Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:16]2[NH:20][N:19]=[C:18]([C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.NCC([N:55]1[CH2:60][CH2:59][CH:58]([O:61][C:62]2[CH:67]=[CH:66][CH:65]=[C:64]([C:68]([F:71])([F:70])[F:69])[CH:63]=2)[CH2:57][CH2:56]1)=O>CN(C=O)C.O>[O:27]=[C:25]([N:55]1[CH2:56][CH2:57][CH:58]([O:61][C:62]2[CH:67]=[CH:66][CH:65]=[C:64]([C:68]([F:69])([F:70])[F:71])[CH:63]=2)[CH2:59][CH2:60]1)[CH2:24][NH:23][C:21]([C:18]1[CH:17]=[C:16]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:20][N:19]=1)=[O:22]
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Reactant: NCC(=O)N1CCC(Oc2cccc(C(F)(F)F)c2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCC(=O)N1CCC(Oc2cccc(C(F)(F)F)c2)CC1)c1cc(-c2ccccc2)[nH]n1
Reaction time: 0.03 h
Yield: 16.2 %

Procedure:
DIPEA (360 mg, 2.8 mmol) was added to a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (200 mg, 0.8 mmol) in DMF (2 mL) followed by HOBt (131 mg, 0.97 mmol) and EDCI.HCl (187 mg, 00.97 mmol). After 2 minutes of stirring, 2-amino-1-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethanone hydrochloride (prepared according to Step 1 and 5 of the General Scheme) (200 mg, 0.8 mmol) was added and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with cold water extracted with ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure. Purification by column chromatography (using neutral alumina and 5% MeOH in CHCl3 as eluent) to afford 62 mg (16.2% Yield) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-oxo-2-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethyl}-amide. LC/MS [M+H]+: 473.17, 91%, 1H NMR (300 MHz, DMSO-d6): δ8.1 (m, 1H), 7.8 (d, 2H), 7.5 (m, 3H), 7.4 (m, 4H), 7.1 (s, 1H), 4.8 (m, 1H), 4.2 (d, 2H), 3.8 (m, 1H), 3.6 (m, 1H), 3.5 (m, 2H), 2.0 (m, 2H), 1.6 (m, 2H).
Reaction SMILES: CS(O[CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1)(=O)=O.[C:20]1([SH:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.FC(F)(F)CSCC1CCN(C(OC(C)(C)C)=O)CC1>>[C:20]1([S:26][CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:11][CH2:12]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Sc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)CC1
Agent: CC(C)(C)OC(=O)N1CCC(CSCC(F)(F)F)CC1
Product: CC(C)(C)OC(=O)N1CCC(CSc2ccccc2)CC1
Yield: 144 %

Procedure:
tert-Butyl 4-[(phenylsulfanyl)methyl]piperidine-1-carboxylate was prepared from tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (Intermediate 181, 0.320 g, 1.091 mmol) and thiophenol (0.117 mL, 1.145 mmol) according to the method described for Intermediate 183 to afford the title compound (0.483 g). 1H NMR (250 MHz, CDCl3) δ ppm 7.22 (5H, m), 4.10 (2H, m), 2.83 (2H d), 2.64 (2H, t), 1.84 (2H, d), 1.63 (1H, m), 1.44 (9H, s) and 1.17 (2H, m).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([NH:8][C:9](=[O:18])[C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:17])[CH:5]=[CH:4][N:3]=1.[NH2:19][C:20]1[N:25]=[C:24]([CH3:26])[CH:23]=[CH:22][N:21]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Cl:17][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([Cl:16])[C:10]=1[C:9]([NH:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:19][C:20]2[N:25]=[C:24]([CH3:26])[CH:23]=[CH:22][N:21]=2)[CH:7]=1)=[O:18]
Reactant: Cc1ccnc(N)n1
Reactant: O=C(Nc1ccnc(Br)c1)c1c(Cl)cccc1Cl
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1ccnc(Nc2cc(NC(=O)c3c(Cl)cccc3Cl)ccn2)n1
Temperature: 25 °C
Yield: 11.8 %

Procedure:
To a microwave tube were added N-(2-bromopyridin-4-yl)-2,6-dichlorobenzamide (0.15 g, 0.43 mmol), 2-amino-4-methylpyrimidine (0.056 g, 0.52 mmol), Pd2(dba)3 (0.040 g, 0.043 mmol), XantPhos (0.050 g, 0.087 mmol), Cs2CO3 (0.28 g, 0.87 mmol) and dioxane (2 mL). The mixture was degassed with N2 for 10 min. The resulting mixture was irradiated in a microwave reactor at 140° C. for 3 hours and then cooled to room temperature. The mixture was filtered through Celite and concentrated under reduced pressure. The residue was dissolved in DMF and purified by prep-HPLC (Gilson GX 281, Shim-pack PRC-ODS 250 mm×20 mm×2, gradient: CH3CN/10 mm/L NH4HCO3, 17 min) to give the desired product as a white solid (19 mg, yield: 12%). 1H NMR (500 MHz, MeOH-d4): δ 8.88 (s, 1H), 8.36 (d, J=5.5 Hz, 1H), 8.16 (d, J=6.0 Hz, 1H), 7.64 (s, 1H), 7.45-7.38 (m, 4H), 6.85 (d, J=5.5 Hz, 1H), 2.50 (s, 3H). LCMS (ESI) m/z: 374.0 [M+H+].
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]#[C:23][CH:24]([NH2:26])[CH3:25])=[CH:18][CH:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27](OC(=O)C)(=[O:29])[CH3:28]>>[CH2:1]([O:8][C:9]1[N:14]=[CH:13][C:12]([O:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]#[C:23][CH:24]([NH:26][C:27](=[O:29])[CH3:28])[CH3:25])=[CH:20][CH:21]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC(N)C#Cc1ccc(Oc2ccc(OCc3ccccc3)nc2)cc1
Product: CC(=O)NC(C)C#Cc1ccc(Oc2ccc(OCc3ccccc3)nc2)cc1

Procedure:
3-[4-(6-Benzyloxypyridin-3-yloxy)phenyl]-1-methylprop-2-ynylamine (705 mg, 6.97 mmol) was reacted with acetic anhydride in analogy to example 2a. Yield: 370 mg (41%), M+H+: 387.42:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:18]4[CH:19]=[C:20]([CH3:27])[C:21]([C:24](O)=[O:25])=[N:22][CH:23]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[N:3]=1.Cl.[CH3:36][NH2:37]>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:18]4[CH:19]=[C:20]([CH3:27])[C:21]([C:24]([NH:37][CH3:36])=[O:25])=[N:22][CH:23]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[N:3]=1
Reactant: CN
Reactant: Cc1cc(-c2ccc3c(c2)CN(c2cc(N4CCN(C)CC4)nc(N)n2)CC3)cnc1C(=O)O
Agent: Cl
Product: CNC(=O)c1ncc(-c2ccc3c(c2)CN(c2cc(N4CCN(C)CC4)nc(N)n2)CC3)cc1C

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 18 starting from 5-{2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-3-methylpyridine-2-carboxylic acid and methylamine hydrochloride. LCMS (M+H)+: m/z=473.2.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][OH:7])[CH:2]=[CH2:3].[CH2:8]1[CH:12]2[CH:13]3C=CC([CH:11]2C=[CH:9]1)C3>>[OH:7][CH2:6][CH2:5][O:4][CH2:1][CH:2]1[CH2:11][CH:12]2[CH2:13][CH:3]1[CH:9]=[CH:8]2
Reactant: C=CCOCCO
Reactant: C1=CC2C3C=CC(C3)C2C1
Product: OCCOCC1CC2C=CC1C2
Temperature: 190 °C

Procedure:
In a 300 mL autoclave equipped with a thermal couple and a mechanical stirrer, a mixture of 2-allyloxyethanol (109.5 g, 1.07 mol) and dicyclopentadiene (35.4 g, 0.27 mol) was stirred and heated to 190° C. The reaction was cooled after 3 h. Three such reactions were run and the reaction mixtures were combined. The mixture was distilled using a short-path distillation column under vacuum at 70° C. at 500 mTorr. The distillate (170 g) was dissolved in a mixture of 250 mL of CH3OH and 150 mL of H2O. Hexane (3×125 mL) was added to the mixture in order to extract out cyclopentadiene impurities. To the remaining methanol/water solution NaCl was added to force the product to oil out from solution. Ethyl acetate (200 mL) was added to extract the oil from water. After the solvents were removed by rotovaporation the product was dried under vacuum. Yield 157 g (58%). 1H NMR (500 MHz, CDCl3): Endo isomer: 6.13 (m, 1H); 5.93 (m, 1H); 3.72 (t, 2H); 3.52 (m, 2H); 3.22 (t, 1H); 3.10 (t, 1H); 2.90 (s, 1H); 2.80 (s, 1H); 2.37 (m, isomer: 6.10 (m, 1H); 6.07 (m, 1H); 3.75 (t, 2H); 3.36 (m, 2H); 3.50 (t, 1H); 3.40 (t, 1H); 2.80 (s, 1H); 2.74 (s, 1H); 2.09 (br s, 1H); 1.71 (m, 1H); 1.33 (d, 1H), 1.30 (d, 1H); 1.24 (m, partially obscured by endo isomer, 1H); 1.11 (d of t, 1H). Endo/exo ratio by 1H NMR was determined to be 82/18.
Reaction SMILES: [CH2:1]([C:4]1[C:5]([O:23][CH2:24][CH:25]([OH:41])[CH2:26][N:27]2[CH2:32][CH2:31][N:30]([CH2:33][C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=3)[CH2:29][CH2:28]2)=[CH:6][CH:7]=[C:8]2[C:13]=1[O:12][C:11](=[O:14])[CH:10]=[C:9]2[O:15]CC1C=CC=CC=1)[CH:2]=[CH2:3].C.[H][H]>CN(C=O)C>[Cl:40][C:37]1[CH:36]=[CH:35][C:34]([CH2:33][N:30]2[CH2:31][CH2:32][N:27]([CH2:26][CH:25]([OH:41])[CH2:24][O:23][C:5]3[C:4]([CH2:1][CH2:2][CH3:3])=[C:13]4[C:8]([C:9]([OH:15])=[CH:10][C:11](=[O:14])[O:12]4)=[CH:7][CH:6]=3)[CH2:28][CH2:29]2)=[CH:39][CH:38]=1
Reactant: [H][H]
Reactant: C=CCc1c(OCC(O)CN2CCN(Cc3ccc(Cl)cc3)CC2)ccc2c(OCc3ccccc3)cc(=O)oc12
Solvent: CN(C)C=O
Product: CCCc1c(OCC(O)CN2CCN(Cc3ccc(Cl)cc3)CC2)ccc2c(O)cc(=O)oc12
Yield: 79.5 %

Procedure:
Hydrogenation of a solution of 1-[3-(8-allyl-4-benzyloxycoumarin-7-yloxy)-2-hydroxypropyl]-4-(4-chlorobenzyl)piperazine (7.2 g) in DMF (200 ml) over 10% palladinized charcoal at atmospheric pressure until two equivalents of hydrogen were absorbed gave 4.85 g (80%) of material of m.p. (aqueous ethanol) 107° C. (Found; C, 63.90; H, 6.59; N, 5.20; Cl, 6.53; C26H31N2O5Cl requires; C, 64.12; H, 6.42; N, 5.75; Cl, 7.28%).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([SH:13])[CH2:10][CH2:11][SH:12]>C(Cl)Cl>[C:2]1([CH:1]2[S:13][CH2:9][CH2:10][CH2:11][S:12]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: SCCCS
Reactant: O=Cc1ccccc1
Solvent: ClCCl
Product: c1ccc(C2SCCCS2)cc1
Reaction time: 8 h
Yield: 89 %

Procedure:
Benzaldehyde (11.5 mL, 112 mmol and 1,3-propanedithiol (120 mL, 92.5 mmol) were stirred in methylene chloride (200 mL) at 0° C. and HCl(g) was bubbled into the solution followed by addition of zinc chloride (9 g). The mixture was stirred overnight after which it was poured onto 10% potassium hydroxide solution. The layers were separated and the organic extract was washed with 10% potassium hydroxide solution, water, brine and dried (MgSO4). Evaporation of solvent at reduced pressure afforded an oil which crystallized upon standing and was recrystallized from diethyl ehter to give 16.2 g (89%) of product. 1H NMR (CDCl3) δ: (m, 2H), 5.16 (s, 1H), 7.25-7.36 (m, 3H), 7.45-7.48 (m, 2H) ppm.
Reaction SMILES: [OH:1][C:2]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH2:33][CH2:34][O:35]C(=O)C)[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([OH:13])=O)[CH2:4][CH2:3]1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:51]([NH2:55])[CH2:52][CH2:53][CH3:54].O>CN(C)C=O>[OH:1][C:2]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH2:33][CH2:34][OH:35])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C:10]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:11]([NH:55][CH2:51][CH2:52][CH2:53][CH3:54])=[O:13])[CH2:4][CH2:3]1
Reactant: CC(=O)OCCOc1ccccc1C1(O)CCN(CCC(C(=O)O)(c2ccccc2)c2ccccc2)CC1
Reactant: CCCCN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: CCCCNC(=O)C(CCN1CCC(O)(c2ccccc2OCCO)CC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.8 %

Procedure:
In 5 mL of anhydrous dimethylformamide was dissolved 81 mg (0.17 mmol) of 4-(4-hydroxy-4-(2-(2-acetoxyethoxy)phenyl)piperidino)-2,2-diphenylbutyric acid. The resulting solution was stirred at room temperature for 1 hour. To the reaction mixture were added 36 mg (0.22 mmol) of carbodiimidazole, and after one hour 16 mg (0.22 mmol) of n-butylamine. After stirring at 70° C. for 24 hours, stirring was conducted for further 3 hours at 130° C., whereby the reaction was completed. Water was added to the reaction mixture, followed by extraction with ethyl acetate, washing with water and drying. The residue obtained by distilling off the solvent under reduced pressure was purified by chromatography on an alumina column and then chromatography on a silica gel column, whereby 35 mg (yield: 38.9%) of 4-(4-hydroxy-4-(2-(2-hydroxyethoxy)phenyl)piperidino)-N-butyl-2,2-diphenylbutaneamide (Compound No. 73) was obtained.
Reaction SMILES: [ClH:1].C([S:5][CH:6]1[CH2:11][CH2:10][N:9]([CH:12]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:13]([CH:15]2[CH2:17][CH2:16]2)=[O:14])[CH2:8]/[C:7]/1=[CH:25]\[C:26]1[N:27]=[N:28][N:29]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH:30]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+].C(#N)C>CO>[ClH:1].[CH:15]1([C:13](=[O:14])[CH:12]([N:9]2[CH2:10][CH2:11][CH:6]([SH:5])/[C:7](=[CH:25]/[C:26]3[N:27]=[N:28][N:29]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH:30]=3)/[CH2:8]2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[CH2:17][CH2:16]1
Reactant: COC(=O)Cn1cc(/C=C2\CN(C(C(=O)C3CC3)c3ccccc3F)CCC2SC(C)=O)nn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CO
Product: COC(=O)Cn1cc(/C=C2\CN(C(C(=O)C3CC3)c3ccccc3F)CCC2S)nn1
Yield: 47.1 %

Procedure:
Following a procedure similar to that described in Example 151, (E)-4-(acetylsulfanyl)-1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-3-{[1-(methoxycarbonylmethyl)-1H-1,2,3-triazol-4-yl]methylidene}piperidine hydrochloride (300 mg) was treated with potassium carbonate in methanol and the concentrated extract was purified by preparative HPLC (YMC-Pack ODS-A; YMC, eluent: acetonitrile/0.024 N hydrochloric acid, 25/75, v/v) to afford the title compound (130 mg, yield: 47%) as a yellow amorphous solid.
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#N.C1(C)C=CC=CC=1.[H-].C([Al+]CC(C)C)C(C)C.Cl.C(=O)([O-])[O-:41].[Na+].[Na+]>ClCCl>[CH:1]([C:3]1[N:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)=[O:41]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C#N)nc2)CC1
Reactant: O=C([O-])[O-]
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C=O)nc2)CC1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 50.4 %

Procedure:
To a solution of tert-butyl 4-(6-cyanopyridin-3-yl)piperazine-1-carboxylate (144.2 mg, 0.500 mmol) in anhydrous dichloromethane (5 ml) was added dropwise at −78° C. 1.5M diisobutylaluminum hydride toluene solution (0.4 ml, 0.6 mmol) over 5 mins. After stirring at −78° C. for 1.5 hrs, 1M hydrochloric acid (1 ml) was added. The mixture was heated to room temperature and stirred for 1 hr. Saturated aqueous sodium carbonate solution was added, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=2:3) to give tert-butyl 4-(6-formylpyridin-3-yl)piperazine-1-carboxylate (73.4 mg, yield 50.4%) as a slightly yellow solid.
Reaction SMILES: C1(N2C(=O)C3C=CC(OCC4C=C(B(O)O)C=CC=4)=CC=3S2)CCCC1.IC1C=CC(OC)=C(C=1)C(OC)=O.[CH:40]1([N:45]2[C:49](=[O:50])[C:48]3[CH:51]=[CH:52][C:53]([O:55][CH2:56][C:57]4[CH:58]=[C:59]([C:63]5[CH:68]=[CH:67][C:66]([O:69][CH3:70])=[C:65]([C:71]([O:73]C)=[O:72])[CH:64]=5)[CH:60]=[CH:61][CH:62]=4)=[CH:54][C:47]=3[S:46]2)[CH2:44][CH2:43][CH2:42][CH2:41]1.[Li+].[I-]>N1C=CC=CC=1>[CH:40]1([N:45]2[C:49](=[O:50])[C:48]3[CH:51]=[CH:52][C:53]([O:55][CH2:56][C:57]4[CH:58]=[C:59]([C:63]5[CH:68]=[CH:67][C:66]([O:69][CH3:70])=[C:65]([C:71]([OH:73])=[O:72])[CH:64]=5)[CH:60]=[CH:61][CH:62]=4)=[CH:54][C:47]=3[S:46]2)[CH2:41][CH2:42][CH2:43][CH2:44]1
Reactant: COC(=O)c1cc(-c2cccc(COc3ccc4c(=O)n(C5CCCC5)sc4c3)c2)ccc1OC
Agent: COC(=O)c1cc(I)ccc1OC
Agent: O=c1c2ccc(OCc3cccc(B(O)O)c3)cc2sn1C1CCCC1
Agent: [I-]
Solvent: c1ccncc1
Product: COc1ccc(-c2cccc(COc3ccc4c(=O)n(C5CCCC5)sc4c3)c2)cc1C(=O)O

Procedure:
A mixture of 3-((2-cyclopentyl-3-oxo-2,3-dihydrobenzo[d]isothiazol-6-yloxy)methyl)phenylboronic acid (0.050 g, 0.14 mmol), methyl 5-iodo-2-methoxybenzoate (0.056 g, 0.20 mmol) were coupled according to the general procedure and the resulting methyl 3′-((2-cyclopentyl-3-oxo-2,3-dihydrobenzo[d]isothiazol-6-yloxy)methyl)-4-methoxybiphenyl-3-carboxylate was hydrolyzed using LiI (0.019 g, 0.14 mmol) in refluxing pyridine (2 mL) to afford the title product. The crude residue was purified using automated prep-HPLC to yield the desired compound as a pale yellow solid (0.013 g, over two steps 10%). δ1 NMR (400 MHz, CDCl3): δ 8.44 (s, 1H), 7.87 (d, 1H, J=8.2 Hz), 7.89 (d, 1H, J=8.7 Hz), 7.63 (s, 1H), 7.58 (d, 1H, J=7.8 Hz), 7.49 (t, 1H, J=7.8 Hz), 7.41-7.39 (m, 1H), 7.28-7.24 (m, 2H), 7.14 (d, 1H, J=8.7 Hz), 5.26 (s, 2H), 4.63-4.59 (m, 1H), 3.89 (s, 3H), 2.16-2.04 (m, 2H), 2.04-1.58 (m, 6H). LC-MS (ESI) Calcd for C27H25NO5S [M+H]+: 475.14. Found: 475.80.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[C:5]([CH2:11][CH2:12][OH:13])=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.[N-:20]=[N+:21]=[N-:22].[Na+]>CS(C)=O.O>[C:14]1([C:4]2[N:3]3[N:20]=[N:21][N:22]=[C:2]3[N:7]3[N:8]=[CH:9][N:10]=[C:6]3[C:5]=2[CH2:11][CH2:12][OH:13])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: [N-]=[N+]=[N-]
Reactant: OCCc1c(-c2ccccc2)nc(Cl)n2ncnc12
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: OCCc1c(-c2ccccc2)n2nnnc2n2ncnc12
Reaction time: 5 h

Procedure:
To a solution containing 27.4 g of 5-chloro-7-phenyl[1,2,4]triazolo[1,5-c]pyrimidine-8-ethanol (0.1 mole) dissolved in 250 ml of dimethylsulfoxide is added 13 g of sodium azide (0.2 mole). The resulting reaction mixture is stirred for 5 hours at a temperature of 65°-70° C. and then stirred overnight at room temperature. The reaction mixture is poured in water with stirring. A precipitate forms and the mixture is filtered and the precipitate is washed with water and dried yielding a crude product. The crude product is recrystallized from diethyl ether to yield 5-phenyltetrazolo[1,5-a][1,2,4]triazolo[1,5-c]pyrimidine-6-ethanol having the structural formula ##STR22## and the azido tautomer thereof as a white solid having a melting point of 110° C. and the following elemental analysis:
Reaction SMILES: C1(S(CC2C=[CH:19][C:18]([C:21]3[O:25][CH:24]=NC=3)=CC=2C(OC)=O)(=O)=O)C=CC=CC=1.Br[C:27]1[C:28]([O:51][CH3:52])=[C:29]([C:34]([CH2:37][S:38]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[CH:47]=[CH:48][CH2:49][OH:50])(=[O:40])=[O:39])=[CH:35][CH:36]=1)[C:30]([O:32][CH3:33])=[O:31].C1(S(CC2C(C(OCC)=O)=C(OC)C(Br)=CC=2)(=O)=O)C=CC=CC=1.O1C=CC(B(O)O)=C1>>[O:25]1[CH:21]=[CH:18][C:19]([C:27]2[C:28]([O:51][CH3:52])=[C:29]([C:34]([CH2:37][S:38]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[CH:47]=[CH:48][CH2:49][OH:50])(=[O:39])=[O:40])=[CH:35][CH:36]=2)[C:30]([O:32][CH3:33])=[O:31])=[CH:24]1
Reactant: COC(=O)c1c(CS(=O)(=O)c2ccccc2C=CCO)ccc(Br)c1OC
Reactant: COC(=O)c1cc(-c2cnco2)ccc1CS(=O)(=O)c1ccccc1
Agent: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(Br)c1OC
Agent: OB(O)c1ccoc1
Product: COC(=O)c1c(CS(=O)(=O)c2ccccc2C=CCO)ccc(-c2ccoc2)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 42, starting from methyl 3-bromo-6-((2-(3-hydroxyprop-1-enyl)benzenesulfonyl)methyl)-2-methoxybenzoate (mixture of E and Z isomers, Intermediate 60) and furan-3-yl boronic acid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][O:5][CH2:6]P(OC)(OC)=O.[H-].[Na+].[CH2:16]([C@@:18]1([CH:38]=O)[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][CH2:25][C:26]2[C:34]3[C:29](=[CH:30][CH:31]=[C:32]([O:35][CH3:36])[CH:33]=3)[NH:28][CH:27]=2)[C:19]1=[O:37])[CH3:17]>O1CCCC1>[CH3:1][O:2][C:3](=[O:13])[C:4]([O:5][CH3:6])=[CH:38][C@:18]1([CH2:16][CH3:17])[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][CH2:25][C:26]2[C:34]3[C:29](=[CH:30][CH:31]=[C:32]([O:35][CH3:36])[CH:33]=3)[NH:28][CH:27]=2)[C:19]1=[O:37]
Reactant: CC[C@@]1(C=O)CCCN(CCc2c[nH]c3ccc(OC)cc23)C1=O
Reactant: COC(=O)COCP(=O)(OC)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[C@@]1(C=C(OC)C(=O)OC)CCCN(CCc2c[nH]c3ccc(OC)cc23)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3.185 g of dimethylphosphonomethoxyacetic acid methyl ester are added dropwise at room temperature to a suspension of 360 mg of sodium hydride in 10 cc of absolute tetrahydrofuran in the absence of moisture. After stirring at room temperature for 30 minutes, a solution of 3.284 g of (S)-3-ethyl-3-formyl-N-[2-(5-methoxy-indol-3-yl)-ethyl]-2-piperidone in 10 cc of absolute tetrahydrofuran is added dropwise at room temperature to the reaction solution while stirring for 30 minutes. The reaction mixture is subsequently stirred at room temperature for a further 2 hours, poured on ice and extracted with methylene chloride. The organic phases are dried and concentrated. A yellowish oil, consisting of a mixture of the Z and E isomers of 3-{(S)-3-ethyl-1-[2-(5-methoxy-indol-3-yl)ethyl]-2-oxo-3-piperidyl}-2-methoxy-propenoic acid methyl ester, is obtained.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[C@@H:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:17]([CH3:26])([CH3:25])[O:16][C:15]3=[O:27])=[CH:10][CH:9]=2)=[CH:6][C:5]([C:28]2[N:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[CH:4][N:3]=1.[O:34]1CCOCC1.Cl>O>[CH3:25][C:17]1([CH3:26])[O:16][C:15](=[O:27])[N:14]([C:11]2[CH:12]=[CH:13][C:8]([C:7]3[C:2](=[O:34])[NH:3][CH:4]=[C:5]([C:28]4[N:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[CH:6]=3)=[CH:9][CH:10]=2)[C@H:18]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC1(C)OC(=O)N(c2ccc(-c3cc(-c4ncccn4)cnc3F)cc2)[C@H]1c1ccccc1
Reactant: C1COCCO1
Agent: Cl
Solvent: O
Product: CC1(C)OC(=O)N(c2ccc(-c3cc(-c4ncccn4)c[nH]c3=O)cc2)[C@H]1c1ccccc1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
A resealable tube was charged with (S)-3-(4-(2-fluoro-5-(pyrimidin-2-yl)pyridin-3-yl)phenyl)-5,5-dimethyl-4-phenyloxazolidin-2-one (0.034 g, 0.077 mmol), dioxane (2.0 mL), and water (0.667 mL). Concentrated HCl (37%) (0.167 mL) was added, the system was flushed with argon, the tube was sealed, and the reaction mixture was stirred at 100° C. for 1.5 hours. The reaction mixture was next partitioned between EtOAc and saturated aqueous NaHCO3 solution. The aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford (S)-5,5-dimethyl-3-(4-(2-oxo-5-(pyrimidin-2-yl)-1,2-dihydropyridin-3-yl)phenyl)-4-phenyloxazolidin-2-one (0.034 g, 0.078 mmol, 100% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.92 (s, 3H), 1.65 (s, 3H), 5.48 (s, 1H), 7.18-7.45 (m, 6H), 7.48-7.59 (m, 2H), 7.65-7.75 (m, 2 H), 8.32 (d, J=2.45 Hz, 1H), 8.43 (d, J=2.54 Hz, 1H), 8.80 (d, J=4.89 Hz, 2H), 12.13 (br. s., 1H). m/z (ESI) 439 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([CH2:13][N:14]([CH3:28])[S:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:9][CH2:8]1.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>>[CH3:28][N:14]([CH2:13][C@H:10]1[CH2:11][CH2:12][C@H:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][O:1][S:30]([CH3:29])(=[O:32])=[O:31])[CH2:8][CH2:9]1)[S:15]([C:18]1[CH:19]=[CH:20][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:22][CH:23]=1)(=[O:16])=[O:17]
Reactant: CN(C[C@H]1CC[C@H](OCCCCO)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: CS(=O)(=O)Cl
Product: CN(C[C@H]1CC[C@H](OCCCCOS(C)(=O)=O)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to the procedure described in example 3.4, trans-N-[4-(4-hydroxy-butoxy)-cyclohexylmethyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide was treated with methanesulfonyl chloride to yield trans-methanesulfonic acid 4-(4-{[methyl-(4-trifluoromethyl-benzenesulfonyl)-amino]-methyl}-cyclohexyloxy)-butyl ester as colorless solid, MS: 502 (M+).