Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3](=[O:23])[CH2:4][C:5]([CH3:22])([C:7]1[C:15]2[O:14][CH2:13][CH2:12][C:11]=2[CH:10]=[C:9]([C:16]2[CH:17]=[N:18][CH:19]=[N:20][CH:21]=2)[CH:8]=1)[CH3:6].[CH3:26][S+](C)(C)=O.[H-].[Na+].[I-].C[S+](C)(C)=O>CS(C)=O.C1COCC1.CS(C)=O.O>[CH3:6][C:5]([C:7]1[C:15]2[O:14][CH2:13][CH2:12][C:11]=2[CH:10]=[C:9]([C:16]2[CH:21]=[N:20][CH:19]=[N:18][CH:17]=2)[CH:8]=1)([CH3:22])[CH2:4][C:3]1([C:2]([F:24])([F:1])[F:25])[CH2:26][O:23]1
Reactant: CC(C)(CC(=O)C(F)(F)F)c1cc(-c2cncnc2)cc2c1OCC2
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(CC1(C(F)(F)F)CO1)c1cc(-c2cncnc2)cc2c1OCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a solution of 1,1,1-trifluoro-4-methyl-4-(5-pyrimidin-5-yl-2,3-dihydrobenzofuran-7-yl)pentan-2-one (620 mg, 1.8 mmol) in 5 mL of anhydrous DMSO-THF (1:1) was added 2.64 mL of a trimethylsulfoxonium ylide solution (stock solution prepared by reaction of NaH (242 mg, 60% dispersion in mineral oil) with trimethylsulfoxonium iodide (1.33 g, 6.0 mmol) in 7.50 mL of anhydrous DMSO for 30 minutes) dropwise over 5 minutes. After stirring for 2 hour at room temperature, the reaction mixture was poured into 40 mL of water and extracted with diethyl ether (200 mL total volume). The combined organic phases were washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 651 mg (99% yield) of the title compound as a pale yellow oil which was used without further purification.
Reaction SMILES: [BH4-].[Na+].[CH2:3]1[CH2:41][O:40][C:5]2([CH2:14][CH2:13][C:12]3[N:11]=[C:10]([CH2:15][CH2:16][CH2:17][CH2:18][N:19]4[CH2:24][CH2:23][N:22]([C:25]5[CH:34]=[CH:33][C:32]6[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=6)[N:26]=5)[CH2:21][CH2:20]4)[N:9]([N:35]=[C:36]([CH3:38])[CH3:37])[C:8](=[O:39])[C:7]=3[CH2:6]2)[O:4]1>CO>[CH2:41]1[CH2:3][O:4][C:5]2([CH2:14][CH2:13][C:12]3[N:11]=[C:10]([CH2:15][CH2:16][CH2:17][CH2:18][N:19]4[CH2:24][CH2:23][N:22]([C:25]5[CH:34]=[CH:33][C:32]6[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=6)[N:26]=5)[CH2:21][CH2:20]4)[N:9]([NH:35][CH:36]([CH3:37])[CH3:38])[C:8](=[O:39])[C:7]=3[CH2:6]2)[O:40]1
Reactant: CC(C)=Nn1c(CCCCN2CCN(c3ccc4ccccc4n3)CC2)nc2c(c1=O)CC1(CC2)OCCO1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)Nn1c(CCCCN2CCN(c3ccc4ccccc4n3)CC2)nc2c(c1=O)CC1(CC2)OCCO1
Temperature: 25 °C
Yield: 61.1 %

Procedure:
To 10 ml of methanol, 300 mg of sodium borohydride was added and into this mixture, a solution of 145 mg of 6,6-ethylenedioxy-3-isopropylideneamino-2-[4-(4-quinolin-2-ylpiperazin-1-yl)butyl]-5,6,7,8-tetrahydro-3H-quinazolin-4-one as synthesized in Example 4-67 in 10 ml of methanol was dropped under cooling with ice. Raising the temperature to room temperature, the reaction mixture was stirred for an hour. Distilling the system under reduced pressure, water was added to the distillation residue, extracted with methylene chloride, washed with water, dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified on silica gel column chromatography (methanol:methylene chloride=2:23) to provide 89 mg (61%) of 6,6-ethylenedioxy-3-isopropylamino-2-[4-(4-quinolin-2-ylpiperazin-1-yl)butyl]-5,6,7,8-tetrahydro-3H-quinazolin-4-one.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][N:8]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16]Br)=[CH:12][CH:11]=1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([OH:33])[CH:30]=[CH:31][CH:32]=1>>[CH:19]1([N:8]([CH3:7])[C:9](=[O:18])[C:10]2[CH:15]=[CH:14][C:13]([CH2:16][O:33][C:29]3[CH:30]=[CH:31][CH:32]=[C:27]([O:26][CH3:25])[CH:28]=3)=[CH:12][CH:11]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CN(C(=O)c1ccc(CBr)cc1)C1CCCCC1
Reactant: COc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cccc(OCc2ccc(C(=O)N(C)C3CCCCC3)cc2)c1

Procedure:
The reaction and workup were carried out in the same manner as for Example 21 using K2CO3 (674 mg, 4.88 mmol), 4-bromomethylbenzoic acid N-methyl-N-cyclohexyl amide (629 mg, 2.03 mmol) and 3-methoxyphenol (251 mg, 2.02 mmol). The crude product was chromatographed on silica gel using mixtures of ethyl acetate and hexane as eluents to give the title compound as a crystalline solid that could be recrystallized from ethyl acetate and hexane, m. pt. 90.38° C. (DSC).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C1([C:19]2=[CH:20][C:21]([O:23][C:24]2=[O:25])=[O:22])C2C(=CC=CC=2)C=C1>CCCCCC>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:21]1(=[O:22])[O:23][C:24](=[O:25])[CH:19]=[CH:20]1
Reactant: O=C1C=C(C2C=Cc3ccccc32)C(=O)O1
Agent: C1=Cc2ccccc2C1
Solvent: CCCCCC
Product: O=C1C=CC(=O)O1
Reaction time: 1 h

Procedure:
Under agitation with the stirrer, the charge was held at the reflux temperature by heating with an external heater. Thereafter, a solution containing 27 g (0.25 mol) of indene and 410 mg of azoisobutyronitrile (AIBN) as a radical polymerization initiator was charged into the overhead dropping funnel and this solution was dripped slowly into the polymerizer over 1 h. After completion of the dripping, the reaction solution was left under reflux for 2 h until the reaction was completed. The reaction solution was thereafter returned to room temperature and gradually added to 200 ml of n-hexane in a precipitating tank (beaker with an inner capacity of 500 ml), whereupon a white precipitate of indenemaleic anhydride copolymer formed. The precipitate was separated by filtration under suction and vacuum-dried to obtain a copolymer of indene and maleic anhydride in a yield of 95 wt% as calculated from equation (1) given hereinabove.
Reaction SMILES: CC(C)=O.[CH2:5]([O:7][C:8](=[O:34])[C@@H:9]1[CH2:13][C@@H:12]([OH:14])[CH2:11][N:10]1[C:15]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:6].C(N(CC)CC)C.O>C(Cl)Cl>[CH2:5]([O:7][C:8](=[O:34])[C@@H:9]1[CH2:13][C:12](=[O:14])[CH2:11][N:10]1[C:15]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:6]
Reactant: CCOC(=O)[C@@H]1C[C@@H](O)CN1C(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)[C@@H]1CC(=O)CN1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.25 h
Yield: 61.3 %

Procedure:
To a 100 mL round bottom flask containing 20 mL CH2Cl2 was added 0.54 mL (6.20 mmol; 1.2 eq) of COCl2 in 2 mL CH2Cl2. The flask was then chilled to −60° C. (acetone bath and cold finger) under argon balloon. To this was added 0.88 mL dry (molecular civ treated) DMSO in 1 mL dry (MgSO4 treated) CH2Cl2 drop wise. The mixture was allowed to stir for 15 min. before being brought up to −30° C. where 2.02 g (6.17 mmol) of N-trityl-trans-4-hydroxy-L-proline ethyl ester in 4 mL CH2Cl2 was added dropwise over 10 min. The resulting solution was allowed to stir for 1 h at −30° C. under argon balloon. To complete the reaction, 3.6 mL (>5 eq) of triethylamine was slowly added. The flask was then allowed to warm to room temperature where 100 mL of water was added. The mixture was then extracted with Et2O (3×100 mL). The organic extracts were combined, dried with Na2SO4 and concentrated via rotovap to a solid crude. The remaining crude was then immediately separated by silica gel (90% hexanes, 9% ethylacetate, 1% TEA, Rf=0.2). The fractions containing the product were combined, concentrated, and placed on a high vacuum pump leaving 1.51 g of N-trityl-4-keto-L-proline ethyl ester, as a white foam, a yield of 75%. This product, once isolated, was then used within 4-6 h in the addition step (trityl group readily decomposes) without further purification.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](Cl)=[O:8])[CH2:2][CH3:3].[NH2:14][C:15]1[C:16]([C:21]([NH2:23])=[O:22])=[N:17][CH:18]=[CH:19][CH:20]=1.C(N(CC)CC)C>C(#N)C>[CH2:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([NH:14][C:15]1[C:16]([C:21]([NH2:23])=[O:22])=[N:17][CH:18]=[CH:19][CH:20]=1)=[O:8])[CH2:2][CH3:3]
Reactant: CCCOc1ccccc1C(=O)Cl
Reactant: NC(=O)c1ncccc1N
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCOc1ccccc1C(=O)Nc1cccnc1C(N)=O

Procedure:
In a similar manner to Example 68 a) reaction of 2-propoxybenzoyl chloride (0.99 g), 3-aminopicolinamide (0.69 g) and triethylamine (0.51 g) in acetonitrile (15 ml) afforded a crude product which was recrystallized from methanol to afford 3-(2-propoxybenzamido) picolinamide, 0.91 g, m.p. 116-118° C.
Reaction SMILES: Cl.[C:2]1([C:8]([C:10]2[CH:11]=[N:12][C:13]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[N:14][CH:15]=2)=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:23]1[N:28]=[CH:27][N:26]=[C:25]([NH:29][C:30]2[CH:31]=[N:32][N:33]([CH2:35][C@H:36]3[O:41][CH2:40][CH2:39][N:38]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:37]3)[CH:34]=2)[N:24]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[C:8]([C:10]1[CH:15]=[N:14][C:13]([N:16]2[CH2:21][CH2:20][N:19]([C:23]3[N:28]=[CH:27][N:26]=[C:25]([NH:29][C:30]4[CH:31]=[N:32][N:33]([CH2:35][C@H:36]5[O:41][CH2:40][CH2:39][N:38]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:37]5)[CH:34]=4)[N:24]=3)[CH2:18][CH2:17]2)=[N:12][CH:11]=1)(=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)c1cnc(N2CCNCC2)nc1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cn2cc(Nc3ncnc(Cl)n3)cn2)C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCO[C@H](Cn2cc(Nc3ncnc(N4CCN(c5ncc(C(=O)c6ccccc6)cn5)CC4)n3)cn2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.4 %

Procedure:
To a mixture of phenyl(2-(piperazin-1-yl)pyrimidin-5-yl)methanone HCl salt (141.6 mg, 0.38 mmol) and (S)-tert-butyl 2-((4-(4-chloro-1,3,5-triazin-2-ylamino)-1H-pyrazol-1-yl)methyl)morpholine-4-carboxylate (150 mg, 0.38 mmol) in dioxane (10 mL) was added diisopropylethylamine (1 mL), and the reaction was stirred at room temperature overnight. LCMS showed the reaction was completed. The solvents were removed under reduced pressure, and the residue was purified by silica gel chromatography (petroleum ether:ethyl acetate=1:1) to give (S)-tert-butyl 2-((4-(4-(4-(5-benzoylpyrimidin-2-yl)piperazin-1-yl)-1,3,5-triazin-2-ylamino)-1H-pyrazol-1-yl)methyl)morpholine-4-carboxylate (230 mg, 95%) as a yellowish solid. (MS (ES+) C31H37N11O4 requires: 627, found: 573 [M-56+H]+.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([CH:14]([O:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH3:24])[C:15](O)=[O:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.N1C=CN=C1.[H-].[Na+].[NH2:46][C:47]1[S:48][S:49][C:50](=[S:52])[N:51]=1.O.[Cl-].[NH4+]>O1CCCC1>[F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([CH:14]([O:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH3:24])[C:15]([NH:46][C:47]3[S:48][S:49][C:50](=[S:52])[N:51]=3)=[O:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: Nc1nc(=S)ss1
Reactant: COCCOCOC(C(=O)O)c1ccc(OCc2ccc(F)cc2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: COCCOCOC(C(=O)Nc1nc(=S)ss1)c1ccc(OCc2ccc(F)cc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 65.2 %

Procedure:
2-{4-[(4-Fluorobenzyl)oxy]phenyl}-2-[(2-methoxyethoxy)methoxy]acetic acid (0.156 g, 0.429 mmol) was dissolved in tetrahydrofuran (1.4 ml), and 1,1′-carbonyidiimidazole (0.083 g, 0.514 mmol) was added thereto. The imidazole mixture was stirred1 hour at room temperature. Sodium hydride (60% oil suspension 0.021 g, 0.514 mmol) was suspended in tetrahydrofuran (1.4 ml), and 3-amino-1,2,4-dithiazole-5-thione (0.077 g, 0.514 mmol) was added thereto. After being stirred for 30 minutes at 0° C., the reaction mixture, with the imidazole mixture added thereto, was stirred for 16 hours at room temperature. The reaction mixture, with saturated ammonium chloride water added thereto, was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over MgSO4, and then concentrated. The obtained residue was purified by silica gel column chromatography (chloroform), to give 2-{4-[(4-fluorobenzyl)oxy]phenyl}-2-[(2-methoxyethoxy)methoxy]-N-(3-thioxo-3H-1,2,4-dithiazol-5-yl)acetoamide (Compound 15) (0.139 g, 65%).
Reaction SMILES: [N:1]1([C:7]([CH2:9][C@@H:10]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:11]([O:13]CC2C=CC=CC=2)=[O:12])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>CO.[Pd]>[N:1]1([C:7]([CH2:9][C@@H:10]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:11]([OH:13])=[O:12])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)C[C@H](CC(=O)N1CCCCC1)C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)C[C@H](CC(=O)N1CCCCC1)C(=O)O
Yield: 94.5 %

Procedure:
A solution of benzyl (2R)-2-(piperidinocarbonylmethyl)-4-methylvalerate (0.625 g) in methanol (10 ml) was hydrogenated over 10% palladium on carbon (80 mg) at 3 atmospheric pressure of hydrogen for 1 hour. After removal of the catalyst by filtration, the filtrate was concentrated in vacuo to give (2R)-2-(piperidinocarbonylmethyl)-4-methylvaleric acid (0.43 g) as an oil.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)[N:11]=2)=[CH:5][C:4]([C:23]2[C:28]([CH:29]=[O:30])=[C:27]([N:31]3[CH2:43][CH2:42][N:34]4[C:35]5[CH2:36][CH2:37][CH2:38][CH2:39][C:40]=5[CH:41]=[C:33]4[C:32]3=[O:44])[N:26]=[CH:25][CH:24]=2)=[CH:3]1.[BH4-].[Na+]>CO>[OH:30][CH2:29][C:28]1[C:27]([N:31]2[CH2:43][CH2:42][N:34]3[C:35]4[CH2:36][CH2:37][CH2:38][CH2:39][C:40]=4[CH:41]=[C:33]3[C:32]2=[O:44])=[N:26][CH:25]=[CH:24][C:23]=1[C:4]1[CH:5]=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)[N:11]=2)[C:7](=[O:8])[N:2]([CH3:1])[CH:3]=1
Reactant: CN1CCN(c2cccc(Nc3cc(-c4ccnc(N5CCn6c(cc7c6CCCC7)C5=O)c4C=O)cn(C)c3=O)n2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN1CCN(c2cccc(Nc3cc(-c4ccnc(N5CCn6c(cc7c6CCCC7)C5=O)c4CO)cn(C)c3=O)n2)CC1
Reaction time: 0.5 h
Yield: 44.1 %

Procedure:
To the solution of 110b (60 mg, 0.1 mmol) in methanol (50 mL) was added sodium borohydride (11.5 mg, 0.3 mmol) at 0° C. and the mixture was stirred for another 30 minutes. Then the reaction mixture was quenched with water (3 mL) and concentrated. The residue was purified with reverse-phase prep-HPLC to afford 110 (26.2 mg, 49%). LCMS: [M+H]+ 595. 1H NMR (500 MHz, CDCl3) δ 8.69 (d, J=1.5, 1H), 8.46 (d, J=5.0, 1H), 7.97 (s, 1H), 7.80 (s, 1H), 7.41-7.37 (m, 1H), 7.34 (d, J=1.5, 1H), 6.89 (s, 1H), 6.22 (d, J=8.0, 1H), 6.15 (d, J=8.5, 1H), 5.10 (t, J=6.5, 1H), 4.66-4.64 (m, 1H), 4.51-4.30 (m, 2H), 4.15-4.12 (m, 2H), 3.93-3.89 (m, 1H), 3.71 (s, 3H), 3.58-3.48 (m, 4H), 2.61-2.56 (m, 7H), 2.47-2.39 (m, 3H), 1.91-1.87 (m, 2H), 1.79-1.78 (d, J=5.0, 3H)
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][N:8]=[C:9]=[O:10].[CH3:11][C:12]1[C:13]([O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=2[N+:29]([O-:31])=[O:30])=[N:14][NH:15][C:16]=1[CH3:17].Cl>C(OCC)(=O)C>[CH3:7][NH:8][C:9]([N:15]1[C:16]([CH3:17])=[C:12]([CH3:11])[C:13]([O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=2[N+:29]([O-:31])=[O:30])=[N:14]1)=[O:10]
Reactant: CN=C=O
Reactant: Cc1[nH]nc(Oc2ccc(C(F)(F)F)cc2[N+](=O)[O-])c1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CNC(=O)n1nc(Oc2ccc(C(F)(F)F)cc2[N+](=O)[O-])c(C)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.5 %

Procedure:
Potassium carbonate (0.50 g, 3.6 mmol) and methyl isocyanate (0.17 g, 3.0 mmol) were added to a solution of 4,5-dimethyl-3-(2-nitro-4-trifluoromethylphenyloxy)pyrazole (1.08 g, 3.6 mmol) in ethyl acetate (20 ml), and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid and extracted with diethyl ether (20 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/3), to give a yellow solid of N-methyl-4,5-dimethyl-3-(2-nitro-4-trifluoromethylphenyloxy)pyrazole-1-carboxamide (0.93 g, yield: 86.5%). mp: 117-119° C.; 1H-NMR (CDCl3, TMS, ppm): δ 1.95 (s, 3H), 2.55 (s, 3H), 2.90 (d, J=5.0 Hz, 3H), 6.50-6.80 (m, 1H), 7.49 (d, J=8.7 Hz, 1H), 7.84 (dd, J=2.0 and 8.7 Hz, 1H), 8.25 (d, J=2.0 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:15]([F:18])([F:17])[F:16])=[CH:4][C:5]([C:9]#[C:10][Si](C)(C)C)=[C:6]([CH:8]=1)[NH2:7].CN(C)C=O>[Cu]I.C(OCC)C>[Cl:1][C:2]1[CH:8]=[C:6]2[C:5]([CH:9]=[CH:10][NH:7]2)=[CH:4][C:3]=1[C:15]([F:18])([F:17])[F:16]
Reactant: C[Si](C)(C)C#Cc1cc(C(F)(F)F)c(Cl)cc1N
Agent: [Cu]I
Solvent: CCOCC
Solvent: CN(C)C=O
Product: FC(F)(F)c1cc2cc[nH]c2cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 46.3 %

Procedure:
A mixture of 5-chloro-4-(trifluoromethyl)-2-[(trimethylsilyl)ethynyl]aniline (16.5 g), copper(I) iodide (20.4 g) and dimethylformamide (100 ml) was stirred at room temperature for 10 min and then stirred with heating at 100° C. for 2.5 hr. The reaction mixture was allowed to cool, diethyl ether was added and the mixture was stirred at room temperature. The reaction mixture was filtered through a celite (trademark) filter, and the filtrate was washed with water and saturated brine, dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give a brown oil. The oil was purified by silica gel column chromatography (elution solvent:ethyl acetate-hexane (1:5-1:3)) to give 6-chloro-5-(trifluoromethyl)-1H-indole (5.75 g, yield 46%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].[F:18][C:19]1[CH:33]=[CH:32][C:22]([O:23][C:24]2[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=2)=[CH:21][CH:20]=1.[Na]>C(Cl)Cl>[F:18][C:19]1[CH:33]=[CH:32][C:22]([O:23][C:24]2[CH:31]=[CH:30][C:27]([CH2:28][NH:1][CH2:2][C:3]3[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=3)[CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:12])([CH3:13])[CH3:11])=[CH:26][CH:25]=2)=[CH:21][CH:20]=1
Reactant: O=Cc1ccc(Oc2ccc(F)cc2)cc1
Reactant: CC(C)(C)OC(=O)NCc1cccc(CN)c1
Agent: [Na]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1cccc(CNCc2ccc(Oc3ccc(F)cc3)cc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.2 %

Procedure:
A solution of tert-butyl 3-(aminomethyl)benzylcarbamate (0.70 g, 2.94 mmol) and 4-(4-fluorophenoxy)benzaldehyde (0.6 g, 2.78 mmol) in CH2Cl2 (15 mL) was stirred at rt under nitrogen for 40 min, and then treated with sodium triacetoxyhydroborate (1.24 g, 5.83 mmol). The resulting mixture was stirred at rt. for 3 h. The reaction mixture was concentrated and the residue was partitioned between saturated NaHCO3 solution and ethyl acetate. The organic layer (clear solution) was washed with brine, dried over MgSO4. The filtrate was concentrated and the residue was dissolved in CH2Cl2 and ethyl acetate. The solution was loaded into solid sample cartridge, vacuum dried. The sample was purified by silica gel flash chromatography. Elution with 0-30% of ethyl acetate in CH2Cl2 gave the desired product as viscous oil (0.73 g, 59%). 1H NMR (DMSO-d6): δ 7.33-7.28 (m, 2H), 7.24-7.19 (m, 5H), 7.13 (m, 1H), 7.08-7.02 (m, 2H), 6.95 (m, 2H), 4.12 (m, 2H), 3.76 (s, 4H), 1.39 (s, 9H); MS (ESI): (M+H)+=437.3.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:10]([C:12]([O:14]C(OCC)C)=[O:13])[OH:11])=O)([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].CS(Cl)(=O)=O.[CH2:37]1[CH2:41][O:40][CH2:39][CH2:38]1>CCCCCC.C(OCC)(=O)C>[C:1]([O:5][C:6]1[O:14][C:12](=[O:13])[CH:10]([O:11][CH:39]([O:40][CH2:41][CH3:37])[CH3:38])[CH:9]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:8]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C1CCOC1
Reactant: CCOC(C)OC(=O)C(O)C(NC(=O)OC(C)(C)C)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: CS(=O)(=O)Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(C)OC1C(=O)OC(OC(C)(C)C)=NC1c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a solution of 409 mg (1.16 mmol) of N-tertbutoxycarbonyl-O-(1-ethoxyethyl)-3-phenylisoserine (3) in 20 mL of THF was added 261 mg (2.33 mmol) of solid potassium tert-butoxide and the mixture was stirred at 25° C. for 30 min. A solution of 134 mg (1.16 mmol) of methanesulfonyl chloride in 3.2 mL of THF was added and the mixture was stirred at 25° C. for 1.5 h. The mixture was diluted with 80 mL of hexane and ethyl acetate and this solution was extracted with 20 mL of saturated aqueous sodium bicarbonate solution and 10 mL of brine. The organic phase was dried over sodium sulfate and concentrated to give 235 mg (70%) of 2-tertbutoxy-4-phenyl-5-(1-ethoxyethoxy)-4,5-dihydro-1,3-oxazin-6-one as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:5]=[C:6]([CH2:10][NH2:11])[CH:7]=[CH:8][CH:9]=1.[F:14][C:15]([F:20])([F:19])[CH:16]1[O:18][CH2:17]1>>[F:1][C:2]([F:12])([F:13])[O:3][C:4]1[CH:5]=[C:6]([CH2:10][NH:11][C:16]([OH:18])([CH3:17])[C:15]([F:20])([F:19])[F:14])[CH:7]=[CH:8][CH:9]=1
Reactant: NCc1cccc(OC(F)(F)F)c1
Reactant: FC(F)(F)C1CO1
Product: CC(O)(NCc1cccc(OC(F)(F)F)c1)C(F)(F)F
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
Ex-632A) 3-Trifluoromethoxybenzenemethanamine (1.15 g, 6 mmol) and 1,1,1-trifluoro-2,3-epoxypropane (0.67 g, 6 mmol) were combined and stirred at 80° C. for 1.5 h. The mixture was cooled to room temperature, and the resulting solid was recrystallized from hot hexanes. The white solid was isolated by vacuum filtration and washed with cold hexanes to give 0.67 g (37%) of pure 3-[[[3-(trifluoromethoxy)-phenyl]methyl]amino-1,1,1-trifluoro-2-propanol. 1H NMR (CDCl3) δ7.37 (t, 1H), 7.24 (d, 1H), 7.15 (m, 2H), 3.99 (m, 1H), 3.85 (d, 2H), 2.98 (dd, 1H), 2.88 (dd, 1H), 2.79 (s, 1H). 19F NMR (CDCl3) δ−58.19 (s, 3F), −78.88 (s, 3F). HRMS calcd. for C11H11F6NO2: 304.0772 [M+H]+, found: 304.0794.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9](=O)[CH2:10][O:11][C:12]2[CH:25]=[CH:24][C:15](/[CH:16]=[C:17]3/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/3)=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1.CN(C=O)C.Cl.[NH2:33][OH:34]>C1COCC1>[OH:34][N:33]=[C:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:10][O:11][C:12]1[CH:25]=[CH:24][C:15](/[CH:16]=[C:17]2/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/2)=[CH:14][CH:13]=1
Reactant: COc1cccc(C(=O)COc2ccc(/C=C3\SC(=O)NC3=O)cc2)c1
Reactant: NO
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cccc(C(COc2ccc(/C=C3\SC(=O)NC3=O)cc2)=NO)c1
Reaction time: 8 h

Procedure:
A stirring suspension of (5Z)-5-{4-[2-(3-methoxyphenyl)-2-oxoethoxy]benzylidene}-1,3-thiazolidine-2,4-dione (1.42 g, 3.84 mmol; Supplier=Kalexsyn; Lot=1003-TTP-149) in THF (15 ml) was heated with a heat gun—no solution. Added DMF (5 ml) and heated—no solution. Added another 5 ml DMF and heated until all solids dissolved. The hydroxylamine hydrochloride was added portionwise. Added HONH2.HCl (100 mg) and allowed to sit at RT overnight. HPLC showed a ratio of ca. 2:1 SM:pdt. Added 100 mg HONH2.HCl. After 4 hours there was little change in HPLC. Added 100 mg HONH2.HCl and left to stir over the weekend. The reaction was complete. The reaction mixture was partitioned between EtOAc (30 ml) and 1M KHSO4 (30 ml). The aqueous phase was extracted with EtOAc (30 ml). The combined organic phases were washed with saturated NaHCO3 (30 ml), brine (30 ml), dried (Na2SO4), filtered and evaporated in vacuo to give 1.34 g yellow solid. 1H-NMR (DMSO-d6): δ 12.53(brs, 1H), 12.02(brs, 1H), 7.73(s, 1H), 7.54(d, J=8.9 Hz, 2H), 7.30(t, J=7.9 Hz, 1H), 7.20(m, 2H), 7.10(d, J=8.9 Hz, 2H), 6.95(dd, J=8.1, 2.5 Hz, 1H), 5.31(s, 2H), 3.74(s, 3H). HPLC: 3.690 min., 10 area %, and 3.788 min., 89 area % @ 210 nm; 3.690 min., 6 area %, and 3.789 min., 94 area % @ 254 nm. MS (ESI−) for C19H16N2O5S m/z 383.3 (M−H)−.