Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:3]=1.CC1(C)C(C)(C)[O:19][B:18](B2OC(C)(C)C(C)(C)O2)[O:17]1.C([O-])(=O)C.[K+]>CS(C)=O>[O:12]1[CH2:13][CH2:14][CH:9]([O:8][C:4]2[CH:3]=[C:2]([B:18]([OH:19])[OH:17])[CH:7]=[CH:6][N:5]=2)[CH2:10][CH2:11]1
Reactant: Brc1ccnc(OC2CCOCC2)c1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: OB(O)c1ccnc(OC2CCOCC2)c1
Temperature: 100 °C

Procedure:
To 4-Bromo-2-(tetrahydro-pyran-4-yloxy)-pyridine (0.2 g, 0.77 mmol) in DMSO (5 ml) (degassed by bubbling N2 through) was added 4,4,5,5,4′,4′,5′,5′-Octamethyl-2,2′-bi-1,3,2-dioxaborolane (0.39 g, 1.55 mmol) and potassium acetate (0.27 g, 2.31 mmol). PdCl2ddpf (0.028, 0.04 mmol) was added, the reaction mixture again degassed and then heated at 100° C. for 5 h. The compound was passed through a C18 reverse phase chromatography column to afford the desired product, used crude. MS: [MH]+ 224.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][C@H:4]1[CH2:8][NH:9][C:10](=[O:35])[C:11]1[C:16]([O:17]CC2C=CC=CC=2)=[CH:15][CH:14]=[C:13]([O:25]CC2C=CC=CC=2)[C:12]=1[O:33][CH3:34])[CH3:2].Cl.[H][H]>CCOCC.C(O)C.[Pd]>[CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][C@H:4]1[CH2:8][NH:9][C:10](=[O:35])[C:11]1[C:16]([OH:17])=[CH:15][CH:14]=[C:13]([OH:25])[C:12]=1[O:33][CH3:34])[CH3:2]
Reactant: [H][H]
Reactant: CCN1CCC[C@H]1CNC(=O)c1c(OCc2ccccc2)ccc(OCc2ccccc2)c1OC
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: CCN1CCC[C@H]1CNC(=O)c1c(O)ccc(O)c1OC
Yield: 113.2 %

Procedure:
A mixture of (S)-(-)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-3,6-dibenzyloxy-2-methoxybenzamide (130 mg, 0.27 mmol), 5% Pd/C (50 mg), 0.5 ml 4 M HCl in ether and 5 ml ethanol was shaken in a hydrogen atmosphere for 1 h. Filtration and evaporation of the solvent gave 90 mg pure title compound as an oily hydrochloride.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:20]1([CH:26]=O)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:20]1([CH2:26][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=CC1CCCCC1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: FC(F)(F)c1nnc2ccc(N3CCN(CC4CCCCC4)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with cyclohexanecarbaldehyde was carried out according to General Synthetic Method 6. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-(cyclohexylmethyl)piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [CH2:1]([N:5]([CH3:26])[C:6]([C:8]1[CH:9]=[C:10]([C:21]([O:23]CC)=[O:22])[CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[CH:13]=1)=[O:7])[CH:2]([CH3:4])[CH3:3].[OH-].[Li+].C(O)C>O>[CH2:1]([N:5]([CH3:26])[C:6]([C:8]1[CH:9]=[C:10]([C:21]([OH:23])=[O:22])[CH:11]=[C:12]([C:14]2[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=2)[CH:13]=1)=[O:7])[CH:2]([CH3:4])[CH3:3]
Reactant: CCOC(=O)c1cc(C(=O)N(C)CC(C)C)cc(-c2ccc(C)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)N(C)CC(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of ethyl 5-(isobutyl(methyl)carbamoyl)-4′-methylbiphenyl-3-carboxylate (165 mg, 0.467 mmol), lithium hydroxide (55 mg, 2.3 mmol), ethanol (10 mL), and water (1 mL) was stirred at room temperature for 5 h. LC-MS indicated completion of the reaction. The solvent was removed in vacuo and the residue was treated with water and acidified with 1N aq. HCl to pH=3 and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine, dried (Na2SO4), and concentrated to yield the product as white foam. LC-MS: 326.0 [M+1]+.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)[CH:2]1[O:4][CH2:3]1.[NH:15]1[CH:20]=[CH:19][CH:18]([C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][CH:22]=2)[CH2:17][CH2:16]1>>[F:14][C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[N:5]([CH2:1][CH:2]([OH:4])[CH2:3][N:15]1[CH2:16][CH:17]=[C:18]([C:21]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[NH:23][CH:22]=3)[CH2:19][CH2:20]1)[CH:6]=[CH:7]2
Reactant: Fc1ccc2c(ccn2CC2CO2)c1
Reactant: C1=CC(c2c[nH]c3ccccc23)CCN1
Product: OC(CN1CC=C(c2c[nH]c3ccccc23)CC1)Cn1ccc2cc(F)ccc21
Yield: 77.9 %

Procedure:
A methanolic solution of 1-N-glycidyl-5-fluoroindole (0.52 g, 3.0 mmole) from example 1 and 3-(4-tetrahydropyridinyl)indole (0.59 g, 3.0 mmole) was refluxed under nitrogen for 15 hours. The reaction mixture was concentrated in vacuo and the product purified by flash silica gel chromatography (ethyl acetate) to afford the titled compound as a light yellow colored solid (0.91 g, 78% yield). Treatment with a 0.25 M ethanolic solution of fumaric acid (0.5 equivalents) gave the required salt as a yellow colored solid. The product was recrystallized from ethanol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O-:22])=[O:21])[CH:14]=3)[NH:9]2)=[CH:4][C:3]=1[N+:23]([O-])=O.[CH:26]1([C:31]([OH:33])=O)[CH2:30][CH2:29][CH2:28][CH2:27]1.[CH:34](N(CC)C(C)C)(C)C.P(Cl)(Cl)(Cl)=O>ClCCl>[CH:26]1([C:31]([NH:23][C:3]2[CH:4]=[C:5]([CH:8]3[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]4[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:34])=[O:21])[CH:14]=4)[NH:9]3)[CH:6]=[CH:7][C:2]=2[F:1])=[O:33])[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)C1CCCC1
Reactant: CC1(C)Cc2cc(C(=O)[O-])ccc2NC1c1ccc(F)c([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(F)c(NC(=O)C3CCCC3)c1)N2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 90 %

Procedure:
To an ice-cold mixture of 2-(4-fluoro-3-nitrophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (0.3 mmol, 1.0 eq.), cyclopentanecarboxylic acid (0.46 mmol, 1.5 eq.), N,N-diisopropyl ethylamine (0.6 mmol, 2.0 eq.) in dichloromethane (5 mL) was added a solution of phosphorus oxychloride (0.36 mmol, 1.2 eq.). Then the reaction mixture was stirred at room temperature for 2.5 hours. LC-MS indicated that the starting material was consumed completely. The reaction was quenched by 20 mL water extracted with ethyl acetate (20 mL×2). The combined organic layer was concentrated and the residue was purified by column chromatography (petroleum ether/ethyl acetate=3:1) to afford methyl 2-(3-(cyclopentanecarboxamido)-4-fluorophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate as a pale yellow solid; Yield: 90%; MS (ESI+APCI) M+1=425.
Reaction SMILES: CN1CCOCC1.C([N:25](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:26]([C:32]([OH:34])=[O:33])[CH2:27][CH2:28][CH2:29][CH2:30][NH2:31])(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.ON1C2C=CC=CC=2N=N1.N[C@H](C([NH:104][C@H:105]([C:107]([OH:109])=[O:108])[CH3:106])=O)CCCCN>CN(C=O)C>[NH2:25][C@H:26]([C:32]([OH:34])=[O:33])[CH2:27][CH2:28][CH2:29][CH2:30][NH2:31].[NH2:104][C@H:105]([C:107]([OH:109])=[O:108])[CH3:106]
Reactant: NCCCC[C@@H](C(=O)O)N(C(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OCC1c2ccccc2-c2ccccc21
Reactant: C[C@H](NC(=O)[C@@H](N)CCCCN)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: C[C@H](N)C(=O)O
Product: NCCCC[C@H](N)C(=O)O

Procedure:
The resin is suspended in 70 ml of activator solution (5% N-methyl-morpholine in DMF). Thereafter, added to the suspension are 8.2 g (14 mmoles) of bis-Fmoc-lysine, 7.28 g of coupling agent, benzotriazol-1-yl-oxy-tris-pyrro-lidinophosphonium hexafluorophosphate (PyBOP), and 2.14 g of catalyst, 1-hydroxybenzotriazole (HOBT). The reaction medium is mixed for 90 minutes and the resultant product is (Fmoc)2 -Lys-Ala-resin, i.e., (Fmoc)2 -K-A-resin. The product of the coupling reaction is washed 3 times with DCM, 1 time with methanol and 5 times with DMF and then subjected to deprotection using a mixture of 30% piperidine, 35% toluene and 35% DMF. The product obtained from the deprotection is Lys-Ala-resin (K-A-resin). This product is washed 5 times with DMF, 1 time with methanol and 3 times with DCM.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[S:7](Cl)(Cl)(=[O:9])=[O:8].Cl.[F:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:23][O:24][CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[O:22])=[CH:16][CH:15]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[F:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:23][O:24][CH:25]2[CH2:30][CH2:29][N:28]([S:7]([N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)(=[O:9])=[O:8])[CH2:27][CH2:26]2)=[O:22])=[CH:16][CH:15]=1
Reactant: O=C(NOC1CCNCC1)Nc1ccc(F)cc1
Reactant: O=S(=O)(Cl)Cl
Reactant: C1CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NOC1CCN(S(=O)(=O)N2CCCCC2)CC1)Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 49.9 %

Procedure:
A solution of piperidine (300 mg, 3.5 mmol) in CH2Cl2 (10 ml) was added at 0° C. over 30 minutes to a suspension of sulfuryl dichloride (952 mg, 7.0 mmol) in CH2Cl2 (35 ml) and the whole was stirred at room temperature for 17 hours. The resulting solid was filtered off and the filtrate was concentrated in vacuo. The residue was dissolved in CH2Cl2 (15 ml), 1-(4-fluorophenyl)-3-(piperidin-4-yloxy)urea hydrochloride (130 mg, 0.45 mmol) and N,N-diisopropylethylamine (174 mg, 1.35 mmol) was added, and the whole was stirred at 50° C. for 24 hours. The reaction mixture was concentrated in vacuo and the residue was diluted with ethyl acetate (50 ml), washed with H2O (20 ml×2), brine (20 ml×2), dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether: 50/50) to give 1-(4-fluorophenyl)-3-(1-(piperidin-1-ylsulfonyl)piperidin-4-yloxy)urea (90 mg, 50%) as a white solid: LCMS: 401 [M+1]+. 1H NMR (DMSO-d6) δ: 1.48 (s, 6H), 1.7 (m, 2H), 1.89 (m, 2H), 2.98 (m, 2H), 3.1 (m, 4H), 3.4 (m, 2H), 3.87 (m, 1H), 7.08 (t, 2H), 7.86 (m, 2H), 8.65 (s, 1H), 9.42 (s, 1H).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:13])([CH3:12])[C:10]#[N:11])=[CH:5][C:4]=1[CH3:14])=O.[BH4-].[Na+].[NH3:17]>CO.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[NH2:17][CH2:1][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:13])([CH3:12])[C:10]#[N:11])=[CH:5][C:4]=1[CH3:14]
Reactant: Cc1cc(C(C)(C)C#N)ccc1C=O
Reactant: N
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(C(C)(C)C#N)ccc1CN
Temperature: 25 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
2-(4-formyl-3-methylphenyl)-2-methylpropanenitrile 1.89 g, 10.2 mmol) is dissolved in 50 ml of 7M NH3 in MeOH. Ti(OiPr)4 (6 mmol, 20 mmol) is added and the mixture stirred for 3 hours at room temperature. NaBH4 (0.6 g, 15 mmol) is added and the reaction left at room temperature overnight. The mixture is quenched by the addition of 25 ml of NH4OH 2 M. The resulting precipitate is filtered off and washed with EtOAc. Phases are separated, the organic phase is dried over magnesium sulfate, filtered and evaporated to dryness, giving 2-[4-(aminomethyl)-3-methylphenyl]-2-methylpropanenitrile (1.325 g, 7.09 mmol, 87%). The crude product is used without further purification. 1H NMR (400 MHz, DMSO-D6) δ 1.64 (s, 6H, first rotamer) 1.65 (s, 6H, second rotamer) 2.28 (s, 3H, first rotamer) 2.29 (s, 3H, second rotamer) 3.32 (broad s, 2 H) 3.67 (s, 2H, first rotamer) 3.68 (s, 2H, second rotamer) 7.24-7.27 (m, 1H) 7.28 (s, 1H) 7.36-7.40 (m, 1H).
Reaction SMILES: CN(C)C(=CC=[C:11]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13])C(OCC)=S.F[B-](F)(F)F.[CH3:29][N:30]([CH3:44])[C:31]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=O)=[CH:32][CH:33]=[N+](C)C.C([Li])CCC.C1([S:56]CC(OCC)=O)C=CC=CC=1>CCCCCC.O1CCCC1>[CH3:29][N:30]([CH3:44])[C:31](=[CH:32][CH:33]=[C:11]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[S:56]
Reactant: CCOC(=O)CSc1ccccc1
Reactant: CN(C)C(=CC=[N+](C)C)C(=O)OC(C)(C)C
Reactant: CCOC(=O)C(=CC=C(C(=S)OCC)N(C)C)c1ccccc1
Agent: F[B-](F)(F)F
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(=CC=C(C(=S)OC(C)(C)C)N(C)C)c1ccccc1

Procedure:
The procedure is as in Example 2 for the preparation of diethyl 2-dimethylamino-5-phenylthio-2,4-hexadienedioate, starting with N(3-dimethylamino-3-t-butyloxycarbonylpropenylidene)-N-methylmethanaminium tetrafluoroborate (4.05 g), a 1.6M solution (8.8 cc) of butyllithium in hexane and ethyl (phenylthio)acetate (2.8 g) in tetrahydrofuran (65 cc). After purification by chromatography on a silica column with a mixture of cyclohexane and ethyl acetate (70:30 by volume) as eluent, 6-ethyl 1-tert-butyl 2-dimethylamino-5-phenylthio-2,4-hexadienedioate (2.6 g), m.p. 85°-88° C., is obtained.
Reaction SMILES: C[Si](C#N)(C)C.[C:7]1([C:13]2[S:14][CH:15]=[C:16]([CH:18]=[O:19])[N:17]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1(C2SC=C([CH:31]([O:34][Si](C)(C)C)C#N)N=2)C=CC=CC=1.[CH3:39][OH:40]>ClCCl.[I-].[Zn+2].[I-]>[OH:19][CH:18]([C:16]1[N:17]=[C:13]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[S:14][CH:15]=1)[C:39]([O:34][CH3:31])=[O:40]
Reactant: C[Si](C)(C)OC(C#N)c1csc(-c2ccccc2)n1
Reactant: CO
Reactant: O=Cc1csc(-c2ccccc2)n1
Agent: C[Si](C)(C)C#N
Agent: [I-]
Agent: [Zn+2]
Solvent: ClCCl
Product: COC(=O)C(O)c1csc(-c2ccccc2)n1
Temperature: 0 °C
Reaction time: 6 h
Yield: 72 %

Procedure:
Under a nitrogen atmosphere, trimethylsilylcyanide (824 μL, 6.6 mmol) was added at 0° C. to a solution of 2-phenyl-1,3-thiazole-4-carbaldehyde (1 g, 5.28 mmol) and zinc iodide (II) (166 mg, 0.52 mmol) in dichloromethane (30 mL). After 6 hours, the reaction mixture was quenched with a saturated aqueous solution of sodium bicarbonate and extracted with dichloromethane (2×20 mL). The organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered, and evaporated under reduced pressure. The residue was used for the hydrolysis without further purification. Then, 2-(2-phenyl-1,3-thiazol-4-yl)-2-[(trimethylsilyl)oxy]acetonitrile was dissolved in anhydrous methanol (30 mL) and cooled at 0° C. and hydrogen chloride was bubbled for 2 minutes. The mixture was then warmed at room temperature for 20 h and concentrated under vacuum. A saturated solution of sodium bicarbonate (10 mL) was added to the residue and extracted with dichloromethane (2×15 mL). The organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 70/30) to afford the desired alcohol (6a) as a white yellow oil (950 mg, 3.81 mmol, 72%).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[O:3][C:4]([F:27])([F:26])[C:5]([F:25])([F:24])[O:6][C:7]([F:23])([F:22])[C:8]([F:21])([F:20])[O:9][C:10]([F:19])([F:18])[CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16]Br.[CH2:30]([C:38]1[CH:39]=[N:40][C:41]([C:44]2[CH:49]=[CH:48][C:47]([OH:50])=[CH:46][CH:45]=2)=[N:42][CH:43]=1)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>>[CH2:30]([C:38]1[CH:43]=[N:42][C:41]([C:44]2[CH:49]=[CH:48][C:47]([O:50][CH2:16][CH2:15][CH2:14][CH2:13][O:12][CH2:11][C:10]([O:9][C:8]([F:20])([F:21])[C:7]([F:22])([F:23])[O:6][C:5]([F:24])([F:25])[C:4]([F:26])([F:27])[O:3][C:2]([F:28])([F:29])[F:1])([F:19])[F:18])=[CH:46][CH:45]=2)=[N:40][CH:39]=1)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: FC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)COCCCCBr
Reactant: CCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Product: CCCCCCCCc1cnc(-c2ccc(OCCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)F)cc2)nc1

Procedure:
The title compound was prepared essentially as in Example 1 by combining 4-(2-(2-(2-(trifluoromethoxy)tetrafluoroethoxy)tetrafluoroethoxy)-2,2-difluoroethoxy)-1-bromobutane (20.9 g, 38.5 mol; prepared from 1,4-dibromobutane and 2-(2-(2-(trifluoromethoxy)tetrafluoroethoxy)tetrafluoroethoxy)-2,2-difluoroethanol) with 5-octyl-2-(4-hydroxyphenyl)pyrimidine (10.0 g, 0.35 mol). The resulting product was further purified by recrystallization from ethanol and subsequent Kugelrohr distillation to provide a yield of 17.5 g (b.p. 195-220° C. at 0.1 torr).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:5]=2[N:6]=1.C([Mg]Cl)(C)C.[NH:17]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:20](=[O:21])[C:18]1=[O:19]>O1CCCC1.[Cl-].[NH4+].C(OCC)(=O)C>[OH:21][C:20]1([C:9]2[C:8]([OH:11])=[CH:7][C:5]3[N:6]=[C:2]([CH3:1])[S:3][C:4]=3[CH:10]=2)[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[NH:17][C:18]1=[O:19]
Reactant: Cc1nc2cc(O)ccc2s1
Reactant: O=C1Nc2ccccc2C1=O
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1nc2cc(O)c(C3(O)C(=O)Nc4ccccc43)cc2s1
Temperature: 25 °C
Reaction time: 48 h
Yield: 62.1 %

Procedure:
To a cooled (0° C.) solution of 2-methylbenzo[d]thiazol-5-ol (4.0 g, 24.0 mmol) in anhydrous tetrahydrofuran (50 mL) was added isopropylmagnesium chloride (2 M solution in tetrahydrofuran, 12.0 mL, 24.0 mmol). The resultant suspension was stirred at 0° C. for 0.5 h and isatin (3.1 g, 21.2 mmol) was added in one portion. The reaction mixture was stirred at ambient temperature for 48 h and was diluted with a saturated aqueous solution of ammonium chloride (80 mL) and ethyl acetate (200 mL). The phases were separated and the aqueous phase was extracted with ethyl acetate (3×50 mL). The combined organic solution was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was triturated with boiling ethyl acetate (10 mL), filtered and dried in vacuo to afford 3-hydroxy-3-(5-hydroxy-2-methyl-1,3-benzothiazol-6-yl)-1,3-dihydro-2H-indol-2-one (4.11 g, 62%) as an off-white microcrystalline solid: 1H NMR (300 MHz, DMSO-d6) δ10.34 (s, 1H), 10.02 (br s, 1H), 8.85 (br s, 1H), 7.78 (d, J=8.6 Hz, 1H), 7.18-7.10 (m, 1H), 7.01-6.74 (m, 4H), 2.77 (br s, 3H); MS (ES+) m/z 313.1 (M+1).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]1([C:27](Cl)=[O:28])[C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:20]2[C:15]1=[CH:16][CH:17]=[CH:18][CH:19]=2>>[CH2:1]([NH:8][C:27]([C:14]1([CH2:13][CH2:12][CH2:11][CH2:10][Br:9])[C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:20]2[C:15]1=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: NCc1ccccc1
Product: O=C(NCc1ccccc1)C1(CCCCBr)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1c from benzylamine and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid chloride.
Reaction SMILES: [NH+]1C=CC=CC=1.[OH:7][C@H:8]1[CH2:25][CH2:24][C@@:23]2([CH3:26])[C@H:10]([CH2:11][CH2:12][C@@H:13]3[C@@H:22]2[CH2:21][CH2:20][C@@:18]2([CH3:19])[C@:14]3([OH:29])[CH2:15][CH2:16][C@@H:17]2[CH:27]=[O:28])[CH2:9]1>ClCCl.C(OCC)C>[O:7]=[C:8]1[CH2:25][CH2:24][C@@:23]2([CH3:26])[C@H:10]([CH2:11][CH2:12][C@@H:13]3[C@@H:22]2[CH2:21][CH2:20][C@@:18]2([CH3:19])[C@:14]3([OH:29])[CH2:15][CH2:16][C@@H:17]2[CH:27]=[O:28])[CH2:9]1
Reactant: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C=O)CC[C@]12O
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: C[C@]12CCC(=O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C=O)CC[C@]12O
Yield: 60.4 %

Procedure:
To a suspension of 0.88 g of pyridinium dicromate in 2.2 ml of dichloromethane a solution of 0.50 g of 3β,14β-dihydroxy-5β-androstane-17β-carboxaldehyde (Boutagy J. and Thomas R., Aust. J. Chem., 1971, 24, 2723) in 2.5 ml of dichloromethane was added at room temperature. After 20 hrs the mixture was diluted with diethyl ether and filtered through celite; the filtrate was evaporated to dryness under reduced pressure. The crude product was purified by flash-chromatography (SiO2) using n-hexane/ethyl acetate 6/4 as eluant; the fractions containing the title compound were collected and evaporated to give 0.30 g of the title compound (II-e) as a white foam.
Reaction SMILES: [NH2:1][C@H:2]1[CH:16]=[C:15]2[C@@H:5]([CH2:6][C:7]3[C:17]4[C:10](=[CH:11][CH:12]=[CH:13][C:14]2=4)[NH:9][CH:8]=3)[N:4]([CH3:18])[CH2:3]1.C(N(CC)CC)C.[C:26](Cl)(=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28]>C(Cl)Cl>[CH3:18][N:4]1[C@H:5]2[C:15]([C:14]3[CH:13]=[CH:12][CH:11]=[C:10]4[C:17]=3[C:7]([CH2:6]2)=[CH:8][NH:9]4)=[CH:16][C@H:2]([NH:1][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:3]1
Reactant: CN1C[C@@H](N)C=C2c3cccc4[nH]cc(c34)C[C@H]21
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1C[C@@H](NC(=O)C(C)(C)C)C=C2c3cccc4[nH]cc(c34)C[C@H]21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 5.5 g 8α-amino-6-methyl-9,10-didehydro-ergoline in 200 ml CH2Cl2 is cooled to 0° and treated with 6.44 ml triethylamine followed by dropwise addition of 2.97 ml pivaloyl chloride. The mixture is stirred for 2 hours at room temperature and washed with water. The organic layer is dried (Na2SO4) and evaporated. The residue is chromatographed on 200 g silica gel using 98:2 CH2Cl2 /CH3OH and then crystallized from ether to yield 6-methyl-8α-pivaloylamino-9,10-didehydro-ergoline, m.p. 158°-159°.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:27]=[O:28])=[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[BH4-].[Na+].Cl>C(O)C>[CH3:1][C:2]1[NH:3][C:4]([CH2:27][OH:28])=[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C1=C(C)NC(C=O)=C(C(=O)OCC)C1c1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC(CO)=C(C(=O)OCC)C1c1ccccc1[N+](=O)[O-]
Yield: 88.6 %

Procedure:
To a solution of diethyl 2-methyl-4-(2-nitrophenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (2.0881 g) in ethanol (20 ml) was gradually added sodium borohydride (0.1892 g) under stirring and the resultant mixture was further stirred at room temperature for an hour. The solution was acidified with dilute hydrochloric acid and stirred at room temperature for 30 minutes. After the resultant solution was filtered, the filtrate was concentrated under reduced pressure and extracted with ethyl acetate. The extract was washed with water and dried and then the solvent was removed to give orange oil (1.8596 g) of diethyl 2-methyl-4-(2-nitrophenyl)-6-hyroxymethyl-1,4-dihydropyridine-3,5-dicarboxylate. After the crude, product was dissolved in ethanol, the solution was filtered. The filtrate was concentrated under reduced pressure and the oily residue was allowed to stand for 3 days. Thus obtained crystals were recrystallized from ether to give pure product, m.p. 112° to 113° C.