Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Br:20])=[CH:4][N:3]=1.[CH3:21][C:22]1[O:26][C:25]([CH:27]=O)=[CH:24][CH:23]=1>>[Br:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:27]([C:25]3[O:26][C:22]([CH3:21])=[CH:23][CH:24]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: Cc1ccc(C=O)o1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Product: Cc1ccc(-c2nc3c(N[C@H]4[C@@H](C(N)=O)[C@@H]5C=C[C@H]4C5)c(Br)cnc3[nH]2)o1
Yield: 30 %

Procedure:
In a similar fashion to Compound LXXXVII, (1S,2S,3R,4R)-3-(2,3-Diamino-5-bromo-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (50 mg, 0.148 mmol) and 5-Methyl-2-furancarboxaldehyde (17.9 mg, 0.163 mmol) were reacted to produce 19 mg (30%) of the title compound. mp: 200-201° C., 1H NMR (300 MHz, DMSO-d6): 13.17 (s, 1H), 8.00 (s, 1H), 7.74 (s, 1H), 7.20 (s, 1H), 7.06 (s, 1H), 6.36 (s, 1H), 6.33 (s, 1H), 5.16 (t, J=8 Hz, 1H), 3.32 (s, 1H), 2.87 (s, 1H), 2.73 (s, 1H), 2.60 (d, J=8 Hz, 1H), 2.40 (s, 3H), 2.23 (d, J=8 Hz, 1H), 1.37 (d, J=8 Hz, 1H). MS: 428, 430 (M+H), HPLC: 2.39 (G method).
Reaction SMILES: [C:1]([CH:4]1[C:9](=[O:10])[CH2:8][C:7]([CH3:12])([CH3:11])[CH2:6][C:5]1=O)(=O)[CH3:2].O.[NH2:15][NH2:16]>C(O)C>[CH3:2][C:1]1[C:4]2[C:9](=[O:10])[CH2:8][C:7]([CH3:12])([CH3:11])[CH2:6][C:5]=2[NH:16][N:15]=1
Reactant: NN
Reactant: CC(=O)C1C(=O)CC(C)(C)CC1=O
Solvent: CCO
Solvent: O
Product: Cc1n[nH]c2c1C(=O)CC(C)(C)C2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 2-acetyl-5,5-dimethyl-cyclohexane-1,3-dione (2 g, 11.04 mmol), prepared as described in example 2, and hydrazine hydrate (1.66 ml, 33.13 mmol) in ethanol (25 ml) was stirred at room temperature for about 3 hours and then the solvent was evaporated. The residue was dissolved in dichloromethane, washed with water and brine, dried over sodium sulfate and evaporated. The title compound was obtained after chromatography on silica gel (dichloromethane:methanol=95:5) as a colourless solid (0.8 g, 45%): m.p. 103-104° C.
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(N(CC)CC)C.[Br:21][CH:22]([CH3:26])[C:23](Br)=[O:24]>C1(C)C=CC=CC=1>[Br:21][CH:22]([CH3:26])[C:23]([O:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:24]
Reactant: CCCCCCCCCCCCO
Reactant: CC(Br)C(=O)Br
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCOC(=O)C(C)Br
Temperature: 57.5 °C
Reaction time: 3 h
Yield: 93.8 %

Procedure:
To a stirred solution of 1-decanol 2 (10 g, 53.7 mmol) in toluene (100 mL) was added triethylamine (7.5 mL, 53.7 mmol)) and followed by 2-bromo propionyl bromide 58 (12.7 g, 59.1 mmol) at 5-10° C. The reaction mixture was stirred for 3 hour at 55-60° C., and the reaction was monitored by TLC. The reaction mixture was quenched with saturated sodium bicarbonate solution and stirred for 15 minutes at 25-35° C. The aqueous and organic layers were separated, the combined organic layers were washed with brine solution. The organic layer was dried over Na2SO4 and concentrated under vacuum to afford crude 59 (16.19 g, yield: 94%) as a liquid.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C@:9]12[C:15]([CH3:17])([CH3:16])[C@H:12]([CH2:13][CH2:14]1)[CH:11]([C:18](Cl)=[O:19])[C:10]2=O.C(O[C:27]([N:29](C)[NH:30][C:31]1[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[CH:33][C:32]=1[F:41])=O)(C)(C)C.Cl.O1CCOCC1>ClCCCl.ClCCl>[F:41][C:32]1[CH:33]=[CH:34][C:35]([C:37]([F:40])([F:39])[F:38])=[CH:36][C:31]=1[N:30]1[C:18](=[O:19])[C:11]2[C@@H:12]3[C:15]([CH3:17])([CH3:16])[C@@:9]([CH3:8])([CH2:14][CH2:13]3)[C:10]=2[N:29]1[CH3:27]
Reactant: CN(Nc1cc(C(F)(F)F)ccc1F)C(=O)OC(C)(C)C
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)C(=O)C2C(=O)Cl
Agent: Cl
Solvent: ClCCCl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cn1c2c(c(=O)n1-c1cc(C(F)(F)F)ccc1F)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 31.3 %

Procedure:
Triethylamine (518 μL, 3.7 mmol) was added dropwise to a cooled (0° C.) solution (1R,4R)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl chloride (418 mg, 1.95 mmol) of in 1,2-dichloroethane (3 mL) over 1 min. The reaction mixture was stirred for 5 min and then a solution of N′-(2-fluoro-5-trifluoromethyl-phenyl)-N-methyl-hydrazinecarboxylic acid tert-butyl ester (380 mg, 1.23 mmol) in 1,2-dichloroethane (6 mL) was added over 2 min. The reaction mixture was stirred at 0° C. for 15 min, at room temperature for 30 min, and then in an oil bath at 50° C. for 2 h. A solution of HCl in dioxane (4 M; 8 mL, 32 mmol) was added and the mixture was heated in an oil bath at 100° C. for 1 h and then allowed to cool to room temperature. Dichloromethane (100 mL) was added and the mixture was washed with 1:1 water/brine (20 mL), dried (magnesium sulfate), filtered, evaporated, and purified using an ISCO 40 g column, eluting with 20-50% ethyl acetate/hexanes. Fractions homogeneous for the product were evaporated, and then co-evaporated with ether and then petroleum ether. The residue was triturated with hexanes, and the solid was dried under high vacuum at 70° C. overnight and then at 85° C. for 1 h to give (4S,7R)-2-(2-fluoro-5-trifluoromethyl-phenyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (142 mg, 30%) as a light yellow solid. ES(+)-MS (M+H) 369.
Reaction SMILES: C[O-].[Na+].S[CH:5]([C:9](=[O:14])[CH2:10][CH:11]([CH3:13])[CH3:12])[CH:6]([CH3:8])[CH3:7].SC(S)=O.C(Br)C=C.[CH2:23]([S:26]C(C(=O)CC(C)C)C(C)C)[CH:24]=[CH2:25]>CO.Cl.O>[CH2:23]([S:26][CH2:7][CH:6]([CH3:8])[CH2:5][C:9](=[O:14])[CH2:10][CH:11]([CH3:13])[CH3:12])[CH:24]=[CH2:25]
Reactant: CC(C)CC(=O)C(S)C(C)C
Reactant: C=CCSC(C(=O)CC(C)C)C(C)C
Agent: C[O-]
Agent: Cl
Agent: O=C(S)S
Solvent: O
Solvent: CO
Solvent: C=CCBr
Product: C=CCSCC(C)CC(=O)CC(C)C
Temperature: 23 °C
Reaction time: 0.25 h

Procedure:
Into a 25 ml, round-bottom, three-necked flask equipped with magnetic stirrer, reflux condenser, nitrogen inlet tube and cold water bath is placed a solution of 0.162 grams (0.003 moles) of sodium methoxide dissolved in 2 ml anhydrous methanol. Using the water bath the temperature of the sodium methoxide solution is reduced to 23° C. At 23° C a solution of 0.522 grams (0.003 moles) of 3-mercapto-2,6-dimethyl-4-heptanone dissolved in 3 ml anhydrous methanol is added to the sodium methoxide solution. Subsequent to the addition of the mercapto ketone, after stirring for 15 minutes at 23° C, a solution of 0.40 grams (0.0033 moles) of allyl bromide dissolved in 2 ml anhydrous methanol is added to the reaction mass with stirring. The reaction mass warms to 33° C and is continued to be stirred at 25°-33° C for a period of 2 hours. It is concentrated on a rotary evaporator using water aspirator vacuum to a volume of 3 ml, thus yielding a white slurry. Eight ml water is then added to the slurry thereby dissolving the solid therein. One drop of 10% HCl is added to the resulting material thereby reducing the pH from about 9 to about 5. The reaction mass now existing in two phases is extracted with three 8 ml volumes of methylene chloride. The extracts are combined and washed with 6 ml water and then dried over anhydrous sodium sulfate, gravity filtered and concentrated on a rotary evaporator to a weight of 0.55 grams (pale yellow oil). GLC analysis (8' × 1/4" SE-30 column), NMR, IR and mass spectral analyses of GLC isolated material confirm that the resulting product is 97% product, 3-allylthio-2,6-dimethyl-4-heptanone, having the structure: ##STR66##
Reaction SMILES: CS(O[CH:6]([CH3:29])[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[O:16][C:17]3[CH:23]=[C:22]([O:24][CH2:25][CH:26]4[CH2:28][CH2:27]4)[CH:21]=[CH:20][C:18]=3[CH:19]=2)[CH2:11][CH2:10]1)(=O)=O.[N-:30]=[N+:31]=[N-:32].[Na+]>CN(C=O)C>[N:30]([CH:6]([CH3:29])[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[O:16][C:17]3[CH:23]=[C:22]([O:24][CH2:25][CH:26]4[CH2:28][CH2:27]4)[CH:21]=[CH:20][C:18]=3[CH:19]=2)[CH2:11][CH2:10]1)=[N+:31]=[N-:32]
Reactant: CC(CO[C@H]1CC[C@H](c2cc3ccc(OCC4CC4)cc3o2)CC1)OS(C)(=O)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(CO[C@H]1CC[C@H](c2cc3ccc(OCC4CC4)cc3o2)CC1)N=[N+]=[N-]
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A suspension of 2-({trans-4-[6-(cyclopropylmethoxy)-1-benzofuran-2-yl]cyclohexyl}oxy)-1-methylethyl methanesulfonate 624 mg) and sodium azide (480 mg) in DMF (5 mL) was stirred at 60° C. overnight. The reaction mixture was allowed to cool to room temperature, and extracted with ethyl acetate and water. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (397 mg).
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][N:5]([CH:10]([CH3:27])[C:11]([NH:13][C:14]2[CH:26]=[CH:25][C:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:16][CH:15]=2)=[O:12])[C:4](=[O:28])[CH:3]=1.[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([C:39]([F:42])([F:41])[F:40])=[C:34](B(O)O)[CH:35]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([C:39]([F:40])([F:41])[F:42])=[C:34]([C:2]2[C:7]([O:8][CH3:9])=[CH:6][N:5]([CH:10]([CH3:27])[C:11]([NH:13][C:14]3[CH:26]=[CH:25][C:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:16][CH:15]=3)=[O:12])[C:4](=[O:28])[CH:3]=2)[CH:35]=1
Reactant: OB(O)c1cc(Cl)ccc1C(F)(F)F
Reactant: COc1cn(C(C)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1cn(C(C)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1C(F)(F)F
Reaction time: 8 h

Procedure:
Under argon (in a flask dried by heating), 113 mg (0.25 mmol) of tert-butyl 4-{[2-(4-bromo-5-methoxy-2-oxopyridin-1(2H)-yl)propanoyl]amino}benzoate (racemate), 67 mg (0.30 mmol, 1.2 eq.) of 5-chloro-2-trifluoromethylphenylboronic acid, 103 mg (0.74 mmol, 3.0 eq.) of potassium carbonate and 20 mg (0.03 mmol, 0.1 eq.) of [1,1-bis(diphenylphosphino)ferrocene]palladium(II) chloride/dichloromethane monoadduct were suspended in 5.0 ml of dioxane and stirred overnight in an oil bath already preheated to 110° C. A further 10 mg (0.01 mmol, 0.05 eq.) of [1,1-bis-(diphenylphosphino)ferrocene]palladium(II) chloride/dichloromethane monoadduct and 22 mg (0.10 mmol, 0.4 eq.) of 5-chloro-2-trifluoromethylphenylboronic acid were added and the reaction mixture was stirred at 110° C. for a further 20 h and then filtered through Celite. The residue was washed with dioxane. The combined filtrates were concentrated under reduced pressure. The residue was triturated with water, filtered off, washed with water and dried under reduced pressure. Yield: 145 mg (purity 84%, 89% of theory)
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[I-].[K+].Br[CH2:16][C:17]1[CH2:18][O:19][C:20]2[C:25]([CH:26]=1)=[C:24]1[O:27][CH2:28][CH2:29][O:30][C:23]1=[CH:22][CH:21]=2>CN(C)C=O.O>[O:27]1[C:24]2=[C:25]3[C:20](=[CH:21][CH:22]=[C:23]2[O:30][CH2:29][CH2:28]1)[O:19][CH2:18][C:17]([CH2:16][N:5]1[C:1](=[O:11])[C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]1=[O:6])=[CH:26]3
Reactant: BrCC1=Cc2c(ccc3c2OCCO3)OC1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [I-]
Agent: [K+]
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CC1=Cc2c(ccc3c2OCCO3)OC1
Reaction time: 10 h

Procedure:
2.36 g (12.75 mmol) of potassium phthalimide and also 0.166 g (1 mmol) of potassium iodide are added to a solution of 2.54 g (8.5 mmol) of the brominated compound obtained in Step E in 20 ml of anhydrous N,N-dimethylformamide; the medium is then stirred under argon for 10 hours. The solvent is evaporated in vacuo; the residue obtained is then taken up in water and extracted with dichloromethane. The organic phase is dried over magnesium sulphate and then concentrated under reduced pressure. Chromatography on a silica column (eluant:ethyl acetate/petroleum ether 10/90) yields the title phthalimide in the form of a white solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[N:10][O:11][CH3:12])[C:7]([OH:9])=[O:8].[C:13](Cl)(=O)C>CO>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[N:10][O:11][CH3:12])[C:7]([O:9][CH3:13])=[O:8]
Reactant: CON=C(C(=O)O)c1ccco1
Reactant: CC(=O)Cl
Solvent: CO
Product: CON=C(C(=O)OC)c1ccco1
Yield: 92 %

Procedure:
The crude 2-(furan-2-yl)-2-(methoxyimino)acetic acid (Example 2a) was dissolved in 100 mL of MeOH and was added to a solution of acetyl chloride (3.82 ml, 53.5 mmol) in 50 mL of MeOH. After refluxing for 16 hr, solvent was removed on the rotary evaporator and the crude product was added to 100 mL EtOAc and 20 mL of water. The organic layer was washed with 20 mL of a saturated solution of NaCl, dried (MgSO4) and solvent removed to give methyl 2-(furan-2-yl)-2-(methoxyimino)acetate (6.35 g, 32.9 mmol, 92% yield) as a yellow oil. The product is a 4:1 mixture of isomers by H NMR. Major Isomer: 1H NMR (400 MHz, Chloroform-d) δ 7.53 (dd, J=1.7, 0.6 Hz, 1H). 7.31 (dd, J=3.5, 0.6 Hz, 1H), 6.54 (dd, J=3.5, 1.8 Hz, 1H), 4.15 (s, 3H), 3.94 (s, 3H); 13C NMR (101 MHz, Chloroform-d) δ 162.77, 144.82, 143.80, 142.47, 119.34, 111.78, 63.95, 53.10. HRMS-ESI (m/z) calc'd for [C8H9NO4]+, 183.0532. found, 183.0539.
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[O:12]C(=O)[N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:9]2[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:34])([F:33])[CH:30]([F:32])[F:31])[CH:23]=2)=[CH:4][CH:3]=1.[OH-].[Na+].O>CO>[F:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([OH:12])[CH:9]([NH:10][C:14](=[O:15])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:33])([F:34])[CH:30]([F:31])[F:32])[CH:23]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)OC(c2ccc(F)nc2)C1Cc1cccc(OC(F)(F)C(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(F)nc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87.2 %

Procedure:
To absolution of 1,1-dimethylethyl(4RS,5SR)-5-(6-fluoropyridin-3-yl)-2-oxo-4-((3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)-1,3-oxazolidine-3-carboxylate (2.40 g, 4.91 mmol) in methanol (12 ml) was added a solution of 0.5N sodium hydroxide in methanol (11.8 ml, 5.90 mmol), and the mixture was stirred at room temperature for 10 min. To the reaction solution was added water (50 ml) and the mixture was extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (1.98 g, 87%).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:8]([C:10](OCC)=[O:11])[N:9]=1)(=[O:3])[CH3:2].[BH4-].[Li+]>C1COCC1>[CH2:15]([C:7]1[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=1[CH:10]=[O:11])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)c1nc(NC(C)=O)sc1Cc1ccccc1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(C=O)c(Cc2ccccc2)s1
Temperature: 25 °C
Reaction time: 12 h
Yield: 29.3 %

Procedure:
Ethyl 2-(acetylamino)-5-benzyl-1,3-thiazole-4-carboxylate (1.0 g) was dissolved in THF(20 ml), and then lithium borohydride (124 mg) was added portionwise to the solution at 0° C. The reaction mixture was refluxed for 4.5 hours and quenched with MeOH. The mixture was concentrated in vacuo, and purified by flash column chromatography over silica gel with CHCl3/MeOH (20:1) as an eluent. The residual amorphous substance was dissolved in MeOH (1 ml) and CHCl3 (8 ml). Then manganase(IV) oxide (1.26 g) was added to the solution under N2 atmosphere. The reaction mixture was stirred at r.t. for 12 hours, and filtered through a celite pad. The filtrate was concentrated in vacuo. The residue was purified by flash column chromatography over silica gel with CHCl3/MeOH (20:1) as an eluent to give N-(5-benzyl-4-formyl-1,3-thiazol-2-yl)acetamide (251 mg) as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=3)[CH:17]=[C:16](Br)[CH:15]=2)=[CH:9][C:8]=1[CH3:33])[CH3:2].[C:35]([C:37]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=1)#[CH:36].C(OC(=O)COC1C=CC(SC2C=C(C#CC3C=CC(CO)=CC=3)C=C(OCCC3C=CC(Cl)=CC=3)C=2)=CC=1C)C>>[CH2:1]([O:3][C:4](=[O:34])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=3)[CH:17]=[C:16]([C:36]#[C:35][C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)[CH:15]=2)=[CH:9][C:8]=1[CH3:33])[CH3:2]
Reactant: CCOC(=O)COc1ccc(Sc2cc(Br)cc(OCc3ccc(S(C)(=O)=O)cc3)c2)cc1C
Reactant: C#Cc1ccc(F)cc1
Agent: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccc(CO)cc3)cc(OCCc3ccc(Cl)cc3)c2)cc1C
Product: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccc(F)cc3)cc(OCc3ccc(S(C)(=O)=O)cc3)c2)cc1C

Procedure:
The title product was prepared from {4-[3-Bromo-5-(4-methanesulfonyl-benzyloxy)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (335 mg; 0.59 mmol), 1-ethynyl-4-fluorobenzene (142.3 mg; 1.19 mmol) applying the procedure described for {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester. The crude product was purified by preparative HPLC (method B). Yield: 140 mg (39%). HPLC-MS: m/z: 605.5 (M+H)+; Rt: 2.80 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:11]2[CH2:14][CH2:13][CH2:12]2)[C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[C:15](=O)([O-])[O-].[K+].[K+].COS(=O)(=O)OC>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:11]2[CH2:12][CH2:13][CH2:14]2)[C:5]([O:10][CH3:15])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Br)cc(C2CCC2)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: COS(=O)(=O)OC
Product: COc1c(C=O)cc(Br)cc1C1CCC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
5-bromo-3-cyclobutyl-2-hydroxybenzaldehyde was dissolved in N,N-dimethylformamide (30 mL), and potassium carbonate (10.79 g) and dimethylsulfuric acid (3.7 mL) were added to the solution under water cooling, and then the mixture was stirred at room temperature for 14 hours. The reaction solution was filtered and water was added, and then the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=20:1) to obtain the title compound (1.27 g) as a yellow oily substance.
Reaction SMILES: [S:1]([NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[O:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:10]=1)([CH3:4])(=[O:3])=[O:2].[BH4-].[Na+]>C(O)C>[OH:17][CH:11]([C:9]1[N:10]=[C:6]([NH:5][S:1]([CH3:4])(=[O:2])=[O:3])[S:7][CH:8]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C(=O)c1csc(NS(C)(=O)=O)n1
Agent: CCOC(=O)C(=O)c1csc(=NS(C)(=O)=O)[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(O)c1csc(NS(C)(=O)=O)n1

Procedure:
To a mixture of ethyl 2-(2-mesylamino-1,3-thiazol-4-yl)glyoxylate, which can be represented as ethyl 2-(2-mesylimino-2,3-dihydro-1,3-thiazol-4-yl)glyoxylate, (3.60 g.) and ethanol (50 ml.) was added sodium borohydride (0.32 g.) under stirring and ice-cooling, and then the mixture was stirred for 40 minutes at room temperature. After the reaction, the reaction mixture was concentrated. The residue was poured into a mixture of ethyl acetate (100 ml.) and dilute hydrochloric acid, and the aqueous solution was separated. Thus obtained aqueous solution (pH 1 to 2) was subjected to salting-out and then extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The extract was treated with activated charcoal and then the solvent was distilled off to give a solid of ethyl 2-hydroxy-2-(2-mesylamino-1,3-thiazol-4-yl)acetate, which can be represented as ethyl 2-hydroxy-2-(2-mesylimino-2,3-dihydro-1,3-thiazol-4-yl)acetate, (2.6 g.)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]([CH3:19])[C:9]2=[O:20])=[C:4]([O:21][CH:22]([CH3:25])[C:23]#[CH:24])[CH:3]=1.[F-].[Cs+]>C(N(CC)C1C=CC=CC=1)C>[Cl:1][C:2]1[C:3]2[CH:25]=[C:22]([CH2:23][CH3:24])[O:21][C:4]=2[C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:16])[F:17])[N:10]([CH3:19])[C:9]2=[O:20])=[CH:6][CH:7]=1
Reactant: C#CC(C)Oc1cc(Cl)ccc1-n1c(=O)cc(C(F)(F)F)n(C)c1=O
Agent: [Cs+]
Agent: [F-]
Solvent: CCN(CC)c1ccccc1
Product: CCc1cc2c(Cl)ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c2o1
Temperature: 185 °C
Reaction time: 0.5 h
Yield: 47.3 %

Procedure:
50 ml of N,N-diethylaniline was added to 1.25 g (3.4 mmol) of 3-[4-chloro-2-(1-methyl-2-propynyloxy)phenyl]-1-methyl-6-trifluoromethyluracil and 1.0 g (6.8 mmol) of cesium fluoride, followed by stirring at 180 to 190° C. for 30 minutes. After completion of the reaction, the reaction mixture was purified directly by silica gel column chromatography to obtain 0.60 g (yield: 50.7%) of the desired product as white crystals. Melting point: 159-160° C.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][C:8]2=[O:13])([O-:3])=[O:2].[BH4-].[Na+].[Cl-].[NH4+]>C(O)C>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][CH:8]2[OH:13])([O-:3])=[O:2]
Reactant: O=C1CCc2c1cccc2[N+](=O)[O-]
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: O=[N+]([O-])c1cccc2c1CCC2O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-nitroindan-1-one (0.381 g, 2.15 mmol) in ethanol (5 ml) was added sodium borohydride (0.048 g, 1.29 mmol) at 0° C., and the mixture was stirred at room temperature for 3 hours. Aqueous solution of ammonium chloride was added to the mixture, and extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to obtain 4-nitroindan-1-ol. 1H NMR (CDCl3) δ 1.90 (d, J=6.5 Hz, 1H), 2.00-2.07 (m, 1H), 2.56-2.63 (m, 1H), 3.25-3.33 (m, 1H), 3.54-3.60 (m, 1H), 5.30-5.35 (m, 1H), 7.44 (t, J=8.2 Hz, 1H), 7.72 (d, J=7.6 Hz, 1H), 8.12 (d, J=8.2 Hz, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][NH:5][S:6]([C:9]1[C:14]([Cl:15])=[CH:13][CH:12]=[C:11]([N+:16]([O-:18])=[O:17])[C:10]=1Cl)(=[O:8])=[O:7].[H-].[Na+].[OH2:23]>>[CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][NH:5][S:6]([C:9]1[C:14]([Cl:15])=[CH:13][CH:12]=[C:11]([N+:16]([O-:18])=[O:17])[C:10]=1[OH:23])(=[O:8])=[O:7]
Reactant: O
Reactant: CN(C)CCNS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Agent: [H-]
Agent: [Na+]
Product: CN(C)CCNS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1O

Procedure:
Following the general hydrolysis procedure outlined in example 15, crude N-[2-(dimethylamino)ethyl]-2,6-dichloro-3-nitrobenzenesulfonamide (480 mg), 60% NaH (168 mg, 4.2 mmol) and water (25 μL, 1.4 mmol) were reacted. The crude product (80 mg) was carried on to the next step without purification. EI-MS (m/z) 321.98, 323.96 (M−).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11]([N:18]3[CH2:22][CH:21]([OH:23])[CH:20]([NH2:24])[CH2:19]3)=[C:12]([F:17])[CH:13]=2)[N:8](CCC#N)[CH:7]=1)=[O:5])C.[OH-].[Na+].Cl>C(O)C>[NH2:24][C@H:20]1[C@@H:21]([OH:23])[CH2:22][N:18]([C:11]2[N:10]=[C:9]3[C:14]([C:15](=[O:16])[C:6]([C:4]([OH:5])=[O:3])=[CH:7][NH:8]3)=[CH:13][C:12]=2[F:17])[CH2:19]1
Reactant: CCOC(=O)c1cn(CCC#N)c2nc(N3CC(N)C(O)C3)c(F)cc2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N[C@@H]1CN(c2nc3[nH]cc(C(=O)O)c(=O)c3cc2F)C[C@@H]1O
Temperature: 50 °C
Reaction time: 18 h

Procedure:
A solution of EXAMPLE 228A (0.1 g) in ethanol (1 mL) at 25° C. was treated with 1N NaOH (1 mL), stirred for 18 hours at 50° C., cooled to 25° C., neutralized using 10% HCl, and filtered. NMR (300 MHz, DMSO-d6) δ ppm 3.7-4.5 (m, 6H), 8.0 (d, 1H), 8.42 (bs, 1H), 8.49 (d, 2H), 13.41 (m, 1H).