Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1.[C:23]([O-:28])(=[O:27])[C:24]([CH3:26])=[O:25].[Na+].C(=O)([O-])[O-].[Na+].[Na+].O>CO>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:22]=[CH:21][C:18](/[CH:19]=[CH:26]/[C:24](=[O:25])[C:23]([OH:28])=[O:27])=[CH:17][CH:16]=1
Reactant: CC(=O)C(=O)[O-]
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(C=O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(/C=C/C(=O)C(=O)O)cc1
Reaction time: 6 h
Yield: 44.5 %

Procedure:
A mixture of 4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzaldehyde (2.9 g), sodium pyruvate (3.3 g), sodium carbonate (3.2 g), water (80 ml) and methanol (80 ml) was stirred for 6 hours under reflux. The reaction mixture was concentrated under reflux to about 1/3 of the initial volume. The concentrate was subjected to extraction with ethyl acetate. The aqueous layer was acidified with conc. HCl. Resulting crystalline precipitate was collected by filtration to obtain (E)-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzylidenepyruvic acid (1.6 g, 44%). Recrystallization from chloroform-methanol gave colorless needles, m.p.197-198° C.
Reaction SMILES: CCN(CC)CC.[CH:8]1([C:11](Cl)=[O:12])[CH2:10][CH2:9]1.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([B:21]2[O:29][C:26]([CH3:28])([CH3:27])[C:23]([CH3:25])([CH3:24])[O:22]2)=[CH:17][CH:16]=1>C(Cl)Cl>[CH3:27][C:26]1([CH3:28])[C:23]([CH3:24])([CH3:25])[O:22][B:21]([C:18]2[CH:19]=[CH:20][C:15]([NH:14][C:11]([CH:8]3[CH2:10][CH2:9]3)=[O:12])=[CH:16][CH:17]=2)[O:29]1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: O=C(Cl)C1CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)OB(c2ccc(NC(=O)C3CC3)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.9 %

Procedure:
Et3N (239 μL, 1.71 mmol) and cyclopropanecarbonyl chloride (114 μL, 1.26 mmol) were added to a solution of 4-aminophenylboronic acid pinacol ester (250 mg, 1.14 mmol) in DCM (5 mL) at 0° C. After stirring the mixture for 4 hours at room temperature, the mixture was concentrated. The residue was diluted with EtOAc and washed with 10% aqueous citric acid, sat. NaHCO3 and brine. The organic layer was dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (EtOAc/hexane=9:1→4:1) to afford desired product (291 mg, 88.9%) as white solid. 1HNMR (CDCl3) 400 MHz δ: 7.82-7.70 (m, 2H), 7.59-7.47 (m, 2H), 7.43 (br s, 1H), 1.54-1.44 (m, 1H), 1.33 (s, 12H), 1.09 (dt, J=7.4, 4.2 Hz, 2H), 0.85 (td, J=7.4, 4.2 Hz, 2H).
Reaction SMILES: [NH2:1][C@H:2]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)[C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:17]([CH2:22][CH:23]2[CH2:25][CH2:24]2)[S:18]([CH3:21])(=[O:20])=[O:19])[CH2:7][CH2:6]1)=[O:4].[N:34]1([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:43][C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:36][C@H:35]1[C:44](O)=[O:45].CCN=C=NCCCN(C)C.CI.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([CH2:26][C@@H:2]([NH:1][C:44]([C@@H:35]2[CH2:36][C:37]3[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH2:43][N:34]2[C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])=[O:45])[C:3]([N:5]2[CH2:6][CH2:7][N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:17]([CH2:22][CH:23]3[CH2:24][CH2:25]3)[S:18]([CH3:21])(=[O:19])=[O:20])[CH2:9][CH2:10]2)=[O:4])=[CH:32][CH:31]=1
Reactant: CS(=O)(=O)N(CC1CC1)c1ccccc1N1CCN(C(=O)[C@H](N)Cc2ccc(Cl)cc2)CC1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CI
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ccccc2N(CC2CC2)S(C)(=O)=O)CC1

Procedure:
tert-Butyl 3-{N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(cyclopropylmethyl)(methylsulfonyl)amino]phenyl}piperazinyl)-2-oxoethyl]carbamoyl}(3S)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate was prepared from (2R)-2-amino-3-(4-chlorophenyl)-1-(4-{2-[(cyclopropylmethyl)(methylsulfonyl)amino]phenyl}-piperazinyl) propan-1-one (Example 58, Step 3) (224 mg, 0.457 mmol), according to the procedure for Preparation XIX using Boc-L-Tic-OH (135 mg, 0.487 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide methiodide (285 mg, 0.959 mmol), HOAT (68 mg, 0.50 mmol), and DMF (7 mL). The compound was isolated (339 mg). MS (ESI, pos. ion) m/z: 750 (M+H), (ESI, neg. ion) m/z: 748 (M−H). Calc'd for C39H48ClN5O6S: 750.35.
Reaction SMILES: [O:1]=[C:2](C)[CH2:3]CC(OCC)=O.BrBr.[C:13]([O:19]CC)(=[O:18])[CH2:14][C:15]([CH3:17])=O.C(OC)(=O)C=C>C(O)(=O)C>[O:1]=[C:2]([CH3:3])[CH2:17][CH2:15][CH2:14][C:13]([OH:19])=[O:18]
Reactant: CCOC(=O)CCC(C)=O
Reactant: CCOC(=O)CC(C)=O
Agent: BrBr
Solvent: C=CC(=O)OC
Solvent: CC(=O)O
Product: CC(=O)CCCC(=O)O

Procedure:
Appropriate α-bromoketone 21b was prepared by bromination of ethyl 4-oxopentanoate by bromine in acetic acid. α-bromoketone 21c was prepared according to literature (Lugtenburg J. et. al., Eur. J. Org. Chem. 2002, 189-2202) from ethyl acetoacetate and methyl acrylate in 1,4-addition reaction and subsequent decarboxylation under acidic conditions to give 5-oxohexanoic acid. Esterification and bromination gave α-bromoketone 21c (methyl 6-bromo-5-oxohexanoic acid) in 4 step procedure. α-Chloroketone 21a
Reaction SMILES: [N+:1]([C:4]1[NH:8][N:7]=[C:6]([C:9]([O:11][CH3:12])=[O:10])[CH:5]=1)([O-:3])=[O:2].[CH3:13]N(C)C=O.CI.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:13][N:7]1[C:6]([C:9]([O:11][CH3:12])=[O:10])=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[N:8]1
Reactant: CN(C)C=O
Reactant: COC(=O)c1cc([N+](=O)[O-])[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Product: COC(=O)c1cc([N+](=O)[O-])nn1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 66 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with methyl 5-nitro-1H-pyrazole-3-carboxylate (156a) (0.94 g, 5.5 mmol), anhydrous N,N-dimethylformamide (11 mL), methyl iodide (0.85 g, 6 mmol) and potassium carbonate (0.83 g, 6.1 mmol). The reaction was stirred at room temperature for 16 h. After this time the reaction was diluted with water (40 mL) and extracted with methylene chloride (3×25 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was subjected to flash chromatography (silica, ethyl acetate/hexanes) to afford methyl 1-methyl-3-nitro-1H-pyrazole-5-carboxylate 156b in 66% yield (0.67 g) as a white solid: MS (ESI+) m/z 186.0 (M+H). Also isolated was the regioisomer methyl 1-methyl-5-nitro-1H-pyrazole-3-carboxylate in 15% yield (0.15 g) as a white solid: MS (ESI−) m/z 186.0 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:13]I.O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][CH3:13])=[CH:4][CH:3]=1
Reactant: CI
Reactant: OCCc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.1 %

Procedure:
2-(4-Bromophenyl)ethanol (2.0 g) was dissolved in N,N-dimethylformamide (50 mL), and sodium hydride (60% in oil) (0.44 g) was added under ice-cooling. After gradually warming to room temperature, the mixture was stirred for 2 hr, and methyl iodide (2.1 g) was added again under ice-cooling. After gradually warming to room temperature, the mixture was stirred overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=20:1 to 10:1) to give the title compound (1.2 g) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]#[N:9])=[C:6](Cl)[N:5]=[C:4]([CH3:11])[CH:3]=1.O.O.O.[O-:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Na+]>C1COCC1>[CH3:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:5]=[C:4]([CH3:11])[CH:3]=1
Reactant: [O-]c1ccccc1
Reactant: Cc1cc(C)c(C#N)c(Cl)n1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C)c(C#N)c(Oc2ccccc2)n1
Temperature: 80 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
4,6-dimethyl-2-chloro-nicotinonitrile (600 mg, 3.60 mmol) was dissolved in 30 mL of anhydrous THF and then added with sodium phenoxide trihydrate (3.06 g, 18.00 mmol) and stirred at 80° C. overnight. The mixture was extracted with methylene chloride, dried with anhydrous sodium sulfate, filtered and then concentrated under reduced pressure. A silica gel column chromatography (10% EtOAc/Hexane) was performed on the resulting residue and 730 mg (90%) of 4,6-dimethyl-2-phenoxy-nicotinonitrile was obtained in white solid.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH3:7][C:8]1([CH:13]2[CH2:18][CH2:17][CH:16]([NH2:19])[CH2:15][CH2:14]2)[O:12][CH2:11][CH2:10][O:9]1.[C:20](Cl)([O:22][CH2:23][CH:24]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:21]>O.O1CCOCC1>[CH:35]1[C:36]2[CH:24]([CH2:23][O:22][C:20](=[O:21])[NH:19][CH:16]3[CH2:17][CH2:18][CH:13]([C:8]4([CH3:7])[O:9][CH2:10][CH2:11][O:12]4)[CH2:14][CH2:15]3)[C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:31]=2[CH:32]=[CH:33][CH:34]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: CC1(C2CCC(N)CC2)OCCO1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC1(C2CCC(NC(=O)OCC3c4ccccc4-c4ccccc43)CC2)OCCO1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A solution of 12.72 g (120 mmol) of sodium carbonate is placed in 120 mL of water and combined with a solution of 7.00 g (38 mmol) of 4-(2-methyl-[1,3]dioxolan-2-yl)cyclohexylamine (cis/trans mixture) in 50 g of dioxane. After cooling to 0° C., a solution of 10.09 g (39 mmol) of Fmoc-chloride in 100 g of dioxane is added dropwise within 0.2 hours. The reaction mixture is stirred for 16 hours with the cooling removed. Then the mixture is poured onto water and extracted with ethyl acetate. The organic phase is washed with water, dried, and evaporated to dryness. The residue is purified by chromatography. Yield: 13.10 g (85%) cis/trans ratio 4:1; NMR: LH201618.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:22]([F:25])([F:24])[F:23])[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([F:21])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.ClC1C=C(C(C(F)(F)F)=C)C=C(Cl)C=1.[Br:40]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>ClCCCl.O>[Br:40][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[CH2:10][C:9]([C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)([C:22]([F:24])([F:23])[F:25])[O:13][N:12]=2)=[CH:15][C:16]=1[F:21]
Reactant: Cc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1F
Reactant: O=C1CCC(=O)N1Br
Agent: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: O
Solvent: ClCCCl
Product: Fc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1CBr
Temperature: 25 °C

Procedure:
In a solution of 1.50 g of 5-(3,5-dichlorophenyl)-3-(3-fluoro-4-methylphenyl)-5-trifluoromethyl-4,5-dihydroisoxazole synthesized from 3-fluoro-4-methylphenylaldoxime and 3,5-dichloro-1-(1-trifluoromethylethenyl)benzene similarly to Step 2 of Synthetic Example 3 in 50 ml of 1,2-dichloroethane, 0.68 g of N-bromosuccinic acid imide and a catalytic amount of azobisisobutyronitrile were added, and stirred under nitrogen atmosphere and under reflux with heat for 1 hour. After the completion of the reaction, the reaction mixture was left and cooled to room temperature, poured in 50 ml of water, extracted with chloroform (50 ml×1). The organic phase was dehydrated with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain crude aimed product as pale yellow oily substance. The resulting product was used as such without purification for the next step.
Reaction SMILES: C([O:4][C@H:5]1[C@@H:31]2[O:32][C@@H:30]2[C@@:29]2([CH3:33])[C:7](=[CH:8][C@@H:9]([O:35][C:36]([O:38][CH3:39])=[O:37])[C@@H:10]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:34])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[CH:15]([CH:17]2[O:22][CH2:21][C:20]([CH3:24])([CH3:23])[CH2:19][O:18]2)[CH3:16])[CH2:6]1)(=O)C.C(O[C@H]1[C@@H]2O[C@@H]2[C@@]2(C)C(=CC=C3[C@@H]2CC[C@@]2(C)[C@H]3CC[C@@H]2C(C2OCC(C)(C)CO2)C)C1)(=O)C>>[CH3:24][C:20]1([CH3:23])[CH2:19][O:18][CH:17]([CH:15]([C@@H:14]2[C@:25]3([CH3:34])[C@H:11]([C@H:10]4[C@H:28]([CH2:27][CH2:26]3)[C@:29]3([CH3:33])[C:7]([CH2:6][C@@H:5]([OH:4])[C@@H:31]5[O:32][C@@H:30]53)=[CH:8][C@H:9]4[O:35][C:36]([O:38][CH3:39])=[O:37])[CH2:12][CH2:13]2)[CH3:16])[O:22][CH2:21]1
Reactant: COC(=O)O[C@@H]1C=C2C[C@@H](OC(C)=O)[C@@H]3O[C@@H]3[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](C(C)C4OCC(C)(C)CO4)CC[C@H]3[C@H]12
Agent: CC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C5OCC(C)(C)CO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@H]2O[C@@H]12
Product: COC(=O)O[C@@H]1C=C2C[C@@H](O)[C@@H]3O[C@@H]3[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](C(C)C4OCC(C)(C)CO4)CC[C@H]3[C@H]12
Yield: 57.5 %

Procedure:
The procedure of Example 23 was repeated except that 5.5 mg (0.01 mmole) of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α--epoxy-7α-methoxycarbonyloxypregn-5-en-3β-yl acetate was used in lieu of 5 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxypregna-5,7-dien-3β-yl acetate to give 2.9 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α--epoxy-7α-methoxycarbonyloxypregn-5-en-3β-ol (yield: 58%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[C:6]([F:15])[CH:5]=1.[C:16]([C:20]1[CH:25]=[CH:24][C:23]([C:26]([CH3:31])=[CH:27][C:28](O)=[O:29])=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17].C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-].O1CCCC1>C(N(CC)CC)C>[F:15][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[NH:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH2:3][NH:2][C:28](=[O:29])[CH:27]=[C:26]([C:23]1[CH:22]=[CH:21][C:20]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:25][CH:24]=1)[CH3:31]
Reactant: CC(=CC(=O)O)c1ccc(C(C)(C)C)cc1
Reactant: CS(=O)(=O)Nc1ccc(CN)cc1F
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=CC(=O)NCc1ccc(NS(C)(=O)=O)c(F)c1)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 18 %

Procedure:
To the 50 ml of round bottom flask were put N-(4-aminomethyl-2-fluoro-phenyl)-methanesulfonamide hydrochloride (0.14 g, 0.55 mmol), 3-(4-t-butylphenyl)-but-2-enoic acid (1.0 eq, 0.12 g) and DMTMM (1.2 eq, 0.183 g). To this mixture was poured 25 ml tetrahydrofuran, added triethylamine (excess, 0.5 ml) and stirred 12 hours at room temperature. After confirming the completion of the reaction with TLC, the reaction mixture was extracted with ethylacetate, washed 1N HCl solution. The combined organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The obtained liquid was purified with column chromatography (n-hexane/ethyl acetate=1/1) to yield the title compound (41.5 mg)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1C=CC=CC=1>CC(C)=O>[C:14]1([S:20]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:6][CH:7]=2)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nc1ccc(CCCC(=O)O)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: O=C(O)CCCc1ccc(NS(=O)(=O)c2ccccc2)cc1

Procedure:
To a solution of 4-(4-aminophenyl)butyric acid (1 g, 5.6 mmol) in dry acetone (30 ml) was added dropwise a solution of benzenesulphonyl chloride (0.99 g) and pyridine (1.1 g) in dry acetone (10 ml). The mixture was heated at reflux for 3 hours, then concentrated in vacuo. The resulting oil was dissolved in dichloromethane (100 ml) and the solution was washed with 2N aqueous HCl (2×100 ml), followed by water (2×100 ml). The dichloromethane solution was extracted with 10% aqueous NaOH (2×50 ml), followed by water (2×50 ml), and these extracts were combined and stirred with dichloromethane (100 ml) while conc. HCl was added to adjust the pH of the mixture to 5. The layers were separated and the organic solution was dried (MgSO04) and concentrated in vacuo. The resulting solid was recrystallised from isopropanol to give 4-[4-(phenyl-sulphonamido)phenyl]butyric acid. (1.03 g, 58%) mp. 128°-130 ° C.
Reaction SMILES: [CH:1]1([CH:4]([N:8]2[CH:12]=[C:11]([C:13]3[N:18]4[CH:19]=[CH:20][N:21]=[C:17]4[CH:16]=[C:15]([C:22]4[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=4)[N:14]=3)[CH:10]=[N:9]2)[CH2:5][C:6]#[N:7])[CH2:3][CH2:2]1.[I:28]N1C(=O)CCC1=O.C(Cl)Cl>CCOC(C)=O>[CH:1]1([CH:4]([N:8]2[CH:12]=[C:11]([C:13]3[N:18]4[C:19]([I:28])=[CH:20][N:21]=[C:17]4[CH:16]=[C:15]([C:22]4[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=4)[N:14]=3)[CH:10]=[N:9]2)[CH2:5][C:6]#[N:7])[CH2:3][CH2:2]1
Reactant: O=C1CCC(=O)N1I
Reactant: Cn1cc(-c2cc3nccn3c(-c3cnn(C(CC#N)C4CC4)c3)n2)cn1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cn1cc(-c2cc3ncc(I)n3c(-c3cnn(C(CC#N)C4CC4)c3)n2)cn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 75.7 %

Procedure:
3-cyclopropyl-3-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)propanenitrile (Example 2; 84.6 mg, 0.236 mmol) and 1-iodopyrrolidine-2,5-dione (79.7 mg, 0.354 mmol) were suspended in DCM (2.36 mL, 0.236 mmol) and stirred at ambient temperature for 15 hours. The reaction mixture was diluted in EtOAc and washed with saturated sodium bicarbonate and brine. The organic layer was dried with MgSO4, filtered and concentrated in vacuo. Purification of the resulting crude material by silica chromatography using 0-5% MeOH/EtOAc gradient afforded 3-cyclopropyl-3-(4-(3-iodo-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)propanenitrile (86.5 mg, 75.7% yield). MS (apci) m/z=485.2 (M+H).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[C@H:13]([C:14]([OH:16])=O)[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].C[N:18](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[Cl-].[NH4+].CCN(C(C)C)C(C)C>CN(C=O)C>[C:2]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]1[C:14](=[O:16])[NH2:18])=[O:7])([CH3:4])([CH3:3])[CH3:1]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)O
Agent: F[B-](F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1C(N)=O

Procedure:
To a solution of N-Boc-L-pipecolinic acid (200 mg, 0.87 mmol) in DMF (3.5 mL) was added TBTU (336 mg, 1.05 mmol), ammonium chloride (93 mg, 1.74 mmol) then DIPEA (182 μL, 1.05 mmol) and the reaction stirred for 16 h. The mixture was partitioned between ethyl acetate (2×30 mL) and water (30 mL), and the organics combined before being washed with 1M sodium hydroxide (3×30 mL) and brine (3×30 mL). The organic solution was dried (MgSO4) and solvent removed in vacuo to give the title compound as a white solid. δH (d6 DMSO): 7.23 (1H, s), 6.97 (1H, s), 4.56–4.39 (1H, br m), 3.43–3.74 (1H, d), 3.14–2.90 (1H, br m), 2.09–2.00 (1H, d), 1.63–1.47 (3H, m), 1.30–1.17 (2H, m).
Reaction SMILES: Br[CH2:2][C:3]1[O:4][C:5]2[C:11]([Cl:12])=[CH:10][C:9]([F:13])=[C:8]([C:14]3[C:15](=[O:25])[N:16]([CH3:24])[C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=3)[C:6]=2[CH:7]=1.[CH3:26][SH:27].C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[Cl:12][C:11]1[C:5]2[O:4][C:3]([CH2:2][S:27][CH3:26])=[CH:7][C:6]=2[C:8]([C:14]2[C:15](=[O:25])[N:16]([CH3:24])[C:17]([C:20]([F:21])([F:23])[F:22])=[CH:18][CH:19]=2)=[C:9]([F:13])[CH:10]=1
Reactant: Cn1c(C(F)(F)F)ccc(-c2c(F)cc(Cl)c3oc(CBr)cc23)c1=O
Reactant: CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CSCc1cc2c(-c3ccc(C(F)(F)F)n(C)c3=O)c(F)cc(Cl)c2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.2 %

Procedure:
0.31 g (0.71 mmol) of 3-(2-bromomethyl-7-chloro-5-fluorobenzofuran-4-yl)-1-methyl-6-trifluoromethyl-2-(1H)-pyridone was dissolved in 20 ml of THF, and 0.014 g (0.85 mmol) of a methanethiol 30% methanol solution and 0.12 g (0.85 mmol) of potassium carbonate were added thereto, followed by stirring at room temperature for 8 hours. THF was distilled off under reduced pressure. Then, the obtained residue was poured into water and extracted with ethyl acetate. After washing with water, the organic layer was dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure. Then, the obtained crude crystals were washed with n-hexane to obtain 0.28 g (yield: 98%) of the desired product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([O:19][CH3:20])[CH:18]=1)[C:12](OC)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:12][OH:13])[CH:16]=[C:17]([O:19][CH3:20])[CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(OC)cc(OCc2ccccc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(CO)cc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.9 %

Procedure:
To a solution of methyl 3-(benzyloxy)-5-methoxybenzoate (8.90 g) in THF (100 mL) was added lithium aluminum hydride (1.30 g) at 0° C., and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (7.50 g) as an oil. This compound was used for the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][C:16]([CH:22]=[CH:23][C:24]([O:26]CC)=[O:25])=[CH:17][CH:18]=2)[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO.C1COCC1>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][C:16]([CH:22]=[CH:23][C:24]([OH:26])=[O:25])=[CH:17][CH:18]=2)[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C=Cc1ccc2c(c1)C[C@@H](NC(=O)OCc1ccccc1)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C=Cc1ccc2c(c1)C[C@@H](NC(=O)OCc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2 g (5.3 mmole) of (2S)-2-benzyloxycarbonylamino-7-(3-ethoxy-3-oxo-1-propenyl)-tetralin were dissolved in 20 ml of methanol and 30 ml of THF, and 5.3 ml of 1N NaOH were added. The solution was stirred overnight at ambient temperature. The solvent was evaporated off, the residue was taken up in water and washed with ethyl ether; the aqueous phase was acidified with 5% citric acid and then extracted with ethyl acetate. It was dried over sodium sulfate and the solvent was evaporated off. The product of the heading was obtained.
Reaction SMILES: [O:1]=[S@@:2]1[C@@H:7]2[C@H:8]([NH:11][C:12](=[O:20])[CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:9](=[O:10])[N:6]2[C:5]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[O:22])=[C:4]([O:33][S:34]([C:37]([F:40])([F:39])[F:38])(=[O:36])=[O:35])[CH2:3]1.ClC1C=CC=C(C(OO)=[O:49])C=1>C(Cl)(Cl)Cl>[O:1]=[S:2]1(=[O:49])[C@@H:7]2[C@H:8]([NH:11][C:12](=[O:20])[CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:9](=[O:10])[N:6]2[C:5]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[O:22])=[C:4]([O:33][S:34]([C:37]([F:39])([F:40])[F:38])(=[O:36])=[O:35])[CH2:3]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(COC(=O)C2=C(OS(=O)(=O)C(F)(F)F)C[S@](=O)[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(COC(=O)C2=C(OS(=O)(=O)C(F)(F)F)CS(=O)(=O)[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1
Yield: 71.3 %

Procedure:
A mixture of p-methoxybenzyl(1S,6R,7R)-1-oxo-7-phenylacetamido-3-(trifluoro-methanesulphonyloxy)ceph-3-em-4-carboxylate (767 mg, 1.27 mmol) and m-chloroperbenzoic acid (939 mg, 3.81 mmol) in chloroform (60 ml) was heated to reflux. After refluxing for 7 hours the mixture was chromatographed to give the title compound (560 mg, 71%); νmax (KBr) 1819, 1740, 1697 cm-1 ; δH (CDCl3) 3.60 (2H, m), 3.81 (3H, s), 3.87 (1H, d, J 18.1 Hz), 4.17 (1H, d, J 18.1 Hz), 4.53 (1H, d, J 4.9), 5.20 (1H, d, J 11.8 Hz), 5.37 (1H, d, J 11.8 Hz), 6.08 (1H, dd, J 4.9, 9.9 Hz), 6.55 (1H, d, J 9.8 Hz), 6.89 (2H, d, J 8.7 Hz), 7.18-7.37 (7H, m).