Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([C:19]2[CH2:20][CH2:21][O:22][C:23]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=4)=[CH:26][C:24]=3[CH:25]=2)=[O:18])=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:45])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([S:8]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17]([C:19]2[CH2:20][CH2:21][O:22][C:23]3[CH:29]=[CH:28][C:27]([C:30]4[CH:31]=[CH:32][C:33]([CH3:36])=[CH:34][CH:35]=4)=[CH:26][C:24]=3[CH:25]=2)=[O:18])=[CH:14][CH:15]=1)=[O:45])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CSCc4ccccc4)cc2)CCO3)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CS(=O)Cc4ccccc4)cc2)CCO3)cc1
Reaction time: 0.17 h
Yield: 64.6 %

Procedure:
To a solution of N-(4-(benzylthiomethyl)phenyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (0.12 g) in dichloromethane (25 ml) was added 70% m-chloroperbenzoic acid (0.06 g) at the temperature ranging from -20 to -10° C., and the mixture was stirred for 10 minutes. To the mixture was added sodium thiosulfate solution, and the mixture was concentrated and extracted with ethyl acetate. The organic layer was washed with sodium hydrogen carbonate solution, water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give crude crystals, which were recrystallized from ethyl acetate-hexane to give N-(4-(benzylsulfinylmethyl)phenyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 109) (0.08 g) as colorless crystals.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.[CH2:15]([NH2:17])[CH3:16]>CC#N>[CH2:15]([NH:17][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1)[CH3:16]
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Reactant: CCN
Solvent: CC#N
Product: CCNc1nc(SC)ncc1C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.5 %

Procedure:
To a 0° C. solution of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (19 g, 82 mmol) in CH3CN (100 mL) was added a solution of aqueous ethylamine (70%, 8.1 g, 126 mmol). The resulting mixture was stirred at RT for 8 h. The organic solution was removed under reduced pressure, and the residue was partitioned between EtOAc and H2O. The aqueous layer was extracted with ethyl acetate (3×30 mL) and the combined organics were washed with brine, dried (MgSO4) and concentrated to give ethyl 4-(ethylamino)-2-(methylthio)pyrimidine-5-carboxylate (19.5 g, 99.1% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.49 (s, 1 H), 8.26 (t, J=4.8 Hz, 1 H), 4.23 (q, J=7.2 Hz, 2 H), 3.48 (q, J=7.2 Hz, 2 H), 2.44 (s, 3 H), 1.26 (t, J=7.2 Hz, 3 H), 1.13 (t, J=7.2 Hz, 3 H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]([CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:6]2[C:11]([C:12]=1[CH2:13][CH2:14][O:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=1)=[CH:10][C:9]([Cl:26])=[CH:8][CH:7]=2.[Cl:40][C:41]1[CH:42]=[C:43]([S:48](Cl)(=[O:50])=[O:49])[CH:44]=[C:45]([Cl:47])[CH:46]=1>>[CH:27]([N:5]1[C:6]2[C:11](=[CH:10][C:9]([Cl:26])=[CH:8][CH:7]=2)[C:12]([CH2:13][CH2:14][O:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=2)=[C:4]1[CH2:3][CH2:2][NH:1][S:48]([C:43]1[CH:42]=[C:41]([Cl:40])[CH:46]=[C:45]([Cl:47])[CH:44]=1)(=[O:50])=[O:49])([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: COC(=O)c1ccc(OCCc2c(CCN)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Product: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)c3cc(Cl)cc(Cl)c3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Yield: 60 %

Procedure:
To the methyl 4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (Step 5, Example 1)was added 3,5-dichlorobenzenesulfonyl chloride according to the procedure in Example 1 Step 7 to generate the product in 60% yield.
Reaction SMILES: Cl.[CH3:2][NH:3][OH:4].[CH3:5][O-:6].[Na+].[Br:8][C:9]1[CH:10]=[C:11]2C(=[CH:17][CH:18]=1)O[CH:14]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)[CH2:13]/[C:12]/2=[N:25]\[C:26]#[N:27]>CO>[Br:8][C:9]1[CH:10]=[C:11]2[C:12]3([O:4][N:3]([CH3:2])[C:26]([NH2:27])=[N:25]3)[CH2:13][CH:14]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[O:6][C:5]2=[CH:17][CH:18]=1
Reactant: CNO
Reactant: N#C/N=C1\CC(c2cccnc2)Oc2ccc(Br)cc21
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CN1OC2(CC(c3cccnc3)Oc3ccc(Br)cc32)N=C1N
Reaction time: 0.17 h
Yield: 26.8 %

Procedure:
To a solution of methylhydroxylamine HCl salt (176 mg, 2.1 mmol) in anhydrous MeOH (15 mL) was added NaOMe (25% in MeOH (Wt. %), 0.47 mL, 1.89 mmol), followed by (E)-N-(6-bromo-2-(pyridine-3-yl)chroman-4-ylidene)cyanamide (687 mg, 2.1 mmol). After stirred for 10 mins, the solvent was removed in vacuo. The residue was redissolved in DCM (15 mL). The mixture was filtered, and the solvent was removed to give the residue, which was purified by preparative TLC to give 6-bromo-2′-methyl-2-(pyridine-3-yl)-2′H-spiro-[chroman-4,5′-[1,2,4]oxadiazol]-3′-amine (190 mg, 24%). 1H-NMR (MeOD): 2.18-2.25 (m, 1H), 2.39 (m, 1H), 3.09 (s, 3H), 5.34-5.38 (m, 1H), 6.81-6.86 (t, 1H), 7.37-7.40 (m, 1H), 7.45-7.55 (m, 1H), 7.62 (s, 1H), 7.97-7.99 (m, 1H), 8.52-8.54 (m, 1H), 8.66 (d, 1H).
Reaction SMILES: CS([C:5]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[S:7][N:6]=1)(=O)=O.[CH2:17]([OH:22])[C:18]#[C:19][CH2:20][CH3:21].[H-].[Na+].[Cl-].[Na+]>CN(C)C=O>[Cl:16][C:12]1[CH:11]=[C:10]([C:8]2[S:7][N:6]=[C:5]([O:22][CH2:17][C:18]#[C:19][CH2:20][CH3:21])[N:9]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: CS(=O)(=O)c1nsc(-c2cccc(Cl)c2)n1
Reactant: CCC#CCO
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC#CCOc1nsc(-c2cccc(Cl)c2)n1
Reaction time: 0.5 h
Yield: 81.7 %

Procedure:
In 2.5 ml of N,N-dimethylformamide, 350 mg of 3-methylsulfonyl-5-(3-chlorophenyl)-1,2,4-thiadiazole and 117 mg of 2-pentyne-1-ol were dissolved, to the resulting solution was added 56 mg of sodium hydride (60% oily) with ice-cooling, and the mixture was stirred for 30 minutes, and further stirred at room temperature for 1 hour. Then, the reaction mixture was poured into an aqueous saturated sodium chloride solution, and the mixture was extracted with t-butyl methyl ether. The residue obtained by concentration of the organic layer was subjected to silica gel column chromatography to obtain 290 mg of 5-(3-chlorophenyl)-3-(2-pentynyloxy)-1,2,4-thiadiazole (the compound (78) of the present invention).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:10]=[C:9](Br)[C:8]2[N:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:14][C:7]=2[C:6]=1[O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:4].[CH3:28][O:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C(OCC)(=O)C.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>[CH3:1][O:2][C:3]([C:5]1[N:10]=[C:9]([C:34]2[CH:33]=[CH:32][CH:31]=[C:30]([O:29][CH3:28])[CH:35]=2)[C:8]2[N:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:14][C:7]=2[C:6]=1[O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:4].[CH3:1][O:2][C:3]([C:5]1[N:10]=[C:9]([C:34]2[CH:33]=[CH:32][CH:31]=[C:30]([O:29][CH3:28])[CH:35]=2)[C:8]2[N:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:14][C:7]=2[C:6]=1[OH:21])=[O:4]
Reactant: COc1cccc(B(O)O)c1
Reactant: COC(=O)c1nc(Br)c2nc(-c3ccccc3)oc2c1OC(=O)C(C)(C)C
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: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)c1nc(-c2cccc(OC)c2)c2nc(-c3ccccc3)oc2c1O
Product: COC(=O)c1nc(-c2cccc(OC)c2)c2nc(-c3ccccc3)oc2c1OC(=O)C(C)(C)C
Temperature: 100 °C

Procedure:
Under a nitrogen atmosphere 4-bromo-7-(2,2-dimethyl-propionyloxy)-2-phenyl-oxazolo[4,5-c]pyridine-6-carboxylic acid methyl ester (51 mg, 0.12 mmol), 3-methoxyphenylboronic acid (21.5 mg, 0.14 mmol), potassium carbonate (58.7 mg, 0.43 mmol), and tetrakis(triphenylphosphine)palladium(0) (20.4 mg, 0.018 mmol) were suspended in 3 mL of anhydrous 1,4-dioxane. The reaction mixture was heated at 100° C. for 16 hours, then cooled to room temperature, and diluted with ethyl acetate. The mixture was successively washed with water, saturated sodium bicarbonate, and brine solutions. The organic fraction was dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography eluting from silica gel with a gradient of 0-50% ethyl acetate in hexanes to give 7.5 mg of 7-(2,2-Dimethyl-propionyloxy)-4-(3-methoxy-phenyl)-2-phenyl-oxazolo[4,5-c]pyridine-6-carboxylic acid methyl ester and 24.7 mg of 7-hydroxy-4-(3-methoxy-phenyl)-2-phenyl-oxazolo[4,5-c]pyridine-6-carboxylic acid methyl ester.
Reaction SMILES: [OH:1][C:2]1([C@H:16]2[CH2:21][CH2:20][CH2:19][CH2:18][N:17]2[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:5][N:4]([C:6]([O:8]CC2C=CC=CC=2)=O)[CH2:3]1.CCN(C(C)C)C(C)C.[F:38][C:39]1[C:40]([NH:49][C:50]2[CH:55]=[CH:54][C:53]([I:56])=[CH:52][C:51]=2[F:57])=[C:41]([CH:45]=[CH:46][C:47]=1[F:48])C(F)=O>[Pd].CO>[F:38][C:39]1[C:40]([NH:49][C:50]2[CH:55]=[CH:54][C:53]([I:56])=[CH:52][C:51]=2[F:57])=[C:41]([C:6]([N:4]2[CH2:5][C:2]([C@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][N:17]3[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])([OH:1])[CH2:3]2)=[O:8])[CH:45]=[CH:46][C:47]=1[F:48]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@H]1C1(O)CN(C(=O)OCc2ccccc2)C1
Reactant: O=C(F)c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Agent: [Pd]
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCCC[C@@H]1C1(O)CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.1 %

Procedure:
1,1-Dimethylethyl(2R)-2-(3-hydroxy-1-{[(phenylmethyl)oxy]carbonyl}azetidin-3-yl)piperidine-1-carboxylate (60.8 mg, 0.16 mmol) and 10% Pd/C (30 mg) were taken into methanol (2 mL) and the mixture hydrogenated at ambient pressure for one hour. The suspension was then filtered through a celite pad and concentrated then dried in vacuo to a colorless solid. The solid amine was taken into THF (1 mL) followed by addition of DIPEA (42 μL, 0.24 mmol) and 3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoyl fluoride (63 mg, 0.16 mmol), prepared using procedures similar to those described in Reference 1, and the mixture stirred at room temperature for 30 minutes. The reaction mixture was partitioned with ethyl acetate and 1 N aqueous hydrochloric acid and the organic layer washed with brine, dried over anhydrous magnesium sulfate then filtered and concentrated. Purification of the residue by silica gel flash chromatography using hexanes:ethyl acetate 3:2 as eluent afforded 1,1-dimethylethyl(2R)-2-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]piperidine-1-carboxylate (74.9 mg, 74% yield) as an amorphous solid. 1,1-Dimethylethyl(2R)-2-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]piperidine-1-carboxylate 1H NMR (400 MHz, CDCl3): 8.53 (br s, 0.5H), 8.40 (br s, 0.5H), 7.41-7.38 (dd, 1H), 7.34-7.31 (dt, 1H), 7.17-7.14 (m, 1H), 6.86-6.79 (m, 1H), 6.63-6.587 (m, 1H), 4.24-3.90 (m, 4H), 3.37-3.23 (m, 1H), 2.90-2.80 (m, 1H), 1.85-1.54 (m, 7H), 1.43 (s, 9H); MS (EI) for C26H29F3IN3O4: 576 (M-C4H9+).
Reaction SMILES: [OH:1][CH:2]([CH2:9][CH3:10])[CH:3]([N+:6]([O-:8])=[O:7])[CH2:4][CH3:5].[C:11](OC(=O)C)(=[O:13])[CH3:12]>S(=O)(=O)(O)O.C(Cl)(Cl)Cl>[C:11]([O:1][CH:2]([CH2:9][CH3:10])[CH:3]([N+:6]([O-:8])=[O:7])[CH2:4][CH3:5])(=[O:13])[CH3:12]
Reactant: CCC(O)C(CC)[N+](=O)[O-]
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Product: CCC(OC(C)=O)C(CC)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 10 h
Yield: 86.1 %

Procedure:
A reaction vessel was charged with 4-hydroxy-3-nitrohexane (14.7 g, 100 mmol), acetic anhydride (14.8 ml, 157.3 mmol), chloroform (50 ml) and a few drops of concentrated sulfuric acid, then stirred for 10 hours at room temperature. After the reaction was finished, chloroform (50 ml) was added, and the resulting solution was washed with water, 5% aqueous sodium bicarbonate solution and saturated saline. The obtained organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure, whereby 4-acetoxy-3-nitrohexane (16.3 g, yield 86%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:13])=[C:4]([C:9](F)(F)F)[CH:5]=[CH:6][C:7]=1[F:8].[Al+3].[Cl-:15].[Cl-:16].[Cl-:17]>C(Cl)Cl>[Cl:1][C:2]1[C:3]([F:13])=[C:4]([C:9]([Cl:17])([Cl:16])[Cl:15])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Fc1ccc(C(F)(F)F)c(F)c1Cl
Reactant: [Cl-]
Agent: [Al+3]
Solvent: ClCCl
Product: Fc1ccc(C(Cl)(Cl)Cl)c(F)c1Cl
Temperature: 42 °C
Yield: 86.9 %

Procedure:
216.5 g of 3-chloro-2,4-difluoro-benzotrifluoride in 440 ml of methylene chloride are initially introduced into a stirred apparatus, and 150 g of AlCl3 are introduced in small portions. The reaction is slightly exothermic. When the addition has ended, the mixture is heated under reflux (42° C.) for 2 hours, cooled and poured onto 1 1 of ice-water. After intensive thorough mixing, the mixture is filtered over a suction filter and the organic phase is then separated off. After drying, the methylene chloride phase is distilled. 231 g of 3-chloro-2,4-difluoro-benzotrichloride with a boiling range of 124°-126° C./18 mbar are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Si:11]([CH3:14])([CH3:13])[CH3:12])[C:3]=1[C:4](Cl)=[O:5].[CH2:15]([SH:17])[CH3:16]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Si:11]([CH3:14])([CH3:13])[CH3:12])[C:3]=1[C:4](=[O:5])[S:17][CH2:15][CH3:16]
Reactant: CCS
Reactant: C[Si](C)(C)c1cccc(Cl)c1C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCSC(=O)c1c(Cl)cccc1[Si](C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
The compound of Example b (1.48 g, 0.006 mol), CH2Cl2 (50 mL), ethanethiol (0.44 g, 0.007 mol), and 4-(N,N-dimethylamino)pyridine (0.86 g, 0.007 mol) were allowed to stir at RT overnight. The mixture was washed with 10% HCl and three times with water, dried (MgSO4), and concentrated. The crude product was purified by RC, eluting with 1:3 ethyl acetate/hexanes. The title compound was obtained as a clear oil in 61% yield.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Si:13]([N:20]1[C@H:23]([C@@H:24]2[CH2:28][O:27][C:26]([CH3:30])([CH3:29])[O:25]2)[CH2:22][C:21]1=[O:31])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].[CH:32](=[O:34])[CH3:33]>CCCCCC.O1CCCC1>[Si:13]([N:20]1[C@H:23]([C@@H:24]2[CH2:28][O:27][C:26]([CH3:30])([CH3:29])[O:25]2)[C@@H:22]([C@H:32]([OH:34])[CH3:33])[C:21]1=[O:31])([C:16]([CH3:19])([CH3:17])[CH3:18])([CH3:15])[CH3:14]
Reactant: CC=O
Reactant: CC1(C)OC[C@@H]([C@@H]2CC(=O)N2[Si](C)(C)C(C)(C)C)O1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: C[C@@H](O)[C@H]1C(=O)N([Si](C)(C)C(C)(C)C)[C@@H]1[C@@H]1COC(C)(C)O1
Reaction time: 0.5 h

Procedure:
16.2 ml of a 1.7M solution of butyl lithium in hexane is added dropwise within 5 minutes to a solution (cooled to -65°) of 2.78 g (27.5 mmol) of diisopropylamine in 100 ml of tetrahydrofuran. The resulting mixture is then cooled to -76° and treated after 15 minutes with a solution of 7.14 g (25 mmol) of (S)-1-(t-butyldimethylsilyl)-4-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-azetidinone in 6 ml of tetrahydrofuran. The mixture is stirred at -76° for 30 minutes and then a solution of 2.65 g of acetaldehyde in 5 ml of tetrahydrofuran is added dropwise within 10 minutes thereto. The mixture is stirred for 15 minutes, the cooling bath is removed, the reaction solution is treated with 20 ml of 14 percent (by volume) aqueous ammonium chloride solution and extracted with 100 ml of ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried over sodium sulphate and evaporated in vacuo. The residual oil is taken up in 10 ml of hexane and the solution is left to stand at -20°. Colourless crystals of melting point 80°-90° are obtained. After repeated recrystallization from ethyl acetate/hexane there is obtained (3S,4S)-1-(t-butyldimethylsilyl)-4-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-3-[(R)-1-hydroxyethyl]-2-azetidinone of melting point 95°-96°; [α]D20 =16.6° (c=1, ethyl acetate).
Reaction SMILES: [O:1]([C:8]1[CH:32]=[CH:31][C:11]([O:12][C:13]2[S:14][C:15]([Sn](CCCC)(CCCC)CCCC)=[CH:16][N:17]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=CC=C[CH:3]=1.Br[C:34]1[S:38][C:37]([C:39](=[O:41])[CH3:40])=[CH:36][CH:35]=1>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:2]([O:1][C:8]1[CH:9]=[CH:10][C:11]([O:12][C:13]2[S:14][C:15]([C:34]3[S:38][C:37]([C:39](=[O:41])[CH3:40])=[CH:36][CH:35]=3)=[CH:16][N:17]=2)=[CH:31][CH:32]=1)([CH3:3])[CH3:7]
Reactant: CC(=O)c1ccc(Br)s1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc(Oc2ccc(Oc3ccccc3)cc2)s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(-c2cnc(Oc3ccc(OC(C)C)cc3)s2)s1
Temperature: 60 °C
Yield: 84.8 %

Procedure:
To a degassed solution of Example 2A (550 mg, 1.05 mmol) in N,N-dimethyl formamide (10 mL) at room temperature, was added 1-(5-bromothiophen-2-yl)ethanone (269 mg, 1.31 mmol) followed by dichlorobis(triphenylphosphine)palladium(II) (45 mg, 0.064 mmol). The reaction mixture was heated at 60° C. overnight. The solvent was evaporated under vacuum and the product was purified via silica gel column chromatography using a gradient of 15 to 35% ethyl acetate in hexane to give the desired compound (320 mg). 1H NMR (300 MHz, CDCl3) δ ppm 7.56 (d, J=4.04 Hz, 1H) 7.43 (s, 1H) 7.15-7.24 (m, 2H) 7.02 (d, J=4.04 Hz, 1H) 6.88-6.97 (m, 2H) 4.44-4.62 (heptet, J=5.88 Hz, 1H) 2.54 (s, 3H) 1.36 (d, J=5.88 Hz, 6H). MS (ESI) m/z 360 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH3:11])[C:8](=[O:12])[C:7]2([CH3:14])[CH3:13].C([O-])(=O)C.[Na+].[Br:20]Br>C(Cl)Cl>[Br:20][C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([F:1])[CH:3]=1)[N:9]([CH3:11])[C:8](=[O:12])[C:7]2([CH3:14])[CH3:13]
Reactant: CN1C(=O)C(C)(C)c2cccc(F)c21
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CN1C(=O)C(C)(C)c2cc(Br)cc(F)c21
Temperature: 25 °C
Reaction time: 16 h
Yield: 82 %

Procedure:
7-Fluoro-1,3,3-trimethyl-1,3-dihydro-2H-indol-2-one (0.10 g, 0.52 mmol) was dissolved in 5 mL of CH2Cl2 and sodium acetate (47 mg, 0.56 mmol) was added followed by bromine (0.029 mL, 0.56 mmol). The mixture was stirred at 25° C. for 16 h then loaded directly onto a silica gel column. The column was eluted with 250 mL of CH2Cl2 and 250 mL 5% Acetone/CH2Cl2 to provide the title compound (116 mg) as a white solid (82%).
Reaction SMILES: B.CSC.[F:5][C:6]([F:18])([F:17])[C:7]([C:13]([F:16])([F:15])[F:14])([OH:12])[CH2:8][C:9]([CH3:11])=[CH2:10].[OH-:19].[Na+]>C1COCC1>[F:5][C:6]([F:17])([F:18])[C:7]([C:13]([F:14])([F:15])[F:16])([OH:12])[CH2:8][CH:9]([CH3:11])[CH2:10][OH:19]
Reactant: [OH-]
Reactant: C=C(C)CC(O)(C(F)(F)F)C(F)(F)F
Agent: B
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CSC
Product: CC(CO)CC(O)(C(F)(F)F)C(F)(F)F
Yield: 83.3 %

Procedure:
To a 3-necked, 500 mL round bottomed flask equipped with an overhead stirrer, digital thermometer and a 125 mL constant-pressure addition funnel with a nitrogen inlet was added 27 mL (0.27 mol) of borane-dimethylsulfide complex (10.0M in THF). The addition funnel was charged with a solution of 50 g (0.23 mol) of 1,1,1-trifluoro-2-trifluoromethyl-4-methyl-pent-4-en-2-ol (1) in 140 mL of anhydrous THF. The flask was cooled and the olefin was added slowly with stirring while maintaining a temperature below 15° C. The mixture was stirred at room temperature overnight after which time it was recooled and 100 mL (0.3 mol) of 3M NaOH (aq) was added carefully. The reaction mixture was reduced in volume on a rotary evaporator and subsequently co-evaporated with two 500 mL portions of diethyl ether. The resulting heavy oil was taken up in 50 mL of THF and the solution transferred to a 250 mL 3-necked round bottomed flask equipped with a 125-mL addition funnel, a digital thermometer, and a magnetic stirbar. The addition funnel was charged with 70 mL of 30% hydrogen peroxide. The flask was cooled and the hydrogen peroxide added slowly with stirring. After stirring overnight at room temperature, the solution was diluted with 500 mL of diethyl ether and adjusted to pH 6 (wet litmus) with 5% HCl. The ether layer was separated and the aqueous layer was extracted with 2×250 mL of ether. The combined organic phases were washed with 2×500 mL of saturated ammonium chloride and brine, dried over MgSO4, and evaporated to a yellow oil. The oil was purified by distillation through a Vigreux column, bp 57° C.@1.0 mm Hg to yield 46 g (85%) of (2) as a low melting solid. The identity of the product was confirmed using 1H NMR spectroscopy and HRMS.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=1.C(N(CC)CC)C.[C:29](Cl)(=[O:32])[CH:30]=[CH2:31].C(=O)(O)[O-].[Na+]>CN(C=O)C.C1COCC1>[C:12]([C:6]1[CH:7]=[N:8][C:9]2[C:4]([C:5]=1[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=1)=[CH:3][C:2]([NH:1][C:29](=[O:32])[CH:30]=[CH2:31])=[CH:11][CH:10]=2)#[N:13]
Reactant: Cc1cccc(Nc2c(C#N)cnc3ccc(N)cc23)c1
Reactant: C=CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=CC(=O)Nc1ccc2ncc(C#N)c(Nc3cccc(C)c3)c2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 39.8 %

Procedure:
Dissolved 500 mg (1.82 mmol) of 6-amino-4-[(3-methylphenyl)amino]-3-quinolinecarbonitrile in 1.0 ml DMF and 6 ml THF and chilled to 0° C. under N2. Added 280 μl (2.00 mmol) triethylamine and 166 μl (2.00 mmol) acryloyl chloride. Removed ice bath at 15 minutes and at 1 hour, stripped solvent and slurried residue with dilute sodium bicarbonate. Collected crystals and washed with water. Boiled solids in ethyl acetate, collected and dried in vacuo, giving 238 mg of yellow-orange solid: mass spectrum (electrospray m/e): M+H=329.1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:14](=O)([O-])[O-].[K+].[K+].[CH3:20][O:21][C:22](=[O:35])[CH:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=1>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:23]([C:22]([O:21][CH2:20][CH3:14])=[O:35])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(Br)c1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(c1cccc(C(F)(F)F)c1)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.7 %

Procedure:
A mixture of Piperazine-1-carboxylic acid tert-butyl ester (1.80 g, 9.68 mmol), potassium carbonate (2.0 g, 14.5 mmole) and Bromo-(3-trifluoromethyl-phenyl)-acetic acid methyl ester (3.0 g, 9.65 mmol) in N,N-dimethylformamide (40 mL) was stirred at room temperature overnight. Concentration gave a crude material which was partitioned between methylene chloride and water. The organic layer was dried over magnesium sulfate and concentrated to give an oil. The crude oil was loaded onto an Isco 120 g column and eluted using 20% ethyl acetate/hexanes to yield 4-[Ethoxycarbonyl-(3-trifluoromethyl-phenyl)-methyl]-piperazine-1-carboxylic acid tert-butyl ester (3.0 g, 74% yield) as a colorless oil. The NMR spectrum obtained on the sample is compatible with its structure.