Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[C:4](Cl)[F:5])([F:3])[F:2].[Li]C(CC)C.[Si:12](OCC)([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15]>CCOCC>[C:1](=[C:4]([Si:12]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[F:5])([F:3])[F:2]
Reactant: CCO[Si](OCC)(OCC)OCC
Reactant: FC(F)=C(F)Cl
Agent: [Li]C(C)CC
Solvent: CCOCC
Product: CCO[Si](OCC)(OCC)C(F)=C(F)F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
200 ml of freshly distilled dry Et2O is added to a 500 ml vessel (under an argon atmosphere). The vessel is cooled down to −80° and 15 g (0.129 mol) of CF2═CFCl gas is bubbled to Et2O. 100 ml (0.13 mol) of sec-BuLi is added dropwise during three hours. The temperature of the solution is kept below −60° C. all the time. The solution is stirred for 15 minutes and 29 ml (27.08 g, 0.130 mol) of Si(OEt)4 is added in small portions. The solution is stirred for over night allowing it to warm up to room temperature. Formed red solution is filtered and evaporated to dryness to result crude trifluorovinyltriethoxysilane, CF2═CFSi(OEt)3.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[NH2:18])[CH2:3]1.N1C=CC=CC=1.[F:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[S:37](Cl)(=[O:39])=[O:38]>ClCCl.O>[CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:13])([F:15])[F:14])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[NH:18][S:37]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[F:30])(=[O:39])=[O:38])[CH2:3]1
Reactant: O=S(=O)(Cl)c1ccccc1F
Reactant: CC1(C)CC(c2ccccc2N)Nc2ccc(C(F)(F)F)cc21
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CC1(C)CC(c2ccccc2NS(=O)(=O)c2ccccc2F)Nc2ccc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4,4-dimethyl-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-2-yl)aniline (100 mg, 0.36 mmol) and pyridine (114 mg, 1.44 mmol) in anhydrous dichloromethane (5 mL) was added 2-fluorobenzene-1-sulfonyl chloride (70.1 mg, 0.36 mmol) at ice-bath. After addition, the resulting mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with water, and extracted with dichloromethane. The combined organic layer was dried over anhydrous sodium sulfate, concentrated. The residue was purified by HPLC to give N-(2-(4,4-dimethyl-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-2-yl)phenyl)-2-fluorobenzenesulfonamide. LC/MS m/e obsd. (ESI+) [(M+H)+] 478.90.
Reaction SMILES: [C:1]([NH:9][C@H:10]([C:19]([OH:21])=O)[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Al+3].[Cl-].[Cl-].[Cl-]>C(OC(=O)C)(=O)C.C(=S)=S>[C:1]([NH:9][CH:10]1[CH2:11][CH2:12][C:13]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:19]1=[O:21])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N[C@@H](CCc1ccccc1)C(=O)O)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(=O)OC(C)=O
Solvent: S=C=S
Product: O=C(NC1CCc2ccccc2C1=O)c1ccccc1
Yield: 817.4 %

Procedure:
A solution of N-benzoyl homophenylalanine (4.4 g, 1.66 mmole) in acetic anhydride (60 ml) was heated on the steam bath for 1/2 hr. The solvent was removed in vacuo, the resulting oil was dissolved in CS2 and then added to a suspension of AlCl3 (6.2 g, 4.6 mmoles) in CS2 (60 ml). This mixture was heated at reflux for 1 hr, the solvent was removed in vacuo and ice was added to the residue. The reaction mixture was extracted with ethyl acetate, the ethyl acetate layer was washed with brine, dried over Na2SO4 and evaporated to dryness to afford 3.6 g (88%) of product, m.p. 175° C. After recrystallization from toluene it had m.p. 175°-178° C.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:44]([CH2:45][CH2:46][CH3:47])[CH:43]=[N:42][N:41]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:57])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:44]([CH2:45][CH2:46][CH3:47])[CH:43]=[N:42][N:41]=5)=[O:57])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nncn4CCC)cc2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nncn4CCC)cc2)CCN3CC(C)C)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 74.3 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-(4-propyl-4H-1,2,4-triazol-3-ylmethylthio)phenyl]-2,3-dihydro-1H-benzazepine-4-carboxamide (826 mg) in dichloromethane (20 ml) was added dropwise a solution of 3-chloroperbenzoic acid (70%, 0.46 g) in dichloromethane (10 ml) at −78° C., and the mixture was stirred for 1 hour at −78° C. To the reaction solution was added sodium thiosulfate solution at room temperature and the mixture was stirred for several minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethanol:ethyl acetate 1:5→1:3), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-(4-propyl-4H-1,2,4-triazol-3-ylmethylsulfinyl)phenyl]-2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 139) (628.7 mg) as yellow amorphous.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.II.[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Cl)=[CH:12][CH:11]=1.[NH4+].[Cl-]>C1COCC1.Cl[Cu].II>[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][C:2]2[S:3][CH:4]=[CH:5][CH:6]=2)=[CH:12][CH:11]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: Brc1cccs1
Agent: Cl[Cu]
Agent: II
Agent: [Cl-]
Solvent: C1CCOC1
Product: Fc1ccc(Cc2cccs2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.2 %

Procedure:
To a suspension of Mg turnings (3 g, 0.123 mol) in THF (40 ml) was added a small amount of solid I2 (20 mg). The mixture was heated to reflux under nitrogen. To the mixture was then added a small reaction-initiating amount (5 ml) of a solution of 19.6 g of 2-bromothiophene in 40 ml of THF. After the iodine color disappeared, the remainder of the 2-bromothiophene solution was added dropwise at a rate to maintainin reflux. After the addition, the mixture was heated under reflux for 2 hours, then was cooled to room temperature. To this mixture was added 0.3 g of CuCl catalyst followed by the dropwise addition of 4-fluorobenzyl chloride (14.4 g), again at a rate to maintain reflux. The mixture was stirred at room temperature for 2 h. After this period, saturated NH4Cl solution (100 ml) was added and the mixture was stirred for 30 min., the organic layer was separated and washed with 10% sodium thiosulfate solution (50 ml), followed by distilled water (100 ml). The organic layer was then dried over MgSO4 and concentrated to give 19 g of 2-(4-fluorobenzyl)thiophene as an oil. Purification was achieved by vacuum distillation (110° C., 5 mmHg).
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[C:3]([CH3:7])[C:2]=1[S:8]Cl.[C:11]([C:15]1[CH:20]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:18]=[CH:17][C:16]=1[OH:25])([CH3:14])([CH3:13])[CH3:12]>>[C:11]([C:15]1[C:16]([OH:25])=[C:17]([S:8][C:2]2[C:3]([CH3:7])=[CH:4][CH:5]=[CH:6][C:1]=2[CH3:10])[CH:18]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:20]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: Cc1cccc(C)c1SCl
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Product: Cc1cccc(C)c1Sc1cc(C(C)(C)C)cc(C(C)(C)C)c1O
Yield: 49.5 %

Procedure:
Under N2, 2.225 g m-xylene-2-sulfenyl chloride (12.9 mmol) were dissolved in 25 mL hexanes. Under air, a 100 mL 3-necked round-bottom flask was charged with stirbar and 2.64 g 2,4-di-tert-butylphenol (12.8 mmol), then reflux condenser with vacuum adapter and addition funnel were attached. The phenol was dried in vacuo for 20 minutes, then placed under N2 and immersed in an oil bath set at 100° C. The solution of m-xylene-2-sulfenyl chloride was then added via addition funnel and the reaction mixture refluxed overnight. Solvent had evaporated by morning, probably through a leaky joint. The resulting brown solid was ground up in mortar and pestle and recrystallized from ethanol, yielding 2.170 g cream-colored solid which melted at 101-102° C. A second, somewhat darker crop of 0.434 g was recovered from the mother liquor. Combined yield: 59% (based on 2,4-di-tert-butylphenol). 1H NMR (CDCl3), δ (ppm): 7.07-7.13 (m), 4H, Ar—H; 6.82 (d, J=2.4 Hz), 1H, Ar—H; 6.28 (s), 1H, OH; 2.41 (s), 6H, CH3; 1.38 (s), 9H, t-Bu; 1.13 (s), 9H, t-Bu.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)([CH2:10][CH2:11]C)C)=[CH:4][CH:3]=1.OC1C=CC(C(C2C=CC(O)=CC=2)(CC)CC)=CC=1>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:13]2[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=2)[CH2:10][CH3:11])=[CH:6][CH:7]=1
Reactant: CCCC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: CCC(CC)(c1ccc(O)cc1)c1ccc(O)cc1
Product: CCC(c1ccc(O)cc1)c1ccc(O)cc1

Procedure:
2,2-bis(4-hydroxyphenyl)pentane; 3,3-bis(4-hydroxyphenyl)pentane;
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([CH3:34])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[S:30][CH:31]=[CH:32][N:33]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)(C(C)(C)C)(C)C.Cl>CO>[CH3:34][C:10]1([CH2:9][OH:8])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:24]=[CH:25][C:26]([C:29]5[S:30][CH:31]=[CH:32][N:33]=5)=[CH:27][CH:28]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(-c5nccs5)cc4)CC3)n2CCS1
Agent: Cl
Solvent: CO
Product: CC1(CO)Cc2nnc(C3(c4ccc(-c5nccs5)cc4)CC3)n2CCS1
Yield: 100.4 %

Procedure:
A solution of the compound (237 mg, 0.46 mmol) obtained in Example 39-1) and 4 M hydrochloric acid (1,4-dioxane solution, 1 mL) in methanol (4 mL) was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogencarbonate was added to the residue, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 12 g, methanol:ethyl acetate=0:100 to 40:60, gradient) to obtain the title compound (184 mg, quant.) as a colorless solid.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[NH:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Br:28])=[CH:24][C:25]=2[F:27])[N:20]=[CH:19][N:18]=1)C1C=CC=CC=1.B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:28][C:23]1[CH:22]=[C:21]2[C:26]([C:17]([NH:16][C:10]3[CH:11]=[CH:12][C:13]([F:15])=[CH:14][C:9]=3[OH:8])=[N:18][CH:19]=[N:20]2)=[C:25]([F:27])[CH:24]=1
Reactant: Fc1ccc(Nc2ncnc3cc(Br)cc(F)c23)c(OCc2ccccc2)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Oc1cc(F)ccc1Nc1ncnc2cc(Br)cc(F)c12
Temperature: 0 °C

Procedure:
A mixture of 47 g (106 mmol) of N-(2-benzyloxy-4-fluoro-phenyl)-7-bromo-5-fluoro-quinazolin-4-amine and DCM is cooled to 0° C. and 159.4 ml (159.4 mmol) 1M BBr3 in DCM are added dropwise. After 3 h aq NaHCO3 solution is added carefully and the precipitate is filtered off, suspended in water and neutralized with 32% aq. ammonia solution. The precipitate is filtered off and dried furnishing 2-[(7-bromo-5-fluoro-quinazolin-4-yl)amino]-5-fluoro-phenol.
Reaction SMILES: C(OC(=O)[NH:10][C:11]([C:14](=[O:35])[NH:15][C:16]1[N:20]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[N:18]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:17]=1)([CH3:13])[CH3:12])C1C=CC=CC=1.C1COCC1>Br.O.CCOC(C)=O.CO>[NH2:10][C:11]([CH3:13])([CH3:12])[C:14]([NH:15][C:16]1[N:20]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[N:18]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:17]=1)=[O:35]
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)Nc1nc(-c2ccc(F)cc2)n(Cc2ccccc2)n1
Agent: Br
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(N)C(=O)Nc1nc(-c2ccc(F)cc2)n(Cc2ccccc2)n1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A flask containing {1-[1-Benzyl-5-(4-fluoro-phenyl)-1H-[1,2,4]triazol-3-ylcarbamoyl]-1-methyl-ethyl}-carbamic acid benzyl ester (777 mg, 1.59 mmol) was chilled to 0° C. The solid was dissolved in 48% aqueous HBr (5 mL) and the mixture stirred at 0° C. After 10 min the mixture was allowed to warm to room temp. After 5.5 hr THF (5 mL) was added and the mixture was stirred for 2 days. The reaction was diluted with water (30 mL) and extracted with Et2O (2×50 mL). The pH of the aqueous phase was adjusted to 10 by addition of 4N NaOH. The basic aqueous phase was extracted with Et2O (2×50 mL). The organics from the second extraction were combined and dried with brine (15 mL) followed by Na2SO4. Concentration resulted in a brown oil. The oil was dissolved in EtOAc/MeOH and the solvent evaporated to yield the title compound as a white solid: 1H NMR (400 MHz, ACETONITRILE-d3) 1.53 (s, 6H) 5.38 (s, 2H) 7.08-7.19 (m, 2H) 7.19-7.28 (m, 2H) 7.28-7.39 (m, 3H) 7.60-7.69 (m, 2H); Rt (method A)=0.96 min (M+H)+=354.2.
Reaction SMILES: [N:1]([CH:4]([CH3:14])[CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[N+:2]=[N-:3].[C:15]([CH2:17][C:18]([NH2:20])=[O:19])#[N:16].[Na].Cl>CS(C)=O.C(O)C>[NH2:16][C:15]1[N:1]([CH:4]([CH3:14])[CH2:5][CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:2]=[N:3][C:17]=1[C:18]([NH2:20])=[O:19]
Reactant: CC(CCCc1ccccc1)N=[N+]=[N-]
Reactant: N#CCC(N)=O
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: CS(C)=O
Product: CC(CCCc1ccccc1)n1nnc(C(N)=O)c1N
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of 997 mg (5.28 mmol) of (4-azidopentyl)-benzene and 672 mg (8 mmol) of cyanoacetamide in 3 ml of DMSO is admixed with a solution, of a temperature of 50° C., of 127 mg (5.5 mmol) of sodium in 3 ml of ethanol. The reaction mixture is stirred at room temperature for 15 h and then poured into 25 ml of ice-water. The pH is adjusted to pH 2 using 1N HCl and the precipitated solid is filtered off with suction, washed with water and dried under reduced pressure. This gives 1.14 g (79%) of a slightly yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[C:6]([NH2:19])[CH:5]=1.C([C:23]1[C:24]([N:29]=[CH:30][N:31]([CH3:33])C)=[N:25][CH:26]=[CH:27][CH:28]=1)#N>>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[C:6]([NH:19][C:33]2[C:23]3[CH:28]=[CH:27][CH:26]=[N:25][C:24]=3[N:29]=[CH:30][N:31]=2)[CH:5]=1
Reactant: COC(=O)c1ccc(Sc2ccc(OC)cc2)c(N)c1
Reactant: CN(C)C=Nc1ncccc1C#N
Product: COC(=O)c1ccc(Sc2ccc(OC)cc2)c(Nc2ncnc3ncccc23)c1

Procedure:
The product from Example 136B and the product from Example 29A were reacted according to the procedure from Example 136C substituting the product from Example 29A for the product from Example 8E to provide the title compound.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:9]=[C:10]([OH:15])[CH:11]=[CH:12][C:13]=1[Cl:14].CS([C:20]1[C:25]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:24][CH:23]=[CH:22][N:21]=1)(=O)=O>C1COCC1>[Cl:7][C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][C:13]=1[Cl:14])[O:15][C:20]1[C:25]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:24][CH:23]=[CH:22][N:21]=1
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: CS(=O)(=O)c1cccnc1S(C)(=O)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CS(=O)(=O)c1cccnc1Oc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Potassium t-butoxide (2.47 g) was dissolved in 30 ml of THF and then 3.46 g of 3,4-dichlorophenol dissolved in THF was added. A solution of 5.00 g of 2,3-bis(methylsulfonyl)pyridine in 20 ml THF/20 ml DMSO was added dropwise. The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was poured onto ice-water which resulted in the formation of an oil which solidified on standing. The product was collected by filtration and dried in a vacuum oven and 5.33 g of material obtained. Recrystallization from CH2Cl2 /hexane gave purified 2-(3,4-dichlorophenoxy)-3-(methylsulfonyl)pyridine, m.p. 95°-96° C.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=1[Cl:20])C1C=CC=CC=1.B(Br)(Br)Br>ClCCl>[Cl:20][C:10]1[CH:11]=[C:12]([CH2:15][C:16]([F:18])([F:19])[F:17])[CH:13]=[CH:14][C:9]=1[OH:8]
Reactant: FC(F)(F)Cc1ccc(OCc2ccccc2)c(Cl)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(CC(F)(F)F)cc1Cl
Temperature: -78 °C

Procedure:
1-Benzyloxy-2-chloro-4-(2,2,2-trifluoro-ethyl)benzene (4.0 g, 13.0 mmol) was dissolved in dichloromethane (50 mL) and cooled to −78° C. A solution of boron tribromide (1.0 M in CH2Cl2, 14.3 mL, 14.3 mmol) was added. The reaction mixture was warmed to 0° C., diluted with dichloromethane and washed with brine. After removal of solvent, the residue was chromatographed on silica gel eluting with 9:1 hexane:ethyl acetate to give the title compound.
Reaction SMILES: [CH:1]1([C:4]#[C:5][CH2:6][NH:7][C:8](=[O:40])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][C:16]2[CH:24]=[C:23]3[C:19]([C:20]([CH:33]=[N:34][N:35]4[CH:39]=[CH:38][CH:37]=[CH:36]4)=[N:21][N:22]3COCC[Si](C)(C)C)=[CH:18][CH:17]=2)[CH2:3][CH2:2]1.C1(N)C=CC=C(N)C=1>O>[CH:1]1([C:4]#[C:5][CH2:6][NH:7][C:8](=[O:40])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][C:16]2[CH:24]=[C:23]3[C:19]([C:20]([CH:33]=[N:34][N:35]4[CH:39]=[CH:38][CH:37]=[CH:36]4)=[N:21][NH:22]3)=[CH:18][CH:17]=2)[CH2:2][CH2:3]1
Reactant: C[Si](C)(C)CCOCn1nc(C=Nn2cccc2)c2ccc(Nc3ccccc3C(=O)NCC#CC3CC3)cc21
Agent: Nc1cccc(N)c1
Solvent: O
Product: O=C(NCC#CC1CC1)c1ccccc1Nc1ccc2c(C=Nn3cccc3)n[nH]c2c1

Procedure:
Prepared in a similar manner to that described for Example 11 in U.S. Pat. No. 6,534,524, issued Mar. 18, 2003, herein incorporated by reference in its entirety for all purposes, except that N-(3-Cyclopropyl-prop-2-ynyl)-2-[3-(pyrrol-1-yliminomethyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-6-ylamino]-benzamide was used instead of N-methyl-N-{3-styryl-1-[2-trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-yl}-benzene-1,3-diamine. 1H NMR (DMSO-d6) δ 13.29 (1H, s), 9.83 (1H, s 8.98 (1H, s), 8.95 (1H, t, J=5.5 Hz), 8.19 (1H, d, J=8.9 Hz), 7.68 (1H, d, J=7.5 Hz), 7.52 (2H, t, J=2.3 Hz), 7.43 (2H, m), 7.29 (1H, s), 7.07 (1H, dd, J=1.9, 8.7 Hz), 6.91 (1H, t, J=7.4 Hz), 6.21 (2H, t, J=2.3 Hz), 4.01 (2H, dd, J=1.7, 5.5 Hz), 1.27 (1H, m), 0.73 (2H, m), 0.55 (2H, m). Anal. Calcd for C25H22N6O. 0.05Hexanes. 0.30 H2O: C, 70.31; H, 5.43; N, 19.45. Found: C, 70.63; H, 5.38; N, 19.18.
Reaction SMILES: [Cl:1][C:2]1[CH:41]=[CH:40][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:39]=[CH:38][C:14]([O:15][C:16]3[C:21]([C:22]4[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=4)=[CH:20][C:19]([CH2:32][C:33]([O:35]CC)=[O:34])=[CH:18][CH:17]=3)=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.[OH-].[Na+].O>O1CCOCC1.C(OCC)(=O)C.Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:12]=[CH:13][C:14]([O:15][C:16]3[C:21]([C:22]4[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=4)=[CH:20][C:19]([CH2:32][C:33]([OH:35])=[O:34])=[CH:18][CH:17]=3)=[CH:38][CH:39]=2)=[O:10])=[CH:40][CH:41]=1
Reactant: CCOC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(-c2ccc(S(C)(=O)=O)cc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(-c2cc(CC(=O)O)ccc2Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)cc1
Reaction time: 3 h
Yield: 52.5 %

Procedure:
Ethyl 2-(6-(4-(4-chlorophenethylcarbamoyl)phenoxy)-4′-(methylsulfonyl)biphenyl-3-yl)acetate (20 mg, 0.0338 mmol) was diluted with dioxane (1 mL) followed by the addition of NaOH (0.0676 ml, 0.338 mmol) and 300 μL of water. After stirring for 3 hours, the reaction was diluted with ethyl acetate and 2N HCl. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated to yield 2-(6-(4-(4-chlorophenethylcarbamoyl)phenoxy)-4′-(methylsulfonyl)biphenyl-3-yl)acetic acid (10 mg, 52.5% yield). (400 MHz, CD3Cl3, CD3OD) 7.90 (d, 2H), 7.70 (d, 2H), 7.60 (d, 2H), 7.40 (s, 1H), 7.35 (d, 1H), 7.25 (d, 2H), 7.15 (d, 2H), 7.05 (d, 1H), 6.85 (d, 2H), 6.55 (t, 1H), 3.63 (m, 4H), 3.05 (s, 3H), 2.90 (t, 2H).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7](=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[CH:9]=1)[CH:2]([CH3:4])[CH3:3].I[CH3:22]>>[CH2:1]([C:5]1[N:6]([CH3:22])[C:7](=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:17])[F:18])[CH:9]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CI
Reactant: CC(C)Cc1cn(-c2ccccc2C(F)(F)F)c(=O)[nH]1
Product: CC(C)Cc1cn(-c2ccccc2C(F)(F)F)c(=O)n1C

Procedure:
This material was obtained in analogy to the procedure outlined in example 23 from 4-isobutyl-1-(2-trifluoromethyl-phenyl)-1,3-dihydro-imidazol-2-one (obtained in example 18, 200 mg) by alkylation with iodomethane (110 mg). 4-Isobutyl-3-methyl-1-(2-trifluoromethyl-phenyl)-1,3-dihydro-imidazol-2-one was obtained as a colorless oil (140 mg). MS (ESI): 299.2 (MH+).
Reaction SMILES: CN1C2C(=CC(S(N3CCC[C@H]3COC3C=CC=CC=3)(=O)=O)=CC=2)C(=O)C1=O.[O:29]([CH2:36][C@@H:37]1[CH2:40][CH2:39][N:38]1[S:41]([C:44]1[CH:45]=[C:46]2[C:50](=[CH:51][CH:52]=1)[NH:49][C:48](=[O:53])[C:47]2=[O:54])(=[O:43])=[O:42])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.Br[CH2:56][C:57]1[N:62]=[C:61]([F:63])[CH:60]=[CH:59][CH:58]=1>>[F:63][C:61]1[N:62]=[C:57]([CH2:56][N:49]2[C:50]3[C:46](=[CH:45][C:44]([S:41]([N:38]4[CH2:39][CH2:40][C@H:37]4[CH2:36][O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)(=[O:43])=[O:42])=[CH:52][CH:51]=3)[C:47](=[O:54])[C:48]2=[O:53])[CH:58]=[CH:59][CH:60]=1
Reactant: O=C1Nc2ccc(S(=O)(=O)N3CC[C@H]3COc3ccccc3)cc2C1=O
Reactant: Fc1cccc(CBr)n1
Agent: CN1C(=O)C(=O)c2cc(S(=O)(=O)N3CCC[C@H]3COc3ccccc3)ccc21
Product: O=C1C(=O)N(Cc2cccc(F)n2)c2ccc(S(=O)(=O)N3CC[C@H]3COc3ccccc3)cc21
Yield: 52 %

Procedure:
(S)-1-(6-Fluoropyridin-2-yl-methyl)-5-(2-phenoxymethylazetidine-1-sulfonyl)-1H-indole-2,3-dione (18i) was prepared according to the same procedure for compound 11a, except using compound 17 and 6-(bromomethyl)-2-fluoropyridine, and purified with ether to afford 62 mg (52%) of 18i as an orange solid, mp 144.7-146.1° C. 1H NMR (300 MHz, CDCl3) δ 8.03 (s, 1H), 8.00 (dd, J=8.25 Hz, J=2.1 Hz, 1H), 7.82 (m, 1H), 7.27-7.11 (m, 4H), 6.92 (m, 2H), 6.79 (m, 2H). Anal. Calcd for C24H20FN3O5S: C, 59.87, H, 4.19; N, 8.73. Found: C, 59.59, H, 4.27; N, 8.48.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.[CH2:10](OC(OCC)CBr)[CH3:11].Br.C([O-])(O)=O.[Na+]>CCO.CCOC(C)=O>[Br:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]2[N:3]([CH:10]=[CH:11][N:1]=2)[CH:4]=1
Reactant: CCOC(CBr)OCC
Reactant: Cc1cc(Br)cnc1N
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cc(Br)cn2ccnc12
Temperature: 23 °C
Yield: 71.5 %

Procedure:
To a solution of commercially available 2-amino-5-bromo-3-picoline (21.48 g, 115 mmol) and bromoacetaldehyde diethyl acetal (90%, 39.6 mL, 230 mmol) in EtOH (110 mL) was added 48% aq. HBr (11 mL) and the mixture was refluxed for 11 h. Cooled to 23° C., diluted with EtOAc, poured into sat. NaHCO3-sol., separated phases, washed with the organic layer with brine, dried over Na2SO4. Removal of the solvent in vacuum (not over 40° C. bath temperature) left an orange liquid, which was directly coated on silica gel for chromatography. Silica gel column filtration with heptane/EtOAc 50:50->0:100 gave the title compound as a light brown solid (17.36 g, 72%). MS (ISP) 211.0 [(M+H)+], 231.1 [(M+2+H)+].