Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12([CH2:11][CH2:12][C:13]3[NH:17][C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[CH3:24])=[N:15][C:14]=3[C:25](O)=[O:26])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[C:28]([O:32][C:33](=[O:43])[CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([NH2:42])[CH:37]=1)([CH3:31])([CH3:30])[CH3:29]>>[C:28]([O:32][C:33](=[O:43])[CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([NH:42][C:25]([C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH3:24])[NH:17][C:13]=2[CH2:12][CH2:11][C:1]23[CH2:10][CH:5]4[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]4)[CH2:8]2)[CH2:2]3)=[O:26])[CH:37]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)CCc1cccc(N)c1
Reactant: Cc1ccccc1-c1nc(C(=O)O)c(CCC23CC4CC(CC(C4)C2)C3)[nH]1
Product: Cc1ccccc1-c1nc(C(=O)Nc2cccc(CCC(=O)OC(C)(C)C)c2)c(CCC23CC4CC(CC(C4)C2)C3)[nH]1
Yield: 63.2 %

Procedure:
5-(2-Adamantan-1-yl-ethyl)-2-o-tolyl-1H-imidazole-4-carboxylic acid (Example 93) (364 mg, 1.00 mmol) was reacted with 3-(3-amino-phenyl)-propionic acid tert-butyl ester (243 mg, 1.10 mmol) according to the procedure of Example 70, step c to afford the product as a colourless foam (359 mg, 63%). 1H NMR (300 MHz, CDCl3) 9.14 (1H, br s), 9.07 (1H, br s), 7.59-7.51 (3H, m), 7.35-7.22 (4H, m), 6.94 (1H, d), 3.16 (2H, m), 2.92 (2H, m), 2.60 (3H, s), 2.56 (2H, m), 1.99 (3H, s), 1.76-1.44 (23H, m).
Reaction SMILES: F[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.Cl.Cl.[N:25]1[CH:30]=[CH:29][C:28]([CH:31]([NH2:33])[CH3:32])=[N:27][CH:26]=1.CCN(C(C)C)C(C)C>CS(C)=O>[CH3:22][C:3]1[C:2]([NH:33][CH:31]([C:28]2[CH:29]=[CH:30][N:25]=[CH:26][N:27]=2)[CH3:32])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:12]2[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=2)[N:4]=1
Reactant: CC(N)c1ccncn1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC(C)c1ccncn1
Yield: 54 %

Procedure:
This compound (41 mg, 56% yield) as a yellow crystalline solid was prepared according the procedures described for Example 318, using 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (126) (55 mg, 0.19 mmol), (1-(pyrimidin-4-yl)ethanamine dihydrochloride (73 mg, 0.37 mmol) (ChemBridge Corporation) and DIEA (0.26 mL, 1.48 mmol) in 2 mL of DMSO (heated in a microwave at 160° C. for 30 min)1H NMR (400 MHz, DMSO-d6) δ ppm 11.73 (1H, br.), 9.15 (1H, s), 8.69 (1H, d, J=5.1 Hz), 7.87 (1H, d, J=7.2 Hz), 7.67 (2H, d, J=4.3 Hz), 7.57 (1H, d, J=8.0 Hz), 7.32 (1H, t, J=7.7 Hz), 6.99 (1H, br.), 6.87 (1H, s), 5.27 (1H, m), 3.48 (2H, m), 3.06 (2H, m), 2.69 (3H, s), 1.69 (3H, d, J=6.8 Hz). m/z (ESI, +ve) 400.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]=[CH2:9].[N+](=[CH2:12])=[N-]>CCOCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:12][CH2:9]1
Reactant: C=Cc1ccncc1Br
Reactant: C=[N+]=[N-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOCC
Product: Brc1cnccc1C1CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 3-bromo-4-vinylpyridine (Z, 0.4 g, 2.2 mmol) in ether (20 mL) was added palladium acetate (catalytic) and diazomethane (required for preparation, N-nitroso-N-methylurea-1.03 g, 10.0 mmol; 40% potassium hydroxide, 10 mL; ether, 20 mL) portion wise at 0° C. for 10 min. The reaction mixture was stirred at 0° C. for 0.5 h. The reaction mixture was filter through CELITE bed and concentrated under vacuum to afford the crude compound to obtain the title compound. 1H NMR (400 MHz, CDCl3) δ: 8.62 (s, 1H), 8.34-8.33 (d, J=5.2 Hz, 1H), 6.72-6.71 (d, J=4.8 Hz, 1H), 2.25-2.18 (m, 1H), 1.17-1.12 (m, 2H), 0.80-0.76 (m, 2H). MS (M+2): 200.2.
Reaction SMILES: [C:1]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:8]=[C:9]([N:12](COC)[S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[S:10][CH:11]=2)[CH:2]=1.Cl.O>O1CCCC1>[C:1]1([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:8]=[C:9]([NH:12][S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[S:10][CH:11]=2)[CH:2]=1
Reactant: COCN(c1nc(-c2cccc(-c3ccccc3)c2)cs1)S(=O)(=O)c1ccc(C)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)Nc2nc(-c3cccc(-c4ccccc4)c3)cs2)cc1
Yield: 45.9 %

Procedure:
A solution of 0.29 g of N-(4-biphenyl-3-yl-thiazol-2-yl)-N-methoxymethyl-4-methyl-benzenesulfonamide in 6 ml of tetra-hydrofuran was stirred at room temperature for 6 hours after the addition of 1.5 ml of 6N hydrochloric acid. The reaction mixture was added to 40 ml of water and extracted with ethyl acetate. The organic phases were combined, dried with magnesium sulphate and concentrated. Recrystallization from 10 ml of 50% ethanol yielded 120 mg of N-(4-biphenyl-3-yl-thiazol-2-yl)-4-methyl-benzenesulfonamide as colorless crystals.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:23](=O)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30](=[O:32])[CH3:31])[CH:12]=[CH:13][C:14]=1[O:15]CC1C=CC=CC=1)C1C=CC=CC=1.Cl(O)(=O)(=O)=O.[H][H]>C(O)C.[C].[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30](=[O:32])[CH3:31])[CH:12]=[CH:13][C:14]=1[OH:15]
Reactant: [H][H]
Reactant: CC(=O)CCCCCCC(=O)c1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Agent: [Pd]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CCO
Product: CC(=O)CCCCCCCc1ccc(O)c(O)c1

Procedure:
Using 0.5 g of 10% palladium-carbon, 3.2 g of 1-(3,4-dibenzyloxyphenyl)-1,8-nonanedione was catalytically reduced in a mixture of 50 ml of ethanol and 1.5 ml of an aqueous 5% perchloric acid solution at room temperature and under atomospheric pressure until the absorption of hydrogen stopped. After the reaction was over, the catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue was applied to silica gel (50 ml) column chromatography and eluted with a mixture of toluene and ethyl acetate (4:1). The crystals thus obtained were recrystallized from a mixture of toluene and n-hexane to provide 1-(3,4-dihydroxyphenyl)-8-nonanone.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[S:9])[NH:8][C:4]=2[CH:3]=1.Cl.[CH:13]([N:16]([CH:20]([CH3:22])[CH3:21])[CH2:17][CH2:18]Cl)([CH3:15])[CH3:14].C(=O)([O-])O.[Na+]>C(O)C>[CH:13]([N:16]([CH:20]([CH3:22])[CH3:21])[CH2:17][CH2:18][S:9][C:7]1[NH:8][C:4]2[CH:3]=[C:2]([CH3:1])[CH:11]=[CH:10][C:5]=2[N:6]=1)([CH3:15])[CH3:14]
Reactant: CC(C)N(CCCl)C(C)C
Reactant: Cc1ccc2[nH]c(=S)[nH]c2c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc2nc(SCCN(C(C)C)C(C)C)[nH]c2c1

Procedure:
6.16 g (37.5 mmoles) of 5-methyl-benzimidazoline-2-thione, 9 g (45 mmoles) of 2-(diisopropylamino)-ethylchloride hydrochloride and 3.52 g (41.9 mmoles) of sodium hydrogencarbonate are refluxed in 60 ml of ethanol for 6 hours. After the filtration of the salt and concentration of the filtrate the residue is extracted with dichloromethane and aqueous sodium hydroxide solution as described in Example 2. The aqueous phase is further extracted with dichloromethane, the combined organic phases are concentrated, the residue is recrystallized from 47 ml of ethylacetate. The title product thus obtained weights 6.65 g (61%) and melts at 109°-110° C.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:12])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][N:8]=[CH:7][CH:6]=2.[H][H]>CO.[Pd].[Pd].[C]>[CH3:1][CH:2]1[NH:11][C:10]2[C:5](=[CH:6][CH:7]=[N:8][CH:9]=2)[NH:4][C:3]1=[O:12]
Reactant: [H][H]
Reactant: Cc1nc2cnccc2[nH]c1=O
Agent: [Pd]
Solvent: CO
Product: CC1Nc2cnccc2NC1=O
Yield: 79.7 %

Procedure:
3-Methyl-1,4,6-triazanaphthalen-2(1H)-one (J. W. Clark-Lewis, R. P. Singh J. Chem. Soc. 1962, 3162) (3.1 g, 0.02 mol) was hydrogenated in 300 ml of methanol with palladium catalysis (10% Pd/carbon) under 1 atm of hydrogen. After hydrogen uptake ceased, the catalyst was filtered off with suction, the solvent was removed, and the residue was stirred with diethyl ether and filtered off with suction. 2.6 g (82%) of the desired product of melting point 230° C. (dec.) were obtained.
Reaction SMILES: CCN=C=NCCCN(C)C.[F:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:24](=[O:25])[C:23]([C:26]([OH:28])=O)=[CH:22][CH:21]=[N:20]2)=[CH:15][CH:14]=1.CCN(C(C)C)C(C)C.[CH3:38][O:39][C:40]1[CH:79]=[CH:78][C:43]([CH2:44][N:45]2[C:49]3=[N:50][CH:51]=[CH:52][C:53]([O:54][C:55]4[CH:60]=[CH:59][C:58]([NH2:61])=[CH:57][C:56]=4[F:62])=[C:48]3[C:47]([NH:63][C@H:64]3[CH2:69][CH2:68][N:67]([C:70]([O:72][C:73]([CH3:76])([CH3:75])[CH3:74])=[O:71])[CH2:66][C@H:65]3[F:77])=[N:46]2)=[CH:42][CH:41]=1.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[CH3:38][O:39][C:40]1[CH:41]=[CH:42][C:43]([CH2:44][N:45]2[C:49]3=[N:50][CH:51]=[CH:52][C:53]([O:54][C:55]4[CH:60]=[CH:59][C:58]([NH:61][C:26]([C:23]5[C:24](=[O:25])[N:19]([C:16]6[CH:15]=[CH:14][C:13]([F:12])=[CH:18][CH:17]=6)[N:20]=[CH:21][CH:22]=5)=[O:28])=[CH:57][C:56]=4[F:62])=[C:48]3[C:47]([NH:63][C@H:64]3[CH2:69][CH2:68][N:67]([C:70]([O:72][C:73]([CH3:76])([CH3:74])[CH3:75])=[O:71])[CH2:66][C@H:65]3[F:77])=[N:46]2)=[CH:78][CH:79]=1
Reactant: O=C(O)c1ccnn(-c2ccc(F)cc2)c1=O
Reactant: COc1ccc(Cn2nc(N[C@H]3CCN(C(=O)OC(C)(C)C)C[C@H]3F)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Cn2nc(N[C@H]3CCN(C(=O)OC(C)(C)C)C[C@H]3F)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 39 %

Procedure:
EDCI (43.6 mg, 0.227 mmol) was added to a stirred mixture of 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (53.2 mg, 0.227 mmol, prepared according to the procedure for Example 19, Step C), HOBt-hydrate (34.8 mg, 0.227 mmol) and DIEA (0.0792 ml, 0.455 mmol) in DCM (1 mL) at ambient temperature, and the reaction mixture was stirred for 15 minutes at ambient temperature. ±(3R*,4S*)-tert-Butyl 4-(1-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)-1H-pyrazolo[3,4-b]pyridin-3-ylamino)-3-fluoropiperidine-1-carboxylate (66 mg, 0.114 mmol) was then added. The resulting solution was stirred for 18 hours at ambient temperature. To a separate 1 dram vial was added an additional equivalent of the 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid, HOBt, DIEA, and EDCI in DCM (0.5 mL). This mixture was stirred for 15 minutes, then added to the original reaction mixture, which was stirred for an additional day at ambient temperature. The crude reaction mixture was loaded directly on to a preparative TLC plate (2 mm thickness) and eluted with 10% MeOH/DCM (Rf=0.70). A second preparative TLC plate (1 mm thickness, Rf=0.17) eluting with 1:1 EtOAc/hexanes was utilized to obtain pure product (35 mg, 39%)
Reaction SMILES: [CH:1]([Mg]Cl)=[CH2:2].[CH3:5][O:6][C:7]1[CH:20]=[CH:19][C:18]2[O:17][C:16]3[C:11](=[CH:12][C:13]([C:21]4[CH:22]=[N:23][CH:24]=[N:25][CH:26]=4)=[CH:14][CH:15]=3)[C:10](=[O:27])[C:9]=2[CH:8]=1>C1COCC1>[CH3:5][O:6][C:7]1[CH:20]=[CH:19][C:18]2[O:17][C:16]3[C:11](=[CH:12][C:13]([C:21]4[CH:26]=[N:25][CH:24]=[N:23][CH:22]=4)=[CH:14][CH:15]=3)[C:10]([CH:1]=[CH2:2])([OH:27])[C:9]=2[CH:8]=1
Reactant: COc1ccc2oc3ccc(-c4cncnc4)cc3c(=O)c2c1
Reactant: C=C[Mg]Cl
Solvent: C1CCOC1
Product: C=CC1(O)c2cc(OC)ccc2Oc2ccc(-c3cncnc3)cc21
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
A vial charged with Pd2(dba)3 (0.150 g, 0.164 mmol), XPhos (0.391 g, 0.819 mmol), 5-(tributylstannyl)pyrimidine (1.81 g, 4.92 mmol), 2-bromo-7-methoxy-9H-xanthen-9-one (1.000 g, 3.28 mmol) and dioxane (10 mL). The reaction mixture was evacuated and backfilled with nitrogen. The reaction mixture was heated to 100° C. overnight. The reaction mixture was cooled to RT and diluted with water and EtOAc. A grey solid precipitated out, which was filtered off. The solid was washed with EtOAc and water. The grey solid dried under reduced pressure to afford 2-methoxy-7-(pyrimidin-5-yl)-9H-xanthen-9-one) (0.600 g, 60.2% yield). Step 2: A solution of vinylmagnesium chloride (1.6M solution in THF; 0.82 mL, 1.314 mmol) was added dropwise to a solution of 2-methoxy-7-(pyrimidin-5-yl)-9H-xanthen-9-one (200 mg, 0.657 mmol) in THF (10 mL) at −78° C. After 30 min, the reaction mixture was allowed to warm to −10° C. and was then quenched with saturated aqueous ammonium chloride. The reaction was extracted with EtOAc, and the organic phase was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by chromatography to give 2-methoxy-7-(pyrimidin-5-yl)-9-vinyl-9H-xanthen-9-ol as a pale yellow gum. Step 3: 2 N HCl (3 mL) was added to solution of 2-methoxy-7-(pyrimidin-5-yl)-9-vinyl-9H-xanthen-9-ol (50 mg, 0.150 mmol) and thiourea (9.25 μL, 0.171 mmol) in HOAc (5 mL). The reaction mixture was allowed to stir overnight at rt and concentrated under reduced pressure. The residue was treated with of TFA (4 mL). The reaction mixture was stirred overnight at rt. The reaction mixture was concentrated under reduced pressure and the residue was treated with aqueous, half-saturated sodium bicarbonate, extracted with EtOAc, and concentrated under reduced pressure. The residue was purified by chromatography (DCM/MeOH 20:1 to 5:1) to give 2′-methoxy-7′-(pyrimidin-5-yl)-5,6-dihydrospiro[[1,3]thiazine-4,9′-xanthen]-2-amine as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](O)=[O:9])=[C:6]([CH3:11])[CH:5]=[CH:4][N:3]=1.O=S(Cl)Cl.[NH3:16]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([C:8]([NH2:16])=[O:9])=[C:6]([CH3:11])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccnc(Cl)c1C(=O)O
Reactant: N
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1ccnc(Cl)c1C(N)=O
Temperature: 25 °C
Yield: 91 %

Procedure:
To a mixture of 2-chloro-4-methyl-3-pyridinecarboxylic acid (24.7 g, 157 mmol) and 75 mL of toluene at 70° C. was added 75 mL of SOCl2 (22.6 g, 190 mmol) within a period of 1 hour. The reaction mixture was refluxed for 4 hours and the resulting solution was cooled to room temperature. Dry NH3 gas was introduced at such a rate so as to maintain the internal temperature below 30° C. After removing toluene, the solid residue was washed successively with cold water and methanol, and dried to yield 22.72 g of the title compound (91%, m.p. 168°-170° C.).
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH2:14])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[CH3:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1.[OH-].[Na+]>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:22](=[O:23])[C:21]3[CH:25]=[CH:26][C:18]([CH3:17])=[CH:19][CH:20]=3)[CH2:9]2)=[O:7])=[CH:15][CH:16]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: Cc1ccc(C(=O)N2CCC[C@@H](N)C2)cc1
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(C(=O)N[C@@H]2CCCN(C(=O)c3ccc(C)cc3)C2)cc1
Temperature: 15 °C
Reaction time: 3 h
Yield: 80.4 %

Procedure:
To the aqueous solution of (R)-1-(p-methylbenzoyl)-3-amino piperidine obtained in Example 13 (amount: 3 g), p-Methylbenzoyl chloride (0.16 g) was added. The pH of the mixture was kept from 8.0 to 9.0 using sodium hydroxide. The mixture was stirred at 15° C. for 3 hours, and the precipitated crystal was filtered off. The crystal was dried under reduced pressure to obtain the title compound as white crystal (0.28 g, yield: 59%).
Reaction SMILES: C(O)C.[O-]CC.[Na+].[C:8]([O:16][CH2:17][CH3:18])(=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].[CH2:19]([O:22][CH:23]([CH3:30])[CH2:24]CS([O-])(=O)=O)[CH2:20][CH3:21]>O>[CH2:19]([O:22][CH:23]([CH3:30])[CH2:24][CH:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:8]([O:16][CH2:17][CH3:18])=[O:15])[CH2:20][CH3:21]
Reactant: CCCOC(C)CCS(=O)(=O)[O-]
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCOC(C)CC(C(=O)OCC)C(=O)OCC
Yield: 65.8 %

Procedure:
Into 345 ml of ethanol, 43.4 g of 95%-sodium ethoxide was added, and under stirring, 114 g of diethyl malonate was added dropwise at 33°-36° C. in 55 min. After further 30 min. of stirring, 114 g of the above 2-propoxypropylmethane sulfonate was added at 34°-38° C. in 1 hour. The mixture was heated and refluxed at 80°-82° C. for 18 hours. After the completion, the product was poured in cold water and extracted with benzene, followed by washing with water, removed by distillation of benzene, and vacuum distillation to obtain 100 g of ethyl 4-propoxy-2-ethoxycarbonylvalerate (75°-115° C./5 mmHg).
Reaction SMILES: C([N:4]1[C:12]2[CH:11]=[C:10]3[C:13](=O)[C:14](=[O:16])[NH:15][C:9]3=[CH:8][C:7]=2[CH2:6][CH2:5]1)(=O)C.[CH:18]1[C:23]([NH:24][NH2:25])=[CH:22][CH:21]=[C:20]([S:26]([NH2:29])(=[O:28])=[O:27])[CH:19]=1.Cl.[BrH:31]>O.CCO>[BrH:31].[O:16]=[C:14]1[NH:15][C:9]2=[CH:8][C:7]3[CH2:6][CH2:5][NH:4][C:12]=3[CH:11]=[C:10]2[C:13]1=[N:25][NH:24][C:23]1[CH:22]=[CH:21][C:20]([S:26]([NH2:29])(=[O:27])=[O:28])=[CH:19][CH:18]=1
Reactant: CC(=O)N1CCc2cc3c(cc21)C(=O)C(=O)N3
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: Br
Agent: Cl
Solvent: CCO
Solvent: O
Product: NS(=O)(=O)c1ccc(NN=C2C(=O)Nc3cc4c(cc32)NCC4)cc1
Temperature: 25 °C
Yield: 17 %

Procedure:
A solution of 0.10 g (0.44 mmol) of 5-acetyl-1,5,6,7-tetrahydro-pyrrolo[2,3-f]indole-2,3-dione in 3 mL of conc. HBr was heated to 100° C. for 18 h. The mixture was cooled to ambient temperature, diluted with 10 mL of water and filtered. The filtrate was concentrated in vacuo and added to a solution of 0.05 g (0.2 mmol) 4-sulfonamidophenylhydrazine hydrochloride in 5 mL of EtOH. The mixture was heated to 80° C. for 1 h and cooled to ambient tempurature. The resulting solid was collected by vacuum filtration, washed with water and dried in a vacuum oven at 70° C. to afford the title compound as a tan solid (0.026 g, 17%): mp>250° C.; 1H NMR (DMSO-d6): δ3.17 (t, J=7.8 Hz, 2H), 3.69 (t, J=7.8 Hz, 2H), 6.96 (s, 1H), 7.25 (s, 2H), 7.52 (s, 1H), 7.57 (d, J=8.8 Hz, 2H), 7.77 (d, J=8.8 Hz, 2H), 10.65 (bs, 2H), 11.24 (s, 1H), 12.73 (s, 1H); APCI−MS: m/z 356 (M−H)−. Anal. Calcd for C16H15N5O3S.0.9HBr.0.5H2O: C, 43.75; H, 3.88; N, 15.94; S, 7.30. Found: C, 44.01; H, 4.14; N, 15.70; S, 7.12.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:15])[CH2:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1.[C:16](OCC)(=[O:23])[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.C(O[K])(C)(C)C.Cl>C1COCC1.O>[OH:23][C:16]([C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1)=[C:4]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)[C:3]([NH:2][CH3:1])=[O:15]
Reactant: CNC(=O)Cc1ccc2ccccc2c1
Reactant: CCOC(=O)c1ccncc1
Agent: CC(C)(C)O[K]
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)C(=C(O)c1ccncc1)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-Methyl-2-naphthalen-2-yl-acetamide (94 g, 470 mmol) and 71.3 g (71 ml) of ethyl isonicotinate (470 mmol) were partially dissolved in 800 mL of anhydrous THF in a 3 L, 3-necked r.b. flask equipped with a mechanical stir, temperature probe, and a 500-mL addition funnel. The flask was cooled to 0–5° C. in an ice-water bath. tBuOK (1M in THF, 470 mL) was added slowly into the heterogeneous mixture. After the addition, the resulting yellow-brown heterogeneous mixture was stirred overnight at RT. The resulting dark solution was cooled to 0–5° C. in an ice-water bath. Distilled water (800 mL) was added. The basic solution was neutralized to pH 7 using 37% HCl. The solvent was removed in vacuum at RT. The resulting solid was filtered off, washed by slurring in water (1 L) and toluene (1 L), respectively. The suspension was then filtered. The solid was dried under vacuum at 50° C. overnight and used crude in the next step.
Reaction SMILES: [CH2:1]1[NH:6][CH2:5][CH2:4][N:3]2[CH2:7][C@H:8]([CH2:11][N:12]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[O:14][C:13]3=[O:21])[CH2:9][CH2:10][C@@H:2]12.Cl[C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=1.Cl>>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([N:6]2[CH2:5][CH2:4][N:3]3[CH2:7][C@H:8]([CH2:11][N:12]4[C:16]5[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=5[O:14][C:13]4=[O:21])[CH2:9][CH2:10][C@H:2]3[CH2:1]2)=[N:24][CH:25]=1
Reactant: Clc1ccc(Cl)nc1
Reactant: O=c1oc2ccccc2n1C[C@@H]1CC[C@H]2CNCCN2C1
Agent: Cl
Product: O=c1oc2ccccc2n1C[C@@H]1CC[C@H]2CN(c3ccc(Cl)cn3)CCN2C1

Procedure:
The title compound was synthesized according to Preparation 11 from 3-[(7R,9aS)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]-pyrazin-7-ylmethyl]-3H-benzoxazol-2-one (Preparation 12) and 2,5-dichloropyridine. mp (.HCl) 247–248° C. HRMS calcd for C21H23ClN4O2: 398.1510, found: 398.1484.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([NH:19][C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[O:18])[C:12]1=[O:26].[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+].O>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[O:26]=[C:12]1[C:13]([C:17]([NH:19][C:20]2[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=2)=[O:18])=[CH:14][CH:15]=[CH:16][N:11]1[CH:6]1[C:2]2[C:3](=[C:7]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:8]=[CH:9][CH:10]=2)[CH2:4][CH2:5]1
Reactant: O=C(Nc1ccncc1)c1cccn(C2CCc3c(Cl)cccc32)c1=O
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=C(Nc1ccncc1)c1cccn(C2CCc3c(-c4ccccc4)cccc32)c1=O
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 10 %

Procedure:
To a mixture of 1-(4-chloro-2,3-dihydro-1H-inden-1-yl)-2-oxo-N-(pyridin-4-yl)-1,2-dihydropyridine-3-carboxamide (200 mg, 1.0 eq) in DME (4 mL) was added phenylboronic acid (3.5 eq), Pd(PPh3)2Cl2 (0.2 eq) and aqueous Na2CO3 (2M, 2 mL). The mixture was stirred at 120° C. for 30 mins by microwave. At the end of reaction 50 mL of H2O was added and extracted with ethyl acetate. The combined organic layer was washed with brine and dried over MgSO4, evaporated the filtrate to give the crude product, which was purified by HPLC to afford 2-oxo-1-(4-phenyl-2,3-dihydro-1H-inden-1-yl)-N-(pyridin-4-yl)-1,2-dihydropyridine-3-carboxamide (21 mg, 10%). MS (ESI) 408.0 (M+H); 1H NMR (300 MHz, DMSO-d6) δ12.93 (s, 1H), 8.71 (br, 2H), 8.53 (d, J=3.9 Hz, 1H), 8.15 (d, J=3.3 Hz, 2H), 7.84 (d, J=3.9 Hz, 1H), 7.57 (d, J=4.5 Hz, 2H), 7.50 (t, J=4.5 Hz, 2H), 7.37-7.43 (m, 3H), 7.17 (d, J=4.5 Hz, 1H), 6.61-6.69 (m, 2H), 3.15-3.25 (m, 1H), 3.05-3.15 (m, 1H), 2.60-2.75 (m, 1H), 2.50 (s, 6H), 2.10-2.15 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[C:8]2[C:13]([C:14]=1[CH:15]=O)=[CH:12][C:11]([F:17])=[CH:10][CH:9]=2)=[O:5])[CH3:2].N1C=CC=CC=1.Cl.[NH2:36][OH:37]>CCO>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[C:8]2[C:13]([C:14]=1[CH:15]=[N:36][OH:37])=[CH:12][C:11]([F:17])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C=O)c2cc(F)ccc2n1Cc1cccc2ccccc12
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CCOC(=O)c1c(C=NO)c2cc(F)ccc2n1Cc1cccc2ccccc12

Procedure:
To a suspension of 5-fluoro-3-formyl-1-naphthalen-1-ylmethyl-1H-indole-2-carboxylic acid ethyl ester (1.16 g) in EtOH (35 ml) was added at 22° C. pyridine (8.0 ml) and hydroxylamine hydrochloride (0.54 g) and the mixture was heated to reflux temperature for 2 h. The mixture was evaporated and the residue partitioned between 1 N HCl and t-butylmethyl ether. The organic layer was dried and evaporated to give 5-fluoro-3-(hydroxyimino-methyl)-1-naphthalen-1-ylmethyl-1H-indole-2-carboxylic acid ethyl ester as a colorless foam. MS: 391.1 ([M+H]+).