Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]2[CH2:14][C@H:15]([CH2:18][N:19]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21][C:20]3=[O:28])[CH2:16][CH2:17][C@H:10]2[CH2:9]1)(OC(C)(C)C)=O.[ClH:29]>C(Cl)(Cl)Cl.C(OCC)C>[ClH:29].[ClH:29].[CH2:9]1[NH:8][CH2:13][CH2:12][N:11]2[CH2:14][C@H:15]([CH2:18][N:19]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21][C:20]3=[O:28])[CH2:16][CH2:17][C@@H:10]12
Reactant: CC(C)(C)OC(=O)N1CCN2C[C@H](CN3C(=O)Cc4ccccc43)CC[C@H]2C1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: O=C1Cc2ccccc2N1C[C@@H]1CC[C@H]2CNCCN2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A solution of 0.53 g (1.38 mmol) of 1-[(7R,9aS)-2-BOC-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazin-7-ylmethyl]-1,3-dihydro-indol-2-one in 10 mL of chloroform was treated with excess HCl(g) in ethyl ether and stirred at room temperature for 1 h. The solvent was evaporated to give 0.49 g (100%) of 1-[(7R,9aS)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazin-7-ylmethyl]-1,3-dihydro-indol-2-one dihydrochloride.
Reaction SMILES: Cl[CH2:2][CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:11]1([O-:22])[C:16]([Cl:17])=[C:15]([Cl:18])[C:14]([Cl:19])=[C:13]([Cl:20])[C:12]=1[Cl:21].[Na+].O.C(O)C>C(O)C>[Cl:17][C:16]1[C:15]([Cl:18])=[C:14]([Cl:19])[C:13]([Cl:20])=[C:12]([Cl:21])[C:11]=1[O:22][CH2:2][CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: [O-]c1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Reactant: ClCC=Cc1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Clc1c(Cl)c(Cl)c(OCC=Cc2ccccc2)c(Cl)c1Cl
Yield: 85 %

Procedure:
In a 500 ml four necked flask equipped with a stirrer, a thermometer and a nitrogen gas inlet, chloromethylstyrene (m/p=60/40) (25 g, 0.161 mole) was dissolved in ethanol (50 ml) at room temperature. A solution of sodium pentachlorophenate (hereinafter abbreviated as Na-PCP) (49 g. 0.170 mole) in a mixed solvent of water/ethanol (1/1, 250 ml) was gradually added dropwise thereto and, after completion of addition, the mixture was reacted at 50° C. for 1 hour. The mixture was cooled and the resulting precipitate was filtered off. The filtrate was concentrated with a rotary evaporator. Then, n-hexane (250 ml) and distilled water (100 ml) were added to the concentrated solution and the mixture was shaken. The aqueous layer was removed and additional distilled water (100 ml) was added. This procedure was repeated to remove unreacted Na-PCP. The hexane layer was evaporated with a rotary evaporator. Then, the solid residue was recrystallized from acetone to obtain (2, 3, 4, 5, 6-pentachlorophenyloxy)methylstyrene of the formula [Ia] as white needle crystals, m.p. 113°-115° C., yield 85%.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([Sn:24]([CH2:33][CH2:34][CH2:35][CH3:36])([CH2:29][CH2:30][CH2:31][CH3:32])/[CH:25]=[CH:26]\[CH2:27]O)[CH2:21][CH2:22][CH3:23].C(Br)(Br)(Br)[Br:38]>C(Cl)Cl>[Br:38][CH2:27]/[CH:26]=[CH:25]\[Sn:24]([CH2:33][CH2:34][CH2:35][CH3:36])([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: BrC(Br)(Br)Br
Reactant: CCCC[Sn](/C=C\CO)(CCCC)CCCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCC[Sn](/C=C\CBr)(CCCC)CCCC
Reaction time: 2.5 h
Yield: 160.6 %

Procedure:
A solution of triphenylphosphine (5.32 g) in DCM (60 mL) was added to a solution of (Z)-3-tributylstannanylprop-2-en-1-ol (Intermediate 5, 6.4 g) and carbon tetrabromide (9.18 g) in DCM (60 mL) and the mixture was stirred for 2.5 hours. The mixture was evaporated to low volume and pentane was added. The solid was removed by filtration and the filtrate was evaporated to dryness. Pentane was added and the solid was again removed by filtration and the filtrate was evaporated to dryness to give ((Z)-3-bromoprop-1-enyl)-tributylstannane (12.14 g) as an oil.
Reaction SMILES: [O:1]=[S:2]1(=[O:21])[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:16]=[C:15]([C:17]([O:19][CH3:20])=[O:18])[CH:14]=[C:13]2[C:9]=1[CH:10]=[CH:11][NH:12]2.[H-].[Na+].[CH2:24](I)[CH3:25]>CN(C=O)C>[O:21]=[S:2]1(=[O:1])[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:16]=[C:15]([C:17]([O:19][CH3:20])=[O:18])[CH:14]=[C:13]2[C:9]=1[CH:10]=[CH:11][N:12]2[CH2:24][CH3:25]
Reactant: COC(=O)c1cc(N2CCCCS2(=O)=O)c2cc[nH]c2c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1ccc2c(N3CCCCS3(=O)=O)cc(C(=O)OC)cc21
Reaction time: 0.25 h
Yield: 56.4 %

Procedure:
To a solution of methyl 4-(1,1-dioxidotetrahydro-2H-1,2-thiazin-2-yl)-1H-indole-6-carboxylate (D231) (180 mg, 0.58 mmol, 1 equiv) in DMF (3 ml) at room temperature was added NaH (60% dispersion in mineral oil, 24 mg, 0.6 mmol, 1 equiv) and the resulting mixture was stirred 15 min at this temperature. Ethyl iodide (64 μl, 0.8 mmol, 1.4 equiv) was added and the resulting solution was stirred for 1 h then concentrated in vacuo. The residue was dissolved in AcOEt and the organic phase was washed with a 2N aqueous HCl solution, dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel gave methyl 4-(1,1-dioxidotetrahydro-2H-1,2-thiazin-2-yl)-1-ethyl-1H-indole-6-carboxylate (B147) (110 mg, 51%) as a yellow solid which was used in the next step without further purification. [M+H]+=337.0, RT=2.82 min.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:20]=[CH:19][C:6]([O:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15](=[O:18])[CH2:16]Cl)[CH:9]=2)=[CH:5][C:4]=1[N+:21]([O-:23])=[O:22].[CH2:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[CH3:25].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][NH:2][C:3]1[CH:20]=[CH:19][C:6]([O:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15](=[O:18])[CH2:16][N:29]3[CH2:30][CH2:31][N:26]([CH2:24][CH3:25])[CH2:27][CH2:28]3)[CH:9]=2)=[CH:5][C:4]=1[N+:21]([O-:23])=[O:22]
Reactant: CNc1ccc(Oc2ccnc(NC(=O)CCl)c2)cc1[N+](=O)[O-]
Reactant: CCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN1CCN(CC(=O)Nc2cc(Oc3ccc(NC)c([N+](=O)[O-])c3)ccn2)CC1

Procedure:
The mixture containing N-(4-(4-(methylamino)-3-nitrophenoxy)pyridin-2-yl)-2-chloroacetamide (1 eq), 1-ethylpiperazine (3 eq), and potassium carbonate (4 eq) was stirred in dimethylformamide at 60° C. for 1 hour. The reaction mixture was then concentrated and partitioned between ethyl acetate and water. The organic layer was separated and washed with water then brine, dried over sodium sulfate and concentrated to give orange solid. Purification on silica gel with 20% methanol in methylene chloride gave N-(4-(4-(methylamino)-3-nitrophenoxy)pyridin-2-yl)-2-(4-ethylpiperazin-1-yl)acetamide as a red solid. HPLC=3.26 min; MS: MH+=415.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:32])=[CH:4][C:5]([Cl:31])=[C:6]([C:8]2[C:9](=[O:30])[N:10]([CH2:28][CH3:29])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:12]=3)[CH:7]=1.[C:33]1([N:39]=[C:40]=[O:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>N1C=CC=CC=1>[Cl:31][C:5]1[C:6]([C:8]2[C:9](=[O:30])[N:10]([CH2:28][CH3:29])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[CH:12]=3)=[CH:7][C:2]([NH:1][C:40]([NH:39][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:41])=[C:3]([F:32])[CH:4]=1
Reactant: CCn1c(=O)c(-c2cc(N)c(F)cc2Cl)cc2cnc(NCCCN3CCOCC3)cc21
Reactant: O=C=Nc1ccccc1
Solvent: c1ccncc1
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3ccccc3)c(F)cc2Cl)cc2cnc(NCCCN3CCOCC3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.2 %

Procedure:
A solution of 3-(5-amino-2-chloro-4-fluorophenyl)-1-ethyl-7-((3-morpholinopropyl)amino)-1,6-naphthyridin-2(1H)-one (0.140 g, 0.304 mmol) in pyridine (4 mL) was treated with phenyl isocyanate (0.040 g, 0.336 mmol) and stirred at RT for 1 h. The mixture was concentrated to dryness, treated with MeOH and the resulting solid was collected via filtration to afford 1-(4-chloro-5-(1-ethyl-7-((3-morpholinopropyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea (120 mg, 61% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.08 (s, 1H), 8.68 (s, 1H), 8.40 (s, 1H), 8.17 (d, J=8.7 Hz, 1H), 7.72 (s, 1H), 7.52 (d, J=11.0 Hz, 1H), 7.41 (d, J=8.0 Hz, 2H), 7.26 (t, J=7.8 Hz, 2H), 7.10 (t, J=5.6 Hz, 1H), 6.97 (t, J=7.4 Hz, 1H), 6.28 (s, 1H), 4.06 (m, 2H), 3.56 (t, J=4.5 Hz, 4H), 3.34 (m, 2H), 2.34 (d, J=6.8 Hz, 6H), 1.70 (t, J=7.0 Hz, 2H), 1.20 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 579.2 [M+H]+.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[S:9]1[C:13]([S:14](Cl)(=[O:16])=[O:15])=[CH:12][C:11]2[CH:18]=[CH:19][CH:20]=[CH:21][C:10]1=2>C(Cl)Cl.N1C=CC=CC=1>[NH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[NH:8][S:14]([C:13]1[S:9][C:10]2[CH:21]=[CH:20][CH:19]=[CH:18][C:11]=2[CH:12]=1)(=[O:15])=[O:16]
Reactant: O=S(=O)(Cl)c1cc2ccccc2s1
Reactant: Nc1ccccc1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: Nc1ccccc1NS(=O)(=O)c1cc2ccccc2s1
Temperature: 25 °C
Yield: 78.8 %

Procedure:
To a solution of o-phenylenediamine (5 mmol) in DCM (25 mL) and pyridine (5 mL) at 0° C., benzo[b]thiophene-2-sulfonyl chloride (5.5 mmol) was added in small portions. The reaction mixture was then gradually warmed to RT with stirring continued until the reaction was complete as determined by TLC or LC-MS. The reaction mixture was then diluted with DCM (25 mL). The organic phase was washed with water (2×25 mL) and 25 mL of brine. The organic phase was dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with DCM/EtOAc to give 1.2 g of benzo[b]thiophene-2-sulfonic acid (2-amino-phenyl)-amide. Tr 0.94 min, MS: 305.7 (M+1)+. 1H NMR (DMSO-d6, 400 MHz): δ 6.40 (t, 1H), 6.60 (d, 1H), 6.78 (d, 1H), 6.89 (t, 1H), 7.45 (t, 1H), 7.50 (t, 1H), 7.80 (s, 1H), 7.90 (d, 1H), 8.80 (d, 1H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].[F:11][C:12]1[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][C:13]=1[C:14]#[N:15]>>[F:11][C:12]1[CH:19]=[C:18]([O:20][C:9]2[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=2[F:1])[CH:17]=[CH:16][C:13]=1[C:14]#[N:15]
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: N#Cc1ccc(O)cc1F
Product: N#Cc1ccc(Oc2ccc(C=O)cc2F)cc1F

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 3,4-difluorobenzaldehyde and 2-fluoro-4-hydroxybenzonitrile.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:17])=[C:5]([C:8]([O:15][CH3:16])=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH:6]=[O:7].[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Mg].[Cl-].[NH4+]>O1CCCC1>[CH3:1][O:2][C:3]1[C:4]([CH3:17])=[C:5]([CH:6]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[O:25][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[OH:7])[C:8]([O:15][CH3:16])=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12]
Reactant: Brc1ccccc1OCc1ccccc1
Reactant: COc1c(C)c(C=O)c(OC)c(OC)c1OC
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1c(C)c(C(O)c2ccccc2OCc2ccccc2)c(OC)c(OC)c1OC
Reaction time: 2 h
Yield: 100 %

Procedure:
An anhydrous tetrahydrofuran (30 ml) solution of 3,4,5,6-tetramethoxy-2-methylbenzaldehyde (5.00 g, 0.021 mol) was added dropwise under ice cooling to a Grignard reagent (35 ml tetrahydrofuran solution) prepared from 2-(benzyloxy)bromobenzene (11.50 g, 0.044 mol) and magnesium (1.16 g, 0.048 mol), and the resulting solution was stirred for 2 hours. The reaction solution was poured in an aqueous solution of saturated ammonium chloride and extracted with ether. The extract was washed with saturated brine and then dried. The reaction solution was filtered, the filtrate was concentrated and the obtained crude product was purified by silica gel column chromatography (hexand:ethyl acetate=4:1) to obtain the titled compound (8.80 g, 0.021 mol, 99%).
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][C:8](Cl)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:11][C:12]1([CH3:20])[O:17][C:16](=[O:18])[CH2:15][C:14](=[O:19])[O:13]1.N1C=CC=CC=1.Cl>C(Cl)Cl>[CH:1]1([CH2:6][CH2:7][C:8]([CH:15]2[C:16](=[O:18])[O:17][C:12]([CH3:20])([CH3:11])[O:13][C:14]2=[O:19])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=C(Cl)CCC1CCCC1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)OC(=O)C(C(=O)CCC2CCCC2)C(=O)O1
Temperature: 0 °C
Reaction time: 2 h
Yield: 96.7 %

Procedure:
3-Cyclopentylpropionyl chloride (0.64 ml, 4.16 mmol) was added to a solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (500 mg, 3.47 mmol) in anhydrous methylene chloride (10 ml). After cooling to 0° C., pyridine (0.56 ml, 6.94 mmol) was added in portions. After stirring for 1 hour at 0° C. and 2 hours at ambient temperature the mixture was poured onto water (20 ml) containing concentrated hydrochloric acid (0.5 ml). The organic layer was separated, washed with water, brine, dried (MgSO4) and the volatiles were removed by evaporation to give 5-(3-cyclopentylpropionyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (900 mg, 96%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9][C:8]=1[NH2:17].[C:18](OC)(OC)(OC)[CH2:19][CH2:20][CH3:21]>Cl.N1C=CC=CC=1>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=[C:18]1[CH2:19][CH2:20][CH3:21]
Reactant: Nc1cnc2ccccc2c1NCCCCCl
Reactant: CCCC(OC)(OC)OC
Agent: Cl
Solvent: c1ccncc1
Product: CCCc1nc2cnc3ccccc3c2n1CCCCCl
Yield: 55.6 %

Procedure:
Using the general method of Example 1 Part D, N4-(4-chlorobutyl)quinoline-3,4-diamine (˜21.45 mmol) was cyclized using trimethyl orthobutyrate (3.8 g, 25.74 mmol) in the presence of pyridine hydrochloride (0.1 g). The crude product was purified by chromatography (silica gel eluting with 95/5 dichloromethane/methanol) to provide 3.6 g of 1-(4-chlorobutyl)-2-propyl-1H-imidazo[4,5-c]quinoline as a light green oil which slowly solidified.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[O:5]1[CH2:9][CH2:8][O:7][CH:6]1[C:10]1[CH:11]=[C:12]([NH2:16])[CH:13]=[CH:14][CH:15]=1.N1C=CC=CC=1>C(Cl)Cl>[O:5]1[CH2:9][CH2:8][O:7][CH:6]1[C:10]1[CH:11]=[C:12]([NH:16][C:1](=[O:3])[CH3:2])[CH:13]=[CH:14][CH:15]=1
Reactant: CC(=O)Cl
Reactant: Nc1cccc(C2OCCO2)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1cccc(C2OCCO2)c1
Reaction time: 1 h
Yield: 89.9 %

Procedure:
A solution of acetyl chloride (3.75 g, 0.048 mol, 3.4 mL) in CH2Cl2 (6.5 mL) was added dropwise over 15 min to an ice-bath chilled solution of 3-[1,3]dioxolan-2-yl-phenylamine (7.18 g, 0.043 mol) and pyridine (3.40 g, 0.043 mol, 3.5 mL) in CH2Cl2 (85 mL). The solution was then brought to room temperature, stirred for 1 hr, and poured onto ice-water (60 mL). The phases were separated, and the organic layer washed with water, saturated NaHCO3, brine and dried with MgSO4. Removal of the solvent in vacuo afforded N-(3-[1,3]dioxolan-2-yl-phenyl)-acetamide (8.01 g, 90%). 1H NMR (CDCl3) δ 2.08 (s, 3H), 4.03 (d of mult., ethylenedioxy), 5.71 (s, 1H), 7.17 (d, J=8 Hz, 1H), 7.26 (t, J=8 Hz, 1H), 7.53 (d, J=8 Hz, 1H), 7.62 (s, 1H), 8.32 (br s, 1H). 13C NMR (CDCl3) δ 168.9, 138.8, 138.3, 129.1, 122.3, 120.8, 118.1, 103.5, 65.4, 24.4.
Reaction SMILES: C([N:8]1[CH2:16][CH:15]2[CH:10]([NH:11][CH2:12][CH2:13][O:14]2)[CH2:9]1)C1C=CC=CC=1.[ClH:17]>CO.[Pd]>[ClH:17].[ClH:17].[CH:15]12[CH2:16][NH:8][CH2:9][CH:10]1[NH:11][CH2:12][CH2:13][O:14]2
Reactant: c1ccc(CN2CC3NCCOC3C2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: C1COC2CNCC2N1

Procedure:
A solution of 4 g (18.2 mmol) of 8-benzyl-2-oxa-5,8-diazabicyclo[4.3.0]nonane in 100 ml of methanol and 3.5 ml of concentrated hydrochloric acid is hydrogenated on 2 g of palladium-on-active charcoal (10% of Pd) at 80° C. under 100 bar. The catalyst is filtered off and washed with water. The filtrates are concentrated and the product is crystallized by trituration with a little methanol. The crystals are filtered off with suction, washed with acetone and dried in air.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[Cl:29])[CH:20]=[C:21]([F:22])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:30][NH2:31]>>[F:22][C:21]1[C:15]2[O:14][CH:13]([CH2:12][NH:31][CH3:30])[CH2:17][C:16]=2[CH:18]=[C:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])[CH:20]=1
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(-c4ccccc4Cl)cc(F)c3O2)cc1
Product: CNCC1Cc2cc(-c3ccccc3Cl)cc(F)c2O1

Procedure:
The title compound was prepared (0.068 g, 47%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-fluoro-5-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.199 g, 0.46 mmol) and methylamine (0.28 g, 9.2 mmol). mp 217-222° C. (dec).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:13](=O)([O-])[O-].[K+].[K+].IC>C(#N)C>[CH3:1][O:2][C:3](=[O:12])[CH2:4][N:5]([CH3:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)CNc1ccccc1
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: COC(=O)CN(C)c1ccccc1
Yield: 76.3 %

Procedure:
The mixture of N-phenylglycine methyl ester (0.99 g, 6 mmol), potassium carbonate (1.66 g, 12 mmol), and iodomethane (1.28 g, 9 mmol) in acetonitrile (20 mL) was refluxed overnight. The solids were filtered and the filtrate was diluted with water (100 mL), extracted with dichloromethane (4×50 mL). The combined organic extracts were washed with brine (100 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, ethyl acetate/hexane) to afford the title compound (0.82 g, 77%). 1H NMR (400 MHz, CDCl3) δ: 7.24 (m, 2H), 6.75 (m, 1H), 6.67 (m, 2H), 4.07 (s, 2H), 3.71 (s, 3H), 3.06 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:22][CH:23]=[CH:24][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[CH2:17][CH2:18][C:19]([OH:21])=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H][H]>C(O)C.[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:22][CH2:23][CH2:24][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[CH2:17][CH2:18][C:19]([OH:21])=[O:20])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(O)CCC(CC=Cc1cccnc1)CCCCNS(=O)(=O)c1ccc(Cl)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: O=C(O)CCC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCc1cccnc1

Procedure:
To a solution of 34 mg of 8-(p-chlorophenylsulfonamido)-4-[3-(3-pyridyl)-2-propenyl]-octanoic acid in 2 ml of ethanol is added 5 mg of 10% palladium on carbon. The mixture is hydrogenated at 1 atmosphere (=1.01 bar) pressure of hydrogen at room temperature for 48 h. Then the mixture is filtered, washed and evaporated to give an oil which is purified by preparative thin layer chromatography using petroleum ether/ethyl acetate/acetic acid (80:18:2) as solvent to yield 8-(p-chlorophenylsulfonamido)-4-[3-(3-pyridyl)propyl]-octanoic acid of example 5a.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6][C:5](=[O:12])[O:4][C:2]2=[O:3].[H-].[Na+].[CH:15](Br)=[CH:16][C:17](=[CH2:19])[CH3:18]>>[CH:15]([N:6]1[C:5](=[O:12])[O:4][C:2](=[O:3])[C:1]2=[CH:11][CH:10]=[CH:9][CH:8]=[C:7]12)=[CH:16][C:17](=[CH2:18])[CH3:19]
Reactant: C=C(C)C=CBr
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Agent: [H-]
Agent: [Na+]
Product: C=C(C)C=Cn1c(=O)oc(=O)c2ccccc21

Procedure:
Reagents: Isatoic anhydride (6.13 mmols, 1 g); Sodium hydride (9.2 mmols, 0.23 g); Isoprenyl bromide (12 mmols, 1.9 g). Yield: 0.95 g (67%), white solid, m.p.=119° C.-120° C.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[O:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]([C@@H:13]2[CH2:17][CH2:16][C@H:15]([CH2:18][OH:19])[N:14]2CC2C=CC=CC=2)=[O:12])[CH:7]=[CH:8][CH:9]=1>C1COCC1.CO.[Pd]>[F:27][C:2]([F:1])([F:28])[O:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]([C@@H:13]2[CH2:17][CH2:16][C@H:15]([CH2:18][OH:19])[NH:14]2)=[O:12])[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(Nc1cccc(OC(F)(F)F)c1)[C@@H]1CC[C@H](CO)N1Cc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Nc1cccc(OC(F)(F)F)c1)[C@@H]1CC[C@H](CO)N1
Reaction time: 8 h

Procedure:
To a solution of (2S,5R)-1-benzyl-5-hydroxymethyl-pyrrolidine-2-carboxylic acid (3-trifluoromethoxy-phenyl)-amide (500 mg, 1.27 mmol) in THF (5 mL) containing 5 drops of MeOH was added Pd/C (10%, 27 mg). The solution was degassed 3 times replacing air by nitrogen and finally nitrogen by hydrogen. The reaction mixture was further stirred under hydrogen atmosphere overnight. The catalyst was removed through a pad of Celite and washed with THF. Solvents were concentrated and the resulting material was used without purification in the next step. MS (LC/MS): 305 [M+H]+; tR (HPLC conditions b): 2.89 min.
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][CH2:7][CH:8]2[C:12](=[O:13])[N:11]([CH:14]([CH:18]([CH3:20])[CH3:19])[C:15]([OH:17])=O)[C:10](=[O:21])[NH:9]2)=[CH:4][CH:3]=1.CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH2:53]([O:60][NH2:61])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1.Cl>CN(C=O)C>[CH2:53]([O:60][NH:61][C:15](=[O:17])[CH:14]([N:11]1[C:12](=[O:13])[CH:8]([CH2:7][O:6][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:23][CH:22]=2)[NH:9][C:10]1=[O:21])[CH:18]([CH3:20])[CH3:19])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1
Reactant: NOCc1ccccc1
Reactant: CC(C)C(C(=O)O)N1C(=O)NC(COc2ccc(Br)cc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)C(C(=O)NOCc1ccccc1)N1C(=O)NC(COc2ccc(Br)cc2)C1=O
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
A solution of the compound obtained in step h above (22h) (300 mg, 0.782 mmol), NMM (0.19 mL, 1.72 mmol) and HOBt (179 mg, 1.329 mmol) in DMF (11 mL) were stirred at 0° C. for 10 minutes, then the reaction was cooled to −15° C., and EDCl (165 mg, 0.860 mmol) was added. The reaction was stirred for 30 minutes at −15° C. and then allowed to warm to room temperature, BnONH2HCl (137 mg, 0.860 mmol) was added. After being stirred overnight, the reaction mixture was concentrated under vacuum, and the residue was diluted with EtOAc and washed with brine. The combined organic layers were dried and concentrated; the residue was purified by silica gel column chromatography which gave the title compound as colorless oil (426 mg, 83% yield).
Reaction SMILES: Cl.Cl.Cl.[CH3:4][C:5]1[C:6]2[O:28][CH2:27][CH2:26][C:7]=2[C:8]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]3[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]3)[CH2:13][CH2:12]2)=[N:9][CH:10]=1.[C:29](O)(=[O:31])[CH3:30]>>[CH3:4][C:5]1[C:6]2[O:28][CH2:27][CH2:26][C:7]=2[C:8]([N:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C@H:19]3[CH2:20][CH2:21][C@H:22]([NH:25][C:29](=[O:31])[CH3:30])[CH2:23][CH2:24]3)[CH2:15][CH2:16]2)=[N:9][CH:10]=1
Reactant: Cc1cnc(N2CCN(CC[C@H]3CC[C@H](N)CC3)CC2)c2c1OCC2
Reactant: CC(=O)O
Agent: Cl
Product: CC(=O)N[C@H]1CC[C@H](CCN2CCN(c3ncc(C)c4c3CCO4)CC2)CC1

Procedure:
The title compound, off-white solid (47 mg, 81%), MS (ISP) m/z=387.4 [(M+H)+], mp 196.5° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(7-methyl-2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate G) (68.1 mg, 0.15 mmol) and acetic acid.