Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10](=O)[CH2:11][C:12]1[C:13]([CH2:19][CH3:20])=[N:14][NH:15][C:16]=1[CH2:17][CH3:18])C.O>O1CCCC1>[CH2:17]([C:16]1[C:12]([CH2:11][CH2:10][OH:9])=[C:13]([CH2:19][CH3:20])[NH:14][N:15]=1)[CH3:18]
Reactant: CCOC(=O)Cc1c(CC)n[nH]c1CC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCc1n[nH]c(CC)c1CCO
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.1 %

Procedure:
Lithium aluminum hydride (190 mg, 4.8 mmol) was added slowly to tetrahydrofuran (10 mL) under 0° C. (3,5-Diethyl-1H-pyrazol-4-yl)-acetic acid ethyl ester (1.0 g, 4.8 mmol) in tetrahydrofuran (5 mL) was slowly added under nitrogen atmosphere. The reaction was allowed to slowly warm to room temperature and stirred for 16 h. After the reaction was cooled at 0° C., water (0.3 mL) was added slowly and the reaction was stirred for 30 minutes, filtered through a short silica gel column, which was rinsed with ethyl acetate followed by 20% methanol/methylene chloride. The solution was concentrated in vacuo to provide 2-(3,5-diethyl-1H-pyrazol-4-yl)-ethanol (0.8 g, 100% yield).
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([NH2:20])[C:14]3=[C:13]([C:21]3[CH:30]=[C:29]4[C:24]([CH:25]=[CH:26][C:27]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)=[N:28]4)=[CH:23][CH:22]=3)[N:12]=2)[CH2:7][CH2:6]1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[NH2:20][C:19]1[C:14]2[N:15]([C:11]([C@H:8]3[CH2:7][CH2:6][C@H:5]([CH2:3][OH:2])[CH2:10][CH2:9]3)=[N:12][C:13]=2[C:21]2[CH:30]=[C:29]3[C:24]([CH:25]=[CH:26][C:27]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[N:28]3)=[CH:23][CH:22]=2)[CH:16]=[CH:17][N:18]=1
Reactant: COC(=O)[C@H]1CC[C@H](c2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(N)nccn32)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Nc1nccn2c1c(-c1ccc3ccc(-c4ccccc4)nc3c1)nc2[C@H]1CC[C@H](CO)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A THF solution (8 mL) of trans-4-[8-amino-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylic acid methyl ester was cooled to −780C and charged with 1M LiAlH4 in THF (1.5 mL, 1.5 mmol) dropwise; the reaction vessel was removed from the −78° C. cooling bath and stirred at rt for 4 h. The reaction mixture was charged with EtOAc, Na2SO4.10H2O, and silica gel and concentrated in vacuo to yellow solids. The crude material was purified by silica gel column chromatography [Jones Flashmaster, 10 g/70 mL cartridge, eluting with 1%˜7N NH3 in MeOH/CH2Cl2] to afford the desired product as a yellow solid; 1H NMR (CDCl3, 400 MHz) δ 1.17-1.29 (m, 2H), 1.63-1.73 (m, 2H), 1.87-2.07 (m, 4H), 2.12-2.23 (m, 2H), 2.92-3.02 (m, 1H), 3.56 (d, 2H, J=6.0 Hz), 5.25 (s, 2H), 7.13 (d, 1H, J=4.8 Hz), 7.27-7.28 (m, 1H), 7.46-7.50 (m, 1H), 7.52-7.57 (m, 2H), 7.89-7.96 (m, 3H), 8.18-8.21 (m, 2H), 8.27 (d, 1H, J=8.8 Hz), 8.40-8.42 (m, 1H); MS (ES+): m/z 450.0 [MH+]; HPLC: tR=2.4 min (Micromass Platform II, polar—5 min).
Reaction SMILES: [Cl:1][C:2]1[C:3]([I:12])=[CH:4][C:5]([N+:9]([O-])=O)=[C:6]([CH:8]=1)[NH2:7].[NH4+].[Cl-]>C(O)C.O.CCOC(C)=O.[Fe]>[Cl:1][C:2]1[C:3]([I:12])=[CH:4][C:5]([NH2:9])=[C:6]([NH2:7])[CH:8]=1
Reactant: Nc1cc(Cl)c(I)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: Nc1cc(Cl)c(I)cc1N
Temperature: 60 °C
Reaction time: 40 h

Procedure:
To a mixture of 5-chloro-4-iodo-2-nitroaniline 1-5 (31.7 g, 106 mmol) and iron powder (59.0 g, 1060 mmol) in 880 mL ethanol was added a solution of NH4Cl (28 g, 530 mmol) in 240 mL of water. The resulting mixture was mechanically stirred at 60° C. for 40 h. After cooling to rt the mixture was filtered and the filtrate reduced to about 500 mL by rotary evaporation. This filtrate was diluted with 1 L of EtOAc and 1 L of water, and shaken. The organic layer separated, washed with brine, dried (MgSO4) and evaporated to provide crude product. The crude product was dissolved in 80 mL of EtOAc, diluted with 80 mL of hexanes and injected onto a 330 g column of SiO2, which was pre-eluted with 33% EtOAc in hexanes. The column was subjected to MPLC eluting at 100 mL/min with 33% EtOAc in hexanes (15 min) and then 50% EtOAc (20 min) to provide 5-chloro-4-iodo-1,2-phenylenediamine 1-6. Impure fractions of residue were resubjected to MPLC on a 330 g column of SiO2 by the same method to provide additional 5-chloro-4-iodo-1,2-phenylenediamine 1-6 as an amorphous solid. 1H NMR (500 MHz, DMSO-d6): δ 4.77 (s, 2H), 4.91 (s, 2H), 6.66 (s, 1H), 6.93 (s, 1H); LC-MS: calculated for C6H6ClIN2 267.9, observed Dole 269.0 (M+H)+.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[NH:7][C:6]=1[C:16]([NH:18][CH3:19])=[O:17].C(N(C(C)C)CC)(C)C.[C:29](Cl)(=[O:32])[CH2:30][CH3:31]>ClCCl>[CH3:15][O:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:16]([NH:18][CH3:19])=[O:17])=[C:5]2[CH2:4][CH2:3][NH:2][C:29](=[O:32])[CH2:30][CH3:31]
Reactant: CNC(=O)c1[nH]c2ccc(OC)cc2c1CCN
Reactant: CCC(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(=O)NCCc1c(C(=O)NC)[nH]c2ccc(OC)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 3-(2-aminoethyl)-5-methoxy-N-methyl-1H-indole-2-carboxamide hydrochloride (80.0 mg) and dichloromethane (4.44 mL) were added diisopropylethylamine (0.145 mL) and propionyl chloride (0.0296 mL), followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=10:0 to 10:1). The obtained residue was solidified with a mixed solvent of hexane:ethyl acetate=2:1 to obtain 5-methoxy-N-methyl-3-[2-(propionylamino)ethyl]-1H-indole-2-carboxamide (56.0 mg) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([N:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=4)=[CH:13][C:12]3=[O:27])[CH:7]=[CH:6][C:5]=2[C:4]2[CH2:28][N:29](C(OC(C)(C)C)=O)[CH2:30][CH2:31][C:3]1=2.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:51].Cl>>[ClH:51].[ClH:51].[CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([N:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:19][N:18]=4)=[CH:13][C:12]3=[O:27])[CH:7]=[CH:6][C:5]=2[C:4]2[CH2:28][NH:29][CH2:30][CH2:31][C:3]1=2
Reactant: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)cn5)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)cn5)cc4=O)cc31)CNCC2
Yield: 78 %

Procedure:
tert-Butyl 5-methyl-7-(2-oxo-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-1(2H)-yl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (83 mg, 0.16 mmol) was deprotected and converted to the dihydrochloride salt according to the procedure of Example 30 (steps e and g) to provide the title compound (51 mg, 78%) as a yellow solid: mp 320-330° C.; 1H NMR (500 MHz, CD3OD) δ 9.06 (s, 1H), 8.28 (dd, J=8.4, 2.1 Hz, 1H), 8.23 (d, J=8.2 Hz, 1H), 7.87 (d, J=7.1 Hz, 1H), 7.64 (d, J=8.3 Hz, 1H), 7.58 (d, J=1.6 Hz, 1H), 7.43 (d, J=1.6 Hz, 1H), 7.29 (dd, J=Hz, 1H), 7.17 (dd, J=8.3, 1.8 Hz, 1H), 4.50 (s, 2H), 3.76 (s, 3H), 3.69 (t, J=6.0 Hz, 2H), 3.22 (t, J=Hz, 2H); ESI MS m/z 425 [M+H]+; HPLC (Method B)>99% (AUC), tR=12.5 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH2:12][CH3:13])[N:8]=[C:7]2[C:14]1[CH:19]=[CH:18][C:17]([O:20]C)=[C:16]([F:22])[CH:15]=1.B(Br)(Br)Br>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH2:12][CH3:13])[N:8]=[C:7]2[C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([F:22])[CH:15]=1
Reactant: CCCn1nc(-c2ccc(OC)c(F)c2)c2cccc(Cl)c21
Agent: BrB(Br)Br
Product: CCCn1nc(-c2ccc(O)c(F)c2)c2cccc(Cl)c21
Yield: 47.6 %

Procedure:
Prepared according to Method D step C from 7-Chloro-3-(3-fluoro-4-methoxyphenyl)-1-propyl-1H-indazole (0.26 g, 0.82 mmol), BBr3 (0.15 mL, 1.63 mmol) to give the title compound as a white solid (0.12 g, 0.39 mmol, 48%).
Reaction SMILES: C[O:2][C:3](=[O:38])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]([CH3:35])[C:18]([OH:34])([C:23]3[CH:24]=[CH:25][C:26]4[O:30][C:29](=[O:31])[N:28]([CH3:32])[C:27]=4[CH:33]=3)[C:19]([F:22])([F:21])[F:20])=[C:13]([Cl:36])[CH:12]=2)=[CH:6][C:5]=1[Cl:37].[Li+].[OH-].Cl>C1COCC1>[Cl:37][C:5]1[CH:6]=[C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]([CH3:35])[C:18]([OH:34])([C:23]3[CH:24]=[CH:25][C:26]4[O:30][C:29](=[O:31])[N:28]([CH3:32])[C:27]=4[CH:33]=3)[C:19]([F:22])([F:21])[F:20])=[C:13]([Cl:36])[CH:12]=2)[CH:8]=[CH:9][C:4]=1[C:3]([OH:38])=[O:2]
Reactant: COC(=O)c1ccc(Oc2ccc(C(C)C(O)(c3ccc4oc(=O)n(C)c4c3)C(F)(F)F)c(Cl)c2)cc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(c1ccc(Oc2ccc(C(=O)O)c(Cl)c2)cc1Cl)C(O)(c1ccc2oc(=O)n(C)c2c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 5 h

Procedure:
2-Chloro-4-{3-chloro-4-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(3-methyl-2-oxo-2,3-dihydro-benzooxazol-5-yl)-propyl]-phenoxy}-benzoic acid methyl ester (33 mg, obtained in Example 173, step 1) was dissolved in THF (2 mL) followed by the addition of aqueous LiOH solution (1.0M, 0.14 mL). The mixture was stirred for 5 hours at r.t. The reaction mixture was poured into ice/water and acified with 1M aqueous HCl to pH 1. The aqueous layer was extracted three times with ethylacetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography (silica gel, CH2Cl2:MeOH:CH3COOH=100:0:0 to 98:2:0.5) to give the title compound as a light yellow foam. The residual acetic acid was removed by co-evaporation with toluene (10 mg, 31%). MS (neg. ion, m/e)=554.3 [(M−H)−].
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1>[Pd].CC#N>[CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][CH2:1][C:2]2[CH:9]=[CH:8][C:5]([CH3:6])=[CH:4][CH:3]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(CN)cc1
Agent: [Pd]
Solvent: CC#N
Product: Cc1ccc(CNCc2ccc(C)cc2)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
4-Methylbenzylamine (0.5 mmol) was also heated with catalyst Pd@ba-GO (10 mg) and solvent CH3CN (0.2 mL) at 90° C. in a flask open to air for 6 hours, and then stirred also at 90° C. under H2 gas (1 atm) for 8 hours to obtain di-(4-methylbenzyl)amine. Again, an unexpectedly high yield of 82% was achieved.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7](Cl)=[N:8][OH:9].[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1)#[CH:13].N>>[F:1][C:2]1[CH:11]=[C:6]([C:7]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:21])([F:22])[F:23])[CH:15]=3)[O:9][N:8]=2)[CH:5]=[N:4][CH:3]=1
Reactant: ON=C(Cl)c1cncc(F)c1
Reactant: C#Cc1cccc(C(F)(F)F)c1
Agent: N
Product: Fc1cncc(-c2cc(-c3cccc(C(F)(F)F)c3)on2)c1

Procedure:
The titled compound was prepared according to Method CB using the product of Example 28B (88 mg, 0.5 mmol) and 1-ethynyl-3-(trifluoromethyl)benzene (Aldrich, 85 mg, 0.5 mmol). 1H NMR (300 MHz, MeOH-d4) δ 7.57 (s, 1H), 7.71-7.96 (m, 2H), 8.09-8.32 (m, 3H), 8.62 (d, J=2.7 Hz, 1H), 8.98 (t, J=1.5 Hz, 1H) ppm; MS (DCI/NH3) m/z 309 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C@@H:19]3[O:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20]3)=[CH:15][CH:14]=2)=[N:4][C:5]([O:8][CH:9]([CH3:11])[CH3:10])=[N:6][CH:7]=1.F[B-](F)(F)F.C1CCN2C(=NCCC2)CC1>CC1C=CC=CC=1C.CN(C)C(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:9]([O:8][C:5]1[N:6]=[CH:7][C:2]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C@@H:19]4[O:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20]4)[CH:17]=3)[NH:12][C:3]=2[N:4]=1)([CH3:11])[CH3:10]
Reactant: CC(C)Oc1ncc(Cl)c(Nc2ccc([C@H]3CN(C(=O)OC(C)(C)C)CCO3)cc2)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: F[B-](F)(F)F
Solvent: CC(=O)N(C)C
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1C
Product: CC(C)Oc1ncc2c(n1)[nH]c1ccc([C@H]3CN(C(=O)OC(C)(C)C)CCO3)cc12
Temperature: 155 °C

Procedure:
(S)-tert-Butyl 2-(4-(5-chloro-2-isopropoxypyrimidin-4-ylamino)phenyl)morpholine-4-carboxylate (55 mg, 0.12 mmol), palladium-(II) acetate (2.8 mg, 0.012 mmol), tricyclohexylphopsphine tetrafluoroborate (9 mg, 0.024 mmol) and DBU (1,8-diazabicyclo[5.4.0]undec-7-ene; 37 mg, 0.245 mmol) were dissolved in a mixture of o-xylene (0.5 ml) and N,N-dimethylacetamide (0.5 ml). The mixture was degassed with Ar for 5 min, the vessel closed and heated at 155° C. for 16 h. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over MgSO4 and evaporated. The residue was purified by column chromatography (SiO2, 5 to 20% EtOAc in heptane, 2 g ISCO column). White solid (11 mg, 22%). MS (ISP): 413.3 ([M+H]+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:20])[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1.[O:30]1[CH2:32][C@H:31]1[CH2:33][O:34][C:35]1[CH:43]=[CH:42][C:38]2[O:39][CH2:40][O:41][C:37]=2[CH:36]=1>>[CH2:22]([NH:21][C:19]([N:16]1[CH2:17][CH2:18][CH:13]([S:10]([C:7]2[CH:6]=[CH:5][C:4]([CH2:3][CH2:2][NH:1][CH2:32][C@H:31]([OH:30])[CH2:33][O:34][C:35]3[CH:43]=[CH:42][C:38]4[O:39][CH2:40][O:41][C:37]=4[CH:36]=3)=[CH:9][CH:8]=2)(=[O:12])=[O:11])[CH2:14][CH2:15]1)=[O:20])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCNC(=O)N1CCC(S(=O)(=O)c2ccc(CCN)cc2)CC1
Reactant: c1cc2c(cc1OC[C@@H]1CO1)OCO2
Product: CCCCCCCCNC(=O)N1CCC(S(=O)(=O)c2ccc(CCNC[C@H](O)COc3ccc4c(c3)OCO4)cc2)CC1
Yield: 31.1 %

Procedure:
4-{[4-(2-Aminoethyl)phenyl]sulfonyl}-N-octyl-1-piperidinecarboxamide (0.920 g, 2.172 mmol) was reacted with 5-[(2S)oxiranylmethoxy]-1,3-benzodioxole(0.211 g, 1.086 mmol) according to Procedure G to give the title compound (eluant: 20:1 chloroform-methanol) (0.209 g, 0.338 mmol).
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4].[CH3:7][C:8]([CH3:10])=O.CS(O)(=O)=O>C1(C)C=CC=CC=1>[OH:1][CH2:2][CH:3]1[CH2:5][O:6][C:8]([CH3:10])([CH3:7])[O:4]1
Reactant: OCC(O)CO
Reactant: CC(C)=O
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Product: CC1(C)OCC(CO)O1
Yield: 83.1 %

Procedure:
Glycerin (250 g), acetone (522 g) and 800 mL of toluene were charged into a 2 L four-neck flask to which a thermometer, a nitrogen inlet tube, a stirrer and a dehydrating column with a condenser were attached, and then, methane sulfonic acid (26 g) was added thereto and refluxed for 30 hours while removing the distilled water. Next, a potassium hydroxide solution was added to neutralize the reaction mixture. The reaction product was washed with ion exchanged water five times, and after that, the toluene was distilled off under reduced pressure, and thus, 298 g of 4-hydroxymethyl-2,2-dimethyl-1,3-dioxolan was obtained.
Reaction SMILES: [I:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.Br[CH2:11][C:12]([O:14][CH3:15])=[O:13]>>[I:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[N:6]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:7]=1
Reactant: O=c1[nH]cc(I)c(=O)[nH]1
Reactant: COC(=O)CBr
Product: COC(=O)Cn1cc(I)c(=O)[nH]c1=O

Procedure:
Astoundingly, as can be seen from FIG. 2, it was the use of a modification of the Heck reaction (Heck, J. Am. Chem. Soc. 90 (1968), 5518), of all possible options, which led to the desired C—C linkage. 5-Iodouracil (5) was first of all alkylated with methyl bromoacetate to give methyl 5-iodouracil-1-acetate (6). The Heck reaction of 6 with Z-protected allylamine in the presence of Pd(OAc)2 and triphenylphosphine in absolute acetonitrile was carried out with the exclusion of air and at a superelevated temperature (bath temperature of 110° C.), and yielded the compound (7) together with a small portion of the oxidized byproduct (8). The methyl ester (7) was then hydrolyzed to give the free acid (9), which was reacted with methyl 2-Boc-aminoethylglycine (10) in analogy with the method of Dueholm et al., (J. Org. Chem. 59 (1994), 5767). The desired amino-modified thymine PNA building block (11) was obtained after the ester had been subjected to alkaline hydrolysis.
Reaction SMILES: [CH:1]1([C:6]([OH:8])=O)[CH2:5][CH:4]=[CH:3][CH2:2]1.O1CCCC1.S(Cl)(Cl)=O.[NH2:18][C:19]1[CH:20]=[C:21]([CH:38]=[CH:39][C:40]=1[CH3:41])[O:22][C:23]1[CH:24]=[CH:25][C:26]2[N:27]([N:29]=[C:30]([NH:32][C:33]([CH:35]3[CH2:37][CH2:36]3)=[O:34])[N:31]=2)[CH:28]=1>CN(C)C=O.CN(C)C(=O)C>[CH:35]1([C:33]([NH:32][C:30]2[N:31]=[C:26]3[CH:25]=[CH:24][C:23]([O:22][C:21]4[CH:38]=[CH:39][C:40]([CH3:41])=[C:19]([NH:18][C:6]([CH:1]5[CH2:2][CH:3]=[CH:4][CH2:5]5)=[O:8])[CH:20]=4)=[CH:28][N:27]3[N:29]=2)=[O:34])[CH2:36][CH2:37]1
Reactant: O=C(O)C1CC=CC1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)cc1N
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)cc1NC(=O)C1CC=CC1
Yield: 59.2 %

Procedure:
In the same manner as in Example 55 and using cyclopenta-3-en-1-carboxylic acid (66.0 mg, 0.592 mmol), tetrahydrofuran (5 mL), thionyl chloride (100 μL, 1.15 mmol), N,N-dimethylformamide (2 drops), N-[6-(3-amino-4-methylphenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (170 mg, 0.526 mmol) and N,N-dimethylacetamide (5 mL) as starting materials, the title compound (130 mg, 59%) was obtained as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=3[N:16]=[C:15]2[CH:25]([F:27])[F:26])[N:3]=1.[NH2:28][CH2:29][CH:30]1[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]1>>[F:26][CH:25]([F:27])[C:15]1[N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([NH:28][CH2:29][CH:30]3[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]3)[N:3]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=2[N:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(NCC2CCN(C(=O)OC(C)(C)C)CC2)nc(N2CCOCC2)n1
Yield: 91 %

Procedure:
Reaction of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole (Example 2) with tert-butyl 4-(aminomethyl)-1-piperidinecarboxylate as in previous examples gave tert-butyl 4-({[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]amino}methyl)-1-piperidinecarboxylate in 91% yield: mp (CH2Cl2/MeOH) 203-205° C.; 1H NMR (DMSO-d6) δ 8.10-7.60 (m, 3H), 7.41-7.36 (m, 1H), 6.94 (dd, J=7.8, 3.8 Hz, 1H), 3.974 and 3.970 (2s, 3H), 3.95-3.92 (m, 2H), 3.78-3.77 (m, 4H), 3.69 (m, 4H), 3.34-3.24 (m, 2H), 2.69 (m, 2H), 1.77-1.67 (m, 3H), 1.389 and 1.381 (2s, 9H), 1.12-1.00 (m, 2H); Anal. Calcd. for C27H36F2N8O4: C, 56.4; H, 6.3; N, 19.5. Found: C, 56.1; H, 6.3; N, 19.6%
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:34]([O:41][CH2:42][CH2:43]O)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH2:34]([O:41][CH2:42][CH2:43][O:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: OCCOCc1ccccc1
Reactant: COC(=O)c1cc(O)ccc1[N+](=O)[O-]
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(OCCOCc2ccccc2)ccc1[N+](=O)[O-]
Reaction time: 18 h
Yield: 93.1 %

Procedure:
To a solution of methyl 5-hydroxy-2-nitro-benzoate (7.97 g, 40.43 mmol), triphenylphosphine (12.73 g, 48.53 mmol), and 2-benzyloxyethanol (5.86 ml, 41.24 mmol) in tetrahydofuran (100 ml) was added DEAD (8.04 ml, 95%, 48.51 mmol) dropwise. After addition of the DEAD, the reaction was stirred under nitrogen for 18 h. The solvent was evaporated, benzene was added, and the triphenylphosphine oxide was filtered off. The solid was washed with some benzene, and the filtrate evaporated. The yellow oil was dissolved in minimal benzene, and chromatographed on silica gel eluting with 25% ethyl acetate/hexanes to give methyl 5-(2-benzyloxy-ethoxy)-2-nitro-benzoate (12.47 g, 93%) as a light yellow oil. Analysis calculated for C17H17NO6 : C, 61.63; H, 5.17; N, 4.23. Found: C, 61.46; H, 5.02; N, 4.28.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH2:11].[C:18](N1C=CN=C1)(N1C=CN=C1)=[O:19]>C(Cl)(Cl)Cl>[CH3:1][N:2]1[C:18](=[O:19])[NH:11][CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CNCc1ccccc1C(N)c1ccccc1
Solvent: ClC(Cl)Cl
Product: CN1Cc2ccccc2C(c2ccccc2)NC1=O
Temperature: 25 °C
Reaction time: 19 h
Yield: 71.1 %

Procedure:
A solution of 32.8 g (145 mmol) of 2-[(methylamino)methyl]-α-phenylbenzenemethanamine in 215 mL of chloroform was treated with 25.9 g (159 mmol) of carbonyldiimidazole. The reaction was stirred at room temperature for 19 hours, washed four times with water, dried over sodium sulfate and stripped in vacuo. The gummy residue was triturated in and recrystallized from ethyl acetate to yield 26 g (71%) of product, mp 198-199.
Reaction SMILES: [N:1]1([C:6]2[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[Cl:13][C:14]1[N:19]=[C:18](Cl)[N:17]=[C:16]([O:21][CH3:22])[N:15]=1>C(N(CC)CC)C>[Cl:13][C:14]1[N:15]=[C:16]([O:21][CH3:22])[N:17]=[C:18]([NH:10][C:9]2[CH:11]=[CH:12][C:6]([N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)=[CH:7][CH:8]=2)[N:19]=1
Reactant: COc1nc(Cl)nc(Cl)n1
Reactant: Nc1ccc(-n2ccnc2)cc1
Solvent: CCN(CC)CC
Product: COc1nc(Cl)nc(Nc2ccc(-n3ccnc3)cc2)n1
Yield: 84 %

Procedure:
This compound was prepared in analogy to example 8 from 4-(imidazol-1-yl)-aniline, triethylamine and 2,4-dichloro-6-methoxy-1,3,5-triazine. The title compound was isolated as a slightly brownish solid in 84% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH:17]([CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][C:22]=3[F:29])=[O:19])=[C:15]3[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)=[N:9]2)=[CH:4][CH:3]=1.[NH4+].[Cl-].[N-:38]=[N+:39]=[N-:40].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]([CH:17]([CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]4[NH:40][N:39]=[N:38][N:28]=4)=[CH:23][C:22]=3[F:29])=[O:19])=[C:15]3[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)=[N:9]2)=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(NC(=O)C(c2c3c(nn2-c2ccc(Cl)cc2)CCCC3)C2CCCCC2)c(F)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(-c2nnn[nH]2)cc1F)C(c1c2c(nn1-c1ccc(Cl)cc1)CCCC2)C1CCCCC1
Temperature: 120 °C
Yield: 34 %

Procedure:
To a stirred solution of [rac]-2-[2-(4-chloro-phenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-N-(4-cyano-2-fluoro-phenyl)-2-cyclohexyl-acetamide (110 mg, 0.22 mmol) in dry DMF (3 ml) was added NH4Cl (48.39 mg, 0.88 mmol) and NaN3 (57.2 mg, 0.88 mmol) at room temperature. The reaction mixture was then heated at 120° C. for 12 h. After cooling, TLC shows formation of new spot, filtered the solid material by sintered funnel and washed the solid residue by EtOAc (3×5 ml). Combined organic layers were reduced under pressure at 50° C. and diluted the residue with EtOAc (15 mL). Organic layer was washed with H2O (10 ml), brine (10 ml) and dried over Na2SO4; which was then concentrated under reduced pressure to give crude material (90 mg). Crude product was then purified by column chromatography [SiO2 (230-400 mesh), MeOH:DCM 0:95/5:95] to give the title compound (40 mg, 33.3%) as brown solid. MS: m/e=534.0 [M+H+].