Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21](O)=[O:22])=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.S(O)(O)(=O)=O.[NH2:61][C:62]1[NH:63][CH:64]=[CH:65][N:66]=1.C(N(C(C)C)CC)(C)C>O.CN(C)C=O>[NH:63]1[CH:64]=[CH:65][N:66]=[C:62]1[NH:61][C:21]([C:20]1[C:14]2[C:15](=[N:16][CH:17]=[C:12]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:8]([CH3:11])[N:7]=3)[N:13]=2)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[CH:19]=1)=[O:22]
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Reactant: Nc1ncc[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nc(-c2cnc3c(n2)c(C(=O)Nc2ncc[nH]2)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Temperature: 70 °C
Reaction time: 18.5 h
Yield: 75.7 %

Procedure:
A solution of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (205 mg, 0.447 mmol), 1 mL of N,N-dimethylformamide and O-(7-azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (208 mg, 0.548 mmol) was stirred 10 min. To the solution was added freshly ground 2-aminoimidazole sulfate (62 mg, 0.468 mmol) and diisopropylethylamine (0.39 mL, 2.2 mmol). The flask was heated to 70° C. and the cloudy yellow solution was stirred 18.5 h, during which time a white precipitate formed. The mixture was allowed to cool, then treated with 20 mL of water. The precipitate was isolated by Buchner filtration, rinsing well with water and dried by air then in vacuo to afford 177 mg of impure 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1H-imidazol-2-yl)-amide as a pale yellow solid. MS: (M+H)+=523.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:11])[CH:3]=1.[CH:12]1([NH2:17])[CH2:16][CH2:15][CH2:14][CH2:13]1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:17][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:8])=[C:4]([F:11])[CH:3]=1
Reactant: NC1CCCC1
Reactant: O=C(O)c1ccc(Br)cc1F
Product: O=C(NC1CCCC1)c1ccc(Br)cc1F

Procedure:
The sub-title compound was prepared by the method of example 18 step a) using 4-bromo-2-fluorobenzoic acid and cyclopentanamine.
Reaction SMILES: CO[N:3]=[C:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1.N.[H][H]>[Pd].CO>[C:13]([C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][CH:10]=1)[CH:4]([NH2:3])[CH2:5][CH2:6]2)([CH3:16])([CH3:14])[CH3:15]
Reactant: [H][H]
Reactant: CON=C1CCc2cc(C(C)(C)C)ccc21
Agent: [Pd]
Agent: N
Solvent: CO
Product: CC(C)(C)c1ccc2c(c1)CCC2N
Temperature: 50 °C
Reaction time: 16 h

Procedure:
5-tert-Butyl-1-indanone O-methyloxime (4.37 g, 20.2 mmol) and 10% palladium on carbon (2.2 g) were combined in methanol (50 ml) and ammonia (10 ml) and placed in a Parr apparatus, which was charged with hydrogen to 60 psi. The reaction was shaken at 50° C. for 16 hours. The reaction mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was treated with diethyl ether (100 ml) and extracted with hydrochloric acid (1N, 3×50 ml). The combined aqueous extracts were neutralized with sodium hydroxide (6 g) in water (25 ml) and extracted with diethyl ether. The organic extracts were combined, dried with magnesium sulfate, and the filtrate was evaporated under reduced pressure to provide the title compound, which was used without further purification in the next step.
Reaction SMILES: N1C=CC=C(CN)C=1.[CH3:9][C:10]1[CH:14]=[C:13]([CH2:15][NH2:16])[NH:12][N:11]=1.[F:17][C:18]1[CH:39]=[CH:38][C:21]([CH2:22][N:23]2[C:27](=[O:28])[N:26]([C:29]3[S:30][C:31]([C:35](O)=[O:36])=[C:32]([CH3:34])[N:33]=3)[CH:25]=[N:24]2)=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:39]=[CH:38][C:21]([CH2:22][N:23]2[C:27](=[O:28])[N:26]([C:29]3[S:30][C:31]([C:35]([NH:16][CH2:15][C:13]4[NH:12][N:11]=[C:10]([CH3:9])[CH:14]=4)=[O:36])=[C:32]([CH3:34])[N:33]=3)[CH:25]=[N:24]2)=[CH:20][CH:19]=1
Reactant: Cc1cc(CN)[nH]n1
Reactant: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)O
Agent: NCc1cccnc1
Product: Cc1cc(CNC(=O)c2sc(-n3cnn(Cc4ccc(F)cc4)c3=O)nc2C)[nH]n1
Yield: 31 %

Procedure:
Following the procedure as described in Example 2, making variations as required to replace pyridin-3-ylmethanamine with (3-methyl-1H-pyrazol-5-yl)methanamine to react with 2-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methylthiazole-5-carboxylic acid instead of (S)-2-(3-(4-fluorobenzyl)-4-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as an off-white solid in 31% yield: mp 234-235° C. (diethyl ether); 1H NMR (300 MHz, DMSO-d6) δ 12.25 (s, 1H), 8.76 (s, 1H), 8.67 (t, J=5.5 Hz, 1H), 7.41-7.36 (m, 2H), 7.27-7.16 (m, 2H), 5.91 (s, 1H), 5.00 (s, 2H), 4.37-4.31 (m, 2H), 2.55 (s, 3H), 2.19-2.12 (m, 3H); 13C NMR (75 MHz, DMSO-d6) δ 161.7 (d, 1JC-F=244 Hz), 160.7, 151.2, 150.5, 149.7, 149.6, 138.7, 132.2 (d, 4JC-F=3 Hz), 132.1, 130.0 (d, 3JC-F=8 Hz), 122.9, 115.4 (d, 2JC-F=22 Hz), 102.3, 47.7, 37.3, 16.9, 10.4; MS (ES+) m/z 427.8 (M+1), MS (ES−) m/z 425.8 (M−1).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:8]=[O:9])(=[O:3])[CH3:2].[BH4-].[Na+].Cl>CO>[C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:8][OH:9])(=[O:3])[CH3:2]
Reactant: CCCCCOc1ccc(C=O)cc1OC(C)=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCCCOc1ccc(CO)cc1OC(C)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
3-Acetoxy-4-pentyloxy-benzaldehyde (0.75 g., 3.0 mmol, 1 equiv.) is dissolved in 15 mL of MeOH, and the mixture cooled to 0° C. Sodium borohydride (0.230 g., 6 mmol., 2 equiv.) is added in portions. After stirring for 30 min., the mixture is neutralized with 1N HCl, and then extracted thrice with ether. The extracts are washed with brine, dried (MgSO4), and evaporated. Chromatography on silica gel using CH2Cl2 /hexane affords 3-acetoxy-4-pentyloxy-benzyl alcohol (12f) (0.680 g., 2.70 mmol., 90%): mp=35°-36° C.; 1H NMR (300 MHz, CDCl3) δ 7.17 (dd, J=2, 8 Hz, 1H, ArH), 7.05 (d, J=2 Hz, 1H, ArH), 6.92 (d, J=8 Hz, 1H, ArH), 4.85 (s, 1H, OH), 4.60 (s, 2H, ArCH2O), 3.95 (t, J=7 Hz, 2H, OCH2R), 2.30 (s, 3H, CH3CO), 1.75 (m, 2H, OCH2CH2), 1.38 (m, 4H, CH2CH2CH3), 0.90 (t, J=7 Hz, 3H, RCH2CH3).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[S:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH:11]([N-:14]C(C)C)(C)C.[Li+].S(C#N)(C1C=CC(C)=CC=1)(=O)=O>C1COCC1>[Cl:1][C:2]1[C:3]2[S:10][C:9]([C:11]#[N:14])=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CC(C)[N-]C(C)C
Reactant: Clc1ncnc2ccsc12
Agent: Cc1ccc(S(=O)(=O)C#N)cc1
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1cc2ncnc(Cl)c2s1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 20 %

Procedure:
To a suspension of compound 6.2 (5.0 mmol) in dry THF (25.0 mL) was added lithium diisopropylamide (“LDA”; 6.0 mmol; 2.0 M in heptane/THF/ethylbenzene) at −78° C. under an atmosphere of N2. After stirring at −78° C. for 30 minutes, the mixture was transferred to a pre-cooled solution of TsCN (8.0 mmol) in dry THF (10 mL) at −78° C. The resulting mixture was slowly warmed to room temperature and stirred for several hours. The reaction was quenched by the addition of several drops of saturated ammonium chloride and then concentrated. The residue was diluted with saturated sodium bicarbonate and extracted with EtOAc. The organic layers was dried, concentrated and purified by flash column chromatography on silica gel to provide 4-chloro-thieno[3,2-d]pyrimidine-6-carbonitrile c (compound 47.1) in 20% yield. EIMS (m/z): calcd. for C7H2CN3S (M+)+H 195.97. found 196.00.
Reaction SMILES: [CH:1]1([CH:4]2[CH2:8][CH:7]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=3)[CH:6]([CH3:19])[NH:5]2)[CH2:3][CH2:2]1.[C:20](Cl)(=[O:22])[CH3:21].C(N(CC)CC)C>C1C=CC=CC=1>[C:20]([N:5]1[CH:6]([CH3:19])[CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:16])[F:17])[CH:10]=2)[CH2:8][CH:4]1[CH:1]1[CH2:2][CH2:3]1)(=[O:22])[CH3:21]
Reactant: CC1NC(C2CC2)CC1c1cccc(C(F)(F)F)c1
Reactant: CC(=O)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC(=O)N1C(C)C(c2cccc(C(F)(F)F)c2)CC1C1CC1

Procedure:
13 G of 2-cyclopropyl-4-(m-trifluoromethylphenyl)-5-methylpyrrolidine, 6 ml of acetyl chloride and 8 ml of triethylamine in 50 ml of anhydrous benzene is stirred at ambient temperature for 18 hours. Ice is added to the reaction mixture and the organic products are extracted with ether; the ethereal extract is washed with water, with 5% sodium hydroxide and then again with water, and dried over sodium carbonate to give 14.4 g of N-acetyl-2-cyclopropyl-4-(m-trifluoromethylphenyl)-5-methylpyrrolidine, which is dissolved in 50 ml of anhydrous tetrahydrofuran and added dropwise to a suspension of 2.9 g of lithium aluminium hydride in 75 ml of anhydrous tetrahydrofuran at reflux temperature. Refluxing is then continued for 4 hours. The excess double hydride is destroyed with cold ethyl acetate. After adding water and ice, the mixture is extracted with ether; the ethereal extract is washed with water and dried over sodium carbonate. After evaporation of the ether, vacuum distillation of the residue gives 9.7 g of N-ethyl-2-cyclopropyl-4-(m-trifluoromethylphenyl)-5-methylpyrrolidine as a liquid. Boiling point 0.3 = 115° C.
Reaction SMILES: [OH:1][C:2]1[CH:38]=[CH:37][C:5]([C:6]([CH2:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=2[CH:20]2[CH2:29][CH2:28][C:27]3[CH:26]=[C:25]([O:30]C(=O)C(C)(C)C)[CH:24]=[CH:23][C:22]=3[CH2:21]2)=O)=[CH:4][CH:3]=1.Cl[CH2:40][C:41]([N:43]1[CH2:48][CH2:47][CH:46]([CH3:49])[CH2:45][CH2:44]1)=O>>[CH3:19][O:18][C:16]1[CH:15]=[CH:14][C:13]([CH:20]2[CH2:29][CH2:28][C:27]3[CH:26]=[C:25]([OH:30])[CH:24]=[CH:23][C:22]=3[CH2:21]2)=[C:12]([NH:11][CH2:10][CH2:9][CH2:8][CH2:6][C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:40][CH2:41][N:43]3[CH2:48][CH2:47][CH:46]([CH3:49])[CH2:45][CH2:44]3)=[CH:38][CH:37]=2)[CH:17]=1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCCC(=O)c2ccc(O)cc2)c1
Reactant: CC1CCN(C(=O)CCl)CC1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(NCCCCc2ccc(OCCN3CCC(C)CC3)cc2)c1
Yield: 60.2 %

Procedure:
Synthesized from pivalic acid 6-{2-[(4-hydroxybenzoyl)propylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (30 mg) and 2-chloro-1-(4-methylpiperidin-1-yl)ethanone (21 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (19 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[N:20]=[C:5]2[CH:6]=[C:7](Br)[CH:8]=[C:9]([C:10]3[O:14][C:13]([CH2:15][C:16](=[O:18])[CH3:17])=[N:12][N:11]=3)[N:4]2[N:3]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23](B(O)O)[CH:22]=1.CC([O-])=O.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1(C)C=CC=CC=1.CCO.O>[NH2:1][C:2]1[N:20]=[C:5]2[CH:6]=[C:7]([C:23]3[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=3)[CH:8]=[C:9]([C:10]3[O:14][C:13]([CH2:15][C:16](=[O:18])[CH3:17])=[N:12][N:11]=3)[N:4]2[N:3]=1
Reactant: OB(O)c1cccnc1
Reactant: CC(=O)Cc1nnc(-c2cc(Br)cc3nc(N)nn23)o1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CC(=O)Cc1nnc(-c2cc(-c3cccnc3)cc3nc(N)nn23)o1
Temperature: 105 °C

Procedure:
1-[5-(2-Amino-7-bromo-[1,2,4]triazolo[1,5-a]pyridine-5-yl)-[1,3,4]oxadiazol-2-yl]-propan-2-one (product of Step 2), (0.37 g, 1.1 mmol), 3-pyridyl boronic acid (0.2 g, 1.65 mmol) and NaOAc, (0.5 g, 5 mmol) were placed in a flask with 100 mL of 8:1:1 toluene/EtOH/water and placed under a N2 atmosphere. PdCl2(dppf), (0.09 g, 0.11 mmol) was added and the mixture was heated to 105° C. for two hours. The mixture was concentrated to dryness under reduced pressure and the residue taken up in 100 mL of 9:1 CH2Cl2/methanol. The mixture was filtered through celite and insoluble residue discarded. The filtrate was extracted with 1 N HCl (3×25 mL), and any residue in the aqueous removed by filtration. The aqueous filtrate was adjusted to pH 8 with K2CO3, resulting in a precipitate that was dried under vacuum to give 1-[5-(2-Amino-7-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridine-5-yl)-[1,3,4]oxadiazol-2-yl]-propan-2-one. MS (APCI+): m/z 336.1.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]3[O:27][CH2:28][O:29][C:23]=3[CH:22]=2)[C:11]2[C:16]([CH3:17])=[C:15]([CH3:18])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]4[O:27][CH2:28][O:29][C:23]=4[CH:22]=3)[C:11]3[C:16]([CH3:17])=[C:15]([CH3:18])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1sc2nc(Cl)nc(NCc3ccc4c(c3)OCO4)c2c1C
Reactant: Cc1ncc[nH]1
Product: Cc1sc2nc(-n3ccnc3C)nc(NCc3ccc4c(c3)OCO4)c2c1C

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-5,6-dimethyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-5,6-dimethyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][N+:2]#[C-:3].[C@@H:4]12[N:11](C)[C@@H:8]([CH2:9][CH2:10]1)[CH2:7][CH2:6][C:5]2=O.CC(C)([O-])C.[K+].C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.C(O)C>[CH3:3][N:2]1[CH:4]2[CH2:10][CH2:9][CH:1]1[CH:7]([C:8]#[N:11])[CH2:6][CH2:5]2
Reactant: [C-]#[N+]C
Reactant: CN1[C@@H]2CCC(=O)[C@H]1CC2
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCO
Product: CN1C2CCC(C#N)C1CC2
Temperature: 0 °C

Procedure:
Methyl isocyanide (5.04 g., 0.026 mol) was added to (±)-tropan-2-one (2 g., 0.0143 mol) in dimethoxyethane (80 ml) and the solution cooled to 0° C. Ethanol (2 ml) was added followed by addition of potassium tert-butoxide (5.64 g, 6.05 mol). The mixture was then heated at 50° C. for three hours, cooled and poured into a saturated potassium carbonate solution (300 ml). This was extracted with ethyl acetate (3×100 ml) and the combined extracts dried (K2CO3), filtered and evaporated to give a crude oil which was abosorbed on alumina (40 g, grade 1 neutralised by addition of 10% water) from ethereal solution. The solution was eluted with a progressively graded mixture of ether, ethyl acetate and methanol to give 8-methyl-8-azabicyclo[3.2.1]octane-2nitrile (1.1 g--46%) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH:9][C:10](=[O:12])[CH3:11])=[CH:7][CH:6]=[CH:5][N:4]=1.[N+:13]([O-])([OH:15])=[O:14]>FC(F)(F)C(OC(=O)C(F)(F)F)=O>[CH3:1][O:2][C:3]1[C:8]([NH:9][C:10](=[O:12])[CH3:11])=[CH:7][C:6]([N+:13]([O-:15])=[O:14])=[CH:5][N:4]=1
Reactant: O=[N+]([O-])O
Reactant: COc1ncccc1NC(C)=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COc1ncc([N+](=O)[O-])cc1NC(C)=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 72.2 %

Procedure:
To a stirred solution of N-(2-methoxypyridin-3-yl)acetamide (23 g, 139 mmol) in trifluoroacetic anhydride (TFAA) (90 mL) was added a solution of HNO3 (5.84 mL, 139 mmol) in TFAA (140 mL) dropwise at rt. The reaction was stirred for 1.5 h at rt before being poured into an ice bath with stirring. The precipitated solid was filtered and washed with Et2O (50 mL), then dissolved in EtOAc (1 L) and washed with saturated aqueous NaHCO3 (100 mL) and brine (100 mL). The phases were separated and the organic phase dried (MgSO4), and concentrated in vacuo to yield the title compound as a light yellow solid (21.2 g, 100.4 mmol).
Reaction SMILES: C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.Br[C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[C:18]2[CH2:24][CH2:25][N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1.C[Si]([N-:35][Si](C)(C)C)(C)C.[Li+]>C1COCC1.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]>[N:26]1([CH2:25][CH2:24][C:18]2[C:17]3[C:21](=[CH:22][CH:23]=[C:15]([NH2:35])[CH:16]=3)[NH:20][CH:19]=2)[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: Brc1ccc2[nH]cc(CCN3CCCC3)c2c1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: Nc1ccc2[nH]cc(CCN3CCCC3)c2c1
Reaction time: 0.17 h
Yield: 64.1 %

Procedure:
A solution of Pd2dba3 (0.187 g, 0.205 mmol) in dry THF (10 mL) was treated with tri-tert-butylphosphine (2.483 mL, 0.819 mmol) at room temperature. After stirring for 10 min., 5-bromo-3-(2-(pyrrolidin-1-yl)ethyl)-1H-indole (1.2 g, 4.09 mmol) in dry THF (10 mL) was added followed by lithium bis(trimethylsilyl)amide 1M THF (10.23 mL, 10.23 mmol) at same temperature. The reaction was placed in a pre-heated oil bath and stirred for 3.5 h at 100° C. in a sealed tube. The reaction was brought to room temperature, quenched with 1 N HCl solution (25 mL) and stirred for 30 min. The reaction was basified with 1 N NaOH solution (50 mL) and product was extracted into ethyl acetate (3×25 mL). The combined ethyl acetate layer was dried (Na2SO4) and solvent was evaporated to obtain crude product. The crude material was purified by column chromatography (2 M NH3 in MeOH:CH2Cl2, 5:95) to obtain 3-(2-(pyrrolidin-1-yl)ethyl)-1H-indol-5-amine (0.6 g, 2.62 mmol, 63.9% yield) as a brown foam. ESI-MS (m/z, %): 230 (MH+, 100).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:18][CH:17]2[O:19][CH:13]([CH2:14][N:15](CC3C=CC=CC=3)[CH2:16]2)[CH2:12]1)([CH3:4])([CH3:3])[CH3:2]>C(O)C.[OH-].[Pd+2].[OH-]>[C:1]([O:5][C:6](=[O:27])[NH:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:12][CH:13]2[O:19][CH:17]([CH2:16][NH:15][CH2:14]2)[CH2:18]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCN1CC2CN(Cc3ccccc3)CC(C1)O2
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCCN1CC2CNCC(C1)O2
Reaction time: 4 h
Yield: 113.1 %

Procedure:
tert-Butyl[3-(7-benzyl-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)propyl]carbamate (0.85 g, 2.2 mmol; see Example 11 below) was dissolved in ethanol (10 mL). Palladium hydroxide (0.5 g) was then added and the reaction mixture was hydrogenated in Parr shaker under 2.45 bar pressure for 4 h. The reaction mixture was filtered and solvent concentrated under reduced pressure to give the title compound (0.71 g, 84%) as an orange solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:12]=2)[C:7]([CH2:19][N:20]2[CH:24]=[CH:23][N:22]=[CH:21]2)=[CH:6]1.[C:25]1([CH:31]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C.C(OCC)(=O)C.O>[CH:31]([N:32]1[CH2:37][CH2:36][N:35]([CH2:2][CH2:3][CH2:4][N:5]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:12]=3)[C:7]([CH2:19][N:20]3[CH:24]=[CH:23][N:22]=[CH:21]3)=[CH:6]2)[CH2:34][CH2:33]1)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)c1ccc2c(Cn3ccnc3)cn(CCCCl)c2c1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc2c(Cn3ccnc3)cn(CCCN3CCN(C(c4ccccc4)c4ccccc4)CC3)c2c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 98.5 %

Procedure:
1-(3-Chloropropyl)-6-ethoxycarbonyl-3-(1H-imidazol-1-ylmethyl)-1H-indole (1.5 g) was dissolved in DMF (15 ml), and thereto were added 1-diphenylmethylpiperazine (1.59 g), potassium carbonate (1.28 g), and potassium iodide (145 mg), followed b stirring at 80° C. for 16 hours. Water and ethyl acetate we added to the reaction mixture for extraction, followed by washing with saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled away under reduced pressure. The residue was purified by silica gel column chromatography (Daisogel 60 g, elution; CHCl3 /MeOH=10/1) to give 2.4 g of the title compound as an oily substance.
Reaction SMILES: CC(C)([O-])C.[K+].[CH:7]([CH:9]([O:16][CH2:17][CH2:18][CH2:19][OH:20])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[CH2:8].Cl[C:22]1[N:30]=[CH:29][N:28]=[C:27]2[C:23]=1[NH:24][CH:25]=[N:26]2>O1CCCC1>[CH:7]([CH:9]([O:16][CH2:17][CH2:18][CH2:19][O:20][C:22]1[N:30]=[CH:29][N:28]=[C:27]2[C:23]=1[NH:24][CH:25]=[N:26]2)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[CH2:8]
Reactant: Clc1ncnc2nc[nH]c12
Reactant: C=CC(OCCCO)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CC(OCCCOc1ncnc2nc[nH]c12)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 56.7 %

Procedure:
Potassium tert-butoxide (35.64 g, 0.317 mol) was added to a stirred solution of 3-(vinylbenzyloxy)-1-propanol (mixture of meta and para isomers) (30.51 g, 0.158 mol) in dry tetrahydrofuran (300 ml) under an atmosphere of nitrogen. After 15 min 6-chloropurine (24.55 g, 0.159 mol) was added, and, after stirring for 15 min at room temperature, the reaction mixture was heated at reflux overnight. The reaction mixture was allowed to cool and then the solvent was removed in vacuo. First water (600 ml) then concentrated hydrochloric acid (17 ml) were added to the residue and stirred for 15 min. The acidic mixture was neutralized with saturated sodium hydrogen carbonate solution. After stirring for 15 min the solid was removed by filtration from the neutral suspension and dried. The solid was extracted with hot tetrahydrofuran (400 ml) for 2 hr and then the undissolved material was removed by filtration whilst hot. The filtrate was concentrated in vacuo and the residue (40.5 g of a yellow solid) recrystallized from tetrahydrofuran. This gave the title compound (27.78 g, 89.6 mmol, 56%) as a yellow solid.
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([CH:12]=O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.[OH-].[Na+].Cl.[N+:19]([CH3:22])([O-:21])=[O:20]>O>[N+:19]([CH:22]=[CH:12][C:10]1[O:11][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:8][CH:9]=1)([O-:21])=[O:20]
Reactant: O=Cc1ccc(-c2ccccc2)o1
Reactant: C[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=[N+]([O-])C=Cc1ccc(-c2ccccc2)o1

Procedure:
Combine 5-phenylfuran-2-carbaldehyde (808 mg, 4.69 mmol), methanol (2.0 mL), and nitromethane (1.13 mL) and cool. Add a combination of 0.20 mL of 1M sodium hydroxide and 0.70 mL of water to the reaction. Stir the reaction for 15 minutes, dilute with water (5 mL), add 1.0 mL of concentrated hydrochloric acid, and stir for 20 additional hours. Extract the reaction with ethyl acetate, dry organics, filter and evaporate to yield 1.14 g of 2-(2-nitrovinyl)-5-phenylfuran as a brown oil which can be used without further purification. MH+ 216.0
Reaction SMILES: [NH:1]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=[CH:15][C:14]([Br:18])=[CH:13]2)C1C=CC=CC=1.[CH3:19][O:20][C:21]([C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26]([OH:28])=O)=[O:22].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O.O>[Br:18][C:14]1[CH:15]=[N:16][C:17]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][C:8]=2[NH:1][C:26](=[O:28])[C:25]1[CH:29]=[CH:30][CH:31]=[C:23]([C:21]([O:20][CH3:19])=[O:22])[CH:24]=1
Reactant: Brc1cnc2c(Nc3ccccc3)cccc2c1
Reactant: COC(=O)c1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc(C(=O)Nc2cccc3cc(Br)cnc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.8 %

Procedure:
A mixture of 8-amiino-3-bromoquinoline (330 mg), 3-methoxycarbonylbenzoic acid (267 mg), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (369 mg) and 1-hydroxybenzotriazole (300 mg) in dimethylformamide (5 ml) was stirred at ambient temperature overnight. To the mixture was added water, and the resulting precipitates were collected by filtration, washed with hot methanol and dried to give 3-bromo-8-[3-(methoxycarbonyl)benzoylamino]quinoline (390 mg) as pale yellow solid.