Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH2:6][CH2:5]2.Br[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[C:20]([F:23])([F:22])[F:21].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[C:20]([F:23])([F:22])[F:21])[CH2:6][CH2:5]2
Reactant: FC(F)(F)c1ccncc1Br
Reactant: O=C1NCCc2cc(F)ccc21
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=C1c2ccc(F)cc2CCN1c1cnccc1C(F)(F)F
Yield: 63.8 %

Procedure:
6-Fluoro-3,4-dihydroisoquinolin-1(2H)-one (I-78d: 500 mg, 3.029 mmol) was reacted with 3-bromo-4-(trifluoromethyl)-pyridine (890 mg, 3.93 mmol), 1,4-dioxane (15 mL), copper iodide (57.5 mg, 0.30 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (43 mg, 0.302 mmol) and potassium phosphate (1.92 g, 9.08 mmol) for 36 hours at 120° C. to afford the crude product. Purification by column chromatography on silica gel (2% methanol in CHCl3), afforded 600 mg of the product (64.5% yield).
Reaction SMILES: [CH3:1][C:2]12[CH2:15][C:6]1([C:7]([O:9][CH2:10][C:11]([Cl:14])([Cl:13])[Cl:12])=[O:8])[N:5]1[C:16](=[O:29])[CH:17]([NH:18][C:19](=[O:28])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)[C@H:4]1[S:3]2.[Br-].[Al+3].[Br-].[Br-]>ClCCl>[CH3:1][CH:2]1[CH:15]=[C:6]([C:7]([O:9][CH2:10][C:11]([Cl:12])([Cl:14])[Cl:13])=[O:8])[N:5]2[C:16](=[O:29])[CH:17]([NH:18][C:19](=[O:28])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)[C@H:4]2[S:3]1
Reactant: CC12CC1(C(=O)OCC(Cl)(Cl)Cl)N1C(=O)C(NC(=O)Cc3cccc(Cl)c3)[C@H]1S2
Agent: [Al+3]
Agent: [Br-]
Solvent: ClCCl
Product: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)Cc3cccc(Cl)c3)[C@H]2S1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.3 %

Procedure:
A solution of 2,2,2-trichloroethyl 2-methyl-2,3-methylene-6-{2-(3-chlorophenyl)acetamido}penam-3-carboxylate (3.4 g.) in dried dichloromethane (50 ml.) was dropwise added at -15° C. to a solution of aluminum bromide (2.8 g.) in dried dichloromethane (20 ml.) and the mixture was stirred for 3 hours at room temperature. After the reaction, the reaction mixture was washed in turn with 5% hydrochloric acid, water, 5% sodium bicarbonate aqueous solution and water and then dried. After the solvent was distilled off, the residue was crystallized from ether to give 2,2,2-trichloroethyl 2-methyl-7-{2-(3-chlorophenyl)acetamido}-3-cephem-4-carboxylate (2.9 g.), mp 144° to 145.5° C. (dec.).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][CH3:19])[CH:13]=[N:12]2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:20][C:21]1[CH:25]=[CH:24][N:23]([CH2:26][C:27]([CH3:30])([OH:29])[CH3:28])[N:22]=1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][CH3:19])[CH:13]=[N:12]2)[C:8]([NH:20][C:21]2[CH:25]=[CH:24][N:23]([CH2:26][C:27]([OH:29])([CH3:28])[CH3:30])[N:22]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cnn(C(CC2CCCC2)C(=O)O)c(=O)c1
Reactant: CC(C)(O)Cn1ccc(N)n1
Product: COc1cnn(C(CC2CCCC2)C(=O)Nc2ccn(CC(C)(C)O)n2)c(=O)c1
Yield: 29 %

Procedure:
Using the method described in Example 80, Step 3,3-cyclopentyl-2-(4-methoxy-6-oxo-6H-pyridazin-1-yl)-propionic acid (as prepared in Example 80, Step 2) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(4-methoxy-6-oxo-6H-pyridazin-1-yl)-propionamide as an off-white solid (45.1 mg, 29%); ES+-HRMS m/e calcd for C20H29N5O4 [M+H+] 404.2293 found 404.2292. 1H-NMR (300 MHz, DMSO-d6) δ ppm 1.04 (m, 1H), 1.05 (s, 3H), 1.06 (s, 3H), 1.18-1.77 (m, 8H), 1.91 (m, 1H), 2.26 (m, 1H), 3.81 (s, 3H), 3.89 (s, 2H), 4.67 (s, 1H), 5.46 (dd, J=4.1, J=11.3 Hz, 1H), 6.29 (d, J=2.7 Hz, 1H), 6.39 (s, 1H), 7.52 (s, 1H), 7.84 (d, J=2.7 Hz, 1H), 10.73 (s, 1H).
Reaction SMILES: [C:1]1([CH2:11][C:12]([OH:14])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:15][NH:16][C@@H:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][C@H:18]1[N:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH3:15][N:16]([C@@H:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][C@H:18]1[N:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1)[C:12](=[O:14])[CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CN[C@@H]1c2ccccc2CC[C@H]1N1CCCC1
Reactant: O=C(O)Cc1cccc2ccccc12
Product: CN(C(=O)Cc1cccc2ccccc12)[C@@H]1c2ccccc2CC[C@H]1N1CCCC1
Yield: 54.9 %

Procedure:
Using the procedure of Step C of Example 1, 2.3 g of 1-naphthylacetic acid and 2 g of the product of Step B of Example 1 were reacted to obtain 5.3 g of crude product which was purified by chromatography on silica (methylene chloride 9-methanol 1). After crystallization from ethyl ether, 1.9 g of product melting at 117° C. were obtained which was crystallized from isopropyl ether to obtain 1.1 g of the expected product melting at 125° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH2:14]1[CH2:18]OC[CH2:15]1>C1([Mg]Br)CC1>[CH:15]1([C:7]([OH:13])([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:14][CH2:18]1
Reactant: CCOC(=O)C(=O)c1ccccn1
Reactant: C1CCOC1
Agent: Br[Mg]C1CC1
Product: CCOC(=O)C(O)(c1ccccn1)C1CC1
Reaction time: 1 h

Procedure:
To a stirred solution of ethyl 2-(2-pyridyl)-2-oxoacetate (1.0 g, 5.6 mmol) in 10 mL of THF at −78° C. under nitrogen atmosphere was added in 0.92M cyclopropyl magnesium bromide in THF solution (6.7 mL, 7.3 mmol). The reaction was then allowed to equilibrate to 0° C. and stir for 1 h. The reaction was quenched with saturated NH4Cl solution and partitioned between EtOAc and water. The EtOAc layer was separated, dried over anhydrous Na2SO4, and filtered. The filtrate solvent was removed under reduced pressure and the residue was purified by flash silica gel chromatography using 1% methanol in dichloromethane as an eluent. After concentration of desired fractions in vacuo ethyl 2-cyclopropyl-2-(2-pyridyl)hydroxyacetate was obtained as a yellow oil (0.9 g; 1H NMR, 400 MHz, CDCl3, 8.52 ppm (d, 1H), 7.76 ppm (m, 2H), 7.25 ppm (m, 1H), 5.18 ppm (s, 1H), 4.23 ppm (q, 2H), 1.8 ppm (m, 1H), 1.24 ppm (t, 3H), 0.72 ppm (m, 1H), 0.47 ppm (m, 2H), 0.37 ppm (m, 1H)).
Reaction SMILES: [C:1]([C:8]([NH2:32])([CH2:12][CH2:13][CH2:14][C:15]1([CH2:21][C:22]([O:24]CC2C=CC=CC=2)=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:9]([OH:11])=[O:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[N+](=[CH2:35])=[N-]>C(Cl)Cl>[C:1]([C:8]([NH2:32])([CH2:12][CH2:13][CH2:14][C:15]1([CH2:21][C:22]([OH:24])=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)[C:9]([O:11][CH3:35])=[O:10])([O:3][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:2]
Reactant: C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)C(N)(CCCC1(CC(=O)OCc2ccccc2)CCCCC1)C(=O)O
Solvent: ClCCl
Product: COC(=O)C(N)(CCCC1(CC(=O)O)CCCCC1)C(=O)OC(C)(C)C

Procedure:
The Boc-benzyl ester (J) (4 mmol) is dissolved in methylene chloride and treated with excess ethereal diazomethane at room temperature. The residual diazomethane is quenched with acetic acid and the solution is evaporated at reduced pressure. The crude diester is dissolved in methanol and hydrogenated over 10% palladium-on-carbon to give, after flash chromatography (silica gel), the titled compound.
Reaction SMILES: [F:1][CH:2]([F:29])[C@@H:3]1[C@@H:11]2[C@@:6]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=3[F:28])([N:7]=[C:8]([NH:12]C(=O)C3C=CC=CC=3)[S:9][CH2:10]2)[CH2:5][O:4]1.N12CCCN=C1CCCCC2>CO>[F:29][CH:2]([F:1])[C@@H:3]1[C@@H:11]2[C@@:6]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=3[F:28])([N:7]=[C:8]([NH2:12])[S:9][CH2:10]2)[CH2:5][O:4]1
Reactant: O=C(NC1=N[C@@]2(c3cccc(F)c3F)CO[C@H](C(F)F)[C@H]2CS1)c1ccccc1
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Product: NC1=N[C@@]2(c3cccc(F)c3F)CO[C@H](C(F)F)[C@H]2CS1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
N-((4aS,5S,7aS)-5-(difluoromethyl)-7a-(2,3-difluorophenyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)benzamide, obtained in Preparation Example 1-(8), (891 mg) was dissolved in methanol (10 mL), 1,8-diazabicyclo[5.4.0]undec-7-ene (1.02 g) was added, and the solution was heated to reflux (heating block temperature 70° C.). After 16 h, the reaction mixture was cooled, concentrated under reduced pressure, and the residue purified by silica gel column chromatography (0% to 80% EtOAc in hexanes) to afford the title compound (565 mg). 1H NMR (400 MHz, CDCl3) δ ppm 2.88 (dd, J=13.4, 4.0 Hz, 1H), 3.13 (dd, J=13.6, 3.3 Hz, 1H), 3.24 (dt, J=7.7, 3.7 Hz, 1H), 3.89 (d, J=8.3 Hz, 1H), 4.33-4.70 (m, 4H), 5.94 (td, J=56.3, 3.8 Hz, 1H), 7.05-7.25 (m, 3H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]#[CH:21])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH3:18])[C:15]([OH:17])=O)[C:10](=[O:19])[CH:9]=2)[CH:7]=1.[NH2:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]#[CH:21])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH3:18])[C:15]([NH:22][C:23]3[CH:24]=[CH:25][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:31][CH:32]=3)=[O:17])[C:10](=[O:19])[CH:9]=2)[CH:7]=1
Reactant: C#Cc1ccc(Cl)cc1-c1ccn(C(C)C(=O)O)c(=O)c1
Reactant: COC(=O)c1ccc(N)cc1
Product: C#Cc1ccc(Cl)cc1-c1ccn(C(C)C(=O)Nc2ccc(C(=O)OC)cc2)c(=O)c1

Procedure:
50 mg (purity 82%, 0.32 mmol) of 2-[4-(5-chloro-2-ethynylphenyl)-2-oxopyridin-1(2H)-yl]propanoic acid (racemate) and 1.2 eq. of methyl 4-aminobenzoate were reacted according to General Method 5A. Yield: 15 mg (25% of theory)
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([Mg]Br)=[CH:13][CH:12]=1>C1COCC1>[Br:1][C:2]1[N:7]=[C:6]([CH:8]([C:14]2[CH:15]=[CH:16][C:11]([F:10])=[CH:12][CH:13]=2)[OH:9])[CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cccc(Br)n1
Reactant: Fc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: OC(c1ccc(F)cc1)c1cccc(Br)n1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a mixture of the 6-Bromo-2-pyridine carboxaldehyde (6.12 g, 32.90 mmol) in anhydrous THF (150 mL) @ −78° C. under N2 was added 4-fluorophenylmagnesium bromide (2M in diethyl ether, 17.27 mL) dropwise. The reaction was warmed to 0° C. and stirred for 1.5 hr. The reaction was quenched with saturated aqueous NH4Cl. The combined organics were dried (anhd. Na2SO4), filtered, and concentrated to give (6-bromopyridin-2-yl)(4-fluorophenyl)methanol. 1H NMR (500 MHz, CDCl3) δ 7.50 (t, 1H, J=7.7), 7.40 (d, 1H, J=7.8), 7.38-7.32 (m, 2H), 7.10 (d, 1H, J=7.6), 7.03 (t, 2H, J=8.7), 5.73 (d, 1H, J=4.2), 4.43 (d, 1H, J=4.4), LRMS m/z (M+H) Calcd.: 282.0, found: 282.0.
Reaction SMILES: [C:1](C1NC=CN=1)(C1NC=CN=1)=O.[Cl:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[CH:21]1[C:26]([C:27]([O:29][CH3:30])=[O:28])=[C:25]([CH3:31])[NH:24][C:23]([CH2:32][O:33][CH2:34][C:35](O)=[O:36])=[C:22]1[C:38]([O:40][CH2:41][CH3:42])=[O:39].N1C=CC=CC=1.CC1(C)OC(=O)CC(=O)O1>ClCCl>[Cl:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[CH:21]1[C:26]([C:27]([O:29][CH3:30])=[O:28])=[C:25]([CH3:31])[NH:24][C:23]([CH2:32][O:33][CH2:34][C:35]([CH3:1])=[O:36])=[C:22]1[C:38]([O:40][CH2:41][CH3:42])=[O:39]
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: CCOC(=O)C1=C(COCC(=O)O)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Agent: CC1(C)OC(=O)CC(=O)O1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C1=C(COCC(C)=O)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 48 h
Yield: 32.6 %

Procedure:
A solution of carbonyl diimidazole (8.00 g) and 2-{[4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyrid-2-yl]methoxy}acetic acid (20.00 g) in dichloromethane (400 ml) was stirred at room temperature under nitrogen for 2 hours and then added to a solution of pyridine (3.60 g) and 2,2-dimethyl-1,3-dioxan-4,6-dione (6.50 g) in dichloromethane over 5 minutes. The mixture was stirred at room temperature for 2 days, washed successively with ice-cold 2.5M hydrochloric acid and saturated brine, dried over magnesium sulphate and evaporated. The residue was dissolved in water (300 ml) and acetic acid (150 ml) and refluxed for 5 hours. The mixture was evaporated and partitioned between diethyl ether (800 ml) and 10% aqueous sodium carbonate. The ether solution was dried over magnesium sulphate and evaporated. The residue was chromatographed on "Kieselgel 60-H" (Trade Mark) silica (50 g) using 30% hexane in dichloromethane. Fractions which contained the pure product were evaporated to give the title compound (6.5 g), m.p. 117°-119°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:20])[C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[S:21]([NH2:24])(=[O:23])=[O:22].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:18])([F:17])[F:19])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[S:21]([NH2:24])(=[O:23])=[O:22]
Reactant: NS(=O)(=O)c1cc(C(O)c2ccc(OC(F)(F)F)cc2)ccc1Cl
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)=O
Product: NS(=O)(=O)c1cc(C(=O)c2ccc(OC(F)(F)F)cc2)ccc1Cl
Reaction time: 0.5 h

Procedure:
2-Chloro-5-[hydroxy-(4-trifluoromethoxy-phenyl)-methyl]-benzenesulfonamide is dissolved in acetone (10 mL), and treated with a solution of Jones reagent (3 M in water, 0.91 mmol). The reaction is allowed to stir for 30 minutes. The reaction is diluted with water and extracted with dichloromethane. The organic phase is separated and concentrated in vacuo. The residue is purified by silica gel chromatography (gradient of ethyl acetate in hexanes 10-50%) affording 92 mg of the title compound. 1H NMR (CDCl3) δ 5.20 (s, 2H), 7.35 (d, 2H, J=8.3 Hz), 7.70 (d, 1H, J=8.3), 7.84 (d, 2H, J=8.7 Hz), 7.95 (dd, 1h, J=1.9, 8.3), 8.48 (d, 1H, J=1.9). MS (m/z): 378 (M−1). CHN Calc C, 44.28; H, 2.39; N, 3.69. Found C, 43.97; H, 2.22; N, 3.60.
Reaction SMILES: [C:1]([C:3]1[C:4]2[N:5]([CH:21]=[N:22][N:23]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)#[N:2].[Br:24]N1C(=O)CCC1=O>C(Cl)Cl>[Br:24][C:21]1[N:5]2[CH:6]=[CH:7][C:8]([N:9]3[CH2:14][CH2:13][CH:12]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH2:11][CH2:10]3)=[C:3]([C:1]#[N:2])[C:4]2=[N:23][N:22]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1c(N2CCC(c3ccccc3)CC2)ccn2cnnc12
Solvent: ClCCl
Product: N#Cc1c(N2CCC(c3ccccc3)CC2)ccn2c(Br)nnc12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of intermediate D8 (0.49 g, 1.615 mmol) in DCM (20 ml) was added N-bromosuccinimide (0.316 g, 1.777 mmol). The resulting mixture was stirred at r.t. for 1.5 h. The mixture was carefully washed with NaHCO3 (aqueous sat. solution) and extracted with DCM. The organic layer was separated, dried (Na2SO4) and concentrated in vacuo to yield intermediate D97 (0.48 g, 78%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH3:9])#[CH:2].[CH3:10][O:11][C:12]([C:14]1[C:19](Br)=[CH:18][N:17]=[C:16]([S:21][CH3:22])[N:15]=1)=[O:13].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl.[Cu]I.CN(C)C=O>[CH3:10][O:11][C:12]([C:14]1[C:19]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[CH3:9])=[CH:18][N:17]=[C:16]([S:21][CH3:22])[N:15]=1)=[O:13]
Reactant: COC(=O)c1nc(SC)ncc1Br
Reactant: C#Cc1ccccc1C
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1nc(SC)ncc1C#Cc1ccccc1C
Temperature: 100 °C
Yield: 79.4 %

Procedure:
A mixture of 1-ethynyl-2-methylbenzene (0.53 g, 4.6 mmol), 5-bromo-2-methylsulfanylpyrimidine-4-carboxylic acid methyl ester (11.0 g, 3.8 mmol), triethylamine (2.5 ml), triphenylphosphine (0.125 g, 0.48 mmol), copper (I) iodide (0.025 g, 0.13 mmol), bistriphenyphosphinepalladium (II) dichloride (0.10 g, 0.14 mmol) and dimethylformamide (1 ml) was stirred in a heavy-walled Smith process vial and irradiated with microwaves to maintain 100° C. for 20 min. The cooled mixture was diluted with dichloromethane (20 ml) and washed with 5% hydrochloric acid (20 ml), water (20 ml), saturated aqueous sodium hydrogencarbonate solution (20 ml) and water (20 ml) then dried (MgSO4) and evaporated in vacuo. The residual oil was purified by flash column chromatography over silica using a 1:4 mixture of hexane and dichloromethane as eluant. Appropriate fractions were combined and the solvents removed in vacuo to give 2-methylsulfanyl-5-(2-methylphenyl)ethynylpyrimidine-4-carboxylic acid methyl ester (0.9 g) as an orange oil. 250 MHz 1H-NMR (CDCl3) δ (ppm): 2.45 (s, 3H) (ArCH3), 2.55 (s, 3H) (—SCH3), 3.95 (s, 3H)(CO2CH3), 7.05-7.25 (m, 3H) (3×ArH), 7.45 (m, 1H) (ArH), 8.7 (s, 1H) (ArH); m/z (M+H)+. 299, HPLC purity 96%, HPLC retention time 4.15 min.
Reaction SMILES: [Br-].[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([CH2:13][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[N:10]2)=[CH:5][CH:4]=1.[Li]CCCC.[CH:38]([C:40]1[CH:41]=[C:42]([CH:46]([S:59][CH2:60][CH:61]([CH3:66])[C:62]([O:64][CH3:65])=[O:63])[CH2:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[C:55]([OH:58])([CH3:57])[CH3:56])[CH:43]=[CH:44][CH:45]=1)=O>C1COCC1>[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([CH:13]=[CH:38][C:40]3[CH:41]=[C:42]([CH:46]([S:59][CH2:60][CH:61]([CH3:66])[C:62]([O:64][CH3:65])=[O:63])[CH2:47][CH2:48][C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=4[C:55]([OH:58])([CH3:57])[CH3:56])[CH:43]=[CH:44][CH:45]=3)=[N:10]2)=[CH:5][CH:4]=1
Reactant: Clc1ccc2ccc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)nc2c1
Reactant: COC(=O)C(C)CSC(CCc1ccccc1C(C)(C)O)c1cccc(C=O)c1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)C(C)CSC(CCc1ccccc1C(C)(C)O)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To ((7-chloro-2-quinolinyl)methyl)triphenylphosphonium bromide (525 mg, 1.01 mmol, U.S. Pat. No. 4,851,409, Example 4, Step 2) in a THF (2 mL) solution at -78° C. was added dropwise 1.6M nBuLi (472 mL, 0.945 mmol). After a few minutes, the aldehyde of Step 11 (140 mg, 0.338 mmol) was then added and the resulting mixture was stirred at -78° C. for 30 min. The reaction mixture was then allowed to warm to r.t. for 30 min and was quenched by the addition of 25% aq NH4OAc. The title product was then extracted with EtOAc, dried on Na2SO4 and evaporated under reduced pressure. After purification by flash chromatography (20% EtOAc in toluene), the title compound was obtained as an oil (170 mg, 89%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)[CH:6]=[CH:5][C:4]=1[NH:15][CH:16]=O.C[Si](C)(C)[N-][Si](C)(C)C.[Na+].[Cl:28][C:29]1[C:34]2[N:35]=C(S(C)(=O)=O)[N:37]=[CH:38][C:33]=2[CH:32]=[C:31]([CH:43]2[CH2:45][CH2:44]2)[N:30]=1.[OH-].[Na+]>C1COCC1.CO>[Cl:28][C:29]1[C:34]2[N:35]=[C:16]([NH:15][C:4]3[CH:5]=[CH:6][C:7]([C:9]4[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=4)=[CH:8][C:3]=3[O:2][CH3:1])[N:37]=[CH:38][C:33]=2[CH:32]=[C:31]([CH:43]2[CH2:44][CH2:45]2)[N:30]=1
Reactant: CS(=O)(=O)c1ncc2cc(C3CC3)nc(Cl)c2n1
Reactant: COc1cc(-c2cnn(C)c2)ccc1NC=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(-c2cnn(C)c2)ccc1Nc1ncc2cc(C3CC3)nc(Cl)c2n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 48 %

Procedure:
N-(2-Methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)formamide (Preparation 56, 50 mg 0.21 mmole) was stirred in THF (1 mL). Sodium hexamethyldisilazide (0.25 mL of 1M solution in THF) was added and the reaction stirred at room temperature for 20 minutes. 8-Chloro-6-cyclopropyl-2-(methylsulfonyl)pyrido[3,4-d]pyrimidine (Preparation 179, 80 mg, 0.28 mmole) was added as a suspension in THF (1.5 mL) and the reaction was stirred at room temperature for 80 minutes. Methanol (1 mL) and 1M sodium hydroxide solution (1 mL) were added to the reaction and stirred for 55 minutes. The solvents were then concentrated in vacuo. The residue was partitioned between chloroform (10 mL) and water (10 mL). The layers were separated and the aqueous was again extracted with chloroform. The combined organic layers were dried and concentrated in vacuo. The residue was purified using preparative TLC eluting with 1:1 acetone:cyclohexane to afford the title compound (41 mg 44%).
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2C(=O)C3=CC=CC=C3C2=O)=[CH:6][C:5]=1[F:21])#[N:2]>CO.O.NN>[C:1]([CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][C:5]=1[F:21])#[N:2]
Reactant: N#CCc1ccc(N2C(=O)c3ccccc3C2=O)cc1F
Agent: NN
Solvent: CO
Solvent: O
Product: N#CCc1ccc(N)cc1F
Yield: 76.3 %

Procedure:
To a solution of the compound (164 mg) obtained in Example 250 in methanol (5 ml), hydrazine monohydrate (0.057 ml) was added and heated under reflux for 3 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=6:4) to give 67 mg of the titled compound (yield, 76%).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[CH2:7]([O:9][C:10]1[CH:11]=[C:12](B(O)O)[CH:13]=[CH:14][CH:15]=1)[CH3:8]>>[CH2:7]([O:9][C:10]1[CH:15]=[C:14]([C:2]2[S:3][CH:4]=[CH:5][CH:6]=2)[CH:13]=[CH:12][CH:11]=1)[CH3:8]
Reactant: CCOc1cccc(B(O)O)c1
Reactant: Brc1cccs1
Product: CCOc1cccc(-c2cccs2)c1

Procedure:
2-Bromothiophene and 3-ethoxyphenylboronic acid were treated in a manner similar to Reference Example 20-(1) to give 2-(3-ethoxyphenyl)thiophene as colorless oil. APCI-Mass m/Z 205 (M+H).
Reaction SMILES: N[C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[C:8]([Br:18])[CH:9]=[C:10]([C:15]([NH2:17])=[O:16])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.C(I)[I:20].N(OCCC(C)C)=O>[Cu]I>[Br:18][C:8]1[CH:9]=[C:10]([C:15]([NH2:17])=[O:16])[C:11]2[NH:12][C:13]3[C:5]([C:6]=2[CH:7]=1)=[CH:4][CH:3]=[C:2]([I:20])[CH:14]=3
Reactant: ICI
Reactant: NC(=O)c1cc(Br)cc2c1[nH]c1cc(N)ccc12
Agent: [Cu]I
Agent: CC(C)CCON=O
Product: NC(=O)c1cc(Br)cc2c1[nH]c1cc(I)ccc12
Temperature: 55 °C
Reaction time: 0.17 h

Procedure:
To a mixture of 7-amino-3-bromo-9H-carbazole-1-carboxamide 470B (1 g, 2.79 mmol) and CH2I2 (15 mL) was slowly added isopentyl nitrite (1 mL, 7.48 mmol). The mixture was heated in microwave at 60° C. for 45 mins copper(I) iodide (0.266 g, 1.397 mmol) was added to the reaction mixture and heated in microwave at 55° C. for additional 30 mins The mixture was concentrated. EtOAc(50 ml) was added and stirred for 10 mins and filtered. The collected solid was washed with H2O 2×50 ml. The remaining solid was purified using preparative HPLC to give titled product. MS (ESI) m/z 412.82 (M−H)−.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18])=[O:11].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH:28](Cl)[C:29]([OH:31])=[O:30]>CC(O)C.O>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][C:3]2[C:10](=[O:11])[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[O:18][CH:28]([C:29]([OH:31])=[O:30])[O:1][C:2]=2[CH:7]=1
Reactant: COc1ccc(C(=O)c2ccccc2O)c(O)c1
Reactant: O=C(O)C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Product: COc1ccc2c(c1)OC(C(=O)O)Oc1ccccc1C2=O
Reaction time: 48 h

Procedure:
(2-Hydroxy-4-methoxyphenyl)(2-hydroxyphenyl)methanone (16.1 g, 65.9 mmol), 36.5 g (258 mmol) of potassium carbonate, and 3.00 g (18 mmol) of potassium iodide were suspended in 250 ml of 2-propanol and heated with stirring. Dichloroacetic acid (6.00 ml, 72.6 mmol) was added slowly with a syringe and the mixture heated at reflux with stirring. After 48 hours another 5.00 ml of dichloroacetic acid was added and the reaction continued for another 48 hours. The mixture was then allowed to cool and was concentrated by evaporation under reduced pressure to obtain a solid residue. The residue was dissolved in 500 ml of water and the solution extracted with 200 ml of ether. The aqueous layer was then acidified with concentrated aqueous hydrochloric acid and then extracted twice with 500 ml portions of ether and once with 300 ml of ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure to obtain 3-methoxy- 12H-dibenzo[d,g][1,3]dioxocin-12-one-6-carboxylic acid as a semi-solid residue. The proton nmr spectrum was consistent with the assigned structure.