Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[CH3:42][O:43][C:44]1[CH:49]=[C:48]([CH3:50])[CH:47]=[CH:46][C:45]=1[S:51](Cl)(=[O:53])=[O:52]>C(#N)C>[CH3:42][O:43][C:44]1[CH:49]=[C:48]([CH3:50])[CH:47]=[CH:46][C:45]=1[S:51]([O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34])(=[O:52])=[O:53]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: COc1cc(C)ccc1S(=O)(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1cc(C)ccc1S(=O)(=O)Oc1ccc(-c2cc3cc(CN4CCCCC4)ccc3n2C(=O)OC(C)(C)C)c2c1CNC2=O
Yield: 50.1 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0324 g, 0.0702 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0590 mL, 0.421 mmol) and 2-methoxy-4-methylbenzenesulfonyl chloride (0.0460 g, 0.211 mmol) to obtain 4-(2-methoxy-4-methylbenzenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0227 g, yield 50%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH:19]4[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]4)=[CH:15][CH:16]=3)[CH2:11][CH2:10][C:9]2=[O:32])=[CH:4][CH:3]=1.[ClH:33]>C(OCC)(=O)C.C(O)C>[ClH:33].[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH:19]4[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]4)=[CH:15][CH:16]=3)[CH2:11][CH2:10][C:9]2=[O:32])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc3c(c2)CCC(=O)N3c2ccc(F)cc2)CC1
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C1CCc2cc(OC3CCNCC3)ccc2N1c1ccc(F)cc1
Reaction time: 16 h
Yield: 99 %

Procedure:
To a solution of tert-butyl 4-(1-(4-fluorophenyl)-2-oxo-1,2,3,4-tetrahydroquinolin-6-yloxy)piperidine-1-carboxylate prepared in Example 7-(2) (6.0 g) in a mixture of ethyl acetate (12 mL) and ethanol (4 mL), 4M hydrochloric acid in ethyl acetate (10 mL) was added dropwise at room temperature and stirred for 16 hours. The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate and stirred at room temperature for 1 hour. The precipitate was collected by filtration and dried to give the titled compound (5.1 g, 99%) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)=[N:4][NH:5][CH:6]=1.C1C(=O)N([I:20])C(=O)C1>CN(C)C=O.[O-]S([O-])(=S)=O.[Na+].[Na+]>[Cl:1][C:2]1[C:3]([CH:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)=[N:4][NH:5][C:6]=1[I:20]
Reactant: Clc1c[nH]nc1C1CCOCC1
Reactant: O=C1CCC(=O)N1I
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1c(C2CCOCC2)n[nH]c1I
Temperature: 80 °C
Reaction time: 8 h
Yield: 80.5 %

Procedure:
To a solution of 4-chloro-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole (compound 294.3, 3.00 g, 16.1 mmol) in N,N-dimethylformamide (20 mL) was added NIS (7.26 g, 32.3 mmol). The reaction mixture was stirred overnight at 80° C. The reaction mixture was diluted with 50 mL Na2S2O3 (sat.). The aqueous phase was extracted with 3×100 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1/8-1/5) as the eluent to furnish 4.05 g (81%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].C(N(CC)CC)C.[Cl:12][C:13]([Cl:18])([Cl:17])[C:14](Cl)=[O:15]>C(Cl)Cl>[Cl:12][C:13]([Cl:18])([Cl:17])[C:14]([NH:4][CH2:1][CH:2]=[CH2:3])=[O:15]
Reactant: C=CCN
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCNC(=O)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 95.4 %

Procedure:
To a stirred solution of allylamine (5 g, 88 mmol) and triethylamine (9.6 g, 95 mmol) in CH2Cl2 (200 mL) at −10° C. was added trichloroacetyl chloride (16.7 g, 92 mmol). The resulting solution was allowed to gradually warm to RT and stir for 24 h. The reaction solution was extracted with brine (satd., 100 mL) and dried (Na2SO4) to yield 17 g (96%) of the title compound as a white solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:8]=[C:9]([C:11]#[N:12])[N:10]=1)=[O:5])C.[OH-].[K+:22]>C(O)C>[K+:22].[C:11]([C:9]1[N:10]=[C:6]([C:4]([O-:5])=[O:3])[N:7]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:18])([CH3:19])[CH3:20])[CH:8]=1)#[N:12]
Reactant: CCOC(=O)c1nc(C#N)cn1COCC[Si](C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Reaction time: 0.17 h
Yield: 100 %

Procedure:
To a solution of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid ethyl ester (0.40 g, 1.3 mmol) (as prepared in the previous step) in ethanol (3 mL) was added a solution of 6M KOH (0.2 mL) and the reaction was stirred for 10 min and then concentrated to give 0.40 g (100%) of the title compound as a yellow solid: 1H-NMR (CD3OD; 400 MHz): δ 7.98 (s, 1H), 5.92 (s, 2H), 3.62 (m, 2H), 0.94 (m, 2H), 0.00 (s, 9H). Mass spectrum (ESI-neg, m/z): Calcd. for C11H16KN3O3Si, 266.1 (M-K). found 266.0.
Reaction SMILES: C(O[C@@H]1[C@@H](OC(=O)C)[C@H](OC(=O)C)[C@@H](O/C(/C(OCC)=O)=C\C2C=CC=CC=2[F:28])O[C@H]1COC(=O)C)(=O)C.Br[C:40]1[CH:41]=[C:42]([CH2:46][C:47](=[O:53])[C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH:43]=[CH:44][CH:45]=1.[H-].[Na+].[Br-].[C:57]([O:60][C@@H:61]1[C@@H:67]([O:68][C:69](=[O:71])[CH3:70])[C@@H:66]([O:72][C:73](=[O:75])[CH3:74])[C@@H:65]([CH2:76][O:77][C:78](=[O:80])[CH3:79])[O:64][C@@H:62]1O)(=[O:59])[CH3:58]>>[C:73]([O:72][C@H:66]1[C@@H:67]([O:68][C:69](=[O:71])[CH3:70])[C@H:61]([O:60][C:57](=[O:59])[CH3:58])[C@@H:62]([O:53]/[C:47](/[C:48]([O:50][CH2:51][CH3:52])=[O:49])=[CH:46]\[C:42]2[CH:43]=[CH:44][CH:45]=[C:40]([F:28])[CH:41]=2)[O:64][C@H:65]1[CH2:76][O:77][C:78](=[O:80])[CH3:79])(=[O:75])[CH3:74]
Reactant: CC(=O)OC[C@H]1O[C@H](O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: CCOC(=O)/C(=C/c1ccccc1F)O[C@H]1O[C@@H](COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CCOC(=O)C(=O)Cc1cccc(Br)c1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)/C(=C/c1cccc(F)c1)O[C@H]1O[C@@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 24 %

Procedure:
The title compound was prepared as described for C4 using Ethyl 3-(3-bromophenyl)-2-oxopropanoate B17 (100 mg, 0.369 mmol), sodium hydride (9.74 mg, 0.406 mmol) and 2,3,4,6-tetra-O-acetyl-α-D-galactose bromide (152 mg, 0.369 mmol). The resulting compound was isolated in the form of white solid in 24% yield.
Reaction SMILES: [C:1]1([N:7]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][S:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:37].C(=O)([O-])[O-].[NH4+:42].[NH4+].C(OCC)(=O)C.C(O)C.N>C(O)C>[ClH:37].[C:1]1([N:7]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][S:18][C:19]4[CH:24]=[CH:23][C:22]([C:25](=[NH:42])[NH2:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [NH4+]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CSc1ccc(C#N)cc1)n2C)c1ccccc1
Agent: Cl
Agent: N
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CSc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Yield: 90 %

Procedure:
Prepared analogously to Example 27 from 1-methyl-2-[(4-cyanophenyl)thiomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide, and ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 90% of theory, C28H29N5O3S (515.64) Rf value:0.24 (silica gel; ethyl acetate/ethanol/ammonia=50:45:5) ##EQU11##
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[C:8]([C:9]([O:11][CH2:12]C)=[O:10])=[C:7](Cl)[C:6]([C:15]([O:17][CH3:18])=[O:16])=[C:5]([C:19]([F:22])([F:21])[F:20])[N:4]=1.[CH2:25]([NH:28][CH2:29][CH2:30][CH3:31])[CH2:26][CH3:27].[CH3:32]N(C=O)C>>[CH2:25]([N:28]([CH2:29][CH2:30][CH3:31])[C:7]1[C:6]([C:15]([O:17][CH3:18])=[O:16])=[C:5]([C:19]([F:20])([F:22])[F:21])[N:4]=[C:3]([C:2]([F:24])([F:23])[F:1])[C:8]=1[C:9]([O:11][CH2:12][CH3:32])=[O:10])[CH2:26][CH3:27]
Reactant: CCCNCCC
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)F)c(C(=O)OC)c1Cl
Reactant: CN(C)C=O
Product: CCCN(CCC)c1c(C(=O)OC)c(C(F)(F)F)nc(C(F)(F)F)c1C(=O)OCC

Procedure:
This compound was prepared as described in Example 37: 7.0 g (0.018 mol) of product of Example 27, 5.1 ml (0.037 mol) of dipropylamine in 30 ml of DMF were reacted at room temperature affording 7.7 g of solid which was recrystallized in hot hexane to give 2.19 g of product as a tan solid; mp 65°-66° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8][CH2:9][C:10]1[CH:27]=[CH:26][CH:25]=[CH:24][C:11]=1[NH:12][C:13](=[O:23])[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=1>[Pd].C(O)C>[NH2:20][C:17]1[CH:16]=[CH:15][C:14]([C:13]([NH:12][C:11]2[CH:24]=[CH:25][CH:26]=[CH:27][C:10]=2[CH2:9][CH2:8][CH:3]2[CH2:4][CH2:5][CH2:6][CH2:7][N:2]2[CH3:1])=[O:23])=[CH:19][CH:18]=1
Reactant: CN1CCCCC1CCc1ccccc1NC(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CN1CCCCC1CCc1ccccc1NC(=O)c1ccc(N)cc1

Procedure:
Reduction of 2'-[2-(1-methyl-2-piperidyl)ethyl]-4-nitrobenzanilide (6.5 g., 0.018 mole) in 100 ml. of ethanol employing 2 g. of palladium on carbon catalyst (10%) according to Example 2a affords 4amino-2'-[2-(1-methyl-2-piperidyl)-ethyl]benzanilide. Crystallization of the product from acetonitrile provides the analytically pure substance, m.p. 147°-148.5°C. (corr.).
Reaction SMILES: Cl.OC[C:4]1[NH:5][CH:6]=[CH:7][N:8]=1.[C:9]1([C:15](Cl)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CN(C)[CH:31]=[O:32]>C(N(CC)CC)C>[OH:32][CH2:31][C:6]1[N:5]=[CH:4][N:8]([C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1
Reactant: OCc1ncc[nH]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CN(C)C=O
Agent: Cl
Solvent: CCN(CC)CC
Product: OCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
3.99 g(29.6 mmol) of hydroxymethylimidazole hydrochloride was dissolved in a mixture of 30 ml of dimethylformamide and 10 ml triethylamine, and then a solution of 9.35 g(33.5 mmol) of triphenylmethyl chloride in 110 ml of dimethylformamide was added slowly thereto. After 2 hours, 500 ml of ice water was added to the reaction mixture to obtain a solid. This solid was recrystallized from dioxane to give 8.82 g(Yield 87%) of the title compound.
Reaction SMILES: [CH3:1][C@@H:2](N(C)C)[C@@H:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:14][C:15](C)([O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1)[C:16]#C.C1(C=O)CCCCC1>[O-]S(C(F)(F)F)(=O)=O.[Zn+2].[O-]S(C(F)(F)F)(=O)=O.C(N(CC)CC)C>[CH:4]1([C@@H:3]([OH:10])[C:2]#[C:1][C:15]([CH3:16])([O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[CH3:14])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: C#CC(C)(C)OC1CCCCO1
Reactant: C[C@H]([C@@H](O)c1ccccc1)N(C)C
Agent: O=CC1CCCCC1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Zn+2]
Solvent: CCN(CC)CC
Product: CC(C)(C#C[C@H](O)C1CCCCC1)OC1CCCCO1
Temperature: 125 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
A flask is charged with zinc triflate (545 mg, 3 mol % based on the aldehyde compound mentioned blow). Vacuum (0.5 hPa or lower) is applied and the flask is heated to 125° C. for 2 hours. The flask is cooled to 23° C., the vacuum released and (+)-N-methylephedrine (296 mg, 3.3 mol % based on the aldehyde compound mentioned below) is added. Vacuum (0.5 hpa or lower) is applied for 0.5 hour and then released. To the flask, triethylamine (607 mg, 12 mol % based on the aldehyde compound mentioned below) and 2-(1,1-dimethyl-prop-2-ynyloxy)-tetrahydropyran as the alkyne compound (55 mmol, 110 mol % based on the aldehyde compound mentioned below) are added, and stirred for 0.25 hour at 25-30° C. And then cyclohexanecarboxaldehyde (50 mmol) as the aldehyde compound is added. The reaction mixture is stirred at 50° C. for 20 hours. Then, the distillation under reduced pressure gives (R)-1-cyclohexyl-4-methyl-4-tetrahydropyranyloxy-2-pentyn-1-ol, bp 130° C. (0.04 hPa), a colorless oil, in 82% yield.
Reaction SMILES: Br[C:2]1[N:6]=[C:5]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[S:4][N:3]=1.[CH3:15][S:16]([C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)(=[O:18])=[O:17].[F-].[Cs+].O1CCOCC1>[Pd].O>[CH3:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([C:2]2[N:6]=[C:5]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[S:4][N:3]=2)=[CH:21][CH:20]=1)(=[O:18])=[O:17]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)Nc1nc(Br)ns1
Agent: [Pd]
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1nc(-c2ccc(S(C)(=O)=O)cc2)ns1
Temperature: 80 °C

Procedure:
To a mixture of tert-butyl 3-bromo-1,2,4-thiadiazol-5-ylcarbamate (1.90 g, 6.78 mmol), 4-(methylsulfonyl)phenylboronic acid (2.07 g, 10.3 mmol), cesium fluoride (2.09 g, 13.8 mmol), and the palladium catalyst (0.271 g, 0.383 mmol) was added dioxane (20 mL) and water (2 mL). The reaction mixture was degassed by bubbling nitrogen through the solution for 5 min and the reaction mixture was heated to 80° C. for 3 h. The reaction mixture was diluted with EtOAc, and the organic phase was washed with saturated NH4Cl (1×), brine (1×), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (eluted with 10% to 50% EtOAc in hexanes) gave tert-butyl 3-(4-(methylsulfonyl)phenyl)-1,2,4-thiadiazol-5-ylcarbamate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[N:9][CH:8]=[CH:7]2.[Br:12]Br.Cl>[N+](C1C=CC=CC=1)([O-])=O.CCOCC>[Br:12][C:7]1[C:6]2[C:11](=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=2)[CH:10]=[N:9][CH:8]=1
Reactant: BrBr
Reactant: Clc1cccc2ccncc12
Agent: Cl
Solvent: O=[N+]([O-])c1ccccc1
Solvent: CCOCC
Product: Clc1cccc2c(Br)cncc12
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of 8-chloroisoquinoline (1.0 g, 6.1 mmol) in nitrobenzene (20 mL) at 180° C. was added bromine (0.35 mL, 6.7 mmol) over 10 min. Heating and stirring were continued for 2 hours. The mixture was allowed to cool to about 80° C., then 2M HCl in Et2O (5 mL) was added, followed by Et2O (5 mL) and hexanes (60 mL). The resulting slurry was filtered, washed with hexane and dried. The collected solid was dissolved in water, then the solution was adjusted to pH 9 with Na2CO3 (aq). The solution was extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with 0-20% EtOAc/hexanes to afford the title compound as a white solid: 1H NMR (500 MHz, CDCl3): δ 9.62 (s, 1H); 8.83 (s, 1H); 8.13 (t, J=5.0 Hz, 1H); 7.74 (d, J=5.0 Hz, 2H). LC6: 4.08 min, (M+H): 242.
Reaction SMILES: [F:1][C:2]([S:5]([O:8]S(C(F)(F)F)(=O)=O)(=[O:7])=[O:6])([F:4])[F:3].O[C:17]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][O:28][CH3:29])=[CH:21][C:18]=1[CH:19]=[O:20].CC1C=CC=C(C)N=1>ClCCl>[F:1][C:2]([F:4])([F:3])[S:5]([O:8][C:17]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][O:28][CH3:29])=[CH:21][C:18]=1[CH:19]=[O:20])(=[O:7])=[O:6]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COCCOc1ccc(O)c(C=O)c1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: COCCOc1ccc(OS(=O)(=O)C(F)(F)F)c(C=O)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Trifluoromethyl sulphonic anhydride (3.88 ml) was added dropwise over a period of 10 minutes to a stirred solution of 2-hydroxy-5-(2-methoxyethoxy)benzaldehyde (4.11 g) and 2,6-dimethylpyridine (2.67 ml) in dichloromethane (20 ml) at 0° C. under an atmosphere of argon. After stirring at room temperature for 16 hours, the mixture was added to ice (100 g). The organic phase was separated, washed with 5% aqueous sodium carbonate solution (2×10 ml), dried (MgSO4) and evaporated to give an oil which was purified by flash column chromatography on silica gel using dichloromethane as eluent to give 2-trifluoromethylsulphonyloxy-5-(2-methoxyethoxy)benzaldehyde (2.2 g) as an oil; NMR(CDCl3): 3.45(3H,s), 3.78(2H,m), 4.19(2H,m), 7.3(2H,m), 7.48(1H,d) and 10.23(1H,d); m/z 329(M+H).
Reaction SMILES: [CH:1]([S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14]1[N:19]2[N:20]=[CH:21][CH:22]=[C:18]2[N:17]=[C:16](S(C)(=O)=O)[N:15]=1)(=[O:6])=[O:5])([CH3:3])[CH3:2].[CH:27]([O:30][C:31]1[CH:37]=[C:36]([CH:38]2[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]2)[C:35]([CH3:45])=[CH:34][C:32]=1[NH2:33])([CH3:29])[CH3:28].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)(C)C>[CH:27]([O:30][C:31]1[CH:37]=[C:36]([CH:38]2[CH2:39][CH2:40][N:41]([CH3:44])[CH2:42][CH2:43]2)[C:35]([CH3:45])=[CH:34][C:32]=1[NH:33][C:16]1[N:15]=[C:14]([NH:13][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:4]([CH:1]([CH3:3])[CH3:2])(=[O:6])=[O:5])[N:19]2[N:20]=[CH:21][CH:22]=[C:18]2[N:17]=1)([CH3:29])[CH3:28]
Reactant: Cc1cc(N)c(OC(C)C)cc1C1CCN(C)CC1
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(S(C)(=O)=O)nc2ccnn12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Product: Cc1cc(Nc2nc(Nc3ccccc3S(=O)(=O)C(C)C)n3nccc3n2)c(OC(C)C)cc1C1CCN(C)CC1
Temperature: 150 °C
Reaction time: 3 h

Procedure:
To a suspension of N-(2-(isopropylsulfonyl)phenyl)-2-(methysulfonyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine (0.5 mmol) in 1 mL of isopropanol, was added 2-isopropoxy-5-methyl-4-(1-methylpiperidin-4-yl)aniline (0.5 mmol) and 4-methylbenzenesulfonic acid (1 mmol). The suspension was stirred at 150° C. for 3 hours. After cooling at RT and work-up, the residue was purified using a preparative HPLC to afford N2-(2-isopropoxy-5-methyl-4-(1-methylpiperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine. 1H NMR (MeOD, 400 MHz) δ 8.51-8.54 (d, 1H), 7.94-8.04 (m, 2H), 7.35-7.47 (m, 3H), 6.90 (s, 1H), 6.34-6.35 (d, 1H), 4.54-4.60 (m. 1H), 3.82-3.85 (m, 2H), 3.23-3.30 (m, 1H), 2.91-3.01 (m, 6H), 2.25-2.33 (m, 5H), 2.03-2.06 (m, 2H), 1.33-1.35 (d, 6H), 1.26-1.28 (d, 6H); MS (ES+); 578.28 (M+1)+.
Reaction SMILES: C(N(CC)CC)C.[C:8](OC(=O)C)(=[O:10])[CH3:9].[NH2:15][C:16]1([CH2:21][C:22]([OH:24])=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17]1.CCOC(C)=O>CN(C1C=CN=CC=1)C.C1COCC1>[C:8]([NH:15][C:16]1([CH2:21][C:22]([OH:24])=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17]1)(=[O:10])[CH3:9]
Reactant: CC(=O)OC(C)=O
Reactant: NC1(CC(=O)O)CCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)NC1(CC(=O)O)CCCC1

Procedure:
Triethylamine (1.2 mL, 8.4 mmol), acetic anhydride (0.8 mL, 8.4 mL) and DMAP (10 mg, 0.09 mmol) are subsequentially added to a suspension of (1-amino-cyclopentyl)-acetic acid (1.00 g, 5.6 mmol) in THF (30 mL). After heating at 60° C. for 2 h AcOEt is added and the organic phase is washed with 1N HCl. Drying (Na2SO4), filtration and evaporation of the solvent yields the desired product. MS (LC-MS): [M+H]+=186.1. tR (HPLC, Waters Symmetry C18 column, 80-95% CH3CN/H2O/3.5 min, 95% CH3CN/H2O, 2 min, CH3CN and H2O containing 0.1% TFA, flow: 0.6 mL/min): 0.53 min.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].C(N(CC)CC)C.[C:12]([NH:16][NH:17][P:18]([O:22][CH3:23])([O:20][CH3:21])=[O:19])([CH3:15])([CH3:14])[CH3:13]>C(Cl)Cl>[C:12]([N:16]([C:1](=[O:3])[CH3:2])[NH:17][P:18]([O:20][CH3:21])([O:22][CH3:23])=[O:19])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(=O)Cl
Reactant: COP(=O)(NNC(C)(C)C)OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COP(=O)(NN(C(C)=O)C(C)(C)C)OC
Temperature: -20 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
Acetylchloride (10.8 g) was added dropwise to a stirred solution of triethylamine (13.9 g) and 1-t-butyl-2-dimethoxyphosphoryl hydrazine (9.0 g) in methylenechloride (120 ml) maintained at -20° C. After the addition was complete, the temperature was allowed to rise to 0° C. and kept at this temperature for 1 hour. The mixture was then allowed to warm up to ambient temperature during 2 hours, and the content of the reaction vessel was then stripped to dryness on the rotary evaporator. The residue was extracted with diethylether and the organic extracts dried over magnesium sulfate, filtered and evaporated to dryness, leaving an oil which was subjected to high vacuum for several hours yielding 10.4 g of product.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1)[C:9](=[O:22])[C@@:8]12[CH2:24][C@@H:23]1[C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)=[O:4].[OH-].[Li+]>CO.C1COCC1.O>[F:21][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[CH2:14][N:10]1[C:11]2[C:7](=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:13][CH:12]=2)[C@@:8]2([CH2:24][C@@H:23]2[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:9]1=[O:22]
Reactant: COC(=O)c1ccc2c(c1)[C@@]1(C[C@@H]1c1ccc(F)cc1)C(=O)N2Cc1cccc(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(c1)[C@@]1(C[C@@H]1c1ccc(F)cc1)C(=O)N2Cc1cccc(F)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 20.7 %

Procedure:
To a solution of (1R,2S) and (1S,2R)-methyl-1′-(3-fluorobenzyl)-2-(4-fluorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-5′-carboxylate (50 mg) in methanol (5 mL), THF (5 mL) and water (1 mL) was added lithium hydroxide (50 mg) at room temperature. The mixture was heated to 60° C. and stirred at 60° C. for 3 hours. HPLC monitored the reaction finished. The solvent was removed under reduced pressure. Purification by preparative HPLC gave the title compound as white powder (10 mg). LC/MS m/e calcd. for C24H17F2lNO3: 405, observed (M+H)+: 406.2 1H NMR (400 MHz, MeOD) δppm 7.83 (dd, J=8.34, 1.52 Hz, 1 H) 7.24-7.38 (m, 5 H) 7.15 (d, J=2.02 Hz, 1 H) 7.18 (d, J=7.83 Hz, 2 H) 7.06 (t, J=8.72 Hz, 2 H) 6.99 (d, J=8.08 Hz, 1 H) 6.75 (d, J=1.52 Hz, 1 H) 5.17 (s, 2 H) 2.24-2.35 (m, 2 H); MS calcd. C24H17F2NO3 406, obsd. (ESI+) [(M+H)+] 406.4.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([Cl:15])=[N:13][CH:14]=1.O>C(Cl)(Cl)(Cl)Cl>[Cl:15][C:12]1[N:13]=[CH:14][C:9]([CH2:8][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[CH:10][CH:11]=1
Reactant: Clc1ccc(CBr)cn1
Reactant: C1COCCN1
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc(CN2CCOCC2)cn1
Temperature: 25 °C
Reaction time: 6 h
Yield: 21 %

Procedure:
Morpholine (7.0 g, 8.8 mmol) was added to the solution of 5-bromomethyl-2-chloro-pyridine in carbon tetrachloride (20 mL) and stirred at room temperature for 6 h. Water was added to the reaction mixture and the separated organic layer was washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford the crude product. Purification by column chromatography using silica gel (60-120 mesh) and ethyl acetate as eluent afforded 4-(6-chloro-pyridin-3-yl-methyl)-morpholine (1.2 g, 21%) as a brown oily liquid.