Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([C:22]([O:24]C)=[O:23])=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:26]=2)=[N:7][C:6]([CH3:27])=[N:5]1)([CH3:3])[CH3:2].[OH-].[Li+]>O1CCCC1.O>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([C:22]([OH:24])=[O:23])=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:26]=2)=[N:7][C:6]([CH3:27])=[N:5]1)([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc2c(c1)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(-c2cn3c(n2)-c2ccc(C(=O)O)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 2-(2-isopropyl-5-methyl-1,2,4-triazol-3-yl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-9-carboxylate; (4.50 g, 12.2 mmol) in Tetrahydrofurane; (100 mL) was added a slurry of Lithium Hydroxide (880 mg, 36.7 mmol) in water (20 mL). The reaction mixture was stirred at room temperature for 1 hour. LC-MS analysis of the reaction mixture showed no more starting material. The solvent was removed and the residue was used in the next step without further purification.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH2:13](O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: OCc1ccccc1
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)c1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.7 %

Procedure:
A solution of indole-5-carboxylic acid (68.3 g), benzyl alcohol (64.9 g) and triphenylphosphine (157.0 g) in tetrahydrofuran (1.2 L) was cooled to 5° C. and treated dropwise with diethyl azodicarboxylate (90.0 g). Upon completion of the addition, the mixture was allowed to warm to room temperature. The reaction was stirred for 24 hours and then evaporated. The residue was taken up in diethyl ether (1 L) and filtered. The filtrate was evaporated to give a yellow syrup which was purified by flash chromatography, eluting sequentially with 2:1, 1:1 and 1:2 hexane:methylene chloride, to afford a yellow-white solid. This material was triturated with 1:1 hexane: methylene chloride (300 mL) and filtered to give benzyl indole-5-carboxylate as a white solid (74.2 g, 70%); mp 127°-129° C.; partial NMR (300 MHz, CDCl3): 5.39 (s, 2H, CH2), 6.61 (m, 1H, indole-H(2)), 8.56 (br, 1H, NH).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6](O)[N:5]2[N:9]=[C:10]([S:22][CH3:23])[C:11]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])=[C:4]2[N:3]=1.O=P(Cl)(Cl)[Cl:26]>>[Cl:26][C:6]1[N:5]2[N:9]=[C:10]([S:22][CH3:23])[C:11]([S:12]([C:15]3[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=3)(=[O:14])=[O:13])=[C:4]2[N:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: CSc1nn2c(O)cc(C)nc2c1S(=O)(=O)c1ccc(C)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: CSc1nn2c(Cl)cc(C)nc2c1S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Yield: 95 %

Procedure:
A suspension of 3.8 g (10.8 mmol) of 5-methyl-2-methylsulphanyl-3-(toluene-4-sulphonyl)-pyrazolo[1,5-a]pyrimidin-7-ol in 20 l of POCl3 was heated at reflux for 1 hr. The reaction solution was cooled to RT and evaporated. The residue was treated with 100 ml of ice-water and the pH value of the solution was adjusted to 8 with sat. NaHCO3 solution. The aqueous phase was extracted three times with CH2Cl2, and the organic phases were dried (MgSO4), filtered and evaporated. Chromatography (SiO2, CH2Cl2/AcOEt 25:1) of the residue yielded 3.8 g (95%) of 7-chloro-5-methyl-2-methylsulphanyl-3-(toluene-4-sulphonyl)-pyrazolo[1,5-a]pyrimidine as pale yellow crystals, m.p. 197-198°.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[Cl:19][CH2:20][CH2:21][CH2:22][N:23]1[C:28](=[O:29])[C:27]([CH2:30][CH3:31])=[CH:26][N:25]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:24]1=[O:39]>>[ClH:19].[CH2:32]([N:25]1[CH:26]=[C:27]([CH2:30][CH3:31])[C:28](=[O:29])[N:23]([CH2:22][CH2:21][CH2:20][N:14]2[CH2:15][CH2:16][N:11]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[O:4][CH2:3][C:2]([F:1])([F:17])[F:18])[CH2:12][CH2:13]2)[C:24]1=[O:39])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CCc1cn(Cc2ccccc2)c(=O)n(CCCCl)c1=O
Reactant: FC(F)(F)COc1ccccc1N1CCNCC1
Product: CCc1cn(Cc2ccccc2)c(=O)n(CCCN2CCN(c3ccccc3OCC(F)(F)F)CC2)c1=O
Product: Cl

Procedure:
substituting 1-[2-(2,2,2-trifluoroethoxy)phenyl]piperazine and 3-(3-chloropropyl)-1-benzyl-5-ethyl-2,4(1H,3H)-pyrimidinedione gave 1-benzyl-3-{3-[4-(2-(2,2,2-trifluoroethoxy)phenyl)piperazin-1-yl]propyl}-5-ethyl-2,4(1H,3H)-pyrimidinedione hydrochloride, m.p. 180°-181° C.; Anal.: Calcd. for C28H33F3N4O3.HCl: C, 58.56; H, 6.11; N, 9.76%; Found: C, 58.83; H, 6.11; N, 9.77%;
Reaction SMILES: [CH3:1][C:2]1[CH2:7][C@@H:6]([OH:8])[CH2:5][C:4]([CH3:10])([CH3:9])[C:3]=1/[CH:11]=[CH:12]/[C:13](/[CH3:42])=[CH:14]/[CH:15]=[CH:16]/[C:17](/[CH3:41])=[CH:18]/[CH:19]=[CH:20]/[CH:21]=[C:22](\[CH3:40])/[CH:23]=[CH:24]/[CH:25]=[C:26](\[CH3:39])/[CH:27]=[CH:28]/[C:29]1[C:34]([CH3:36])([CH3:35])[CH2:33][C@H:32]([OH:37])[CH2:31][C:30]=1[CH3:38].Cl([O-])(=O)=[O:44].[Na+].[I-].[Na+].S(=O)(=O)(O)O.[OH2:55]>C(Cl)(Cl)Cl>[CH3:38][C:30]1[C:31](=[O:55])[C@@H:32]([OH:37])[CH2:33][C:34]([CH3:36])([CH3:35])[C:29]=1/[CH:28]=[CH:27]/[C:26](/[CH3:39])=[CH:25]/[CH:24]=[CH:23]/[C:22](/[CH3:40])=[CH:21]/[CH:20]=[CH:19]/[CH:18]=[C:17](\[CH3:41])/[CH:16]=[CH:15]/[CH:14]=[C:13](\[CH3:42])/[CH:12]=[CH:11]/[C:3]1[C:4]([CH3:9])([CH3:10])[CH2:5][C@H:6]([OH:8])[C:7](=[O:44])[C:2]=1[CH3:1]
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C2=C(C)C[C@@H](O)CC2(C)C)C(C)(C)C[C@H](O)C1
Reactant: [O-][Cl+2]([O-])[O-]
Reactant: O
Agent: O=S(=O)(O)O
Agent: [I-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C2=C(C)C(=O)[C@@H](O)CC2(C)C)C(C)(C)C[C@H](O)C1=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Zeaxanthin (50 mg) was stirred in 20 ml of chloroform under nitrogen. To this stirred mixture, 200 mg of sodium chlorate and 50 mg of sodium iodide in 10 ml of water was added. The mixture was acidified slowly with 1 ml of 27% sulfuric acid. The reaction was stirred at room temperature. After 5 hours, a significant quantity of astaxanthin had formed. The reaction was worked up by addition of 1 ml of 40% sodium hydroxide, separation of the organic solution and evaporation to yield astaxanthin.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.CC1(C)N[CH2:27][CH2:26][NH:25][C:24]1=[O:29].CN(C(ON1N=[N:46][C:41]2[CH:42]=[CH:43]C=[CH:45][C:40]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:46]3[CH2:27][CH2:26][NH:25][C:24](=[O:29])[C:41]3([CH2:40][CH3:45])[CH2:42][CH3:43])=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC1(C)NCCNC1=O
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCC1(CC)C(=O)NCCN1C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with 3,3-dimethylpiperazin-2-one hydrochloride (CAN 907973-05-1) in the presence of TBTU and DIEA to obtain the title compound as colorless solid; MS (EI): m/e=423.4 [MH+].
Reaction SMILES: [CH2:1]([N:8]1[CH:13]=[CH:12][C:11](=[O:14])[CH2:10][CH:9]1C1C=CC=CC=1OC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4]C=1.[CH3:23][OH:24]>[OH-].[OH-].[Pd+2]>[CH3:23][O:24][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:1]=1[N:8]1[CH2:9][CH2:10][CH:11]([OH:14])[CH2:12][CH2:13]1
Reactant: CO
Reactant: COc1ccccc1C1CC(=O)C=CN1Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Product: COc1ccccc1N1CCC(O)CC1

Procedure:
To a solution of N-benzyl-2,3-dihydro-2-(2-methoxyphenyl)-4-pyridone (5.5 g, 18.77 mmol) (which was prepared by the procedures of Yamamoto et al., Tetrahedron, 1993, 49, 1749) in methanol (80 mL) was added Pd(OH)2 (1.7 g) and the resulting suspension was hydrogenated (50 psi) for 20 hours. Pd-C was then filtered off and the crude reaction mixture was concentrated in vacuo to give a residue, which was purified by silica gel flash chromatography (5% MeOH-0.5% NH3♦H2O-94.5% CH2Cl2) to afford the title compound as a solid (1.5 g). 13C NMR (CDCl3, 100 MHz) ) δ: 156.5, 131.4, 128.1, 126.9, 120.8, 110.3, 69.6, 55.3, 53.8, 45.1, 41.7, and 35.6.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](Cl)=[O:18]>C1COCC1>[CH3:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([NH:1][C:2]1[C:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:6]=2[CH:5]=[CH:4][CH:3]=1)=[O:18]
Reactant: c1ccncc1
Reactant: Nc1ccccc1
Reactant: Cc1ccccc1C(=O)Cl
Solvent: C1CCOC1
Product: Cc1ccccc1C(=O)Nc1cccc2c1CCCC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 65 %

Procedure:
To a 25° C. solution of aniline (1 eq) in anhydrous THF (2 mL per mmol aniline) was added polymer bound pyridine (1.5 eq) followed by 2-methyl-benzoyl chloride (1 eq). The mixture was stirred at 25° C. for 12-24 h. The reaction mixture was filtered and the filtrate concentrated in vacuo. Hexane was added to the residue and the resulting precipitate was collected by filtration, resulting in a white solid (yield 65%). LC/MS (M+H)+ m/z 266. The crude material was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][C@@H:12]([NH2:17])[C:13]([O:15][CH3:16])=[O:14])=[CH:4][C:3]=1[CH3:20].[CH3:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[C:26]([CH3:29])[C:27]=1[F:28].C(N(CC)CC)C>ClCCl.CC([O-])=O.CC([O-])=O.[Cu+2]>[F:28][C:27]1[C:26]([CH3:29])=[CH:25][C:24]([NH:17][C@H:12]([CH2:11][CH2:10][CH2:9][CH2:8][O:7][CH2:6][C:5]2[CH:18]=[CH:19][C:2]([F:1])=[C:3]([CH3:20])[CH:4]=2)[C:13]([O:15][CH3:16])=[O:14])=[CH:23][C:22]=1[CH3:21]
Reactant: Cc1cc(B(O)O)cc(C)c1F
Reactant: COC(=O)[C@H](N)CCCCOCc1ccc(F)c(C)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H](CCCCOCc1ccc(F)c(C)c1)Nc1cc(C)c(F)c(C)c1
Temperature: 25 °C
Reaction time: 44 h
Yield: 68.6 %

Procedure:
To a suspension of crude (R)-methyl 6-(4-fluoro-3-methylbenzyloxy)-2-aminohexanoate (0.128 g, 0.453 mmol), 3,5-dimethyl-4-fluorophenylboronic acid (0.152 g, 0.906 mmol), Cu(OAc)2 (0.090 g, 0.498 mmol), and molecular sieves 4 Å (0.400 g) in 5 mL of dichloromethane, was added triethylamine (0.13 mL, 0.906 mmol). After stirring at room temperature under O2 (1 atm) for 44 h, the reaction mixture was filtered through a pad of Celite and washed with dichloromethane. The filtrate was concentrated under reduced pressure. The product was isolated by Flash column chromatography (silica gel column) eluting with 0-30% ethyl acetate/hexanes to give the title compound as light yellow oil (0.126 g, 68% yield). GC-MS: tR=7.0 min; m/z 405 (M+).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH2:30]O)=[CH:24][CH:23]=1.[C:32]([NH:39][C:40]([N:49]1[CH:53]=[CH:52][CH:51]=[N:50]1)=[N:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33].N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.CCCC(C)C>C(Cl)Cl>[C:45]([O:44][C:42](=[O:43])[N:41](/[C:40](=[N:39]/[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])/[N:49]1[CH:53]=[CH:52][CH:51]=[N:50]1)[CH2:30][CH2:29][CH2:28][C:25]1[CH:24]=[CH:23][C:22]([O:21][CH3:20])=[CH:27][CH:26]=1)([CH3:48])([CH3:47])[CH3:46]
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)n1cccn1
Reactant: COc1ccc(CCCO)cc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCCC(C)C
Product: COc1ccc(CCCN(C(=O)OC(C)(C)C)/C(=N/C(=O)OC(C)(C)C)n2cccn2)cc1
Temperature: 4 °C
Reaction time: 0.08 h

Procedure:
PS-Triphenylphosphine (6.40 g, 12.03 mmol) is added to a solution of 3-(4-methoxyphenyl)-1-propanol (1.00 g, 6.02 mmol) in DCM (300 mL), followed by N,N′-di-Boc-1H-pyrazole-1-carboxamidine (1.87 g, 6.02 mmol). The reaction mixture is cooled to 4° C., and di-tert-butyl azodicarboxylate (1.39 g, 6.02 mmol) is added portionwise. The reaction is stirred for 5 minutes at 4° C., and then allowed to warm to RT. The resulting yellow suspension is stirred at RT overnight. The reaction is filtered to remove the PS-triphenylphosphine, which is rinsed with MeOH (20 mL). The combined filtrates are concentrated in vacuo to afford a colourless oil. iso-Hexane (50 mL) is added, and a fine cream solid precipitates out of solution, which is removed by filtration. The filtrate is concentrated in vacuo, and the resulting white solid is washed with iso-hexane (50 mL). The iso-hexane is concentrated in vacuo, and the resulting pale yellow oil is purified by chromatography (SiO2, EtOAc in iso-hexane, 0%-25%) to afford the title compound crude as a colourless oil. The oil is used in further reactions with no further purification. [M+H]+ 459.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:20][CH:21]([CH3:23])[CH3:22])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC1(C)C(C)(C)OB([C:43]2[CH:44]=[C:45]([N:49]3[CH:53]=[CH:52][CH:51]=[N:50]3)[CH:46]=[CH:47][CH:48]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)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>[N:49]1([C:45]2[CH:44]=[C:43]([C:19]([C:11]3[N:10]([S:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)(=[O:9])=[O:8])[C:14]4=[N:15][CH:16]=[CH:17][CH:18]=[C:13]4[CH:12]=3)=[CH:20][CH:21]([CH3:23])[CH3:22])[CH:48]=[CH:47][CH:46]=2)[CH:53]=[CH:52][CH:51]=[N:50]1
Reactant: CC1(C)OB(c2cccc(-n3cccn3)c2)OC1(C)C
Reactant: Cc1ccc(S(=O)(=O)OC(=CC(C)C)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)C=C(c1cccc(-n2cccn2)c1)c1cc2cccnc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Yield: 120.1 %

Procedure:
A suspension of toluene-4-sulfonic acid-1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methyl-but-1-enyl ester (prepared as in Example 130, 3.0 g, 6.04 mmol), 1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazole (4.08 g, 15.1 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.5 g, 0.71 mmol) in dioxane (30 mL) and an aqueous sodium carbonate solution (2N, 15 mL) was heated at 100° C. in a microwave for 2 h. At this time, the reaction mixture was cooled to 25° C., diluted with ethyl acetate (350 mL) and washed with a saturated aqueous sodium carbonate solution (2×75 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Silica gel column chromatography (300-400 mesh, 50% ethyl acetate/petroleum ether) afforded 2-(1-(3-(1H-pyrazol-1-yl)phenyl)-3-methylbut-1-enyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (3.4 g, 60.1%) as a gray solid: 1H NMR (300 MHz, CDCl3) δ ppm 8.49 (d, 1H, J=2.1 Hz), 8.40 (dd, 1H, J1=4.8 Hz, J2=1.8 Hz), 8.10 (dd, 2H, J1=7.8 Hz, J2=1.8 Hz), 7.44 (dd, 1H, J1=7.8 Hz, J2=1.2 Hz), 7.68-7.61 (m, 4H), 7.55 (t, 1H, J=8.1 Hz), 7.42-7.33 (m, 4H), 7.06 (d, 1H, J=7.8 Hz), 6.89 (s, 1H), 6.52 (t, 1H, J=1.8 Hz), 6.35 (d, 1H, J=9.6 Hz), 1.14 (d, 3H, J=5.1 Hz), 1.12 (d, 3H, J=4.8 Hz).
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[N:12]=[CH:13][C:14]([C:17]([OH:19])=O)=[N:15][CH:16]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:42][CH2:43][C:44]([N:46]1[CH2:51][CH2:50][N:49]([C:52](=[O:63])[C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=2[C:59]([F:62])([F:61])[F:60])[CH2:48][CH2:47]1)=[O:45]>CN(C=O)C>[O:45]=[C:44]([N:46]1[CH2:47][CH2:48][N:49]([C:52](=[O:63])[C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=2[C:59]([F:62])([F:61])[F:60])[CH2:50][CH2:51]1)[CH2:43][NH:42][C:17]([C:14]1[CH:13]=[N:12][C:11]([OH:10])=[CH:16][N:15]=1)=[O:19]
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Reactant: O=C(O)c1cnc(O)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1cnc(O)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33 %

Procedure:
DIPEA (553 mg, 0.732 mL, 4.28 mmol) was added to a stirred solution of 5-hydroxy-pyrazine-2-carboxylic acid (200 mg, 1.42 mmol) in DMF (3 mL). HOBT (231 mg, 1.71 mmol) and EDCI (328 mg, 1.71 mmol) were then added at room temperature. After 2 minutes 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone hydrochloride salt (600 mg, 1.71 mmol) was added and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated, methanol was then added, filtered the solid precipitated. The solid obtained was purified by column chromatography (using silica gel of 60-120 mesh and 10% MeOH in CHCl3 as eluent) to afford 205 mg (32.85%) of 5-hydroxy-pyrazine-2-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide. LCMS Purity: 91.22%. 1H NMR (DMSO-d6): δ 8.3 (bt, 1H), δ 8.0 (m, 2H), 7.9-7.76 (m, 2H), 7.7 (m, 1H), 7.6-7.5 (d, 2H), 4.26-4.1 (dd, 2H), 3.8-3.68 (m, 2H), 3.6-3.5 (m, 2H), 3.4 (m, 2H), δ 3.2-3.0 (m, 2H).
Reaction SMILES: [NH2:1][NH2:2].Cl[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]2[CH:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)=[N:6][N:5]=1.[CH2:22](O)C>>[CH3:21][O:20][C:17]1[N:16]=[CH:15][C:14]([C:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:4]3=[N:5][N:6]=[CH:22][N:2]3[N:1]=2)=[CH:19][CH:18]=1
Reactant: CCO
Reactant: NN
Reactant: COc1ccc(-c2nnc(Cl)c3ccccc23)cn1
Product: COc1ccc(-c2nn3cnnc3c3ccccc23)cn1
Temperature: 60 °C
Reaction time: 4 h
Yield: 51 %

Procedure:
100 μl (2 mmol) of hydrazine was added to an ethanol solution (10 ml) of 300 mg of 1-chloro-4-(6-methoxypyridin-3-yl)-phthalazine, and the reaction liquid was stirred at 60° C. for 4 hours. The reaction liquid was concentrated under reduced pressure, and formic acid (10 ml) was added to the resulting solid and stirred at 120° C. for 30 minutes. This was concentrated under reduced pressure, aqueous saturated sodium hydrogencarbonate solution was added to the reaction liquid, extracted with chloroform, and the organic layer was washed with saturated saline water. This was dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 141 mg (yield: 51%) of 6-(6-methoxypyridin-3-yl)-[1,2,4]triazolo[3,4-a]phthalazine as a brown solid.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:10])[NH:4][C:5](=O)[NH:6][C:7]=1[Cl:8].[C:11]([O-:14])([O-])=O.[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CN(C=O)C.CCOC(C)=O>[CH2:5]([N:6]1[C:7]([Cl:8])=[C:2]([Br:1])[C:3](=[O:10])[N:4]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:11]1=[O:14])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=c1[nH]c(Cl)c(Br)c(=O)[nH]1
Reactant: BrCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=c1c(Br)c(Cl)n(Cc2ccccc2)c(=O)n1Cc1ccccc1
Temperature: 75 °C
Reaction time: 1.5 h
Yield: 97.5 %

Procedure:
To a stirring solution of 5-bromo-6-chloropyrimidine-2,4(1H,3H)-dione (9.4 g, 41.7 mmol) in DMF (100 mL) at room temperature under argon was added K2CO3 (12.7 g, 91.8 mmol), followed by benzyl bromide (10.5 mL, 88.3 mmol). The reaction mixture was stirred at 75° C. for 1.5 h. After the reaction mixture was cooled to room temperature, water (100 mL) and EtOAc (150 mL) were added. The layers were separated. The organic layer was washed with water (50 mL×2), followed by saturated aqueous NaCl (50 mL), then dried (MgSO4) and concentrated at reduced pressure to obtain crude product. This crude product was passed through a bed of silica gel eluted with CH2Cl2 to obtain 16.5 g of the title compound as a white solid. HPLC/MS: retention time=3.818 min, [M+H]30 =405.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.CS(O[CH:22]([CH3:42])[CH2:23][N:24]1[C:32]2[N:31]=[C:30]([NH2:33])[N:29]3[N:34]=[C:35]([C:37]4[O:38][CH:39]=[CH:40][CH:41]=4)[N:36]=[C:28]3[C:27]=2[CH:26]=[CH:25]1)(=O)=O>CN(C=O)C>[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[N:11]1[CH2:12][CH2:13][N:14]([CH:22]([CH3:42])[CH2:23][N:24]2[C:32]3[N:31]=[C:30]([NH2:33])[N:29]4[N:34]=[C:35]([C:37]5[O:38][CH:39]=[CH:40][CH:41]=5)[N:36]=[C:28]4[C:27]=3[CH:26]=[CH:25]2)[CH2:15][CH2:16]1
Reactant: Fc1ccc(N2CCNCC2)c(F)c1
Reactant: CC(Cn1ccc2c1nc(N)n1nc(-c3ccco3)nc21)OS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(Cn1ccc2c1nc(N)n1nc(-c3ccco3)nc21)N1CCN(c2ccc(F)cc2F)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a suspension of NaH (13.0 mg, 60 wt % in mineral oil, 0.3 mmol) in 2.0 mL of anhydrous DMF is added 2,4-difluorophenylpiperazine (63 mg, 0.32 mmol). After stirring the solution at RT for 15 min, a solution of 1-(5-amino-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-7-yl)propan-2-yl methanesulfonate (80 mg, 0.21 mmol) in 1.5 mL of anhydrous DMF is added. The reaction is stirred at RT under N2 for 12 h. However, very little of product formation is seen by LC/MS. The reaction is then heated at 100° C. for 12 h to complete the reaction as detected by LC/MS. The crude reaction mixture is purified by chromatography to afford 7-(2-(4-(2,4-difluorophenyl)piperazin-1-yl)propyl)-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine: 1H NMR (400 MHz, CD2Cl2) δ 1.05 (d, 3H, J=6.83 Hz), 2.62-272 (m, 2H), 2.83-3.05 (m, 8H), 3.13-3.22 (m, 1H), 4.10 (dd, 1H, J=14.06 Hz and 6.64 Hz), 4.27 (dd, 1H, J=13.96 Hz and 7.52 Hz), 6.61 (dd, 1H, J=3.51 Hz and 1.76 Hz), 6.73 (d, 1H, J=3.51 Hz), 6.76-6.96 (m, 4H), 7.00 (d, 1H, J=3.32 Hz), 7.22 (dd, H, J=3.51 Hz and 0.78 Hz), 7.63 (dd, 1H, J=1.76 HZ and 0.78 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[I:16]I.[N+:18]([O-:21])(O)=[O:19].OO>CO>[OH:1][C:2]1[C:3]([N+:18]([O-:21])=[O:19])=[CH:4][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:14][C:15]=1[I:16]
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Reactant: II
Reactant: O=[N+]([O-])O
Agent: OO
Solvent: CO
Product: O=C(c1ccccc1)c1cc(I)c(O)c([N+](=O)[O-])c1
Reaction time: 15 h
Yield: 76 %

Procedure:
A solution of 4-hydroxybenzophenone (1.98 g, 10 mmol), iodine (10.15 g, 40 mmol), and concentrated nitric acid (5 mL) in 100 mL methanol was stirred for 72 hours at room temperature. Hydrogen peroxide, 30% (4.1 mL, 40 mmol) was then added, and the solution was stirred for another 15 hours. The solvent and excess iodine was removed in vacuo, and the crude product was crystallized from methanol, yielding the title compound as bright orange crystals (2.80 g, 76%). 1H NMR (400 MHz, CDCl3): δ 11.70 (s, 1H), 8.61 (d, J=2.4 Hz, 1H), 8.57 (d, J=2.4 Hz, 1H), 7.75 (d, J=8.0 Hz, 2H), 7.67 (t, J=7.4 Hz, 1H), 7.55 (appar. t, J=7.6 Hz, 2H). HPLC (40-90), 12.60 min.