Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:10][C:11]([O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:12])=[CH:5][CH:4]=1)#[N:2].[Al](Br)(Br)Br.[Cl:24][C:25]([Cl:29])([Cl:28])[C:26]#[N:27]>>[Cl:24][C:25]([Cl:29])([Cl:28])[C:26]1[N:27]=[C:26]([C:25]([Cl:29])([Cl:28])[Cl:24])[N:27]=[C:1]([C:3]2[CH:4]=[CH:5][C:6]([S:9][CH2:10][C:11]([O:13][CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)=[O:12])=[CH:7][CH:8]=2)[N:2]=1
Reactant: N#Cc1ccc(SCC(=O)OC2CCCCC2)cc1
Reactant: N#CC(Cl)(Cl)Cl
Agent: Br[Al](Br)Br
Product: O=C(CSc1ccc(-c2nc(C(Cl)(Cl)Cl)nc(C(Cl)(Cl)Cl)n2)cc1)OC1CCCCC1
Reaction time: 24 h
Yield: 89 %

Procedure:
A mixed solution containing 10 g of cyclohexyl 2-(4-cyanophenylthio)acetate (36.3 mmol), 0.8 g of AlBr3 and 50 g of trichloroacetonitrile was bubbled with dry HCl at room temperature. The process of reaction was checked by TLC. The reaction product was formed gradually with the lapse of time while precipitation was formed. After 24 hours, the reaction mixture was quenched and extracted with 500 mL of chloroform. The resultant product was washed with deionized water and dried over anhydrous magnesium sulfate. Volatile substances were removed from the dried product under vacuum and the target product was separated by column chromatography using hexane/ethyl acetate (3/1) as eluent (yield: 89%). Then, the product was subjected to structural analysis by NMR, FT-IR and UV-Vis. spectrophotometers.
Reaction SMILES: C(O)C.B([O-])([O-])O[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH3:15])=[C:8]([CH3:16])[CH:7]=1.Br[C:20]1[CH:21]=[CH:22][C:23]2[S:29](=[O:31])(=[O:30])[CH2:28][CH2:27][C:26]([C:32]([NH:34][C:35]3[CH:40]=[CH:39][C:38]([CH2:41][N:42]([CH3:49])[CH:43]4[CH2:48][CH2:47][O:46][CH2:45][CH2:44]4)=[CH:37][CH:36]=3)=[O:33])=[CH:25][C:24]=2[CH:50]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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.O>[CH3:16][C:8]1[CH:7]=[C:6]([C:20]2[CH:21]=[CH:22][C:23]3[S:29](=[O:31])(=[O:30])[CH2:28][CH2:27][C:26]([C:32]([NH:34][C:35]4[CH:40]=[CH:39][C:38]([CH2:41][N:42]([CH3:49])[CH:43]5[CH2:48][CH2:47][O:46][CH2:45][CH2:44]5)=[CH:37][CH:36]=4)=[O:33])=[CH:25][C:24]=3[CH:50]=2)[CH:11]=[CH:10][C:9]=1[O:12][CH2:13][CH2:14][CH3:15]
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Reactant: CCCOc1ccc(OB([O-])[O-])cc1C
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: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)cc1C
Reaction time: 0.5 h
Yield: 47.4 %

Procedure:
In toluene (23 ml), ethanol (2.3 ml) and water (2.3 ml) were suspended 3-methyl-4-propoxyphenyl borate (219 mg), 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (450 mg) and potassium carbonate (312 mg), and the suspension was stirred under argon atmosphere for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (70 mg), and the mixture was stirred, under argon atmosphere, at 100° C. for 8 hours and cooled. To the mixture was added water, and the mixture was extracted with ethyl acetate (twice). The organic layer was washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography and recrystallized from ethanol (125 ml) to give colorless crystals of 7-(3-methyl-4-propoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 137) (242 mg).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:10][CH2:11][O:12][CH2:13][CH:14]=2)O1.Br[C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([N+:26]([O-:28])=[O:27])[CH:24]=2)[N:19]([C:29]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:18]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[O:12]1[CH2:13][CH:14]=[C:9]([C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([N+:26]([O-:28])=[O:27])[CH:24]=3)[N:19]([C:29]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[N:18]=2)[CH2:10][CH2:11]1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: O=[N+]([O-])c1ccc2c(c1)c(Br)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc2c(c1)c(C1=CCOCC1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 80 °C
Yield: 64.8 %

Procedure:
A mixture containing 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyran (0.8 g, 3.8 mmol), 3-Bromo-5-nitro-1-trityl-1H-indazole (2 g, 4.0 mmol), PdCl2(dppf) (150 mg, 0.2 mmol) and potassium phosphate (2.6 g, 12 mmol) in dioxane (10 mL) was flushed with Ar and was heated at 80° C. for overnight under Ar. LC-MS indicated the completion of reaction and the mixture was filter through celite. The filtrate was concentrated and was purified on a column (10 hexane in dichloromethane) to give 1.2 g of product (64% yield).
Reaction SMILES: [F:1][C:2]1[C:12]2[O:11][CH2:10][CH2:9][CH2:8][O:7][C:6]=2[C:5]([O:13][CH3:14])=[CH:4][C:3]=1[CH:15]([NH:31][C:32]1[CH:37]=[CH:36][C:35]([C:38](=[NH:41])[NH:39]O)=[CH:34][CH:33]=1)[C:16]1[NH:20][C:19](=[O:21])[N:18]([C:22]2[N:30]=[CH:29][CH:28]=[CH:27][C:23]=2[C:24]([OH:26])=[O:25])[N:17]=1.O.C(O)(=O)C>CO.[Fe]>[C:38]([C:35]1[CH:36]=[CH:37][C:32]([NH:31][CH:15]([C:3]2[CH:4]=[C:5]([O:13][CH3:14])[C:6]3[O:7][CH2:8][CH2:9][CH2:10][O:11][C:12]=3[C:2]=2[F:1])[C:16]2[NH:20][C:19](=[O:21])[N:18]([C:22]3[N:30]=[CH:29][CH:28]=[CH:27][C:23]=3[C:24]([OH:26])=[O:25])[N:17]=2)=[CH:33][CH:34]=1)(=[NH:39])[NH2:41]
Reactant: COc1cc(C(Nc2ccc(C(=N)NO)cc2)c2nn(-c3ncccc3C(=O)O)c(=O)[nH]2)c(F)c2c1OCCCO2
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: COc1cc(C(Nc2ccc(C(=N)N)cc2)c2nn(-c3ncccc3C(=O)O)c(=O)[nH]2)c(F)c2c1OCCCO2
Temperature: 60 °C
Reaction time: 30 h

Procedure:
To a solution of 61 mg of 2-(3-{(6-fluoro-9-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-[4-(N-hydroxycarbamimidoyl)phenylamino]methyl}-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl)nicotinic acid in 6 ml of a methanol:water:acetic acid=1:1:1 mixed solvent there was added 60 mg of iron powder, and the mixture was stirred at 60° C. for 30 hours under a nitrogen atmosphere. Upon cooling, the reaction mixture was filtered through celite and purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% trifluoroacetic acid) to give 2-{3-[(4-carbamimidoylphenylamino)-(6-fluoro-9-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)methyl]-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl}nicotinic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]#[N:11].Cl.[N:13]1[CH:18]=[CH:17][C:16]([CH2:19]Cl)=[CH:15][CH:14]=1.[OH-].[Na+].O>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C1(C)C=CC=CC=1>[N:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:9]([CH2:19][C:16]2[CH:17]=[CH:18][N:13]=[CH:14][CH:15]=2)([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[C:10]#[N:11])=[CH:15][CH:14]=1
Reactant: ClCc1ccncc1
Reactant: COc1ccccc1CC#N
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccccc1C(C#N)(Cc1ccncc1)Cc1ccncc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 73 %

Procedure:
To a mechanically stirred slurry of (2-methoxyphenyl)acetonitrile (10.0 g, 68 nmol ), 4-picolyl chloride hydrochloride (25.0 g, 152 nmol), and 1.2 g benzyltriethylammonium chloride in toluene (200 ml) at room temperature was added 50% NaOH (50 ml) over a period of 15 min. After addition was complete, the reaction mixture was slowly heated to 50° and maintained at that temperature for approx. 3 h. Completion of the reaction was determined by TLC. While still stirring the reaction mixture at 50°, 70 ml of water was added, and stirring was continued for 15 min. The mixture was cooled to room temperature, and the layers were separated. To the toluene layer was added 14.0 g Magnesol (an intimate mixture of silica gel and magnesium sulfate), and the solution was stirred at 50° for 30 min. The solution was filtered, and the solvent was removed under reduced pressure. The subsequent oil was purified via column chromatography (silica gel, 10% methanol/methylene chloride) to give α,α-Bis(4-pyridinylmethyl)2-methoxybenzeneacetonitrile as a solid, 16.4 g, 73% yield. NMR (200 MHz, CDCl3) δ 3.26 (d, 2H, J=13 Hz); 3.88 (d, 2H, J=13 Hz); 4.07 (s, 3H); 6.70 (m, 6H); 7.00 (m, 6H); 7.30 (m, 1H); 8.38 (m, 4H). Mass Calcd. for C21H19N3O: 329.1528. Found: 329.1505.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].CCN(C(C)C)C(C)C.[C:15]([N:22]1[CH2:30][CH2:29][CH:25]([C:26]([OH:28])=O)[CH2:24][CH2:23]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CNOC>ClCCl.CN(C=O)C>[C:18]([O:17][C:15]([N:22]1[CH2:23][CH2:24][CH:25]([C:26](=[O:28])[N:3]([O:4][CH3:5])[CH3:2])[CH2:29][CH2:30]1)=[O:16])([CH3:19])([CH3:20])[CH3:21]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Yield: 79.2 %

Procedure:
N,O-dimethylhydroxylamine hydrochloride (851 mg, 8.72 mmols) was suspended in dichloromethane (6 ml) and cooled to 0 C. N,N′-diisopropylethylamine (1.66 ml, 9.53 mmols) was added and the mixture was stirred at 0 C until a clear solution was obtained. The resulting solution was kept at 0 C for further use. Boc-isonipecotic acid (2 g, 8.72 mmol), 1-hydroxybenzotriazole (1.2 g, 8.88 mmols) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCl) (1.83 g, 9.58 mmols) were dissolved in DMF (15 ml) and cooled to 0 C. The solution of N,O-dimethylhydroxylamine in dichloromethane was added with stirring, and the resulting reaction mixture was allowed to stir overnight at room temperature. DMF was removed under reduced pressure and residue was partitioned between ethyl acetate and 10% citric acid. Organic layer was isolated, washed with water, saturated NaHCO3, water and brine and dried over MgSO4. Solvent was removed under reduced pressure and the residue was purified on silica gel eluting with ethyl acetate in hexanes (2:1) to provide the title compound (1.88 g, 79%). LCMS m/e (295, M+Na).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]2[CH:18]=[CH:19][C:20]([NH:23]CC3C=CC(OC)=CC=3)=[N:21][CH:22]=2)=[N:5][C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[N:7][CH:8]=1)#[N:2].C([O-])(O)=O.[Na+]>C(#N)C.CO.ClCCl.O>[NH2:23][C:20]1[CH:19]=[CH:18][C:17]([C:4]2[C:3]([C:1]#[N:2])=[CH:8][N:7]=[C:6]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[N:5]=2)=[CH:22][N:21]=1
Reactant: COc1ccc(CNc2ccc(-c3nc(Nc4ccc(F)cc4)ncc3C#N)cn2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: N#Cc1cnc(Nc2ccc(F)cc2)nc1-c1ccc(N)nc1
Yield: 57.1 %

Procedure:
To a suspension of 5-cyano-N-(4-fluorophenyl)-4-[2-(4-methoxy-benzylamino)pyridin-5-yl]pyrimidine-2-amine (104 mg, 0.24 mmol) in acetonitrile (4 mL), MeOH (2 mL) and dichloromethane (2 mL), was added dropwise a solution of ceric ammonium nitrate (133 mg, 0.24 mmol) in water (1 mL). After 0.5 h the reaction was poured into saturated NaHCO3 and extracted with CHCl2. The organic phase was dried (MgSO4) and concentrated under reduced pressure to give the title compound (42 mg) as a buff solid, m.p. 289°. δH (d6 DMSO) 9.93 (1H, s), 8.76 (1H, d, J 2.3 Hz), 8.74 (1H, s), 8.09 (1H, dd, J 8.8, 2.5 Hz), 7.77-7.73 (2H, bm), 7.18-7.13 (2H, m), 6.85 (1H, s) and 6.63 (1H, d, J 8.8 Hz).
Reaction SMILES: C([Li])CCC.[CH2:6]([NH:10][C:11](=[O:15])[C:12]([CH3:14])=[CH2:13])[CH2:7][CH2:8][CH3:9].[C:16]([O:20][C:21]([NH:23][C@@H:24]([CH2:27][C@H:28]([CH3:42])[CH2:29][CH2:30][O:31][Si:32]([CH:39]([CH3:41])[CH3:40])([CH:36]([CH3:38])[CH3:37])[CH:33]([CH3:35])[CH3:34])[CH:25]=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17].[Cl-].[NH4+]>CCCCCC.O1CCCC1.Cl[Ti](OC(C)C)(OC(C)C)OC(C)C>[CH2:6]([NH:10][C:11](=[O:15])[C:12](=[CH2:14])[CH2:13][C@H:25]([OH:26])[C@@H:24]([NH:23][C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])[CH2:27][C@H:28]([CH3:42])[CH2:29][CH2:30][O:31][Si:32]([CH:36]([CH3:37])[CH3:38])([CH:39]([CH3:40])[CH3:41])[CH:33]([CH3:35])[CH3:34])[CH2:7][CH2:8][CH3:9]
Reactant: CC(C)[Si](OCC[C@@H](C)C[C@@H](C=O)NC(=O)OC(C)(C)C)(C(C)C)C(C)C
Reactant: C=C(C)C(=O)NCCCC
Agent: CC(C)O[Ti](Cl)(OC(C)C)OC(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=C(C[C@H](O)[C@H](C[C@H](C)CCO[Si](C(C)C)(C(C)C)C(C)C)NC(=O)OC(C)(C)C)C(=O)NCCCC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
23.9 ml of a 1.6M n-butyllithium solution in hexane are added to a solution of 2.7 g of methacrylic acid butylamide in 80 ml of tetrahydrofuran at -75° C. under argon in the course of 30 min. The reaction mixture is then stirred at 0° C. for 30 min. After cooling to -75° C., 29.0 ml of a 1.0M chlorotriisopropyloxytitanium solution in hexane is added dropwise to the clear solution in the course of 30 min, the dark-coloured reaction mixture is stirred at -75° C. for a further 15 min, and a solution of 3.1 g of 2(S)-tert-butoxycarbonylamino-4(S)-methyl-6-triisopropylsilyloxyhexanal in 18 ml of tetrahydrofuran is then added in the course of 10 min. After the mixture has been stirred at -75° C. for 1 h, 19 ml of saturated ammonium chloride solution are added dropwise and, after warming to room temperature, the white suspension is extracted with diethyl ether. The organic phase is washed with 25 ml of water and 25 ml of saturated sodium chloride solution, dried over sodium sulfate and concentrated. The crude product is purified by means of FC over 400 g of silica gel (mobile phase gradient from D to B), the stereoisomers being separated. This gives the title compound (diastereomer I): Rf (A)=0.53; and diastereomer II: Rf (A)=0.45.
Reaction SMILES: [OH:1][CH:2]1[CH:6]=[CH:5][C:4](=O)[CH:3]1[CH2:8][CH2:9][CH2:10][CH2:11][S:12][CH2:13][C:14]([O:16]CC)=[O:15].S(=O)(=O)(O)[OH:20].[Cl-].[Na+]>>[OH:20][CH:5]1[CH2:6][C:2](=[O:1])[C:3]([CH2:8][CH2:9][CH2:10][CH2:11][S:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:4]1
Reactant: CCOC(=O)CSCCCCC1C(=O)C=CC1O
Reactant: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Product: O=C(O)CSCCCCC1=CC(O)CC1=O

Procedure:
The solution, containing crude 3-hydroxy-2-[4-(carbethoxymethylthio)butyl]cyclopent-4-en-1-one, is cooled and treated during 10 minutes with 75 ml of sulfuric acid (d=1.84) with stirring. The stirred solution is refluxed for about 16 hours, cooled, saturated with sodium chloride, and extracted with ethyl acetate. The extract is washed with brine, dried over magnesium sulfate, and concentrated. The residue is chromatographed on silica gel and is eluted with chloroform progressively enriched in ether, ether, and ether progressively enriched in acetone to afford the subject compound as an oil; pmr spectrum (CDCl3): δ3.24 (singlet, --SCH2CH3) 5.0 (broad singlet, --CHOH--), and 7.38 (singlet, vinyl hydrogen).
Reaction SMILES: OC(C)(C)[C@@H:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])C)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10].CC(C)([O-])C.[K+].CCOC(C)=O>C1COCC1.CCCCCC>[CH3:17][C:14]1([CH3:16])[O:13][C:12](=[O:18])[NH:11][C@H:3]1[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10]
Reactant: Cc1ccccc1[C@H](NC(=O)OC(C)(C)C)C(C)(C)O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1ccccc1[C@@H]1NC(=O)OC1(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-tert-butyl (2-hydroxy-2-methyl-1-(o-tolyl)propyl)carbamate (1 g, 3.5 mmol) in THF (20 mL) was added potassium tert-butoxide (803.37 mg, 7.1 mmol) at 0-5° C. The resulting reaction mixture was stirred for 2 hours at ambient temperature. After completion of the reaction (monitored by TLC, TLC system: 50% EtOAc in hexane), the reaction mixture was quenched with ice water and extracted with EtOAc. The combined organic layers were washed with, water, washed with saturated NaCl solution, dried with Na2SO4, filtered and evaporated to afford (S)-5,5-dimethyl-4-(o-tolyl)oxazolidin-2-one, 0.7 g (95.28% Y) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 7.96 (s, 1H), 7.27-7.25 (m, 1H), 7.22-7.19 (m, 3H), 4.83 (s, 1H), 2.29 (s, 3H), 1.55 (s, 3H), 0.81 (s, 3H). m/z (ESI) 206.1 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([F:20])=[CH:18][C:17]([F:21])=[C:16](F)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].COCCO[AlH2-]OCCOC.[Na+]>C1(C)C=CC=CC=1.[Cl-].[Cl-].C1([Ti+2]C2C=CC=C2)C=CC=C1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[C:19]([F:20])=[CH:18][C:17]([F:21])=[CH:16][N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(F)c(F)cc2F)CC1
Agent: C1=CC([Ti+2]C2C=CC=C2)C=C1
Agent: COCCO[AlH2-]OCCOC
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(F)cc2F)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(Analogous to the procedure of Hee-Gweon Woo; Bo-Hye, Kim and Sun-Jung Song, Bull. Korean Chem. Soc. 1999, 20, 865-866). 4-(3,5,6-Trifluoro-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester from step (a) above (950 mg, 3 mmol) was added to a mixture of bis(cyclopentadienyl)titanium dichloride (37 mg, 0.15 mmol, Aldrich) and Red-Al (1.32 mL, Aldrich) in toluene (3 mL). The reaction mixture was stirred at room temperature for 3 h and quenched by the addition of water (50 mL). The mixture was extracted with EtOAc (2×40 mL) and the combined organic phases were washed with brine (50 mL), dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography, eluting with 20% EtOAc/hexane to give the title compound as a light-yellow oil. MS (ESI, pos. ion) m/z: 300 (M+1).
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[C:14]([CH3:15])=[CH:13][N:12]=[CH:11][C:10]=2[CH3:16])=[C:4]([CH3:17])[CH:3]=1.[C:18]([C:22]1[CH:27]=[C:26]([CH:28]=[CH2:29])[CH:25]=[C:24]([C:30]([CH3:33])([CH3:32])[CH3:31])[C:23]=1[OH:34])([CH3:21])([CH3:20])[CH3:19].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CC([O-])=O.CC([O-])=O.[Pd+2]>[C:18]([C:22]1[CH:27]=[C:26]([CH:28]=[CH:29][C:2]2[CH:7]=[C:6]([CH3:8])[C:5]([C:9]3[C:14]([CH3:15])=[CH:13][N:12]=[CH:11][C:10]=3[CH3:16])=[C:4]([CH3:17])[CH:3]=2)[CH:25]=[C:24]([C:30]([CH3:33])([CH3:32])[CH3:31])[C:23]=1[OH:34])([CH3:21])([CH3:20])[CH3:19]
Reactant: C=Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: Cc1cncc(C)c1-c1c(C)cc(I)cc1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1cncc(C)c1-c1c(C)cc(C=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc1C
Temperature: 100 °C
Reaction time: 36 h
Yield: 91 %

Procedure:
A flame-dried sealable Schlenk tube was charged with 11 (1.69 g, 5.0 mmol), 12 (2.32 g, 10.0 mmol), Pd(OAc)2 (112 mg, 0.50 mmol), and PPh3 (131 mg, 0.50 mmol), evacuated, and then backfilled with N2. Next, dry Et3N (10 mL) was added under an N2 flow. The Schlenk tube was next sealed, the mixture was degassed by 3 freeze-thaw cycles, and backfilled with N2. The Schlenk tube was then wrapped with aluminum foil and stirred at 100° C. for 36 h. The reaction mixture was then cooled to room temperature, diluted with methylene chloride (50 mL), filtered through a thin pad of silica gel, and concentrated in vacuo to afford a red solid. The crude product was purified by flash chromatography on silica gel, eluting with 3:1 hexane:ethyl acetate to give the title compound 2.01 g (91.2%) as a colorless solid: mp 234-235° C.; 1H NMR (400 MHz, CDCl3): δ 8.402 (s, 2H), 7.371 (s, 2H), 7.307 (s, 2H), 7.133 (d, 1H, J=16.4 Hz), 6.936 (d, 1H, J=16.0 Hz), 5.331 (s, 1H), 1.951 (s, 6H), 1.911 (s, 6H), 1.499 (s, 18H); 13C NMR (100 MHz, CDCl3): δ 153.971, 148.630, 148.502, 137.347, 136.301, 135.928, 134.817, 131.251, 129.595, 128.876, 125.837, 125.709, 123.598, 34.638, 30.534, 19.997, 16.822; HRMS (EI): m/z 441.3023 [M+]; calcd, 441.3032; Anal. Calcd. for C31H39NO.H2O: C, 81.00; H, 8.99; N, 3.05. Found; C, 81.01; H, 8.64; N, 3.02.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[N:17]=[CH:16][N:15]=[C:14]([O:18][C:19]2[C:24]3[N:25]=[C:26]([NH:28][C:29](=[O:31])[CH3:30])[S:27][C:23]=3[CH:22]=[CH:21][CH:20]=2)[CH:13]=1.[CH:32]1([CH:38]=O)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[CH:32]1([CH2:38][NH:1][C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:5]=[CH:4][C:3]=2[C:12]2[N:17]=[CH:16][N:15]=[C:14]([O:18][C:19]3[C:24]4[N:25]=[C:26]([NH:28][C:29](=[O:31])[CH3:30])[S:27][C:23]=4[CH:22]=[CH:21][CH:20]=3)[CH:13]=2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: O=CC1CCCCC1
Reactant: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4N)ncn3)cccc2s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4NCC4CCCCC4)ncn3)cccc2s1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
To a solution of N-{4-[6-(2-amino-4-tri-fluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide, (Example 151), (0.17 g, 0.3 mmol) in 1,2-dichloroethane (10 mL) was added cyclohexanecarboxaldehyde (0.1 g, 0.9 mmol, Aldrich) and the mixture was stirred at 40° C. for 2 h. Sodium triacetoxyborohydride (0.40 g, 1.9 mmol, Aldrich) was added and the reaction mixture was stirred for 18 h at room temperature. After the addition of water (2 mL), the reaction mixture was evaporated in vacuum. The residue was diluted with H2O (10 mL) and extracted with EtOAc (2×20 mL), dried over Na2SO4, filtered, and concentrated in vacuum. Purification of the residue by silica gel chromatography (6:1, hexanes: EtOAc) afforded the title compound as an yellow solid. Mp: 232-234° C. MS(ESI, pos. ion) m/z: 542 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].CC(C)([O-])C.[K+].Br[CH:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:18]>CS(C)=O.[Cl-].[Na+].O>[C:19]1([CH:17]([O:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[CH:5]=[O:6])[CH3:18])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=Cc1cccc(O)c1
Reactant: CC(Br)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(Oc1cccc(C=O)c1)c1ccccc1
Reaction time: 0.33 h
Yield: 60.2 %

Procedure:
To a solution of 3-hydroxybenzaldehyde (5.28 g, 43.2 mmol) in DMSO (80 mls) was added potassium t-butoxide (5.58 g, 49.7 mmol) and the mixture was stirred for 20 mins. (1-Bromoethyl)benzene (10.00 g, 54 mmol) was then added dropwise and the reaction was stirred for 18 hrs. It was then diluted with brine (250 mls) and extracted with ethylacetate (3×250 mls). The organics were combined, dried with MgSO4 and concentrated. The resulting residue was chromatographed (silica gel, hexanes:ether, 92.5:7.5) to afford 5.88 g (60%) of 3-(1-phenylethoxy)benzaldehyde as a pale yellow oil.