Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[C:20]=4[C:27]([F:30])([F:29])[F:28])[CH2:15][CH2:14]3)=[O:12])=[N:9][N:10]=2)[CH:7]=1.[CH3:31][N:32](C=O)C>O.[C-]#N.[Zn+2].[C-]#N.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>[F:26][C:21]1[C:20]([C:27]([F:30])([F:29])[F:28])=[C:19]([CH:16]2[CH2:17][CH2:18][N:13]([C:11]([C:8]3[N:6]4[CH:7]=[C:2]([C:31]#[N:32])[CH:3]=[CH:4][C:5]4=[N:10][N:9]=3)=[O:12])[CH2:14][CH2:15]2)[CH:24]=[C:23]([F:25])[CH:22]=1
Reactant: CN(C)C=O
Reactant: O=C(c1nnc2ccc(Br)cn12)N1CCC(c2cc(F)cc(F)c2C(F)(F)F)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: N#Cc1ccc2nnc(C(=O)N3CCC(c4cc(F)cc(F)c4C(F)(F)F)CC3)n2c1
Temperature: 130 °C
Yield: 49 %

Procedure:
A mixture of (6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)(4-(3,5-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl) methanone (0.115 g, 0.235 mmol), zinc cyanide (0.055 g, 0.470 mmol), tetrakis(triphenylphosphine)palladium (0.027 g, 0.0235 mmol), and DMF (4 mL) was heated under microwave irradiation at 130° C. for 30 min. After cooling to ambient temperature, the mixture was diluted with water (80 mL) and extracted with EtOAc (80 mL). The extract was washed with brine (2×80 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (0-50% EtOAc in hexanes) to give 3-(4-(3,5-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carbonitrile as a white solid (0.050 g, 49%): 1H NMR (300 MHz, CDCl3) δ9.71 (m, 1H), 7.98 (dd, J=9.5, 1.0 Hz, 1H), 7.51 (dd, J=9.5, 1.6 Hz, 1H), 6.95 (d, J=9.5 Hz, 1H), 6.84-6.77 (m, 1H), 5.76 (m, 1H), 5.01-4.96 (m, 1H), 3.46-3.31 (m, 2H), 3.03-2.94 (m, 1H), 2.07-1.70 (m, 4H); MS (ESI+) m/z 436 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:5]2=[N:6][CH:7]=1.CCN(CC)CC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH3:47][OH:48].CN([CH:52]=[O:53])C>CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:47][O:48][C:52]([C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:5]2=[N:6][CH:7]=1)=[O:53]
Reactant: CO
Reactant: Cc1ccc(S(=O)(=O)n2ccc3cc(Br)cnc32)cc1
Reactant: CN(C)C=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COC(=O)c1cnc2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1
Reaction time: 6 h

Procedure:
Under N2 purge, 5-Bromo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (1.0 g, 2.8 mmol), Et3N (0.75 mL, 5.4 mmol), Pd(OAc)2 (64 mg, 0.28 mmol), Ph3P (0.45 g, 1.7 mmol) and MeOH (5.0 mL, 120 mmol) were loaded in 20 mL DMF. The vessel was purged with CO 5 minutes and fixed with a condenser tube with CO balloon. The reaction was heated to 100 C for 6 hours and monitored by TLC (rf 5-Bromo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine=0.72, rf 1-(Toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid methyl ester=0.43, CH2Cl2). After 6 hours, the reaction was removed from heat, diluted to 100 mL with water and extracted with EtOAC (100 mL). The phases were separated and organic was washed with additional water (2×100 mL) and brine (1×100 mL), dried over Na2SO4, filtered, and dried in vacuo. The resulting yellow powder was purified over a short plug of silica gel with CH2Cl2 until all material was recovered. Yield 0.94 g, white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:14]2=[C:15]3[N:10]([CH2:11][CH2:12][CH2:13]2)[CH2:9][CH2:8][CH2:7][C:6]3=[CH:5][C:4]=1[CH:16]=[CH:17][C:18]1[S:22][C:21]([CH:23]=O)=[CH:20][CH:19]=1.[C:25]([C:27]1[C:28](=[C:38]([C:41]#[N:42])[C:39]#[N:40])[O:29][C:30]([CH3:37])([C:33]([F:36])([F:35])[F:34])[C:31]=1[CH3:32])#[N:26]>C(O)C.O1CCCC1>[C:25]([C:27]1[C:28](=[C:38]([C:39]#[N:40])[C:41]#[N:42])[O:29][C:30]([CH3:37])([C:33]([F:36])([F:34])[F:35])[C:31]=1[CH:32]=[CH:23][C:21]1[S:22][C:18]([CH:17]=[CH:16][C:4]2[CH:5]=[C:6]3[C:15]4[N:10]([CH2:9][CH2:8][CH2:7]3)[CH2:11][CH2:12][CH2:13][C:14]=4[C:3]=2[O:2][CH3:1])=[CH:19][CH:20]=1)#[N:26]
Reactant: COc1c(C=Cc2ccc(C=O)s2)cc2c3c1CCCN3CCC2
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(C)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCO
Product: COc1c(C=Cc2ccc(C=CC3=C(C#N)C(=C(C#N)C#N)OC3(C)C(F)(F)F)s2)cc2c3c1CCCN3CCC2
Temperature: 60 °C
Yield: 77.4 %

Procedure:
In 5 ml of ethanol and 1.5 ml of tetrahydrofuran were dissolved 135 mg (0.40 mmol) of 5-[2-(8-methoxy-2,3,6,7-tetrahydro-1H,5H-benzo[ij]quinolizine-9-yl)vinyl]thiophene-2-carboaldehyde and 110 mg (0.43 mmol) of 2-(3-cyano-4,5-dimethyl-5-trifluoromethyl-2(5H)-furanylidene)propanedinitrile. The mixture was stirred with heating at 60° C. for 3.5 hours. The solvent was evaporated off and the residue was washed with ethanol. The residue was purified by silica gel column chromatography and washed with methanol to give 178 mg of a dark brown crystal (yield: 78.1%; mp: 159-161° C.)
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)#[CH:2].Cl[C:10]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:27]([C:35]3[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=3)([C:29]3[N:33]([CH3:34])[CH:32]=[N:31][CH:30]=3)[OH:28])[CH:16]=2)[N:11]=1.CN(C=O)C>C(NCC)C.C(OCC)C.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.[Cu]I>[Cl:26][C:22]1[CH:21]=[C:20]([C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:27]([C:35]4[CH:36]=[CH:37][C:38]([Cl:41])=[CH:39][CH:40]=4)([C:29]4[N:33]([CH3:34])[CH:32]=[N:31][CH:30]=4)[OH:28])[CH:16]=3)[N:11]=[C:10]([C:2]#[C:1][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH:19]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: C#Cc1ccccc1
Reactant: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2nc(Cl)cc(-c3cccc(Cl)c3)c2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCNCC
Product: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2nc(C#Cc3ccccc3)cc(-c3cccc(Cl)c3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.8 %

Procedure:
A mixture of ethynyl-benzene (0.0021 mol), Pd(PPh3)2Cl2(0.0002 mol) and copper (I) iodide (0.0002 mol) was added at room temperature to a mixture of (±)-2-chloro-4-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-6-quinolinemethanol (0.0014 mol), described in International Patent Specification WO 00/39082, in N-ethyl-ethanamine (7ml) and DMF (7 ml) under N2 flow. The mixture was stirred at room temperature overnight, then at room temperature for 3 days, poured out into ice water and extracted with EtOAc. The organic layer was separated, washed three times with water, dried (MgSO4), filtered and the solvent was evaporated. The residue (1.2 g) was purified by column chromatography over silica gel (eluent: CH2Cl2 100 to CH2Cl2/CH3OH 98/2 98/2; 35–70 μm). The pure fractions were collected and the solvent was evaporated, yielding 0.5 g of a fraction which was taken up in diethyl ether. The precipitate was filtered off and dried. The residue (0.28 g) was purified by column chromatography over kromasil (eluent: CH3CN/CH3COONH4 1% 75/25; 10 μm). The pure fractions were collected and the solvent was evaporated, yielding: 0.279 g of a product which was dried at 90° C. in a vacuum for 4 hours, yielding 0.14 g (18%) of 4-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-2-(phenylethynyl)-6-quinolinemethanol, mp. 154° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].N[C:7](N)=[O:8].[CH2:10]([CH:12]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:13][OH:14])[CH3:11].C([Sn](=O)CCCC)CCC.N>>[CH3:1][O:2][CH2:3][CH2:4][NH:5][C:7](=[O:8])[O:14][CH2:13][CH:12]([CH2:10][CH3:11])[CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: NC(N)=O
Reactant: CCCCC(CC)CO
Reactant: COCCN
Agent: CCCC[Sn](=O)CCCC
Agent: N
Product: CCCCC(CC)COC(=O)NCCOC
Temperature: 180 °C

Procedure:
225 g (3.0 mols) of 2-methoxyethylamine, 180 g (3.0 mols) of urea, 1,950 g (15 mols) of 2-ethylhexanol and 3 g of dibutyltin oxide are introduced into a 4 liter round-bottom flask equipped with reflux condenser, and the mixture is heated while stirring. A vigorous evolution of ammonia sets in at temperatures above 110° C. Ammonia gas is removed through the reflux condenser and absorbed in water. Over the course of 3 hours, the temperature is increased to 180° C. (reflux), the elimination of ammonia virtually ceasing. After a further 2 hours under reflux, the mixture is freed of remaining ammonia by flushing with nitrogen and subsequently subjected to fractional distillation. After a first cut comprising mainly ethylhexanol, the desired urethane distills over at 98°-100° C./0.1 mbar as a colorless liquid (yield: 617 g=89% of theory). 27 g of a brown liquid remain as the distillation residue and solidify to give a pasty product on cooling.
Reaction SMILES: [N+:1]1([O-:10])[CH:6]=[CH:5][C:4]([C:7]([OH:9])=O)=[CH:3][CH:2]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:23][C:24]1[CH:25]=[C:26]([NH2:32])[C:27]([NH2:31])=[CH:28][C:29]=1[Cl:30]>CN(C)C=O.ClCCl>[NH2:32][C:26]1[CH:25]=[C:24]([Cl:23])[C:29]([Cl:30])=[CH:28][C:27]=1[NH:31][C:7]([C:4]1[CH:3]=[CH:2][N+:1]([O-:10])=[CH:6][CH:5]=1)=[O:9]
Reactant: O=C(O)c1cc[n+]([O-])cc1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Nc1cc(Cl)c(Cl)cc1NC(=O)c1cc[n+]([O-])cc1
Reaction time: 4 h
Yield: 16.4 %

Procedure:
A suspension of 4-pyridinecarboxylic acid-1-oxide (2.84 g, 20.4 mmol) and 1,1'-carbonyldiimidazole (3.64 g, 22.4 mmol) in dry dimethylformamide (50 ml) was stirred for 4 hours under an air-lock and the resulting solution added dropwise over 1 hour to a stirred solution of 4,5-dichloro-1,2-benzenediamine (7.23 g, 40.8 mmol) in dichloromethane (50 ml) under air lock. After 2.5 days, the mixture was evaporated in vacuo and the residue purified by chromatography [SiO2 ; dichloromethane-methanoltriethylamine (100:3:1)]. Recrystallisation from ethanol-methanol gave the title compound (1.00 g), m.p. >300°. The compound exhibited infra-red spectral bands at 859, 1182, 1260, 1534, 1671, 3253, 3335 and 3417 cm-1. The NMR spectrum of the compound in DMSO-d6 exhibited the following signals: (δ in ppm from TMS) broad 2 proton signal at 5.5; 1 proton singlet at 6.97; 1 proton singlet at 7.42; 2 proton doublet (J7 Hz) at 7.96; 2 proton doublet (J7 Hz) at 8.37 and broad 1 proton singlet at 9.9.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:20]COC(C)=O.CCCCCCC>CO>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([O:14][CH3:20])=[O:13])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Br)c2ccccc12
Reactant: CCOC(C)=O
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: CCCCCCC
Product: COC(=O)c1ccc(Br)c2ccccc12
Yield: 91 %

Procedure:
To a solution of 4-bromo naphthoic acid (4.0 g, 15.9 mmol) in MeOH (75 mL) was added sulfuric acid (0.5 mL) and the reaction was heated to reflux for 18 hours. TLC 50:50 EtOAc:heptane showed consumption of starting material. The reaction was cooled and concentrated under vacuum to remove MeOH. The residue was diluted with EtOAc (150 mL), washed with water (100 mL), diluted with saturated NaHCO3 (100 mL), dried over Na2SO4 and concentrated under vacuum to afford a solid (3.85 g, 91%). 1H NMR (CDCl3) δ ppm: 8.96 (1H), 8.36 (1H), 8.02 (1H), 7.85 (1H), 7.70-7.66 (2H), 4.03 (3H).
Reaction SMILES: [CH2:1]1[C:16]2[C:15]3[C:14]4[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=4[NH:8][C:7]=3[CH:6]=[CH:5][C:4]=2[C:3](=[O:17])[CH2:2]1.[Al+3].[Cl-].[Cl-].[Cl-].[C:22](Cl)([CH3:24])=[O:23]>C(Cl)Cl>[C:22]([C:12]1[CH:11]=[CH:10][C:9]2[NH:8][C:7]3[CH:6]=[CH:5][C:4]4[C:3](=[O:17])[CH2:2][CH2:1][C:16]=4[C:15]=3[C:14]=2[CH:13]=1)(=[O:23])[CH3:24]
Reactant: O=C1CCc2c1ccc1[nH]c3ccccc3c21
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc2[nH]c3ccc4c(c3c2c1)CCC4=O
Temperature: 0 °C
Yield: 56.1 %

Procedure:
1,2-dihydro-6H-cyclopenta[c]carbazole-3-one 90 (6 g, 27.1 mmol) was suspended in dry CH2Cl2 (100 mL). Anhydrous AlCl3 (6 g, 45 mmol) was added with stirring on ice bath, followed by the dropwise addition of AcCl (2.4 mL, 33.2 mmol). The reaction mixture was stirred at about 5° C. for 24 h, and poured into ice water. The precipitated grey solid was filtered off, washed with water (2×100 mL), acetone (3×50 mL), diethyl ether (3×50 mL) to give 4 g (56.3%) of 9-acetyl-1,2-dihydro-6H-cyclopenta[c]carbazole-3-one 91.
Reaction SMILES: [C:1]([NH:18][C@H:19]([C:24]([OH:26])=O)[CH2:20][CH2:21][S:22][CH3:23])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:35]>ClCCl>[C:1]([NH:18][C@H:19]([C:24]([F:35])=[O:26])[CH2:20][CH2:21][S:22][CH3:23])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2]
Reactant: CSCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: Fc1nc(F)nc(F)n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CSCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)F
Temperature: 0 °C
Reaction time: 8 h

Procedure:
FMOC-L-Methionine (5.00 g, 13.46 mmol) (Bachem) was dissolved in dichloromethane (70 mL). Pyridine (1.09 mL, 13.46 mmol) (Aldrich) and cyanuric fluoride (1.82 g, 13.46 mmol) (Aldrich) were successively added at room temperature and the mixture was stirred overnight. Ice cold water (100 mL) was added and the resulting slurry was filtered. The filtrate was poured into a separatory funnel and the layers were separated. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford FMOC-L-methionyl fluoride as a white powder. (Yield 3.7 g., 74%).
Reaction SMILES: CN(C)C=O.[CH3:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12]([CH3:33])=[CH:13][C:14](=[O:32])[N:15]2[CH2:18][CH2:19][CH2:20][C:21]2([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:41][CH2:42][S:43][C:44]1[S:45][CH:46]=[CH:47][CH:48]=1>C(OCC)(=O)C.O>[CH3:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12]([CH3:33])=[CH:13][C:14](=[O:32])[N:15]2[CH2:18][CH2:19][CH2:20][C:21]2([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:26][CH2:25][N:24]([CH2:41][CH2:42][S:43][C:44]3[S:45][CH:46]=[CH:47][CH:48]=3)[CH2:23][CH2:22]2)=[CH:10][CH:9]=1
Reactant: BrCCSc1cccs1
Reactant: CCOC(=O)C1(CCCn2c(=O)cc(C)c3ccc(OC)cc32)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1(CCCn2c(=O)cc(C)c3ccc(OC)cc32)CCN(CCSc2cccs2)CC1
Temperature: 65 °C
Reaction time: 2 h
Yield: 68.1 %

Procedure:
To 4 mL of an N,N-dimethylformamide solution containing 0.29 g of ethyl 4-(3-(7-methoxy-4-methyl-2-oxoquinolin-1(2H)-yl)propyl)piperidine-4-carboxylate, 0.25 g of potassium carbonate and 0.20 g of 2-(2-bromoethylthio)thiophene were added and stirred at 60-70° C. for 2 hours. Water and ethyl acetate were added, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; chloroform:methanol=100:1] to give 0.27 g of ethyl 4-(3-(7-methoxy-4-methyl-2-oxoquinolin-1(2H)-yl)propyl)-1-(2-(2-thienylthio)ethyl)piperidine-4-carboxylate as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[C:5]2[NH:6][C:7](=[O:17])[C:8]3[CH:13]=[N:12][C:11]4[NH:14][N:15]=[CH:16][C:10]=4[C:9]=3[N:4]2[N:3]=1.C(N1C2N=CC3C(=O)NC4N(N=C(C)C=4)C=3C=2C=N1)C.[CH2:39](I)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.CI>>[CH3:1][C:2]1[CH:18]=[C:5]2[N:6]([CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:7](=[O:17])[C:8]3[CH:13]=[N:12][C:11]4[NH:14][N:15]=[CH:16][C:10]=4[C:9]=3[N:4]2[N:3]=1
Reactant: ICc1ccccc1
Reactant: Cc1cc2[nH]c(=O)c3cnc4[nH]ncc4c3n2n1
Agent: CCn1ncc2c1ncc1c(=O)[nH]c3cc(C)nn3c12
Solvent: CI
Product: Cc1cc2n(Cc3ccccc3)c(=O)c3cnc4[nH]ncc4c3n2n1

Procedure:
By substituting the 2-methyl-4H-pyrazolo[1,5-a]pyrazolo-[4',3':5,6]pyrido[3,4-e]pyrimidin-5(8H)-one of Example 8 for the 8-ethyl-2-methyl-4H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]-pyrido[3,4-e]pyrimidin-5(8H)-one and benzyl iodide for the methyl iodide in the procedure of Example 1 c, 2-methyl-4-phenylmethyl-4H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido-[3,4-e]pyrimidin-5(8H)-one is obtained.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[CH:2]1.O=S(Cl)[Cl:11].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[S:24][C:23]3[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=3[C:21]=2[CH2:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][N:39]3[CH2:43][CH2:42][CH2:41][CH2:40]3)=[CH:32][CH:31]=2)=[CH:16][CH:15]=1>ClC(Cl)C.CN(C=O)C.C([O-])(O)=O.[Na+]>[ClH:11].[ClH:11].[N:39]1([CH2:38][CH2:37][O:36][C:33]2[CH:34]=[CH:35][C:30]([CH2:29][C:21]3[C:22]4[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=4[S:24][C:20]=3[C:17]3[CH:18]=[CH:19][C:14]([NH:13][C:6]([C:4]4[N:3]=[CH:2][NH:1][CH:5]=4)=[O:8])=[CH:15][CH:16]=3)=[CH:31][CH:32]=2)[CH2:40][CH2:41][CH2:42][CH2:43]1
Reactant: O=S(Cl)Cl
Reactant: Nc1ccc(-c2sc3ccccc3c2Cc2ccc(OCCN3CCCC3)cc2)cc1
Reactant: O=C(O)c1c[nH]cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(Cl)Cl
Product: Cl
Product: O=C(Nc1ccc(-c2sc3ccccc3c2Cc2ccc(OCCN3CCCC3)cc2)cc1)c1c[nH]cn1

Procedure:
A slurry of 40 mg (0.35 mmol) of 4-imidazolecarboxylic acid in 5 mL of dichloroethane was treated with 1 drop DMF followed by 0.10 mL (1.37 mmol) of SOCl2. The mixture was heated to mild reflux for 2 h, concentrated in vacuo, and the residue reconstituted in 5 mL dichloroethane. A solution of 300 mg (0.70 mmol) of 2-(4-aminophenyl)-3-[4-[2-(1-pyrrolidinyl)ethoxy]benzyl]benzo[b]thiophene (Part D) in 5 mL of dichloroethane was added and the mixture heated to mild reflux for 16 h. The reaction was diluted with 10 mL of sat'd aq NaHCO3, the two layers were separated, and the aqueous layer extracted with CHCl3 (3×10 mL). The combined organic layers were dried (K2CO3), filtered and concentrated in vacuo. Radial chromatography (SiO2; 2% then 4% then 5% MeOH in CHCl3 sat'd with NH4OH) afforded 90 mg (0.17 mmol; 49%) of the free base of the title compound as a solid. The product was taken up in 2 mL of H2O and was treated with 1 mL of 1 N aq HCl. The solution was lyophilized to give the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:20][C:21]([C:24]([OH:26])=O)([CH3:23])[CH3:22])[CH:18]=2)[NH:13][C:12]=1[CH3:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]([NH:30][CH2:31][CH3:32])[CH3:29].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCCCCC.C(OCC)(=O)C>C(OC(=O)C)C>[CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:20][C:21]([C:24](=[O:26])[N:30]([CH2:31][CH3:32])[CH2:28][CH3:29])([CH3:22])[CH3:23])[CH:18]=2)[NH:13][C:12]=1[CH3:27])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1[nH]c2ccc(OC(C)(C)C(=O)O)cc2c1C(=O)OCc1ccccc1
Reactant: CCNCC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCN(CC)C(=O)C(C)(C)Oc1ccc2[nH]c(C)c(C(=O)OCc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 9.3 %

Procedure:
5-(1-Carboxy-1-methyl-ethoxy)-2-methyl-1H-indole-3-carboxylic acid benzyl ester (1.0 g, 2.76 mmol, 1.0 eq) was dissolved in ethylacetate (100 mL), and treated with diethylamine (0.241 g, 3.3 mmol, 1.2 eq) followed by HBTU (0.446 g, 3.3 mmol, 1.2 eq). The reaction mixture was stirred at room temperature for 24 hours and was followed by TLC (hexane/ethyl acetate 1/1). The reaction was quenched with aqueous sodium bicarbonate, extracted with ethyl acetate, and the organic layers dried over sodium sulfate, evaporated, and loaded on silica gel, followed by flash chromatography (hexane/ethyl acetate 1/1). 0.109 g of the product was obtained, 12% yield. LC/MS (ESI+) 422.52 (M+1) (C25H30N2O4).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].[CH:15]([C:17]1[NH:18][CH:19]=[CH:20][N:21]=1)=O>CO.CCOC(C)=O.C(Cl)Cl>[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH:6][C:19]1[N:18]=[C:17]([CH3:15])[NH:21][CH:20]=1
Reactant: O=Cc1ncc[nH]1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CO
Product: COC(=O)[C@H](Cc1ccccc1)Nc1c[nH]c(C)n1

Procedure:
N-(2-methylimidazolyl)-L-phenylalanine methyl ester was prepared from L-phenylalanine methyl ester hydrochloride (3.30 mmol) and 2-formyl-imidazole (3.63 mmol) utilizing the procedure of Example 9, first paragraph, to yield, after flash chromatography (3:50:50 v/v/v CH3OH/EtOAc/CH2Cl2 ; SiO2 gel), 0.55 g (65% yield) of pure product.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[C:21]([Cl:23])[C:20](B4OC(C)(C)C(C)(C)O4)=[CH:19][C:18]=3[O:33][CH3:34])=[O:16])[CH2:6][C:5]=12.FC(F)(F)S([O:40][C:41]1[CH2:46][CH2:45][CH2:44][C:43](=O)[C:42]=1[CH3:48])(=O)=O>>[Cl:23][C:21]1[CH:22]=[C:17]([C:15]([N:7]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][N:4]3[CH:3]=[CH:2][CH:1]=[C:5]3[CH2:6]2)=[O:16])[C:18]([O:33][CH3:34])=[CH:19][C:20]=1[C:43]1[CH2:44][CH2:45][CH2:46][C:41](=[O:40])[C:42]=1[CH3:48]
Reactant: CC1=C(OS(=O)(=O)C(F)(F)F)CCCC1=O
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)c(Cl)cc1C(=O)N1Cc2cccn2Cc2ccccc21
Product: COc1cc(C2=C(C)C(=O)CCC2)c(Cl)cc1C(=O)N1Cc2cccn2Cc2ccccc21
Yield: 40.1 %

Procedure:
(10,11-Dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-[5-chloro-2-methoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanone of Example 1, Step E (0.700 g, 1.46 mmol) and 2-methyl-3-oxo-cyclohex-1-en-1-yl trifluoromethanesulfonate (0.416 g, 1.61 mmol) were reacted by the procedure described in Example 1, Step F. Purification by flash column chromatography on silica gel, eluting with 50% ethyl acetate in hexane followed by precipitation from diethyl ether with pentane afforded the title compound (0.270 g) as an amorphous yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Br[CH2:23][CH2:24][CH2:25][C:26]#[N:27]>O>[CH3:1][N:2]([CH3:10])[C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[O:9][CH2:23][CH2:24][CH2:25][C:26]#[N:27]
Reactant: CN(C)c1cccc(O)c1
Reactant: N#CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)c1cccc(OCCCC#N)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A suspension of 3-dimethylaminophenol (5 g), potassium carbonate (10.05 g) and dimethylformamide (85 ml) was stirred at room temperature for 5 hours. 4-Bromobutyronitrile (7.3 ml) was added and the suspension stirred for 17 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The extracts were washed with water, dried and the solvent removed to yield 4-(3-dimethylaminophenoxy)butyronitrile.
Reaction SMILES: Br.[Br:2][C:3]1[CH:4]=[N:5][C:6](=[O:9])[NH:7][CH:8]=1.Br[CH2:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13]>C(N(CC)CC)C.C(O)C>[Br:2][C:3]1[CH:4]=[N:5][C:6](=[O:9])[N:7]([CH2:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])[CH:8]=1
Reactant: O=c1ncc(Br)c[nH]1
Reactant: O=C(CBr)c1ccccc1
Agent: Br
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(Cn1cc(Br)cnc1=O)c1ccccc1

Procedure:
A solution of 5-bromopyrimidin-2-one hydrobromide (512 mg) and α-bromoacetophenone (398 mg) in triethylamine (2 ml) and ethanol (10 ml) was stirred at ambient temperature for three and a half hours. After evaporation of solvents, the residue was triturated with water. The product was filtered off and recrystallised from ethanol to give the title pyrimidinone: yield 253 mg: m.p. 161°-163°, λmaxEtOH 241.5 nm (ε 18810), 285 nm (ε 1690), 334.5 nm (ε 3190).