Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([CH3:26])([CH3:25])[C:3]#[C:4][C:5]1[CH:6]=[C:7]2[C:18]3([CH2:22][O:21][C:20]([NH2:23])=[N:19]3)[C:17]3[C:12](=[N:13][CH:14]=[C:15]([Br:24])[CH:16]=3)[O:11][C:8]2=[CH:9][CH:10]=1.CO.[CH3:29]S(O)(=O)=O.C(OCC)(=O)C>C(=O)(O)[O-].[Na+]>[CH3:29][O:1][C:2]([CH3:26])([CH3:25])[C:3]#[C:4][C:5]1[CH:6]=[C:7]2[C:18]3([CH2:22][O:21][C:20]([NH2:23])=[N:19]3)[C:17]3[C:12](=[N:13][CH:14]=[C:15]([Br:24])[CH:16]=3)[O:11][C:8]2=[CH:9][CH:10]=1
Reactant: CC(C)(O)C#Cc1ccc2c(c1)C1(COC(N)=N1)c1cc(Br)cnc1O2
Reactant: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(C)(C)C#Cc1ccc2c(c1)C1(COC(N)=N1)c1cc(Br)cnc1O2
Temperature: 60 °C
Yield: 87 %

Procedure:
To a flask charged with 7-(3-hydroxy-3-methyl-1-butyn-1-yl)-3-bromo-spiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazol]-2′-amine (340 mg, 0.821 mmol) was added methanol (9962 μL, 246 mmol) and methane sulfonic acid (533 μL, 8.21 mmol). The flask was sealed and heated at 60° C. for 3 hours. The reaction was diluted with saturated sodium bicarbonate (100 mL) and poured into a separatory funnel containing ethyl acetate (50 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to provide a tan solid that was purified by silica gel chromatography (Redi-Sep pre-packed silica gel column (40 g), 0-10% methanol in methylenechloride with 0.1% ammonium hydroxide) to provide 7-(3-methoxy-3-methyl-1-butyn-1-yl)-3-bromo-spiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazol]-2′-amine (306 mg, 0.714 mmol, 87% yield) as a tan solid. MS m/z=428.0 [M+H]+. Calc'd for C20H19BrN3O3: 428.1.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@@H:10]([C@@H:13]([OH:20])[CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH2:9]1)=O)(C)(C)C.[H-].[Na+].[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26](F)[C:25]=1[Cl:31].CCO>CN(C=O)C.Cl>[Cl:23][C:24]1[C:25]([Cl:31])=[CH:26][CH:27]=[CH:28][C:29]=1[O:20][C@@H:13]([CH:14]1[CH2:15][CH2:16][O:17][CH2:18][CH2:19]1)[C@@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1
Reactant: Fc1cccc(Cl)c1Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]([C@@H](O)C2CCOCC2)C1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: Clc1cccc(O[C@@H](C2CCOCC2)[C@@H]2CCNC2)c1Cl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(R)-3-[(S)-Hydroxy(tetrahydropyran-4-yl)methyl]pyrrolidine-1-carboxylic acid t-butyl ester (30 mg, 0.1 mmol) was dissolved in DMF (380 μL). NaH (3.0 mg, 126 μmol) was added and the mixture was stirred at room temperature for 15 minutes. 1,2-Dichloro-3-fluorobenzene (34.7 mg, 210 μmol) was added and the mixture was stirred at 100° C. overnight. The mixture was concentrated then dissolved in 1.2M HCl in EtOH (510 μL, 610 μmol) and stirred overnight. The product was concentrated and purified by preparative HPLC to yield the title compound as a mono-TFA salt (10.8 mg, purity 100%). MS m/z: [M+H]+ calcd for C16H21Cl2NO2, 330.10. found 330.0.
Reaction SMILES: [NH2:1][C@@H:2]([CH:5]([CH3:7])[CH3:6])[CH2:3][OH:4].[CH2:8]1[CH2:14][S:11](=[O:13])(=[O:12])[O:10][CH2:9]1>O1CCCC1.O>[OH:4][CH2:3][C@@H:2]([NH:1][CH2:9][CH2:8][CH2:14][S:11]([OH:13])(=[O:12])=[O:10])[CH:5]([CH3:7])[CH3:6]
Reactant: CC(C)[C@H](N)CO
Reactant: O=S1(=O)CCCO1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[C@@H](CO)NCCCS(=O)(=O)O
Temperature: 25 °C

Procedure:
To a solution of (S)-(−)-2-amino-3-methyl-1-butanol (2.50 g, 24.2 mmol) in tetrahydrofuran (35 mL) was slowly added 1,3-propane sultone (2.89 g, 23.0 mmol). The mixture was stirred at reflux for 3 h. The reaction mixture was cooled to room temperature. The solid material was collected by filtration, washed with acetone (2×25 mL). The crude product was suspended in 80% acetone/ethanol (75 mL). The suspension was stirred at reflux for 30 seconds. The solid product was collected by filtration, and dried in a vacuum oven (50° C.), to afford compound EP (2.9 g, 56%). 1H NMR (D2O, 500 MHz) δ ppm 3.78 (dd, 1H), 3.62 (dd, 1H), 3.13 (m, 2H), 2.90 (m, 1H), 2.88 (t, 3H), 1.90 (m, 3H), 0.90 (d, 3H), 0.84 (d, 3H). 13C NMR (D2O, 125 MHz) δ ppm 64.74, 57.24, 48.20, 44.44, 26.98, 21.49, 18.53, 17.00. [α]D=+4.1° (c=0.0017 in water), ES-MS 224 (M−1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[CH2:5][CH:6]([C:9]#[N:10])[C:7]#[N:8].[H-].[Na+].Br[CH2:17][CH2:18][F:19]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[CH2:5][C:6]([CH2:17][CH2:18][F:19])([C:7]#[N:8])[C:9]#[N:10]
Reactant: FCCBr
Reactant: N#CC(C#N)Cc1cccc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCF)Cc1cccc(Br)c1
Yield: 38.3 %

Procedure:
Using 0.24 g of (3-bromobenzyl)malononitrile, 3 ml of N,N-dimethylformamide, 0.10 g of sodium hydride (60% in oil), and 0.13 g of 1-bromo-2-fluoroethane, and according to the process described in the Production Example 1, there was obtained 0.11 g of 2-(3-bromobenzyl)-2-(2-fluoroethyl)malononitrile (the present compound (65)).
Reaction SMILES: F[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].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>CC(N(C)C)=O.C(OCC)(=O)C>[O:17]1[CH2:18][CH2:19][N:14]([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])[CH2:15][CH2:16]1
Reactant: N#Cc1ccc(F)c(C(F)(F)F)c1
Reactant: C1COCCN1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N2CCOCC2)c(C(F)(F)F)c1
Temperature: 25 °C
Yield: 77.5 %

Procedure:
4-Fluoro-3-(trifluoromethyl)benzonitrile (2.0 g, 10.58 mmol) was dissolved in dimethyl acetamide (35 mL), morpholine (2.88 mL, 31.73 mmol) was added thereto, and the mixture was subjected to a reaction at 145° C. for 19 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (50 mL), and the organic layer was washed with an aqueous sodium hydrogen carbonate solution (50 mL). The organic layer was washed with water, dried with sodium sulfate, and the solvent was distilled under reduced pressure. The concentrated mixture was crystallized with ethyl acetate (10 mL) and n-hexane (80 mL) to obtain the title compound as a brown solid (2.1 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13].C(O)(=O)C>S(=O)(=O)(O)O>[C:12]([O:8][C:7](=[O:9])[C:6]1[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=1)[OH:11])(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1cc(Cl)ccc1O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC(=O)OC(=O)c1cc(Cl)ccc1O
Temperature: 70 °C
Yield: 76 %

Procedure:
5-Chlorosalicylic acid (17.3 g, 100 mmol) and three drops of concentrated sulfuric acid (98%) were added to a solution of acetic anhydride (14 g, 137 mmol) and glacial acetic acid (16.4 g, 274 mmol) with stirring. The reaction mixture was slowly heated to 70° C. and stirred for 2 hours. The reaction mixture was cooled to room temperature and was gradually added to ice water (500 mL) to precipitate the acetylated product. These solids were collected and washed with water. The two batches of product were combined and recrystallized in ethyl acetate. The pure crystals were collected via vacuum filtration to give 16.3 g of O-acetyl-5-chlorosalicylic acid (76 mmol, 76% yield).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][CH2:4][O:5][C:6]1[N:11]=[CH:10][C:9]([C:12](=O)[CH3:13])=[CH:8][CH:7]=1.[CH3:17][C:18]([S@:21]([NH2:23])=[O:22])([CH3:20])[CH3:19]>>[CH3:17][C:18]([S@:21]([NH:23][CH:12]([C:9]1[CH:10]=[N:11][C:6]([O:5][CH2:4][CH2:3][C:2]([F:16])([F:15])[F:1])=[CH:7][CH:8]=1)[CH3:13])=[O:22])([CH3:20])[CH3:19]
Reactant: CC(=O)c1ccc(OCCC(F)(F)F)nc1
Reactant: CC(C)(C)[S@](N)=O
Product: CC(N[S@](=O)C(C)(C)C)c1ccc(OCCC(F)(F)F)nc1
Yield: 80 %

Procedure:
The title compound is prepared in 80% yield (0.95 g, white solid) from 1-(6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethanone (0.82 g, 3.51 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18](=O)[C:19]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:20]N(C)C)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[NH2:32][C:33]([NH2:35])=[NH:34].CO[Na]>CN(C=O)C.CC(=O)OCC>[C:1]([O:5][C:6](=[O:31])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:20][N:32]=[C:33]([NH2:35])[N:34]=3)=[CH:16][CH:17]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C=C(C(=O)c1ccc(C2(NC(=O)OC(C)(C)C)CCC2)cc1)c1ccccc1
Reactant: N=C(N)N
Agent: CO[Na]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc(N)ncc3-c3ccccc3)cc2)CCC1
Temperature: 100 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
To a solution of compound 1 (3 g, 7.2 mmol) and guanidine (2 g, 35 mmol) in DMF (15 mL) was added MeONa (1.8 g, 35 mmol) and the mixture was heated to 100° C. and stirred for 4 h. The solution was cooled to r.t. and diluted with 80 mL of EA. The organic phase was washed with 0.1N HClaq and brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography to give 2.1 g of 5-1 as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:6][C:3]=1[CH:4]=[O:5].N1C=CN=C1.[C:23]1(=[O:28])[CH2:27][CH2:26][CH:25]=[CH:24]1>CO.O>[Cl:1][C:2]1[C:3]([CH:4]([OH:5])[C:24]2[C:23](=[O:28])[CH2:27][CH2:26][CH:25]=2)=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:8][N:9]=1
Reactant: O=C1C=CCC1
Reactant: COc1ccc(-c2cnc(Cl)c(C=O)c2)cc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CO
Product: COc1ccc(-c2cnc(Cl)c(C(O)C3=CCCC3=O)c2)cc1
Yield: 90 %

Procedure:
The clear solution of 2-Chloro-5-(4-methoxyphenyl)-nicotinaldehyde (10 mmol, 2.45 g) and imidazole (10 mmol) in 50 ml. of MeOH was slowly charged with 50 ml. of deionized water. To a stirred homogeneous reaction mixture was added 2-cyclopenten-1-one (10.2 mmol. 0.88 g) at room temperature and reaction progress was monitored by TLC. Upon completion of the reaction, excess MeOH was removed under reduced pressure, washed with water and extracted with CHCl3 thrice. Combined organic layers were washed with brine solution twice. The organic layer was concentrated and column chromatography of the crude product on silica gel, using 30% EtOAC in hexane as eluent, gave pure Baylis-Hillman adduct in 90% yield (2.97 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]3[O:18][C:17](=[O:19])[C:16]4[CH:20]=[CH:21][CH:22]=[C:23]([CH3:24])[C:15]=4[N:14]=3)=[CH:11][C:10]([C:25]([F:28])([F:27])[F:26])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH:29]([NH2:32])([CH3:31])[CH3:30].C(OCC)C>ClCCl>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([NH:14][C:15]3[C:16]([C:17]([NH:32][CH:29]([CH3:31])[CH3:30])=[O:19])=[CH:20][CH:21]=[CH:22][C:23]=3[CH3:24])=[O:18])=[CH:11][C:10]([C:25]([F:27])([F:26])[F:28])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc2c(=O)oc(-c3cc(C(F)(F)F)nn3-c3ncccc3Cl)nc12
Reactant: CC(C)N
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1cccc(C(=O)NC(C)C)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.3 %

Procedure:
To a suspension of the benzoxazinone product of Step D (124 g, 300 mmol) in dichloromethane (500 mL) was added dropwise isopropylamine (76 mL, 900 mmol) at room temperature. The temperature of the reaction mixture rose and the suspension thinned during the addition. The reaction mixture was then warmed to reflux for 1.5 h. A new suspension formed. The reaction mixture was cooled to room temperature and diethyl ether (1.3 L) was added and the mixture stirred at room temperature overnight. The solids were collected and washed with ether. The solids were air-dried and then dried in vacuo at 90° C. for 5 h to yield 122 g of the title compound, a compound of the present invention, as a fluffy white solid, melting at 194-196° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[S:10]([OH:13])(=[O:12])=[O:11].[C:14]([O:18][C:19](=[O:39])[NH:20][CH2:21][CH2:22][N:23]1[CH2:30][CH:29]2[O:31][CH:25]([CH2:26][N:27](CC3C=CC=CC=3)[CH2:28]2)[CH2:24]1)([CH3:17])([CH3:16])[CH3:15].C(O)(C)C.[H][H]>[Pd].O>[CH3:9][C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[C:3]=1[S:10]([OH:13])(=[O:12])=[O:11].[C:14]([O:18][C:19](=[O:39])[NH:20][CH2:21][CH2:22][N:23]1[CH2:24][CH:25]2[O:31][CH:29]([CH2:28][NH:27][CH2:26]2)[CH2:30]1)([CH3:17])([CH3:15])[CH3:16]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NCCN1CC2CN(Cc3ccccc3)CC(C1)O2
Agent: [Pd]
Agent: Cc1cc(C)c(S(=O)(=O)O)c(C)c1
Solvent: O
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)NCCN1CC2CNCC(C1)O2
Temperature: 73 °C
Reaction time: 1 h

Procedure:
[2-(7-Benzyl-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)ethyl]carbamic acid tert-butyl ester 2,4,6-trimethylbenzenesulfonic acid salt (150 g; see Preparation P above), isopropanol (IPA; 225 mL) and water (75 mL) were combined in a metal hydrogenation vessel. Solid 5% Pd/C catalyst (4.7 g, 61% water wet, Johnson Matthey type 440) was added. Hydrogen was introduced to the vessel and stirring was started. The mixture was hydrogenated under 2.5 bar of hydrogen pressure and was simultaneously heated to 55° C. (temperature overshot to 73° C.). Gas uptake measurement showed the reaction to be complete after 1 hour. After cooling to 47° C. the catalyst was removed by filtration through a glass fibre filter paper. The catalyst was washed on the filter with IPA (75 mL) and the combined filtrate and washings used in the next step.
Reaction SMILES: CC(=C)C.[CH3:5][NH:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[C:29]3[CH:30]=[CH:31][C:32]([C:34]([F:37])([F:36])[F:35])=[CH:33][C:28]=3[CH2:27][CH2:26][C@@H:25]([NH:38][C:39](=[O:45])[CH2:40][C:41]([NH2:44])([CH3:43])[CH3:42])[C:24]2=[O:46])=[CH:18][CH:17]=1)=[O:8].[CH2:47]([O:49][CH2:50]C)[CH3:48]>>[O:49]1[CH2:47][CH2:48][N:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2[CH:17]=[CH:18][C:19]([CH2:22][N:23]3[C:29]4[CH:30]=[CH:31][C:32]([C:34]([F:36])([F:37])[F:35])=[CH:33][C:28]=4[CH2:27][CH2:26][C@@H:25]([NH:38][C:39](=[O:45])[CH2:40][C:41]([NH2:44])([CH3:43])[CH3:42])[C:24]3=[O:46])=[CH:20][CH:21]=2)=[O:8])[CH2:5][CH2:50]1
Reactant: CNC(=O)Nc1ccccc1-c1ccc(CN2C(=O)[C@H](NC(=O)CC(C)(C)N)CCc3cc(C(F)(F)F)ccc32)cc1
Reactant: CCOCC
Agent: C=C(C)C
Product: CC(C)(N)CC(=O)N[C@@H]1CCc2cc(C(F)(F)F)ccc2N(Cc2ccc(-c3ccccc3NC(=O)N3CCOCC3)cc2)C1=O

Procedure:
Reaction of isobutylene with N-chlorosulfonylisocyanate 37 in diethyl ether gives the azetidinone derivative 38. Removal of the chlorosulfonyl group with aqueous sodium sulfite followed by reaction with di-t-butyl-dicarbonate gives the BOC-protected intermediate 40. Alkaline hydrolysis gives the protected amino acid derivative 41 in good overall yield.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:29]=[CH:28][C:10]([C:11]([C:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[O:15][C:14]=2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:12])=[CH:9][CH:8]=1.[CH2:30]([NH:32][CH2:33][CH3:34])[CH3:31]>C(O)C>[CH2:30]([N:32]([CH2:33][CH3:34])[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:29]=[CH:28][C:10]([C:11]([C:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[O:15][C:14]=2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:12])=[CH:9][CH:8]=1)[CH3:31]
Reactant: CCNCC
Reactant: O=C(c1ccc(OCCCCBr)cc1)c1c(-c2ccccc2)oc2ccccc12
Solvent: CCO
Product: CCN(CC)CCCCOc1ccc(C(=O)c2c(-c3ccccc3)oc3ccccc23)cc1

Procedure:
3-[4-(4-Bromobutoxy)benzoyl]-2-phenylbenzofuran (13.0 g., 0.029 mol.) is dissolved in 75 ml. of ethanol containing 8 ml. of diethylamine and refluxed for 24 hours. The solvent is removed under reduced pressure and the residue is dissolved in ether. The ethereal solution is extracted with 5% aqueous sodium hydroxide, water and saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated to give the title compound.
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[C:14]([O:15][CH3:16])=[C:13]([S:17][CH2:18][CH3:19])[CH:12]=[CH:11][C:5]=1[C:6]([O:8]CC)=[O:7]>O.C(O)C>[Br:3][C:4]1[C:14]([O:15][CH3:16])=[C:13]([S:17][CH2:18][CH3:19])[CH:12]=[CH:11][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)c1ccc(SCC)c(OC)c1Br
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCSc1ccc(C(=O)O)c(Br)c1OC

Procedure:
A solution of potassium hydroxide (1.46 g) in water was added to a mixture of ethyl 2-bromo-4-ethylsulphenyl-3-methoxybenzoate (3.98 g) in ethanol with stirring. The mixture was stirred and heated at reflux for 4 hours. It was cooled and evaporated then water was added and the mixture was washed with ethyl acetate then acidified to pH1. It was extracted with ethyl acetate, washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness to give 2-bromo-4-ethylsulphenyl-3-methoxybenzoic acid as an off-white solid NMR (CDCl3) 1.5(t,3H) 3.05(q,2H) 3.9(s,3H) 7.15(d, 1H) 7.6(d, 1H).
Reaction SMILES: C([N+](CCCC)(CCCC)CCCC)CCC.[P:18]([O:22][CH2:23][C@@H:24]1[C@@H:28]([O:29][P:30]([O:33][CH2:34][C@@H:35]2[C@@H:39]([OH:40])[C@@H:38]([OH:41])[C@H:37]([N:42]3[CH:50]=[N:49][C:48]4[C:43]3=[N:44][CH:45]=[N:46][C:47]=4[NH2:51])[O:36]2)([OH:32])=[O:31])[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25]1)([OH:21])([OH:20])=[O:19].C(C[O:63][C:64](=O)[C@@H:65]([NH:78][C:79]([O:81][C:82]([CH3:85])([CH3:84])[CH3:83])=[O:80])[CH2:66][CH:67]([S:72][S:73][C:74]([CH3:77])([CH3:76])[CH3:75])[CH2:68][N:69]=[N+:70]=[N-:71])#N>O.O1CCCC1>[N:69]([CH2:68][CH:67]([S:72][S:73][C:74]([CH3:77])([CH3:76])[CH3:75])[CH2:66][C@@H:65]([NH:78][C:79]([O:81][C:82]([CH3:83])([CH3:84])[CH3:85])=[O:80])[C:64]([O:40][C@H:39]1[C@@H:38]([OH:41])[C@H:37]([N:42]2[CH:50]=[N:49][C:48]3[C:43]2=[N:44][CH:45]=[N:46][C:47]=3[NH2:51])[O:36][C@H:35]1[CH2:34][O:33][P:30]([O:29][C@H:28]1[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25][C@@H:24]1[CH2:23][O:22][P:18]([OH:21])([OH:20])=[O:19])([OH:32])=[O:31])=[O:63])=[N+:70]=[N-:71]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(CN=[N+]=[N-])SSC(C)(C)C)C(=O)OCC#N
Reactant: Nc1ccn([C@H]2C[C@H](OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](COP(=O)(O)O)O2)c(=O)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CC(CN=[N+]=[N-])SSC(C)(C)C)C(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.7 %

Procedure:
A solution of ((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-(((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) (hydroxy)phosphoryl)oxy)tetrahydrofuran-2-yl)methyl dihydrogenphosphate (Compound 1h) (56 mg, 0.088 mmol) in water (1 ml) and a solution of (S)-5-azido-2-tert-butoxycarbonylamino-4-tert-butyldisulfanyl-pentanoic acid cyanomethyl ester (Compound 41) (110 mg, 0.263 mmol) in tetrahydrofuran (1 ml) were added to buffer A (29 mL), and the mixture was stirred at room temperature for 3 hours. Following lyophilization, the resulting residue was purified by reverse-phase silica gel column chromatography (0.05% aqueous trifluoroacetic acid solution/0.05% trifluoroacetic acid-acetonitrile solution) to afford a crude product of (2S)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 5-azido-2-((tert-butoxycarbonyl)amino)-4-(tert-butyldisulfanyl)pentanoate (Compound 42) (55 mg).
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:28]=[CH:27][C:21]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:20][CH:19]=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[CH2:30][CH:31]([OH:33])[CH3:32].B(F)(F)F.CCOCC>>[CH2:1]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([CH:22]=[CH:23][C:24]([O:26][CH2:30][CH:31]([OH:33])[CH3:32])=[O:25])=[CH:27][CH:28]=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]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(CCC(=O)O)cc1
Reactant: CC(O)CO
Agent: FB(F)F
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCNc1ccc(C=CC(=O)OCC(C)O)cc1

Procedure:
The title ester is prepared as in Example 23 by the reaction of 4-(hexadecylamino)hydrocinnamic acid with 1,2-dihydroxypropane and boron trifluoride etherate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[C@@H:4]([NH:15][CH2:16][CH2:17][N:18]([C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[CH2:19][CH2:20][C:21](O)=[O:22])[CH2:5][CH2:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>ClCCl>[CH2:27]([O:26][C:24]([N:18]1[CH2:19][CH2:20][C:21](=[O:22])[N:15]([C@H:4]([C:3]([O:2][CH3:1])=[O:34])[CH2:5][CH2:6][O:7][CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:16][CH2:17]1)=[O:25])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COC(=O)[C@H](CCOCc1ccccc1)NCCN(CCC(=O)O)C(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CCOCc1ccccc1)N1CCN(C(=O)OCc2ccccc2)CCC1=O
Reaction time: 15 h

Procedure:
A solution of 4.40 g (8.64 mmol) of (S)-4-benzyloxy-2-{2-[benzyloxycarbonyl-(2-carboxy-ethyl)-amino]-ethylamino}-butyric acid methyl ester; hydrochloride in 85 ml dichloromethane was treated with 1.20 (8.64 mmol) of triethylamine and at 0° C. with 1.99 g (10.37 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride. The cooling bath was allowed to come to room temperature and after 15 h the reaction was extracted with 10% aq. potassium hydrogensulfate solution/diethyl ether (3×). The organic phases were washed with 10% aq. potassium hydrogensulfate solution, 10% sodium chloride solution and dried over Na2SO4 to yield after evaporation of the solvent 3.74 g (95%) of the titled compound as light yellow oil. MS: 455.2 (MH+).
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.BrCC1C=C(C=CC=1)C=O.[C:21]([O-:24])(=[S:23])[CH3:22].[K+].O>CC(C)=O>[C:21]([S:23][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1)(=[O:24])[CH3:22]
Reactant: O=Cc1ccc(CBr)cc1
Reactant: CC([O-])=S
Agent: O=Cc1cccc(CBr)c1
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)SCc1ccc(C=O)cc1
Temperature: 25 °C
Yield: 85 %

Procedure:
To a solution of 4-(bromomethyl)-benzaldehyde (Hsung et al. (1995) Organometallics, 14: 4808-4815; Bookser and Bruice (1991) Am. Chem. Soc. 113: 4208-4218; Wagner et al. (1997) Tetrahedron 53: 6755-6790 for the synthesis of 3-(bromomethyl)benzaldehyde) (0.43 g, 2.2 mmol) in acetone (10 mL) was added potassium thioacetate (280 mg, 2.5 mmol) under stirring at rt, then the mixture was refluxed. A precipitate formed after a few minutes. The reaction was monitored by TLC and cooled to rt when no starting material was detectable (3.5 h). Water (25 mL) was added, the mixture was extracted with ethyl acetate (3×30 mL), and the combined organic phases were dried (Na2SO4) and evaporated. Column chromatography over flash silica gel (ethyl ether/hexanes, 1:1) gave 359 mg (85% yield) of a brown oil which darkened upon standing (nonetheless elementary analysis four weeks after exposure to air at rt indicated a high level of purity as listed below). IR (neat): {tilde over (v)} 3052, 2923, 2830, 2737, 1694, 1606, 1576; 1H NMR δ 2.36 (s, 3H), 4.15 (s, 2H), 7.45, 7.81 (AA′BB′, 2×2H), 9.97 (s, 1H); 13C NMR (APT) δ 30.1 (−), 32.9 (+), 129.3 (−), 129.9 (−), 135.2 (+), 144.7 (+), 191.5 (−), 194.3 (+); GC-MS (EI) obsd 194, 152, 119, 91, 43; Anal. Calcd for C10H10O2S: C, 61.83; H, 5.19; S, 16.51. Found: C, 61.97; H, 5.20; S, 16.60.