Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:21]3[C:22]4=[C:23]5[C:18](=[CH:19][CH:20]=3)[CH:17]=[CH:16][CH:15]=[C:14]5[CH:13]=[CH:12][C:11]4=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Br:24]N1C(=O)CCC1=O.CN(C)C=O>O>[Br:24][C:15]1[C:14]2[C:23]3=[C:22]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)=[C:21]4[CH:20]=[CH:19][C:18]3=[CH:17][CH:16]=1
Reactant: Cc1ccc(-c2ccc3ccc4cccc5ccc2c3c45)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-c2ccc3ccc4c(Br)ccc5ccc2c3c54)cc1
Temperature: 40 °C
Reaction time: 7 h
Yield: 22.4 %

Procedure:
A mixed solution of 40 g of 1-(4-methylphenyl)pyrene, 24.4 g of N-bromosuccinimide and 1.4 l of dimethylformamide was then heated and stirred at 40° C. for 7 hours under a nitrogen stream. After the mixture was cooled to room temperature, 1 l (liter) of water was added thereto, and the mixture was extracted with 500 ml of dichloromethane. The organic layer was washed twice with 200 ml of water, dried over magnesium sulfate, and then filtered through celite. The filtrate was evaporated, and the resulting residue was washed twice with 200 ml of ethyl acetate. The precipitated solid was separated by filtration and dried under vacuum to give 11.4 g of 1-bromo-6-(4-methylphenyl)pyrene.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>C(Cl)Cl>[ClH:21].[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[O:27])=[CH:24][CH:23]=1
Reactant: NCCCSc1ccncc1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCCSc1ccncc1)c1ccc(Cl)cc1
Yield: 118.6 %

Procedure:
To a solution of 1.00 g (4.15 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 2.77 ml (19.8 mmol) of triethylamine in 40 ml of methylene chloride was added 0.63 ml (4.96 mmol) of 4-chlorobenzoyl chloride under ice-cooling with stirring and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution and water and dried. The solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain the powder which was washed with ether and dried to obtain 1.01 g of the desired compound (free base) (79.3%, pale yellow powder), mp: 95.0°-96.0° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH3:17])[CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=[C:4]([CH2:18][CH3:19])[C:3]=1[C:20]([NH2:22])=[O:21].CC(C)([O-])C.[K+].[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH2:41][C:42](OC)=O)[CH:34]=[C:35]([O:39][CH3:40])[C:36]=1[O:37][CH3:38]>C(O)C>[CH3:40][O:39][C:35]1[CH:34]=[C:33]([CH:32]=[C:31]([O:30][CH3:29])[C:36]=1[O:37][CH3:38])[CH2:41][C:42]1[NH:22][C:20](=[O:21])[C:3]2[C:4]([CH2:18][CH3:19])=[N:5][N:6]([CH:7]([CH3:17])[CH2:8][CH2:9][CH2:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:2]=2[N:1]=1
Reactant: COC(=O)Cc1cc(OC)c(OC)c(OC)c1
Reactant: CCc1nn(C(C)CCCc2ccccc2)c(N)c1C(N)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Product: CCc1nn(C(C)CCCc2ccccc2)c2nc(Cc3cc(OC)c(OC)c(OC)c3)[nH]c(=O)c12
Yield: 41.6 %

Procedure:
400 mg (1.4mmol) of 5-amino-3-ethyl-1-(1-methyl-4-phenyl-butyl)-1H-pyrazole-4-carboxamide, 750 mg (6.7 mmol) of potassium tert-butoxide and 720 mg (3.0 mmol) of methyl 3,4,5-trimethoxy-phenylacetate are refluxed for 16 hours in 10 ml of ethanol. After the solvent has been removed, the mixture is acidified with 1N HCl, extracted 3 times with dichloromethane, the organic phase is dried over sodium sulphate and the solvent is removed in vacuo. Purification by chromatography gives 286 mg (40%) of a solid, Rf=0.62 (ethyl acetate/cyclohexane=2:1).
Reaction SMILES: Cl([O-])(=O)(=O)=O.[Mg+2].Cl([O-])(=O)(=O)=O.[Br:12][C:13]1[CH:14]=[C:15]([C@@H:19]2[O:21][C@H:20]2[CH2:22][OH:23])[CH:16]=[CH:17][CH:18]=1.[CH2:24]([O:31][C:32]1[CH:33]=[CH:34][CH:35]=[C:36]2[C:40]=1[NH:39][CH2:38][CH2:37]2)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(OCC)(=O)C>C(#N)C>[Br:12][C:13]1[CH:14]=[C:15]([C@@H:19]([N:39]2[C:40]3[C:36](=[CH:35][CH:34]=[CH:33][C:32]=3[O:31][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:37][CH2:38]2)[C@H:20]([OH:21])[CH2:22][OH:23])[CH:16]=[CH:17][CH:18]=1
Reactant: c1ccc(COc2cccc3c2NCC3)cc1
Reactant: OC[C@@H]1O[C@H]1c1cccc(Br)c1
Agent: [Mg+2]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: OC[C@@H](O)[C@@H](c1cccc(Br)c1)N1CCc2cccc(OCc3ccccc3)c21
Yield: 84.5 %

Procedure:
Magnesium perchlorate (16.63 g, 74.52 mmol) was added in portions to a magnetically stirred solution of (2S-trans)-3-(3-bromophenyl)oxiranemethanol (16.32 g, 71.26 mmol) in dry acetonitrile (100 ml) at 5° C. under nitrogen. After stirring for 10 min. all of the magnesium salts had dissolved and the resulting intense yellow solution was treated with 7-benzyloxyindoline (16.77 g, 74.52 mmol) in acetonitrile (30.0 ml) dropwise at 0° C. for 20 h, quenched with saturated aqueous NaHCO3 (300 ml), extracted with ethyl acetate (3×200 ml), the combined organic phases were washed with brine (3×200 ml), dried (Na2SO4) and the solvent removed in vacuo to provide a yellow/brown gum. Column chromatography (ethyl acetate--light petroleum (b.p. 40-60° C.), 3:7) provided the title compound (27.37 g, 87%) as a grey/green oil which crystallised on standing. Recrystallised from diethyl ether at -20° C. as white crystals, m.p. 61-66° C. (Found: C, 63.51; H, 5.78; N, 2.84. C24H24BrNO3 requires C, 63.44; H, 5.32; N, 3.08%); [α]D25 -311.1 (c=0.009 gml-1, CHCl3); Vmax (nujol)/cm-1 3353.0 (br. OH), 1584.0, 1565.0; δH (270 MHz) 2.27 (1H, bs, OH); 2.66 (3H, m, OH, 2×indoline 2-H); 3.10 (1H, m, indoline 3-H); 3.30 (1H, m, indoline 3-H); 3.85 (2H, dq, 2×1-H, 2J1,1 =11.5, 3J1,2 =4.0 Hz); 4.22 (1H, m, 2-H); 5.16 (2H, s, CH2Ph); 5.38 (1H, d, 3-H, 3J3,2 =10.2 Hz); 6.65-7.49 (12H, m, 12 ArH). δC (67.8 MHz) 29.2 (indoline 2-C); 46.5 (indoline 3-C); 61.7 (3-C); 64.8 (1-C); 69.9 (C-2); 70.9 (CH2Ph); 112.2 (indoline 6-C); 118.1 (indoline 5-C); 120.3 (indoline 4-C); 122.4 (3'-C); 136.4 (1'-C); 138.5 indoline 7a-C); 139.5 (bensyl ipso-C); 145.0 (indoline 7-C). The remaining signals lie between 127.5-136.4 ppm and could not be assigned with any certainty; m/z 455.3, 453.3 (0.58, 0.74, M+), 394.2, 392.2 (7.81, 7.90), 304.1, 302.1 (4.80, 9.32), 225.2 (8.35), 171.0, 169.0 (5.29, 5.79), 134.1 (34.82), 118.1 (1.35), 59.1 (100).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([CH2:12][NH2:13])[CH2:4][CH2:3]1.F[C:16]1[CH:24]=[N:23][CH:22]=[CH:21][C:17]=1[C:18]([OH:20])=[O:19]>>[CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([CH2:12][NH:13][C:21]2[CH:22]=[N:23][CH:24]=[CH:16][C:17]=2[C:18]([OH:20])=[O:19])[CH2:4][CH2:3]1
Reactant: CC1(C)CCC(CN)c2ccccc21
Reactant: O=C(O)c1ccncc1F
Product: CC1(C)CCC(CNc2cnccc2C(=O)O)c2ccccc21
Yield: 17 %

Procedure:
The title compound was prepared in 17% yield from 1-(4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)methanamine and 3-fluoroisonicotinic acid according to the procedure for the preparation of Example 5. 1H NMR (400 MHz, DMSO-d6): δ 13.36 (br s, 1H), 8.37 (s, 1H), 7.83 (d, 1H, J=5.0 Hz), 7.59 (br s, 1H), 7.55 (d, 1H, J=5.0 Hz), 7.38 (d, 1H, J=7.8 Hz), 7.26 (d, 1H, J=6.8 Hz), 7.07-7.19 (m, 2H), 3.47-3.58 (m, 2H), 3.07-3.11 (m, 1H), 1.77-1.90 (m, 3H), 1.51-1.57 (m, 1H), 1.31 (s, 3H), 1.21 (s, 3H). [M+H] calc'd for C19H22N2O2, 311. Found 311.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][CH:12]=[C:13]([CH2:15][C:16]([OH:18])=[O:17])[N:14]=2)=[CH:6][CH:5]=1>C(O)(=O)C>[Br:1][C:12]1[S:11][C:10]([C:7]2[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=2)=[N:14][C:13]=1[CH2:15][C:16]([OH:18])=[O:17]
Reactant: O=C(O)Cc1csc(-c2ccc(Cl)cc2)n1
Reactant: BrBr
Solvent: CC(=O)O
Product: O=C(O)Cc1nc(-c2ccc(Cl)cc2)sc1Br
Temperature: 0 °C
Yield: 75.2 %

Procedure:
Bromine (15.9 g, 5.15 ml, 0.1 mol) was added dropwise to 2-(4-chlorophenyl) thiazol-4-yl acetic acid (24 g, 0.096mol) suspended in glacial acetic acid (200 ml) and the resulting mixture was heated at 60°-70° C. for 5 hours. The reaction mixture was cooled to 0° C. (ice bath) and the solid which separated was filtered and washed with CHCl3. The residue was then washed with cold ethanol to afford the desired product (24 g, 75%)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[F:9].C([Mg]Cl)(C)C.[Cl-].[Li+].[C:17]1(=[O:21])[CH2:20][CH2:19][CH2:18]1>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:17]2([OH:21])[CH2:20][CH2:19][CH2:18]2)=[CH:4][C:3]=1[F:9]
Reactant: O=C1CCC1
Reactant: Fc1cc(I)ccc1Br
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OC1(c2ccc(Br)c(F)c2)CCC1
Temperature: -40 °C
Reaction time: 0.17 h
Yield: 87.8 %

Procedure:
To 1-bromo-2-fluoro-4-iodobenzene (2390 mg, 7.90 mmol) in tetrahydrofuran (20 mL) at −40° C. was added isopropyl magnesium chloride.lithium chloride (1.3 M in THF, 6.4 mL, 5.1 mmol) dropwise. The reaction mixture was stirred at −40° C. for 10 minutes, and treated with additional isopropyl magnesium chloride.lithium chloride (1.3 M in THF, 1 mL, 1.3 mmol). The reaction mixture was stirred at −40° C. for an additional 20 minutes and then treated with cyclobutanone (624 mg, 8.72 mmol) dropwise at −40° C. The reaction mixture was warmed to room temperature, and stirred at room temperature for 16 hours. The reaction mixture was quenched with water and extracted with ethyl acetate (3×240 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound (1.7 g, 91%) as an oil.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4]1[C:5]2[N:14]=[C:13]([C:15]3[CH:16]=[C:17]([S:24]([N:27]4[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]4)(=[O:26])=[O:25])[CH:18]=[CH:19][C:20]=3[O:21][CH2:22][CH3:23])[NH:12][C:10](=[O:11])[C:6]=2[N:7]([CH3:9])[N:8]=1.C(C(O)(C(O)=O)CC(O)=O)C(O)=O.CO.[ClH:49]>C(O)C>[CH3:1][CH2:2][CH2:3][C:4]1[C:5]2[NH:14][C:13]([C:15]3[CH:16]=[C:17]([S:24]([N:27]4[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]4)(=[O:25])=[O:26])[CH:18]=[CH:19][C:20]=3[O:21][CH2:22][CH3:23])=[N:12][C:10](=[O:11])[C:6]=2[N:7]([CH3:9])[N:8]=1.[ClH:49]
Reactant: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)N4CCN(C)CC4)ccc3OCC)nc12
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CO
Solvent: CCO
Product: CCCc1nn(C)c2c(=O)nc(-c3cc(S(=O)(=O)N4CCN(C)CC4)ccc3OCC)[nH]c12

Procedure:
Sildenafil citrate (9.5 g) is dissolved in a mixture of ethanol (10 mL) and HCl (1N, 60 mL), then reacted at 50° C. for 10 mins. Under room temperature, the methanol is added for incubating over night and crystallization. Then, the crystal is filtrated to obtain precipitate of Sildenafil HCl (6.4 g) for use.
Reaction SMILES: C(N(CC)CC)C.[C:8]([OH:14])(=[O:13])[CH2:9][CH:10]([CH3:12])[CH3:11].[F:15][CH:16]([CH2:18][C:19](Cl)=[S:20])[F:17]>O1CCCC1>[C:8]([O:14][C:19](=[S:20])[CH2:18][CH:16]([F:17])[F:15])(=[O:13])[CH2:9][CH:10]([CH3:12])[CH3:11]
Reactant: CC(C)CC(=O)O
Reactant: FC(F)CC(=S)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)CC(=O)OC(=S)CC(F)F
Reaction time: 1 h

Procedure:
To a stirred solution of triethylamine (1.4 equivalents) and isovaleric acid (1.3 equivalents) in tetrahydrofuran (5 parts by weight) is dropwise added difluoromethylthioacetyl chloride at -30° C., and the mixture is left standing for 1 hour. After removing separated crystals by filtration, the reaction mixture is concentrated in vacuum to leave difluoromethylthioacetic isovaleric anhydride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:13]=[C:12]([CH3:21])[C:11]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[BH4-].[Na+]>CO.O>[Cl:8][C:6]1[CH:5]=[C:4]([S:9][C:10]2[N:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:13]=[C:12]([CH3:21])[C:11]=2[CH:22]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[OH:23])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: Cc1nn(-c2ccccc2)c(Sc2cc(Cl)cc(Cl)c2)c1C(=O)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1nn(-c2ccccc2)c(Sc2cc(Cl)cc(Cl)c2)c1C(O)c1ccccc1
Yield: 83.6 %

Procedure:
A solution of 100 mg of [5-(3,5-dichlorophenylthio)-3-methyl-1-phenyl-1H-pyrazol-4-yl]-phenyl-methanone and 23 mg of sodium borohydride in 5 ml of methanol was stirred at rt for 17 h. The mixture was diluted with 4 ml of water and extracted four times with diethyl ether. Combined extracts were dried over magnesium sulphate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using ethyl acetate/petroleum spirit 40°–60° C. for the elution to give 84 mg of [5-(3,5-dichlorophenylthio)-3-methyl-1-phenyl-1H-pyrazol-4-yl]-phenyl-methanol as a colourless gum. Mass spectrum (EI) m/z 440 [M]+.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[C:5]([O:9][C:10](=[O:26])[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]2[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][N:20]=2)[CH:13]=1)([CH3:8])([CH3:7])[CH3:6].BrBr>C(O)(=O)C>[C:5]([O:9][C:10](=[O:26])[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]2[N:20]=[C:21]3[S:1][C:2]([NH2:3])=[N:25][C:22]3=[CH:23][CH:24]=2)[CH:13]=1)([CH3:8])([CH3:6])[CH3:7]
Reactant: N#C[S-]
Reactant: CC(C)(C)OC(=O)Nc1cccc(Oc2ccc(N)cn2)c1
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)Nc1cccc(Oc2ccc3nc(N)sc3n2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.2 %

Procedure:
Potassium thiocyanate (4.30 g, 44.2 mmol) was suspended in acetic acid (50 mL), and the suspension was stirred at room temperature for 30 min. To the obtained solution was added tert-butyl{3-[(5-aminopyridin-2-yl)oxy]phenyl}carbamate (3.33 g, 11.1 mmol), and the mixture was further stirred at room temperature for 10 min. To the obtained solution was added dropwise a solution of bromine (1.85 g, 11.6 mmol) in acetic acid (10 mL) for 10 min or more. After the completion of the dropwise addition, the mixture was stirred at room temperature for 1.5 hr. The yielded yellow solid was filtered off, and washed with acetic acid. The filtrate and the washing solution were combined, and concentrated under reduced pressure. The residue was suspended in ethyl acetate (200 mL), and the suspension was washed with saturated aqueous sodium hydrogen carbonate solution (50 mL) and saturated brine (30 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was washed with ethyl acetate to give the title compound (3.51 g, 88%) as a pale-yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:15][CH2:14][CH:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH2:12]2)=[C:6]([CH:10]=1)[C:7]([O-:9])=O.[Li+].Cl.[NH2:29][C:30]1([C:33]2[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=2)[CH2:32][CH2:31]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:15][CH2:14][CH:13]([O:16][C:17]3[CH:18]=[CH:19][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:21][CH:22]=3)[CH2:12]2)=[C:6]([CH:10]=1)[C:7]([NH:29][C:30]1([C:33]2[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=2)[CH2:32][CH2:31]1)=[O:9]
Reactant: O=C([O-])c1cc(Cl)cnc1N1CCC(Oc2ccc(C(F)(F)F)cc2)C1
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Agent: Cl
Agent: [Li+]
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CCC(Oc4ccc(C(F)(F)F)cc4)C3)CC2)cc1
Yield: 12.9 %

Procedure:
The title compound (D199) (24 mg) was prepared according to the experimental procedure described in Description 148 starting from lithium 5-chloro-2-(3-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)nicotinate (D136) (130 mg, 0.331 mmol) and methyl 4-(1-aminocyclopropyl)benzoate (D7) (75.36 mg, 0.331 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:22][N:23]([CH3:33])[C:24]([C:26]1[CH:31]=[C:30](Cl)[CH:29]=[CH:28][N:27]=1)=[O:25].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:22][N:23]([CH3:33])[C:24]([C:26]1[CH:31]=[C:30]([O:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=2)[CH:29]=[CH:28][N:27]=1)=[O:25]
Reactant: CN(C)C(=O)c1cc(Cl)ccn1
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1cc(Oc2ccc(N)c([N+](=O)[O-])c2)ccn1
Temperature: 90 °C
Reaction time: 72 h

Procedure:
A mixture containing 4-amino-3-nitrophenol (1 eq) and potassium bis(trimethylsilyl)amide (2 eq) was stirred in dimethylformamide for 2 hours at room temperature. To this mixture was added 4-Chloro-pyridine-2-carboxylic acid dimethylamide (1 eq) and potassium carbonate (1.2 eq) and then it was stirred at 90° C. for 3 days. The reaction mixture was then concentrated before partitioning between ethyl acetate and water. The organic layer was separated, washed with brine, dried, filtered and concentrated in vacuum to give brown solid. Purification by flash chromatography with ethyl acetate and hexane (1:1) gave the desired product as a yellow syrup. HPLC, 1.69 min; MS: MH+=303.1.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[F:12].[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.CCN(CC)CC>C(Cl)Cl>[F:12][C:4]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:3]=1[CH2:2][N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1ccc(CBr)c(F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(CN2CCOCC2)c(F)c1
Yield: 65.6 %

Procedure:
To a solution of 1-(bromomethyl)-2-fluoro-4-nitrobenzene (3.04 g, 13 mmol) in CH2Cl2 (50 mL) were added morpholine (1.74 g, 20 mmol) and Et3N (2.63 g, 26 mmol). The reaction was refluxed overnight, and then concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=4:1) to give the title compound as a yellow solid (2.05 g, 65%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][C:11]([CH:13]=O)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:15]([O:17][C:18](=[O:27])[CH2:19][N:20]1[C:24](=[O:25])[CH2:23][S:22][C:21]1=[S:26])[CH3:16].N1CCCCC1>ClCCl>[CH2:15]([O:17][C:18](=[O:27])[CH2:19][N:20]1[C:24](=[O:25])/[C:23](=[CH:13]/[C:11]2[O:12][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([I:1])[CH:3]=3)=[CH:9][CH:10]=2)/[S:22][C:21]1=[S:26])[CH3:16]
Reactant: O=Cc1ccc(-c2cccc(I)c2)o1
Reactant: CCOC(=O)CN1C(=O)CSC1=S
Solvent: C1CCNCC1
Solvent: ClCCl
Product: CCOC(=O)CN1C(=O)/C(=C/c2ccc(-c3cccc(I)c3)o2)SC1=S
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.2 %

Procedure:
5-(3-Iodophenyl)furan-2-carbaldehyde (30 mg, 0.1 mmol) and ethyl-2-(4-oxo-2-thioxothiazolidin-3-yl)acetate (22 mg, 0.1 mmol) were dissolved in dichloromethane (7 mL), piperidine (20 μL) was added thereto, and the mixture was stirred at room temperature (25° C.) for 3 hours. After the reaction was completed the solvent was removed by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography using ethyl acetate/hexane (3/7 (volume ratio)) as an eluent, to give the target compound 1 in a yield of 38 mg (yield 76.2%).
Reaction SMILES: [Na].N.[NH2:3][CH2:4][C@@H:5]1[CH2:19][C@H:18]2[C@@H:8]([CH2:9][C:10]3[C:20]4[C:13](=[CH:14][CH:15]=[CH:16][C:17]2=4)[NH:12][CH:11]=3)[N:7]([CH3:21])[CH2:6]1.[CH3:22]I>CCOCC.C(O)C>[NH2:3][CH2:4][C@@H:5]1[CH2:19][C@H:18]2[C@@H:8]([CH2:9][C:10]3[C:20]4[C:13](=[CH:14][CH:15]=[CH:16][C:17]2=4)[N:12]([CH3:22])[CH:11]=3)[N:7]([CH3:21])[CH2:6]1
Reactant: CI
Reactant: CN1C[C@H](CN)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Agent: N
Agent: [Na]
Solvent: CCOCC
Solvent: CCO
Product: CN1C[C@H](CN)C[C@@H]2c3cccc4c3c(cn4C)C[C@H]21

Procedure:
A mixture of 8 ml. of dry ethanol and 10 ml. of dry ether is added dropwise, within 20 minutes to the stirred solution of 1.9 g. of metallic sodium in 300 ml. of liquid ammonia. Upon this procedure the initially deep blue solution turns gradually colorless. Thereafter 2.53 g. of dried 8β-aminomethyl-6-methyl-ergoline, prepared as described in Step B above, are added, the mixture is stirred until complete dissolution occurs (for 5 minutes), and then a solution of 6.6 g. of methyl iodide in 8 ml. of dry ether is added dropwise, within 5 minutes to the mixture at -40° C. The mixture is stirred at the same temperature for an additional 30 minutes, thereafter it is warmed cautiously and ammonia is removed in vacuo. The residue is dissolved in a mixture of 100 ml. of isopropanol and 400 ml. of chloroform, 150 ml. of water are added to the solution, and the pH of the aqueous phase is adjusted to 8 with acetic acid. The mixture is shaken, the organic phase is separated, and the aqueous phase is extracted with 3×100 ml. of a 1:4 mixture of isopropanol and chloroform. The organic phases are combined, dried over sodium sulfate, filtered and evaporated. The residue is subjected to chromatography using a column filled with 40 g. of silica gel in order to remove the impurities optionally present. A 30:2:11 mixture of chloroform, water and methanol is used as eluting agent.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH:9]([C:11]1[N:12]=[CH:13][NH:14][CH:15]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH2:9][C:11]2[N:12]=[CH:13][NH:14][CH:15]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1c[nH]cn1
Reactant: Nc1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Fc1ccc(NCc2c[nH]cn2)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 15.5 %

Procedure:
To a solution of 4-fluoroaniline (0.60 g, 5.40 mmol) in 1,2-dichloroethane (5 ml) were added 4-formylimidazole (0.78 g, 8.10 mmol), sodium triacetoxyborohydride (2.29 g, 10.8 mmol) and acetic acid (0.06 ml). The reaction mixture was stirred at 50° C. for 4 h. The reaction mixture was then concentrated in vacuo and the residue was purified using flash chromatography (column: Isolute® Flash-NH2 (Separtis); eluent: methanol/dichloromethane gradient) to yield a white solid (160 mg, 16%); MS (ISP): 192.2 ((M+H)+.).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]1[C:21]2[N:20]=[C:19]([S:22][CH2:23][C:24]3[C:29]([CH3:30])=[C:28]([CH3:31])[CH:27]=[CH:26][N:25]=3)[NH:18][C:17]=2[CH:16]=[C:15]([CH3:32])[C:14]=1[O:33][CH3:34].[OH-].[Na+]>C(Cl)Cl.O>[CH3:12][C:13]1[C:21]2[N:20]=[C:19]([S:22]([CH2:23][C:24]3[C:29]([CH3:30])=[C:28]([CH3:31])[CH:27]=[CH:26][N:25]=3)=[O:9])[NH:18][C:17]=2[CH:16]=[C:15]([CH3:32])[C:14]=1[O:33][CH3:34]
Reactant: COc1c(C)cc2[nH]c(SCc3nccc(C)c3C)nc2c1C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: COc1c(C)cc2[nH]c(S(=O)Cc3nccc(C)c3C)nc2c1C
Temperature: -10 °C
Reaction time: 0.08 h
Yield: 32 %

Procedure:
m-Chloroperbenzoic acid, 91% (0.53 g, 0.0028 mol) dissolved in CH2Cl2 (25 ml) and cooled to -10° C. was added under stirring to 4,6-dimethyl-5-methoxy-2-[[(3,4-dimethyl-2-pyridinyl)methyl]thio]-1H-benzimidazole (0.91 g, 0.0028 mol) dissolved in CH2CI2 (50 ml) maintaining the temperature at -5° C. Stirring was continued at -5° C. for 5 min and then NaOH (0.34 g, 0.0085 mol) dissolved in water (25 ml) was added under vigorous stirring. The two phases were separated and the aqueous phase was washed with CH2Cl2 (10 ml). More CH2Cl2 (50 ml) was added to the aqueous phase, the pH was adjusted to 9.5 by adding 2M HCl and after stirring the phases were separated. The organic phase was dried (Na2SO4), filtered and the solvent was evaporated off giving an oil which was crystallized from CH3CN (15 ml) yielding the desired product (0.3 g, 32%), m.p. 161° C.