Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16](=[O:31])[C:17]3[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=3)[CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[CH2:41]([S:43](Cl)(=[O:45])=[O:44])[CH3:42]>C(Cl)Cl.C(OCC)(=O)C>[CH2:41]([S:43]([NH:1][C:2]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16](=[O:31])[C:17]3[CH:22]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:20]=[C:19]([C:27]([F:28])([F:29])[F:30])[CH:18]=3)[CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3]1)(=[O:45])=[O:44])[CH3:42]
Reactant: CCS(=O)(=O)Cl
Reactant: NC1(CN2CCC(CNC(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)NC1(CN2CCC(CNC(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)CCCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of N-((1-((1-aminocyclopentyl)methyl)piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl)benzamide (100 mg, 0.28 mmol) and i-Pr2NEt (0.2 mL, 1.1 mmol) in CH2Cl2 (5 mL) was added ethanesulfonyl chloride (0.05 mL, 0.53 mmol). The reaction mixture was allowed to stir at room temperature for 18 hours and then diluted with ethyl acetate. The organic fraction was washed with sat. NaHCO3, and then brine and dried over Na2SO4. The solvent was removed and the crude was purified by High Throughput Purification System (HiTOPs) to provide N-((1-((1-(ethylsulfonamido)cyclopentyl)methyl)piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl)benzamide.
Reaction SMILES: [C:1]1(=[O:17])[N:5]([CH2:6][C:7]2[NH:11][N:10]=[N:9][N:8]=2)[C:4](=[O:12])[C:3]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:2]12.[CH3:18]CCC[Sn](O[Sn](CCCC)(CCCC)CCCC)(CCCC)CCCC.CI>>[CH3:18][N:11]1[C:7]([CH2:6][N:5]2[C:4](=[O:12])[C:3]3=[CH:13][CH:14]=[CH:15][CH:16]=[C:2]3[C:1]2=[O:17])=[N:8][N:9]=[N:10]1
Reactant: O=C1c2ccccc2C(=O)N1Cc1nnn[nH]1
Reactant: CCCC[Sn](CCCC)(CCCC)O[Sn](CCCC)(CCCC)CCCC
Solvent: CI
Product: Cn1nnnc1CN1C(=O)c2ccccc2C1=O
Reaction time: 72 h

Procedure:
A mixture of 5-phthalimidomethyltetrazole (5 g; J. Org. Chem., 1959, 24, 1643), bis(tributyltin) oxide (11 ml) and methyl iodide (9 ml) was stirred vigorously at laboratory temperature for 3 days. The mixture was evaporated to dryness and the residue was washed with hexane and then triturated under ethanol. There was thus obtained as a white solid 1-methyl-5-phthalimidomethyltetrazole (3.1 g).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[NH2:14][C:15]1[CH:23]=[C:22]2[C:18]([CH:19]=[N:20][NH:21]2)=[CH:17][CH:16]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:14][C:15]2[CH:23]=[C:22]3[C:18]([CH:19]=[N:20][NH:21]3)=[CH:17][CH:16]=2)=[O:8])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: Nc1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Nc1ccc(C(=O)Nc2ccc3cn[nH]c3c2)cc1[N+](=O)[O-]

Procedure:
4-Amino-3-nitrobenzoic acid (27 mmol) was coupled with 6-aminoindazole (30 mmol) using HBTU (30 mmol) in dry DMF as the solvent employing the general procedure D to afford 4-amino-N-(1H-indazol-6-yl)-3-nitrobenzamide which was used for further transformation without further purification.
Reaction SMILES: [C:1]([CH:4]1[NH:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]1)(=[O:3])[NH2:2].CCN(CC)CC.[C:24](Cl)(=[O:27])[CH:25]=[CH2:26]>C(Cl)Cl>[C:24]([N:9]1[CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5][CH:4]1[C:1](=[O:3])[NH2:2])(=[O:27])[CH:25]=[CH2:26]
Reactant: CC(C)(C)OC(=O)N1CCNC(C(N)=O)C1
Reactant: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)N1CCN(C(=O)OC(C)(C)C)CC1C(N)=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 53.9 %

Procedure:
To a solution of tert-butyl 3-carbamoylpiperazine-1-carboxylate (300 mg, 1.31 mmol) and Et3N (396 mg, 3.93 mmol) in DCM (5 mL) at 0° C., acryloyl chloride (130 mg, 1.44 mmol) in DCM (1 mL) was added and the resulting mixture was stirred at room temperature for 1.5 h. The mixture was partitioned between DCM and saturated NaHCO3 aqueous solution. The organic layer was washed with saturated NaHCO3 and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (DCM/MeOH=30:1) to afford the desired product (200 mg, 53.9% yield) as an off-white solid.
Reaction SMILES: C(Cl)CCl.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:17][CH2:16][CH:15]([C:18]([OH:20])=O)[CH2:14][CH2:13]2)=[CH:8][CH:7]=1.C1C=CC2N(O)N=NC=2C=1.Cl.[CH3:32][NH:33][O:34][CH3:35].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl.O>[CH3:35][O:34][N:33]([CH3:32])[C:18]([CH:15]1[CH2:16][CH2:17][CH:12]([C:9]2[CH:10]=[CH:11][C:6]([Cl:5])=[CH:7][CH:8]=2)[CH2:13][CH2:14]1)=[O:20]
Reactant: CNOC
Reactant: O=C(O)C1CCC(c2ccc(Cl)cc2)CC1
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)C1CCC(c2ccc(Cl)cc2)CC1
Temperature: 25 °C

Procedure:
EDC (3.21 g, 16.8 mmol) was added portionwise to a stirred solution of 4-(4-chlorophenyl)-cyclohexanecarboxylic acid (2.0 g, 8.4 mmol), DMAP (5 mg), HOBt (5 mg) and N,O-dimethylhydroxylamine hydrochloride (1.63 g, 16.8 mmol) in dichloromethane (40 mL). Triethylamine (3.4 g, 4.7 mL, 33.5 mmol) was added dropwise, and the reaction mixture was stirred at room temperature. After stirring overnight the reaction mixture was poured into water and extracted with ethyl acetate (3×). The combined organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give 4-(4-chlorophenyl)-cyclohexanecarboxylic acid, methoxy-methyl amide as a colorless oil (1.85 g. 78%); MS (+CI): m/z for C15H20ClNO2: expected 281.1. found 282.2 (M+H)+.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]#[N:8].C[O:10][C:11](=O)[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH2:22][CH2:23][O:24][CH3:25])[CH:14]=1.[NH4+].[Cl-]>C1COCC1.O>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][C:11](=[O:10])[CH2:6][C:7]#[N:8])=[CH:14][C:15]=1[O:21][CH2:22][CH2:23][O:24][CH3:25]
Reactant: COCCOc1cc(CC(=O)OC)ccc1OC
Reactant: CC#N
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: COCCOc1cc(CC(=O)CC#N)ccc1OC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 67.9 %

Procedure:
To a 250 mL three-necked round-bottomed flask was added 10 mL of anhydrous THF and cooled to −78° C. n-Butyl lithium (2.5 M in hexane, 8.06 mL, 12.9 mmol) was added and the mixture was stirred for 5 min. Anhydrous CH3CN (0.696 mL, 13.3 mmol) in 5 mL of anhydrous THF was added dropwise at −78° C. After 1 h of stirring, 4-methoxy-3-(2-methoxyethoxy)phenylacetic acid methyl ester (1.10 g, 4.3 mmol) in 10 mL of anhydrous THF was added dropwise to the resulting white colloidal mixture. The reaction mixture was stirred for an additional 2 h, followed by the addition of saturated NH4Cl solution at −78° C. The solution was warmed to r.t., diluted with 100 mL water and extracted with EtOAc (3×100 mL). The combined organics were washed with brine, dried with anhydrous MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel eluting with gradient 30-60% EtOAc in hexanes to yield 769 mg (68% yield) of 4-[4-methoxy-3-(2-methoxyethoxy)phenyl]-3-oxo-butyronitrile as a colorless oil.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[Cl:5][C:6]([Cl:12])([Cl:11])[CH2:7][CH:8]1[O:10][CH2:9]1.C1OC1C>C(O)(C)C.C(O)C>[CH2:1]([NH2:4])[CH2:2][NH2:3].[Cl:5][C:6]([Cl:12])([Cl:11])[CH2:7][CH:8]([OH:10])[CH3:9]
Reactant: ClC(Cl)(Cl)CC1CO1
Agent: CC1CO1
Solvent: NCCN
Solvent: CCO
Solvent: CC(C)O
Product: CC(O)CC(Cl)(Cl)Cl
Temperature: 70 °C
Reaction time: 5 h

Procedure:
To a solution of 10.0g (0.17 mole) ethylenediamine in 100 ml isopropanol and 50 ml ethanol heated at 60° C. under nitrogen was added, dropwise, a mixture of 58.5g (0.33 mole) 4,4,4-trichloro-1,2-epoxybutane and 58.5g (1.0 mole) propylene oxide over a period of one hour. The reaction mixture was refluxed at 70° C. for one hour and an additional 17.2g (0.30 mole) of propylene oxide was then added dropwise. Refluxing with agitation was continued for an additional five hours and the mixture allowed to stand overnight. Evaporation of the solvent via vacuum afforded 74g of an addition product between ethylenediamine, 2-hydroxypropane, and 4,4,4-trichloro-2-hydroxybutane; hydroxyl number = 518. Analysis: (Calculated) %Cl, 29.52; %N, 6.47. (Found) %Cl, 29.22; %N, 6.31. On the basis of the analytical data one mole of ethylenediamine reacted with 1.2 moles 4,4,4-trichloro-1,2-epoxybutane and 2.8 moles propylene oxide.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](Cl)=[O:5].[Cl:12][C:13]1[C:14]([C:24]2[N:25]=[CH:26][C:27]([NH2:30])=[N:28][CH:29]=2)=[CH:15][C:16]2[O:20][C:19]([F:22])([F:21])[O:18][C:17]=2[CH:23]=1.CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.ClCCl.O1CCCC1.CO.[OH-].[Li+]>[Cl:12][C:13]1[C:14]([C:24]2[N:25]=[CH:26][C:27]([NH:30][C:4](=[O:5])[C:3]3[C:2]([F:1])=[CH:10][CH:9]=[CH:8][C:7]=3[F:11])=[N:28][CH:29]=2)=[CH:15][C:16]2[O:20][C:19]([F:22])([F:21])[O:18][C:17]=2[CH:23]=1
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: Nc1cnc(-c2cc3c(cc2Cl)OC(F)(F)O3)cn1
Agent: CN(C)c1ccncc1
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cnc(-c2cc3c(cc2Cl)OC(F)(F)O3)cn1)c1c(F)cccc1F
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 55.1 %

Procedure:
Under an atmosphere of argon, 2,6-difluorobenzoyl chloride (17 mg, 98 μmol) was added to a stirred solution of 117 (14 mg, 49 μmol), Hünig's base (51 μl, 38 mg, 290 μmol), and DMAP (1 mg, 8 μmol) in dichloromethane (780 μL) at room temperature. The reaction was stirred for 0.5 h. The solution was diluted with tetrahydrofuran (1.5 mL), methanol (1 mL) and 1.2 M lithium hydroxide solution (500 μL). The mixture was stirred and heated to 60° C. for 45 min then cooled to room temperature and diluted with dichloromethane (5 mL) and dried with sodium sulfate. The mixture was concentrated under reduced pressure. Flash chromatography (ISCO system, silica, 0-30% ethyl acetate in hexane) provided 118 (11.5 mg, 55%) as a solid: LRESIMS m/z 426.1 [M+H]+, calcd. for C18H9Cl1F4N3O3 426.0.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:11])[NH:9][CH3:10])[C:5]([NH:12][C:13]2[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:55]=[CH:54][C:27]([CH2:28][CH2:29][CH2:30][CH2:31][PH:32](=[O:53])[O:33][CH2:34][C:35]([CH3:52])([CH3:51])[CH2:36][N:37]4[CH:41]=[C:40]([B:42]5[O:46][C:45]([CH3:48])([CH3:47])[C:44]([CH3:50])([CH3:49])[O:43]5)[CH:39]=[N:38]4)=[CH:26][C:25]=3[O:56][CH3:57])[N:14]=2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB(C2C=NN(CC3(CO)CC3)C=2)O1>>[Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:11])[NH:9][CH3:10])[C:5]([NH:12][C:13]2[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:55]=[CH:54][C:27]([CH2:28][CH2:29][CH2:30][CH2:31][PH:32](=[O:53])[O:33][CH2:34][C:35]4([CH2:36][N:37]5[CH:41]=[C:40]([B:42]6[O:46][C:45]([CH3:47])([CH3:48])[C:44]([CH3:49])([CH3:50])[O:43]6)[CH:39]=[N:38]5)[CH2:51][CH2:52]4)=[CH:26][C:25]=3[O:56][CH3:57])[N:14]=2)=[CH:4][CH:3]=1
Reactant: CNC(=O)c1nc(Br)ccc1Nc1nc(Nc2ccc(CCCC[PH](=O)OCC(C)(C)Cn3cc(B4OC(C)(C)C(C)(C)O4)cn3)cc2OC)ncc1C(F)(F)F
Agent: CC1(C)OB(c2cnn(CC3(CO)CC3)c2)OC1(C)C
Product: CNC(=O)c1nc(Br)ccc1Nc1nc(Nc2ccc(CCCC[PH](=O)OCC3(Cn4cc(B5OC(C)(C)C(C)(C)O5)cn4)CC3)cc2OC)ncc1C(F)(F)F

Procedure:
Prepared analogously to Compound 74A replacing Compound 47B with (1-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]methyl}cyclopropyl)methanol (Compound 63B). MS (ESI): m/z 877.90/879.86 [M+H]+. UPLC: tR=1.60 min (UPLC-SQD: analytical—2 min).
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[F:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[N:21][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>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.C(Cl)Cl.O>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:19]2[CH:20]=[N:21][CH:22]=[C:17]([F:16])[CH:18]=2)[C:11]=1[CH3:12]
Reactant: OB(O)c1cncc(F)c1
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: Cc1c(-c2cncc(F)c2)nc2cc(F)cc(F)c2c1Cl

Procedure:
Prepared according to procedure F by stirring 2,4-dichloro-5,7-difluoro-3-methylquinoline (1 g, 4.03 mmol), 5-fluoropyridine-3-boronic acid (0.568 g, 4.03 mmol), PdCl2(PPh3)2 (0.283 g, 0.403 mmol), sodium carbonate (0.505 mL, 12.09 mmol), 1,4-dioxane (5 mL), and water (1.25 mL) at 95° C. for 3 h. Trituration of the crude product with DCM afforded 4-chloro-5,7-difluoro-2-(5-fluoropyridin-3-yl)-3-methylquinoline. Mass Spectrum (ESI) m/e=309.0 (M+1).
Reaction SMILES: [OH-:1].[Na+].[C:3]([O:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[C:27]([C:28]#[N:29])=[C:26]([CH:30]([OH:34])[CH:31]([CH3:33])[CH3:32])[N:25]=[C:24]2[CH2:35][CH2:36][CH2:37][CH3:38])=[CH:18][CH:17]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>C(O)C>[C:3]([O:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[C:27]([C:28]([NH2:29])=[O:1])=[C:26]([CH:30]([OH:34])[CH:31]([CH3:32])[CH3:33])[N:25]=[C:24]2[CH2:35][CH2:36][CH2:37][CH3:38])=[CH:18][CH:17]=1)=[O:9])([CH3:5])([CH3:4])[CH3:6]
Reactant: [OH-]
Reactant: CCCCc1nc(C(O)C(C)C)c(C#N)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: [Na+]
Solvent: CCO
Product: CCCCc1nc(C(O)C(C)C)c(C(N)=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1

Procedure:
20 ml of a 1N aqueous solution of sodium hydroxide were added to a solution of 297 mg of 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-2-butyl-4-(1-hydroxy-2-methylpropyl)imidazole-5-carbonitrile [prepared as described in step (b) above] in 20 ml of ethanol, and the resulting mixture was heated under reflux for 8 hours. At the end of this time, the reaction mixture was worked up in a similar manner to that described in Example 45(c), to afford 151 mg of the title compound as an amorphous solid.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:6](O)=[O:7].C1(C)C=CC=CC=1>S(Cl)(Cl)=O>[ClH:1].[F:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:6]([Cl:1])=[O:7]
Reactant: O=C(O)c1ccc(OCCN2CCCCC2)c(F)c1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: O=C(Cl)c1ccc(OCCN2CCCCC2)c(F)c1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 188.6 %

Procedure:
To a solution of 3-fluoro-4-(2-piperidin-1-ylethoxy)benzoic acid hydrochloride (2.0 g) in thionyl chloride (20 ml) was added toluene (20 ml), the solution was stirred for 30 minutes at 100° C., then the reaction solution was concentrated in vacuo to provide 3-fluoro-4-(2-piperidin-1-ylethoxy)benzoyl chloride hydrochloride (2.0 g). To a solution of 2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenylamine (253 mg) in dichloromethane (8 ml) were sequentially added an aqueous solution of 1N sodium hydroxide (4 ml) and 3-fluoro-4-(2-piperidin-1-ylethoxy)benzoyl chloride hydrochloride (400 mg), and the solution was stirred overnight at room temperature. The solution was extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, then the solvent was evaporated in vacuo. Synthesized from the resulting 3-fluoro-N-[2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]-4-(2-piperidin-1-ylethoxy)benzamide (423 mg) according to an analogous synthetic method to Example 337 described below, the title compound (418 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH3:11])=[CH:4][C:3]=1[CH2:12][C:13]1[N:17]2[N:18]=[C:19]([CH:22]=C)[CH:20]=[CH:21][C:16]2=[N:15][CH:14]=1.C[N+]1([O-])CC[O:28]CC1.I([O-])(=O)(=O)=O.[Na+]>CC(C)=O.O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH3:11])=[CH:4][C:3]=1[CH2:12][C:13]1[N:17]2[N:18]=[C:19]([CH:22]=[O:28])[CH:20]=[CH:21][C:16]2=[N:15][CH:14]=1
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=Cc1ccc2ncc(Cc3cc4cnn(C)c4cc3F)n2n1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC(C)=O
Solvent: O
Product: Cn1ncc2cc(Cc3cnc4ccc(C=O)nn34)c(F)cc21
Temperature: 46 °C
Reaction time: 4 h
Yield: 39.7 %

Procedure:
To a mixture of 3-((6-fluoro-1-methyl-1H-indazol-5-yl)methyl)-6-vinylimidazo[1,2-b]pyridazine (50 mg, 0.163 mmol) osmium(VIII) oxide (103 mg, 8.13 μmol), was added a solution of NMO (29.5 mg, 0.252 mmol) in acetone (2 ml) and H2O (0.16 ml). The reaction mixture was heated to 46° C. After stirring for 4 h, the solvent was removed and a mixture of THF (6 ml) and H2O (1.5 ml) was added to dissolve the residue, then sodium periodate (69.6 mg, 0.325 mmol) was added and the resulting mixture was stirred at 46° C. for 12 h. The reaction mixture was then quenched with Na2SO3(aq), extracted with DCM, dried over Na2SO4, filtered through Celite and concentrated in vacuo to give a residue, which was purified by silica gel column chromatography with gradient Hex:EA to give 3-((6-fluoro-1-methyl-1H-indazol-5-yl)methyl)imidazo[1,2-b]pyridazine-6-carbaldehyde (20 mg), yield 38%. 1H-NMR (400 MHz, CDCl3) δ ppm 10.09 (s, 1H), 8.07 (dd, 1H), 7.89 (d, 1H), 7.74 (s, 1H), 7.63 (m, 2H), 7.10 (d, 1H), 4.54 (s, 2H), 4.03 (s, 3H). LCMS (method A): [MH]+=310, tR=3.95 min.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C([O:9][C:10](=O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])C.S([O-])(O)(=O)=O.[K+]>CCOCC>[CH3:18][CH:17]([CH3:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][OH:9]
Reactant: CCOC(=O)CCCCCCC(C)C
Agent: O=S(=O)([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: CC(C)CCCCCCCO
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.1 %

Procedure:
LAH (lithium aluminum hydride, 1.10 g, 29.0 mmol) was suspended in ether (50 ml), and the slurry was kept at 0° C. Thereto was slowly added dropwise a solution of 8-methylnonanoic acid ethyl ester (5.81 g, 29.0 mmol) in ether (20 ml). After the completion of the dropwise addition, the slurry was stirred at room temperature for 2 hr and 10% aqueous potassium hydrogen sulfate solution (50 ml) was slowly added to the reaction mixture. Ether (100 ml) was further added, and the aqueous layer was separated from the organic layer. The organic layer was washed with saturated brine (50 ml), and dried over anhydrous magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was distilled under reduced pressure (60 to 65° C./2 mmHg) to give 8-methyl-1-nonanol (4.27 g, 27.0 mmol) as a colorless oil.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[CH3:15][C:16]([CH3:18])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)C.C(O)(=O)C>[CH:16]([NH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1)([CH3:18])[CH3:15]
Reactant: CC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)N[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 60 °C

Procedure:
Commercially available tert-butyl (3R)-3-aminopiperidine-1-carboxylate (6.67 g) was dissolved in ethanol (100 ml), and thereto were added acetone (12.2 ml) and acetic acid (2.0 ml), and the mixture was heated at 60° C. with stirring. Seven hours later, to the mixture was added sodium triacetoxyborohydride (9.67 g), and the mixture was stirred at room temperature for 14 hours. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium hydrogen sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (the developing solvent: chloroform/methanol=30/1, 15/1, 10) to give the title compound (7.78 g) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=[O:13])[NH:8]2)#N.C(O)=[O:15]>[Ni]>[O:13]=[C:7]1[CH2:6][CH2:5][C:4]2[C:3]([CH:1]=[O:15])=[CH:12][CH:11]=[CH:10][C:9]=2[NH:8]1
Reactant: N#Cc1cccc2c1CCC(=O)N2
Reactant: O=CO
Agent: [Ni]
Product: O=Cc1cccc2c1CCC(=O)N2
Yield: 76 %

Procedure:
5-Cyano-3,4-dihydro-1H-quinolin-2-one (100 mg) and Raney nickel (100 mg) were suspended in formic acid (10 ml), and the suspension was heated under reflux for 2 hours. An additional 100 mg of Raney nickel was added, followed by heating under reflux for 1 hour. The reaction mixture was filtered to remove the insoluble matter, and the filtrate was concentrated. Ethyl acetate and water were added to the residue, and after stirring, the mixture was filtered through Celite. The filtrate was separated into layers, and the organic layer was washed with water and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was recrystallized from an ethyl acetate-n-hexane mixed solvent to thereby obtain 77 mg (yield: 76%) of 2-oxo-1,2,3,4-tetrahydroquinoline-5-carboxaldehyde as a light brown powder.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[O:11])=[CH:4][CH:3]=1.[C:27]([O-])([OH:29])=[O:28].[Na+].C(OCC)(=O)C.[C]=O>[CH-]1C=C(P(C2C=CC=CC=2)C2C=CC=CC=2)C=C1.[CH-]1C=C(P(C2C=CC=CC=2)C2C=CC=CC=2)C=C1.Cl[Pd]Cl.[Fe+2].O>[CH3:18][N:16]1[C:15](=[O:19])[CH:14]=[CH:13][C:12]([C:10](=[O:11])[CH2:9][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([C:27]([OH:29])=[O:28])=[CH:7][CH:6]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])=[CH:17]1
Reactant: O=C([O-])O
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [C]=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Yield: 94 %

Procedure:
A mixture of 5-[3-(4-bromo-phenyl)-3-o-tolyl-propionyl]-1-methyl-1H-pyridin-2-one (150 mg, example 162, step 3), dichloro(1,1′-bis(diphenylphosphino)ferrocene)palladium(II) dichloromethane adduct (30 mg), NaHCO3 (77 mg), ethyl acetate (4.5 ml) and water (1.5 ml) was treated with carbon monoxide at 150° C./80 bar for 20 h. After cooling to room temperature, the mixture was filtered. The filter cake was washed with ethyl acetate and with aqueous KHSO4 solution. The combined filtrate was extracted with ethyl acetate. The organic phase was washed with brine, dried (MgSO4), filtered and concentrated to dryness. The residue was taken up in 1 M aqueous NaOH solution and washed with diethyl ether. The aqueous phase was acidified using concentrated aqueous HCl and extracted with ethyl acetate. The organic phase was washed with brine, dried (MgSO4), filtered and concentrated to dryness to give the title compound (129 mg) as a light brown solid, MS (ESI−): m/z=374.1 [M−H]−.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][Cl:18]>>[Cl:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][O:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: ClCCCCCCBr
Reactant: CC(=O)c1cccc(O)c1
Product: CC(=O)c1cccc(OCCCCCCCl)c1

Procedure:
Prepared by Procedure U and Scheme AK using 1-(3-hydroxyphenyl)ethanone and 1-bromo-6-chlorohexane.