Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[OH:2][CH2:3][CH2:4][CH2:5][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[C:30]([O:33][CH2:34][C@@H:35]1[C@:43]2([CH3:44])[C@@:38]([OH:47])([CH2:39][C@@H:40]([CH:45]=O)[CH2:41][CH2:42]2)[CH2:37][CH2:36]1)(=[O:32])[CH3:31]>C1COCC1.CCCCCC>[C:30]([O:33][CH2:34][C@@H:35]1[C@:43]2([CH3:44])[C@@:38]([OH:47])([CH2:39][C@@H:40](/[CH:45]=[CH:5]/[CH2:4][CH2:3][OH:2])[CH2:41][CH2:42]2)[CH2:37][CH2:36]1)(=[O:32])[CH3:31]
Reactant: CC(=O)OC[C@H]1CC[C@]2(O)C[C@@H](C=O)CC[C@]12C
Reactant: OCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(=O)OC[C@H]1CC[C@]2(O)C[C@@H](/C=C/CCO)CC[C@]12C
Temperature: -25 °C
Reaction time: 1 h
Yield: 59.8 %

Procedure:
To a suspension of 23.0 g of (3-hydroxypropyl)triphenylphosphonium bromide in 280 ml of anhydrous THF cooled at -25° C., 36.0 ml of 1.6N n-butyllithium in n-hexane were added dropwise under a nitrogen atmosphere and the mixture was stirred at -25° C. for 1 hr. A solution of 3.20 g of (1S,3aS,5S,7aR)-1-acetoxymethyl-3a-hydroxy-5-formyl-7a-methylperhydroindene in 32 ml of anhydrous THF was added and the reaction mixture was kept at -20° C. for 4 hrs, then warmed to room temperature and stirred for 3 hrs. The mixture was diluted with 5% aqueous NaH2PO4.H2 O, concentrated under reduced pressure and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by flash-chromatography (SiO2) with n-hexane/chloroform/acetone 6:2:2 to give 2.23 g of (1S,3aS,5S,7aR)-1-acetoxymethyl-5-[(E)-4-hydroxy-1-butenyl)-7a-methylperhydro-inden-3a-ol from which, by reaction with tert-butyldimethyl-chlorosilane, following the procedure, described in Prepn. 1, 2.94 g of (1S,3aS,5S,7aR)-1-acetoxymethyl-5-[(E)-4-tert-butyldimethylsilyl-oxy-1-butenyl)-7a-methylperhydroinden-3a-ol were obtained as a white foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:6][CH2:7][C:8](=[O:12])[NH:9][C:10]=2[N:11]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:19](Cl)[C:20]1[CH:27]=[CH:26][C:23]([O:24][CH3:25])=[CH:22][CH:21]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:6][CH2:7][C:8](=[O:12])[N:9]([CH2:19][C:20]3[CH:27]=[CH:26][C:23]([O:24][CH3:25])=[CH:22][CH:21]=3)[C:10]=2[N:11]=1
Reactant: O=C1CSc2ccc(Cl)nc2N1
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(CN2C(=O)CSc3ccc(Cl)nc32)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A suspension of 6-chloro-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one (prepared as described in WO 2010/041194, 0.8 g, 3.99 mmol), Cs2CO3 (1.56 g, 4.78 mmol) and PMB-Cl (0.61 mL, 4.39 mmol) in DMF (8 mL) was stirred at rt for 4 h. The solvent was evaporated to dryness and the residue was partitioned between EA (20 mL) and water (25 mL). The aq. layer was extracted once with EA (15 mL) and the combined org. layers were washed with brine (20 mL), dried over Na2SO4 and concentrated to dryness. The residue (1.39 g) was crystallized in a mixture of ether/Hept (2:3). After filtration, the title compound was obtained as an orange solid (1.2 g, 93% yield).
Reaction SMILES: [CH:1]([N:4]([CH:29]([CH3:31])[CH3:30])[CH2:5][CH2:6][C@@H:7]([C:14]1[CH:19]=[C:18](Br)[CH:17]=[CH:16][C:15]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:3])[CH3:2].[Li]CCCC.CN([CH:40]=[O:41])C.[NH4+].[Cl-]>C(OCC)C.[Li]CCCC.O>[CH:1]([N:4]([CH:29]([CH3:31])[CH3:30])[CH2:5][CH2:6][C@@H:7]([C:14]1[CH:19]=[C:18]([CH:40]=[O:41])[CH:17]=[CH:16][C:15]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)N(CC[C@H](c1ccccc1)c1cc(Br)ccc1OCc1ccccc1)C(C)C
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: CCOCC
Product: CC(C)N(CC[C@H](c1ccccc1)c1cc(C=O)ccc1OCc1ccccc1)C(C)C
Reaction time: 1.5 h
Yield: 100.6 %

Procedure:
n-BuLi (2.5 M in hexane, 19 mL, 47.5 nmol) was added to a solution of to (R)-N,N-diisopropyl-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropanamine (prepared as described in WO 94/11337, Example 1) (8.9 g, 18.52 mmol) in dry diethyl ether (100 mL) kept at −40° C. under nitrogen atmosphere. After 1.5 hour of stirring, additional n-BuLi (10 mL, 25 mmol) was added and after 2 hours another n-BuLi (5 mL, 12.5 mmol) was added. The reaction was then stirred for 15 minutes and DMF (6 mL, 77.8 mmol) was added followed by additional DMF (5 mL, 64.8 mmol) after 20 minutes of stirring. The temperature was allowed to rise to room temperature and after 35 minutes of stirring, NH4Cl (sat.) was added followed by water and diethyl ether. The layers were separated and the aqueous layer was extracted with diethyl ether. The combined organic layers were dried (MgSO4) and the solvent was evaporated. The residue was chromatographed on silica (toluene-triethylamine 90:10) to afford 8 g (100%) of a yellowish oil; 1H NMR (CDCl3) δ0.90 (m, 12H), 2.12-2.40 (m, 4H), 2.95 (m, 2H), 4.44 (t, 1H), 5.10 (s, 2H), 6.95 (d, 1H), 7.15-7.36 (m, 10H), 7.70 (dd, 1H), 7.91 (s, 1H), 9.88 (s, 1H).
Reaction SMILES: Cl.[C:2]([NH2:5])(=[NH:4])[CH3:3].C[O-].[Na+].[F:9][C:10]1[CH:24]=[CH:23][C:13]([CH2:14][CH:15]([C:20](=O)[CH3:21])[C:16](OC)=[O:17])=[CH:12][CH:11]=1.O>CO>[F:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:14][C:15]2[C:16]([OH:17])=[N:4][C:2]([CH3:3])=[N:5][C:20]=2[CH3:21])=[CH:23][CH:24]=1
Reactant: COC(=O)C(Cc1ccc(F)cc1)C(C)=O
Reactant: CC(=N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1nc(C)c(Cc2ccc(F)cc2)c(O)n1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 89.2 %

Procedure:
To a suspension of acetamidine hydrochloride (0.54 g, 5.71 mmol) in methanol (8 mL) was added a 30% solution of sodium methoxide in methanol (1.1 mL, 5.7 mmol), and the resulting solution was stirred at room temperature for 45 min. Then, a solution of methyl 2-(4-fluorobenzyl)-3-oxobutanoate (0.80 g, 3.57 mmol) in methanol (3 mL) was added dropwise, and the resulting mixture was stirred at room temperature for 22 h. Water (100 mL) was added, and the mixture was extracted with chloroform (4×50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated to provide 5-(4-fluorobenzyl)-2,6-dimethylpyrimidin-4-ol (0.74 g, 89% yield) as a colorless solid. 1H NMR (400 MHz, methanol-d4): 7.21 (m, 2H), 6.96 (m, 2H), 3.84 (s, 2H), 2.35 (s, 3H), 2.25 (s, 3H); MS (EI) for C13H13FN2O: 233 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH:15]1([NH2:18])[CH2:17][CH2:16]1.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4]([NH:18][CH:15]1[CH2:17][CH2:16]1)=[O:5]
Reactant: NC1CC1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(F)cc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC1CC1)c1cc([N+](=O)[O-])c(F)cc1Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
2 g (9.11 mmol) of 2-chloro-4-fluoro-5-nitrobenzoic acid were dissolved in 91 g of dichloroethane, 22.66 g of thionyl chloride were added and the mixture was boiled until the evolution of gas had ended. The volatile constituents were distilled off and the acid chloride thus obtained was used directly in the next step. 2.166 g (9.1 mmol) of 2-chloro-4-fluoro-5-nitrobenzoyl chloride were dissolved in 100 ml of dichloromethane, this solution was cooled to 0° C., and 0.52 g (9.1 mmol) of cyclopropylamine and 1.38 g (13.65 mmol) of triethylamine were added together, predissolved in 5 ml of dichloromethane. After stirring at room temperature for two hours, the volatile constituents were distilled off, the resulting residue was slurried with a little diethyl ether, the diethyl ether phase was decanted off and the residue was stirred with water.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([CH:13]=[CH2:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=C(C#N)C=1.[OH:23]O>C[Re](=O)(=O)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([CH:13]2[CH2:14][O:23]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Reactant: OO
Agent: C[Re](=O)(=O)=O
Agent: N#Cc1cccnc1
Product: CC(C)(C)OC(=O)N1CC[C@@H](C2CO2)C1
Yield: 64.8 %

Procedure:
To (S)-3-Vinyl-pyrrolidine-1-carboxylic acid t-butyl ester (50 g, 253.4 mmol, 1.0 eq.) was added 3-pyridinecarbonitrile (2.7 g, 25.3 mmol, 0.1 eq.) and methyltrioxorhenium (VII) (1.3 g, 5.1 mmol, 0.02 eq.). The mixture was stirred until homogeneous. 30% Hydrogen peroxide (11.2 g, 329.5 mmol, 1.3 eq.) was added, and the mixture was maintained below 35° C. The mixture was then extracted with EtOAc, washed with water, dried over Na2SO4, and purified by column chromatography (hexanes:EtOAc=1:3, 3 L) to give (R)-3-Oxiranylpyrrolidine-1-carboxylic acid t-butyl ester (35 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12](Br)=[C:11]([Br:16])[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:17][CH:18]([CH3:21])[CH2:19][OH:20]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([O:20][CH2:19][CH:18]([CH3:21])[CH3:17])=[C:11]([Br:16])[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)CO
Reactant: O=c1c(Br)c(Br)cnn1-c1cccc(Cl)c1
Product: CC(C)COc1c(Br)cnn(-c2cccc(Cl)c2)c1=O

Procedure:
The title compound was prepared according to the method of Example 194B, starting with 2-(3-chlorophenyl)-4,5-dibromo-3(2H)-pyridazinone (Example 207A) in place of 2-(4-fluorophenyl)-4,5-dibromo-3(2H)-pyridazinone and substituting 2-methyl-1-propanol in place of methanol.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-])=O)[N:4]([CH2:14][C:15]2N=C(C)S[CH:19]=2)[N:3]=1.[CH3:21][C:22]1[S:23]C(C(OCC)=O)=C[N:26]=1.[NH4+].[Cl-]>CCO.O.[Fe]>[I:1][C:2]1[C:10]2[C:9]([NH2:11])=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]([CH2:14][C:15]2[S:23][C:22]([CH3:21])=[N:26][CH:19]=2)[N:3]=1
Reactant: CCOC(=O)c1cnc(C)s1
Reactant: Cc1nc(Cn2nc(I)c3c([N+](=O)[O-])cccc32)cs1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Cc1ncc(Cn2nc(I)c3c(N)cccc32)s1
Temperature: 85 °C

Procedure:
To a solution 4-((3-iodo-4-nitro-1H-indazol-1-yl)methyl)-2-methylthiazole (prepared according the method of Example 15, Steps A-D, using ethyl 2-methylthiazole-5-carboxylate) in EtOH/H2O (8 mL/2 mL) was added iron (463 mg, 8.30 mmol) and NH4Cl (44.4 mg, 0.830 mmol). The reaction mixture was heated at 85° C. for 3 hours. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. EtOAc/Et3N (40 mL/10 mL) was added to the residue. The mixture was heated at 85° C. for 20 minutes, cooled to 45° C., and filtered through Celite. The Celite pad was washed with MeOH (30 mL). The combined filtrate was concentrated under reduced pressure to remove EtOAc and MeOH. The aqueous suspension was extracted with DCM. The combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure to give the product (156 mg).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][C:5]=1[OH:18])[CH:2]=[CH2:3].[H][H]>C(OCC)(=O)C.[Pd]>[CH2:11]([O:10][C:8]1[CH:7]=[CH:6][C:5]([OH:18])=[C:4]([CH2:1][CH2:2][CH3:3])[CH:9]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: C=CCc1cc(OCc2ccccc2)ccc1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCc1cc(OCc2ccccc2)ccc1O
Yield: 56 %

Procedure:
2-Allyl-4-benzyloxyphenol (WO 9728137 A1 19970807, Adams, A. D. et al.) (5.00 g, 20.8 mmol) in ethyl acetate (40 mL) is treated with 5% Pd/C (0.25 g) and hydrogen (1 atm) at ambient temperature for 18 h. The mixture is filtered and concentrated. The crude product is purified on a Biotage medium pressure chromatography system using a 40 L normal phase cartridge and eluted with 10% ethyl acetate in hexanes to give a tan solid (2.8 g, 56%). Rf=0.33 (25% EtOAc/Hexanes); 1H NMR (400 MHz, CDCl3) δ 7.44-7.31 (m, 5H), 6.78 (s, 1H), 6.69 (d, J=1.5 Hz, 2H), 5.00 (s, 2H), 4.31 (s, 1H), 2.55 (t, J=7.6 Hz, 2H), 1.64 (q, J=7.5 Hz, 2H), 0.97 (t, J=7.3 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][C:9](=[O:20])[C@H:10]([CH3:19])[NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].[CH3:21][O:22][CH2:23][CH2:24][O:25][CH2:26]COCCO.C(N[C@H](C(O)=O)C)(OC(C)(C)C)=O.C1CCC(N=C=NC2CCCCC2)CC1>ClCCl.CO>[CH3:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][C:9](=[O:20])[C@H:10]([CH3:19])[NH:11][C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13]
Reactant: COCCOCCOC(=O)[C@H](C)NC(=O)OC(C)(C)C
Reactant: COCCOCCOCCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: CO
Solvent: ClCCl
Product: COCCOCCOCCOCCOC(=O)[C@H](C)NC(=O)OC(C)(C)C

Procedure:
Compound 2b was prepared using the same procedure as described for the synthesis of 2a with the following reactants and solvents: 2-(2-(2-methoxyethoxy)ethoxy)ethanol (1.32 g, 8 mmol), 4-N,N′-(dimethyl)aminopyridine (100 mg, 0.81 mmol), N-Boc-(L)-Alanine (1.51 g, 8 mmol) and DCC (1.67 g, 8.1 mmol) in dichloromethane (25 mL). Column chromatography (SiO2, 0.060-0.200 mm/1% MeOH in CH2Cl2) yielded compound 2b as a colorless to pale yellow oil (2.35 g, 7.1 mmol, 86%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[N:8]([C:9]=1[C:10]([OH:12])=O)[CH:7]=[CH:6][S:5]2.[N:13]1([CH2:19][C:20]2[CH:34]=[CH:33][C:23]3[NH:24][C:25]([C:27]4[C:31]([NH2:32])=[CH:30][NH:29][N:28]=4)=[N:26][C:22]=3[CH:21]=2)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[N:13]1([CH2:19][C:20]2[CH:34]=[CH:33][C:23]3[NH:24][C:25]([C:27]4[C:31]([NH:32][C:10]([C:9]5[N:8]6[C:4]([S:5][CH:6]=[CH:7]6)=[N:3][C:2]=5[CH3:1])=[O:12])=[CH:30][NH:29][N:28]=4)=[N:26][C:22]=3[CH:21]=2)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: Nc1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1
Reactant: Cc1nc2sccn2c1C(=O)O
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1nc2sccn2c1C(=O)Nc1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1
Reaction time: 20 h
Yield: 19 %

Procedure:
A mixture of 6-methyl-imidazo[2.1-b]thiazole-5-carboxylic acid (Bionet) (61 mg, 0.33 mmol), 3-(5-morpholin-4-ylmethyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-ylamine (100 mg, 0.33 mmol), EDC (77 mg 0.39 mmol) and HOAt (54 mg, 0.39 mmol) was stirred in DMF (3 ml) at 80° C. for 1 h then at ambient temperature for 20 h. The mixture was reduced in vacuo and the residue was partitioned between EtOAc and saturated NaHCO. The organic portion was washed with brine, dried (MgSO4) and reduced in vacuo. The residue was purified by preparative LC/MS to give 6-methyl-imidazo[2.1-b]thiazole-5-carboxylic acid [3-(5-morpholin-4-ylmethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide (29 mg). (LC/MS Basic: Rt 2.56 [M+H]+ 463).
Reaction SMILES: C(O[C@H]1C[N:8]([C:10]([O:12][C:13]([CH3:16])(C)C)=O)[C@@H](C(O)=O)C1)C=C.COC[C@H]1CCCN1C(C1C=C(C=C(C2OC=CN=2)C=1)C(OC)=O)=O.O1C=CN=C1.C([Li])CCC.[CH2:55]([Sn:59](Cl)([CH2:64][CH2:65][CH2:66][CH3:67])[CH2:60][CH2:61][CH2:62][CH3:63])[CH2:56][CH2:57][CH3:58]>C1COCC1>[CH2:64]([Sn:59]([CH2:55][CH2:56][CH2:57][CH3:58])([CH2:60][CH2:61][CH2:62][CH3:63])[C:10]1[O:12][CH:13]=[CH:16][N:8]=1)[CH2:65][CH2:66][CH3:67]
Reactant: C=CCO[C@@H]1C[C@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: COC[C@H]1CCCN1C(=O)c1cc(C(=O)OC)cc(-c2ncco2)c1
Agent: [Li]CCCC
Agent: c1cocn1
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ncco1
Temperature: -78 °C
Reaction time: 1.2 h

Procedure:
Step H (2): Preparation of methyl 3-((R)-2-(methoxymethyl)pyrrolidine-1-carbonyl)-5-(oxazol-2-yl)benzoate. To a solution of oxazole (2.0 g, 29.0 mmol) in THF (30 mL) was added n-butyl lithium (2.0 M solution in cyclohexanes, 16 mL, 31.9 mmol) at −78° C. slowly. The reaction mixture was stirred at −78° C. for 1.2 h, then tributylstannyl chloride (5.0 g, 15.4 mmol) was added. The reaction mixture was warmed up to rt over 3 h. Hexanes (200 mL) was added and the mixture was washed with H2O, dried over Na2SO4 and concentrated under vacuum to give 5.6 g of the 2-(tributylstannyl)oxazole ready for use.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[CH2:15][CH2:16][NH2:17].CCN(CC)CC>C1COCC1>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH2:15][CH2:16][NH:17][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1cccc(CCN)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cccc(CCNC(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 107.3 %

Procedure:
Benzoyl chloride (0.922 g, 6.61 mmol) was added to a solution of 3-methoxyphenethylamine (1.000 g, 6.61 mmol) and Et3N (2.8 ml, 19.8 mmol) in anhydrous THF (30 ml) at rt under N2. The resulting suspension was stirred at rt under N2 for 20 hr. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give 1.811 g of white solid. Purification by flash chromatography, eluting with hexane:EtOAc (7:3) gave 1.689 g (100% yield) of white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH:9]([CH:11]2[CH2:13][CH2:12]2)O)=[C:4]([F:14])[CH:3]=1.FC(F)(F)C(O)=O.[CH3:22][S:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]2[C:33]=1[NH:32][CH:31]=[CH:30]2>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH:9]([CH:11]2[CH2:13][CH2:12]2)[C:30]2[C:29]3[C:33](=[C:25]([CH2:24][S:23][CH3:22])[CH:26]=[CH:27][CH:28]=3)[NH:32][CH:31]=2)=[C:4]([F:14])[CH:3]=1
Reactant: OC(c1c(F)cc(Cl)cc1F)C1CC1
Reactant: CSCc1cccc2cc[nH]c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSCc1cccc2c(C(c3c(F)cc(Cl)cc3F)C3CC3)c[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
617 mg (2.82 mmol) of the compound from Example 156A and 0.26 ml (3.39 mmol) of trifluoroacetic acid were added to 500 mg (2.82 mmol) of the compound from Example 8A in 20 ml of dichloromethane. The reaction mixture was stirred at RT overnight, the solvent was removed in vacuo, and the crude product was then purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 155 mg (14% of theory) of the title compound were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1.[CH2:9](O)[CH2:10][OH:11]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]2[O:11][CH2:10][CH2:9][O:8]2)[S:5][CH:6]=1
Reactant: OCCO
Reactant: O=Cc1cc(Br)cs1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Brc1csc(C2OCCO2)c1
Yield: 97.8 %

Procedure:
A mixture of 4-bromo-thiophene-2-carbaldehyde (175 g, 916 mmol), ethylene glycol (71.1 g, 1.15 mol) and p-toluenesulfonic acid (0.19 g, 1.0 mmol) in toluene (250 mL) is heated to reflux for 7 h using a Dean-Stark apparatus. After cooling, the solution is washed with aq NaHCO3, dried over Na2SO4, filtered and concentrated in vacuo. The residue is distilled to give 2-(4-bromo-thiophen-2-yl)-[1,3]dioxolane (210.6 g, 98%) as a colorless liquid: bp 133-143/11-14 mBar; 1H NMR (CDCl3, 300 MHz) δ 7.21 (s, 1 H), 7.04 (s, 1 H), 6.04 (s, 1 H), 3.95-4.18 (m, 4 H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH2:14][F:15])([CH2:12][F:13])[C@@H:9](O)[C@H:8]([N:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]3=[O:23])[C:7]=2[CH:24]=1)#[N:2].[OH-].[Na+].O1CCOCC1>O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH2:14][F:15])([CH2:12][F:13])[CH:9]=[C:8]([N:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]3=[O:23])[C:7]=2[CH:24]=1)#[N:2]
Reactant: N#Cc1ccc2c(c1)[C@@H](n1ccccc1=O)[C@H](O)C(CF)(CF)O2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1ccc2c(c1)C(n1ccccc1=O)=CC(CF)(CF)O2

Procedure:
A mixture of 0.13 g of trans-6-cyano-2,2-bisfluoromethyl-3,4-dihydro-4-(1,2-dihydro-2-oxo-1-pyridyl)-2H-1-benzopyran-3-ol, 0.13 g of sodium hydroxide on support and 2 ml of dioxane was refluxed for 45 minutes. Water was added thereto and the mixture was extracted with ethyl acetate. After the organic layer was washed with water and dried, the solvent was distilled off. The resultant residue was recrystallized from ethyl acetate to obtain 6-cyano-2,2-bisfluoromethyl-4-(1,2-dihydro-2-oxo-1-pyridyl)-2H-1-benzopyran represented by the following formula having melting point of 174°-175° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])[N:3]=1.[C:16](#[N:19])[CH:17]=[CH2:18].C(Cl)(Cl)Cl>C(O)(C)(C)C>[C:16]([CH2:17][CH2:18][NH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][NH:9][C:4]1[N:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[N:3]=1)#[N:19]
Reactant: C=CC#N
Reactant: Cc1cc(C)nc(NCCCCCN)n1
Solvent: ClC(Cl)Cl
Solvent: CC(C)(C)O
Product: Cc1cc(C)nc(NCCCCCNCCC#N)n1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 85.8 %

Procedure:
To a stirred solution of (XII) (966 mg) in t-butanol was added 250 mg of acrylonitrile dissolved in 1 ml t-butanol over a period of 1 hour. Continued stirring for 3.5 hours at room temperature and finally refluxed for 1.5 hours. Chloroform was added and the product was extracted into 1N H2SO4. The aqueous phase was washed once with CHCl3, then basified to pH 10 with 2N NaOH and the free amine extracted into CHCl3. The product (XIII) 1.04 g was obtained by evaporation of the solvents under vacuum.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:13][CH2:12]3)=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1.C1C(=O)N([I:34])C(=O)C1>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[O:18])[CH2:13][CH2:12]3)=[N:9][C:10]=2[I:34])[CH:5]=[CH:6][N:7]=1
Reactant: O=C(OCc1ccccc1)N1CCC(c2ncc3c(Cl)nccn23)CC1
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)N1CCC(c2nc(I)c3c(Cl)nccn23)CC1
Temperature: 55 °C
Reaction time: 20 h

Procedure:
To a solution of benzyl 4-(8-chloroimidazo[1,5-a]pyrazin-3-yl)piperidine-1-carboxylate (1.31 g, 0.00354 mol) in DMF (0.6 mL) was added NIS (1.6 g, 0.0071 mol). The reaction mixture was left to stir at 55° C. for 20 h. then the mixture was diluted with EtOAc (20 mL), washed with water (2×40 mL) and brine, then dried over Na2SO4 and concentrated in vacuo. The crude reaction mixture was chromatographed over silica gel eluting with hexane→hexane:EtOAc 1:1 yielding 1.63 g of desired product. 1H NMR (400 MHz, CDCl3): δ 1.95-2.04 (m, 4H), 3.02-3.15 (m, 3H), 4.29-4.32 (m, 2H), 5.15 (s, 2H), 7.32 (d, J=5.2 Hz, 1H), 7.34-7.37 (m, 5H), 7.66 (d, J=5.2 Hz, 1H). MS (ES+): m/z 497.03 [MH+].
Reaction SMILES: O1CCCC1.C1(C)C=CC=CC=1.[C:13]1([Mg]Br)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:21][C:22](=[O:26])[C:23](=[O:25])[CH3:24]>C1COCC1.C1(C)C=CC=CC=1>[OH:26][C:22]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:21])[C:23](=[O:25])[CH3:24]
Reactant: CC(=O)C(C)=O
Reactant: Br[Mg]c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(=O)C(C)(O)c1ccccc1
Yield: 68 %

Procedure:
The process can also be run in mixtures of tetrahydrofuran and toluene, thereby making the process more economical. When 1.1 equivalent of phenylmagnesium bromide (1.9M in 50% THF/PhMe) was added to 2,3-butanedione in 50% THF/PhMe, crude product was isolated in 82.4% yield (Run 10, Table IV) after work-up. Short path vacuum distillation gave 3-hydroxy-3-phenylbutan-2-one in 68% yield. Alternatively, preparation of phenylmagnesium bromide in 38% THF/PhMe, followed by reaction with 2,3-butanedione in 38% THF/PhMe afforded 3-hydroxy-3-phenylbutan-2-one in 66.4% yield (Run 11, Table IV) after work-up and distillation. Similarly phenylmagnessium bromide in 25% THR/PheMe reacted with 2,3-butanedione in 25% THF/PheMe yielded 3-hydroxy-3-phenylbutan-2-one in 56.9% yield after work-up and distillation.