Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][N+:10]([O-])=O)=[CH:4][C:3]=1[F:13].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.CCOCC>[F:13][C:3]1[CH:4]=[C:5]([CH2:8][CH2:9][NH2:10])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: O=[N+]([O-])C=Cc1ccc(F)c(F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: NCCc1ccc(F)c(F)c1
Temperature: 40 °C
Yield: 63.6 %

Procedure:
To a solution of 1,2-difluoro-4-(2-nitro-vinyl)benzene (1.5 g) in THF (50 mL) is added dropwise lithium aluminum hydride (23 mL, 1M in ether) and the solution is heated at 40° C. for 3 hours. The solution is cooled, diluted with ether and quenched with Na2SO4.10H2O (104 g) overnight. The solid is filtered, and the solution is evaporated in vacuo and chromatographed on silica gel eluting with EtOAc to afford 2-(3,4-difluoro-phenyl)-ethylamine (0.81 g). MS: 170 (M+H); 1H NMR (300 MHz, CDCl3) □6.9-7 (3H, m); 2.95 (2H, t); 2.7 (2H, t).
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([O:19][C:20](=[O:22])[CH3:21])=[CH:7][C:8]2[S:13][CH:12]=[C:11]([C:14](O)=[O:15])[C:10](=[O:17])[C:9]=2[CH:18]=1)(=[O:3])[CH3:2].S(Cl)([Cl:25])=O>CN(C)C=O.C1C=CC=CC=1>[C:1]([O:4][C:5]1[C:6]([O:19][C:20](=[O:22])[CH3:21])=[CH:7][C:8]2[S:13][CH:12]=[C:11]([C:14]([Cl:25])=[O:15])[C:10](=[O:17])[C:9]=2[CH:18]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc2scc(C(=O)O)c(=O)c2cc1OC(C)=O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CC(=O)Oc1cc2scc(C(=O)Cl)c(=O)c2cc1OC(C)=O

Procedure:
A mixture of 6,7-diacetoxy-4-oxo-4H-1-benzothiopyran-3-carboxylic acid (50 mg), thionyl chloride (40 μL), and dimethylformamide (one drop) was heated under reflux for 2 hours in benzene (20 mL), and then the solvent was distilled off. To the residue was added benzene (20 mL). Benzene was evaporated again and the residue was vacuum dried to give 6,7-diacetoxy-4-oxo-4H-1-benzothiopyran-3-carbonyl chloride.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:6][CH:5]=1.C([Si]([O:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][CH2:45][CH:46]2[CH2:48][O:47]2)=[CH:40][CH:39]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>C(Cl)(Cl)Cl.CO>[OH:47][C@@H:46]([CH2:48][NH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:6][CH:5]=1)[CH2:45][O:44][C:41]1[CH:42]=[CH:43][C:38]([OH:37])=[CH:39][CH:40]=1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Reactant: NCCc1ccc(Nc2ncccc2[N+](=O)[O-])cc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1cccnc1Nc1ccc(CCNC[C@H](O)COc2ccc(O)cc2)cc1
Yield: 6.3 %

Procedure:
N-[4-(2-Aminoethyl)phenyl]-3-nitro-2-pyridinamine (0.87 g, 3.37 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (1.36 g, 3.36 mmol) according to Procedure G (eluant: 20:1 going to 5:1 chloroform-methanol) to give the title compound (0.59 g, 0.21 mmol).
Reaction SMILES: FC(F)(F)S(O[C:7]1[N:8]=[C:9]([N:12]2[C:16]([CH3:18])([CH3:17])[CH2:15][O:14][C:13]2=[O:19])[S:10][CH:11]=1)(=O)=O.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(N(CC)CC)C>O1CCCC1.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>[CH3:18][C:16]1([CH3:17])[CH2:15][O:14][C:13](=[O:19])[N:12]1[C:9]1[S:10][CH:11]=[C:7]([C:27]2[CH:28]=[CH:29][C:24]([C:23]([F:34])([F:33])[F:22])=[CH:25][CH:26]=2)[N:8]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CC1(C)COC(=O)N1c1nc(OS(=O)(=O)C(F)(F)F)cs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1(C)COC(=O)N1c1nc(-c2ccc(C(F)(F)F)cc2)cs1
Reaction time: 16 h

Procedure:
A vial under nitrogen was charged with 2-(4,4-dimethyl-2-oxo-1,3-oxazolidin-3-yl)-1,3-thiazol-4-yl trifluoromethanesulfonate (100 mg, 0.28 mmol), [4-(trifluoromethyl)phenyl]-boronic acid (58 mg, 0.31 mmol), and tetrakis(triphenylphosphine)palladium (65 mg, 0.056 mmol) followed by tetrahydrofuran (0.6 mL) and triethylamine (0.13 mL, 0.92 mmol). The mixture was stirred for 16 h, diluted with tetrahydrofuran, passed through a plug of silica gel (2 g) and concentrated. The crude product was purified by reverse phase HPLC to give the title compound. HRMS: calcd for C15H13F3N2O2S+H+, 343.07226; found (ESI-FT/MS, [M+H]1+), 343.0725; Analytical HPLC: purity 100% at 210-370 nm, 10.7 min; 100% at 268 nm, 10.7 min; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[N:12]=[CH:11][C:10]([C:13]([OH:15])=O)=[CH:9][N:8]=2)[N:3]=1.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[O:37]1[CH2:42][CH2:41][CH:40]([NH2:43])[CH2:39][CH2:38]1>C(Cl)Cl>[O:37]1[CH2:42][CH2:41][CH:40]([NH:43][C:13]([C:10]2[CH:11]=[N:12][C:7]([C:4]3[N:3]=[C:2]([CH3:1])[O:6][N:5]=3)=[N:8][CH:9]=2)=[O:15])[CH2:39][CH2:38]1
Reactant: Cc1nc(-c2ncc(C(=O)O)cn2)no1
Reactant: NC1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: Cc1nc(-c2ncc(C(=O)NC3CCOCC3)cn2)no1
Reaction time: 0.17 h
Yield: 47.5 %

Procedure:
To a solution of 2-(5-methyl-[1,2,4]oxadiazol-3-yl)-pyrimidine-5-carboxylic acid (50 mg, 0.24 mmol) in DCM (10 mL) is added 1-[3-(dimethylamino)propyl-3-ethylcarbodiimide (50 mg, 0.26 mmol) and N-hydroxybenzotriazole (35 mg, 0.26 mmol) at room temperature. The mixture is stirred for 10 min, and tetrahydro-pyran-4-ylamine (27 mg, 0.26 mmol) is added. The mixture is stirred overnight, washed with 2N HCl (1×5 mL), saturated NaHCO3, (1×5 mL), water (lx 5 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by column chromatography eluting with 5% MeOH in DCM to afford 2-(5-methyl-[1,2,4]oxadiazole-3-yl)-pyrimidine-5-carboxylic acid (tetrahydro-pyran-4-yl)-amide (33 mg) as a solid. MS: 290 (M+H); 1H NMR (300 MHz, CDCl3): δ 1.70 (m, 2H), 2.04 (m, 2H), 2.76 (s, 3H), 3.59 (m, 2H), 4.06 (m, 2H), 4.28 (m, 1H), 9.26 (s, 2H); IC50=513.5 nM.
Reaction SMILES: O[C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C:5]3=[O:12])[CH2:3]1)[CH2:9]2.[IH:13]>>[I:13][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C:5]3=[O:12])[CH2:3]1)[CH2:9]2
Reactant: O=C1C2CC3CC1CC(O)(C3)C2
Reactant: I
Product: O=C1C2CC3CC1CC(I)(C3)C2

Procedure:
Simple unit processes allow the conversion of several of the abovementioned X or X1 substituents, or others known in the art, to 5-X- or 5-X1 -adamantane-2-ones where X or X1 may be trialkylsilyloxy, iodo or cyano groups. These moities are stable under the mild conditions used in step 4 of the foregoing reaction sequence. For example, when 5-hydroxyadamantan-2-one is refluxed for 7 hours with 57% hydriodic acid, 5-iodoadamantan-2-one (m.p. 73°-76° C.) is obtained. 5-Carboxyadamantan-2-one, prepared as described in Lantvoev, J.Obshch.Khim,, 12, 2361 (1976) or Le Noble, et al., J.Org.Chem,, 48, 1101 (1983), after saponification of the methyl ester, can be converted to 5-cyanoadamantan-2-one by the three step procedure of Tabushi, et al., J.Org.Chem., 38, 3447 (1973), used for access to the isomeric 1-cyanoadamantan-2-one through the intermediacy of a keto amide. 5-Trimethylsilyloxyadamantan-2-one (m.p. 34°-38° C.), useful as a protected version of 5-hydroxyadamantan-2-one, allows the use of only one equivalent of base in step 4 of the foregoing reaction sequence to prepare the corresponding enol ether, which can then be desilylated using standard techniques.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:29])[N:4]([C:21]2[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=2[F:28])[C:5]([CH3:20])=[C:6]([CH:18]=[CH2:19])[C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].C[N+]1([O-])CCOCC1.C(#N)C.[OH2:41].[OH2:42].CC(C)=O>[Os](=O)(=O)(=O)=O>[Br:1][C:2]1[C:3](=[O:29])[N:4]([C:21]2[C:22]([F:28])=[CH:23][CH:24]=[CH:25][C:26]=2[F:27])[C:5]([CH3:20])=[C:6]([CH:18]([OH:42])[CH2:19][OH:41])[C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: C=Cc1c(OCc2ccc(F)cc2F)c(Br)c(=O)n(-c2c(F)cccc2F)c1C
Reactant: O
Agent: O=[Os](=O)(=O)=O
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Solvent: CC(C)=O
Product: Cc1c(C(O)CO)c(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1c(F)cccc1F
Reaction time: 1 h

Procedure:
To a room temperature solution of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-methyl-5-vinylpyridin-2(1H)-one (0.970 g, 2.07 mmol) in water/acetone 1:3 (8.7 mL) was added, sequentially, osmium tetroxide (0.110 g, 0.433 mmol) and N-methyl morpholine oxide (1.32 g, 11.2 mmol). The resulting solution was stirred for one hour until complete consumption of starting material by LCMS analysis, and the reaction was concentrated in vacuo. The resulting dark residue was subjected to SiO2 chromatography with ethyl acetate/hexanes (3:7) to furnish a solid. 1H NMR (400 MHz, CDCl3) δ 7.59 (app q, J=8.2 Hz, 1H), 7.45 (ddd, J=14.7, 8.5, 6.8 Hz, 1H), 7.08 (app t, J=8.5 Hz, 2H), 6.94 (app t, J=8.2 Hz, 1H), 6.88 (app t, J=8.5 Hz, 1H), 5.31 (AB-q, J=10.6 Hz, Δ=38.3 Hz, 2H), 5.07 (dd, J=9.1, 3.8 Hz, 1H), 3.83 (t, J=10.8 Hz, 1H), 3.60 (dd, J=11.4, 3.9 Hz, 1H), 2.94 (br s, 1H), 2.16 (s, 3H); LC/MS C-18 column, tr=2.26 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50° C.). ES-MS m/z 502 (M+H). ES-HRMS m/z 502.0276 (M+H calcd for C21H17BrF4NO4 requires 502.0272).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][N:6]([C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[CH2:5]2.C([O-])(O)=O.[Na+].[I:26]Cl>C(Cl)Cl.CO>[NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[I:26])[CH2:7][N:6]([C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12])[CH2:5]2
Reactant: Nc1ccc2c(c1)CN(C(=O)OCc1ccccc1)C2
Reactant: ClI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Nc1cc2c(cc1I)CN(C(=O)OCc1ccccc1)C2
Reaction time: 0.5 h

Procedure:
To a solution of benzyl 5-amino-1,3-dihydro-2H-isoindole-2-carboxylate (560 mg, 2.09 mmol) in a mixture of CH2Cl2 (10 mL) and MeOH (2.5 mL), was added NaHCO3 (263 mg, 3.13 mmol) followed by 1M ICl in CH2Cl2 (2.1 mL, 2.1 mmol). The mixture was stirred for 30 min and then quenched with sat. aq. NaHSO3. The resulting mixture was extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel to provide benzyl 5-amino-6-iodo-1,3-dihydro-2H-isoindole-2-carboxylate. LCMS calc.=395.0; found=394.7 (M+H)+. 1H NMR (500 MHz, CDCl3): δ 7.58-7.51 (2 s, 1H); 7.45-7.35 (m, 5H); 6.70-6.64 (2 s, 1H); 5.24 (s, 2H); 4.67 (s, 2H); 4.65 (s, 2H); 4.15 (br, s, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([CH3:25])[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29](=[O:49])[CH2:30][C:31]1([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)[CH3:27]>>[CH2:26]([O:28][C:29](=[O:49])[CH2:30][C:31]1([C:34]2[CH:39]=[CH:38][C:37]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][CH:15]([CH3:25])[CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=4)=[CH:4][CH:3]=3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)[CH3:27]
Reactant: CCOC(=O)CC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(C)CCc1ccc(Cl)cc1
Product: CCOC(=O)CC1(c2ccc(-c3ccc(-c4onc(C)c4NC(C)CCc4ccc(Cl)cc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 108, Step 2, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-[3-(4-chloro-phenyl)-1-methyl-propyl]-amine and {1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropyl}-acetic acid ethyl ester.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][NH:11][C@H:12]([CH3:29])[C@:13]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28])([OH:20])[CH2:14][N:15]1[CH:19]=[N:18][CH:17]=[N:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:37][C:38]([F:49])([F:48])[C:39]1[CH:47]=[CH:46][C:42]([C:43](Cl)=[O:44])=[CH:41][CH:40]=1>C(Cl)Cl>[F:28][C:22]1[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:21]=1[C@:13]([OH:20])([C@H:12]([N:11]([C:43](=[O:44])[C:42]1[CH:46]=[CH:47][C:39]([C:38]([F:37])([F:48])[F:49])=[CH:40][CH:41]=1)[CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:29])[CH2:14][N:15]1[CH:19]=[N:18][CH:17]=[N:16]1
Reactant: C[C@@H](NCCOCc1ccccc1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](N(CCOCc1ccccc1)C(=O)c1ccc(C(F)(F)F)cc1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 140 %

Procedure:
To a solution of (2R*,3R*)-3-[(2-benzyloxyethyl)amino]-2-[2,4-difluorophenyl]-1-(1H-1,2,4-triazol-1-yl)-2-butanol (4.40 g, 11.4 mmol) (obtained as described in reference example 2) in CH2Cl2 (40 mL) was added triethylamine (1.74 mL, 12.5 mmol). The resulting mixture was cooled in an ice bath and a solution of 4-(trifluoromethyl)benzoyl chloride (2.61 g, 12.5 mmol) in CH2Cl2 (5 mL) was carefully added and the mixture was stirred for 1 h at 0° C. and then for 18 h at room temperature. The resulting solution was diluted with CH2Cl2 and washed with 5% aqueous NaHCO3 solution. The organic phase was separated, dried over Na2SO4 and the solvent was removed, to afford a thick oil (9.17 g) that was purified by chromatography on silica gel (EtOAc: hexane 1:1). The title compound of the example was obtained as a white foam.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][C:18](=[O:29])[C@@H:19]([NH:23][S:24]([CH2:27][CH3:28])(=[O:26])=[O:25])[CH:20]([CH3:22])[CH3:21])=[CH:11][CH:10]=1)C1C=CC=CC=1>O1CCCC1.[Pd]>[CH2:27]([S:24]([NH:23][C@@H:19]([CH:20]([CH3:21])[CH3:22])[C:18]([NH:17][CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=1)=[O:29])(=[O:25])=[O:26])[CH3:28]
Reactant: CCS(=O)(=O)N[C@H](C(=O)NCCc1ccc(OCc2ccccc2)cc1)C(C)C
Agent: [Pd]
Solvent: C1CCOC1
Product: CCS(=O)(=O)N[C@H](C(=O)NCCc1ccc(O)cc1)C(C)C
Reaction time: 5 h

Procedure:
18.6 g of (S)-N-[2-(4-benzyloxy-phenyl)-ethyl]-2-ethanesulfonylamino-3-methyl-butyramide and 16.8 g of palladium (5% on charcoal) in 400 ml of tetrahydrofuran are shaken under a hydrogen atmosphere at +30 to +−35° C. and at normal pressure for 5 hours. The reaction mixture is filtered and evaporated. (S)-2-ethanesulfonylamino-N-[2-(4-hydroxy-phenyl)-ethyl]-3-methyl-butyramide is obtained in form of an oil [MS (m/e): 329 (M+H)+].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]([O:12][Si:13]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])([CH3:11])[CH3:10])[CH:5]=[C:6]([F:8])[CH:7]=1.C([Li])CCC.C(O[B:32]1[O:36][C:35]([CH3:38])([CH3:37])[C:34]([CH3:40])([CH3:39])[O:33]1)(C)C>C1COCC1>[F:8][C:6]1[CH:5]=[C:4]([C:9]([O:12][Si:13]([CH:14]([CH3:15])[CH3:16])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])([CH3:10])[CH3:11])[CH:3]=[C:2]([F:1])[C:7]=1[B:32]1[O:36][C:35]([CH3:38])([CH3:37])[C:34]([CH3:40])([CH3:39])[O:33]1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: CC(C)[Si](OC(C)(C)c1cc(F)cc(F)c1)(C(C)C)C(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)[Si](OC(C)(C)c1cc(F)c(B2OC(C)(C)C(C)(C)O2)c(F)c1)(C(C)C)C(C)C
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of (2-(3,5-difluorophenyl)propan-2-yloxy)triisopropylsilane (1.0 eq) in dry THF (0.2M) under an atmosphere of N2 at −78° C. was added n-butyllithium (1 eq, 1.6M in hexanes) slowly keeping the internal temperature below −65° C. The reaction was stirred for 2 hrs at −78° C., followed by the addition of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.15 eq). The reaction was allowed to warm to room temperature. Upon completion, the reaction was quenched with NaHCO3(sat) and extracted with EtOAc. The organics were washed with brine, dried over Na2SO4, filtered and concentrated to yield (2-(3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-yloxy)triisopropylsilane in 99%. 1H NMR (400 MHz, <cdcl3>) δ ppm 1.03-1.08 (m, 21 H) 1.24 (s, 12 H) 1.38 (s, 3 H) 1.57 (s, 3 H) 6.92-7.03 (m, 2 H).
Reaction SMILES: C([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:19]([OH:21])=O)[N:13]2[CH3:18])C1C=CC=CC=1.[CH2:22]([NH2:24])[CH3:23]>>[CH2:22]([NH:24][C:19]([C:12]1[N:13]([CH3:18])[C:14]2[C:10]([CH:11]=1)=[C:9]([OH:8])[CH:17]=[CH:16][CH:15]=2)=[O:21])[CH3:23]
Reactant: Cn1c(C(=O)O)cc2c(OCc3ccccc3)cccc21
Reactant: CCN
Product: CCNC(=O)c1cc2c(O)cccc2n1C

Procedure:
From 4-benzyloxy-1-methyl-1H-indole-2-carboxylic acid and ethyl amine the title compound was prepared by a method analogous to that described in Example 11. MS ES (M++H)=219.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH2:9][O:10][C:4]=2[CH:3]=1.C([Li])CCC.[F:16][C:17]([F:27])([F:26])[C:18](N1CCCCC1)=[O:19].[Cl-].[NH4+]>C(OCC)C>[F:16][C:17]([C:18]([C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH2:9][O:10][C:4]=2[CH:3]=1)=[O:19])([F:27])[F:26]
Reactant: O=C(N1CCCCC1)C(F)(F)F
Reactant: Brc1ccc2c(c1)OCO2
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Product: O=C(c1ccc2c(c1)OCO2)C(F)(F)F
Temperature: -30 °C
Reaction time: 0.25 h
Yield: 50.4 %

Procedure:
4-Bromo-1,2-methylenedioxybenzene (4.02 g, 0.020 mole) was dissolved in dry diethylether (100 ml) and cooled to -30° C. under a dry argon atmosphere. At -30° C. to -40° C. n-butyllithium (12 ml, 0.002 mole; 1.85 molar solution in n-hexane) were added with stirring over 15 minutes. After 50 minutes at -30° C. the mixture was cooled to -50° C. and the solution of N-trifluoroacetyl piperidine (3.62 g, 0.020 mole) in dry ether (20 ml) was added over 5 minutes. After 45 minutes at -50° C. the reaction mixture was warmed up to -40° C. for 30 minutes, and to room temperature over another 30 minutes. Saturated aqueous ammonium chloride (25 ml) was added with vigorous stirring. The layers were separated and the organic top layer washed with 10% aqueous ammonium chloride (3× 50 ml) and dried over anhydrous sodium sulfate. After filtration and removal of the ether under reduced pressure the residual liquid was distilled in vacuo to give trifluoromethyl (3,4-methylenedioxyphenyl)-methanone (2.2 g), (50.4%) b.p. 60° C./0.2 mm Hg.
Reaction SMILES: [CH3:1][C@H:2]1[C:10]2[C:9](O)=[N:8][CH:7]=[N:6][C:5]=2[CH2:4][CH2:3]1.O=P(Cl)(Cl)[Cl:14]>>[Cl:14][C:9]1[C:10]2[C@H:2]([CH3:1])[CH2:3][CH2:4][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: C[C@@H]1CCc2ncnc(O)c21
Reactant: O=P(Cl)(Cl)Cl
Product: C[C@@H]1CCc2ncnc(Cl)c21
Yield: 49 %

Procedure:
A mixture of (R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol (5.8 g, 38.62 mmol) in POCl3 (20 mL) was refluxed for about 5 minutes. Excess POCl3 was removed under vacuum, and the residue was dissolved in DCM (50 mL). The mixture was then added to saturated NaHCO3 (200 mL). The aqueous phase was extracted with DCM (3×100 mL), and the combined organic phases were dried and concentrated. The residue was purified by silica gel chromatography, eluting with ethyl acetate to give (R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (3.18 g, 49%). 1H NMR (CDCl3, 400 MHz) δ 8.81 (s, 1H), 3.47 (m, 1H), 3.20 (m, 1H), 3.05 (m, 1H), 2.41 (m, 1H), 1.86 (m, 3H), 1.47 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:12][OH:13])=[N:8][C:7]([SH:18])=[N:6][C:5]=2[N:19]=1.Cl[C@@H:21]([C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[C:26]#[N:27])[CH3:22]>>[NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@@H:11]([CH2:12][OH:13])[CH2:14][CH:15]([CH3:16])[CH3:17])=[N:8][C:7]([S:18][C@H:21]([C:23]3[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=3)[C:26]#[N:27])[CH3:22])=[N:6][C:5]=2[N:19]=1
Reactant: CC(C)C[C@H](CO)Nc1nc(S)nc2nc(N)sc12
Reactant: C[C@@H](Cl)c1cccc(C#N)c1
Product: CC(C)C[C@H](CO)Nc1nc(S[C@@H](C)c2cccc(C#N)c2)nc2nc(N)sc12
Yield: 31 %

Procedure:
The title compound was prepared in 31% yield from (2R)-2-[(2-amino-5-mercapto[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]-4-methylpentan-1-ol (200 mg, 0.67 mmol) and 3-[(1R)-1-chloroethyl]benzonitrile (166 mg, 1.0 mmol) according to general method A.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]2[C:10]([C:11]3[CH:12]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:15][CH:16]=3)=[CH:9][CH:8]=[N:7][C:6]=12.[CH3:21][N:22](C)C=O>>[F:18][C:17]([F:20])([F:19])[C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:10]2[N:5]3[N:4]=[CH:3][C:2]([C:21]#[N:22])=[C:6]3[N:7]=[CH:8][CH:9]=2)[CH:12]=1
Reactant: CN(C)C=O
Reactant: FC(F)(F)c1cccc(-c2ccnc3c(Br)cnn23)c1
Product: N#Cc1cnn2c(-c3cccc(C(F)(F)F)c3)ccnc12

Procedure:
A mixture of 0.95 g. of 3-bromo-7-(α,α,α-trifluoro-m-tolyl)pyrazolo[1,5-a]pyrimidine, 0.45 g. cuprous cyanide and 25 ml. of dimethylformamide is refluxed for 16 hours. Evaporation of the reaction mixture gave a residue which has triturated with methylene chloride. The methylene chloride solution is passed through a short column of hydrous magnesium silicate. The effluent is collected and refluxed on a steam bath with gradual addition of n-hexane and the desired nitrile crystallized from solution, m.p. 141°-143° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]([CH3:28])[C:12]([C:14]1[S:27][C:17]2[C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1)=[O:13])[C:5](O)=[O:6].[NH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[O:6])[CH:8]=[CH:9][C:10]=1[N:11]([CH3:28])[C:12]([C:14]1[S:27][C:17]2[C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1)=[O:13]
Reactant: C1CNCCN1
Reactant: CN(C(=O)c1cc2c(s1)-c1ccccc1OCC2)c1ccc(C(=O)O)cc1Cl
Product: CN(C(=O)c1cc2c(s1)-c1ccccc1OCC2)c1ccc(C(=O)N2CCNCC2)cc1Cl

Procedure:
3-Chloro-4-(N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)benzoic acid and piperazine were reacted by a procedure similar to Example 47 to give 253. MS: (ESI+) 482.1
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[C:10]2[C:15](=O)[C:14](=[CH:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[CH2:13][S:12][CH2:11]2)=[CH:5][CH:4]=1.[CH2:26]([NH:29][NH2:30])[CH2:27][CH3:28]>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[NH:30][N:29]([CH2:26][CH2:27][CH3:28])[C:15]3[C:14](=[CH:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)[CH2:13][S:12][CH2:11][C:10]2=3)=[CH:5][CH:4]=1
Reactant: CCCNN
Reactant: COc1ccc(C=C2CSCC(=Cc3ccc(OC)cc3)C2=O)cc1
Solvent: CO
Product: CCCN1NC(c2ccc(OC)cc2)C2=C1C(=Cc1ccc(OC)cc1)CSC2
Reaction time: 8 h

Procedure:
A mixture of tetrahydro-3,5-bis-(4-methoxyphenyl-methylene)-4H-thiopyran-4-one (6 g, 17 mmole) and propylhydrazine (1.4 g, 19 mmole) in methanol (250 ml) is heated at reflux temperature for 4.5 hours. After the reaction mixture is left at room temperature overnight, yellow solids precipitate out and are collectd by filtration. The crude product is applied to a Al2O3 column (Activity I, neutral). The major product is eluted with 10-20% ethyl acetate/acetic acid. Continued elution with 10-60% CHCl3 /hexane yields the title compound. Recrystallization from acetone/hexane gives 0.65 g of final product in crystalline form (99% pure), m.p. 131.5°-133.5°.