Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3](=[O:19])[CH2:4][N:5]1[N:9]=[N:8][C:7]([NH:10][C:11]([C:13]2[S:14][C:15]([Cl:18])=[CH:16][CH:17]=2)=[O:12])=[N:6]1.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]2=[O:33])=[CH:23][C:22]=1[F:34]>>[F:34][C:22]1[CH:23]=[C:24]([N:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]2=[O:33])[CH:25]=[CH:26][C:21]=1[NH:20][C:3]([CH2:4][N:5]1[N:9]=[N:8][C:7]([NH:10][C:11]([C:13]2[S:14][C:15]([Cl:18])=[CH:16][CH:17]=2)=[O:12])=[N:6]1)=[O:19]
Reactant: Nc1ccc(-n2ccccc2=O)cc1F
Reactant: COC(=O)Cn1nnc(NC(=O)c2ccc(Cl)s2)n1
Product: O=C(Cn1nnc(NC(=O)c2ccc(Cl)s2)n1)Nc1ccc(-n2ccccc2=O)cc1F

Procedure:
63.3 Using general method F, {5-[(5-chloro-thiophene-2-carbonyl)-amino]-tetrazol-2-yl}-acetic acid methyl ester was reacted with 1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one (CAS 536747-52-1, prepared according to C. F. Bigge et al., patent application WO 2003045912) to give 5-chloro-thiophene-2-carboxylic acid (2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-methyl}-2H-tetrazol-5-yl)-amide. Off-white solid. MS 474.3 ([M+H]+)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[F:23].[CH3:24][N:25]([CH3:43])[CH2:26][CH2:27][C:28]1[C:29]([C:40](O)=[O:41])=[N:30][N:31]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[CH:32]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:40]([C:29]2[C:28]([CH2:27][CH2:26][N:25]([CH3:43])[CH3:24])=[CH:32][N:31]([C:33]3[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=3)[N:30]=2)=[O:41])=[CH:18][C:17]=1[F:23]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Reactant: CN(C)CCc1cn(-c2ccc(F)cc2)nc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1cc2nccc(Oc3ccc(NC(=O)c4nn(-c5ccc(F)cc5)cc4CCN(C)C)cc3F)c2cc1OC
Temperature: 60 °C
Reaction time: 12 h

Procedure:
To a solution of A2 (50 mg, 0.16 mmol, 1.0 eq), O2 (44 mg, 0.16 mmol, 1.0 eq.) and DIPEA (62 mg, 0.48 mmol, 3.0 eq.) in dry DMF (4 mL) was added HATU (121 mg, 0.32 mmol, 2.0 eq.). The mixture was stirred for 12 h at 60° C. Then the mixture was diluted with EtOAc and washed three times with aq. NaHCO3-solution. The organic phase was dried over MgSO4 and evaporated in vacuo. The residue was purified by reverse phase RP-HPLC (column: C18), using H2O and ACN as eluents. The desired fractions were lyophilized to yield the desired compound O3 with impurities. A subsequent purification by chromatography on silica gel (DCM/MeOH=20:1) yielded the product O3 (15 mg, 0.026 mmol, 16%) as a white solid. 1H NMR (400 MHz, d6-DMSO, 300K) δ 2.34 (s, 6H), 2.72 (m, 2H), 2.98 (t, J=7.4 Hz, 2H), 3.94 (s, 6H), 6.47 (d, J=5.3 Hz, 1H), 7.40 (s, 1H), 7.44 (m, 3H), 7.53 (s, 1H), 7.77 (d, J=8.8 Hz, 1H), 8.03 (m, 3H), 8.48 (d, J=5.3 Hz, 1H), 8.51 (s, 1H), 10.44 (s, 1H). MS (ES) C31H29F2N5O4 requires: 573. Found: 574 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:23][C:12]2=[CH:13][C:14]3[C:15](=[O:22])[N:16]([CH3:21])[C:17](=[O:20])[C:18]=3[CH:19]=[C:11]2[N:10]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[CH2:32][CH:33]([NH2:35])[CH3:34].C(N(CC)C(C)C)(C)C>C(O)CCC>[F:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[CH2:32][CH:33]([NH:35][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:23][C:12]2=[CH:13][C:14]3[C:15](=[O:22])[N:16]([CH3:21])[C:17](=[O:20])[C:18]=3[CH:19]=[C:11]2[N:10]=1)[CH3:34]
Reactant: CC(N)Cc1cc(F)ccc1F
Reactant: CN1C(=O)c2cc3nc(-c4c(Cl)cc[nH]c4=O)[nH]c3cc2C1=O
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(Cc1cc(F)ccc1F)Nc1cc[nH]c(=O)c1-c1nc2cc3c(cc2[nH]1)C(=O)N(C)C3=O
Yield: 61.3 %

Procedure:
2-(4-Chloro-2-oxo-1,2-dihydropyridin-3-yl)-6-methylimidazo[4,5-f]isoindole-5,7(1H,6H)-dione (0.44 g, 1.34 mmol), 1-(2,5-difluorophenyl)propan-2-amine (0.27 g, 1.61 mmol), n-butanol (30 mL) and N,N-diisopropylethylamine (5 mL) were mixed together in a flask. The reaction mixture was stirred and heated to reflux overnight under argon. Solvents were removed under reduced pressure. The residue solid was purified by column chromatography (silica-gel, CH2Cl2/MeOH=9/1 v/v) to give a bown solid product, 0.38 g, 61.3% yield. MS: 461.9 [M−H]−. 1H NMR (DMSO-d6, 500 MHz): δ 13.40 (s, 1H), 11.31 (s, 1H), 10.92 (d, 1H, J=8.0 Hz), 8.13 (s, 1H), 8.00 (s, 1H), 7.42-7.37 (m, 2H), 7.20-7.18 (m, 1H), 7.09-7.04 (m, 1H), 6.18 (d, 1H, J=8.0 Hz), 4.19-4.14 (m, 1H), 3.06 (s, 3H), 3.04-2.98 (m, 2H), 1.33 (d, 3H, J=6.0 Hz).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[C:10]1[N:11]=[C:12]([N:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)[S:13][CH:14]=1>C(OCC)(=O)C>[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[C:10]1[N:11]=[C:12]([N:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]2)[S:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(-c3ccc(Cl)cc3Cl)cs2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: Clc1ccc(-c2csc(N3CCNCC3)n2)c(Cl)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 83.3 %

Procedure:
A 4 N solution (70 ml) of hydrogen chloride in ethyl acetate was added to a solution of tert-butyl 4-[4-(2,4-dichlorophenyl)-1,3-thiazol-2-yl]piperazine-1-carboxylate (2.31 g, 5.58 mmol) in ethyl acetate (70 ml), the mixture was stirred at room temperature for 12 hours, and the solvent was distilled off under reduced pressure. The residue was dissolved in water, neutralized with a 1 N sodium hydroxide aqueous solution, and extracted with chloroform. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give 1.46 g (83.3%) of the desired product as a solid.
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)([C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].Br[C:40]1[CH:41]=[C:42]([CH:49]=[CH:50][CH:51]=1)[C:43]([NH:45][CH:46]1[CH2:48][CH2:47]1)=[O:44]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:46]1([NH:45][C:43]([C:42]2[CH:41]=[C:40]([C:33]3[CH:32]=[CH:31][C:30]([C:2]([OH:1])([C:6]4[N:7]=[CH:8][N:9]([C:11]([C:12]5[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=5)([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[C:18]5[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=5)[CH:10]=4)[CH:3]([CH3:4])[CH3:5])=[CH:35][CH:34]=3)[CH:51]=[CH:50][CH:49]=2)=[O:44])[CH2:48][CH2:47]1
Reactant: CC(C)C(O)(c1ccc(B(O)O)cc1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: O=C(NC1CC1)c1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CC(C)C(O)(c1ccc(-c2cccc(C(=O)NC3CC3)c2)cc1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Yield: 46.7 %

Procedure:
By the reaction in the same manner as in Example 33-(ii) using 4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenylboronic acid (3.40 g), 3-bromo-N-cyclopropylbenzamide (1.53 g) and tetrakis(triphenylphosphine)palladium(0) (0.290 g), the title compound (1.84 g) was obtained as a pale-yellow amorphous powder.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C@@H:8]([NH:11][C:12]([C:14]2[C:15]3[CH:22]=[N:21][N:20]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[C:16]=3[CH:17]=[N:18][CH:19]=2)=[O:13])[CH2:9][CH3:10])[CH:5]=[CH:4][N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:49][N:50](C=O)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[C-]#N.[Zn+2].[C-]#N>[C:49]([C:2]1[CH:7]=[C:6]([C@@H:8]([NH:11][C:12]([C:14]2[C:15]3[CH:22]=[N:21][N:20]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[C:16]=3[CH:17]=[N:18][CH:19]=2)=[O:13])[CH2:9][CH3:10])[CH:5]=[CH:4][N:3]=1)#[N:50]
Reactant: CC[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1ccnc(Br)c1
Reactant: CN(C)C=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [C-]#N
Product: CC[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1ccnc(C#N)c1
Temperature: 140 °C
Reaction time: 0.5 h

Procedure:
A microwave vial charged with 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid[(S)-1-(2-bromopyridin-4-yl)-propyl]-amide (0.10 g, 0.22 mmol), PS-triphenylphosphine (20 mg, 0.04 mmol), palladium (II) acetate (5 mg, 0.02 mmol), zinc cyanide (26 mg, 0.22 mmol) and DMF (2 mL) was warmed in a microwave at 140° C. After 30 minutes, additional zinc cyanide (25 mg, 0.22 mmol) was added and the mixture was warmed in a microwave at 140° C. After 30 minutes, the mixture was filtered washing with diethyl ether. The filtrate was diluted with ether and washed with water (2×40 mL) and brine (40 mL). The organic layer was dried over sodium sulfate and concentrated. The crude material was purified by reversed-phase HPLC. The desired fractions from the column were concentrated diluted with saturated aqueous sodium bicarbonate and extracted with dichloromethane (2×25 mL), dried with sodium sulfate and concentrated to afford the title compound.
Reaction SMILES: [C:1]([NH:9][C@H:10]([C:24]([OH:26])=[O:25])[CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCOCC1>[C:16]([NH:15][CH2:14][CH2:13][CH2:12][CH2:11][C:10]1[C:24](=[O:25])[O:26][CH:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[N:9]=1)(=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(NCCCC[C@H](NC(=O)c1ccccc1)C(=O)O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1COCCO1
Product: O=C1OC(c2ccccc2)N=C1CCCCNC(=O)c1ccccc1
Reaction time: 2 h
Yield: 85.9 %

Procedure:
N,N'-Dibenzoyl lysine (140.4 g, 0.36 mol) dissolved in dioxan (350 ml) was added over 45 min to dicyclohexylcarbodiimide (88.0 g, 0.43 mol) in dioxan (193 ml). After stirring for 2 hours the mixture was set aside overnight, filtered from dicyclohexylurea (88.1 g), concentrated to half volume and added to H2O. The precipitate was collected and recrystallised from methylal to give 4-(4-benzamidobutyl)-2-phenyl-5-oxazolone (104 g, 86%) m.p. 118°-122°.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[N:5]2[C:6]=1[C:7](=[O:13])[NH:8]3.[H-].[Na+].Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]1[C:26](=[O:27])[C:25]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]2[C:23]1=[O:32].O>CN(C=O)C>[CH3:1][C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[N:5]2[C:6]=1[C:7](=[O:13])[N:8]3[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]1[C:23](=[O:32])[C:24]2=[CH:31][CH:30]=[CH:29][CH:28]=[C:25]2[C:26]1=[O:27]
Reactant: O=C1c2ccccc2C(=O)N1CCCCCBr
Reactant: Cc1nc2cccc3[nH]c(=O)c1n23
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc2cccc3n(CCCCCN4C(=O)c5ccccc5C4=O)c(=O)c1n23
Yield: 59.5 %

Procedure:
To a suspension of 5.20 g (30 mmol) of 1,2-dihydro-3-methyl-1,4,7b-triazacyclopent[cd]inden-2-one in 60 ml of DMF was added, while stirring under ice-cooling, 1.44 g (36 mmol) of 60% sodium hydride (dispersion in oil). The mixture was stirred for 15 minutes at the same temperature. To the reaction mixture was added a solution of 8.89 g (30 mmol) of N-(5-bromopentyl)phthalimide in DMF (20 ml). The mixture was stirred for 1.5 hour at 110° C. After cooling, the reaction mixture was poured into water, extracted with ethyl acetate. The extract solution was washed with water, dried over anhydrous magnesium sulfate and concentrated. The concentrate was purified by column chromatography (eluent: ethyl acetate/ethanol=10:1) to afford 6.93 g of the desired compound (59.4%, pale brown solid).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]/[CH:10]=[C:11]1\[C@:12]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])([O:17][Si](C)(C)C)[CH:13]=[CH:14][C:15]\1=[O:16])=[O:4].[N+](CCCC)(CCCC)(CCCC)CCCC.[F-].CCOCC.[Cl-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]/[CH:10]=[C:11]1\[C@@:12]([OH:17])([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:13]=[CH:14][C:15]\1=[O:16])=[O:4]
Reactant: CCCCCCCC[C@@]1(O[Si](C)(C)C)C=CC(=O)/C1=C/CCCCCC(=O)OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCCCC[C@@]1(O)C=CC(=O)/C1=C/CCCCCC(=O)OC
Reaction time: 0.25 h
Yield: 32.8 %

Procedure:
113 mg (0.27 mmole) of (4R)-5-[(E)-6-methoxycarbonylhexylidene)-4-octyl-4-trimethylsilyloxy-2-cyclopentenone was dissolved in 20 ml of tetrahydrofuran, and at 0° C., 1 ml (1 mmole) of n-Bu4NF (1 M in THF) was added. The mixture was stirred for 15 minutes. Ether and a saturated aqueous solution of sodium chloride were added. The aqueous layer was extracted with ethyl acetate. After filtration and concentration, the residue was subjected to TLC (n-hexane:AcOEt=1:1) to obtain 31 mg (33%) of (4R)-5-[(E)-6-methoxycarbonylhexylidene)-4-hydroxy-4-octyl-2-cyclopentenone.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][C:15]([OH:17])=O)=[CH:4][CH:3]=1.[CH3:18][CH:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][C:15]([NH:26][CH:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH3:18])=[O:17])=[CH:6][CH:7]=1
Reactant: CC(N)c1ccccc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1noc(-c2ccc(Br)cc2)c1CC(=O)NC(C)c1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
[5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]acetic acid (0.154 g, 0.52 mmol), α-methylbenzylamine (0.07 mL, 0.52 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.120 g, 0.62 mmol), 1-hydroxybenzotriazole (0.087 g, 0.62 mmol), and triethylamine (0.22 mL, 1.56 mmol) were combined in CH2Cl2 (1.5 mL). The reaction was stirred at room temperature for 2.5 hours. After aqueous workup the crude material was purified by silica gel chromatography (0-60% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:6]([CH2:8][N:9]2[CH:13]=[C:12]([NH2:14])[CH:11]=[N:10]2)[CH:7]=1.[Cl:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:25]=1[C:26](O)=[O:27]>>[Cl:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:25]=1[C:26]([NH:14][C:12]1[CH:11]=[N:10][N:9]([CH2:8][C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:13]=1)=[O:27]
Reactant: Nc1cnn(Cc2cc(Cl)ccc2OCc2ccccc2)c1
Reactant: O=C(O)c1c(F)cccc1Cl
Product: O=C(Nc1cnn(Cc2cc(Cl)ccc2OCc2ccccc2)c1)c1c(F)cccc1Cl

Procedure:
The title compound was prepared in a similar fashion to the preparation of example 16, replacing 1-[(2,4-dichlorophenyl)methyl]-1H-pyrazol-4-amine with 1-({5-chloro-2-[(phenylmethyl)oxy]phenyl}methyl)-1H-pyrazol-4-amine (for a preparation see intermediate 9) and replacing 2,6-dichlorobenzoic acid with 2-chloro-6-fluorobenzoic acid (Aldrich); LCMS (System 3): MH+=470, tRET=1.28 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[C:15]([CH:17]3[CH2:21][CH2:20][C:19](=O)[CH2:18]3)[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].C(O)(=O)C.[NH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31].C([BH3-])#N.[Na+]>CO.ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[C:15]([CH:17]3[CH2:21][CH2:20][CH:19]([NH:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])[CH2:18]3)[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)Oc1ccc(-c2noc(C3CCC(=O)C3)n2)cc1Cl
Reactant: NCCC(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)Oc1ccc(-c2noc(C3CCC(NCCC(=O)O)C3)n2)cc1Cl

Procedure:
To a slurry of 3-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)cyclopentanone (0.178 g, 0.555 mmol) in MeOH (6.94 ml) and DCE (6.94 ml) was added acetic acid (0.254 ml, 4.44 mmol) followed by 3-aminopropanoic acid (0.494 g, 5.55 mmol). After about 1 h sodium cyanoborohydride (0.017 g, 0.277 mmol) was added to the reaction mixture. After about 15 h the reaction mixture was filtered, rinsing with MeOH. The filtrate was concentrated in vacuo and purified by RP HPLC to provide 3-(3-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)cyclopentylamino)propanoic acid. LCMS (Table 1, Method c) Rt=1.64 min, m/z 394 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[F:12].[OH-].[Na+].Cl[O-].[Na+]>C(O)(C)(C)C>[Br:1][C:2]1[CH:8]=[CH:7][C:5]2[C:4]([C:3]=1[F:12])=[N+:9]([O-:11])[O:10][N:6]=2
Reactant: Nc1ccc(Br)c(F)c1[N+](=O)[O-]
Agent: [Na+]
Agent: [O-]Cl
Agent: [OH-]
Solvent: CC(C)(C)O
Product: [O-][n+]1onc2ccc(Br)c(F)c21
Reaction time: 0.17 h
Yield: 93.9 %

Procedure:
4-Bromo-3-fluoro-2-nitroaniline (1.5 g, 6.4 mmol) was added to cooled (0-5° C.) solution of sodium hydroxide (96 ml, 2 M, 190 mmol) in 80 mL t-butanol. After stirring for 10 min, 5% sodium hypochlorite solution (46 g, 31 mmol) was added dropwise over 10 min. After stirring for 1 h at 0-5° C., the mixture was extracted twice with 100 mL portions of dichloromethane. The combined extracts were washed with 50 mL saturated NaCl, dried (Na2SO4) and evaporated. The material was purified by silica gel chromatography using a 0-20% ethyl acetate-hexane gradient to give 1.4 g of the title compound as red oil that crystallized on standing (1.4 g, 94%): 1H NMR (400 MHz, CDCl3) δ 7.26 (q, J=5.9 Hz, 1H), 7.14 (d, J=9.2 Hz, 1H); 19F NMR (376 MHz, CDCl3) δ −117.47; EIMS m/z 232.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)(=O)=O)=CC=1.C(OCC)(=O)[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30].[O-]CC.[Na+].[Cl-].[NH4+].[Cl-].[Li+].O>C(O)C>[CH2:32]([O:31][C:29]([CH2:28][CH2:11][CH2:12][CH:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:17][CH2:18]1)=[O:30])[CH3:33]
Reactant: Cc1ccc(S(=O)(=O)OCCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CCCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 44.2 %

Procedure:
tert-Butyl 4-(2-(toluene-4-sulfonyloxy)ethyl)piperidine-1-carboxylate (7.55 g, 19.7 mmol, CAS No. 89151-45-1) as described in WO 02/32872 was dissolved in ethanol; diethyl malonate (3.3 ml, 21.3 mmol) and sodium ethoxide (1.45 g, 21.3 mmol) were added; and the reaction mixture was heated to reflux under nitrogen atmosphere for 2.5 hours. After naturally cooled to room temperature, the saturated aqueous solution of ammonium chloride was added; this was subjected to extraction with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. After the residue was dissolved in dimethyl sulfoxide (20 ml); lithium chloride (1.7 g, 40 mmol) and water (0.36 ml, 20 mmol) were added; and the reaction mixture was stirred at 185° C. for 1.5 hours and further stirred at 195° C. for 2 hours. After naturally cooled to room temperature, the reaction mixture was partitioned between ethyl acetate-brine. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Fuji Silysia BW-300, hexane-ethyl acetate system) to yield the title compound (2.60 g, 8.7 mmol, 43%) as a pale yellow oil.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[C:19](=O)[CH2:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[CH:22]=1.O.[NH2:33][NH2:34]>CN(C=O)C>[CH3:30][O:29][C:23]1[CH:22]=[C:21]([CH:26]=[C:25]([O:27][CH3:28])[CH:24]=1)[CH2:20][C:19]1[C:3]2[C:4](=[O:18])[N:5]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[NH:34][N:33]=1
Reactant: COc1cc(CC(=O)c2c(O)c3cccnc3n(-c3ccccc3)c2=O)cc(OC)c1
Reactant: NN
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(Cc2n[nH]c3c2c(=O)n(-c2ccccc2)c2ncccc32)cc(OC)c1
Yield: 90.4 %

Procedure:
To a suspension of 4-hydroxy-3-[1-oxo-2-(3,5-dimethoxyphenyl)ethyl]-1-phenyl-1,8-naphthyridin-2 (1H)-one (200 mg, 0.48 mmol, prepared in Synthetic Example 23) in DMF (5 ml) was added hydrazine monohydrate (80%, 100 μl, 2.50 mmol, 5.2 eq.), and the mixture was treated in the same manner as in Example 16 to give 3-(3,5-dimethoxybenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (179 mg, 90%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[C:9]([C@:11]2([O:29][C@H:28]([CH2:30][O:31]C(=O)C)[C@@H:23]([O:24]C(=O)C)[C@H:18]([O:19]C(=O)C)[C@H:13]2[O:14]C(=O)C)[OH:12])[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[CH:35]1([C:38]2[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=2)[CH2:37][CH2:36]1.C(=O)([O-])[O-].[K+].[K+].CC(C)=O>[Cl-].[Na+].O.[Pd](Cl)Cl.O>[CH:35]1([C:38]2[CH:43]=[CH:42][C:41]([CH2:2][C:3]3[CH:10]=[C:9]([C@:11]4([O:29][C@H:28]([CH2:30][OH:31])[C@@H:23]([OH:24])[C@H:18]([OH:19])[C@H:13]4[OH:14])[OH:12])[CH:8]=[CH:7][C:4]=3[C:5]#[N:6])=[CH:40][CH:39]=2)[CH2:37][CH2:36]1
Reactant: OB(O)c1ccc(C2CC2)cc1
Reactant: CC(=O)OC[C@H]1O[C@](O)(c2ccc(C#N)c(CBr)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CC(C)=O
Solvent: O
Product: N#Cc1ccc([C@@]2(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1Cc1ccc(C2CC2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
An Ar filled flask is charged with a stir bar, 2-bromomethyl-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl)-benzonitrile (1.78 g), 4-cyclopropyl-phenylboronic acid (1.00 g), potassium carbonate (1.85 g) and a 3:1 mixture of degassed acetone and water (22 mL). The mixture is stirred at room temperature for 5 min, before it is cooled in an ice-bath. Then palladium dichloride (30 mg) is added and the reaction mixture is stirred for 16 h at ambient temperature. The mixture is then diluted with brine and extracted with ethyl acetate. The combined extracts are dried over sodium sulfate and the solvent is removed under reduced pressure. The residue is dissolved in methanol (20 mL) and treated with 4 M aqueous potassium hydroxide solution (3.8 mL). The resulting solution is stirred at ambient temperature for 1 h and then neutralized with 1 M hydrochloric acid. The methanol is evaporated, and the residue is diluted with brine and extracted with ethyl acetate. The organic extracts collected are dried over sodium sulfate, and the solvent is removed. The residue is chromatographed on silica gel (dichloromethane/methanol 1:0->8:1).