Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:19]=[O:20])[CH:5]=[C:6]2[C:14]=1[CH:13]([CH2:15][OH:16])[C:12]1([OH:18])[O:17][N:7]2[CH2:8][CH:9]2[CH:11]1[NH:10]2.[C:21](OC(=O)C)(=[O:23])[CH3:22]>CO>[C:21]([N:10]1[CH:9]2[CH:11]1[C:12]1([OH:18])[O:17][N:7]([CH2:8]2)[C:6]2[C:14](=[C:2]([OH:1])[CH:3]=[C:4]([CH:19]=[O:20])[CH:5]=2)[CH:13]1[CH2:15][OH:16])(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: O=Cc1cc(O)c2c(c1)N1CC3NC3C(O)(O1)C2CO
Solvent: CO
Product: CC(=O)N1C2CN3OC(O)(C(CO)c4c(O)cc(C=O)cc43)C21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6,9-dihydroxy-8-hydroxymethyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-triene-4-carbaldehyde (98 mg) in methanol (3 ml) was added acetic anhydride (40 μl). The mixture was stirred for 1 hour at ambient temperature and evaporated in vacuo. The residue was subjected to preparative thin layer chromotography, which was developed with a mixture of chloroform and methanol (10:1, v/v) to afford 11-acetyl-6,9-dihydroxy-8-hydroxymethyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-triene-4-carbaldehyde (71 mg).
Reaction SMILES: COP([CH2:7][C:8](=[O:22])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])(=O)OC.C(=O)([O-])[O-].[K+].[K+].[CH3:29][C:30]1[N:35]=[CH:34][C:33]([CH:36]=O)=[CH:32][N:31]=1>C1COCC1.O>[C:18]([O:17][C:15](=[O:16])[NH:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:8](=[O:22])[CH:7]=[CH:36][C:33]1[CH:32]=[N:31][C:30]([CH3:29])=[N:35][CH:34]=1)([CH3:19])([CH3:20])[CH3:21]
Reactant: COP(=O)(CC(=O)CCCCCNC(=O)OC(C)(C)C)OC
Reactant: Cc1ncc(C=O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ncc(C=CC(=O)CCCCCNC(=O)OC(C)(C)C)cn1
Yield: 58.9 %

Procedure:
A solution of 24-2 (3.13 g, 9.28 mmol), potassium carbonate (1.75 g, 12.6 mmol), and 2-methyl-pyrimidine-5-carbaldehyde (1.04 g, 8.51 mmol) in THF (20 mL) was warmed to 40 ° C. for 5 h. The mixture was diluted with water and extracted four times with ether. The combined organics were washed with brine and dried (Na2SO4). Purification via silica chromatography (hexane/ethyl acetate) afforded the title compound 24-3 (1.67 g).
Reaction SMILES: [C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][C:4]([CH:7]([S:9]([CH2:12][C:13]([OH:15])=[O:14])(=[O:11])=[O:10])[CH3:8])=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)=O.[CH3:27]O>>[CH3:27][O:14][C:13](=[O:15])[CH2:12][S:9]([CH:7]([C:4]1[CH:3]=[CH:2][C:1]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:6][CH:5]=1)[CH3:8])(=[O:11])=[O:10]
Reactant: CO
Reactant: CC(c1ccc(-c2ccccc2)cc1)S(=O)(=O)CC(=O)O
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)CS(=O)(=O)C(C)c1ccc(-c2ccccc2)cc1
Temperature: 35 °C
Reaction time: 8 h

Procedure:
17.0 gm (56 millimols) of [1-(4-biphenylyl)-ethyl-sulfonyl]-acetic acid were dissolved in 100 ml of methanol, and 3 ml of phosphorus oxychloride were added to the solution while cooling on ice. The mixture was heated to 35° C and was then allowed to stand overnight at room temperature. The crystalline reacton product which had separated out was suction-filtered off and recrystallized from 50 ml of isopropanol. Yield: 14.8 gm (83% of theory); m.p. 79°-80° C.
Reaction SMILES: [CH2:1](/[C:3](=[CH:9]\[CH:10]=[CH:11]\[CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19]/[CH:20]=[CH:21]\[CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH3:26])/[C:4]([O:6]CC)=[O:5])[CH3:2].[Li+].[OH-].Cl>C(O)C.O>[CH2:1](/[C:3](=[CH:9]\[CH:10]=[CH:11]\[CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19]/[CH:20]=[CH:21]\[CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH3:26])/[C:4]([OH:6])=[O:5])[CH3:2]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\CC/C=C/C=C(\CC)C(=O)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC/C=C\C/C=C\C/C=C\C/C=C\CC/C=C/C=C(\CC)C(=O)O
Temperature: 25 °C
Reaction time: 15 h
Yield: 76.1 %

Procedure:
Ethyl-(2E,4E,8Z,11Z,14Z,17Z)-2-ethyl-eicosa-2,4,8,11,14,17-hexaneoate (17) (0.040 g, 0.112 mmol) was dissolved in ethanol (4 mL) and added a solution of LiOH×H2O (0.038 g, 0.898 mmol) in water (1 mL). The mixture was stirred at ambient temperature for 15 hours, followed by five hours at 70° C. The mixture was cooled, added 1M HCl until pH=1 and diluted with water (2 mL). The mixture was extracted twice with heptane (10 mL) and the combined organic extracts were dried (Na2SO4). Purification by flash chromatography (heptane:EtOAc 95:5 then 4:1) afforded 0.028 g (76%) of the title compound as a pale yellow oil. 1H-NMR (200 MHz, CDCl3): δ 0.90-1.07 (2×t, 6H), 2.00-2.10 (m, 2H), 2.20-2.30 (m, 4H), 2.35-2.50 (q, 2H), 2.75-2.90 (m, 6H), 5.27-5.44 (m, 8H), 6.05-6.20 (m, 1H), 6.30-6.43 (m, 1H), 7.50-7.70 (m, 1H); MS (electrospray): 327.2 [M−H]−.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)[Cl:2].[O:6]([C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CC(O)C>[O:6]([C:13]1[CH:14]=[CH:15][C:16]([N:17]([CH2:4][CH:3]([OH:5])[CH2:1][Cl:2])[CH2:4][CH:3]([OH:5])[CH2:1][Cl:2])=[CH:18][CH:19]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: Nc1ccc(Oc2ccccc2)cc1
Reactant: ClCC1CO1
Solvent: CC(C)O
Product: OC(CCl)CN(CC(O)CCl)c1ccc(Oc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
To a four-necked flask equipped with a thermometer, a cooling tube, and a stirrer were charged with 610.6 g (6.6 mol) of epichlorohydrin and 509.3 g of 2-propanol, and then the inside of the four-necked flask was purged with nitrogen. The temperature was raised to 60° C. and 203.7 g (1.1 mol) of a powder of 4-phenoxyaniline was added over three hours. Moreover, the temperature was raised to 80° C. and the reaction was continued at 80° C. for 18 hours under stirring to produce 4-phenoxy-N,N-bis(2-hydroxy-3-chloropropyl)aniline.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([Cl:11])[CH:3]=1>C(O)(=O)C.[Zn]>[Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([Cl:11])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Cl)cc(Br)c1
Agent: [Zn]
Solvent: CC(=O)O
Product: Nc1cc(Cl)cc(Br)c1
Yield: 99.6 %

Procedure:
1-bromo-3-chloro-5-nitrobenzene (4.27 g, 18.0 mmol) was dissolved in acetic acid (24.1 mL μl, 18.0 mmol) then zinc dust (11.82 g, 180 mmol) was added. After 4 h the reaction was filtered and concentrated to afford 3-bromo-5-chlorobenzenamine (3.7 g, 99% yield).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])=O.[CH2:13]([OH:16])[CH2:14][OH:15].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[O:15]1[CH2:14][CH2:13][O:16][CH:1]1[C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cccc(C=O)c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(C2OCCO2)c1

Procedure:
A stirred solution of methyl 3-formylbenzoate (10.0 g., 61 mmol), ethylene glycol (5.0 ml, 91 mmol) and p-toluene sulphonic acid (10 mb) in toluene (100 ml) was refluxed under a Dean and Stark water trap for 4 hours. The cooled solution was washed with sodium bicarbonate solution, dried and evaporated to a pale oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Si:20]([O:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]O)([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(C=P(CCCC)(CCCC)CCCC)#N.C(OCC)(=O)C>C1(C)C=CC=CC=1>[Si:20]([O:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH:11]([C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[F:19])[S:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])([C:33]([CH3:34])([CH3:35])[CH3:36])([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)[Si](OCCCCCCO)(c1ccccc1)c1ccccc1
Reactant: O=S(=O)(Cc1cc(F)ccc1F)c1ccc(Cl)cc1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](OCCCCCCC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1)(c1ccccc1)c1ccccc1
Yield: 79.4 %

Procedure:
The 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (470 mg, 1.55 mmol) obtained in Example 5 and 6-(t-butyldiphenylsilyloxy)-1-hexanol (740 mg, 2.08 mmol) were dissolved in toluene (20 ml), followed by the addition of cyanomethylenetri-n-butylphosphorane (500 mg, 2.07 mmol). Under an argon atmosphere, the resulting mixture was heated under reflux for 7 hours. After the reaction mixture was allowed to cool down, the residue obtained by concentrating the reaction mixture under reduced pressure was subjected to flash silica gel chromatography. The fraction obtained from the hexane:ethyl acetate=10:1 eluate was concentrated under reduced pressure, whereby the title compound (786 mg, 1.23 mmol, 79%) was obtained as a pale yellowish brown oil.
Reaction SMILES: CN(C)C=O.S(Cl)(Cl)=O.[N+:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][C:20](=[O:24])[C:21]([OH:23])=[O:22])([O-:12])=[O:11]>>[OH:24][CH:20]([CH2:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[N+:10]([O-:12])=[O:11])[C:21]([OH:23])=[O:22]
Reactant: O=C(O)C(=O)Cc1ccccc1[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: O=C(O)C(O)Cc1ccccc1[N+](=O)[O-]
Yield: 95 %

Procedure:
To magnetically stirred N,N-dimethylformamide (23 ml., 297.3 mmol) cooled in ice was slowly added dropwise thionyl chloride (139 ml., ca. 1.91 mol). A solution of (+)-α-hydroxy-2-nitrobenzenepropanoic acid [11.60 g., 54.9 mmol, [α]D25 +49.94° (c, 2.465, 95% EtOH)], obtained from the chiral reduction of 2-nitro-α-oxobenzenepropanoic acid described in Example 1, in dichloromethane (133 ml.) was then added dropwise to the cold Vilsmeier reagent. The ice bath was removed and the solution, protected from moisture, was left at room temperature (25° C.) for 18 hours. The resulting yellow solution was evaporated to syrup. The syrup was dissolved in dichloromethane and the solution was poured cautiously onto stirred ice. The mixture was stirred for one hour during which time it warmed to room temperature. The organic phase was separated, washed (×3) with water and dried (MgSO4). Evaporation gave a syrup which was subjected to an oil pump vacuum for 0.5 hour. The syrup was dissolved in ether and 2,6-dimethylpiperidine was added to approximate neutrality (ca. pH 8 by pH paper). The crude titled compound (12.40 g., 66%) crystallized readily, m.p. 148°-153° C. Three crystallizations (with decolorization) from methanol-ether gave 6.01 g. (32% of pure product, m.p. 164°-167° C. dec., [α]D25 -41.49° (c 1.005, 95% EtOH).
Reaction SMILES: Cl[CH2:2][CH:3]([OH:32])[CH2:4][NH:5][C@H:6]1[C:14]2[C:9](=[C:10]([C:15]3[N:19]=[C:18]([C:20]4[CH:21]=[CH:22][C:23]([O:28][CH:29]([CH3:31])[CH3:30])=[C:24]([CH:27]=4)[C:25]#[N:26])[O:17][N:16]=3)[CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7]1>CC#N>[OH:32][CH:3]1[CH2:4][N:5]([C@H:6]2[C:14]3[C:9](=[C:10]([C:15]4[N:19]=[C:18]([C:20]5[CH:21]=[CH:22][C:23]([O:28][CH:29]([CH3:31])[CH3:30])=[C:24]([CH:27]=5)[C:25]#[N:26])[O:17][N:16]=4)[CH:11]=[CH:12][CH:13]=3)[CH2:8][CH2:7]2)[CH2:2]1
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@H]4NCC(O)CCl)no2)cc1C#N
Solvent: CC#N
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@H]4N3CC(O)C3)no2)cc1C#N
Temperature: 75 °C
Yield: 27 %

Procedure:
To a flask containing 5-(3-((1R)-1-(3-chloro-2-hydroxypropylamino)-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile INT-15 (77.0 mg, 0.17 mmol) in CH3CN (4 mL) was added TEA (44.5 μL, 0.32 mmol). The reaction mixture was heated at 75° C. overnight then concentrated in vacuo, dissolved in DCM and purified by chromatography (MeOH/DCM) to provide 19 mg (27%) of (R)-5-(3-(1-(3-hydroxyazetidin-1-yl)-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile 83 as a white solid. LCMS-ESI (m/z) calculated for C24H24N4O3: 416.5; found 417.1 [M+H]+, tR=6.19 min (Method 2). 1H NMR (400 MHz, CDCl3) δ 8.42 (d, J=2.2 Hz, 1H), 8.33 (dd, J=8.9, 2.2 Hz, 1H), 8.09 (dd, J=7.7, 0.7 Hz, 1H), 7.44 (d, J=7.4 Hz, 1H), 7.35 (t, J=7.6 Hz, 1H), 7.11 (d, J=9.0 Hz, 1H), 4.79 (dt, J=12.2, 6.1 Hz, 1H), 4.46 (p, J=5.8 Hz, 1H), 3.99 (dd, J=7.0, 3.5 Hz, 1H), 3.70 (dt, J=19.2, 5.6 Hz, 2H), 3.47 (d, J=6.7 Hz, 1H), 3.41 (dd, J=16.6, 8.7 Hz, 1H), 3.28 (ddd, J=17.5, 8.8, 4.2 Hz, 1H), 3.20-3.13 (m, 1H), 3.13-3.05 (m, 1H), 2.13 (dddd, J=16.9, 12.6, 8.4, 5.5 Hz, 2H), 1.47 (d, J=6.1 Hz, 6H). (S)-5-(3-(1-(3-hydroxyazetidin-1-yl)-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile 84 was prepared in an analogous fashion from (S)-5-(3-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile 50.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][OH:12])=[CH:6][CH:5]=1)[NH2:3].[F:13][C:14]([F:27])([F:26])[C:15](=O)[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)=O>>[N:22]1[CH:23]=[CH:24][C:19]([C:17]2[N:2]([C:4]3[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][OH:12])=[CH:8][CH:9]=3)[N:3]=[C:15]([C:14]([F:13])([F:26])[F:27])[CH:16]=2)=[CH:20][CH:21]=1
Reactant: NNc1ccc(CCO)cc1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccncc1
Agent: Cl
Product: OCCc1ccc(-n2nc(C(F)(F)F)cc2-c2ccncc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 1 from 2-(4-hydrazinophenyl)ethanol hydrochloride and 4,4,4-trifluoro-1-pyridin-4-ylbutane-1,3-dione: MS (ESI) m/z 334 [M+H]+, 1H-NMR (CDCl3) δ 8.60-8.58 (2H, m), 7.28-7.24 (4H, m), 7.14-7.12 (2H, m), 6.88 (1H, s), 3.90-3.86 (2H, m), 2.92 (2H, t, J=6.6 Hz), 1.52 (1H, br.s).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:33]=[CH:32][C:31]([C:34]([O:36]C)=[O:35])=[CH:30][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][CH:19]=[C:20]([O:21][CH2:22][CH2:23][N:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)[C:14]=2[O:13][CH2:12][CH2:11]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[ClH:40]>O1CCCC1.CO>[ClH:40].[CH:1]1([C:7]2[C:8]3[CH:33]=[CH:32][C:31]([C:34]([OH:36])=[O:35])=[CH:30][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][CH:19]=[C:20]([O:21][CH2:22][CH2:23][N:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)[C:14]=2[O:13][CH2:12][CH2:11]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCOc1c(OCCN2CCCCC2)cccc1-3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCOc1c(OCCN2CCCCC2)cccc1-3
Temperature: 60 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
To a solution of methyl 12-cyclohexyl-4-[2-(piperidin-1-yl)ethoxy]-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylate (240 mg, 0.48 mmol) in tetrahydrofuran (4 ml) and methanol (4 ml) was added 4N aqueous sodium hydroxide (2.5 ml), and the mixture was stirred at 60° C. for 2 hr. 2N Hydrochloric acid (5.1 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate:tetrahydrofuran (2:1). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. To a solution of the obtained residue in tetrahydrofuran (1 ml) was added 4N HCl-ethyl acetate solution (2 ml). The solvent was evaporated under reduced pressure, and hexane:ethyl acetate (4:1) solution was added to the obtained residue. The precipitated solid was collected by filtration and washed with hexane:ethyl acetate (4:1) solution. The obtained solid was dried in vacuo to give 12-cyclohexyl-4-[2-(piperidin-1-yl)ethoxy]-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylic acid hydrochloride (160 mg, yield 64%).
Reaction SMILES: Cl[C:2](=[CH2:26])[CH2:3][N:4]([CH2:17][CH:18](O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[S:5]([C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)(=[O:7])=[O:6].[OH:27]S(O)(=O)=O>C(Cl)Cl.O>[N+:14]([C:11]1[CH:10]=[CH:9][C:8]([S:5]([N:4]2[CH2:17][CH:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:26][C:2](=[O:27])[CH2:3]2)(=[O:7])=[O:6])=[CH:13][CH:12]=1)([O-:16])=[O:15]
Reactant: O=S(=O)(O)O
Reactant: C=C(Cl)CN(CC(O)c1ccccc1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: O
Product: O=C1CC(c2ccccc2)CN(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)C1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
N-(2-chloroprop-2-enyl)-N-(2-hydroxy-2-phenylethyl)-4-nitrobenzenesulfonamide (1-3, 6.6 g, 16.6 mmol) was dissolved in 40 mL CH2Cl2 and cooled to −78° C. The resulting solution was treated dropwise with conc. H2SO4 (20 mL) and H2O (2 mL). The reaction was placed in a 0° C. bath and stirred 1 h to completion. The reaction was diluted carefully with CH2Cl2 (200 mL) and H2O (400 mL) and the organic layer was separated, dried (MgSO4) and filtered. Concentration of the organic layer followed by flash column chromatography (SiO2, 0-100% EtOAc-hexanes graident over 40 min) provided 1-[(4-nitrophenyl)sulfonyl]-5-phenylpiperidin-3-one (1-4) as a pale yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.39 (d, J=8.8 Hz, 2H), 7.94 (d, J=8.8 Hz, 2H), 7.34 (m, 3H), 7.16 (m, 2H), 4.13 (d, J=15.9 Hz, 1H), 3.98 (m, 1H), 3.42 (d, J=15.9 Hz, 1H), 3.36 (m, 1H), 3.00 (dd, J=12.2, 10.4 Hz, 1H), 2.80 (m, 1H), 2.61 (dd, J=16.2, 11.3 Hz, 1H); MS 361.1 found 361.4 (M+H+) required (ionizes poorly).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([CH3:9])[N:3]=1.[CH3:10][C:11]1[S:15][C:14]([CH2:16][NH2:17])=[N:13][N:12]=1>>[Cl:8][C:6]1[N:5]=[C:4]([CH3:9])[N:3]=[C:2]([NH:17][CH2:16][C:14]2[S:15][C:11]([CH3:10])=[N:12][N:13]=2)[CH:7]=1
Reactant: Cc1nc(Cl)cc(Cl)n1
Reactant: Cc1nnc(CN)s1
Product: Cc1nc(Cl)cc(NCc2nnc(C)s2)n1

Procedure:
The title compound was prepared from 4,6-dichloro-2-methylpyrimidine and (5-methyl-1,3,4-thiadiazol-2-yl)methanamine according to the protocol outlined in Example 1, to afford 8-1 as a solid. LRMS (ES) (M+H)+: observed=256.1, calculated=256.7.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N:11]1[C:19]2[C:14](=[C:15]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:16]=[C:17]([CH3:20])[N:18]=2)[C:13](C#N)=[CH:12]1.[OH-].[NH4+]>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N:11]1[C:19]2[C:14](=[C:15]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:16]=[C:17]([CH3:20])[N:18]=2)[CH:13]=[CH:12]1
Reactant: Cc1cc(-c2ccccc2)c2c(C#N)cn(-c3ccc(C(C)C)cc3Br)c2n1
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: Cc1cc(-c2ccccc2)c2ccn(-c3ccc(C(C)C)cc3Br)c2n1
Yield: 91.5 %

Procedure:
A mixture of 130 mg (0.302 mmole) of 1-(2-bromo-4-isopropylphenyl)-3-cyano-6-methyl-4-phenyl-7-azaindole (Example 66) and 10 mL of 65% sulfuric acid were refluxed for one hour. The mixture was poured onto ice. Conc. ammonium hydroxide was added until the mixture was basic to pH paper. The mixture was extracted with ethyl acetate. The extract was evaporated and chromatographed on silica gel with 70:30 hexane-ethyl acetate. There was obtained 112 mg (92% yield) of 1-(2-bromo-4-isopropylphenyl)-6-methyl-4-phenyl-7-azaindole. Mass spec: (M+H)+ =4.05.10; calculated, 405.10.
Reaction SMILES: [Cl:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[O-:12][CH2:13][CH3:14].[Na+]>C(O)C.O1CCOCC1>[Cl:1][C:2]1[N:6]2[N:7]=[C:8]([O:12][CH2:13][CH3:14])[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1
Reactant: CC[O-]
Reactant: Clc1ccc2nnc(Cl)n2n1
Agent: [Na+]
Solvent: CCO
Solvent: C1COCCO1
Product: CCOc1ccc2nnc(Cl)n2n1

Procedure:
The 3-chloro-6-ethoxy[1,2,4]triazolo[4,3-b]pyridazine was prepared according to the method described in Example 16b, but using 1 g of commercial 3,6-dichloro[1,2,4]triazolo[4,3-b]pyridazine, 1.71 g of a solution at 21% of sodium ethoxide in ethanol and 30 cm3 of dioxane, after reaction at reflux for 5.5 h. 874 mg of 3-chloro-6-ethoxy[1,2,4]triazolo[4,3-b]pyridazine are thus obtained in the form of a whitish powder, the characteristics are as follows:
Reaction SMILES: [CH3:1][N:2]([CH2:18][C:19]([OH:21])=O)[NH:3][C:4](=[O:17])[NH:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1.[NH2:22][C@@H:23]([CH2:46][C:47]([NH:49][C:50]([C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)=[O:48])[C:24]([N:26]([CH2:36][C:37]1[C:38]2[CH:45]=[CH:44][CH:43]=[CH:42][C:39]=2[S:40][CH:41]=1)[C@@H:27]([CH3:35])[CH:28]([O:32][CH2:33][CH3:34])[O:29][CH2:30][CH3:31])=[O:25]>>[S:40]1[CH:41]=[C:37]([CH2:36][N:26]([C@@H:27]([CH3:35])[CH:28]([O:29][CH2:30][CH3:31])[O:32][CH2:33][CH3:34])[C:24](=[O:25])[C@@H:23]([NH:22][C:19](=[O:21])[CH2:18][N:2]([CH3:1])[NH:3][C:4]([NH:5][CH2:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][CH:8]=2)=[O:17])[CH2:46][C:47](=[O:48])[NH:49][C:50]([C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=2)[C:38]2[CH:45]=[CH:44][CH:43]=[CH:42][C:39]1=2
Reactant: CN(CC(=O)O)NC(=O)NCc1cccc2ccccc12
Reactant: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@@H](N)CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)CN(C)NC(=O)NCc1cccc2ccccc12

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(1-methyl-2-(naphthalen-1-ylmethylcarbamoyl)hydrazinyl)acetic acid (Compound VI-8) 66 mg (0.23 mmol) was coupled with (S)-2-amino-N1-(benzo[b]thiophen-3-ylmethyl)-N1—((S)-1,1-diethoxypropan-2-yl)-N4-tritylsuccinamide (Compound IV-21) 100 mg (0.15 mmol) to obtain the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9]Cl)=[CH:5][CH:4]=1.[P:11]([O:18][CH2:19][CH3:20])([O:15][CH2:16][CH3:17])[O:12]CC>>[C:6]1([CH2:9][P:11](=[O:12])([O:15][CH2:16][CH3:17])[O:18][CH2:19][CH3:20])[CH:7]=[CH:8][C:3]([CH2:2][P:11](=[O:12])([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17])=[CH:4][CH:5]=1
Reactant: ClCc1ccc(CCl)cc1
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(Cc1ccc(CP(=O)(OCC)OCC)cc1)OCC
Temperature: 180 °C

Procedure:
A mixture of α,α′-dichloro-p-xylene (20 g, 0.114 mol) and triethyl phosphite (60 ml) was refluxed at 180° C. overnight. 80 ml of hexanes was added, and white crystals were formed immediately. Then the mixture was cooled at 0° C., and the product was collected, washed three times with 40 ml of hexanes and isolated in 94.4% (40.8 g) yield.