Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[CH2:5][C:6]1[C:7]([CH2:16][CH3:17])=[N:8][N:9]([CH2:13][CH2:14][NH2:15])[C:10]=1[CH2:11][CH3:12].[F:22][C:23]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:24]=1[C:25]([N:27]=[C:28]=[O:29])=[O:26]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[CH2:5][C:6]1[C:7]([CH2:16][CH3:17])=[N:8][N:9]([CH2:13][CH2:14][NH:15][C:28]([NH:27][C:25](=[O:26])[C:24]2[C:30]([F:34])=[CH:31][CH:32]=[CH:33][C:23]=2[F:22])=[O:29])[C:10]=1[CH2:11][CH3:12]
Reactant: O=C=NC(=O)c1c(F)cccc1F
Reactant: CCc1nn(CCN)c(CC)c1Cc1cc(Cl)cc(Cl)c1
Solvent: CN(C)C=O
Product: CCc1nn(CCNC(=O)NC(=O)c2c(F)cccc2F)c(CC)c1Cc1cc(Cl)cc(Cl)c1
Reaction time: 18 h

Procedure:
A solution of the amine of Example 43 (6.5 mg, 201 mol) in dimethylformamide (250 μL) was treated with 2,6-difluorobenzoylisocyanate (4.0 mg, 221 mol) and the mixture was shaken for 18 hours. The reaction mixture was filtered and the filtrate was purified by HPLC (Hypersil Thermoquest Luna C8 150×10 mm column; a gradient mobile phase was used, 10:90 (by volume)→95:5 (by volume) acetonitrile:(water, 95% by volume/trifluoroacetic acid, 0.1% by volume/acetonitrile 5%, by volume)).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6](=[O:29])[CH2:7][CH2:8][N:9]2[CH2:16][CH:15]3[N:17]([C:19]4[CH:28]=[CH:27][C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[CH:20]=4)[CH2:18][CH:10]2[CH2:11][CH:12]=[CH:13][CH2:14]3)[C:3]2[CH:30]=[CH:31][CH:32]=[CH:33][C:2]1=2.[BH4-].[Na+].CO.[OH-].[Na+]>C(OCC)(=O)C>[S:1]1[CH:5]=[C:4]([CH:6]([OH:29])[CH2:7][CH2:8][N:9]2[CH2:16][CH:15]3[N:17]([C:19]4[CH:28]=[CH:27][C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[CH:20]=4)[CH2:18][CH:10]2[CH2:11][CH:12]=[CH:13][CH2:14]3)[C:3]2[CH:30]=[CH:31][CH:32]=[CH:33][C:2]1=2
Reactant: O=C(CCN1CC2CC=CCC1CN2c1ccc2ccccc2c1)c1csc2ccccc12
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: OC(CCN1CC2CC=CCC1CN2c1ccc2ccccc2c1)c1csc2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-Benzo[b]thiophen-3-yl-3-(9-naphthalen-2-yl-7,9-diaza-bicyclo[4.2.2]dec-3-en-7-yl)-propan-1-one (8 mg, 0.0176 mmol), sodium borohydride (20 mg, 0.5 mmol) and methanol (1 ml), were placed in a round bottom flask and the reaction mixture stirred for one hour at room temperature. To the reaction mixture were then added a solution of 1N NaOH (10 mL) and ethyl acetate (10 mL). The resulting mixture was separated and the organic layer was dried with magnesium sulfate, filtered and evaporated under reduced pressure to yield the title compound as a solid.
Reaction SMILES: [C:1]1([C:7]2([CH2:14][NH:15][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])=[O:17])[CH2:12][CH2:11][C:10](=[CH2:13])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[OH2:32].[OH:33]S([O-])=O.[Na+]>C1COCC1.O=[Os](=O)(=O)=O>[OH:32][C:10]1([CH2:13][OH:33])[CH2:9][CH2:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([CH2:14][NH:15][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[O:17])[CH2:12][CH2:11]1
Reactant: O=S([O-])O
Reactant: O
Reactant: C=C1CCC(CNC(=O)c2ccccc2OC)(c2ccccc2)CC1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1ccccc1C(=O)NCC1(c2ccccc2)CCC(O)(CO)CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 1-phenyl-1-(3-(2-methoxyphenyl)-3-oxo-2-azaprop-1-yl)-4-methylidenecyclohexane (Example 165, 22.3 mg, 0.66 mmol) in 1.0 mL of THF was added OsO4 (33.8 mg, 0.13 mmol), pyridine (0.5 mL) and water (0.5 mL). The mixture was stirred at rt for 17 h. To the reaction mixture was then added 1 mL of saturated NaHSO3 solution. After 1 h, the volatiles were removed by vacuum and the residue was loaded onto silica gel and eluted with first EtOAc/Hexane (1:1) then EtOAc to give the title compound as a 2:1 mixture of diastereomers.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[NH:11][C:10]([Cl:15])=[N:9][C:8]=2[N:7]=[C:6]1[N:16]1[CH2:21][CH2:20][CH2:19][CH:18]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:17]1)[C:2]#[C:3][CH3:4].CI.[C:32](=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH3:32])[C:10]([Cl:15])=[N:9][C:8]=2[N:7]=[C:6]1[N:16]1[CH2:21][CH2:20][CH2:19][CH:18]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:17]1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCn1c(N2CCCC(NC(=O)OC(C)(C)C)C2)nc2nc(Cl)[nH]c(=O)c21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CI
Solvent: O
Product: CC#CCn1c(N2CCCC(NC(=O)OC(C)(C)C)C2)nc2nc(Cl)n(C)c(=O)c21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.7 %

Procedure:
700 mg of t-butyl [1-[7-(2-butynyl)-2-chloro-6-oxo-6,7-dihydro-1H-purin-8-yl]piperidin-3-yl]carbamate was dissolved in 7.0 ml of dimethyl sulfoxide, and then 114 μl of methyl iodide and 299 mg of potassium carbonate were added thereto. The mixture was stirred at room temperature for 30 minutes, and 40 ml of water was added to the reaction solution. The mixture was stirred at room temperature for 30 minutes, and the white precipitate was collected by filtration. The resulting white solid was washed with water and then with hexane to give 540 mg of the title compound.
Reaction SMILES: Cl.Cl.[C:3]1([CH:9]([NH2:19])[C:10]2[NH:18][C:13]3=[CH:14][N:15]=[CH:16][CH:17]=[C:12]3[CH:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.[C:29](O)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[N:32][CH:31]=1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:3]1([CH:9]([C:10]2[NH:18][C:13]3=[CH:14][N:15]=[CH:16][CH:17]=[C:12]3[CH:11]=2)[NH:19][C:29](=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[N:32][CH:31]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)c1cccnc1
Reactant: NC(c1ccccc1)c1cc2ccncc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC(c1ccccc1)c1cc2ccncc2[nH]1)c1cccnc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 32.2 %

Procedure:
To a solution of 1-phenyl-1-(1H-pyrrolo[2,3-c]pyridin-2-yl)methylamine dihydrochloride (Example 40) (51 mg, 0.17 mmol), N,N-diisopropylethylamine (DIPEA) (0.15 mL, 0.85 mmol) and nicotinic acid (22 mg, 0.18=mmol) in methylene chloride (2.0 mL) was added 1-ethyl-3-dimethylaminopropylcarbodiimide hydrochloride (EDC-HCl) (30 mg, 0.20 mmol) followed by a catalytic amount of 4-dimethylaminopyridine (DMAP). The reaction mixture was stirred at room temperature overnight (20 h) under a N2 atmosphere. TLC analysis showed the starting amine, therefore the reaction mixture was heated to reflux. After refluxing overnight, the reaction mixture was concentrated to dryness. The residue was dissolved in EtOAc and water. The organic layer was washed with water, 1 M citric acid, saturated NaHCO3, and saturated NaCl. TLC analysis showed that the majority of desired product was extracted into the 1 M citric acid washing. The citric acid extracts were made basic with 15% NaOH solution and extracted with methylene chloride. The organic extracts were dried over Na2SO4, filtered and concentrated to dryness. Trituration with Et2O/CH2Cl2 (1:1) provided N-[phenyl(1H-pyrrolo[2,3-c]pyridin-2-yl)methyl]nicotinamide (18 mg, 32%) as a light yellow solid after drying: mp 178-188° C.; 1H NMR (300 MHz, CD3OD) δ6.30 (1H, s), 6.67 (1H, s), 7.35-7.55 (7H, m), 8.03 (1H, d, J=5.5 Hz), 8.30-8.38 (1H, m), 8.61 (1H, s), 8.69-8.71 (1H, m), 9.05-9.07 (1H, m); ESI MS m/z 329 [C20H16N4O+H]+; HPLC (Method A) >99% (AUC) tR=13.3 min.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH2:15][CH2:14]3)(=[O:10])=[O:9])[CH2:4][CH2:3]1>ClCCl.O=[Mn]=O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH:15]=[CH:14]3)(=[O:10])=[O:9])[CH2:4][CH2:3]1
Reactant: CN1CCN(S(=O)(=O)c2ccc3c(c2)CCN3)CC1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CN1CCN(S(=O)(=O)c2ccc3[nH]ccc3c2)CC1

Procedure:
A suspension of 5-[(4-methylpiperazin-1-yl)sulfonyl]indoline (1-7, 8.00 g, 28.4 mmol, 1 equiv) and MnO2 (8.00 g, 92.0 mmol, 3.24 equiv) in dichloromethane (300 mL) was heated at reflux for 1 hour. More MnO2 (8.00 g, 92.0 mmol, 3:24 equiv) was added, and the resulting suspension was heated for 2 hours. The manganese oxides were filtered off onto a pad of celite and washed with dichloromethane (500 mL). The filtrate was concentrated to give 5-[(4-methylpiperazin-1-yl) sulfonyl]-1H-indole (1-8) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.59 (br s, 1H), 8.10 (d, 1H, J=1.8 Hz), 7.55 (dd, 1H, J=8.5, 1.8 Hz), 7.46 (d, 1H, J=8.5 Hz), 7.34 (m, 1H), 6.67 (m, 1H), 3.04 (br m, 4H), 2.48 (br t, 4H, J=4.9 Hz), 2.25 (s, 3).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][NH:11][C@@H:10]([CH3:14])[CH2:9]2)=[C:4]([C:15]([F:18])([F:17])[F:16])[CH:3]=1.[Br:19][C:20]1[CH:21]=[C:22]([S:26](Cl)(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1>>[Br:19][C:20]1[CH:21]=[C:22]([S:26]([N:11]2[CH2:12][CH2:13][C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=3[C:15]([F:18])([F:16])[F:17])[CH2:9][C@@H:10]2[CH3:14])(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1
Reactant: C[C@H]1C[C@@H](c2ccc(F)cc2C(F)(F)F)CCN1
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Product: C[C@H]1C[C@@H](c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1cccc(Br)c1
Yield: 97 %

Procedure:
Prepared from (2S,4S)-4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methylpiperidine (120 mg, 0.46 mmol) and 3-bromophenylsulfonyl chloride (99.4 mL, 0.69 mmol) according to scheme III-11 in 97% yield. HRMS: calcd for C19H18BrF4NO2S+H+, 480.02505. found (ESI-FTMS, [M+H]1+), 480.02396.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]([OH:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:13].[CH3:14]O>O1CCOCC1>[ClH:13].[CH2:1]([NH:8][CH2:9][C:10]([O:12][CH3:14])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CNCc1ccccc1
Reactant: CO
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)CNCc1ccccc1
Reaction time: 8 h
Yield: 99 %

Procedure:
To a N-benzyl glycine 26 (500 mg, 3.0 mmol) in MeOH (6 mL) was added 4M solution of HCl in dioxane (4 mL) and stirred overnight. The reaction mixture was concentrated to afford compound 27 (649 mg, 99%) as a white solid. The crude compound was carried forward without further purification. LRMS (ESI): (calc) 179.2 (found) 180.1 (MH)+.
Reaction SMILES: [CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]([CH3:21])=[CH:10][CH2:11][CH2:12][C:13]([CH3:20])=[CH:14][CH2:15][CH2:16][C:17](=[O:19])[CH3:18])[C:3]([OH:5])=O.[CH2:22]([NH:26][CH2:27][CH:28]([CH3:30])[CH3:29])[CH:23]([CH3:25])[CH3:24]>>[CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]([CH3:21])=[CH:10][CH2:11][CH2:12][C:13]([CH3:20])=[CH:14][CH2:15][CH2:16][C:17](=[O:19])[CH3:18])[C:3]([N:26]([CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:22][CH:23]([CH3:25])[CH3:24])=[O:5]
Reactant: CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)O
Reactant: CC(C)CNCC(C)C
Product: CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)N(CC(C)C)CC(C)C

Procedure:
Starting materials: 2,6,10-trimethyl-14-oxo-2,6,10-pentadecatrienoic acid and diisobutylamine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]2[CH2:16][CH:15]2[C:17]([OH:19])=O)=[CH:4][CH:3]=1.[CH3:20][NH:21][C@@H:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH3:23]>>[CH3:20][N:21]([C@@H:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH3:23])[C:17]([CH:15]1[CH2:16][CH:14]1[C:9]1[C:10]([CH3:13])=[N:11][O:12][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)=[O:19]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C1CC1C(=O)O
Reactant: CN[C@H](C)c1ccccc1
Product: Cc1noc(-c2ccc(Br)cc2)c1C1CC1C(=O)N(C)[C@H](C)c1ccccc1

Procedure:
Prepared according to the procedure described in Example 2, Step 1, using 2-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-cyclopropanecarboxylic acid and methyl-((R)-1-phenyl-ethyl)-amine
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[Na+].[Na+].[NH2:7][C:8]1[CH:13]=[CH:12]C=[CH:10][C:9]=1O.O.[C:16](Cl)(=[O:34])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>C(OCC)(=O)C>[C:16]([NH:7][C:8]1[CH:13]=[CH:12][C:1]([OH:4])=[CH:10][CH:9]=1)(=[O:34])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: Nc1ccccc1O
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)Cl
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCCCCC/C=C\CCCCCCCC(=O)Nc1ccc(O)cc1
Reaction time: 2 h
Yield: 91.1 %

Procedure:
Sodium carbonate (1.27 g) was added to a solution of 1.09 g of 2-aminophenol in a mixed solvent composed of 20 ml of ethyl acetate and 20 ml of water. To the resulting mixture was added a solution of 3.01 g of oleoyl chloride in 10 ml of ethyl acetate portion-wise with stirring under ice cooling. The stirring was continued for additional 2 hours. After completion of the reaction, the organic layer was separated, washed with water and then with saturated saline, and dried over anhydrous sodium sulfate. After removal of the solvent by evaporation, the residue obtained was purified by silica gel column chromatography to obtain 3.40 g of the objective compound (yield: 91%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1([CH3:20])[CH2:19][CH2:18][CH2:17][C:12]2(OCC[O:13]2)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)=O.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>O.C(OCC)(=O)C>[CH2:1]([O:8][CH2:9][C:10]1([CH3:20])[CH2:19][CH2:18][CH2:17][C:12](=[O:13])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(COCc2ccccc2)CCCC2(C1)OCCO2
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CC1(COCc2ccccc2)CCCC(=O)C1
Temperature: 80 °C
Yield: 88.4 %

Procedure:
To a solution of 7-benzyloxymethyl-7-methyl-1,4-dioxaspiro[4.5]decane (5.3 g, 19 mmol) in a mixed solvent of acetone (42 ml) and water (11 ml) was added pyridinium p-toluenesulfonate (4.8 g, 19 mmol), and the mixture was stirred with heating at 80° C. for 2 hr. After cooling, to the reaction mixture were added ethyl acetate and water, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed successively with water and saturated brine, and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (3.9 g, yield 88%).
Reaction SMILES: N[C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:27]=1[C:28](Cl)=[O:29].C([N:38](CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[CH:19]1[C:10]2[CH2:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[CH2:14][N:8]([C:6]([C:5]3[CH:23]=[CH:24][C:2]([C:34]4[C:26]([Cl:25])=[C:27]([CH:31]=[C:32]([Cl:35])[CH:33]=4)[C:28]([NH2:38])=[O:29])=[CH:3][CH:4]=3)=[O:7])[C:9]=2[CH:22]=[CH:21][CH:20]=1
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Reactant: CCN(CC)CC
Reactant: O=C(Cl)c1cc(Cl)ccc1Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: NC(=O)c1cc(Cl)cc(-c2ccc(C(=O)N3Cc4ccccc4Cc4ccccc43)cc2)c1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 16.4 %

Procedure:
A mixture of 0.625 g (2 mmol) of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine, 0.629 g (3 mmol) of 2,5-dichlorobenzoyl chloride, 0.303 g (3 mmol) of triethylamine and 15 mg of 4-(dimethylamino)pyridine in 10 ml of dichloromethane is stirred at room temperature for 3 hours. The mixture is washed with water, 1N HCl, H2O, 1M NaHCO3, brine and dried (Na2SO4). The solvent is removed to give crystals. Recrystallization from hexane-CH2Cl2 gives 0.16 g of white crystals, m.p. 203°-231° C.
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C:18]1=[O:23].[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>ClCCl.CN(C1C=CC=CN=1)C>[CH3:34][C:24]1[CH:29]=[CH:28][C:27]([S:30]([O:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C:18]2=[O:23])(=[O:32])=[O:31])=[CH:26][CH:25]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1CCCCN1c1ccccc1CCO
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCc2ccccc2N2CCCCC2=O)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 88.4 %

Procedure:
Dimethylaminopyridine (1.83 g, 15 mmol, 0.05 eq) and triethylamine (63.5 ml, 450 mmol, 1.5 eq) are added to a solution of 1-[2-(2-hydroxyethyl)phenyl]piperidin-2-one a2-2 (65.7 g, 300 mmol, 1 eq) in dichloromethane (250 ml) at 0° C. The mixture is stirred at 0° C. for 15 minutes, then a solution of 4-toluenesulfonyl chloride (63 g, 330 mmol, 1.1 eq) in dichloromethane (250 ml) is added dropwise. The reaction mixture is then warmed up to room temperature and stirred overnight. The reaction mixture is washed with water, 1N HCl, then dried over MgSO4, filtered and evaporated under vacuum. The residue is purified by chromatography over silicagel (gradient: CH2Cl2/MeOH from 100/0 to 98/2) to afford 99 g of 2-[2-(2-oxopiperidin-1-yl)phenyl]ethyl 4-methylbenzenesulfonate a2-3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:27])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([O:30][CH2:31][CH2:32][N:33]3C(=O)C4=CC=CC=C4C3=O)[C:6]=2[CH:44]=1.O.NN.O.Cl>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:27])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([O:30][CH2:31][CH2:32][NH2:33])[C:6]=2[CH:44]=1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(OCCN3C(=O)c4ccccc4C3=O)c3cc(Cl)ccc32)cn1
Agent: Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(OCCN)c3cc(Cl)ccc32)cn1
Yield: 127.2 %

Procedure:
To a solution of 7-chloro-5-(2-phthalimidoethoxy)-1-[6-(2-methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.26 g) in ethanol (10 ml) is added hydrazine hydrate (0.04 ml), and the mixture is refluxed for 2 hours, and cooled. Water is added to the reaction solution, and the mixture is made acidic with diluted hydrochloric acid, and washed with diethyl ether. Aqueous sodium hydroxide solution is added to the aqueous layer in order to make it basic, and the mixture is extracted with dichloromethane. The extract is washed with water, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography to give 7-chloro-5-(2-aminoethoxy)-1-[6-(2-methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.26 g) as colorless amorphous.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH:8]=[O:9])=[C:5]([CH3:7])[N:6]=1.C(=O)([O-])[O-].[K+].[K+].[F:16][C:17]([Si](C)(C)C)([F:19])[F:18]>CN(C)C=O>[CH3:1][C:2]1[S:3][C:4]([CH:8]([OH:9])[C:17]([F:19])([F:18])[F:16])=[C:5]([CH3:7])[N:6]=1
Reactant: Cc1nc(C)c(C=O)s1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(C)c(C(O)C(F)(F)F)s1
Yield: 74.8 %

Procedure:
According to Reference Example 8-2, by use of 2,4-dimethylthiazole-5-carbaldehyde (300 mg, 2.12 mmol) dissolved in N,N-dimethylformamide (4 mL), potassium carbonate (59 mg, 0.42 mmol) and (trifluoromethyl)trimethylsilane (0.376 mL, 2.54 mmol), the mixture was stirred and reacted at room temperature for 1.5 hours. Then, purification by preparative thin-layer chromatography (chloroform/methanol=15/1) was performed to give 1-(2,4-dimethylthiazol-5-yl)-2,2,2-trifluoroethanol (Compound DS) (335 mg, yield: 75%).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C:13]2[O:17][N:16]=[C:15]([C:18]([OH:22])([C:20]#[CH:21])[CH3:19])[CH:14]=2)(=O)=O)=CC=1.[F-:23].[K+]>C(#N)C>[F:23][CH2:12][C:13]1[O:17][N:16]=[C:15]([C:18]([OH:22])([C:20]#[CH:21])[CH3:19])[CH:14]=1
Reactant: C#CC(C)(O)c1cc(COS(=O)(=O)c2ccc(C)cc2)on1
Reactant: [F-]
Agent: [K+]
Solvent: CC#N
Product: C#CC(C)(O)c1cc(CF)on1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of [3-(2-hydroxybut-3-yn-2-yl)isoxazol-5-yl]methyl 4-methylbenzenesulfonate (259 mg, 0.81 mmol) in dry acetonitrile (10 mL) was introduced potassium fluoride (94 mg, 1.61 mmol) and Kryptopfix® 222 (606 mg, 1.61 mmol). After 5 hr rapid stirring at RT, the reaction mixture was concentrated in vacuo and the residue partitioned between EtOAc (40 mL) and water (2×40 mL). The organic extract was washed with brine (30 mL), dried (Na2SO4), filtered and the filtrate adsorbed onto silica gel in vacuo. Purification by silica gel flash column chromatography (heptane/EtOAc gradient of increasing polarity) furnished the title compound as a colorless oil: 1H NMR (500 MHz, CDCl3) delta 1.91 (3H, s), 2.69 (1H, s), 2.86 (1H, s), 5.42 (1H, d, J=47.3 Hz), 6.55 (1H, d, J=2.8 Hz); 19F NMR-decoupled (235 MHz, CDCl3) delta −218.8 (s); LC-MS: m/z=+169.9 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].O1CCOCC1.CC1(C)C(C)(C)OB([C:29]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH:30]=2)O1.C(=O)(O)[O-].[Na+]>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.CCOC(C)=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([C:29]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH:30]=2)=[C:3]([C:11]([F:14])([F:13])[F:12])[CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Br)c(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
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: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc([N+](=O)[O-])cc2C(F)(F)F)CC1
Temperature: 120 °C
Reaction time: 8 h
Yield: 83.8 %

Procedure:
Add 2-bromo-5-nitrobenzotrifluoride (250 mg, 0.926 mmol) to dioxane (3 mL), then add tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (207 mg, 0.926 mmol), tetrakis(triphenylphosphine)palladium [Pd(PPh3)4, 35 mg, 0.03 mmol] and saturated sodium bicarbonate solution (1 mL) under nitrogen atmosphere. Stir the reaction mixture overnight at 120° C. TLC (PE:EtOAc=5:1) shows the reaction is complete. Partition the mixture between EtOAc and water, dry the organic layer over sodium sulfate, filter and concentrate the filtrate under reduced pressure. Purify the residue by flash chromatography (silica gel, PE:EtOAc=5:1) to afford the desired product (289 mg, 84%).
Reaction SMILES: [OH:1][CH:2]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:3][CH2:4][CH2:5][N:6]([CH2:11][C:12]1[CH:13]=[C:14]([CH:20]=[CH:21][CH:22]=1)[CH:15]=[CH:16][C:17]([OH:19])=[O:18])[S:7]([CH3:10])(=[O:9])=[O:8]>C(O)C.[Pd]>[OH:1][CH:2]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:3][CH2:4][CH2:5][N:6]([CH2:11][C:12]1[CH:13]=[C:14]([CH:20]=[CH:21][CH:22]=1)[CH2:15][CH2:16][C:17]([OH:19])=[O:18])[S:7]([CH3:10])(=[O:8])=[O:9]
Reactant: CCCCCC(O)CCCN(Cc1cccc(C=CC(=O)O)c1)S(C)(=O)=O
Agent: [Pd]
Solvent: CCO
Product: CCCCCC(O)CCCN(Cc1cccc(CCC(=O)O)c1)S(C)(=O)=O

Procedure:
m-[N-(4-Hydroxynonyl)methanesulfonamidomethyl]-cinnamic acid (3.0 g., 0.075 mole) dissolved in ethanol (80 ml.) is hydrogenated over 0.8 g. of a 5% Pd on charcoal catalyst at one atmosphere of pressure and room temperature. After the theoretical amount of hydrogen is absorbed, the catalyst is removed by filtration. The ethanol is evaporated and the residual solid is purified by crystallization to afford the pure title compound.