Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[CH:4]=1.C(#N)C.[O:21]([C:23]#[N:24])[Na].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>O>[CH3:1][O:2][C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:23]([NH2:24])=[O:21])[C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[CH:4]=1
Reactant: N#CO[Na]
Reactant: COC1=Cc2ccccc2Nc2ccccc21
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CC#N
Solvent: O
Product: COC1=Cc2ccccc2N(C(N)=O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 50.7 %

Procedure:
10-methoxy-5H-dibenz(b,f)azepine (29.9 g, 0.134 mol) was added to 300 ml acetonitrile in a three-neck flask (500 ml) equipped with a mechanical stirring apparatus. The mixture was stirred at room temperature for 15 minutes, and then NaOCN (18 g, 0.277 mol) was added, followed by pyridinium p-toluenesulfonate (75 g, 0.3 mol). The mixture was stirred at room temperature for about 4 hours, at which time TLC indicated that the reaction was complete (disappearance of 10-methoxy-5H-dibenz(b,f)azepine). 30 ml water was added, and the mixture stirred for 15 minutes. The solids were filtered and the filtrate was concentrated under vacuum. The semi-solid residue was triturated with acetone to provide a creamy solid, which was dried at 80° C. to provide 18 g (0.068 mol, 50% yield) of 10-methoxy-5H-dibenz[b,f]azepine-5-carboxamide (10-methoxycarbamazepine).
Reaction SMILES: C(OC([N:8]1[C:13](=[O:14])[CH:12]2[CH:10]([CH:11]2[C:15]([O-:17])=[O:16])[CH:9]1[C:18]([O-:20])=[O:19])=O)(C)(C)C.[C:21]([NH:29][NH2:30])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1.[C-]#N.[K+]>[C:21]([NH:29][NH:30][C:13]([CH:12]1[CH:10]([CH:9]([C:18]([OH:20])=[O:19])[NH2:8])[CH:11]1[C:15]([OH:17])=[O:16])=[O:14])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)C2C(C(=O)[O-])C2C1C(=O)[O-]
Reactant: NNC(=O)c1ccccc1
Agent: [C-]#N
Agent: [K+]
Solvent: C1CCOC1
Product: NC(C(=O)O)C1C(C(=O)O)C1C(=O)NNC(=O)c1ccccc1
Reaction time: 8 h
Yield: 104.6 %

Procedure:
To a solution of ethyl (1SR, 2 SR, 5RS, 6RS) 3-tert -butoxycarbonyl-4-oxo-3-azabicyclo[3.1.0]hexane-2,6-dicarboxylate (88 mg, 0.25 mmol) in dry THF (2 mL) under argon was added benzoic hydrazide (209 mg, 1.54 mmol) and potassium cyanide (0.83 mg, 0.01 mmol). After stirring overnight in an ultrasonic bath, the solvent was removed under reduced pressure. The residue was directly purified by flash chromatography (hexane/ethyl acetate 1/1) to give 84 mg of the desired compound (72% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15]O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CS(Cl)(=O)=O.S([O-])(=O)(=O)C.[NH:27]1[C:35]2[N:30]3[C:31](=[N:36][CH:37]=[C:29]3[C:28]1=[O:38])[CH:32]=[CH:33][CH:34]=2.C1CCN2C(=NCCC2)CC1>CCOCC.O.CN(C=O)C.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][N:27]2[C:35]3[N:30]4[C:31](=[N:36][CH:37]=[C:29]4[C:28]2=[O:38])[CH:32]=[CH:33][CH:34]=3)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=c1[nH]c2cccc3ncc1n32
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(CCn2c(=O)c3cnc4cccc2n43)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.2 %

Procedure:
To a solution prepared by dissolving 8.26 g (36.0 mM) of 2-(1-tert-butoxycarbonylpiperidin-4-yl)ethanol and 10.0 ml (72.0 mM) of triethylamine in 50 ml of ether was added 3.34 ml (43.2 mM) of methanesulfonyl chloride dropwise at 0° C. After completion of dropwise addition, the reaction mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the reaction mixture was poured in 100 ml of iced water and the mixture was extracted with 100 ml of ethyl acetate. The organic layer was washed with 100 ml of saturated aqueous NaCl solution and dried over anhydrous magnesium sulfate (MgSO4) and the solvent was distilled off under reduced pressure to recover the mesylate as solid. To a solution prepared by dissolving this mesylate and 10.37 g (36.0 mM) of 1,2-dihydro-1,4,7b-triazacyclopent[cd]inden-2-one.2NaCl in 25 ml of DMF was added 6.46 ml (43.2 mM) of DBU and the mixture was heated at 80° C. for 2 hours. After completion of the reaction, the reaction mixture was poured in iced water and the mixture was extracted with 200 ml of ethyl acetate. The organic layer was washed with 200 ml of purified water 3 times and further with 200 ml of saturated aqueous NaCl solution and dried over MgSO4. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel column chromatography (eluent: ethyl acetate) to provide 9.10 g (yield 68.2%) of the title compound as light-yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].[Cl:12][C:13]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:14]=1[C:15](Cl)=[O:16]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[O:11][C:15](=[O:16])[C:14]1[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:13]=1[Cl:12]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Nc1c(OC(=O)c2ccc(Cl)cc2Cl)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.7 %

Procedure:
To a 500 mL, round-bottomed, one-necked flask equipped with a magnetic stir bar and a septum was added 2-amino-3-nitrophenol (4.25 g, 27.6 mmol), anhydrous CH2Cl2 (140 mL), 4-(dimethylamino)pyridine (3.37 g, 27.6 mmol) and 2,4-dichlorobenzoyl chloride (5.78 g, 3.87 mL, 27.6 mmol). The reaction mixture was allowed to stir at room temperature overnight. TLC analysis indicated the complete consumption of starting material. The reaction mixture was diluted with CH2Cl2 (300 mL) and the mixture was washed with H2O (2×200 mL), dried (Na2SO4), and concentrated to give 8.91 g (98.7%) of a yellow-orange solid. 1H NMR analysis indicated the material, I-113 was pure enough to carry on to the next step. 1H NMR (500 MHz, CDCl3).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11]([Cl:12])=[C:10]([CH3:13])[C:9](=[O:14])[N:8]([CH3:15])[C:7]=1[C:16](=[O:18])[CH3:17])=[O:5])C.[Li+].[OH-].Cl>C1COCC1.O>[C:16]([C:7]1[N:8]([CH3:15])[C:9](=[O:14])[C:10]([CH3:13])=[C:11]([Cl:12])[C:6]=1[C:4]([OH:5])=[O:3])(=[O:18])[CH3:17]
Reactant: CCOC(=O)c1c(Cl)c(C)c(=O)n(C)c1C(C)=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1c(C(=O)O)c(Cl)c(C)c(=O)n1C
Reaction time: 0.5 h

Procedure:
To a solution of 2-acetyl-4-chloro-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid ethyl ester (1.00 equivalent) in THF:water (4:1) is added 1 M aqueous LiOH solution (2.05 equivalents). After 30 minutes, the reaction mixture is acidified to pH ˜1 with 1 N HCl solution and extracted with ethyl acetate. The combined organic extracts are dried (MgSO4) and concentrated under reduced pressure to give the desired product which is used directly without further purification.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH3:23][O:24][C:25](=[O:36])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[S:32](Cl)(=[O:34])=[O:33]>ClCCl>[CH3:23][O:24][C:25](=[O:36])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[S:32]([N:13]1[CH2:14][CH2:15][N:10]([C:7]2[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=2)[CH2:11][CH2:12]1)(=[O:33])=[O:34]
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: COC(=O)c1ccccc1S(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccccc1S(=O)(=O)N1CCN(c2ccc(Cl)cc2)CC1
Reaction time: 0.25 h
Yield: 5.5 %

Procedure:
To stirred suspension of 4-(4-chlorophenyl)piperazine dihydrochloride (3.0 g) in dichloromethane (100 ml) at 0° C. was added triethylamine (4.6 ml). After 15 mins, a solution of 2-chlorosulfonylbenzoic acid methyl ester (2.90 g) in dichloromethane (30 ml) was added. Stirring was continued overnight with the temperature rising to RT. The reaction mixture was diluted with dichloromethane (100 ml) and then washed with 10% aqueous citric acid (3×50 ml), saturated aqueous sodium hydrogen carbonate solution (3×50 ml), water (3×50 ml) and brine (50 ml). The organic layer was then dried (MgSO4), filtered and the solvent removed under reduced pressure to give the title compound (0.24 g, 48%) as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[CH:6][S:5][CH:4]=1.[CH3:8][C:9]([CH3:14])=[CH:10][C:11](Cl)=[O:12].[Sn](Cl)(Cl)(Cl)Cl.[K+].[Br-]>ClCCl>[CH3:1][O:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:11](=[O:12])[CH:10]=[C:9]([CH3:14])[CH3:8]
Reactant: CC(C)=CC(=O)Cl
Reactant: COc1ccsc1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Product: COc1ccsc1C(=O)C=C(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 3-methoxythiophene (21.3 g, 0.187 mol) [S. Gronowitz, Arkiv. Kemi., 1958, 12, 239] in dichloromethane (50 mL) was slowly added to a solution of 3,3-dimethylacryloyl chloride (22 mL, 0.195 mol) and tin(IV) chloride (23 mL, 0.195 mol) in dichloromethane (350 mL) at 0°-5° C. After stirring at 0°-5° C. an additional 1 h, the solution was poured into ice water (1 L). The organic layer was separated, washed with water, and dried over magnesium sulfate. The solvent was evaporated in vacuo. The resulting oil was purified by flash chromatography using dichloromethane as the eluant to give the product, 29.6 g (81%): mp 49°-51° C.; IR (KBr): 1671, 1628 and 1430 cm-1 ; MS: m/z 197 (MH+); 1H NMR (CDCl3): δ1.98 (d, J=1.2 Hz, 3H), 2.23 (d, J=1.1 Hz, 3H), 3.98 (s, 3H), 6.85 (d, J=5.5 Hz, 1H), 6.89 (dd, J=1.1 Hz, J=1.2 Hz, 1H) and 7.47 (d, J=5.5 Hz, 1H). Anal. Calcd. for C10H12O2S: C, 61.20; H, 6.16; S, 16.34.
Reaction SMILES: COP([CH2:7][C:8]([C:10]1[CH:11]=[N:12][N:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:14]=1[CH3:15])=[O:9])(=O)OC.CC(C)([O-])C.[K+].[CH3:28][C@@:29]12[C:35]([CH3:37])([CH3:36])[C@@H:32]([CH2:33][CH2:34]1)[C:31](=O)[C:30]2=[O:39]>C(O)(C)(C)C>[CH3:28][C@@:29]12[C:35]([CH3:37])([CH3:36])[C@@H:32]([CH2:33][CH2:34]1)/[C:31](=[CH:7]\[C:8]([C:10]1[CH:11]=[N:12][N:13]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:14]=1[CH3:15])=[O:9])/[C:30]2=[O:39]
Reactant: COP(=O)(CC(=O)c1cnn(-c2ccccc2)c1C)OC
Reactant: CC1(C)[C@H]2CC[C@]1(C)C(=O)C2=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: Cc1c(C(=O)/C=C2/C(=O)[C@@]3(C)CC[C@@H]2C3(C)C)cnn1-c1ccccc1
Reaction time: 0.5 h
Yield: 74.6 %

Procedure:
[2-(5-Methyl-1-phenyl-1H-pyrazol-4-yl)-2-oxo-ethyl]-phosphonic acid dimethyl ester (1.1 g) in tert-butanol (60 mL) at RT under an argon atmosphere was treated with potassium tert-butoxide (0.412 g) and the mixture was stirred for 30 minutes. Then (1S,4R)-1,7,7-trimethyl-bicyclo[2.2.1]heptane-2,3-dione (0.499 g) was added at RT and the mixture was heated at reflux for 12 h under an argon atmosphere. The reaction mixture was partitioned between water and AcOEt, the layers were separated, the aqueous layer extracted twice with AcOEt. The combined organic layers were washed with water, dried over Na2SO4, filtered and evaporated. The residue was purified by flash chromatography (heptane/AcOEt 100% to 80%) to give (1S,4R)-1,7,7-trimethyl-3-[2-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-2-oxo-eth-(E)-ylidene]-bicyclo[2.2.1]heptan-2-one (0.78 g) as a light yellow solid. MS (EI): 348.2 (M+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][CH:8]([CH2:11][OH:12])[CH2:9][CH3:10])([CH3:4])([CH3:3])[CH3:2].[CH2:14]([O:16][C:17](=[O:21])[CH:18]=[N+]=[N-])[CH3:15]>ClCCCl>[CH2:14]([O:16][C:17](=[O:21])[CH2:18][O:12][CH2:11][CH:8]([NH:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:13])[CH2:9][CH3:10])[CH3:15]
Reactant: CCC(CO)NC(=O)OC(C)(C)C
Reactant: CCOC(=O)C=[N+]=[N-]
Solvent: ClCCCl
Product: CCOC(=O)COCC(CC)NC(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 40 %

Procedure:
To a solution of (1-(hydroxymethyl)propyl)carbamic acid tert-butylester (7.2 g, 39 mmol) in 1,2-dichloroethane (500 ml) rhodium(II)acetate (180 mg) was added and the mixture was heated to 80° C. Ethyldiazoacetate (6.0 ml, 57 mmol) in 1,2-dichloroethane (180 ml) was added over a period of 60 min and the mixture was heated at 80° C. for 6 hours. Then another portion of ethyldiazoacetate (2.0 ml, 19 mmol) in 1,2-dichloroethane (40 ml) was added and the mixture was refluxed for 7 hours. The mixture was cooled to room temperature and washed with sodium bicarbonate (2×100 ml) and brine (100 ml), dried over magnesium sulfate and concentrated in vacuo. The crude product was chromatographed on silica (300 g) with pentane/ethyl acetate 7:3 as eluent to give 4.3 g of (2-(tert-butoxycarbonylamino)butoxy)acetic acid ethylester. The product was dissolved in of 1 M lithium hydroxide in water/methanol 1:3 (40 ml) and stirred at room temperature for 4 hours. The mixture was concentrated in vacuo and water (100 mL) was added and the solution was washed with ether (20 mL). The aqueous phase was acidified to pH 4 with 1 M aqueous hydrogen chloride and extracted with ethyl acetate (200 ml), dried over magnesium sulfate and concentrated in vacuo to give 2.46 g of (2-(tert butoxycarbonylamino)butoxy)acetic acid.
Reaction SMILES: [H-].[Na+].[Br:3][CH:4]1[CH:8]=[N:7][N:6]=[CH:5]1.[CH3:9][O:10][C:11](=[O:15])[CH:12](Cl)[CH3:13]>CN(C=O)C>[CH3:9][O:10][C:11](=[O:15])[CH:12]([N:6]1[CH:5]=[C:4]([Br:3])[CH:8]=[N:7]1)[CH3:13]
Reactant: BrC1C=NN=C1
Reactant: COC(=O)C(C)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)n1cc(Br)cn1
Reaction time: 0.17 h
Yield: 77 %

Procedure:
Sodium hydride (0.12 g, 4.9 mmol) was added to a solution of 4-bromo-4H-pyrazole (0.60 g, 4.1 mmol) in DMF (10 mL). After stirring for 10 minutes, a solution of 2-chloro-propionic acid methyl ester in DMF (4 mL) was added. After stirring for 4 hours, the reaction was partitioned between ethyl acetate and water. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over MgSO4 and concentrated by rotary evaporation. The residue was purified by silica gel chromatography using gradient elution of ethyl acetate and hexanes to afford 2-(4-bromo-pyrazol-1-yl)-propionic acid methyl ester (733 mg, 77%).
Reaction SMILES: [C:1]([O:10]C(=O)CCCCC)(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[OH-:18].[Na+].Cl>CCO.O>[C:7]([C:7]1[CH:8]=[C:2]([C:1]([OH:10])=[O:9])[C:3]([OH:4])=[CH:5][CH:6]=1)(=[O:18])[CH2:8][CH2:2][CH2:3][CH3:5]
Reactant: [OH-]
Reactant: CCCCCC(=O)OC(=O)c1ccccc1O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCCC(=O)c1ccc(O)c(C(=O)O)c1
Yield: 90 %

Procedure:
97.5 g of compound 17 (412 mmole) was dissolved in 530 ml EtOH and 1050 ml water. 87 g NaOH (2.19 mole) was added and the mixture was refluxed for 5 hours. Afterwards the mixture was acidified with concentrated HCl to pH 1. The formed precipitate was filtered off and dried under reduced pressure. 82 g was obtained (90% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6](B(O)O)=[CH:5][N:4]=1.[F:14][C:15]1[C:20](I)=[CH:19][CH:18]=[C:17]([CH3:22])[N:16]=1.C([O-])([O-])=O.[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(O)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:14][C:15]1[C:20]([C:6]2[C:7]([O:9][CH3:10])=[N:8][C:3]([O:2][CH3:1])=[N:4][CH:5]=2)=[CH:19][CH:18]=[C:17]([CH3:22])[N:16]=1
Reactant: Cc1ccc(I)c(F)n1
Reactant: COc1ncc(B(O)O)c(OC)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCCO
Product: COc1ncc(-c2ccc(C)nc2F)c(OC)n1
Yield: 75.5 %

Procedure:
2,4-Dimethoxy-pyrimidine-5-boronic acid (1.16 g, 6.32 mmol) was dissolved in degassed n-PrOH (22 ml) and then 2-fluoro-6-methyl-3-iodopyridine (870 mg, 3.67 mmol), Na2CO3 (778 mg, 7.34 mmol), PPh3 (96 mg, 0.37 mmol) and Pd(OAc)2 (41 mg added in three portions) were added. The suspension was stirred at reflux for 2.5 hours. The solvent was evaporated under vacuum and the crude was partitioned between water and DCM. The organic phase was dried (Na2SO4) and evaporated. The crude was triturated with iPrOH to give 691 mg of the title compound (75% yield).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[N+:22]([C:19]1[CH:20]=[CH:21][C:16]([O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=2)=[CH:17][CH:18]=1)([O-:24])=[O:23]
Reactant: CCOC(=O)CCc1ccc(O)cc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl 3-(4-hydroxyphenyl)-propionate (6.00 g, 30.9 mmol) in DMF (60 mL) were added 4-fluoronitrobenzene (6.54 g, 46.3 mmol) and potassium carbonate (5.12 g, 37.1 mmol). The resulting reaction solution was stirred for 1 hour at 80° C. To the reaction solution was added water and extracted with ethyl acetate. The resulting ethyl acetate layer was washed with water and then with brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1), to thereby yield 9.64 g of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:10]=[CH:11][C:12]=1[I:13])[NH2:9].[Cl:15][C:16]1[CH:29]=[CH:28][C:19]2[S:20][C:21]([S:24](Cl)(=[O:26])=[O:25])=[C:22]([CH3:23])[C:18]=2[CH:17]=1>>[CH3:1][N:2]([CH3:14])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([NH:9][S:24]([C:21]2[S:20][C:19]3[CH:28]=[CH:29][C:16]([Cl:15])=[CH:17][C:18]=3[C:22]=2[CH3:23])(=[O:26])=[O:25])[CH:10]=[CH:11][C:12]=1[I:13]
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(Cl)cc12
Reactant: CN(C)CCOc1cc(N)ccc1I
Product: Cc1c(S(=O)(=O)Nc2ccc(I)c(OCCN(C)C)c2)sc2ccc(Cl)cc12

Procedure:
The title compound was prepared from 3-(2-dimethylaminoethoxy)-4-iodoaniline (WO95/15954, Description 50) (109 mg, 0.36 mmol) and 5-chloro-3-methylbenzo[b]thiophene-2-sulfonyl chloride (100 mg, 0.36 mmol) using the method of Example 1 (70 mg, 36%) MH+=551/553.
Reaction SMILES: [CH2:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[N:20]([CH3:21])[N:19]=[CH:18][C:17]=2[NH:22][C:23]([C:25]2[N:26]=[C:27](Br)[S:28][C:29]=2[NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:24])[CH2:12][CH2:11]1)=[O:7])[CH2:2][CH2:3][CH3:4].C([O-])([O-])=O.[Na+].[Na+].[CH:45]1(/[CH:51]=[CH:52]/B(O)O)[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[N:20]([CH3:21])[N:19]=[CH:18][C:17]=2[NH:22][C:23]([C:25]2[N:26]=[C:27](/[CH:52]=[CH:51]/[CH:45]3[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]3)[S:28][C:29]=2[NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:24])[CH2:12][CH2:11]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)NCC1CCN(c2c(NC(=O)c3nc(Br)sc3NC(=O)OC(C)(C)C)cnn2C)CC1
Reactant: OB(O)/C=C/C1CCCCC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: CCCCOC(=O)NCC1CCN(c2c(NC(=O)c3nc(/C=C/C4CCCCC4)sc3NC(=O)OC(C)(C)C)cnn2C)CC1
Temperature: 130 °C
Yield: 67.8 %

Procedure:
A mixture of tert-butyl 4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamate (0.203 g, 0.33 mmol), Na2CO3 (70 mg, 0.66 mmol) and trans-(2-cyclohexylvinyl)boronic acid (0.102 g, 0.66 mmol) in DME (1.5 mL) and water (0.5 mL) was degassed by gently bubbling nitrogen through the mixture for 15 min. [1,1′-Bis(diphenylphosphino)ferrocene]dichloro-palladium(II) (27 mg, 0.033 mmol) was then added and the mixture degassed for a further 10 min before being heated in a microwave at 130° C. for 45 min. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic extracts were passed through a phase separator cartridge and concentrated under reduced pressure. The residue was purified via silica gel column chromatography (0-100% EtOAc/isohexane) to afford (E)-tert-butyl 4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-(2-cyclohexylvinyl)thiazol-5-ylcarbamate as a brown gum (0.144 g, 68%). A solution of this gum (0.142 g, 0.22 mmol) in MeOH (5 mL) and acetic acid (0.5 mL) was passed through the H-Cube® (70 bar, 70° C., flow rate: 1 mL/min, 30 mm 10% Pd/C cartridge). The solvent was removed under reduced pressure to afford crude tert-butyl 4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-(2-cyclohexylethyl)thiazol-5-ylcarbamate as a clear gum (0.122 g, 99%). This gum (0.122 g, 0.188 mmol) was stirred in HCl in 1,4-dioxane (4.0 M, 2 mL) at room temperature for 18 hr. The solvents were removed under reduced pressure and the crude residue was re-dissolved in MeOH and loaded onto an SCX column. The column was washed with MeOH and 7N ammonia in MeOH to yield 281 as a pink solid (39 mg, 63%). 1H NMR (400 MHz, d4-MeOD) δ 7.43 (s, 1H), 3.71 (s, 3H), 3.21-3.06 (m, 4H), 2.86 (t, J=7.8 Hz, 2H), 2.62 (d, J=6.6 Hz, 2H), 1.87-1.59 (m, 9H), 1.58-1.45 (m, 1H), 1.43-1.15 (m, 6H), 0.99 (q, J=11.9 Hz, 2H). LCMS (ES+) m/z 446 (M+1)
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]2[C:3]=1[CH:4]=[C:5]([CH3:14])[C:6](=[O:13])[NH:7]2.Br[CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19]>>[CH3:19][C:18]([CH3:20])=[CH:17][CH2:16][O:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]2[C:3]=1[CH:4]=[C:5]([CH3:14])[C:6](=[O:13])[NH:7]2
Reactant: Cc1cc2c(O)ccc(C)c2[nH]c1=O
Reactant: CC(C)=CCBr
Product: CC(C)=CCOc1ccc(C)c2[nH]c(=O)c(C)cc12
Yield: 73.9 %

Procedure:
Reaction, post-treatment, and recrystallization (chloroform-n-hexane) were performed in a manner similar to that described in Reference Example 31 using 5-hydroxy-3,8-dimethylcarbostyril (1.4 g, 7.41 mmol) and 4-bromo-2-methyl-2-butene (1.21 g, 8.15 mmol). As a result, 1.41 g of the title compound was obtained as colorless crystals (74.1%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]23[CH2:19][CH:14]4[CH2:15][CH:16]([CH2:18][C:12]([C:20]([O:22][CH3:23])=[O:21])([CH2:13]4)[CH2:11]2)[CH2:17]3)=[CH:6][CH:5]=1)([O-])=O.NC1C=CC(C2CCC(C(OC)=O)C2)=CC=1>>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]23[CH2:19][CH:14]4[CH2:15][CH:16]([CH2:18][C:12]([C:20]([O:22][CH3:23])=[O:21])([CH2:13]4)[CH2:11]2)[CH2:17]3)=[CH:8][CH:9]=1
Reactant: COC(=O)C12CC3CC(C1)CC(c1ccc([N+](=O)[O-])cc1)(C3)C2
Agent: COC(=O)C1CCC(c2ccc(N)cc2)C1
Product: COC(=O)C12CC3CC(C1)CC(c1ccc(N)cc1)(C3)C2

Procedure:
Methyl 3-(4-Nitrophenyl)adamantane-1-carboxylate was reduced by the method of Intermediate 84, step (ii), to give the title compound (Intermediate 85); 1H NMR δ 6.99 (d, 2H), 6.51 (d, 2H), 4.80 (s, 2H), 3.59 (s, 3H), 2.17-2.10 (m, 2H), 1.87-1.79 (m, 6H), 1.77-1.72 (m, 4H), 1.69-1.63 (m, 2H); MS m/e M+MeCN 327.