Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.Br[C:28]1[CH:33]=[CH:32][C:31]([C:34]2[NH:35][C:36](=[O:50])[C:37]3[C:42]([CH:43]4[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]4)=[N:41][N:40]([CH3:49])[C:38]=3[N:39]=2)=[C:30]([O:51][CH3:52])[CH:29]=1>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[CH:43]1([C:42]2[C:37]3[C:36](=[O:50])[NH:35][C:34]([C:31]4[CH:32]=[CH:33][C:28]([N:5]5[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]5)=[CH:29][C:30]=4[O:51][CH3:52])=[N:39][C:38]=3[N:40]([CH3:49])[N:41]=2)[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1
Reactant: CN1CCNCC1
Reactant: COc1cc(Br)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc(N2CCN(C)CC2)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Yield: 84.6 %

Procedure:
In a stream of argon, 207 μl (1.87 mmol) of N-methylpiperazine, 120 mg (1.25 mmol) of sodium tert-butoxide, 12.6 mg (0.062 mmol) of tri-tert-butylphosphine, and 7.0 mg (0.031 mmol) of palladium(II) acetate were added to an 8 ml toluene solution of 260 mg (0.623 mmol) of the compound obtained in Example 26, and the mixture was heated under reflux for 5 hours. Then, the reaction mixture was brought to room temperature, diluted with water, and then extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=20/1) to obtain 230 mg (85%) of the captioned compound.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:23])[N:7]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:8]([CH3:14])=[N:9]2.[C:24](Cl)(=[O:28])[CH2:25][CH2:26][CH3:27].C(N(CC)C(C)C)(C)C>C(#N)C>[O:22]=[C:16]1[CH:15]([N:7]2[C:6](=[O:23])[C:5]3[C:10](=[CH:11][CH:12]=[CH:13][C:4]=3[CH2:3][NH:2][C:24](=[O:28])[CH2:25][CH2:26][CH3:27])[N:9]=[C:8]2[CH3:14])[CH2:20][CH2:19][C:18](=[O:21])[NH:17]1
Reactant: Cc1nc2cccc(CN)c2c(=O)n1C1CCC(=O)NC1=O
Reactant: CCCC(=O)Cl
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(=O)NCc1cccc2nc(C)n(C3CCC(=O)NC3=O)c(=O)c12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 45.6 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.53 g, 1.6 mmol) in acetonitrile (10 mL), was added butyryl chloride (0.25 mL, 2.4 mmol) and N,N-diisopropyl ethylamine (0.65 mL, 3.9 mmol). The mixture was stirred at room temp for 15 minutes. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-butyramide as a light yellow solid (270 mg, 46% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, gradient to 95/5 in 5 min, kept for 5 min, 5.18 min (98.6%); mp, 250-252° C.; 1HNMR (DMSO-d6)0.88 (t, J=7 Hz, 3H, CH3), 1.56 (m, J=7 Hz, 2H, CH2CH2CH3), 2.15-2.20 (m, 3H, CH2, CHH), 2.57-2.89 (m, 6H, CHCH2, CH3), 4.77-4.85 (m, 2H, CH2NH), 5.23 (dd, J=6, 11 Hz, 1H, CH), 7.30-7.76 (m, 3H, Ar), 8.18 (t, J=5 Hz, 1H, CH2NH), 11.02 (s, 1H, NH); 13C NMR (DMSO-d6) δ 13.65, 18.67, 20.77, 23.27, 30.58, 37.32, 41.39, 56.47, 117.63, 124.28, 125.38, 133.83, 141.23, 148.44, 154.76, 160.95, 169.51, 172.14, 172.60. LCMS MH=371; Anal Calcd For C19H22N4O4: C, 61.61; H, 5.99; N, 15.13. Found: C, 61.49; H, 5.76; N, 15.00.
Reaction SMILES: [H-].[Na+].[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]1=[N:12][CH2:13][CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1.[CH:24]1[C:29]([CH2:30]Cl)=[CH:28][CH:27]=[C:26]([Cl:32])[CH:25]=1.O>COCCOC>[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]1=[N:12][CH2:13][CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]([CH2:30][C:29]2[CH:28]=[CH:27][C:26]([Cl:32])=[CH:25][CH:24]=2)[CH:16]=1
Reactant: c1ccc2c(CCN=c3sc4ccccc4s3)c[nH]c2c1
Reactant: ClCc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Clc1ccc(Cn2cc(CCN=c3sc4ccccc4s3)c3ccccc32)cc1
Reaction time: 4 h

Procedure:
Sodium hydride (50% dispersion in mineral oil; 155 mg) is slurried in 5 ml of anhydrous 1,2-dimethoxyethane and treated dropwise with N-(1,3-benzodithiol-2-ylidene)-1H-indol-3-ethanamine (1g, prepared as described in Example 30) in 5 ml of anhydrous 1,2-dimethoxyethane. The mixture is heated at reflux for 3 hours. A solution of α,p-dichlorotoluene (520 mg) in 5 ml of anhydrous 1,2-dimethoxyethane is added dropwise to the refluxing reaction mixture. Refluxing is continued for four hours after addition is complete. The reaction mixture is then poured into water (50 ml) and extracted with two 50 ml portions of dichloromethane. The combined dichloromethane extracts are washed with water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resultant solid is chromatographed on silica gel (200 ml) eluting with dichloromethanepentane (1:1). The fractions containing product with Rf =0.8 (silica gel, dichloromethane) are concentrated. The solid thus obtained is recrystallized from hexane to yield 600 mg of the title compound, melting point 120°-121° C.
Reaction SMILES: [C:1]([NH:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.Cl[C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24]>C(Cl)Cl>[CH:26]([O:25][C:23]([N:12]1[CH2:13][CH2:14][CH:9]([NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:10][CH2:11]1)=[O:24])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: CC(C)OC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)OC(=O)N1CCC(NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 87.6 %

Procedure:
To a solution of 4-(N-Boc amino)piperidine (2.61 g, 13 mmol) and triethylamine (3 mL, 21.5 mmol) in 25 mL of DCM, was added isopropyl chloroformate (1 M in toluene, 13.1 mL, 13.1 mmol). The mixture was stirred at room temperature for 20 h. It was then washed with a saturated solution of NaHCO3 (50 mL), followed by brine (50 mL). The solution was dried, filtered and evaporated to afford 3.26 g (87%) of 18a.
Reaction SMILES: [NH2:1][CH:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:20]=[C:21]([Cl:23])[CH:22]=1)[C:14]([NH:16][C:17](N)=[O:18])=[O:15]>N1C=CC=CC=1>[N:4]12[CH2:9][CH2:8][CH:7]([CH2:6][CH2:5]1)[CH:2]([NH:1][C:17]([NH:16][C:14](=[O:15])[C:13]1[CH:20]=[C:21]([Cl:23])[CH:22]=[C:11]([Cl:10])[CH:12]=1)=[O:18])[CH2:3]2
Reactant: NC1CN2CCC1CC2
Reactant: NC(=O)NC(=O)c1cc(Cl)cc(Cl)c1
Solvent: c1ccncc1
Product: O=C(NC(=O)c1cc(Cl)cc(Cl)c1)NC1CN2CCC1CC2
Temperature: 25 °C
Yield: 28.8 %

Procedure:
3-Aminoquinuclidine (1.26 g, 10 mmol) and 3,5-dichlorobenzoylurea (2.2 g, 9.44 mmol) in pyridine (15 ml) were stirred and refluxed overnight under nitrogen, filtered hot and allowed to cool to room temperature. The precipitated solid was collected, washed with ethyl acetate and dried to give the title compound (0.93 g) which was converted to the hydrochloride, monohydrate mp 253°-254° C.
Reaction SMILES: [C:1]([CH2:23][OH:24])([C:4]([C:7]([C:10]([C:13]([C:16]([C:19]([F:22])([F:21])[F:20])([F:18])[F:17])([F:15])[F:14])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].[CH2:25](Br)[CH:26]=[CH2:27].[OH-].[K+]>CS(C)=O.O>[C:1]([CH2:23][O:24][CH2:27][CH:26]=[CH2:25])([C:4]([C:7]([C:10]([C:13]([C:16]([C:19]([F:20])([F:21])[F:22])([F:17])[F:18])([F:15])[F:14])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2]
Reactant: C=CCBr
Reactant: OCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: C=CCOCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reaction time: 4 h
Yield: 75.5 %

Procedure:
To a stirred solution of 124 g of C7F15CH2OH and 62 g of allyl bromide in 1240 g of dimethyl sulfoxide was dropwise added a solution of 28.1 g of potassium hydroxide in 35 g of water. The mixture was allowed to stir for 4 hr, during which time it separated into two immiscible liquid phases. The reaction mixture was poured into a separatory funnel, and the lower layer was isolated and washed 3 times with water to remove any remaining solvent. The crude product was dried over anhydrous magnesium sulfate, filtered, and vacuum distilled to yield 103 g of C7F15CH2OCH2CH═CH2 (E1), b.p. 88-89° C. at 30 torr (4 kilopascals (kPa)).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[NH:14][CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1.[H-].[Na+].[CH2:21]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]Br)[CH2:22][C:23]#[CH:24].Cl>CN(C=O)C>[CH2:21]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][N:14]1[CH2:13][C@@H:12]([C:10]2[CH:9]=[CH:8][C:6]3[O:7][C:2]([CH3:18])([CH3:1])[O:3][CH2:4][C:5]=3[CH:11]=2)[O:16][C:15]1=[O:17])[CH2:22][C:23]#[CH:24]
Reactant: CC1(C)OCc2cc([C@@H]3CNC(=O)O3)ccc2O1
Reactant: C#CCCOCCCCCCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCCOCCCCCCN1C[C@@H](c2ccc3c(c2)COC(C)(C)O3)OC1=O
Reaction time: 1 h
Yield: 86.2 %

Procedure:
(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (10 g) in DMF (100 ml) was added dropwise to a stirred suspension of sodium hydride (60% oil dispersion, 2.33 g) in DMF (50 ml) with stirring under nitrogen and maintaining the internal temperature at 0°. Stirring was continued at 0–5° for 1 h. The mixture was recooled to 0° and a solution of 6-bromohexyl but-3-ynyl ether (14.7 g) in DMF (50 ml) was added over 1 min. The mixture was then stirred at 20–30° for 2 h. 2M HCl (9 ml) was added and the mixture was partitioned between water and diethyl ether. The aqueous layer was extracted with more diethyl ether and the combined organic layers were washed twice with brine. After drying (MgSO4) the solution was concentrated and loaded onto a column of silica gel (600 g) set up in diethyl ether: petroleum ether (bp 40–60°) (1:2). The column was eluted successively with this mixture, then (1:1) and then diethyl ether to give the title compound (13.88 g) LCMS RT=3.45 min.
Reaction SMILES: [C:1]12([NH2:11])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(N(CC)CC)C.[Br:19][CH2:20][C:21](Br)=[O:22]>C1(C)C=CC=CC=1>[C:1]12([NH:11][C:21](=[O:22])[CH2:20][Br:19])[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: O=C(Br)CBr
Reactant: NC12CC3CC(CC(C3)C1)C2
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(CBr)NC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 71.8 %

Procedure:
To an anhydrous toluene solution (25 ml) at 0° C. containing 1-adamantanamine (4.445 g, 29.39 mmol) and triethylamine (4.92 ml, 35.27 mmol) under a nitrogen atmosphere was added dropwise with strirring a solution of bromoacetyl bromide (2.56 ml, 29.39 mmol in 10 ml of toluene). The solution was warmed to ambient temperature and stirred for 2.5 hours. The triethylamine (TEA) salts were filtered and washed with toluene. The filtrate was extracted with 1 M HCl and brine, dried (Na2SO4) and concentrated in vacuo to yield 5.74 g (71%) of the title compound as a light brown solid which was crystallized from ether/hexane.
Reaction SMILES: C(OP([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=O)OCC)C.C[O-].[Na+].[CH2:19]([O:21][C:22](=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]=O)[CH:24]=1)[CH3:20].C1(C)C=CC=CC=1>O1CCCC1>[CH2:19]([O:21][C:22](=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]=[CH:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:24]=1)[CH3:20]
Reactant: CCOC(=O)c1cccc(C=O)c1
Reactant: CCOP(=O)(Cc1ccccc1)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cccc(C=Cc2ccccc2)c1
Temperature: 0 °C
Yield: 37.7 %

Procedure:
45.6 g (0.2 mol) of benzylphosphonic acid diethyl ester, dissolved in 50 ml of tetrahydrofuran, were added dropwise to a mixture of 300 ml of tetrahydrofuran and 46.4 g (0.22 mol) of a methanolic sodium methylate solution at 0°-5° C., whilst stirring. The mixture was subsequently stirred at 0° C. for 2 hours and 35.6 g (0.2 mol) of 3-formyl-benzoic acid ethyl ester, dissolved in 50 ml of tetrahydrofuran, were then added dropwise, also at 0° C. and whilst stirring. The reaction mixture was then stirred at 20°-25° C. for 12 hours, 300 ml of toluene were subsequently added and the mixture was then extracted by shaking twice with 600 ml of water each time. The organic phase was separated off and dried over magnesium sulphate and the solvent was distilled off under a waterpump vacuum. The oily residue was distilled at 160°-190° C. and under a pressure of 3 mm Hg. The semi-crystalline product thus obtained was dissolved in a little petroleum ether and the solution was cooled to 0° C. The crystals which had precipitated were filtered off and dried. 19 g (37.7% of theory) of 3-(2-phenyl-vinyl)-benzoic acid ethyl ester were obtained as colourless crystals with the melting point 82° C. (isomer mixture, about 90% transconfiguration). ##STR65##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:4]=1[CH2:5][N:6]1[C:15]2[CH:14]=[C:13](B3OC(C)(C)C(C)(C)O3)[CH:12]=[CH:11][C:10]=2[C:9]2[N:25]([CH:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[N:26]=[CH:27][C:8]=2[C:7]1=[O:34].Br[C:42]1[C:43]([O:49][CH3:50])=[N:44][CH:45]=[CH:46][C:47]=1[CH3:48].C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCOCC1.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>[CH3:1][O:2][C:3]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:4]=1[CH2:5][N:6]1[C:15]2[CH:14]=[C:13]([C:42]3[C:43]([O:49][CH3:50])=[N:44][CH:45]=[CH:46][C:47]=3[CH3:48])[CH:12]=[CH:11][C:10]=2[C:9]2[N:25]([CH:28]3[CH2:29][CH2:30][O:31][CH2:32][CH2:33]3)[N:26]=[CH:27][C:8]=2[C:7]1=[O:34]
Reactant: COc1ccc(Cn2c(=O)c3cnn(C4CCOCC4)c3c3ccc(B4OC(C)(C)C(C)(C)O4)cc32)c(OC)c1
Reactant: COc1nccc(C)c1Br
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(Cn2c(=O)c3cnn(C4CCOCC4)c3c3ccc(-c4c(C)ccnc4OC)cc32)c(OC)c1

Procedure:
5-(2,4-dimethoxybenzyl)-1-(tetrahydro-2H-pyran-4-yl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[4,3-c]quinolin-4(5H)-one (100 mg) obtained in Preparation Example 1(5) was dissolved in 1,4-dioxane (4 mL). 3-bromo-2-methoxy-4-methylpyridine obtained in Preparation Example 37 (2) (55.6 mg), Pd(PPh3)4 (10.6 mg), cesium carbonate (179 mg) and water (1 mL) were added to the solution, and the mixture was reacted using a microwave reactor at 130° C. for three hours. The reaction mixture was returned to room temperature and then partitioned by adding ethyl acetate. The organic layer was washed with brine and then dried over magnesium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 30% to 50% to 80%) to give 5-(2,4-dimethoxybenzyl)-7-(2-methoxy-4-methylpyridin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[4,3-c]quinolin-4(5H)-one (78 mg). The 5-(2,4-dimethoxybenzyl)-7-(2-methoxy-4-methylpyridin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[4,3-c]quinolin-4(5H)-one (78 mg) was dissolved in TFA (1 mL), and the mixture was stirred at 65° C. for two hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The resulting residue was neutralized by adding a saturated aqueous sodium bicarbonate solution. The aqueous solution was extracted with DCM. The organic layer was dried over anhydrous magnesium sulfate. The desiccant was removed by filtration. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 50% to 70% to 80% to 100%) to give the title compound (30 mg).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.[C:14](O)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[N:17][CH:16]=1.C1(N=C=NC2CCCCC2)CCCCC1>N1C=CC=CC=1>[NH:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]([CH2:4][CH2:3][NH:2][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[N:17][CH:16]=2)=[CH:6]1
Reactant: O=C(O)c1cccnc1
Reactant: NCCc1c[nH]c2ccccc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(NCCc1c[nH]c2ccccc12)c1cccnc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 72.4 %

Procedure:
To a solution of 1.97 g (10 mmol) of tryptamine hydrochloride and 1.23 g (10 mmol) of nicotinic acid in 10 ml of dry pyridine at 0° C. were added 2.20 g (10.7 mmol) of dicyclohexylcarbodiimide. The reaction mixture was stirred at room temperature for 24 hrs, and the formed dicyclohexylurea was removed by filtration (2.34 g). The pyridine was removed in vacuo, and 10 ml of methanol were added to the residue. Insoluble dicyclohexylurea in methanol was removed by filtration (0.05 g). The methanol was removed in vacuo and 10 ml of methylene chloride was added to the residue. Insoluble compound in methylene chloride was removed by filtration (0.04 g). The methylene chloride was removed in vacuo and the residue was crystallized from isopropanol. Recrystallization from methanol/isopropanol gave 1.92 g (72.5%) of N-[2-(3-indolyl)ethyl]nicotinamide as pale brown plates, m.p. 150°-152° C. IR (KBr) 3280, 3050, 2940, 1646, 1526, 1412, 1302, 1102, 740, 697 cm-1. Anal. calc. for C16H15N3O: C, 72.42; H, 5.91; N, 15.84. Found: C, 72.51; H, 5.74; N, 15.77.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH3:7][NH2:8].[C:9]([C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Br)=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10]>CO>[C:9]([C:13]1[CH:20]=[CH:19][C:16]([CH2:17][CH2:7][NH2:8])=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: CN
Reactant: CC(C)(C)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)c1ccc(CCN)cc1
Temperature: 25 °C
Reaction time: 41 h
Yield: 53.7 %

Procedure:
p-tert-butyltoluene (14.8 g; 0.10 mol) was dissolved in carbon tetrachloride, and N-bromosuccinimide (17.8 g; 0.10 mol) and benzoyl peroxide (200 mg) were added thereto. The mixture was refluxed for 2 hours, and then cooled. Insoluble matter was filtered off, followed by washing with carbon tetrachloride. The filtrate was concentrated under reduced pressure, and the residue was dissolved in n-hexane, followed by drying over magnesium sulfate. The solvent was evaporated under reduced pressure, to thereby yield 22.7 g of p-tert-butylbenzyl bromide (yield: 100%). The thus-obtained product was analyzed by 1H-NMR, and was found to be a mixture of the target compound, starting compounds, and a dibromo compound (10:1:1). Sodium carbonate (10.6 g; 0.10 mol) was added to 40% solution of methylamine in methanol (200 ml). While the mixture was cooled in an ice bath, p-tert-butyl benzyl bromide (22.7 g; 0.10 mol) in methanol (20 ml) was added dropwise thereto. The mixture was removed from the ice bath, and stirred for 41 hours at room temperature. Methanol was removed under reduced pressure, and the residue was taken up in water, followed by extraction with ether (400 ml). The ether layer was extracted with 1N hydrochloric acid twice (200 ml and 100 ml), and the aqueous layer was extracted with ethyl acetate. The aqueous layer was alkalinized with aqueous 2N sodium hydroxide solution, and extracted with ether (400 ml), followed by drying over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol=200:1→100:1→20:1), to thereby yield 9.51 g of the target compound (yield: 53.7%).
Reaction SMILES: [F:1][C:2]1([C:6]2[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:8][C:9]([C:12]([OH:14])=O)=[N:10][CH:11]=2)[CH2:5][O:4][CH2:3]1.[CH3:21][C:22]1[O:26][N:25]=[C:24]([C:27]([NH2:34])([CH3:33])[CH2:28][S:29]([CH3:32])(=[O:31])=[O:30])[N:23]=1.Br>>[F:1][C:2]1([C:6]2[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:8][C:9]([C:12]([NH:34][C:27]([C:24]3[N:23]=[C:22]([CH3:21])[O:26][N:25]=3)([CH3:33])[CH2:28][S:29]([CH3:32])(=[O:31])=[O:30])=[O:14])=[N:10][CH:11]=2)[CH2:3][O:4][CH2:5]1
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2(F)COC2)cn1
Reactant: Cc1nc(C(C)(N)CS(C)(=O)=O)no1
Agent: Br
Product: Cc1nc(C(C)(CS(C)(=O)=O)NC(=O)c2cc(OCC(F)(F)F)c(C3(F)COC3)cn2)no1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-(3-fluorooxetan-3-yl)-4-(2,2,2-trifluoroethoxy)pyridine-2-carboxylic acid (Example 131b) and 2-(5-methyl-1,2,4-oxadiazol-3-yl)-1-methylsulfonyl-propan-2-amine;hydrobromide (enantiomer B) (example 125b) as starting materials and isolated (35 mg, 42%); MS (ESI, m/z): 497.6 (M+H+).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[CH2:32]([O:39][C:40]1[C:41]2[CH2:60][C@:59]3([CH3:73])[C@@H:61]([CH3:72])[CH2:62][CH2:63][C@H:64]4[C:65]([CH3:71])([CH3:70])[C@@H:66](O)[CH2:67][CH2:68][C@@:58]34[O:57][C:42]=2[C:43]2[CH2:44][N:45]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[C:46](=[O:49])[C:47]=2[CH:48]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1C=CC=CC=1>[CH2:32]([O:39][C:40]1[C:41]2[CH2:60][C@:59]3([CH3:73])[C@@H:61]([CH3:72])[CH2:62][CH2:63][C@H:64]4[C:65]([CH3:71])([CH3:70])[CH:66]=[CH:67][CH2:68][C@@:58]34[O:57][C:42]=2[C:43]2[CH2:44][N:45]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[C:46](=[O:49])[C:47]=2[CH:48]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: C[C@H]1CC[C@H]2C(C)(C)[C@@H](O)CC[C@]23Oc2c(c(OCc4ccccc4)cc4c2CN(C(=O)OC(C)(C)C)C4=O)C[C@]13C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: C[C@H]1CC[C@H]2C(C)(C)C=CC[C@]23Oc2c(c(OCc4ccccc4)cc4c2CN(C(=O)OC(C)(C)C)C4=O)C[C@]13C
Temperature: 25 °C
Yield: 88.9 %

Procedure:
Under nitrogen, 344 mg (1.31 mmol) of triphenylphosphine and 170 μl (1.08 mmol) of diethyl azodicarboxylate were added to a solution of Compound (39a) (503 mg, 0.875 mmol) in 35 ml of dry benzene, and the mixture heated to reflux for 25 min. After cooling to room temperature, the same amounts of triphenylphosphine and diethyl azodicarboxylate were added to the reaction mixture. The mixture was then heated to reflux for 25 min, and concentrated under reduced pressure to a half volume. The residue was purified by a silica gel column chromatography (silica gel 55 g; n-hexane:ethyl acetate=6:1) to give 434 mg (89%) of Compound (40a).
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:33])[CH:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([CH2:31][CH3:32])=[CH:27][CH:26]=2)[CH2:22][CH3:23])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:51])[C@@H:15]2[CH2:34][CH2:35][C@H:36]2[O:41][C:40](=[O:42])[CH2:39][C@H:38]([O:43][Si](C(C)(C)C)(C)C)[CH2:37]2)=[CH:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:33])[CH:21]([O:24][C:25]2[CH:26]=[CH:27][C:28]([CH2:31][CH3:32])=[CH:29][CH:30]=2)[CH2:22][CH3:23])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:51])[C@@H:15]2[CH2:34][CH2:35][C@H:36]2[O:41][C:40](=[O:42])[CH2:39][C@H:38]([OH:43])[CH2:37]2)=[CH:10]1
Reactant: CCc1ccc(OC(CC)C(=O)O[C@H]2C[C@H](O[Si](C)(C)C(C)(C)C)C=C3C=C[C@H](C)[C@H](CC[C@@H]4C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O4)[C@H]32)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCc1ccc(OC(CC)C(=O)O[C@H]2C[C@H](O)C=C3C=C[C@H](C)[C@H](CC[C@@H]4C[C@@H](O)CC(=O)O4)[C@H]32)cc1

Procedure:
A procedure similar to that described in Example 2, above, was followed, but using 850 mg of (4R,6R)-6-([1S,2S,6S,8S,8aR]-2-{1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-[(2RS)-2-(4-ethylphenoxy)butyryloxy]-2-methyl-1-naphthyl}ethyl)tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example 67, above] and 20.0 ml of a 1.0 molar solution of tetrabutylammonium fluoride in tetrahydrofuran, to give 84 mg of the titlecompound as white crystals, melting at between 139° and 140° C.