Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH:3]=O.Cl.[C:6]([O:10][NH2:11])([CH3:9])([CH3:8])[CH3:7]>>[C:6]([O:10][N:11]=[CH:3][CH2:2][Cl:1])([CH3:9])([CH3:8])[CH3:7]
Reactant: O=CCCl
Reactant: CC(C)(C)ON
Agent: Cl
Product: CC(C)(C)ON=CCCl
Temperature: 25 °C
Yield: 93.7 %

Procedure:
To 9.81 g of 40% aqueous chloroacetaldehyde solution was added 3.77 g of O-tert-butylhydroxylamine hydrochloride with stirring at room temperature. After stirring at room temperature for 2 hours, the reaction mixture was extracted twice with diethyl ether. The diethyl ether layers were combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated, which afforded 4.21 g (yield, 94%) of chloroacetaldehyde O-tert-butyloxime, nD23.2 1.4418.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]3[C:11]([CH:12]=[N:13][C:14](S(C)=O)=[N:15]3)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)C(C)C)(C)C.[N:29]1([C:34]2[CH:39]=[CH:38][C:37]([NH2:40])=[CH:36][CH:35]=2)[CH2:33][CH2:32][CH2:31][CH2:30]1>COCCO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]3[C:11]([CH:12]=[N:13][C:14]([NH:40][C:37]4[CH:36]=[CH:35][C:34]([N:29]5[CH2:33][CH2:32][CH2:31][CH2:30]5)=[CH:39][CH:38]=4)=[N:15]3)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)c1ncc2ccc(-c3cccc(Cl)c3)n2n1
Reactant: Nc1ccc(N2CCCC2)cc1
Solvent: COCCO
Solvent: CCN(C(C)C)C(C)C
Product: Clc1cccc(-c2ccc3cnc(Nc4ccc(N5CCCC5)cc4)nn23)c1
Yield: 16.1 %

Procedure:
7-(3-Chloro-phenyl)-2-methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazine (125.0 mg, 0.0004284 mol), N,N-Diisopropylethylamine (0.112 mL, 0.000643 mol) and 4-Pyrrolidin-1-yl-phenylamine (139 mg, 0.000857 mol) were dissolved in 2-Methoxyethanol (3.01 mL) and The reaction was microwaved on 300 watts, 180° C. for 40 minutes or until HPLC showed consumption of starting material. The reaction mixture was then reduced en vacuo and the product was isolated and purified by Gilson prep HPLC to afford 26.91 mg of [7-(3-Chloro-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-(4-pyrrolidin-1-yl-phenyl)-amine as a lyophilized powder. (M+H)=390.09. 1H NMR (400 MHz, CDCl3) δ 9.63 (s, 1H), 8.63 (s, 1H), 8.32 (s, 1H), 7.84 (m, 1H), 7.76 (d, 2H, J=8.93 Hz), 7.48 (m, 2H), 7.34 (d, 2H, J=8.93 Hz), 7.21 (m, 1H), 7.18 (m, 1H), 3.66 (m, 4H), 2.25 (m, 4H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]2[CH:9]=[C:10]([CH:18]=[CH:19][CH:20]=2)[O:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:3]1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C@H:25]1[O:27][CH2:26]1>C(O)C>[Cl:21][C:22]1[CH:23]=[C:24]([C@@H:25]([OH:27])[CH2:26][NH:1][CH:2]2[CH2:7][CH2:6][CH2:5][CH:4]([C:8]3[CH:20]=[CH:19][CH:18]=[C:10]([O:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:9]=3)[CH2:3]2)[CH:28]=[CH:29][CH:30]=1
Reactant: Clc1cccc([C@@H]2CO2)c1
Reactant: CCOC(=O)COc1cccc(C2CCCC(N)C2)c1
Solvent: CCO
Product: CCOC(=O)COc1cccc(C2CCCC(NC[C@H](O)c3cccc(Cl)c3)C2)c1
Yield: 61.8 %

Procedure:
Ethyl 3-(3-aminocyclohexyl)phenoxyacetate (8.47 g) was dissolved in ethanol (50 ml), and (R)-3-chlorostyrene oxide (4.72 g) was added prior to heating to reflux for 7.5 hours. After allowing the mixture to cool, the solvent was concentrated under reduced pressure to obtain an oily substance which was then separated and purified by silica gel column chromatography (n-hexane:ethyl acetate=1:5), to give 8.15 g of (1R)-1-(3-chlorophenyl)-2-[3-(3-ethoxycarbonylmethoxyphenyl) cyclohexylamino]ethanol (trans-H) (compound of Example 11) as an oily substance (61.8% yield).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[C:6]1=[O:20].[NH2:22][OH:23].[OH-].[Na+]>C1COCC1>[OH:23][NH:22][C:3](=[O:2])[CH2:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[C:6]1=[O:20]
Reactant: NO
Reactant: COC(=O)CC1Cc2ccccc2N(CCC(C)C)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)CCN1C(=O)C(CC(=O)NO)Cc2ccccc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The crude [1-(3-methyl-butyl)-2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl]-acetic acid methyl ester obtained in the previous step is dissolved in 0.5 mL of anhydrous THF. Freshly prepared NH2OH (0.77 M in MeOH) (0.44 mL) (also containing 0.77M NaOH) is then added and the mixture is stirred at room temperature for 12 hours. The final product N-hydroxy-2-[1-(3-methyl-butyl)-2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl]-acetamide is obtained by preparative LC/MS using 1 to 99% ACN as gradient. 1H NMR (400 MHz, MeOD): δ 7.29 (t, 1H), 7.20 (d, 1H), 7.11 (d, 1H), 7.04 (t, 1H), 3.97 (m, 2H), 3.02-2.89 (m, 2H), 2.77-2.65 (m, 2H), 2.17 (dd, 1H), 1.65 (m, 1H), 1.50 (m, 2H), 0.97 (2d, 6H). MS: (ES+): 291.3 [M+1].
Reaction SMILES: C(O)C.[SH:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.Cl.Br[CH2:14][CH2:15][NH2:16].C(=O)([O-])[O-].[K+].[K+]>O>[NH2:16][CH2:15][CH2:14][S:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1
Reactant: Oc1ccc(S)cc1
Reactant: NCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: NCCSc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 105.6 %

Procedure:
To 30 ml of ethanol, 1.2 g of 4-mercaptophenol, 2.1 g of 2-bromoethylamine hydrochloride and 1.4 g of potassium carbonate were added, followed by stirring for 3 hours at room temperature. Water was added, and the resulting mixture was extracted with ethyl ether. The extract was dried over MgSO4 and the ethyl ether was distilled off under reduced pressure, whereby 1.7 g of the compound (7) were obtained (yield: stoichiometric).
Reaction SMILES: [ClH:1].[O:2]1[C@@H:14]2[C@@:15]34[CH2:17][CH2:18][NH:19][C@@H:9]([C@:10]3([O:21][CH2:22][CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:11][CH2:12][C:13]2=[O:20])[CH2:8][C:7]2=[C:16]4[C:3]1=[C:4]([O:31][CH3:32])[CH:5]=[CH:6]2.C(=O)([O-])[O-].[K+].[K+].[C:39]1([CH2:45][CH2:46]Br)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>O>[ClH:1].[O:2]1[C@@H:14]2[C@@:15]34[CH2:17][CH2:18][N:19]([CH2:46][CH2:45][C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)[C@@H:9]([C@:10]3([O:21][CH2:22][CH2:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:11][CH2:12][C:13]2=[O:20])[CH2:8][C:7]2=[C:16]4[C:3]1=[C:4]([O:31][CH3:32])[CH:5]=[CH:6]2
Reactant: BrCCc1ccccc1
Reactant: COc1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(OCCCc5ccccc5)[C@@H](C2)NCC[C@]314
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COc1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(OCCCc5ccccc5)[C@@H](C2)N(CCc2ccccc2)CC[C@]314
Temperature: 80 °C
Reaction time: 12 h

Procedure:
A mixture of 4,5α-epoxy-3-methoxy-14β-(3-phenylpropyloxy)morphinan-6-one hydrochloride (1.0 g, 2.38 mmol), potassium carbonate (3.00 g, 21.7 mmol) and 2-phenylethylbromide (1.19 ml, 8.8 mmol) in water-free N,N-dimethylformamide (10 ml) was stirred for 12 h under exclusion of moisture and under nitrogen at 80° C. (bath temperature). After filtration from the inorganic residue, which was washed three times each time with 50 ml dichloromethane, the filtrate was evaporated down under reduced pressure. The oily residue was dissolved in 300 ml dichloromethane, washed with water (3×200 ml) and saturated sodium chloride solution (4×200 ml), dried over sodium sulphate and evaporated down. The evaporation residue (960 mg of brown oil) was purified by column chromatography (silica gel; CH2Cl2/MeOH/conc. NH4OH 250:2:0.5), the oily evaporation residue dissolved in 50 ml ether and precipitated by the addition of etherial HCl up to the acidic reaction. Yield: 0.45 g (36%) of the compound 4.HCl as colourless crystals. Fp. 128-130° C.; MS (CI): 524 (M++1); IR (KBr): 1726 (C═O) cm−1; 1H-NMR (DMSO-d6, δ in ppm): δ 8.84 (s, wide, HN+), 7.39-7.17 (m, 10 arom. H), 6.89 (d, 1 arom. H, J=8.2 Hz), 6.79 (d, 1 arom. H, J=8.2 Hz), 4.95 (s, CH-5), 3.81 (s, CH3O).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][N:12]([CH3:17])[CH2:13][CH2:14][NH:15][CH3:16].CCN(C(C)C)C(C)C>CCO>[CH3:11][N:12]([CH3:17])[CH2:13][CH2:14][N:15]([CH3:16])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: CNCCN(C)C
Reactant: O=[N+]([O-])c1cnccc1Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCN(C)c1ccncc1[N+](=O)[O-]

Procedure:
The method of Example 1 was followed using 4-chloro-3-nitropyridine (1.0 eq), N1,N1,N2-trimethyl ethane-1,2-diamine (2.0 eq), and DIEA (2.0 eq) in EtOH yielding N1,N1,N2-trimethyl-N2-(3-nitropyridin-4-yl)ethane-1,2-diamine which was concentrated and taken on as is. LCMS (m/z): 225.1 (MH+); LC Rt=0.574 min.
Reaction SMILES: [C:1]([O:4][CH:5]1[O:27][C@@H:26]([CH2:28][O:29][C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@H:16]([O:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@H:6]1[O:7][C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:3])[CH3:2]>C(O)(C)C>[C:1]([O:4][C@H:5]1[O:27][C@@H:26]([CH2:28][O:29][C:30](=[O:37])[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C@H:16]([O:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@H:6]1[O:7][C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:3])[CH3:2].[OH:4][CH:5]1[O:27][C@@H:26]([CH2:28][OH:29])[C@H:16]([OH:17])[C@@H:6]1[OH:7]
Reactant: CC(=O)OC1O[C@@H](COC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Solvent: CC(C)O
Product: CC(=O)O[C@H]1O[C@@H](COC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Product: OC[C@@H]1OC(O)[C@@H](O)[C@H]1O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
59.40 g out of 62.69 g of the crude 2,3,5-tri-O-benzoyl-1-O-methyl-L-ribofuranose synthesized in (2) above was added to a 1-L flask. Thereafter, acetic anhydride (31.2 ml; 2.65 equivalents), acetic acid (26.7 ml; 3.73 equivalents), and pyridine (7.1 ml; 0.8 equivalents) were added to the flask. The obtained mixture was cooled to an ice-cooled temperature, and thereafter, concentrated sulfuric acid (13.5 ml; 2.03 equivalents) was slowly added dropwise thereto. After completion of the reaction for 30 minutes, cold water (200 ml) was slowly added dropwise to the reaction product, and crystals were then filtrated. The obtained solid was dried. Thus, 69.83 g of crude 1-O-acetyl-2,3,5-tri-O-benzoyl-L-ribofuranose was obtained in the form of a light yellow solid. The obtained compound was analyzed by HPLC. As a result, the ratio of α-/β-anomers in the 1-O-acetyl-2,3,5-tri-O-benzoyl-L-ribofuranose was 4/96, and the reaction yield of the β-anomer from the total 3 steps was 84%. 69.83 g of the crude 1-O-acetyl-2,3,5-tri-O-benzoyl-L-ribofuranose was suspended in isopropyl alcohol (92 ml), and the suspension was then heated to reflux for 1 hour. Thereafter, the reaction solution, in which the aforementioned compound had been completely dissolved, was cooled to an ice-cooled temperature, and it was then stirred for 30 minutes. Thereafter, the resultant mixture was filtrated, and the obtained crystals were then dried under reduced pressure. Thus, 1-O-acetyl-2,3,5-tri-O-benzoyl-β-L-ribofuranose was obtained from L-ribofuranose in the form of white crystals with a purity of 99% or more at a total yield of 75%.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH:11][C:12]3[CH:17]=[C:16](Cl)[N:15]=[C:14]([O:19][CH3:20])[N:13]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1.[C:21]([C:24]([C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1)([CH3:26])[CH3:25])([OH:23])=[O:22].C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH:11][C:12]3[N:13]=[C:14]([O:19][CH3:20])[N:15]=[C:16]([C:29]4[CH:28]=[C:27]([C:24]([CH3:26])([CH3:25])[C:21]([OH:23])=[O:22])[CH:32]=[CH:31][CH:30]=4)[CH:17]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: CC(C)(C(=O)O)c1cccc(B(O)O)c1
Reactant: COc1nc(Cl)cc(NCc2ccc3occc3c2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: COc1nc(NCc2ccc3occc3c2)cc(-c2cccc(C(C)(C)C(=O)O)c2)n1
Temperature: 90 °C
Reaction time: 6 h
Yield: 34.2 %

Procedure:
Argon is bubbled through a mixture of benzofuran-5-ylmethyl-(6-chloro-2-methyoxy-pyrimidin-4-yl)-amine (100 mg, 0.35 mmol), 3-(1-carboxy-1-methyl-ethyl)-phenyl boronic acid [131 mg, 0.63 mmol, see Example 49(b) step 2], Cs2CO3 (342 mg, 1.05 mmol), and tetrakis(triphenylphosphine)palladium (0) (46 mg, 0.04 mmol) in ethylene glycol dimethyl ether (1.7 mL) and water (0.3 mL), for a period of 10 minutes. The reaction vessel is sealed and heated to 90° C. After stirring for 6 hours the heating is turned off and the mixture is allowed to cool to ambient temperature upon standing for 24 hours. The mixture is diluted with water (20 mL) and extracted twice with EtOAc (30 μL). The organic extracts are combined and dried over magnesium sulfate, filtered and concentrated to afford 2-(3-{6-[(benzofuran-5-ylmethyl)-amino]-2-methyoxy-pyrimidin-4-yl}-phenyl)-2-methyl-propionic acid [50 mg, 34%, Example 93] as a solid. LCMS RT=2.05 minutes, MS: 418 (M+H).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Br:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[CH2:10][CH2:9]2>>[Br:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][C:14]=1[N+:1]([O-:4])=[O:2])[C:11](=[O:15])[CH2:10][CH2:9]2
Reactant: O=C1CCc2cc(Br)ccc21
Reactant: O=[N+]([O-])O
Product: O=C1CCc2cc(Br)c([N+](=O)[O-])cc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Fuming nitric acid (166 ml) is cooled to −15° C., and 5-bromoindan-1-one (25 g, 0.118 mol) is then added portionwise. After stirring for 4 hours 30 minutes at between −10° C. and −15° C., the reaction mass is poured into ice-cold water (1600 ml).
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:29]=[CH:28][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[C@H:18]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:17][CH2:16]3)=[C:6]([O:30][CH3:31])[CH:5]=1)=[S:3].[CH2:32](OC(OCC)CBr)[CH3:33]>CCO.O>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][C@H:18]1[C:19]2[C:15](=[CH:14][C:13]([O:12][CH2:11][CH2:10][CH2:9][O:8][C:7]3[CH:28]=[CH:29][C:4]([C:2]4[S:3][CH:32]=[CH:33][N:1]=4)=[CH:5][C:6]=3[O:30][CH3:31])=[CH:21][CH:20]=2)[CH2:16][CH2:17]1)[CH3:27]
Reactant: CCOC(CBr)OCC
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCOc3ccc(C(N)=S)cc3OC)ccc21
Solvent: CCO
Solvent: O
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCOc3ccc(-c4nccs4)cc3OC)ccc21
Temperature: 70 °C
Yield: 56.7 %

Procedure:
Ethyl ((1S)-5-{3-[4-(aminocarbonothioyl)-2-methoxyphenoxy]propoxy}-2,3-dihydro-1H-inden-1-yl)acetate (1.00 g, 2.3 mmol) (Example 146) and bromoacetaldehyde diethyl acetal (1.78 g, 9.2 mmol) were dissolved in EtOH (30 mL) and water (2 drops) was added. The mixture was heated at 70° C. for 18 h, and then the reaction mixture was cooled to rt, and concentrated under reduced pressure. Purification by silica gel flash chromatography (EtOAc:hexane (v/v)=1:1) gave 610 mg (58%) of the title compound as a clear oil. LC-MS: RT=3.81 min; (M+H)+ 468.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:13]2[C:21]3[C:16](=[C:17]([N:22]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[S:23]([CH3:26])(=[O:25])=[O:24])[CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14]2)([CH2:11][CH3:12])[C:9]#[CH:10])=[CH:4][CH:3]=1.[Li]CCCC.[C:40](Cl)(=[O:43])[O:41][CH3:42]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:13]2[C:21]3[C:16](=[C:17]([N:22]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[S:23]([CH3:26])(=[O:25])=[O:24])[CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14]2)([CH2:11][CH3:12])[C:9]#[C:10][C:40]([O:41][CH3:42])=[O:43])=[CH:4][CH:3]=1
Reactant: C#CC(CC)(c1ccc(Cl)cc1)n1ccc2c(N(COCC[Si](C)(C)C)S(C)(=O)=O)cccc21
Reactant: COC(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC(C#CC(=O)OC)(c1ccc(Cl)cc1)n1ccc2c(N(COCC[Si](C)(C)C)S(C)(=O)=O)cccc21
Reaction time: 0.5 h

Procedure:
To a solution of compound N-(1-(3-(4-chlorophenyl)pent-1-yn-3-yl)-1H-indol-4-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)methanesulfonamide (2.9 g, 5.6 mmol, enantiomer A), as described in Example 55 Step A, in dry THF (10 mL) was added BuLi (4.5 mL, 11.2 mmol, 2.5 M in hexane) at −78° C. After stirring for 30 min, methyl carbonchloridate (0.88 mL, 6.2 mmol) was added to the mixture at −78° C. The resulting mixture was stirred for another 2 h and then quenched with saturated NH4Cl (10 mL), extracted with ethyl acetate, washed with brine (50 mL), dried over sodium sulfate, then filtered. After removing the organic solvent, the residue was purified by column chromatography (EA/PE=1:10) to obtain the title compound. LC/MS m/z=597.0 [M+Na]+.
Reaction SMILES: C([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])(C)(C)C.Br[C:20]1[CH:21]=[C:22]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:23]=[N:24][CH:25]=1>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:5])=[O:18])=[C:10]([C:16]#[C:17][C:20]2[CH:25]=[N:24][CH:23]=[C:22]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:21]=2)[CH:11]=1
Reactant: CS(=O)(=O)c1cncc(Br)c1
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Product: CS(=O)(=O)c1cncc(C#Cc2cc(Cl)ccc2OCC(=O)O)c1

Procedure:
Following the general method as outlined in Example 35, starting from tert-butyl(4-chloro-2-ethynyl phenoxy)acetate (Intermediate 3) and 5-bromo-3-methylsulfonylpyridine (Combiblocks), the title compound was obtained as a white solid after purification by flash column chromatography (silica).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])=[CH:8][CH:7]=1.C(N(CC)CC)C.[C:28](Cl)(=[O:32])[C:29]([CH3:31])=[CH2:30]>ClCCl>[CH3:1][O:2][C:3]([CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:28](=[O:32])[C:29]([CH3:31])=[CH2:30])=[CH:8][CH:7]=1)=[O:20]
Reactant: COC(=O)C=Cc1ccc(OCCCCCCO)cc1
Reactant: C=C(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCCCCCCOc1ccc(C=CC(=O)OC)cc1
Temperature: 0 °C
Yield: 72.2 %

Procedure:
To an ice-cooled solution of 20 g (72 mmol) 3-[4-(6-hydroxy-hexyloxy)-phenyl]-acrylic acid methyl ester, 11.7 g (116 mmol) triethylamine and 4 crystals of BHT in 150 ml of dichloromethane was added dropwise 11.3 g (108 mmol) of methacryloyl chloride in 5 ml dichloromethane. The mixture was allowed to react for 2 hours, at which time the dichloromethane was removed under reduced pressure. The mixture was partitioned between water (100 ml) and ethyl acetate (100 ml) and the aqueous layer subsequently extracted twice more with 100 ml portions of ethyl acetate. The combined organic layers were washed with 100 ml portions of 1M HCl, water, 5% sodium hydrogen carbonate and brine and then dried with magnesium sulfate and concentrated. Recrystallization from ethanol gave 18 g (72% yield) of a white solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH:13]=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].Cl.[O:16]([NH2:18])[CH3:17].B.Cl>CO.N1C=CC=CC=1>[CH3:17][O:16][NH:18][CH2:13][CH2:12][CH2:11][C:8]1[CH:7]=[CH:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:10][CH:9]=1
Reactant: CC(=O)Nc1ccc(CCC=O)cc1
Reactant: CON
Agent: B
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: CONCCCc1ccc(NC(C)=O)cc1
Temperature: 70 °C

Procedure:
A mixture of 3-(4-acetamidophenyl)propanal (96 mg, 0.50 mmol), methoxylamine hydrochloride (92 mg, 1.1 mmol), and pyridine (110 μL) in methanol (0.7 mL) is heated in a 70° C. oil bath for 18 hours and then allowed to cool to room temperature. Methanol (1 mL) is added and the mixture is cooled to 0° C. in an ice-water bath. Borane.pyridine complex (0.11 mL, 1.1 mmol) is added, followed by the dropwise addition of 10% aqueous hydrochloric acid. The mixture is allowed to warm to room temperature and then concentrated under reduced pressure. The residue is purified by reverse-phase HPLC to give N-[4-(3-methoxyamino-propyl)-phenyl]-acetamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[C:18]([O:20][CH3:21])=[O:19])[C:5]([O:7]N1C(=O)CCC1=O)=O.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:29]=[C:30]([O:32][CH3:33])[CH:31]=1)[CH2:27][NH2:28].C(N(CC)CC)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:28][CH2:27][C:26]2[CH:29]=[C:30]([O:32][CH3:33])[CH:31]=[C:24]([O:23][CH3:22])[CH:25]=2)=[O:7])[CH:15]=[CH:16][C:17]=1[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)c1ccc(C(=O)ON2C(=O)CCC2=O)cc1Cl
Reactant: COc1cc(CN)cc(OC)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(=O)NCc2cc(OC)cc(OC)c2)cc1Cl
Yield: 72.6 %

Procedure:
A solution of 1-[[3-chloro-4-(methoxycarbonyl)benzoyl]oxy]-2,5-pyrrolidinedione (Example 5; 2.00 g, 6.4 mmol), 3,5-dimethoxybenzylamine (1.25 g, 7.5 mmol) and triethylamine (1.00 g, 9.9 mmol) in N,N-dimethylformamide (100 mL) was stirred at room temperature overnight. The solvent was evaporated (<0.5 mm Hg, 40° C.), ethyl acetate (200 mL) was added, and the solution was allowed to stand over the weekend at room temperature. The white solid was filtered off and discarded. Silica gel was added, the solvent was evaporated and the residue was chromatographed (30-50% ethyl acetate/hexanes) to give 2-chloro-4-[[[(3,5-dimethoxyphenyl) methyl]amino]carbonyl]benzoic acid, methyl ester (1.69 g, 72%) as a white solid, mp 101-103° C.
Reaction SMILES: [CH3:1][S:2]([CH:5]([CH2:16][CH2:17][CH2:18][CH:19]([O:25]C(=O)C)[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14]C)=[O:13])(=[O:4])=[O:3].CS(C(CC#CC1(OC(=O)C)CCCCC1)CCCCCCC(OC)=O)(=O)=O>>[CH3:1][S:2]([CH:5]([CH2:16][C:17]#[C:18][C:19]1([OH:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])(=[O:3])=[O:4]
Reactant: CCCCCC(CCCC(CCCCCCC(=O)OC)S(C)(=O)=O)OC(C)=O
Agent: COC(=O)CCCCCCC(CC#CC1(OC(C)=O)CCCCC1)S(C)(=O)=O
Product: CS(=O)(=O)C(CC#CC1(O)CCCCC1)CCCCCCC(=O)O

Procedure:
The synthesis of this compound is carried out by the procedure of Example 3, Step E, except that methyl 8-methylsulfonyl-12-acetoxyheptadecanoate is replaced by an equivalent quantity of methyl 8-methylsulfonyl-11-(1-acetoxycyclohexyl)-10-undecynoate.
Reaction SMILES: C([O:3][C:4](=[O:26])[C:5]([CH3:25])([O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[CH3:27][C:28]1[O:32][C:31]([C:33]2([CH3:39])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)=[N:30][C:29]=1[CH2:40][CH2:41]OS(C1C=CC(C)=CC=1)(=O)=O>>[CH3:25][C:5]([O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:17][CH:16]=1)([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:41][CH2:40][C:29]2[N:30]=[C:31]([C:33]3([CH3:39])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)[O:32][C:28]=2[CH3:27])=[CH:9][CH:8]=1)[C:4]([OH:3])=[O:26]
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(C(F)(F)F)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(C3(C)CCCCC3)oc2C)cc1
Product: Cc1oc(C2(C)CCCCC2)nc1CCOc1ccc(CC(C)(Oc2ccc(C(F)(F)F)cc2)C(=O)O)cc1

Procedure:
The title compound was prepared from 3-(4-hydroxyphenyl)-2-methyl-2-(4-trifluoromethyl-phenoxy)-propionic acid ethyl ester and toluene-4-sulfonic acid 2-[5-methyl-2-(1-methylcyclohexyl)oxazol-4-yl)-ethyl ester using the procedure of Example 50. 1H NMR (400 MHz, CDCl3) δ 7.49 (d, 2H, J=8.60 Hz), 7.15 (d, 2H, J=8.60 Hz), 6.94 (d, 2H, J=8.60 Hz), 6.78 (d, 2H, J=8.60 Hz), 4.13 (t, 2H, J=6.25 Hz), 3.25 (d, 1H, J=14.08 Hz), 3.15 (d, 1H, J=14.08 Hz), 2.99 (t, 2H, J=6.25 Hz), 2.33 (s, 3H), 2.14-2.06 (m, 2H), 1.61-1.41 (m, 8H), 1.49 (s, 3H), 1.30 (s, 3H); MS (ES+) calcd for C30H35NO5F3: Found m/e 546.3 (M+1, 100%).