Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:17]2[C:12]([CH:13]=[N:14][C:15](OS(C(F)(F)F)(=O)=O)=[N:16]2)=[CH:11][CH:10]=1.[NH2:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[CH2:32][N:31]([CH2:36][C:37]([NH2:39])=[O:38])[CH2:30]2>COC(O)CC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:17]2[C:12]([CH:13]=[N:14][C:15]([NH:26][C:27]3[CH:28]=[C:29]4[C:33](=[CH:34][CH:35]=3)[CH2:32][N:31]([CH2:36][C:37]([NH2:39])=[O:38])[CH2:30]4)=[N:16]2)=[CH:11][CH:10]=1
Reactant: NC(=O)CN1Cc2ccc(N)cc2C1
Reactant: COc1ccccc1-c1ccc2cnc(OS(=O)(=O)C(F)(F)F)nn12
Agent: CCC(O)OC
Product: COc1ccccc1-c1ccc2cnc(Nc3ccc4c(c3)CN(CC(N)=O)C4)nn12

Procedure:
Trifluoro-methanesulfonic acid 7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl ester (0.111 g, 0.298 mmol) and 2-(5-Amino-1,3-dihydro-isoindol-2-yl)-acetamide (0.077 g, 0.40 mmol) were reacted in an analogous manner to Example 908D at 50° C. for 16 h in methoxypropanol. Pale yellow solid was filtered off, washed with water. Found to be pure product (35 mg, 28%). LCMS=414.9 (M+H), HPLC rt=2.256 min, purity=99%. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.40 (s, 1H), 8.95 (s, 1H), 7.78 (d, J=7.4 Hz, 1H), 7.75 (s, 1H), 7.47 (dd, J=7.6 Hz, 1H), 7.39 (d, J=8.6 Hz, 1H), 7.32 (s, 1H), 7.21 (d, J=8.6 Hz, 1H), 7.13-7.05 (m, 3H), 6.94 (d, J=4.6 Hz, 1H), 6.90 (d, J=4.6 Hz, 1H), 3.89 (s, 4H0, 3.78 (s, 3H), 3.27 (s, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([O:17][C@@H:18]([CH3:22])[CH2:19][O:20][CH3:21])[CH:16]=1)[C:5]([NH:7][C:8]1[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=1)=[O:6].C(=O)([O-])[O-].[K+].[K+].[Cl:29][C:30]1[CH:31]=[C:32]([S:37]([N:40]([CH3:42])[CH3:41])(=[O:39])=[O:38])[CH:33]=[CH:34][C:35]=1F>C(#N)C>[Cl:29][C:30]1[CH:31]=[C:32]([S:37]([N:40]([CH3:42])[CH3:41])(=[O:39])=[O:38])[CH:33]=[CH:34][C:35]=1[O:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([O:17][C@@H:18]([CH3:22])[CH2:19][O:20][CH3:21])[CH:16]=1)[C:5]([NH:7][C:8]1[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=1)=[O:6]
Reactant: CN(C)S(=O)(=O)c1ccc(F)c(Cl)c1
Reactant: COC[C@H](C)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(=O)(=O)N(C)C)cc2Cl)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 160 °C
Yield: 688.3 %

Procedure:
To a solution of 3-hydroxy-5-[(1S)-2-methoxy-(1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide (152 mg, 0.50 mmol) in acetonitrile (3.5 mL) was added potassium carbonate (345 mg, 2.5 mmol) and 3-chloro-4-fluoro-N,N-dimethylbenzenesulfonamide (237 mg, 1.0 mmol) and the mixture was heated under microwave conditions at 160° C. for 2 hours. The mixtures were filtered and evaporated. The residue was purified by flash chromatography (eluting with an increasing gradient of 60 to 100% ethyl acetate in isohexane) to afford the title compound (1.8 g, 98%).
Reaction SMILES: [CH:1]1([NH:5][C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13](=[O:34])[CH2:14][O:15][C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[C:18]([C:27]([NH:29][CH2:30][C:31](O)=[O:32])=[O:28])[CH:17]=2)=[O:7])[CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:68]([O:70][C:71]([N:73]1[CH2:78][CH2:77][NH:76][CH2:75][CH2:74]1)=[O:72])[CH3:69]>CN(C=O)C.ClCCl>[CH2:68]([O:70][C:71]([N:73]1[CH2:74][CH2:75][N:76]([C:31](=[O:32])[CH2:30][NH:29][C:27]([C:18]2[CH:17]=[C:16]([O:15][CH2:14][C:13]([N:9]3[CH2:10][CH2:11][CH2:12][C@H:8]3[C:6](=[O:7])[NH:5][CH:1]3[CH2:2][CH2:3][CH2:4]3)=[O:34])[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=2)=[O:28])[CH2:77][CH2:78]1)=[O:72])[CH3:69]
Reactant: CCOC(=O)N1CCNCC1
Reactant: O=C(O)CNC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)N1CCN(C(=O)CNC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1
Reaction time: 1 h

Procedure:
To a solution of 100 mg ({5-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-acetic acid in 2 ml DMF were added 0.15 ml DIPEA, 81 mg HATU and 0.03 ml 1-ethoxycarbonylpiperazine. After stirring for 1 h it was diluted with dichlormethane and extracted with aqueous LiCl (4% w/w), aqueous NaHCO3 and 0.1 M HCl. The crude product obtained after evaporation of the solvent was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA) to give the title compound.
Reaction SMILES: [F:1][CH:2]1[CH2:5][N:4]([C:6](=[O:42])[C@H:7]([NH:11][C:12]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([C:23]4[C:31]5[C:26](=[CH:27][C:28]([Cl:32])=[CH:29][CH:30]=5)[N:25]([CH3:33])[N:24]=4)[N:21]=3)[N:16](COCC[Si](C)(C)C)[CH:15]=2)=[O:13])[CH2:8][O:9][CH3:10])[CH2:3]1.C(O)(C(F)(F)F)=O.C(N)CN>ClCCl>[F:1][CH:2]1[CH2:3][N:4]([C:6](=[O:42])[C@H:7]([NH:11][C:12]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([C:23]4[C:31]5[C:26](=[CH:27][C:28]([Cl:32])=[CH:29][CH:30]=5)[N:25]([CH3:33])[N:24]=4)[N:21]=3)[NH:16][CH:15]=2)=[O:13])[CH2:8][O:9][CH3:10])[CH2:5]1
Reactant: COC[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12)C(=O)N1CC(F)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: NCCN
Product: COC[C@@H](NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12)C(=O)N1CC(F)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 65 %

Procedure:
In a 25 mL round-bottom flask, 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-fluoro-azetidin-1-yl)-1-methoxymethyl-2-oxo-ethyl]-amide (47 mg, 0.076 mmol) and TFA (1.2 ml, 15.6 mmol) were combined with dichloromethane (4 ml) to give an orange solution. The reaction mixture was stirred at room temperature for 2.5 h then concentrated under reduced pressure. The resultant crude solid was dissolved in dichloromethane (4 mL) and ethylenediamine (0.36 ml, 5.3 mmol) was added. The reaction mixture was stirred at room temperature for 18 h then concentrated and the residue was precipitated with water. The suspension was stirred for 1 h and the crude solid collected by filtration. The crude solid was purified by trituration (dichloromethane/heptane) to afford 24 mg (64%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-fluoro-azetidin-1-yl)-1-methoxymethyl-2-oxo-ethyl]-amide as an off-white solid. MS: [M+H]+=486; 1H NMR (300 MHz, DMSO-d6) δ: 12.85 (br. s., 1H), 9.16 (s, 1H), 8.76 (dd, J=8.7, 5.3 Hz, 1H), 8.55 (d, J=8.3 Hz, 1H), 8.49 (s, 1H), 7.97 (d, J=1.5 Hz, 1H), 7.24 (d, J=9.1 Hz, 1H), 5.23-5.58 (m, 1H), 4.97 (dt, J=8.1, 5.8 Hz, 1H), 4.56-4.82 (m, 1H), 4.21-4.56 (m, 2H), 4.18 (s, 3H), 3.87-4.10 (m, 1H), 3.68 (qd, J=9.8, 5.7 Hz, 2H), 3.28 (app. d, J=3.4 Hz, 3H).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[C:9]([F:12])[CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[C@@H:19]([NH2:21])[CH3:20])[CH3:2].[NH2:22][C:23]1[C:28]([C:29]#[N:30])=[C:27](Cl)[N:26]=[CH:25][N:24]=1.CCN(C(C)C)C(C)C>CC(O)C>[NH2:22][C:23]1[C:28]([C:29]#[N:30])=[C:27]([NH:21][C@H:19]([C:4]2[N:3]([CH2:1][CH3:2])[C:7]3[C:8]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=4)=[C:9]([F:12])[CH:10]=[CH:11][C:6]=3[N:5]=2)[CH3:20])[N:26]=[CH:25][N:24]=1
Reactant: CCn1c([C@H](C)N)nc2ccc(F)c(-c3ccccn3)c21
Reactant: N#Cc1c(N)ncnc1Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CCn1c([C@H](C)Nc2ncnc(N)c2C#N)nc2ccc(F)c(-c3ccccn3)c21
Temperature: 80 °C
Reaction time: 16 h
Yield: 33 %

Procedure:
A mixture of (S)-1-(1-ethyl-6-fluoro-7-pyridin-2-yl-1H-benzoimidazol-2-yl)ethylamine (0.203 g, 0.715 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (0.11 g, 0.715 mmol) and DIPEA (0.65 mL, 3.58 mmol) in IPA (5 mL) was stirred at 80° C. in a sealed microwave tube for 16 hours. After cooling, the mixture was concentrated in vacuo and the residue was purified chromatography, (Si—PPC, gradient 0-5% MeOH in DCM), to give 410 as a solid (0.095 g, 33%). LCMS (Method K): RT 3.03 min [M+H]+ 403. 1H NMR (DMSO-d6, 400 MHz): δ 8.71-8.67 (1H, m), 7.96 (1H, s), 7.92 (1H, td, J=7.8, 1.9 Hz), 7.73 (1H, d, J=7.7 Hz), 7.70-7.62 (2H, m), 7.47 (1H, ddd, J=7.7, 5.0, 1.1 Hz), 7.25 (2H, br s), 7.12 (1H, dd, J=10.4, 8.8 Hz), 5.60 (1H, quin, J=7.2 Hz), 3.80-3.67 (2H, m), 1.55 (3H, d, J=6.8 Hz), 0.69 (3H, t, J=7.1 Hz)
Reaction SMILES: C([Li])CCC.CC1(C)CCCC(C)(C)N1.[I:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1.C([O:27][B:28](OC(C)C)[O:29]C(C)C)(C)C.Cl>O1CCCC1>[F:23][C:20]1[CH:21]=[CH:22][C:17]([I:16])=[CH:18][C:19]=1[B:28]([OH:29])[OH:27]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Fc1ccc(I)cc1
Agent: CC1(C)CCCC(C)(C)N1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1cc(I)ccc1F
Temperature: -78 °C
Reaction time: 3 h

Procedure:
Add a 2 M solution of n-butyllithium in hexanes (63 mL, 157.5 mmol) to a −20° C. solution of 2,2,6,6-tetramethylpiperidine (28 mL, 165 mmol) in tetrahydrofuran (400 μL). Cool to −78° C. and add 1-iodo-4-fluorobenzene (17.3 mL, 150 mmol) dropwise over 10 min. Stir the reaction mixture at −78° C. for 3 h and add triisopropylborate (40 mL, 172.5 mmol) dropwise over 20 min. Stir for another 30 min and warm the reaction to 40° C. and add of 5 N hydrochloric acid (75 mL). Partition the reaction mixture between diethyl ether (500 mL) and add 1 N hydrochloric acid (500 mL). Separate the organic layer and extract with 2 N sodium hydroxide (400 mL). Make the aqueous layer slightly acidic (pH ˜5-6) by dropwise addition of 5 N hydrochloric acid and collect the resulting white precipitate by filtration. Dry the precipitate overnight under vacuum to provide 2-fluoro-5-iodophenylboronic acid as a white solid, which is used directly without further purification (39g, 98%).
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH3:24])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].COC(C1NN=C([O:34][CH2:35][C:36]2[C:37]([C:42]3C=CC=CC=3)=[N:38]OC=2C)C=1)=O.NC1CCOC1>>[O:34]1[CH2:35][CH2:36][CH:37]([NH:38][C:3]([C:5]2[N:6]([CH3:24])[N:7]=[C:8]([O:10][CH2:11][C:12]3[C:13]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[N:14][O:15][C:16]=3[CH3:17])[CH:9]=2)=[O:4])[CH2:42]1
Reactant: COC(=O)c1cc(OCc2c(-c3ccccc3)noc2C)nn1C
Reactant: COC(=O)c1cc(OCc2c(-c3ccccc3)noc2C)n[nH]1
Agent: NC1CCOC1
Product: Cc1onc(-c2ccccc2)c1COc1cc(C(=O)NC2CCOC2)n(C)n1
Yield: 80 %

Procedure:
As described for example 1b, 2-methyl-5-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-2H-pyrazole-3-carboxylic acid methyl ester (30 mg, 0.09 mmol), instead of 5-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-2H-pyrazole-3-carboxylic acid methyl ester, was converted, using rac-3-aminotetrahydrofuran instead of morpholine, to the title compound (28 mg, 80%) which was obtained as a colorless oil. MS: m/e=383.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[CH3:20][C:21]1[CH:22]=[C:23]2[C:28](=O)[O:27][C:25](=[O:26])[C:24]2=[CH:30][CH:31]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[F:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[C:28](=[O:27])[C:23]5=[CH:22][C:21]([CH3:20])=[CH:31][CH:30]=[C:24]5[C:25]4=[O:26])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Cc1ccc2c(c1)C(=O)OC2=O
Reactant: NCCN1CCC(c2noc3cc(F)ccc23)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: Cc1ccc2c(c1)C(=O)N(CCN1CCC(c3noc4cc(F)ccc34)CC1)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.7 %

Procedure:
A mixture of 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethylamine (2.44 gm, 9.24 mmoles), 4-methylphthalic anhydride (1.76 gm, 10.8 mmoles) and dicyclohexylcarbodiimide (2 gm, 1.0 mmoles) in dichloromethane (DCM, 100 ml) was stirred at room temperature for 2 hr. The insolubles were filtered off. The DCM solution was concentrated to a crude solid. This was purified on a flash chromatography column (35 gm, SiO2, Sorbsil-C-30; eluted with 1% CH3OH in 99% DCM). The material thus purified weighed 1.0 gm (26%) as a white solid. Recrystallization from hot ethanol gave 665 mg of crystals, m.p.=138°-140° C.
Reaction SMILES: Cl.[CH3:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][NH:4]1.C([O-])([O-])=O.[K+].[K+].[C:14]([O:18][CH2:19][CH3:20])(=[O:17])[CH:15]=[CH2:16].CCO>CC#N>[CH2:19]([O:18][C:14](=[O:17])[CH2:15][CH2:16][N:4]1[CH2:5][CH2:6][CH2:7][C@H:3]1[CH3:2])[CH3:20]
Reactant: C=CC(=O)OCC
Reactant: C[C@@H]1CCCN1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCO
Product: CCOC(=O)CCN1CCC[C@H]1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.8 %

Procedure:
In a round-bottom flask, 2-(R)-methylpyrrolidine HCl (5.5 g, 45 mmol) was dissolved in CH3CN (20 mL). To the stirred solution was added milled K2CO3 (8.3 g, 60 mmol). The suspension was stirred at room temperature for approximately 1 h. Ethyl acrylate (3.25 mL, 30 mmol) and EtOH (40 mL) were then added. The reaction mixture was stirred until analysis by GC showed completion (the Area % of ethyl acrylate was less than 1% (approximately 2 h)). The reaction mixture was filtered and the wet cake (excess K2CO3) was washed with CH3CN (5-10 mL). The filtered solution was then concentrated under reduced pressure to minimum volume (white slurry). Methyl t-butyl ether (MTBE) and H2O were added, at which time all solids dissolved. The organic layer was washed a second time with water and then concentrated to yield 5.6 g of the title compound. The oil product was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][N:6]=[CH:5]2.[I:12]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][N:6]=[C:5]2[I:12]
Reactant: Fc1cc2[nH]ncc2cc1Br
Reactant: O=C1CCC(=O)N1I
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Fc1cc2[nH]nc(I)c2cc1Br
Temperature: 70 °C
Reaction time: 48 h
Yield: 91.5 %

Procedure:
To a solution of 10.0 g of 5-bromo-6-fluoro-1H-indazole in 150 mL of N,N-dimethylformamide was added 10.5 g of N-iodosuccinimide at room temperature, and stirred at 70° C. for 2 days. Then the solution was diluted with ethyl acetate, washed successively with aqueous ammonium chloride and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The crystals precipitated by adding diethyl ether to the residue were collected by filtration. The filtrate was further concentrated and purified and separated by silica gel column chromatographsy (ethyl acetate:n-hexane=1:10-1:5) and combined with the previous crystals, to afford 14.5 g of the title compound as colorless crystals.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]([C:11]1[CH:16]=[N:15][C:14](Br)=[C:13]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[N:12]=1)=[O:10].[CH:25]1([CH2:30][OH:31])[CH2:29][CH2:28][CH2:27][CH2:26]1>>[OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]([C:11]1[CH:16]=[N:15][C:14]([O:31][CH2:30][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[C:13]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[N:12]=1)=[O:10]
Reactant: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(Br)c(-c2ccc(Cl)cc2)n1
Reactant: OCC1CCCC1
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(OCC2CCCC2)c(-c2ccc(Cl)cc2)n1

Procedure:
The title compound was prepared in analogy to example 26 starting from 5-bromo-6-(4-chloro-phenyl)-pyrazine-2-carboxylic acid ((1R,2R)-2-hydroxy-cyclohexyl)-amide and replacing ethylenglycolmonomethylether by cyclopentylmethanol. MS (ISP) (M+H+)=430.1.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10](=O)[CH2:11][CH2:12][CH3:13])=[N:8][CH:9]=1)([OH:3])=[O:2].Cl.[NH2:16][OH:17]>N1C=CC=CC=1>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10](=[N:16][OH:17])[CH2:11][CH2:12][CH3:13])=[N:8][CH:9]=1)([OH:3])=[O:2]
Reactant: NO
Reactant: CCCC(=O)c1ccc(C(=O)O)cn1
Agent: Cl
Solvent: c1ccncc1
Product: CCCC(=NO)c1ccc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred solution of 1-(5-carboxy-2-pyridinyl)-1-butanone (2 mmol) in 20 ml of pyridine, hydroxylamine hydrochloride (4 mmol) is added. The reaction mixture is stirred at room temperature for 5 h. The solvent is distilled off and the residue crystallized from ethyl acetate; m.p. 203°-205°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7](OC)=[O:8])=[C:5]([CH3:13])[CH:4]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([CH2:7][OH:8])=[C:5]([CH3:13])[CH:4]=1
Reactant: COC(=O)c1ccc(OC)cc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CO)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.1 %

Procedure:
To a solution of methyl 4-methoxy-2-methylbenzoate (11.4 g, 63.3 mmol) in THF (65 mL) at 0° C., LiAlH4 (1M in ether, 76.0 mL, 75.9 mmol) was added via addition funnel over 50 min. The ice water bath was removed, and the reaction was allowed to stir at room temperature for 30 min. Upon completion, the reaction was cooled to 0° C. and sodium sulfate decahydrate was added portionwise until the bubbling ceased. The reaction was then diluted with ether and filtered. The filtrate was concentrated under reduced pressure to give (4-methoxy-2-methylphenyl)methanol (8.2 g) as a clear oil. 1H NMR (300 MHz, CDCl3): δ 7.23 (d, 1H), 6.72 (m, 2H), 4.63 (d, 2H), 3.79 (s, 3H), 2.36 (s, 3H), 1.42 (t, 1H).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:30]([CH3:31])=[CH:29][C:13]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([N:23]4[CH2:28][CH2:27]O[CH2:25][CH2:24]4)[CH:18]=3)[S:16][C:12]=2[C:11]=1[C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:39][N:40]1CCN(C2C=CC=CN=2)CC1.N1C=CC(B(O)O)=CC=1>>[C:1]([O:5][C@@H:6]([C:10]1[C:30]([CH3:31])=[CH:29][C:13]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([N:23]4[CH2:28][CH2:27][N:40]([CH3:39])[CH2:25][CH2:24]4)[CH:18]=3)[S:16][C:12]=2[C:11]=1[C:32]1[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][CH:37]=1)[C:7]([OH:9])=[O:8])([CH3:3])([CH3:2])[CH3:4]
Reactant: CN1CCN(c2ccccn2)CC1
Reactant: Cc1cc2nc(-c3ccnc(N4CCOCC4)c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Agent: OB(O)c1ccncc1
Product: Cc1cc2nc(-c3ccnc(N4CCN(C)CC4)c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
Prepared in a manner similar to (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(2-morpholinopyridin-4-yl)benzo[d]thiazol-6-yl)acetic acid except 2-(4-methylpiperazino)pyridine-4-pyridine boronic acid using instead of 2-morpholinopyridine-4-boronic acid. LCMS-ESI+: calc'd for C30H34ClN3O3S: 565.2 (M+H+); Found: 565.3 (M+H+); 1H NMR (400 MHz, CD3OD) δ 8.30 (d, J=4.8 Hz, 1H), 7.89 (s, 1H), 7.68 (d, J=8.9 Hz, 1H), 7.64-7.47 (m, 4H), 7.34 (d, J=5.1 Hz, 1H), 5.26 (s, 1H), 4.77-4.38 (m, 2H), 3.78-3.04 (m, 2H), 2.97 (s, 3H), 2.62 (s, 3H), 0.97 (s, 9H).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][N:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[C:31]([NH:35][CH3:36])([CH3:34])([CH3:33])[CH3:32]>>[C:31]([N:35]([CH3:36])[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][N:18]=3)=[CH:13][C:11]=2[CH:12]=1)([CH3:34])([CH3:33])[CH3:32]
Reactant: CNC(C)(C)C
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cn3)ccc2o1
Product: CN(CCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cn3)ccc2o1)C(C)(C)C

Procedure:
The product from Example 44E and tert-butyl(methyl)amine were processed as described in Example 1D to provide the titled compound. 1H NMR (300 MHz, CD3OD) δ 8.70 (m, 1H), 8.24 (d, J=1.8 Hz, 1H), 7.96 (m, 3H), 7.59 (d, J=8.7 Hz, 1H), 6.85 (s, 1H), 3.3-3.8 (m, 12H), 2.93 (s, 3H), 1.48 (s, 9H); MS (DCI) m/z 422 (M+H)+;
Reaction SMILES: [Cl:1][C:2]1[CH:41]=[CH:40][C:5]([CH2:6][NH:7][C:8]2[N:13]=[C:12]([C:14]3[C:22]4[C:17](=[N:18][C:19]([NH:23][CH2:24][CH2:25][N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)=[N:20][CH:21]=4)[N:16](COCC[Si](C)(C)C)[N:15]=3)[CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]2[N:13]=[C:12]([C:14]3[C:22]4[C:17](=[N:18][C:19]([NH:23][CH2:24][CH2:25][N:26]5[CH2:27][CH2:28][O:29][CH2:30][CH2:31]5)=[N:20][CH:21]=4)[NH:16][N:15]=3)[CH:11]=[CH:10][CH:9]=2)=[CH:40][CH:41]=1
Reactant: C[Si](C)(C)CCOCn1nc(-c2cccc(NCc3ccc(Cl)cc3)n2)c2cnc(NCCN3CCOCC3)nc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1ccc(CNc2cccc(-c3n[nH]c4nc(NCCN5CCOCC5)ncc34)n2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of [3-[6-(4-chloro-benzylamino)-pyridin-2-yl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-(2-morpholin-4-yl-ethyl)-amine (100 mg, 0.168 mmol) in dichloromethane (2 mL) was added TFA (2 mL). The reaction mixture was stirred for 2 hours at room temperature. The pH of mixture was then adjusted to about 8 with saturated NaHCO3 solution. The resulting mixture was extracted with dichloromethane. The organic layer was dried and concentrated under reduced pressure. The residue was purified by prep-HPLC to give {3-[6-(4-Chloro-benzylamino)-pyridin-2-yl]-1H-pyrazolo[3,4-d]pyrimidin-6-yl}-(2-morpholin-4-yl-ethyl)-amine. (Yield 20 mg, 26%).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[P:6]([OH:8])[OH:7].[CH2:9](N(CC)CC)[CH3:10].ClC(OCC)=O>ClCCl>[CH2:9]([O:7][P:6]([CH:2]1[CH2:3][CH2:4][CH2:5][O:1]1)[OH:8])[CH3:10]
Reactant: OP(O)C1CCCO1
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Solvent: ClCCl
Product: CCOP(O)C1CCCO1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 2.6 g of P-tetrahydrofuran-2-yl-phosphonous acid in 20 ml of anhydrous dichloromethane is cooled to 5° under inert gas and treated with 2.03 g of triethylamine. A dichloromethane solution of 2.17 gof ethyl chloroformate is added dropwise whereupon an exothermic reaction and a gas evolution ensues. The suspension is warmed to room temperature and stirred for 3 hours. The reaction mixture is then diluted with dichloromethane and washed with water. Drying of the organic phase with anhydrous magnesium sulphate and removal of the solvent in vacuo affords P-tetrahydrofuran-2-ylphosphonous acid ethyl ester, b.p. 90°/8×10-2 mbar.
Reaction SMILES: S([O-])([O-])(=O)=O.[Na+].[Na+].Cl.[NH2:9][C@@H:10]([CH2:14][CH3:15])[C:11]([NH2:13])=[O:12].[OH-].[K+].Cl[CH2:19][CH2:20][CH2:21][C:22](Cl)=[O:23]>ClCCl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:14]([C@H:10]([N:9]1[CH2:19][CH2:20][CH2:21][C:22]1=[O:23])[C:11]([NH2:13])=[O:12])[CH3:15]
Reactant: CC[C@H](N)C(N)=O
Reactant: O=C(Cl)CCCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CC[C@@H](C(N)=O)N1CCCC1=O
Temperature: 0 °C
Yield: 74 %

Procedure:
This example illustrates a varient of the process of Example 3, in which the intermediate 4-chlorobutanamide obtained in situ is not isolated. 84 g of anhydrous sodium sulfate are added to a suspension of 69.25 g (0.5 mole) of (S)-2-amino-butanamide hydrochloride in 600 ml of dichloromethane at ambient temperature. The mixture is cooled to 0° C. and 115 g of ground potassium hydroxide are added, followed by 8.1 g (0.025 mole) of tetrabutylammonium bromide dissolved in 100 ml of dichloromethane. A solution of 77.5 g of 4-chlorobutyryl chloride in 100 ml of dichloromethane is added dropwise at 0° C., with vigorous stirring. After 5 hours' reaction, a further 29 g of ground potassium hydroxide are added. Two hours later, the reaction mixture is filtered over Hyflo-cel and the filtrate evaporated under reduced pressure. The residue (93.5 g) is dispersed in 130 ml of hot toluene for 45 minutes. The resultant mixture is filtered and the filtrate evaporated under reduced pressure. The residue (71.3 g) is dissolved hot in 380 ml of ethyl acetate to which 23 g of 0.4 nm molecular sieve in powder form are added. This mixture is heated to reflux temperature and filtered hot. After cooling the filtrate, the desired product crystallizes to give 63 g of (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide.