Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:26]([Si:29]([CH:43]([CH3:45])[CH3:44])([CH:40]([CH3:42])[CH3:41])[O:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1)([CH3:28])[CH3:27]>C(#N)C.C(Cl)Cl>[CH:43]([Si:29]([CH:26]([CH3:28])[CH3:27])([CH:40]([CH3:42])[CH3:41])[O:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([NH:1][C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][CH:8]=[C:9]3[N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)=[CH:4][CH:3]=2)=[O:36])=[CH:33][CH:32]=1)([CH3:45])[CH3:44]
Reactant: CC(C)[Si](Oc1ccc(C(=O)Cl)cc1)(C(C)C)C(C)C
Reactant: CN1CCN(c2cccc3ccc(N)cc23)CC1
Solvent: ClCCl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)[Si](Oc1ccc(C(=O)Nc2ccc3cccc(N4CCN(C)CC4)c3c2)cc1)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
A mixture of 7-amino-1-(4-methyl-1-piperazinyl)-naphthalene (0.118 g, 0.489 mmol) and triethylamine (0.13 mL, 0.98 mmol) in acetonitrile (10 mL) was chilled to 0° C. and 4-triisopropylsilyloxybenzoyl chloride (0.16 g, 0.51 mmol) dissolved in methylene chloride was added all at once. The mixture was gently refluxed overnight; then 7-amino-1-(4-methyl-1-piperazinyl)-naphthalene (0.038 g, 0.16 mmol), 4-triisopropylsilyloxybenzoyl chloride (0.5 g, 1.6 mmol), and triethylamine (0.13 mL, 0.93 mmol) were added. The reaction was refluxed for an additional 24 hours, cooled and the solvent was removed at reduced pressure. The residue was partitioned between methylene chloride and saturated aqueous sodium bicarbonate and stirred vigorously for 5 hours. The phases were separated and the organic layer was washed with brine, dried over calcium sulfate and concentrated to a tan foam which was purified by flash chromatography on silica gel (1×3.5 inches). Elution with 25% ethyl acetate/hexane removed unweighed recovered acid chloride. Continued elution with an ethyl acetate/hexane gradient of from 1:3 to 3:1 followed by 100% ethyl acetate gave 0.238 g of 7-(4-triisopropylsilyloxybenzamido)-1-(4-methyl-1-piperazinyl)-naphthalene as a viscous tan oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[C:5]2[CH:12]([CH3:24])[N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:15][O:16][C:4]=12.[H-].[Na+].[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34](Cl)(=[O:36])=[O:35]>CN(C=O)C.O>[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34]([N:9]1[C:10]2[C:6](=[C:5]3[CH:12]([CH3:24])[N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:15][O:16][C:4]3=[C:3]([O:2][CH3:1])[CH:11]=2)[CH:7]=[CH:8]1)(=[O:36])=[O:35]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: COc1cc2[nH]ccc2c2c1OCCN(C(=O)OC(C)(C)C)C2C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(ccn2S(=O)(=O)c2ccccc2Cl)c2c1OCCN(C(=O)OC(C)(C)C)C2C
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.1 %

Procedure:
tert-Butyl 6-methoxy-1-methyl-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 36, 25 mg, 0.059 mmol) was dissolved in DMF (1 mL) and sodium hydride (60% in mineral oil, 4.0 mg, 0.15 mmol) was added. The reaction mixture was stirred at room temperature for 15 minutes before 2-chlorobenzenesulfonyl chloride (24 mg, 0.11 mmol) was added. The reaction mixture was allowed to stir at room temperature overnight and a few drops of water were added. The crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give tert-butyl 8-[(2-chlorophenyl)sulfonyl]-6-methoxy-1-methyl-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (6 mg) which was dissolved in DCM (1 mL) and TFA (1 mL) was added. The reaction mixture was stirred at room temperature for 3 hours and evaporated to give the title compound (5.8 mg). MS m/z 407 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH2:9])[N:3]=1.C[CH2:11][N:12](C(C)C)[CH:13](C)C.CNC.O>C(#N)C>[Cl:8][C:6]1[N:5]=[C:4]([NH2:9])[N:3]=[C:2]([N:12]([CH3:13])[CH3:11])[CH:7]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: CNC
Solvent: O
Solvent: CC#N
Product: CN(C)c1cc(Cl)nc(N)n1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 104.5 %

Procedure:
To a solution of 4,6-dichloropyrimidinamine (2.0 g, 12.2 mmol) in acetonitrile were added Hunig's base (2.34 mL, 13.4 mmol) and dimethylamine (6.7 mL, 13.4 mmol), and the reaction mixture was stirred for 1.5 hours at 50° C. The mixture was poured onto CH2Cl2 and water. The organic layer was separated, washed with brine, and concentrated to afford the title compound (2.2 g, 94%) as an off-white solid. LC-MS (ES) m/z=173, 175 [M+H]+.
Reaction SMILES: [C]=O.[CH3:3][O:4][C:5](=[O:8])[CH2:6]Cl.C[O-].[K+].[CH3:12][O:13][C:14](=[O:16])C.COC(=O)COC>>[CH3:3][O:4][C:5](=[O:8])[CH2:6][C:14]([O:13][CH3:12])=[O:16]
Reactant: COC(C)=O
Reactant: COC(=O)CCl
Agent: COCC(=O)OC
Agent: C[O-]
Agent: [C]=O
Product: COC(=O)CC(=O)OC
Yield: 90 %

Procedure:
In a one-liter glass flask equipped with stirrer, 2 dropping funnels, a reflux condenser, a glass electrode and a glass inlet tube for carbon monoxide, 108.5 g (1 mole) of chloroacetic acid methyl ester is reacted for 61/2 hours with 1 mole of potassium methylate (28.75% solution in methanol) in the presence of 10 g of Co2 (CO)8, at 70° C., 0.8 at. CO, and a pH of approximately 8.5. The processing yields 119 g of malonic acid dimethyl ester (90% yield), and small amounts of acetic acid methyl ester and methoxyacetic acid methyl ester, plus 5 g of higher-boiling substances.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]3[CH:13]=[CH:14][C:15]([N+:17]([O-:19])=[O:18])=[CH:16][C:9]=3[CH2:8][O:7][C:6]=2[CH:20]=1.Br[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][CH3:29].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC([O-])(C)C.[K+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2].CC(O)(C)C>[CH3:29][O:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[NH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]3[CH:13]=[CH:14][C:15]([N+:17]([O-:19])=[O:18])=[CH:16][C:9]=3[CH2:8][O:7][C:6]=2[CH:20]=1
Reactant: COc1ccccc1Br
Reactant: Nc1ccc2c(c1)OCc1cc([N+](=O)[O-])ccc1C2=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: COc1ccccc1Nc1ccc2c(c1)OCc1cc([N+](=O)[O-])ccc1C2=O
Temperature: 100 °C

Procedure:
In accordance with general method Z, 0.80 g (2.96 mmol) of (6), 0.70 g (3.80 mmol) of 2-bromoanisole, 2 spatula tips of Pd(OAc)2, 0.10 g of 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (phosphine ligand), 0.50 g of KOt-Bu, 2.0 ml of t-BuOH are weighed out and dissolved in 10 ml of toluene (anhydrous). The mixture is refluxed at 100° C. under an argon atmosphere for 4 h. The crude product is purified by chromatography over silica gel with MC/EtOH (98/2). Yield: 0.025 g (2.2%); melting point: 200.3° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[N:7]=[C:6]2[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=1.[I-:26].[Na+]>CC(C)=O>[F:25][C:21]1[CH:20]=[C:19]([C:6]2[C:5]3[C:9](=[CH:10][CH:11]=[C:3]([CH2:2][I:26])[CH:4]=3)[N:8]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[N:7]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: [I-]
Reactant: CC(C)(C)OC(=O)n1nc(-c2cccc(F)c2)c2cc(CCl)ccc21
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)n1nc(-c2cccc(F)c2)c2cc(CI)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.8 %

Procedure:
To a solution of 500 mg of tert-butyl 5-(chloromethyl)-3-(3-fluorophenyl)-1H-1-indazolecarboxylate produced in Production Example I-24-b in 2.5 ml acetone was added 218 mg of sodium iodide, and the mixture was stirred at room temperature for 2 hours. After filtering off the resulting sodium chloride through Celite, the solvent was evaporated, to give 638 mg of the title compound as bright yellow crystals.
Reaction SMILES: [ClH:1].[NH2:2][C@@H:3]1[CH2:5][C@H:4]1[C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)=[CH:8][CH:7]=1.[CH:25]1([CH:28]=O)[CH2:27][CH2:26]1.C(=O)([O-])O.[Na+].[BH4-].[Na+]>CO.C1COCC1>[ClH:1].[CH:25]1([CH2:28][NH:2][C@@H:3]2[CH2:5][C@H:4]2[C:6]2[CH:7]=[CH:8][C:9]([NH:12][C:13](=[O:24])[C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:22])([F:23])[F:21])[CH:15]=3)=[CH:10][CH:11]=2)[CH2:27][CH2:26]1
Reactant: N[C@@H]1C[C@H]1c1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1
Reactant: O=CC1CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Nc1ccc([C@@H]2C[C@H]2NCC2CC2)cc1)c1cccc(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 45.7 %

Procedure:
To a solution of N-[4-(trans-2-aminocyclopropyl)phenyl]-3-(trifluoromethyl)benzamide hydrochloride (150 mg) in methanol (10 mL)/THF (10 mL) were added cyclopropanecarbaldehyde (38.3 mg) and sodium hydrogen carbonate (70.6 mg). The mixture was stirred at 60° C. for 1 hr, and ice-cooled to 0° C. and sodium borohydride (31.8 mg) was added. The mixture was stirred at room temperature for 2 hr, and ice-cooled to 0° C., and aqueous sodium hydrogen carbonate solution was added. The mixture was extracted with ethyl acetate, and the extract was washed with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol). To the obtained product was added 10% hydrochloric acid methanol solution, and the solvent was evaporated under reduced pressure. The residue was recrystallized from methanol/diisopropyl ether to give the title compound (79 mg).
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[N:8][CH:7]=[CH:6][N:5]=1.[C:11]([C:13]1[CH:14]=[C:15]([F:21])[C:16]([F:20])=[C:17]([F:19])[CH:18]=1)#[CH:12].N>>[N:5]1[CH:6]=[CH:7][N:8]=[CH:9][C:4]=1[C:3]1[CH:12]=[C:11]([C:13]2[CH:14]=[C:15]([F:21])[C:16]([F:20])=[C:17]([F:19])[CH:18]=2)[O:1][N:2]=1
Reactant: ON=C(Cl)c1cnccn1
Reactant: C#Cc1cc(F)c(F)c(F)c1
Agent: N
Product: Fc1cc(-c2cc(-c3cnccn3)no2)cc(F)c1F

Procedure:
The titled compound was prepared according to Method CB using the product of Example 83D (79 mg, 0.5 mmol) and 5-ethynyl-1,2,3-trifluorobenzene (Apollo, 78 mg, 0.5 mmol). 1H NMR (300 MHz, MeOH-d4) δ 7.53 (s, 1H), 7.79 (dd, J=8.5, 6.4 Hz, 2H), 8.70 (d, J=2.4 Hz, 1H), 8.76 (dd, J=2.5, 1.5 Hz, 1H), 9.29 (d, J=1.7 Hz, 1H) ppm; MS (DCI/NH3) m/z 278 (M+H)+.
Reaction SMILES: [CH:1]#[C:2][CH:3]([OH:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].N1C=CN=C1.CN(C)C=O.Cl[Si:21]([CH2:26][CH3:27])([CH2:24][CH3:25])[CH2:22][CH3:23]>CCCCCC.O.C1C=CC=CC=1.C(OCC)(=O)C>[CH2:22]([Si:21]([CH2:26][CH3:27])([CH2:24][CH3:25])[O:9][CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:2]#[CH:1])[CH3:23]
Reactant: C#CC(O)CCCCC
Reactant: CC[Si](Cl)(CC)CC
Agent: c1c[nH]cn1
Solvent: O
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: C#CC(CCCCC)O[Si](CC)(CC)CC
Temperature: 25 °C

Procedure:
To a magnetically stirred solution of 50 g of 1-octyn-3-ol, 83 g of imidazole, and 500 ml of anhydrous dimethylformamide, cooled in an ice-water bath under an argon atmosphere, is slowly added 90 g of chlorotriethylsilane. After several minutes the reaction mixture is warmed to ambient temperature, and the progress of the reaction is monitored by tlc (1:4/ethyl acetate:benzene). On completion, the reaction mixture is poured into 500 ml of an iced mixture of 1:1 hexane-water. The organic phase is separated, washed with water and brine, dried over sodium sulfate and concentrated in vacuo. The resulting oil is distilled to provide 83 g (bp 70°-72° C., 0.35 mm).
Reaction SMILES: [F:1][CH:2]([F:33])[C:3]1[N:7]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([NH:20][C@H:21]3[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]3)[N:9]=2)[C:6]2[CH:28]=[C:29]([CH3:32])[CH:30]=[CH:31][C:5]=2[N:4]=1.C(N(CC)CC)C.Cl[CH2:42][CH2:43][CH2:44][C:45](Cl)=[O:46]>C(Cl)Cl>[F:33][CH:2]([F:1])[C:3]1[N:7]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([NH:20][C@H:21]3[CH2:22][CH2:23][C@H:24]([N:27]4[CH2:42][CH2:43][CH2:44][C:45]4=[O:46])[CH2:25][CH2:26]3)[N:9]=2)[C:6]2[CH:28]=[C:29]([CH3:32])[CH:30]=[CH:31][C:5]=2[N:4]=1
Reactant: O=C(Cl)CCCCl
Reactant: Cc1ccc2nc(C(F)F)n(-c3cc(N4CCOCC4)nc(N[C@H]4CC[C@H](N)CC4)n3)c2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc2nc(C(F)F)n(-c3cc(N4CCOCC4)nc(N[C@H]4CC[C@H](N5CCCC5=O)CC4)n3)c2c1
Reaction time: 1 h

Procedure:
To a solution of trans-N-{4-[2-(difluoromethyl)-6-methyl-1H-benzimidazol-1-yl]-6-(morpholin-4-yl)pyrimidin-2-yl}cyclohexane-1,4-diamine (50 mg) in methylene chloride (1 mL) were added triethylamine (46 μL) and 4-chlorobutyryl chloride (16 mg), followed by stirring for 1 hour in a water bath. The reaction solution was concentrated under reduced pressure and to the residue were added tetrahydrofuran (5 mL) and 60% sodium hydride (13 mg), followed by stirring at 0° C. for 30 minutes and at room temperature for 1 hour. To the reaction solution was added water, followed by extraction with ethyl acetate, and the extracts were washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration and then the solvent was evaporated under reduced pressure. The residue was purified by amino silica gel column chromatography (hexane:ethyl acetate=50:50-0:100 and chloroform:methanol=100:0-90:10) to obtain 1-[trans-4-({4-[2-(difluoromethyl)-6-methyl-1H-benzimidazol-1-yl]-6-(morpholin-4-yl)pyrimidin-2-yl}amino)cyclohexyl]pyrrolidin-2-one (40 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH2:7][CH2:6][CH2:5][CH:4]([NH:8][C:9]([NH:11][C:12]2[N:13]=[C:14]3[CH:20]=[CH:19][N:18](COCC[Si](C)(C)C)[C:15]3=[N:16][CH:17]=2)=[O:10])[CH2:3]1.C(O)(=O)C>Cl.O.[OH-].[Na+]>[CH3:1][C:2]1([CH3:29])[CH2:7][CH2:6][CH2:5][CH:4]([NH:8][C:9]([NH:11][C:12]2[N:13]=[C:14]3[CH:20]=[CH:19][NH:18][C:15]3=[N:16][CH:17]=2)=[O:10])[CH2:3]1
Reactant: CC1(C)CCCC(NC(=O)Nc2cnc3c(ccn3COCC[Si](C)(C)C)n2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CC1(C)CCCC(NC(=O)Nc2cnc3[nH]ccc3n2)C1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 35.3 %

Procedure:
1-(3,3-Dimethyl-cyclohexyl)-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea (0.095 g, 0.227 mmol) was dissolved in 1M HCl in acetic acid (2 mL, 2.04 mmol) and the resulting yellow solution stirred at 50° C. for 1.5 hours. The reaction mixture was diluted with 2 mL of H2O and basified with 3M NaOH. Light yellow precipitate forms. The solvent was evaporated. The yellow solid was taken up in MeOH:H2O:Et3N 8:1:1 and stirred at RT for 1 hour. The mixture was absorbed onto SiO2 and purified by SiO2 chromatography (12 g SiO2, DCM/magic (DCM:MeOH:NH4OH 60:10:1) 0-35% magic) to give 0.023 g of 1-(3,3-dimethyl-cyclohexyl)-3-(5H-pyrrolo[2,3-b]pyrazin-2-yl)-urea as an off-white solid (35% yield).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[F:14])[CH2:6]1)=[O:4]>CC(O)=O>[F:14][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[CH2:13][CH:5]([C:3]([OH:4])=[O:2])[CH2:6]2
Reactant: COC(=O)C1Cc2cccc(F)c2C1
Solvent: CC(=O)O
Product: O=C(O)C1Cc2cccc(F)c2C1

Procedure:
4-Fluoro-indan-2-carboxylic acid methyl ester in HOAc containing 20% HCl was hydrolyzed according to the protocols as outlined in general procedure G to afford the desired title acid. Spectroscopic data: 1H NMR (300 MHz, DMSO-d6) δ 3.09-3.23 (m, 4H), 3.29-3.40 (m, 1H), 7.0 (t, 1H, J=8.5 Hz), 7.1 (d, 1H, J=7.3 Hz), 7.14-7.24 (m, 1H), 12.4 (br s, 1H).
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.C([Mg]Cl)(C)C.[Cl-].[Li+].[CH:14]([CH:16]1[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]1)=[O:15]>O1CCCC1>[OH:15][CH:14]([C:2]1[CH:6]=[CH:5][S:4][CH:3]=1)[CH:16]1[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCCC(C=O)C1
Reactant: Brc1ccsc1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(C(O)c2ccsc2)C1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 112.9 %

Procedure:
Under a nitrogen atmosphere, 5.0 g (30.67 mmol) of 3-bromothiophene in 5 ml of tetrahydrofuran were slowly added dropwise to 24.77 ml (32.2 mmol) of isopropylmagnesium chloride/lithium chloride complex (1.3 M in tetrahydrofuran) at 5° C. After the mixture had been stirred at 5° C. for 0.5 h, 6.54 g (30.67 mmol) of tert-butyl 3-formylpiperidine-1-carboxylate were slowly added dropwise. After removal of the cold bath, the reaction mixture was stirred for a further 1 h. Conventional work-up gave 10.3 g of tert-butyl 3-(hydroxythiophen-3-ylmethyl)piperidine-1-carboxylate; HPLC/MS (M+H-tBuO)+=244 as oil (diastereomers).
Reaction SMILES: [F:1][C:2]1[CH:13]=[C:6]2[C:7]([O:9][C:10](=O)[NH:11][C:5]2=[CH:4][CH:3]=1)=[O:8].[NH:14]([CH2:16]C(O)=O)[CH3:15].O>CS(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:9])[CH2:15][N:14]([CH3:16])[C:7](=[O:8])[C:6]=2[CH:13]=1
Reactant: O=c1[nH]c2ccc(F)cc2c(=O)o1
Reactant: CNCC(=O)O
Solvent: CS(C)=O
Solvent: O
Product: CN1CC(=O)Nc2ccc(F)cc2C1=O
Temperature: 100 °C

Procedure:
24 g (132.5 mmol) of 5-fluoroisatoic acid anhydride are dissolved in 140 ml of dimethyl sulphoxide and treated with 11.8 g (132.5 mmol) of sarcosine. The solution is stirred at 100° C. until the gas evolution ceases (duration: ca 1.5 hours) and subsequently poured into ca 1.2 liters of water. After stirring for 10 minutes, a solid crystallises out. The crystals are filtered off under suction, washed with 1 liter of water and dried. There is obtained 7-fluoro-3,4-dihydro-4-methyl-2H-1,4-benzodiazepine-2,5(1H)-dione of melting point 262°-263° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]([CH2:7][N:8]2[CH:12]=[N:11][CH:10]=[N:9]2)=[CH:5][CH:4]=1.C([Li])CCC.[CH2:20]([CH:22]([CH2:25][CH3:26])[CH:23]=[O:24])[CH3:21]>C1COCC1>[CH2:20]([CH:22]([CH2:25][CH3:26])[CH:23]([C:12]1[N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:14][CH:13]=2)[N:9]=[CH:10][N:11]=1)[OH:24])[CH3:21]
Reactant: COc1ccc(Cn2cncn2)cc1
Reactant: CCC(C=O)CC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC(CC)C(O)c1ncnn1Cc1ccc(OC)cc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 114.1 %

Procedure:
To a solution of 1-(4-methoxybenzyl)-1H-1,2,4-triazole (2.12 g, 11.2 mmol) in THF (120 mL) at −78° C. was added a solution of n-butyllithium (2.5 M in hexanes, 4.9 mL, 12.3 mmol) over a period of 20 min. The solution was stirred at −78° C. for 2 h and 45 min. Then 2-ethylbutyraldehyde (0.65 mL, 5.3 mmol) was added. After 1.5 h the reaction mixture was warmed to room temperature, quenched with saturated aqueous ammonium chloride, extracted with EtOAc and dried over Na2SO4. After removal of the solvents, the product was purified by recrystallization from EtOAc/hexanes to give 1.75 g (54%) of 2-ethyl-1-[1-(4-methoxybenzyl)-1H-1,2,4-triazol-5-yl]butan-1-ol as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:31][CH:32]([F:34])[F:33])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[N:9]=2)[CH:7]=1.O.O=[CH:37][C:38]([O:40][CH2:41][CH3:42])=[O:39].CC(O)=O.[BH3-]C#N.[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:31][CH:32]([F:33])[F:34])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH:25]3[CH2:26][CH2:27][N:28]([CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:29][CH2:30]3)[N:9]=2)[CH:7]=1
Reactant: CCOC(=O)C=O
Reactant: O=C(Nc1cn(C2CCNCC2)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: CCOC(=O)CN1CCC(n2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Temperature: 60 °C
Reaction time: 12 h
Yield: 6.7 %

Procedure:
To a solution of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(piperidin-4-yl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (320 mg, 0.66 mmol) in ethanol (20 mL) was added 50% ethyl 2-oxoacetate hydrate (268 mg, 1.31 mmol), AcOH (0.1 mL, 1.75 mmol) and NaBH3CN (83 mg, 1.32 mmol). The resulting solution was stirred at 60° C. for 12 h and concentrated under vacuum. The residue was passed through a short pad of silica gel eluting with 2% MeOH in DCM. The crude product (100 mg) was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, silica gel; mobile phase, CH3CN:H2O=5:95 increasing to CH3CN:H2O=55:75 within 12 min; Detector, UV 254 nm. 25.3 mg product was obtained. This resulted in 25.3 mg (7%) of ethyl 2-(4-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]piperidin-1-yl)acetate as an off-white solid. LCMS (Method 20) [M+H]+=574.2, RT=2.70 min. 1H NMR (300 MHz, DMSO-d6) δ: (ppm) 9.73 (s, 1H), 9.36 (s, 1H), 8.69-8.67 (m, 2H), 8.36 (s, 1H), 7.63-7.25 (m, 5H), 4.25-4.23 (m, 1H), 4.13-4.10 (m, 2H), 3.28-3.27 (m, 2H), 3.01-2.98 (m, 2H), 2.42-2.40 (m, 2H), 2.12-1.98 (m, 4H), 1.25-1.20 (m, 3H).
Reaction SMILES: [C:1]([C:4]1[C:5]([NH:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=2[O:24][CH3:25])=[N:6][C:7]([S:11][CH3:12])=[N:8][C:9]=1Cl)(=[O:3])[NH2:2].[OH-].[NH4+:27].O>CS(C)=O>[NH2:27][C:9]1[N:8]=[C:7]([S:11][CH3:12])[N:6]=[C:5]([NH:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=2[O:24][CH3:25])[C:4]=1[C:1](=[O:3])[NH2:2]
Reactant: COC(=O)c1ccc(Nc2nc(SC)nc(Cl)c2C(N)=O)c(OC)c1
Reactant: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1ccc(Nc2nc(SC)nc(N)c2C(N)=O)c(OC)c1
Temperature: 100 °C

Procedure:
To a solution of the product of Example 10A (1.3 g, 3.4 mmol) in dimethylsulfoxide (50 mL) was added ammonium hydroxide (5.2 mL, 34 mmol). The mixture was heated to 100° C. for 4 hours and was allowed to cool to ambient temperature. Water (50 mL) was added and the precipitate was filtered and washed with ethanol (20 mL) to give the title compound. MS: 364 (M+H+).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[N:18]=[C:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:20][C:21]=1[CH3:22])[CH:8]=[CH:9][CH:10]=O)([CH3:3])[CH3:2].[O:29]1[CH2:33][C:32](=[O:34])[NH:31][C:30]1=[O:35]>>[CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH2:8][CH2:9][CH2:10][CH:33]2[O:29][C:30](=[O:35])[NH:31][C:32]2=[O:34])[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[N:18]=[C:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:20][C:21]=1[CH3:22])([CH3:2])[CH3:3]
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(C=CC=O)cc1OC(C)C
Reactant: O=C1COC(=O)N1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CCCC2OC(=O)NC2=O)cc1OC(C)C

Procedure:
In substantially the same manner as in Working Example 11, 3-isopropoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)cinnamaldehyde was condensed with 2,4-oxazolidinedione. The condensate was subjected to catalytic hydrogenation to yield 5-[3-[3-isopropoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]propyl]-2,4-oxazolidinedione, which was recrystallized from ethyl acetate-hexane to give colorless needles, m.p.120-121° C.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:13][CH2:14]OC)[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1)=[O:5])C.[CH2:17]([C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][NH2:27])=[CH:21][CH:20]=1)[CH3:18]>>[CH2:17]([C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][N:27]2[CH2:14][CH2:13][C:6]3([CH2:7][CH2:8][CH:9]([OH:12])[CH2:10][CH2:11]3)[C:4]2=[O:5])=[CH:21][CH:20]=1)[CH3:18]
Reactant: CCOC(=O)C1(CCOC)CCC(O)CC1
Reactant: CCc1ccc(CCN)cc1
Product: CCc1ccc(CCN2CCC3(CCC(O)CC3)C2=O)cc1

Procedure:
The title compound was prepared in analogy to example 1, step 4 from 4-hydroxy-1-(2-methoxy-ethyl)-cyclohexanecarboxylic acid ethyl ester (obtained in example 2, step 3) by treatment with 2-(4-ethylphenyl)-ethylamine [CAS Reg. No. 64353-29-3]. MS (m/e): 302.3 [MH+].