Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][C@H:15]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:16]([N:18]1[CH2:22][CH2:21][CH2:20][C@H:19]1[C:23](=[O:37])[NH:24][CH2:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[C:32]([NH2:36])=[N:31][CH:30]=[CH:29]2)=[O:17])(C)(C)C>ClCCl>[NH2:36][C:32]1[C:33]2[C:28](=[CH:27][C:26]([CH2:25][NH:24][C:23]([C@@H:19]3[CH2:20][CH2:21][CH2:22][N:18]3[C:16](=[O:17])[C@H:15]([NH2:14])[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:37])=[CH:35][CH:34]=2)[CH:29]=[CH:30][N:31]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)NCc1ccc2c(N)nccc2c1)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1nccc2cc(CNC(=O)[C@@H]3CCCN3C(=O)[C@H](N)c3ccccc3)ccc12
Yield: 62.4 %

Procedure:
Trifluoroacetic acid (3.0 mL) was added to 150 mg of (2-{2(S)-[(1-amino-isoquinolin-6-ylmethyl)-carbamoyl]-pyrrolidin-1-yl}-2-oxo-1(R)-phenyl-ethyl)-carbamic acid tert-butyl ester (prepared according to the procedures described in example 110) in 3.0 mL dichloromethane. Stirring was continued for 2h at ambient temperature. The solvent was removed i.vac, the residue was dissolved in methanol and applied to a reversed-phase chromatography column (lenght 100 mm, diameter 14 mm; Merck Lichroprep RP-18, 15-25 p). Elution was started with 25 mL of methanol/water containing 0.3% acetic acid (10:90), then a linear gradient to pure methanol over a period of 75 mL was applied followed by 50 mL of pure methanol. Fractions of 5 mL each were sampled. The solvent was removed to give 75 mg (62%) of the title compound. MS: 404.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][N:6]=[CH:5]2.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O.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]>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH:20][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8](=[O:12])[NH:7][N:6]=[CH:5]3)=[CH:17][CH:16]=1
Reactant: O=c1[nH]ncc2cc(Br)ccc12
Reactant: COc1ccc(CN)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc(CNc2ccc3c(=O)[nH]ncc3c2)cc1
Yield: 35.5 %

Procedure:
A mixture of 6-bromo-2H-phthalazin-1-one (50 mg, 0.22 mmol), 4-methoxybenzylamine (0.030 mL, 0.24 mmol), Pd2(dba)3 (20 mg, 0.022 mmol), rac-BINAP (41 mg, 0.066 mmol) and NaOt-Bu (52 mg, 0.55 mmol) in toluene (10 mL) was heated at reflux for 3 h. The mixture was allowed to cool, diluted with EtOAc (25 mL) and washed with NaHCO3 (25 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. Chromatography on silica (EtOAc/hexanes) yielded the title compound (22 mg, 35%). 1H-NMR (DMSO-d6) δ: 12.1 (s, 1H), 8.05 (s, 1H), 7.88 (d, 1H), 7.30 (m, 3H), 7.10 (dd, 1H), 6.90 (d, 2H), 6.75 (s, 1H), 4.20 (d, 2H), 3.85 (s, 3H); m/z (M+1)=282.22.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH2:44]([NH:48][CH2:49][C:50]1[CH:55]=[CH:54][C:53]([C:56]([CH3:59])([CH3:58])[CH3:57])=[CH:52][CH:51]=1)[CH2:45][CH2:46][CH3:47]>CN(C=O)C.O>[CH2:44]([N:48]([CH2:49][C:50]1[CH:55]=[CH:54][C:53]([C:56]([CH3:57])([CH3:59])[CH3:58])=[CH:52][CH:51]=1)[C:10]([C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[NH:1][CH:2]=[CH:3]2)=[O:12])[CH2:45][CH2:46][CH3:47]
Reactant: CCCCNCc1ccc(C(C)(C)C)cc1
Reactant: O=C(O)c1cccc2cc[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCN(Cc1ccc(C(C)(C)C)cc1)C(=O)c1cccc2cc[nH]c12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 84.8 %

Procedure:
To a solution of 110 mg of 1H-indole-7-carboxylic acid (0.68 mmol) and 220 mg of TBTU (0.68 mmol) in 10 ml DMF, were added 0.59 ml (3.42 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 150 mg (0.68 mmol) of butyl-(4-tert-butyl-benzyl)-amine were added. After stirring for 2 h at rt, the reaction mixture was diluted with 100 ml water and extracted twice with EtOAc. The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (8 g silica gel; heptane/EtOAc 2:1) to give 209 mg (82%) of a light yellow viscous oil. MS (EI) 362.2 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=O)[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][N:18]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:33].[Na+].O1CCCC1>CO.C(#N)C>[Cl:1][C:2]1[CH:11]=[C:10]([CH:12]([NH2:33])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][N:18]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: [BH3-]C#N
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCN(C2CCCCC2)CC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Solvent: C1CCOC1
Product: CC(N)c1cc(Cl)c2cccnc2c1N1CCN(C2CCCCC2)CC1
Temperature: 65 °C

Procedure:
A mixture of 1-[5-chloro-8-(4-cyclohexylpiperazin-1-yl)quinolin-7-yl]ethanone (0.094 g, 0.25 mmol) and ammonium acetate (0.195 g, 2.53 mmol) in methanol (1 mL) and acetonitrile (1 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, to the resulting mixture was added 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.632 mL, 0.632 mmol). The reaction was heated at 65° C. overnight. The mixture was cooled to room temperature, quenched with sat. NaHCO3 solution and extracted with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated to give the desired product. LCMS calculated for C21H30ClN4 (M+H)+: m/z=373.2; Found: 373.3.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[CH2:13]([O:15][C:16](=[O:25])[CH:17]([CH:22]([CH3:24])[CH3:23])[CH2:18][C:19]([OH:21])=O)[CH3:14].[C:26]1([CH:32]2[CH2:37][CH2:36][CH:35]([NH2:38])[CH2:34][CH2:33]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C)C1C=CN=CC=1.ClCCl>[CH2:13]([O:15][C:16](=[O:25])[CH:17]([CH2:18][C:19](=[O:21])[NH:38][CH:35]1[CH2:34][CH2:33][CH:32]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:37][CH2:36]1)[CH:22]([CH3:24])[CH3:23])[CH3:14]
Reactant: NC1CCC(c2ccccc2)CC1
Reactant: CCOC(=O)C(CC(=O)O)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)C(CC(=O)NC1CCC(c2ccccc2)CC1)C(C)C
Reaction time: 0.5 h
Yield: 26.4 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.80 g) was added to a solution of 4-dimethylaminopyridine (0.04g) and Intermediate 10 (0.54 g) in dichloromethane (30 ml) and the solution was stirred for 30 min, then a solution of Intermediate 14 (0.50 g) in dichloromethane (5 ml) was added and the mixture was stirred overnight. The solvent was removed in vacuo and the resulting slurry dissolved in ethyl acetate (100 ml), washed with water (10 ml), aqueous sodium bicarbonate (10 ml) and brine (10 ml), dried over magnesium sulphate (1 g) and the solvent removed in vacuo. The resulting oil was purified by flash chromatography (silica, eluent 30% ethyl acetate/hexane) to yield the title compound as a yellow solid (0.26 g).
Reaction SMILES: [S:1]([N:11]1[C:15]2=[N:16][CH:17]=[C:18]([CH2:20][NH:21][CH:22]=O)[N:19]=[C:14]2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].O=P(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>ClCCCl>[S:1]([N:11]1[C:15]2[N:16]=[CH:17][C:18]3[N:19]([CH:22]=[N:21][CH:20]=3)[C:14]=2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(CNC=O)cnc32)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2cncn23)cc1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 99.8 %

Procedure:
N-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methyl)formamide (3.66 g, 11.1 mmol, prepared using J.3 from Example #2, Step C with ethyl formate) was suspended in DCE (80 mL) then POCl3 (1.08 mL, 11.6 mmol) was added. The mixture was heated to about 80° C. for about 90 min and then cooled to rt. The mixture was treated with about 50 mL saturated aqueous NaHCO3 and then stirred for about 15 min. The layers were separated and aqueous layer was extracted with DCM (40 mL). The combined organics were dried over MgSO4, filtered and evaporated under reduced pressure to give 6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine (3.46 g, 100%): LC/MS (Table 2, Method a) Rt=1.97 min; MS m/z 313 (M+H)+.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:38][CH2:39][CH:40]([OH:52])[CH2:41][N:42]1[CH2:51][CH2:50][C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH2:43]1>C(Cl)Cl.O>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:38][CH2:39][CH:40]([OH:52])[CH2:41][N:42]2[CH2:51][CH2:50][C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[CH2:43]2)=[O:11])=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: NCC(O)CN1CCc2ccccc2C1
Reactant: CC(=O)Nc1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CC(=O)Nc1ccc(C(=O)NCC(O)CN2CCc3ccccc3C2)cc1
Temperature: 22 °C
Reaction time: 3 h
Yield: 23.6 %

Procedure:
A solution of 4-acetamidobenzoic acid (100 mg, 0.56 mmol), HATU (234 mg, 0.62 mmol) and TEA (63 mg, 0.62 mmol) in DCM (10 mL) was stirred at 22° C. for 10 min. 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (116 mg, 0.56 mmol) was then added and the solution was stirred at 22° C. for another 3 h. The reaction mixture was then diluted with water and extracted with DCM. The organic layers were combined and dried over anhydrous Na2SO4, filtered and concentrated and the residue was purified by prep-HPLC to give the title compound (48.5 mg, Yield 24%). 1H NMR (CD3OD, 400 MHz): δ 7.77-7.72 (m, 2H), 7.63-7.57 (m, 2H), 7.17-7.08 (m, 3H), 7.04 (d, J=7.0 Hz, 1H), 4.12 (t, J=6.0 Hz, 1H), 3.75 (s, 2H), 3.58-3.46 (m, 2H), 2.92-2.85 (m, 4H), 2.74-2.63 (m, 2H), 2.16 (s, 3H). LCMS (m/z): 368.1 (M+1).
Reaction SMILES: C([Mg]Cl)(C)C.[Cl:6][C:7]1[CH:8]=[CH:9][C:10](I)=[N:11][CH:12]=1.CN([CH:17]=[O:18])C>C1COCC1>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([CH:17]=[O:18])=[N:11][CH:12]=1
Reactant: Clc1ccc(I)nc1
Reactant: CN(C)C=O
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: O=Cc1ccc(Cl)cn1
Temperature: -15 °C
Reaction time: 1 h
Yield: 37.2 %

Procedure:
Isopropyl magnesium chloride (11.5 mL, 2 M in THF, 23 mmol) was added dropwise to a cold (−15° C.) solution of 5-chloro-2-iodo-pyridine (5 g, 20.9 mmol) in THF (35 mL). The mixture was stirred for 1 h at −15° C. DMF (2.3 g, 31.3 mmol) was added dropwise keeping the internal temperature below 0° C. The mixture was allowed to warm to rt, stirred for 1 h, cooled to 0° C., quenched by addition of a saturated aqueous solution of ammonium chloride, and extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by silica gel column chromatography (hexane/EtOAc, 95:5) to provide 1.1 g of the title compound. tR: 0.39 min (LC-MS 2); ESI-MS: 142 [M+H]+ (LC-MS 2); Rf=0.22 (hexane/EtOAc, 4:1).
Reaction SMILES: FC1C(F)=CC=CC=1C1C=C[C:12]([O:15]CCCCCCOC(=O)C=C)=[CH:11][CH:10]=1.[Br:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][OH:36].BrCCCCCCO>>[C:12]([O:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][Br:27])(=[O:15])[CH:11]=[CH2:10]
Reactant: OCCCCCCCCBr
Reactant: C=CC(=O)OCCCCCCOc1ccc(-c2cccc(F)c2F)cc1
Agent: OCCCCCCBr
Product: C=CC(=O)OCCCCCCCCBr
Yield: 78 %

Procedure:
The same procedure as in the synthesis (a) of Example 2 was repeated except that 34.7 g of 8-bromo-1-octanol were used instead of 30 g of 6-bromo-1-hexanol to give 34.1 g (Y., 78%) of 8-acryloyloxy-1-bromooctane.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[CH2:11]([CH:13]1[O:15][CH2:14]1)Cl>>[O:15]1[CH2:14][CH:13]1[CH2:11][O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2
Reactant: Oc1cccc2[nH]ccc12
Reactant: ClCC1CO1
Product: c1cc(OCC2CO2)c2cc[nH]c2c1

Procedure:
4-Hydroxy indole is allowed to react with epichlorohydrin to give 4-(2,3-epoxypropoxy)indole, (cf. Netherlands Pat. No. 6,601,040).
Reaction SMILES: C(P(CCCC)CCCC)CCC.[CH3:14][O:15][C:16](=[O:30])[CH2:17][C:18]1[C:22]2[C:23]([Cl:29])=[CH:24][C:25]([OH:28])=[C:26]([F:27])[C:21]=2[S:20][CH:19]=1.[CH3:31][N:32]1[C:36]([CH2:37]O)=[CH:35][C:34]([C:39]([F:42])([F:41])[F:40])=[N:33]1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1COCC1>[CH3:14][O:15][C:16](=[O:30])[CH2:17][C:18]1[C:22]2[C:23]([Cl:29])=[CH:24][C:25]([O:28][CH2:37][C:36]3[N:32]([CH3:31])[N:33]=[C:34]([C:39]([F:42])([F:40])[F:41])[CH:35]=3)=[C:26]([F:27])[C:21]=2[S:20][CH:19]=1
Reactant: Cn1nc(C(F)(F)F)cc1CO
Reactant: COC(=O)Cc1csc2c(F)c(O)cc(Cl)c12
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)Cc1csc2c(F)c(OCc3cc(C(F)(F)F)nn3C)cc(Cl)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.9 %

Procedure:
To a mixture of tri-n-butylphosphine (0.249 mL), methyl(4-chloro-7-fluoro-6-hydroxy-1-benzothiophen-3-yl)acetate (109.7 mg), (1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanol (86 mg) and THF (4.0 mL) was added ADDP (202 mg) at room temperature. The mixture was stirred at room temperature under nitrogen atmosphere for 1 h. The mixture was concentrated. To the residue was added IPE and the precipitate was filtered off. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (155 mg).
Reaction SMILES: [NH2:1][CH:2]([CH2:29][CH:30]([CH3:32])[CH3:31])[CH2:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]([CH:26]2[CH2:28][CH2:27]2)[S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)(=[O:15])=[O:14])[CH2:8][CH2:7]1)=[O:5].C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:37](C)=O.[Na+].CC(O)=O>CO.CCOC(C)=O>[CH:26]1([N:12]([CH:9]2[CH2:10][CH2:11][N:6]([C:4](=[O:5])[CH2:3][CH:2]([NH:1][CH3:37])[CH2:29][CH:30]([CH3:32])[CH3:31])[CH2:7][CH2:8]2)[S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)(=[O:15])=[O:14])[CH2:27][CH2:28]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(C)CC(N)CC(=O)N1CCC(N(C2CC2)S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CNC(CC(=O)N1CCC(N(C2CC2)S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1)CC(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of a compound 46 prepared in Example 30 (0.325 mmol, 150 mg) in methanol (5 mL) was added paraformaldehyde (0.813 mmol, 25 mg), Na(OAc)3BH and a catalytic amount of HOAc at room temperature. The resulting mixture was kept stirred at room temperature overnight. Then EtOAc (20 mL) was added to the mixture and the mixture was washed with saturated NaHCO3 and water. The organic layer was dried over Na2SO4 and concentrated to dryness. The crude product was purified through a column of silica gel with a gradient of 0% to 50% MeOH in DCM to afford the title compound 47. 1H NMR (CDCl3): δ 8.21 (d, J=8.1 Hz, 1H), 8.18 (br s, 1H), 8.04 (d, J=8.1 Hz, 1H), 7.87 (dd, J=7.84, 7.86 Hz, 1H), 4.63 (m, 1H), 4.15 (m, 1H), 3.95 (m, 1H), 3.52 (m, 1H), 3.23 (m, 1H), 2.90-2.55 (m, 3H), 2.70 (d, J=5.4 Hz, 3H), 2.07-1.54 (m, 8H), 1.00 (m, 6H), 0.92 (m, 2H), 0.80 (m, 2H). LC: 100%. MS: 490.2 (M+1).
Reaction SMILES: [C:1]([NH:9][C:10]1[C:11]2[N:12]=[CH:13][N:14]([C:23]=2[N:24]=[CH:25][N:26]=1)[C@@H:15]1[O:22][C@H:19]([CH2:20][OH:21])[C@@H:17]([OH:18])[CH2:16]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N#N.C([C@@]1(N2C3N=C(N)NC(=O)C=3N=C2)O[C@H](CO[C:41]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)([C:50]2[CH:55]=[CH:54][C:53]([O:56][CH3:57])=[CH:52][CH:51]=2)[C:42]2[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=2)[C@@H](O)C1)(=O)C(C)C>>[C:1]([NH:9][C:10]1[C:11]2[N:12]=[CH:13][N:14]([C:23]=2[N:24]=[CH:25][N:26]=1)[C@@H:15]1[O:22][C@H:19]([CH2:20][O:21][C:41]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)([C:50]2[CH:55]=[CH:54][C:53]([O:56][CH3:57])=[CH:52][CH:51]=2)[C:42]2[CH:43]=[CH:44][C:45]([O:48][CH3:49])=[CH:46][CH:47]=2)[C@@H:17]([OH:18])[CH2:16]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Nc1ncnc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1)c1ccccc1
Reactant: COc1ccc(C(OC[C@H]2O[C@@](C(=O)C(C)C)(n3cnc4c(=O)[nH]c(N)nc43)C[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: N#N
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(NC(=O)c5ccccc5)ncnc43)C[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1

Procedure:
This compound was prepared from N6 -benzoyl-2'-deoxyadenosine by the same procedure used for the preparation of N2 -isobutyryl-5'-O-(4,4'-dimethoxytrityl)-2'-deoxyguanosine.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]1[N:12]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[C:26]3[N:30]=NN[N:27]=3)=[CH:18][CH:19]=2)[C:11]2[C:10]([C:31]([O:33]C(OC(OC3CCCCC3)=O)C)=[O:32])=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=1.CCOC1N(CC2C=CC(C3C=CC=CC=3C3NN=NN=3)=CC=2)C2C([C:76]([OH:78])=[O:77])=CC=CC=2N=1>>[CH3:1][CH2:2][O:3][C:4]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[C:26]3[N:27]=[C:76]([OH:78])[O:77][N:30]=3)=[CH:16][CH:15]=2)[C:11]2[C:10]([C:31]([OH:33])=[O:32])=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=1
Reactant: CCOc1nc2cccc(C(=O)O)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reactant: CCOc1nc2cccc(C(=O)OC(C)OC(=O)OC3CCCCC3)c2n1Cc1ccc(-c2ccccc2-c2nn[nH]n2)cc1
Product: CCOc1nc2cccc(C(=O)O)c2n1Cc1ccc(-c2ccccc2-c2noc(O)n2)cc1

Procedure:
TCV-116 or candesartan,
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2.[C:12]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:17]=[CH:16][C:15]([C:18](O)=[O:19])=[CH:14][CH:13]=1>>[CH:8]1[C:9]2[C:4](=[CH:3][C:2]([NH:1][C:18]([C:15]3[CH:16]=[CH:17][C:12]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[CH:13][CH:14]=3)=[O:19])=[CH:11][CH:10]=2)[CH:5]=[CH:6][N:7]=1
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Reactant: Nc1ccc2cnccc2c1
Product: O=C(Nc1ccc2cnccc2c1)c1ccc(-c2ccccc2)cc1

Procedure:
Using the procedure outlined in Example 56, the title compound was prepared from 6-aminoisoquinoline (D97) (37 mg, 0.25 mmol) and 4-biphenylcarboxylic acid (75 mg, 0.38 mmol) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ (ppm): 9.20 (s, 1H), 8.52 (d, 1H), 8.46 (d, 1H), 8.09 (br.s, 1H), 8.00 (m, 3H), 7.77 (d, 2H), 7.65-7.70 (m, 4H), 7.50 (t, 2H), 7.43 (t, 1H).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].[Cl:18][C:19]1[CH:20]=[CH:21][C:22]2[S:26][C:25]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[N:24][C:23]=2[CH:33]=1>O1CCCC1>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]2[S:26][C:25]([N:27]3[CH2:28][CH2:29][N:30]([C:7]([C:6]4[CH:10]=[C:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:12]=[CH:13][C:5]=4[O:4][CH:1]([CH3:2])[CH3:3])=[O:9])[CH2:31][CH2:32]3)=[N:24][C:23]=2[CH:33]=1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: Clc1ccc2sc(N3CCNCC3)nc2c1
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2nc3cc(Cl)ccc3s2)CC1

Procedure:
Prepared in analogy to example 1.1 b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.2) and 5-chloro-2-piperazin-1-yl-benzothiazole in tetrahydrofuran. The crude material was purified by chromatography (SiO2, heptane/ethyl acetate), and the residue was then triturated in ether to yield the title compound as a white solid.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:5]=1[OH:14])[CH:2]=[CH2:3].C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)(C)(C)C>[CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:5]=1[O:14][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:2]=[CH2:3]
Reactant: C=CCc1cccc(C(C)(C)C)c1O
Reactant: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(C)(C)O
Product: C=CCc1cccc(C(C)(C)C)c1OCc1ccccc1
Yield: 87.5 %

Procedure:
Treatment of 2-allyl-6-tert-butylphenol (12.5 g, 0.066 mol) with potassium carbonate (27.24 g, 0.197 mol), benzyl bromide (11.80 g, 0.069 mol), and tetrabutylammonium iodide (2.43 g, 6.57 mmol) generally according to the procedure described for Intermediate 1 provided 16.2 g (88%) of 1-allyl-2-(benzyloxy)-3-tert-butylbenzene as a colorless oil. Anal. calcd. for C20H240: C, 85.67; H, 8.63. Found: C, 86.27; H, 8.77.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:22]#[C:23][C:24]4[CH:29]=[CH:28][N:27]=[C:26](S(C)(=O)=O)[N:25]=4)[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH3:34]>CO>[NH2:34][C:26]1[N:25]=[C:24]([C:23]#[C:22][C:15]2([C:9]3[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH:8]=3)[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]2)[CH:29]=[CH:28][N:27]=1
Reactant: COc1ccc(C2(C#Cc3ccnc(S(C)(=O)=O)n3)CCC(=O)CC2)cc1OC1CCCC1
Reactant: N
Solvent: CO
Product: COc1ccc(C2(C#Cc3ccnc(N)n3)CCC(=O)CC2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 73 %

Procedure:
Into a solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-methylsulfonylpyrimidin-4-ylethynyl)cyclohexan-1-one (0.26 g, 0.56 mmol) in methanol (4 mL) at -78° C. was condensed liquid ammonia (4 mL), the pressure tube was sealed and the reaction was stirred at room temperature for 2.5 h. After cooling, the solvents were evaporated. Purification required two flash chromatographies, eluting first with 2:98 methanol:dichloromethane and secondly with 4:6 ethyl acetate:hexanes, to provide 4-(2-aminopyrimidin-4-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one as a white solid (0.18 g, 73%), mp 68°-70° C. Anal. (C24H27N3O3.0.2 H2O) calcd: C, 70.46; H, 6.75; N, 10.27; found: C, 70.73; H, 6.79; N, 9.87.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([F:11])([F:10])[F:9])=[N:6][CH:7]=1.CON(C)[C:15]([C:17]1[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=1)=[O:16]>C1COCC1.[Ni].Cl>[CH3:22][N:20]1[CH:21]=[C:17]([C:15]([C:2]2[CH:7]=[N:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=2)=[O:16])[CH:18]=[N:19]1
Reactant: FC(F)(F)c1ccc(Br)cn1
Reactant: CON(C)C(=O)c1cnn(C)c1
Agent: [Ni]
Agent: Cl
Solvent: C1CCOC1
Product: Cn1cc(C(=O)c2ccc(C(F)(F)F)nc2)cn1
Temperature: -78 °C
Yield: 34.1 %

Procedure:
A solution of 5-bromo-2-(trifluoromethyl)pyridine (3.80 g, 16.82 mmol) in THF (24 ml) was cooled at −18° C. A solution of isopropylmagnesium chloride lithium chloride complex in THF (17.97 ml, 14.02 mmol, 0.78 molar) was added dropwise over a period of 30 minutes. The reaction was then cooled at −78° C. kept there for 1½ hour. The reaction was allowed to reach −3° C. before being cooled to −10° C. A solution of N-methoxy-N,1-dimethyl-1H-pyrazole-4-carboxamide (2.372 g, 14.02 mmol) in THF (8 ml) was added dropwise over a period of 5 minutes. The reaction was allowed to warm to room temperature and stirred over night. Cooled to 0° C. and a 2 Ni HCl solution (150 mL) was added slowly. The crude mixture was extracted with AcOEt (3×150 mL), the combined org. phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The crude product was purified by comlumn chromatography to yield (1-methyl-1H-pyrazol-4-yl)(6-(trifluoromethyl)pyridin-3-yl)methanone 1.22 g (34%) as a light yellow solid.