Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:13][C@H:14]3[N:26]([CH2:27][CH:28]4[CH2:30][CH2:29]4)[CH2:25][CH2:24][C@:20]45[C:21]=2[C:22]=1[O:23][C@H:19]4[C@@H:18]([N:31]1[CH2:35][CH2:34][CH2:33][C:32]1=[O:36])[CH2:17][CH2:16][C@@:15]35[OH:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[CH3:39][CH:40]([N-]C(C)C)C.C1COCC1.ICC.C(=O)([O-])O.[Na+]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:13][C@H:14]3[N:26]([CH2:27][CH:28]4[CH2:29][CH2:30]4)[CH2:25][CH2:24][C@:20]45[C:21]=2[C:22]=1[O:23][C@H:19]4[C@@H:18]([N:31]1[CH2:35][CH2:34][CH:33]([CH2:39][CH3:40])[C:32]1=[O:36])[CH2:17][CH2:16][C@@:15]35[OH:37])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCCN1[C@H]1CC[C@@]2(O)[C@H]3Cc4ccc(OCc5ccccc5)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Reactant: CC(C)[N-]C(C)C
Agent: O=C([O-])O
Agent: [Li+]
Agent: [Na+]
Solvent: CCI
Solvent: C1CCOC1
Product: CCC1CCN([C@H]2CC[C@@]3(O)[C@H]4Cc5ccc(OCc6ccccc6)c6c5[C@@]3(CCN4CC3CC3)[C@H]2O6)C1=O
Reaction time: 1 h
Yield: 66.6 %

Procedure:
In 5 mL of THF, 248 mg (0.50 mmol) of 1-(3-benzyloxy-17-cyclopropylmethyl-4,5α-epoxy-14-hydroxy-morphinan-6α-yl)-pyrrolidin-2-one obtained in Example 36-1 was dissolved, and 4.1 mL (1.48 mmol) of 0.36N LDA/THF solution was added at 0° C., followed by stirring the mixture for 1 hour. Thereafter, 0.08 mL (0.99 mmol) of iodoethane was added thereto and the resulting mixture was stirred for 3 hours. Aqueous saturated sodium hydrogen carbonate solution was added to the reaction mixture, and the resulting mixture was extracted with chloroform. Organic layers were combined, washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated to obtain a crude product. The obtained crude product was purified by silica gel column chromatography to obtain 176 mg (yield: 67%) of the captioned compound.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.CC(C)(C)C(Cl)=O.[CH:33]([C@H:36]1[CH2:40][O:39][C:38](=[O:41])[NH:37]1)([CH3:35])[CH3:34].C([Li])CCC>O1CCCC1>[CH:1]1([CH2:6][C@@H:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([N:37]2[C@@H:36]([CH:33]([CH3:35])[CH3:34])[CH2:40][O:39][C:38]2=[O:41])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)[C@H]1COC(=O)N1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Agent: CC(C)(C)C(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)[C@H]1COC(=O)N1C(=O)[C@@H](CC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 32.6 %

Procedure:
A solution of 3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionic acid (prepared in Example 12, 5.00 g, 17.4 mmol) in tetrahydrofuran (150 ML) cooled to −78° C. was treated with triethylamine (2.77 mL, 19.9 mmol) followed by trimethylacetyl chloride (2.24 mL, 18.2 mmol). The resulting white slurry was stirred at −78° C. for 15 min and then at 0° C. for 45 min. In a separate flask, a solution of (S)-4-isopropyl-2-oxazolidinone (2.14 g, 16.57 mmol) in tetrahydrofuran (80 mL) cooled to −78° C. was treated with a 2.0M solution of n-butyllithium in hexanes (8.7 mL, 17.4 mmol). This solution was stirred at −78° C. for 10 min. It was then warmed 25° C. and stirred for an additional 10 min. At this time, the first reaction mixture was re-cooled to −78° C. The second reaction mixture was added to the first reaction mixture over a period of 5 min via cannula. The combined reaction was then stirred at −78° C. for 15 min. It was then warmed to 25° C. and was stirred for an additional 1.5 h. At this time, the reaction was quenched by the addition of a saturated aqueous sodium bisulfite solution (50 mL) and extracted with ethyl acetate (3×40 mL). The organic layers were combined, washed with a saturated aqueous sodium bicarbonate solution (1×20 mL), a saturated aqueous sodium chloride solution (1×20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 85/15 hexanes/ethyl acetate) afforded (1) 3-[3-cyclopentyl-2(S)-(3,4-dichloro-phenyl)-propionyl]-4(S)-isopropyl-oxazolidin-2-one (2.15 g, 33%) as a clear oil: [α]23589=+87.5° (c=0.160, chloroform); EI-HRMS m/e calcd for C20H25Cl2NO3(M+) 397.1211, found 397.1215 and (2) 3-[3-cyclopentyl-2(R)-(dichloro-phenyl)-propionyl]-4(S)-isopropyl-oxazolidin-2-one (1.88 g, 28%) as a white solid: mp 71.9-74.6° C.; [α]23589=−27.6° (c=0.188, chloroform); EI-HRMS m/e calcd for C20H25Cl2NO3(M+) 397.1211, found 397.1212.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[NH2:32][CH2:33][CH2:34][CH2:35][OH:36].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:29])([F:30])[F:31])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([NH:32][CH2:33][CH2:34][CH2:35][OH:36])=[O:5]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: NCCCO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(NCCCO)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 25.7 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 30 mg, 0.070 mmol), 3-aminopropan-1-ol (7.84 mg, 0.104 mmol), 4-methylmorpholine (28.1 mg, 0.278 mmol), and HATU (34.4 mg, 0.090 mmol) were dissolved in DMF (1 mL). The mixture was stirred for 1 h and then purified by prep HPLC (PHENOMENEX® Luna 5u 21×250 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 30 min, 25 mL/min, 220 nM, product retention=29.4 min) to provide (R/S)-2-hydroxy-N-(3-hydroxypropyl)-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (12 mg, 0.018 mmol, 26.5% yield): LCMS=489.1 [M+H]+; 1H NMR (400 MHz, chloroform-d) δ ppm 8.12-8.30 (2 H, m), 7.47-7.74 (7 H, m), 7.06 (1 H, br. s.), 5.22 (1 H, d, J=4.83 Hz), 4.38 (1 H, t, J=5.71 Hz), 3.56-3.75 (2 H, m), 3.31-3.52 (2 H, m), 1.91-2.08 (1 H, m), 1.63-1.81 (2 H, m); HPLC peak RT=8.4 min (Method A).
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]#[N:8])=[CH:5][NH:4][N:3]=1.CN(C)[CH:11]=[CH:12][C:13]([C:15]1[CH:16]=[C:17]([NH:21][C:22](=[O:24])[CH3:23])[CH:18]=[CH:19][CH:20]=1)=O>C(O)(=O)C>[C:7]([C:6]1[CH:5]=[N:4][N:3]2[C:13]([C:15]3[CH:16]=[C:17]([NH:21][C:22](=[O:24])[CH3:23])[CH:18]=[CH:19][CH:20]=3)=[CH:12][CH:11]=[N:1][C:2]=12)#[N:8]
Reactant: N#Cc1c[nH]nc1N
Reactant: CC(=O)Nc1cccc(C(=O)C=CN(C)C)c1
Solvent: CC(=O)O
Product: CC(=O)Nc1cccc(-c2ccnc3c(C#N)cnn23)c1

Procedure:
A mixture of 6.0 g of 3-aminopyrazole-4-carbonitrile, 13.0 g of N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]acetamide and 100 ml of glacial acetic acid was heated at reflux for 4 hours. On standing at room temperature a precipitate formed. The precipitate was isolated, washed with hexane, then ether and dried. The solid was recrystallized from acetonitrile-N,N-dimethylformamide and gave the product of the example, mp 252°-254° C.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[N:4]1.Cl[CH2:9][CH2:10][CH:11]1[CH2:17][N:16]([CH3:18])[C:15](=[O:19])[C:14]2[CH:20]=[CH:21][CH:22]=[N:23][C:13]=2[CH2:12]1>CN(C)C=O>[N:3]1([CH2:9][CH2:10][CH:11]2[CH2:17][N:16]([CH3:18])[C:15](=[O:19])[C:14]3[CH:20]=[CH:21][CH:22]=[N:23][C:13]=3[CH2:12]2)[CH:7]=[CH:6][CH:5]=[N:4]1
Reactant: CN1CC(CCCl)Cc2ncccc2C1=O
Reactant: c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CC(CCn2cccn2)Cc2ncccc2C1=O

Procedure:
To a suspension of sodium hydride in dimethylformamide (DMF) is added a solution of pyrazole in DMF. This solution is then added to a solution of 8-(2-chloroethyl)-6,7,8,9-tetrahydro-6-methyl-5H-pyrido[3,2-c]azepin-5-one in DMF. After reaction has occurred, DMF is removed by evaporation (80° C., vacuum pump) and the residue is taken up in chloroform. The chloroform solution is washed with dilute aqueous sodium hydroxide, dried over anhydrous sodium sulfate and concentrated by rotary evaporation (70° C., water aspirator). The residue is subjected to high pressure liquid chromatography using a suitable solvent on a silica gel column.
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[F:16][C:17]1[CH:18]=[CH:19][C:20]([S:25]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)(=[O:27])=[O:26])=[C:21]([CH2:23][NH2:24])[CH:22]=1.C(N(CC)CC)C>CO>[ClH:12].[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:24]([CH2:23][C:21]2[CH:22]=[C:17]([F:16])[CH:18]=[CH:19][C:20]=2[S:25]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)(=[O:27])=[O:26])[CH:10]=1
Reactant: NCc1cc(F)ccc1S(=O)(=O)N1CCOCC1
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: N=c1c(C(N)=O)cc(Cl)cn1Cc1cc(F)ccc1S(=O)(=O)N1CCOCC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 47.7 %

Procedure:
(Step 2) To a suspension of 2-cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide (0.36 g) in methanol (10 ml) was added a solution of 1-[5-fluoro-2-(morpholin-4-ylsulfonyl)phenyl]methanamine hydrochloride obtained in Step 1 (0.58 g) and triethylamine (0.65 ml) in methanol (5 ml) at room temperature, and the mixture was stirred overnight at 50° C. The reaction solvent was evaporated under reduced pressure, acetic acid (5 ml) was added, and the mixture was stirred at 50° C. for 2 hr. The solvent was evaporated under reduced pressure, the residue was extracted with 1N hydrochloric acid, and the extract was washed with ethyl acetate. The aqueous layer was basified with 1N aqueous sodium hydroxide solution, the mixture was partitioned with ethyl acetate, and the organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=7:3→1:0). The obtained residue was dissolved in methanol, 4N hydrogen chloride-ethyl acetate solution (1 ml) was added, and the mixture was crystallized from methanol-ethyl acetate. The precipitated crystals were collected by filtration, and recrystallized from methanol-ethyl acetate to give the title compound (0.17 g).
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].[N:6]1([CH2:11][CH2:12][CH2:13][NH2:14])[CH2:10][CH2:9][CH2:8][CH2:7]1>C(Cl)(Cl)Cl>[CH2:1]([NH:3][C:4]([NH:14][CH2:13][CH2:12][CH2:11][N:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCN=C=O
Reactant: NCCCN1CCCC1
Solvent: ClC(Cl)Cl
Product: CCNC(=O)NCCCN1CCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.9 %

Procedure:
To a solution of 27.7 g (0.39 mol) ethyl isocyanate in 250 mL chloroform was added 50 g (0.39 mol) 3-(1-pyrrolidinyl)propylamine dropwise with cooling. Once the addition was complete, the cooling bath was removed and the reaction mixture stirred at room temperature for 4 hours. The reaction mixture was then concentrated under reduced pressure to give 74.5 g (96.4%) of the desired urea as a clear oil.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH2:10][CH3:11])[CH:3]=1.[B:12](OC(C)C)([O:17]C(C)C)[O:13]C(C)C.Cl>CCCCCC.O1CCCC1>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([B:12]([OH:17])[OH:13])=[CH:3][C:4]=1[CH2:10][CH3:11])#[N:7]
Reactant: CCc1cc(Br)ccc1C#N
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCc1cc(B(O)O)ccc1C#N
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
3.66 ml of n-butylithium solution (1.6M in hexane) are added dropwise to a solution of 1.14 g of 4-bromo-2-ethylbenzonitrile in 20 ml of dry tetrahydrofuran at −78° C. After stirring at this temperature for 20 minute, 1.51 ml of triisopropyl borate are added. After 45 minutes, 12 ml of 1N HCl are added to the reaction mixture, which is warmed to room temperature. The phases are separated and the aqueous phase is extracted three more times with 100 ml of diethyl ether/tetrahydrofuran (1.1) each time. The combinred organic phases are dried with sodium sulphate, filtered and concentrated to 4 ml in vacuo. The remainig oil is mixed with 40 ml of pentane, and the precipitate which has separated out is filtered off with suction and washed twice with pentane. Drying under high vacuum results in the title compound as a yellow solid. Rt=3.27.
Reaction SMILES: [NH:1]1[C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=[N:2]1.C(=O)(O)[O-].[Na+].[Cl:15][CH2:16][C:17](Cl)=[O:18]>CCOC(C)=O>[Cl:15][CH2:16][C:17]([NH:9][NH:8][C:6]([C:5]1[NH:1][N:2]=[CH:3][CH:4]=1)=[O:7])=[O:18]
Reactant: O=C(Cl)CCl
Reactant: NNC(=O)c1ccn[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(CCl)NNC(=O)c1ccn[nH]1
Yield: 67 %

Procedure:
To a suspension of 1H-pyrazole-5-carbohydrazide (102 mg, 0.81 mmol) in 7 mL AcOEt was added 1.8 mL of 1M sodium bicarbonate solution and the initial white suspension was stirred for a few minutes until it became completely clear two-phase solution. Upon cooling in an ice-water bath to it was added 0.7 ml AcOEt solution of chloroacetyl chloride (110 mg, 0.97 mmol). After stirring overnight, the reaction mixture was poured into a separatory funnel. The organic layer was separated and the aqueous layer was extracted twice with AcOEt. The combined org layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a white solid (110 mg).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4](I)[CH:3]=1.[Cu](C#N)[C:14]#[N:15].[Cl-].[NH4+].N>CN1CCCC1=O>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([C:14]#[N:15])[CH:3]=1
Reactant: N#C[Cu]C#N
Reactant: COC(=O)c1ccc(Br)cc1I
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc(Br)cc1C#N
Temperature: 60 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
To a mixture of methyl 4-bromo-2-iodobenzoate (3.52 g) described in Preparation Example 74 and copper cyanide (1.16 g) was added N-methylpyrrolidone (21 mL), and the mixture was stirred at 60° C. for 1 hr. The reaction mixture was cooled, a solution of saturated aqueous ammonium chloride solution and aqueous ammonia (1:1) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a solution of saturated aqueous ammonium chloride solution and aqueous ammonia (1:1), saturated aqueous ammonium chloride solution, and saturated brine. The organic layer was dried over sodium sulfate, and the solvent was evaporated to give the title compound (2.39 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[C:12]([CH3:13])=[N:11][C:10]([CH3:14])=[N:9]2)[N:5]=[C:4]([S:15][CH3:16])[N:3]=1.[CH2:17]([Sn](CCCC)(CCCC)C=C)[CH2:18]CC>C1(C)C=CC=CC=1.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>[CH3:14][C:10]1[N:11]=[C:12]([CH3:13])[N:8]([C:6]2[CH:7]=[C:2]([CH:17]=[CH2:18])[N:3]=[C:4]([S:15][CH3:16])[N:5]=2)[N:9]=1
Reactant: CSc1nc(Cl)cc(-n2nc(C)nc2C)n1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1cc(-n2nc(C)nc2C)nc(SC)n1
Temperature: 110 °C

Procedure:
To a solution of 4-chloro-6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-(methylthio)pyrimidine (1-2) (1.01 g, 3.96 mmol, 1.0 eq.) in degassed toluene (20 mL) under nitrogen was added tetrakis(triphenylphosphine)palladium(0) (228 mg, 0.198 mmol, 0.050 eq.) followed by tributyl(vinyl)tin (1.16 mL, 3.96 mmol, 1.0 eq.) and the reaction heated to 110° C. for 2 hours. Toluene was removed by roto-evaporation and the resulting residue was purified by silica gel column chromatography (0-100% ethyl acetate in hexanes) to afford 4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-(methylthio)-6-vinylpyrimidine (1-3) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 7.48 (s, 1H), 6.72 (dd, 1H, J=17.3, 10.3 Hz), 6.57 (dd, 1H, J=17.3, 1.4 Hz), 5.73 (dd, 1H, J=10.3, 1.4 Hz), 2.91 (s, 3H), 2.61 (s, 3H), 2.42 (s, 3H). LRMS m/z (M+H) 248 found, 248 required.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[N:10]([C:16]1[C:17]([CH2:49][OH:50])=[C:18]([N:22]3[CH:26]=[C:25]([C:27]#[N:28])[C:24]([NH:29]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)=[N:23]3)[CH:19]=[CH:20][CH:21]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].CO.Cl>CCOCC>[NH2:29][C:24]1[C:25]([C:27]#[N:28])=[CH:26][N:22]([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([N:10]3[N:9]=[CH:8][C:7]4[C:12](=[CH:13][CH:14]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH:6]=4)[C:11]3=[O:15])[C:17]=2[CH2:49][OH:50])[N:23]=1
Reactant: CC(C)(C)c1ccc2c(=O)n(-c3cccc(-n4cc(C#N)c(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)c3CO)ncc2c1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: CC(C)(C)c1ccc2c(=O)n(-c3cccc(-n4cc(C#N)c(N)n4)c3CO)ncc2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73.8 %

Procedure:
1-(3-(6-tert-butyl-1-oxophthalazin-2(1H)-yl)-2-(hydroxymethyl)phenyl)-3-(tritylamino)-1H-pyrazole-4-carbonitrile (382 mg 0.582 mmol) was dissolved in Et2O (30 mL) and cooled to 0° C. in. MeOH (2 mL) was added followed by saturated ethereal HCl (2 mL, prepared by bubbling HCl gas into 100 mL of ether). The reaction mixture was allowed to stir at 0° C. for 30 minutes, after which, it was judged to be complete by TLC. The volatiles were removed in vacuo and residue was partitioned between saturated aqueous NaHCO3 (100 mL) and EtOAc (100 mL) and stirred vigorously. The aqueous layer was separated and extracted with EtOAc (50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The oily residue was bound to silica gel and the crude product was purified over a 25 g silica gel cartridge eluting the column with a 20-70% EtOAc/hexanes gradient to give 3-Amino-1-[3-(6-tert-butyl-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-1H-pyrazole-4-carbonitril (178 mg, 74%) as a white-powdery solid.
Reaction SMILES: C1(CCCCCCCCNC([C:18]2[CH:19]=[C:20]([C:35]3[CH:40]=[CH:39][CH:38]=[C:37](C(F)(F)F)[CH:36]=3)[C:21]([OH:34])=[C:22](C3C=CC=C(C(F)(F)F)C=3)[CH:23]=2)=O)C=CC=CC=1.Br[C:46]1[CH:51]=[C:50](I)[C:49](O)=[C:48](I)[CH:47]=1>>[C:46]1([C:18]2[CH:23]=[C:22]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:21]([OH:34])=[C:20]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:19]=2)[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: Oc1c(I)cc(Br)cc1I
Reactant: O=C(NCCCCCCCCc1ccccc1)c1cc(-c2cccc(C(F)(F)F)c2)c(O)c(-c2cccc(C(F)(F)F)c2)c1
Product: Oc1c(-c2ccccc2)cc(-c2ccccc2)cc1-c1ccccc1

Procedure:
The title compound was prepared as a solid (0.055 g, 28%, product 2: tris-arylation) from 4-bromo-2,6-diiodophenol using the procedure to step 2 of Example 40; 1H NMR (CDCl3) δ 5.45 (s, 1H), 7.27-7.57 (m, 1 1H), 7.62 (d, J=8.3 Hz, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([NH2:24])[S:12][C:13]=2[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[C:30](Cl)=[O:31]>>[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[C:30]([NH:24][C:11]1[S:12][C:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:10]=1)=[O:31]
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: COc1ccc(-c2nc(N)sc2Cc2ccc([N+](=O)[O-])cc2)cc1
Product: COc1ccc(-c2nc(NC(=O)c3ccc(OC)c(OC)c3)sc2Cc2ccc([N+](=O)[O-])cc2)cc1
Yield: 60.8 %

Procedure:
A procedure similar to that in Example 4 was used. 4-(4-methoxy-phenyl)-5-(4-nitro-benzyl)-thiazol-2-ylamine prepared in Example 6 and 3,4-dimethoxy-benzoyl chloride prepared in the step 1 of Example 12 were used as starting materials, allowed to react at room temperature overnight, followed by post-treatment to obtain a crude product, which was purified by a silica gel column chromatography eluted with a gradient of dichloromethane and ethyl acetate (100:0-10:1) to obtain a product as a white solid in a yield of 60.8%, mp: 106-108└. 1H-NMR (CDCl3, 400 MHz) δ: 3.83 (3H, s, OCH3), 3.92 (3H, s, OCH3), 3.97 (3H, s, OCH3), 4.33 (2H, s, CH2), 6.85˜6.89 (3H, m, ArH), 7.37˜7.45 (6H, m, ArH), 8.18 (2H, t, J=8.68 Hz, ArH), 10.48 (1H, br, CONH, exchangable); EI-MS m/e (%): 505.0 (M+, 54), 165.0 (100); HREI-MS Calcd. for C26H23N3O6S: 505.1308. found: 505.1315. Anal. Calcd. for C26H23N3O6S: C, 61.77; H, 4.59; N, 8.31. found: C, 61.90; H, 4.70; N, 8.05.
Reaction SMILES: [OH:1][CH:2]([C:7]1[S:11][C:10]([C:12](=O)[CH2:13][CH2:14][C:15](=O)[CH:16]([C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)[CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[N:9][CH:8]=1)[C:3]([OH:6])([CH3:5])[CH3:4].C([O-])(=O)C.[NH4+:40].[OH-].[Na+]>C(O)(=O)C>[CH3:4][C:3]([OH:6])([CH3:5])[CH:2]([C:7]1[S:11][C:10]([C:12]2[NH:40][C:15]([CH:16]([C:24]3[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:31])=[O:32])=[CH:26][CH:25]=3)[CH2:17][CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:14][CH:13]=2)=[N:9][CH:8]=1)[OH:1]
Reactant: [NH4+]
Reactant: CC(C)(O)C(O)c1cnc(C(=O)CCC(=O)C(CC2CCOCC2)c2ccc(S(C)(=O)=O)cc2)s1
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC(C)(O)C(O)c1cnc(-c2ccc(C(CC3CCOCC3)c3ccc(S(C)(=O)=O)cc3)[nH]2)s1
Temperature: 90 °C
Reaction time: 2 h
Yield: 77.3 %

Procedure:
A mixture of 1-[5-(1,2-dihydroxy-2-methylpropyl)-1,3-thiazol-2-yl]-5-[4-(methylsulfonyl)phenyl]-6-(tetrahydro-2H-pyran-4-yl)hexane-1,4-dione (0.51 g), ammonium acetate (0.39 g) and acetic acid (5 mL) was stirred at 90° C. for 2 hr. The reaction mixture was neutralized with 8M aqueous sodium hydroxide solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (0.38 g, yield 77%) was obtained as a yellow amorphous solid from a fraction eluted with ethyl acetate. MS: 505 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:16](=[O:18])[CH3:17])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[N:14][CH:13]=[CH:12][N:11]=1.CC1(C)C(C)(C)OB([C:27]2[CH:44]=[CH:43][C:30]3[CH2:31][CH2:32][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:34][CH2:35][C:29]=3[CH:28]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC>[C:16]([C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]2[CH:15]=[N:14][CH:13]=[CH:12][N:11]=2)=[C:2]([C:27]2[CH:44]=[CH:43][C:30]3[CH2:31][CH2:32][N:33]([C:36]([O:38][C:39]([CH3:40])([CH3:41])[CH3:42])=[O:37])[CH2:34][CH2:35][C:29]=3[CH:28]=2)[CH:3]=1)(=[O:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(B3OC(C)(C)C(C)(C)O3)cc2CC1
Reactant: CC(=O)c1ccc(OCc2cnccn2)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(=O)c1ccc(OCc2cnccn2)c(-c2ccc3c(c2)CCN(C(=O)OC(C)(C)C)CC3)c1
Yield: 30 %

Procedure:
To a stirred solution of 1-{3-bromo-4-[(2-pyrazinylmethyl)oxy]phenyl}ethanone (0.2 g) and 1,1-dimethylethyl 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (0.34 g) in DME (4 ml) was added aqueous sodium carbonate (2M, 0.98 ml). This was degassed with nitrogen for 15 min before adding Tetrakis (37 mg). The reaction was heated under reflux overnight. TLC indicated the reaction had gone to completion and so it was cooled, diluted with water and extracted with ethyl acetate. The combined organics were dried over sodium sulphate and concentrated in vacuo to yield a crude product which was purified by column chromatography, eluting with 0-18% ethyl acetate in hexane. The appropriate fractions were concentrated in vacuo to yield the title compound, 0.093 g, 30% yield.