Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][NH:12][C:13]3[C:22]4[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][N:21]=4)[N:16]=[CH:15][CH:14]=3)=[N:9][N:10]=2)[N:7]=1.[NH:25]1[CH:29]=[C:28](B(O)O)[CH:27]=[N:26]1.CN(C=O)C.C(=O)([O-])[O-].[K+].[K+].O>>[NH:25]1[CH:29]=[C:28]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([CH2:11][NH:12][C:13]4[C:22]5[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][N:21]=5)[N:16]=[CH:15][CH:14]=4)=[N:9][N:10]=3)[N:7]=2)[CH:27]=[N:26]1
Reactant: OB(O)c1cn[nH]c1
Reactant: COc1cnc2c(NCc3nnc4ccc(Cl)nn34)ccnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cnc2c(NCc3nnc4ccc(-c5cn[nH]c5)nn34)ccnc2c1

Procedure:
A 48 mL sealed tube was charged with N-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-7-methoxy-1,5-naphthyridin-4-amine (0.150 g, 0.439 mmol), 1H-pyrazol-4-ylboronic acid (0.0737 g, 0.658 mmol), and DMF (3.00 ml, 38.6 mmol). A solution of potassium carbonate (0.182 g, 1.32 mmol) and water (0.696 ml, 38.6 mmol) was added, followed by PdCl2(dppf)-CH2Cl2Adduct (0.0358 g, 0.0439 mmol). The tube was flushed with argon, sealed, then placed in a 90° C. oil bath for 5 hours. The mixture was concentrated and the black solid was triturated with water to remove K2CO3, then purified by column chromatography using a 40 g RediSep column, eluting with 30-70% (90:10:1 DCM:MeOH:NH4OH solution) in DCM over 40 minutes. Pure fractions were collected to give N-((6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-7-methoxy-1,5-naphthyridin-4-amine as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[NH:34][C:35]([C:37]1([C:40](=[O:49])[NH:41][C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=2)[CH2:39][CH2:38]1)=[O:36])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([N:12](C(OC2C=CC=CC=2)=O)[C:13](=[O:21])OC2C=CC=CC=2)[CH:7]=1.[CH3:50][N:51]1[CH2:56][CH2:55][N:54]([CH:57]2[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]2)[CH2:53][CH2:52]1>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([O:5][C:6]2[CH:11]=[CH:10][N:9]=[C:8]([NH:12][C:13]([N:60]3[CH2:59][CH2:58][CH:57]([N:54]4[CH2:53][CH2:52][N:51]([CH3:50])[CH2:56][CH2:55]4)[CH2:62][CH2:61]3)=[O:21])[CH:7]=2)[CH:31]=[CH:32][C:33]=1[NH:34][C:35]([C:37]1([C:40]([NH:41][C:42]2[CH:43]=[CH:44][C:45]([F:48])=[CH:46][CH:47]=2)=[O:49])[CH2:39][CH2:38]1)=[O:36]
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1
Reactant: CN1CCN(C2CCNCC2)CC1
Solvent: CN(C)C=O
Product: CN1CCN(C2CCN(C(=O)Nc3cc(Oc4ccc(NC(=O)C5(C(=O)Nc6ccc(F)cc6)CC5)c(F)c4)ccn3)CC2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 72.6 %

Procedure:
To a solution of phenyl N-[4-(3-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-phenoxycarbonylcarbamate (50.0 mg) in N,N-dimethylformamide (2.0 ml) was added 1-methyl-4-(piperidin-4-yl)piperazine (68.7 mg), followed by stirring at room temperature for 12 hr. The reaction mixture was partitioned between ethyl acetate and a 1N aqueous solution of sodium hydroxide. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (Fuji Silysia NH, ethyl acetate, ethyl acetate:methanol=20:1, then 10:1). Fractions containing the target compound were concentrated. To the residue was added diethyl ether:hexane=1:3, and the precipitate was collected by filtration. This was washed with hexane and dried under aeration to provide the titled compound as white powder (34.6 mg, 72.8%). The titled compound could be synthesized by the following method.
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([C@@H:28](/[CH:35]=[CH:36]/[CH3:37])[CH2:29][C:30]([O:32]CC)=[O:31])=[CH:24][CH:23]=2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[OH-].[Li+]>C1COCC1.CCO>[CH3:4][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:23]=[CH:24][C:25]([C@@H:28](/[CH:35]=[CH:36]/[CH3:37])[CH2:29][C:30]([OH:32])=[O:31])=[CH:26][CH:27]=2)=[CH:7][CH:6]=1)([CH3:1])[CH3:3]
Reactant: C/C=C/[C@@H](CC(=O)OCC)c1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3F)c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: C/C=C/[C@@H](CC(=O)O)c1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3F)c2)cc1
Reaction time: 20 h
Yield: 81.6 %

Procedure:
To a stirred solution of 3.2 (0.0313 g, 0.062 mmol) in THF (2.00 mL) and EtOH (2.00 mL) at 23° C. was added 1N lithium hydroxide (2.00 mL, 2.00 mmol). Stirring continued for 20 hours. The reaction mixture was concentrated in vacuo, 1N HCl was added to reach pH 1, and the resulting mixture was extracted with EtOAc (3×10 mL), dried over MgSO4 and concentrated in vacuo. The residue was then purified by flash chromatography (SiO2 gel 60, eluted with 0%-20% EtOAc in hexanes) to give a clear oil (0.0241 g, 82% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.58 (I H, d, J=8.2 Hz), 7.40 (1H, dd, J=8.4, 2.2 Hz), 7.13 (2H, d, J=8.6 Hz), 7.08 (1H, d, J=1.5 Hz), 7.00 (1H, t, J=8.6 Hz), 6.92 (2H, d, J=8.6 Hz), 6.86 (1H, m), 6.79 (1H, m), 5.57 (1H, m), 5.50 (1H, m), 4.99 (2H, s), 3.79 (3H, s), 3.76 (1H, dd, J=14.5, 7.8 Hz), 2.71 (2H, dd, J=7.8, 2.3 Hz), 1.66 (3H, d, J=6.3 Hz), 1.23 (9H, m). MS ESI (neg.) m/e: 951.4 (2M−H)+, 475.1 (M−H)+.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:4][CH:3]=1.[Cu](C#N)[C:19]#[N:20]>CN(C)C=O>[C:19]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:4][CH:3]=1)#[N:20]
Reactant: Brc1cnc(-c2ccccc2)c2ccccc12
Reactant: N#C[Cu]C#N
Solvent: CN(C)C=O
Product: N#Cc1cnc(-c2ccccc2)c2ccccc12
Yield: 35.3 %

Procedure:
20.5 g of 1-phenylisoquinoline are dissolved in 100 ml of carbon tetrachloride, and 16 g of bromine are added at room temperature. The temperature is raised slowly and the mixture is kept under reflux for 1 hour. 7.9 g of pyridine in 10 ml of carbon tetrachloride are added dropwise to the boiling reaction mixture in the course of 2 hours, and the mixture is then heated at reflux temperature for a further 18 hours. The reaction solution is decanted off from the resinous precipitate and is concentrated, and the residue is crystallized from diisopropyl ether. 11.7 g of 4-bromo-1-phenylisoquinoline of melting point 123°-125° C. are obtained. 0.7 g of 4-bromo-1-phenylisoquinoline, 0.45 g of copper cyanide and 10 ml of dimethylformamide are heated at 160° C. for 6 hours. The reaction solution is decanted off, diluted with methylene chloride and washed with water. 0.75 g of crude product are isolated from the methylene chloride phase, and 0.2 g of 4-cyano-1-phenylisoquinoline of melting point 138°-140° is obtained from this crude product by column chromatography over silica gel using a 98:2 mixture of chloroform and ethyl acetate. 0.2 g of 4-cyano-1-phenylisoquinoline is heated with 10 ml of 20% strength sodium hydroxide solution at 100° C. for 4 hours. The solution is cooled and acidified with acetic acid. The precipitate is filtered off and dried. 0.18 g of 1-phenylisoquinoline-4-carboxylic acid of melting point 215°-217° is isolated.
Reaction SMILES: [F:1][C:2]([S:5][C:6]1[CH:7]=[C:8]([C:12](=O)[CH:13]=O)[CH:9]=[CH:10][CH:11]=1)([F:4])[F:3].I.[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[C:25]([NH:27][NH2:28])=[NH:26]>>[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[C:25]1[N:27]=[N:28][CH:13]=[C:12]([C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([S:5][C:2]([F:4])([F:3])[F:1])[CH:7]=2)[N:26]=1
Reactant: N=C(NN)c1ccc(F)cc1F
Reactant: O=CC(=O)c1cccc(SC(F)(F)F)c1
Agent: I
Product: Fc1ccc(-c2nncc(-c3cccc(SC(F)(F)F)c3)n2)c(F)c1

Procedure:
(3-Trifluoromethylsulfanylphenyl)oxoacetaldehyde was reacted with 2,4-difluorobenzenecarboximidic hydrazide hydriodide salt (1.13 g, 3.78 mmol) using the method described in Example 1 to give 3-(2,4-difluorophenyl)-5-(3-trifluoromethylsulfanylphenyl)-[1,2,4]triazine as a yellow solid (1.0 g): δH (400 MHz, CDCl3) 7.01-7.13 (2H, m), 7.68 (1H, t, J 7.8 Hz), 7.92 (1H, d, J 7.4 Hz), 8.32-8.39 (2H, m), 8.55 (1H, s), 9.67 (1H, s); m/z (ES+) 370.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[OH:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[F:10][C:9]([F:12])([F:11])[C:5]1[CH:6]=[C:7]([F:8])[C:2]([O:13][C:14]2[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=2)=[N:3][CH:4]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: Fc1cc(C(F)(F)F)cnc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=Cc1ccc(Oc2ncc(C(F)(F)F)cc2F)cc1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
To a solution of 36.6 g (0.20 mol) of 2,3-difluoro-5-(trifluoromethyl)pyridine in 150 ml of acetonitrile was added 25.6 g (0.21 mol) of p-hydroxybenzaldehyde, 29.0 g (0.21 mol) of powdered potassium carbonate and 50 mL of acetonitrile. The slurry was stirred at ambient temperature for 21 hours and then diluted with 300 mL of water. The organic layer was separated in a separatory funnel and washed twice with 150 mL portions of water followed by washing with 100 mL of a 10 percent potassium carbonate solution. The mixture was then dried over sodium sulfate and the solvent removed in vacuo leaving 48.0 g (84 percent of theoretical) of the above named compound, a light yellow oil, as the product; 1H NMR (CDCl3): 7.3-8.3 (m, 6H, Ar), 10.0 (s, 1H, CH(O).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:6]([C:7]([NH2:9])=[O:8])[C:5]([NH2:11])=[CH:4][CH:3]=1.[OH-].[Na+].[CH2:14](Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O>[CH2:14]([O:1][C:2]1[CH:10]=[C:6]([C:7]([NH2:9])=[O:8])[C:5]([NH2:11])=[CH:4][CH:3]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NC(=O)c1cc(O)ccc1N
Reactant: ClCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NC(=O)c1cc(OCc2ccccc2)ccc1N

Procedure:
A mixture of 5-hydroxyanthranilamide (15.2 g), 250 ml water, 5.1 ml 50% NaOH, and 11.7 ml of benzyl chloride was heated 1/2 at 95°, filtered and the solid recrystallized from 200 ml butanol to give 16.6 g product, m.163-5°.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=[CH:17]3)[CH:10]=2)[CH:3]=1.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].O>C(COC)OC>[N:16]1([CH2:15][C:11]2[CH:10]=[C:9]([NH:8][C:4]3[CH:3]=[C:2]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[O:26][CH3:25])[N:7]=[CH:6][N:5]=3)[CH:14]=[CH:13][CH:12]=2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17]1
Reactant: Clc1cc(Nc2cccc(Cn3ccc4ccccc43)c2)ncn1
Reactant: COc1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ccccc1-c1cc(Nc2cccc(Cn3ccc4ccccc43)c2)ncn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.6 %

Procedure:
234 mg (6-Chloro-pyrimidin-4-yl)-(3-indol-1-ylmethyl-phenyl)-amine (pre-pared in Example 90) (0.70 mmol) was suspended in 30 cm3 dimethoxyethane and the flask was filled with argon properly. 58 mg Tetrakis(thriphenylphosphine) palladium[0] (0.05 mmol) was added and the mixture was stirred at room temperature for 30 minutes. Then 152 mg 2-methoxyphenyl-boronic acid (1 mmol), 318 mg anhydrous Na2CO3 (3 mmol) and 6 ml water were added. The mixture was ferluxed overnight while slow argon flow was being applied. The reaction mixture was poured to 80 cm3 1M NaH2PO4 solution and it was extracted three times with 50-50 cm3 of ethyl-acetate. The combined organic layer was washed with brine, dried over MgSO4, decolorized with activated carbon and evaporated to dryness. The residual solid was recrystallized from minimal amount of acetonitrile and air-dried to give the desired product (90 mg, 32% yield). For analitical results and compound identification see Table 1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:35])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:23]4[CH:24]=[CH:25][CH:26]=[N:27][C:22]=4[CH2:21][O:20][C:19]4[CH:28]=[CH:29][C:30]([OH:32])=[CH:31][C:18]3=4)[CH2:10][C:9]2([CH3:34])[CH3:33])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:39][CH2:40][O:41][C:42](=[O:44])[CH3:43]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:35])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:23]4[CH:24]=[CH:25][CH:26]=[N:27][C:22]=4[CH2:21][O:20][C:19]4[CH:28]=[CH:29][C:30]([O:32][CH2:39][CH2:40][O:41][C:42](=[O:44])[CH3:43])=[CH:31][C:18]3=4)[CH2:10][C:9]2([CH3:33])[CH3:34])=[CH:4][CH:3]=1
Reactant: CC(=O)OCCBr
Reactant: CC1(C)CN(CCC=C2c3cc(O)ccc3OCc3ncccc32)CCC1(O)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Product: CC(=O)OCCOc1ccc2c(c1)C(=CCCN1CCC(O)(c3ccc(Cl)cc3)C(C)(C)C1)c1cccnc1CO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-{3-[4-(4-Chloro-phenyl)-4-hydroxy-3,3-dimethyl-piperidin-1-yl]-propylidene}-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-ol (64.5 mg, 0.131 mmol) in N,N-dimethylormamide (2.5 ml) was added sodium hydride (6 mg, 0.158 mmol), 60% dispersion in mineral oil, then acetic acid 2-bromo-ethyl ester (17 μl, 0.158 mmol). The reaction stirred at room temperature overnight under a nitrogen atmosphere. The reaction was quenched the following day with water and diluted with ethyl acetate. The organic layer was washed twice with water, then brine. After the organic layer was dried over magnesium sulfate the solvent was distilled off under reduced pressure to give the title compound, 132 mg (100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6].[C:13](=[C:16]([OH:21])[C@H:17]([OH:20])[CH:18]=O)([CH3:15])[CH3:14].S([O-])([O-])(=O)=O.[Mg+2]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][N:6]=[CH:18][C@H:17]([C:16](=[C:13]([CH3:15])[CH3:14])[OH:21])[OH:20]
Reactant: COc1ccc(CN)c(OC)c1
Reactant: CC(C)=C(O)[C@H](O)C=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: COc1ccc(CN=C[C@@H](O)C(O)=C(C)C)c(OC)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution, stirred at room temperature, of 0.9 g (5.4 mmol) of 2,4-dimethoxybenzylamine in 100 ml of methylene chloride are added 3 g of molecular sieve 4 Å and, after 20 minutes, 0.7 g (5.4 mmol) of isopropylidene-L-glyceraldehyde and 5 g of anhydrous magnesium sulphate. The mixture is subsequently stirred at room temperature for 1 hour. The organic solution of isopropylidene-L-glyceraldehyde (2,4-dimethoxybenzyl)imine obtained is cooled to -20° C. under argon and treated while stirring with 0.88 ml (5.4 mmol) of triethylamine. A solution of 1.25 g (5.6 mmol) of phthaloylglycyl chloride in 20 ml of dry methylene chloride is then added dropwise within 1 hour and the mixture is subsequently stirred at room temperature overnight. The mixture is washed three times with 100 ml of water each time and with 100 ml of sodium chloride solution and then dried ovr sodium sulphate. The organic solution is evaporated and the residue is chromatographed on silica gel (230-400 mesh) while eluting with hexane/ethyl acetate (1:1). There are obtained 1.77 g (70%) of N-[(3S,4S)-cis-1-(2,4-dimethoxybenzyl)-4-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-oxo-3-azetidinyl]phthalimide as a foam; [α]D =+41° (c=0.8 in chloroform); MS: 466 (M+).
Reaction SMILES: [CH3:1][N:2]1[C:6](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:5][C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:3]1.[CH:24]#[C:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>CCCCCCC.C(Cl)Cl>[C:24]([C:6]1[N:2]([CH3:1])[N:3]=[C:4]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:5]=1)#[C:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: Cc1ccc(S(=O)(=O)Oc2cc(-c3ccccc3)nn2C)cc1
Reactant: C#CCCCCC
Solvent: CCCCCCC
Solvent: ClCCl
Product: CCCCCC#Cc1cc(-c2ccccc2)nn1C

Procedure:
This product was prepared from toluene-4-sulfonic acid 2-methyl-5-phenyl-2H-pyrazol-3-yl ester and 1-heptyne following the general procedure for the Sonogashira cross-coupling reaction described above. Chromatography eluent: heptane/DCM 1:1; yield (120 mg, 95%); 1H NMR δ (CDCl3): 7.78 (d, J=8.20 Hz, 2H), 7.42-7.33 (t, J=8.05 Hz, 2H), 7.32 (m, 1H), 6.62 (s, 1H), 3.93 (s, 3H), 2.48 (t, J=7.25 Hz, 2H), 1.65 (p, J=7.18 Hz, 2H), 1.5-1.32 (m, 4H), 0.94 (t, J=7.22 Hz, 3H); LCMS m/z: 252.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[CH:15][C:14](N)=[CH:13][CH:12]=3)=[O:5])[CH3:2].N([O-])=O.[Na+].[BrH:24]>O.[Cu]Br>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[CH:15][C:14]([Br:24])=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2c(cn1)[nH]c1ccc(N)cc12
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1cc2c(cn1)[nH]c1ccc(Br)cc12
Temperature: 80 °C
Yield: 35 %

Procedure:
1 mmole of 6-amino-β-carbolin-3-carboxylic acid ethyl ester is diazotized at 0° C. in 2 ml of 24% aqueous hydrobromic acid with 1 mmole of sodium nitrite in 1 ml of water. This mixture is added dropwise to a solution of 40 mg of copper (I) bromide in 1 ml of 48% aqueous hydrobromic acid at room temperature. After addition is complete, the mixture is heated to 80° C. The temperature is increased to 100° C. until nitrogen evolution has ceased. 10 ml of water is then added and filtration with suction is carried out. The residue is stirred with ammonia and filtered with suction. It is then extracted by boiling with ethanol and concentrated by evaporation. By chromatography on silica gel with an eluant comprising 9 parts of chloroform and 1 part of ethanol, 6-bromo-β-carbolin-3-carboxylic acid ethyl ester of melting point 308°-313° C. is obtained in 35% yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([Cl:10])=[C:6]([CH:9]=1)[CH:7]=O.[C:11]([CH:16]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:13][CH2:14][CH3:15])=[O:12]>C1COCC1>[Br:1][C:2]1[CH:9]=[C:6](/[CH:7]=[CH:16]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]([Cl:10])=[N:4][CH:3]=1
Reactant: O=Cc1cc(Br)cnc1Cl
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1cc(Br)cnc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100.2 %

Procedure:
A vial was charged with 5-bromo-2-chloronicotinaldehyde (500 mg, 2.268 mmol, Small Molecules, Inc.) and THF (9072 μl). (Carbethoxymethylene)triphenylphosphorane (830 mg, 2.381 mmol) was added to the solution, and the mixture was stirred at RT for 1.5 h. The crude mixture was loaded onto silica gel and purified using a gradient of 0-50% EtOAc/heptane to provide (E)-ethyl 3-(5-bromo-2-chloropyridin-3-yl)acrylate (660 mg, 2.272 mmol, 100% yield) as a white solid. m/z (ESI) 291.8 (M+H)+.
Reaction SMILES: [NH2:1][N:2]1[C:7]2[CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:17])([CH3:16])[CH2:3]1.[C:18](O)(=[O:20])[CH3:19]>>[C:18]([NH:1][N:2]1[C:7]2[CH:8]=[C:9]([C:12]([F:15])([F:13])[F:14])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:17])([CH3:16])[CH2:3]1)(=[O:20])[CH3:19]
Reactant: CC1(C)CN(N)c2cc(C(F)(F)F)ccc2O1
Reactant: CC(=O)O
Product: CC(=O)NN1CC(C)(C)Oc2ccc(C(F)(F)F)cc21
Yield: 63 %

Procedure:
Acetic acid (3 ml) was added to 123 mg of 4-amino-2,2-dimethyl-6-trifluoromethyl-1,4-benzoxazine, followed by refluxing for 1 hour. The acetic acid was distilled off under reduced pressure and the residue was dissolved in ethyl acetate. The resulting solution was washed first with a 1N aqueous solution of sodium hydroxide and then with water, and was dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by chromatography on a silica gel column, whereby 90 mg of Compound No. 2 were obtained (yield: 63%). EXAMPLE 2
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li].[Cl:11][C:12]1[CH:35]=[CH:34][C:15]([O:16][C:17]2[CH:25]=[CH:24][C:20]([C:21]([NH2:23])=[O:22])=[CH:19][C:18]=2[C:26]2[C:31]([O:32][CH3:33])=[CH:30][CH:29]=[CH:28][N:27]=2)=[CH:14][CH:13]=1.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>C1COCC1>[Cl:11][C:12]1[CH:35]=[CH:34][C:15]([O:16][C:17]2[CH:25]=[CH:24][C:20]([C:21]([NH:23][S:37]([CH3:36])(=[O:39])=[O:38])=[O:22])=[CH:19][C:18]=2[C:26]2[C:31]([O:32][CH3:33])=[CH:30][CH:29]=[CH:28][N:27]=2)=[CH:14][CH:13]=1
Reactant: COc1cccnc1-c1cc(C(N)=O)ccc1Oc1ccc(Cl)cc1
Reactant: CS(=O)(=O)Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Product: COc1cccnc1-c1cc(C(=O)NS(C)(=O)=O)ccc1Oc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 5.4 %

Procedure:
Lithium hexamethyldisilazane (1.5 mL, 1.55 mmol) was added to a solution of 4-(4-chlorophenoxy)-3-(3-methoxypyridin-2-yl)benzamide (Preparation 11, 0.184 g, 0.52 mmol) in THF (10 mL) and then the mixture was stirred at room temperature for 10 minutes. Methansulfonyl chloride (0.14 mL, 1.81 mmol) was added to the yellow solution and the mixture was stirred at room temperature for 18 hours. The reaction was quenched by the addition of aqueous ammonium chloride (10 mL) and extracted with DCM (3×30 mL). The organic layer was washed with water (2×30 mL), dried over magnesium sulfate, and concentrated in vacuo to afford the crude product (0.294 g). The crude material was purified by preparative A-HPLC to afford the title compound (12.2 mg).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([Cl:12])[CH:6]=1)=O.[CH3:13][O:14][C:15]([C:17]1[C:18]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[N+:32]([O-:34])=[O:33])=[CH:19][CH:20]=[C:21]([C:23](=[S:25])[NH2:24])[CH:22]=1)=[O:16]>C1COCC1>[CH3:13][O:14][C:15]([C:17]1[C:18]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[N+:32]([O-:34])=[O:33])=[CH:19][CH:20]=[C:21]([C:23]2[S:25][CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([F:11])=[C:7]([Cl:12])[CH:6]=3)[N:24]=2)[CH:22]=1)=[O:16]
Reactant: O=C(CBr)c1ccc(F)c(Cl)c1
Reactant: COC(=O)c1cc(C(N)=S)ccc1-c1ccccc1[N+](=O)[O-]
Solvent: C1CCOC1
Product: COC(=O)c1cc(-c2nc(-c3ccc(F)c(Cl)c3)cs2)ccc1-c1ccccc1[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 20 h

Procedure:
2-Bromo-3′-chloro-4′-fluoroacetophenone (available from Aldrich Chemical Company, Inc.; 80.5 mg, 0.32 mmol) was added to a solution of 2′-nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for Intermediate 4; 100 mg, 0.32 mmol) in THF (2 mL), and the resulting mixture was stirred at 40° C. for 20 h. The reaction mixture was evaporated to dryness and the residue was stirred with ethanol (5 mL). The precipitate was collected by filtration (100 mg) and used directly in the next step without purification.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH:13](C)C)=[CH:9][CH:8]=1)=[O:6].[Br:16]N1C(=O)CCC1=O>C(Cl)Cl>[Br:16][CH2:13][C:10]1[CH:9]=[CH:8][C:7]([C:5]([CH:4]2[CH2:3][CH2:2]2)=[O:6])=[CH:12][CH:11]=1
Reactant: CC(C)c1ccc(C(=O)CCCCl)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: O=C(c1ccc(CBr)cc1)C1CC1
Temperature: 5 °C
Reaction time: 7.5 h
Yield: 165.6 %

Procedure:
Dissolve 4-chloro-1-(4-isopropyl-phenyl)-butan-1-one (20 g, 124 mmol) and 2,2′-Azolons (2-methylpropionitrile) (0.5 g) in methylene chloride (100 mL) and cool to 5° C. Add a suspension of N-bromosuccinimide (12 g) in methylene chloride (50 mL) and irradiate with light (150 Watt lamp), maintaining the temperature at 5° C. After 2, 3 and 7 hour time periods, add additional N-bromosuccinimide (6 g, 6 g, 2.8 g) and continue stirring. After 7.5 hours, wash with water (200 mL) and with 0.4 M sodium hydrogen carbonate (2×200 mL). Dry (Na2SO4), evaporate the solvent in vacuo and recrystallize (hexane) to give the title compound as a crystalline solid (26.7 g).