Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][C:12]1[S:13][CH:14]=[C:15]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([CH3:26])[C:21]2[N:27]([CH3:39])[C:28](=[O:38])[C:29]([C:31]4[CH:36]=[CH:35][C:34]([Br:37])=[CH:33][CH:32]=4)=[CH:30][C:20]3=2)[N:16]=1)C1C=CC=CC=1.C1(SC)C=CC=CC=1.O>C(O)(C(F)(F)F)=O>[NH2:10][CH2:11][C:12]1[S:13][CH:14]=[C:15]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([CH3:26])[C:21]2[N:27]([CH3:39])[C:28](=[O:38])[C:29]([C:31]4[CH:36]=[CH:35][C:34]([Br:37])=[CH:33][CH:32]=4)=[CH:30][C:20]3=2)[N:16]=1
Reactant: Cn1c(=O)c(-c2ccc(Br)cc2)cc2c3cc(-c4csc(CNC(=O)OCc5ccccc5)n4)ccc3n(C)c21
Solvent: O
Solvent: CSc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(=O)c(-c2ccc(Br)cc2)cc2c3cc(-c4csc(CN)n4)ccc3n(C)c21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of compound A {4-[3-(4-bromophenyl)-1,9-dimethyl-2-oxo-2,9-dihydro-1H-pyrido[2,3-b]indol-6-yl]thiazol-2-ylmethyl}carbamic acid benzyl ester (200 mg, 0.32 mmol) and thioanisole (308 μl, 2.60 mmol) in 2 ml of TFA is left to stir overnight at ambient temperature. H2O is added, the mixture is extracted with EtOAc, the organic phases are washed with H2O and the product is dried over MgSO4, filtered and concentrated. Purification is carried out by chromatography on a silica column, elution being carried out with 100% EtOAc and then with an EtOAc/5% MeOH mixture then with an EtOAc/5% MeOH/1% TEA mixture. The residue is taken up in a 1/1 EtOAc/Et2O mixture and the product is filtered and washed with a minimum amount of Et2O.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[NH2:13][C@H:14]([C:19]([OH:21])=[O:20])[CH2:15][CH2:16][CH2:17][NH2:18].Cl[CH:23]([F:25])[F:24].Cl>CCCCCC.O1CCCC1>[F:24][CH:23]([F:25])[C:14]([NH2:13])([CH2:15][CH2:16][CH2:17][NH2:18])[C:19]([OH:21])=[O:20]
Reactant: NCCC[C@H](N)C(=O)O
Reactant: FC(F)Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: NCCCC(N)(C(=O)O)C(F)F
Temperature: 40 °C

Procedure:
Under nitrogen a solution (500 ml) of 2 M butyllithium in hexane is added to a stirred solution of 143.1 ml of diisopropylamine in 1.5 liters of tetrahydrofuran at -78° C. after which 261 g (0.81 mole) of ornithine dibenzaldimine methyl ester in 1.5 liters of tetrahydrofuran is added. Upon completion of the addition the reaction temperature is raised to 40° C. and maintained between 40° and 50° C. for 3 hours during which time chlorodifluoromethane gas is bubbled through the mixture with stirring. The reaction mixture is then treated with a saturated solution of sodium chloride. The organic material is extracted with ether, and the ether extract washed several times with sodium chloride solution, dried over magnesium sulfate and evaporated to give a viscous oil. The oil is stirred with 1 N HCl (1.5 l) for 3 hours, the mixture extracted several times with chloroform and the aqueous solution evaporated to dryness. The oily residue is refluxed with 12 N hydrochloric acid (1.5 l) for 16 hours, the cooled solution clarified by chloroform extraction before concentration, decolorization (charcoal), and further concentration to about 750 ml. The pH of the solution is adjusted to 3.5 by the addition of triethylamine, the solution treated again with charcoal before concentration to about 500 ml and dilution with 7-8 liters of acetone. The precipitated product is filtered off and washed with ethanol. The crude product is recrystallized by dissolving in about 150 ml hot water and treatment of the solution with hot ethanol (450 ml). On cooling crystals of 2-difluoromethyl-2,5-diaminopentanoic acid hydrochloride monohydrate separate 71 g (37%), m.p. 183° C.
Reaction SMILES: ClC(OCC(C)C)=O.[C:9]([C:11]1[CH:16]=[CH:15][C:14]([C@H:17]2[C@:21]3([N:25]([CH3:26])[C:24](=[O:27])[N:23]([C:28]4[CH:33]=[C:32]([Cl:34])[CH:31]=[C:30]([Cl:35])[CH:29]=4)[C:22]3=[O:36])[CH2:20][N:19]([CH2:37][C:38](O)=[O:39])[CH2:18]2)=[CH:13][CH:12]=1)#[N:10].C[N:42]1CCOCC1.N>C(Cl)Cl.O>[C:9]([C:11]1[CH:12]=[CH:13][C:14]([C@H:17]2[C@:21]3([N:25]([CH3:26])[C:24](=[O:27])[N:23]([C:28]4[CH:33]=[C:32]([Cl:34])[CH:31]=[C:30]([Cl:35])[CH:29]=4)[C:22]3=[O:36])[CH2:20][N:19]([CH2:37][C:38]([NH2:42])=[O:39])[CH2:18]2)=[CH:15][CH:16]=1)#[N:10]
Reactant: CN1CCOCC1
Reactant: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CN(CC(=O)O)C[C@H]2c1ccc(C#N)cc1
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: ClCCl
Solvent: O
Product: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CN(CC(N)=O)C[C@H]2c1ccc(C#N)cc1
Reaction time: 1 h
Yield: 55.3 %

Procedure:
Isobutyl chloroformate (27 μl, 0.21 mmol) was added to a cooled (5° C.) suspension of Example 64 (90 mg, 0.19 mmol) and N-methyl morpholine (23 μl, 0.2 mmol) in DCM (4 ml). After 1 h, ammonia (420 μl, 0.5 M in dioxane, 0.21 mmol) was added. After 1 h at 5° C. and 3 h at RT, water (2 ml) was added. The organic layer was separated and the aqueous layer extracted with DCM. The combined organic layers were concentrated in vacuo and the resulting material was purified by chromatography over silica gel (eluent: DCM/MeOH 95/5) to yield the above-titled compound as a solid (49.6 mg). 1H NMR (CDCl3): 7.64 (2H, d, J=8.2 Hz), 7.25-7.30 (3H, m), 6.84 (1H, br s), 6.65 (2H, d, J=1.5 Hz), 6.18 (1H, br s), 3.87 (1H, t), 3.4-3.5 (5H, m), 3.24 (3H, s), 3.15 (1 H, d, J=10.9 Hz).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[Cl:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[Cl:25])[NH2:21]>C(O)C>[Cl:17][C:18]1[CH:19]=[C:20]([NH:21][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:15]#[N:16])[CH:22]=[CH:23][C:24]=1[Cl:25]
Reactant: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Cl
Reactant: Nc1ccc(Cl)c(Cl)c1
Solvent: CCO
Product: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Nc1ccc(Cl)c(Cl)c1
Reaction time: 3.5 h
Yield: 27.3 %

Procedure:
A mixture of 5.00 g (21.5 mmol) 4chloro-6-nitro-3quinolinecarbonitrile, 250 ml ethanol, and 4.17 g (25.6 mmol) 3,4-dichloroaniline was heated to reflux under N2. At 3.5 hours, removed head and made basic with saturated sodium bicarbonate. Stripped solvents and azeotroped with ethanol. Slurried residue with hexane, collected solids and washed with water. Dissolved in ethyl acetate, stirred with Darco, filtered, stripped solvent and dried in vacuo, giving 2.106 g of yellow solid: mass spectrum (electrospray m/e): M+H=359.1, 361.0.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[N:8]=[C:9]([NH2:12])[S:10][CH:11]=2)=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([CH3:21])[C:15]=1[S:22](Cl)(=[O:24])=[O:23]>>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([CH3:21])[C:15]=1[S:22]([NH:12][C:9]1[S:10][CH:11]=[C:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:8]=1)(=[O:24])=[O:23]
Reactant: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Cl
Reactant: Nc1nc(-c2ccc(Cl)s2)cs1
Product: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Nc1nc(-c2ccc(Cl)s2)cs1

Procedure:
The title compound was prepared from 4-(5-chloro-2-thienyl)-1,3-thiazol-2-amine (METHOD H) and 2,4-dichloro-6-methylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (19.5 mg) with purity >90%. MS (pos) m/z 439.0, 441.0.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].CN1CCCC1=O.[CH:21]1([Mg]Br)[CH2:25][CH2:24][CH2:23][CH2:22]1.Cl>C1COCC1.C(OCC)C.C/C(/O)=C/C(C)=O.C/C(/O)=C/C(C)=O.C/C(/O)=C/C(C)=O.[Fe]>[CH:21]1([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[C:10]([F:13])([F:12])[F:11])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: N#Cc1ccc(Cl)c(C(F)(F)F)c1
Reactant: Br[Mg]C1CCCC1
Agent: [Fe]
Agent: CC(=O)/C=C(/C)O
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: N#Cc1ccc(C2CCCC2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-chloro-3-(trifluoromethyl)benzonitrile (1.5 g), iron (III) acetylacetonate (130 mg), and 1-methylpyrrolidin-2-one (4 mL) in THF (45 mL) was added a 1 M solution of cyclopentyl magnesium bromide in THF (8.8 mL) at 5° C., followed by stirring at room temperature for 0.5 hours and diluting with diethylether. 1 M hydrochloric acid was slowly added thereto, followed by extraction with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:EtOAc=100:0 to 95:5) to obtain 4-cyclopentyl-3-(trifluoromethyl)benzonitrile (367 mg) as a white solid.
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][CH2:4][C@H:5](O)[C:6]([O:8][CH3:9])=[O:7].S(Cl)([Cl:13])=O>>[ClH:13].[NH2:2][CH2:3][CH2:4][C@@H:5]([Cl:1])[C:6]([O:8][CH3:9])=[O:7]
Reactant: O=S(Cl)Cl
Reactant: COC(=O)[C@@H](O)CCN
Agent: Cl
Product: COC(=O)[C@H](Cl)CCN
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To methyl (S)-4-amino-2-hydroxybutyrate hydrochloride (521.6 mg; 409.5 mg when calculated as methyl (S)-4-amino-2-hydroxybutyrate) was added 1.8 mL of thionyl chloride. The mixture was stirred at room temperature for 3 hours and then at 50 C for 4 hours. Thereafter, the solvent was distilled off under reduced pressure to give 576.2 mg of methyl (R)-4-amino-2-chlorobutyrate hydrochloride (yield quantitative, optical purity 96.9% ee). The analysis of the optical purity was carried out by derivatizing into (R)-3-chloro-2-pyrrolidinone with sodium hydrogen carbonate, followed by high performance liquid chromatography using a chiral column (Chiralcel OB-H (Daicel)).
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:19]1([S:29](Cl)(=[O:31])=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1>>[C:19]1([S:29]([N:4]2[CH2:5][CH2:6][N:1]([C:7]3[CH:16]=[CH:15][CH:14]=[C:13]4[C:8]=3[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]4)[CH2:2][CH2:3]2)(=[O:31])=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: Nc1nc(N)c2c(N3CCNCC3)cccc2n1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Product: Nc1nc(N)c2c(N3CCN(S(=O)(=O)c4cccc5ccccc45)CC3)cccc2n1
Yield: 39 %

Procedure:
Title compound was prepared via Resin Method using 5-piperazin-1-yl-quinazoline-2,4-diamine (50 mg; 0.2 mmol) and 1-Naphthalene-sulfonyl chloride (92.9 mg; 0.41 mmol) to obtain 33.7 mg. (39% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.69 (d, J=8.4 Hz, 1H), 8.38 (br s, 1H), 8.32 (d, J=8.4 Hz, 1H), 8.21 (d, J=7.2 Hz, 1H), 8.14 (d, J=7.6 Hz, 1H), 7.73 (m, 3H), 7.36 (t, J=7.6 Hz, 1H), 6.95 (d, J=8.0 Hz, 1H), 6.91 (br s, 1H), 6.77 (d, J=7.2 Hz, 1H), 5.91 (br s, 2H), 3.83 (d, J=12 Hz, 2H), 3.10 (d, J=12.0 Hz, 2H), 2.90 (t, J=11.5 Hz, 1H), 2.75 (t, J=11.5 Hz, 2H). ESIMS+436.0 m/z
Reaction SMILES: C(OC([O:6][CH2:7][CH2:8][CH2:9][Li])C)C.[Cl:11][C:12]1[CH:13]=[C:14]([C:19]2([C:23]#[N:24])[CH2:22][CH2:21][CH2:20]2)[CH:15]=[CH:16][C:17]=1[Cl:18].[BH4-].[Na+].Cl>CCOCC.CC(O)C.O>[ClH:11].[NH2:24][CH:23]([C:19]1([C:14]2[CH:15]=[CH:16][C:17]([Cl:18])=[C:12]([Cl:11])[CH:13]=2)[CH2:20][CH2:21][CH2:22]1)[CH2:9][CH2:8][CH2:7][OH:6]
Reactant: [Li]CCCOC(C)OCC
Reactant: N#CC1(c2ccc(Cl)c(Cl)c2)CCC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCOCC
Solvent: O
Product: NC(CCCO)C1(c2ccc(Cl)c(Cl)c2)CCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A 0.25M solution of 3-[1-(ethoxy)ethoxy]propyllithium [prepared from 3-[1-(ethoxy)ethoxy]propyl bromide (20 g), lithium strips (1.6 g) and ether (75 ml)] was added to a solution of 1-(3,4-dichlorophenyl)cyclobutanecarbonitrile (4.44 g) in dry ether (100 ml) at 0° C. under argon. The mixture was stirred for 16 hours at ambient temperature and propan-2-ol (50 ml) and then a solution of sodium borohydride (1.5 g) in propan-2-ol (60 ml) were added and the mixture stirred at ambient temperature for 2 days and then heated under reflux for 21/2 hours. The mixture was cooled, poured into water (500 ml) and excess concentrated hydrochloric acid was added. The mixture was heated at 90°-95° C. for one hour, cooled, basified and extracted with ether. The extract was dried and evaporated to given an oil which was treated with a further mixture of sodium borohydride (1 g) and propan-2-ol (50 ml) at reflux for 41/2 hours. The mixture was cooled, and water was added and the resulting mixture extracted with ether. The extract was dried, and evaporated to give an oil which was distilled (170° C./0.65-0.25 mm Hg). The distillate was dissolved in propan-2-ol, 5N-hydrochloric acid was added and the solution evaporated to dryness. The residue was dried by azeotropic distillation with propan-2-ol to give a solid which was triturated with propan-2-ol to give 4-amino-4-[1-(3,4-dichlorophenyl)cyclobutyl]butan-1-ol hydrochloride (m.p. 211° C. (dec)-shrinks 203° C.).
Reaction SMILES: C[C:2](C)([O-:4])C.[K+].S(OC)(OC)(=O)=O.C([O-])([O-])=O.[K+].[K+].[CH:20]12[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]3)[CH:21]1[C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=1)=O)[CH2:27]2>CCCCCC>[CH3:2][O:4][C:20]12[CH2:27][CH:26]3[CH2:25][CH:24]([CH2:23][CH:22]([CH2:28]3)[C:21]1=[CH:30][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=1)[CH2:29]2
Reactant: COc1cccc(C(=O)C2C3CC4CC(C3)CC2C4)c1
Reactant: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CCCCCC
Product: COc1cccc(C=C2C3CC4CC(C3)CC2(OC)C4)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A quantity (11.3 g, 0.042 mol) or 3-methoxyphenyl adamant-2-yl ketone obtained according to Example 1 was suspended in 90 ml of molecular sieve-dried (3 Å) dimethylsulfoxide (DMSO). Heat was applied to dissolve the suspended solid. Upon cooling to room temperature with stirring, a fine suspension was formed. Potassium tertbutoxide (8.5 g, 0.070 mol) was added under an argon atmosphere. After 5 minutes, a nearly homogenous orange solution resulted, which was placed in a water bath at 50° C. Dimethyl sulfate (4 ml, 0.042 mol) was added dropwise by syringe over a period of 10 minutes. After 15 minutes of further stirring, an additional 3.3 ml of dimethyl sulfate (0.034 mol) was added in the same fashion. Subsequently, the colorless solution was stirred overnight at room temperature. After cooling in an ice bath, 0.5 g of K2CO3 and 125 ml of ice water added and the mixture extracted with three 50 ml portions of ethyl acetate. The combined organic fractions were washed with three portions of water, once with 50 ml of saturated aqueous NaCl solution, and dried over K2CO3. The solvent was removed in vacuo to yield an oil. The oil was dissolved in hexane, and the resulting solution filtered through Celite and concentrated in vacuo to provide 11.5 g (96% yield) of a viscous, straw-colored oily substance. TLC indicated a clean conversion to an enol ether (Rf 0.68; E. Merck Al2O3 --CH2Cl2 : hexanes--50:50) with a trace of the ketone starting material. The oil was distilled from K2CO3 (b.p. 148°-150° C., 0.25 mm Hg). Under these conditions, slight yellowing occurred in the still head. I.R. analysis of this distillate revealed a small ketone absorption band at 1670 cm-1. I.R. (CH2 Cl2): 2900 cm-1, 1670 cm-1 (weak), 1600 cm-1, 1590 cm-1, 1580 cm-1, 1570 cm-1, 1095 cm-1, 1080 cm-1 ; 1H-NMR 60 MHz (CDCl3): δ1.5-2.0 (m, 12H), δ2.55 (s, 1H), δ3.2 (s, 1H), δ3.25 (s, 3H), δ3.75 (s, 3H), and δ6.7-7.3 (m, 4H). These data confirmed that the structure of the product was: ##STR23##
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:19])=[C:10]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH:11]=2)[C:6](=[O:20])[C:5]([C:21]([OH:23])=[O:22])=[CH:4]1)[CH3:2].C(N([CH2:29][CH3:30])CC)C.C([CH:33](Cl)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=C>O>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:19])=[C:10]([N:13]3[CH2:18][CH2:17][N:16]([CH2:33][C:34]4[CH:39]=[CH:38][C:37]([CH:29]=[CH2:30])=[CH:36][CH:35]=4)[CH2:15][CH2:14]3)[CH:11]=2)[C:6](=[O:20])[C:5]([C:21]([OH:23])=[O:22])=[CH:4]1)[CH3:2]
Reactant: CCN(CC)CC
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNCC3)cc21
Reactant: C=CC(Cl)c1ccccc1
Solvent: O
Product: C=Cc1ccc(CN2CCN(c3cc4c(cc3F)c(=O)c(C(=O)O)cn4CC)CC2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 91.9 %

Procedure:
Under a nitrogen atmosphere, 400 mg (1.252 mmol) of 1-ethyl-6-fluoro-1,4-dihydro-7-(1-piperazinyl)-4-oxo-3-quinoline carboxylic acid were mixed with 0.349 ml (2.505 mmol) of triethylamine in a round flask of 50 ml and stirred at room temperature for 10 minutes. While the temperature of the inside of the container was kept at −10° C., 0.177 ml (1.252 mmol) of vinylbenzylchloride was slowly dripped thereinto. Under a nitrogen atmosphere, the reaction was conducted for three hours while keeping the temperature at −10° C., and then distilled water was added to the reactants which were then extracted with dichloromethane. The extracts were concentrated and then chromatographed (20 gm silica, 5% MeOH/CH2Cl2) to give 501 mg (91.9%) of 1-ethyl-6-fluoro-1,4-dihydro-7-[4-(4-vinylbenzyl)-1-piperazinyl]-4-oxo-3-quinoline carboxylic acid.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)(O)[CH3:4].N1C=CC=CC=1.S(Cl)([Cl:25])(=O)=O>C1(C)C=CC=CC=1.CCOC(C)=O>[Cl:25][C:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)([CH3:4])[C:2]([F:15])([F:14])[F:1]
Reactant: O=S(=O)(Cl)Cl
Reactant: COc1ccc(C(C)(O)C(F)(F)F)cc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COc1ccc(C(C)(Cl)C(F)(F)F)cc1
Temperature: 55 °C

Procedure:
A solution of 1,1,1-trifluoro-2-(4-methoxyphenyl)propan-2-ol (22.5 g, 102 mmol) in 150 ml of anhydrous toluene was treated sequentially with pyridine (8.26 ml, 102 mmol) and dropwise sulfuryl dichloride (11.2 ml, 153 mmol) at 0° C. The resulting mixture was then heated at 55° C. for 18 h. The reaction was diluted with 100 ml of EtOAc, washed with 100 ml of H2O and 100 ml of 1N HCl, dried over Na2SO4, and concentrated to give an oil which was filtered through a silica gel pad eluting with 0-5% EtOAc in hexanes to afford the title compound.
Reaction SMILES: [CH2:1]([Li])CCC.CCCCCC.Br[C:13]1[CH:14]=[CH:15][C:16]([Cl:34])=[C:17]([CH:33]=1)[CH2:18][C:19]1[CH:32]=[CH:31][C:22]([O:23][Si](C(C)(C)C)(C)C)=[CH:21][CH:20]=1.C[Si](C)(C)[O:37][C@@H:38]1[C@@H:43]([O:44][Si](C)(C)C)[C@H:42]([O:49][Si](C)(C)C)[C@@H:41]([CH2:54][O:55][Si](C)(C)C)[O:40][C:39]1=[O:60]>C1COCC1.C1(C)C=CC=CC=1>[Cl:34][C:16]1[CH:15]=[CH:14][C:13]([C@@:39]2([O:60][CH3:1])[C@H:38]([OH:37])[C@@H:43]([OH:44])[C@H:42]([OH:49])[C@@H:41]([CH2:54][OH:55])[O:40]2)=[CH:33][C:17]=1[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([OH:23])=[CH:31][CH:32]=1
Reactant: [Li]CCCC
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(Cc2cc(Br)ccc2Cl)cc1
Reactant: C[Si](C)(C)OC[C@H]1OC(=O)[C@H](O[Si](C)(C)C)[C@@H](O[Si](C)(C)C)[C@@H]1O[Si](C)(C)C
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(O)cc3)c2)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33 %

Procedure:
A 2.5 M solution of n-butyl lithium in hexane (15 mL, 37.5 mmol) was slowly added to a stirred solution of [4-(5-bromo-2-chloro-benzyl)-phenoxy]-tert-butyl-dimethyl-silane (12.6 g, 30.6 mmol) in 75 mL of a dry THF (25 mL) and toluene (50 mL) solution cooled at −78 degrees Celsius under nitrogen. After stirring for 30 minutes following the addition, the solution was transferred by cannula to a stirring solution of (3R,4S,5R,6R)-3,4,5-tris-trimethylsilanyloxy-6-trimethylsilanyloxymethyl-tetrahydro-pyran-2-one (18.6 g, 40 mmol) in 50 mL of toluene at −78 degrees Celsius. After 1.5 hours following the addition the reaction was quenched at −78 degrees Celsius by the dropwise addition of 5 mL of methanol containing methanesulfonic acid (0.5 mL) and the resulting mixture was allowed to warm to room temperature overnight (˜16 hours). An additional 4.5 mL of methylsulfonic acid in 50 mL of methanol was added dropwise at room temperature and the reaction mixture was stirred at room temperature for an additional 24 hours. A solution of saturated aqueous sodium bicarbonate (300 mL) and ethyl acetate (100 mL) were added and the resulting mixture was stirred for 1 hour. The layers were separated and the aqueous layer was extracted two additional times with ethyl acetate (100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography over silica gel using the ISCO automated chromatography unit (two 120 g silica gel columns) and eluting with a gradient of 0 to 30% methanol in dichloromethane. 4.2 g (33% yield) of product obtained as an off white solid. LCMS 433 (M+Na+, positive mode). 1H NMR (500 MHz, METHANOL-d4) delta ppm 3.08 (s, 3 H), 3.10 (d, J=9.5 Hz, 1 H), 3.43 (t, J=9.3 Hz, 1 H), 3.60 (ddd, J=9.9, 5.7, 2.0 Hz, 1 H), 3.76 (t, J=9.1 Hz, 1 H), 3.82 (dd, J=12.0, 5.6 Hz, 1 H), 3.94 (dd, J=12.1, 1.8 Hz, 1 H), 3.96-4.10 (m, 2 H), 6.69 (d, J=8.3 Hz, 2 H), 7.02 (d, J=8.3 Hz, 2 H), 7.37 (d, J=8.3 Hz, 1 H), 7.46 (dd, J=8.3, 2.0 Hz, 1 H), 7.54 (d, J=1.7 Hz, 1 H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].[H-].[Na+].Cl[CH2:14][CH:15]1[CH2:17][O:16]1>CN(C=O)C.[OH-].[Na+]>[OH:16][CH2:17][CH:15]1[O:10][C:9]2[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=2[O:1][CH2:14]1
Reactant: ClCC1CO1
Reactant: O=Cc1ccc(O)c(O)c1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=Cc1ccc2c(c1)OCC(CO)O2
Reaction time: 8 h
Yield: 11.8 %

Procedure:
To a cold (5° C.) solution of 3,4-dihydroxybenzaldehyde (3.20 g, 23.2 mmol) in DMF (70 mL) is carefully added NaH (1.96 g 55% in mineral oil, 48.5 mmol) in portions. The temperature rises to 12° C. Upon completion of the addition, the cooling is removed and a solution of 2-chloromethyl-oxirane (2.57 g, 27.7 mmol) in DMF (3 mL) is added. The reaction mixture is stirred at it overnight. The mixture is diluted with 1N aq. NaOH (150 mL) and extracted with EA (2×200 mL). The organic extracts are washed with 1 M aq. NaOH (2×200 mL) and water (200 mL), combined, dried over MgSO4, filtered and concentrated. The remaining residue is purified by column chromatography on silica gel eluting with heptene/EA 5:1 to 1:1 to afford the title aldehyde (0.53 g) as a solid. LC: tR=0.69 min. 1H NMR (D6-DMSO): δ 9.77 (s, 1H), 7.41 (dd, J=2.3, 8.2 Hz, 1H), 7.36 (d, J=2.3 Hz, 1H), 7.04 (d, J=8.2 Hz, 1H), 5.10 (t, J=5.9 Hz, 1H, D2O exchangeable), 4.37 (dd, J=2.3, 11.1 Hz, 1H), 4.30-4.23 (m, 1H), 4.05 (dd, J=7.6, 11.1 Hz, 1H), 3.67-3.60 (m, 2H).
Reaction SMILES: [NH:1]([C:8](=[O:29])[C:9]([C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[CH:22][CH:21]=1)([C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:12])[OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.[CH:41]1[CH:42]=[CH:43][C:44]2[N:49](O)N=[N:47][C:45]=2[CH:46]=1.C1(N)C=CC=CC=1N>CN(C=O)C>[NH2:47][C:45]1[CH:46]=[CH:41][CH:42]=[CH:43][C:44]=1[NH:49][C:24]([C:23]1[CH:27]=[CH:28][C:20]([C:9]([OH:10])([C:8]([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:29])[C:11]([NH:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:12])=[CH:21][CH:22]=1)=[O:26]
Reactant: O=C(O)c1ccc(C(O)(C(=O)Nc2ccccc2)C(=O)Nc2ccccc2)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Nc1ccccc1N
Solvent: CN(C)C=O
Product: Nc1ccccc1NC(=O)c1ccc(C(O)(C(=O)Nc2ccccc2)C(=O)Nc2ccccc2)cc1
Reaction time: 0.5 h
Yield: 68.5 %

Procedure:
To a solution of 4-[2-anilino-1-(anilinocarbonyl)-1-hydroxy-2-oxoethyl]benzoic acid (31 mg, 0.079 mmol) in DMF (1.5 mL) at room temperature was added EDCI (18 mg, 0.094 mmol) and HOBT (13 mg, 0.096 mmol). The solution was stirred for 30 min and 1,2-phenylenediamine (31 mg, 0.29 mmol) was added in one portion. The reaction mixture was stirred at room temperature for 18 h and purified by reverse phase HPLC (30% to 95% MeCN in water) to give 2-(4-{[(2-aminophenyl)amino]carbonyl}phenyl)-2-hydroxy-N,N′-diphenylmalonamide (26 mg, TFA salt, 55%) as a white solid: 1H NMR (600 MHz, DMSO-d6) δ 10.10 (s br, 2H), 9.64 (s br, 1H), 7.97 (d, J=8.5 Hz, 2H), 7.82 (d, J=8.5 Hz, 2H), 7.70 (s, 1H), 7.69 (d, J=7.6 Hz, 2H), 7.32 (td, J=7.3, 2.1 Hz, 4H), 7.15 (d, J=7.3 Hz, 1H), 7.09 (t, J=6.4 Hz, 2H), 6.95 (td, J=8.2, 1.8 Hz, 1H), 6.76 (dd, J=7.9, 1.5 Hz, 1H), 6.58 (t, J=7.6 Hz, 1H), 4.89 (s br, 2H); ESIMS calcd 481.2 (M++H), found 481.1 (M++H).