Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[N:2]=[C:3]([S:10][C:11]2[N:16]=[N:15][C:14]([NH2:17])=[CH:13][CH:12]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.Br[CH2:19][C:20]([NH:22][C:23]([CH:25]1[CH2:27][CH2:26]1)=[O:24])=O.P([O-])([O-])(O)=O.[K+].[K+].[I-].[K+]>CC(N(C)C)=O.CO>[N:1]1[N:2]=[C:3]([S:10][C:11]2[CH:12]=[CH:13][C:14]3[N:15]([CH:19]=[C:20]([NH:22][C:23]([CH:25]4[CH2:27][CH2:26]4)=[O:24])[N:17]=3)[N:16]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: O=C(CBr)NC(=O)C1CC1
Reactant: Nc1ccc(Sc2nnc3ccccn23)nn1
Agent: O=P([O-])([O-])O
Agent: [I-]
Agent: [K+]
Solvent: CO
Solvent: CC(=O)N(C)C
Product: O=C(Nc1cn2nc(Sc3nnc4ccccn34)ccc2n1)C1CC1
Temperature: 120 °C
Reaction time: 2 h
Yield: 34.2 %

Procedure:
A mixture of 6-([1,2,4]triazolo[4,3-a]pyridin-3-ylthio)pyridazin-3-amine (2.443 g, 10 mmol), N-(2-bromoacetyl)cyclopropanecarboxamide (3.09 g, 15.00 mmol), potassium hydrogenphosphate (5.23 g, 30.0 mmol) and potassium iodide (0.830 g, 5.00 mmol) in DMA (100 mL) was stirred at 120° C. for 2 hrs. Additional amounts of N-(2-bromoacetyl)cyclopropanecarboxamide (2.06 g, 10 mmol) and potassium hydrogenphosphate (1.74 g, 10 mmol) were added to the mixture and the reaction was stirred at 120° C. for another 2 hrs. The reaction was then stirred at room temperature overnight. The reaction mixture was again stirred at 140° C. for 3 hrs and then cooled to room temperature. The resulting solid was filtered off and rinsed with DMA. The filtrate was concentrated to 100 mL and then poured into water (300 mL). The resulting precipitate was collected by filtration and rinsed thoroughly with water. The solid material was re-suspended in 10% MeOH/CH2Cl2 (100 mL), sonicated, refluxed for 30 min and cooled to room temperature. The MeOH/CH2Cl2 solution was filtered through a silica plug, rinsed with 10% MeOH/CH2Cl2 (200 mL). To above organic solution, activated charcoal (0.5 g) was added, the solution was refluxed for 30 min, and then stirred at room temperature overnight. The charcoal was filtered through Celite, and the filtrate was concentrated to dryness to provide an off white solid. This solid was refluxed in MeOH (10 mL) for 30 min. and cooled to room temperature. The resulting off white solid was collected by filtration, rinsed with MeOH (2 mL) and dried in vacuum to provide the title compound, N-(6-([1,2,4]Triazolo[4,3-a]pyridin-3-ylthio)imidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (1.2 g). 1H NMR (400 MHz, DMSO-d6) δ=11.17 (s, 1 H), 8.57-8.44 (m, 1 H), 8.03-7.94 (m, 1 H), 7.96-7.88 (m, 2 H), 7.59 (ddd, J=1.0, 6.6, 9.3 Hz, 1 H), 7.22-7.11 (m, 1 H), 7.11-7.03 (m, 1 H), 1.97-1.84 (m, 1 H), 0.83-0.73 (m, 4 H) ESI-MS:m/z 352.3 (M+H)+. MP 193-195° C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl.[F:14][C:15]([F:49])([F:48])[C:16]1[CH:21]=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[N:19]=[C:18]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([C:38]3[CH:39]=[C:40]([S:44](Cl)(=[O:46])=[O:45])[CH:41]=[CH:42][CH:43]=3)[CH:33]=2)[N:17]=1>C1COCC1>[N:1]1([S:44]([C:40]2[CH:39]=[C:38]([C:34]3[CH:33]=[C:32]([C:18]4[N:17]=[C:16]([C:15]([F:14])([F:48])[F:49])[CH:21]=[C:20]([C:22]5[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:24][CH:23]=5)[N:19]=4)[CH:37]=[CH:36][N:35]=3)[CH:43]=[CH:42][CH:41]=2)(=[O:45])=[O:46])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: O=S(=O)(Cl)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=S(=O)(c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1)N1CCCC1
Temperature: 0 °C
Yield: 86.4 %

Procedure:
To a cooled (ice-water bath) and stirred mixture of pyrrolidine (0.065 g, 0.91 mmol), triethylamine (0.09 ml, 0.63 mmol) and THF (2 ml) was added drop wise a solution of 3-{4-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonyl chloride hydrochloride (example 1.1) (0.20 g, 0.34 mmol) in THF (3 ml). The mixture was allowed to stir at room temperature for 16 h. Purification of the reaction mixture by flash chromatography on silica gel (ethyl acetate/hexane) and crystallization (dichloromethane/hexane) yielded the title compound as a white solid (0.17 g, 85%). MS (ISP) 578.6 [(M+H)+]; mp 184° C.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([C:19]4[CH:20]=[C:21]5[C:26](=[CH:27][CH:28]=4)[CH:25]=[C:24]([CH2:29]O)[CH:23]=[CH:22]5)[CH:14]=[CH:15][C:16]=3[O:17][CH3:18])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:55]I>C1COCC1.CCOC(C)=O>[C:1]12([C:11]3[CH:12]=[C:13]([C:19]4[CH:20]=[C:21]5[C:26](=[CH:27][CH:28]=4)[CH:25]=[C:24]([CH2:29][I:55])[CH:23]=[CH:22]5)[CH:14]=[CH:15][C:16]=3[O:17][CH3:18])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: COc1ccc(-c2ccc3cc(CO)ccc3c2)cc1C12CC3CC(CC(C3)C1)C2
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc3cc(CI)ccc3c2)cc1C12CC3CC(CC(C3)C1)C2
Yield: 44.9 %

Procedure:
To a solution of 6-[3-(1-adamantyl)-4-methoxyphenyl]-naphthalen-2-yl-methyl alcohol (0.365 g, 0.92 mmol), triphenylphosphine (0.366 g, 1.39 mmol) and imidazole (0.095 g, 1.39 mmol) in 7 mL of anhydrous THF at 0° C. was added dropwise a solution of I2 (0.303 g, 1.19 mmol) in 4 mL of anhydrous THF. After 30 minutes the mixture was diluted with EtOAc and washed with sodium thiosulfate aq. (100 mL), brine (100 mL), dried with magnesium sulfate, filtered and evaporated. The residue was purified on silica gel (eluent: hexane:EtOAc 100 to 95:5) to give 0.210 g of 6-[3-(1-adamantyl)-4-methoxyphenyl]-naphthalen-2-yl-methyliodide (45%). 1H NMR (300 MHz; CDCl3): δ 1.80 (s, 6H), 2.10–2.18 (m, 9H), 3.89 (s, 3H), 4.65 (s, 2H), 6.98 (d, J=8.7 Hz, 1H), 7.46–7.57 (m, 3H), 7.71–7.93(m, 5H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[C:9]([CH3:10])=[CH:8][C:7]([F:11])=[CH:6][C:5]=1[C:12]#[N:13].[Br:15]NC(=O)CCC(N)=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:14])[C:4]1[C:5]([C:12]#[N:13])=[CH:6][C:7]([F:11])=[CH:8][C:9]=1[CH2:10][Br:15]
Reactant: COC(=O)c1c(C)cc(F)cc1C#N
Reactant: NC(=O)CCC(=O)NBr
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1c(C#N)cc(F)cc1CBr

Procedure:
A mixture of 4-fluoro-2-cyano-6-methyl-benzoic acid methyl ester (1.04 g, 5.38 mmol), N-bromosuccinamide (1.25 g, 7.0 mmol), and benzoyl peroxide (0.024 g, 0.146 mmol) in carbon tetrachloride (50 mL) was heated at reflux until majority of ester was consumed (as analyzed by GC/MS). The resulting mixture was filtered, the filtrate was concentrated to afford 2-bromomethyl-4-fluoro-6-cyano-benzoic acid methyl ester. The material was used without further purification.
Reaction SMILES: [CH2:1](C(CC)(CC)C([O-])([O-])[O-])[CH3:2].[CH:12]1([N:16]2[CH2:22][CH2:21][C:20]3[CH:23]=[CH:24][C:25]([O:27][C:28]4[N:33]=[CH:32][C:31]([C:34]([NH:36][NH2:37])=[O:35])=[CH:30][CH:29]=4)=[CH:26][C:19]=3[CH2:18][CH2:17]2)[CH2:15][CH2:14][CH2:13]1>>[CH:12]1([N:16]2[CH2:22][CH2:21][C:20]3[CH:23]=[CH:24][C:25]([O:27][C:28]4[CH:29]=[CH:30][C:31]([C:34]5[O:35][C:1]([CH3:2])=[N:37][N:36]=5)=[CH:32][N:33]=4)=[CH:26][C:19]=3[CH2:18][CH2:17]2)[CH2:13][CH2:14][CH2:15]1
Reactant: NNC(=O)c1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)nc1
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Product: Cc1nnc(-c2ccc(Oc3ccc4c(c3)CCN(C3CCC3)CC4)nc2)o1

Procedure:
A mixture of triethylorthoacetate (3 ml) and 6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinecarbohydrazide (D54) (185 mg, 0.52 mmol) was heated at reflux for 16 hours. The reaction mixture was concentrated and the resulting residue was purified by column chromatography eluting with a mixture of 0.880 ammonia:methanol:dichloromethane (0.1:5:95) to afford the title compound (E216). MS (ES+) m/e 377 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][C:7]([CH2:8][N:9]2[C:13]([C:14]([NH2:16])=[O:15])=[C:12]([OH:17])[N:11]=[CH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:20](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]2[C:13]([C:14]([NH2:16])=[O:15])=[C:12]([O:17][CH3:20])[N:11]=[CH:10]2)=[CH:18][CH:19]=1)([O-:3])=[O:2]
Reactant: NC(=O)c1c(O)ncn1Cc1ccc([N+](=O)[O-])cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ncn(Cc2ccc([N+](=O)[O-])cc2)c1C(N)=O
Temperature: 50 °C

Procedure:
3.93 g (15 mmol) of the derivative 3-(4-nitrobenzyl)-5-hydroxy-3H-imidazole-4-carboxamide are added to 80 ml of DMF in a three-necked flask under argon, followed by addition of 8.29 g (60 mmol; 4 eq.) of potassium carbonate. The stirred medium is maintained at 50° C. for 30 minutes and then cooled to room temperature. Methyl iodide (5.75 g; 40.5 mmol; 2.7 eq.) is then added.
Reaction SMILES: C1C=CC=CC=1.[CH3:7][C:8]1[CH:24]=[CH:23][C:11]2[O:12][C:13]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:14]=3[C:15](=O)[CH2:16][C:10]=2[CH:9]=1.[CH2:25]([O:27][C:28]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)=[O:29])[CH3:26].C(=O)(O)[O-].[Na+]>[Ti](Cl)(Cl)(Cl)Cl.O>[CH2:25]([O:27][C:28]([N:30]1[CH2:31][CH2:32][N:33]([C:15]2[C:14]3[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:13]=3[O:12][C:11]3[CH:23]=[CH:24][C:8]([CH3:7])=[CH:9][C:10]=3[CH:16]=2)[CH2:34][CH2:35]1)=[O:29])[CH3:26]
Reactant: Cc1ccc2c(c1)CC(=O)c1cc(C)ccc1O2
Reactant: CCOC(=O)N1CCNCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)N1CCN(C2=Cc3cc(C)ccc3Oc3ccc(C)cc32)CC1

Procedure:
A solution of 11.35 ml. of titanium (IV) chloride in 135 ml. of benzene is added dropwise with stirring and cooling at 20°-25° C. to a solution of 30 g. of 10,11-dihydro-2,8-dimethyl-dibenz[b,f]oxepin-10-one and 80 ml. of N-ethoxycarbonylpiperazine in 300 ml. of benzene. Then, the mixture is stirred for 4 hours at reflux and cooled. The cooled mixture is poured into a solution of 12 g. of sodium bicarbonate in 300 ml. of water. The precipitated titanium dioxide is removed by filtration and washed well with benzene. The filtrate is washed four additional times with water. The aqueous phases are extracted again with benzene. The combined benzene extracts are dried over sodium sulfate and evaporated in vacuo, and there is obtained 4-[2,8-dimethyl-dibenz[b,f]oxepin-10-yl]-1-piperazinecarboxylic acid ethyl ester as an oil.
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([Br:11])=[CH:4][N:3]=1.[F:12][C:13]1[C:14](B(O)O)=[CH:15][C:16]([O:19][CH3:20])=[N:17][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([C:14]2[C:13]([F:12])=[CH:18][N:17]=[C:16]([O:19][CH3:20])[CH:15]=2)=[N:3][CH:4]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Br
Reactant: COc1cc(B(O)O)c(F)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(-c2ncc(Br)cc2[N+](=O)[O-])c(F)cn1
Temperature: 90 °C
Reaction time: 21.5 h

Procedure:
A mixture of 2,5-dibromo-3-nitropyridine, commercially available from Matrix Scientific (0.72 g, 2.55 mmol), 5-fluoro-2-methoxypyridin-4-ylboronic acid, commercially available from Asymchem (0.39 g, 2.34 mmol), dichlorobis(triphenyl-phosphine)palladium (II) (90 mg, 0.13 mmol), and 1.0M sodium carbonate (3.5 mL, 7.0 mmol) in 1,4-dioxane (10 mL) was degassed by nitrogen. The mixture was heated to 90° C. After 21.5 h, the reaction was cooled to rt then treated with water. After extracting twice with EtOAc, the organic layer was combined and dried over anhydrous magnesium sulfate. After filtration and concentration, the yellowish brown residue was treated with MeOH and placed on the rotoevaporator (without vac.) in a 45° C. water bath. After 30 min, the solid was filtered and rinsed twice with MeOH to afford a tan solid as 5-bromo-5′-fluoro-2′-methoxy-3-nitro-2,4′-bipyridine. 1H NMR (500 MHz, CDCl3) δ ppm 9.01 (1H, d, J=2.0 Hz), 8.56 (1H, d, J=2.0 Hz), 8.06 (1H, d, J=1.2 Hz), 7.02 (1H, d, J=4.6 Hz), 4.04 (3H, m).
Reaction SMILES: [NH:1]([C:3]1[N:4]=[N:5][C:6]2[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:7]=2[N:8]=1)[NH2:2].[C:14]([CH2:17][C:18](=O)[CH3:19])(=O)[CH3:15]>C(O)C>[CH3:15][C:14]1[CH:17]=[C:18]([CH3:19])[N:1]([C:3]2[N:4]=[N:5][C:6]3[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:7]=3[N:8]=2)[N:2]=1
Reactant: CC(=O)CC(C)=O
Reactant: NNc1nnc2cc(Cl)ccc2n1
Solvent: CCO
Product: Cc1cc(C)n(-c2nnc3cc(Cl)ccc3n2)n1
Yield: 85.9 %

Procedure:
19.5 g (0.1 mol) of 3-hydrazino-7-chloro-benzo-1,2,4-triazine and 10 g (0.1 mol) of acetylacetone were boiled under reflux in 125 ml of ethanol for 5 hours. The residue after distilling off the solvent was recrystallized from wash benzine. 22.3 g of 3-(3,5-dimethyl-pyrazol-1-yl)-7-chloro-benzo-1,2,4-triazine of melting point 174° C. were obtained, that is to say 86% of theory.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][C:10]=1[N+:18]([O-])=O.CN(C)C=O.[CH3:26][C:27]1[CH:28]=[C:29]([CH:31]=[C:32]([CH3:34])[CH:33]=1)[NH2:30]>>[NH2:18][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:9]=1[O:8][CH3:7])[C:13]([NH:30][C:29]1[CH:31]=[C:32]([CH3:34])[CH:33]=[C:27]([CH3:26])[CH:28]=1)=[O:15]
Reactant: COc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: Cc1cc(C)cc(N)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Nc2cc(C)cc(C)c2)cc1N
Yield: 69.9 %

Procedure:
Prepared according to the procedure described for Example 1 using oxalyl chloride (3.0 mL, 4.39 mmol), 4-methoxy-3-nitrobenzoic acid (5.00 g, 25.36 mmol), dimethylformamide (0.5 mL, 6.5 mmol), and 3,5-dimethylaniline (6.4 mL, 51.33 mmol) to afford the product (4.79 g); m.p. 155-162° C.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[C:10]([C:24]([NH:26]O)=[NH:25])=[CH:11][C:12]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[NH:14][C:13]=2[CH:23]=1>[Zn].C(O)(=O)C>[F:8][C:9]1[C:10]([C:24]([NH2:26])=[NH:25])=[CH:11][C:12]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[NH:14][C:13]=2[CH:23]=1
Reactant: N=C(NO)c1cc2nc(-c3ccccn3)[nH]c2cc1F
Agent: [Zn]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: N=C(N)c1cc2nc(-c3ccccn3)[nH]c2cc1F

Procedure:
A mixture comprising 6-fluoro-N-hydroxy-2-pyridin-2-yl-1H-benzimidazole-5-carboxamidine trifluoroacetate (108 mg, 0.4 mmol), Zn (55 mg, 1.2 mmol) and acetic acid (5 mL) was heated at reflux under nitrogen for 2 hours. The mixture was filtered and concentrated to dryness. The residue was taken up and purified by preparative reverse phase HPLC. The combined pure fractions were lyophilized to provide 6-fluoro-2-pyridin-2-yl-1H-benzimidazole-5-carboxamidine; MS (ESI), Calculated for C13H10FN5 : 255.09, Found (MH+): 255.9; 1H-NMR (300 Mhz, DMSO-d6): 7.64-7.69 (m, 2H), 7.97 (d, 1H), 8.08 (m, 1H), 8.42 (d, 1H), 8.78 (d, 1H), 8.48 (d, 4H).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[S:7][C:8]2[N:9]=[C:10]([N:15]([CH3:36])[C:16]3[CH:17]=[C:18]([NH:22][C:23](=[O:35])[C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([C:33]#[N:34])([CH3:32])[CH3:31])[CH:25]=4)[CH:19]=[CH:20][CH:21]=3)[N:11]=[CH:12][C:13]=2[N:14]=1)=[O:4].C(N(CC)CC)C.[NH:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1.C(=O)([O-])O.[Na+]>O1CCCC1>[C:33]([C:30]([C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=1)[C:23]([NH:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([N:15]([CH3:36])[C:10]2[N:11]=[CH:12][C:13]3[N:14]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:44]4[CH2:49][CH2:48][O:47][CH2:46][CH2:45]4)[S:7][C:8]=3[N:9]=2)[CH:17]=1)=[O:35])([CH3:32])[CH3:31])#[N:34]
Reactant: CN(c1cccc(NC(=O)c2cccc(C(C)(C)C#N)c2)c1)c1ncc2nc(NC(=O)CCl)sc2n1
Reactant: C1COCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(c1cccc(NC(=O)c2cccc(C(C)(C)C#N)c2)c1)c1ncc2nc(NC(=O)CN3CCOCC3)sc2n1
Temperature: 60 °C
Reaction time: 4 h
Yield: 65.3 %

Procedure:
To a solution of N-{3-[{2-[(chloroacetyl)amino][1,3]thiazolo[5,4-d]pyrimidin-5-yl}(methyl)amino]phenyl}-3-(1-cyano-1-methylethyl)benzamide (141 mg, 271 μmol) produced in Example D10 in tetrahydrofuran (4 mL) were added triethylamine (113 μL, 813 μmol) and morpholine (71 μL, 813 μmol), and the mixture was stirred at 60° C. for 4 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (15 mL), and the mixture was extracted with ethyl acetate (15 mL, 10 mL). The combined organic layer was washed with saturated brine (5 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/methanol=100/0=98/2), and the fractions containing the object product were concentrated under reduced pressure. To the obtained residue were added diisopropyl ether and ethyl acetate, and the precipitate was collected by filtration to give the title compound (101 mg, 50%) as a pale-red amorphous solid.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1.Br[CH2:19][C:20]([O:22][CH3:23])=[O:21].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:23][O:22][C:20]([CH2:19][O:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1)=[O:21]
Reactant: COC(=O)CBr
Reactant: O=C(OCc1ccccc1)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(C(=O)OCc2ccccc2)cc1

Procedure:
A mixture of benzyl 4-hydroxybenzoate (169.0g.), methyl bromoacetate (122.4g.) and anhydrous potassium carbonate (200g.) in acetone (500ml.) (analytical grade) was stirred and heated under reflux for 16 hours. The mixture was then filtered and the filtrate evaporated in vacuo. The semi-solid residue obtained was separated by filtration. The solid thus obtained was washed with cold (0°-5° C.) petroleum ether (b.p. 60°-80° C.) (50ml.) to give benzyl 4-(methoxycarbonylmethoxy)benzoate, m.p. 63°-66° C.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[F:25]>>[F:18][C:19]1[CH:20]=[C:21]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([F:17])[CH:3]=2)[CH:22]=[CH:23][C:24]=1[F:25]
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: O=C1NCCCn2c1cc1cc(F)cc(Br)c12
Product: O=C1NCCCn2c1cc1cc(F)cc(-c3ccc(F)c(F)c3)c12

Procedure:
The title compound, light yellow solid (79 mg, 96%), MS (ISP) m/z=331.1 [(M+H)+], mp 230.5° C., was prepared in accordance with the general method of example 1 from 7-bromo-9-fluoro-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indol-1-one (intermediate 2) (74.3 mg, 0.25 mmol) and commercially available 3,4-difluoro-phenylboronic acid (51.3 mg, 0.325 mmol).
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[N:4][C:5]([CH3:8])=[CH:6][N:7]=1.[H-].[Na+].Cl[CH2:20][N:21]1[C:25]([Cl:26])=[C:24]([Cl:27])[N:23]=[CH:22]1.C(OCC)(=O)C>CN(C)C=O>[CH3:1][C:2]1[C:3]([O:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:20][N:21]3[C:25]([Cl:26])=[C:24]([Cl:27])[N:23]=[CH:22]3)=[CH:12][CH:11]=2)=[N:4][C:5]([CH3:8])=[CH:6][N:7]=1
Reactant: Cc1cnc(C)c(Oc2ccc(O)cc2)n1
Reactant: ClCn1cnc(Cl)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cnc(C)c(Oc2ccc(OCn3cnc(Cl)c3Cl)cc2)n1
Temperature: 70 °C
Reaction time: 1 h
Yield: 67.6 %

Procedure:
At room temperature (about 20° C.), 7.8 g of 4-(3,6-dimethyl-2-pyrazinyloxy)-phenol in 20 ml of anhydrous dimethylformamide is dripped into 1.3 g of 80% strength sodium hydride in 30 ml of anhydrous dimethylformamide. The mixture is stirred for one hour at 70° C., and then 6.68 g of 1-chloromethyl- 4,5-dichloroimidazole in 30 ml of anhydrous dimethylformamide is dripped in. The mixture is stirred for 8 hours at 70° C. and overnight at room temperature. It is then stirred into 200 ml of ethyl acetate, and this mixture is washed twice with water, four times with 5% strength sodium hydroxide solution and twice with saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and the solvent is evaporated off under reduced pressure. The crude product obtained is crystallized with n-hexane. There is obtained 8.9 g of 1-[4-(3,6-dimethyl-2-pyrazinyloxy)-phenoxymethyl]-4,5-dichloroimidazole: m.p.: 84°-85° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[OH:9].[NH:10]1[CH2:15][CH2:14][CH:13]([C:16](O)=O)[CH2:12][CH2:11]1.[OH-].[Na+].CCOC(C)=O.O>O>[Br:8][C:6]1[CH:5]=[CH:4][C:3]2[O:9][C:16]([CH:13]3[CH2:14][CH2:15][NH:10][CH2:11][CH2:12]3)=[N:1][C:2]=2[CH:7]=1
Reactant: Nc1cc(Br)ccc1O
Reactant: O=C(O)C1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: Brc1ccc2oc(C3CCNCC3)nc2c1
Temperature: 190 °C
Yield: 49.1 %

Procedure:
2-amino-4-bromophenol (1.2 g, 5.8 mmol) and piperidine-4-carboxylic acid (0.74 g, 5.8 mmol) were dissolved in polyphosphoric acid (30 g). This mixture was heated at 190° C. for three and half hours. Reaction mixture cooled to rt and diluted with water (100 ml). Aqueous layer basified with sodium hydroxide pellets to pH 9. Work up (AcOEt/H2O) followed removal of AcOEt afforded the titled compound (0.8 g) as a pale-yellow gummy solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[N:3]=1.Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(N(C(C)C)C(C)C)C>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:13]=[CH:12][C:10]([NH:11][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:9][CH:8]=2)[N:3]=1
Reactant: Cc1nc(-c2ccc(N)cc2)no1
Reactant: CCOC(=O)CBr
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CNc1ccc(-c2noc(C)n2)cc1

Procedure:
Prepared analogously to Example 9a from 4-(5-methyl-1,2,4-oxadiazol-3-yl)-aniline and ethyl bromoacetate in N-ethyl-diisopropylamine.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23]([OH:25])=O)[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[O:26]1[CH2:31][CH2:30][CH:29]([CH2:32][CH2:33][NH2:34])[CH2:28][CH2:27]1>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23]([NH:34][CH2:33][CH2:32][CH:29]3[CH2:30][CH2:31][O:26][CH2:27][CH2:28]3)=[O:25])[N:21]=2)[CH:7]=[N:6]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)n1ncc(-c2nc(CC(=O)O)cs2)c1-c1ccc(F)cc1
Reactant: NCCC1CCOCC1
Product: CC(C)(C)n1ncc(-c2nc(CC(=O)NCCC3CCOCC3)cs2)c1-c1ccc(F)cc1

Procedure:
Using 2-(2-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl)thiazol-4-yl)acetic acid and 2-(tetrahydro-2H-pyran-4-yl)ethanamine and by reaction and purification in the same manner as in the method described in Example 1, step 7, the title compound was obtained.