Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([C:7]1[CH:20]=[CH:19][C:10]([C:11]([CH2:13][CH2:14][C:15](OC)=[O:16])=O)=[CH:9][C:8]=1[OH:21])[CH:5]=[CH2:6]>C(O)(=O)C>[CH2:4]([C:7]1[CH:20]=[CH:19][C:10]([C:11]2[CH2:13][CH2:14][C:15](=[O:16])[NH:2][N:3]=2)=[CH:9][C:8]=1[OH:21])[CH:5]=[CH2:6]
Reactant: C=CCc1ccc(C(=O)CCC(=O)OC)cc1O
Reactant: NN
Solvent: CC(=O)O
Solvent: O
Product: C=CCc1ccc(C2=NNC(=O)CC2)cc1O
Yield: 94.4 %

Procedure:
Hydrazine hydrate (4.5 ml, 0.09 mole) was added to a stirred solution of methyl 3-(4-allyl-3-hydroxybenzoyl)propionate (5.6 g, 0.023 mole) in glacial acetic acid (60 ml) and the mixture heated under reflux for one hour. Evaporation under reduced pressure gave a residue which was triturated with water to give 6-(4-allyl-3-hydroxyphenyl)-4,5-dihydro-3(2H)-pyridazinone (5 g, m.p. 175°-178°C, 96%). The pure pyridazinone, recrystallised from ethanol had m.p. 178°-180°C.
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][N:9]=1)[CH3:2].[N+:19]([O-])(O)=O.O.N>S(=O)(=O)(O)O.C(Cl)(Cl)Cl>[CH2:17]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([NH2:19])[CH:15]=2)[NH:10][N:9]=1)[CH3:18]
Reactant: O=[N+]([O-])O
Reactant: CCN(CC)CCCNc1n[nH]c2ccccc12
Agent: N
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCN(CC)CCCNc1n[nH]c2ccc(N)cc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 44 %

Procedure:
In 2.58 ml of sulfuric acid was dissolved 1.5 g of 3-(3-diethylaminopropylamino)indazole. To the solution were added dropwise 0.41 ml of nitric acid(d=1.42) and 0.41 ml of sulfuric acid(sp. gr. 1.84) under cooling with ice, and the solution was stirred for 2 hours at 5°-10° C. To 12.1 ml of ice and water was added the solution, and the pH of the solution was adjusted to at least 11 with an aqueous ammonia solution. Then the solution was extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate and chloroform was removed under reduced pressure. The residue was dissolved in 50 ml of anhydrous benzene. To the solution were added 10 g of iron powder and 2 ml of hydrochloric acid, and the solution was stirred for 30 minutes at 80° C. The reaction solution was added with 0.5 ml of water and stirred for 10 hours at 80° C. After cooling, the solution was filtered. The benzene layer of the filtrate was extracted three times with 20 ml of lN hydrochloric acid. The pH of the hydrochloric acid layer was adjusted to at least 11 and the alkali layer was extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate and chloroform was removed under reduced pressure. The residue thus obtained was subjected to an alumina-column chromatography(alumina: 100 g) using chloroform as the developing solvent to give 0.69 g of 3-(3-diethylaminopropylamino)-5-aminoindazole having the following analytical values in a yield of 44%.
Reaction SMILES: [OH:1][CH:2]1[CH2:11][C:10]2[C:9]([NH:12][C:13](=[O:21])[C:14]3[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=3)=[CH:8][CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1.CN(C=O)C.[F:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][C:33]=1[F:34].C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[F:27][C:28]1[CH:29]=[C:30]([C:17]2[CH:18]=[CH:19][C:14]([C:13]([NH:12][C:9]3[C:10]4[CH2:11][CH:2]([OH:1])[CH2:3][CH2:4][C:5]=4[CH:6]=[CH:7][CH:8]=3)=[O:21])=[CH:15][CH:16]=2)[CH:31]=[CH:32][C:33]=1[F:34]
Reactant: O=C(Nc1cccc2c1CC(O)CC2)c1ccc(I)cc1
Reactant: OB(O)c1ccc(F)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1cccc2c1CC(O)CC2)c1ccc(-c2ccc(F)c(F)c2)cc1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 54.7 %

Procedure:
Next, to a solution of N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-4-iodobenzamide (100 mg, 0.25 mmol) in a 3 to 1 mixture of DMF and H2O was added 3,4-difluorophenylboronic acid (80.3 mg, 0.51 mmol), tetrakis(triphenylphosphine)palladium(0) (8.82 mg, 0.01 mmol), and sodium carbonate (80.9 mg, 0.76 mmol). The mixture was stirred at 80° C. for 2.5 hours, and after cooled to room temperature, the product was extracted with diethyl ether. The organic layer was washed with water then brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. After triturated with ethylacetate and hexane, the solid was filtered to afford 3′,4′-difluoro-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)biphenyl-4-carboxamide (51.9 mg, 54%).
Reaction SMILES: C[N:2]([CH3:19])[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[C:9]([N:13]([CH2:17][CH3:18])[C:14](=[O:16])[CH3:15])[CH:10]=[CH:11][CH:12]=1)=O.Cl.N[C:22]1[C:26]([C:27]#[N:28])=C[NH:24][N:23]=1.Cl>O.CO>[CH3:18][CH2:17][N:13]([C:14]([CH3:15])=[O:16])[C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:5]2[N:24]3[N:23]=[CH:22][C:26]([C:27]#[N:28])=[C:19]3[N:2]=[CH:3][CH:4]=2)[CH:8]=1
Reactant: N#Cc1c[nH]nc1N
Reactant: CCN(C(C)=O)c1cccc(C(=O)C=CN(C)C)c1
Agent: Cl
Solvent: O
Solvent: CO
Product: CCN(C(C)=O)c1cccc(-c2ccnc3c(C#N)cnn23)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-ethylacetamide (2.6 g, 0.01 mol) and 3-amino-4-cyanopyrazole-hydrochloride (1.44 g, 0.01 mol) were dissolved in the mixture of water (35 cm3) and methanol (20 cm3). Concentrated (37%) hydrochloric acid (0.83 cm3, 0.01 mol) was then added and the mixture was stirred at room temperature for about 2 hours. The reaction mixture was then cooled to about 5° C. and the crystalline product formed was collected, washed with water and dried at about 60° C. to yield zaleplon (2.93 g, 96.1%) in 99.16% purity as determined by HPLC.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[NH2:7])([O-:3])=[O:2].CO[CH:16]1[CH2:20][CH2:19][CH:18](OC)O1.O>CC(O)=O>[N+:1]([C:4]1[CH:5]=[C:6]([N:7]2[CH:16]=[CH:20][CH:19]=[CH:18]2)[CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)([O-:3])=[O:2]
Reactant: Nc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: COC1CCC(OC)O1
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(-n2cccc2)cc([N+](=O)[O-])c1

Procedure:
According to Scheme 16, a solution of 3,5-dinitroaniline (1.83 g, 10 mmol) and 2,5-dimethoxytetrahydrofuran in 20 mL of HOAc was refluxed overnight. The reaction mixture was poured into water and extracted with EtOAc. The ethyl acetate layer was washed with water followed by aq NaHCO3 and brine. After drying, the solvent was removed to provide 1.52 g of 1-(3,5-dinitrophenyl)pyrrole.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([CH3:7])([SH:6])[CH3:5].C(N(CC)CC)C.[C:15]1(=[O:21])[O:20][C:18](=[O:19])[CH2:17][CH2:16]1>C(Cl)Cl>[CH3:5][C:4]([SH:6])([CH3:7])[CH2:3][NH:2][C:15]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[O:21]
Reactant: O=C1CCC(=O)O1
Reactant: CC(C)(S)CN
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(S)CNC(=O)CCC(=O)O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 94.5 %

Procedure:
To an ice-cooled suspension of 1-amino-2-methylpropan2-thiol hydrochloride (5.06 g, 35.72 mmol) in methylene chloride (100 mL) was added triethylamine (5.0 mL, 35.87 mmol) followed by succinic anhydride (3.50 g, 34.96 mmol). The resulting clear solution was stirred at 0° C. or 10 minutes, then at room temperature for 2 hours. Evaporation of the volatiles under reduced pressure gave a residue which was partitioned between 2 N hydrochloric acid (100 mL) and ethyl acetate (100 mL). The aqueous layer was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (5 mL), dried over sodium sulfate and evaporated to dryness. The residue was triturated with ether-hexane to afford the title compound as a white solid (6.78 g, 94.4%). Mp. 86-87° C.; 1H NMR (300 MHz, CDCl3): δ 1.34 (s, 6H), 1.55 (s, 1H), 2.59 (t, J=6.6 Hz, H), 2.70 (t, J=6.6 Hz, 2H), 3.32 (d, J=8.0 Hz, 2H), 6.58 (br t, J=5.9 Hz, 1H), 10.73 (br s, 1H); 13C NMR (75 MHz, CDCl3): δ 29.57, 29.79, 30.79, 172.50, 176.81; LCMS (m/e): 223 (M+H2O), 206 (M+1).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C:3](=[O:6])[NH:2]1.[F:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11](O)=[O:12].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl>[F:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([N:1]1[CH2:5][CH2:4][C:3](=[O:6])[NH:2]1)=[O:12]
Reactant: O=C1CCNN1
Reactant: O=C(O)c1cccc(F)c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CCN(C(=O)c2cccc(F)c2)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32422.5 %

Procedure:
To a solution of pyrazolidin-3-one (6.9 gm, 0.080 mmol, 1 equiv.) in dry dichloromethane (70 ml), 3-fluorobenzoic acid (12.3 gm, 0.088 mmol, 1.1 equiv.), triethylamine (24.3 gm, 0.240 mmol, 3 equiv.) and 1-propane phosphonic acid cyclic anhydride (60% by weight in ethyl acetate) (51 gm, 0.16 mmol, 2 equiv.) were added in cooling condition and stirred for overnight at room temperature. The reaction mixture was concentrated and the residue was poured in water (500 ml), extracted with dichloromethane (100 ml×2) and concentrated. The crude product was purified by silica gel column using (60-120) mesh to get the pure product as yellow oil (5.4 gm, 32% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[N:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH:10]2[CH3:22])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH:10]2[CH3:22])=[CH:28][CH:27]=1
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1CNCCN1C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 259.4 %

Procedure:
A 50 mL round-bottom flask was charged with tert-butyl 4-[bis(4-chlorophenyl)methyl]-3-methylpiperazine-1-carboxylate (0.800 g, 1.84 mmol, 1.00 equiv), dichloromethane (15 mL). The mixture was cooled to 0° C. and trifluoroacetic acid (2 mL) was added dropwise. The resulting solution was stirred for 3 hours at room temperature and concentrated under reduced pressure to yield 1.60 g (crude) of 1-[bis(4-chlorophenyl)methyl]-2-methylpiperazine as a light yellow semi-solid. LCMS: (ESI, m/z): 335 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:20])=[C:6]([CH:8]2[CH2:17][C:16]3[N:15]=[CH:14][CH:13]=[C:12]([CH3:18])[C:11]=3[C:10](=O)[CH2:9]2)[CH:7]=1.[C:21]([NH:24][NH2:25])([NH2:23])=[NH:22].[ClH:26].Cl.O>C(O)C>[ClH:26].[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:20])=[C:6]([CH:8]2[CH2:17][C:16]3[N:15]=[CH:14][CH:13]=[C:12]([CH3:18])[C:11]=3[C:10](=[N:25][NH:24][C:21]([NH2:23])=[NH:22])[CH2:9]2)[CH:7]=1
Reactant: N=C(N)NN
Reactant: Cc1ccc(F)cc1C1CC(=O)c2c(C)ccnc2C1
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1ccc(F)cc1C1CC(=NNC(=N)N)c2c(C)ccnc2C1
Yield: 94.7 %

Procedure:
To a solution of 7-(5-fluoro-2-methylphenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (1.1 g) and aminoguanidine hydrochloride (0.54 g) in ethanol (30 ml) were added concentrated hydrochloric acid (1.0 ml) and water (1.0 ml), and the mixture was refluxed for 6 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in water. The mixture was washed with ethyl acetate, and to the aqueous layer was added sodium hydrogen carbonate solution to make it alkaline. The solution was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in ethanol, and to the mixture was added 1N hydrochloric acid (10 ml). The mixture was concentrated, and precipitated crystals were recrystallized from ethanol to give 7-(5-fluoro-2-methylphenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 165) (1.4 g) as colorless crystals.
Reaction SMILES: ClCCl.[OH-].[Na+].Cl.[CH3:7][NH:8][OH:9].[Br:10][CH:11]([CH2:15][CH2:16]Br)[C:12](Cl)=[O:13]>O>[Br:10][CH:11]1[CH2:15][CH2:16][O:9][N:8]([CH3:7])[C:12]1=[O:13]
Reactant: O=C(Cl)C(Br)CCBr
Reactant: CNO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CN1OCCC(Br)C1=O
Temperature: 5 °C
Reaction time: 2 h

Procedure:
A mixture of 65 mL of dichloromethane and 2.6 g (33 mmol) of 50% aqueous sodium hydroxide in 8 mL of water was treated with 2.5 g (30 mmol) of N-methylhydroxylamine hydrochloride. After cooling to 5° C., 8.5 g (32 mmol) of 2,4-dibromobutyryl chloride* was added dropwise, with the temperature maintained at 5° to 8° C. An additional 2.6 g of 50% aqueous sodium hydroxide was added, and the mixture was stirred for 2 hours at 5° C. A final 2.6 g of 50% aqueous sodium hydroxide was added, and the mixture was stirred at room temperature for 18 hours. The organic layer was separated, and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried (anhydrous magnesium sulfate) and evaporated.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=O)=[CH:5][CH:4]=1.S(Cl)([Cl:22])=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([Cl:22])=[O:19])=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(CCCCCCCCC(=O)O)cc1
Solvent: ClCCl
Product: COc1ccc(CCCCCCCCC(=O)Cl)cc1
Temperature: 25 °C

Procedure:
To an ice-cold, stirring solution of 3 gm 9(4-methoxyphenyl)nonanoic acid in 10 ml. CH2Cl2 was added dropwise 1.2 ml thionyl chloride. The solution was then allowed to warm up to room temperature. The solvent and excess thionyl chloride were removed in vacuo to give a brown oil, which was used directly in the last step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH:5]([O:10][CH2:11][CH:12]=[CH2:13])[CH:6]([OH:9])[CH:7]=[CH2:8])[CH3:2].[CH3:15][C:16](OC(C)=O)=[O:17]>CN(C1C=CN=CC=1)C.C(Cl)Cl.CCN(CC)CC.C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:14])[CH:5]([O:10][CH2:11][CH:12]=[CH2:13])[CH:6]([O:9][C:16](=[O:17])[CH3:15])[CH:7]=[CH2:8])[CH3:2]
Reactant: C=CCOC(C(=O)OCC)C(O)C=C
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCOC(C(=O)OCC)C(C=C)OC(C)=O
Temperature: 25 °C

Procedure:
To a solution of 2-allyloxy-3-hydroxy-pent-4-enoic acid ethyl ester (100 mg, 0.5 mmol) and DMAP (30 mg, 0.25 mmol) in CH2Cl2-Et3N (9:1, 10 mL) was added Ac2O (76 mg, 0.75 mmol). The resulting solution was stirred at ambient temperature for 1H. The solution was diluted with CH2Cl2 (40 mL), washed with H2O (20 mL×2), dried over Na2SO4, concentrated in vacuo and purified by flash chromatography with 20% EtOAc-hexane.
Reaction SMILES: CC1NC(C2C=CC=CC=2)=N[C:3]=1[C:13]([C:15]1[N:16]=[C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[NH:18][C:19]=1C)=O.[C:27]([O:31][CH3:32])(=[O:30])[NH:28][NH2:29]>>[CH3:32][O:31][C:27](=[O:30])[NH:28][N:29]=[C:13]([C:15]1[N:16]=[C:17]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:18][CH:19]=1)[CH3:3]
Reactant: COC(=O)NN
Reactant: Cc1[nH]c(-c2ccccc2)nc1C(=O)c1nc(-c2ccccc2)[nH]c1C
Product: COC(=O)NN=C(C)c1c[nH]c(-c2ccccc2)n1
Yield: 91 %

Procedure:
By the method of Example 104, the title product is prepared from methyl-2-phenyl-4-imidazolyl ketone and methyl carbazate. The product is obtained in 91% yield, m.p. 226.5°-227° C.
Reaction SMILES: [CH2:1]([CH:3]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:4](Cl)=[O:5])[CH3:2].[NH2:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[CH3:26])[C:20]([OH:22])=[O:21]>>[CH2:1]([CH:3]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:4]([NH:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[CH3:26])[C:20]([OH:22])=[O:21])=[O:5])[CH3:2]
Reactant: CCCCCCCCCC(CC)C(=O)Cl
Reactant: Cc1ccc(C(=O)O)cc1N
Product: CCCCCCCCCC(CC)C(=O)Nc1cc(C(=O)O)ccc1C
Temperature: 140 °C
Yield: 95.7 %

Procedure:
A mixture of (RS)-2-ethylundecanoyl chloride (1.16 g) and 3-amino-4-methylbenzoic acid (0.75 g) was placed in an oil bath at 90° C. and the temperature was gradually raised to 140° C. for 2 hours. After cooling, the solid was recrystallised from a mixture of ethanol (25 ml) and water (1 ml) to yield (RS)-3-(2-ethylundecanamido)-4-methylbenzoic acid (1.65 g) in the form of a white solid, m.p. 217°-220° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:9]2[N:10]=[C:11]([C:13]3[NH:22][C:16]4[CH2:17][CH2:18][NH:19][CH2:20][CH2:21][C:15]=4[N:14]=3)[S:12][C:8]=2[C:7]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:6][CH:5]=1.C(N(C(C)C)C(C)C)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>O1CCCC1>[CH3:38][S:39]([N:19]1[CH2:20][CH2:21][C:15]2[N:14]=[C:13]([C:11]3[S:12][C:8]4[C:7]([N:23]5[CH2:24][CH2:25][O:26][CH2:27][CH2:28]5)=[CH:6][CH:5]=[C:4]([O:3][CH3:2])[C:9]=4[N:10]=3)[NH:22][C:16]=2[CH2:17][CH2:18]1)(=[O:41])=[O:40]
Reactant: COc1ccc(N2CCOCC2)c2sc(-c3nc4c([nH]3)CCNCC4)nc12
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(N2CCOCC2)c2sc(-c3nc4c([nH]3)CCN(S(C)(=O)=O)CC4)nc12
Yield: 32 %

Procedure:
To a suspension of 0.04 g 2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-1,4,5,6,7,8-hexahydro-imidazo[4,5-d]azepine hydrochloride in 3.4 ml tetrahydrofurane were added at 0–4° C. 0.07 ml N-ethyldiisopropylamine and 0.009 ml methanesulfonyl chloride. The mixture was refluxed for 17 hours, silicagel was added and the solvent was distilled off. The residue was transferred to a column prefilled with silicagel and was chromatographed with dichloromethane/methanol 96:4 to yield 0.015 g (32%) 6-methanesulfonyl-2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-1,4,5,6,7,8-hexahydro-imidazo[4,5-d]azepine as yellow solid; MS (ISP): m/e=464 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[C:9]3[N:10]([C:29]([CH2:32][CH3:33])=[CH:30][CH:31]=3)[N:11]=[C:12]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:13]=2[CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])[CH:5]=[CH:4][N:3]=1.[CH3:34][S-:35].[Na+].Cl>C1(C)C=CC=CC=1.O1CCCC1>[CH2:32]([C:29]1[N:10]2[N:11]=[C:12]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:13]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([S:35][CH3:34])[CH:7]=3)[C:9]2=[CH:31][CH:30]=1)[CH3:33]
Reactant: C[S-]
Reactant: CCOC(=O)CCCCc1c(-c2ccccc2)nn2c(CC)ccc2c1-c1ccnc(Cl)c1
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCc1ccc2c(-c3ccnc(SC)c3)c(CCCCC(=O)O)c(-c3ccccc3)nn12
Yield: 73.4 %

Procedure:
To a solution of ethyl 5-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate (120 mg) in toluene (5 mL) and tetrahydrofuran (10 mL) was added sodium thiomethoxide (91.0 mg) and the mixture was heated under reflux for 4 hours. The solution was acidfied with 1N hydrochloric acid and extracted with chloroform. The organic layer was separated, washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (10:1–3:1) to give 5-{7-ethyl-4-[2-(methylthio)-4-pyridinyl]-2-phenylpyrrolo-[1,2-b]pyridazin-3-yl}pentanoic acid as an yellow powder (85.0 mg).
Reaction SMILES: Cl.Cl.[N:3]1[N:11]2[C:6]([O:7][CH2:8][CH2:9][CH2:10]2)=[C:5]([C@H:12]([NH2:14])[CH3:13])[CH:4]=1.[F:15][C:16]([F:34])([F:33])[C:17]([C:20]1[CH:29]=[CH:28][C:27]2[CH2:26][C@@H:25]([C:30](O)=[O:31])[CH2:24][CH2:23][C:22]=2[N:21]=1)([CH3:19])[CH3:18].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1>CN1CCCC1=O>[N:3]1[N:11]2[C:6]([O:7][CH2:8][CH2:9][CH2:10]2)=[C:5]([C@H:12]([NH:14][C:30]([C@H:25]2[CH2:24][CH2:23][C:22]3[N:21]=[C:20]([C:17]([CH3:19])([CH3:18])[C:16]([F:34])([F:33])[F:15])[CH:29]=[CH:28][C:27]=3[CH2:26]2)=[O:31])[CH3:13])[CH:4]=1
Reactant: CC(C)(c1ccc2c(n1)CC[C@H](C(=O)O)C2)C(F)(F)F
Reactant: C[C@@H](N)c1cnn2c1OCCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](NC(=O)[C@H]1CCc2nc(C(C)(C)C(F)(F)F)ccc2C1)c1cnn2c1OCCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.6 %

Procedure:
A 2 mL vial was charged with (R)-1-(6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl)ethanamine dihydrochloride (35 mg, 0.15 mmol), (S)-2-(1,1,1-trifluoro-2-methylpropan-2-yl)-5,6,7,8-tetrahydroquinoline-6-carboxylic acid (38 mg, 0.13 mmol), N-methylpyrrolidinone (200 μL) and N,N-diisopropylethylamine (93 μL, 0.53 mmol). A solution of N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (61 mg, 0.16 mmol) in N-methylpyrrolidinone (300 μL) was added and the resulting mixture was stirred at room temperature for 2 hours. The mixture was filtered and purified by reverse-phase HPLC (20-75% MeCN in 10 mM Et2NH/H2O) to afford the product as a foam (31.0 mg, 53%). 1H NMR (400 MHz, DMSO-d6) δ 8.04 (d, J=7.9 Hz, 1H), 7.53 (d, J=8.1 Hz, 1H), 7.35 (d, J=8.1 Hz, 1H), 7.20 (s, 1H), 4.78 (app pentet, J=7.3 Hz, 1H), 4.27 (app t, J=5.2 Hz, 2H), 4.04 (t, J=6.2 Hz, 2H), 2.93-2.73 (m, 4H), 2.61-2.52 (m, 1H), 2.19-2.10 (m, 2H), 2.03-1.94 (m, 1H), 1.85-1.72 (m, 1H), 1.54 (s, 6H), 1.29 (d, J=6.9 Hz, 3H); m/z=437.4 (M+1)+.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].Cl.[CH2:15]([NH:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1)[CH2:16][CH2:17][CH:18]=[CH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>COCCOC>[CH2:15]([NH:29][C:30]1[CH:31]=[CH:32][C:33]([C:34]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])=[O:35])=[CH:37][CH:38]=1)[CH2:16][CH2:17][CH:18]=[CH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCC=CCCCNc1ccc(C(=O)Cl)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCCCCCCCCC=CCCCNc1ccc(C(=O)C(C(=O)OCC)C(=O)OCC)cc1

Procedure:
A solution of 26.6 g. of diethyl malonate and 10 ml. of 1,2-dimethoxyethane is added to a suspension of 4.0 g. of sodium hydride in 1,2-dimethoxyethane under argon. A solution of 17.3 g. of 4-(1-tetradec-4-enylamino)benzoyl chloride hydrochloride in 1,2-dimethoxyethane is then added. The reaction mixture is refluxed for 4.5 hours, cooled, poured on ice, acidified, and extracted with ether. The ether solution is washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to dryness. Addition of a small amount of ethanol to the residue gives a solid which is filtered and discarded. The ethanol filtrate is concentrated and the residue is recrystallized from ether to yield diethyl 4-(1-tetradec-4-enylamino)benzoylmalonate.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[S:7](Cl)(=[O:9])=[O:8].[H-].[Na+].[CH3:13][C:14]([CH3:27])([CH3:26])[C:15]([O:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:16]>>[CH3:13][C:14]([CH3:27])([CH3:26])[C:15]([O:17][N:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[S:7]([C:3]1[S:4][CH:5]=[CH:6][C:2]=1[Cl:1])(=[O:9])=[O:8])=[O:16]
Reactant: CC(C)(C)OC(=O)NOC(=O)C(C)(C)C
Reactant: O=S(=O)(Cl)c1sccc1Cl
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N(OC(=O)C(C)(C)C)S(=O)(=O)c1sccc1Cl

Procedure:
N-[(tert-Butoxy)carbonyl]3-chlorothiophene-2-sulfonamido 2,2-dimethylpropanoate (107) is synthesised from 3-chlorothiophene-2-sulfonyl chloride, sodium hydride and [(tert-butoxy)carbonyl]amino 2,2-dimethylpropanoate according to Scheme 2. δH (500 MHz, DMSO-d6) 8.29 (1H, d, 5.3 Hz), 7.40 (1H, d, 5.2 Hz), 1.39 (9H, s), 1.28 (9H, s).