Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]1([S:19]([N:22]2[C:26]3[N:27]=[CH:28][N:29]=[C:30]([Cl:31])[C:25]=3[CH:24]=[CH:23]2)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.I[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>O1CCCC1.[Cl-].[Zn+2].[Cl-].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:13]1([S:19]([N:22]2[C:26]3[N:27]=[CH:28][N:29]=[C:30]([Cl:31])[C:25]=3[CH:24]=[C:23]2[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)(=[O:21])=[O:20])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(Cl)ncnc21
Reactant: Ic1ccccc1
Agent: [Pd]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1c(-c2ccccc2)cc2c(Cl)ncnc21
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
In a flame-dried flask under nitrogen, 0.53 mL (3.79 mmol) of diisopropylamine were dissolved in 5 mL of tetrahydrofuran (THF) and the solution cooled to −78° C. n-Butyllithium (3.75 mmol as a 2.5 M solution in hexanes) was added and the resulting mixture brought to 0° C. with continued stirring for 10 min. The reaction mixture was again cooled to −78° C. and to this mixture added a solution of 1.0 g (3.40 mmol) of the product from Method C in 10 mL of THF over a 10 min period. The reaction mixture was stirred for 1 h at −78° C., at which time, 8.2 mL (4.10 mmol) of a 0.5 M solution of zinc chloride in THF was added, the reaction mixture was brought to room temperature and stirred for 1 h. Iodobenzene (0.46 mL/4.11 mmol) and a suspension of 197 mg of tetrakis(triphenylphosphine) palladium in 2 mL of THF were added. The resulting mixture was stirred at reflux for 3 h., cooled to room temperature, and partitioned between dichloromethane and water. The aqueous layer was acidified with 1 N HCl and extracted twice with dichloromethane. The dichloromethane layers were combined; washed with 1 N HCl and brine, dried over magnesium sulfate (MgSO4), filtered and concentrated in vacuo to obtain the title compound. LRMS: 370, 372 (M+2).
Reaction SMILES: [CH2:1]([NH:13][CH2:14][CH2:15][CH2:16][NH2:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:18]([O:24]CC)(=O)[CH2:19][C:20]([CH3:22])=O>>[CH2:1]([N:13]1[CH2:14][CH2:15][CH2:16][N:17]=[C:20]([CH3:22])[CH2:19][C:18]1=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCNCCCN
Reactant: CCOC(=O)CC(C)=O
Product: CCCCCCCCCCCCN1CCCN=C(C)CC1=O

Procedure:
Into an apparatus similar to that in Example 1, were charged 242.1 g (1 mole) of N-dodecyl-1,3-propylenediamine and 130.1 g (1 mole) of ethyl acetoacetate. At 150° to 160° C., 18 g of water and 46 g of ethanol were distilled off to obtain 1-dodecyl-4-methyl-3,6,7,8-tetrahydro-1,5-diazocin-2-one.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[NH:10][C:9]=2[C:8](=[O:15])[N:7]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]2ON=[C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:21]=2)[C:6]1=[O:31])[CH2:2][CH2:3][CH3:4].C(N1C2N=C(Cl)N(CC=C)C=2C(=O)NC1=O)CCC.C1(CC2C=C(CCCO)[O:60][N:59]=2)C=CC=CC=1>>[CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[NH:10][C:9]=2[C:8](=[O:15])[N:7]([CH2:16][CH2:17][CH2:18][C:19]2[O:60][N:59]=[C:21]([CH2:22][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:20]=2)[C:6]1=[O:31])[CH2:2][CH2:3][CH3:4]
Reactant: OCCCc1cc(Cc2ccccc2)no1
Reactant: CCCCn1c(=O)n(CCCCc2cc(-c3ccccc3)no2)c(=O)c2[nH]c(Cl)nc21
Agent: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CCCC
Product: CCCCn1c(=O)n(CCCc2cc(Cc3ccccc3)no2)c(=O)c2[nH]c(Cl)nc21

Procedure:
Prepared analogously to 3-butyl-8-chloro-1-[4-(3-phenyl-5-isoxazolyl)butyl]-3,7-dihydro-1H-purine-2,6-dione (Example 213) using half the molar quantities, starting from 3-butyl-8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (50 mg, 0.177 mmol) and 3-[3-(phenylmethyl)-5-isoxazolyl]-1-propanol (38.4 mg, 0.177 mmol). Yield 24.2 mg,
Reaction SMILES: [OH:1][NH:2][CH2:3][CH2:4][CH2:5][P:6](=[O:9])([OH:8])[OH:7].C[Si](C([Si](C)(C)C)C(N)=O)(C)C.ClCCl.[CH3:25][N:26]=[C:27]=[S:28]>O>[OH:1][N:2]([CH2:3][CH2:4][CH2:5][P:6](=[O:8])([OH:7])[OH:9])[C:27](=[S:28])[NH:26][CH3:25]
Reactant: O=P(O)(O)CCCNO
Reactant: CN=C=S
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Solvent: O
Solvent: ClCCl
Product: CNC(=S)N(O)CCCP(=O)(O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 13.3 %

Procedure:
A mixture of 3-(N-hydroxyamino)propylphosphonic acid (1.64 g), bis(trimethylsilyl)acetamide (10 g) and dichloromethane (30 ml) was stirred at ambient temperature for 3 hours and cooled to 0°-5° C. To the mixture was added methylisothiocyanate (800 mg) under ice-cooling. The reaction mixture was stirred at the same temperature for an hour and concentrated under reduced pressure to give a residue. To this residue was added water (50 ml) and stirred at ambient temperature for 30 minutes. After the remaining dichloromethane was removed by evaporation under reduced pressure, an additional 50 ml of water was added. The aqueous solution was subjected to a column chromatography using activated charcoal. The column was washed with water (650 ml) and then the object compound was eluted with 70% aqueous acetone. The eluate was concentrated under reduced pressure to give crystals, which were separated by filtration, washed with ethanol and dried to give crystalline 3-[N-hydroxy-N-{(N-methyl)thiocarbamoyl}amino]propylphosphonic acid (320 mg). Further, the ethanol washing was concentrated under reduced pressure to give a residue which was pulverized to give the same object compound (450 mg). Mp 190°-194° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH2:4].C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC.[CH3:47][S:48]([N:51]=[C:52]=[O:53])(=[O:50])=[O:49]>C1C=CC=CC=1.C(N(CC)CC)C>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH:4][C:52]([NH:51][S:48]([CH3:47])(=[O:50])=[O:49])=[O:53]
Reactant: CS(=O)(=O)N=C=O
Reactant: Nc1c(Cl)cccc1Cl
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NC(=O)Nc1c(Cl)cccc1Cl
Reaction time: 72 h

Procedure:
A solution was prepared containing 3.2 g (0.02 mole) of 2,6-dichloroaniline in 30 ml benzene, and one drop each of triethylamine and dibutyltin dilaurate. A second solution of 2.4 g (0.02 mole) of methanesulfonylisocyanate in 6 ml of benzene was added to the first solution. The temperature of the reaction mixture was allowed to rise to 35° C. The mixture was then allowed to stand for three days.
Reaction SMILES: C([NH:4][C:5]1[C:6]([F:16])=[CH:7][C:8]([Cl:15])=[C:9]([CH2:11][C:12]([OH:14])=[S:13])[CH:10]=1)(=O)C.Cl.[OH-].[Na+]>>[NH2:4][C:5]1[C:6]([F:16])=[CH:7][C:8]([Cl:15])=[C:9]([CH2:11][C:12]([OH:14])=[S:13])[CH:10]=1
Reactant: CC(=O)Nc1cc(CC(O)=S)c(Cl)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1cc(CC(O)=S)c(Cl)cc1F
Yield: 73 %

Procedure:
A suspension of 5-(N-acetylamino)-2-chloro-4-fluorophenylthioacetic acid (89.8 g) in a 10% aqueous hydrochloric acid solution was refluxed for 2 hours under heating. After being allowed to cool, an aqueous solution of sodium hydroxide was added to make the suspension at pH 4. After ice-cooling, the precipitated crystals were collected by filteration, washed with ice-water and dried to give 55.0 g of 5-amino-2-chloro-4-fluorophenylthioacetic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([NH2:22])[N:11]=[N:12][C:13]=2[C:14]2[CH:19]=[C:18]([CH3:20])[N:17]=[C:16](Cl)[CH:15]=2)=[CH:4][CH:3]=1.[NH:23]1[CH2:26][CH2:25][CH2:24]1>>[N:23]1([C:16]2[CH:15]=[C:14]([C:13]3[N:12]=[N:11][C:10]([NH2:22])=[N:9][C:8]=3[C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH:19]=[C:18]([CH3:20])[N:17]=2)[CH2:26][CH2:25][CH2:24]1
Reactant: Cc1cc(-c2nnc(N)nc2-c2ccc(F)cc2)cc(Cl)n1
Reactant: C1CNC1
Product: Cc1cc(-c2nnc(N)nc2-c2ccc(F)cc2)cc(N2CCC2)n1
Yield: 3.7 %

Procedure:
6-[2-(azetidin-1-yl)-6-methylpyridin-4-yl]-5-(4-fluorophenyl)-1,2,4-triazin-3-amine (6.0 mg, 4%) was prepared from 5-(4-fluorophenyl)-6-(2-chloro-6-methyl-pyridin-4-yl)-1,2,4-triazin-3-amine (150 mg, 0.48 mmol) and azetidine (136 mg, 0.16 ml, 2.38 mmol) according to the general procedure for Preparation 4a.
Reaction SMILES: C[O:2][C:3](=O)[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH3:30])=[CH:19][CH:18]=1)[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].[BH4-].[Na+].CO.C(O)(=O)C>COC(C)(C)C.O1CCCC1.O>[CH2:9]([O:8][C:6]([NH:5][CH:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH3:30])=[CH:19][CH:18]=1)[CH2:3][OH:2])=[O:7])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COCCOCCOc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)OC)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COCCOCCOc1ccc(CC(CO)NC(=O)OCc2ccccc2)cc1
Reaction time: 4 h

Procedure:
7.35 g (17 mmol) of N-benzyloxycarbonyl-3-[4-(1,4,7-trioxaoctyl)-phenyl]-alanine-methyl ester (Example a) is dissolved in 35 ml of tert-butyl methyl ether and mixed with 0.9 g (23.8 mmol) of sodium borohydride. At 5° C., 10 ml of methanol is added, and it is stirred for four hours under argon at constant temperature. Then, 1.5 ml of acetic acid, dissolved in 5 ml of tetrahydrofuran, is added, mixed with 5 ml of water and stirred for ten minutes at room temperature. The organic phase is separated, washed with water and dried on sodium sulfate. The drying agent is suctioned off, the filtrate is concentrated by evaporation and the residue is chromatographed for purification on silica gel.
Reaction SMILES: [OH-].[Li+].[OH:3][CH2:4][CH:5]([C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=1)[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>O1CCCC1.C1(C)CCC(C(C)C)C(O)C1.O>[OH:3][CH2:4][CH:5]([C:13]1[CH:14]=[CH:15][C:16]([C:17]([OH:19])=[O:18])=[CH:21][CH:22]=1)[O:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: COC(=O)c1ccc(C(CO)Oc2ccccc2)cc1
Agent: CC1CCC(C(C)C)C(O)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(C(CO)Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
To a solution of lithium hydroxide (400 mg, 10.2 mmol) in tetrahydrofuran, menthol and water (20 mL, 3:1:1, V/V) was added methyl 4-(2-hydroxy-1-phenoxyethyl)benzoate (400 mg, 1.47 mmol). The reaction mixture was stirred at room temperature for 1 hour. The mixture was quenched with 10% HCl (aqueous, 5 mL), extracted with dichloromethane and menthol (60 mL, 10:1), the combine organic layer was dried with anhydrous sodium sulfate, filtered and evaporated to give 4-(2-hydroxy-1-phenoxyethyl)benzoic acid (300 mg, 70%). LCMS (M+H+) m/z: calcd 258.09. found 258
Reaction SMILES: [F:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18].CS(Cl)(=O)=O.[CH2:24](O)[CH2:25][CH2:26][OH:27]>>[F:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH:26]([OH:27])[CH2:25][CH3:24]
Reactant: OCCCO
Reactant: OCCCCCCCCCCCCCCCCF
Agent: CS(=O)(=O)Cl
Product: CCC(O)OCCCCCCCCCCCCCCCCF

Procedure:
A general procedure for the preparation of terminal fluorinated alkoxyalkyl esters of acyclic nucleoside phosphonates is illustrated in Scheme 7, below. Fluoroalkoxyalkyl esters of acyclic nucleoside phosphonates such as 3-(16-fluorohexadecyloxy)propyl cidofovir (16-F-HDP-CDV) 49 and 3-(16-fluorohexadecyloxy)propyl (S)-HPMPA 50 (16-F-HDP-(S)-HPMPA) can be prepared using this process. Briefly, with reference to Scheme 7, the Grignard reagent prepared from 1-bromo-4-fluorobutane and magnesium is reacted with 12-bromododecanol 44 to obtain 16-fluorohexadecanol 45. Reaction of 45 with methanesulfonyl chloride followed by reaction with 1,3-propanediol provides 16-fluorohexadecyloxy-1-propanol 46. Coupling of 46 with cyclic cidofovir or cyclic (S)-HPMPA as described generally in Example 2 (step a), provides the cyclic esters (47 and 48, respectively) which can then be converted to the desired compounds (49 and 50, respectively) using the general method set forth in Example 2 (step b).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH:20]=[O:21])[CH:16]=2)[O:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)=[O:24].OS(O)(=O)=O.O=[Cr](=O)=O.S(=O)(=O)(O)O>CC(C)=O.[O-2].[O-2].[O-2].[Cr+6].O.C(O)(C)C>[CH2:1]([O:8][CH2:9][CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:20]([OH:24])=[O:21])[CH:16]=2)[O:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)=O
Reactant: O=Cc1ccc2c(c1)CCC(COCc1ccccc1)O2
Agent: O=[Cr](=O)=O
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)O
Product: O=C(O)c1ccc2c(c1)CCC(COCc1ccccc1)O2
Temperature: 25 °C
Reaction time: 18 h
Yield: 60 %

Procedure:
A solution of 2-(benzyloxymethyl)-6-chromane-carbaldehyde (0.921 g, 3.27 mmol) in acetone (5 ml) was added at 0° C. with Jones reagent, consisting of a mixture of chromium trioxide (0.326 g, 3.27 mmol), water (0.95 ml) and concentrated sulfuric acid (0.27 ml). The mixture was left under stirring at room temperature for 18 h. After that, a mixture of isopropyl alcohol (10 ml) and water (50 ml) was added, extracting with ethyl ether (3×30 ml). The organic phase was dried and the solvents were evaporated off under reduced pressure to obtain a residue which was purified by chromatography through a silica gel column. Eluting with hexane:ethyl acetate, 7:3, 0.580 g of the title compound were obtained (60% yield).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].C(N(CC)CC)C.ON1C(=O)CCC1=O.FC(F)(F)C(O)=O.[NH2:28][CH2:29][C:30]1[C:31]([F:49])=[C:32]([F:48])[C:33]([NH:39][C:40]2[CH:45]=[CH:44][C:43]([I:46])=[CH:42][C:41]=2[F:47])=[C:34]([CH:38]=1)[C:35]([OH:37])=[O:36]>C(Cl)Cl>[C:1]([NH:28][CH2:29][C:30]1[C:31]([F:49])=[C:32]([F:48])[C:33]([NH:39][C:40]2[CH:45]=[CH:44][C:43]([I:46])=[CH:42][C:41]=2[F:47])=[C:34]([CH:38]=1)[C:35]([OH:37])=[O:36])(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)Cl
Reactant: NCc1cc(C(=O)O)c(Nc2ccc(I)cc2F)c(F)c1F
Agent: O=C1CCC(=O)N1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CC(=O)NCc1cc(C(=O)O)c(Nc2ccc(I)cc2F)c(F)c1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Acryloyl chloride (100 μL, 0.986 mmol) and triethylamine (689 μL, 4.93 mmol) were added to a solution of hydroxy-pyrrolidine-2,5-dione (commercially available, 227 mg, 1.973 mmol) in methylene chloride (anhydrous, 2 mL), and the mixture was stirred at room temperature for 30 minutes. 5-aminomethyl-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoic acid (150 mg, 0.355 mmol) obtained in Step A was added to this solution, and the mixture was stirred for 1 hour. After completion of the reaction, the reaction mixture was evaporated under reduced pressure, and the resultant residue was extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 5-(acryloylamino-methyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoic acid as a white solid. This product was confirmed for the structure by LC/MS. LC/MS (positive mode) m/z 477 (M+1). This compound was dissolved in methylene chloride (anhydrous, 10 mL) under argon flow. N,N-diisopropylethylamine (250 μL, 1.42 mmol), O-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-hydroxylamine (135 mg, 0.71 mmol), 1-hydroxy-1H-benzotriazole (71 mg, 0.533 mmol), and (3-dimethylamino-propyl)-ethyl-carbodiimide hydrochloride (102 mg, 0.533 mmol) were added sequentially to the solution. The mixture was stirred at room temperature for 20 hours.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11])[CH2:3][OH:4].[N:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:25]=[CH:24][N:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=3)[N:22]=2)=[CH:17][CH:16]=1)=[C:13]=[S:14]>>[Cl:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[CH:2]([NH:1][C:13]([NH:12][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[N:25]=[CH:24][N:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:34])[F:35])=[CH:28][CH:27]=3)[N:22]=2)=[CH:19][CH:20]=1)=[S:14])[CH2:3][OH:4]
Reactant: NC(CO)c1ccccc1Cl
Reactant: FC(F)(F)Oc1ccc(-n2cnc(-c3ccc(N=C=S)cc3)n2)cc1
Product: OCC(NC(=S)Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1)c1ccccc1Cl

Procedure:
The title compound was prepared with 2-amino-2-(2-chlorophenyl)ethanol (Brueggemeier, U.; et al., WO 2010105770) and 3-(4-isothiocyanato-phenyl)-1-(4-trifluoromethoxy-phenyl)-1H-1,2,4-triazole and isolated as a white solid (1.44 g, quantitative): 1H NMR (300 MHz, CDCl3) δ 7.97 (d, J=1.1 Hz, 1H), 7.64 (d, J=8.2 Hz, 1H), 7.47-7.41 (m, 1H), 7.23-7.13 (m, 2H), 6.87-6.55 (m, 11H), 5.39 (d, J=8.3 Hz, 1H), 3.48-3.30 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[C:12]([NH2:16])([CH3:15])([CH3:14])[CH3:13]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:16][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])=[O:9]
Reactant: CC(C)(C)N
Reactant: O=S(=O)(Cl)c1ccccc1Br
Solvent: ClC(Cl)Cl
Product: CC(C)(C)NS(=O)(=O)c1ccccc1Br
Temperature: 25 °C
Reaction time: 12 h
Yield: 83.9 %

Procedure:
To a stirred solution of 2-bromobenzenesulfonyl chloride (Lancaster Synthesis) (2.21 g, 8.65 mmol) in chloroform (40 ml) under nitrogen at room temperature was added tert-butylamine (Aldrich) (2.30 ml, 21.9 mmol). The orange solution was stirred at room temperature for 12 hours, then the mixture evaporated to dryness. Flash chromatography (silica gel, 15% ethyl acetate-hexane) afforded the title compound (2.12 g, 84%) as a white solid; 1H NMR (300 MHz, CDCl3) δ8.18 (d, J=8.5 Hz, 1H), 7.73 (d, J=8.5 Hz, 1H), 7.50-7.35 (m, 2H), 5.11 (s, 1H), 1.20 (s, 9H).
Reaction SMILES: [Na].[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]#[N:11].[N:12]([C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([OH:19])=O)=[N+:13]=[N-:14].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C.O>[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:14]=[N:13][N:12]2[C:15]3[C:16](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:17](=[O:19])[NH:11][C:10]=12
Reactant: N#CCc1ccccc1F
Reactant: [N-]=[N+]=Nc1ccccc1C(=O)O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na]
Solvent: CCO
Solvent: O
Product: O=c1[nH]c2c(-c3ccccc3F)nnn2c2ccccc12
Yield: 108.4 %

Procedure:
Sodium metal (1.4 g, 60 mmol) was dissolved in ethanol (100 ml) at room temperature under nitrogen. 2-Fluorophenylacetonitrile (3.85 ml, 30 mmol) was added, followed by the dropwise addition of a solution of 2-azidobenzoic acid (4.71 g, 29 mmol) in ethanol (60 ml). The thick white suspension was refluxed for 18 h then cooled and poured into water (800 ml). The mixture was acidified to pH 3-4 with aqueous 1M citric acid and the precipitated solid was collected. The solid was washed with diethyl ether (20 ml) and dried in vacuo to give 3-(2-fluorophenyl)-[1,2,3]triazolo[1,5-α]quinazolin-5(4H)-one (8.81 g, 100%), m.p. 238-241° C. (DMF). Found: C, 64.33; H, 3.06; N, 20.29. C15H9FN4O requires C, 64.28; H, 3.24; N, 19.99%. δH (360 MHz; DMSO) 7.33-7.38 (2H, m), 7.46-7.55 (1H, m), 7.69-7.73 (2H, m), 8.02 (1H, ddd, J=9, 9 and 1), 8.24 (1H, dd, J=8 and 1), 8.38 (1H, d, J=8) and 12.40 (1H, br s); m/z (ES+) 821 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@@H:15]([OH:17])[CH3:16])[C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[Br:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([NH:26][NH2:27])=[O:25])=[CH:22][CH:21]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CCN(CC)CC>C1COCC1>[Br:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([NH:26][NH:27][C:12](=[O:14])[C@H:11]([NH:10][C:4]2[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([Cl:1])[C:3]=2[CH3:18])[C@@H:15]([OH:17])[CH3:16])=[O:25])=[CH:22][CH:21]=1
Reactant: NNC(=O)c1ccc(Br)cc1
Reactant: Cc1c(N[C@@H](C(=O)O)[C@H](C)O)ccc(C#N)c1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(Br)cc2)[C@H](C)O)ccc(C#N)c1Cl
Temperature: -20 °C
Reaction time: 8 h
Yield: 76.2 %

Procedure:
(2R,3S)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid (5.0 g, 18.6 mmol), 4-bromobenzhydrazide (CAS 5933-32-4, 4.0 g, 18.6 mmol) and 1-Hydroxybenzotriazole hydrate (2.52 g, 18.6 mmol) were placed in a 250 mL round bottomed flask. Anhydrous THF (120 mL) was added and the mixture was cooled to −20° C. N-(3-Dimethylaminopropyl)-N′-ethylcarbodimide HCl (5.35 g, 27.9 mmol) was added, Followed by Et3N (3.9 mL, 28.0 mmol). The reaction mixture was stirred at −20° C. for 1 h and room temperature for overnight. The reaction was quenched by adding water and extracted with EtOAc, which was washed with 5% aqueous NaOH, water, brine and dried over Na2SO4. The extracts were filtered and the filtrate was concentrated to provide a brown solid, which was purified by flash chromatography washed with 80% EtOAc in hexanes to afford the title compound (6.6 g, 76%). 1H NMR (400 MHz, acetone-d6, δ in ppm) 7.87 (d, J=8.6 Hz, 2H), 7.71 (d, J=8.6 Hz, 2H), 7.54 (d, J=8.6 Hz, 1H), 6.67 (d, J=8.6 Hz, 1H), 5.55 (d, J=7.4 Hz, 1H), 4.39 (m, 1H), 4.10 (dd, J=3.3, 7.4 Hz, 1H), 2.36 (s, 3H), 1.35 (d, J=6.4 Hz, 3H).
Reaction SMILES: [O:1]=[C:2]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C@H:3]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:4][CH:5]=[CH2:6].C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+]>C1COCC1>[OH:1][C@H:2]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C@H:3]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH2:4][CH:5]=[CH2:6]
Reactant: C=CC[C@@H](NC(=O)OCc1ccccc1)C(=O)c1ccccc1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC[C@@H](NC(=O)OCc1ccccc1)[C@H](O)c1ccccc1
Reaction time: 0.75 h

Procedure:
To (R)-benzyl 1-oxo-1-phenylpent-4-en-2-ylcarbamate (2.13 g, 6.89 mmol) in THF (50 mL) at −78° C. under argon was added lithium tri-sec-butylborohydride (20.7 ml, 20.7 mmol). Allowed the mixture to stir for 45 min. Quenched the reaction with saturated aqueous Rochelle's salt (50 mL) and the volatiles were removed in vacuo. The aqueous residue was extracted with ether (3×50 mL). The ether was combined and washed with brine (20 mL), dried over Na2SO4 and filtered. The filtrate was evaporated onto silica gel and purified via flash chromatography (0% to 20%; EtOAc in hexanes). MS m/z=334 [M+Na]+. Calc'd for C19H21NO3: 311.
Reaction SMILES: CO[C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]2[S:15][CH:16]=[CH:17][C:18]=2[NH:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]3[NH:26][CH:27]=[CH:28][C:21]=23)=[O:13])=[CH:5][CH:4]=1.[Cl:31]C1C=C(C=CC=1)C=O>>[Cl:31][C:4]1[CH:5]=[C:6]([CH:29]=[CH:30][CH:3]=1)[CH2:7][NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[S:15][CH:16]=[CH:17][C:18]=1[NH:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]2[NH:26][CH:27]=[CH:28][C:21]=12)=[O:13]
Reactant: O=Cc1cccc(Cl)c1
Reactant: COc1ccc(CNCCNC(=O)c2sccc2Nc2ccnc3[nH]ccc23)cc1
Product: O=C(NCCNCc1cccc(Cl)c1)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid [2-(4-methoxy-benzylamino)-ethyl]-amide using 3-chlorobenzaldehyde instead of 4-methoxy benzaldehyde. LCMS (ESI) 426 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.50 (1H, br. s.) 10.43 (1H, s) 10.26 (1H, s) 7.94-8.11 (1H, m) 7.72-7.80 (1H, m) 7.37-7.52 (1H, m) 7.18-7.33 (1H, m) 7.05-7.14 (1H, m) 6.75-6.85 (1H, m) 6.36-6.44 (1H, m) 3.70 (2H, s) 3.31-3.38 (2H, m) 2.62 (2H, t, J=6.44 Hz)
Reaction SMILES: C[O:2][C:3]([CH3:15])([CH3:14])[C:4]([CH3:13])([CH3:12])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CC(C)(CC1C=CC=CC=1)C(=O)C.[Br-].[I-]>>[CH3:15][C:3]([OH:2])([C:4]([CH3:13])([CH3:12])[CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[CH3:14]
Reactant: COC(C)(C)C(C)(C)Cc1ccccc1
Agent: CC(=O)C(C)(C)Cc1ccccc1
Agent: [Br-]
Agent: [I-]
Product: CC(C)(O)C(C)(C)Cc1ccccc1

Procedure:
Finally, 3-methoxy-2,2,3-trimethyl-1-phenylbutane (see line (3) of the scheme below) is prepared from 3,3-dimethyl-4-phenyl-2-butanone which is reacted with a methyl magnesium halide, e.g. the bromide or iodide, to obtain 2,3,3-trimethyl-4-phenyl-2-butanol. As in the synthesis described above for the other compounds of the invention, this alcohol is then etherified to obtain the desired product. ##STR1##