Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C@@H:3]([C@@H:21]1[CH2:25][CH2:24][CH2:23][N:22]1[C:26](=[O:45])[CH2:27][C@@H:28]([O:43][CH3:44])[C@@H:29]([N:34]([CH3:42])[C:35](=[O:41])[C@H:36]([CH:38]([CH3:40])[CH3:39])[NH2:37])[C@@H:30]([CH3:33])[CH2:31][CH3:32])[C@@H:4]([CH3:20])[C:5]([NH:7][C@H:8]([C:16]([O:18][CH3:19])=[O:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:6].C1C2C(COC([NH:63][C@:64]([C:69](O)=[O:70])([CH3:68])[CH:65]([CH3:67])[CH3:66])=O)C3C(=CC=CC=3)C=2C=CC=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(NCC)C>ClCCl>[CH3:66][CH:65]([CH3:67])[C@@:64]([C:69]([NH:37][C@H:36]([C:35]([N:34]([C@@H:29]([C@@H:30]([CH3:33])[CH2:31][CH3:32])[C@H:28]([O:43][CH3:44])[CH2:27][C:26]([N:22]1[CH2:23][CH2:24][CH2:25][C@H:21]1[C@H:3]([O:2][CH3:1])[C@@H:4]([CH3:20])[C:5]([NH:7][C@@H:8]([CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:16]([O:18][CH3:19])=[O:17])=[O:6])=[O:45])[CH3:42])=[O:41])[CH:38]([CH3:39])[CH3:40])=[O:70])([CH3:68])[NH2:63]
Reactant: CC(C)[C@@](C)(NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC)OC)N(C)C(=O)[C@@H](N)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCNCC
Solvent: ClCCl
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC)OC)N(C)C(=O)[C@@H](NC(=O)[C@](C)(N)C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 81.8 %

Procedure:
A solution of #114 (224 mg, 0.354 mmol, 1.0 eq.) in 2 mL of dichloromethane was added to a solution of N-[(9H-fluoren-9-ylmethoxy)carbonyl]-3-methyl-L-isovaline (125 mg, 0.354 mmol, 1.0 eq.) in 4 mL of dichloromethane. Hunig's base (0.187 mL, 1.06 mmol, 3.0 eq.) was added followed by HATU (167 mg, 0.425 mmol, 1.2 eq.). The reaction was allowed to stir at room temperature for 12 hours. The reaction was concentrated in vacuo and then taken up in ethyl acetate before being washed two times with 1M HCl and once with brine. The organic layer was dried over sodium sulfate and decanted. The organic solvent was removed in a genevac. THF (4 mL) was added followed diethylamine (2 mL, 19 mmol, 53.7 eq.). The reaction was allowed to stir for ˜12 hours. Reaction was concentrated using a genevac followed by silica chromatography (Gradient: 0%-30% methanol in ethyl acetate) producing #147 (216 mg, 82%) as a solid. LC-MS (Protocol Q): m/z 746.6 [M+H+] retention time=1.29 minutes. 1H NMR (400 MHz, DMSO-d6), δ 8.56 (m), 8.31-8.39 (m), 8.50 (d), 8.30 (br d), 7.87-8.01 (m), 7.80 (d), 7.40-7.53 (m), 7.14-7.30 (m), 4.45-4.78 (m), 3.94-4.04 (m), 3.70-3.79 (m), 3.61-3.69 (m), 3.42-3.59 (m), 2.97-3.37 (m), 2.80-2.92 (m), 2.32-2.49 (m), 2.05-2.30 (m), 1.61-1.89 (m), 1.37-1.56 (m), 1.14-1.135 (m), 0.70-1.11 (m).
Reaction SMILES: [OH-].[Li+].C[O:4][C:5](=[O:34])[C:6]1[CH:11]=[CH:10][N:9]=[C:8]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[C:23]([OH:30])[C:22]=3[CH2:31][CH2:32][CH3:33])[CH:14]=2)[CH:7]=1.O.Cl>O1CCCC1>[C:27]([C:24]1[CH:25]=[CH:26][C:21]([O:20][CH2:19][C:15]2[CH:14]=[C:13]([NH:12][C:8]3[CH:7]=[C:6]([CH:11]=[CH:10][N:9]=3)[C:5]([OH:34])=[O:4])[CH:18]=[CH:17][CH:16]=2)=[C:22]([CH2:31][CH2:32][CH3:33])[C:23]=1[OH:30])(=[O:29])[CH3:28]
Reactant: CCCc1c(OCc2cccc(Nc3cc(C(=O)OC)ccn3)c2)ccc(C(C)=O)c1O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCc1c(OCc2cccc(Nc3cc(C(=O)O)ccn3)c2)ccc(C(C)=O)c1O
Temperature: 80 °C
Reaction time: 1 h
Yield: 21.6 %

Procedure:
Add 1M aqueous lithium hydroxide (2.14 mL, 2.14 mmol) to a solution of 2-[3-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenylamino]-isonicotinic acid methyl ester (282 mg, 0.649 mmol) in tetrahydrofuran (20 mL):water (20 mL) and stir. Heat to 80° C. After 1 hour, pour reaction into 1N aqueous hydrochloric acid (50 mL) and filter the resulting precipitate to yield the title compound as a yellow solid (59 mg, 22%): 1H NMR (DMSO-d6) δ 0.86 (t, 3H), 1.52 (sextet, 2H), 2.57 (s, 3H), 2.63 (t, 2H), 5.25 (s, 2H), 6.72 (d, 1H), 6.99 (d, 1H), 7.13 (d, 1H), 7.30 (t, 1H), 7.37 (s, 1H), 7.56 (d, 1H), 7.80 (d, 1H), 7.91 (s, 1H), 8.28 (d, 1H), 9.37 (s, 1H), 12.85 (s, 1H), 13.44 (bs, 1H); MS (esi negative) m/z (rel intensity) 419 (100).
Reaction SMILES: [OH-].[Na+].CN([CH2:6][C:7]1[C:11]2[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:10]=2[NH:9][CH:8]=1)C.C([O:19][C:20](=[O:26])[CH2:21][NH:22]C(=O)C)C.CNC>C1(C)C(C)=CC=CC=1>[Cl:16][C:14]1[CH:15]=[C:10]2[C:11](=[CH:12][CH:13]=1)[C:7]([CH2:6][C@@H:21]([C:20]([OH:26])=[O:19])[NH2:22])=[CH:8][NH:9]2
Reactant: CN(C)Cc1c[nH]c2cc(Cl)ccc12
Reactant: CCOC(=O)CNC(C)=O
Agent: CNC
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Product: N[C@@H](Cc1c[nH]c2cc(Cl)ccc12)C(=O)O
Temperature: 90 °C
Reaction time: 12 h
Yield: 84 %

Procedure:
Under inert atmosphere and rapid stirring 52 mg of NaOH are pulverized into anhydrous xylene (20 ml), heating the suspension at approximately 90° C. 550 mg of 6-chlorogramine (prepared as described in example 1) and 460 mg of ethyl-acetamido-acetate are then added. The mixture is refluxed for approximately 7 hours and the development of dimethylamine, extremely vigorous at the start of the heating, practically ceases after about 6 hours of heating. The reaction mixture is cooled for 12 hours at 5° C. and then filtered to recover the abundant precipitate. This crude solid is treated with a hot solution of benzene/absolute ethanol, and the insoluble material is hot-filtered. The solution is left to rest at 5° C. for 12 hours. Crystals slowly separate, which are filtered and dried. 750 mg of ethyl-α-acetamido-α-cyano-β-(6-chloro-indole-3-yl)-propioanate are recovered, with a yield of 84%. 600 mg of this compound are added to 15 ml of water, containing 40 mg of NaOH and the mixture is boiled for 24 hours. During this time the solid material dissolves and ammonia is developed. After the reflux time, the reaction mixture is cooled at room temperature and neutralized with acetic acid at 50%. It is filtered, recovering and washing with cold water the solid which has formed. After drying 410 mg of 6-chloro-DL-tryptophan are recovered, with a yield of 95%.
Reaction SMILES: O=[C:2]([N:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1)[CH2:3][N:4]([CH2:33][C:34]([N:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1)=O)[C:5]1[C:18]2[O:17][CH2:16][CH2:15][N:14]3[C:10](=[C:11]([CH:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)[C:12]4[CH:22]=[CH:21][C:20]([C:23]([O:25][CH3:26])=[O:24])=[CH:19][C:13]=43)[C:9]=2[CH:8]=[CH:7][CH:6]=1.Cl.[OH-].[Na+].C(=O)([O-])O.[Na+]>O1CCCC1>[N:36]1([CH2:34][CH2:33][N:4]([CH2:3][CH2:2][N:42]2[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47]2)[C:5]2[C:18]3[O:17][CH2:16][CH2:15][N:14]4[C:10](=[C:11]([CH:27]5[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]5)[C:12]5[CH:22]=[CH:21][C:20]([C:23]([O:25][CH3:26])=[O:24])=[CH:19][C:13]=54)[C:9]=3[CH:8]=[CH:7][CH:6]=2)[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCOc1c-3cccc1N(CC(=O)N1CCCCC1)CC(=O)N1CCCCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCOc1c-3cccc1N(CCN1CCCCC1)CCN1CCCCC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 83.9 %

Procedure:
To a solution of methyl 4-{bis[2-oxo-2-(piperidin-1-yl)ethyl]amino}-12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylate (500 mg, 0.78 mmol) in tetrahydrofuran (2.0 ml) was added a solution (5.0 ml) of 1M BH3 THF complex in tetrahydrofuran, and the mixture was stirred at room temperature for 14 hr. 2N Hydrochloric acid was added to the reaction mixture, and the mixture was stirred at 70° C. for 4 hr. The reaction mixture was allowed to cool to room temperature, neutralized with 4N aqueous sodium hydroxide solution and saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (chloroform:methanol-10:1-5:1) to give methyl 4-{bis[2-(piperidin-1-yl)ethyl]amino}-12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylate (401 mg, yield 84%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C@H:9]2[CH:14]([CH3:16])[CH3:15])[N:5]=[C:4]([NH2:17])[N:3]=1.[C:18]([C:20]1[C:25]([F:26])=[CH:24][C:23](B(O)O)=[CH:22][C:21]=1[F:30])#[N:19].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.O1CCOCC1>[NH2:17][C:4]1[N:3]=[C:2]([C:23]2[CH:24]=[C:25]([F:26])[C:20]([C:18]#[N:19])=[C:21]([F:30])[CH:22]=2)[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C@H:9]2[CH:14]([CH3:16])[CH3:15])[N:5]=1
Reactant: CC(C)[C@@H]1COCCN1c1cc(Cl)nc(N)n1
Reactant: N#Cc1c(F)cc(B(O)O)cc1F
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CC(C)[C@@H]1COCCN1c1cc(-c2cc(F)c(C#N)c(F)c2)nc(N)n1
Temperature: 100 °C
Yield: 88.4 %

Procedure:
4-Chloro-6-[(3R)-3-(1-methylethyl)-4-morpholinyl]-2-pyrimidinamine (2.36 g, 9.19 mmol), (4-cyano-3,5-difluorophenyl)boronic acid (2.52 g, 13.19 mmol, 1.5 equiv), tricyclohexylphosphine (0.39 g, 1.38 mmol, 0.15 equiv), Pd2(dba)3 (0.63 g, 0.69 mmol, 0.075 equiv), and K3PO4 (3.32 g, 15.63 mmol, 1.7 equiv) were charged into a 250 mL RB flask, followed by addition of 1,4-dioxane (30 mL) and water (10 mL). The mixture was degassed and back flushed with nitrogen, which was repeated five times. The mixture was heated in an oil bath at 100° C. for 20 hours. LCMS showed conversion complete. The mixture was filtered through celite and rinsed with EtOAc (100 mL). The filtrate was concentrated in vacuo. The residue was partitioned between EtOAc (200 mL) and brine (50 mL). The organic was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography using gradient elution of 1% EtOAc in CHCl3 to 100% EtOAc, providing the title compound (2.92 g) as a yellowish foam. LC-MS (ES) m/z=360 [M+H]+.
Reaction SMILES: Cl[C:2]1(Cl)[C:9](=[O:10])[CH2:8][CH:7]2[CH:3]1[CH2:4][CH2:5][CH:6]2[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][Si](C(C)(C)C)(C)C.CCOCC>C(O)(=O)C.[Zn]>[OH:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH:6]1[CH2:5][CH2:4][CH:3]2[CH:7]1[CH2:8][C:9](=[O:10])[CH2:2]2
Reactant: CC(C)(C)[Si](C)(C)OCCCCCC1CCC2C1CC(=O)C2(Cl)Cl
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCOCC
Product: O=C1CC2CCC(CCCCCO)C2C1
Temperature: 70 °C

Procedure:
The starting material, 6,6-dichloro-2-(5-[(1,1-dimethylethyl)dimethylsiloxy]pent-1-yl)bicyclo[3.3.0]octan-7-one {1,1-dichloro-4-[5-[[(1,1-dimethylethyl)dimethylsilyl]oxy]pentyl]hexahydro-2(1H)-pentalenone}(12.1 g, 0.30 moles) is dissolved in glacial acetic acid (85 ml) and the solution is stirred while zinc (25 g) is slowly added. The reaction is heated at 70° C. for 1 hour, after which time ether (100 ml) is added and the solution filtered. The filtrate is washed with brine and then neutralized with saturated sodium bicarbonate. The ether layer is separated and dried over anhydrous sodium sulfate. The solvent is removed under vacuum leaving a clear yellow oil. The crude product is chromatographed on silica gel and subsequently kugelrohred under vacuum leaving a clear, colorless oil (0.72 g, 3.4 mmoles).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]2[N:19]3[CH2:20][CH2:21][CH2:22][CH:23]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=4)[C:18]3=[N:17][N:16]=2)[CH:6]=[CH:7][C:8]=1[C:9]1[O:13][C:12]([CH3:14])=[N:11][CH:10]=1.[H-].[Na+].[CH3:36]I.O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]2[N:19]3[CH2:20][CH2:21][CH2:22][C:23]([CH3:36])([C:24]4[CH:25]=[CH:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=4)[C:18]3=[N:17][N:16]=2)[CH:6]=[CH:7][C:8]=1[C:9]1[O:13][C:12]([CH3:14])=[N:11][CH:10]=1
Reactant: CI
Reactant: COc1cc(-c2nnc3n2CCCC3c2ccc(C(F)(F)F)cc2)ccc1-c1cnc(C)o1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(-c2nnc3n2CCCC3(C)c2ccc(C(F)(F)F)cc2)ccc1-c1cnc(C)o1
Reaction time: 0.5 h

Procedure:
To a mixture of 3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-8-[4-(trifluoromethyl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine (175 mg) in DMF (1.8 mL) was added sodium hydride (600, 17.2 mg) at 0° C., and the mixture was stirred for 30 min. Methyl iodide (0.0446 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was 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 (32.2 mg).
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.[NH:22]1[CH2:26][CH2:25][CH2:24][CH:23]1[C:27]([O:29][CH3:30])=[O:28].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:30][O:29][C:27]([CH:23]1[CH2:24][CH2:25][CH2:26][N:22]1[C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])=[O:28]
Reactant: COC(=O)C1CCCN1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCCN1C(=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 methyl pyrrolidine-2-carboxylate hydrochloride (79397-50-5) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=396.5 [MH+].
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[S:16][C:15]3[C:10](=[N:11][CH:12]=[CH:13][C:14]=3[O:17][C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=3[F:25])[CH:9]=2)[N:5]=[CH:4]1)[CH3:2].C(N1C=C(C2SC3C(=NC=CC=3OC3C=CC(NC(NC(=O)CC4C=CC=CC=4F)=S)=CC=3F)C=2)N=C1)C.[CH3:64][O:65][C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][C:67]=1[CH2:72][C:73]([N:75]=[C:76]=[S:77])=[O:74]>>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[S:16][C:15]3[C:10](=[N:11][CH:12]=[CH:13][C:14]=3[O:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:76]([NH:75][C:73](=[O:74])[CH2:72][C:67]4[CH:68]=[CH:69][CH:70]=[CH:71][C:66]=4[O:65][CH3:64])=[S:77])=[CH:20][C:19]=3[F:25])[CH:9]=2)[N:5]=[CH:4]1)[CH3:2]
Reactant: CCn1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)c1
Reactant: COc1ccccc1CC(=O)N=C=S
Agent: CCn1cnc(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5F)cc4F)c3s2)c1
Product: CCn1cnc(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5OC)cc4F)c3s2)c1
Yield: 82 %

Procedure:
Starting from the compound 308, following the procedure described above for the synthesis of 310a but replacing 2-(2-fluorophenyl)acetyl isothiocyanate with (2-methoxy-phenyl)-acetyl isothiocyanate, title compound 310b was obtained in 82% yield. 1H NMR (DMSO-d6) δ (ppm): 12.57 (s, 1H), 11.76 (s, 1H), 8.45 (d, J=5.5 Hz, 1H), 8.07 (m, 1H), 7.96 (d, J=1 Hz, 1H), 7.79 (d, J=1 Hz, 1H), 7.69 (s, 1H), 7.6 (m, 2H), 7.26 (m, 2H), 7.0 (d, J=7.4 Hz, 1H), 6.92 (m, 1H), 6.59 (d, J=5.5 Hz, 1H), 4.06 (q, J=7.5 Hz, 2H), 3.82 (s, 2H), 3.79 (s, 3H), 1.4 (t, J=7.4 Hz, 3H). MS (m/z): 562.0 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:32]=[C:31]([N+:33]([O-])=O)[CH:30]=[CH:29][C:5]=1[O:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[N:8]=1)([O-])=O.[H][H]>O1CCCC1.[Pd]>[NH2:1][C:4]1[CH:32]=[C:31]([NH2:33])[CH:30]=[CH:29][C:5]=1[O:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[N:8]=1
Reactant: CCCCCCCCCCCCCCCCc1ncnc(Oc2ccc([N+](=O)[O-])cc2[N+](=O)[O-])n1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCc1ncnc(Oc2ccc(N)cc2N)n1

Procedure:
14.5 g of 2,4-dinitrophenoxy-6-hexadecyl-1,3,5-triazine prepared in Preparative Example 2 was dissolved in 300 ml of tetrahydrofuran, and then 1.4 g of Pd/C was added thereto. Hydrogen gas at 50 psi was fed to the mixture, and then reacted at 60° C. for 12 hours. After the reaction, the reaction mixture was filtered to remove palladium, and evaporated under reduced pressure to obtain a crude product. The crude product was recrystallized to afford pure 2,4-diaminophenoxy-6-hexadecyl-1,3,5-triazine as a white solid. The final product was relatively stable under ambient conditions. The structure of the final product was identified through 1H-NMR spectrum, and the differential scanning calorimetry (DSC) was performed (see, FIGS. 1 and 2).
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]3[CH:21]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([N:31]([CH3:39])[CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])=[O:30])=[CH:25][CH:24]=1>>[CH:1]1([CH:7]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]([N:31]([CH3:39])[CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:30])=[CH:27][CH:28]=2)[C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]3[CH:21]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC(c1cn2cc(C(F)(F)F)ccc2n1)C1CCCCC1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Product: CN(CCC(=O)O)C(=O)c1ccc(NC(c2cn3cc(C(F)(F)F)ccc3n2)C2CCCCC2)cc1
Yield: 0.2 %

Procedure:
Using cyclohexyl[6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]methanol (1.1 g) synthesized above and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (0.94 g) synthesized in Example 2(2) and in the same manner as in Example 4, the title object compound (3.0 mg, 2%) was obtained as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([NH:14]CC2C=CC=CC=2)[C@H:10]([F:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([NH2:14])[C@H:10]([F:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](NCc2ccccc2)[C@H](F)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@H](N)[C@H](F)C1
Yield: 85.9 %

Procedure:
A mixture of (+/−)-(cis)-tert-butyl-4-(benzylamino)-3-fluoropiperidine-1-carboxylate (100 mg, 0.32 mmol) and 10% Pd/C (10 mg) in methanol (20 mL) was stirred under a balloon of hydrogen for 2 h at room temperature. The reaction mixture was purged with argon, filtered over Celite, rinsed with methanol (10 mL) and the resulting filtrate was concentrated under vacuum to give the title compound as a colorless oil (60 mg, 85%). 1H-NMR (400 MHz, CDCl3) δ ppm: 4.49-4.61 (d, J=48.4 Hz, 1H), 4.30 (s, 1H), 4.07 (s, 1H), 2.84-3.08 (m, 3H), 1.67-1.69 (m, 2H), 1.47 (s, 9H), 1.32 (s, 2H). 19F-NMR (400 MHz in CDCl3): δ ppm: −205.75-206.03 (1F).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:24])=[CH:5][C:6]([Cl:23])=[C:7]([C:9]2[NH:10][C:11](=[O:22])[N:12]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([Cl:21])[CH:15]=3)[N:13]=2)[CH:8]=1.[C:25](Cl)(=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27]>C1COCC1>[Cl:23][C:6]1[C:7]([C:9]2[NH:10][C:11](=[O:22])[N:12]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([Cl:21])[CH:15]=3)[N:13]=2)=[CH:8][C:3]([CH2:2][NH:1][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[C:4]([F:24])[CH:5]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1ccc(-n2nc(-c3cc(CN)c(F)cc3Cl)[nH]c2=O)cc1Cl
Solvent: C1CCOC1
Product: Cc1ccc(-n2nc(-c3cc(CNC(=O)C(C)(C)C)c(F)cc3Cl)[nH]c2=O)cc1Cl

Procedure:
The title compound was prepared according to the procedure described in Example-108 by using 5-(5-(aminomethyl)-2-chloro-4-fluorophenyl)-2-(3-chloro-4-methylphenyl)-2H-1,2,4-triazol-3(4H)-one (Intermediate-88, 0.200 g), pivaloyl chloride (0.5 mL), TEA (2.0 mL), dry THF (5 mL) to afford 0.074 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 1.11 (s, 9H), 2.32 (s, 3H), 4.29 (d, J=8.8 Hz, 2H), 7.43 (d, J=11.6 Hz, 1H), 7.60-7.67 (m, 1H), 7.79 (d, J=10.4 Hz, 1H), 7.96 (s, 1H), 8.15 (m, 1H), 12.60 (s, 1H); MS (m/z): 451.52 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][N:6]=[C:5]2[Cl:13].[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([CH3:23])=[C:19]([CH:22]=1)[CH2:20][NH2:21].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>CC(N(C)C)=O.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:13][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:21][CH2:20][C:19]3[CH:22]=[C:15]([Cl:14])[CH:16]=[CH:17][C:18]=3[CH3:23])[CH:3]=2)[C:8](=[O:12])[NH:7][N:6]=1
Reactant: O=c1[nH]nc(Cl)c2cc(Br)ccc12
Reactant: Cc1ccc(Cl)cc1CN
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: Cc1ccc(Cl)cc1CNc1ccc2c(=O)[nH]nc(Cl)c2c1

Procedure:
A mixture 6-bromo-4-chloro-2H-phthalazin-1-one (150 mg, 0.58 mmol), 5-chloro-2-methyl-benzylamine (100 mg, 0.64 mmol), Pd2(dba)3 (53 mg, 0.058 mmol), rac-BINAP (132 mg, 0.17 mmol) and NaOt-Bu (140 mg, 1.45 mmol) in DMA (6 mL) was heated at 80° C. for 1 h. The mixture was allowed to cool, diluted with EtOAc (25 mL) and washed with water (25 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. Chromatography on silica (EtOAc/hexanes) yielded the title compound. 4-Chloro-6-(5-chloro-2-methyl-benzylamino)-2H-phthalazin-1-one: 20 mg (10.3%): m/z (M+H)=334. 1H-NMR (DMSO-d6) δ: 12.63 (s, 1H), 8.21 (d, 1H), 7.78 (m, 1H), 7.56 (m, 1H), 7.50 (m, 2H), 7.42 (dd, 1H), 7.10 (s, 1H), 4.66 (d, 2H), 2.60 (s, 3H).
Reaction SMILES: [BH4-].[Na+].[N:3]1[CH:8]=[C:7]([C:9]([CH:11]([CH3:13])[CH3:12])=[O:10])[CH:6]=[N:5][CH:4]=1>O.CO>[OH:10][CH:9]([C:7]1[CH:6]=[N:5][CH:4]=[N:3][CH:8]=1)[CH:11]([CH3:13])[CH3:12]
Reactant: CC(C)C(=O)c1cncnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)C(O)c1cncnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
1.27 g (0.034 mole) of sodium borohydride in 10 ml of water are added to 15 g (0.1 mole) of isopropyl 5-pyrimidinyl ketone in 100 ml of methanol at room temperature. The reaction mixture is subsequently stirred at room temperature for 1 hour and is concentrated in vacuo, the residue is taken up in methylene chloride and the mixture is concentrated again in vacuo. 15.1 g (99.3% of theory) of 5-(1-hydroxy-2-methyl-propyl)-pyrimidine of refractive index nD20 =1.5082 are obtained.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[N:55]([C:58]1[CH:59]=[N:60][CH:61]=[CH:62][CH:63]=1)=[C:56]=[O:57]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:56]([NH:55][C:58]2[CH:59]=[N:60][CH:61]=[CH:62][CH:63]=2)=[O:57])[CH2:49][CH2:48]1
Reactant: O=C=Nc1cccnc1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CCN(C(=O)Nc2cccnc2)CC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 46 %

Procedure:
The desired compound was prepared according to the procedure of Example A9, step H using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 3-isocyanatopyridine as starting materials in 46% yield. 1H NMR (300 MHz, DMSO-d6): δ 10.00 (s, 1H), 9.41 (m, 2H), 9.24 (s, 1H), 8.98 (s, 2H), 8.40 (m, 1H), 8.30 (m, 3H), 8.20 (s, 1H), 7.72 (m, 1H), 7.65 (s, 1H), 7.30 (d, 1H), 7.05 (d, 1H), 4.15 (m, 2H), 2.98 (m, 6H), 2.32 (m, 2H), 2.12 (m, 1H), 1.80 (m, 2H), 1.20 (m, 2H). LCMS for C30H31ClN9O2 (M+H)+: m/z=584.2.