Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C(O[C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=[NH:6])C.[C:23]([NH:31][NH2:32])(=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[F:22][C:19]1[CH:18]=[CH:17][C:16]([C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[C:7]([C:5]4[NH:6][C:23]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)=[N:31][N:32]=4)[CH:8]=3)[NH:12][N:11]=2)=[CH:21][CH:20]=1
Reactant: CCOC(=N)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Reactant: NNC(=O)c1ccccc1
Agent: Cl
Product: Fc1ccc(-c2n[nH]c3ccc(-c4nnc(-c5ccccc5)[nH]4)cc23)cc1
Yield: 47.7 %

Procedure:
The procedure described in example 119 using ethoxy[3-(4-fluorophenyl)(1H-indazole-5-yl)]methanimine hydrochloride (200 mg, 0.62 mmol), triethylainine (0.25 mL, 1.86 mmol) and benzoic hydrazide (170 mg, 1.25 mmol) was followed to yield the title compound (105 mg, 48% yield). 1H NMR (DMSO-d6) δ 13.5 (br s, 1H), 8.74 (s, 1H), 8.0–8.2 (m, 5H), 7.75 (d, 1H), 7.35–7.6 (m, 5H), ES-MS 356 [M+1]+.
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]2[C:6]=1[C:7]([CH3:25])=[C:8]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)[C:9]([CH3:16])=[N:10]2.[OH-].[Li+]>CO>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([CH2:17][C:8]2[C:9]([CH3:16])=[N:10][C:11]3[C:6]([C:7]=2[CH3:25])=[C:5]([CH2:4][C:3]([OH:26])=[O:2])[CH:14]=[C:13]([CH3:15])[CH:12]=3)=[CH:23][CH:22]=1
Reactant: COC(=O)Cc1cc(C)cc2nc(C)c(Cc3ccc(Cl)cc3)c(C)c12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(CC(=O)O)c2c(C)c(Cc3ccc(Cl)cc3)c(C)nc2c1

Procedure:
A solution of [3-(4-chlorobenzyl)-2,4,7-trimethylquinolin-5-yl]acetic acid methyl ester (0.10 g), methanol (2.0 mL) and 4.0 M aqueous lithium hydroxide solution (2.0 mL) was stirred at room temperature for 2 hours. The methanol was removed under reduced pressure and the pH of the residue adjusted to 5-6 by the addition of saturated aqueous sodium dihydrogenphosphate solution. The resulting mixture was extracted with ethyl acetate and the combined extracts dried over magnesium sulfate and the solvent removed under reduced pressure. Trituration of the residue with acetonitrile gave title compound, 0.010 g.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[S:25][CH:26]=[CH:27][C:28]=3[NH:29][S:30]([CH:33]([CH3:35])[CH3:34])(=[O:32])=[O:31])=[CH:20][CH:19]=2)=[C:7]([NH:11][S:12]([CH:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH:8]=[CH:9][CH:10]=1)=[O:4].[Li+].[OH-]>C1COCC1.CO.O.O>[CH3:17][CH:15]([S:12]([NH:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([C:3]([OH:4])=[O:2])[C:6]=1[C:18]1[CH:19]=[CH:20][C:21]([C:24]2[S:25][CH:26]=[CH:27][C:28]=2[NH:29][S:30]([CH:33]([CH3:34])[CH3:35])(=[O:31])=[O:32])=[CH:22][CH:23]=1)(=[O:13])=[O:14])[CH3:16]
Reactant: COC(=O)c1cccc(NS(=O)(=O)C(C)C)c1-c1ccc(-c2sccc2NS(=O)(=O)C(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)S(=O)(=O)Nc1ccsc1-c1ccc(-c2c(NS(=O)(=O)C(C)C)cccc2C(=O)O)cc1

Procedure:
Heat the mixture of 6-(propane-2-sulfonylamino)-4′-[3-(propane-2-sulfonylamino)-thiophen-2-yl]-biphenyl-2-carboxylic acid methyl ester (46 mg, 0.08 mmol) and LiOH (30 mg, 1.25 mmol) in 3 ml of THF/Methanol/water (3/2/1, v/v/v) to 60 C for 3 h. Remove solvent and dissolve in water (35 mL). Wash with methylene chloride (2×20 mL). Neutralize the aq. solution to a pH between 2 and 3. Further purification with flash chromatography affords the title compound. MS (m/e): 521.1(M−1).
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([O:22][CH3:23])[C:14](Br)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:25]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26]1.C(Cl)Cl.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.O>[C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([O:22][CH3:23])[C:14]([C:27]3[CH:28]=[CH:29][O:25][CH:26]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(Br)c1OC
Reactant: OB(O)c1ccoc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1OC
Temperature: 140 °C
Yield: 63.5 %

Procedure:
A mixture of ethyl 6-(benzenesulphonylmethyl)-3-bromo-2-methoxybenzoate (Intermediate 61, 0.13 g), furan-3-yl boronic acid (0.036 g), palladium chloride dppf adduct with DCM (0.026 g) and cesium carbonate (0.3 g) in THF (3.5 ml) and water (0.5 ml) was sealed in a microwave vial and degassed. The mixture was then heated in the microwave at 140° C. for 10 minutes. After cooling, the mixture was poured into water and extracted with ethyl acetate. The organic phase was dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-60% to give ethyl 6-(benzenesulphonylmethyl)-3-(furan-3-yl)-2-methoxy-benzoate (0.08 g) as a colourless gum.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9](=[O:11])[CH3:10].C1C=C[NH+]=CC=1.[O-:18][Cr](Cl)(=O)=O.N1C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:18])[C:9](=[O:11])[CH3:10]
Reactant: O=[Cr](=O)([O-])Cl
Reactant: CC(=O)Cc1ccccc1Cl
Agent: c1cc[nH+]cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)C(=O)c1ccccc1Cl
Reaction time: 21.5 h

Procedure:
To a solution of 2-chlorophenylacetone (7.14 g, 42 mmol) in CH2Cl2 (184 mL), PCC (27 g, 127 mmol, 3 eq) and pyridine (10 mL, 127 mmol, 3 eq) in three portions were added over five hours at reflux under vigorous stirring. After the addition was complete, the mixture was further refluxed under vigorous stirring for 21.5 h. The mixture was filtered through a pad of silica gel, washed the pad with CH2Cl2, and concentrated under reduced pressure to provide a dark red syrup. The residue was purified by column chromatography on a 120 g of Redi-Sep™ column using 0-15% gradient of EtOAc in hexane over 40 min as eluent to provide 1-(2-chlorophenyl)propane-1,2-dione as yellow liquid. 1H NMR (choroform-d) δ ppm 7.66 (1H, dd, J=7.6, 1.8 Hz), 7.48-7.54 (1H, m), 7.37-7.46 (2H, m), 2.58 (3H, s). Mass Spectrum (ESI) m/e=182.9 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([F:10])[C:7]([OH:11])=[C:6]([Br:12])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[C:20]([O:23][CH2:24][CH2:25]Br)(=[O:22])[CH3:21]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([F:10])[C:7]([O:11][CH2:25][CH2:24][O:23][C:20](=[O:22])[CH3:21])=[C:6]([Br:12])[CH:5]=1
Reactant: CC(=O)OCCBr
Reactant: COC(=O)c1cc(F)c(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(F)c(OCCOC(C)=O)c(Br)c1

Procedure:
3-Bromo-5-fluoro-4-hydroxybenzoic acid methyl ester (500 mg, 2.01 mmol; T. Kline et al., J. Med. Chem. 45 (2002), 3112-3129), potassium carbonate (971 mg, 7.03 mmol) and 2-bromoethyl acetate (503 mg, 3.01 mmol) were reacted in DMF (5 ml) at room temperature for 72 h. Then the mixture was partitioned between EA and 2 N hydrochloric acid, and the combined organic extracts were dried over sodium chloride, decanted and evaporated to dryness. The raw material was purified by silica gel chromatography (EA/HEP gradient 0:1 to 4:6) to yield the title compound.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]2[C:9]3[S:18][C:17]([CH2:19][CH2:20][CH3:21])=[N:16][C:10]=3[C:11]([NH2:15])=[N:12][C:13]=2[CH:14]=1)(=O)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.BrC(C)[CH2:35][N:36]1[CH:40]=[CH:39][CH:38]=[CH:37]1>ClCCl>[CH2:19]([C:17]1[S:18][C:9]2[C:8]3[CH:7]=[CH:6][C:5]([O:4][CH2:1][CH2:2][CH2:35][N:36]4[CH:40]=[CH:39][CH:38]=[CH:37]4)=[CH:14][C:13]=3[N:12]=[C:11]([NH2:15])[C:10]=2[N:16]=1)[CH2:20][CH3:21]
Reactant: CC(Br)Cn1cccc1
Reactant: CCCc1nc2c(N)nc3cc(OC(C)=O)ccc3c2s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCc1nc2c(N)nc3cc(OCCCn4cccc4)ccc3c2s1
Temperature: 75 °C
Reaction time: 0.17 h
Yield: 45.8 %

Procedure:
A mixture of 4-amino-2-propylthiazolo[4,5-c]quinolin-7-ol acetate (318 mg, 1.0 mmol), cesium carbonate (1.3 g, 4.0 mmol), and DMF (20 mL) was stirred at 75° C. for 10 minutes. 1-(2-Bromopropyl)pyrrole (206 mg, 1.1 mmol) was added dropwise over a period of 10 minutes. After 3 hours an additional equivalent of cesium carbonate was added in a single portion followed by the dropwise addition of an equivalent of 1-(2-bromopropyl)pyrrole. After 1 additional hour the heat source was removed; the reaction mixture was diluted with water (250 mL), stirred for 1 hour, and then filtered. The isolated solid was rinsed with water and then dried to provide a brown powder. This material was dissolved in dichloromethane and then purified by HPFC eluting with a gradient of 0-20% CMA in chloroform over 1500 mL. The resulting solid was recrystallized from acetonitrile to provide 168 mg of 2-propyl-7-[3-(pyrrol-1-yl)propoxy]thiazolo[4,5-c]quinolin-4-amine as an off-white solid, mp 152.0-154.0° C. MS (ESI) m/z 367 (M+H)+; Anal. calcd for C20H22N4OS: C, 65.55; H, 6.05; N, 15.29. Found C, 65.52; H, 5.80; N, 15.37.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C@@H:4]([O:15][CH2:16][CH3:17])[CH2:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([OH:13])=[CH:8][C:7]=1[CH3:14].Cl[CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[C:29]([CH3:34])[CH:28]=2)[O:24][C:25]=1[CH3:26].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>>[CH3:1][O:2][C:3](=[O:18])[C@@H:4]([O:15][CH2:16][CH3:17])[CH2:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([O:13][CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[C:29]([CH3:34])[CH:28]=3)[O:24][C:25]=2[CH3:26])=[CH:8][C:7]=1[CH3:14]
Reactant: Cc1cc(-c2nc(CCl)c(C)o2)ccc1F
Reactant: CCO[C@@H](Cc1c(C)cc(O)cc1C)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Product: CCO[C@@H](Cc1c(C)cc(OCc2nc(-c3ccc(F)c(C)c3)oc2C)cc1C)C(=O)OC

Procedure:
In analogy to the procedure described in example 1 f], (2S)-2-ethoxy-3-(4-hydroxy-2,6-dimethyl-phenyl)-propionic acid methyl ester (example 29 e]) was reacted with 4-chloromethyl-2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazole (example 5 b]) in the presence of cesium carbonate and potassium iodide to yield (S)-2-ethoxy-3-{4-[2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2,6-dimethyl-phenyl}-propionic acid methyl ester as colorless liquid.
Reaction SMILES: CS(O)(=O)=O.CS(O[CH2:11][CH2:12][C:13]1[O:14][C:15]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=3)=[CH:18][C:16]=2[CH:17]=1)(=O)=O.[N-:30]=[N+:31]=[N-:32].[Na+].ClCCl>CN(C=O)C>[N:30]([CH2:11][CH2:12][C:13]1[O:14][C:15]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=3)=[CH:18][C:16]=2[CH:17]=1)=[N+:31]=[N-:32]
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C#N)cc3)ccc2o1
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1ccc(-c2ccc3oc(CCN=[N+]=[N-])cc3c2)cc1
Yield: 71 %

Procedure:
Methanesulfonic acid (109 mg, 0.32 mmol), the product from Example 1C and sodium azide (83 mg, 1.28 mmol) was stirred in DMF for 4 days, then poured into dichloromethane and washed with water. The crude product was purified by flash chromatography, eluting with 2:1 dichloromethane/hexane to provide the title compound as a clear syrup (65 mg, 71%).
Reaction SMILES: C(N[C:5]1[C:6]([N+:15]([O-:17])=[O:16])=[C:7]([CH:11]=[CH:12][C:13]=1[CH3:14])[C:8]([OH:10])=[O:9])(=O)C.[OH-:18].[K+].Cl>O>[OH:18][C:5]1[C:6]([N+:15]([O-:17])=[O:16])=[C:7]([CH:11]=[CH:12][C:13]=1[CH3:14])[C:8]([OH:10])=[O:9]
Reactant: [OH-]
Reactant: CC(=O)Nc1c(C)ccc(C(=O)O)c1[N+](=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: Cc1ccc(C(=O)O)c([N+](=O)[O-])c1O
Yield: 93.1 %

Procedure:
A solution of 3-(acetylamino)-4-methyl-2-nitrobenzoic acid (237.5 g, 0.997 mol) and KOH (451.2 g, 8.04 mol) in water (2830 mL) was refluxed for 48 h. The dark red solution was cooled and acidified to pH 1 with concentrated HCl. The yellow solid was filtered and re-crystallized from water (1800 mL) to give the title compound (183 g, 93.4%) as a yellow solid.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[Cl:27][C:28]1[C:29]([F:54])=[C:30]([CH:51]=[CH:52][CH:53]=1)[NH:31][C:32]1[C:41]2[C:36](=[CH:37][C:38]([O:49][CH3:50])=[C:39]([O:42][CH:43]3[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]3)[CH:40]=2)[N:35]=[CH:34][N:33]=1.[C:55](O)(=[O:58])[CH2:56][OH:57].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:27][C:28]1[C:29]([F:54])=[C:30]([CH:51]=[CH:52][CH:53]=1)[NH:31][C:32]1[C:41]2[C:36](=[CH:37][C:38]([O:49][CH3:50])=[C:39]([O:42][CH:43]3[CH2:48][CH2:47][N:46]([C:56](=[O:57])[CH2:55][OH:58])[CH2:45][CH2:44]3)[CH:40]=2)[N:35]=[CH:34][N:33]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCNCC1
Reactant: O=C(O)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCN(C(=O)CO)CC1

Procedure:
HATU (28.9 g) was added to a stirred solution of 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-(piperidin-4-yloxy)quinazoline dihydrochloride (30 g), glycolic acid (5.40 g) and di-isopropylethylamine (44.70 ml) in methylene chloride (900 ml). After 1.5 hours the reaction mixture was washed with sodium hydroxide solution (2M), water and saturated brine. The resulting product was then purified by flash chromatography on silica eluting with 3% MeOH/methylene chloride. The fractions containing the desired product were combined and reduced in vacuo to give the title product as a white solid which was recrystallised from acetonitrile (29.6 g); NMR Spectrum: (DMSO d6) 1.65–1.81 (m, 2H), 1.99–2.10 (m, 2H), 3.26–3.34 (m, 1H), 3.37–3.47 (m, 1H), 3.60–3.68 (m, 1H), 3.81–3.89 (m, 1H), 3.95 (s, 3H), 4.14 (d, 2H), 4.50 (t, 1H), 4.78 (m, 1H), 7.25 (s, 1H), 7.30 (t, 1H), 7.46–7.55 (m, 2H), 7.88 (s, 1H), 8.40 (s, 1H), 9.55 (s, 1H); Mass Spectrum: (M+H)+ 460.94.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:42])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([CH2:38][CH:39]([CH3:41])[CH3:40])[CH:33]=2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:38]([C:34]1[CH:33]=[C:32]([C:28]2[CH:27]=[C:26]([C:24]3[CH2:23][C:22](=[O:42])[NH:21][C:9]4[CH:10]=[C:11]([C:17]([F:18])([F:20])[F:19])[C:12]([O:14][CH2:15][CH3:16])=[CH:13][C:8]=4[N:7]=3)[CH:31]=[CH:30][CH:29]=2)[CH:37]=[CH:36][N:35]=1)[CH:39]([CH3:40])[CH3:41]
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(CC(C)C)c3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccnc(CC(C)C)c3)c1)=N2

Procedure:
The title compound was prepared from [2-{3-[3-(2-isobutyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-ethoxy-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M257) (0.30 g, 0.50 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (210 mg, 87%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[O:18][CH2:17][C@:13]2([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[NH:14][O:15][CH2:16][C@@H:12]2[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.[Zn]>[NH2:14][C@@:13]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])[CH2:17][O:18][C@@H:10]([CH2:9][O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:11][C@H:12]1[CH2:16][OH:15]
Reactant: Fc1ccccc1[C@]12CO[C@@H](COCc3ccccc3)C[C@H]1CON2
Agent: [Zn]
Solvent: CC(=O)O
Product: N[C@@]1(c2ccccc2F)CO[C@@H](COCc2ccccc2)C[C@H]1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.3 %

Procedure:
Zinc powder (4.36 g) was added to a solution of (3aR,5R,7aS)-5-benzyloxymethyl-7a-(2-fluorophenyl)hexahydropyrano[3,4-c]isoxazole (2.29 g) in acetic acid (50 ml), and the mixture was stirred at room temperature overnight. The insoluble matter was removed by filtration through celite, and the solvent was evaporated under reduced pressure. Ice was added to the residue, followed by neutralization with a 5 N sodium hydroxide solution. The aqueous layer was extracted with dichloromethane, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (2.08 g).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[C:4]([NH:11][C:12]([C:14]2[N:15]=[C:16]([CH3:19])[S:17][CH:18]=2)=[O:13])[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1.CC1(C)C(C)(C)OB([C:40]2[CH:41]=[C:42]([CH2:46][S:47]([NH2:50])(=[O:49])=[O:48])[CH:43]=[CH:44][CH:45]=2)O1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[NH2:50][S:47]([CH2:46][C:42]1[CH:43]=[C:44]([C:2]2[CH:10]=[C:9]3[C:5]([CH:6]=[N:7][NH:8]3)=[C:4]([NH:11][C:12]([C:14]3[N:15]=[C:16]([CH3:19])[S:17][CH:18]=3)=[O:13])[CH:3]=2)[CH:45]=[CH:40][CH:41]=1)(=[O:48])=[O:49]
Reactant: Cc1nc(C(=O)Nc2cc(Br)cc3[nH]ncc23)cs1
Reactant: CC1(C)OB(c2cccc(CS(N)(=O)=O)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc(C(=O)Nc2cc(-c3cccc(CS(N)(=O)=O)c3)cc3[nH]ncc23)cs1
Temperature: 150 °C

Procedure:
N-(6-Bromo-1H-indazol-4-yl)-2-methyl-1,3-thiazole-4-carboxamide (50 mg, 0.148 mmol), Pd(dppf)Cl2 (12 mg, 0.015 mmol), 2 M sodium carbonate (aq) (0.222 ml, 0.444 mmol), 1,4-dioxane (1 ml) and water (1 ml) were added to 1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanesulfonamide (53 mg, 0.178 mmol). The reaction was heated in a Biotage microwave at 150° C. for 15 mins. The reaction mixture was extracted with DCM (2×20 ml) and the separated, combined organic layer was evaporated to dryness. The residue was dissolved in MeOH:DMSO (1 ml, 1:1, v/v) and purified by MDAP (Method B). Appropriate fractions were dried under a stream of nitrogen to give title compound, 5 mg.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].ICCCCCCCCCC=C.S(C1C=CC(C)=CC=1)([O-])(=O)=O.[CH2:36]([O:38][P:39]([O:43]CC)[O:40][CH2:41][CH3:42])[CH3:37]>>[CH2:36]([O:38][P:39]([O:40][CH2:41][CH3:42])([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11])=[O:43])[CH3:37]
Reactant: CCOP(OCC)OCC
Reactant: C=CCCCCCCCCCO
Agent: C=CCCCCCCCCCI
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: C=CCCCCCCCCCP(=O)(OCC)OCC

Procedure:
10-undecen-1-ol (1)(numbering from Scheme 1) was converted to iodinated compound 3 through a tosylate intermediate (2). Reaction of 3 with excess triethylphosphite under reflux conditions afforded the diethoxy phosphonate 4, which was converted to the ethoxyhydroxy phosphonate 5 by treatment with trimethylsilylbromide (TMSBr). The double bond of 6 was oxidatively cleaved with ruthenium trichloride and sodium periodate (Carlsen, et al. (1981) J. Org. Chem. 46, 3k936-3938) to yield the terminal carboxylic acid product 6. Treatment of 6 with excess diethylaminosulfur trifluoride (DAST) and N-hydoxysuccinimide (NHS) afforded an N-succinyl fluorophosphonate intermediate which was reacted with 5-(biotinamido) pentylamine (NH2-biotin) to generate FP-biotin (7). This synthetic route also allowed for the facile coupling of 6 to other reporter groups, including fluorescein cadaverine, which generated a fluorescent fluorophosphonate, FP-fluorescein [8; MALDI-FTMS (DHB) m/z 778.2671 (C38H47FN3O8PS+Na+ requires 778.2703)].
Reaction SMILES: C(OC([NH:8][CH:9]([C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:16][CH:15]=1)[C:10]([O:12][CH3:13])=[O:11])=O)(C)(C)C.C(O)(C(F)(F)F)=O.Cl>C(Cl)Cl.CCOCC.CO.CCOCC>[NH2:8][CH:9]([C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:16][CH:15]=1)[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)Cc1ccc(C(NC(=O)OC(C)(C)C)C(=O)OC)cc1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)Cc1ccc(C(N)C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl α-tert-butoxycarbonylamino-p-methoxycarbonylmethyl-phenylacetate (2.86 g, 8.5 mmol) in CH2Cl2 (10 ml) cooled at 0° C. was added 10 ml of TFA. After stirring for 1 hour at room temperature the reaction mixture was evaporated to dryness. The resulting solid was dissolved in ethyl acetate and water and the pH was adjusted to 8 with NaHCO3. After extraction with ethyl acetate the organic layers were washed with brine, dried and evaporated to give a yellow oil. After dissolution of this oil in a mixture of ether:methanol (10:1 v/v) a saturated solution of HCl in ether was added to give, after filtration, methyl α-amino-p-methoxycarbonyl-methylphenylacetate (2.2 g, 96%) as a white solid, m.p. 189.2°-189.6° C.;
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([CH2:13][NH2:14])[CH:3]=1.[Cl:15][CH2:16][C:17](Cl)=[O:18].CCCCCC.C([O-])(O)=O.[Na+]>C(Cl)Cl.C(OCC)(=O)C>[Cl:15][CH2:16][C:17]([NH:14][CH2:13][C:4]1[CH:3]=[C:2]([CH3:1])[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=1)=[O:18]
Reactant: O=C(Cl)CCl
Reactant: Cc1cc(CN)nn1-c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cc(CNC(=O)CCl)nn1-c1ccccc1
Temperature: 25 °C

Procedure:
5-Methyl-3-aminomethyl-1-phenylpyrazole (2.434 g, 15 mmol) was dissolved in 20 mL of purified methylene chloride, dropwisely added with chloroacetyl chloride (1.194 mL, 15 mmol) at 0° C. and then stirred at room temperature. Completion of the reaction was confirmed by TLC (hexane:ethyl acetate=1:1). Upon completion of reaction, the reaction mixture was adjusted to pH 7 using saturated aq. NaHCO3 and then extracted with methylene chloride. The resulting organic layer was dried with anhydrous magnesium sulfate and filtered, and the filtrate was concentrated and dried in vacuo to obtain the title compound, 3-(2-chloroacetamido)methyl-1-phenyl-5-methylpyrazole.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].Br[C:20]1[CH:21]=[C:22]([CH:31]=[CH:32][CH:33]=1)[C:23]([N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[O:24]>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:20]1[CH:33]=[CH:32][CH:31]=[C:22]([C:23]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[O:24])[CH:21]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(c1cccc(Br)c1)N1CCOCC1
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)COc1ccc(Cl)cc1C#Cc1cccc(C(=O)N2CCOCC2)c1

Procedure:
Following the general method as outlined in Intermediate 20, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 4-(3-bromobenzoyl)morpholine (Intermediate 178), the title compound was obtained as a brown sticky solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[C:26]1([CH2:32][C:33](Cl)=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:26]1([CH2:32][C:33]([NH:1][CH2:2][CH2:3][C:4]2[CH:5]=[CH:6][C:7]([C:10]3[CH:15]=[CH:14][C:13]([CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][CH:11]=3)=[CH:8][CH:9]=2)=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccc(CCN)cc2)cc1
Reactant: O=C(Cl)Cc1ccccc1
Product: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccc(CCNC(=O)Cc3ccccc3)cc2)cc1

Procedure:
The title compound was prepared following the method of Example 147 and using 1 mL of a stock solution of 0.6 g (1.8 mmol) of material from Example 50 and 14 μL (0.11 mmol) phenylacetyl chloride. NMR was consistent with the proposed compound.