Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][C:56]([O:59][CH3:60])=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]([N+:43]([O-])=O)[C:39]([NH2:42])=[N:40][CH:41]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[CH3:69][O:70][C:71]1[CH:76]=[CH:75][C:74]([CH:77]=O)=[CH:73][CH:72]=1>C(O)C.CN(C=O)C>[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][C:56]([O:59][CH3:60])=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]2[N:43]=[C:77]([C:74]3[CH:75]=[CH:76][C:71]([O:70][CH3:69])=[CH:72][CH:73]=3)[NH:42][C:39]2=[N:40][CH:41]=1
Reactant: COc1ccc(CN2CCN(c3c(Br)cnc(N)c3[N+](=O)[O-])CC2)cn1
Reactant: COc1ccc(C=O)cc1
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: COc1ccc(-c2nc3c(N4CCN(Cc5ccc(OC)nc5)CC4)c(Br)cnc3[nH]2)cc1
Reaction time: 6 h
Yield: 55.3 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-bromo-4-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)-3-nitropyridin-2-amine (30 mg, 0.071 mmol), DMF (0.15 mL), ethanol (0.85 mL), 1M Na2S2O4 (3 eq, 0.21 mmol, 0.21 mL) and 4-methoxybenzene carboxaldehyde (1.1 eq, 0.078 mmol, 10 mg). After 6 h, concentration in vacuo and purification by preparative tlc (CH2Cl2-MeOH, 95:5) gave the product (20 mg, 56%) as a colourless solid; δH (500 MHz, DMSO-d6) 2.60 (s, br, 4H, piperazine N(CH2)2), 3.52 (s, 2H, NCH2), 3.64 (t, J=4.5 Hz, 4H, piperazine N(CH2)2), 3.84 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 6.81 (d, J=8.5 Hz, 1H, methoxypyridine H-5), 7.09 (d, J=8.9 Hz, 2H, methoxyphenyl H-2 & H-6), 7.70 (dd, J=8.5, 2.6 Hz, 1H, methoxypyridine H-4), 8.11 (d, J=2.3 Hz, 1H, methoxypyridine H-2), 8.20 (s, 1H, imidazo[4,5-b]pyridine H-5), 13.34 (s, br, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: [P:1]([CH2:5][C:6]([OH:8])=[O:7])([OH:4])([OH:3])=[O:2].Cl.[CH2:10](O)[CH3:11]>>[P:1]([CH2:5][C:6]([O:8][CH2:10][CH3:11])=[O:7])([OH:4])([OH:3])=[O:2]
Reactant: O=C(O)CP(=O)(O)O
Reactant: CCO
Agent: Cl
Product: CCOC(=O)CP(=O)(O)O
Reaction time: 8 h

Procedure:
Into 100 ml. of absolute ethanol was placed 28 g. (0.2 mole) of phosphonoacetic acid. The solution was treated with a stream of dry hydrogen chloride at 0° C. for 45 minutes. After refluxing for 3 hours the solution was allowed to stand overnight at room temperature. Evaporation of the solvent yielded a viscous oil, which was dried in vacuo over P2O5 and NaOH.
Reaction SMILES: [OH-].[K+].F[C:4]1[C:14]([F:15])=[C:13]([F:16])[CH:12]=[CH:11][C:5]=1[NH:6][C@@H:7]([CH3:10])[CH2:8][OH:9].C(O[CH:20]=[C:21]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:22]([O:24][CH2:25][CH3:26])=[O:23])C.O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[F:16][C:13]1[CH:12]=[CH:11][C:5]2[N:6]([CH:20]=[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[C@@H:7]([CH3:10])[CH2:8][O:9][C:4]=2[C:14]=1[F:15]
Reactant: C[C@@H](CO)Nc1ccc(F)c(F)c1F
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(=CN1c2ccc(F)c(F)c2OC[C@@H]1C)C(=O)OCC
Temperature: 60 °C
Reaction time: 1 h

Procedure:
At room temperature, KOH (330 mg) and tetrabutylammonium hydrogensulfate (82.7 mg) were dissolved in DMF (15 ml). After adding a solution (5 ml) of (2S)-2-(2,3,4-trifluoroanilino)propanol (1 g, 99.8% ee) and diethyl ethoxymethylenemalonate (2.09 g) in DMF, the mixture was stirred for 1 hour. Next, it was heated to 60° C. and a solution (5 ml) of KOH (330 mg) and diethyl ethoxymethylenemalonate (120 mg) in DMF was added thereto. The resultant mixture was stirred at the same temperature for 5 hours. After adding water, the liquid reaction mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. After evaporating the solvent, the obtained residue was subjected to silica gel column chromatography. Thus, 1.3 g (99.8% ee) of the title compound was obtained as a yellow oily substance. Various spectral data was identical with those described in Japanese Patent No. 2,769,174.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:16]([CH3:17])=[CH:15][C:14]([OH:18])=[CH:13][C:12]=2[CH3:19])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:27][N:28]([CH3:32])[C:29](Cl)=[S:30]>O1CCOCC1.CN(C)C1C=CN=CC=1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:12]([CH3:19])=[CH:13][C:14]([O:18][C:29](=[S:30])[N:28]([CH3:32])[CH3:27])=[CH:15][C:16]=2[CH3:17])=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(O)cc(C)c1-c1ccc(C(C)(C)C)cc1
Reactant: CN(C)C(=S)Cl
Agent: CN(C)c1ccncc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cc1cc(OC(=S)N(C)C)cc(C)c1-c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Yield: 95.8 %

Procedure:
To a solution of 4′-tert-butyl-2,6-dimethyl-biphenyl-4-ol (10 g, 37.3 mmol) in dioxane (157 mL) is added 4-dimethylaminopyridine (476 mg, 3.9 mmol), triethylamine (10 mL, 78.6 mmol), and dimethylthiocarbamoyl chloride (6.1 g, 49.1 mmol). The reaction mixture is heated to reflux overnight. After cooling to room temperature, the reaction mixture is partitioned between ethyl acetate and water. The aqueous layer is back-extracted with ethyl acetate, and the combined organic layers are dried and concentrated. The resulting residue is applied to silica gel and eluted using 20% ethyl acetate in hexanes to give dimethyl-thiocarbamic acid O-(4′-tert-butyl-2,6-dimethyl-biphenyl-4-yl) ester (12.2 g).
Reaction SMILES: B(Br)(Br)Br.C(N(CC)C(C1C2C(=CC=CC=2)C([C:27]2[C:32]([CH3:33])=[CH:31][CH:30]=[C:29]([O:34]C)[C:28]=2[CH3:36])=NC=1)CCC)C1C=CC=CC=1.Cl.[OH-].[Na+]>C(Cl)Cl.CO>[CH3:36][C:28]1[CH:27]=[C:32]([CH3:33])[CH:31]=[CH:30][C:29]=1[OH:34]
Reactant: CCCC(c1cnc(-c2c(C)ccc(OC)c2C)c2ccccc12)N(CC)Cc1ccccc1
Agent: BrB(Br)Br
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc(O)c(C)c1
Temperature: 25 °C

Procedure:
BBr3 (2 ml of 1M solution in DCM, 2.0 mmol) is added to a solution of benzyl-ethyl-{1-[1-(3-methoxy-2,6-dimethyl-phenyl)-isoquinolin-4-yl]-butyl}-amine (95 mg, 0.21 mmol) in DCM (8 ml) at −78° C. The mixture is allowed to warm to room temperature slowly, and after 2h, the mixture is cooled to 0° C. MeOH (1 ml) and 1N—HCl (20 uL) are added carefully. After heating for 10 min at 80° C., the mixture is cooled and then basified with 1N—NaOH to pH 10. The resulting mixture is extracted with DCM and the combined extracts are washed with saturated brine. Drying over Na2SO4, and removal of the solvent in vacuo gave a yellow residue that is purified by PTLC affording 19 mg of 3-{4-[1-benzyl-ethyl-amino)-butyl]-isoquinolin-1-yl}-2,4-dimethyl-phenol as a white solid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([C:9]1[C:10]([CH3:31])=[C:11]([S:23][C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)[C:12](=[O:22])[N:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[N:14]=1)(=[O:8])[CH3:7].O>N1C=CC=CC=1>[C:6]([C:9]1[C:10]([CH3:31])=[C:11]([S:23][C:24]2[CH:25]=[CH:26][C:27]([NH:30][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:28][CH:29]=2)[C:12](=[O:22])[N:13]([C:15]2[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)[N:14]=1)(=[O:8])[CH3:7]
Reactant: CC(=O)c1nn(-c2ccc(F)cc2)c(=O)c(Sc2ccc(N)cc2)c1C
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)c1nn(-c2ccc(F)cc2)c(=O)c(Sc2ccc(NS(C)(=O)=O)cc2)c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methanesulfonyl chloride (0.1 ml) was added to a solution of 6-acetyl-4-(4-aminophenylthio)-2-(4-fluorophenyl)-5-methyl-3(2H)-pyridazinone (185 mg) in pyridine (2 ml) at 5° C., followed by stirring at room temperature for 1 hour. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. After washing with a saturated aqueous sodium hydrogen carbonate solution and a brine, the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by evaporation, and the resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1), and was crystallized from ether to obtain 6-acetyl-2-(4-fluorophenyl)-5-methyl-4-(4-methylsulfonylaminophenylthio)-3(2H)-pyridazinone (180 mg) (Compound No. 4-01).
Reaction SMILES: Cl[CH2:2][S:3][C:4]1[N:5]([CH3:9])[CH:6]=[CH:7][N:8]=1.Cl.[Cl:11][C:12]1[CH:13]=[N:14][C:15](=[O:18])[NH:16][CH:17]=1.CC(C)([O-])C.[K+]>CN(C=O)C>[CH3:9][N:5]1[CH:6]=[CH:7][N:8]=[C:4]1[S:3][CH2:2][N:16]1[CH:17]=[C:12]([Cl:11])[CH:13]=[N:14][C:15]1=[O:18]
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: Cn1ccnc1SCCl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1ccnc1SCn1cc(Cl)cnc1=O
Temperature: 60 °C
Reaction time: 2 h

Procedure:
2-Chloromethylsulfenyl-1-methylimidazole [see Preparation 10] (10 mmol) in DMF (12 ml) was added to a mixture of 5-chloropyrimidin-2-one hydrochloride (10 mmol) and potassium tert-butoxide (20 mmol) in DMF (72 ml). The mixture was stirred at 60° C. for 51/2 hours before the product was distilled off and the residue washed with water and ether. The product was oily. 1H HMR (DMSO d6, δ): 3.57 (CH3), 5.27 (--CH2 --), 6.95-7.22 (imidazole), 8.19 (H-4, d, j 4 Hz), 8.54 (H-6, d, J 4 Hz).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:14][CH3:15])[C:5]([N:8]2[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]2)=[N:6][CH:7]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)C(C)C)(C)C.[C:47](#[N:50])[CH:48]=[CH2:49]>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].CN(C=O)C>[CH3:15][O:14][C:4]1[CH:3]=[C:2](/[CH:49]=[CH:48]/[C:47]#[N:50])[CH:7]=[N:6][C:5]=1[N:8]1[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]1
Reactant: COc1cc(Br)cnc1-n1cnc(C)c1
Reactant: C=CC#N
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(/C=C/C#N)cnc1-n1cnc(C)c1
Temperature: 110 °C
Reaction time: 5 h

Procedure:
A mixture of 5-bromo-3-methoxy-2-(4-methyl-1H-imidazol-1-yl)pyridine (3.8 g), tris(dibenzylideneacetone)dipalladium (650 mg), tri-o-tolylphosphine (433 mg), N,N-diisopropylethylamine (4.86 mL), DMF (14.1 mL) and acrylonitrile (2.82 mL) was stirred in a nitrogen atmosphere at 110° C. for five hours. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure. The residue was diluted with ethyl acetate and then filtered through celite, and the filtrate was washed with water. The organic layer was concentrated under reduced pressure, and the precipitated crystals were hot dissolved in ethyl acetate. After leaving to cool to room temperature, the precipitated crystals were collected by filtration and air-dried to obtain 1.79 g of the title compound. The filtrate was concentrated under reduced pressure. Then, the residue was purified by silica gel column chromatography (heptane-ethyl acetate system) and then recrystallized from ethyl acetate to obtain 0.312 g of the title compound. The property value of the compound is as follows.
Reaction SMILES: [NH2:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[N-:11]=[N+:12]=[N-:13].[Na+].Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:3]([C:4]2[NH:13][N:12]=[N:11][N:5]=2)[C:2]=1[NH2:1]
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1cccc(Cl)c1N
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Nc1c(Cl)cccc1-c1nnn[nH]1
Temperature: 100 °C
Yield: 90 %

Procedure:
To a mixture of 2-amino-3-chlorobenzonitrile (500 mg, 3.3 mmol), sodium azide (4.3 mmol, 1.3 eq.), and triethylamine hydrochloride (4.3 mmol, 1.3 eq.) in a sealed tube, 8 mL of toluene was added. The tube was tightly capped and the reaction was stirred and heated to 100° C. overnight. The mixture was cooled to room temperature, diluted with another 10 mL of toluene, transferred to a separatory funnel and washed 3×20 mL with water. The aqueous extractions were collected and acidified to a pH of 4 with concentrated HCl. The solid was collected by filtration, washed with acetonitrile, and dried under vacuum to afford 581 mg of 2-chloro-6-(1H-tetrazol-5-yl)aniline. MS (EI) for C7H6ClN5: 196 (MH+). Step 2: N-[2-Chloro-6-(1H-tetrazol-5-yl)phenyl]thiophene-2-carboxamide: To a solution of 2-chloro-6-(1H-tetrazol-5-yl)aniline (300 mg, 1.5 mmol) in 8 mL of DCM, DIPEA (3.1 mmol, 2.0 eq.) was added followed by thiophene-2-carbonyl chloride (2.3 mmol, 1.5 eq.). The reaction was stirred at room temperature overnight. The organic solution of the crude reaction mixture was extracted twice with aqueous HCl (0.1 M), twice with aqueous sodium hydroxide (0.1 M), and once with a saturated aqueous solution of sodium chloride. The basic aqueous extractions and final brine extraction were combined and acidified to a pH of 4 with concentrated HCl. The resulting solid was collected by filtration. The material was then washed with acetonitrile, and dried under vacuum to afford 33 mg of desired product. 1H-NMR (400 MHz, d6-DMSO): δ 10.32 (s, 1H), 7.96 (d, 1H), 7.87-7.81 (m, 3H), 7.58 (t, 1H), 7.23 (t, 1H). MS (EI) C12H8ClN5OS: 306 (M+H).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:25]=[C:9]2[C:10](=[O:24])[NH:11][C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=3)=[CH:13][N:8]2[N:7]=1)=[O:5])C.[OH-].[Na+]>COCCOC>[C:20]([C:17]1[CH:16]=[CH:15][C:14]([C:12]2[NH:11][C:10](=[O:24])[C:9]3[N:8]([N:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:25]=3)[CH:13]=2)=[CH:19][CH:18]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CCOC(=O)c1cc2c(=O)[nH]c(-c3ccc(C(C)(C)C)cc3)cn2n1
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Product: CC(C)(C)c1ccc(-c2cn3nc(C(=O)O)cc3c(=O)[nH]2)cc1
Temperature: 100 °C
Reaction time: 48 h

Procedure:
A solution of 547 mg (1.61 mmol) 6-(4-tert-butyl-phenyl)-4-oxo-4,5-dihydro-pyrazolo[1,5-a]pyrazine-2-carboxylic acid ethyl ester in 10 ml 1,2-dimethoxyethane is treated with 5 ml 1 N aqueous NaOH solution. The resulting suspension is heated to 100° C. and the resulting solution is stirred at this temperature for 48 hours. The reaction mixture is cooled to room temperature and evaporated. The residue is triturated with water and the solids are filtered off and washed with water. The filtrate is acidified with 2 N HCl. The resulting precipitate is filtered off, washed with 2 N HCl and with water and dried under vacuum to give 6-(4-tert-butyl-phenyl)-4-oxo-4,5-dihydro-pyrazolo[1,5-a]pyrazine-2-carboxylic acid as colourless solid; HPLC/MS 2.03 (A), [M+H] 312.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[CH:9][CH:10]=2)[NH:5][CH2:4][CH2:3]1.[C:16](OC(=O)C)(=[O:18])[CH3:17].O>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[CH:9][CH:10]=2)[N:5]([C:16](=[O:18])[CH3:17])[CH2:4][CH2:3]1
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)CCNc2cc([N+](=O)[O-])ccc21
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)N1CCC(C)(C)c2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 10 h
Yield: 91.5 %

Procedure:
To a stirred solution of 1,2,3,4-tetrahydro-4,4-dimethyl-7-nitroquinoline (Rami et al, WO 03/068749) (500 mg, 2.42 mmol), DMAP (5 mg) in pyridine (2 mL) was added acetic anhydride (0.46 mL, 4.9 mmol). The mixture was stirred at room temperature for 10 h, and then heated at 60° C. for 5 h. After cooling, the mixture was treated with water and extracted with EtOAc. The combined organic layers were washed with sat. aq. NaHCO3, 1N HCl, brine, dried, and evaporated. The residue was purified by chromatography to give a light yellow solid (550 mg, 92%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C:9]2=[O:14])=[C:4]([F:15])[CH:3]=1.[C:16]([CH:19]=[C:20]=[O:21])(=[O:18])[CH3:17]>CCOC(C)=O>[F:15][C:4]1[CH:3]=[C:2]([NH:1][C:20](=[O:21])[CH2:19][C:16](=[O:18])[CH3:17])[CH:7]=[CH:6][C:5]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][C:9]1=[O:14]
Reactant: CC(=O)C=C=O
Reactant: Nc1ccc(N2CCOCC2=O)c(F)c1
Solvent: CCOC(C)=O
Product: CC(=O)CC(=O)Nc1ccc(N2CCOCC2=O)c(F)c1
Temperature: 80 °C
Reaction time: 24 h
Yield: 61.4 %

Procedure:
A mixture of 4-(4-amino-2-fluorophenyl)morpholin-3-one (2.51 g, 11.9 mmol) and acetyl ketene (2.51 g, 29.9 mmol) in EtOAc (40 mL) was stirred at 80° C. for 24 h. The mixture was cooled to rt and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:4) to give the title compound as a yellow solid (2.15 g, 61%).
Reaction SMILES: C(OC)(OC)OC.[Br:8][C:9]1[CH:10]=[C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([NH:15][NH2:16])=[N:13][CH:14]=1.[C:23](O)(C(F)(F)F)=O>C(Cl)Cl>[Br:8][C:9]1[CH:10]=[C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]2[N:13]([CH:23]=[N:16][N:15]=2)[CH:14]=1
Reactant: O=C(O)C(F)(F)F
Reactant: NNc1ncc(Br)cc1-c1ccccc1
Solvent: ClCCl
Solvent: COC(OC)OC
Product: Brc1cc(-c2ccccc2)c2nncn2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
Trimethyl orthoformate (564 μL, 5.16 mmol) was added into a solution of 1-(5-bromo-3-phenylpyridin-2-yl)hydrazine (1.29 mmol, crude) in CH2Cl2 (12 mL). TFA (100 μL, 1.29 mmol) was added after 15 mins. The reaction mixture was stirred at room temperature for 30 mins and then concentrated. The residue was purified by a flash column using a gradient of ethyl acetate (50-80%) in heptane as an eluent. The product containing fractions were concentrated to give 6-bromo-8-phenyl-[1,2,4]triazolo[4,3-a]pyridine (328.7 mg, 85% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]([CH2:17]Cl)=[C:5]2[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[NH3:25]>O1CCCC1.C(O)C>[NH2:25][CH2:17][C:6]1[N:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:8](=[O:12])[C:9]2[C:4]([C:5]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2
Reactant: N
Reactant: CC(C)Cn1c(CCl)c(-c2ccccc2)c2cc(Br)ccc2c1=O
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)Cn1c(CN)c(-c2ccccc2)c2cc(Br)ccc2c1=O
Temperature: 140 °C
Reaction time: 5 h
Yield: 53 %

Procedure:
A solution of 6-bromo-3-chloromethyl-2-isobutyl-4-phenyl-1(2H)-isoquinolinone (10 g, 24.7 mmol) in tetrahydrofuran (20 mL) and a solution of 2M ammonia in ethanol (200 mL) were sealed in a stainless tube and stirred at 140° C. for 5 h. The reaction mixture was cooled and concentrated. The residue was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from diethyl ether and the precipitated crystals were collected by filtration to give 3-aminomethyl-6-bromo-2-isobutyl-4-phenyl-1(2H)-isoquinolinone (5.6 g, 53%) as crystals.
Reaction SMILES: Br[CH2:2][C:3]1[C:11]2[N:10]=[CH:9]N(C(OC(C)(C)C)=O)[C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH3:19][N:20]([CH:22]([C:28](OCC)=O)[C:23](OCC)=O)[CH3:21]>C1COCC1.CCOCC>[CH3:19][N:20]([CH3:21])[CH:22]1[CH2:28][C:7]2[C:11]3=[C:3]([CH:2]=[CH:9][N:10]3[CH2:23]1)[CH:4]=[CH:5][CH:6]=2
Reactant: CCOC(=O)C(C(=O)OCC)N(C)C
Reactant: CC(C)(C)OC(=O)n1cnc2c(CBr)cccc21
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN(C)C1Cc2cccc3ccn(c23)C1

Procedure:
This compound was prepared by following the procedure of Example 18, but substituting methyl 7-(bromomethyl)-1H-indole-1-carboxylate for t-butyl 4-(bromomethyl) -1 H-benzimidazole-1-carboxylate and diethyl (dimethylamino)malonate for diethyl (dipropylamino) malonate. The bulk of the product was converted to the maleate salt, mp 114°-115° C. from THF/ether.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)/[CH:5]=[CH:6]/[C:7]1[S:8][C:9]([CH3:14])=[C:10]([CH2:12][CH3:13])[N:11]=1.Cl.N([O-])=[O:20].[Na+]>O>[OH:20][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)/[CH:5]=[CH:6]/[C:7]1[S:8][C:9]([CH3:14])=[C:10]([CH2:12][CH3:13])[N:11]=1
Reactant: O=N[O-]
Reactant: CCc1nc(/C=C/c2cccc(N)c2)sc1C
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCc1nc(/C=C/c2cccc(O)c2)sc1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 69.7 %

Procedure:
An amount of 3.0 g of 2-(trans-3-aminostyryl)-4-ethyl-5-methylthiazole was added to 18 ml of 20% hydrochloric acid and to the mixture was added dropwise slowly 3 ml of an aqueous solution of 0.86 g of sodium nitrite while maintaining the inner temperature at 4° to 5° C. After the mixture was stirred at the above temperature for 1.5 hours, the reaction mixture was added into 50 ml of boiling water over 20 minutes. After the mixture was cooled to room temperature, the precipitates formed were collected by filtration, washed with aqueous saturated sodium hydrogen carbonate solution and with water, followed by drying under reduced pressure. The crude product was washed with toluene and dried under reduced pressure to obtain 2.1 g (yield 70%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([NH:15][C:16]([C:18]2[CH:19]=[N:20][N:21]3[CH:26]=[CH:25][CH:24]=[N:23][C:22]=23)=[O:17])=[C:5]([C:7]2[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=2[OH:14])[N:6]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:34]([F:39])([F:38])C([O-])=O.[Na+]>CN(C=O)C.O>[Br:1][C:2]1[S:3][C:4]([NH:15][C:16]([C:18]2[CH:19]=[N:20][N:21]3[CH:26]=[CH:25][CH:24]=[N:23][C:22]=23)=[O:17])=[C:5]([C:7]2[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=2[O:14][CH:34]([F:39])[F:38])[N:6]=1
Reactant: O=C([O-])C(F)(F)Cl
Reactant: O=C(Nc1sc(Br)nc1-c1cc(Cl)ccc1O)c1cnn2cccnc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1sc(Br)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 59.1 %

Procedure:
To a solution of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [2-bromo-4-(5-chloro-2-hydroxy-phenyl)-thiazol-5-yl]-amide (1.1 g, 2.4 mmol) in DMF (20 mL) and water (2 mL) was added cesium carbonate (1.1 g, 3.4 mmol) and then sodium chlorodifluoroacetate (839 mg, 5.5 mmol). The mixture was stirred at 100° C. for 16 hours before further cesium carbonate (2.2 g, 6.8 mmol) and sodium chlorodifluoroacetate (1.7 g, 11 mmol) was added and stirring continued at 100° C. for 6 hours. The mixture was allowed to cool to room temperature and partitioned between ethyl acetate and water and the phases separated. The organic layer was washed with brine. The combined aqueous layer was extracted with ethyl acetate once and the combined organic layer dried (Na2SO4), filtered and evaporated. The resultant residue was purified by flash chromatography on silica eluting with 50% ethyl acetate in cyclohexane to give the title compound as a yellow solid (710 mg, 59%). LCMS (Method 3) [M+H]+=500.1, RT=3.97 min. 1H NMR (400 MHz, DMSO-d6) δ: 10.84 (s, 1H), 9.42 (dd, 1H, J=1.6, 6.9 Hz), 8.79 (s, 1H), 8.66 (dd, 1H, J=1.6, 4.3 Hz), 7.76 (d, 1H, J=2.8 Hz), 7.51 (d, 1H, J=8.8 Hz), 7.36 (dd, 1H, J=4.2, 7.0 Hz), 7.22 (t, 1H, J=73.1 Hz).