Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:9]1[N:13]=[C:12]([C:14]2[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=2)[O:11][N:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Cl:22][C:23]1[CH:24]=[C:25]([CH2:29][CH2:30][NH2:31])[CH:26]=[CH:27][CH:28]=1>>[Cl:22][C:23]1[CH:24]=[C:25]([CH2:29][CH2:30][NH:31][CH2:18][C:17]2[CH:20]=[CH:21][C:14]([C:12]3[O:11][N:10]=[C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[N:13]=3)=[CH:15][CH:16]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: CCCCCCCCc1noc(-c2ccc(C=O)cc2)n1
Reactant: NCCc1cccc(Cl)c1
Product: CCCCCCCCc1noc(-c2ccc(CNCCc3cccc(Cl)c3)cc2)n1
Yield: 76 %

Procedure:
The same procedure as employed in the preparation of Example 226 (step a) but using 4-(3-octyl-1,2,4-oxadiazol-5-yl)benzaldehyde and [2-(3-chlorophenyl)ethyl]amine gave the title compound as a colorless oil (76%). 1H NMR (CDCl3, 300 MHz) δ 8.06 (d, J=8.3 Hz, 2H), 7.44 (d, J=8.3 Hz, 2H), 7.23-7.00 (m, 4H), 3.88 (s, 2H), 2.95-2.68 (m, 6H), 1.75-1.65 (m, 2H), 1.41-1.20 (m, 10H), 0.87 (t, J=7.1 Hz, 3H). M+(LC/MS(ESI)): 426.4. HPLC (Condition A), Rt: 4.35 min (HPLC purity: 99.6%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([S:8]([CH2:11][C@H:12]([CH3:23])[C:13]([O:15]CC2C=CC=CC=2)=[O:14])(=[O:10])=[O:9])[CH2:4][CH2:3]1>CO>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([S:8]([CH2:11][C@H:12]([CH3:23])[C:13]([OH:15])=[O:14])(=[O:10])=[O:9])[CH2:6][CH2:7]1
Reactant: C[C@@H](CS(=O)(=O)N1CCN(C)CC1)C(=O)OCc1ccccc1
Solvent: CO
Product: C[C@@H](CS(=O)(=O)N1CCN(C)CC1)C(=O)O

Procedure:
A 100 mL Fisher/Porter vessel was charged with benzyl 3-[(4-methylpiperizin-1-yl)sulfonyl]-2(R)-methylpropionate in 15 mL MeOH with a catalytic amount of 10% pd—C. Hydrogenation at 50 psi for 48 hours afforded, after filtration through Celite and concentration in vacuo to yield 3-[(4-methylpiperizin-1-yl)sulfonyl]-2(R)-methylpropionic acid as a hygroscopic foam suitable for use without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:14][C:15]1[C:16]([CH3:21])=[CH:17][CH:18]=[CH:19][CH:20]=1.N1C=CC=CC=1.Cl>ClCCCl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ccccc1N
Agent: Cl
Solvent: ClCCCl
Solvent: c1ccncc1
Product: Cc1ccccc1NS(=O)(=O)c1ccc([N+](=O)[O-])cc1

Procedure:
(RK1-1-22) I A solution of 4-nitrobenzenesulfonyl chloride (200 mg, 0.90 mmol), o-toluidine (106 mg, 0.99 mmol), and pyridine (79 mg, 0.08 ml, 0.993 mmol) in 5.0 mL 1,2-dichloroethane was heated to 150° C. for 10 minutes in the microwave. A 1M HCl solution was added until the pH of the mixture indicated pH=2, and the acidified aqueous layer was separated and extracted with CH2Cl2 (3×10 mL). The combined organic fractions were washed successively with brine and water then dried over Na2SO4 and evaporated to dryness to afford the title compound as a peach solid (127 mg, 47%). Mp=139-142° C. (lit. 157-159° C., Tetrahedron 62(25), 6100-6106; 2006); 1H NMR (400 MHz, CDCl3) δ 8.28 (d, J=9.0 Hz, 2H), 7.89 (d, J=9.0 Hz, 2H), 7.28-7.27 (m, 1H), 7.20-7.12 (m, 3H), 6.30 (br s, 1H), 2.01 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[O:8]=[C:9]1[C@@H:16]2[C@@H:12]([CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15]2)[CH2:11][CH2:10]1>>[OH:8][C:9]1([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[C@@H:16]2[C@@H:12]([CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15]2)[CH2:11][CH2:10]1
Reactant: Brc1cccnc1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CCC(=O)[C@H]2C1
Product: CC(C)(C)OC(=O)N1C[C@H]2CCC(O)(c3cccnc3)[C@H]2C1
Yield: 26.6 %

Procedure:
3-Bromopyridine (4.36 g, 27.6 mmol) and the product from Example 44A (2.07 g, 9.19 mmol) were processed as described in Example 1E to afford the title compound (0.743 g, 27%). MS (DCI/NH3) m/z 305 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH3:11])=[CH:5][C:3]=1[NH2:4].[H-].[Na+].Cl[C:15]1[C:20]([C:21]#[N:22])=[CH:19][N:18]=[C:17]2[S:23][CH:24]=[CH:25][C:16]=12>O1CCCC1>[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH3:11])=[CH:5][C:3]=1[NH:4][C:15]1[C:20]([C:21]#[N:22])=[CH:19][N:18]=[C:17]2[S:23][CH:24]=[CH:25][C:16]=12
Reactant: N#Cc1cnc2sccc2c1Cl
Reactant: COc1cc(N)c(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(Nc2c(C#N)cnc3sccc23)c(Cl)cc1Cl
Yield: 21.4 %

Procedure:
A mixture of 2,4-dichloro-5-methoxyaniline (300 mg, 1.57 mmol) and 60% sodium hydride (70 mg, 1.75 mmol) in 10 mL of tetrahydrofuran is heated at reflux for 30 minutes The solution is cooled and 4-chlorothieno[2,3-b]pyridine-5-carbonitrile (150 mg, 0.8 mmol) [Khan, M. A.; Guarconi, A. E., J. Heterocyclic Chem., 14, 807 (1977)] is added. The reaction mixture is heated at reflux for 3.5 hours. The resultant black solution is partitioned between ethyl acetate and water. The organic layer is washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with 2:3 ethyl acetate:hexane. The fractions containing product are combined and concentrated. Diethyl ether is added and the insoluble material is collected by filtration to provide 60 mg of 4-[(2,4-dichloro-5-methoxyphenyl)amino]thieno[2,3-b]pyridine-5-carbonitrile as a tan solid, mp 197–199° C.; 1H NMR (DMSO-d6) δ 3.85 (s, 3H), 7.38 (s, 1H), 7.68 (d, J=5.7 Hz, 1H), 7.76 (s, 1H), 7.81 (d, J=5.7 Hz, 1H), 8.43 (s, 1H), 9.80 (s, 1); MS 348.2 (M−H)−.
Reaction SMILES: [Li+].[F:2][C:3]([F:23])([F:22])[C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][C:19]([O-:21])=O)[CH2:12][CH2:11]2)=[N:8][CH:9]=1.F[P-](F)(F)(F)(F)F.CN(C)C(ON1C2C=CC=CC=2N=N1)=[N+](C)C.Cl.[N+:49]([C:52]1[CH:57]=[CH:56][C:55]([NH:58][CH:59]2[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]2)=[CH:54][C:53]=1[C:65]([F:68])([F:67])[F:66])([O-:51])=[O:50].C(N(C(C)C)CC)(C)C.[O-2].[Al+3].[O-2].[O-2].[Al+3]>O1CCCC1.CN(C)C=O>[N+:49]([C:52]1[CH:57]=[CH:56][C:55]([NH:58][CH:59]2[CH2:60][CH2:61][N:62]([C:19](=[O:21])[CH2:18][CH2:17][CH2:16][N:13]3[CH2:12][CH2:11][N:10]([C:7]4[CH:6]=[CH:5][C:4]([C:3]([F:2])([F:23])[F:22])=[CH:9][N:8]=4)[CH2:15][CH2:14]3)[CH2:63][CH2:64]2)=[CH:54][C:53]=1[C:65]([F:68])([F:66])[F:67])([O-:51])=[O:50]
Reactant: O=C([O-])CCCN1CCN(c2ccc(C(F)(F)F)cn2)CC1
Reactant: O=[N+]([O-])c1ccc(NC2CCNCC2)cc1C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCCN1CCN(c2ccc(C(F)(F)F)cn2)CC1)N1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Reaction time: 3 h
Yield: 62 %

Procedure:
To a solution of 4-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-butyric acid lithium salt (16 mg; 0.05 mmol, prepared in accordance with Example 150) in tetrahydrofuran (0.5 mL) is added tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (19 mg; 0.05 mmol) in dimethylformamide (0.25 mL). A solution of (4-nitro-3-trifluoromethyl-phenyl)-piperidin-4-yl-amine hydrochloride (16 mg; 0.05 mmol, prepared in accordance with Example 8) in dimethylformamide (0.25 mL) and diisopropylethyl amine (25 μL; 0.15 mmol) are then added and the reaction is stirred. After 3 hours at room temperature, aluminium oxide (90 active basic) is added and stiffing is continued for 40 minutes. The solids are removed by filtration and the filtrate is concentrated under high vacuum. The obtained residue is purified by preparative HPLC to afford the desired compound (18 mg; 0.031 mmol). The structure was confirmed using Protocol I-D. Calculated mass=588; observed mass=589; HPLC retention time=1.50 min.
Reaction SMILES: Cl.[CH3:2][C:3]([CH3:50])([CH2:48][CH3:49])[CH2:4][C:5]1[N:6]=[C:7]([CH2:29][CH:30]([NH:44][C:45](=[O:47])[CH3:46])[C:31]2[CH:36]=[CH:35][C:34]([C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][N:38]=3)=[CH:33][CH:32]=2)[N:8](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:9]=1>O1CCOCC1.CO>[CH3:2][C:3]([CH3:50])([CH2:48][CH3:49])[CH2:4][C:5]1[N:6]=[C:7]([CH2:29][CH:30]([NH:44][C:45](=[O:47])[CH3:46])[C:31]2[CH:32]=[CH:33][C:34]([C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][N:38]=3)=[CH:35][CH:36]=2)[NH:8][CH:9]=1
Reactant: CCC(C)(C)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC(NC(C)=O)c2ccc(-c3ccc(F)cn3)cc2)n1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CCC(C)(C)Cc1c[nH]c(CC(NC(C)=O)c2ccc(-c3ccc(F)cn3)cc2)n1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Hydrogen chloride (4N, 2 mL) in dioxane was added to a solution of N-{2-[4-(2,2-dimethylbutyl)-1-trityl-1H-imidazol-2-yl]-1-[4-(5-fluoropyridin-2-yl)phenyl]-ethyl}acetamide in methanol (4 mL) at ambient temperature. The solution was stirred at 50° C. for 2 hr. Concentration of the solution afforded the title compound as a white solid. 1H NMR (500 MHz, CD3OD) δ 8.95-8.92 (m, 1H), 8.45-8.39 (m, 1H), 8.33 (dd, J=4.5, 9.0 Hz, 1H), 7.97 (d, J=8.5 Hz, 2H), 7.67 (d, J=8.0 Hz, 2H), 7.18 (s, 1H), 5.49 (t, J=8.0 Hz, 1H), 3.56-3.48 (m, 3H), 2.52 (s, 2H), 1.96 (s, 3H), 1.25 (q, J=7.5, 15.0 Hz, 2H), 0.87 (t, J=7.5 Hz, 3H), 0.84 (s, 3H), 0.83 (s, 3H).
Reaction SMILES: C(OC(N1CCC(C([O:20][C:21]2[CH:43]=[CH:42][C:24]3[C:25]4[N:29]([CH2:30][CH2:31][O:32][C:23]=3[CH:22]=2)[CH:28]=[C:27]([C:33]2[N:34]([CH:39]([CH3:41])[CH3:40])[N:35]=[C:36]([CH3:38])[N:37]=2)[N:26]=4)CC)CC1)=O)C1C=CC=CC=1.[H-].[Na+].[CH2:46]([O:48][C:49](=[O:63])[C:50](Br)([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[C:51]([O:53][CH2:54][CH3:55])=[O:52])[CH3:47]>CN(C=O)C>[CH2:46]([O:48][C:49](=[O:63])[C:50]([O:20][C:21]1[CH:43]=[CH:42][C:24]2[C:25]3[N:29]([CH2:30][CH2:31][O:32][C:23]=2[CH:22]=1)[CH:28]=[C:27]([C:33]1[N:34]([CH:39]([CH3:41])[CH3:40])[N:35]=[C:36]([CH3:38])[N:37]=1)[N:26]=3)([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[C:51]([O:53][CH2:54][CH3:55])=[O:52])[CH3:47]
Reactant: CCOC(=O)C(Br)(C(=O)OCC)c1ccccc1
Reactant: CCC(Oc1ccc2c(c1)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Oc1ccc2c(c1)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2)(C(=O)OCC)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 76.2 %

Procedure:
To a suspension of 2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-ol from Example 4 (300 mg, 0.922 mmol) in DMF (3 mL) was added sodium hydride (37 mg, 60% in oil, 0.925 mmol). The mixture was stirred at RT for 15 min, then a solution of 2-bromo-2-phenylmalonic acid diethyl ester (435 mg, 1.38 mmol) in DMF (0.5 mL) was added. The reaction mixture was stirred at RT for 30 min, and then at 90° C. for 2 h. The cooled reaction mixture was partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc and the combined organic layers were washed with water, followed by brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 2-10% MeOH in DCM) affording the title compound as a colourless gum (0.3933 g, 76%). LCMS (Method J): RT 3.73 min [M+H]+ 560
Reaction SMILES: C(OC(N[C@H](C(O)=O)CC1C2C(=CC=CC=2)NC=1)=O)(C)(C)C.[NH2:23][CH:24]1[N:30]=[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[F:37])[C:28]2[CH:38]=[CH:39][CH:40]=[CH:41][C:27]=2[N:26]([CH2:42][C:43]([N:45]2[CH2:51][CH:50]3[CH2:52][CH2:53][CH:47]([CH2:48][CH2:49]3)[CH2:46]2)=[O:44])[C:25]1=[O:54]>C(#N)C.C(Cl)Cl>[NH2:23][C@H:24]1[N:30]=[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[F:37])[C:28]2[CH:38]=[CH:39][CH:40]=[CH:41][C:27]=2[N:26]([CH2:42][C:43]([N:45]2[CH2:51][CH:50]3[CH2:52][CH2:53][CH:47]([CH2:48][CH2:49]3)[CH2:46]2)=[O:44])[C:25]1=[O:54]
Reactant: NC1N=C(c2ccccc2F)c2ccccc2N(CC(=O)N2CC3CCC(CC3)C2)C1=O
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Solvent: ClCCl
Solvent: CC#N
Product: N[C@H]1N=C(c2ccccc2F)c2ccccc2N(CC(=O)N2CC3CCC(CC3)C2)C1=O
Temperature: 25 °C
Yield: 46 %

Procedure:
To a solution of N-tert-butoxycarbonyl-L-tryptophan (0.70 g) in acetonitrile (20 ml) was added dropwise a solution of (3RS)-3-amino-1-{(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl}-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one (1.00 g) in methylene chloride (5 ml) under stirring at ambient temperature. The mixture was stirred overnight. The precipitate was collected by filtration and the colorless solid was partitioned between methylene chloride and 0.5N NaOH. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford (3S)-3-amino-1-{(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl}-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one (0.46 g) as s colorless crystal.
Reaction SMILES: [OH:1][C:2]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[S:15][C:14]([N+:16]([O-])=O)=[C:13]([C:19]([NH2:21])=[O:20])[CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3]>CO.[Pt]>[NH2:16][C:14]1[S:15][C:11]([C:8]2[CH:9]=[N:10][C:5]([C:2]([OH:1])([CH3:3])[CH3:4])=[CH:6][CH:7]=2)=[CH:12][C:13]=1[C:19]([NH2:21])=[O:20]
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c([N+](=O)[O-])s2)cn1
Agent: [Pt]
Solvent: CO
Product: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(N)s2)cn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 5-[6-(1-hydroxy-1-methylethyl)pyridin-3-yl]-2-nitrothiophene-3-carboxamide (245 mg, 0.80 mmol) in MeOH (20 mL) was added 3% Pt/C doped with 0.6% V (52 mg, 8.0 μmol). The reaction was stirred under a hydrogen balloon at room temperature for 4 h. The solution was diluted with MeOH, filtered through Celite, and evaporated to give the title compound as a gray solid.
Reaction SMILES: [K].CC(C)([O-])C.[CH3:7][CH:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10].[CH2:19]([N:26]1[C:30]2[CH:31]=[CH:32][C:33]([C:35](=[O:40])[CH:36](Cl)[CH2:37][CH3:38])=[CH:34][C:29]=2[O:28][C:27]1=[O:41])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CS(C)=O.C(O)(=O)C>[CH2:19]([N:26]1[C:30]2[CH:31]=[CH:32][C:33]([C:35]([CH:36]([C:8]([CH3:7])([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:37][CH3:38])=[O:40])=[CH:34][C:29]=2[O:28][C:27]1=[O:41])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: CCC(Cl)C(=O)c1ccc2c(c1)oc(=O)n2Cc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K]
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)C(C)(C(=O)OCC)C(CC)C(=O)c1ccc2c(c1)oc(=O)n2Cc1ccccc1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
23.00 g (204.96 mmol) potassium-tert.-butoxide are placed in 1200 mL DMSO and 36.00 g (206.67 mmol) diethyl 2-methyl-malonate are added. 64.00 g (194.07 mmol) 3-benzyl-6-(2-chloro-butyryl)-3H-benzoxazol-2-one are added batchwise while being cooled at 40° C. Then the mixture is stirred for 1 h, the reaction mixture is diluted with ice water and neutralised with 15 mL glacial acetic acid. The reaction mixture is extracted with DCM, the org. phase is concentrated by rotary evaporation i. V. and the residue is separated on silica gel (eluant cyclohexane/EA).
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[NH2:5][C:6]1[N:11]=[CH:10][N:9]=[C:8]2[N:12]([CH:33]3[CH2:38][CH2:37][CH2:36][NH:35][CH2:34]3)[N:13]=[C:14]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]4[O:23][C:24]5[C:30]([CH3:31])=[CH:29][C:28]([CH3:32])=[CH:27][C:25]=5[N:26]=4)=[CH:17][CH:16]=3)[C:7]=12.[CH3:39][N:40]([CH3:45])[CH2:41][C:42](O)=[O:43].Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.ON1C2N=CC=CC=2N=N1>ClCCl>[C:1]([OH:4])(=[O:3])[CH3:2].[NH2:5][C:6]1[N:11]=[CH:10][N:9]=[C:8]2[N:12]([CH:33]3[CH2:38][CH2:37][CH2:36][N:35]([C:42](=[O:43])[CH2:41][N:40]([CH3:45])[CH3:39])[CH2:34]3)[N:13]=[C:14]([C:15]3[CH:16]=[CH:17][C:18]([NH:21][C:22]4[O:23][C:24]5[C:30]([CH3:31])=[CH:29][C:28]([CH3:32])=[CH:27][C:25]=5[N:26]=4)=[CH:19][CH:20]=3)[C:7]=12
Reactant: CN(C)CC(=O)O
Reactant: Cc1cc(C)c2oc(Nc3ccc(-c4nn(C5CCCNC5)c5ncnc(N)c45)cc3)nc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Product: Cc1cc(C)c2oc(Nc3ccc(-c4nn(C5CCCN(C(=O)CN(C)C)C5)c5ncnc(N)c45)cc3)nc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 38.5 %

Procedure:
A mixture of N2-{4-[4-amino-1-(3-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]phenyl}-5,7-dimethyl-1,3-benzoxazol-2-amine acetate (0.04 g, 0.000078 mol), dimethylglycine (0.01 g, 0.000097 mol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.019 g, 0.000097 mol), N,N-diisopropylethylamine (0.033 g, 0.00026 mol) and 1-hydroxy-7-azabenzotriazole (0.011 g, 0.000078 mol) in anhydrous dichloromethane (5 mL) was stirred for 18 hours at room temperature. The solvent was removed under reduced pressure. The residue was partitioned between water and dichloromethane. The aqueous layer was extracted with dichloromethane, and the combined organic solvent was washed with brine. The solvent was removed under reduced pressure, and the residue was purified by RP-HPLC (Hypersilprep HS C18, 8 μm, 250×21.1 mm; 5%-100% over 35 min with 0.1 M ammonium acetate, 21 mL/min) to yield 1-[3-(4-amino-3-{4-[(5,7-dimethyl-1,3-benzoxazol-2-yl)amino]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidino]-2-(dimethylamino) 1-ethanone acetate (0.015 g, 0.00003 mol). 1H NMR (DMSO-d6, 400 MHz) δ 10.85 (s, 1H), 8.27 (d, 1H), 7.94 (d, 2H), 7.67 (d, 2H), 7.11 (s, 1H), 6.51 (s, 1H), 4.81-1.91 (br, 1H), 2.40 (s, 3H), 2.34 (s, 3H), 2.26 (s, 3H), 2.22 (s, 3H), 1.91 (s, 3H). RP-HPLC (Delta Pak C18, 5 μm, 300 A, 15 cm; 5%-85% acetonitrile-0.1M ammonium acetate over 10 min, 1 mL/min) Rt 9.7 min.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:10][C:11]1[N:12]([C:17]2[N:22]=[CH:21][C:20]([C:23](=[O:25])[CH3:24])=[CH:19][CH:18]=2)[C:13]([CH3:16])=[CH:14][CH:15]=1.Cl>[OH-].[Na+].CCO>[CH3:10][C:11]1[N:12]([C:17]2[N:22]=[CH:21][C:20]([C:23](=[O:25])/[CH:24]=[CH:4]/[C:3]3[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=3[OH:1])=[CH:19][CH:18]=2)[C:13]([CH3:16])=[CH:14][CH:15]=1
Reactant: CC(=O)c1ccc(-n2c(C)ccc2C)nc1
Reactant: O=Cc1ccccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(C)n1-c1ccc(C(=O)/C=C/c2ccccc2O)cn1
Yield: 36 %

Procedure:
To a vigorously stirred solution of 2-hydroxybenzaldehyde in 2.5N NaOH (2.2 mL) at 0° C. was added 1-[6-(2,5-dimethyl-1H-pyrrol-1-yl)pyridin-3-yl]ethanone (prepared by a method analogous to that described by Scott et al., Org. Proc. Res. And Dev., 8:587 (2004)) (0.58 g, 2.7 mmol) in EtOH (2 mL). The reaction mixture was allowed to stir and warm to rt whereupon an additional 1 mL of EtOH was added. The mixture turned a dark red color and was allowed to stir for 25 h. The reaction was neutralized by the addition of 1M HCl and the mixture was extracted with EtOAc. The organic solutions were combined, dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography to give (2E)-1-[6-(2,5-dimethyl-1H-pyrrol-1-yl)pyridin-3-yl]-3-(2-hydroxyphenyl)prop-2-en-1-one as a yellow solid (0.31 g, 36%). LCMS: (FA) ES+ 319.2 (M+1).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[NH:11][C:12]4[C:17]([C:18]=3[CH:19]=2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:21]1[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=1[C:23]([O:25][CH3:26])=[O:24].C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C=O)C.[Cu]>[C:1]1([C:7]2[CH:8]=[C:9]([C:21]3[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=3[C:23]([O:25][CH3:26])=[O:24])[C:10]3[NH:11][C:12]4[C:17]([C:18]=3[CH:19]=2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2ccc3[nH]c4ccccc4c3c2)cc1
Reactant: COC(=O)c1ccccc1I
Agent: [Cu]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1-c1cc(-c2ccccc2)cc2c1[nH]c1ccccc12
Temperature: 1300 °C

Procedure:
85 g (350 mmol) of 3-phenyl-9H-carbazole, 63 ml (262 mmol) of methyl 2-iodobenzoate, 20 g (315 mmol) of copper powder, 87 g (631 mmol) of potassium carbonate and 9.3 g (35 mmol) of 18-crown-6 are initially introduced in 1200 ml of DMF under a protective gas and heated at 1300° C. for 86 h. The mixture is subsequently evaporated and washed by stirring with hot heptane and purified by chromatography (heptane, dichloromethane 1:1). The product is washed by stirring with hot hexane, and the solid is isolated.
Reaction SMILES: [SH:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[C:9]([N:13]3[CH2:22][C@H:21]4[N:17]([CH2:18][CH2:19][CH2:20]4)[C:16]4[N:23]=[C:24]([S:27][CH3:28])[N:25]=[CH:26][C:15]=4[C:14]3=[O:29])[CH:10]=[CH:11][CH:12]=2)=[N:4][N:3]=1.[C:30](=O)([O-])[O-].[K+].[K+].CI.O>CN(C=O)C>[CH3:28][S:27][C:24]1[N:25]=[CH:26][C:15]2[C:14](=[O:29])[N:13]([C:9]3[CH:10]=[CH:11][CH:12]=[C:7]([C:5]4[O:6][C:2]([S:1][CH3:30])=[N:3][N:4]=4)[CH:8]=3)[CH2:22][C@H:21]3[N:17]([CH2:18][CH2:19][CH2:20]3)[C:16]=2[N:23]=1
Reactant: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3nnc(S)o3)c1)C2=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3nnc(SC)o3)c1)C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
(S)-5-[3-(5-Mercapto-1,3,4-oxadiazol-2-yl)phenyl]-9-methylthio-1,2,3,3a,4,5-hexahydro-5,8,10,10b-tetraazabenzo[e]azulen-6-one (37 mg, 0.09 mmol) obtained in Step 1 was dissolved in DMF (1.0 mL), and the mixture was stirred at room temperature for 1 hour after adding potassium carbonate (36 mg, 0.26 mmol) and methyl iodide (0.012 mL, 0.19 mmol). Thereafter, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was then purified by silica gel column chromatography to give (S)-9-methylthio-5-[3-(5-methylthio-1,3,4-oxadiazol-2-yl)phenyl]-1,2,3,3a,4,5-hexahydro-5,8,10,10b-tetraazabenzo[e]azulen-6-one (23 mg, 59%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[CH:7][C:4]=1[CH:5]=O.[C:16]([C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1)(=[O:18])[CH3:17]>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[CH:7][C:4]=1/[CH:5]=[CH:17]/[C:16]([C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1)=[O:18]
Reactant: COc1ccc(-c2cccs2)cc1C=O
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Product: COc1ccc(-c2cccs2)cc1/C=C/C(=O)c1ccc(C(=O)O)cc1

Procedure:
The title compound was prepared by condensing 2-methoxy-5-(thiophen-2-yl)-benzaldehyde (Ex-45A) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellow solid, mp 195–196° C. 1H-NMR (DMSO-d6) δ 8.23–8.20 (m, 3H), 8.08–7.96 (m, 4H), 7.67 (dd, J=2.1, 6.8 Hz, 1H), 7.55 (d, J=3.8 Hz, 1H), 7.49 (d, J=5.1 Hz, 1H), 7.16–7.11 (m, 2H), 3.90 (s, 3H). MS m/z=364 (M+, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH:11]([C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17])([CH3:13])[CH3:12]>>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH:17][C:16]1[CH:18]=[CH:19][CH:20]=[C:14]([CH:11]([CH3:13])[CH3:12])[CH:15]=1)=[O:9]
Reactant: O=C(O)c1cncc(Br)c1
Reactant: CC(C)c1cccc(N)c1
Product: CC(C)c1cccc(NC(=O)c2cncc(Br)c2)c1

Procedure:
In a manner similar to that described in Preparation 17, 5-bromonicotinic acid and 3-isopropylaniline were converted to the title compound
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:16][C:17]2[O:21][C:20]([C:22]([O:24]C)=[O:23])=[CH:19][CH:18]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[OH-].[Na+].Cl>CO.O>[CH3:1][C:2]1[C:3]([CH2:16][C:17]2[O:21][C:20]([C:22]([OH:24])=[O:23])=[CH:19][CH:18]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=1
Reactant: COC(=O)c1ccc(Cc2cc3c(cc2C)C(C)(C)CCC3(C)C)o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc2c(cc1Cc1ccc(C(=O)O)o1)C(C)(C)CCC2(C)C
Reaction time: 8 h
Yield: 104.4 %

Procedure:
To a solution containing methyl 5-[(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenyl) methyl]-2-furoate 6 (15.1 g, 44 mmol) in MeOH (175 mL) and water (175 mL), a solution of NaOH (3.53 g, 88.3 mmol) in water (29 mL) is added. The reaction mixture is stirred overnight. After completion as judged by tlc, the solution is acidified with 1M HCl to pH 2. The crude product is extracted into organic layer using ethyl acetate, and concentrated to afford 5-[(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenyl)methyl]-2-furoic acid 7 (15.0 g, 99% yield). NMR 1.26 (s, 6H), 1.28 (s, 6H), 1.68 (s, 4H), 2.24 (s, 3H), 4.00 (s, 2H), 6.01 (d, 1H), 7.10 (s, 21), 7.23 (d, 1H).