Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([O:13][CH2:14][C@@H:15]2[O:20][C:19]3[C:21]([NH2:26])=[C:22]([NH2:25])[CH:23]=[CH:24][C:18]=3[O:17][CH2:16]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1.[C:27](C1NC=CN=1)(C1NC=CN=1)=[O:28].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([O:13][CH2:14][CH:15]2[O:20][C:19]3[C:21]4[NH:26][C:27](=[O:28])[NH:25][C:22]=4[CH:23]=[CH:24][C:18]=3[O:17][CH2:16]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc(N)c(N)c3O2)cc1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccc4[nH]c(=O)[nH]c4c3O2)cc1
Reaction time: 15 h

Procedure:
To a solution of 0.30 g (0.71 mmole) of [(2R)-7,8-diamino-2,3-dihydro-1,4 benzodioxin-2-yl]methyl 4-methylbenzenesulfonate dihydrochloride in 50 mL of methylene chloride was added 0.50 g (3.0 mmole) of carbonyl diimidazole and 0.65 g (5.0 mmole) of diisopropylethylamine. The reaction mixture was stirred under nitrogen for 15 hours. The mixture was then concentrated in vacuum and 250 mL of ethyl acetate added. This solution was washed with 250 mL portions each of 2 N aqueous HCl, saturated aqueous sodium bicarbonate and saturated brine, dried over sodium sulfate, filtered and concentrated in vacuum. The residue was column chromatographed on 25 g of silica gel, using a gradient elution commencing with chloroform and ending with 3% methanol in chloroform. The product fractions were combined and evaporated in vacuum to give 0.21 g of the (R)-enantiomer of the title compound as an off-white solid, m.p. 202-204° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]#[N:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[Br:16]N1C(=O)CCC1=O.C1(=O)NC(=O)CC1>N(C(C)(CC(C)C)C#N)=NC(C)(CC(C)C)C#N.C(Cl)Cl.O>[Br:16][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:14]#[N:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)CC(C)(C#N)N=NC(C)(C#N)CC(C)C
Agent: O=C1CCC(=O)N1
Solvent: ClCCl
Solvent: O
Product: N#Cc1ccccc1-c1ccc(CBr)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 80.4 %

Procedure:
A four-necked glass flask equipped with a stirrer and reflux condenser was charged with 180 g of methylene chloride, 63.2 g of 4'-methylbiphenyl-2-carbonitrile, 58.8 g of N-bromosuccinimide and 90 mg of 2,2'-azobis (2,4-dimethylvaleronitrile) and the reaction was conducted under reflux with stirring at an internal temperature of 45°-47° C. for 3 hours. Refluxing was further continued for 1 hour and after cooling to an internal temperature of 35°-38° C., the reaction mixture was treated with 200 g of water twice to transfer the byproduct succinimide into the water layer. The methylene chloride layer was allowed to cool gradually to 0° C., whereupon white crystals separated. The crystals were recovered by filtration, washed with cold methylene chloride and dried to give 71.6 g of 4'-bromomethylbiphenyl-2-carbonitrile. Yield 80.5%.
Reaction SMILES: [NH2:1][C@H:2]([CH2:5][CH3:6])[CH2:3][OH:4].[C:7]([C:11]1[CH:18]=[CH:17][CH:16]=[C:13]([CH:14]=O)[C:12]=1[OH:19])([CH3:10])([CH3:9])[CH3:8]>CO>[C:7]([C:11]1[CH:18]=[CH:17][CH:16]=[C:13]([CH:14]=[N:1][C@H:2]([CH2:5][CH3:6])[CH2:3][OH:4])[C:12]=1[OH:19])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC[C@@H](N)CO
Reactant: CC(C)(C)c1cccc(C=O)c1O
Solvent: CO
Product: CC[C@H](CO)N=Cc1cccc(C(C)(C)C)c1O
Yield: 81.9 %

Procedure:
0.98 g of (R)-2-amino-1-butanol and 1.78 g of 3-tertbutylsalicylaldehyde were disolved in 15 ml of methanol to prepare a methanol solution. The methanol solution was heated under reflux over 6 hours to obtain a reaction mixture. The solvent of the mixture was removed by distillation in vacuo to obtain a concentrated solution. The concentrated solution was placed on a silica gel column and eluted with a mixture of hexane and ethyl acetate (hexane:ethyl acetate=3:1) to give 2.04 g of (R)-2-[N-(3-tert-butylsalicylidene)amino]-1-butanol as yellow syrup (yield: 82%).
Reaction SMILES: C(O)(=O)C.[F:5][C:6]1[CH:15]=[C:14]2[C:9]([N:10]=[CH:11][C:12](=[O:20])[N:13]2[CH2:16][CH2:17][CH:18]=O)=[CH:8][CH:7]=1.[NH2:21][C@H:22]1[CH2:26][N:25]([C:27]2[CH:28]=[CH:29][C:30]3[O:31][CH2:32][C:33](=[O:37])[NH:34][C:35]=3[N:36]=2)[C:24](=[O:38])[CH2:23]1.C(OC(=O)N[C@@H]1CC(=O)NC1)(C)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>CN(C)C=O>[F:5][C:6]1[CH:15]=[C:14]2[C:9]([N:10]=[CH:11][C:12](=[O:20])[N:13]2[CH2:16][CH2:17][CH2:18][NH:21][C@H:22]2[CH2:26][N:25]([C:27]3[CH:28]=[CH:29][C:30]4[O:31][CH2:32][C:33](=[O:37])[NH:34][C:35]=4[N:36]=3)[C:24](=[O:38])[CH2:23]2)=[CH:8][CH:7]=1
Reactant: O=CCCn1c(=O)cnc2ccc(F)cc21
Reactant: N[C@@H]1CC(=O)N(c2ccc3c(n2)NC(=O)CO3)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)(C)OC(=O)N[C@H]1CNC(=O)C1
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=C1COc2ccc(N3C[C@H](NCCCn4c(=O)cnc5ccc(F)cc54)CC3=O)nc2N1
Reaction time: 12 h
Yield: 29 %

Procedure:
Acetic acid (0.042 ml, 0.70 mmol) was added to a mixture of 3-(7-fluoro-2-oxoquinoxalin-1(2H)-yl)propanal (0.120 g, 0.54 mmol), 6-[(4R)-4-amino-2-oxopyrrolidin-1-yl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (synthesized using [(3R)-5-oxopyrrolidin-3-yl]carbamic acid tert-butyl ester synthesized with reference to WO2004/22536 in the same manner as in Reference Examples 20, 21 and 22; 0.185 g, 0.70 mmol) and N,N-dimethylformamide (1.6 ml). The mixture was stirred for 0.5 hours, to which sodium triacetoxyborohydride (0.15 g, 0.70 mmol) was gradually added and stirred for 12 hours. An aqueous solution of sodium hydrogen carbonate was added to the reaction mixture under cooling on ice and the mixture was extracted with ethyl acetate. The obtained crude product was purified by thin layer chromatography (dichloromethane/methanol) to yield 70 mg (29%) of the title compound.
Reaction SMILES: [CH:1](=O)[CH2:2][CH:3]([CH3:5])[CH3:4].[NH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.O>C1(C)C=CC=CC=1>[N:7]1([CH:1]=[CH:2][CH:3]([CH3:5])[CH3:4])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CC(C)CC=O
Reactant: C1CCNC1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)C=CN1CCCC1
Temperature: 0 °C

Procedure:
194 g (2.25 mol) of isovaleraldehyde are diluted in 1115 ml of toluene and cooled to 0° C. with stirring. 190.3 g (2.68 mol) of pyrrolidine, dissolved in 185.8 ml of toluene, were then added dropwise to this solution, such that the reaction temperature did not rise above 5° C. After the addition had ended, the reaction solution was stirred at 5° C. for another 1 hour. Subsequently, the mixture was warmed to room temperature and the water formed was removed completely by extraction with toluene. Thereafter, the solvent was removed by evaporation and the crude product (329.1 g; 95% of theory) was stored at 4° C. in a refrigerator.
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH:28]2[CH2:33][CH2:32][N:31]([C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]2)=[CH:22][CH:21]=1.C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC>[N:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([C:20]3[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH:28]4[CH2:29][CH2:30][N:31]([C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35])[CH2:32][CH2:33]4)=[CH:24][CH:25]=3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=S(=O)(c1ccc(B(O)O)cc1)N1CCOCC1
Reactant: CC(C)OC(=O)N1CCC(COc2ccc(Br)cc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(=O)(=O)N4CCOCC4)cc3)cc2)CC1
Yield: 9.9 %

Procedure:
The title compound (10 mg, 8%) was prepared as a white solid from [4-(4-morpholinylsulfonyl)phenyl]boronic acid (54 mg, 0.2 mmol), 1-methylethyl 4-{[(4-bromophenyl)oxy]methyl}-1-piperidinecarboxylate (prepared as in Example 9, Step 2, 71 mg, 0.2 mmol), Pd(PPh3)2Cl2 (50 mg, 0.07 mmol), 2M Na2CO3 (1 mL) and DME (1 mL) in a manner similar to Example 21, Step 3, and worked up in a manner similar to Example 9, Step 3. 1H NMR (400 MHz, CDCl3): δ 7.78 (m, 2H), 7.70 (m, 2H), 7.54 (d, 2H, J=8.8 Hz), 6.99 (d, 2H, J=8.8 Hz), 4.97-4.86 (m, 1H), 4.22 (bs, 2H), 3.86 (d, 2H, J=6.4 Hz), 3.78-3.73 (m, 4H), 3.07-3.01 (m, 4H), 2.84-2.74 (m, 2H), 2.05-1.95 (m, 1H), 1.91-1.81 (m, 2H), 1.37-1.27 (m, 2H), 1.25 (d, 6H, J=6.4 Hz); LRMS (ESI), m/z 503 (M+H).
Reaction SMILES: C[O:2][C:3]1[C:4]([N+:13]([O-:15])=[O:14])=[CH:5][C:6]([N+:10]([O-:12])=[O:11])=[C:7]([OH:9])[CH:8]=1.CN(C)C=O.Cl.Cl>CN(C)C=O>[N+:10]([C:6]1[CH:5]=[C:4]([N+:13]([O-:15])=[O:14])[C:3]([OH:2])=[CH:8][C:7]=1[OH:9])([O-:12])=[O:11]
Reactant: COc1cc(O)c([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: Cl
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c(O)cc1O
Temperature: 130 °C
Yield: 94.9 %

Procedure:
To a 100 mL round-bottom flask is added 2.14 g (10 mmol) of 5-methoxy-2,4-dinitrophenol (MDNP) and 1.31 g (12 mmol) of DMF-HCl in 30 mL of N,N-dimethylformamide (DMF). This mixture is stirred at 130° C. and monitored by High Pressure Liquid Chromatography (HPLC). After 8.5 hours essentially no MDNP is observed by HPLC. The reaction mixture is poured into 100 mL of 1N HCl, and extracted with ethyl acetate (EtOAc, 3×30 mL). The combined organics are washed with a single portion of 0.1N HCl, dried (Na2SO4) and concentrated by rotary evaporation to give crude 4,6-dinitroresorcinol (DNR) as a yellow solid (1.9 g, 95% yield): melting point (m.p.) 205° C. to 210° C., 1H NMR (CDCl3)δ11.03 (s,2H), 9.08 (s,1H), 6.82 (s,1H).
Reaction SMILES: Br[C:2]1[C:3](=[O:19])[C:4]([CH3:18])([CH3:17])[O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1.[C:20]1(B(O)O)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1>>[CH3:17][C:4]1([CH3:18])[C:3](=[O:19])[C:2]([C:28]2[C:29]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:25]=[CH:26][CH:27]=2)=[C:6]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[O:5]1
Reactant: OB(O)c1cccc2ccccc12
Reactant: CC1(C)OC(c2ccc(S(C)(=O)=O)cc2)=C(Br)C1=O
Product: CC1(C)OC(c2ccc(S(C)(=O)=O)cc2)=C(c2cccc3ccccc23)C1=O

Procedure:
200 mg of 4bromo-2,2-dimethyl-5-{4-(methylsulfonyl)phenyl}-3(2H)-furanone was coupled with 114 mg of naphthalene-1-boronic acid by a procedure similar to the procedure employed for Example 2 to afford 2,2-dimethyl-5-{4-(methylsulfonyl)phenyl}-4-(1-naphthyl)-3(2H)-furanone as a solid. mp: 194-195° C. NMR: δ1.67 (s, 3H), 1.71 (s, 3H), 2.97 (s, 3H), 7.33-7.43 (m, 2H), 7.48-7.60 (m, 2H), 7.51-7.52 (m, 1H), 7.66-7.69 (m, 2H), 7.76-7.78 (m, 2H), 7.90-7.94 (m, 2H), IR (cm−1): 1698, 1404, 1318, 1149, 1092, 772.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[C:6]([Br:8])[CH:7]=1.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[Br:8][C:6]1[CH:7]=[C:2]([NH:1][S:14]([CH3:13])(=[O:16])=[O:15])[CH:3]=[C:4]([C:9]([F:12])([F:10])[F:11])[CH:5]=1
Reactant: Nc1cc(Br)cc(C(F)(F)F)c1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Nc1cc(Br)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.6 %

Procedure:
To a solution of 3-Amino-5-bromobenzotrifluoride (200 mg) in pyridine (2 mL) was added methane sulphonyl chloride (115 mg) and one crystal of 4-(dimethyl-amino)pyridine. The mixture was stirred at room temperature for four hours then diluted with ethyl acetate (50 mL) and washed with HCl (2M, 50 mL) and saturated sodium chloride solution (50 mL). Organics were separated, dried over sodium sulphate, filtered, and solvent was removed under reduced pressure to yield N-(3-bromo-5-trifluoromethyl-phenyl)-methanesulfonamide (264 mg).
Reaction SMILES: Cl.[CH2:2]1O[C:5]([C:9]2[CH:10]=[N:11][C:12]3[CH2:13][CH2:14][C:15](=[O:20])[CH2:16][C:17]=3[C:18]=2[OH:19])([O:6]CC)[O:4][CH2:3]1.[OH-].[Na+]>C(O)C>[OH:19][C:18]1[C:17]2[CH2:16][C:15](=[O:20])[CH2:14][CH2:13][C:12]=2[N:11]=[CH:10][C:9]=1[C:5]([O:4][CH2:3][CH3:2])=[O:6]
Reactant: CCOC1(c2cnc3c(c2O)CC(=O)CC3)OCCO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)c1cnc2c(c1O)CC(=O)CC2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a mixture of 2N HCl (50 mL) and ethanol (200 mL), ethyl 4-hydroxy-6-oxo-5,6,7,8-tetrahydroquinoline-3-carboxylate ethylene ketal (10.0 g) is added. Resultant suspension is stirred at room temperature for 24 hours under nitrogen atmosphere. The reaction mixture is neutralized with NaOH and concentrated to remove most of ethanol. The resulting precipitate is collected, washed with water, air dried, then dried in a vacuum oven at 80° to yield ethyl 4-hydroxy-6-oxo-5,6,7,8-tetrahydroquinoline-3-carboxylate.
Reaction SMILES: [CH2:1]1[CH2:11][C:9](=O)[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.Cl.[NH2:13][OH:14].O.C(=O)([O-])[O-].[Na+].[Na+]>CO>[C:9]1(=[N:13]/[OH:14])\[CH2:11][CH2:1][CH2:2][C:3]2[C:8]\1=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: O=C1CCCc2ccccc21
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O/N=C1/CCCc2ccccc21
Temperature: 25 °C
Reaction time: 36 h

Procedure:
To a solution of α-tetralone (50 g, 45.5 mL, 342 mmol) in anhydrous methanol (500 mL) was added hydroxylamine hydrochloride (24.7 g, 377 mmol) and sodium carbonate monohydrate (45 g, 363 mmol). The resulting slurry was stirred at ambient temperature for 36 h and the solvent was removed. The residue was titurated with water and the resulting solid was recrystallized from ether/hexanes to supply the product (37.1 g) as greenish tan crystals.
Reaction SMILES: N[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([Br:12])=[CH:7][CH:8]=2)[CH:3]=1.N([O-])=O.[Na+].[Cl:17]CCl>O.Cl.[Cu]Cl>[Br:12][C:6]1[CH:5]=[C:4]2[C:9]([CH:10]=[CH:11][CH:2]=[C:3]2[Cl:17])=[CH:8][CH:7]=1
Reactant: Nc1ccc2ccc(Br)cc2c1
Reactant: ClCCl
Agent: Cl[Cu]
Agent: Cl
Agent: O=N[O-]
Solvent: O
Product: Clc1cccc2ccc(Br)cc12
Temperature: 25 °C
Yield: 43 %

Procedure:
A mixture of the product from Step C (6.0 g, 30 mmol) and 6 M HCl (13.4 ml) was stirred at room temperature until a solid formed. The mixture was cooled to 0° C. and a solution of sodium nitrite (1.9 g, 30 mmol) in water (5.6 ml) was slowly added keeping the temperature below 5° C. The resulting brown slurry was stirred at 0° C. for 15 minutes and then a solution of copper(I) chloride (3.3 g, 30 mmol) in 6 M HCl (15.4 ml) was added. The mixture was stirred at 0° C. for 10 minutes, then warmed to room temperature and stirred at 60° C. for 30 minutes. After cooling to room temperature, dichloromethane was added. The mixture was filtered through diatomaceous earth and the filtrate was extracted with dichloromethane three times. The combined organic layers were washed with water and dried over magnesium sulfate to give 7-bromo-1-chloronaphthalene (2.8 g, 43%) after chromatography (100% hexanes): 1H NMR (300 MHz, DMSO-d6) δ 8.30 (d, J=1.8 Hz, 1H), 7.96-8.02 (m, 2H), 7.74-7.78 (m, 2H), 7.55 (t, J=7.8 Hz, 1H).
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:12]2[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[N:16]=1>>[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:15]1[N:16]=[C:11]([NH:9][CH2:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:12]2[CH:25]=[C:24]([C:26]([F:28])([F:29])[F:27])[S:23][C:13]=2[N:14]=1
Reactant: NCCc1ccccc1
Reactant: FC(F)(F)c1cc2c(Cl)nc(-c3ccccn3)nc2s1
Product: FC(F)(F)c1cc2c(NCCc3ccccc3)nc(-c3ccccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of phenethylamine with 4-chloro-2-(pyridin-2-yl)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-phenethylamino-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][C:2]1[C:12]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:19][C:20]([F:43])([F:42])[CH2:21][NH:22][C:23]([C:25]1([CH2:38][CH2:39][CH2:40]Br)[C:37]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:24]>>[CH2:1]=[C:2]1[C:12]([N:13]2[CH2:14][CH2:15][N:16]([CH2:40][CH2:39][CH2:38][C:25]3([C:23](=[O:24])[NH:22][CH2:21][C:20]([F:19])([F:42])[F:43])[C:37]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[C:31]4[C:26]3=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH2:17][CH2:18]2)=[CH:11][CH:10]=[CH:9][CH:3]1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1cccc(N2CCNCC2)c1C
Reactant: O=C(NCC(F)(F)F)C1(CCCBr)c2ccccc2-c2ccccc21
Product: C=C1C(N2CCN(CCCC3(C(=O)NCC(F)(F)F)c4ccccc4-c4ccccc43)CC2)=CC=CC1C(=O)OCC

Procedure:
The procedure of step (b) of Example 1 was repeated, except that the compound prepared in step (a) of Example 53 and the compound prepared in step (a) of Example 93 were used as the starting compound. Thus, ethyl 2-methyly-3-[4-[3-[9-(2,2,2-trifluoroethylcarbamoyl)-9H-fluoren-9-yl]propyl]piperazin-1-yl]-benzoate was obtained.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].Cl[C:10]1[S:11][C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1.[I-]>CC(CC(C)C)=O.C(=O)([O-])[O-].[Na+].[Na+]>[OH:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:1])[C:10]1[S:11][C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1
Reactant: CNCCCCCO
Reactant: Clc1nc2ccccc2s1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: CN(CCCCCO)c1nc2ccccc2s1
Yield: 97.3 %

Procedure:
A mixture of 5-(methylamino)pentanol (0.23 mol), 2-chlorobenzothiazole (0.3 mol), sodium carbonate (0.4 g) and potssium iodide (catalytic quantity) in methylisobutyl-keton (1000 ml) was stirred and refluxed overnight. The reaction mixture was cooled, washed with water, dried, filtered and the filtrate was evaporated. The residue was stirred in water, acidified with HCl, stirred, washed with diisopropylether, and the acidic layer was alkalized with NH4OH. This mixture was extracted twice with CH2Cl2. The separated organic layer was dried, filtered, and the solvent was evaporated, yielding 56 g of N-(5-hydroxypentyl)-N-methyl-2-benzothiazolamine (interm. 7).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:10][C@H:11]1[CH2:16][CH2:15][C@H:14]2[C@H:17]3[C@H:27]([CH2:28][CH2:29][C@:12]12[CH3:13])[C@:25]1([CH3:26])[C@H:20]([C:21](=[O:30])[CH2:22][CH2:23][CH2:24]1)[CH2:19][CH2:18]3.[Cl-]>N1C=CC=CC=1>[C:1]([O:10][C@H:11]1[CH2:16][CH2:15][C@H:14]2[C@H:17]3[C@H:27]([CH2:28][CH2:29][C@:12]12[CH3:13])[C@:25]1([CH3:26])[C@H:20]([C:21](=[O:30])[CH2:22][CH2:23][CH2:24]1)[CH2:19][CH2:18]3)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@]12CCCC(=O)[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Reactant: O=C(Cl)c1ccccc1
Agent: [Cl-]
Solvent: c1ccncc1
Product: C[C@]12CCCC(=O)[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](OC(=O)c3ccccc3)CC[C@@H]12
Temperature: 0 °C

Procedure:
To 12 ml of dry pyridine and 6 ml of benzoyl chloride is added 2.0 g of the product of Step F to form a solution which is heated on a steam bath for 30 min. and then poured into 175 ml of ice water and stirred to decompose the excess chloride. The reaction mixture is filtered, washed with water, and pumped dry under high vacuum at 50° C. to yield 1.7 g of final product.
Reaction SMILES: [C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][CH2:10][O:9][C:8]2=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH3:19]>[Cl-].[Zn+2].[Cl-].C(O)C>[C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][CH2:10][NH:19][C:8]2=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N
Reactant: O=C1OCCC1(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCO
Product: O=C1NCCC1(c1ccccc1)c1ccccc1
Temperature: 225 °C

Procedure:
3,3-Diphenyldihydrofuran-2(3H)-one (3.98 g, 16.70 mmol) and zinc chloride (0.080 g) were placed in an autoclave. Ammonia (8 mL) was added, and the reactor was sealed and heated at 225° C. for 21 hours under an argon atmosphere at an equilibrium pressure of 800 pounds per square inch. The vessel was cooled, the ammonia was vented, and a mixture of solids was obtained. The solid was treated with ethanol (100 mL), filtered and concentrated. Silica gel chromatography eluting with 5% methanol/dichloromethane gave the title compound. MS (DCI+) m/z 238.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH2:16][CH2:17][CH3:18])[NH:5][C:6]=1[CH2:7][O:8]CC1C=CC=CC=1.CS(O)(=O)=O.[OH-].[Na+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[N:3]=[C:4]([CH2:16][CH2:17][CH3:18])[NH:5][C:6]=1[CH2:7][OH:8]
Reactant: CCCc1nc(Cl)c(COCc2ccccc2)[nH]1
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCCc1nc(Cl)c(CO)[nH]1
Temperature: 0 °C
Yield: 81.7 %

Procedure:
A solution of 4-chloro-5-{[(phenylmethyl)oxy]methyl}-2-propyl-1H-imidazole (1.72 g, 6.5 mmol) and methanesulfonic acid (16 mL, 247 mmol) in chloroform (36 mL) was stirred at RT for 1 h. The reaction mixture was poured into ice (˜70 g) and the solution was neutralized by addition of 5N NaOH until the pH was 10. The solution was extracted with methyl tert-butyl ether (2×60 mL) and then with n-butanol (3×40 mL). The combined n-butanol extracts were concentrated, washed with brine, and dried in vacuo to provide the title compound (0.927 g, 82%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.09 (br. s., 1H), 5.10 (br. s., 1H), 4.31 (s, 2H), 2.45-2.51 (m, 2H), 1.60 (sex, 2H), 0.87 (t, 3H).
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].[NH:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15](=[O:38])[CH2:16][CH2:17][CH2:18][CH2:19][N:20]([CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[O:36][CH3:37])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:12][CH:13]=2)[CH2:8][CH2:7]1>O1CCCC1>[CH2:1]([NH:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15](=[O:38])[CH2:16][CH2:17][CH2:18][CH2:19][N:20]([CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[O:36][CH3:37])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:12][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: COc1ccccc1CCN(CCCCC(=O)c1ccc2c(c1)CCN2)C(=O)OC(C)(C)C
Reactant: CCN=C=O
Solvent: C1CCOC1
Product: CCNC(=O)N1CCc2cc(C(=O)CCCCN(CCc3ccccc3OC)C(=O)OC(C)(C)C)ccc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 60.6 %

Procedure:
Ethyl isocyanate (85 mg) was added to a solution of tert-butyl 5-(2,3-dihydro-1H-indol-5-yl)-5-oxopentyl[2-(2-methoxyphenyl)ethyl]carbamate (362 mg) obtained in Reference Example 50 in tetrahydrofuran (2 ml), and the mixture was stirred at 60° C. for 2 hours. The solvent was evaporated under reduced pressure, water was added to the resulting residue, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was-purified by silica gel chromatography (eluting solvent; hexane:ethyl acetate=1:1) to give the title compound as a pale yellow oil (254 mg).