Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([C:12]([OH:14])=O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][O:16][C:17](=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][NH2:25])[CH:19]=1>>[CH3:15][O:16][C:17](=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][NH:25][C:12]([C:10]2[O:11][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][CH:9]=2)=[O:14])[CH:19]=1
Reactant: O=C(O)c1ccc(-c2ccccc2)o1
Reactant: COC(=O)c1cccc(CN)c1
Product: COC(=O)c1cccc(CNC(=O)c2ccc(-c3ccccc3)o2)c1

Procedure:
5-Phenyl-furan-2-carboxylic acid (6) (17 mg, 0.10 mmol) was coupled to 3-aminomethyl-benzoic acid methyl ester (19.4 mg, 0.10 mmol) using Method D to give the title compound
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[C:10](O)([CH2:15][NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH:9]([N:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]3=[O:30])[C:8]=2[CH:31]=1)([O-:3])=[O:2].[H-].[Na+].O.C(OCC)(=O)C>O1CCCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:13])([CH3:14])[C:10]([CH2:15][NH:16][C:17](=[O:22])[C:18]([F:21])([F:19])[F:20])=[C:9]([N:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]3=[O:30])[C:8]=2[CH:31]=1)([O-:3])=[O:2]
Reactant: CC1(C)Oc2ccc([N+](=O)[O-])cc2C(n2ccccc2=O)C1(O)CNC(=O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)Oc2ccc([N+](=O)[O-])cc2C(n2ccccc2=O)=C1CNC(=O)C(F)(F)F
Yield: 27.2 %

Procedure:
A solution of 6-nitro-2,2-dimethyl-3-hydroxy-3,4-dihydro-3-(trifluoroacetamido)methyl-4-(2-oxo-1,2-dihydropyridin-1-yl)-2H-1-benzopyran (0.5 g, 1.13 mmol) in tetrahydrofuran (20 ml) containing sodium hydride (80%, 0.034 g, 1.13 mol) was refluxed for one hour. Water and ethyl acetate were added to the cooled solution and the organic phase was separated and evaporated under reduced pressure. The residue was chromatographed on silica gel, eluting with dichloromethane/acetone (95/5), to give 0.13 g of 6-nitro-2,2-dimethyl-3-(trifluoroacetamido)methyl-4-(2-oxo-1,2-dihydropyridin-1-yl)-2H-1-benzopyran, m.p. 189° C.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]3([C:26]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:20]4[C:15]3=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:4]=2[CH:3]=1.[Cu][C:28]#[N:29].N>CN1C(=O)CCC1>[C:28]([C:17]1[CH:18]=[CH:19][C:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:5]3([C:4]4[CH:3]=[CH:2][CH:14]=[CH:13][C:12]=4[C:11]4[C:6]3=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:15]=2[CH:16]=1)#[N:29]
Reactant: Brc1ccc2c(c1)C1(c3ccccc3-c3ccccc31)c1ccccc1-2
Reactant: N#C[Cu]
Agent: N
Solvent: CN1CCCC1=O
Product: N#Cc1ccc2c(c1)C1(c3ccccc3-c3ccccc31)c1ccccc1-2
Temperature: 160 °C
Reaction time: 0.5 h

Procedure:
A suspension of 158.1 g (0.4 mol) of 2-bromo-9,9′-spirobifluorene and 89.6 g (1 mol) of copper(I) cyanide in 1100 ml of NMP was heated to 160° C. for 16 h. After cooling to 30° C., the mixture was admixed with 1000 ml of saturated ammonia solution and stirred for a further 30 min. The precipitate was filtered off with suction, washed three times with 300 ml of saturated ammonia solution and three times with 300 ml of water, and suction-dried. After the solid had been dissolved in 1000 ml of dichloromethane, the solution was dried over sodium sulfate, filtered through silica gel and concentrated to dryness. The thus obtained crude product was recrystallized once from dioxane:ethanol (400 ml:750 ml). After the crystals had been dried under reduced pressure at 80° C., 81.0 g (237 mmol), corresponding to 59.3% of theory, were obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][Br:19])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:21][NH:22][CH3:23]>>[BrH:19].[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][N:22]([CH3:23])[CH3:21])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(OCCCCBr)cc1
Reactant: CNC
Product: Br
Product: CN(C)CCCCOc1ccc(NC(=O)OC(C)(C)C)cc1

Procedure:
In analogy to example 1.8, reaction of [4-(4-Bromo-butoxy)-phenyl]-carbamic acid tert-butyl ester with 10 eq dimethylamine (33% in ethanol, 5.6 M) yielded (without extraction with aqueous saturated NaHCO3 solution) [4-(4-Dimethylamino-butoxy)-phenyl]-carbamic acid tert-butyl ester hydrobromid (1:1), MS: 309 (MH+).
Reaction SMILES: B(Br)(Br)Br.[Cl:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][N:12]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][C:22]=3[CH3:23])[C:13]2=[O:16])=[CH:8][C:7]=1[O:24]C.CO>C(Cl)Cl.C(Cl)(Cl)Cl>[Cl:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][N:12]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][C:22]=3[CH3:23])[C:13]2=[O:16])=[CH:8][C:7]=1[OH:24]
Reactant: COc1cc2c(cc1Cl)C(=O)N(c1cnccc1C)CC2
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1ccncc1N1CCc2cc(O)c(Cl)cc2C1=O
Temperature: 25 °C
Reaction time: 14 h
Yield: 70.2 %

Procedure:
BBr3 (4.4 mL) was added to a stirred solution of 7-chloro-6-methoxy-2-(4-methylpyridin-3-yl)-3,4-dihydroisoquinolin-1(2H)-one (86A: 450 mg, 1.480 mmol) in DCM (10 mL) at 0° C. The resulting mixture was stirred for 14 hours at room temperature. The reaction was monitored by TLC (5% methanol in CHCl3). The mixture was slowly quenched with ice water extracted with chloroform (2×50 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to afford the crude product. Purification by column chromatography on silica gel (2% methanol in CHCl3), afforded 300 mg of the product (70.4% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[F:12].O.NN.C([O-])(=O)C.[Na+].Br[CH:22]([CH3:24])[CH3:23]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:22]([CH3:24])[CH3:23])(=[O:10])=[O:9])=[CH:4][C:3]=1[F:12]
Reactant: O=S(=O)(Cl)c1ccc(Br)c(F)c1
Reactant: CC(C)Br
Agent: CC(=O)[O-]
Agent: NN
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)S(=O)(=O)c1ccc(Br)c(F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 12 %

Procedure:
To a solution of 4-bromo-3-fluorobenzene-1-sulfonyl chloride (5.40 mL, 36.5 mmol) in THF (150 mL) at 0° C. was added hydrazine monohydrate (6.20 mL, 63.9 mmol) dropwise under a nitrogen atmosphere. The reaction mixture was stirred for 1.5 hours. The solvent was removed in vacuo and replaced with heptanes (150 mL) and the resulting precipitate was collected by filtration. The solid was dissolved in industrial methylated spirit (150 mL) and to this solution was added sodium acetate (17.9 g, 218 mmol) and 2-bromopropane (17.2 mL, 183 mmol). The resultant reaction mixture was stirred at 85° C. for 16 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and quenched with water (300 mL) before being extracted with CH2Cl2 (3×300 mL). The combined organic extracts were washed with brine (300 mL), dried over MgSO4, filtered and evaporated in vacuo. The crude material was purified by silica gel column chromatography eluting with EtOAc:heptanes 20/80 to afford title compound as a colourless solid in 12% yield, 1.19 g.
Reaction SMILES: [CH:1]1([N:5]2[C:9]3[N:10]=[C:11]([CH:17]4[CH2:19][CH2:18]4)[CH:12]=[C:13]([C:14](O)=[O:15])[C:8]=3[C:7]([CH3:20])=[N:6]2)[CH2:4][CH2:3][CH2:2]1.[NH2:21][CH2:22][C:23]1[C:24](=[O:31])[NH:25][C:26]([CH3:30])=[CH:27][C:28]=1[CH3:29].ON1C2N=CC=CC=2N=N1.C(Cl)CCl.CN1CCOCC1>CS(C)=O>[CH:1]1([N:5]2[C:9]3[N:10]=[C:11]([CH:17]4[CH2:18][CH2:19]4)[CH:12]=[C:13]([C:14]([NH:21][CH2:22][C:23]4[C:24](=[O:31])[NH:25][C:26]([CH3:30])=[CH:27][C:28]=4[CH3:29])=[O:15])[C:8]=3[C:7]([CH3:20])=[N:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1nn(C2CCC2)c2nc(C3CC3)cc(C(=O)O)c12
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Agent: On1nnc2cccnc21
Solvent: CS(C)=O
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: Cc1cc(C)c(CNC(=O)c2cc(C3CC3)nc3c2c(C)nn3C2CCC2)c(=O)[nH]1

Procedure:
The title compound was prepared in the same manner as described for intermediate 56 using 1-cyclobutyl-6-cyclopropyl-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (164 mg, 0.604 mmol), 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (129 mg, 0.846 mmol), 1-hydroxy-7-azabenzotriazole (165 mg, 1.209 mmol), EDC (232 mg, 1.209 mmol), N-methylmorpholine (0.266 mL, 2.418 mmol), and DMSO(10 mL). The final product was collected as 0.240 g (98%). LCMS E-S (M+H)=406.3. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.03 (d, J=6.06 Hz, 4 H), 1.85 (dd, J=9.35, 5.05 Hz, 3 H), 2.12 (s, 4 H), 2.16-2.28 (m, 6 H), 2.30-2.44 (m, 7 H), 2.63 (d, J=19.96 Hz, 3 H), 4.34 (d, J=4.29 Hz, 2 H), 5.31 (t, J=8.34 Hz, 1 H), 5.87 (s, 1 H), 7.01 (s, 1 H), 8.59 (br. s., 1 H), 11.52 (br. s., 1 H).
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:16][CH:15]=1>>[C:1]([N:23]1[CH2:24][CH2:25][CH:20]([C:17]2[CH:16]=[CH:15][C:14]([Cl:13])=[CH:19][CH:18]=2)[CH2:21][CH2:22]1)(=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: Clc1ccc(C2CCNCC2)cc1
Reactant: CCCCCCC/C=C/C(=O)O
Product: CCCCCCC/C=C/C(=O)N1CCC(c2ccc(Cl)cc2)CC1

Procedure:
The same procedures as in Example 2 were carried out using (E)-2-decenoic acid and 4-(4-chlorophenyl)piperidine as starting raw materials, to produce an intended compound.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[CH2:19][CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].CN1C(=O)N(C)CCC1.[CH3:42][O:43][C:44]1[CH:45]=[C:46]([CH:49]=[CH:50][CH:51]=1)[CH2:47]I>C1COCC1>[C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH2:47][C:46]2[CH:49]=[CH:50][CH:51]=[C:44]([O:43][CH3:42])[CH:45]=2)[CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1CCC(=O)O1
Reactant: COc1cccc(CI)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: COc1cccc(C[C@@H]2C[C@@H]([C@H](Cc3ccccc3)NC(=O)OC(C)(C)C)OC2=O)c1

Procedure:
In analogy with Example 44c), 1.5 g of 5(S)-[l(S)-(Boc-amino)-2-phenylethyl]-dihydrofuran-2-(3H)-one [Example 2b)] in 3 ml of abs. THF are deprotonated (-75° C.) with 9.62 ml of a 1M solution of lithium bis(trimethylsilyl)amide in THF, and with the addition of 0.998 ml of DMPU and alkylated with 1.22 g of 3-methoxybenzyl iodide. Chromatography on silica gel (eluent E) affords the pure title compound. TLC Rf (hexane/ethyl acetate, 2.5:1)=0.32. FAB-MS (M+H)+ =426.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH:13]([CH3:15])[CH3:14])=[C:11]([NH2:16])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Cl:17][C:18]1[C:19]([C:29]([F:32])([F:31])[F:30])=[N:20][N:21]([CH:24]([CH3:28])[C:25](O)=[O:26])[C:22]=1[CH3:23].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[Cl:17][C:18]1[C:19]([C:29]([F:31])([F:30])[F:32])=[N:20][N:21]([CH:24]([CH3:28])[C:25]([NH:16][C:11]2[CH:10]=[N:9][N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:12]=2[CH:13]([CH3:14])[CH3:15])=[O:26])[C:22]=1[CH3:23]
Reactant: CC(C)c1c(N)cnn1-c1ccc(F)cc1
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1C(C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1c(Cl)c(C(F)(F)F)nn1C(C)C(=O)Nc1cnn(-c2ccc(F)cc2)c1C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.4 %

Procedure:
To a solution of 1-(4-fluorophenyl)-5-isopropylpyrazol-4-amine (0.03 g, 0.14 mmol) in DMF (1.0 mL) was added 2-[4-chloro-5-methyl-3-(trifluoromethyl)pyrazol-1-yl]propanoic acid (0.035 g, 0.14 mmol), followed by diisopropylethylamine (0.042 g, 0.32 mmol) and HATU (0.057 g, 0.15 mmol). After stirring at room temperature for 1 h, the reaction was diluted with water and the aqueous layer was extracted with ethyl acetate (2×5 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resulting crude product was purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the title compound as a white solid (0.020 g, 0.044 mmol, 32%). 1H NMR (400 MHz, CDCl3) δ 8.18 (s, 1H), 8.02 (s, 1H), 7.34-7.24 (m, 2H), 7.21-7.11 (m, 2H), 5.05 (q, J=7.2 Hz, 1H), 3.03-2.91 (m, 1H), 2.38 (s, 3H), 1.90 (d, J=7.2 Hz, 3H), 1.25 (dd, J=13.9, 7.1 Hz, 3H), 1.08 (d, J=7.2 Hz, 3H); MS: (ES) m/z calculated for C20H20ClF4N5O [M+H]+ 458.1, found 457.9.
Reaction SMILES: [CH:1]([NH:3][CH:4]1[C:28](=[O:29])[N:6]2[CH:7]([C:12]([O:14][CH:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])[C:8](=C)[CH2:9][S:10][C@H:5]12)=[O:2].[O:30]=[O+][O-].CSC>C(Cl)Cl.CO>[CH:1]([NH:3][CH:4]1[C:28](=[O:29])[N:6]2[C:7]([C:12]([O:14][CH:15]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])=[C:8]([OH:30])[CH2:9][S:10][C@H:5]12)=[O:2]
Reactant: O=[O+][O-]
Reactant: C=C1CS[C@@H]2C(NC=O)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Solvent: CSC
Solvent: ClCCl
Solvent: CO
Product: O=CNC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(O)CS[C@H]12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of benzhydryl 7-formamido-3-methylenecepham-4-carboxylate (40.8 g) in methylene chloride (300 ml) and methanol (1.2 l) was cooled at -74° C. in a dry ice-acetone bath. A theoretical amount of ozone was blown through the solution at -74° C. for 10 minutes with stirring, and nitrogen gas was blown through the solution at -74° C. for 10 minutes Dimethyl sulfide (20 ml) was added to the solution at -74° C. The mixture was slowly warmed to ambient temperature and evaporated in vacuo. The residue was subjected to column chromatography on silica gel and eluted with ethyl acetate. The eluent was evaporated in vacuo to give benzhydryl 7-formamido-3-hydroxy-3-cephem-4-carboxylate (34.4 g).
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][CH3:5].S(Cl)([Cl:9])=O.[NH2:11][C@H:12]([C:14](O)=[O:15])[CH3:13]>>[ClH:9].[CH2:1]([O:6][C:14](=[O:15])[C@H:12]([CH3:13])[NH2:11])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: O=S(Cl)Cl
Reactant: C[C@H](N)C(=O)O
Reactant: CCCCCO
Product: CCCCCOC(=O)[C@H](C)N
Product: Cl
Yield: 73.7 %

Procedure:
This was synthesised according to Standard Procedure 1, using pentanol (36.3 ml, 0.337 mol), thionyl chloride (4.92 ml, 67.4 mmol) and L-Alanine (3.0 g, 33.7 mmol). The product was isolated as a white solid pure product (4.86 g, 73.7%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:8][CH2:9][CH3:10])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:11]([C:16](=[CH:22]OCC)[C:17]([O:19][CH2:20][CH3:21])=[O:18])(=[O:15])[CH2:12][CH2:13][CH3:14]>>[C:11]([C:16](=[CH:22][NH:1][C:2]1[C:3]([O:8][CH2:9][CH3:10])=[N:4][CH:5]=[CH:6][CH:7]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18])(=[O:15])[CH2:12][CH2:13][CH3:14].[C:11]([C:16]1[C:17](=[O:18])[C:7]2[C:2](=[C:3]([O:8][CH2:9][CH3:10])[N:4]=[CH:5][CH:6]=2)[NH:1][CH:22]=1)(=[O:15])[CH2:12][CH2:13][CH3:14]
Reactant: CCOc1ncccc1N
Reactant: CCCC(=O)C(=COCC)C(=O)OCC
Product: CCCC(=O)C(=CNc1cccnc1OCC)C(=O)OCC
Product: CCCC(=O)c1c[nH]c2c(OCC)nccc2c1=O
Yield: 86 %
Yield: 93 %

Procedure:
Ethyl 2-butyryl-3-(2-ethoxypyridin-3-yl)aminoacrylate (93%) was prepared from 3-amino-2-ethoxypyridine and ethyl 2-butyryl-3-ethoxyacrylate by following the procedure similar to that of Example 18(A), and then the product was subjected to cyclization in a similar manner to that of Example 18(B) to give 3-butyryl-8-ethoxy-1,7-naphthyridin-4(1H)-one (86%), which is then subjected to methanesulfonylation in a similar manner to that of Example 18(C) to give 3-butyryl-8-ethoxy-4-methanesulfonyloxy-1,7-naphthyridine (67%).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]([N:9]([CH2:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]([OH:20])=O)[CH2:14][CH2:13]2)[CH3:10])=[O:8])=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH3:29][NH:30][CH2:31][CH2:32][CH2:33][OH:34]>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7](=[O:8])[N:9]([CH2:11][C@H:12]2[CH2:13][CH2:14][C@H:15]([C:18](=[O:20])[N:30]([CH2:31][CH2:32][CH2:33][OH:34])[CH3:29])[CH2:16][CH2:17]2)[CH3:10])=[CH:21][CH:22]=1
Reactant: CNCCCO
Reactant: CN(C[C@H]1CC[C@H](C(=O)O)CC1)C(=O)Oc1ccc(Cl)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(C[C@H]1CC[C@H](C(=O)N(C)CCCO)CC1)C(=O)Oc1ccc(Cl)cc1
Reaction time: 1.5 h

Procedure:
A solution of 0.09 g (0.276 mmol) of trans-4-{[(4-chloro-phenoxycarbonyl)-methyl-amino]-methyl}-cyclohexanecarboxylic acid in 2.5 mL of CH2Cl2 was treated at RT with 1 drop of DMF. 0.026 mL (0.304 mmol, 1.1 eq) of oxalyl chloride was added within 5 min and stirring was continued for 90 min. The solution was evaporated, redissolved in 2.5 mL of CH2Cl2 and added to a solution of 0.197 mL (2.21 mmol, 7.2 eq) of 3-(methylamino)-1-propanol [Powell et al., Synthesis (1986), (4), 338-40]at 0° C. The reaction was kept over night at RT, then partitioned between Et2O (×3)/aqueous saturated NaHCO3. The organic phases were washed once with aqueous 10% NaCl, dried over Na2SO4 and evaporated. Purification by flash-chromatography on 5 g silica gel (EtOAc:CH2Cl2 1:9 to 9:1) gave 0.064 g (58%) of pure trans-{4-[(3-hydroxy-propyl)-methyl-carbamoyl]-cyclohexylmethyl}-methyl-carbamic acid 4-chloro-phenyl ester, MS: 397 (MH+, 1Cl).
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH2:11])=[CH:10][C:5]=2[N:4]([C:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1.C1N=CN([C:36](N2C=NC=C2)=[O:37])C=1.N1C=CN=C1.[C:48]1([C@H:54]([NH2:56])[CH3:55])[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>C(Cl)Cl>[Br:1][C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH:11][C:36]([NH:56][C@@H:54]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH3:55])=[O:37])=[CH:10][C:5]=2[N:4]([C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C[C@@H](N)c1ccccc1
Reactant: Nc1cc2c(cn1)c(Br)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: C[C@@H](NC(=O)Nc1cc2c(cn1)c(Br)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88 %

Procedure:
3-bromo-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-amine (Intermediate 9a, 500 mg, 1.098 mmol), CDI (356 mg, 2.196 mmol), imidazole (150 mg, 2.196 mmol) and DCM (11 mL) were charged in a flask. The mixture was stirred at room temperature for 16 h and then treated with (R)-1-phenylethanamine (272 mg, 2.245 mmol). The mixture was stirred at room temperature for 1 h and then purified by chromatography on silica gel (EtOAc in hexane, 0-40%, 25 CV) to afford (R)-1-(3-bromo-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (582 mg, 0.966 mmol, 88%) as a white solid. MS ESI calcd. For C34H29BrN5O [M+H]+ 602, found 602.
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]([CH:22]([CH3:24])[CH3:23])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([N:34]([CH3:42])[CH2:35][CH2:36][C:37]([O:39]CC)=[O:38])=[O:33])=[CH:28][CH:27]=1>>[CH:1]1([CH:7]([NH:25][C:26]2[CH:27]=[CH:28][C:29]([C:32]([N:34]([CH3:42])[CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[O:33])=[CH:30][CH:31]=2)[C:9]2[C:10]([CH:22]([CH3:24])[CH3:23])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(-n2cc(C(O)C3CCCCC3)c(C(C)C)n2)cc1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Product: COc1ccc(-n2cc(C(Nc3ccc(C(=O)N(C)CCC(=O)O)cc3)C3CCCCC3)c(C(C)C)n2)cc1
Yield: 24.7 %

Procedure:
Using cyclohexyl[1-(4-methoxyphenyl)-3-(1-methylethyl)-1H-pyrazol-4-yl]methanol (0.70 g) synthesized in Example 52(3) and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (0.55 g) synthesized in Example 2(2) and in the same manner as in Example 1(7), the title object compound (0.28 g, 24%) was obtained as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[S:4][C:3]=1/[CH:8]=[CH:9]/[C:10](N(C)C)=O.[N+]([O-])(O)=O.[CH3:19][S:20]([C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH2:32])=[NH:31])=[CH:25][CH:24]=1)(=[O:22])=[O:21]>CC#N>[CH3:7][C:5]1[S:4][C:3]([C:8]2[CH:9]=[CH:10][N:32]=[C:30]([NH:29][C:26]3[CH:25]=[CH:24][C:23]([S:20]([CH3:19])(=[O:21])=[O:22])=[CH:28][CH:27]=3)[N:31]=2)=[C:2]([CH3:1])[N:6]=1
Reactant: CS(=O)(=O)c1ccc(NC(=N)N)cc1
Reactant: Cc1nc(C)c(/C=C/C(=O)N(C)C)s1
Solvent: O=[N+]([O-])O
Solvent: CC#N
Product: Cc1nc(C)c(-c2ccnc(Nc3ccc(S(C)(=O)=O)cc3)n2)s1

Procedure:
By condensation of 3-dimethylamino-1-(2,4-dimethyl-thiazol-5-yl)-propenone and N-(4-methanesulfonyl-phenyl)-guanidine nitrate. Yellow solid. Anal. RP-HPLC: tR=16.6 min (0-60% MeCN, purity >97%). 1H-NMR (DMSO-d6) δ: 2.65 (s, 3H, CH3), 2.66 (s, 3H, CH3), 3.15 (s, 3H, CH3), 7.22 (d, 1H, J=5.5 Hz, pyrimidinyl-H), 7.84 (d, 2H, J=9.0 Hz, Ph-H), 8.03 (d, 2H, J=9.0 Hz, Ph-H), 8.61 (d, 1H, J=5.5 Hz, pyrimidinyl-H), 10.23 (sbr, 1H, NH). MS (ESI+) m/z 361.17 [M+H]+ (C16H16N4O2S2 requires 361.46).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH:11]([CH2:13][OH:14])[O:10][C:9]2=[O:15])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].S(O[CH2:33][CH2:34][CH:35]([OH:37])[CH3:36])(C1C=CC(C)=CC=1)(=O)=O>CC(CC)=O>[OH:37][CH:35]([CH3:36])[CH2:34][CH2:33][O:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][CH:11]([CH2:13][OH:14])[O:10][C:9]2=[O:15])=[CH:6][CH:7]=1
Reactant: O=C1OC(CO)CN1c1ccc(O)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCC(C)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(O)CCOc1ccc(N2CC(CO)OC2=O)cc1
Yield: 52 %

Procedure:
To a solution of 7.8 g of 3-[(4-hydroxy)phenyl]-5-hydroxymethyl-2-oxazolidinone (MD 760172) in 75 ml of methylethylketone, are added 10.2 g (0.074 mol) of K2CO3, 0.1 g of KI and 10.84 g (0.044 mol) of 3-hydroxy-1-butanol tosylate, the mixture is heated under reflux for 12 hours. After filtration, the reaction medium is concentrated and the product is obtained after chromatography (silica, eluent: CH2Cl2 : 92; CH3OH: 8) with a 52% yield,
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[C:16](=[O:17])[CH2:15][C:14]([CH3:19])([CH3:18])[CH2:13][C:12]3=O)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.NC1C=C([F:31])C(F)=CC=1C(O)=O.C(O)(=O)[C:34]1[C:35](=CC=CC=1)[NH2:36]>>[F:1][C:2]1[C:3]([F:31])=[CH:4][C:5]2[C:6]3[C:11]4[C:16](=[O:17])[CH2:15][C:14]([CH3:18])([CH3:19])[CH2:13][C:12]=4[N:36]=[C:35]([CH3:34])[C:7]=3[NH:8][C:9]=2[CH:10]=1
Reactant: CC1(C)CC(=O)C(c2c[nH]c3cc(F)ccc23)C(=O)C1
Reactant: Nc1ccccc1C(=O)O
Reactant: Nc1cc(F)c(F)cc1C(=O)O
Product: Cc1nc2c(c3c1[nH]c1cc(F)c(F)cc13)C(=O)CC(C)(C)C2

Procedure:
Utilizing the procedures described in Example 3 a-c except substituting 2-(5,6-difluoro-1H-indol-3-yl)-5,5-dimethyl-cyclohexane-1,3-dione for 2-(6-fluoro-1H-indol-3-yl)-5,5-dimethylcyclohexane-1,3-dione in step 3a, and 2-amino-4,5-difluorobenzoic acid for anthranilic acid in step 1a of Example 1, the title compound was prepared and crystallized from toluene; m.p. 260-252° C.