Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[Br:11][CH2:12][CH2:13]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:11][CH2:12][CH2:13][O:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][OH:1])=[CH:5][CH:6]=1
Reactant: OCCc1ccc(O)cc1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: OCCc1ccc(OCCBr)cc1
Temperature: 80 °C
Reaction time: 48 h
Yield: 73 %

Procedure:
To a solution of 4-(2-hydroxyethyl)phenol (5 g, 0.035 mol) in acetone (50 mL) was added 1,2-dibromoethane (15.6 mL, 1.3 mol) and potassium carbonate (13 g, 0.09 mol). The mixture was stirred at 80° C. for 48 hours. The salts were filtered and the mixture was evaporated. The crude obtained was partitioned between ethyl acetate/water. The organic layer was washed with sodium hydroxide 2N, water and brine, dried, filtered and the solvent was removed under reduced pressure to give the title compound as a white solid (73%), which was used in the next step without further purification.
Reaction SMILES: Cl[CH:2]([CH3:9])[C:3]([NH:5][C:6]([NH2:8])=[O:7])=[O:4].[OH:10][C:11]1[C:16]2[C:17]3[CH2:18][NH:19][CH2:20][CH2:21][C:22]=3[C:23]([CH3:26])([CH3:25])[O:24][C:15]=2[CH:14]=[C:13]([CH:27]([CH3:35])[CH:28]([CH3:34])[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:12]=1.C(N(CC)CC)C>CN(C)C=O>[OH:10][C:11]1[C:16]2[C:17]3[CH2:18][N:19]([CH:2]([CH3:9])[C:3]([NH:5][C:6]([NH2:8])=[O:7])=[O:4])[CH2:20][CH2:21][C:22]=3[C:23]([CH3:25])([CH3:26])[O:24][C:15]=2[CH:14]=[C:13]([CH:27]([CH3:35])[CH:28]([CH3:34])[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:12]=1
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CNCC1
Reactant: CC(Cl)C(=O)NC(N)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CN(C(C)C(=O)NC(N)=O)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 1.66 g. (0.011 mole) of 2-chloropropionylurea in 20 ml. of dimethylformamide was added dropwise to a stirred solution of 3.57 g. (0.01 mole) of 10-hydroxy-5,5-dimethyl-8-(1,2-dimethylheptyl)-1,2,3,4-tetrahydro-5H-[1]benzopyrano[4,3-c]pyridine in 20 ml. of dimethylformamide and 1.11 g. (0.011 mole) of triethylamine. The reaction mixture was stirred at room temperature for 72 hours, diluted with 60 ml. of water, and extracted with ether. The ether extracts were washed with water, dried over anhydrous sodium sulfate, and evaporated in vacuo. The residue was purified by chromatography on a 100-200 mesh Florisil activated magnesium silicate column and chloroform; m.p. 95°-100°.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][NH:4][C@@H:3]1[CH2:8][N:9]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:19].[CH3:20][C:21]1[CH:22]=[CH:23][C:24]([C:30]2[N:31]=[N:32][CH:33]=[CH:34][CH:35]=2)=[C:25]([CH:29]=1)[C:26](O)=[O:27].CCN(C(C)C)C(C)C.CCCP(=O)=O>C(Cl)Cl>[CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:26](=[O:27])[C:25]2[CH:29]=[C:21]([CH3:20])[CH:22]=[CH:23][C:24]=2[C:30]2[N:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[C@@H:3]1[CH2:8][N:9]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:19]
Reactant: C[C@@H]1CCCN[C@@H]1CN1C(=O)c2ccccc2C1=O
Reactant: Cc1ccc(-c2cccnn2)c(C(=O)O)c1
Agent: CCCP(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(-c2cccnn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN2C(=O)c3ccccc3C2=O)c1
Temperature: 40 °C

Procedure:
To a mixture of 2-(((2S,3R)-3-methylpiperidin-2-yl)methyl)isoindoline-1,3-dione (1.09 g, 4.20 mmol), 5-methyl-2-(pyridazin-3-yl)benzoic acid (0.75 g, 3.5 mmol) and DIPEA (1.8 mL, 10.5 mmol) in DCM (20 mL) was added propylphosphonic anhydride (T3P) (50% in EtOAc, 4.2 mL, 7.0 mmol). The mixture was heated at 40° C. for 16 h. The mixture was cooled to rt and diluted with DCM. The mixture was washed with satd. aq. NaHCO3, brine, and dried (MgSO4). The solvent was removed in vacuo. The crude was purified by chromatography on silica gel (EtOAc/hexanes) to afford the title compound. ESI-MS (m/z): 455 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]([C:11]#[C:12][CH2:13][CH2:14][CH2:15][OH:16])[CH:9]=[CH:10][C:4]=2[C:3]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>>[CH3:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]([C:11]#[C:12][CH2:13][CH2:14][CH2:15][O:16][S:28]([CH3:27])(=[O:30])=[O:29])[CH:9]=[CH:10][C:4]=2[C:3]=1[C:17]1[CH:18]=[CH:19][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:21][CH:22]=1
Reactant: Cc1sc2cc(C#CCCCO)ccc2c1-c1ccc(C(F)(F)F)cc1
Reactant: CS(=O)(=O)Cl
Product: Cc1sc2cc(C#CCCCOS(C)(=O)=O)ccc2c1-c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to example 21.1, the 5-[2-Methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yl]-pent-4-yn-1-ol was treated with methanesulfonic acid chloride to yield the Methanesulfonic acid 5-[2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yl]-pent-4-ynyl ester as yellow oil, MS: 452 (M+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:31])=[C:14]([C:24]([NH:26][CH2:27][CH2:28][O:29][CH3:30])=[O:25])[C:15](=[O:23])[N:16]3[CH2:19][C:20]([OH:22])=O)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.Cl.[CH3:33][NH:34][O:35][CH3:36]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:31])=[C:14]([C:24]([NH:26][CH2:27][CH2:28][O:29][CH3:30])=[O:25])[C:15](=[O:23])[N:16]3[CH2:19][C:20]([N:34]([CH3:33])[O:35][CH3:36])=[O:22])=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CNOC
Reactant: COCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)O)c1=O
Agent: Cl
Product: COCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N(C)OC)c1=O

Procedure:
This compound was prepared from [7-[(4-fluorophenyl)methyl]-4-hydroxy-3-({[2-(methyloxy)ethyl]amino}carbonyl)-2-oxo-1,5-naphthyridine-1(2H)-yl]acetic acid and N,O-dimethylhydroxylamine hydrochloride employing methods similar to those described in Example 558 and was obtained as a white solid: 1H NMR (d6-DMSO) δ 10.17 (1H, br t, J=5 Hz), 8.53 (1H, s), 7.82 (1H, s), 7.32 (2H, t, J˜8 Hz), 7.12 (2H, t, J˜9 Hz), 5.19 (2H, s), 4.12 (2H, s), 3.83 (3H, s), 3.53-3.48 (4H, m), 3.26 (3H, s), 3.12 (3H, s); AP+ MS: 473 (M+H+, 100).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][N:11]2[N:10]=[C:9]1[CH:18]([NH:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[CH2:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][N:11]2[N:10]=[C:9]1[CH:18]([N:21]([CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[C:33](=[O:34])[C:32]1[CH:36]=[CH:37][C:29]([Cl:28])=[CH:30][CH:31]=1)[CH2:19][CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CCC(NC1CCCCC1)c1nn2cccc2c(=O)n1Cc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCC(c1nn2cccc2c(=O)n1Cc1ccccc1)N(C(=O)c1ccc(Cl)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 12.4 %

Procedure:
3-Benzyl-2-(1-cyclohexylamino-propyl)-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one (Example 28, 26.3 mg, 0.072 mmol) in CHCl3 (1.5 mL) at 25° C. was treated with 4-chlorobenzoyl chloride (43.4 mg, 0.248 mmol) and triethylamine (16.8 mg, 0.166 mmol). The resulting mixture was stirred at 25° C. for 18 h, then concentrated under vacuum and purified by preparative HPLC using a YMC S10 ODS 20×100 mm column affording the desired compound (4.5 mg, 12.4%) as a colorless film: LC/MS 80% at 4.47 min (ESI+) 503 (M++H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]/[C:9](=[C:16]2\[C:17](=[O:25])[NH:18][C:19]3[C:24]\2=[CH:23][CH:22]=[CH:21][CH:20]=3)/[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH2:26]([N:28]=[C:29]=[O:30])[CH3:27]>C1COCC1>[CH2:26]([NH:28][C:29]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]/[C:9](=[C:16]2\[C:17](=[O:25])[NH:18][C:19]3[C:24]\2=[CH:23][CH:22]=[CH:21][CH:20]=3)/[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1)=[O:30])[CH3:27]
Reactant: CCN=C=O
Reactant: Nc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCNC(=O)Nc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 140 h

Procedure:
196 mg (0.6 mmol) of (Z)-3-[1-(4-aminophenylamino)-1-phenyl-methylidene]-2-indolinone are suspended in 10 ml of THF and after the addition of 70 mg (0.1 mmol) of ethyl isocyanate stirred for 140 hours at ambient temperature. The product precipitated is suction filtered, washed with ether and dried.
Reaction SMILES: Cl[CH2:2][C:3]([CH3:5])=[O:4].[F:6][C:7]1[CH:8]=[C:9]([OH:17])[CH:10]=[C:11]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:12]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:6][C:7]1[CH:8]=[C:9]([CH:10]=[C:11]([S:13]([CH3:16])(=[O:14])=[O:15])[CH:12]=1)[O:17][CH2:2][C:3](=[O:4])[CH3:5]
Reactant: CC(=O)CCl
Reactant: CS(=O)(=O)c1cc(O)cc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)COc1cc(F)cc(S(C)(=O)=O)c1
Temperature: 120 °C

Procedure:
1-Chloroacetone (95%, 2.66 g, 27.34 mmol) was added to a stirred solution of 3-fluoro-5-methylsulfonyl-phenol (80%, 1.3 g, 5.46 mmol) and potassium carbonate (2.26 g, 16.40 mmol) in dry dimethyl formamide (10 ml), the mixture was heated to 120° C. for 20 minutes, the mixture was allowed to cool to ambient temperature and water (100 ml) was added. The aqueous phase was extracted with ethyl acetate (3×100 ml), the combined organic phase was washed with LiCl (5% aqueous solution, 4×50 ml), brine (50 ml) and dried with Na2SO4 and evaporated. Purification on flash chromatography (isooctane:ethyl acetate 1:0 to 3:2). 0.905 g, 67%. MS m/z (relative intensity, 70 eV) 246 (M+, 79), 204 (55), 203 (bp), 141 (30), 94 (67).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]3[CH:42]=[CH:41][C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:34]=3)=[CH:27][CH:26]=2)([CH3:24])[CH2:20][CH2:21][CH2:22][OH:23])=[CH:15][CH:14]=1.C(OCC)(=O)C>CS(C)=O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]3[CH:42]=[CH:41][C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:34]=3)=[CH:27][CH:26]=2)([CH3:24])[CH2:20][CH2:21][CH:22]=[O:23])=[CH:15][CH:14]=1
Reactant: CC(CCCO)(c1ccc(OCc2ccc3ccccc3n2)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(CCC=O)(c1ccc(OCc2ccc3ccccc3n2)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 68.5 %

Procedure:
To a solution in DMSO (20 mL) of 4,4-bis(4-(2-quinolylmethoxy)phenyl)-pentan-1-ol (410 mg, 0.74 mmol), prepared as in Example 4, and 1,3-dicyclo-hexylcarbodiimnide (515 mg, 2.5 mmol) was added aqueous IM phosophoric acid (0.5 mL) and the resulting mixture was stirred at room temperature for 4 hours. Ethyl acetate (80 mL) was added and dicyclohexylurea was filtered off. The filtrate was washed with water and brine dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica gel (methylene chloride-ethyl acetate 9:1) to afford 280 mg of 4,4-bis(4-(2-quinolylmethoxy)phenyl)pentanal.
Reaction SMILES: P(O)(O)(O)=O.[CH3:6][C@@H:7]1[CH2:19][NH:18][CH2:17][C@@H:16]2[N:8]1[C:9]1[N:10]=[C:11]3[CH2:22][O:21][CH2:20][C:12]3=[CH:13][C:14]=1[CH2:15]2.[C:23](OC(=O)C)(=[O:25])[CH3:24].[OH-].[Na+]>O.ClCCl>[CH3:6][C@@H:7]1[CH2:19][N:18]([C:23](=[O:25])[CH3:24])[CH2:17][C@@H:16]2[N:8]1[C:9]1[N:10]=[C:11]3[CH2:22][O:21][CH2:20][C:12]3=[CH:13][C:14]=1[CH2:15]2
Reactant: CC(=O)OC(C)=O
Reactant: C[C@@H]1CNC[C@H]2Cc3cc4c(nc3N21)COC4
Agent: O=P(O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC(=O)N1C[C@H]2Cc3cc4c(nc3N2[C@H](C)C1)COC4
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 0.33 (5R,8aR)-5-Methyl-1,3,5,6,7,8,8a,9-octahydro-2-oxa-4,4b,7-triaza-cyclopenta[b]fluorene dihydrogenphosphate in 4 ml water was added a solution of 1.3 ml acetic acid anhydride in 4 ml dichloromethane and the pH of the mixture was adjusted to 12.00 by addition of 1N aqueous sodium hydroxide. The mixture was stirred at room temperature for 15 minutes. The phases were separated and the organic phase was washed with 10% aqueous citric acid, saturated aqueous sodium bicarbonate and brine dried over sodium sulfate and evaporated to dryness to yield 0.25 g of the title compound as slightly yellow oil (MS: 274.1 (M+H+)).
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][CH3:4].[C:24]([C:26]1[CH:31]=[CH:30][C:29]([C@H:32]2[CH2:37][CH2:36][C@H:35]([CH2:38][CH:39]=O)[CH2:34][CH2:33]2)=[CH:28][CH:27]=1)#[N:25].O>COC(C)(C)C>[CH2:38]([C@H:35]1[CH2:36][CH2:37][C@H:32]([C:29]2[CH:30]=[CH:31][C:26]([C:24]#[N:25])=[CH:27][CH:28]=2)[CH2:33][CH2:34]1)[CH:39]=[CH:2][CH2:3][CH3:4]
Reactant: N#Cc1ccc([C@H]2CC[C@H](CC=O)CC2)cc1
Reactant: CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: COC(C)(C)C
Solvent: O
Product: CCC=CC[C@H]1CC[C@H](c2ccc(C#N)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 5.1 g of propyl-triphenylphosphonium bromide in 80 ml of t-butyl methyl ether was treated within 5 minutes with 1.48 g of potassium t-butylate while gassing with argon at -10° C. and the mixture was stirred at room temperature for a further 60 minutes. Thereafter, the mixture was treated within 5 minutes at 0° C. with a solution of 2.0 g of [trans-4-(p-cyanophenyl)cyclohexyl]acetaldehyde in 25 ml of t-butyl methyl ether and the resulting mixture was stirred for a further 45 minutes at room temperature. The reaction mixture was subsequently poured into 100 ml of water and extracted three times with 100 ml of diethyl ether each time. The organic phases were washed twice with 100 ml of water each time, dried over magnesium sulphate and concentrated. The residue was dissolved in 20 ml of ethyl acetate and the solution was treated with 250 ml of petroleum ether. After leaving to stand for 10 minutes at -20° C. the precipitated triphenylphosphine oxide was filtered off and the filtrate was concentrated to dryness. Low-pressure chromatography (0.5 bar) of the yellowish, oily residue (3.33 g) on silica gel with ethyl acetate/petroleum ether (vol. 3:97) gave 2.1 g of p-[trans-4-(2-pentenyl)cyclohexyl]benzonitrile as a colourless oil containing 92.7% of p-[trans-2-(2Z-pentenyl)cyclohexyl]benzonitrile and 6.6% of p-[trans-4-(2E-pentenyl)cyclohexyl]benzonitrile. The material was reacted further without additional purification. If desired, however, this mixture of isomers can be separated by chromatography on silica gel coated with silver nitrate (as illustrated in paragraph d).
Reaction SMILES: [Br:1][C:2]1[C:17]([F:18])=[CH:16][C:5]2[O:6][C:7]3[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:8]=3[CH:9]=[N:10][C:4]=2[CH:3]=1.[C:19]1(=[O:26])[O:25][C:23](=[O:24])[CH2:22][CH2:21][CH2:20]1>C(OCC)(=O)C>[Br:1][C:2]1[C:17]([F:18])=[CH:16][C:5]2[O:6][C:7]3[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:8]=3[C@H:9]3[C@H:22]([C:23]([OH:25])=[O:24])[CH2:21][CH2:20][C:19](=[O:26])[N:10]3[C:4]=2[CH:3]=1
Reactant: O=C1CCCC(=O)O1
Reactant: Fc1cc2c(cc1Br)N=Cc1c(F)cccc1O2
Solvent: CCOC(C)=O
Product: O=C(O)[C@@H]1CCC(=O)N2c3cc(Br)c(F)cc3Oc3cccc(F)c3[C@@H]12
Yield: 99.6 %

Procedure:
Preparation analogous to Example 5, step e, from 8-bromo-1,7-difluorodibenz[b,f][1,4]oxazepine (8 g, 25.8 mmol) and glutaric anhydride (5.9 g, 51.6 mmol). After cooling down, the reaction mixture was dissolved in ethyl acetate, washed with water, dried (Na2SO4) and evaporated to afford the title carboxylic acid (10.9 g, 100%)
Reaction SMILES: [CH2:1]([C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH:10]=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[OH:16][C:17]1[CH:22]=[C:21]([O:23][CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27])[CH:20]=[CH:19][C:18]=1[C:29](=[O:31])[CH3:30].[OH-].[Na+]>C(O)(C)C.O>[CH2:1]([C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH:10]=[CH:30][C:29]([C:18]1[CH:19]=[CH:20][C:21]([O:23][CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27])=[CH:22][C:17]=1[OH:16])=[O:31])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCc1ccccc1C=O
Reactant: CC(=O)c1ccc(OCC=C(C)C)cc1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CCCCCCCc1ccccc1C=CC(=O)c1ccc(OCC=C(C)C)cc1O
Temperature: 45 °C
Reaction time: 8 h
Yield: 52.2 %

Procedure:
To a solution of 3.11 g of 2-heptylbenzaldehyde and 3.35 g of 2'-hydroxy-4'-(3-methyl-2-butenyloxy)-acetophenone in 65 ml of isopropanol was added a solution of 2.9 g of sodium hydroxide in 6 ml of water under a nitrogen atmosphere, and the mixture was stirred at 45° C. for 8 hours. After neutralization with dilute hydrochloric acid with ice cooling, the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography with n-hexane including 1% ethyl acetate. The resulting fractions containing the end compound was recrystallized from isopropanol to give 3.23 g of 2-n-heptyl-2'-hydroxy-4'-(3-methyl-2-butenyloxy)-chalcone as yellow needles.
Reaction SMILES: C(OC([N:8]([C@@H:16]1[CH2:22][CH2:21][C@@H:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=2[F:30])[CH:19]([CH2:31][OH:32])[NH:18][C:17]1=[O:33])C(OC(C)(C)C)=O)=O)(C)(C)C.[C:34]([OH:40])([C:36]([F:39])([F:38])[F:37])=[O:35]>C(Cl)Cl>[NH2:8][C@@H:16]1[CH2:22][CH2:21][C@@H:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=2[F:30])[CH:19]([CH2:31][OH:32])[NH:18][C:17]1=[O:33].[C:34]([OH:40])([C:36]([F:39])([F:38])[F:37])=[O:35]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@@H]1CC[C@@H](c2cccc(F)c2F)C(CO)NC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H]1CC[C@@H](c2cccc(F)c2F)C(CO)NC1=O
Reaction time: 2 h

Procedure:
Di-tert-butyl[(3R,6S)-6-(2,3-difluorophenyl)-7-(hydroxymethyl)-2-oxoazepan-3-yl]imidodicarbonate (100 mg, 0.213 mmol) was diluted DCM (30 mL) and TFA (8 mL) was added. After 2 h, the reaction was concentrated to give the title compound as its TFA salt (57 mg). MS 271.0 (M+1).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1)=[O:2].C([O-])(O)=O.[Na+].[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>C(Cl)Cl>[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([S:9]([C:6]2[CH:7]=[CH:8][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=2)(=[O:11])=[O:10])[CH2:21][CH2:20]1
Reactant: CN1CCNCC1
Reactant: O=Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CN1CCN(S(=O)(=O)c2ccc(C=O)cc2)CC1
Reaction time: 1 h

Procedure:
To a solution of 4-formylbenzenesulfonyl chloride (1.0 g) in DCM (10 mL) was added NaHCO3 (sat'd aq, 10 mL) followed by 1-methyl-piperazine (0.6 mL). The reaction mixture was vigorously stirred for 1 h, the organic layer separated, and the aqueous layer extracted with DCM (2×20 mL). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure to give 4-(4-methyl-piperazine-1-sulfonyl)-benzaldehyde (1.28 g) without further purification.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([C:9]1[CH:14]=[C:13]([C:15]2[S:16][CH:17]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=3)[N:19]=2)[CH:12]=[CH:11][N:10]=1)[CH2:7][CH3:8].N1C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[CH2:6]([C:9]1[CH:14]=[C:13]([C:15]2[S:16][CH:17]=[C:18]([C:20]3[CH:21]=[CH:22][C:23]([NH:26][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:24][CH:25]=3)[N:19]=2)[CH:12]=[CH:11][N:10]=1)[CH2:7][CH3:8]
Reactant: CCCc1cc(-c2nc(-c3ccc(N)cc3)cs2)ccn1
Reactant: CS(=O)(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCc1cc(-c2nc(-c3ccc(NS(C)(=O)=O)cc3)cs2)ccn1
Reaction time: 0.5 h
Yield: 86.9 %

Procedure:
In reaction (d) methanesulfonyl chloride (0.23 mL, 2.97 mmol) was added to a stirred solution of 16 (800 mg, 2.71 mmol) and pyridine (0.66 mL, 8.1 mmol) in CH2Cl2 (20 mL) at 0° C. After being stirred for 0.5 h, the mixture was poured into 2 M citric acid solution and extracted with EtOAc. The combined extracts were washed with saturated NaHCO3 solution and brine, dried over Na2SO4, and concentrated to produce N-(4-(2-(2-propylpyridin-4-yl)thiazol-4-yl)phenyl)methanesulfonamide 19 (880 mg, 87%) as a yellow foam.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[Br:14]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.CC(O)=O>[Br:14][C:11]1[S:10][C:9]([CH2:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:13][CH:12]=1
Reactant: Fc1ccc(Cc2cccs2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: Fc1ccc(Cc2ccc(Br)s2)cc1
Yield: 98.1 %

Procedure:
The above thiophene (9.61 g, 50.0 mmol) was brominated using N-bromosuccinimide (8.90 g, 50.0 mmol) in CHCl3 and CH3COOH (1:1) to provide 13.3 g (98%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20](=O)[C:21](F)(F)F)[CH2:16][CH2:15]2)[CH:10]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[CH2:9]1)=[O:7].[CH2:42](OC1(O[Si](C)(C)C)CC1)C>C(Cl)(Cl)Cl>[F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([C:6]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:15][CH2:16][N:17]([CH:20]4[CH2:42][CH2:21]4)[CH2:18][CH2:19]3)[CH:10]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[CH2:9]2)=[O:7])[CH:33]=[C:34]([C:36]([F:39])([F:37])[F:38])[CH:35]=1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC(N2CCN(C(=O)C(F)(F)F)CC2)C(c2ccc(Cl)cc2)C1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Solvent: ClC(Cl)Cl
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC(N2CCN(C3CC3)CC2)C(c2ccc(Cl)cc2)C1

Procedure:
The title compound, MS: m/e=560.2 (M+H+), [α]58920=−24.38, [α]54620=−30.39, [α]43620=−64.51 (c=0.6154, chloroform), was prepared in accordance with the general methods of example 102 (step1) and example 110 (step2) from (−)-(1-{4-[1-(3,5-bis-trifluoromethyl-benzoyl)-3-(4-chloro-phenyl)-piperidin-4-yl]-piperazin-1-yl}-2,2,2-trifluoro-ethanone and [(1-ethoxycyclopropyl)-oxy]trimethylsilane.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=[CH2:9].[I-:10].[Na+]>CC(=O)CC>[I:10][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=[CH2:9]
Reactant: C=CCCCCCCBr
Reactant: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: C=CCCCCCCI

Procedure:
A mixture of 8-bromo-1-octene (1.34 g, 7 mmol) and sodium iodide (5.25 g, 35 mmol) in 2-butanone (15 ml) was stirred under reflux for 1 h. The mixture was concentrated in vacuo to a half of its original volume and hexane and water was added. Organic layer was washed with 5% aqueous sodium thiosulfate, saturated sodium bicarbonate and brine, dried over anhydrous sodium sulfate and concentrated in vacuum. Purification by flash chromatography on silica gel (hexane) gave 8-iodo-1-octene as colorless oil. yield: 1.54 g (92%).
Reaction SMILES: [NH2-].[Na+].[C:3]1([CH2:13][C:14]#[N:15])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.Cl[CH2:17][CH2:18][N:19]([CH3:21])[CH3:20].O>C1C=CC=CC=1>[CH3:20][N:19]([CH3:21])[CH2:18][CH2:17][CH:13]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1)[C:14]#[N:15]
Reactant: N#CCc1cccc2ccccc12
Reactant: CN(C)CCCl
Agent: [NH2-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CN(C)CCC(C#N)c1cccc2ccccc12
Temperature: 80 °C
Yield: 57.3 %

Procedure:
6.9 g of sodium amide are added in small portions to 29.4 g of naphth-1-ylacetonitrile in 250 ml of anhydrous benzene and the mixture is heated at 80° C. for 2 hours. It is cooled to +40° C., 19 g of 2-chlorodimethylaminoethane are added dropwise and the mixture is then heated again at 80° C. for 4 hours. It is cooled and 200 ml of water are added. After decantation, the organic phase is extracted with a 10% solution of hydrochloric acid. The aqueous phase is washed with ether, neutralized with a 10% solution of sodium hydroxide and extracted with ether and the extract is then washed with water and dried over sodium sulfate. 24 g of the expected product are obtained after evaporation of the solvent.