Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1([CH2:15][C:16]2([CH3:19])[CH2:18][CH2:17]2)[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4][CH2:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:19][C:16]1([CH2:15][C:2]2([OH:1])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]2)[CH2:17][CH2:18]1
Reactant: CC1(CC2(O)CCN(C(=O)OC(C)(C)C)CC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(CC2(O)CCNCC2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of compound 12C (1 eq.) in DCM, was added TFA (10 eq.), the reaction mixture was stirred at room temperature for about 2 hours, when TLC detected no s.m. The reaction mixture was concentrated to afford the desired product 12D. The crude product was used for the next step directly without further purification. LC-MS: m/z 170.3 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:3]=1[CH2:4][O:5][N:6]=[C:7]([C:13](=[O:15])[CH3:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9].S(Cl)([Cl:24])(=O)=O>C(O)(=O)C>[Cl:24][CH2:14][C:13](=[O:15])[C:7](=[N:6][O:5][CH2:4][C:3]1[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:2]=1[Cl:1])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)C(=NOCc1ccc(Cl)cc1Cl)C(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)C(=NOCc1ccc(Cl)cc1Cl)C(=O)CCl
Yield: 108.4 %

Procedure:
Ethyl 2-(2,4-dichlorobenzyloxyimino)-3-oxobutyrate (syn isomer, 33.7 g.), sulfuryl chloride (15.7 g.) and acetic acid (35 ml) treated in a similar manner to that of Example A - (2) to give ethyl 4-chloro-2-(2,4-dichlorobenzyloxyimino)-3-oxobutyrate (syn isomer, 40.5 g.).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][C:12]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:13][CH:14]=2)[O:9][C:8]=1[C:28]1[CH:33]=[C:32]([O:34]C)[C:31]([O:36]C)=[CH:30][C:29]=1[O:38]C.CO>C(Cl)Cl>[OH:6][C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][C:12]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:13][CH:14]=2)[O:9][C:8]=1[C:28]1[CH:33]=[C:32]([OH:34])[C:31]([OH:36])=[CH:30][C:29]=1[OH:38]
Reactant: CCCCCCCCCCc1ccc2c(=O)c(OC)c(-c3cc(OC)c(OC)cc3OC)oc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: CCCCCCCCCCc1ccc2c(=O)c(O)c(-c3cc(O)c(O)cc3O)oc2c1
Reaction time: 8 h
Yield: 97.8 %

Procedure:
Boron tribromide (1.0 M solution in DCM) (4.0 ml, 4.06 mmol, 5.0 eq) was added slowly to a solution of 69 (392 mg, 0.81 mmol) in dry DCM (3 ml) at 0° C. under argon. The solution was then stirred overnight and then methanol (5 ml) added slowly. The solution was heated under reflux for 30 min. then concentrated under vacuum. Water (20 ml) was added to the residue and the flask placed in a sonic bath for 5 min. The resulting fine precipitate was filtered off and washed with water (10 ml) then freeze dried to give the flavonol as a red/brown amorphous solid (338 mg, 98%). m.p. decomp >90° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[N:19]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:18]=[N:17][N:16]=2)=[CH:5][CH:4]=1.[CH2:39]([NH2:44])[CH2:40][CH2:41][CH2:42][CH3:43].C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[CH2:39]([NH:44][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[N:19]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:18]=[N:17][N:16]=2)=[CH:5][CH:4]=1)[CH2:40][CH2:41][CH2:42][CH3:43]
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCCN
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCNCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.9 %

Procedure:
A mixture of 10.0 g (16.5 mmole) of 5-[4'-(bromomethyl)biphenyl-2-yl]-N-trityltetrazole [P. E. Aldrich, M. E. Pierce, and J. J. V. Duncia, European Patent Application 291,969 (1988)], 9.5 mL (7.14 g, 8.2 mmole) of n-pentylamine, 2.8 mL (2.03 g, 20 mmole) of triethylamine, and 100 mL of dry methylene chloride was stirred under N2 at room temperature overnight. Next, the mixture was shaken with 100 mL of 0.25M citric acid (aqueous). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The viscous oil was flash chromatographed on silica gel (elution initially with 1:1 hexane-EtOAc and then with a larger volume of EtOAc alone) to yield 4.57 g (49%) of the title compound as a very viscous oil, homogeneous by TLC (EtOAc); FAB-MS m/e 563 (M+1)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([CH3:19])[C:15]([O:17]C)=[O:16])=[CH:10][C:9]=2[CH:20]([CH3:22])[CH3:21])=[CH:4][CH:3]=1.Br[CH2:24][C:25]1[C:30]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[C:29]([O:38]C(OC(C)(C)C)=O)[C:28]([C:46]([F:49])([F:48])[F:47])=[CH:27][CH:26]=1>>[C:34]([O:33][C:31]([C:30]1[C:29]([OH:38])=[C:28]([C:46]([F:49])([F:47])[F:48])[CH:27]=[CH:26][C:25]=1[CH2:24][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([CH3:19])[C:15]([OH:17])=[O:16])=[CH:10][C:9]=2[CH:20]([CH3:22])[CH3:21])=[CH:6][CH:7]=1)=[O:32])([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)OC(=O)Oc1c(C(F)(F)F)ccc(CBr)c1C(=O)OC(C)(C)C
Reactant: COC(=O)C(C)c1ccc(-c2ccc(O)cc2)c(C(C)C)c1
Product: CC(C)c1cc(C(C)C(=O)O)ccc1-c1ccc(OCc2ccc(C(F)(F)F)c(O)c2C(=O)OC(C)(C)C)cc1
Yield: 45 %

Procedure:
According to a method similar to Example (2-3), Example (33-5) and Example (17-4), from methyl 2-(4′-hydroxy-2-isopropyl-1,1′-biphenyl-4-yl)propanoate (290 mg, 0.97 mmol) obtained in Example (107-1) and tert-butyl 6-(bromomethyl)-2-[(tert-butoxycarbonyl)oxy]-3-(trifluoromethyl)benzoate (487 mg, 1.07 mmol) obtained in Example (28-5), the title compound was obtained as a colorless powder (246 mg, three-step total yield: 45%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](C)[C:3]=1[C:4]#[N:5].[C:11]([N:19]=[C:20]=[S:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[NH:1][C:20]([NH:19][C:11](=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[S:21])#[N:5]
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Cc1cccc(N)c1C#N
Product: N#Cc1ccccc1NC(=S)NC(=O)c1ccccc1

Procedure:
Prepared as in example 1a from 2-amino-6-methylbenzonitrile and benzoyl isothiocyanate as a pale-yellow solid. 1H NMR (400 MHz, DMSO-d6) δ7.40 (m, 1H), 7.52-7.69 (m, 5H), 7.98-8.01 (m, 2H), 11.99 (s, 1H), 12.54 (s, 1H). MS 296 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[NH:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[Cl:22].[C:23](OC)(=[O:27])[C:24]([CH3:26])=O>C1(C)C=CC=CC=1>[Cl:22][C:16]1[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=1[CH2:14][N:13]1[C:3]2[C:2](=[CH:12][CH:11]=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:4]=2)[N:1]=[C:24]([CH3:26])[C:23]1=[O:27]
Reactant: CCOC(=O)c1ccc(N)c(NCc2ccc(Cl)cc2Cl)c1
Reactant: COC(=O)C(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc2nc(C)c(=O)n(Cc3ccc(Cl)cc3Cl)c2c1

Procedure:
A mixture of ethyl 4-amino-3-(2,4-dichlorobenzylamino)benzoate (1.90 g) and methyl pyruvate (0.55 ml) in toluene (15 ml) was heated under reflux for 1 hr. The reaction mixture was concentrated. The residue was washed with methanol and dried to give the object compound (0.50 g) as yellow crystals.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[I:12]I>CCO.S([O-])([O-])(=O)=O.[Ag+2]>[I:12][C:9]1[CH:10]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=[CH:7][C:8]=1[NH2:11]
Reactant: CS(=O)(=O)c1ccc(N)cc1
Reactant: II
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: CS(=O)(=O)c1ccc(N)c(I)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 242.6 %

Procedure:
To a vigorously stilted solution of 100 g of 4-(methylsulfonyl)-phenylamine dissolved in 5.5 L of EtOH at 50° C. was added a mixture of 49.3 g of iodine and 110 g of silver sulfate in 1 L of EtOH. This was repeated after 1 h of stirring. After another hour, a mixture of 49.3 g of iodine and 43.8 g of silver sulfate in 1 L of EtOH was added and the mixture stirred overnight. The hot solution was then filtered through Celite and the solvent stripped. The residue was triturated with 1 L of EtOH at 50° C. for 45 min and cooled to 0° C. The product was filtered and collected to give 140 g of the title compound as a brown solid.
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.[CH3:14][CH:15]([C:31](=[O:37])[CH2:32][CH:33]=[C:34]([CH3:36])[CH3:35])[CH2:16][CH2:17][CH2:18][C:19]1([CH3:30])[CH:25]2[O:26][C:22]([CH2:27][CH2:28][OH:29])([CH2:23][CH2:24]2)[CH2:21][O:20]1.CC(C)=O.CC(O)C>O>[CH3:14][CH:15]([C:31](=[O:37])[CH2:32][CH:33]=[C:34]([CH3:36])[CH3:35])[CH2:16][CH2:17][CH2:18][C:19]1([CH3:30])[CH:25]2[O:26][C:22]([CH2:27][C:28]([OH:3])=[O:29])([CH2:23][CH2:24]2)[CH2:21][O:20]1
Reactant: CC(C)=CCC(=O)C(C)CCCC1(C)OCC2(CCO)CCC1O2
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: O
Product: CC(C)=CCC(=O)C(C)CCCC1(C)OCC2(CC(=O)O)CCC1O2

Procedure:
A slight excess of Jones reagent is added to a mixture of (1RS,4SR,5RS)-4-(4,8-dimethyl-5-oxo-7-nonenyl)-4-methyl-3,8-dioxabicyclo[3.2.1]octane-1-ethanol (13 mg, 0.04 mM) and acetone (3 ml) at 0° C. under nitrogen for thirty minutes. The resulting mixture is treated with 2-propanol (1 ml) and stirred for ten minutes. The mixture is treated with water (10 ml) and extracted with ether (3×20 ml). The combined organic layers are dried (Na2SO4) and evaporated in vacuo to give crude (1RS,4SR,5RS)-4-(4,8-dimethyl-5-oxo-7-nonenyl)-4-methyl-3,8-dioxabicyclo[3.2.1]octane-1-acetic acid (10 mg) as a yellowish oil. This material is dissolved in methanol (2 ml) and treated with sodium borohydride (50 mg) at 0° C. under nitrogen. After stirring for five minutes, the mixture is allowed to warm to room temperature, acetone (0.5 ml) is added and the resulting mixture is stirred for thirty minutes. Most of the solvent is removed in vacuo, 2 N hydrochloric acid (5 ml) is added and the resulting mixture is extracted with ether (3×10 ml). The combined organic layers are dried (Na2SO4), evaporated in vacuo and the residue is purified by column chromatography on silica gel (5 g) with ether to give (1RS,4SR,5RS)-4-(4,8-dimethyl-5-hydroxy-7-nonenyl)-4-methyl-3,8-dioxabicyclo[3.2.1]octane-1-acetic acid (7 mg) as a colorless oil.
Reaction SMILES: ClCCl.C(#N)C.[CH2:7]([O:9][C:10]1[CH:33]=[CH:32][C:13]([O:14][CH2:15][CH:16]2[CH2:21][CH2:20][CH:19]([CH:22]3[CH2:27][O:26][C:25]([CH2:29][CH2:30][CH3:31])(O)[CH2:24][CH2:23]3)[CH2:18][CH2:17]2)=[C:12]([F:34])[C:11]=1[F:35])[CH3:8].C([SiH](CC)CC)C>O>[CH2:7]([O:9][C:10]1[CH:33]=[CH:32][C:13]([O:14][CH2:15][CH:16]2[CH2:17][CH2:18][CH:19]([CH:22]3[CH2:27][O:26][CH:25]([CH2:29][CH2:30][CH3:31])[CH2:24][CH2:23]3)[CH2:20][CH2:21]2)=[C:12]([F:34])[C:11]=1[F:35])[CH3:8]
Reactant: CCCC1(O)CCC(C2CCC(COc3ccc(OCC)c(F)c3F)CC2)CO1
Agent: CC[SiH](CC)CC
Solvent: O
Solvent: ClCCl
Solvent: CC#N
Product: CCCC1CCC(C2CCC(COc3ccc(OCC)c(F)c3F)CC2)CO1
Yield: 57.8 %

Procedure:
In a reactor under nitrogen atmosphere, 100 mL of dichloromethane and 20 mL of acetonitrile were added to 3.6 g of 5-[4-(4-ethoxy-2,3-difluorophenoxymethyl)cyclohexyl]2-propyltetrahydropyran-2-ol obtained in the thirteenth step, and the mixture was cooled to −20° C., to which 2.7 mL of triethylsilane was added dropwise, and subsequently 1.5 mL of boron trifluoride diethyl ether complex was added dropwise. The temperature of the reaction solution was increased to 0° C., to which 50 mL of iced water was added, followed by extracting three times with 30 mL of diethyl ether. The mixture including the organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography and recrystallization to provide 2.0 g of 5-[4-(4-ethoxy-2,3-difluorophenoxymethyl)cyclohexyl]2-propyltetrahydropyran.
Reaction SMILES: [C:1]1(=O)[CH2:5][CH2:4][CH2:3][C:2]1=O.[O:8]=[C:9]([CH3:17])[CH2:10][S:11][CH2:12][C:13]([O:15][CH3:16])=[O:14].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:16][O:15][C:13]([C:12]1[S:11][C:10]([C:9](=[O:8])[CH3:17])=[C:1]2[CH2:5][CH2:4][CH2:3][C:2]=12)=[O:14]
Reactant: COC(=O)CSCC(C)=O
Reactant: O=C1CCCC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc(C(C)=O)c2c1CCC2
Yield: 4.5 %

Procedure:
Stir a mixture of Cyclopentane-1,2-dione (2.00 g, 20.4 mmol), methyl 2-(2-oxopropylthio)acetate (3.31 g, 20.4 mmol) and potassium carbonate (5.63 g, 40.8 mmol) in DMF (40 mL) at 80° C. for 4 hours. Filter off the mixture and remove the solvent under vacuum. Purify the residue by a flash column on silica gel eluting with PE:EtOAc (8:1 to 6:1) to afford 3-Acetyl-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxylic acid methyl ester as a pale yellow solid (206 mg, 4.5%). MS (m/z): 225 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]2[CH:22]=[CH:21][N:20]=[N:19]2)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[CH2:27][C:28]1[N:29]=[C:30]([CH:33]=[CH:34][C:35]2[CH:40]=[CH:39][C:38]([S:41]([C:43]([F:46])([F:45])[F:44])=[O:42])=[CH:37][CH:36]=2)[O:31][CH:32]=1.[Cl-].[NH4+]>CN(C)C=O>[C:1]([O:5][C:6](=[O:23])[N:7]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]2[CH:22]=[CH:21][N:20]=[N:19]2)=[CH:10][CH:9]=1)[CH2:27][C:28]1[N:29]=[C:30](/[CH:33]=[CH:34]/[C:35]2[CH:36]=[CH:37][C:38]([S:41]([C:43]([F:46])([F:44])[F:45])=[O:42])=[CH:39][CH:40]=2)[O:31][CH:32]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(CCCCn2ccnn2)cc1
Reactant: O=S(c1ccc(C=Cc2nc(CCl)co2)cc1)C(F)(F)F
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(Cc1coc(/C=C/c2ccc(S(=O)C(F)(F)F)cc2)n1)c1ccc(CCCCn2ccnn2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 28.4 %

Procedure:
To an ice-cold solution of [4-(4-[1,2,3]triazol-1-yl-butyl)phenyl]-carbamic acid tert-butyl ester (188 mg, 0.6 mmol) in N,N-dimethylformamide (5 ml) was added sodium hydride (16.5 mg, 0.65 mmol) and the mixture stirred for 30 min. After addition of 4-chloromethyl-2-[2-(4-trifluoromethanesulfinyl-phenyl)-vinyl]-oxazole (200 mg, 0.6 mmol), the mixture was stirred at room temperature over night, then mixed with 40 ml ammonium chloride solution, thoroughly extracted with ethyl acetate and the extract dried and evaporated. Flash column chromatography (ethyl acetate/heptane 2:1) yielded 105 mg (29%) [4-(4-[1,2,3]triazol-1-yl-butyl)phenyl]-{2-[(E)-2-(−4-trifluoromethanesulfinyl-phenyl)-vinyl]-oxazol-4-ylmethyl}-carbamic acid tert-butyl ester as oily residue.
Reaction SMILES: [CH3:1][C@:2]12[C:11]([CH3:13])([CH3:12])[C@H:8]([CH2:9][CH2:10]1)[C:4]1([CH2:7][CH2:6][CH2:5]1)[C:3]2=O.[CH:15]([NH2:17])=[O:16]>C(O)=O>[CH3:1][C:2]12[C:11]([CH3:13])([CH3:12])[CH:8]([CH2:9][CH2:10]1)[C:4]1([CH2:7][CH2:6][CH2:5]1)[CH:3]2[NH:17][CH:15]=[O:16]
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)C(=O)C21CCC1
Reactant: NC=O
Solvent: O=CO
Product: CC1(C)C2CCC1(C)C(NC=O)C21CCC1
Temperature: 175 °C
Reaction time: 72 h
Yield: 84.2 %

Procedure:
A mixture of (1S,4R)-4,7,7-trimethylspiro[bicyclo[2.2.1]heptane-2,1′-cyclobutan]-3-one (1.60 g, 8.32 mmol) and formamide (10 mL) in formic acid (7 mL) was stirred at 175° C. for 72 h. The reaction mixture was cooled to ambient temperature, poured into 200 mL of ice-water, and extracted with ether (2×50 mL). The combined ether extracts were washed with water (40 mL), dried over anhydrous sodium sulfate and concentrated to obtain N-(4,7,7-trimethylspiro[bicyclo[2.2.1]heptane-2,1′-cyclobutan]-3-yl)formamide (1.55 g, 84.2% yield) as gum.
Reaction SMILES: O=[C:2]([CH3:10])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[C:11]1([O:21][CH2:22][CH:23]([OH:33])[CH2:24][NH:25]C(C)CCC(O)=O)[C:20]2[C:15](=CC=CC=2)[CH:14]=[CH:13][CH:12]=1>>[CH3:22][O:21][CH2:11][CH2:12][C:14]1[CH:13]=[CH:12][C:11]([O:21][CH2:22][CH:23]([OH:33])[CH2:24][NH:25][CH:2]([CH3:10])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])=[CH:20][CH:15]=1
Reactant: CC(CCC(=O)O)NCC(O)COc1cccc2ccccc12
Reactant: CC(=O)CCCCC(=O)O
Product: COCCc1ccc(OCC(O)CNC(C)CCCCC(=O)O)cc1

Procedure:
The title compound was synthesized from Compound V [R=4-(β-methoxyethyl)-phenyl] and 6-oxoheptanoic acid p-toluide on a 2 mmol scale using the general procedure described above for Compound 7.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:12]([OH:14])=O)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.CN(C)CCCN=C=NCC.[CH3:27][O:28][C:29](=[O:39])[C@H:30]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[NH2:31]>CN(C=O)C>[CH3:27][O:28][C:29](=[O:39])[CH:30]([NH:31][C:12]([C:9]1[S:10][CH:11]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=1)=[O:14])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(O)c1nc(-c2ccccc2)cs1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1ccccc1)NC(=O)c1nc(-c2ccccc2)cs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 4-Phenyl-thiazole-2-carboxylic acid (100 mg, 0.4 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.44 mmol) in DMF (4 mL) at 25° C. was added phenylalanine methyl ester (72 mg, 0.4 mmol), the resulting mixture was stirring at 25° C. for overnight and concentrated in vacuo, and the residue was dissolved in CH2Cl2 (20 mL) was washed with 5% NaHCO3, dried with MgSO4 and concentrated in vacuo. The residue was purified by HPLC. The product was obtained 92 mg (61%) as white solid.
Reaction SMILES: C(OC([N:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[C:10]([CH2:17][N:18]2[CH2:23][CH:22]=[C:21](/[CH:24]=[CH:25]/[C:26]3[O:27][C:28]([CH3:31])=[CH:29][CH:30]=3)[CH2:20][CH2:19]2)=[CH:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[OH-].[NH4+]>ClCCl>[CH3:31][C:28]1[O:27][C:26](/[CH:25]=[CH:24]/[C:21]2[CH2:22][CH2:23][N:18]([CH2:17][C:10]3[C:11]4[C:12](=[N:13][CH:14]=[CH:15][CH:16]=4)[NH:8][CH:9]=3)[CH2:19][CH:20]=2)=[CH:30][CH:29]=1
Reactant: Cc1ccc(/C=C/C2=CCN(Cc3cn(C(=O)OC(C)(C)C)c4ncccc34)CC2)o1
Agent: [NH4+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(/C=C/C2=CCN(Cc3c[nH]c4ncccc34)CC2)o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (E)-1-tert-butyloxycarbonyl-3-(4-[2-(5-methylfuran-2-yl)ethenyl]-1,2,3,6-tetrahydropyridin-1-yl)methylpyrrolo[2,3-b]pyridine (160 mg, 0.38 mmol) in anhydrous dichloromethane (5 ml) was treated with trifluoroacetic acid (500 ml, 6.5 mmol) and stirred at room temperature for two hours. Ammonium hydroxide solution (5 ml) was added and the whole mixture evaporated in vacuo. The residue was azeotroped with toluene. The crude material was chromatographed on silica gel with 5% methanol in dichloromethane as eluant to afford the title compound as a pale lemon solid (70 mg, 57%), m.p. 180° C. (dec.); (Found: C, 71.47; H, 6.46; N, 12.01. C20 H21N3O.H2O requires C, 71.19; H, 6.87; N, 12.42%); δH (DMSO-d6) 2.15-2.30 (5H, m, tetrahydropyridinyl CH2 and ArCH3), 2.59 (2H, t, J 5.5 Hz, tetrahydropyridinyl CH2), 3.02-3.10 (2H, m, tetrahydropyridinyl CH2), 3.71 (2H, s, NCH2Ar), 5.78-5.86 (1H, m, tetrahydropyridinyl 5-H), 6.05-6.10 (1H, m, furan 4-H), 6.16-6.30 (2H, m, CH=CHAr and furan 3-H), 6.55 (1H, d, J 16.1 Hz, CH=CHAr), 7.02 (1H, dd, J 7.8, 4.8 Hz, 5-H), 7.34-7.38 (1H, m, 2-H), 8.01 (1H, d, J 7.8 Hz, 4-H), 8.18 (1H, d, J 4.6 Hz, 6-H), and 11.45 (1H, s, NH); m/z (CI+, NH3) 320 (M+1)+.
Reaction SMILES: [OH:1][C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][CH2:5][C:4](=O)[C:3]=1[CH:14]=O.[NH2:16]/[C:17](/[CH3:21])=[CH:18]\[C:19]#[N:20]>C(O)C>[CH3:21][C:17]1[N:16]=[CH:14][C:3]2[C:2](=[O:1])[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[O:6][CH2:5][C:4]=2[C:18]=1[C:19]#[N:20]
Reactant: C/C(N)=C/C#N
Reactant: O=CC1=C(O)c2ccccc2OCC1=O
Solvent: CCO
Product: Cc1ncc2c(c1C#N)COc1ccccc1C2=O

Procedure:
A solution of 8.16 g (0.04 mole) of 2,3-dihydro-5-hydroxy-3-oxo-1-benzoxepin-4-carboxaldehyde, 4.92 g (0.06 mole) of 3-aminocrotononitrile and 50 ml of absolute ethanol was maintained at reflux for 10 min. and cooled. The separated crystals were filtered, washed with 10 ml ethanol and dried, wt. 5.2 g (52%); mp 124°-126°. Recrystallization was effected by dissolution in 75 ml of 50% dichloromethane-ethanol and removal, by distillation, of most of the dichloromethane. The pure product separated as tan crystals; wt. 2.9 g (29%), mp 126°-128°.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[C:7](=[O:8])[CH:6]=[CH:5][CH2:4][CH2:3]1.[CH3:10][C:11]([CH:13]=[CH:14][CH3:15])=[CH2:12].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:9])[CH2:3][CH2:4][CH:5]2[CH:6]([CH:14]([CH3:15])[CH:13]=[C:11]([CH3:12])[CH2:10]2)[C:7]1=[O:8]
Reactant: C=C(C)C=CC
Reactant: CC1(C)CCC=CC1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC1=CC(C)C2C(=O)C(C)(C)CCC2C1
Reaction time: 4 h

Procedure:
124 G (1M) of 6,6-dimethyl-cyclohex-2-en-1-one, 200 ml of toluene and 10 ml of trifluoro-boro-etherate are placed under nitrogen atmosphere in a three-necked reaction vessel of 1000 ml capacity equipped with a thermometer and a stirrer. The mixture was cooled to 10° and 2-methyl-penta-1,3-diene was added thereto in small portions over 4 hours. After the addition was over, the mixture was left under stirring for 1 additional hour, whereupon it was hydrolyzed with an aqueous sodium carbonate solution. The excess of toluene was removed by means of a rotary evaporator under reduced pressure and the residue was distilled to give 101.7 g of the desired product having b.p. 70°-80°/26.6 Pa. A spectroscopic analysis indicated that the product obtained consisted of about 90% of isomer cis (a) and about 10% of trans (b).
Reaction SMILES: [F:1][C:2]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:3]=1[O:4][C:5]1[C:19]([O:20][C:21]2[CH:22]=[N:23][C:24]([S:27]([CH2:30][CH3:31])(=[O:29])=[O:28])=[CH:25][CH:26]=2)=[CH:18][C:8]2[NH:9][C:10](C3C=CC=CN=3)=[N:11][C:7]=2[CH:6]=1.[CH3:37][N:38]1[CH:42]=[CH:41][C:40](C(O)=O)=[N:39]1>>[F:1][C:2]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:3]=1[O:4][C:5]1[C:19]([O:20][C:21]2[CH:22]=[N:23][C:24]([S:27]([CH2:30][CH3:31])(=[O:29])=[O:28])=[CH:25][CH:26]=2)=[CH:18][C:8]2[NH:9][C:10]([C:40]3[CH:41]=[CH:42][N:38]([CH3:37])[N:39]=3)=[N:11][C:7]=2[CH:6]=1
Reactant: CCS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4ccccn4)nc3cc2Oc2c(F)cccc2F)cn1
Reactant: Cn1ccc(C(=O)O)n1
Product: CCS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4ccn(C)n4)nc3cc2Oc2c(F)cccc2F)cn1

Procedure:
The entitled compound was obtained as a colorless solid in the same method as in Example 203 or in accordance with the method or by combining it with an ordinary method but using 4-(2,6-difluoro-phenoxy)-5-(6-ethanesulfonyl-pyridin-3-yloxy)-benzene-1,2-diamine obtained in Example 235 and 1-methyl-1H-pyrazole-3-carboxylic acid.
Reaction SMILES: [NH3:1].[C:2]([O:8][CH2:9][CH2:10][CH3:11])(=[O:7])[CH2:3][C:4]([CH3:6])=O>C(OCC)C>[NH:1]=[C:4]([CH3:6])[CH2:3][C:2]([O:8][CH2:9][CH2:10][CH3:11])=[O:7]
Reactant: CCCOC(=O)CC(C)=O
Reactant: N
Solvent: CCOCC
Product: CCCOC(=O)CC(C)=N

Procedure:
Ammonia gas was passed into a stirred solution of n-propyl acetoacetate (prepared by the method of Fisher, J.A.C.S., 1934, 56, 1766; 72 g.) in diethyl ether (100 ml.) at ambient temperature for 20 hours. The solution was then dried over sodium sulphate, filtered and distilled under reduced pressure to give n-propyl 3-iminobutyrate (18.2 g.), b.p. 114°-118° C./20 mm Hg.