Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:26])=[C:4]([NH:8][C:9]([C:11]2[C:19]3[N:18]=[C:17]([N:20]([CH3:22])[CH3:21])[NH:16][C:15]=3[CH:14]=[C:13]([N+:23]([O-])=O)[CH:12]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.Cl.CCO>CO.C1COCC1.[Pt]>[NH2:23][C:13]1[CH:12]=[C:11]([C:9]([NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[CH3:26])=[O:10])[C:19]2[N:18]=[C:17]([N:20]([CH3:21])[CH3:22])[NH:16][C:15]=2[CH:14]=1
Reactant: Cc1c(Cl)cccc1NC(=O)c1cc([N+](=O)[O-])cc2[nH]c(N(C)C)nc12
Agent: [Pt]
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(Cl)cccc1NC(=O)c1cc(N)cc2[nH]c(N(C)C)nc12
Reaction time: 3 h
Yield: 49.7 %

Procedure:
To a suspension of N-(3-chloro-2-methylphenyl)-2-(dimethylamino)-6-nitro-1H-benzimidazole-4-carboxamide (580 mg) in MeOH-THF (1:1, 60 mL), was added 2N hydrogen chloride/EtOH (1 mL). To the mixture was added 1% platinum+0.1% copper-activated carbon (Degussa type CF105 R/W) (150 mg) and it was stirred vigorously under hydrogen atmosphere (0.2 MPa) for 3 hours. The reaction mixture was filtered off through celite, and the mother liquid was concentrated. To the residue was added saturated aqueous sodium bicarbonate, and it was extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified on column chromatography to obtain the titled compound (265 mg) as brown powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[CH2:11][C:10](=O)[CH2:9]2)=[CH:4][CH:3]=1.Cl.[NH2:17][CH2:18][C:19]#[C:20][CH3:21].O1CCCC1>C(N(CC)CC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][C:10]3[N:17]=[CH:18][CH:19]=[C:20]([CH3:21])[C:11]=3[C:12](=[O:14])[CH2:13]2)=[CH:6][CH:7]=1
Reactant: CC#CCN
Reactant: O=C1CC(=O)CC(c2ccc(F)cc2)C1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccnc2c1C(=O)CC(c1ccc(F)cc1)C2
Temperature: 220 °C
Reaction time: 6 h
Yield: 28.9 %

Procedure:
To a mixture of 5-(4-fluorophenyl)cyclohexane-1, 3-dione (0.98 g), 1-amino-2-butyne hydrochloride (0.5 g), molecular sieves 4A (2 g) and tetrahydrofuran (20 ml) was added triethylamine (0.48 g), and the mixture was refluxed for 14 hours and cooled. Insoluble materials were filtered off. Under reduced pressure, the solvent was evaporated, and the residue was stirred for 6 hours at 220° C. and cooled, to which were added ethyl acetate and sodium hydrogen carbonate solution. The organic layer was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure, and the residue was purified with silica gel column chromatography (EtoAc/hexane) to give oil of 7-(4-fluorophenyl)-4methyl-5,6,7,8-tetrahydroquinolin-5-one (0.35 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH:17]1(Br)[CH2:21][CH2:20][CH2:19][CH2:18]1.Cl>CN(C=O)C.O>[CH:17]1([O:10][C:9]2[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=2[OH:1])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: BrC1CCCC1
Reactant: O=Cc1ccc(O)c(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(OC2CCCC2)c(O)c1
Temperature: 80 °C
Reaction time: 24 h
Yield: 67 %

Procedure:
A suspension of 3,4-dihydroxybenzaldehyde (5.0 gm, 0.0362 mol), anhydrous potassium carbonate (6.0 gm, 0.0434 mol) and cyclopentyl bromide (6.5 gm, 0.0434 mol) in dry DMF (50 ml) was heated and stirred at 80° C. for 24 hrs. Reaction mixture was then cooled and diluted with water (500 ml), acidified with 1N HCl and extracted with ethyl acetate (3×100 ml). The ethyl acetate extract was washed 5% sodium bicarbonate and brine and dried over anhydrous sodium sulfate. The dried extract on concentration afforded a residue which was purified by silica gel chromatography using 10% ethyl acetate in petroleum ether as the eluent to provide 5.0 gm of the title product as white solid. mp: 87–89° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=2[F:37])=[C:6]([C:8]2[C:9]3[CH:18]=[CH:17][N:16]([S:19]([C:22]4[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=4)(=[O:21])=[O:20])[C:10]=3[C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)[CH:7]=1.[CH2:38]([S:40](Cl)(=[O:42])=[O:41])[CH3:39]>ClCCl>[F:37][C:31]1[CH:32]=[C:33]([F:36])[CH:34]=[CH:35][C:30]=1[O:29][C:5]1[CH:4]=[CH:3][C:2]([N:1]([S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])[S:40]([CH2:38][CH3:39])(=[O:42])=[O:41])=[CH:7][C:6]=1[C:8]1[C:9]2[CH:18]=[CH:17][N:16]([S:19]([C:22]3[CH:23]=[CH:24][C:25]([CH3:26])=[CH:27][CH:28]=3)(=[O:20])=[O:21])[C:10]=2[C:11](=[O:15])[N:12]([CH3:14])[CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4cc(N)ccc4Oc4ccc(F)cc4F)cn(C)c(=O)c32)cc1
Reactant: CCS(=O)(=O)Cl
Solvent: ClCCl
Product: CCS(=O)(=O)N(c1ccc(Oc2ccc(F)cc2F)c(-c2cn(C)c(=O)c3c2ccn3S(=O)(=O)c2ccc(C)cc2)c1)S(=O)(=O)CC
Temperature: 25 °C
Reaction time: 2 h
Yield: 181.4 %

Procedure:
A solution of Example 36c (4.35 g, 8.34 mmol) in dichloromethane (50 mL) was cooled to 0° C. To this solution was added ethanesulfonyl chloride (2.37 mL, 25.0 mmol). The reaction mixture was stirred at room temperature for 2 hours. The solvent was evaporated, and the residue was partitioned between ethyl acetate and water. The aqueous layer was extracted with additional ethyl acetate twice. The combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 80% ethyl acetate/hexanes) to provide the title compound (5.34 g, 91% yield).
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[NH:18][CH2:19][CH3:20])[CH2:11][CH:10]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:9]1=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1[CH:35]=[CH:34]C=CC=1.C(Cl)(=[O:38])C>ClCCCl>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[N:18]([CH2:34][CH3:35])[C:19](=[O:38])[CH3:20])[CH2:11][CH:10]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:27])[CH3:26])[C:9]1=[O:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Cl
Reactant: CCNc1cccc2c1N(Cc1ccccc1)C(=O)C(NC(=O)OC(C)(C)C)C2
Reactant: c1ccncc1
Solvent: ClCCCl
Product: CCN(C(C)=O)c1cccc2c1N(Cc1ccccc1)C(=O)C(NC(=O)OC(C)(C)C)C2

Procedure:
tert-Butyl 1-benzyl-8-ethylamino-1,2,3,4-tetrahydro-2-oxoquinolin-3-ylcarbamate (300 mg) was dissolved in 1,2-dichloroethane (2.5 mL), and pyridine (180 mg) was added to the solution. Under cooling on ice, a solution of acetyl chloride (179 mg) in 1,2-dichloroethane (2.5 mL) was added dropwise to the mixture. The resultant mixture was stirred at room temperature for two hours, and the reaction mixture was concentrated under reduced pressure. Water was added to the thus-recovered residue, and the mixture was subjected to extraction with ethyl acetate. The organic layer was sequentially washed with 0.1N HCl, saturated aqueous sodium bicarbonate solution, and saturated aqueous sodium chloride solution, and dried over sodium sulfate. Solvent was evaporated under reduced pressure, whereby the title compound (330 mg) was yielded.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([Cl:27])[C:15]=1[O:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([CH:24]([CH3:26])[CH3:25])[CH:18]=1)[CH:5]=[C:6]1[S:10][C:9](=[O:11])[NH:8][C:7]1=[O:12].[C:28](OCC)(=O)C.CO>[Pd]>[Cl:27][C:14]1[CH:13]=[C:4]([CH:3]=[C:2]([Cl:1])[C:15]=1[O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:28])=[C:19]([CH:24]([CH3:25])[CH3:26])[CH:18]=1)[CH2:5][CH:6]1[S:10][C:9](=[O:11])[NH:8][C:7]1=[O:12]
Reactant: CCOC(C)=O
Reactant: CC(C)c1cc(Oc2c(Cl)cc(C=C3SC(=O)NC3=O)cc2Cl)ccc1O
Agent: [Pd]
Solvent: CO
Product: COc1ccc(Oc2c(Cl)cc(CC3SC(=O)NC3=O)cc2Cl)cc1C(C)C
Reaction time: 2 h

Procedure:
To a solution of the title compound from Step D (31 mg, 0.072 mmol) was dissolved in ethyl acetate/methanol (1 ml/1 ml) and placed in a hydrogenation bottle with 10% palladium on carbon (90 mg). The mixture was placed on Parr shaker for two hours under 50 p.s.i. of hydrogen, then filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate/methanol. The combined filtrate was concentrated to give the title compound (26 mg) as a clear, viscous oil that was used in the next step without purification. MS (APCI−) Calc: 439.0, Found: 438.1 (M−1).
Reaction SMILES: [O:1]=[C:2]1[CH2:5][CH:4]([C:6]([OH:8])=O)[CH2:3]1.Cl.[CH3:10][O:11][NH:12][CH3:13].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>ClCCl.O>[CH3:10][O:11][N:12]([CH3:13])[C:6]([CH:4]1[CH2:3][C:2](=[O:1])[CH2:5]1)=[O:8]
Reactant: O=C1CC(C(=O)O)C1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)C1CC(=O)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 85 %

Procedure:
A mixture of 3-oxo-cyclobutanecarboxylic acid (2.28 g, 20.0 mmol), O,N-dimethyl-hydroxylamine hydrochloride (1.94 g, 20.0 mmol), 1-hydroxybenzotriazole (2.99 g, 22.0 mmol), (3-dimethylamino-propyl)-ethyl-carbodiimide hydrochloride (4.22 g, 22.0 mmol) and triethylamine (4.04 g, 40.0 mmol) in dichloromethane (50 mL) was stirred at room temperature for 24 hours. The mixture was diluted with water (30 mL), and extracted with dichloromethane (2×30 mL). The combined organic extracts were washed with water (20 mL) and brine (20 mL), and dried over sodium sulfate. The filtrate was evaporated in vacuo and the residue was purified by silica chromatography to provide N-methoxy-N-methyl-3-oxocyclobutanecarboxamide (2.68 g, 17.0 mmol, yield: 85%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[NH:7][C:6](=[O:12])[C:5]2=O.Cl.[NH2:15][CH2:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)=O.[OH2:26]>>[NH2:15][C:16]1[C:17]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[N:7][C:8]2[C:4]([C:5]=1[C:6]([OH:12])=[O:26])=[CH:3][C:2]([Cl:1])=[CH:10][C:9]=2[Cl:11]
Reactant: NCC(=O)c1ccc(Cl)cc1
Reactant: O=C1Nc2c(Cl)cc(Cl)cc2C1=O
Reactant: O
Agent: Cl
Product: Nc1c(-c2ccc(Cl)cc2)nc2c(Cl)cc(Cl)cc2c1C(=O)O

Procedure:
A solution of 5.4 g of 5,7-dichloroisatin in water was reacted with 7.21 g of 2-amino-1-(4-chlorophenyl)ethanone hydrochloride by the procedure described in example 33, giving 5.2 g of the desired compound as a yellow solid, mp 260°-261° C.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[F:17][C:4]1[CH:3]=[C:2]([C:23]2[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: O=C1NCCCn2c1cc1cc(F)cc(Br)c12
Product: COc1ccc(-c2cc(F)cc3cc4n(c23)CCCNC4=O)cc1

Procedure:
The title compound, light brown solid (62 mg, 76%), MS (ISP) m/z=325.3 [(M+H)+], mp 225.5° C., was prepared in accordance with the general method of example 1 from 7-bromo-9-fluoro-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indol-1-one (intermediate 2) (74.3 mg, 0.25 mmol) and commercially available 4-methoxy-phenylboronic acid (49.4 mg, 0.325 mmol).
Reaction SMILES: [Cl:1][N:2]1[C:6]([Cl:7])=[CH:5][N:4]=[CH:3]1.[H-].[Na+].[CH3:10][O:11][CH2:12][CH2:13]Cl.O>CN(C=O)C.C(OCC)(=O)C>[CH3:10][O:11][CH:12]([C:3]1[N:2]([Cl:1])[C:6]([Cl:7])=[CH:5][N:4]=1)[CH3:13]
Reactant: COCCCl
Reactant: Clc1cncn1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(C)c1ncc(Cl)n1Cl
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
A solution of 1 mmol of 3,4-dichloroimidazole in anhydrous DMF (5 n-L) is treated with sodium hydride (1.05 mmol) at 0° C. under nitrogen with magnetic stirring. After 30 min., 2-chloroethyl methyl ether (1 mmol) is added and the reaction mixture is warmed to 60° C. for 2 h. The reaction mixture is cooled, portioned between water and ethyl acetate. The organic layer is separated, washed with water, brine and dried over sodium sulfate. The reaction mixture is filtered, evaporated and purified by chromatography on silica gel to obtain 1-methoxyethyl-3,4-dichloroimidazole.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:8]([C:24]([F:27])([F:26])[F:25])=[CH:7][N:6]=1)(=O)=O.[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]2[CH2:40][CH2:39][N:38](C(OC(C)(C)C)=O)[CH2:37][CH2:36]2)=[CH:31][C:30]=1[CH3:48].C(O)(C(F)(F)F)=O>>[CH3:48][C:30]1[CH:31]=[C:32]([CH:35]2[CH2:36][CH2:37][NH:38][CH2:39][CH2:40]2)[CH:33]=[CH:34][C:29]=1[NH:28][C:5]1[N:10]=[C:9]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:8]([C:24]([F:27])([F:26])[F:25])=[CH:7][N:6]=1
Reactant: COC(=O)Cc1ccccc1CCc1nc(S(C)(=O)=O)ncc1C(F)(F)F
Reactant: Cc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ccc1N
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CCNCC3)cc2C)ncc1C(F)(F)F

Procedure:
A solution of methyl 2-(2-(2-(2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetate (I15) (450 mg, 1.11 mmol), tert-butyl 4-(4-amino-3-methylphenyl)piperidine-1-carboxylate (I53) (390 mg, 1.34 mmol) and TFA (0.25 mL) in 2,2,2-TFE (3 mL) was heated at 120° C. under microwave irradiation for 30 minutes. The resulting mixture was adsorbed onto silica gel and chromatographed (0-50% MeOH/DCM) to give the title compound (I54) (478 mg, 83%) as a viscous liquid; 1H NMR (400 MHz, CDCl3) δ 9.14 (bs, 1H), 8.76 (bs, 1H), 8.51 (s, 1H), 7.58 (d, J=8.2 Hz, 1H), 7.21 (ddt, J=10.7, 7.4, 4.3 Hz, 4H), 7.15-7.06 (m, 1H), 3.65 (s, 2H), 3.60 (d, J=12.6 Hz, 2H), 3.49 (s, 3H), 3.15-3.02 (m, 6H), 2.87-2.71 (m, 1H), 2.32 (s, 3H), 2.07 (d, J=7.8 Hz, 4H). LCMS Method C: rt 5.24 min; m/z 513.2 [M+1]+.
Reaction SMILES: N[C@@H:2]1[C:21](=[O:22])[N:4]2[C:5]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[C:6]([CH2:9][O:10][C:11](=[O:13])[CH3:12])[CH2:7][S:8][C@H:3]12.N([O-])=O.[Na+].[Cl-:27].[Na+]>C(O)C.O.Cl>[Cl:27][C@H:2]1[C:21](=[O:22])[N:4]2[C:5]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[C:6]([CH2:9][O:10][C:11](=[O:13])[CH3:12])[CH2:7][S:8][C@H:3]12
Reactant: [Cl-]
Reactant: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@H](Cl)[C@H]2SC1
Temperature: 0 °C
Yield: 73 %

Procedure:
To an ice-cooled solution of t-butyl 7β-amino-3-acetoxymethyl-3-cephem-4-carboxylate (4.0 g, 0.0122 mol) in 75 ml of ethanol, 16.7 ml of water and 16.7 ml of concentrated hydrochloric acid and sodium nitrite (1.18 g, 0.017 mol) were added portionwise over 15-20 minutes. The reaction mixture was stirred at 0°-5° C. for 2.5 hours, saturated with sodium chloride, extracted with methylene chloride, washed with water, brine, dried (Na2SO4) and concentrated to give 3.1 g (73%) of t-butyl 7α-chloro-3-acetoxymethyl-3-cephem-4-carboxylate.
Reaction SMILES: [CH3:1][CH:2]1[CH:6]([CH3:7])[O:5][C:4]2([CH2:12][C:11]([CH3:14])([CH3:13])[C:10](/[CH:16]=[CH:17]/[Sn](CCCC)(CCCC)CCCC)([OH:15])[C:9]([CH3:31])=[CH:8]2)[O:3]1.[F:32][C:33]([F:43])([F:42])/[C:34](/I)=[CH:35]/[C:36]([O:38][CH2:39][CH3:40])=[O:37].[F-].[K+]>CC#N.CC#N.Cl[Pd]Cl.CN(C)C=O>[OH:15][C:10]1(/[CH:16]=[CH:17]/[C:34](/[C:33]([F:32])([F:42])[F:43])=[CH:35]\[C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:11]([CH3:14])([CH3:13])[CH2:12][C:4]2([O:5][CH:6]([CH3:7])[CH:2]([CH3:1])[O:3]2)[CH:8]=[C:9]1[CH3:31]
Reactant: CCCC[Sn](/C=C/C1(O)C(C)=CC2(CC1(C)C)OC(C)C(C)O2)(CCCC)CCCC
Reactant: CCOC(=O)/C=C(\I)C(F)(F)F
Agent: Cl[Pd]Cl
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCOC(=O)/C=C(\C=C\C1(O)C(C)=CC2(CC1(C)C)OC(C)C(C)O2)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.2 %

Procedure:
Under argon, 2,3,7,9,9-pentamethyl-8-[(E)-2-(tributylstannyl)vinyl]-1,4-dioxaspiro[4.5]dec-6-en-8-ol (300 mg, 0.55 mmol) and ethyl (2Z)-4,4,4-trifluoro-3-iodobut-2-enoate (163 mg, 0.55 mmol) in a round-bottom flask that had been dried by heating were dissolved in abs. N,N-dimethylformamide (4 ml), dichlorobis(acetonitrile)palladium(II) (7 mg, 0.03 mmol) was added and the mixture was stirred at room temperature for 3 h. After the addition of potassium fluoride solution, the reaction mixture was stirred further at room temperature overnight. The aqueous phase was then repeatedly extracted thoroughly with diethyl ether, and the combined organic phases were then dried over magnesium sulfate, filtered and concentrated under reduced pressure. By final column chromatography purification of the resulting crude product (ethyl acetate/heptane gradient), ethyl (2E,4E)-5-(8-hydroxy-2,3,7,9,9-pentamethyl-1,4-dioxaspiro[4.5]dec-6-en-8-yl)-3-(trifluoromethyl)penta-2,4-dienoate (150 mg, 61% of theory) was obtained in the form of a colorless oil. 1H-NMR (400 MHz, CDCl3 δ, ppm) 7.47 (d, 1H), 6.29 (d, 1H), 6.25 (s, 1H), 5.48 (s, 1H), 4.26 (q, 2H), 3.68 (m, 1H), 3.59 (m, 1H), 1.93 (d, 1H), 1.83 (br. m, 1H, OH), 1.77 (d, 1H), 1.69 (s, 3H), 1.32 (t, 3H), 1.25 (m, 3H), 1.18 (m, 3H), 1.10 (s, 3H), 0.91 (s, 3H).
Reaction SMILES: C([O:4][C:5]1[C:16]2[S:17][CH:18]=[CH:19][C:15]=2[CH:14]=[C:7]2[S:8][C:9]([C:11](=[O:13])[CH3:12])=[CH:10][C:6]=12)(=O)C.CC([OH:23])C.C(Cl)(Cl)Cl>CC(O)=O>[C:11]([C:9]1[S:8][C:7]2[C:14](=[O:23])[C:15]3[CH:19]=[CH:18][S:17][C:16]=3[C:5](=[O:4])[C:6]=2[CH:10]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)Oc1c2cc(C(C)=O)sc2cc2ccsc12
Reactant: CC(C)O
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CC(=O)c1cc2c(s1)C(=O)c1ccsc1C2=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
To a suspension of crude 8 (7.5 g) in HOAc (30 mL) was added CrO3 (5.7 g, 57 mmol). After stirring for 1 h, i-PrOH (20 mL) and CHCl3 (300 mL) were added and stirred for 30 min. The resulting solution was poured into ice water, and the aqueous layer was extracted with CHCl3 three times. The combined extracts were dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, CHCl3) to give 9 (mp 223-225 ° C.) in a 45% yield. IR (KBr) 1650, 1670 (C═O) cm−1; 1H NMR (CDCl3) δ 2.67 (s, 3H, CH3), 7.68 (d, J=5.1 Hz, 1H, H-7), 7.74 (d, J=5.1 Hz, 1H, H-6), 8.12 (s, 1H, H-3); 13C NMR (CDCl3): δ 26.9 (C-2-CH3), 126.9 (C-7), 129.4 (C-3), 134.3 (C-6), 170.0 (C-4), 174.4 (C-8), 190.7 (C-2-C═O); MS m/z 262 (M+); Anal. (C12H6O3S2) C, H.
Reaction SMILES: [N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].O[N:17]1[C:21](=[O:22])[CH2:20][CH2:19][C:18]1=[O:23].C1(N=C=NC2CCCCC2)CCCCC1>>[N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([O:5][N:17]1[C:21](=[O:22])[CH2:20][CH2:19][C:18]1=[O:23])=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)ON1C(=O)CCC1=O
Yield: 75 %

Procedure:
Condesation of BocProOH (6.46 g.) and N-hydroxysuccinimide (3.5 g.) using dicyclohexylcarbodiimide gave BocProOSu in 75% yield. Condensation of BocProOSu (5.0 g.) and HDPheOH (2.75 g.) by the salt coupling method gave BocPro-DPheOH in 67% yield. Condensation of BocPro-DPheOH (3.98 g.) and HPheOMe hydrochloride salt (2.4 g.) using dicyclohexylcarbodiimide and N-hydroxysuccinimide gave BocPro-DPhe-PheOMe in 74% yield. Hydrazinolysis of Boc-Pro-DPhe-PheOMe (3.14 g.) gave BocPro-DPhe-PheNHNH2 in 79% yield.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][C:20](=[O:22])[CH3:21])=[CH:15][CH:14]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO[CH:25](OC)[N:26]([CH3:28])[CH3:27]>>[CH3:25][N:26]([CH3:28])[CH:27]=[C:19]([C:16]1[CH:17]=[CH:18][C:13]([N:10]2[CH2:9][CH2:8][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:12][CH2:11]2)=[CH:14][CH:15]=1)[C:20](=[O:22])[CH3:21]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)Cc1ccc(N2CCC(c3ccccc3)CC2)cc1
Product: CC(=O)C(=CN(C)C)c1ccc(N2CCC(c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4.0 g of 1-[4-(4-phenyl-1-piperidinyl)phenyl]-2-propanone and 16 ml of dimethylformamide dimethylacetal is stirred at room temperature overnight, followed by heating at 45°-60° C. for six hours. The solvent is evaporated and the residue triturated with two 100 ml portions of hexane. The solid is filtered and dried to give 3.5 g of orange powder, mp 93°-100° C. Upon standing overnight at 0° C., the filtrate gave an additional 0.7 g of the product, mp 103.5°-105° C. This material is used directly for the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[N:15]=[N:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([CH:22]4[CH2:27][CH2:26][CH:25]([CH2:28][C:29]([NH2:31])=O)[CH2:24][CH2:23]4)=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.C1COCC1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(N(CC)CC)C>[F:33][C:2]([F:1])([F:32])[C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[N:15]=[N:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([CH:22]4[CH2:23][CH2:24][CH:25]([CH2:28][C:29]#[N:31])[CH2:26][CH2:27]4)=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)=[CH:5][CH:4]=1
Reactant: NC(=O)CC1CCC(c2ccc(-c3ccc(Nc4ccc(C(F)(F)F)nc4)nn3)cc2)CC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: N#CCC1CCC(c2ccc(-c3ccc(Nc4ccc(C(F)(F)F)nc4)nn3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2-(4-{4-[6-(6-Trifluoromethyl-pyridin-3-ylamino)-pyridazin-3-yl]-phenyl}-cyclohexyl)-acetamide (0.18 g, 0.41 mmol, 1.0 equiv) in 3 Ml THF was added trifluoroacetic anhydride (0.068 Ml, 0.49 mmol, 1.2 equiv) followed by triethylamine (0.12 Ml, 0.90 mmol, 2.2 equiv). The reaction was stirred at ambient temperature overnight, and then concentrated in vacuo. Purification by silica gel chromatography (10-50% EtOAc in hexanes) afforded the title compound: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.39-1.50 (m, J=12.82, 12.54, 12.54, 3.54 Hz, 2 H) 1.69-1.80 (m, J=12.88, 12.69, 12.69, 3.41 Hz, 2 H) 1.86-1.97 (m, J=11.91, 11.91, 6.06, 5.87, 2.91 Hz, 1 H) 2.09 (d, J=15.92 Hz, 1 H) 2.09 (dd, J=5.94, 3.66 Hz, 3 H) 2.76 (t, J=3.03 Hz, 1 H) 7.53 (d, J=9.35 Hz, 1 H) 7.59 (d, J=8.34 Hz, 2 H) 8.08 (d, J=8.59 Hz, 1 H) 8.20 (d, J=8.34 Hz, 2 H) 8.30 (d, J=9.35 Hz, 1 H) 8.91 (dd, J=8.59, 2.27 Hz, 1H) 9.16 (d, J=2.53 Hz, 1 H) 10.25 (s, 1 H); (M+H)+ 438.3.
Reaction SMILES: [CH:1]1([N:7]([CH3:11])[CH2:8][CH2:9]O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:14])=O>C(OCC)C>[CH:1]1([N:7]([CH2:8][CH2:9][Cl:14])[CH3:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: CN(CCO)C1CCCCC1
Solvent: CCOCC
Product: CN(CCCl)C1CCCCC1
Temperature: 70 °C

Procedure:
N-Cyclohexyl-N-methyl-2-aminoethanol (25 g) is added dropwise to thionyl chloride (120 cc) and then the mixture is heated for 24 hours at 70° C. After the excess thionyl chloride has been distilled off, the orange oil obtained is stirred into ethyl ether (200 cc) to give a white solid, which is separated off by filtrattion and then washed with ether. 2-(N-Cyclohexyl-N-methyl-amino)-1-chloroethane (30 g) is obtained in the form of a white solid melting at 154° C.
Reaction SMILES: [C:1]12([NH:11][C:12]#[N:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Cl.[NH2:15][C:16]1[C:17]([CH3:22])=[CH:18][CH:19]=[CH:20][CH:21]=1>ClC1C=CC=CC=1>[C:1]12([NH:11][C:12]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])=[NH:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: Cc1ccccc1N
Reactant: N#CNC12CC3CC(CC(C3)C1)C2
Agent: Cl
Solvent: Clc1ccccc1
Product: Cc1ccccc1NC(=N)NC12CC3CC(CC(C3)C1)C2

Procedure:
A suspension of adamantan-1-ylcyanamide (151 mg, 0.857 mmol) and o-toluidine hydrochloride (186 mg, 0.857 mmol) in dry chlorobenzene was heated between 100°-130° C. for 4.5 hrs. The chlorobenzene was evaporated in vacuo with heating and the residue (285 mg) taken up in 18 ml of water. A gummy, insoluble material was discarded. On adjusting the aqueous extract to pH 9-9.5, a precipitate formed (194 mg, 71%). Two recrystallizations from EtOH/H2O gave the analytical sample; mp 160°-161°, 1H (CD3OD) 1.742 (s, 6 H), 2.050 (d, 6H, J=2.4 Hz), 2.029 (s, 3 H), 6.956 (j, 1 H, J=8.1 Hz), 7.056 (t, 1H, J=8.1 Hz), 7.168 (t, 1H, J=7.5 Hz), 7.213 (d, 1H, J=7.5 Hz). Anal. Calcd for C18H25N3 : C, 76.28; H, 8.89; N, 14.83. Found: C, 76.25; H, 8.86; N, 14.60.