Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([C:37]1[CH:46]=[CH:45][C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=1)=[O:36]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([C:37]3[CH:46]=[CH:45][C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH:38]=3)=[O:36])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: O=C(CCCCCBr)c1ccc2ccccc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCC(=O)c2ccc3ccccc3c2)CC1
Yield: 37.9 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (0.75 g) as starting compound, potassium carbonate (2.0 g) and 6-bromo-1-(2-naphthyl)-1-hexanone (0.80 g) were reacted and treated in the same manner as in Example 172 to give 0.40 g of 4-amino-5-chloro-N-((1-(6-(2-naphthyl)-6-oxohexyl)piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]1[C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]1)[N:20]=[CH:19]2.[ClH:40].C(Cl)[Cl:42]>CO.CCOCC>[ClH:42].[ClH:40].[CH2:8]([C:6]1[CH:5]=[CH:4][N:3]([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[N:21]([CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[N:20]=[CH:19]3)[C:2](=[O:1])[CH:7]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N1CCN(CCn2ncc3cc(-n4ccc(CCc5ccccc5)cc4=O)ccc32)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: O=c1cc(CCc2ccccc2)ccn1-c1ccc2c(cnn2CCN2CCNCC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
A solution of tert-butyl 4-(2-(5-(2-oxo-4-phenethylpyridin-1(2H)-yl)-1H-indazol-1-yl)ethyl)piperazine-1-carboxylate (247 mg, 0.468 mmol) in MeOH (2 mL) was treated with 2N HCl in ether (7 mL) under a nitrogen atmosphere. The solution was stirred at room temperature for 2 h and then treated with CH2Cl2 (20 mL) to precipitate product. The liquid was decanted off, and the solids were triturated with ether (3×100 mL) and concentrated to yield the title compound (161.7 mg, 69%) as yellow solid: mp 280-290° C.; 1H NMR (500 MHz, CD3OD) δ 8.23 (s, 1H), 7.83 (s, 2H), 7.62 (d, J=6.95 Hz, 1H), 7.46 (d, J=1.4 Hz, 1H), 7.30-7.17 (m, 5H), 6.51 (dd, J=7.0, 1.1 Hz, 1H), 6.48 (s, 1H), 4.95 (t, J=5.85, 2H), 3.57 (m, 2H), 3.61-3.56 (m, 8H), 3.01-2.98 (m, 2H), 2.94-2.91 (m, 2H); ESI MS m/z 428 [M+H]+. HPLC (Method D) 95.4% (AUC), tR=12.9 min.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C@H:6]1[CH2:10][CH2:9][C:8](=[O:11])[N:7]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:5].O.[Cl:20][C:21]1[CH:22]=[C:23]([Mg]Br)[CH:24]=[CH:25][CH:26]=1>O1CCCC1>[C:15]([O:14][C:12]([NH:7][C@H:6]([CH2:10][CH2:9][C:8]([C:25]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:20])[CH:26]=1)=[O:11])[C:4]([O:3][CH2:2][CH3:1])=[O:5])=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: Clc1cccc([Mg]Br)c1
Reactant: CCOC(=O)[C@H]1CCC(=O)N1C(=O)OC(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](CCC(=O)c1cccc(Cl)c1)NC(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
To a solution of (R)-5-oxopyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (2.0 g) in tetrahydrofuran (100 mL), 3-chlorophenylmagnesium bromide (0.5 M solution in tetrahydrofuran; 17.1 mL) was added dropwise at −40° C. over 20 minutes, and the reaction solution was stirred at −40° C. to 0° C. for one hour. Water was added to the solution in small portions at 0° C., followed by extraction with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system) to obtain 2.5 g of the title compound as a colorless oil. The property values of the compound are as follows.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][N:9]2[CH3:12])=[CH:4][CH:3]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[C:22]([CH3:29])[N:21]=2)=[CH:16][CH:15]=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CN(C)C1C=CN=CC=1>[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:28]=[CH:27][C:23]([C:24]([NH:1][C:2]3[CH:11]=[C:10]4[C:5]([CH2:6][CH2:7][CH2:8][N:9]4[CH3:12])=[CH:4][CH:3]=3)=[O:25])=[C:22]([CH3:29])[N:21]=2)=[CH:16][CH:15]=1
Reactant: CN1CCCc2ccc(N)cc21
Reactant: Cc1nc(-c2ccc(F)cc2)ccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1nc(-c2ccc(F)cc2)ccc1C(=O)Nc1ccc2c(c1)N(C)CCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 7-amino-1-methyl-1,2,3,4-tetrahydroquinoline (D3) (31 mg, 0.19 mmol) in DCM (1 ml) was added 6-(4-fluorophenyl)-2-methylnicotinic acid (D24) (44 mg, 0.19 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (44 mg, 0.23 mmol) and 4-dimethylaminopyridine (11 mg, 0.09 mmol) and the reaction stirred at ambient temperature overnight. The crude reaction mixture was loaded directly onto a silica SPE column and eluted with 0-2% methanol/DCM to give the title compound as a solid. 1H NMR (400 MHz, CDCl3) δ (ppm): 8.02 (dd, 2H), 7.84 (d, 1H), 7.57 (d, 1H), 7.35 (br, 1H), 7.17 (t, 2H), 7.00 (s, 1H), 6.93 (d, 1H), 6.74 (d, 1H), 3.25 (m, 2H), 2.93 (s, 3H), 2.80 (s, 3H), 2.74 (m, 2H), 1.96 (m, 2H)
Reaction SMILES: [CH2:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[C:6]([NH2:13])=[CH:5][CH:4]=[C:3]3[CH2:2]1.C(N(CC)CC)C.[C:21]([C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1)([CH3:24])([CH3:23])[CH3:22]>C1(C)C=CC=CC=1>[CH2:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[C:6]([NH:13][CH2:29][C:28]2[CH:31]=[CH:32][C:25]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:26][CH:27]=2)=[CH:5][CH:4]=[C:3]3[CH2:2]1
Reactant: Nc1ccc2c3c(cccc13)CC2
Reactant: CC(C)(C)c1ccc(CBr)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(CNc2ccc3c4c(cccc24)CC3)cc1
Temperature: 4 °C

Procedure:
A mixture of 5-acenaphthylamine (1.0 g, 6 mmol) and triethylamine (0.76 g, 7.5 mmol) in toluene (50 mL) was stirred at 4° C., and 4-tert-butylbenzyl-bromide (1.36 g, 6 mmol) was added in slowly. The reaction mixture was stirred at 23° C. for 15 hours and precipitates formed. The precipitates (triethylamine.HBr) were filtered out; the filtrate was concentrated to dryness. Then the crude reaction mixture was purified by column chromatography (SiO2, hexane/CH2Cl2=5/1). N-(5-acenaphthyl)-4-tert-butylbenzylamine (1.67 g, an oil) was obtained.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].I[CH2:9][CH:10]1[CH2:14][S:13][C:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[N:11]1.[Cl-].[NH4+]>CS(C)=O>[N:1]1([CH2:9][CH:10]2[CH2:14][S:13][C:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[N:11]2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: CC(C)(C)OC(=O)NC1=NC(CI)CS1
Reactant: c1nc[nH]n1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)NC1=NC(Cn2cncn2)CS1
Temperature: 20 °C
Reaction time: 0.75 h
Yield: 41.1 %

Procedure:
0.6 g of 1,2,4-triazole is added, at a temperature in the region of 20° C. and under an inert atmosphere, to a solution of 0.35 g of sodium hydride in 7 cm3 of dimethyl sulphoxide. The mixture is stirred at a temperature in the region of 20° C. for 45 minutes, followed by addition of 1 g of tert-butyl N-[(4RS)-4-(iodomethyl)-4,5-dihydro-2-thiazolyl]carbamate. After stirring for 3 hours at a temperature in the region of 60° C., 30 cm3 of saturated ammonium chloride solution are added to the reaction medium and the resulting mixture is extracted with 4 times 10 cm3 of ethyl acetate. The organic phases are washed with 10 cm3 of saturated sodium chloride solution, dried over magnesium sulphate, filtered and then concentrated under reduced pressure (1 kPa) at a temperature in the region of 40° C. The residue is chromatographed under an argon pressure of 70 kPa on a column of silica gel (particle size 40-63μ; diameter 4 cm; height 18 cm), eluting with a dichloromethane/methanol mixture (5/1 by volume). The fractions containing the expected product are combined and then concentrated under the above conditions. 0.34 g of tert-butyl N-[(4RS)-4-(1,2,4-triazol-1-ylmethyl)-4,5-dihydro-2-thiazolyl]carbamate is obtained in the form of a white foam [mass spectrum: EI m/z=283 M+ m/z=201 C8H13N2O2S+ m/z=145 C4H5N2O2S+ m/z=101 C3H5N2S30 m/z=82 C3H4N3+ m/z=57 C4H9+]
Reaction SMILES: S([O:6][CH3:7])(OC)(=O)=O.O[C:9]12[C:25]3[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=3)[C:19](=[O:30])[N:10]1[CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=12>CO>[CH3:29][O:28][C:22]1[C:23]([O:26][CH3:27])=[CH:24][C:25]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][N:10]=2)=[C:20]([C:19]([O:6][CH3:7])=[O:30])[CH:21]=1
Reactant: COS(=O)(=O)OC
Reactant: COc1cc2c(cc1OC)C1(O)c3ccccc3CCN1C2=O
Solvent: CO
Product: COC(=O)c1cc(OC)c(OC)cc1C1=NCCc2ccccc21

Procedure:
Dimethyl sulphate (48 cc) is added to a suspension of 12b-hydroxy-10,11-dimethoxy-5,6,8,12b-tetrahydroisoindolo[1,2-a]isoquinol-8-one (80.65 g) in methanol (563 cc) and the reaction mixture is heated under reflux for 6 hours. After concentration to 100 cc and the successive addition of water (300 cc) and then of 10N sodium hydroxide (70 cc), the mixture is extracted three times with ethyl acetate (total 400 cc). The combined organic solutions are washed three times with distilled water (total 400 cc), dried over anhydrous sodium sulphate, treated with decolourising charcoal (1 g), filtered and evaporated. 1-(4,5-Dimethoxy-2-methoxycarbonylphenyl)-3,4-dihydroisoquinoline (67.8 g), melting at 133° C., is thus obtained.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2=[C:14](OS(C(F)(F)F)(=O)=O)[N:15]([CH:17]([CH3:19])[CH3:18])[N:16]=[C:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2=[C:14]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:15]([CH:17]([CH3:19])[CH3:18])[N:16]=[C:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: CC(C)n1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(Cc1ccccc1)C2
Product: CC(C)n1nc2c(c1-c1ccccc1)CCN(Cc1ccccc1)C2
Yield: 32.9 %

Procedure:
The title compound (54 mg) was prepared as in Example 263 using 200 mg of trifluoro-methanesulfonic acid 6-benzyl-2-isopropyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-3-yl ester and 85 mg of phenylboronic acid. MS (ESI): exact mass calculated for C22H25N3, 331.20; found, m/z 332.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.60-7.48 (m, 7H), 7.39-7.37 (m, 2H), 4.59-4.48 (m, 3H), 4.44-4.34 (m, 2H), 3.81-3.79 (m, 1H), 3.46-3.40 (m, 1H), 2.94-2.84 (m, 2H), 1.46-1.29 (m, 6H).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][CH2:10][NH:11][CH2:12][C:13]([CH3:36])=[CH:14][CH2:15][C:16]1[C:17]([O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])=[C:18]2[C:22](=[C:23]([CH3:27])[C:24]=1[O:25][CH3:26])[CH2:21][O:20][C:19]2=[O:28])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[CH3:37][S:38](Cl)(=[O:40])=[O:39].N1C=CC=CC=1>C(Cl)Cl>[CH2:1]([O:3][P:4]([CH2:9][CH2:10][N:11]([S:38]([CH3:37])(=[O:40])=[O:39])[CH2:12][C:13]([CH3:36])=[CH:14][CH2:15][C:16]1[C:17]([O:29][CH2:30][CH2:31][Si:32]([CH3:33])([CH3:34])[CH3:35])=[C:18]2[C:22](=[C:23]([CH3:27])[C:24]=1[O:25][CH3:26])[CH2:21][O:20][C:19]2=[O:28])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOP(=O)(CCNCC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)OCC
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOP(=O)(CCN(CC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)S(C)(=O)=O)OCC
Yield: 63.1 %

Procedure:
A solution of (2-{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enylamino}-ethyl)-phosphonic acid diethyl ester (45 mg, 0.092 mmol) in CH2Cl2 (0.5 mL) was stirred with methanesulfonyl chloride (21 μL, 0.28 mmol) and pyridine (45 μL, 0.55 mmol) at ambient temperature overnight. The reaction was quenched by addition of 2 drops of water. The reaction mixture was concentrated and purified by RP HPLC using a C18 column with a gradient of H2O, 0.1% TFA-acetonitrile, 0.1% TFA to provide 36 mg of the product (63%) as a clear gel. 1H NMR (300 MHz, CDCl3) δ 0.05 (s, 9H), 1.18-1.29 (m, 2H), 1.29 (t, 6H, J=7 Hz), 1.85 (s, 3H), 2.00-2.13 (m, 2H), 2.19 (s, 3H), 2.85 (s, 3H), 3.32-3.43 (m, 2H), 3.47 (d, 2H, J=7 Hz), 3.69 (s, 2H), 3.79 (s, 3H), 4.05 (pent, 4H, J=7 Hz), 4.30-4.37 (m, 2H), 5.13 (s, 2H), 5.45 (t, 1H, J=7 Hz) ppm; 31P (121.4 MHz, CD3Cl) δ 27.5 ppm; MS (m/z) 642.2 [M+Na]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH2:4][CH2:3]1.[C:15]1([CH:21]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:22][C:23](O)=[O:24])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:23](=[O:24])[CH2:22][CH:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:11][CH2:10]2)[CH2:4][CH2:3]1
Reactant: CN1CCC(CN2CCNCC2)CC1
Reactant: O=C(O)CC(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CN1CCC(CN2CCN(C(=O)CC(c3ccccc3)c3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
To a solution of 1-(1-methyl-piperidin-4ylmethyl)-piperazine (0.25 g, 1.26 mmol) in dry CH2Cl2 (25 ml) was added 3,3-diphenylpropanoic acid (0.26 g, 1.15 mmol) under nitrogen. To the reaction was added EDC (0.48 g, 2.53 mmol) and DMAP (cat) and the reaction mixture stirred under nitrogen at room temperature overnight. The reaction was then concentrated under reduced pressure. The residue dissolved in ethyl acetate:water (10:1) (100 ml). The organic was washed with water (25 ml, 2×) and 10% NaOH (25 ml) and dried over MgSO4 and evaporated to dryness. The resulting residue was purified by column chromatography using CH2Cl2:MeOH (5:1) to give desired product in 69% yield.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH2:16])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1.[CH2:24]([N:26]1[C:30]([C:31](O)=[O:32])=[CH:29][C:28]([CH3:34])=[N:27]1)[CH3:25]>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH:16][C:31]([C:30]3[N:26]([CH2:24][CH3:25])[N:27]=[C:28]([CH3:34])[CH:29]=3)=[O:32])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1
Reactant: NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1nc(N)sc1-c1cccc(F)c1
Reactant: CCn1nc(C)cc1C(=O)O
Product: CCn1nc(C)cc1C(=O)NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1nc(N)sc1-c1cccc(F)c1

Procedure:
prepared by reaction of [2-amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl)-methanone with 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. LC-MS (basic): tR=0.78 min; [M+H]+=469.2.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:8]2[N:9]=[C:10]([C:18]3[CH:22]=[CH:21][S:20][CH:19]=3)[CH:11]=[C:12]([C:13]([O:15]CC)=[O:14])[C:7]=2[CH:6]=[N:5]1)[CH3:3].[OH-].[Na+]>C(O)C>[CH3:3][CH:2]([N:4]1[C:8]2[N:9]=[C:10]([C:18]3[CH:22]=[CH:21][S:20][CH:19]=3)[CH:11]=[C:12]([C:13]([OH:15])=[O:14])[C:7]=2[CH:6]=[N:5]1)[CH3:1]
Reactant: CCOC(=O)c1cc(-c2ccsc2)nc2c1cnn2C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)n1ncc2c(C(=O)O)cc(-c3ccsc3)nc21

Procedure:
The title compound was prepared in the same manner as described for intermediate 58 using ethyl 1-(1-methylethyl)-6-(3-thienyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (400 mg, 1.268 mmol), Ethanol (5 mL) THF (1 mL), and sodium hydroxide (2.114 mL, 6.34 mmol). The final product was collected as 370 mg (100%). LCMS E-S (M+H)=287.9. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.55 (d, J=6.8 Hz, 6H), 5.34 (quin, J=6.6 Hz, 1H), 7.72 (dd, J=5.0, 3.0 Hz, 1H), 7.93 (dd, J=5.0, 1.3 Hz, 1H), 8.15 (s, 1H), 8.34 (s, 1H), 8.49 (dd, J=3.0, 1.3 Hz, 1H), 13.97 (s, 1H).
Reaction SMILES: [Na].[C:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[N:12])=[N:9][CH:10]=1)([OH:4])=[O:3].C[O-].[Na+:15].[CH2:16](N)[CH2:17][NH2:18].Cl>CO>[CH3:2][O-:3].[Na+:15].[C:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[NH:18][CH2:17][CH2:16][N:12]=2)=[N:9][CH:10]=1)([OH:4])=[O:3]
Reactant: NCCN
Reactant: N#Cc1ccc(C(=O)O)cn1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=C(O)c1ccc(C2=NCCN2)nc1
Reaction time: 0.25 h

Procedure:
A solution of sodium methoxide is prepared by careful addition of sodium metal (13.6 g, 0.59 mol) to a flask containing methanol (500 ml) which is stirred. A solution of 5-carboxy-2-cyano-pyridine (36.0 g, 0.24 mol) in methanol (200 ml) is added to the sodium methoxide and the mixture heated for 2 h at 50°. After this time, freshly distilled ethylenediamine (28.8 g, 0.48 mol) and concentrated hydrochloric acid (64 ml) is added to the solution, which is then heated to 80° for 2.5 h. The reaction mixture is evaporated in vacuo to dryness. The residue is slurried in hot water (75 ml) for 15 min, filtered, washed with cold methanol (2×25 ml) and dried in vacuo at 60° to yield the title compound; m.p. 344°-345°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([C:15]([N:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]([CH:27]4[CH2:29][CH2:28]4)[CH2:19][CH2:18]3)=[O:16])=[CH:13][CH:12]=[CH:11][N:10]=2)[C:5]([Cl:30])=[CH:4][C:3]=1[CH2:31][CH2:32][C:33](O)=[O:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[NH2:69][CH2:70][C:71]([OH:73])=[O:72]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([C:15]([N:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]([CH:27]4[CH2:28][CH2:29]4)[CH2:19][CH2:18]3)=[O:16])=[CH:13][CH:12]=[CH:11][N:10]=2)[C:5]([Cl:30])=[CH:4][C:3]=1[CH2:31][CH2:32][C:33]([NH:69][CH2:70][C:71]([OH:73])=[O:72])=[O:34]
Reactant: O=C(O)CCc1cc(Cl)c(Oc2ncccc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Reactant: NCC(=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
Product: O=C(O)CNC(=O)CCc1cc(Cl)c(Oc2ncccc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Reaction time: 0.17 h
Yield: 16.1 %

Procedure:
To a solution of 3-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-2-yloxy]-phenyl}-propionic acid (50 mg, 0.098 mmol, 1.0 equiv; Example 173) in anhydrous DMF (1 mL) was added HATU (44.5 mg, 0.12 mmol, 1.2 equiv; [CAS RN 148893-10-1]) and N-ethyldiisopropylamine (25 mg, 33 μL, 0.20 mmol, 2.0 equiv; [CAS RN 7087-68-5]). After stirring the reaction mixture for 10 min, glycine (8.1 mg, 0.11 mmol, 1.1 equiv; [CAS RN 56-40-6]) was added and stirring continued at rt over night. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 9 mg (16%) of the title compound as a light yellow oil. MS (ISP): 569.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:13]([C:19](=[O:30])[C:20]3[CH:25]=[C:24]([N+:26]([O-])=O)[CH:23]=[CH:22][C:21]=3[Cl:29])=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:31]([F:34])([F:33])[F:32]>CC(O)=O.CCOC(C)=O.[Fe]>[NH2:26][C:24]1[CH:23]=[CH:22][C:21]([Cl:29])=[C:20]([CH:25]=1)[C:19]([C:13]1[C:12]([NH:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:31]([F:34])([F:33])[F:32])[CH:4]=2)(=[O:10])=[O:9])=[CH:17][C:16]([CH3:18])=[CH:15][N:14]=1)=[O:30]
Reactant: Cc1cnc(C(=O)c2cc([N+](=O)[O-])ccc2Cl)c(NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)c1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1cnc(C(=O)c2cc(N)ccc2Cl)c(NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 91.8 %

Procedure:
To Fe powder (61.3 mg, 1.09 mmol), AcOH (2 mL) was added dropwise and heated to 80° C. To it, a solution of 4-chloro-N-[2-(2-chloro-5-nitro-benzoyl)-5-methyl-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide (136 mg, 0.255 mmol) in AcOH (2 mL) was added slowly. After 30 min, reaction mixture was allowed to cool to room temperature and diluted with EtOAc (25 mL), filtered through a pad of Celite. The filter cake was washed with EtOAc (25 mL) and the filtrate was concentrated. The residual liquid was slowly treated with saturated aqueous NaHCO3 solution, followed by small portions of solid NaHCO3 to neutralize the AcOH, extracted with EtOAc (2×25 mL) and the extracts were dried (anhydrous Na2SO4), concentrated under reduced pressure and purified (SiO2, EtOAc) to get N-[2-(5-amino-2-chloro-benzoyl)-5-methyl-pyridin-3-yl]-4-chloro-3-trifluoromethyl-benzenesulfonamide (118 mg) in 92.2% yield. ESMS m/z (relative intensity): 504 (M+H)+ (100).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[CH3:11][O:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[C:15]([CH3:20])[CH:14]=1>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([NH:17][C:16]2[CH:18]=[CH:19][C:13]([O:12][CH3:11])=[CH:14][C:15]=2[CH3:20])=[O:7])=[CH:9][CH:10]=1
Reactant: COc1ccc(N)c(C)c1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Product: COc1ccc(NC(=O)c2ccc(Cl)nc2)c(C)c1

Procedure:
The title compound was prepared from 6-chloronicotinoyl chloride and 4-methoxy-2-methylaniline and was obtained as a white solid as described in Example 1. 1H NMR (CDCl3): 8.88 (bs, 1H), 8.19 (d, J=7.2, 1H), 7.61-7.47 (m, 3H), 6.81-6.79 (m, 2H), 3.81 (s, 3H), 2.30 (s, 3H).
Reaction SMILES: C([N:8]1[C:16]2[N:15]=[CH:14][N:13]([CH2:17][CH3:18])[C:12]=2[C:11](=[O:19])[N:10]([CH2:20][CH3:21])[C:9]1=[O:22])C1C=CC=CC=1.C>C(O)(=O)C.[Pd]>[CH2:20]([N:10]1[C:11](=[O:19])[C:12]2[N:13]([CH2:17][CH3:18])[CH:14]=[N:15][C:16]=2[NH:8][C:9]1=[O:22])[CH3:21]
Reactant: CCn1c(=O)c2c(ncn2CC)n(Cc2ccccc2)c1=O
Agent: [Pd]
Solvent: CC(=O)O
Product: CCn1c(=O)[nH]c2ncn(CC)c2c1=O
Reaction time: 47 h
Yield: 64.5 %

Procedure:
18 g of 3-benzyl-1,7-diethylxanthine (melting point 119° C.) in 1,500 ml of glacial acetic acid were hydrogenated in the presence of 2.5 g of 10% palladium on active charcoal at 80° C. and under 3.4 bar while shaking for 47 hours. After cooling down, the mixture was covered with an atmosphere of nitrogen while the catalyst was filtered off and the filtrate was evaporated under reduced pressure. The residue was dissolved in a mixture of 250 ml of methylene chloride and 100 ml of 1N sodium hydroxide solution. After washing the methylene chloride phase again with 1N sodium hydroxide solution, the combined aqueous phases were adjusted to pH 6 by adding 33% strength sulfuric acid dropwise with stirring. After washing to neutrality and drying the precipitate produced, 8.1 g (64.5% of theory) of 1,7-diethylxanthine, of melting point 204°-205° C., were obtained.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][OH:7].[F:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1F)[CH:12]=[O:13].[NH4+].[Cl-]>CN(C=O)C>[F:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:7][CH2:6][CH2:5][O:4][CH3:3])[CH:12]=[O:13]
Reactant: COCCO
Reactant: O=Cc1ccc(F)c(F)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COCCOc1ccc(C=O)cc1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
NaH (7.3 g) was carefully added to a solution of 2-Methoxy-ethanol (15 ml) in DMF (200 ml) and the solution was stirred for 4 hours. 3,4-difluoro-benzaldehyde (14 g) was added to the mixture under N2 at 0° C., and the resulting mixture was slowly warmed to room temperature and stirred for another 6 hours. Saturated aqueous NH4Cl (200 ml) was added to the solution, and the mixture was extracted by ethyl acetate (500 ml×3). The organic layer was evaporated to give 3-Fluoro-4-(2-methoxy-ethoxy)-benzaldehyde as oil (15 g). LC-MS: m/e 199 (MH+).