Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]=[N+:14]=[N-:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:16]#[CH:17]>CC(C)=O.C(=O)=O.CC(C)=O>[CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]2[CH:17]=[CH:16][N:15]=[N:14]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=NC1CCN(Cc2ccccc2)C1
Reactant: C#C
Agent: O=C=O
Solvent: CC(C)=O
Product: c1ccc(CN2CCC(n3ccnn3)C2)cc1

Procedure:
A solution of N-benzyl-3-azido-pyrrolidine (1.5 g, 0.0074 mol) in acetone was taken in a steel bomb and cooled in dry ice/acetone bath. To this cold solution acetylene (2.5 mg, 0.096 mol) was added under N2 atmosphere. The sealed steel bomb was then heated in an oil bath at 75° C. for 20 h. The vessel was cooled again in dry ice/acetone bath and excess of acetylene released slowly, while the temperature rose to the room temperature (r.t.). The reaction mixture was concentrated to yellow-brown oil. Crude yield: 2.02 g. Crude compound was purified on silica gel column to obtain the title compound as a light yellow-brown oil. Yield: 1.02 g (60%). 1H NMR (CDCl3) δ: 2.0-3.3 (m, 6H), 3.7 (S, 2H), 5.3 (m, 1H), 7.45 (s, 5H), 7.8 (s, 1H), 7.95 (s, 1H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[SH:10].Cl[CH2:12][C:13]1[N:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=2)[O:15][N:14]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C.CCCCCC>[CH3:25][O:24][C:20]1[CH:19]=[C:18]([C:16]2[O:15][N:14]=[C:13]([CH2:12][S:10][C:2]3[NH:3][C:4]4[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=4[N:1]=3)[N:17]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: Sc1nc2ccccc2[nH]1
Reactant: COc1cccc(-c2nc(CCl)no2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: COc1cccc(-c2nc(CSc3nc4ccccc4[nH]3)no2)c1

Procedure:
1H-Benzoimidazole-2-thiol (150 mg, 1 mmol) was added to a solution of the 3-chloromethyl-5-(3-methoxy-phenyl)-[1,2,4]oxadiazole (30 mg, 0.13 mmol) and potassium carbonate (50 mg, 0.36 mmol) in DMF (2 ml) at room temperature. The solvent was removed in vacuo and the product obtained by flash chromatography using 20-100% ethyl acetate in hexane. 1H NMR (CDCl3), δ (ppm): 7.71 (d, 1H), 7.62 (d, 1H), 7.53 (m, 2H), 7.42 (t, 1H), 7.18 (overlapping, m, 3H), 4.52 (s, 2H), 3.87 (s, 3H).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([C:13]([O:15][CH3:16])=[O:14])[C:7]2[CH:8]=[CH:9][NH:10][C:11]=2[CH:12]=1.Br[CH:18]([CH2:20][CH3:21])[CH3:19].[CH3:22][N:23]([CH:25]=[O:26])C>O>[Br:3][C:4]1[CH:5]=[C:6]([C:13]([O:15][CH3:16])=[O:14])[C:7]2[CH:8]=[CH:9][N:10]([CH:18]([CH2:20][CH3:21])[CH3:19])[C:11]=2[CH:12]=1.[NH2:10][CH2:9][C:8]1[C:25](=[O:26])[NH:23][C:22]([CH3:18])=[CH:11][C:7]=1[CH2:6][CH2:5][CH3:4]
Reactant: COC(=O)c1cc(Br)cc2[nH]ccc12
Reactant: CCC(C)Br
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCC(C)n1ccc2c(C(=O)OC)cc(Br)cc21
Product: CCCc1cc(C)[nH]c(=O)c1CN
Reaction time: 0.33 h
Yield: 40.1 %

Procedure:
To a stirred suspension of sodium hydride (5.66 g, 141.7 mmol) in DMF (100 mL) was added a solution of methyl 6-bromo-1H-indole-4-carboxylate (4) (30 g, 118.1 mmol) in DMF (50 mL) at 0° C. and stirred for 20 min. Then 2-Bromo butane (29.1 g, 212.5 mmol) was added at 0° C. and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with cold water and extracted with ethyl acetate (4×150 mL). The combined organic layer was washed with cold water (150 mL), brine (100 mL) and dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude, which was purified by column chromatography over silica gel (60-120 mesh) using 5% EtOAc: Pet ether as eluent to afford the title compound methyl 6-bromo-1-sec-butyl-1H-indole-4-carboxylate, 5 (14 g, 40.1%) as pale yellow solid. 1H NMR (CDCl3, 400 MHz) δ 0.843-0.870 (m, 3H), 1.512 (d, J=6.4 Hz, 3H), 1.844-1.926 (m, 2H), 3.976 (s, 3H), 4.333-4.385 (m, 1H), 7.132 (d, J=3.2 Hz, 1H), 7.302 (d, J=3.6 Hz, 1H), 7.707 (s, 1H), 7.984 (d, J=1.6 Hz, 1H).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][NH:10][C:11]([C:13]2[S:23][C:22]3[N:24]4[C:15](=[CH:16][N:17]=[C:18]4[CH:19]=[CH:20][CH:21]=3)[CH:14]=2)=[O:12])[CH2:5][CH2:4]1.C(N(CC)CC)C.S(O[CH2:37][CH2:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[F:46])(=O)(=O)C>C(O)C>[F:46][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=1[CH2:39][CH2:38][CH2:37][N:3]1[CH2:8][CH2:7][CH:6]([CH2:9][NH:10][C:11]([C:13]2[S:23][C:22]3[N:24]4[C:15](=[CH:16][N:17]=[C:18]4[CH:19]=[CH:20][CH:21]=3)[CH:14]=2)=[O:12])[CH2:5][CH2:4]1
Reactant: O=C(NCC1CCNCC1)C1=Cc2cnc3cccc(n23)S1
Reactant: CS(=O)(=O)OCCCc1ccccc1F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(NCC1CCN(CCCc2ccccc2F)CC1)C1=Cc2cnc3cccc(n23)S1

Procedure:
Under nitrogen gas, 0.38 ml (4.90 mM) of methanesulfonyl chloride was added to a solution of 499 mg (3.24 mM) of 2-fluorophenylpropanol and 0.90 ml (6.47 mM) of triethylamine in methylene chloride (6 ml) at 0° C. and the mixture was stirred at the prevailing temperature for 20 minutes. The reaction was stopped by adding saturated aqueous solution of sodium hydrogen carbonate. The reaction mixture was then extracted with diethyl ether. The organic layer was washed with water and saturated aqueous solution of sodium chloride and dried over MgSO4. The solvent was then distilled off under reduced pressure to provide 0.722 g (3.24 mM) of 2-fluorophenylpropyl mesylate. To a solution of 0.58 g (1.5 mM) of N-(piperidin-4-ylmethyl)-5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride and 1.0 ml (7.2 mM) of triethylamine in ethanol was added 0.60 g (2.69 mM) of 2-fluorophenylpropyl mesylate at room temperature, and the mixture was refluxed under nitrogen for 16 hours. The solvent was then distilled off under reduced pressure and the residue was diluted with water and extracted with chloroform. The organic -layer was washed with saturated aqueous solution of sodium chloride and dried over MgSO4. The resulting crude product was purified by column chromatography (methanol/ethyl acetate 20-50%) to provide the title compound.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=[C:4]([F:11])[N:3]=1.F[C:13]1[C:18]([C:19](O)=O)=[CH:17]C=CN=1.C([NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(C)(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:1][C:2]1[C:7]([C:8]([NH:26][C:27]2[CH:28]=[CH:29][C:30]([C:18]([CH3:19])([CH3:13])[CH3:17])=[CH:31][CH:32]=2)=[O:10])=[CH:6][CH:5]=[C:4]([F:11])[N:3]=1
Reactant: O=C(O)c1cccnc1F
Reactant: CC(C)(C)Nc1ccccc1
Reactant: O=C(O)c1ccc(F)nc1F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)c1ccc(NC(=O)c2ccc(F)nc2F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2,6-difluoropyridine-3-carboxylic acid (prepared similar to that described for 2-fluoropyridine-3-carboxylic acid, Example 64) (3.2 g, 20 mmol), t-butylaniline 11 (3.0 g, 20 mmol), HOBt (2.6 g, 20 mmol), EDAC (8 g, 40 mmol), and DIEA (8 mL) in CH2Cl2 (80 mL) was stirred at RT for 1 h. The mixture was washed with aq. NaHCO3 and brine. The organic solution was dried over Na2SO4 and concentrated in vacuo. The residue was purified via flash chromatography on silica (Hex:EtOAc=4:1) to give a light yellow flaky crystal as the desired product.
Reaction SMILES: [CH:1](=[C:8]1[NH:12][C:11](=[O:13])[NH:10][C:9]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]([O:19][CH2:20][CH:21]([CH2:26][CH3:27])[CH2:22][CH2:23][CH2:24][CH3:25])(=[O:18])[CH:16]=[CH2:17].[OH-:28].[K+]>CN(C=O)C>[CH:1](=[C:8]1[C:9](=[O:14])[N:10]([CH2:17][CH2:16][C:15]([O:19][CH2:20][CH:21]([CH2:26][CH3:27])[CH2:22][CH2:23][CH2:24][CH3:25])=[O:18])[C:11](=[O:13])[N:12]1[CH2:17][CH2:16][C:15]([O:19][CH2:20][CH:21]([CH2:26][CH3:27])[CH2:22][CH2:23][CH2:24][CH3:25])=[O:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [OH-]
Reactant: O=C1NC(=O)C(=Cc2ccccc2)N1
Reactant: C=CC(=O)OCC(CC)CCCC
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCC(CC)COC(=O)CCN1C(=O)C(=Cc2ccccc2)N(CCC(=O)OCC(CC)CCCC)C1=O
Temperature: 110 °C
Reaction time: 2 h
Yield: 335.5 %

Procedure:
10 g (53.1 mmol) of benzalhydantoin, 23.6 g (127.6 mmol) of 2-ethylhexyl acrylate and 0.6 g (10.6 mmol) of potassium hydroxide were added to 100 ml of DMF, and the mixture was stirred at 110° C. for 2 hours. After cooling, the reaction solution was extracted with ethyl acetate, and the organic layer was washed with water, dried with sodium sulfate and concentrated under reduced pressure. The residue was dissolved in toluene and crystallized by adding hexane. The crystals were filtered out and dried to obtain 19.8 g of bis(2-ethylhexyl) 4-benzylidene-2,5-dioxo-1,3-imidazolidinedipropionate (yield: 42.3%).
Reaction SMILES: [C:1]([CH:8]([NH2:14])[CH2:9][O:10][CH2:11][CH2:12][OH:13])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1C=C([O:21][C:22](OC2N=CC=CC=2)=[S:23])N=CC=1.[N:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)(Cl)Cl>[N:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[SH:23]=[C:22]([O:13][CH2:12][CH2:11][O:10][CH2:9][CH:8]([NH2:14])[C:1]([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2])[OH:21]
Reactant: CC(C)(C)OC(=O)C(N)COCCO
Reactant: c1ccncc1
Reactant: S=C(Oc1ccccn1)Oc1ccccn1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)C(N)COCCOC(O)=[SH]c1ccccn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 2 (1.0 g, 4.88 mmol), di-2-pyridyl thionocarbonate prepared as described by Kim, S., et al., “Di-2-pyridyl Thionocarbonate. A New Reagent For The Preparation Of Isothiocyanates And Carbodiimides,” Tet. Left. 1985, 26, 1661-1664, the contents of which are incorporated herein by reference, (17, 1.36 g, 5.86 mmol), and anhydrous pyridine (474 mg, 6.0 mmol) in anhydrous chloroform (25 mL) is stirred for 3 hours at room temperature. The reaction mixture is washed with 0.5 N HCl then dried over anhydrous MgSO4, followed by evaporation of the solvent to give the product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:22])=[C:6]([C:8]([C:10]2[CH:15]=[C:14]([Cl:16])[N:13]=[C:12]([F:17])[C:11]=2[O:18]COC)=[O:9])[CH:7]=1.Cl.O.CCOC(C)=O>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:22])=[C:6]([C:8]([C:10]2[CH:15]=[C:14]([Cl:16])[N:13]=[C:12]([F:17])[C:11]=2[OH:18])=[O:9])[CH:7]=1
Reactant: COCOc1c(C(=O)c2cc(Br)ccc2F)cc(Cl)nc1F
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=C(c1cc(Br)ccc1F)c1cc(Cl)nc(F)c1O
Temperature: 60 °C
Yield: 77 %

Procedure:
To a solution of (5-bromo-2-fluorophenyl)(6-chloro-2-fluoro-3-(methoxymethoxy)pyridin-4-yl)methanone (1200 g, 3.06 mol) in THF (4.8 L) was added 6 N aqueous HCl solution (1600 mL, 9.17 mol) and the reaction mixture was heated to 60° C. for 5 hours. The reaction mixture was cooled to RT, and then water (3 L) and EtOAc (3 L) were added. After the phases were separated, the aqueous layer was extracted with EtOAc (3 L×2). The combined organic layers was washed with brine (2 L×1) and dried over Na2SO4. The solution was concentrated under reduced pressure. The residue was dissolved in hot MTBE (700 mL). The solution was triturated with hexanes until a solid began to precipitate. The slurry was cooled to RT overnight. The solid was filtered, washed with hexanes (500 mL×2), and dried to give 821 g of (5-bromo-2-fluorophenyl)(6-chloro-2-fluoro-3-hydroxypyridin-4-yl)methanone as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([S:10][CH3:11])[N:5]=[C:4]([S:12][CH2:13][CH3:14])[N:3]=1.CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>>[C:8]([C:7]1[C:2]([N:1]=[CH:17][N:18]([CH3:20])[CH3:19])=[N:3][C:4]([S:12][CH2:13][CH3:14])=[N:5][C:6]=1[S:10][CH3:11])#[N:9]
Reactant: CCSc1nc(N)c(C#N)c(SC)n1
Reactant: COC(OC)N(C)C
Product: CCSc1nc(N=CN(C)C)c(C#N)c(SC)n1

Procedure:
The title compound was prepared from the reaction of 4-Amino-2-ethylsulfanyl-6-methylsulfanyl-pyrimidine-5-carbonitrile with N,N-dimethylformamide dimethyl acetal using the procedure from Example 156B to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8]O)=[N:6][CH:7]=1.S(Cl)([Cl:12])=O>C(Cl)Cl>[ClH:12].[Cl:12][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(F)cn1
Solvent: ClCCl
Product: Cl
Product: Fc1ccc(CCl)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.7 %

Procedure:
To (5-fluoropyridin-2-yl)methanol (10.6 g, 83.39 mmol) in DCM (166 mL) was added thionyl chloride (12.17 mL, 166.8 mmol) dropwise. The mixture was allowed to stir at ambient temperature for 18 hours. The mixture was concentrated under reduced pressure to afford 2-(chloromethyl)-5-fluoropyridine hydrochloride (11.8 g, 78% yield) as white solids.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=1)[CH2:8][C:9]#[CH:10])([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=1.N(C(C)C)C(C)C>ClCCl.CCOCC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:1]([O:5][C:6](=[O:20])[N:7]([CH2:8][C:9]#[C:10][C:25]1[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=1)[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C#CCN(Cc1ccc(F)c(F)c1)C(=O)OC(C)(C)C
Reactant: Clc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOCC
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)N(CC#Cc1ccc(Cl)cc1)Cc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.2 %

Procedure:
A mixture of (3,4-difluoro-benzyl)-prop-2-ynyl-carbamic acid tert-butyl ester (3.2 g, 11.4 mmol), 4-chloroiodobenzene (4.1 g, 17.2 mmol, 1.5 eq.), Pd(PPh3)2Cl2 (0.4 g. 0.57 mmol, 5 mol %), iPr2NH (4 mL, 28.5 mmol, 2.5 eq.) and CuI (0.435 g, 2.3 mmol, 0.2 eq.) in 100 mL dichloromethane was stirred overnight at room temperature. The solution was diluted with 300 mL ether and filtered through a CELITE pad to remove the insoluble components. The filtrate washed with 2×100 mL 1N HCl, 100 mL brine, dried over MgSO4, filtered, concentrated and chromatographed with 6% ethyl acetate in hexanes to provide 2.6 g of [3-(4-chloro-phenyl)-prop-2-ynyl]-(3,4-difluoro-benzyl)-carbamic acid tert-butyl ester.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:8]=[C:9]([C:12]([OH:14])=O)[S:10][CH:11]=2)[N:6]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[N:33]([C:37]([NH2:39])=[O:38])[C:32](=[O:40])[CH2:31]2>CN(C)C=O.CN(C1C=CN=CC=1)C>[Cl:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[N:33]([C:37]([NH2:39])=[O:38])[C:32](=[O:40])[CH:31]2[C:12](=[O:14])[C:9]1[S:10][CH:11]=[C:7]([C:5]2[N:6]=[C:2]([CH3:1])[S:3][CH:4]=2)[CH:8]=1
Reactant: Cc1nc(-c2csc(C(=O)O)c2)cs1
Reactant: NC(=O)N1C(=O)Cc2cc(Cl)ccc21
Agent: CN(C)c1ccncc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: Cc1nc(-c2csc(C(=O)C3C(=O)N(C(N)=O)c4ccc(Cl)cc43)c2)cs1

Procedure:
The title compound was prepared according to the procedure of Example 55. A 1.25 g (5.55 mmoles) sample of 4-(2-methyl-4-thiazolyl)-2-thiophenecarboxylic acid (prepared as described in Example 18) was converted to the acyl imidazole by reaction with 0.98 g (6.05 mmoles) of 1,1′-carbonyldiimidazole in 15 ml of N,N-dimethylformamide. After complete reaction this solution was transferred to an addition funnel and slowly added 1.06 g (5.04 mmoles) of 5-chloro-2-oxindole-1-carboxamide and 1.66 g (13.59 mmoles) of 4-(N,N-dimethylamino)pyridine in 50 ml of N,N-dimethylformamide. Acidic workup followed by filtration and trituration with 2-butanone gave 0.50 g (1.20 mmoles) of title compound as a yellow solid, m.p. 238-241° C.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][N:11]=[N:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:14].[Na+]>C(O)(=O)C>[C:2]1([C:1]([C:8]2[CH:13]=[CH:12][N:11]=[N:10][CH:9]=2)=[O:14])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [OH-]
Reactant: c1ccc(Cc2ccnnc2)cc1
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(c1ccccc1)c1ccnnc1
Temperature: 100 °C

Procedure:
To a 100° C. suspension of SeO2 (4.75 g, 0.043 mole) in acetic acid (216 mL) was added dropwise to a solution of 4-benzylpyridazine (11; 7.6 g, 0.044.6 mole) in acetic acid (216 mL). The mixture was heated for 1 hour at 100° C. The reaction mixture was cooled to room temperature and was neutralized to a pH ˜6-7 with 50% NaOH. The neutralized mixture was extracted twice with CH2Cl2. The combined extracts were dried over MgSO4 and were evaporated to dryness. The crude product was purified by crystallization in refluxing isopropyl alcohol (10 vol). The yield of phenylpyridazin-4-yl-methanone (12) obtained was 5.8 g or 66%. MS (ESI+): [M+H]+=185.33; 1H NMR (300 MHz, CDCl3), δ ppm: 7.5-7.60(m, 2H), 7.64-7.83 (m, 4H), 9.42-9.51 (m, 2H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6]([N:8](CC)[CH2:9][CH3:10])[CH3:7].[O:13]=[P:14](Cl)(Cl)[Cl:15].O=P(Cl)(Cl)Cl.C1C=CC=CC=1>C1C=CC=CC=1>[N:1]1([P:14](=[O:13])([N:8]2[CH2:9][CH2:10][CH2:7][CH2:6]2)[Cl:15])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCN(CC)CC
Solvent: c1ccccc1
Product: O=P(Cl)(N1CCCC1)N1CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The bis-pyrrolidinochlorophosphine oxide was prepared as follows: 56.8 g (0.8 mole) pyrrolidine, 80.8 g (0.8 mole) triethylamine and 300 ml dry benzene were charged into a 1 liter three-necked flask equipped with a stirrer, condenser and dropping funnel. A solution of POCl3 in 70 mls dry benzene was added dropwise under a stream of dry nitrogen. The reaction was exothermic. On complete addition of the POCl3 /benzene solution, the reaction mixture was stirred for 11/2 hours at room temperature. The precipitated triethylamine hydrochloride was filtered off and the filtrate evaporated using a rotary evaporator under reduced pressure (60 mm). The product was fractionally distilled under reduced pressure (0.3 - 0.5 mm) and the fraction distilling between 138°-140° collected. This fraction was identified as ##EQU59##
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH:7]([Cl:8])[CH2:6][N:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4]1.[C:16](Cl)(=[O:18])[CH3:17]>C(O)C>[C:16]([NH:1][CH2:2][CH:3]1[CH:7]([Cl:8])[CH2:6][N:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4]1)(=[O:18])[CH3:17]
Reactant: CC(=O)Cl
Reactant: NCC1CN(Cc2ccccc2)CC1Cl
Solvent: CCO
Product: CC(=O)NCC1CN(Cc2ccccc2)CC1Cl
Yield: 78.3 %

Procedure:
To 3-aminomethyl-1-benzyl-4-chloropyrrolidine (2.69 g) is added ethanol (50 ml) and thereto is added dropwise acetyl chloride (1.02 g) with stirring under ice-cooling. The mixture is stirred at room temperature overnight, then concentrated, neutralized with saturated aqueous sodium hydrogen carbonate, and extructed with dichloromethane. The dichloromethane layer is dried and concentrated to give 3-acetylaminomethyl-1-benzyl-4-chloropyrrolidine (2.50 g) as an yellow oil.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[C:7]([OH:11])([CH3:10])([CH3:9])[CH3:8]>CN(C)C1C=CN=CC=1>[O:6]=[C:2]([CH3:1])[CH2:3][C:4]([O:11][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5]
Reactant: C=C1CC(=O)O1
Reactant: CC(C)(C)O
Agent: CN(C)c1ccncc1
Product: CC(=O)CC(=O)OC(C)(C)C
Yield: 98.6 %

Procedure:
To a mixture of tert-butyl alcohol [74.1 g] and 4-(dimethylamino)pyridine [0.61 g] was added dropwise diketene [84.1 g] at 50° to 60° C. in the course of one hour while stirring. The stirring was continued for one further hour at 30° to 50° C. to obtain a colorless and clear reaction mixture, which was subjected to distillation under reduced pressure (b.p. 85° C./20 mmHg) to yield tert-butyl 3-oxobutyrate [156 g] as an oily product. The yield was 98.6%. NMR(CDCl3): δ3.34(2H,s), 2.25(3H,s), 1.47(9H,s)ppm .
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([NH:23][C:24]([NH:26][C:27]3[CH:32]=[C:31]([Cl:33])[CH:30]=[C:29]([Cl:34])[CH:28]=3)=[O:25])[C:14]3[CH:22]=[CH:21][C:17](C(O)=O)=[CH:16][CH:15]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.FC(F)(F)[C:58]([O-])=[O:59].CC1(C)[O:68][C@@H:67]([CH2:69][NH3+:70])[C:66](=[O:71])[O:65]1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([NH:23][C:24]([NH:26][C:27]3[CH:32]=[C:31]([Cl:33])[CH:30]=[C:29]([Cl:34])[CH:28]=3)=[O:25])[C:14]3[CH:22]=[CH:21][C:17]([C:58]([NH:70][CH2:69][C@H:67]([OH:68])[C:66]([OH:65])=[O:71])=[O:59])=[CH:16][CH:15]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: O=C(Nc1cc(Cl)cc(Cl)c1)NC(c1ccc(C(=O)O)cc1)c1ccc(C2=CCCCC2)cc1
Reactant: O=C([O-])C(F)(F)F
Reactant: CC1(C)OC(=O)[C@H](C[NH3+])O1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cc(Cl)cc(Cl)c1)NC(c1ccc(C(=O)NC[C@H](O)C(=O)O)cc1)c1ccc(C2=CCCCC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-[1-(4-Cyclohex-1-enylphenyl)-3-(3,5-dichlorophenyl)ureidomethyl]benzoic acid (130 mg, 0.26 mmol) was dissolved in DMF (2 mL), then EDAC (50 mg, 0.26 mmol) and HOBt (43 mg, 0.32 mmol) were added and the reaction mixture was stirred at room temperature for 1 hour. The above crude (S)-2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylmethylammonium trifluoroacetate was dissolved in DMF (1 mL) and added to the reaction mixture together with diisopropylethylamine (450 mg, 3.5 mmol). The mixture was stirred at room temperature for 16 hours.
Reaction SMILES: [CH2:1]([N:3]([CH2:25][CH3:26])[CH2:4][CH2:5][O:6][CH:7]1[C:12](=O)[CH2:11][CH2:10][N:9]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH2:8]1)[CH3:2].C1(C[NH2:34])C=CC=CC=1.S1C=CC=C1.[H][H]>C(O)C.[Pd].CO>[CH2:1]([N:3]([CH2:25][CH3:26])[CH2:4][CH2:5][O:6][C@H:7]1[C@@H:12]([NH2:34])[CH2:11][CH2:10][N:9]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH2:8]1)[CH3:2]
Reactant: CCN(CC)CCOC1CN(CCCOc2ccc(F)cc2)CCC1=O
Reactant: NCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: c1ccsc1
Solvent: CO
Product: CCN(CC)CCO[C@@H]1CN(CCCOc2ccc(F)cc2)CC[C@@H]1N
Yield: 45 %

Procedure:
A mixture of 8.0 parts of 3-[2-(diethylamino)ethoxy]-1-[3-(4-fluorophenoxy)propyl]-4-piperidinone, 2.5 parts of benzenemethanamine, 1 part of a solution of thiophene in ethanol 4% and 120 parts of methanol was hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) saturated with ammonia, as eluent. The pure fractions were collected and the eluent was evaporated, yielding 3.6 parts (45%) of cis-3-[2-(diethlamino)ethoxy]-1-[3-(4-fluorophenoxy)-propyl]-4-piperidinamine as a residue (intermediate 126).
Reaction SMILES: [Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:29]=2[CH:30]=[CH:31][NH:32]3)[CH:23]=1.[OH2:37]>CC(O)(C)C.C(O)C.C(O)(=O)C.[Zn]>[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:29]=2[CH2:30][C:31](=[O:37])[NH:32]3)[CH:23]=1
Reactant: c1cncc(-c2cccc3[nH]ccc23)c1
Reactant: O
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CC(C)(C)O
Solvent: CC(=O)O
Solvent: CCO
Product: O=C1Cc2c(cccc2-c2cccnc2)N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
Pyridinium tribromide (90% (Aldrich), 5.5 g, 15.3 mmol) was added portion-wise over 10 minutes to a suspension of 4-pyridin-3-yl-1H-indole (1 g, 5.1 mmol) in 2-methyl-2-propanol (30 mL), ethanol (20 mL) and acetic acid (10 mL). The mixture was stirred at room temperature for 2 hours and then acetic acid (50 mL) was added. After stirring for an additional hour, water (0.5 mL) and zinc dust (3.3 g, 51 mmol) were added and stirring was continued for another hour. Residual zinc dust was filtered and washed with methanol. The filtrate was concentrated and the syrupy residue was stirred in water (100 mL) overnight. The solid which formed was filtered, washed with water to remove zinc and pyridine salts and dried under high vacuum to give 1.1 g (100%) of 4-pyridin-3-yl-1,3-dihydro-indol-2-one.