Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]1([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18]C)[CH:14]=3)[C:9]=2[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)=[CH:23][CH:22]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Cl)(Cl)Cl.CO>ClCCCl>[C:2]1([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:18])[CH:14]=3)[C:9]=2[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][N:30]3[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]3)=[CH:23][CH:22]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c(Cc3ccc(OCCN4CCCCC4)cc3)c(-c3ccccc3)ccc2c1
Agent: Cl
Agent: ClB(Cl)Cl
Solvent: ClCCCl
Solvent: CO
Product: Oc1ccc2c(Cc3ccc(OCCN4CCCCC4)cc3)c(-c3ccccc3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.1 %

Procedure:
To a solution of the product of Example 9 (4.0 g, 8.0 mmol) stirring in 1,2-dichloroethane (50 mL) at 0° C. was added boron trichloride (10 mL, 117.0 mmol). The resulting dark purple solution was stirred at room temperature overnight in a sealed tube then cooled to 0° C. Methanol (50 mL) was carefully added dropwise over a 30 minute period (caution: gas evolution). The resulting solution was concentrated and dissolved in ethyl acetate. The organic extract was washed with saturated aqueous sodium bicarbonate, brine, dried (sodium sulfate), filtered, and concentrated. The resulting brown foam was purified by flash chromatography (silica gel, methanol/chloroform gradient) to give 2.7 g (63%) of desired product as a white foam: 1 -NMR (300 MHz, DMSO) δ 9.72 (br s, 1H), 7.62-7.80 (m, 2H), 7.22-7.50 (m, 6H), 7.10-7.22 (m, 2H), 7.00 (m, 1H), 6.80-6.90 (m, 2H), 6.78 (m, 1H), 4.23 (s, 2H), 3.85-4.10 (m, 2H), 2.50-2.75 (m, 2H), 2.25-2.50 (m, 4H), 1.25-1.56 (m, 6H); Anal. Calc'd. for: C, 82.35; H, 7.14; N, 3.20. Found: C, 82.17; H, 7.11; N, 3.35; MS (FD) m/e 437 (M+); IR (KBr) 2935.07, 2855.01, 1621.38, 1597.26 cm-1.
Reaction SMILES: [O:1]=[C:2]1[NH:15][CH:14]=[C:5]2[S:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[NH:9][C:4]2=[C:3]1[C:16]#[N:17].C(O)(=O)C.[Br:22]Br>C(Cl)(Cl)(Cl)Cl>[Br:22][C:12]1[CH:11]=[CH:10][C:8]2[NH:9][C:4]3[C:5](=[CH:14][NH:15][C:2](=[O:1])[C:3]=3[C:16]#[N:17])[S:6][C:7]=2[CH:13]=1
Reactant: N#Cc1c2c(c[nH]c1=O)Sc1ccccc1N2
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC(=O)O
Product: N#Cc1c2c(c[nH]c1=O)Sc1cc(Br)ccc1N2

Procedure:
To a solution of 20 parts of 2,3-dihydro-3-oxo-5H-pyrido[3,4-b][1,4]benzothiazine-4-carbonitrile in 1575 parts of glacial acetic acid is added a solution of 34 parts of bromine in 320 parts of carbon tetrachloride. The resultant mixture is heated at the boiling point under reflux for 23/4 hours, then chilled. The precipitate which forms is filtered off and recrystallized from N,N-dimethylformamide to give 8-bromo-2,3-dihydro-3-oxo-5H-pyrido[3,4-b][1,4]benzothiazine-4-carbonitrile melting above 305°.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1.[CH2:15]([OH:18])[C:16]#[CH:17].[H-].[Na+].O>CN(C)C=O>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:7]=[C:2]([O:18][CH2:15][C:16]#[CH:17])[N:3]=[CH:4][N:5]=2)=[CH:9][CH:10]=1
Reactant: Fc1ccc(-c2cc(Cl)ncn2)cc1
Reactant: C#CCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCOc1cc(-c2ccc(F)cc2)ncn1
Temperature: 25 °C
Reaction time: 9 h
Yield: 68.9 %

Procedure:
In 7 ml of N,N-dimethylformamide were dissolved 199 mg of 4-chloro-6-(4-fluorophenyl)pyrimidine and 64 mg of 2-propyn-1-ol, to which 46 mg of sodium hydride (60% in oil) was added, followed by stirring at room temperature for 9 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to give 150 mg of 4-(4-fluorophenyl)-6-(2-propynyloxy)pyrimidine (the present compound (58)).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:19]=[C:20]([CH:24]([CH3:28])[C:25](O)=[O:26])[CH:21]=[CH:22][CH:23]=3)[CH:16]=2)[N:11]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[N:10]=1.[CH3:37][NH:38][CH3:39].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:19]=[C:20]([CH:24]([CH3:28])[C:25]([N:38]([CH3:39])[CH3:37])=[O:26])[CH:21]=[CH:22][CH:23]=3)[CH:16]=2)[N:11]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:34])([CH3:35])[CH3:36])[N:10]=1
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cccc(C(C)C(=O)O)c3)cc12
Reactant: CNC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cccc(C(C)C(=O)N(C)C)c3)cc12
Temperature: 60 °C

Procedure:
To a solution of 2-{3-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-propionic acid, (100 mg, 0.20 mmol), dimethylamine (2 N in THF, 0.143 mL, 0.29 mmol), and diisopropylethylamine (37 mg, 0.29 mmol) in THF (2 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (110 mg, 0.29 mmol.). The resulting suspension was heated to 60° C. with stirring until all was dissolved. The solvent was evaporated and the residue was used in next step without purification. MS: m/z 547 (M+H+).
Reaction SMILES: [CH2:1]=[CH:2][CH:3]=[CH2:4].[C:5]([C:13]1C=CC=[CH:15][CH:14]=1)(=[O:12])C1C=CC=CC=1.S(=O)(=O)(O)[OH:20]>C(O)(=O)C>[C:5]1([C:13]2[C:2](=[CH:3][CH:4]=[CH:15][CH:14]=2)[CH2:1][O:20]1)=[O:12]
Reactant: C=CC=C
Reactant: O=S(=O)(O)O
Reactant: O=C(c1ccccc1)c1ccccc1
Solvent: CC(=O)O
Product: O=C1OCc2ccccc21

Procedure:
Then, one mol of the butadiene derivative and one mol of a benzophenone derivative (compound of the following formula (X)) are condensated under the presence of a dehydrating agent such as anhydrous acetic acid, polyphosphoric acid or sulfuric acid to obtain a phthalide compound represented by the general formula (I) as substantially colorless crystals. ##STR10##
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4](F)[CH:3]=1.[NH:11]1[CH2:15][CH2:14][C@@H:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:12]1>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([N:11]2[CH2:15][CH2:14][C@@H:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[CH2:12]2)[CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1F
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(c2cc(Cl)ccc2C=O)C1

Procedure:
The title compound was prepared from 4-chloro-2-fluoro-benzaldehyde and (R)-tert-butyl pyrrolidin-3-ylcarbamate as described in Example 70, Step 1 (30.0 mg, 81%). 1H NMR 400 MHz (CDCl3) δ 9.98 (s, 1H), 7.63 (d, J=8.3 Hz, 1H), 6.89-6.79 (m, 2H), 4.77 (s, 1H), 3.57 (dd, J=10.7, 6.0 Hz, 2H), 3.34 (s, 1H), 3.25-3.18 (m, 1H), 2.28 (td, J=12.9, 7.0 Hz, 1H), 2.00 (td, J=12.5, 6.4 Hz, 2H), 1.46 (s, 9H). LCMS (ESI, an/z): 325 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH2:6][NH:7][CH:8]1[CH2:13][CH:12]2[CH2:14][CH:9]1[CH2:10][CH2:11]2)[CH3:2].[CH2:16]([O:18][C:19]([C:21]1[C:22](Cl)=[N:23][C:24]([S:27][CH3:28])=[N:25][CH:26]=1)=[O:20])[CH3:17].C(N(CC)CC)C.O>C(Cl)Cl>[CH2:16]([O:18][C:19]([C:21]1[C:22]([N:7]([CH:8]2[CH2:13][CH:12]3[CH2:14][CH:9]2[CH2:10][CH2:11]3)[CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:15])=[N:23][C:24]([S:27][CH3:28])=[N:25][CH:26]=1)=[O:20])[CH3:17]
Reactant: CCOC(=O)CCNC1CC2CCC1C2
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)CCN(c1nc(SC)ncc1C(=O)OCC)C1CC2CCC1C2
Reaction time: 16 h
Yield: 62.2 %

Procedure:
3-(Bicyclo[2.2.1]hept-2-ylamino)-propionic acid ethyl ester (1.5 g, 7.1 mmol) and 4-chloro-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester (1.6 g, 7.1 mmol) were combined in CH2Cl2 (20 mL) and triethylamine (1.0 g, 10 mmol) was added. After 16 h, water (10 mL) was added the organic layer was separated, dried (MgSO4), and concentrated. Chromatography (10-50% EtOAc/hexanes gradient) provided 1.8 g of 4-[bicyclo[2.2.1]hept-2-yl-(2-ethoxycarbonyl-ethyl)-amino]-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester. Sodium (30 wt % dispersion in paraffin wax, 0.55 g, 7.2 mmol) was added to t-butanol (5.0 mL) at rt. After 30 minutes, a solution of 4[bicyclo[2.2.1]hept-2-yl-(2-ethoxycarbonyl-ethyl)-amino]-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester (1.8 g, 4.4 mmol) in 20 mL of toluene was added to the sodium t-butoxide solution and the resulting mixture was heated at 90° C. for 30 minutes. The reaction mixture was then cooled and the solution was adjusted to pH 7 using a 1N HCl solution. The solution was then extracted with EtOAc (2×20 mL) and the organic layer was dried (MgSO4), and concentrated. Recrystallization from i-PrOH provided 0.51 g of 8-bicyclo[2.2.1]hept-2-yl-2-methylsulfanyl-5-oxo-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester. 8-Bicyclo[2.2.1]hept-2-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (46 mg, 0.12 mmol) and 4-(4-methyl-piperazin-1-yl)-phenylamine (22 mg, 0.12 mmol) were combined in i-PrOH (2 mL) and heated to 90° C. After 3 h, the reaction mixture was concentrated and purified by preparative HPLC (C-18 column, 32 mL/min 5-100% MeCN/H2O gradient over 15 min) and lyophilized to provide 11.4 mg of 8-bicyclo[2.2.1]hept-2-yl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester. 1H NMR (400 MHz, CDCl3) δ (ppm): 9.21 (s, 1H), 8.59 (s, 1H), 7.52 (d, 2H, J=8.9 Hz), 6.87 (d, 2H, J=9.0 Hz), 4.31 (q, 2H, J=7.1 Hz), 3.52-3.62 (m, 4H), 3.28 (br s, 2H), 2.98 (br s, 2H), 2.82 (s, 3H), 2.14-2.53 (m, 5H), 1.58-1.75 (m, 4H), 1.22-1.42 (m, 5H).
Reaction SMILES: Cl[C:2]1[C:3]([C:8]#N)=[N:4][CH:5]=[CH:6][CH:7]=1.C[Mg]Br.Cl.[SH:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].[C:21](=O)([O-])[O-].[K+].[K+]>O1CCCC1.C(OCC)C.O>[CH3:21][C:8]1[C:3]2=[N:4][CH:5]=[CH:6][CH:7]=[C:2]2[S:14][C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)CS
Reactant: N#Cc1ncccc1Cl
Reactant: O=C([O-])[O-]
Agent: C[Mg]Br
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)c1sc2cccnc2c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
To a solution (100 mL) of 3-chloropyridine-2-carbonitrile (10.0 g) in tetrahydrofuran was added a 3.0M solution (48.0 mL) of methylmagnesium bromide in diethyl ether, and the mixture was stirred at room temperature for 3 hr. To the reaction mixture was added 2N hydrochloric acid (300 mL), tetrahydrofuran was evaporated in an evaporator, and the residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30-70% ethyl acetate/hexane) to give a pale-yellow oil. To a mixture of the obtained oil, ethyl mercaptoacetate (4.23 mL) and N,N-dimethylformmide (60 mL) was added and potassium carbonate (16.0 g), and the mixture was stirred overnight at 50° C. Water was added to quench the reaction, and the precipitated solid was collected by filtration to give the title object compound (6.75 g, 79%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[Br:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1>CN(C)C=O.C(OCC)(=O)C>[BrH:12].[Cl:11][C:8]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:2](=[NH:1])[N:10]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:18][CH:19]=2)[CH:9]=1
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Reactant: NC(=O)c1cc(Cl)cnc1N
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Br
Product: CS(=O)(=O)c1ccc(Cn2cc(Cl)cc(C(N)=O)c2=N)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 34.3 %

Procedure:
To a solution of 2-amino-5-chloronicotinamide (0.15 g) in N,N-dimethylformamide (3 ml) was added 1-(bromomethyl)-4-(methylsulfonyl)benzene (0.33 g), and the mixture was stirred at 100° C. for 8 hr. The reaction mixture was diluted with ethyl acetate. The precipitate was collected by filtration and washed with ethyl acetate. The obtained precipitate was recrystallized from methanol-ethyl acetate to give the title compound (126 mg).
Reaction SMILES: C1(C[O:5][C:6]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:7]=2[C:8]([C:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH:20]=2)=[CH:9][NH:10]3)CC1.C[Si](I)(C)C>C(#N)C>[OH:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8]([C:15]1[CH2:16][CH2:17][NH:18][CH2:19][CH:20]=1)=[CH:9][NH:10]2
Reactant: C1=C(c2c[nH]c3cccc(OCC4CC4)c23)CCNC1
Agent: C[Si](C)(C)I
Solvent: CC#N
Product: Oc1cccc2[nH]cc(C3=CCNCC3)c12
Temperature: 25 °C
Reaction time: 18 h
Yield: 14.9 %

Procedure:
To a solution of 0.30 gm (1.1 mMol) 4-cyclopropylmethoxy-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole in 10 mL acetonitrile were added 0.64 mL (4.4 mMol) trimethylsilyliodide and the reaction mixture was allowed to stir at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure and the residue partitioned between dilute ammonium hydroxide and ethyl acetate. The phases were separated and the aqueous phase extracted well with ethyl acetate. The organics were combined, washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to radial chromatography, eluting with 15% methanol in dichloromethane containing a trace of ammonium hydroxide. Fractions shown to contain product were combined and concentrated under reduced pressure to provide 0.035 gm (14%) of the title compound as a light tan solid.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]>CN(C=O)C>[N:1]1([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CBr
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
To a solution of pyrrolidine (1.2 g, 16.3 mmol, 1.0 eq) in DMF were added K2CO3 (5.63 g, 40.7 mmol, 2.5 eq.) and ethyl 2-bromoacetate (1.73 g, 24.4 mmol, 1.5 eq.). The mixture was stirred at RT for 16 h and quenched and extracted as in Intermediate Example 5(a). The solvent was distilled off to afford the product in 80% yield (2 g). LC-MS (ESI): Calculated mass: 157.2; Observed mass 158.1 [M+H]+ (rt: 0.2 min).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C:3]1=O.[OH-:8].[K+].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1.[Cl-].[K+]>C(O)(=O)C>[CH3:1][NH:2][CH2:6][CH2:5][CH:4]([O:8][C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)[C:3]1[CH:13]=[CH:12][CH:11]=[CH:16][CH:15]=1.[ClH:10]
Reactant: CN1CCCC1=O
Reactant: [OH-]
Reactant: FC(F)(F)c1ccc(Cl)cc1
Agent: [Cl-]
Agent: [K+]
Solvent: CC(=O)O
Product: CNCCC(Oc1ccc(C(F)(F)F)cc1)c1ccccc1
Product: Cl
Temperature: 90 °C
Reaction time: 10 h

Procedure:
30 g of 1-phenyl-3-(N-methylamine)propane-1-ol and 150 ml of N-methyl-pyrrolidone are added in a 0.5 l flask under nitrogen atmosphere. When the solution has completely turned to yellow, 28.2 g of KOH 90.4% are added and a moderate exothermia is observed. Then, n-exane is added in an amount sufficient to have reflux at a temperature of 90° C. The inner temperature is raised at 90° C. under constant and azeothropic reflux, optionally by varying the amount of n-exane and in 1 hour 42.6 g of 1-chloro-4-trifluoromethylbenzene is added dropwise. It is observed that the flakes of potassium hydroxide dissolve completely, while a microcrystalline precipitate of KCl is obtained. The solution slowly turns to brown-orange. Stirring is continued for ten hours, while simultaneously monitoring the reaction by TLC. Initially, the reaction seems to be slightly exotermic. After 10 hours the control by TLC does not show traces of non reacted product. The temperature is then brought below 60° C. and 20,5 g of acetic acid 80% is carefully added. Vacuum is then slowly made and a mixture of solvents is distilled off until a temperature of 100° C. is reached at a residual pressure of 16 mm Hg. 22 ml of head (mainly n-exane) and 113 g of high boiling solvents (mainly N-methyl-pirrolidone) are thus recoverd. The temperature is then reduced to 0° C. and 240 ml of toluene is added to dilute. 100 ml of water is then slowly added dropwise in about 30 minutes under cooling. The aqueous phase containing salts, part of the reaction solvent and the non-reacted product of reaction is set aside; the organic phase is subjected to four washings with 100 ml of water. Then, 180 ml of water at ambient temperature are added to the toluenic phase and then about 16 ml of HCl 37% are slowly added dropwise at constant pH 3 (at this pH value fluoxetine is stable in these conditions). During acidification, the precipitation of the hydrochloride is observed. Temperature is then kept at 20° C. for 15 minutes till pH stabilization at the value of 3 (optionally by further adding HCl 37%). Temperature is then reduced to 0° C. and stirring is conducted at this temperature for at least two hours. A very pure crystalline product is obtained, which is quickly filtered, leaving in the mother liquor almost all the colour. The product is filtered off at 0° C. and then washed with 10 ml×3 of water at 0° C. and pH 7, then with 20 ml×4 of toluene.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:30]([NH2:32])=[O:31])[CH:17]=[C:18](B4OC(C)(C)C(C)(C)O4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].Cl.Br[C:35]1[CH:36]=[C:37]2[C:41](=[CH:42][CH:43]=1)[CH2:40][NH:39][CH2:38]2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[CH2:38]1[C:37]2[C:41](=[CH:42][C:43]([C:18]3[CH:19]=[C:20]4[C:15](=[C:16]([C:30]([NH2:32])=[O:31])[CH:17]=3)[NH:14][CH:13]=[C:12]4[CH:9]3[CH2:10][CH2:11][N:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])[CH2:7][CH2:8]3)=[CH:35][CH:36]=2)[CH2:40][NH:39]1
Reactant: Brc1ccc2c(c1)CNC2
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(B4OC(C)(C)C(C)(C)O4)cc23)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc5c(c4)CNC5)cc23)CC1
Yield: 7.5 %

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxamide (150 mg, 0.325 mmol) in dioxane (0.75 mL) and water (0.25 mL), was added 5-bromo-2,3-dihydro-1H-isoindole hydrochloride (130 mg, 0.651 mmol), and cesium carbonate (636 mg, 1.952 mmol). The reaction mixture was kept under argon for 10 min before addition of tetrakis(tripehnylphosphine)palladium(0) (19 mg, 0.016 mmol). The resultant mixture was heated in a microwave for 20 min at 150° C. Mixture was then purified by HPLC to give 11 mg of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([F:9])[CH:3]=1.C([Li])CCCCC.[Cl:17][CH2:18][C:19]([CH2:21][Cl:22])=[O:20]>C(OCC)C>[Cl:17][CH2:18][C:19]([C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([F:9])[CH:3]=1)([OH:20])[CH2:21][Cl:22]
Reactant: Fc1ccc(Br)cc1F
Reactant: O=C(CCl)CCl
Agent: [Li]CCCCCC
Solvent: CCOCC
Product: OC(CCl)(CCl)c1ccc(F)c(F)c1

Procedure:
Preparation according to Preparation 1: 1-bromo-3,4-difluorobenzene (5 g, 25.9 mmol), dry diethyl ether (100 mL), n-hexyllithium (2.3 M in hexane, 11.2 ml, 25.9 mmol) and 1,3-dichloroacetone (3.29 g, 25.9 mol). Yield: 4.54 g (73%). MS m/z (rel. intensity, 70 eV) 241 (M+, 1), 193 (32), 191 (bp), 141 (14), 127 (64).
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].[H-].[Na+].[H][H].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C)C=O>[C:14]1([CH2:13][C:6]#[C:5][CH2:4][CH2:3][CH2:2][C:1]([OH:8])=[O:7])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: C#CCCCC(=O)O
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)CCCC#CCc1ccccc1
Temperature: 80 °C

Procedure:
A solution of hex-5-ynoic acid (1 mmole) in dimethylformamide (50 ml) is treated with sodium hydride (2 mmole; 50% dispersion in oil) first at room temperature, then at 60° C. A copious evolution of hydrogen occurs. Then, the solution is cooled and benzyl bromide (1.5 mmole) is added. The reaction mixture is heated to 80° C. and maintained thereat until then layer chromatography indicates the consumption of all the hex-5-ynoic acid. After cooling, the solution is poured onto a 10% sodium hydroxide solution and extracted with ethyl ether to remove unreacted benzyl bromide. The aqueous layer is then acidified to pH2 with concentrated hydrochloric acid, and extracted with chloroform. Removal of the solvent from the chloroform layer affords a residue which is distilled under reduced pressure to give the desired title product, 7-phenylhept-5-ynoic acid.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([C:9]([NH:11][O:12][CH2:13][CH2:14][OH:15])=[O:10])[C:3]=1[NH:16][C:17]1[CH:36]=[CH:35][C:20]([C:21](OC2C(F)=C(F)C(F)=C(F)C=2F)=[O:22])=[CH:19][CH:18]=1.[BH4-].[Na+].Cl>C1COCC1.O>[F:1][C:2]1[C:3]([NH:16][C:17]2[CH:36]=[CH:35][C:20]([CH2:21][OH:22])=[CH:19][CH:18]=2)=[C:4]([CH:5]=[CH:6][C:7]=1[F:8])[C:9]([NH:11][O:12][CH2:13][CH2:14][OH:15])=[O:10]
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(NOCCO)c1ccc(F)c(F)c1Nc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.7 %

Procedure:
The product of Example 17, Step C, 2,3,4,5,6-pentafluorophenyl 4-[[2,3-difluoro-6-[[(2-hydroxyethoxy)amino]carbonyl]phenyl]amino]benzoate (150 mg, 0.29 mmol) was dissolved in THF (2 mL), then added dropwise to a solution of NaBH4 (110 mg, 2.90 mmol) in water (2 mL). This mixture was stirred at room temperature for 2 hours, acidified with 1 M HCl, and diluted with water (50 mL). The resulting aqueous mixture was extracted with EtOAc (2×50 mL), then the combined EtOAc fractions washed with water (50 mL), saturated NaCl (50 mL), and dried (Na2SO4). The solvent was removed under reduced pressure and the resulting residue purified by column chromatography on flash silica (50% EtOAc/hexanes as eluant) to afford 3,4-difluoro-N-(2-hydroxyethoxy)-2-[[4-(hydroxymethyl)phenyl]amino]benzamide as a cream solid (36 mg, 37%); m.p. (EtOAc/hexanes) 73–77° C. 1H NMR [400 MHz, (CD3)2SO] δ 11.73 (br s, 1 H), 8.68 (br s, 1 H), 7.41–7.35 (m, 1H), 7.15 (d, J=8.5 Hz, 2 H), 7.14–7.06 (m, 1 H), 6.79 (dd, J=8.5, 2.3 Hz, 2 H), 4.99 (t, J=5.7 Hz, 1 H), 4.72 (br s, 1 H), 4.38 (d, J=5.6, 2 H), 3.80 (t, J=4.9 Hz, 2 H), 3.54 (t, J=4.9 Hz, 2 H). Anal. Calcd for C16H16F2N2O4: C, 56.8; H, 4.8; N, 8.3. Found: C, 56.3; H, 4.7; N, 8.1.