Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][S:10]1(=[O:19])=[O:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:39][CH2:40][CH2:41]O.CC(OC(/N=N/C(OC(C)C)=O)=O)C>>[Br:39][CH2:40][CH2:41][N:11]1[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[Cl:1])[S:10]1(=[O:18])=[O:19]
Reactant: OCCBr
Reactant: O=S1(=O)Nc2ccccc2N1c1ccc(F)cc1Cl
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=S1(=O)N(CCBr)c2ccccc2N1c1ccc(F)cc1Cl

Procedure:
1-(2-chloro-4-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (made analogously as in general procedure I, 0.33 g, 1.1 mmol) was treated with triphenylphosphine (0.36 g, 1.4 mmol), 2-bromo ethanol (0.16 g, 1.4 mmol), and diisopropylazodicarboxylate (0.28 g, 1.4 mmol) to provide 0.30 g of 1-(2-bromoethyl)-3-(2-chloro-4-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide. HRMS: calculated for C14H11BrClFN2O2S, 403.93971; found (EI, M+), 403.9386
Reaction SMILES: [CH3:1][N:2]([CH3:23])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[O:16])=[CH:10][CH:9]=2)[CH2:4]1.Cl[C:25]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:26]=1[C:27]#[N:28]>>[CH3:1][N:2]([CH3:23])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:25]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:26]=4[C:27]#[N:28])[CH2:19][CH2:18]3)=[O:16])=[CH:12][CH:13]=2)[CH2:4]1
Reactant: N#Cc1cc(Cl)ccc1Cl
Reactant: CN(C)C1CCN(c2ccc(NC(=O)C3CCNCC3)cc2)C1
Product: CN(C)C1CCN(c2ccc(NC(=O)C3CCN(c4ccc(Cl)cc4C#N)CC3)cc2)C1

Procedure:
Piperidine-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide was reacted with 2,5-dichlorobenzonitrile as described in example 323. This resulted in the product with the molecular weight of 452.00 (C25H30ClN5O); MS (ESI): 452 (M+H+).
Reaction SMILES: I[CH3:2].[H-].[Na+].[OH:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]3[C:21](=[O:22])[N:20]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([C:30]5[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=5)=[CH:26][CH:25]=4)[C:19]([CH2:38][CH2:39][CH3:40])=[N:18][C:17]=3[CH3:41])[CH:14]=2)[O:9][C:8]([CH3:43])([CH3:42])[CH2:7]1>CN(C)C=O.C(OCC)(=O)C>[CH3:2][O:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]3[C:21](=[O:22])[N:20]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([C:30]5[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=5)=[CH:26][CH:25]=4)[C:19]([CH2:38][CH2:39][CH3:40])=[N:18][C:17]=3[CH3:41])[CH:14]=2)[O:9][C:8]([CH3:42])([CH3:43])[CH2:7]1
Reactant: CI
Reactant: CCCc1nc(C)c(-c2ccc3c(c2)C(O)CC(C)(C)O3)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1nc(C)c(-c2ccc3c(c2)C(OC)CC(C)(C)O3)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 1 h
Yield: 66.1 %

Procedure:
A mixture of iodomethane (0.76 g), 60% sodium hydride (0.22 g) and 4′-{[5-(4-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile (0.56 g) in N,N-dimethylformamide (5 mL) was stirred for 1 hr. The reaction mixture was diluted with ethyl acetate, washed with water, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.38 g, 66%).
Reaction SMILES: B(Br)(Br)Br.[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[C:21]2[C:16](=[C:17](C)[CH:18]=[C:19]([CH3:22])[CH:20]=2)[N:15]=[CH:14][C:13]=1[NH:24][C:25](=[O:38])[CH:26]=[CH:27][C:28]1[CH:33]=[CH:32][C:31]([O:34]C)=[C:30]([O:36]C)[CH:29]=1.[C:39](=O)([O-])O.[Na+]>ClCCl>[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[C:21]2[C:16](=[CH:17][C:18]([CH3:39])=[C:19]([CH3:22])[CH:20]=2)[N:15]=[CH:14][C:13]=1[NH:24][C:25](=[O:38])[CH:26]=[CH:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([OH:36])[CH:29]=1
Reactant: O=C([O-])O
Reactant: COc1ccc(C=CC(=O)Nc2cnc3c(C)cc(C)cc3c2-c2ccccc2Cl)cc1OC
Agent: BrB(Br)Br
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc2ncc(NC(=O)C=Cc3ccc(O)c(O)c3)c(-c3ccccc3Cl)c2cc1C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 44.8 %

Procedure:
A solution of boron tribromide in dichloromethane (1:2, 1 ml) was added to a solution of 4-(2-chlorophenyl)-3-(3,4-dimethoxycinnamoylamino)-6,8-dimethylquinoline (473 mg) in dichloromethane (5 ml) under ice-cooling. After being stirred for 20 minutes under ice-cooling, and further for 30 minutes at room temperature, the mixture was poured into ice water. The solution was made neutral with a sodium hydrogen carbonate saturated solution and was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4). The solvent was removed, and the residue was crystallized to give crystals of 4-(2-chlorophenyl)-3-(3,4-dihydroxycinnamoylamino)-6,7-dimethylquinoline (212 mg, 44.8%). The crystals were recrystallized from acetone to obtain yellowish prisms (1/2 acetone solvate).
Reaction SMILES: Cl[CH2:2][C@@H:3]([OH:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])[CH:6]=1.[N-:21]=[N+:22]=[N-:23].[Na+]>>[N:21]([CH2:2][C@@H:3]([OH:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])[CH:6]=1)=[N+:22]=[N-:23]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCC(CCC)COc1cccc(C[C@H](O)CCl)c1
Agent: [Na+]
Product: CCCC(CCC)COc1cccc(C[C@H](O)CN=[N+]=[N-])c1

Procedure:
Treatment of (S)-1-chloro-3-(3-(2-propylpentyloxy)phenyl)propan-2-ol with sodium azide following the method used in Example 66 gave (S)-1-azido-3-(3-(2-propylpentyloxy)phenyl)propan-2-ol which was used without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[O:15][CH3:16])[CH:5]=[CH:4][N:3]=1.[CH:17]1([OH:21])[CH2:20][CH2:19][CH2:18]1.[K].[O-]CCCC>O1CCOCC1>[Cl:14][C:12]1[CH:11]=[CH:10][C:9]([O:15][CH3:16])=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([O:21][CH:17]3[CH2:20][CH2:19][CH2:18]3)[CH:7]=2)[CH:13]=1
Reactant: COc1ccc(Cl)cc1-c1ccnc(Cl)c1
Reactant: OC1CCC1
Agent: CCCC[O-]
Agent: [K]
Solvent: C1COCCO1
Product: COc1ccc(Cl)cc1-c1ccnc(OC2CCC2)c1
Temperature: 101 °C
Reaction time: 15 h
Yield: 114.1 %

Procedure:
2-Chloro-4-(5-chloro-2-methoxyphenyl)pyridine (Preparation 864, 150 mg, 0.00059 mol) and cyclobutanol (76.6 mg, 0.00106 mol) were dissolved in 1,4-dioxane (2 mL). Potassium Pert-butoxide (132 mg, 0.00118 mol) was added and the solution stirred at 101° C. for 15 hours. The reaction was partitioned between ethyl acetate (15 mL) and a 10% aqueous solution of citric acid (10 mL). The organic layer was washed with water (10 mL) followed by a saturated aqueous sodium chloride solution (10 mL). The organics were dried over anhydrous magnesium sulphate, filtered and the solvents removed in vacuo to give a yellow oil (195 mg). The material was purified using an ISCO™ companion (12 g column, eluting with 100% heptane to 7:3 heptane/ethyl acetate). Fractions containing product were combined and concentrated in vacuo to obtain the title compound as a colourless oil (84 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][O:12][CH2:11][C@H:10]2[CH3:15])[C:5]([N+:16]([O-:18])=[O:17])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[N:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[NH:27][CH:26]=1>C(#N)C.CCOC(C)=O>[N:25]1([C:2]2[N:7]=[C:6]([NH:8][C@H:9]3[CH2:14][CH2:13][O:12][CH2:11][C@H:10]3[CH3:15])[C:5]([N+:16]([O-:18])=[O:17])=[CH:4][N:3]=2)[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[N:27]=[CH:26]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: C[C@@H]1COCC[C@@H]1Nc1nc(Cl)ncc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C[C@@H]1COCC[C@@H]1Nc1nc(-n2cnc3ccccc32)ncc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 2.5 h
Yield: 66.2 %

Procedure:
To a solution of 2-chloro-N-(cis-3-methyl-tetrahydro-2H-pyran-4-yl)-5-nitropyrimidin-4-amine (115 mg) in acetonitrile (5 mL) was added potassium carbonate (300 mg) and benzimidazole (150 mg). The mixture was stirred at 70° C. for 2.5 hours. After diluting with 70 mL EtOAc, the mixture was washed with brine, dried over sodium sulfate, and concentrated in vacuo. Column chromatography (50→100% EtOAc/hexanes) provided 99 mg of the title compound.
Reaction SMILES: [C:1](O)(=O)/C=C\C(O)=O.[C:9]([O:16][CH3:17])(=[O:15])/[CH:10]=[CH:11]\[C:12]([O-:14])=[O:13]>CO>[C:12]([O:14][CH3:1])(=[O:13])/[CH:11]=[CH:10]\[C:9]([O:16][CH3:17])=[O:15]
Reactant: O=C(O)/C=C\C(=O)O
Reactant: COC(=O)/C=C\C(=O)[O-]
Solvent: CO
Product: COC(=O)/C=C\C(=O)OC

Procedure:
This example is particularly relevant to the arrangement of FIG. 2. A butane oxidation reactor (not shown) produces 100 moles per hour of maleic anhydride, of which 40 kmols are condensed by cooling the gases in condensers (not shown). The remaining 60 moles per hour are recovered as a 50 wt % aqueous solution of maleic acid from an absorber (2) in line (5). This is fed to an evaporator system (6) and the maleic acid is concentrated (line 5a/37) and mixed together with the crude maleic anhydride from the partial condensers (line 8′) to form a 95 wt % solution of maleic acid. The aqueous maleic acid feed is mixed with recycled methanol from the refining section (line 38/16a′) and fed to a plug flow, mono-ester reactor (36), where more than 80% of the maleic acid is converted to mono-methyl maleate. The product from this is fed to a reaction column (19′) to react the mono-methyl maleate with methanol to produce di-methyl maleate. 540 mols per hour of methanol (lines 42 and 41) are fed to the bottom of the reaction column (19′). Di-methyl maleate (line 26′) is fed to hydrogenation (20). Recycle methanol from the refining section is fed to the top of the reaction column as wash (line 16b′) to minimise the di-methyl maleate and maleic acid in the overhead of the column. Methanol and water from the overhead (line 31′) of the reaction column is fed to the methanol column (25′) where the methanol is separated and recycled to the reaction column (line 39). Water and a small amount of recovered maleic acid and di-methyl maleate from the bottom of the methanol column are recycled to absorber (2) in line 3′.
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:31])[C@@H:15]([NH:20]C(OCC2C=CC=CC=2)=O)[CH2:16][CH:17]([F:19])[F:18])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:31])[C@@H:15]([NH2:20])[CH2:16][CH:17]([F:18])[F:19])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@H](CC(F)F)NC(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCOC(=O)N1CCN(C(=O)[C@@H](N)CC(F)F)CC1
Reaction time: 1 h

Procedure:
To a solution of 168 mg 4-((S)-2-Benzyloxycarbonylamino-4,4-difluoro-butyryl)-piperazine-1-carboxylic acid butyl ester in 15 ml ethyl acetate were added 100 mg Pd/C (10%) and the suspension stirred under an atmosphere of hydrogen (1 bar) for 1 h. The reaction mixture was filtrated over a plug of Celite®, washed with ethyl acetate and concentrated. Yield: 97 mg colorless oil
Reaction SMILES: C[O:2][C:3](=[S:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][N:6]=1.[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][C:21](=[O:33])[NH:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30](O)=[O:31])=[CH:25][CH:24]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][C:21](=[O:33])[NH:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]([NH:11][C:8]2[CH:9]=[CH:10][C:5]([CH2:4][C:3]([OH:2])=[S:12])=[N:6][CH:7]=2)=[O:31])=[CH:25][CH:24]=1
Reactant: COC(=S)Cc1ccc(N)cn1
Reactant: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)Nc2ccc(CC(O)=S)nc2)cc1

Procedure:
A mixture of 5-amino-(pyrid-2-yl)-thioacetic acid methyl ester [930 mg, Reference Example 1(a)], 4-[3-(2-methylphenyl)ureido]phenylacetic acid (1.26 g, prepared as described in Example 21 of International Patent Application Publication No. WO 96/22966), O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (1.69 g) and diisopropylethylamine (1.2 g) in dimethylformamide (50 ml) was stirred at ambient temperature for 1 hour. The mixture was evaporated then poured into water (500 ml). The resultant solid was washed with water (50 ml) and then washed twice with diethyl ether (50 ml). The solid was suspended in methanol (100 ml), then treated with sodium hydroxide solution (10 ml, 1M). The mixture was heated at reflux for 5 hours, then cooled, then evaporated. The residue was treated with hydrochloric acid (200 ml, 1M). The resultant solid was filtered, washed with water (20 ml), then washed twice with diethyl ether (20 ml), then recrystallised from ethanol to give the title compound (220 mg) as a yellow solid, m.p. >235° C. (with decomposition). MS: MH+ 451.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:27]([OH:29])=[O:28])=[N:11][CH:12]=[C:13]([C:16](=[O:26])[NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:31]N(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C.CO>[CH3:31][O:28][C:27]([C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:14]([OH:15])[C:13]([C:16](=[O:26])[NH:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)=[CH:12][N:11]=1)=[O:29]
Reactant: O=C(NCc1ccc(F)cc1)c1cnc(C(=O)O)c(OCc2ccccc2)c1O
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1ncc(C(=O)NCc2ccc(F)cc2)c(O)c1OCc1ccccc1
Yield: 68.7 %

Procedure:
A solution of the compound 13 (198 mg, 0.500 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (115 mg, 0.600 mmol) and 1-hydroxybenzotriazole (81 mg, 0.600 mmol) in dimethylformamide (3 ml) was stirred at room temperature for 1.5 hours. Then, methanol (3 ml) and triethylamine (153 ul, 1.10 mmol) were added, and the mixture was heated to reflux for 1.5 hours. The reaction solution was diluted with ethyl acetate, washed with an aqueous saturated sodium bicarbonate solution, a 10% aqueous citric acid solution, and an aqueous saturated sodium chloride solution, and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was washed with diethyl ether to obtain 3-benzyloxy-5-(4-fluoro-benzylcarbamoyl)-4-hydroxy-pyridine-2-carboxylic acid methyl ester 14 (141 mg, 69%) as a colorless crystal.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[N:6][C:7]=1[O:8][CH3:9].[CH2:14]1CCC(N=C=NC2CCCCC2)C[CH2:15]1.CCO.O>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[CH2:14]([O:12][C:11](=[O:13])[CH2:10][C:4]1[CH:5]=[N:6][C:7]([O:8][CH3:9])=[C:2]([Br:1])[CH:3]=1)[CH3:15]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: COc1ncc(CC(=O)O)cc1Br
Agent: CN(C)c1ccncc1
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)Cc1cnc(OC)c(Br)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of (5-bromo-6-methoxy-pyridin-3-yl)-acetic acid (Step AN2) (400 mg, 1.6 mmol) in CH2Cl2 (0.8 mL) was added DCC (18 mg, 0.09 mmol), DMAP (one spatula) and EtOH (4.88 mmol) and the mixture was stirred at rt for 15 h. H2O and EtOAc were added and the phases were separated. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography (heptane/EtOAc, 85:15→0:100). ESI-MS: tR=1.05 min, [M+H]+ 274.1/276.1 (LC-MS 1).
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].Cl.Cl[CH2:14][C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:18]1[CH:19]=[CH:20][C:15]([CH2:14][O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1]([O:10][CH3:11])=[O:9])=[CH:16][CH:17]=1
Reactant: ClCc1ccncc1
Reactant: COC(=O)c1ccccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1OCc1ccncc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.7 %

Procedure:
To a solution of methyl salicylate (10 g, 66 mmol) and 4-chloromethylpyridine hydrochloride (11 g, 67 mmol) in N,N-dimethylformamide (150 mL) was added potassium carbonate (19 g, 140 mmol) under ice-cooling, and then the mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was poured into an ice water and the aqueous layer was extracted with ethyl acetate (150 mL, twice). The ethyl acetate layer was washed with a saturated brine solution (200 mL), dried over anhydrous sodium sulfate, and concentrated under a reduced pressure to dryness, and the resultant residue was purified with a silica gel column chromatography (hexane/ethyl acetate) and dried to give 12 g (75%) of the titled compound as a colorless solid.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH2:6][NH2:7].[C:16]([C:20]1[N:25]=[C:24]([Cl:26])[C:23]([O:27][CH2:28][C:29](O)=[O:30])=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17].CN1CCOCC1>C1COCC1>[C:16]([C:20]1[N:25]=[C:24]([Cl:26])[C:23]([O:27][CH2:28][C:29]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:10]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:3]([F:2])[CH:4]=2)=[O:30])=[CH:22][CH:21]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)c1ccc(OCC(=O)O)c(Cl)n1
Reactant: CS(=O)(=O)Nc1ccc(CN)cc1F
Agent: Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(OCC(=O)NCc2ccc(NS(C)(=O)=O)c(F)c2)c(Cl)n1
Yield: 28.2 %

Procedure:
3-Fluoro-4-methanesulfonylaminobenzylamine hydrochloride (21 mg, 0.08 mmol) was reacted with (6-tert-butyl-2-chloro-pyridin-3-yloxy)-acetic acid (1.0 eq, 20 mg) DMTMM (1.2 eq, 27 mg) and NMM (1.5 eq, 14 μl) in THF to give the title compound (10 mg, 28.2%) after purification by column chromatography (Hex/EtOAc=1/1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([N:18]=[C:19]=[S:20])[C:15]=2[CH3:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([NH2:24])[CH2:22][NH2:23]>C(Cl)Cl>[NH2:23][CH2:22][CH2:21][NH:24][C:19](=[S:20])[NH:18][C:14]1[C:15]([CH3:17])=[C:16]2[C:11]([CH2:10][CH2:9][N:8]2[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[CH:12][CH:13]=1
Reactant: NCCN
Reactant: Cc1c(N=C=S)ccc2c1N(C(=O)OC(C)(C)C)CC2
Solvent: ClCCl
Product: Cc1c(NC(=S)NCCN)ccc2c1N(C(=O)OC(C)(C)C)CC2
Reaction time: 0.5 h
Yield: 101.1 %

Procedure:
A solution of the above crude 1-t-butoxycarbonyl-2,3-dihydro-6-isothiocyanato-7-methylindole (0.59 g) in methylene chloride (10 mL) is slowly added to a solution of ethylenediamine (0.60 g, 10 mmol) in methylene chloride (10 mL). After 30 minutes, the solution is washed with four 50-mL portions of aqueous potassium carbonate, dried over anhydrous potassium carbonate, filtered and rotary evaporated to yield 6-[N'-(2-aminoethyl)thioureido]-1-t-butoxycarbonyl-2,3-dihydro-7-methylindole as an amber glassy solid (0.72 g). This material is taken on into the next reaction without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:12])[C:10]=1[OH:11])[C:5]([OH:7])=O.S(Cl)(Cl)=O.[NH:17]1[CH2:22][CH2:21][O:20][C:19]2[N:23]=[CH:24][CH:25]=[CH:26][C:18]1=2.O>CN(C)C(=O)C>[Br:12][C:9]1[CH:8]=[C:4]([C:5]([N:17]2[CH2:22][CH2:21][O:20][C:19]3[N:23]=[CH:24][CH:25]=[CH:26][C:18]2=3)=[O:7])[CH:3]=[C:2]([Br:1])[C:10]=1[OH:11]
Reactant: c1cnc2c(c1)NCCO2
Reactant: O=C(O)c1cc(Br)c(O)c(Br)c1
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=C(c1cc(Br)c(O)c(Br)c1)N1CCOc2ncccc21
Reaction time: 0.5 h
Yield: 31 %

Procedure:
3,5-dibromo-4-hydroxy-benzoic acid (65 mg, 0.22 mmol) was dissolved in N,N-dimethyl acetamide (1.5 ml) and then cooled to −5□. Thionyl chloride (0.024 ml, 0.33 mmol) was added thereto and stirred at −5□ for 30 minutes. 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine dissolved in N,N-dimethyl acetamide (0.7 ml) was added thereto and then stirred at −5□ for 20 minutes, and subsequently stirred at room temperature for 15 hours. Water was added and the mixture was extracted with dichloromethane, and then the (extracted) combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with a solvent of n-hexane:ethyl acetate=1:1. The fractions containing the product were collected and evaporated to obtain pale-yellow solid (28 mg, 31%).
Reaction SMILES: C=O.[C:3](=O)([O-])O.[Na+].[Br-].[C:9]1([CH2:15][C:16]([NH:18][C@@H:19]2[C:54](=[O:55])[N:21]3[C:22]([C:46]([O:48][CH2:49][C:50]([Cl:53])([Cl:52])[Cl:51])=[O:47])=[C:23]([CH2:26][P+](C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH2:24][S:25][C@H:20]23)=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl>[C:9]1([CH2:15][C:16]([NH:18][C@@H:19]2[C:54](=[O:55])[N:21]3[C:22]([C:46]([O:48][CH2:49][C:50]([Cl:51])([Cl:53])[Cl:52])=[O:47])=[C:23]([CH:26]=[CH2:3])[CH2:24][S:25][C@H:20]23)=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)=C(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12
Reactant: O=C([O-])O
Agent: C=O
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Product: C=CC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2SC1
Reaction time: 0.42 h
Yield: 9 %

Procedure:
40%-Formaldehyde solution (3 ml.) and 4%-sodium hydrogen carbonate solution (6 ml.) were added to a solution of [7β-Phenylacetamido-4-(2,2,2-trichloroethoxycarbonyl)ceph-3-em-3-ylmethyl]-triphenylphosphonium bromide (403 mg., 0.5 mmole) in methylene chloride (10 ml.), and the two phase mixture was stirred vigorously for 25 minutes. The organic phase was washed with 2N-hydrochloric acid and water (10 ml of each), dried (MgSO4), and evaporated to an orange oil which was crystallised from ethanol (ca. 2 ml.) to give the title ester (22 mg., 9%), λmax. (EtOH) 297 nm (ε 14,100).