Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl-].[CH3:14][O:15][CH2:16][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O=[C:37]([CH2:44][CH:45]([CH3:52])[CH2:46][CH:47]([CH3:51])[CH2:48][CH2:49][CH3:50])[CH2:38][CH:39]([CH3:43])[C:40]([OH:42])=[O:41]>C1COCC1.CCCCCC>[CH3:52][CH:45]([CH2:46][CH:47]([CH3:51])[CH2:48][CH2:49][CH3:50])[CH2:44][C:37](=[CH:14][O:15][CH3:16])[CH2:38][CH:39]([CH3:43])[C:40]([OH:42])=[O:41]
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCC(C)CC(C)CC(=O)CC(C)C(=O)O
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: CCCC(C)CC(C)CC(=COC)CC(C)C(=O)O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of diisopropylamine (5.40 ml, 38.53 mmol) in 50 ml dry THF at -78° C. was mixed with 15.41 ml (38.53 mmol) of a 2.5M solution of n-butyllithium in hexane with stirring. After 15 minutes, (methoxymethyl)triphenyl-phosphonium chloride (13.87 g, 39.25 mmol, 97% purity) was slowly added. The temperature of the solution was raised to 0° C. and stirred for another 15 minutes. A solution of 4-oxo-2,6,8-trimethylundecanoic acid (10) (1.90 g, 7.85 mmol) in 20 ml of THF was then added to the reaction mixture and this mixture was stirred at room temperature for 11 hours.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([S:11](Cl)(=[O:13])=[O:12])[N:10]=[C:6]2[N:5]=[C:4]([CH3:15])[CH:3]=1.[CH2:16]([OH:18])[CH3:17].[O-]CC.[Na+]>>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([S:11]([O:18][CH2:16][CH3:17])(=[O:13])=[O:12])[N:10]=[C:6]2[N:5]=[C:4]([CH3:15])[CH:3]=1
Reactant: Cc1cc(Cl)n2nc(S(=O)(=O)Cl)nc2n1
Reactant: CCO
Agent: CC[O-]
Agent: [Na+]
Product: CCOS(=O)(=O)c1nc2nc(C)cc(Cl)n2n1

Procedure:
To a suspension of the product obtained in Step 2 (3.5 g) was dropwise added 8.6 ml of 1M sodium ethoxide ethanol solution with vigorous stirring under ice cooling over a period of ten minutes. The mixture was stirred at room temperature for one hour, and the resulting yellow solution was concentrated under reduced pressure. The remaining yellow oil was shaken with 100 ml of chloroform and 50 ml of water. The chloroform layer was separated and the aqueous layer was again extracted with 100 ml of fresh chloroform. The chloroform layers were joined and washed with 100 ml of saturated sodium chloride solution and dried over anhydrous sodium sulfate. The chloroform solution was concentrated under reduced pressure, and 20 ml of n-hexane was added to the concentrate to give 1.8 g of the objective compound as faint yellow crystals.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.Cl.[CH3:11][O:12][C:13](=[O:16])[CH2:14][NH2:15].C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O.S([O-])([O-])(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:11][O:12][C:13](=[O:16])[CH2:14][NH:15][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([Br:1])=[CH:3][CH:4]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: COC(=O)CN
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)CNCc1ccc(Br)cc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
i)—To a solution of p-bromobenzyl bromide (10 g, 40 mmol) in THF (100 ml) and water (7.2 ml) were added glycine methyl ester hydrochloride (10 g, 80 mmol), potassium carbonate (22.1 g, 160 mmol) and tetrabutylammonium sulfate (136 mg, 0.4 mmol). After 1 h stirring at 40° C., the reaction mixture was poured in water and the product was extracted into ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. Column chromatography afforded (4-bromo-benzylamino)acetic acid methyl ester (6.4 g) as a colorless oil.
Reaction SMILES: CO[C:3]([C:5]1[S:6][C:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:8][C:9]=1[NH:10][C:11]([NH:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)=[O:12])=[O:4].C[O-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[O:12]=[C:11]1[NH:10][C:9]2[CH:8]=[C:7]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[S:6][C:5]=2[C:3](=[O:4])[N:13]1[CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:21])[CH2:16][CH2:15]1
Reactant: COC(=O)c1sc(-c2ccccc2)cc1NC(=O)NC1CCN(C(=O)OC(C)(C)C)CC1
Agent: C[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3cc(-c4ccccc4)sc3c2=O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 4-({[2-(methoxycarbonyl)-5-phenyl-3-thienyl]carbamoyl}amino)piperidine-1-carboxylate (2.00 g; compound B51) in MeOH (20 ml) is added sodium methoxide (300 mg) in three portions at RT. The reaction mixture is refluxed for 3 d and then allowed to come to RT. Ice cold water (30 ml) is added and the pH is adjusted to 4 by addition of citric acid. The resulting suspension is stirred for 2 h at RT; then the precipitate is filtered off, washed with water and dried in vacuo at 50° C. The crude title compound is taken up in MeOH (25 ml) and refluxed for 3 h. The hot suspension is filtered, and the filter cake is washed with hot MeOH three times and dried in vacuo at 45° C. to afford the title compound as a solid.
Reaction SMILES: [O:1]=[C:2]([CH:4]=[C:5]([CH3:7])[CH3:6])[CH3:3].[CH:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[CH3:6][C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:7])[CH2:4][C:2](=[O:1])[CH3:3]
Reactant: c1ccccc1
Reactant: CC(=O)C=C(C)C
Product: CC(=O)CC(C)(C)c1ccccc1

Procedure:
CMP can be prepared by reacting benzene with mesityl oxide to form 4-methyl-4-phenyl-2-pentanone which is then subjected to appropriate hydrogenation.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[NH:5][C:4]([CH3:11])([CH3:10])N=1.CC(C)=[O:14]>>[CH3:10][C:4]1([CH3:11])[NH:5][C:6]([CH3:9])([CH3:8])[CH2:7][C:2](=[O:14])[CH2:1]1
Reactant: CC1=NC(C)(C)NC(C)(C)C1
Reactant: CC(C)=O
Product: CC1(C)CC(=O)CC(C)(C)N1
Temperature: 60 °C

Procedure:
5.0 g. of Acetonine was dissolved in a mixed solvent comprising 19 g. of acetone and 9.5 g. of another solvent listed below. The solution was added with a catalyst listed below and the mixture was heated at 60°C. for 10 hours in a sealed equipment to effect the reaction. After completion of the reaction, the reaction mixture was purified in the same manner as in Example 1 to obtain triacetonamine in a yield as shown hereinbelow.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:6]=[C:7]3[C:11](=[CH:12][CH:13]=2)[N:10]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]4[O:27][CH:26]=[N:25][CH:24]=4)=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:9]=[CH:8]3)[CH2:2]1.[ClH:28].FC(F)O[C:32]1[CH:37]=CC(S(N2C3C(=CC(C4CN(CCC)C4)=CC=3)C=C2)(=O)=O)=C[CH:33]=1>>[ClH:28].[O:27]1[C:23]([C:20]2[CH:19]=[CH:18][C:17]([S:14]([N:10]3[C:11]4[C:7](=[CH:6][C:5]([CH:3]5[CH2:2][N:1]([CH2:33][CH2:32][CH3:37])[CH2:4]5)=[CH:13][CH:12]=4)[CH:8]=[CH:9]3)(=[O:16])=[O:15])=[CH:22][CH:21]=2)=[CH:24][N:25]=[CH:26]1
Reactant: O=S(=O)(c1ccc(-c2cnco2)cc1)n1ccc2cc(C3CNC3)ccc21
Reactant: CCCN1CC(c2ccc3c(ccn3S(=O)(=O)c3ccc(OC(F)F)cc3)c2)C1
Agent: Cl
Product: CCCN1CC(c2ccc3c(ccn3S(=O)(=O)c3ccc(-c4cnco4)cc3)c2)C1

Procedure:
This compound was prepared from 5-azetidin-3-yl-1-(4-oxazol-5-yl-benzensulfonyl)-1H-indole by the method outlined for compound 4. ESI-MS [m/z]: 422.15 [M+H]+. 1H-NMR (500 MHz, d6-DMSO): δ=10.75 (bs, 1H), 8.55 (s, 1H), 8.1 (d, 2H), 7.9 (m, 5H), 7.7 (s, 1H), 7.4 (m, 1H), 6.85 (d, 1H), 4.4 (m, 2H), 4.25 (m, 1H), 4.1 (m, 2H), 3.15 (m, 2H), 1.55 (m, 2H), 0.95 ppm (t, 3H).
Reaction SMILES: C1(C2NN=C(NC3C(C#C)=CN=C(C4C=C(S(N)(=O)=O)C=CC=4)N=3)C=2)CC1.Br[C:29]1[N:34]=[C:33]([NH:35][C:36]2[CH:40]=[C:39]([CH:41]3[CH2:43][CH2:42]3)[NH:38][N:37]=2)[C:32]([C:44]#[C:45][Si](C)(C)C)=[CH:31][N:30]=1.[CH3:50][C:51]1[CH:59]=[CH:58][C:57](B2OC(C)(C)C(C)(C)O2)=[CH:56][C:52]=1[C:53]([NH2:55])=[O:54]>>[CH:41]1([C:39]2[NH:38][N:37]=[C:36]([NH:35][C:33]3[C:32]([C:44]#[CH:45])=[CH:31][N:30]=[C:29]([C:57]4[CH:58]=[CH:59][C:51]([CH3:50])=[C:52]([CH:56]=4)[C:53]([NH2:55])=[O:54])[N:34]=3)[CH:40]=2)[CH2:43][CH2:42]1
Reactant: C[Si](C)(C)C#Cc1cnc(Br)nc1Nc1cc(C2CC2)[nH]n1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1C(N)=O
Agent: C#Cc1cnc(-c2cccc(S(N)(=O)=O)c2)nc1Nc1cc(C2CC2)[nH]n1
Product: C#Cc1cnc(-c2ccc(C)c(C(N)=O)c2)nc1Nc1cc(C2CC2)[nH]n1

Procedure:
Using the same coupling procedure as described in Compound 110, 5-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-ethynylpyrimidin-2-yl)-2-methyl benzamide (Compound 110) (7.4 mg, 2.6%) was prepared from 2-bromo-N-(5-cyclopropyl-1H-pyrazol-3-yl)-5-((trimethylsilyl)ethynyl) pyrimidin-4-amine and 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide. LC-MS (m/z)=359.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 0.74-0.78 (m, 2H), 0.95-1.00 (m, 2H), 1.91-1.95 (m, 1H), 2.43 (s, 3H), 4.88 (s, 1H), 6.47 (s, 1H), 7.39 (d, J=8.0 Hz, 1H), 7.49 (s, 1H), 7.91 (s, 1H), 8.24 (d, J=8.0 Hz, 1H), 8.33 (d, J=1.2 Hz, 1H), 8.57 (s, 1H), 8.73 (s, 1H), 12.37 (bs, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][CH3:9])=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[CH:3]=1.[Cl:17][C:18]1[CH:19]=[C:20]([C:25]([CH3:30])([CH3:29])[C:26](Cl)=[O:27])[CH:21]=[C:22]([Cl:24])[CH:23]=1.C1(C)C=CC=CC=1>C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([N:8]([CH3:9])[C:26](=[O:27])[C:25]([C:20]2[CH:19]=[C:18]([Cl:17])[CH:23]=[C:22]([Cl:24])[CH:21]=2)([CH3:30])[CH3:29])=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[CH:3]=1
Reactant: CNc1cnc(Cl)cc1-c1ccccc1Cl
Reactant: CC(C)(C(=O)Cl)c1cc(Cl)cc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CN(C(=O)C(C)(C)c1cc(Cl)cc(Cl)c1)c1cnc(Cl)cc1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 48 h
Yield: 85.6 %

Procedure:
To a solution of 1.20 g (4.74 mmol) [6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-methyl-amine and 1.43 g (5.68 mmol) 2-(3,5-dichloro-phenyl)-2-methyl-propionyl chloride in 20 ml toluene 1.27 g (10.42 mmol) 4-dimethylaminopyridine was added and the resulting solution stirred at 120° for 48 h. After cooling to ambient temperature, the solution was poured into 100 ml 0.5 N NaHCO3-solution and extracted three times with 50 ml CH2Cl2. The combined organic layers were dried (Na2SO4), filtered and evaporated. The residue was purified by flash-chromatography (SiO2, hexanes/ethyl acetate 4:1) to give 1.90 g (85%) of the title compound as a white solid.
Reaction SMILES: N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[Cl:19][C:20]1[CH:39]=[CH:38][C:23]([NH:24][C:25]2[C:34]3[C:29](=[CH:30][C:31]([OH:37])=[C:32]([O:35][CH3:36])[CH:33]=3)[N:28]=[CH:27][N:26]=2)=[C:22]([F:40])[CH:21]=1.O[CH2:42][C:43]1[CH:48]=[CH:47][N:46]=[C:45]([C:49]([O:51][CH2:52][CH3:53])=[O:50])[CH:44]=1.C(P(CCCC)CCCC)CCC>C(Cl)Cl>[Cl:19][C:20]1[CH:39]=[CH:38][C:23]([NH:24][C:25]2[C:34]3[C:29](=[CH:30][C:31]([O:37][CH2:42][C:43]4[CH:48]=[CH:47][N:46]=[C:45]([C:49]([O:51][CH2:52][CH3:53])=[O:50])[CH:44]=4)=[C:32]([O:35][CH3:36])[CH:33]=3)[N:28]=[CH:27][N:26]=2)=[C:22]([F:40])[CH:21]=1
Reactant: CCOC(=O)c1cc(CO)ccn1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: ClCCl
Product: CCOC(=O)c1cc(COc2cc3ncnc(Nc4ccc(Cl)cc4F)c3cc2OC)ccn1
Temperature: 25 °C
Yield: 59 %

Procedure:
1,1′-(azodicarbonyl)dipiperidine (840 mg, 3 mmol) was added in portions to a mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (315 mg, 1 mmol), ethyl 4-hydroxymethyl-2-pyridinecarboxylate (250 mg, 1.4 mmol), (J. Het. Chem. 1993, 30, 631-635) and tributylphosphine (800 μl, 3 mmol) in methylene chloride (50 ml) at 0° C. The mixture was allowed to warm to ambient temperature over 2 hours, the insolubles were removed by filtration and the filtrate was washed with water and brine, dried (Na2SO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol (10:0 increasing to 9:1). The purified product was recrystallised from methylene chloride/hexane to give 4-(4-chloro-2-fluoroanilino)-7-(2-ethoxycarbonylpyrid-4-yl)methoxy-6-methoxyquinazoline (285 mg, 60%).
Reaction SMILES: FC1C=C(C[C@H](C2C([C:34]3[CH:35]=[CH:36][C:37]([F:43])=[C:38]([CH:42]=3)[C:39]([NH2:41])=[O:40])=CN=C(NCCOC)N=2)NC(=O)CN2C3CCCCC=3C(C(F)(F)F)=N2)C=C(F)C=1.Br[C:50]1[C:51]([C@@H:63]([NH:73][C:74](=[O:92])[CH2:75][N:76]2[C:84]3[C:83]([F:86])([F:85])[CH2:82][CH2:81][C:80]([F:88])([F:87])[C:79]=3[C:78]([CH:89]([F:91])[F:90])=[N:77]2)[CH2:64][C:65]2[CH:70]=[C:69]([F:71])[CH:68]=[C:67]([F:72])[CH:66]=2)=[N:52][C:53]([N:56]2[CH2:62][C:58]3([CH2:61][O:60][CH2:59]3)[CH2:57]2)=[N:54][CH:55]=1>>[F:90][CH:89]([F:91])[C:78]1[C:79]2[C:80]([F:88])([F:87])[CH2:81][CH2:82][C:83]([F:86])([F:85])[C:84]=2[N:76]([CH2:75][C:74]([NH:73][C@H:63]([C:51]2[C:50]([C:34]3[CH:35]=[CH:36][C:37]([F:43])=[C:38]([CH:42]=3)[C:39]([NH2:41])=[O:40])=[CH:55][N:54]=[C:53]([N:56]3[CH2:57][C:58]4([CH2:61][O:60][CH2:59]4)[CH2:62]3)[N:52]=2)[CH2:64][C:65]2[CH:70]=[C:69]([F:71])[CH:68]=[C:67]([F:72])[CH:66]=2)=[O:92])[N:77]=1
Reactant: O=C(Cn1nc(C(F)F)c2c1C(F)(F)CCC2(F)F)N[C@@H](Cc1cc(F)cc(F)c1)c1nc(N2CC3(COC3)C2)ncc1Br
Reactant: COCCNc1ncc(-c2ccc(F)c(C(N)=O)c2)c([C@@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)(F)F)c3c2CCCC3)n1
Product: NC(=O)c1cc(-c2cnc(N3CC4(COC4)C3)nc2[C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)CCC3(F)F)ccc1F

Procedure:
The title compound (15B) was prepared according to the method presented for the synthesis of compound 11J of Example 11 utilizing 15A. 1H NMR (400 MHz, CD3OD) δ 8.69 (d, J=8.0 Hz, 1H), 8.09 (s, 1H), 7.45-7.31 (m, 2H), 7.21 (dd, J=10.7, 8.6 Hz, 1H), 7.03-6.63 (m, 2H), 6.42 (d, J=6.1 Hz, 2H), 5.23 (dd, J=15.1, 7.6 Hz, 1H), 5.05 (s, 2H), 4.88 (s, 4H), 4.39 (q, J=9.9 Hz, 4H), 3.00 (m, 2H), 2.50 (m, 4H). MS (m/z) 754.24 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:10][NH:11][C:12](=O)[CH2:13][CH2:14][C:15]2[N:19]([CH3:20])[N:18]=[C:17]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[N:16]=2)=[N:5][C:6]([CH3:9])=[N:7][CH:8]=1)[CH3:2].CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH2:1]([C:3]1[C:4]2[N:5]([C:12]([CH2:13][CH2:14][C:15]3[N:19]([CH3:20])[N:18]=[C:17]([N:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)[N:16]=3)=[N:11][N:10]=2)[C:6]([CH3:9])=[N:7][CH:8]=1)[CH3:2]
Reactant: CCc1cnc(C)nc1NNC(=O)CCc1nc(N2CCCC2)nn1C
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1cnc(C)n2c(CCc3nc(N4CCCC4)nn3C)nnc12
Temperature: 80 °C
Yield: 128.3 %

Procedure:
N′-(5-Ethyl-2-methylpyrimidin-4-yl)-3-(1-methyl-3-(pyrrolidin-1-yl)-1H-1,2,4-triazol-5-yl)propanehydrazide (56.6 mg, 158 μmol) in tetrahydrofuran (4 ml) was added to Burgess reagent (155 mg, 632 μmol). The mixture was heated in a sealed tube at 80° C. for 1 h. Saturated sodium bicarbonate solution was added and extracted with dichloromethane. The organic layers were dried over sodium sulfate and concentrated to an oil to afford the desired product (69 mg) as a yellow solid which was used without further purification in the next step. MS: m/z=341.2 (M+H+)
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:4][C:5]([CH2:8][CH2:9][C:10]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)=O)=[N:6][CH:7]=1.O.NN.[OH-].[K+]>C(O)COCCOCCO>[CH3:1][C:2]1[C:3]([N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)=[N:6][CH:7]=1
Reactant: Cc1cnc(CCC(=O)c2cccc3ccccc23)cc1N1CCCCC1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCOCCO
Product: Cc1cnc(CCCc2cccc3ccccc23)cc1N1CCCCC1
Temperature: 185 °C

Procedure:
To a solution of 86 mg of 5-methyl-2-[3-(1-naphthyl)-3-oxopropyl]-4-piperidinopyridine in 2 ml of triethylene glycol was added 48 mg of 100% hydrazine hydrate, and the mixture was heated at 110° to 120° C. for 2 hours. Then, 68 mg of potassium hydroxide was added, and the bath temperature was raised to about 185° C. The mixture was further heated at this temperature for 5 hours. The reaction mixture was poured into ice and extracted with ether. The ether layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with chloroform) to give 5-methyl-2-[3-(1-naphthyl)propyl]-4-piperidinopyridine as an oil. The product was treated witn an ethanol solution of hydrogen chloride, and recrystallized from acetone/ether to give 28 mg (yield 28%) of the captioned compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]([N:20]3[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][C@@H:21]3[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:19])[CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][C:3]=1[NH:39][CH2:40][CH3:41].C(O)(C(F)(F)F)=O.C(Cl)Cl.C(Cl)Cl.[OH-].[Na+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][C@@H:21]3[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[O:19])[CH2:14][CH2:13]2)(=[O:9])=[O:10])=[CH:4][C:3]=1[NH:39][CH2:40][CH3:41]
Reactant: CCNc1cc(S(=O)(=O)N[C@H]2CC[C@H](C(=O)N3CCN(C(=O)OC(C)(C)C)C[C@@H]3c3ccccc3)CC2)ccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CCNc1cc(S(=O)(=O)N[C@H]2CC[C@H](C(=O)N3CCNC[C@@H]3c3ccccc3)CC2)ccc1Cl

Procedure:
(S)-tert-Butyl 4-(trans-4-(4-chloro-3-(ethylamino)phenylsulfonamido)cyclo-hexanecarbonyl)-3-phenylpiperazine-1-carboxylate (Example 1, 77 mg, 0.127 mmol) was stirred in 20% v/v TFA/DCM overnight. The reaction was dilutee with DCM and water and the pH was adjusted to 13 with 1N NaOH. The layers were separated, and the organic layer was concentrated and chromatographed on reverse phase Phenomenex Gemini Axia C18 30×100 mm column using a gradient of 15-100% AcCN in water containing 5 mM ammonium hydroxide. The product was lyophilized to yield the title compound (31.5 mg, 0.62 mmol). MS MH+ 505.4.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[CH:7]=[CH:8][C:9]([OH:11])=O)([O-:3])=[O:2].P(Cl)(OCC)(OCC)=O.C(N(CC)CC)C.[CH3:31][N:32]([CH3:43])[CH2:33][CH2:34][NH:35][C@H:36]1[CH2:41][CH2:40][C@H:39]([CH3:42])[CH2:38][CH2:37]1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:31][N:32]([CH3:43])[CH2:33][CH2:34][N:35]([C@H:36]1[CH2:37][CH2:38][C@H:39]([CH3:42])[CH2:40][CH2:41]1)[C:9](=[O:11])[CH:8]=[CH:7][C:6]1[CH:12]=[CH:13][CH:14]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: O=C(O)C=Cc1cccc([N+](=O)[O-])c1
Reactant: CN(C)CCN[C@H]1CC[C@H](C)CC1
Agent: CCOP(=O)(Cl)OCC
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)CCN(C(=O)C=Cc1cccc([N+](=O)[O-])c1)[C@H]1CC[C@H](C)CC1

Procedure:
Using 2.0 g of 3-nitrocinnamic acid, 1.9 ml of diethyl chlorophosphate, 3.5 ml of triethylamine, 60 ml of methylene chloride, 2.3 ml of N-(2-dimethylaminoethyl)-trans-4-methylcyclohexylamine (Example 78), and 0.04 g of 4-dimethylaminopyridine, a reaction similar to that conducted in Example 81 was conducted. As a result, 1.54 g of N-(2-dimethylaminoethyl)-N-(trans-4-methylcyclohexyl)-3-nitrocinnamamide (a compound of the present invention) was obtained as white crystal, which had the following physiochemical properties:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:20](=[O:24])[CH:21](O)O)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH:34]([NH2:36])[CH3:35])=[CH:29][CH:28]=1>CS(C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:20](=[O:24])[CH:21]=[N:36][CH:34]([CH3:35])[CH2:33][C:30]2[CH:31]=[CH:32][C:27]([O:26][CH3:25])=[CH:28][CH:29]=2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12)C(O)O
Reactant: COc1ccc(CC(C)N)cc1
Solvent: CS(C)=O
Product: COc1ccc(CC(C)N=CC(=O)c2ccc(OCc3ccccc3)c3[nH]c(=O)ccc23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.8 %

Procedure:
10.84 g of 8-benzyloxy-5-(dihydroxyacetyl)carbostyril 1/3 hydrate and 5.66 g of N-(2-(p-methoxyphenyl)-1-methylethyl)amine are dissolved in 100 ml of dimethylsulfoxide, and the solution is stirred at room temperature for one hour. The mixture is extracted with chloroform, and the extract is washed with water and a saturated sodium chloride solution, successively. The chloroform solution is dried and concentrated under reduced pressure to remove solvent. The residue is crystallized with a mixture of ethyl acetate and n-hexane, and crystalline precipitates are collected by filtration. 13 g of 8-benzyloxy-5-{1-oxo-2-[N-(2-(p-methoxyphenyl)-1-methylethyl)imino]ethyl}carbostyril are obtained as yellow solid. Yield: 87.6%
Reaction SMILES: [OH:1][C@H:2]([C:9]1[N:10]=[C:11]([C:14](=O)[CH3:15])[NH:12][CH:13]=1)[C@H:3]([OH:8])[C@H:4]([OH:7])[CH2:5][OH:6].[C:17]([NH:25][NH2:26])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=1>CO.O.Cl>[OH:1][C@H:2]([C:9]1[N:10]=[C:11](/[C:14](=[N:26]/[NH:25][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=2)/[CH3:15])[NH:12][CH:13]=1)[C@H:3]([OH:8])[C@H:4]([OH:7])[CH2:5][OH:6]
Reactant: NNC(=O)c1cccnc1
Reactant: CC(=O)c1nc([C@@H](O)[C@H](O)[C@H](O)CO)c[nH]1
Agent: Cl
Solvent: CO
Solvent: O
Product: C/C(=N\NC(=O)c1cccnc1)c1nc([C@@H](O)[C@H](O)[C@H](O)CO)c[nH]1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
1-[4-((1R,2S,3R)-1,2,3,4-Tetrahydroxy-butyl)-1H-imidazol-2-yl]-ethanone (215 mg, 0.93 mmol) was suspended in methanol (3 ml) and water (1 ml). Nicotinic acid hydrazide (137 mg, 1.0 mmol, 1.1 eq.) and hydrochloric acid (one drop, 12 N) were added, and the suspension was stirred at 50° C. for 48 hours. LCMS analysis indicated the formation of the product and the absence of starting material. The reaction mixture was cooled to room temperature, and partially concentrated in vacuo. The resulting white precipitate was collected and washed with water to yield the product, one apparent isomer, as a white solid: 311 mg (95%).
Reaction SMILES: C1(Cl)C(=O)C(Cl)=C(Cl)C(=O)C=1Cl.N1C2C(=CC=CC=2)CC1.[H][H].N1C2C(=CC=CC=2)C=C1.[CH3:33][O:34][C:35]1[CH:36]=[C:37]2[C:41](=[CH:42][CH:43]=1)[NH:40][CH2:39][CH2:38]2.C1(C)C=C(C)C=C(C)C=1>[Ni].[Pd].[Pt]>[CH3:33][O:34][C:35]1[CH:36]=[C:37]2[C:41](=[CH:42][CH:43]=1)[NH:40][CH:39]=[CH:38]2
Reactant: [H][H]
Reactant: COc1ccc2c(c1)CCN2
Agent: [Ni]
Agent: [Pd]
Agent: [Pt]
Solvent: Cc1cc(C)cc(C)c1
Product: COc1ccc2[nH]ccc2c1
Yield: 90 %

Procedure:
Ikan et al. [Israel J. of Chemistry, Vol. 2 (1964), p. 37-42] and Terent'ev et al. [Proc. Acad. Sci. USSR, Vol. 118 (2) (1958), p. 49-52] describe the dehydration of 5-chloro-indoline with chloranil to obtain 5-chloro-indole but due to the expense of chloranil, the process is not commercially feasible. French Pat. No. 1,576,807, DOS No. 1,770,977, Chem. Abs., Vol. 72 (1970), p. 121360n and Bader et al. [J.A.C.S., Vol. 83 (1961), p. 3319] tried to avoid this difficulty with partial success by heating indoline and its derivatives to high temperatures in the presence of palladium, platinum of Raney nickel catalysts, sometimes in the presence of a hydrogen acceptor. For example, indoline can be dehydrated at 100 to 150° C. in aromatics with a good yield of indole with hydrogen in the presence of finely divided palladium. Hunt et al. [J. Chem. Soc., (C) (1966), p. 344-345] teach reacting 5-methoxy-indoline in refluxing mesitylene in the presence of palladized carbon to obtain a 90% yield of 5-methoxy-indole.