Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(Cl)Cl.[CH3:5][O:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][C:20](=[O:22])[C:19]([C:23](=O)[CH2:24][CH3:25])=[C:18]([OH:27])[CH2:17]2)=[CH:12][CH:11]=1)=[O:8].[CH2:28]([O:30][NH2:31])[CH3:29]>O>[CH2:28]([O:30][N:31]=[C:23]([C:19]1[C:20](=[O:22])[CH2:21][CH:16]([C:13]2[CH:14]=[CH:15][C:10]([NH:9][C:7]([O:6][CH3:5])=[O:8])=[CH:11][CH:12]=2)[CH2:17][C:18]=1[OH:27])[CH2:24][CH3:25])[CH3:29]
Reactant: CCC(=O)C1=C(O)CC(c2ccc(NC(=O)OC)cc2)CC1=O
Reactant: CCON
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCON=C(CC)C1=C(O)CC(c2ccc(NC(=O)OC)cc2)CC1=O
Temperature: 40 °C
Reaction time: 15 h
Yield: 58.7 %

Procedure:
Into 30 ml of chloroform was dissolved 1.8 g of 5-[4-(methoxycarbonylamino)phenyl]-2-propionyl-3-hydroxy-2-cyclohexen-1-one and to the solution was added 0.5 g of ethoxyamine. The mixture was agitated for 15 hours at 40° C. and the chloroform containing produced water and a surplus amount of ethoxyamine was distilled off from it under a reduced pressure. And then, the ethyl ether was added in the residue and the crystal sedimented was collected with a filtering step and 1.2 g of desired compound was obtained. It was in the form of colorless crystals having a melting point of 160°-161° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2I)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].C(NC(C)C)(C)C.[CH:33]#[C:34][CH2:35][CH2:36][CH3:37]>CN(C=O)C.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.[Cu]I>[CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[C:33]#[C:34][CH2:35][CH2:36][CH3:37])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2I)Cc2ccccc2C1
Reactant: C#CCCC
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: CCCC#Cc1c(C)cccc1C(=O)NC1(C(=O)OCC)Cc2ccccc2C1
Yield: 24 %

Procedure:
To a solution of 2-(2-iodo-3-methyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (693 mg, 1.54 mmol) in anhydrous DMF (5 mL) and DIPA (diisopropylamine, 10 mL) is added Pd(PPh3)4 (89 mg, 7.7% mmol), CuI (29 mg, 0.154 mmol) and pent-1-yne (1.5 mL, 15.4 mmol). The resulting solution is covered in argon and run in a microwave reaction: 110° C., 35 minutes. After the removal of DMF and DIPA in vacuo, the residue is dissolved in EtOAc (100 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (120 g silica gel, gradient elution: 0%-40% EtOAc in heptane) to give a pure product (122) as a pale yellow solid (144 mg, 24%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]2[CH:23]=[CH:22][N:21]=[N:20][CH:19]=2)[C:13]=1[C:24]#[N:25])[C:5](O)=[O:6].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[NH2:48][CH2:49][C:50]1[C:51](=[O:58])[NH:52][C:53]([CH3:57])=[CH:54][C:55]=1[CH3:56]>O.ClCCl.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]2[CH:23]=[CH:22][N:21]=[N:20][CH:19]=2)[C:13]=1[C:24]#[N:25])[C:5]([NH:48][CH2:49][C:50]1[C:51](=[O:58])[NH:52][C:53]([CH3:57])=[CH:54][C:55]=1[CH3:56])=[O:6]
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: N#Cc1c(Oc2ccc(C(=O)O)cc2Cl)cccc1-c1ccnnc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2ccc(Oc3cccc(-c4ccnnc4)c3C#N)c(Cl)c2)c(=O)[nH]1
Temperature: 25 °C
Yield: 72 %

Procedure:
A mixture of 3-chloro-4-(2-cyano-3-(pyridazin-4-yl)phenoxy)benzoic acid (70 mg, 0.2 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (60 mg, 0.3 mmol) and N-hydroxybenzotriazole (45 mg, 0.3 mmol), triethylamine (0.1 mL) and dichloromethane (5 mL) were stirred at 25° C. for half an hour and then 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one (30 mg, 0.2 mmol) was added. The mixture was stirred at 25° C. for 12 hours. To the mixture, water (10 mL) was added and the mixture was extracted with dichloromethane (10 mL×3). The combined organic phase was dried by sodium sulfate and then filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to give 3-chloro-4-(2-cyano-3-(pyridazin-4-yl)phenoxy)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzamide as a white solid (70 mg, 70%).
Reaction SMILES: CC([NH:4][C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11](=[O:13])[NH:10][C:9]=2[CH:14]=1)C.[N+](C1C=CC2OC(=O)NC=2C=1)([O-])=O>C(O)(=O)C>[NH2:4][C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11](=[O:13])[NH:10][C:9]=2[CH:14]=1
Reactant: CC(C)Nc1ccc2oc(=O)[nH]c2c1
Agent: O=c1[nH]c2cc([N+](=O)[O-])ccc2o1
Solvent: CC(=O)O
Product: Nc1ccc2oc(=O)[nH]c2c1
Reaction time: 2 h

Procedure:
5-(2-Propylamino)-2(3H)-benzoxazolone. To a Parr bottle containing 5-nitro-2(3H)-benzoxazolone (8.08 g, 44.9 mmol) was added acetic acid (230 mL) and then Ar was bubbled for 10 min. Palladium on C (10%. 0.5 g) was added carefully and the hydrogenation was carried out under 45 psi of hydrogen on a Parr hydrogenator. The reaction was complete within 2 h, and mixture was filtered through a pad of Celite. The solvent was then removed in vacuo, and 5-amino-2(3H)-benzoxazolone was obtained as a pale solid. Without further purification, to this solid was added MeOH (70 mL), THF (70 mL), acetic acid (12 mL), and acetone (4.15 mL). The mixture was then cooled to 0° C., and NaCNBH3 (3.6 g) was added slowly. The reaction mixture became a brown colored solution within 20 min. The reaction mixture was concentrated in vacuo, and water (60 mL) was added along with NaOH (2 N) to bring the pH to around 7. The product was then extracted with EtOAc (2×350 mL) and purified by flash chromatography (CH2CH2:MeOH:TEA=49:1:0.15, Rf=0.17) to result in the product (5.32 g, 62%). 1H NMR (300 MHz, CDCl3) δ 6.98 (d, J=8.7 Hz, 1H), 6.34-6.27 (m, 2H), 3.55 (p, J=6.3 Hz, 1H), 3.43 (bs, 1H), 1.20 (d, J=6.3 Hz, 6H).
Reaction SMILES: [NH2:1][C:2]1=[N:3][C:4](=[O:30])[N:5]([CH3:29])/[C:6]/1=[CH:7]/[CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[C:25]([F:28])([F:27])[F:26])[CH2:10][CH2:9]1.[CH2:31](N)[C:32]#[CH:33]>C1(C)C=CC=CC=1>[F:27][C:25]([F:26])([F:28])[C:16]1[CH:17]=[C:18]([C:21]([F:22])([F:23])[F:24])[CH:19]=[CH:20][C:15]=1[CH2:14][N:11]1[CH2:12][CH2:13][CH:8](/[CH:7]=[C:6]2\[C:2]([NH:1][CH2:33][C:32]#[CH:31])=[N:3][C:4](=[O:30])[N:5]\2[CH3:29])[CH2:9][CH2:10]1
Reactant: C#CCN
Reactant: CN1C(=O)N=C(N)/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Solvent: Cc1ccccc1
Product: C#CCNC1=NC(=O)N(C)/C1=C/C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 60.1 %

Procedure:
To a solution of (5E)-4-amino-5-({1-[2,4-bis(trifluoromethyl)benzyl]piperidin-4-yl}methylidene)-1-methyl-1,5-dihydro-2H-imidazol-2-one (133 mg) in toluene (1 mL) was added propargylamine (843 mg) at room temperature. The reaction mixture was stirred at 100° C. overnight. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (87 mg).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:23]=[CH:22][C:15]3[N:16]=[C:17](S(C)=O)[S:18][C:14]=3[CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4].Cl.[NH2:25][C@H:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@@H:27]1[OH:32].C(N(C(C)C)CC)(C)C>CC(N(C)C)=O>[OH:32][C@H:27]1[CH2:28][CH2:29][CH2:30][CH2:31][C@@H:26]1[NH:25][C:17]1[S:18][C:14]2[CH:13]=[C:12]([O:11][C:9]3[CH:8]=[CH:7][N:6]=[C:5]([C:3]([NH:2][CH3:1])=[O:4])[CH:10]=3)[CH:23]=[CH:22][C:15]=2[N:16]=1
Reactant: N[C@H]1CCCC[C@@H]1O
Reactant: CNC(=O)c1cc(Oc2ccc3nc(S(C)=O)sc3c2)ccn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CNC(=O)c1cc(Oc2ccc3nc(N[C@H]4CCCC[C@@H]4O)sc3c2)ccn1
Temperature: 110 °C

Procedure:
To the solution of 4-(2-methanesulfinyl-benzothiazol-6-yloxy)-pyridine-2-carboxylic acid methylamide (70 mg, 0.202 mmol, 1.0 eq) in DMA (600 μL was added (1S,2S)-2-aminocyclohexanol hydrochloride (92 mg, 0.606 mmol, 3.0 eq) followed by diisopropylethylamine (0.21 mL, 1.21 mmol). The reaction was heated at 110° C. for 24-hours. The neat reaction mixture was purified on reverse phase preparatory HPLC. Pure fractions were lyophilized as TFA salts. M+H=398
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([CH:21]=1)[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)=[O:8].[N:23]1[CH:28]=[CH:27][CH:26]=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>C1COCC1.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]2[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=2)=[C:6]([CH:21]=1)[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)=[O:8]
Reactant: CC1(C)OB(c2cccnc2)OC1(C)C
Reactant: COc1ccc(CNC(=O)c2cc(Br)ccc2I)cc1OC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(CNC(=O)c2cc(Br)ccc2-c2cccnc2)cc1OC
Temperature: 120 °C

Procedure:
A solution of 1-2 (100 mg, 0.210 mmol, 1.0 equiv) in THF (2 ml) in a microwave vial was treated with pyridine-3-boronic acid pinacol ester (47.4 mg, 0.231 mmol, 1.1 equiv), cesium carbonate (163 mg, 0.500 mmol, 2.4 equiv), PdCl2(dppf)-CH2Cl2 adduct (17.15 mg, 0.021 mmol, 0.1 equiv), and 0.5 mL water. The mixture was heated to 120° C. in a microwave reactor for 10 min. The mixture was cooled to RT and diluted with EtOAc. The mixture was washed with sat. aq. NH4Cl, dried over Na2SO4, filtered and concentrated. The crude material (1-3) was used as is in the next step. ESI+ MS [M+H]+ C21H19BrN2O3: 428.0 found, 427.3 required.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[C:16](=[O:32])[C:15]=2[C:33]#[N:34])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:35]>O1CCOCC1>[ClH:35].[F:31][C:28]1[CH:27]=[CH:26][C:25]([CH2:24][N:17]2[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[C:15]([C:33]#[N:34])[C:16]2=[O:32])=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2c(C#N)c(=O)n(Cc3ccc(F)cc3)c3ccccc23)CC1
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1c(N2CCNCC2)c2ccccc2n(Cc2ccc(F)cc2)c1=O
Reaction time: 24 h

Procedure:
To a solution of 4-[3-Cyano-1-(4-fluoro-benzyl)-2-oxo-1,2-dihydro-quinolin-4-yl]-piperazine-1-carboxylic acid tert-butyl ester (0.250 g, 0.54 mmole) in 1,4-dioxane (2mL) was treated with 4N HCl in dioxane (5.0 ml). Reaction stirred for 24 h before concentrating to residue and triturating with diethyl ether to afford 1-(4-Fluoro-benzyl)-2-oxo-4-piperazin-1-yl-1,2-dihydro-quinoline-3-carbonitrile hydrochloride salt as a yellow solid (0.195 g, quantitative yield, calc M+H 363, obs M+H 363).
Reaction SMILES: C(OC([N:6]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[N:17]([CH2:18][C:19]3[O:20][C:21]([CH2:24][OH:25])=[CH:22][CH:23]=3)[C:16]3[CH:26]=[CH:27][CH:28]=[CH:29][C:15]=3[N:14]=2)[CH2:8][CH2:7]1)=O)C.[OH-].[Na+].C(OCC)(=O)C>C(O)(C)C>[OH:25][CH2:24][C:21]1[O:20][C:19]([CH2:18][N:17]2[C:16]3[CH:26]=[CH:27][CH:28]=[CH:29][C:15]=3[N:14]=[C:13]2[N:9]2[CH2:10][CH2:11][CH2:12][NH:6][CH2:7][CH2:8]2)=[CH:23][CH:22]=1
Reactant: CCOC(=O)N1CCCN(c2nc3ccccc3n2Cc2ccc(CO)o2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: OCc1ccc(Cn2c(N3CCCNCC3)nc3ccccc32)o1
Reaction time: 48 h

Procedure:
Combine 1-ethoxycarbonyl-4-(1-(5-hydroxymethylfur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (4 mmol) and sodium hydroxide (8 mmol) in isopropanol (20 mL). Heat to reflux. After 2 days, evaporate the reaction mixture in vacuo to give a residue. Combine the residue and ethyl acetate. Extract with water and brine. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give the title compound.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:2]1[C:3]([OH:5])=[O:4].C(=O)([O-])[O-].[K+].[K+].Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18]>O>[CH2:20]([O:19][C:17]([N:1]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:2]1[C:3]([OH:5])=[O:4])=[O:18])[CH3:21]
Reactant: O=C(O)C1CCCCN1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)N1CCCCC1C(=O)O

Procedure:
15.0 g (0.116 moles) of (±) pipecolic acid were dissolved in 180 ml of water. 25.5 g (0.185 moles) of potassium carbonate were added and the solution cooled to +5° C. 19.83 g (0.183 moles) of ethyl chloroformate were added dropwise under mechanical stirring, maintaining the temperature below +10° C. After 4 hours the reaction mixture was extracted with methylene chloride; the aqueous layer were treated with conc. HCl to acidic pH, extracted with methylene chloride (400 ml) which was dried over Na2SO4 and the solvent evaporated to dryness to afford 23.8 g of the crude product. Crystallization from isopropyl ether/n-hexane gave 21.7 g (93% of the theoretical) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:17][CH2:16][C:9]2([O:13][CH:12]([CH3:14])[C:11](=O)[CH2:10]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(N(CC)CC)C.Cl.[NH2:26][OH:27]>C(O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:17][CH2:16][C:9]2([O:13][CH:12]([CH3:14])[C:11](=[N:26][OH:27])[CH2:10]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: NO
Reactant: CCOC(=O)N1CCC2(CC1)CC(=O)C(C)O2
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCC2(CC1)CC(=NO)C(C)O2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
8-Ethoxycarbonyl-2-methyl-1-oxa-8-azaspiro [4.5 ]decan-3-one (20 g, 0.083 mol) was dissolved in absolute ethanol (1 L) and combined with triethylamine (11.5 ml) and hydroxylamine hydrochloride (5.7 g). The mixture was stirred at room temperature overnight. The ethanol was evaporated in vacuo and the residue was stirred with ether. The insoluble solids were filtered and the ether filtrate was evaporated. The residual oxime was purified by chomatography on silica gel and elution with ammoniated 2-10% MeOH/CHCl3. Evaporation of the solvents afforded the oxime, 11.5 g.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[C:15]2[C:10]([C:11](=[O:19])[CH2:12][C:13]([CH3:18])([CH3:17])[O:14]2)=[C:9]([OH:20])[CH:8]=1)(=O)=O.[Cl-].[Li+].[CH:25]([Zn]C(C)C)([CH3:27])[CH3:26].Cl>CN(C)C=O.C1(C)C=CC=CC=1.O>[OH:20][C:9]1[CH:8]=[C:7]([CH2:26][CH2:25][CH3:27])[CH:16]=[C:15]2[C:10]=1[C:11](=[O:19])[CH2:12][C:13]([CH3:18])([CH3:17])[O:14]2
Reactant: CC(C)[Zn]C(C)C
Reactant: CC1(C)CC(=O)c2c(O)cc(OS(=O)(=O)C(F)(F)F)cc2O1
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O
Product: CCCc1cc(O)c2c(c1)OC(C)(C)CC2=O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
At 0° C., 450 mg (550 μmol) of bis(diphenylphosphino)ferrocenepalladium(II) chloride/dichloromethane complex are added to a solution of 4.25 g (12.5 mmol) of 5-hydroxy-2,2-dimethyl-4-oxo-3,4-dihydro-2H-chromen-7-yl trifluoromethanesulfonate (Example 16A) and 1.59 g (37.5 mmol) of lithium chloride in 80 ml of degassed dimethylformamide. 24.98 ml (24.98 mmol) of a 1 M solution of diisopropylzinc in toluene are then slowly added dropwise. After 10 min of stirring at 0° C., the mixture is warmed to room temperature and stirred at this temperature for a further 5 h. The reaction solution is hydrolyzed carefully with water, acidified with 1 M hydrochloric acid, diluted with 500 ml of water and extracted twice with in each case 500 ml of ethyl acetate. After washing with 100 ml of water and 50 ml of saturated sodium chloride solution, the combined organic phases are dried over magnesium sulfate and concentrated under reduced pressure. Chromatography of the residue on silica gel (mobile phase: cyclohexane/ethyl acetate 10:1) gives the target product as a 2:1 mixture with the isomer 5-hydroxy-2,2-dimethyl-7-propyl-2,3-dihydro-4H-chromen-4-one.
Reaction SMILES: [C:1]1(=[O:5])[O:4][CH2:3][CH2:2]1.C[O-].[Na+].[CH2:9]([OH:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[OH:5][CH2:1][CH2:2][C:3]([O:16][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:4]
Reactant: O=C1CCO1
Reactant: OCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Product: O=C(CCO)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
β-Propiolactone (5 g, 25 mmol) was added slowly to a stirred solution of sodium methoxide (0.18 g, 3.5 mmol) in benzyl alcohol (45 g, 420 mmol) at 0° C. Stirring was continued for a further 2 hours at 0° C. Then the mixture was warmed to room temperature. After stirred for 7 hours, the reaction mixture was washed with water, dried and distilled to give the title compound. 1H NMR (300 MHz, CDCl3): δ 7.33 (m, 5H), 5.13 (s, 2H), 3.86 (t, J=5.6 Hz, 2H), 2.59 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]2[CH:18]([C:19]3[O:20][C:21]([S:24][C:25]4[NH:29][C:28]5[CH:30]=[CH:31][C:32]([OH:34])=[CH:33][C:27]=5[N:26]=4)=[CH:22][CH:23]=3)[C:17]3[C:16](=[O:35])[CH2:15][N:14](OC(C)(C)C)[CH2:13][C:12]=3[NH:11][C:10]=12)=[O:5])[CH3:2].[ClH:41]>O1CCOCC1>[ClH:41].[CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]2[CH:18]([C:19]3[O:20][C:21]([S:24][C:25]4[NH:29][C:28]5[CH:30]=[CH:31][C:32]([OH:34])=[CH:33][C:27]=5[N:26]=4)=[CH:22][CH:23]=3)[C:17]3[C:16](=[O:35])[CH2:15][NH:14][CH2:13][C:12]=3[NH:11][C:10]=12)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]cc2c1NC1=C(C(=O)CN(OC(C)(C)C)C1)C2c1ccc(Sc2nc3cc(O)ccc3[nH]2)o1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1[nH]cc2c1NC1=C(C(=O)CNC1)C2c1ccc(Sc2nc3cc(O)ccc3[nH]2)o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73 %

Procedure:
A solution of 6-tert-butyloxy-9-[5-(5-hydroxy-1H-benzimidazol-2-ylsulfanyl)-furan-2-yl]-8-oxo-2,4,5,7,8,9-hexahydro-pyrrolo[3,4-b]-1,7-naphthyridine-3-carboxylic acid ethyl ester (0.27 g, 0.46 mmol) in dioxane (20 ml) is combined with 4N HCl in dioxane (1.7 ml). The reaction mixture is stirred at room temperature for 16 hours. The formed insoluble material is collected by filtration, washed with dioxane (50 ml), pentane (20 ml), diisopropylether (20 ml) and dried under vacuum to yield 176 mg of 9-[5-(5-hydroxy-1H-benzimidazol-2-ylsulfanyl)-furan-2-yl]-8-oxo-4,5,6,7,8,9-hexahydro-2H-pyrrolo[3,4-b]-1,7-naphthyridine-3-carboxylic acid ethyl ester hydrochloride as a white powder. Yield=73%. Analytical L/MS (method C): m/z=490 (negative ion mode [M−H]−), m/z=492 (positive ion mode [M+H]+).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:17])[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14]#[N:15])=[N:8][C:7]=1[NH2:16].Cl>CO>[NH2:16][C:7]1[N:8]=[C:9]([CH2:12][CH2:13][C:14]#[N:15])[CH:10]=[CH:11][C:6]=1[C:5]([OH:17])=[O:4]
Reactant: COC(=O)c1ccc(CCC#N)nc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N#CCCc1ccc(C(=O)O)c(N)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.9 %

Procedure:
To a solvent mixture of 2N-sodium hydroxide aqueous solution (5 mL) and methanol (5 mL) was added 2-amino-6-(2-cyanoethyl)-nicotinic acid methyl ester (90 mg, 0.439 mmol), and the solution was stirred for 18 hours at room temperature. This mixed solution was neutralized with 5N-hydrochloric acid, then, extracted with ethyl acetate. This organic layer was dried over anhydrous magnesium sulfate, then, the solvent was evaporated in vacuo, and the title compound (68 mg, 0.355 mmol, 81%) was obtained as a yellowish brown solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([OH:10])[C:5](=[CH:8][CH:9]=1)[CH:6]=O.[CH3:11][O:12][C:13]1[CH:26]=[CH:25][C:16]([CH2:17][S:18]([CH2:21][C:22](O)=[O:23])(=[O:20])=[O:19])=[CH:15][CH:14]=1>C(O)(=O)C>[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:17][S:18]([C:21]2[C:22](=[O:23])[O:10][C:4]3[C:5]([CH:6]=2)=[CH:8][CH:9]=[C:2]([OH:1])[CH:3]=3)(=[O:19])=[O:20])=[CH:25][CH:26]=1
Reactant: COc1ccc(CS(=O)(=O)CC(=O)O)cc1
Reactant: O=Cc1ccc(O)cc1O
Solvent: CC(=O)O
Product: COc1ccc(CS(=O)(=O)c2cc3ccc(O)cc3oc2=O)cc1
Yield: 30 %

Procedure:
A solution of 4-hydroxysalicylaldehyde (1 mmol) and 2-(4-methoxybenzylsulfonyl)acetic acid (1 mmol) in acetic acid (10 mL) was subjected to the General Procedure 2, Method A to generate a 30% yield of the title compound; m.p. 231-232° C.
Reaction SMILES: [N+:1]([C:4]1[C:12]2[S:11][C:10]([NH2:13])=[N:9][C:8]=2[CH:7]=[C:6]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:5]=1)([O-:3])=[O:2].[CH2:20]([N:22]=[C:23]=[O:24])[CH3:21]>O1CCOCC1>[CH2:20]([NH:22][C:23]([NH:13][C:10]1[S:11][C:12]2[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[CH:7][C:8]=2[N:9]=1)=[O:24])[CH3:21]
Reactant: CCN=C=O
Reactant: Nc1nc2cc(-c3cccnc3)cc([N+](=O)[O-])c2s1
Solvent: C1COCCO1
Product: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc([N+](=O)[O-])c2s1
Temperature: 100 °C
Yield: 23.8 %

Procedure:
A stirred mixture of 7-Nitro-5-pyridin-3-yl-benzothiazol-2-ylamine (100 mg, 0.3676 mmol), ethyl isocyanate (0.18 ml, 1.831 mmol) and dibutyltindiacetate (10 drops) in anhydrous 1,4-dioxane (10 ml) was heated in a sealed vessel at 100° C. for 16 h. After cooling to ambient temperature, the precipitated solid was collected by filtration, washed with 1,4-doxane and dried in vacuo to give 1-Ethyl-3-(7-nitro-5-pyridin-3-yl-benzothiazol-2-yl)-urea as a yellow solid (30 mg, 24%).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[N:12][C:11]([NH:14][NH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][C:9]=2[CH3:21])[CH:5]=[CH:6][CH:7]=1.Cl.N([O-])=O.[Na+].[C-:27]#[N:28].[K+]>C1(C)C=CC=CC=1.O>[C:27]([C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[N:12][C:11]([NH:14][NH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][C:9]=2[CH3:21])[CH:5]=[CH:6][CH:7]=1)#[N:28]
Reactant: CCOC(=O)NNc1cc(C)c(-c2cccc(N)c2)nn1
Reactant: [C-]#N
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)NNc1cc(C)c(-c2cccc(C#N)c2)nn1
Reaction time: 0.25 h

Procedure:
A solution of 2.87 g. of ethyl 3-[6-(m-aminophenyl)-5-methyl-3-pyridazinyl]carbazate, 80 ml. of water, 10 ml. of concentrated hydrochloric acid is stirred at 0° and a solution of 0.76 g. of sodium nitrite in 10 ml. of water added dropwise over 10 minutes. After stirring for 15 minutes, the cold solution is added dropwise to a cold solution of 2.5 g. of cuprous cyanide, 2.27 g. of potassium cyanide, 50 ml. of water and 35 ml. of toluene. After stirring at 0° for 1 hour and at room temperature overnight, the mixture is filtered and the solid washed with water to give 4.3 g. of gray crystals. Purification gives product as crystals, m.p. 189°-190° C.