Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[C:17]2[CH:18]=[CH:19][C:20]([C:23]([NH:25][CH2:26][CH2:27][C:28]([O:30]CC)=[O:29])=[O:24])=[N:21][CH:22]=2)=[CH:4][CH:3]=1.[C:33]([C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1)(=[O:35])[CH3:34].C([O-])([O-])=O.[Na+].[Na+].Cl>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:33]([C:36]1[CH:41]=[CH:40][C:39]([C:2]2[CH:3]=[CH:4][C:5]([NH:8][CH2:9][C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=3[C:17]3[CH:18]=[CH:19][C:20]([C:23]([NH:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[O:24])=[N:21][CH:22]=3)=[CH:6][CH:7]=2)=[CH:38][CH:37]=1)(=[O:35])[CH3:34]
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(Cl)ccc2CNc2ccc(Br)cc2)cn1
Reactant: CC(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)c1ccc(-c2ccc(NCc3ccc(Cl)cc3-c3ccc(C(=O)NCCC(=O)O)nc3)cc2)cc1
Temperature: 90 °C

Procedure:
Ethyl 3-(5-(2-(((4-bromophenyl)amino)methyl)-5-chlorophenyl)picolinamido)propanoate (84 mg, 0.16 mmol), (4-acetylphenyl)boronic acid (32 mg, 0.20 mmol), Pd(dppf)Cl2 (18 mg, 0.02 mmol), 2M aqueous Na2CO3 (0.22 mL, 0.44 mmol) were dissolved in 1,4-dioxane (1.2 mL) and the resulting mixture was heated to 90° C. After 16 h the resulting mixture was cooled to room temperature, acidified with 2N HCl, filtered through CELITE and the filtrate was diluted with EtOAc, washed with water and saturated aqueous NaHCO3. The organic layer was dried (Na2SO4), concentrated and purified via column chromatography to yield the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([CH3:20])([CH3:19])[CH2:10][C:11]([OH:18])([C:14]([F:17])([F:16])[F:15])[CH:12]=O.[NH2:21][C:22]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:23]=1[CH2:24][O:25][C:26]2=[O:27].B(Br)(Br)Br>>[OH:18][C:11]1([C:14]([F:15])([F:17])[F:16])[CH2:10][C:9]([CH3:19])([CH3:20])[C:4]2[C:5](=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH:12]1[NH:21][C:22]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:23]=1[CH2:24][O:25][C:26]2=[O:27]
Reactant: Nc1cccc2c1COC2=O
Reactant: COc1ccccc1C(C)(C)CC(O)(C=O)C(F)(F)F
Agent: BrB(Br)Br
Product: COc1cccc2c1C(C)(C)CC(O)(C(F)(F)F)C2Nc1cccc2c1COC2=O
Yield: 19 %

Procedure:
Analogously to Example 10, the corresponding imine is produced starting from 600 mg of 4-(2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 308 mg of 4-amino-phthalide (Bull. Soc. Sci. Bretagne 26, 1951, Special Edition 5, p. 7, 96). As in Example 2, 650 mg of the imine is reacted by reaction with 7.7 ml of BBr3 (1 M in dichloromethane), and 165 mg of the title compound is obtained.
Reaction SMILES: O[CH:2]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH:17]([CH3:19])[CH3:18])=[CH:12][CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].S(Cl)([Cl:22])=O>>[Cl:22][CH:2]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH:17]([CH3:19])[CH3:18])=[CH:12][CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)C(O)CCc1ccc(OC(C)C)cc1
Product: CCOC(=O)C(Cl)CCc1ccc(OC(C)C)cc1
Yield: 27 %

Procedure:
According to the same manner as that described in Reference Example 34, ethyl 2-hydroxy-4-(4-isopropoxyphenyl)-butyrate was chlorinated with thionyl chloride to give ethyl 2-chloro-4-(4-isopropoxypheyl)butyrate as an oil (yield: 27%).
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]2[CH2:13][CH2:12]S[CH2:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.C[N+]1([O-])CCOCC1.[S:22]([O-:25])(O)=[O:23].[Na+]>CC(C)=O.O.[Os](=O)(=O)(=O)=O>[O:23]=[S:22]1(=[O:25])[CH2:10][CH2:9][CH:8]([C:7]2[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=2)[CH2:13][CH2:12]1
Reactant: O=S([O-])O
Reactant: Fc1ncccc1C1CCSCC1
Agent: O=[Os](=O)(=O)=O
Agent: C[N+]1([O-])CCOCC1
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=S1(=O)CCC(c2cccnc2F)CC1
Reaction time: 8 h

Procedure:
To a stirred mixture of 2-fluoro-3-(tetrahydro-2H-thiopyran-4-yl)pyridine (1.2 g, 6.08 mmol), 4-methylmorpholine 4-oxide (1.781 g, 15.21 mmol) in acetone/water (7:3, 30 mL) was added osmium(VIII) oxide (0.631 mL, 0.304 mmol). Stirring was continued at RT overnight. A saturated solution of sodium hydrogensulfite (10 mL) was added and stirred in 15 min., extracted with EtOAc (3×), dried over MgSO4, concentrated to give the tan solid. MS (M+1): 230.2.
Reaction SMILES: Br.[CH3:2][NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9]2[CH:10]=[C:11]([NH:15]C(=O)OCC)[CH:12]=[CH:13][CH:14]=2)[N:8]=1.[OH-].[Na+]>Cl>[CH3:2][NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[CH:10]=2)[N:8]=1
Reactant: CCOC(=O)Nc1cccc(-c2csc(NC)n2)c1
Agent: Br
Agent: Cl
Agent: [Na+]
Product: CNc1nc(-c2cccc(N)c2)cs1
Yield: 86 %

Procedure:
A mixture of ethyl N-[3-(2-methylamino-4-thiazolyl)-phenyl]-carbamate hydrobromide (33.5 g) and 10% hydrochloric acid (500 ml) was refluxed for 48 hours. After cooling, the solution was made alkaline with 10% sodium hydroxide and the precipitate was filtered off, washed with water and dried to give 16.5 g of 2-methylamino-4-(3-amino-phenyl)-thiazole; M.p. 118°-121° C. 2-Methylamino-4-(4-amino-phenyl)-thiazole; M.p. 178°-180° C., was prepared in analogous manner, starting from the appropriate carbamate derivative.
Reaction SMILES: [C:1]([OH:13])(=O)/[CH:2]=[CH:3]/[C:4]1[CH:11]=[CH:10][C:8]([OH:9])=[C:6]([OH:7])[CH:5]=1.C1(N=C=NC2CCCCC2)CCCCC1.[CH2:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O1CCCC1>[CH2:29]([NH:36][C:1](=[O:13])/[CH:2]=[CH:3]/[C:4]1[CH:11]=[CH:10][C:8]([OH:9])=[C:6]([OH:7])[CH:5]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(O)/C=C/c1ccc(O)c(O)c1
Reactant: NCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: O=C(/C=C/c1ccc(O)c(O)c1)NCc1ccccc1
Temperature: 50 °C
Reaction time: 6 h

Procedure:
To 5 ml of tetrahydrofuran containing 180 mg of caffeic acid were added 206 mg of dicyclohexyl carbodiimide and 107 mg of benzylamine. The mixture was stirred at 50° C. for 6 hours and then filtrated. The filtrate was concentrated and the residue obtained was recrystallized from ethyl acetate/hexane to give 100 mg of granular crystals.
Reaction SMILES: [Na].[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:9])=[N:7][CH:8]=1.[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl>CO.CS(C)=O.O>[CH2:10]([O:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:9])=[N:7][CH:8]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrCc1ccccc1
Reactant: Cc1ccc(O)cn1
Agent: Cl
Agent: [Na]
Solvent: CS(C)=O
Solvent: CO
Solvent: O
Product: Cc1ccc(OCc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 88 %

Procedure:
3.3 g of sodium were dissolved in 60 ml of methanol and stirred with 15 g of 5-hydroxy-2-methylpyridine in 230 ml of DMSO for 1 hour at a temperature of 80° to 90° C. The methanol was spun or rotated out after cooling the mixture. 23.5 g of benzylbromide were then added, followed by stirring for 20 hours at room temperature. The reaction mixture was then acidified with 2N HCl and mixed with 1500 ml of water. The mixture was then extracted with diethyl ether and the ether phase was discarded. The pH-value of the aqueous phase was then adjusted to approximately 8 and the solution was extracted with ether. The organic phase was evaporated. 24.1 g of 5-benzyloxy-2-methylpyridine were obtained. The latter was dissolved in 200 ml of glacial acetic acid, mixed with 12 ml of hydrogen peroxide (30%) and refluxed for 2 hours. The mixture was then neutralized with 40% caustic soda solution and 1000 ml of water were added. The solution was extracted with dichloromethane and the organic phase evaporated. 25 g of 5-benzyloxy-2-methylpyridine-N-oxide were obtained.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[C:6]([NH:13][C:14]1[CH:15]=[C:16]2[C:27](=[O:28])[O:26][C:24](=[O:25])[C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([CH:23]=1)[C:17]2=3)([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:7]>S(=O)(=O)(O)O>[C:6]([NH:13][C:14]1[CH:15]=[C:16]2[C:27](=[O:28])[O:26][C:24](=[O:25])[C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([C:23]=1[N+:1]([O-:4])=[O:2])[C:17]2=3)([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:7]
Reactant: CCOC(=O)C(=O)Nc1cc2c3c(cccc3c1)C(=O)OC2=O
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCOC(=O)C(=O)Nc1cc2c3c(cccc3c1[N+](=O)[O-])C(=O)OC2=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
Powdered potassium nitrate (0.51 g, 5 mmol) was added to a stirred solution of 3-ethoxalylamino-1,8-naphthalenedicarboxylic anhydride (1.57 g, 5 mmol) in 15 ml of conc. sulfuric acid at 0° C. Stirring was continued for 2 h at the same temperature, then the reaction mixture was poured into 150 ml of ice-water. The separated yellow solid was isolated by filtration and washed with water ethanol and ether. Trituration with a small amount of ethyl acetate afforded 1.38 g (77%) of the title compound. M.p. 221°-222° C.; 1H-NMR CDCl3 +DMSO-d6): 1.43 (t,J=7Hz, 3H, CH3), 4.37 (q,J=7Hz, 2H, CH2), 7.70-8.60 (m, 3H, ArH), 8.82 (s, 1H, H-2), 11.3 (broad s, 1H, NH).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=3)[CH:11]=[C:10]([C:22]([O:24][CH3:25])=[O:23])[C:9]=2[C:26]([O:28][CH3:29])=[O:27])[CH:5]=[CH:4][N:3]=1.F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.[Si:48]([O:55][C@@H:56]1[C:65]2[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=2)[NH:59][CH2:58][CH2:57]1)([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:50])[CH3:49].CC(C)([O-])C.[Na+].[Cl-].[NH4+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.O.C1(C)C=CC=CC=1>[C:51]([Si:48]([CH3:50])([CH3:49])[O:55][C@@H:56]1[C:65]2[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=2)[N:59]([C:2]2[CH:7]=[C:6]([C:8]3[C:17]4[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=4)[CH:11]=[C:10]([C:22]([O:24][CH3:25])=[O:23])[C:9]=3[C:26]([O:28][CH3:29])=[O:27])[CH:5]=[CH:4][N:3]=2)[CH2:58][CH2:57]1)([CH3:54])([CH3:53])[CH3:52]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CCNc2ccccc21
Reactant: COC(=O)c1cc2cc(OC)c(OC)cc2c(-c2ccnc(Br)c2)c1C(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2cc(OC)c(OC)cc2c(-c2ccnc(N3CC[C@H](O[Si](C)(C)C(C)(C)C)c4ccccc43)c2)c1C(=O)OC
Temperature: 100 °C
Reaction time: 4 h
Yield: 79.9 %

Procedure:
200 mL of a toluene solution containing 20.00 g of 1-(2-bromo-4-pyridyl)-2,3-bis(methoxycarbonyl)-6,7-dimethoxy-naphthalene was sonicated under reduced pressure, then, 975 mg of palladium acetate, 1009 mg of tri-tert-butyl-phosphonium tetrafluoroborate, 13.72 g of (4S)-4-(tert-butyldimethylsilyloxy)-1,2,3,4-tetrahydroquinoline and 6.26 g of sodium tert-butoxide were added to the mixture under room temperature, and after replacing the atmosphere with nitrogen, the mixture was stirred at 100° C. for 4 hours. After cooling the mixture by allowing to stand, 100 mL of a saturated aqueous ammonium chloride solution, 100 mL of water and 100 mL of ethyl acetate were added to the reaction mixture, and said mixture was filtered with Celite. Celite was washed with 100 mL of ethyl acetate, and the organic layer was separated. Said organic layer was washed with 100 g of 20% saline solution, dried over anhydrous magnesium sulfate and then concentrated. The resulting residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=5:1 to 4:1) to obtain 22.31 g (Yield: 80%) of 1-[2-[(4S)-4-(tert-butyldimethyl-silyloxy)-1,2,3,4-tetrahydroquinolin-1-yl]-4-pyridyl]-2,3-bis(methoxycarbonyl)-6,7-dimethoxynaphthalene.
Reaction SMILES: [CH2:1]=[C:2]([CH2:6][C:7]([NH2:9])=[O:8])[C:3](O)=[O:4].C([N:12](CC)CC)C.ClC(OCC)=O>C(Cl)(Cl)Cl>[C:3]([NH2:12])(=[O:4])[C:2]([CH2:6][C:7]([NH2:9])=[O:8])=[CH2:1]
Reactant: C=C(CC(N)=O)C(=O)O
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Product: C=C(CC(N)=O)C(N)=O
Temperature: 5 °C
Reaction time: 2 h

Procedure:
38.7 grams (0.3 mole) of 2-methylenesuccinamic acid, prepared as described in Example 1, were dissolved in 150 ml of chloroform in a 500 ml. 3-necked round bottom flask equipped with a magnetic stirrer, condenser, drying tube, thermometer, and dropping funnel. The solution was cooled to about 5° C. and a mixture of 41.7 ml. (1 equivalent) of triethylamine and 90 ml. of chloroform was added dropwise over 1/2 hour to the stirring solution. The solution was then cooled to about -45° C. by means of a dry ice-acetone bath. A mixture of 28.5 ml. (1 equivalent) of ethyl chloroformate and 70 ml. of chloroform was added to the solution over a 1/2 hour period, maintaining the solution temperature at about -45° C. The reaction mixture was allowed to stir at -45° C., ±15° C., for an additional 2 hours. The reaction mixture was then transferred to a 1-liter 3-necked round bottom flask fitted with a mechanical stirrer, gas inlet, thermometer, condenser, and drying tube. The solution was maintained at -10° C. while ammonia gas was bubbled into the reaction mixture for 1/2 hour. Additional portions of chloroform, totaling 400 ml., were then added. The reaction mixture was allowed to warm to room temperature and the precipitated product was isolated by suction filtration and air-dried overnight. Repeated recrystallizations from water, methanol/water, and water gave 16.3 gms of itaconamide, a white solid melting at 226°-229° C.
Reaction SMILES: [C:1]([O:4][C:5]([CH3:16])([CH3:15])[CH2:6][NH:7]C(OC(C)(C)C)=O)(=[O:3])[CH3:2].[ClH:17]>C(OCC)(=O)C>[ClH:17].[C:1]([O:4][C:5]([CH3:16])([CH3:15])[CH2:6][NH2:7])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)(C)CNC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(=O)OC(C)(C)CN
Temperature: 25 °C
Reaction time: 20 h

Procedure:
2-(tert-Butoxycarbonylamino)-1,1-dimethylethyl acetate (508 mg, 2.2 mmol) was dissolved in ethyl acetate (6 ml). 3 M hydrogen chloride in ethyl acetate (4 ml, 12 mmol) was added. The reaction mixture was stirred for 20 h at room temperature. The precipitation was filtered off and washed with diethyl ether (50 ml). It was dried in vacuo to give 246 mg of 2-amino-I,1-dimethylethyl acetate hydrochloride.
Reaction SMILES: [OH-].[Na+].Cl.[CH3:4][C:5]1[NH:9][CH:8]=[N:7][C:6]=1[CH2:10][SH:11].[C:12]([NH:14][C:15]([NH:20][CH3:21])=[N:16][CH2:17][CH2:18][SH:19])#[N:13].II>>[C:12]([NH:14][C:15]([NH:20][CH3:21])=[N:16][CH2:17][CH2:18][S:19][S:11][CH2:10][C:6]1[N:7]=[CH:8][NH:9][C:5]=1[CH3:4])#[N:13]
Reactant: CNC(=NCCS)NC#N
Reactant: Cc1[nH]cnc1CS
Agent: Cl
Agent: II
Agent: [Na+]
Product: CNC(=NCCSSCc1nc[nH]c1C)NC#N

Procedure:
Aqueous sodium hydroxide (3.60 g, 0.9 mol) was added to a stirred ethanolic solution of 5-methyl-4-mercaptomethylimidazole hydrochloride (5.92 g, 0.03 mol) and N-cyano-N'-methyl-N"-(2-mercaptoethyl)guanidine (5.74 g, 0.0363 mol). The solution was cooled to 0° and a saturated ethanolic solution of iodine was added until the iodine color remained. The solvent was removed under reduced pressure to yield an oil which was purified using preparative high pressure liquid chromatography (silica gel; 13% methanol in ethyl acetate). The glassy product obtained was triturated with acetonitrile to yield N-cyano-N'-methyl-N"-[2-(5-methyl-4-imidazolylmethyldithio)ethyl]guanidine, m.p. 137°-142°; Ms m/e 284.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][SH:7].Cl[C:9]1[CH:19]=[C:13]2[N:14]([CH3:18])[CH2:15][CH2:16][CH2:17][N:12]2[C:11](=[O:20])[N:10]=1>>[CH3:18][N:14]1[CH2:15][CH2:16][CH2:17][N:12]2[C:11](=[O:20])[N:10]=[C:9]([S:7][CH2:6][C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)[CH:19]=[C:13]12
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Reactant: SCc1cccs1
Product: CN1CCCn2c1cc(SCc1cccs1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E62 starting from thiophen-2-ylmethanethiol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: Br[C:2]([Br:5])(Br)Br.OC[CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[C:29]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:28][S:27][C:16]=3[N:17]=[C:18]([CH2:20][N:21]3[CH2:25][CH2:24][CH2:23][C:22]3=[O:26])[N:19]=2)[CH2:10][CH2:9]1>ClCCl>[Br:5][CH2:2][CH:8]1[CH2:9][CH2:10][N:11]([C:14]2[C:15]3[C:29]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:28][S:27][C:16]=3[N:17]=[C:18]([CH2:20][N:21]3[CH2:25][CH2:24][CH2:23][C:22]3=[O:26])[N:19]=2)[CH2:12][CH2:13]1
Reactant: BrC(Br)(Br)Br
Reactant: O=C1CCCN1Cc1nc(N2CCC(CO)CC2)c2c(-c3ccccc3)csc2n1
Solvent: ClCCl
Product: O=C1CCCN1Cc1nc(N2CCC(CBr)CC2)c2c(-c3ccccc3)csc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 136.5 %

Procedure:
Tetrabromomethane (120 mg) was added to a solution of 1-[[4-[4-(hydroxymethyl)-1-piperidyl]-5-phenyl-thieno[2,3-d]pyrimidin-2-yl]methyl]pyrrolidin-2-one (102 mg) in dichloromethane (10 mL). Polystyrene-supported triphenylphosphine (0.35 g, 2.04 mmol g-1) was added and the mixture was stirred overnight at room temperature. The solid material was filtered off and the solvent was evaporated to give the target compound as a yellow solid (160 mg). m/z [M+H]+ 484.9/486.9. Retention time 4.97 min (LCMS method+ve 6 min).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([N:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=4)=[CH:13][C:12]3=[O:24])[CH:7]=[CH:6][C:5]=2[C:4]2[CH2:25][N:26](C(OC(C)(C)C)=O)[CH2:27][CH2:28][C:3]1=2.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:48].Cl>>[ClH:48].[ClH:48].[CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([N:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=4)=[CH:13][C:12]3=[O:24])[CH:7]=[CH:6][C:5]=2[C:4]2[CH2:25][NH:26][CH2:27][CH2:28][C:3]1=2
Reactant: Cc1ccc(-c2ccn(-c3ccc4c5c(n(C)c4c3)CCN(C(=O)OC(C)(C)C)C5)c(=O)c2)cn1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: Cc1ccc(-c2ccn(-c3ccc4c5c(n(C)c4c3)CCNC5)c(=O)c2)cn1
Yield: 29 %

Procedure:
tert-Butyl 5-methyl-7-(4-(6-methylpyridin-3-yl)-2-oxopyridin-1(2H)-yl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (220 mg, 0.47 mmol) was deprotected and converted to the dihydrochloride salt according to the procedure of Example 30 (steps e and g) to provide the title compound (50.2 mg, 29%) as a yellow solid: mp 295-305° C.; 1H NMR (500 MHz, CD3OD) δ 8.80 (d, J=2.2 Hz, 1H), 8.12 (dd, J=8.1, 2.5 Hz, 1H), 7.79 (d, J=7.0 Hz, 1H), 7.59 (d, J=8.3 Hz, 1H), 7.52 (d, J=1.7 Hz, 1H), 7.47 (d, J=8.2 Hz, 1H), 7.10 (dd, J=8.3, 1.9 Hz, 1H), 6.93 (d, J=1.8 Hz, 1H), 6.85 (dd, J=7.1, 2.0 Hz, 1H), 4.34 (s, 2H), 3.73 (s, 3H), 3.52 (t, J=6.1 Hz, 2H), 3.10 (t, J=6.1 Hz, 2H), 2.62 (s, 3H); ESI MS m/z 371 [M+H]+; HPLC (Method B)>99% (AUC), tR=8.7 min.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:13]([OH:15])=[O:14])[C:7](=[CH:11][CH:12]=1)[C:8]([OH:10])=[O:9])([O-])=O>O1CCOCC1>[NH2:1][C:4]1[CH:5]=[C:6]([C:13]([OH:15])=[O:14])[C:7](=[CH:11][CH:12]=1)[C:8]([OH:10])=[O:9]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1C(=O)O
Solvent: C1COCCO1
Product: Nc1ccc(C(=O)O)c(C(=O)O)c1
Yield: 50 %

Procedure:
124.9 g (0.69mol) of 4-aminophthalic acid freshly obtained by reduction of 4-nitrophthalic acid in dioxane are reacted with 109.8 g (0.72 mol) of cis-1,2,3,6-tetrahydrophthalic anhydride in the manner described in Example 9, and the product is worked up as follows: after the batch has stood for 20 hours, the clear reaction solution is concentrated in vacuo to approx. 200 ml and heated with 200 ml of acetic anhydride and 170 ml of pyridine to 60°C for 10 hours. The solvents are then stripped off in vacuo and the solid residue is recrystallised from benzene, whereupon the yellow-coloured phthalic anhydride derivative is obtained in a yield of about 50%, melting point = 188°C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:10][CH2:9]2)=[C:4]([N+:22]([O-])=O)[CH:3]=1>C(#N)C.[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:12][CH2:13]2)=[C:4]([NH2:22])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1N1CCC(CCN2CCCCC2)CC1
Agent: [Pd]
Solvent: CC#N
Product: Nc1cc(Cl)ccc1N1CCC(CCN2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of 0.351 g (1.00 mmol) of 1-(4-chloro-2-nitro-phenyl)-4-(2-piperidin-1-yl-ethyl)-piperidine dissolved in acetonitrile (5 mL) is added 0.010 g (0.01 mmol) of 10% palladium on carbon. The mixture is placed under an atmosphere of hydrogen and stirred at room temperature for 2 hours. The mixture is concentrated under reduced pressure to provide 0.322 g (quant.) of 5-chloro-2-[4-(2-piperidin-1-yl-ethyl)-piperidin-1-yl]-phenylamine.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([OH:18])=[C:10]([C:19](OCC)=[O:20])[C:9]1=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C[O-].[Na+].[NH2:28][OH:29]>CO>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([OH:18])=[C:10]([C:19]([NH:28][OH:29])=[O:20])[C:9]1=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCn1c(=O)c(C(=O)OCC)c(O)c2ccccc21
Reactant: NO
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCCCCn1c(=O)c(C(=O)NO)c(O)c2ccccc21
Reaction time: 24 h
Yield: 40 %

Procedure:
A round-bottomed flask was charged with the product from step (1) (493 mg, 1.49 mmole), sodium methoxide (208 mg, 3.85 mmole), hydroxylamine (278 mg, 4.0 mmole) and methanol (10 mL). The reaction was stirred for 24 hrs and the precipitated product was collected by filtration, washed with water and dried in vacuo to give the title compound (40% yield). That the expected product was obtained was confirmed by the spectral data: M.S. (FAB): m/e 319 (M·+ +H); NMR (DMSO-d6): δ8.25 (1 H, d), 7.85 (1H, dd), 7.7 (1H, d), 7.45 (dd), 4.4 (2H, m, CH2N), 2.95 (br s, exchangeable protons), 1.8 (2H, m), 1.55 (8H, m), 0.95 (3H, t, CH3).
Reaction SMILES: C([O:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[CH:18]=[CH:17][N:16]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[N:15]=1)C1C=CC=CC=1>[C].[Pd].C(O)C>[O:20]1[CH2:21][CH2:22][CH2:23][CH2:24][CH:19]1[N:16]1[CH:17]=[CH:18][C:14]([C@@H:10]2[CH2:11][CH2:12][CH2:13][C@H:9]2[OH:8])=[N:15]1
Reactant: c1ccc(CO[C@@H]2CCC[C@H]2c2ccn(C3CCCCO3)n2)cc1
Agent: [Pd]
Solvent: CCO
Product: O[C@@H]1CCC[C@H]1c1ccn(C2CCCCO2)n1
Yield: 88.9 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 106b by using the 3-[(1S,2R)-2-(benzyloxy)cyclopentyl]-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol (419 mg, 1.28 mmol) prepared in Example 149b, palladium carbon (5%; 400 mg) and ethanol (20 mL), to yield the title compound (269 mg, 89%) in the form of a diastereomeric mixture as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5]/[C:4](=[C:12]2/[C:13]([CH2:18][CH2:19][CH3:20])=[N:14][NH:15][C:16]/2=[O:17])/[CH:3]=1.[C:21]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([SH:31])=[CH:27][CH:26]=1)(=[O:23])[CH3:22]>C(O)C>[O:17]=[C:16]1[NH:15][N:14]=[C:13]([CH2:18][CH2:19][CH3:20])/[C:12]/1=[C:4]1/[NH:5][C:6]2[C:11]([C:2]([S:31][C:28]3[CH:27]=[CH:26][C:25]([NH:24][C:21](=[O:23])[CH3:22])=[CH:30][CH:29]=3)=[CH:3]/1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: CC(=O)Nc1ccc(S)cc1
Reactant: CCCC1=NNC(=O)/C1=C1/C=C(Cl)c2ccccc2N1
Solvent: CCO
Product: CCCC1=NNC(=O)/C1=C1/C=C(Sc2ccc(NC(C)=O)cc2)c2ccccc2N1
Temperature: 180 °C

Procedure:
(Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-propyl-1H-pyrazol-5(4H)-one (0.045 g, 0.013 mmol) was dissolved in ethanol (1.5 mL) and 4-acetamidothiophenol (0.023 g, 0.013 mmol) was added. The reaction mixture was heated to 180° C. using a microwave reactor for 5-10 minutes. The mixture was then concentrated and the resulting solid filtered and washed with ether. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.70 (t, J=7.33 Hz, 3H) 1.32 (qd, J=7.45, 7.20 Hz, 2H) 2.11 (s, 3H) 2.25 (t, J=7.07 Hz, 2H) 6.76 (s, 1H) 7.63-7.71 (m, 3H) 7.89 (t, J=8.84 Hz, 3H) 7.93-7.99 (m, 1H) 8.17 (d, J=8.34 Hz, 1H) 10.36 (s, 1H); ESI-MS: m/z calc'd for C23H22N4O2S 418.51. found 419.3 (M+H)+.