Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8]([N:10]2[CH2:14][CH2:13][O:12][C:11]2=[O:15])[CH:7]=[C:6]([N:16]2[C:24]3[C:19](=[CH:20][C:21]([F:25])=[CH:22][CH:23]=3)[C@@:18]3([CH2:27][C:26]3([CH3:29])[CH3:28])[C:17]2=[O:30])[CH:5]=1.Cl>O1CCCC1.[OH-].[Na+].O.C(OCC)(=O)C>[F:25][C:21]1[CH:20]=[C:19]2[C:24](=[CH:23][CH:22]=1)[N:16]([C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([N:10]3[CH2:14][CH2:13][O:12][C:11]3=[O:15])[CH:7]=1)[C:3]([OH:31])=[O:2])[C:17](=[O:30])[C@@:18]12[CH2:27][C:26]1([CH3:29])[CH3:28]
Reactant: COC(=O)c1cc(N2CCOC2=O)cc(N2C(=O)[C@]3(CC3(C)C)c3cc(F)ccc32)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)C[C@]12C(=O)N(c1cc(C(=O)O)cc(N3CCOC3=O)c1)c1ccc(F)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.6 %

Procedure:
A mixture of (R) and (S)-methyl-3-(5′-fluoro-2,2-dimethyl-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)-5-(2-oxooxazolidin-3-yl)benzoate (850 mg, 2.4 mmol) in tetrahydrofuran (10 mL) and 30% sodium hydroxide in water (5 mL) was stirred at 25° C. for 16 hours. The mixture was neutralized with a 2N aqueous hydrochloric acid solution, diluted with ethyl acetate (50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% trifluoro-acetic acid in water) afforded the title compound (410 mg, 50%) as a white solid: LC/MS m/e calcd. for C20H18FNO3: 340, observed (M+H)+: 340.; 1H NMR (400 MHz, MeOD) δppm 1.50 (s, 3 H) 1.57 (s, 3 H) 1.86 (d, J=4.29 Hz, 1 H) 1.93 (d, J=4.55 Hz, 1 H) 4.22 (t, J=7.96 Hz, 2 H) 4.56 (t, J=7.96 Hz, 2 H) 6.86-6.94 (m, 1 H) 6.94-7.02 (m, 1 H) 7.06 (d, J=8.59 Hz, 1 H) 7.84 (s, 1 H) 8.03 (br. s., 1 H) 8.25 (br. s., 1 H).
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[H-].[Na+].Cl.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18]Cl)[CH:13]=1>CN(C)C=O>[N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:18][C:14]2[CH:13]=[N:12][CH:17]=[CH:16][CH:15]=2)[N:5]=1)([O-:3])=[O:2]
Reactant: ClCc1cccnc1
Reactant: O=[N+]([O-])c1cc[nH]n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccn(Cc2cccnc2)n1
Reaction time: 1.5 h
Yield: 55.8 %

Procedure:
3-Nitro-1H-pyrazole (prepared as in Example 15, 113 mg, 1.00 mmol) was dissolved in N,N-dimethylformamide (5 mL) and cooled in an ice bath. A 60% suspension of sodium hydride in mineral oil (88 mg, 2.2 mmol) was added in portions and the cooling bath was removed. After stirring 1.5 h, a mixture of 3-picolyl chloride hydrochloride (164 mg, 1.00 mmol) in N,N-dimethylformamide (1 mL) was added. The reaction mixture was stirred 65 h, then evaporated in vacuo. The residue was treated with saturated aqueous sodium bicarbonate solution (1 mL) and extracted with chloroform (2×3 mL). The combined organic phases were dried over sodium sulfate and evaporated in vacuo. The residue was stirred in ethyl acetate (50 mL) and filtered. The filtrate was evaporated in vacuo and the remaining material was purified by flash column chromatography (Merck silica gel 60, 40-63 μm; (50% ethyl acetate/hexanes to 100% ethyl acetate) to afford 3-(3-nitro-pyrazol-1-ylmethyl)-pyridine (114 mg, 56%) as a clear, faintly yellow oil which began to solidify over time: LC-MS (ESI) m/e calcd for C9H8N4O2 [M+] 204.06, found 205 [M+H+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:39]=[CH:40][C:41]=1[O:42][CH3:43])[C:6]([NH:8][C@@H:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17](=[O:38])[NH:18][C:19]2[S:20][C:21]3[CH2:27][C@@H:26]([N:28]([CH2:35][CH2:36][CH3:37])C(=O)C(F)(F)F)[CH2:25][CH2:24][C:22]=3[N:23]=2)[CH:12]=1)[CH3:10])=[O:7].C([O-])([O-])=O.[K+].[K+].FC(F)(F)C(O)=O>CO.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:39]=[CH:40][C:41]=1[O:42][CH3:43])[C:6]([NH:8][C@@H:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17](=[O:38])[NH:18][C:19]2[S:20][C:21]3[CH2:27][C@@H:26]([NH:28][CH2:35][CH2:36][CH3:37])[CH2:25][CH2:24][C:22]=3[N:23]=2)[CH:12]=1)[CH3:10])=[O:7]
Reactant: CCCN(C(=O)C(F)(F)F)[C@H]1CCc2nc(NC(=O)c3cccc([C@@H](C)NC(=O)c4ccc(OC)c(OC)c4)c3)sc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CO
Product: CCCN[C@H]1CCc2nc(NC(=O)c3cccc([C@@H](C)NC(=O)c4ccc(OC)c(OC)c4)c3)sc2C1
Yield: 66.5 %

Procedure:
Dissolve 3,4-dimethoxy-N—[(R)-1-(3-{(S)-6-[propyl-(2,2,2-trifluoro-acetyl)-amino]-4,5,6,7-tetrahydro-benzothiazol-2-ylcarbamoyl}-phenyl)-ethyl]-benzamide (109 mg, 0.18 mmol) into 10 mL of MeOH and add 5 mL of H2O. To this add K2CO3 (200 mg, 1.50 mmol) and heat the mixture overnight at 55° C. LC-MS analysis indicates the desired material. Add trifluoroacetic acid, dissolve into MeOH and purify via the Gilson Prep HPLC system (5%-70% CH3CN/H2O) to give 62.6 mg of the title compound. MS, electrospray 523.67 (M+H), rt 1.14 min.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:25]2[CH:26]=[N:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=2)[C:8]([OH:24])=[C:9]([CH:23]=1)[CH2:10][NH:11][CH:12]([CH3:22])[CH2:13][NH:14]C(=O)OC(C)(C)C)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.C(Cl)[Cl:43]>>[ClH:43].[ClH:43].[NH2:14][CH2:13][CH:12]([NH:11][CH2:10][C:9]1[CH:23]=[C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])[CH:6]=[C:7]([C:25]2[CH:26]=[N:27][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:29][CH:30]=2)[C:8]=1[OH:24])[CH3:22]
Reactant: CC(CNC(=O)OC(C)(C)C)NCc1cc(C(C)(C)C)cc(-c2ccc(C(F)(F)F)nc2)c1O
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(CN)NCc1cc(C(C)(C)C)cc(-c2ccc(C(F)(F)F)nc2)c1O
Product: Cl
Reaction time: 16 h
Yield: 32 %

Procedure:
The free base of 2-(aminomethyl)-4-(tert-butyl)-6-(6-(trifluoromethyl)pyridin-3-yl)phenol hydrochloride (Example 64), was prepared by partitioning the hydrochloride salt (560 mg, 1.55 mmol) between ethyl acetate and a saturated aqueous sodium bicarbonate solution. The organic phase was separated, dried (Na2SO4), filtered and the solvent removed under reduced pressure. The residue was redissolved in a solution of tert-butyl (2-oxopropyl)carbamate in ethanol (5 mL) and stirred for three days. Sodium borohydride (290 mg, 7.75 mmol) was added portionwise and the reaction mixture stirred at room temperature for one hour. The reaction was quenched with saturated aqueous ammonium chloride solution (1 mL) and the reaction mixture partitioned between ethyl acetate and a saturated aqueous sodium bicarbonate solution. The organic phase was separated, dried (Na2SO4), filtered and the solvent was removed under reduced pressure. The residue was purified using flash chromatography on silica eluting with a solvent gradient of 0-100% ethyl acetate in hexanes to give tert-butyl (2-((5-(tert-butyl)-2-hydroxy-3-(6-(trifluoromethyl)pyridin-3-yl)benzyl)amino)propyl)carbamate (500 mg, 67%) as a white solid. The carbamate (500 mg, 1.04 mmol) was dissolved in methylene chloride (20 mL) and trifluoroacetic acid (10 mL) added and the reaction was stirred for 16 h. The solvent was removed under reduced pressure, the residue azeotroped twice with toluene (20 mL) and then redissolved in a 1:1 mixture of methylene chloride and trifluoracetic acid (40 mL) and stirred at room temperature for four hours. The solvent was removed under reduced pressure, the residue azeotroped twice with toluene (20 mL) and the residue partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic phase was separated, dried (Na2SO4), filtered and the solvent removed under pressure. The residue was purified using flash chromatography on silica eluting with a solvent gradient of 0 to 100% of (89% methylene chloride, 10% methanol and 1% ammonium hydroxide) in methylene chloride. The purified residue was dissolved in a 1.25 M hydrochloric acid solution in ethanol, the solution stood for 10 minutes, and then the solvent removed under reduced pressure and the residue triturated with diethyl ether to give 2-(((1-aminopropan-2-yl)amino)methyl)-4-(tert-butyl)-6-(6-(trifluoromethyl)pyridin-3-yl)phenol dihydrochloride (150 mg, 32% yield) as a white solid.
Reaction SMILES: [NH2:1][CH:2]([P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])[P:3](=[O:10])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6].[C:19]1([S:25](Cl)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>N1C=CC=CC=1.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[C:19]1([S:25]([NH:1][CH:2]([P:3](=[O:10])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6])[P:11](=[O:18])([O:12][CH2:13][CH3:14])[O:15][CH2:16][CH3:17])(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCOP(=O)(OCC)C(N)P(=O)(OCC)OCC
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOP(=O)(OCC)C(NS(=O)(=O)c1ccccc1)P(=O)(OCC)OCC
Reaction time: 4 h

Procedure:
To a solution of tetraethyl (aminomethylene)bis(phosphonate) (661 mg) in pyridine (2 ml) were added benzenesulfonyl chloride (0.35 ml) and then 4-(dimethylamino)pyridine (50 mg) at ambient temperature with stirring. After stirring for 4 hours at the same temperature, the reaction mixture was diluted with ethyl acetate (20 ml). The mixture was washed with 1N hydrochloric acid four times, water and saturated aqueous hydrogen bicarbonate solution successively. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel (20 g) eluted with a mixture of chloroform and methanol (20:1 V/V) to give tetraethyl (phenylsulfonylaminomethylene)bis(phosphonate) as a yellow syrup (364 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7](Cl)(=[O:9])=[O:8])[CH:2]=1.[Na].[CH3:12][C:13]1[C:14]([CH2:25][S:26]([C:28]2[NH:32][C:31]3[CH:33]=[CH:34][CH:35]=[CH:36][C:30]=3[N:29]=2)=[O:27])=[N:15][CH:16]=[CH:17][C:18]=1[O:19][CH2:20][CH2:21][CH2:22][O:23][CH3:24]>C(N(CC)CC)C.ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([N:29]2[C:30]3[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=3[N:32]=[C:28]2[S:26]([CH2:25][C:14]2[C:13]([CH3:12])=[C:18]([O:19][CH2:20][CH2:21][CH2:22][O:23][CH3:24])[CH:17]=[CH:16][N:15]=2)=[O:27])(=[O:9])=[O:8])[CH:2]=1
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: COCCCOc1ccnc(CS(=O)c2nc3ccccc3[nH]2)c1C
Agent: [Na]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCCOc1ccnc(CS(=O)c2nc3ccccc3n2S(=O)(=O)c2cccnc2)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.8 %

Procedure:
100 mg of pyridine-3-sulfonyl chloride was added to 191 mg of 2-[[[3-methyl-4-(3-methoxypropoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole sodium salt in a mixture of 0.15 ml of triethylamine and 10 ml of dichloromethane. The reaction mixture was stirred at room temperature overnight. Dichloromethane (20 ml) was added and washed with water, and 0.1M sodium bicarbonate solution. Organic layer was dried over anhydrous magnesium sulfate and evaporated. Residue was dissolved in minimum amounts of acetonitrile and ethyl ether was added for precipitation. Solids was collected and dried to give 127 mg of the titled product.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:7])[CH2:5][NH2:6].[CH2:8]=[C:9]1[O:13][C:11](=[O:12])[CH2:10]1.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[O:13]=[C:9]([CH3:8])[CH2:10][C:11]([NH:6][CH2:5][C:4]([O:3][CH3:2])=[O:7])=[O:12]
Reactant: COC(=O)CN
Reactant: C=C1CC(=O)O1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)CNC(=O)CC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.2 %

Procedure:
29.87 g (0.24 mol) of glycine methyl ester hydrochloride were added to a solution of 20.00 g (0.24 mol) of diketene in 250 ml toluene at 0° C. Then, 40.00 g (0.48 mol) NaHCO3 were added and the reaction mixture was stirred overnight at room temperature. Since thin-layer chromatography detected no more starting material, the reaction mixture was filtered, evaporated and the residue purified by column chromatography. This gave 33.4 g (0.19 mol, 81% yield) oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][N:11]=[CH:10][C:9]=1[N+:13]([O-:15])=[O:14].[CH:16](=O)[CH3:17]>O.C(O)(=O)C.C(O)C>[N+:13]([C:9]1[CH:10]=[N:11][N:12]2[C:8]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][CH:16]2[CH3:17])([O-:15])=[O:14]
Reactant: CC=O
Reactant: Nc1ccccc1-c1[nH]ncc1[N+](=O)[O-]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CC1Nc2ccccc2-c2c([N+](=O)[O-])cnn21
Yield: 91.2 %

Procedure:
20.4 g (0.1 mole) of 5-(o-aminophenyl)-4-nitropyrazole are dissolved in a mixture of 250 ml of water, 400 ml of acetic acid and 175 ml of ethanol, then 10 ml (about 0.1 mole) of acetaldehyde in 10 ml of ethanol are added. Yellow crystals separate, immediately. Thus, 21.0 g (92%) of 1-nitro-5-methyl-5,6-dihydropyrazolo[1,5-c]quinazoline are obtained. M.p.: 173°-175° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH:9][CH2:10][CH2:11][N:12]1[CH2:16][CH2:15]OC1=O>COCCOCCO>[OH:9][CH2:10][CH2:11][NH:12][CH2:16][CH2:15][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C1OCCN1CCO
Reactant: Nc1ccccc1
Agent: Cl
Solvent: COCCOCCO
Product: OCCNCCNc1ccccc1
Temperature: 168 °C
Yield: 67 %

Procedure:
A mixture of aniline hydrochloride (19.5 g, 0.15 mole), 3-(2-hydroxyethyl)-2-oxazolidinone (20.6 g, 0.157 mole) and 50 ml of 2-(2-methoxyethoxy)ethanol was heated to 168° C. for 16 hours. The orange solution was cooled to room temperature and worked up in a procedure similar to that cited in Example 1. Kugelrohr distillation at 150° C. to 160° C. (0.2 to 0.3 mm) gave a 67 percent yield of the material as a pale yellow oil. Spectral evidence confirmed its structure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=O)=O)=[CH:4][CH:3]=1.[C:19]1([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][C:26](=[O:40])[CH2:27][C:28]2[CH:29]=[C:30]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH:31]=[CH:32][CH:33]=2)[CH:20]=1.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C(O)(C)(C)C>[C:30]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:31]=[CH:32][CH:33]=[C:28]([C:27]2[C:26](=[O:40])[C:25]([C:21]3[CH:20]=[C:19]([C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)[CH:24]=[CH:23][CH:22]=3)=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[C:10]=2[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH:29]=1
Reactant: O=C(Cc1cccc(-c2ccccc2)c1)Cc1cccc(-c2ccccc2)c1
Reactant: O=C(C(=O)c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: O
Solvent: CC(C)(C)O
Product: O=C1C(c2cccc(-c3ccccc3)c2)=C(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)=C1c1cccc(-c2ccccc2)c1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 76.6 %

Procedure:
To a degassed solution of 940 mg of 4,4′-dichlorobenzil (3.37 mmol) and 1.22 g of 1,3-di(biphenyl-3-yl)propan-2-one (7, 3.37 mmol) in 20 ml of tert-butanol was added, at 80° C., a methanolic tetrabutylammonium hydroxide solution (1M, 1.7 ml, 1.7 mmol). The reaction solution was stirred at 80° C. for 20 minutes, and the reaction then stopped by adding water. The mixture was extracted three times with dichloromethane and the collected organic phases were washed with saturated sodium chloride solution and dried over magnesium sulfate, before the solvent was distilled off under reduced pressure. The crude product was purified by column chromatography (silica gel, eluent: hexane with 20% DCM) and gave 1.56 g of the tetraarylcyclopentadienone 8b as a pale violet solid (77%, 2.58 mmol). Elemental analysis measured: C 81.3; H 3.3% (calculated for C41H26Cl2O: C, 81.3; H, 4.3%); 1H NMR (700 MHz, d8-THF) δ=7.52 (s, 2H, CH), 7.50 (d, J=7.8 Hz, 2H, CH), 7.42 (d, J=7.2 Hz, 4H, CH), 7.36 (t, J=7.7 Hz, 4H, CH), 7.32 (m, 6H, CH), 7.27 (t, J=7.3 Hz, 2H, CH), 7.23 (d, J=7.8 Hz, 2H, CH), 7.06 (d, J=8.5 Hz, 4H, CH); 13C NMR (175 MHz, d8-THF) δ=199.86, 154.28, 141.91, 141.82, 135.61, 133.14, 132.14, 132.10, 129.98, 129.90, 129.70, 129.69, 129.52, 128.27, 127.78, 127.20, 126.73; MS (MALDI-TOF): m/z (%): 604.6 (100) [M+] (calculated for C41H26Cl2: 604.1); Rf (hexane with 10% ethyl acetate)=0.47.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.Br[C:12]1[CH:13]=[CH:14][C:15]([Cl:21])=[C:16]([CH:20]=1)[C:17]([OH:19])=[O:18].C([O-])([O-])=O.[Na+].[Na+].O>C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C>[Cl:21][C:15]1[CH:14]=[CH:13][C:12]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[CH:20][C:16]=1[C:17]([OH:19])=[O:18]
Reactant: OB(O)c1cccc(F)c1
Reactant: O=C(O)c1cc(Br)ccc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CN(C)C=O
Product: O=C(O)c1cc(-c2cccc(F)c2)ccc1Cl
Temperature: 100 °C
Reaction time: 8 h
Yield: 66.5 %

Procedure:
A solution of 3-fluorophenyl boronic acid (500 mg, 3.5 mmol, 1.2 eq), 5-bromo-2-chlorobenzoic acid (700 mg, 3.0 mmol, 1.0 eq), Pd(PPh3)4 (687 mg, 0.60 mmol, 0.2 eq) and Na2CO3 (2.52 g, 24 mmol, 8.0 eq) in a mixture of ethanol (5 mL), H2O (5 mL) and DMF (20 mL) was stirred at 100° C. under N2 overnight. The reaction was quenched by addition of diluted HCl (to pH 3) and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4) filtered and evaporated in vacuo. The residue was purified by chromatography (petroleum ether:EtOAc 20:1 to 1:1) to give the title compound as a white solid (500 mg, 67%).
Reaction SMILES: [CH2:1]([S:16]([CH:19]([CH2:25][CH3:26])[C:20]([O:22]CC)=[O:21])(=[O:18])=[O:17])[CH2:2]/[CH:3]=[CH:4]\[CH2:5]/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH3:15].[Li+].[OH-].O.Cl>C(O)C>[CH2:1]([S:16]([CH:19]([CH2:25][CH3:26])[C:20]([OH:22])=[O:21])(=[O:17])=[O:18])[CH2:2]/[CH:3]=[CH:4]\[CH2:5]/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH3:15]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\CCS(=O)(=O)C(CC)C(=O)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC/C=C\C/C=C\C/C=C\C/C=C\CCS(=O)(=O)C(CC)C(=O)O
Temperature: 60 °C
Reaction time: 3 h
Yield: 72.7 %

Procedure:
Ethyl 2-((3Z,6Z,9Z,12Z)-pentadeca-3,6,9,12-tetraenylsulfonyl)butanoate (370 mg, 0.97 mmol) was dissolved in ethanol (10 mL) and added a solution of LiOH in H2O (1 M, 3.9 mL, 3.9 mmol). The resulting mixture was stirred at 60° C. for three hours, cooled, added 0.1 M HCl until pH=2 and extracted twice with diethyl ether (15 mL each). The combined organic layer was washed with brine (15 mL), dried, filtrated, concentrated in vacuo and purified by flash chromatography on silica gel (heptane:EtOAc w/5% HCOOH 4:1). Concentration of the appropriate fractions afforded 250 mg (73% yield) of the title compound as an oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11](O)[C:12]2[C:13]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)=[C:14]3[C:22](=[CH:23][C:24]=2[CH:25]([CH3:27])[CH3:26])[O:21][C:17]2([CH2:20][CH2:19][CH2:18]2)[CH2:16][C:15]3=[O:28])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(S(F)(F)[F:43])CC)C.O>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([F:43])[C:12]2[C:13]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)=[C:14]3[C:22](=[CH:23][C:24]=2[CH:25]([CH3:26])[CH3:27])[O:21][C:17]2([CH2:18][CH2:19][CH2:20]2)[CH2:16][C:15]3=[O:28])=[CH:7][CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(O)c1ccc(C(C)(C)C)cc1)C(=O)CC1(CCC1)O2
Reactant: CCN(CC)S(F)(F)F
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(F)c1ccc(C(C)(C)C)cc1)C(=O)CC1(CCC1)O2
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Under argon, 110 mg (0.23 mmol) of 6-[(4-tert-butylphenyl)(hydroxy)methyl]-5-(4-fluorophenyl)-7-isopropylspiro[chromen-2,1′-cyclobutan]-4(3H)-one (Example 55A) are dissolved in 2.3 ml of toluene, 36 μl (0.27 mmol) of diethylaminosulfur trifluoride are added slowly at −78° C. and the mixture is stirred at −78° C. for 1 h. The temperature is then slowly increased to −60° C. After 2 h, water is added and the mixture is extracted twice with ethyl acetate. The combined organic phases are washed once with saturated sodium bicarbonate solution and once with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The crude product is purified on a silica gel column (mobile phase: cyclohexane/ethyl acetate 12:1). This gives 92 mg (83% of theory) of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]([CH:7]=[CH:8][C:9]=1[I:10])[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH3:18][C:19]([SH:22])([CH3:21])[CH3:20].O>CN(C=O)C>[Br:1][C:2]1[C:3]([S:22][C:19]([CH3:21])([CH3:20])[CH3:18])=[C:4]([CH:7]=[CH:8][C:9]=1[I:10])[CH:5]=[O:6]
Reactant: O=Cc1ccc(I)c(Br)c1F
Reactant: CC(C)(C)S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)Sc1c(C=O)ccc(I)c1Br
Temperature: 80 °C
Yield: 62.6 %

Procedure:
A mixture of 3-bromo-2-fluoro-4-iodo-benzaldehyde (1.3 g, 4.0 mmol), potassium carbonate (0.66 g, 4.7 mmol), and 2-methylpropane-2-thiol (0.53 mL, 4.7 mmol) in dry DMF (2 mL) was heated at 80° C. in a sealed tube for 16 h. The reaction mixture was cooled to RT, water was added, and the mixture was extracted with dichloromethane (2×30 mL). The combined organic fractions were washed with water (60 mL), dried over sodium sulfate, filtered, and concentrated. Purification of the residue by column chromatography (5% ethyl acetate:hexanes) afforded 1.0 g (64%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 1.30 (s, 9H), 7.54 (d, J=8.1 Hz, 1H), 7.87 (d, J=8.1 Hz, 1H), 10.29 (s, 1H).
Reaction SMILES: [N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:20][CH:19]=[C:18]([CH3:21])[N:9]2[C:10](=[O:17])[C:11]=1[C:12]1[N:13]=[CH:14][S:15][CH:16]=1)[CH3:5])=[N+]=[N-].CP(C)C.C(OCC)(=O)C>O1CCCC1.O>[NH2:1][CH:4]([C:6]1[N:7]=[C:8]2[S:20][CH:19]=[C:18]([CH3:21])[N:9]2[C:10](=[O:17])[C:11]=1[C:12]1[N:13]=[CH:14][S:15][CH:16]=1)[CH3:5]
Reactant: Cc1csc2nc(C(C)N=[N+]=[N-])c(-c3cscn3)c(=O)n12
Agent: CP(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1csc2nc(C(C)N)c(-c3cscn3)c(=O)n12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 7-(1-azidoethyl)-3-methyl-6-(1,3-thiazol-4-yl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.030 g, 0.094 mmol) in tetrahydrofuran (0.3 mL) and water (0.068 mL) was added 1.00 M of trimethylphosphine in tetrahydrofuran (0.113 mL, 0.113 mmol) at room temperature and the mixture was stirred at room temperature for 1 hour. To the mixture was added ethyl acetate and the mixture was extracted with 1 N HCl two times. The combined extracts were neutralized with solid sodium bicarbonate, and extracted with dichloromethane. The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was used directly in next step. LCMS calculated for C12H13N4OS2(M+H)+: m/z=293.1. Found: 293.0.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]2[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[C:13]([C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][C:17]=1[F:25])([OH:15])=O.[CH3:26][C@@H:27]1[CH2:31][CH2:30][CH2:29][N:28]1[CH2:32][C@@H:33]1[CH2:37][CH2:36][CH2:35][NH:34]1>>[CH:10]1([C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:19]3[CH:20]=[CH:21][C:16]([C:13]([N:34]4[CH2:35][CH2:36][CH2:37][C@H:33]4[CH2:32][N:28]4[CH2:29][CH2:30][CH2:31][C@H:27]4[CH3:26])=[O:15])=[C:17]([F:25])[CH:18]=3)=[CH:3][CH:4]=2)=[O:9])[CH2:12][CH2:11]1
Reactant: O=C(c1ccc(Br)cc1)C1CC1
Reactant: C[C@@H]1CCCN1C[C@@H]1CCCN1
Reactant: O=C(O)c1ccc(B(O)O)cc1F
Product: C[C@@H]1CCCN1C[C@@H]1CCCN1C(=O)c1ccc(-c2ccc(C(=O)C3CC3)cc2)cc1F

Procedure:
The title compound is prepared in a manner, substantially analogous to Procedures QQ and B′ starting from commercially available (4-Bromo-phenyl)-cyclopropyl-methanone and (4-carboxy-3-fluorophenyl)boronic acid (CAS# 120153-08-4), then 2-(R)-Methyl-1-(2-(S)-pyrrolidinylmethyl)pyrrolidine. MS (M+H) 435.2