Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][N:6]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([Cl:21])=[CH:12]2)=[C:7]1[C:22]([O:24][CH2:25][CH3:26])=[O:23])C.[OH-].[Na+]>C(O)C>[CH2:25]([O:24][C:22]([C:7]1[N:6]([CH2:5][C:4]([OH:27])=[O:3])[C:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[C:13]2[C:8]=1[CH:9]=[CH:10][C:11]([Cl:21])=[CH:12]2)=[O:23])[CH3:26]
Reactant: CCOC(=O)Cn1c(C(=O)OCC)c2ccc(Cl)cc2c1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)c1c2ccc(Cl)cc2c(-c2ccccc2)n1CC(=O)O
Reaction time: 2 h

Procedure:
A suspension of 19.5 g. of 1-ethoxycarbonyl-5-chloro-3-phenylisoindole-2-acetic acid ethyl ester in 150 ml. of ethanol is treated with 60 ml. of 1.0-N sodium hydroxide and boiled at reflux for 30 minutes. After allowing the mixture to stand for 2 hours in an ice-bath, the crystallized sodium salt is removed by filtration under vacuum, washed with ethanol and then dissolved in a mixture of 400 ml. of ethanol and 250 ml. of water. The obtained solution is acidified with 160 ml. of 0.5-N hydrochloric acid with stirring at 40°-45° C. and then left to stand in an ice-bath for 2 hours. The separated acid is removed by filtration under vacuum, washed with water and then dissolved in 750 ml. of methylene chloride. The aqueous layer is separated, the organic phase dried over sodium sulfate and concentrated to about 200 ml. Then, the crystallized colorless acid is removed by filtration under suction and washed with a small amount of methylene chloride, and there is obtained 1-ethoxycarbonyl-5-chloro-3-phenylisoindole-2-acetic acid; melting point 217°-220° C. (decomposition).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9](=[O:18])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[C:4]([O:19][CH3:20])[CH:3]=1>C(O)(=O)C>[NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9](=[O:18])[CH2:10][CH2:11][CH:12]2[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]2)=[C:4]([O:19][CH3:20])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)C=Cc1ccncc1
Solvent: CC(=O)O
Product: COc1cc(N)c(Cl)cc1C(=O)CCC1CCNCC1
Yield: 70.6 %

Procedure:
1-(4-Amino-5-chloro-2-methoxyphenyl)-3-(pyridin-4-yl)-2-propen-1-one (0.5 g, 1.7 mmol), prepared as in Example 6, Step (b), was dissolved in acetic acid (25 mL) and the solution was hydrogenated over 5% rhodium-alumina catalyst (0.2 g) at 50 psi for 24 hours. The solution was filtered, diluted with water, basified with ammonium hydroxide, and extracted three times with methylene chloride. The combined extracts were dried over sodium sulfate. Evaporation gave 1-(4-amino-5-chloro-2-methoxyphenyl)-3-(piperidin-4-yl)propan-1-one (0.35 g, 1.2 mmol).
Reaction SMILES: [Cl:1][C:2]1[C:16]([Cl:17])=[CH:15][C:5]2[NH:6][C:7]([C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.[CH2:18]([Mg]Br)[CH2:19][CH:20]=[CH2:21]>C1COCC1.CCOCC>[Cl:17][C:16]1[C:2]([Cl:1])=[CH:3][C:4]2[NH:8][C:7]([C:9]([OH:14])([CH2:21][CH2:20][CH:19]=[CH2:18])[C:10]([F:13])([F:11])[F:12])=[N:6][C:5]=2[CH:15]=1
Reactant: O=C(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Reactant: C=CCC[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CCCC(O)(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To 1-(5,6-dichloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanone (595 mg) in THF (3 mL) at −78° C. was added 3-butenyl magnesium bromide (7.8 mL of 0.5 M in THF) dropwise. The resulting mixture was then stirred at 0° C. for 4 hr. The reaction was quenched with H2O and 1 N HCl, extracted with EtOAc, dried over Na2SO4, filtered, and concentrated to yield a residue. The residue was purified by flash chromatography with Biotage 40s+ column and elution with 10%-40% EtOAc/hexanes to yield a yellow solid. The yellow solid was dissolved in a minimal amount of Et2O and triturated with hexanes to yield the title compound as a tan solid.
Reaction SMILES: [NH2:1][C@@H:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[OH-].[Na+].Cl[C:15]([O:17][CH3:18])=[O:16]>O1CCOCC1.CCOC(C)=O>[CH3:18][O:17][C:15]([NH:1][C@@H:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4])=[O:16]
Reactant: N[C@H](C(=O)O)c1ccccc1
Reactant: COC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)N[C@H](C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.5 %

Procedure:
To a solution of (S)-2-amino-2-phenylacetic acid (0.5 g, 3.31 mmol) in dioxane at 0° C. was added NaOH (5.46 g, 10.92 mmol) followed by dropwise addition of methyl chloroformate (0.51 mL, 6.62 mmol) and the solution was warmed to room temperature with stirring over 1 h. Diluted with EtOAc, washed with 1 N HCl, brine, dried (Na2SO4), filtered and removed solvent in vacuo to give the title compound (0.35 g, 1.673 mmol, 51%).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([N:7]([C:17]([O:19][CH2:20][C:21]([Cl:24])([Cl:23])[Cl:22])=[O:18])[C@H:8]([C:13]([O:15][CH3:16])=[O:14])[CH2:9][CH:10]([CH3:12])[CH3:11])[S:4][N:3]=1.[Br:25]Br>C(Cl)Cl.CC(O)=O>[Br:25][C:6]1[C:2]([CH3:1])=[N:3][S:4][C:5]=1[N:7]([C:17]([O:19][CH2:20][C:21]([Cl:23])([Cl:24])[Cl:22])=[O:18])[C@H:8]([C:13]([O:15][CH3:16])=[O:14])[CH2:9][CH:10]([CH3:12])[CH3:11]
Reactant: BrBr
Reactant: COC(=O)[C@H](CC(C)C)N(C(=O)OCC(Cl)(Cl)Cl)c1cc(C)ns1
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)[C@H](CC(C)C)N(C(=O)OCC(Cl)(Cl)Cl)c1snc(C)c1Br
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of methyl N-(3-methylisothiazol-5-yl)-N-[(2,2,2-trichloroethoxy)carbonyl]-L-leucinate (28.5 g, 68 mmol) in CH2Cl2 (250 mL) and AcOH (125 mL) was added bromine (8.5 mL, 165 mmol). The resulting red solution was stirred at room temperature for 4 h. A further aliquot of bromine (8.5 mL, 165 mmol) was added and the resulting solution was stirred at room temperature for 18 h. The reaction mixture was partitioned between EtOAc and water+aqueous NaHSO3 until the decolorization was complete. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography using EtOAc in hexane to afford methyl N-(4-bromo-3-methylisothiazol-5-yl)-N-[(2,2,2-trichloroethoxy)carbonyl]-L-leucinate as a yellow syrup.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([C:5]1[NH:9][C:8]2[CH:10]=[C:11]([C:16]([F:19])([F:18])[F:17])[C:12]([C:14]#[N:15])=[CH:13][C:7]=2[N:6]=1)=[O:4].[CH2:22](Br)[CH:23]=[CH2:24].[In].Cl>C1COCC1.O.C(OCC)(=O)C>[OH:4][C:3]([C:5]1[NH:9][C:8]2[CH:10]=[C:11]([C:16]([F:17])([F:18])[F:19])[C:12]([C:14]#[N:15])=[CH:13][C:7]=2[N:6]=1)([C:2]([F:20])([F:1])[F:21])[CH2:24][CH:23]=[CH2:22]
Reactant: N#Cc1cc2nc(C(=O)C(F)(F)F)[nH]c2cc1C(F)(F)F
Reactant: C=CCBr
Agent: Cl
Agent: [In]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCC(O)(c1nc2cc(C#N)c(C(F)(F)F)cc2[nH]1)C(F)(F)F

Procedure:
2-(2,2,2-Trifluoro-acetyl)-6-trifluoromethyl-1H-benzoimidazole-5-carbonitrile (0.31 g; 0.95 mmol), allyl bromide (0.82 mL; 9.5 mmol) and indium (1.09 g; 9.5 mmol) were suspended in THF (12 mL) and 0.03 M HCl (10 mL) and stirred vigorously overnight. The reaction mixture was then diluted with water (60 mL) and ethyl acetate (40 mL), the layers were separated and the aqueous layer was extracted with ethyl acetate (3×20 mL). The combined extracts were washed with brine (50 mL) and dried over Na2SO4 to yield a crude material. The crude material was purified by column chromatography (SiO2; 20% ethyl acetate/hexanes) to yield the title compound as an off-white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([C:33]2[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=2)[CH2:36]Cl)[CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30]>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:36][C:35]2[CH:38]=[CH:39][CH:40]=[C:33]([C:25]3[CH:26]=[C:27]([O:31][CH3:32])[C:28]([O:29][CH3:30])=[C:23]([O:22][CH3:21])[CH:24]=3)[CH:34]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2)CC1
Reactant: COc1cc(-c2cccc(CCl)c2)cc(OC)c1OC
Product: COc1cc(-c2cccc(CN(c3ccccc3)C3CCN(C(=O)OC(C)(C)C)CC3)c2)cc(OC)c1OC

Procedure:
1-(tert-Butoxycarbonyl)-4-phenylaminopiperidine (553 mg) and 3-(3,4,5-trimethoxyphenyl)benzyl chloride (586 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[N:6]=[C:5]2[OH:18].[O:19]([C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)[CH3:20].COC1N=CC(C2C=C3C(=CC=2)N=C(C2C=NC=CC=2)N=C3NC)=CC=1>>[CH3:20][O:19][C:21]1[CH:26]=[C:25]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[C:7]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:6]=[C:5]3[OH:18])[CH:24]=[CH:23][CH:22]=1
Reactant: Oc1nc(-c2cccnc2)nc2ccc(Br)cc12
Reactant: COc1cccc(B(O)O)c1
Agent: CNc1nc(-c2cccnc2)nc2ccc(-c3ccc(OC)nc3)cc12
Product: COc1cccc(-c2ccc3nc(-c4cccnc4)nc(O)c3c2)c1

Procedure:
6-(3-methoxyphenyl)-2-(pyridine-3-yl)quinazoline-4-ol was prepared from 6-bromo-2-(pyridin-3-yl)quinazolin-4-ol (synthesized following Scheme 70 substituting 2-amino-5-bromobenzamide for 2-amino-5-bromo-3-methylbenzamide) and 3-methoxylphenylboronic acid as described in Scheme 72 using method AQ2. The resultant product, 6-(6-methoxypyridin-3-yl)-N-methyl-2-(pyridine-3-yl)quinazoline-4-amine, was a pale yellow solid (19.1 mg, 51%). LCMS m/z=344 (M+1) (Method C) (retention time=2.01 min). 1H NMR (300 MHz, DMSO) δ 9.64 (d, J=1.3 Hz, 1H), 8.84-8.74 (m, 1H), 8.68 (dd, J=6.2, 1.7 Hz, 2H), 8.57 (d, J=1.6 Hz, 2H), 8.16 (ddd, J=14.4, 8.7, 2.2 Hz, 2H), 7.85 (d, J=8.7 Hz, 1H), 7.54 (dd, J=7.9, 4.8 Hz, 1H), 7.00 (d, J=8.7 Hz, 1H), 3.93 (s, 3H), 3.18 (d, J=4.3 Hz, 3H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]=[CH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C(=O)N(Br)C(=[O:17])C1.[OH-].[Na+]>O.FC(F)(F)C(O)=O>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]2[CH:12]([O:17]2)[CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: C1=CCN(Cc2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: c1ccc(CN2CCC3OC3C2)cc1
Reaction time: 8 h
Yield: 3337.2 %

Procedure:
3.36 g of 1-benzyl-1,2,3,6-tetrahydropyridine (0.19 mmol) was dissolved in 35 mL of water containing 1.5 mL of trifluoroacetic acid (0.2 mmol). To that solution 5.87 g of NBS was added in small portions. After 4 hs reaction mixture was transferred to 50 mL of 20% NaOH solution and stirred overnight. On the morning reaction mixture was extracted with dichloromethane and combined organic fractions were dried over sodium sulfate and concentrated. The residue was purified on silica gel column using hexane-ethyl acetate 3:1 as eluent. Evaporation of solvent produced 1.2 g of 3-benzyl-7-oxa-3-azabicyclo[4.1.0]heptane as colorless oil.
Reaction SMILES: C([O:4][CH2:5][C:6]1[O:11][CH2:10][N:9]([C:12]([CH3:20])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[C:8](=[O:21])[C:7]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[OH:4][CH2:5][C:6]1[O:11][CH2:10][N:9]([C:12]([CH3:13])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:20])[C:8](=[O:21])[C:7]=1[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(=O)OCC1=C(c2ccccc2)C(=O)N(C(C)(C)c2ccccc2)CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)(c1ccccc1)N1COC(CO)=C(c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.6 %

Procedure:
6-Acetyloxymethyl-3-(1-methyl-1-phenylethyl)-5-phenyl-2,3-dihydro-4H-1,3-oxazin-4-one (Compound No. 66, 4.99 g) was dissolved in methanol (55 ml), and an aqueous solution (14 ml) of potassium carbonate (1.3 g) was added slowly thereto. This mixture was allowed to react by stirring at room temperature for one hour. Methanol was removed by evaporation, and the residue was acidified with 2N hydrochloric acid, and extracted with ethyl acetate. The organic layer was rinsed with saturated saline solution, and dried with magnesium sulfate to afford the captioned product (4.0 g, yield 91%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][CH:26]=1)[CH2:6][CH2:7][C:8]1[S:9][C:10]2[N:11]=[C:12]([NH2:23])[N:13]=[C:14]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[C:15]=2[N:16]=1.[CH3:27][O:28][C:29]1[CH:39]=[CH:38][C:32]([O:33][CH2:34][C:35](O)=[O:36])=[CH:31][CH:30]=1>>[NH2:23][C:12]1[N:13]=[C:14]([N:17]2[CH2:22][CH2:21][N:20]([C:35](=[O:36])[CH2:34][O:33][C:32]3[CH:38]=[CH:39][C:29]([O:28][CH3:27])=[CH:30][CH:31]=3)[CH2:19][CH2:18]2)[C:15]2[N:16]=[C:8]([CH2:7][CH2:6][C:5]3[CH:24]=[CH:25][CH:26]=[C:3]([O:2][CH3:1])[CH:4]=3)[S:9][C:10]=2[N:11]=1
Reactant: COc1cccc(CCc2nc3c(N4CCNCC4)nc(N)nc3s2)c1
Reactant: COc1ccc(OCC(=O)O)cc1
Product: COc1ccc(OCC(=O)N2CCN(c3nc(N)nc4sc(CCc5cccc(OC)c5)nc34)CC2)cc1
Yield: 66 %

Procedure:
This compound was prepared from 2-(3-methoxyphenethyl)-7-(piperazin-1-yl)thiazolo[5,4-d]pyrimidin-5-amine using 4-methoxyphenoxyacetic acid in a yield of 66%, according to the procedure for the synthesis of example 50.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]([N+:16]([O-:18])=[O:17])[C:11](=O)[N:12]=[CH:13][CH:14]=2)=[C:5]([CH3:19])[CH:4]=1.C([O-])([O-])=O.[Na+].[Na+].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.CCN(CC)CC.Cl.[CH:49]1([CH:52]([NH2:55])[CH2:53][CH3:54])[CH2:51][CH2:50]1>>[CH:49]1([CH:52]([NH:55][C:11]2[C:10]([N+:16]([O-:18])=[O:17])=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[CH3:19])[CH:14]=[CH:13][N:12]=2)[CH2:53][CH3:54])[CH2:51][CH2:50]1
Reactant: CCC(N)C1CC1
Reactant: COc1ccc(C2=CC=NC(=O)C2[N+](=O)[O-])c(C)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Product: CCC(Nc1nccc(-c2ccc(OC)cc2C)c1[N+](=O)[O-])C1CC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 52.4 %

Procedure:
To a solution of 4-(4-methoxy-2-methyl-phenyl)-3-nitro-3H-pyridin-2-one (0.321 g, 1.23 mmol) CH2Cl2 (13 mL), was added Na2CO3 (0.317 g, 3.02 mmol). The reaction was cooled to −78° C., and trifluoromethanesulfonic anhydride (617 μL, 3.65 mmol) was added dropwise. After the addition, the reaction stirred for 15 min at −78° C., then warmed to 0° C. for 1 h. The reaction mixture was filtered and the collected solid was washed with CHCl3. The filtrate was concentrated in vacuo and dissolved in toluene (20 mL) followed by Et3N (343 μL, 2.4 mmol) and 1-cyclopropyl propyl amine HCl (0.331 g, 2.4 mmol), and heated at 130° C. overnight. The reaction was cooled and poured onto ice/H2O. The mixture was extracted with CH2Cl2, washed with H2O, brine, dried Na2SO4, filtered, and concentrated in vacuo. Purification using flash chromatography (10% EtOAc/Hexane) gave 0.220 g (54%) of (1-cyclopropyl-propyl)-[4-(4-methoxy-2-methyl-phenyl)-3-nitro-pyridin-2-yl]-amine: MS(AP) m/z 342.1 [(M+H)+, 100]. The purified intermediate was used in the following step.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[NH:20][C:19]([C:21](=[O:24])[CH2:22][CH3:23])=[CH:18][C:17]=2[CH3:25])=[CH:12][CH:11]=1.C(OCC)(=O)C>C1COCC1>[Br:1][C:18]1[C:17]([CH3:25])=[C:16]([C:13]2[CH:14]=[CH:15][C:10]([Cl:9])=[CH:11][CH:12]=2)[NH:20][C:19]=1[C:21](=[O:24])[CH2:22][CH3:23]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCC(=O)c1cc(C)c(-c2ccc(Cl)cc2)[nH]1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(=O)c1[nH]c(-c2ccc(Cl)cc2)c(C)c1Br
Temperature: -78 °C
Reaction time: 5 h
Yield: 76.8 %

Procedure:
A solution of N-bromosuccinimide (1.25 g, 7.06 mmol) in THF (20 ml) was added dropwise to a stirred solution of 1-(5-(4-chlorophenyl)-4-methyl-1H-pyrrol-2-yl)propan-1-one (compound 53a, 1.75 g, 7.06 mmol) in THF (40 ml) at about −78° C. The resulting reaction mixture was stirred at about −78° C. for 5 hr. The reaction mixture was then allowed to warm to 25° C. slowly during further 3 to 4 hr. The progress of the reaction was monitored by TLC. The solvent was evaporated from the reaction mixture under reduced pressure and to the residue so obtained was added ethyl acetate (200 ml). The mixture so obtained was washed with saturated sodium bicarbonate solution (1×50 ml) followed by washing with water (1×50 ml). The combined organic layer was then dried over anhydrous Na2SO4. The solvent was evaporated from the dried organic layer under reduced pressure to obtain a crude product, which was then purified by flash column chromatography using 10 ethyl acetate in hexanes to obtain the title compound (1.77 g, 77%)
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([Cl:9])=[CH:4][C:3]=1[NH2:10].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.CCN(CC)CC.[CH3:43][C:44]1([CH3:51])[C:48]([CH3:50])([CH3:49])[O:47][BH:46][O:45]1>CC([O-])=O.CC([O-])=O.[Pd+2].O1CCOCC1>[Cl:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([B:46]2[O:47][C:48]([CH3:50])([CH3:49])[C:44]([CH3:51])([CH3:43])[O:45]2)=[C:3]([NH2:10])[CH:4]=1
Reactant: CC1(C)OBOC1(C)C
Reactant: Cc1cc(Cl)cc(N)c1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cc1cc(Cl)cc(N)c1B1OC(C)(C)C(C)(C)O1
Temperature: 80 °C

Procedure:
2-Bromo-5-chloro-3-methyl-phenylamine (595 mg, 2.7 mmol, Example 135: step c), Pd(OAc)2 (30.3 mg, 0.14 mmol), 2-(dicyclohexylphosphino)biphenyl (189.2 mg, 0.54 mmol) and Et3N (1.5 mL, 10.8 mmol) were dissolved into dioxane (10 mL). To this was added 4,4,5,5-Tetramethyl-[1,3,2]dioxaborolane (1.2 mL, 8.1 mmol) slowly. The reaction was heated to 80° C. overnight. The solvents were removed in vacuo and the resulting residue was dissolved into EtOAc and washed with brine. The combined organic layers were dried (MgSO4) and removal of the solvents in vacuo resulted in a mixture of the title compound and 3-Methyl-2,5-bis-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine were obtained and used with out further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[H-].[Na+].Cl[C:25]1[N:30]=[CH:29][CH:28]=[CH:27][N:26]=1>CN(C=O)C>[CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:25]2[N:30]=[CH:29][CH:28]=[CH:27][N:26]=2)=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7]
Reactant: Clc1ncccn1
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(Oc2ncccn2)cc1)NC(=O)OC(C)(C)C
Reaction time: 0.17 h

Procedure:
A solution of N-BOC-L-tyrosine methyl ester (3.0 g, 10.2 mmol) in DMF (5 ml) was added to a suspension of NaH (60% in oil, 11.2 mmol, 447 mg) in DMF (10 ml). After 10 min, a solution of 2-chloropyrimidine (11.2 mmol, 1.28 g) in DMF (3 ml) was added and the mixture stirred overnight. The reaction was quenched with water, diluted EtOAc and washed with water and brine. The EtOAc layer was dried (Na2SO4) and concentrated in vacuo. Purification by column chromatography [SiO2, EtOAc/hexane, 1:1] gave the title compound. δH (DMSO d6) 8.62 (2H, d, J 4.8 Hz), 7.37 (1H, d, J 8.1 Hz), 7.28 (2H, d, J 8.4 Hz), 7.24 (1H, t, J 4.8 Hz), 7.09 (2H, d, J 8.4 Hz), 4.18 (1H, m), 3.01 (1H, dd, J 13.8, 4.6 Hz), 1.33 (9H, s).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH:30]=[O:31])=[C:19]([N:23]3[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[N:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].C(Cl)Cl.[NH4+].[Cl-]>CO>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:30][OH:31])=[C:19]([N:23]3[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[N:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4ccc(C#N)n4)c3C=O)ncc2c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4ccc(C#N)n4)c3CO)ncc2c1
Reaction time: 1 h
Yield: 88.5 %

Procedure:
In a 25 mL container, 1-(3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-2-formylphenyl)-1H-pyrazole-3-carbonitrile (18 mg, 43.3 μmol, Eq: 1.00), sodium borohydride (6.56 mg, 173 μmol, Eq: 4) were combined with CH2Cl2 (2 mL) and MeOH (1 mL) to give a white suspension. The mixture was stirred for 1 hr. The reaction mixture was poured into 25 mL sat NH4Cl and extracted with EtOAc (3×25 mL). The organic layers were dried over MgSO4 and concentrated in vacuo. The organic layer was concentrated to give 1-(3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-2-(hydroxymethyl)phenyl)-1H-pyrazole-3-carbonitrile (16 mg, 99%) of white product.
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[CH:6][C:5]=1[Cl:24].[OH-].[Na+].C(Cl)Cl>CO>[C:20]([O:19][C:17]([N:14]1[CH2:13][CH2:12][CH:11]([O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:25])=[O:2])=[C:5]([Cl:24])[CH:6]=2)[CH2:16][CH2:15]1)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: COC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C(=O)O)c(Cl)c2)CC1
Yield: 90 %

Procedure:
4-(N-t-Butoxycarbonyl-4-piperidinyloxy)-2-chlorobenzoic acid methyl ester was saponified to the carboxylic acid with aqueous NaOH in MeOH using the procedure of Step 3 in Example 11. 4-(N-t-Butoxycarbonyl-4-piperidinyloxy)-2-chlorobenzoic acid was obtained as a foam by evaporation of a DCM solution under reduced pressure (90% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][N:3]=1.[NH2:9][CH2:10][CH2:11][N:12]1[C:17](=[O:18])[CH:16]=[CH:15][C:14]([C:19]2[S:20][CH:21]=[C:22]([CH3:24])[CH:23]=2)=[N:13]1.C([O-])([O-])=O.[K+].[K+].C([O-])(O)=O.[Na+]>CN(C=O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([NH:9][CH2:10][CH2:11][N:12]2[C:17](=[O:18])[CH:16]=[CH:15][C:14]([C:19]3[S:20][CH:21]=[C:22]([CH3:24])[CH:23]=3)=[N:13]2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1csc(-c2ccc(=O)n(CCN)n2)c1
Reactant: Fc1ccnc(Cl)c1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1csc(-c2ccc(=O)n(CCNc3ccnc(Cl)c3)n2)c1
Temperature: 75 °C
Reaction time: 4 h

Procedure:
A suspension of 2-chloro-4-fluoropyridine (904 mg, 6.87 mmol), 2-(2-aminoethyl)-6-(4-methylthiophen-2-yl)pyridazin-3(2H)-one (1470 mg, 6.25 mmol), and K2CO3 (1727 mg, 12.5 mmol) in DMF (8 mL) was stirred at 75° C. for 4 h. The mixture was partioned between CH2Cl2 (100 mL) and 5% NaHCO3 (50 mL). The organic layer was dried over MgSO4, concentrated, then purified on 40 g silica eluting with 20>60% of 2M NH3 in MeOH/CH2Cl2. Product isolated as a white solid. MS (ESI pos. ion) m/z (MH+): 347. Calc'd exact mass for C16H15ClN4OS: 346. 1H NMR (400 MHz, Chloroform-d) δ ppm 2.29 (s, 3 H) 3.61 (q, J=5.35 Hz, 2 H) 4.44-4.51 (m, 2 H) 5.31 (br. s., 1 H) 6.46 (s, 1 H) 6.94-7.01 (m, 2 H) 7.19 (s, 1 H) 7.57 (d, J=9.54 Hz, 1 H) 7.91 (d, J=6.02 Hz, 1 H). 13C NMR (101 MHz, Chloroform-d) δ ppm 15.76, 42.71, 50.46, 106.06, 107.27, 123.73, 128.21, 129.82, 130.08, 138.12, 138.76, 141.69, 149.32, 152.31, 155.06, 160.44.