Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(CC1C=CC=CC=1)(C1C=CC=CC=1)=O.[OH:24][C:25]1[CH:35]=[CH:34][C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:27][CH:26]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O.CN(C=O)C>[CH2:1]([O:24][C:25]1[CH:26]=[CH:27][C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:34][CH:35]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: O=C(Cc1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Yield: 100 %

Procedure:
35 mmol of benzyl bromide (BzBn, 35 mmol of ethyl 4-hydroxybenzoate (10), 14 g of Cs2CO3 and 40 ml of DMF were combined and stirred at RT ove night. Then the reaction mixture was poured into water and the product was collected by extraction. The organic solution was washed with brine and dried over MgSO4. After evaporation of solvent, pure product was obtained in yield of 100%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[S:5][C:6]=1[Br:7].CO[CH:13](OC)[N:14]([CH3:16])[CH3:15]>>[Br:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH:9]=[CH:13][N:14]([CH3:16])[CH3:15])[S:5][C:6]=1[Br:7]
Reactant: CC(=O)c1cc(Br)c(Br)s1
Reactant: COC(OC)N(C)C
Product: CN(C)C=CC(=O)c1cc(Br)c(Br)s1
Temperature: 25 °C
Yield: 98.5 %

Procedure:
A mixture of 1-(4,5-dibromo-2-thienyl)ethanone (9.7 mmol) and N,N-dimethylformamide dimethyl acetal (44.8 mmol) was refluxed for 3 h and then allowed to cool to room temperature. The reaction mixture was concentrated under reduced pressure and dried in vacuo to afford 3.24 g (94% yield) of 1-(4,5-dibromo-2-thienyl)-3-(dimethylamino)prop-2-en-1-one which was used in the next step without further purification.
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[C:14]([O:29][CH2:30][CH2:31]Br)=[C:15]([C:20]2([CH3:28])[O:25]CC(C)(C)CO2)[CH:16]=[C:17]([Cl:19])[CH:18]=1>O1CCCC1.O>[C:20]([C:15]1[C:14]2[O:29][CH2:30][CH2:31][C:13]=2[CH:18]=[C:17]([Cl:19])[CH:16]=1)(=[O:25])[CH3:28]
Reactant: CC1(C)COC(C)(c2cc(Cl)cc(Br)c2OCCBr)OC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1cc(Cl)cc2c1OCC2
Reaction time: 1.5 h
Yield: 25 %

Procedure:
1.6 M n-Butyllithium in hexane solution (4.7 mL, 7.6 mmol) was added dropwise to a solution of 2-[3-bromo-2-(2-bromoethoxy)-5-chlorophenyl]-2,5,5-trimethyl-1,3-dioxane (Reference compound No. 5-1, 2.8 g, 6.3 mmol) in anhydrous tetrahydrofuran (30 mL) over 5 minutes at −70° C. and the whole was stirred for 1.5 hours. The whole was stirred under ice cooling for 1 hour and at room temperature overnight. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL). The organic layer was washed with saturated aqueous ammonium chloride solution (50 mL), saturated aqueous sodium hydrogen carbonate solution (50 mL), and brine (50 mL), and then dried over anhydrous magnesium sulfate. The solvent was removed in vacuo and tetrahydrofuran (30 mL), methanol (5 mL) and 1N aqueous hydrogen chloride solution (30 mL) were added to the residue, and the whole was stirred at room temperature for 5 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL). The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution (50 mL) and brine (50 mL), and then dried over anhydrous magnesium sulfate. The solvent was removed in vacuo and the obtained solid was filtered off with hexane (10 mL) to give the title reference compound (0.31 g) as a pale yellow solid (Yield 25%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].C([Li])CCC.[CH3:14][S:15]SC>O1CCCC1.O>[Cl:1][C:2]1[C:3]([F:8])=[C:4]([S:15][CH3:14])[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1ccccc1Cl
Reactant: CSSC
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CSc1cccc(Cl)c1F
Temperature: 25 °C

Procedure:
A solution of 10 g (grams) (76 mmol (millimoles)) of 1-chloro-2-fluorobenzene in 75 mL (milliliters) of dry tetrahydrofuran (THF) was cooled with a dry ice/acetone bath and 34 mL (84 mmol) of 2.5M butyllithium was added dropwise under a nitrogen blanket over 45 min with stirring and cooling. The resulting solution was stirred for 2 hours at -78° C. A solution of 8.1 mL (91 mmol) of dimethyl disulfide in 10 mL of dry THF was added with stirring over a 30-min period keeping the temperature below -65° C. The mixture was allowed to warm to ambient temperature for 1 hour. It was then diluted with 75 mL of water. The resulting mixture was extracted with diethyl ether and the ether extract was dried over sodium sulfate and concentrated by evaporation under reduced pressure to obtain a yellow oil. This oil was purified by flash chromatography on 230-400 mesh silica gel eluting with a hexane/ethyl acetate mixture to obtain 9.0 g (69 percent of theory) of the title compound as a light yellow oil.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:11]2=[O:20])=[CH:6][CH:5]=1.O=C(Cl)[O:25][C:26](Cl)(Cl)Cl.[CH2:31]([NH:38][CH2:39][CH3:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:31]([N:38]([CH2:39][CH3:40])[C:26]([N:17]1[CH2:16][CH2:15][C:12]2([C:11](=[O:20])[N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:5][CH:6]=3)[CH2:14][CH2:13]2)[CH2:19][CH2:18]1)=[O:25])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CCNCc1ccccc1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Product: CCN(Cc1ccccc1)C(=O)N1CCC2(CC1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O
Temperature: 80 °C
Reaction time: 1 h

Procedure:
This material was prepared in analogy to example 251 step B) from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one, diphosgene and benzyl-ethyl-amine. The reaction mixture was stirred for 1 h at room temperature, 2 h at 50° C. and 1 h at 80° C. before subjecting to work-up and purification. MS (ESI): 476.5 (MH+).
Reaction SMILES: [CH3:1][C@:2]12[C@@:19]3([CH3:20])[CH:10]([C@:11]4([CH3:31])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:22])([CH3:21])[C:14](OS(C(F)(F)F)(=O)=O)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:32]([C:35]([CH3:37])=[CH2:36])[CH2:33][CH2:34][C@:5]1(C(OCC1C=CC=CC=1)=O)[CH2:4][CH2:3]2.B([C:51]1[CH:56]=[CH:55][C:54]([CH2:57][CH2:58][C:59]([OH:61])=[O:60])=[CH:53][CH:52]=1)(O)O.[C:62](=[O:65])([O-:64])[O-].[Na+].[Na+]>COCCOC.O.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>[CH2:1]([O:64][C:62]([C@:5]12[CH2:34][CH2:33][C@@H:32]([C:35]([CH3:37])=[CH2:36])[C@@H:6]1[C@@H:7]1[C@@:2]([CH3:1])([CH2:3][CH2:4]2)[C@@:19]2([CH3:20])[CH:10]([C@:11]3([CH3:31])[C@@H:16]([CH2:17][CH2:18]2)[C:15]([CH3:22])([CH3:21])[C:14]([C:51]2[CH:56]=[CH:55][C:54]([CH2:57][CH2:58][C:59]([OH:61])=[O:60])=[CH:53][CH:52]=2)=[CH:13][CH2:12]3)[CH2:9][CH2:8]1)=[O:65])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)OCc3ccccc3)CC[C@]3(C)[C@H](CCC4[C@@]5(C)CC=C(OS(=O)(=O)C(F)(F)F)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: O=C(O)CCc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)OCc3ccccc3)CC[C@]3(C)[C@H](CCC4[C@@]5(C)CC=C(c6ccc(CCC(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 100 °C

Procedure:
A mixture of (1R,3aS,5aR,5bR,7aR,11aR,13aR,13bR)-benzyl 5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-9-(trifluoromethylsulfonyloxy)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysene-3a-carboxylate (100 mg, 0.148 mmol), 3-(4-boronophenyl)propanoic acid (43.0 mg, 0.222 mmol), Pd(Ph3P)4 (17.07 mg, 0.015 mmol) and sodium carbonate (78 mg, 0.739 mmol) in DME (1 mL) and Water (1 mL) was heated to 100° C. for 1.5 hours. LCMS indicated desired product was formed. The reaction mixture was cooled to the room temperature and neutralized to pH=4-5 using 1N HCl. The reaction mixture was extracted with ethyl acetate. The extracts were dried over Na2SO4, filtered through a celite pad and concentrated under reduced pressure. The residue was purified by 80-100% ethyl acetate/hexanes to give the desired product, 3-(4-((1R,3aS,5aR,5bR,7aR,11aS,13aR,13bR)-3a-(benzyloxycarbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)phenyl)propanoic acid, as colorless oil (60 mg, 55%). LCMS: m/e 675.63 (M−H)−, 4.78 min (method 5). 1H NMR (500 MHz, CHLOROFORM-d) d ppm 0.82 (s, 3H), 0.89 (s, 3H), 0.90 (s, 3H), 0.95 (s, 3H), 0.97 (s, 3H), 0.99-1.73 (m, 17H), 1.69 (s, 3H), 1.80-1.97 (m, 2H), 2.04-2.11 (m, 1H), 2.19-2.37 (m, 2H), 2.62-2.73 (m, 2H), 2.93 (t, J=7.78 Hz, 2H), 3.04 (td, J=10.91, 4.73 Hz, 1H), 4.60 (s, 1H), 4.73 (d, J=2.14 Hz, 1H), 5.05-5.20 (m, 2H), 5.21-5.29 (m, 1H), 6.92-7.00 (m, 2H), 7.06 (d, J=7.63 Hz, 1H), 7.17 (t, J=7.48 Hz, 1H), 7.28-7.41 (m, 5H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.[NH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[N:16][C:17]([O:23][CH:24]([CH3:26])[CH3:25])=[CH:18][CH:19]=2)[N:14]=1.O.C(OC(C)C)(C)C>C(OCC)C>[CH:24]([O:23][C:17]1[N:16]=[C:15]2[C:20]([CH:21]=[CH:22][C:13]([NH:12][C:7](=[O:9])[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)=[N:14]2)=[CH:19][CH:18]=1)([CH3:26])[CH3:25]
Reactant: CC(C)Oc1ccc2ccc(N)nc2n1
Reactant: COc1ccc(C(=O)O)cc1
Solvent: CCOCC
Solvent: CC(C)OC(C)C
Solvent: O
Product: COc1ccc(C(=O)Nc2ccc3ccc(OC(C)C)nc3n2)cc1
Temperature: 4 °C
Yield: 34.8 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 4-methoxybenzoic acid (16.7 g), N,N'-carbonyldiimidazole (19.4 g) and 2-amino-7-isopropoxy-1,8-naphthyridine (25 g). The reaction mixture is poured into water and extracted with ethyl acetate. After concentration to dryness under reduced pressure (4 kPa), the oil produced (39 g) is stirred in the presence of diethyl ether (100 cc) to give a crystallised solid (23 g; m.p. 78° C.). The product produced is dissolved in boiling isopropyl ether (100 cc). After 2 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with diethyl ether (2×10 cc) and dried at 40° C. under reduced pressure (0.067 kPa). N-(7-isopropoxy-1,8-naphthyridin-2-yl)-4-methoxybenzamide (12.9 g) is produced, m.p. 82° C.
Reaction SMILES: [C:1]1(=[O:13])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][C:3](=[O:12])[NH:2]1.[Br:14][CH2:15][CH2:16][CH2:17][CH2:18]Br.[H-].[Na+]>CN(C)C=O>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][N:2]1[C:3](=[O:12])[CH2:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:1]1=[O:13]
Reactant: O=C1CCc2ccccc2C(=O)N1
Reactant: BrCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCc2ccccc2C(=O)N1CCCCBr
Yield: 60 %

Procedure:
A solution of 200 mg of 1,3,4,5-tetrahydro-2-benzazepine-1,3-dione dissolved in 20 ml of dimethylformamide was ice-cooled, and then 0.209 ml (1.5 equivalents) of 1,4-dibromobutane, 54.8 mg (1.2 equivalents) of 60% sodium hydride were added, followed by stirring under ice-cooling for 1.5 hours. The reaction treatment and purification were conducted in the same manner as in Example 13, to obtain 213 mg of the desired compound (yield 60%).
Reaction SMILES: [Br-:1].[OH:2][CH2:3][CH2:4][CH2:5][N+:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH3:16])=[CH:8][CH:7]=1.[CH3:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][N:24]1[C:36]2[CH:35]=[CH:34][C:33]([CH:37]=O)=[CH:32][C:31]=2[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2.N1CCCCC1>C(O)C>[Br-:1].[OH:2][CH2:3][CH2:4][CH2:5][N+:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](/[CH:16]=[CH:37]/[C:33]2[CH:34]=[CH:35][C:36]3[N:24]([CH2:23][CH2:22][O:21][CH2:20][CH2:19][O:18][CH3:17])[C:25]4[C:30]([C:31]=3[CH:32]=2)=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:8][CH:7]=1
Reactant: COCCOCCn1c2ccccc2c2cc(C=O)ccc21
Reactant: Cc1cc[n+](CCCO)c2ccccc12
Agent: [Br-]
Solvent: CCO
Solvent: C1CCNCC1
Product: COCCOCCn1c2ccccc2c2cc(/C=C/c3cc[n+](CCCO)c4ccccc34)ccc21
Temperature: 25 °C
Yield: 41 %

Procedure:
A solution mixture of 7 (0.17 g, 0.6 mmol), 3a (0.24 g, 0.8 mmol) and piperidine (0.1 mL) in ethanol (40 mL) was heated to reflux overnight. After cooling down to room temperature, the organic solvent was removed. The residue was purified by precipitation from methanol and ethyl acetate to afford SLOH-Pr (0.14 g) in 41% yield.1H NMR (400 MHz, DMSO-d6) δ 9.29 (d, J=6.8 Hz, 1H), 9.15 (d, J=8.4 Hz, 1H), 8.88 (s, 1H), 8.51 (d, J=6.8 Hz, 1H), 8.45 (d, J=16 Hz, 1H), 8.37 (d, J=16 Hz, 1H), 8.28-8.24 (m, 2H), 8.13 (d, J=8.4 Hz, 1H), 8.05 (t, J=8.0 Hz, 1H), 7.77 (d, J=8.8 Hz, 1H), 7.70 (d, J=8.4 Hz, 1H), 7.52 (t, J=7.6 Hz, 1H), 7.31 (t, J=7.2 Hz, 1H), 5.01 (t, J=7.2 Hz, 2H), 4.86 (t, J=5.2 Hz, 1H), 4.63 (t, J=4.8 Hz, 2H), 3.84 (t, J=5.2 Hz, 2H), 3.55 (tr, J=5.2 Hz, 2H), 3.47 (t, J=5.6 Hz, 2H), 3.31 (t, J=4.8 Hz, 2H), 3.11 (s, 3H), 2.13 (t, J=6.0 Hz, 2H). 13C NMR (400 MHz, DMSO-d6) δ 153.3, 147.3, 145.1, 142.2, 140.9, 137.9, 135.0, 128.8, 127.4, 126.8, 126.7, 126.5, 126.4, 122.8, 122.2, 121.8, 120.4, 119.9, 119.0, 116.3, 115.2, 110.5, 110.4, 71.3, 69.8, 68.9, 58.1, 57.6, 54.2, 42.9, 32.0. HRMS (MALDI-TOF) m/z Calcd for C31H33N2O3 481.2485 Found 481.2458 [M]+.
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][C@H:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])[CH2:11]1)=[O:7])(C)(C)C.[CH2:20]([N:23]=[C:24]=[O:25])[CH2:21][CH3:22].[NH2:26][C:27]1[C:35]([Cl:36])=[CH:34][C:30](C(O)=O)=[C:29]([O:37][CH3:38])[CH:28]=1>>[NH2:26][C:27]1[C:35]([Cl:36])=[CH:34][C:30]([C:6]([NH:8][CH2:9][C@H:10]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:24]([NH:23][CH2:20][CH2:21][CH3:22])=[O:25])[CH2:11]2)=[O:7])=[C:29]([O:37][CH3:38])[CH:28]=1
Reactant: CCCN=C=O
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: CC(C)(C)OC(=O)NC[C@H]1CCN(CCCCN)C1
Product: CCCNC(=O)NCCCCN1CC[C@H](CNC(=O)c2cc(Cl)c(N)cc2OC)C1

Procedure:
4-((3R)-3 -tert-Butoxycarbonylaminomethylpyrrolidin-1-yl)butylamine (2.00 g) as starting compound was reacted and treated in the same manner as in Example 34 using n-propyl isocyanate (0.76 ml) and 4-amino-5-chloro-2-methoxybenzoic acid (1.49 g) to give 4-amino-5-chloro-2-methoxy-N-((3R)-1-(4-(3-n-propylureido)butyl)pyrrolidin-3-ylmethyl)benzamide.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=1)[C:11]1[CH2:10][CH2:9][CH:8]([NH:24][C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])[CH2:7][C:6]2=1)#[N:2].N[NH:31][C:32]([NH2:34])=[S:33].[NH4+].[OH-]>FC(F)(F)C(O)=O>[NH2:34][C:32]1[S:33][C:1]([C:3]2[CH:4]=[C:5]3[C:13](=[CH:14][CH:15]=2)[N:12]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)[C:11]2[CH2:10][CH2:9][CH:8]([NH:24][C:25](=[O:29])[CH:26]([CH3:27])[CH3:28])[CH2:7][C:6]3=2)=[N:2][N:31]=1
Reactant: CC(C)C(=O)NC1CCc2c(c3cc(C#N)ccc3n2Cc2cccc(F)c2)C1
Reactant: NNC(N)=S
Agent: [NH4+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C(=O)NC1CCc2c(c3cc(-c4nnc(N)s4)ccc3n2Cc2cccc(F)c2)C1
Yield: 16.9 %

Procedure:
Heat a mixture of N-[6-cyano-9-(3-fluorobenzyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]isobutyramide (example 51) (0.500 g, 1.28 mmol) and thiosemicarbazide (0.129 g, 1.41 mmol) in trifluoroacetic acid (5 ml) at 70° C. under nitrogen for 18 h. Pour the mixture onto dilute NH4OH solution and collect 0.510 g of the resultant precipitate by filtration. Azetrope the precipitate with absolute EtOH and purify by silica chromatography eluting with 0.05% NH4OH in EtOAc to give 0.10 g of a white solid. MS (ES): m/z 464 (M+1); HPLC: Rt=1.89 min, (100%); m.p.=251-254° C.
Reaction SMILES: [CH2:1]([NH:3][S:4]([C:7]1[C:8]([F:17])=[CH:9][C:10]([F:16])=[C:11]([CH:15]=1)[C:12]([OH:14])=O)(=[O:6])=[O:5])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH:32]1([C:37]2[S:41][C:40]([NH2:42])=[N:39][N:38]=2)[CH2:36][CH2:35][CH2:34][CH2:33]1>CN(C)C=O.ClCCl>[CH:32]1([C:37]2[S:41][C:40]([NH:42][C:12](=[O:14])[C:11]3[CH:15]=[C:7]([S:4]([NH:3][CH2:1][CH3:2])(=[O:5])=[O:6])[C:8]([F:17])=[CH:9][C:10]=3[F:16])=[N:39][N:38]=2)[CH2:33][CH2:34][CH2:35][CH2:36]1
Reactant: Nc1nnc(C2CCCC2)s1
Reactant: CCNS(=O)(=O)c1cc(C(=O)O)c(F)cc1F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: ClCCCl
Product: CCNS(=O)(=O)c1cc(C(=O)Nc2nnc(C3CCCC3)s2)c(F)cc1F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2,4-difluorobenzoic acid (200 mg, 0.765 mmol) in chlorosulfonic acid (1.535 ml, 22.92 mmol) was stirred at room temperature for 30 seconds, then microwave 200 degree for 10 mins. The reaction mixture was cooled to room temperature and dumped on ice (10 g) slowly. Ethyl acetate (25 ml) was added and extracted twice with ethyl acetate (10 mL X2). The combined organic phase was dried over MgSO4. Ethylamine (1833 μl, 3.67 mmol) in THF (2.0 M) was added, stirred at room temperature for 10 mins and washed with 1 N HCl (10 ml). The organic phase was dried over MgSO4 and concentrated to give 5-[(ethylamino)sulfonyl]-2,4-difluorobenzoic acid, which was purified by HPLC 5%-60% CH3CN/H2O TFA (0.1%) to give 60 mg. To 5-[(ethylamino)sulfonyl]-2,4-difluorobenzoic acid in N,N-dimethylformamide (3 ml) and dichloromethane (3 ml) was added to EDC (32.5 mg, 0.170 mmol) and HOBt (26.0 mg, 0.170 mmol). After 10 mins, 5-cyclopentyl-1,3,4-thiadiazol-2-amine was added. The reaction mixture was stirred at rt overnight, concentrated and purifed by HPLC. The solvents were removed and purified by HPLC (30-70% with TFA 0.1% CNCH3 and H2O, 18 mins) to give the title compound (5 mg).
Reaction SMILES: [C:1]([NH:5][NH2:6])([CH3:4])([CH3:3])[CH3:2].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([N:17]2[CH:22]3[CH2:23][CH2:24][CH2:25][CH:18]2[C:19](=[CH:27]O)[C:20](=O)[CH2:21]3)(=[O:16])=[O:15])=[CH:10][CH:9]=1>>[C:1]([N:5]1[C:20]2[CH2:21][CH:22]3[N:17]([S:14]([C:11]4[CH:12]=[CH:13][C:8]([Cl:7])=[CH:9][CH:10]=4)(=[O:16])=[O:15])[CH:18]([CH2:25][CH2:24][CH2:23]3)[C:19]=2[CH:27]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CC2CCCC(C1=CO)N2S(=O)(=O)c1ccc(Cl)cc1
Reactant: CC(C)(C)NN
Product: CC(C)(C)n1ncc2c1CC1CCCC2N1S(=O)(=O)c1ccc(Cl)cc1

Procedure:
Prepared as described in Example 5 using tert-butyl hydrazine and 9-(4-chlorophenylsulfonyl)-2-(hydroxymethylene)-9-azabicyclo[3.3.1]nonan-3-one which was prepared as described in Example 34.
Reaction SMILES: OC1C=CC=CC=1C1SC=C(CC(O)=O)N=1.C([O:19][C:20](=[O:34])[CH2:21][C:22]1[N:23]=[C:24]([C:27]2[C:32]([OH:33])=[CH:31][CH:30]=[CH:29][N:28]=2)[S:25][CH:26]=1)C.[Li+].[OH-]>>[OH:33][C:32]1[C:27]([C:24]2[S:25][CH:26]=[C:22]([CH2:21][C:20]([OH:34])=[O:19])[N:23]=2)=[N:28][CH:29]=[CH:30][CH:31]=1
Reactant: CCOC(=O)Cc1csc(-c2ncccc2O)n1
Agent: O=C(O)Cc1csc(-c2ccccc2O)n1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)Cc1csc(-c2ncccc2O)n1
Yield: 98.7 %

Procedure:
The procedure used for the preparation of 5a was repeated with 4c (335 mg, 1.27 mmol) and 2N LiOH (2.22 mL) to provide 5c (296 mg, 99%) as a white solid, which was recrystallized from EtOAc/hexane. mp 175.0°-176.0° C.; IR KBr) 3450, 3300-2500 (br), 1729, 1697, 1449, 1189 cm-1 ; 1H NMR (DMSO-d6) δ 3.83 (2H s, CH2), 7.37 (1H dd, J=8.5 and 4.4 Hz, Ar), 7.44 (1H, d, J=8.5 Hz, Ar), 7.63 (1H, s), 8.14 (1H, d, J=4.4 Hz, Ar), 11.70 (1H, s, OH), 12.54 (1H, s, CO2H); FDMS m/z 237 (M+ +1); Anal. Calcd for C10H8N2O3S: C, 50.84; H, 3.41; N, 11.86. Found: C, 50.77; H, 3.42; N, 11.74.
Reaction SMILES: [Br:1][C:2]1[C:3]([S:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[C:4]([CH:7]=[CH:8][C:9]=1[I:10])[CH:5]=O.Cl.[NH2:17][OH:18]>C(O)C.O>[Br:1][C:2]1[C:3]([S:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[C:4]([CH:7]=[CH:8][C:9]=1[I:10])[CH:5]=[N:17][OH:18]
Reactant: CC(C)(C)Sc1c(C=O)ccc(I)c1Br
Reactant: NO
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC(C)(C)Sc1c(C=NO)ccc(I)c1Br
Yield: 70 %

Procedure:
A mixture of 3-bromo-2-tert-butylsulfanyl-4-iodo-benzaldehyde (1.5 g, 3.8 mmol) and hydroxylamine hydrochloride in ethanol (20 mL) and water (4 mL) was heated to reflux for 2 h. The reaction mixture was cooled and concentrated. The residue was treated with water (40 mL) and then saturated aqueous sodium bicarbonate solution until the pH was ˜8.0. The mixture was extracted with ethyl acetate (2×40 mL). The combined organic fractions were dried over anhydrous sodium sulfate, filtered and concentrated. Purification by column chromatography (25% ethyl acetate:hexanes) afforded 1.1 g (70%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 1.34 (s, 9H), 7.41 (d, J=8.7 Hz, 1H), 7.77 (d, J=8.7 Hz, 1H), 8.47 (s, 1H), 8.51 (br. s, 1H); MS (ESI): 414, 416 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:15]=[CH:14][C:13]([I:16])=[CH:12][N:11]3[CH:17]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][CH2:27][F:28]>O>[F:28][CH2:27][CH2:26][CH2:25][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:15]=[CH:14][C:13]([I:16])=[CH:12][N:11]3[CH:17]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(-c2cn3cc(I)cnc3n2)cc1
Reactant: FCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: FCCCOc1ccc(-c2cn3cc(I)cnc3n2)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 59.4 %

Procedure:
339 mg (corresponding to 1.0 mmol) of 2-(4′-hydroxyphenyl)-6-iodoimidazo[1,2-a]pyrimidine that was sufficiently dried to remove moisture was dissolved in 20 mL of N,N-dimethylformamide, and 414 mg (corresponding to 3.0 mmol) of potassium carbonate was added thereto. The mixture was supplemented with 138 μL (corresponding to 1.5 mmol) of 1-bromo-3-fluoropropane, and then stirred at room temperature for 22 hours. After the completion of the reaction, the reaction solution was poured into water and extracted three times with chloroform. The combined chloroform layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting crude product was recrystallized from N,N-dimethylformamide to obtain 236 mg (corresponding to 0.594 mmol) of 2-[4′-(3″-fluoropropoxy)phenyl]-6-iodoimidazo[1,2-a]pyrimidine (FIG. 1-8, Step 3).
Reaction SMILES: [OH:1][NH:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([CH3:16])=[CH:14][CH:13]=[C:12]2[CH3:17])=[CH:7][CH:6]=1)[CH3:4].Cl.[C:19](Cl)(Cl)=[O:20].[OH-].[NH4+:24]>C1(C)C=CC=CC=1.O>[C:19]([N:2]([CH:3]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:15]([CH3:16])=[CH:14][CH:13]=[C:12]2[CH3:17])=[CH:9][CH:10]=1)[CH3:4])[OH:1])(=[O:20])[NH2:24]
Reactant: [NH4+]
Reactant: O=C(Cl)Cl
Reactant: Cc1ccc(C)n1-c1ccc(C(C)NO)cc1
Agent: Cl
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(C)n1-c1ccc(C(C)N(O)C(N)=O)cc1
Reaction time: 7 h

Procedure:
A solution of 1.4 g of N-hydroxy-1-[4-(2,5-dimethyl-1H-pyrrol-1-yl)-phenyl]-ethylamine in 60 ml of toluene is stirred and treated first with one mole equivalent of 4.0 M ethanolic HCl, followed by 15 ml of 2.0 M phosgene in toluene. The solution is stirred for 7 hours, 50 ml of concentrated ammonium hydroxide is added and the mixture is stirred overnight. Excess water is then added and the mixture is again stirred for 2 hours. The organic layer is separated, washed with brine, dried over magnesium sulfate, treated with charcoal and evaporated to dryness. The residue is crystallized from ether to yield N-carbamoyl-N-hydroxy-1-[4-(2,5-dimethyl-1H-pyrrol-1-yl)-phenyl]-ethyl-amine;