Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:30]=[CH:29][C:13]3[N:14]4[CH:19]=[C:18]([C:20]5[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][CH:21]=5)[N:17]=[C:15]4[S:16][C:12]=3[CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl-].[NH4+]>C(O)C.[Fe]>[N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:30]=[CH:29][C:13]3[N:14]4[CH:19]=[C:18]([C:20]5[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=5)[N:17]=[C:15]4[S:16][C:12]=3[CH:11]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=[N+]([O-])c1ccc(-c2cn3c(n2)sc2cc(OCCN4CCOCC4)ccc23)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: Nc1ccc(-c2cn3c(n2)sc2cc(OCCN4CCOCC4)ccc23)cc1
Yield: 32 %

Procedure:
This product was prepared according to J. Med. Chem. 2009, 52, 7808-7816 with some modifications. A mixture of 2-amino-1,3-benzothiazol-6-ol (2.0 g, 12.18 mmol) and 2-bromo-4′-nitroacetophenone (2.97 g, 12.18 mmol) in IPA (40 ml) was heated to reflux for 24 h. The reaction mixture was then cooled to 0° C. and the resulting precipitate was filtrated and washed with IPA to afford 2-(4-nitrophenyl)imidazo[2,1-b][1,3]benzothiazol-7-ol (65% c.y.). To a DMF (52 ml) solution of 2-(4-nitrophenyl)imidazo[2,1-b][1,3]benzothiazol-7-ol was added potassium carbonate (2.94 g) and 4-(2-chloroethyl)morpholine hydrochloride (1.97 g). The reaction mixture was heated to 85° C. and stirred at the same temperature for 48 h. Then it was poured into water (100 ml), filtered and washed with water and ethyl ether to give 7-(2-morpholin-4-yl-ethoxy)-2-(4-nitrophenyl)imidazo[2,1-b][1,3]benzothiazole (86% c.y.). A mixture of 7-(2-morpholin-4-yl-ethoxy)-2-(4-nitrophenyl)imidazo[2,1-b][1,3]benzothiazole and ammonium chloride (0.77 g) in ethanol (50 ml) was heated to reflux, and then iron powder (3.0 g) was added. The mixture was refluxed for 5 h and then immediately filtered though Celite and washed with hot ethanol. The filtrate was concentrated, neutralized with saturated NaHCO3 solution and extracted with DCM. The organic solution was dried with Na2CO3 and the solvent was removed under reduced pressure to afford the desired product [4-(7-(2-morpholin-4-yl-ethoxy)imidazo[2,1-b]benzothiazol-2-yl]aniline (32% c.y.).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C@@H:10](O)[CH3:11])=[CH:2]1.C1C=CC(P([N:27]=[N+:28]=[N-:29])(C2C=CC=CC=2)=O)=CC=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C@H:10]([N:27]=[N+:28]=[N-:29])[CH3:11])=[CH:2]1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: C[C@H](O)c1csc2ccccc12
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: C[C@@H](N=[N+]=[N-])c1csc2ccccc12
Reaction time: 0.5 h
Yield: 93.4 %

Procedure:
The process was carried out with reference to a method of Thompson, et al. (J. Org. Chem. 1993, 58, 5886). Under an argon atmosphere, a mixture of 5.50 g of (1S)-1-(1-benzothiene-3-yl)ethanol and 7.98 g of DPPA was dissolved in toluene, and 5.54 mL of DBU was then added thereto in an ice bath. After stirring for 30 min under ice-cooling, it was further stirred at room temperature for 15 hours. The reaction mixture was washed with water and 1 M hydrochloric acid in this order, and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 5.86 g of (1R)-1-(1-benzothiene-3-yl)ethylazide as a colorless oily substance. EI: 203
Reaction SMILES: [F:1][C:2]([F:11])([CH:5]([F:10])[C:6]([F:9])([F:8])[F:7])[CH2:3][OH:4].[F:12][C:13]([F:28])([S:24](F)(=[O:26])=[O:25])[C:14]([F:23])([F:22])[C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17].[OH-].[K+]>O>[F:28][C:13]([F:12])([S:24]([O:4][CH2:3][C:2]([F:11])([F:1])[CH:5]([F:10])[C:6]([F:9])([F:7])[F:8])(=[O:26])=[O:25])[C:14]([F:22])([F:23])[C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17]
Reactant: OCC(F)(F)C(F)C(F)(F)F
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=S(=O)(OCC(F)(F)C(F)C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2,2,3,4,4,4-hexafluorobutan-1-ol (202 grams, 1.1 moles, Sinochem Corp.), 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonyl fluoride (332 grams, 1.1 moles, 3M Company) and water (300 g) were combined in a 3-liter, 3-necked round bottom flask. The flask was equipped with a magnetic stirrer, cold water condenser, thermocouple, and addition funnel. Aqueous potassium hydroxide, 45 percent (149.3 grams, 1.22 moles, Aldrich Chemical Co.) was added dropwise via an addition funnel at such a rate that the temperature did not exceed 35° C. Once the addition of the base was complete the mixture was stirred for 16 hours at room temperature. Precipitated salts were then filtered from the mixture and the lower liquid fluorochemical product phase was separated from the upper aqueous phase. Unreacted 2,2,3,4,4,4-hexafluorobutan-1-ol and 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonyl fluoride were removed by atmospheric distillation. Approximately 400 grams of 2,2,3,4,4,4-hexafluorobutyl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate were recovered at a purity of 98.9 percent as measured by gas chromatographic analysis.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30](Br)[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[F:35][C:36]1[CH:37]=[CH:38][C:39]([O:45][CH3:46])=[C:40](B(O)O)[CH:41]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:38]5[CH:37]=[C:36]([F:35])[CH:41]=[CH:40][C:39]=5[O:45][CH3:46])[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: COc1ccc(F)cc1B(O)O
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Br)n4)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(-c5cc(F)ccc5OC)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using 1-{4′-[4-(6-bromo-pyridin-2-ylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 5-fluoro-2-methoxy-phenylboronic acid.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[N:17]=[CH:16][N:15]=[C:14]2[C:10]=1[N:11]=[CH:12][N:13]2[C@H:18]1[C@@H:22]2[O:23]C(C)(C)[O:25][C@@H:21]2[C@@H:20]([CH2:28][N:29]([CH3:47])[CH2:30][CH2:31][CH2:32][NH:33][C:34]([NH:36][C:37]2[CH:42]=[CH:41][C:40]([C:43]([CH3:46])([CH3:45])[CH3:44])=[CH:39][CH:38]=2)=[O:35])[CH2:19]1>O>[NH2:8][C:9]1[N:17]=[CH:16][N:15]=[C:14]2[C:10]=1[N:11]=[CH:12][N:13]2[C@@H:18]1[CH2:19][C@H:20]([CH2:28][N:29]([CH3:47])[CH2:30][CH2:31][CH2:32][NH:33][C:34]([NH:36][C:37]2[CH:38]=[CH:39][C:40]([C:43]([CH3:45])([CH3:46])[CH3:44])=[CH:41][CH:42]=2)=[O:35])[C@@H:21]([OH:25])[C@H:22]1[OH:23]
Reactant: CN(CCCNC(=O)Nc1ccc(C(C)(C)C)cc1)C[C@H]1C[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@H]12
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CN(CCCNC(=O)Nc1ccc(C(C)(C)C)cc1)C[C@H]1C[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1O
Reaction time: 0.5 h
Yield: 103.4 %

Procedure:
A cooled (ice bath) solution of trifluoroacetic acid (5.2 mL, 67 mmol) in water (0.60 mL) was added to the precooled (ice bath) flask of 1-(3-((((3aR,4R,6R,6aS)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methyl)(methyl)amino)propyl)-3-(4-(tert-butyl)phenyl)urea (0.10 g, 0.18 mmol). The reaction mixture was stirred for 30 min, the cold bath was removed, and the clear, pale yellow reaction mixture was stirred at rt for 1 h; HPLC indicated complete consumption of starting material. The reaction mixture was concentrated in vacuo and diluted with MeOH and concentrated (2×10 mL). The resultant residue was taken up in 10% MeOH/CH2Cl2 (60 mL) and washed with 10% aqueous NH4OH (1×18 mL). The separated aqueous layer was extracted with 10% MeOH/CH2Cl2 (3×18 mL) and the cloudy combined organics (pH>7) were diluted with MeOH (5 mL) to afford a clear solution, which was dried (Na2SO4) and concentrated in vacuo to afford the title compound (95 mg, quant) as a slightly off-white gum/foam: MS (ESI+) for C26H38N8O3 m/z 511.4 [M+H]+; MS (ESI−) for C26H38N8O3 m/z 509.3 [M−H]−, 555.3 [M+CO2H]−; HPLC purity>95% (ret. time, 2.701 min); 1H NMR (400 MHz, d4-MeOH) δ 8.17 (s, 1H), 8.16 (s, 1H), 7.27-7.20 (m, 4H), 4.78 (dt, J=10.7, 8.14 Hz, 1H), 4.52 (dd, J=8.5, 6.01 Hz, 1H), 4.01 (dd, J=5.8, 4.15 Hz, 1H), 3.31-3.23 (m, 2H), 2.78-2.70 (m, 1H), 2.67-2.55 (m, 3H), 2.48-2.31 (m, 2H), 2.39 (bs, 3H), 1.95-1.87 (m, 1H), 1.81-1.74 (m, 2H), 1.28 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH2:14][C:15]1[N:16]=[CH:17][N:18]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:19]=1)[N:7]=[C:6]2[CH2:39]O.S(Cl)([Cl:43])=O.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:43][CH2:39][C:6]1[C:5]2[C:9](=[CH:10][C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:8]([CH2:14][C:15]2[N:16]=[CH:17][N:18]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:19]=2)[N:7]=1
Reactant: COc1cc2c(CO)nn(Cc3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)c2cc1OC
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc2c(CCl)nn(Cc3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)c2cc1OC
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
5,6-Dimethoxy-1(1-trityl-4-imidazolyl)methyl-1H -indazole-3-methanol (180.0 g), which had been ground in a mortar, was suspended in dichloromethane (1700 ml) at room temperature and then cooled with ice/water. Next, thionyl chloride (48.6 ml) was dropped thereinto within 5 minutes. The reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate (2000 ml) and extracted with chloroform (5000 ml). After drying over sodium sulfate, filtering and evaporating under reduced pressure, a colorless solid was obtained (165.1 g). This solid product was used in the subsequent reaction without purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=1)[C:10]([CH3:24])([CH3:23])[CH2:9]2)=[O:5])[CH3:2].N1C=CC=CC=1.[CH2:31]([N:33]([CH2:37][CH3:38])[C:34](Cl)=[O:35])[CH3:32]>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:34]([N:33]([CH2:37][CH3:38])[CH2:31][CH3:32])=[O:35])[CH:17]=1)[C:10]([CH3:23])([CH3:24])[CH2:9]2)=[O:5])[CH3:2]
Reactant: CCN(CC)C(=O)Cl
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(N)c1)N2
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(NC(=O)N(CC)CC)c1)N2
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.9 %

Procedure:
To a solution of 2-(3-amino-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (648 mg, 2 mmol) in dichloromethane (5 mL) and pyridine (1 mL, 12 mmol) was added a solution of diethylcarbamyl chloride (0.28 mL, 2.2 mmol) in dichloromethane (2 mL) dropwise at 0° C. The reaction mixture was stirred at 25° C. for 16 h. Then the reaction mixture was extracted with dichloromethane (2×50 mL), washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-[3-(3,3-diethyl-ureido)-phenyl}-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (846 mg, 100%) as a brown oil which was used for next step without further purification: LC/MS m/e calcd for C25H33N3O3 (M+H)+: 424.56, observed: 424.2.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]1[NH:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([S:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=1)=[O:14].ClC1C=C(C=CC=1)C(OO)=[O:32]>C(Cl)(Cl)Cl.ClCCl>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]1[NH:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([C:23]([F:26])([F:25])[F:24])=[O:32])=[CH:18][CH:17]=1)=[O:14]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(Nc1ccc(SC(F)(F)F)cc1)Nn1cnc2ccccc2c1=O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: O=C(Nc1ccc(S(=O)C(F)(F)F)cc1)Nn1cnc2ccccc2c1=O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A mixture of 1-(3,4-dihydro-4-oxo-3-quinazolinyl)-3-{p-[(trifluoromethyl)thio]phenyl}urea (1.0 g, 2.63 mmol) in chloroform is cooled with an ice-water bath, treated with a solution of 3-chloroperoxybenzoic acid (0.57 g, 80% real, 2.64 mmol) in chloroform, stirred for 3 hours at 0° C., stirred for 32 hours at room temperature, cooled to 0° C., treated with additional 3-chloroperoxybenzoic acid (0.114 g, 0.53 mmol) in chloroform, stirred for 36 hours at room temperature, diluted with dichloromethane, washed sequentially with saturated sodium sulfite solution, saturated sodium hydrogen carbonate solution and brine, dried over anhydrous MgSO4 and concentrated in vacuo to obtain a yellow solid. Chromatography of the solid using silica gel and a 4:1 ethyl acetate/hexanes solution gives the title product as a white solid, 0.50 g, mp 148°-150° C., which is identified by 1HNMR spectral analysis.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[S:3]([C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1)(=[O:5])=[O:4].[CH3:15][C:16](OC(C)=O)=[O:17]>CC(O)=O>[F:14][C:2]([F:13])([F:1])[S:3]([C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:16](=[O:17])[CH3:15])=[CH:10][CH:11]=1)(=[O:4])=[O:5]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(S(=O)(=O)C(F)(F)F)cc1
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(S(=O)(=O)C(F)(F)F)cc1

Procedure:
Reflux 4-trifluoromethylsulfonyl-phenylamine (5 g) and Ac2O (2.2 mL) for 1.5 hours in HOAc (20 mL). Evaporate the solvent in vacuo, then crystallize the residue in EtOAc/EtOH to obtain N-(4-trifluoromethylsulfonyl-phenyl)-acetamide. B. N-(2-Nitro-4-trifluoromethylsulfonyl-phenyl)-acetamide
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][N:18]([C:21]([C@H:23]2[CH2:28][CH2:27][C@H:26]([CH2:29][N:30]3[C:34]4[CH:35]=[C:36]([O:39][CH3:40])[CH:37]=[CH:38][C:33]=4[N:32]([CH3:41])[C:31]3=[O:42])[CH2:25][CH2:24]2)=[O:22])[CH2:17][CH2:16]1)=O)(C)(C)C.O>C(Cl)Cl>[CH3:40][O:39][C:36]1[CH:37]=[CH:38][C:33]2[N:32]([CH3:41])[C:31](=[O:42])[N:30]([CH2:29][C@H:26]3[CH2:27][CH2:28][C@H:23]([C:21]([N:18]4[CH2:17][CH2:16][NH:15][CH2:20][CH2:19]4)=[O:22])[CH2:24][CH2:25]3)[C:34]=2[CH:35]=1
Reactant: COc1ccc2c(c1)n(C[C@H]1CC[C@H](C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)CC1)c(=O)n2C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1ccc2c(c1)n(C[C@H]1CC[C@H](C(=O)N3CCNCC3)CC1)c(=O)n2C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trifluoro acetic acid (8 ml) was added to a solution of trans-4-[4-(6-Methoxy-3-methyl-2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-cyclohexanecarbonyl]-piperazine-1-carboxylic acid tert-butyl ester in DCM (19 ml). The solution was stirred at room temperature overnight and then 10 ml of water were added. The mixture was concentrated under reduced pressure and DCM (20 ml) were added. The organic solution was washed with a saturated solution of NaHCO3 (2×20 ml), dried over Na2SO4, filtered and the solvent evaporated to give the titled compound
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([O:19]C)=[O:18])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.O.CO>[C:1]([O:5][C:6]([N:8]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CCc1ccc(N(C(=O)OC(C)(C)C)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N(c1ccccc1)c1ccc(CCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of methyl 3-(4-(tert-butoxycarbonyl(phenyl)amino)phenyl)propanoate (S34), 390 mg, 1.10 mmol) in a mixture of THF/H2O/MeOH (3/1/0.4, 4 mL), was treated with NaOH (100 mg, 2.5 mmol) and was stirred for 4 h at 25° C. The reaction mixture was concentrated, diluted with aqueous 1 N HCl and extracted with CH2Cl2. The organic layer was washed with saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated to afford S35 (370 mg, 1.08 mmol, 99%) as a yellow oil: 1H NMR (CDCl3, 400 MHz) 7.34-7.29 (m, 2H), 7.23-7.15 (m, 7H), 2.94 (t, 2H, J=7.6 Hz), 2.66 (t, 2H, J=7.6 Hz), 1.46 (s, 9H); 13C NMR (CDCl3, 100 MHz) 178.7, 153.9, 142.9, 141.2, 137.6, 128.6, 128.5, 126.9 (2C), 125.6, 81.1, 35.5, 30.0, 28.2.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]2[N:15]=[C:14]([C:16]([OH:18])=O)[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]=2)[N:3]=[CH:2]1.Cl.[OH:20][C:21]1[C:30]([N:31]([CH3:33])[CH3:32])=[CH:29][CH:28]=[C:27]2[C:22]=1[CH2:23][CH2:24][NH:25][CH2:26]2>>[S:1]1[CH:5]=[C:4]([C:6]2[N:15]=[C:14]([C:16]([N:25]3[CH2:24][CH2:23][C:22]4[C:27](=[CH:28][CH:29]=[C:30]([N:31]([CH3:33])[CH3:32])[C:21]=4[OH:20])[CH2:26]3)=[O:18])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]=2)[N:3]=[CH:2]1
Reactant: CN(C)c1ccc2c(c1O)CCNC2
Reactant: O=C(O)c1nc(-c2cscn2)nc2ccccc12
Agent: Cl
Product: CN(C)c1ccc2c(c1O)CCN(C(=O)c1nc(-c3cscn3)nc3ccccc13)C2
Yield: 39 %

Procedure:
Reaction of 2-(4-thiazolyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-dimethylamino-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 82 (39% yield) as a light yellow solid. 1H NMR (300 MHz, CD3OD) δ 2.63 and 2.67 (2s, 6H), 2.82 and 3.06 (2m, 2H), 3.58 and 4.17 (2t, 2H), 4.46 and 5.03 (2s, 2H), 6.31 and 6.81 (2d, 1H), 6.91 and 7.12 (2d, 1H), 7.69-7.95 (m, 2H), 8.04-8.12 (m, 2H), 8.22-8.28 (m, 1H), 8.63-8.73 (2s, 1H), 9.21-9.23 (m, 1H); MS (ESI) m/z 432 ([M+H]+).
Reaction SMILES: [C:1]1([Li])[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:15][C:16]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[C:17]1[CH:21]=[CH:20][CH:19]=[CH:18]1.O>C1COCC1.[Cl-].[Cl-].C1(C(=[Zr+2](C2C3C=CC=CC=3C3C2=CC=CC=3)C2C=CC=C2)C)C=CC=CC=1>[CH:17]1([C:16]2[CH:15]=[CH:25][CH:26]=[CH:27][C:22]=2[CH2:23][CH2:24][CH:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH2:18][CH2:19][CH:20]=[CH:21]1
Reactant: CC(=C1C=CC=C1)c1ccccc1
Reactant: [Li]c1cccc2c1Cc1ccccc1-2
Agent: CC(c1ccccc1)=[Zr+2](C1C=CC=C1)C1c2ccccc2-c2ccccc21
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: C1=CC(c2ccccc2CCC2c3ccccc3-c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.7 %

Procedure:
(Phenyl(methyl)methylene)(9-fluorenyl)(cyclopentadienyl)zirconium dichloride ##STR9## A solution of 67.8 mmol of fluorenyllithium of 50 cm3 of THF was added at room temperature to a solution of 11.4 g (67.8 mmol) of 6-methyl-6-phenylfulvene in 40 cm3 of THF. The mixture was stirred at room temperature for 2 hours, and 60 cm3 of water were added. The substance which precipitated was filtered off with suction, washed with diethyl ether and dried in an oil-pump vacuum. 19.1 g (84.2%) of 2,2-cyclopentadienyl(9-fluorenyl)ethylbenzene (correct elemental analyses; 1H-NMR spectrum) were obtained.
Reaction SMILES: [CH:1]1([N:7]2[CH2:11][CH2:10][CH:9]([CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][C:16]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([N:28]5[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]5)=[O:27])=[CH:22][CH:21]=4)=[CH:15][C:14]=3[Cl:34])[C:8]2=[O:35])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[C:38](Cl)(=[O:40])[CH3:39]>ClCCl>[C:38]([N:31]1[CH2:30][CH2:29][N:28]([C:26]([C:23]2[CH:22]=[CH:21][C:20]([C:16]3[CH:15]=[C:14]([Cl:34])[C:13]([CH2:12][CH:9]4[CH2:10][CH2:11][N:7]([CH:1]5[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]5)[C:8]4=[O:35])=[C:18]([Cl:19])[CH:17]=3)=[CH:25][CH:24]=2)=[O:27])[CH2:33][CH2:32]1)(=[O:40])[CH3:39]
Reactant: CC(=O)Cl
Reactant: O=C(c1ccc(-c2cc(Cl)c(CC3CCN(C4CCCCC4)C3=O)c(Cl)c2)cc1)N1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(=O)N1CCN(C(=O)c2ccc(-c3cc(Cl)c(CC4CCN(C5CCCCC5)C4=O)c(Cl)c3)cc2)CC1
Yield: 73.9 %

Procedure:
Dissolve racemic 1-cyclohexyl-3-[3,5-dichloro-4′-(piperazine-1-carbonyl)-biphenyl-4-ylmethyl]-pyrrolidin-2-one (0.082 g, 0.158 mmol) in dichloromethane (5 mL), add 1.0 N sodium hydroxide solution (0.5 mL) and acetyl chloride (0.020 mL, 0.281 mmol). Stir the mixture, sealed, overnight at room temperature. Dilute reaction with dichloromethane (20 mL) and wash with 1.0 N sodium hydroxide (10 mL) then brine (5 mL). Collect the organic phase, dry over anhydrous magnesium sulfate and concentrate under reduced pressure. Purify via flash chromatography by eluding with a gradient (100%) dichloromethane to 5% ammonia methanol/95% dichloromethane to obtain 0.065 g (74%) of product as a white foam: MS (m/z): 556 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:10]([CH3:12])([CH3:11])[S:9][CH2:8][CH2:7][N:6]1[S:13]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14])=[O:4].[O:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[O:29][CH2:30][CH2:31][C:32]#[C:33][CH2:34]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C(OCC)(=O)C>[CH3:11][C:10]1([CH3:12])[S:9][CH2:8][CH2:7][N:6]([S:13]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:34][C:33]#[C:32][CH2:31][CH2:30][O:29][CH:24]3[CH2:25][CH2:26][CH2:27][CH2:28][O:23]3)=[CH:20][CH:21]=2)(=[O:15])=[O:14])[CH:5]1[C:3]([O:2][CH3:1])=[O:4]
Reactant: OCC#CCCOC1CCCCO1
Reactant: COC(=O)C1N(S(=O)(=O)c2ccc(O)cc2)CCSC1(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)C1N(S(=O)(=O)c2ccc(OCC#CCCOC3CCCCO3)cc2)CCSC1(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.7 %

Procedure:
To a solution of 3.31 g (9.6 mmol) of 4-(4-hydroxy-benzenesulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylic acid methyl ester and 2.12 g (11.5 mmol) of 5-(tetrahydro-2H-pyran-2-yloxy)-2-pentyn-1-ol in 15 mL of THF was added 3.0 g (11.5 mmol) of triphenylphosphine, followed by dropwise addition of 1.8 mL (11.5 mmol) of diethyl azodicarboxylate. The resulting solution was stirred at room temperature for 18 h. The reaction was diluted with ethyl acetate, washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate:hexanes (1:9) to provide 3.03 g (62%) of methyl 2,2-dimethyl-4-[(4-{[5-(tetrahydro-2H-pyran-2-yloxy)-2-pentynyl]oxy}phenyl)sulfonyl]-3-thiomorpholine carboxylate as a colorless oil.
Reaction SMILES: [CH2:1]([NH:4][CH:5]([CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:6][OH:7])[CH2:2][CH3:3].[C:17](OC(=O)CC)(=O)[CH2:18][CH3:19]>>[CH2:1]([N:4]([CH2:17][CH2:18][CH3:19])[CH:5]([CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH2:6][OH:7])[CH2:2][CH3:3]
Reactant: CCC(=O)OC(=O)CC
Reactant: CCCNC(CO)CCOc1ccccc1
Product: CCCN(CCC)C(CO)CCOc1ccccc1

Procedure:
2-(propylamino)-4-phenoxy-1-butanol, described in Example 6, with propionic anhydride, followed by reduction, gives 2-(dipropylamino)-4-phenoxy-1-butanol,