Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[C:5]#[N:6].[F:11][C:12]([F:17])([F:16])[CH:13]([OH:15])[CH3:14].[H-].[Na+].[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:15][CH:13]([CH3:14])[C:12]([F:17])([F:16])[F:11])[C:5]#[N:6]
Reactant: CC(O)C(F)(F)F
Reactant: N#Cc1ccc(F)c(Cl)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(Oc1ccc(C#N)cc1Cl)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.4 %

Procedure:
To a solution of 3-chloro-4-fluorobenzonitrile (300 mg) and 1,1,1-trifluoro-2-propanol (263 mg) in THF (15 ml) was added 60% NaH (92.5 mg) at 5° C., followed by stirring at room temperature for 2 hours, addition of a saturated NH4Cl solution to complete the reaction, and extraction with EtOAc. The obtained organic layer was dried over anhydrous MgSO4, and concentrated. The residue was purified by silica gel chromatography (n-hexane:EtOAc=97:3 to 85:15) to obtain 3-chloro-4-(2,2,2-trifluoro-1-methylethoxy)benzonitrile (435 mg) as a colorless oily substance.
Reaction SMILES: ClC1C([C:12]2[C:13](F)=[CH:14][C:15]3[O:20][CH2:19][C:18](=[O:21])[NH:17][C:16]=3[CH:22]=2)=NN(C)C=1C(F)(F)F.C([O-])([O-])=O.[K+].[K+].C(Br)C#C>CC(C)=O.O>[O:20]1[C:15]2[CH:14]=[CH:13][CH:12]=[CH:22][C:16]=2[NH:17][C:18](=[O:21])[CH2:19]1
Reactant: Cn1nc(-c2cc3c(cc2F)OCC(=O)N3)c(Cl)c1C(F)(F)F
Agent: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: O=C1COc2ccccc2N1
Temperature: 40 °C
Reaction time: 6 h
Yield: 231.5 %

Procedure:
At 25° C., 3.0 g (8.6 mmole) of the product of step A, 1.22 g (6.0 mmole) K2CO3 and 0.79 mL (8.8 mmole) 80% propargyl bromide were slurried in 50 mL acetone. The reaction was stirred at 40° C. for 6 hours. The reaction was cooled, diluted with 100 mL cold water, and extracted four times with ethyl acetate. The ethyl acetate extracts were washed with brine, dried over anhydrous MgSO4, and stripped in vacuo. The residue was recrystallized from methylcyclohexane to give 2.97 g (89%) of 2H-1,4-benzoxazin-3(4H)-one, 6-(4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-7-fluoro-4-(2-propynyl)-2H-1,4-benzoxazin-3(4H)-one as a beige solid, mp 142°-143° C.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[NH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C.[CH2:27]([S:31](Cl)(=[O:33])=[O:32])[CH2:28][CH2:29][CH3:30]>C(Cl)Cl>[C:1]([OH:4])(=[O:3])[CH3:2].[CH2:13]([O:12][C:11]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:5][S:31]([CH2:27][CH2:28][CH2:29][CH3:30])(=[O:33])=[O:32])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCCCS(=O)(=O)Cl
Reactant: Nc1ccccc1OCc1ccccc1
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCS(=O)(=O)Nc1ccccc1OCc1ccccc1
Temperature: 30 °C
Reaction time: 4 h

Procedure:
5.0 g (0.00194 mol) of 3-amino-4-benzyloxybenzene acetate are mixed under a nitrogen atmosphere in 15 ml of methylene chloride, and 3.3 ml of triethylamine (0.0236 mol) and 3.3 ml (0.0245 mol) of 1-butansulfonyl chloride are added thereto. The mixture is stirred at ambient temperature overnight and afterwards at 30° C. for 4 hours. Washing with water is carried out, the two phases are separated, the organic phase is dried over sodium sulfate and filtered, and the solvent is evaporated under reduced pressure. Purification is carried out by chromatography on a column of silica gel, elution being carried out with a cyclohexane/ethyl acetate=9:1 mixture. The title compound is obtained.
Reaction SMILES: COC(OC)[N:4]([CH3:6])[CH3:5].[CH3:9][C:10]1[CH:11]=[CH:12][N:13]=C2[C:24](=[O:25])[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:16](=O)[C:15]=12>CN(C)C=O>[CH:20]1[CH:21]=[CH:22][C:23]2[C:24](=[O:25])[C:5]3[C:15]4[C:10]([CH:9]=[CH:6][N:4]=3)=[CH:11][CH:12]=[N:13][C:16]=4[C:18]=2[CH:19]=1
Reactant: Cc1ccnc2c1C(=O)c1ccccc1C2=O
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: O=C1c2ccccc2-c2nccc3ccnc1c23

Procedure:
Dimethylformamide dimethyl acetal (1.50 mL, 11.34 mmol, Aldrich) was added to a solution of cleistopholine, (1.95 g, 8.73 mmol) in dimethylformamide (5 mL). The mixture was then heated for 30 min by submerging
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[CH2:12][CH:11]1[CH:13]1[CH2:15][CH2:14]1)([O-])=O.[H][H]>C(O)C.[Pt].[C]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[CH2:12][CH:11]1[CH:13]1[CH2:15][CH2:14]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccccc1C1CC1C1CC1
Agent: [Pt]
Solvent: CCO
Product: Nc1ccccc1C1CC1C1CC1
Reaction time: 2.5 h
Yield: 102.5 %

Procedure:
In a hydrogenation reactor, 1 g of 2-(2-nitrophenyl)-bicyclopropane (4.9 mmol, trans:cis ratio: 4.1:1), dissolved in 20 ml of ethanol, is hydrogenated at ambient temperature using 0.1 g of 5% platinum-carbon catalyst. After 2.5 hours and after 101% of the amount of hydrogen theoretically required for the reduction has been taken up, the reaction is stopped. Following filtration of the reaction mixture, the solvent is removed by concentration by evaporation. 0.87 g of 2-(2-aminophenyl)-bicyclopropane (100% of theory) is obtained in the form of a brownish liquid (trans:cis ratio: 4.4:1).
Reaction SMILES: [N:1]([C@H:4]([C@H:14]1[O:18][C:17](=[O:19])[C@H:16]([CH2:20][CH3:21])[CH2:15]1)[CH2:5][O:6]CC1C=CC=CC=1)=[N+]=[N-].[ClH:22].O1CCOCC1.[H][H]>C(O)C.[C].[Pd]>[ClH:22].[NH2:1][C@H:4]([C@H:14]1[O:18][C:17](=[O:19])[C@H:16]([CH2:20][CH3:21])[CH2:15]1)[CH2:5][OH:6]
Reactant: [H][H]
Reactant: CC[C@@H]1C[C@@H]([C@H](COCc2ccccc2)N=[N+]=[N-])OC1=O
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: CC[C@@H]1C[C@@H]([C@@H](N)CO)OC1=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A suspension of 23.5 g of (3R,5S)-5-[(S)-1-azido-2-benzyloxyethyl]-3-ethyldihydrofuran-2-one obtained in Example (106e) (81.3 mmol), 40.0 ml of a solution of 4 N hydrochloric acid in dioxane (160 mmol) and 5.21 g of 10% palladium-carbon (50% wet) in ethanol (400 ml) was stirred under a hydrogen atmosphere at room temperature for 12 hours. Hydrogen in the reaction vessel was replaced by nitrogen, and then the reaction mixture was diluted with 300 ml of ethanol. Palladium-carbon was separated by filtration and washed with ethanol. The solvent was evaporated from the filtrate under reduced pressure to obtain crude (3R,5S)-5-[(S)-1-amino-2-hydroxyethyl]-3-ethyldihydrofuran-2-one hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.ClCCl.[OH-].[Na+].[F:14][C:15]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:16]=1[CH2:17]Br>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].O>[NH2:1][C:2]1[C:7]([O:8][CH2:17][C:16]2[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:15]=2[F:14])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Nc1ncccc1O
Reactant: COc1ccc(CBr)c(F)c1
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COc1ccc(COc2cccnc2N)c(F)c1
Reaction time: 0.08 h

Procedure:
A mixture of 2-amino-3-hydroxy pyridine (1.45g, 0.013 mol), dichloromethane (10 ml) and 40% aqueous sodium hydroxide solution (10 ml) was stirred for five minutes, then 2-fluoro-4-methoxybenzyl bromide (2.9 g, 0.013 mol) and Adogen 464 (1.5 ml) were added and stirring continued for 16 hours. The mixture was diluted with water and extracted with dichloromethane. Drying and evaporation of the organic extracts, and trituration with ether gave the desired product. Yield 1.11 g (34%), m.p. 135°-138 ° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[C:5]([F:17])=[CH:4][C:3]=1[Si:18]([CH3:21])([CH3:20])[CH3:19].[NH2:22][C:23]1[N:28]=[C:27](Cl)[N:26]=[C:25]([C:30]([O:32][CH3:33])=[O:31])[C:24]=1[O:34][CH3:35].C(=O)([O-])[O-].[Na+].[Na+].C(#N)C>[Cl-].[Na+].O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[NH2:22][C:23]1[N:28]=[C:27]([C:6]2[CH:7]=[C:2]([F:1])[C:3]([Si:18]([CH3:19])([CH3:20])[CH3:21])=[CH:4][C:5]=2[F:17])[N:26]=[C:25]([C:30]([O:32][CH3:33])=[O:31])[C:24]=1[O:34][CH3:35]
Reactant: CC1(C)OB(c2cc(F)c([Si](C)(C)C)cc2F)OC1(C)C
Reactant: COC(=O)c1nc(Cl)nc(N)c1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1nc(-c2cc(F)c([Si](C)(C)C)cc2F)nc(N)c1OC
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 58.8 %

Procedure:
In a microwave vessel, a suspension of (2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)trimethylsilane (e.g., WO 2013003740 A1) (1.925 g, 5.05 mmol), methyl 6-amino-2-chloro-5-methoxypyrimidine-4-carboxylate (Head C) (1 g, 4.60 mmol), bis(triphenyl phosphine)palladium(II) chloride (0.323 g, 0.460 mmol) and sodium carbonate (0.584 g, 5.51 mmol) in a 3:1 mixture of acetonitrile (8.62 mL) and water (2.87 mL) was stirred under microwave irradiation (120° C., 20 min). The reaction mixture was poured into an half saturated brine solution and was extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by preparative reverse phase HPLC (water/acetonitrile gradient) to afford the title compound as a white solid (0.994 g, 58.9%): mp 130-131° C.; 1H NMR (400 MHz, CDCl3) δ 7.53 (dd, J=8.4, 5.6 Hz, 1H), 7.10 (dd, J=10.2, 4.1 Hz, 1H), 5.44 (s, 2H), 4.00 (s, 3H), 3.94 (s, 3H), 0.32 (d, J=0.9 Hz, 9H); 19F NMR (376 MHz, CDCl3) δ −107.45, −107.51, −122.32, −122.37; ESIMS m/z 367 ([M]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[F:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[C:21]([C:28]([F:31])([F:30])[F:29])[CH:20]=1.N1C=CC=CC=1>C1COCC1>[F:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([N:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[O:24])=[C:21]([C:28]([F:29])([F:30])[F:31])[CH:20]=1
Reactant: COc1ccc(Nc2ccc(OC)cc2)cc1
Reactant: O=C(Cl)c1ccc(F)cc1C(F)(F)F
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1ccc(N(C(=O)c2ccc(F)cc2C(F)(F)F)c2ccc(OC)cc2)cc1
Temperature: 90 °C
Yield: 84.2 %

Procedure:
1 equivalent of bis-(4-methoxyphenyl)amine (1a) (0.73 g, 3.18 mmol) was mixed with 1.2 equivalents of 4-fluoro-2-trifluoromethylbenzoyl chloride (0.87 g, 3.82 mmol) and 6 equivalents of pyridine (1.51 g, 19.08 mmol) in a dry three-necked round-bottomed flask equipped with a magnetic stirring bar and a reflux condenser. The mixture was dissolved in anhydrous THF (20 mL) and heated to 90° C. for 20 hours. The reaction solution was cooled to room temperature and filtered. The solvent was removed under reduced pressure. The residue was purified by flash column chromatography using silica-gel with EtOAc/hexanes (3/7 v/v) to afford the pure corresponding benzamide compound as a colorless oil, 1.12 g, 84.2% yield. . 1H NMR (CDCl3, 300 MHz) δ 7.34-7.26 (m, 4H), 7.09-7.01 (m, 3H), 6.91 (d, 2H, J=8.7 Hz), 6.87 (d, 2H, J=8.7 Hz), 3.80 (s, 3H), 3.71 (s, 3H). MS m/z 442.1(M+Na)+.
Reaction SMILES: [CH2:1]([O:4][NH:5][C@H:6]1[C:11]([CH2:12][O:13][CH3:14])=[CH:10][CH:9]([CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[NH:8][CH2:7]1)[CH:2]=[CH2:3].C(N(C(C)C)C(C)C)C.Cl[C:34](Cl)([O:36]C(=O)OC(Cl)(Cl)Cl)Cl>C(#N)C.CCOC(C)=O>[CH2:1]([O:4][N:5]1[C:34](=[O:36])[N:8]2[CH2:7][CH:6]1[C:11]([CH2:12][O:13][CH3:14])=[CH:10][C@H:9]2[CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:18])[CH3:19])[CH:2]=[CH2:3]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C=CCON[C@@H]1CNC(CO[Si](C)(C)C(C)(C)C)C=C1COC
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C=CCON1C(=O)N2CC1C(COC)=C[C@H]2CO[Si](C)(C)C(C)(C)C
Yield: 193.8 %

Procedure:
To a stirred solution of Intermediate 121 (2.04 g, 5.96 mmol) in acetonitrile (500 mL), N-ethyl-N-isopropylpropan-2-amine (4.15 mL, 23.82 mmol) was added triphosgene (0.721 g, 2.38 mmol) as a solution in 20 mL CH3CN via syringe pump (0.1 ml/min) at 0° C. The reaction was stirred and allowed to warm from 0° C. to rt overnight. LCMS showed complete conversion to product. The solution was concentrated to give a residue, which was then taken up in 150 mL EtOAc and washed with 5% citric acid, NaHCO3, brine, dried over MgSO4, filtered and concentrated. The residue was purified by silica gel column (40 g, 0-60% Hex/EA) to afford the title compound (1.700 g, 77%) as an oil.
Reaction SMILES: Cl[C:2]1[C:3]([N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:4][C:5]2[N:6]([C:8]([NH2:11])=[N:9][N:10]=2)[N:7]=1.[O-:17][CH2:18][CH3:19].[Na+]>C(O)C>[CH2:18]([O:17][C:2]1[C:3]([N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:4][C:5]2[N:6]([C:8]([NH2:11])=[N:9][N:10]=2)[N:7]=1)[CH3:19]
Reactant: CCN(CC)c1cc2nnc(N)n2nc1Cl
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1nn2c(N)nnc2cc1N(CC)CC
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.9 %

Procedure:
6-Chloro-N*7*,N*7*-diethyl-[1,2,4]triazolo[4,3-b]pyridazine-3,7-diamine (W2.021, 38 mg) were initially charged in ethanol (7 ml) and admixed with sodium ethoxide (24 mg). The reaction mixture stirred at RT for 4 h. It was then stirred at 45° C. for another 2 h. Subsequently, the mixture was dried, the residue was admixed with water and extracted three times with EA, and the combined EA phases were dried with magnesium sulfate, filtered and concentrated. 30 mg of the title compound were obtained as a crude product, which was clean enough for the next reaction.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:11]([CH3:22])[CH2:10]2)=[CH:4][CH:3]=1.[CH:23](=O)[CH3:24].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>ClCCCl>[CH2:23]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:11]([CH3:22])[CH2:10]2)=[CH:4][CH:3]=1)[CH3:24]
Reactant: C[C@H]1CN(Cc2ccc(N)cc2)CCN1C(=O)OC(C)(C)C
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CCNc1ccc(CN2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 71.7 %

Procedure:
1,1-dimethylethyl (2S)-4-[(4-aminophenyl)methyl]-2-methyl-1-piperazinecarboxylate (D2) (0.30 g, 1 mmol), acetaldehyde (0.055 mL, 1 mmol), sodium triacetoxyborohydride (0.417 g, 2 mmol) and triethylamine (0.151 mL, 1.1 mmol) were combined in dry 1,2-DCE (15 mL) and stirred under Ar at room temperature for 48 hours. Saturated NaHCO3 (15 mL) was added and reaction mixture stirred for a further 2 hours. The aqueous layer was then extracted with DCM (×3) and the combined organic layers were dried (Na2SO4) and concentrated in vacuo. The crude material was purified by column chromatography eluting with 0-100% ether/petroleum ether to give the title compound (0.239 g). δH (CDCl3, 400 MHz) 7.11 (2H, d), 6.56 (2H, dd), 4.16 (1H, br.s), 3.78 (1H, d), 3.51 (1H, br.s), 3.42 (1H, d), 3.29 (1H, d), 3.15 (2H, q), 3.08 (1H, td), 2.75 (1H, d), 2.59 (1H, d), 2.06 (1H, dd), 1.93 (1H, m), 1.45 (9H, s), 1.25 (3H, t), 1.21 (3H, d). MS (ES+): 234.2, no molecular ion (MH+) observed.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([OH:12])=[CH:7]2.S(Cl)(Cl)(=O)=O.[CH2:18]([N:36]([CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66])[C:37](=[O:48])[C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([S:44](Cl)(=[O:46])=[O:45])[CH:39]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].Cl>N1C=CC=CC=1>[CH2:49]([N:36]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:37](=[O:48])[C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([S:44](=[O:45])(=[O:46])[NH:1][C:2]2[C:3]3[C:8](=[CH:7][C:6]([OH:12])=[CH:5][CH:4]=3)[CH:9]=[CH:10][CH:11]=2)[CH:39]=1)[CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66]
Reactant: Nc1cccc2cc(O)ccc12
Reactant: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)c1cccc(S(=O)(=O)Cl)c1
Agent: Cl
Solvent: O=S(=O)(Cl)Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)c1cccc(S(=O)(=O)Nc2cccc3cc(O)ccc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.5 %

Procedure:
To a stirred solution of 5-amino-2-naphthol (8.0 g, 0.05 mol) in pyridine (80 ml) was added the sulfonyl chloride, N,N-dioctadecyl-3-chlorosulfonylbenzamide (Example 5) (36.2 g, 0.05 mol). The reaction was stirred overnight at room temperature and then poured into excess dilute hydrochloric acid. The mixture was extracted with dichloromethane, washed with water, dried over magnesium sulfate and suction-filtered through a pad of decolorizing carbon. The filtrate was concentrated to an oil which was crystallized from acetonitrile to yield 26.5 g of product.
Reaction SMILES: N(C(N(C)C)=O)=NC(N(C)C)=O.C([N:21]1[CH2:38][CH2:37][CH:25]2[N:26]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][C:34]=4[CH:24]2[CH2:23][CH2:22]1)[CH:29]([OH:36])[CH2:28][CH2:27]3)(=O)C1C=CC=CC=1.[C:39]1(O)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(P(CCCC)CCCC)CCC>C1C=CC=CC=1>[O:36]([CH:29]1[C:30]2[C:35]3=[C:34]([C:24]4[CH2:23][CH2:22][NH:21][CH2:38][CH2:37][C:25]=4[N:26]3[CH2:27][CH2:28]1)[CH:33]=[CH:32][CH:31]=2)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: Oc1ccccc1
Reactant: O=C(c1ccccc1)N1CCC2c3cccc4c3N(CCC4O)C2CC1
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Solvent: c1ccccc1
Product: c1ccc(OC2CCn3c4c(c5cccc2c53)CCNCC4)cc1
Temperature: 60 °C
Reaction time: 5 h
Yield: 62.8 %

Procedure:
1,1′-Azobis(N,N-dimethylformamide) (0.34 g, 2.0 mmol) was added to a solution of 10-benzoyl-5,6,8,9,10,11,12,12a-octahydro-4H,7aH-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline-4-ol (0.45 g, 1.3 mmol), phenol (0.18 g, 1.9 mmol), and tributylphosphine (0.49 mL, 2.0 mmol) in dry benzene (4.0 mL) at room temperature under N2. The reaction mixture immediately congealed but resumed stirring upon heating to 60° C. After 5 h, the reaction was cooled to room temperature and filtered to remove white precipitate. The filtrate was concentrated under reduced pressure and purified by silica gel chromatography with heptanes/EtOAc (gradient 3:1 to 3:2) to give 0.26 g (47%) of the title compound as a beige foam. 1H NMR (CDCl3) δ 7.52-7.38, 7.32, 7.11-6.95, 5.68, 4.21-3.90, 3.69, 3.21, 2.91, 2.63, 2.34; IR (drift) 1630, 1596, 1492, 1458, 1421, 1359, 1327, 1291, 1267, 1226, 1192, 786, 750, 706, 694 cm−1; MS (ESI) 423.3 (M++H).
Reaction SMILES: ClC(OC1C=CC=CC=1)=O.Cl.[Cl:12][C:13]1[S:17][C:16]([NH2:18])=[N:15][CH:14]=1.C(N(CC)CC)C.[C:26]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)(OC(C)(C)C)=[O:27]>C1COCC1.[OH-].[Na+]>[Cl:12][C:13]1[S:17][C:16]([NH:18][C:26]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[O:27])=[N:15][CH:14]=1
Reactant: Nc1ncc(Cl)s1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: Cl
Agent: O=C(Cl)Oc1ccccc1
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ncc(Cl)s1)N1CCNCC1

Procedure:
Phenyl chloroformate (0.305 mL) was added slowly to a stirring solution of 5-chloro-1,3-thiazol-2-amine hydrochloride (400 mg) in THF (5 mL) containing triethylamine (0.98 mL) under an argon atmosphere. After 1 h N-Boc piperazine was added and the reaction was heated to reflux for 1 h. The reaction mixture was taken up in 1M NaOH (10 mL) and DCM (30 mL) and organic layer was separated and washed with 1 MHCl (aq.) (10 mL). The DCM layer was then dried (MgSO4), filtered and evaporated. Purification by column chromatography 1:4 to 1:1 EtOAc:isohexanes afforded the title compound (278 mg) as a white solid which was used without purification
Reaction SMILES: C([NH:4][C:5]1[CH:21]=[CH:20][C:8]([N:9]([CH2:17][CH2:18][OH:19])[CH2:10][CH2:11][NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:7][CH:6]=1)(=[O:3])C.[ClH:22]>O>[OH2:3].[ClH:22].[ClH:22].[OH:19][CH2:18][CH2:17][N:9]([CH2:10][CH2:11][NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[C:8]1[CH:7]=[CH:6][C:5]([NH2:4])=[CH:21][CH:20]=1
Reactant: CC(=O)Nc1ccc(N(CCO)CCNS(C)(=O)=O)cc1
Agent: Cl
Solvent: O
Product: CS(=O)(=O)NCCN(CCO)c1ccc(N)cc1

Procedure:
0.0178 mol (5.6 g) of 4-acetylamino-N-(β-hydroxyethyl)-N-(β-mesylaminoethyl)-aniline in 12 ml of a 5 N aqueous solution of hydrochloric acid is heated for 30 minutes in a boiling water bath. The water is then driven off in vacuo. After keeping the residue for two hours in vacuo at 60° C., a crystalline product, which is chromatographically pure, is obtained.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([CH3:30])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26](Cl)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)(C(C)(C)C)(C)C.[CH3:31][N:32]([CH3:44])[C:33]([C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1)=[O:34].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl>O1CCOCC1.O.CO.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]>[OH:8][CH2:9][C:10]1([CH3:30])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:37]5[CH:38]=[CH:39][CH:40]=[C:35]([C:33]([N:32]([CH3:44])[CH3:31])=[O:34])[CH:36]=5)=[CH:25][CH:24]=4)[CH2:21][CH2:22]3)=[N:18][N:19]=[C:12]2[CH2:11]1
Reactant: CN(C)C(=O)c1cccc(B(O)O)c1
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(Cl)cc4)CC3)n2CCS1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: Cl
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: CN(C)C(=O)c1cccc(-c2ccc(C3(c4nnc5n4CCSC(C)(CO)C5)CC3)cc2)c1
Yield: 140 %

Procedure:
A solution of the compound (232 mg, 0.5 mmol) obtained in Example 1-2), 3-(N,N-dimethylaminocarbonyl)phenylboronic acid (97 mg, 0.5 mmol), tris(dibenzylideneacetone)dipalladium(0) (23 mg, 0.05 mmol), tricyclohexylphosphine (17 mg, 0.12 mmol), and tripotassium phosphate (186 mg, 0.85 mmol) in dioxane (2 mL) and water (1 mL) was stirred at 140° C. for 2 h under microwave irradiation. The reaction mixture was partially purified by silica gel chromatography (Isco Combiflash, 12 g, methanol:ethyl acetate=0:100 to 20:80, gradient). A solution of the obtained partially purified product (238 mg, 0.7 mmol) and 4 M hydrochloric acid (1,4-dioxane solution, 0.26 mL) in methanol (2 mL) was stirred at room temperature for 21 h. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogencarbonate was added to the residue, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 12 g, methanol:ethyl acetate=0:100 to 40:60, gradient) to obtain the title compound (149 mg, 46%) as a colorless solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.O.[NH2:10][NH2:11].CC(O)CC>O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:10][NH2:11])=[N:3][CH:4]=1
Reactant: NN
Reactant: Brc1ccc(Br)nc1
Solvent: CCC(C)O
Solvent: O
Product: NNc1ccc(Br)cn1
Reaction time: 20 h
Yield: 86.7 %

Procedure:
A mixture of 2,5-dibromopyridine (44.2 g, 0.187 moles), hydrazine hydrate (55% by weight, 105.7 mL, 1.87 mol), poly(ethylene glycol) (187.0 mL), 2-butanol (37.3 mL) and water (187.0 mL) under nitrogen is refluxed gently for 29 hours. The mixture is cooled and stirred for 20 hours. To the resulting slurry, cold water (220.0 mL) is added. The slurry is stirred for an additional 30 minutes and filtered. The cake is washed with cold water (3×) and dried in a vacuum-oven (40-45° C.) for 48 hours. The title compound (30.5 g, 87%) may be obtained as off-white flakes.