Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH3:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>C1COCC1.CCOC(C)=O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([N:13]2[CH2:14][CH2:15][N:10]([CH3:9])[CH2:11][CH2:12]2)=[N:3][CH:4]=1
Reactant: CN1CCNCC1
Reactant: Fc1ccc(Br)cn1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN1CCN(c2ccc(Br)cn2)CC1
Yield: 64.2 %

Procedure:
Heat 2-fluoro-5-bromopyridine (2.15 g, 12.22 mmol) with 1-methyl-piperazine (3.4 mL, 30.54 mmol) in THF (10 mL) in a microwave reactor at 120° C. for 45 min. Dilute with EtOAc (60 mL), then wash with NaHCO3 (2×30 mL) and brine (20 mL). Dry with Na2SO4, filter, and concentrate to give 2.01 g (64%) of the title compound. MS/ES m/z (79Br) 256 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[C:7]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[C:8]3[C:13](=[CH:14][C:4]=2[O:3]1)[CH:12]=[CH:11][CH:10]=[CH:9]3.Br[CH2:22][CH2:23][CH2:24][CH2:25][N:26]1[C:30](=[O:31])[C:29]2[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=2[S:27]1(=[O:37])=[O:36]>>[O:36]=[S:27]1(=[O:37])[C:28]2[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=2[C:30](=[O:31])[N:26]1[CH2:25][CH2:24][CH2:23][CH2:22][N:18]1[CH2:19][CH2:20][CH:15]([C:7]2[C:5]3[NH:6][C:2](=[O:1])[O:3][C:4]=3[CH:14]=[C:13]3[C:8]=2[CH:9]=[CH:10][CH:11]=[CH:12]3)[CH2:16][CH2:17]1
Reactant: O=c1[nH]c2c(C3CCNCC3)c3ccccc3cc2o1
Reactant: O=C1c2ccccc2S(=O)(=O)N1CCCCBr
Product: O=C1c2ccccc2S(=O)(=O)N1CCCCN1CCC(c2c3ccccc3cc3oc(=O)[nH]c23)CC1

Procedure:
From the hydrochloride salt of 4-(2-oxonaphth[2,3-d]oxazolinyl)-piperidine and 2-(4-bromobutyl)-1,1-dioxido-1,2-benzothiazol-3(2H)-one using the procedure described for Example 15, Step 5 there was obtained a white solid, HC1 salt: 1H NMR (400 MHz, CD3OD) 8.11 (td, J=6.5, 0.9 Hz, 2H), 8.02-7.94 (m, 2H), 7.89 (d, J=8.2 Hz, 2H), 7.68 (d, J=5.3 Hz, 2H), 7.50-7.42 (m, 2H), 4.58 (tt, J=12.3, 4.0 Hz, 1H), 3.90 (t, J=6.4 Hz, 2H), 3.72 (d, J=13.0 Hz, 2H), 3.22-3.15 (m, 4H), 2.80 (qd, J=12.8, 3.0 Hz, 2H), 2.21 (d, J=13.7 Hz, 2H), 2.00-1.92 (m, 4H).
Reaction SMILES: [CH:1](=O)[CH2:2][CH:3]([CH3:5])[CH3:4].[CH3:7][C:8]([CH3:10])=[O:9]>>[CH3:4][CH:3]([CH3:5])[CH2:2][CH:1]=[CH:7][C:8](=[O:9])[CH3:10]
Reactant: CC(C)=O
Reactant: CC(C)CC=O
Product: CC(=O)C=CCC(C)C
Yield: 35 %

Procedure:
In contrast, the processes comprising subjecting isovaleraldehyde and acetone to aldol condensation in the presence of an aqueous alkali have an advantage that the reaction can be carried out under mild conditions, using inexpensive materials. The process (iv), however, can give 6-methyl-3-hepten-2-one, the aldol condensate, only in a 35 to 40% yield at most. Also, the process (v) mainly forms 6-methyl-4-hydroxyheptan-2-one, and requires successive dehydration reaction in order to obtain the yield of the 6-methyl-3-hepten-2-one. In addition, the yield of the 6-methyl-3-hepten-2-one thus obtained is 51%, which is not satisfactory. Moreover, the process (v) must use acetone in excess, so it is not industrially advantageous in view of the necessity for recovering the excessive acetone and the volumetric efficiency of reaction.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4](N)[CH:3]=1.N([O-])=O.[Na+].[ClH:16]>>[Cl:16][C:4]1[CH:3]=[C:2]([Cl:1])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=1
Reactant: Nc1cc(Cl)c([N+](=O)[O-])cn1
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Product: O=[N+]([O-])c1cnc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 33 %

Procedure:
To 4-chloro-5-nitropyridine-2-amine (Method 92, 4.40 g, 21.0 mmol) in concentrated HCl (70 ml) was added sodium nitrite (4.36 g, 63.1 mmol) potion wise at 0-5° C. After 1 hour at 0-5° C., the reaction was warmed to room temperature and stirred for 50 hours. Ice (100 g) was added and the mixture was extracted with ether (2×50 ml) and dried over sodium sulfate. The solvent was removed under reduced pressure and the resulted residue was purified by column chromatography (hexane-DCM=1:5) to give the title compound as a white solid (1.47 g, 33%). 1H NMR (400 MHz) 9.18 (s, 1H), 8.22 (s, 1H).
Reaction SMILES: [CH:1]1([NH:4][CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[N:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][N:12]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[CH3:19][C:20]1[N:21]([C:25]2[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=2)[CH:22]=[CH:23][N:24]=1>>[CH:1]1([N:4]([CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[N:12]=[CH:13][C:14]([CH2:17][CH3:18])=[CH:15][N:16]=3)[CH2:7][CH2:6]2)[C:29](=[O:30])[C:28]2[CH:27]=[CH:26][C:25]([N:21]3[CH:22]=[CH:23][N:24]=[C:20]3[CH3:19])=[CH:33][CH:32]=2)[CH2:2][CH2:3]1
Reactant: CCc1cnc(N2CCC(NC3CC3)CC2)nc1
Reactant: Cc1nccn1-c1ccc(C(=O)O)cc1
Product: CCc1cnc(N2CCC(N(C(=O)c3ccc(-n4ccnc4C)cc3)C3CC3)CC2)nc1

Procedure:
The title compound is prepared from cyclopropyl-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yl]-amine and 4-(2-methyl-imidazol-1-yl)-benzoic acid following a procedure analogous to that described in Example 90. LC (method 19): tR=3.84 min; Mass spectrum (ESI+): m/z=431 [M+H]+.
Reaction SMILES: Cl.Cl.[NH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]([NH:12][C:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[O:15][C:14]=2[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][N:26]=2)=[O:23])=[O:11])[CH2:6][CH2:5]1.[Cl:32][C:33]1[N:38]=[CH:37][CH:36]=[CH:35][N:34]=1>>[ClH:31].[ClH:32].[N:34]1[CH:35]=[CH:36][CH:37]=[N:38][C:33]=1[NH:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]([NH:12][C:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[O:15][C:14]=2[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][N:26]=2)=[O:23])=[O:11])[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3ccccc23)CC1
Reactant: Clc1ncccn1
Agent: Cl
Product: O=C(Nc1ccc(Cl)cn1)c1oc2ccccc2c1NC(=O)[C@H]1CC[C@H](Nc2ncccn2)CC1

Procedure:
Trans-3-[4-aminocyclohexylcarbonylamino]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide dihydrochloride (350 mg) obtained in Example 219 and 2-chloropyrimidine (99 mg) are treated in a similar manner to Example 373 to give the title compound (65 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19](O)=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)=[O:23].[CH2:38]([S:40]([NH2:43])(=[O:42])=[O:41])[CH3:39]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([NH:43][S:40]([CH2:38][CH3:39])(=[O:42])=[O:41])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:25][CH2:26][CH:27]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)[CH2:28][CH2:29]1)=[O:23]
Reactant: COc1ccc(C2CCN(C(=O)c3cnc4c(C(=O)O)cnn4c3Nc3cc(C)ccc3F)CC2)cc1
Reactant: CCS(N)(=O)=O
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3cc(C)ccc3F)c(C(=O)N3CCC(c4ccc(OC)cc4)CC3)cnc12
Yield: 75.7 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2-fluoro-5-methylphenylamino)-6-[4-(4-methoxyphenyl)piperidine-1-carbonyl]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.3 g, 0.60 mmol) obtained in step 2 and ethanesulfonamide (0.31 g, 2.98 mmol), the title compound (0.27 g, 75%) was obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[ClH]1C=CC=C1[S:15]([N:18]=[C:19]=[O:20])(=[O:17])=[O:16].[NH:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26]([O:28][CH3:29])=[O:27].[Cl-].[Al+3].[Cl-].[Cl-]>[N+](C)([O-])=O.O>[CH3:9][C:4]1[CH:5]=[C:6]([CH3:8])[N:7]=[C:2]([NH:1][C:19]([NH:18][S:15]([C:24]2[CH:23]=[C:22]([C:26]([O:28][CH3:29])=[O:27])[NH:21][CH:25]=2)(=[O:17])=[O:16])=[O:20])[N:3]=1
Reactant: COC(=O)c1ccc[nH]1
Reactant: Cc1cc(C)nc(N)n1
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: O
Product: COC(=O)c1cc(S(=O)(=O)NC(=O)Nc2nc(C)cc(C)n2)c[nH]1
Reaction time: 0.5 h

Procedure:
To a stirred suspension of 2.58 g (0.021 mol) of 2-amino-4,6-dimethylpyrimidine in 75 ml dry nitromethane at -10° was added dropwise, via syringe, under nitrogen, 2.0 ml (0.023 mol) of chlorolsulfonyl isocyanate at such a rate to maintain the temperature below 0°. The resulting clear solution was stirred 0.5 hour at -5° to -10°, then treated dropwise with a solution of 2.29 g (0.021 mole) of methyl pyrrole-2-carboxylate in 25 ml dry nitromethane. Upon completion of the addition, 2.95 gm (0.022 mole) of aluminum (III) chloride was added in one portion. The reaction mixture was heated at reflux for 2 hours, then allowed to stand overnight at ambient temperatures. The mixture was poured into 300 ml H2O and the two phase system extracted with three portions of CH2Cl2. The organic solutions were washed with water, dried over MgSO4 and evaporated to a tan foam which was triturated with minimal CH2Cl2 to afford the product as a white solid, m.p. 202°-204°.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:9])[NH:4][N:5]=[CH:6][C:7]=1[Br:8].[N+:10]([O-])([OH:12])=[O:11]>S(=O)(=O)(O)O>[Br:1][C:2]1[C:3](=[O:9])[NH:4][N:5]=[C:6]([N+:10]([O-:12])=[O:11])[C:7]=1[Br:8]
Reactant: O=[N+]([O-])O
Reactant: O=c1[nH]ncc(Br)c1Br
Agent: O=S(=O)(O)O
Product: O=c1[nH]nc([N+](=O)[O-])c(Br)c1Br
Temperature: 25 °C
Yield: 93.5 %

Procedure:
To 4,5-dibromopyridazin-3(2H)-one (2 g, 7.87 mmol) in concentrated sulfuric acid (12 mL), fuming nitric acid (978 μL, 23.8 mmol) was gradually added at 100° C. with stirring, and the resulting reaction solution was stirred at 100° C. for 3 hours. After completion of the reaction, the reaction solution was cooled to room temperature and poured onto ice-cold water. The precipitated crystals were collected by filtration and dried under reduced pressure to give the desired product (2.2 g, 93%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][C:3]=1[C:4]#[N:5].[N:18]([O-])=O.[Na+]>Cl.O>[CH2:11]([O:10][C:7]1[CH:6]=[C:3]2[C:2](=[CH:9][CH:8]=1)[NH:1][N:5]=[C:4]2[NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=N[O-]
Reactant: N#Cc1cc(OCc2ccccc2)ccc1N
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Nc1n[nH]c2ccc(OCc3ccccc3)cc12
Temperature: 0 °C
Yield: 109.4 %

Procedure:
To an ice-cooled suspension of 63.27 g (0.282 mol) of 2-amino-5-(benzyloxy)benzonitrile in 500 ml of concentrated hydrochloric acid, a solution of 23.32 g (0.338 mol) of sodium nitrite in 75 ml of water was added dropwise. After 2 hours the cold suspension was added dropwise to a preformed solution of 509.25 g (2.26 mol) of stannous chloride in 380 ml of concentrated HCl, at 2° C. After 3 hours the cold suspension was filtered and the moist solid was treated with 1.8 l of boiling water and 300 ml of ethanol 950 for 30 min. The hot cloudy solution was clarified by filtration through a cloth filter. The liquors were concentrated to eliminate ethanol and treated dropwise with 0.35 l of 35% NaOH at 4° C. The solid was filtered off and dried under vacuum at 50° C.: 73.82 g of product were obtained as light brown solid. mp=193-195° C. HPLC r.t. 4.7 [M]+=240 [2M+H]+=479
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=2)=[O:5])[CH2:3][CH2:2]1.[CH3:16][Si](C)(C)N[Si](C)(C)C.[Li].IC.[Cl-].[NH4+]>O1CCCC1>[CH3:16][C:1]1([C:4]([C:6]2[CH:7]=[CH:8][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:14][CH:15]=2)=[O:5])[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(C(=O)C2CC2)cc1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Agent: [Cl-]
Agent: [Li]
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(=O)C2(C)CC2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 8 %

Procedure:
To a solution of methyl 4-(cyclopropylcarbonyl)benzoate (500 mg, 2.45 mmol) in tetrahydrofuran (12 mL) was added dropwise a solution of 1 mol/L lithium hexamethyldisilazane in tetrahydrofuran (3.0 mL, 3.00 mmol) at −78° C. under argon atmosphere, and the mixture was stirred for 15 minutes. To the mixture was added dropwise iodomethane (200 μL, 3.21 mmol) at the same temperature, and the reaction solution was slowly warmed to room temperature and stirred overnight. To the reaction solution was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate three times. The organic layer was combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→97:3) to give methyl 4-[(1-methylcyclopropyl)carbonyl]benzoate (45 mg, 8%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.Br[CH2:13][C:14]#[N:15]>>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:7][CH2:8][N:9]([CH2:13][C:14]#[N:15])[CH2:10][CH2:11]1
Reactant: N#CCBr
Reactant: COCCCN1CCNCC1
Product: COCCCN1CCN(CC#N)CC1

Procedure:
The title compound is synthesized by coupling of 1-(3-Methoxy-propyl)-piperazine (commercially available from CHESS GmbH) and bromoacetonitrile analogously to the preparation of Intermediate 149.2 as a colorless oil; ES-MS: M+=198.2: 1HNMR(DMSO-d6) 3.65 (s, 2H), 3.30 (s, 3H), 2.45-2.20 (m, 12H), 1.65-1.55 (m, 2H).
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][CH:4]=1)=[CH2:2].C(Cl)(=O)C([Cl:15])=O>C1C=CC=CC=1>[CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:15])=[O:8])=[CH:5][CH:4]=1)=[CH2:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: C=Cc1ccc(C(=O)O)cc1
Solvent: c1ccccc1
Product: C=Cc1ccc(C(=O)Cl)cc1
Reaction time: 8 h

Procedure:
To a clean round bottom flask with an argon atmosphere and equipped with a magnetic stir bar is added para-vinyl benzoic acid (10 g, 0.067 mole) which is suspended in benzene (25 ml). Oxalyl chloride (25 g, 0.197 mole) is added to the flask. The mixture is stirred for 8 hours and continuously flushed with a continuous stream of argon to purge the system of the gases generated during the reaction. Solvent and excess oxalyl chloride is stripped off under vacuum. Finally, the product is distilled under vacuum to yield para-vinyl benzoyl chloride. Approximately 90% of the theoretical yield is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[N+:9]([C:12]1[CH:22]=[CH:21][CH:20]=[C:14]2[C:15]([O:17][C:18](=O)[C:13]=12)=[O:16])([O-:11])=[O:10].O>C(O)(=O)C>[N+:9]([C:12]1[CH:22]=[CH:21][CH:20]=[C:14]2[C:15]([N:1]([C:2]3[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=3)[C:18](=[O:17])[C:13]=12)=[O:16])([O-:11])=[O:10]
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Reactant: Nc1ccc(O)cc1
Solvent: O
Solvent: CC(=O)O
Product: O=C1c2cccc([N+](=O)[O-])c2C(=O)N1c1ccc(O)cc1
Yield: 78.3 %

Procedure:
The starting material used in the above example can be prepared as follows: 34.3 g (0.31 mol) of 4-aminophenol and 59.9 g (0.31 mol) of 3-nitrophthalic anhydride in 600 ml of acetic acid are refluxed for 6 hours and the mixture is then stirred into 3,000 ml of water. The product which has precipitated is washed with water and dried for 24 hours at 70° C./30 mm Hg. 69 g (78% of theory) of 4-(3-nitrophthalimidyl)-phenol are obtained; melting point 202° C. IR spectrum (KBr): 1785 cm-1 and 1725 cm-1 (CO--N--CO); 1550 and 1350 cm-1 (NO2).
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl-].[Al+3].[Cl-].[Cl-]>Cl>[CH2:7]([C:8]([C:15]1[CH:16]=[CH:17][C:12]([Cl:11])=[CH:13][CH:14]=1)=[O:9])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Clc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(Cc1ccccc1)c1ccc(Cl)cc1
Temperature: 44 °C
Reaction time: 0.5 h

Procedure:
To a 2 liter 4 necked flask equipped with a mechanical stirrer, thermometer, and reflux condensor was added 155 g (1.0 mole) of phenyl acetyl chloride and 500 ml (4.9 mole) of chlorobenzene. A total of 145 g (1.08 mole) of anhydrous aluminum chloride was added portionwise over 10 minutes. The mixture self warmed to 44° C. and evolved HCl gas over the course of the next 30 minutes The mixture was stirred at about 50° C. for an additional 30 minutes and then poured onto about 500 g of ice and 110 ml of concentrated aqueous HCl. The organic layer (lower) was separated and the aqueous layer was washed with ethyl ether. The combined organic layers were washed with water, dilute aqueous NaOH, and water and then concentrated in vacuo. The resulting crude solid was recrystalized from 2200 ml of hexane yielding 132 g of 4-chlorophenyl benzyl ketone, mp 85°-90° C. NMR data was consistent with the structure.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:18]([CH:20]1[O:22][CH2:21]1)Cl>CC(C)=O>[O:22]1[CH2:21][CH:20]1[CH2:18][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCC2CO2)cc1
Yield: 67.2 %

Procedure:
A mixture of 15.2 gm (0.1 mole) of methyl 4-hydroxybenzoate, 27.6 gm (0.2 mole) potassium carbonate and 31 mL (0.4 mole) epichlorohydrin in 250 mL acetone was heated to reflux for 24 hours. The reaction medium was then filtered and evaporated. The residue was taken up in 100 mL toluene and washed with 100 mL 1.0 N NaOH and 2×100 mL water. The toluene phase was then dried over magnesium sulfate and evaporated to provide the crude product as an oil. Purification was effected by vacuum distillation (66°-67°; 75 u pressure) and provided 14 gm (67%) of a clear oil when gradually crystallized at room temperature: mp 54°-55° C. The NMR and IR spectra and elemental analysis data were consistent with the assigned structure.
Reaction SMILES: [CH3:1][C@@H:2]([NH2:10])[C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.O.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[C:37]([N:45]1[C@H:49]([C:50](O)=[O:51])[CH2:48][S:47](=[O:54])(=[O:53])[CH2:46]1)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>CN(C)C=O>[C:37]([N:45]1[C@H:49]([C:50](=[O:51])[NH:10][C@H:2]([CH3:1])[C:3]2[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=2)[CH2:48][S:47](=[O:53])(=[O:54])[CH2:46]1)(=[O:44])[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: C[C@@H](N)c1ccc(O)cc1
Reactant: O=C(O)[C@@H]1CS(=O)(=O)CN1C(=O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](NC(=O)[C@@H]1CS(=O)(=O)CN1C(=O)c1ccccc1)c1ccc(O)cc1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
1.00 g (7.29 mmole) of (R)-α-methyl-p-hydroxybenzylamine (prepared as described in Preparation 13), 1.12 g (7.29 mmole) of N-hydroxybenzotriazole monohydrate and 1.51 g (7.29 mmole) of dicyclohexylcarbodiimide were added in that order to a solution of 1.96 g (7.29 mmole) of (4R)-3-benzoyl-1,1-dioxothiazolidine-4-carboxylic acid (prepared as described in Preparation 12) in 100 ml of dimethylformamide cooled at 5° C., and then the mixture was stirred at a temperature between 3° and 6° C. for 30 minutes and then at room temperature for a further 23 hours. The reaction mixture was filtered, the insolubles were washed with 20 ml of ethyl acetate, and the filtrate and the washings were combined. 50 ml of ethyl acetate were added to the combined mixture, which was washed twice, each time with 50 ml of a 4% w/v aqueous solution of sodium bicarbonate, and the organic phase was separated and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by Lobar column chromatography through silica gel (Merck, Art-10402), eluted with a 2:1 by volume mixture of ethyl acetate and cyclohexane. The eluate was concentrated by evaporation under reduced pressure and the residue was lyophilized with a mixture of acetone and benzene to give 2.04 g (72.0%) of the title compound in the form of a colorless powder.
Reaction SMILES: I[CH2:2][CH3:3].[CH3:4][C@@:5]12[C@@H:13]([OH:14])[CH2:12][CH2:11][C@H:10]1[C@@H:9]1[CH2:15][CH2:16][C:17]3[C@@:23]([CH3:24])([C@H:8]1[CH2:7][CH2:6]2)[CH2:22][CH2:21][C:19](=[O:20])[CH:18]=3.CC(C)([O-])C.[K+]>C(O)(C)(C)C>[OH:14][C@H:13]1[CH2:12][CH2:11][C@H:10]2[C@H:9]3[C@H:8]([CH2:7][CH2:6][C@:5]12[CH3:4])[C@:23]1([CH3:24])[C:17](=[C:18]([CH2:2][CH3:3])[C:19](=[O:20])[CH2:21][CH2:22]1)[CH2:16][CH2:15]3
Reactant: CCI
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCC1=C2CC[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@@H]3[C@@]2(C)CCC1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 51.7 %

Procedure:
Iodoethane (1.60 g) in dry tert-butanol (150 ml) was added dropwise under N2, over 6 h to a vigorously stirred solution heated to reflux, of testosterone (3.00 g) and potassium tert-butoxide (1.75 g) in dry tert-butanol (100 ml). The mixture was refluxed for further 3 h. After cooling to RT, the mixture was quenched by addition of a saturated aqueous NH4Cl solution (170 ml). After stirring for 10 minutes, tert-butanol was evaporated and the mixture was extracted with toluene. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and evaporated to dryness. The mixture was purified by flash chromatography (SiO2, n-hexane/EtOAc 70/30) to give 17β-hydroxy-4-ethylandrost-4-ene-3-one (1.68 g, 51%).
Reaction SMILES: Br[C:2]1[C:3]2[CH2:10][CH2:9][CH:8]([NH:11][C:12](=[O:15])[CH2:13][CH3:14])[C:4]=2[CH:5]=[N:6][CH:7]=1.[F:16][C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=1B(O)O>>[F:16][C:17]1[CH:22]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:20]=[CH:19][C:18]=1[C:2]1[C:3]2[CH2:10][CH2:9][CH:8]([NH:11][C:12](=[O:15])[CH2:13][CH3:14])[C:4]=2[CH:5]=[N:6][CH:7]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1F
Reactant: CCC(=O)NC1CCc2c(Br)cncc21
Product: CCC(=O)NC1CCc2c(-c3ccc(C(F)(F)F)cc3F)cncc21
Yield: 76 %

Procedure:
In analogy to the procedure described for the preparation of example 1, (rac)-N-(4-bromo-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)propionamide (intermediate A-4) was reacted with 2-fluoro-4-(trifluoromethyl)phenylboronic acid to give the title compound as grey solid in 76% yield. MS: 353.1 (M+H+).
Reaction SMILES: C[O:2][C:3](=[O:17])[CH:4]([CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].O[Li].O>CC(O)C.O>[C:9]([O:8][C:6](=[O:7])[CH2:5][CH:4]([CH2:13][CH:14]([CH3:15])[CH3:16])[C:3]([OH:17])=[O:2])([CH3:12])([CH3:11])[CH3:10]
Reactant: COC(=O)C(CC(=O)OC(C)(C)C)CC(C)C
Agent: [Li]O
Solvent: O
Solvent: CC(C)O
Product: CC(C)CC(CC(=O)OC(C)(C)C)C(=O)O
Yield: 76.5 %

Procedure:
2-Isobutylsuccinic acid-4-t-butyl ester-1-methyl ester (11.1 g, 45.4 mmol) and LiOH.H2O (2.0 g, 47.7 mmol) are stirred in 180 mL of 3:1 IPA/H2O at room temperature overnight. The reaction mixture is extracted with Et2O (3×25 mL). The aqueous phase is acidified to pH=4, with saturated KH2PO4 and extracted with Et2O (3×50 mL). The Et2O is dried over MgSO4, and evaporated to give 8.0 g (77% yield) of 2-isobutyl-succinic acid-4-t-butyl ester as an oil. NMR (H1, 400 MHz, CDCl3) δ 0.9 (6H, m); δ 1.3 (1H, m); δ 1.4 (9H, s); δ 1.6 (2H, m); δ 2.3 (1H, dd); δ 2.6 (1H, dd); δ 2.8 (1H, m).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:25]=[CH:24][C:10]2[O:11][C:12]3[CH:17]=[CH:16][C:15]([C:18](=[O:23])[CH2:19][CH2:20][CH2:21]Cl)=[CH:14][C:13]=3[C:9]=2[CH:8]=1)=[O:6].[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.[I-].[K+]>CC(=O)CC>[N:26]1([CH2:2][CH2:3][CH2:4][C:5]([C:7]2[CH:25]=[CH:24][C:10]3[O:11][C:12]4[CH:17]=[CH:16][C:15]([C:18](=[O:23])[CH2:19][CH2:20][CH2:21][N:26]5[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]5)=[CH:14][C:13]=4[C:9]=3[CH:8]=2)=[O:6])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: C1CCNCC1
Reactant: O=C(CCCCl)c1ccc2oc3ccc(C(=O)CCCCl)cc3c2c1
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C(CCCN1CCCCC1)c1ccc2oc3ccc(C(=O)CCCN4CCCCC4)cc3c2c1

Procedure:
A mixture of 17.0 g (0.045 mole) of 2,8-bis(4-chlorobutyryl)dibenzofuran, 68.0 g (0.8 mole) of piperidine and 2.0 g of potassium iodide in 500 ml of butanone was heated at reflux for 72 hours then filtered. The filtrate was concentrated to one-half its original volume then diluted with 600 ml of water. The resulting semi-solid was purified by chromatography on neutral alumina using methylenechloride as the eluant. The solvent was removed from the fraction collected leaving a solid residue which was recrystallized from pentane to give the desired product. M.P. 70°-71° C., λmaxEtOH 251, E1cm1% 1520.