Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH2:11])[CH:2]=1.[F:12][C:13]([F:31])([F:30])[C:14]([C:17]1[CH:26]=[CH:25][C:24]2[CH2:23][C@H:22]([C:27](O)=[O:28])[CH2:21][CH2:20][C:19]=2[N:18]=1)([CH3:16])[CH3:15].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.C1C=NC2N(O)N=NC=2C=1>CN1CCCC1=O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11][C:27]([C@@H:22]2[CH2:21][CH2:20][C:19]3[N:18]=[C:17]([C:14]([CH3:16])([CH3:15])[C:13]([F:31])([F:30])[F:12])[CH:26]=[CH:25][C:24]=3[CH2:23]2)=[O:28])[CH:2]=1
Reactant: Nc1cnc2ccccc2c1
Reactant: CC(C)(c1ccc2c(n1)CC[C@@H](C(=O)O)C2)C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(c1ccc2c(n1)CC[C@@H](C(=O)Nc1cnc3ccccc3c1)C2)C(F)(F)F
Temperature: 60 °C
Reaction time: 0.03 h
Yield: 74.7 %

Procedure:
To a mixture of 3-quinolinamine (26 mg, 0.18 mmol), (R)-2-(1,1,1-trifluoro-2-methylpropan-2-yl)-5,6,7,8-tetrahydroquinoline-6-carboxylic acid (40 mg, 0.14) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (79 mg, 0.21 mmol) in N-methylpyrrolidinone (0.7 mL), followed by N,N-diisopropylethylamine (73 μL, 0.42 mmol) was added. Aliquot after 2 min: LCMS showed formation of the HOAt and Me ester, and some amide. After 1.3 h, the reaction was heated at 60° C. Aliquot after 25 h: LCMS showed the reaction was complete—all HOAt ester had been consumed. The material was filtered and purified by reverse-phase HPLC (20-80% ACN in 10 mM Et2NH/H2O; 3 injections of 400 μL, each) to afford the amide (43 mg, 75%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ 10.56 (s, 1H), 8.95 (d, J=2.4 Hz, 1H), 8.76 (d, J=2.4 Hz, 1H), 7.96 (d, J=8.4 Hz, 1H), 7.92 (dd, J=1.1, 8.0 Hz, 1H), 7.68-7.54 (m, 3H), 7.40 (d, J=8.0 Hz, 1H), 3.08-3.00 (m, 2H), 2.99-2.87 (m, 3H), 2.29-2.20 (m, 1H), 2.03-1.91 (m, 1H), 1.56 (s, 6H); m/z=414.1 (M+1)+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.C(N(CC)CC)C.[N+:16]([C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1)([O-:18])=[O:17]>O1CCCC1.O.C(=O)(O)[O-].[Na+]>[CH3:8][N:5]1[CH2:6][CH2:7][CH:2]([NH:1][C:23](=[O:24])[C:22]2[CH:21]=[CH:20][C:19]([N+:16]([O-:18])=[O:17])=[CH:27][CH:26]=2)[CH2:3][CH2:4]1
Reactant: CN1CCC(N)CC1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CN1CCC(NC(=O)c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 54.9 %

Procedure:
To an ice cooled solution of 3.43 g (0.030 mole) of 4-amino-1-methylpiperidine, 4.58 g (0.045 mole) of triethylamine and 75 mL of tetrahydrofuran, was added a solution of 6.44 g (0.0347 mole) of 4-nitrobenzoyl chloride in 25 mL of tetrahydrofuran. The mixture was stirred at room temperature for 6 hours, then diluted with 50 mL of water and 100 mL of saturated sodium bicarbonate. After stirring another 30 minutes, the mixture was extracted twice with 200 mL of ethyl acetate. The ethyl acetate layers were washed with 200 mL of water, 200 mL of brine, combined, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 4.34 g of N-(1-methyl-piperidin-4-yl)-4-nitro-benzamide as off-white powder.
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[N:4]([C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1)[CH2:3][CH2:2]2.[F:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([Cl:22])=[O:21]>>[ClH:22].[N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[N:4]([C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:20](=[O:21])[C:19]3[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=3[F:17])=[CH:12][CH:11]=1)[CH2:3][CH2:2]2
Reactant: Nc1ccc(N2CCN3CCC2CC3)cc1
Reactant: O=C(Cl)c1ccccc1F
Product: Cl
Product: O=C(Nc1ccc(N2CCN3CCC2CC3)cc1)c1ccccc1F

Procedure:
Was prepared by Method G from 4-(1,4-diaza-bicyclo[3.2.2]non-4-yl)-phenylamine and 2-fluorobenzoyl chloride. Mp. >268° C. (decomp.).
Reaction SMILES: [NH:1]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C@H:2]([C:11]([OH:13])=O)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Cl.C(O[C:32](=[O:43])[C@H:33]([CH2:35][C:36]1[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=1)[NH2:34])CCCCC.N=C=N>>[NH:1]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C@H:2]([C:11]([NH:34][C@H:33]([C:32]([CH2:11][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[O:43])[CH2:35][C:36]1[CH:37]=[CH:38][C:39]([OH:42])=[CH:40][CH:41]=1)=[O:13])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1
Reactant: CCCCCCOC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: O=C(N[C@@H](Cc1ccc(O)cc1)C(=O)O)OCc1ccccc1
Agent: Cl
Agent: N=C=N
Product: CCCCCCC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1

Procedure:
Z-Tyr-Tyr-Hex was prepared from Z-Tyr and Tyr-Hex.HCl by the carbodiimide coupling technique. Yield of crude product: 89%.
Reaction SMILES: [NH2:1][C:2]1[CH2:6][CH2:5][C:4](=[O:7])[CH:3]=1.[Br:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[F:17])[CH:12]=O.[CH2:18]([N:25]1[CH2:30][C:29](=O)[CH2:28][C:27](=[O:32])[CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[CH2:18]([N:25]1[CH2:30][C:29]2[NH:1][C:2]3[CH2:6][CH2:5][C:4](=[O:7])[C:3]=3[CH:12]([C:11]3[CH:14]=[CH:15][C:16]([F:17])=[C:9]([Br:8])[CH:10]=3)[C:28]=2[C:27](=[O:32])[CH2:26]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C1CC(=O)CN(Cc2ccccc2)C1
Reactant: O=Cc1ccc(F)c(Br)c1
Reactant: NC1=CC(=O)CC1
Solvent: CCO
Product: O=C1CCC2=C1C(c1ccc(F)c(Br)c1)C1=C(CN(Cc3ccccc3)CC1=O)N2
Temperature: 25 °C
Yield: 64.2 %

Procedure:
A solution of 3-amino-2-cyclopenten-1-one (Kikani, B. B., Synthesis, (1991), 2, 176) (0.97 g, 10 mmol), 3-bromo-4-fluorobenzaldehyde (2.0 g, 10 mmol) and N-benzylpiperidine-3,5-dione (Ziegler, J. Amer. Chem. Soc. (1973), 95, 7458-7464) (2.2 g, 10 mmol) in ethyl alcohol (10 mL) was heated to reflux for 72 hours and then allowed to cool to ambient temperature. The solvent was evaporated and the residue was purified by flash chromatography over silica gel (5% ethanol/methylene chloride) to provide the title compound (3.0 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5](=[O:11])[CH2:6][CH2:7]/[CH:8]=[CH:9]\[CH3:10].C1(C)C=CC(S([N:22]=[N+:23]=[N-])(=O)=O)=CC=1>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:12])[C:4](=[N+:22]=[N-:23])[C:5](=[O:11])[CH2:6][CH2:7]/[CH:8]=[CH:9]\[CH3:10]
Reactant: C/C=C\CCC(=O)CC(=O)OC
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Solvent: CCN(CC)CC
Product: C/C=C\CCC(=O)C(=[N+]=[N-])C(=O)OC
Yield: 87 %

Procedure:
In accordance with the process of Example 2, (Z)-3-oxo-6-octenoic acid methyl ester (0.77 g; 4.52 m mol), triethylamine (0.46 g; 4.52 m mol), p-toluenesulfonylazide (0.89 g; 4.52 m mol) were used as starting materials to obtain 0.77 g of (Z)-2-diazo-3-oxo-6-octenoic acid methyl ester as yellow oily product.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[Br:21][C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1>>[Br:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:14][C:15]3[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=3)[N:3]=2)=[CH:24][CH:23]=1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Reactant: Nc1ccc(Br)cc1
Product: COc1ccc2c(Nc3ccc(Br)cc3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 273 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 4-bromo-phenylamine to give N1-(4-bromo-phenyl)-6-methoxy-N3-(5-methyl-1H-pyrazol-3-yl)-isoquinoline-1,3-diamine. LC-MS m/e 424(MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH3:12])[CH2:9][CH2:10][O:11][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][O:13]2)=[CH:6][CH:7]=1
Reactant: C1=COCCC1
Reactant: CC(CCO)c1ccc(Br)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CC(CCOC1CCCCO1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 96.6 %

Procedure:
To the solution of 3-(4-bromophenyl)butan-1-ol (791 mg, 3.47 mmol) in dichloromethane (50 mL) was added 3,4-dihydro-2H-pyran (437 mg, 5.2 mmol) and p-toluenesulfonic acid (60 mg, 0.347 m mol), the solution was stirred for 12 hours at room temperature, then the solution was washed with water and dried with sodium sulfate, concentrated to give 2-(3-(4-bromophenyl)butoxy)-tetrahydro-2H-pyran (1.05 g, 97%).
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:8]=[C:7]([C:9]2[C:14]([F:15])=[CH:13][C:12]([C:16]([OH:19])([CH3:18])[CH3:17])=[CH:11][C:10]=2[F:20])[S:6][C:5]=1[NH:21][C:22]1[N:27]=[C:26]([CH2:28][N:29]2[CH:33]=[C:32]([C:34]([O:36]C)=[O:35])[N:31]=[N:30]2)[CH:25]=[CH:24][CH:23]=1)=[O:3].[OH-].[K+:39]>C1COCC1.CO>[NH2:1][C:2]([C:4]1[CH:8]=[C:7]([C:9]2[C:10]([F:20])=[CH:11][C:12]([C:16]([OH:19])([CH3:17])[CH3:18])=[CH:13][C:14]=2[F:15])[S:6][C:5]=1[NH:21][C:22]1[N:27]=[C:26]([CH2:28][N:29]2[CH:33]=[C:32]([C:34]([O-:36])=[O:35])[N:31]=[N:30]2)[CH:25]=[CH:24][CH:23]=1)=[O:3].[K+:39]
Reactant: COC(=O)c1cn(Cc2cccc(Nc3sc(-c4c(F)cc(C(C)(C)O)cc4F)cc3C(N)=O)n2)nn1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3cccc(Cn4cc(C(=O)[O-])nn4)n3)s2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 1-{[6-({3-(aminocarbonyl)-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-2-thienyl}amino)pyridin-2-yl]methyl}-1H-1,2,3-triazole-4-carboxylate (425 mg, 0.80 mmol) was taken up in THF (5.0 mL) and MeOH (5.0 mL), and KOH (1.0 M, 1.05 mL, 1.05 mmol) was added. The reaction was stirred at room temperature overnight. Additional KOH (1.0 M, 160 μL, 0.16 mmol) was added, and the reaction was stirred for another 8 h at room temperature. The mixture was then concentrated, resuspended in MeOH, and concentrated again to give the title compound as a yellow solid that was carried on without purification.
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]1[C@H:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][N:6]1C(=O)C)C.Cl.O1CCOCC1.[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>CC(O)=O.[OH-].[Na+]>[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33]([N:6]2[CH2:7][CH2:8][C@@H:9]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[C@H:5]2[C:4]([OH:3])=[O:19])(=[O:35])=[O:34])=[CH:29][CH:28]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)[C@@H]1[C@H](c2ccccc2)CCN1C(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: Cc1ccc(S(=O)(=O)N2CC[C@@H](c3ccccc3)[C@H]2C(=O)O)cc1
Temperature: 25 °C
Yield: 94.2 %

Procedure:
N-Acetyl-cis-3-phenylproline ethyl ester (614 mg, 2.35 mmol) (prepared via the method of Chung, et al., J. Org. Chem.55: 270-275 (1990)) was dissolved in HOAc (4 mL) and 6N HCl (12 mL) and heated at reflux for 18 hr. The mixture was cooled to room temperature and the volatiles were evaporated in vacuo to give a white solid. The solid was dissolved in 1N NaOH (15 mL) and dioxane was added (10 mL), followed by 4-toluene-sulfonyl chloride (458 mg, 2.40 mmol). The mixture was stirred at room temp for 18 hr before addition of 6N HCl to bring the pH<4. The mixture was extracted with Et2O (3×40 mL) and the extracts were dried (MgSO4), filtered, and evaporated in vacuo to give N-(toluene-4-sulfonyl)-cis-3-phenylproline as a white solid (765 mg, 94%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:35])([CH2:29][N:30]1[CH:34]=[N:33][CH:32]=[N:31]1)[C@H:10]([N:12]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH:27]=[N:26][N:25]=[N:24]3)=[CH:19][CH:18]=2)[C:13]1=[O:28])[CH3:11].[C:36]([O:42][CH2:43][Cl:44])(=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38].C(#N)C>C(OC(C)C)(C)C>[Cl-:44].[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:35])([C@H:10]([N:12]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH:27]=[N:26][N:25]=[N:24]3)=[CH:19][CH:18]=2)[C:13]1=[O:28])[CH3:11])[CH2:29][NH+:30]1[CH2:34][N:33]([CH2:43][O:42][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38])[CH:32]=[N:31]1
Reactant: C[C@@H](N1CCN(c2ccc(-n3cnnn3)cc2)C1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: CC(C)(C)C(=O)OCCl
Solvent: CC(C)OC(C)C
Solvent: CC#N
Product: C[C@@H](N1CCN(c2ccc(-n3cnnn3)cc2)C1=O)[C@](O)(C[NH+]1CN(COC(=O)C(C)(C)C)C=N1)c1ccc(F)cc1F
Product: [Cl-]
Temperature: 100 °C
Reaction time: 6.5 h
Yield: 48.6 %

Procedure:
A mixture of 1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-tetrazol-1-yl)phenyl]-2-imidazolidinone(0.5 g), chloromethyl pivalate (15.7 g) and acetonitrile (2.4 g) was stirred for 6.5 hours at 100° C. After having been cooled, the mixture was diluted with diisopropyl ether (10 ml), and the resulting powder was collected by filtration. The powder was subjected to silica gel column chromatography (eluent: ethyl acetate→acetone→acetone/ethanol=10/1→acetone/ethanol=5/1) to give 1-[(2R,3R)-2-(2,4-difluorophenyl)-2-hydroxy-3-[2-oxo-3-[4-(1H-tetrazol-1-yl)phenyl]-1-imidazolidinyl]butyl]-4-[(2,2-dimethylpropanoyloxy)methyl]-1H-1,2,4-triazolium chloride(Compound 2, 0.32 g) as a white powder. The above Compound 2 (0.4 g) was crystallized from ethyl acetate (20 ml) to give white crystals (0.3 g) of Compound -2.
Reaction SMILES: CC(C)=[O:3].[CH3:5][O:6][C:7]1[N:12]=[C:11]([C:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH:14]=2)[CH:10]=[CH:9][CH:8]=1.C[N+]1([O-])CCOCC1.[OH2:34]>[Os](=O)(=O)(=O)=O>[OH:34][CH:18]1[C:13]([OH:3])([C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([O:6][CH3:5])[N:12]=2)[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17]1
Reactant: COc1cccc(C2=CCN(C(=O)OC(C)(C)C)CC2)n1
Reactant: O
Reactant: CC(C)=O
Agent: O=[Os](=O)(=O)=O
Agent: C[N+]1([O-])CCOCC1
Product: COc1cccc(C2(O)CCN(C(=O)OC(C)(C)C)CC2O)n1
Yield: 91 %

Procedure:
To an acetone (10 mL)-water (1.0 mL) solution of tert-butyl 6-methoxy-5′,6′-dihydro-[2,4′-bipyridine]-1′(2′H)-carboxylate (1.00 g, 3.44 mmol) synthesized in Reference Synthesis Example 184, supported osmium tetroxide (276 mg, 0.102 mmol, osmium content 9.4%, manufactured by Wako Pure Chemical Industries, Ltd.) and N-methylmorpholine-N-oxide (1.20 g, 10.3 mmol) were added and the resultant mixture was stirred at room temperature for 6 days. After completion of the reaction, the reaction solution was filtered and ethyl acetate was added to the filtrate, followed by washing the resultant mixture with saturated ammonium chloride aqueous solution and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (1.01 g, yield 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)=[C:6]([CH:16]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15])=[O:8].[CH2:22]=[O:23]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:17]2[CH:21]=[CH:20][N:19]=[C:18]2[CH2:22][OH:23])=[C:6]([CH:16]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15])=[O:8]
Reactant: O=C(c1ccccc1F)c1cc(Cl)ccc1-n1ccnc1
Reactant: C=O
Product: O=C(c1ccccc1F)c1cc(Cl)ccc1-n1ccnc1CO

Procedure:
In the manner given in Example 1, 5-chloro-2'-fluoro-2-(imidazol-1-yl)benzophenone is heated in a bomb with 37% aqueous formaldehyde solution to give 5-chloro-2'-fluoro-2-[2-(hydroxymethyl)imidazol-1-yl]benzophenone.
Reaction SMILES: O[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].Cl[C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14]N=1.O([CH3:22])[Na]>C1COCC1>[C:15]1([CH:16]=[CH:2][C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:4])[CH:18]=[CH:19][CH:12]=[CH:22][CH:14]=1
Reactant: O=Cc1ccc(Cl)nc1
Reactant: O=C(CO)c1ccccc1
Reactant: CO[Na]
Solvent: C1CCOC1
Product: O=C(C=Cc1ccccc1)c1ccccc1
Yield: 15 %

Procedure:
2.08 g (15.3 mmol) of 2-hydroxyacetophenone, 2.05 g of 6-chloronicotinaldehyde (14.5 mmol), and 10 ml of 25% wt NaOCH3 were reacted in 50 ml of dry THF to give 0.55 g (15%) of chalcone after purification. 1H NMR (300 MHz, CDCl3): δ 12.61 (s, 1H), 8.66 (d, J=2.4 Hz, 1H), 7.97-7.92 (m, 2H), 7.90 (D, J=15.9 Hz, 1H), 7.71 (d, J=15.6 Hz, 1H), 7.55 (d, d, d, J=1.5, 7.2, 8.7 Hz, 1H), 7.43 (d, J=8.1 Hz, 1H), 7.06 (d, d, J=0.9, 8.4 Hz, 1H), 6.98 (d, d, d, J=1.2, 7.5, 8.1 Hz, 1H).
Reaction SMILES: CC1(C)C2C=C(C#CC3C=CC(C(O)=O)=CC=3)C=CC=2C(=O)CC1.[CH3:25][C:26]1([CH3:50])[C:35]2[CH:34]=[CH:33][C:32]([C:36]#[C:37][C:38]3[CH:48]=[CH:47][C:41]([C:42]([O:44]CC)=[O:43])=[CH:40][CH:39]=3)=[CH:31][C:30]=2[C:29](=[O:49])[CH2:28][CH2:27]1>>[CH3:25][C:26]1([CH3:50])[C:35]2[CH:34]=[CH:33][C:32]([C:36]#[C:37][C:38]3[CH:39]=[CH:40][C:41]([C:42]([OH:44])=[O:43])=[CH:47][CH:48]=3)=[CH:31][C:30]=2[C:29](=[O:49])[CH2:28][CH2:27]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(=O)CCC3(C)C)cc1
Agent: CC1(C)CCC(=O)c2ccc(C#Cc3ccc(C(=O)O)cc3)cc21
Product: CC1(C)CCC(=O)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21

Procedure:
Employing the same general procedure as for the preparation of 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl) ethynyl]benzoic acid (Compound 7), 500 mg (1.45 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-3-yl)ethynyl]benzoate (Compound 2) was converted into the title compound using 4 ml (4 mmol) of LiOH (1 N aqueous solution).
Reaction SMILES: I[C:2]1[C:3]([O:20][CH3:21])=[CH:4][C:5]([CH:17]([CH3:19])[CH3:18])=[C:6]([CH:16]=1)[O:7][C:8]1[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1.[C:22]([O-:25])(=O)[CH3:23].[K+].S1[CH:31]=[CH:30]N=C1>>[O:25]1[CH:22]=[CH:23][CH:31]=[C:30]1[C:2]1[C:3]([O:20][CH3:21])=[CH:4][C:5]([CH:17]([CH3:19])[CH3:18])=[C:6]([CH:16]=1)[O:7][C:8]1[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1
Reactant: c1cscn1
Reactant: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1I
Reactant: CC(=O)[O-]
Agent: [K+]
Product: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1-c1ccco1
Temperature: 155 °C

Procedure:
5-(5-Iodo-2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine (400 mg, 1.0 mmol), potassium acetate ((147 mg), Pd(Ph3)2Cl2 (40 mg in 2 mL dimethyl acetamide) and thiazole were added to a screw cap pressure vial and heated to 155° C. for 40 hours. The reaction mixture was cooled and partitioned between water and ethyl acetate. The organic phase was separated, dried (MgSO4), filtered, and evaporated under reduced pressure. The residue was purified by flash chromatography (3% to 5% MeOH in methylene chloride with 1% ammonium hydroxide) to yield 61 mg of 5-(5-Furan-2-yl-2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine (M+H)=356. Mp=199.1-203.3° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[C:11]2[C:16]([CH3:17])=[C:15]([CH3:18])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[C:11]3[C:16]([CH3:17])=[C:15]([CH3:18])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1sc2nc(Cl)nc(NCc3ccc(F)cc3)c2c1C
Reactant: Cc1ncc[nH]1
Product: Cc1sc2nc(-n3ccnc3C)nc(NCc3ccc(F)cc3)c2c1C

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-5,6-dimethyl-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-5,6-dimethyl-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Cl[CH:2]1[CH2:7][CH:6]2[CH2:8][CH2:9][N:3]1[CH2:4][CH2:5]2.[CH2:10](O)[CH3:11]>[Ni]>[N:3]1[CH:2]=[CH:7][CH:6]=[C:10]([CH:11]=[C:2]2[CH2:7][CH:6]3[CH2:8][CH2:9][N:3]2[CH2:4][CH2:5]3)[CH:4]=1
Reactant: CCO
Reactant: ClC1CC2CCN1CC2
Agent: [Ni]
Product: C(=C1CC2CCN1CC2)c1cccnc1
Reaction time: 6 h

Procedure:
Quinuclidin-3-one hydrochloride (4.6 g, 28.3 mmol) and powdered anhydrous potassium hydroxide (2.1 g, 37.2 mmol) were dissolved in methanol (25 ml) and stirred for 15 mins. Pyridine-3-carboxaldehyde (3.2 g, 29.5 mmol) was then added in one portion and the mixture was stirred for an additional 20 hrs. The reaction mixture was then diluted with 40 m water and cooled to 0° C. yielding 2-((3-pyridyl)methylene)-1-azabicyclo[2.2.2]octan-3-one as a yellow precipitate, which was collected, washed with distilled water and dried under vacuum (5.16 g, 81.4%). 2-((3-Pyridyl)methylene)-1-azabicyclo[2.2.2]octan-3-one (3 g, 14.0 mmol) was dissolved in 200 ml methanol and sodium borohydride (3 g, 79.6 mmol) was added in portions (exothermic reaction) with vigorous stirring. After 1 hr of continued stirring, acetone (100 ml) was slowly added to neutralize the remaining borohydride reagent. The mixture was evaporated to dryness and the resulting residue suspended in water (200 ml) and extracted three times with 200 ml portions of chloroform. The chloroform phases were combined, dried over MgSO4, and rotary evaporated to give a clear oil; crystallization of the free base gave a quantitative yield of 2-((3-pyridyl)methylene)-1-azabicyclo[2.2.2]octan-3-ol as a white precipitate. 2-((3-pyridyl)methylene)-1-azabicyclo[2.2.2]octan-3-ol (1 g, 4.7 mmol) was combined with neat thionyl chloride (20 ml, 26.9 mmol) under a nitrogen atmosphere at 0° C., the reaction was than brought to room temperature and stirred for one additional hour. Rotary evaporation at 60° C. produced a viscous oil which, when suspended in ether, afforded 3-chloro-2-((3-Pyridyl)methylene)-1-azabicyclo[2.2.2]octane dihydrochloride as a hygroscopic precipitate (0.98 g, 91%). This chloroquinuclidine (0.3 g, 15 mmol) was dissolved in ethanol (50 ml) and wet Rainey nickel (0.5 g) was carefully added under nitrogen. The suspension was hydrogenated at 50 psig in a Parr hydrogenation apparatus for 6 hrs followed by filtration through a pad of Celite filter aid and additional washing of the pad with methanol. Rotary evaporation of the pooled solvents gave 2-((3-pyridyl)methylene)-1-azabicyclo[2.2.2]octane as a clear oil that solidified upon cooling (0.2 g, 70%). This material (120 mg) was dissolved in 50 ml methanol followed by the careful addition of 0.1 g 10% palladium on charcoal. The suspension was hydrogenated at 50 psig in a Parr hydrogenation apparatus for 28 hrs followed by filtration through a pad of Celite filter aid and additional washing of the pad with methanol. Evaporation of the solvents afforded a white residue which was crystallized from ethanol-ether to give the desired material, 2-((3-pyridyl)methyl)-1-azabicyclo[2.2.2]octane, as a white solid (99 mg, 81%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][NH:12][CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.[CH2:14](N(CC)CC)C.CI.[Cl-].[NH4+]>CC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[NH:9][CH2:10][CH2:11][N:12]([CH3:14])[CH2:13]2)=[CH:6][CH:7]=1
Reactant: CCN(CC)CC
Reactant: Brc1ccc(C2CNCCN2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CI
Solvent: CC(C)=O
Product: CN1CCNC(c2ccc(Br)cc2)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 46.3 %

Procedure:
To a cooled (0° C.) solution of 2-(4-bromophenyl)piperazine (4.07 g, 16.0 mmol) and triethylamine (17 mL, 122 mmol) in acetone (50 mL) was added a solution of methyl iodide (1.4 mL, 22 mmol) in acetone (20 mL) over 50 min and the reaction mixture was stirred at 0° C. for 15 minutes, warmed to room temperature, and stirred for 16 h. The reaction mixture was slowly treated with saturated ammonium chloride (150 mL) and extracted with ethyl acetate (200 mL×3). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated in vacuo. Purification via flash silica gel column chromatography (heptane/ethyl acetate) gave 3-(4-bromo-phenyl)-1-methyl-piperazine (1.89 g, 46% yield). LCMS (m/z): 257.00 (M+1).