Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][C:10](=[O:16])[NH:11]2.[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C([O-])(O)=O.[Na+]>>[N:17]1([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:7]=2[CH2:8][CH2:9][C:10](=[O:16])[NH:11]3)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1
Reactant: O=C1CCc2c(cccc2OCCCCl)N1
Reactant: C1CNCCN1
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C1CCc2c(cccc2OCCCN2CCNCC2)N1

Procedure:
(a)-1 3.0 Grams of 5-(3-chloropropoxy)-3,4-dihydrocarbostyril, 10 g of piperazine are mixed with 20 ml of hexamethylphosphoryl triamide and heated at 80°-90° C. for 5 hours. The reaction mixture is distilled under a reduced pressure to remove hexamethylphosphoryl triamide and unreacted piperazine. To the residue thus obtained are added 30 ml of 5%-NaHCO3 aqueous solution, followed by extraction with chloroform. The chloroform layer is washed with water and chloroform is removed by distillation. The residue thus obtained is purified by silica-gel chromatography to obtain 1.8 g of 5-(3-piperazinylpropoxy)-3,4-dihydrocarbostyril having a melting point of 192°-195° C.
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]1[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=1[OH:15].[CH2:16]([O:18][C:19](=[O:24])[CH:20]=[C:21](Cl)[CH3:22])[CH3:17]>O1CCCC1>[CH2:16]([O:18][C:19](=[O:24])/[CH:20]=[C:21](/[O:15][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([F:14])[C:8]=1[F:7])\[CH3:22])[CH3:17]
Reactant: CCOC(=O)C=C(C)Cl
Reactant: Oc1cccc(F)c1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\C)Oc1cccc(F)c1F
Temperature: 23 °C
Yield: 66.1 %

Procedure:
Potassium t-butoxide (11.2 g, 0.100 mol) was added to a stirred solution of 2,3-difluoro-phenol (6.58 g, 0.051 mol) in tetrahydrofuran (30 mL) at 23° C. under nitrogen and the reaction mixture was heated to reflux for 0.75 h. The reaction mixture was cooled to 23° C. and a solution of 3-chloro-but-2-enoic acid ethyl ester (prepared as in Example 191 7.50 g, 0.050 mol) in tetrahydrofuran (40 mL) was added to the reaction mixture. The reaction mixture was refluxed for an additional 3 h. After this time, the mixture was concentrated in vacuo and the residue was diluted with water and extracted with diethyl ether. The organic layer was then washed with 5% aqueous sodium hydroxide solution followed by a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo to afford (E)-3-(2,3-difluoro-phenoxy)-but-2-enoic acid ethyl ester (8.01 g, 66%) as a yellow oil.
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:16])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].[C:23](Br)#[C:24][CH2:25]C>CC(C)=O>[CH2:1]([O:5][C:6](=[O:16])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:25][C:24]#[CH:23])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCC#CBr
Reactant: CCCCOC(=O)C=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C#CCOc1ccc(C=CC(=O)OCCCC)cc1
Temperature: 56 °C

Procedure:
903 g (4.1M) of p-hydroxy cinnamic acid n-butyl ester (see above) are dissolved in 4 liter acetone. 622 g (4.5M) of finely powdered potassium carbonate and 523.5 g (4.4M) freshly distilled butinyl bromide are added. Under stirring the suspension is heated to reflux (temperature in the mixture 56° C.). After refluxing for about 18 hours the starting material is consumed. The yellow suspension is cooled to about 10° C. and filtered. The filtrate is evaporated to dryness in vacuo (about 12 mbar) at 35° C. The yellow oily residue is added with stirring to about 6 liters of water. A white crystalline precipitate is obtained which is isolated by filtration. The solid material is washed with water and dried. It is crystallised from 1 liter of hexane. The product, 805.5 g, is obtained in colourless prisms, mp 38.5° to 39.0° C. From the mother liquor another 183.0 g of product could be isolated. Total yield 988.5 g (93.3% of theory).
Reaction SMILES: C[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1C=O.C(N/[C:15](/[CH3:22])=[CH:16]\[C:17]([O:19][CH2:20][CH3:21])=[O:18])CCC.C([O:26][CH2:27][C:28](=O)[CH2:29][CH2:30][C:31]([O:33][CH2:34]C)=[O:32])(=O)C.Cl>O.C(O)C>[OH:26][C:27]1[CH2:28][C:29]2[CH2:34][O:33][C:31](=[O:32])[C:30]=2[CH:15]([C:22]2[CH:8]=[CH:9][CH:2]=[CH:3][C:6]=2[CH3:7])[C:16]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)CCC(=O)COC(C)=O
Reactant: CCCCN/C(C)=C\C(=O)OCC
Reactant: Cc1ccccc1C=O
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCOC(=O)C1=C(O)CC2=C(C(=O)OC2)C1c1ccccc1C

Procedure:
50 mmol of 2-methylbenzaldehyde, 50 mmol of ethyl 3-butylaminocrotonate and 50 mmol of ethyl 4-acetoxy-3-oxobutanecarboxylate together with 100 ml of ethanol were boiled under reflux overnight, then 10 ml of concentrated HCl and 20 ml of water were added, and the mixture was boiled for a further hour. The product is recrystallized from ethanol.
Reaction SMILES: Br[C:2]1[NH:22][C:5]2=[N:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[CH:13]=3)[N:9]=[C:4]2[CH:3]=1.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32](B3OC(C)(C)C(C)(C)O3)[CH:31]=2)[CH2:26][CH2:25]1>>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([CH:17]=[C:16]([O:18][CH3:19])[CH:15]=1)[CH2:11][CH2:10][C:8]1[N:9]=[C:4]2[CH:3]=[C:2]([C:32]3[CH:33]=[CH:34][CH:35]=[C:30]([N:27]4[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]4)[CH:31]=3)[NH:22][C:5]2=[N:6][CH:7]=1
Reactant: CN1CCN(c2cccc(B3OC(C)(C)C(C)(C)O3)c2)CC1
Reactant: COc1cc(CCc2cnc3[nH]c(Br)cc3n2)cc(OC)c1
Product: COc1cc(CCc2cnc3[nH]c(-c4cccc(N5CCN(C)CC5)c4)cc3n2)cc(OC)c1

Procedure:
The compound was prepared by using procedures analogous to those described for the synthesis of Example 53, Step 2 starting from 6-bromo-2-[2-(3,5-dimethoxyphenyl)ethyl]-5H-pyrrolo[2,3-b]pyrazine and 1-methyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine. LCMS calculated for C27H32N5O3 (M+H)+: m/z=458.3. Found 458.3.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[C:7]([NH2:11])([CH3:10])([CH3:9])[CH3:8].[ClH:12].Cl[O-].[Na+]>O>[Cl:12][CH:3]([C:2]([CH3:1])=[O:6])[C:4]([NH:11][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5]
Reactant: CC(C)(C)N
Reactant: Cl
Reactant: C=C1CC(=O)O1
Agent: [Na+]
Agent: [O-]Cl
Solvent: O
Product: CC(=O)C(Cl)C(=O)NC(C)(C)C
Temperature: 0 °C
Yield: 81.8 %

Procedure:
Diketene (42 g, 0.5 mol) was mixed with ca. 200 ml of ice and water in a 2 l., 3-neck flask. A solution of t-butylamine (37.5 g, 0.5 mol) in water (150 ml) was added gradually with stirring and more ice was added as needed to keep the reaction at or below 20°. The solution was stirred for 20 minutes after completing the addition, acidified with concentrated HCl (400 ml), and cooled to 10° with an ice/acetone bath. Aqueous sodium hypochlorite ("Chlorox", 750 ml, 0.5 mol) was then added dropwise with rapid mechanical stirring. The product was filtered out, washed with water and air-dried for several hours to give 78.5 g (81.8%) of colorless solid.
Reaction SMILES: COC([C:5]1[CH2:11][CH2:10][N:9]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[C:8]2[CH:22]=[CH:23][CH:24]=[CH:25][C:7]=2[C:6]=1[OH:26])=O.C(OC(C1CCN(S(C2C=CC(C)=CC=2)(=O)=O)C2C=CC=CC=2C=1O)=O)C.C(O)(=O)C.Cl>C(O)C.O>[C:18]1([CH3:21])[CH:17]=[CH:16][C:15]([S:12]([N:9]2[CH2:10][CH2:11][CH2:5][C:6](=[O:26])[C:7]3[CH:25]=[CH:24][CH:23]=[CH:22][C:8]2=3)(=[O:14])=[O:13])=[CH:20][CH:19]=1
Reactant: COC(=O)C1=C(O)c2ccccc2N(S(=O)(=O)c2ccc(C)cc2)CC1
Agent: CCOC(=O)C1=C(O)c2ccccc2N(S(=O)(=O)c2ccc(C)cc2)CC1
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(S(=O)(=O)N2CCCC(=O)c3ccccc32)cc1
Temperature: 25 °C
Yield: 60 %

Procedure:
A mixture of 5-hydroxy-1-(toluene-4-sulfonyl)-2,3-dihydro-1H-benzo[b]azepine-4-carboxylic acid methyl ester and 5-hydroxy-1-(toluene-4-sulfonyl)-2,3-dihydro-1H-benzo[b]azepine-4-carboxylic acid ethyl ester from Example E5.3 were heated at reflux in a mixture of ethanol (100 ml), acetic acid (300 ml), concentrated HCl (100 ml) and water (50 ml) for 18 h. The mixture was cooled to room temperature, diluted with water (800 ml) and extracted with chloroform. The combined organic ex-tracts were dried, filtered and reduced in vacuo. The residue was crystallised twice from methanol to yield the title compound (44 g, 60% over two steps).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21](O)=[O:22])[CH:19]=3)[CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:55]([O:57][C:58](=[O:66])[CH2:59][C:60]1[N:61]=[C:62]([NH2:65])[S:63][CH:64]=1)[CH3:56]>CN(C)C=O.CN(C)C1C=CN=CC=1>[CH2:55]([O:57][C:58](=[O:66])[CH2:59][C:60]1[N:61]=[C:62]([NH:65][C:21]([C:18]2[CH:19]=[C:20]3[C:15]([CH2:14][CH2:13][N:12]3[S:9]([C:4]3[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[CH:3]=3)(=[O:11])=[O:10])=[CH:16][CH:17]=2)=[O:22])[S:63][CH:64]=1)[CH3:56]
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: Cc1cc(C)cc(S(=O)(=O)N2CCc3ccc(C(=O)O)cc32)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1csc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(C)cc(C)c2)CC3)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 1-(3,5-dimethyl-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carboxylic acid (0.20 g, 0.60 mmol) in dimethylformamide (1.00 mL) under argon was treated with N-methyl morpholine (0.31 g, 0.33 mL, 3.01 mmol), HATU (0.34 g, 0.90 mmol) and (2-amino-thiazol-4-yl)-acetic acid ethyl ester (0.17 g, 0.91 mmol). The mixture was stirred at room temperature for 30 min, then treated with 4-dimethylaminopyridine (0.07 g, 0.60 mmol). The mixture was warmed to 60° C. and stirred for 50 hours. After cooling to room temperature the mixture was partitioned between water and ethyl acetate. The organic phase was washed with brine, dried over magnesium sulphate and evaporated. The residue was purified via flash chromatography (heptane/ethyl acetate gradient) to yield (2-{[1-(3,5-dimethyl-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-thiazol-4-yl)-acetic acid ethyl ester as an off-white solid, 0.10 g (35%), MS (ISP): m/e=500.4 (M+H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[CH2:18][C@H:17]([C:19]2([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH2:20]2)[C@H:16]([C:30](OCC)=[O:31])[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>O1CCCC1>[CH2:7]([N:14]1[CH2:18][C@H:17]([C:19]2([NH:22][C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[CH2:20][CH2:21]2)[C@H:16]([CH2:30][OH:31])[CH2:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)[C@@H]1CN(Cc2ccccc2)C[C@@H]1C1(NC(=O)OC(C)(C)C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1([C@H]2CN(Cc3ccccc3)C[C@H]2CO)CC1
Temperature: -15 °C
Reaction time: 0.25 h
Yield: 93.4 %

Procedure:
Under a nitrogen gas stream, lithium aluminum hydride (195.6 mg, 5.135 mmol) was suspended in dry tetrahydrofuran (40 ml). Under stirring at -15° C., a solution of ethyl cis-1-benzyl-4-(1-tert-butoxycarbonylaminocyclopropyl)-pyrrolidine-3-carboxylate (1.001 g, 2.577 mmol) in dry tetrahydrofuran (10 ml) was added dropwise thereinto over a period of 15 minutes. After stirring the reaction suspension under ice cooling for 3.5 hours, cooling water (5 ml) was slowly added thereto and the mixture was stirred at room temperature for an additional 15 minutes. The reaction suspension was filtered through celite (washed with diethyl ether). The filtrate was concentrated under reduced pressure and dried to obtain 833.9 mg (93.4%) of the title compound as a colorless oily substance.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:26]=[CH:25][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=3)[C:18]([O:20][CH3:21])=[O:19])[O:12][C:13]=2[CH3:14])=[C:5]([O:27][CH3:28])[CH:4]=1.O[C:30]1[C:34]([CH:35]=[O:36])=[CH:33][N:32]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:31]=1.CN(C)C=[O:46].[H-].[Na+]>O>[CH:35]([C:34]1[CH2:30][N:31]([O:46][CH2:2][C:3]2[CH:26]=[CH:25][C:6]([O:7][CH2:8][C:9]3[N:10]=[C:11]([C:15]4[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=4)[C:18]([O:20][CH3:21])=[O:19])[O:12][C:13]=3[CH3:14])=[C:5]([O:27][CH3:28])[CH:4]=2)[N:32]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:33]=1)=[O:36]
Reactant: O=Cc1cn(-c2ccccc2)nc1O
Reactant: COC(=O)c1cccc(-c2nc(COc3ccc(CCl)cc3OC)c(C)o2)c1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COC(=O)c1cccc(-c2nc(COc3ccc(CON4CC(C=O)=CN4c4ccccc4)cc3OC)c(C)o2)c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
To a mixture of methyl 3-{4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}benzoate (1.00 g), 3-hydroxy-1-phenyl-1H-pyrazole-4-carbaldehyde (0.45 g), and N,N-dimethylformamide (30 mL) was added sodium hydride (60% in oil, 0.10 g) at room temperature, and the mixture was stirred at 90° C. for 1 hr. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give methyl 3-{4-[(4-{[(4-formyl-1-phenyl-1H-pyrazol-2-yl)oxy]methyl}-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}benzoate as colorless crystals (1.03 g, yield 77%) from a fraction eluted with ethyl acetate-hexane (1:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 164-165° C.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[C:11]([F:30])=[C:12]([C:16]2[CH:17]=[N:18][C:19]([O:22][CH2:23][CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[N:20][CH:21]=2)[CH:13]=[CH:14][CH:15]=1)(C(C)(C)C)(C)C.[CH2:31]1[CH2:35][O:34]CC1.[CH2:36]([N:38]=C=O)[CH3:37].CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>CCOC(C)=O.O>[CH2:36]([NH:38][C:35]([CH2:31][N:27]1[CH2:26][CH2:25][CH:24]([CH2:23][O:22][C:19]2[N:18]=[CH:17][C:16]([C:12]3[CH:13]=[CH:14][CH:15]=[C:10]([CH2:9][OH:8])[C:11]=3[F:30])=[CH:21][N:20]=2)[CH2:29][CH2:28]1)=[O:34])[CH3:37]
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(-c2cnc(OCC3CCNCC3)nc2)c1F
Reactant: CCN=C=O
Reactant: C1CCOC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: CCOC(C)=O
Product: CCNC(=O)CN1CCC(COc2ncc(-c3cccc(CO)c3F)cn2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]-2-(piperidin-4-ylmethoxy)pyrimidine (200 mg) was mixed with THF (4 ml), and ethylisocyanate (91 mg) was added thereto, followed by stirring at room temperature overnight. A 1M TBAF/THF solution (1 ml) was added to the reaction mixture, followed by further stirring at room temperature for 3 hours. Water and EtOAc were added to the reaction mixture, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (MeOH/CHCl3) to obtain N-ethyl-4-[({5-[2-fluoro-3-(hydroxymethyl)phenyl]pyrimidin-2-yl}oxy)methyl]piperidine-1-carboxyamide (159.3 mg).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[CH2:13][CH2:12]3)O1.Br[C:21]1[N:26]=[C:25]([CH3:27])[CH:24]=[CH:23][N:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[CH3:27][C:25]1[CH:24]=[CH:23][N:22]=[C:21]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[CH2:13][CH2:12]3)[N:26]=1
Reactant: Cc1ccnc(Br)n1
Reactant: CC1(C)OB(c2ccc3c(c2)CCC3=O)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccnc(-c2ccc3c(c2)CCC3=O)n1

Procedure:
To a 25 mL flask containing 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indan-1-one (SM-1a, 50.0 mg, 0.19 mmol) was added 2-bromo-4-methyl pyrimidine (33.6 mg, 0.16 mmol) and sodium carbonate (23 mg, 0.76 mmol). The mixture was dissolved in 2 mL DME and 0.5 mL water. The mixture was purged with nitrogen for 15 minutes. Pd(dppf)Cl2 (2.9 mg, 5 mol %) was added and the solution was degassed for an additional 15 minutes. The reaction was heated under reflux for 16 hours. The reaction was concentrated to dryness and was partitioned between ethyl acetate and water. The water layer was extracted with ethyl acetate and the combined organic layers were washed twice with water and once with brine. The solution was dried over anhydrous sodium sulfate, filtered and concentrated. The final product was purified by silica chromatography on a Combiflash ISCO purification system (Teledyne Corp., Lincoln, Nebr.) eluting with 0-50% ethyl acetate in heptanes. The product was obtained as a white solid (SM-1e, 8.7 mg, 20%). MS (ES+) 225.2 (M+H+). 1H NMR (CDCl3) δ 2.61 (s, 3H), 2.74-2.78 (m, 2H), 3.20 (t, 2H), 7.15 (d, 1H), 7.85 (d, 1H), 8.53 (d, 1H), 8.59 (s, 1H), 8.75 (d, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[C:16]([F:22])[C:17](Cl)=[CH:18][CH:19]=3)[N:14]([C:23]#[N:24])[C:13]=2[CH3:25])[CH:6]=1)[CH3:2].[ClH:27].[NH2:28][OH:29].C(=O)([O-])[O-].[K+].[K+]>CCO>[CH2:1]([O:3][C:4](=[O:26])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[C:16]([F:22])[C:17]([Cl:27])=[CH:18][CH:19]=3)[N:14]([C:23](=[NH:24])[NH:28][OH:29])[C:13]=2[CH3:25])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cccc(Sc2c(C)n(C#N)c3c(F)c(Cl)ccc23)c1
Reactant: NO
Reactant: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)c1cccc(Sc2c(C)n(C(=N)NO)c3c(F)c(Cl)ccc23)c1

Procedure:
3-(6-Chloro-1-cyano-7-fluoro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid ethyl ester (0.45 g, 1.15 mmol), hydroxylamine hydrochloride (0.40 g, 5.79 mmol), and potassium carbonate (0.80 g, 5.79 mmol) were combined in absolute EtOH (4 mL) and stirred at reflux for overnight. The heterogeneous mixture was then filtered, and the solids were washed with hot absolute EtOH (2×10 mL). The resulting filtrate was concentrated to dryness under reduced pressure to afford the title compound.
Reaction SMILES: [CH2:1]([C:7]1([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:19]2[CH:18]=[C:17](Br)[CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Br:27][C:28]1[C:29](=O)[C:30]2[C:38](=[CH:39][CH:40]=1)[C:37]1[C:32](=[CH:33][C:34]([Br:41])=[CH:35][CH:36]=1)[CH:31]=2.[OH2:43]>C1COCC1>[CH2:21]([C:7]1([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:19]2[CH:18]=[C:17]([C:31]3([OH:43])[C:30]4[CH:29]=[C:28]([Br:27])[CH:40]=[CH:39][C:38]=4[C:37]4[C:32]3=[CH:33][C:34]([Br:41])=[CH:35][CH:36]=4)[CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: O=C1C(Br)=CC=C2C1=Cc1cc(Br)ccc12
Reactant: CCCCCCC1(CCCCCC)c2ccccc2-c2ccc(Br)cc21
Reactant: O
Solvent: C1CCOC1
Product: CCCCCCC1(CCCCCC)c2ccccc2-c2ccc(C3(O)c4cc(Br)ccc4-c4ccc(Br)cc43)cc21
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To 5.64 g of Mg placed into a 1000 ml three-neck flask, 80 g of 9,9-dihexyl-2-bromofluorene in 300 ml THF was slowly added dropwise, to prepare a Grignard reagent. After a temperature of a reaction chamber was decreased to −40° C. or less, 52 g of 2,7-dibromofluorenone was added to the reaction bath in a nitrogen atmosphere. The temperature was gradually increased to room temperature, followed by stirring for 10 hours. The resulting reaction solution was poured into water, after which an extraction was performed using diethyl ether. The solvent was evaporated using a rotary evaporator. A column chromatography separation resulted in 60 g (58%) of (9-(9,9-dihexylfluoren-2-yl)-2,7-dibromofluoren-9-ol) (1).
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[C:9]([OH:11])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[Sn](Cl)(Cl)(Cl)Cl.[CH2:28]([C:35]1[O:36][C:37]([CH3:41])=[C:38]([CH3:40])[CH:39]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C)C=O.C(Cl)Cl>[CH2:28]([C:35]1[O:36][C:37]([CH3:41])=[C:38]([CH3:40])[C:39]=1[C:9]([C:8]1[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH:7]=1)=[O:11])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: Cc1cc(Cc2ccccc2)oc1C
Reactant: COc1ccc(C(=O)O)cc1C1CCCC1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)c2c(Cc3ccccc3)oc(C)c2C)cc1C1CCCC1

Procedure:
The title compound was prepared according to the procedure in Example 5, step 2 using 3-cyclopentyl-p-anisic acid (10.0 g, 45.5 mmol, RN-59216-82-9), oxalyl chloride (4.4 mL, 50.6 mmol), N,N-dimethylformamide (2 drops), tin (IV) chloride (15.8 mL, 49.6 mmol) and 2-benzyl-4,5-dimethyl-furan (10.1 g, 54.3 mmol) in CH2Cl2 to give 18.8 g (crude) of the title compound. 1H NMR (DMSO-d6) consistent.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[C:10]([C:18]#N)[C:9]2=[O:20])=[CH:4][CH:3]=1.[OH2:21].[OH-:22].[Na+]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[C:10]([C:18]([OH:22])=[O:21])[C:9]2=[O:20])=[CH:4][CH:3]=1
Reactant: O
Reactant: [OH-]
Reactant: N#Cc1ccc(C(F)(F)F)n(-c2ccc(F)cc2)c1=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C(O)c1ccc(C(F)(F)F)n(-c2ccc(F)cc2)c1=O
Temperature: 25 °C
Yield: 75 %

Procedure:
A solution of 1-(4-fluorophenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carbonitrile (200 mg, 0.709 mmol) in conc. sulfuric acid (1.5 mL)/water (1.5 mL) was stirred at 120° C. for 17 hr. The reaction solution was allowed to cool to room temperature, 6N aqueous sodium hydroxide solution was added, and the aqueous layer was washed with ethyl acetate. 1N Hydrochloric acid was added to the aqueous layer, and the precipitate was filtered and washed with water to give the title compound (160 mg, 75%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:11]=[C:12]([C:16]([N:18]=[S@:19]([CH2:27][C:28](OCC)=[O:29])([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:20])=[O:17])[CH:13]=[N:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:33]([CH2:35][NH2:36])[OH:34]>>[OH:34][CH2:33][CH2:35][NH:36][C:28](=[O:29])[CH2:27][S:19](=[O:20])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[N:18][C:16](=[O:17])[C:12]1[CH:11]=[C:10]([C:9]#[C:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=2)[CH:15]=[N:14][CH:13]=1
Reactant: NCCO
Reactant: CCOC(=O)C[S@@](=O)(=NC(=O)c1cncc(C#Cc2cccc(O)c2)c1)c1ccccc1
Product: O=C(CS(=O)(=NC(=O)c1cncc(C#Cc2cccc(O)c2)c1)c1ccccc1)NCCO
Yield: 80 %

Procedure:
In a manner similar to that described for Example 471, (S)-Ethyl [N-({5-[(3-hydroxyphenyl)ethynyl]pyridin-3-yl}carbonyl)-S-phenylsulfonimidoyl]acetate (75 mg, 0.17 mmol) and ethanolamine (0.05 mL, 0.84 mmol) were reacted to give the title compound as colorless oil (63 mg, 81%).
Reaction SMILES: B(Br)(Br)Br.[Br:5][C:6]1[CH:11]=[CH:10][C:9]([O:12]C)=[CH:8][C:7]=1[N:14]1[C:19](=[O:20])[NH:18][C:17](=[O:21])[N:16]([CH3:22])[C:15]1=[O:23]>C(Cl)Cl>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[N:14]1[C:19](=[O:20])[NH:18][C:17](=[O:21])[N:16]([CH3:22])[C:15]1=[O:23]
Reactant: COc1ccc(Br)c(-n2c(=O)[nH]c(=O)n(C)c2=O)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cn1c(=O)[nH]c(=O)n(-c2cc(O)ccc2Br)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of boron tribromide in methylene chloride (98.75 mL of a 1M solution in methylene chloride) is added to a mixture of 1-(2-bromo-5-methoxyphenyl)-3-methyl-s-triazine-2,4,6(1H,3H,5H)-trione (14.4 g, 0.438 mol) in methylene chloride at 0° C. The reaction mixture is stirred at room temperature for 1 hour and filtered to obtain a solid. The solid is washed with water and air-dried to give the title product as a white solid, mp 265°-270° C.