Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([OH:29])=[C:24]([O:27][CH3:28])[CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH:12]=[CH:13][C:14]=1[Cl:15].Br[CH2:31][CH2:32][NH:33]C(=O)OC(C)(C)C.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C(=O)C.CO.O1CCOCC1>[ClH:8].[NH2:33][CH2:32][CH2:31][O:29][C:23]1[CH:22]=[C:21]2[C:26]([C:17]([NH:16][C:11]3[CH:12]=[CH:13][C:14]([Cl:15])=[C:9]([Cl:8])[CH:10]=3)=[N:18][CH:19]=[N:20]2)=[CH:25][C:24]=1[O:27][CH3:28]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CO
Product: COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1OCCN
Temperature: 100 °C
Yield: 170.3 %

Procedure:
A solution of 4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-ol trifluoroacetate (salt) (1.00 g, 2.15 mmol), 1,1-dimethylethyl (2-bromoethyl)carbamate (0.480 g, 2.15 mmol), and potassium carbonate (1.78 g, 12.9 mmol) in N,N-dimethylacetamide (2.2 mL) was heated to 100° C. for 2.5 h. An additional 0.23 g (1.03 mmol) of 1,1-dimethylethyl (2-bromoethyl)carbamate was added and the reaction mixture was further heated to 100° C. for a total of 7 h. The crude reaction mixture was partitioned between water and ethyl acetate and the layers were separated. The aqueous layer was extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Column chromatography (SiO2, 3:2 hexanes:acetone) gave N-Boc product, which was then taken up in methanol and treated with 4M hydrogen chloride in dioxane while heating. Dilution with ethyl ether precipitated a pale yellow solid, which was collected by filtration and dried to give 0.761 g (94%) of 7-[(2-aminoethyl)oxy]-N-(3,4-dichlorophenyl)-6-(methyloxy)quinazolin-4-amine hydrochloride. 1H NMR (400 MHz, d6-DMSO): 12.01 (s, 1H), 8.94 (s, 1H), 8.67 (s, 1H), 8.35 (broad s, 2H), 8.21 (s, 1H), 7.90 (dd, 1H), 7.75 (d, 1H), 7.53 (s, 1H), 4.43 (t, 2H), 4.08 (s, 3H), 3.36 (m, 2H).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]5[CH2:26][N:25]([CH2:27][C:28]([NH2:30])=[O:29])[CH2:24]5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].OC(C(F)(F)F)=O.N1CC(C2C=CC3C4N=C(C5N(C(C)C)N=CN=5)SC=4[CH2:51][CH2:52][O:53][C:44]=3[CH:43]=2)C1.ClCC(N1CCOCC1)=O>>[CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]5[CH2:24][N:25]([CH2:27][C:28]([N:30]6[CH2:43][CH2:44][O:53][CH2:52][CH2:51]6)=[O:29])[CH2:26]5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CNC3)ccc1-2
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(CC(N)=O)C3)ccc1-2
Agent: O=C(CCl)N1CCOCC1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(CC(=O)N4CCOCC4)C3)ccc1-2

Procedure:
Following the procedure of 319, a suspension of 8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene TFA salt 235 (200 mg, 0.42 mmol) and 4-(2-chloroacetyl)morpholine gave 471 isolated as a yellow solid (79 mg, 22%). LCMS: RT=3.17 min, [M+H]+=495. 1H NMR δ (ppm) (DMSO-d6): 8.25 (1 H, d, J=8.17 Hz), 8.05 (1 H, s), 7.17 (1 H, dd, J=8.24, 1.82 Hz), 7.03 (1H, d, J=1.77 Hz), 5.82-5.73 (1 H, m), 4.35-4.29 (2 H, m), 3.67-3.56 (2 H, m), 3.58-3.45 (5 H, m), 3.44-3.34 (6 H, m), 3.31 (2 H, s), 3.16 (2 H, t, J=6.11 Hz), 1.50 (6 H, d, J=6.59 Hz)
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]([CH3:31])[C:10]([NH:12][CH2:13][C:14]2[C:15]([C:24]3[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=3)=[N:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>ClCCl>[CH3:39][S:40]([NH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]([CH3:31])[C:10]([NH:12][CH2:13][C:14]2[C:15]([C:24]3[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=3)=[N:16][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:18][CH:19]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1)(=[O:42])=[O:41]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cccc(-c2nc(C(F)(F)F)ccc2CNC(=O)C(C)c2cccc(CN)c2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(-c2nc(C(F)(F)F)ccc2CNC(=O)C(C)c2cccc(CNS(C)(=O)=O)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 0.6 %

Procedure:
A cooled solution of 2-(3-(aminomethyl)phenyl)-N-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide (90 mg, 21 mmol) in dichloromethane was added triethylamine (45 μL, 42 mmol) at 0° C. The resulting solution was treated dropwise with methanesulfonyl chloride (24.4 μL, 31.6 mmol) over 10 min and stirred for 1 h at room temperature. After aqueous workup, the residue was purified by flash column chromatography to obtain 2-(3-(methylsulfonamidomethyl)phenyl)-N-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide (example 1) (67 mg, 60%).
Reaction SMILES: F[C:2](F)(F)[C:3](O)=[O:4].[CH3:8][O:9][C:10](=[O:21])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([NH:19][NH2:20])=[S:18])[CH:12]=1.Cl.C(OC(=N)CCl)C>CCO.CCOC(C)=O>[CH3:8][O:9][C:10](=[O:21])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[S:18][C:2]([CH2:3][OH:4])=[N:20][N:19]=2)[CH:12]=1
Reactant: COC(=O)c1cccc(C(=S)NN)c1
Reactant: O=C(O)C(F)(F)F
Agent: CCOC(=N)CCl
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(-c2nnc(CO)s2)c1
Temperature: 80 °C
Yield: 39.7 %

Procedure:
A mixture of 3-hydrazinothiocarbonyl-benzoic acid methyl ester trifluoroacetate (0.49 g) and 2-chloro-acetimidic acid ethyl ester hydrochloride (0.47 g) in EtOH (6 mL) was heated to 80° C. for 2.5 h. The mixture was diluted with AcOEt and washed with 1N HCl and with brine. The organic layer was dried and evaporated. The residual oil (0.8 g) was dissolved in MeOH (5 mL), MeONa (0.08 g) was added and the solution was heated to 65° C. for 0.5 h. The mixture was diluted with AcOEt and washed with 1N HCl and with brine. The organic layer was dried and evaporated and the residue was crystallized from AcOEt/hexane to give 3-(5-hydroxymethyl-[1,3,4]thiadiazol-2-yl) -benzoic acid methyl ester (0.15 g) as a white solid, MS (ISP) 251.2 [(M+H)+].
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([NH2:16])=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[B-](F)(F)(F)F.[CH3:26][CH2:27][O+](CC)CC>C(Cl)Cl>[CH2:1]([O:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](=[NH:16])[O:15][CH2:26][CH3:27])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CC[O+](CC)CC
Reactant: CCCCCCCCCCOc1ccccc1C(N)=O
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CCCCCCCCCCOc1ccccc1C(=N)OCC
Reaction time: 8 h

Procedure:
2-Decyloxybenzamide (38.4 g.) was added to a solution of triethyloxonium borofluoride (30 g.) in anhydrous methylene chloride (90 ml.), and the mixture allowed to stand at room temperature overnight. The solution was concentrated to about 30 ml., diluted with anhydrous diethyl ether (150 ml.), and filtered to give ethyl 2-decyloxybenzimidate borofluoride (45.5 g.), m.p. 93°-96° C., pure enough for use in the next stage. An aliquot was recrystallised from a mixture of anhydrous methylene chloride and anhydrous diethyl ether to give pure ethyl 2-decyloxybenzimidate borofluoride, m.p. 96.5°-98.5° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]#[CH:11].I[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[OH:20]>>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[O:20][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH:11]=1)=[O:12]
Reactant: C#Cc1ccccc1C(=O)OC
Reactant: Oc1ccccc1I
Product: COC(=O)c1ccccc1-c1cc2ccccc2o1

Procedure:
The general procedure was used to convert 2-Ethynyl-benzoic acid methyl ester and 2-iodophenol to the title product. Purification by flash chromatography (10% ethyl acetate in hexanes) gave the analytically pure product as an oil (458 mg, 67% yield). 1H NMR δ 7.75-7.70 (m, 2H), 7.61-7.40 (m, 4H), 7.31-7.22 (m, 2H), 6.92 (s, 1H), 3.81 (s, 3H). 3C NMR δ 169.35, 155.10, 154.67, 131.09, 130.94, 129.61, 129.36, 128.99, 128.88, 128.64, 124.54, 122.94, 121.21, 111.09, 104.38, 52.48. Anal. Calcd. for C16H12O3: C, 76.18; H, 4.79. Found C, 75.95; H, 4.75.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7].[H-].[Na+].[CH2:14]([O:18]CC1C=CC(C(O)=O)=CC=1)[CH2:15]C=C>C(O)C>[CH2:14]([O:18][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])[CH3:15]
Reactant: O=C(O)c1cccc(CCl)c1
Reactant: C=CCCOCc1ccc(C(=O)O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: CCOCc1cccc(C(=O)O)c1

Procedure:
The reaction of ethanol and 3-Chloromethyl-benzoic acid in the presence of sodium hydride was performed as described for Compound 33 to give 3-ethoxymethyl-benzoic acid as white powder. 1H-NMR (400 MHz, d6-DMSO): 7.89 (m, 1 arom.H); 7.84 (m, 1 arom.H); 7.54 (m, 1 arom.H); 7.46 (m, 1 arom.H); 4.49 (s, OCH2C6H4—); 3.48 (q, J=6.9, CH3CH2); 1.15 (t, J=6.9, CH3CH2). 13C-NMR (100 MHz, d6-DMSO): 167.24 (—C═O); 139.26; 131.67; 130.76; 128.51; 128.23; 128.06; 71.01; 65.14; 15.07.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15]=[O:16]>C(O)CCC>[C:1]1([C@@H:7]([N:9]([CH2:10][Si:11]([CH3:13])([CH3:12])[CH3:14])[CH2:15][O:16][CH2:6][CH2:1][CH2:2][CH3:3])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=O
Reactant: C[C@H](NC[Si](C)(C)C)c1ccccc1
Solvent: CCCCO
Product: CCCCOCN(C[Si](C)(C)C)[C@@H](C)c1ccccc1

Procedure:
The title compound was prepared from (S)-(-)-N-1-phenylethyl-N-trimethylsilylmethylamine by reaction with n-butanol and aqueous formaldehyde following the procedure of Example 2 to give the crude acetal (85% pure) as a colourless oil (7.1 g, 80%)δC (CD2Cl2)--1.09 (SiMe3), 14.35, 20.16, 24.72, 67.38 (OBu), 19.57 (CMe), 40.30 (NCH2Si), 62.30 (CH), 84.73 (NCH2O), 127.01, 128.15, 128.51, 146.15 (Ph).
Reaction SMILES: [Br-].[Li+].[CH2:3]([Mg]Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:12]([O:19][C:20]([NH:22][C@@H:23]([CH2:28][C:29](Cl)=[O:30])[C:24]([O:26][CH3:27])=[O:25])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1>[CH2:12]([O:19][C:20]([NH:22][C@@H:23]([CH2:28][C:29](=[O:30])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:24]([O:26][CH3:27])=[O:25])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)[C@H](CC(=O)Cl)NC(=O)OCc1ccccc1
Reactant: Cl[Mg]Cc1ccccc1
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)[C@H](CC(=O)Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 53.1 %

Procedure:
To a suspension of copper(I) bromide-dimethyl sulfide complex (2.6 g, 12.72 mmol, 1.2 eq.) in dry THF was added a solution of lithium bromide (2.2 g, 25.44 mmol, 2.4 eq.) in dry THF. The mixture was stirred at room temperature (RT) for 20 min, and then was cooled to −78° C. A solution of benzyl magnesium chloride (13 mL, 12.72 mmol, 1.2 eq.) followed by a solution of (S)-methyl 2-(benzyloxycarbonylamino)-4-chloro-4-oxobutanoate (3.16 g, 10.6 mmol, 1 eq.) in dry THF were added. The mixture was stirred at −78° C. for 30 min and then was quenched with sat. ammonium chloride. The mixture was extracted with ethyl acetate. The organic layers were dried over magnesium sulfate and then concentrated in vacuo. The residue was purified by flash column (1:1 ethyl acetate:hexane) to give 2 g of (S)-methyl 2-(benzyloxycarbonylamino)-4-oxo-5-phenylpentanoate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8]Cl)[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[CH:3]=1.C(O)C.[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=2[F:36])=[C:22](B(O)O)[CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][C:20]2[CH:19]=[C:18]([Cl:17])[CH:23]=[CH:22][C:21]=2[O:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=2[F:36])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[CH:3]=1
Reactant: OB(O)c1cc(Cl)ccc1OCc1ccc(Cl)cc1F
Reactant: COC(=O)c1cc(Cl)cc(CCl)n1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(Cl)cc(Cc2cc(Cl)ccc2OCc2ccc(Cl)cc2F)n1
Yield: 12.8 %

Procedure:
To a stirring solution of methyl 4-chloro-6-(chloromethyl)-2-pyridinecarboxylate (175 mg), in dry toluene (4 ml) and ethanol (4 ml) was added (5-chloro-2-{[(4-chloro-2-fluorophenyl)methyl]oxy}phenyl)boronic acid (250 mg), potassium carbonate (330 mg) and tetrakis(triphenylphosphine)-palladium(0) (92 mg). The mixture was stirred under reflux for 2 hours. Solvent was removed u.r.p. (under reduced pressure) and water (20 ml) and ether (20 ml) added to the residue. Insoluble solid was filtered off over Hyflo and washed with ether. The aqueous layer was separated off and washed with ether (15 ml), and the combined ether layers washed with brine (10 ml), dried over MgSO4 and evaporated down u.r.p. The residue was purified by mass-directed autopreparation to give a white solid (46.3 mg, 12.8%). LC/MS [MH+]=468/470/472, Rt=4.11 min. NMR and LC/MS indicated that trans-esterification had occurred to give the ethyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1)[C:6]([CH:24]=[O:25])=[C:5]2[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[F:32][C:33]([Si](C)(C)C)([F:35])[F:34].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([S:20]([CH3:23])(=[O:21])=[O:22])=[CH:18][CH:19]=1)[C:6]([CH:24]([OH:25])[C:33]([F:35])([F:34])[F:32])=[C:5]2[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CS(=O)(=O)c1ccc(Cn2c(C=O)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(Cn2c(C(O)C(F)(F)F)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1
Reaction time: 0.5 h
Yield: 50.8 %

Procedure:
To a solution (5 ml) of 6-bromo-2-(4-methanesulfonylbenzyl)-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carbaldehyde (500 mg) and (trifluoromethyl)trimethylsilane (170 mg) in THF was added a solution of tetra-N-butylammonium fluoride (1M, 0.03 ml) in THF at room temperature, and the mixture was stirred for 30 min. Then a solution (1M, 2 ml) of tetra-N-butylammonium fluoride in THF was added, and the mixture was stirred for 30 min. The reaction mixture was concentrated under reduced pressure and the residue was diluted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (THF) and basic silica gel column chromatography (THF) and the crystals were washed with a mixture of ethyl acetate and diisopropyl ether, and recrystallized (MeOH-hexane) to give the title compound (290 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([S:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=2[CH3:21])=[C:7]([S:9](Cl)(=[O:11])=[O:10])[CH:8]=1)#[N:2].[CH3:22][N:23]([CH3:30])[CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>C(Cl)Cl>[CH3:22][N:23]([CH3:30])[CH:24]1[CH2:29][CH2:28][N:27]([S:9]([C:7]2[CH:8]=[C:3]([CH:4]=[CH:5][C:6]=2[S:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=2[CH3:21])[C:1]#[N:2])(=[O:11])=[O:10])[CH2:26][CH2:25]1
Reactant: CN(C)C1CCNCC1
Reactant: Cc1ccc(C)c(Sc2ccc(C#N)cc2S(=O)(=O)Cl)c1
Solvent: ClCCl
Product: Cc1ccc(C)c(Sc2ccc(C#N)cc2S(=O)(=O)N2CCC(N(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of compound 26 (0.200 g, 0.59 mmol) in DCM was added TEA (0.090 g, 0.89 mmol) and 4-dimethylaminopiperidine (0.114 g, 0.89 mmol). The reaction was monitored by HPLC. The reaction was complete after stirring at room temperature for 16 hrs. DCM was removed in vacuo, and the resulting solid was dissolved in a minimal amount of DCM and purified with chromatography with a gradient of 10 to 30% MeOH in DCM. Pure fractions were combined and evaporated in vacuo to yield an oil, which was triturated with DCM and hexanes, and then filtered to yield compound 72 as a peach solid (0.124 g, 49% yield). HPLC purity: 96.5%; 1H NMR (500 MHz, DMSO-d6): δ 8.22 (d, J=2 Hz, 1H), 7.84 (dd, J1=2 Hz, J2=8 Hz, 1H), 7.41 (d, J=6 Hz, 1H), 7.39 (s, 1H), 7.34 (d, J=8 Hz, 1H), 6.70 (d, J=8 Hz, 1H), 3.8 (d, J=13 Hz, 2H), 2.84 (t, J=12 Hz, 2H), 2.31 (s, 3H), 2.26 (m, 1H), 2.25 (s, 3H), 2.15 (s, 6H), 1.79 (d, J=12 Hz, 2H), 1.43 (m, 2H); MS (ESI, EI+): m/z=430 (MH+); melting point: 136-139° C.
Reaction SMILES: Br[CH:2]([O:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][Cl:6].[NH:18]1[CH:22]=[CH:21][N:20]=[CH:19]1.[C:23]1([S:37]([OH:40])(=[O:39])=[O:38])[C:32]2[CH:31]=[CH:30][CH:29]=[C:28]([S:33]([OH:36])(=[O:35])=[O:34])[C:27]=2[CH:26]=[CH:25][CH:24]=1>C(#N)C.CC(C)=O>[C:23]1([S:37]([OH:40])(=[O:39])=[O:38])[C:32]2[CH:31]=[CH:30][CH:29]=[C:28]([S:33]([OH:36])(=[O:35])=[O:34])[C:27]=2[CH:26]=[CH:25][CH:24]=1.[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([O:10][CH:2]([N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)[C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][Cl:6])=[CH:12][CH:13]=1
Reactant: c1c[nH]cn1
Reactant: CC(C)(CCl)C(=O)C(Br)Oc1ccc(Cl)cc1
Agent: O=S(=O)(O)c1cccc2c(S(=O)(=O)O)cccc12
Solvent: CC#N
Solvent: CC(C)=O
Product: CC(C)(CCl)C(=O)C(Oc1ccc(Cl)cc1)n1ccnc1
Reaction time: 2 h
Yield: 84.7 %

Procedure:
17 g (0.05 mol) of crude 1-bromo-1-(4-chlorophenoxy)-3,3-dimethyl-4-chloro-butan-2-one were dissolved in 100 ml of absolute acetonitrile. 12 g (0.175 mol) of imidazole were added to this solution and the mixture was heated under reflux for 40 hours. Thereafter, it was concentrated by distilling off the solvent in vacuo and the residue was taken up in 300 ml of methylene chloride. The methylene chloride mixture was washed three times with 100 ml of water each time, dried over sodium sulphate and concentrated again in vacuo. The residue was taken up in 100 ml of acetone, and a solution of 9 g (0.038 mol) of 1,5-naphthalenedisulphonic acid in 50 ml of acetone was added. After 2 hours, the precipitate which had formed was filtered off and dried. 19.8 g (80.7% of theory) of 1-(4-chlorophenoxy)-1-(imidazol-1-yl)-3,3-dimethyl-4-chloro-butan-2-one naphthalene-1,5-disulphonate of melting point 266°- 267° C. were obtained. ##STR14##
Reaction SMILES: C([BH3-])#N.[Na+].[Br:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([S:16](=[O:19])(=[O:18])[NH2:17])[CH:10]=1)=[O:8].CN(C1C=CC(N=NC2C=CC(S(O)(=O)=O)=CC=2)=CC=1)C.Cl.[Cl-].[Na+]>O1CCCC1.O.C(OCC)(=O)C.C(O)(=O)C>[Br:5][CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([S:16](=[O:19])(=[O:18])[NH2:17])[CH:10]=1)[OH:8]
Reactant: NS(=O)(=O)c1cc(C(=O)CBr)ccc1Cl
Agent: CN(C)c1ccc(N=Nc2ccc(S(=O)(=O)O)cc2)cc1
Agent: Cl
Agent: [BH3-]C#N
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: NS(=O)(=O)c1cc(C(O)CBr)ccc1Cl
Temperature: 0 °C

Procedure:
0.94 g of sodium cyanoborohydride are added to an ice-cold solution of 3.1 g of 2-bromo-4'-chloro-3'-sulfamoylacetophenone and 1 ml of aqueous methyl orange solution in 20 ml of tetrahydrofuran, with stirring, and the pH is then rapidly adjusted to 3-4 by the dropwise addition of a 1:1 mixture of glacial acetic acid and 2 N HCl (indicator red in color) and the pH is then kept at this value by the occasional dropwise addition of the acid mixture. After about 11/2 hours no further starting material can be detected in a thin layer chromatogram (Merck silica gel ready-for-use plates, ethyl acetate as the solvent). The reaction mixture is poured into 300 ml of water and the resulting mixture is saturated with sodium chloride and extracted several times with ethyl acetate. After the combined organic phases have been washed with water and dried over sodium sulfate, they are concentrated in a rotary evaporator. Colorless crystals with a melting point of 145° C. (with decomposition).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:9]([CH2:15][C:16]([O:18][CH2:19][CH2:20][OH:21])=[O:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[C:22](O)(=O)/C=C/C(O)=O.C(O)C(O)C.[PH2](O)=O.C(OP(OCC)OCC)C.[P]>>[CH2:7]([O:6][P:4]([CH:9]([CH2:15][C:16]([O:18][CH2:19][CH:20]([OH:21])[CH3:22])=[O:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: O=C(O)/C=C/C(=O)O
Reactant: CCOC(=O)C(CC(=O)OCCO)P(=O)(OCC)OCC
Agent: CCOP(OCC)OCC
Agent: O=[PH2]O
Agent: [P]
Solvent: CC(O)CO
Product: CCOC(=O)C(CC(=O)OCC(C)O)P(=O)(OCC)OCC

Procedure:
The procedure according to Example 1 was repeated using similar apparatus and under essentially similar conditions allowing for the differences in quantities of materials employed. In this example, for the materials of Example 1, 1 mol fumaric acid, 1 mol of propylene glycol, 0.1% of hypophosphorous acid and 1 mol of triethylphosphite were employed. The product of the reaction had analytical values of acid value, hydroxyl, free triethylphosphite and phosphorus content comparable to those reported in Example 1.
Reaction SMILES: O[C:2]1[C:3](=[O:17])[N:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH:5]=[CH:6][N:7]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[F:60][C:61]([F:71])([F:70])[O:62][C:63]1[CH:68]=[CH:67][C:66]([SH:69])=[CH:65][CH:64]=1>CN(C=O)C.C([O-])(O)=O.[Na+]>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][N:4]2[CH:5]=[CH:6][N:7]=[C:2]([S:69][C:66]3[CH:65]=[CH:64][C:63]([O:62][C:61]([F:60])([F:70])[F:71])=[CH:68][CH:67]=3)[C:3]2=[O:17])=[CH:10][CH:11]=1
Reactant: FC(F)(F)Oc1ccc(S)cc1
Reactant: COc1ccc(Cn2ccnc(O)c2=O)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(Cn2ccnc(Sc3ccc(OC(F)(F)F)cc3)c2=O)cc1
Yield: 74.6 %

Procedure:
A mixture of 3-hydroxy-1-(4-methoxybenzyl)pyrazin-2(1H)-one (2.0 g, 8.61 mmol), PyBOP (7.84 g, 15.07 mmol) and N,N-diisopropylethylamine (4.51 mL, 25.8 mmol) in DMF (40 mL) was stirred at RT under N2 for 3 hours whereupon 4-(trifluoromethoxy)benzenethiol (2.007 g, 10.33 mmol) was added. After having stirred for 18 additional hours, the reaction was diluted with saturated aq. NaHCO3 (65 ml) and was then extracted with EtOAc (60 ml). The EtOAc layer was dried over Na2SO4 and concentrated. The crude product was purified by silica gel chromatography employing a solvent gradient (hexane to 75% EtOAc/hexane) to elute 1-(4-methoxybenzyl)-3-(4-(trifluoromethoxy)phenylthio)pyrazin-2(1H)-one (2.76 g, 6.42 mmol, 74.6% yield) as white solid. 1H NMR (400 MHz, chloroform-d) δ ppm 7.58 (2H, d, J=8.78 Hz), 7.21-7.35 (4H, m), 7.02 (1H, d, J=4.52 Hz), 6.90 (2H, d, J=8.78 Hz), 6.85 (1H, d, J=4.27 Hz), 5.03 (2H, s), 3.81 (3H, s).