Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([CH:11]=[O:12])=[C:4]2[N:3]=1.[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=2)[CH2:16][CH2:15]1>O1CCOCC1>[CH3:13][N:14]1[CH2:15][CH2:16][N:17]([C:20]2[CH:26]=[CH:25][C:23]([NH:24][C:2]3[CH:7]=[CH:6][N:5]4[N:8]=[CH:9][C:10]([CH:11]=[O:12])=[C:4]4[N:3]=3)=[CH:22][CH:21]=2)[CH2:18][CH2:19]1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: O=Cc1cnn2ccc(Cl)nc12
Solvent: C1COCCO1
Product: CN1CCN(c2ccc(Nc3ccn4ncc(C=O)c4n3)cc2)CC1
Temperature: 120 °C

Procedure:
To 5-chloropyrazolo[1,5-a]pyrimidine-3-carbaldehyde (50 mg, 0.276 mmol) in dioxane was added 4-(4-methylpiperazin-1-yl)aniline (264 mg, 1.381 mmol). The mixture was heated in microwave for 20 minutes at 120° C. The solid formed was isolated by filtration to yield 5-(4-(4-methylpiperazin-1-yl)phenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde. The residue was used in the next step without further purification. LCMS (M+1=337).
Reaction SMILES: Cl(O)(=O)(=O)=O.[CH3:6][O:7][C:8]1[N:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C@H:22]3[O:31][C@H:25]4[O:26]C(C)(C)[O:28][C@H:24]4[C@H:23]3[CH2:32][CH2:33][N:34]3[C:42](=[O:43])[C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[C:35]3=[O:44])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1>C(#N)C.C(OCC)(=O)C.O>[OH:28][C@@H:24]1[C@H:25]([OH:26])[O:31][C@H:22]([CH2:21][CH2:20][C:17]2[CH:18]=[CH:19][C:14]([C:11]3[CH:12]=[N:13][C:8]([O:7][CH3:6])=[CH:9][CH:10]=3)=[CH:15][CH:16]=2)[C@@H:23]1[CH2:32][CH2:33][N:34]1[C:35](=[O:44])[C:36]2[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:42]1=[O:43]
Reactant: COc1ccc(-c2ccc(CC[C@H]3O[C@H]4OC(C)(C)O[C@H]4[C@H]3CCN3C(=O)c4ccccc4C3=O)cc2)cn1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(-c2ccc(CC[C@H]3O[C@@H](O)[C@@H](O)[C@H]3CCN3C(=O)c4ccccc4C3=O)cc2)cn1
Temperature: 55 °C

Procedure:
Perchloric acid (0.4 mL) was added to a solution of the compound obtained from step f above (0.5 g) in acetonitrile (4 mL) and water (0.8 mL) at room temperature. The reaction mixture was heated to 55° C. for 30 minutes. The reaction mixture was then quenched using sodium bicarbonate solution. The solvents were evaporated under reduced pressure. The residue thus obtained was taken up in ethyl acetate and water. The organic layer was separated, washed with water and brine solution, and dried over anhydrous sodium sulphate. The solvent was concentrated under reduced pressure to yield the title compound (0.51 g).
Reaction SMILES: [CH2:1]([OH:23])[C@H:2]1[O:7][C@H:6]([O:8][C@]2(CO)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@@H:3]1[OH:22].[Cl-].[Mg+2].[Cl-].[OH-].[Na+]>O>[O:8]=[CH:6][C@@H:5]([C@H:4]([C@@H:3]([C@@H:2]([CH2:1][OH:23])[OH:7])[OH:22])[OH:21])[OH:20]
Reactant: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Agent: [Cl-]
Agent: [Mg+2]
Agent: [Na+]
Solvent: O
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
Food-grade sucrose, 250 g was dissolved in 250 ml of water and magnesium chloride was added to a concentration of 0.005 M. The pH was adjusted to 6.5 and maintained at this value by the addition of 0.5 N sodium hydroxide solution was needed. To the sucrose solution was added 7500 units of fructosyl transferase enzyme preparation, obtained as in Example 1, and 5000 units of glucose isomerase enzyme preparation, obtained as described by Cory, U.S. Pat. No. 4,077,842. After the mixture had been stirred at 55° C. for 24 hours, the enzyme reaction was stopped by placing the material in a boiling water bath for 10 minutes. The resulting syrup was then analyzed by high pressure liquid chromatography. The results of two different runs using different batches of enzymes are given in Table I.
Reaction SMILES: [C:1]1(=[O:25])[N:5]([CH2:6][CH2:7][CH2:8][CH:9]([C:17]([O:19]C(C)(C)C)=[O:18])[C:10]([O:12]C(C)(C)C)=[O:11])[C:4](=[O:24])[CH:3]=[CH:2]1>FC(F)(F)C(O)=O>[C:4]1(=[O:24])[N:5]([CH2:6][CH2:7][CH2:8][CH:9]([C:17]([OH:19])=[O:18])[C:10]([OH:12])=[O:11])[C:1](=[O:25])[CH:2]=[CH:3]1
Reactant: CC(C)(C)OC(=O)C(CCCN1C(=O)C=CC1=O)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C(CCCN1C(=O)C=CC1=O)C(=O)O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
The di-t-butyl ester 79 is dissolved in 20% trifluoroacetic acid and the mixture is stirred at rt for 5 h. The solvents are evaporated and the residue flushed with methylene chloride several times. The residue is triturated with ether and the resulting solid product is collected by filtration, washed with ether, and dried in vacuo.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C:7]2[N:8]=[C:9]3[N:19]([CH:20]=2)[CH2:18][CH2:17][O:16][C:15]2[C:10]3=[CH:11][CH:12]=[C:13]([C:21]3[CH:22]=[N:23][N:24]([CH3:32])[C:25]=3[CH:26]3[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]3)[CH:14]=2)[N:4]([CH:33]([CH3:35])[CH3:34])[N:3]=1.[O:36]1[CH2:41][CH2:40][C:39](=O)[CH2:38][CH2:37]1.[BH3-]C#N.[Na+]>C(O)C>[CH:33]([N:4]1[C:5]([C:7]2[N:8]=[C:9]3[C:10]4[CH:11]=[CH:12][C:13]([C:21]5[CH:22]=[N:23][N:24]([CH3:32])[C:25]=5[CH:26]5[CH2:31][CH2:30][CH2:29][N:28]([CH:39]6[CH2:40][CH2:41][O:36][CH2:37][CH2:38]6)[CH2:27]5)=[CH:14][C:15]=4[O:16][CH2:17][CH2:18][N:19]3[CH:20]=2)=[N:6][C:2]([CH3:1])=[N:3]1)([CH3:35])[CH3:34]
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(-c4cnn(C)c4C4CCCNC4)cc2OCC3)n(C(C)C)n1
Reactant: O=C1CCOCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: Cc1nc(-c2cn3c(n2)-c2ccc(-c4cnn(C)c4C4CCCN(C5CCOCC5)C4)cc2OCC3)n(C(C)C)n1
Temperature: 20 °C
Reaction time: 0.33 h
Yield: 48.4 %

Procedure:
To a solution of 4-[3-methyl-1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-12-[1-methyl-5-(piperidin-3-yl)-1H-pyrazol-4-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14), 2,4,10,12-pentaene (60 mg, 0.13 mmol) and tetrahydropyran-4-one (26 mg, 0.26 mmol) in ethanol (10 mL) was added Ti(Oi-Pr)4 (74 mg, 0.26 mmol). After being stirred at 20° C. for 20 min, NaBH3CN (16 mg, 0.26 mmol) was added and stirred at 20° C. for 16 h. The solvent was removed and several drops of water were added. The solid was filtered off and the filtrate was evaporated to afford the crude product, which was purified by reverse phase Combiflash eluting with a 0-50% gradient of CH3CN in 0.3% NH4HCO3 to give 226 (35 mg, 50% yield). LCMS (ESI): RT=4.97 min, m/z: 557.4 [M+H+]. 1H NMR (500 MHz, MeOH-d4) δ 8.48 (d, J=8 Hz, 1H), 7.25 (s, 1H), 7.41 (s, 1H), 7.09 (d, J=8 Hz, 1H), 7.00 (s, 1H), 5.94 (t, J=13 Hz, 1H), 4.54 (d, J=5 Hz, 4H), 3.95 (d, J=6.5 Hz, 5H), 3.35 (t, J=25 Hz, 3H), 3.25 (s, 1H), 3.00 (d, J=6.5 Hz, 2H), 2.51-2.54 (m, 2H), 2.38 (s, 3H), 2.12 (d, J=11 Hz, 1H), 1.86-1.62 (m, 6H), 1.56-1.49 (m, 6H)
Reaction SMILES: Cl.[CH:2]([O:5][CH2:6][CH2:7][N:8]([C:16]1[CH:38]=[CH:37][C:19]([C:20]([N:22]2[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)[CH2:24][CH2:23]2)=[O:21])=[CH:18][CH:17]=1)C(=O)COC(=O)C)([CH3:4])[CH3:3].C(OCC(Cl)=O)(=O)C>>[CH:2]([O:5][CH2:6][CH2:7][NH:8][C:16]1[CH:38]=[CH:37][C:19]([C:20]([N:22]2[CH2:23][CH2:24][N:25]([CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)[CH2:26][CH2:27]2)=[O:21])=[CH:18][CH:17]=1)([CH3:4])[CH3:3]
Reactant: CC(=O)OCC(=O)N(CCOC(C)C)c1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Agent: CC(=O)OCC(=O)Cl
Agent: Cl
Product: CC(C)OCCNc1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1

Procedure:
In a manner analogous to that described in Example 23, 1-{4-[N-(2-isopropyloxyethyl)-N-acetoxyacetylamino]benzoyl}-4-[2-(4-chlorophenyl)ethyl]piperazine hydrochloride having a melting point of 130°-132° is obtained from 5 g of 1-{4-[N-(2-isopropyloxyethyl)amino]benzoyl}-4-[2-(4-chlorophenyl)ethyl]piperazine (Example 21) by reaction with acetoxyacetic acid chloride.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:13]([CH3:23])[CH2:12][C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1.[Cl:24][C:25]1[CH:39]=[CH:38][C:28]([CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][NH:34][C:33](=[O:37])[CH2:32]2)=[CH:27][CH:26]=1>>[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][N:34]([C:2]3[CH:3]=[CH:4][C:5]4[C:6]5[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:13]([CH3:23])[CH2:12][C:7]=5[N:8]([CH3:11])[C:9]=4[CH:10]=3)[C:33](=[O:37])[CH2:32]2)=[CH:38][CH:39]=1
Reactant: O=C1CN(CCc2ccc(Cl)cc2)CCN1
Reactant: CC1Cc2c(c3ccc(Br)cc3n2C)CN1C(=O)OC(C)(C)C
Product: CC1Cc2c(c3ccc(N4CCN(CCc5ccc(Cl)cc5)CC4=O)cc3n2C)CN1C(=O)OC(C)(C)C
Yield: 58.9 %

Procedure:
tert-Butyl 7-bromo-3,5-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (120 mg, 0.316 mmol) and 4-(4-chlorophenethyl)piperazin-2-one (75 mg, 0.316 mmol) were reacted following the procedure for Example 2 (step f) to provide the title compound (100 mg, 59%) as a white solid: ESI MS m/z 537 [M+H]+.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=[O:19])[C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[F:18])[CH2:6][CH2:5]1)(=O)C.[ClH:20]>>[ClH:20].[F:18][C:12]1[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:11]=1[C:10]([CH:7]1[CH2:8][CH2:9][NH:4][CH2:5][CH2:6]1)=[O:19]
Reactant: CC(=O)N1CCC(C(=O)c2ccc(C)cc2F)CC1
Agent: Cl
Product: Cc1ccc(C(=O)C2CCNCC2)c(F)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A sample of 17.1 g of 1-acetyl-4-(2-fluoro-4-methylbenzoyl)piperidine is refluxed in 200 ml of 6N HCl for 24 hours and then stirred for an additional 6 hours at ambient temperature. The solution is extracted with ether, the aqueous layer is basified with 6N NaOH, extracted with benzene, dried and the solvent is removed under reduced pressure, leaving a yellow oil. The oil is added to ethereal hydrogen chloride and the resulting precipitate is collected, washed well with ether and dried. The solid is recrystallized from a methanol-ether mixture to give the final solid product, mp 220°-221° C. of 4-(2-fluoro-4-methylbenzoyl)piperidine hydrochloride.
Reaction SMILES: Cl[CH:2]([F:14])[CH2:3][CH:4]([OH:13])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[O:15]=[C:16]1[N:20]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[C:19]2[CH:27]=[CH:28][CH:29]=[CH:30][C:18]=2[NH:17]1.C(=O)([O-])O.[Na+].[I-].[K+]>C1(C)C=CC=CC=1>[O:15]=[C:16]1[N:20]([CH:21]2[CH2:22][CH2:23][N:24]([CH:2]([F:14])[CH2:3][CH:4]([OH:13])[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[O:6])[CH2:25][CH2:26]2)[C:19]2[CH:27]=[CH:28][CH:29]=[CH:30][C:18]=2[NH:17]1
Reactant: O=C(c1ccccc1)C(O)CC(F)Cl
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C(c1ccccc1)C(O)CC(F)N1CCC(n2c(=O)[nH]c3ccccc32)CC1
Temperature: 0 °C

Procedure:
A mixture of 10 g of γ-chloro-2-hydroxy-4-fluorobutyrophenone, 6.6 g of 4-(2-keto-1-benzimidazolinyl)piperidine, 2.6 g of sodium hydrogen carbonate, 0.05 g of potassium iodide and 300 ml of toluene was refluxed for 27 hours. The resulting mixture was poured into ice water and extracted with chloroform. The extract was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residual viscous oil was chromatographed over silica gel (100-200 mesh) with ethyl acetate as an eluting agent to give γ-[4-(2-keto-1-benzimidazolinyl)piperidin-1-yl]-2-hydroxy-4-fluorobutyrophenone, M.P. 175°-181° C.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:22]=[CH:21][CH:20]=[CH:19][C:7]=1[CH2:8][S:9][C:10]1[NH:11][C:12]2[C:13]([N:18]=1)=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:2]([CH3:4])[CH3:3].ClC1C=CC=C(C(OO)=[O:31])C=1.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[CH2:1]([NH:5][C:6]1[CH:22]=[CH:21][CH:20]=[CH:19][C:7]=1[CH2:8][S:9]([C:10]1[NH:11][C:12]2[C:13]([N:18]=1)=[N:14][CH:15]=[CH:16][CH:17]=2)=[O:31])[CH:2]([CH3:4])[CH3:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)CNc1ccccc1CSc1nc2ncccc2[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)CNc1ccccc1CS(=O)c1nc2ncccc2[nH]1
Temperature: 0 °C

Procedure:
In 20 ml of chloroform was dissolved 900 mg of 2-[2-(isobutylamino)benzylthio]imidazo[4,5-b]pyridine. To the resulting solution was portionwise added under chilling with ice 618 mg of m-chloroperbenzoic acid (purity: 80%) over a period of 30 min. To the mixture was added a saturated NaHCO3 solution, and the resulting mixture was then stirred. The organic phase was separated and extracted successively with 20 ml of 0.1N NaOH and 10 ml of 0.1N NaOH. The alkaline extracts were combined and neutralized by NH4Cl, and the deposited oil was extracted with chloroform. The chloroform extract was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and placed under reduced pressure to distill off the solvent. The residue was crystallized by addition of diethyl ether. The crystalline product was washed with diethyl ether to give 195 mg of 2-[2-(isobutylamino)benzylsulfinyl]imidazo[4,5-b]pyridine as a pale yellow crystalline powder. m.p.: 116° C. (decompn.).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:9]=[C:8]([S:10][CH3:11])[N:7]=[C:6]([OH:12])[CH:5]=1.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[NH2:3][C:4]1[N:9]=[C:8]([S:10][CH3:11])[N:7]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6](=[O:12])[CH:5]=1
Reactant: CSc1nc(N)cc(O)n1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nc(N)cc(=O)n1Cc1ccccc1
Reaction time: 1.5 h

Procedure:
To a slurry of 60% NaH dispersion (1.8 g=45 mmol) in 25 ml DMF at 10° C. add dropwise a solution of 6-amino-2-methylthio-4-hydroxypyrimidine (6.3 g=40 mmol) in 150 ml DMF. When gas evolution subsides, add benzyl bromide (7.5 g=44 mmol). Stir 1.5 hr. at room temperature. Remove DMF and partition the residue between EtOAc and water. Wash the organic layer with water, dry and concentrate. Recrystallize the residue from CH3CN to give the title compound, a white solid. FAB MS: M+1=248.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][N:10]=[CH:9]2)([O-:3])=[O:2].[C:13](=O)([O:19]C(C)(C)C)[O:14][C:15]([CH3:18])([CH3:17])[CH3:16].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(#N)C>[N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[N:11]([C:13]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:19])[N:10]=[CH:9]2)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc2cn[nH]c12
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1ncc2cccc([N+](=O)[O-])c21
Yield: 59 %

Procedure:
A solution of 7-nitro-1H-indazole (2.81 g, 17.23 mmol), di-tertbutyl carbonate (7.52 g, 34.5 mmol), triethylamine (4.81 mL, 34.5 mmol) and 4-dimethylamino-pyridine (2.11 g, 17.2 mmol) in anhydrous acetonitrile (100 mL) is stirred under nitrogen at ambient temperature for approximately 3 hrs. After removing the solvent in vacuo, the residue is partitioned between ethyl acetate and aqueous sodium hydrogen sulfate (1N). The organic layer is separated, washed with saturated aqueous brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The crude product is purified by chromatography on flash grade silica gel using DCM. Fractions containing the product are combined, concentrated in vacuo to a solid and dried under high vacuum to provide the title compound as a yellow solid (2.674 g, 10.16 mmol). 1H NMR (300 MHz, d6-DMSO) δ=1.55 (s, 9H); 7.58 (t, J=8.0 Hz, 1H); 8.20 (d, J=7.4 Hz, 1H); 8.30 (d, J=7.7 Hz, 1H); 8.67 (s, 1H), TLC: Rf =0.5 (DCM).
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([CH2:7][CH2:8][OH:9])=[CH:5][CH:4]=1.[Cl:13][C:14]1[CH:19]=[N:18][CH:17]=[C:16](Cl)[N:15]=1>O1CCOCC1>[Cl:13][C:14]1[CH:19]=[N:18][CH:17]=[C:16]([O:9][CH2:8][CH2:7][C:6]2[CH:10]=[CH:11][C:3]([N:2]([CH3:1])[CH3:12])=[CH:4][CH:5]=2)[N:15]=1
Reactant: Clc1cncc(Cl)n1
Reactant: CN(C)c1ccc(CCO)cc1
Solvent: C1COCCO1
Product: CN(C)c1ccc(CCOc2cncc(Cl)n2)cc1
Temperature: 0 °C
Reaction time: 0.2 h

Procedure:
K-t-BuO (2.27 g, 20.3 mmol) was added to a stirred solution of 4-(dimethylamino)phenethyl alcohol (3.55 g, 21.5 mmol) in dioxane (35 mL) at 0° C. (ice-bath). After being stirred for 5 min at 0° C. and 12 min at room temperature, the mixture was chilled to 0° C. (ice-bath) and 2,6-dichloropyrazine (2.62 g, 17.6 mmol) was added.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.ClC[C:45]1[CH:50]=[CH:49][CH:48]=C[C:46]=1[O:51][CH3:52]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[CH:48]=[CH:49][CH:50]=[CH:45][C:46]=3[O:51][CH3:52])[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ccccc1CCl
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: COc1ccccc1Cn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-(chloromethyl)-2-methoxybenzene and isolated as colorless gum (6.6 mg, 40%). MS (m/e): 403.4 (MH+).
Reaction SMILES: [CH2:1]([P:3]([O-:9])[O:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:2].[C:10](#[N:14])[C:11]([CH3:13])=[CH2:12]>C1(C)C=CC=CC=1>[CH2:1]([P:3]([CH2:12][CH:11]([C:10]#[N:14])[CH3:13])(=[O:9])[O:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:2]
Reactant: C=C(C)C#N
Reactant: CCCCOP([O-])CC
Solvent: Cc1ccccc1
Product: CCCCOP(=O)(CC)CC(C)C#N
Yield: 83.8 %

Procedure:
150 g (1 mol) of the butyl ethylphosphonite (produced as in Example 2) and 80 g (1.2 mol) of methacrylonitrile in 217 g of toluene are heated to about 100° C. While stirring, 124 g of a 10% strength solution of WakoV65 in toluene are metered in. The solvent is distilled off in vacuo to obtain 182 g (84% of theory) of butyl ethyl(2-cyano-2-methylethyl)phosphinate.
Reaction SMILES: C[C:2](C)([O-:4])C.[K+].C1(C)C=C(C)C=C(C)C=1S([O-])(=O)=O.[NH2:20][N+:21]1[CH:26]=[CH:25][C:24](OC)=[CH:23][C:22]=1[C:29]#[C:30][CH2:31][CH3:32].O.C(OCC)(=O)C>O1CCCC1.CN(C)C=O>[CH2:31]([C:30]1[CH:29]=[C:22]2[C:23]([O:4][CH3:2])=[CH:24][CH:25]=[CH:26][N:21]2[N:20]=1)[CH3:32]
Reactant: CCC#Cc1cc(OC)cc[n+]1N
Reactant: CC(C)(C)[O-]
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCc1cc2c(OC)cccn2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.5 %

Procedure:
Potassium tert-butoxide (11.1 g) was added to a solution of N-amino-2-(1-butynyl)-4-methoxypyridinium mesitylenesulfonate (20.7 g) in tetrahydrofuran (300 mL) and N,N-dimethylformamide (15 mL), and the mixture was stirred at room temperature for 1 hour. Water was added while cooling on ice, extraction was performed with ethyl acetate, the extract was washed with brine and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (200 g), and the title compound (6.44 g) was obtained from the n-hexane:ethyl acetate (3:1) fraction as a yellow oil.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]([N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[N:29]3[C:24]([C:25]([NH2:30])=[N:26][CH:27]=[N:28]3)=[C:23]([C:31]3[CH:32]=[CH:33][C:34]4[C:38]([CH:39]=3)=[N:37][N:36]([CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH:35]=4)[CH:22]=2)[CH2:17][CH2:16]1)=[O:14])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:40]([N:36]1[CH:35]=[C:34]2[C:38]([CH:39]=[C:31]([C:23]3[CH:22]=[C:21]([CH:18]4[CH2:17][CH2:16][N:15]([C:13](=[O:14])[C@@H:9]5[CH2:10][CH2:11][CH2:12][NH:8]5)[CH2:20][CH2:19]4)[N:29]4[C:24]=3[C:25]([NH2:30])=[N:26][CH:27]=[N:28]4)[CH:32]=[CH:33]2)=[N:37]1)[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)N1CCC(c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncnn2c(C3CCN(C(=O)[C@@H]4CCCN4)CC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Temperature: 25 °C
Reaction time: 5 h
Yield: 17.7 %

Procedure:
To a solution of 2-{4-[4-Amino-5-(2-benzyl-2H-indazol-6-yl)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-piperidine-1-carbonyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (73.5 mg, 0.1 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (0.2 mL). The reaction was stirred at rt for 5 h. The sample was concentrated and the residue taken up in 1.5 mL of methanol, 0.5 mL of acetonitrile and 0.5 mL of water. The sample was then free-based using Phenomenex's Strata-X-C cation mixed mode polymer SPE plate (500 mg/6 mL/well) to give 9.20 mg (17%) of desired product. 1H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1 H), 7.80 (d, J=8.56 Hz, 1 H), 7.60 (s, 1 H), 7.29-7.39 (m, 5 H), 7.15 (d, J=8.56 Hz, 1 H), 6.63 (d, J=11.49 Hz, 1 H), 4.52 (d, J=12.59 Hz, 1 H), 4.05 (d, J=11.62 Hz, 1 H), 2.78 (t, J=12.47 Hz, 1 H), 2.56-2.66 (m, 1 H), 2.17 (s, 1 H), 1.99-2.10 (m, 5 H), 1.77-1.85 (m, 5 H), 1.63-1.69 (m, 2 H), 1.52-1.62 (m, 3 H), 1.17-1.27 (m, 2 H); MS LC-MS [M+H]+=521.5, RT=2.96 min.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([S:20]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)(=[O:22])=[O:21])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[NH2:29][C:30]([CH3:35])([CH3:34])[C:31]([OH:33])=[O:32].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[CH3:18][C:16]1([CH3:19])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([S:20]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)(=[O:22])=[O:21])[CH:14]=2)[NH:9][CH:8]([C:4]2[CH:3]=[C:2]([NH:29][C:30]([CH3:35])([CH3:34])[C:31]([OH:33])=[O:32])[CH:7]=[CH:6][CH:5]=2)[CH2:17]1
Reactant: CC(C)(N)C(=O)O
Reactant: CC1(C)CC(c2cccc(Br)c2)Nc2ccc(S(=O)(=O)N3CCOCC3)cc21
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(Nc1cccc(C2CC(C)(C)c3cc(S(=O)(=O)N4CCOCC4)ccc3N2)c1)C(=O)O
Temperature: 25 °C
Yield: 55.9 %

Procedure:
A mixture solution of 2-(3-bromo-phenyl)-4,4-dimethyl-6-(morpholine-4-sulfonyl)-1,2,3,4-tetrahydro-quinoline (150 mg, 0.33 mmol), copper(I) iodide (20 mg, 0.1 mmol), 2-amino-2-methyl-propionic acid (135 mg, 1.3 mmol) and potassium carbonate (110 mg, 1.0 mmol) in dimethyl sulfoxide (2.0 mL) was stirred at 120° C. for 16 h. Then the reaction mixture was cooled to room temperature and extracted with ethyl acetate (70 mL×2), washed with water (30 mL×3) and saturated aqueous ammonium chloride solution (30 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-{3-[4,4-dimethyl-6-(morpholine-4-sulfonyl)-1,2,3,4-tetrahydro-quinolin-2-yl]-phenylamino}-2-methyl-propionic acid (90 mg, 56.0%) as a white solid: MS (ESI) M+1=488.0.