Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[O:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([Mg]Br)=[CH:24][CH:23]=1>C1COCC1>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:25]3[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=3)([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[OH:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc2nccc(Br)c2c1
Solvent: C1CCOC1
Product: OC(c1ccc(Cl)cc1)(c1ccc(Cl)cc1)c1ccc2nccc(Br)c2c1
Reaction time: 3 h

Procedure:
To a solution of (4-bromoquinolin-6-yl)(4-chlorophenyl)methanone (0.25 g, 0.72 mmol) in THF (5 mL) was slowly added (4-chlorophenyl)magnesium bromide (1.08 mL, 1 M in THF) at 0° C. under the argon. The resulting solution was kept at 0° C. for 3 hr. The reaction was quenched with saturated NH4Cl at 0° C. and the aqueous mixture was extracted with EtOAc 2 times. The combined organics were concentrated and purified by silica column chromatography (20-30% EtOAc/hexanes) to yield (4-bromoquinolin-6-yl)bis(4-chlorophenyl)methanol. (M+H)+: 458, 460.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:6]=1[N+:14]([O-])=O)[CH:2]=[CH2:3].[CH2:17](N)[CH2:18][CH2:19][CH3:20]>C(O)(C)C>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:6]=1[NH:14][CH2:17][CH2:18][CH2:19][CH3:20])[CH:2]=[CH2:3]
Reactant: CCCCN
Reactant: C=CCOc1cccc([N+](=O)[O-])c1[N+](=O)[O-]
Solvent: CC(C)O
Product: C=CCOc1cccc([N+](=O)[O-])c1NCCCC
Reaction time: 2 h

Procedure:
A mixture of 9.0 g of 1-allyloxy-2,3-dinitrobenzene and 40 ml of n-butylamine in 400 ml of isopropanol is heated under reflux, and stirred, for two hours. After evaporating off the solvent and the excess n-butylamine under reduced pressure, the resulting oil is dried at 50°/0.01 mm Hg for 2 hours. The 1-allyloxy-2-butylamino-3-nitrobenzene which is thus obtained can be further used without purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:9][CH:8]=1)[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C=Cc1ccc(N2CCCCCC2)cc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1ccc(N2CCCCCC2)cc1

Procedure:
A solution of 3-(4-azepan-1-yl-phenyl)-acrylic acid ethyl ester (1.0 g, 3.65 mmol) in ethanol (20 Ml) was hydrogenated at 55 psi over 10% palladium (0.1 g) for 18 hours. The catalyst was removed by filtration, and the solvent was evaporated in vacuo. The crude product was purified by flash silica gel chromatography, using 5% ethyl acetate in hexane as the eluant, to give the product, 1.0 g (99%), a color less oil. MS: m/z 276 (MH+). 1H NMR (CDCl3): 1.24 (t, 3 H), 1.48-1.61 (m, 4 H), 1.76 (m, 4 H), 2.56 (t, 2 H), 2.84 (t, 2 H), 3.42 (t, 4 H), 4.13 (q, 2 H), 6.61 (d, 2 H) and 7.03 (d, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([NH:10][C:11]2[CH:12]=[C:13]([CH:23]=[CH:24][CH:25]=2)[CH2:14][NH:15]C(=O)OC(C)(C)C)=[O:9])[CH:5]=[CH:4][N:3]=1.Cl>C(Cl)Cl.O1CCOCC1>[NH2:15][CH2:14][C:13]1[CH:12]=[C:11]([NH:10][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=2)=[O:9])[CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)NCc1cccc(NC(=O)c2ccnc(Cl)c2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: NCc1cccc(NC(=O)c2ccnc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of tert-butyl (3-{[(2-chloropyridin-4 yl)carbonyl]amino}benzyl)carbamate in methylene chloride (10 mL) at 0° C. was added 4 M HCl in dioxane (10 mL). The solution was allowed to warm to room temperature and stirred for 18 h. The reaction was concentrated in vacuo to dryness. Methanol was added and removed in vacuo (3×) to afford N-[3-(aminomethyl)phenyl]-2-chloropyridine-4-carboxamide.
Reaction SMILES: Cl[C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:3].[CH3:8][O:9][C:10]1[N:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[NH:16][C@@H:15]([CH3:20])[CH2:14][C@H:13]2[NH:21][C:22](=[O:24])[CH3:23].N1C=CC=CC=1>ClCCl>[CH:5]([O:4][C:2]([N:16]1[C:17]2[C:12](=[N:11][C:10]([O:9][CH3:8])=[CH:19][CH:18]=2)[C@H:13]([NH:21][C:22](=[O:24])[CH3:23])[CH2:14][C@@H:15]1[CH3:20])=[O:3])([CH3:7])[CH3:6]
Reactant: CC(C)OC(=O)Cl
Reactant: COc1ccc2c(n1)[C@H](NC(C)=O)C[C@H](C)N2
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc2c(n1)[C@H](NC(C)=O)C[C@H](C)N2C(=O)OC(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 90.7 %

Procedure:
Add isopropyl chloroformate (8.50 mL, 8.50 mmol) to a solution of (+/−)-cis-N-(6-methoxy-2-methyl-1,2,3,4-tetrahydro-[1,5]naphthyridin-4-yl)acetamide (0.404 g, 1.702 mmol), pyridine (1.370 mL, 17.02 mmol) in dichloromethane (10 mL) at 0° C. and slowly warm to room temperature. After 12 h, remove the solvent under reduced pressure. Purify the crude material using silica gel chromatography, eluting with ethyl acetate (neat), to afford the title compound (0.496 g, 91%). MS (ES+): 322 (M+H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][N:6]=[CH:5][CH:4]=1.[NH2:14][CH:15]1[C:20](=[O:21])[N:19]2[CH:22]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)[C:23](=[O:29])[N:24]([CH:26]([CH3:28])[CH3:27])[CH2:25][CH:18]2[N:17]([S:38]([C:41]2[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][C:42]=2[Cl:48])(=[O:40])=[O:39])[CH2:16]1>>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][CH:22]2[N:19]3[C:20](=[O:21])[CH:15]([NH:14][C:9](=[O:11])[C:8]4[C:3]([C:2]([F:1])([F:13])[F:12])=[CH:4][CH:5]=[N:6][CH:7]=4)[CH2:16][N:17]([S:38]([C:41]4[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][C:42]=4[Cl:48])(=[O:40])=[O:39])[CH:18]3[CH2:25][N:24]([CH:26]([CH3:28])[CH3:27])[C:23]2=[O:29])=[CH:32][CH:33]=1
Reactant: O=C(O)c1cnccc1C(F)(F)F
Reactant: CC(C)N1CC2N(C(=O)C(N)CN2S(=O)(=O)c2ccc(Cl)cc2Cl)C(Cc2ccc(Cl)cc2)C1=O
Product: CC(C)N1CC2N(C(=O)C(NC(=O)c3cnccc3C(F)(F)F)CN2S(=O)(=O)c2ccc(Cl)cc2Cl)C(Cc2ccc(Cl)cc2)C1=O

Procedure:
Synthesis took place in analogy to Example 29e using 4-(trifluoromethyl)nicotinic acid and 3-amino-6-(4-chlorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-8-isopropyl-hexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW=731.08 (calculated, monoisotopic); measured value (M+H)+: 732.07
Reaction SMILES: [Li]CCCC.[S:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1.[CH2:11](Br)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>C1COCC1>[CH2:24]([C:7]1[S:6][CH:10]=[CH:9][CH:8]=1)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH3:11]
Reactant: CCCCCCCCCCCCCCBr
Reactant: c1ccsc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCc1cccs1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 97.1 %

Procedure:
n-BuLi (1.6 M, 48 mL, 76 mmol) was added dropwise to a solution of thiophene (7.0 g, 83 mmol) in THF (70 mL) at −78° C. and stirred for 45 min. Tetradecyl bromide (23 mL, 76 mmol) in THF (25 mL) was added dropwise to the resultant suspension and then gradually warmed to room temperature and stirred for 18 h. The reaction mixture was quenched with water (60 mL) and extracted with diethyl ether (2×100 mL). The combined organic extracts were dried over MgSO4 and concentrated to give brown oil (20.7 g, 97%), which was used directly in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 7.10 (d, 1H, J=5.2 Hz), 6.91 (dd, 1H, J=5.7, 4.4 Hz), 6.77 (d, 1H, J=3.2 Hz), 2.82 (t, 2H, J=7.6 Hz), 1.68 (q, 2H, J=6.8 Hz), 1.50-1.20 (m, 22H), 0.88 (t, 3H, J=6.8 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:22][CH2:21][C@@H:9]2[N:10]3[C:19]4[C:18]([C@@H:8]2[CH2:7]1)=[CH:17][CH:16]=[CH:15][C:14]=4[NH:13][C:12](=O)[CH2:11]3)=[O:5])[CH3:2].[OH-].[Na+]>Cl>[CH2:11]1[N:10]2[C@H:9]3[CH2:21][CH2:22][N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7][C@H:8]3[C:18]3[C:19]2=[C:14]([CH:15]=[CH:16][CH:17]=3)[NH:13][CH2:12]1
Reactant: CCOC(=O)N1CC[C@H]2[C@@H](C1)c1cccc3c1N2CC(=O)N3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)N1CC[C@H]2[C@@H](C1)c1cccc3c1N2CCN3
Temperature: 25 °C
Yield: 97.7 %

Procedure:
To ethyl-(6bR,10aS)-2-oxo-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate (4.41 g, 14.6 mmol) was added 1M BH3 THF complex solution (36.6 mL). The reaction was heated under reflux for 5 hr. After the reaction cooled down to r.t, 6N HCl ( 40 mL) was added dropwise with chilling. The reaction solution was heated under reflux for 30 minutes. After cooled down to r.t., 1N NaOH was added to adjust the pH to 8. The reaction was extracted with CH2Cl2 (2×200 mL). The combined organic layers were washed with brine, dried over MgSO4, and concentrated to afford ethyl (6bR,10aS)-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate (4.10 g, 98%). The product was used in next step without further purification. MS-APcI: 288 [MH]+
Reaction SMILES: [C:1]1([C:7]2[N:12]=[N:11][C:10]([C:13]3[CH:54]=[CH:53][C:16]([CH2:17][C:18]4[N:19]([C:31]5[CH:32]=[C:33]([N:37]6[S:41](=[O:43])(=[O:42])[N:40](COCC[Si](C)(C)C)[C:39](=[O:52])[CH2:38]6)[CH:34]=[CH:35][CH:36]=5)[CH:20]=[C:21]([C:23]5[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=5[Cl:30])[N:22]=4)=[CH:15][CH:14]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[C:1]1([C:7]2[N:12]=[N:11][C:10]([C:13]3[CH:54]=[CH:53][C:16]([CH2:17][C:18]4[N:19]([C:31]5[CH:32]=[C:33]([N:37]6[S:41](=[O:43])(=[O:42])[NH:40][C:39](=[O:52])[CH2:38]6)[CH:34]=[CH:35][CH:36]=5)[CH:20]=[C:21]([C:23]5[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=5[Cl:30])[N:22]=4)=[CH:15][CH:14]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: C[Si](C)(C)CCOCN1C(=O)CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(C5=CCCCC5)nn4)cc3)c2)S1(=O)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: O=C1CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(C5=CCCCC5)nn4)cc3)c2)S(=O)(=O)N1

Procedure:
5-{3-[2-[4-(6-Cyclohex-1-enyl-pyridazin-3-yl)-benzyl]-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,1-dioxo-2-(2-trimethylsilanyl-ethoxymethyl)-[1,2,5]thiadiazolidin-3-one (16 mg, 0.02 mmol) was treated as described in general procedure W using tetrabutylammonium fluoride (26 mg, 0.1 mmol) to give 5-{3-[2-[4-(6-cyclohex-1-enyl-pyridazin-3-yl)-benzyl]-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:17]#[N:18])=[C:4]([CH:14]=[CH:15][CH:16]=1)[O:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11](=[O:13])[CH3:12].[S:19](Cl)(=[O:22])(=[O:21])[NH2:20]>>[C:17]([C:3]1[C:2]([NH:1][S:19](=[O:22])(=[O:21])[NH2:20])=[CH:16][CH:15]=[CH:14][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11](=[O:13])[CH3:12])#[N:18]
Reactant: CC(=O)NCCCCOc1cccc(N)c1C#N
Reactant: NS(=O)(=O)Cl
Product: CC(=O)NCCCCOc1cccc(NS(N)(=O)=O)c1C#N
Yield: 100 %

Procedure:
Prepared as in Example 215a from N-(4-(3-amino-2-cyanophenoxy)butyl)acetamide (Example 234b) and sulfamoyl chloride in 100% yield. 1H NMR (400 MHz, DMSO-d6) δ 1.51-1.54 (m, 2H), 1.70-1.73 (m, 2H), 1.77 (s, 3H), 3.04-3.09 (m, 2H), 4.09 (t, J=6.4 Hz, 2H), 6.93 (d, J=8.4 Hz, 1H), 7.13 (d, J=8.0 Hz, 1H), 7.25 (s, 2H), 7.54 (t, J=8.0 Hz, 1H), 7.85 (brs, 1H), 9.42 (s, 1H).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[CH2:17][CH2:16][N:15]([C:18]([NH2:20])=[O:19])[C:12]3=[N:13][CH:14]=2)O1.Br[C:23]1[CH:24]=[N:25][CH:26]=[CH:27][C:28]=1[CH3:29].C([O-])([O-])=O.[Na+].[Na+]>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:29][C:28]1[CH:27]=[CH:26][N:25]=[CH:24][C:23]=1[C:9]1[CH:10]=[C:11]2[CH2:17][CH2:16][N:15]([C:18]([NH2:20])=[O:19])[C:12]2=[N:13][CH:14]=1
Reactant: Cc1ccncc1Br
Reactant: CC1(C)OB(c2cnc3c(c2)CCN3C(N)=O)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Product: Cc1ccncc1-c1cnc2c(c1)CCN2C(N)=O
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A crude solution of 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3-dihydro-pyrrolo[2,3-b]pyridine-1-carboxylic acid amide (0.41 mmol) is added to 3-bromo-4-methyl-pyridine (64 mg, 0.37 mmol) followed by the addition of aqueous 2.0 M Na2CO3 solution (0.41 mL, 0.82 mmol) and 1,1′-bis(diphenylphosphino)ferrocene palladium (II) chloride (420 mg, 0.52 mmol). The vial is sealed and the mixture is sparged with Ar (10 seconds). The reaction is stirred for 3 hours at 100° C. The reaction mixture is concentrated to dryness and dissolved in 2 mL of DMF, filtered and purified by reverse phase HPLC to afford the titled product.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][CH2:13][CH:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:11]1)([O-])=O>C(O)C.C(OCC)(=O)C>[NH2:1][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][CH2:13][CH:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[CH2:11]1
Reactant: CC(C)(C)OC(=O)NC1CCCN(c2cnccc2[N+](=O)[O-])C1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1CCCN(c2cnccc2N)C1
Yield: 79 %

Procedure:
The method of Example 90 (Method 5) was followed using 1 eq of tert-butyl 1-(4-nitropyridin-3-yl)piperidin-3-ylcarbamate in 1:1 ethanol/ethyl acetate at 30 psi for 72 hours, yielding tert-butyl 1-(4-aminopyridin-3-yl)piperidin-3-ylcarbamate (79%). LCMS (m/z): 293.1 (MH+); LC Rt=2.14 min.
Reaction SMILES: [ClH:1].[CH2:2]([O:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N:17]([O-])=O.[Na+]>O.Cl>[ClH:1].[CH2:2]([O:9][C:10]1[CH:11]=[CH:12][C:13]([NH:14][NH2:17])=[CH:15][CH:16]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=N[O-]
Reactant: Nc1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccc(OCc2ccccc2)cc1
Reaction time: 2 h
Yield: 68 %

Procedure:
p-Benzyloxyphenylhydrazine hydrochloride was prepared by the method of Mentzer, et al., [C.A. 48:33412]. Thus, p-benzyloxyaniline hydrochloride (72.6 g) was diazotized with conc. HCl (174 ml) and sodium nitrite (23.2 g) in water (40 ml) at 0° C. A solution of stannous chloride (169.3 g) in conc. HCl (435 ml) was added rapidly and the reaction mixture stirred for two hours. The solid product was filtered and washed with absolute ethanol, then partially dissolved in boiling methanol/ethanol (1:1) and filtered hot, yielding 52.5 g of p-benzyloxyphenylhydrazine hydrochloride.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][NH:22][C:23]3[N:24]([C:34]4[N:35]=[CH:36][N:37]=[C:38]([NH2:41])[C:39]=4[N:40]=3)[C@@H:25]3[O:33][C@H:30]([CH2:31][OH:32])[C@@H:28]([OH:29])[C@H:26]3[OH:27])=[CH:17][CH:16]=2)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1>[Pd].CO>[OH:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][NH:22][C:23]3[N:24]([C:34]4[N:35]=[CH:36][N:37]=[C:38]([NH2:41])[C:39]=4[N:40]=3)[C@@H:25]3[O:33][C@H:30]([CH2:31][OH:32])[C@@H:28]([OH:29])[C@H:26]3[OH:27])=[CH:17][CH:16]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: Nc1ncnc2c1nc(NCc1ccc(-c3cccc(OCc4ccccc4)c3)cc1)n2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: [Pd]
Solvent: CO
Product: Nc1ncnc2c1nc(NCc1ccc(-c3cccc(O)c3)cc1)n2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 17.5 h
Yield: 93.9 %

Procedure:
A mixture of 8-(3′-benzyloxybiphenyl-4-ylmethyl-amino)adenosine (0.103 g) and 10% palladium on carbon (55.4 wt % H2O, 0.047 g) in methanol (7.4 mL) was stirred at room temperature for 17.5 hours under a hydrogen atmosphere. The insoluble material was filtered out and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=8/1 to 6/1) to give the title compound (0.081 g).
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14](=O)[CH2:15][CH2:16][CH3:17])[CH:8]=2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[NH2:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:8]=2)=[CH:4][CH:3]=1
Reactant: CCCC(=O)Nc1cc(Oc2ccc(N)cc2)ccn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCNc1cc(Oc2ccc(N)cc2)ccn1
Temperature: 25 °C

Procedure:
After dissolving 80 mg of 4-(4-aminophenoxy)-2-butyrylaminopyridine in 8 ml of tetrahydrofuran, 67 mg of lithium aluminum hydride was added while stirring at room temperature, and the mixture was stirred at 70° C. for 10 minutes. Water was added, extraction was performed with ethyl acetate, and then silica gel was added to the extract and the solvent was distilled off under reduced pressure. The silica gel was charged into a dry column packed with silica gel and purified by column chromatography (ethyl acetate) to obtain 54 mg of the target substance as a brown oil.
Reaction SMILES: [CH3:1][N:2]1[C@@H:19]2[CH2:20][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][C@H:13]5[C:14]([CH2:16][CH2:17][C@:18]2([OH:21])[C@:5]5([C:6]=34)[CH2:4][CH2:3]1)=[O:15].[C:24](OC(=O)C)(=[O:26])[CH3:25]>>[CH3:25][C:24]([O:21][C@@:18]12[C@H:19]3[CH2:20][C:7]4[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]5[O:12][C@H:13]([C@@:5]1([C:6]=45)[CH2:4][CH2:3][N:2]3[CH3:1])[C:14](=[O:15])[CH2:16][CH2:17]2)=[O:26]
Reactant: COc1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(O)[C@@H](C2)N(C)CC[C@]314
Reactant: CC(=O)OC(C)=O
Product: COc1ccc2c3c1O[C@H]1C(=O)CC[C@]4(OC(C)=O)[C@@H](C2)N(C)CC[C@]314

Procedure:
315 g of oxycodone was refluxed with 1600 ml of acetic anhydride for one hour. After cooling the mixture to 50°, acetic anhydride and acetic acid were removed with the rotary evaporator. The solid remaining was dissolved in water and the solution was basified to pH9 with ammonia. The precipitated product was filtered off, washed with water and vacuum dried to yield 357 g of 14-acetyloxycodone (m.p. 215°-216°).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH2:20])([CH3:4])([CH3:3])[CH3:2].C([O:26][C:27](=O)[CH2:28][C:29](=[O:42])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=2)[CH:31]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH:20][C:27](=[O:26])[CH2:28][C:29](=[O:42])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=2)[CH:31]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccccn2)c1
Reactant: COc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: COc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccccn3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-methoxy-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J7) (230 mg, 0.75 mmol) and 3-oxo-3-(3-pyridin-2-yl-phenyl)-propionic acid tert-butyl ester (Example K3) (223 mg, 0.75 mmol) according to the general procedure M. Obtained as an off-white solid (240 mg).
Reaction SMILES: Br[C:2]1([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7](=[O:8])[NH:6][C:5](=[O:9])[NH:4][C:3]1=[O:10].[OH:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(N(CC)CC)C>C(O)C>[CH2:11]([C:2]1([CH:22]2[CH2:23][NH:24][CH2:25][CH2:26][N:21]2[CH2:20][CH2:19][OH:18])[C:7](=[O:8])[NH:6][C:5](=[O:9])[NH:4][C:3]1=[O:10])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1NC(=O)C(Br)(Cc2ccccc2)C(=O)N1
Reactant: OCCN1CCNCC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C1NC(=O)C(Cc2ccccc2)(C2CNCCN2CCO)C(=O)N1
Temperature: 25 °C

Procedure:
A solution of 5-Bromo-5-benzylbarbituric Acid (2.15 g) and N-(2-hydroxyethyl)piperazine in 50 ml of ethanol is refluxed for 4 hours, then it is cooled to room temperature and added with 4 ml of triethylamine. The solvent is evaporated off and the white residue is redissolved in a ethyl acetate/methanol 3:1 mixture. An ornage solid crystallizes, which is recovered by filtration. After recrystallization from ethanol 0.62 g of the product are obtained, m.p. 243-246° C.
Reaction SMILES: Cl.C(=[N:9][N:10]([CH:12]=[C:13]([C:19]#[N:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH3:11])C1C=CC=CC=1>C(O)C>[NH2:20][C:19]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][N:10]([CH3:11])[N:9]=1
Reactant: CCOC(=O)C(C#N)=CN(C)N=Cc1ccccc1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cn(C)nc1N
Yield: 103 %

Procedure:
At room temperature, 100 ml of concentrated hydrochloric acid were added dropwise over a period of 20 min to a suspension of 220 g (0.855 mol) of ethyl 3-(N′-benzylidene-N-methylhydrazino)2-cyanoacrylate (XVI-1) in 1000 ml of ethanol. The mixture was then heated at the boil for 1 hour. After removal of the solvent, the oily residue was triturated with gentle heating with 200 ml of diethyl ether, resulting in the precipitation of a solid. Filtration with suction gave 149 g (95% of theory) of ethyl 3-amino-1-methyl-1H-pyrazole-4-carboxylate [logP (pH 2.3)=0.72].
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[F:29].C([O-])([O-])=O.[K+].[K+]>Cl>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[N:4]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[F:29])[C:3](=[O:18])[C:2]2([CH3:1])[CH3:19]
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Reactant: Fc1ccc(CBr)c(F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC1(C)C(=O)N(Cc2ccc(F)cc2F)c2cc([N+](=O)[O-])c(N)cc21
Yield: 60 %

Procedure:
Analogously to general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (1.2 g) is alkylated using 1-bromomethyl-2,4-difluoro-benzene (0.6 ml; 4.6 mmol) and K2CO3 (1.8 g; 13 mmol) at RT for 18 h. After aqueous work-up the crude material is de-acetylated using hydrochloric acid (60 ml; 6 N) at reflux. After aqueous work-up 5-amino-1-(2,4-difluoro-benzyl)-3,3-dimethyl-6-nitro-1,3-dihydro-indol-2-one (0.95 g) is obtained and used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2C(=O)C3C(=CC=CC=3)C2=O)=[C:4]([CH2:20][CH3:21])[CH:3]=1.NN>C(Cl)(Cl)Cl.C(O)C>[Br:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][NH2:7])=[C:4]([CH2:20][CH3:21])[CH:3]=1
Reactant: CCc1cc(Br)ccc1CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CCc1cc(Br)ccc1CN
Temperature: 25 °C

Procedure:
2-(4-Bromo-2-ethyl-benzyl)-isoindole-1,3-dione (4 g, 11.7 mmol) and hydrazine (1.8 mL, 58.3 mmol) in chloroform:ethanol (1:1.5, 250 mL) were refluxed for 4 h. The mixture was cooled to room temperature and filtered through a pad of celite. The solution was diluted in water and partitioned. The organic layer was washed with water, saturated sodium bicarbonate, then saturated sodium chloride, dried (Na2SO4), filtered, and then concentrated in vacuo to a yellow oil (2.2 g, 88%). 1H NMR (300 MHz, CDCl3): δ ppm 1.23 (t, J=7.54 Hz, 3 H) 1.65 (s, 2 H) 2.66 (q, J=7.60 Hz, 2 H) 3.84 (s, 2 H) 7.19–7.23 (m, 1 H) 7.30–7.34 (m, 2 H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([I:10])=[C:6]([N+:11]([O-])=O)[CH:5]=1>C(O)(=O)C.[Fe]>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([I:10])=[C:6]([NH2:11])[CH:5]=1
Reactant: COC(=O)c1ccc(I)c([N+](=O)[O-])c1
Agent: [Fe]
Solvent: CC(=O)O
Product: COC(=O)c1ccc(I)c(N)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 88.8 %

Procedure:
A solution of 4-iodo-3-nitrobenzoic acid methyl ester (2.0 g, 6.50 mmol) in 25 mL of absolute alcohol and 15 mL of glacial acetic acid was treated with iron powder (3.6 g, 65.0 mmol) and the mixture was heated at 80° C. After 1 hour, the reaction mixture was filtered through a pad of silica, washed with ethanol, and concentrated in vacuo. The residue was diluted with a solution of potassium carbonate and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give 1.6 g of 3-amino-4-iodobenzoic acid methyl ester as a white solid (88% yield).