Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(O[C:18]([CH3:48])=[C:19]([N:33]1[C:39](=[O:40])[CH:38]2[CH:34]1[S:35][C:36]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[N:37]2)[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1)=[O:21])(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.[NH:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1.O>C(#N)C>[CH2:41]([C:36]1[S:35][CH:34]2[CH:38]([C:39](=[O:40])[N:33]2[C:19](=[C:18]([N:49]2[CH2:54][CH2:53][O:52][CH2:51][CH2:50]2)[CH3:48])[C:20]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([N+:30]([O-:32])=[O:31])=[CH:28][CH:29]=2)=[O:21])[N:37]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: C1COCCN1
Reactant: CC(OP(=O)(Oc1ccccc1)Oc1ccccc1)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C2N=C(Cc3ccccc3)SC21
Solvent: O
Solvent: CC#N
Product: CC(=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C2N=C(Cc3ccccc3)SC21)N1CCOCC1
Reaction time: 2 h

Procedure:
To a solution of diphenyl 1-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-(p-nitrobenzyloxycarbonyl)-prop-1-en-2-yl phosphate (6.86 g) in acetonitrile (50 ml) at 0°-5° C. was added morpholine (1.83 ml) dropwise and the reaction mixture stirred at this temperature for 2 hours. Water (50 ml) was added and the mixture was extracted with ethyl acetate (40 ml). The organic layer was separated, washed with water (30 ml) and saturated sodium chloride solution (30 ml), dried with magnesium sulphate, filtered and evaporated to give the title compound as a yellow foam in almost quantitative yield. The product obtained was a mixture of geometric isomers (ca. 1:1.4) about the enamine double bond and was identical to that produced in Example 6.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:9][N:10]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]1[C:16]([O:18]CC)=O.CC(C)([O-])C.[K+].O>CS(C)=O>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:16](=[O:18])[C:11]3=[CH:12][C:13]([CH3:15])=[CH:14][N:10]3[CH2:9][C:3]=2[CH:4]=1
Reactant: CCOC(=O)c1cc(C)cn1Cc1cc(Cl)ccc1N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc2n(c1)Cc1cc(Cl)ccc1NC2=O
Temperature: 77.5 °C
Reaction time: 1.5 h
Yield: 88.5 %

Procedure:
To a solution of ethyl 1-[(2-amino-5-chloro-phenyl)methyl]-4-methyl-pyrrole-2-carboxylate (20 g, 68.3 mmoles) in dimethyl sulfoxide (60 mL) add potassium t-butoxide (8.4 g, 74.9 mmoles) in DMSO (40 mL) and heat the reaction mixture to 75-80° C. for 1-2 hr. Add water (200 mL) slowly, cool to room temperature, and stir for 1-2 hr. Filter the solids, wash the filtercake with water (75 mL), and transfer the solids to a clean reaction vessel. Add THF (100 mL) and heat the reaction mixture to 30-35° C. until the solids dissolve. Add DCM (350 mL) and continue to stir at 30-35° C. for 1-2 hr. Add 1N hydrochloric acid (250 mL) and continue to stir at 30-35° C. for 1-2 hr. Separate the layers, wash the organic layer with 1N hydrochloric acid (250 mL) followed by a 25% aqueous solution of sodium chloride (50 mL), and concentrate the solution, at below 50° C., to arrive at a volume of approximately 25 mL. Add ethanol (50 mL), concentrate the solution, at below 50° C., to arrive at a volume of approximately 25 mL, and add additional ethanol (50 mL). Concentrate the solution, at below 50° C., to arrive at a volume of approximately 25 mL, heat the reaction mixture to 45-50° C., and stir for 1-2 hr. Cool the reaction mixture to 5-10° C. with stirring for 2-3 hr., and filter the resulting solids. Rinse the filtercake with ethanol (25 mL) and dry in an oven at less than 50° C. under reduced pressure to give 7-chloro-2-methyl-5,10-dihydro-11H-pyrrolo[2,1-c][1,4]benzodiazepin-11-one as an off-white solid (14.9 g, 99.9% purity, 88.5% yield).
Reaction SMILES: C([O:4][C@H:5]1[CH2:10][CH2:9][C@@H:8]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([CH3:20])[C:14]3=[C:13]([Br:21])[N:12]=2)[CH2:7][CH2:6]1)(=O)C.[OH-].[K+].Cl>C(#N)C.O>[Br:21][C:13]1[N:12]=[C:11]([C@@H:8]2[CH2:9][CH2:10][C@H:5]([OH:4])[CH2:6][CH2:7]2)[N:15]2[CH:16]=[CH:17][N:18]=[C:19]([CH3:20])[C:14]=12
Reactant: CC(=O)O[C@H]1CC[C@@H](c2nc(Br)c3c(C)nccn32)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: Cc1nccn2c1c(Br)nc2[C@H]1CC[C@@H](O)CC1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A solution of (cis)-4-(1-bromo-8-methylimidazo[1,5-a]pyrazin-3-yl)cyclohexyl acetate (43.6 mmol, 15.34 g) in acetonitrile (40 ml) was added potassium hydroxide (218 mmol, 12.22 g) in water (40 ml) and the mixture was stirred at 100° C. overnight. Then the reaction mixture was cooled to room temperature, acidified with 2N hydrochloric acid and extracted with dichloromethane twice. The combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo to give (cis)-4-(1-bromo-8-methylimidazo[1,5-a]pyrazin-3-yl)cyclohexanol (9.37 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:24]2[CH:36]=[CH:35][C:27]([C:28]([N:30]=[CH:31][N:32](C)C)=[O:29])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.NO.Cl.[OH-].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:24]2[CH:36]=[CH:35][C:27]([C:28]3[O:29][N:32]=[CH:31][N:30]=3)=[CH:26][CH:25]=2)=[CH:4][CH:3]=1
Reactant: CN(C)C=NC(=O)c1ccc(-c2nc3c(cnn3-c3ccccc3)c(=O)n2-c2ccc(Cl)cc2)cc1
Agent: Cl
Agent: NO
Agent: [Na+]
Solvent: CC(=O)O
Product: O=c1c2cnn(-c3ccccc3)c2nc(-c2ccc(-c3ncno3)cc2)n1-c1ccc(Cl)cc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 85.7 %

Procedure:
To a solution of 4-[5-(4-chloro-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-N-dimethylaminomethylene-benzamide (10 mg, 0.02 mmol) in acetic acid (200 μL) is added a mixture of NH2OH.HCl (5 mg, 0.072 mmol) in NaOH (1M, 50 μL, 0.05 mmol)). The mixture is stirred at 90° C. for 1 h. and cooled down to room temperature. Solvent is removed under vacuum and the residue is treated with saturated aqueous NaHCO3 solution (1 mL) and extracted with EtOAc (3×2 mL). The organic layers are combined and concentrated. The residue is purified by preparative thin layer chromatography (silica gel, 30% EtOAc/hex) to provide the titled compound 5-(4-chloro-phenyl)-6-(4-[1,2,4]oxadiazol-5-yl-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one as white solid (8 mg, 85%). 1H NMR (CDCl3) δ(ppm) 8.50(s, 1H), 8.35(s, 1H), 8.12(d, 2H), 8.06(d, 2H), 7.48-7.54 (m, 4H), 7.37(t, 1H), 7.34(d, 2H), 7.11(d, 2H); HPLC-MS calculated for C25H16ClN6O2 (M+H+): 467.1. Found: 467.1.
Reaction SMILES: [C:1]([C:5]1[CH:22]=[CH:21][CH:20]=[CH:19][C:6]=1[O:7][C:8]1[C:13]([NH:14][C:15](=[S:18])[NH:16][NH2:17])=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[Br:23][CH2:24][CH2:25][CH2:26][C:27](Cl)=O>>[Br:23][CH2:24][CH2:25][CH2:26][C:27]1[S:18][C:15]([NH:14][C:13]2[C:8]([O:7][C:6]3[CH:19]=[CH:20][CH:21]=[CH:22][C:5]=3[C:1]([CH3:4])([CH3:2])[CH3:3])=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:16][N:17]=1
Reactant: O=C(Cl)CCCBr
Reactant: CC(C)(C)c1ccccc1Oc1ncccc1NC(=S)NN
Product: CC(C)(C)c1ccccc1Oc1ncccc1Nc1nnc(CCCBr)s1

Procedure:
Example 102a was synthesized following the procedure for Example 1 using 4-(2-(2-tert-butylphenoxy)pyridin-3-yl)thiosemicarbazide (Example 1b) with 4-bromobutanoyl chloride.
Reaction SMILES: [NH2:1][C:2]1[C:6]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:5][N:4]([CH3:15])[N:3]=1.[CH2:16]([O:23][C:24]([NH:26][C@H:27]([C:32](OC)=[O:33])[CH2:28][C:29](O)=[O:30])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[BH4-].[Li+]>CN(C=O)C.C1COCC1.CO.O>[C:10]([O:9][C:8]([NH:7][C:6]1[C:2]([NH:1][C:29](=[O:30])[CH2:28][C@H:27]([NH:26][C:24](=[O:25])[O:23][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:32][OH:33])=[N:3][N:4]([CH3:15])[CH:5]=1)=[O:14])([CH3:11])([CH3:12])[CH3:13]
Reactant: Cn1cc(NC(=O)OC(C)(C)C)c(N)n1
Reactant: COC(=O)[C@H](CC(=O)O)NC(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [BH4-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CO
Product: Cn1cc(NC(=O)OC(C)(C)C)c(NC(=O)C[C@@H](CO)NC(=O)OCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.9 %

Procedure:
To a solution of tert-butyl (3-amino-1-methyl-1H-pyrazol-4-yl)carbamate (1.0 g), (3S)-3-(((benzyloxy)carbonyl)amino)-4-methoxy-4-oxobutanoic acid (1.5 g) and HATU (2.2 g) in DMF (24 mL) was added diisopropylethylamine (1.2 mL), and the mixture was stirred overnight at room temperature. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed successively with saturated aqueous ammonium chloride solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give a crude product (2.6 g). To a suspension of lithium borohydride (0.26 g) in THF (20 mL) was added a solution of the crude product (2.2 g) in methanol (10 mL) under ice-cooling, and the mixture was stirred at 0° C. for 1 hr. To the reaction mixture was added water, and the mixture was concentrated under reduced pressure. The residue was extracted with ethyl acetate, the extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.6 g).
Reaction SMILES: [N:1]([CH:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1)[CH3:5])=[N+]=[N-].[H][H]>CO.[Pd]>[F:22][C:18]1[CH:17]=[C:16]([C:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:14]=[CH:15][C:6]=2[CH:4]([NH2:1])[CH3:5])[CH:21]=[CH:20][CH:19]=1
Reactant: [H][H]
Reactant: CC(N=[N+]=[N-])c1ccc2ccccc2c1-c1cccc(F)c1
Agent: [Pd]
Solvent: CO
Product: CC(N)c1ccc2ccccc2c1-c1cccc(F)c1

Procedure:
A mixture of 2-(1-azidoethyl)-1-(3-fluorophenyl)naphthalene (0.035 g, 0.12 mmol) in 1 mL of methanol was hydrogenated in the presence of 5% Pd/C, under balloon pressure of hydrogen, for 1 hour. After filtering off the catalyst, the filtrate was concentrated under reduced pressure and the resulting residue was used directly in next step. LCMS calculated for C18H14F(M−NH2)+: m/z=249.1; found: 249.3.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([CH:12]=[C:13]([NH:15][C:16](=[O:21])[CH2:17][CH2:18][CH2:19]Cl)[CH:14]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]>C1COCC1>[Br:3][C:4]1[CH:5]=[C:6]([CH:12]=[C:13]([N:15]2[CH2:19][CH2:18][CH2:17][C:16]2=[O:21])[CH:14]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1cc(Br)cc(NC(=O)CCCCl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(Br)cc(N2CCCC2=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.9 %

Procedure:
Sodium hydride, 60% suspension in oil (186 mg, 4.65 mmol) was added portionwise over 2 mins to a solution of ethyl 3-bromo-5-[(4-chlorobutanoyl)amino]benzoate (1.35 g, 3.87 mmol) in dry THF (50 ml) under nitrogen. The reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched by the careful addition of water (25 ml). Diethyl ether (50 ml) was added. The organic phase was washed with water, dried and evaporated to give the title compound as a yellow solid (990 mg, 82%).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[NH:4][CH:3]=1.Cl[CH2:13][C:14]1[S:18][C:17]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)=[N:16][C:15]=1[CH3:29].C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][CH2:13][C:14]3[S:18][C:17]([C:19]4[CH:20]=[CH:21][C:22]([C:25]([F:28])([F:26])[F:27])=[CH:23][CH:24]=4)=[N:16][C:15]=3[CH3:29])=[CH:8][CH:9]=2)[NH:4][CH:3]=1
Reactant: Cc1c[nH]c2cc(O)ccc12
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc2c(C)c[nH]c2c1

Procedure:
In analogy to the procedure described in example 27 e], 3-methyl-1H-indol-6-ol was reacted with 5-chloromethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole [PCT Int. Appl. (2002), WO 0292590 A1] in the presence of cesium carbonate to give 3-methyl-6-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-1H-indole as light brown crystals.
Reaction SMILES: [CH3:1][CH:2]([CH3:13])[CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4]([OH:6])=O.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.[CH2:35]1[C@H:39]2[CH2:40][CH2:41][C@H:42]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[C@H:38]2[CH2:37][NH:36]1>ClCCl>[CH3:13][CH:2]([CH3:1])[CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4]([N:36]1[CH2:37][C@@H:38]2[C@@H:42]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:48])([CH3:47])[CH3:49])[CH2:41][CH2:40][C@@H:39]2[CH2:35]1)=[O:6]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H]2CNC[C@@H]21
Reactant: CC(C)C(C(=O)O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)C(C(=O)N1C[C@H]2CC[C@H](NC(=O)OC(C)(C)C)[C@H]2C1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
3-Methyl-2-phenylbutanoic acid (63 mg, 0.353 mmol), 1-hydroxybenzotriazole (54.1 mg, 0.353 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (0.063 mL, 0.353 mmol) were combined in dichloromethane (5 mL). The reaction was stirred at room temperature for 20 minutes, and then tert-butyl(3aR,4S,6aS)-octahydrocyclopenta[c]pyrrol-4-ylcarbamate (80 mg, 0.353 mmol) from Step B was added. After 30 minutes, the reaction was quenched with water and extracted with dichloromethane. The combined extracts were concentrated, and the crude material purified using 10-100% ethyl acetate/hexanes to give tert-butyl(3aR,4S,6aS)-2-(3-methyl-2-phenylbutanoyl)octahydrocyclopenta[c]pyrrol-4-ylcarbamate: MS (ESI+) m/z 387 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][C:13]3([CH2:24][C:23](=[O:25])[C:22]4[C:17](=[CH:18][CH:19]=[C:20](/[CH:26]=[CH:27]/[C:28](O)=[O:29])[CH:21]=4)[O:16]3)[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[NH2:31][O:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][O:34]1>C(Cl)Cl>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:11][CH2:12][C:13]3([CH2:24][C:23](=[O:25])[C:22]4[C:17](=[CH:18][CH:19]=[C:20](/[CH:26]=[CH:27]/[C:28]([NH:31][O:32][CH:33]5[CH2:38][CH2:37][CH2:36][CH2:35][O:34]5)=[O:29])[CH:21]=4)[O:16]3)[CH2:14][CH2:15]2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(CCN2CCC3(CC2)CC(=O)c2cc(/C=C/C(=O)O)ccc2O3)cc1
Reactant: NOC1CCCCO1
Solvent: ClCCl
Product: Nc1ccc(CCN2CCC3(CC2)CC(=O)c2cc(/C=C/C(=O)NOC4CCCCO4)ccc2O3)cc1

Procedure:
(E)-3-{1′-[2-(4-Amino-phenyl)-ethyl]-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid (108 mg, 0.225 mmol) was suspended in DCM (5 ml). TEA (0.09 ml, 0.67 mmol) was added and the clear solution was treated with NH2OTHP following the procedure described in Example 1, Step B, giving (E)-3-{1′-[2-(4-amino-phenyl)-ethyl]-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide (37 mg) as a yellow solid, which was then dissolved in DCM (3 ml) and treated with 4 M HCl in dioxane (0.1 ml, 0.4 mmol) as described in Example 55, Step D, giving a light yellow solid (28 mg, di-hydrochloride salt).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14](=[O:27])[C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)([O-])=O.C[N:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:40]=[CH:39][C:38]([NH:41][C:42]([C:44]3[CH:51]=[CH:50][C:47]([CH:48]=O)=[CH:46][CH:45]=3)=[O:43])=[CH:37][CH:36]=2)[CH2:31][CH2:30]1>>[N:21]1([C:18]2[CH:19]=[CH:20][C:15]([C:14]([NH:13][C:6]3[CH:7]=[CH:8][C:9]4[NH:10][C:48]([C:47]5[CH:50]=[CH:51][C:44]([C:42](=[O:43])[NH:41][C:38]6[CH:39]=[CH:40][C:35]([N:32]7[CH2:31][CH2:30][NH:29][CH2:34][CH2:33]7)=[CH:36][CH:37]=6)=[CH:45][CH:46]=5)=[N:1][C:4]=4[CH:5]=3)=[O:27])=[CH:16][CH:17]=2)[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1
Reactant: O=C(Nc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)c1ccc(N2CCNCC2)cc1
Reactant: CN1CCN(c2ccc(NC(=O)c3ccc(C=O)cc3)cc2)CC1
Product: O=C(Nc1ccc(N2CCNCC2)cc1)c1ccc(-c2nc3cc(NC(=O)c4ccc(N5CCNCC5)cc4)ccc3[nH]2)cc1

Procedure:
Compound 251 was prepared according to the procedure similar to that described in Scheme III from N-(3,4-dinitrophenyl)-4-piperazinylbenzamide and 4-(4-(4-methylpiperazinyl)phenyl)aminocarbonylbenzaldehyde. [M+H]+ calcd for C35H36N8O2: 601.30; found: 601.19.
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].[CH:5]([NH:8][CH:9]([CH3:11])[CH3:10])([CH3:7])[CH3:6].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[CH:5]([N:8]([CH:9]([CH3:11])[CH3:10])[CH2:3][C:2]#[CH:1])([CH3:7])[CH3:6]
Reactant: CC(C)NC(C)C
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: C#CCN(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.7 %

Procedure:
Propargyl bromide (23.5 g, 197 mmol) was added dropwise to a mixture of diisopropyl amine (20 g, 197 mmol) and cesium carbonate (64 g, 197 mmol) in 350 mL of acetone. The mixture was stirred overnight under nitrogen at room temperature. The inorganic salts were then filtered off, and the solvent was removed. The residue was dissolved in saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic extracts were then evaporated to give 12 g of diisopropyl-prop-2-ynyl-amine: mass spectrum (m/e): M+H 139.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][N:11]([CH2:24][C:25]([F:28])([F:27])[F:26])[C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([C:20]([F:23])([F:22])[F:21])[CH:13]=2)=[CH:4][CH:3]=1.[Si]([N:33]=[C:34]=[O:35])(C)(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:16]([C:15]1[CH:18]=[CH:19][C:12]([N:11]([CH2:24][C:25]([F:26])([F:27])[F:28])[CH2:10][CH2:9][O:8][C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:34]([NH2:33])=[O:35])=[CH:3][CH:4]=2)=[CH:13][C:14]=1[C:20]([F:21])([F:22])[F:23])#[N:17]
Reactant: C[Si](C)(C)N=C=O
Reactant: N#Cc1ccc(N(CCOc2ccc(N)cc2)CC(F)(F)F)cc1C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: N#Cc1ccc(N(CCOc2ccc(NC(N)=O)cc2)CC(F)(F)F)cc1C(F)(F)F
Reaction time: 8 h
Yield: 40.1 %

Procedure:
To a solution of 4-[{2-[(4-aminophenyl)oxy]ethyl}(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile (0.105 g, 0.25 mmol; Example 28A) in dry CH2Cl2 (5 mL) at room temp, under N2, was added TMS-isocyanate (0.05 mL, 0.29 mmol) and the mixture was stirred overnight. After 12 h, an additional portion of TMS-isocyanate (0.09 mL, 0.58 mmol) and DMAP (0.003 g, 0.025 mmol) was added and stirring continued. After 2 h, the mixture was quenched with 10% v/v HCl and the whole extracted with EtOAc (×3). Combined organics were washed (water, brine), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc/hexanes), followed by preparative RP-HPLC (C18 column, MeCN/water), affording 0.0448 g of the title compound as a colorless gum: MS (ES) m/z 447 (M+1).
Reaction SMILES: C([O:4][C:5]1[C:14]([CH3:15])=[C:13]2[C:8]([C:9]([CH3:29])=[C:10]([CH2:17][N:18]3[C:22](=[O:23])[C:21]4=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]4[C:19]3=[O:28])[C:11](=[O:16])[O:12]2)=[CH:7][CH:6]=1)(=O)C.OS(O)(=O)=O>CO>[OH:4][C:5]1[C:14]([CH3:15])=[C:13]2[C:8]([C:9]([CH3:29])=[C:10]([CH2:17][N:18]3[C:19](=[O:28])[C:20]4=[CH:27][CH:26]=[CH:25][CH:24]=[C:21]4[C:22]3=[O:23])[C:11](=[O:16])[O:12]2)=[CH:7][CH:6]=1
Reactant: CC(=O)Oc1ccc2c(C)c(CN3C(=O)c4ccccc4C3=O)c(=O)oc2c1C
Agent: O=S(=O)(O)O
Solvent: CO
Product: Cc1c(CN2C(=O)c3ccccc3C2=O)c(=O)oc2c(C)c(O)ccc12
Temperature: 25 °C

Procedure:
A solution of 7-acetoxy-4,8-dimethyl-3-phthalimidomethylcoumarin (15.9 g, 40.6 mol) was stirred in methanol (2000 mL) while concentrated H2SO4 (75 mL) was added dropwise. The resulting mixture was refluxed for 3 hours, allowed to cool to room temperature, then chilled in an ice water bath. The precipitate was collected in a Buchner funnel and rinsed with ice cold methanol to give 7-hydroxy-4,8-dimethyl-3-phthalimidomethylcoumarin, a white solid (12.1 g, 85.6%). 1H NMR (CD3OD): δ7.87-7.78 (m, 4H), 7.55 (d, J=8.7 Hz, 1H), 6.84 (d, J=8.8 Hz, 1H), 2.61 (s, 3H), 2.23 (s, 3H), the methylene peak is presumably obscured by solvent hydroxy peak at 4.88.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:13]=[CH:12][N:11](C(OC(C)(C)C)=O)[N:10]=2)=[N:6][C:7]=1[CH3:8].[CH:21]([N:24]1[C:29]2=[N:30][C:31](B3OC(C)(C)C(C)(C)O3)=[CH:32][N:33]=[C:28]2[NH:27][CH2:26][C:25]1=[O:43])([CH3:23])[CH3:22].C(=O)([O-])[O-].[Na+].[Na+]>CC(N(C)C)=O.O.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>[CH:21]([N:24]1[C:29]2=[N:30][C:31]([C:2]3[C:7]([CH3:8])=[N:6][C:5]([C:9]4[NH:13][CH:12]=[N:11][N:10]=4)=[CH:4][CH:3]=3)=[CH:32][N:33]=[C:28]2[NH:27][CH2:26][C:25]1=[O:43])([CH3:23])[CH3:22]
Reactant: CC(C)N1C(=O)CNc2ncc(B3OC(C)(C)C(C)(C)O3)nc21
Reactant: Cc1nc(-c2ncn(C(=O)OC(C)(C)C)n2)ccc1Br
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: CC(=O)N(C)C
Solvent: O
Product: Cc1nc(-c2nnc[nH]2)ccc1-c1cnc2c(n1)N(C(C)C)C(=O)CN2
Temperature: 100 °C
Yield: 41 %

Procedure:
1-Isopropyl-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (alternate approach). 7-Bromo-1-isopropyl-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (1 equiv), bis(pinacolato)diboron) (1 equiv), potassium acetate (3 equiv) and bis(1,1′-bis(diphenylphosphino)ferrocene)palladium (0.01 equiv) were combined in dioxane, degassed with nitrogen and heated to 95° C. under nitrogen. Dilution with ethyl acetate, filtration through Celite, concentration, trituration with ethyl acetate and hexanes, filtration and drying gave the boronate ester in 60% yield. tert-Butyl 3-(5-bromo-6-methylpyridin-2-yl)-1H-1,2,4-triazole-1-carboxylate (1 equiv), 1-isopropyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (1.2 equiv), tetrakis(triphenylphosphine)palladium(0) (0.05 equiv), sodium carbonate (3 equiv) were combined in (3:1) dimethyl acetamide and water. The mixture was degassed and heated to 100° C. overnight. Standard ethyl acetate/water work up and subsequent trituration in ethyl acetate gave the desired product in 41% yield.
Reaction SMILES: [C:1]([CH:3]=[C:4]([NH:13][C:14](=O)[O:15]CC)[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12])#[N:2].[F:19][C:20]([F:26])([F:25])[C:21]([NH:23][NH2:24])=O.O.C(OCC)(=O)C>CN1C(=O)CCC1>[Cl:12][C:6]1[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]=1[C:4]1[N:13]=[C:14]([OH:15])[N:24]2[N:23]=[C:21]([C:20]([F:26])([F:25])[F:19])[N:2]=[C:1]2[CH:3]=1
Reactant: NNC(=O)C(F)(F)F
Reactant: CCOC(=O)NC(=CC#N)c1ccc(Cl)cc1Cl
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCOC(C)=O
Product: Oc1nc(-c2ccc(Cl)cc2Cl)cc2nc(C(F)(F)F)nn12
Temperature: 160 °C
Reaction time: 4 h

Procedure:
2.10 g (7.4 mmol) of ethyl [2-cyano-1-(2,4-dichlorophenyl)ethenyl]carbamate (Example 128A) and 0.95 g (7.4 mmol) of 2,2,2-trifluoroacetohydrazide are dissolved in NMP (10 ml) under argon and stirred in a flask with a calcium chloride drying tube at an oil-bath temperature of 160° C. for 4 h. The reaction mixture is cooled to RT, and water (20 ml) is added. Ethyl acetate (150 ml) and water (100 ml) are added, and the organic phase is separated off, dried with magnesium sulphate and concentrated. The residue is chromatographed on silica gel (mobile phase cyclohexane/ethyl acetate 4:1 to 1:1). 0.97 g (38% of theory) of the product is obtained.