Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[C:19]2[C:11](=[C:12]3[C:16](=[CH:17][CH:18]=2)N[CH:14]([C:20](OCCC2C=CC([N+]([O-])=O)=CC=2)=O)[CH2:13]3)[CH:10]=[CH:9]1)=O)(C)(C)C.[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37]>>[C:36]([OH:38])([C:35]([F:40])([F:39])[F:34])=[O:37].[CH3:35][CH2:20][CH2:14][CH2:13][CH2:12][CH2:16][CH2:17][CH2:18][CH2:19][CH2:11][CH2:10][CH2:9][NH2:8]
Reactant: CC(C)(C)OC(=O)n1ccc2c3c(ccc21)NC(C(=O)OCCc1ccc([N+](=O)[O-])cc1)C3
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCCCCCN

Procedure:
2-(4-Nitrophenyl)ethyl 3-[(tert-butyl)oxycarbonyl]pyrrolo[4,5-e]indoline-7-carboxylate (1.62 g) (Compound 1-1 of Scheme I) was selectively deprotected by treatment with 15 mL of trifluoroacetic acid (i.e., TFA) for 1 h. TFA was evaporated to afford a TFA salt of amine 12. Residual TFA was removed by co-evaporation with ether followed by drying under vacuum. The TEA salt was dissolved in 30 mL of anhydrous DMF in the presence of 0.9 mL of triethylamine. Compound 1-2 of Scheme II (see Example 1) (1.86 g) was added and the reaction was stirred at room temperature overnight. The solvent was evaporated under vacuum and the semi-solid residue was triturated with 10% MeOH/dichloromethane. The resulting yellow solid was collected by filtration and washed with the MeOH/dichloromethane mixture followed by ether. Drying under vacuum afforded 2.2 g of the dimer 13. The product contained about 1 equivalent of DMF according to the NMR analysis. 1H MNR (d6-DMSO) δ: 11.96 (s, 1H, NH), 10.27 (s, 1H, NH), 8.84 (br s, 1H), 8.33 (d, J=8.8 Hz, 1H), 8.19 (d, J=8.8 Hz, 2:H), 8.12 (br s, 1H), 7.65 (d, J=8.8 Hz, 2H), 7.35 (d, J=8.8 Hz, 1H), 7.08 (s, 1H), 7.07 (s, 1H), 4.64 (t, J=8 Hz, 2H), 4.57 (t, J=6.4 Hz, 2H), 4.03 (t, J=8.5 Hz, 2H), 3.44 (t, J=8 Hz, 2H), 3.27 (t, J=8.5 Hz, 2H), 3.22 (t, J=6.6 Hz, 2H), 3.09 (m, 6H), 1.52 (s, 9H) and 1.16 (t, J=7.4 Hz, 9H).
Reaction SMILES: [ClH:1].[C:2]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH2:7][CH2:6]1)(=[NH:4])[NH2:3].[NH:16]([C:20]1[CH:25]=[CH:24][C:23](O)=[CH:22][CH:21]=1)[C:17]([CH3:19])=[O:18].C1(N=C=NC2CCCCC2)CCCCC1>N1C=CC=CC=1>[ClH:1].[C:2]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][C:13]([O:15][C:23]2[CH:24]=[CH:25][C:20]([NH:16][C:17]([CH3:19])=[O:18])=[CH:21][CH:22]=2)=[O:14])[CH2:7][CH2:6]1)(=[NH:3])[NH2:4]
Reactant: N=C(N)N1CCC(CCC(=O)O)CC1
Reactant: CC(=O)Nc1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(OC(=O)CCC2CCN(C(=N)N)CC2)cc1
Yield: 47.9 %

Procedure:
A mixture of 2.0 g of 1-amidino-4-piperidinepropionic acid hydrochloride and 1.29 g of p-acetaminophenol was dissolved in 20 ml of dry pyridine. To the solution was added with stirring and ice-cooling 1.75 g of dicyclohexylcarbodiimide, and the resulting mixture was stirred overnight at room temperature. The reaction mixture was filtered to give crystals which were then washed with ethyl acetate and further with ether and dried. The crystals were refluxed with 600 ml of dichloromethane, and the resulting mixture was filtered to give an insoluble substance. The substance was washed with dichloromethane and recrystallized from methanol-ethyl acetate to obtain 1.5 g (yield: 48.4%) of p-acetaminophenyl 1-amidino-4-piperidinepropionate hydrochloride as colorless crystals having a melting point of 258° to 261° C.
Reaction SMILES: [CH3:1][C:2]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].CO[CH:13](OC)[N:14]([CH3:16])[CH3:15]>>[CH3:13][N:14]([CH3:16])[CH:15]=[C:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:2](=[O:3])[CH3:1]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)Cc1ccccc1
Product: CC(=O)C(=CN(C)C)c1ccccc1

Procedure:
A stirred mixture of benzyl methyl ketone (26.8 ml) and dimethylformamide dimethyl acetal (30.0 ml) was heated in a distillation apparatus on an oil bath at 95°-100° C. for 11/2 hours. Methanol slowly distilled off. The residual volatiles were removed under vacuum and the resulting oil was crystallised from ether-petroleum spirit (40°-60° C.) to yield the title compound (mp 66° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7](Cl)[C:6]=2[C:13]#[N:14]>C(N)CCC>[CH2:3]([NH:4][C:7]1[C:6]([C:13]#[N:14])=[C:5]2[C:10]([CH:11]=[C:2]([Cl:1])[CH:3]=[N:4]2)=[CH:9][CH:8]=1)[CH2:2][CH2:11][CH3:10]
Reactant: N#Cc1c(Cl)ccc2cc(Cl)cnc12
Solvent: CCCCN
Product: CCCCNc1ccc2cc(Cl)cnc2c1C#N
Yield: 150.5 %

Procedure:
44.5 g of 3,7-dichloro-8-cyanoquinoline in 200 g of n-butylamine were heated at 80° C. for 14 hours, the solution was poured onto ice water and extracted with twice 100 ml of methylene chloride, the combined extracts were dried with Na2SO4 and evaporated down, the oily residue was treated with ether, and the precipitated solid was filtered off under suction. 39 g of 7-n-butylamino-3-chloro-8-cyanoquinoline of melting point 89° C. were obtained. Yield: 75% of theory.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH:13]=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].Cl.[O:16]([NH2:18])[CH3:17].B.Cl>CO.N1C=CC=CC=1>[CH3:17][O:16][NH:18][CH2:13][CH2:12][CH2:11][C:8]1[CH:7]=[CH:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:10][CH:9]=1
Reactant: CON
Reactant: CC(=O)Nc1ccc(CCC=O)cc1
Agent: B
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: CONCCCc1ccc(NC(C)=O)cc1
Temperature: 70 °C

Procedure:
A mixture of 3-(4-acetamidophenyl)propanal (96 mg, 0.50 mmol), methoxylamine hydrochloride (92 mg, 1.1 mmol), and pyridine (110 μL) in methanol (0.7 mL) is heated in a 70° C. oil bath for 18 hours and then allowed to cool to room temperature. Methanol (1 mL) is added and the mixture is cooled to 0° C. in an ice-water bath. Borane.pyridine complex (0.11 mL, 1.1 mmol) is added, followed by the dropwise addition of 10% aqueous hydrochloric acid. The mixture is allowed to warm to room temperature and then concentrated under reduced pressure. The residue is purified by reverse-phase HPLC to give N-[4-(3-methoxyamino-propyl)-phenyl]-acetamide.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1C=CN=C1.[I:25]I.[CH2:27]([O:34][C:35]1[C:36](=[O:44])[O:37][CH:38]([CH2:41][CH2:42]O)[C:39]=1[OH:40])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CC#N.CCOCC>[CH2:27]([O:34][C:35]1[C:36](=[O:44])[O:37][CH:38]([CH2:41][CH2:42][I:25])[C:39]=1[OH:40])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: II
Reactant: O=C1OC(CCO)C(O)=C1OCc1ccccc1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CC#N
Product: O=C1OC(CCI)C(O)=C1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
To an oven dried 250 mL round bottom flask flushed with argon was added 5.8 g (22 mmol) of PPh3, 1.5 g (22 mmol) of imidazole and 80 mL of ether/CH3CN (3/1). The mixture was cooled in an ice water bath with magnetic stirring and 5.6 g (22 mmol) of iodine was added in 4 equal portions with vigorous stirring. The resulting slurry was warmed at room temperature for 20 minutes, cooled to 0° C., and 5.0 g (20 mmol) of 3-benzyloxy-4-hydroxy-5-(2-hydroxyethyl)-2(5H)-furanone dissolved in 20 mL of CH3CN/ether (1/1) was added in one portion and the remainder was rinsed in with 5 mL of ether. The mixture was stirred at 0° C. for 10 minutes, then at room temperature for 30 minutes and quenched by pouring into 150 mL of 10% HCl solution and extracting with 500 mL of ether/hexanes (1/1). The aqueous layer was separated and extracted with 100 mL of ether. The combined organic fractions were washed with 50 mL of H2O and extracted with 5×50 mL of saturated NaHCO3 solution. The combined bicarbonate extracts were washed with 50 mL of ether/hexanes (1/1), acidified to pH below 2 with 10% HCl solution and extracted with 3×200 mL of ether. The combined ether extracts were washed with 100 mL of brine, dried (MgSO4) and concentrated to give 6.7 g, (93% yield) of 3-benzyloxy-4-hydroxy-5-(2-iodoethyl)-2(5H)-furanone as a white solid, which was not further purified: mp 100-104° C., 1H NMR (CDCl3) δ 7.40-7.27 (m, 5H), 5.06, (dd, J=11.4 Hz, 2H), 4.69 (dd, J=3.4, 8.0 Hz, 1H), 3.06 (t, J=7.3 Hz, 2H), 2.41-2.29 (m, 1H), 2.02-1.90 (m, 1H); 13C NMR (CDCl3) δ 170.33, 160.61, 136.32, 128.77, 128.69, 128.58, 120.11, 75.76, 73.39, 35.77, -2.03; Anal Calcd for C13H13O4I: C, 43.35; H, 3.64. Found: C, 43.94; H, 3.69.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:6]=[CH:7][CH:8]=1.C(N(CC)C(C)C)(C)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[CH3:26][S:27]([O:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH:9][C:10]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:16])[CH:4]=1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)Nc1cccc(CO)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1cccc(COS(C)(=O)=O)c1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
A solution of tert-butyl [3-(hydroxymethyl)phenyl]carbamate (0.6 g, 2.7 mmol) [J. Med. Chem. 1989, 32, 807-826] in dichloromethane (8.4 mL) at −10° C. was treated with N,N-diisopropylethylamine (0.7 mL, 4.0 mmol) followed by methanesulfonyl chloride (0.31 mL, 4.0 mmol and stirred at −10° C. for 1 h. The reaction mixture was quenched with water (50 mL) and extracted with dichloromethane (100 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and evaporated to give the desired product as a crude yellow oil that was used without further purification. LCMS for C13H19NO5SNa (M+Na)+: m/z=323.9.
Reaction SMILES: [Mg].II.[F:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7]Cl.CN(C)[C:15]([CH:17]1[CH2:19][CH2:18]1)=[O:16]>O1CCCC1.COC(C)(C)C>[F:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7][C:15]([CH:17]1[CH2:19][CH2:18]1)=[O:16]
Reactant: CN(C)C(=O)C1CC1
Reactant: Fc1ccccc1CCl
Agent: II
Agent: [Mg]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: O=C(Cc1ccccc1F)C1CC1

Procedure:
A 1000 ml round-bottomed flask is filled with magnesium (10.7 g, 0.44 mol). Iodine (0.2 g) is sublimated to the magnesium, then tert-butyl methyl ether (240 ml) is added and under boiling, a solution of 2-fluorobenzyl chloride (47.8 ml, 0.4 mol) and tert-butyl methyl ether (80 ml) is added to the reaction mixture. The mixture is refluxed for 2 hours and at this temperature a solution of cyclopropanecarboxylic acid dimethylamide (36.2 g, 0.32 mol), prepared according to example 1, and tetrahydrofuran (200 ml) are added. The reaction mixture is stirred for half an hour and under cooling aqueous hydrogen chloride (160 ml, 1:1) is added dropwise to the mixture. The organic layer is dried and the residue is fractionated in vacuo.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]2[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=2[C:33](O)=[O:34])=[CH:26][CH:25]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(Cl)Cl.C(N(C(C)C)C(C)C)C>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:33](=[O:34])[C:32]2[CH:36]=[CH:37][CH:38]=[CH:39][C:31]=2[NH:30][C:27]2[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=2)=[CH:20][CH:21]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(O)c1ccccc1Nc1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2nccc(Oc3ccc(NC(=O)c4ccccc4Nc4ccc(F)cc4)cc3)c2cc1OC
Temperature: 25 °C

Procedure:
4-(6,7-Dimethoxyquinolin-4-yloxy)benzenamine (60 mg, 202 μmol), 2-(4-fluorophenylamino)benzoic acid (56 mg, 243 μmol), and HATU (108 mg, 283 μmol) were combined in a resealable tube. DCM (1012 μl, 202 μmol) and N-ethyl-N-isopropylpropan-2-amine (71 μl, 405 μmol) were added, and the reaction mixture in the tube was allowed to stir at RT. Upon completion (as judged by LCMS), the reaction mixture was concentrated in vacuo, dissolved in minimal DMSO and purified by preparative HPLC {15-85% (0.1% TFA in CH3CN) in H2O over 20 min}. Fractions containing pure product were combined and neutralized with saturated aqueous NaHCO3 then extracted with EtOAc, dried over MgSO4, filtered, and concentrated in vacuo to afford pure N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-2-(4-fluorophenylamino)benzamide as a off-white solid. MS Calcd for C30H24FN3O4: [M]+=509. Found: [M+H]+=510.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:29])[NH:6][C@@H:7]1[CH2:28][C:10]2[N:11]([CH2:20][C:21]3[C:26](Cl)=[N:25][CH:24]=[CH:23][N:22]=3)[C:12]3[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][C:17]=3[C:9]=2[CH2:8]1)([CH3:3])[CH3:2].C[N:31]1C(=O)CCC1>>[CH:1]([O:4][C:5](=[O:29])[NH:6][C@@H:7]1[CH2:28][C:10]2[N:11]([CH2:20][C:21]3[C:26]([NH2:31])=[N:25][CH:24]=[CH:23][N:22]=3)[C:12]3[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][C:17]=3[C:9]=2[CH2:8]1)([CH3:3])[CH3:2]
Reactant: CN1CCCC1=O
Reactant: CC(C)OC(=O)N[C@H]1Cc2c(n(Cc3nccnc3Cl)c3ccc(C#N)cc23)C1
Product: CC(C)OC(=O)N[C@H]1Cc2c(n(Cc3nccnc3N)c3ccc(C#N)cc23)C1
Temperature: 0 °C
Yield: 18 %

Procedure:
Dissolve (S)-[4-(3-chloro-pyrazin-2-ylmethyl)-7-cyano-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl]-carbamic acid isopropyl ester (8.89 g, 21.7 mmol) in NMP (36 mL) and distribute the mixture evenly between three 10-20 mL microwave reactor vials. Cool each reaction vessel to 0° C. and sparge with anhydrous NH3 for 15 min. Seal each vessel and heat to 200° C. for 1 h in a microwave reactor. Combine the reaction mixtures together in water (500 mL) and sonicate for 20 min. Filter off a tan solid, then dissolve the solid in EtOAc (500 mL). Dry the organics (MgSO4), filter, and concentrate to a volume of 10 mL. Dilute the organics with MeOH (20 mL) and CH2Cl2 (10 mL) and absorb onto silica gel in vacuo. Purify on silica gel (340 g) using 1-10% (2 M NH3/MeOH)/(1:1 CH2Cl2/hexanes) to afford 1.50 g (18%) of the title compound as a yellow solid. MS (m/z) 391 (M+1), 389 (M−1). Pool and concentrate fractions containing impure product (1.2 g), and re-purify on silica gel (80 g) using 3-8% (2 M NH3/MeOH)/(1:1 CH2Cl2/hexanes) to afford a second crop (503 mg, 6%) of the title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.[CH:17]1([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:32]2[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>C(Cl)Cl>[CH:17]1([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:32]2[CH:40]=[CH:39][C:35]([C:36]([O:8][C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[O:37])=[CH:34][CH:33]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Oc1ccc(Cl)cc1
Reactant: O=C(Cl)c1ccc(NCCCCCCCCC2CCCCC2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Oc1ccc(Cl)cc1)c1ccc(NCCCCCCCCC2CCCCC2)cc1

Procedure:
To a solution of 6.4 g. 4-chlorophenol and 7.6 g. triethylamine in 500 ml. methylene chloride is added 10.4 g. 4-(8-cyclohexyloctylamino)benzoyl chloride hydrochloride in 250 ml. methylene chloride. After four hours at reflux, the solution is cooled, washed with water and dilute phosphoric acid, and dried. After passing the solution through a column of alumina, the solvent is evaporated an the residue is crystallized from diisopropyl ether.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH2:12][CH3:13])[C:6]=1[C:14](=O)[C:15]([N:17]([CH3:24])[N:18]=[C:19]([CH3:23])[CH2:20][S:21][CH3:22])=[O:16])[CH3:4].O>O1CCCC1>[CH2:3]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH2:12][CH3:13])[C:6]=1[C:14]1[C:15](=[O:16])[N:17]([CH3:24])[N:18]=[C:19]([CH3:23])[C:20]=1[S:21][CH3:22])[CH3:4]
Reactant: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N=C(C)CSC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCc1cc(C)cc(CC)c1-c1c(SC)c(C)nn(C)c1=O
Yield: 40.6 %

Procedure:
To a 200 ml volume four-necked flask, tetrahydrofuran (anhydrous) (27.0 ml) and sodium hydride (1.90 g) were added under a nitrogen atmosphere at about 0° C., and stirred. Then, 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methyl-2-(1-methylsulfanyl-2-propylidene)hydrazine ((4-4)-(1)-39) (14.2 g) dissolved in tetrahydrofuran (anhydrous) (45 ml) was added dropwise over 30 minutes, and then the mixture was stirred at 0° C. for 2 hours. Then, to the mixture was added water (100 ml) at room temperature, and extracted with tert-butyl methyl ether. The organic layer was concentrated under reduced pressure. The residue was subjected to column chromatography (hexane: ethyl acetate=4:1) to give 5.45 g of 4-(2,6-diethyl-4-methylphenyl)-2,6-dimethyl-5-methylsulfanyl-2,3-dihydro-3-pyridazinone.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[C:30]([O:35][CH2:36][CH2:37][N:38]3[C:42]4=[CH:43][CH:44]=[CH:45][CH2:46][CH:41]4[NH:40][CH2:39]3)=[CH:31][CH:32]=[C:33]([CH3:34])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[C:30]([O:35][CH2:36][CH2:37][N:38]3[C:42]4=[CH:43][CH:44]=[CH:45][CH2:46][CH:41]4[NH:40][CH2:39]3)=[CH:31][CH:32]=[C:33]([CH3:34])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(C)ccc(OCCN3CNC4CC=CC=C43)c2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2c(C)ccc(OCCN3CNC4CC=CC=C43)c2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1 from tert.-butyl 4'-[[2-n-butyl-7-[2-(tetrahydrobenzimidazol-1-yl)-ethoxy]-4-methyl-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=2)[CH:9]=[O:10])=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].[CH3:20][C:21]([CH3:23])=[O:22]>>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([CH:9]([OH:10])[CH2:20][C:21](=[O:22])[CH3:23])[CH:11]=[CH:12][CH:13]=2)=[CH:2]1
Reactant: O=Cc1cccc(-c2ccsc2)c1
Reactant: CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(=O)CC(O)c1cccc(-c2ccsc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
300 mg of 3-(3-thienyl)benzaldehyde was dissolved in 3 ml of acetone, and 441 mg of potassium carbonate was added. The mixture was stirred overnight at s room temperature, and then the solvent was evaporated. The residue was worked up in a customary manner, and purified by medium-pressure liquid chromatography [hexane/ethyl acetate =3/1]to give 1-[3-(3-thienyl)phenyl]-3-oxo-1-butanol as a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].C(N(CC)CC)C.[C:16](OC(=O)C)(=[O:18])[CH3:17]>CO>[C:16]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8])(=[O:18])[CH3:17]
Reactant: NCCCCCCO
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(=O)NCCCCCCO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 6-amino-1-hexanol (0.650 g, 6.31 mmol) in methanol (15 mL) is cooled to 0° C. and treated with triethylamine (1.62 mL, 11.6 mmol) followed by acetic anhydride (0.891 mL, 9.45 mmol). The reaction mixture is stirred at room temperature overnight. Additional triethylamine (1.6 mL, 11.6 mmol) and acetic anhydride (0.9 mL, 9.5 mmol) is added at room temperature and the solution is stirred 16 h further. Concentration in vacuo and flash chromatography affords 6-acetamido-1-hexanol. To a solution of 6-acetamido-1-hexanol (22.2 mmol) in dry dichloromethane (50 mL) is added 2,6-di-tert-butyl-4-methylpyridine (4.6 g, 22.2 mmol) and triflic anhydride (3.7 mL, 22.2 mmol) at 0° C. The reaction is stirred at room temperature for 20 min, poured into water, and extracted with dichloromethane. The combined extracts are dried over anhydrous sodium sulfate and concentrated in vacuo and to afford 6-acetamido-1-hexyl triflate (25) which is used without further purification.
Reaction SMILES: [CH2:1]([C:5]1([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]#[N:24])[CH:6]1[OH:25])[CH2:2][CH2:3][CH3:4].[OH-:30].[Na+].OO>C(O)C.C(OCC)(=O)C>[CH2:1]([C:5]1([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23](=[O:30])[NH2:24])[CH:6]1[OH:25])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1(CCCC)CCc2c(OCc3ccccc3C#N)cccc2C1O
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCCC1(CCCC)CCc2c(OCc3ccccc3C(N)=O)cccc2C1O
Temperature: 50 °C
Reaction time: 5 h

Procedure:
To a solution of 2,2-dibutyl-5-(2-cyanobenzyloxy)-1,2,3,4-tetrahydro-1-naphthol (500 mg) in a mixture of ethanol (3.5 ml) and aqueous 6N-sodium hydroxide solution (0.275 ml) was added aqueous 30% hydrogen peroxide (2.62 ml) in one portion at ambient temperature. The mixture was stirred for 5 hours at 50° C. and allowed to stand overnight at ambient temperature. The reaction mixture was diluted with ethyl acetate (40 ml). The separated organic layer was washed with aqueous hydrochloric acid, aqueous sodium bicarbonate solution, and brine, and then dried, and evaporated under reduced pressure. The residue was crystallized from aqueous ethanol to yield 2,2-dibutyl-5-(2-carbamoylbenzyloxy)-1,2,3,4-tetrahydro-1-naphthol (425 mg).
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:18]1[CH2:22]OC[CH2:19]1>>[C:10]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([CH2:22][CH:18]=[CH2:19])[C:8]#[N:9])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: N#CC(c1ccccc1)c1ccccc1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: C=CCC(C#N)(c1ccccc1)c1ccccc1

Procedure:
A solution of 2,2-diphenylacetonitrile (9.15 g) in THF (22.5 ml) was added dropwise to a stirred slurry of 80% sodium hydride (2.85 g, washed twice with hexane) and THF, under nitrogen. The mixture was stirred vigorously until the evolution of gas ceased. Allyl bromide (6.3 g) was added by syringe, and the resultant mixture was stirred at room temperature for 18 hours. The mixture was carefully poured into ice water, and the aqueous mixture was extracted with ethyl acetate (3×). The combined extracts were washed with water and brine (once each), dried (MgSO4), and rotary evaporated to yield 11.1 g of 2,2-diphenyl-4-pentenenitrile, as an oily product.
Reaction SMILES: C(OC([NH:8][C:9]([NH:27]C(OC(C)(C)C)=O)=[N:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:12]=1)=O)(C)(C)C.[ClH:35]>ClCCl.O1CCOCC1>[ClH:35].[ClH:35].[F:25][C:23]([F:24])([F:26])[C:22]1[C:17]([C:13]2[CH:12]=[C:11]([NH:10][C:9]([NH2:27])=[NH:8])[CH:16]=[CH:15][CH:14]=2)=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)NC(=Nc1cccc(-c2ncccc2C(F)(F)F)c1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: N=C(N)Nc1cccc(-c2ncccc2C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of N,N′-bis(tert-butoxycarbonyl)-N″-(3-(3-trifluoromethylpyridin-2-yl)phenyl)guanidine (200 mg) in dichloromethane (2 ml) was added 4N hydrogen chloride in 1,4-dioxane (4 ml), and the mixture was stirred at room temperature for 18 hours. The solvent was evaporated under reduced pressure. To the residue was added 5% ethanol in ethyl acetate (100 ml), and the precipitate was collected by filtration and dried under reduced pressure to give 3-(3-trifluoromethylpyridin-2-yl) phenylguanidine dihydrochloride (111 mg).