Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[S:20])[CH2:10][N:9]=1.[OH-].[K+].O1CCCC1.Cl.[CH3:29][N:30]([CH2:32][CH:33](Cl)[CH3:34])[CH3:31]>[Cl-].[Na+]>[CH3:34][CH:33]([S:20][C:11]1[CH2:10][N:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:14]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=2[N:12]=1)[CH2:32][N:30]([CH3:31])[CH3:29]
Reactant: CC(Cl)CN(C)C
Reactant: S=C1CN=C(c2ccccc2Cl)c2cc(Cl)ccc2N1
Agent: Cl
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(CN(C)C)SC1=Nc2ccc(Cl)cc2C(c2ccccc2Cl)=NC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.2 %

Procedure:
To a solution of 4.8 g of 1,3-dihydro-5-(2-chlorophenyl)-7-chloro-2H-1,4-benzodiazepine-2-thione in a solvent mixture comprising 28 ml of a 10% aqueous potassium hydroxide solution and 1 ml of tetrahydrofuran is added at room temperature with stirring 3.6 g of N,N-dimethyl-2-chloropropylamine hydrochloride, and the resulting mixture is stirred at room temperature for 2 hours and 30 minutes. The mixture is diluted with a saturated aqueous sodium chloride solution and then extracted with ether. The extract is washed with water and dried, and the solvent is removed by distillation under reduced pressure. An oily product obtained as the residue is subjected to column chromatography on silica gel to obtain 3.9 g of crude 2-(1-methyl-2-dimethylaminoethylthio)-5-(2-chlorophenyl)-7-chloro-3H-1,4-benzodiazepine as free base. The crude product is dissolved in acetone and added with 1.1 g of fumaric acid. The solvent is removed by distillation under reduced pressure to obtain crude 2-(1-methyl-2-dimethylaminoethylthio)-5-(2-chlorophenyl)-7-chloro-3H-1,4-benzodiazepine fumarate. Recrystallization from a mixture of isopropyl alcohol, methyl alcohol and ether gives 4.1 g of 2-(2-dimethylamino-1-methylethylthio)-5-(2-chlorophenyl)-7-chloro-3H-1,4-benzodiazepine fumarate, m.p. 178°-180° C., yield 52.5%.
Reaction SMILES: I[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:14][C:9]=3[O:8][CH2:7][CH2:6][N:5]2[CH:19]=1.[CH:20]([N:23]1[CH:27]=[N:26][CH:25]=[N:24]1)([CH3:22])[CH3:21].C(=O)([O-])[O-].[Cs+].[Cs+].[OH-].[NH4+].O>[Cu]I.CC([O-])=O.CC([O-])=O.[Pd+2].CCOC(C)=O.CN(C=O)C>[CH:20]([N:23]1[C:27]([C:2]2[N:3]=[C:4]3[C:10]4[CH:11]=[CH:12][C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:14][C:9]=4[O:8][CH2:7][CH2:6][N:5]3[CH:19]=2)=[N:26][CH:25]=[N:24]1)([CH3:22])[CH3:21]
Reactant: CC(C)n1cncn1
Reactant: COC(=O)c1ccc2c(c1)OCCn1cc(I)nc1-2
Agent: [Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)OCCn1cc(-c3ncnn3C(C)C)nc1-2
Temperature: 100 °C
Yield: 28.3 %

Procedure:
To methyl 2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate (1.0 g, 2.7 mmol), 1-isopropyl-1H-1,2,4-triazole (0.30 g, 2.7 mmol), CuI (1.5 g, 8.1 mmol), Pd(OAc)2 (0.061 g, 0.27 mmol), and cesium carbonate (2.2 g, 6.8 mmol) was added DMF (26 mL). The reaction mixture was allowed to stir and heat at 100° C. for 24 hours in a sealed vial. The reaction mixture was cooled to room temperature and poured into a mixture of ammonium hydroxide/water (1:2) and EtOAc and filtered through a pad of silica. The layers were separated and the aqueous portion was extracted with EtOAc. The combined organic extracts were washed with ammonium hydroxide (1:2), water, brine, dried over MgSO4, and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel eluting with EtOAc to provide 184 (0.270 g, 28%). 1H NMR (400 MHz, DMSO) δ 8.54 (d, J=8.4, 1H), 7.97 (d, J=35.2, 2H), 7.70 (dd, J=8.4, 1.7, 1H), 7.57 (d, J=1.7, 1H), 5.99-5.70 (m, 1H), 4.57 (q, J=5.9, 4H), 3.87 (s, 3H), 1.49 (d, J=6.6, 6H). MS (ESI(+)): m/z 354.1 (M+H).
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[CH3:19][O:20][C:21]1[C:26]2[C:27](=[O:52])[N:28]3[CH2:43][C@H:42]([O:44][Si](C(C)(C)C)(C)C)[CH2:41][C@H:29]3[C:30](=[O:40])[N:31]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:25]=2[CH:24]=[CH:23][C:22]=1[O:53][CH3:54]>C1COCC1.C(Cl)Cl>[CH3:19][O:20][C:21]1[C:26]2[C:27](=[O:52])[N:28]3[CH2:43][C@H:42]([OH:44])[CH2:41][C@H:29]3[C:30](=[O:40])[N:31]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:37])[CH3:38])[C:25]=2[CH:24]=[CH:23][C:22]=1[O:53][CH3:54]
Reactant: COc1ccc2c(c1OC)C(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(=O)N2COCC[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc2c(c1OC)C(=O)N1C[C@H](O)C[C@H]1C(=O)N2COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 107 %

Procedure:
A solution of 1 N TBAF in THF (19.58 mL, 19.58 mmol) was added to a stirred solution of 172 (7.0 g, 13.05 mmol) in THF (50 mL). The reaction mixture was allowed to stir at room temperature for 2 hours and diluted with DCM (200 mL), washed with water (2×200 mL), brine (2×200 mL) and dried over anhydrous MgSO4. Filtration and removal of excess solvent afforded the crude product, which was purified by flash column chromatography using 50:50 petroleum ether:EtOAc as eluent. Evaporation in vacuo of the pure fractions afforded the product (173) (5.9 g). 1HNMR (270 MHz, CDCl3) δ 7.30 (s, 1H, ArH), 7.24 (s, 1H, ArH), 5.52 (d, 1H, J=9.9 Hz, SEM amino acetal CH2), 4.68-4.64 (m, 2H, SEM amino acetal CH, +2), 4.30 (dd, 1H, J=5.86, 8.24 Hz), 3.91 (s, 3H, OMe), 3.90 (s, 3H, OMe), 3.87-3.51 (m, 4H, SEM 1′ CH2+3), 2.95 (dt, 1H, J=5.31, 13.56 Hz, 1), 2.17-2.08 (m, 1H, 1), 1.02-0.93 (m, 2H, SEM 2′ CH2), 0.03 (s, 9H, 3×SiCH3); 1C NMR (67.8 MHz, CDCl3) δ 169.7, 165.9, 151.9, 147.1, 134.0, 121.1, 111.2, 105.5, 78.2, 69.1, 67.1, 56.5, 56.1, 53.9, 34.9, 18.4, −1.3.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11](=[O:26])[CH2:12][N:13]3[CH2:22][CH2:21][C:20]4[C:15](=[CH:16][CH:17]=[C:18]([C:23](O)=[O:24])[CH:19]=4)[CH2:14]3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.O>C(Cl)Cl>[CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11](=[O:26])[CH2:12][N:13]3[CH2:22][CH2:21][C:20]4[C:15](=[CH:16][CH:17]=[C:18]([C:23]([N:27]5[CH2:31][CH2:30][CH2:29][CH2:28]5)=[O:24])[CH:19]=4)[CH2:14]3)[CH2:7][CH2:6]2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=C(O)c1ccc2c(c1)CCN(CC(=O)N1CCN(C3CCC3)CC1)C2
Reactant: C1CCNC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: ClCCl
Product: O=C(CN1CCc2cc(C(=O)N3CCCC3)ccc2C1)N1CCN(C2CCC2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 2-[2-(4-cyclobutyl-piperazin-1-yl)-2-oxo-ethyl]-1,2,3,4-tetrahydro-isoquinoline-6-carboxylic acid (179 mg, 0.5 mmol) and pyrrolidine (71 mg, 1.0 mmol, 2.0 eq.) in DCM (5.0 ml) are added BOP (265 mg, 0.6 mmol, 1.2 eq.) and TEA (101 mg, 1 mmol, 2.0 eq.). The mixture is stirred at rt for 2 hr. Water (5.0 ml) is added to quench the reaction, and the organic layer is collected, dried over sodium sulfate, and concentrated. The residue is purified by PTLC (EtOAc/4% TEA) to give the title compound. 1H NMR (300 MHz, CDCl3) δ 7.23-7.30 (2H, m), 7.01 (1H, d), 3.69 (2H, s), 3.55-3.66 (6H, m), 3.40 (2H, t), 3.35 (2H, s), 2.90 (2H, t), 2.78 (2H, t), 2.66 (1H, m), 2.26 (4H, m), 1.60-2.05 (10H, m); MS (+VE) m/z 411.1 (M++1).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([S:21][CH3:22])[CH:19]=3)[CH:14]([CH3:23])[NH:13][N:12]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH2:24]([N:26]=[C:27]=[O:28])[CH3:25]>C(Cl)(Cl)Cl>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([S:21][CH3:22])[CH:19]=3)[CH:14]([CH3:23])[N:13]([C:27](=[O:28])[NH:26][CH2:24][CH3:25])[N:12]=2)=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CSc1ccc2c(c1)C(c1ccc(NC(C)=O)cc1)=NNC2C
Reactant: CCN=C=O
Solvent: ClC(Cl)Cl
Product: CCNC(=O)N1N=C(c2ccc(NC(C)=O)cc2)c2cc(SC)ccc2C1C
Yield: 50 %

Procedure:
To a solution of dihydrophthalazine 8 in chloroform was added ethyl isocyanate (3 eq) at room temperature. The resulting solution was stirred at such temperature for a few days until there is no starting material left from TLC. The solvent was removed under reduced pressure. Purification of the crude product by using a silica gel gave the desired products 9 (Yield: 50%). 1HNMR (CDCl3): 7.70-7.55 (m, 5H), 7.35 (dd, J=4.3 Hz, 1H), 7.19 (m, 2H), 6.53 (br, 1H), 5.73 (q, J=13.2 Hz, 1H), 3.42 (m, 2H), 2.40 (s, 3H), 2.25 (s, 3H), 1.22 (m, 6H).
Reaction SMILES: [CH3:1][O-:2].[Na+].Br[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[C:11]([NH:15][C:16]([CH:18]1[CH2:20][C:19]1([CH3:22])[CH3:21])=[O:17])[C:12]([OH:14])=[O:13]>CO>[CH3:21][C:19]1([CH3:22])[CH2:20][CH:18]1[C:16]([NH:15]/[C:11](=[CH:10]\[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][O:2][CH3:1])/[C:12]([OH:14])=[O:13])=[O:17]
Reactant: CC1(C)CC1C(=O)NC(=CCCCCCBr)C(=O)O
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COCCCCC/C=C(\NC(=O)C1CC1(C)C)C(=O)O
Yield: 49.4 %

Procedure:
To a solution of 2.43 mmoles of sodium methoxide in 5 ml of methanol was added 332 mg (1 mmole) of 8-bromo-2-(2,2-dimethylcyclopropanecarboxamido)-2-octenoic acid. The solution was heated under reflux in a nitrogen atmosphere for 1 hr. The reaction mixture was evaporated under reduced pressure, the residue dissolved in water and acidified with 2.5 N hydrochloric acid. The oil which precipitated was extracted with ether (3×). The ether extracts were washed with water, and saturated brine and dried over MgSO4. Removal of the ether under reduced pressure gave a colorless oil that crystallized upon standing. It was recrystallized from ether-hexane to give 140 mg of Z-2-(2,2-dimethylcyclopropanecarboxamido)-8-methoxy-2-octenoic acid, m.p. 71°-72° C. Homogeneous by TLC (toluene-HOAc, 4:1). The NMR spectrum was in accord with the desired structure.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][Si](C(C)(C)C)(C)C)[CH2:10][C@H:9]1[C@H:21]([OH:27])[CH2:22][C:23]([O:25][CH3:26])=[O:24])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C@H:21]([OH:27])[CH2:22][C:23]([O:25][CH3:26])=[O:24])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)C[C@@H](O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)C[C@@H](O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reaction time: 4 h
Yield: 70.9 %

Procedure:
To a solution of (2S,4R)-1-tert-butoxycarbonyl-4-tert-butyldimethylsiloxy-2-[(R)-1-hydroxy-2-(methoxycarbonyl)ethyl]pyrrolidine (2.40 g, 5.95 mmol) in tetrahydrofuran (24 ml) was dropwise added a 1M tetrabutylammonium fluoride--tetrahydrofuran solution (7.14 ml) at room temperature. The mixture was stirred at the same temperature for 4 h. The reaction solution was washed with saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography (heptane-ethyl acetate=3:7) to obtain (2S,4R)-N-tert-butoxycarbonyl-4-hydroxy-2-[(R)-1-hydroxy-2-(methoxycarbonyl)ethyl]pyrrolidine diastereomer B (1.22 g, yield: 70.9%). ##STR399##
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([NH2:11])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[C:12]([C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13]>>[C:12]([C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:11][C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:5]=2[CH:4]=[CH:3][N:2]=[CH:1]3)(=[O:24])=[O:23])=[CH:18][CH:17]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: Nc1cccc2cnccc12
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2cccc3cnccc23)cc1

Procedure:
prepared by reaction of isoquinolin-5-ylamine with 4-tert-butyl-benzenesulfonyl chloride
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([F:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1.Cl.[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH2:33][C:34](O)=[O:35]>>[ClH:16].[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([C@@H:9]2[O:8][CH2:7][CH2:6][NH:5][CH2:4][C@H:3]2[CH2:2][NH:1][C:34](=[O:35])[CH2:33][O:32][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][N:26]=2)=[CH:11][C:12]=1[F:17]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](CN)C1
Reactant: O=C(O)COc1ccccn1
Agent: Cl
Product: O=C(COc1ccccn1)NC[C@@H]1CNCCO[C@H]1c1ccc(Cl)c(F)c1

Procedure:
Using tert-butyl (6R,7R)-6-(aminomethyl)-7-(4-chloro-3-fluorophenyl)-1,4-oxazepane-4-carboxylate and (pyridin-2-yloxy)acetic acid monohydrochloride, and by a method similar to that of Example 39, the title compound was obtained.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].[C:7]([NH2:11])([CH3:10])([CH3:9])[CH3:8]>>[C:7]([NH:11][CH2:2][CH2:3][CH2:4][C:5]#[CH:6])([CH3:10])([CH3:9])[CH3:8]
Reactant: C#CCCCI
Reactant: CC(C)(C)N
Product: C#CCCCNC(C)(C)C

Procedure:
A solution of 5-iodo-pent-1-yne (1.0 g, 5.2 mmol) in tert-BuNH2 (2.0 g. 27 mmol) was heated to reflux for 4 h, evaporated, diluted with Et2O, filtered, and concentrated to afford the title compound. 1H NMR (CDCl3) δ 2.67 (t, 2H), 2.27 (td, 2H), 1.96 (t, 1H), 1.70 (quint., 2H), 1.11 (s, 9H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([OH:19])=[CH:16][CH:17]=2)[O:12][C:11](=[O:20])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Na].[Cl:24][C:25]1[CH:41]=[CH:40][C:28]([CH2:29][N:30]2[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][CH2:38]Cl)[CH2:32][CH2:31]2)=[CH:27][CH:26]=1>>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH2:38][CH2:37][CH2:36][N:33]3[CH2:34][CH2:35][N:30]([CH2:29][C:28]4[CH:27]=[CH:26][C:25]([Cl:24])=[CH:41][CH:40]=4)[CH2:31][CH2:32]3)=[CH:16][CH:17]=2)[O:12][C:11](=[O:20])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: O=c1cc(OCc2ccccc2)c2ccc(O)cc2o1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Product: O=c1cc(OCc2ccccc2)c2ccc(OCCCN3CCN(Cc4ccc(Cl)cc4)CC3)cc2o1
Reaction time: 1 h
Yield: 74.3 %

Procedure:
To a solution of 4-benzyloxy-7-hydroxycoumarin (9.4 g, 0.035 mole) in dry NN-dimethylformamide (35 ml) was added sodium hydride (0.84 g; 0.035 mole) and the mixture stirred for 1 hour at 100° to complete formation of the sodium salt. To this was added a solution of 1-(4-chlorobenzyl)-4-(3-chloropropyl)piperazine (9.3 g; 0.035 mole) in dry NN-dimethylformamide (40 ml) over 1 hour and the resulting mixture stirred for 4 hours at 100°. The precipitated sodium chloride was filtered from the cooled mixture and the filtrate evaporated in vacuo to a red oil which was extracted with dry ether. Concentration of the extracts afforded 13.5 g (74%) of white crystalline material of m.p. (EtOH) 115°-116°, νmax (mull) 1725, 1625, 1610 cm-1. δ (CDCl3) 2.01 (2H, m); 2.48 (10H, m); 3.46 (2H, s); 4.07 (2H, t, J 6 Hz); 5.17 (2H, s); 5.65 (1H, s); 6.80 (2H, s); 7.27 (4H, s); 7.43 (5H, s); 7.72 (1H, d, J 9.6 Hz). (Found; C, 69.23; H, 6.12; Cl, 7.00; N, 5.22; C30H31ClN2O4 requires; C, 69.42; H, 6.02; Cl, 6.83; N, 5.40%).
Reaction SMILES: [C:1]([C:3]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:7]3[N:20]=[CH:21][CH:22]=[C:23]([N:24]4[CH2:28][CH2:27][C@H:26]([NH:29]C(=O)OC(C)(C)C)[CH2:25]4)[C:6]=3[C:5]=2[CH:4]=1)#[N:2].FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:29][C@H:26]1[CH2:27][CH2:28][N:24]([C:23]2[C:6]3[C:5]4[CH:4]=[C:3]([C:1]#[N:2])[N:11]=[CH:10][C:9]=4[N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:7]=3[N:20]=[CH:21][CH:22]=2)[CH2:25]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(c2ccnc3c2c2cc(C#N)ncc2n3COCC[Si](C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2c(N3CC[C@H](N)C3)ccnc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of (S)-tert-butyl 1-(6-cyano-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-4-yl)pyrrolidin-3-ylcarbamate (401 mg, 0.79 mmol) in methylene chloride (9.0 mL) was added trifluoroacetic acid (9.0 mL), and the mixture was stirred at ambient temperature for 10 minutes. The solvent was evaporated in vacuo, and the resulting residue was dissolved in methylene chloride and treated with a solution of saturated aqueous sodium bicarbonate solution. The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo to afford the title compound as a yellow foam, which was used in the next step without any further purification (268 mg, 83%).
Reaction SMILES: [O-]CC.[Na+].C(O)C.[C:8]1([CH3:28])[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:15])=[CH:10][CH:9]=1.[Br:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33]Br>C(O)C>[Br:29][C:30]1[CH:37]=[CH:36][CH:35]=[C:32]([CH2:33][C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])([C:18]([O:20][CH2:21][CH3:22])=[O:19])[NH:16][C:14]([C:11]2[CH:12]=[CH:13][C:8]([CH3:28])=[CH:9][CH:10]=2)=[O:15])[CH:31]=1
Reactant: BrCc1cccc(Br)c1
Reactant: CCOC(=O)C(NC(=O)c1ccc(C)cc1)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(Cc1cccc(Br)c1)(NC(=O)c1ccc(C)cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 107.5 %

Procedure:
To 100 ml of dry ethanol, 21.45 g of 20% sodium ethoxide-ethanol solution and 17.61 g of diethyl p-toluoylaminomalonate were added and stirred for 30 minutes at room temperature under argon atmosphere. After 15.00 g of 3-bromobenzyl bromide was added dropwise, the reaction solution was stirred for 8 hours at 55° C. and then concentrated. To the residue was added water, and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to provide 29.82 g of the objective compound as yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[O:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18](OCC)=[O:19])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.CO.[Cl-].[NH4+]>C1(C)C=CC=CC=1.CCCCCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[O:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([CH:18]=[O:19])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1CCN(CCOC(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CO
Product: O=CC1CCN(CCOC(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: -68 °C
Reaction time: 1 h
Yield: 91.5 %

Procedure:
3.03 g of ethyl 1-[2-bis(4-fluorophenyl)methoxyethyl]-4-piperidinecarboxylate (prepared as described in preparation 8) were dissolved in 30 ml of toluene, under a stream of nitrogen, and the resulting solution was cooled at -68° C. 8.2 ml of a 1M solution of diisobutylaluminum hydride in hexane was then added dropwise to the cooled mixture over a period of 10 minutes, and the mixture was stirred for 1 hour at -68° C. At the end of this time, 2 ml of methanol and 3 ml of a saturated aqueous solution of ammonium chloride were added to the reaction solution. The mixture was then extracted with ethyl acetate, to give 2.47 g (yield 91%) of the title compound as an oil, whose properties were the same as those of the product of step (a).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1Cl.[NH:12]1[CH2:17][CH2:16][CH2:15][C@H:14]([NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:13]1.C(N(CC)CC)C>C(O)(C)C.CCOC(C)=O.O>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[N:12]1[CH2:17][CH2:16][CH2:15][C@H:14]([NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:13]1
Reactant: O=C(N[C@H]1CCCNC1)OCc1ccccc1
Reactant: O=[N+]([O-])c1cncc(Br)c1Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: O=C(N[C@H]1CCCN(c2c(Br)cncc2[N+](=O)[O-])C1)OCc1ccccc1
Temperature: 90 °C
Yield: 91.9 %

Procedure:
A mixture of 3-bromo-4-chloro-5-nitropyridine (from Ark Pharm, 0.050 g, 0.21 mmol), benzyl (3S)-piperidin-3-ylcarbamate (0.059 g, 0.25 mmol), and triethylamine (0.088 mL, 0.63 mmol) in isopropyl alcohol (0.8 mL) was heated at 90° C. in a sealed vial for 16 h. The reaction mixture was diluted with EtOAc (40 mL) and water (3 mL). The layers were separated and the organic layer was washed with water (3×3 mL) and the combined aqueous phases were extracted with EtOAc (3 mL). The combined organic layers were washed with brine (3 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford the sub-title compound (0.084 g). The crude product was used without further purification in the subsequent reaction. LCMS (ESI) calc. for C18H20BrN4O4[M+H]+: m/z=435.1. found 435.0/437.0.
Reaction SMILES: C(O)C(C)C.[OH-].[NH3+:7][NH2:8].[CH2:9]([O:16][C:17]1[CH:26]=[CH:25][C:20]([C:21](OC)=[O:22])=[C:19]([CH2:27][CH3:28])[C:18]=1[CH3:29])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CC(O)C>[CH2:9]([O:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([NH:7][NH2:8])=[O:22])=[C:19]([CH2:27][CH3:28])[C:18]=1[CH3:29])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: N[NH3+]
Reactant: CCc1c(C(=O)OC)ccc(OCc2ccccc2)c1C
Agent: [OH-]
Solvent: CC(C)O
Solvent: CC(C)CO
Product: CCc1c(C(=O)NN)ccc(OCc2ccccc2)c1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
20 ml of 2-propanol and 10 ml of isobutanol (2-methylpropan-1-ol) and also 20.0 ml of hydrazinium hydroxide are added to 17.5 g of methyl 4-benzyloxy-2-ethyl-3-methylbenzoate (C1). The reaction mixture is subsequently heated under reflux for 18 h overnight. After cooling, a further 30 ml of 2-propanol are added to the solution, which is subsequently stirred at room temperature for 30 min. The precipitate is filtered off with suction, and the filter cake is rinsed a number of times with a little 2-propanol. The product is subsequently recrystallised from 2-propanol, and the precipitate obtained is dried overnight in vacuo, giving 12.3 g of the title compound as a colourless, amorphous solid having a melting point of 179° C.; MS: 284.2 (M+); TLC: Rf=0.27 (ethyl acetate/ethanol 97:3 parts by volume).
Reaction SMILES: [CH2:1]([N:8]([CH3:12])[CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:20](OC(=O)C)(=[O:22])[CH3:21].C(Cl)Cl>CN(C)C1C=CN=CC=1.CC(OC)(C)C>[C:20]([O:11][CH2:10][CH2:9][N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:12])(=[O:22])[CH3:21]
Reactant: CN(CCO)Cc1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: COC(C)(C)C
Product: CC(=O)OCCN(C)Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.5 %

Procedure:
To a 500 mL dry round bottom flask were added 2-(benzyl(methyl)amino)ethanol (46.3 g, 280.2 mmol), triethylamine (150 mL, 1.08 mol), acetic anhydride (31.8 mL, 336.2 mmol), anhydrous CH2Cl2 (100 mL) and a crystal piece of DMAP (4-Dimethylaminopyridine). The mixture was stirred at room temperature for 3 hours. MTBE (700 mL) was added into the reaction mixture, and this mixture was washed, respectively, with cold 2N NaOH (150 mL), water (100 mL), brine (150 mL). The MTBE layer was concentrated, and the residue was poured onto a silica gel pad (200.0 g). The pad was eluted with a co-solvents of ethyl acetate: heptane=3:1 to give 2-(benzyl(methyl)amino)ethyl acetate (50.8 g) as a yellow oil. Yield: 87%. 1H NMR (CDCl3, 300 MHz): δ=7.41-7.25 (m, 5H), 4.29 (t, J=6.3 Hz, 2H), 3.65 (s, 2H), 2.74 (t, J=6.0 Hz, 2H), 2.38 (s, 3H), 2.14 (s, 3H). 13C NMR (CDCl3, 75.5 MHz): δ=170.9, 138.7, 128.9, 128.2, 127.1, 62.5, 62.2, 55.3, 42.6, 21.0.