Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[C:31]1([O:37][C:38](Cl)=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C1(C)C=CC=CC=1>CCCCCC>[O:37]([C:38]([N:8]1[CH2:9][CH2:10][C:11]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)([O:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:19][CH:20]=2)[CH2:12][CH2:13]1)=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: FC(F)(F)c1ccc(OC2(c3ccccc3)CCN(Cc3ccccc3)CC2)cc1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: O=C(Oc1ccccc1)N1CCC(Oc2ccc(C(F)(F)F)cc2)(c2ccccc2)CC1

Procedure:
A solution of 10.0 g of 1-benzyl-4-phenyl-4-(p-trifluoromethylphenoxy)piperidine and 4.1 g of phenylchloroformate in 100 ml. of toluene was refluxed for 17 hours. The toluene was removed under reduced pressure to give a colorless oil which when rubbed with a glass rod in the presence of hexane gave a white solid of 1-phenoxycarbonyl-4-phenyl-4-(p-trifluoromethylphenoxy)piperidine.
Reaction SMILES: O.[OH-].[Li+].[N:4]1([CH2:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[C:11]([C:19]([O:21]CC)=[O:20])[CH:10]=2)[CH2:7][CH2:6][CH2:5]1.[ClH:24].C(#N)C>O1CCCC1.O>[ClH:24].[ClH:24].[N:4]1([CH2:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[C:11]([C:19]([OH:21])=[O:20])[CH:10]=2)[CH2:7][CH2:6][CH2:5]1
Reactant: CCOC(=O)c1cc(CN2CCC2)nc(C(F)(F)F)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CC#N
Product: O=C(O)c1cc(CN2CCC2)nc(C(F)(F)F)n1
Reaction time: 0.25 h

Procedure:
Lithium hydroxide, monohydrate (108 mg, 2.57 mmol) was added to a mixture of ethyl 6-(azetidin-1-ylmethyl)-2-(trifluoromethyl)pyrimidine-4-carboxylate (0.34 g, 1.2 mmol, from Step A) in tetrahydrofuran (6.0 mL) and water (1.5 mL). After 15 minutes, the THF was removed in vacuo and the mixture was treated with 1.0M hydrogen chloride in water (5.3 mL, 5.3 mmol), and acetonitrile (7.0 mL). The mixture was then filtered and concentrated to afford the product as a yellow solid. LCMS (M+H)+: 262.1.
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[NH2:9][C@H:10]([C:16]([OH:18])=[O:17])[CH2:11][CH2:12][C:13](O)=O.OCCC[NH:23][C@H:24]([C:30](O)=O)[CH2:25][CH2:26]C(=O)N>C([O-])(O)=O.[Na+]>[NH2:23][C:24]1[CH:25]=[CH:26][C:12]([CH2:11][C@@H:10]([C:16]([OH:18])=[O:17])[NH2:9])=[CH:13][CH:30]=1
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Reactant: NC(=O)CC[C@H](NCCCO)C(=O)O
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Product: Nc1ccc(C[C@H](N)C(=O)O)cc1

Procedure:
The polymer of either Examples I and II were reduced by treating a solution of 2 g of the polymer in 0.5 M NaHCO3 (50 ml) with 5% (w/v) sodium dithionite at 50° C for 1 hour. A copolypeptide, as in Example III, containing either glutamic acid or hydroxypropylglutamine and p-aminophenylalanine was obtained, following purification of the low molecular weight material by gel chromatography or dialysis.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:23][OH:24])[C:8](N2[C@@H](CC3C=CC=CC=3)COC2=O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:25]O.O.[OH-].[Li+]>C1COCC1.O>[CH:1]1([CH2:6][C@H:7]([CH2:23][OH:24])[C:8]([OH:9])=[O:25])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: OO
Reactant: O=C1OC[C@H](Cc2ccccc2)N1C(=O)[C@@H](CO)CC1CCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@@H](CO)CC1CCCC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
(4S)-3-[(2R)-3-Cyclopentyl-2-(hydroxymethyl)propanoyl]-4-(phenylmethyl)-1,3-oxazolidin-2-one (33.1 g, 0.1 mol) was stirred in a mixture of THF (330 mL) and water (55 mL) and cooled to 0° C. 30% Hydrogen peroxide (96 mL, 1 mol) was added, followed by lithium hydroxide monohydrate (8.4 g, 0.2 mol). The reaction was warmed to room temperature, and then stirred overnight. The THF was removed by rotary evaporation. The aqueous residue was washed with dichloromethane (3×100 mL), was acidified with 6N HCl, and was extracted with ethyl acetate (4×100 mL). The organic extracts were dried (MgSO4) and were evaporated to provide (2R)-3-cyclopentyl-2-(hydroxymethyl)propanoic acid as a clear, colorless oil (18.5 g, >100%). LCMS: (M+H)+: not detected. 1H NMR (400 MHz, CDCl3): δ 7.3 (br s, 1H), 3.79 (d, J=5.83 Hz, 2H), 2.64-2.71 (m, 1H), 1.45-1.87 (m, 9H), 1.05-0.14 (m, 2H).
Reaction SMILES: C(S[C:9]1[CH:18]=[C:17]2[C:12]([C:13]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=3[O:29][CH3:30])=[CH:14][CH:15]=[N:16]2)=[CH:11][N:10]=1)C1C=CC=CC=1.C(Cl)Cl.C(O)(=O)C.[S:38]([Cl:42])(Cl)(=[O:40])=[O:39]>O>[CH3:30][O:29][C:20]1[CH:21]=[C:22]([C:25]([F:28])([F:26])[F:27])[CH:23]=[CH:24][C:19]=1[C:13]1[C:12]2[C:17](=[CH:18][C:9]([S:38]([Cl:42])(=[O:40])=[O:39])=[N:10][CH:11]=2)[N:16]=[CH:15][CH:14]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: COc1cc(C(F)(F)F)ccc1-c1ccnc2cc(SCc3ccccc3)ncc12
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1cc(C(F)(F)F)ccc1-c1ccnc2cc(S(=O)(=O)Cl)ncc12
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 76.5 %

Procedure:
A round bottomed flask cooled to 0° C., was charged with 7-(benzylthio)-4-(2-methoxy-4-(trifluoromethyl)phenyl)-1,6-naphthyridine (0.129 g, 0.302 mmol), DCM (2.88 ml), acetic acid (0.072 ml), and water (0.072 ml). After stirring for 5 minutes at 0° C., sulfuryl chloride (0.025 ml, 0.302 mmol) was added and stirring was continued for an additional 1 hour at 0° C. The reaction was concentrated, dissolved in minimal DCM and purified via column chromatography (silica gel 40 g, gradient elution 0 to 50% EtOAc:Heptane) to afford 0.093 g of 4-(2-methoxy-4-(trifluoromethyl)phenyl)-1,6-naphthyridine-7-sulfonyl chloride as an off white solid. m/z (ESI) 402.9 (M+H)+.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4](S(O)(=O)=O)=[CH:3][CH:2]=1.O.[C:13]1(C)C=CC=C[CH:14]=1>>[CH2:13]1[C:6]2[C:1](=[CH:2][CH:3]=[CH:4][CH:5]=2)[CH:11]=[CH:14]1
Reactant: Cc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: C1=Cc2ccccc2C1
Yield: 72 %

Procedure:
The crude product was taken up in 500 cm3 of toluene, 1.5 g of p-toluene sulfonic acid was added, the reaction mixture was refluxed for 2 hours on a water separator and washed 3 times with 50 cm3 of saturated aqueous NaHCO3 solution, and the solvent was removed in vacuo. Filtration through 200 g of silica gel (hexane/methylene chloride) gave 18.4 g (72%) of 29 as a colorless oil.
Reaction SMILES: C(S([C:11]1[C:12]2[CH:19]=[CH:18][N:17]([C@H:20]3[CH2:36][C@@H:23]4[O:24][CH:25]([C:28]5[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=5)[O:26][CH2:27][C@@H:22]4[CH2:21]3)[C:13]=2[N:14]=[CH:15][N:16]=1)(=O)=O)C1C=CC=CC=1.[NH2:37][C@H:38]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH2:40][CH2:39]1.CCN(C(C)C)C(C)C>C(O)C>[C@H:38]1([NH:37][C:11]2[C:12]3[CH:19]=[CH:18][N:17]([C@H:20]4[CH2:36][C@@H:23]5[O:24][CH:25]([C:28]6[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=6)[O:26][CH2:27][C@@H:22]5[CH2:21]4)[C:13]=3[N:14]=[CH:15][N:16]=2)[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH2:40][CH2:39]1
Reactant: COc1ccc(C2OC[C@@H]3C[C@@H](n4ccc5c(S(=O)(=O)Cc6ccccc6)ncnc54)C[C@@H]3O2)cc1
Reactant: N[C@@H]1CCc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: COc1ccc(C2OC[C@@H]3C[C@@H](n4ccc5c(N[C@@H]6CCc7ccccc76)ncnc54)C[C@@H]3O2)cc1
Temperature: 110 °C
Yield: 73.3 %

Procedure:
In a 0.5-2 mL microwave vial, 4-(benzylsulfonyl)-7-[(4aS,6R,7aS)-2-(4-methoxyphenyl)hexahydrocyclopenta[d][1,3]dioxin-6-yl]-7H-pyrrolo[2,3-d]pyrimidine (100 mg, 0.198 mmol), (R)-(−)-1-aminoindan (0.127 mL, 0.989 mmol), and DIPEA (0.172 mL, 0.989 mol) were dissolved in ethanol (1.22 mL). The vial was sealed and heated to 110° C. overnight. The solution was then concentrated in vacuo and the resulting material was purified via silica gel chromatography eluting with a gradient of 20 to 50% EtOAc in hexanes to afford the product as an orange oil (70.0 mg, 73%). LC/MS: Rt=1.42 min, ES+ 483 (FA standard).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:7]2[C:12]([C:13](=[O:26])[C:14]=1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([O:24]C)=[O:23])=[CH:18][CH:17]=1)=[CH:11][CH:10]=[C:9]([Cl:27])[CH:8]=2)=[O:4].[OH-].[Li+].Cl.C(OC)(=O)C>O1CCOCC1.O>[CH3:1][O:2][C:3]([C:5]1[N:6]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:7]2[C:12]([C:13](=[O:26])[C:14]=1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([OH:24])=[O:23])=[CH:18][CH:17]=1)=[CH:11][CH:10]=[C:9]([Cl:27])[CH:8]=2)=[O:4]
Reactant: COC(=O)c1ccc(Cc2c(C(=O)OC)n(-c3ccccc3)c3cc(Cl)ccc3c2=O)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: COC(C)=O
Solvent: O
Product: COC(=O)c1c(Cc2ccc(C(=O)O)cc2)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Temperature: 25 °C
Yield: 83.4 %

Procedure:
A 2 L three necked round bottom flask equipped with a mechanical stirrer, a nitrogen bubbler and a thermometer was charged with 7-chloro-3-(4-methoxycarbonyl-benzyl)-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester (34 g, 73.6 mmol) methanol (600 mL) and 1,4-dioxane (300 mL). The resulting mixture was treated with lithium hydroxide (3.52 g, 146 mmol). The reaction was stirred at 25° C. over the weekend. At this time, the reaction was warmed to 35° C. and was stirred at 35° C. overnight. The reaction was then treated with additional lithium hydroxide (3.5 g, 1.46 mmol) and water (10 mL) and continued to stir at 35° C. overnight. At this time, additional 1,4-dioxane (300 mL) was added to the reaction. The reaction was stirred at 35° C. overnight. The reaction was then warmed to 40° C. where it stirred for 8 h and then was stirred at 35° C. overnight. At this time, the reaction was cooled to 25° C., treated with concentrated hydrochloric acid (25 mL) and methyl acetate (500 mL) and concentrated in vacuo. The resulting solids were collected by filtration, washed with methanol and dried in vacuo to afford 3-(4-carboxy-benzyl)-7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester (27.5 g). An additional amount of 3-(4-carboxy-benzyl)-7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester (3 g, total yield: 92.5%) was obtained through concentration of the filtrate and collection of the resulting solids. This material was used without further purification.
Reaction SMILES: N(CCO)(CCO)CCO.[NH2:11][CH2:12][CH2:13][CH2:14][N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1.F[C:21]1[CH:22]=[CH:23][C:24]([N+:28]([O-:30])=[O:29])=[C:25]([CH3:27])[CH:26]=1>CS(C)=O>[N+:28]([C:24]1[CH:23]=[CH:22][C:21]([NH:11][CH2:12][CH2:13][CH2:14][N:15]2[CH:19]=[CH:18][N:17]=[CH:16]2)=[CH:26][C:25]=1[CH3:27])([O-:30])=[O:29]
Reactant: NCCCn1ccnc1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Solvent: CS(C)=O
Solvent: OCCN(CCO)CCO
Product: Cc1cc(NCCCn2ccnc2)ccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 17 h

Procedure:
150 ml of dimethyl sulfoxide were introduced into a 500 ml three-necked flask and treated with 22.6 g of triethanolamine (99% strength), 28.7 g of 1-(3-amino-propyl)imidazole (98% strength) and 24.2 g of 5-fluoro-2-nitrotoluene (96% strength). The mixture was stirred at 80° C. for 17 h. Following this, the batch was cooled to room temperature and poured onto 1 l of ice, a yellow oil depositing, which crystallized thoroughly after about 1 h. The precipitate thus resulting was filtered off with suction, washed with water and dried in vacuo at 40° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9]([CH3:11])[CH3:10])=[C:4](Cl)[N:3]=1.[CH3:13][C:14]1[CH:15]=[C:16]([OH:21])[CH:17]=[C:18]([CH3:20])[CH:19]=1.[H-].[Na+]>CN(C=O)C.CCOCC>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9]([CH3:11])[CH3:10])=[C:4]([O:21][C:16]2[CH:17]=[C:18]([CH3:20])[CH:19]=[C:14]([CH3:13])[CH:15]=2)[N:3]=1
Reactant: Cc1cc(C)cc(O)c1
Reactant: CC(C)c1c(Cl)nc(Cl)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cc1cc(C)cc(Oc2nc(Cl)nc(Cl)c2C(C)C)c1
Temperature: -40 °C
Yield: 90.1 %

Procedure:
To a stirred mixture of 2,4,6-Trichloro-5-isopropyl-pyrimidine (23.68 g, 0.105M), 3,5-dimethylphenol (12.2 g, 0.2M) in anhydrous DMF (200 ml) cooled in a dry ice-acetone bath (−40° C.) under nitrogen atmosphere, was portionwise added 60% sodium hydride (4.2 g, 0.105M). The reaction temperature was then slowly raised to room temperature during 3 hr. The reaction mixture was then diluted with ether, washed with water twice, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo to give a crude product as a pale yellow solid. The crude product was purified by silica gel column chromatography (eluent, ether:hexanes (1:9)) to afford 28 g (90%) a white solid. m.p. 107-108° C.; 1H NMR (200 MHz, CDCl3) δ 1.40 (6H, d, J=7.0 Hz), 2.35 (6H, s), 3.58 (1H, m), 6.72 (2H, s), 6.91 (1H, s).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].[C:13](Cl)(=[O:23])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].Cl>O.C(O)(C)C>[C:13]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)(=[O:23])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCC(=O)Cl
Reactant: O=C(O)c1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CCCCCCCCCC(=O)Oc1ccc(C(=O)O)cc1
Temperature: 12.5 °C
Reaction time: 0.5 h

Procedure:
69.1 g (0.5 mol) of para-hydroxybenzoic acid were first dissolved in 200 ml of water and 300 ml of isopropanol and this solution was admixed at 10 to 15° C. with 127.5 g of NaOH solution (32% strength by weight aqueous solution, 1.02 mol). The resulting pH was 13.7. Metered into this solution over the course of three hours, then, at 10 to 55° C., were 95.4 g (0.5 mol) of decanoyl chloride, and the batch was stirred for 30 minutes at 10 to 15° C. thereafter. The complete solution was subsequently heated to 55 to 60° C. and then adjusted to a pH of 1.5 to 3 using 60.0 g of HCl solution (32% strength by weight aqueous solution). The reaction mixture was cooled to 20 to 25° C. and the solid was filtered off on a suction filter and washed ten times with 75 ml of water. The yield after drying under reduced pressure at 100° C. was 124.8 g (85.4% of theory). According to HPLC and NMR measurement, the product was free from decanoic acid and from unreacted para-hydroxybenzoic acid. The purity of the product is >99.9% by weight.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH2:2][OH:3].C(N)CN.C(O)(=[O:14])C(C)C.CCC(COC(C(N(CC[NH+](C)C)C)=O)(C1C=CC=CC=1)C1C=CC=CC=1)CC.[Cl-]>>[C:1]([OH:5])(=[O:4])[CH:2]=[O:3].[C:2]([OH:14])(=[O:3])[C:1]([OH:5])=[O:4]
Reactant: O=C(O)CO
Reactant: CC(C)C(=O)O
Agent: CCC(CC)COC(C(=O)N(C)CC[NH+](C)C)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Solvent: NCCN
Product: O=C(O)C(=O)O
Product: O=CC(=O)O
Temperature: 5 °C
Reaction time: 4.5 h

Procedure:
A 300-mL EZE-Seal stirred autoclave reactor equipped with Dispersimax Impeller (Autoclave Engineers) was charged with 100 mL of a solution containing glycolic acid (1.500M), ethylenediamine (1.575M), isobutyric acid (0.300M, HPLC internal standard), and flavin mononucleotide (0.01 mM), at pH 9.25, and the solution cooled to 5° C. To the reactor was then added 2.0 g of Pichia pastoris transformant strain GS115-MSP10 (114 IU glycolate oxidase and 148,000 IU catalase) which had been permeabilized by treatment with 0.1% Triton X-100/1 freeze-thaw, and the reactor purged with oxygen. The mixture was then stirred at 1000 rpm, which bubbled oxygen through the mixture via the action of the turbine impeller, and at 5° C. under 120 psig of oxygen. The reaction was monitored by taking a 0.4 mL aliquot of the reaction mixture at regular intervals, filtering the aliquot using a Millipore Ultrafree-MC 10,000 NMWL Filter Unit, and analyzing the filtrate by HPLC. After 4.5 h, the yields of glyoxylic acid, oxalic acid, and formic acid were 98.0%, 0.4%, and 0%, respectively, with no glycolic acid remaining. The final activities of permeabilized-cell glycolate oxidase and catalase were 136% and 113% of their initial values, respectively.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([OH:18])=[C:13]([C:15](=[O:17])[CH3:16])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].CC1C=CC(S(O[CH2:32][C@H:33]2[CH2:35][O:34]2)(=O)=O)=CC=1>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:18][CH2:32][C@H:33]2[CH2:35][O:34]2)=[C:13]([C:15](=[O:17])[CH3:16])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1cc(OCc2ccccc2)ccc1O
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)c1cc(OCc2ccccc2)ccc1OC[C@H]1CO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.5 %

Procedure:
To a stirred solution of 1-(5-benzyloxy-2-hydroxyphenyl)ethanone (3.0 g, 12.4 mmol) in anhydrous DMF (15 ml) was added NaH (0.55 g, 13.6 mmol). The mixture was allowed to stir at RT for 30 min and then heated to 60° C. A solution of (R)-oxiran-2-ylmethyl 4-methylbenzenesulfonate (2.83 g, 12.4 mmol) in DMF was added dropwise at 60° C. during 1 h. Stirring was then continued at 60° C. for 3 h. The cooled reaction was quenched by addition of water (80 ml) and extracted three times with EtOAc. The combined organic layers were extracted twice with aq 1 M NaOH and washed with water and brine. The organic layer was dried with Na2SO4 and concentrated. The crude product obtained was purified by column chromatography with EtOAc/toluene as eluent to afford the title compound (2.35 g) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[C:11]([N+:13]([O-])=O)[C:10]([N:16](CC)[C:17](=O)[C:18](F)(F)F)=[C:9]([I:25])[CH:8]=2)=[C:5]([CH3:26])[O:4][N:3]=1.C[O-].[Na+].[OH-].[Na+]>CO.O>[CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[C:11]([NH2:13])[C:10]([NH:16][CH2:17][CH3:18])=[C:9]([I:25])[CH:8]=2)=[C:5]([CH3:26])[O:4][N:3]=1
Reactant: CCN(C(=O)C(F)(F)F)c1c(I)cc(-c2c(C)noc2C)cc1[N+](=O)[O-]
Agent: C[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCNc1c(N)cc(-c2c(C)noc2C)cc1I
Temperature: 25 °C
Yield: 28 %

Procedure:
Crude N-(4-(3,5-dimethylisoxazol-4-yl)-2-iodo-6-nitrophenyl)-N-ethyl-2,2,2-trifluoroacetamide (1.5 g, 3.1 mmol) was dissolved in 100 mL of methanol. To the mixture was added 1M sodium methoxide in methanol (15.5 mL, 15.5 mmol) and reaction stirred at room temperature until complete. Reaction was then quenched with 15 mL of 1M HCl or until pH is approximately neutral then diluted with aqueous ammonium chloride. Methanol was removed under reduced pressure and then remaining suspension was extracted with EtOAc. The solution was washed with water, brine then dried over sodium sulfate. Solvents were removed under reduced pressure the residue was then dissolved in 20 mL of ethanol and placed in a sealed pressure tube with stannous chloride (2.2 g, 11.62 mmol). The mixture was heated at 120° C. for 1 hour. Reaction mixture was cooled to room temperature. To the mixture was added 1M NaOH (10 mL) and the mixture was stirred at room temperature for 30 minutes. At this point the reaction mixture was diluted with water and extracted with EtOAc (3 times). The solution was washed with water, brine and dried over sodium sulfate. Solvents were removed under reduced pressure and crude product was purified by silica gel chromatography (Hexanes/EtOAc as the eluent) to provide 4-(3,5-dimethylisoxazol-4-yl)-N1-ethyl-6-iodobenzene-1,2-diamine (310 mg, 22%).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:23]=[CH:22][C:6]([O:7][CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:9](O)=[O:10])=[CH:5][CH:4]=1.S(Cl)([Cl:28])=O.CN(C)C=O>ClCCl>[F:1][C:2]([F:25])([F:24])[C:3]1[CH:23]=[CH:22][C:6]([O:7][CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:9]([Cl:28])=[O:10])=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C(Oc1ccc(C(F)(F)F)cc1)c1cccc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)C(Oc1ccc(C(F)(F)F)cc1)c1cccc(C(F)(F)F)c1
Reaction time: 2 h

Procedure:
(4-Trifluoromethyl-phenoxy)-(3-trifluoromethyl-phenyl)-acetic acid 39 (0.05 mol) was dissolved in dichloromethane (50 mL) and thionyl chloride (5 mL) and dimethylformamide (0.1 mL) were added. After 2 hours, the solvents were removed under vacuum to afford (4-trifluoromethyl-phenoxy)-(3-trifluoromethyl-phenyl)-acetyl chloride, 123. This compound (0.01 mol) was dissolved in ether (25 mL) and the solution was cooled to −80° C. and lithium aluminum tri-tertiarybutoxy hydride (0.01 mol) was added. The progress of the reaction was monitored by TLC. When the reaction was complete, the mixture was warmed to room temperature and water was added. The organic phase was dried and concentrated and the residue was chromatographed to afford the title compound 124.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][OH:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N2CCN(CC2)C1.C(Cl)Cl.[S:33](Cl)([C:36]1[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=1)(=[O:35])=[O:34]>CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][O:21][S:33]([C:36]2[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=2)(=[O:35])=[O:34])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccccc2CO)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: C1CN2CCN1CC2
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)OCc2ccccc2C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 112.2 %

Procedure:
4-(2-Hydroxymethylphenyl)piperidine-1-carboxylic acid t-butyl ester (0.4 g, 1.0 mmol, 1.0 eq.) and triethylenediamine (220 mg, 2.0 mmol, 1.4 eq.) were dissolved in DCM (11 mL, 170 mmol). The mixture was cooled at 0° C. under nitrogen, TsCl (290 mg, 1.5 mmol, 1.1 eq.) was added, and the mixture was stirred at 0° C. for an additional 60 minutes. The mixture was diluted with EtOAc (50 mL) and washed with water (2×25 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated by rotary evaporation to yield the title compound (500 mg), which was used without further purification.
Reaction SMILES: C[Si](N([Si](C)(C)C)C(=O)C(F)(F)F)(C)C.[NH2:16][C@@H:17]([CH2:21][C:22]#[N:23])[C:18]([OH:20])=[O:19].[CH2:24]([O:31][C:32](Cl)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(#N)C>[C:25]1([CH2:24][O:31][C:32]([NH:16][C@@H:17]([CH2:21][C:22]#[N:23])[C:18]([OH:20])=[O:19])=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N#CC[C@H](N)C(=O)O
Agent: C[Si](C)(C)N(C(=O)C(F)(F)F)[Si](C)(C)C
Solvent: CC#N
Product: N#CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reaction time: 3 h

Procedure:
Bis (trimethylsilyl)trifluoroacetamide (9.4 mL, 35 mmol.) was added to a suspension of (αS)-amino-3-cyanopropanoic acid (2.0 g., 17.5 mmol.) in 10 mL of dry acetonitrile and the reaction mixture was stirred for 3 hours. Benzylchloroformate (2.5 mL, 17.5 mmol) was added, the reaction mixture was stirred overnight, concentrated in vacuo, and dissolved in ethyl acetate (200 mL). The organic solution was washed with water (2 x) and brine, dried (Na2SO4), and concentrated in vacuo. Crystallization from isopropyl ether yielded 3.82 g. of the title A product.
Reaction SMILES: [NH3:1].[CH:2](=O)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CS(O[CH2:15][C:16]#[CH:17])(=O)=O>C1(C)C=CC=CC=1>[CH:2](=[N:1][CH2:15][C:16]#[CH:17])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C#CCOS(C)(=O)=O
Reactant: O=Cc1ccccc1
Reactant: N
Solvent: Cc1ccccc1
Product: C#CCN=Cc1ccccc1
Reaction time: 3 h

Procedure:
An aqueous 28% ammonia solution (166.4 g, 2.74 mol) and benzaldehyde (30.6 g, 0.288 mol) were mixed and a solution prepared by dissolving propargyl methanesulfonate (36.7 g, 0.274 mol) in 147 g of toluene was added dropwise at 20°-25° C. over 3 hours to the solution, followed by stirring at the same temperature for 3 hours. After separating, the organic phase and aqueous phase were obtained. The organic phase obtained by washing the aqueous phase twice with 25 g of toluene was combined with the above organic phase and concentrated until the weight became 78 g to obtain a toluene solution of N-benzylidene-2-propynylamine.