Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([OH:4])[CH3:3].C(N(CC)CC)C.[F:12][C:13]1[C:14]([C:22](F)=[O:23])=[N:15][C:16]([F:21])=[C:17]([F:20])[C:18]=1[F:19]>>[F:12][C:13]1[C:14]([C:22]([O:4][CH:2]([CH3:3])[CH3:1])=[O:23])=[N:15][C:16]([F:21])=[C:17]([F:20])[C:18]=1[F:19]
Reactant: O=C(F)c1nc(F)c(F)c(F)c1F
Reactant: CC(C)O
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)c1nc(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
Anhydrous 2-propanol (1.803 g, 30 mmol) and anhydrous tri-ethylamine (2.024 g, 20 mmol) were added drop-wise at 5-10° C. to the solution of 3,4,5,6-tetrafluoropicolinoyl fluoride provided above. The mixture was stirred at room temperature overnight. The mixture was discharged from the vessel and the salts were removed by filtration and washed with a little acetonitrile. The solvent was removed with a rotary evaporator. The crude mixture was re-dissolved in ethyl ether. The organic phase was then washed with water and dried over MgSO4. The solvent was removed with a rotary evaporator. The concentrated crude product was purified using column chromatography (silica gel) with ethyl acetate/hexanes mixture (4/50) as eluent to give 3.77 g (79% yield, 99% GC purity, 97% LC purity) of desired product as a pale yellow liquid. GC/MS results were consistent with the chemical formula of isopropyl 3,4,5,6-tetrafluoropicolinate: 70 eV EIMS (GC) m/z=196 (32%), 178 (100%), 150 (49%), 100 (33%), 43 (75%). 1H NMR (400 MHz, CDCl3) δ 5.32 (hept, J=6.3 Hz, 1H), 1.42 (d, J=6.3 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 159.82 to 159.74 (m), 149.22 to 148.85 (m), 148.02 to 147.89 (m), 146.47 to 146.17 (m), 145.63 to 145.47 (m), 138.54 (dd, J=34.3, 11.2 Hz), 135.79 (dd, J=34.3, 11.4 Hz), 129.03 to 128.74 (m), 70.98 (s), 21.61 (s). 19F NMR (376 MHz, CDCl3) δ −80.26 to −80.44 (m), −135.99 to −136.13 (m), −137.07 to −137.22 (m), −149.77 to −149.91 (m).
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[CH3:10][N:11]([CH:13](OC)OC)[CH3:12]>>[CH3:10][N:11]([CH:13]=[C:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])[CH3:12]
Reactant: COC(=O)CC(=O)OC
Reactant: COC(OC)N(C)C
Product: COC(=O)C(=CN(C)C)C(=O)OC
Yield: 98.7 %

Procedure:
A solution of dimethyl malonate (5 g, 37.9 mmol, 1 equiv) in DMF-DMA (11.3 g, 94.8 mmol, 2.5 equiv) was stirred at room temperature overnight. Then the reaction mixture was concentrated to give 7 g of the desired product, which was directly used for the next step without further purification. MS (ESI): 188 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([O:26][CH:27]([CH3:29])[CH3:28])[C:7]([F:25])=[C:8]([N:10]([CH2:19][C:20]2[CH:24]=[CH:23][NH:22][N:21]=2)[C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)[CH:9]=1)[CH3:2].N1C=CC=CC=1.[C:36]1(B(O)O)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.B(O)O>C(Cl)Cl.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([O:26][CH:27]([CH3:28])[CH3:29])[C:7]([F:25])=[C:8]([N:10]([CH2:19][C:20]2[CH:24]=[CH:23][N:22]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[N:21]=2)[C:11]2[CH:12]=[CH:13][C:14]([C:15]#[N:16])=[CH:17][CH:18]=2)[CH:9]=1)[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: CCOc1cc(OC(C)C)c(F)c(N(Cc2cc[nH]n2)c2ccc(C#N)cc2)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: OBO
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOc1cc(OC(C)C)c(F)c(N(Cc2ccn(-c3ccccc3)n2)c2ccc(C#N)cc2)c1
Reaction time: 5.5 h
Yield: 71 %

Procedure:
To a mixture of Intermediate 183.1 (39.5 mg, 0.100 mmol) and 3A molecular sieves (30 mg) in 1 mL CH2Cl2 at rt, was added TEA (0.028 mL, 0.20 mmol), pyridine (16 mg, 0.20 mmol) and phenylboronic acid (24.4 mg, 0.20 mmol). The mixture was stirred until the boronic acid dissolved, then Cu(OAc)2 (27.3 mg, 0.150 mmol) was added. The mixture was stirred for 5.5 h, then was diluted with EtOAc. The organic phase was washed with 0.5N HCl, H2O, sat. NaHCO3 and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0 to 50% EtOAc/hexanes gradient) to afford 33.4 mg of Intermediate 183.2 as a pale yellow solid.
Reaction SMILES: C(OC([N:8]1[CH2:26][CH2:25][C@@H:11]2[N:12]([CH3:24])[C:13]3[C:14]([C:20]([F:23])([F:22])[F:21])=[CH:15][C:16](Br)=[CH:17][C:18]=3[C@@H:10]2[CH2:9]1)=O)(C)(C)C.[NH2:27][C:28]1[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[N:32][CH:33]=1.CC([O-])(C)C.[Na+]>>[CH3:35][O:34][C:31]1[N:32]=[CH:33][C:28]([NH:27][C:16]2[CH:15]=[C:14]([C:20]([F:22])([F:23])[F:21])[C:13]3[N:12]([CH3:24])[C@H:11]4[CH2:25][CH2:26][NH:8][CH2:9][C@H:10]4[C:18]=3[CH:17]=2)=[CH:29][CH:30]=1
Reactant: CN1c2c(cc(Br)cc2C(F)(F)F)[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]21
Reactant: COc1ccc(N)cn1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Product: COc1ccc(Nc2cc3c(c(C(F)(F)F)c2)N(C)[C@H]2CCNC[C@@H]32)cn1

Procedure:
The title compound was prepared by following the general Method A as a yellow solid (85 mg, 45%) from (4aS,9bR)-8-bromo-5-methyl-6-trifluoromethyl-1,3,4,4a,5,9b-hexahydro-pyrido[4,3-b]indole-2-carboxylic acid tert-butyl ester (Example 45, 217 mg, 0.5 mmol), 5-amino-2-methoxy-pyridine (186 mg, 1.5 mmol) and NaOt-Bu (144 mg, 1.5 mmol). MS (ESI): 379 (base, M+H).
Reaction SMILES: Cl[CH2:2][CH2:3][S:4](Cl)(=[O:6])=[O:5].[H-].[Na+].[CH:10](/[C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:25]([NH2:30])=[N:26][CH:27]=[CH:28][CH:29]=2)=[CH:20][CH:19]=1)=[CH:11]\[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1>[C:12]1(/[CH:11]=[CH:10]/[C:18]2[CH:23]=[CH:22][C:21]([C:24]3[C:25]4=[N:30][S:4](=[O:6])(=[O:5])[CH2:3][CH2:2][N:26]4[CH:27]=[CH:28][CH:29]=3)=[CH:20][CH:19]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=S(=O)(Cl)CCCl
Reactant: Nc1ncccc1-c1ccc(/C=C/c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S1(=O)CCN2C=CC=C(c3ccc(/C=C/c4ccccc4)cc3)C2=N1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
2-Chloroethanesulfonyl chloride (0.410 mL) was added to a mixture of NaH (60%, 390 mg) in THF (dry) (8 mL) at 0° C. under nitrogen flow. The mixture was stirred at 0° C. for 5 min. The mixture of (E)-3-(4-styrylphenyl)pyridin-2-amine (531 mg) in THF (dry) (20 mL) was added dropwise and the mixture was stirred at room temperature under atmosphere overnight. The mixture was quenched with water at 0° C., and water, EtOAc and THF were added. The insoluble material was collected by filtration and crystallized from DMSO-EtOH to give the title compound (340 mg) as slightly pale yellow crystals.
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:17][CH3:18])=[C:11]([N+:14]([O-])=O)[CH:12]=2)[CH2:7][CH2:6]1)=[O:4].C([O-])([O-])=O.[K+].[K+].[NH:25]1[CH2:29][CH2:28][CH:27]([OH:30])[CH2:26]1>ClCCl.O>[NH2:14][C:11]1[CH:12]=[C:13]2[C:8]([CH2:7][CH2:6][N:5]2[C:3](=[O:4])[CH2:2][N:25]2[CH2:29][CH2:28][CH:27]([OH:30])[CH2:26]2)=[CH:9][C:10]=1[O:17][CH3:18]
Reactant: COc1cc2c(cc1[N+](=O)[O-])N(C(=O)CBr)CC2
Reactant: OC1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: COc1cc2c(cc1N)N(C(=O)CN1CCC(O)C1)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.1 %

Procedure:
The 1-(bromoacetyl)-5-(methyloxy)-6-nitro-2,3-dihydro-1H-indole (4.0 g, 12.7 mmol) was dissolved in 50 mL of dichloromethane, then K2CO3 (4.4 g, 31.7 mmol) and 3-pyrrolidinol (1.33 g, 15.2 mmol) in 10 mL dichloromethane were added, and the reaction was stirred at RT overnight. The reaction mixture was diluted with 100 mL of water, the organic solvents were washed with water (2×100 mL), dried over Na2SO4, and the solvent was removed under reduced pressure. The resulting residue was dissolved in 10 mL of EA, 25 mL of MeOH and 15 mL of THF, then 0.8 g 10% Pd/C was added, and the reaction was stirred at RT overnight under a balloon of H2 pressure. The catalyst was removed via filtration and the solvent was evaporated under reduced pressure to yield the 1-{2-[6-amino-5-(methyloxy)-2,3-dihydro-1H-indol-1-yl]-2-oxoethyl}-3-pyrrolidinol as a white solid (3.0 g, 92%).1H NMR (400 MHz, DMSO-d6) δ ppm: 1.60 (m, 1 H), 1.97 (m, 1 H), 2.47(s, 1H), 2.59 (m, 1 H), 2.72 (m, 1 H), 2.85 (m, 1 H), 2.96 (m, 4 H), 3.50(s, 2H), 3.68(s, 3H), 4.00 (t, J=8.33 Hz, 2 H), 4.86 (s, 2H), 6.68 (s, 1 H), 7.51 (s, 1 H).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([NH2:13])[C:7]2[CH:8]=[N:9][NH:10][C:11]=2[CH:12]=1.[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>CN(C=O)C>[Br:3][C:4]1[CH:5]=[C:6]([NH2:13])[C:7]2[CH:8]=[N:9][N:10]([S:21]([C:18]3[CH:19]=[CH:20][C:15]([CH3:14])=[CH:16][CH:17]=3)(=[O:23])=[O:22])[C:11]=2[CH:12]=1
Reactant: Nc1cc(Br)cc2[nH]ncc12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ncc3c(N)cc(Br)cc32)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 51.1 %

Procedure:
To a suspension of sodium hydride (5.66 g) in anhydrous DMF (75 ml) stirring at 0° C. was added a solution of 6-bromo-1H-indazol-4-amine (30 g), also in anhydrous DMF (125 ml), dropwise. The reaction mixture was stirred for 1 h at 0° C. then a solution of 4-methylbenzenesulfonyl chloride (27 g) in anhydrous DMF (100 ml) was added dropwise. The reaction was stirred for 2 h. A further portion of sodium hydride (0.57 g) was added followed by 4-methylbenzenesulfonyl chloride (2.70 g). The reaction mixture was left to stand overnight at room temperature, before pouring onto ice/water (1800 ml). A precipitate formed that was collected by filtration, tritrurated using diethyl ether:methanol (1:1, v/v), then re-collected by filtration and dried in vacuo at 40° C. over the weekend to give title compound, (26.5 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9](Br)[N+:8]=1[O-:14])=[O:5])[CH3:2].[CH2:15]([SH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C[O-].[Na+]>CO.O>[CH2:1]([O:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([S:22][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N+:8]=1[O-:14])=[O:5])[CH3:2]
Reactant: CCOC(=O)Nc1cccc(Br)[n+]1[O-]
Reactant: SCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOC(=O)Nc1cccc(SCc2ccccc2)[n+]1[O-]

Procedure:
A suspension of 1.0 g (0.0038 mole) of 2-ethoxycarbonylamino-6-bromopyridine-1-oxide, as prepared in Step 2 of Example 3, in 25 ml of methanol containing equivalent amounts of benzyl mercaptan and sodium methoxide, is heated under reflux for 2 hours. The reaction mixture is diluted with 150 ml water and the impure product is collected by filtration. Recrystallization from ethyl acetate-cyclohexane gave white needles having a m.p. of 139.8°-140.2° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.Br[C:17]1[N:18]=[CH:19][S:20][CH:21]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O>CN(C=O)C.O.[Cu]I>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([C:17]3[N:18]=[CH:19][S:20][CH:21]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: Brc1cscn1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2-c2cscn2)CCN(C)C1
Yield: 20.8 %

Procedure:
A solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.2 g, 1 mmol), 4-bromo-thiazole (0.246 g, 1.5 mmol), K3PO4 (0.636 g, 3 mmol), CuI (19 mg, 0.1 mmol) and L-Proline (23 mg, 0.2 mmol) in dry DMF (5 mL) was stirred at 150° C. for 16 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 2,8-dimethyl-5-thiazol-4-yl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (59 mg). 1H NMR (TFA salt, CD3OD) d (ppm): 9.10 (s, 1H), 7.62 (s, 1H), 7.38 (d, 1H), 7.30 (s, 1H), 7.10 (d, 1H), 4.70 (d, 1H), 4.30 (d, 1H), 3.80 (m, 1H), 3.50 (m, 1H), 3.26 (m, 1H), 3.18 (s, 3H), 3.16 (m, 1H), 2.42 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=3[OH:19])=[N:10][C:9]=2[CH:20]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[CH:32](I)([CH3:34])[CH3:33]>O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=3[O:19][CH:32]([CH3:34])[CH3:33])=[N:10][C:9]=2[CH:20]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc2oc(-c3ccncc3O)nc2c1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Oc1cnccc1-c1nc2cc(C(C)(C)C)ccc2o1
Temperature: 60 °C
Yield: 60.5 %

Procedure:
To a mixture of 0.30 g of 4-(5-tert-butylbenzoxazole-2-yl)pyridin-3-ol, 0.17 g of potassium carbonate and 3 ml of DMF, 0.21 g of isopropyl iodide was added at room temperature. The reaction mixture was stirred while heating at 60° C. for two hours. The mixture was cooled to room temperature, and then water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.21 g of 5-tert-butyl-2-(3-isopropoxypyridin-4-yl)benzoxazole (hereinafter, referred to as “active compound 104”).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([N:10]2[CH2:15][CH2:14][NH:13][C@H:12]([CH3:16])[CH2:11]2)=[C:6]([CH3:9])[C:7]=1[CH3:8].[F:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C1(C)C=CC=CC=1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[N:3]=[N:4][C:5]([N:10]3[CH2:15][CH2:14][NH:13][C@H:12]([CH3:16])[CH2:11]3)=[C:6]([CH3:9])[C:7]=2[CH3:8])=[CH:20][CH:19]=1
Reactant: Cc1c(Cl)nnc(N2CCN[C@H](C)C2)c1C
Reactant: OB(O)c1ccc(F)cc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccc(F)cc2)nnc(N2CCN[C@H](C)C2)c1C
Temperature: 110 °C
Yield: 77.2 %

Procedure:
To a round bottom flask is added 3-chloro-4,5-dimethyl-6-((R)-3-methyl-piperazin-1-yl)-pyridazine (500 mg, 2.07 mmol), 4-fluorophenylboronic acid (580 mg, 4.15 mmol) sodium carbonate (440 mg, 4.15 mmol), toluene (16 mL) and water (8 mL). The reaction mixture is purged with nitrogen for 20 min. Tetrakis(triphenylphosphine) palladium (50 mg, 0.103 mmol) is added and the mixture is heated to 110° C. for 18 h. The reaction mixture is concentrated and partitioned between ethylacetate and water. It is extracted with ethylacetate twice and the combined organic phases are dried with sodium sulfate and concentrated. It is purified by column chromatography (0-25% methanol/methylene chloride) to give 480 mg of 3-(4-fluoro-phenyl)-4,5-dimethyl-6-((R)-3-methyl-piperazin-1-yl)-pyridazine (83%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=1)[C:7]([CH3:23])=[C:6]2[CH2:24][C:25]([NH:27][NH2:28])=[O:26].[CH2:29]([O:31]C(=O)CC1C2C(=CC=C(OC)C=2)N(CC2C=CC3C(=CC=CC=3)N=2)C=1C)C.NN>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=1)[C:7]([CH3:23])=[C:6]2[CH2:24][C:25]([NH:27][NH2:28])=[O:26].[CH3:29][OH:31]
Reactant: CCOC(=O)Cc1c(C)n(Cc2ccc3ccccc3n2)c2ccc(OC)cc12
Agent: COc1ccc2c(c1)c(CC(=O)NN)c(C)n2Cc1ccc2ccccc2n1
Agent: NN
Product: CO
Yield: 55 %

Procedure:
5-Methoxy-2-methyl-1-[(2-quinolyl)methyl]-1H-indole-3-acetic acid hydrazide. Using the method described in Example 1, Part G, 446 mg (1.15 mmol) of 5-methoxy-2-methyl-1-[(2-quinolyl)methyl]-1H-indole-3-acetic acid ethyl ester was reacted with 1.0 mL of hydrazine to give on crystallization from MeOH 238 mg (55% yield) of 5-methoxy-2-methyl-1-[(2-quinolyl)methyl]-1H-indole-3-acetic acid hydrazide, mp, 173°-175° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH:10]([C:15]([O:28][CH3:29])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11]([O:13]C)=[O:12])[CH:6]=[C:5]([O:30][CH3:31])[N:4]=1.[OH-].[K+]>O1CCOCC1.O>[CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH:10]([C:15]([O:28][CH3:29])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11]([OH:13])=[O:12])[CH:6]=[C:5]([O:30][CH3:31])[N:4]=1
Reactant: COC(=O)C(Oc1cc(OC)nc(OC)n1)C(OC)(c1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(OC(C(=O)O)C(OC)(c2ccccc2)c2ccccc2)nc(OC)n1
Temperature: 100 °C
Reaction time: 3 h
Yield: 38.4 %

Procedure:
550 mg (1.3 mmol) of methyl 2-(2,6-dimethoxy-4-pyrimidinyl-oxy)-3-methoxy-3,3-diphenylpropionate were dissolved in 5 ml of dioxane, 2.6 ml of 1N KOH solution were added, and the mixture was stirred at 100° C. for 3 h. The solution was diluted with 300 ml of water and extracted with ethyl acetate to remove unreacted ester. The aqueous phase was then adjusted to pH 1-2 with dilute hydrochloric acid and was extracted with ethyl acetate. After drying over magnesium sulfate and removal of the solvent by distillation, the residual foam (425 mg) was purified by MPLC, resulting in 205 mg (40%) of product as foam.
Reaction SMILES: [CH2:1]([C:4]1[C:5]([OH:19])=[C:6]([CH:11]=[C:12]([Cl:18])[C:13]=1[NH:14][C:15](=[O:17])[CH3:16])[C:7]([O:9][CH3:10])=[O:8])[CH:2]=[CH2:3].[H-].[Na+].S(OC)(O[CH3:26])(=O)=O>CN(C=O)C>[CH2:1]([C:4]1[C:5]([O:19][CH3:26])=[C:6]([CH:11]=[C:12]([Cl:18])[C:13]=1[NH:14][C:15](=[O:17])[CH3:16])[C:7]([O:9][CH3:10])=[O:8])[CH:2]=[CH2:3]
Reactant: COS(=O)(=O)OC
Reactant: C=CCc1c(O)c(C(=O)OC)cc(Cl)c1NC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCc1c(NC(C)=O)c(Cl)cc(C(=O)OC)c1OC
Reaction time: 0.25 h

Procedure:
A mixture of the phenolic compound of step 6 above (4 g) and NaH (0.7 g) in DMF (50 ml) is stirred for 15 minutes. Dimethyl sulfate (2 g) is added and the mixture is stirred for 16 hours. The mixture is partitioned between CH2Cl2 and H2O, and the organic layer is separated and washed with H2O, dried (MgSO4) and evaporated. The solid residue is twice recrystallized from MeOH-H2O and chromatographed on silica gel affording the desired product which is used in the next step.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][C:5]1[CH:14]=[C:13]([CH:15]2[CH2:20][CH2:19][N:18]([S:21]([C:24]3[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=3[Cl:31])(=[O:23])=[O:22])[CH2:17][CH2:16]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:32])[CH:11]=2)[CH:6]=1.O.[OH-].[Li+]>C1COCC1.O>[Cl:31][C:25]1[CH:26]=[CH:27][C:28]([Cl:30])=[CH:29][C:24]=1[S:21]([N:18]1[CH2:19][CH2:20][CH:15]([C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([F:32])[CH:11]=3)[CH:6]=[C:5]([CH2:4][C:3]([OH:33])=[O:2])[CH:14]=2)[CH2:16][CH2:17]1)(=[O:23])=[O:22]
Reactant: COC(=O)Cc1cc(C2CCN(S(=O)(=O)c3cc(Cl)ccc3Cl)CC2)c2cc(F)ccc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)Cc1cc(C2CCN(S(=O)(=O)c3cc(Cl)ccc3Cl)CC2)c2cc(F)ccc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 88.1 %

Procedure:
To a stirred solution of {4-[1-(2,5-dichloro-benzenesulfonyl)-piperidin-4-yl]-6-fluoro-naphthalen-2-yl}-acetic acid methyl ester (120 mg, 0.24 mmol) in THF (6 mL) was added a solution of lithium hydroxide monohydrate (50 mg, 1.2 mmol) in water (1.5 mL) and the reaction mixture was stirred for 24 h at RT. The reaction mixture was concentrated under reduced pressure and washed with diethyl ether (3×5 mL). The washings were discarded. Water (5 mL) was added to the residue, and the mixture acidified (pH ˜2-3) with an aqueous solution of hydrochloric acid (2 N) and extracted with ethyl acetate (3×5 mL). The combined organic extracts were dried over Na2SO4 and evaporated under reduced pressure to give {4-[1-(2,5-dichloro-benzenesulfonyl)-piperidin-4-yl]-6-fluoro-naphthalen-2-yl}-acetic acid (105 mg, 90%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.38 (br s, 1H), 7.96-8.01 (m, 2H), 7.94 (d, J=4.4 Hz, 1H), 7.80-7.83 (m, 2H), 7.69 (s, 1H), 7.41 (t, J=8.8 Hz, 1H), 7.36 (s, 1H), 3.91 (d, J=12.2 Hz, 2H), 3.72 (s, 2H), 3.08 (t, J=11.5 Hz, 2H), 1.90-1.96 (m, 2H), 1.67-1.77 (m, 2H); MS cald. for C23H19Cl2FNO4S [(M−H)−]: 494, obsd. 494.3.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][C@H:6]([CH3:8])[CH2:5][N:4]([CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19](=O)[CH2:20][CH:21]=O)=[CH:15][CH:14]=2)[CH2:3]1.O.[NH2:25][NH2:26]>CO.O>[CH3:1][C@H:2]1[CH2:7][C@H:6]([CH3:8])[CH2:5][N:4]([CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:20]=[CH:21][NH:26][N:25]=3)=[CH:15][CH:14]=2)[CH2:3]1
Reactant: NN
Reactant: C[C@H]1C[C@H](C)CN(CCCOc2ccc(C(=O)CC=O)cc2)C1
Solvent: CO
Solvent: O
Product: C[C@H]1C[C@H](C)CN(CCCOc2ccc(-c3cc[nH]n3)cc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of trans-3,5-dimethyl-1-{3-[4-(3-oxopropanoyl)phenoxy]propyl}-piperidine (200 mg) in a mixture of hydrazine hydrate (50 μL) and methanol (4 mL) is stirred for one hour at room temperature. The mixture is diluted with water and extracted twice with ethyl acetate, dried over magnesium sulphate, concentrated under reduced pressure and purified by chromatography over silica gel. Fractions containing the expected product are pooled, concentrated under reduced pressure and salted with oxalic acid to afford 142 mg of trans-3,5-dimethyl-1-{3-[4-(pyrazol-3-yl)phenoxy]propyl}piperidine, oxalate as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:8][C:9]=1[N:10]([C:17]([CH:19]1[CH2:24][CH2:23][CH:22]([CH3:25])[CH2:21][CH2:20]1)=[O:18])[CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:4].[CH:32](=O)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:8][C:9]=1[N:10]([CH:11]1[CH2:16][CH2:15][N:14]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:13][CH2:12]1)[C:17]([CH:19]1[CH2:20][CH2:21][CH:22]([CH3:25])[CH2:23][CH2:24]1)=[O:18])=[O:4]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)C1CCC(C)CC1)C1CCNCC1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)C1CCC(C)CC1)C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.5 %

Procedure:
To 3-[(4-Methyl-cyclohexanecarbonyl)-piperidin-4-yl-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (43 mg, 0.098 mmol) in dichloroethane (1.0 ml) was added benzaldehyde (15 ul, 0.146 mmol), followed by sodium triacetoxyborohydride (41 mg, 0.195 mmol). The reaction mixture was stirred at room temperature for 4 h, quenched with a saturated NaHCO3 solution, and then extracted with Ethyl acetate (3×5 ml). The combined extracts were then washed with brine and dried on Na2SO4, filtered and concentrated. The residue was purified by preparative chromatography (50% EtOAc/Hex) to give 32 mg (61%) of 3-[(1-Benzyl-piperidin-4-yl)-(4-methyl-cyclohexanecarbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[C:7](=[O:12])[CH2:6][CH2:5]2.CS(O)(=O)=O.[N-:18]=[N+]=[N-].[Na+].[OH-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[C:7](=[O:12])[NH:18][CH2:6][CH2:5]2
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1CCc2cc(Br)cc(F)c21
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C1NCCc2cc(Br)cc(F)c21
Temperature: 0 °C
Reaction time: 2 h
Yield: 47.1 %

Procedure:
To a mixture of 144d (10.35 g, 45.19 mmol) in DCM (75 mL) was added methanesulfonic acid (52.73 mL, 70.92 g, 737.90 mmol) at 0° C., followed by sodium azide (5.88 g, 90.44 mmol) in several portions. See FIG. 3. The reaction mixture was stirred at 0° C. for 2 h, and 20% aq. NaOH solution (40 mL) was added. The reaction mixture was stirred for 30 min, and the aqueous phase was extracted with DCM (400 mL×3). The combined organic layers were washed with saturated brine (200 mL×2), dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE/EA=10/1 to 2/1) to afford the 5.2 g (47.1%) of 6-bromo-8-fluoro-3,4-dihydroisoquinolin-1(2H)-one 144e. 1H NMR (400 MHz, CDCl3) δ 7.22-7.25 (d, J=10.4 Hz, 1H), 7.20 (s, 1H), 6.94 (s, 1H), 3.46-3.53 (m, 2H), 2.88-2.97 (m, 2H); MS-ESI [M+H]+=243.9/245.9.