Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C(SCC2C=CC=CC=2)=[N:4]C=CC=1.ClCl.C([O-])(=O)C.[Na+].[Cl:23][C:24]1[C:25]([S:30](Cl)(=[O:32])=[O:31])=[N:26][CH:27]=[CH:28][CH:29]=1.Cl>O.C(O)(=O)C>[Cl:23][C:24]1[C:25]([S:30]([NH2:4])(=[O:32])=[O:31])=[N:26][CH:27]=[CH:28][CH:29]=1
Reactant: Clc1cccnc1SCc1ccccc1
Reactant: O=S(=O)(Cl)c1ncccc1Cl
Agent: CC(=O)[O-]
Agent: Cl
Agent: ClCl
Solvent: CC(=O)O
Solvent: O
Product: NS(=O)(=O)c1ncccc1Cl
Temperature: -30 °C

Procedure:
53.0 Grams (0.225 mole) of 3-chloro-2-((phenylmethyl)thio)pyridine were added to 250 ml of acetic acid containing 16.2 grams (0.90 mole) of water. The mixture was cooled in an ice bath and passed in a stream of chlorine at 10°-15° C. for 31/2 hours. The resulting cold acetic acid solution was poured, with stirring, into a mixture of 180 grams (2.2 moles) of sodium acetate, 500 ml water and 250 grams crushed ice. (The sodium acetate converts the 3-chloro-2-pyridine sulfonyl chloride present as the hydrochloride, into free 3-chloro-2-pyridine sulfonyl chloride.) The resulting mixture was extracted with methylene chloride, washed with water, and dried over anhydrous sodium sulfate. The methylene chloride extract was evaporated to 150 ml and cooled to -30° C. in a dry ice bath.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([NH2:8])=[N:6][CH:7]=1.[H-].[Na+].Br[CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[C@H:21]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:20][CH2:19]2.[NH4+].[Cl-]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][C:5]([NH:8][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[C@H:21]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:20][CH2:19]3)=[N:6][CH:7]=1
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCBr)ccc21
Reactant: Nc1ncc(Br)cn1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCNc3ncc(Br)cn3)ccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 20.5 %

Procedure:
To a solution of 5-bromo-2-aminopyrimidine (2.35 g, 13.5 mmol) in DMF (50 mL) was added NaH (539 mg, 13.5 mmol of a 60% dispersion in mineral oil) [H2 evolution]. Then, ethyl [(1S)-5-(3-bromopropoxy)-2,3-dihydro-1H-inden-1-yl]acetate (Example 45, 2.3 g, 6.74 mmol) was added over 5 min, and the reaction mixture was stirred at rt for 4 h, after which NH4Cl (10% aqueous solution) was added, and the mixture was concentrated under reduced pressure. The residue was taken up in EtOAc and washed with water and brine successively. The organic phase was dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to provide the product (600 mg, 21%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 1.27 (t, 3H), 1.70-1.81 (m, 1H), 2.02-2.12 (m, 2H), 2.34-2.43 (m, 1H), 2.41 (dd, 1H), 2.73 (dd, 1H), 2.77-2.94 (m, 2H), 3.48-3.56 (m, 1H), 3.58 (q, 2H), 4.03 (t, 2H), 4.18 (q, 2H), 5.95 (b t, 1H), 6.69 (dd, 1H), 6.75 (d, 1H), 7.04 (d, 1H), 8.22 (s, 2H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][C:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)/[C:10](=[N:19]/[S:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:25][CH:24]=3)(=[O:22])=[O:21])/[CH:9]=2)=[N:5][N:4]=[N:3]1.[Cl:35]C1C=CC(S(/N=C2\C=C(Cl)C(=O)C3C\2=CC=CC=3)(=O)=O)=CC=1>>[Cl:35][C:26]1[CH:27]=[CH:28][C:23]([S:20](/[N:19]=[C:10]2\[CH:9]=[C:8]([S:7][C:6]3[N:2]([CH3:1])[N:3]=[N:4][N:5]=3)[C:17](=[O:18])[C:16]3[C:11]\2=[CH:12][CH:13]=[CH:14][CH:15]=3)(=[O:22])=[O:21])=[CH:24][CH:25]=1.[CH3:1][N:2]1[C:6]([S:7][C:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)/[C:10](=[N:19]/[S:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:25][CH:24]=3)(=[O:21])=[O:22])/[CH:9]=2)=[N:5][N:4]=[N:3]1
Reactant: O=C1C(Cl)=C/C(=N\S(=O)(=O)c2ccc(Cl)cc2)c2ccccc21
Agent: Cn1nnnc1SC1=C/C(=N\S(=O)(=O)c2ccc(-c3ccccc3)cc2)c2ccccc2C1=O
Product: Cn1nnnc1SC1=C/C(=N\S(=O)(=O)c2ccc(Cl)cc2)c2ccccc2C1=O

Procedure:
(E)-4-chloro-N-(3-(1-methyl-1H-tetrazol-5-ylthio)-4-oxonaphthalen-1(4H)-ylidene) benzenesulfonamide (13y) was prepared according to the procedure for 13x except using 12e, affording 88.7 mg (99.4%) title compound as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](/[N:10]=[CH:11]/[N:12](C)C)=O)=[N:6][CH:7]=1.[NH2:15]N>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:10]=[CH:11][NH:12][N:15]=2)=[N:6][CH:7]=1
Reactant: CN(C)/C=N/C(=O)c1ccc(Br)cn1
Reactant: NN
Product: Brc1ccc(-c2nc[nH]n2)nc1
Yield: 83.2 %

Procedure:
A solution of (E)-5-bromo-N-((dimethylamino)methylene)picolinamide (0.604 mg, 2.36 mmol) and hydrazine (2.12 g, 66.1 mmol) was stirred at 25° C. for 3 h. The reaction was concentrated and diluted with water. The resulting precipitate was collected by filtration and dried under vacuum to give the title compound (0.442 g, 83% yield). MS (ESI) m/z 226.1 [M+1]+.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[N:8][C:6]=2[N:7]=1.[O:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][OH:29])[CH2:23][CH2:22]1.[Na]>O1CCCC1>[N:15]1([C:4]2[C:5]3[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[N:8][C:6]=3[N:7]=[C:2]([O:29][CH2:28][CH2:27][N:24]3[CH2:25][CH2:26][O:21][CH2:22][CH2:23]3)[N:3]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: OCCN1CCOCC1
Reactant: O=[N+]([O-])c1cnc2nc(Cl)nc(N3CCOCC3)c2c1
Agent: [Na]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cnc2nc(OCCN3CCOCC3)nc(N3CCOCC3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.2 %

Procedure:
Chloro-4-morpholino-6-nitro-pyrido[2,3-d]pyrimidine (4.4 g; 15 mmol) was dissolved in tetrahydrofuran (100 mL). To the solution was added morpholino-2-ethanol (2.4 g; 18 mmol), and it was chilled in a dry ice bath. Sodium 400 mg; 18 mmol). was then added, and it was allowed to warm to room temperature and stirred overnight. The solvent was then evaporated, and the solid was dissolved in dichloromethane (50 mL), washed with water (3×10 mL), dried over magnesium sulfate, and purified by column chromatography to give 4-morpholin-4-yl-2-(2-morpholin-4-yl-ethoxy)-6-nitro-pyrido[2,3-d]pyrimidine (3.35 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]([O:8][CH3:9])=[N:6][S:5][N:4]=1.ClC1C=CC=C(C(OO)=[O:18])C=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[C:7]([O:8][CH3:9])=[N:6][S:5](=[O:18])[N:4]=1
Reactant: COc1nsnc1OC
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: COC1=NS(=O)N=C1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 3,4-dimethoxy-1,2,5-thiadiazole (35.2 g; 24.1 mmoles) [prepared according to the procedure described in J. Org. Chem., 40, 2749 (1975)] in 100 ml of chloroform was added over a period of 3 minutes to a stirred solution of m-chloroperbenzoic acid (50.7 g; 25.0 mmoles; 85% assay) in 900 ml of chloroform at 20°, using a cooling bath to keep the exothermic reaction from rising above 32°. After stirring for 3 hours at ambient temperature, the excess peracid was reacted with an additional 2.0 g of 3,4-dimethoxy-1,2,5-thiadiazole and stirred for 1 hour.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C@H:5]([CH:7]([CH2:17][O:18][CH3:19])[C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[NH2:6])[CH3:2].[CH2:21]=O.O>C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:5]1[N:6]=[CH:21][C:9]2[NH:10][C:11]3[C:16]([C:8]=2[C:7]=1[CH2:17][O:18][CH3:19])=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:20])[CH3:2]
Reactant: C=O
Reactant: CCOC(=O)[C@@H](N)C(COC)c1c[nH]c2ccccc12
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)c1ncc2[nH]c3ccccc3c2c1COC
Yield: 30.6 %

Procedure:
20.3 g of beta-methoxymethyl-tryptophane-ethylester is dissolved in 350 ml of benzene, mixed with 2.48 g of paraformaldehyde and heated for 3.5 h in the water separator. After cooling, the benzene is distilled off, the residue is absorbed in 350 ml of toluene, and after adding 4.5 g of 10% palladium carbon, the mixture is heated with reflux for 20 h. The cooled solution is filtered and concentrated. The residue is chromatographed on silica gel with hexane/ethyl-acetate. The crystallization of the main fraction out of ethylacetate/diisopropylether yields 6.4 g of 4-methoxymethyl-beta-carboline-3-carboxylic-acid-ethylester with a m.p. 118°-119° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[CH:16]([NH2:18])[CH3:17].[CH3:19][O:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=1[S:29](Cl)(=[O:31])=[O:30].C(N(CC)C(C)C)(C)C>ClCCl>[CH3:19][O:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=1[S:29]([NH:18][CH:16]([C:10]1[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:9]=1[C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])[CH3:17])(=[O:30])=[O:31]
Reactant: CC(N)c1cc(F)ccc1-c1ccc(F)cc1F
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(S(=O)(=O)NC(C)c2cc(F)ccc2-c2ccc(F)cc2F)c(OC)c1
Temperature: 25 °C
Yield: 72.9 %

Procedure:
A stirred solution of 1-(2′,4,4′-trifluoro-1,1′-biphenyl-2-yl)ethylamine (0.71 g, 2.84 mmol) in dichloromethane (5 mL) was treated with 2,4-dimethoxybenzenesulfonyl chloride (0.71 g, 3.0 mmol), and N,N-diisopropylethylamine (0.77 g, 6.0 mmol). The reaction was stirred at room temperature for twelve hours, and the solvent was evaporated in vacuo to a crude oil. The crude oil was purified by preparative liquid chromatography on a Biotage® 40 Mi column of pre-packed silica gel (90 g), eluting with a gradient of between 5% and 50% methyl tert-butyl ether in hexane at a flow rate of 40 mL/min to afford, after evaporation of the solvent, a colorless oil. Crystallization of the colorless oil from ethyl acetate-hexane yielded the title compound (0.93 g, 2.07 mmol, 73%) as a homogeneous, colorless, crystalline solid, m.p. 192-194° C.;
Reaction SMILES: Cl.[CH2:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH:4]([C:12]([OH:14])=[O:13])[NH:3]1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.C(N(CC)CC)C>ClCCl>[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([S:23]([N:3]2[CH:4]([C:12]([OH:14])=[O:13])[CH2:5][C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:2]2)(=[O:25])=[O:24])=[CH:21][CH:22]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(O)C1Cc2ccccc2CN1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)N2Cc3ccccc3CC2C(=O)O)cc1

Procedure:
1,2,3,4-Tetrahydro-3-isoquinolinecarboxylic acid hydrochloride is reacted with 4-methoxybenzenesulfonyl chloride in dichloromethane in the presence of triethylamine, to give 2-[(4-methoxyphenyl)sulfonyl]-1,2,3,4-tetrahydro-3-isoquinoline carboxylic acid.
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[N:15]=[N:16][CH:17]=[CH:18][C:19]=1Cl)(OC(C)(C)C)=O.[NH4+].[OH-].C(Cl)(Cl)[Cl:24]>CO>[Cl:24][C:17]1[N:16]=[N:15][C:14]([O:13][CH2:12][C@@H:9]2[CH2:10][CH2:11][N:8]2[CH3:1])=[CH:19][CH:18]=1
Reactant: ClC(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1nnccc1Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: CN1CC[C@H]1COc1ccc(Cl)nn1
Yield: 66 %

Procedure:
The compound from step 13a (805 mg, 2.68 mmol) was treated in a similar fashion as that described under Example 7d. The crude was subject to flash chromatography on silica gel with 10% MeOH in CHCl3 to 0.5% NH4OH in 10% MeOH in CHCl3 used as the elutant to give 352 mg of a yellow oil (66% yield). MS (CI) m/e 200 (M+H)+. The amine deprotected material (330 mg, 1.66 mmol) was then subjected to reductive amination conditions previously described in Example 8. The crude product was purified by flash chromatography on silica gel using 2% MeOH in CHCl3 to 5% MeOH in CHCl3 as the elutant to give 125 mg of a clear oil (35% yield). MS (CI) m/e 214 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ: 7.36 (d, J=9.2 Hz, 1H), 7.02 (d, J=9.2 Hz, 1H, 4.54 (dd, J=11.6 Hz, 3.8 Hz, 1H), 4.47 (dd, J=11.6 Hz, 5.7 Hz, 1H, 3.48-3.39 (m, 2H), 2.89-2.81 (m, 1H), 2.38 (s, 3H), 2.17-2.03 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11](O)[CH2:10][C@H:9]1[C:14]([O:16][CH3:17])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].[Na+].C(N(/C(/F)=C(\F)/C(F)(F)[F:28])CC)C.C(N(C(F)(F)C(F)C(F)(F)F)CC)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([F:28])[CH2:10][C@H:9]1[C:14]([O:16][CH3:17])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(CC)/C(F)=C(\F)C(F)(F)F
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: CCN(CC)C(F)(F)C(F)C(F)(F)F
Agent: [F-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@H](F)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 93.2 %

Procedure:
Methyl(2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylate (4.91 g, 0.020 mol) and sodium fluoride (1.01 g, 0.024 mol) were suspended in dichloromethane (50 mL), followed by addition of Ishikawa reagent (4.35 mL, 0.024 mol) under ice cooling. The reaction mixture was slowly warmed to room temperature and then stirred for 20 hours. After the reaction, the reaction mixture was poured into ice-cold saturated aqueous sodium bicarbonate (70 mL) and then separated into organic and aqueous layers. The aqueous layer was extracted with ethyl acetate. This extracted solution was combined with the organic layer obtained above, washed sequentially with 10% aqueous potassium bisulfate and saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate. After drying, the solvent and the decomposition product of Ishikawa reagent (N,N-diethyl-2,3,3,3-tetrafluoropropionamide) were distilled off under reduced pressure, and the residue was applied to silica gel column chromatography (developing solvent; hexane:ethyl acetate=5:1 to 0:1) to give the titled compound (4.61 g, colorless oil).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:28])[N:4]([CH2:18][C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[NH:24][CH2:23][CH2:22]3)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].C([O:32][C:33]([C:36](Cl)=[O:37])(C)C)(=O)C.C(N(CC)CC)C.[OH-].[Na+]>CO.O1CCCC1>[Cl:1][C:2]1[C:3](=[O:28])[N:4]([CH2:18][C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[N:24]([C:33](=[O:32])[CH2:36][OH:37])[CH2:23][CH2:22]3)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: O=c1c(Cl)c(OCc2ccc(F)cc2F)ccn1Cc1ccc2c(c1)CCN2
Reactant: CC(=O)OC(C)(C)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(CO)N1CCc2cc(Cn3ccc(OCc4ccc(F)cc4F)c(Cl)c3=O)ccc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A 10 mL round bottomed flask equipped with stirbar and nitrogen inlet was charged with compound of Example 88 (200 mg, 0.50 mmol), 1-chlorocarbonyl-1-methylethyl acetate (80 μL, 0.55 mmol), triethylamine (140 μL, 1.0 mmol) and tetrahydrofuran (4.0 mL). After stirring at 25° C. for 20 min the reaction was completed by LC-MS. NaOH (2.5M, 2.24 mmol, 1.5 mL) and MeOH (2.0 mL) was added and stirred for 20 min to give the title compound. The compound precipitated out of solution. The precipitated was filtered and washed with water and diethyl ether to obtain the title compound (136 mg, 55%) a white solid. 1H NMR (400 MHz, (DMSO) δ 7.98 (d, J=8.1, 1H), 7.9 (d, J=7.8 Hz, 1H), 7.6 (q, J=8.6 and 6.6 Hz, 1H), 7.3 (m, 1H), 7.1 (m, 2H), 6.56 (d, J=7.8 Hz, 1H), 5.25 (s, 2H), 5.0 (s, 2H), 4.3 (t, J=7.8 Hz, 2H), 3.0 (t, J=7.9 Hz, 2H), 1.3 (s, 6H) ppm. ES-HRMS m/z 489.1376 (M+H calcd for C25H24ClF2N2O4 requires 489.1387).
Reaction SMILES: O[CH2:2][CH:3]1[CH2:7][S:6][C:5]2([CH2:12][CH2:11][CH2:10][CH:9]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:8]2)[S:4]1.S(Cl)([Cl:21])=O>C1C=CC=CC=1>[Cl:21][CH2:2][CH:3]1[CH2:7][S:6][C:5]2([CH2:12][CH2:11][CH2:10][CH:9]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:8]2)[S:4]1
Reactant: CCOC(=O)CC1CCCC2(C1)SCC(CO)S2
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CCOC(=O)CC1CCCC2(C1)SCC(CCl)S2

Procedure:
The titled compound was prepared according to the procedure described in Example E using 6.2 g (0.021 mole) of the product of Example D and 2.75 g (0.025 mol) of thionyl chloride in benzene (60 ml). The crude product was chromatographed on silica gel using 5% ethyl acetate/hexane to give two sets of two racemates. The less polar pair of racemates weighed 0.62 g. The more polar pair of racemates weighed 1.3 g.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=3)[CH:8]=2)[NH:3]1.[CH:27]([NH2:30])([CH3:29])[CH3:28].CCOC(C)=O>C(Cl)Cl>[CH:27]([NH:30][S:23]([C:20]1[CH:21]=[CH:22][C:17]([CH2:16][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[NH:3][C:2](=[O:1])[CH:11]=[C:10]3[C:12]([F:15])([F:14])[F:13])=[CH:18][CH:19]=1)(=[O:25])=[O:24])([CH3:29])[CH3:28]
Reactant: CC(C)N
Reactant: O=c1cc(C(F)(F)F)c2cc(Cc3ccc(S(=O)(=O)Cl)cc3)ccc2[nH]1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)NS(=O)(=O)c1ccc(Cc2ccc3[nH]c(=O)cc(C(F)(F)F)c3c2)cc1
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 44.9 %

Procedure:
A stirred solution of 4-(2-oxo4-trifluoromethyl-1,2-dihydroquinolin-6-ylmethyl)-benzenesulfonyl chloride (Preparation 1, 17 mg, 42 μmol) in anhydrous CH2Cl2 (0.5 mL) was treated dropwise with an excess of i-PrNH2 (145 μL, 1680 μmol). After stirring at 20° C. for 10 min, the reaction mixture was submitted to column chromatography (EtOAc) to furnish the title compound (8 mg, 45%): δH (CD3OD)=1.00 (d, 6H), 3.35 (sept, 1H), 4.20 (s, 2H), 7.00 (s, 1H), 7.15–7.20 (m, 3H), 7.50 (dd, 1H), 7.60 (d, 1H), 7.80 (d, 2H); m/z (ES+)=466.1 [M+H+MeCN]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH2:13]I)[N:12]=2)=[CH:4][CH:3]=1.[N-:15]=[N+:16]=[N-:17].[Na+]>CN(C=O)C.CCOC(C)=O>[N:15]([CH2:13][C:11]1[N:12]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[O:9][CH:10]=1)=[N+:16]=[N-:17]
Reactant: Fc1ccc(-c2nc(CI)co2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1coc(-c2ccc(F)cc2)n1
Temperature: 70 °C
Yield: 84.5 %

Procedure:
A solution of 2-(4-fluorophenyl)-4-(iodomethyl)oxazole (1.2 g, 3.96 mmol) in dry DMF (10 mL) was added sodium azide (515 mg, 7.9 mmol) and the reaction mixture was heated to 70° C. for 8 h. The reaction mixture was allowed to cool down to room temperature and diluted with EtOAc. The mixture was extracted with EtOAc and the combined extracts were washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford 4-(azidomethyl)-2-(4-fluorophenyl)oxazole (0.73 g, yield 85%) as a pale orange liquid, which was carried through without further purification. 1H NMR (400 MHz, CDCl3) δ 8.04-8.01 (m, 2H), 7.67 (s, 1H), 7.16-7.12 (m, 2H), 4.34 (s, 2H). MS (ESI) m/z: Calculated for C10H7FN4O: 218.06. found: 219.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH2:7]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:30]N1C(=O)CCC1=O>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH2:7][Br:30]
Reactant: OCc1cc(Br)ccc1F
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Fc1ccc(Br)cc1CBr
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 96.7 %

Procedure:
To a solution of 5-bromo-2-fluoro-benzyl alcohol (3.10 g, 15.1 mmol) in 30 mL of THF at 10° C. is added triphenyl phosphine (4.10 g, 15.6 mmol) followed by N-bromosuccinimide (2.67 g, 15.0 mmol). The ice bath is removed and the resulting solution is stirred for 20 min at room temperature. The crude product is purified by column chromatography eluting with 5% EtOAc/hexanes to give the title compound (3.90 g, 14.5 mmol).
Reaction SMILES: [C:1]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[S:16])O)[N:13]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].O([CH2:27][P:28]([O:33][CH2:34][CH3:35])([O:30][CH2:31][CH3:32])=[O:29])S(C(F)(F)F)(=O)=O>C1COCC1>[C:1]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14]([CH2:27][P:28]([O:33][CH2:34][CH3:35])([O:30][CH2:31][CH3:32])=[O:29])=[S:16])[N:13]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)Nc1nc(C(O)=S)cs1
Reactant: CCOP(=O)(COS(=O)(=O)C(F)(F)F)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOP(=O)(CC(=S)c1csc(NC(=O)OC(C)(C)C)n1)OCC
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of give 2-[N-Boc(amino)]-4-thiazolethiocarboxylic acid (1 mmole) in THF (5 mL) was cooled to −78° C. and treated with NaH (2 mmole) in small portions. After 10 min the reaction was treated with a solution of diethylphosphonomethyl triflate in THF (5 mL). The reaction was stirred at −78° C. for 1 h, and then quenched with H2O. Extraction and chromatography gave 2-[N-Boc(amino)]-4-diethylphosphonomethylthiocarbonylthiazole as a thick oil, which was subjected to Step D of Example 18 followed by Step C of Example 3 to give 2-amino-4-phosphonomethylthiocarbonylthiazole (18.5) as a solid. Mp>230° C. (decomp). Anal. Calcd. for C5H7N2O4PS2: C: 23.62; H: 2.78; N: 11.02. Found: C: 23.77; H: 2.61; N: 10.73.
Reaction SMILES: OS(O)(=O)=O.[S:6]1[CH:10]=[CH:9][C:8]([C:11](O)([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH3:12])=[C:7]1[C:23]1[S:24][CH:25]=[CH:26][CH:27]=1.C(Cl)Cl>O>[CH2:13]([C:11]1([CH3:12])[C:27]2[CH:26]=[CH:25][S:24][C:23]=2[C:7]2[S:6][CH:10]=[CH:9][C:8]1=2)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCCC(C)(O)c1ccsc1-c1cccs1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: O
Product: CCCCCCCCCC1(C)c2ccsc2-c2sccc21
Temperature: 25 °C

Procedure:
H2SO4 (1.33 mL) was added dropwise to 2-(2,2′-bithiophene-3-yl)undecan-2-ol (IIc) (0.70 g, 2.08 mmol) under stirring at room temperature. After stirring for 12 h, CH2Cl2 (15 mL) and water (15 mL) were added. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined organic extracts were successively washed with saturated NaHCO3 and brine. After drying over MgSO4, the solvent was removed in vacuo. The crude oil was purified with column chromatography (eluent hexane) to afford a pure dark yellow oil (Ic) (0.106 g, 16.0%). 1H-NMR (CDCl3): δ=7.13 (d, J=4.8 Hz, 2H), 6.94 (d, J=4.9 Hz, 2H), 1.82-1.75 (m, 2H), 1.41 (s, 3H), 1.29-1.07 (m, 14H), 0.84 (t, J=6.6 Hz, 3H). 13C-NMR (CDCl3): δ=160.04, 136.50, 125.27, 121.95, 49.53, 39.66, 32.50, 30.63, 30.36, 30.20, 30.07, 29.91, 25.65, 24.36, 23.32, 14.77.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:16]([CH3:17])=[CH:15][C:14]([S:18]C(=O)N(C)C)=[CH:13][C:12]=2[CH3:24])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+].Cl>CO>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:12]([CH3:24])=[CH:13][C:14]([SH:18])=[CH:15][C:16]=2[CH3:17])=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(SC(=O)N(C)C)cc(C)c1-c1ccc(C(C)(C)C)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cc1cc(S)cc(C)c1-c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Yield: 83.7 %

Procedure:
To a solution of dimethyl-thiocarbamic acid S-(4′-tert-butyl-2,6-dimethyl-biphenyl-4-yl) ester (8.8 g, 25.8 mmol) in methanol (65 mL) is added sodium methoxide (1.39 g, 25.8 mmol). The reaction mixture is heated to reflux overnight. After cooling to room temperature, the reaction mixture is neutralized with 5N HCl, concentrated to ⅓ volume, treated with brine, and extracted into dichloromethane. The aqueous layer is back-extracted with dichloromethane, and the combined organic layers are dried and concentrated. The resulting residue is applied to silica gel and eluted using hexanes with an ethyl acetate gradient from 0% to 50% to give the title compound (5.84 g).