Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:24][CH3:25])=[C:4]([CH:8]([CH2:22][CH3:23])[CH2:9][C:10]2([C:18]([F:21])([F:20])[F:19])[O:14]C=N[CH:11]2[O:15]CC)[CH:5]=[CH:6][CH:7]=1.Cl>C1COCC1>[Cl:1][C:2]1[C:3]([O:24][CH3:25])=[C:4]([CH:8]([CH2:22][CH3:23])[CH2:9][C:10]([OH:14])([C:18]([F:21])([F:20])[F:19])[CH:11]=[O:15])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC1N=COC1(CC(CC)c1cccc(Cl)c1OC)C(F)(F)F
Agent: Cl
Solvent: C1CCOC1
Product: CCC(CC(O)(C=O)C(F)(F)F)c1cccc(Cl)c1OC
Temperature: 55 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
A solution of 5-[2-(3-chloro-2-methoxyphenyl)butyl]-4-ethoxy-5-(trifluoromethyl)-4,5-dihydro-1,3-oxazole in THF (30 ml) is admixed with 2N HCl (10 ml). The mixture is stirred at 50-60° C. overnight. Following dilution with water (150 ml) and extraction with diethyl ether, the combined organic extracts are washed with water and brine and then dried and the solvent is removed on a rotary evaporator. Flash chromatography on silica gel (eluent toluene) gives 2.7 g (50%) of the desired compound as a racemic mixture of the two diastereomers. The 1H-NMR spectrum below describes the signals for the mixture:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:26])[CH2:9][CH2:10][CH2:11][C:12]([N:14]2[C@@H:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:17][O:16][C:15]2=O)=[O:13])=[CH:4][CH:3]=1.FC1C=CC([C@@H](O)CCCC(N2[C@@H](C3C=CC=CC=3)COC2=O)=[O:39])=CC=1.[O-]S([O-])(=O)=O.[Mg+2]>C(O)(C)C>[O:39]=[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:19]1[C@H:18]1[CH2:17][O:16][CH2:15][N:14]1[C:12](=[O:13])[CH2:11][CH2:10][CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[O:26]
Reactant: O=C(CCC[C@H](O)c1ccc(F)cc1)N1C(=O)OC[C@@H]1c1ccccc1
Reactant: O=C(CCCC(=O)N1C(=O)OC[C@@H]1c1ccccc1)c1ccc(F)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC(C)O
Product: O=C(CCCC(=O)N1COC[C@@H]1C1C=CC=CC1=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Improved ADH-LK variants for the reduction of (S)-1-(4-Fluoro-phenyl)-5-(2-oxo-4-phenyl-oxazolidin-3-yl)-pentane-1,5-dione to (4S)-3-[(5S)-5-(4-Fluoro-phenyl)-5-hydroxy-pentanoyl]-4-phenyl-oxazolidin-2-one were analyzed in small scale chemical reactions. In a glass vial with a teflon stirring bar, 500 mg (S)-1-(4-Fluoro-phenyl)-5-(2-oxo-4-phenyl-oxazolidin-3-yl)-pentane-1,5-dione, 100 mg KRED variant, 0.5 mg Na-NADP (Oriental Yeast), 2.5 ml isopropyl alcohol, and 2.5 ml 100 mM triethanolamine(chloride) buffer, pH 7.0, 2 mM MgSO4 was mixed and stirred overnight at 25° C. Reaction samples were analyzed by the method of Example 4.
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.[NH2:12]N>C(O)C>[NH2:12][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]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: NN
Solvent: CCO
Product: NN1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Yield: 75.2 %

Procedure:
To an ice-cold suspension of 14.7 g (0.1 mole) of phthalimide in 100 ml of 95% ethyl alcohol at 5° C., with stirring, 3.6 ml (0.11 mole) of 96.8% hydrazine was added dropwise. A slight exothermic reaction was observed and the mixture was allowed to stir at 5° C. for two hours. The mixture was diluted with 200 ml of ice water, stirred, filtered, washed with water and dried to give 12.2 g (75%) of white powder, m.p. 199°-202°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:29]([OH:32])[C:30]#[CH:31].C(N(C(C)C)CC)(C)C>[Cl-].[Na+].O.[Cu]I.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd].O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:31]#[C:30][CH2:29][OH:32]
Reactant: Fc1ccc(I)c(F)c1
Reactant: C#CCO
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: O
Product: OCC#Cc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of 2,4-difluoroiodobenzene (5.00 g), copper(I) iodide (79.4 mg), triphenylphosphine (273 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (432 mg), propargyl alcohol (1.35 ml), diisopropylethylamine (14.5 ml) and tetrahydrofuran (80 ml) was stirred at room temperature for 15 hr. The reaction mixture was added to brine, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=99:1-80:20) to give the object product (1.03 g) as a brown oil.
Reaction SMILES: O[C:2]([CH3:9])(C)[C:3]([O:5][CH2:6][CH3:7])=O.CS(C1C=C[C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][N:15]=1)(=O)=O.[H-].[Na+]>CN(C=O)C>[CH2:6]([O:5][C:3]1[CH:2]=[CH:9][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][N:15]=1)[CH3:7]
Reactant: CS(=O)(=O)c1ccc(S(C)(=O)=O)nc1
Reactant: CCOC(=O)C(C)(C)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1ccc(S(C)(=O)=O)cn1
Temperature: 80 °C

Procedure:
A mixture of ethyl 2-hydroxyisobutyrate (0.41 mL, 3.0 mmol), 2,5-bis(methyl sulfonyl) pyridine (J. Heterocycl. Chem. 1985, 22, 1583) (0.70 g, 3.0 mmol) and sodium hydride (60% dispersion in mineral oil, 0.14 g, 3.6 mmol) in 30 mL of anhydrous DMF was heated at 80° C. overnight. The reaction mixture was cooled to room temperature, and was partitioned between saturated aqueous ammonium chloride (200 mL) and ether (200 mL). The organic layer was separated and was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness, and the residue was purified by flash column chromatography on silica gel eluting with 0 to 80% ethyl acetate in hexane to give the title compound as a 1:1 mixture with 2-ethoxy-5-methylsulfonylpyridine. LC-MS: m/e 288 (M+H)+ (0.70 min).
Reaction SMILES: Br[C:2]1[C:14](=[O:15])[N:13]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:5]2[N:6]=[C:7]([NH:11][CH3:12])[N:8]=[C:9]([CH3:10])[C:4]=2[CH:3]=1.[N:21]1[CH:26]=[C:25](B(O)O)[CH:24]=[N:23][CH:22]=1>>[CH:16]1([N:13]2[C:5]3[N:6]=[C:7]([NH:11][CH3:12])[N:8]=[C:9]([CH3:10])[C:4]=3[CH:3]=[C:2]([C:25]3[CH:26]=[N:21][CH:22]=[N:23][CH:24]=3)[C:14]2=[O:15])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: OB(O)c1cncnc1
Reactant: CNc1nc(C)c2cc(Br)c(=O)n(C3CCCC3)c2n1
Product: CNc1nc(C)c2cc(-c3cncnc3)c(=O)n(C3CCCC3)c2n1
Yield: 10 %

Procedure:
Following the procedure described in Preparation of Example 14, using 6-bromo-8-cyclopentyl-4-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one in place of 6-bromo-8-cyclopentyl-2-(2-hydroxy-2-methylpropylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one, pyrimidin-5-ylboronic acid in place of 3-hydroxyphenylboronic acid, the title compound was obtained in 10% yield.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:18])[N:5]=[C:4]2[S:19][C:20]3[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=3[C:3]=12.C(=O)([O-])[O-].[K+].[K+].[CH3:32][N:33]1[CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=[N:34]1.C(OCC)(=O)C>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>[CH3:18][C:6]1[N:5]=[C:4]2[S:19][C:20]3[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=3[C:3]2=[C:2]([C:36]2[CH:35]=[N:34][N:33]([CH3:32])[CH:37]=2)[C:7]=1[CH:8]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:9]([O:11][CH3:12])=[O:10]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2sc3c(c2c1Cl)CCCC3
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: [K+]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)C(OC(C)(C)C)c1c(C)nc2sc3c(c2c1-c1cnn(C)c1)CCCC3
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 58 %

Procedure:
To a solution of methyl 2-[4-chloro-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyacetate (0.100 g; 0.262 mmol) in a mixture of DME-water (3:1) (1 mL) were added potassium carbonate (0.109 g; 0.786 mmol), tetrakis(triphenylphosphine)palladium(0) (0.015 g; 0.013 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.109 g; 0.524 mmol). The solution was stirred for 30 min at 140° C. under microwave irradiation. Ethyl acetate was added to the reaction mixture and the solution was washed with brine. The organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethylacetate (5-80%) in heptane furnished 0.065 g (58%) of the title compound as a light yellow oil.
Reaction SMILES: [CH2:1]([CH:8]1[NH:14][CH2:13][CH2:12][S:11][C:10]2[C:15](=[O:20])[N:16]([CH3:19])[N:17]=[CH:18][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I([O-])(=O)(=O)=[O:22].[Na+]>C(O)(=O)C.O>[CH2:1]([CH:8]1[NH:14][CH2:13][CH2:12][S:11](=[O:22])[C:10]2[C:15](=[O:20])[N:16]([CH3:19])[N:17]=[CH:18][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1ncc2c(c1=O)SCCNC2Cc1ccccc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cn1ncc2c(c1=O)S(=O)CCNC2Cc1ccccc1
Temperature: 0 °C
Yield: 63.2 %

Procedure:
To a solution of 0.84 g (2.92 mmol) of 5-benzyl-8-methyl-2,3,4,5-tetrahydro-9(8H)-pyridazino[4,5-b][1,5]thiazepinone in 7.5 ml of glacial acetic acid the solution of 0.75 g (3.6 mmol) of sodium metaperiodate in 6 ml of water are added dropwise while stirring and cooling with ice-water. The reaction mixture is stirred for 3 hours while cooling with ice-water. The obtained suspension is filtered and washed with a small amount of water. The aqueous phase is extracted with 3×20 ml of dichloromethane. The organic phase is washed with 2×5 ml of 10% aqueous sodium carbonate solution and then with 2×10 ml of water. The organic phase is dried and evaporated in vacuum. The residue is crystallized from a 9:1 mixture of ethyl acetate and methanol. In this way 0.56 g (63%) of the title compound is obtained with a melting point of 162-163° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][C:14]([CH3:16])=[CH2:15])[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4].[ClH:17].O>C(Cl)(Cl)(Cl)Cl.[Cl-].C([N+](CCCCCCCC)(CCCCCCCC)C)CCCCCCC>[CH2:1]([O:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][C:14]([Cl:17])([CH3:16])[CH3:15])[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4]
Reactant: Cl
Reactant: C=C(C)COc1cc(OCC#CC)ncn1
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CC#CCOc1cc(OCC(C)(C)Cl)ncn1
Temperature: 0 °C
Reaction time: 0.83 h

Procedure:
In 1.2 ml of carbon tetrachloride were dissolved 0.15 g of 4-(2-butynyloxy)-6-(2-methylallyloxy)pyrimidine and 0.01 g of trioctylmethylammonium chloride, to which 1 ml of concentrated hydrochloric acid was added dropwise at 0° C., followed by stirring at 0° C. for 30 minutes and at room temperature for 50 minutes. The reaction mixture was then poured into water, which was extracted three times with t-butyl methyl ether. The combined organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution, a saturated aqueous sodium chloride solution, dried over anhydrous magnesium, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.08 g of 4-(2-butynyloxy)-6-(2-chloro-2-methylpropyloxy)pyrimidine (the present compound (20)).
Reaction SMILES: CC1(C)C2C=CC(C#CC3C=CC(C(O)=O)=CC=3)=CC=2C(C#CCCC)=CC1.[CH3:29][C:30]1([CH3:58])[C:39]2[CH:38]=[CH:37][C:36]([C:40]#[C:41][C:42]3[CH:52]=[CH:51][C:45]([C:46]([O:48]CC)=[O:47])=[CH:44][CH:43]=3)=[CH:35][C:34]=2[C:33]([C:53]2[S:54][CH:55]=[CH:56][CH:57]=2)=[CH:32][CH2:31]1>>[CH3:29][C:30]1([CH3:58])[C:39]2[CH:38]=[CH:37][C:36]([C:40]#[C:41][C:42]3[CH:43]=[CH:44][C:45]([C:46]([OH:48])=[O:47])=[CH:51][CH:52]=3)=[CH:35][C:34]=2[C:33]([C:53]2[S:54][CH:55]=[CH:56][CH:57]=2)=[CH:32][CH2:31]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2cccs2)=CCC3(C)C)cc1
Agent: CCCC#CC1=CCC(C)(C)c2ccc(C#Cc3ccc(C(=O)O)cc3)cc21
Product: CC1(C)CC=C(c2cccs2)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21

Procedure:
Employing the same general procedure as for the preparation of 4-[(7,8-dihydro-8,8-dimethyl-5-(1-pentynyl)naphth-2-yl)ethynyl]benzoic acid (Compound 84), 70.0 mg (0.17 mmol) of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(2-thienyl)naphth-3-yl)ethynyl]benzoate (Compound 123) was converted into the title compound (colorless solid) using 17.8 mg (0.42 mmol) of LiOH in H2O.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)=[N:4][N:3]=1.[F:21][C:22]1[C:30]([OH:31])=[CH:29][CH:28]=[C:27]2[C:23]=1[CH:24]=[C:25]([CH3:32])[NH:26]2.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:21][C:22]1[C:30]([O:31][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH2:12][C:13]3[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)=[N:4][N:3]=2)=[CH:29][CH:28]=[C:27]2[C:23]=1[CH:24]=[C:25]([CH3:32])[NH:26]2
Reactant: COc1ccc(Cc2nnc(Cl)c3ccccc23)cn1
Reactant: Cc1cc2c(F)c(O)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(Cc2nnc(Oc3ccc4[nH]c(C)cc4c3F)c3ccccc23)cn1

Procedure:
Heating of a mixture of 1-chloro-4-[6-methoxy-(pyridin-3-yl)-methyl]phthalazine (Ex. 3e), 4-fluoro-5-hydroxy-2-methyl-1H-indole (preparation see WO 00/47212; Ex. 237) and K2CO3 in DMF yields the title compound.
Reaction SMILES: [CH2:1]=[O:2].C(N(CC)CC)C.[CH2:10]1[CH2:37][O:36][C:12]2([CH2:29][CH2:28][C@@:27]3([CH3:30])[C:14](=[CH:15][CH2:16][C@@H:17]4[C@:26]3([OH:31])[CH2:25][CH2:24][C@@:22]3([CH3:23])[C@H:18]4[CH2:19][CH2:20][C:21]3=[CH:32][N+:33]([O-:35])=[O:34])[CH2:13]2)[O:11]1.O>CC(O)C.C(O)(=O)C>[CH2:37]1[CH2:10][O:11][C:12]2([CH2:29][CH2:28][C@@:27]3([CH3:30])[C:14](=[CH:15][CH2:16][C@@H:17]4[C@:26]3([OH:31])[CH2:25][CH2:24][C@@:22]3([CH3:23])[C@H:18]4[CH2:19][CH:20]=[C:21]3[CH:32]([N+:33]([O-:35])=[O:34])[CH2:1][OH:2])[CH2:13]2)[O:36]1
Reactant: C=O
Reactant: C[C@]12CCC3(CC1=CC[C@H]1[C@@H]4CCC(=C[N+](=O)[O-])[C@@]4(C)CC[C@@]12O)OCCO3
Solvent: O
Solvent: CC(C)O
Solvent: CC(=O)O
Product: C[C@]12CCC3(CC1=CC[C@H]1[C@@H]4CC=C(C(CO)[N+](=O)[O-])[C@@]4(C)CC[C@@]12O)OCCO3
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
Under a nitrogen atmosphere formaline (2 ml, 40% solution in water) and triethylamine (1 ml) were added to a stirred suspension of 3,3-ethylenedioxy-17-(nitromethylene)androst-5-en-9α-ol (0.50 g) in 2-propanol (10 ml). After stirring for one hour at room temperature the reaction was found to be complete as evidenced by TLC. The reaction mixture was poured into a mixture of water (200 ml) and acetic acid (3 ml) and stirred for 30 minutes. The resulting precipitate was filtered, washed with water and dried to afford 0.46 g of the title compound (85%). According to NMR the product was a 4:1 mixture of the two C20 diastereomers which were separated by chromotagraphy (silica gel; toluene/acetone 3/1) and analysed.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:10]2[CH:11]=[C:12]([CH3:16])[CH:13]=[CH:14][CH:15]=2)=[C:5]([C:7]([OH:9])=O)[N:6]=1.[NH:17]1[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:23][C:24]([C:26]2[N:33]3[C:29]([S:30][CH:31]=[CH:32]3)=[N:28][C:27]=2[CH3:34])=[O:25])[CH2:18]1>>[CH3:1][C:2]1[S:3][C:4]([C:10]2[CH:11]=[C:12]([CH3:16])[CH:13]=[CH:14][CH:15]=2)=[C:5]([C:7]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:23][C:24]([C:26]3[N:33]4[C:29]([S:30][CH:31]=[CH:32]4)=[N:28][C:27]=3[CH3:34])=[O:25])[CH2:18]2)=[O:9])[N:6]=1
Reactant: Cc1nc2sccn2c1C(=O)N[C@@H]1CCCNC1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)O)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2CCC[C@@H](NC(=O)c3c(C)nc4sccn34)C2)c1

Procedure:
prepared by reaction of 2-methyl-5-m-tolyl-thiazole-4-carboxylic acid with (R)-6-methyl-imidazo[2,1-b]-thiazole-5-carboxylic acid-piperidin-3-ylamide.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].[H-].[Na+].[C:17]1([S:23](Cl)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.ClCCl>CN(C=O)C.O>[C:17]1([S:23]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[C:2]2[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2ccccc2n1S(=O)(=O)c1ccccc1

Procedure:
To a stirred and cooled (to about 0° C.) solution of ethyl indole-2-carboxylate 10 (1 eq.) in DMF (2 ml/mmol) under N2, was added NaH (60% in oil, 1.2 eq.) portionwise. When gas evolution stopped, benzenesulfonyl chloride (1.2 eq.) was added. The reaction mixture was stirred for about 1 hour (TLC monitoring, eluent dichloromethane); a small amount of water then was added carefully and the DMF was evaporated. The crude residue was dissolved in ethyl acetate and washed with water and brine. After drying and evaporation of the solvents, the compound was purified by chromatography on silica gel (eluent: C6H12/EtOAc 9/1 to 7/3) to give the ethyl 1-phenylsulfonylindole-2-carboxylate.
Reaction SMILES: [F:1][C:2]1[C:10]2[C:6](=[C:7]([CH3:12])[N:8]([CH3:11])[N:9]=2)[CH:5]=[C:4]2[NH:13][C:14](=[O:24])[N:15]([C:16]3[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:17]=3[F:23])[C:3]=12.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH:35]1([S:38](Cl)(=[O:40])=[O:39])[CH2:37][CH2:36]1>C1COCC1>[CH:35]1([S:38]([N:13]2[C:4]3=[CH:5][C:6]4[C:10]([C:2]([F:1])=[C:3]3[N:15]([C:16]3[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:17]=3[F:23])[C:14]2=[O:24])=[N:9][N:8]([CH3:11])[C:7]=4[CH3:12])(=[O:40])=[O:39])[CH2:37][CH2:36]1
Reactant: Cc1c2cc3[nH]c(=O)n(-c4ccc(I)cc4F)c3c(F)c2nn1C
Reactant: O=S(=O)(Cl)C1CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c2cc3c(c(F)c2nn1C)n(-c1ccc(I)cc1F)c(=O)n3S(=O)(=O)C1CC1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 57.3 %

Procedure:
To a solution of 8-fluoro-7-(2-fluoro-4-iodophenyl)-2,3-dimethyl-2,7-dihydro-5H-imidazo[4,5-f]indazol-6-one (34 mg, 0.077 mmol) in THF (5 ml) at −78° C. was added LiHMDS (0.12 ml, 1 M in THF, 0.12 mmol). The reaction mixture was stirred at −78° C. for 10 min and cyclopropylsulfonyl chloride (22 mg, 0.15 mmol) was added to the mixture. The reaction was slowly warmed to room temperature and stirred at the temperature for 16 h. The reaction was quenched with saturated aqueous NH4Cl solution (10 ml) and extracted with EtOAc (2×10 ml). The combined organic solution was washed with brine (20 ml), dried over MgSO4 and concentrated. Silica gel chromatography (EtOAc:Hexanes=25:75) yields 24 mg (57%) of the title compound as a yellow solid.
Reaction SMILES: C[O:2][CH:3]([O:28]C)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C:14](=[O:27])[C:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=1>CC(C)=O.O>[CH3:13][O:12][C:7]1[C:8]([O:10][CH3:11])=[CH:9][C:4]([C:3]([OH:28])=[O:2])=[C:5]([C:14](=[O:27])[C:15]2[CH:16]=[C:17]([O:25][CH3:26])[C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=2)[CH:6]=1
Reactant: COc1cc(C(=O)c2cc(OC)c(OC)c(OC)c2)c(C(OC)OC)cc1OC
Solvent: CC(C)=O
Solvent: O
Product: COc1cc(C(=O)O)c(C(=O)c2cc(OC)c(OC)c(OC)c2)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 1.1 %

Procedure:
4,5-Dimethoxy-2-(3,4,5-trimethoxybenzoyl)benzaldehyde dimethyl acetal (1.0 g) is dissolved with heating in a mixture of acetone (15 ml) and water (0.5 ml), and thereto is added an acidic ion-exchange resin (IRA-20) (50 nig). The mixture is stirred at room temperature for two hours. After the reaction is complete, the acidic resin is removed by filtration, and the filtrate is concentrated under reduced pressure. The residue is dissolved in dioxane (12 ml), and thereto are added resorcinol (456 nig) and acetate buffer (pH 3.8, 12 ml). To the mixture is added dropwise and gradually aqueous solution of sodium chlorite (374 mg), and the mixture is stirred at room temperature overnight. After the reaction is complete, the pH value of the mixture is adjusted to pH 1 with conc. hydrochloric acid, and the mixture is extracted with chloroform. The chloroform layer is washed, dried, and concentrated under reduced pressure. The precipitated crystals are collected by filtration with diethyl ether to give 4,5-dimethoxy-2-(3,4,5-trimethoxybenzoyl)benzoic acid (8 10 mg) as listed in Table 51.
Reaction SMILES: C(N(CCCC)C(=O)C[N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[C:10]([C:19](=O)[C:20]([CH3:23])([CH3:22])[CH3:21])=N1)CCC.[Li]CCCC>C1COCC1>[C:20]([C:19]1[NH:8][C:16]2[C:11]([CH:10]=1)=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)([CH3:23])([CH3:22])[CH3:21]
Reactant: CCCCN(CCCC)C(=O)Cn1nc(C(=O)C(C)(C)C)c2ccc(OC)cc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc2cc(C(C)(C)C)[nH]c2c1
Reaction time: 1 h

Procedure:
To a solution of 17.20 g N-(5-methoxy-2-methylphenyl)-2,2-dimethylpropanamide prepared in Step A above in 300 mL anhydrous THF under nitrogen in a −3° C. bath was added 62.2 mL 2.5 M n-BuLi in hexanes. After stirring for 1 hour, the cooling bath was removed. After four days, it was quenched by addition of saturated ammonium chloride solution and concentrated under reduced pressure to remove solvents. The residue was diluted with 1 N HCl and extracted with ether. The combine ether extract was washed with 5% NaHCO3, and saturated brine, dried over anhydrous Na2SO4 and evaporated to give a crude product. It was purified by SGC with 10-25% EtOAc in hexanes to give title compound as yellowish solid followed by recovered starting material. 1H NMR (CDCl3, 500 MHz) δ 7.85 (br s, 1NH), 7.42 (d, J=8.7 Hz, 1H), 6.87 (d, J=2.3 Hz, 1H), 6.77 (dd, J=2.3 & 8.4 Hz, 1H), 6.19 (d, J=2.2 Hz, 1H), 3.86 (s, 3H), 1.40 (s, 9H). LC-MS: 3.68 min. (m/Z=204.1).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH:9]([OH:33])[CH2:10][NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][CH2:21][C:22]2[CH:23]=[C:24]([CH2:28][C:29]([O:31]C)=[O:30])[CH:25]=[N:26][CH:27]=2)=[CH:4][C:3]=1[Cl:34]>CO.[OH-].[Na+]>[NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH:9]([OH:33])[CH2:10][NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][CH2:21][C:22]2[CH:23]=[C:24]([CH2:28][C:29]([OH:31])=[O:30])[CH:25]=[N:26][CH:27]=2)=[CH:4][C:3]=1[Cl:34]
Reactant: COC(=O)Cc1cncc(CCCOCCCCCCNCC(O)c2cc(Cl)c(N)c(Cl)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1c(Cl)cc(C(O)CNCCCCCCOCCCc2cncc(CC(=O)O)c2)cc1Cl
Yield: 42.8 %

Procedure:
A solution of methyl 5-[3-[[6-[[2-(4-amino-3,5-dichlorophenyl)-2-hydroxyethyl]amino]hexyl]oxy]propyl]-3-pyridineacetate (600 mg) in methanol (10 ml) and 2N sodium hydroxide (10 ml) was stirred at room temperature for 10 min. Dowex (50) H+ methanol washed resin was added portionwise until pH 7. The resin was filtered off, the solution concentrated in vacuo to give a brown solid which was triturated in ethanol/methanol (1:2) to give the title compound as a light brown solid (250 mg), m.p. 191°-192° t.l.c. (methanol) Rf 0.6.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[C:11]([F:14])([F:13])[F:12])=[CH:4][CH:3]=1.Cl.[NH:18]([C:20]1[CH:21]=[CH:22][C:23]([S:26]([NH2:29])(=[O:28])=[O:27])=[N:24][CH:25]=1)[NH2:19]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:18]([C:20]3[CH:21]=[CH:22][C:23]([S:26]([NH2:29])(=[O:28])=[O:27])=[N:24][CH:25]=3)[N:19]=[C:10]([C:11]([F:14])([F:13])[F:12])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: NNc1ccc(S(N)(=O)=O)nc1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(Br)cc1
Agent: Cl
Solvent: CCO
Product: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(Br)cc2)cn1
Yield: 87 %

Procedure:
A mixture of 1-(4-bromophenyl)-4,4,4-trifluoro-1,3-butanedione (prepared according to the method of J. Med. Chem., 1997, 40, 1347. 1.09 g, 3.71 mmol) and 5-hydrazino-2-pyridinesulfonamide hydrochloride (1.00 g, 4.45 mmol) in ethanol (50 ml) was refluxed for 18 hr. After evaporation, the obtained residue was chromatographed on a column of silica gel (200 g) eluting with ethyl acetate/hexane (1:2) to afford 1.44 g (87%) of the title compound as a white solid.