Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][NH:27][C@@H:26]([CH3:30])[CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].CCN(C(C)C)C(C)C>CS(C)=O.O>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:2]2[C:3](=[O:16])[NH:4][C:5]3[C:10]([N:11]=2)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=3)[C@@H:26]([CH3:30])[CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: COC(=O)c1ccc2[nH]c(=O)c(Cl)nc2c1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)c1ccc2[nH]c(=O)c(N3CCN(C(=O)OC(C)(C)C)C[C@@H]3C)nc2c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 18.4 %

Procedure:
To a solution of methyl 3-chloro-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (1.0 g, crude) in DMSO (10 mL) was added tert-butyl-(3S)-3-methylpiperazine-1-carboxylate (1.0 g, 4.99 mmol) and DIEA (1.0 g, 7.74 mmol). The resulting solution was stirred overnight at 80° C. in an oil bath and then diluted with water (100 mL), extracted with ethyl acetate (4×40 mL) and the organic layers combined and dried over anhydrous magnesium sulfate. The solids were filtered out and filtrate was concentrated in vacuo to give a residue, which was purified by a silica gel column chromatography (2% ethyl acetate in petroleum ether) to afford methyl 3-[(2S)-4-[(tert-butoxy)carbonyl]-2-methylpiperazin-1-yl]-2-oxo-1,2-dihydroquinoxaline-6-carboxylate as a light yellow solid (310 mg).
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]2[O:6][CH2:7][CH2:8][C:9]3[S:13][C:12]([C:14]([NH2:16])=[O:15])=[N:11][C:10]=3[C:4]=2[CH:3]=1.[C:19]([C:21]1([OH:28])[CH2:25][CH2:24][N:23]([CH3:26])[C:22]1=[O:27])#[CH:20]>>[OH:28][C:21]1([C:19]#[C:20][C:2]2[CH:18]=[CH:17][C:5]3[O:6][CH2:7][CH2:8][C:9]4[S:13][C:12]([C:14]([NH2:16])=[O:15])=[N:11][C:10]=4[C:4]=3[CH:3]=2)[CH2:25][CH2:24][N:23]([CH3:26])[C:22]1=[O:27]
Reactant: NC(=O)c1nc2c(s1)CCOc1ccc(Br)cc1-2
Reactant: C#CC1(O)CCN(C)C1=O
Product: CN1CCC(O)(C#Cc2ccc3c(c2)-c2nc(C(N)=O)sc2CCO3)C1=O
Yield: 48 %

Procedure:
Similar to as described in General Procedure G, 9-bromo-4,5-dihydrobenzo[2,3]oxepino[4,5-d]thiazole-2-carboxamide) was reacted with 3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one (WO2009/158011 A1) to give the titled compound as a brown solid (56.1 mg, 48%).
Reaction SMILES: ClC(Cl)(Cl)C(=N)O[CH:5]([C:7]1[C:15]2[C:11](=[CH:12][N:13]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[N:14]=2)[CH:10]=[C:9]([F:24])[CH:8]=1)[CH3:6].[F:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2([CH2:48][OH:49])[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH2:36]2)=[CH:31][CH:30]=1.C1CCCCC1>ClCCl>[F:24][C:9]1[CH:8]=[C:7]([CH:5]([O:49][CH2:48][C:35]2([C:32]3[CH:31]=[CH:30][C:29]([F:28])=[CH:34][CH:33]=3)[CH2:36][CH2:37][N:38]([C:41]([O:43][C:44]([CH3:45])([CH3:46])[CH3:47])=[O:42])[CH2:39][CH2:40]2)[CH3:6])[C:15]2[C:11](=[CH:12][N:13]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:22])([CH3:21])[CH3:23])[N:14]=2)[CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccc(F)cc2)CC1
Reactant: CC(OC(=N)C(Cl)(Cl)Cl)c1cc(F)cc2cn(COCC[Si](C)(C)C)nc12
Solvent: ClCCl
Solvent: C1CCCCC1
Product: CC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(F)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of (±)-1-(5-fluoro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole-7-yl)ethyl 2,2,2-trichloroacetimidate (1.121 g, 2.465 mmol) and tert-butyl 4-(4-fluorophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate (0.839 g, 2.71 mmol) in dichloromethane (6 mL) at 0° C. was added cyclohexane (5.61 mL) and tetrafluoroboric acid diethyl ether complex (0.017 mL, 0.123 mmol). The reaction was stirred at 0° C. for 10 min. The reaction was treated with an additional portion of tetrafluoroboric acid diethyl ether complex (9 μL, 0.065 mmol) and stirred at 0° C. for 30 min. The reaction was quenched by addition of saturated sodium bicarbonate, diluted with diethyl ether, and poured into water. The ethereal was washed with water (2×), then brine, dried over magnesium sulfate, and concentrated. Column chromatography (15%→22% EtOAc/Hex) gave 922 mg (62.2%) as an amorphous foam solid. 1H-NMR (CDCl3, 300 MHz) δ 7.98 (s, 1H), 7.26-7.32 (m, 2H), 6.97-7.08 (m, 3H), 6.64-6.68(m, 1H), 5.62 (s, 2H), 4.92 (q, J=6.0 Hz, 1H), 3.65-3.75 (m, 2H), 3.58 (m, 2H), 3.35 (m, 2H), 2.9-3.1 (m, 2H), 1.8-2.2 (m, 4H), 1.39-1.42(m, 12H), 0.88(m, 2H), −0.07 (s, 9H); Mass spec.: 602.54 (MH)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[CH:3]=1.[Cl-].[Li+].[F-].[K+].[O:20]1CC[CH2:22][CH2:21]1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:21](=[O:20])[CH3:22])=[CH:3][C:4]=1[CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15]
Reactant: C1CCOC1
Reactant: COCCCCc1cc(Br)ccc1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [F-]
Product: COCCCCc1cc(C(C)=O)ccc1OC
Temperature: 80 °C
Reaction time: 20 h

Procedure:
To a solution of 4-bromo-1-methoxy-2-(4-methoxybutyl)benzene (523 mg) in tetrahydrofuran (10 mL) were added lithium chloride (326 mg), tetrakis(triphenylphosphine)palladium (0) (381 mg) and tri-n-butyltin-1-ethoxyvinyl 91.11 mL), and the mixture was heated to stir at 80° C. for 20 hours. The reaction solution was cooled to room temperature, and then thereto was added aqueous potassium fluoride solution, and the mixture was stirred for 30 minutes. The mixture was extracted with diethyl ether, and then thereto was added 10% hydrochloric acid, and the mixture was stirred for 1 hour. The organic layer was separated, dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=9/1→1/1) to give 1-[4-methoxy-3-(4-methoxybutyl)phenyl]ethanone [REx(24-1)] (195 mg) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10](=[O:13])[CH2:11][Cl:12].[C:14](O)(=[O:16])[CH3:15]>>[Cl:12][CH2:11][C:10]([C:3]1[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=1[NH:1][C:14](=[O:16])[CH3:15])=[O:13]
Reactant: CC(=O)O
Reactant: COc1ccc(C(=O)CCl)c(N)c1
Product: COc1ccc(C(=O)CCl)c(NC(C)=O)c1
Yield: 100 %

Procedure:
A solution of 1-(2-amino-4-methoxyphenyl)-2-chloroethanone (9.93 g, 49.74 mmol) (Example 10) in acetic acid (100 mL) was heated at 85° C. for 4 h. The solvent was evaporated under reduced pressure to yield a yellow solid (12.00 g, 100%). LC/MS m/z 242 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ 11.77 (s, 1H), 8.45 (d, 1H), .73 (d, 1H), 6.63 (dd, 1H), 4.71 (s, 2H), 3.89 (s, 3H), 2.25 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:12]([O:13]C)=[N:11][C:10]2[C:5]1=[N:6][C:7]([O:16][CH2:17][CH2:18][CH2:19][CH3:20])=[N:8][C:9]=2[NH2:15].C(N(CC)CC)C.Cl[S:29]([C:32]1[CH:33]=[C:34]([CH2:38][C:39]([O:41][CH3:42])=[O:40])[CH:35]=[CH:36][CH:37]=1)(=[O:31])=[O:30]>C(#N)C>[NH2:15][C:9]1[N:8]=[C:7]([O:16][CH2:17][CH2:18][CH2:19][CH3:20])[N:6]=[C:5]2[C:10]=1[NH:11][C:12](=[O:13])[N:4]2[CH2:3][CH2:2][NH:1][S:29]([C:32]1[CH:33]=[C:34]([CH2:38][C:39]([O:41][CH3:42])=[O:40])[CH:35]=[CH:36][CH:37]=1)(=[O:31])=[O:30]
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCN)c2n1
Reactant: COC(=O)Cc1cccc(S(=O)(=O)Cl)c1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCNS(=O)(=O)c3cccc(CC(=O)OC)c3)c2n1

Procedure:
The compound obtained in Example 2-1 step (vii) (245 mg), triethylamine (0.13 ml) and methyl [3-(chlorosulfonyl)phenyl]acetate (217 mg) were dissolved in acetonitrile (5 ml) and the same manner to Example 2-13 step (iii) was conducted to give the titled compound as a white solid. Yield: 40 mg (9%); MS APCI+ve 479 (M+H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[CH:6][N:5]=[C:4]([Cl:11])[CH:3]=1.[I:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16][NH2:17].CCN(C(C)C)C(C)C.O>CN1C(=O)CCC1.CCOC(C)=O>[Cl:11][C:4]1[CH:3]=[C:2]([NH:17][CH2:16][C:15]2[CH:18]=[CH:19][CH:20]=[C:13]([I:12])[CH:14]=2)[C:7]([C:8]([NH2:10])=[O:9])=[CH:6][N:5]=1
Reactant: NCc1cccc(I)c1
Reactant: NC(=O)c1cnc(Cl)cc1Cl
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: O
Product: NC(=O)c1cnc(Cl)cc1NCc1cccc(I)c1
Yield: 32.8 %

Procedure:
A solution of 4,6-dichloronicotinamide (400 mg, 2.09 mmol), 3-iodobenzylamine (0.285 mL, 2.13 mmol) and DIEA (0.500 mL, 2.87 mmol) in NMP (5 mL) was stirred at 90 C for 48 h. Water and EtOAc were added. Organic phase was separated, dried over Na2SO4, concentrated in vacuo. The residue was purified by a silica gel column, eluted with 0-100% EtOAc in hexane to give 6-chloro-4-(3-iodobenzylamino)nicotinamide as a solid (266 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:14])[CH3:2].[CH:19]1([CH:22]([C:24]2[S:28][C:27]([C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=3)=[N:26][C:25]=2[CH3:39])O)[CH2:21][CH2:20]1.C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:22]([CH:19]2[CH2:20][CH2:21]2)[C:24]2[S:28][C:27]([C:29]3[CH:30]=[CH:31][C:32]([C:35]([F:37])([F:38])[F:36])=[CH:33][CH:34]=3)=[N:26][C:25]=2[CH3:39])=[CH:9][C:8]=1[CH3:14])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1C)OCC
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(O)C1CC1
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)C(Cc1ccc(OC(c2sc(-c3ccc(C(F)(F)F)cc3)nc2C)C2CC2)cc1C)OCC

Procedure:
In analogy to the procedure described in example 10 c], [rac]-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester (example 10 b]) was reacted with [rac]-cyclopropyl-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methanol in the presence of tributylphosphine and N,N,N′,N′-tetramethyl azodicarboxamide to yield 3-(4-{cyclopropyl-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methoxy}-2-methyl-phenyl)-2-ethoxy-propionic acid ethyl ester as a mixture of two diastereomeric racemates as yellow liquid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([NH:16]N)=[C:7]2[C:11]=1[C:10](=[O:12])[N:9]([CH:13]([CH3:15])[CH3:14])[CH2:8]2.CO.S(=O)(=O)(O)O.[OH-].[Na+].[CH3:27][C:28](O)=O>>[NH:9]1[CH2:8][CH2:7][CH2:6][NH:16][C:28]1=[CH:27][NH:16][C:6]1[CH:5]=[CH:4][C:3]([Cl:2])=[C:11]2[C:7]=1[CH2:8][N:9]([CH:13]([CH3:15])[CH3:14])[C:10]2=[O:12]
Reactant: CC(=O)O
Reactant: CC(C)N1Cc2c(NN)ccc(Cl)c2C1=O
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: CC(C)N1Cc2c(NC=C3NCCCN3)ccc(Cl)c2C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A stirred solution of 4.3 grams (0.016 mole) of [7-chloro-2-(1-methylethyl)isoindolin-1-on-4-yl]hydrazine hydrochloride and 10 mL of methanol in 40 mL of HOAc was cooled in an ice-water bath and 2.6 grams (0/023 mole) of O-methylvalerolactin was added dropwise, followed by 0.5 gram (catalyst) of concentrated sulfuric acid. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature where it stirred for about 18 hours. After this time the reaction mixture was cooled, cold aqueous 10% sodium hydroxide was added, and the mixture was extracted with EtOAc. The combined extracts were washed with water, then with aqueous concentrated sodium chloride solution. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was purified by column chromatography on silica gel using mixtures of EtOAc, hexane, and methanol as eluants. The fractions containing product were combined and concentrated under reduced pressure, yielding 1.4 grams of subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C([O:4][C@H:5]1[CH2:33][CH2:32][C@@:31]2([CH3:34])[C:7](=[C:8]([CH2:36][N:37]([CH2:42][CH2:43][CH2:44][CH3:45])[CH2:38][CH2:39][CH2:40][CH3:41])[CH2:9][C@@H:10]3[C@@H:30]2[CH2:29][CH2:28][C@@:27]2([CH3:35])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:26])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:25])[CH2:20]OC(=O)C)[CH2:6]1)(=O)C.CO.C(=O)([O-])[O-].[K+].[K+]>O>[CH2:38]([N:37]([CH2:36][C:8]1[CH2:9][C@@H:10]2[C@@H:30]([C@:31]3([CH3:34])[C:7]=1[CH2:6][C@@H:5]([OH:4])[CH2:33][CH2:32]3)[CH2:29][CH2:28][C@@:27]1([CH3:35])[C@H:11]2[CH2:12][CH2:13][C@@H:14]1[C@H:15]([CH3:26])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:20])[CH3:25])[CH2:42][CH2:43][CH2:44][CH3:45])[CH2:39][CH2:40][CH3:41]
Reactant: CCCCN(CCCC)CC1=C2C[C@@H](OC(C)=O)CC[C@]2(C)[C@H]2CC[C@]3(C)[C@@H]([C@H](C)CCCC(C)COC(C)=O)CC[C@H]3[C@@H]2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCCCN(CCCC)CC1=C2C[C@@H](O)CC[C@]2(C)[C@H]2CC[C@]3(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@H]3[C@@H]2C1

Procedure:
To a solution of approximately 10 parts of 3β-acetoxy-acetoxy-6-(dibutylaminomethyl)cholest-5-ene in 80 parts of methanol is added 10 parts of aqueous 20% potassium carbonate. The resultant mixture is heated to the boiling point under reflux for 2 hours, whereupon 100 parts of water is introduced. The oil which separates is extracted with hexane. The extract is washed with water, dried over anhydrous sodium sulfate, and stripped of solvent by vacuum distillation. The residual oil is taken up in benzene; and the benzene solution is chromatographed on alumina, using benzene and mixtures thereof with increasing amounts of ethanol as developing solvents. From an eluate comprising 2% ethanol in benzene, on evaporation of solvent, 6-(dibutylaminomethyl)cholest-5-en-3β-ol is obtained as the residue.
Reaction SMILES: FC(F)(F)S(O[C:7]1[N:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)(=O)=O.[F:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C(=O)(O)[O-].[Na+].O1CCCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Cl)(Cl)Cl>[F:25][C:26]1[CH:31]=[CH:30][C:29]([C:7]2[N:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][CH:11]=[C:10]3[CH:16]2[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]2)=[CH:28][CH:27]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CN1CCC(c2c[nH]c3ccc(OS(=O)(=O)C(F)(F)F)nc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CN1CCC(c2c[nH]c3ccc(-c4ccc(F)cc4)nc23)CC1
Temperature: 75 °C
Reaction time: 18 h
Yield: 69 %

Procedure:
O-Trifluoromethanesulfonyl-3-(1-methylpiperidin-4-yl)-5-hydroxy-4-aza-1H-indole (150 mg, 0.412 mmol), 4-fluorophenylboronic acid (87 mg, 0.619 mmol), tetrakis(triphenylphosphine)palladium(0) (48 mg, 0.041 mmol), 4 mL of 2M aqueous sodium bicarbonate, and 30 mL of tetrahydrofuran were placed in a round bottom flask. The mixture was heated to reflux (about 75° C.) and allowed to stir for about 18 hours. The reaction was poured into 3:1 chloroform:isopropyl alcohol, extracted three times each with 1N aqueous sodium hydroxide and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed (silica gel, 0-10% methanol/dichloromethane) to give 87.9 mg of the title compound. (79%). MS(FD) m/e 309.6 (M+). EA calculated for C19H20FN3: C, 73.79; H, 6.47; N, 13.59. Found: C, 73.69; H, 6.73; N, 13.40.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2[C:5]([O:7][C:8](=[O:9])[C:3]=12)=O.Cl.[NH2:14][CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22].C([O-])(=O)C.[Na+].O>C(O)(=O)C>[O:22]=[C:16]1[CH:15]([N:14]2[C:8](=[O:9])[C:3]3[C:4](=[CH:10][CH:11]=[CH:12][C:2]=3[CH3:1])[C:5]2=[O:7])[CH2:20][CH2:19][C:18](=[O:21])[NH:17]1
Reactant: NC1CCC(=O)NC1=O
Reactant: Cc1cccc2c1C(=O)OC2=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Yield: 82.3 %

Procedure:
A stirred solution of 3-methylphthalic anhydride (2.96 g, 18.2 mmol), 3-aminopiperidine-2,6-dione hydrogen chloride (3.00 g, 18.2 mmol) and sodium acetate (1.57 g, 19.1 mmol) in acetic acid (30 mL) was heated at reflux for 23 hours. The solvent was removed in vacuo to give a solid which was stirred with water (40 mL) for 1 hour, filtered, washed with water (30 mL), and then heated with decolorizing charcoal (1 g) in acetone (2 L) at reflux temperature for 30 min. The suspension was filtered through a pad of Celite to give a clear solution. The solvent of filtrate was removed in vacuo to give 2-(2,6-dioxopiperid-3-yl)-4-methylisoindoline-1,3-dione as a white solid (4.08 g, 82% yield); mp 290.0-292.0° C.; 1H NMR (DMSO-d6); δ2.03-2.09 (m, 1H, CHH), 2.50-2.60 (m, 2H, CH2), 2.63 (s, 3H, CH3), 2.83-2.95 (m, IH, CHH), 5.13 (dd, J=5.4,12.3 Hz, IH, NCH), 7.65-7.79 (m, 3H, Ar), 11.13 (br s, IH, NH); 13C NMR (DMSO-d6) δ17.04, 21.99, 30.93, 48.76, 121.05, 127.89, 131.63, 134.37, 136.91, 137.61, 167.04, 167.83, 169.87, 172.74; Anal Calcd for C14H12N2O4: C, 61.76; H, 4.44; N, 10.29. Found: C, 61.68; H, 4.37; N, 10.17.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:29](O)=[O:30])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([N:22]1[CH2:27][CH2:26][NH:25][C:24](=[O:28])[CH2:23]1)[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:32][C:33]1[CH:34]=[N:35][CH:36]=[CH:37][C:38]=1[N:39]1[CH2:44][C@H:43]([CH3:45])[CH2:42][C@H:41]([NH:46]C(=O)OC(C)(C)C)[CH2:40]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O.[OH-].[Na+]>[NH2:46][C@H:41]1[CH2:42][C@@H:43]([CH3:45])[CH2:44][N:39]([C:38]2[CH:37]=[CH:36][N:35]=[CH:34][C:33]=2[NH:32][C:29]([C:13]2[C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:21][C:20]3[C:15](=[CH:16][C:17]([N:22]4[CH2:27][CH2:26][NH:25][C:24](=[O:28])[CH2:23]4)=[CH:18][CH:19]=3)[N:14]=2)=[O:30])[CH2:40]1
Reactant: O=C1CN(c2ccc3cc(NC(=O)OCc4ccccc4)c(C(=O)O)nc3c2)CCN1
Reactant: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2ccncc2N)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H]1C[C@H](N)CN(c2ccncc2NC(=O)c2nc3cc(N4CCNC(=O)C4)ccc3cc2NC(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.8 %

Procedure:
To a mixture of 3-{[(benzyloxy)carbonyl]amino}-7-(3-oxopiperazin-1-yl)quinoline-2-carboxylic acid (0.014 g, 0.033 mmol), tert-butyl [(3S,5R)-1-(3-aminopyridin-4-yl)-5-methylpiperidin-3-yl]carbamate (0.014 g, 0.046 mmol) and HATU (0.034 g, 0.089 mmol) in DMF (0.3 mL), DIPEA (0.020 mL, 0.11 mmol) was added. The mixture was stirred at room temperature for 2 h. The mixture was then diluted with 5 mL of EtOAc and 3 mL of 1 M NaOH. The layers were separated and the aqueous layer was extracted with EtOAc. The organic layers were combined and concentrated under reduced pressure. To the resulting residue, 2 mL of 4 M HCl in dioxane and 1 mL of MeOH were added. The mixture was stirred at room temperature for 1 h, then concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at a flow rate of 60 mL/min.) to afford the sub-title compound (0.0088 g, 43%). LCMS calc. for C33H37N8O4 [M+H]+: m/z=609.3. found: 609.3.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[C:17](#[N:20])[CH:18]=[CH2:19].C(N(CCCC)CCCC)CCC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([CH:9]=[CH:8][C:5]2[CH:6]=[CH:7][C:2]([CH:19]=[CH:18][C:17]#[N:20])=[CH:3][CH:4]=2)=[CH:11][CH:12]=1
Reactant: C=CC#N
Reactant: Brc1ccc(C=Cc2ccc(Br)cc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCN(CCCC)CCCC
Solvent: Cc1ccccc1
Product: N#CC=Cc1ccc(C=Cc2ccc(Br)cc2)cc1
Reaction time: 7 h
Yield: 16.1 %

Procedure:
6.76 g (0.02 mol) of 4,4'-dibromostilbene, 1.06 g (0.02 mol) of acrylonitrile, 4.08 g (0.022 mol) of tri-n-butylamine, 0.0898 g (0.4 mmol) of palladium acetate and 0.2098 g (0.8 mmol) of triphenylphosphine are added under argon to 10 ml of toluene. The reaction mixture is stirred at 100°-115° C. for 7 hours. Working up gives 1 g (16% of theory) of 4-bromostilbene-4'-acrylonitrile in the form of a pale yellow powder. Melting point 258° C.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:21]3[N:22]4[CH:28]=[C:27]([NH:29][C:30](=[O:36])[CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:26]=[CH:25][C:23]4=[N:24][C:20]=3[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:37])=[CH:8][CH:7]=1)([O-:5])=[O:4].[CH3:38]I.O>CN(C=O)C>[N+:3]([C:6]1[CH:7]=[CH:8][C:9]([N:12]2[C:21]3[N:22]4[CH:28]=[C:27]([N:29]([CH3:38])[C:30](=[O:36])[CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:26]=[CH:25][C:23]4=[N:24][C:20]=3[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:37])=[CH:10][CH:11]=1)([O-:5])=[O:4]
Reactant: CCCCCC(=O)Nc1ccc2nc3c4ccccc4c(=O)n(-c4ccc([N+](=O)[O-])cc4)c3n2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCC(=O)N(C)c1ccc2nc3c4ccccc4c(=O)n(-c4ccc([N+](=O)[O-])cc4)c3n2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
Sodium hydride (1.6 equiv., 1.029 mmol, 0.041 g (60%)) was added to a solution of 86 (1.0 equiv., 0.643 mmol, 0.302 g) in DMF (15 ml), the reaction mixture was stirred for 1 h at room temperature. Methyl iodide (1.2 equiv., 0.772 mmol, 0.110 g) was added and the mixture was stirred at room temperature for 24 h. Water was added to the reaction mixture, and the formed precipitate was filtered off and washed with water and isopropyl ether to give N-[5,6-dihydro-6-(4-nitrophenyl)-5-oxo-pyrido[2′,1′:2,3]-imidazo[4,5-c]isoquinolin-9-yl]-N-methyl-hexanamide (87) (0.296 g, yield=95%, purity (LC)=93%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]([NH:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9]2)[CH:3]=1.[H-].[Na+].Cl[C:24]1[S:25][C:26]([C:29]#[N:30])=[CH:27][N:28]=1>>[C:29]([C:26]1[S:25][C:24]([NH:1][C:2]2[N:7]=[CH:6][N:5]=[C:4]([N:8]3[CH2:13][CH2:12][N:11]([CH2:14][C:15]([NH:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9]3)[CH:3]=2)=[N:28][CH:27]=1)#[N:30]
Reactant: CC(C)NC(=O)CN1CCN(c2cc(N)ncn2)CC1
Reactant: N#Cc1cnc(Cl)s1
Agent: [H-]
Agent: [Na+]
Product: CC(C)NC(=O)CN1CCN(c2cc(Nc3ncc(C#N)s3)ncn2)CC1

Procedure:
2-[4-(6-aminopyrimidin-4-yl)piperazin-1-yl]-N-isopropylacetamide 13-2 (0.45 g, 1.62 mmol), sodium hydride (0.13 g, 3.25 mmol) and 2-chloro-1,3-thiazole-5-carbonitrile 2-2 (0.235 g, 1.62 mmol) were treated as in Scheme 4 above. The product was purified on a C18 preparative column and isolated via lyophilization. Hi-Res MS: calc: 387.1710 found: 387.1691. 1NMR (DMSO): 8.51 ppm (s, 1H); 8.47 ppm (s, 1H); 8.28 ppm (s, 1H); 6.30 ppm (s, 1H); 4.35 ppm (m, 2H); 3.91 ppm (m, 4H); 3.39 ppm (m, 2H); 3.18 ppm (m, 2H); 1.11 ppm (d, 6H).