Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1COCC1.C(Br)(Br)(Br)[Br:26].[CH2:30]([NH:42][C:43](=[O:63])[C:44]1[CH:49]=[C:48]([C:50]2[CH:55]=[CH:54][CH:53]=[C:52]([O:56][CH3:57])[CH:51]=2)[C:47]([O:58][CH2:59][CH2:60]O)=[C:46]([Br:62])[CH:45]=1)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>CCOC(C)=O>[CH2:30]([NH:42][C:43](=[O:63])[C:44]1[CH:49]=[C:48]([C:50]2[CH:55]=[CH:54][CH:53]=[C:52]([O:56][CH3:57])[CH:51]=2)[C:47]([O:58][CH2:59][CH2:60][Br:26])=[C:46]([Br:62])[CH:45]=1)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: CCCCCCCCCCCCNC(=O)c1cc(Br)c(OCCO)c(-c2cccc(OC)c2)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCNC(=O)c1cc(Br)c(OCCBr)c(-c2cccc(OC)c2)c1
Temperature: 25 °C
Yield: 67.3 %

Procedure:
To a flamed dried flask was added triphenylphosphine (98 mg, 0.373 mmol) and 1.5 mL anhydrous THF. This was stirred until all the triphenylphosphine had dissolved. Then CBr4 (123 mg, 0.373 mmol) was added. The reaction mixture was stirred for one-half hour at room temperature then it was cooled to ° C. before N-dodecyl-3-bromo-4-(2-hydroxyethoxy)-5-(3-methoxyphenyl)benzamide (200 mg, 0.373 mmol) was added. The cooling bath was removed after the addition was complete. After the reaction mixture had warmed up to room temperature, 0.2 eq each of triphenylphosphine (19.6 mg, 0.075 mmol) and CBr4 (24.8 mg, 0.075 mmol) were added. The reaction was stirred for one-half hour then the solvent was removed under vacuum to give a yellow semisolid. This material was subjected to flash chromatography (25% EtOAc:75% Hexanes) to yield 150 mg, 67% of a yellow oil. 1H NMR (CDCl3) δ 1.25 (t, J=8.13 Hz, 3H); 1.22-1.40 (m, 18H); 1.52-1.63 (m, 2H); 3.35 (t, J=8.18 Hz, 2H); 3.40 (q, J=6.54 Hz, 2H); 3.84-3.90 (m, 5H); 6.00 (m, 1H); 6.93 (dd, J=8.18 Hz, 2.45 Hz, 1H); 7.07-7.11 (m, 2H); 7.35 (t, J=8.18 Hz, 1H); 7.65 (d, J=2.45 Hz, 1H); 7.39 (d, J=2.45 Hz, 1H).
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[CH2:7]([O:10][CH:11](OCC#C)[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[C:8]#[CH:9].Cl>ClCCl.[Bi](Br)(Br)Br>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([CH:11]([O:10][CH2:7][C:8]#[CH:9])[C:5]#[N:6])=[CH:17][CH:16]=1
Reactant: C#CCOC(OCC#C)c1ccc(Cl)cc1
Reactant: C[Si](C)(C)C#N
Agent: Br[Bi](Br)Br
Agent: Cl
Solvent: ClCCl
Product: C#CCOC(C#N)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 63 %

Procedure:
Under an atmosphere of nitrogen, trimethylsilyl cyanide (3.1 g) is added to bismuth (III)bromide (0.22 g) and 1-(bis-prop-2-ynyloxy-methyl)-4-chloro-benzene (6.7 g) in dichloromethane (50 ml) at room temperature. The reaction mixture is stirred for 48 hours at room temperature and then poured into 0.5 M hydrochloric acid (50 ml). The organic phase is separated, dried (magnesium sulfate) and evaporated. Crude (4-chloro-phenyl)-prop-2-ynyloxy-acetonitrile (3.7 g) is obtained as oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C@@:8]2([CH3:20])[NH:16][C:15](=O)[C:11]3([CH2:14][CH2:13][CH2:12]3)[S:10](=[O:19])(=[O:18])[CH2:9]2)[CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1.C([O-])(O)=O.[Na+]>O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C@@:8]2([CH3:20])[NH:16][C:15](=[S:31])[C:11]3([CH2:14][CH2:13][CH2:12]3)[S:10](=[O:19])(=[O:18])[CH2:9]2)[CH:7]=1
Reactant: C[C@@]1(c2cc(Br)ccc2F)CS(=O)(=O)C2(CCC2)C(=O)N1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: C[C@@]1(c2cc(Br)ccc2F)CS(=O)(=O)C2(CCC2)C(=S)N1
Temperature: 80 °C
Reaction time: 2 h
Yield: 91.8 %

Procedure:
To a solution of (R)-7-(5-bromo-2-fluoro-phenyl)-7-methyl-5,5-dioxo-5λ6-thia-8-aza-spiro[3.5]nonan-9-one (1.1 g, 2.92 mmol, Eq: 1.00) in dioxane (50 ml) was added Lawesson's reagent (1.18 g, 2.92 mmol, Eq: 1.00). The reaction mixture was stirred at 80° C. for 2 hours. More Lawesson's reagent (1.55 g, 3.84 mmol, Eq: 1.00) was added and stirring continued at 80° C. for 8 hours. The reaction mixture was poured into sat. NaHCO3 solution and extracted twice with ethyl acetate. The organic layers were washed with brine, dried over Na2SO4, filtered and evaporated to give light yellow oil. The residue was chromatographed on 20 g silica gel with 0-50% ethyl acetate in heptane to give (R)-7-(5-bromo-2-fluoro-phenyl)-7-methyl-5,5-dioxo-5λ6-thia-8-aza-spiro[3.5]nonan-9-thione (1.05 g, 2.68 mmol, 91.5% yield) as a light yellow foam. MS (ISP): m/z=392.0 [M+H]+ and 394.3 [M+2+H]+.
Reaction SMILES: [C:1]([CH2:6][CH:7]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:3][CH2:4][CH3:5])=[O:2].[CH:27](O)(O)[C:28]([F:31])([F:30])[F:29]>O1CCCC1>[CH3:7]/[C:6](=[CH:27]\[C:28]([F:31])([F:30])[F:29])/[C:1]([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OC(O)C(F)(F)F
Solvent: C1CCOC1
Product: CCOC(=O)/C(C)=C/C(F)(F)F
Reaction time: 15 h

Procedure:
A suspension of (carbethoxyethylidene)triphenylphosphorane (400 g, 1.10 mole) in tetrahydrofuran (600 mL) was treated with aqueous fluoral hydrate (71.5% w/w, 180 g, 1.10 mole) over a period of 4 hours. During the addition the reaction temperature rose to 45° C. and all of the solid dissolved to give a clear brown solution. The mixture was allowed to stand for 15 hours and was then heated under reflux for 3.5 hours. The solution was distilled at 2,700 Pa until the temperature in the distillation flask reached 140° C., giving ethyl (E)-2-methyl-4,4,4-trifluorobut-2-enoate as a solution in tetrahydrofuran (Solution A, 0.75 L, containing a maximum of 201 g of alkene); NMR (270 MHz, CDCl3): 1.3 (t, 3H, J=7Hz), 2.1 (br, s, 3H), 4.3 (q, 2H, J=7Hz) and 6.7 (m, 1H), (plus signals due to tetrahydrofuran).
Reaction SMILES: Cl.[F:2][C:3]([F:15])([F:14])[C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][NH:10][CH2:11]2)=[CH:6][CH:5]=1.[O:16]=[C:17]1[CH:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:21][CH2:20][CH2:19][N:18]1[CH2:29][C:30](O)=[O:31].C(N=C=NCCCN(C)C)C>ClCCl>[O:31]=[C:30]([N:10]1[CH2:9][CH2:8][C:7]2[C:12](=[CH:13][C:4]([C:3]([F:2])([F:14])[F:15])=[CH:5][CH:6]=2)[CH2:11]1)[CH2:29][N:18]1[CH2:19][CH2:20][CH2:21][CH:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]1=[O:16]
Reactant: O=C(O)CN1CCCC(c2ccccc2)C1=O
Reactant: FC(F)(F)c1ccc2c(c1)CNCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCCC(c2ccccc2)C1=O)N1CCc2ccc(C(F)(F)F)cc2C1
Reaction time: 39 h

Procedure:
To a solution of 7-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (0.056 g, 0.236 mmol) and 2-(2-oxo-3-phenylpiperidin-1-yl)acetic acid (Example 91D, 0.050 g, 0.214 mmol) in dichloromethane (0.5 mL) was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine (0.049 mL, 0.279 mmol), and the reaction was stirred for approximately 39 hours. The reaction was loaded directly onto a SF15-12 silica gel column (Analogix®, Burlington, Wis.), and the title compound was eluted using a gradient of 5% to 100% ethyl acetate/hexane over 20 minutes (flow=30 mL/minute). The product was dissolved in a minimal amount of ethyl acetate, and hexanes were added which caused the product to precipitate. Concentration gave the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.16-7.48 (m, 8H), 4.80 (s, 1H), 4.71 (s, 1H), 4.48-4.57 (m, 1H), 4.09-4.23 (m, 1H), 3.78-3.99 (m, 1H), 3.68-3.79 (m, 2H), 3.54-3.67 (m, 1H), 3.40-3.54 (m, 1H), 2.90-3.03 (m, 2H), 2.13-2.30 (m, 1H), 1.93-2.11 (m, 2H), 1.76-1.96 (m, 1H); MS (ESI+) m/z 417 (M+H)+.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][NH:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].Br[CH2:32][CH:33]1[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]1>>[C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:32][CH:33]3[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:43])([CH3:45])[CH3:44])=[O:40])[CH2:35][CH2:34]3)[C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([OH:9])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2[nH]ccc2c1-c1ccc2c(c1)CCCO2
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Product: Cc1nc2c(ccn2CC2CCN(C(=O)OC(C)(C)C)CC2)c(-c2ccc3c(c2)CCCO3)c1C(OC(C)(C)C)C(=O)O

Procedure:
The title compound was prepared in a manner similar to that described in Example 27, Step H from methyl 2-(tert-butoxy)-2-(4-(chroman-6-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate and tert-butyl 4-(bromomethyl)piperidine-1-carboxylate. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.48-7.42 (m, 1 H), 7.21-7.14 (m, 1 H), 7.12-7.08 (m, 1 H), 6.95 (dd, J=4.9, 8.4 Hz, 1 H), 6.33 (dd, 1 H), 5.53 (d, J=3.7 Hz, 1 H), 4.30 (t, J=5.2 Hz, 2 H), 4.13 (dd, J=7.0, 14.2 Hz, 3 H), 3.50 (s, 1 H), 2.98-2.77 (m, 5 H), 2.67 (br. s., 2 H), 2.25-2.14 (m, 1 H), 2.14-2.02 (m, 2 H), 1.64 (d, J=12.7 Hz, 1 H), 1.56 (br. s., 1 H), 1.50-1.42 (m, 10 H), 1.31-1.13 (m, 2 H), 0.99-0.89 (s, 9 H); LC/MS (m/z) ES+=592.32 (M+1).
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:14]=1[C:15](Cl)=[O:16]>O1CCCC1>[Cl:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:14]=1[C:15]([N:11]1[CH:10]=[CH:9][N:8]=[C:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:16]
Reactant: c1ccc(-c2ncc[nH]2)cc1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Solvent: C1CCOC1
Product: O=C(c1c(Cl)cccc1Cl)n1ccnc1-c1ccccc1

Procedure:
173 g of 2-phenylimidazole are dissolved in 600 ml of tetrahydrofuran. To this solution are added dropwise at boiling temperature 129.4 g of 2,6-dichlorobenzoyl chloride, dissolved in 400 ml of tetrahydrofuran, and the mixture is refluxed for 1 hour. The phenylimidazole hydrochloride which precipitates is separated at room temperature by vacuum filtration. The solvent of the filtrate is subsequently removed in the rotary evaporator, and the residue is recrystallised from 600 ml of acetonitrile. The yield after filtration with suction, washing with acetonitrile and drying is 153 g (80.4% of theory) of the product, m.p. 116°-117° C. There are obtained by concentrating the mother liquor by evaporation a further 22.3 g (11.7% of theory) of the product, m.p. 110°-114° C. For the analysis, 3.0 g of the compound are recrystallised from 5 ml of acetonitrile, washed with acetonitrile and dried at 60° C. in vacuo; yield: 2.6 g, m.p. 117°-118° C.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:17][O:18]C(=O)C1C=CC=CC=1)(=[O:5])[CH:2]([CH3:4])[CH3:3].[F:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[C:30]([CH3:35])[CH:29]=1.[OH-].[Na+]>O1CCOCC1.CO>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:32][C:31]1[CH:33]=[CH:34][C:28]([F:27])=[CH:29][C:30]=1[CH3:35])=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:17][OH:18])(=[O:5])[CH:2]([CH3:3])[CH3:4]
Reactant: CC(C)C(=O)c1cnc2c(COC(=O)c3ccccc3)cccc2c1Cl
Reactant: Cc1cc(F)ccc1N
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: Cc1cc(F)ccc1Nc1c(C(=O)C(C)C)cnc2c(CO)cccc12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 3-isobutyryl-4-chloro-8-(benzoyloxymethyl)quinoline (1.84 g, 5 mmol) and 4-fluoro-2-methylaniline (0.78 ml, 7 mmol) in dioxan (25 ml) was heated at reflux for 2 hours, then the solvent evaporated. A solution of sodium hydroxide (0.8 g, 20 mmol) in methanol (50 ml) was added and the mixture stirred at room temperature for 1.5 hours. The resulting precipitate was filtered off and recrystallised from methanol to give (0.48 g, 27%), m.p. 139°-140°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]([CH3:15])([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=1)[CH3:5].C(O)(=O)C>C1COCC1.[Zn]>[CH3:1][O:2][C:3](=[O:16])[C:4]([C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[CH:10][CH:11]=1)([CH3:15])[CH3:5]
Reactant: COC(=O)C(C)(C)c1ccc([N+](=O)[O-])cc1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)c1ccc(N)cc1
Reaction time: 1 h

Procedure:
2-Methyl-2-(4-nitro-phenyl)-propionic acid methyl ester (2.1 g) was dissolved in THF (70 ml) and acetic acid (5 ml) and Zn (10 g) were added. The mixture was stirred for 1 h and filtered through Celite®. The filtrate was rinsed with EtOAc and the organics were evaporated to a residue which was purified on silica gel chromatography (40% EtOAc/hexanes) to provide the desired compound as a yellow oil. M+H 194.
Reaction SMILES: Cl.[O:2]([NH2:4])[CH3:3].C(N(CC)CC)C.Cl[C:13]1[C:22]([C:23]([C:25](=[CH:31]N(C)C)[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:24])=[CH:21][C:20]2[C:15](=[CH:16][C:17]([F:36])=[C:18]([F:35])[CH:19]=2)[N:14]=1>ClC(Cl)Cl>[CH2:29]([O:28][C:26]([C:25]1[C:23](=[O:24])[C:22]2[CH:21]=[C:20]3[CH:19]=[C:18]([F:35])[C:17]([F:36])=[CH:16][C:15]3=[N:14][C:13]=2[N:4]([O:2][CH3:3])[CH:31]=1)=[O:27])[CH3:30]
Reactant: CON
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc2cc(F)c(F)cc2nc1Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn(OC)c2nc3cc(F)c(F)cc3cc2c1=O
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 79.8 %

Procedure:
A suspension of methoxylamine hydrochloride (1.7 g) in trichloromethane (40 cc) is treated with triethylamine (2.13 g). After 15 minutes' stirring at a temperature in the region of 20° C., the solution obtained is treated with ethyl 2-(2-chloro-6,7-difluoro-3-quinolinecarbonyl)-3-(dimethylamino)acrylate (3.69 g) and stirred for 4 hours and a half at approximately 20° C. The reaction mixture is concentrated to dryness under reduced pressure (20 kPa) at a temperature in the region of 50° C. The residue is taken up with ethanol (70 cc) and triethylamine (3.6 g) and heated for 30 minutes to a temperature in the region of 75° C. After cooling to approximately 20° C., the precipitate obtained is drained and washed with ethanol (3×30 cc). 3-Ethoxycarbonyl-7,8-difluoro-1-methoxy-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine (2.67 g) is obtained in the form of a pale yellow solid, m.p. 266°-268° C.).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:15]#[N:16])[CH2:14][CH2:13][S:12][CH2:11][CH2:10]2)=[CH:5][C:4]=1[CH3:17])#[N:2].[CH3:18][Li].[BH4-].[Na+].Cl>C1COCC1.CCOCC>[NH2:2][CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:15]#[N:16])[CH2:10][CH2:11][S:12][CH2:13][CH2:14]2)=[CH:5][C:4]=1[CH3:17])[CH3:18]
Reactant: [Li]C
Reactant: Cc1cc(C2(C#N)CCSCC2)ccc1C#N
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cc(C2(C#N)CCSCC2)ccc1C(C)N
Temperature: -20 °C
Reaction time: 3 h

Procedure:
4-(4-Cyano-3-methylphenyl)tetrahydro-2H-thiopyran-4-carbonitrile (983 mg, 4.06 mmol) is stirred in THF (40.0 mL) at −78° C. under nitrogen as a 1.6 M solution of methyllithium in Et2O is added slowly via syringe to the vessel. The contents are stirred for 3 hours at −20° C. before being quenched with MeOH (40.0 mL) and warmed to room temperature. NaBH4 (460 mg, 12.2 mmol) is slowly added at 0° C. in an ice bath and the mixture is warmed to room temperature and stirred for 16 hours. 1.0 N aqueous HCl is added until a pH of 3.0 is reached and the solvent is removed by rotary evaporator. To the residue is added concentrated aqueous HCl (3.0 mL) and the mixture is stirred for 16 hours. The contents are neutralized with 1.0 M aqueous NaOH and EtOAc (40.0 mL) is added. The layers are separated and the organic is dried with Na2SO4 and concentrated to a residue that is purified by silica get column chromatography (10% MeOH in DCM) (253 mg, 1.05 mmol, 26%).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:27]=[C:28]([C:30]2([O:36][CH3:37])[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[CH:29]=1)[O:5][C:6]1[O:7][C:8]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:10]=1.CN(C=O)C.C(=O)([O-])[O-].[K+].[K+].OC1C=C(C2CC(OC)CCO2)C=CC=1>C(OCC)(=O)C>[CH3:37][O:36][C:30]1([C:28]2[CH:27]=[C:4]([CH:3]=[CH:2][CH:29]=2)[O:5][C:6]2[O:7][C:8]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)=[C:9]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:10]=2)[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1
Reactant: COC1(c2cc(F)cc(Oc3nc(-c4ccccc4)c(-c4ccc(S(N)(=O)=O)cc4)o3)c2)CCOCC1
Agent: COC1CCOC(c2cccc(O)c2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC1(c2cccc(Oc3nc(-c4ccccc4)c(-c4ccc(S(N)(=O)=O)cc4)o3)c2)CCOCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 43.9 %

Procedure:
4-[2-Chloro-4-phenyl-5-oxazolyl]benzenesulfonamide from Example 4, Step 3, (0.6 g, 1.8 mmol), DMF (20 mL), potassium carbonate (0.5 g, 3.6 mmol), and 4 (3-hydroxyphenyl)-4-methoxy-3,4,5,6-tetrahydro-2H-pyran (0.37 g, 1.8 mmol) [prepared as described by G. C. Crawley, et al, J. Med. Chem., 35, 2600-2609 (1992)]were stirred at room temperature for 16.0 hours. The solution was diluted with ethyl acetate (100 mL), washed with 1N HCl, brine and water, dried over MgSO4 and concentrated. The residue was dissolved in ethyl acetate/hexanes (1:1) and filtered through silica. The eluant was concentrated and the residue recrystallized from ethyl acetate/hexanes to give 4-[2-[3-(4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl)phenoxy]-4-phenyl-5-oxazolyl]benzenesulfonamide as a white solid (0.4 g, 44%): mp 145°-147° C. 1H NMR (CDCl3) 300 MHz δ 7.88 (d, J=8.9 Hz, 2H) 7.70 (d, J=8.9 Hz, 2H) 7.6 (m, 2H) 7.36-7.5 (m, 6H) 7.0-7.1 (dt, J=6.4 Hz and J=2.2 Hz, 1H) 4.85 (bs, 2H) 3.7 (m, 4H) 3.05 (s, 3H) 2.0 (m, 4H). Anal. Calc'd. for C27H26N2O6S: C, 64.02; H, 5.17; N, 5.53. Found: C, 63.94; H, 5.17; N, 5.55.
Reaction SMILES: [CH2:1]([N:4]([CH2:10]Cl)[C:5](=[O:9])[CH:6]([Cl:8])[Cl:7])[CH2:2][CH3:3].[CH2:12]([O:14][CH2:15][CH2:16][OH:17])[CH3:13].[Na].C(OC(O)C)C>O>[CH2:1]([N:4]([CH2:10][O:17][CH2:16][CH2:15][O:14][CH2:12][CH3:13])[C:5](=[O:9])[CH:6]([Cl:8])[Cl:7])[CH2:2][CH3:3]
Reactant: CCCN(CCl)C(=O)C(Cl)Cl
Reactant: CCOCCO
Agent: CCOC(C)O
Agent: [Na]
Solvent: O
Product: CCCN(COCCOCC)C(=O)C(Cl)Cl

Procedure:
A solution containing N-propyl-N-chloromethyldichloroacetamide (21.9 g., 0.1 mole) and 2-ethoxyethanol (30 ml.) is weighed in a flask equipped as in Example 1. A solution prepared from metallic sodium (2.3 g., 0.1 mole) with ethoxyethanol (20 ml.) is added to the solution under stirring and cooling by water in such a rate that the temperature of the mixture is maintained below 35° C. After the addition is complete, the mixture is stirred for an additional 2 hours at room temperature. Then, the bulk of ethoxyethanol is removed under reduced pressure and the residue is dissolved in chloroform (80 ml.). The chloroform solution is washed with water (2×100 ml.), dried over anhydrous sodium sulfate and the solvent is distilled under reduced pressure to give 32.2 g. (90.0%) of the named product as an oil; nD25 =1.4651.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.Br[CH2:12][CH2:13][OH:14].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([S:1][CH2:12][CH2:13][OH:14])=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: OCCBr
Reactant: O=[N+]([O-])c1ccc(S)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc(SCCO)nc1
Temperature: 55 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
A heterogeneous mixture of 2-mercapto-5-nitropyridine (4) (0.50 g, 3.2 mmol), 2-bromoethanol (1) (0.238 mL, 3.3 mmol), and K2CO3 (2.0 g, 14 mmol) in acetone (11 mL) was stirred at 55° C. for 1 h. The cooled reaction mixture was filtered through Celite®, concentrated, and then purified by silica gel chromatography to give 2-[(5-nitro-2-pyridinyl)thio]ethanol (7) as an orange solid (0.545 g, 2.72 mmol). 1H NMR (CDCl3): δ 9.20 (d, J=3.0 Hz, 1H), 8.23 (dd, J=3.0 and 8.7 Hz, 1H), 7.36 (d, J=8.7 Hz, 1H), 3.94 (t, J=6.0 Hz, 2H), 3.46 (d, J=6.0 Hz, 2H); LCMS: purity: 96%; MS (m/e): 201(MH+).
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[N:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH2:16]>CN(C=O)C>[C:8]([NH:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)([NH:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:16]
Reactant: O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 4 °C
Reaction time: 8 h

Procedure:
To N-TeocT4 (0.017 g, 17 μmol) in 1 mL dry DMF was added dicyclohexylcarbodiimide (0.004 g, 18 μmol). After stirring for 30 minutes N-dimethyl-4-aminopyridine (0.004 g, 36 μmol) and Gly18 (0.017 g, 17 μmol) were added and the reaction stirred overnight. The cloudy solution was poured into 20 mL H2O and extracted twice with 10 mL CH2Cl2. The aqueous component was acidified to pH 3 with 1 N HCl and chilled to 4° C. The material was isolated by centrifugation and the pellet washed 3 times with 8 mL H2O. The pellet was dried in vacuum to yield dicyclohexylurea and N-TeocT4-Gly18.(SEQ ID NO: 6)
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]2[C:10]=1[C:11]([CH3:40])=[C:12]([CH2:24][C:25]1[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][CH:26]=1)[C:13]([O:20][CH:21]([F:23])[F:22])=[N:14]2)([CH3:4])([CH3:3])[CH3:2].[CH:42]([C:45]1[NH:46][CH:47]=[CH:48][N:49]=1)([CH3:44])[CH3:43]>>[C:1]([O:5][C:6](=[O:41])[CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]2[C:10]=1[C:11]([CH3:40])=[C:12]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([N:46]3[CH:47]=[CH:48][N:49]=[C:45]3[CH:42]([CH3:44])[CH3:43])=[CH:27][CH:26]=1)[C:13]([O:20][CH:21]([F:23])[F:22])=[N:14]2)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)c1ncc[nH]1
Reactant: Cc1c(Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c(OC(F)F)nc2c(Cl)ccc(OCC(=O)OC(C)(C)C)c12
Product: Cc1c(Cc2ccc(-n3ccnc3C(C)C)cc2)c(OC(F)F)nc2c(Cl)ccc(OCC(=O)OC(C)(C)C)c12

Procedure:
The title compound was prepared by the method of Preparation 18a using {8-chloro-2-difluoromethoxy-4-methyl-3-[4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)benzyl]quinolin-5-yloxy}acetic acid tert-butyl ester and 2-isopropyl-1H-imidazole.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.[H-].[Na+].[Br:10][C:11]1[CH:12]=[CH:13][C:14](Cl)=[N:15][CH:16]=1.O>CN(C=O)C>[Br:10][C:11]1[CH:12]=[CH:13][C:14]([O:7][CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[N:15][CH:16]=1
Reactant: OC1CCOCC1
Reactant: Clc1ccc(Br)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccc(OC2CCOCC2)nc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 79.2 %

Procedure:
tetrahydro-2H-pyran-4-ol (850 mg, 8.32 mmol) was dissolved in DMF (10 mL), cooled to 0° C., NaH (500 mg, 10.4 mmol) was added and stirred for 45 minutes at room temperature, then 5-bromo-2-chloropyridine (2 g, 10.4 mmol) was added and the mixture was stirred overnight at 60° C. The mixture was poured into water, extracted by EA, the organic layer was washed by brine, dried over Na2SO4, concentrated and purified by flash chromatography, gave 1.7 g white solid. MS: (m/z): 258 (M−H)+, 260 (M+H)+