Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[N:5]2[C:6]3[CH2:17][C:16]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[C:7]=3[NH:8][C:9](=[O:10])[C:4]2=[N:3][CH:2]=1.[H-].[Na+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CS(C)=O.C(O)(=O)C>[CH2:20]([C:17]1([CH2:7][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:6]2[N:5]3[CH:1]=[CH:2][N:3]=[C:4]3[C:9](=[O:10])[NH:8][C:7]=2[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:16]1=2)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=c1[nH]c2c(n3ccnc13)Cc1ccccc1-2
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Solvent: O
Product: O=c1[nH]c2c(n3ccnc13)C(Cc1ccccc1)(Cc1ccccc1)c1ccccc1-2
Temperature: 45 °C
Reaction time: 2 h

Procedure:
To a solution of 0.45 g of 5H,10H-imidazo-[1,2-a]indeno[1,2-e]pyrazin-4-one in 20 ml of dimethyl sulphoxide under nitrogen are added, at a temperature in the region of 20° C. and with stirring, 60 mg of sodium hydride. The stirring is continued for 2 hours and a further 66 mg of sodium hydride are then added. The reaction medium is heated to 45° C. for 30 minutes, cooled to 20° C. and 0.25 ml of benzyl bromide are added. After continuing the stirring for 3 hours, the reaction mixture is poured into 150 ml of water, acidified to pH 4 with acetic acid and extracted with three times 60 ml of chloroform. The organic phases are combined, washed with twice 100 ml of water, dried over magnesium sulphate, filtered and concentrated on a rotary evaporator. The black solid obtained (0.78 g) is purified by chromatography on a column of silica (70 g) with a mixture of dichloromethane and methanol (95/5 by volume) to give 0.1 g of 10,10-dibenzyl-5H,10H-imidazo-[1,2-a]indeno[1,2-e]pyrazin-4-one in the form of a pale green solid melting above 260° C. [N.M.R. spectrum: (200 MHz; DMSO d6 ; δ in ppm): 3.63 and 3.85 (2d, J=14 Hz, 2H each: --CH2 --Ar); 6.36 (d, J=7 Hz, 4H: ortho-H of the benzyls); from 6.75 to 6.95 (mt, 6H: meta-H and para-H of the benzyls); from 7.29 to 7.45 (2t, J=7.5 Hz, 1H each: --H7 and --H8); 7.82 and 8.80 (2s broad, 1H each: --H of the imidazole); 7.38 and 8.02 (2d, J=7.5 Hz, 1H each: --H6 and --H9); 11.9 (cplx, 1H: --NH--)].
Reaction SMILES: [C:1]1([NH2:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>C1COCC1>[C:1]1([NH:11][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Nc1cccc2ccccc12
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CNc1cccc2ccccc12

Procedure:
In 5 ml of THF, 500 mg of 1-naphthylamine was added, then 168 mg of sodium hydride (60% in oil) was added and the resultant mixture was stirred for 30 min under ice cooling. To the reaction mixture, 0.46 ml of ethyl bromoacetate was added and the mixture was refluxed for 5 hr. The reaction mixture was evaporated under reduced pressure and the resultant residue was re-dissolved in ethyl acetate. The obtained solution was washed with 5% sodium hydrogencarbonate aqueous solution and saturated sodium chloride aqueous solution, successively, and dried over anhydrous sodium sulfate. The dried solution was evaporated under reduced pressure and subjected to a silica gel column chromatography (n-hexane:ethyl acetate=10:1) to give 720 mg of ethyl 1-naphthylaminoacetate. In 10 ml of ethanol, 460 mg of the ester was dissolved, 3.78 ml of 1N—NaOH aqueous solution was added and the resultant mixture was stirred for 1 hr. The reaction mixture was evaporated under reduced pressure, neutralized by the addition of 1N—HCl and extracted with ethyl acetate. The extract was washed with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The dried solution was evaporated under reduced pressure and crystallized by the treatment with ether to give 188 mg of the title compound.
Reaction SMILES: C([O:3][CH:4]1[CH:8]([NH:9][C:10]([CH2:12][N:13]2[C:19](=[O:20])[CH:18]([NH:21][C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:17][S:16](=[O:31])(=[O:30])[CH2:15][CH2:14]2)=[O:11])[CH2:7][C:6](=[O:32])[O:5]1)C.FC(F)(F)C(O)=O>C(#N)C.O>[OH:3][CH:4]1[CH:8]([NH:9][C:10]([CH2:12][N:13]2[C:19](=[O:20])[CH:18]([NH:21][C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:17][S:16](=[O:31])(=[O:30])[CH2:15][CH2:14]2)=[O:11])[CH2:7][C:6](=[O:32])[O:5]1
Reactant: CCOC1OC(=O)CC1NC(=O)CN1CCS(=O)(=O)CC(NC(=O)c2ccccc2)C1=O
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(CN1CCS(=O)(=O)CC(NC(=O)c2ccccc2)C1=O)NC1CC(=O)OC1O
Reaction time: 3 h

Procedure:
A solution of N-{4-[(2-ethoxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl)-methyl]-1,1,5-trioxo-1λ6-[1,4]thiazepan-6-yl}-benzamide, 45, (0.03 g, 0.05 mmol) in acetonitrile/water is treated with trifluoroacetic acid. After stirring for 3 hours the solution is concentrated in vacuo and the crude product purified by preparative reverse phase HPLC to afford 0.02 g (77% -yield) of the desired product as a white solid.) 1H NMR (CD3OD): δ 7.90 (m, 2H), 7.62–7.46 (m, 3H), 5.46 (d, J=10.5 Hz, 1H), 4.61 (m, 1H), 4.51 (dd, J=16.3, 5.1 Hz, 1H), 4.36 (m, 2H), 4.02 (dd, J=16.0, 3.3 Hz, 1H), 3.84–3.64 (m, 3H), 3.42 (m, 1H), 3.26 (m, 1H), 2.68 (m, 1H), 2.52 (m, 1H); ESI MS 440.06 (M+H).
Reaction SMILES: [CH3:1][Si:2]([C:5]#[C:6][C:7]1[CH:8]=[C:9]([N+:13]([O-])=O)[CH:10]=[CH:11][CH:12]=1)([CH3:4])[CH3:3]>CC(O)C>[CH3:1][Si:2]([C:5]#[C:6][C:7]1[CH:8]=[C:9]([CH:10]=[CH:11][CH:12]=1)[NH2:13])([CH3:3])[CH3:4]
Reactant: C[Si](C)(C)C#Cc1cccc([N+](=O)[O-])c1
Solvent: CC(C)O
Product: C[Si](C)(C)C#Cc1cccc(N)c1
Reaction time: 22 h
Yield: 93 %

Procedure:
A mixture of the nitro compound, 3-[(trimethylsilyl)ethynyl]nitrobenzene, prepared as described above (0.86 g, 3.92 mmol) in 2-propanol (30 mL) was degassed with nitrogen and treated with 5% platinum on alumina (268 mgs). The mixture was shaken under an atmosphere of hydrogen (30 psi) on a Parr shaker apparatus for 22 hours. The reaction mixture was filtered through a short pad of Celite™ (diatamaceous earth) and concentrated by evaporation to give an oil which was dried in vacuo overnight to give the title product (692 mg, 93%) as a yellow brown oil.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10](=[O:19])[C:11]([C:16]([OH:18])=[O:17])=[CH:12][O:13]2)=[CH:8][CH:7]=1.Cl.[F:21][C:22]1[CH:36]=[CH:35][C:25]2[C:26]([CH:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[N:27][O:28][C:24]=2[CH:23]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl>CN(C)C=O.O>[ClH:1].[F:21][C:22]1[CH:36]=[CH:35][C:25]2[C:26]([CH:29]3[CH2:30][CH2:31][N:32]([CH2:2][CH2:3][CH2:4][O:5][C:6]4[CH:15]=[C:14]5[C:9]([C:10](=[O:19])[C:11]([C:16]([OH:18])=[O:17])=[CH:12][O:13]5)=[CH:8][CH:7]=4)[CH2:33][CH2:34]3)=[N:27][O:28][C:24]=2[CH:23]=1
Reactant: O=C(O)c1coc2cc(OCCCCl)ccc2c1=O
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1coc2cc(OCCCN3CCC(c4noc5cc(F)ccc45)CC3)ccc2c1=O
Yield: 41.1 %

Procedure:
A mixture of 0.87 g (3 mmoles) of 7-(3-chloropropoxy)-4-oxochromene-3-carboxylic acid, 0.7 g (3 mmoles) of 6-fluoro-3-(4-piperidinyl)-benzo[d]isoxazole hydrochloride, 0.85 g (6 mmoles) of anhydrous potassium carbonate and a catalytic amount of potassium iodide in 25 mL of N,N-dimethylformamide was heated to 89-90° C. for 24 hours. After being cooled, the solution was poured onto 125 mL of water and then neutralized with HCl at pH 7. The precipitate obtained was filtered, washed with water and dried at vaccum. The solid was dissolved in 60 mL of 0.1M NaOH, diluted with water to 300 mL and the solution was washed with ethyl acetate. The aqueous solution was acidified with HCl to pH 1-2, and the precipitate obtained was filtered and dried at vaccum to give 0.62 g of 7-[3-[4-(6-fluorobenzo[d]isoxazole-3-yl)piperidin-1-yl]propoxy]-4-oxochromene-3-carboxylic acid hydrochloride in 40% yield.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[N:9]=[C:10](Cl)[C:11]2[S:16][CH:15]=[CH:14][C:12]=2[N:13]=1>>[Cl:7][C:8]1[N:9]=[C:10]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[C:11]2[S:16][CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: C1COCCN1
Reactant: Clc1nc(Cl)c2sccc2n1
Product: Clc1nc(N2CCOCC2)c2sccc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.5 %

Procedure:
Morpholine (87 ml, 1.00 mol, 2.2 equiv.) was added to a solution of 2,4-dichloro-thieno[3,2-d]pyrimidine 3 (93.4 g, 0.456 mol, 1.0 equiv.). The reaction mixture was stirred at ambient temperature for 1 h and the resulting slurry was filtered, rinsed with water (500 ml). The cake was dried in a vacuum oven at 40° C. for 24 hours to give 442-chlorothieno[3,2-d]pyrimidin-4-yl)morpholine 4 as an off-white solid (109 g, 94% yield). 1H NMR (400 MHz, DMSO-d6) δ 3.74 (t, J=4.9 Hz, 4H), 3.90 (t, J=4.9 Hz, 4H), 7.40 (d, J=5.6 Hz, 1H), 8.30 (d, J=5.6 Hz, 1H). LCMS (ESI pos) m/e 257 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:14]3[CH:15]=[N:16][CH:17]=[CH:18][C:13]=3[N:12]([CH:19]([CH3:29])[CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.CC(C1C=C(C(C)C)C(C2C(P(C(C)(C)C)C(C)(C)C)=CC=CC=2)=C(C(C)C)C=1)C.CC([O-])(C)C.[Na+].[C:66](=[NH:79])([C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1)[C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Si:22]([O:21][CH2:20][C@@H:19]([N:12]1[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:10]([C:8]([C:4]2[CH:5]=[N:6][CH:7]=[C:2]([N:79]=[C:66]([C:67]3[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=3)[C:73]3[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=3)[CH:3]=2)=[O:9])=[CH:11]1)[CH3:29])([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: CC(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(Br)c2)c2cnccc21
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: C[C@@H](CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(N=C(c3ccccc3)c3ccccc3)c2)c2cnccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 30.6 %

Procedure:
To a solution of (5-bromopyridin-3-yl)[1-(2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethyl)-1H-pyrrolo[3,2-c]pyridin-3-yl]methanone (Enantiomer 1, Preparation 41, 3.2 g, 0.067 mol) in toluene (90 mL) was added tBuXphos (785 mg, 0.0018 mol), NaOtBu (605 mg, 0.0018 mol), benzophenone imine (1.34 g, 0.0074 mol) and Pd2(dba)3 and the reaction was stirred at room temperature for 18 hours. The reaction was filtered through celite and the filtrate extracted into EtOAc. The organic layer was collected, washed with brine, dried over sodium sulphate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 50% EtOAc in heptanes to afford the title compound (1.3 g, 33%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:19](=[O:35])[CH2:20][C:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]2[N:29]=[N:30][CH:31]=[CH:32][CH:33]=2)[CH:23]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:30]1[CH:31]=[CH:32][CH:33]=[C:28]([C:24]2[CH:23]=[C:22]([C:21]3[CH2:20][C:19](=[O:35])[NH:18][C:9]4[CH:10]=[C:11]([C:14]([F:17])([F:16])[F:15])[CH:12]=[CH:13][C:8]=4[N:7]=3)[CH:27]=[CH:26][CH:25]=2)[N:29]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2cccnn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-c3cccnn3)c2)=Nc2ccc(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from {2-[3-oxo-3-(3-pyridazin-3-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M185) (245 mg, 0.49 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (144 mg, 77%).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([OH:14])[C@@H:10]([NH2:13])[CH2:11][OH:12])=[CH:5][CH:4]=1.[C:15]1(C)[CH:20]=CC=C[CH:16]=1.O>CC(C)=O>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([C@@H:9]2[O:14][C:15]([CH3:20])([CH3:16])[NH:13][C@H:10]2[CH2:11][OH:12])=[CH:7][CH:8]=1
Reactant: CSc1ccc([C@H](O)[C@@H](N)CO)cc1
Reactant: Cc1ccccc1
Solvent: O
Solvent: CC(C)=O
Product: CSc1ccc([C@@H]2OC(C)(C)N[C@H]2CO)cc1

Procedure:
A stirred mixture of enantiomerically pure (+)-thiomicamine (100 g; 0.469 mol), toluene (920 ml) and acetone (100 ml) was heated at reflux for 18 hours beneath a Dean Stark trap: a mixture of toluene, water and acetone (11 g) was collected. The solvent (200 ml) was distilled at ambient pressure and then under vacuum (internal temperature 80° C.) to give compound 7 (118.6 g) as residue.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([I:15])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:18]I>CN(C)C=O>[C:1]([O:5][C:6]([N:8]([CH3:18])[C:9]1[CH:14]=[CH:13][C:12]([I:15])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1ccc(I)cc1
Reaction time: 2 h

Procedure:
A solution of N-tertiary-butyloxycarbonyl-4-iodoaniline (11.5 g, see P G Ciattini et al, Tet. Lett, 1995, 36, 4133-4136 for preparation) in dimethylformamide (70 mL), under nitrogen, was treated portionwise with sodium hydride (1.6 g, 60% dispersion in mineral oil). When effervescence had ceased (after about 5 minutes) the mixture was treated with methyl iodide and stirring was continued at room temperature for 2 hours. The reaction mixture was partitioned between ethyl acetate (500 mL) and water (500 mL). The organic phase was dried and then evaporated to give the title compound (11.5 g) as a pink oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[CH:30][C:29]=1[O:37][CH3:38].CN(C)C=O>O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:11]3[CH2:12][CH2:13][N:14]([CH2:24][CH2:25][CH2:26][O:27][C:28]4[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[CH:30][C:29]=4[O:37][CH3:38])[CH2:15][CH2:16]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: COc1cc(C(C)=O)ccc1OCCCCl
Reactant: Fc1ccc2c(N3CCNCC3)n[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(C)=O)ccc1OCCCN1CCN(c2n[nH]c3cc(F)ccc23)CC1
Temperature: 90 °C
Yield: 106.6 %

Procedure:
A stirred mixture of 6-fluoro-3-(1-piperazinyl)-1H-indazole (2.3 g, 100 mmol), K2CO3 (1.5 g), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (2.8 g, 11 mmol), several crystals of KI and dimethylformamide (60 ml) was heated at 90° C. for 16 hours. The reaction was poured into H2O, and the aqueous suspension was extracted with ethyl acetate. The ethyl acetate was washed (H2O), dried (MgSO4) and concentrated to afford 5.0 g of a yellow oil. The oil was chromatographed on a Waters Prep 500 utilizing silica gel columns and eluting with methylene chloride/methanol (7%). Concentration of the desired fractions yielded 2.0 g (46%) of an off-white solid. This sample was combined with 1.0 g of a previous sample, and this was recrystallized from toluene to afford 2.6 g of 1-[4-[3-[4-(6-fluoro-1H-indazol-1-yl)-1-piperazinyl]-propoxy]-3-methoxyphenyl]ethanone as a white solid, m.p.=135°-137° C.
Reaction SMILES: [CH3:1][SiH:2](Cl)Cl.[CH3:5][C:6]([CH3:8])=[O:7]>>[CH3:1][SiH:2]([O:7][C:6]([CH3:8])=[CH2:5])[O:7][C:6]([CH3:8])=[CH2:5]
Reactant: C[SiH](Cl)Cl
Reactant: CC(C)=O
Product: C=C(C)O[SiH](C)OC(=C)C

Procedure:
Methyl di(isopropenyloxy)silane of the structural formula HSiMe(OCMe=CH2)2 was synthesized according to a known procedure by the reaction of acetone and methyl dichlorosilane followed by purification by distillation.
Reaction SMILES: CON(C)[C:4](=[O:19])[CH2:5][CH:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[F:21][C:22]1[CH:27]=[C:26](I)[CH:25]=[C:24]([CH3:29])[N:23]=1>>[F:21][C:22]1[CH:27]=[C:26]([C:4](=[O:19])[CH2:5][CH:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:25]=[C:24]([CH3:29])[N:23]=1
Reactant: Cc1cc(I)cc(F)n1
Reactant: CON(C)C(=O)CC(c1ccccc1)c1ccccc1
Product: Cc1cc(C(=O)CC(c2ccccc2)c2ccccc2)cc(F)n1

Procedure:
In analogy to example 55, step 2, from N-methoxy-N-methyl-3,3-diphenyl-propionamide and 2-fluoro-4-iodo-6-picoline was prepared the title compound as an off-white solid, MS (ESI+): m/z=320.1449 ([M+H]+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12].O[N:15]1[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]2[C:16]1=[O:25].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][N:15]1[C:16](=[O:25])[C:17]2=[CH:24][CH:23]=[CH:22][CH:21]=[C:18]2[C:19]1=[O:20])=[O:12]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: O=C(O)CCCCCCCCCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(CCCCCCCCCO)ON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 51 %

Procedure:
To a solution of 10-hydroxydecanoic acid (1.880 g, 10 mmol) in dichloromethane (25 mL) at room temperature was added N-hydroxyphthalimide (NHP) (1.63 g, 10 mmol) followed by N, N′-dicyclohexylcarbodimide (DCC) (2.1 g, 10 mmol). Quantitative conversion to product was achieved after stirring at room temperature for 45 minutes as determined by tlc using silica gel (ethyl acetate/heptane 4:1; Rf=0.28). The precipitate was removed by filtration and the filtrate was evaporated to dryness. The residue was chromatographed on silica gel column (2.5×30 cm) using chloroform/methanol (98:2) to give 1.7 g product (yield 52%) as a colorless syrup.
Reaction SMILES: [F:1][C:2]1[CH:39]=[CH:38][C:5]([O:6][CH:7]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][NH:23][C:24](=[O:37])[C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=4)=[CH:27][CH:26]=3)=[CH:16][CH:15]=2)[C:8]([O:10]CC)=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][NH:23][C:24](=[O:37])[C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=4)=[CH:27][CH:26]=3)=[CH:18][CH:19]=2)[C:8]([OH:10])=[O:9])=[CH:38][CH:39]=1
Reactant: CCOC(=O)C(Cc1ccc(OCCNC(=O)c2ccc(-c3ccccn3)cc2)cc1)Oc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(NCCOc1ccc(CC(Oc2ccc(F)cc2)C(=O)O)cc1)c1ccc(-c2ccccn2)cc1
Yield: 99.1 %

Procedure:
In a similar manner to that described in Example 2, ethyl 2-(4-fluorophenoxy)-3-[4-[2-(4-pyridine-2-ylbenzoylamino)ethoxy]phenyl]propionate (2.45 g), which is the product of Example 118, was reacted with aqueous sodium hydroxide solution (1N, 15.0 ml) and the reaction mixture was treated to give the title compound (2.30 g) as a white powder.
Reaction SMILES: [OH:1][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][S:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:13][CH:12]=1)[CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].C([O-])(=O)C.[Na+].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(OCC)C>ClCCl>[CH3:24][O:23][C:21](=[O:22])[CH2:20][CH2:19][S:18][CH2:17][C:14]1[CH:15]=[CH:16][C:11]([C:2](=[O:1])[CH2:3][C:4]([O:6][C:7]([CH3:8])([CH3:9])[CH3:10])=[O:5])=[CH:12][CH:13]=1
Reactant: COC(=O)CCSCc1ccc(C(O)CC(=O)OC(C)(C)C)cc1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)CCSCc1ccc(C(=O)CC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.5 %

Procedure:
To a solution (15 ml) of tert-butyl 3-hydroxy-3-(4-{[(3-methoxy-3-oxopropyl)thio]methyl}phenyl)propionate (695 mg, 1.96 mmol) in dichloromethane were added sodium acetate (810 mg, 9.87 mmol) and pyridinium dichromate (885 mg, 2.35 mmol), and the mixture was stirred overnight at room temperature. Ethyl ether was added to the reaction mixture, and the mixture was filtered. The filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel chromatography (hexane:ethyl acetate=5:1) to give the title compound (494 mg, 71%).
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][CH:8]=[C:7]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=3)[C:6]=2[CH:5]=[C:4]([F:19])[CH:3]=1.[C:20](Cl)(=[O:22])[CH3:21].ClCCl.[Cl-].[Al+3].[Cl-].[Cl-]>Cl>[Br:1][C:2]1[C:10]2[O:9][C:8]([C:20](=[O:22])[CH3:21])=[C:7]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=3)[C:6]=2[CH:5]=[C:4]([F:19])[CH:3]=1
Reactant: CC(=O)Cl
Reactant: Fc1cccc(Cc2coc3c(Br)cc(F)cc23)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1oc2c(Br)cc(F)cc2c1Cc1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.2 %

Procedure:
7-Bromo-5-fluoro-3-(3-fluoro-benzyl)-benzofuran (1.29 gm, 4 mmol), acetyl chloride (0.57 ml, 8 mmol) and dichloromethane (16 ml) were added to an oven dried flask and chilled in ice bath. Aluminum chloride (1.067 gm, 8 mmol) was added and after 5 minutes the reddish brown mixture was allowed to warm to room temperature and stir overnight. The mixture was diluted with hydrochloric acid (0.1M) and extracted three times with dichloromethane. The extracts were dried over magnesium sulfate and purified by column chromatography (ethyl acetate/hexane gradient) to give 1-[7-Bromo-5-fluoro-3-(3-fluoro-benzyl)-benzofuran-2-yl]-ethanone (1.2 gm, 82% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[O:14][CH:15]([CH3:17])[CH3:16])[C:5]([O:7]C(C)C)=[O:6].[OH-].[Na+].[Cl-].[NH4+]>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[O:14][CH:15]([CH3:17])[CH3:16])[C:5]([OH:7])=[O:6]
Reactant: CC(C)OC(=O)c1ccc(OC(C)C)c(F)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC(C)Oc1ccc(C(=O)O)cc1F
Temperature: 60 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
Isopropyl 3-fluoro-4-(1-methylethoxy)benzoate (618 mg, 2.57 mmol) was dissolved in methanol (13 mL). The resultant mixture was added with 1N aqueous solution of sodium hydroxide (13 mL) under ice-cold conditions and stirred at 60° C. for 1 hour. The reaction solution was added with a saturated solution of ammonium chloride and extracted with ethyl acetate. The organic layer was washed with brine, dried using anhydrous sodium sulfate, and concentrated in vacuo. 3-Fluoro-4-(1-methylethoxy)benzoic acid (505 mg, yield 99%) was obtained as a white crystal.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([CH:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)[CH2:5][CH2:4]1)[CH3:2].CO.ClCCl.Cl>C(O)(C)C.O>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCN(C2CCN(C(=O)OC(C)(C)C)CC2)CC1
Agent: Cl
Solvent: CC(C)O
Solvent: O
Solvent: CO
Product: CCN1CCN(C2CCNCC2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 86.7 %

Procedure:
The protective group was removed by introducing 40 g (135 mmol) of tert-butyl 4-(4-ethylpiperazin-1-yl)piperidine-1-carboxylate from example b.1.1 into 200 ml of methanol and 1.8 l of dichloromethane and adding 100 ml of 5-6M HCl solution in isopropanol. A suspension resulted, and slight gas evolution was also observable. The reaction mixture was stirred at 40° C. (water bath temperature) for one hour and then stirred at room temperature for 48 hours. For complete deprotection, 50 ml of the 5-6M HCl solution in isopropanol were again added and the reaction mixture was stirred at 40° C. The dichloromethane was distilled out in a rotary evaporator. 200 ml of methanol and 30 ml of the 5-6M HCl solution in isopropanol were again added. The reaction mixture was stirred under reflux for one hour, during which a white suspension formed with strong evolution of gas. A mobile suspension then resulted and was cooled to room temperature. The precipitate was filtered off with suction and washed with methanol and diethyl ether. After drying, 36 g (117 mmol, 87%) of 1-ethyl-4-piperidin-4-ylpiperazine were isolated as chloride salt.