Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[OH:13])[C:5]([O:7]CC)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:21]1[CH:26]=[CH:25][N:24]=[C:23]([C:27]([NH2:29])=[O:28])[CH:22]=1.O>CN(C=O)C>[C:27]([C:23]1[CH:22]=[C:21]([O:13][C:12]2[CH:11]=[CH:10][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=2[F:1])[CH:26]=[CH:25][N:24]=1)(=[O:28])[NH2:29]
Reactant: CCOC(=O)c1ccc(O)c(F)c1
Reactant: NC(=O)c1cc(Cl)ccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1cc(Oc2ccc(C(=O)O)cc2F)ccn1
Temperature: 130 °C
Yield: 29.7 %

Procedure:
To a solution of ethyl 3-fluoro-4-hydroxybenzoate (2.0 mmol, 368 mg) in DMF (5 mL), were added cesium carbonate (Aldrich, 6.0 mmol, 1.95 g) and 4-chloropicolinamide (2.0 mmol, 312 mg). The reaction mixture was heated at 130° C. for 20 h. After cooling to room temperature, 5 mL of cold water was added. The aqueous solution was washed with EtOAc (2×20 mL), and neutralized with 1N HCl to pH 3-4. The precipitate that formed was collected by filtration, washed with water, and dried under vacuum to give the desired product (164 mg, 27% yield). MS(ESI+) m/z 277.32 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.[H-].[Na+].I[CH2:19][CH3:20]>CN(C=O)C>[CH2:19]([O:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2)[CH3:20]
Reactant: CCI
Reactant: CCOC(=O)c1cc(O)c2[nH]ncc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(OCC)c2[nH]ncc2c1
Temperature: 25 °C
Yield: 38.4 %

Procedure:
To a solution of ethyl 7-hydroxy-1H-indazole-5-carboxylate (918 mg, 4.45 mmol) in DMF (35 mL) at 0° C. was added 60% oil dispersion of NaH (178 mg, 4.45 mmol). The mixture was aged for 1 hour at 0° C. before dropwise addition of a solution of iodoethane (694 mg, 0.36 mL, 4.45 mmol) in DMF (15 mL). The mixture was aged at 0° C. for several hours before removal of the ice bath. The reaction was allowed to warm to room temperature and aged overnight. The mixture was diluted with EtOAc, washed with water, saturated aqueous NaCl, dried over Na2SO4, filtered concentrated. Purify by silica gel chromatography (40 g column) eluting with 0-30% EtOAc/hexanes gradient to afford ethyl 7-ethoxy-1H-indazole-5-carboxylate (400 mg, 38%).
Reaction SMILES: [C:1]1([NH:7][NH:8][C:9](=[O:17])[CH2:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Ca+2].[H-].[CH3:21]N(C)C=O>>[C:1]1([N:7]2[CH:21]=[C:10]([C:11]3[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=3)[C:9](=[O:17])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccncc1)NNc1ccccc1
Reactant: CN(C)C=O
Agent: [Ca+2]
Agent: [H-]
Product: O=c1[nH]n(-c2ccccc2)cc1-c1ccncc1
Temperature: 170 °C
Reaction time: 8 h

Procedure:
N′-Phenyl-2-pyridin-4-ylacetohydrazide (460 mg, 2.02 mmol) and calcium hydride (141 mg, 3.34 mmol) were dissolved in dimethylformamide (8 mL) and heated at 170° C. After 8 h, the reaction cooled to ambient temperature and was filtered. The mixture was concentrated and redissolved in dichloromethane (50 mL). The precipitate was filtered and dried under high vacuum overnight to give the desired product. MS 238.04 (M+1)
Reaction SMILES: [CH3:1][C:2]1[C:3](=O)[O:4][C:5]2[CH2:6][CH2:7][CH2:8][C:9](=[O:12])[C:10]=2[CH:11]=1.[CH3:14][NH2:15]>>[CH3:14][N:15]1[C:5]2[CH2:6][CH2:7][CH2:8][C:9](=[O:12])[C:10]=2[CH:11]=[C:2]([CH3:1])[C:3]1=[O:4]
Reactant: CN
Reactant: Cc1cc2c(oc1=O)CCCC2=O
Product: Cc1cc2c(n(C)c1=O)CCCC2=O

Procedure:
Prepared analogously to Example 5(b) from 3-methyl- 5,6,7,8-tetrahydro-cumarin-5-one and methanolic methylamine solution a ambient temperature. After evaporation of the methanolic ammonia the residue is recrystallised from water with the addition of charcoal.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH:15]2[CH2:18][CH2:17][CH2:16]2)[C:10]=1[C:11]([F:14])([F:13])[F:12])=[O:5])C.[Li+].[OH-]>CO.O>[CH:15]1([N:9]2[C:10]([C:11]([F:12])([F:13])[F:14])=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]2)[CH2:16][CH2:17][CH2:18]1
Reactant: CCOC(=O)c1cnn(C2CCC2)c1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cnn(C2CCC2)c1C(F)(F)F
Yield: 88.3 %

Procedure:
To a solution of 1-cyclobutyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (117 mg, 0.45 mmol) in methanol (5 mL) and water (5 mL) was added LiOH (13 mg, 0.54 mmol). The reaction mixture was stirred at reflux overnight, and then the solution was concentrated under reduced pressure to remove the methanol. The residue was diluted with water and the solution was acidified to pH=2 with concentrated HCl. The resulting mixture was then extracted with ethyl acetate three times. The combined organic extracts were concentrated in vacuo to give 1-cyclobutyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (93 mg, 89%), which was used without further purification.
Reaction SMILES: BrBr.[OH-:3].[Na+].[Br:5][C:6]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:7]=1[C:8](C1C=CC=CC=1)=[O:9]>>[Br:5][C:6]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:7]=1[C:8]([OH:9])=[O:3]
Reactant: COc1ccc(C(=O)c2ccccc2)c(Br)c1
Reactant: [OH-]
Agent: BrBr
Agent: [Na+]
Product: COc1ccc(C(=O)O)c(Br)c1

Procedure:
Bromine is added into aqueous sodium hydroxide, and then 2-bromo-4-methoxy benzophenone is added to give 2-bromo-4-methoxy benzoic acid (IV).
Reaction SMILES: Cl[Si](C)(C)C.[CH3:6][O:7][C:8](=[O:21])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1.[Br:22]N1C(=O)CCC1=O>C1COCC1>[CH3:6][O:7][C:8](=[O:21])[CH:9]([Br:22])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)CCc1ccc(OC)c(OC)c1
Agent: C[Si](C)(C)Cl
Solvent: C1CCOC1
Product: COC(=O)C(Br)Cc1ccc(OC)c(OC)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 102.3 %

Procedure:
85.68 ml 1.6N butyllithium solution in hexane (0,136 mol) was admixed with 19.27 ml (0.136 mol) diisopropylamine at -10° C. under nitrogen. Afterwards the white suspension was stirred for 30 minutes at -10° C., admixed with 200 ml absolute tetrahydrofuran (abs. THF) and the lithium diisopropylamide solution obtained was cooled to -78° C. Subsequently a solution of 25.6 ml (0.2 mol) freshly distilled chlorotrimethylsilane in 20 ml abs. THF was quickly added, a solution of 24.5 g (0.109 mol) 3-(3,4-dimethoxyphenyl)-propionic acid methyl ester in 50 ml abs. THF was then added dropwise within 10 minutes and afterwards the reaction mixture was stirred for one hour at -78° C. Subsequently 22.6 g (0.127 mol) N-bromosuccinimide was added, the reaction mixture was allowed to reach room temperature (1 h) and it was stirred for a further 8 hours. After removing the precipitate that formed by filtration, the mother liquor was concentrated in a vacuum, the residue was taken up in 100 ml diethyl ether, the ether solution was washed with saturated sodium thiosulfate solution and dried over sodium sulfate. After removing the ether, 33.8 g 2-bromo-3-(3,4-dimethoxyphenyl)-propionic acid methyl ester was obtained as a light brown oil. 1H-NMR (CDCl3): δ=6.75 (m, 3H); 4.35 (dd, 1H); 3.85 (s, 3H); 3.83 (s, 3H); 3.7 (s, 3H); 3.4 (dd, 1H); 3.15 (dd, 1H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][C:9]([C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1[O:21][CH:22]([CH3:24])[CH3:23])=[CH:8][C:7]2=[O:25])([OH:3])=[O:2].S(Cl)(Cl)=O.O1CCO[CH2:32][CH2:31]1>>[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][C:9]([C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1[O:21][CH:22]([CH3:23])[CH3:24])=[CH:8][C:7]2=[O:25])([O:3][CH2:31][CH3:32])=[O:2]
Reactant: C1COCCO1
Reactant: Cc1ccc(OC(C)C)c(-c2cc(=O)c3cc(C(=O)O)ccc3o2)c1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ccc2oc(-c3cc(C)ccc3OC(C)C)cc(=O)c2c1

Procedure:
6-carboxy-2'-isopropoxy-5'-methyl-flavone (4.8 g) in dioxane (30 ml) was treated with thionyl chloride (4 ml) at the reflux temperature for 2 hours. After cooling, the reaction mixture was evaporated to dryness and reacted with an excess of anhydrous ethanol at 50° C. for 1 hour. The mixture was concentrated to a small volume and diluted with water so obtaining, by filtration, 6-carbethoxy-2'-isopropoxy-5'-methyl-flavone (4.7 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[NH:5][C:6]1[C:7]2[N:15]=[C:14](F)[CH:13]=[CH:12][C:8]=2[N:9]=[CH:10][N:11]=1.Cl.CN.[CH2:23]([N:25](CC)CC)C>C(O)C>[CH3:23][NH:25][C:14]1[CH:13]=[CH:12][C:8]2[N:9]=[CH:10][N:11]=[C:6]([NH:5][C:4]3[CH:17]=[CH:18][CH:19]=[C:2]([Br:1])[CH:3]=3)[C:7]=2[N:15]=1
Reactant: Fc1ccc2ncnc(Nc3cccc(Br)c3)c2n1
Reactant: CCN(CC)CC
Agent: CN
Agent: Cl
Solvent: CCO
Product: CNc1ccc2ncnc(Nc3cccc(Br)c3)c2n1
Yield: 81.4 %

Procedure:
Reaction of 4-(3-bromoanilino)-6-fluoropyrido[3,2-d) pyrimidine (50 mg, 0.16 mmol) (described in a previous experimental) with methylamine hydrochloride (32 mg, 0.47 mmol) and triethylamine (70 μL, 0.55 mmol) in ethanol (10 mL) in a pressure vessel at 100° C. for 18 h gives 6-methylamino-4-(3-bromoanilino)pyrido[3,2-d]pyrimidine (43 mg, 81%). 1H NMR (CDCl3) δ 8.81 (1H, brs), 8.61 (1H, s), 8.19 (1H, t, J=1.8 Hz), 7.86 (1H, d, J=9.1 Hz,), 7.83 (1H, dt, Jd =7.7 Hz, Jt =1.8 H), 7.28-7.21 (2H, m), 6.92 (1H, d, J=9.1 Hz), 4.97 (1H, q, J=5.0 Hz), 3.13 (3H, d, J=5.0 Hz).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([NH2:11])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Br-:12].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl.CO>[Br:12][C:6]1[C:7]([NH2:11])=[CH:8][CH:9]=[C:10]2[C:5]=1[CH:4]=[CH:3][CH:2]=[N:1]2
Reactant: [Br-]
Reactant: Nc1ccc2ncccc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Nc1ccc2ncccc2c1Br
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 31.6 %

Procedure:
To a solution of quinolin-6-ylamine (503 mg, 3.49 mmol) in dichloromethane (17 mL) and methanol (8.6 mL) was added tetra-n-butylammonium tribromide (1.68 g, 3.49 mmol). The mixture was stirred at 25° C. for 90 minutes, and then 10 5 mL of aqueous sodium thiosulfate was added. The mixture was extracted with dichloromethane, and the combined extracts were washed with water, dried (Na2SO4), filtered and concentrated to dryness under reduced pressure. Purification by flash column (hexanes/ethylacetate gradient) gave 5-bromo-quinolin-6-ylamine (246 mg, 32%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[N:20]3[C:14]([CH2:15][N:16]([C:25]([C:27]4[CH:36]=[CH:35][C:30]([C:31]([O:33]C)=[O:32])=[CH:29][CH:28]=4)=[O:26])[C:17]4[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=4[CH2:19]3)=[CH:13][CH:12]=2)=[O:10])[CH:2]=1.[OH-].[Li+]>CO.O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[N:20]3[C:14]([CH2:15][N:16]([C:25]([C:27]4[CH:28]=[CH:29][C:30]([C:31]([OH:33])=[O:32])=[CH:35][CH:36]=4)=[O:26])[C:17]4[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=4[CH2:19]3)=[CH:13][CH:12]=2)=[O:10])[CH:2]=1
Reactant: COC(=O)c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1
Reaction time: 16 h
Yield: 88.6 %

Procedure:
To a solution of methyl 4-{[3-{[(pyridin-3-ylmethyl)amino]carbonyl}-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-yl]carbonyl}benzoate of Example 87 (0.315 g, 0.656 mmol) in methanol (4 mL) and water (2 mL) was added lithium hydroxide (31.4 mg, 1.31 mmol) and the reaction mixture heated to reflux for 1 hour. The cooled reaction mixture was diluted with water (20 mL) and washed with ethyl acetate (2×20 mL). The aqueous phase was then acidified to pH 4.5 by the addition of 2 M hydrochloric acid and the resulting milky suspension allowed to stand at 4° C. for 16 hours. The solid product was filtered, washed with water, and dried at 50° C. in vacuo overnight to afford the title compound (0.271 g, 89%) as a white solid.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([C:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([CH2:21][CH:22]=[CH2:23])[CH:15]=2)([CH3:13])[CH3:12])[CH:7]=[CH:8][C:9]=1[OH:10])[CH:2]=[CH2:3].[OH-].[K+].Cl>CO>[CH:21]([C:16]1[CH:15]=[C:14]([C:11]([C:6]2[CH:7]=[CH:8][C:9]([OH:10])=[C:4]([CH:1]=[CH:2][CH3:3])[CH:5]=2)([CH3:12])[CH3:13])[CH:19]=[CH:18][C:17]=1[OH:20])=[CH:22][CH3:23]
Reactant: C=CCc1cc(C(C)(C)c2ccc(O)c(CC=C)c2)ccc1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC=Cc1cc(C(C)(C)c2ccc(O)c(C=CC)c2)ccc1O
Temperature: 110 °C

Procedure:
400 ml of methanol is slowly added, with stirring, to a mixture of 3 mols of 2,2-bis-(3-allyl-4-hydroxyphenyl)-propane (A1) and potassium hydroxide pellets. The mixture is subsequently carefully heated to 110° C. with the distilling off of 116 ml of methanol. The reaction solution is then held, with refluxing, for a further 6 hours at 110° C. The reaction mixture is afterwards cooled, neutralised with concentrated HCl, and extracted with methylene chloride. The extract is dried, and evaporated completely to dryness. There is obtained essentially pure 2,2-bis-[3-(1-propenyl)-4-hydroxyphenyl]-propane (A2), which at room temperature is a very highly viscous yellowish liquid. The structural formula A2 is confirmed by microanalysis, H-NMR, MS and UV spectroscopy, as well as by means of gel-permeation chromatography.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][N:10]=1.[C:16](O)(=[O:18])[CH3:17]>>[Br:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:16](=[O:18])[CH3:17])=[N:10][CH:11]=1
Reactant: Nc1ccc(Br)cn1
Reactant: CC(=O)O
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(Br)cn1
Yield: 41.4 %

Procedure:
Triethylamine (17.7 mL, 75 mmol) is added to a mixture of 2-amino-5-bromopyridine (5.0 g, 29 mmol) and acetic acid (7.1 mL, 75 mmol). The solution is heated to reflux for 48 hours. After this time, the solution is concentrated. The reside is dissolved in water and the pH is adjusted to 10 with 1N NaOH. The solids are collected by filtration. The crude product is recrystallized from boiling water to give the title compound (2.6 g 12.0 mmol) as a white solid. 1H NMR (300 MHz, CDCl3) δ10.62 (1H, bs), 8.42 (s, 1H), 8.01 (m, 2H), 2.05 (s, 3H).
Reaction SMILES: [Cl-].[C:2]([O:6][C:7]([CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:8])([CH3:5])([CH3:4])[CH3:3].CC(C)([O-])C.[K+].[C:35]([C:38]1[CH:45]=[CH:44][CH:43]=[CH:42][C:39]=1[CH:40]=O)([OH:37])=[O:36]>O1CCCC1>[C:35]([C:38]1[CH:45]=[CH:44][CH:43]=[CH:42][C:39]=1[CH:40]=[CH:9][C:7]([O:6][C:2]([CH3:5])([CH3:4])[CH3:3])=[O:8])([OH:37])=[O:36]
Reactant: CC(C)(C)OC(=O)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccccc1C(=O)O
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C=Cc1ccccc1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of (t-butoxycarbonylmethyl)-triphenylphosphonium chloride (20.7 g) in tetrahydrofuran (200 ml) was added potassium t-butoxide (5.60 g) portionwise and the mixture was stirred for 30 minutes at ambient temperature. 2-Carboxybenzaldehyde was added to the mixture. After being stirred for 1 hour the reaction mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was dissolved in 1N aqueous sodium hydroxide solution and washed with ethyl acetate. The aqueous layer was acidified by conc. hydrochloric acid solution and extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated under reduced pressure to afford t-butyl 3-(2-carboxyphenyl)acrylate (8.3 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:21][O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: COc1ccccc1C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccccc1C1CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.6 %

Procedure:
1-t-Butoxycarbonyl-4-(2-methoxyphenyl)piperidine (120 mg, 0.41 mmol) was dissolved in methylene chloride (2 ml). Thereto was added trifluoroacetic acid (2 ml) and the resulting solution was stirred at a room temperature for 1 hour. The solvent was evaporated under a reduced pressure, and the thus obtained residue was mixed with ethyl acetate. This was washed with 1 N sodium hydroxide aqueous solution and saturated brine in that order, and then the solvent was evaporated under a reduced pressure to obtain 82 mg of the aforementioned compound of interest (0.43 mmol, 104% in yield).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([C:10]([NH:12][NH2:13])=[O:11])=[CH:7][CH:6]=1)=[O:4].Cl.[C:15](=N)(OCC)[CH3:16]>N1C=CC=CC=1>[CH3:15][C:16]1[O:11][C:10]([C:8]2[S:9][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=2)=[N:12][N:13]=1
Reactant: CCOC(C)=N
Reactant: COC(=O)c1ccc(C(=O)NN)s1
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(-c2nnc(C)o2)s1
Temperature: 25 °C

Procedure:
A stirred suspension of 5-methoxycarbonyl-2-thiophenecarboxylic acid hydrazide (548 mg, 2.74 mmoles) and ethyl acetimidate hydrochloride (372 mg, 3.01 mmoles) in 10 ml of pyridine was refluxed for four hours, cooled to room temperature and evaporated in vacuo. The residual oily solid was dissolved in ethyl acetate and washed with water, 1N hydrochloric acid and 5% sodium bicarbonate. The ethyl acetate was dried (magnesium sulfate) and evaporated in vacuo to a pale tan solid (242 mg, 39%), m.p. 142°-5° C. This material was used directly without further purification. Exact Mass: 224.0253, Calculated: 224.0256; EIMS (m/z): 224 (M+, base), 193 (M+ -CH3O, 33%), 169 (C7H7O3S, 83%); 1HNMR (DMSO-d6) delta, 7.88 (1H, d, J=3.9Hz), 7.80 (1H, d, J=3.9Hz), 3.87 (3H, s), 2.58 (3H, s); ir (potassium bromide): 1705, 1571, 1291, 1101, 751 cm-1.
Reaction SMILES: C([O:5][C:6](=[O:51])[C:7]([O:10]/[N:11]=[C:12](/[C:38]1[N:39]=[C:40]([NH:43]C(OC(C)(C)C)=O)[S:41][CH:42]=1)\[C:13]([NH:15][C@@H:16]1[C:19](=[O:20])[N:18]([S:21]([O-:24])(=[O:23])=[O:22])[C@@H:17]1[CH2:25][N:26]1[CH:30]=[C:29]([C:31]2[CH:36]=[CH:35][N+:34]([CH3:37])=[CH:33][CH:32]=2)[N:28]=[N:27]1)=[O:14])([CH3:9])[CH3:8])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:43][C:40]1[S:41][CH:42]=[C:38](/[C:12](=[N:11]/[O:10][C:7]([C:6]([OH:51])=[O:5])([CH3:8])[CH3:9])/[C:13]([NH:15][C@@H:16]2[C:19](=[O:20])[N:18]([S:21]([O-:24])(=[O:22])=[O:23])[C@@H:17]2[CH2:25][N:26]2[CH:30]=[C:29]([C:31]3[CH:32]=[CH:33][N+:34]([CH3:37])=[CH:35][CH:36]=3)[N:28]=[N:27]2)=[O:14])[N:39]=1
Reactant: C[n+]1ccc(-c2cn(C[C@@H]3[C@H](NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c4csc(NC(=O)OC(C)(C)C)n4)C(=O)N3S(=O)(=O)[O-])nn2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[n+]1ccc(-c2cn(C[C@@H]3[C@H](NC(=O)/C(=N\OC(C)(C)C(=O)O)c4csc(N)n4)C(=O)N3S(=O)(=O)[O-])nn2)cc1
Yield: 41.6 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (2R,3S)-3-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-((4-(1-methylpyridin-1-ium-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-4-oxoazetidine-1-sulfonate (24 mg, 0.032 mmol), DCM (1.2 mL) and TFA (0.3 mL, 3.9 mmol). The crude residue was purified by reverse phase prep HPLC (XBridge, 30×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 1 mL/min), affording the title compound (7.9 mg, 41%) as a white solid. LCMS: m/z=592.0 (M−1); 1H NMR (400 MHz, D2O): δ 8.76 (s, 1H), 8.62 (d, J=6.8 Hz, 2H), 8.19 (d, J=6.4 Hz, 2H), 6.76 (s, 1H), 5.42 (d, J=5.2 Hz, 1H), 4.98-4.81 (m, 2H; partially obscured by residual solvent peak), 4.66-4.54 (m, 1H assumed: obscured by residual solvent peak), 4.22 (s, 3H), 1.30 (s, 3H), 1.27 (s, 3H).
Reaction SMILES: [C:1](#[N:5])[CH:2]([CH3:4])[CH3:3].C([N-]C(C)C)(C)C.[Li+].Br[CH2:15][CH2:16][CH2:17][Cl:18]>>[Cl:18][CH2:17][CH2:16][CH2:15][C:2]([CH3:4])([CH3:3])[C:1]#[N:5]
Reactant: CC(C)C#N
Reactant: ClCCCBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: CC(C)(C#N)CCCCl
Reaction time: 2 h
Yield: 34.3 %

Procedure:
To a solution of isobutyronitrile (13.8 g, 0.2 mol; Aldrich) in hexanes (200 mL) was added a 2M solution of lithium diisopropylamide (100 mL, 0.2 mol; Aldrich), and the mixture stirred for 2 hrs under nitrogen. This mixture was added to a solution of 1-bromo-3-chloropropane (34.6 g, 0.22 mol; Aldrich) and stirred for 1 h. The reaction was quenched by careful addition of water, and the hexane layer was dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography (SiO2, 20–50% CH2Cl2 in Hexanes) to provide 10 g (68.7 mmol, Yield=34%) of the title compound as an amber oil: 1H NMR (CDCl3, 500 MHz) δ ppm: 1.35 (6H, s, gem-Me), 1.67 (2H, m, CH2), 1.95 (2H, m, CH2), 3.57 (2H, t, J=6.5 Hz, Cl-CH2); 13C NMR (CDCl3, 125.8 Hz) δ ppm 26.73, 28.50, 32.08, 38.47, 44.58, 124.72.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([F:23])[CH:17]=1.C(O)C.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([N:36]=[C:37]=[S:38])=[O:35])=[CH:30][CH:29]=1>C1(C)C=CC=CC=1>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([NH:36][C:37]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:17][C:18]=2[F:23])=[S:38])=[O:35])=[CH:30][CH:29]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Reactant: O=C(N=C=S)c1ccc(Cl)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(Cl)cc4)c(F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 4-chloro-1-benzenecarbonyl isothiocyanate (50 μl) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (77 mg, yield 94%).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[CH:12]=[C:11]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[NH:10][N:9]=1)=[O:7])C>CO>[CH3:16][CH:15]([CH3:17])[CH2:14][CH2:13][C:11]1[NH:10][N:9]=[C:8]([C:6]([OH:7])=[O:5])[CH:12]=1
Reactant: CCOC(=O)c1cc(CCC(C)C)[nH]n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)CCc1cc(C(=O)O)n[nH]1
Yield: 97.6 %

Procedure:
Freshly prepared aq. NaOH (10 M in H2O, 80.85 mmol) was added to a stirring, room temperature solution of 47 (3.40 g, 16.17 mmol) in MeOH (40.4 mL, 0.4 M) under N2. The reaction was then heated to reflux until the reaction was judged complete by HPLC (6 min): The reaction was concentrated and then dissolved in 14 mL H2O. 10% aq. HCl was added dropwise until the pH=2. The white solid that precipitated from the reaction was filtered off and washed with cold H2O. The solid was dried under vacuum overnight to obtain 2.8753 g (97.6%) of 48. (Note: An undesired impurity has a retention time of 9.522 min by HPLC). 1H (CDCl3, 400 MHz): δ 6.61 (1H, s), 2.70 (2H, t, J=7.8 Hz), 1.63-1.51 (3H, m), 0.94 (6H, d, J=6.3 Hz) ppm. 13C (CDCl3, 100 MHz): δ 164.35, 149.48, 143.00, 107.34, 39.35, 28.71, 24.69, 22.65 ppm. DEPT (CDCl3, 100 MHz): CH3 carbons: 22.65; CH2 carbons: 39.35, 24.69; CH carbons: 107.34, 28.71 ppm. HPLC: 9.522 min.