Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:11][C@H:12]([CH2:30][CH2:31][CH2:32][NH:33]C(OCC1C=CC=CC=1)=O)[CH2:13][C:14]([NH:16][CH2:17][CH2:18][NH:19]C(OCC1C=CC=CC=1)=O)=[O:15])=O)C1C=CC=CC=1.[H][H]>CO.O.[C].[Pd]>[NH2:11][C@H:12]([CH2:30][CH2:31][CH2:32][NH2:33])[CH2:13][C:14]([NH:16][CH2:17][CH2:18][NH2:19])=[O:15]
Reactant: O=C(C[C@@H](CCCNC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1)NCCNC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: O
Product: NCCC[C@@H](N)CC(=O)NCCN
Yield: 98.9 %

Procedure:
In 180 ml of methanol were suspended 1.41 g (2.39 mmol) of (R)-3,6-bis(benzyloxycarbonylamino)-N-(2-benzyloxycarbonylaminoethyl)hexanamide. To the resulting suspension was added a suspension of 718 mg of 10% palladium-carbon in 20 ml of water. After stirring, hydrogen gas was passed through the resulting mixture at room temperature for 3 hours to effect the reaction. The palladium-corbon was filtered off from the reaction mixture obtained, and the filtrate was concentrated to dryness. The residue obtained was dissolved in 15 ml of water and then subjected to a chromatography on a column of "Amberlite CG-50" (trade name, NH4+ -form, 50 ml). After the column was washed with 200 ml of water, the column was eluted with aqueous ammonia at concentrations gradiently varying from 0.5% to 4.0% (0.5%-increased steps; 200 ml at each concentration). Fractions of the eluate as eluted with 2.5% to 3.5% aqueous ammonia were combined together and concentrated to dryness, to afford 445 mg of (R)-3,6-diamino-N-(2-aminoethyl)hexanamide as a colorless paste.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:6][C:7]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])=[CH:8][CH:9]=1)[CH3:3].[N+](N[C:19]1[NH:24][C:23](=[O:25])[C:22]([CH2:26][C:27]2[CH:32]=[CH:31][N:30]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:29](=[O:40])[CH:28]=2)=[CH:21][N:20]=1)([O-])=O>N1C=CC=CC=1>[CH3:3][N:2]([CH2:4][C:5]1[O:6][C:7]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:19]2[NH:24][C:23](=[O:25])[C:22]([CH2:26][C:27]3[CH:32]=[CH:31][N:30]([CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:29](=[O:40])[CH:28]=3)=[CH:21][N:20]=2)=[CH:8][CH:9]=1)[CH3:1]
Reactant: CN(C)Cc1ccc(CSCCN)o1
Reactant: O=c1[nH]c(N[N+](=O)[O-])ncc1Cc1ccn(Cc2ccccc2)c(=O)c1
Solvent: c1ccncc1
Product: CN(C)Cc1ccc(CSCCNc2ncc(Cc3ccn(Cc4ccccc4)c(=O)c3)c(=O)[nH]2)o1
Yield: 83.1 %

Procedure:
2-(2-Dimethylaminomethyl-5-furylmethylthio)ethylamine (2.28 g) and 2-nitroamino-5-(1-benzyl-2-oxopyridin-4-ylmethyl)pyrimidin-4-one (2.80 g) were refluxed in pyridine (12 ml) for 20 hours. The reaction mixture was evaporated under reduced pressure and the resultant oily residue was washed with hot water. The mixture was allowed to cool and the water was washed twice with cold water and recrystallised from isopropanol to yield 2-[2-(2-dimethylaminomethyl-5-furylmethylthio)ethylamino]-5-(1-benzyl-2-oxopyridin-4-ylmethyl)pyrimidin-4-one (3.33 g), m.p. 95.5°-98° C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1.Cl[C:15]1[C:16]2[N:17]([CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:19][N:20]=1>CCN(C(C)C)C(C)C.F[B-](F)(F)F.C([N+]1C=CN(C)C=1)CCC>[C:15]1([N:1]2[CH2:5][CH2:4][C@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH2:2]2)[C:16]2[N:17]([CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:19][N:20]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: Clc1nccn2cccc12
Agent: CCCC[n+]1ccn(C)c1
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H]1CCN(c2nccn3cccc23)C1
Temperature: 110 °C
Yield: 59.2 %

Procedure:
To a solution of (S)-tert-butyl pyrrolidin-3-ylcarbamate (0.91 g, 4.9 mmol, 1 eq) in 2.6 mL of DIPEA was added 1-chloropyrrolo[1,2-a]pyrazine (0.75 g, 4.9 mmol, 1 eq) and 1 drop of 1-butyl-3-methylimidazolium tetrafluorborate. After heating for 3 h at 110° C., the mixture was concentrated and purified by silica gel flash chromatography (100% EtOAc) to afford (S)-tert-butyl N-(1-(pyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl)carbamate (0.88 g, 2.9 mmol, 59%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:16][OH:17])=[C:6]([CH:15]=1)[CH:7]([OH:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Se](=O)=O>C(O)(=O)C>[C:7]([C:6]1[CH:15]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[CH:16]=[O:17])(=[O:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: OCc1ccc(Cl)cc1C(O)c1ccccc1
Agent: O=[Se]=O
Solvent: CC(=O)O
Product: O=Cc1ccc(Cl)cc1C(=O)c1ccccc1

Procedure:
A solution of 9.3 g. of 5-chloro-2-hydroxymethylbenzhydrol in 50 ml. of acetic acid and 5.2 g. of selenium dioxide was refluxed for 3 hours. The mixture was filtered, cooled, poured on ice, made alkaline and extracted with ether. Concentration and addition of petroleum ether gave the product as prisms which after recrystallization from a mixture of ether and petroleum ether melted at 82°-84°. Ultraviolet maxima (2-propanol) at 230 mμ (ε = 19,500) and 257 mμ (ε = 23,500); infrared absorption (CHCl3) at 1675 cm-1 and 1705 cm-1.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([F:19])=[CH:7][C:8]([Cl:18])=[C:9]([NH:11][C:12]([NH:14][CH2:15][C:16]#[CH:17])=[O:13])[CH:10]=1)(=[O:3])[CH3:2].N1C=CC=CC=1.[C:26](=[O:31])=[N:27][C:28](Cl)=[O:29]>C(Cl)Cl>[Cl:18][C:8]1[C:9]([N:11]2[C:28](=[O:29])[NH:27][C:26](=[O:31])[N:14]([CH2:15][C:16]#[CH:17])[C:12]2=[O:13])=[CH:10][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[C:6]([F:19])[CH:7]=1
Reactant: O=C=NC(=O)Cl
Reactant: C#CCNC(=O)Nc1cc(NC(C)=O)c(F)cc1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: C#CCn1c(=O)[nH]c(=O)n(-c2cc(NC(C)=O)c(F)cc2Cl)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-(5-acetamido-2-chloro-4-fluorophenyl)-3-(2-propynyl)urea (4.50 g, 15.9 mmol), and pyridine (2.56 mL, 31.8 mmol) in methylene chloride is treated with N-(chlorocarbonyl) isocyanate (1.92 mL, 23.9 mmol), stirred at room temperature overnight, refluxed for 90 minutes, cooled to room temperature, treated with additional pyridine (1.30 mL) and N-(chlorocarbonyl) isocyanate (1.92 mL), stirred for 10 minutes, cooled to room temperature, and filtered to obtain a solid. The solid is washed sequentially with water and hexanes, and dried to give the title product as a tan solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:12])[CH2:5][NH:6][CH2:7][C:8]([O:10][CH3:11])=[O:9].CN1CCOCC1.[I:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[CH3:11][O:10][C:8](=[O:9])[CH2:7][N:6]([C:25](=[O:26])[C:24]1[CH:28]=[CH:29][C:21]([I:20])=[CH:22][CH:23]=1)[CH2:5][C:4]([O:3][CH3:2])=[O:12]
Reactant: O=C(O)c1ccc(I)cc1
Reactant: COC(=O)CNCC(=O)OC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: COC(=O)CN(CC(=O)OC)C(=O)c1ccc(I)cc1
Temperature: 45 °C
Reaction time: 0.08 h

Procedure:
Iminodiacetic dimethyl ester hydrochloride (624 mg, 3.24 mmol) was suspended in 5 mL of anhydrous DMF under nitrogen, and N-methylmorpholine (360 μL, 3.27 mmol) was added. After 5 minutes, 4-iodobenzoic acid (805 mg, 3.25 mmol) was added, followed by HOBt (450 mg, 3.33 mmol) and EDC (1.0 g, 5.28 mmol). The reaction was stirred overnight at 45° C. The solvent was removed and the residue was dissolved in EtOAc (20 mL) and washed with 0.5 M HCl, sat. NaHCO3 and water. The organic phase was collected, the solvent removed and the mixture purified by column chromatography (silica; hexanes:EtOAc 90:10-65:45), yielding the product as a white solid. MS (ES+): Cal'd. 392.00 (MH+), exp. 391.98 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[C:20]([N+:25]([O-:27])=[O:26])[CH:21]=[N:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][N:22]=[CH:21][C:20]=4[N+:25]([O-:27])=[O:26])[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2c1cncc2[N+](=O)[O-]
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1c2cncc([N+](=O)[O-])c2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-5-nitro-1,2,3,4-tetrahydro-[2,7]naphthyridine to provide the title compound in moderate yield.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[C:9]([C:10]([OH:12])=[O:11])[C:8]=2[OH:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]1([CH3:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH2:24]=[O:25].S(=O)(=O)(O)O>C(O)(=O)C>[C:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[C:9]([C:10]([OH:12])=[O:11])[C:8]=2[OH:16])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[C:17]1([CH3:23])[C:18]([CH:24]=[O:25])=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: C=O
Reactant: Cc1ccccc1
Agent: O=C(O)c1cccc(-c2ccccc2)c1O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1ccccc1C=O

Procedure:
To a mixture of 21.4 parts of 3-phenylsalicylic acid, 18.4 parts of toluene, 3.8 parts of 87% paraformaldehyde and 30 parts of acetic acid was added 2.0 parts of 95% sulfuric acid (catalyst). After being heated under reflux for 4 hours, the reaction mixture was washed with water, and unreacted toluene and water were removed by vacuum distillation to give 32 parts of 3-phenylsalicylic acid-toluene-formaldehyde co-condensation product. 10 parts of the co-condensation product was converted into its zinc salt in a similar manner as in Synthesis Example 4. There was obtained 10.8 parts of zinc salt of 3-phenylsalicylic acid-toluene-formaldehyde co-condensation product.
Reaction SMILES: I[C:2]1[S:6][CH:5]=[C:4]([P:7]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])=[O:8])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:20]1[S:21][CH:22]=[CH:23][C:24]=1[P:25]([O:30][CH2:31][CH3:32])([O:27][CH2:28][CH3:29])=[O:26])CCC.[F-].[K+]>C1(C)C=CC=CC=1.[Cu]Cl>[CH2:10]([O:9][P:7]([C:4]1[CH:3]=[C:2]([C:20]2[S:21][CH:22]=[CH:23][C:24]=2[P:25]([O:30][CH2:31][CH3:32])([O:27][CH2:28][CH3:29])=[O:26])[S:6][CH:5]=1)([O:12][CH2:13][CH3:14])=[O:8])[CH3:11]
Reactant: CCOP(=O)(OCC)c1csc(I)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1sccc1P(=O)(OCC)OCC
Agent: Cl[Cu]
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCOP(=O)(OCC)c1csc(-c2sccc2P(=O)(OCC)OCC)c1
Yield: 84 %

Procedure:
At room temperature, 1.4875 g (4.3 mmols) of 5-iodo-3-(diethoxyphosphoryl)thiophene and 0.0994 g (0.086 mmols) of commercially available tetrakistriphenylphosphine palladium were dissolved in 43 ml of toluene, to which 2.1899 g (4.3 mmols) of 2-tributylstannyl-3-(diethoxyphosphoryl)thiophene and 0.0347 g (0.39 mmols) of commercially available copper(I) chloride were added at room temperature. Thereafter, the reaction mixture was heated and stirred under reflux for 3.5 hours. After the reaction, the reaction mixture was cooled down to room temperature, to which a potassium fluoride aqueous solution was added, followed by stirring for 1 hour. Thereafter, the solid was removed by celite filtration and the filtrate was extracted with ethyl acetate. The resulting organic phase was washed with a saturated saline solution and dried over anhydrous sodium sulfate. The solvent was removed by distilling off under reduced pressure, and the resulting crude product was purified with a silica gel column (gradiated with acetone from ethyl acetate) to obtain the specified substance in the form of a yellow oil at a yield of 1.5836 g (yield: 84%).
Reaction SMILES: [SH:1][CH2:2][CH2:3][OH:4].[H-].[Na+].[C:7]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH:20][C:21]2[C:26]([O:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[CH:29]=3)=[C:25](Cl)[N:24]=[CH:23][N:22]=2)(=[O:19])=[O:18])=[CH:13][CH:12]=1)([CH3:10])([CH3:9])[CH3:8].Cl>CC(N(C)C)=O>[C:7]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH:20][C:21]2[C:26]([O:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[CH:29]=3)=[C:25]([S:1][CH2:2][CH2:3][OH:4])[N:24]=[CH:23][N:22]=2)(=[O:19])=[O:18])=[CH:13][CH:12]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: OCCS
Reactant: COc1cccc(Oc2c(Cl)ncnc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1cccc(Oc2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2SCCO)c1
Yield: 69.5 %

Procedure:
To a solution of 2-mercaptoethanol (1.31 g) in dimethylacetamide (15 ml) is added sodium hydride (62.3% dispersion-type, 520 mg) under argon atmosphere. Five minutes later, to the mixture is added 4-tert-butyl-N-{6-chloro-5-(3-methoxyphenoxy)pyrimidin-4-yl}benzenesulfonamide (1.5 g), and the mixture is reacted under argon atmosphere at 70° C. for two hours, at 100° C. for three hours, and further reacted at 130° C. for two hours. The reaction solution is treated with hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer is washed, dried, and evaporated to remove the solvent. The residue is purified by silica gel column chromatography (solvent; chloroform/methanol=70:1), and recrystallized from ethyl acetate/n-hexane to give 4-tert-butyl-N-{6-(2-hydroxyethylthio)-5-(3-methoxyphenoxy)pyrimidin-4-yl}benzenesulfonamide (1.14 g) as crystals.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([O:10][C:11]3[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19](O)=[O:20])=[CH:13][CH:12]=3)=[C:8]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)[S:7][C:6]=2[CH:32]=1.Cl.CN.[CH3:36][N:37](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([O:10][C:11]3[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([NH:37][CH3:36])=[O:20])=[CH:13][CH:12]=3)=[C:8]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)[S:7][C:6]=2[CH:32]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)/C=C/c1ccc(Oc2c(-c3ccc(C(F)(F)F)cc3)sc3cc(O)ccc23)cc1
Agent: CN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)/C=C/c1ccc(Oc2c(-c3ccc(C(F)(F)F)cc3)sc3cc(O)ccc23)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 82.9 %

Procedure:
To a vial containing (E)-3-(4-((6-hydroxy-2-(4-(trifluoromethyl)phenyl)-benzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid (15.9 mg, 0.035 mmol) was added DMF (1.0 mL), followed by methylamine hydrochloride (7.1 mg, 0.105 mmol), HATU (19.9 mg, 0.052 mmol), and DIEA (0.030 mL, 0.174 mmol). The mixture was stirred at room temperature for 12 h after which the reaction was quenched with water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the crude product which was purified by reverse phase HPLC (neutral condition, 3% 1-propanol in 1-100% CH3CN/H2O) to afford (E)-3-(4-((6-hydroxy-2-(4-(trifluoromethyl)phenyl)benzo[b]thiophen-3-yl)oxy)phenyl)-N-methylacrylamide (13.8 mg, 0.029 mmol, 84% yield). 1H NMR (400 MHz, CD3OD) δ ppm=2.82 (s, 3H), 6.43 (d, J=15.66 Hz, 1H), 6.82 (dd, J=8.59, 2.02 Hz, 1H), 6.89-7.02 (m, 2H), 7.13-7.30 (m, 2H), 7.37-7.52 (m, 3H), 7.61 (d, J=8.08 Hz, 2H), 7.85 (d, J=8.08 Hz, 2H). HRMS (m/z, MH+): 470.1018.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH3:19])=[C:15]([CH2:20][O:21][CH2:22][CH3:23])[CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2].[H][H]>C(O)C.[C].[Pd]>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[CH2:12][CH2:13][CH2:14][CH:15]([CH2:20][O:21][CH2:22][CH3:23])[C:16]=3[C:17]=2[C:18]=1[CH3:19])=[O:5])[CH3:2]
Reactant: CCOCc1cccc2[nH]c3cnc(C(=O)OCC)c(C)c3c12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOCC1CCCc2[nH]c3cnc(C(=O)OCC)c(C)c3c21
Reaction time: 2 h

Procedure:
5-Ethoxymethyl-4-methyl-beta-carboline-3-carboxylic acid ethyl ester (1 g) is shaken in ethanol (80 ml) with 10% palladium carbon (0.3 g) at a hydrogen pressure of 40 bars and a temperature of 70° C. for 2 hours. After filtering off of the catalyst, the reaction solution is evaporated, the residue is crystallized by treatment with a mixture of acetic acid and ethanol. The yield in 5,6,7,8-tetrahydro-5-ethoxymethyl-4-methyl-beta-carboline-3-carboxylic acid ethyl ester is 0.66 g.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][N:7]1[C:11]([NH2:12])=[C:10]2[CH2:13][CH2:14][CH2:15][C:9]2=[N:8]1.N1C=CC=CC=1.[CH3:22][O:23][C:24]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][C:25]=1[C:26](Cl)=[O:27]>C(Cl)Cl>[CH3:22][O:23][C:24]1[CH:32]=[CH:31][C:30]([C:33]([F:34])([F:35])[F:36])=[CH:29][C:25]=1[C:26]([NH:12][C:11]1[N:7]([CH2:6][C@H:2]2[CH2:3][CH2:4][CH2:5][O:1]2)[N:8]=[C:9]2[CH2:15][CH2:14][CH2:13][C:10]=12)=[O:27]
Reactant: COc1ccc(C(F)(F)F)cc1C(=O)Cl
Reactant: Nc1c2c(nn1C[C@@H]1CCCO1)CCC2
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(C(F)(F)F)cc1C(=O)Nc1c2c(nn1C[C@H]1CCCO1)CCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.9 %

Procedure:
To a solution of the product of Example 32A (340 mg, 1.64 mmol) and pyridine (535 μL, 6.56 mmol) in CH2Cl2 (20 mL) was added 2-methoxy-5-(trifluoromethyl)benzoyl chloride (470 mg, 1.97 mmol) dropwise. The mixture was stirred at ambient temperature for 1 h. The mixture was concentrated under reduced pressure and was purified by column chromatography (SiO2, 40% hexanes/EtOAc) to provide the title compound 550 mg (82%). MS (DCI/NH3) m/z 410 (M+H)+.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].CON(C)[C:11]([CH:13]1[CH2:17][S:16][C:15](=[O:18])[N:14]1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[O:12].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O>[CH3:27][O:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][N:14]2[C@H:13]([C:11](=[O:12])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4])[CH2:17][S:16][C:15]2=[O:18])=[CH:25][CH:24]=1
Reactant: COP(C)(=O)OC
Reactant: COc1ccc(CN2C(=O)SCC2C(=O)N(C)OC)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)SC[C@H]2C(=O)CP(=O)(OC)OC)cc1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 94.8 %

Procedure:
A dry three-necked round bottom flask fitted with an internal temperature probe and a mechanical stirrer was charged with dimethyl methylphosphonate (36.7 mL, 0.338 mol) and 0.5 L of THF. The solution was purged with nitrogen and cooled to −70° C. 126 mL of a 2.55 M solution of n-butyllithium was added dropwise maintaining an internal reaction temperature less than −60° C. In a separate flask, 3-(4-methoxy-benzyl)-2-oxo-thiazolidine-4-carboxylic acid methoxy-methyl-amide (50.0 g, 0.161 mol) was dissolved in 300 mL of dry THF. The resulting solution was added to the solution of dimethyl methylphosphonate anion at a rate maintaining an internal reaction temperature less than −60° C. The reaction was monitored by HPLC and was considered complete upon the disappearance of starting material. The reaction mixture was slowly added to 50 mL of a 10% citric acid solution at a rate that maintained a temperature of less than 5° C. The mixture was diluted with 0.35 L of water. The THF was removed by distillation at atmospheric pressure. The product was extracted with 300 mL of ethyl acetate. The organic phase was separated and a suspension was formed by the addition of 250 mL of n-heptane. The suspension was stirred for 30 minutes. The resulting solid was isolated by filtration and was dried in a vacuum oven at 40° C. for 12 hours. Approximately 57 g of (R)-dimethyl 2-(3-(4-methoxybenzyl)-2-oxothiazolidin-4-yl)-2-oxoethylphosphonate was obtained (94% yield). 1H NMR (300 MHz, DMSO) δ 7.16 (d, 8.5 Hz, 2H), 6.89 (d, 8.5 Hz, 2H), 4.78 (d, J=15.2 Hz, 1H), 4.69-4.61 (m, 1H), 3.79-3.55 (m, 11H), 3.51-3.27 (m, 3H). 13C NMR (75 MHz, DMSO) δ 36.3, 38.0, 46.9, 53.5, 55.08, 66.1, 114.7, 129.0, 129.9, 159.4, 171.9, 199.0; [α]25.0D-29.60 (c=1.00, EtOH).
Reaction SMILES: O[CH:2]([NH:7][C:8](=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])[C:3]([Cl:6])([Cl:5])[Cl:4].S(Cl)([Cl:19])=O>CN(C)C=O.ClCCl>[Cl:19][CH:2]([NH:7][C:8](=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])[C:3]([Cl:6])([Cl:5])[Cl:4]
Reactant: O=S(Cl)Cl
Reactant: O=C(NC(O)C(Cl)(Cl)Cl)c1ccccc1O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(NC(Cl)C(Cl)(Cl)Cl)c1ccccc1O
Yield: 99.9 %

Procedure:
To 14.2 g of N-(1-hydroxy-2,2,2-trichloroethyl)-2-hydroxybenzamide were added 100 ml of dichloromethane, 0.1 g of N,N-dimethylformamide and 7.2 g of thionyl chloride, and the reaction was effected while stirring under reflux for three hours. Excess thionyl chloride was distilled off together with the solvent under reduced pressure to obtain 15.1 g of N-(1,2,2,2-tetrachloroethyl)-2-hydroxybenzamide.
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][CH2:5][NH2:6].Cl.[CH2:8]([NH:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1)[CH2:9][CH2:10][CH:11]=[CH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.COCCOC>[Br:2][CH2:3][CH2:4][CH2:5][NH:6][C:27](=[O:28])[C:26]1[CH:25]=[CH:24][C:23]([NH:22][CH2:8][CH2:9][CH2:10][CH:11]=[CH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:31][CH:30]=1
Reactant: CCCCCCCCCC=CCCCNc1ccc(C(=O)Cl)cc1
Reactant: NCCCBr
Agent: Br
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: CCCCCCCCCC=CCCCNc1ccc(C(=O)NCCCBr)cc1

Procedure:
To a slurry of 21.80 g. of 3-bromopropylamine hydrobromide in 200 ml. of glyme at 3° C. is added a solution of 23.9 g. of 4-(4-tetradecenylamino)benzoyl chloride hydrochloride in 65 ml. of glyme, concurrently with 26 ml. of triethylamine diluted to 39 ml. with 1,2-dimethoxyethane. The solution is warmed to reflux and 0.2 g. of 4-dimethylaminopyridine is added. The solution was heated for four hours and cooled overnight. The solid is removed and the mother liquor diluted with 200 ml. of water to yield a solid which is crystallized from cyclohexane and recrystallized from acetonitrile to yield the product.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:12](Cl)(=[O:14])=[O:13])=[CH:7]2.[NH3:16]>>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:12]([NH2:16])(=[O:14])=[O:13])=[CH:7]2
Reactant: N
Reactant: O=S(=O)(Cl)c1ccc2c(Cl)cccc2c1
Product: NS(=O)(=O)c1ccc2c(Cl)cccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.8 %

Procedure:
5-Chloronaphthalene-2-sulfonyl chloride (Toronto, 531 mg, 2.03 mmol) was treated with NH3 (10.2 mL, 5.08 mmol, 0.5M solution in dioxanes) and stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo, redissolved in sat. aq. NaHCO3 solution and extracted with CHCl3 (3×). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (200 mg, 37%). 1H NMR (DMSO-d6) δ 8.53 (d, J=1.8 Hz, 1H), 8.36 (d, J=9.0 Hz, 1H), 8.18 (d, J=8.6 Hz, 1H), 8.06 (d, J=9.0 Hz, 1H), 7.87 (d, J=7.5 Hz, 1H), 7.70-7.62 (m, 1H); MS(ESI−) m/z 240.3 (M−H)−.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[C:18]=2F)=[N:15][OH:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+]>C1COCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[C:18]=3[O:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cccc(C(=NO)C2CCN(C(=O)OC(C)(C)C)CC2)c1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cccc2c(C3CCN(C(=O)OC(C)(C)C)CC3)noc12
Temperature: 25 °C
Yield: 64.4 %

Procedure:
To a room temperature mixture of 4-[(2-Fluoro-3-methoxy-phenyl)-hydroxyimino-methyl]-piperidine-1-carboxylic acid tert-butyl ester (5.00 g, 14.2 mmol) in THF (50 mL) under nitrogen was added potassium tert-butoxide (15.0 mL of a 1M THF solution, 15.0 mmol) rapidly and the reaction refluxed for 4 h. After cooling to room temperature, the reaction was diluted with ethyl acetate (250 mL) and washed with water (100 mL) and brine (100 mL) successively. The organics were dried over magnesium sulfate, filtered, and concentrated to give a waxy solid. Recrystallization of the solid did not remove impurities so the crude product was chromatographed on silica using a step gradient elution of 10% ethyl acetate/dichloromethane to 40% ethyl acetate/dichloromethane to afford 3.04 g (64%) of the desired product as a white powder, mp:130–132° C.