Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH3:30])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([OH:28])=O)[N:9]=2)[CH:7]=1.Cl.[CH3:32][C:33]1([CH3:38])[CH2:37][CH2:36][NH:35][CH2:34]1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH3:30])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:35]3[CH2:36][CH2:37][C:33]([CH3:38])([CH3:32])[CH2:34]3)=[O:28])[N:9]=2)[CH:7]=1
Reactant: CC1(C)CCNC1
Reactant: COc1ccc(Cl)cc1-c1nn(CC(=O)O)cc1NC(=O)c1cnn2cccnc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(Cl)cc1-c1nn(CC(=O)N2CCC(C)(C)C2)cc1NC(=O)c1cnn2cccnc12

Procedure:
To 2-(3-(5-chloro-2-methoxyphenyl)-4-(pyrazolo[1,5-a]pyrimidine-3-carboxamido)-1H-pyrazol-1-yl)acetic acid (31.9 mg, 0.075 mmol) in 1 mL DMF was added 3,3-dimethylpyrrolidine HCl (15 mg, 0.11 mmol) followed by N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (43 mg, 0.11 mmol), then triethylamine (42 uL, 0.30 mmol) and the whole stirred 30 min. The crude mixture was purified by reverse phase HPLC and lyophilized to afford 28.9 mg (76%) as a colorless solid. LCMS (ESI) m+H=508.1. 1H NMR (400 MHz, DMSO) δ 9.72 (s, 1H), 9.34 (d, J=6.9 Hz, 1H), 8.77 (s, 1H), 8.67 (s, 1H), 8.28 (s, 1H), 7.50 (d, J=8.9 Hz, 1H), 7.37 (s, 1H), 7.30 (t, J=9.3 Hz, 2H), 5.09 (d, J=17.8 Hz, 2H), 3.85 (s, 3H), 3.62 (t, J=6.7 Hz, 1H), 3.43 (t, J=7.1 Hz, 1H), 3.29 (s, 1H), 3.12 (s, 1H), 1.74 (t, J=7.0 Hz, 1H), 1.63 (t, J=6.9 Hz, 1H), 1.08 (d, J=9.9 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[NH3:11]>C1COCC1>[NH2:11][C:6]1[C:7]([C:8]#[N:9])=[C:2]([Cl:1])[N:3]=[CH:4][N:5]=1
Reactant: N
Reactant: N#Cc1c(Cl)ncnc1Cl
Solvent: C1CCOC1
Product: N#Cc1c(N)ncnc1Cl
Reaction time: 0.83 h

Procedure:
The white solid, 4,6-dichloropyrimidine-5-carbonitrile (5.82 g, 33.5 mmol) was dissolved in THF (66.9 mL) in a 500 mL round-bottom flask and to the mixture was bubbled through ammonia gas (0.570 g, 33.5 mmol) for 3 min in 10 min intervals with stirring. After 50 min, a white precipitate (ammmonium chloride) was filtered and the solid was washed with THF (100 mL). To the filtrate was added silica gel and concd under reduced pressure. The mixture was purified by silica gel column chromatography on a 120 g of Redi-Sep™ column using 0 to 100% gradient of EtOAc in hexane over 27 min and then 100% isocratic of EtOAc in hexane for 20 min as eluent to give 4-amino-6-chloropyrimidine-5-carbonitrile as an off-white solid. The off-white solid was suspended in EtOAc-hexane (1:1, 20 mL), filtered, washed with EtOAc-hexane (1:1, 30 mL), and dried to give 4-amino-6-chloropyrimidine-5-carbonitrile as a white solid: 1H NMR (500 MHz, DMSO-d6) δ ppm 7.91-8.77 (3 H, m); Mass Spectrum (ESI) m/e=154.9 (M+1).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([F:27])[N:6]([C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1.[N+:28]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])#[C-:29].CC(C)([O-])C.[K+]>C1COCC1>[CH2:34]([O:33][C:31]([CH:30]([N+:28]#[C-:29])[CH2:2][C:3]1[N:4]=[C:5]([F:27])[N:6]([C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1)=[O:32])[CH3:35]
Reactant: Fc1nc(CCl)cn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [C-]#[N+]CC(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: [C-]#[N+]C(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1)C(=O)OCC

Procedure:
Reaction of 4-chloromethyl-2-fluoro-1-triphenylmethylimidazole with ethyl isocyanoacetate/potassium t-butoxide in THF followed by chromatography on silica gel gave 4-(2-ethoxycarbonyl-2-isocyanoethyl)-2-fluoro-1-triphenylmethylimidazole having the following n.m.r. in CDCl3 : 1.24 (t, 2H); 2.7-3.17 (d, 2H); 4.18 (q, 1H); 4.5 (dd, 1H); 6.4 (s, 1H); 7.0-7.4 (m, 15H).
Reaction SMILES: C[O:2][C:3]([C:5]1([NH:14][C:15]([C:17]2[C:18]3[CH2:19][CH2:20][C:21]([CH3:31])([CH3:30])[C:22]=3[CH:23]=[C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:25]=2)=[O:16])[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].[OH-].[K+].O>CCO>[C:26]([C:24]1[CH:25]=[C:17]([C:15]([NH:14][C:5]2([C:3]([OH:4])=[O:2])[CH2:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:13]2)=[O:16])[C:18]2[CH2:19][CH2:20][C:21]([CH3:31])([CH3:30])[C:22]=2[CH:23]=1)([CH3:27])([CH3:28])[CH3:29]
Reactant: COC(=O)C1(NC(=O)c2cc(C(C)(C)C)cc3c2CCC3(C)C)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1cc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)c2c(c1)C(C)(C)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
A mixture of 2-[(6-tert-butyl-1,1-dimethyl-indane-4-carbonyl)-amino]-indan-2-carboxylic acid methyl ester (600 mg, 1.4 mmol) and KOH (1.8 g, 30.8 mmol) is dissolved in EtOH (25 mL) and water (2 mL) under water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is neutralized with 1N HCl and extracted with EtOAc (3×150 mL), the organic washes are combined and concentrated in vacuo. The residue is purified by preparative HPLC (C18 column 10 micron, gradient elution: 20-100% ACN 0.1% TFA in H2O 0.1% TFA). Product crystallizes out of the collected fractions on standing. Filtration and drying gave pure product as white solid (454 mg, 78%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:33])=[C:11]([CH2:13][O:14][C@@H:15]3[CH2:20][CH2:19][CH2:18][C@H:17]([CH2:21][O:22][C:23]([CH3:32])([CH3:31])[C:24]([O:26]C(C)(C)C)=[O:25])[CH2:16]3)[N:12]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]([CH3:33])=[C:11]([CH2:13][O:14][C@@H:15]3[CH2:20][CH2:19][CH2:18][C@H:17]([CH2:21][O:22][C:23]([CH3:31])([CH3:32])[C:24]([OH:26])=[O:25])[CH2:16]3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: Cc1oc(-c2ccc(F)cc2)nc1CO[C@@H]1CCC[C@H](COC(C)(C)C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1oc(-c2ccc(F)cc2)nc1CO[C@@H]1CCC[C@H](COC(C)(C)C(=O)O)C1
Temperature: 25 °C

Procedure:
0.07 g of tert-butyl 2-{cis-3-[2-(4-fluorophenyl)-5-methyloxazol-4-yl-methoxy]cyclohexylmethoxy}-2-methylpropionate is dissolved in 1 ml of dichloromethane, 1 ml of trifluoroacetic acid is added and the mixture is stirred at room temperature. The reaction is monitored (LCMS), showing complete conversion after 30 minutes. The reaction mixture is extracted with water/dichloromethane and, after removal of the solvent under reduced pressure, purified by preparative HPLC. This gives 0.06 g of the carboxylic acid 2-{cis-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]-cyclohexylmethoxy}-2-methylpropionic acid as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][NH:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]2)=[CH:12][CH:11]=1)=[O:8])[CH3:2].[NH2:24][CH2:25][C@@H:26]([C:28]1[CH:29]=[CH:30][C:31]([OH:39])=[C:32]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[CH:33]=1)[OH:27]>>[OH:27][C@H:26]([C:28]1[CH:29]=[CH:30][C:31]([OH:39])=[C:32]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[CH:33]=1)[CH2:25][NH:24][CH:19]1[CH2:20][CH2:21][N:16]([C:13]2[CH:14]=[CH:15][C:10]([NH:9][C:7]([NH:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:23])=[O:8])=[CH:11][CH:12]=2)[CH2:17][CH2:18]1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Reactant: CCOC(=O)CNC(=O)Nc1ccc(N2CCC(=O)CC2)cc1
Product: CCOC(=O)CNC(=O)Nc1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1

Procedure:
The title compound was prepared from {3-[4-(4-oxo-piperidin-1-yl)-phenyl]-ureido}-acetic acid ethyl ester (which was obtained in Example 366) and N-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 10) according to the procedure of Example 278 as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.20 (t, J=7.1 Hz, 3 H), 1.20–1.40 (m, 2 H), 1.80–1.95 (m, 2 H), 2.50–2.70 (m, 5 H), 2.92 (s, 3 H), 3.40–3.50 (m, 2 H), 3.83 (d, J=5.9 Hz, 2 H), 4.10 (q, J=7.1 Hz, 2 H), 4.47 (dd, J=8.0, 4.3 Hz, 1 H), 6.28 (t, J=5.9 Hz, 1 H), 6.75–6.85 (m, 3 H), 7.00 (dd, J=8.3, 2.0 Hz, 1 H), 7.15–7.25 (m, 3 H), 8.45 (s, 1 H); MS (ES) m/z: 550.5 (MH+); HRMS Calcd. for C25H36N5O7S (MH+): 550.2330. Found: 550.2319.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([N:6]1[CH:14]2[CH:9]([CH2:10][CH2:11][CH2:12][CH2:13]2)[CH2:8][C@H:7]1[C:15]([OH:17])=[O:16])=[O:5])[CH3:3].O=[C:19]([CH2:23][CH2:24][C:25]([OH:27])=[O:26])[C:20]([OH:22])=[O:21].C([BH3-])#N.[Na+]>>[C:20]([CH:19]([NH:1][C@H:2]([C:4]([N:6]1[CH:14]2[CH:9]([CH2:10][CH2:11][CH2:12][CH2:13]2)[CH2:8][C@H:7]1[C:15]([OH:17])=[O:16])=[O:5])[CH3:3])[CH2:23][CH2:24][C:25]([OH:27])=[O:26])([OH:22])=[O:21]
Reactant: O=C(O)CCC(=O)C(=O)O
Reactant: C[C@H](N)C(=O)N1C2CCCCC2C[C@H]1C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Product: C[C@H](NC(CCC(=O)O)C(=O)O)C(=O)N1C2CCCCC2C[C@H]1C(=O)O

Procedure:
As described in Example 5, treat 1-[(S)-alanyl]octahydroindole-2(S)-carboxylic acid (prepared as described in Example 1) and 2-oxoglutaric acid with sodium cyanoborohydride to isolate the title compound.
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[F:13][C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[NH2:16].F[C:22]1[CH:30]=[C:29]([F:31])[C:28]([F:32])=[CH:27][C:23]=1[C:24]([OH:26])=[O:25]>>[F:13][C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[NH:16][C:22]1[CH:30]=[C:29]([F:31])[C:28]([F:32])=[CH:27][C:23]=1[C:24]([OH:26])=[O:25]
Reactant: Nc1ccccc1F
Reactant: O=C(O)c1cc(F)c(F)cc1F
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Product: O=C(O)c1cc(F)c(F)cc1Nc1ccccc1F
Yield: 89.8 %

Procedure:
Using General Method 1, the reaction of 2.5 M solution of n-BuLi in hexanes (21 mL, 53 mmol), diisopropylamine (7.2 mL, 51 mmol), 2-fluoro-aniline (1.6 mL, 17 mmol), and 2,4,5-trifluorobenzoic acid (3.0 g, 17 mmol) provided 4.08 g of the crude title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[C:6]([NH2:11])[CH:7]=[CH:8][CH:9]=2)[C@H:4]([CH3:12])[CH2:3]1.[H][H]>C1(C)C=CC=CC=1.[C].[Pd]>[CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[C:6]([NH2:11])[CH:7]=[CH:8][CH:9]=2)[CH:4]([CH3:12])[CH2:3]1
Reactant: C[C@@H]1CC(C)(C)c2cccc(N)c21
Reactant: [H][H]
Agent: [Pd]
Solvent: Cc1ccccc1
Product: CC1CC(C)(C)c2cccc(N)c21
Reaction time: 1 h

Procedure:
2.88 parts by weight of the recovered palladium-carbon and 0.64 part, by weight of fresh 5% palladium-carbon (E-type, manufactured by N. E. Chemcat Corporation) were charged into an autoclave reaction vessel, and 104.0 parts by weight of (3R)-1,1,3-trimethyl-4-aminoindane (optical purity of 67.0% ee) and 1.5 parts by weight of toluene were added thereto, thereby obtaining a mixture. The reaction vessel was sealed and the gas in the reaction vessel was replaced with nitrogen. While the mixture was stirred, into the reaction vessel was charged hydrogen until the internal pressure of hydrogen in the reaction vessel reached 0.5 MPa, and the mixture was stirred at an internal temperature of 60° C. After 1 hour, the gas in the reaction vessel was replaced with nitrogen, and the mixture was stirred at an internal temperature of 150° C. and an internal pressure of 0.1 MPa for 14 hours, thereby obtaining a reaction mixture. The obtained reaction mixture was cooled and filtered using Celite. The obtained solid was washed with 150 parts by weight of toluene. The washing liquid recovered after washing and the filtrate obtained by filtration were combined to obtain a solution of 244.6 parts by weight of 1,1,3-trimethyl-4-aminoindane in toluene. The combined 1,1,3-trimethyl-4-aminoindane had an optical purity of 0.11% ee and a recovery rate of 98.5%.
Reaction SMILES: C(=O)([O-])[O-:2].[Ca+2:5].[P:6]([O-:10])([O-:9])([OH:8])=[O:7].[Ca+2]>O>[OH2:2].[P:6]([O-:10])([O-:9])([O-:8])=[O:7].[Ca+2:5].[P:6]([O-:10])([O-:9])([O-:8])=[O:7].[Ca+2:5].[Ca+2:5]
Reactant: O=P([O-])([O-])O
Reactant: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Product: O=P([O-])([O-])[O-]

Procedure:
Powdery calcium carbonate and a powdery dihydrate of calcium monohydrogenohosphate are weighed to get a Ca/P ratio of 1.45 to 1.67. The powdery mixture thus prepared is then added pure water at a temperature of 30° C. or higher to obtain an aqueous slurry having a concentration of about 10% by weight. Thereafter, the aqueous slurry is subjected to a rotational attrition by using a ball mill to conduct a mechanochemical reaction of the calcium carbonate with the dihydrate of calcium monohydrogenphosphate. The slurry is then dried completely at 80° C., followed by pulverization to yield a dry powder of calcium phosphate hydrate. The dry powder is calcinated at a temperature ranging from 720° to 1,150° C. for 1-10 hours or more to give calcium phosphate powder, which is molded in a desired shape and is sintered at a certain temperature to obtain a sintered body of calcium phosphate. The calcium phosphate and the sintered body thereof, thus prepared, have an assured biological safety in that the calcium phosphate is free from hemolysis, antigenicity and cytotoxicity.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SC)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[NH:34]1[CH2:39][CH2:38][CH:37]([NH:40][C:41](=[O:43])[CH3:42])[CH2:36][CH2:35]1>>[F:1][C:2]([F:33])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:31])([F:29])[F:30])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:34]4[CH2:39][CH2:38][CH:37]([NH:40][C:41](=[O:43])[CH3:42])[CH2:36][CH2:35]4)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CC(=O)NC1CCNCC1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Product: CC(=O)NC1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)CC1

Procedure:
N-(1-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidin-4-yl)-acetamide was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and N-Piperidin-4-yl-acetamide following General Procedure B.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][CH2:16][C@H:8]3[C:7](=[O:17])[NH:6][C:5]=2[CH:4]=1.Cl.Cl.[CH:20]1([NH:23][C:24](=[O:38])[C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)=[C:27]([CH3:37])[CH:26]=2)[CH2:22][CH2:21]1.[I-].C(C[P+](C)(C)C)#N.C(N(CC)C(C)C)(C)C>C(#N)CC>[CH:20]1([NH:23][C:24](=[O:38])[C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:32][CH2:33][N:34]([CH2:2][C:3]4[CH:12]=[N:11][C:10]5[N:9]6[CH2:13][CH2:14][CH2:15][CH2:16][C@H:8]6[C:7](=[O:17])[NH:6][C:5]=5[CH:4]=4)[CH2:35][CH2:36]3)=[C:27]([CH3:37])[CH:26]=2)[CH2:22][CH2:21]1
Reactant: Cc1cc(C(=O)NC2CC2)ccc1N1CCNCC1
Reactant: O=C1Nc2cc(CO)cnc2N2CCCC[C@@H]12
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)NC2CC2)ccc1N1CCN(Cc2cnc3c(c2)NC(=O)[C@@H]2CCCCN32)CC1
Temperature: 90 °C
Yield: 24.9 %

Procedure:
(S)-3-(hydroxymethyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one (100 mg, 0.429 mmol), N-cyclopropyl-3-methyl-4-(piperazin-1-yl)benzamide dihydrochloride (143 mg, 0.430 mmol), (cyanomethyl)trimethylphosphonium iodide (167 mg, 0.686 mmol) and N,N-diisopropylethylamine (374 μl, 2.143 mmol) were suspended in Propiononitrile (Volume: 1287 μl) and heated in a closed vial at 90° C. for 4 h. The reaction mixture became a dark brown solution. It was cooled to room temperature and purified using HPLC(NH4HCO3 buffered, 20-70% ACN in water). The fractions were concentrated in vacuo and the resulting solid was recrystallized from MeCN (20 mL), filtered off, washed with water (2 mL) and dried in vacuum to afford (S)—N-cyclopropyl-3-methyl-4-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide (50.7 mg, 0.107 mmol, 24.92% yield) as a light brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.49-0.59 (m, 2H) 0.60-0.71 (m, 2H) 1.33-1.57 (m, 3H) 1.64 (d, J=12.88 Hz, 1H) 1.85 (d, J=12.63 Hz, 1H) 2.04 (d, J=12.88 Hz, 1H) 2.25 (s, 3H) 2.42-2.56 (m, 4H) 2.60 (td, J=12.63, 2.78 Hz, 1H) 2.76-2.93 (m, 5H) 3.38 (s, 2H) 3.84 (dd, J=11.37, 2.78 Hz, 1H) 4.50 (d, J=13.14 Hz, 1H) 6.98 (d, J=2.02 Hz, 1H) 7.00 (d, J=8.34 Hz, 1H) 7.56-7.63 (m, 2H) 7.66 (d, J=2.02 Hz, 1H) 8.22 (d, J=4.29 Hz, 1H) 10.49 (s, 1H); [M+H] calc'd for C27H34N6O2, 475; found, 475.
Reaction SMILES: [C:1]1([C:7]2[C:8](=O)[O:9][C:10](=[O:12])[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[NH2:15][NH2:16]>C(O)C>[C:1]1([C:7]2[C:8](=[O:9])[NH:15][NH:16][C:10](=[O:12])[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NN
Reactant: O=C1C=C(c2ccccc2)C(=O)O1
Solvent: O
Solvent: CCO
Product: O=c1cc(-c2ccccc2)c(=O)[nH][nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.1 %

Procedure:
4.0 g (23 mmole) of 3-phenylfuran-2,5-dione was added to a 100 ml single-necked round bottom flask followed by 2.9 g (27.6 mmole) of hydrazine monohydrate and then 20 ml of reagent grade ethanol (95%). The flask was fitted with a reflux condenser and the reaction mixture was heated to reflux in an oil bath at 110 degree (temperature of oil bath) and stirred for 2 h. The flask was then removed from the oil bath and the reaction mixture cooled to ambient temperature. The stir bar was removed and the solvent was evaporated in vacuo in a water bath at 45 degree. The residue was then treated with 50 ml of Milli-Q water and stirred for 10 minutes to give a suspension. The precipitate was collected by filtering, washed with 100 ml of Milli-Q water, and dried over a medium frit sintered glass funnel in vacuo to give 3.9 g of white solid. Yield, 91%, confirmed by ESI-MS. ESI-MS: m/z 189.2 (M+H+).
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([C:7](=[O:13])[CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:3][CH:2]=1.C(N(CC)CC)C.Br[CH:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:30](=[O:31])[O:29]1>C(Cl)(Cl)Cl>[C:1]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:2]=[CH:3][C:4]([C:7](=[O:13])[CH2:8][CH2:9][C:10]([O:12][CH:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:30](=[O:31])[O:29]2)=[O:11])=[CH:5][CH:6]=1
Reactant: O=C1OC(Br)c2ccccc21
Reactant: O=C(O)CCC(=O)c1ccc(-c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(CCC(=O)c1ccc(-c2ccccc2)cc1)OC1OC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 73 %

Procedure:
To a solution of 7.5 g of 4-(4-biphenylyl)-4-oxobutyric acid in 40 ml of chloroform and 3.4 g of triethylamine is added a solution of 6.2 g of 3-bromophthalide in 20 ml of chloroform. The solution thus obtained is stirred 24 hours at room temperature, the organic phase is washed with an aqueous solution of sodium bicarbonate, then with water and finally it is dried on anhydrous sodium sulfate and evaporated to dryness to give the phthalidyl 4-(4-biphenylyl)-4-oxobutyrate; yield 73%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N:15]2[CH:19]=[C:18]([F:20])[C:17]([F:21])=[CH:16]2)[CH:12]=[CH:11][C:10]=1[NH:22][N:23]=[C:24]([C:29](=[O:33])[CH2:30][O:31][CH3:32])[C:25]([O:27][CH3:28])=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34]OC(OC)N(C)C>>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N:15]2[CH:19]=[C:18]([F:20])[C:17]([F:21])=[CH:16]2)[CH:12]=[CH:11][C:10]=1[N:22]1[CH:34]=[C:30]([O:31][CH3:32])[C:29](=[O:33])[C:24]([C:25]([O:27][CH3:28])=[O:26])=[N:23]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(OC)N(C)C
Reactant: COCC(=O)C(=NNc1ccc(-n2cc(F)c(F)c2)cc1OCc1ccccc1)C(=O)OC
Product: COC(=O)c1nn(-c2ccc(-n3cc(F)c(F)c3)cc2OCc2ccccc2)cc(OC)c1=O
Temperature: 25 °C

Procedure:
A mixture of methyl 2-{[2-(benzyloxy)-4-(3,4-difluoro-1H-pyrrol-1-yl)phenyl]hydrazono}-4-methoxy-3-oxobutanoate (4.85 g) and N,N-dimethylformamide dimethyl acetal (100 mL) was heated under reflux for 3 hr. The mixture was allowed to be cooled to room temperature, and the precipitate was collected by filtration, and recrystallized from methanol to give the title compound (4.57 g).
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([CH3:19])[CH:17]=2)[NH:12][CH:11]=1.[C:20]1(=O)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(#N)C>[CH:20]1([NH:8][C:6]2[CH:5]=[CH:4][C:3]([CH2:9][C:10]3[C:18]4[C:13](=[N:14][CH:15]=[C:16]([CH3:19])[CH:17]=4)[NH:12][CH:11]=3)=[C:2]([F:1])[N:7]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C1CCCCC1
Reactant: Cc1cnc2[nH]cc(Cc3ccc(N)nc3F)c2c1
Agent: CC[SiH](CC)CC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: Cc1cnc2[nH]cc(Cc3ccc(NC4CCCCC4)nc3F)c2c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 87.1 %

Procedure:
To 6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamine (49, 100 mg, 0.39 mmol) and cyclohexanone (67, 0.0465 mL, 0.449 mmol) in 3.00 mL of acetonitrile, triethylsilane (0.400 mL, 2.50 mmol) and trifluoroacetic acid (0.300 mL, 3.89 mmol) were added. The reaction was stirred at 80° C. overnight, then extracting with ethyl acetate and 1N aqueous sodium bicarbonate. The organic layer was washed with brine, dried with magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography, eluting with 0-60% ethyl acetate in hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound (P-3008, 115 mg). MS (ESI) [M+H+]+=339.0.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@@H:16]([C:18]([NH:20][C@@H:21]([C:38]([OH:40])=[O:39])[CH2:22][CH2:23][C:24]([N:26]1[CH:34]2[CH:29]([CH2:30][CH2:31][CH2:32][CH2:33]2)[CH2:28][CH:27]1[C:35]([OH:37])=[O:36])=[O:25])=[O:19])[NH2:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:47][O:48][C:49]1[CH:63]=[CH:62][CH:61]=[CH:60][C:50]=1[CH2:51][O:52]N1C(=O)CCC1=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O.C1COCC1>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@@H:16]([C:18]([NH:20][C@@H:21]([C:38]([OH:40])=[O:39])[CH2:22][CH2:23][C:24]([N:26]1[C@@H:34]2[C@@H:29]([CH2:30][CH2:31][CH2:32][CH2:33]2)[CH2:28][C@H:27]1[C:35]([OH:37])=[O:36])=[O:25])=[O:19])[NH:17][C:51](=[O:52])[C:50]1[CH:60]=[CH:61][CH:62]=[CH:63][C:49]=1[O:48][CH3:47])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)N[C@H](CCC(=O)N1C(C(=O)O)CC2CCCCC21)C(=O)O
Reactant: COc1ccccc1CON1C(=O)CCC1=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccccc1C(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)N[C@H](CCC(=O)N1[C@H](C(=O)O)C[C@@H]2CCCC[C@@H]21)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(2S,3aS,7aS)-1-(N6 -benzyloxycarbonyl-L-lysyl-gamma-D-glutamyloctahydro-1H-indole-2carboxylic acid was dissolved in 6 ml of water, and sodium carbonate and 10 ml of THF were added. With vigorous stirring, N-(2-methoxybenzyloxy)succinimide was added. The mixture was stirred overnight at room temperature. The reaction mixture was acidified with 10% citric acid, and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was chromatographed on a column of CHP20P using acetonitrile/water (30%→70% gradient) as an eluent. Fractions containing the desired product were concentrated to dryness under reduced pressure to give 1.0 g of (2S,3aS,7aS)-1-[N6 -benzyloxycarbonyl-N2 -(2-methoxybenzoyl)-L-lysyl-gamma-D-glutamyl]octahydro-1H-indole-2-carboxylic acid.