Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=CC(S(O[N:12]=[C:13]2[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]2)(=O)=O)=CC=1.C(O)(=[O:26])C>>[O:26]=[C:13]1[NH:12][CH2:18][CH2:17][CH:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]1
Reactant: CCOC(=O)C1CCC(=NOS(=O)(=O)c2ccc(C)cc2)CC1
Reactant: CC(=O)O
Product: CCOC(=O)C1CCNC(=O)CC1

Procedure:
A solution of ethyl 4-({[(4-methylphenyl)sulfonyl]oxy}imino)cyclohexanecarboxylate (22.0 g) in acetic acid (150 mL) was stirred at room temperature for 1 hr, and the reaction mixture was concentrated under reduced pressure. Saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (8.62 g).
Reaction SMILES: Cl.[NH:2]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12]3[C:13]4[CH:20]=[C:19]([C:21]5[CH2:22][CH2:23][NH:24][CH2:25][CH:26]=5)[NH:18][C:14]=4[N:15]=[CH:16][N:17]=3)=[CH:8][CH:9]=2)[CH:4]=[N:3]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:60](O)(=[O:62])[CH3:61]>CN(C=O)C>[NH:2]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12]3[C:13]4[CH:20]=[C:19]([C:21]5[CH2:22][CH2:23][N:24]([C:60](=[O:62])[CH3:61])[CH2:25][CH:26]=5)[NH:18][C:14]=4[N:15]=[CH:16][N:17]=3)=[CH:8][CH:9]=2)[CH:4]=[N:3]1
Reactant: C1=C(c2cc3c(Nc4ccc5[nH]ncc5c4)ncnc3[nH]2)CCNC1
Reactant: CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CC=C(c2cc3c(Nc4ccc5[nH]ncc5c4)ncnc3[nH]2)CC1
Reaction time: 0.5 h

Procedure:
(1H-Indazol-5-yl)-[6-(1,2,3,6-tetrahydro-pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine hydrochloride (60 mg, 0.137 mmol), HATU (63 mg, 0.164 mmol) and Hunigs base (100 μL, 0.576 mmol) were combined in DMF (4 mL) and stirred for 30 min. Acetic acid (8 μL, 0.168 mmol) was added and the solution was stirred overnight. Another portion of acetic acid (8 μL, 0.168 mmol) was added and the stirred for a further 4 h. The DMF was removed in vacuo and the residue was loaded onto silica. Purification on silica by elution with dichloromethane:methanol (95:5) yielded the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=2.03 & 2.07 (2s, rotamers, 3H), 2.44 & 2.53 (2s, rotamers, 2H), 3.62-3.67 (m, 2H), 4.11 & 4.18 (2s, rotamers, 2H), 6.39 (s, 1H), 6.72 & 6.76 (2s, rotamers, 1H), 7.50 (d, J=8.8 Hz, 1H), 7.63 (d, J=8.8 Hz, 1H), 8.03 (s, 1H), 8.24 (s, 1H), 8.33 (brs, 1H), 9.35 (brs, 1H), 11.90 (brs, 1H). MS (ES+): m/z 374.5 (100) [MH+].
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]([C:10]1[CH:11]=[N:12][C:13]2[C:18]([C:19]=1[NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=1)=[CH:17][C:16]([S:29]([C:32]1[CH:33]=[C:34]([CH:39]=[CH:40][CH:41]=1)[C:35](OC)=[O:36])(=[O:31])=[O:30])=[CH:15][C:14]=2[CH3:42])(=[O:9])[NH2:8].O.[OH-].[Na+]>C1COCC1>[OH:36][CH2:35][C:34]1[CH:33]=[C:32]([S:29]([C:16]2[CH:17]=[C:18]3[C:13](=[C:14]([CH3:42])[CH:15]=2)[N:12]=[CH:11][C:10]([C:7]([NH2:8])=[O:9])=[C:19]3[NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=2)(=[O:31])=[O:30])[CH:41]=[CH:40][CH:39]=1
Reactant: COC(=O)c1cccc(S(=O)(=O)c2cc(C)c3ncc(C(N)=O)c(Nc4cccc(OC)c4)c3c2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(CO)c4)cc23)c1
Reaction time: 0.33 h
Yield: 69.8 %

Procedure:
LAH (158 mg, 3.96 mmol) was added to a stirring solution of methyl 3-[[3-carbamoyl-4-[(3-methoxyphenyl)amino]-8-methylquinolin-6-yl]sulfonyl]benzoate (500 mg, 0.99 mmol) in THF (10 mL) at 0° C. After stirring for 20 min, H2O (0.158 mL), 15% (w/v) NaOH (0.158 mL), and H2O (0.474 mL) were added sequentially. The resulting suspension was stirred for 1 h then the precipitate was filtered, washed with water (20 mL), and dried to give the title compound (330 mg) as a yellow solid. The compound was used with no further purification. ES/MS calcd. for C25H24N3O5S+ 478.1. Found m/z=478.1 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][C:5]1([CH2:32][C:33](=[O:36])[O:34]C)[O:9][N:8]=[C:7]([C:10]2[CH:15]=[C:14]([OH:16])[CH:13]=[CH:12][C:11]=2[CH2:17][CH2:18][C:19]([N:21]2[CH2:26][CH2:25][CH:24]([C:27]([O:29]CC)=[O:28])[CH2:23][CH2:22]2)=[O:20])[CH2:6]1.C1COCC1.[OH-].[Na+].Cl>CO>[C:33]([CH2:32][C:5]1([CH2:4][C:3]([OH:37])=[O:2])[O:9][N:8]=[C:7]([C:10]2[CH:15]=[C:14]([OH:16])[CH:13]=[CH:12][C:11]=2[CH2:17][CH2:18][C:19]([N:21]2[CH2:22][CH2:23][CH:24]([C:27]([OH:29])=[O:28])[CH2:25][CH2:26]2)=[O:20])[CH2:6]1)([OH:36])=[O:34]
Reactant: CCOC(=O)C1CCN(C(=O)CCc2ccc(O)cc2C2=NOC(CC(=O)OC)(CC(=O)OC)C2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CC1(CC(=O)O)CC(c2cc(O)ccc2CCC(=O)N2CCC(C(=O)O)CC2)=NO1
Yield: 98 %

Procedure:
A mixture of ethyl 1-(3-(2-(5,5-bis(2-methoxy-2-oxoethyl)-4,5-dihydro-1,2-oxazol-3-yl)-4-hydroxyphenyl)propanoyl)piperidine-4-carboxylate (760 mg), THF (8 mL), methanol (8 mL), and a 1 M aqueous sodium hydroxide solution (8 mL) was stirred at room temperature for 2 hours. The reaction mixture was rendered acidic using 6 M hydrochloric acid at 0 C, followed by extraction with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure to obtain the title compound (664 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]([OH:11])[CH2:7][S:8][C:9]=1[CH3:10])=[O:4].S(Cl)(Cl)(=O)=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:11])=[CH:7][S:8][C:9]=1[CH3:10])=[O:4]
Reactant: COC(=O)C1=C(C)SCC1O
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1c(O)csc1C
Yield: 75 %

Procedure:
17.4 parts of 3-hydroxy-5-methyl-dihydrothiophene-4-carboxylic acid methyl ester are dissolved in 100 parts by volume of methylene chloride. 14.9 parts of sulfuryl chloride in 20 parts by volume of methylene chloride are added in the course of 30 minutes at 10° C., whilst passing nitrogen into the mixture. The end product is isolated from the reaction mixture by the method described in Example 1c. 12.9 parts (75% of theory) of 3-hydroxy-5-methyl-thiophene-4-carboxylic acid methyl ester of boiling point 67°-70° C./0.025 mbar are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5](C(C)C)=[C:6]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:13][C:11]=3[N:12]=2)[CH:7]=1.[CH:26]1[C:31]([C:32]([OH:34])=[O:33])=[CH:30][C:29]2[C:35]([O:37][C:38](=[O:39])[C:28]=2[CH:27]=1)=O>>[CH:10]([O:9][C:5]1[CH:4]=[CH:3][C:2]([N:1]2[C:35](=[O:37])[C:29]3[C:28](=[CH:27][CH:26]=[C:31]([C:32]([OH:34])=[O:33])[CH:30]=3)[C:38]2=[O:39])=[CH:7][C:6]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:13][C:11]=2[N:12]=1)([CH3:16])[CH3:11]
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Reactant: CC(C)c1ccc(N)cc1-c1nc2cc(-c3ccccc3)ccc2o1
Product: CC(C)Oc1ccc(N2C(=O)c3ccc(C(=O)O)cc3C2=O)cc1-c1nc2cc(-c3ccccc3)ccc2o1

Procedure:
Prepared by the method of Example 1b), from 2-(5-amino-2-isopropylphenyl)-5-phenylbenzoxazole (188 mg, 0.55 mmol) and 1,2,4-benzenetricarboxylic anhydride (106 mg, 0.55 mmol) the title compound was obtained (102 mg, 36%). 1H NMR (DMSO) δ 8.42(dd, 1H), 8.32(s, 1H), 8.18(d, 1H), 8.09(m, 2H), 7.85(d, 1H), 7.71(m, 3H), 7.50(m, 3H), 7.39(t, 1H), 4.87(m, 1H), 1.41(d, 6H). MS 519 m/z (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH2:5][C:4]2([CH2:10][C@@H:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:8]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:7]2)[O:3]1.[Cl:25][C:26]1[CH:27]=[C:28](Br)[CH:29]=[CH:30][CH:31]=1>>[Cl:25][C:26]1[CH:31]=[C:30]([N:6]2[CH2:5][C@@:4]3([CH2:10][C@@H:9]([C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[N:8]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:7]3)[O:3][C:2]2=[O:1])[CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1CC2(CNC(=O)O2)CN1C(=O)OC(C)(C)C
Reactant: Clc1cccc(Br)c1
Product: CC(C)(C)OC(=O)[C@@H]1C[C@@]2(CN(c3cccc(Cl)c3)C(=O)O2)CN1C(=O)OC(C)(C)C
Yield: 19.3 %

Procedure:
Following the procedure from Example 1 step C using (8S)-di-tert-butyl 2-oxo-1-oxa-3,7-diazaspiro[4.4]nonane-7,8-dicarboxylate (B2) (189 mg, 0.55 mmol, 1 eq.) and 3-chloro bromobenzene (60 μl, 0.55 mmol, 1 eq.) gave 48 mg (0.106 mmol) of (5S,8S)-di-tert-butyl 3-(3-chlorophenyl)-2-oxo-1-oxa-3,7-diazaspiro[4.4]nonane-7,8-dicarboxylate (A5). 1H NMR (300 MHz, DMSO) 7.68 (m, 1H), 7.55-7.38 (m, 2H), 7.2 (m, 1H), 4.23-4.05 (m, 3H), 3.8-3.7 (m, 1H), 3.5 (m, 1H), 2.7-2.6 (m, 1H), 2.25-2.1 (m, 1H), 1.4 (m, 18H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18](OS(C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)(=O)=O)[CH:17]=[CH:16][C:15]=2[CH:37]2[CH2:42][C:41]([CH3:44])([CH3:43])[CH2:40][C:39]([CH3:46])([CH3:45])[CH2:38]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:52]([O:54]CC)=[CH2:53])CCC.[Cl-].[Li+].C(=O)([O-])O.[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C.CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[C:18]([C:52](=[O:54])[CH3:53])[CH:17]=[CH:16][C:15]=2[CH:37]2[CH2:38][C:39]([CH3:46])([CH3:45])[CH2:40][C:41]([CH3:43])([CH3:44])[CH2:42]2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC1(C)CC(c2ccc(OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2N2CCN(C(=O)OC(C)(C)C)CC2)CC(C)(C)C1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc(C2CC(C)(C)CC(C)(C)C2)c(N2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 96.4 %

Procedure:
A mixture of 4-[5-(nonafluorobutane-1-sulfonyloxy)-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine-1-carboxylic acid t-butyl ester (267 mg, 0.382 mmol) produced in Example (81c), tributyl(1-ethoxyvinyl)tin (0.16 mL, 0.458 mmol), dichlorobis(triphenylphosphine)palladium(II) (41 mg, 0.0573 mmol), lithium chloride (48.6 mg, 1.15 mmol) and dimethylformamide (3 mL) was stirred for 6 hours and 10 minutes at an external temperature of 90° C. under a nitrogen atmosphere. Saturated aqueous solution of sodium hydrogencarbonate and ethyl acetate were then added to the reaction mixture. The mixture was filtered through Celite, and the resultant filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 163 mg of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])[CH:3]=1.[Cl:20]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Cl:20][CH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])[CH:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1cc(C)nc(N2C(=O)c3ccccc3C2=O)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(CCl)cc(N2C(=O)c3ccccc3C2=O)n1
Temperature: 25 °C
Yield: 17.2 %

Procedure:
A mixture of (29) (2.52 g, 10 mmol)), N-chlorosuccinimide (1.6 g, 12 mmol), and benzoyl peroxide (1.21 g, 5 mmol) in carbon tetrachloride (50 ml) was refluxed for 2 hr. After cooling to room temperature, the mixture was filtered and the filtrate was evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent, dichloromethane:EA (95:5)) to afford 493 mg (17%) of a yellow solid; 1H NMR (200 MHz, CDCl3) δ 2.63 (3H, s), 4.48 (2H, s), 7.27 (1H, s), 7.28 (1H, s), 7.76-7.98 (4H, m); m/z (EI) 286 (M+).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C:23]([OH:25])=[O:24])=[C:5]([C:7]2[C:17]3[CH:18]=[CH:19][C:20]([OH:22])=[CH:21][C:16]=3[O:15][C:14]3[C:8]=2[CH:9]=[CH:10][C:11]([CH:13]=3)=[O:12])[CH:6]=1.[OH-].[Na+]>[Zn]>[CH:1]1[CH:2]=[CH:3][C:4]([C:23]([OH:25])=[O:24])=[C:5]([CH:7]2[C:17]3[CH:18]=[CH:19][C:20]([OH:22])=[CH:21][C:16]=3[O:15][C:14]3[CH:13]=[C:11]([OH:12])[CH:10]=[CH:9][C:8]2=3)[CH:6]=1
Reactant: O=C(O)c1ccccc1-c1c2ccc(=O)cc-2oc2cc(O)ccc12
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Product: O=C(O)c1ccccc1C1c2ccc(O)cc2Oc2cc(O)ccc21

Procedure:
According to another aspect of the invention, there is provided a method of producing an aqueous fluorescin solution, in which about 1 g of fluorescein is mixed with about 100 ml of a 10% sodium hydroxide aqueous solution and heated in the presence of about 10 g of zinc to produce a colorless fluorescin solution, wherein the improvement of the method includes heating the mixture of fluorescein and 10% sodium hydroxide aqueous solution with about 20 mesh zinc particles to about boiling in a non-refluxing container to produce a nearly colorless fluorescin solution containing zinc particles, and decanting the colorless fluorescin solution from the zinc particles.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12](OS(C(F)(F)F)(=O)=O)[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].[CH3:24][O:25][CH2:26][C:27]#[CH:28].C(N(CC)CC)C.C(OCC)(=O)C.CCCCCC>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([C:28]#[C:27][CH2:26][O:25][CH3:24])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc2cccc(OS(=O)(=O)C(F)(F)F)c2c1C
Reactant: C#CCOC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: CCOC(=O)c1oc2cccc(C#CCOC)c2c1C
Temperature: 90 °C
Yield: 53 %

Procedure:
To the product of Example 20, Step 1, 3-methyl-4-trifluoromethanesulfonyloxy-benzofuran-2-carboxylic acid ethyl ester (860 mg, 2.4 mmol, 1 eq), in 7 mL of DMF under nitrogen was added 98 mg of PdCl2(PPh3)2 (0.14 mmol, 0.06 eq), 0.42 mL of 3-methoxy-propyne (5.0 mmol, 2.1 eq) and 1.36 mL of triethylamine (9.7 mmol, 4.0 eq). The reaction mixture was heated to 90° C. for 18 h. After work up and column chromatography (4% ethyl acetate/hexane), 4-(3-methoxy-prop-1-ynyl)-3-methyl-benzofuran-2-carboxylic acid ethyl ester was obtained in 53% yield (343 mg). 1H NMR (400 MHz, CDCl3) δ ppm 1.4 (t, J=7.2 Hz, 3 H) 2.8 (t, 3 H) 3.5 (s, 3 H) 4.4 (s, 2 H) 4.5 (q, J=7.2 Hz, 2 H) 7.4 (m, 2 H) 7.5 (dd, J=7.7, 1.6 Hz, 1 H)
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Si:13]([CH3:16])([CH3:15])[CH3:14])[C:3]=1[C:4]([NH:6][CH2:7][CH3:8])=[O:5].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl[CH2:28][S:29][CH3:30]>C1COCC1>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Si:13]([CH3:15])([CH3:14])[CH3:16])[C:3]=1[C:4]([N:6]([CH2:7][CH3:8])[CH2:28][S:29][CH3:30])=[O:5]
Reactant: CSCCl
Reactant: CCNC(=O)c1c(Cl)cccc1[Si](C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(CSC)C(=O)c1c(Cl)cccc1[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 44.6 %

Procedure:
To a solution of 2.0 g (7.8 mmol) of the compound of Example 45 in 30 mL dry THF was added 7.9 mL (7.9 mmol) sodium bis(trimethylsilyl)amide (1.0M in THF). To the resulting mixture was added 1.0 g (10.4 mmol) chloromethyl methylsulfide. The mixture was stirred for 15 min and another 0.65 g (6.7 mmol) of chloromethyl methylsulfide was added. Stirring at RT was continued for 1 h and the mixture was then heated to reflux for 28 hours. The mixture was allowed to cool to RT and was then partitioned between ether and water. The organic layer was washed with brine, dried (MgSO4), and was filtered through silica gel. The filtrate was evaporated in vacuo and the residue was chromatographed (HPLC, 8% ethyl acetate/hexane) to yield 1.1 g (45%) of a colorless oil. nD25 =1.5526.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][NH:21][C:20](=[S:23])[C@H:19]([NH:24]C(=O)OC(C)(C)C)[CH2:18][CH2:17]1>ClCCl>[NH2:24][C@@H:19]1[CH2:18][CH2:17][C@@H:16]([C:10]2[CH:11]=[CH:12][CH:13]=[C:14]([F:15])[C:9]=2[F:8])[CH2:22][NH:21][C:20]1=[S:23]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)CNC1=S
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H]1CC[C@@H](c2cccc(F)c2F)CNC1=S
Reaction time: 1 h
Yield: 99885.4 %

Procedure:
Trifluoroacetic acid (5 mL, 49.6 mmol) was added to a solution of tert-butyl (3R,6S)-6-(2,3-difluorophenyl)-2-thioxoazepan-3-ylcarbamate (680 mg, 1.91 mmol) in dichloromethane (10 mL). After 1 h, the reaction was concentrated. Saturated aqueous sodium bicarbonate was added and the mixture was extracted with dichloromethane (3×). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated to give the title compound (489 g). MS 257.0 (M+1).
Reaction SMILES: [OH-].[Na+].C(O)(=O)C.[O:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[O:13][C@@H:14]([CH3:20])[C:15]([O:17]CC)=[O:16]>C(O)C>[O:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[O:13][C@@H:14]([CH3:20])[C:15]([OH:17])=[O:16]
Reactant: CCOC(=O)[C@H](C)OC1CCCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: C[C@H](OC1CCCCO1)C(=O)O

Procedure:
In ethanol (450 ml) was dissolved ethyl(2S)-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propionate, to which was added, under ice-cooling, 2N sodium hydroxide solution (150 ml), and the mixture was stirred for one hour at room temperature. The reaction mixture was cooled with ice, to which was added a 27° C. aqueous solution of acetic acid (100 ml), followed by extraction with dichloromethane (200 ml) three times. Dichloromethane layers were combined and washed with a saturated aqueous saline solution (100 ml) twice, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to leave (2S)-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propionic acid (29.5 g) as a colorless waxy product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH2:27][C@@H:28]([CH3:33])[C:29]([O:31]C)=[O:30])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+].Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH2:27][C@@H:28]([CH3:33])[C:29]([OH:31])=[O:30])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: COC(=O)[C@H](C)Cc1cn(C)c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(C[C@@H](C)C(=O)O)cn(C)c34)no2)cc1Cl
Temperature: 50 °C
Reaction time: 16 h
Yield: 64.4 %

Procedure:
To a solution of methyl (2R)-3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]-2-methylpropanoate (D60) (80 mg) in THF (5 mL) was added aqueous NaOH (2 M, 1 mL). The reaction was stirred at 50° C. for 16 h. The mixture was acidified with aqueous HCl (2 M) to pH 4-5, partitioned between ethyl acetate (50 mL) and water (50 mL). The organic phase was washed with water (25 mL) and brine (25 mL), dried over anhydrous sodium sulphate and evaporated to give the crude product, which was purified by Mass Directed Auto Prep to afford (2R)-3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]-2-methylpropanoic acid (E36) (50 mg). δH (DMSO-d6, 400 MHz): 1.11 (3H, d), 1.35 (6H, d), 2.75 (2H, m), 3.04 (1H, m), 3.62 (3H, s), 4.88 (1H, m), 7.17 (2H, m), 7.43 (2H, m), 7.79 (1H, d), 8.13 (1H, dd), 8.20 (1H, d), 12.13 (1H, br s). MS (ES): C24H24ClN3O4 requires 453; found 454.2 (M+H+).
Reaction SMILES: [C:1]([O:24][CH:25]1[CH2:30][C:29]([CH3:32])([CH3:31])[NH:28][C:27]([CH3:34])([CH3:33])[CH2:26]1)(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH:13]1[CH2:18][C:17]([CH3:20])([CH3:19])[NH:16][C:15]([CH3:22])([CH3:21])[CH2:14]1)=[O:11].[C:35]([O:39]O)([CH3:38])(C)C>[Mo](=O)(=O)=O.CCCCCCC>[C:1]([O:24][CH:25]1[CH2:30][C:29]([CH3:32])([CH3:31])[N:28]([O:39][CH2:35][CH2:38][CH2:17][CH2:18][CH2:13][CH2:14][CH3:15])[C:27]([CH3:34])([CH3:33])[CH2:26]1)(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH:13]1[CH2:18][C:17]([CH3:19])([CH3:20])[N:16]([O:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH3:4])[C:15]([CH3:21])([CH3:22])[CH2:14]1)=[O:11]
Reactant: CC1(C)CC(OC(=O)CCCCCCCCC(=O)OC2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1
Reactant: CC(C)(C)OO
Agent: O=[Mo](=O)=O
Solvent: CCCCCCC
Product: CCCCCCCON1C(C)(C)CC(OC(=O)CCCCCCCCC(=O)OC2CC(C)(C)N(OCCCCCCC)C(C)(C)C2)CC1(C)C
Temperature: 140 °C
Reaction time: 7 h
Yield: 72 %

Procedure:
A mixture of 35.0 g (72.8 mmol) of di-(2,2,6,6-tetramethylpiperidin-4-yl) sebacate, 58.3 (582 mmol) of 90% aqueous t-butyl hydroperoxide, 2.0 g of molybdenum trioxide, and 250 ml of heptane is heated at 140° C. in a Fischer-Porter bottle. The pressure is maintained at 40-50 psi by occasional venting. Heating is discontinued after 7 hours. An additional portion (20.0 g) of 90% t-butyl hydroperoxide is added and the reaction mixture is heated for one hour at 140° C. The reaction is nearly colorless by this time. The reaction mixture is cooled and filtered to remove the catalyst. The organic phase is separated, dried over magnesium sulfate, and concentrated to 100 ml total volume. This solution is passed through silica gel with heptane as the eluent. The filtrate is evaporated to yield 36.9 g (72% yield) of the title compound, a nearly colorless oil.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[CH:21]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[CH2:20][CH2:19]3)=[C:13]([NH2:15])[CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:34]1[CH:48]=[CH:47][C:37]([O:38][CH2:39][CH2:40][N:41]2[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]2)=[CH:36][CH:35]=1>>[Si:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[CH:21]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:27])[CH3:28])[CH2:20][CH2:19]3)=[C:13]([NH:15][C:34]2[CH:35]=[CH:36][C:37]([O:38][CH2:39][CH2:40][N:41]3[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46]3)=[CH:47][CH:48]=2)[CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2ccc3c(c2)CCC3O[Si](C)(C)C(C)(C)C)c(N)c1
Reactant: Brc1ccc(OCCN2CCCCC2)cc1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(-c2ccc3c(c2)CCC3O[Si](C)(C)C(C)(C)C)c(Nc2ccc(OCCN3CCCCC3)cc2)c1
Yield: 65.2 %

Procedure:
Synthesized from 5-(tert-butyldimethylsilyloxy)-2-[1-(tert-butyldimethylsilyloxy)indan-5-yl]phenylamine (635 mg) and 1-[2-(4-bromophenoxy)ethyl]piperidine (385 mg) according to an analogous synthetic method to Example 116, the title compound (593 mg) was obtained.
Reaction SMILES: Cl.O[CH:3]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH2:21][C:22]#[C:23][Si](C)(C)C)[CH2:4][C:5](=[N:12][OH:13])[C:6](OC)([O:8]C)[CH3:7].C(=O)([O-])O.[Na+]>>[CH2:21]([O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH:3]1[O:13][N:12]=[C:5]([C:6](=[O:8])[CH3:7])[CH2:4]1)[C:22]#[CH:23]
Reactant: COC(C)(OC)C(CC(O)c1ccccc1OCC#C[Si](C)(C)C)=NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: C#CCOc1ccccc1C1CC(C(C)=O)=NO1
Reaction time: 0.25 h

Procedure:
A solution of hydrochloric acid (4M in dioxane, 3.80 ml) was added to 1-hydroxyl-4,4-dimethoxy-1-(2-{[3-(trimethylsilyl)prop-2-yn-1-yl]oxy}phenyl)pentan-3-one oxime. After stirring for a further 15 minutes, concentrated sodium hydrogencarbonate solution was added to the reaction mixture, and the aqueous phase was removed and extracted with dichloromethane. The combined organic phases were dried over magnesium sulphate and concentrated. This gave 1-[5-(2-{[prop-2-yn-1-yl]oxy}phenyl)-4,5-dihydro-1,2-oxazol-3-yl]ethanone (315 mg, 99%).