Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:23])[CH:15]=[CH:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH2:5][CH2:4]1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.Cl[CH:39]1[C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=2[CH2:43][S:42][C:41]2[CH:50]=[CH:51][CH:52]=[CH:53][C:40]1=2>ClCCl>[CH:53]1[C:40]2[CH:39]([N:3]3[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:23])[CH:15]=[CH:16][C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH2:5][CH2:4]3)[C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=3[CH2:43][S:42][C:41]=2[CH:50]=[CH:51][CH:52]=1
Reactant: ClC1c2ccccc2CSc2ccccc21
Reactant: O=C(C=Cc1cccnc1)NCCCCC1CCNCC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: ClCCl
Product: O=C(C=Cc1cccnc1)NCCCCC1CCN(C2c3ccccc3CSc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
7.02 g (21.5 mmol) N-[4-(piperidin-4-yl)-butyl]-3-(pyridin-3-yl)-acrylamide dihydrochloride (substance 14 as a dihydrochloride) are suspended in 100 ml abs. dichlormethane and added to 7.08 g (70.0 mmol) TEA. The mixture is cooled to ca 0° C. under moisture exclusion and a solution of 5.30 g (21.5 mmol) 11-chlor-6,11-dihydro-dibenzo[b,e]thiepine in 10 ml abs. dichlormethane is added dropwise. The mixture is stirred for 24 hours at RT without further cooling. Subsequently, the batch is washed with 50 ml 10% sodium hydroxide solution and 30 ml water. The organic phase is dried over sodium sulfate and the solvent is removed under vacuum. The red brown residue is chromatographically purified three times over silica gel with CHCl3/CH3OH (100/0, 97/3 and 96/4 to 94/6). Subsequently, a further purification occurs by means of MPLC with CHCl3CH3OH (98/2). Yield: 0.5 g (5%) of a brittle, vitreous solid with a MP of 89–91° C.
Reaction SMILES: [CH2:1]1[O:3][CH:2]1[CH2:4][OH:5].C1O[C@@H]1CO.[N+:11]([C:14]1[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1)([O-:13])=[O:12].C(N(CC)CC)C>C1(C(C)C)C=CC=CC=1>[N+:11]([C:14]1[CH:15]=[C:16]([S:20]([O:5][CH2:4][C@H:2]2[O:3][CH2:1]2)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: OCC1CO1
Agent: OC[C@@H]1CO1
Solvent: CC(C)c1ccccc1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1

Procedure:
To demonstrate that the heterogeneous distillate obtained as described hereinabove may be subsequently employed in the synthesis of aromatic sulfonate derivates of optically active glycidol, the distillate containing 84% (R)-glycidol in cumene was reacted with stoichiometric amounts of 3-nitrobenzene sulfonyl chloride and triethylamine to obtain optically pure (S)-glycidyl 3-nitrobenzene sulfonate as follows: 3-nitrobenzenesulfonyl chloride (10 g) was dissolved in toluene (100 g) and then combined with triethylamine (4.6 g). After cooling the solution to 5° C., the 84% (R)- glycidol distillate (3.96 g) was added. After 2 hours at 5° C. and 2 hours at 25° C., the reaction mixture was washed with water (100 g) to remove the triethylamine hydrochloride salt. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the bulk of the solvent removed under vacuum. On cooling to 0° C., (S)-glycidyl 3-nitrobenzenesulfonate crystallized out of solution. The crystalline derivative (8.2 g; 69% overall yield) was collected by filtration and washed with a small quantity of hexanes. The derivative had a melting point of 57°-59° C. and an optical purity of 96% e.e.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][C:11](=O)[CH2:10][CH2:9][CH2:8][C:7]=2[CH:14]=1.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[BH3-]C#N.[Na+]>CO.C(O)(=O)C.ClCCl>[CH2:15]([NH:22][CH:11]1[CH2:10][CH2:9][CH2:8][C:7]2[CH:14]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[CH2:12]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COc1ccc2c(c1)CCCC(=O)C2
Reactant: NCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: ClCCl
Product: COc1ccc2c(c1)CCCC(NCc1ccccc1)C2
Reaction time: 8 h
Yield: 83.2 %

Procedure:
Dissolve 2-Methoxy-5,7,8,9-tetrahydro-benzocyclohepten-6-one (prepared according to JCS Perkin Trans. 1, 1992, 1475-1481, 83 mg, 0.44 mmol) in 1 mL of 19:1 methanol/acetic acid as solvent, and treat the solution with benzylamine (60 uL, 65 mg, 0.60 mmol) and NaCNBH3 (80 mg, 1.27 mmol). Agitate the reaction mixture overnight, then dilute with 25 mL dichloromethane. Wash the organic layer with 25 mL 10%/aqueous potassium carbonate solution, the 25 mL brine, dry over MgSO4 and evaporate to yield 103 mg product, used in subsequent chemistry without further purification; 80% crude yield.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:16][CH:15]3[CH2:17][N:11]4[CH2:12][CH:13]([CH2:18][CH:9]2[CH2:10]4)[CH2:14]3)[CH:5]=[N:6][CH:7]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[CH:3]=[C:4]([N:8]3[CH2:16][CH:15]4[CH2:17][N:11]5[CH2:12][CH:13]([CH2:18][CH:9]3[CH2:10]5)[CH2:14]4)[CH:5]=[N:6][CH:7]=2)=[CH:23][CH:22]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Brc1cncc(N2CC3CC4CC2CN(C4)C3)c1
Product: COc1ccc(-c2cncc(N3CC4CC5CC3CN(C5)C4)c2)cc1

Procedure:
The title compound was prepared from the product of Example 65A and 4-methoxyphenylboronic acid according to General Method B: LC-MS Method D (ESI+) m/z 336.0 (M+H)+, retention time 1.32 minutes.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1B(O)O.[CH2:14]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH2:27][CH:26]([C:30](=[O:39])[NH:31][C:32]2[CH:37]=[C:36](Cl)[N:35]=[CH:34][N:33]=2)[CH2:25]1)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.O>[CH2:14]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH2:27][CH:26]([C:30](=[O:39])[NH:31][C:32]2[CH:37]=[C:36]([C:4]3[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][C:5]=3[O:9][CH3:10])[N:35]=[CH:34][N:33]=2)[CH2:25]1)=[O:23])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(Nc1cc(Cl)ncn1)C1CCCN(C(=O)OCc2ccccc2)C1
Reactant: COc1cccc(OC)c1B(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: COc1cccc(OC)c1-c1cc(NC(=O)C2CCCN(C(=O)OCc3ccccc3)C2)ncn1
Temperature: 90 °C
Yield: 76.3 %

Procedure:
To a solution of 2,6-dimethoxyphenyl boronic acid (0.60 g, 3.3 mmol) in a mixture of dimethoxyethane/water (8 ml, 3:1), 3-(6-chloro-pyrimidin-4-ylcarbamoyl)-piperidine-1-carboxylic acid benzyl ester (0.82 g, 2.2 mmol) was added followed by tetrakis(triphenylphospine) palladium(0) (0.15 g, 0.13 mmol) and saturated solution of potassium carbonate (2 ml). The reaction mixture was heated at 90° C. for 2 h, then it was cooled to room temperature and filtered through a celite bed which was washed with ethyl acetate. The aqueous layer was extracted with ethyl acetate, the organic layers were combined, washed with brine, dried (Na2SO4) and evaporated under reduced pressure. The crude product was purified by column chromatography, using hexane/ethyl acetate (4:1) as eluent, to provide 0.80 g (yield: 53%) of 3-[6-(2,6-dimethoxy-phenyl)-pyrimidin-4-ylcarbamoyl]-piperidine-1-carboxylic acid benzyl ester.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7])[CH3:2].P([O-])(O)(O)=[O:17].[Na+].Cl([O-])=O.[Na+].O>CS(C)=O>[CH2:1]([O:3][C:4]1[CH:11]=[C:10]([C:12]([F:13])([F:14])[F:15])[CH:9]=[CH:8][C:5]=1[C:6]([OH:17])=[O:7])[CH3:2]
Reactant: CCOc1cc(C(F)(F)F)ccc1C=O
Reactant: O=P([O-])(O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CS(C)=O
Solvent: O
Product: CCOc1cc(C(F)(F)F)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 420.6 %

Procedure:
0.60 g of 2-ethoxy-4-(trifluoromethyl)benzaldehyde was dissolved in 5 ml dimethyl sulfoxide and an aqueous solution (1 ml) of 67 mg sodium dihydrogen phosphate, and an aqueous solution (3 ml) of 0.35 g sodium chlorite was added dropwise. After stirring at room temperature for 12 hours, water was added thereto, followed by extracting with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was subjected to silica gel column chromatography, and from fractions eluted with hexane-ethyl acetate (2:1), 0.55 g of 2-ethoxy-4-(trifluoromethyl)benzoic acid was obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[NH:7][C:6](=[O:8])[C:5]2[S:9][C:10]([N:12]3[C:17]4[CH:18]=[C:19](B5OC(C)(C)C(C)(C)O5)[CH:20]=[CH:21][C:16]=4[O:15][CH2:14][CH2:13]3)=[N:11][C:4]=2[CH2:3]1.C(=O)([O-])[O-].[Na+].[Na+].I[C:39]1[CH:44]=[N:43][CH:42]=[CH:41][N:40]=1>C1COCC1.O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:1][C:2]1([CH3:31])[NH:7][C:6](=[O:8])[C:5]2[S:9][C:10]([N:12]3[C:17]4[CH:18]=[C:19]([C:39]5[CH:44]=[N:43][CH:42]=[CH:41][N:40]=5)[CH:20]=[CH:21][C:16]=4[O:15][CH2:14][CH2:13]3)=[N:11][C:4]=2[CH2:3]1
Reactant: CC1(C)Cc2nc(N3CCOc4ccc(B5OC(C)(C)C(C)(C)O5)cc43)sc2C(=O)N1
Reactant: Ic1cnccn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)Cc2nc(N3CCOc4ccc(-c5cnccn5)cc43)sc2C(=O)N1
Temperature: 120 °C
Yield: 7.5 %

Procedure:
To a solution of Example 292 (60 mg, 0.167 mol) in THF (3 mL) and water (1 mL) was added tetra-n-butylammonium bromide (107 mg, 0.334 mmol), sodium carbonate (36 mg, 0.334 mmol), iodopyrazine (69 mg, 0.509 mmol) and tetrakis-(triphenylphosphine)palladium(0) (19 mg, 0.017 mmol). The reaction was heated at 120° C. under microwave irradiation for 20 minutes. The resulting mixture was partitioned between DCM (50 mL) and water (50 mL); the organic phase was washed with brine (50 mL), dried (MgSO4), and concentrated in vacuo. The residue was purified by preparative HPLC (Method 6) to yield the title compound (15 mg, 23%) as an off-white solid. δH (CDCl3) 9.00 (1H, s), 8.75 (1H, d, J 2.1 Hz), 8.60 (1H, dd, J 2.4 and 1.7 Hz), 8.48 (1H, d, J 2.4 Hz), 7.74 (1H, dd, J 8.5 and 2.1 Hz), 7.09 (1H, d, J 8.7 Hz), 5.34 (1H, s), 4.43-4.39 (2H, m), 4.22-4.18 (2H, m), 2.90 (2H, s), 1.41 (6H, s). LCMS (ES+) 394.0 (M+H)+, RT 2.93 minutes (Method 1).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:35]([O:36][CH3:37])=[CH:34][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][C:7]=2[CH:6]=1)[N:14]=[CH:13][C:12]([C:17]#[N:18])=[C:11]3[NH:19][C:20]1[CH:25]=[CH:24][C:23]([S:26][C:27]2[N:28]([CH3:32])[CH:29]=[CH:30][N:31]=2)=[C:22]([Cl:33])[CH:21]=1.[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.[I-].[Na+].C(=O)(O)[O-].[Na+]>COCCOC>[Cl:33][C:22]1[CH:21]=[C:20]([NH:19][C:11]2[C:10]3[C:15](=[CH:16][C:7]4[CH:6]=[C:5]([O:4][CH2:3][CH2:2][N:38]5[CH2:43][CH2:42][O:41][CH2:40][CH2:39]5)[C:35]([O:36][CH3:37])=[CH:34][C:8]=4[CH:9]=3)[N:14]=[CH:13][C:12]=2[C:17]#[N:18])[CH:25]=[CH:24][C:23]=1[S:26][C:27]1[N:28]([CH3:32])[CH:29]=[CH:30][N:31]=1
Reactant: C1COCCN1
Reactant: COc1cc2cc3c(Nc4ccc(Sc5nccn5C)c(Cl)c4)c(C#N)cnc3cc2cc1OCCCl
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc2cc3c(Nc4ccc(Sc5nccn5C)c(Cl)c4)c(C#N)cnc3cc2cc1OCCN1CCOCC1

Procedure:
A mixture of 1.27 g (2.3 mmol) of 8-(2-chloroethoxy)-4-[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-7-methoxybenzo[g]quinoline-3-carbonitrile, 4.0 mL of morpholine and 0.1 g of sodium iodide in 10 mL of 1,2-dimethoxyethane is heated under reflux for 16 hours. After allowing the reaction to cool, the solvent is evaporated to yield a residue, which is stirred with saturated sodium bicarbonate. The solid is collected by filtration, washed with water and dried. The crude product is purified by silica gel chromatography, utilizing a gradient of 98:2 to 90:10 of methylene chloride/methanol to give 0.53 g of 4-[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-7-methoxy-8-(2-morpholin-4-yl-ethoxy)benzo[g]quinoline-3-carbonitrile as a yellow solid, mp>300° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[Se:11][C:12]([CH:15]=[CH:16][CH2:17][CH3:18])=[CH:13][CH:14]=2)=[C:6]([F:19])[C:5]=1[F:20])[CH3:2]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[Se:11][C:12]([CH2:15][CH2:16][CH2:17][CH3:18])=[CH:13][CH:14]=2)=[C:6]([F:19])[C:5]=1[F:20])[CH3:2]
Reactant: CCC=Cc1ccc(-c2ccc(OCC)c(F)c2F)[se]1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCc1ccc(-c2ccc(OCC)c(F)c2F)[se]1

Procedure:
2.30 g (6.22 mmol) of 2-(4-ethoxy-2,3-difluorophenyl)-5-but-1-enylselenophene are hydrogenated in 70 ml of ethyl acetate, in the presence of Pd/C (5% of Pd) at atmospheric pressure and RT. The reaction soln. is filtered and concentrated to dryness, and the crude product is purified by recrystallisation from n-heptane. 2-(4-Ethoxy-2,3-difluorophenyl)-5-butylselenophene is obtained as a colourless solid (m.p. 47° C.).
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][C:8]#[C:9][CH2:10][NH:11][C:12](=[O:44])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH:19][C:20]1[CH:28]=[C:27]2[C:23]([C:24]([CH:37]=[N:38][N:39]3[CH:43]=[CH:42][CH:41]=[CH:40]3)=[N:25][N:26]2COCC[Si](C)(C)C)=[CH:22][CH:21]=1)(C)(C)C.C1(N)C=CC=C(N)C=1>O>[OH:6][CH2:7][C:8]#[C:9][CH2:10][NH:11][C:12](=[O:44])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH:19][C:20]1[CH:28]=[C:27]2[C:23]([C:24]([CH:37]=[N:38][N:39]3[CH:40]=[CH:41][CH:42]=[CH:43]3)=[N:25][NH:26]2)=[CH:22][CH:21]=1
Reactant: CC(C)(C)[Si](C)(C)OCC#CCNC(=O)c1ccccc1Nc1ccc2c(C=Nn3cccc3)nn(COCC[Si](C)(C)C)c2c1
Agent: Nc1cccc(N)c1
Solvent: O
Product: O=C(NCC#CCO)c1ccccc1Nc1ccc2c(C=Nn3cccc3)n[nH]c2c1

Procedure:
Prepared in a similar manner to that described for Example 11, in U.S. Pat. No. 6,534,524, issued Mar. 18, 2003, herein incorporated by reference in its entirety for all purposes, except that N-[4-(tert-Butyl-dimethyl-silanyloxy)-but-2-ynyl]-2-[3-(pyrrol-1-yliminomethyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-6-ylamino]-benzamide was used instead of N-methyl-N-{3-styryl-1-[2-trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-yl}-benzene-1,3-diamine. 1H NMR (DMSO-d6) δ 13.30 (1H, s), 9.87 (1H, .s 9.04 (1H, t, J=5.3 Hz), 8.99 (1H, s), 8.19 (1H, d, J=8.5 Hz), 7.70 (1H, d, J=7.3 Hz), 7.46 (4H, m), 7.31 (1H, s), 7.08 (1H, dd, J=1.7, 8.7 Hz), 6.91 (1H, t, J=7.3 Hz), 6.21 (2H, t, J=2.1 Hz), 5.14 (1H, t, J=5.8 Hz), 4.10 (2H, d, J=5.5 Hz), 4.06 (2H, d, J=5.8 Hz). Anal. Calcd for C23H20N6O2. 0.35Hexanes. 0.20 H2O: C, 67.45; H, 5.86; N, 18.81. Found: C, 67.70; H, 5.73; N, 18.56.
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][CH:6]=1.C(Cl)(Cl)Cl>CO>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([OH:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][CH:6]=1
Reactant: COc1ccc(C(=O)c2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccc(C(O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.8 %

Procedure:
Solid NaBH4 (2.55 g, 0.067 mol) was added portion-wise to a solution of p-methoxybenzophenone (25.14 g, 0.118 mol) in MeOH (150 mL) at room temperature over 10 min. After the exothermic reaction had subsided, the reaction mixture was stirred at room temperature for 2 h. TLC (SiO2, CHCl3) indicated incomplete reaction; therefore, additional NaBH4 (2.55 g) was added and the reaction mixture was stirred at room temperature an additional 2 h. The MeOH was evaporated and the residue partitioned between water (100 mL) and CH2Cl2 (100 mL). The layers were separated, and the aqueous layer was extracted with CH2Cl2 (200 mL). The combined organic layers were dried (Na2SO4), filtered and evaporated to give the alcohol (25.24 g, 99%) as a white solid: m.p. 66-67° C. The structure was confirmed by 1H--NMR in CDCl3.
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[CH2:7][N:8]([CH2:28][C:29]1[CH:30]=[C:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[S:32][CH:33]=1)[CH2:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])=[CH:15][C:14]=1[Cl:27])=[O:11])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:45].[Cl-].[NH4+]>O1CCCC1.O.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:41])[CH2:7][N:8]([CH2:28][C:29]1[CH:30]=[C:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[S:32][CH:33]=1)[CH2:9][C:10]([N:12]([C:13]1[CH:18]=[CH:17][C:16]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])=[CH:15][C:14]=1[Cl:27])[CH3:45])=[O:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)CN(CC(=O)Nc1ccc(O[Si](C)(C)C(C)(C)C)cc1Cl)Cc1csc(C(=O)OC(C)(C)C)c1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(C(=O)CN(CC(=O)OC(C)(C)C)Cc1csc(C(=O)OC(C)(C)C)c1)c1ccc(O[Si](C)(C)C(C)(C)C)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 4-{[(2-tert-butoxy-2-oxoethyl){2-[(4-{[tert-butyl(dimethyl)silyl]oxy}-2-chlorophenyl)amino]-2-oxoethyl}amino]methyl}thiophene-2-carboxylate (375 mg) in tetrahydrofuran (7.50 mL) was added 55% sodium hydride (25.2 mg) under ice-cooling, followed by stirring at room temperature for 30 minutes. Iodomethane (0.187 mL) was added thereto at room temperature, followed by stirring at room temperature for 2 hours. To the reaction mixture was added ethyl acetate, and water and a saturated aqueous ammonium chloride solution was added thereto under ice-cooling. The organic layer was extracted, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain tert-butyl 4-{[(2-tert-butoxy-2-oxoethyl) {2-[(4-{[tert-butyl(dimethyl)silyl]oxy}-2-chlorophenyl)(methyl)amino]-2-oxoethyl}amino]methyl}thiophene-2-carboxylate (209 mg).
Reaction SMILES: [C:1]([O:5][C:6](/[CH:8]=[CH:9]/[C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][C:11]=1[CH3:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20][N:21]1[C:30]2[NH:29][C:28]3[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=3[NH:26][CH2:25][C:24]=2[CH:23]=[N:22]1>ClCCl.C(N(CC)CC)C.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6](=[O:7])/[CH:8]=[CH:9]/[C:10]1[CH:18]=[CH:17][C:13]([C:14]([N:26]2[CH2:25][C:24]3[CH:23]=[N:22][N:21]([CH3:20])[C:30]=3[NH:29][C:28]3[CH:31]=[CH:32][CH:33]=[CH:34][C:27]2=3)=[O:16])=[CH:12][C:11]=1[CH3:19])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc(C(=O)O)ccc1/C=C/C(=O)OC(C)(C)C
Reactant: Cn1ncc2c1Nc1ccccc1NC2
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1/C=C/C(=O)OC(C)(C)C
Yield: 82 %

Procedure:
4-((E)-2-tert-Butoxycarbonyl-vinyl)-3-methyl-benzoic acid from Example E45.1 (1.1 g, 4.2 mmol) and 3-methyl-3,4,9,10-tetrahydro-2,3,4,9-tetraaza-benzo[f]azulene from Example E11 (720 mg, 3.6 mmol) were dissolved in dichloromethane (50 ml) and triethylamine (0.75 ml). DMAP (4.45 g, 3.6 mmol) and WSCD (1.36 g, 7.1 mmol) were added and the mixture was heated at re-flux for 2 days. The solution was diluted with di-chloromethane, washed with 0.3M KHSO4, saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; EtOAc) to yield the title compound (1.35 g, 82%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:5]([I:16])=[CH:4][N:3]=1.[CH2:17](I)[CH2:18][CH3:19].C(OCC)(=O)C.O>CN1CCCC1=O.[H-].[Na+]>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]([CH2:17][CH2:18][CH3:19])[C:9](=[O:15])[O:10][C:11]([CH3:13])([CH3:12])[CH3:14])[C:5]([I:16])=[CH:4][N:3]=1
Reactant: CCCI
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)ncc1I
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCCN(C(=O)OC(C)(C)C)c1cc(Cl)ncc1I
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl (2-chloro-5-iodopyridin-4-yl)carbamate (S8, 239 mg) and propyl iodide (131 μL) in N-methylpyrrolidone (3 mL), sodium hydride (60% wt, 80 mg) was added under ice cooling, and the mixture was stirred at room temperature for 2 hours, and then stirred at 50° C. for 3 hours. The reaction mixture was cooled to room temperature, and then ethyl acetate and water were added to the reaction mixture. The organic layer was separated, washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (eluent, 100 to 70% hexane in ethyl acetate) to obtain tert-butyl (2-chloro-5-iodopyridin-4-yl)(propyl)carbamate (S9, 155 mg).
Reaction SMILES: [OH-].[Li+].C[O:4][C:5](=[O:25])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][C:14](=[O:24])[NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=2)[CH:7]=1.CO.O1CCCC1>O>[C:22]([C:19]1[CH:18]=[CH:17][C:16]([NH:15][C:14]([CH2:13][O:12][C:8]2[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=2)[C:5]([OH:25])=[O:4])=[O:24])=[CH:21][CH:20]=1)#[N:23]
Reactant: COC(=O)c1cccc(OCC(=O)Nc2ccc(C#N)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1ccc(NC(=O)COc2cccc(C(=O)O)c2)cc1
Temperature: 25 °C
Reaction time: 36 h
Yield: 60.8 %

Procedure:
Add lithium hydroxide (0.10 g, 4.18 mmol) to a suspension of 3-[(4-cyano-phenylcarbamoyl)-methoxy]-benzoic acid methyl ester (0.50 g, 1.61 mmol) in a 1:1:1 mixture of water: MeOH: tetrahydrofuran. Stir the mixture at room temperature for 36 h then dilute with water and wash with EtOAc. Adjust the pH of the aqueous phase by the addition of a 1 N solution of hydrochloric acid. Extract the mixture with EtOAc and dry the combined organic phase over anhydrous sodium sulfate. Concentrate under reduced pressure to provide 0.290 g of 3-[(4-cyano-phenylcarbamoyl)-methoxy]-benzoic acid as a solid.
Reaction SMILES: C(OC([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]([N:18]1[CH2:23][CH2:22][CH:21]([N:24]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:28][CH2:27][C:25]2=[O:26])[CH2:20][CH2:19]1)=[O:17])=O)C1C=CC=CC=1>C(O)C.[C].[Pd]>[NH:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]([N:18]1[CH2:19][CH2:20][CH:21]([N:24]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:28][CH2:27][C:25]2=[O:26])[CH2:22][CH2:23]1)=[O:17]
Reactant: O=C(C1CCCN1C(=O)OCc1ccccc1)N1CCC(N2C(=O)CCc3ccccc32)CC1
Agent: [Pd]
Solvent: CCO
Product: O=C(C1CCCN1)N1CCC(N2C(=O)CCc3ccccc32)CC1
Temperature: 25 °C
Yield: 33.2 %

Procedure:
1-[1-(1-Benzyloxycarbonyl-2-pyrrolidinylcarbonyl)-4-piperidinyl]-3,4-dihydrocarbostyril (0.87 g) is dissolved in ethanol (20 ml) and thereto is added 5% palladium-carbon (0.1 g). The mixture is stirred at room temperature under 1 atm. under hydrogen atmosphere. After the completion of the reaction, the catalyst is filtered off and the filtrate is concentrated. The resultant is purified by silica gel column chromatography (solvent; dichloromethane:methanol=8:1) to give 1-[1-(2-pyrrolidinylcarbonyl)-4-piperidinyl]-3,4-dihydrocarbostyril (205 mg).
Reaction SMILES: [N:1]([CH2:4][CH2:5][NH:6][C:7](=[O:21])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[N+:2]=[N-:3].N([CH2:25][CH2:26]N)=[N+]=[N-].C(N(CC)CC)C>ClCCl>[N:1]([CH2:4][CH2:5][NH:6][C:7](=[O:21])[C:8]1[CH:26]=[CH:25][C:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:10][CH:9]=1)=[N+:2]=[N-:3]
Reactant: CCCCCCCCCCCCCC(=O)NCCN=[N+]=[N-]
Reactant: [N-]=[N+]=NCCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCc1ccc(C(=O)NCCN=[N+]=[N-])cc1
Yield: 97.5 %

Procedure:
As in the synthesis of N-(2-azidoethyl)tetradecanamide, (0.383 g, 1.43 mmol) the acid chloride was reacted with 2-azidoethanamine (0.124 g, 1.43 mmol) and triethylamine (0.290 g, 2.87 mmol) in dichloromethane (5 mL) to give N-(2-azidoethyl)-4-nonylbenzamide (0.441 g, 97% yield). 1H NMR (300 MHz, CDCl3) δ 7.72 (d, 2H), δ 7.26 (t, 1H), δ 7.18 (d, 2H), δ 3.57 (q, 2H), δ 3.45 (t, 2H), δ 2.60 (t, 2H), δ 1.58 (m, 2H), δ 1.27 (m, 12H), δ 0.86 (t, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 168.5, 147.3, 131.7, 128.8, 127.4, 50.9, 39.7, 36.1, 32.1, 31.5, 29.8, 29.7, 29.6, 29.5, 22.9, 14.4 ppm; HRMS (ESI) calcd for C18H28N4O (M+) 316.2263. found 316.2268.