Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:16]3[C:24]4[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=4)[N:18]([CH3:26])[N:17]=3)[N:14]=2)[N:9](COCC[Si](C)(C)C)[CH:8]=1)=[O:6])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.C(N)CN.O>ClCCl.C(OCC)(=O)C>[CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:16]3[C:24]4[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=4)[N:18]([CH3:26])[N:17]=3)[N:14]=2)[NH:9][CH:8]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12
Solvent: O
Solvent: NCCN
Solvent: O=C(O)C(F)(F)F
Product: CC(C)NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 63.3 %

Procedure:
2-(6-Chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid isopropylamide (45 mg, 0.09 mmol) was dissolved in dichloromethane (0.9 ml) and cooled in ice bath. Trifluoroacetic acid (0.3 ml) was added slowly and the reaction was stirred at room temperature for 3.5 h. The reaction was evaporated and the residue was dissolved in dichloromethane (2 ml). Ethylenediamine (0.36 ml, 5.4 mmol) was added and the mixture was stirred at room temperature for 18 h. Water and then ethyl acetate were added to the mixture. The resulting precipitate was filtered off, rinsed with water and dried under high vacuum to give 21 mg (81%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid isopropylamide. (M+Na)+=391; mp=356-362° C. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.79-12.90 (m, 1H) 9.09 (s, 1H) 8.44 (d, J=9.1 Hz, 1H) 8.42 (s, 1H) 8.02 (d, J=7.6 Hz, 1H) 8.00 (d, J=1.5 Hz, 1H) 7.30 (dd, J=8.8, 1.8 Hz, 1H) 4.19-4.27 (m, 1H) 4.17 (s, 3H) 1.32 (d, J=6.6 Hz, 6H).
Reaction SMILES: [CH:1]([CH:4]1[C:9](=O)[NH:8][CH2:7][CH2:6][N:5]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])([CH3:3])[CH3:2].Br[C:19]1[CH:25]=[C:24]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:23]=[CH:22][C:20]=1[NH2:21].CN[C@@H]1CCCC[C@@H]1NC>CN1C(=O)CCC1.O>[CH:1]([CH:4]1[N:5]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:7][N:8]2[C:19]3[CH:25]=[C:24]([S:26]([CH3:29])(=[O:27])=[O:28])[CH:23]=[CH:22][C:20]=3[N:21]=[C:9]12)([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)c1ccc(N)c(Br)c1
Reactant: CC(C)C1C(=O)NCCN1C(=O)OC(C)(C)C
Agent: CN[C@H]1CCCC[C@H]1NC
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)C1c2nc3ccc(S(C)(=O)=O)cc3n2CCN1C(=O)OC(C)(C)C
Temperature: 150 °C
Reaction time: 1 h
Yield: 33.7 %

Procedure:
To a solution of tert-butyl 2-isopropyl-3-oxopiperazine-1-carboxylate (200 mg, 0.83 mmol) in NMP (3 mL) were added 2-bromo-4-(methylsulfonyl)aniline (207 mg, 0.83 mmol), (1R,2S)—N1,N2-dimethylcyclohexane-1,2-diamine (12.0 mg, 0.08 mmol), K3PO4.3H2O (660 mg, 2.48 mmol) and Cul (16 mg, 0.08 mmol). The mixture was stirred at 150° C. for 1 h in a microwave oven. The mixture was diluted with water (10 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, concentrated and purified by preparative TLC with CH2Cl2/MeOH 35/1 to afford tert-butyl 1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazine-2(1H)-carboxylate (110 mg, 34% yield) as a white solid. LC-MS m/z 394.1 [M+H]+. 1H NMR (CDCl3 400 MHz): δ 7.94 (s, 1H), 7.83-7.76 (m, 2H), 5.35-5.17 (m, 1H), 4.73-4.42 (m, 1H), 4.22-4.12 (m, 1H), 4.11-3.99 (m, 1H), 3.53-3.37 (m, 1H), 3.03 (s, 3H), 2.38-2.27 (m, 1H), 1.42 (s, 9H), 1.19 (d, J=6.8 Hz, 3H), 0.97 (d, J=6.8 Hz, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]([CH:14]([F:16])[F:15])=[C:7]([CH:13]=1)[C:8]([N:10]=[C:11]=[O:12])=O)#[N:2].[F:17][C:18]([F:35])([F:34])[C:19]1[CH:24]=[CH:23][C:22]([NH:25][NH:26]C(OC(C)(C)C)=O)=[CH:21][CH:20]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:15][CH:14]([F:16])[C:6]1[C:7]([C:8]2[NH:10][C:11](=[O:12])[N:25]([C:22]3[CH:23]=[CH:24][C:19]([C:18]([F:17])([F:35])[F:34])=[CH:20][CH:21]=3)[N:26]=2)=[CH:13][C:3]([C:1]#[N:2])=[CH:4][N:5]=1
Reactant: CC(C)(C)OC(=O)NNc1ccc(C(F)(F)F)cc1
Reactant: N#Cc1cnc(C(F)F)c(C(=O)N=C=O)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cnc(C(F)F)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1
Yield: 22.8 %

Procedure:
The title compound was prepared by following the procedure as described in Example-83 by using 5-cyano-2-(difluoromethyl)nicotinoyl isocyanate (Intermediate-145, 0.900 g, 4.03 mmol), tert-butyl 2-(4-(trifluoromethyl)phenyl)hydrazinecarboxylate (Intermediate-53, 1.0 g, 163 mmol), TFA (10 mL), DCM (40 mL) to afford 0.350 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 7.45-7.56 (t, J=53.4 Hz, 1H), 7.90 (d, J=9.3 Hz, 2H), 8.20 (d, J=8.7 Hz, 2H), 8.77 (s, 1H), 9.32 (s, 1H), 13.01 (s, 1H); MS (m/z): 382.15 (M+H)+.
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([C:12]2[C:17]([CH2:18][O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][CH:15]=[C:14]([C:26]([O:28][CH3:29])=[O:27])[CH:13]=2)=[C:7]([CH3:30])[CH:6]=1.CO.Cl.CO>C(COC)OC>[OH:4][C:5]1[CH:6]=[C:7]([CH3:30])[C:8]([C:12]2[C:17]([CH2:18][O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][CH:15]=[C:14]([C:26]([O:28][CH3:29])=[O:27])[CH:13]=2)=[C:9]([CH3:11])[CH:10]=1
Reactant: COCOc1cc(C)c(-c2cc(C(=O)OC)ccc2COc2ccccc2)c(C)c1
Agent: Cl
Solvent: CO
Solvent: COCCOC
Product: COC(=O)c1ccc(COc2ccccc2)c(-c2c(C)cc(O)cc2C)c1
Temperature: 45 °C
Reaction time: 16 h
Yield: 93.2 %

Procedure:
To a solution of methyl 4′-(methoxymethoxy)-2′,6′-dimethyl-6-(phenoxymethyl)biphenyl-3-carboxylate (1.77 g, 4.35 mmol) in a mixed solvent of methanol (10 mL) and dimethoxyethane (5 mL) was added 10% hydrogen chloride-methanol solution (1 mL), and the mixture was stirred at 45° C. for 16 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=10:90-25:75) to give the title compound (1.47 g, yield 93%) as a colorless amorphous powder.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[CH3:20][C:21]1([CH3:32])[C@H:26]2[CH2:27][C@@H:22]1[CH2:23][CH2:24][C@H:25]2[CH2:28][C:29](O)=[O:30]>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:19])[N:2]([NH:1][C:29](=[O:30])[CH2:28][C@@H:25]3[CH2:24][CH2:23][C@H:22]4[CH2:27][C@@H:26]3[C:21]4([CH3:20])[CH3:32])[N:11]=2)=[CH:13][CH:14]=1
Reactant: CC1(C)[C@H]2CC[C@@H](CC(=O)O)[C@@H]1C2
Reactant: Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O
Product: CC1(C)[C@H]2CC[C@@H](CC(=O)Nn3nc(-c4ccc(Cl)cc4)c4ccccc4c3=O)[C@@H]1C2

Procedure:
The product of Example 86A and 2-[(1S,2S,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-yl]acetic acid (Eigenmann, G. W.; Arnold, R. T. JACS 1959, 81, 3440-2) were processed using a method similar to that described in Example 17C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.38-11.39 (bs, 1H), 8.39-8.42 (m, 1H), 7.90-8.03 (m, 2H), 7.70-7.75 (m, 1H), 7.61-7.67 (m, 4H), 2.20-2.43 (m, 3H), 1.73-2.06 (m, 6H), 1.36-1.69 (m, 1H), 1.20 (s, 3H), 1.07 (s, 3H), 0.91 (d, J=9.5 Hz, 1H); MS (ESI+) m/z 436 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[CH:9]=[CH:10][C:3]=12.[NH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]1>>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:8]2[C:4]3=[N:5][CH:6]=[CH:7][C:2]([NH:20][CH:21]4[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]4)=[C:3]3[CH:10]=[CH:9]2)=[CH:13][CH:14]=1
Reactant: COc1ccc(Cn2ccc3c(Br)ccnc32)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1
Product: COc1ccc(Cn2ccc3c(NC4CCCN(C(=O)OC(C)(C)C)C4)ccnc32)cc1

Procedure:
Reaction of 4-bromo-1-(4-methoxybenzyl)-1H-pyrrolo[2,3-b]pyridine with tert-butyl 3-aminopiperidine-1-carboxylate following the method of Example 13 affords the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[I:15]I>O>[I:15][C:6]1[C:5]([OH:8])=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=1
Reactant: II
Reactant: Cc1ccc(O)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(O)c(I)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.3 %

Procedure:
To a mixture of 6-methylpyridin-3-ol (235 g, 2.75 mol) and water (5.28 L) at 0° C. was added Na2CO3 (440 g, 5.5 mol) and the mixture was stirred at room temperature for 30 minutes. A solution of I2 (760 g, 3.85 mol) and KI (760 g, 5.83 mol) in water (5.28 L) was added dropwise to the reaction over a period of 1 hour. The mixture was stirred at room temperature for 3 hours and the resulting precipitate was collected by filtration to afford 2-iodo-6-methylpyridin-3-ol (390 g, 77.0%) as a yellow solid which was used without further purification.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:19]([O-:21])=[O:20])=[C:6]([NH:8][CH:9]([C:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=2)[CH3:10])[CH:7]=1.[N:22]1([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:18][C:13]1[CH:12]=[C:11]([CH:9]([NH:8][C:6]2[CH:7]=[C:2]([N:25]3[CH2:24][CH2:23][N:22]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:27][CH2:26]3)[CH:3]=[CH:4][C:5]=2[N+:19]([O-:21])=[O:20])[CH3:10])[CH:16]=[C:15]([CH3:17])[CH:14]=1
Reactant: Cc1cc(C)cc(C(C)Nc2cc(F)ccc2[N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C)cc(C(C)Nc2cc(N3CCN(C(=O)OC(C)(C)C)CC3)ccc2[N+](=O)[O-])c1
Yield: 43 %

Procedure:
5-fluoro-N-(1-(3,5-dimethylphenyl)ethyl)-2-nitrobenzenamine (762 mg, 2.4 mmol), t-butyl piperazine-1-carboxylate (443 mg, 2.4 mmol), N,N-diisopropylethylamine (614 mg, 4.8 mmol) were stirred at 80° C. in dry acetonitrile (50 mL) for 48 h. The solvent was evaporated and the residue was dissolved in dichloromethane and washed with water. The dichloromethane was evaporated and the crude compound was purified by silica chromatography using 25% ethyl acetate in hexanes to afford the title compound (469 mg, 41% yield). 1H NMR (400 MHz, CDCl3): δ 8.68 (s, 1H), 8.05 (d, 1H), 6.49 (s, 2H), 6.33 (s, 1H), 6.14 (d, 1H), 5.70 (s, 1H), 4.47 (m, 1H), 3.76 (s, 6H), 3.43 (m, 4H), 3.23 (m, 2H), 3.15 (m, 2H), 1.62 (d, 3H), 1.46 (s, 9H).
Reaction SMILES: C(OC([NH:8][C:9]1[CH:29]=[CH:28][C:12]([O:13][C:14]2[CH:15]=[C:16]3[C:20](=[N:21][CH:22]=2)[NH:19][CH:18]([NH:23][C:24](=[O:27])[O:25][CH3:26])[NH:17]3)=[CH:11][CH:10]=1)=O)(C)(C)C.Cl>CO>[NH2:8][C:9]1[CH:29]=[CH:28][C:12]([O:13][C:14]2[CH:15]=[C:16]3[C:20]([NH:19][CH:18]([NH:23][C:24](=[O:27])[O:25][CH3:26])[NH:17]3)=[N:21][CH:22]=2)=[CH:11][CH:10]=1
Reactant: COC(=O)NC1Nc2cc(Oc3ccc(NC(=O)OC(C)(C)C)cc3)cnc2N1
Agent: Cl
Solvent: CO
Product: COC(=O)NC1Nc2cc(Oc3ccc(N)cc3)cnc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.1 %

Procedure:
The same procedure described in Intermediate 9D gave methyl (5-(4-(tertbutoxycarbonyl)aminophenoxy)-3,7-diazaindolin-2-yl)carbamate. To a solution of methyl (5-(4-(tert-butoxycarbonyl)aminophenoxy)-3,7-diazaindolin-2-yl)carbamate (160.8 mg, 0.4 mmol) in methanol (10 mL) was added 2N HCl (aq) (10 mL) then stirred at room temperature overnight. The solution was removed by evaporation then the residue was extracted with ethyl acetate. The organic layer was washed with NaHCO3 (aq) and brine, dried over Na2SO4 then evaporated. The residual solid was washed with ethyl acetate then dried under reduced pressure to give the title compound (95.3 mg, 80%): MS m/e 300 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:11](/[CH:12]=[CH:13]/[CH2:14][OH:15])=[C:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:22]>C(OCC)C.[O-2].[O-2].[Mn+4]>[CH3:1][N:2]1[C:11](/[CH:12]=[CH:13]/[CH:14]=[O:15])=[C:10]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:22]
Reactant: Cn1c(/C=C/CO)c(-c2ccccc2)c2ccccc2c1=O
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOCC
Product: Cn1c(/C=C/C=O)c(-c2ccccc2)c2ccccc2c1=O
Reaction time: 4 h
Yield: 85.6 %

Procedure:
A stirred solution of (E)-3-(2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl)prop-2-en-1-ol (0.4 g) in dry diethyl ether (125 ml) under an atmosphere of nitrogen was treated with activated manganese dioxide (1.8 g). The mixture was stirred for 4 hours. The manganese dioxide was then filtered off and washed well with diethyl ether (4×100 ml) during 15 minutes. The combined ethereal solutions were evaporated, to give (E)-3-(2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl)propenal (0.34 g) in the form of a yellow solid, m.p. 228° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:6]([N:11]=1)=[N:7][CH:8]=[CH:9][N:10]=2.[CH:12]([Sn](CCCC)(CCCC)CCCC)=[CH2:13]>C1COCC1>[CH:12]([C:2]1[CH:3]=[CH:4][C:5]2[C:6]([N:11]=1)=[N:7][CH:8]=[CH:9][N:10]=2)=[CH2:13]
Reactant: Clc1ccc2nccnc2n1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: C=Cc1ccc2nccnc2n1
Temperature: 65 °C
Reaction time: 3 h
Yield: 80.8 %

Procedure:
6-chloropyrido[2,3-b]pyrazine (Intermediate 4.2) (3 g, 18.12 mmol, 1.00 eq.) was dissolved in THF (150 mL) and degassed with nitrogen at rt for 10 minutes. Tetrakis (triphenylphosphine)palladium(0) (1.46 g, 1.27 mmol, 0.07 eq.) and vinyltributylstannane (7.47 mL, 23.5 mmol, 1.3 eq.) were added and reaction mixture was stirred at 65° C. for 3 hours. THF was evaporated and crude purified directly by flash chromatography using cyclohexane/ethyl acetate (8/2) to give 2.3 g of the expected compound (Intermediate 4.3) as an orange oil. Amount: 2.3 g; Yield: 81%; Formula: C9H7N3; HPLC Purity: 98%; HPLC (H2O TFA 0.1%-ACN TFA 0.05%): Rt (min); Area %=1.32 min; 98%; 1H NMR (DMSO-d6) δ 9.10 (s, 1H), 8.98 (s, 1H), 8.46 (d, 1H, J=8 Hz), 7.95 (d, 1H, J=8 Hz), 6.90 (dd, 1H, Jtrans=17 Hz, Jcis=10 Hz), 6.50 (dd, 1H, Jtrans=17 Hz, Jgem=1.5 Hz), 5.80 (dd, 1H, Jcis=10 Hz, Jgem=1.5 Hz). LC-MS: M/Z ESI: Rt (min) 0.78 min, 158.13 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>CN(C)C=O>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:27]2[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]2)=[O:8])=[CH:4][N:3]=1
Reactant: CN1CCNCC1
Reactant: Nc1ccc(C(=O)O)cn1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)c2ccc(N)nc2)CC1
Temperature: 70 °C

Procedure:
3.00 g 6-amino-nicotinic acid are dissolved in 30 ml of dimethylformamide and 4.05 g of N,N-carbonyldiimidazole are added. The mixture is briefly heated to 70° C. and then stirred for a further hour at ambient temperature. After this time 4.85 ml of N-methylpiperazine are added and the mixture is stirred for 12 hours at ambient temperature. The solvent is eliminated and the residue is purified through a silica gel column with methylene chloride/ethanol/ammonia 7:1:0.1 as eluant.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][C:9]([NH:11][C@H:12]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([OH:24])=[O:23])[C:15]=3[O:14][B:13]2[OH:25])=[O:10])[CH2:4][CH2:3]1.C[CH2:27][N:28](C(C)C)C(C)C.Cl.C(=N)OC(C)C>CO>[CH:27](=[NH:28])[NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][C:9]([NH:11][C@H:12]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([OH:24])=[O:23])[C:15]=3[O:14][B:13]2[OH:25])=[O:10])[CH2:4][CH2:3]1
Reactant: CCN(C(C)C)C(C)C
Reactant: N[C@H]1CC[C@H](CC(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)CC1
Agent: CC(C)OC=N
Agent: Cl
Solvent: CO
Product: N=CN[C@H]1CC[C@H](CC(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (R)-3-(2-(trans-4-aminocyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid (Example 6) in MeOH was added DIEA (2.5 eq), followed by isopropyl formimidate hydrochloride (1.2 eq). The reaction mixture was stirred at RT overnight. The mixture was then concentrated in vacuo and the crude product was purified using reverse phase HPLC to afford the title compound. ESI-MS m/z 374 (MH)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH:5]([CH3:9])[C:6](=O)[CH3:7])[CH3:2].[CH:11]1([NH2:16])[CH2:15][CH2:14][CH2:13][CH2:12]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C>[CH2:1]([O:3][C:4](=[O:10])[CH:5]([CH3:9])[CH:6]([NH:16][CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)[CH3:7])[CH3:2]
Reactant: CCOC(=O)C(C)C(C)=O
Reactant: NC1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CCOC(=O)C(C)C(C)NC1CCCC1
Reaction time: 1.5 h
Yield: 50.2 %

Procedure:
To a solution of 2.1 g (0.014 mole) of 2-methyl-3-oxo-butanoic acid ethyl ester and 40 mL of dichloroethane was added 1.37 g (0.016 mole) of cyclopentylamine. The mixture was stirred for 1.5 hours, then 4.63 g (0.020 mole) of sodium triacetoxyborohydride and 0.84 g (0.014 mole) of acetic acid were added. The mixture was stirred at room temperature for 24 hours and then quenched by the addition of 50 mL of saturated aqueous sodium bicarbonate. After 20 minutes, the organic layer was separated and the aqueous layer was extracted twice with 30 mL of dichloromethane. The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated to afford the crude product as yellow oil. Purification of the residue by silica gel chromatography, eluting with hexanes-ethyl acetate (30:70) gave 1.5 g of (rac)-3-cyclopentylamino-2-methyl-butanoic acid ethyl ester.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[NH:11][C:12]([C:14]2[N:18]3[CH:19]=[CH:20][C:21]([CH2:23][CH:24]=O)=[CH:22][C:17]3=[N:16][CH:15]=2)=[O:13])[N:4]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[N:28]=2)[N:3]=1.[CH3:34][NH:35][CH3:36].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.CCO>[CH3:34][N:35]([CH3:36])[CH2:24][CH2:23][C:21]1[CH:20]=[CH:19][N:18]2[C:14]([C:12]([NH:11][C:9]3[CH:8]=[CH:7][CH:6]=[C:5]4[C:10]=3[C:2]([CH3:1])=[N:3][N:4]4[CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[N:28]=3)=[O:13])=[CH:15][N:16]=[C:17]2[CH:22]=1
Reactant: Cc1cccc(Cn2nc(C)c3c(NC(=O)c4cnc5cc(CC=O)ccn45)cccc32)n1
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: Cc1cccc(Cn2nc(C)c3c(NC(=O)c4cnc5cc(CCN(C)C)ccn45)cccc32)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.8 %

Procedure:
A solution of N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2-oxoethyl)imidazo[1,2-a]pyridine-3-carboxamide (33 mg, 0.068 mmol) and dimethylamine (0.34 mL, 0.68 mmol) in 1.4 mL of a 1:1 MeOH/EtOH mixture was treated at ambient temperature with excess (10 equivalents) sodium triacetoxyborohydride. The reaction mixture was stirred overnight at ambient temperature. Another 10 equivalents of sodium triacetoxyborohydride were added, and stirring was continued for a few more hours. The reaction mixture was quenched with an equal volume of saturated, aqueous sodium bicarbonate, and extracted with DCM and EtOAc. The combined organic extracts were dried over anhydrous sodium sulfate, concentrated, and subjected to preparative thin-layer chromatography on silica, with an 8% MeOH-2% 7N NH3/MeOH/DCM mixture as eluent, to afford 6.6 mg of desired product. MS (ES+APCI) m/z=468 (M+H) detected.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][Mg]Cl)=[CH:4][CH:3]=1.FC1C=CC(CCl)=CC=1.[Mg].Cl[Si:22]([CH2:25][Cl:26])([CH3:24])[CH3:23].Cl>CCOCC.CCCCCC>[Cl:26][CH2:25][Si:22]([CH3:24])([CH3:23])[CH2:6][C:5]1[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: C[Si](C)(Cl)CCl
Reactant: Fc1ccc(C[Mg]Cl)cc1
Agent: Cl
Agent: Fc1ccc(CCl)cc1
Agent: [Mg]
Solvent: CCOCC
Solvent: CCCCCC
Product: C[Si](C)(CCl)Cc1ccc(F)cc1
Yield: 93 %

Procedure:
To the 4-fluorobenzylmagnesiumchloride, prepared from parafluorobenzylchloride (1.59 g, 11 mmol) and magnesium (0.25 g, 11 mmol) in ether (20 ml), was added dropwise, at 0° C., chloro-chloromethyl-dimethylsilane (1.43 g, 10 mmol )in ether (5 ml) Then the mixture was refluxed 6 hours, cooled to 0° C. hydrolyzed with 3N HCl (20 ml) and extracted with ether. The ether solution was washed with water, brine, dried and evaporated. Chromatography (silica gel, hexane) afforded chloromethyl-dimethyl-4-fluorobenzyl silane as an oil (2.01 g, 93% yield) 1H NMR, CDCl3, TMS) δ: 0.20 (s,6H), 2.27 (s,2H), 2.63 (s,2H), 6.90-7.13 (m,4H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:31])[C:10]([NH:12][CH2:13][C:14]2[C:15]([C:24]3[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=3)=[N:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=2)=[O:11])=[CH:5][C:4]=1[Cl:32].[CH3:33][S:34](Cl)(=[O:36])=[O:35]>N1C=CC=CC=1.ClCCl>[Cl:32][C:4]1[CH:5]=[C:6]([CH:9]([CH3:31])[C:10]([NH:12][CH2:13][C:14]2[C:15]([C:24]3[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=3)=[N:16][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:18][CH:19]=2)=[O:11])[CH:7]=[CH:8][C:3]=1[CH2:2][NH:1][S:34]([CH3:33])(=[O:36])=[O:35]
Reactant: Cc1cccc(-c2nc(C(F)(F)F)ccc2CNC(=O)C(C)c2ccc(CN)c(Cl)c2)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cccc(-c2nc(C(F)(F)F)ccc2CNC(=O)C(C)c2ccc(CNS(C)(=O)=O)c(Cl)c2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 82.6 %

Procedure:
To a stirred solution of 2-(4-(aminomethyl)-3-chlorophenyl)-N-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide (90 mg, 0.195 mmol) in pyridine, cooled to 0° C., were added methanesulfonyl chloride (90 mg). The resulting reaction mixture was stirred for 15 h at room temperature. The mixture dissolved in dichloromethane and washed with 1N HCl. The organic layer was dried over magnesium sulfate and filtered. The filtrate removed in vacuo. The crude was purified by column chromatography. 2-(3-Chloro-4-(methylsulfonamidomethyl)phenyl)-N-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide (example 77) (87 mg) was obtained as 83% yield. 1H NMR (300 MHz, CDCl3) 7.77 (d, 1H, J=8.04 Hz, Ar), 7.58 (d, 1H J=8.07 Hz, Ar), 7.39 (d, 1H, J=7.86 Hz, Ar), 7.28 (m, 4H, Ar), 7.13 (m, 2H, Ar), 5.59 (t, 1H, NH), 4.82 (t, 1H, NH), 4.47 (d, 2H, J=6.03 Hz, CH2), 4.37 (d, 2H, J=6.39, CH2), 3.44 (q, 1H, CH), 2.88 (s, 3H, mesyl), 2.38 (s, 3H, methyl), 1.44 (d, 3H, J=7.14 Hz, CH3)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:3]=1.Cl.Cl.[CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]([CH2:30][NH2:31])[N:21]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([NH:31][CH2:30][C:22]2[N:21]=[CH:20][C:29]3[C:24]([CH:23]=2)=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:5]([C:11]#[N:12])=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-n2cccn2)c1C#N
Reactant: NCc1cc2ccccc2cn1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(NCc2cc3ccccc3cn2)nc(N)nc1-n1cccn1

Procedure:
From 2-amino-4-methanesulfinyl-6-pyrazol-1-yl-pyrimidine-5-carbonitrile, C-isoquinolin-3-yl-methylamine dihydrochloride and DBU in DME. ES-MS m/e (%): 343 (M+H+, 100).
Reaction SMILES: O[CH2:2][C:3]1[CH:23]=[C:6]2[C:7](=[O:22])[NH:8][C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=3)=[CH:10][N:5]2[N:4]=1.S(Cl)([Cl:26])=O>ClCCl>[Cl:26][CH2:2][C:3]1[CH:23]=[C:6]2[C:7](=[O:22])[NH:8][C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=3)=[CH:10][N:5]2[N:4]=1
Reactant: O=c1[nH]c(-c2ccc(OC(F)(F)F)cc2)cn2nc(CO)cc12
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=c1[nH]c(-c2ccc(OC(F)(F)F)cc2)cn2nc(CCl)cc12

Procedure:
82 mg (0.252 mmol) 2-Hydroxymethyl-6-(4-trifluoromethoxy-phenyl)-5H-pyrazolo[1,5-a]pyrazin-4-one are treated with thionyl chloride in dichloromethane similar to WO2010/043676 (example G02) to give 2-chloromethyl-6-(4-trifluoromethoxy-phenyl)-5H-pyrazolo[1,5-a]pyrazin-4-one as pale pink crystals; HPLC/MS 1.91 min (C), [M+H] 344;