Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[N:3][N:4]=[C:5](Cl)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Br:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1.CN(C)C1C=CC=CC=1>C1(C)C=CC=CC=1>[Br:19][C:20]1[CH:26]=[CH:25][C:23]([N:24]2[C:5]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)=[N:4][N:3]=[C:2]2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:22][CH:21]=1
Reactant: Nc1ccc(Br)cc1
Reactant: ClC(=NN=C(Cl)c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CN(C)c1ccccc1
Product: Brc1ccc(-n2c(-c3ccccc3)nnc2-c2ccccc2)cc1
Temperature: 135 °C
Reaction time: 5 h

Procedure:
4.5 g (16 mmol) of 1,2-bis(chloro(phenyl)methylene)hydrazine, 2.0 g (16 mmol) of 4-bromoaniline, and 30 mL of N,N-dimethylaniline were put into a 100 mL three-neck flask, and nitrogen substitution was performed on the contents of the flask. The mixture was stirred at 135° C. for 5 hours. After the reaction, a solid was precipitated out with the reactive solution being added to approximately 100 mL of 1 N diluted hydrochloric acid and the mixture being stirred for 30 minutes. Suction filtration was performed on the precipitated solid, and a solid was obtained. The obtained solid was dissolved in toluene and washed with water and a saturated sodium carbonate solution, in the order given. Magnesium sulfate was added to an organic layer, and the mixture was dried. Suction filtration was performed on the mixture to remove the magnesium sulfate, and thus a filtrate was obtained. The solid, which was obtained by condensation of the obtained filtrate, was recrystallized with a mixed solvent of ethanol and hexane, so that 2.3 g of a powdery white solid, which was the object of the synthesis, was obtained at a yield of 38%.
Reaction SMILES: [CH3:1][N-:2][CH3:3].[Li+].[F:5][C:6]([F:12])([F:11])[S:7]([O-:10])(=[O:9])=[O:8].[CH3:13][N:14]([C+:16]([N:18]([CH3:20])[CH3:19])Cl)[CH3:15]>C(#N)C>[F:5][C:6]([F:12])([F:11])[S:7]([O-:10])(=[O:9])=[O:8].[CH3:13][N:14]([CH3:15])[C:16](=[N+:2]([CH3:3])[CH3:1])[N:18]([CH3:20])[CH3:19]
Reactant: CN(C)[C+](Cl)N(C)C
Reactant: C[N-]C
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Li+]
Solvent: CC#N
Product: CN(C)C(N(C)C)=[N+](C)C
Reaction time: 12 h
Yield: 96.6 %

Procedure:
0.225 g (4.41 mmol) of lithium dimethylamide are added at room temperature to 1.26 g (4.42 mmol) of bis(dimethylamino)chlorocarbenium trifluoromethanesulfonate in 20 ml of acetonitrile. The reaction mixture is stirred for 12 hours, and LiCl is subsequently filtered off. The solvent is distilled off, and the residue is washed with 20 ml of diethyl ether and subsequently dried under reduced pressure (8.0 Pa), giving 1.25 g of hexamethylguanidinium trifluoromethanesulfonate, corresponding to a yield of 96.7%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:18])[CH2:9][C:10]2[NH:11][CH:12]=[C:13]([CH:15]([CH3:17])[CH3:16])[N:14]=2)=[CH:4][CH:3]=1.[C:19](O)(=[O:22])[C:20]#[CH:21].N1(C(N2C=CN=C2)=O)C=CN=C1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:9]2[CH:21]=[CH:20][C:19](=[O:22])[N:11]3[CH:12]=[C:13]([CH:15]([CH3:16])[CH3:17])[NH:14][C:10]=23)=[O:18])=[CH:4][CH:3]=1
Reactant: C#CC(=O)O
Reactant: CC(C)c1c[nH]c(CC(=O)c2ccc(F)cc2)n1
Agent: O=C(n1ccnc1)n1ccnc1
Product: CC(C)c1cn2c(=O)ccc(C(=O)c3ccc(F)cc3)c2[nH]1

Procedure:
The compound is prepared as described in example 10 with 65 mg (0.26 mmol) of 1-(4-fluorophenyl)-2-(4-isopropyl-1H-imidazol-2-yl)ethanone (example XXX), 27.7 mg (0.40 mmol) of propiolic acid and 77 mg (0.48 mmol) of 1-(1H-imidazol-1-yl-carbonyl)-1H-imidazole.
Reaction SMILES: C(=O)([O-])O[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:11](=O)([O:14]C1C=CC=CC=1)[O:12][CH3:13].C(=O)(OC1C=CC=CC=1)OC1C=CC=CC=1>>[C:11]([O:12][CH3:13])(=[O:14])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)Oc1ccccc1
Reactant: O=C([O-])Oc1ccccc1
Agent: O=C(Oc1ccccc1)Oc1ccccc1
Product: COC(=O)c1ccccc1
Yield: 41 %

Procedure:
The same procedures as in Example 1 were used, except that the reaction temperature of the phenyl carbonate preparation step was 210° C. As a result, the yield of methyl phenyl carbonate was 17%, and the yield of diphenyl carbonate was 24%. Furthermore, at the same time, methyl benzoate was produced as a by-product with a yield of 41% (the yield was based on phenyl benzoate).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[F:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1.C([O-])(=O)C.[Na+].O>C(O)C>[F:8][C:9]1[CH:15]=[CH:14][C:12]([NH:13][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:11][CH:10]=1
Reactant: Nc1ccc(F)cc1
Reactant: CCOC(=O)CBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CNc1ccc(F)cc1
Temperature: 80 °C

Procedure:
Ethyl bromoacetate (8.09 g, 48.4 mmol) was slowly added to a solution of 4-fluoroaniline (5.38 g, 48.4 mmol) and sodium acetate (5.16 g, 62.9 mmol) in ethanol (62 mL) and the mixture was heated at 80° C. for 2 h. Water was added and the reaction was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (0-20% EtOAc in hexanes) to afford ethyl 2-((4-fluorophenyl)amino)acetate (1).
Reaction SMILES: [ClH:1].Cl.[N:3]1([C:8]2[CH:17]=[CH:16][C:11]([O:12][CH2:13][CH2:14][NH2:15])=[CH:10][CH:9]=2)[CH:7]=[CH:6][N:5]=[CH:4]1.[OH-].[Na+].[O:20]1[CH2:22][CH:21]1[CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])=[CH:27][CH:26]=1>CO.O>[ClH:1].[OH:20][CH:21]([CH2:22][NH:15][CH2:14][CH2:13][O:12][C:11]1[CH:16]=[CH:17][C:8]([N:3]2[CH:7]=[CH:6][N:5]=[CH:4]2)=[CH:9][CH:10]=1)[CH2:23][O:24][C:25]1[CH:26]=[CH:27][C:28]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])=[CH:29][CH:30]=1
Reactant: CS(=O)(=O)Nc1ccc(OCC2CO2)cc1
Reactant: NCCOc1ccc(-n2ccnc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CS(=O)(=O)Nc1ccc(OCC(O)CNCCOc2ccc(-n3ccnc3)cc2)cc1
Reaction time: 0.25 h

Procedure:
To a solution of 2.3 g (0.008 mol) of 2-[4-(1H-imidazol-1-yl)phenoxy]ethanamine dihydrochloride in 100 ml of methanol add a solution of 0.66 g of sodium hydroxide in 5 mL of water. Stir for 15 minutes. Add 2.0 g (0.008 mol) of N-[4-(oxiranylmethoxy)phenyl]methanesulfonamide and reflux for 16 h. Monitor the progress of the reaction by thin-layer chromatography on silica gel (methylene chloride, methanol, triethylamine, 84:15:1). Remove the solvent in vacuo. Chromatograph the oil on 350 g of silica gel using amixture of methylene chloride:methanol:triethylamine (94:5:1). Combine the fractions containing residue and remove the solvent in vacuo. Dissolve theresidue in methanol and add a solution of hydrogen chloride in methanol. Remove the solvent in vacuo. Recrystallize the salt from acetonitrile:methanol to obtain the title compound.
Reaction SMILES: Cl.[C:2]1([CH3:10])[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.Cl[CH2:12][C:13]([NH:15][CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:14].C(N(CC)CC)C>C(O)C>[C:2]1([CH3:10])[CH:7]=[CH:6][C:5]([N:8]([CH2:12][C:13]([NH:15][CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:14])[NH2:9])=[CH:4][CH:3]=1
Reactant: O=C(CCl)NCC1CCCCC1
Reactant: Cc1ccc(NN)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1ccc(N(N)CC(=O)NCC2CCCCC2)cc1
Yield: 100 %

Procedure:
p-Tolylhydrazine hydrochloride (500 mg, 3.16 mmol), 2-chloro-N-(cyclohexylmethyl)acetamide (600 mg, 3.16 mmol), triethylamine (1.31 ml, 9.4 mmol) and ethanol (20 ml) were stirred together to obtain 870 mg of 2-(1-p-tolylhydrazinyl)-N-(cyclohexylmethyl)acetamide. The intermediate (870 mg, 3.15 mmol) and N-methyl-4-piperidone hydrochloride (471 mg, 3.16 mmol) were taken in ethanolic HCl (20 ml) and stirred at RT for 15 min, after which the solvent was removed in vacuo. The reaction mixture obtained was taken in ethanol and heated at 90 deg C. for 14 h. After completion of the reaction (monitored by LCMS), the reaction mixture was concentrated to dryness and basified with aqueous saturated sodium bicarbonate, extracted with ethyl acetate. The organic layer was separated, dried over sodium sulfate and concentrated to obtain the crude product which was purified by silica gel chromatography (Eluent: 10% MeOH in dichloromethane) to yield 70 mg (yield: 6.27%) of N-(cyclohexylmethyl)-2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)acetamide. The freebase obtained (70 mg, 0.19 mmol) was dissolve d in THF (10.0 ml), oxalic acid (24 mg, 0.19 mmol) in THF (10.0 ml) was added slowly, the mixture was stirred at RT for 20 min and the solid obtained was filtered, washed with ether and dried to get 70 mg (yield: 80.4%) of N-(cyclohexylmethyl)-2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)acetamide as oxalate salt. 1H NMR (DMSO-D2O) OXALATE SALT 8.3-8.2 (t, 1H), 7.30 (d, 1H), 7.2 (s, 1H), 7.0-6.9 (d, 1H), 4.70 (s, 2H), 4.3 (bs, 2H), 3.80-3.2 (m, 4H), 3.1 (bs, 2H), 2.90 (s, 3H), 2.30 (s, 3H), 1.70-1.50 (m, 5H), 1.40-1.30 (m, 1H), 1.20-1.0 (m, 4H), 0.90-0.70 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6]4=[C:7]([C:17](=[O:27])[C:18]([CH2:20][C:21]5[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=5)=[CH:19][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([OH:16])[CH:10]=3.Cl[CH2:29][C:30]1[CH:31]=[N:32][CH:33]=[C:34]([CH3:36])[CH:35]=1.CC1C=NC=C(C)C=1>>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6]4=[C:7]([C:17](=[O:27])[C:18]([CH2:20][C:21]5[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=5)=[CH:19][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([O:16][CH2:29][C:30]1[CH:31]=[N:32][CH:33]=[C:34]([CH3:36])[CH:35]=1)[CH:10]=3
Reactant: O=c1c(Cc2cccnc2)cn2c3c(cc(O)cc13)Sc1ccc(Br)cc1-2
Reactant: Cc1cncc(CCl)c1
Agent: Cc1cncc(C)c1
Product: Cc1cncc(COc2cc3c4c(c2)c(=O)c(Cc2cccnc2)cn4-c2cc(Br)ccc2S3)c1
Yield: 10 %

Procedure:
According to Example 34, the compound (150 mg) produced in Example 37 was reacted with 3-chloromethyl-5-methylpyridine synthesized from 3,5-dimethylpyridine (500 mg) to obtain the title compound (180 mg; 10%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9](O)=[O:10])=[CH:5][CH:4]=1.C(Cl)(=O)C([Cl:17])=O>ClC(Cl)C.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([Cl:17])=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(C=CC(=O)O)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CC(Cl)Cl
Solvent: CN(C)C=O
Product: COc1ccc(C=CC(=O)Cl)cc1
Reaction time: 0.5 h

Procedure:
p-Methoxycinnamic acid (52.7 g=0.45 mole) was slurried under N2 in 500 mL of sieve-dried dichloroethane. Oxalyl chloride (146.0 gm=1.15 moles) was added in one portion followed by three drops of DMF. Complete solution was achieved in 30 minutes. The solution was stirred an additional 2 hours, and then the dichloroethane containing excess oxalyl chloride was removed on a 50° C. rotary evaporator. Fresh dichloroethane was twice added to the residue and removed on the rotary evaporator. The amber oil was used without purification. Yield 90.4 gm.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH:9]([CH:13]=[CH2:14])[C:10]([OH:12])=[O:11])=[O:7])=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1.S(Cl)(Cl)=O.[CH3:25]O>>[F:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH:9]([CH:13]=[CH2:14])[C:10]([O:12][CH3:25])=[O:11])=[O:7])=[C:4]([C:17]([F:18])([F:19])[F:20])[CH:3]=1
Reactant: CO
Reactant: C=CC(NC(=O)c1ccc(F)cc1C(F)(F)F)C(=O)O
Solvent: O=S(Cl)Cl
Product: C=CC(NC(=O)c1ccc(F)cc1C(F)(F)F)C(=O)OC
Temperature: 25 °C
Reaction time: 72 h
Yield: 100 %

Procedure:
25 g (90.3 mmol) of 2-(4-fluoro-2-trifluoromethylbenzoylamino)but-3-enoic acid were dissolved in methanol, and 9.9 g (82.8 mmol) of thionyl chloride were added dropwise over a period of 30 min. The solution was stirred at RT for three days. Removal of the solvent gave 25.2 g of product (100% of theory) of the title compound as a colorless solid.
Reaction SMILES: C(O[C:4]([C:6]1[C:14]2[C:9](=[CH:10][N:11]=[CH:12][CH:13]=2)[NH:8][C:7]=1[NH2:15])=[O:5])C.C([O-])=O.[NH4+].Cl.[CH:21]([NH2:23])=O>>[N:15]1[C:7]2[NH:8][C:9]3[CH:10]=[N:11][CH:12]=[CH:13][C:14]=3[C:6]=2[C:4]([OH:5])=[N:23][CH:21]=1
Reactant: NC=O
Reactant: CCOC(=O)c1c(N)[nH]c2cnccc12
Agent: Cl
Agent: O=C[O-]
Agent: [NH4+]
Product: Oc1ncnc2[nH]c3cnccc3c12
Temperature: 170 °C

Procedure:
A mixture of 2-Amino-1H-pyrrolo[2,3-c]pyridine-3-carboxylic acid ethyl ester (1.80 g, 8.8 mmol) and ammonium formate (0.62 g, 9.8 mmol) in formamide (10 mL) was heated at 170° C. for 18 hours. 1 M HCl was added to the cooled reaction mixture and the resulting suspension was filtered to remove insolubles. The filtrate was then adjusted to pH 7 with saturated sodium bicarbonate solution. The resulting precipitate was collected by filtration and dried to a constant weight in a vacuum oven to give the title compound (0.74 g, 4.0 mmol). 1H NMR (DMSO) δ 12.5 (s, br), 8.83 (1H, s), 8.37 (1H, d, J=4.0), 8.26 (1H, s), 7.89 (1H, d, J=4.0); LC-MS (1) Rt 0.75 min; m/z 185 (ES−).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][NH:5][CH2:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=1.[CH2:18]([N:22]=[C:23]=[O:24])[CH2:19][CH2:20][CH3:21].C(=O)([O-])O.[Na+]>C(Cl)Cl.C(Cl)(Cl)Cl>[CH2:18]([NH:22][C:23]([N:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:15][CH:16]=1)[CH2:4][CH2:3][N:2]([CH3:1])[CH3:17])=[O:24])[CH2:19][CH2:20][CH3:21]
Reactant: COC(=O)c1ccc(CNCCN(C)C)cc1
Reactant: CCCCN=C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCCCNC(=O)N(CCN(C)C)Cc1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92 %

Procedure:
To a solution of methyl 4-[[[2-(dimethylamino)ethyl]amino]methyl]benzoate (compound obtained in Reference Example 36(1), 200 mg) in methylene chloride (4 mL) is added n-butyl isocyanate (143 μL) and the mixture is stirred at room temperature for 4 hours. The reaction mixture is diluted with chloroform (5 mL) and thereto is added a saturated sodium hydrogencarbonate solution (10 mL). After stirring, the organic layer is separated and concentrated. The resultant crude product is purified by column chromatography on silica gel (Solvent; chloroform:methanol=100:0→90:10) to give methyl 4-[[N-(butylcarbamoyl)-N-[2-(dimethylamino)ethyl]amino]methyl]-benzoate (261 mg, yield; 92%) as a pale yellow oil. MS (APCI) m/z: 336 [M+H]+
Reaction SMILES: [CH3:1][N:2]([C:16]1[S:17][CH:18]=[CH:19][N:20]=1)[S:3]([C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12]C)=[O:11])=[CH:8][CH:7]=1)(=[O:5])=[O:4].O1CCOCC1.[OH-].[Na+].Cl>C(OCC)(=O)C>[CH3:1][N:2]([C:16]1[S:17][CH:18]=[CH:19][N:20]=1)[S:3]([C:6]1[CH:7]=[CH:8][C:9]([C:10]([OH:12])=[O:11])=[CH:14][CH:15]=1)(=[O:4])=[O:5]
Reactant: COC(=O)c1ccc(S(=O)(=O)N(C)c2nccs2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CN(c1nccs1)S(=O)(=O)c1ccc(C(=O)O)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 90.1 %

Procedure:
To methyl 4-[methyl(thiazol-2-yl)sulfamoyl]benzoate (4.22 g, 13.5 mmol) and 1,4-dioxane (32 mL) was added aq. NaOH (62 mL of 2.5 M, 155 mmol) and the mixture was stirred at 50° C. for 1 hour. The reaction mixture was cooled to room temperature. Ethyl acetate (135 mL) was added before acidifying it to pH 1 with HCl (37%). The organic and aqueous layers were separated. The aqueous layer was extracted with ethyl acetate (1×50 mL). The organic layers were dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure to yield 4-[methyl(thiazol-2-yl)sulfamoyl]benzoic acid (3.63 g, 87%) as a white solid. ESI-MS m/z calc. 298.0, found 299.1 (M+1)+; Retention time: 1.31 minutes (3 minutes run). 1H NMR (400 MHz, DMSO) δ 13.56 (s, 1H), 8.14 (d, J=8.6 Hz, 2H), 7.92 (d, J=8.5 Hz, 2H), 7.46 (d, J=3.6 Hz, 1H), 7.44 (d, J=3.6 Hz, 1H), 3.39 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([C:12]([OH:14])=O)[C:9]([OH:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1.P(Cl)(Cl)Cl>O>[Br:1][C:2]1[CH:11]=[C:10]([C:12]([NH:21][C:20]2[CH:22]=[CH:23][C:17]([Cl:16])=[CH:18][CH:19]=2)=[O:14])[C:9]([OH:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: O=C(O)c1cc(Br)c2cccnc2c1O
Reactant: Nc1ccc(Cl)cc1
Solvent: ClP(Cl)Cl
Solvent: O
Product: O=C(Nc1ccc(Cl)cc1)c1cc(Br)c2cccnc2c1O
Reaction time: 8 h
Yield: 52.2 %

Procedure:
A solution of 5-bromo-8-hydroxyquinoline-7-carboxylic acid (2.68 g) of Preparation 2 and 4-chloroaniline (1.28 g) in 250 mL xylenes is heated to reflux. To this is added dropwise PCl3 (0.69 g). Refluxing is continued overnight. The reaction is then cooled and water is added to destroy excess PCl3. The resulting solid is collected, washed with water and dried. The crude product is recrystallized from EtOAc/hexanes to yield 1.97 g of the title product as an orange solid.
Reaction SMILES: [C:1]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11]([OH:13])=O)=[CH:7][C:6]=1[Cl:16])([CH3:4])([CH3:3])[CH3:2].[Cl-].ClC1N(C)CC[NH+]1C.Cl.[NH2:27][C@@H:28]([C:30]1[CH:35]=[CH:34][C:33]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])=[CH:32][CH:31]=1)[CH3:29]>C(N(CC)CC)C>[C:1]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11]([NH:27][C@@H:28]([C:30]2[CH:31]=[CH:32][C:33]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])=[CH:34][CH:35]=2)[CH3:29])=[O:13])=[CH:7][C:6]=1[Cl:16])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1ccc(OCC(=O)O)cc1Cl
Reactant: C[C@@H](N)c1ccc(NS(C)(=O)=O)cc1
Agent: CN1CC[NH+](C)C1Cl
Agent: Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Product: C[C@@H](NC(=O)COc1ccc(C(C)(C)C)c(Cl)c1)c1ccc(NS(C)(=O)=O)cc1
Yield: 41.5 %

Procedure:
(4-tert-Butyl-3-chlorophenoxy)acetic acid (121 mg, 0.50 mmol), 2-chloro-1,3-dimethylimidazolinium chloride (CDI) (86 mg, 0.53 mmol), triethylamine (0.5 ml) and N-{4-[(1R)-1-aminoethyl]phenyl}methanesulfonamide hydrochloride (125 mg, 0.50 mmol, Bioorganic & Medicinal Chemistry Letters, 2004, 14, 1751–1755) were treated in the same procedure described in Example 2(b) to give 91 mg (40% yield) of the titled compound as a white solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:10]=[N:9][C:8]2[O:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[O:14][C:7]=2[CH:6]=1)=O.O1CCCC1CO.[BH4-].[Na+]>O>[N:9]1[C:8]2[O:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[O:14][C:7]=2[CH:6]=[C:5]([CH2:3][OH:2])[N:10]=1
Reactant: COC(=O)c1cc2c(nn1)Oc1ccccc1O2
Agent: [BH4-]
Agent: [Na+]
Solvent: OCC1CCCO1
Solvent: O
Product: OCc1cc2c(nn1)Oc1ccccc1O2
Yield: 66.6 %

Procedure:
To methyl[1,4]benzodioxino[2,3-c]pyridazine-3-carboxylate (950 mg) was added a mixed solvent of tetrahydrofuran-methanol (1:1) (20 ml), and the mixture was stirred under ice-cooling. To the mixture was added sodium borohydride (450 mg), and the mixture was stirred at 0° C. for 2 hr. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, and the residue was washed with water to give [1,4]benzodioxino[2,3-c]pyridazin-3-ylmethanol (560 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH:9]([CH:11]2[CH:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[CH2:14][N:13]([C:24](Cl)=[O:25])[CH2:12]2)[CH3:10])=[N:6][CH:7]=1.CCN(CC)CC.[CH3:34][N:35]([CH3:44])[CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH:9]([CH:11]2[CH:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[CH2:14][N:13]([C:24]([N:41]3[CH2:42][CH2:43][N:38]([CH2:37][CH2:36][N:35]([CH3:44])[CH3:34])[CH2:39][CH2:40]3)=[O:25])[CH2:12]2)[CH3:10])=[N:6][CH:7]=1
Reactant: CN(C)CCN1CCNCC1
Reactant: CC(Oc1ccc(Cl)cn1)C1CN(C(=O)Cl)CC1c1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(Oc1ccc(Cl)cn1)C1CN(C(=O)N2CCN(CCN(C)C)CC2)CC1c1ccc(Cl)c(Cl)c1
Reaction time: 8 h
Yield: 35 %

Procedure:
To a stirred solution of (3SR,4RS)-3-[(RS)-1-(5-chloro-pyridin-2-yloxy)-ethyl]-4-(3,4-dichloro-phenyl)-pyrrolidine-1-carbonyl chloride (80 mg, 0.18 mmol) in CH2Cl2 (2 mL) were added Et3N (0.03 mL, 0.15 mmol) and dimethyl-(2-piperazin-1-yl-ethyl)-amine (0.035 mL) (commercially available). Stirring was continued overnight, and the reaction mixture was concentrated under vacuo and directly purified by flash chromatography (SiO2, CH2Cl2/MeOH/NH3, 9/4/1) to yield 36 mg (35%) the title compound as light yellow oil. ES-MS m/e: 553.8 (M+H+).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:18]=[C:17]3[C:13]([C:14]([C:21]4[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=4)=[C:15](Br)[C:16]3=[O:19])=[CH:12][CH:11]=2)[CH2:3][CH2:2]1.O1CCN(CCOC2C=C3C(C(C4C=CC=CC=4)=C(Br)C3=O)=CC=2)CC1.[F:55][C:56]1[CH:57]=[C:58](B(O)O)[CH:59]=[CH:60][C:61]=1[F:62]>>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:18]=[C:17]3[C:13]([C:14]([C:21]4[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=4)=[C:15]([C:59]4[CH:58]=[CH:57][C:56]([F:55])=[C:61]([F:62])[CH:60]=4)[C:16]3=[O:19])=[CH:12][CH:11]=2)[CH2:3][CH2:2]1
Reactant: O=C1C(Br)=C(c2cc(F)cc(F)c2)c2ccc(OCCN3CCOCC3)cc21
Reactant: OB(O)c1ccc(F)c(F)c1
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Product: O=C1C(c2ccc(F)c(F)c2)=C(c2cc(F)cc(F)c2)c2ccc(OCCN3CCOCC3)cc21
Yield: 47 %

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using 6-(2-morpholinoethoxy)-2-bromo-3-(3,5-difluorophenyl)-1H-inden-1-one obtained in Step 6 of Example 36 as a starting material instead of 6-(2-morpholinoethoxy)-2-bromo-3-phenyl-1H-inden-1-one, 3,4-difluorophenylboronic acid instead of 3-pyridinylboronic acid, and being purified by prep HPLC (CH3CN/H2O=7:3) to obtain the title compound (47%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([NH:8][CH2:9][C:10]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[S:14][C:13]([NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[N:12][N:11]1[C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])(=[O:7])=[O:6].[I-].[Na+].[N-:36]=[N+:37]=[N-:38].[Na+].O>CN(C=O)C>[N:36]([CH2:2][CH2:3][CH2:4][S:5]([NH:8][CH2:9][C:10]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[S:14][C:13]([NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[N:12][N:11]1[C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])(=[O:7])=[O:6])=[N+:37]=[N-:38]
Reactant: CC(C)(C)C(=O)NC1=NN(C(=O)C(C)(C)C)C(CNS(=O)(=O)CCCCl)(c2ccccc2)S1
Reactant: [N-]=[N+]=[N-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)NC1=NN(C(=O)C(C)(C)C)C(CNS(=O)(=O)CCCN=[N+]=[N-])(c2ccccc2)S1
Temperature: 90 °C
Reaction time: 4 h
Yield: 119.8 %

Procedure:
The optically active N-[5-(3-chloropropanesulfonylaminomethyl)-4-(2,2-dimethylpropionyl)-5-phenyl-4,5-dihydro-1,3,4-thiadiazol-2-yl]-2,2-dimethylpropanamide (1.50 g, 2.90 mmol) obtained in Step 1 mentioned above, sodium iodide (8.69 g, 58.0 mmol) and sodium azide (1.89 g, 29.0 mmol) were suspended in DMF (20 mL), and the suspension was stirred at 90° C. for 4 hours. To the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was triturated with diethyl ether to give optically active N-[5-(3-azidopropanesulfonylaminomethyl)-4-(2,2-dimethylpropionyl)-5-phenyl-4,5-dihydro-1,3,4-thiadiazol-2-yl]-2,2-dimethylpropanamide (1.82 g).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[O:15][CH3:16].[Br:17][C:18]1[N:19]=[C:20]([C:24](O)=[O:25])[NH:21][C:22]=1[CH3:23].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>>[Br:17][C:18]1[N:19]=[C:20]([C:24]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][C@H:3]2[O:15][CH3:16])=[O:25])[NH:21][C:22]=1[CH3:23]
Reactant: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Reactant: Cc1[nH]c(C(=O)O)nc1Br
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NC(=O)c1nc(Br)c(C)[nH]1
Yield: 83 %

Procedure:
The same operation as in Example (1g) was performed using tert-butyl cis(±)-4-amino-3-methoxypiperidine-1-carboxylate obtained by the method described in Example (1e) (0.88 g, 3.82 mmol), 4-bromo-5-methyl-1H-imidazole-2-carboxylic acid obtained in Example (31b) (0.37 g, 1.80 mmol), WSC hydrochloride (1.03 g, 5.37 mmol) and HOBT (0.25 g, 1.81 mmol), to obtain 0.63 g of the title compound as a white solid (83%).