Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[N:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10](O)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCCC1.B.O1CCCC1.[NH4+]>[O:1]([C:8]1[C:9]([CH2:10][OH:11])=[CH:13][CH:14]=[CH:15][N:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccnc1Oc1ccccc1
Agent: B
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Product: OCc1cccnc1Oc1ccccc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of 2-phenoxynicotinic acid (2.0 g) in tetrahydrofuran (20 ml), 9.5 ml of borane-tetrahydrofuran complex (1.17M tetrahydrofuran solution) was added, and the reaction solution was stirred overnight at 50° C. The reaction solution was cooled, 14 ml of 1N aqueous sodium hydroxide was added under ice-cooling, and the reaction solution was stirred for 1 hour. The reaction solution was diluted with saturated aqueous ammonium solution, extracted with diethyl ether, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluent: ethyl acetate/hexane (0:100-50:50)) to afford the title compound as a colorless oil.
Reaction SMILES: [CH:1]([N:14]=[C:15]=[S:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:18][NH:19][O:20][CH2:21][C:22]([OH:24])=[O:23].C(N(CC)CC)C>C(Cl)(Cl)Cl.CCOCC>[CH:1]([NH:14][C:15]([N:19]([CH3:18])[O:20][CH2:21][C:22]([OH:24])=[O:23])=[S:16])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNOCC(=O)O
Reactant: S=C=NC(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: CN(OCC(=O)O)C(=S)NC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.7 %

Procedure:
A mixture of benzhydryl-isothiocyanate (13.75 g), N-methyl aminooxy acetic acid hydrochloride (8.6 g), triethylamine (16 g) and chloroform (200 mL) was heated at reflux for three hours, stirred at ambient temperature for one hour. The mixture was diluted with chloroform (200 mL) and washed with 2N HCl (2×300 mL) then with water (300 mL). The organic phase was dried over anhydrous magnesium sulfate and evaporated to dryness to give a solid. The solid was stirred in ether (200 mL) and filtered to give 18.8 g of [[[[(benzhydryl)amino]thioxomethyl]methylamino]oxy]acetic acid as a white solid, m.p. 160-162° C. Mass spectrum (−FAB, [M−H]−) m/z 329. 1H-NMR (DMSO-d6; 400 MHz) δ13.55 (br s, 1H), 9.75 (d, 1H), 7.35-7.23 (m, 10H), 6.63 (d, 1H), 4.63 (s, 2H), and 3.42 ppm (s, 3H).
Reaction SMILES: [C:1]1(=O)[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.Cl.[Sn]>C(O)(=O)C>[C:4]1(=[O:6])[C:3]2[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:1][NH:5]1
Reactant: O=C1NC(=O)c2ccccc21
Agent: Cl
Agent: [Sn]
Solvent: CC(=O)O
Product: O=C1NCc2ccccc21
Yield: 75.1 %

Procedure:
Phthalimide (1.47 g, 10 mmol) was added to a mixture of glacial acetic acid (15 mL), concentrated hydrochloric acid (7 mL), and tin powder (2.97 g). The slurry was heated at reflux for 2 h. After this time GC-MS indicated that the reaction was completed. The residual tin was removed by filtration and the majority of the acetic acid evaporated. The resulting creamy material was dissolved in dichloromethane (60 mL) and washed with water (10 mL) and saturated aqueous NaCl solution (15 mL). The resulting organic solution was dried over anhydrous MgSO4, filtered and concentrated. Silica gel column chromatography of the resulting material using ethyl acetate afforded 2,3-dihydro-isoindol-1-one (1 g, 75%) as an off-white solid. 1H NMR (300 MHz, CDCl3): δ (ppm) 4.48 (s, 2H), 6.98 (s, 1H), 7.42-7.61 (m, 3H), 7.88 (d, 1H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[OH-].[Na+].Br[CH2:13][CH:14]([CH3:17])[CH2:15][Cl:16]>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.O1CCCC1>[Cl:16][CH2:15][CH:14]([CH3:17])[CH2:13][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CC(CCl)CBr
Reactant: c1ccc2[nH]cnc2c1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(CCl)Cn1cnc2ccccc21
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
To a stirred and warm (40° C.) mixture of 9.5 parts of 1H-benzimidazole, 2 parts of N,N,N-triethylbenzenemethanaminium chloride, 225 parts of a sodium hydroxide solution 50% and 90 parts of tetrahydrofuran are added 17 parts of 1-bromo-3-chloro-2-methylpropane. The whole is heated to about 60° C. and stirring is continued for 15 minutes at this temperature. The reaction mixture is cooled and the product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The oily residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5) as eluent. The pure fractions are collected and the eluent is evaporated, yielding 1-(3-chloro-2-methylpropyl)-1H-benzimidazole as an oily residue.
Reaction SMILES: [CH2:1]([C:3]1[C:8](/[CH:9]=[CH:10]/[O:11]C)=[CH:7][CH:6]=[CH:5][C:4]=1[C:13]1[N:17]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=2)[S:15][N:14]=1)[CH3:2].Cl>O1CCCC1>[CH2:1]([C:3]1[C:4]([C:13]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([C:28]([F:30])([F:29])[F:31])[CH:19]=3)[S:15][N:14]=2)=[CH:5][CH:6]=[CH:7][C:8]=1[CH2:9][CH:10]=[O:11])[CH3:2]
Reactant: CCc1c(/C=C/OC)cccc1-c1nsc(-c2ccc(OC(C)C)c(C(F)(F)F)c2)n1
Agent: Cl
Solvent: C1CCOC1
Product: CCc1c(CC=O)cccc1-c1nsc(-c2ccc(OC(C)C)c(C(F)(F)F)c2)n1
Temperature: 70 °C
Reaction time: 5 h
Yield: 79.6 %

Procedure:
To a solution of 3-{2-ethyl-3-[(E)-2-(methyloxy)ethenyl]phenyl}-5-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,2,4-thiadiazole (D49) (140 mg) in tetrahydrofuran (THF) (10 mL) stirred under nitrogen at room temperature was added hydrochloric acid (0.2 mL). The reaction mixture was stirred at 70° C. for 5 h. After cooling the reaction, the solution was condensed under reduced pressure to give (2-ethyl-3-{5-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,2,4-thiadiazol-3-yl}phenyl)acetaldehyde (D50) (108 mg) as a colorless oil, which was used directly in the next step without further purification. MS (ES): C22H21F3N2O2S requires 434. found 435.2 (M+H+).
Reaction SMILES: C([O:5][C:6]([C:8]1([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16](=[O:30])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([CH3:29])([CH3:28])[C:23]([O:25]CC)=[O:24])[CH2:10][CH2:9]1)=[O:7])(C)(C)C.[OH-].[Na+]>C(O)=O.CCO.O>[C:6]([C:8]1([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16](=[O:30])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([CH3:28])([CH3:29])[C:23]([OH:25])=[O:24])[CH2:10][CH2:9]1)([OH:7])=[O:5]
Reactant: CCOC(=O)C(C)(C)CCCCCC(=O)CCCCCC1(C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: O=CO
Product: CC(C)(CCCCCC(=O)CCCCCC1(C(=O)O)CC1)C(=O)O
Reaction time: 8 h
Yield: 64.2 %

Procedure:
A solution of ethyl 13-[1-(t-butoxycarbonyl)cyclopropyl]-2,2-dimethyl-8-oxotridecanoate (18.34 g, 43.3 mmol) in HCO2H (50 mL) was stirred for 1.5 h, evaporated in vacuo and coevaporated in vacuo from toluene (10 mL). The remaining residue was dissolved in a mixture of EtOH and H2O (2:1, 250 mL) and NaOH (9.68 g, 241 mmol) was added. The resulting clear solution was warmed to 80° C. and after 5 h EtOH was evaporated in vacuo. The remaining solution was diluted with H2O to ˜250 mL, extracted with Et2O (3×250 mL), acidified to pH ˜1 with conc aqueous HCl (˜18 mL) and extracted with Et2O (3×250 mL). The latter organic layers were combined, dried (Na2SO4) and evaporated in vacuo to give a yellow oil which solidified overnight. The remaining residue was recrystallized from iPr2O/heptane to give 13-(1-carboxycyclopropyl)-2,2-dimethyl-8-oxotridecanoic acid (9.47 g, 57%) as a white solid. The mother liquor was evaporated in vacuo and the remaining residue was purified by column chromatography (heptane:EtOAc=2:1 (containing 1% (v/v) HOAc)) and recrystallization from iPr2O/heptane to give a second batch 13-(1-carboxycyclopropyl)-2,2-dimethyl-8-oxotridecanoic acid (2.23 g, 14%) as a white solid. mp=65-66° C. 1H NMR: (CD3OD): δ=2.43 (t, J=7.2 Hz, 4H), 1.58-1.42 (m, 10H), 1.35-1.20 (m, 6H), 1.14 (s, 6H), 1.15-1.06 (m, 2H), 0.70 (dd, J=6.6, 3.9 Hz, 2H). 13C NMR: (CD3OD): δ=213.8, 181.6, 179.0, 43.6, 43.5, 43.1, 41.9, 35.1, 31.0, 30.6, 28.7, 26.2, 25.9 (2×), 25.02, 24.96, 24.4, 16.4 (2×). Anal. calcd for C19H32O5: C, 67.03; H, 9.47, found: C, 66.86; H, 9.50.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([SH:11])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:26]([S:28][CH2:29]Cl)[CH3:27]>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:27][CH2:26][S:28][CH3:29])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1nc(S)nc2c1nc(O)n2Cc1ccccc1
Reactant: CCSCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CSCCSc1nc(N)c2nc(O)n(Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 16.4 %

Procedure:
Crude 6-amino-9-benzyl-8-hydroxy-2-mercaptopurine (134 mg, 0.49 mmol) was suspended in dimethylformamide (60 ml). To the suspension were added potassium carbonate (100 mg, 0.72 mmol) and chloromethyl ethyl sulfide (0.08 ml, 0.7 mmol) in order. The mixture was stirred at room temperature for 2 hours. The solvent was removed in vacuo, and the residue was purified by silica gel chromatography (3% methanol/chloroform) to give the subject compound (28 mg, yield 16%).
Reaction SMILES: [C:1]1([C:7]2[C:16]3[N:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:10](=[O:17])[N:9]3[CH2:18][CH2:19][NH:20][C:8]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>N1C=CC=CC=1>[C:21]([N:20]1[C:8]2[N:9]([C:10](=[O:17])[C:11]3[CH:12]=[CH:13][CH:14]=[N:15][C:16]=3[C:7]=2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:18][CH2:19]1)(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: O=c1c2cccnc2c(-c2ccccc2)c2n1CCN2
Solvent: c1ccncc1
Product: CC(=O)N1CCn2c1c(-c1ccccc1)c1ncccc1c2=O

Procedure:
Reflux a mixture of 2,3-dihydro-10-phenylimidazo-[1,2-g][1,6]naphthyridin-5(1H)-one (5.5 g), acetic anhydride (10 ml), and pyridine (60 ml) for 30 hours. Cool the reaction mixture and evaporate the volatile reagents--i.e., excess pyridine and acetic anhydride. Partition the residue between chloroform and water, and dry, filter, and concentrate the organic solution Chromatograph the residue over silica gel, elute the column with chloroform, and crystallize the eluate from chloroform-petroleum ether to obtain 1-acetyl-2,3-dihydro-10-phenyl-imidazo[1,2-g][1,6]naphthyridin-5(1H)-one, mp 229°-231° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH2:22]CCCCCCCC(CCCC(F)(F)C(F)(F)F)C(O)=O)[C:7]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)([CH2:12][CH2:13][CH3:14])[CH2:8][S:9]2)=[CH:4][CH:3]=1.[F:44][C:45]([F:67])([C:63]([F:66])([F:65])[F:64])[CH2:46][CH2:47][CH2:48][CH:49]([CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH:61]=[CH2:62])[C:50]([O:52]CC)=[O:51]>>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH2:22][CH2:62][CH2:61][CH2:60][CH2:59][CH2:58][CH2:57][CH2:56][CH2:55][CH:49]([CH2:48][CH2:47][CH2:46][C:45]([F:44])([F:67])[C:63]([F:64])([F:65])[F:66])[C:50]([OH:52])=[O:51])[C:7]([C:15]3[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=3)([CH2:12][CH2:13][CH3:14])[CH2:8][S:9]2)=[CH:4][CH:3]=1
Reactant: C=CCCCCCCC(CCCC(F)(F)C(F)(F)F)C(=O)OCC
Reactant: CCCC1(c2ccc(O)cc2)CSc2cc(O)ccc2C1CCCCCCCCC(CCCC(F)(F)C(F)(F)F)C(=O)O
Product: CCCC1(c2ccc(O)cc2)CSc2cc(O)ccc2C1CCCCCCCCCC(CCCC(F)(F)C(F)(F)F)C(=O)O

Procedure:
Starting with the allyl compound prepared in Example 29 and ethyl 2-(4,4,5,5,5,-pentafluoropentyl)-9-decenoate prepared separately, the same procedure as shown in Example 13 was repeated to give 11-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-propylthiochroman-4-yl]-2-(4,4,5,5,5,-pentafluoropentyl)undecanoic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][C:5]=1[NH:15][C:16](=[O:24])[O:17][CH2:18][CH:19]1[CH2:22][N:21]([CH3:23])[CH2:20]1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][C:5]=1[NH:15][C:16](=[O:24])[O:17][CH2:18][CH:19]1[CH2:22][N:21]([CH3:23])[CH2:20]1
Reactant: CN1CC(COC(=O)Nc2cc(-c3cccs3)ccc2[N+](=O)[O-])C1
Agent: [Pd]
Solvent: CO
Product: CN1CC(COC(=O)Nc2cc(-c3cccs3)ccc2N)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.1 %

Procedure:
To a stirred solution of (1-methylazetidin-3-yl)methyl (2-nitro-5-(thiophen-2-yl)phenyl)carbamate (0.06 g, 0.16 mmol, 1 eq.) in MeOH (5 mL) was added Pd/C (0.03 g, 0.24 mmol, 1.5 eq). The reaction was stirred at room temperature under H2 atmosphere for 2 h. The reaction mixture was filtered through Celite and concentrated. The crude solid, which was washed with ether and pentane to obtain (1-methylazetidin-3-yl)methyl (2-amino-5-(thiophen-2-yl)phenyl)carbamate (0.03 g, 62% yield) as ash color solid. ESI+ MS: m/z 318 ([M+H]+), 1H NMR (500 MHz, d6-DMSO): δ 8.69 (bs, 1H), 7.50 (bs, 1H), 7.34 (d, J=4.5 Hz, 1H), 7.22-7.16 (m, 2H), 7.06-7.02 (m, 1H), 6.72 (d, J=8.0 Hz, 1H), 5.13 (bs, 2H), 4.19 (d, J=6.5 Hz, 2H), 3.54-3.45 (m, 2H), 3.25-3.15 (m, 2H), 2.82-2.70 (m, 1H), 2.35 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([OH:11])=[O:10])[N:5]=[N:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:22][C:23](C)=O>>[CH2:22]([O:10][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=1[N:6]1[C:2]([CH3:1])=[N:3][N:4]=[N:5]1)[CH3:23]
Reactant: CC(C)=O
Reactant: Cc1nnnn1-c1ccccc1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)c1ccccc1-n1nnnc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acetone (3.2 L) and 2-(5-methyl-1H-tetrazol-1-yl)benzoic acid (228 g) were combined then stirred at ambient temperature for 15 minutes. Potassium carbonate (228 g) was added to the reaction mixture in a single portion. Idoethane (366.8 g) was added dropwise to the reaction mixture producing a slight exotherm. The reaction mixture was heated at reflux for about 4 hours then stirred overnight while cooling to ambient temperature. The precipitated salts were removed by filtration then rinsed with acetone. The combined filtrates were evaported under vacuum. The residue was dissolved in dichloromethane (1.5 L). The dichloromethane solution was washed with water (1.5 L), dried over magnesium sulfate then concentrated under vacuum to provide 277 g of ethyl-2-(5-methyl-1H-tetrazol-1-yl)benzoate as a white solid m.p. 98°-100° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[N+:12]([O-])([O-:14])=[O:13].[K+].[OH-].[Na+]>S(=O)(=O)(O)O>[CH3:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:7][CH:6]=2
Reactant: Cc1cc2ccccc2cn1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [Na+]
Product: Cc1cc2c([N+](=O)[O-])cccc2cn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 42 %

Procedure:
To a 0° C. solution of 3-methylisoquinoline (3.00 g, 20.9 mmol) in concentrated sulfuric acid (35 mL) was added solid potassium nitrate (2.33 g, 23.0 mmol) in four portions. The mixture was stirred 2 hours at 0° C. then was diluted with ice. This mixture was basified (pH 10) with 50% aqueous NaOH extracted with CH2Cl2 (60 mL). The organic phase was washed with brine (25 mL), dried (Na2SO4), filtered, and the volatiles were removed in vacuo. The resulting solid was triturated with 1:1 EtOAc-hexanes, filtered and air-dried to provide the title compound (1.60, 8.78 mmol, 42%) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 9.30 (s, 1H), 8.53 (dd, J=7.7, 1.1 Hz, 1H), 8.35 (s, 1H), 8.26 (d, J=8.1 Hz, 1H), 7.64 (dd, J=9.9, 5.9 Hz, 1H), 2.80 (s, 3H); MS (ESI) m/z 189 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([OH:21])[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([OH:21])[CH2:13][CH2:12][NH:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cccc(F)c2F)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: OC1(c2cccc(F)c2F)CCNC1
Reaction time: 3 h

Procedure:
Preparation according to Preparation 2: tert-butyl 3-(2,3-difluorophenyl)-3-hydroxy-pyrrolidin-1-carboxylate (1.72 g, 5.75 mmol), dichloromethane (3 mL) and trifluoroacetic acid (3 mL). Stirred for 3 h. Yield: 0.31 g. MS m/z (rel. intensity, 70 eV) 199 (M+, bp), 141 (87), 127 (60), 114 (38), 113 (63).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([N:20]2[S:24](=[O:26])(=[O:25])[NH:23][C:22](=[O:27])[CH2:21]2)=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[C:14](Br)[CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:28]1[CH2:32][CH2:31][CH2:30][CH:29]=1.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[CH2:1]([O:8][C:9]1[C:10]([N:20]2[S:24](=[O:26])(=[O:25])[NH:23][C:22](=[O:27])[CH2:21]2)=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[C:14]([C:28]1[CH2:32][CH2:31][CH2:30][CH:29]=1)[CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CN(c2cc3cc(Br)ccc3cc2OCc2ccccc2)S(=O)(=O)N1
Reactant: C1=CCCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C1CN(c2cc3cc(C4=CCCC4)ccc3cc2OCc2ccccc2)S(=O)(=O)N1
Reaction time: 0.25 h
Yield: 13 %

Procedure:
In a microwave vial is added 5-(3-benzyloxy-7-bromonaphthalen-2-yl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (0.100 g, 0.224 mmol), cyclopentene (0.04 mL, 0.453 mmol), palladium acetate (0.010 g, 0.0445 mmol), triethylamine (0.063 mL, 0.448 mmol) and acetonitrile (2 mL). The vial is capped and placed in the microwave for 15 min at 110° C. The reaction mixture is filtered over Celite and washed with acetonitrile. The filtrate is concentrated and the residue is purified via Biotage Sp1, eluting with 15-60% EtOH/H2O to afford 5-(3-benzyloxy-7-cyclopent-1-enyl-naphthalen-2-yl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (0.0127 g): (M−H)−=433.
Reaction SMILES: Br[C:2]1[C:6]2[NH:7][C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:9][C:5]=2[O:4][CH:3]=1.[Cl:15]C1C2NC(C(OCC)=O)=CC=2SC=1>CCCCCCC.CCOC(C)=O>[Cl:15][C:2]1[C:6]2[NH:7][C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:9][C:5]=2[O:4][CH:3]=1
Reactant: CCOC(=O)c1cc2scc(Cl)c2[nH]1
Reactant: CCOC(=O)c1cc2occ(Br)c2[nH]1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCOC(=O)c1cc2occ(Cl)c2[nH]1
Yield: 42 %

Procedure:
The title compound was synthesized from ethyl 3-bromo-4H-furo[3,2-b]pyrrole-5-carboxylate (200 mg, 0.774 mmol) using the conditions to synthesize ethyl 3-chloro-4H-thieno[3,2-b]pyrrole-5-carboxylate. Chromatography (silica gel, heptane/EtOAc) yielded ethyl 3-chloro-4H-furo[3,2-b]pyrrole-5-carboxylate (70 mg, 42% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([O:11][CH3:12])=[C:5]([CH3:13])[C:4]=1[CH2:14][CH2:15]/[C:16](/[CH3:22])=[CH:17]\[C:18](OC)=[O:19].COCCO[AlH2-]OCCOC.[Na+].[Cl-].[NH4+]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([O:11][CH3:12])=[C:5]([CH3:13])[C:4]=1[CH2:14][CH2:15]/[C:16](/[CH3:22])=[CH:17]\[CH2:18][OH:19]
Reactant: COC(=O)/C=C(/C)CCc1c(C)c(OC)c(C)c(C)c1OC
Agent: COCCO[AlH2-]OCCOC
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: COc1c(C)c(C)c(OC)c(CC/C(C)=C\CO)c1C
Yield: 53.9 %

Procedure:
A solution of 0.8 g (2.6 mmol) of methyl (Z)-5-(2,5-dimethoxy-3,4,6-trimethylphenyl)-3-methyl-2-pentenoate in toluene (5 ml) was treated dropwise with 0.75 ml of a 3.5 molar Red-Al solution in toluene. After 2 hours at room temperature the mixture was poured into saturated ammonium chloride solution and extracted with ether. The combined extracts were washed with water, dried and concentrated to a colourless oil which was purified on silica gel with hexane/ethyl acetate 9:1→6:1, yielding 0.39 g of crystalline (Z)-5-(2,5-dimethoxy-3,4,6-trimethylphenyl)-3-methyl-2-penten-1-ol. M.P. 58.5°-60° C.
Reaction SMILES: [CH:1]1([N:4]2[C:11](=[O:12])[CH2:10][CH2:9][NH:8][C:7]3[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:6]=3[CH2:5]2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:26][C:27]1[O:31][N:30]=[C:29]([C:32](Cl)=[O:33])[CH:28]=1>ClC(Cl)C>[CH:1]1([N:4]2[C:11](=[O:12])[CH2:10][CH2:9][N:8]([C:32]([C:29]3[CH:28]=[C:27]([CH3:26])[O:31][N:30]=3)=[O:33])[C:7]3[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:6]=3[CH2:5]2)[CH2:2][CH2:3]1
Reactant: Cc1cc(C(=O)Cl)no1
Reactant: COc1ccc2c(c1)CN(C1CC1)C(=O)CCN2
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)CN(C1CC1)C(=O)CCN2C(=O)c1cc(C)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.5 %

Procedure:
To a solution of 5-cyclopropyl-8-methoxy-2,3,5,6-tetrahydrobenzo[b][1,5]diazocin-4(1H)-one (50.0 mg, 0.203 mmol) from Example 1 in dichloroethane (2.0 ml) was added triethylamine (0.057 ml, 0.406 mmol) and 5-methylisoxazole-3-carbonyl chloride (32.5 mg, 0.223 mmol). The reaction mixture was stirred at room temperature overnight and then quenched with saturated aqueous sodium bicarbonate, followed by extraction with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. Preparative thin layer chromatography (ethyl acetate/methanol:98/2) of the crude residue gave the desired compound (53 mg, 74%).
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].FF.[Cl:11]Cl>Cl>[Cl:11][C:7]1[C:5](=[O:6])[NH:4][C:2](=[O:3])[NH:1][CH:8]=1
Reactant: ClCl
Reactant: O=c1cc[nH]c(=O)[nH]1
Agent: Cl
Agent: FF
Product: O=c1[nH]cc(Cl)c(=O)[nH]1

Procedure:
In a suitable reaction vessel as in the previous examples a suspension of uracil (1.00g) in an aqueous solution of 18% HCl (10 ml, representing 5 ml of concentrated HCl and 5 ml of water) was introduced. Gaseous fluorine (0.024 moles) was bubbled through the suspension when the reaction temperature of 72°-80° C. was reached. The reaction continued for about 140 minutes until the presence of fluorine was detected leaving the reaction vessel. The ratio of fluorine to uracil was 2.73. During the course of the reaction the odor of chlorine gas was observed. A white solid was present throughout the reaction and a final product of 0.98g was collected by filtration. Elemental analysis of the compound detected no fluorine and indicated the compound to be 5-chlorouracil.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)[NH:7][C:8]2=[O:13].Br[CH2:21][CH:22]([OH:24])[CH3:23]>>[CH3:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([CH:14]1[CH2:19][CH2:18][N:17]([CH2:21][CH:22]([OH:24])[CH3:23])[CH2:16][CH2:15]1)[NH:7][C:8]2=[O:13]
Reactant: Cc1cccc2c(=O)[nH]c(C3CCNCC3)cc12
Reactant: CC(O)CBr
Agent: Cl
Product: Cc1cccc2c(=O)[nH]c(C3CCN(CC(C)O)CC3)cc12
Yield: 13.6 %

Procedure:
By the reaction in the same manner as in Example 2a, using 5-methyl-3-(piperidin-4-yl)-2H-isoquinolin-1-one hydrochloride (1 g) and 1-bromo-2-propanol (994 mg), 5-methyl-3-[1-(2-hydroxypropyl)piperidin-4-yl]-2H-isoquinolin-1-one (147 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:17]([N:19]3[CH2:24][CH2:23][N:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[F:31])[CH2:21][CH2:20]3)=[O:18])=[CH:7][N:8]2[CH2:11][CH2:12][NH:13][C:14](=[O:16])[CH3:15])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:34]I>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:17]([N:19]3[CH2:24][CH2:23][N:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[F:31])[CH2:21][CH2:20]3)=[O:18])=[CH:7][N:8]2[CH2:11][CH2:12][N:13]([CH3:34])[C:14](=[O:16])[CH3:15])=[CH:4][CH:3]=1
Reactant: CC(=O)NCCn1cc(C(=O)N2CCN(c3ccccc3F)CC2)c2ccc(Cl)cc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)N(C)CCn1cc(C(=O)N2CCN(c3ccccc3F)CC2)c2ccc(Cl)cc21

Procedure:
N-(2-{6-Chloro-3-[4-(2-fluoro-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-ethyl)-acetamide (preparation described herein) was treated with NaH (1.05 eq), MeI (1.05 eq) in dry DMF under argon at RT for 2 h to give after purification by prep. HPLC the title compound.