Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:8]([O:10]C)=[O:9])([C:4]([O:6][CH3:7])=[O:5])[CH2:3][CH2:2]1.[OH-].[Na+].O>CO>[CH3:7][O:6][C:4]([C:1]1([C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1)=[O:5]
Reactant: COC(=O)C1(C(=O)OC)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)C1(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dimethyl 1,1-cyclopropanedicarboxylate (5 ml) was mixed with NaOH (1.4 g) in MeOH (40 ml)/water (4 ml). The reaction mixture was stirred at RT overnight and the solvent was evaporated. To the residue was added ether (50 ml), water (50 ml) and extracted once. The aqueous layer was acidified with 6N HCl and extracted three times with ether, the combined organic layer was washed with brine, dried and evaporated to give 1-(methoxycarbonyl)cyclopropanecarboxylic acid (4 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([OH:17])([C:14]([OH:16])=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.Cl.[CH:28]1([CH:34]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH2:37][CH2:36][NH:35]2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>CN(C=O)C>[CH2:1]([N:8]1[CH2:9][CH2:10][C:11]([C:14]([N:35]2[CH2:36][CH2:37][C:38]3[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH:34]2[CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[O:16])([OH:17])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1(O)CCN(Cc2ccccc2)CC1
Reactant: c1ccc2c(c1)CCNC2C1CCCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N1CCc2ccccc2C1C1CCCCC1)C1(O)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 6.6 %

Procedure:
1-benzyl-4-hydroxypiperidine-4-carboxylic acid (951 mg) was dissolved in DMF (25 mL), and N,N′-carbonyldiimidazole (720 mg) was added thereto, followed by stirring at room temperature for 18 hours. Thereafter, N,N-diisopropylethylamine (784 mg) and 1-cyclohexyl-1,2,3,4-tetrahydroisoquinoline hydrochloride (1.22 g) were added to the reaction liquid, followed by stirring at 60° C. for 18 hours. The solvent was evaporated, and water and EtOAc were added to the reaction liquid. The resulting insoluble materials were separated through celite, extracted with EtOAc and dried over magnesium sulfate, and the solvent was evaporated. The resulting residue was purified by silica gel column chromatography (chloroform-MeOH) and dissolved in 1,4-dioxane (12 mL), and di-tert-butyl dicarbonate (1.3 g) was added thereto, followed by stirring at room temperature for 1 hour. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography (hexane-EtOAc and then chloroform-MeOH) to obtain 1-benzyl-4-[(1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl]piperidin-4-ol (115 mg).
Reaction SMILES: [N+](=[CH2:3])=[N-].[C:4]([C:7]1[CH:8]=[CH:9][C:10]2[O:15][C:14]([CH3:17])([CH3:16])[N:13]=[C:12]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[C:11]=2[CH:24]=1)([OH:6])=[O:5]>C(OCC)C.O1CCCC1>[CH3:3][O:5][C:4]([C:7]1[CH:8]=[CH:9][C:10]2[O:15][C:14]([CH3:17])([CH3:16])[N:13]=[C:12]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[C:11]=2[CH:24]=1)=[O:6]
Reactant: CC1(C)N=C(c2ccccn2)c2cc(C(=O)O)ccc2O1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)C(c1ccccn1)=NC(C)(C)O2

Procedure:
A solution of diazomethane in diethyl ether was added to a solution of Compound 113 (0.70 g) in tetrahydrofuran (5 ml) at room temperature until the starting material disappeared. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 6-methoxycarbonyl-2,2-dimethyl-4-(2-pyridyl)-2H-1,3-benzoxazine (0.49 g) (Compound 6).
Reaction SMILES: [CH:1]1([C:7]([NH:9][C:10]2[S:11][C:12]3[CH2:23][CH2:22][CH2:21][CH2:20][C:13]=3[C:14]=2[C:15]([O:17]CC)=O)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([NH:31][C:15]([C:14]1[C:13]2[CH2:20][CH2:21][CH2:22][CH2:23][C:12]=2[S:11][C:10]=1[NH:9][C:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:8])=[O:17])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)c1c(NC(=O)C2CCCCC2)sc2c1CCCC2
Reactant: NCc1ccccc1
Product: O=C(NCc1ccccc1)c1c(NC(=O)C2CCCCC2)sc2c1CCCC2

Procedure:
The product of Example 13 and benzylamine were processed as in Examples 29A and 29B to afford the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.19-1.41 (m, 3H), 1.45-1.62 (m, 2H), 1.64-1.73 (m, 1H), 1.76-1.88 (m, 6H), 1.96-2.06 (m, 2H), 2.38 (tt, J=11.5, 3.6 Hz, 1H), 2.61-2.72 (m, 4H), 4.63 (d, J=5.4 Hz, 2H), 6.18-6.26 (m, 1H), 7.27-7.42 (m, 5H), 12.15 (s, 1H); MS (DCI/NH3) m/z 397 (M+H)+; anal. calculated for C23H28N2O2S: C, 69.66; H, 7.12; N, 7.06. Found: C, 69.62; H, 7.07; N, 6.88.
Reaction SMILES: CN1CC[CH:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]([NH2:17])[CH3:16])=[CH:11][C:10]=2[C:18]([F:21])([F:20])[F:19])[CH2:4][CH2:3]1.FC1C=CC(C#N)=CC=1C(F)(F)F.[CH3:35][O:36][C@@H](C)CO>>[CH3:35][O:36][C@@H:4]([CH3:3])[CH2:5][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([NH2:17])[CH3:16])=[CH:11][C:10]=1[C:18]([F:21])([F:20])[F:19]
Reactant: CO[C@@H](C)CO
Reactant: CC(N)c1ccc(OC2CCN(C)CC2)c(C(F)(F)F)c1
Agent: N#Cc1ccc(F)c(C(F)(F)F)c1
Product: CO[C@@H](C)COc1ccc(C(C)N)cc1C(F)(F)F

Procedure:
The title compound was synthesized according to the procedure described for the synthesis of 1-[4-[(1-methylpiperidin-4-yl)oxy]-3-(trifluoromethyl)phenyl]ethanamine, part A and B, starting from 4-fluoro-3-(trifluoromethyl)benzonitrile and (S)-(+)-2-methoxypropanol.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[NH:11][C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O.O.[Sn](Cl)Cl.C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([NH:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:2]([CH3:1])[CH:7]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1NC(=O)c1ccccc1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(N)ccc1NC(=O)c1ccccc1
Temperature: 70 °C
Yield: 97.2 %

Procedure:
A suspension of N-(2-methyl-4-nitrophenyl)benzamide (0.256 g, 1.0 mmol) and tin (II) chloride dihydrate (0.89 g, 3.96 mmol) in ethyl acetate (6 mL) was heated at 70° C. for 19 hr. The reaction mixture was then chilled, poured onto 50 mL ice, basified with 5% NaHCO3 (20 mL), extracted into EtOAc, washed with brine, dried and concentrated in vacuo to give N-(4-amino-2-methylphenyl)-benzamide (0.22 g, 97%). ES-MS (M+H)+=227, (M+Na)+=249.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][C:19]=1[Cl:20])[O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][C:9]=1[F:16].Cl[C:22]1[CH:23]=[C:24]2[N:31]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:30][CH2:29][N:25]2[C:26](=[O:28])[N:27]=1>>[Cl:3][C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][C:19]=1[Cl:20])[O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][O:15][C:22]2[CH:23]=[C:24]3[N:31]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:30][CH2:29][N:25]3[C:26](=[O:28])[N:27]=2)=[CH:10][C:9]=1[F:16]
Reactant: OCc1ccc(Oc2ccc(Cl)c(Cl)c2)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCn2c1cc(Cl)nc2=O
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCn2c1cc(OCc1ccc(Oc3ccc(Cl)c(Cl)c3)c(F)c1)nc2=O

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from NaH, (4-(3,4-dichlorophenoxy)-3-fluorophenyl)methanol and tert-butyl 7-chloro-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[N:16][C:5]2[NH:6][C:7]3[CH2:8][CH2:9][N:10]4[CH:14]([C:15]=3[C:4]=2[CH:3]=1)[CH2:13][CH2:12][CH2:11]4.[H-].[Na+].CC1C=CC(S(O[CH2:31][CH2:32][C:33]2[CH:34]=[N:35][C:36]([CH3:39])=[CH:37][CH:38]=2)(=O)=O)=CC=1>CN(C=O)C.O>[CH3:1][C:2]1[CH:17]=[N:16][C:5]2[N:6]([CH2:31][CH2:32][C:33]3[CH:34]=[N:35][C:36]([CH3:39])=[CH:37][CH:38]=3)[C:7]3[CH2:8][CH2:9][N:10]4[CH:14]([C:15]=3[C:4]=2[CH:3]=1)[CH2:13][CH2:12][CH2:11]4
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(C)nc2)cc1
Reactant: Cc1cnc2[nH]c3c(c2c1)C1CCCN1CC3
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cnc2c(c1)c1c(n2CCc2ccc(C)nc2)CCN2CCCC12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 10-methyl-2,3,5,6,7,11c-hexahydro-1H-pyrido[3′,2′:4,5]pyrrolo[2,3-g]indolizine (110 mg, 0.484 mmol) in DMF (1 mL) was added a suspension of NaH (60.0 mg, 1.45 mmol) in DMF (1 mL). After stirring for 5 min at RT, a solution of 2-(6-methylpyridin-3-yl)ethyl 4-methylbenzenesulfonate (423 mg, 1.45 mmol) in DMF (1 mL) was added dropwise into the reaction mixture and stirring continued for another 2 h. The progress of reaction was monitored by TLC and LCMS. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3×25 mL). The organic layer was washed with water (3×20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 10-methyl-7-(2-(6-methylpyridin-3-yl)ethyl)-2,3,5,6,7,11c-hexahydro-1H-pyrido[3′,2′:4,5]pyrrolo[2,3-g]indolizine. 1H NMR (CD3OD, Tri-HCl salt) δ (ppm): 8.7 (s, 1H), 8.4 (d, 1H), 8.25 (s, 2H), 7.8 (d, 1H), 5.1 (m, 1H), 4.8-4.6 (m, 2H), 3.9-3.7 (m, 3H), 3.4 (m, 2H), 3.4-3.2 (m, 2H), 2.9-2.7 (m, 2H), 2.8 (s, 3H), 2.5 (s, 3H), 2.3-2.15 (m, 3H). Separation by chiral HPLC provided enantiomers 74a and 74b.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:55][C:56]1[S:57][C:58]2[CH:64]=[CH:63][CH:62]=[CH:61][C:59]=2[N:60]=1>C(Cl)Cl>[S:57]1[C:58]2[CH:64]=[CH:63][CH:62]=[CH:61][C:59]=2[N:60]=[C:56]1[NH:55][C:8](=[O:10])[CH:7]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=1)[CH2:6][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1nc2ccccc2s1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2nc3ccccc3s2)cc1
Yield: 65.9 %

Procedure:
A solution of 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionic acid (50 mg, 0.17 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (119 mg, 0.27 mmol), triethylamine (70 mL, 0.51 mmol), and 2-aminobenzthiazole (41 mg, 0.27 mmol) in methylene chloride (5 mL) was stirred at 25° C. under nitrogen for 2.33 h. The reaction mixture was partitioned between water and methylene chloride. The organic layer was sequentially washed with a 1N aqueous hydrochloric acid solution (1×10 mL), water (1×10 mL), and a saturated aqueous sodium chloride solution (1×10 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 1/1 hexanes/ethyl acetate) afforded N-benzothiazol-2-yl-3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionamide (48 mg, 66%) as a white solid: mp 206-209° C.; EI-HRMS m/e calcd for C22H24N2O3S2(M+) 428.1228, found 428.1233.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C@H:24]([OH:26])[CH3:25])=[CH:19][CH:18]=1>>[Cl:1][C:2]1[C:3]([C:12]([F:15])([F:14])[F:13])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([CH2:23][C@H:24]([OH:26])[CH3:25])=[CH:21][CH:22]=2)[CH:7]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)cc1Cl
Reactant: C[C@@H](O)Cc1ccc(N)cc1
Product: C[C@@H](O)Cc1ccc(Nc2cc(Cl)c(C(F)(F)F)cc2[N+](=O)[O-])cc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 162 from 2,4-dichloro-5-nitrobenzotrifluoride and (2R)-1-(4-aminophenyl)-2-propanol (step 2 of Example 249).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[CH:9]2)[CH3:2].I[CH:14](C)C>>[CH:1]([O:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[CH:9]2)([CH3:14])[CH3:2]
Reactant: CCOc1cccc2cc[nH]c12
Reactant: CC(C)I
Product: CC(C)Oc1cccc2cc[nH]c12

Procedure:
Made according to the procedure described for 7-ethoxy-1H-indole using 2-iodopropane.
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]=[O:12])[C:5]=2[S:4][CH:3]=1.[H][H]>[Pd].O1CCCC1.C(N(CC)CC)C>[S:4]1[C:5]2[C:10]([CH:11]=[O:12])=[CH:9][CH:8]=[CH:7][C:6]=2[CH:2]=[CH:3]1
Reactant: O=Cc1cccc2c(Br)csc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=Cc1cccc2ccsc12

Procedure:
2 g of 5% palladium-on carbon catalyst are added to a solution of 10.4 g (43.15 mmoles) of 3-bromo-7-benzothiophene-carbaldehyde in 130 ml of tetrahydrofuran and 5.6 ml of triethylamine and the mixture is hydrogenated with hydrogen in a hydrogenating apparatus for 45 hours at 20°-22° C. under atmospheric pressure. The catalyst is then filtered off and the solvent is evaporated in vacuo from the filtrate. The residue is dissolved with 50 ml each of water and ethyl acetate, and 5.2 g (67.5% of the theoretical amount) of 7-benzothiophene-carbaldehyde are obtainable as residue from the separated organic phase after evaporation of the solvent in vacuo.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[C:13]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=3)=[N:12]2)[CH2:7][CH2:6]1)=[O:4].[O:29]=[C:30]1[CH2:35][CH2:34][CH2:33][C:32](=[O:36])[NH:31]1>>[CH3:28][O:27][C:21]1[CH:20]=[C:19]([C:13]2[C:14]([CH3:17])([CH3:18])[C:15](=[O:16])[N:11]([CH:8]3[CH2:7][CH2:6][N:5]([C:3](=[O:4])[CH2:2][N:31]4[C:32](=[O:36])[CH2:33][CH2:34][CH2:35][C:30]4=[O:29])[CH2:10][CH2:9]3)[N:12]=2)[CH:24]=[CH:23][C:22]=1[O:25][CH3:26]
Reactant: COc1ccc(C2=NN(C3CCN(C(=O)CCl)CC3)C(=O)C2(C)C)cc1OC
Reactant: O=C1CCCC(=O)N1
Product: COc1ccc(C2=NN(C3CCN(C(=O)CN4C(=O)CCCC4=O)CC3)C(=O)C2(C)C)cc1OC

Procedure:
Prepared analogously as described for example 1 using 2-[1-(chloroacetyl)piperidin-4-yl]-5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one (compound A1) and 2,6-dioxopiperidine as starting compounds.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][C@@H:12]([C:14](=[O:21])[CH2:15][C:16](OCC)=[O:17])[CH2:11][CH2:10][N:9]1[C:22]([O:24][CH3:25])=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl.[NH2:29]O.Cl>CO.CO.O.O>[CH2:1]([C@H:8]1[CH2:13][C@@H:12]([C:14]2[O:21][NH:29][C:16](=[O:17])[CH:15]=2)[CH2:11][CH2:10][N:9]1[C:22]([O:24][CH3:25])=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](Cc2ccccc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of cis-methyl 2-benzyl-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (2.15 g, 6.18 mmol) (from Example 1, Step 1) in MeOH (0.75 mL) was added to a solution of NaOH (0.26 g, 6.55 mmol) in MeOH/H2O (5 mL/0.3 mL) at −30° C. After 10 minutes was added a solution of hydroxylamine hydrochloride (0.86 g, 12.4 mmol) and NaOH (0.49 g, 12.4 mmol) in MeOH (6.1 mL) and H2O (6.1 mL). Stirring was continued at −30° C. for 30 minutes. The reaction mixture was then poured into concentrated HCl (7 mL) held at 80° C. The solution was stirred for 30 minutes. The organic solvent was evaporated and the aqueous phase extracted with ether (×3). The combined organic phases were dried over Na2SO4, and evaporated to yield a solid, 2.2 g. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×20 ID mm) using a gradient of 20-70% acetonitrile in H2O/MeCN/FA 95/5/0.2 buffer, over 18 minutes with a flow of 19 mL/minutes. The title compound was isolated (1.1 g, 57%). 1H NMR (600 MHz, cdcl3) δ 1.76-2.15 (m, 4H), 2.63 (m, 1H), 2.82 (m, 1H), 2.87-3.03 (m, 1H), 3.03-3.22 (m, 1H), 3.61 (s, 3H), 3.99 (m, 1H), 4.19-4.33 (m, 1H), 5.71 (s, 1H), 7.01-7.37 (m, 5H). MS m/z 317 (M+H)+.
Reaction SMILES: [ClH:1].C[O:3][C:4]1[N:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[CH:6][C:5]=1[NH:16][C@@H:17]1[CH2:22][CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18]1>O1CCOCC1.C(O)C>[ClH:1].[NH:19]1[CH2:20][CH2:21][CH2:22][C@@H:17]([NH:16][C:5]2[C:4](=[O:3])[NH:9][CH:8]=[C:7]([C:10]3[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=3)[CH:6]=2)[CH2:18]1
Reactant: COc1ncc(-c2ccncc2)cc1N[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: O=c1[nH]cc(-c2ccncc2)cc1N[C@@H]1CCCNC1
Temperature: 80 °C

Procedure:
A solution of HCl in dioxane (20 mL) was added to (R)-tert-butyl 3-((6-methoxy-[3,4′-bipyridin]-5-yl)amino)piperidine-1-carboxylate (1.00 g, 2.60 mmol) in ethanol (10 mL). The mixture was heated at 80° C. for 12 h in a sealed tube. After cooling to room temperature the mixture was concentrated and the crude residue was triturated with diethyl ether to afford 0.60 g of the desired compound: 1H NMR (300 MHz, DMSO-d6) 12.29 (br s, 1H), 9.30-9.50 (m, 1H), 8.90-9.10 (m, 1H), 8.76 (br s 2H), 8.32 (br s, 2H), 7.74 (s, 1H), 7.04 (s, 1H), 5.65-5.90 (m, 1H), 3.20-4.10 (m, 5H), 2.60-2.90 (m, 1H), 1.60-2.05 (m, 3H); MS (ES) m/z 271 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:28]=[C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:30]=1)[C:12]1[O:13][C:14]2[C:19]([C:20](=[O:22])[CH:21]=1)=[CH:18][CH:17]=[C:16]([O:23][CH2:24][CH:25]1[O:27][CH2:26]1)[CH:15]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:39]([NH2:42])([CH3:41])[CH3:40]>CO>[CH2:32]([O:31][C:29]1[CH:28]=[C:11]([CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:30]=1)[C:12]1[O:13][C:14]2[C:19]([C:20](=[O:22])[CH:21]=1)=[CH:18][CH:17]=[C:16]([O:23][CH2:24][CH:25]([OH:27])[CH2:26][NH:42][CH:39]([CH3:41])[CH3:40])[CH:15]=2)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC(C)N
Reactant: O=c1cc(-c2cc(OCc3ccccc3)cc(OCc3ccccc3)c2)oc2cc(OCC3CO3)ccc12
Solvent: CO
Product: CC(C)NCC(O)COc1ccc2c(=O)cc(-c3cc(OCc4ccccc4)cc(OCc4ccccc4)c3)oc2c1

Procedure:
3′,5′-Dibenzyloxy-7-(2,3-epoxy-propoxy)-flavone, 28 (2.5 g, 4.9 mmol) and iso-propyl amine (1.8 mL, 14.7 mmol) in dry methanol (150 mL) were reacted in a similar manner to that described under 34 to afford 35. Yield 2.2 g (79%); mp 173-174° C.; MS (FAB) 566 (M++1); IR (KBr) 3431, 1637; 1H NMR (200 MHz, CDCl3) δ 8.05 (d, J=8.6 Hz, 1H), 7.59-7.34 (m, 10H), 7.15 (d, J=1.8 Hz, 2H), 7.06 (s, 1H), 7.03 (d, J=9.4 Hz, 1H), 6.78 (s, 1H), 6.71 (s, 1H), 5.13 (s, 4H), 4.14-4.11 (m, 3H), 3.18-3.16 (m, 1H), 2.93-2.79 (m, 2H), 1.11 (d, J=6.2 Hz, 6H); 13C NMR δ 177.9, 163.8, 162.9, 160.6, 158.1, 136.7, 133.9, 128.9, 128.5, 127.8, 127.1, 118.1, 115.3, 108.0, 105.8, 105.3, 101.5, 71.7, 70.7, 68.4, 49.8, 49.3, 23.1, 23.0. Analysis Calcd for C35H35NO6: C, 74.32; H, 6.24; N, 2.48. Found: C, 74.16; H, 6.17; N, 2.29.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:18]2[CH:22]=[CH:21][CH:20]=[N:19]2)[CH:6]=[CH:7][C:8]=1B1OC(C)(C)C(C)(C)O1.ClC1N=NC(C2C=CC(N3C=CC=N3)=CC=2OC)=CC=1.Cl[C:44]1[N:49]=[N:48][C:47]([N:50]([CH3:61])[CH:51]2[CH2:56][C:55]([CH3:58])([CH3:57])[NH:54][C:53]([CH3:60])([CH3:59])[CH2:52]2)=[CH:46][CH:45]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:18]2[CH:22]=[CH:21][CH:20]=[N:19]2)[CH:6]=[CH:7][C:8]=1[C:44]1[N:49]=[N:48][C:47]([N:50]([CH3:61])[CH:51]2[CH2:56][C:55]([CH3:57])([CH3:58])[NH:54][C:53]([CH3:60])([CH3:59])[CH2:52]2)=[CH:46][CH:45]=1
Reactant: CN(c1ccc(Cl)nn1)C1CC(C)(C)NC(C)(C)C1
Reactant: COc1cc(-n2cccn2)ccc1B1OC(C)(C)C(C)(C)O1
Agent: COc1cc(-n2cccn2)ccc1-c1ccc(Cl)nn1
Product: COc1cc(-n2cccn2)ccc1-c1ccc(N(C)C2CC(C)(C)NC(C)(C)C2)nn1

Procedure:
1-(3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazole from Step 3 of Intermediate 2-1, was coupled with Intermediate 1-1 under standard Suzuki coupling methods as described in GENERAL METHOD 1-2 to provide 6-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethyl-piperidin-4-yl)pyridazin-3-amine.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6](Cl)[N:5]=[C:4]([C:10]#[N:11])[C:3]=1[Cl:12].[Cl:13][C:14]1[CH:19]=[CH:18][C:17](B2OCCCO2)=[C:16]([F:26])[C:15]=1[O:27][CH3:28].[F-].[K+].C(#N)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:17]2[CH:18]=[CH:19][C:14]([Cl:13])=[C:15]([O:27][CH3:28])[C:16]=2[F:26])[N:5]=[C:4]([C:10]#[N:11])[C:3]=1[Cl:12]
Reactant: COc1c(Cl)ccc(B2OCCCO2)c1F
Reactant: N#Cc1nc(Cl)c(F)c(N)c1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1c(Cl)ccc(-c2nc(C#N)c(Cl)c(N)c2F)c1F
Temperature: 75 °C
Yield: 57.2 %

Procedure:
A mixture of 4-amino-3,6-dichloro-5-fluoropicolinonitrile (0.37 g, 1.80 mmol), 2-(4-chloro-2-fluoro-3-methoxyphenyl)-1,3,2-dioxaborinane (0.549 g, 2.24 mmol) and KF (0.209 g, 3.59 mmol) was taken into acetonitrile (6.75 mL) and water (2.25 mL). The mixture was stirred and sparged with a nitrogen atmosphere. Pd(PPh3)2Cl2 (63mg, 0.1 mmol) was added, and the mixture was again sparged with nitrogen. The solution was then heated to 75° C. under nitrogen for 2 h. Upon cooling down, a precipitate formed and was collected by filtration, washed with water and dried under vacuum to give the product (0.34 g) as an off-white solid. The aqueous phase was extracted with EtOAc (3×), and the combined organic extracts were washed with brine, dried, and concentrated. Purification by silica gel chromatography gave additional product (0.12 g) as a white solid. Total yield 78%. 1H NMR (400 MHz, DMSO-d6) δ 7.50 (dd, J=8.5, 1.4 Hz, 1H), 7.45 (s, 2H), 7.33 (dd, J=8.5, 7.2 Hz, 1H), 3.94 (s, 3H); 13C NMR (101 MHz, DMSO-d6) δ 152.97 (d, J=253.2 Hz), 145.73 (d, J=260.8 Hz), 143.82 (d, J=13.7 Hz), 141.83 (d, J=14.7 Hz), 138.45 (d, J=14.8 Hz), 133.93-132.79 (m), 128.93 (d, J=3.3 Hz), 127.74 (s), 126.37-125.10 (m), 122.08 (dd, J=13.6, 3.9 Hz), 119.34 (d, J=4.5 Hz), 114.99 (s), 61.61 (s); 19F NMR (376 MHz, DMSO-d6) δ −129.00 (dd, J=28.2, 7.0 Hz, 1F), −133.76 (d, J=28.2 Hz, 1F); ESIMS m/z 330.1 ([M+H]+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([O:10][CH2:11][CH2:12][CH2:13]Cl)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[OH:15][C:16]1([C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[N:24][CH:23]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[NH:1]1[C:9]2[C:4](=[C:5]([O:10][CH2:11][CH2:12][CH2:13][N:19]3[CH2:20][CH2:21][C:16]([OH:15])([C:22]4[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[CH:25]=[N:24][CH:23]=4)[CH2:17][CH2:18]3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: OC1(c2cncc3ccccc23)CCNCC1
Reactant: ClCCCOc1cccc2[nH]ccc12
Product: OC1(c2cncc3ccccc23)CCN(CCCOc2cccc3[nH]ccc23)CC1
Yield: 47.8 %

Procedure:
Beginning with 0.184 gm (0.88 mMol) 3-chloropropyl indol-4-yl ether and 0.200 gm (0.88 mMol) 4-hydroxy-4-(isoquinolin-4-yl)piperidine, 0.169 gm (48%) of the title compound were recovered as a light yellow solid.
Reaction SMILES: C(O[CH:5]([C:12]1[CH:13]=[N:14][C:15]([Cl:18])=[CH:16][CH:17]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=O)C.[CH3:19][O:20][C:21]([O:25][Si](C)(C)C)=[C:22]([CH3:24])[CH3:23].C(=O)(O)[O-].[Na+].C(OCC)(=O)C>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[Cl:18][C:15]1[N:14]=[CH:13][C:12]([CH:5]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:22]([CH3:24])([CH3:23])[C:21]([O:20][CH3:19])=[O:25])=[CH:17][CH:16]=1
Reactant: COC(O[Si](C)(C)C)=C(C)C
Reactant: CC(=O)OC(c1ccccc1)c1ccc(Cl)nc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)C(C)(C)C(c1ccccc1)c1ccc(Cl)nc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 80 %

Procedure:
To a stirred solution of (6-chloropyridin-3-yl)(phenyl)methyl acetate (0.52 g, 2.0 mmol) and (1-methoxy-2-methylprop-1-enyloxy)trimethylsilane (2.0 mL, 9.8 mmol) in anhydrous dichloromethane (10 mL) was added titanium tetrachloride solution (1M in toluene, 4.4 mL, 4.4 mmol) dropwise at 0° C. under argon. After stirring at 0° C. for 48 hrs (refrigerator) and room temperature for 5 hours, the mixture was poured into a saturated aqueous sodium bicarbonate solution (40 mL) maintained at 0° C. The mixture was extracted with ethyl acetate (2×40 mL). The combined organic solutions were dried (Na2SO4) and concentrated. Silica gel flash chromatography (0-100% ethyl acetate in hexanes) gave methyl 3-(6-chloropyridin-3-yl)-2,2-dimethyl-3-phenylpropanoate (0.48 g, 1.6 mmol, 80% yield) as a colorless liquid. MS found: (M+H)+=304.25.