Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[S:2]1(=[O:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[F:31][C:32]([F:43])([F:42])[C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[O:30]=[S:2]1(=[O:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:37]3[CH:36]=[CH:35][CH:34]=[C:33]([C:32]([F:43])([F:42])[F:31])[CH:38]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCS(=O)(=O)CC4)cc3c2)CC1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCS(=O)(=O)CC2)n3-c2cccc(C(F)(F)F)c2)CC1
Yield: 35 %

Procedure:
The title compound was synthesized in analogy to example 66, from [2-(1,1-dioxo-thiomorpholine-4-carbonyl)-1H-indol-5-yl]-(4-isopropyl-piperazin-1-yl)-methanone (example 1), 3-(trifluoromethyl)phenylboronic acid, copper(II) acetate and pyridine, in dichloromethane, to give the desired product as a light yellow foam (35%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]2[C@H:13]([NH2:16])[CH2:14][CH2:15][C@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]1([C@H:23]([CH2:27]C)[C:24](O)=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:1]([N:8]1[CH2:12][C@@H:11]2[C@@H:13]([NH:16][C:24](=[O:25])[C@@H:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:27])[CH2:14][CH2:15][C@@H:10]2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@H](C(=O)O)c1ccccc1
Reactant: N[C@@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21
Product: C[C@@H](C(=O)N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21)c1ccccc1

Procedure:
The title compound was prepared by substituting (3aR,4S,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine from Step A of Example 33 for (3aS,4R,6aR)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine and substituting (R)-2-phenylpropanoic acid for (S)-2-phenylbutanoic acid in Step F of the procedure used to prepare Example 16: 1H NMR (500 MHz, CDCl3) δ ppm 7.37-7.26 (m, J=5.5, 7.5, 8H), 7.25-7.18 (m, 2H), 5.19 (d, J=5.9, 1H), 4.06-3.89 (m, 1H), 3.59 (d, J=13.0, 1H), 3.48 (ddd, J=7.6, 13.7, 21.0, 2H), 2.60-2.46 (m, 3H), 2.43-2.33 (m, J=7.0, 14.4, 1H), 2.26 (dd, J=3.8, 9.0, 1H), 2.20-2.07 (m, J=34.2, 1H), 2.03-1.93 (m, 1H), 1.49 (d, J=7.2, 3H), 1.44-1.22 (m, 3H); MS (ESI+) m/z 349 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.B(F)(F)F.[C:15]1([S:21]([N:24]2[CH:28]=[CH:27][CH:26]=[CH:25]2)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClCCl>[C:15]1([S:21]([N:24]2[CH:25]=[CH:26][CH:27]=[C:28]2[C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)(=[O:23])=[O:22])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=S(=O)(c1ccccc1)n1cccc1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: FB(F)F
Solvent: ClCCl
Product: O=C(c1ccc(F)cc1)c1cccn1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 33 %

Procedure:
To a solution of 4-fluorobenzoylchloride (1.74 g, 11 mmol) in dichloromethane (2 ml) was added dropwise a solution of boron trifluoride diethyletherate (3.4 ml, 27.6 mmol) in dichloromethane (20 ml). The mixture was stirred for 10 minutes at room temperature. Subsequently, to the mixture was added dropwise a solution of 1-benzenesulfonylpyrrole (1.9 g, 9.2 mmol) in accordance with a method described in Example 8 (1) in dichloromethane (5 ml). The mixture was stirred for 12 hours. The reaction mixture was poured into ice-water and extracted with ethylacetate. The extract was washed with water and dried. The solvent was evaporated. The obtained crude crystal was recrystallized from isopropylether to give 1-benzenesulfonyl-2-(4-fluorobenzoyl)pyrrole (1.0 g) as a crystal. Yield: 19.8%.
Reaction SMILES: C[Si](C)(C)[O-].[K+].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([C:17]#[N:18])([CH3:16])[CH3:15])=[CH:10][CH:9]=1.[OH2:19]>C1(C)C=CC=CC=1>[NH2:18][C:17]([C:14]([C:11]1[CH:10]=[CH:9][C:8]([Br:7])=[CH:13][CH:12]=1)([CH3:16])[CH3:15])=[O:19]
Reactant: O
Reactant: CC(C)(C#N)c1ccc(Br)cc1
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)(C(N)=O)c1ccc(Br)cc1
Temperature: 25 °C
Yield: 92 %

Procedure:
Potassium trimethylsilanolate (purity: 90%)(250 g, 1,800 mmol) was added at room temperature to a solution of 100 g (450 mmol) of 1-bromo-4-(1-cyano-1-methylethyl)benzene (referential compound 1-1) in 1,000 ml of toluene with stirring in an argon stream and the mixture was stirred for 4.5 hours under a condition of heating to reflux. After the reaction was finished, the reaction solution was cooled down to room temperature and 500 ml of water was dropped thereinto. The mixed solution was stirred for 25 minutes at room temperature and the resulting solid was filtered off and washed with 400 ml of water to give 99 g of the title compound as white powder (yield: 92%).
Reaction SMILES: [I-:1].F[C:3]1[CH:12]=[CH:11][C:10]2[N+:9]3[CH:13]=[C:14]4[CH:23]=[CH:22][C:21]5[CH:20]=[C:19]([CH:24]([CH3:26])[CH3:25])[CH:18]=[CH:17][C:16]=5[N:15]4[C:8]=3[CH:7]=[CH:6][C:5]=2[CH:4]=1.[CH3:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>CN(C)C=O>[I-:1].[CH3:25][CH:24]([C:19]1[CH:18]=[CH:17][C:16]2[N:15]3[C:8]4[CH:7]=[CH:6][C:5]5[CH:4]=[C:3]([N:31]6[CH2:32][CH2:33][CH:28]([CH3:27])[CH2:29][CH2:30]6)[CH:12]=[CH:11][C:10]=5[N+:9]=4[CH:13]=[C:14]3[CH:23]=[CH:22][C:21]=2[CH:20]=1)[CH3:26]
Reactant: CC(C)c1ccc2c(ccc3c[n+]4c5ccc(F)cc5ccc4n32)c1
Reactant: CC1CCNCC1
Agent: [I-]
Solvent: CN(C)C=O
Product: CC1CCN(c2ccc3c(ccc4n5c(ccc6cc(C(C)C)ccc65)c[n+]34)c2)CC1

Procedure:
A mixture of 4.7 g. of 3-fluoro-10-(1-methylethyl)imidazo[1,2-a:3,4-a']diquinolin-15-ium iodide, 20 ml. of dimethylformamide and 4.0 ml. of 4-methylpiperidine is stirred and heated at reflux for 1 hour, then evaporated at reduced pressure. The residue is stirred with 75 ml. of ethyl acetate and the resulting precipitate is collected by filtration. The solid is stirred with 150 ml. of 1% aqueous triethylamine hydroiodide, collected by filtration, washed with water and dried. This product is 10-(1-methylethyl-3-(4-methyl-1-piperidinyl)imidazo[1,2-a:3,4-a']diquinolin-15-ium iodide; m.p. 266°-269° C., after crystallization from methanol/acetonitrile.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)=[C:19]([O:28][CH2:29][CH2:30][O:31][C:32]3[CH:37]=[CH:36][C:35]([N+:38]([O-])=O)=[CH:34][N:33]=3)[N:18]=[CH:17][N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>C(O)(C)C.O1CCCC1.[C].[Pd]>[NH2:38][C:35]1[CH:36]=[CH:37][C:32]([O:31][CH2:30][CH2:29][O:28][C:19]2[N:18]=[CH:17][N:16]=[C:15]([NH:14][S:11]([C:8]3[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=3)(=[O:13])=[O:12])[C:20]=2[C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)=[N:33][CH:34]=1
Reactant: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ccc([N+](=O)[O-])cn2)cc1
Agent: [Pd]
Solvent: CC(C)O
Solvent: C1CCOC1
Product: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ccc(N)cn2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 89.8 %

Procedure:
To a solution of 4-tert-butyl-N-{5-(4-methylphenyl)-6-{2-(5-nitropyridin-2-yloxy)ethoxy}pyrimidin-4-yl}benzenesulfonamide (975 mg) in isopropanol/tetrahydrofuran (1:1) (20 ml) is added 10% palladium-carbon (200 mg), and the mixture is stirred at room temperature for 1.5 hour under hydrogen atmosphere (1 atm). The catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography (solvent; chloroform/ethyl acetate=2:1), and recrystallized from ethyl acetate/n-hexane to give N-{6-{2-(5-aminopyridin-2-yloxy)ethoxy}-5-(4-methylphenyl)pyrimidin-4-yl}-4-tert-butylbenzenesulfonamide (829 mg) as crystals.
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:14])[NH:6][C:7]1[O:11][N:10]=[C:9]([CH3:12])[C:8]=1[CH3:13].[C:17]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:22]=[CH:21][CH:20]=[C:19]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:18]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[C:17]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:22]=[CH:21][CH:20]=[C:19]([N:23]2[CH2:24][CH2:25][N:26]([C:5]([NH:6][C:7]3[O:11][N:10]=[C:9]([CH3:12])[C:8]=3[CH3:13])=[O:14])[CH2:27][CH2:28]2)[CH:18]=1
Reactant: Cc1noc(NC(=O)OCC(Cl)(Cl)Cl)c1C
Reactant: c1ccc(-c2cccc(N3CCNCC3)c2)cc1
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1noc(NC(=O)N2CCN(c3cccc(-c4ccccc4)c3)CC2)c1C
Yield: 62.7 %

Procedure:
A mixed solution of 2,2,2-trichloroethyl(3,4-dimethylisoxazol-5-yl)carbamate (265 mg, 0.923 mmol), 1-biphenyl-3-ylpiperazine (200 mg, 0.839 mmol) and diisopropylethylamine (0.292 ml, 1.68 mmol) in dimethylsulfoxide (2.5 ml) was stirred at 70° C. for 14 hours. To the reaction solution was added water, and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled away under reduce pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1), and then recrystallized from a mixed solvent of hexane and tetrahydrofuran to give the titled compound (198 mg, 62.6%) as solid product.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[H-].[Na+].Cl[C:21]1[N:22]=[CH:23][C:24]([C:27]([O:29][CH3:30])=[O:28])=[N:25][CH:26]=1>CN(C)C=O>[F:17][C:2]([F:1])([F:16])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([O:15][C:21]3[N:22]=[CH:23][C:24]([C:27]([O:29][CH3:30])=[O:28])=[N:25][CH:26]=3)[CH2:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: OC1CCN(c2ccc(C(F)(F)F)cc2)CC1
Reactant: COC(=O)c1cnc(Cl)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(OC2CCN(c3ccc(C(F)(F)F)cc3)CC2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
1-(4-(Trifluoromethyl)phenyl)piperidin-4-ol (0.59 g, 2.41 mmol) was dissolved in anhydrous N,N-dimethylformamide (10 mL), cooled in an ice bath and treated with 60% sodium hydride (0.1 g, 2.55 mmol). The mixture was allowed to warm to room temperature over 1 h. A solution of methyl 5-chloropyrazine-2-carboxylate (0.5 g, 2.9 mmol) in anhydrous N,N-dimethylformamide (1 mL) was added and the mixture was stirred at room temperature overnight. The mixture was quenched by water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated. The residue obtained was purified by flash chromatography (silica gel, ethyl acetate/hexanes=1/4) to afford methyl 5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)pyrazine-2-carboxylate as a white solid (0.23 g, 25%). 1H-NMR (CD3Cl, 300 MHz): δ 8.86 (m, 1H), 8.28 (m, 1H), 7.48 (m, 2H), 6.96 (m, 2H), 5.36 (m, 1H), 4.00 (s, 3H), 3.64 (m, 2H), 3.26 (m, 2H), 2.16 (m, 2H), 1.99 (m, 2H) ppm; MS (ESI): 382.6 (M+1).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].O.[CH:8]1([O:13][C:14]2[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=2[O:24][C:25]([F:28])([F:27])[F:26])[C:17]([O:19]C)=[O:18])[CH2:12][CH2:11][CH2:10][CH2:9]1>CO>[CH:8]1([O:13][C:14]2[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=2[O:24][C:25]([F:26])([F:27])[F:28])[C:17]([OH:19])=[O:18])[CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: COC(=O)c1ccc(OC(F)(F)F)c(OC2CCCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(OC(F)(F)F)c(OC2CCCC2)c1
Yield: 71.2 %

Procedure:
Potassium carbonate (0.43 g) and water (2 mL) are added to a solution of methyl 3-Cyclopentyloxy-4-trifluoromethoxybenzoate (0.78 g) in methanol (10 mL) and the mixture is heated under reflux for 2 hours. Methanol is evaporated off under reduced pressure, and the crude material is partitioned between water (75 mL) and ethyl acetate (75 mL). The organic layer is separated, and the aqueous layer is acidified with hydrochloric acid (2N) and extracted with ethyl acetate (2×75 mL). The combined organic extracts are dried over magnesium sulfate and evaporated under reduced pressure, to give 3-cyclopentyloxy-4-trifluoromethoxybenzoic acid (0.53 g), in the form of a white solid, m.p. 116°-118° C. [NMR (CDCl3): 7.72(d, 1H,J=2 Hz); 7.7(dd, 1H,J=8 Hz, 2 Hz); 7.3(d, 1H,J=8 Hz); 4.9(m, 1H,);2.0-1.6(m,8H)].
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][C:11]([F:14])([F:13])[F:12])[N+:5]=1[O-:15].[N+:18]([O-])([OH:20])=[O:19].[OH-].[Na+]>OS(O)(=O)=O>[N+:18]([C:8]1[CH:7]=[C:6]([CH2:10][C:11]([F:14])([F:12])[F:13])[N+:5]([O-:15])=[C:4]([CH2:3][C:2]([F:1])([F:16])[F:17])[CH:9]=1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])O
Reactant: [O-][n+]1c(CC(F)(F)F)cccc1CC(F)(F)F
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=[N+]([O-])c1cc(CC(F)(F)F)[n+]([O-])c(CC(F)(F)F)c1
Temperature: 0 °C

Procedure:
2,6-Bis-(2,2,2-trifluoro-ethyl)-pyridine 1-oxide (2.65 g, 10.22 mmol)was dissolved in H2SO4 (4 mL) and cooled to 0° C. HNO3 (3.2 mL) was added slowly and after the addition was complete the reaction mixture was heated to 90° C. for 2 hours. The mixture was poured into ice, made basic with 15% NaOH and extracted with CH2Cl2. The organic layers were washed with brine, dried over Na2SO4 and concentrated to a red oil (2.72 g, 81%). 1H NMR (400 MHz, CDCl3): δ 3.95 (t, J=10.1 Hz, 4 H), 8.31 (s, 2 H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:24][C:25]1[C:34]2[C:29](=[CH:30][C:31]([OH:35])=[CH:32][CH:33]=2)[N:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:24][C:25]1[C:34]2[C:29](=[CH:30][C:31]([O:35][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]5[CH2:23][CH2:22][O:21][CH2:20][CH2:19]5)=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][N:3]=3)=[CH:32][CH:33]=2)[N:28]=[CH:27][CH:26]=1
Reactant: Oc1ccc2c(Cl)ccnc2c1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4c(Cl)ccnc4c3)ncnc2cc1OCCCN1CCOCC1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 46.6 %

Procedure:
To 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (250 mg, 0.74 mmol), (prepared as described for the starting material in Example 1), in suspension in DMF (4 ml) were successively added 4-chloro-7-hydroxyquinoline (133 mg, 0.74 mmol) and potassium carbonate (153 mg, 1 mmol) and the reaction mixture heated to 100° C. More 4-chloro-7hydroxyquinoline (27 mg, 0.15 mmol) was added after one hour and heating was continued for a further 30 minutes. The product precipitated upon cooling to ambient temperature. The reaction mixture was diluted with water, the product was collected by filtration and washed with more water. The dried solid was triturated with ether and filtered to give 4-(4-chloroquinolin-7-yloxy)-6-methoxy-7-(3-morpholinopropoxy)quinazoline (166 mg, 47%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:12][C:13]1[CH:14]=[C:15]2[CH2:30][C:20]3([C:28]4[C:23](=[N:24][CH:25]=[CH:26][CH:27]=4)[NH:22][C:21]3=[O:29])[CH2:19][C:16]2=[N:17][CH:18]=1.C1CN(C(Cl)=[N+]2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C1COCC1>[O:29]=[C:21]1[NH:22][C:23]2=[N:24][CH:25]=[CH:26][CH:27]=[C:28]2[C:20]21[CH2:19][C:16]1=[N:17][CH:18]=[C:13]([NH:12][C:9](=[O:11])[CH2:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:14]=[C:15]1[CH2:30]2
Reactant: Nc1cnc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Reactant: O=C(O)CCc1ccccc1
Agent: ClC(N1CCCC1)=[N+]1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCc1ccccc1)Nc1cnc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 3-phenylpropionic acid (35 mg, 0.23 mmol), (±)-3-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (71 mg, 0.28 mmol, described in Intermediate 4), N,N,N′,N′-bis(tetramethylene)chloroformamidinium hexafluorophosphate (153 mg, 0.46 mmol), and N,N-diisopropylethylamine (0.20 mL, 1.15 mmol) in THF (2 mL) is stirred at ambient temperature for 18 h. The reaction mixture is purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. The pure, product-containing fractions are combined and made basic with saturated aqueous NaHCO3. The resulting mixture is extracted with EtOAc (3×20 mL), and the combined organic extracts are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to provide the title compound.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([CH:15]=1)[C:11]([O:13][CH3:14])=[O:12])[CH:2]([CH3:4])[CH3:3].NC(N)=[O:18].OO.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(=O)([O-])O.[Na+]>C(#N)C>[CH2:1]([O:5][C:6]1[CH:7]=[N+:8]([O-:18])[CH:9]=[C:10]([C:11]([O:13][CH3:14])=[O:12])[CH:15]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: COC(=O)c1cncc(OCC(C)C)c1
Reactant: NC(N)=O
Agent: O=C([O-])O
Agent: OO
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CC#N
Product: COC(=O)c1cc(OCC(C)C)c[n+]([O-])c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 127.5 %

Procedure:
Under a nitrogen atmosphere, to a mixture of methyl 5-isobutoxynicotinate (5.13 g), urea-hydrogen peroxide adduct (4.84 g) and acetonitrile (82 mL) was added trifluoroacetic anhydride (8.25 mL) at 0° C., and the mixture was stirred at 0° C. for 2 hr. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the solvent was evaporated under reduced pressure. The residue was filtered, and washed with acetonitrile. The solvent in the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) and silica gel column chromatography (ethyl acetate/hexane) to give a crude product of the title compound (7.04 g) as a white amorphous solid. This compound was used for the next step without further purification.
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:13]([O:15]C)=[O:14])=[N:9][CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].P(=O)(O)(O)O>C(O)C.O>[C:1]1([C:7]2[C:8]([C:13]([OH:15])=[O:14])=[N:9][CH:10]=[CH:11][CH:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ncccc1-c1ccccc1
Agent: O=P(O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ncccc1-c1ccccc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
To a solution of methyl 3-phenylpyridine-2-carboxylate (61.0 g, 286 mmol) in absolute ethanol was added potassium hydroxide (32.0 g, 572 mmol). After stirring at 50° C. for 2 h, the reaction mixture was cooled and adjusted to pH ˜7.5 with 1M phosphoric acid. The mixture was diluted with water (1 L) and extracted with EtOAc (2×600 ml). The organic portion was dried over magnesium sulfate, filtered, and concentrated in vacuo to yield 3-phenylpyridine-2-carboxylic acid as a solid (54.7 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9]O)=[CH:3][CH:2]=1.[CH3:11][CH:12]([CH3:28])[C:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:17]=1)=[O:14]>>[CH3:11][CH:12]([CH3:28])[C:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]2[CH2:27][CH2:26][N:25]([CH2:9][CH2:8][CH2:7][C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)[CH2:24][CH2:23]2)[CH:17]=1)=[O:14]
Reactant: OCCCc1ccncc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3ccncc3)CC2)c1

Procedure:
Prepared by Procedure O and Scheme W using 3-(4-pyridinyl)-1-propanol and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 366.2 (M+H)+.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[C:8]([C:10]([OH:12])=O)[CH:7]=[CH:6][C:5]=12.[NH:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[CH2:25][C@H:14]12.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[N:13]1([C:10]([C:8]2[CH:7]=[CH:6][C:5]3[N:4]([CH:3]=[CH:2][N:1]=3)[CH:9]=2)=[O:12])[CH2:18][CH2:17][CH2:16][C@@H:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[CH2:25][C@H:14]12
Reactant: c1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Reactant: O=C(O)c1ccc2nccn2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(c1ccc2nccn2c1)N1CCC[C@@H]2c3ccccc3C[C@@H]21
Yield: 85 %

Procedure:
The title compound is prepared from imidazo[1,2-a]pyridine-6-carboxylic acid and cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate is used]. Yield: 85% of theory; LC (method 3): tR=1.81 min; Mass spectrum (ESI+): m/z=318 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:36]=[CH:35][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[N:20]=[C:19]([N:21]3[C:25]([C:26]([F:29])([F:28])[F:27])=[C:24]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:23]=[N:22]3)[CH:18]=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.O[C:38]1[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][CH:39]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[F:28][C:26]([F:29])([F:27])[C:25]1[N:21]([C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[O:8][CH2:7][C:6]3[CH:5]=[CH:4][C:3]([CH2:2][O:1][C:38]4[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][CH:39]=4)=[CH:36][CH:35]=3)[N:20]=2)[N:22]=[CH:23][C:24]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: CCOC(=O)c1cnn(-c2cccc(-c3ccccc3OCc3ccc(CO)cc3)n2)c1C(F)(F)F
Reactant: Oc1ccc(C(F)(F)F)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn(-c2cccc(-c3ccccc3OCc3ccc(COc4ccc(C(F)(F)F)cc4)cc3)n2)c1C(F)(F)F
Temperature: 60 °C
Reaction time: 3.5 h

Procedure:
To a solution of the title compound from Example 7 Step A (30.0 mg, 0.060 mmol) and 4-hydroxybenzotrifluoride (29.3 mg, 0.181 mmol) in THF (0.400 mL) were added triphenylphosphine (47.5 mg, 0.181 mmol) and diisopropyl azodicarboxylate (0.035 mL, 0.181 mmol). The resulting mixture was stirred at 60° C. After 3.5 h, the mixture was allowed to cool to ambient temperature, then was concentrated in vacuo. Purification by flash chromatography on silica gel (0 to 50% EtOAc in hexanes, then 50 to 100% EtOAc in hexanes) provided the title compound: LCMS m/z 642.3 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].[OH-].[K+].[NH2:7][C:8]1[C:13]([Cl:14])=[CH:12][N:11]=[C:10](Cl)[C:9]=1[Cl:16]>CS(C)=O>[NH2:7][C:8]1[C:13]([Cl:14])=[CH:12][N:11]=[C:10]([O:4][CH2:3][CH2:2][NH2:1])[C:9]=1[Cl:16]
Reactant: NCCO
Reactant: Nc1c(Cl)cnc(Cl)c1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: NCCOc1ncc(Cl)c(N)c1Cl
Temperature: 150 °C

Procedure:
A mixture containing 21.4 grams (0.35 mole) of 2-aminoethanol, 50 milliliters of dimethylsulfoxide and 20 grams (0.36 mole) of potassium hydroxide was heated at 110° C. until all of the potassium hydroxide was reacted. The solution was added to a mixture containing 69 grams (0.35 mole) of 4-amino-2,3,5-trichloropyridine dissolved in 200 milliliters of dimethylsulfoxide. The mixture was heated for 11/2 hours at 138° C. to 150° C. under agitation and thereafter quenched by pouring into ice water. The solid which precipitated was recovered by filtration under reduced pressure, dried and recrystallized from a mixture of hexane and chloroform. The solid was dissolved in 100 milliliters of dimethylsulfoxide and mixed with a solution composed of 21.4 grams (0.35 mole) of 2-aminoethanol and 20 grams (0.36 mole) of potassium hydroxide dissolved in 50 milliliters of dimethylsulfoxide. This mixture was heated for 2 hours at 150° C., cooled by quenching with ice water to precipitate the product as a solid which was recovered by filtration under reduced pressure. This product was distilled under azeotropic conditions with benzene to remove water from the 4-amino-2-(2-aminoethoxy)-3,5-dichloropyridine product which has a melting point of 115°-116.5° C.