Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:9][C:10]([C:12]1[C:13]([CH3:24])=[N:14][O:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=1)=[O:11])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=2)[CH2:32][CH2:31]1)=[O:29])[CH3:26]>>[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36]([C:20]3[CH:21]=[CH:22][C:17]([C:16]4[O:15][N:14]=[C:13]([CH3:24])[C:12]=4[C:10](=[O:11])[NH:9][CH2:1][CH2:2][C:3]4[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=4)=[CH:18][CH:19]=3)=[CH:35][CH:34]=2)[CH2:31][CH2:32]1)=[O:29])[CH3:26]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(=O)NCCc1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(=O)NCCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using 5-(4-bromo-phenyl)-3-methyl-isoxazole-4-carboxylic acid phenethyl-amide and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C@H:12]([CH2:16][CH2:17][S:18][CH3:19])[C:13]([OH:15])=[O:14].[OH:20]O>CO>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C@H:12]([CH2:16][CH2:17][S:18]([CH3:19])=[O:20])[C:13]([OH:15])=[O:14]
Reactant: CSCC[C@H](C(=O)O)N1C(=O)c2ccccc2C1=O
Reactant: OO
Solvent: CO
Product: CS(=O)CC[C@H](C(=O)O)N1C(=O)c2ccccc2C1=O
Temperature: -20 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-2-(1,3-dioxoisoindolin-2-yl)-4-(methylthio)butanoic acid (87.124 g, 312 mmol) from preparation 54 in methanol (750 ml) was added hydrogen peroxide (pre-cooled to −30° C.; 38.9 g, 343 mmol) in methanol (250 ml) at −20° C. The reaction mixture was stirred at −20° C. overnight (by use of a cryostat) then warmed to rt over a further 24 hours then to 30° C. for 5 h, LCMS suggesting 95% conversion. The reaction mixture was evaporated under vacuum to give the title compound as a mixture of diastereoisomers that were progressed directly in preparation 3.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[C:4]=1[NH:5][C:6](=[O:9])[CH2:7][Cl:8].C(N(CC)CC)C>C(OCC)(=O)C.[Pd]>[CH3:2][C:3]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[C:4]=1[NH:5][C:6](=[O:9])[CH2:7][Cl:8]
Reactant: O=C(CCl)Nc1c(CCl)cccc1C(F)(F)F
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1cccc(C(F)(F)F)c1NC(=O)CCl
Reaction time: 19 h
Yield: 88.4 %

Procedure:
A solution of 2.02 g (7.06 mmol) of 2'-(chloromethyl)-6'-(trifluoromethyl)-2-chloroacetanilide and 1.0 ml (7.2 mmol) of triethylamine in 60 ml of ethyl acetate was shaken with 79.8 mg of 10% Pd/C under an initial H2 pressure of 50 psi. After 19 hr., the mixture was filtered and evaporated to give 1.57 g of 2'-methyl-6'-(trifluoromethyl)-2-chloroacetanilide assaying 94.2% (yield 83.3%) and contaminated with 1.3% of overreduced product.
Reaction SMILES: [H][H].[N+:3]([C:6]1[CH:7]=[C:8]([C:23]([O:25][CH3:26])=[O:24])[C:9]2[CH2:10][N:11]([CH:16]([CH2:20][CH2:21][CH3:22])[CH2:17][CH2:18][CH3:19])[C:12](=[O:15])[C:13]=2[CH:14]=1)([O-])=O>CO.[Pd]>[NH2:3][C:6]1[CH:7]=[C:8]([C:23]([O:25][CH3:26])=[O:24])[C:9]2[CH2:10][N:11]([CH:16]([CH2:20][CH2:21][CH3:22])[CH2:17][CH2:18][CH3:19])[C:12](=[O:15])[C:13]=2[CH:14]=1
Reactant: [H][H]
Reactant: CCCC(CCC)N1Cc2c(C(=O)OC)cc([N+](=O)[O-])cc2C1=O
Agent: [Pd]
Solvent: CO
Product: CCCC(CCC)N1Cc2c(C(=O)OC)cc(N)cc2C1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 75.9 %

Procedure:
In an autoclave, 1.52 g of methyl 6-nitro-1-oxo-2-(1-propylbutyl)isoindoline-4-carboxylate are dissolved in 15 cm3 of methanol. 100 mg of 5% palladium-on-carbon in suspension in 1 cm3 of methanol are added. The autoclave is placed under 2 bar of hydrogen pressure and the mixture is stirred for 5 min at a temperature in the vicinity of 25° C. The reaction medium is filtered through a celite pellet. The celite is rinsed using 2×10 cm3 of methanol, then the organic phase is concentrated using a rotary evaporator under reduced pressure (5 kPa). The residual yellow oil is purified by column chromatography (silica 60 column—particle size 15-40 μm—150 g—eluent: 60% cyclohexane/40% ethyl acetate). The fractions are concentrated under reduced pressure (5 kPa). 1.05 g of methyl 6-amino-1-oxo-2-(1-propylbutyl)isoindoline-4-carboxylate are obtained in the form of a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1Cl)[N:8]([CH2:13][CH3:14])[CH:7]=[C:6]([C:15]([OH:17])=[O:16])[C:5]2=[O:18].[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>CN(C=O)C.COCCO.C(O)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[N:8]([CH2:13][CH3:14])[CH:7]=[C:6]([C:15]([OH:17])=[O:16])[C:5]2=[O:18]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(Cl)c(Cl)cc21
Reactant: C1CCNCC1
Solvent: CN(C)C=O
Solvent: COCCO
Solvent: CC(C)O
Product: CCn1cc(C(=O)O)c(=O)c2cc(Cl)c(N3CCCCC3)cc21
Temperature: 110 °C

Procedure:
A solution of 4.3 g of 6,7-dichloro-1-ethyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid and 5.5 cm3 of piperidine in a mixture of 20 cm3 of DMF and 20 cm3 of methyl cellosolve was heated for 5 hours at 110° C. After concentration of the solution in vacuo, the residue was taken up in 50 cm3 of isopropanol. The solid was filtered off and recrystallised from methyl cellosolve (50 cm3). 2.4 g of 6-chloro-1-ethyl-4-oxo-7-piperidino-1,4-dihydro-quinoline-3-carboxylic acid, m.p. 230° C., were obtained.
Reaction SMILES: [NH2:1][C@H:2]1[C:7]([F:9])([F:8])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:10][C:11]1[N:12]=[C:13]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]([C:17]#[N:18])=[N:15][CH:16]=1.[OH-].[Na+].OO.CC(O)=[O:32]>CCO.CS(C)=O>[NH2:1][C@H:2]1[C:7]([F:8])([F:9])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:10][C:11]1[N:12]=[C:13]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]([C:17]([NH2:18])=[O:32])=[N:15][CH:16]=1
Reactant: N#Cc1ncc(N[C@@H]2CCCC(F)(F)[C@@H]2N)nc1Nc1ccccc1
Reactant: CC(=O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCO
Product: NC(=O)c1ncc(N[C@@H]2CCCC(F)(F)[C@@H]2N)nc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound 5-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)-3-(phenylamino)pyrazine-2-carbonitrile (47 mg, 0.136 mmol) was dissolved in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1.0 mL) and aq. H2O2 (30%, 1.0 mL) were added. The mixture was stirred at room temperature for 30 min. HOAc (0.5 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (31 mg). MS 363.3 (M+H); UV 203.6, 248.7, 301.5 nm; t 0.477 min.
Reaction SMILES: [NH2:1][C@H:2]1[C@@H:14]2[C:15](=[O:18])[O:16][CH2:17][C@H:13]2[C@H:12]([C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([OH:27])=[C:21]([O:28][CH3:29])[CH:20]=2)[C:11]2[C:3]1=[CH:4][C:5]1[O:9][CH2:8][O:7][C:6]=1[CH:10]=2.N1C=CN=C1.[Si:35](Cl)([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36].O>CN(C)C=O.CCOCC>[NH2:1][C@H:2]1[C@@H:14]2[C:15](=[O:18])[O:16][CH2:17][C@H:13]2[C@H:12]([C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])=[C:21]([O:28][CH3:29])[CH:20]=2)[C:11]2[C:3]1=[CH:4][C:5]1[O:9][CH2:8][O:7][C:6]=1[CH:10]=2
Reactant: COc1cc([C@@H]2c3cc4c(cc3[C@@H](N)[C@@H]3C(=O)OC[C@@H]23)OCO4)cc(OC)c1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: COc1cc([C@@H]2c3cc4c(cc3[C@@H](N)[C@@H]3C(=O)OC[C@@H]23)OCO4)cc(OC)c1O[Si](C)(C)C(C)(C)C

Procedure:
A solution of 7.4 mmol of the compound of Example 14, 58.8 mmol of imidazole and 13 mmol of tert-butyldimethylsilyl chloride in 225 ml of anhydrous dimethylformarnide is stirred at ambient temperature. After reaction for 17 hours, the mixture is poured into a mixture of water and ether. After exraction with ether, the combined organic phases are dried, filtered and then concentrated under reduced pressure. The residue is subsequently recrystallised from a heptane/benzene mixture enabling the expected product to be isolated.
Reaction SMILES: [C:1]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11](/[N:14]=[N:15]/[C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=O)=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].[CH2:26]([NH2:29])[CH2:27][NH2:28]>CO.O.C(Cl)(Cl)Cl>[NH2:28][CH2:27][CH2:26][NH:29][C:20](=[O:22])[C:19]1[CH:18]=[CH:17][C:16](/[N:15]=[N:14]/[C:11]2[CH:10]=[CH:9][C:8]([CH2:7][NH:6][C:1](=[O:5])[CH2:2][CH2:3][CH3:4])=[CH:13][CH:12]=2)=[CH:25][CH:24]=1
Reactant: CCCC(=O)NCc1ccc(/N=N/c2ccc(C(=O)OC)cc2)cc1
Reactant: NCCN
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCCC(=O)NCc1ccc(/N=N/c2ccc(C(=O)NCCN)cc2)cc1

Procedure:
The solution of compound 10 (170 mg, 0.5 mmol) and ethylenediamine (601 mg, 10 mmol) in methanol (10 mL), water (5 mL) and chloroform (2.5 mL) was refluxed for 24 h. The solvents were evaporated, the residue dissolved in aqueous potassium hydroxide (15 mL, 1 M), and extracted with methylene chloride (4×15 mL). The combined organic phases were washed with water and brine, dried over magnesium sulfate, and the residue chromatographed on silica gel using chloroform—chloroform:methanol (10%) step-gradient as an eluent to give pure MPD021 (113 mg, 62%) as orange crystals. 1H NMR (400 MHz, DMSO-d6): δ 8.15 (d, J=8.4 Hz, 2H), 7.93-7.86 (m, 4H), 7.46 (d, J=8.4 Hz, 2H), 4.35 (s, 2H), 3.98 (t, J=6.0 Hz, 2H), 3.13 (t, J=6.0 Hz, 2H), 2.06 (t, J=7.2 Hz, 2H), 1.54-1.58 (m, 2H), 0.83 (t, J=7.2 Hz, 3H). 13C NMR (100.61 MHz, DMSO-d6): δ 174.22, 166.43, 155.51, 153.37, 139.21, 137.12, 127.14, 127.09, 122.89, 122.78, 61.11, 43.66, 42.69, 37.04, 19.14, 13.06. HRMS (m/z): [M+H]+ calcd. for C20H25N5O2 368.2081. found 368.2099.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:19][N:18]2[C:10]([C:11]3[NH:12][C:13]([CH:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)=[N:14][C:15]=3[N:16]=[C:17]2Cl)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C-:32]#[N:33].[K+].O>CN(C)C=O>[CH2:1]([C@@H:8]1[CH2:19][N:18]2[C:10]([C:11]3[NH:12][C:13]([CH:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)=[N:14][C:15]=3[N:16]=[C:17]2[C:32]#[N:33])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClC1=Nc2nc(C3CCCC3)[nH]c2C2=N[C@H](Cc3ccccc3)CN12
Reactant: [C-]#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CC1=Nc2nc(C3CCCC3)[nH]c2C2=N[C@H](Cc3ccccc3)CN12
Temperature: 100 °C
Reaction time: 4 h
Yield: 68.6 %

Procedure:
Compound 67a (217 mg, 0.529 mmol) obtained in Example 67 was dissolved in N,N-dimethylformamide (4 mL), to the solution were added cesium carbonate (245 mg, 0.750 mmol, 1.5 equivalents) and potassium cyanide (39 mg, 0.600 mmol, 1.2 equivalents), and the mixture was stirred at 100° C. for 4 hours. To the reaction mixture was added water, and the deposited crystals were collected by filtration to obtain the title compound (125 mg, 73%) as a yellow solid.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1([CH3:12])[CH2:11][CH2:10]1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:13](Br)[CH:14]=C>>[C:1]([NH:5][S:6]([C:9]1([CH2:12][CH:13]=[CH2:14])[CH2:11][CH2:10]1)(=[O:8])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CCBr
Reactant: CC(C)(C)NS(=O)(=O)C1(C)CC1
Product: C=CCC1(S(=O)(=O)NC(C)(C)C)CC1
Yield: 97 %

Procedure:
This compound was obtained in 97% yield according to the procedure described in the synthesis of N-tert-butyl-(1-methyl)cyclopropylsulfonamide except 1.25 equivalents of allyl bromide were used as electrophile. The compound was taken directly into the next reaction without purification: 1H NMR (CDCl3) δ 0.83 (m, 2H), 1.34 (s, 9H), 1.37 (m, 2H), 2.64 (d, J=7.3 Hz, 2H), 4.25 (br s, 1H), 5.07-5.10 (m, 2H), 6.70-6.85 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:8](Cl)(Cl)Cl)[NH:5][C:6]=1[Cl:7].ClC1C(Cl)=NC(=C(Cl)Cl)[N:14]=1.Cl.N>C(O)C>[Cl:1][C:2]1[N:3]=[C:4]([C:8]#[N:14])[NH:5][C:6]=1[Cl:7]
Reactant: ClC1=NC(=C(Cl)Cl)N=C1Cl
Reactant: Clc1nc(C(Cl)(Cl)Cl)[nH]c1Cl
Agent: Cl
Agent: N
Solvent: CCO
Product: N#Cc1nc(Cl)c(Cl)[nH]1
Yield: 90 %

Procedure:
25.4 g (0.1 mol) of 4,5-dichloro-2-trichloromethyl-imidazole prepared by treating 4,5-dichloro-2-dichloromethylene-imidazole with dry HCl at -20° to +600° C., were introduced in small portions into 200 ml of ethanol saturated with ammonia, whilst cooling with ice and stirring vigorously. The mixture was stirred for a further 30 minutes at 50° C., the constituents which had not dissolved were then filtered off and the filtrate was evaporated under reduced pressure. The combined residues were dissolved in hot water. On acidifying the solution with dilute hydrochloric acid, the reaction product precipited out. This was filtered off, washed with water and dried. In this way 14.6 g (90% of theory) of 4,5-dichloro-2-cyano-imidazole were obtained and after recrystallisation from toluene this had a melting point of 187°-189° C.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([C:17]([C@H:19]2[CH2:24][N:23]([CH:25]([CH3:27])[CH3:26])[CH2:22][CH2:21][N:20]2[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:18])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>[Pd]>[CH:25]([N:23]1[CH2:22][CH2:21][N:20]([C:28]([O:30][C:31]([CH3:34])([CH3:32])[CH3:33])=[O:29])[C@@H:19]([C:17]([N:14]2[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]2)=[O:18])[CH2:24]1)([CH3:27])[CH3:26]
Reactant: CC(C)N1CCN(C(=O)OC(C)(C)C)[C@@H](C(=O)N2CCN(C(=O)OCc3ccccc3)CC2)C1
Agent: [Pd]
Product: CC(C)N1CCN(C(=O)OC(C)(C)C)[C@@H](C(=O)N2CCNCC2)C1
Reaction time: 16 h
Yield: 97.6 %

Procedure:
To tert-butyl (2R)-2-({4-[(benzyloxy)carbonyl]piperazin-1-yl}carbonyl)-4-isopropylpiperazine-1-carboxylate (660 mg) in ethyl acetatec (20 mL, degassed) was added Pd/C (10%) (200 mg) and the mixture was degassed again. The reaction was placed under an H2 atmosphere and stirred vigorously for 16 h. The reaction was filtered and 500 mg of 10% Pd/C added and place under hydrogen atmosphere and stirred for an additional 5 h. The reaction was filtered through a PTFE filter and evaporated to give the title compound (462 mg) as a solid on further drying.
Reaction SMILES: N1C=CC=CC=1.[OH:7][CH2:8][CH2:9][N:10]1[C:14](=[O:15])[CH:13]([CH3:16])[S:12][CH:11]1[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>>[C:23]([O:7][CH2:8][CH2:9][N:10]1[C:14](=[O:15])[CH:13]([CH3:16])[S:12][CH:11]1[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)(=[O:25])[CH3:24]
Reactant: CC1SC(c2cccnc2)N(CCO)C1=O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCCN1C(=O)C(C)SC1c1cccnc1
Reaction time: 2 h
Yield: 77 %

Procedure:
Pyridine (0.5 ml) was added to a solution of 3-(2-hydroxyethyl)-5-methyl-2-(3-pyridyl)thiazolidin-4-one (0.5 g, 2.1 mmol) in acetic anhydride (2 ml) under cooling with ice. This cooling with ice was further continued for 2 hours. The product mixture was concentrated by evaporation under reduced pressure, and subjected to medium-pressure chromatography (hexaneacetone), giving 3-(2-acetoxyethyl)-5-methyl-2-(3-pyridyl)thiazolidin-4-one (0.45 g, 77% yield). NMR (CDCl3) δ [ppm]; 1.62 (1 H, d, J=7.1 Hz), 1.66 (2 H, d, J=7.1 Hz), 2.06 (3 H, s), 5.74 (1 H, s). IR (CHCl3) [cm-1 ]; 2960, 1740, 1693, 1590, 1579, 1350, 1020.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[CH3:12][N:13]1CCCC1=O.CN>O>[CH3:12][NH:13][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1
Reactant: CN1CCCC1=O
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: CN
Solvent: O
Product: CNc1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 2-chloro-5-trifluoromethylpyridine (18.2) and N-methylpyrrolidone (100 ml), 40% of aqueous methylamine solution (23.3 g) was added, and stirred at room temperature for 3 hours. Water was poured thereinto, and extracted with ethyl acetate 3 times. The combined organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 17.3 g of N-methyl-(5-trifluoromethyl-pyridin-2-yl)-amine.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Cl.[C:10]([O:14][C:15](=[O:28])[CH2:16][CH2:17][NH:18][CH2:19][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])([CH3:13])([CH3:12])[CH3:11].C(N(CC)CC)C>C(#N)C>[C:10]([O:14][C:15](=[O:28])[CH2:16][CH2:17][N:18]([CH2:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[Cl:1])[CH2:19][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)CCNCCC(=O)OC(C)(C)C
Reactant: ClCc1ccccc1Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)CCN(CCC(=O)OC(C)(C)C)Cc1ccccc1Cl
Reaction time: 5 h
Yield: 89.5 %

Procedure:
45.06 g (0.27 mol) of 2-chlorobenzylchloride and 51 g (0.19 mol) of di-tert-butyl-3,3'-iminodipropionate were dissolved in 350 ml of acetonitrile, mixed with 28.3 g (0.28 mol) of triethylamine and refluxed. After 5 hours, 8.85 g (0.06 :mol) of 2-chlorobenzylchloride and 9.34 g (0.09 mol) of triethylamine were again in added. After being refluxed for 15 hours, the reaction mixture was concentrated by evaporation. The residue was taken up in 300 ml of water, 100 ml of HCl 5n and 300 ml of ether. The acidic water phase was made basic with NaOH (20 percent) and extracted three times with 100 ml of ether. 67.7 g (91 percent) of the subtitle compound (noted above) was obtained from the ether phase. Data concerning the compound was:
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)=[N:18]4)=[CH:13][CH:12]=3)=[CH:9][N:8]([C@H:27]3[CH2:30][C@H:29]([CH2:31][OH:32])[CH2:28]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[O:33](S(C1C=CC(C)=CC=1)(=O)=O)[S:34]([C:37]1[CH:43]=[CH:42][C:40]([CH3:41])=[CH:39][CH:38]=1)(=O)=[O:35].O.C([O-])(O)=O.[Na+]>C(Cl)Cl.N1C=CC=CC=1>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)=[N:18]4)=[CH:13][CH:12]=3)=[CH:9][N:8]([C@H:27]3[CH2:28][C@H:29]([CH2:31][O:32][S:34]([C:37]4[CH:43]=[CH:42][C:40]([CH3:41])=[CH:39][CH:38]=4)(=[O:35])=[O:33])[CH2:30]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Cc1ccc(S(=O)(=O)OS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: Nc1ncnc2c1c(-c1ccc3ccc(-c4ccccc4)nc3c1)cn2[C@H]1C[C@H](CO)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@H]2C[C@H](n3cc(-c4ccc5ccc(-c6ccccc6)nc5c4)c4c(N)ncnc43)C2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of trans-{3-[4-amino-5-(2-phenylquinolin-7-yl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutyl}-methanol (105.7 mg, 0.251 mmol) in CH2Cl2 (5 mL) and pyridine (1 mL), cooled in a dry ice/acetone bath, was added a solution of Ts2O (92 mg, 0.28 mmol) in CH2Cl2 (2 mL) over 5 min, then the reaction mixture was warmed up to ambient temperature and stirred for 16 h. More Ts2O (70 mg, 0.21 mmol) was added, and stirring at ambient temperature was continued for 4.5 h. The reaction solution was diltuted with CH2Cl2 (25 mL), water and saturated NaHCO3 sol. were added, the layers were separated, the aqueous layer was extracted with CH2Cl2 (3×25 mL), and the combined CH2Cl2 extracts were washed with water and brine and dried over MgSO4. Filtration and concentration after adding toluene (10 mL; to remove remaining pyridine as azeotrop) gave the desired product. No purification before the next step. 1H NMR (CDCl3, 400 MHz) δ 2.43-2.51 (m, 2H), 2.47 (s, 2H), 2.67-2.86 (m, 3H), 4.22 (d, J=6.6 Hz, 2H), 5.19 (brs, 2H), 5.36 (quint, J=8.0 Hz, 1H), 7.29 (s, 1H), 7.37-7.41 (m, 2H), 7.46-7.51 (m, 1H), 7.52-7.58 (m, 2H), 7.68 (dd, J=1.8, 8.4 Hz, 1H), 7.83-7.87 (m, 2H), 7.92 (d, J=8.6 Hz, 1H), 7.93 (d, J=8.4 Hz, 1H), 8.17-8.22 (m, 2H), 8.25-8.29 (m, 2H), 8.33 (s, 1H). MS (ES+): m/z 576.1 (54) [MH+], 338.2 (10) [MH+-cyclobutene-CH2OTs]. HPLC: tR=2.8 min (OpenLynx, nonpolar—5 min).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18](O)=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:25][CH2:24]1)=[O:22].[CH2:35]([S:37]([NH2:40])(=[O:39])=[O:38])[CH3:36]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([NH:40][S:37]([CH2:35][CH3:36])(=[O:39])=[O:38])=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:24][CH2:25][CH:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:27][CH2:28]1)=[O:22]
Reactant: Cc1ccccc1Nc1c(C(=O)N2CCC(c3ccccc3)CC2)cnc2c(C(=O)O)cnn12
Reactant: CCS(N)(=O)=O
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3ccccc3C)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 58.2 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2-methylphenylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.30 g, 0.66 mmol) obtained in step 2 and ethanesulfonamide (0.35 g, 3.30 mmol), the title compound (0.21 g, 58%) was obtained.
Reaction SMILES: [NH2:1][C@@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N+:13]([O-])([O-:15])=[O:14].[K+]>>[N+:13]([C:7]1[CH:8]=[CH:9][C:4]([CH2:3][C@H:2]([C:10]([OH:12])=[O:11])[NH2:1])=[CH:5][CH:6]=1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])[O-]
Reactant: N[C@H](Cc1ccccc1)C(=O)O
Agent: [K+]
Product: N[C@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O

Procedure:
D-Phenylalanine (12.0 g, 73 mmol) and potassium nitrate (11 g, 109 mmol) were loaded into a teflon HF apparatus commonly used for the deprotection of peptides. The mixture was treated with liquid HF at approximately 0° C. for one hour. After removal of the HF by vacuum, the residue was dissolved in water and treated with concentrated ammonia until pH 6. The precipitate was recrystallized from hot water. Yield 9.31 g (61%) of a nearly white solid, mp 236.5°-237° C., [α]D25 =-8.63° (c=1.7, 1N HCl).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]#[N:9])[CH:3]=1.[NH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.C([O-])([O-])=O.[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[N:13]1[CH:14]=[CH:15][CH:16]=[C:11]([NH:10][C:2]2[CH:7]=[CH:6][N:5]=[C:4]([C:8]#[N:9])[CH:3]=2)[CH:12]=1
Reactant: Nc1cccnc1
Reactant: N#Cc1cc(Cl)ccn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: N#Cc1cc(Nc2cccnc2)ccn1
Temperature: 100 °C
Yield: 100 %

Procedure:
4-Chloro-2-pyridinecarbonitrile (1 g, 7 mmol, 1 eq), 3-aminopyridine (0.815 mg, 8.66 mmol, 1.20 eq), Cs2CO3 (3.29 g, 10.1 mmol, 1.40 eq), Pd2(dba)3 (332 mg, 0.577 mmol, 0.0800 eq), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (501 mg, 0.866 mmol, 0.120 eq) and dioxane (18 mL) were added to a microwave vial. The vial was purged with argon, capped and heated at 100° C. for 18 h. After cooling the reaction was filtered over a plug of celite and the plug was washed with 5% MeOH/CH2Cl2. The solvents were removed in vacuo and the crude mixture was purified by flash chromatography on silica gel afforded 1.374 g (97%) of the title compound as an orange solid: 1H NMR (400 MHz, CDCl3) δ1H NMR (400 MHz, DMSO-d6) δ 9.42 (s, 1H), 8.49 (d, J=2.6 Hz, 1H), 8.34-8.31 (m, 2H), 7.73 (dq, J=1.3, 8.2 Hz, 1H), 7.43-7.40 (m, 1H), 7.39 (d, J=2.3 Hz, 1H), 7.13 (dd, J=2.4, 5.9 Hz, 1H); ES-MS [M+1]+:197.1.