Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[OH:23])[N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[OH:31][C@H:32]([CH2:36][CH3:37])[C:33](O)=[O:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[OH:31][C@H:32]([CH2:36][CH3:37])[C:33]([N:4]1[CH2:3][CH2:2][N:1]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[OH:23])[N:8]=2)[CH2:6][CH2:5]1)=[O:34]
Reactant: Oc1ccccc1-c1nc(N2CCNCC2)c2ccccc2n1
Reactant: CC[C@@H](O)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@@H](O)C(=O)N1CCN(c2nc(-c3ccccc3O)nc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
To a solution of 2-(4-(piperazin-1-yl)quinazolin-2-yl)phenol (250 mg, 0.82 mmol) in CH2Cl2 (6 mL) was added triethylamine (227 μL, 1.63 mmol) followed by the addition of (R)-2-hydroxybutanoic acid (110 mg, 1.06 mmol) and HATU (380 mg, 1.00 mmol). The reaction mixture was stirred at room temperature for 3 h and then quenched with H2O. The aqueous layer was extracted twice with CH2Cl2, dried over MgSO4, filtered, and concentrated. Purification via silica gel chromatography using 0-10% EtOAc in 50:50 CH2Cl2:hexanes gave (R)-2-hydroxy-1-(4-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)butan-1-one (280 mg, 88%). LC/MS: m/z 393.3 (M+H)+ at 2.17 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, DMSO-d6) d 8.47 (m, 1H), 8.12 (d, J=8.3 Hz, 1H), 7.89 (m, 2H), 7.57 (m, 1H), 7.40 (m, 1H), 6.96 (m, 2H), 4.92 (d, J=7.1 Hz, 1H), 3.88 (m, 8H), 1.67 (m, 1H), 1.51 (m, 1H), 0.91 (t, J=7.4 Hz, 3H) ppm.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[C:10]([CH3:18])[CH:9]=1)=[O:6].[CH3:19][O:20][C:21]([C:23]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:22]>>[CH3:19][O:20][C:21]([C:23]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:24][CH2:25][N:26]([CH2:2][CH2:3][NH:4][C:5]([NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]([CH3:18])[CH:9]=2)=[O:6])[CH2:27][CH2:28]1)=[O:22]
Reactant: COC(=O)C1(c2ccccc2)CCNCC1
Reactant: Cc1cc(NC(=O)NCCCl)c2ccccc2n1
Product: COC(=O)C1(c2ccccc2)CCN(CCNC(=O)Nc2cc(C)nc3ccccc23)CC1

Procedure:
The compound is prepared from 1-(2-chloro-ethyl)-3-(2-methyl-quinolin-4-yl)-urea (Example 1A, 2.6 g, 10 mmol)) and 4-phenyl-piperidine-4-carboxylic acid methyl ester (4.38 g, 20 mmol) using the method of Example 1.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8]C)=[C:6]([F:10])[CH:5]=[CH:4][C:3]=1[NH:11][C:12]([NH:26][C:27]1[NH:31][N:30]=[C:29]([C:32]2[CH:37]=[CH:36][C:35]([O:38]C)=[C:34]([F:40])[CH:33]=2)[CH:28]=1)=[N:13][C:14]([C:16]1[C:17]([C:22]([F:25])([F:24])[F:23])=[N:18][N:19]([CH3:21])[CH:20]=1)=[O:15].B(Br)(Br)Br.CCOC(C)=O>ClCCl>[F:1][C:2]1[C:7]([OH:8])=[C:6]([F:10])[CH:5]=[CH:4][C:3]=1[NH:11][C:12]([NH:26][C:27]1[NH:31][N:30]=[C:29]([C:32]2[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([F:40])[CH:33]=2)[CH:28]=1)=[N:13][C:14]([C:16]1[C:17]([C:22]([F:25])([F:23])[F:24])=[N:18][N:19]([CH3:21])[CH:20]=1)=[O:15]
Reactant: COc1ccc(-c2cc(NC(=NC(=O)c3cn(C)nc3C(F)(F)F)Nc3ccc(F)c(OC)c3F)[nH]n2)cc1F
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cn1cc(C(=O)N=C(Nc2cc(-c3ccc(O)c(F)c3)n[nH]2)Nc2ccc(F)c(O)c2F)c(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.7 %

Procedure:
N-(((2,4-Difluoro-3-methoxyphenyl)amino)((3-(3-fluoro-4-methoxyphenyl)-1H-pyrazol-5-yl)amino)methylene)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide (110 mg, 0.194 mmol) was suspended in dichloromethane (4 mL), and a solution of boron tribromide in DCM (1 mL of 1 M, 5 equivalents) was added carefully. The mixture was stirred at room temperature overnight. Then, the reaction was quenched by the addition of ice, and the resulting slurry was then treated with aqueous sodium bicarbonate (pH approximately neutral). The mixture was stirred for 30 minutes, and then partitioned between water and EtOAc. Next, the organic phase was dried over sodium sulfate, and concentrated onto silica gel. The crude product was purified by chromatography (gradient: 8:2 hexanes:EtOAc to 2:8 hexanes:EtOAc to provide the title compound as a white solid (29 mg, 28% yield). 1H NMR (DMSO-d6) δ 13.16 (s, 1H), 12.69 (s, 1H), 10.72 (s, 1H), 10.32 (s, 1H), 10.23 (s, 1H), 8.09 (s, 1H), 7.56 (m, 2H), 7.40 (d, 1H), 7.04 (m, 2H), 6.62 (s, 1H), 3.89 (s, 3H). MS: calc.=539.39; obs. M+H=540.03. HPLC (Method E): retention time was 4.828 minutes.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:12]([NH2:16])([CH3:15])([CH3:14])[CH3:13]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:16][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(C)(C)N
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: ClCCl
Product: CC(C)(C)NS(=O)(=O)c1ccc(Br)cc1
Yield: 26.3 %

Procedure:
According to general procedure C, 4-Bromobenzene sulfonyl chloride (0.40 g, 1.56 mmol) and tert-butylamine (0.41 mL, 3.90 mmol) were stirred together in dry dichloromethane (5 mL) for 16 hours. 4-bromo-N-(tert-butyl)benzenesulfonamide (0.12 g) was provided after purification. MS (ESI) m/z 292. HPLC purity 100.0% at 210-370 nm, 9.2 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[C:11]2[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:21](=[O:30])[C:22]3[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:29])[C:12]=2[O:13][C:14]=1[CH3:15])=O)(C)(C)C>FC(F)(F)C(O)=O>[NH2:8][CH2:9][C:10]1[C:11]2[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:21](=[O:30])[C:22]3[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:29])[C:12]=2[O:13][C:14]=1[CH3:15]
Reactant: Cc1oc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1CNC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1oc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1CN
Yield: 86.6 %

Procedure:
A solution of 3-tert-butoxycarbonylaminomethyl-7-(2,6-dichlorobenzoylamino)-2-methylbenzo[b]furan (312 mg) in trifluoroacetic acid (2 ml) was stirred at ambient temperature for 10 minutes. The reaction mixture was concentrated in vacuo and to the residue was added aqueous saturated sodium bicarbonate. The separated solid was collected, washed with water and dried to give 3-aminomethyl-7-(2,6-dichlorobenzoylamino)-2-methylbenzo[b]furan (210 mg).
Reaction SMILES: CO[C:3](=[O:16])[CH2:4][NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].[C:17]([O:21][CH:22]([N:26](C)C)[N:23](C)[CH3:24])(C)(C)C.C[O-].[Na+].Cl.COC(=N)N>CO.C(#N)C.C1(C)C=CC=CC=1>[CH3:17][O:21][C:22]1[NH:26][C:3](=[O:16])[C:4]([NH:5][C:6]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:7])=[CH:24][N:23]=1
Reactant: COC(=O)CNC(=O)OCc1ccccc1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Agent: COC(=N)N
Agent: C[O-]
Agent: Cl
Solvent: CC#N
Solvent: Cc1ccccc1
Solvent: CO
Product: COc1ncc(NC(=O)OCc2ccccc2)c(=O)[nH]1
Temperature: 70 °C
Reaction time: 8 h
Yield: 77.3 %

Procedure:
Toluene (10 ml) was added to N-benzyloxycarbonyl-glycine methyl ester (1.50 g, 6.73 mmol) and tert-butoxybisdimethylaminomethane (1.83 ml, 8.91 mmol) and the mixture was stirred overnight at 70° C. The mixture was washed with saturated brine and concentrated under reduced pressure. MTBE (20 ml) and 1N hydrochloric acid (15 ml) were added to the residue in an ice bath and the mixture was stirred at room temperature for 2 hr. Thereafter, the mixture was separated and the organic layer was washed with saturated brine. A solution (1.23 g, 6.39 mmol) of 28% sodium methoxide in methanol was added drop-wise and the mixture was concentrated under reduced pressure. The solvent was substituted by acetonitrile and O-methylisourea hydrochloride (0.72 g, 6.50 mmol) was added. The mixture was stirred overnight at 70° C. and concentrated. Water (5 ml) was added and the mixture was stirred for 1 hr. The precipitate was collected by filtration and vacuum dried to give 2-methoxy-6-oxo-5-benzyloxycarbonylamino-1,6-dihydropyrimidine (1.43 g, 5.20 mmol).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH2:7][N:6]1[C:14]1[N:15]([C:20]2[CH:25]=[CH:24][N:23]=[C:22]([Cl:26])[CH:21]=2)[N:16]=[C:17]([CH3:19])[CH:18]=1)=[O:4].[OH-].[Li+]>>[Cl:26][C:22]1[CH:21]=[C:20]([N:15]2[C:14]([N:6]3[CH2:7][C@H:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH2:9][C@H:5]3[C:3]([OH:4])=[O:2])=[CH:18][C:17]([CH3:19])=[N:16]2)[CH:25]=[CH:24][N:23]=1
Reactant: COC(=O)[C@@H]1C[C@@H](S(C)(=O)=O)CN1c1cc(C)nn1-c1ccnc(Cl)c1
Agent: [Li+]
Agent: [OH-]
Product: Cc1cc(N2C[C@H](S(C)(=O)=O)C[C@H]2C(=O)O)n(-c2ccnc(Cl)c2)n1

Procedure:
In analogy to the procedure described in example 253e, (2S,4R)-1-[2-(2-chloro-pyridin-4-yl)-5-methyl-2H-pyrazol-3-yl]-4-methanesulfonyl-pyrrolidine-2-carboxylic acid methyl ester was saponified in the presence of lithium hydroxide to give the title compound which was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2.[CH:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O)=[O:22].[Li+].[Cl-].CCO.C1(C)C=CC=CC=1>C([O-])([O-])=O.[Na+].[Na+].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:11]1([C:10]2[C:9]3[C:4](=[CH:5][C:6]([C:17]([O:19][CH3:20])=[O:18])=[CH:7][CH:8]=3)[N:3]3[CH:21]([OH:22])[C:23]4[C:28]([C:2]=23)=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=Cc1ccccc1B(O)O
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
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: [Cl-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C(O)c1ccccc1-3
Temperature: 85 °C
Yield: 69.4 %

Procedure:
A stirred mixture of methyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (10.1 g, 30 mmol), 2-formylphenylboronic acid (5.4 g, 36 mmol), LiCl (3.8 g (90 mmol) and Pd (PPh3)4 (1.6 g, 1.38 mmol) in 1M Na2CO3 (40 mL) and 1:1 EtOH-toluene (180 mL) was heated under nitrogen at 85° C. for 3 hours. The reaction mixture was then cooled to RT, and extracted with EtOAc (2×100 mL). The extracts were washed sequentially with water and brine, then dried (MgSO4), filtered and conventrated in-vacuo to afforded 13.3 g of crude product. This material was triturated with DCM and hexanes to provide pure desired product (7.52 g, 70%). LC-MS: m/e 360 (M−H); 344 (M−17) +. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.33-1.60 (m, 4H) 1.77-2.01 (m, 6H) 2.80 (d, J=11.83 Hz, 1H) 3.02-3.18 (m, 1H) 3.89 (s, 3H) 6.49 (d, J=11.33 Hz, 1H) 7.34 (t, J=7.55 Hz, 1H) 7.46 (t, J=7.55 Hz, 1H) 7.62 (d, J=7.30 Hz, 1H) 7.66-7.74 (m, 2H) 7.77 (d, J=7.81 Hz, 1H) 8.21 (s, 1H).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[F:7][C:8]([F:12])([F:11])[CH2:9]I.[F:13][C:14]1[CH:42]=[CH:41][CH:40]=[CH:39][C:15]=1[CH2:16][N:17]1[C:21]2=[N:22][CH:23]=[CH:24][CH:25]=[C:20]2[C:19]([C:26]2[N:27]=[C:28]([OH:38])[C:29]3[C:34]([CH3:36])([CH3:35])[C:33](=[O:37])[NH:32][C:30]=3[N:31]=2)=[N:18]1>CN(C=O)C>[F:13][C:14]1[CH:42]=[CH:41][CH:40]=[CH:39][C:15]=1[CH2:16][N:17]1[C:21]2=[N:22][CH:23]=[CH:24][CH:25]=[C:20]2[C:19]([C:26]2[N:27]=[C:28]([O:38][CH2:9][C:8]([F:12])([F:11])[F:7])[C:29]3[C:34]([CH3:36])([CH3:35])[C:33](=[O:37])[NH:32][C:30]=3[N:31]=2)=[N:18]1
Reactant: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(O)c21
Reactant: FC(F)(F)CI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(OCC(F)(F)F)c21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
177 mg (0.54 mmol) of caesium carbonate and 114 mg (0.54 mmol) of 2,2,2-trifluoroethyl iodide were added to a suspension of 200 mg (0.5 mmol) of the compound from example 109 in DMF (1.97 ml) and it was stirred overnight at RT. Then it was heated in the microwave to 120° C. for 1 h. The reaction mixture was purified by preparative HPLC (Chromatorex C18, gradient of acetonitrile/0.01% aq. formic acid). Yield: 14.5 mg (6% of theor.).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[C:7](=O)[CH2:6][C:5]2([CH3:14])[CH3:13].S(=O)(=O)(O)O>CO>[CH3:13][C:5]1([CH3:14])[C:4]2[C:8](=[CH:9][C:10]([CH3:11])=[C:2]([OH:1])[CH:3]=2)[CH2:7][CH2:6]1
Reactant: Cc1cc2c(cc1O)C(C)(C)CC2=O
Agent: O=S(=O)(O)O
Solvent: CO
Product: Cc1cc2c(cc1O)C(C)(C)CC2
Yield: 64 %

Procedure:
Compound 135 was prepared by the catalytic hydrogenation (40 psi.) of 5-hydroxy-3,3,6-trimethyl-1-indanone (134) (1.54 g, 8.1 mmol) in methanol (13 mL) followed by the addition of sulfuric acid (169 μL). The content was degassed several times with nitrogen before palladium-on-charcoal (10%) was added. The hydrogenation was allowed to react overnight under hydrogen pressure. The reaction content was filtered through celite then brought to dryness. The residue was redissolved in diethyl ether, neutralized with sodium bicarbonate (10%) and washed with water and brine. 3,3,6-Trimethyl-5-indanol was purified with ethyl acetate and hexane (3%, 10% and 30%) to obtain 0.91 g of light yellow solid. (64% yield) Ref. Qd419-161, Wilt, J. W.; Schneider, C. A.; J. Org. Chem, 1961, 26, 4196. 1H NMR (300 MHz, CDCl3) δ 6 1.22 (s, 6H), 1.94 (dd, 2H, J=7.37, 6.99 Hz), 2.25 (s, 3H), 2.54 (s, 3H), 2.56 (s, 3H), 2.85 (d, 2H, J=7.18 Hz), 3.89 (s, 3H), 5.31 (d, 1H, J=3.59 Hz), 6.31 (s, 1H), 6.84 (s, 1H), 6.99 (bs, 1H), 7.07 (s, 1H), 7.16 (d, 1H, J=3.59 Hz), 8.33 (bs, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][CH:12]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:13]([NH:20][C:21]([NH:23][C:24]2[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=2)[C:27]([O-:29])=[O:28])=[O:22])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:10])=[CH:4][CH:3]=1.O.[OH-].[Li+].O>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([NH:11][CH:12]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:13]([NH:20][C:21]([NH:23][C:24]2[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=2)[C:27]([OH:29])=[O:28])=[O:22])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(Nc1ccc(Cl)cc1)NC(c1ccccc1)C(NC(=O)Nc1cccc(C(=O)[O-])c1)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(Nc1ccc(Cl)cc1)NC(c1ccccc1)C(NC(=O)Nc1cccc(C(=O)O)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl-(-)-[S-(R*,R*)]-3-[[[[2-[[[(4-chlorophenyl)amino]carbonyl]amino]-1,2-diphenylethyl]amino]carbonyl]amino]benzoate (0.15 g, 0.27 mmol) in MeOH (8 mL) is added lithium hydroxide monohydrate (0.01 g, 0.27 mmol) followed by water to the cloud point. The resulting mixture is stirred overnight at room temperature. The mixture is warmed to 50° C. for 3 hours. The solvent is removed in vacuo and the residue partitioned between water and diethyl ether. The layers are separated and the aqueous layer is acidified to pH=2 with 2 M HCl. The resulting solid is filtered and dried in vacuo at 114° C. for 5 hours, mp 172.5°-173° C. IR (KBr): 3383, 1662, 1550, 1493, 1234, 698 cm-1. NMR (DMSO-d6): δ5.02 (m, 2H), 6.95-7.53 (m, 19H), 8.06 (s, 1H), 8.80 (s, 1H), 8.88 (s, 1H), 12.83 (br s, 1H). Analysis calculated for C29H25ClN4O4.0.5H2O: C, 64.74; H, 4.87; N, 10.41. Found: C, 64.57; H, 4.83; N, 10.10. [α]D25 =-22.3° (c=1, DMF).
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][C:15]2[N:20]=[CH:19][N:18]=[C:17]([NH2:21])[CH:16]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].CN1CCOCC1.[C:29](Cl)(=[O:34])[O:30][C:31]([CH3:33])=[CH2:32]>C1COCC1>[N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][C:15]2[N:20]=[CH:19][N:18]=[C:17]([NH:21][C:29](=[O:34])[O:30][C:31]([CH3:33])=[CH2:32])[CH:16]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: C=C(C)OC(=O)Cl
Reactant: Nc1cc(Oc2ccc([N+](=O)[O-])c3ccccc23)ncn1
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: C=C(C)OC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])c3ccccc23)ncn1
Yield: 94.5 %

Procedure:
To a solution of 6-(4-nitronaphthalen-1-yloxy)pyrimidin-4-amine (89 mg, 0.315 mmol) and NMM (45 μl, 0.410 mmol) in THF (2.0 mL) at 0° C. was added, dropwise, a solution of prop-1-en-2-yl carbonochloridate (45 μl, 0.410 mmol) in THF (1.0 mL) and the reaction mixture warmed to RT for 15 hr and then partitioned between EtOAc (20 mL) and water (5.0 mL). The aq layer was separated and extracted with EtOAc and the combined organic layers were dried (MgSO4) and then evaporated in vacuo to afford the title compound as a yellow oil (109 mg, 87%); Rt 2.54 min (Method 2); m/z 367 (M+H)+ (ES+). This material was used directly in the next step (below) without further purification.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([CH2:42][OH:43])[C:38]2=[N:44][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:49][CH2:48][C:16]([CH3:50])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:47])[O:23][C:24]2[CH:25]=[CH:26][C:27]([F:46])=[CH:28][C:29]=2[C:30]2[CH:45]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].C(O[C@@H](C1C(C)=CC2=NC3=C([Cl:93])N2C=1N1CCC(C)(OCCCC[C@H](C)OC2C=C(C)C(F)=CC=2C2C=C3C=CC=2)CC1)C(OC)=O)(C)(C)C>>[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([CH2:42][OH:43])[C:38]2=[N:44][C:35]3=[C:36]([Cl:93])[N:37]2[C:12]=1[N:13]1[CH2:14][CH2:15][C:16]([CH3:50])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:47])[O:23][C:24]2[CH:25]=[CH:26][C:27]([F:46])=[CH:28][C:29]=2[C:30]2[CH:45]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:48][CH2:49]1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3c(Cl)n2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1cc(C)c(F)cc1-c1cccc-3c1
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(CO)c2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(F)cc1-c1cccc-3c1
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(CO)c2nc3c(Cl)n2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(F)cc1-c1cccc-3c1
Yield: 70 %

Procedure:
Prepared in 70.0% yield from Methyl(2S)-2-(tert-butoxy)-2-[(22S)-17-fluoro-5-(hydroxymethyl)-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate following the procedure for methyl(2S)-2-(tert-butoxy)-2-[(22S)-8-chloro-17-fluoro-4,18,22,28-tetramethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate. LCMS (ESI, M+1): 722.3.
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:17]([OH:19])=O)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14](=[O:16])[CH3:15])=[CH:9][CH:8]=1)(=[O:3])[CH3:2].C(N1CCCCC1)C.ClC(OCC)=O.[CH3:34][O:35][C:36](=[O:40])[C@H:37]([CH3:39])[NH2:38].Cl>O1CCCC1>[CH3:34][O:35][C:36](=[O:40])[C@H:37]([CH3:39])[NH:38][C:17](=[O:19])[C@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][C:14](=[O:16])[CH3:15])=[CH:11][CH:12]=1)[NH:4][C:1](=[O:3])[CH3:2]
Reactant: COC(=O)[C@H](C)N
Reactant: CC(=O)N[C@@H](Cc1ccc(OC(C)=O)cc1)C(=O)O
Agent: CCN1CCCCC1
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)[C@H](C)NC(=O)[C@H](Cc1ccc(OC(C)=O)cc1)NC(C)=O
Reaction time: 0.25 h
Yield: 60 %

Procedure:
To a solution of N,O-diacetyltyrosine (13.3 g, 50 mmoles) and N-ethylpiperidine (7 ml) in tetrahydrofurane (100 ml) precooled to -15° C. was added ethyl chloroformate (5 ml). After 15 minutes of stirring and cooling (-15° C.) alanine methyl ester liberated from its hydrochloride (7.0 g, 50 mmoles) with N-ethylpiperidine (7 ml) was admixed. After 2 hours of stirring at 0° C. and 12 hours of standing at room temperature, the solution was evaporated, the residue was taken into ethyl acetate and the organic phase was successively washed with 1M hydrochloric acid, water, 5% sodium hydrogencarbonate and water, dried over anhydrous sodium sulfate and evaporated. Crystallization from 2-propanol-petroleum ether yielded 10.6 g (60%) of the title product. An analytical sample was recrystallized similarly, m.p. 173° to 176° C. [α]D20 -7.5°.
Reaction SMILES: [CH:1]([NH:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][N:23]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:17][CH2:16]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>C(O)C>[NH2:23][CH2:22][CH2:21][N:18]1[CH2:19][CH2:20][CH:15]([NH:14][CH:1]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:16][CH2:17]1
Reactant: O=C1c2ccccc2C(=O)N1CCN1CCC(NC(c2ccccc2)c2ccccc2)CC1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCN1CCC(NC(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.9 %

Procedure:
The crude 2-{2-[4-(benzhydryl-amino)-piperidin-1-yl]-ethyl}-isoindole-1,3-dione (2.70 g) was dissolved in ethanol (5 ml), followed by the addition of hydrazine hydrate (large excess, 2-3 ml). The solution was stirred at room temperature overnight. The white solid was precipitated. The white solid was filtered off and washed with small amount of ethanol. The filtrates were combined and concentrated. The resulted residue was dissolved in toluene (100 ml). The solution was washed with water (3×15 ml) and dried over anhydrous Na2SO4. After evaporated the solvent, the crude product [1-(2-amino-ethyl)-piperidin-4-yl]-benzhydryl-amine was obtained (0.150 g, 7.9% yield).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([Cl:12])=[N:4][N:3]=1.[CH3:13][C@@H:14]1[NH:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]1.C(N(CC)CC)C.O>CS(C)=O>[Cl:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([N:19]2[CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15][C@@H:14]2[CH3:13])=[N:3][N:4]=1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: Clc1nnc(Cl)c2ccccc12
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1nnc(Cl)c2ccccc12
Yield: 32.9 %

Procedure:
Heat a mixture of 1,4-dichlorophthalazine (10.0 g, 50.2 mmol), (S)-tert-butyl 3-methylpiperazine-1-carboxylate (15.1 g, 75.4 mmol) and triethylamine (21.0 mL, 150.7 mmol) in DMSO (200 mL) at 120° C. for 2 d. Pour the reaction mixture into water, rinsing with CH2Cl2. Extract with Et2O. Wash the organic layer with water (2×), dry over Na2SO4, and concentrate under reduced pressure. Purify the resulting residue by flash silica gel chromatography (gradient of 0 to 20% EtOAc in CH2Cl2) to provide the title compound as a pale yellow solid (6.0 g, 33%). ES/MS m/z (35Cl) 363.0 (M+1).