Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:27]=[CH:26][C:18]([C:19]([O:21]C(C)(C)C)=[O:20])=[C:17]([NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=3)[CH:16]=2)[CH:12]=[CH:13][CH:14]=1>>[Cl:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:27]=[CH:26][C:18]([C:19]([OH:21])=[O:20])=[C:17]([NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=3)[CH:16]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2cccc(Cl)c2)cc1Nc1cccc(O)c1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(-c2cccc(Cl)c2)cc1Nc1cccc(O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Trifluoroacetic acid 5.0 mL was added to the obtained tert-butyl 4-(3-chlorophenyl)-2-((3-hydroxyphenyl)amino)benzoate, and it was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure, and the obtained residue was refined by reversed-phase silica gel column chromatography [eluent; 80-100% acetonitrile/0.1% trifluoroacetic acid aqueous solution] to give 4-(3-chlorophenyl)-2-((3-hydroxyphenyl)amino)benzoic acid 22 mg of a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](=[O:15])[CH2:13][CH3:14].[C:16](Cl)(=[O:18])[CH3:17]>>[C:16]([NH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](=[O:15])[CH2:13][CH3:14])(=[O:18])[CH3:17]
Reactant: CC(=O)Cl
Reactant: CCC(=O)c1[nH]c2cc(Cl)ccc2c1N
Product: CCC(=O)c1[nH]c2cc(Cl)ccc2c1NC(C)=O

Procedure:
The title compound was prepared according to the procedure described in Example 19 employing 3-amino-6-chloro-2-propionylindole (Example 87) and acetyl chloride. m.p.: >270° C. 1H-NMR (DMSO-d6) δ: 11.72 (1H, br s), 9.93 (1H, br s), 7.59 (1H, d, J=8.4 Hz), 7.43 (1H, s), 7.07 (1H, d, J=8.4 Hz), 2.94 (2H, q, J=7.0 Hz), 2.15 (3H, s), 1.09 (3H, t, J=7.0 Hz)
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3]1.[CH2:8](Br)[CH2:9][CH2:10][CH3:11]>>[CH2:8]([N:4]1[CH2:5][CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3]1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCBr
Reactant: CC1CCCNC1
Product: CCCCN1CCCC(C)C1

Procedure:
The first N-substitution of 3-methylpiperidine was carried out using butyl bromide as an N-alkylating agent to form 1-butyl-3-methylpiperidine. An equimolar amount of butyl bromide was added dropwise to a solution of 3-methylpiperidine in methanol keeping the temperature at 20° C. by an ice-water bath. The mixture was hydrolyzed with potassium carbonate, extracted with ether, and dried over Na2SO4. The solution was fractionally distilled at reduced pressure and the fraction with bp 195° C. was collected. 1H-NMR (300 MHz, CDCl3) δ 0.82 (d, 3H), 0.90 (t, 3H), 1.30 (m, 2H), 1.48 (m, 2H), 1.65 (m, 5H), 2.24 (m, 2H), 2.82 (m, 4H).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[C:5]([Cl:10])=[CH:4][C:3]=1[S:11]([N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])(=[O:13])=[O:12].O.O.O.O.O.O.O.O.O.[S-2:28].[Na+].[Na+]>CO>[Cl:8][C:7]1[C:2]([SH:28])=[C:3]([S:11]([N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])(=[O:13])=[O:12])[CH:4]=[C:5]([Cl:10])[C:6]=1[Cl:9]
Reactant: [S-2]
Reactant: CCN(CC)S(=O)(=O)c1cc(Cl)c(Cl)c(Cl)c1Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCN(CC)S(=O)(=O)c1cc(Cl)c(Cl)c(Cl)c1S

Procedure:
To a mixture of 50 grams (0.15 mole) of 2,3,4,5-tetrachloro-N,N-diethylbenzenesulfonamide in 400 milliliters of methanol at reflux was added over a period of 1/2 hour, a solution of 100 grams (0.42 mole) of sodium sulfide-nonahydrate (Na2S-9H2O) in 400 milliliters of methanol. After the addition was complete, the mixture was refluxed for 3 hours. At the completion of this reaction, the mixture was allowed to cool and the sodium chloride which precipitated, was removed by filtration. The filtrate was diluted with 1 liter of water and the water insoluble materials were removed by filtration. The filtrate was thereafter acidified with concentrated hydrochloric acid and the crude product, a pale yellow solid precipitated out. The product was recovered by filtration, dried and recrystallized from hexane. The 3,4,5-trichloro-N,N-diethyl-2-(mercapto)benzenesulfonamide product was recovered in a yield of 46.0 grams (100 percent of theoretical) and melted at 96°-99° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][C:15]([O:18]C)=[C:14]([F:20])[CH:13]=2)=[C:5]([O:21]C)[CH:4]=1)[CH3:2].B(Br)(Br)Br>ClCCl>[CH2:1]([C:3]1[CH:4]=[C:5]([OH:21])[C:6]2[CH:7]=[CH:8][N:9]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([F:20])[CH:13]=3)[C:10]=2[CH:11]=1)[CH3:2]
Reactant: CCc1cc(OC)c2ccn(-c3ccc(OC)c(F)c3)c2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCc1cc(O)c2ccn(-c3ccc(O)c(F)c3)c2c1
Temperature: 0 °C
Yield: 4.9 %

Procedure:
To a solution of 6-ethyl-1-[3-fluoro-4-(methyloxy)phenyl]-4-(methyloxy)-1H-indole (D10) (180 mg, 0.60 mmol) in dichloromethane (6 mL) at −78° C. was added boron tribromide (1 M solution in dichloromethane, 2.5 mL, 2.5 mmol). The reaction mixture was allowed to warm to 0° C. and then quenched by the addition of water and dichloromethane. The solution was neutralised by the addition of dilute sodium hydrogen carbonate solution. The organic phase was separated and then the aqueous phase re-extracted with ethyl acetate. The combined organic phases were dried over magnesium sulphate, filtered and concentrated at reduced pressure. The product was purified by MDAP to yield the title compound (E6), (8 mg).
Reaction SMILES: [C:1]([NH:9][CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([N:17]2[C:26]3[CH:25]=[CH:24][CH:23]=[C:22]([C:27](O)=[O:28])[C:21]=3[C:20]3=[N:30][O:31][C:32]([CH3:33])=[C:19]3[C:18]2=[O:34])[CH2:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:39][NH2:40]>C1(C)C=CC=CC=1.CN(C1C=CN=CC=1)C.ClCCl>[CH3:39][NH:40][C:27]([C:22]1[C:21]2[C:20]3[C:19](=[C:32]([CH3:33])[O:31][N:30]=3)[C:18](=[O:34])[N:17]([CH:13]3[CH2:14][CH2:15][CH2:16][CH:11]([CH2:10][NH:9][C:1](=[O:8])[C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH2:12]3)[C:26]=2[CH:25]=[CH:24][CH:23]=1)=[O:28]
Reactant: CN
Reactant: Cc1onc2c1c(=O)n(C1CCCC(CNC(=O)c3ccccc3)C1)c1cccc(C(=O)O)c21
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CNC(=O)c1cccc2c1c1noc(C)c1c(=O)n2C1CCCC(CNC(=O)c2ccccc2)C1
Reaction time: 8 h
Yield: 55.8 %

Procedure:
To a solution of Example 598 (0.05 g, 0.11 mmol) in toluene (1.5 ml) under N2 was added thionyl chloride (0.5 ml) and heated at reflux for 3 h. The solution was concentrated using toluene to azeotrope. The residue was dissolved in dichloromethane (2 ml) under N2 and added methylamine (0.55 ml, 1.1 mmol) and DMAP (0.025 g, 0.22 mmol). The reaction was stirred overnight, diluted with dichloromethane, washed (0.1 N HCl, H2O, and brine), dried (MgSO4), filtered, and concentrated. Column chromatography (silica gel, acetone/CH2Cl2 gradient) gave the title compound (0.029 g, 56%). MS(ES+) (m/z) 473.2 [M+1].
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[C:15](=O)[C:14]3[C:9](=[C:10]([OH:18])[CH:11]=[CH:12][C:13]=3[OH:17])[C:7](=O)[C:5]=2[CH:6]=1.[BH4-].[Na+].Cl>CO>[C:13]1(=[O:17])[C:14]2[C:9](=[CH:7][C:5]3[C:4]([CH:15]=2)=[CH:3][CH:2]=[CH:1][CH:6]=3)[C:10](=[O:18])[CH:11]=[CH:12]1
Reactant: O=C1c2ccccc2C(=O)c2c(O)ccc(O)c21
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C1C=CC(=O)c2cc3ccccc3cc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 67.5 %

Procedure:
To a solution of quinizarin (10.00 g, 42.0 mmol, 1 molar equivalent) in methanol (200 mL) cooled to −0° C. was added sodium borohydride (6.38 g, 169.0 mmol, 4 molar equivalent). The resulting mixture was stirred at −0° C. for 2 h. A solution of 5M hydrochloric acid (150 mL) was then added dropwise to the reaction mixture at −0° C. The precipitated orange solid was filtered, washed twice with water, and dried under vacuum. Purification by column chromatography on silica gel (eluent: dichloromethane) gave the title compound as yellow needles (5.9 g, 68%). 1H NMR (300.13 MHz, CDCl3) (ppm) 7.08 (s, 2H) 7.68-7.72 (m, 2H) 8.05-8.10 (m, 2H) 8.63 (s, 2H).
Reaction SMILES: O[C:2]1[C:7](CC=C(C)C)=[C:6]([O:13][CH3:14])[CH:5]=[CH:4][C:3]=1[C:15](=[O:17])C>C(O)C>[CH:15](=[O:17])[C:3]1[CH:2]=[CH:7][C:6]([O:13][CH3:14])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(C)=O)c(O)c1CC=C(C)C
Solvent: CCO
Product: COc1ccc(C=O)cc1

Procedure:
In 5 ml of ethanol were dissolved 0.4 g of the 2'-hydroxy-4'-methoxy-3'-(3-methyl-2-butenyl)acetophenone obtained in Production Example 2 and 0.3 ml of p-anisaldehyde, and the solution was cooled to 0° C. and 7.5 ml of a saturated solution of potassium hydroxide in ethanol was added to the solution. In a nitrogen current, the mixture was stirred at 0° C. for 30 minutes and at room temperature for 4 days. After the reaction, hydrochloric acid was added to the reaction liquid under cooling and the reaction liquid was gradually made acidic, and the formed precipitate was recovered by filtration and recrystallized from methanol to obtain 0.4 g (yield=64.7%) of 2'-hydroxy-4,4'-dimethoxy3'-(3-methyl-2-butenyl)chalcone in the form of a yellow needle.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16]([C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])[C:28]=1[OH:29])[C:23](Cl)=[O:24])([CH3:19])([CH3:18])[CH3:17]>>[C:30]([C:27]1[CH:26]=[C:22]([CH:21]=[C:20]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:28]=1[OH:29])[C:23]([C:11]1[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[O:8][C:7]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:24])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1O
Reactant: c1ccc(-c2cc3ccccc3o2)cc1
Product: CC(C)(C)c1cc(C(=O)c2c(-c3ccccc3)oc3ccccc23)cc(C(C)(C)C)c1O

Procedure:
Acylation of 2-phenylbenzofuran with 3,5-di-t-butyl-4-hydroxybenzoyl chloride as described above gives 3-(3,5-di-t-butyl-4-hydroxybenzoyl)-2-phenylbenzofuran which, upon reaction with 3-diethylaminopropyl chloride and potassium hydroxide in ethanol according to procedures described above, gives the title compound.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.[OH-].[Na+]>C1COCC1.[Pd].C(OCC)(=O)C>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH:4]=[CH:5][NH:6]3)=[CH:15][CH:14]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Brc1cccc2[nH]ccc12
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(-c2cccc3[nH]ccc23)cc1
Temperature: 70 °C
Reaction time: 16 h
Yield: 82.9 %

Procedure:
To a mixture of 4-bromoindole (1.96 g, 10 mmol), and 4-methoxyphenylboronic acid (1.52 g, 10 mmol) in THF (34 mL)) were added Palladium catalyst Pd(PPh3)4 (347 mg, 0.3 mmol) and the freshly prepared sodium hydroxide solution (1.20 g, 30 mmol in 14 mL water). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen at 70° C. oil bath for 16 hours. TLC showed the completion of the coupling reaction. The mixture was cooled to room temperature, diluted with ethyl acetate, and separated from water layer. The ethyl acetate solution was washed by brine, dried over Na2SO4, and concentrated. The crude product was purified by a silica gel column eluting with hexanes—EtOAc (9:1) to provide 1.85 g (83%) of the product 4-(4-Methoxy-phenyl)-1H-indole as a white solid.
Reaction SMILES: [ClH:1].Cl.[NH2:3][CH2:4][C:5]1[O:9][C:8]([C:10]([O:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:23](=[NH:25])[NH2:24])[CH:19]=3)[CH:14]=2)=[O:11])=[CH:7][CH:6]=1.[C@H:26]1([C:35](O)=[O:36])[CH2:31][CH2:30][C@@H:29]([C:32]([OH:34])=[O:33])[CH2:28][CH2:27]1>>[ClH:1].[C:32]([C@@H:29]1[CH2:30][CH2:31][C@H:26]([C:35]([NH:3][CH2:4][C:5]2[O:9][C:8]([C:10]([O:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[C:18]([C:23](=[NH:24])[NH2:25])[CH:19]=4)[CH:14]=3)=[O:11])=[CH:7][CH:6]=2)=[O:36])[CH2:27][CH2:28]1)([OH:34])=[O:33]
Reactant: N=C(N)c1ccc2cc(OC(=O)c3ccc(CN)o3)ccc2c1
Reactant: O=C(O)[C@H]1CC[C@@H](C(=O)O)CC1
Agent: Cl
Product: N=C(N)c1ccc2cc(OC(=O)c3ccc(CNC(=O)[C@H]4CC[C@@H](C(=O)O)CC4)o3)ccc2c1

Procedure:
The same procedures as in Example 3 were followed except for using 11.5 g of 6-amidino-2-naphthyl 5-aminomethylfuran-2-carboxylate dihydrochloride and 15.5 g of cis-1,4-cyclohexanedicarboxylic acid, to obtain 5.0 g of the above-mentioned compound in crude form. The crude compound was dissolved in 100 ml of aqueous 90% methanol, 2% aqueous sodium hydrogencarbonate solution was added thereto, and the precipitated carbonate was collected by filtration and washed with water. The washed product was made into solution by addition of 10 ml of DMF and 0.5 ml of hydrochloric acid, and the solution was added dropwise to 150 ml of acetone while stirring and cooling with ice. The white solid thus precipitated was collected by filtration to obtain 1.3 g of the intended product.
Reaction SMILES: [ClH:1].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH:10]2[CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]3[O:23][CH2:24][O:25][C:19]=3[CH:18]=2)=[CH:5][CH:4]=1.Br[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].C([O-])([O-])=O.[K+].[K+]>C(O)C>[ClH:1].[CH2:24]1[O:23][C:20]2[CH:21]=[CH:22][C:17]([O:16][CH2:15][C@H:10]3[C@H:9]([C:6]4[CH:7]=[CH:8][C:3]([O:2][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:4][CH:5]=4)[CH2:14][CH2:13][N:12]([CH2:5][CH2:4][CH2:3][CH2:8][CH3:7])[CH2:11]3)=[CH:18][C:19]=2[O:25]1
Reactant: CCCCCBr
Reactant: Oc1ccc(C2CCNCC2COc2ccc3c(c2)OCO3)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCCCCOc1ccc([C@@H]2CCN(CCCCC)C[C@H]2COc2ccc3c(c2)OCO3)cc1

Procedure:
(+-)-trans-3-(3,4-methylenedioxyphenoxymethyl)-1-pentyl-4-(4-pentyloxyphenyl)piperidine hydrochloride was prepared by refluxing 4-(4-hydroxyphenyl)-3-(3,4-methylenedioxyphenoxymethyl)piperidine hydrochloride (0.35 g) with 1-bromopentane (1.8 ml) and K2CO3 (1 g) in abs. ethanol (25 ml) for 2 h. The rinse-up procedure described in example 1 gave the title compound. M.p. 148.2° C.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH2:8]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C@H:24]([CH2:36][OH:37])[CH2:25][CH2:26][N:27]2[CH2:34][CH2:33][C:30]3([CH2:32][CH2:31]3)[C@H:29]([OH:35])[CH2:28]2)[C:20](=[O:38])[C@@H:19]1[CH3:39])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.N1C=CC=CC=1.C(NCC)C>>[CH2:8]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C@H:24]([CH2:36][O:37][C:1](=[O:3])[CH3:2])[CH2:25][CH2:26][N:27]2[CH2:34][CH2:33][C:30]3([CH2:32][CH2:31]3)[C@H:29]([OH:35])[CH2:28]2)[C:20](=[O:38])[C@@H:19]1[CH3:39])=[O:17])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(=O)OC(C)=O
Reactant: C[C@H]1C(=O)N([C@H](CO)CCN2CCC3(CC3)[C@H](O)C2)CCN1C(=O)OCc1ccccc1
Solvent: CCNCC
Solvent: c1ccncc1
Product: CC(=O)OC[C@H](CCN1CCC2(CC2)[C@H](O)C1)N1CCN(C(=O)OCc2ccccc2)[C@@H](C)C1=O
Yield: 71.5 %

Procedure:
Acetic anhydride (42 mg, 0.41 mmol) was added at 0° C. to a solution of (S)-4-[(S)-3-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-1-hydroxymethyl-propyl]-2-methyl-3-oxo-piperazine-1-carboxylic acid benzyl ester (intermediate 39; 182 mg, 0.41 mmol) and pyridine (32 mg, 0.41 mmol). The ice bath was removed, then after 16 h excess reagent was destroyed by addition of diethylamine (15 mg, 0.21 mmol). After evaporation of volatile material, chromatography (SiO2; dichloromethane to dichloromethane/methanol/25% aq. ammonia solution 90:10:0.25) produced the title compound (143 mg, 72%). Colorless gum, MS (ISP)=488.4 (M+H)+.
Reaction SMILES: Cl.[NH:2]([C:6]1[S:7][C:8]([C:12]([O:14]CC)=[O:13])=[C:9]([CH3:11])[N:10]=1)[C:3]([NH2:5])=[NH:4]>C(O)C.[OH-].[Na+]>[NH:2]([C:6]1[S:7][C:8]([C:12]([OH:14])=[O:13])=[C:9]([CH3:11])[N:10]=1)[C:3]([NH2:5])=[NH:4]
Reactant: CCOC(=O)c1sc(NC(=N)N)nc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc(NC(=N)N)sc1C(=O)O
Yield: 90.8 %

Procedure:
2.65 g of ethyl 2-guanidino-4-methyl-thiazole-5-carboxylate hydrochloride (prepared according to Example 3) are heated to 75° C. for 7 hrs. in 70 ml of ethanol and 11 ml of 2N NaOH. The reaction mixture is evaporated to dryness in a vacuum. The residue is taken up in 40 ml of ethanol, the solution is filtered clear and the product is precipitated with 2 ml of acetic acid. There are obtained 1.82 g of 2-guanidino-4-methyl-thiazole-5-carboxylic acid of m.p. 1 96° C.
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:32]=[CH:31][CH:30]=[CH:29][C:8]=2[C:9]=1[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]#[N:28])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)=[O:11])[CH2:2][CH2:3][CH3:4].[N-:33]=[N+:34]=[N-:35].[Na+].[Cl-].[NH4+]>C(OCC)(=O)C>[CH2:1]([C:5]1[O:6][C:7]2[CH:32]=[CH:31][CH:30]=[CH:29][C:8]=2[C:9]=1[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[NH:35][N:34]=[N:33][N:28]=3)=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)=[O:11])[CH2:2][CH2:3][CH3:4]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCc1oc2ccccc2c1C(=O)Nc1ccc(-c2ccc(OCC#N)cc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCCCc1oc2ccccc2c1C(=O)Nc1ccc(-c2ccc(OCc3nnn[nH]3)cc2)cc1
Reaction time: 5.5 h
Yield: 58.4 %

Procedure:
A mixture of 2-butyl-N-(4′-cyanomethoxy[1,1′-biphenyl]-4-yl)-1-benzofuran-3-carboxamide (400 mg, 0.942 mmol), prepared in the previous step, sodium azide (184 mg, 2.83 mmol) and ammonium chloride (151 mg, 2.83 mmol) was stirred under nitrogen at 100+ C. for 5.5 h. The reaction was diluted with ethyl acetate and extracted with 1 N NaOH. The aqueous layer was separated, extracted one additional time with ethyl acetate and acidified by the addition of 1 N HCl. The solid that formed was collected by filtration and dried under reduced pressure to give the title compound (257 mg, 59%) as a white solid, mp 210-212° C.; MS (APCI) m/z 468 ([M+H]+. Elemental Analysis for C27H25N5O3+0.06 H2O: Calc'd: C, 69.20; H, 5.40; N, 14.94; Found: C, 68.83; H, 5.29; N, 14.98
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([N+:17]([O-:19])=[O:18])[CH:10]=2)=[N:5]1.[C:20]([C:23]1[CH:27]=[C:26]([C:28](O)=[O:29])[NH:25][N:24]=1)(=[O:22])[CH3:21]>>[C:20]([C:23]1[CH:27]=[C:26]([C:28]([NH:1][CH2:2][CH2:3][N:4]2[CH:8]=[CH:7][C:6]([C:9]3[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([N+:17]([O-:19])=[O:18])[CH:10]=3)=[N:5]2)=[O:29])[NH:25][N:24]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)c1cc(C(=O)O)[nH]n1
Reactant: N#Cc1ccc(-c2ccn(CCN)n2)cc1[N+](=O)[O-]
Product: CC(=O)c1cc(C(=O)NCCn2ccc(-c3ccc(C#N)c([N+](=O)[O-])c3)n2)[nH]n1

Procedure:
The title compound was prepared from 4-(1-(2-aminoethyl)-1H-pyrazol-3-yl)-2-nitrobenzonitrile (150 mg) and 3-acetyl-1H-pyrazole-5-carboxylic acid (94 mg) using the method of Example 34(d). Yield 84 mg. 1H-NMR (400 MHz; d6-DMSO): δ 3.30 (s, 3H), 3.71 (q, 2H), 4.39 (t, 2H), 7.05 (d, 1H), 7.27 (br. s, 1H), 7.88 (d, 1H), 8.18 (d, 1H), 8.33 (d, 1H), 8.45-8.75 (m, 1H), 8.66 (d, 1H), 14.16 (s, 1H).
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[CH:6]([N:9]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1)C1C=CC=CC=1)([CH3:8])[CH3:7].C(N(CC)CC)C>C(Cl)Cl>[CH:6]([N:9]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1)[C:3](=[O:4])[CH2:2][Br:1])([CH3:8])[CH3:7]
Reactant: O=C(Br)CBr
Reactant: COc1cccc(N(c2ccccc2)C(C)C)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(N(C(=O)CBr)C(C)C)c1
Reaction time: 8 h

Procedure:
Bromoacetyl bromide (8.76 mL) in methylene chloride (100 mL) is added dropwise to a 0° C. solution of N-Isopropyl-N-(3-methoxy-phenyl) aniline, prepared as in Part A, (16.22 g, 98.3 mmol) in methylene chloride (200 mL) and triethylamine (13.8 mL) and the resultant mixture is allowed to attain RT overnight. The reaction mixture is washed with 1N hydrochloric acid (3×100 mL), water (2×100 mL), brine (100 mL), dried (MgSO4), and concentrated in vacuo to afford N-Isopropyl-N-(3-methoxy-phenyl) bromoacetamide(23.16 g) as a dark mobile oil which is used without further purification: 1H NMR (300 MHz, CDCl3) δ7.38 (t, 1H, J=8.0), 7.01 (dd, 1H, J=8.1, 2.2), 6.81(d, 1H, J=7.6), 6.79 (s, 1H), 4.95 (m, 1H, J=6.8), 3.88 (s, 3H), 3.60 (s, 2H), 1.06 (d, 6H, J=6.8).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:38])[NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH:14]([NH:18][C:19]([C:21]2[C:22]([C:27]3[C:32](Cl)=[CH:31][C:30]([C:34]([F:37])([F:36])[F:35])=[CH:29][N:28]=3)=[N:23][O:24][C:25]=2[CH3:26])=[O:20])[CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+]>CN(C)C=O>[CH2:1]([O:8][C:9](=[O:38])[NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH:14]([N:18]2[C:32]3[C:27](=[N:28][CH:29]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:31]=3)[C:22]3=[N:23][O:24][C:25]([CH3:26])=[C:21]3[C:19]2=[O:20])[CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1onc(-c2ncc(C(F)(F)F)cc2Cl)c1C(=O)NC1CCCC(CNC(=O)OCc2ccccc2)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1onc2c1c(=O)n(C1CCCC(CNC(=O)OCc3ccccc3)C1)c1cc(C(F)(F)F)cnc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 35.7 %

Procedure:
Dissolve (3-{[3-(3-chloro-5-trifluoromethyl-pyridin-2-yl)-5-methyl-isoxazole-4-carbonyl]-amino}-cyclohexylmethyl)-carbamic acid benzyl ester (600 mg, 1.09 mmol) in N,N-dimethylformamide (5 mL) at ambient temperature under a nitrogen atmosphere. Add a solution of potassium bis(trimethylsilyl)amide (0.5 M in toluene, 2.62 mL, 1.31 mmol) and stir for 10 min. at ambient temperature. Quench the dark mixture with water and follow by the adding solid sodium chloride. Extract with ethyl acetate and wash with water and dry over sodium sulfate. Concentrate and elute over silica gel with methanol/dichloromethane to give 200 mg (36%) of the desired product as a light foam. MS(ES): (M+1)+ 515.2, 516.2 m/z.
Reaction SMILES: [C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:8][CH:9]2[CH2:14][CH:13]3[CH2:15][CH2:16][N:10]2[CH2:11][CH2:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:23]1[CH2:28]CCC[CH2:24]1.C([Li])CCC.BrCC=C>CCCCCC>[C:17]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([CH2:28][CH:23]=[CH2:24])[CH2:8][CH:9]2[CH2:14][CH:13]3[CH2:15][CH2:16][N:10]2[CH2:11][CH2:12]3)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: c1ccc(C(CC2CC3CCN2CC3)c2ccccc2)cc1
Reactant: C1CCCCC1
Agent: [Li]CCCC
Solvent: C=CCBr
Solvent: CCCCCC
Product: C=CCC(CC1CC2CCN1CC2)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2.91 parts of 2-(2,2-diphenylethyl)-1-azabicyclo[2.2.2]octane in 40 parts by volume of cyclohexane are added under a nitrogen atmosphere 4.6 parts by volume of a 2.5 M solution of butyl lithium in hexane and 1.5 parts by volume of N,N,N'N'-tetramethylethylenediamine. The mixture is heated to reflux, with stirring, for 12/3 hour and then cooled to room temperature. 1.45 Parts of 3-bromopropene is then added during a 5-second period. Stirring is continued for about 6 minutes during which time the internal temperature reaches a maximum of 43° C. and then subsides. The resulting yellow mixture is washed with seven portions of water and then extracted with dilute hydrochloride acid. The acidic, aqueous extract is washed with ethyl ether and then basefied with aqueous sodium hydroxide resulting in the liberation of an oil. This oil is then extracted with ethyl ether. The ethereal extract is dried over anhydrous sodium sulfate and stripped in vacuo to give a light brown oil. This oil is crystallized from methanol and water to afford as a white solid, 2-(2,2-diphenyl-4-pentenyl)-1-azabicyclo[2.2.2]octane melting at about 95.5°-98° C. This compound is represented by the following structural formula: ##STR7##