Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.C(OC([NH:20][CH2:21][CH2:22][CH2:23]Br)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[CH2:12][CH2:11][N:10]([CH2:23][CH2:22][CH2:21][NH2:20])[CH2:9][CH2:8]1
Reactant: c1ccc(C2CCNCC2)nc1
Reactant: CC(C)(C)OC(=O)NCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: NCCCN1CCC(c2ccccn2)CC1
Temperature: 25 °C
Yield: 74.4 %

Procedure:
To 1-benzyl-4-(2-pyridyl)-piperidine (3.26 g, 12.9 mmol) in dry methanol (25 mL), 10% palladium hydroxide (1.9 g) was added and the solution was hydrogenated at 200 psi for 24 hours. The solution was filtered over celite, concentrated to give 2.1 g (99%) of 4-(2-pyridyl)-piperidine which was used as such for the subsequent step. A mixture of 3-bromopropylamine hydrobromide (20 g, 91.3 mmol), potassium carbonate (37.85 g, 273.9 mmol) and di-tert-butyldicarbonate (21.90 g, 100 mmol) in methanol was stirred at room temperature for 24 hours. The reaction mixture was concentrated and partitioned between 250 mL EtOAc and 50 mL water, dried over sodium sulfate, filtered and concentrated. Purification of the crude product by column chromatography (hexane: EtOAc, 4.5:0.5) gave 17.5 g (80%) of the product as a pale yellow oil. To a stirred solution of the 4-(2-pyridyl)-piperidine (1.86 g, 11.4 mmol) in dioxane (20 mL), N-(tert-butoxycarbonyl)-3-bromopropylamine (2.82 g, 11.4 mmol) and potassium carbonate (3.16 g, 22.9 mmol) were added and the solution was refluxed for 24 hours. The reaction mixture was cooled to room temperature, concentrated and partitioned between 40 mL chloroform and 5 mL water. The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (ethyl acetate: methanol, 4:1) to yield 1.86 g (49%) of the required product as a colorless oil; 1H-NMR (CDCl3): δ1.45 (s, 9 H), 1.54-1.69 (m, 8 H), 2.21-2.68 (m, 2 H), 2.74-2.80 (m, 1 H), 3.02-3.22 (m, 4 H), 5.41 ( s, 1 H), 7.13-7.17 (m, 1 H), 7.33 (d, J=7.93 Hz, 1 H), 7.63 (t, J=7.6 Hz, 1 H), 8.54 (d, J=4.6 Hz, 1 H). To N-(tert-butoxycarbonyl)-3-[4-(2-pyridyl)-piperidin-1-yl]propylamine (0.15 g, 0.45 mmol) in 5 mL of dichloromethane, 1 mL of trifluoroacetic acid was added and the solution was stirred at room temperature for 1 hour. The solution was concentrated, neutralized with 10% KOH solution and extracted into 25 mL of dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated to give 0.098 g (100%) of 3-[4-2-pyridyl)-piperidin-1-yl]propylamine which was used as such for the subsequent step.
Reaction SMILES: C(N(CC)CC)C.C1C(=O)OCC1=[O:10].[CH:15]([N:18]=[C:19]=[N:20][CH:21]([CH3:23])[CH3:22])([CH3:17])[CH3:16]>ClCCl>[CH:15]([NH:18][C:19]([NH:20][CH:21]([CH3:23])[CH3:22])=[O:10])([CH3:17])[CH3:16]
Reactant: O=C1COC(=O)C1
Reactant: CC(C)N=C=NC(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)NC(=O)NC(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Triethylamine (0.75 mL, 5.5 mmol) was added to a suspension of tetronic acid (500 mg, 5.00 mmol) in dichloromethane (25 mL) to obtain a homogeneous solution. The solution was cooled to 0° C., mixed with 4-N,N-dimethylaminopyridine (200 mg, 1.7 mmol), 3-cyclohexne-1-carboxylic acid (0.65 mL, 5.6 mmol), and then, diisopropylcarbodiimide (1.0 mL, 6.3 mmol), followed by stirring for 30 min. The resulting mixture was removed from the ice bath, stirred for 14 hours at room temperature, and filtered to remove thus-produced insoluble diisopropyl urea; the reaction solution was washed twice with 5% hydrochloric acid (20 mL) and the water layer was extracted twice with dichloromethane (10 mL). The organic layers were combined, dried over sodium sulfate anhydride, and concentrated; the thus-obtained residue was purified by silica gel column chromatography (silica gel, ethyl acetate:methanol=15:1). The resultant was arranged to be a sodium salt by adding an excess amount of sodium hydrogencarbonate and distilled water (100 mL), and then washed with dichloromethane; the water layer was acidified by adding 5% hydrochloric acid and extracted four times with dichloromethane (20 mL). The resultant was dried over sodium sulfate anhydride and concentrated to give pale yellow crystals (394 mg, 38%).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:6]2[N:5]=[C:4]([CH3:25])[CH:3]=1.CCN(C(C)C)C(C)C.[C:35]([O:39][C:40]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)=[O:41])([CH3:38])([CH3:37])[CH3:36]>ClCCCl>[C:35]([O:39][C:40]([N:42]1[CH2:47][CH2:46][N:45]([C:2]2[N:7]3[N:8]=[C:9]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[Cl:24])[C:10]([C:11]4[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=4)=[C:6]3[N:5]=[C:4]([CH3:25])[CH:3]=2)[CH2:44][CH2:43]1)=[O:41])([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1cc(Cl)n2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: Cc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)n2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2n1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
To a solution of 7-chloro-3-(4-chlorophenyl)-2-(2-chlorophenyl)-5-methylpyrazolo[1,5-a]pyrimidine (I-3A-4b; 109 mg, 0.280 mmol) and Argonaut™ PS-DIEA (97 mg, 0.38 mmol) in 1,2-dichloroethane (2.8 ml) was added piperazine-1-carboxylic acid tert-butyl ester (70.5 mg, 0.378 mmol). The mixture was stirred at room temperature for 19 hours, filtered, concentrated and then purified on a Biotage™ Flash 12M column using 0–35% ethyl acetate in hexanes as eluant to afford, after trituration from hexanes/methylene chloride, product 5A-1 (132 mg, 88%) as an off-white solid: +ESI MS (M+1) 538.4; 1H NMR (400 MHz, CD2Cl2) δ 7.48–7.32 (m, 6H), 7.22 (d, J=8.7 Hz, 2H), 6.13 (s, 1H), 3.73–3.61 (m, 8H), 2.56 (s, 3H), 1.45 (s, 9H).
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH:8]([S:11]([C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:21]=[C:22]([C:34]3[O:38][N:37]=[C:36]([C:39]4[CH:44]=[CH:43][C:42]([CH2:45][NH:46][CH3:47])=[CH:41][CH:40]=4)[CH:35]=3)[C:23]([NH:26]C(=O)OC(C)(C)C)=[N:24][CH:25]=2)=[N:18][CH:19]=1)(=[O:13])=[O:12])([CH3:10])[CH3:9]>C(Cl)Cl>[CH:8]([S:11]([C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:21]=[C:22]([C:34]3[O:38][N:37]=[C:36]([C:39]4[CH:40]=[CH:41][C:42]([CH2:45][NH:46][CH3:47])=[CH:43][CH:44]=4)[CH:35]=3)[C:23]([NH2:26])=[N:24][CH:25]=2)=[N:18][CH:19]=1)(=[O:12])=[O:13])([CH3:10])[CH3:9]
Reactant: CNCc1ccc(-c2cc(-c3cc(-c4ccc(S(=O)(=O)C(C)C)cn4)cnc3NC(=O)OC(C)(C)C)on2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCc1ccc(-c2cc(-c3cc(-c4ccc(S(=O)(=O)C(C)C)cn4)cnc3N)on2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.7 %

Procedure:
TFA (1 mL, 12.98 mmol) was added to a stirred suspension of tert-butyl N-[5-(5-isopropylsulfonyl-2-pyridyl)-3-[3-[4-(methylaminomethyl)phenyl]isoxazol-5-yl]-2-pyridyl]carbamate (105 mg, 0.1863 mmol) in DCM (5 mL) and the reaction stirred at ambient temperature overnight. The solvent was removed in vacuo and the residue azeotroped with DCM (×2) and ether (×2). The reaction mixture was passed through a 2 g SCX-2 cartridge and washed with MeOH/DCM. The product was eluted by washing the cartridge with 2M NH3 in MeOH. The fractions were collected, concentrated in vacuo and the residue freeze-dried to give the title compound as a cream solid (30 mg, 35% Yield). NMR (400.0 DMSO) δ 1.22 (d, J=6.9 Hz, 6H), 2.30 (s, 3H), 3.56 (sept, 1H), 3.73 (s, 2H), 7.06 (br s, 2H), 7.51 (d, 2H), 7.63 (s, 1H), 7.93 (d, 2H), 8.24-8.31 (m, 2H), 8.74 (d, 1H), 8.99 (dd, 1H) and 9.02 (d, 1H) ppm; MS (ES+) 464.1.
Reaction SMILES: [C:1]([C:5]1[C:6]([O:30][CH3:31])=[C:7](/[CH:17]=[CH:18]/[C:19]2[CH:24]=[CH:23][C:22]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[CH:21][CH:20]=2)[CH:8]=[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:33]CC(Cl)=O>>[C:1]([C:5]1[C:6]([O:30][CH3:31])=[C:7](/[CH:17]=[CH:18]/[C:19]2[CH:24]=[CH:23][C:22]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[CH:21][CH:20]=2)[CH:8]=[C:9]([N:11]2[CH2:33][CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH:10]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: COc1c(/C=C/c2ccc(NS(C)(=O)=O)cc2)cc(N2CCCC2=O)cc1C(C)(C)C
Reactant: O=C(Cl)CCBr
Product: COc1c(/C=C/c2ccc(NS(C)(=O)=O)cc2)cc(N2CCCCC2=O)cc1C(C)(C)C

Procedure:
N-(4-{(E)-2-[3-tert-Butyl-2-methoxy-5-(2-oxo-pyrrolidin-1-yl)-phenyl]-vinyl}-phenyl)-methanesulfonamide can be prepared analogously except in step 2,4-bromo-butyryl chloride is replaced with 3-bromo-propionyl chloride.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:7](Br)[C:8]#[CH:9]>C(OCC)C>[CH2:9]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:8]#[CH:7]
Reactant: C1CCNCC1
Reactant: C#CCBr
Solvent: CCOCC
Product: C#CCN1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of piperidine (8.5 ml) in diethyl ether (100 ml) was added propargyl bromide (3 ml) on an ice bath, the solution was stirred overnight at room temperature, then diethyl ether was added thereto followed by filtering, and the solvent was evaporated in vacuo to provide the title compound (6.0 g).
Reaction SMILES: [CH3:1][C:2]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]1[NH:7][CH2:8][CH2:9][N:10]=1.C(Cl)(Cl)Cl.[CH3:20][S:21](Cl)(=[O:23])=[O:22].CC1(C)CCCN(C)C1(C)C>CCOCC>[CH3:20][S:21]([N:10]1[CH2:9][CH2:8][N:7]=[C:6]1[CH2:5][O:4][C:3]1[CH:11]=[CH:12][CH:13]=[C:14]([CH3:15])[C:2]=1[CH3:1])(=[O:23])=[O:22]
Reactant: Cc1cccc(OCC2=NCCN2)c1C
Reactant: CS(=O)(=O)Cl
Agent: CN1CCCC(C)(C)C1(C)C
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: Cc1cccc(OCC2=NCCN2S(C)(=O)=O)c1C

Procedure:
2-(2,3-Dimethylphenoxymethyl)-2-imidazoline (8.0 g; 0.0392 moles) was dissolved in dry ether (75 ml) and sufficient dry chloroform (50 ml) and the solution cooled in ice (sufficient chloroform was used to prevent precipitation of the imidazoline on cooling). Methanesulphonyl chloride (4.50 g; 0.0393 moles) was added dropwise to the cold, stirred solution. When the addition was complete pentamethylpiperidine (6.08 g; 0.0392 moles) was added and the reaction mixture heated under reflux until tlc showed that reaction was complete (~3 hrs). The reaction mixture was then concentrated under reduced pressure and the residue extracted with a water/chloroform mixture (1:1; ~100 ml). The chloroform layer was washed with water, dried over magnesium sulphate and evaporated under reduced pressure to give a residue which was recrystallised from isopropanol to give 1-methanesulphonyl-2-(2,3-dimethylphenoxymethyl)-2-imidazoline, m.p. 142°-143° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[N:13][OH:14])[CH2:8][CH2:7][CH2:6]2.C([Li])CCC.[CH2:20]([C:23]1[CH:32]=[CH:31][C:26]([C:27](OC)=O)=[CH:25][CH:24]=1)[CH2:21][CH3:22].OS(O)(=O)=O>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]1=[N:13][O:14][C:27]([C:26]3[CH:31]=[CH:32][C:23]([CH2:20][CH2:21][CH3:22])=[CH:24][CH:25]=3)=[C:8]1[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCCC2=NO
Reactant: CCCc1ccc(C(=O)OC)cc1
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCc1ccc(-c2onc3c2CCc2cc(OC)ccc2-3)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
To 6-methoxy-3,4-dihydronaphthalen-1(2H)-one oxime (Intermediate 2, 0.483 g, 2.52 mmol) in 4 mL of THF, cooled to 0° C. was added butyllithium (2.5 M, 2.020 mL, 5.05 mmol) dropwise over a period of 3 min. The contents were stirred at 0° C. for 30 min. A solution of methyl 4-propylbenzoate (Preparation 9A, 0.3 g, 1.683 mmol) dissolved in 2 mL of THF was added over a period of 3 min. The pale yellow reaction mixture was allowed to come to room temperature and stirred for 20 min. at room temperature. To the reaction mixture was added 0.5 mL of conc. H2SO4 dropwise over a period of 3 min. at 0° C. The reaction was allowed to come to room temperature over a period of 10 min. and stirred at room temperature for 40 min. The reaction mixture was concentrated under reduced pressure and partitioned between ethyl acetate (25 mL) and water (10 mL). The ethyl acetate layer was washed with sat. aq. sodium bicarbonate (15 mL), dried over sodium sulfate, concentrated and purified by silica gel column chromatography employing hexane/ethyl acetate. Product containing fractions were collected and concentrated to yield 7-methoxy-3-(4-propylphenyl)-4,5-dihydronaphtho[1,2-c]isoxazole (0.355 g, 1.111 mmol, 66.0% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.93 (d, J=8.28 Hz, 1H) 7.69 (d, J=8.28 Hz, 2H) 7.30 (d, J=8.28 Hz, 2H) 6.83-6.91 (m, 2H) 3.86 (s, 3H) 2.95-3.06 (m, 4H) 2.61-2.68 (m, 2H) 1.62-1.74 (m, J=7.47, 7.47, 7.47, 7.47, 7.28 Hz, 2H) 0.97 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12](O)[CH:11]=[C:10]([CH:15]([CH3:17])[CH3:16])[N:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:12]1[CH:11]=[C:10]([CH:15]([CH3:17])[CH3:16])[N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:13]=1
Reactant: CC(C)c1cc(O)nc(-c2ccc(Cl)cc2)n1
Reactant: O=P(Cl)(Cl)Cl
Product: CC(C)c1cc(Cl)nc(-c2ccc(Cl)cc2)n1
Temperature: 90 °C

Procedure:
The mixture of 12 g of 2-(4-chlorophenyl)-4-hydroxy-6-isopropylpyrimidine and 35 ml of phosphorus oxychloride was heated at 90° C. for 3 hours with stirring. Most of the excess of the phosphorus oxychloride was distilled off in vacuo, and the residue was added to 100 ml of ice water and stirred. The solid white precipitate forming was filtered off with suction and dried in vacuo at room temperature.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]#[N:23])[C:10](Cl)=[N:9][C:8]=2[N:7]=[C:6]1[N:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1)[C:2]#[C:3][CH3:4].[C-:38]#[N:39].[Na+]>CN(C)C=O>[CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]#[N:23])[C:10]([C:38]#[N:39])=[N:9][C:8]=2[N:7]=[C:6]1[N:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2nc(Cl)n(Cc3ccccc3C#N)c(=O)c21
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2nc(C#N)n(Cc3ccccc3C#N)c(=O)c21
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.7 %

Procedure:
A mixture consisting of 8 mg of t-butyl 4-[7-(2-butynyl)-2-chloro-1-(2-cyanobenzyl)-6-oxo-6,7-dihydro-1H-purin-8-yl]piperazine-1-carboxylate obtained in Example 96(a), 10 mg of sodium cyanide and 0.3 ml of N,N-dimethylformamide was stirred at room temperature for 4 hours. The reaction mixture was extracted with ethyl acetate-water, and the organic layer was washed with water and then with saturated brine. The organic layer was concentrated. The residue was purified by thin layer chromatography (50% ethyl acetate/hexane) to give 6.1 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]2[C:10]=1[S:11]([OH:14])(=O)=[O:12].P(Cl)(Cl)([Cl:17])=O>>[Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]2[C:10]=1[S:11]([Cl:17])(=[O:14])=[O:12]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=S(=O)(O)c1c(Cl)nc2ccccn12
Product: O=S(=O)(Cl)c1c(Cl)nc2ccccn12
Temperature: 0 °C

Procedure:
In 30 ml of phosphorus oxychloride is suspended 5.0 g of 2-chloroimidazo[1,2-a]pyridine-3-sulfonic acid and the suspension is refluxed for 5 hours. After cooling, the reaction mixture is poured in 250 ml of ice-water and extracted with dichloromethane. The dichloromethane layer is separated and dried over anhydrous sodium sulfate and the dichloromethane is distilled off under reduced pressure to give 4.6 g of the title compound as pale yellow crystals.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH2:13]Br)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:19]1([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C([O-])([O-])=O.[K+].[K+].C1COCC1>CC(C)=O>[C:1]1([S:7]([CH2:10][C:11]2[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH2:13][N:22]2[CH2:21][CH2:20][N:19]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:24][CH2:23]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CN1CCNCC1
Reactant: O=S(=O)(Cc1ccccc1CBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CCOC(=O)CN1CCN(Cc2ccccc2CS(=O)(=O)c2ccccc2)CC1
Temperature: 25 °C

Procedure:
To a round-bottom flask were added 2-[(Phenylsulfonyl)methyl]benzyl bromide (4{29}, 1.0 g, 3.08 mmol, 1.0 equiv.), 10 (1.06 g, 6.16 mmol, 2.0 equiv.), K2CO3 (1.70 g, 12.32 mmol, 4.0 equiv.), and 3:2 THF:acetone (15 mL). The reaction mixture was stirred at reflux overnight. The reaction mixture was cooled to room temperature. The solid was filtered and washed with acetone. The filtrate was concentrated and purified by silica gel column chromatography (gradient, 25-50% EtOAc/hexanes) to afford 6{29} (920.1 mg, 72%) as an off-white solid. 1H-NMR (500 MHz, CDCl3): δ 7.64 (dd, 2H, J=0.5, 8.0 Hz), 7.60-7.57 (m, 1H), 7.44 (t, 2H, J=8.0 Hz), 7.21 (t, 1H, J=8.0 Hz), 7.12 (d, 2H, J=7.5 Hz), 6.98 (d, 1H, J=7.5 Hz), 4.81 (s, 2H), 4.14 (q, 2H, J=7.0), 3.31 (s, 2H), 3.15 (s, 2H), 2.50 (br s, 4H), 2.36 (br s, 4H), 1.22 (t, 3H, J=7.0 Hz). 13C-NMR (125 MHz, CDCl3): δ 170.1, 138.6, 138.1, 133.6, 132.4, 131.0, 128.8, 128.5, 128.4, 127.9, 127.3, 61.1, 60.4, 59.2, 58.9, 52.8, 52.6, 14.1.
Reaction SMILES: [Cl:1][CH:2]1[S:7][C:6]2[S:8][CH:9]=[CH:10][C:5]=2[C:4](=[O:11])[CH2:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[F:22][C:23]([F:32])([F:31])[C:24](C1NC=CN=1)=[O:25].Cl>O1CCCC1>[Cl:1][CH:2]1[S:7][C:6]2[S:8][CH:9]=[C:10]([C:24](=[O:25])[C:23]([F:32])([F:31])[F:22])[C:5]=2[C:4](=[O:11])[CH2:3]1
Reactant: O=C1CC(Cl)Sc2sccc21
Reactant: O=C(c1ncc[nH]1)C(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1CC(Cl)Sc2scc(C(=O)C(F)(F)F)c21
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
The compound from Step 3 (1.03 g, 5.0 mmol) was dissolved in tetrahydrofuran (50 mL) and cooled to -78° C. A solution of sodium bistrimethylsilylamide (5.0 mL of a 1.0M tetrahydrofuran solution) was added and the reaction stirred for 0.75 hours at -78° C. Trifluoroacetyl imidazole (0.68 mL, 6.0 mmol) was added and the reaction was warmed to room temperature and stirred under a nitrogen atmosphere for 16 hours. At this time, 1N hydrochloric acid (300 mL) was added to the reaction followed by extraction with ether (350 mL). The organics were washed with brine (200 mL), dried over MgSO4 and concentrated in vacuo. The resulting yellow oil was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[O:7][CH:6]=[C:5]2[C:13]([O:15][CH3:16])=[O:14].C([O-])(=O)C.[NH4+:21]>C(O)(=O)C.O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:7])[NH:21][CH:6]=[C:5]2[C:13]([O:15][CH3:16])=[O:14]
Reactant: [NH4+]
Reactant: COC(=O)c1coc(=O)c2ccc(F)cc12
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1c[nH]c(=O)c2ccc(F)cc12
Temperature: 80 °C

Procedure:
A mixture of methyl 6-fluoro-1-oxo-1H-isochromene-4-carboxylate (1.53 g) and ammonium acetate (2.5 g) in 4 ml of glacial acetic acid was heated at 80° C. for 16 h. The reaction was cooled to 40° C., diluted with 8 ml of water and the solid collected by filtration (1.38 g).
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[C:16]([C:20]1[O:24][N:23]=[C:22]([OH:25])[CH:21]=1)([CH3:19])([CH3:18])[CH3:17].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[C:16]([C:20]1[O:24][N:23]([C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=2[N+:13]([O-:15])=[O:14])[C:22](=[O:25])[CH:21]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CCOC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CC(C)(C)c1cc(O)no1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(-n2oc(C(C)(C)C)cc2=O)c([N+](=O)[O-])c1
Yield: 94.7 %

Procedure:
In 100 ml of dimethyl sulfoxide were dissolved 23.0 g of ethyl 4-chloro-3-nitrobenzoate and 17 g of 5-t-butyl-3-hydroxyisoxazole and after adding thereto 17 g of potassium carbonate, the reaction was performed for 8 hours at 75° C. After the reaction was over, the reaction mixture obtained was poured into cold diluted hydrochloric acid followed by stirring, whereby colorless crystals deposited immediately. The crystals were recovered by filtration and recrystallized from ethanol to provide 31.7 g of the desired compound with a yield of 94.8%. The melting point thereof was 88° C.
Reaction SMILES: [CH3:1][Li].Cl[CH2:4][CH2:5][CH2:6][C:7]([CH3:11])([CH3:10])[C:8]#[N:9]>CCOCC>[CH3:1][C:8]1[C:7]([CH3:11])([CH3:10])[CH2:6][CH2:5][CH2:4][N:9]=1
Reactant: [Li]C
Reactant: CC(C)(C#N)CCCCl
Solvent: CCOCC
Product: CC1=NCCCC1(C)C
Reaction time: 0.5 h

Procedure:
0.1 mol of methyl lithium dissolved in 200 ml of ether anhydride is added drop by drop in an inert atmosphere (argon or nitrogen) to 15 g of 5-chloro-2,2-dimethyl pentane nitrile diluted in 60 ml of anhydrous ether. The reaction mixture is maintained between 0° and 5° C. during the addition and then for a further 30 minutes and then kept at room temperature for 4 hours. After hydrolysis it is extracted with ether. The 2,3,3-trimethyl-3,4,5,6-tetrahydropyridine is then isolated by distillation. A colorless liquid of B.P.14 =60° C. is obtained in a yield of 76% of 1-piperideine.
Reaction SMILES: Cl.[O:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([NH:9][C:10]1([C:16]([NH:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH:20]2[OH:25])=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:8].F[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[N+:34]([O-:36])=[O:35].C(N(CC)CC)C>C(O)C>[O:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([NH:9][C:10]1([C:16]([NH:18][CH:19]2[CH2:24][CH2:23][N:22]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=3[N+:34]([O-:36])=[O:35])[CH2:21][CH:20]2[OH:25])=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:8]
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Reactant: O=C(NC1(C(=O)NC2CCNCC2O)CCCCC1)c1ccco1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(NC1(C(=O)NC2CCN(c3ccc(F)cc3[N+](=O)[O-])CC2O)CCCCC1)c1ccco1

Procedure:
To the solution of 4-[N-[1-[N-(furan-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-3-piperidinol hydrochloride (6.0 g) obtained in Step 4 of Example 76 in 50 ml of ethanol, were added 2,5-difluoronitrobenzene (3.7 ml) and triethylamine (4.8 ml). The reaction mixture was refluxed overnight and concentrated. The resulting yellow solid was filtered and dried to give 7.2 g of the titled compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:28]3[CH2:32][CH2:31][CH2:30][NH:29]3)=[N:9][C:10]=2[C:11]2[CH:27]=[CH:26][C:14]([C:15]([NH:17][C:18]3[CH:23]=[C:22]([CH2:24][CH3:25])[CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[CH3:33][O:34][CH2:35]/[CH:36]=[CH:37]/[C:38](O)=[O:39]>>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:28]3[CH2:32][CH2:31][CH2:30][N:29]3[C:38](=[O:39])/[CH:37]=[CH:36]/[CH2:35][O:34][CH3:33])=[N:9][C:10]=2[C:11]2[CH:27]=[CH:26][C:14]([C:15]([NH:17][C:18]3[CH:23]=[C:22]([CH2:24][CH3:25])[CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1
Reactant: CCc1ccnc(NC(=O)c2ccc(-c3nc([C@@H]4CCCN4)n4ccnc(N)c34)cc2)c1
Reactant: COC/C=C/C(=O)O
Product: CCc1ccnc(NC(=O)c2ccc(-c3nc([C@@H]4CCCN4C(=O)/C=C/COC)n4ccnc(N)c34)cc2)c1
Yield: 28.8 %

Procedure:
This compound was prepared, in an analogous manner as described in Example 2, from (S)-4-(8-amino-3-(pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(4-ethylpyridin-2-yl)benzamide (intermediate 13) and (E)-4-methoxybut-2-enoic acid (Intermediate 3), to afford the title compound (10.6 mg, 28.8%). Data: UPLC (C) Rt: 1.60 min; m/z 526.3 (M+H)+.