Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([NH:13][CH:14]([C:17]([F:20])([F:19])[F:18])[CH2:15][OH:16])[S:11][CH:12]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:29](Cl)([O:31]C(=O)OC(Cl)(Cl)Cl)Cl.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:13]3[CH:14]([C:17]([F:18])([F:20])[F:19])[CH2:15][O:16][C:29]3=[O:31])[S:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OCC(Nc1nc(-c2ccc(Br)cc2)cs1)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1OCC(C(F)(F)F)N1c1nc(-c2ccc(Br)cc2)cs1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 74.7 %

Procedure:
2-{[4-(4-Bromophenyl)-1,3-thiazol-2-yl]amino}-3,3,3-trifluoropropan-1-ol (0.61 g, 1.6 mmol), prepared in the previous step, was dissolved in 48 mL methylene chloride. Triethylamine (2.2 mL, 16 mmol) was added and the solution was cooled to 0° C. Triphosgene (1.20 g, 4.15 mmol) was added in two portions and the mixture was stirred at 0° C. for 45 min and then at 25° C. for 2 h. The mixture was poured into 250 mL of saturated aqueous sodium bicarbonate and the layers were separated. The organics were washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. Flash chromatography (gradient 2% acetone/hexane to 10% acetone/hexane) afforded the title compound (0.47 g, 75%) as a white solid, mp 154-156° C. HRMS: calcd for C13H8BrF3N2O2S+H, 392.95202; found (ESI, [M+H]+), 392.9518. Analytical HPLC: retention time 10.6 min, 210-370 nm the Xterra® RP18 column, 3.5μ, 150×4.6 mm 40° C. 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min 1.2 mL/min 5 μL injection.
Reaction SMILES: O[C:2]1[N:9]=[C:8]([CH3:10])[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:3]=1[C:4]#[N:5].P(Cl)(Cl)(Cl)(Cl)[Cl:15].C(O)C>P(Cl)(Cl)(Cl)=O>[Cl:15][C:2]1[N:9]=[C:8]([CH3:10])[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: Cc1nc(O)c(C#N)cc1[N+](=O)[O-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCO
Product: Cc1nc(Cl)c(C#N)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.9 %

Procedure:
A suspension of the compound prepared in Example 442 (5.00 g) and phosphorus pentachloride (6.97 g) in phosphorus oxychloride (25 mL) was stirred and heated in an oil bath set to 110° C. for 30 minutes. The resulting solution was cooled to ambient temperature and concentrated. The residual liquid was cooled in an ice bath, whereupon a solid formed. This solid was carefully treated with 50% aqueous ethanol (10 mL), and then the mixture was stirred and heated in the 110° C. oil bath for 5 minutes. This redissolved the solid, and then the flask was again placed in the ice bath. The solid reappeared on cooling, and it was collected by filtration, washed with water, and air-dried. The solid was then recrystallized by stirring it with methanol (20 mL), and heating to boiling until all solid dissolved. On cooling to ambient temperature crystallization began, and the mixture was stored in the refrigerator overnight. The crystals were collected by filtration, washed with cold methanol, and dried under vacuum to provide the title compound (2.09 g) with the following physical data.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].[CH3:12][C:13]([C:16]([CH2:18]Cl)=[O:17])([CH3:15])[CH3:14]>CC(C)=O>[CH3:12][C:13]([CH3:15])([CH3:14])[C:16](=[O:17])[CH2:18][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: CC(C)(C)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)C(=O)Cn1ccnc1
Temperature: 25 °C
Yield: 89 %

Procedure:
136.2 g (2 moles) of imidazole were added in portions, at room temperature, to 276.4 g (2 moles) of ground potassium carbonate and 269.2 g (2 moles) of α-chloropinacolin in 500 ml of acetone, whereupon the internal temperature rose to the boiling point. The mixture was stirred under reflux for 5 hours and then cooled to room temperature. The reaction mixture was filtered and the filtrate was concentrated by distilling off the solvent in vacuo. The oily residue was distilled. 296 g (89% of theory) of 3,3-dimethyl-1-(imidazol-1-yl)-butan-2-one of melting point ~20° C. were obtained. ##STR45##
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][C:5]([OH:10])=[C:4]([O:11][CH3:12])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[CH:24]1(Br)[CH2:28][CH2:27][CH2:26][CH2:25]1>O>[CH:24]1([O:10][C:5]2[CH:6]=[C:7]([C:2]([F:1])=[CH:3][C:4]=2[O:11][CH3:12])[CH:8]=[O:9])[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: COc1cc(F)c(C=O)cc1O
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(F)c(C=O)cc1OC1CCCC1

Procedure:
A mixture of 6-fluoro-3-hydroxy-4-methoxybenzaldehyde (2 g), potassium carbonate (1.66 g) and anhydrous dimethylformamide (20 mL) is treated with cyclopentyl bromide (1.62 mL) and heated on a steam bath for 43 hours. The mixture is cooled, poured into water (200 mL) and extracted with diethyl ether (3×100 mL). The combined ethereal extracts are washed with sodium hydroxide solution (2×50 mL; 2 N), and brine (2×50 mL), dried over magnesium sulphate and concentrated. The residual brown oil is subjected to flash chromatography [a solvent gradient of 9:1 to 4:1 v/v petroleum ether (b.p. 60-80° C.) and ethyl acetate is used as eluent on a silica gel column] to give 3-cyclopentyloxy-6-fluoro-4-methoxybenzaldehyde (1.42 g) in the form of a yellow oil. [NMR (CDCl3): 10.22 (s, 1H), 7.27 (d, 1H, J=8 Hz), 6.63 (d, 1H, J=16 Hz), 4.81-4.76 (m, 1H), 3.91 (s, 3H), 2.01-1.57 (m, 8H)].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][N:10]([C:13]3[CH:14]=[CH:15][C:16]4[O:21][CH2:20][C:19]([C:22]([O:24]C)=[O:23])=[CH:18][C:17]=4[CH:26]=3)[N:9]=2)=[CH:4][C:3]=1[CH2:27][NH:28][C:29]([O:31][CH3:32])=[O:30].[OH-].[Na+]>O1CCCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][N:10]([C:13]3[CH:14]=[CH:15][C:16]4[O:21][CH2:20][C:19]([C:22]([OH:24])=[O:23])=[CH:18][C:17]=4[CH:26]=3)[N:9]=2)=[CH:4][C:3]=1[CH2:27][NH:28][C:29]([O:31][CH3:32])=[O:30]
Reactant: COC(=O)NCc1cc(-c2ccn(-c3ccc4c(c3)C=C(C(=O)OC)CO4)n2)ccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)NCc1cc(-c2ccn(-c3ccc4c(c3)C=C(C(=O)O)CO4)n2)ccc1Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 73 %

Procedure:
To a solution of methyl 6-[3-[4-chloro-3-[[(methoxycarbonyl)amino]methyl]phenyl]-1H-pyrazol-1-yl]-2H-1-benzopyran-3-carboxylate (i.e. the product of Step C) (100 mg, 0.22 mmol) in 1:1 tetrahydrofuran/water was added NaOH (35 mg 0.85 mmol) and the reaction mixture was stirred at ambient temperature for 6 hrs. After TLC analysis (50% ethyl acetate/pet ether) showed completion of reaction, the organic solvent was concentrated. The resultant aqueous solution was cooled to 0° C., acidified with 1N HCl and extracted three times with ethyl acetate. The combined the organic phases were washed with water, brine, dried over Na2SO4. The solvent was concentrated under vacuum to give compound number 24, a compound of the present invention, (70 mg, 73% yield) as solid.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[CH3:25][C:26]1[CH:31]=[C:30]([C:32]2[C:40]3[C:35](=[CH:36][CH:37]=[C:38]([C:41](O)=[O:42])[CH:39]=3)[N:34]([C:44]([C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[N:33]=2)[CH:29]=[CH:28][N:27]=1.[N:63]1([CH2:72][CH:73]2[CH2:78][CH2:77][CH2:76][CH:75]([NH2:79])[CH2:74]2)[C:71]2[C:66](=[CH:67][CH:68]=[CH:69][CH:70]=2)[CH:65]=[N:64]1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[N:63]1([CH2:72][CH:73]2[CH2:78][CH2:77][CH2:76][CH:75]([NH:79][C:41]([C:38]3[CH:39]=[C:40]4[C:35](=[CH:36][CH:37]=3)[N:34]([C:44]([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[C:57]3[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=3)[N:33]=[C:32]4[C:30]3[CH:29]=[CH:28][N:27]=[C:26]([CH3:25])[CH:31]=3)=[O:42])[CH2:74]2)[C:71]2[C:66](=[CH:67][CH:68]=[CH:69][CH:70]=2)[CH:65]=[N:64]1
Reactant: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(C(=O)O)cc23)ccn1
Reactant: NC1CCCC(Cn2ncc3ccccc32)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(C(=O)NC4CCCC(Cn5ncc6ccccc65)C4)cc23)ccn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (0.11 mmol) was added to a suspension of 3-(2-methylpyridin-4-yl)-1-trityl-1H-indazole-5-carboxylic acid (0.1 mmol) in DMF (0.5 mL) and was stirred at room temperature for 15 minutes. A solution of 3-((1H-indazol-1-yl)methyl)cyclohexanamine (0.1 mmol) in DMF (0.5 mL) was added to the reaction and followed by diisopropyl ethyl amine (DIEA) (0.1 mL). The mixture was stirred at room temperature for an additional 30 minutes. The reaction was quenched with water (5 mL) and extracted with ethyl acetate (3×10 mL). The extracts were combined, dried using anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was progressed to the next step without purification.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[CH2:7]([NH:14][C:15](=O)[C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:25])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[N:27]([Si](C)(C)C)=[N+:28]=[N-:29].C(=O)(O)[O-].[Na+]>C(Cl)Cl.O>[CH2:7]([N:14]1[C:15]([C:16]2[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:25])=[N:29][N:28]=[N:27]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cc1cccc([N+](=O)[O-])c1C(=O)NCc1ccccc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1cccc([N+](=O)[O-])c1-c1nnnn1Cc1ccccc1
Reaction time: 0.5 h
Yield: 71.2 %

Procedure:
Phosphorous pentachloride (0.42 g, 2 mmol) was added to a solution of N-benzyl-2-methyl-6-nitrobenzamide (Intermediate 19, 0.54 g) in DCM (10 mL). The mixture was stirred under nitrogen for 30 minutes and then azidotrimethylsilane (0.48 g) was added and the mixture was stirred for a further 72 hours. The mixture was diluted with DCM (50 mL) and water (50 mL). Solid sodium bicarbonate was then added to the mixture until there was no further gaseous evolution. The organic solution was washed with saturated aqueous sodium bicarbonate, then with 1N hydrochloric acid, dried with magnesium sulfate and filtered. The solvent was evaporated to give an orange solid which was recrystallised from ethyl acetate to give the title compound as a white solid (0.42 g).
Reaction SMILES: [C:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:11][CH:10]=2)[CH2:5][CH2:4]1)#[CH:2].C([Li])CCC.C1(O[C:32]#[N:33])C=CC=CC=1.O>O1CCCC1.CCCCCC>[CH2:15]([C:12]1[CH:13]=[CH:14][C:9]([C@H:6]2[CH2:5][CH2:4][C@H:3]([C:1]#[C:2][C:32]#[N:33])[CH2:8][CH2:7]2)=[CH:10][CH:11]=1)[CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: C#C[C@H]1CC[C@H](c2ccc(CCCCC)cc2)CC1
Reactant: N#COc1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCCCc1ccc([C@H]2CC[C@H](C#CC#N)CC2)cc1
Temperature: -45 °C
Reaction time: 0.25 h

Procedure:
A solution of 254 mg of 1-(trans-4-ethynylcyclohexyl)-4-pentylbenzene (prepared according to Example 12) in 60 ml of absolute tetrahydrofuran was placed at -45° C. in a 100 ml sulphonation flask under argon gasification and treated within 1 minute with 1.2 ml of a 1.0N solution of butyl lithium in hexane. After completion of the addition, the mixture was stirred at -45° C. for a further 15 minutes, then cooled to -78° C. and treated with 182 μl of phenyl cyanate. The mixture was stirred at -78° C. for a further 90 minutes, then poured into 200 ml of water and extracted three times with 100 ml of diethyl ether each time. The organic phases were washed a further twice with 100 ml of water each time and once with 100 ml of saturated sodium chloride solution, dried over magnesium sulphate and concentrated. Low-pressure chromatography (0.5 bar) of the residue (380 mg) on silica gel with 2% ethyl acetate/petroleum ether gave 186 mg (66.6%) of trans-4-(p-pentylphenyl)cyclohexanepropiolonitrile as colourless crystals (purity 97.3%) which were recrystallized further from hexane (purity 99.3%); m.p. (C-I) 46.9° C., cl.p. (N-I) 45.4° C.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:25]=[CH:24][CH:23]=[CH:22][C:6]=1[CH2:7][NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.[C:33](Cl)(=[O:35])[CH3:34].O>O1CCCC1>[C:33]([N:8]([CH2:7][C:6]1[CH:22]=[CH:23][CH:24]=[CH:25][C:5]=1[O:4][CH:1]([CH3:3])[CH3:2])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)(=[O:35])[CH3:34]
Reactant: CC(C)Oc1ccccc1CNc1ccccc1Oc1ccccc1
Reactant: CC(=O)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)N(Cc1ccccc1OC(C)C)c1ccccc1Oc1ccccc1

Procedure:
In 30 ml of tetrahydrofuran were dissolved 2.65 g of N-(2-isopropoxybenzyl)-2-phenoxyaniline and 1.5 ml of triethylamine, and then 0.8 ml of acetyl chloride was added dropwise to the solution with stirring, followed by stirring for 30 minutes. The reaction mixture was poured to water and extracted with ethyl acetate, and the extract was washed with 0.5 N hydrochloric acid, a saturated aqueous sodium bicarbonate solution and then with a saturated aqueous sodium chloride solution, successively, and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate−hexane=1:4) to give 2.92 g of N-acetyl-N-(2-isopropoxybenzyl)-2-phenoxyaniline as an oil.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Br:13]Br>C(OCC)C.O.[Cl-].[Al+3].[Cl-].[Cl-]>[C:10]([C:7]1[CH:8]=[CH:9][C:4]([C:1](=[O:3])[CH2:2][Br:13])=[CH:5][CH:6]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)c1ccc(C(C)=O)cc1
Reactant: BrBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CCOCC
Product: CC(=O)c1ccc(C(=O)CBr)cc1
Reaction time: 0.5 h
Yield: 88.8 %

Procedure:
To a stirred solution of 1,4-diacetylbenzene (5.3 g, 32.7 mmol), aluminum chloride (0.05 g, 0.38 mmol) in diethylether (50 ml) was added bromine (5.3 g, 32.7 mmol) dropwise over 20 minutes. The mixture was stirred for 30 minutes, and diluted with water. The whole was concentrated to remove diethylether, and the aqueous suspension was filtered to give 7.0 g of white solid. The compound was used for next reaction without purification.
Reaction SMILES: ClC1C(NC2C=C(C)NN=2)=NC([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][N:12]=2)[CH3:10])=NC=1.C[Mg]Cl.C(O[C:32](=[O:34])[CH3:33])(=O)C.C(=O)([O-])O.[Na+]>C1COCC1.C(Cl)Cl>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]([NH:8][C:32](=[O:34])[CH3:33])=[CH2:10])=[N:12][CH:13]=1
Reactant: Cc1cc(Nc2nc(N[C@@H](C)c3ccc(F)cn3)ncc2Cl)n[nH]1
Reactant: CC(=O)OC(C)=O
Agent: C[Mg]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: C=C(NC(C)=O)c1ccc(F)cn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 5-fluoropicolinonitrile (Method 35; 1875 g 1 equivalent) in THF (3.7 volumes) was added to methyl magnesium chloride (3N in THF, 1.2 equivalents) maintaining the temperature at 0° C. The reaction mixture was stirred for 30 minutes at 0° C. and then diluted with DCM (3.2 volumes) at 0° C. Acetic anhydride (2.0 equivalents) in DCM (1.6 volumes.) was added at a rate to maintain the temperature at 0° C. The batch was allowed to warm to room temperature and stirred overnight. Saturated, aqueous sodium hydrogen carbonate (13.9 volumes) was added and the product was extracted into EtOAc (1×0.53 volumes, 1×0.26 volumes). The combined extracts were dried, filtered and evaporated in vacuo and purification carried out by chromatography (5 w/w silica; 20-100% DCM in hexane). The mixture of N-mono and N,N-di-acetylated compounds was treated with potassium carbonate (0.1 w/w on mixture) in methanol (5 volumes) for 30 minutes. The inorganic solids were filtered and washed with methanol. Silica was added to the methanol solution to remove residual potassium carbonate prior to evaporation. The product, pre-adsorbed on silica, was eluted through a silica pad (2 w/w silica; 90-100% DCM in hexane) and evaporated to give an orange solid. Mp 61.0-62.2° C., 636 g, 23.0% theory.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]2[CH:9]=[N:10][NH:11][C:3]=12.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:19][CH2:20][O:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][O:23]1>CN(C=O)C>[Cl:1][C:2]1[C:3]2[C:4](=[CH:9][N:10]([CH2:19][CH2:20][O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)[N:11]=2)[N:5]=[CH:6][C:7]=1[F:8].[Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]2[CH:9]=[N:10][N:11]([CH2:19][CH2:20][O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)[C:3]=12
Reactant: Fc1cnc2cn[nH]c2c1Cl
Reactant: BrCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Fc1cnc2cn(CCOC3CCCCO3)nc2c1Cl
Product: Fc1cnc2cnn(CCOC3CCCCO3)c2c1Cl

Procedure:
A solution of 7-chloro-6-fluoro-1H-pyrazolo[4,3-b]pyridine (200 mg, 1.166 mmol) in DMF (5 mL), Cs2CO3 (570 mg, 1.749 mmol), and 2-(2-bromoethoxy)tetrahydro-2H-pyran (0.194 mL, 1.282 mmol) in a sealed pressure vessel was heated at 110° C. for 3 hours. The reaction mixture was then concentrated and partitioned between water (20 mL) and EtOAc (2×50 mL). The organics were dried over Na2SO4 and evaporated to give 7-chloro-6-fluoro-2-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-2H-pyrazolo[4,3-b]pyridine and 7-chloro-6-fluoro-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazolo[4,3-b]pyridine which was used without further purification. MS [M+H] found 300.2.
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:21])([CH3:20])[C:8]1[N:9]=[CH:10][N:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:22]([Li])CCC.IC>C1COCC1.CCCCCC>[C:1]([SiH2:5][O:6][C:7]([CH3:21])([CH3:20])[C:8]1[N:9]=[C:10]([CH3:22])[N:11]([C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)[CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [Li]CCCC
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cn(-c2ccc(F)cc2)cn1
Solvent: CI
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1nc(C(C)(C)O[SiH2]C(C)(C)C)cn1-c1ccc(F)cc1
Temperature: -25 °C
Reaction time: 0.17 h

Procedure:
4-(tert-Butyl-dimethyl-silanyloxymethyl)-1-(4-fluoro-phenyl)-1H-imidazole is dissolved in THF and cooled to −78° C. n-Butyl lithium in hexane is added dropwise. The reaction mixture is warmed up to −25° C., kept at −25° C. for 10 min and then cooled again to −78° C. Iodomethane is added dropwise. The reaction mixture is slowly warmed up to room temperature and stirred at room temperature overnight. The desired compound 4-(tert-butyl-dimethyl-silanyloxymethyl)-1-(4-fluoro-phenyl)-2-methyl-1H-imidazole is obtained.
Reaction SMILES: [Na].C[O-].[Na+].[C:5]([C:7]1[C:16]([C:17]#[N:18])=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1)#[N:6].[NH3:19]>CO>[NH:18]=[C:17]1[C:16]2[CH:15]=[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]3=[CH:8][C:7]=2[C:5](=[NH:19])[NH:6]1
Reactant: N
Reactant: N#Cc1cc2ccccc2cc1C#N
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: N=C1NC(=N)c2cc3ccccc3cc21
Yield: 86 %

Procedure:
Next, in an atmosphere of nitrogen, 0.64 g (28 mmoles) of metallic sodium was added in five portions to 90 ml of anhydrous methanol to prepare a methanolic solution of sodium methoxide. To the methanolic solution was added 10.2 g (57.3 mmoles) of 2,3-dicyanonaphthalene. While thoroughly stirring the mixture, anhydrous ammonia gas was bubbled into the mixture slowly over a period of about one hour at room temperature. Then, the mixture was heated under reflux for about 3 hours while bubbling anhydrous ammonia gas. After cooling the mixture, the deposited yellow-colored solid product was collected by filtration, thoroughly washed with methanol and dried in vacuum. Thus, about 9.5 g (86%) of 1,3-diiminobenzo(f)isoindoline was obtained as a yellow colored solid. It was used in the subsequent reaction without purification.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:23])([F:22])[C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)=[N:9][N:10]=2)[N:7]=1.C([Sn](CCCC)(CCCC)[C:29]([O:31]CC)=[CH2:30])CCC.N1C2C(=CC(CC3N4N=C(C(=O)C)C=CC4=NN=3)=CC=2)C=CC=1>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>[F:22][C:11]([F:23])([C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[CH:17][CH:16]=[CH:15]2)[C:8]1[N:6]2[N:7]=[C:2]([C:29](=[O:31])[CH3:30])[CH:3]=[CH:4][C:5]2=[N:10][N:9]=1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: FC(F)(c1ccc2ncccc2c1)c1nnc2ccc(Cl)nn12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)c1ccc2nnc(Cc3ccc4ncccc4c3)n2n1
Solvent: C1COCCO1
Product: CC(=O)c1ccc2nnc(C(F)(F)c3ccc4ncccc4c3)n2n1
Yield: 35.2 %

Procedure:
The title compound as a light yellow oil (180 mg, 30%, 80% purity) was synthesized from 6-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)difluoromethyl)quinoline (intermediate R) (500 mg, 1.507 mmol), tributyl(1-ethoxyvinyl)stannane (2.55 mL, 7.54 mmol) and PdCl2(PPh3)2 (106 mg, 0.151 mmol) in 1,4-dioxane using the similar procedure as described in the synthesis of compound 41.2. 1H-NMR (400 MHz, MeOH-d4) δ ppm 9.17 (s, 1H), 8.91 (d, 1H), 8.65 (s, 1H), 8.43 (d, 1H), 8.28 (q, 2H), 7.96 (d, 1H), 7.92 (m, 1H), 2.61 (s, 3H). LCMS (method B): [MH]+=340.1, tR=2.16 min.
Reaction SMILES: Cl.[C:2](=N)(OCC)[CH3:3].[F:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([NH2:16])[CH:10]=1>C(O)C>[CH3:2][C:3]1[NH:16][C:11]2[CH:10]=[C:9]([F:8])[CH:14]=[CH:13][C:12]=2[N:15]=1
Reactant: CCOC(C)=N
Reactant: Nc1ccc(F)cc1N
Agent: Cl
Solvent: CCO
Product: Cc1nc2ccc(F)cc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.3 %

Procedure:
Ethyl acetimidate hydrochloride (37.1 g, 0.3 mol) was added to a stirred suspension of 4-fluoro-ortho-phenylenediamine (12.6 g, 0.1 mol) in ethanol (150 ml) at 0° C. The mixture was allowed to warm up to room temperature and stirred overnight. The solvent was removed under, reduced pressure and the residue extracted into ethyl acetate (100 ml), washed with water (3×100 ml), dried over anhydrous magnesium sulphate, filtered and evaporated. Crystallisation from ethyl acetate gave 2-methyl-5-fluorobenzimidazole (7.7 g, 51%) as a brown crystalline solid.
Reaction SMILES: [C:1]12([CH2:11][C:12]([OH:14])=O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.S(Cl)([Cl:17])=O>>[C:1]12([CH2:11][C:12]([Cl:17])=[O:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=C(O)CC12CC3CC(CC(C3)C1)C2
Reactant: O=S(Cl)Cl
Product: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Reaction time: 16 h

Procedure:
In this preparation a mixture containing 15 g. of 1-adamantyl acetic acid and 40 ml. of thionyl chloride is allowed to stand for 16 hours at room temperature. The excess thionyl chloride is then removed by evaporation, under reduced pressure, at 60° C affording adamant-1-yl acetyl chloride as an oil. The oil is then dissolved in 800 ml. of ethyl ether and then ammonia is bubbled through the solution until about 12.8 g. is absorbed. The solution is then washed twice with water, dried over anhydrous magnesium sulfate and filtered. The filtrate is evaporated under vacuum affording adamant-1-yl acetamide. 12.8 G. of adamant-1-yl acetamide is added to a mixture containing 3 g. of lithium aluminum hydride in 500 ml. of anhydrous tetrahydrofuran at 25°0 C and refluxed for 5 minutes. The mixture is cooled to 5° C, a slight excess of an aqueous saturated solution of sodium sulfate is added dropwise. Thereafter the tetrahydrofuran solution is dried over sodium sulfate, filtered and the solvent evaporated to dryness under vacuum. From the remaining oil, 2-(adamant-1-yl)ethylamine is distilled bulb to bulb, 10.1 g.