Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[NH:4][CH2:3]1.[C:15]([N:22]1[CH2:27][CH2:26][CH:25]([CH:28]=O)[CH2:24][CH2:23]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].C([O-])(O)=O.[Na+]>ClC(Cl)C>[N+:11]([C:7]1[CH:6]=[C:5]2[C:10]([C:2]([CH3:14])([CH3:1])[CH2:3][N:4]2[CH2:28][CH:25]2[CH2:26][CH2:27][N:22]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH2:23][CH2:24]2)=[CH:9][CH:8]=1)([O-:13])=[O:12]
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: CC1(C)CNc2cc([N+](=O)[O-])ccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(CN2CC(C)(C)c3ccc([N+](=O)[O-])cc32)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3,3-Dimethyl-6-nitroindoline (450 mg) was dissolved in 20 mL of dichloroethane, N-boc-4-formylpiperidine (750 mg) was added to the mixture, followed by 2 g NaHB(OAc)3 and 1 mL of glacial ACOH. The mixture was stirred at RT overnight. Saturated NaHCO3 solution (20 mL) was added to the reaction mixture and stirred for 1 h. The resulting mixture was separated by separation funnel, the organic layer was extracted once with saturated NaHCO3 solution and once with brine. The resulting organic layer was dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel with 9:1 Hexane:EtOAc to afford an orange oil. MS: 290 (M−99). Calc'd. for C21H31N3O4−389.5.
Reaction SMILES: [CH2:1]([O:8][NH:9][C@H:10]1[CH2:15][NH:14][C@H:13]([C:16]([NH2:18])=[O:17])[CH:12]=[C:11]1[CH2:19][CH2:20][N+:21]([O-:23])=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24]([O:27]N1C(=O)N2C[C@H]1C(C)=C[C@H]2C(N)=O)C=C>>[CH2:1]([O:8][N:9]1[C:24](=[O:27])[N:14]2[CH2:15][C@H:10]1[C:11]([CH2:19][CH2:20][N+:21]([O-:23])=[O:22])=[CH:12][C@H:13]2[C:16]([NH2:18])=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)[C@@H]1C=C(CC[N+](=O)[O-])[C@@H](NOCc2ccccc2)CN1
Reactant: C=CCON1C(=O)N2C[C@H]1C(C)=C[C@H]2C(N)=O
Product: NC(=O)[C@@H]1C=C(CC[N+](=O)[O-])[C@@H]2CN1C(=O)N2OCc1ccccc1

Procedure:
The title compound was prepared from (2S,5R)-5-(benzyloxyamino)-4-(2-nitroethyl)-1,2,5,6-tetrahydropyridine-2-carboxamide (Intermediate 225, 0.600 g, 1.87 mmol) according to the procedure described for Intermediate 16. The desired product was obtained as a light yellow oil (0.510 g, 79%).
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[NH:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[NH2:18].C(N(CC)C(C)C)(C)C>ClCCl.CN(C)C=O>[F:1][C:2]1[N:7]=[C:6]([C:8]([NH:18][NH:17][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C(O)c1cccc(F)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NNC(=O)c1cccc(F)n1
Reaction time: 2 h

Procedure:
6-Fluoro-2-pyridinecarboxylic acid (2.83 g, 20.06 mmol, CAS[402-69-7], commercially available e.g. from Sigma-Aldrich or Apollo Scientific) was dissolved in Dichloromethane (DCM) (100 mL) at 0° C. Oxalyl chloride (2.107 mL, 24.07 mmol) and a drop of N,N-dimethylformamide (DMF) was added and the mixture was stirred for 2 hours. The solvents were removed in vacuo and azeotroped with toluene (3×20 ml). The residue was dissolved in dichloromethane (DCM) (100 ml) whereupon 1,1-dimethylethyl hydrazinecarboxylate (2.92 g, 22.06 mmol) and N,N-diisopropylethylamine (DIPEA) (7.71 mL, 44.1 mmol) were added. The mixture was stirred at room temperature for 3 hours and concentrated in vacuo. The residue was partitioned between ethyl acetate (100 ml) and saturated sodium bicarbonate solution (50 ml). The aqueous phase was extracted with ethyl acetate (3×100 ml), the combined organic extracts were washed with brine (50 ml), were dried over anhydrous sodium sulphate and were concentrated in vacuo. The residue was purified by flash chromatography (Biotage SP4, 40+M, 0-100% ethyl acetate/iso-hexane) to afford 1,1-dimethylethyl 2-[(6-fluoro-2-pyridinyl)carbonyl]hydrazinecarboxylate (5.04 g, 19.75 mmol).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH:16]=[C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[CH:18]=[CH:19][C:12]2=[N:11][C:10]=1[C:26]([NH:28][O:29][C:30](=O)[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1)=[NH:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH:16]=[C:17]([N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)[CH:18]=[CH:19][C:12]2=[N:11][C:10]=1[C:26]1[N:27]=[C:30]([CH2:31][C:32]2[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=2)[O:29][N:28]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N=C(NOC(=O)Cc1ccc(F)cc1)c1nc2ccc(N3CCOCC3)cn2c(=O)c1OCc1ccccc1
Solvent: Cc1ccccc1
Product: O=c1c(OCc2ccccc2)c(-c2noc(Cc3ccc(F)cc3)n2)nc2ccc(N3CCOCC3)cn12
Temperature: 25 °C
Yield: 75.5 %

Procedure:
The solution of the product of example 21 (261 mg, 0.49 mmol) in toluene (5 ml) was heated at reflux for 2 h. After cooled to room temperature, the solids were collected by filtration, washed with diethyl ether and dried to give the titled product (190 mg, yield 75.3%).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18]>>[Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[S:8]([NH:18][C:17]2[CH:19]=[CH:20][CH:21]=[C:15]([Cl:14])[CH:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Nc1cccc(Cl)c1
Reactant: O=S(=O)(Cl)/C=C/c1ccc(Cl)cc1
Product: O=S(=O)(/C=C/c1ccc(Cl)cc1)Nc1cccc(Cl)c1
Yield: 31.8 %

Procedure:
A solution of (E)-4-chlorostyrylsulfonyl chloride (10 mmol) and 3-chloroaniline (10 mmol) was subjected to General Procedure 1, part B. The title compound, melting point 118-120° C., was obtained in 31.8% yield.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[S:10][C:9](S(C)(=O)=O)=[N:8][C:6]=2[N:7]=1.[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[S:10][C:9]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:8][C:6]=2[N:7]=1
Reactant: Nc1ccccc1
Reactant: CS(=O)(=O)c1nc2nc(Cl)nc(N3CCOCC3)c2s1
Solvent: Cc1ccccc1
Product: Clc1nc(N2CCOCC2)c2sc(Nc3ccccc3)nc2n1

Procedure:
5-Chloro-2-(methylsulfonyl)-7-morpholinothiazolo[4,5-d]pyrimidine (1.0 eq) and aniline (1.0 eq) were heated in toluene at 60° C. for 15 h. Upon completion, reaction mixture was concentrated in vacuo and crude mixture was purified by silica gel chromatography to give intermediate 5-chloro-7-morpholino-N-phenylthiazolo[4,5-d]pyrimidin-2-amine which was reacted with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (2.0 eq) and bis(triphenylphosphine)palladium(II) dichloride (0.10 eq) in 1M KOAc aqueous solution (3.0 eq) and a 4× volume of acetonitrile and heated to 150° C. in a sealed microwave reactor for 10 min Upon completion, reaction mixture was concentrated in vacuo and crude mixture was purified by silica gel chromatography to give 146. MS (Q1) 406 (M+)
Reaction SMILES: [CH3:1][C:2]1[C:3]([C@H:21]([OH:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:4]([O:13][S:14]([C:17]([F:20])([F:19])[F:18])(=[O:16])=[O:15])[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH3:12])=[CH:7][CH:6]=2.Cl(O)(=O)(=O)=O>C(OC(C)=O)(C)(C)C>[C:2]([O:27][C@@H:21]([C:3]1[C:2]([CH3:1])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:12])[CH:9]=2)[C:4]=1[O:13][S:14]([C:17]([F:19])([F:20])[F:18])(=[O:15])=[O:16])[C:22]([O:24][CH2:25][CH3:26])=[O:23])([CH3:3])([CH3:11])[CH3:1]
Reactant: CCOC(=O)[C@@H](O)c1c(C)cc2cc(C)ccc2c1OS(=O)(=O)C(F)(F)F
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)OC(C)(C)C
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2cc(C)ccc2c1OS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (S)-ethyl 2-(3,6-dimethyl-1-(trifluoromethyl-sulfonyloxy)naphthalen-2-yl)-2-hydroxyacetate (7.5 g, 18.5 mmol) in tBuOAc (100 mL) at room temperature was treated with perchloric acid (70%, 0.16 mL, 1.8 mmol) and allowed to stir at room temperature overnight. The reaction was slowly poured into ice-cold saturated NaHCO3 (150 mL). The aqueous layer was extracted with EtOAc and the combined organics washed with brine and dried over anhydrous MgSO4 and filtered. Following concentration in vacuo, purification of the residue by Yamazen silica gel column chromatography (2-20-50% EtOAc/hex) afforded (S)-ethyl 2-tert-butoxy-2-(3,6-dimethyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate. LCMS-ESI+ (m/z): [M+Na]+ calcd for C21H25F3O6SNa: 485.5. found: 485.8.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9]O)[CH:2]=1.P(Cl)(Cl)([Cl:13])=O.[ClH:16]>C(OCC)(=O)C.[OH-].[Na+]>[ClH:13].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][Cl:16])[CH:2]=1
Reactant: OCCCc1cccnc1
Reactant: O=P(Cl)(Cl)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: ClCCCc1cccnc1

Procedure:
3-(3-Pyridyl)propyl chloride hydrochloride was prepared in quantitative yield by reacting 3-(3-pyridyl)propanol with phosphorus oxychloride in ethyl acetate at reflux temperature. The free base was generated by dissolving the hydrochloride in a 10% sodium hydroxide solution and extracting with an organic solvent (toluene or ether).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:13]([CH3:14])=[CH:12][C:11](Cl)=[CH:10][CH:9]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]C)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Li+].[Li+].[H][H]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[C:13]([CH3:14])=[CH:12][CH2:11][CH2:10][CH:9]1[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CCCCCCC1C=C(Cl)C=C(C)N1C(=O)OC(C)(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CO
Product: CCCCCC1CCC=C(C)N1C(=O)OC(C)(C)C

Procedure:
To a stirred solution of 1-(tert-Butoxycarbonyl)-4-chloro-6-methyl-2-n-hexyl-1,2-dihydropyridine (3.74 g, 11.91 mmol) in 250 mL of MeOH at 0° C. was added of lithium carbonate (0.88 g, 11.91 mmol) followed by 5% Pd/C. The mixture was placed under a positive pressure of hydrogen gas from a balloon, and the reaction progress was monitored by removing aliquots with a syringe, concentrating the aliquot in vacuo, and examining its 1H NMR spectrum. Upon completion, the mixture was filtered through Celite and evaporated. The residue was dissolved in ether (100 mL) and water (50 mL) was added, and the aqueous phase was extracted twice with ether. The combined organic extracts were washed with 1M NaOH and brine. The organic phase was dried with potassium carbonate, filtered through Celite, and concentrated in vacuo to give the crude product. Purification by column chromatography (silica gel, 5% EtOAc in hexanes) afforded 2.09 g (62%) as a clear oil that was homogeneous by TLC analysis. 1H NMR (300 MHz) δ 4.85 (br s, 1H), 4.43-4.38 (m, 1H), 2.01 (s, 3H), 1.99-1.91 (m, 2H), 1.83-1.12 (m, 23H), 0.89-0.84 (t, 3H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[O:17][CH:18]=[C:19]([C:21]([O:23][CH3:24])=[O:22])[N:20]=2)=[CH:12][CH:11]=1.Br[CH2:26][CH:27]1[CH2:30][CH2:29][CH2:28]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH:27]1([CH2:26][N:1]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=[C:2]2[C:10]2[CH:11]=[CH:12][C:13]([C:16]3[O:17][CH:18]=[C:19]([C:21]([O:23][CH3:24])=[O:22])[N:20]=3)=[CH:14][CH:15]=2)[CH2:30][CH2:29][CH2:28]1
Reactant: COC(=O)c1coc(-c2ccc(-c3nc4ccccc4[nH]3)cc2)n1
Reactant: BrCC1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1coc(-c2ccc(-c3nc4ccccc4n3CC3CCC3)cc2)n1
Temperature: 120 °C
Yield: 54 %

Procedure:
A mixture of methyl {2-[4-(1H-benzimidazol-2-yl)phenyl]-1,3-oxazol-4-yl}carboxylate (200 mg, 0.62 mmol), bromomethylcyclobutane (140 mg, 0.94 mmol) and K2CO3 (103 mg, 0.75 mmol) in dry acetonitrile was heated to 120° C. with microwave irradiation for 1.5 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The resultant residue was dissolved in CH2Cl2, washed with water, dried over Na2SO4 and evaporated to dryness under reduced pressure. This residue was purified by column chromatography (silica, CH2Cl2:MeOH 98:2) to afford the title compound in 54% yield, identified by NMR and mass spectral analyses. LCMS (ESI+) 388 (MH+).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([C@H:15]3[CH2:17][C@H:16]3[CH2:18][CH2:19][OH:20])[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2].CC(C)([O-])C.[K+].[N:27]1([C:31](=[O:40])[CH2:32][C:33]2[CH:34]=[N:35][C:36](Cl)=[CH:37][CH:38]=2)[CH2:30][CH2:29][CH2:28]1>CN(C=O)C.CC#N>[N:27]1([C:31](=[O:40])[CH2:32][C:33]2[CH:34]=[N:35][C:36]([O:20][CH2:19][CH2:18][C@@H:16]3[CH2:17][C@@H:15]3[CH:12]3[CH2:13][CH2:14][N:9]([C:6]4[N:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][N:5]=4)[CH2:10][CH2:11]3)=[CH:37][CH:38]=2)[CH2:30][CH2:29][CH2:28]1
Reactant: O=C(Cc1ccc(Cl)nc1)N1CCC1
Reactant: CCc1cnc(N2CCC([C@H]3C[C@H]3CCO)CC2)nc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCc1cnc(N2CCC([C@H]3C[C@H]3CCOc3ccc(CC(=O)N4CCC4)cn3)CC2)nc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
2-((1S,2R)-2-(1-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)cyclopropyl)ethanol (40 mg, 0.145 mmol) was dissolved in DMF (2 ml) at RT under N2 and potassium tert-butoxide (0.218 ml, 0.218 mmol) was added. The mixture was stirred at RT for 5 min and 1-(azetidin-1-yl)-2-(6-chloropyridin-3-yl)ethanone (36.7 mg, 0.174 mmol) was added. The mixture was microwaved at 100° C. for 30 min. and 150° C. for 30 min. The mixture was diluted with CH3CN, filtered and purified by reverse-phase HPLC (SunFire Prep C18 OBD Sum 19×100 mm column; 25-95% acetonitrile in 0.1% formic acid in water gradient) to afford the title compound. 1H NMR (500 MHz, CDCl3) δ 8.10 (s, 2H), 8.01 (s, 1H), 7.61 (d, 1H), 6.75 (d, 1H), 4.70 (m, 2H), 4.39 (t, 2H), 4.21 (t, 2H), 4.03 (t, 2H), 3.38 (s, 2H), 2.85 (m, 2H), 2.45 (m, 2H), 2.31 (m, 2H), 2.18 (m, 1H), 1.84 (m, 2H), 1.58 (m, 1H), 1.40 (m, 2H), 1.10-1.20 (m, 5H), 0.95 (m, 2H), 0.68 (m, 2H), −0.40 (m, 1H). LC/MS (m/z): 450 (M+H)+, GPR119 Human EC50: 7.4 nM.
Reaction SMILES: [Cl-].[NH4+].C(O)C.[CH3:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[N:14]1[CH2:19][CH2:18][N:17]([C:20]([C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:32][CH2:31][CH2:30][S:29]3(=[O:34])=[O:33])=[CH:24][C:23]=2[N+:35]([O-])=O)=[O:21])[CH2:16][CH2:15]1>[Fe].O>[NH2:35][C:23]1[CH:24]=[C:25]([N:28]2[CH2:32][CH2:31][CH2:30][S:29]2(=[O:34])=[O:33])[CH:26]=[CH:27][C:22]=1[C:20]([N:17]1[CH2:18][CH2:19][N:14]([C:8]2[CH:9]=[CH:10][C:11]([CH3:13])=[CH:12][C:7]=2[CH3:6])[CH2:15][CH2:16]1)=[O:21]
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3[N+](=O)[O-])CC2)c(C)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3N)CC2)c(C)c1
Yield: 52.8 %

Procedure:
Ammonium chloride (504 mg) and iron (364 mg) were added to a solution of ethanol (9 mL) and water (2.3 mL), [4-(2,4-dimethylphenyl)piperazin-1-yl][4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-nitrophenyl]methanone (770 mg) described in Example 100 was added while stirring at 60° C.-70° C. After completion of the reaction, the insoluble material was collected by filtration, and the filtrate was concentrated. To the obtained residue was added aqueous sodium hydrogen carbonate solution, the mixture was extracted with ethyl acetate, and the solvent was evaporated. The obtained residue was purified by column chromatography (chloroform:methanol) to give the title compound (380 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:10]2[C:5](=[C:6]([CH3:11])[CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:3]1=[O:20].[Br:22]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:22][CH2:11][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[N:4]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:18])([CH3:17])[CH3:19])[C:3](=[O:20])[C:2]2([CH3:21])[CH3:1]
Reactant: Cc1cccc2c1N(COCC[Si](C)(C)C)C(=O)C2(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)C(=O)N(COCC[Si](C)(C)C)c2c(CBr)cccc21
Reaction time: 2 h

Procedure:
The mixture of 3.10 g of 3,3,7-trimethyl-1-(2-trimethylsilanylethoxymethyl)-1,3-dihydroindol-2-one, 1.86 g of N-bromosuccinimide, 0.050 g of dibenzoyl peroxide and 0.033 g of 2,2′-azobis(2-methylpropionitrile) in 100 ml of carbon tetrachloride is kept at reflux with stirring over 2 hours. The reaction mixture is cooled and clarified by filtration, and the filtrate is concentrated by evaporation. The title compound is obtained as a beige solid from the residue by means of flash chromatography (SiO2 60F). Rf=0.42 (1:10 EtOAc-heptane); Rt=26.45 (II).
Reaction SMILES: C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+].[CH2:53]([NH2:60])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1.FC(F)(F)S(O[C:67]1[C:76]2[CH2:75][CH2:74][CH2:73][C:72](=[O:77])[C:71]=2[C:70]([F:78])=[CH:69][CH:68]=1)(=O)=O>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[CH2:53]([NH:60][C:67]1[CH:68]=[CH:69][C:70]([F:78])=[C:71]2[C:76]=1[CH2:75][CH2:74][CH2:73][C:72]2=[O:77])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1
Reactant: NCc1ccccc1
Reactant: O=C1CCCc2c(OS(=O)(=O)C(F)(F)F)ccc(F)c21
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1CCCc2c(NCc3ccccc3)ccc(F)c21
Temperature: 85 °C
Reaction time: 1 h

Procedure:
A mixture of tris(dibenzylideneacetone)dipalladium(0) (0.36 g, 0.34 mmol) under nitrogen in toluene (136 mL) was treated with (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.96 g, 1.5 mmol), treated with sodium tert-butoxide (0.98 g, 10 mmol), treated with benzyl amine (1.1 mL, 10 mmol), warmed to 85° C., treated dropwise over 45 minutes with a solution of Example 44B (2.1 g, 6.8 mmol) in toluene (30 mL), stirred at 85° C. for 1 hour and treated with water (50 mL). The organic layer was isolated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried (Na2SO4) and concentrated. Purification of the residue on silica gel with 30% ethyl acetate/hexanes provided the desired product.
Reaction SMILES: Cl.[O:2]=[C:3]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:4][NH2:5].[CH2:12]([O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[CH:29]=[C:28]([C:33](Cl)=[O:34])[CH:27]=[CH:26]2)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].O1CCOCC1.N1C=CC=CC=1>O>[O:2]=[C:3]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:4][NH:5][C:33]([C:28]1[CH:27]=[CH:26][C:25]2[C:30](=[CH:31][CH:32]=[C:23]([O:22][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:24]=2)[CH:29]=1)=[O:34]
Reactant: CCCCCCCCCCOc1ccc2cc(C(=O)Cl)ccc2c1
Reactant: CCCCCCC(=O)CN
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CCCCCCCCCCOc1ccc2cc(C(=O)NCC(=O)CCCCCC)ccc2c1
Yield: 81.2 %

Procedure:
In a 50 ml-three-necked flask, 0.20 g (1.11 mM) of 2-oxooctylamine hydrochloride, 0.46 g (1.33 mM) of 6-decyloxy-2-naphthoyl chloride and 5 ml of dioxane were placed. To the mixture, 1.6 ml of pyridine was added at about 85° C. under heat-stirring, followed by heat-stirring for 30 minutes at 92°-94° C. After the reaction, the reaction mixture was poured into water to precipitate a crystal. The crystal was recovered by filtration and washed with water, followed by recrystallization from a mixture solvent of acetonemethanol to provide 0.41 g of 2-oxooctyl-(6-decyloxy-2-naphthoyl)amine (Yield: 81.2%).
Reaction SMILES: [BrH:1].Cl.[NH:3]1[CH2:9][CH2:8][CH2:7][C:6](=[O:10])[CH2:5][CH2:4]1.BrBr>C(O)(=O)C>[BrH:1].[Br:1][CH:7]1[CH2:8][CH2:9][NH:3][CH2:4][CH2:5][C:6]1=[O:10]
Reactant: O=C1CCCNCC1
Agent: Br
Agent: BrBr
Agent: Cl
Solvent: CC(=O)O
Product: O=C1CCNCCC1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
27 mL 33% HBr solution was added to 20 g hexahydro-azepin-4-one hydrochloride in 225 mL conc. acetic acid. Subsequently 6.9 mL bromine in 25 mL conc. acetic acid was added dropwise to the reaction mixture and the mixture was stirred 30 min at RT. The solvent was removed and the residue was crystallized with acetonitrile to give 27.9 g of the desired compound.
Reaction SMILES: C(OC(=O)C)(=O)C.C([O-])(=O)C.[Na+].C([O-])(=O)C.[K+].[CH3:18][O:19][N:20]=[C:21]([C:38](=[O:42])[CH:39]([Br:41])[Br:40])[C:22]([NH:24][CH:25]1[C:36](=[O:37])[N:27]2[CH:28]([C:33]([OH:35])=[O:34])[CH:29](O)[CH2:30][S:31][C@H:26]12)=[O:23].Br>O1CCCC1>[CH3:18][O:19][N:20]=[C:21]([C:38](=[O:42])[CH:39]([Br:40])[Br:41])[C:22]([NH:24][CH:25]1[C:36](=[O:37])[N:27]2[C:28]([C:33]([OH:35])=[O:34])=[CH:29][CH2:30][S:31][C@H:26]12)=[O:23]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)C(O)CS[C@H]12)C(=O)C(Br)Br
Agent: Br
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)C(=O)C(Br)Br
Reaction time: 4 h
Yield: 59.1 %

Procedure:
Acetic anhydride (5 ml), sodium acetate (0.61 g) and potassium acetate (0.73 g) were added a solution of 7-(2-methoxyimino-3-oxo-4,4-dibromobutyramido)-3-hydroxycepham-4-carboxylic acid (syn isomer, 5 g) in dry tetrahydrofuran (50 ml), and stirred at 28° to 29° C. for 4 hours. After hydrogen bromide (5 ml) was added to the resultant solution, tetrahydrofuran was removed under reduced pressure therefrom. To the residue was added water (30 ml) and ethyl acetate (100 ml). The organic layer was separated, washed with water and 30% aqueous solution of sodium bromide in turn, and then dried over anhydrous magnesium sulfate. The solution was treated with activated charcoal, and concentrated under reduced pressure, and then the residue was pulverized with diisopropyl ether. The precipitates were collected by filtration, washed with diisopropyl ether and dried to give 7-(2-methoxyimino-3-oxo-4,4-dibromobutyramido)-3-cephem-4-carboxylic acid (syn isomer, 2.85 g).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1([NH:11][C:12]2[S:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[N:16]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl[C:22](=[O:26])[CH:23]([Cl:25])[CH3:24]>ClCCCl>[S:13]1[C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=[C:12]1[NH:11][C:5]1[CH:6]=[CH:7][C:8]([C:22](=[O:26])[CH:23]([Cl:25])[CH3:24])=[CH:9][CH:10]=1
Reactant: c1ccc(Nc2nc3ccccc3s2)cc1
Reactant: CC(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(Cl)C(=O)c1ccc(Nc2nc3ccccc3s2)cc1
Temperature: 80 °C
Yield: 96.7 %

Procedure:
Aluminium(III)chloride (0.666 mol) was added portionwise at RT to a solution of N-phenyl-2-benzothiazolylamine (0.222 mol) and 1,2-dichloro-1-propanone (0.233 mol) in 1,2-dichloroethane (500 ml) and the mixture was stirred and heated at 80° C. for 2 hours. The mixture was poured into ice and extracted with CH2Cl2. The organic layer was decanted, dried filtered and the solvent was evaporated, yielding 68 g of (±)-1-[4-(2-benzothiazolylamino)phenyl]-2-chloro-1-propanone (95.7%) (interm. 22).