Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=[N:8]/[OH:9])\[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10]N1C(=O)CCC1=O>CN(C)C=O.O>[OH:9]/[N:8]=[C:1](\[Cl:10])/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O/N=C/c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: O/N=C(\Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.5 %

Procedure:
To a colorless, homogeneous solution of (E)-benzaldehyde oxime (24.4 g, 201 mmol) in N,N-dimethylformamide (60 mL) at room temperature was added N-chlorosuccinimide (26.9 g, 201 mmol) portion-wise over 30 min. During each addition, the reaction mixture became yellow and then gradually returned to near colorlessness. Additionally, an exotherm was noted with each portion added. (It is extremely important to make sure the reaction initiates after the addition of the first ˜1/5 of the NCS; an ice-bath was readily available.). After the addition was complete, the homogeneous reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with 250 mL of water and extracted with ether (3×100 mL). The organic layers were combined, washed with water (2×100 mL), washed with a 10% aqueous solution of lithium chloride (2×100 mL), and washed with brine (100 mL). The aqueous layers were back extracted with ether (100 mL), and the combined organic layers (400 mL) were dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded (Z)—N-hydroxybenzimidoyl chloride (30.84 g, 198 mmol, 98% yield) as a fluffy, pale yellow solid. The product had an HPLC ret. time=1.57 min.-Column: CHROMOLITH® SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=155.8. 1H-NMR (500 MHz, DMSO-d6) δ ppm 7.30-7.64 (m, 3H), 7.73-7.87 (m, 2H), and 12.42 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>ClCCl.CN(C)C=O>[C:26]1([NH:25][C:9](=[O:11])[CH2:8][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)Cc1ccc(Br)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Cc1ccc(Br)cc1)Nc1ccccc1
Temperature: 25 °C
Yield: 68.3 %

Procedure:
A mixture of 4-bromophenyl acetic acid (5.0 g, 23.3 mmol), and oxalyl chloride (3.25 g, 25.6 mmol) in dichloromethane (100 mL), was stirred at ambient temperature, treated with 3 drops of N,N-dimethylformamide, then stirred for 2.5 hours. The solvents were removed under reduced pressure then the residue was dissolved in dichloromethane (100 mL) and triethylamine (5.9 g, 58.3 mmol). Aniline (2.4 g, 25.6 mmol) was added and the mixture was stirred an additional 1 hour. The solution was washed with 1N aqueous hydrochloric acid (2×50 mL), saturated sodium bicarbonate (100 mL), brine (50 mL), then dried over magnesium sulfate, filtered and the filtrate evaporated under reduced pressure to give N1-phenyl-2-(4-bromophenyl)acetamide (4.62 g, 68%) [RP-HPLC (Hypersil HS C18, 5 m, 100 A, 250×4.6 mm; 25%-00% acetonitrile over 10 min, 1 mL/min) tr 10.85 min.] which was used without further purification. A mixture of N1-phenyl-2-(4-bromophenyl)acetamide (4.62 g, 15.9 mmol), diboron pinacol ester (4.45 g, 17.5 mmol), potassium acetate (4.68 g, 47.8 mmol) and [ 1.1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1: 1) (0.39 g, 0.5 mmol) in N,N-dimethylformamide (90 mL) was heated at 100° C. under an atmosphere of nitrogen for 18 hours then cooled to ambient temperature. The solvent was removed under reduced pressure and the residue was triturated with dichloromethane (100 mL). The insoluble material was removed by filtration through a pad of celite and then the filtrate was concentrated under reduced pressure and purified by flash chromatography on silica gel using dichloromethane/ethyl acetate (95:5) as an eluent to provide N1-phenyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetamide (4.82 g, 89%):1H NMR (DMSO-d6, 400 MHz) 10.15(s, 1H), 7.64(d, 2H), 2.59(d, 2H), 7.36(d, 2H), 7.29(t, 2H), 7.03 (t, 1H), 3.67(s, 2H), 1.29(s, 12H); RP-HPLC (Hypersil HS C18, 5 m, 100 A, 250×4.6 mm; 5%-50% acetonitrile over 25 min, 1 mL/min) tr 11.7 min.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:28])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:16][CH:15]=1)[NH:5]C(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O.C(Cl)[Cl:37]>>[ClH:37].[CH3:1][NH:2][C:3](=[O:28])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:16][CH:15]=1)[NH2:5]
Reactant: ClCCl
Reactant: CNC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1
Product: Cl

Procedure:
N-tertiarybutoxycarbonyl-O-benzyl-L-tyrosine N-methylamide (3 g) was added to a mixture of TFA and CH2Cl2 (1:1 100 ml) at room temperature. After 15 minutes volatiles were removed in vacuo and the residue was dissolved in water. Neutralisation with solid sodium bicarbonate, extraction into CH2Cl2 and evaporation of the organic extract in vacuo then gave a solid. Co-evaporation of this with ethereal HCl gave O-benzyl-L-tyrosine N-Methylamide hydrochloride.
Reaction SMILES: [C:1]1([S:7][CH:8]2[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:11]OS([O-])=O.[K+].[OH2:17]>CO>[CH:8]1([S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:11])=[O:17])[CH2:10][CH2:9]1
Reactant: O=S([O-])OO
Reactant: c1ccc(SC2CC2)cc1
Reactant: O
Agent: [K+]
Solvent: CO
Product: O=S(=O)(c1ccccc1)C1CC1

Procedure:
A solution of cyclopropyl phenyl sulfide (10.5 g, 70 mmol) and Oxone™ (55.13 g, 175 mmol) in methanol (30 ml) was stirred at room temperature for 5 hours. The mixture was diluted was water and extracted with ethyl acetate. The combined organic layers were dried (MgSO4) and concentrated in vacuo.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH:11]([CH3:13])C)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:17][C:18]([F:38])([F:37])[C:19]1[CH:24]=[CH:23][C:22]([S:25]([N:28]2[CH2:32][C@@H:31]3[C@@H:33]([NH2:36])[CH2:34][CH2:35][C@@H:30]3[CH2:29]2)(=[O:27])=[O:26])=[CH:21][CH:20]=1.[CH2:39](N1C[C@@H]2[C@@H](N)CC[C@@H]2C1)C1C=CC=CC=1>>[CH3:39][N:8]([C@@H:9]([CH2:10][CH2:11][CH3:13])[C:14](=[O:16])[NH:36][C@@H:33]1[C@@H:31]2[C@@H:30]([CH2:29][N:28]([S:25]([C:22]3[CH:21]=[CH:20][C:19]([C:18]([F:17])([F:37])[F:38])=[CH:24][CH:23]=3)(=[O:26])=[O:27])[CH2:32]2)[CH2:35][CH2:34]1)[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4]
Reactant: N[C@H]1CC[C@@H]2CN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)C[C@@H]21
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21
Product: CCC[C@@H](C(=O)N[C@H]1CC[C@@H]2CN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)C[C@@H]21)N(C)C(=O)OC(C)(C)C

Procedure:
The title compound was prepared by substituting N-(tert-butoxycarbonyl)-N-methyl-L-norvaline for N-(tert-butoxycarbonyl)-L-leucine and (3aR,4S,6aS)-2-(4-(trifluoromethyl)phenylsulfonyl)octahydrocyclopenta[c]pyrrol-4-amine from Step A of Example 256 for (3aR,4S,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine in the procedure described in Example 221: 1H NMR (400 MHz, pyridine-d5, temperature 90° C.) δ ppm 8.06-8.09 (m, 2H), 7.79-7.82 (m, 2H), 7.40 (d, J=3.1 Hz, 1H), 4.66-4.76 (m, 1H), 4.07 (p, J=6.8 Hz, 1H), 3.65 (dd, J=10.2, 3.4 Hz, 1H), 3.28 (dd, J=10.2, 7.7 Hz, 1H), 3.06-3.17 (m, 2H), 2.93 (s, 3H), 2.53-2.62 (m, 1H), 2.45-2.53 (m, 1H), 1.93-2.02 (m, 1H), 1.86-1.95 (m, 1H), 1.70-1.85 (m, 2H), 1.47-1.57 (m, 1H), 1.45 (s, 9H), 1.27-1.37 (m, 2H), 1.22-1.32 (m, 1H), 0.86 (t, J=7.4 Hz, 3H); MS (ESI+) m/z 548 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)=O.C(=O)([O-])O.[Na+].O>C(O)CC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:8]=2)[CH:7]=1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: Nc1ccc(Br)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCO
Solvent: O
Product: Clc1ccc(-c2cn3cc(Br)ccc3n2)cc1
Temperature: 80 °C
Yield: 69.9 %

Procedure:
2.33 g of 5-bromopyridin-2-ylamine and 3.14 g of 2-bromo-1-(4-chlorophenyl)-ethanone are placed in 110 ml of n-propanol in a round-bottomed flask. 1.58 g of sodium hydrogencarbonate are added. The mixture is heated at 80° C. for 16 h and allowed to cool to ambient temperature. 400 ml of water are added. The precipitate is collected by filtration, washed with water and dried in an oven under reduced pressure. 2.89 g of compound are obtained. 1H NMR spectrum (d6-DMSO, δ in ppm): 7.4 (d, 1H); 7.5 (d, 2H); 7.6 (d, 1H); 8.0 (d, 2H); 8.4 (s, 1H); 8.9 (s, 1H). M+H=308.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][C:14]([CH3:45])([CH3:44])[CH2:15][N:16]1[C:21](=[O:22])[C:20]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=3)=[CH:26][CH:25]=2)=[C:19]([CH2:38][CH2:39][CH3:40])[N:18]2[N:41]=[CH:42][N:43]=[C:17]12>C(OCC)(=O)C>[CH3:45][C:14]([CH3:44])([CH3:13])[CH2:15][N:16]1[C:21](=[O:22])[C:20]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]3[NH:3][C:4](=[O:7])[O:5][N:37]=3)=[CH:28][CH:29]=2)=[C:19]([CH2:38][CH2:39][CH3:40])[N:18]2[N:41]=[CH:42][N:43]=[C:17]12
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CC(C)(C)C)c2ncnn12
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(CC(C)(C)C)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 39.7 %

Procedure:
A mixture of hydroxylammonium chloride (0.95 g), sodium hydrogen carbonate (1.53 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-{[4-(2,2-dimethylpropyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.4 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (15 mL). N,N′-Carbonyldiimidazole (0.18 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.15 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.18 g, 40%).
Reaction SMILES: [CH2:1]([N:17]1[CH:21]=[CH:20][N:19]=[C:18]1[CH2:22][CH2:23][CH3:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH2:25]([Br:33])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>>[Br-:33].[CH2:1]([N:17]1[CH:21]=[CH:20][N:19]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:18]1[CH2:22][CH2:23][CH3:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCBr
Reactant: CCCCCCCCCCCCCCCCn1ccnc1CCC
Product: CCCCCCCCCCCCCCCCN1C=CN(CCCCCCCC)C1CCC
Product: [Br-]

Procedure:
1 mole of 1-n-hexadecyl-2-n-propylimidazole and 1.2 moles of n-octyl bromide are heated together at 150° C for 5 hours. Then the unreacted n-octyl bromide is distilled off and the residue is washed with ether.
Reaction SMILES: [NH2:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:11][CH3:12])[CH:8]=2)[CH2:3]1.Cl[C:14]1[C:15]2[C:22]([CH3:23])=[CH:21][S:20][C:16]=2[N:17]=[CH:18][N:19]=1.C(N(CC)CC)C>C(O)C>[CH3:12][O:11][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH2:3][CH:2]([NH:1][C:14]1[C:15]3[C:22]([CH3:23])=[CH:21][S:20][C:16]=3[N:17]=[CH:18][N:19]=1)[CH2:10]2
Reactant: COc1ccc2c(c1)CC(N)C2
Reactant: Cc1csc2ncnc(Cl)c12
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)CC(Nc1ncnc3scc(C)c13)C2
Yield: 12.8 %

Procedure:
Using 2-amino-5-methoxyindan (90 mg) synthesized in b) in the above Preparation Example 1, 4-chloro-5-methylthieno[2,3-d]pyrimidine (90 mg, 0.50 mmol), triethylamine (0.23 ml, 1.7 mmol) and ethanol (1 ml), a similar procedure to b) in Example 19 was carried out. The product obtained was purified by silica gel chromatography (hexane:ethyl acetate=4:1) to obtain the title compound (20 mg, 0.064 mmol) having the following physical properties:
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[S:3][C:4]1[CH:15]=[CH:14][C:7]([CH2:8][CH:9]([C:12]#[N:13])[C:10]#[N:11])=[CH:6][CH:5]=1.[H-].[Na+].Br[CH2:21][CH2:22][C:23]([F:27])=[C:24]([F:26])[F:25]>CN(C)C=O>[F:27][C:23](=[C:24]([F:26])[F:25])[CH2:22][CH2:21][C:9]([CH2:8][C:7]1[CH:6]=[CH:5][C:4]([S:3][C:2]([F:16])([F:1])[F:17])=[CH:15][CH:14]=1)([C:12]#[N:13])[C:10]#[N:11]
Reactant: FC(F)=C(F)CCBr
Reactant: N#CC(C#N)Cc1ccc(SC(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)=C(F)F)Cc1ccc(SC(F)(F)F)cc1
Yield: 16.9 %

Procedure:
Using 0.50 g of (4-(trifluoromethylthio)benzyl)malononitrile, 10 ml of N,N-dimethylformamide, 86 mg of sodium hydride (60% in oil), and 0.74 g of 4-bromo-1,1,2-trifluoro-1-butene, and according to -the process described in the Production Example 1, there was obtained 0.12 g of 2-(3,4,4-trifluoro-3-butenyl)-2-(4-(trifluoromethylthio)benzyl)malononitrile (the present compound (54)).
Reaction SMILES: [CH2:1]([N:3]([CH2:23][CH3:24])[C:4]([CH:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[F:19])[N:11]([CH2:20][CH2:21][OH:22])[C:10]=2[CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].C(N(CC)C(C1C2C3C(=CC(F)=CC=3)N(CCO)C=2CCC1)=O)C.N1C=CC=CC=1.[CH3:55][S:56](Cl)(=[O:58])=[O:57]>ClCCl>[CH2:1]([N:3]([CH2:23][CH3:24])[C:4]([CH:6]1[C:18]2[C:13]3[C:12](=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[N:11]([CH2:20][CH2:21][O:22][S:56]([CH3:55])(=[O:58])=[O:57])[C:10]=2[CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCN(CC)C(=O)C1CCCc2c1c1c(F)cccc1n2CCO
Reactant: CS(=O)(=O)Cl
Agent: CCN(CC)C(=O)C1CCCc2c1c1ccc(F)cc1n2CCO
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCN(CC)C(=O)C1CCCc2c1c1ccc(F)cc1n2CCOS(C)(=O)=O
Temperature: 0 °C
Yield: 1 %

Procedure:
To a solution of a mixture of 5-fluoro-9-(2-hydroxy-ethyl)-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid diethylamide (42) and 7-fluoro-9-(2-hydroxy-ethyl)-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid diethylamide (743 mg, 2.2 mmol) in dichloromethane (30 mL) was added pyridine (1.74 g, 22.0 mmol, 1.8 mL). The reaction was cooled to 0° C. and methanesulfonyl chloride (1.01 g, 8.8 mmol, 0.7 mL) was added. The reaction was allowed to warm to room temperature overnight. The mixture was washed with 2 N HCl (2×50 mL) and water (2×50 mL), dried and concentrated in vacuo. The crude material was purified by semi preparative HPLC eluting with water (A) and methanol (B) (Gemini 5 u, C18, 110A, 150×21 mm, 50-95% B over 20 min, 21 mL/min) to afford 10 mg (1%) of methanesulfonic acid 2-(4-diethylcarbamoyl-7-fluoro-1,2,3,4-tetrahydro-carbazol-9-yl)-ethyl ester as a white solid and 30 mg (9%) of a mixture of methanesulfonic acid 2-(4-diethylcarbamoyl-7-fluoro-1,2,3,4-tetrahydro-carbazol-9-yl)-ethyl ester and methanesulfonic acid 2-(4-diethylcarbamoyl-5-fluoro-1,2,3,4-tetrahydro-carbazol-9-yl)-ethyl ester (precursor compound 10) as a white solid. Using these purification conditions, methanesulfonic acid 2-(4-diethylcarbamoyl-5-fluoro-1,2,3,4-tetrahydro-carbazol-9-yl)-ethyl ester (precursor compound 10) could not be isolated as a single component. The structure of methanesulfonic acid 2-(4-diethylcarbamoyl-7-fluoro-1,2,3,4-tetrahydro-carbazol-9-yl)-ethyl ester was confirmed by 1H NMR (300 MHz, CDCl3) δH 1.18 (3H, t, J=7 Hz, N(CH2CH3)2), 1.39 (3H, t, J=7 Hz, N(CH2CH3)2) 1.70-2.30 (4H, m, 2- and 3-CH2), 2.58 (3H, s, OSO2CH3), 2.60-2.80 (2H, m, 1-CH2), 3.40-3.65 (4H, m, N(CH2CH3)2), 4.02 (1H, t, J=6 Hz, 4-CH), 4.20 (2H, t, J=7 Hz, NCH2CH2O Ms), 4.35 (2H, t, J=7 Hz, NCH2CH2O Ms), 6.70-6.85 (1H, m, NCCHCFCHCH), 6.90-7.00 (1H, m, NCCHCFCHCH), and 7.05-7.15 (2H, m, NCCHCFCHCH).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH2:11])=[O:10])=[CH:4][C:3]=1[NH:12][CH3:13].[NH2:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[C:29](N1C=CN=C1)(N1C=CN=C1)=S.C(Cl)CCl>CN(C=O)C>[CH3:13][N:12]1[C:3]2[CH:4]=[C:5]([CH2:8][C:9]([NH2:11])=[O:10])[CH:6]=[CH:7][C:2]=2[N:1]=[C:29]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:26])[F:27])[CH:21]=[CH:20][C:18]=2[N:19]=1
Reactant: Nc1nc2ccc(OC(F)(F)F)cc2s1
Reactant: CNc1cc(CC(N)=O)ccc1N
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2ccc(CC(N)=O)cc21
Yield: 22.2 %

Procedure:
2-[3-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-3H-benzoimidazol-5-yl]-acetamide (240 mg) was prepared by following General Procedure D beginning with 2-(4-amino-3-methylamino-phenyl)acetamide (554 mg), 2-amino-6-(trifluoromethoxy)-benzothiazole (600.0 mg), 1,1′-thiocarbonyldiimidazole (600.0 mg), and EDC (600.0 mg) in DMF (6.0 ml). LCMS: m/z 423.
Reaction SMILES: [CH:1]1([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]4[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=4)[N:13]=3)=[C:10]([CH3:26])[O:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:58][CH2:59][CH2:60]O>C1COCC1>[Br:58][CH2:59][CH2:60][O:25][C:21]1[CH:20]=[C:19]([NH:18][C:14]2[N:13]=[C:12]([C:11]3[C:7]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)=[N:8][O:9][C:10]=3[CH3:26])[CH:17]=[CH:16][N:15]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: OCCBr
Reactant: Cc1onc(C2CCCCC2)c1-c1ccnc(Nc2cccc(O)c2)n1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1onc(C2CCCCC2)c1-c1ccnc(Nc2cccc(OCCBr)c2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.9 %

Procedure:
To a solution of phenol 11 (880 mg, 2.51 mmol) in THF (anhydrous, 5 ml) was added diethyl azodicarboxylate (0.52 ml, 3.27 mmol) and triphenylphosphine (857 mg, 3.27 mmol) followed by 2-bromoethanol (0.23 ml, 3.27 mmol) at 0° C. The resulting mixture was stirred at room temperature for 4 hours and the solvent was removed in vacuo. The crude product was purified by silica gel chromatography (30% EtOAC:hexanes) to afford the desired bromo derivative 12 (745 mg) as a white solid in 65% yield. 1H NMR (CDCl3) δ 1.2-2.0 (m, 10H), 2.5 (s, 3H), 3.1 (m, 1H), 3.6 (t, 2H), 4.3 (t, 2H), 6.6 (d, 1H), 6.7 (d, 1H), 7.1 (d, 1H), 7.1(s, 1H), 7.3 (dd, 1H), 7.4 (s, 1H), 8.4 (d, 1H)
Reaction SMILES: [CH2:1]([C:4]1[CH:13]=[CH:12][C:7]2[C:8](=[O:11])[O:9][CH2:10][C:6]=2[CH:5]=1)[CH:2]=C.[O:14]=[O+][O-].[BH4-].[Na+]>C(Cl)Cl.CO>[OH:14][CH2:2][CH2:1][C:4]1[CH:13]=[CH:12][C:7]2[C:8](=[O:11])[O:9][CH2:10][C:6]=2[CH:5]=1
Reactant: O=[O+][O-]
Reactant: C=CCc1ccc2c(c1)COC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: O=C1OCc2cc(CCO)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-prop-2-en-1-yl-2-benzofuran-1(3H)-one (13.5 g, 45.2 mmol) in 200 mL DCM/MeOH (V/V=1:1) was bubbled O3 at −78° C. for 30 min, and N2 was bubbled for another 15 min at −78° C. Then 20 mL of Me2S were added, and the mixture was stirred at r.t. overnight before concentrating to dryness. The residue was dissolved in MeOH (100 mL) and then cooled to 0° C. NaBH4 (5.90 g, 155 mmol) was added in portions. The resulting mixture was stirred at 0° C. for 1 h, then quenched with citric acid (aq.) and extracted three times with EtOAc. The combined organic layers were washed with NaHCO3 (aq.) and brine, dried over anhydrous Na2SO4 and concentrated to dryness. The residue was purified via column chromatography (EtOAc/Petrol Ether=1:5) to give the title compound. 1H-NMR (400 MHz, CDCl3) δ ppm 7.86 (d, J=7.8 Hz, 1H), 7.41 (d, J=7.8 Hz, 1H), 7.38 (s, 1H), 5.29 (s, 2H), 3.92-3.98 (m, 2H), 3.01 (t, J=6.4 Hz, 2H).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[F:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1>>[F:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:2]2[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=2[C:4]#[N:5])=[CH:15][CH:14]=1
Reactant: Oc1ccc(F)cc1
Reactant: N#Cc1cc(C=O)ccc1F
Product: N#Cc1cc(C=O)ccc1Oc1ccc(F)cc1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 2-fluoro-5-formylbenzonitrile and 4-fluorophenol.
Reaction SMILES: C(CCCCCCCCCCN)C=C.C(N(CC)C(C)C)(C)C.ClC([O:27][CH2:28][CH:29]1C2C=CC=CC=2C2C1=CC=CC=2)=O.[C:42]([NH:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69]CC=C)([O:44][CH2:45][CH:46]1[C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[C:52]2[C:47]1=[CH:48][CH:49]=[CH:50][CH:51]=2)=[O:43]>ClCCl>[C:42]([N:59]([CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH3:69])[CH2:29][CH:28]=[O:27])([O:44][CH2:45][CH:46]1[C:47]2[C:52](=[CH:53][CH:54]=[CH:55][CH:48]=2)[C:51]2[C:58]1=[CH:57][CH:56]=[CH:49][CH:50]=2)=[O:43]
Reactant: C=CCCCCCCCCCCCNC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: C=CCCCCCCCCCCCN
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCCCCN(CC=O)C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 5 °C

Procedure:
A three-necked, 500 mL round bottom flask equipped with a thermometer, mechanic stirrer and an addition funnel was purged with nitrogen and charged with N-allyldecylamine (˜0.11 mol) in dichloromethane from step a (210 mL) and N,N-diisopropylethylamine (20.0 mL, 14.8 g, 0.113 mol). The mixture was cooled in a 5° C. ice bath and a solution of 9-fluorenylmethyl chloroformate (25.6 g, 0.099 mol) dissolved in dichloromethane (50 mL) was added dropwise (total volume approximately 330 mL). The reaction was exothermic and the internal temperature was controlled below 10° C. throughout the 9-fluorenylmethyl chloroformate addition. The reaction mixture was warmed to 21° C. when the addition was finished, and monitored by the disappearance of 9-fluorenylmethyl chloroformate and the formation of N-FMOC-N-allyldecylamine using HPLC (retention time for FMOC-chloride=3.08 min; retention time for product=7.96 min). The reaction mixture was washed with 0.01 N HCl (100 mL). The organic layer was collected and used without further purification.