Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].C([O:5][C:6](=[O:34])[C:7]([CH3:33])([CH3:32])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15](=[O:31])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][C:23]([C:26]([O:28]CC)=[O:27])([CH3:25])[CH3:24])[CH:17]=2)[CH:10]=1)C>O.C(O)C>[C:26]([C:23]([CH3:25])([CH3:24])[CH2:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[C:15]([C:11]1[CH:10]=[C:9]([CH2:8][C:7]([CH3:33])([CH3:32])[C:6]([OH:34])=[O:5])[CH:14]=[CH:13][CH:12]=1)=[O:31])([OH:28])=[O:27]
Reactant: CCOC(=O)C(C)(C)Cc1cccc(C(=O)c2cccc(CC(C)(C)C(=O)OCC)c2)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(Cc1cccc(C(=O)c2cccc(CC(C)(C)C(=O)O)c2)c1)C(=O)O
Yield: 101.5 %

Procedure:
To a solution of potassium hydroxide (1.57 g, 28 mmol) in water (1.5 mL) and absolute ethanol (5 mL) was added 3-{3-[3-(2-ethoxycarbonyl-2-methyl-propyl)-benzoyl]-phenyl}-2,2-dimethyl-propionic acid ethyl ester (4.38 g, 10 mmol) in portions. The mixture was heated to reflux for 3 h and the ethanol was distilled off under reduced pressure on a water-bath. The residual aqueous solution was extracted with chloroform (2×50 mL), then cooled with an ice-bath, and acidified with hydrochloric acid to pH 1. The mixture was extracted with diethyl ether (3×50 mL). The ethereal extracts were dried over sodium sulfate and concentrated in vacuo to give 3-{3-[3-(2-carboxy-2-methylpropyl)benzoyl]-phenyl}-2,2-dimethyl-propanoic acid (3.88 g, 100%) as a solid. Mp.: 46-48° C. 1H NMR (300 MHz, CDCl3): δ (ppm): 7.8-7.2 (m, 8H), 2.83 (s, 4H), 1.25 (s,12H). 13C NMR (75 MHz, CDCl3): δ (ppm): 198.02, 184.0, 139.2, 137.3, 134.5, 129.5, 128.4, 128.3, 127.6, 43.8, 24.7. HRMS (LSIMS, gly): Calcd. for C23H27O5 (MH+): 383.1858, found: 383.1858.
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH:13]=[N:12][CH:11]=[CH:10][C:9]=3[C:5]=2[C:4](O)=[N:3][CH:2]=1.C(N(CC)CC)C.C1(C)C=CC=CC=1.O=P(Cl)(Cl)[Cl:31]>>[Cl:31][C:4]1[C:5]2[C:9]3[CH:10]=[CH:11][N:12]=[CH:13][C:8]=3[NH:7][C:6]=2[N:1]=[CH:2][N:3]=1
Reactant: Oc1ncnc2[nH]c3cnccc3c12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Clc1ncnc2[nH]c3cnccc3c12
Temperature: 75 °C

Procedure:
A mixture of 9H-pyrido[4′,3′:4,5]pyrrolo[2,3-d]pyrimidin-4-ol (264 mg, 1.4 mmol) and triethylamine (750 μL) in 5 mL POCl3 was heated at 75° C. for 18 hours. Toluene was added to the cooled reaction mixture and the solvents were then removed in vacuo to give the title compound as a brown oil (290 mg). LC-MS (1) Rt 1.25 min; m/z (ES+) 205/207.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])(=O)=O.[I-:19].[Na+]>CC(C)=O.O>[F:14][C:13]([F:16])([F:15])[C:12]([F:18])([F:17])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][I:19]
Reactant: [I-]
Reactant: CS(=O)(=O)OCCCCCCC(F)(F)C(F)(F)F
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: FC(F)(F)C(F)(F)CCCCCCI
Reaction time: 8 h
Yield: 89.3 %

Procedure:
1-Methylsulfonyloxy-7,7,8,8,8-pentafluorooctane(14 g, 47.01 mmol) prepared in Step 1 was dissolved in acetone(200 ml), sodium iodide(19.62 g, 130 mmol) was added thereto, and the resulting mixture was stirred overnight under reflux-heating condition. The reaction solution was diluted with excess water(1 l), extracted twice with diethylether (100 ml), washed with 1% aqueous sodiumthiosulfate solution(100 ml) and saturated saline solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give 14 g(42 mmol, Yield 89%) of the title compound.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([Br:15])[CH:9]=2)=[O:5])C.Br[CH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1>>[Br:15][C:10]1[CH:9]=[C:8]2[C:13]([CH:14]=[C:6]([C:4]([OH:3])=[O:5])[N:7]2[CH2:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=2)=[CH:12][CH:11]=1
Reactant: BrCc1cccc2ccccc12
Reactant: CCOC(=O)c1cc2ccc(Br)cc2[nH]1
Product: O=C(O)c1cc2ccc(Br)cc2n1Cc1cccc2ccccc12

Procedure:
Using general procedure B, 6-bromo-1H-indole-2-carboxylic acid ethyl ester was coupled with 1-bromomethyl-naphthalene and the product obtained was hydrolyzed to give the title compound as white solid. MS: 380.1 ([M−H]−).
Reaction SMILES: Br[CH:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][CH:8]=1)=[O:4].[CH2:21]([S-:23])[CH3:22].[Na+]>>[C:13]([C:10]1[CH:11]=[CH:12][C:7]([CH2:6][NH:5][C:3](=[O:4])[CH:2]([S:23][CH2:21][CH3:22])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:8][CH:9]=1)#[N:14]
Reactant: CC[S-]
Reactant: N#Cc1ccc(CNC(=O)C(Br)c2ccccc2)cc1
Agent: [Na+]
Product: CCSC(C(=O)NCc1ccc(C#N)cc1)c1ccccc1

Procedure:
In analogy to example 83.1 (RS)-2-bromo-N-(4-cyano-benzyl)-2-phenyl-acetamide (example 81.1) was reacted with sodium ethanethiolate to give (RS)-N-(4-cyano-benzyl)-2-ethylsulfanyl-2-phenyl-acetamide. Off-white solid. MS 311.2 ([M+H]+)
Reaction SMILES: [ClH:1].[I:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C@H:13]([C:16]([OH:18])=[O:17])[CH2:14][NH2:15])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH3:19][CH2:20]O>>[ClH:1].[CH2:19]([NH:15][CH2:14][C@H:13]([NH:12][S:9]([C:6]1[CH:5]=[CH:4][C:3]([I:2])=[CH:8][CH:7]=1)(=[O:11])=[O:10])[C:16]([OH:18])=[O:17])[CH3:20]
Reactant: NC[C@H](NS(=O)(=O)c1ccc(I)cc1)C(=O)O
Reactant: CCO
Agent: Cl
Product: CCNC[C@H](NS(=O)(=O)c1ccc(I)cc1)C(=O)O
Temperature: 60 °C
Reaction time: 18 h

Procedure:
HCl gas was rapidly bubbled through a suspension of acid 5-3 (4.0 g, 10.81 mmol) in EtOH (50 ml) at 0° C. for 10 minutes. The cooling bath was removed and the reaction was heated to 60° C. After 18 h, the reaction was concentrated to provide ester 5-4 as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][C:9]2[CH:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:12]=[CH:13][CH:14]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.O=[C:22]([CH2:26][CH2:27][C:28](O)=[O:29])[C:23]([OH:25])=[O:24]>C(O)C>[C:11]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:12]=[CH:13][CH:14]=[C:9]([N:8]2[C:28](=[O:29])[C:27]([CH2:26][CH2:22][C:23]([OH:25])=[O:24])=[N:1][C:2]3[CH:7]=[CH:6][CH:5]=[N:4][C:3]2=3)[CH:10]=1
Reactant: Nc1cccnc1Nc1cccc(-c2ccccc2)c1
Reactant: O=C(O)CCC(=O)C(=O)O
Solvent: CCO
Product: O=C(O)CCc1nc2cccnc2n(-c2cccc(-c3ccccc3)c2)c1=O
Yield: 44.6 %

Procedure:
A mixture of 3-amino-2-[(3-biphenylyl)amino]pyridine (350 mg) and 2-ketoglutaric acid (235 mg) in ethanol (5 ml) was stirred under reflux for 1 hour. After evaporation of the solvent, the residue was chromatographed on silica gel column (2.5%-3% methanol in chloroform) to give 4-(3-biphenylyl)-2-(2-carboxyethyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (222 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:7]2Cl.C(N(CC)CC)C.[H][H]>[Pd].O1CCOCC1>[NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7]2
Reactant: [H][H]
Reactant: CCOC(=O)c1cnc2c(N)cccc2c1Cl
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc2c(N)cccc2c1
Yield: 63.1 %

Procedure:
A mixture of 8-amino-4-chloro-3-ethoxycarbonylquinoline (45 mg), triethylamine (0.026 ml) and 10%o palladium on carbon (15 mg) in dioxane was stirred for 7 hours at ambient temperature under 3 atmospheric pressure of hydrogen. Insoluble material was filtered off and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (ethyl acetate-dichloromethane) to give 8-amino-3-ethoxycarbonylquinoline (24.5 mg).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.S(Cl)(Cl)=O.[CH3:14][C:15]([CH3:20])=[CH:16][C:17](O)=[O:18]>ClCCl>[N:1]1([C:17](=[O:18])[CH:16]=[C:15]([CH3:20])[CH3:14])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: c1ccc2[nH]nnc2c1
Reactant: CC(C)=CC(=O)O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)=CC(=O)n1nnc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.5 %

Procedure:
1H-Benzotriazole (2.14 g, 18.0 mmol, 4 equiv.) was dissolved in dichloromethane (25 ml) and thionyl chloride (330 μl, 4.5 mmol, 1 equiv.) was added at room temperature. (450 mg, 4.5 mmol) 3-Methyl-but-2-enoic acid [CAS 541-47-9] was added and the mixture was stirred for 2 hours at room temperature. The suspension was filtered and the filtrate was extracted once with 2N NaOH solution and twice with dichloromethane. The organic extracts were combined, dried over sodium sulfate and evaporated to dryness. The crude product was purified by flash chromatography on a silica gel column eluting with an ethyl acetate:cyclohexane gradient 0:100 to 50:50. The desired 1-benzotriazol-1-yl-3-methyl-but-2-en-1-one (810 mg, 90% yield) was obtained as a light yellow solid, MS: m/e=202.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:13]([F:15])[F:14])[NH:6]2.Br[CH:17]([CH3:21])[C:18]([NH2:20])=[O:19].C([O-])([O-])=O.[Cs+].[Cs+]>>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:13]([F:14])[F:15])[N:6]2[CH:17]([CH3:21])[C:18]([NH2:20])=[O:19]
Reactant: CC(Br)C(N)=O
Reactant: N#Cc1ccc2[nH]c(C(F)F)cc2c1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(C(N)=O)n1c(C(F)F)cc2c(Cl)c(C#N)ccc21
Temperature: 90 °C

Procedure:
Synthesized as described in Example 4 using 4-chloro-2-(difluoromethyl)-1H-indole-5-carbonitrile, 2-bromo-propionamide (2 eq) and Cs2CO3 (2 eq). After heating at 90° C. for 4 h, additional 2-bromo-propionamide (2 eq) and Cs2CO3 (2 eq) were added and the reaction mixture heated at 110° C. for 15 h: MS (ES) m/z 298 (M+1).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].ON1C(=O)CCC1=O.C(N(CC)C(C)C)(C)C.[NH2:24][C:25]([CH3:29])([CH3:28])[CH2:26][OH:27]>C(Cl)Cl>[OH:27][CH2:26][C:25]([NH:24][C:2](=[O:3])[O:4][CH2:5][CH3:6])([CH3:29])[CH3:28]
Reactant: CCOC(=O)Cl
Reactant: CC(C)(N)CO
Agent: O=C1CCC(=O)N1O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)NC(C)(C)CO
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of ethyl chloroformate (3 g, 0.027 mol.) and N-hydroxysuccinimide (3.8 g, 0.033 mol.) in 10 mL of DCM at 0° C. under nitrogen atmosphere was added N,N-Diisopropylethylamine (7.0 mL, 0.04 mol). The progress of the reaction was monitored by thin layer chromatography (TLC). After stirring for 3 hrs at room temperature. DCM was evaporated and the residue was dissolved in 10 mL of acetonitrile, cooled in an ice-bath and then added dropwise a solution of 2-amino-2-methyl-1-propanol (3.1 mL, 1.2 eq). The resulting mixture was stirred at ice-bath temperature for 1 h and then overnight at room temperature. The progress of the reaction was monitored by thin layer chromatography (TLC). The reaction mixture was filtered, and the precipitate was washed with 2×10 mL DCM and dried over sodium sulfate. After removing the solvent under reduce pressure, the residue was purified by silica gel column chromatography to give ethyl (1-hydroxy-2-methylpropan-2-yl)carbamate as a colorless oil
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[Cl:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[F:25])[NH2:21]>C(O)C>[Cl:17][C:18]1[CH:19]=[C:20]([NH:21][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:15]#[N:16])[CH:22]=[CH:23][C:24]=1[F:25]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Cl
Solvent: CCO
Product: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Nc1ccc(F)c(Cl)c1
Yield: 81.9 %

Procedure:
A mixture of 5.00 g (21.5 mmol) 4-chloro-6-nitro-quinoline-3-carbonitrile, 200 ml ethanol, and 3.75 g (25.8 mmol) 3-chloro-4-fluoroaniline was heated to reflux under N2. Removed heat at 3½ hours and added a solution of saturated sodium bicarbonate until mixture was basic. Stripped solvents and azeotroped with ethanol. Slurried residue with hexane, collected solids, washed with water and dried in vacuo. Dissolved solids in 250 ml boiling ethyl acetate, stirred with Darco, and filtered. Stripped solvent and dried in vacuo, giving 6.036 g of yellow solid: mass spectrum (electrospray m/e): M+H=343.1, 345.1.
Reaction SMILES: [CH:1]1([P:7]([CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)([C@@H:9]2[CH2:13][NH:12][C@H:11]([CH2:14][P:15]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=O)[CH2:10]2)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:35][N:36]=[C:37]=[O:38]>C(Cl)Cl>[CH3:35][NH:36][C:37]([N:12]1[CH2:13][C@@H:9]([P:7]([CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:10][C@H:11]1[CH2:14][P:15]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:38]
Reactant: CN=C=O
Reactant: O=P(C[C@@H]1C[C@H](P(=O)(C2CCCCC2)C2CCCCC2)CN1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CNC(=O)N1C[C@@H](P(C2CCCCC2)C2CCCCC2)C[C@H]1CP(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
Using 300 mg (0.60 m-mol) of (2S,4S)-4-dicyclohexylphosphinyl-2-diphenylphosphinylmethylpyrrolidine, the reaction and after-treatment were carried out in the same manner as described in Example 2(b) to obtain CPM. This CPM was dissolved in 8 ml of methylene chloride and 38 mg (0.66 m-mol) of methyl isocyanate was slowly added dropwise to the solution under ice-cooling. The mixture was stirred in a stream of argon for 2 hours at room temperature. The reaction liquid was concentrated at a lower temperature under reduced pressure, and the residue was dried. This product was recrystallized from methanol to obtain 292 mg (yield: 96%) of MCCPM as white crystals.
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([S-:11])[CH3:10].[Na+]>>[C:2]1([CH2:1][S:11][CH2:9][CH3:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccccc1
Reactant: CC[S-]
Agent: [Na+]
Product: CCSCc1ccccc1

Procedure:
Commercially available benzyl chloride and sodium ethanethiolate are subjected to a nucleophilic substitution reaction to produce PhCH2SC2H5 after isolation and purification. In a Parr pressure vessel, 2.0 g (0.013 moles) of PhCH2SC2H5 is added to 200 ml of t-butanol. With stirring, 2.94 g (0.026 moles) of potassium t-butoxide is slowly added. The head space is flushed with an inert gas before exposure to 60 psi NO gas. The reaction is allowed to proceed at room temperature for 24 hours or until no further consumption of NO gas is observed. The resulting diazeniumdiolate salt is filtered, washed with t-butanol and diethyl ether, and vacuum dried before analysis.
Reaction SMILES: [N-]=C=S.N1CCC(N2C3C=CC=CC=3N(CCC[N:22]3[C:26](=[O:27])[C:25]4=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]4[C:23]3=[O:32])C2=O)CC1>C(Cl)Cl.O>[C:26]1(=[O:27])[NH:22][C:23](=[O:32])[C:24]2=[CH:31][CH:30]=[CH:29][CH:28]=[C:25]12
Reactant: O=C1c2ccccc2C(=O)N1CCCn1c(=O)n(C2CCNCC2)c2ccccc21
Agent: [N-]=C=S
Solvent: ClCCl
Solvent: O
Product: O=C1NC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Di(2-pyridyl)thionocarbonate (0.286 g, 1.2 mM) was added to a cold (0° C.) solution of 1,1-di(p-anisyl)methyl amine (0.3 g, 1.2 mM) and triethylamine (0.17 ml) in methylene chloride (10 ml). The resulting mixture was slowly warmed up to RT over a 4 hour period then stirred at RT for additional 1 hour to provide the 1,1-di(p-anisyl)methyl isothiocyanate. The prepared isothiocyanate was added to Compound 53 (0.94 g, 0.43 mM), prepared in Example 53, dissolved in methylene chloride (10 ml). The mixture was stirred at RT overnight, diluted with water (20 ml) and the layers were separated. The aqueous layer was again extracted with methylene chloride (2×20 ml). The combined CH2Cl2 extracts were dried over MgSO4, evaporated in vacuo and chromatoraphed (EM silica gel 60, 10% EtOAc in CH2Cl2) to give the pthalimide intermediate. This intermediate, substituted for Compound 54, was treated as described in Example 55 to give the HCl salt of the product. m/z (MH+) 560
Reaction SMILES: Cl.[Cl:2][C:3]1[C:40]([C:41]([F:44])([F:43])[F:42])=[CH:39][CH:38]=[CH:37][C:4]=1[CH2:5][N:6]([CH2:23][CH:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[N:12]=1.Br[CH2:46][C:47]([O:49][CH3:50])=[O:48].C(N(C(C)C)CC)(C)C>CCO>[CH3:50][O:49][C:47](=[O:48])[CH2:46][N:20]1[CH2:21][CH2:22][N:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([O:10][CH2:9][CH2:8][CH2:7][N:6]([CH2:5][C:4]3[CH:37]=[CH:38][CH:39]=[C:40]([C:41]([F:42])([F:43])[F:44])[C:3]=3[Cl:2])[CH2:23][CH:24]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:12]=2)[CH2:18][CH2:19]1
Reactant: COC(=O)CBr
Reactant: FC(F)(F)c1cccc(CN(CCCOc2cccc(N3CCNCC3)n2)CC(c2ccccc2)c2ccccc2)c1Cl
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CN1CCN(c2cccc(OCCCN(Cc3cccc(C(F)(F)F)c3Cl)CC(c3ccccc3)c3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a stirring solution of (2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-[3-(6-piperazin-1-yl-pyridin-2-yloxy)-propyl]-amine hydrochloride (0.1 g, 0.16 mmol) in EtOH (6 ml) was added methyl bromo-acetate (16 uL, 0.17 mmol) and diisopropylethylamine (89 uL, 0.51 mmol). The reaction mixture was stirred for 10 h at RT and then concentrated. Purification by flash silica gel chromatograpy afforded the title compound as a clear oil, 47 mg (42%). MS (ESI) 681.2 (M+).
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([O:12][CH:13]([CH3:17])[C:14]#[C:15][CH3:16])[CH:3]=1.[C:18](Cl)(=[O:25])[O:19][CH2:20][C:21]([Cl:24])([Cl:23])[Cl:22].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>ClCCl>[Cl:11][C:10]1[C:2]([NH:1][C:18]([O:19][CH2:20][C:21]([Cl:24])([Cl:23])[Cl:22])=[O:25])=[CH:3][C:4]([O:12][CH:13]([CH3:17])[C:14]#[C:15][CH3:16])=[C:5]([CH:9]=1)[C:6]([NH2:8])=[O:7]
Reactant: CC#CC(C)Oc1cc(N)c(Cl)cc1C(N)=O
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC#CC(C)Oc1cc(NC(=O)OCC(Cl)(Cl)Cl)c(Cl)cc1C(N)=O

Procedure:
0.75 g of (S)-N-(8-methyl-8-azabicyclo 3.2.1!oct-3α-yl)-4-amino-5-chloro-2-(1-methyl-2-butynyl)oxybenzamide, 0.51 g of 2,2,2-trichloroethyl chlorocarbonate and 0.41 g of potassium carbonate were added to toluene. The obtained mixture was refluxed for 3 hours and cooled, followed by the addition thereto of dichloromethane. The resulting mixture was washed with 1N hydrochloric acid, dried over magnesium sulfate, and freed from the solvent. The residue was purified by silica gel column chromatography (ethyl acetate/n-hexane (1:4) mixture) to give 0.50 g of (S)-N-(8-(2,2,2-trichloroethoxycarbonyl)-8-azabicyclo 3.2.1!oct-3α-yl)-5-chloro-2-(1-methyl-2-butynyl)oxy-4-(2,2,2-trichloroethoxycarbonylamino)benzamide.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[O:5]([C:12]1[CH:28]=[CH:27][C:15]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]3[O:24][CH2:25][O:26][C:20]=3[CH:19]=2)=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(C(C)C)C(C)C)C>C1C=CC=CC=1>[O:5]([C:12]1[CH:28]=[CH:27][C:15]([N:16]([C:1](=[O:3])[CH3:2])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]3[O:24][CH2:25][O:26][C:20]=3[CH:19]=2)=[CH:14][CH:13]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: c1ccc(Oc2ccc(NCc3ccc4c(c3)OCO4)cc2)cc1
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccccc1
Product: CC(=O)N(Cc1ccc2c(c1)OCO2)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.2 ml of acetyl chloride dissolved in 10 ml of anhydrous benzene is added dropwise at 0° - 5° C in the course of one hour, with stirring, to a solution of 12.7 g of 4-phenoxy-N-(3,4-methylenedioxybenzyl)-aniline and 6 g of N-ethyl-diisopropylamine in 100 ml of anhydrous benzene. The whole is subsequently heated to room temperature and stirred for a further 8 hours. The precipitated N-ethyl-diisopropylamine-hydrochloride is separated by filtration; the filtrate is washed with 10% sodium carbonate solution and then with water. After drying of the organic phase by means of sodium sulphate, the benzene is distilled off in vacuo, and the residue recrystallised in hexane to obtain 4-phenoxy-N-acetyl-N-(3,4-methylenedioxybenzyl)-aniline, M.P. 75° - 76° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C(N(CC)CC)C.[NH2:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][N:28]([CH3:36])[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32]>C(Cl)Cl>[CH3:36][N:28]([CH2:27][CH2:26][O:25][CH2:24][CH2:23][NH:22][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:32])[CH3:33]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: CN(CCOCCN)C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CCOCCNc1c([N+](=O)[O-])cnc2ccccc12)C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 77.2 %

Procedure:
A stirred solution of 4-chloro-3-nitroquinoline (32.3 g, 155 mmol) in 400 mL of anhydrous CH2Cl2, under N2, was treated with triethylamine (43.1 mL, 310 mmol) and tert-butyl 2-(2-aminoethoxy)ethyl(methyl)carbamate (37.2 g, 171 mmol). After stirring overnight, the reaction mixture was washed with H2O (2×300 mL) and brine (300 mL). The organic portion was dried over Na2SO4 and concentrated to give a brown oil. Column chromatography (SiO2, 33% ethyl acetate/hexanes-67% ethyl acetate/hexanes) gave 46.7 g of tert-butyl methyl(2-{2-[(3-nitroquinolin-4-yl)amino]ethoxy}ethyl)carbamate as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][NH2:9])=[CH:6][CH:5]=1.C[O:15][C:16](=O)[C:17]1[C:22]([I:23])=[CH:21][C:20]([N+:24]([O-:26])=[O:25])=[CH:19][C:18]=1[CH2:27]Br.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1>[N+:24]([C:20]1[CH:19]=[C:18]2[C:17](=[C:22]([I:23])[CH:21]=1)[C:16](=[O:15])[N:9]([CH2:8][C:7]1[CH:10]=[CH:11][C:4]([O:3][C:2]([F:12])([F:13])[F:1])=[CH:5][CH:6]=1)[CH2:27]2)([O-:26])=[O:25]
Reactant: NCc1ccc(OC(F)(F)F)cc1
Reactant: COC(=O)c1c(I)cc([N+](=O)[O-])cc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C1c2c(I)cc([N+](=O)[O-])cc2CN1Cc1ccc(OC(F)(F)F)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 10.2 %

Procedure:
A mixture of 4-trifluoromethoxy-benzyl amine (0.586 mL, 3.84 mmol), 2-bromomethyl-4-nitro-6-iodo-benzoic acid methyl ester (1.18 g, 2.95 mmol), and K2CO3 (0.815 g, 0.815 mmol) in toluene (7 mL) was heated with stirring at 100° C. for 2 h. The resulting mixture was filtered and concentrated. Silica gel column chromatography using 30% ethyl acetate in hexane afforded 5-nitro-7-iodo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.144 g, 10%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.31 (s, 2H), 4.82 (s, 2H), 7.19 (d, 2H), 7.38 (d, 2H), 8.24 (s, 1H), 8.78 (s, 1H). GC-MS: m/z 478 (M)+, 409 (M−69)+.
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OS([O-])=O.[Na+].[CH3:21][O:22][C:23](=[O:32])[C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[C:26]([NH2:31])[CH:25]=1.C(O)C>O>[O:1]([C:8]1[CH:15]=[CH:14][C:11]([C:12]2[NH:30][C:27]3[CH:28]=[CH:29][C:24]([C:23]([O:22][CH3:21])=[O:32])=[CH:25][C:26]=3[N:31]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Reactant: COC(=O)c1ccc(N)c(N)c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COC(=O)c1ccc2[nH]c(-c3ccc(Oc4ccccc4)cc3)nc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.5 %

Procedure:
To 4-phenoxybenzaldehyde (3.0 g, 0.02 mol) was added 21 mL of 40% NaHSO3 (aq). The mixture was stirred for 1 h at 25° C. Methyl-3,4-diaminobenzoate (2.5 g, 0.02 mol) and ethanol (15 mL) were added. The mixture was refluxed for 4 h. The reaction was then poured into water. The precipitate filtered and recrystallized from EtOAc to afford 2-(4-phenoxyphenyl)-1H-benzimidazole-5-carboxylic acid, methyl ester (5.06 g, 97%) as a white solid.