Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]3[CH2:9][NH:10][CH2:11][CH2:12][C:13]=3[C:14]([CH3:17])([CH3:16])[O:15][C:6]=2[CH:5]=[C:4]([CH:18]([CH3:26])[CH:19]([CH3:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:3]=1.Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>>[OH:1][C:2]1[C:7]2[C:8]3[CH2:9][N:10]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:11][CH2:12][C:13]=3[C:14]([CH3:16])([CH3:17])[O:15][C:6]=2[CH:5]=[C:4]([CH:18]([CH3:26])[CH:19]([CH3:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:3]=1
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CNCC1
Reactant: CCOC(=O)CBr
Product: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CN(CC(=O)OCC)CC1

Procedure:
The above-titled compound was prepared by reacting 10-hydroxy-5,5-dimethyl-8-(1,2,-dimethylheptyl)-1,2,3,4-tetrahydro-5H-[1]benzopyrano[4,3-c]pyridine with ethyl bromoacetate according to the method of Example 1. The product was purified by chromatography on a 60-100 mesh Florisil and graded ethanol-chloroform mixtures.
Reaction SMILES: C(OC(=O)[NH:7][C:8](=[NH:33])[C:9]1[S:10][C:11]([S:31][CH3:32])=[C:12]([S:14]([C:17]2[CH:18]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3C=C)[CH:20]=[CH:21][CH:22]=2)(=[O:16])=[O:15])[CH:13]=1)(C)(C)C.[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38]>>[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38].[OH:38][CH:37]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([S:14]([C:12]2[CH:13]=[C:9]([C:8]([NH2:7])=[NH:33])[S:10][C:11]=2[S:31][CH3:32])(=[O:15])=[O:16])[CH:18]=1)[CH3:36]
Reactant: C=Cc1ccccc1-c1cccc(S(=O)(=O)c2cc(C(=N)NC(=O)OC(C)(C)C)sc2SC)c1
Solvent: O=C(O)C(F)(F)F
Product: CSc1sc(C(=N)N)cc1S(=O)(=O)c1cccc(-c2ccccc2C(C)O)c1
Reaction time: 0.17 h
Yield: 33 %

Procedure:
{Imino-[5-methylsulfanyl-4-(2′-vinyl-biphenyl-3-sulfonyl)-thiophen-2-yl]-methyl}-carbamic acid tert-butyl ester (25 mg, 0.05 mmol) was treated with trifluoroacetic acid (50% in DCM) for 1 hr at rt. The reaction mixture was concentrated in vacuo and then basified with 1 M NaOH to pH 8 and allowed to stand for 10 min. The solution was then re-acidified with TFA and purified using C18-HPLC (10–80% CH3CN in H2O (0.1% TFA) over 30 min) to give 7 mg (33%) of the title compound as a white solid (Rt: 12.3 min). 1H-NMR (CD3OD): δ 8.32 (s, 1H), 8.01–8.05 (m, 1H), 7.98–8.00 (m, 1H), 7.64–7.71 (m, 3H), 7.44–7.49 (m, 1H), 7.32–7.36 (m, 1H), 7.16–7.18 (m, 1H), 4.75 (q, 1H, J=6.5 Hz), 2.72 (s, 3H), 1.28 (d, 3H, J=6.5 Hz). ESI-MS (m/z): Calcd. for C20H20N2O3S3: 433.6 (M+H); found: 433.1.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1I.C(=O)([O-])O.[Na+].[N:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.CCOCC>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:30]1[CH:31]=[CH:32][N:27]=[CH:28][CH:29]=1
Reactant: OB(O)c1ccncc1
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Solvent: O
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1-c1ccncc1
Reaction time: 8 h

Procedure:
To a rapidly stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-iodopyrazole (0.25 g) in toluene (2 ml) containing tetrakis(triphenylphosphine)palladium(0) (0.02 g) was added saturated aqueous sodium hydrogen carbonate solution (1 ml) and a solution of 4-pyridylboronic acid (0.153 g) in ethanol (1 ml). The mixture was heated under reflux for 12 hours, then left at room temperature overnight and then poured into ether (25 ml) and water (25 ml). The organic layer was separated, dried (MgSO4) and evaporated. The residue was taken up the minimum amount of ethyl acetate and purified by chromatography on silica gel (20 g) eluted with dichloromethane:methanol (100:1). Combination and evaporation of suitable fractions followed by recrystallisation from ether/hexane dichloromethane gave the title compound as a white solid, m.p. 226-8° C. (decomp.).
Reaction SMILES: [CH3:1][SiH:2]([CH3:4])[Cl:3].[CH2:5]=[CH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12]>C(Cl)Cl>[Cl:3][Si:2]([CH3:4])([CH3:1])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][Si:2]([Cl:3])([CH3:4])[CH3:1]
Reactant: C=CCCCCC=C
Reactant: C[SiH](C)Cl
Solvent: ClCCl
Product: C[Si](C)(Cl)CCCCCCCC[Si](C)(C)Cl
Reaction time: 3 h
Yield: 60 %

Procedure:
Dimethylchlorosilane (6.8 mL, 60 mmol) in CH2Cl2 (10 mL) was added by dropping funnel over 10 minutes to a mixture of 1,7-octadiene (4.5 mL, 30 mmol) and bis (tetrabutylammonium) hexachloroplatinate (272 mg, 0.3 mmol). After 3 hours at room temperature, the solvent was removed in vacuo and the residue taken up in pentane. The majority of the catalyst was removed by filtration under nitrogen and the filtrate was concentrated in vacuo to provide as an oily liquid 1,8bis(chlorodimethyl silyl) octane 1H NMR (200 MHz, CDCl3)δ 1.94-1.75 (m,10H), 0.80 (t,4H), 0.40 (s.12H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[O:5][C:4](=[O:12])[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl[CH2:20][CH2:21][CH2:22][N:23]([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH2:26][CH3:27]>>[CH2:28]([N:23]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:22][CH2:21][CH2:20][O:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[O:5][C:4](=[O:12])[C:3]=1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH2:29][CH2:30][CH3:31]
Reactant: CCCCN(CCCC)CCCCl
Reactant: O=c1oc2c(c(O)c1-c1ccccc1)CCCC2
Product: CCCCN(CCCC)CCCOc1c2c(oc(=O)c1-c1ccccc1)CCCC2
Yield: 80.5 %

Procedure:
As in Example 14, Stage B, 14.5 g. (0.06 mol) of 4-hydroxy-3-phenyl-5,6,7,8-tetrahydrocoumarin are caused to react with 16.2 g. (0.078 mol) of 1-chloro-3-dibutylaminopropane. 19.8 g. of an oil which cannot be crystallised are obtained. Yield 80.5% (theoretical yield 24.6 g.).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][C:16]3([C:19]([O:21][CH3:22])=[O:20])[CH2:18][CH2:17]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[F:23][C:24]1[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[CH:27]=[CH:26][C:25]=1[OH:33]>N1C=CC=CC=1>[F:23][C:24]1[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[CH:27]=[CH:26][C:25]=1[O:33][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][C:16]3([C:19]([O:21][CH3:22])=[O:20])[CH2:18][CH2:17]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C1(COc2cc3nccc(Cl)c3cc2OC)CC1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Solvent: c1ccncc1
Product: COC(=O)C1(COc2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3cc2OC)CC1
Temperature: 110 °C
Yield: 55432.1 %

Procedure:
A mixture of Methyl 1-((4-chloro-6-methoxyquinolin-7-yloxy)methyl)cyclopropane-carboxylate (29.2 g, US12036244) and 2-fluoro-4-nitrophenol (20.5 mg) in pyridine (50 ml) was heated at 110° C. for 4 hours and cooled. The reaction was evaporated and water (300 ml) was added and further sonicated for 20 minutes. The solid was filtered and washed with water followed by acetone to give the product as methyl 1-((4-(2-fluoro-4-nitrophenoxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropanecarboxylate (32 g). This product (3.9 g) was mixed with LiOH (0.82 g) in THF/H2O (40 ml/20 ml) and the mixture was refluxed for 4 hours. The solution was evaporated and acidified with AcOH, the precipitated was filtered and washed with water followed by acetone to give the product as 1-((4-(2-fluoro-4-nitrophenoxy)-6-methoxyquinolin-7-yloxy)methyl)cyclo-propanecarboxylic acid. This acid (1 g) was mixed with DIPEA (0.53 ml) in acetone (50 ml) and cooled at 0° C. To the reaction mixture was added isobutylchloroformate slowly and further stirred for 1 hour at 0° C. To the reaction was added NaN3 (1.52 g) in water (2 ml) and further stirred for 2 hours at 0° C. EtOAc (100 ml) was added to the reaction and washed with brine, dried over Na2SO4. The solution was evaporated to around 10 ml and toluene (70 ml) was added followed by addition of 4-methoxybenzyl alcohol. The solution was refluxed for 4 hours and cooled, EtOAc (50 ml) and water (50 ml) were added and further extracted with EtOAc two times. The combined organic layer was washed with water, brine and dried over Na2SO4. The solution was evaporated and purified with silica gel column to give 4-methoxybenzyl 1-((4-(2-fluoro-4-nitrophenoxy)-6-methoxyquinolin-7-yloxy)-methyl)cyclopropyl-carbamate (850 mg) that was mixed with Fe power (1 g) and NH4Cl (100 mg) in EtOH/H2O (20 ml, 16 ml/4 ml). The solution was refluxed for two hours and filtered through the Celite and washed with MeOH. The filtrate was evaporated and partitioned with water and DCM, the aqueous layer was further extracted with DCM twice. The combined organic layer was washed with water, brine and dried over Na2SO4. The solution was evaporated to give 4-methoxybenzyl 1-((4-(2-fluoro-4-aminophenoxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropylcarbamate (650 mg) for next step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:11][CH3:12])[C:5]([O:9][CH3:10])=[C:6]([Cl:8])[CH:7]=1.[CH:13]1([CH:18]([OH:21])[CH:19]=[CH2:20])[CH2:17][CH2:16][CH2:15][CH2:14]1.C(=O)(O)[O-].[Na+]>CN1CCCC1=O>[Cl:8][C:6]1[CH:7]=[C:2]([CH2:20][CH2:19][C:18]([CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:21])[CH:3]=[C:4]([CH2:11][CH3:12])[C:5]=1[O:9][CH3:10]
Reactant: C=CC(O)C1CCCC1
Reactant: CCc1cc(Br)cc(Cl)c1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCc1cc(CCC(=O)C2CCCC2)cc(Cl)c1OC
Temperature: 140 °C
Yield: 80.6 %

Procedure:
A mixture of 5-bromo-1-chloro-3-ethyl-2-methoxy-benzene (2 g, 8 mmol), 1-Cyclopentyl-2-propen-1-ol (1.3 g, 10.4 mmol), dichlorobis (triphenylphosphine) palladium (II) (110 mg, 0.16 mmol), and sodium bicarbonate (0.81 g, 9.6 mmol) in N-methylpyrrolidinone (15 mL) was heated to 140° C. under N2 for 5 h. The reaction mixture was partitioned between 1N HCl and EtOAc. The organic layer was washed with saturated NaHCO3, brine, dried over Na2SO4 and concentrated to black oil. The oil was purified by flash column chromatography (0% to 10% EtOAc in hexanes) to give the desired product (1.9 g, 82%). 1H NMR (400 MHz, CDCl3): δ 1.20 (t, J=7.6 Hz, 3 H), 1.53–1.81 (m, 8 H), 2.65 (q, J=7.6 Hz, 2 H), 2.74 (m, 2 H), 2.79–2.87 (m, 3 H), 3.81 (s, 3 H), 6.90 (s, 1 H), 7.03 (m, 1 H).
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][NH:15][CH:16]=2)=[CH:6][CH:5]=1>CO.[Pd]>[ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14][NH:15][CH2:16]2)=[CH:8][CH:9]=1
Reactant: COc1ccc(C2=CNCCCC2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COc1ccc(C2CCCCNC2)cc1
Reaction time: 12 h
Yield: 66.1 %

Procedure:
A mixture of 6-(4-methoxyphenyl)-2,3,4,5-tetrahydro-1H-azepine hydrochloride (0.3 g, 1.251 mmol) and 10% Pd-C (0.133 g, 1.251 mmol) in methanol (5 mL), was hydrogenated at 50 psi for 12 h. The reaction mixture was filtered through Celite and and concentrated to yield crude 3-(4-methoxyphenyl)azepane hydrochloride (0.2 g, 57%) as a black gum, used without further purification. LCMS: RT 0.62 min. LCMS (ES-API), m/z 206.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[N:10]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([CH:26]([CH:41]4[CH2:45][CH2:44][CH2:43][CH2:42]4)[C:27]([NH:29][CH2:30][C:31]4[CH:36]=[CH:35][C:34]([C:37]([O:39]C)=[O:38])=[CH:33][CH:32]=4)=[O:28])=[CH:22][CH:21]=3)[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>O1CCOCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[N:10]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([CH:26]([CH:41]4[CH2:45][CH2:44][CH2:43][CH2:42]4)[C:27]([NH:29][CH2:30][C:31]4[CH:32]=[CH:33][C:34]([C:37]([OH:39])=[O:38])=[CH:35][CH:36]=4)=[O:28])=[CH:22][CH:21]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(CNC(=O)C(c2ccc(Cn3nc(-c4ccc(Cl)cc4)c4ccccc4c3=O)cc2)C2CCCC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1ccc(CNC(=O)C(c2ccc(Cn3nc(-c4ccc(Cl)cc4)c4ccccc4c3=O)cc2)C2CCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
270 mg (0.435 mmol) of methyl 4-({[(4-{[4-(4-chlorophenyl)-1-oxophthalazin-2(1H)-yl]methyl}phenyl)(cyclopentyl)acetyl]amino}methyl)benzenecarboxylate (Example 112A) were dissolved in 10 ml of dioxane/water (3:1 v/v), and 0.652 ml (0.652 mmol) of 1 N aqueous sodium hydroxide solution was added. The mixture was stirred at room temperature overnight. The reaction mixture was then acidified with 1 N hydrochloric acid and extracted repeatedly with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. This gave 269 mg of the target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([CH3:12])=[C:7]2[C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1.C[O:21][C:22](=[O:33])[CH:23]([C:25]1[CH:30]=[CH:29][C:28]([CH2:31]Br)=[CH:27][CH:26]=1)[CH3:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([CH3:12])=[C:7]2[C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=1)[O:19][CH2:31][C:28]1[CH:27]=[CH:26][C:25]([C@H:23]([CH3:24])[C:22]([OH:33])=[O:21])=[CH:30][CH:29]=1
Reactant: Cc1cnc2c(Cl)cccc2c1-c1cccc(O)c1
Reactant: COC(=O)C(C)c1ccc(CBr)cc1
Product: Cc1cnc2c(Cl)cccc2c1-c1cccc(OCc2ccc([C@H](C)C(=O)O)cc2)c1

Procedure:
This compound was prepared according to the procedure of example 41, substituting 3-(8-chloro-3-methyl-quinolin-4-yl)-phenol and 2-(4-bromomethyl-phenyl)-propionic acid methyl ester. Purification by supercritical fluid chromatography (MeOH/CO2). Electronic circular dichroism CD λmax=−4 mdeg @ 225 nm (EtOH). MS (ESI) m/z 432.
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH:10]=[CH:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].Cl.C(O)C>O>[CH2:1]([C@H:4]1[CH2:5][CH2:6][C@H:7](/[CH:10]=[CH:11]/[C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[CH2:8][CH2:9]1)[CH2:2][CH3:3]
Reactant: CCC[C@H]1CC[C@H](C=Cc2ccc(C#N)cc2)CC1
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCC[C@H]1CC[C@H](/C=C/c2ccc(C#N)cc2)CC1

Procedure:
This nitrile in an amount of 11.7 g (0.05 ml) was added to a mixture of 13.9 g (0.07 ml) of dihydrated sodium benzenesufinate, 12 ml of 6N-HCl, and 70 ml of ethanol, and reacted under reflux for 4 hours. After finishing of the reaction, 50 ml of water was added to the reaction product and then extracted with 150 ml of toluene. The organic layer thus obtained was washed with saturated aqueous sodium carbonate solution thrice and with water thrice, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under a reduced pressure, and the residue was subjected to silica gel column chromatography (eluent: toluene) to obtain 12.0 g of a crude (E)-4-(2-(trans-4-propylcyclohexyl)vinyl)benzonitrile.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([N:9]2[CH2:13][CH2:12][C:11]([CH3:15])([CH3:14])[C:10]2=[O:16])=[N:5][N:6]([CH3:8])[CH:7]=1.[C:17]([C:20]1[N:25]=[C:24]([C:26](O)=[O:27])[CH:23]=[CH:22][CH:21]=1)(=[O:19])[CH3:18].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C>CN(C=O)C.C(OCC)(=O)C.O>[C:17]([C:20]1[N:25]=[C:24]([C:26]([NH:2][C:3]2[C:4]([N:9]3[CH2:13][CH2:12][C:11]([CH3:14])([CH3:15])[C:10]3=[O:16])=[N:5][N:6]([CH3:8])[CH:7]=2)=[O:27])[CH:23]=[CH:22][CH:21]=1)(=[O:19])[CH3:18]
Reactant: Cn1cc(N)c(N2CCC(C)(C)C2=O)n1
Reactant: CC(=O)c1cccc(C(=O)O)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(=O)c1cccc(C(=O)Nc2cn(C)nc2N2CCC(C)(C)C2=O)n1
Reaction time: 20 h
Yield: 101.9 %

Procedure:
To a solution of 1-(4-amino-1-methyl-1H-pyrazol-3-yl)-3,3-dimethylpyrrolidin-2-one hydrochloride (50 mg), 6-acetylpyridine-2-carboxylic acid (37 mg) and HATU (101 mg) in DMF (3.0 mL) was added ethyldiisopropylamine (71 μL) at room temperature, and the mixture was stirred for 20 hr. The reaction mixture was diluted with ethyl acetate, and water was added thereto. The extract was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (74 mg).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.Br[CH2:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[C:26]#[N:27]>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][N:15]([CH2:22][C:23]4[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=4)[C:26]#[N:27])[C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1
Reactant: N#Cc1cccc(CBr)c1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Product: Cc1noc(C)c1Cn1cc(N2C(=O)CN(Cc3cccc(C#N)c3)C2=O)cn1
Yield: 21 %

Procedure:
Prepared as in example 10-5 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) and 3-(bromomethyl)benzonitrile. Yield 21%. MS M+H calculated 411.1. found 411.1. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 1 uM.
Reaction SMILES: [CH:1]1([CH:4]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[N:5]([CH2:9][CH2:10][CH3:11])[C:6]([NH2:8])=[S:7])[CH2:3][CH2:2]1.Br[CH:19]([CH3:30])[C:20]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[Cl:29])=O>>[Cl:29][C:23]1[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:22]=1[C:20]1[N:8]=[C:6]([N:5]([CH:4]([CH:1]2[CH2:3][CH2:2]2)[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[CH2:9][CH2:10][CH3:11])[S:7][C:19]=1[CH3:30]
Reactant: CC(Br)C(=O)c1ccc(Cl)cc1Cl
Reactant: CCCN(C(N)=S)C(c1ccncc1)C1CC1
Product: CCCN(c1nc(-c2ccc(Cl)cc2Cl)c(C)s1)C(c1ccncc1)C1CC1

Procedure:
This compound was prepared according to the process described in Example 1, starting with 1.2 g of N-[cyclopropyl(4-pyridyl)methyl]-N-propylthiourea (Compound 74) and 1.52 g of 2-bromo-1-(2,4-dichlorophenyl)-1-propanone Compound 15). The product was purified on a silica column, using a mixture of methylene chloride and methanol (98:2 V/V) as eluent.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.FC(F)(F)C(O)=O.[CH2:29]([O:31][C:32](=[O:41])[C:33]([N:35]1[CH2:39][CH2:38][CH:37]([NH2:40])[CH2:36]1)=[O:34])[CH3:30]>C1COCC1.CCN(C(C)C)C(C)C>[CH2:29]([O:31][C:32](=[O:41])[C:33]([N:35]1[CH2:39][CH2:38][CH:37]([NH:40][C:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:9])[CH2:36]1)=[O:34])[CH3:30]
Reactant: CCOC(=O)C(=O)N1CCC(N)C1
Reactant: O=C(O)c1ccc(Cl)s1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(=O)N1CCC(NC(=O)c2ccc(Cl)s2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 109.8 %

Procedure:
106.3 5-Chloro-thiophene-2-carboxylic acid (0.94 g) was dissolved in THF (10 ml) and CDI (0.94 g) was added. This mixture was stirred at 25° C. for 30 min. A solution of (3-amino-pyrrolidin-1-yl)-oxo-acetic acid ethyl ester trifluoroacetate (1.57 g), dissolved in THF (10 ml) and DIEA (0.89 ml), is added to the reaction mixture. The obtained reaction mixture was stirred for 18 h at 25° C. Finally, the reaction mixture was evaporated to dryness. The crude product was purified by chromatography (silica gel; gradient: CH2Cl2 to CH2Cl2/MeOH 98:2) to give {3-[(5-chloro-thiophene-2-carbonyl)-amino]-pyrrolidin-1-yl}-oxo-acetic acid ethyl ester (1.9 g) as an orange oil. MS 331.3 ([M+H]+, Cl-isotopes).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+]([O-])=O)=[CH:7][N:6]=1.[Cl-].[NH4+:17]>[Fe].C(O)C>[F:1][C:2]([F:15])([F:14])[CH2:3][O:4][C:5]1[C:10]([NH2:17])=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: [NH4+]
Reactant: O=[N+]([O-])c1ccc(OCC(F)(F)F)nc1
Agent: [Fe]
Agent: [Cl-]
Solvent: CCO
Product: Nc1cccnc1OCC(F)(F)F
Yield: 23.1 %

Procedure:
2-(2,2,2-Trifluoroethoxy)-5-nitropyridine (5.0 grams), powdered iron (15 grams), and ammonium chloride (25 grams) were refluxed in 3A ethanol until TLC detected no starting material (about 4 hours). The reaction mixture was filtered, washed with water, and solvents removed, yielding 1.0 gram of the product as a thin brownish liquid. NMR confirmed the identity of the product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH:5]([C:7]1[C:12]([F:13])=[CH:11][C:10]([O:14][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:9][C:8]=1[F:32])[OH:6])[CH3:2].I[CH2:35][CH3:36]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:33])[CH:5]([C:7]1[C:12]([F:13])=[CH:11][C:10]([O:14][Si:15]([C:28]([CH3:29])([CH3:31])[CH3:30])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:9][C:8]=1[F:32])[O:6][CH2:35][CH3:36])[CH3:2]
Reactant: CCI
Reactant: CCOC(=O)C(O)c1c(F)cc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1F
Solvent: ClCCl
Product: CCOC(=O)C(OCC)c1c(F)cc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1F
Temperature: 25 °C

Procedure:
To a well stirred solution under N2 of (RS)-[4-(tert-butyl-diphenyl-silanyloxy)-2,6-difluoro-phenyl]-hydroxy-acetic acid ethyl ester (14.9 g) in Tol (100 ml) was added Ag2O (14.7 g). The mixture was heated in an oil bath at 115–120° C. and iodoethane (12.8 ml) in Tol (50 ml) was slowly added from a dropping funnel. After a total of 2 h and 4 h more iodoethane (7.7 ml each) was added. After a total of 5.5 h heating was stopped and the mixture was left to stir over night at RT. The solids were filtered away over 1 cm of dicalite and were washed with AcOEt. The solvent was evaporated to obtain 16.3 g of crude product as a yellow oil. CC (Hept/CH2Cl2 9:1 to pure CH2Cl2) afforded 10.5 (66%) of (RS)-[4-(tert-butyl-diphenyl-silanyloxy)-2,6-difluoro-phenyl]-ethoxy-acetic acid ethyl ester next to 2.6 g (17%) of recovered starting material. Colorless oil. MS 453.2 (4, [M−OEt]+), 441.1 (24, [M−tBu]+)425.2 (100, [M−COOEt]+).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[CH2:8][C:9]([CH3:12])([CH3:11])[O:10][C:6]=2[C:5]([C:13]([O:15][CH3:16])=[O:14])=[CH:4][C:3]=1[NH2:17].[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:20]=1[N:26]=[C:27]=S>C(#N)C>[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:20]=1[NH:26][C:27]1[NH:1][C:2]2[C:7]3[CH2:8][C:9]([CH3:12])([CH3:11])[O:10][C:6]=3[C:5]([C:13]([O:15][CH3:16])=[O:14])=[CH:4][C:3]=2[N:17]=1
Reactant: Cc1cccc(Cl)c1N=C=S
Reactant: COC(=O)c1cc(N)c(N)c2c1OC(C)(C)C2
Solvent: CC#N
Product: COC(=O)c1cc2nc(Nc3c(C)cccc3Cl)[nH]c2c2c1OC(C)(C)C2
Yield: 51 %

Procedure:
The title compound was prepared following the procedure described for Step-1 of Intermediate-3 using methyl 4,5-diamino-2,2-dimethyl-2,3-dihydro-1-benzofuran-7-carboxylate (Intermediate-1, 0.600 g, 2.54 mmol), acetonitrile (10.0 mL), 1-chloro-2-isothiocyanato-3-methylbenzene (Intermediate-34, 0.500 g, 2.73 mmol) and N,N-di-isopropyl carbodimide (0.300 g) to afford 0.500 g of the desired product. 1HNMR (DMSO-d6): δ 1.42 (s, 6H), 2.23 (s, 3H), 2.98 (s, 2H), 3.71 (s, 3H), 7.02 (d, J=7.5 Hz, 1H), 7.23-7.41 (m, 3H), 9.00 (s, 1H), 10.82 (s, 1H); MS [M+H]+: 386.32.