Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)(O)O.[C:5]1([NH:11][C:12]([NH2:14])=[NH:13])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH:15]1([C:18](=O)[CH2:19][C:20](=O)[CH3:21])[CH2:17][CH2:16]1.C(=O)=O>C(OCC)C>[C:5]1([NH:11][C:12]2[N:14]=[C:20]([CH3:21])[CH:19]=[C:18]([CH:15]3[CH2:17][CH2:16]3)[N:13]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(=O)CC(=O)C1CC1
Reactant: N=C(N)Nc1ccccc1
Agent: O=C(O)O
Agent: O=C=O
Solvent: CCOCC
Product: Cc1cc(C2CC2)nc(Nc2ccccc2)n1
Temperature: 25 °C

Procedure:
10 g (51 mmol) of phenylguanidine hydrogen carbonate and 9.6 g (77 mmol) of 1-cyclopropyl-1,3-butanedione are heated at 110° C. for 6 hours with stirring the evolution of carbon dioxide which occurs subsiding as the reaction progresses. After the dark brown emulsion has been cooled to room temperature, 50 ml of diethyl ether are added and the mixture is washed twice with 20 ml of water each time, dried over sodium sulfate and filtered, and the solvent is evaporated. The dark brown oil which remains (=13.1 g) is purified by column chromatography over silica gel (diethyl ether/toluene: 5/3). After the eluant mixture has been evaporated off, the brown oil is made to crystallise and recrystallised from diethyl ether/petroleum ether at 30°-50° C. Light-brown crystals are obtained. Melting point: 67°-69° C.; yield: 8.55 g (38 mmol) (=74.5% of the theoretical yield).
Reaction SMILES: C([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]#[C:12][CH2:13][CH2:14][CH2:15][C:16](=[O:20])[N:17]([CH3:19])[CH3:18])[CH:6]=1)C.[OH-].[Na+].Cl>>[CH3:19][N:17]([CH3:18])[C:16]([CH2:15][CH2:14][CH2:13][C:12]#[C:11][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=1)[C:4]([OH:21])=[O:3])=[O:20]
Reactant: CCOC(=O)c1cccc(C#CCCCC(=O)N(C)C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CN(C)C(=O)CCCC#Cc1cccc(C(=O)O)c1
Yield: 73.7 %

Procedure:
3-(5-Dimethylcarbamoyl-pent-ynyl)benzoic acid ethyl ester (0.800 g, 2.78 mmol) was treated with sodium hydroxide 1M solution (6 mL) overnight. To the reaction mixture 7 mL of HCl 1M solution was added and the solvent was removed under vacuum. The residue was triturated with ethyl acetate, to give 3-(5-dimethylcarbamoyl-pent-1-ynyl)-benzoic acid (24)(0.590 g, 2.05 mmol; yield 74%) as white off powder.
Reaction SMILES: [OH:1][N:2]=[CH:3][C:4]1[N:5]=[C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[S:7][CH:8]=1.ClN1C(=O)CCC1=O.[Cl:30][C:31]1[C:32]([CH:38]=[CH2:39])=[C:33]([OH:37])[CH:34]=[CH:35][CH:36]=1.C(=O)([O-])O.[K+]>C(OCC)(=O)C.O>[Cl:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([OH:37])[C:32]=1[CH:38]1[O:1][N:2]=[C:3]([C:4]2[N:5]=[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]3)[S:7][CH:8]=2)[CH2:39]1
Reactant: C=Cc1c(O)cccc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C=NO)cs2)CC1
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Cl
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2nc(C3=NOC(c4c(O)cccc4Cl)C3)cs2)CC1

Procedure:
To a solution of tert-butyl 4-{4-[(hydroxyimino)methyl]-1,3-thiazol-2-yl}piperidine-1-carboxylate (400 mg) in ethyl acetate (10 ml) was added N-chlorosuccinimide (206 mg). The reaction mixture is stirred at reflux for 30 min. To the reaction mixture were added 3-chloro-2-vinylphenol (397 mg) and potassium hydrogencarbonate (257 mg) at room temperature, and then one drop of water. After stirring at room temperature overnight, the reaction mixture was admixed with ethyl acetate and water and extracted with ethyl acetate. The organic extracts were dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by chromatography. This gave tert-butyl 4-{4-[5-(2-chloro-6-hydroxyphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidine-1-carboxylate (345 mg).
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([C@@H:28]([C:45]3[CH:49]=[CH:48][O:47][N:46]=3)[CH2:29][C:30](N3[C@@H](CC4C=CC=CC=4)COC3=O)=[O:31])=[CH:24][CH:23]=2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].C1C[O:53]CC1.O.OO.[OH-].[Li+].[O-]S([O-])=O.[Na+].[Na+]>>[CH3:3][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([C@@H:28]([C:45]3[CH:49]=[CH:48][O:47][N:46]=3)[CH2:29][C:30]([OH:53])=[O:31])=[CH:24][CH:23]=2)=[CH:7][CH:6]=1)([CH3:1])[CH3:4]
Reactant: C1CCOC1
Reactant: COc1ccc(F)c(-c2cc(COc3ccc([C@H](CC(=O)N4C(=O)OC[C@@H]4Cc4ccccc4)c4ccon4)cc3)ccc2C(C)(C)C)c1
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Li+]
Solvent: O
Product: COc1ccc(F)c(-c2cc(COc3ccc([C@H](CC(=O)O)c4ccon4)cc3)ccc2C(C)(C)C)c1
Reaction time: 0.67 h
Yield: 47.6 %

Procedure:
To a stirred solution of 6.6 (0.0282 g, 0.043 mmol) in THF (3.00 mL, 37 mmol) and water (1.00 mL, 56 mmol) at 0° C. was added 35% hydrogen peroxide (0.025 mL, 0.26 mmol) followed by lithium hydroxide (0.0020 g, 0.085 mmol). Stirring continued for 1 hour and 40 minutes. A saturated solution of Na2SO3 was added, and stirring was continued at 0° C. for 30 minutes. The mixture was extracted with EtOAc (3×10 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was then purified by flash chromatography (SiO2 gel 60, eluted with 0%-30% EtOAc/hexane) to give compound 6 as a clear oil (0.0103 g, 48% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.28 (1H, d, J=1.6 Hz), 7.58 (1H, d, J=8.6 Hz), 7.40 (1H, dd, J=8.2, 2.0 Hz), 7.17 (2H, d, J=8.8 Hz), 6.86 (1H, dt, J=8.0, 3.9 Hz), 6.78 (1H, dd, J=5.9, 3.1 Hz), 6.07 (1H, d, J=1.6 Hz), 4.99 (2H, s), 4.54 (1H, dd, J=7.9, 7.4 Hz), 3.79 (3H, s), 3.35 (1H, dd, J=16.6, 7.9 Hz), 2.98 (1H, dd, J=16.4, 7.4 Hz), 1.23 (9H, s). MS ESI (neg.) m/e: 502.1 (M−H)+.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[O:28]1[C:32]2[CH:33]=[CH:34][C:35]([CH2:37][C:38](O)=[O:39])=[CH:36][C:31]=2[O:30][CH2:29]1>>[O:28]1[C:32]2[CH:33]=[CH:34][C:35]([CH2:37][C:38]([NH:27][C@H:24]3[CH2:25][CH2:26][C@H:21]([CH2:20][CH2:19][N:16]4[CH2:17][CH2:18][N:13]([C:8]5[C:7]6[CH2:6][CH2:5][O:4][C:12]=6[CH:11]=[CH:10][N:9]=5)[CH2:14][CH2:15]4)[CH2:22][CH2:23]3)=[O:39])=[CH:36][C:31]=2[O:30][CH2:29]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: O=C(O)Cc1ccc2c(c1)OCO2
Agent: Cl
Product: O=C(Cc1ccc2c(c1)OCO2)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (110 mg, 89%), MS (ISP) m/z=493.4 [(M+H)+], mp 212° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and 2-(benzo[1,3]dioxol-5-yl)-acetic acid.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][O:9][C:10]2[CH:15]=[C:14]([CH:16]([CH3:18])[CH3:17])[CH:13]=[CH:12][C:11]=2[CH3:19])=[C:6]([CH3:20])[N:5]=[C:4]([C:21]2[C:26]([CH2:27][CH3:28])=[CH:25][CH:24]=[CH:23][C:22]=2[CH2:29][CH3:30])[N:3]=1.CC1(C)C(C)(C)OB([C:39]2[CH2:44][CH2:43][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:41][CH:40]=2)O1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:27]([C:26]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:29][CH3:30])[C:21]=1[C:4]1[N:3]=[C:2]([C:39]2[CH2:44][CH2:43][N:42]([C:45]([O:47][C:48]([CH3:49])([CH3:50])[CH3:51])=[O:46])[CH2:41][CH:40]=2)[C:7]([CH2:8][O:9][C:10]2[CH:15]=[C:14]([CH:16]([CH3:18])[CH3:17])[CH:13]=[CH:12][C:11]=2[CH3:19])=[C:6]([CH3:20])[N:5]=1)[CH3:28]
Reactant: CCc1cccc(CC)c1-c1nc(C)c(COc2cc(C(C)C)ccc2C)c(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1cccc(CC)c1-c1nc(C)c(COc2cc(C(C)C)ccc2C)c(C2=CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 80 °C

Procedure:
To a solution of 4-chloro-2-(2,6-diethylphenyl)-5-((5-isopropyl-2-methylphenoxy)methyl)-6-methylpyrimidine (423 mg, 1 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (Wustrow and Wise, Synthesis, 1991, 993) (371 mg, 1.2 mmol) in anhydrous DMF (5 mL) is added K2CO3 (414 mg, 3 mmol). The mixture is bubbled with N2 for 15 min and PdCl2dppf (28 mg) is added. The mixture is then heated under N2 at 80° C. for 16 h. After cooling to room temperature, the mixture is diluted with ether, washed with water and brine. The organic layer is dried over anhydrous MgSO4, concentrated and purified by silica gel column chromatography to provide the title product. [mass expected (569.8); mass found (M+1: 570.6)].
Reaction SMILES: O=[C:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([OH:13])=[O:12])[C:5]=2[CH2:4][CH2:3]1.Cl.[I:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22]N)=[CH:18][CH:17]=1>C(O)=O.Cl>[I:15][C:16]1[CH:21]=[CH:20][C:19]2[NH:22][C:2]3[C:10]4[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([OH:13])=[O:12])[C:5]=4[CH2:4][C:3]=3[C:18]=2[CH:17]=1
Reactant: O=C(O)c1cccc2c1CCC2=O
Reactant: NNc1ccc(I)cc1
Agent: Cl
Solvent: O=CO
Product: O=C(O)c1cccc2c1Cc1c-2[nH]c2ccc(I)cc12

Procedure:
1-Oxo-indan-4-carboxylic acid (0.528 g, 2.99 mmol) and 4-iodophenylhydrazine hydrochloride (0.698 g, 2.58 mmol) were mixed together in a Teflon PFA vessel to form a paste in formic acid (2 mL, 96%) containing 3 drops of concentrated HCl. The vessel was irradiated at full power (760W) in a CEM Microwave (MDS2000) for one minute (T=140C, P<50 PSI), allowed to cool for 2 min, then irradiated again for one min (T=140C, P<50 PSI). The mixture was vacuum filtered hot. The solid was washed with formic acid, and dried on the frit. Chromatography (acetone/hexane) and trituration with diethyl ether have the title compound (0.059 g, 5%) as an tan solid: mp 251° C.; 1H NMR (DMSO-d6): δ 3.98 (s, 2H), 7.30-7.37 (m, 2H), 7.49 (t, 1H), 7.77-7.80 (m, 2H), 7.98 (d, 1H), 11.82 (s, 1H), 13.53 (s, 1H); MS [EI, m/z]: 375 [M]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.Br[CH:16]([CH3:20])[CH2:17][C:18]#[N:19].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH3:1][C:2]1([CH3:14])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH:13]=[N:12][N:11]([CH:16]([CH3:20])[CH2:17][C:18]#[N:19])[CH:10]=2)[O:3]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CC(Br)CC#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(CC#N)n1cc(B2OC(C)(C)C(C)(C)O2)cn1

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (50 mg, 0.2 mmol), 3-bromobutanenitrile (46 mg, 0.31 mmol, TCI America, Cat. No. B 1452), and cesium carbonate (250 mg, 0.77 mmol) in acetonitrile (1 mL) was stirred at 90° C. for 3 hours. After cooling it was quenched with water, extracted with ethyl acetate. The extract was washed with water twice, brine once; dried over Na2SO4. After filtration the filtrate was concentrated to yield 60 mg product. It was directly used in the next step reaction without further purification.
Reaction SMILES: [CH2:1]([C:5]1[C:9]([CH2:10][CH2:11][C:12]2[S:13][C:14]([C:18]([OH:20])=O)=[C:15]([CH3:17])[N:16]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:53][CH2:54][C:55]([CH3:58])([OH:57])[CH3:56]>CN(C=O)C>[OH:57][C:55]([CH3:58])([CH3:56])[CH2:54][NH:53][C:18]([C:14]1[S:13][C:12]([CH2:11][CH2:10][C:9]2[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:6][O:7][C:8]=2[CH3:21])=[N:16][C:15]=1[CH3:17])=[O:20]
Reactant: CC(C)(O)CN
Reactant: CCCCc1noc(C)c1CCc1nc(C)c(C(=O)O)s1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCc1noc(C)c1CCc1nc(C)c(C(=O)NCC(C)(C)O)s1
Reaction time: 15 h
Yield: 55.7 %

Procedure:
To a solution of 2-[2-(3-butyl-5-methyl-isoxazol-4-yl)-ethyl]-4-methyl-thiazole-5-carboxylic acid (80 mg, 0.26 mmol) in DMF (4 mL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (92 mg, 0.29 mmol), N,N-diisopropyl ethyl amine (168 mg, 1.3 mmol) and 1-amino-2-methyl-propan-2-ol (25 mg, 0.29 mmol). The resulting reaction mixture was stirred for 15 h and then evaporated. Purification by chromatography (silica, 0 to 10% methanol in dichloromethane) afforded the title compound (55 mg, 56%) as a colourless oil MS: m/e=380.4 [M+H]+.
Reaction SMILES: [ClH:1].Cl.Cl.[CH:4]([N:7]([CH2:21]/[CH:22]=[CH:23]/[C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27]([NH2:29])=[NH:28])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:10][CH:9]=1)([CH3:6])[CH3:5].Cl.[C:34](=[NH:39])(OCC)[CH3:35].C(N(CC)CC)C.Cl>CO.O1CCOCC1>[ClH:1].[ClH:1].[ClH:1].[C:34]([N:18]1[CH2:17][CH2:16][CH:15]([O:14][C:11]2[CH:10]=[CH:9][C:8]([N:7]([CH2:21]/[CH:22]=[CH:23]/[C:24]3[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=3)[C:27]([NH2:29])=[NH:28])[CH:4]([CH3:6])[CH3:5])=[CH:13][CH:12]=2)[CH2:20][CH2:19]1)(=[NH:39])[CH3:35]
Reactant: CCOC(C)=N
Reactant: CC(C)N(C/C=C/c1cccc(C(=N)N)c1)c1ccc(OC2CCNCC2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(=N)N1CCC(Oc2ccc(N(C/C=C/c3cccc(C(=N)N)c3)C(C)C)cc2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 231.7 %

Procedure:
To a solution of 3-[3-[N-isopropyl-N-[4-(piperidin-4-yloxy)phenyl]amino]-1-(E)-propenyl]benzamidine trihydrochloride (310 mg) in methanol (20 ml) were added ethyl acetimidate hydrochloride (229 mg) and triethylamine (0.52 ml) at room temperature. The resulting mixture was stirred at room temperature for 12 hours. To the reaction mixture was added a 4M solution of hydrogen chloride in dioxane (1 ml) and the solution was concentrated in vacuo. The residue was purified by preparative HPLC (YMC-Pack ODS YMC) using 15% aqueous acetonitrile as an eluant to afford an amorphous solid. To a solution of the solid in methanol (10 ml) was added a 4M solution of hydrogen chloride in dioxane (0.5 ml) and the mixture was concentrated to dryness in vacuo. A solution of the residual solid in water (about 10 ml) was lyophilized to give the title compound (259 mg, yield 77%) as a pale brown amorphous solid.
Reaction SMILES: [CH:1]1[C:6]2[NH:7][C:8](=O)[C:9]3[C:10]4[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=4[C:12](=[O:15])[NH:13][C:14]=3[C:5]=2[CH:4]=[CH:3][CH:2]=1.O=P(Cl)(Cl)[Cl:23]>>[Cl:23][C:8]1[N:7]=[C:6]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=[C:14]2[C:9]=1[C:10]1[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=1[C:12](=[O:15])[NH:13]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c2c3ccccc3[nH]c(=O)c2c2ccccc12
Product: O=c1[nH]c2c3ccccc3nc(Cl)c2c2ccccc12

Procedure:
chlorinating a dibenzo[c,h][1,6]naphthyridine-6,11(5H,12H)-dione with a chlorinating reagent comprising POCl3 to give the corresponding 11-chlorodibenzo[c,h][1,6]-naphthyridin-6(5H)-one; and/or
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][N:15]3[CH:19]=[CH:18][N:17]=[N:16]3)[O:11][C:10]2=[O:20])[CH:5]=[CH:6][C:7]=1I.C([Sn](CCCC)(CCCC)[C:26]1[O:30][N:29]=[C:28]([CH3:31])[CH:27]=1)CCC>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][N:15]3[CH:19]=[CH:18][N:17]=[N:16]3)[O:11][C:10]2=[O:20])[CH:5]=[CH:6][C:7]=1[C:26]1[O:30][N:29]=[C:28]([CH3:31])[CH:27]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C)no1
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(I)c(F)c1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Cc1cc(-c2ccc(N3C[C@H](Cn4ccnn4)OC3=O)cc2F)on1
Temperature: 100 °C
Reaction time: 16 h
Yield: 49.7 %

Procedure:
A suspension of (5R)-3-(3-fluoro-4-iodophenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (Intermediate 6, 582 mg, 1.50 mmol) in 1,4-dioxane (14 ml) was placed under argon. Bis(triphenylphospine)palladium (II) chloride (42 mg, 0.060 mmol) was added, followed by the dropwise addition of 5-(tributylstannyl)-3-methylisoxazole (Sakamoto, T. et al; Tetrahedron, 1991, 47, 5111–5118; 0.84 g, 2.25 mmol) in 1,4-dioxane (1 ml). The mixture was heated at 100° C. After approximately 16 hours, the solution was concentrated under vacuum. The crude material was dissolved in acetonitrile and washed with hexanes (3×). The acetonitrile phase was concentrated under vacuum. Purification by chromatography on silica gel using EtOAc, followed by recrystallization from EtOAc/MeOH gave 256 mg of the title product.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][CH3:31])[CH2:25][CH2:24]2)=[O:22])=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1.[C:32]1(=O)[CH2:37]CCC[CH2:33]1.C([BH3-])#N.[Na+].[OH-].[Na+]>CO.C(O)(=O)C.C(N(CC)CC)C>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([CH:29]3[CH2:37][CH2:32][CH2:33][CH2:31][CH2:30]3)[CH2:25][CH2:24]2)=[O:22])=[CH:19][CH:20]=1)[CH2:8][C:9]1[NH:13][CH:12]=[CH:11][N:10]=1
Reactant: CCCN1CCN(C(=O)c2ccc(CN(Cc3ncc[nH]3)Cc3ncc[nH]3)cc2)CC1
Reactant: O=C1CCCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1)N1CCN(C2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 168 h

Procedure:
The compound (57.7 mg) obtained in Example 32-3 was dissolved in methanol (1.73 ml) and then added with cyclohexanone (21.6 mg), sodium cyanoborohydride (13.8 mg), and triethylamine (76.5 μl). The solution was adjusted to pH 5 with acetic acid and stirred at room temperature for 7 days. The reaction solution was added with a 1 mol/l sodium hydroxide aqueous solution and then the whole was separated and extracted with chloroform. The organic layer was dried with anhydrous sodium sulfate. The solvent was distilled off and the residue was then purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining hydrochloride (7.9 mg) of the subject compound as a pale-yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH:11]([C:13]2[CH:14]=[N:15][C:16]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[C:17]([Cl:19])[CH:18]=2)[CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=1.[C:26](Cl)(=[O:30])[CH:27]([CH3:29])[CH3:28]>>[Cl:19][C:17]1[CH:18]=[C:13]([CH:11]([NH:10][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[N:7]=2)=[O:9])[CH3:12])[CH:14]=[N:15][C:16]=1[O:20][CH2:21][C:22]([F:24])([F:23])[F:25]
Reactant: CC(NC(=O)c1ccnc(N)n1)c1cnc(OCC(F)(F)F)c(Cl)c1
Reactant: CC(C)C(=O)Cl
Product: CC(C)C(=O)Nc1nccc(C(=O)NC(C)c2cnc(OCC(F)(F)F)c(Cl)c2)n1

Procedure:
The title compound is prepared from 2-amino-N-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)pyrimidine-4-carb oxamide (20 mg, 0.05 mmol, Step-1 of Example 210, single enantiomer) and isobutyryl chloride (28 mg, 0.27 mmol) according to the procedure similar to that described in Step-2 of Example 8.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:22])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2Br)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:22])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccccc2Br)CC1
Reactant: C1CNCCN1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccccc2N2CCNCC2)CC1

Procedure:
Boc protected piperazine (849 mg, 4.56 mmol) was dissolved in DCM (20 mL) and triethyl amine (2.54 mL, 18.2 mmol) was added. To the stirred solution, ortho-bromo benzoyl chloride (2 g, 9.11 mmol) was added via syringe under nitrogen. The system was stirred for about 12 hours at r.t. The reaction was washed with water, dried, filtered, and concentrated. The residue was subjected to chromatography on silica gel to give 1-Boc-4-(2-bromo-)-piperazine (1.48 g, 8.85 mmol) as a white foam. 1-Boc-4-(2-bromo-benzoyl)-piperazine was coupled to piperazine in a manner similar to Preparation 1A. LRMS (ESI+): 375.2 (M+1)
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:16])(=[O:3])[CH3:2].[C:17](OC)(OC)([O:22][CH3:23])[CH2:18][CH2:19][CH2:20][CH3:21]>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[C:6](=[C:17]([O:22][CH3:23])[CH2:18][CH2:19][CH2:20][CH3:21])[C:5]1=[O:16])(=[O:3])[CH3:2]
Reactant: CCCCC(OC)(OC)OC
Reactant: CC(=O)c1ccc2c(c1)CC(=O)N2C(C)=O
Product: CCCCC(OC)=C1C(=O)N(C(C)=O)c2ccc(C(C)=O)cc21

Procedure:
Prepared from 1,5-diacetyl-2-indolinone and trimethyl orthovalerate
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[CH2:15][C:9]1([CH2:14][CH2:13][CH2:12][CH2:11][NH:10]1)[CH2:8][CH2:7]2.C(=O)([O-])[O-].[K+].[K+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C=O)C>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[CH2:15][C:9]1([CH2:14][CH2:13][CH2:12][CH2:11][N:10]1[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:8][CH2:7]2
Reactant: BrCc1ccccc1
Reactant: COc1cc2c(cc1OC)CC1(CCCCN1)CC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OC)CC1(CCCCN1Cc1ccccc1)CC2

Procedure:
3,4-Dihydro-6,7-dimethoxyspiro[naphthalene-2(1H),2'-piperidine] hydrochloride (10 mg) was treated with potassium carbonate (10 g) and benzyl bromide (4 ml) in DMF (300 ml) at 60° C. for 2 hours. The reaction product was extracted with ethyl acetate-water, washed with water, dried, and concentrated. Purification with silica gel column chromatography (eluent; ethyl acetate) gave 3,4-dihydro-6,7-dimethoxy-1'-benzylspiro[naphthalene-2(1H),2'-piperidine] (10.8 g) which was dissolved in hydrobromic acid (33 ml) at 60° C. After being refluxed for 1.5 hr, the reaction mixture was poured into water and neutralized with sodium bicarbonate followed by extraction with ethyl acetate. The extract was washed with water, dried, and concentrated. The residue was crystallized from hexane to give 3,4-dihydro-6,7-hydroxy-1'-benzylspiro[naphthalene-2(1H),2'-piperidine] (5.92 g).