Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][C:15]([F:25])([F:24])[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29]([C@@H:31]1[CH2:33][C@@H:32]1[C:34]1[CH:39]=[CH:38][C:37](B2OC(C)(C)C(C)(C)O2)=[CH:36][CH:35]=1)=[O:30])[CH3:27]>>[CH2:26]([O:28][C:29]([C@@H:31]1[CH2:33][C@@H:32]1[C:34]1[CH:39]=[CH:38][C:37]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:12][N:11]=[C:10]([CH3:13])[C:9]=3[CH2:14][C:15]([F:25])([F:24])[CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:4][CH:3]=2)=[CH:36][CH:35]=1)=[O:30])[CH3:27]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CC(F)(F)CCc1ccccc1
Reactant: CCOC(=O)[C@@H]1C[C@@H]1c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CCOC(=O)[C@@H]1C[C@@H]1c1ccc(-c2ccc(-c3onc(C)c3CC(F)(F)CCc3ccccc3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using 5-(4-bromo-phenyl)-4-(2,2-difluoro-4-phenyl-butyl)-3-methyl-isoxazole and (cis)-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([SH:10])=[N:7][C:6]=2[CH:11]=1.[OH-].[Na+].I[CH3:15]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10][CH3:15])=[N:7][C:6]=2[CH:11]=1
Reactant: CI
Reactant: Sc1nc2cc(Cl)ccc2s1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CSc1nc2cc(Cl)ccc2s1
Yield: 98.1 %

Procedure:
With stirring under ice cooling, 2.00 g (9.92 mmols) of 5-chloro-2-mercaptobenzothiazole was added gradually to 10 ml of a solution of 0.24 g (10.00 mmols) of sodium hydroxide in dimethylformamide (DMF). The mixture was dropwise added to 20 ml of a solution of 0.62 ml (9.96 mmols) of iodomethane in 20 ml of DMF with stirring under ice cooling and the mixture was stirred for further 30 minutes under ice cooling. The mixture was concentrated under reduced pressure, and to the residue was added an aqueous saturated sodium bicarbonate followed by extraction of the solution with chloroform. The chloroform layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform/methanol =100/1) to afford 2.10 g (yield: 98%) of 5-chloro-2-methylthiobenzothiazole.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][O:4][CH2:3]1.C(N(CC)CC)C.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>C(Cl)Cl>[O:4]1[CH2:5][CH2:6][C@@H:2]([O:1][S:15]([CH3:14])(=[O:17])=[O:16])[CH2:3]1
Reactant: O[C@@H]1CCOC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@@H]1CCOC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 86.5 %

Procedure:
A solution of 4.86 g (55.18 mmol) of (R)-(−)-3-hydroxytetrahydrofuran in 55 mL of anhydrous DCM (1M) was cooled to 0° C. with an ice bath. Then 8.5 mL (60.7 mmol, 1.1 eq.) of triethylamine and 4.8 mL (60.7 mmol, 1.1 eq.) of methanesulfonyl chloride were added successively. The reaction mixture was stirred for 2 hours at 0° C. and quenched with a saturated solution of sodium bicarbonate (70 mL). The aqueous layer was extracted with DCM (50 mL). Then the organic layers were washed with water (2×50 mL), brine (50 mL) and dried over sodium sulfate. After filtration and concentration in vacuo, a yellowish oil (7.93 g, 86.4%) was obtained corresponding to the methanesulfonic acid(R)-(tetrahydrofuran-3-yl)ester.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([CH:23]5[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1.[CH2:36]=O>>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([CH:23]5[CH2:28][CH2:27][N:26]([CH3:36])[CH2:25][CH2:24]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1C1CCNCC1
Reactant: C=O
Product: CN1CCC(N2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)CC1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-(1-methylpiperidin-4-yl)-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-piperidin-4-yl-1,3-thiazolidine-2,4-dione (Example 113) and formaldehyde following General Procedure R.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)=[CH:3][CH:2]=1.[CH:17]([C:19]1[NH:23][C:22]([CH3:24])=[C:21]([CH2:25][C:26]([OH:28])=[O:27])[C:20]=1[CH3:29])=O>>[CH3:24][C:22]1[NH:23][C:19]([CH:17]=[C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[CH:15][C:7]=3[C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[NH:11][C:10]2=[O:16])=[C:20]([CH3:29])[C:21]=1[CH2:25][C:26]([OH:28])=[O:27]
Reactant: O=C1Cc2c(cccc2-c2ccncc2)N1
Reactant: Cc1[nH]c(C=O)c(C)c1CC(=O)O
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4ccncc4)c32)c(C)c1CC(=O)O

Procedure:
4-Pyridin-4-yl-1,3-dihydroindol-2-one was condensed with (5-formyl-2,4-dimethyl-1H-pyrrol-3-yl)-acetic acid to give the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:34]=[C:35]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:36]=1)[CH:8]=[CH:9][C:10]1[CH:11]=[C:12]([CH:15]=[C:16]([CH:18]=[CH:19][C:20]2[CH:25]=[C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:23]=[C:22]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:21]=2)[CH:17]=1)[CH:13]=[O:14])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>O1CCCC1>[C:1]([C:5]1[CH:6]=[C:7]([CH:34]=[C:35]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:36]=1)[CH:8]=[CH:9][C:10]1[CH:11]=[C:12]([CH:15]=[C:16]([CH:18]=[CH:19][C:20]2[CH:21]=[C:22]([C:30]([CH3:31])([CH3:32])[CH3:33])[CH:23]=[C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:25]=2)[CH:17]=1)[CH2:13][OH:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(C=Cc2cc(C=O)cc(C=Cc3cc(C(C)(C)C)cc(C(C)(C)C)c3)c2)cc(C(C)(C)C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(C=Cc2cc(C=Cc3cc(C(C)(C)C)cc(C(C)(C)C)c3)cc(CO)c2)cc(C(C)(C)C)c1
Yield: 74.1 %

Procedure:
A mixture of 3,5-bis(3′,5′-di-tert-butylstyryl)benzaldehyde (3.00 g, 6.61 mmol) and sodium borohydride (840 mg, 22.2 mmol) in tetrahydrofuran (150 cm3) was heated at reflux for 110 min. The solvent was then completely removed and light petroleum (30-40) and aqueous hydrochloric acid (3 M, 30 cm3) were added and stirred until effervescence had ceased. The white precipitate was then filtered and dried under vacuum to give 3,5-bis(3′,5′-di-tert-butylstyryl)benzyl alcohol (2.63 g, 87%). A sample for analysis was recrystallised from a dichloromethane-light petroleum (60-80) mixture, mp 226-228° C. (Found: C, 87.28; H, 9.47. C39H52O requires C, 87.26; H, 9.76%); νmax(CHCl3)/cm−1 3608 w (OH), 1596 (C═C) and 964 (C═C—H trans); λmax(CH2Cl2)/nm (logε) 230 (4.42), 307 (4.80), 312 (4.80), 315 (4.80) and 330 sh (4.66); δH(500 MHz, CDCl3) 1.41 (36 H, s, t-Bu), 1.81 (1 H, t, J 6, OH), 4.79 (2 H, d, J 6, CH2), 7.16 and 7.27 (4H, d, J 16, 7′,8′-H), 7.40 (2 H, dd, J 1.5, 4′-H), 7.43(4 H, d, J 1.5, 2′,6′-H), 7.49 (2 H, s, 2,6-H) and 7.66 (1 H, s, 4-H); m/z (APCI+) 519 ((M-OH)+, 100%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[C@H:7]([CH3:19])[NH:8][C:9](OCC1C=CC=CC=1)=O)([CH3:4])([CH3:3])[CH3:2].[CH2:21](I)[CH:22]=C.[H-].[Na+]>C1COCC1>[C:1]([O:5][C:6](=[O:20])[C@H:7]([CH3:19])[NH:8][CH2:9][CH:21]=[CH2:22])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=CCI
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCN[C@@H](C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.5 %

Procedure:
Benzyloxycarbonyl-L-alanine t-butyl ester (10.0 g, 35.8 mmol) was dissolved in dry THF. Allyl iodide (7.4 mL, 78.8 mmol) was added followed by sodium hydride (1.80 g, 45.0 mmol). The reaction was left stirring at room temperature overnight. The reaction was evaporated and taken up in ethyl acetate. It was extracted with water and treated with sodium metabisulfite. The ethyl acetate was extracted with 1N aqueous sodium carbonate, dried over anhydrous magnesium sulfate, filtered and evaporated under vacuum. The crude product was flash chromatographed (silica gel, hexane followed by hexane:ethyl acetate 95:5) to give N-benzyloxycarbonyl, N-allyl-L-alanine t-butyl ester (6.8 g, 60%). 1H NMR (CDCl3) δ7.33 (s, 5H), 6.17-5.67 (m, 1H), 5.20 (d, 4H), 1.75-1.70 (s/d, 12H).
Reaction SMILES: [CH2:1]([N:8]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C@H:9]([CH2:20][OH:21])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S([O-])([O-])(=O)=O.[Na+].[Na+].[F:36][C:37]([F:45])(S(F)(=O)=O)C(O)=O>C(#N)C>[CH2:22]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@H:9]([CH2:20][O:21][CH:37]([F:45])[F:36])[C:10]([O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:11])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C(OCc1ccccc1)[C@@H](CO)N(Cc1ccccc1)Cc1ccccc1
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: O=C(OCc1ccccc1)[C@@H](COC(F)F)N(Cc1ccccc1)Cc1ccccc1
Yield: 13.4 %

Procedure:
To a mixture of Benzyl (2R)-2-(dibenzylamino)-3-hydroxypropanoate (22.2 g, 59.2 mmol) and sodium sulfate (2.0 g, 14 mmol) in acetonitrile (200 mL) at 40° C., difluoro(fluorosulfonyl)acetic acid (10.5 g, 59.2 mmol) was added dropwise for 1.5 hrs. The reaction mixture was concentrated to dryness. The residue was mixed with ethyl acetate and silica gel, then concentrated again and purified by column chromatography, eluting with 1.5-2.5% ethyl acetate in hexanes to give benzyl (2R) 2-dibenzylamino-3-difluoromethoxy-propionate (3.375 g, 13.4%) as a colorless oil. 1H NMR (300 MHz, CDCl3): δ(ppm) 7.20-7.40 (m, 15H), 6.17 (wt, 1H), 5.27 (q, 2H), 4.22 (dd, 1H), 4.10 (dd, 1H), 3.88 (d, 2H), 3.74 (t, 1H) and 3.65 (d, 2H).
Reaction SMILES: [CH3:1][NH2:2].O[CH:4]1[NH:10][C:9](=[O:11])[C:8]2[S:12][CH:13]=[CH:14][C:7]=2[N:6]2[CH:15]=[CH:16][CH:17]=[C:5]12>O>[CH3:1][NH:2][CH:4]1[NH:10][C:9](=[O:11])[C:8]2[S:12][CH:13]=[CH:14][C:7]=2[N:6]2[CH:15]=[CH:16][CH:17]=[C:5]12
Reactant: O=C1NC(O)c2cccn2-c2ccsc21
Reactant: CN
Solvent: O
Product: CNC1NC(=O)c2sccc2-n2cccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 60 %

Procedure:
3 ml of 35% aqueous solution of methylamine are added in a single portion to a suspension of 1.1 g (0.005 mol) of 6-hydroxy-5,6-dihydro-4-oxo-4H-pyrrolo -[1,2-a]thieno[2,3-f][1,4]diazepine in 20 ml of water, and the reaction mixture is then stirred for 4 hours at room temperature The product is gradually solubilized and then reprecipitates The precipitate is drained, washed with water, dried and recrystallized. 0.7 g of 6-methylamino-5,6-dihydro-4-oxo-4H -pyrrolo[1,2-a]thieno[2,3-f][1,4]diazepine is obtained in the form of white crystals, melting point 146° C. (ethyl ether).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([SH:13])=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[H-].[Na+].Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][C:28]1[C:29](=[O:42])[CH:30]=[C:31]([CH2:34][O:35][CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][O:37]2)[O:32][CH:33]=1>CN(C=O)C.O>[F:15][C:2]([F:1])([F:14])[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([S:13][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][C:28]3[C:29](=[O:42])[CH:30]=[C:31]([CH2:34][O:35][CH:36]4[CH2:41][CH2:40][CH2:39][CH2:38][O:37]4)[O:32][CH:33]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: FC(F)(F)c1ccc2c(S)ccnc2c1
Reactant: O=c1cc(COC2CCCCO2)occ1OCCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1cc(COC2CCCCO2)occ1OCCCCCCCCSc1ccnc2cc(C(F)(F)F)ccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
7-Trifluoromethyl-4-quinoline-thiol (300 mg, 1.3 mmol) was charged in a 50 mL round-bottomed flask equipped with a magnetic stirrer and under inert atmosphere. Anhydrous DMF (10 mL) and NaH 60% dispersion in oil (53 mg, 1.3 mmol) were successively added at 4° C. After 30 min a solution of 5-(8-bromo-octyloxy)-2-(tetrahydro-pyran-2-yloxymethyl)-4H-pyran-4-one 5 (500 mg, 1.2 mmol) in DMF (5 mL) was added at room temperature. The reaction mixture was stirred for 2 h at room temperature. The reaction mixture was poured in 150 mL of H2O, extracted with EtOAc (3×80 mL). The organic layer was washed with brine (2×20 mL), dried over MgSO4, filtered and evaporated to dryness. The crude compound was purified by column chromatography (SiO2; CH2Cl2:MeOH=95:5 to 98:2) to give 5-(8-(7-(trifluoromethyl)quinolin-4-ylthio)octyloxy)-2-((tetrahydro-2H-pyran-2-yloxy)methyl)-4H-pyran-4-one EHT 1006 (320 mg, 47% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][CH2:10][C:11]([OH:13])=O)=[C:4]([OH:14])[CH:3]=1.[NH:15]1[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22][NH:23][C:24](=[O:27])[CH:25]=[CH2:26])[CH2:17][CH2:16]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(CC)CC>CN(C=O)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][CH2:10][C:11]([N:15]2[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22][NH:23][C:24](=[O:27])[CH:25]=[CH2:26])[CH2:17][CH2:16]2)=[O:13])=[C:4]([OH:14])[CH:3]=1
Reactant: C=CC(=O)NCCC1CCNCC1
Reactant: O=C(O)CNc1cc(Cl)c(Cl)cc1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=CC(=O)NCCC1CCN(C(=O)CNc2cc(Cl)c(Cl)cc2O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.3 %

Procedure:
To a stirred solution of 2-((4,5-dichloro-2-hydroxyphenyl)amino)acetic acid (200 mg, 0.85 mmol) in DMF (30 mL) at room temperature, N-(2-(piperidin-4-yl)ethyl)acrylamide (222.8 mg, 1.02 mmol) was added followed by HOBt (172.9 mg, 1.28 mmol), EDCI.HCl (244.7 mg, 1.28 mmol) and Et3N (257.9 mg, 2.55 mmol). The reaction mixture was stirred at room temperature for 1 h and then partitioned between ethyl acetate and brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (1-3% methanol/dichloroethane) to afford the desired product (120 mg, 29% yield) as a solid. 1H NMR (400 MHz, DMSO-d6) δ: 10.15 (s, 1H), 8.07 (t, J=5.2 Hz, 1H), 6.78 (s, 1H), 6.72 (s, 1H), 6.18 (dd, J=10.0, 17.2 Hz, 1H), 6.06 (dd, J=2.4, 17.2 Hz, 1H), 5.56 (dd, J=2.4, 10.4 Hz, 1H), 5.34 (t, J=4.0 Hz, 1H), 4.36 (d, J=12.8 Hz, 1H), 3.94-3.87 (m, 3H), 3.20-3.15 (m, 2H), 2.98-2.92 (m, 1H), 2.63-2.57 (m, 1H), 1.74-1.69 (m, 2H), 1.57-1.52 (m, 1H), 1.41-1.35 (m, 2H), 1.12-0.95 (m, 2H). ESI-MS m/z: 400.4[M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:9][CH3:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([O:9][CH3:10])[C:5]([NH:8][S:18]([C:15]2[CH:16]=[CH:17][C:12]([F:11])=[CH:13][CH:14]=2)(=[O:20])=[O:19])=[N:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: COc1cc(Br)cnc1N
Solvent: c1ccncc1
Product: COc1cc(Br)cnc1NS(=O)(=O)c1ccc(F)cc1
Temperature: 20 °C
Reaction time: 16 h
Yield: 74.7 %

Procedure:
To a solution of 5-bromo-3-methoxypyridin-2-amine (100 mg, 0.493 mmol) in pyridine (1 mL) stirred in air at room temperature was added a solution of 4-fluorobenzene-1-sulfonyl chloride (115 mg, 0.591 mmol) in pyridine (1 mL). The reaction mixture was stirred at 20° C. for 16 hours then the solvent was evaporated in vacuo to give the crude product. The crude was passed through an aminopropyl (NH2) solid phase extraction (SPE) cartridge eluting with methanol followed by 2M ammonia/methanol, then a sulphonic acid (SCX) SPE cartridge eluting with methanol followed by 2M ammonia/methanol. The appropriate fractions were combined and evaporated under a stream of nitrogen to give the crude product. Final purification by flash silica (Si) chromatography (0-100% ethyl acetate-cyclohexane+0-20% methanol gradient), gave the title product (133 mg) as an off-white solid. LCMS (2 min, formic) Rt 1.03 min, m/z (ES+) 361/363 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:19]([C:21]3[O:22][C:23]4[C:28]([C:29](=[O:38])[C:30]=3[C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=3)=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH3:20])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17]C)[CH:12]=3)[C:3]=12>ClCCl.B(Br)(Br)Br>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:19]([C:21]3[O:22][C:23]4[C:28]([C:29](=[O:38])[C:30]=3[C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=3)=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH3:20])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=3)[C:3]=12
Reactant: COc1cccc(-c2nn(C(C)c3oc4ccccc4c(=O)c3-c3cccc(F)c3)c3ncnc(N)c23)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(c1oc2ccccc2c(=O)c1-c1cccc(F)c1)n1nc(-c2cccc(O)c2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of Example 51 (0.150 g, 0.290 mmoles) in dichloromethane (25 ml), BBr3 (1M in dichloromethane, 1.5 ml) was added at 0° C. and the reaction mixture was warmed to RT and then stirred for 12 h. The reaction mixture was quenched with 1.5N HCl solution and extracted with dichloromethane. The organic layer was dried over sodium sulphate and concentrated. The crude product was purified by column chromatography with methanol:dichloromethane to afford the title compound as grey colour solid (0.110 g, 75% yield). MP: 282-285° C. 1H-NMR (δ ppm, DMSO-D6, 400 MHz): δ 9.69 (s, 1H), 8.06 (s, 1H), 8.05 (dd, J=8.0, 1.6 Hz, 1H), 7.86 (dt, J=7.2, 1.6 Hz, 1H), 7.68 (t, J=8.2 Hz, 1H), 7.53 (dt, J=8.0, 0.9 Hz, 1H), 7.34 (t, J=8.0 Hz, 1H), 7.29 (br s, 1H), 7.06-6.84 (m, 6H), 6.03 (q, J=7.1 Hz, 1H), 1.89 (d, J=7.1 Hz, 3H). Mass: 493.95 (M+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:17][CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.O>CN(C)C(=O)C>[OH:17][CH:18]1[CH2:23][CH2:22][N:21]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:20][CH2:19]1
Reactant: OC1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=[N+]([O-])c1ccc(N2CCC(O)CC2)cc1
Temperature: 130 °C

Procedure:
4-chloronitrobenzene (31.5 g, 200 mmol) was dissolved in N,N-dimethylacetamide (80 ml), and potassium carbonate (35.9 g, 260 mmol) and 4-hydroxypiperidine (22.3 g, 220 mmol) were added thereto, followed by stirring under heat at 130° C. for 3 hours. After cooling to room temperature, water was added to the mixture, and the precipitate was collected by filtration. The obtained solid was dried under reduced pressure, thereby obtaining 4-hydroxy-N-(4-nitrophenyl)piperidine (41.3 g, 93%) as a yellow solid.
Reaction SMILES: C(OP([CH:9]([C:17]#[N:18])[CH2:10][CH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)(=O)OCC)C.[O:19]1[CH2:24][CH2:23][CH2:22][O:21][CH:20]1[C:25]1[CH:26]=[C:27]([S:31][C:32]2[C:33]([F:43])=[CH:34][C:35]([N+:40]([O-:42])=[O:41])=[C:36]([CH:39]=2)[CH:37]=O)[CH:28]=[CH:29][CH:30]=1>C1COCC1.C(OCC)(=O)C>[O:19]1[CH2:24][CH2:23][CH2:22][O:21][CH:20]1[C:25]1[CH:26]=[C:27]([S:31][C:32]2[C:33]([F:43])=[CH:34][C:35]([N+:40]([O-:42])=[O:41])=[C:36]([CH:37]=[C:9]([CH2:10][CH:11]3[CH2:12][CH2:13][O:14][CH2:15][CH2:16]3)[C:17]#[N:18])[CH:39]=2)[CH:28]=[CH:29][CH:30]=1
Reactant: O=Cc1cc(Sc2cccc(C3OCCCO3)c2)c(F)cc1[N+](=O)[O-]
Reactant: CCOP(=O)(OCC)C(C#N)CC1CCOCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#CC(=Cc1cc(Sc2cccc(C3OCCCO3)c2)c(F)cc1[N+](=O)[O-])CC1CCOCC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
[1-Cyano-2-(tetrahydro-pyran-4-yl)-ethyl]-phosphonic acid diethyl ester (0.614 g, 2.23 mmol), prepared as described in Example 1, Steps A and B, was dissolved in THF (75 mL) and the resulting mixture cooled to 0° C. Lithium (bistrimethylsilyl)amide (2.2 mL, 2.2 mmol, [1M]) was then added dropwise. The resulting mixture was stirred 15 min, and then 5-(3-[1,3]dioxan-2-yl-phenylsulfanyl)-4-fluoro-2-nitro-benzaldehyde (0.6 g, 1.65 mmol) was added. Stirring was continued at room temperature overnight. The resulting mixture was then diluted with ethyl acetate and washed with saturated aqueous NaHCO3. The organic phase was separated and dried with MgSO4, and filtered. The solvent was removed to yield an oil, which was used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][CH:9]2[C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1.[O:15]=[S:16]1(=[O:39])[CH2:21][CH2:20][CH:19]([O:22][C:23]2[CH:28]=[C:27]([CH3:29])[C:26]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36]O)[CH:31]=3)=[C:25]([CH3:38])[CH:24]=2)[CH2:18][CH2:17]1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[O:15]=[S:16]1(=[O:39])[CH2:21][CH2:20][CH:19]([O:22][C:23]2[CH:28]=[C:27]([CH3:29])[C:26]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36][O:1][C:2]4[CH:3]=[CH:4][C:5]([CH:8]5[CH2:10][CH:9]5[C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:7]=4)[CH:31]=3)=[C:25]([CH3:38])[CH:24]=2)[CH2:18][CH2:17]1
Reactant: Cc1cc(OC2CCS(=O)(=O)CC2)cc(C)c1-c1cccc(CO)c1
Reactant: COC(=O)C1CC1c1ccc(O)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: COC(=O)C1CC1c1ccc(OCc2cccc(-c3c(C)cc(OC4CCS(=O)(=O)CC4)cc3C)c2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.2 %

Procedure:
A solution of methyl 2-(4-hydroxyphenyl)cyclopropanecarboxylate (0.156 g, 0.813 mmol), {4′-[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy]-2′,6′-dimethylbiphenyl-3-yl}methanol (0.395 g, 0.739 mmol) and tributylphosphine (0.298 g, 1.47 mmol) in toluene (15 mL) was stirred, 1,1′-(azodicarbonyl)dipiperidine (0.372 g, 1.47 mmol) was added, and the mixture was stirred at room temperature for 4 hr. Hexane (15 mL) was added to the reaction mixture and the precipitated insoluble material was filtrated. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=20:80-40:60) to give the title compound (0.396 g, yield 91%) as a colorless oil.
Reaction SMILES: [C:1]([CH2:3][O:4][C:5]1[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7]Br)#[N:2].[C:14]1([CH:21]=[CH:20][CH:19]=[C:17]([OH:18])[CH:16]=1)[OH:15].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CCOCC>[OH:15][C:14]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[O:18][CH2:7][C:6]1[CH:9]=[CH:10][CH:11]=[C:12]([CH3:13])[C:5]=1[O:4][CH2:3][C:1]#[N:2]
Reactant: Oc1cccc(O)c1
Reactant: Cc1cccc(CBr)c1OCC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOCC
Product: Cc1cccc(COc2cccc(O)c2)c1OCC#N
Temperature: 60 °C

Procedure:
Heated (60° C.) a mixture of 2-cyanomethoxy-3-methylbenzyl bromide (10.2 g, 42.7 mmoles, example 24), resorcinol (18.8 g, 171 mmoles), and potassium carbonate (47.2 g, 342 mmoles) in acetonitrile (140 mL) for two hours. The reaction is diluted with ether and washed three times with distilled water, once with brine, and dried over MgSO4. The organic layer is isolated and concentrated, and the resulting residue is purified by column chromatography (silica, 5% EtOAc/CH2Cl2) to yield the title compound as a white crystalline solid. MS(EI) 269 (M)+.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[CH:11][C:10]([CH2:13]O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:17])=O.C(=O)([O-])O.[Na+]>ClCCl>[Cl:17][CH2:13][C:10]1[CH:9]=[CH:8][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:12][CH:11]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(-c2ccccc2)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: ClCc1ccc(-c2ccccc2)nc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 81.8 %

Procedure:
(6-Phenylpyridin-3-yl)methanol (15.0 g) synthesized in Reference Example 20 was dissolved in dichloromethane (150 mL) and, after ice-cooling, thionyl chloride (12.5 g) was added to, and the mixture was stirred at 0° C. for 2 hr. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=4:1) to give the title compound (13.5 g) as a white solid.