Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[C:9]([NH:12][C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1)(=[O:11])[CH3:10]>CCOC(C)=O>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([O:19][C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([NH:12][C:9](=[O:11])[CH3:10])[CH:14]=2)[N:3]=1
Reactant: CC(=O)Nc1cccc(O)c1
Reactant: Clc1cncc(Cl)n1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1cccc(Oc2cncc(Cl)n2)c1
Yield: 99 %

Procedure:
Using Method DD with 2,6-dichloropyrazine (200 mg, 1.34 mmol) and 3-acetamidophenol (202 mg, 1.49 mmol), and crystallisation in AcOEt, the title compound was obtained (350 mg). Yield: 99%. 1H NMR (250 MHz, DMSO-d6) δ 2.06 (s, 3H, CH3—NH), 6.90-6.95 (m, 1H, Harom 5), 7.76 (dd, 2H, Harom 4+6, Jm=2.0 Hz, Jo=7.6 Hz), 7.59 (s, 1H, Harom 2), 8.52 (s, 1H, HPz 5), 8.54 (s, 1H, HPz 3), 10.12 (s, 1H, NH).
Reaction SMILES: COC(CCC([O:9][C:10]1[C:11]([CH3:27])=[C:12]([CH3:26])[C:13]2[O:17][CH:16]([CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])[S:15][C:14]=2[C:24]=1[CH3:25])=O)=O.N>CO>[OH:9][C:10]1[C:11]([CH3:27])=[C:12]([CH3:26])[C:13]2[O:17][CH:16]([CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])[S:15][C:14]=2[C:24]=1[CH3:25]
Reactant: COC(=O)CCC(=O)Oc1c(C)c(C)c2c(c1C)SC(CCC(=O)OC)O2
Agent: N
Solvent: CO
Product: COC(=O)CCC1Oc2c(C)c(C)c(O)c(C)c2S1

Procedure:
4.2 g of methyl 3-[5-(3-methoxycarbonylpropionyloxy)-4,6,7-trimethyl-1,3-benzoxathiole-2-yl]propionate (prepared as described in Example 31) were added to a mixture of 50 ml of methanol and 14 g of 28% w/v aqueous ammonia, and the mixture was reacted for 20 hours at room temperature. The volatile matter was then evaporated from the reaction mixture under reduced pressure, and ethyl acetate was added to the residue. The ethyl acetate solution was washed with water and dried over anhydrous sodium sulfate. The ethyl acetate was then distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography, and the desired compound was obtained from the fraction eluted with a 20:1 by volume mixture of benzene and ethyl acetate.
Reaction SMILES: [CH2:1]([CH:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH:6]=O)[CH2:2][CH2:3][CH3:4].[CH2:21]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1.C1COCC1.CCCCCC>[Si:14]([O:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH:6]=[CH2:21])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: CCCCC(C=O)CCCCCO[Si](C)(C)C(C)(C)C
Reactant: C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=CC(CCCC)CCCCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
2-Butyl-7-(tert-butyldimethylsilyloxy)heptanaI (6.01 g, 20 mmol) in 15 ml of anhydrous THF was added dropwise to a freshly prepared solution of methylidene(triphenyl)phosphorane (22 mmol in 125 ml of anhydrous THF/hexane at 0° C. over a period of 15 min. The mixture was warmed to room temperature, stirred for 8 h, and poured into 300 ml of ice/water and extracted (3×75 ml) with ether. The combined organic extracts were washed with water and dried over anhydrous MgSO4. Solvents were removed by evaporation and pentane (250 ml) was added to the red oily residue. The mixture was chilled to 0° C. and the precipitated Ph3PO removed by filtration The precipitate was washed with ice-cold pentane and the filtrate concentrated in vacuo. The crude product was purified by PMPLC yielding 4.06 g (68%) of 8-(tert-butyldimethylsilyloxy)-3-butyloct-1-ene.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][NH:11][N:12]=2)=[CH:4][CH:3]=1.[C:13](O)([CH3:16])([CH3:15])[CH3:14].S(=O)(=O)(O)O>FC(F)(F)C(O)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][N:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[N:12]=2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(-c2nn[nH]n2)cc1
Reactant: CC(C)(C)O
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)n1nnc(-c2ccc(Br)cc2)n1
Yield: 70.9 %

Procedure:
5-(4-Bromophenyl)-2H-tetrazole (19.0 g, 81.9 mmol), t-butanol (12.1 g, 164 mmol), trifluoroacetic acid (80 mL) and concentrated sulfuric acid (4.6 g, 41 mmol) were stirred at ambient temperature for 24 hours. The mixture was concentrated and dissolved in ethyl acetate (200 mL). After washing with water (3×25 mL), 1M NaOH (3×25 mL) and brine (25 mL) the organic layer was dried (Na2SO4), filtered and concentrated. The oil was purified by chromatography on a Waters Prep 500 liquid chromatograph fitted with two silica gel cartridges eluting with a mixture of hexanes and ethyl acetate (9:1) to provide 5-(4-bromophenyl)-2-(1,1-dimethylethyl)-2H-tetrazole (17.1 g, 58.1 mmol) as a yellow oil in 71% yield.
Reaction SMILES: [OH:1][OH:2].[C:3](Cl)(=[O:7])[CH:4]([CH3:6])[CH3:5]>O>[C:3]([O:1][O:2][C:3](=[O:7])[CH:4]([CH3:6])[CH3:5])(=[O:7])[CH:4]([CH3:6])[CH3:5]
Reactant: CC(C)C(=O)Cl
Reactant: OO
Solvent: O
Product: CC(C)C(=O)OOC(=O)C(C)C

Procedure:
In Example A, the procedure of WO 01/32613 was repeated. First, a solution of Na2O2 was prepared by combining 108.3 g of demineralized water, 18.5 g of NaOH-33 solution, and 3.7 g of the aqueous H2O2. A second reactor was charged with 33.3 g of demineralized water, 27.7 g of the PVA solution, and 16.3 g of isobutanoyl chloride while controlling the temperature between 5–10° C. Next, the Na2O2 solution was dosed while the system was homogenized. No diisobutanoyl peroxide was obtained and only an aqueous phase formed.
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[NH2:7][C:8]1[C:12]2[CH:13]=[N:14][C:15]([NH:17][C:18]([NH:20][C@@H:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH3:22])=[O:19])=[CH:16][C:11]=2[N:10](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:9]=1.C(O)C(N)(CO)CO.C([SiH](CC)CC)C>C(Cl)Cl.N1C=CC=CC=1>[C:23]1([C@H:21]([NH:20][C:18](=[O:19])[NH:17][C:15]2[N:14]=[CH:13][C:12]3[C:8]([NH:7][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[N:9][NH:10][C:11]=3[CH:16]=2)[CH3:22])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCS(=O)(=O)Cl
Reactant: C[C@@H](NC(=O)Nc1cc2c(cn1)c(N)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1
Agent: CC[SiH](CC)CC
Agent: NC(CO)(CO)CO
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1n[nH]c2cc(NC(=O)N[C@H](C)c3ccccc3)ncc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To an 8 mL vial charged with ethanesulfonyl chloride (10.53 μL, 0.111 mmol) was added (R)-1-(3-amino-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (Example 47, Step 1; 20 mg, 0.037 mmol) in DCM (1 mL) and pyridine (0.1 mL). The reaction mixture was stirred at room temperature for 2 h. Excess sulfonyl chloride was quenched by shaking with MP-Trisamine (91 mg, 0.186 mmol) for 3 h. The resin was filtered, the volatiles removed in vacuo, and the resulting residue dissolved in TFA (1 mL) and stirred at room temperature for 1 h. Triethylsilane (5.93 μL, 0.037 mmol) was added and the reaction mixture was stirred for an additional 5 min. The reaction mixture was concentrated in vacuo, the resulting crude residue dissolved in DMSO (1.5 mL), filtered, and purified by mass-triggered reverse phase HPLC to afford (R)—N-(6-(3-(1-phenylethyl)ureido)-1H-pyrazolo[4,3-c]pyridin-3-yl)ethanesulfonamide. MS ESI calc'd. For C17H20N6O3S [M+1]+ 389. found 389. 1H NMR (500 MHz, DMSO-d6) δ 12.74 (1H, s), 10.63 (1H, s), 9.20 (1H, s), 8.76 (1H, s), 7.70 (1H, s), 7.50 (1H, s), 7.31 (4H, d, J=4.4 Hz), 7.20-7.21 (1H, m), 4.84 (1H, t, J=7.2 Hz), 3.30 (2H, q, J=7.4 Hz), 1.38 (3H, d, J=7.0 Hz), 1.23 (3H, t, J=7.4 Hz).
Reaction SMILES: [C:1]([O:9][C@H:10]1[CH2:15][C@H:14]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][N:12](C(OCC2C=CC=CC=2)=O)[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.CCN(C(C)C)C(C)C.Cl[C:46]1[CH:51]=[CH:50][N:49]=[CH:48][C:47]=1[N+:52]([O-:54])=[O:53]>[Pd].CCOC(C)=O>[C:1]([O:9][C@H:10]1[CH2:15][C@H:14]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][N:12]([C:46]2[CH:51]=[CH:50][N:49]=[CH:48][C:47]=2[N+:52]([O-:54])=[O:53])[CH2:11]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](OC(=O)c2ccccc2)CN(C(=O)OCc2ccccc2)C1
Reactant: O=[N+]([O-])c1cnccc1Cl
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1C[C@H](OC(=O)c2ccccc2)CN(c2ccncc2[N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
To a solution of (3S,5S)-benzyl 3-(benzoyloxy)-5-(tert-butoxycarbonylamino)-piperidine-1-carboxylate (1 eq) in 15 methanol and 15 mL of EtOAc was added 10% Pd/C (0.1 eq). The resulting suspension was stirred at H2 atmosphere for 4 hours. The crude solids were filtered through a pad of Celite on a paper lined Buchner funnel, washed with MeOH, then concentrated in vacuo. The residue was dissolved in 20 mL of isopropanol and DIPEA (1.8 eq) and 4-chloro-3-nitropyridine (1.2 eq) were added. The reaction mixture was stirred at 75° C. for 2 hours, at which point the reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure. The residue was diluted with 150 mL of EtOAc, washed with brine, then dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (EtOAc:hexanes=1:1) to yield (3S,5S)-5-(tert-butoxycarbonylamino)-1-(3-nitropyridin-4-yl)-piperidin-3-yl benzoate (90%). LC/MS (m/z): 443.2 (MH+). HPLC: Rt:2.89 min.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].[F:17][C:18]1[CH:19]=[C:20]([CH:29]=[CH:30][C:31]=1[N:32]1[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]1)[CH:21]=[C:22]1[S:26][C:25](=[O:27])[NH:24][C:23]1=[O:28]>>[O:27]=[C:25]1[NH:24][C:23](=[O:28])[C:22](=[CH:21][C:20]2[CH:29]=[CH:30][C:31]([N:32]3[CH2:37][CH2:36][CH:35]([NH:1][CH2:2][CH:3]([C:5]4[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=4)[OH:4])[CH2:34][CH2:33]3)=[C:18]([F:17])[CH:19]=2)[S:26]1
Reactant: CS(=O)(=O)Nc1cc(C(O)CN)ccc1O
Reactant: O=C1CCN(c2ccc(C=C3SC(=O)NC3=O)cc2F)CC1
Product: CS(=O)(=O)Nc1cc(C(O)CNC2CCN(c3ccc(C=C4SC(=O)NC4=O)cc3F)CC2)ccc1O

Procedure:
The title compound was prepared from N-[5-(2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 9) and 5-[3-fluoro-4-(4-oxo-piperidine-1-yl)-benzylidene]-thiazolidine-2,4-dione (which was obtained in Example 62) according to the procedure of Example 63 as a yellow solid; mp >225° C.; 1H NMR (300 MHz, DMSO-d6) δ 1.62-1.71 (m, 2H), 2.03-2.12 (m, 2H), 2.70-2.83 (m, 3H), 2.95 (s, 3H), 3.12-3.33 (m, 2H), 3.49-3.52 (m, 2H), 4.72-4.75 (m, 1H), 5.96 (brs, 1H), 6.89 (d, J=8.1 Hz, 1H), 7.05-7.13 (m, 3H), 7.25-7.38 (m, 3H), 8.70 (brs, 1H), 9.8 (brs, 1H); MS (ES) m/z: 551.0 (MH+); HRMS for C24H27FN4O6S2 (MH+): 551.1434. Found: 551.1438.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]([NH:13][NH:14][C:15](=[O:17])[CH3:16])=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)=O>C(#N)C.O>[C:1]1([S:7]([CH2:10][C:11]2[O:17][C:15]([CH3:16])=[N:14][N:13]=2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)NNC(=O)CS(=O)(=O)c1ccccc1
Solvent: O
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nnc(CS(=O)(=O)c2ccccc2)o1
Yield: 68.7 %

Procedure:
To a stirred solution of 1.40 g (5.5 mmol) of acetic acid N′-(2-benzenesulfonyl-acetyl)-hydrazide in 50 mL of acetonitrile, 1.02 g (6.5 mmol, 1.2 eq) of phosphorus oxychloride were added, and the solution heated at reflux for 3 hours. The reaction mixture was diluted with water, extracted with EtOAc, the organic phase dried over Na2SO4, filtered and evaporated. Column chromatography on silica gel with EtOAc yielded 0.90 g (70%) of 2-benzenesulfonylmethyl-5-methyl-[1,3,4]oxadiazole as a white solid, MS: 239 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[P:22]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=O.C(N(CC)CC)C.Cl[SiH](Cl)Cl>C1(C)C(C)=CC=CC=1>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[P:22]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Nc1ccc2ccccc2c1-c1c(P(=O)(c2ccccc2)c2ccccc2)ccc2ccccc12
Agent: Cl[SiH](Cl)Cl
Solvent: Cc1ccccc1C
Solvent: CCN(CC)CC
Product: Nc1ccc2ccccc2c1-c1c(P(c2ccccc2)c2ccccc2)ccc2ccccc12
Temperature: 150 °C
Reaction time: 18 h
Yield: 81.2 %

Procedure:
7.16 gram (15.2 mmol) of (−)-2-amino-2′-diphenylphosphinyl-1,1′-binaphthyl (the formula (1-1a-1) was dissolved in 381 ml of xylene in an autoclave, followed by the addition of 42.5 ml (305.0 mmol) of triethylamine at 0° C. over 20 minutes and 7.70 ml (76.3 mmol) of trichlorosilane over 1 hour. The mixture was stirred at 150° C. for 18 hours in a tightly sealed condition. The reaction mixture was then extracted with 500 ml of ether. The extract was washed with 200 ml of saturated aqueous solution of ammonium chloride and 200 ml of brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure. The residue was purified using a silica gel column chromatography (eluent: 1:4 mixture of ethyl acetate and hexane) to obtain 5.60 gram of the titled compound.
Reaction SMILES: [CH3:1][N:2]1[S:11](=[O:13])(=[O:12])[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]([OH:14])=[C:3]1[C:15]([NH:17][C:18]1C=C[CH:21]=[CH:22][N:23]=1)=[O:16].CC1ON=C(NC(C2N(C)[S:41](=O)(=O)C3C=CC=CC=3C=2O)=O)C=1>>[OH:14][C:4]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[S:11](=[O:13])(=[O:12])[N:2]([CH3:1])[C:3]=1[C:15]([NH:17][C:18]1[S:41][CH:21]=[CH:22][N:23]=1)=[O:16]
Reactant: CN1C(C(=O)Nc2ccccn2)=C(O)c2ccccc2S1(=O)=O
Reactant: Cc1cc(NC(=O)C2=C(O)c3ccccc3S(=O)(=O)N2C)no1
Product: CN1C(C(=O)Nc2nccs2)=C(O)c2ccccc2S1(=O)=O

Procedure:
The oxicams may be combined with the special 1,2-diacyl-glycero-3-phosphocholines in a molar ratio of 1:1 to 1:20, preferably in a molar ratio of 1:1 to 1:10. A unit dose for the therapeutic application to humans amounts to 5-300 mg oxicam combined with 10-500 mg 1,2-diacyl-glycerol-3-phosphocholine per day, preferably 10-20 mg for piroxicam and 100-300 mg for isoxicam combined with 50-250 mg 1,1-diacyl-glycero-3-phosphocholine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]3[CH:19]=[C:18](I)[N:17]=[CH:16]3)[N:9]=2)=[CH:4][CH:3]=1.[C:21]([NH:25][S:26]([C:29]1[S:30][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:32][CH:33]=1)(=[O:28])=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([NH:25][S:26]([C:29]1[S:30][C:31]([C:18]2[N:17]=[CH:16][N:15]([C:10]3[N:11]=[C:12]([CH3:14])[CH:13]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:9]=3)[CH:19]=2)=[CH:32][CH:33]=1)(=[O:27])=[O:28])([CH3:24])([CH3:22])[CH3:23]
Reactant: Cc1cc(-c2ccc(Cl)cc2)nc(-n2cnc(I)c2)n1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Product: Cc1cc(-c2ccc(Cl)cc2)nc(-n2cnc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)c2)n1

Procedure:
N-tert-Butyl-5-{1-[6-(4-chloro-phenyl)-4-methyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-thiophene-2-sulfonamide was prepared from 4-(4-chloro-phenyl)-2-(4-iodo-imidazol-1-yl)-6-methyl-pyrimidine (example E.69) (0.40 g, 1.0 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example F.1) (0.41 g, 1.2 mmol) according to the general procedure VI. Obtained as a light brown solid (0.15 g) which was subsequently deprotected.
Reaction SMILES: [CH:1]([NH:3][NH:4][C:5]([NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:6])=O.[OH-].[K+].Cl>>[C:15]1([CH2:14][N:11]2[CH2:12][CH2:13][CH:8]([N:7]3[CH:1]=[N:3][NH:4][C:5]3=[O:6])[CH2:9][CH2:10]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=CNNC(=O)NC1CCN(Cc2ccccc2)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: O=c1[nH]ncn1C1CCN(Cc2ccccc2)CC1
Temperature: 90 °C
Yield: 94.1 %

Procedure:
2-Formyl-N-[1-(phenylmethyl)-4-piperidinyl]-hydrazinecarboxamide (Example 64(a)) (2.5 g) was divided between S x 10 mL vials. Potassium hydroxide (5 mL, 1 M solution in methanol) was added to each vial and the reactions were heated at 90° C. for 35 minutes within a microwave. The combined products were acidified to pH6 with aqueous 2M hydrochloric acid and were then evaporated to dryness. Purification (SiO2, methanol:dichloromethane:acetic acid 15:85:1 as eluant) gave the sub-title compound as an oil (2.2 g).
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.CS(C)=O.N1(CC(O)CO[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N+:34]([O-:36])=[O:35])CCOCC1>>[N+:34]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:28]=1)([O-:36])=[O:35]
Reactant: O=[N+]([O-])c1ccccc1OCC(O)CN1CCOCC1
Solvent: CS(C)=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: O=[N+]([O-])c1ccccc1
Temperature: -65 °C
Reaction time: 0.5 h

Procedure:
A five liter round bottom flask was charged with 63.8 ml (0.45 mole) of trifluoroacetic anhydride and 400 ml of MDC under nitrogen. The resulting solution was cooled to -65° C. with a dry ice bath, treated with 42.6 g (0.54 mole) of dimethylsulfoxide over a period of 15 minutes, stirred for 30 minutes, and then treated with a solution of 90 g (0.32 mole) of 2-[3-(4-morpholinyl)-2-hydroxy-1-propyloxy]nitrobenzene in 200 ml of MDC over a 35 minute period. The reaction mixture was stirred for 30 minutes, quenched with 261 ml of diisopropylethylamine, the reaction temperature allowed to rise to -10° C. and the mixture treated with one liter of diethyl ether. The pale yellow solid which separated was collected by filtration, slurried in 1.5 liters of diethyl ether and the product collected and dried to give 73.7 g of 2-3-(4-morpholinyl)-2-keto-1-propyloxy] nitrobenzene.
Reaction SMILES: [N:1]([CH2:4][C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10]2)=[O:6])=[N+]=[N-].[C:17](Cl)(=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CCN(C(C)C)C(C)C.O>CN(C=O)C.[Pd].CCOC(C)=O>[C:18]1([C:17]2[O:6][C:5]([C:7]3[CH:8]=[C:9]4[C:13](=[CH:14][CH:15]=3)[NH:12][C:11](=[O:16])[CH2:10]4)=[CH:4][N:1]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: [N-]=[N+]=NCC(=O)c1ccc2c(c1)CC(=O)N2
Reactant: O=C(Cl)c1ccccc1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1Cc2cc(-c3cnc(-c4ccccc4)o3)ccc2N1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 23 %

Procedure:
To a solution of 5-(2-azidoacetyl)indolin-2-one (0.20 g, 1.1 mmol) in DMF (5 ml) was added 10% Pd—C (0.20 g), and the mixture was stirred for 3.5 h at room temperature under H2 atmosphere. The mixture was passed through Celite. To the filtrate was added benzoyl chloride (0.12 ml, 1.1 mmol) and iPr2NEt (0.36 ml, 2.2 mmol), and the reaction mixture was stirred for 1 h at 0° C. H2O and EtOAc were added to the mixture, and insoluble solid was removed by filtration. The filtrate was separated and the organic layer was washed with H2O and brine, dried over Na2SO4 and evaporated. The residue was dissolved in sulfuric acid (2.0 ml) and the mixture was heated for 2 h at 90° C. The mixture was cooled to room temperature, and H2O was added. The mixture was extracted with EtOAc, washed with H2O and brine, dried over Na2SO4 and evaporated. Purification by column chromatography (EtOAc/hex) gave 5-(2-phenyloxazol-5-yl)indolin-2-one (0.07 g, 24%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[C:3]=1[C:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:18][CH:17]=1)=[O:15].N#N.N1C=CC=CC=1.[F:39][C:40]([F:46])([F:45])[S:41](Cl)(=[O:43])=[O:42]>C(Cl)Cl>[CH3:13][O:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[C:3]([C:14](=[O:15])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:18][CH:17]=1)=[C:2]([O:1][S:41]([C:40]([F:46])([F:45])[F:39])(=[O:43])=[O:42])[CH:11]=[CH:10]2
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(O)ccc2c1
Reactant: O=S(=O)(Cl)C(F)(F)F
Agent: N#N
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Reaction time: 0.25 h

Procedure:
Dissolve (2-hydroxy-6-methoxy-naphthalen-1-yl)-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone in CH2Cl2 (10 volumes) in a three neck round bottom flask equipped with a stir bar and N2 source and chill to 0° C. in an ice/brine bath. Add pyridine (1.3 equivalents). Add trifluoromethane sulfonyl chloride (1.2 equivalents) via syringe over 15 minutes. The yellow slurry turns clear orange with this addition. The reaction is determined to be complete by HPLC analysis after 15 minutes. Quench the reaction with H2O (10 volumes), wash with 1 N HCl (5 volumes), wash with 1.0 N NaHCO3, and dry over Na2SO4. After concentration, trifluoro-methanesulfonic acid 6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-naphthalen-2-yl ester as a clean yellow foam is obtained in quantitative yield. Use the product without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:28]C(OC(C)(C)C)=O)[C:10](=[O:27])[N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]([F:26])([F:25])[F:24])[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.Cl>CCOC(C)=O>[ClH:1].[NH2:28][C@H:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:10]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]([F:26])([F:24])[F:25])[CH2:13][CH2:12]1)=[O:27]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCC(c2ccccc2C(F)(F)F)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCC(c2ccccc2C(F)(F)F)CC1

Procedure:
The title compound was prepared according to the procedure described in Example 1 (Step e) from N-((1R)-1-[(4-chlorophenyl)methyl]-2-oxo-2-{4-[2-(trifluoromethyl)phenyl]-piperidyl}ethyl)(tert-butoxy)-carboxamide (Step d) (1.02 g, 2.0 mmol) and satd HCl in EtOAc (50 mL). The title compound was obtained as white solid (0.89 g). MS (ESI, pos. ion) m/z: 411 (M+1); MS (ESI, neg. ion) m/z: 409 (M−1). Calc'd for C21H22ClF3N2O: 410.14.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][CH2:6][N:7]1[CH2:10][CH:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH2:8]1)[CH2:3][OH:4].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([N:29]=[C:30]=[O:31])[CH:24]=[C:25]([O:27][CH3:28])[CH:26]=1>ClCCl>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([O:11][CH:9]2[CH2:10][N:7]([CH2:6][CH2:5][C@H:2]([NH:1][C:30]([NH:29][C:23]3[CH:22]=[C:21]([O:20][CH3:19])[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=3)=[O:31])[CH2:3][OH:4])[CH2:8]2)=[CH:17][CH:16]=1
Reactant: COc1cc(N=C=O)cc(OC)c1
Reactant: N[C@H](CO)CCN1CC(Oc2ccc(Cl)cc2)C1
Solvent: ClCCl
Product: COc1cc(NC(=O)N[C@H](CO)CCN2CC(Oc3ccc(Cl)cc3)C2)cc(OC)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of (S)-2-amino-4-[3-(4-chloro-phenoxy)-azetidin-1-yl]-butan-1-ol (0.2 g, 0.74 mmol) in dichloromethane (6 ml) is treated with 3,5-dimethoxy-phenyl-isocyanate (0.12 g, 0.667 mmol). The reaction mixture is stirred at ambient temperature for 24 hours and then evaporated. The crude product is purified by flash silica chromatography (elution gradient 3:97 to 7:93 methanol/dichloromethane) to afford 1-{(S)-3-[3-(4-chloro-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3-(3,5-dimethoxy-phenyl)-urea. [MH]+ 449.9.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14].C([O:17][C:18]1[CH2:23][CH2:22][CH2:21][C:20](=O)[CH:19]=1)C.Cl>CCCCCC.C(OCC)C>[CH3:14][O:13][C:8]1[CH:9]=[CH:10][C:11]([C:20]2[CH2:21][CH2:22][CH2:23][C:18](=[O:17])[CH:19]=2)=[CH:12][CH:7]=1
Reactant: CCOC1=CC(=O)CCC1
Reactant: COc1ccccc1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: COc1ccc(C2=CC(=O)CCC2)cc1
Reaction time: 2 h

Procedure:
100 ml of n-butyllithium 1.6M in hexane are added dropwise at 0° C. to a solution of 20 ml of bromoanisole in 600 ml of diethyl ether. After 2 hours, 20.2 ml of 3-ethoxy-2-cyclohexenone in 80 ml of diethyl ether are added dropwise. After 3 hours, 100 ml of 3N hydrochloric acid are added dropwise. The organic phase is separated off and concentrated, and the residue is purified over silica gel. 3-(4-Methoxyphenyl)-2-cyclohexen-1-one is obtained in the form of colourless crystals, m.p.: 83-85° C.