Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:12])[N:10]=2)[CH:7]=1.C([Sn](CCCC)(CCCC)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)CCC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C)C=O>[C:14]1([NH:13][C:11]([C:9]2[N:10]=[C:5]3[CH:4]=[CH:3][C:2]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=4)=[CH:7][N:6]3[CH:8]=2)=[O:12])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: O=C(Nc1ccccc1)c1cn2cc(I)ccc2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1)c1cn2cc(-c3ccccn3)ccc2n1
Reaction time: 0.08 h
Yield: 28.1 %

Procedure:
230 mg of 6-iodo-N-phenylimidazo[1,2-a]pyridine-2-carboxamide (Intermediate 2), 690 mg of 2-tributylstannylpyridine, 120 mg of tetrakis(triphenylphosphine)palladium and 4 mL of N,N-dimethylformamide are placed in a microwave tube. The reaction mixture is heated for 5 minutes in a microwave machine set at 100° C., and then for 5 minutes at 150° C. and concentrated to dryness. The residue is chromatographed on a silica cartridge, eluting with a mixture of dichloromethane and ethyl acetate. The fractions containing the expected product are combined and evaporated to dryness under reduced pressure to give 56 mg of N-phenyl-6-(pyrid-2-yl)imidazo[1,2-a]pyridine-2-carboxamide in the form of a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:12][C@H:11]([C:13]([OH:15])=[O:14])[C:10]1([CH3:17])[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH:24]1[CH:29]=[CH:28][C:27]([CH2:30]Br)=[CH:26][CH:25]=1>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:12][C@H:11]([C:13]([O:15][CH2:30][C:27]2[CH:28]=[CH:29][CH:24]=[CH:25][CH:26]=2)=[O:14])[C:10]1([CH3:17])[CH3:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H](C(=O)O)C1(C)C
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H](C(=O)OCc2ccccc2)C1(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
A stirred solution of (1S,3R)-3-(tert-butoxycarbonylamino)-2,2-dimethylcyclobutanecarboxylic acid (0.5 g, 2.05 mmol) in DMF (about 5 ml), Cs2CO3 (0.804 g, 2.47 mmol) and BnBr (0.3 ml, 2.47 mmol) were added slowly portion wise at about 0° C., then the reaction was stirred at room temperature for about 2 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc and washed with water, brine and dried over Na2SO4. The solvent was evaporated and purified by silica gel column (60-120 mesh, elution 4% EtOAc in hexane) to afford title compound as a pale yellow syrup. Wt: 0.35 g; Yield: 51%; 1H NMR (300 MHZ, CDCl3): δ 7.39-7.28 (m, 5H), 5.12 (Brs, 2H), 4.60 (Brs, 1H), 3.88-3.79 (m, 1H), 2.65-2.53 (m, 1H), 2.38-2.27 (m, 1H), 2.01-1.99 (m, 1H), 1.43 (s, 9H), 1.28 (s, 3H), 0.86 (s, 3H); IR (KBr, cm−1): 3387, 2962, 1710, 1523, 1456, 1366, 1253, 1173, 1079, 1009, 979, 746, 698.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[O:19][C:20]([CH2:30][CH2:31][CH3:32])=[C:21]([C:23]([O:25]CCCC)=[O:24])[N:22]=3)[CH2:14][C@H:13]2[O:33][CH3:34])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+].CO>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[O:19][C:20]([CH2:30][CH2:31][CH3:32])=[C:21]([C:23]([OH:25])=[O:24])[N:22]=3)[CH2:14][C@H:13]2[O:33][CH3:34])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCCCOC(=O)c1nc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OC)C2)oc1CCC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCc1oc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OC)C2)nc1C(=O)O
Yield: 90.9 %

Procedure:
The same operation as in Example (91d) was performed using butyl cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-5-propyl-3-methoxypiperidin-1-yl)-1,3-oxazole-4-carboxylate obtained in Example (116d) (0.22 g, 0.44 mmol), 2 N lithium hydroxide (3 mL, 6 mmol), methanol (2 mL) and THF (3 mL), to obtain 176 mg of the title compound as a colorless solid (91%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH2:8].[Na].[C:10]([O:16][CH2:17][CH3:18])(=[O:15])[CH2:11][C:12]([CH3:14])=O>CN(C=O)C.C(OC)(C)(C)C.O.N>[CH2:17]([O:16][C:10]([C:11]1[C:2]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[NH:8][C:12]=1[CH3:14])=[O:15])[CH3:18]
Reactant: Nc1ccccc1I
Reactant: CCOC(=O)CC(C)=O
Agent: N
Agent: [Na]
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Solvent: O
Product: CCOC(=O)c1c(C)[nH]c2ccccc12
Temperature: 120 °C
Reaction time: 8 h
Yield: 26.4 %

Procedure:
A mixture of 2-iodo-phenylamine (44.30 g, 202 mmol), sodium salt of ethyl acetoacetate (42.1 g, 263 mmol), and Cu(I)I (50.1 g, 263 mmol) in DMF (200 mL) was stirred at 120° C. overnight. Then the reaction mixture was cooled to room temperature, then diluted with methyl tert-butyl ether (MTBE) and water, and concentrated ammonia was added to dissolve the solid, the two layers were separated, the water layer was back extracted with MTBE; all MTBEs were combined and washed with sat. NaCl aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated sequentially. The residue was crystallized in hexanes/EtOAc, giving the desired product (10.84 g), the mother liquor was concentrated and purified on column to give an additional batch of product (4.76 g). The title compound, 1H NMR (200 MHz, CDCl3): δ (ppm)=8.32 (1H), 8.09 (m, 1H), 7.31-7.13 (m, 3H), 4.39 (q, 2H, J=6.8 Hz), 2.74 (s, 3H), 1.45 (t, 3H, J=6.8 Hz).
Reaction SMILES: F[B-](F)(F)F.C([O+](CC)CC)C.[C:13]([O:17][C:18](=[O:25])[NH:19][C@H:20]([C:22](=O)[NH2:23])[CH3:21])([CH3:16])([CH3:15])[CH3:14].[F:26][C:27]1[CH:28]=[C:29]([NH:34][C:35]2[N:36]([CH3:40])[N:37]=[CH:38][CH:39]=2)[C:30](N)=[CH:31][CH:32]=1>C(Cl)Cl>[C:13]([O:17][C:18](=[O:25])[NH:19][C@H:20]([C:22]1[N:34]([C:35]2[N:36]([CH3:40])[N:37]=[CH:38][CH:39]=2)[C:29]2[CH:28]=[C:27]([F:26])[CH:32]=[CH:31][C:30]=2[N:23]=1)[CH3:21])([CH3:16])([CH3:15])[CH3:14]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(N)=O
Reactant: Cn1nccc1Nc1cc(F)ccc1N
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)cc2n1-c1ccnn1C
Yield: 130.3 %

Procedure:
Triethyloxonium tetrafluoroborate (1.06 g, 5.60 mmol) was added to a solution of ((S)-1-carbamoylethyl)carbamic acid tert-butyl ester (1.26 g, 6.67 mmol) in DCM (20 mL) at 20° C. under nitrogen and the resultant mixture stirred for 3 h then concentrated in vacuo. The resultant residue was dissolved in ethanol (20 mL) and 4-fluoro-N2-(2-methyl-2H-pyrazol-3-yl)-benzene-1,2-diamine (0.55 g, 2.67 mmol) added, and the reaction mixture stirred at reflux for 16 h under nitrogen. The reaction mixture was concentrated in vacuo and residue partitioned between DCM (×3) and saturated aqueous NaHCO3. The combined DCM extracts were dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by chromatography (SiO2, 0-5% (2M ammonia in methanol) in DCM) to give the title compound as a yellow oil (1.25 g, 100%). LCMS (Method C): RT 3.08 min [M+H]+ 360.2. 310091751
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)([CH3:6])([CH3:5])[CH3:4].[CH2:20]([O:22][C:23](=[O:28])[CH2:24][C:25](O)=[O:26])[CH3:21].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C(#N)C>[C:3]([C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[N:14]1[CH2:15][CH2:16][N:17]([C:25](=[O:26])[CH2:24][C:23]([O:22][CH2:20][CH3:21])=[O:28])[CH2:18][CH2:19]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CCOC(=O)CC(=O)O
Reactant: Cc1ccc(N2CCNCC2)c(C(C)(C)C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(=O)N1CCN(c2ccc(C)cc2C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 68.9 %

Procedure:
A suspension of 1-(2-tert-butyl-4-methylphenyl)piperazine dihydrochloride (Reference Example 10, 0.300 g, 0.98 mmol), 3-ethoxy-3-oxopropanoic acid (0.169 g, 1.28 mmol), EDCI (0.245 g, 1.28 mmol), HOBt (0.173 g, 1.28 mmol) and triethylamine (411 μl, 2.95 mmol) in acetonitrile (10 mL) was stirred at room temperature for 3 days. The reaction mixture was poured into saturated sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated sodium hydrogen carbonate solution and brine, dried over MgSO4, and the solvent was evaporated in vacuum to give the crude product. The product was purified by flash column chromatography (silica gel, n-hexane/ethyl acetate=90:20 to 50:50) to provide ethyl 3-[4-(2-tert-butyl-4-methylphenyl)piperazin-1-yl]-3-oxopropanoate (0.234 g, 69%) as a colorless gum.
Reaction SMILES: [C:1]([NH:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH2:22])=[O:21])=[C:18]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([N:32]4[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]4)=[CH:28][CH:27]=3)[N:17]=2)[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:38][C:39](=O)[CH3:40].C([BH3-])#N.[Na+]>CO>[C:1]([NH:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH2:22])=[O:21])=[C:18]([NH:25][C:26]3[CH:27]=[CH:28][C:29]([N:32]4[CH2:33][CH2:34][N:35]([CH:39]([CH3:40])[CH3:38])[CH2:36][CH2:37]4)=[CH:30][CH:31]=3)[N:17]=2)[CH2:11]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)=O
Reactant: NC(=O)c1ccc(N2CCC[C@@H](NC(=O)c3ccccc3)C2)nc1Nc1ccc(N2CCNCC2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(C)N1CCN(c2ccc(Nc3nc(N4CCC[C@@H](NC(=O)c5ccccc5)C4)ccc3C(N)=O)cc2)CC1
Yield: 55.4 %

Procedure:
To a mixture of (R)-6-(3-benzamidopiperidin-1-yl)-2-(4-(piperazin-1-yl)phenylamino)nicotinamide (50 mg, 0.100 mmol) and propan-2-one (58.1 mg, 1.001 mmol) in MeOH (1 mL) was added sodium cyanoborohydride (12.58 mg, 0.200 mmol). The reaction mixture was quenched with satd. NaHCO3, extracted twice with CH2Cl2, and concentrated. The residue was purified by prep-HPLC. The product containing fractions were collected, basified with 1N NaOH, extracted with CH2Cl2, and concentrated to give 30 mg of (R)-6-(3-benzamidopiperidin-1-yl)-2-(4-(4-isopropylpiperazin-1-yl)phenylamino)nicotinamide as yellow solid. LCMS: (M+H)+=542.21. 1H NMR (500 MHz, CDCl3-MIX) δ ppm 7.57 (2H, d, J=7.15 Hz), 7.53 (1 H, d, J=8.80 Hz), 7.35-7.43 (3H, m), 7.31 (2H, t, J=7.70 Hz), 6.77 (2H, d, J=9.35 Hz), 6.01 (1H, d, J=8.80 Hz), 4.07-4.13 (1H, m), 3.75-3.81 (1H, m), 3.66-3.73 (1H, m), 3.58-3.66 (1H, m), 3.49-3.56 (1H, m), 2.98-3.03 (4H, m), 2.60-2.66 (1H, m), 2.56-2.60 (4H, m), 1.82-1.95 (2H, m), 1.66-1.76 (1H, m), 1.60 (1H, td, J=6.74, 3.57 Hz), 1.03 (6H, d, J=6.05 Hz).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C@@H:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[CH3:11])[C:6]=2[CH:20]=1.C(O[C:26]([N:28]1[CH2:33][CH:32]=[C:31](B(O)O)[CH2:30][CH2:29]1)=[O:27])(C)(C)C.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[C@H:10]([N:7]1[C:6]2[CH:20]=[C:2]([C:31]3[CH2:30][CH2:29][N:28]([C:26]([C@H:29]4[CH2:30][CH2:31][CH2:32][CH2:33][NH:28]4)=[O:27])[CH2:33][CH:32]=3)[CH:3]=[CH:4][C:5]=2[N:9]=[CH:8]1)[CH3:11]
Reactant: C[C@H](c1ccc(Cl)cc1Cl)n1cnc2ccc(Br)cc21
Reactant: CC(C)(C)OC(=O)N1CC=C(B(O)O)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: C[C@H](c1ccc(Cl)cc1Cl)n1cnc2ccc(C3=CCN(C(=O)[C@H]4CCCCN4)CC3)cc21
Temperature: 100 °C

Procedure:
A mixture of (R)-6-bromo-1-(1-(2,4-dichlorophenyl)ethyl)-1H-benzo[d]imidazole (1.3 g, 3.5 mmol), (N-t-butoxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl)boronic acid pincol ester (1.2 g, 3.9 mmol), tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4, 0.20 g, 0.18 mmol), and 2 M aqueous potassium carbonate (5.3 mL, 10.5 mmol) in toluene (10 mL) and ethanol (5 mL). The mixture was purged with nitrogen for 5 min, and then heated at 100° C. for 2 h. After cooling to room temperature, the mixture was extracted with ethyl acetate (20 mL). The organic layer was washed with brine, dried (Na2SO4), and concentrated in vacuo. The resulting crude material was purified by flash chromatography (SiO2, 0-100% ethyl acetate in hexanes) to afford the desired product in 90% purity (1.6 g, 3.4 mmol, 97%). MS: (ES) m/z calculated for C25H28Cl2N3O [M+H]+ 472.2. found 472.
Reaction SMILES: [Si]([O:8][C@@H:9]([C@H:11]1[C:19](=[O:20])[N:18]2[C@@H:12]1[CH2:13][C:14]([S:34][CH3:35])=[CH:15][CH:16]=[C:17]2[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1)=[O:22])[CH3:10])(C(C)(C)C)(C)C.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[OH:8][C@@H:9]([C@H:11]1[C:19](=[O:20])[N:18]2[C@@H:12]1[CH2:13][C:14]([S:34][CH3:35])=[CH:15][CH:16]=[C:17]2[C:21]([O:23][CH2:24][C:25]1[CH:26]=[CH:27][C:28]([N+:31]([O-:33])=[O:32])=[CH:29][CH:30]=1)=[O:22])[CH3:10]
Reactant: CSC1=CC=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H]2C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CSC1=CC=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@@H](C)O)[C@H]2C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 61.5 %

Procedure:
To a solution of 4-nitrobenzyl (7R,8S)-8-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-5-methylthio-9-oxo-1-azabicyclo [5.2.0]non-2,4-diene-2-carboxylate (213 mg, 0.41 mmol) in anhydride THF (8 ml) was added acetic acid (0.35 ml) and a 1.1M solution in tetrahydrofuran of tetrabutylammonium fluoride (1.9 ml; 2.04 mmol). After stirring for 3 days at ambient temperature, the reaction mixture was diluted with ethyl acetate (20 ml) and then washed with an 5% aqueous solution of NaHCO3 and water. After evaporation of the solvents, the residue was taken up with methylene chloride. The insoluble material was filtered off and identified as 4-nitrobenzyl (7R,8S)-8-[(1R)-1-hydroxyethyl]-5-methylthio-9-oxo-1-azabicyclo[5.2.0]non-2,4-diene-2-carboxylate: The filtrate was concentrated and the residue was purified by chromatography on silica gel eluting with ethyl acetate/dichloromethane 3:7 to give an other batch of the 4-nitrobenzyl (7R,8S)-8-[(1R)-1-hydroxyethyl]-5-methylthio-9-oxo-1-azabicyclo-[5.2.0]non-2,4-diene-2-carboxylate (total=102 mg, 62% overall yield).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([C@@H:29]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:30][CH2:31][N:32]([CH:36]([CH3:38])[CH3:37])[CH:33]([CH3:35])[CH3:34])[CH:23]=2)=[CH:12][CH:11]=1)(C)(C)C.C(O)C.[ClH:49]>ClCCl.C(OCC)C>[ClH:49].[ClH:49].[NH2:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([C@@H:29]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH2:30][CH2:31][N:32]([CH:36]([CH3:37])[CH3:38])[CH:33]([CH3:34])[CH3:35])[CH:23]=2)=[CH:14][CH:15]=1
Reactant: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCCCCOc2ccc(CCNC(=O)OC(C)(C)C)cc2)ccc1O)C(C)C
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCO
Product: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCCCCOc2ccc(CCN)cc2)ccc1O)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Tert-butyl(2-{4-[(5-{3-[(1R)-3-(diisopropylamino)-1-phenylpropyl]-4-hydroxyphenyl}pentyl)oxy]phenyl}ethyl)carbamate (Preparation 58, 1.66 g, 2.69 mmol) was dissolved in dichloromethane (20 ml) and ethanol (3 ml) and hydrochloric acid (12 ml of a 2M solution in diethyl ether) was added, and the mixture stirred overnight at room temperature. Solvent was removed in vacuo and the residue dissolved in dichloromethane and solvent removed in vacuo again to furnish the title compound as a yellow foam, 1.6 g
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]#[C:15][C:16]3[CH:17]=[CH:18][C:19]([O:24][CH2:25][CH2:26][N:27]4[CH2:32][CH2:31][CH:30]([CH3:33])[CH2:29][CH2:28]4)=[C:20]([CH:23]=3)[CH:21]=O)=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[NH2:34][OH:35]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]#[C:15][C:16]3[CH:17]=[CH:18][C:19]([O:24][CH2:25][CH2:26][N:27]4[CH2:28][CH2:29][CH:30]([CH3:33])[CH2:31][CH2:32]4)=[C:20]([CH:23]=3)[CH:21]=[N:34][OH:35])=[N:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: CC1CCN(CCOc2ccc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)cc2C=O)CC1
Product: CC1CCN(CCOc2ccc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)cc2C=NO)CC1

Procedure:
The product was obtained analogously to Example 14.1d starting from 5-[5-(4-chlorophenyl)pyridin-2-ylethynyl]-2-[2-(4-methylpiperidin-1-yl)ethoxy]benzaldehyde (Example 14.1c) and hydroxylamine. Yield: 40 mg (46% of theoretical); C28H28ClN3O2 (M=473.994); calc.: molpeak (M+H)+: 474/476 (Cl); found: molpeak (M+H)+: 474/476 (Cl); HPLC-MS: 5.68 minutes (method A).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([F:11])[C:3]=1[C:4]#[N:5].[NH2:12][OH:13]>CCO>[OH:13][NH:12][C:4](=[NH:5])[C:3]1[C:6]([F:11])=[CH:7][C:8]([F:10])=[CH:9][C:2]=1[F:1]
Reactant: NO
Reactant: N#Cc1c(F)cc(F)cc1F
Solvent: CCO
Product: N=C(NO)c1c(F)cc(F)cc1F

Procedure:
To a solution of 2,4,6-trifluorobenzonitrile (1.5 g, 9.6 mmol) in EtOH (5 mL), hydroxylamine (50% wt. aqueous solution, 2.5 mL, 38 mmol) was added at room temperature and the solution was stirred under reflux for 1 h. The solvent was removed under reduced pressure to afford N-hydroxy-2,4,6-trifluoro-benzamidine that was used immediately for the next step.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]([CH3:20])([CH3:19])[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])[CH3:2].[BrH:22]>C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:21])[C:5]([CH3:20])([CH3:19])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([Br:22])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])[CH3:2]
Reactant: Br
Reactant: CCOC(=O)C(C)(C)CCCCC=Cc1ccccc1Cl
Solvent: CC(=O)O
Product: CCOC(=O)C(C)(C)CCCCCC(Br)c1ccccc1Cl
Temperature: 15 °C
Yield: 81.8 %

Procedure:
8-(2-Chlorophenyl)-2,2-dimethyl-oct-7-enoic acid ethyl ester (7 g, 22.8 mmol) was dissolved in glacial acetic acid (60 mL). The solution was cooled in an ice-bath (ca. 15° C.), while dry hydrogen bromide was passed into the solution for 8 h. The reaction mixture was poured into ice-water (130 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with saturated NaHCO3 solution (100 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude product (10 g) was purified by column chromatography (200 g silica gel, eluting with ethyl acetate/heptane=1/20 to 1/10) to furnish 8-bromo-8-(2-chlorophenyl)2,2-dimethyloctanoic acid ethyl ester (7.46 g, 81.8% yield) as a yellow oil. 1H NMR (Field: 300 MHz, Solvent: CDCl3/TMS) δ (ppm): 7.59 (d, 1H, J=7.8 Hz), 7.34 (t, 1H, J=7.5 Hz), 7.26 (d, 1H, J=6.9 Hz), 7.19 (t, 1H, J=7.2 Hz), 5.45 (t, 1H, J=7.5 Hz), 4.09 (q, 2H, J=7.2 Hz), 2.26-2.09 (m, 4H), 1.52-1.46 (m, 2H), 1.41-1.31 (m, 2H), 1.28-1.18 (m, 2H), 1.20 (t, 3H, J=7.2 Hz), 1.14 (s, 6H). 13C NMR (Field: 75 MHz, Solvent: CDCl3/TMS) δ (ppm): 177.80, 139.43, 132.65, 129.64, 129.24, 128.88, 127.45, 60.28, 50.30, 42.25, 39.21, 29.48, 27.98, 25.36, 24.88, 14.49. HRMS (GC-Cl): Calculated for C18H26BrClO2 (M+H)+389.0883. found 389.0867.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:13]=[CH:12][C:11]([Mg]Br)=[CH:10][CH:9]=1.[CH3:16][N:17]1[C:21]([CH:22]=[O:23])=[CH:20][N:19]=[CH:18]1>C1COCC1>[CH3:16][N:17]1[C:21]([CH:22]([C:11]2[CH:12]=[CH:13][C:8]([O:7][CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)=[CH:9][CH:10]=2)[OH:23])=[CH:20][N:19]=[CH:18]1
Reactant: Br[Mg]c1ccc(OC2CCCCO2)cc1
Reactant: Cn1cncc1C=O
Solvent: C1CCOC1
Product: Cn1cncc1C(O)c1ccc(OC2CCCCO2)cc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
4-(2-Tetrahydro-3H-pyranoxy)phenylmagnesium bromide (110 mL, 0.5 M in THF, 55 mmol) was added dropwise to a solution of 1-methyl-1H-imidazole-5-carbaldehyde (4.7 g, 50 mmol) in THF (790 mL) at −78° C. After stirring −78° C. for 2 hours, the reaction was quenched with saturated NH4Cl (aq) and warmed to room temperature. The mixture was extracted with EtOAc (500 mL), and the organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 14 g of the crude product 74.1, which was used in the next reaction without further purification.
Reaction SMILES: [Si]([C@@:8]1([OH:48])[C@@H:12]([CH2:13][O:14][Si](C(C)(C)C)(C)C)[O:11][C@@H:10]([N:22]2[CH:29]=[C:28]([CH2:30][O:31][C@H:32]([C:37]3[CH:42]=[C:41]([O:43][CH3:44])[CH:40]=[CH:39][C:38]=3[N+:45]([O-:47])=[O:46])[C:33]([CH3:36])([CH3:35])[CH3:34])[C:26]([NH2:27])=[N:25][C:23]2=[O:24])[CH2:9]1)(C(C)(C)C)(C)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH3:44][O:43][C:41]1[CH:40]=[CH:39][C:38]([N+:45]([O-:47])=[O:46])=[C:37]([C@@H:32]([O:31][CH2:30][C:28]2[C:26]([NH2:27])=[N:25][C:23](=[O:24])[N:22]([CH:29]=2)[C@@H:10]2[O:11][C@H:12]([CH2:13][OH:14])[C@@H:8]([OH:48])[CH2:9]2)[C:33]([CH3:36])([CH3:35])[CH3:34])[CH:42]=1
Reactant: COc1ccc([N+](=O)[O-])c([C@@H](OCc2cn([C@H]3C[C@@](O)([Si](C)(C)C(C)(C)C)[C@@H](CO[Si](C)(C)C(C)(C)C)O3)c(=O)nc2N)C(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccc([N+](=O)[O-])c([C@@H](OCc2cn([C@H]3C[C@H](O)[C@@H](CO)O3)c(=O)nc2N)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.6 %

Procedure:
To a solution of compound 49 (130 mg, 0.18 mmol) in THF (10 mL), n-Bu4NF (141 mg, 0.44 mmol) was added. The mixture was stirred at room temperature for four hours, concentrated in vacuo, and the residue was purified by silica gel column chromatography to yield 5-[(S)-1-(5-methoxy-2-nitrophenyl)-2,2-dimethyl-propyloxy]methyl-2′-deoxycytidine 50 (72 mg, 82%). 1H NMR (400 MHz, DMSO-d6): δ 7.99 (d, J=8.0 Hz, 1H, Ph-H), 7.65 (s, 1H, H-6), 7.42 (br s, 1H, D2O exchangeable, NH2a), 7.06 (m, 2H, Ph-H), 6.72 (br s, 1H, D2O exchangeable, NH2b), 6.11 (t, 1H, J=6.4 Hz, H-1′), 5.17 (d, 1H, D2O exchangeable, 3′-OH), 5.12 (s, 1H, Ph-CH), 4.78 (t, 1H, D2O exchangeable, 5′-OH), 4.25 (d, 1H, J=12.4 Hz, 5-CH2a), 4.15 (m, 1H, H-3′), 4.05 (d, 1H, J=12.4 Hz, 5-CH2b), 3.87 (s, 3H, OCH3), 3.72 (m, 1H, H-4′), 3.44 (m, 2H, H-5′), 3.76 (dd, 1H, J=2.8 Hz, H-5′b), 2.08 (m, 1H, H-2′a), 1.95 (m, 1H, H-2′b), 0.77 (s, 9H, C(CH3)3).