Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N.[OH:2]O.[C:4]([C:6]1[C:7]([CH3:36])=[C:8]([C:12]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]3[C:13]=2[CH2:14][CH2:15][C@H:16]3[O:22][C:23]2[CH:35]=[CH:34][C:26]3[C@H:27]([CH2:30][C:31]([OH:33])=[O:32])[CH2:28][O:29][C:25]=3[CH:24]=2)[CH:9]=[CH:10][CH:11]=1)#[N:5]>C(O)C>[C:4]([C:6]1[C:7]([CH3:36])=[C:8]([C:12]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]3[C:13]=2[CH2:14][CH2:15][C@H:16]3[O:22][C:23]2[CH:35]=[CH:34][C:26]3[C@H:27]([CH2:30][C:31]([OH:33])=[O:32])[CH2:28][O:29][C:25]=3[CH:24]=2)[CH:9]=[CH:10][CH:11]=1)(=[O:2])[NH2:5]
Reactant: OO
Reactant: Cc1c(C#N)cccc1-c1ccc(F)c2c1CC[C@H]2Oc1ccc2c(c1)OC[C@H]2CC(=O)O
Agent: N
Solvent: CCO
Product: Cc1c(C(N)=O)cccc1-c1ccc(F)c2c1CC[C@H]2Oc1ccc2c(c1)OC[C@H]2CC(=O)O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
30% Aqueous NH3 solution (4.2 mL) and 35% aqueous H2O2 solution (1.4 ml) are added at 0° C. to a solution of 2-((3S)-6-((1R)-4-(3-cyano-2-methylphenyl)-7-fluoro-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetic acid (30 mg) in ethanol (5 mL). The mixture is stirred at room temperature for 12 hours, while warming to room temperature. The mixture is concentrated, diluted with water and neutralized with 4 M aqueous HCl solution. The resulting mixture is extracted with dichloromethane. The organic phase is dried (MgSO4). The solvent is evaporated to give the title compound. Yield: 29 mg; LC (method 20): tR=5.02 min; Mass spectrum (ESI+): m/z=462 [M+H]+.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:8][CH:7]=[CH:6][C@@H:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:4]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:3]1=[O:20].[F:21][C:22]1[CH:23]=[C:24]([CH2:29][C:30]([NH:32][C@H:33]([C:35](O)=[O:36])[CH3:34])=[O:31])[CH:25]=[C:26]([F:28])[CH:27]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CN1CCOCC1>C(Cl)Cl>[CH:15]1([N:4]2[C@H:5]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:6]=[CH:7][CH2:8][C@@H:2]([NH:1][C:35](=[O:36])[C@H:33]([CH3:34])[NH:32][C:30](=[O:31])[CH2:29][C:24]3[CH:25]=[C:26]([F:28])[CH:27]=[C:22]([F:21])[CH:23]=3)[C:3]2=[O:20])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: N[C@@H]1CC=C[C@@H](c2ccccc2)N(C2CCCC2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)N[C@@H]1CC=C[C@@H](c2ccccc2)N(C2CCCC2)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (3R,7S)-3-amino-1-cyclopentyl-7-phenyl-1,3,4,7-tetrahydro-2H-azepin-2-one (8f) (65 mg) in DCM (4 ml) at RT under N2 was added N-[(3,5-difluorophenyl)acetyl]-L-alanine (59 mg), HOBt (65 mg), EDAC.HCl (69 mg), and N-methylmorpholine (24 mg). The reaction was stirred at RT overnight, then diluted with DCM (10 ml) and washed with 1N HCl, 1N K2CO3, dried (Na2SO4), filtered and evaporated. The crude product was purified by flash chromatography (2% MeOH/DCM) to afford the title compound as an off white solid (60 mg, 50%). 1H NMR (300 MHz, CDCl3) δ 1.28 (d, 3H, J=7 Hz), 1.37-1.70 (m, 6H), 1.94-2.16 (m, 3H), 2.50-2.60 (m, 1H), 3.48 (s, 2H), 4.36-4.55 (m, 2H), 4.96 (d, 1H, J=8 Hz), 5.20 (tt, 1H, J=9 Hz, J=9 Hz), 5.87-5.94 (m, 1H), 6.18-6.33 (m, 2H), 6.67-6.80 (m, 3H), 7.00 (d, 1H, J=6 Hz), 7.25-7.38 (m, 5H). MS APCI, m/z=496 (M+1), LC/MS, 2.54 min.
Reaction SMILES: O=S(Cl)Cl.[CH3:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:11][CH:10]=1)(=[O:8])=[O:7].[CH3:19][CH2:20]O>>[CH3:5][S:6]([C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:13][CH:14]=1)(=[O:7])=[O:8]
Reactant: CS(=O)(=O)c1ccc(CC(=O)O)cc1
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)Cc1ccc(S(C)(=O)=O)cc1
Temperature: 20 °C

Procedure:
SOCl2 (8.2 mL, 112.0 mmol) was added to a stirred suspension of (4-methanesulfonylphenyl)acetic acid (20.00 g, 93.3 mmol) in EtOH (80 mL) at −10° C. The mixture was allowed to warm up to 20° C. over 16 h, then the solvents were removed under reduced pressure. The remainder was dissolved in EtOAc, then the resulting solution was washed with H2O until the pH of the aqueous phase was neutral. The EtOAc solution was washed further with saturated aqueous Na2CO3, before being dried (MgSO4). Filtration and solvent evaporation furnished the title compound: m/z (ES+)=284.1 [M+MeCN+H]+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH:21][C:22](=[O:37])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]2[CH:35]=[N:34][N:33]=[N:32]2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:20][C:17]1[CH:16]=[CH:15][C:14]([C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:24]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([N:31]5[CH:35]=[N:34][N:33]=[N:32]5)[CH:26]=4)[CH2:23][C:22](=[O:37])[NH:21][C:9]=3[CH:10]=2)=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1NC(=O)CC(=O)c1cccc(-n2cnnn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-n3cnnn3)c2)=Nc2ccc(-c3ccc(F)cc3)cc2N1

Procedure:
Prepared from {4′-fluoro-3-[3-oxo-3-(3-tetrazol-1-yl-phenyl)-propionylamino]-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example K56) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow solid (54 mg).
Reaction SMILES: N1C2C(=CC=CC=2)C=NC=1.[Cl:11][C:12]1[CH:13]=[C:14]([C:16]([F:20])=[CH:17][C:18]=1[Cl:19])[NH2:15].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([F:35])=[C:29]([N+:32]([O-:34])=[O:33])[CH:30]=2)[N:25]=[CH:24][N:23]=1>>[Cl:11][C:12]1[CH:13]=[C:14]([NH:15][C:22]2[C:31]3[C:26](=[CH:27][C:28]([F:35])=[C:29]([N+:32]([O-:34])=[O:33])[CH:30]=3)[N:25]=[CH:24][N:23]=2)[C:16]([F:20])=[CH:17][C:18]=1[Cl:19]
Reactant: Nc1cc(Cl)c(Cl)cc1F
Reactant: O=[N+]([O-])c1cc2c(Cl)ncnc2cc1F
Agent: c1ccc2ncncc2c1
Product: O=[N+]([O-])c1cc2c(Nc3cc(Cl)c(Cl)cc3F)ncnc2cc1F

Procedure:
In another particular, which includes a quinazoline that is substituted by two different reactive groups at positions 6 and 7 thereof, 3,4-dichloro-6-fluoroaniline is reacted with 4-chloro-7-fluoro-6-nitroquinazoline, so as to produce 4-[(3,4-dichloro-6-fluorophenyl)amino]-7-fluoro-6-nitroquinazoline. The 4-[(3,4-dichloro-6-fluorophenyl)amino]-7-fluoro-6-nitroquinazoline is then reacted with a sodium salt of 3-(4-morpholinyl-1-propanol), so as to produce 4-[(3,4-dichloro-6-fluoro-phenyl)amino]-7-[3-(4-morpholinyl)propoxy]-6-nitroquinazoline, which is reduced, by means of an ethanolic solution of hydrazine hydrate and Raney®Nickel, so as to produce 6-amino-4-[(3,4-dichloro-6-fluorophenyl)amino]-7-[3-(4-morpholinyl)propoxy]quinazoline. The product is then reacted with a carbon-11 labeled acryloyl chloride so as to produce a carbon-11 labeled N-{4-[(3,4-dichloro-6-fluorophenyl)amino]-7-[3-(4-morpholinyl)propoxy]quinazoline-6-yl}acrylamide (carbon-11 labeled morpholino-substituted Compound 3).
Reaction SMILES: O[CH:2]([C:18]1[N:19]=[CH:20][NH:21][CH:22]=1)[CH2:3][CH2:4][CH:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.S([O-])(O)(=O)=O.[K+].[OH-].[Na+]>C(O)C>[C:12]1([CH:5]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:4][CH:3]=[CH:2][C:18]2[N:19]=[CH:20][NH:21][CH:22]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: OC(CCC(c1ccccc1)c1ccccc1)c1c[nH]cn1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Product: C(=Cc1c[nH]cn1)CC(c1ccccc1)c1ccccc1

Procedure:
4-(1-hydroxy-4,4-diphenylbutyl)-1H-imidazole (3,0 g) and 20 g of anhydrous potassium hydrogen sulfate are heated at 150° C. for 4 hours. The mixture is cooled and 90 ml ethanol is added to dissolve the product. The mixture is made alkaline with sodium hydroxide. The product is extracted into methylene chloride, washed with water and evaporated to dryness. The product is then made to hydrochloride salt with dry hydrogen chloride in ethyl acetate. M.p. above 240° C.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[N:8]=[C:7]2[CH:9]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:11][C:6]2=[CH:5][CH:4]=1.[N:19]1[CH:24]=[CH:23][C:22]([CH2:25]O)=[CH:21][CH:20]=1>>[N:19]1[CH:24]=[CH:23][C:22]([CH2:25][N:11]2[C:6]3[C:7](=[N:8][C:3]([C:2]([F:1])([F:17])[F:18])=[CH:4][CH:5]=3)[CH:9]=[C:10]2[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:21][CH:20]=1
Reactant: OCc1ccncc1
Reactant: CCOC(=O)c1cc2nc(C(F)(F)F)ccc2[nH]1
Product: CCOC(=O)c1cc2nc(C(F)(F)F)ccc2n1Cc1ccncc1
Yield: 65.3 %

Procedure:
According to a process similar to that described in Example 24.1, using 5 g (18.4 mmol) of ethyl 5-tri-fluoromethyl-1H-pyrrolo[3,2-b]pyridine-2-carboxylate (Example 23.3) and 3.04 g (27.6 mmol) of (pyridin-4-yl)methanol, 4.2 g of the expected compound are isolated.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[CH:11][C:10]([CH2:23][CH2:24][NH2:25])=[C:9]2[CH3:26])=[CH:4][CH:3]=1.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:15][CH:14]=3)=[CH:11][C:10]([CH2:23][CH2:24][NH:25][C:27](=[O:34])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[C:9]2[CH3:26])=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1c(CCN)cc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(F)cc1
Solvent: CN(C)C=O
Product: Cc1c(CCNC(=O)c2ccccc2)cc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(F)cc1
Reaction time: 0.17 h
Yield: 70 %

Procedure:
To a solution of 2-(1-(4-fluorophenyl)-2-methyl-5-(4-(methylsulphonyl)phenyl)-1H-pyrrol-3-yl)ethanamine (0.20 mmol) in dry DMF (10 mL) cooled at 0° C. and under an atmosphere of N2, TEA (0.20 mmol) was added and the mixture was stirred for 10 min. Then benzoyl chloride (0.20 mmol) was added at 0° C., and the reaction was stirred for 24 h at r.t.; the reaction mixture was washed with water, dried over Na2SO4 and evaporated to dryness in vacuo. The residue, purified by flash-chromatography (EtOAc/hexane 7:3 v/v), gave the expected compound as yellow oil (yield 70%). 1H-NMR (CDCl3) δ ppm: 2.03 (s, 3H), 2.80 (t, 2H, J=7.1), 2.97 (s, 3H), 3.67 (m, 2H), 6.43-6.48 (m, 2H), 7.10 (m, 6H), 7.34-7.46 (m, 3H), 7.64 (m, 2H), 7.75 (m, 2H).
Reaction SMILES: Br.[Br:2][C:3]1[CH:4]=[C:5]([CH2:10]Br)[C:6]([NH2:9])=[N:7][CH:8]=1.[CH2:12]([O:14][C:15](=[O:27])[CH2:16][NH:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[CH3:13].C(N(CC)CC)C>CN(C=O)C.O>[CH2:12]([O:14][C:15](=[O:27])[CH2:16][N:17]([CH2:10][C:5]1[C:6]([NH2:9])=[N:7][CH:8]=[C:3]([Br:2])[CH:4]=1)[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=1)[CH3:13]
Reactant: Nc1ncc(Br)cc1CBr
Reactant: CCOC(=O)CNCc1ccc(OC)cc1
Agent: Br
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)CN(Cc1ccc(OC)cc1)Cc1cc(Br)cnc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.8 %

Procedure:
A solution of 5-bromo-3-bromomethyl-pyridin-2-ylamine hydrobromide (11.9 g, 34.3 mmol) and (4-methoxy-benzylamino)acetic acid ethyl ester (7.70 g, 34.5 mmol) in DMF (200 mL) was treated with triethylamine (10.0 mL, 71.2 mmol). After stirring at room temperature overnight, the cloudy mixture was diluted with H2O (400 mL) and extracted with EtOAc (2×300 mL). The combined organic layers were washed with H2O (3×100 mL) and brine (100 mL), dried over Na2SO4, filtered and the solvent was removed in vacuo to give the title compound (13.0 g, 93%) as a yellow syrup: MS (ESI) m/e 408 (M+H)+.
Reaction SMILES: Cl.C1(NC2C(C)=C(C)N=C(NCC3C=CC=CN=3)N=2)CCCCC1.[CH3:25][C:26]1[CH:31]=[CH:30][N:29]=[C:28]([CH2:32][NH2:33])[CH:27]=1.Cl[C:35]1[N:40]=[C:39]([NH:41][CH:42]2[CH2:47][CH2:46][C:45]([F:49])([F:48])[CH2:44][CH2:43]2)[C:38]([CH3:50])=[C:37]([CH3:51])[N:36]=1>>[F:49][C:45]1([F:48])[CH2:46][CH2:47][CH:42]([NH:41][C:39]2[C:38]([CH3:50])=[C:37]([CH3:51])[N:36]=[C:35]([NH:33][CH2:32][C:28]3[CH:27]=[C:26]([CH3:25])[CH:31]=[CH:30][N:29]=3)[N:40]=2)[CH2:43][CH2:44]1
Reactant: Cc1nc(Cl)nc(NC2CCC(F)(F)CC2)c1C
Reactant: Cc1ccnc(CN)c1
Agent: Cc1nc(NCc2ccccn2)nc(NC2CCCCC2)c1C
Agent: Cl
Product: Cc1ccnc(CNc2nc(C)c(C)c(NC3CCC(F)(F)CC3)n2)c1
Yield: 45 %

Procedure:
The titled compound was synthesized according to the general procedure described for preparation of N4-cyclohexyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 1) using [(4-methylpyridin-2-yl)methyl]amine instead of (pyridin-2-ylmethyl)amine and 2-chloro-N-(4,4-difluorocyclohexyl)-5,6-dimethylpyrimidin-4-amine (Step A) instead of 2-chloro-N-cyclohexyl-5,6-dimethylpyrimidin-4-amine. The product was purified by crystallization from ethanol to afford the titled compound (45% yield) as the hydrochloride salt as a light-yellow solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.45-1.55 (m, 4H), 1.80-2.05 (m, 7H), 2.28 (s, 3H), 2.52 (s, 3H), 4.05 (bs, 1H), 4.99 (d, J=5.37 Hz, 2H), 7.65-7.78 (m, 3H) 8.31 (s, 1H), 8.67 (d, J=5.91 Hz, 1H), 13.42 (s, 1H); MS (ESI) m/z 362.4 (M+1)+.
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[CH2:6]([C:13]1[S:17][C:16]2[CH:18]=[C:19]([O:22][CH3:23])[CH:20]=[CH:21][C:15]=2[CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:24](Cl)(=[O:33])[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1.ClCCl>O>[CH2:6]([C:13]1[S:17][C:16]2[CH:18]=[C:19]([O:22][CH3:23])[CH:20]=[CH:21][C:15]=2[C:14]=1[C:24]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)=[O:33])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: COc1ccc2cc(Cc3ccccc3)sc2c1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: COc1ccc(C(=O)c2c(Cc3ccccc3)sc3cc(OC)ccc23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.5 %

Procedure:
Tin tetrachloride (2.0 mL, 17.09 mmol) was added dropwise over a 10 minute period to a stirred, -78° C. solution of 2-benzyl-6-methoxy-benzo[b]thiophene (2.71 g, 10.65 mmol), anisoyl chloride (1.93 g, 11.29 mmol) and dichloromethane (41 mL) under a dry nitrogen atmosphere. After 1 hours at -78° C., the reaction mixture was slowly warmed to room temperature and stirred for 16 h period. The reaction mixture was added to water and extracted with ether. The ether phase was washed with brine and silica gel was added to it. The solvent was removed and the adsorbate was flash chromatographed (eluent: 9:1 petroleum ether: ethyl acetate) to provide the title compound as a white solid (2.42 g, 58%): mp 110-112° C.: NMR (CDCl3); δ 7.84 (d, J=9 Hz, 2H), 7.31-7.18 (m, 7H), 7.92 (d, J=9 Hz, 2H), 6.97 (dd, J=9, 2 Hz, 1H), 4.17 (s, 2H), 3.88 (s, 3H), 3.883 (s, 3H); MS (FAB+): 389 (80%, M+H); Anal. Calc. for C24H20O3S: C, 74.20, H, 5.19, N, 0.00. Found: C, 74.94, H, 5.10, N, 0.03.
Reaction SMILES: [C:1]([Cl:6])(=[O:5])[C:2](Cl)=[O:3].Cl.[NH2:8][C:9]1[C:10]([CH3:15])=[CH:11][CH:12]=[CH:13][CH:14]=1>O1CCCC1>[Cl:6][C:1](=[O:5])[C:2]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])=[O:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1ccccc1N
Agent: Cl
Solvent: C1CCOC1
Product: Cc1ccccc1NC(=O)C(=O)Cl

Procedure:
Oxalyl chloride (5.8 g, 46 mmol) in tetrahydrofuran (2 mL) was heated to reflux and o-toluidine hydrochloride was added portionwise over ten minutes. After addition, the reaction mixture was refluxed for four hours and concentrated in vacuo to yield 1-Chloro-2-[(2-methylphenyl)amino]ethandione. This intermediate was dissolved in chloroform (4 mL) and aluminum chloride (2.6 g) was added portionwise. The reaction mixture was heated at reflux overnight, and chromatographed through Merck silica gel (100 g) using (9:1:0.1) toluene:acetone:acetic acid solvent system. The appropriate fractions were combined and concentrated to yield the title compound (90 mg, 5.6%).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C@H:12]2[CH2:17][CH2:16][C@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:3]=1.[CH2:25]([O:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:25]([O:32][C:33]1[CH:38]=[CH:37][C:36]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[N:8][C:9]=3[NH2:11])[N:4]([C@H:12]3[CH2:17][CH2:16][C@H:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[CH2:14][CH2:13]3)[N:3]=2)=[CH:35][CH:34]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CN1CCN([C@H]2CC[C@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CN1CCN([C@H]2CC[C@H](n3nc(-c4ccc(OCc5ccccc5)cc4)c4c(N)ncnc43)CC2)CC1
Temperature: 85 °C

Procedure:
A mixture of trans-3-iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1.50 g, 3.4 mmol) in ethylene glycol dimethyl ether (100 mL) was treated with 4-(benzyloxy)phenylboronic acid (0.853 g, 3.74 mmol), tetrakis(triphenylphosphine)palladium (0.236 g, 0.204 mmol), and a solution of sodium carbonate (0.864 g, 8.16 mmol) in water (35 mL). The reaction mixture was stirred over night at 85° C. under a nitrogen atmosphere. The organic solvent was removed under reduced pressure. Ethyl acetate (100 mL) was added to the aqueous layer. The layers were partitioned and the aqueous layer was extracted with ethyl acetate (300 mL). The combined organic layers were washed with water and brine (500 mL each), dried over magnesium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with 5% methanol in dichloromethane, 10% methanol in dichloromethane, 20% methanol in dichloromethane, then 30% methanol in dichloromethane. The column afforded 0.817 g (49%) of trans-3-[4-(benzyloxy)phenyl]-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine. 1H NMR (DMSO-d6, 400 MHz) δ 8.22 (s, 1H), 7.59-7.57 (m, 2H), 7.53-7.50 (m, 2H), 7.48-7.21 (m, 3H), 7.19-7.17 (d, 2H, J=8 Hz), 5.18 (s, 2H), 4.65-4.60 (m, 1H), 2.5 (s, 3H), 2.45-2.25 (m, 5H), 2.15 (s, 3H), 2.04-1.92 (m, 7H), 1.50-1.44 (m, 2H); HPLC Waters 2690 Alliance HPLC (Symmetry Shield RP18 3.5 μm, 2.1×50 mm; 5%-95% acetonitrile-0.1 M ammonium acetate over 15 min, 0.5 mL/min) Rt 5.021 min (95%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:18])=O>CN1CCCC1=O>[Cl:1][C:2]1[CH:10]=[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:8]=[CH:7][C:3]=1[C:4]([Cl:18])=[O:5]
Reactant: O=C(O)c1ccc(N2CCCC2)cc1Cl
Reactant: O=S(Cl)Cl
Solvent: CN1CCCC1=O
Product: O=C(Cl)c1ccc(N2CCCC2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 2-chloro-4-pyrrolidinylbenzoic acid (1 g) is added thionyl chloride (10 ml), and a drop of N-methylpyrrolidone is added to the mixture. The mixture is stirred at room temperature for one hour. Subsequently, the mixture is concentrated under reduced pressure, and the residue is dissolved in toluene (10 ml), and further concentrated under reduced pressure to give 2-chloro-4-pyrrolidinylbenzoyl chloride (acid chloride) as a pale yellow powder. Separately, (5R)-5-isopropylaminocarbonylmethyl-2,3,4,5-tetrahydro-1H-benzazepine (1 g) is dissolved in dichloromethane (20 ml), and thereto is added pyridine (1.64 ml). To the mixture is added drowpise with stirring a solution of the above obtained acid chloride in dichloromethane (5 ml) at room temperature. The mixture is stirred for one hour, and thereto is added 1N aqueous sodium hydroxide solution (10 ml), and then stirred for 30 minutes. The mixture is extracted with ethyl acetate (20 ml), and the extract is dried over sodium carbonate, crystallized from acetonitrile, and further recrystallized from acetone--n-hexane to give (5R)-5-isopropylaminocarbonylmethyl-1-[4-(1-pyrrolidinyl)-2-chlorobenzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.45 g).
Reaction SMILES: Cl[C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:10]=2)=[O:7])=[C:4]([CH3:24])[N:3]=1.[NH2:25][CH2:26][CH2:27][CH2:28][N:29]1[CH:33]=[CH:32][N:31]=[CH:30]1>C(O)CCC>[N:29]1([CH2:28][CH2:27][CH2:26][NH:25][C:2]2[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=4)[CH:10]=3)=[O:7])=[C:4]([CH3:24])[N:3]=2)[CH:33]=[CH:32][N:31]=[CH:30]1
Reactant: Cc1nc(Cl)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: NCCCn1ccnc1
Solvent: CCCCO
Product: Cc1nc(NCCCn2ccnc2)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1

Procedure:
Procedure F was performed using 55 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide and 92 μL of 1-(3-aminopropyl)-imidazole in 0.5 mL of BuOH. Purified by reverse phase HPLC to yield 6-(3-(1H-imidazol-1-yl)propylamino)-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide. MS (Q1) 446.1 (M)+.
Reaction SMILES: C([O:3][C:4](=[O:41])[CH2:5][N:6]([CH2:35][C:36]([O:38]CC)=[O:37])[C:7](=[O:34])[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][C:15](=[O:33])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:9]=1)C.[OH-].[Na+]>CO>[C:36]([CH2:35][N:6]([C:7](=[O:34])[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][C:15](=[O:33])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:9]=1)[CH2:5][C:4]([OH:41])=[O:3])([OH:38])=[O:37]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Nc1cccc(C(=O)N(CC(=O)OCC)CC(=O)OCC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCCCCCCCCCCC(=O)Nc1cccc(C(=O)N(CC(=O)O)CC(=O)O)c1
Yield: 74.2 %

Procedure:
A solution of 3.0 g (5.2 mmol) of N-(2-ethoxy-2-oxoethyl)-N-[3-(1-oxooctadecylamino)benzoyl]glycine ethyl ester and 25 ml (25 mmol) of 1N NaOH in 100 ml of methanol was stirred at reflux for 6 hours. The solvent was removed at reduced pressure, the residue was acidified and the precipitate was filtered and recrystallized from ethyl acetate-hexane to give 2.0 g (74% yield, mp 132°-142° ) of N-(carboxymethyl)-N-[3-(1-oxooctadecylamino)benzoyl]glycine.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=2[Cl:19])=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:5])C.[OH-].[Na+]>C(O)C>[Cl:19][C:13]1[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:12]=1[C:7]1[C:6]([C:4]([OH:5])=[O:3])=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCOC(=O)c1ccccc1-c1ccc(C)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(-c2ccccc2C(=O)O)c(Cl)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 67.1 %

Procedure:
To a mixture of ethanol (728 ml) and 2′-chloro-4′-methyl-biphenyl-2-carboxylic acid ethyl ester (337 g) was added 4N aqueous sodium hydroxide solution (728 ml), and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was cooled to room temperature, activated carbon (17 g) was added and the mixture was stirred overnight. The activated carbon was filtered off, and washed with 50v/v % ethanol-water (200 ml). The filtrate was acidified by dropwise addition of acetic acid (500 ml) at room temperature. To this mixture, water (414 ml) was added dropwise at room temperature, and the mixture was stirred for 2 hr. This suspension was filtered, and the obtained solid was washed with 40v/v % ethanol-water (250 ml), and dried under reduced pressure at 80° C. to give the title compound (203 g, 2 steps 85%).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:13][CH:12]=[CH:11][CH2:10][CH2:9][CH:8]=[CH:7][CH2:6][CH:5]([CH:14]([CH3:16])[CH3:15])[N:4]=[CH:3]1.Cl.Cl.[NH2:20][NH:21][C:22]([NH2:24])=[O:23]>O>[CH3:1][C:2]([CH3:17])([CH2:13][CH:12]=[CH:11][CH2:10][CH2:9][CH:8]=[CH:7][CH2:6][CH:5]([CH:14]([CH3:16])[CH3:15])[NH2:4])[CH:3]=[N:20][NH:21][C:22]([NH2:24])=[O:23]
Reactant: CC(C)C1CC=CCCC=CCC(C)(C)C=N1
Reactant: NNC(N)=O
Agent: Cl
Solvent: O
Product: CC(C)C(N)CC=CCCC=CCC(C)(C)C=NNC(N)=O
Yield: 86 %

Procedure:
The procedure described in Example 1(b) is repeated, except that 23.3 g (0.1 mol) of 3,3-dimethyl-12-isopropyl-1-aza-1,5,9-cyclododecatriene, 20 g of 37% hydrochloric acid, 20 ml of water and 11.15 g (0.1 mol) of semicarbazide hydrochloride are used. Working up yields 26.5 g (0.086 mol) of 2,2-dimethyl-11-isopropyl-11-amino-undeca-4,8-dienal semicarbazone; yield 86% of theory.