Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH:2]([C:8]([CH3:10])=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH2:11][C:12]([NH2:14])=[S:13].C([O-])([O-])=O.[Na+].[Na+]>CC#N.C1COCC1>[NH2:14][C:12]1[S:13][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:8]([CH3:10])[N:11]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)C(Cl)C(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Product: CCOC(=O)c1sc(N)nc1C
Temperature: 120 °C
Yield: 37.6 %

Procedure:
To a stirred solution of ethyl 2-chloroacetoacetate (6.0 mL, 43.35 mmol) in MeCN (24 mL) and THF (6 mL) was added thiourea (3.0 g, 39.41 mmol) and Na2CO3 (0.417 g, 39.41 mmol). The reaction mixture was heated at 120° C. under microwave irradiation for 30 minutes, cooled to r.t., partitioned between EtOAc and water, and the organic fraction was dried (MgSO4), filtered and concentrated in vacuo to give the title compound (2.76 g, 38%) as a cream solid. δH (CDCl3) 5.47 (2H, br. s), 4.27 (2H, q, J 7.2 Hz), 2.53 (3H, s), 1.33 (3H, t, J 7.2 Hz). MS (ES+) 187.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[OH:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.CCOC(C)=O>[N:11]1[CH:12]=[CH:13][C:8]([C:7]2[C:2]([O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)=[N:9][CH:10]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: Clc1ncccc1-c1ccncn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=C(O)c1ccc(Oc2ncccc2-c2ccncn2)cc1
Temperature: 200 °C

Procedure:
A mixture of 4-(2-chloro-pyridin-3-yl)-pyrimidine, 4-hydroxy-benzoic acid and Cs2CO3 in DMSO was heated in a microwave (Personal Chemistry, Emrys Optimizer) at 200° C. for 10 minutes. The reaction mixture was cooled to RT and diluted with 60 mL of EtOAc. The product was precipitated from the solution. The mixture was then washed with 20 mL of water twice. The solid was collected by filtration and dried in an oven at 50° C. to afford off white solid as desired product. MS m/z=294 [M+1]+. Calc'd for C16H11N3O3: 293.28.
Reaction SMILES: [C:1]1([C:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])=[CH:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([NH2:18])=[O:17])[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>CO.C(Cl)Cl.[Pd]>[C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([NH2:18])=[O:17])[CH:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: Cc1ccccc1C(=Cc1ccnc(NC(N)=O)c1)c1ccccc1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: Cc1ccccc1C(Cc1ccnc(NC(N)=O)c1)c1ccccc1
Yield: 14 %

Procedure:
[4-(2-Phenyl-2-o-tolyl-vinyl)-pyridin-2-yl]-urea (140 mg, 0.43 mmol) is dissolved in methanol (2 mL) and DCM (2 mL). Then 5% palladium on carbon (90 mg, 0.043 mmol) is added. The reaction is stirred for 16 hours under the hydrogen atmosphere. The palladium on carbon is filtered and the filtrate is concentrated to give the crude product. Purification by Gilson preparative HPLC affords 20 mg of the titled product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][N:32]([CH3:34])[CH3:33])[CH:26]=4)[N:19]=3)=[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][N:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[S:35]1[CH:39]=[CH:38][CH:37]=[C:36]1[CH2:40][C:41](Cl)=[O:42]>C1COCC1.CCOC(C)=O>[CH3:33][N:32]([CH2:31][C:27]1[CH:26]=[C:25]([NH:24][C:20]2[N:19]=[C:18]([C:17]3[C:9]([C:4]4[CH:5]=[CH:6][C:7]([F:8])=[C:2]([NH:1][C:41](=[O:42])[CH2:40][C:36]5[S:35][CH:39]=[CH:38][CH:37]=5)[CH:3]=4)=[N:10][N:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=34)[CH:23]=[CH:22][N:21]=2)[CH:30]=[CH:29][CH:28]=1)[CH3:34]
Reactant: O=C(Cl)Cc1cccs1
Reactant: CN(C)Cc1cccc(Nc2nccc(-c3c(-c4ccc(F)c(N)c4)nn4ccccc34)n2)c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C)Cc1cccc(Nc2nccc(-c3c(-c4ccc(F)c(NC(=O)Cc5cccs5)c4)nn4ccccc34)n2)c1
Reaction time: 20 h
Yield: 77.2 %

Procedure:
To a stirred solution of 4-[2-(3-amino-4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-{3-[(dimethylamino)methyl]phenyl}-2-pyrimidinamine (58 mg, 0.13 mmol) in THF (3 mL) was added TEA (27 μL, 0.19 mmol) and 2-thiopheneacetyl chloride (17 μL, 0.13 mmol). After 20 h, the reaction mixture was diluted with EtOAc (20 mL), adsorbed onto silica gel, and purified by column chromatography to give the title compound (58 mg, 77% yield). 1H NMR (400 MHz, d6-DMSO) 610.15 (s, 1H), 9.54 (s, 1H), 8.83 (d, J=7.0 Hz, 1H), 8.48 (d, J=8.8 Hz, 1H), 8.26-8.29 (m, 2H), 7.69 (s, 1H), 7.63 (d, J=8.2 Hz, 1H), 7.47 (t, J=7.9 Hz, 1H), 7.36-7.39 (m, 2H), 7.18 (t, J=7.8 Hz, 1H), 7.13 (t, J=6.9 Hz), 6.96-6.98 (m, 2H), 6.87 (d, J=7.1 Hz, 1H), 6.52 (d, J=5.3 Hz, 1H), 3.99 (s, 2H), 3.32 (s, 2H), 2.15 (s, 6H). ES-LC/MS m/z=578 [M+H]+.
Reaction SMILES: Br.Br[CH2:3][C:4]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:5].[CH3:12][O:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([NH2:22])[CH:16]=1.C([O-])(O)=O.[Na+]>CCO>[CH3:12][O:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([NH:22][CH2:3][C:4](=[O:5])[C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)[CH:16]=1
Reactant: O=C(CBr)c1cccnc1
Reactant: COC(=O)c1ccc(C)c(N)c1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COC(=O)c1ccc(C)c(NCC(=O)c2cccnc2)c1
Reaction time: 2 h
Yield: 16.7 %

Procedure:
To a solution of 2-bromo-1-pyridin-3-yl-ethanone hydrobromide (Barlin, G. B. et al. Australian J. Chem, 1989, 1735) (500 mg, 1.78 mmol) in 2 ml of EtOH was added 3-amino-4-methyl-benzoic acid methyl ester (Lancaster; 294 mg, 1.78 mmol) and NaHCO3 (750 mg, 8.9 mmol), and the mixture was stirred for 2 h. The mixture was then filtered and washded with MeOH, then the filtrated was concentrated to a small volume and dissolved in EtOAc. The EtOAc slurry was washed with water and brine, and the washes were extracted once more with EtOAc. The combined organic portions were dried with Na2SO4, filtered, concentrated, and chromatographed (0–5% MeOH in dichloromethane) to provide 84.5 mg of 4-methyl-3-(2-oxo-2-pyridin-3-yl-ethylamino)-benzoic acid methyl ester.
Reaction SMILES: [C:1]([C:3]1[C:4](F)=[C:5]([F:22])[CH:6]=[C:7]2[C:12]=1[N:11]([CH:13]1[CH2:15][CH2:14]1)[CH:10]=[C:9]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8]2=[O:21])#[N:2].[C@@H:24]12[CH2:32][NH:31][CH2:30][C@@H:29]1[CH2:28][CH2:27][CH2:26][NH:25]2.C(N(CC)CC)C>C(#N)C>[C:1]([C:3]1[C:4]([N:31]2[CH2:32][C@@H:24]3[C@@H:29]([CH2:28][CH2:27][CH2:26][NH:25]3)[CH2:30]2)=[C:5]([F:22])[CH:6]=[C:7]2[C:12]=1[N:11]([CH:13]1[CH2:15][CH2:14]1)[CH:10]=[C:9]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8]2=[O:21])#[N:2]
Reactant: CCOC(=O)c1cn(C2CC2)c2c(C#N)c(F)c(F)cc2c1=O
Reactant: C1CN[C@@H]2CNC[C@@H]2C1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)c1cn(C2CC2)c2c(C#N)c(N3C[C@@H]4CCCN[C@@H]4C3)c(F)cc2c1=O
Yield: 81.7 %

Procedure:
14.32 g (45 mmol) of ethyl 8-cyano-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate, 6.31 g (50 mmol) of (1S,6S)-2,8-diazabicyclo[4.3.0]nonane and 10.22 g (101 mmol) of triethylamine are boiled under reflux in 270 ml of acetonitrile for 4 hours. The reaction mixture is left to stand at room temperature for some hours and the solid which has crystallized out is filtered off with suction, rinsed with acetonitrile and dried. 15.6 g of a beige solid are obtained (82% of theory).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[N:16][N:15]4[C:18]([C:21]5[CH:22]=[C:23]([NH:27][C:28]([NH:30][CH2:31][C:32]([F:35])([F:34])[F:33])=[O:29])[CH:24]=[CH:25][CH:26]=5)=[CH:19][N:20]=[C:14]4[CH:13]=3)[CH:9]=[N:8]2)[CH2:3][CH2:2]1.[CH2:36]([N:43]=[C:44]=[O:45])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[CH2:36]([NH:43][C:44]([N:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[N:16][N:15]4[C:18]([C:21]5[CH:26]=[CH:25][CH:24]=[C:23]([NH:27][C:28]([NH:30][CH2:31][C:32]([F:33])([F:35])[F:34])=[O:29])[CH:22]=5)=[CH:19][N:20]=[C:14]4[CH:13]=3)[CH:9]=[N:8]2)[CH2:3][CH2:2]1)=[O:45])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C=NCc1ccccc1
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4cnn(C5CCNCC5)c4)cnn23)c1
Product: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4cnn(C5CCN(C(=O)NCc6ccccc6)CC5)c4)cnn23)c1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 30 (Step 6) starting from N-{3-[7-(1-piperidin-4-yl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-3-yl]phenyl}-N′-(2,2,2-trifluoroethyl)urea and benzyl isocyanate (Aldrich, Cat. No. 227269). LCMS (M+H)+: m/z=618.2.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)=O.[CH3:19][O:20][C:21](=[O:32])[CH2:22][CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Cl[Si](C)(C)C>CN(C=O)C>[C:25]1([C:24]2[N:1]=[C:2]3[S:6][C:5]4[CH2:7][CH2:8][CH2:9][C:4]=4[C:3]3=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)[C:23]=2[CH2:22][C:21]([O:20][CH3:19])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)CCC(=O)c1ccccc1
Reactant: Cc1ccc(C(=O)c2c(N)sc3c2CCC3)cc1
Agent: C[Si](C)(C)Cl
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(-c2ccccc2)nc2sc3c(c2c1-c1ccc(C)cc1)CCC3
Yield: 47.9 %

Procedure:
This compound was prepared according to the procedure B from (2-amino-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)-p-tolylmethanone (0.257 g; 1 mmol), methyl-3-benzoylpropionate (0.211 g; 1.1 mmol), chlorotrimethylsilane (0.526 mL; 4 mmol) in DMF (4 mL) for 18 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-50%) in heptane furnished 0.198 g (48%) of the title compound as a yellow oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.[OH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[F:9][C:8]([F:11])([F:10])[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([O:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:18]=2)[CH:7]=1
Reactant: FC(F)(F)c1ccnc(Cl)c1
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1ccc(Oc2cc(C(F)(F)F)ccn2)cc1
Yield: 45.2 %

Procedure:
2-Chloro-4-trifluoromethylpyridine (1.0 g), methyl 4-hydroxybenzenecarboxylate (838.3 mg) and potassium carbonate (2.28 g) were suspended in acetonitrile (10 mL), heated under reflux for 27 hours, and methyl 4-hydroxybenzenecarboxylate (838.3 mg) was added thereto and further heated under reflux for 24 hours. Water (100 mL) was added to the reaction liquid, extracted with ethyl acetate (100 mL), and the organic layer was washed with aqueous 2 N sodium hydroxide solution (100 mL), water (100 mL) and saturated saline water (100 mL) in that order, dried with magnesium sulfate, and evaporated under reduced pressure to obtain a pale yellow oil. The resulting oil was purified through silica gel column chromatography (hexane/ethyl acetate=8/2) to obtain the entitled compound (740 mg) as a colorless solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][CH:17]=[CH:16]4)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:22][CH3:23].[CH3:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30]O>>[NH:18]1[C:19]2[C:15](=[CH:14][C:13]([O:12][C:6]3[C:5]4[C:10](=[CH:11][C:2]([O:1][CH2:30][CH2:29][O:28][CH2:27][CH2:26][O:25][CH3:24])=[C:3]([O:22][CH3:23])[CH:4]=4)[N:9]=[CH:8][N:7]=3)=[CH:21][CH:20]=2)[CH:16]=[CH:17]1
Reactant: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1O
Reactant: COCCOCCO
Product: COCCOCCOc1cc2ncnc(Oc3ccc4[nH]ccc4c3)c2cc1OC
Yield: 42.2 %

Procedure:
Using an analogous procedure to that described in Example 91, 7-hydroxy-4-(indol-5-yloxy)-6-methoxyquinazoline (89 mg) was reacted with 2-(2-methoxyethoxy)ethanol (70 mg) to give 4-(indol-5yloxy)-6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)quinazoline (50 mg, 42%).
Reaction SMILES: C([O:4][CH2:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:16]=[CH:17][C:18]([C:21]([NH:23][C:24]3[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][C:25]=3[C:26]([NH:28][C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][N:30]=3)=[O:27])=[O:22])=[N:19][CH:20]=2)[CH2:10][CH2:9]1)=[O:7])(=O)C.C(=O)([O-])[O-].[K+].[K+].O>CO>[OH:4][CH2:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:16]=[CH:17][C:18]([C:21]([NH:23][C:24]3[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][C:25]=3[C:26]([NH:28][C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][N:30]=3)=[O:27])=[O:22])=[N:19][CH:20]=2)[CH2:10][CH2:9]1)=[O:7]
Reactant: CC(=O)OCC(=O)N1CCCN(c2cnc(C(=O)Nc3ccc(C)cc3C(=O)Nc3ccc(Cl)cn3)cn2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1ccc(NC(=O)c2cnc(N3CCCN(C(=O)CO)CC3)cn2)c(C(=O)Nc2ccc(Cl)cn2)c1
Reaction time: 8 h

Procedure:
To a solution of 2-[5-[4-(acetoxyacetyl)hexahydro-1,4-diazepin-1-yl]pyrazin-2-ylcarbonylamino]-5-methyl-N-(5-chloropyridin-2-yl)benzamide (Example 86, 0.22 g) in methanol (5 mL) was added potassium carbonate (0.1 g) and water (1 mL). The mixture was stirred overnight, the methanol was evaporated, and the resulting solution acidified to pH 5 with acetic acid. The solids were filtered, washed with water (2×3 mL), ether (3 mL) and dried under vacuum. Yield=0.19 g.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C(OCC)C.C([Li:19])CCC>O1CCCC1>[CH:1]1([Li:19])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: C1=Cc2ccccc2C1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: [Li]C1C=Cc2ccccc21

Procedure:
Ten mL (85.7 mmol) of indene, which is a cyclopentacarbyl compound, was added to a container that contained 150 mL of diethyl ether and 15 mL of tetrahydrofuran to form a first mixture. This first mixture was then reacted with 53.6 mL (85.7 mmol) of n-butyllithium (1.6M in hexane) to form indenyllithium, which is a cyclopentacarbyl metal compound. This reaction took place at -78° C. A yellow solution was formed. This yellow solution was then stirred at room temperature (about 25° C.) for four hours and then cooled again to -78° C. An equivalent quantity of 1-bromopropene, a haloalkene compound, was added dropwise to the yellow solution to form a second mixture. This second mixture was then stirred overnight at room temperature (about 25° C.). Thereafter, this second mixture was then hydrolyzed with 50 mL of water to form an organic phase and a water phase. The organic phase was dried over sodium sulfate and then the solvent was evaporated under a vacuum to produce a third mixture. This third mixture was then distilled using a high vacuum (10-2 torr) to obtain a product. The product obtained was allyl-1-indene, which is an (omega-alkenyl) cyclopentacarbyl compound.
Reaction SMILES: [F:1][C:2]1[C:15]([N:16]2[C:21](=[O:22])[CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[NH:18][C:17]2=[O:27])=[CH:14][C:5]2[N:6]([CH2:11][C:12]#[CH:13])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.[H-].[Na+].[CH3:30]OS(=O)(=O)OC>CN(C)C=O>[F:1][C:2]1[C:15]([N:16]2[C:21](=[O:22])[CH:20]=[C:19]([C:23]([F:24])([F:25])[F:26])[N:18]([CH3:30])[C:17]2=[O:27])=[CH:14][C:5]2[N:6]([CH2:11][C:12]#[CH:13])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: COS(=O)(=O)OC
Reactant: C#CCN1C(=O)COc2cc(F)c(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCN1C(=O)COc2cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc21
Reaction time: 0.33 h
Yield: 80.4 %

Procedure:
0.18 g of 3-(7-fluoro-3-oxo-4-propargyl-2H-1,4-benzoxazin-6-yl)-6-trifluoromethyl-2,4(1H,3H) -pyrimidinedione was added at room temperature in a dimethylformamide solution (2 ml) having suspended therein 0.02 g of sodium hydride (purity: 55%). After standing for 20 minutes, the solution was further added with 0.09 g of dimethylsulfuric acid and stirred overnight. Then dimethylformamide was distilled off and the residue was extracted with ethyl acetate by adding water. The extract was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and then ethyl acetate was distilled off to obtain a crude product. This crude product was purified by preparative thin-layer chromatography using hexane/ethyl acetate (3:1) as developing solvent to obtain 0.15 g of the objective compound as a colorless viscous oil. It was solidified when left as it was.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]2[C:7]([Br:14])=[N:8][NH:9][C:10]=2[CH:11]=[CH:12][CH:13]=1)=[O:4].[F:15][C:16]1[CH:21]=[CH:20][C:19](N2C3C=CC=C(C(O)=O)C=3C=N2)=[CH:18][CH:17]=1>>[Br:14][C:7]1[C:6]2[C:5]([C:3]([OH:2])=[O:4])=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]([C:19]2[CH:20]=[CH:21][C:16]([F:15])=[CH:17][CH:18]=2)[N:8]=1
Reactant: COC(=O)c1cccc2[nH]nc(Br)c12
Reactant: O=C(O)c1cccc2c1cnn2-c1ccc(F)cc1
Product: O=C(O)c1cccc2c1c(Br)nn2-c1ccc(F)cc1

Procedure:
3-Bromo-1H-indazole-4-carboxylic acid methyl ester was then subjected to the reaction conditions described in Example 2, for the synthesis of 1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid, to yield 3-bromo-1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid. Using the methods described in Example 2,3-bromo-1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid was used to provide the following compounds:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]=O)[CH:5]=1.C([O-])(=O)C.[NH4+].[N+:18]([CH2:21][CH3:22])([O-:20])=[O:19]>>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]=[C:21]([N+:18]([O-:20])=[O:19])[CH3:22])[CH:5]=1
Reactant: CC[N+](=O)[O-]
Reactant: COC(=O)c1cccc(C=O)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: COC(=O)c1cccc(C=C(C)[N+](=O)[O-])c1
Reaction time: 1.5 h

Procedure:
To a 250 mL round bottom flask was added 3-formyl-benzoic acid methyl ester (2.20 g, 13.4 mmol), ammonium acetate (1.03 g, 13.4 mmol), and nitroethane (60 mL). Mixture heated to reflux under an atmosphere of nitrogen while stirring for 1.5 h. Solvent removed under vacuum then residue partitioned between ethyl acetate (100 mL) and 5% sodium bicarbonate. Organic washed with saturated sodium chloride, dried with magnesium sulfate, then concentrated to a oil under vacuum. Product purified on silica and isolated as a yellow solid. 1H NMR (CDCl3) s (3H, 2.47 ppm), s (3H, 3.96 ppmm), t (1H, 7.55 ppm), d (2H, 7.61 ppm) m (3H, 8.09 ppm).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH:7]1[CH:15]=[C:13]([CH3:14])[C:11](=[O:12])[NH:10][C:8]1=[O:9].Br[CH2:17][CH2:18][CH2:19][CH2:20][B:21]([OH:23])[OH:22]>CN(C)C=O>[OH:22][B:21]([OH:23])[CH2:20][CH2:19][CH2:18][CH2:17][N:7]1[CH:15]=[C:13]([CH3:14])[C:11](=[O:12])[NH:10][C:8]1=[O:9]
Reactant: OB(O)CCCCBr
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cn(CCCCB(O)O)c(=O)[nH]c1=O
Reaction time: 0.5 h
Yield: 44.2 %

Procedure:
Potassium carbonate (0.6 g, 4.4 mmol) was added to a solution of thymine (0.56 g, 4.4 mmol) in dimethylformamide (15 mL) and stirred for 30 minutes. To this reaction mixture, 4-bromobutyl boronic acid (0.4 g, 2.2 mmol) dissolved in dimethylformamide (5 mL) was added dropwise, and stirring was continued 2 days at room temperature. After the potassium carbonate was filtered, the dimethylformamide was evaporated under high vacuum. The residue was purified on a silica gel column eluting with a discontinuous gradient of chloroform/methanol (95:5, 85:15). The appropriate TLC-homogenous fractions were pooled and evaporated to give 0.22 g of pure product. Yield 44%; mp 130°-132° C.; 1H NMR (DMSO-d6) 0.55-0.68 (t, B CH2), 1.22-1.35 (m, B CH2 CH2), 1.42-1.60 (m, B CH2 CH2 CH2), 1.72-1.78 (s, CH3 C5 thymine), 3.52-3.63 (CH2 CH2 N), 7.40-7.43 (s, (HO)2 B), 7.48-7.51 (s, H C6 thymine), 11.12-11.18 (s, HN thymine). Elemental Analysis (C9H15BO4N2); Calcd. C, 47.82%; H, 6.69%; N, 12.40%; Found C, 47.71%; H, 6.72%; N, 12.35%.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.F[C:12]1[C:13]([CH:18]=O)=[N:14][CH:15]=[CH:16][CH:17]=1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>O>[F:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:12]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[CH:18]=[N:10]2)=[CH:5][CH:4]=1
Reactant: NNc1ccc(F)cc1
Reactant: O=Cc1ncccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc(-n2ncc3ncccc32)cc1
Temperature: 120 °C
Yield: 67.7 %

Procedure:
To a 500-mL round-bottomed flask was added 4-fluorophenylhydrazine hydrochloride (18.9 g, 116 mmol), 3-fluoro-2-formylpyridine (14.2 g, 113 mmol), K2CO3 (47.0 g, 340 mmol), and DMF (150 mL). The slurry was heated to 120° C. in an oil bath for 41 hours at which point the reaction mixture was cooled and poured into 1.2 L of H2O. The tan precipitate was collected via vacuum filtration and washed with 3×H2O. The solid was dissolved in CH2Cl2 and the resulting solution was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a brown solid. The solid was triturated with 200 mL of 9:1 hexanes:EtOAc and dried to provide 1-(4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine (16.3 g, 68%) as a tan powder. MS: (ES) m/z calculated for C12H9FN3 [M+H]+ 214.1, found 214.1.
Reaction SMILES: [Mg].[F:2][C:3]([F:18])([F:17])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[CH:19](=[O:21])[CH3:20]>O1CCCC1.BrBr>[F:2][C:3]([F:18])([F:17])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:19]([OH:21])[CH3:20])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1
Reactant: CC=O
Reactant: FC(F)(F)c1ccc(-c2ccc(Br)cc2)cc1
Agent: BrBr
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 0 °C

Procedure:
To a stirred suspension of 1.5 g of magnesium turnings in 10 ml of dry tetrahydrofuran, add a small amount of 4'-trifluoromethyl-4-bromo[1,1']biphenyl and a few drops of bromine. When the reaction is started, add (dropwise) a solution of 16 g of 4'-trifluoromethyl-4-bromo-[1,1']biphenyl in 50 ml of tetrahydrofuran at 50°-60° C. Heat the mixture for one hour, cool to 0° C., and slowly (dropwise) add 7 g of acetaldehyde. Stir the reaction mixture at room temperature for twenty hours. Work-up the reaction mixture following the procedure of example 2, and isolate the desired product by chromatography, m.p. 116°-117°.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=O.[NH2:11][C:12]1[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=1[C:14]([NH:16][OH:17])=[O:15]>O1CCOCC1>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]1[N:16]([OH:17])[C:14](=[O:15])[C:13]2[C:12](=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:11]=1
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: Nc1ccccc1C(=O)NO
Solvent: C1COCCO1
Product: O=c1c2ccccc2nc(-c2ccccc2Cl)n1O
Yield: 51.7 %

Procedure:
35 g (0.2 mol) of o-chlorobenzoyl chloride are added to a solution of 30.4 g (0.2 mol) of o-aminobenzhydroxamic acid in 250 ml of dioxane at 20°-30° C. The mixture is boiled under reflux for 3 hours, the solvent is then distilled in vacuo, 100 ml of ether are added to the residue, and the crystalline product is filtered off under suction. It is dissolved in 300 ml of 5% strength sodium hydroxide solution, the solution is filtered and the filtrate is acidified with concentrated hydrochloric acid. The precipitated product is then filtered off under suction and rinsed with water. In this manner, 28.2 g (52% of theory) of 2-(2-chlorophenyl)-3-hydroxy-3,4-dihydro-4-oxo-quinazoline are obtained in the form of crystals of melting point 211° C.