Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]([C:17]([OH:19])=O)=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[F:20][C:21]([F:30])([F:29])[C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1.Cl>ClCCl.CN(C)C=O.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]([C:17](=[O:19])[NH:26][C:25]3[CH:27]=[CH:28][C:22]([C:21]([F:20])([F:29])[F:30])=[CH:23][CH:24]=3)=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(C(=O)O)nn1-c1ncccc1Cl
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1cc(C(=O)Nc2ccc(C(F)(F)F)cc2)nn1-c1ncccc1Cl
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A solution of 1.00 g (3.55 mmol) of 1-(3-chloropyridin-2-yl)-5-(methoxycarbonyl)-1H-pyrazole-3-carboxylic acid in 13 ml of dichloromethane and 1.3 ml of N,N-dimethylformamide was cooled to 0° C., a solution of 0.86 g (5.33 mmol) of 4-(trifluoromethyl)aniline in 3 ml of dichloromethane was added dropwise and 0.68 g (3.55 mmol) of N-ethyl-N′-3-(dimethylaminopropyl)carbodiimide×HCl and 87 mg (710 μmol) of 4-dimethylaminopyridine were added a little at a time. The mixture was stirred at 0° C. for 2 hours and at 20° C. for 16 hours. The mixture was then diluted with dichloromethane and washed successively with 1 N aqueous hydrochloric acid and water. The organic phase was dried over sodium sulphate, the solvent was removed under reduced pressure and the residue was purified on silica gel using cyclohexane/ethyl acetate=3:1→2:1. (logP: 3.54).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[C:7]([C:10]([OH:12])=[O:11])[C:6]=2[CH:13]=1.Cl.[CH3:15]O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[C:7]([C:10]([O:12][CH3:15])=[O:11])[C:6]=2[CH:13]=1
Reactant: CO
Reactant: O=C(O)c1coc2ccc(F)cc12
Agent: Cl
Product: COC(=O)c1coc2ccc(F)cc12
Reaction time: 24 h

Procedure:
A solution of 5-fluorobenzofuran-3-carboxylic acid (56 g) and saturated etheral solution of hydrochloric gas (300 mL) in methanol (600 mL) was stirred for 16 h at room temperature. Further etheral HCl was added (300 mL) followed by stirring for 24 h. Concentration in vacuo gave a dark crystalline material, methyl 5-fluorobenzofuran-3-carboxylate (58 g). Lithium aluminium hydride (15 g) was suspended in tetrahydrofuran (400 mL) under a nitrogen atmosphere followed by dropwise addition of a solution of methyl 5-fluorobenzofuran-3-carboxylate (58 g) in tetrahydrofuran (300 mL). The temperature increased to 55° C. during the addition. After stirring for 2 h the reaction was quenched successively with water (30 mL), 15% aq. sodium hydroxide (15 mL), and water (75 mL). Further tetrahydrofuran (500 mL) was added and the mixture stirred for 1 h. The mixture was filtered and the precipitate extracted with a mixture of methylene chloride (1 L) and ethanol (0.5 L). The combined organic phases were concentrated in vacuo giving an oil which was applied to silica gel flash chromatography (eluent: methylene chloride/25% aq. NH3 99:1). The resulting yellow oil, 5-fluorobenzofuran-3-ylmethanol (14.4 g) crystallised on standing.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].C([Li])CCC.B(F)(F)F.[CH2:19]([C@@H:21]1[O:23][CH2:22]1)[Cl:20]>O1CCCC1>[Cl:20][CH2:19][C@H:21]([OH:23])[CH2:22][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9]
Reactant: ClC[C@H]1CO1
Reactant: COc1ccccc1Br
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccccc1C[C@@H](O)CCl
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-bromoanisole (11.21 g, 59.93 mmol) in dry tetrahydrofuran (Aldrich sure-seal, 160 mL) at −70° C. was added n-butyllithium (1.05 eq. of 2.5M in hexanes, freshly opened, 25.2 mL, 62.93 mmol). After 30 mins stirring at −70° C., BF3 etherate (9.36 g, 65.9 mmol) was added. After a further 30 mins at −70° C. (R)-epichlorohydrin (5.55 g, 59.93 mmol) in tetrahydrofuran (50 mL) was added. After 2 hrs the reaction mixture was quenched by the addition of 10% aqueous ammonium chloride (50 mL) followed by warming to ambient temperature. ethyl acetate was added and the organic phase washed with water and brine. Drying (Na2SO4) and concentration under reduced pressure afforded the crude product as a pale yellow semi-solid (9.88 g). Purification by silica gel chromatography (5% ethyl acetate/iso-hexane) afforded the intermediate (e), (R)-1-chloro-3-(2-methoxyphenyl)-2-propanol, as colorless oil (6.04 g, 50% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C@@H:8]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:21][Si]([N-][Si](C)(C)C)(C)C.[Li+].CI>O1CCCC1>[C:1]([O:5][C:6](=[O:20])[NH:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH3:21])[C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[NH:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N[C@H]1CNc2ccccc2NC1=O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CNc2ccccc21
Temperature: -75 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5.0 g (18 mmol) (S)-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-carbamic acid tert-butyl ester in 80 ml of tetrahydrofuran at −75° C. 18 ml (18 mmol) of lithium bis(trimethylsilyl)amide solution (1M in tetrahydrofurane) was added. After stirring for 30 min at −75° C. the mixture was allowed to reach room temperature and 3.07 g (21.6 mmol) of methyl iodide was added. The mixture was stirred for 2.5 hours at room temperature and concentrated in vacuo. The residue was distributed between 1M NaHSO4 solution and ethyl acetate. The combined organic layers were reextracted with water and dried (MgSO4). After evaporation of the solvent, (S)-(1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-carbamic acid tert-butyl ester was obtained in sufficient purity for the next step.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8](O)[C:9]2[CH:15]=[CH:14][C:13]([C:16]3[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][N:17]=3)=[N:12][C:10]=2[N:11]=1)=[O:5])[CH3:2].S(Cl)([Cl:26])=O>>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([Cl:26])[C:9]2[CH:15]=[CH:14][C:13]([C:16]3[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][N:17]=3)=[N:12][C:10]=2[N:11]=1)=[O:5])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)c1nc(O)c2ccc(-c3ncccc3C)nc2n1
Product: CCOC(=O)c1nc(Cl)c2ccc(-c3ncccc3C)nc2n1
Temperature: 25 °C

Procedure:
Dissolve 4-hydroxy-7-(3-methyl-pyridin-2-yl)-pyrido[2,3-d]pyrimidine-2-carboxylic acid ethyl ester (345 mg, 1.11 mmol) in thionyl chloride (15 mL) and heat the mixture at reflux overnight. Cool the mixture to room temperature and remove the excess thionyl chloride in vacuo. Dissolve the crude reaction mixture in CH2Cl2 (50 mL) and wash with saturated NaHCO3 (aq). Dry the organic layer over Na2SO4 and remove the solvent under reduced pressure to yield the title compound. MS 329.12 (M+1)
Reaction SMILES: Br[C:2]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]2[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:3]=12.[Li]CCCC.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:31])(=O)=O)=CC=1>O1CCCC1>[F:31][C:2]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]2[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:3]=12
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: O=C1NCCn2c3c(c(Br)c21)CCCC3
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C1NCCn2c3c(c(F)c21)CCCC3
Temperature: -78 °C
Yield: 16.3 %

Procedure:
Into a 2-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of 134a (40 g, 148.62 mmol, 1.00 equiv) in tetrahydrofuran (200 mL), followed by the addition of n-BuLi (2.4 M) (218 mL, 3.50 equiv) dropwise with stirring at −78° C. The resulting solution was stirred at −40° C. for 3 h. To this was added a solution of N-fluorobenzenesulfonimide (98.7 g, 313.33 mmol, 2.10 equiv) in tetrahydrofuran (200 mL) dropwise with stirring at −78° C. The resulting solution was stirred at room temperature for 3 h, quenched by the addition of 200 mL of water and extracted with 3×500 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (30 g) was purified by Prep-HPLC with the following conditions (mobile phase, A: 0.05% trifluoroacetic acid/water; B: CH3CN; gradient: 10% B-25% B) to afford 5.05 g (16%) of 134b as a white solid. MS: [M+H]+ 209. 1H NMR (300 MHz, CDCl3) δ 6.16 (br, 1H), 3.90-3.86 (m, 2H), 3.65-3.62 (m, 2H), 2.53-2.47 (m, 4H), 1.88-1.80 (m, 2H), 1.77-1.72 (m, 2H).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:9][C:8]=1[CH2:21][N:22]([CH3:24])[CH3:23].[CH3:25][Si:26]([CH3:29])([CH3:28])Cl.O>C1COCC1>[CH3:23][N:22]([CH2:21][C:8]1[CH:9]=[C:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:11]=[CH:12][C:7]=1[Si:26]([CH3:29])([CH3:28])[CH3:25])[CH3:24]
Reactant: CN(C)Cc1cc(NC(=O)OC(C)(C)C)ccc1Br
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CN(C)Cc1cc(NC(=O)OC(C)(C)C)ccc1[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
At −78° C., n-butyl lithium (2.5 ml/L, 3 ml) was slowly added dropwise into a solution of tert-butyl 4-bromo-3-((dimethylamino)methyl)phenylcarbamate (compound 28) (2.7 g, 8 mmol) in THF. The reaction mixture was stirred at low-temperature for 30 minutes, followed by adding trimethylchlorosilane (1.1 g, 9.6 mmol). And then the reaction mixture was stirred at low-temperature for 1 hour. After the mixture was warmed to RT and stirred overnight, three times of water was added into the reaction solution. The reaction mixture was extracted by ethyl acetate. The solvent was dried and evaporated to give a crude product, which can be directly used for the next step.
Reaction SMILES: C([O:4][CH2:5]/[C:6](/[CH3:14])=[CH:7]/[C:8]1[CH:13]=CC=C[CH:9]=1)C=C.[CH:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH3:14][CH:6]([CH2:7]/[C:8](/[CH3:13])=[CH:9]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:5]=[O:4]
Reactant: c1ccccc1
Reactant: C=CCOC/C(C)=C/c1ccccc1
Product: C/C(=C\c1ccccc1)CC(C)C=O
Temperature: 25 °C
Yield: 10 %

Procedure:
The (1E)-[3-(allyloxy)-2-methyl-1-propenyl]benzene (107.79 g, 0.571 mol), [RuCl2(PPh3)3] (3.13 g), BHT (1 g) and benzene (500 ml) were heated together in an autoclave in an oil bath at 190° C. for 4 hours. After cooling to room temperature, solvents were evaporated and the product purified by column chromatography on silica gel (eluent: heptanes/ethyl acetate 10:1) followed by bulb-to-bulb distillation (88° C./0.009 mbar) to give 11.21 g of the desired compound (0.060 mol, 10%).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH3:4][C:5]1([CH3:28])[O:9][N:8]=[C:7]([S:10][CH2:11][C:12]2[C:13]([C:24]([F:27])([F:26])[F:25])=[N:14][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:16]=2F)[CH2:6]1.O>CN(C)C=O>[CH3:4][C:5]1([CH3:28])[O:9][N:8]=[C:7]([S:10][CH2:11][C:12]2[C:13]([C:24]([F:27])([F:26])[F:25])=[N:14][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:16]=2[N:2]([CH3:3])[CH3:1])[CH2:6]1
Reactant: CC1(C)CC(SCc2c(C(F)(F)F)nn(-c3ccccc3)c2F)=NO1
Reactant: CNC
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)c1c(CSC2=NOC(C)(C)C2)c(C(F)(F)F)nn1-c1ccccc1
Temperature: 100 °C
Reaction time: 9 h
Yield: 80.6 %

Procedure:
0.8 g (6.7 mmoles) of a 40% aqueous dimethylamine solution was added to a solution of 0.5 g (1.3 mmoles) of 5,5-dimethyl-3-(5-fluoro-1-phenyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazoline dissolved in 10 ml of N,N-dimethylformamide. The mixture was stirred at 100° C. for 9 hours in a sealed tube. Thereto was added 3.0 g (26.6 mmoles) of a 40% aqueous dimethylamine solution, and the resulting mixture was stirred for 9 hours to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 0.4 g (yield: 80.6%) of 5,5-dimethyl-3-(5-dimethylamino-1-phenyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazoline.
Reaction SMILES: [SH:1][CH2:2][C:3]1([CH2:6][C:7]([OH:9])=[O:8])[CH2:5][CH2:4]1.S(=O)(=O)(O)O.[CH3:15]O>>[CH3:15][O:8][C:7](=[O:9])[CH2:6][C:3]1([CH2:2][SH:1])[CH2:5][CH2:4]1
Reactant: CO
Reactant: O=C(O)CC1(CS)CC1
Agent: O=S(=O)(O)O
Product: COC(=O)CC1(CS)CC1
Temperature: 20.5 °C
Reaction time: 5 h

Procedure:
To a 3 L flask, a solution of 1-(mercaptomethyl)cyclopropaneacetic acid (330.7 g) in methanol (1500 ml) was charged. 96% sulfuric acid (36 g) was added, and the reaction mixture was stirred for 5 h at 19-22° C. The reaction mixture was concentrated to ¼ of its volume at 50° C. under reduced pressure, and the residue was partitioned between water (1000 ml) and ethyl acetate (500 ml). The organic phase was separated, washed with 10% NaHCO3 and 5% NaCl (200 ml), and dried overnight over anhydrous sodium sulfate. The mixture was filtered and evaporated at 50° C. under reduced pressure, to afford 315.7 g of the crude 1-(mercaptomethyl)cyclopropaneacetic acid methyl ester, as a colored liquid with a strong, unpleasant odor.
Reaction SMILES: [CH2:1]([O:17][CH2:18][CH:19]([CH2:22][O:23][CH3:24])[CH2:20][NH2:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[Cl:25][CH2:26][CH2:27][CH2:28][S:29](NCC(OC)CSCCCCCCCCCCCCCCCC)(=[O:31])=[O:30]>>[Cl:25][CH2:26][CH2:27][CH2:28][S:29]([NH:21][CH2:20][CH:19]([CH2:22][O:23][CH3:24])[CH2:18][O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])(=[O:31])=[O:30]
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)OC
Reactant: CCCCCCCCCCCCCCCCOCC(CN)COC
Product: CCCCCCCCCCCCCCCCOCC(CNS(=O)(=O)CCCCl)COC

Procedure:
3-Hexadecyloxy-2-methoxymethylpropylamine IVk1 is allowed to react and worked up by the same procedure as described in (4). m.p. 44°-46.5° C. The summary of the experimental condition and the physical data of the product are listed in Table 7.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]=[N:10][C:11]1(C)[C:16](=O)O[C:14](C)([CH3:18])[O:13][C:12]1=[O:20].[Na].O>C(O)C>[CH2:14]([O:13][C:12](=[O:20])/[C:11](=[N:10]/[NH:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[Br:1])/[CH3:16])[CH3:18]
Reactant: CC1(C)OC(=O)C(C)(N=Nc2ccc(F)cc2Br)C(=O)O1
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CCOC(=O)/C(C)=N/Nc1ccc(F)cc1Br
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a cooled (ice-bath) suspension of 126 g 5-(2-Bromo-4-fluoro-phenylazo)-2,2,5-trimethyl-[1,3]dioxane-4,6-dione in 550 ml ethanol was added a solution of 7.8 g sodium in 200 ml ethanol. The mixture was stirred 5 h at room temperature, poured into 200 ml water and the organics extracted with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate and evaporated. The resulting orange oil solidified upon drying under vacuum to afford the title compound. Yield:102 g. ISP-MS: m/e 303.2 ([M+H]+).
Reaction SMILES: [OH:1][C@H:2]([C@@H:13]([OH:24])[C:14]([O:16]N1C(=O)CCC1=O)=[O:15])[C:3]([O:5]N1C(=O)CCC1=O)=O.[NH2:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][NH:37][S:38]([C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([CH:47]2[C:56]3[C:51](=[C:52]([Cl:58])[CH:53]=[C:54]([Cl:57])[CH:55]=3)[CH2:50][N:49]([CH3:59])[CH2:48]2)[CH:42]=1)(=[O:40])=[O:39]>>[Cl:57][C:54]1[CH:55]=[C:56]2[C:51](=[C:52]([Cl:58])[CH:53]=1)[CH2:50][N:49]([CH3:59])[CH2:48][CH:47]2[C:43]1[CH:42]=[C:41]([S:38]([NH:37][CH2:36][CH2:35][O:34][CH2:33][CH2:32][O:31][CH2:30][CH2:29][O:28][CH2:27][CH2:26][NH:25][C:3](=[O:5])[C@H:2]([OH:1])[C@@H:13]([OH:24])[C:14]([OH:16])=[O:15])(=[O:39])=[O:40])[CH:46]=[CH:45][CH:44]=1
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCOCCN)c2)C1
Reactant: O=C(ON1C(=O)CCC1=O)[C@H](O)[C@@H](O)C(=O)ON1C(=O)CCC1=O
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCOCCNC(=O)[C@H](O)[C@@H](O)C(=O)O)c2)C1
Yield: 31.9 %

Procedure:
Compound 221 was prepared by isolating the mono-addition byproduct from the procedure outlined in Example 168 using (2R,3R)-bis(2,5-dioxopyrrolidin-1-yl) 2,3-dihydroxysuccinate (70.4 mg, 0.205 mmol) and Compound 28 (223 mg, 0.409 mmol). Purification by preparative HPLC gave the title compound (44.4 mg) as a TFA salt. 1H-NMR (400 MHz, CD3OD): δ 7.89 (d, 1H), 7.81 (d, 1H), 7.63 (t, 1H), 7.55 (s, 1H), 7.50 (t, 1H), 6.84 (s, 0.5H), 3.88-3.84 (m, 1H), 3.64-3.34 (m, 22H), 3.14 (s, 4H), 3.07 (m, 2H). MS (m/z): 677.36 [M+H]+.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C@H:17]([OH:22])[C:18]([O:20][CH3:21])=[O:19])=[CH:12][CH:11]=1>C(OCC)C.[Ag]=O>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][C@H:17]([O:22][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:18]([O:20][CH3:21])=[O:19])=[CH:14][CH:15]=1
Reactant: COC(=O)[C@@H](O)Cc1ccc(Br)cc1
Reactant: BrCc1ccccc1
Agent: O=[Ag]
Solvent: CCOCC
Product: COC(=O)[C@H](Cc1ccc(Br)cc1)OCc1ccccc1
Temperature: 50 °C
Reaction time: 12 h
Yield: 88.1 %

Procedure:
1.9 ml (16 mmol) of benzyl bromide are added to a mixture of 4.4 g (19 mmol) of silver oxide and 3.5 g (13 mmol) of methyl (S)-3-(4-bromophenyl)-2-hydroxypropionate in 20 ml of diethyl ether. The reaction mixture is stirred at 50° C. for 12 hours. The mixture is filtered and then the solvents are evaporated. The residue is chromatographed on silica gel (heptane/ethyl acetate 80/20). 4 g of methyl (S)-3-(4-bromophenyl)-2-benzyloxypropanoate are obtained in the form of an oil. Yield=85%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[CH:9]([OH:11])[CH3:10]>ClCCl.[O-2].[O-2].[Mn+4]>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10]
Reactant: CC(O)c1ccc(I)cc1F
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CC(=O)c1ccc(I)cc1F
Yield: 91.3 %

Procedure:
To a solution of 1-(2-fluoro-4-iodo-phenyl)-ethanol (15.50 g, 58.26 mmol) in dichloromethane (250 mL) was added manganese dioxide (101.26 g, 1.17 mole) and the reaction mixture was heated to reflux for 24 hours. The reaction mixture was cooled, filtered through a pad of celite coated with a thin layer of silica gel and concentrated in vacuo to give 1-(2-fluoro-4-iodo-phenyl)-ethanone (14.04 g, 91%).
Reaction SMILES: C[O:2][P:3]([CH2:7][N:8]([S:10]([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)(=[O:12])=[O:11])[CH3:9])(=[O:6])[O:4]C.Br[Si](C)(C)C>ClCCl>[S:14]1[CH:15]=[CH:16][CH:17]=[C:13]1[S:10]([N:8]([CH2:7][P:3](=[O:2])([OH:4])[OH:6])[CH3:9])(=[O:11])=[O:12]
Reactant: COP(=O)(CN(C)S(=O)(=O)c1cccs1)OC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: CN(CP(=O)(O)O)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.7 %

Procedure:
To a solution of [(2-thiophenesulfonyl-N-methylamino)methyl]-phosphonic acid dimethyl ester (obtained as described in Example 46, step 2) (180 mg, 0.6 mmol) in dichloromethane (3 mL) at 0° C. was slowly added bromotrimethylsilane (190 μL, 1.4 mmol). The reaction was gradually warmed to room temperature and allowed to stir overnight. The reaction mixture was concentrated, the residue was redissolved in dichloromethane, and the solution was again concentrated. Methanol (10 mL) was added to the residue, and the solution was stirred at room temperature for 30 min. The solution was then filtered and concentrated. The oily residue was triturated with 1:1 ether-hexanes, and an orange solid was collected by filtration. The orange solid was boiled in dichloromethane (3 mL), cooled, and filtered to yield the title compound (120 mg, 74%) as a colorless solid: 1H NMR (400 MHz, CD3OD) δH 7.87 (dd, J=1.5, 4 Hz, 1H, Ar—H), 7.66 (dd, J=1.5, 3.5 Hz, 1H, Ar—H), 7.25 (dd, J-4, 5 Hz, 1H, Ar—H), 3.31 (d, J=12.5 Hz, 2H, CH2P), 2.92 (s, 3H, NCH3).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:9]=[C:8]([NH2:10])[C:7]([NH2:11])=[C:6]([NH2:12])[CH:5]=1.Br.Br[CH2:15][C:16]([C:18]1[C:23]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:21]=[CH:20][N:19]=1)=O.C([O-])(O)=O.[Na+].O1CCOCC1>O>[CH3:1][O:2][CH2:3][C:4]1[CH:5]=[C:6]([NH2:12])[C:7]2[C:8]([N:9]=1)=[N:10][C:16]([C:18]1[C:23]([C:24]([F:27])([F:25])[F:26])=[CH:22][CH:21]=[CH:20][N:19]=1)=[CH:15][N:11]=2
Reactant: O=C(CBr)c1ncccc1C(F)(F)F
Reactant: COCc1cc(N)c(N)c(N)n1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COCc1cc(N)c2ncc(-c3ncccc3C(F)(F)F)nc2n1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
6-Methoxymethyl-2,3,4-triamino-pyridine (353 mg, 2.10 mmol), 2-bromo-1-(3-trifluoromethyl-pyridin-2-yl)-ethanone hydrobromide (771 mg, 2.21 mmol; synthesis described in Example 2E, below), and NaHCO3 (554 mg, 6.59 mmol) are dissolved into a solution of dioxane (20 mL) and water (20 mL). The reaction mixture is stirred 1 hour at room temperature and 3 hours at 100° C. The mixture is cooled and filtered through Celite. The Celite bed is washed with EtOAc (20 mL). The aqueous mixture is extracted with EtOAc (4×100 mL). The combined organic extracts are washed with brine and dried over Na2SO4. The solvent is removed under reduced pressure and the crude product purified by column chromatography on silica gel eluting with acetone/hexanes (1:1) to yield the title compound as a white solid.
Reaction SMILES: O1[CH2:5][CH2:4][NH:3]C1=O.[ClH:7].[F:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=1)[NH2:12].C(O)C>C(OCC)C>[ClH:7].[F:8][C:9]1[CH:10]=[C:11]([NH:12][CH2:5][CH2:4][NH2:3])[CH:13]=[CH:14][CH:15]=1
Reactant: O=C1NCCO1
Reactant: Nc1cccc(F)c1
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: NCCNc1cccc(F)c1
Temperature: 165 °C
Reaction time: 18 h

Procedure:
Equimolar quantities (45.7 mmol) of 2-oxazolidinone and 3-fluoroaniline hydrochloride were combined, heated to 165° C., and stirred for 18 hours. The dark-colored mixture was allowed to cool to ambient temperature and treated with ethanol (125 mL). The suspension was heated to reflux for 1 hour, allowed to cool to ambient temperature, treated with diethyl ether (125 mL), and the suspension was cooled to 0° C. for 2 hours. Filtration provided 5.53 g of the desired product as colorless crystals which were used without further purification.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[C:3]([NH2:6])([CH3:5])[CH3:4].Cl[C:10]([O:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)=[O:11].C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>ClCCl>[F:1][C:2]([F:8])([F:7])[C:3]([NH:6][C:10](=[O:11])[O:12][C:13]1[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=1)([CH3:5])[CH3:4]
Reactant: CC(C)(N)C(F)(F)F
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(NC(=O)Oc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Temperature: -15 °C
Reaction time: 2 h
Yield: 26.1 %

Procedure:
To a solution of 0.35 g (2.75 mmol) of 1,1,1-trifluoro-2-methylpropan-2-ylamine (CAS 812-18-0) in 20 ml of dichloromethane, cooled to −15° C., is added dropwise 1.00 g (4.96 mmol) of 4-nitrophenyl chloroformate (CAS 7693-46-1) dissolved in 15 ml of dichloromethane, while maintaining the temperature at −15° C. 0.48 ml (2.75 mmol) of diisopropylethylamine in 10 ml of dichloromethane is then added, still at −15° C. Stirring is continued at −15° C. for 2 hours, and the temperature of the mixture is then allowed to return to 0° C. over 1 hour. 20 ml of saturated aqueous sodium hydrogen carbonate solution are then added. The organic phase is separated out by settling and dried over sodium sulfate, and the solvent is partially evaporated off under reduced pressure to a volume of about 8 ml. This solution is chromatographed on a column of 40 g of silica gel, eluting with a mixture of 20% cyclohexane in dichloromethane, to give 0.21 g of 4-nitrophenyl 1,1,1-trifluoro-2-methylpropan-2-ylcarbamate in the form of a white solid.