Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:17]([OH:19])=O.[CH3:20][O:21][C:22](=[O:44])[C@@H:23]([NH:27][S:28]([C:31]1[CH:36]=[CH:35][C:34]([C:37]2[CH:42]=[CH:41][C:40]([NH2:43])=[CH:39][CH:38]=2)=[CH:33][CH:32]=1)(=[O:30])=[O:29])[CH:24]([CH3:26])[CH3:25].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C.[Cl-].[Na+].O>[CH3:20][O:21][C:22](=[O:44])[C@@H:23]([NH:27][S:28]([C:31]1[CH:36]=[CH:35][C:34]([C:37]2[CH:38]=[CH:39][C:40]([NH:43][C:17]([C:3]3[O:4][C:5]4[CH:10]=[CH:9][CH:8]=[C:7]([C:11]5[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=5)[C:6]=4[C:2]=3[CH3:1])=[O:19])=[CH:41][CH:42]=2)=[CH:33][CH:32]=1)(=[O:30])=[O:29])[CH:24]([CH3:26])[CH3:25]
Reactant: COC(=O)[C@@H](NS(=O)(=O)c1ccc(-c2ccc(N)cc2)cc1)C(C)C
Reactant: Cc1c(C(=O)O)oc2cccc(-c3ccncc3)c12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](NS(=O)(=O)c1ccc(-c2ccc(NC(=O)c3oc4cccc(-c5ccncc5)c4c3C)cc2)cc1)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.2 %

Procedure:
To 3-methyl-4-pyridin-4-yl-benzofuran-2-carboxylic acid (88 mg, 0.35 mmol) in 4 mL of DMF was added (S)-2-(4′-amino-biphenyl-4-sulfonylamino)-3-methyl-butyric acid methyl ester (252 mg, 0.7 mmol), BOP (307 mg, 0.7 mmol), and N,N-diisopropylethylamine (0.12 mL, 0.7 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was poured into brine, and extracted with ethyl acetate. The combined organic solution was washed with brine and water. Removal of the solvent in vacuo gave the crude product, which was purified by column chromatography on silica gel to give 172 mg of (S)-3-methyl-2-{4′-[(3-methyl-4-pyridin-4-yl-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-butyric acid methyl ester, obtained as white solid.
Reaction SMILES: [OH:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH3:13])[CH:3]=1.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>[OH-].[Na+].O>[CH3:14][S:15]([O:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH3:13])[CH:3]=1)(=[O:17])=[O:16]
Reactant: Cn1cc(O)c(=O)c2ccccc21
Reactant: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cn1cc(OS(C)(=O)=O)c(=O)c2ccccc21
Reaction time: 0.25 h

Procedure:
3-Hydroxy-1-methyl-4-quinolone (30 g) was dissolved in a solution of sodium hydroxide (8 g) in water (440 ml). Activated carbon (3 g) was added and the mixture stirred at 40° for 15 minutes. The mixture was filtered and the filtrate cooled in an ice/salt bath at 0 to 5° under nitrogen. Methanesulphonyl chloride (1 5.5 ml) was added dropwise over 30 minutes and the mixture then stirred at 0 to 5° for 30 minutes. Aqueous sodium hydroxide (5M, 40 ml) was added and the mixture stirred at 0 to 5° for a further 90 minutes. The resultant solid was collected by filtration and washed with water (2×50 ml) to yield crude product. The filtrate was treated with further methanesulphonyl chloride (15.5 ml) in a similar manner to that described above to give a second crop of crude product. The two crops of crude product were combined and crystallised from industrial methylated spirit (2 1) to give the novel compound 1-methyl-4-oxo-1,4-dihydroquinol-3-yl methanesulphonate, m.p. 208°-209°.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]([NH:21][CH3:22])=[O:20])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1.[Cl:29][C:30]1[CH:35]=[C:34](F)[CH:33]=[CH:32][C:31]=1[N+:37]([O-:39])=[O:38].C(=O)([O-])[O-].[K+].[K+]>COCCOC.O>[Cl:29][C:30]1[CH:35]=[C:34]([N:24]([C:5]2[C:4]([CH:1]3[CH2:3][CH2:2]3)=[CH:23][C:8]3[C:9]([C:19]([NH:21][CH3:22])=[O:20])=[C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)[O:11][C:7]=3[CH:6]=2)[S:25]([CH3:28])(=[O:27])=[O:26])[CH:33]=[CH:32][C:31]=1[N+:37]([O-:39])=[O:38]
Reactant: O=[N+]([O-])c1ccc(F)cc1Cl
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(NS(C)(=O)=O)c(C3CC3)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc([N+](=O)[O-])c(Cl)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 100 °C
Yield: 128.5 %

Procedure:
A mixture of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (12.5 g, 31.1 mmol), 2-chloro-4-fluoronitrobenzene (10.9 g, 62.1 mmol) and potassium carbonate (12.9 g, 93.0 mmol) in 130 mL of 4:1 DME/water in a sealed flask was heated to 100° C. with stirring. An identical 12.5 g scale reaction was set up in a second sealed vessel. The reaction vessels were maintained at 100° C. for 70 hours, cooled to RT, and stirred for an additional 18 hours. The combined reaction mixtures were partitioned between EtOAc (300 mL) and water (600 mL), and the phases separated. The aqueous solution was extracted with two additional 150 mL portions of EtOAc. The combined EtOAc solutions were washed with half saturated brine (1×), saturated brine (1×), dried over sodium sulfate and concentrated to dryness at reduced pressure. The resulting yellow-brown solid was recrystallized from EtOAc/ether to give the title compound (22.3 g, 64%) as an off-white solid. LCMS (m/z, ES+)=558 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:17]3[CH:25]=[C:24](Cl)[N:23]=[CH:22][C:18]=3[N:19]=[CH:20][N:21]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:27]1[CH2:31][CH2:30][O:29][CH:28]1[C:32]1[CH:33]=[C:34]([Sn](CCCC)(CCCC)CCCC)[CH:35]=[CH:36][CH:37]=1>O1CCOCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:17]3[CH:25]=[C:24]([C:34]4[CH:35]=[CH:36][CH:37]=[C:32]([CH:28]5[O:27][CH2:31][CH2:30][O:29]5)[CH:33]=4)[N:23]=[CH:22][C:18]=3[N:19]=[CH:20][N:21]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(C2OCCO2)c1
Reactant: Clc1cc2c(Nc3ccc(OCc4ccccc4)cc3)ncnc2cn1
Solvent: C1COCCO1
Product: c1ccc(COc2ccc(Nc3ncnc4cnc(-c5cccc(C6OCCO6)c5)cc34)cc2)cc1
Yield: 13.7 %

Procedure:
(4-Benzyloxy-phenyl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine (1.4 g) and 3-(1,3-dioxolan-2-yl)-phenyl-tributylstannane (3.08 g) [A. Lee and W-C. Dai, Tetrahedron (1997), 53(3), 859-868] in dioxan (30 ml) were reacted together as in Procedure B. The mixture was evaporated and the residue suspended in dichloromethane. This was then filtered through celite and the solvent evaporated. The gummy residue was then triturated with hexane giving a beige solid. This material was further purified by column chromatography, giving a brown foam (252 mg); m/z 477 (M+1)+.
Reaction SMILES: [SH:1][CH2:2][C@@H:3]([CH3:14])[C:4]([N:6]1[C@H:10]([C:11]([OH:13])=[O:12])[CH2:9][S:8][CH2:7]1)=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH:21]1([C:27](Cl)=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>O>[CH:21]1([C:27]([S:1][CH2:2][C@@H:3]([CH3:14])[C:4]([N:6]2[C@H:10]([C:11]([OH:13])=[O:12])[CH2:9][S:8][CH2:7]2)=[O:5])=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: C[C@H](CS)C(=O)N1CSC[C@H]1C(=O)O
Reactant: O=C(Cl)C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: C[C@H](CSC(=O)C1CCCCC1)C(=O)N1CSC[C@H]1C(=O)O
Temperature: 25 °C

Procedure:
2.4 g of (4R)-3-[(2S)-3-mercapto-2-methylpropanoyl]-4-thiazolidinecarboxylic acid and 2.8 g of potassium carbonate are dissolved in 50 ml of water. To this solution, 1.8 g of cyclohexanecarbonyl chloride is added dropwise with stirring under ice-cooling. After the addition, the mixture is stirred under ice-cooling for 1 hour and at room temperature for additional 1 hour. This reaction solution is washed with ethyl acetate, acidified with conc. hydrochloric acid, and extracted with ethyl acetate. The organic layer is washed with saturated sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo to give oil, yield 3.5 g. The oil is purified by silica gel column chromatography to give the titled compound, yield 2.8 g (81%), mp. 79.5°-80° C. (benzene-n-hexane), [α]D23 -176.2° (c=1.0, methanol).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[S:10][C:9]([CH:11]=[C:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH:24](O)=O.C=O>O.ClCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[S:10][C:9]([CH:11]=[C:12]3[CH2:13][CH2:14][N:15]([CH3:24])[CH2:16][CH2:17]3)=[CH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2sc(C=C3CCNCC3)cc2n1
Reactant: O=CO
Agent: C=O
Solvent: O
Solvent: ClCCl
Product: CN1CCC(=Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To a mixture of 2-chloro-4-morpholin-4-yl-6-piperidin-4-ylidenemethyl-thieno[3,2-d]pyrimidine (500 mg) and formic acid (2.5 mL) at room temperature was added formaldehyde (0.5 mL of a 37 wt % solution in water). The reaction mixture was stirred at 60° C. for 16 h. The mixture was then diluted with dichloromethane (2 mL) and washed with 2 M aqueous sodium hydroxide solution (20 mL) and brine (20 mL), dried (MgSO4), reduced in vacuo and purified by column chromatography to give 2-chloro-6-(1-methyl-piperidin-4-ylidenemethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine as a yellow solid (0.15 g).
Reaction SMILES: [F:1][C:2]([F:44])([C:40]([F:43])([F:42])[F:41])[CH2:3][CH2:4][CH2:5][S:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20](/[C:23](/[C:33]2[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=2)=[C:24](\[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)/[CH2:25][CH3:26])=[CH:19][CH:18]=1.[OH:45]O>C(OCC)(=O)C.C(O)(=O)C.O>[F:44][C:2]([F:1])([C:40]([F:41])([F:42])[F:43])[CH2:3][CH2:4][CH2:5][S:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20](/[C:23](/[C:33]2[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=2)=[C:24](\[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)/[CH2:25][CH3:26])=[CH:19][CH:18]=1)=[O:45]
Reactant: OO
Reactant: CC/C(=C(\c1ccc(O)cc1)c1ccc(OCCNCCCCCCSCCCC(F)(F)C(F)(F)F)cc1)c1ccccc1
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC/C(=C(\c1ccc(O)cc1)c1ccc(OCCNCCCCCCS(=O)CCCC(F)(F)C(F)(F)F)cc1)c1ccccc1

Procedure:
(Z)-4-(1-(4-(2-(6-(4,4,5,5,5-pentafluoropentylthio)hexylamino)ethoxy)phenyl)-2-phenylbut-1-enyl)phenol from the previous reaction is dissolved in ethyl acetate and acetic acid. To this solution is added hydrogen peroxide solution in water. The mixture is stirred until the reaction is complete (TLC). Excess hydrogen peroxide is destroyed by addition of sodium sulfite solution in water. The phases are separated and the aqueous phase is washed with ethyl acetate. The combined organic phases are dried over sodium sulfate, filtered and concentrated under reduced pressure to afford (Z)-4-(1-(4-(2-(6-(4,4,5,5,5-pentafluoropentylsulfinyl)hexylamino)ethoxy)phenyl)-2-phenylbut-1-enyl)phenol among other products.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C:9]2[C:12]3[C:13](=[C:15]([O:22][CH3:23])[CH:16]=[CH:17][C:18]=3[C:19]([OH:21])=[O:20])[O:14][C:8]=2[CH2:7]1)=[O:5])[CH3:2].[N+:24]([C:27]1[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=1)([O-:26])=[O:25].CCN=C=NCCCN(C)C.Cl.O>CN(C1C=CN=CC=1)C.O1CCCC1>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C:9]2[C:12]3[C:13](=[C:15]([O:22][CH3:23])[CH:16]=[CH:17][C:18]=3[C:19]([O:21][C:30]3[CH:31]=[CH:32][C:27]([N+:24]([O-:26])=[O:25])=[CH:28][CH:29]=3)=[O:20])[O:14][C:8]=2[CH2:7]1)=[O:5])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CCOC(=O)N1CCc2c(oc3c(OC)ccc(C(=O)O)c23)C1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)N1CCc2c(oc3c(OC)ccc(C(=O)Oc4ccc([N+](=O)[O-])cc4)c23)C1

Procedure:
A solution of 2-(ethoxycarbonyl)-8-methoxy-1,2,3,4-tetrahydro[1]benzofuro[2,3-c]pyridine-5-carboxylic acid (from step 7) (0.352 g, 1.1 mmol), 4-nitrophenol (0.229 g, 1.65 mmol), EDCl (0.253 g, 1.32 mmol) and 4-(N,N-dimethyl)aminopyridine (0.027 g, 0.22 mmol) in tetrahydrofuran was stirred overnight. Water was added to RM, extracted with ethyl acetate and org layer was concentrated after drying on anhy. Sod. Sulphate. The solid was chromatographed on silica gel to yield 4-nitrophenyl 2-(ethoxycarbonyl)-8-methoxy-1,2,3,4-tetrahydro[1]benzofuro[2,3-c]pyridine-5-carboxylate.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:28][C:12]2=[CH:13][C:14]3[C:15](=[O:27])[N:16]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[C:17](=[O:21])[C:18]=3[C:19]([CH3:20])=[C:11]2[N:10]=1.[F:29][C:30]1[C:35]([F:36])=[CH:34][C:33]([F:37])=[C:32]([F:38])[C:31]=1[CH2:39][CH:40]([NH2:42])[CH3:41].CCN(C(C)C)C(C)C>C(O)CCC>[CH3:25][N:24]([CH3:26])[CH2:23][CH2:22][N:16]1[C:15](=[O:27])[C:14]2[CH:13]=[C:12]3[NH:28][C:9]([C:3]4[C:4](=[O:8])[NH:5][CH:6]=[CH:7][C:2]=4[NH:42][CH:40]([CH3:41])[CH2:39][C:31]4[C:32]([F:38])=[C:33]([F:37])[CH:34]=[C:35]([F:36])[C:30]=4[F:29])=[N:10][C:11]3=[C:19]([CH3:20])[C:18]=2[C:17]1=[O:21]
Reactant: CC(N)Cc1c(F)c(F)cc(F)c1F
Reactant: Cc1c2c(cc3[nH]c(-c4c(Cl)cc[nH]c4=O)nc13)C(=O)N(CCN(C)C)C2=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1c2c(cc3[nH]c(-c4c(NC(C)Cc5c(F)c(F)cc(F)c5F)cc[nH]c4=O)nc13)C(=O)N(CCN(C)C)C2=O
Yield: 42.8 %

Procedure:
A mixture of 2-(4-chloro-2-oxo-1,2-dihydropyridin-3-yl)-6-(2-(dimethylamino)ethyl)-4-methylimidazo[4,5-f]isoindole-5,7(1H,6H)-dione, (0.54 g, 1.35 mmol), 1-(2,3,5,6-tetrafluorophenyl)propan-2-amine (0.34 g, 1.62 mmol), Hunig's base (0.87 g, 6.75 mmol), and 12 mL of anhydrous 1-butanol was heated at reflux for 13-14 h under an argon atmosphere. Product was purified by a silica gel column using methylene chloride and methanol (9:1 v/v) as eluent to afford 0.33 g of the designed compound as yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 13.33 (s, 1H, NH), 11.29 (br s, 1H, NH), 11.00 (d, J=5.7 Hz, 1H, NH), 7.97 (s, ArH), 7.73-7.70 (m, 1H, ArH), 7.40 (d, J=7.6 Hz, 1H, ArH), 6.21 (d, J=7.6 Hz, 1H, ArH), 4.32-4.28 (m, 1H, CH), 3.65 (t, J=6.3 Hz, 2H, CH2), 3.08 (d, J=5.1 Hz, 2H, CH2), 2.72 (s, 3H, CH3), 2.19 (S, 6H, 2×CH3); 1.36 (d, J=6.3 Hz, 3H, CH3), 1.11 (t, J=6.3 Hz, 2H, CH2); Mass (ESI, negative) m/z 568.8 [M−H]−.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][OH:12])=[CH:9][C:4]=2[CH:3]=[CH:2]1.[OH-].[K+].[C:15]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:18])[CH:16]=[CH2:17].Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.O>[S:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][O:12][CH2:17][CH2:16][C:15]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: OCCc1ccc2sccc2c1
Reactant: C=CC(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)CCOCCc1ccc2sccc2c1
Temperature: 47.5 °C
Reaction time: 2 h

Procedure:
To 4.60 g of 2-(1-benzothiophen-5-yl)-1-ethanol were added 29 mg of potassium hydroxide, 83 mg of tetra-n-butylammonium bromide and 5.67 mL of tert-butyl acrylate, and the resulting mixture was stirred at 45 to 50° C. for 2 hours. After the reaction mixture was cooled, water and toluene were added thereto and the pH was adjusted to 1 with 6 mol/L hydrochloric acid, and the organic layer was separated. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The residue was purified by a column chromatography (eluent; hexane ethyl acetate=5:1) to obtain 7.70 g of tert-butyl 3-[2-(1-benzothiophen-5-yl)ethoxy]propionate as a colorless oil.
Reaction SMILES: II.[C:3]1(=[O:12])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.Br[CH2:14]/[CH:15]=[CH:16]/[C:17]([O:19][CH3:20])=[O:18].[Cl-].[NH4+]>O1CCCC1.[Zn]>[OH:12][C:3]1([CH2:14]/[CH:15]=[CH:16]/[C:17]([O:19][CH3:20])=[O:18])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1
Reactant: COC(=O)/C=C/CBr
Reactant: O=C1CCc2ccccc21
Agent: II
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)/C=C/CC1(O)CCc2ccccc21
Yield: 44.4 %

Procedure:
A suspension of activated zinc (80 g) in dry tetrahydrofuran (200 ml) was heated to reflux and a few crystals of iodine was added. A solution of 1-indanone (100 g) and methyl 4-bromo-crotonate (200 g) in 500 ml of dry tetrahydrofuran was added dropwise followed by reflux for 1 h. After cooling, ice and aq. ammonium chloride was added followed by extraction with dichloromethane. Removal of the solvent in vacuo gave a viscous oil which was purified on a silica gel column (eluent:dichloromethane/ether =1:1) giving methyl 4-(1-hydroxyindan-1-yl)-crotonate (78 g). A solution of the crotonate (20 g) was dissolved in 200 ml dry ether and added dropwise to a suspension of lithium aluminium hydride (10 g) in 150 ml of dry ether. After reflux for 1 h, the reaction mixture was hydrolyzed with water. Filtration, drying of the ether phase over magnesium sulfate, and removal of solvent in vacuo gave 4-(1-hydroxyindan-1-yl)-1-butanol (18 g) as an oil. The alcohol (16 g) was dissolved in methanol (250 ml) and concentrated hydrochloric acid (40 ml) was added. After stirring for 30 min at room temperature, the reaction mixture was concentrated in vacuo, water was added and the mixture extracted with ether. Drying of the ether phase over magnesium sulfate and removal of solvent in vacuo gave a viscous oil which was applied to a silica gel column (eluent:dichloromethane/ether=9:1) giving 4-((1H)inden-3-yl)-1-butanol (1.8 g). By the method described in EXAMPLE 2, the alcohol was converted to the corresponding methanesulfonate and the title compound, 27, was obtained using spiro[isobenzofuran-1(3H),4'-pi-peridine], mp: 79°-80° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([F:10])[C:7](F)=[CH:6][C:5]=1[Cl:12].Cl.[CH3:15][NH:16][CH3:17].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([F:10])[C:7]([N:16]([CH3:17])[CH3:15])=[CH:6][C:5]=1[Cl:12]
Reactant: CNC
Reactant: COC(=O)c1cc(F)c(F)cc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1cc(F)c(N(C)C)cc1Cl
Temperature: 60 °C
Reaction time: 24 h
Yield: 89.5 %

Procedure:
To a stirred solution of 23.1 g (112 mmol) 22a and 231 ml dimethylsulphoxid were added 10.0 g (123 mmol) dimethylamine hydrochloride and 32.4 g (234 mmol) potassium carbonate. The reaction mixture was stirred for 24 h at 60° C. in an autoclave and was reduced with high vacuum rotation evaporator at 65° C. The residue was diluted with dichloromethane, washed twice with water. The combined water phases were extracted with dichloromethane. The combined dichloromethane phases were washed with diluted sodium hydrogen carbonate solution, dried with sodium sulphate and concentrated. The oily crude was purified by column chromatography and the desired product 22b was obtained in 89.5% yield (23.1 g 100 mmol).
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]([NH2:7])=[NH:6])=[NH:3].Br[CH2:9][C:10](=O)[CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]2[C:16]1=[O:25].C(O)(=O)C>CN(C)C=O>[NH:4]([C:5]1[NH:7][CH:9]=[C:10]([CH2:11][CH2:12][CH2:13][CH2:14][N:15]2[C:16](=[O:25])[C:17]3=[CH:24][CH:23]=[CH:22][CH:21]=[C:18]3[C:19]2=[O:20])[N:6]=1)[C:2]([NH2:1])=[NH:3]
Reactant: O=C(CBr)CCCCN1C(=O)c2ccccc2C1=O
Reactant: N=C(N)NC(=N)N
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: N=C(N)Nc1nc(CCCCN2C(=O)c3ccccc3C2=O)c[nH]1
Reaction time: 3 h

Procedure:
Biguanide (1.01 g.) was stirred in dry dimethylformamide (15 ml.) and N-(6-bromo-5-oxohexyl)phthalimide (1.5 g.) added. The mixture was stirred for 3 hours, acetic acid (5 ml.) was then added and the total reaction mixture evaporated to dryness. The residue was dissolved in water (10 ml.) and extracted with ethyl acetate (5×20 ml.). The combined ethyl acetate extracts were evaporated to give a brown foam which was purified by column chromatography on silica gel using chloroform/methanol/ammonia (s.g. 0.880) 80:20:0.5 v/v/v. The appropriate fractions were evaporated to give 2-guanidino-4-(4-phthalimidobutyl)imidazole as a brown foam (0.3 g.).
Reaction SMILES: [C:1]1(=[O:8])[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:9].[OH2:10]>>[ClH:9].[NH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([OH:8])=[O:10]
Reactant: O=C1CCCCCN1
Reactant: O
Agent: Cl
Product: NCCCCCC(=O)O
Temperature: 25 °C

Procedure:
ε-Caprolactam (750.00 g, 6.63 mol), water (1500 mL), and concentrated HCl (675 mL, 36-38%) are combined in a 5000 mL three-necked round bottomed flask fitted with a mechanical stirrer and condenser. The mixture is heated for 4 h at reflux, cooled to room temperature, and concentrated by rotary evaporation at 50° C. (water aspirator vacuum) to give 1 as a white solid. The absence of ε-caprolactam by TLC (Rf =0.21, THF) indicates the reaction is complete.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12]([O:16][C:17]([N:19]1[CH:24]([CH:25]=[O:26])[CH:23]2[CH:27]([CH2:28][O:29][CH3:30])[CH:20]1[CH2:21][CH2:22]2)=[O:18])([CH3:15])([CH3:14])[CH3:13].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(OCC)(=O)C>[C:12]([O:16][C:17]([N:19]1[CH:24]([CH:25]([OH:26])[CH:8]([N+:9]([O-:11])=[O:10])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:23]2[CH:27]([CH2:28][O:29][CH3:30])[CH:20]1[CH2:21][CH2:22]2)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: COCC1C2CCC1N(C(=O)OC(C)(C)C)C2C=O
Reactant: O=[N+]([O-])CCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Product: COCC1C2CCC1N(C(=O)OC(C)(C)C)C2C(O)C(Cc1ccccc1)[N+](=O)[O-]
Yield: 51.4 %

Procedure:
Add 1-phenyl-2-nitroethane (0.350 g, 2.23 mmol) to a solution of 3-formyl-7-methoxymethyl-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (0.400 g, 1.48 mmol) in anhydrous tetrahydrofaran (5 mL) cooled in an ice bath. Add tetrabutylammonium fluoride (1.0 M in tetrahydrofuran, 1.48 mL, 1.48 mmol) and stir the mixture in an ice bath for 1 h. Dilute the mixture with ethyl acetate, and wash the solution with saturated aqueous sodium chloride, dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with 20:80 to 30:70 ethyl acetate:hexanes) to give the title compound (0.320 g, 51%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7](=[O:23])[CH2:8][O:9][CH:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)[CH2:3][CH2:2]1.Cl.CC(O)C>>[O:1]1[CH2:6][CH2:5][N:4]([C:7](=[O:23])[CH2:8][O:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(OCC(=O)N2CCOCC2)CC1
Agent: Cl
Solvent: CC(C)O
Product: O=C(COC1CCNCC1)N1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.1 %

Procedure:
Tert-butyl 4-(2-morpholino-2-oxoethoxy)piperidine-1-carboxylate (75) (5 g, 15.23 mmol) was added to 6.0 HCl in propan-2-ol (30 mL, 180.00 mmol) and the reaction was stirred at 25° C. for 2 hours. The reaction mixture was evaporated to dryness and the crude material was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH and fractions were evaporated to dryness to afford a yellow gum. The crude product was purified by distillation at 0.72 mBar, collecting fractions that distilled at 155° C. to afford the desired material as a colourless gum (1.950 g, 56.1% yield); 1H NMR (400.132 MHz, CDCl3) δ 1.50-1.41 (2H, m), 1.96-1.89 (2H, m), 2.64-2.58 (2H, m), 3.10-3.04 (2H, m), 3.50-3.43 (1H, m), 3.63-3.56 (4H, m), 3.70-3.67 (4H, m), 4.17 (2H, s); NH proton missing.