Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[C:24]([N:32]1[CH:36]([CH3:37])[CH2:35][NH:34][C:33]1=[O:38])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:24]([N:32]1[CH:36]([CH3:37])[CH2:35][N:34]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([N:10]3[CH2:15][CH2:14][N:13]([C:16]4[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=4)[CH2:12][CH2:11]3)=[O:9])=[CH:4][CH:3]=2)[C:33]1=[O:38])(=[O:31])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3)CC2)c(C)c1
Reactant: CC1CNC(=O)N1C(=O)c1ccccc1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CC(C)N(C(=O)c5ccccc5)C4=O)cc3)CC2)c(C)c1
Yield: 16 %

Procedure:
Using (4-bromophenyl) [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (150 mg) described in Preparation Example 165 and 1-benzoyl-5-methylimidazolidin-2-one (98 mg) described in Preparation Example 56 and by the reaction and treatment in the same manner as in Example 1, the title compound (32 mg) was obtained.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[Br:34][C:35]1[C:43]2[C:38](=[CH:39][C:40]([O:44][CH2:45][CH2:46][OH:47])=[CH:41][CH:42]=2)[NH:37][C:36]=1[C:48]([OH:50])=O.[NH2:51][CH2:52][C:53]1[C:54]([F:70])=[C:55]([O:60][C:61]2[CH:62]=[C:63]([CH:66]=[C:67]([Cl:69])[CH:68]=2)[C:64]#[N:65])[C:56]([Cl:59])=[CH:57][CH:58]=1>CN(C=O)C>[Br:34][C:35]1[C:43]2[C:38](=[CH:39][C:40]([O:44][CH2:45][CH2:46][OH:47])=[CH:41][CH:42]=2)[NH:37][C:36]=1[C:48]([NH:51][CH2:52][C:53]1[CH:58]=[CH:57][C:56]([Cl:59])=[C:55]([O:60][C:61]2[CH:62]=[C:63]([C:64]#[N:65])[CH:66]=[C:67]([Cl:69])[CH:68]=2)[C:54]=1[F:70])=[O:50]
Reactant: O=C(O)c1[nH]c2cc(OCCO)ccc2c1Br
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
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: CN(C)C=O
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]c4cc(OCCO)ccc4c3Br)c2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.8 %

Procedure:
HATU (0.061 g, 0.161 mmol) and DIPEA (0.028 mL, 0.161 mmol) were added to a solution of 3-bromo-6-[(2-hydroxyethyl)oxy]-1H-indole-2-carboxylic acid (0.048 g, 0.161 mmol) and 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.050 g, 0.161 mmol) in DMF (2 mL). This solution was stirred overnight at room temperature. The mixture was partitioned between water and EtOAc, followed by washing of the organic layer with a 15% solution of Na2CO3. The organic layer was separated and dried over MgSO4. The EtOAc was evaporated to yield a residue which was triturated in acetone to afford the title compound (0.059 g, 59%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 11.78 (s, 1H), 8.37 (t, 1H), 7.80 (s, 1H), 7.48-7.54 (m, 2H), 7.40-7.47 (m, 2H), 7.35 (d, 1H), 6.87 (s, 1H), 6.82 (d, 1H), 4.86 (t, 1H), 4.59 (d, 2H), 3.97 (t, 2H), 3.72 (q, 2H). MS m/z 592 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[C:18]([CH3:43])=[CH:19][C:20]([CH:39]4[CH2:42][CH2:41][CH2:40]4)=[C:21]([C:23]4[NH:38][C:26]5[CH2:27][N:28](C(OC(C)(C)C)=O)[CH2:29][CH2:30][C:25]=5[N:24]=4)[CH:22]=3)=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2]>ClCCl.FC(F)(F)C(O)=O.Cl.O>[CH:39]1([C:20]2[C:21]([C:23]3[NH:38][C:26]4[CH2:27][NH:28][CH2:29][CH2:30][C:25]=4[N:24]=3)=[CH:22][C:17]([C:15]([N:12]3[CH2:11][CH2:10][CH:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=4)[CH2:14][CH2:13]3)=[O:16])=[C:18]([CH3:43])[CH:19]=2)[CH2:40][CH2:41][CH2:42]1
Reactant: Cc1cc(C2CCC2)c(-c2nc3c([nH]2)CN(C(=O)OC(C)(C)C)CC3)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1cc(C2CCC2)c(-c2nc3c([nH]2)CNCC3)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Yield: 47.1 %

Procedure:
A solution of tert-butyl 2-(5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-4-methylphenyl)-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate (406.2, 600 mg, 0.620 mmol, 1.00 equiv, 60%) in dichloromethane (3 mL) and trifluoroacetic acid (1.5 mL) was stirred for 3 h at 25° C., then diluted with 5 mL of hydrochloric acid (3 mol/L) and 10 mL of water. The resulting mixture was washed with 3×20 mL of ethyl acetate and the pH was then adjusted to ˜9 with sodium hydroxide (aq, 3 M). The resulting mixture was extracted with 4×20 mL of dichloromethane. The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to yield 140 mg (37%) of the title compound as a brown solid.
Reaction SMILES: [CH3:1][C:2]([CH3:37])([CH3:36])[C@H:3]([NH:10][C:11]([C:13]1[N:14]=[C:15]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:16]2[CH2:22][CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][C:17]=12)=[O:12])[C:4]1[O:8][N:7]=[C:6]([CH3:9])[N:5]=1.FC(F)(F)C(O)=O>ClCCl.CO>[CH3:1][C:2]([CH3:37])([CH3:36])[C@H:3]([NH:10][C:11]([C:13]1[N:14]=[C:15]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:16]2[CH2:22][CH2:21][CH2:20][NH:19][CH2:18][C:17]=12)=[O:12])[C:4]1[O:8][N:7]=[C:6]([CH3:9])[N:5]=1
Reactant: Cc1noc([C@@H](NC(=O)c2nc(-c3ccccc3)n3c2CN(C(=O)OC(C)(C)C)CCC3)C(C)(C)C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: Cc1noc([C@@H](NC(=O)c2nc(-c3ccccc3)n3c2CNCCC3)C(C)(C)C)n1
Reaction time: 3 h

Procedure:
To Compound 517 (219 mg, 0.43 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (1.26 mL, 16.36 mmol). After 3 hours of stirring, the solution was concentrated under reduced pressure. The residue was brought to pH 8 with saturated aqueous NaHCO3. The aqueous solution was extracted twice with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to yield a colorless oil which was dissolved in methanol and loaded onto an ion exchange column (Phenomenex®, SCX). The column was washed with methanol to remove impurities, and the title compound was eluted with a solution of 2N ammonia in methanol. After concentration of the methanol solution, Compound 519 was obtained as a pale yellow solid (148 mg, 84% yield). 1H-NMR (400 MHz, (CD3)2SO) δ: 0.99 (s, 9H), 1.72 (m, 2H), 2.34 (s, 3H), 3.00 (m, 2H), 3.29 (s, 1H), 4.14 (t, 2H), 4.27 (m, 2H), 5.15 (d, 1H), 7.53 (m, 5H), 7.85 (d, 1H). LCMS (+ESI) m/z 409.2 [M+H]+.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[O:15][CH2:16][CH2:17][CH3:18].C(=O)(O)[O-].[Na+].Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26].C1COCC1>O>[CH2:28]([O:27][C:25]([NH:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][C@H:3]1[O:15][CH2:16][CH2:17][CH3:18])=[O:26])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCCO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NC(=O)OCc1ccccc1
Yield: 99.2 %

Procedure:
The same operation as in Example (103a) was performed using tert-butyl cis(±)-4-amino-3-propoxypiperidine-1-carboxylate obtained in Example (113d) (3.41 g, 13.2 mmol), sodium bicarbonate (1.26 g, 15 mmol), benzyl chloroformate (2.81 g, 16 mmol), THF (15 mL) and water (15 mL). The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/4, 1/2, 1/1) to obtain 5.14 g of the title compound as a colorless oily substance (99%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5](S(C2C=CC(C)=CC=2)(=O)=O)[N:4]=1.[OH:21][CH:22]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:23]([O:25][CH3:26])=[O:24].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([O:21][CH:22]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:23]([O:25][CH3:26])=[O:24])[N:6]=1
Reactant: COC(=O)C(O)C(C)(C)C
Reactant: COc1cc(OC)nc(S(=O)(=O)c2ccc(C)cc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(Oc1nc(OC)cc(OC)n1)C(C)(C)C
Reaction time: 5 h

Procedure:
2.94 g (10.0 mmol) of 4,6-dimethoxy-2-(p-toluenesulfonyl)pyrimidine and 1.55 g (10.5 mmol) of methyl (+/-)-2-hydroxy-3,3-dimethylbutanoate were heated in the presence of 2.07 g (15.0 mmol) of potassium carbonate in 20 ml of N,N-dimethylformamide to 100° C. with stirring. After 5 hours, the solvent was removed in a rotary evaporator at 60° C./20 mbar. The residue was taken up in 30 ml of water and 30 ml of dichloromethane. After the organic phase had been separated off, the aqueous phase was again extracted with 20 ml of dichloromethane. The combined organic phases were washed with water, dried over magnesium sulfate and evaporated. The title product was obtained in a yield of 2.30 g (80.9 percent of theory) in the form of yellowish crystals (GC content 100 percent).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[C:15](Br)=[C:14]([CH3:17])[O:13][N:12]=2)[CH2:7][CH2:6]1)=[O:4].[Cl-].C[Zn+].[CH3:21]N1CCN(C)C1=O>C(N1C=CN(C(C)C)C1=[Pd-2](Cl)C1C(Cl)=CC=CN=1)(C)C.O1CCCC1>[CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[C:15]([CH3:21])=[C:14]([CH3:17])[O:13][N:12]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)[C@H]1CC[C@H](c2noc(C)c2Br)CC1
Reactant: CN1CCN(C)C1=O
Agent: CC(C)n1ccn(C(C)C)c1=[Pd-2](Cl)c1ncccc1Cl
Agent: C[Zn+]
Agent: [Cl-]
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CC[C@H](c2noc(C)c2C)CC1
Temperature: 50 °C

Procedure:
To a solution of trans-4-(4-bromo-5-methyl-isoxazol-3-yl)-cyclohexanecarboxylic acid methyl ester (660 mg, 2.18 mmol) and 2 M methyl zinc chloride solution in tetrahydrofuran (1.64 ml, 3.28 mmol) in a 4:1 mixture of tetrahydrofuran and 1,3-dimethyl-2-imidazolidinone (12 ml) was added (1,3-diisopropylimidazol-2-ylidene)(3-chloropyridyl)palladium(II) chloride (29.7 mg, 43.7 μmol) at room temperature. The reaction mixture was heated at 50° C. for 2 h. The reaction mixture was partitioned between tert-butyl methyl ether (100 ml) and 0.1 M aqueous hydrochloric acid solution (100 ml). The layers were separated. The aqueous layer was extracted with one 100 ml-portion of tert-butyl methyl ether. The combined organic layers were washed with two 50 ml-portions of water and one 50-ml portion of brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification with n-heptane/ethyl acetate as eluent gave the title compound (460 mg, 84%) as light yellow oil, with a purity of 90% according to GC. MS m/e: 238 ([M+H]+)
Reaction SMILES: [C:1]1([CH:7]=[CH:8][C:9]([NH:11][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16](OS(C(F)(F)F)(=O)=O)[CH:15]=2)[CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>COCCOC.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]>[C:1]1([CH:7]=[CH:8][C:9]([NH:11][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)[CH:15]=2)[CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@H](NC(=O)C=Cc1ccccc1)c1cccc(OS(=O)(=O)C(F)(F)F)c1
Reactant: C1COCCN1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: COCCOC
Product: C[C@H](NC(=O)C=Cc1ccccc1)c1cccc(N2CCOCC2)c1
Temperature: 80 °C

Procedure:
To a solution of (S)-3-phenyl-N-[1-(3-trifluoromethanesulfonyloxy-phenyl)-ethyl]acrylamide (50 mg) in DME (0.5 mL) at room temperature was added Pd2(dba)3 (29 mg), potassium phosphate (37 mg), morpholine (0.02 mL), and the resulting suspension was heated at 80° C. for 15 hours. The solvent was removed in vacuo, and the residue was purified by preparative HPLC to afford the title compound as the trifluoacetic acid salt.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[CH:15][N:14]([CH3:17])[C:13](=[N:18][C:19]3[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=3[CH3:27])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[BH4-].[Na+]>C(O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[NH:16][CH2:15][N:14]([CH3:17])[C:13](=[N:18][C:19]3[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=3[CH3:27])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2cc(=Nc3c(C)cc(C)cc3C)n(C)cn2)cc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(C2=CC(=Nc3c(C)cc(C)cc3C)N(C)CN2)cc1OC
Yield: 58.7 %

Procedure:
To a suspension of 3,4-dihydro-6-(3,4-dimethoxyphenyl)-3-methyl-4-(2,4,6-trimethylphenylimino)pyrimidine (2.0 g) in a mixture of ethanol (10 ml) and water (10 ml) was added sodium borohydride (1.04 g), and the mixture was stirred under reflux for 1.5 hours. After removal of the organic solvent, the mixture was suspended in water, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, evaporated, and triturated in ethanol, to give 6-(3,4-dimethoxyphenyl)-3-methyl-1,2,3,4-tetrahydro-4-(2,4,6-trimethylphenylimino)pyrimidine (1.18 g).
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH2:8][C@@H:9]([C:14]([OH:16])=[O:15])[C:10]([SH:13])([CH3:12])[CH3:11]>O>[C:14]([CH:9]1[C:10]([CH3:12])([CH3:11])[S:13][CH:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[NH:8]1)([OH:16])=[O:15]
Reactant: CC(C)(S)[C@@H](N)C(=O)O
Reactant: CCCCCC=O
Solvent: O
Product: CCCCCC1NC(C(=O)O)C(C)(C)S1
Reaction time: 0.5 h
Yield: 60 %

Procedure:
4 g of hexanal were added to a vigorously stirred solution of 9 g of D-penicillamine in 100 ml of H2O. After stirring for 30 minutes, the solid substance was filtered off, washed successively with water and diethyl ether and dried. Yield 60%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][O:19][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:12][CH:11]=2)[CH:3]=1.[Li]CCCC.C[Si](C)(C)[O:33][C@@H:34]1[C@@H:39]([O:40][Si](C)(C)C)[C@H:38]([O:45][Si](C)(C)C)[C@@H:37]([CH2:50][O:51][Si](C)(C)C)[O:36][C:35]1=O.[SiH](CC)(CC)CC.B(F)(F)F.CCOCC>C1(C)C=CC=CC=1.C1COCC1.C1(C)C=CC=CC=1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C@H:35]2[C@H:34]([OH:33])[C@@H:39]([OH:40])[C@H:38]([OH:45])[C@@H:37]([CH2:50][OH:51])[O:36]2)=[CH:3][C:4]=1[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:12][CH:11]=1
Reactant: Clc1ccc(Br)cc1Cc1ccc(OCCOC2CCCCC2)cc1
Reactant: C[Si](C)(C)OC[C@H]1OC(=O)[C@H](O[Si](C)(C)C)[C@@H](O[Si](C)(C)C)[C@@H]1O[Si](C)(C)C
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(OCCOC4CCCCC4)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-bromo-1-chloro-2-(4-(2-(cyclohexyloxy)ethoxy)benzyl) benzene (intermediate AE) (0.3 g, 0.64 mmol) in anhydrous toluene/THF (v/v 2:1, 6 mL), n-BuLi (2.5 N, 0.39 mL, 0.96 mmol) was added dropwise at −78° C. and stirred for 1 h. Then the mixture was transferred to a solution of 2,3,4,6-tetra-O-trimethylsilyl-β-D-glucolactone (also called (3R,4S,5R,6R)-3,4,5-tris(trimethylsilyloxy)-6-((trimethylsilyloxy)methyl)tetrahydro-2H-pyran-2-one) (0.447 g, 0.96 mmol) in anhydrous toluene (5 mL) at −78° C. The mixture was stirred at −78° C. for 2 h until starting material was consumed. The reaction was quenched with methanesulfonic acid (0.3 g in 10 mL MeOH), and the mixture was allowed to warm to room temperature and stirred overnight. Then 20 mL of water was added. The organic phase was separated, and the water phase was extracted with EtOAc. The organic phases were combined, washed with saturated NaHCO3, water and brine, and then dried with anhydrous Na2SO4, filtered and concentrated. The residue was dissolved in anhydrous CH3CN (4 mL), Et3SiH (0.2 mL, 1.25 mmol) was added and the mixture was cooled to −20° C. Then BF3.Et2O (0.12 mL, 0.94 mmol) was added dropwise, and the mixture was allowed to warm to 20° C. and stirred overnight. After the reaction reached completion, it was quenched with saturated aqueous NaHCO3. The solvent was removed under reduced pressure and the residue was extracted with EtOAc and washed with water and brine. The product was dried with anhydrous Na2SO4, filtered, concentrated to a solid, and purified by preparative HPLC to obtain compound AF as a white powder upon freeze-drying. 1H NMR (400 MHz, CD3OD): δ 7.37-7.30 (m, 3H), 7.12 (d, 2H, J=8.8 Hz) 6.85 (d, 2H, J=8.8 Hz), 4.11-4.03 (m, 5H), 3.87-3.79 (m, 4H), 3.47-3.33 (m, 4H); 3.32-3.30 (m, 1H), 2.00-1.90 (m, 2H), 1.76-1.75 (m, 2H), 1.60-1.50 (m, 1H), 1.33-1.28 (m, 5H); MS ESI (m/z): 508 (M+H)+, calc. 507.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][CH2:10][OH:11].[CH2:12]([O:19][C:20]1[CH:44]=[CH:43][C:42]([O:45][CH2:46][CH2:47][N:48]2[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]2)=[CH:41][C:21]=1[C:22]([NH:24][C:25]1[CH:34]=[C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:32]=[CH:31][C:26]=1[C:27]([O:29][CH3:30])=[O:28])=[O:23])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.CC(=O)CC>[CH2:12]([O:19][C:20]1[CH:44]=[CH:43][C:42]([O:45][CH2:46][CH2:47][N:48]2[CH2:53][CH2:52][N:51]([CH2:8][CH2:9][CH2:10][OH:11])[CH2:50][CH2:49]2)=[CH:41][C:21]=1[C:22]([NH:24][C:25]1[CH:34]=[C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:32]=[CH:31][C:26]=1[C:27]([O:29][CH3:30])=[O:28])=[O:23])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(OCCN2CCNCC2)ccc1OCc1ccccc1
Reactant: OCCCBr
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(OCCN2CCN(CCCO)CC2)ccc1OCc1ccccc1
Temperature: 25 °C

Procedure:
Potassium carbonate (0.031 g) and 3-bromo-1-propanol (0.013 mL) were added to a 2-butanone (1.3 mL) solution of methyl 2-(2-(benzyloxy)-5-(2-(piperazin-1-yl)ethoxy)benzamido)-4-phenylbenzoate (0.084 g), followed by heating to reflux for 1 hour. The reaction mixture was cooled to room temperature, and then a saturated aqueous solution of sodium bicarbonate and ethyl acetate were added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 100-91% chloroform/methanol] to obtain 0.036 g of methyl 2-(2-(benzyloxy)-5-(2-(4-(3-hydroxypropyl)piperazin-1-yl)ethoxy)benzamido)-4-phenylbenzoate as a light yellow oily substance.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[C@H:22]4[CH2:23][CH2:24][C@@H:18]3[CH2:19][N:20]([CH3:25])[CH2:21]4)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[C:26]([O:29][CH2:30][C:31]1[C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][CH:34]=[CH:33][C:32]=1[N:46]1[N:55]=[CH:54][C:53]2[C:48](=[C:49]([F:60])[CH:50]=[C:51]([C:56]([CH3:59])([CH3:58])[CH3:57])[CH:52]=2)[C:47]1=[O:61])(=[O:28])[CH3:27].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.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]>[C:26]([O:29][CH2:30][C:31]1[C:36]([C:2]2[CH:3]=[C:4]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH:22]5[CH2:23][CH2:24][CH:18]4[CH2:19][N:20]([CH3:25])[CH2:21]5)=[CH:13][N:12]=3)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=2)=[CH:35][CH:34]=[CH:33][C:32]=1[N:46]1[N:55]=[CH:54][C:53]2[C:48](=[C:49]([F:60])[CH:50]=[C:51]([C:56]([CH3:58])([CH3:57])[CH3:59])[CH:52]=2)[C:47]1=[O:61])(=[O:28])[CH3:27]
Reactant: CN1C[C@H]2CC[C@@H](C1)N2c1ccc(Nc2cc(Cl)nn(C)c2=O)nc1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(N4C5CCC4CN(C)C5)cn3)c(=O)n(C)n2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Temperature: 100 °C
Yield: 23.9 %

Procedure:
This reaction was carried out under similar conditions to those described above instep 7 of preparation of Example 6. A solution of 6-chloro-2-methyl-4-(5-((1R,5S)-3-methyl-3,8-diazabicyclo[3.2.1]-octan-8-yl)pyridin-2-ylamino)pyridazin-3(2H)-one (150 mg, 416 μmol), 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate (206 mg, 416 μmol), xPhos (19.8 mg, 41.6 μmol) and potassium phosphate (221 mg, 1.04 mmol) in 10 ml of dioxane/water (9:1) was degassed with nitrogen for 10 minutes and bis(dibenzylideneacetone)palladium (0) (12.0 mg, 20.8 μmol) was added. The reaction mixture was heated to 100° C. for 2 hr. After work up, the product was purified by preparative HPLC on silica gel, using a gradient of 10% to 20% methanol/dichloromethane to afford 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(1-methyl-5-(5-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridazin-3-yl)benzyl acetate as light yellow solid (69 mg, 24%). %). (M+H)+=693, 694 m/e.
Reaction SMILES: O[CH2:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1.C(Br)(Br)(Br)[Br:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:17][CH2:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1
Reactant: BrC(Br)(Br)Br
Reactant: CCOC(=O)COc1ccc(CO)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)COc1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.2 %

Procedure:
To a 1 L round bottomed flask with a stirring bar, addition funnel and an argon inlet was added ethyl 2-(4-hydroxymethylphenoxy)acetate 35-4 (7.47 g, 35.53 mmol), CBr4 (13.26 g, 39.97 mmol) and dry CH2Cl2 (300 mL). This solution was cooled in an ice bath and and a solution of triphenyl phosphine (10.48 g, 39.97 mmol) in CH2Cl2 (100 mL) was added dropwise over 1 h. The ice bath was allowed to expire and and the mixture was stirred at ambient temperature 18 h. The solvent was removed in vacuo and the residue was chromatographed directly on 200 g of silica gel useing 15% EtOAc-hexane as eluant. There was obtained ethyl 2-(4-bromomethylphenoxy)acetate 35-5 (7.2 g, 74%) as a low melting solid, mp.: 44°-45° C. 1H NMR (CDCl3): δ 1.29 (t, J=7 Hz, 3H), 4.26 (q, J=7 Hz, 2H), 4.48 (s, 2H), 4.61 (s, 2H), 6.86 (d, J=9 Hz, 2H), 7.32 (d, J=9HZ, 2H).
Reaction SMILES: [C:1]([C:4]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12](=[O:24])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]C(C)(C)C(O)=O)[CH2:6][CH2:5]1)([OH:3])=[O:2].[OH-].[Na+].[BH4-].[Na+].Cl>CC(O)C.O>[OH:24][CH:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:4]([CH3:5])([CH3:6])[C:1]([OH:3])=[O:2]
Reactant: CC(C)(CCCCCC(=O)CCCCCC1(C(=O)O)CC1)C(=O)O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CCCCCC(O)CCCCCC(C)(C)C(=O)O
Reaction time: 0.08 h
Yield: 143 %

Procedure:
To a mixture of 13-(1-carboxycyclopropyl)-2,2-dimethyl-8-oxotridecanoic acid (3.67 g, 10.8 mmol) in iPrOH (20 mL) and H2O (20 mL) was added NaOH (0.90 g, 22.5 mmol). After 5 min of stirring, NaBH4 (0.20 g, 5.3 mmol) was added to the resulting clear solution. Additional NaBH4 (0.10 g) was added after 100 min of stirring. After 16 h, the mixture was acidified to pH˜1 with aqueous HCl (1M) and extracted with Et2O (3×50 mL). The combined organic phases were washed with brine (2×50 mL), dried (Na2SO4), evaporated in vacuo and coevaporated in vacuo from EtOAc (2×15 mL) to give 1341-carboxycyclopropyl)-8-hydroxy-2,2-dimethyltridecanoic acid (3.99 g, 97%, contains 10% (W/W) EtOAc) as a viscous colorless oil. 1H NMR (CD3OD): δ=3.48 (m, 1H), 1.50-1.21 (m, 20H), 1.14 (s, 6H), 1.14-1.12 (m, 2H), 0.70 (dd, J=3.9, 6.3 Hz, 2H). 13C NMR (CD3OD): δ=181.6, 179.0, 72.4, 43.2, 42.0, 38.6, 38.5, 35.2, 31.5, 31.2, 28.9, 26.94, 26.87, 26.3, 25.94, 25.92, 24.4, 13.67, 16.36. HRMS calcd for C19H35O5 (M+H)+: 343.2484. found 343.2487.