:1 ethyl acetate:hexane to give N-[(2-bromo-5-methoxyphenyl)carbonyl]-4-(5-bromo-1-methyl-2-oxo-3-pyridinyl)-L-phenylalanine methyl ester (130 mg, 76%). HRMS: Obs. Mass 576.9959. Calcd. Mass 576.9973 (M+H)
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:21])[NH:6][C:7](=[O:20])[NH:8][C:9]=1[C:10](=[O:19])[C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].Cl[CH2:23][C:24]1[C:25]2[C:30]([CH:31]=[C:32]3[C:37]=1[CH:36]=[CH:35][CH:34]=[CH:33]3)=[CH:29][CH:28]=[CH:27][CH:26]=2>>[CH:26]1[C:25]2[C:30](=[CH:31][C:32]3[C:37]([C:24]=2[CH2:23][N:8]2[C:9]([C:10](=[O:19])[C:11]4[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=4)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:21])[NH:6][C:7]2=[O:20])=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:29]=[CH:28][CH:27]=1
Reactant: Cc1cc(C)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: ClCc1c2ccccc2cc2ccccc12
Product: Cc1cc(C)cc(C(=O)c2c(C(C)C)c(=O)[nH]c(=O)n2Cc2c3ccccc3cc3ccccc23)c1
Yield: 40.3 %

Procedure:
5-Isopropyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and 9-chloromethyl anthracene were reacted by the same way with the example 1 to obtain the titled compound (192 mg, yield: 40.3%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH+:2]=1.[C:11]1([CH3:22])[CH:16]=[CH:15][C:14]([S:17]([O:20]C)(=[O:19])=[O:18])=[CH:13][CH:12]=1>CO>[C:5]1([CH3:4])[C:10]([S:17]([O-:20])(=[O:19])=[O:18])=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:3][N+:2]1[CH2:1][CH2:10][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:22]=1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: C1=[NH+]CCc2ccccc21
Solvent: CO
Product: C[N+]1=Cc2ccccc2CC1
Product: Cc1ccccc1S(=O)(=O)[O-]
Temperature: 0 °C
Yield: 88 %

Procedure:
The title compound was prepared using the procedure described by Koelsch et al in J. Am. Chem. Soc. (1953) 75, 2095. In a 250-ml one-necked round-bottomed flask equipped with a magnetic stir bar and a reflux condenser were placed 3,4-dihydroisoquinolinium (8.27 grams, 63 mmol) and 40 ml of methanol. The mixture was stirred and cooled to 0° C. A solution of methyl p-toluenesulfonate (11.73 g, 63 mmol) and 70 ml of methanol was added dropwise. The color of the solution remained clear and yellow. The mixture was heated to reflux for 6 hours. The methanol was then removed in vacuo to provide a quantitative yield (20 g) of an off-white solid (mp 115°-119° C.). The solid was pulverized and washed with 40 ml of acetone at room temperature. Suction filtration provided a white solid in 88% yield: mp 124°-127° C. 1H NMR (D2O): δ 2.27 (s,3H), 3.15 (t,2H), 3.73 (S,3H), 3.93 (t,2H), 7.18 (m,8H), 8.77 (s, 1H). Impurities observed at 4.46 (s), 8.0-8.3 (m), 9.4 (s) were due to N-methyl-isoquinoline p-toluenesulfonate.
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:36](=[O:37])[N:14]2[C:15]([C:20]([O:22][CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])=[C:16]([OH:19])[CH2:17][S:18][C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Br:40][C:41]1[CH:46]=[CH:45][C:44]([S:47](Cl)(=[O:49])=[O:48])=[CH:43][CH:42]=1>C(#N)C.[H][H]>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:36](=[O:37])[N:14]2[C:15]([C:20]([O:22][CH:23]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:21])=[C:16]([O:19][S:47]([C:44]3[CH:45]=[CH:46][C:41]([Br:40])=[CH:42][CH:43]=3)(=[O:49])=[O:48])[CH2:17][S:18][C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: [H][H]
Reactant: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(O)CS[C@H]12
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(OS(=O)(=O)c3ccc(Br)cc3)CS[C@H]12
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 54.1 %

Procedure:
The title compound was prepared via a modification of the synthesis described in U.S. Pat. No. 3,985,737. A solution of 0.51 g (0.001 mole) of diphenylmethyl 7-phenoxyacetamido-3-hydroxy-3-cephem- 4-carboxylate in 5 mL of acetonitrile was cooled to 0° C. under a nitrogen atmosphere. Then 0.030 g (0.001 mole) of sodium hydride (80% in mineral oil) was added resulting in hydrogen evolution. The reaction mixture was stirred at 0° C. for 5 minutes, and 0.229 g (0.009 mole) of 4-bromobenzenesulfonyl chloride was added. The cooling bath was removed, and the reaction mix stirred at room temperature for 19 hours. The reaction mixture was filtered and the filtrate carbon treated. The carbon was removed followed by the solvent to leave a foam residue. The residue was crystallized from 1-propanol to yield 0.398 g (54%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N:11]([CH3:21])[S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)(=[O:14])=[O:13])[CH:10]=1)[NH:7][C:6]([C:22]1[S:23][CH:24]([CH2:27][N:28]3[CH2:33][CH2:32][S:31][CH2:30][CH2:29]3)[CH2:25][N:26]=1)=[CH:5]2.C(P(CCCC)CCCC)CCC.[CH3:47][O:48][CH2:49][C@H:50](O)[CH3:51].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.O1CCCC1>[CH3:47][O:48][CH2:49][C@H:50]([CH3:51])[O:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N:11]([CH3:21])[S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)(=[O:14])=[O:13])[CH:10]=1)[NH:7][C:6]([C:22]1[S:23][CH:24]([CH2:27][N:28]3[CH2:33][CH2:32][S:31][CH2:30][CH2:29]3)[CH2:25][N:26]=1)=[CH:5]2
Reactant: COC[C@@H](C)O
Reactant: CN(c1cc(O)cc2cc(C3=NCC(CN4CCSCC4)S3)[nH]c12)S(=O)(=O)c1ccccn1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC[C@H](C)Oc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C3=NCC(CN4CCSCC4)S3)cc2c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 48 %

Procedure:
To a solution of N-{5-hydroxy-2-[5-(thiomorpholinomethyl)-4,5-dihydro-1,3-thiazol-2-yl]-1H-indol-7-yl}-N-methylpyridine-2-sulfonamide (145 mg) in toluene (2 mL) and tetrahydrofuran (1 mL) were added tributylphosphine (0.22 mL), (2R)-1-methoxypropan-2-ol (0.057 mL) and 1,1′-(azodicarbonyl)dipiperidine (220 mg), and the mixture was stirred at 80° C. for 3 hr, and concentrated. The residue was diluted with ethyl acetate, and subjected to basic silica gel column chromatography (eluate: ethyl acetate), and the obtained crude product was purified by silica gel column chromatography (hexane:ethyl acetate=3:1-1:2) to give the title compound (80 mg, yield 48%) as a colorless powder.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CC=CC=1.C[C:27]1([C:51]([NH2:53])=[O:52])[C:32]([CH3:34])([CH3:33])[S:31][CH2:30][CH2:29][N:28]1[S:35]([C:38]1[CH:43]=[CH:42][C:41]([O:44][CH2:45][C:46]#[C:47][CH2:48][CH2:49]O)=[CH:40][CH:39]=1)(=[O:37])=[O:36].C(Br)(Br)(Br)[Br:55]>C1COCC1>[Br:55][CH2:49][CH2:48][C:47]#[C:46][CH2:45][O:44][C:41]1[CH:42]=[CH:43][C:38]([S:35]([N:28]2[CH2:29][CH2:30][S:31][C:32]([CH3:34])([CH3:33])[CH:27]2[C:51]([NH2:53])=[O:52])(=[O:36])=[O:37])=[CH:39][CH:40]=1
Reactant: BrC(Br)(Br)Br
Reactant: CC1(C)SCCN(S(=O)(=O)c2ccc(OCC#CCCO)cc2)C1(C)C(N)=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC1(C)SCCN(S(=O)(=O)c2ccc(OCC#CCCBr)cc2)C1C(N)=O
Reaction time: 3 h

Procedure:
To a solution of 2.123 g (8.093 mmol) of triphenylphosphine and 0.373 mL (4.61 mmol) of pyridine in 40 mL of dry THF under nitrogen was added 1.73 g (4.046 mmol) of methyl 4-({4-[(5-hydroxy-2-pentynyl)oxy]phenyl}sulfonyl)-2,2-dimethyl-3-thiomorpholine carboxamide. The solution was cooled in a water bath and 1.34 g (4.046 mmol) of carbon tetrabromide was added and the resulting mixture was stirred for 3h. The resulting suspension was filtered and the filtrate was concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate:hexanes (1:8) to provide 1.726 g (87%) of methyl 4-({4-[(5-bromo-2-pentynyl)oxy]phenyl}sulfonyl-2,2-dimethyl-3-thiomorpholine carboxamide as a pale yellow oil. Electrospray Mass Spec: 492.0 (M+H)+
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][C@H:22]([CH3:24])[NH:21][C@H:20]([CH3:25])[CH2:19]3)[CH:15]=[CH:14][C:13]=2[O:26][CH3:27])(=[O:10])=[O:9])=[C:4]([F:28])[CH:3]=1.[O:29]1[CH:33]=[CH:32][CH:31]=[C:30]1B(O)O.CC(C)([O-])C.[K+]>COCCOC.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>[CH3:25][C@H:20]1[NH:21][C@@H:22]([CH3:24])[CH2:23][N:18]([C:16]2[CH:15]=[CH:14][C:13]([O:26][CH3:27])=[C:12]([NH:11][S:8]([C:5]3[CH:6]=[CH:7][C:2]([C:30]4[O:29][CH:33]=[CH:32][CH:31]=4)=[CH:3][C:4]=3[F:28])(=[O:10])=[O:9])[CH:17]=2)[CH2:19]1
Reactant: OB(O)c1ccco1
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(Br)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(-c2ccco2)cc1F
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 4-bromo-N-[5-(cis-3,5-dimethyl-1-piperazinyl)-2-(methyloxy)phenyl]-2-fluorobenzenesulfonamide (E103) (100 mg, 0.21 mmol) and 2-furanylboronic acid (50 mg, 0.42 mmol) in DME (3 ml) was added potassium tert-butoxide (220 mg, 1.96 mmol) and tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.01 mmol) in water (1 ml) and the resulting mixture stirred in a microwave (set at high absorbance) at 100° C. for 30 minutes. The resulting mixture was then evaporated in vacuo and purified using an SCX cartridge eluting with methanol followed by ammonia (2M in methanol). The appropriate fractions were combined and evaporated in vacuo and the residue purified further by mass directed autoprep HPLC to afford the title compound (E112). MS (ES+) m/e 460 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[N+:10]([C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O)([O-:12])=[O:11]>C(O)C>[N+:10]([C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=[N:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)([O-:12])=[O:11]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: N#Cc1ccc(N)cc1
Solvent: CCO
Product: N#Cc1ccc(N=Cc2cccc([N+](=O)[O-])c2)cc1
Temperature: 25 °C
Yield: 83.6 %

Procedure:
A mixture of 4-amino-benzonitrile (11.8 g, 100 mmol) and 3-nitro-benzaldehyde (16.6 g, 110 mmol) in ethanol (100 mL) was prepared. The reaction mixture was heated to reflux for 3 h. Then the reaction mixture cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 4-[(3-nitro-benzylidene)-amino]-benzonitrile (21 g, 83%) as a white solid: LC/MS m/e calcd for C14H9N3O2 (M+H)+: 252.25, observed: 252.1.