Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@H:11]3[C@@H:15]([O:16][CH3:17])[CH2:14][N:13]([C:18]([C:20]4([C:23]#[N:24])[CH2:22][CH2:21]4)=[O:19])[CH2:12]3)=[C:8]([C:25]([NH2:27])=[O:26])[CH:7]=[N:6][N:5]2[CH:28]=1.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1>[C:23]([C:20]1([C:18]([N:13]2[CH2:14][C@H:15]([O:16][CH3:17])[C@H:11]([NH:10][C:9]3[C:4]4[N:5]([CH:28]=[C:2]([C:34]5[CH:35]=[CH:36][C:31]([O:30][CH3:29])=[CH:32][CH:33]=5)[CH:3]=4)[N:6]=[CH:7][C:8]=3[C:25]([NH2:27])=[O:26])[CH2:12]2)=[O:19])[CH2:22][CH2:21]1)#[N:24]
Reactant: CO[C@H]1CN(C(=O)C2(C#N)CC2)C[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Reactant: COc1ccc(B(O)O)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1ccc(-c2cc3c(N[C@@H]4CN(C(=O)C5(C#N)CC5)C[C@@H]4OC)c(C(N)=O)cnn3c2)cc1
Temperature: 85 °C
Reaction time: 0.42 h
Yield: 42.1 %

Procedure:
A solution of 6-bromo-4-(((3R,4S)-1-(1-cyanocyclopropanecarbonyl)-4-methoxypyrrolidin-3-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide (20 mg, 0.045 mmol) in 1,4-dioxane (0.3 mL), was added (4-methoxyphenyl)boronic acid (10.2 mg, 0.07 mmol), [1,1′-(diphenylphosphino)ferrocene]-dichloropalladium (II) (3.27 mg, 4.5 μmol), potassium phosphate (0.08 mL, 0.16 mmol). The reaction vial was purged with N2, sealed and heated at 85° C. overnight. The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 25-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give the title compound (9 mg 42% yield). 1H NMR (400 MHz, METHANOL-d4) δ 8.19 (d, J=7.0 Hz, 1H), 7.95 (d, J=7.0 Hz, 1H), 7.72-7.65 (m, 2H), 7.28 (d, J=14.5 Hz, 1H), 7.02-6.95 (m, 2H), 5.23-5.11 (m, 1H), 4.57 (dd, J=10.1, 7.0 Hz, 1H), 4.32-4.24 (m, 1H), 4.24-4.16 (m, 1H), 4.14-4.06 (m, 1H), 3.94-3.88 (m, 1H), 3.86 (s, 3H), 3.78-3.71 (m, 1H), 3.60-3.53 (m, 2H), 3.40 (s, 3H), 1.79-1.52 (m, 3H), 1.45-1.35 (m, 1H); MS (ES+) m/z: 475.2 (M+H); LC retention time: 3.49 min (analytical HPLC Method B).
Reaction SMILES: [F:1][C:2]1([F:16])[O:7][C:6]2[CH:8]=[CH:9][C:10]([N+:12]([O-])=O)=[CH:11][C:5]=2[NH:4][C:3]1=[O:15]>CO.[Pd]>[NH2:12][C:10]1[CH:9]=[CH:8][C:6]2[O:7][C:2]([F:16])([F:1])[C:3](=[O:15])[NH:4][C:5]=2[CH:11]=1
Reactant: O=C1Nc2cc([N+](=O)[O-])ccc2OC1(F)F
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2c(c1)NC(=O)C(F)(F)O2
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.4 %

Procedure:
In a flask, 10% Pd/C (0.819 g, 0.769 mmol) was added. The flask was placed under vacuum and purged with N2 three times and then MeOH (25 mL) was added. To the flask was added a solution of 2,2-difluoro-6-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one (5.90 g, 25.6 mmol, WO2008024634A1, Page 161, Intermediate C) in MeOH (20 mL). The mixture was then evacuated, purged with N2 and evacuated again. The mixture was placed under an atmosphere of H2 and stirred at rt for about 16 h. The mixture was placed under vacuum and purged with N2 three times. The mixture was filtered over a Celite Pad®, washed with MeOH (300 mL) and concentrated under reduced pressure to give 6-amino-2,2-difluoro-2H-benzo[b][1,4]oxazin-3(4H)-one (3.4 g, 66%); LC/MS (Table 2, Method c) Rt=1.42 min.; MS m/z: 201 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([C:5]([C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([C:18]3[CH:19]=[C:20]([CH:37]=[CH:38][CH:39]=3)[CH2:21][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[O:30])[CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)([CH3:7])[CH3:6])(=[O:4])=[O:3].[CH:40]1([Mg]Br)[CH2:42][CH2:41]1>C1COCC1.[NH4+].[Cl-]>[CH:40]1([C:29]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[O:22][CH2:21][C:20]2[CH:37]=[CH:38][CH:39]=[C:18]([C:16]3[CH:17]=[C:8]([C:5]([S:2]([CH3:1])(=[O:4])=[O:3])([CH3:7])[CH3:6])[CH:9]=[C:10]4[C:15]=3[N:14]=[CH:13][CH:12]=[CH:11]4)[CH:19]=2)([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[OH:30])[CH2:42][CH2:41]1
Reactant: CC(C)(c1cc(-c2cccc(COc3ccccc3C(=O)c3ccccc3)c2)c2ncccc2c1)S(C)(=O)=O
Reactant: Br[Mg]C1CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(c1cc(-c2cccc(COc3ccccc3C(O)(c3ccccc3)C3CC3)c2)c2ncccc2c1)S(C)(=O)=O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To solution of (2-{3-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-benzyloxy}-phenyl)-phenyl-methanone (EXAMPLE 74) (1.0 eq) in THF (0.03M) was added CeCl3 (2.7 eq). The resulting mixture was stirred for 1 h, then cooled to −78° C. Cyclopropyl magnesium bromide (0.24M in THF; 4.8 eq) was added and the final mixture was allowed to warm-up to room temperature. After stirring for 1 h the mixture was poured in saturated aqueous NH4Cl and extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. Flash chromatography (Hex:EtOAc; 40 to 100% in 15 min) afforded the title compound as a foam.
Reaction SMILES: [CH2:1]1[CH:7]([OH:8])[NH:6][P:4]([N:9]([CH2:13][CH2:14][Cl:15])[CH2:10][CH2:11][Cl:12])(=[O:5])[O:3][CH2:2]1.[CH2:16]([O:18][C:19](=[O:22])[NH:20]O)[CH3:17].ClC(Cl)(Cl)C(O)=O>C(Cl)Cl>[CH2:16]([O:18][C:19](=[O:22])[NH:20][O:8][CH:7]1[CH2:1][CH2:2][O:3][P:4]([N:9]([CH2:13][CH2:14][Cl:15])[CH2:10][CH2:11][Cl:12])(=[O:5])[NH:6]1)[CH3:17]
Reactant: O=P1(N(CCCl)CCCl)NC(O)CCO1
Reactant: CCOC(=O)NO
Agent: O=C(O)C(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)NOC1CCOP(=O)(N(CCCl)CCCl)N1
Reaction time: 72 h

Procedure:
550 mg (2 mmol) of 4-hydroxycyclophosphamide and 210 mg (2 mmol) of ethylhydroxycarbamate (hydroxyurethane) are dissolved in 5 ml of dry methylenechloride free of alcohol. A catalytic amount of trichloroacetic acid and molecular sieve 4 A are added thereto. The reaction mixture is allowed to stand at -25° C. for 3 days. Thereafter, the molecular sieve is separated and washed once with a diluted solution of NaHCO3. The methylenechloride phase is dried over sodium sulfate and part of the solvent is evaporated in a vacuum and thereafter diluted with ether. After standing for 20 hours at -25° C., the separated crystals are filtered off, washed and dried.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.C(N(CC)CC)C.[C:14](Cl)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[N:4][N:5]([C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:6]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Brc1cn[nH]c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Brc1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 70 °C
Reaction time: 3 h
Yield: 86.5 %

Procedure:
To a solution of 4-bromopyrazole (10.0 g, 68.0 mmol) in N,N-dimethylformamide (100 mL) was added dropwise triethylamine (23.7 mL, 170 mmol) under nitrogen atmosphere at room temperature. Trityl chloride (37.9 g, 136 mmol) was added to the reaction solution on an ice bath (0° C.), and stirred for 3 hours at 70° C. Water (400 mL) was added to the reaction solution to precipitate the solids. The precipitated solids were filtered and dried under a reduced pressure. The solids were then azeotropically dried with toluene to obtain the title compound (22.9 g, 87%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:20][CH3:21])=[C:16]([OH:19])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=1.O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:20][CH3:21])=[C:16]([O:19][CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24]
Reactant: ClCc1ccccn1
Reactant: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(O)cc23)cc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OCc4ccccn4)cc23)cc1Cl
Temperature: 120 °C
Reaction time: 3 h
Yield: 55 %

Procedure:
A starting compound (N-{2-chloro-4-[(6-hydroxy-7-methoxy-4-quinazolinyl)oxy]phenyl}-N′-propylurea, 80 mg), potassium carbonate (138 mg), and 2-(chloromethyl)pyridine hydrochloride (41 mg) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at 120° C. for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was washed with ethyl acetate to give 54 mg (yield 55%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.[CH3:15][C:16]1[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=1[NH2:18]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:12]([NH2:14])=[O:13])=[CH:7][C:8]=1[C:9]([NH:18][C:17]1[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=1[CH3:15])=[O:11]
Reactant: Cc1ccccc1N
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Product: COc1ccc(C(N)=O)cc1C(=O)Nc1ccccc1C

Procedure:
The captioned compound was synthesized from 6-methoxyisophthalamic acid and 2-methylaniline by the same procedure as in the manufacturing method described in step C of Example 1-3-1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:13]([O:15]CC)=[O:14])[C:5](=[O:12])[N:6]([CH:9]([CH3:11])[CH3:10])[C:7]=1[CH3:8].ClC1C=C(C(OCC)=O)C(=O)N(C(C)C)C=1C>>[F:1][C:2]1[CH:3]=[C:4]([C:13]([OH:15])=[O:14])[C:5](=[O:12])[N:6]([CH:9]([CH3:11])[CH3:10])[C:7]=1[CH3:8]
Reactant: CCOC(=O)c1cc(F)c(C)n(C(C)C)c1=O
Agent: CCOC(=O)c1cc(Cl)c(C)n(C(C)C)c1=O
Product: Cc1c(F)cc(C(=O)O)c(=O)n1C(C)C

Procedure:
The title compound was prepared according to the procedure of Example 1(7), but using ethyl 5-fluoro-1-isopropyl-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate as prepared in 5(1) instead of ethyl 5-chloro-1-isopropyl-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate.
Reaction SMILES: [Na].Cl.[C:3]([NH2:6])(=[NH:5])[CH3:4].[F:7][CH:8]([C:14](OCC)=[O:15])[C:9](OCC)=[O:10]>>[CH3:4][C:3]1[N:6]=[C:14]([OH:15])[C:8]([F:7])=[C:9]([OH:10])[N:5]=1
Reactant: CC(=N)N
Reactant: CCOC(=O)C(F)C(=O)OCC
Agent: Cl
Agent: [Na]
Product: Cc1nc(O)c(F)c(O)n1
Temperature: 23 °C
Reaction time: 0.08 h

Procedure:
According to the procedure of J. Chem. Soc. 1959, 3286, a solution of 0.92 g (40 mmol) of sodium metal dissolved in 20 mL of methaol was treated with 2.08 g (22 mmol) of acetamidine hydrochloride. After 5 minutes, to this stirred mixture was added 3.6 g (20 mmol) of diethyl fluoromalonate. The reaction mixture was heated to reflux for 18 hours, cooled to 23° C., and then concentrated in vacuo. The residue was dissolved in water, neutralized with aqueous 3N HCl (6 mL), and chilled. A precipitate which formed was isolated by filtration and triturated with a 1:1 mixture of diethyl ether/ethyl acetate. The resulting crude product (1.36 g, 47%) was used without further purification.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:10]([C:12]([O:14]CC)=[O:13])=[CH:9][NH:8][C:7]=2[CH2:6][CH2:5][CH2:4][CH2:3]1.Cl>[OH-].[Na+].C(O)C>[O:1]=[C:2]1[C:11]2[C:10]([C:12]([OH:14])=[O:13])=[CH:9][NH:8][C:7]=2[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CCOC(=O)c1c[nH]c2c1C(=O)CCCC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1c[nH]c2c1C(=O)CCCC2

Procedure:
A mixture of ethyl 4-oxo-5,6,7,8-tetrahydro-4H-cyclohepta[b]furan-3-carboxylate (3.48 g, 15.7 mmol) and ammonium acetate (2.41 g, 31.3 mmol) in N,N-dimethylformamide (25 mL) was heated at 115° C. for 6 hours. The mixture was concentrated in vacuo, ice water was added, then extracted 2× with dichloromethane. The combined organic layers were washed with saturated aqueous sodium bicarbonate then brine, dried over sodium sulfate, filtered through a small pad of Silica gel (1:19 methyl alcohol/dichloromethane), and the filtrate concentrated in vacuo to give ethyl 4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxylate (1.76 g). A solution of this ester in aqueous 5N sodium hydroxide (30 mL) and ethyl alcohol (6 mL) was heated at reflux for 1 hour, then cooled in an ice bath. The mixture was acidified with hydrochloric acid, and the precipitate collected, rinsed with water followed by diethyl ether and allowed to dry to give 4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxylic acid (1.17 g). m.p. 225°-227° C.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:17][CH2:16][CH2:15][C:4]=2[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[N:7]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]#[N:27])=[C:21]([CH3:28])[CH:20]=1>>[Cl:14][C:10]1[CH:9]=[C:8]([C:6]2[N:7]=[C:2]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][C:26]#[N:27])=[C:21]([CH3:28])[CH:20]=3)[C:3]3[CH2:17][CH2:16][CH2:15][C:4]=3[N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Cc1cc(N)ccc1CC#N
Reactant: Clc1cccc(-c2nc(Cl)c3c(n2)CCC3)c1
Product: Cc1cc(Nc2nc(-c3cccc(Cl)c3)nc3c2CCC3)ccc1CC#N
Yield: 30.6 %

Procedure:
Following procedure A2, 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (0.120 g, 0.47 mmol) was reacted with 2-(4-amino-2-methylphenyl)acetonitrile (0.104 g, 0.71 mmol) to afford the title compound (0.054 g, 45%) as an off-white solid. MW=374.87. 1H NMR (DMSO-d6, 500 MHz) δ 9.31 (s, 1H), 8.28 (s, 1H), 8.22 (d, J=7.0 Hz, 1H), 7.79 (s, 1H), 7.63-7.54 (m, 3H), 7.36 (d, J=8.2 Hz, 1H), 3.99 (s, 2H), 3.01-2.94 (m, 2H), 2.93-2.87 (m, 2H), 2.36 (s, 3H), 2.14 (t, J=7.6 Hz, 2H); APCI MS m/z 375 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([C:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:12]=2[O:18][CH3:19])[N:3]=1.[NH:20]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].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].C1(C)C=CC=CC=1>[CH3:19][O:18][C:12]1[CH:13]=[CH:14][C:15]([CH3:17])=[CH:16][C:11]=1[C:4]1[N:3]=[C:2]([N:20]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[NH:21][C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=1
Reactant: CC(C)(C)OC(=O)NNC(=O)OC(C)(C)C
Reactant: COc1ccc(C)cc1-c1cc([N+](=O)[O-])cc(Cl)n1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COc1ccc(C)cc1-c1cc([N+](=O)[O-])cc(N(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n1
Temperature: 100 °C
Reaction time: 20 h

Procedure:
A mixture of the title compound from Example 19 Step A (1.5 g, 5.4 mmol), di-tert-butyl hydrazine-1,2-dicarboxylate (1.375 g, 5.92 mmol), DPPF (360 mg, 0.65 mmol), Pd2 dba3 (0.4 g, 0.43 mmol), Cs2CO3 (1.90 g, 5.83 mmol) and 12 mL toluene was stirred at 100° C. After 20 h, the mixture was allowed to cool to ambient temperature, then purification by flash chromatography on silica gel using hexane-EtOAc (20:1 to 4:1 v/v) as mobile phase provided the title compound: LCMS m/z 375.6 (observed [M+H]+ for the ion corresponding to loss of one Boc group); 1H NMR (400 MHz, acetone-d6) δ 7.86 (d, J=2.1 Hz, 1H), 7.26 (dd, J=8.4, 2.1 Hz, 1H), 7.07 (d, J=8.4, 2.1 Hz, 1H), 3.93 (s, 3H), 2.31 (s, 3H), 1.54 (s, 9H), 1.47 (s, 9H).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15]C)[CH:10]=1)(=[O:8])=[O:7].B(Br)(Br)[Br:18]>C(Cl)Cl>[Br:18][CH2:2][CH2:3][CH2:4][NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=1)(=[O:8])=[O:7]
Reactant: BrB(Br)Br
Reactant: COc1cccc(S(=O)(=O)NCCCO)c1
Solvent: ClCCl
Product: O=S(=O)(NCCCBr)c1cccc(O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-(3-Hydroxy-propyl)-3-methoxy-benzenesulfonamide (0.478 g, 1.95 mmol) in CH2Cl2(10 mL) at 0° C. was treated with BBr3 (9.74 mL of a 1M solution in CH2Cl2, 9.74 mmol) then left to warm to room temperature. After 1 h, the reaction mixture was concentrated in vacuo, neutralized to pH 6 with aqueous saturated NaHCO3 solution, and extracted with CH2Cl2 (3×20 mL), dried (MgSO4), filtered and concentrated to give the title compound. MS (M+1) 294.
Reaction SMILES: [H-].[Na+].C1(CC[OH:11])C=CC=CC=1.[NH2:12][C:13]1[N:14]=[C:15]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:16]([C:23]2[CH:24]=[CH:25][C:26](=[O:30])[N:27]([CH3:29])[N:28]=2)=[N:17][C:18]=1S(C)(=O)=O.Cl>>[NH2:12][C:13]1[N:14]=[C:15]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:16]([C:23]2[CH:24]=[CH:25][C:26](=[O:30])[N:27]([CH3:29])[N:28]=2)=[N:17][C:18]=1[OH:11]
Reactant: OCCc1ccccc1
Reactant: Cn1nc(-c2nc(S(C)(=O)=O)c(N)nc2-c2ccccc2)ccc1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: Cn1nc(-c2nc(O)c(N)nc2-c2ccccc2)ccc1=O
Temperature: 27.5 °C
Reaction time: 0.5 h

Procedure:
To a suspension of NaH (60% in oil suspension) (33.6 mg) in 1,2-dimethyl-2-imidazolidinone (0.6 ml) was added 2-phenylethanol (0.101 ml) and the mixture was stirred at 25-30° C. for 30 minutes. 6-[5-Amino-6-(methylsulfonyl)-3-phenyl-2-pyrazinyl]-2-methyl-3(2H)-pyridazinone (150 mg) was added and the mixture was heated at 100-105° C. for 15 hours. To the mixture was added 0.1N HCl (3 ml) and a precipitate was collected by filtration. The precipitate was suspended in CHCl3 and collected by filtration to give 6-(5-amino-6-hydroxy-3-phenyl-2-pyrazinyl)-2-methyl-3(2H)-pyridazinone (60 mg). The CHCl3 solution was dried over MgSO4, concentrated under reduced pressure and purified by column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (50:50 v/v) to give a solid. The solid was suspended in acetone and collected by filtration to give 6-[5-amino-3-phenyl-6-(2-phenylethoxy)-2-pyrazinyl]-2-methyl-3(2H)-pyridazinone (7 mg).
Reaction SMILES: [Cl:1][C:2]1([Cl:11])[C:6]([Cl:7])=[C:5]([Cl:8])[C:4]([Cl:9])=[C:3]1[Cl:10].[C:12]1(=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:22])[CH:14]=[CH:13]1>C1(C)C=CC=CC=1>[Cl:7][C:6]12[C:2]([Cl:11])([Cl:1])[C:3]([Cl:10])([CH:14]3[CH:13]1[C:12](=[O:23])[C:21]1[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:15]3=[O:22])[C:4]([Cl:9])=[C:5]2[Cl:8]
Reactant: ClC1=C(Cl)C(Cl)(Cl)C(Cl)=C1Cl
Reactant: O=C1C=CC(=O)c2ccccc21
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)C2C1C1(Cl)C(Cl)=C(Cl)C2(Cl)C1(Cl)Cl
Temperature: 25 °C

Procedure:
Hexachlorocyclopentadiene (60 g.), 1,4-naphthoquinone (31.6 g.), and 30 ml. of toluene were mixed, heated to reflux temperature, and maintained at this temperature for 4 hours. After cooling to room temperature and extracting the excess hexachlorocyclopentadiene with Skelly "B" solvent, the mixture solidified slowly. This crude brown solid was recrystallized repeatedly from benzene/Skelly "B" mix-solvent (70/30) to yield white crystals, m.p. 116°-118° C.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=2)[CH:3]=[N:2]1.[C:12]1(B(O)O)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1.N1C=CC=CC=1>ClCCl.CC([O-])=O.CC([O-])=O.[Cu+2]>[C:20]1([N:1]2[CH:5]=[C:4]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=3)[CH:3]=[N:2]2)[C:21]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: OB(O)c1cccc2ccccc12
Reactant: c1ccc(-c2cn[nH]c2)nc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: c1ccc(-c2cnn(-c3cccc4ccccc34)c2)nc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To 2-(1H-pyrazol-4-yl)pyridine (292 mg, 2 mmol), 1-napthaleneboronic acid (690 mg, 4 mmol), Cu(OAc)2 (547 mg, 3 mmol) and pyridine (0.32 mL, 4 mmol) in dichloromethane (4 mL) was added 0.5 g of 4 Å molecular sieves. The resulting reaction mixture was stirred at ambient temperature under atmospheric conditions for 48 h, whereupon it was filtered through Celite, washing with dichloromethane. The reaction mixture was concentrated on to silica gel in vacuo and purified by liquid chromatography onto silica gel eluting with EtOAc:hex (2:8 to 3:7) to afford 2-[1-(1-naphthyl)-1H-pyrazol-4-yl]pyridine as a white solid. 1H NMR (CD3Cl, 300 MHz) δ 8.63-8.65 (1H, m), 8.39 (1H, s), 8.34 (1H, s), 7.94-7.99 (3H, m), 7.73 (1H, ddd), 7.53-7.64 (5H, m), 7.18 (1H, m). MS (ESI) 272 (M+H)+
Reaction SMILES: [N+:1]([CH2:4][CH2:5][O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][O:8]1)([O-:3])=O.[CH2:13]([O:15][C:16](=[O:26])[C:17]#[C:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:25])[CH3:14].C1(N=C=O)C=CC(N=C=O)=CC=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:13]([O:15][C:16]([C:17]1[C:4]([CH2:5][O:6][CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)=[N:1][O:3][C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:25])=[O:26])[CH3:14]
Reactant: CCOC(=O)C#Cc1ccccc1Cl
Reactant: O=[N+]([O-])CCOC1CCCCO1
Agent: O=C=Nc1ccc(N=C=O)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(COC2CCCCO2)noc1-c1ccccc1Cl
Temperature: 70 °C
Yield: 94.2 %

Procedure:
Add 2-(2-nitroethoxy)tetrahydropyran (41 mL, 270 mmol) dropwise in toluene (100 mL) to a solution of (2-chloro-phenyl)-propynoic acid ethyl ester (28.3 g, 135 mmol), 1,4-phenylene diisocyanate (67 g, 420 mmol) and triethylamine (15 mL) in toluene (900 mL). Stir at reflux for 10 h. While still warm (˜70° C.), filter the reaction mixture through Celite®, washing the solids with EtOAc. Wash the filtrate with 1N HCl (500 mL) and brine (500 mL). Dry the organics over Na2SO4, filter and concentrate under reduced pressure. Purification by flash chromatography (silica gel, 85:15 Hexanes/EtOAc) gives the title compound (46.5 g, 94%). MS (m/e): 282 (M−C5H8O+H+); 1H NMR (300 MHz, CDCl3) δ 7.35–7.55 (m, 4H), 5.09 (d, J=13 Hz, 1), 4.85–4.91 (m, 2H), 4.15–4.22 (m, 2H), 3.91–4.01 (m, 1H), 3.52–3.61 (m, 1H), 1.49–1.92 (m, 6H), 1.12 (t, J=7 Hz, 3H); TLC Rf=0.53 (7:3 Hexanes/EtOAc).
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]3)=[CH:20][N:19]=2)[C:3]1=[O:31].[C:32]([O:35][CH2:36][C:37]1[C:42]([N:43]2[CH2:54][CH2:53][N:52]3[C:45](=[CH:46][C:47]4[CH2:48][C:49]([CH3:56])([CH3:55])[CH2:50][C:51]=43)[C:44]2=[O:57])=[CH:41][CH:40]=[CH:39][C:38]=1Br)(=[O:34])[CH3:33]>C([O-])([O-])=O.[Na+].[Na+].COCCOC.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>[C:32]([O:35][CH2:36][C:37]1[C:38]([C:6]2[CH:5]=[C:4]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]4)=[CH:20][N:19]=3)[C:3](=[O:31])[N:2]([CH3:1])[CH:7]=2)=[CH:39][CH:40]=[CH:41][C:42]=1[N:43]1[CH2:54][CH2:53][N:52]2[C:45](=[CH:46][C:47]3[CH2:48][C:49]([CH3:56])([CH3:55])[CH2:50][C:51]=32)[C:44]1=[O:57])(=[O:34])[CH3:33]
Reactant: CN1CCN(c2ccc(Nc3cc(B4OC(C)(C)C(C)(C)O4)cn(C)c3=O)nc2)CC1
Reactant: CC(=O)OCc1c(Br)cccc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
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: [Na+]
Solvent: COCCOC
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C)CC4)cn3)c(=O)n(C)c2)cccc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 125 °C
Reaction time: 0.12 h
Yield: 23.3 %

Procedure:
In a 10-mL glass vessel equipped with a magnetic stirring bar were placed 1-methyl-3-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyridin-2-one 197e (210 mg, 0.49 mmol), 10-[2-(acetoxymethyl)-3-bromophenyl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-9-one 167f (143 mg, 0.33 mmol), Pd(PPh3)4 (30 mg, 0.0.26 mmol) in 2 N Na2CO3 (2 mL) and 1,2-dimethoxyethane (5 mL). The vessel was sealed with a septum and placed into the microwave cavity. After the reaction mixture was stirred at 125° C. for 7 min., it was purified by flash chromatography (dichloromethane:methanol, 85:15) to give 26% (50 mg) of 173a as a solid.