Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[C:15]([C:16]([OH:18])=O)=[C:11]3[CH2:12][CH2:13][O:14][C:10]3=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl.C(Cl)Cl>S(Cl)(Cl)=O>[CH2:12]1[CH2:13][O:14][C:10]2[CH:9]=[CH:8][C:7]3[C:1]4[C:2]([C:16](=[O:18])[C:15]=3[C:11]1=2)=[CH:3][CH:4]=[CH:5][CH:6]=4
Reactant: O=C(O)c1c(-c2ccccc2)ccc2c1CCO2
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: O=C1c2ccccc2-c2ccc3c(c21)CCO3
Temperature: 0 °C
Yield: 77.7 %

Procedure:
A magnetically stirred solution of 2,3-dihydro-5-phenyl-4-benzofurancarboxylic acid (0.730 g, 3.04 mmol) in thionyl chloride (250 mL) was heated at reflux for 3 h. The solvent was removed by concentration in vacuo. The residue was digested with CH2Cl2 (150 mL) and the solution concentrated in vacuo. This process was repeated twice. The residue was digested with CH2Cl2 (260 mL) and treated with anhydrous aluminum chloride (0.40 g, 3.00 mmol). The resultant suspension was stirred for 2 h, poured over ice (250 g), treated with 1 N HCl (250 mL) and CH2Cl2 (250 mL), the layers were separated, and the aqueous layer further extracted with fresh CH2Cl2 (3×200 mL). The combined organic extracts were washed with brine (500 mL), dried (K2CO3), filtered, and concentrated in vacuo to give 0.525 g of 2,10-dihydro-1H-fluoreno[2,1-b]furan-10-one: 1H NMR (300 MHz, CDCl3) δ 3.44 (t, J=8.5 Hz, 2H), 4.65 (t, J=8.5 Hz, 2H), 6.78 (d, J=8 Hz, 1H), 7.18 (dt, J=1.5, 8 Hz, 1H), 7.25 (d, J=8 Hz, 1H), 7.39 (d, J=8 Hz, 1H), 7.41 (dt, J=2, 8 Hz, 1H), 7.57(d, J=8 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15]([OH:17])=[O:16])=[CH:13][N:12]=[C:11]([Cl:18])[CH:10]=2)=[C:4]([Cl:19])[CH:3]=1.C1C(=O)N([Cl:27])C(=O)C1.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15]([OH:17])=[O:16])=[CH:13][N:12]=[C:11]([Cl:18])[C:10]=2[Cl:27])=[C:4]([Cl:19])[CH:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C(O)c1cnc(Cl)cc1Nc1ccc(Br)cc1Cl
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1cnc(Cl)c(Cl)c1Nc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 89.9 %

Procedure:
To a thick suspension of 4-(4-bromo-2-chlorophenylamino)-6-chloronicotinic acid (13.25 g, 36.8 mmol) in 350 ml DMF was added NCS (4.94 g, 37 mmol) and the suspension was stirred at room temperature for 3 days. Since the reaction did not go to completion (NMR control), an additional 1.987 g NCS was added and the mixture was stirred for 18 h, upon which the reaction went to completion. The mixture was poured into a solution of 20 g sodium metabisulfite in H2O (1 l) and the thick suspension was rest for 30 min. It was filtered, and the precipitate was washed with water, then with hexanes and it was dried in oil pump vacuo at 50° C. for 24 hours to obtain the desired compound as a white solid (13.11 g, 90%). 1H-NMR (500 MHz, DMSO-D6): δ=9.90 (s, br, 1H), 8.63 (s, 1H), 7.74 (s, 1H), 7.43-7.42 (dd, 1H), 6.99-6.97 (dd, 1H).
Reaction SMILES: [CH3:1][C@H:2]1[C@H:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[CH2:4][NH:3]1.[CH2:17]([N:20]=[C:21]=[O:22])[CH:18]=[CH2:19]>O1CCCC1.O>[CH3:1][C@H:2]1[C@H:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:14])([F:16])[F:15])[CH:8]=2)[CH2:4][N:3]1[C:21]([NH:20][CH2:17][CH:18]=[CH2:19])=[O:22]
Reactant: C=CCN=C=O
Reactant: C[C@@H]1NC[C@H]1Oc1cccc(C(F)(F)F)c1
Solvent: O
Solvent: C1CCOC1
Product: C=CCNC(=O)N1C[C@@H](Oc2cccc(C(F)(F)F)c2)[C@@H]1C
Reaction time: 16 h
Yield: 8.5 %

Procedure:
A solution of 6 g (0.015 mole) of crude trans-2-methyl-3-[3-(trifluoromethyl)phenoxy]azetidine (56.6%) in 50 ml of tetrahydrofuran was treated with 1.54 g (0.0165 mole) of 2-propenyl isocyanate all at once and stirred under a blanket of nitrogen for 16 hr. The reaction mixture was diluted with water until an oil separated. The oil failed to crystallize and after 7 weeks it was triturated with isopropyl ether (3×25 ml). The combined triturates gave 400 mg of white granular crystals (8.5%), m.p. 55°-57° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:21]=[CH:22][CH:23]=2)[CH2:11][NH:12][CH2:13][CH2:14][CH2:15][N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[CH:5]=[CH:4][N:3]=1.[NH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1>>[CH2:17]([N:16]([CH2:19][CH3:20])[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][C:10]1[CH:9]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:24][CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=3)[N:7]=2)[CH:23]=[CH:22][CH:21]=1)[CH3:18]
Reactant: NCCc1ccc(O)cc1
Reactant: CCN(CC)CCCNCc1cccc(-c2ccnc(Cl)n2)c1
Product: CCN(CC)CCCNCc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Intermediate 64 was coupled with tyramine following procedure F. LC-MS showed the product had the expected M+H+ of 434. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 8.4 (d, 1H), 8.2 (m, 2H), 8.1 (m, 1H), 8.0 (m, 1H), 7.5 (m, 3H), 7.2 (m, 1H), 7.1 (m, 4H), 6.6 (m, 2H), 4.2 (m, 1H), 3.5 (m, 2H), 2.7 (m, 3H), 2.6 (m, 6H), 1.7 (m, 2H), 1.0 (m, 6H).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][CH:8]2[CH2:14][CH2:13][CH2:12][CH2:11][NH:10][CH2:9]2)=[CH:4][C:3]=1[CH3:17].[N:18]1[N:19]([C:23]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:24]=2[C:25](O)=[O:26])[N:20]=[CH:21][CH:22]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][CH:8]2[CH2:14][CH2:13][CH2:12][CH2:11][N:10]([C:25](=[O:26])[C:24]3[CH:28]=[C:29]([CH3:32])[CH:30]=[CH:31][C:23]=3[N:19]3[N:20]=[CH:21][CH:22]=[N:18]3)[CH2:9]2)=[CH:4][C:3]=1[CH3:17]
Reactant: Cc1ccc(-n2nccn2)c(C(=O)O)c1
Reactant: Cc1cc(OCC2CCCCNC2)ccc1F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCCCC(COc3ccc(F)c(C)c3)C2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 1-6 (164 mg, 0.691 mmol) in DMF (4 ml) was treated with 1-7 (154 mg, 0.760 mmol), EDC (159 mg, 0.829 mmol), HOBT (127 mg, 0.829 mmol), and TEA (0.289 ml, 2.073 mmol). After stirring at RT for 30 min, the mixture was diluted with EtOAc, washed with water (3×s) and once with brine. The organic phase was dried over Na2SO4, filtered and concentrated. The crude material was purified by gradient elution on silica gel (0 to 100% EtOAc in Hex) to yield 1-8 as a pale yellow oil. Data for 1-8: LRMS m/z (M+H): 423.1.
Reaction SMILES: C(OC([N:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][N:23]([CH2:25][CH:26]=[CH2:27])[CH3:24])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:25]([N:23]([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19][O:18][C:14]1[CH:13]=[C:12]2[C:17](=[CH:16][CH:15]=1)[NH:8][CH2:9][CH2:10][CH2:11]2)[CH:26]=[CH2:27]
Reactant: C=CCN(C)CCCCOc1ccc2c(c1)CCCN2C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CCN(C)CCCCOc1ccc2c(c1)CCCN2
Temperature: 40 °C
Reaction time: 1 h
Yield: 69.5 %

Procedure:
3.64 g (9.7 mmol) 6-[4-(Allyl-methyl-amino)-butoxy]-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester in 5 ml CH2Cl2 were treated with 3.5 ml TFA at 0° C., and the solution was stirred at 40° C. for 1 h. The solution was concentrated and the residue dissolved in a mixture of a saturated aqueous solution of NaHCO3 and ether. The inorganic phase was extracted with ether and the combined organic phases were washed with water and dried over Na2SO4 to yield 1.85 g (69%) Allyl-methyl-[4-(1,2,3,4-tetrahydro-quinolin-6-yloxy)-butyl]-amine, MS: 275 (MH+).
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[Cl:5][C:6]1[N:7]=[C:8]([N:21]2[CH2:24][C:23](=O)[CH2:22]2)[C:9]2[CH2:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:10]=2[N:11]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[Cl:5][C:6]1[N:7]=[C:8]([N:21]2[CH2:24][C:23]3([O:4][CH2:1][CH2:2][O:3]3)[CH2:22]2)[C:9]2[CH2:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:10]=2[N:11]=1
Reactant: O=C1CN(c2nc(Cl)nc3c2CCC3c2ccccc2)C1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: Clc1nc2c(c(N3CC4(C3)OCCO4)n1)CCC2c1ccccc1

Procedure:
Azetidin-3-one was reacted with Preparation G in the manner of Preparation Gi to afford 1-(2-chloro-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)azetidin-3-one. LC-MS (M+H)+=300.0 A mixture of ethylene glycol (119 μL, 2.135 mmol), 1-(2-chloro-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)azetidin-3-one (320 mg, 1.068 mmol) and 4-methylbenzenesulfonic acid, H2O (20.31 mg, 0.107 mmol) in Benzene (2965 μL) was heated at reflux for 24 h in a Dean-stark apparatus. The resulting mixture was concentrated and purified by Prep-HPLC to afford the title compound. LC-MS (M+H)+=344.0. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.21-7.40 (m, 3 H) 7.15 (d, J=7.63 Hz, 2 H) 4.35-4.53 (m, 4 H) 4.23 (dd, J=9.00, 6.26 Hz, 1 H) 4.03 (s, 4 H) 2.96-3.09 (m, 1 H) 2.80-2.96 (m, 1 H) 2.51-2.70 (m, 1 H) 2.03-2.16 (m, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[NH:5][CH3:6].Br.Br[CH:13]([C:15]1[CH:16]=[C:17]([C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH:18]=[C:19]2[C:24]=1[O:23][C:22]([N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[CH:21][C:20]2=[O:31])[CH3:14]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:5]([CH3:6])[CH:13]([C:15]2[CH:16]=[C:17]([C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH:18]=[C:19]3[C:24]=2[O:23][C:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[CH:21][C:20]3=[O:31])[CH3:14])[CH:7]=[C:8]([F:10])[CH:9]=1
Reactant: CC(Br)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Reactant: CNc1cc(F)cc(Cl)c1
Agent: Br
Product: CC(c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12)N(C)c1cc(F)cc(Cl)c1
Yield: 25.1 %

Procedure:
3-chloro-5-fluoro-N-methylaniline (195 mg, 1.22 mmol) was reacted with 8-(1-bromoethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide hydrobromide (150 mg, 0.31 mmol) using an analogous procedure to the one described in Example 3.03 to give 8-(1-((3-chloro-5-fluorophenyl)(methyl)amino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (38 mg, 25%) as a white solid. Mass Spectrum: M+H+ 488. NMR Spectrum (DMSOd6): 1.55 (d, 3H), 2.61 (s, 3H), 2.93 (bs, 3H), 3.01 (bs, 3H), 3.20-3.27 (m, 2H), 3.33-3.37 (m partially hidden by H2O, 2H), 3.42-3.48 (m, 2H), 3.49-3.55 (m, 2H), 5.55 (s, 1H), 5.61 (q, 1H), 6.61 (d, 1H), 6.66 (d, 1H), 6.75 (s, 1H), 7.71 (d, 1H), 7.89 (d, 1H).
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:16]=[C:17]([N:26](C)[C:27](=O)C)[CH:18]=[C:19]([N:21](C(=O)C)[CH3:22])[CH:20]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=O)C.[ClH:31]>[OH-].[Na+]>[ClH:31].[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:16]=[C:17]([NH:26][CH3:27])[CH:18]=[C:19]([NH:21][CH3:22])[CH:20]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2cc(N(C)C(C)=O)cc(N(C)C(C)=O)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CNc1cc(NC)cc(NS(=O)(=O)c2ccc(N)cc2)c1
Yield: 74 %

Procedure:
0.113 g (0.00026 mol) of N-[3-(4-acetylamino-phenyl-sulfonylamino)-5-(acetyl-methyl-amino)-phenyl]-N-methyl-acetamide was dissolved in 10 ml of 1N NaOH and boiled at reflux for 2 hours. The mixture was neutralized with 1N HCl, extracted with ethyl acetate and the organic phase was dried over sodium sulfate. After removal of the solvent the residue was dissolved in 4 ml of methanol and treated with 3 ml of 2M HCl. After the addition of 7-8 ml of ethyl acetate the product separated out slowly. It was filtered off and dried in a vacuum. There was obtained 0.085 g (74%) of 4-amino-N-(3,5-bis-methylamino-phenyl)-benzenesulfonamide hydrochloride (1:2.6) as a pink coloured amorphous solid. MS (ISN): me/e=305 (C14H17N4O2S-).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]1[S:13][C:12](=[O:14])[NH:11][N:10]=1.[CH:15]1([C:18]([CH2:20]Br)=[O:19])[CH2:17][CH2:16]1>O1CCOCC1>[CH:15]1([C:18](=[O:19])[CH2:20][N:11]2[N:10]=[C:9]([O:8][CH3:7])[S:13][C:12]2=[O:14])[CH2:17][CH2:16]1
Reactant: COc1n[nH]c(=O)s1
Reactant: O=C(CBr)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1nn(CC(=O)C2CC2)c(=O)s1
Reaction time: 20 h

Procedure:
55 g of potassium carbonate are added to a solution of 26.4 g of 5-methoxy-3H-[1,3,4]-thiadiazol-2-one in 700 ml of dioxane and the reaction mixture is heated to 60°. Then 35 g of bromomethyl cyclopropyl ketone are added dropwise within a short period of time and the reaction mixture is stirred at 70° for 20 hours and then, at 20°, is filtered over Celite. The filtrate is concentrated by evaporation. The residue is stirred with diisopropyl ether and filtered with suction. 41 g of crystals of the title compound having a melting point of 98°-100° are thus obtained.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[ClH:6].[C:7]1([C:13]2([CH2:19][C:20](=O)[CH3:21])[CH:18]=[CH:17][CH2:16][CH:15]=[CH:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([BH3-])#N.[Na+]>CO>[ClH:6].[CH3:21][CH:20]([N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[CH2:19][C:13]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:18]=[CH:17][CH2:16][CH:15]=[CH:14]1
Reactant: CCNCC
Reactant: CC(=O)CC1(c2ccccc2)C=CCC=C1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCN(CC)C(C)CC1(c2ccccc2)C=CCC=C1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To 27.5 ml. (about 6 equivalents) of diethylamine and 10 g. of molecular sieve 3A in 200 ml. of methanol are added at 0° C. 17.6 ml. of 5 N methanolic hydrochloric acid (2 equivalents) and then 9.4 g. of (1-phenyl-2,5-cyclohexadien-1-yl)-2-propanone in a small amount of methanol and finally 1.95 g. (0.7 equivalents) of sodium cyanoborohydride. The mixture is stirred at room temperature for 5 days and then worked-up in exactly the same manner as described in Example 16. There is obtained an oily residue which is chromatographed on a silica gel thick-layer plate with ethyl acetate/triethylamine (15:1). Two products are scratched off and eluted with methylene chloride/methanol (4:1). The product of RF 0.32 is α-methyl-N-ethyl-1-phenyl-2,5-cyclohexadien-1-ethylamine. The other product (RF 0.54) is the desired product, namely, α-methyl-N,N-diethyl-1-phenyl-2,5-cyclohexadien-1-ethylamine. This is converted as usual into the hydrochloride and recrystallized from methylene chloride/ether. According to melting point and mixed melting point, the product is identical with that obtained in accordance with Example 18.
Reaction SMILES: [CH3:1][C:2]([CH:4]=O)=O.[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([NH2:16])[CH:10]=1)([O-:8])=[O:7].C(O)(C)C>O>[CH3:1][C:2]1[CH:4]=[N:16][C:11]2[C:12](=[CH:13][CH:14]=[C:9]([N+:6]([O-:8])=[O:7])[CH:10]=2)[N:15]=1
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Reactant: CC(=O)C=O
Solvent: CC(C)O
Solvent: O
Product: Cc1cnc2cc([N+](=O)[O-])ccc2n1

Procedure:
15.3 ml (0.1 mol) of a 40% w/v aqueous solution of pyruvic aldehyde were added to a suspension of 15.3 g (0.1 mol) of 4-nitro-1,2-phenylenediamine in 800 ml of a 1:1 by volume mixture of isopropanol and water, and the resulting mixture was heated under reflux for 3 hours. At the end of this time, the mixture was cooled, and the crystals which had precipitated were collected by filtration and recrystallized from ethanol. The filtrate was concentrated by distillation under reduced pressure, and the concentrate was triturated with ethanol to cause crystallization. A total of 15.5 g of 2-methyl-6-nitroquinoxaline were obtained as crude yellow-brown crystals. 12.5 g (0.066 mol) of this crude 2-methyl-6-nitroquinoxaline were suspended in 200 ml of toluene, and 13.2 g of selenium dioxide were added to the suspension. The resulting mixture was then heated under reflux for 4 hours. It was then cooled, after which insoluble materials were filtered off and the filtrate was freed from the solvent by distillation under reduced pressure. The residue was mixed with 400 ml of acetone. 420 ml (0.13 mol) of a 5% aqueous solution of potassium permanganate were then slowly added at room temperature and with stirring to the resulting mixture, which was then stirred at room temperature for 2.5 hours. At the end of this time, insoluble materials were filtered off and the filtrate was freed from acetone by distillation under reduced pressure. The aqueous layer thus obtained was washed with diethyl ether and then acidified with concentrated hydrochloric acid to precipitate crystals. These crystals were dissolved in a 1N aqueous solution of sodium hydroxide, and insoluble materials were filtered off. The filtrate was again acidified with concentrated hydrochloric acid to precipitate crystals, which were recrystallized from a mixture of acetone and diethyl ether, to give 9.9 g of the title compound as pale yellow-brown crystals, melting at 208°-210° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[C:5]#[N:6].[F:13][C:14]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:15]=1[NH2:16].C(=O)([O-])[O-].[K+].[K+].O>C(OCC)(=O)C>[F:13][C:14]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:15]=1[NH:16][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[C:5]#[N:6]
Reactant: N#Cc1ccc([N+](=O)[O-])c(Cl)c1
Reactant: Nc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1ccc([N+](=O)[O-])c(Nc2ccc(F)cc2F)c1
Temperature: 200 °C
Reaction time: 5 h
Yield: 46.4 %

Procedure:
A mixture of 3-chloro-4-nitrobenzonitrile (5 g), 2,4-difluoroaniline (17.7 g), cupric oxide (0.5 g) and potassium carbonate (4.5 g) was stirred for 5 hours at 200° C. To the mixture were added water (100 ml) and ethyl acetate (200 ml). The organic layer was separated, washed with 3N hydrochloric acid and water, dried, and evaporated to dryness. The oil (10 g) was purified by column chromatography on silica gel (200 g) eluting with toluene to give red crystals of 3-(2,4-difluorophenylamino)-4-nitrobenzonitrile (3.5 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[C:6]([CH3:8])([CH3:7])[O:5][BH:4][O:3]1.Br[C:11]1[C:19]2[S:18][CH:17]=[CH:16][C:15]=2[C:14]([F:20])=[CH:13][CH:12]=1.C(N(CC)CC)C>O1CCOCC1.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>[F:20][C:14]1[C:15]2[CH:16]=[CH:17][S:18][C:19]=2[C:11]([B:4]2[O:5][C:6]([CH3:8])([CH3:7])[C:2]([CH3:9])([CH3:1])[O:3]2)=[CH:12][CH:13]=1
Reactant: CC1(C)OBOC1(C)C
Reactant: Fc1ccc(Br)c2sccc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC1(C)OB(c2ccc(F)c3ccsc23)OC1(C)C
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 53 %

Procedure:
4,4,5,5-Tetramethyl-1,3,2-dioxaborolane (768 mg, 6 mmole) was added drop wise to a solution of 7-bromo-4-fluoro-1-benzothiophene BL (462 mg, 2.0 mmole) and triethylamine (607 mg, 6 mmole) in 12 mL dioxane. The solution was bubbling with argon with stirring for 10 min. PdCl2(PPh3)2 (70 mg, 0.01 mmole) was added to the reaction and continued to bubbling argon for another 10 min. The reaction was heated to 80° C. for 4 hr and cooled down to 25° C. Dioxane was removed in vacuo the residue dissolved in 60 mL Et2O washed with water (60 mL), brine (20 mL), dried (Na2SO4), filtered, concentrated in vacuo, and purified by CombiFlash silica gel column chromatography (eluted with Hexane/EtOAc stepping gradient 100:0 to 80:20) to yield 295 mg (53%) of product.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([C:14]2[CH:18]=[C:17]([CH2:19][CH2:20][CH:21]=O)[O:16][N:15]=2)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH2:23]([N:30]1[CH2:35][CH2:34][N:33]([CH2:21][CH2:20][CH2:19][C:17]2[O:16][N:15]=[C:14]([C:10]3[CH:11]=[CH:12][CH:13]=[C:8]([O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:9]=3)[CH:18]=2)[CH2:32][CH2:31]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=CCCc1cc(-c2cccc(Oc3ccccc3)c2)no1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: c1ccc(CN2CCN(CCCc3cc(-c4cccc(Oc5ccccc5)c4)no3)CC2)cc1
Yield: 95.1 %

Procedure:
About 2 min after dissolving 3-[3-(3-phenoxypheny)isoxazol-5-yl]propanal (20 mg, 0.07 mmol) and 1-benylpiperazine (11.9, 0.07 mmol) in 2 mL of dry methylene chloride, were added NaBH(OAc)3 (43 mg, 0.20 mmol) and molecular sieves (5 beads). The reaction mixture was reacted for 4.5 hr and followed the same processes as in Example 1 to obtain 30.2 mg (97.6%) of the target compound.
Reaction SMILES: [C:1]([N:3]=[C:4]([NH:7][CH:8]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[Cl:17])[CH3:9])[CH2:5][CH3:6])#[N:2].[H-].[Na+].I[CH3:21]>CN(C)C=O>[C:1]([N:3]=[C:4]([N:7]([CH:8]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[Cl:17])[CH3:9])[CH3:21])[CH2:5][CH3:6])#[N:2]
Reactant: CI
Reactant: CCC(=NC#N)NC(C)c1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(=NC#N)N(C)C(C)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.00 g of N′-cyano-N-[1-(2,4-dichlorophenyl)ethyl]propaneimidamide was dissolved in 25 ml of dimethylformamide, and 0.16 g of sodium hydride (60% pure in paraffin oil) was added at room temperature. After 30 minutes, 0.63 g of iodomethane was added. The mixture was stirred at room temperature overnight and, after removal of the solvent, purified chromatographically. This gave 0.86 g of N′-cyano-N-[1-(2,4-dichlorophenyl)ethyl]-N-methylpropaneimidamide of logP 2.80 and m.p. 148° C.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1.C(O)(=O)C>ClCCCl>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Nc1ccccn1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Solvent: ClCCCl
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(CNc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.6 %

Procedure:
To a solution of 4-nitrobenzaldehyde (3.02 g) and 2-aminopyridine (1.88 g) in 1,2-dichloroethane (70 ml) were added triacetoxy sodium boro hydride (5.93 g) and acetic acid (1.14 ml), and the mixture was stirred under nitrogen atmosphere at room temperature for 2 hours and concentrated. To the residue was added sodium bicarbonate solution, and the mixture was extracted with ethyl acetate, washed with brine, dried (anhydrous magnesium sulfate) and concentrated. The residue was purified with silica gel column chromatography (ethyl acetate/hexane=1/1), and to the purified materials were added ethyl acetate/diethylether and 1N hydrochloric acid. The aqueous layer was extracted and washed with diethylether, and to the mixture was added sodium carbonate. The mixture was extracted with ethyl acetate, and the extract was dried (anhydrous magnesium sulfate), concentrated and recrystallized from ethyl acetate/hexane to give 2-[(4-nitrophenyl)methylamino]pyridine (1.63 g) as pale yellow crystals.
Reaction SMILES: C(O[C:9]([C:11]1[N:12]=[C:13]([CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[NH:14][C:15]=1[CH2:16][O:17][C:18]12[CH2:27][CH:22]3[CH2:23][CH:24]([CH2:26][CH:20]([CH2:21]3)[CH2:19]1)[CH2:25]2)=[O:10])C1C=CC=CC=1.[CH2:34]([O:41][C:42](=[O:50])[C:43]1[CH:48]=[CH:47][CH:46]=[C:45]([NH2:49])[CH:44]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH2:34]([O:41][C:42](=[O:50])[C:43]1[CH:48]=[CH:47][CH:46]=[C:45]([NH:49][C:9]([C:11]2[N:12]=[C:13]([CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[NH:14][C:15]=2[CH2:16][O:17][C:18]23[CH2:27][CH:22]4[CH2:21][CH:20]([CH2:26][CH:24]([CH2:23]4)[CH2:25]2)[CH2:19]3)=[O:10])[CH:44]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: O=C(OCc1ccccc1)c1nc(C2CCCCC2)[nH]c1COC12CC3CC(CC(C3)C1)C2
Reactant: Nc1cccc(C(=O)OCc2ccccc2)c1
Product: O=C(OCc1ccccc1)c1cccc(NC(=O)c2nc(C3CCCCC3)[nH]c2COC23CC4CC(CC(C4)C2)C3)c1
Yield: 65.3 %

Procedure:
The product of step d (0.76 g, 2.122 mmol) was reacted with 3-amino-benzoic acid benzyl ester (0.48 g, 2.12 mmol) according to the procedure of Example 20, step d. The crude material was purified by flash chromatography (silica, DCM/ethyl acetate 98:2, then 95:5) to afford colourless foam (786 mg, 65.5%). 1H NMR (300 MHz, CDCl3) 9.50 and 8.90 (1H, 2× br s), 8.15 (2H, m), 7.81 (1H, d), 7.40 (6H, m), 5.38 (2H, s), 4.98 (2H, br s), 2.71 (1H, m), 2.16 (3H, br s), 2.00 (2H, m), 1.85-1.24 (20H, m).