Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[C:4]([O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH:17]2[CH2:21][N:20]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=3)[C:19](=[O:33])[N:18]2[CH3:34])=[CH:10][C:9]=1I)([CH3:6])[CH3:5].[CH2:37]([Sn](CCCC)(CCCC)C=C)[CH2:38]CC>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:36])[C:4]([O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH:17]2[CH2:21][N:20]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=3)[C:19](=[O:33])[N:18]2[CH3:34])=[CH:10][C:9]=1[CH:37]=[CH2:38])([CH3:6])[CH3:5]
Reactant: COC(=O)C(C)(C)Oc1ccc(CCCC2CN(Cc3ccc(C(C)(C)C)cc3)C(=O)N2C)cc1I
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1cc(CCCC2CN(Cc3ccc(C(C)(C)C)cc3)C(=O)N2C)ccc1OC(C)(C)C(=O)OC
Temperature: 80 °C
Yield: 71.7 %

Procedure:
2-(4-{3-[1-(4-tert-Butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl}-2-iodo-phenoxy)-2-methyl-propionic acid methyl ester (0.264 g, 0.435 mmole) and tributyl(vinyl) tin (0.207 g, 0.652 mmole) were mixed in toluene (4.0 mL). After bubbled with nitrogen for 15 minutes, tetrakis(triphenylphosphine) palladium(0) (0.050 g, 0.043 mmole) was added. The reaction was heated at 80° C. overnight. The solvent was removed on rota-vapor, and the crude product was purified by column chromatography (silica gel, gradient elution 0-30% acetone in hexane) to provide a colorless oil (0.158 g, 71%). Mass [EI+] 507 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:14][CH2:15][CH3:16])[CH2:5][P:6]([O:11][CH2:12][CH3:13])([O:8][CH2:9][CH3:10])=[O:7])C.[Br:17]C[C@H](O)CO.CC1C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[Br:17][CH2:16][C@H:15]1[CH2:1][O:3][C@H:4]([CH2:5][P:6]([O:8][CH2:9][CH3:10])([O:11][CH2:12][CH3:13])=[O:7])[O:14]1
Reactant: CCOC(CP(=O)(OCC)OCC)OCC
Reactant: OC[C@@H](O)CBr
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOP(=O)(C[C@H]1OC[C@H](CBr)O1)OCC
Temperature: 25 °C
Yield: 96.7 %

Procedure:
To a solution of diethylphosphonoacetaldehyde diethylacetal (4.20 g, 16.5 mmol) and (2R)-3-bromo-1,2-propanediol (example 90) (3.00 g, 19.4 mmol, 1.2 eq.) in toluene (30 mL) was added pTSA (few crystals). The mixture was stirred at reflux for 50 hr. After, the solution was cooled to room temperature, and a saturated solution of sodium bicarbonate was added, and the aqueous phase was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulphate and evaporated under reduced pressure. The crude material was pure by TLC and NMR, and gave 5.06 g of the compound in a 97% yield.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].CC(C)([O-])C.[K+].[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:26]=1[O:27][CH3:28])[N:23]=[CH:22][CH:21]=[C:20]2[CH3:29].[C:30](=[O:32])=[O:31].Cl.N1C=CC=CC=1>C1COCC1>[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:26]=1[O:27][CH3:28])[N:23]=[CH:22][CH:21]=[C:20]2[CH2:29][C:30]([OH:32])=[O:31]
Reactant: O=C=O
Reactant: COc1cc2nccc(C)c2cc1OC
Agent: CC(C)(C)[O-]
Agent: CC(C)[N-]C(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1cc2nccc(CC(=O)O)c2cc1OC
Temperature: 25 °C

Procedure:
Lithium diisopropylamide (2M pentane solution 2.46 ml, 4.92 mmol) and potassium t-butoxide (0.552 g, 4.92 mmol) are added to THF (10 ml) at −70° C., followed by 6,7-dimethoxy-4-methyl-quinoline [J. Org. Chem., 1997, 623, 568 ] (1.0 g, 4.92 mmol). After 1 hour the reaction is poured on to an excess of crushed dry ice and warmed to room temperature overnight. Pyridine hydrochloride (0.57 g, 4.92 mmol) is added and the reaction partitioned between ether and water. The aqueous phase is evaporated, taken into hot methanol, treated with charcoal, filtered through celite and evaporated to afford (6,7-dimethoxy-quinolin-4-yl)-acetic acid, MH+ 248. This intermediate is then converted to the xanthine acording to the general procedure of Method C, mp >250° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[N:3]=1.[Na].[N:15]12CCN(CC1)C[CH2:16]2.O>CS(C)=O>[NH2:1][C:2]1[N:7]=[C:6]([C:16]#[N:15])[CH:5]=[C:4]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[N:3]=1
Reactant: Nc1nc(Cl)cc(-c2ccco2)n1
Reactant: C1CN2CCN1CC2
Agent: [Na]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1cc(-c2ccco2)nc(N)n1
Temperature: 0 °C
Reaction time: 96 h
Yield: 762.7 %

Procedure:
A solution of 2-amino-4-chloro-6-(2-furyl)pyrimidine (9.78 g, 50.0 mmol) in DMSO (200 mL) was treated with sodium cyamide (14.7 g, 300 mmol) and 1,4-diazabicyclo[2.2.2]octane (DABCO) (0.56 g, 5.0 mmol). The suspension was stirred for 4 days, and more DABCO (5.04 g, 45 mmol) and DMSO (100 mL) were added. The suspension was stirred for a further 2 days, poured onto a mixture of ice (750 g) and water (750 mL), the crude product was filtered off, washed with water and MeCN, and dried in air to give the title compound (7.1 g, 77%) as a brown solid; m.p. 193-194° C.; NMR δH (400 MHz, DMSO) 6.74 (1H, q, J 1.6 Hz), 7.32 (2H, br s), 7.39 (1H, d, J 3.6 Hz), 7.43 (1H, s) and 7.98 (1H, d, J 1.2 Hz); M/Z 187 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[Cl:28])[C:5]([NH:7][C@@H:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([N+:18]([O-])=O)[CH:16]=2)[CH2:11][CH2:10][C@H:9]1[O:21][C:22](=[O:24])[CH3:23])=[O:6]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[Cl:28])[C:5]([NH:7][C@@H:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([NH2:18])[CH:16]=2)[CH2:11][CH2:10][C@H:9]1[O:21][C:22](=[O:24])[CH3:23])=[O:6]
Reactant: CC(=O)O[C@@H]1CCc2ccc([N+](=O)[O-])cc2[C@H]1NC(=O)c1ccc(Cl)c(Cl)c1
Solvent: CN(C)C=O
Product: CC(=O)O[C@@H]1CCc2ccc(N)cc2[C@H]1NC(=O)c1ccc(Cl)c(Cl)c1
Reaction time: 4 h
Yield: 107.6 %

Procedure:
A solution of 114 (1.9 g) in DMF (100 mL) was treated with SnCl2H2O (4 g). After 4 h, additional SnCl2—2H2O (1 g) was added three times over three days. The solvent was then evaporated, the residue suspended in H2O-EtOAc, the mixture neutralized with 5N NaOH, and the mixture filtered. The organics were separated, washed with brine, dried, and the solvent evaporated to give a brown foam (1.9 g).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])(=[O:10])=[O:9])[N:3]=1.[C:18](O)(=O)/[C:19](=[C:21](\C=O)/Cl)/[Cl:20]>CN(C=O)C>[Cl:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[S:8]([NH:7][C:4]1[N:3]=[C:2]2[N:1]=[CH:18][C:19]([Cl:20])=[CH:21][N:6]2[N:5]=1)(=[O:9])=[O:10]
Reactant: O=C/C(Cl)=C(/Cl)C(=O)O
Reactant: Nc1nc(NS(=O)(=O)c2ccccc2Cl)n[nH]1
Solvent: CN(C)C=O
Product: O=S(=O)(Nc1nc2ncc(Cl)cn2n1)c1ccccc1Cl
Temperature: 25 °C
Yield: 22.6 %

Procedure:
A mixture of 2.46 g (9.00 mmol) of N-(5-amino-1,2,4-triazol-3-yl)-2-chlorobenzenesulfonamide and 1.67 g (9.90 mmol) of mucochloric acid in 20 ml of DMF was heated to reflux for 16.5 hours. After cooling to room temperature, the solvent was removed by evaporation at reduced pressure and the residue was treated with 20 ml of 0.5N NaOH. After stirring vigorously for ~30 minutes the mixture was filtered through celite and the filtrate was acidified with 2N HCl. The solid which separated was collected by filtration, washed with water and recrystallized from acetic acid--water to yield 0.70 g (23 percent) of the desired product as a light brown solid, mp 256.5°-260.5° C. IR and 1H NMR spectra were in agreement with the assigned structure.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]([C:19]#[N:20])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:7][C:8](OCC)=[O:9])[CH3:2].[H][H]>[Ni].CO>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7][C:8](=[O:9])[NH:20][CH2:19]1)[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)CC(C#N)(CC(=O)OCC)c1ccccc1
Agent: [Ni]
Solvent: CO
Product: CCOC(=O)CC1(c2ccccc2)CNC(=O)C1
Reaction time: 30 h

Procedure:
45 g of Raney nickel are added to 254.2 g of 3-cyano-3-phenylglutaric acid diethyl ester in 1.5 liters of absolute methanol, and hydrogenation is effected in a 5 liter autoclave for 30 hours at 80° and a hydrogen pressure of 81 atmospheres. After cooling, the catalyst is filtered off, the filtrate is concentrated on a rotary evaporator, the resulting light yellow oil is taken up in 1.5 liters of chloroform and is successively washed with 25 cc of 2 N hydrochloric acid, 100 cc of saturated sodium bicarbonate solution and 100 cc of water. The 5-oxo-3-phenyl-3-pyrrolidine acetic acid ethyl ester, obtained after concentrating the chloroform phase, crystallizes upon triturating with ether. M.P. 49°-51° (from ethyl acetate/petroleum ether).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:20][CH:21]([CH3:23])[CH3:22])[S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=1)(=[O:12])=[O:11].[O:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH2:31]O)[CH2:26][CH2:25]1.FC(F)(C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)CCC1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>CN(C=O)C.O.CO.O.CN(C=O)C.O1CCCC1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:20][CH:21]([CH3:23])[CH3:22])[S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:31][CH2:30][N:27]2[CH2:28][CH2:29][O:24][CH2:25][CH2:26]2)[CH:14]=1)(=[O:11])=[O:12]
Reactant: Cc1ccc(N(CC(C)C)S(=O)(=O)c2cccc(O)c2)c(C)c1
Reactant: OCCN1CCOCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)CCc1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(N(CC(C)C)S(=O)(=O)c2cccc(OCCN3CCOCC3)c2)c(C)c1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
N-(2,4-dimethylphenyl)-3-hydroxy-N-isobutylbenzenesulfonamide (76.9 mg, 0.231 mmol), 2-morpholinoethanol (0.035 mL, 0.288 mmol) and (4-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadecafluorodecyl)phenyl)diphenylphosphine (204 mg, 0.288 mmol) were added to a vessel. Tetrahydrofuran (THF) (4 mL) was added followed by diisopropyl diazene-1,2-dicarboxylate (DIAD) (0.056 ml, 58.3 mg 0.288 mmol). The reaction vial was sealed and left to stir overnight at 20° C. The reaction mixture was concentrated in vacuo and then diluted with ethyl acetate (25 mL) and water (25 mL). The organic fraction was separated, dried and concentrated in vacuo to give the crude product. The crude product was dissolved in DMF:H2O (9:1) (1 mL) and loaded onto a fluorous column (pre-conditioned with 1 mL DMF, followed by 6 mL MeOH:H2O (5:1)). The semi-purified material was eluted with 6 mL MeOH:H2O (5:1). This was concentrated and dissolved in 1:1 MeOH:DMSO (1 mL) then further purified by mass directed autoprep (formic acid modifier). The relevant fractions were concentrated under a stream of nitrogen to give the required product, 17 mg. LCMS [LCMS1] Rt 1.03 min, m/z (ES+) 447 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)/[C:12](=[N:19]\O)/[C:11]([CH3:22])([CH3:21])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]>C(O)(=O)C.[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C@H:12]([NH2:19])[C:11]([CH3:22])([CH3:21])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC1(C)C[C@@H](c2ccc(Cl)c(Cl)c2)c2ccccc2/C1=N\O
Agent: [Pd]
Solvent: CC(=O)O
Product: CC1(C)C[C@@H](c2ccc(Cl)c(Cl)c2)c2ccccc2[C@@H]1N
Reaction time: 1 h
Yield: 43.9 %

Procedure:
To a solution of 60 (30 mg, 0.089 mmol) in acetic acid (3 mL) was added palladium on charcoal (30 mg, 5%). The mixture was then stirred under hydrogen (1 atm) for 1 h. The catalyst was filtrated away through a pad of Celite. The filtrate was concentrated. The resultant residue was purified by chiral OJ column (ethanol/methanol/hexane/DEA=3:2:95:0.1) to give 59 (12.5 mg, 44%). 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J=8.0 Hz, 1 H), 7.44-7.38 (m, 2 H), 7.38-7.24 (m, 2 H), 6.81 (d, J=7.6 Hz, 1 H), 7.03 (dd, J=1.6, 8.0 Hz, 1 H), 4.28 (dd, J=4.4, 12.4 Hz, 1 H), 2.19 (dd, J=13.6, 12.4 Hz, 1 H), 2.06 (dd, J=13.6, 4.4 Hz, 1 H), 1.58 (s, 1 H), 1.27 (s, 6 H); 13C NMR (100 MHz, CDCl3) δ 145.39, 144.92, 133.53, 133.01, 133.68, 131.19, 131.09, 131.01, 129.24, 128.51, 128.31
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][S:12]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH:8]=[CH:7][C:5]=2[N:6]=1.[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([CH2:35][C:36](O)=[O:37])[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(NC(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C.O>[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([CH2:35][C:36](=[O:37])[NH:1][C:2]2[S:3][C:4]3[CH:10]=[C:9]([O:11][S:12]([C:15]4[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=4)(=[O:13])=[O:14])[CH:8]=[CH:7][C:5]=3[N:6]=2)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)O)CC1
Reactant: Nc1nc2ccc(OS(=O)(=O)c3ccc(F)cc3)cc2s1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CC(=O)Nc2nc3ccc(OS(=O)(=O)c4ccc(F)cc4)cc3s2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 96 %

Procedure:
A solution of 4-fluorobenzenesulfonic acid 2-aminobenzothiazol-6-yl ester (intermediate 16) (580 mg, 1.32 mmol), 4-carboxymethylpiperidine-1-car-boxylic acid tert-butyl ester (640 mg, 2.63 mmol), HBTU (1.1 g, 2.9 mmol), and N,N-diisopropylamine (1.2 ml, 6.89 mmol) in 12 ml of dimethylformamide, in a test tube equipped with a magnetic bar, is stirred for 3 days at room temperature. 200 ml of water are added to the reaction medium and the mixture is extracted with ethyl acetate. The organic phase is then washed with water and with saturated sodium chloride solution, and then dried over magnesium sulfate and evaporated. The residue obtained is taken up in ethyl acetate and purified on a Varian flash cartridge containing 50 g of silica of porosity 15-35μ, with a gradient of from 5% to 30% of ethyl acetate in cyclohexane, over 100 minutes. After evaporating off the solvent, 700 mg of 4-{[6-(4-fluorobenzenesulfonyloxy)benzothiazol-2-ylcarbamoyl]methyl}piperidine-1-carboxylic acid tert-butyl ester are obtained (yellow oil) in a yield of 96%.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH2:16][CH:17]([CH2:23][NH:24][C:25](=O)[CH2:26][CH3:27])[CH2:18]3)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].Cl>C1COCC1.C(OCC)(=O)C>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH2:16][CH:17]([CH2:23][NH:24][CH2:25][CH2:26][CH3:27])[CH2:18]3)(=[O:11])=[O:12])=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CCC(=O)NCC1Cc2cccc(NS(=O)(=O)c3ccc(C(C)C)cc3)c2C1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCNCC1Cc2cccc(NS(=O)(=O)c3ccc(C(C)C)cc3)c2C1
Yield: 48.3 %

Procedure:
N-[4-(4-Isopropyl-benzenesulfonylamino)-indan-2-ylmethyl]propionamide (0.30 g, 0.75 mmol) was dissolved in 10 mL of THF and 2.5 mL (26.1 mmol) of a borane-THF complex was introduced dropwise. The resulting mixture was stirred at reflux for 1 h. The solution was cooled, 3 mL of 2 N HCl was added slowly, and the mixture was stirred at reflux for 2 h. The cooled solution was quenched with water, then NaOH (2N) and extracted with ethyl acetate. The organic phase was dried over MgSO4, filtered, and the filtrate was evaporated in vacuo to give product as a white solid which was further purified by column chromatography using (dichloromethane-MeOH, 7-12%) to give an oil. The oil was dissolved in ethyl acetate and HCl (4M, dioxane) was added to give the product as a white solid (140 mg, 43%).
Reaction SMILES: [I-:1].C([O:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([S+:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[C:16]3[CH:23]=[CH:24][CH:25]=[CH:26][C:15]2=3)=[CH:10][CH:9]=1)(=O)C.[OH-].C[N+](C)(C)C.O.C(Cl)(Cl)Cl>CO>[I-:1].[OH:5][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([S+:14]2[C:15]3[CH:26]=[CH:25][CH:24]=[CH:23][C:16]=3[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]2=3)=[CH:12][CH:13]=1
Reactant: CC(=O)OCCc1ccc(-[s+]2c3ccccc3c3ccccc32)cc1
Agent: C[N+](C)(C)C
Agent: [I-]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O
Product: OCCc1ccc(-[s+]2c3ccccc3c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
While cooling with ice, 10.0 g of dibenzothiophene-S-oxide synthesized in the above step (1) is added to 30 g of diphosphorus pentoxide/methanesulfonic acid (9/1), and further 10 ml of 2-phenylethyl acetate is added thereto. The reaction solution is stirred at room temperature for 6 hours, and then poured into ice water. The obtained aqueous solution is filtered, and 23 g of potassium iodide is added. Crystals precipitated are recovered by filtration to obtain 11.1 g of 5-[(4-(2-acetoxyethyl)-phenyl]dibenzothiophenium iodide. The obtained 11.1 g of 5-[4-(2-acetoxyethyl)-phenyl]dibenzothiophenium iodide is dissolved in 200 ml of methanol, 10.7 g of a 20% aqueous solution of tetramethylammonium hydroxide is added to the solution, followed by stirring at room temperature for 2 hours. Subsequently, 100 ml of ion exchange water and 100 ml of chloroform are added to the solution to extract a chloroform layer. After the solvent is distilled off under reduced pressure, the reaction product is washed with ethyl acetate to obtain 8.5 g of the aiming 5-[4-(2-hydroxyethyl)phenyl]dibenzothiophenium iodide.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:31]([CH3:33])[CH3:32])[C:6]2[O:10][C:9]([C:11]3[CH:29]=[CH:28][C:14]([C:15]([NH:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([CH2:25][CH2:26][OH:27])[CH2:21][CH2:20]4)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:30]=1)#[N:2].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[CH3:65][C:66](O)([C:71]([F:74])([F:73])[F:72])[C:67]([F:70])([F:69])[F:68]>C1(C)C=CC=CC=1.O1CCCC1>[C:1]([C:3]1[CH:4]=[C:5]([CH:31]([CH3:33])[CH3:32])[C:6]2[O:10][C:9]([C:11]3[CH:29]=[CH:28][C:14]([C:15]([NH:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([CH2:25][CH2:26][O:27][C:66]([CH3:65])([C:71]([F:74])([F:73])[F:72])[C:67]([F:70])([F:69])[F:68])[CH2:23][CH2:24]4)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:30]=1)#[N:2]
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NC[C@H]4CC[C@H](CCO)CC4)cc3)oc12
Reactant: CC(O)(C(F)(F)F)C(F)(F)F
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NC[C@H]4CC[C@H](CCOC(C)(C(F)(F)F)C(F)(F)F)CC4)cc3)oc12
Reaction time: 0.17 h

Procedure:
To a solution of 4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)-N-{[trans-4-(2-hydroxyethyl)cyclohexyl]methyl}benzamide (50 mg, 0.112 mmol, EXAMPLE 43, Step A) and 1,1′-(azodicarbonyl)dipiperidine (57 mg, 0.226 mmol) in toluene (2 ml) was added tri-n-butylphosphine (0.06 ml, 0.241 mmol). After stirring for 10 min, hexafluoro-2-methylisopropanol (0.03 ml, 0.245 mmol) was added. Tetrahydrofuran (2 ml) was added to solubilize starting material, and the mixture was stirred overnight at room temperature. The mixture was concentrated and the residue was purified by flash chromatography on a Biotage Horizon, 25S column, eluting with 1 column volume of 100% dichloromethane followed by a gradient of 0 to 100% ethyl acetate in dichloromethane over 10 column volumes to provide the title compound (8.7 mg, 0.014 mmol, 12.72% yield). Mass spectrum (ESI) 610.2 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.33 (d, J=8.5 Hz, 2H); 7.94 (d, J=8.5 Hz, 2H), 7.94 (d, J=1.5 Hz, 1H); 7.51 (s, 1H), 6.27 (br s, 1H), 3.72 (t, J=6.5 Hz, 2H), 3.46 (septet, J=6.5 Hz, 1H), 3.36 (t, J=6.0 Hz, 2H), 1.83 (m, 4H), 1.50-1.65 (m, 5H), 1.46 (d, J=7.0 Hz, 6H), 1.40-1.50 (m, 2H), 0.85-1.22, (m, 6H).
Reaction SMILES: [CH:1]1[CH:6]=[C:5](Cl)[CH:4]=[C:3]([C:8]([O:10]O)=O)[CH:2]=1.[CH2:12]([N:16]1CCCCC1)[CH2:13]C#C>C(Cl)Cl>[CH2:3]1[CH:2]2[N:16]([CH2:4][CH2:5][CH2:6][CH2:1]2)[CH2:12][CH2:13][C:8]1=[O:10]
Reactant: C#CCCN1CCCCC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C1CCN2CCCCC2C1

Procedure:
m-CPBA (600 mg, 3.65 mmol) was added into a solution of 1-(but-3-ynyl)piperidine (500 mg, 3.65 mmol and 4 Å MS (5× weight of m-CPBA) in DCM under N2 at 0° C. The N-oxide formation was monitored by TLC. After completion, Ph3PAuNTf2 (134 mg, 0.18 mmol) was added to the reaction at 0° C. Upon completion, the mixture was diluted with DCM and the molecular sieves were filtered off. The filtrate was washed with 5% aqueous Na2CO3, dried over Na2SO4 and concentrated under vacuum. The residue was used for the next reaction without further purification. MS (ESI): 154 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([CH:14]=[N:15]O)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].O=P(Cl)(Cl)Cl>C1C=CC=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([C:14]#[N:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(-c2ccc(C=NO)o2)cc1
Solvent: c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1ccc(-c2ccc(C#N)o2)cc1
Yield: 68.7 %

Procedure:
A stirred mixture of 5-(4-cyanophenyl)-2-furaldehyde oxime (16 g, 0.075 mole) and benzene (400 ml) was heated to reflux and a solution of POCl3 (4 ml) in benzene (20 ml) was added dropwise over 15 minutes. The mixture was refluxed for 11/2 hours and filtered while hot. The filtrate was washed with 5% NaHCO3 (500 ml), H2O (500 ml), dried over MgSO4 and Darco and filtered. The filtrate was stripped of solvent under reduced pressure to yield 10 g (69%) of 5-(4-cyanophenyl)-2-furonitrile.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)[CH:5]=[CH:6][CH:7]=1.Cl.[CH3:33][C:34]1[CH:39]=[CH:38][C:37]([NH:40]N)=[CH:36][CH:35]=1>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:40][C:37]3[C:38]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:39][C:34]([CH3:33])=[CH:35][CH:36]=3)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc(Br)c3)CC2)c1
Reactant: Cc1ccc(NN)cc1
Agent: Cl
Product: Cc1ccc2[nH]c(-c3cccc(Br)c3)c(CCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c2c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(3-bromophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-methylphenylhydrazine hydrochloride: ESMS m/e: 572 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[N:7]=[C:8]([CH2:11][OH:12])[S:9][CH:10]=1>C(Cl)Cl.CO.O=[Mn]=O>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[N:7]=[C:8]([CH:11]=[O:12])[S:9][CH:10]=1
Reactant: OCc1nc(-c2nccs2)cs1
Agent: O=[Mn]=O
Solvent: ClCCl
Solvent: CO
Product: O=Cc1nc(-c2nccs2)cs1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
A mixture of [2,4′]bithiazol-2′-ylmethanol (1.53 g; 7.72 mmol), obtained as described in the above step, and MnO2 (13.93 g; 160.2 mmol) in CH2Cl2 (76.5 ml) and methanol (7.65 ml) was stirred at room temperature for about 23 hours.