Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1(=[O:12])(=[O:11])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3](=[O:10])[NH:2]1.FC(F)(F)C(O)=[O:16]>C(Cl)Cl.F[B-](F)(F)F.C([N+](CC)(CC)CC)C>[OH:16][C:9]1[C:4]2[C:3](=[O:10])[NH:2][S:1](=[O:11])(=[O:12])[C:5]=2[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)C(F)(F)F
Reactant: O=C1NS(=O)(=O)c2ccccc21
Agent: CC[N+](CC)(CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: O=C1NS(=O)(=O)c2cccc(O)c21
Yield: 58 %

Procedure:
4.6 g (25 mmol) of 1,2-benzisothiazol-3(2H)-one-1,1-dioxide (Saccharin®) were dissolved in a mixture of 65 ml of methylene chloride, 35 ml of trifluoroacetic acid and 2.1 g of tetraethylammonium tetrafluoroborate. The solution was electrolysed at ambient temperature in an electrolysis trough without any separation of the cathode and anode spaces (undivided cell) using a platinum coil (diameter of wire 1 mm, diameter of coil 0.5 cm, length of coil 7.5 cm) as cathode and a cylindrical platinum wire gauze (cylinder diameter 3.5 cm, cylinder height 5 cm, cylinder surface area 5 cm2) as anode. A dry rectifier with potentiometer was used as the source of current. An ammeter connected in series was used to determine the ampere hours and a voltage meter served to measure the potential between the cathode and anode (about 5 to 7 volts). After a charge quantity of about 0.5 Ah had been used up, electrolysis was stopped. The solution was added to ice water. The organic phase was separated off and combined with the chloroform extracts of the aqueous phase. After evaporation of the solvent the residue was distributed between an aqueous iron (III) chloride solution and methylene chloride. 2.7 g of starting material were recovered from the methylene chloride phase. The iron (III) chloride solution was made alkaline and filtered. The filtrate was then acidified and extracted with methylene chloride. After evaporation and recrystallisation from water, 1.2 g of 4-hydroxy-1,2-benzisothiazol-3(2H)-one-1,1-dioxide were obtained. This corresponds to a yield of 58% based on the starting material reacted and a current yield of 67%.
Reaction SMILES: [ClH:1].[NH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][C@H:4]1[C:8]([OH:10])=[O:9].[CH3:11][Si](C=[N+]=[N-])(C)C>C1C=CC=CC=1.CO>[ClH:1].[CH3:11][O:9][C:8]([C@@H:4]1[CH2:5][CH2:6][CH2:7][C@@H:3]1[NH2:2])=[O:10]
Reactant: N[C@H]1CCC[C@H]1C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: Cl
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)[C@@H]1CCC[C@@H]1N
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
(1R,2S)-2-Amino-cyclopentanecarboxylic acid hydrochloride (96 mg, 0.58 mmol) was dissolved in a 1:1 mixture of benzene and methanol (6 mL). The mixture was cooled to 0° C. A 2.0 M solution of (trimethylsilyl)diazomethane in hexanes (0.44 mL, 0.87 mmol) was added and the reaction was stirred at 25° C. for 30 min. The mixture was concentrated and dried in vacuo. The crude product was directly used in the next step.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:8]2[CH2:9][CH2:10][C:11]3[C:12]4[C:17]([S:18][C:19]=3[C:7]=2[CH:6]=[N:5]1)=[N:16][CH:15]=[N:14][C:13]=4[O:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1.[CH3:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[CH3:32][N:33]1[CH2:38][CH2:37][N:36]([CH2:2][CH2:3][N:4]2[C:8]3[CH2:9][CH2:10][C:11]4[C:12]5[C:17]([S:18][C:19]=4[C:7]=3[CH:6]=[N:5]2)=[N:16][CH:15]=[N:14][C:13]=5[O:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)[CH2:35][CH2:34]1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1ccc(CCOc2ncnc3sc4c(c23)CCc2c-4cnn2CCBr)cc1
Product: CN1CCN(CCn2ncc3c2CCc2c-3sc3ncnc(OCCc4ccc([N+](=O)[O-])cc4)c23)CC1
Yield: 100 %

Procedure:
This compound was prepared in a similar fashion as described in Example 48 step 6 starting from 3-(2-bromo-ethyl)-6-[2-(4-nitro-phenyl)-ethoxy]-4,5-dihydro-3H-10-thia-2,3,7,9-tetraaza-cyclopenta[a]fluorene (2.6 g, 5.2 mmol) and N-methyl piperazine (1.56 g, 15.59 mmol). The crude desired product was obtained as a light yellow solid (2.7 g) in 100% yield.
Reaction SMILES: C([O:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([C:20](=[O:24])[CH:21](O)O)=[CH:11][CH:10]=1)C1C=CC=CC=1.[CH3:25][O:26][C:27]1[CH:37]=[CH:36][C:30]([CH2:31][C:32]2([NH2:35])[CH2:34][CH2:33]2)=[CH:29][CH:28]=1.FC(F)(F)C([O-])=O>>[OH:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([CH:20]([OH:24])[CH2:21][NH:35][C:32]2([CH2:31][C:30]3[CH:36]=[CH:37][C:27]([O:26][CH3:25])=[CH:28][CH:29]=3)[CH2:34][CH2:33]2)=[CH:11][CH:10]=1
Reactant: COc1ccc(CC2(N)CC2)cc1
Reactant: O=C1COc2c(C(=O)C(O)O)ccc(OCc3ccccc3)c2N1
Agent: O=C([O-])C(F)(F)F
Product: COc1ccc(CC2(NCC(O)c3ccc(O)c4c3OCC(=O)N4)CC2)cc1

Procedure:
Reaction of 329 mg (1 mmol) 5-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and 177 mg (1 mmol) 1-(4-methoxy-benzyl)-cyclopropylamine according to general method 3. Yield: 39 mg (8%, trifluoroacetate); mass spectroscopy: [M+H]+=385.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([N+:23]([O-])=O)=[C:12]([CH:14]([C:16]3[N:20]([CH3:21])[N:19]=[CH:18][C:17]=3I)[OH:15])[CH:13]=2)=[CH:5][CH:4]=1.ClC1C=CC(CC2C=CC([N+]([O-])=O)=C(C(C3N(C)N=CC=3I)O)C=2)=CC=1>>[CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]3[NH:23][C:17]4[CH:18]=[N:19][N:20]([CH3:21])[C:16]=4[C:14](=[O:15])[C:12]=3[CH:13]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Cc2ccc([N+](=O)[O-])c(C(O)c3c(I)cnn3C)c2)cc1
Agent: Cn1ncc(I)c1C(O)c1cc(Cc2ccc(Cl)cc2)ccc1[N+](=O)[O-]
Product: COc1ccc(Cc2ccc3[nH]c4cnn(C)c4c(=O)c3c2)cc1

Procedure:
The title compound was prepared according to the procedure of step 4 in the EXAMPLE 13 using [5-(4-methoxybenzyl)-2-nitrophenyl](4-iodo-1-methyl-1H-pyrazol-5-yl)methanol (EXAMPLE 16, step 2), instead of [5-(4-chlorobenzyl)-2-nitrophenyl](4-iodo-1-methyl-1H-pyrazol-5-yl)methanol.
Reaction SMILES: Br[C:2]1[CH:11]=[N:10][C:5]2[O:6][CH2:7][CH2:8][NH:9][C:4]=2[CH:3]=1.[C:12]1(B(O)O)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][N:13]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O>[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([C:2]2[CH:11]=[N:10][C:5]3[O:6][CH2:7][CH2:8][NH:9][C:4]=3[CH:3]=2)=[CH:14][N:13]=1
Reactant: Brc1cnc2c(c1)NCCO2
Reactant: OB(O)c1nccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: c1ccc2c(-c3cnc4c(c3)NCCO4)cncc2c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 50.8 %

Procedure:
Under nitrogen atmosphere, in a 10 ml flask, 7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (36.3 mg, 0.169 mmol), isoquinoline boronic acid (44 mg, 0.253 mmol), tetrakis triphenylphosphine palladium (19.5 mg, 0.017 mmol) and potassium carbonate (58.3 mg, 0.423 mmol) were dissolved in a solvent of tetrahydrofuran/water (6/1, 1.4 ml/0.3 ml). The reaction mixture was stirred for 30 minutes at 80° C. using microwave (40 W) device. After cooling to room temperature, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated saline solution. The combined organic layer was dried over anhydrous magnesium sulfate (MgSO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on amine silica eluting with a solvent of dichloromethane. The fractions containing the product were collected and evaporated to obtain brown oil (22.6 mg, 51%).
Reaction SMILES: COC1N=CC(C#N)=CC=1.[CH3:11][O:12][C:13]1[N:18]=[C:17]([CH3:19])[C:16]([C:20]#[N:21])=[CH:15][CH:14]=1.CO[C:24](OC)([N:26]([CH3:28])[CH3:27])[CH3:25].CN(C)C=O>CO>[CH3:27][N:26]([CH3:28])[C:24]([CH3:25])=[CH:19][C:17]1[C:16]([C:20]#[N:21])=[CH:15][CH:14]=[C:13]([O:12][CH3:11])[N:18]=1
Reactant: COc1ccc(C#N)c(C)n1
Reactant: COC(C)(OC)N(C)C
Agent: COc1ccc(C#N)cn1
Solvent: CN(C)C=O
Solvent: CO
Product: COc1ccc(C#N)c(C=C(C)N(C)C)n1
Temperature: 130 °C
Reaction time: 0.75 h

Procedure:
2-2-(Dimethylamino)-1-propenyl]-6-methoxy-3-pyridinecarbonitrile--A mixture containing 47.2 g of 6-methoxy-2-methyl-3-pyridinecarbonitrile, 100 ml of dimethylacetamide dimethyl acetal and 100 ml of dimethylformamide was heated with stirring in an oil bath at 130° C. for 1 hour and 45 minutes. The temperature of the oil bath was raised to 150° C. and the methanol formed by the reaction was distilled off using a 12" distillation column (Vigreux) while continuing the heating at 150° C. for 14 hours. The reaction mixture was concentrated, 50 ml of ether was added to the concentrated solution whereupon the product crystallized out. The mixture was chilled and the crystalline solid collected. The solid was washed with cold ether, dried and recrystallized from ethyl acetate using decolorizing charcoal to yield 33.5 g of 2-[2-(dimethylamino)-1-propenyl]-6-methoxy-3-pyridinecarbonitrile, m.p. 103°-104° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH3:31])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([OH:18])=O)=[N:14][CH:15]=1.[NH2:32][CH2:33][CH2:34][OH:35].ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:24]=[CH:25][C:26]([O:29][CH2:30][CH3:31])=[CH:27][CH:28]=1)(=[O:21])=[O:22])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([NH:32][CH2:33][CH2:34][OH:35])=[O:18])=[N:14][CH:15]=1
Reactant: NCCO
Reactant: CCOc1ccc(S(=O)(=O)C(c2cnc(C(=O)O)cc2C)c2cc(F)ccc2F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCOc1ccc(S(=O)(=O)C(c2cnc(C(=O)NCCO)cc2C)c2cc(F)ccc2F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 5-[(2,5-difluorophenyl)[(4-ethoxyphenyl)sulfonyl]methyl]-4-methylpyridine-2-carboxylic acid (112 mg, 0.25 mmol) in methylene chloride (3 ml), 2-aminoethanol (0.017 ml, 0.28 mmol), 1-hydroxybenzotriazole (37 mg, 0.28 mmol), 4-methylmorpholine (0.030 ml, 0.28 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (53 mg, 0.28 mmol) were added at room temperature. After stirring for 3 hours at room temperature, the reaction mixture was washed with water and then saturated brine. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the obtained residue was subjected to flash silica gel chromatography. The fraction obtained from an elution with hexane:ethyl acetate=1:2 was concentrated under reduced pressure, and the resulting residue was washed with a mixed solvent of ethanol and diethyl ether, and was collected by filtration to obtain the title compound mg, 0.20 mmol, 79%) as a white solid.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([C:16](=[C:18]2[S:22][C:21](=[S:23])[NH:20][C:19]2=[O:24])[CH3:17])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].IC.[CH:27](N(C(C)C)CC)(C)C.O>C(O)C>[CH3:15][C:12]([C:9]1[CH:8]=[C:7]([C:16](=[C:18]2[S:22][C:21]([S:23][CH3:27])=[N:20][C:19]2=[O:24])[CH3:17])[CH:6]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[C:10]=1[OH:11])([CH3:13])[CH3:14]
Reactant: CC(=C1SC(=S)NC1=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: CI
Solvent: O
Product: CSC1=NC(=O)C(=C(C)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)S1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.7 %

Procedure:
A mixture of 5-[1-[3,5-bis(1,1-dimethylethyl)-4hydroxyphenyl]ethylidene]-2-thioxo-4-thiazolone (1.6 g, 4 mmoles), iodomethane (0.45 mL, 7 mmoles), and diisopropylethylamine (1.1 mL, 6 mmoles) in 20 mL of ethanol is stirred under N2 at room temperature for 16 hours, then stirred into 200 mL of water. The precipitate is filtered off, rinsed with water, and dried to afford the product (1.4 g) of 5-[1-[3,5bis(1,1-dimethylethyl)-4-hydroxyphenyl]-ethylidene]-2-(methylthio)-4(5H)-thiazolone, mp 206°-209° C. A sample recrystallized from acetonitrile was analytically pure, mp 224°-226° C.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[Cl:6][C:7]1[S:8][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:10][N:11]=1>C([O-])(O)=O.[Na+].C(OCC)(=O)C>[C:1]([NH:5][S:12]([C:9]1[S:8][C:7]([Cl:6])=[N:11][CH:10]=1)(=[O:14])=[O:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: O=S(=O)(Cl)c1cnc(Cl)s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C)NS(=O)(=O)c1cnc(Cl)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
To a stirred solution of commercially available tert-butylamine (5.03 g, 68.8 mmol) in saturated NaHCO3 solution (35 mL) and ethyl acetate (17 mL) was added at 0° C. (ice water bath) a solution of 2-chloro-thiazole-5-sulfonyl chloride [CAS-No. 88917-11-7] (5.0 g, 22.9 mmol). The reaction mixture was stirred at room temperature for 2 h, ethyl acetate (50 mL) was added followed by extraction. The water layer was again extracted with ethyl acetate (50 mL). The combined organic layers were washed with 2N HCl solution (40 mL) and brine (40 mL), dried (MgSO4) and evaporated to yield the title compound (4.9 g, 84%) as a yellow solid. MS (ISN) 253.1 [(M−H)−], mp 75° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1([CH2:11][OH:12])[CH2:9][CH2:8][CH2:7][NH:6][C:5]1=[O:10].C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22].C(=O)([O-])O.[Na+]>ClCCl>[CH3:20][S:21]([O:1][CH2:2][CH2:3][C:4]1([CH2:11][O:12][S:21]([CH3:20])(=[O:23])=[O:22])[CH2:9][CH2:8][CH2:7][NH:6][C:5]1=[O:10])(=[O:23])=[O:22]
Reactant: O=C1NCCCC1(CO)CCO
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCC1(COS(C)(=O)=O)CCCNC1=O
Temperature: 0 °C

Procedure:
A solution of 1 mmol of 3-(2-hydroxy-ethyl)-3-hydroxymethyl-piperidin-2-one in 3 ml of dichloromethane is admixed at 0° C. with 3 mmol of triethylamine, followed by 2.2 mmol of methanesulphonyl chloride. The reaction mixture is stirred at 0° C. for an hour and then at room temperature for an hour. The reaction mixture is poured into saturated aqueous sodium hydrogen carbonate solution and extracted with dichloromethane (2×). The combined organic extracts are washed with brine, dried with sodium sulphate and evaporated. From the residue the title compound is identified by means of flash chromatography (SiO2 60 F) on the basis of the Rf value.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:8][C:7]([CH3:10])([CH3:9])[O:6][C@@H:5]([CH2:11][C:12]([O:14]C(C)(C)C)=O)[CH2:4]1.[CH2:19]([NH2:23])[CH2:20][CH2:21][CH3:22]>CO>[CH2:19]([NH:23][C:12](=[O:14])[CH2:11][C@H:5]1[CH2:4][C@@H:3]([CH2:2][OH:1])[O:8][C:7]([CH3:9])([CH3:10])[O:6]1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCCN
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CO)OC(C)(C)O1
Solvent: CO
Product: CCCCNC(=O)C[C@H]1C[C@@H](CO)OC(C)(C)O1
Temperature: 65 °C

Procedure:
Mixture of tert-butyl 2-((4R,6S)-6-(hydroxymethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate (50 grams), methanol (300 ml) and n-butyl amine (200 ml) was heated to 60-70° C. under nitrogen pressure and stirred. After the completion of the reaction, distilled off the reaction mixture completely followed by co-distillation with methylene chloride at below 55° C. Methylene chloride (500 ml) was added to the obtained residue at 25-30° C. and stirred for 15 minutes. The unwanted solid was filtered off and the filtrate was distilled off under reduced pressure to get the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][S:17][CH2:18][C@H:19]([O:35][C:36](=[O:48])[NH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH2:20][O:21][C:22](=[O:34])[NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:13](O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:82][CH2:83][CH2:84][O:85][CH2:86][CH2:87][O:88][CH2:89][CH2:90][O:91][CH2:92][CH2:93][P:94](=[O:101])([O:98][CH2:99][CH3:100])[O:95][CH2:96][CH3:97]>C(Cl)Cl>[CH2:99]([O:98][P:94]([CH2:93][CH2:92][O:91][CH2:90][CH2:89][O:88][CH2:87][CH2:86][O:85][CH2:84][CH2:83][NH:82][C:13](=[O:14])[C@@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])[CH2:16][S:17][CH2:18][C@H:19]([O:35][C:36](=[O:48])[NH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH2:20][O:21][C:22](=[O:34])[NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])(=[O:101])[O:95][CH2:96][CH3:97])[CH3:100]
Reactant: CCCCCCCCCCNC(=O)OC[C@H](CSC[C@H](NC(=O)OCc1ccccc1)C(=O)O)OC(=O)NCCCCCCCCCC
Reactant: CCOP(=O)(CCOCCOCCOCCN)OCC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCCCCCCCNC(=O)OC[C@H](CSC[C@H](NC(=O)OCc1ccccc1)C(=O)NCCOCCOCCOCCP(=O)(OCC)OCC)OC(=O)NCCCCCCCCCC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (R)-2-(benzyloxycarbonylamino)-3-((R)-2,3-bis(decylcarbamoyloxy)propylthio) propanoic acid (15, 1 eq) and HBTU (1.2 eq) in DCM (0.06 M) was added DIEA (2.4 eq), followed by diethyl 2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethylphosphonate (1.2 eq, from example 18, step 4). The reaction was stirred at room temperature for 4 hours. The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using a gradient of 0-10% MeOH/DCM to afford the title compound as a clear viscous oil.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[C:11]2[OH:14])=[CH:6][CH:5]=1.[N:15]([O-])=[O:16].[Na+].S(=O)(=O)(O)O>O>[Cl:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10]([N:15]=[O:16])=[C:11]2[OH:14])=[CH:6][CH:5]=1
Reactant: Oc1cccc2ccc(Cl)cc12
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=Nc1ccc2ccc(Cl)cc2c1O
Temperature: 0 °C

Procedure:
To a solution of sodium hydroxide, 22.4 g in 1.0 liter of water, is added 100 g (0.56 mole) of the chloronaphthol (V). The mixture is stirred with slight heating until solution is complete. The solution is then cooled to -5° to 0° and treated with sodium nitrite, 40.0 g, (0.6 mole) followed by the addition of concentrated sulfuric acid (176 ml) over a 90-minute period. Ice-water (600 ml) is added periodically to prevent clumping of the solid which forms. When addition of the acid is complete, the reaction mixture is stirred for another hour at -5° to 0°. The product is filtered, washed with 4.0 liters of cold water, air-dried overnight and then dried in vacuum oven at 60° for 2.5 days. Yield: 108.6 g (93.4%) light yellow-green solid.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:10][C:11](=[O:20])[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO>[CH2:1]([O:8][C@@H:9]([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:10][C@H:11]([OH:20])[CH2:12][C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC[C@@H](CC(=O)CC(=O)OC(C)(C)C)OCc1ccccc1
Solvent: CO
Product: CCCC[C@@H](C[C@H](O)CC(=O)OC(C)(C)C)OCc1ccccc1
Yield: 73.6 %

Procedure:
In a 500 ml autoclave were charged 95 ml of dried methanol, 22.0 g of the compound obtained in Step 2, and 0.634 g of (S)-iodo-π-p-cymene[2,2'-bis(di-p-tolylphosphino)-1,1'-binaphthyl]ruthenium iodide in a nitrogen stream, and the mixture was allowed to react at room temperature under a hydrogen pressure of 75 to 80 kg/cm2 for 18 hours. The solvent was removed by distillation under reduced pressure to obtain 22.3 g of a crude product. Purification by silica gel column chromatography gave 16.3 g (73.4%) of the titled compound.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][O:21][C:22](=[O:31])[C:23]1[CH:28]=[CH:27][C:26]([I:29])=[C:25]([OH:30])[CH:24]=1.CCOC(/N=N/C(OCC)=O)=O.[Cl:44][C:45]1[CH:50]=[C:49]([Cl:51])[CH:48]=[CH:47][C:46]=1[CH2:52][CH2:53]O>C1COCC1>[CH3:20][O:21][C:22](=[O:31])[C:23]1[CH:28]=[CH:27][C:26]([I:29])=[C:25]([O:30][CH2:53][CH2:52][C:46]2[CH:47]=[CH:48][C:49]([Cl:51])=[CH:50][C:45]=2[Cl:44])[CH:24]=1
Reactant: COC(=O)c1ccc(I)c(O)c1
Reactant: OCCc1ccc(Cl)cc1Cl
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(I)c(OCCc2ccc(Cl)cc2Cl)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
6.6 g of triphenylphosphine and 5 g of 4-Iodo-3-hydroxy-benzoic acid methyl ester were dissolved in 65 ml of anhydrous THF. The solution was cooled to 0° C. to 10° C. and a solution of 3.7 ml DEAD in 7.5 ml anhydrous THF was added dropwise over 20 min. The reaction was warmed to RT and stirred for 45 min. A solution of 2.8 ml 2-(2,4-Dichlorophenyl)-ethanol in 3 ml anhydrous THF was added with cooling. The reaction was stirred at RT for 3 h, then the solvents were removed under reduced pressure. The residue was treated with n-heptane:ethyl acetate/1:1. The filtrate was dried under reduced pressure. The product was purified by silica gel chromatography, eluting with n-heptane:ethyl acetate/4:1 to n-heptane:ethyl acetate/1:1.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][C@H:6]2[CH2:8][C@@H:3]1[CH2:4][C@@H:5]2[NH:9][C:10]1[S:11][C:12]([CH:17]([CH3:19])[CH3:18])([CH3:16])[C:13](=[O:15])[N:14]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[CH:17]([C:12]1([CH3:16])[S:11][C:10]([NH:9][C@H:5]2[CH2:4][C@H:3]3[CH2:8][C@@H:6]2[CH2:7][C:2]3=[O:1])=[N:14][C:13]1=[O:15])([CH3:19])[CH3:18]
Reactant: CC(C)C1(C)SC(N[C@H]2C[C@H]3C[C@@H]2C[C@@H]3O)=NC1=O
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)C1(C)SC(N[C@H]2C[C@H]3C[C@@H]2CC3=O)=NC1=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Silica gel 60 (particle size, 0.040-0.063 mm, CAS # 63231-67-4, from EMD Chemical Inc., 2.4 g) was added to a solution of 2-((1R,2S,4R,5S)-5-hydroxybicyclo[2.2.1]heptan-2-ylamino)-5-isopropyl-5-methylthiazol-4(5H)-one (0.709 g, 2.51 mmol) in anhydrous dichloromethane (40 mL). The mixture was cooled to 0° C. Pyridinium chlorochromate (1.08 g, 5.02 mmol) was added, and the reaction mixture was gradually warmed to ambient temperature and stirred overnight. The mixture was diluted with dichloromethane, and filtered through a pad of Celite. The solvents were removed in vacuo and the residue was purified by flash column chromatography (0 to 100% of EtOAc in hexanes) to give the title compound as a tan solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:8]=[CH:7]2.Br[CH2:17][CH2:18][O:19][CH3:20]>>[CH3:20][O:19][CH2:18][CH2:17][O:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:8]=[CH:7]2
Reactant: COC(=O)c1ccc2cccc(O)c2c1
Reactant: COCCBr
Product: COCCOc1cccc2ccc(C(=O)OC)cc12

Procedure:
Analogously to method C, 2.02 g of methyl 8-hydroxynaphthalene-2-carboxylate [115399-09-2] and 2.08 g of 1-bromo-2-methoxyethane are reacted. The title compound is identified on the basis of the Rf value.
Reaction SMILES: [CH2:1]([N:19]=[C:20]=[O: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][CH2:16][CH2:17][CH3:18].[C:22]([CH2:47][CH2:48][SH:49])([C:25]([C:28]([C:31]([C:34]([C:37]([C:40]([C:43]([F:46])([F:45])[F:44])([F:42])[F:41])([F:39])[F:38])([F:36])[F:35])([F:33])[F:32])([F:30])[F:29])([F:27])[F:26])([F:24])[F:23].N1(C2CCCCCCC2)CCCCCCN1>>[CH2:1]([NH:19][C:20]([S:49][CH2:48][CH2:47][C:22]([C:25]([C:28]([C:31]([C:34]([C:37]([C:40]([C:43]([F:44])([F:45])[F:46])([F:41])[F:42])([F:38])[F:39])([F:35])[F:36])([F:33])[F:32])([F:30])[F:29])([F:27])[F:26])([F:24])[F:23])=[O: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][CH2:16][CH2:17][CH3:18]
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)CCS
Reactant: CCCCCCCCCCCCCCCCCCN=C=O
Agent: C1CCCC(N2CCCCCCN2)CCC1
Product: CCCCCCCCCCCCCCCCCCNC(=O)SCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 100 °C
Reaction time: 6 h

Procedure:
Octadecyl Isocyanate (29.5 g, 0.1 mole), C8F17CH2CH2SH (48 g, 0.1 moles) and 2.2.2 diazabicyclooctane (0.1 g) were mixed under nitrogen and heated to 100° C. with stirring for 6 hours. An infrared spectrum showed no -NCO absorption, indicating completion of the reaction. The product is a white wax, melting at 85°-89° C. NMR showed proton resonances at 4.7 ppm (1 proton NH), 3.2 ppm (2 protons CH2CH2NH), 3.1 ppm (2 protons CH2SCO), 2.5 ppm (2 protons C8F17CH2), 1.3 ppm (32 protons CH3 (CH2)16) and 0.8 ppm (3 protons CH3 (CH2)16).