Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[C@H:4]([CH:6]([CH3:8])[CH3:7])[NH2:5].N1C=CC=CC=1.[Br:16][CH2:17][CH2:18][CH2:19][C:20](Cl)=[O:21]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:9])[C@H:4]([CH:6]([CH3:8])[CH3:7])[NH:5][C:20](=[O:21])[CH2:19][CH2:18][CH2:17][Br:16]
Reactant: O=C(Cl)CCCBr
Reactant: COC(=O)[C@@H](N)C(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)[C@@H](NC(=O)CCCBr)C(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 77.3 %

Procedure:
To a solution of 1.08 g (8.4 mmole) of L-valine methyl ester in 30 ml of CH2Cl2 was added 1.36 ml (16.8 mmole) of pyridine, cooled to 0° C. and 1.55 g (8.4 mmole) of 4-bromobutanoyl chloride added. The solution was stirred at 0° C. for 40 minutes and at RT for 1 h. The solution was washed with satd. NaHCO3, brine and dried with anrhy. Na2SO4; filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (5% EtOAc/CH2Cl2) to provide 1.82 g (77%) of desired product. 300 MHz 1H NMR (CDCl3) δ 0.92 (d, J=6 Hz, 3H), 0.96 (d, J=6 Hz, 3H) 2.20 (m, 3H), 2.46 (m, 2H), 3.50 (m, 2H), 3.76 (s, 3H), 4.58 (dd, J=4.7 Hz, 1H), 5.97 (br d, J=7 Hz, 1H). Mass spectrum: (M+H)+297.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]([CH3:15])([CH3:14])[C:10](OC)=[O:11])[C:5]([N+:16]([O-])=O)=[CH:4][CH:3]=1.[H][H]>CO.[Ni]>[Cl:1][C:2]1[N:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:16][C:10](=[O:11])[C:9]([CH3:15])([CH3:14])[NH:8]2
Reactant: [H][H]
Reactant: COC(=O)C(C)(C)Nc1nc(Cl)ccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Product: CC1(C)Nc2nc(Cl)ccc2NC1=O
Yield: 61.2 %

Procedure:
Methyl N-(6-chloro-3-nitro-2-pyridyl)-2-aminoisobutyrate (4.0 g, 14.6 mmol) was hydrogenated in 250 ml of methanol with Raney nickel catalysis under 1 atm of hydrogen. After hydrogen uptake ceased, the catalyst was filtered off with suction, and the filtrate was concentrated and chromatographed on silica gel (ethyl acetate/heptane=1:2). 1.89 g (61%) of the compound of Example 15, of melting point 229° C., were obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH:9]([CH3:14])[CH2:10][SiH:11]([Cl:13])[Cl:12].[CH2:15]=[CH:16][CH2:17][CH2:18][CH2:19][CH3:20]>C(O)(C)C.[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[Cl:13][Si:11]([Cl:12])([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:10][CH:9]([C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[CH3:1])[CH3:14]
Reactant: C=CCCCC
Reactant: Cc1ccc(C)c(C(C)C[SiH](Cl)Cl)c1
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Solvent: CC(C)O
Product: CCCCCC[Si](Cl)(Cl)CC(C)c1cc(C)ccc1C
Yield: 65.7 %

Procedure:
In the same apparatus and procedures as EXAMPLE 1, 8.5 g (0.034 mole of 3-(2,5-dimethylphenyl)-1,1-dichloro-1-silabutane, 8.7 g (0.10 mole) of 1-hexene, and 120 μl of 1% chloroplatinic acid in isopropanol were placed and refluxed under the dry nitrogen atmosphere for 3 hours. Vacuum distillation of the reaction products gave 7.4 g (bp, 130°-3° C./0.6 mmHg) of 4,4-dichloro-2-(2,5-dimethylphenyl)-4-siladecane.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:10]([C:12]([OH:14])=O)=[CH:9][O:8][C:7]=2[CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:15][O:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1>>[CH3:15][O:16][C:17]1[CH:23]=[CH:22][C:20]([NH:21][C:12]([C:10]2[C:11]3[C:2](=[O:1])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]=3[O:8][CH:9]=2)=[O:14])=[CH:19][CH:18]=1
Reactant: O=C(O)c1coc2c1C(=O)CCCC2
Reactant: COc1ccc(N)cc1
Product: COc1ccc(NC(=O)c2coc3c2C(=O)CCCC3)cc1

Procedure:
Starting from 4-oxo-5,6,7,8-tetrahydro-4H-cylohepta[b]furan-3-carboxylic acid and 4-methoxyaniline, General Procedure B provided the title compound:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([NH2:10])=[S:9].O.[CH2:12](N)[C:13]#[CH:14]>C(O)C>[CH2:14]([NH:10][C:8](=[S:9])[CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[C:13]#[CH:12]
Reactant: NC(=S)Cc1ccccn1
Reactant: C#CCN
Solvent: O
Solvent: CCO
Product: C#CCNC(=S)Cc1ccccn1
Reaction time: 8 h

Procedure:
To 4.0 g. (0.026 mole) of 2-(2-pyridyl)thioacetamide in 20 ml. of water at 0°C. is added 2.9 g. (0.053 mole) of propargylamine with stirring and the resulting suspension is allowed to stand overnight at 5°C. Ethanol (5 ml.) is added and the mixture is stirred for 5 hours, then extracted with dichloromethane. The extracts are dried and concentrated. The residue is chromatographed on a silica gel "dry-column", using 1:10 ethyl acetate/ether as the eluant. The product fraction is treated with charcoal, filtered, concentrated and the residue is recrystallized from benzene/ligroin to give N-propargyl-2-(2-pyridyl)thioacetamide, m.p. 62°-63°C.
Reaction SMILES: [H-].[Na+].ClC1C=C(N)C(I)=CN=1.S(OC[C@H]1OCCN(C(OC(C)(C)C)=O)C1)(C1C=CC(C)=CC=1)(=O)=O.[Cl:37][C:38]1[CH:43]=[C:42]([NH:44][CH2:45][C@H:46]2[O:51][CH2:50][CH2:49][N:48]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:47]2)[C:41](I)=[CH:40][N:39]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:66][O:67][C:68]1[CH:73]=[CH:72][C:71](B(O)O)=[CH:70][CH:69]=1>CN(C=O)C.C(#N)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.O>[Cl:37][C:38]1[CH:43]=[C:42]([NH:44][CH2:45][C@@H:46]2[O:51][CH2:50][CH2:49][N:48]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:47]2)[C:41]([C:71]2[CH:72]=[CH:73][C:68]([O:67][CH3:66])=[CH:69][CH:70]=2)=[CH:40][N:39]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](CNc2cc(Cl)ncc2I)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1ccc(S(=O)(=O)OC[C@@H]2CN(C(=O)OC(C)(C)C)CCO2)cc1
Agent: Nc1cc(Cl)ncc1I
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: O
Product: COc1ccc(-c2cnc(Cl)cc2NC[C@H]2CN(C(=O)OC(C)(C)C)CCO2)cc1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 94.3 %

Procedure:
NaH (0.024 g, 0.569 mmol) was added to a solution of 2-chloro-5-iodopyridin-4-amine (0.121 g, 0.474 mmol) in DMF (2.8 mL) at room temperature and stirred for 10 min. The temperature was raised to 80° C. and (S)-tert-butyl 2-(tosyloxymethyl)morpholine-4-carboxylate (0.264 g, 0.711 mmol) in DMF (0.6 mL) was added. The reaction mixture was stirred for 2 h, then further NaH (0.024 g, 0.569 mmol) was added at room temperature. The reaction mixture was further heated at 80° C. for 1 h then cooled. Water was added and the mixture was partitioned between ethyl acetate (20 mL) and aq. NaHCO3 (20 mL). The organic phase was washed with brine, dried (MgSO4) and concentrated. The mixture was purified by flash column chromatography on silica gel, eluting with ethyl acetate/hexane (2/4), to give an inseparable mixture of starting material and product. LCMS (4) Rt=2.66 min; m/z (ESI+) 397 [MH+]. A solution of the crude (R)-tert-butyl 2-((2-chloro-5-iodopyridin-4-ylamino)methyl)morpholine-4-carboxylate (0.040 g, 0.088 mmol), sodium carbonate (0.5 M, 0.26 mL), 4-methoxyphenyl boronic acid (0.013 g, 0.088 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.011 g, 0.01 mmol) in acetonitrile (2 mL) was heated under microwave irradiation at 100° C. for 20 min. The reaction mixture was concentrated. The crude product was purified by flash column chromatography on silica gel, eluting with ethyl acetate/hexane (1/1), to give the title compound as a colorless oil (0.036 g, 94%).
Reaction SMILES: [S:1]1(=[O:14])(=[O:13])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5](=O)[CH2:4][CH2:3][CH2:2]1.[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[N:15]1([C:5]2[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[S:1](=[O:14])(=[O:13])[CH2:2][CH2:3][CH:4]=2)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: C1CCNC1
Reactant: O=C1CCCS(=O)(=O)c2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: O=S1(=O)CCC=C(N2CCCC2)c2ccccc21
Yield: 102.5 %

Procedure:
A solution of 20.6 g (0.1 mol) of 3,4-dihydro-1-benzothiepin-5(2H)-one 1,1-dioxide, 9.6 g of pyrrolidine and 250 mg of p-toluenesulfonic acid in 250 ml of benzene was refluxed under a nitrogen atmosphere for 20 hours, using a Dean-Stark apparatus to remove the water which formed. Removal of the solvent under reduced pressure gave 27 g of a viscous oil which was used without further purification. The infrared spectrum showed the absence of a ketone band and the presence of a strong enamine band at 1620 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][C:20]4[CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23][CH2:22][C:21]=4[CH:34]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].Cl.O1CCOCC1>CCOCC>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][C:20]4[CH2:26][NH:25][CH2:24][CH2:23][CH2:22][C:21]=4[CH:34]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)CCCN(C(=O)OC(C)(C)C)C4)no2)cc1Cl
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)CCCNC4)no2)cc1Cl
Reaction time: 1.5 h

Procedure:
1,1-Dimethylethyl 7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1,3,4,5-tetrahydro-2H-2-benzazepine-2-carboxylate (Preparation 7) (75 mg, 0.155 mmol) was treated with 4N HCl in dioxan (1162 μl, 4.65 mmol) and the clear solution left standing for 1.5 hours. A white precipitate formed. Ether (1 ml) was added and the white solid was filtered off, washing with ether. The title compound was obtained on drying of the solid (45 mg). δH (400 MHz, d6DMSO) 1.36 (6H, d), 1.91-1.98 (2H, m), 3.11-3.14 (2H, m), 3.36-3.39 (2H, m), 4.41 (2H, s), 4.85-4.94 (1H, m), 7.46 (1H, d), 7.64 (1H, d), 7.95-7.80 (2H, m), 8.11 (1H, dd), 8.19 (1H, d), 9.04 (2H, broad s); MS (ES) C21H2235ClN3O2 requires 383; found 384.0 [M+H]+.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[N:7][C:8]([NH:11][CH2:12][C:13]2[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:15][O:16][C:17]=2[CH3:18])=[CH:9][CH:10]=1)=[O:4].[F:25][C:26]([F:30])([F:29])[CH2:27][NH2:28]>>[F:25][C:26]([F:30])([F:29])[CH2:27][NH:28][C:3]([C:5]1[N:6]=[N:7][C:8]([NH:11][CH2:12][C:13]2[C:14]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[N:15][O:16][C:17]=2[CH3:18])=[CH:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1ccc(NCc2c(-c3ccccc3)noc2C)nn1
Reactant: NCC(F)(F)F
Product: Cc1onc(-c2ccccc2)c1CNc1ccc(C(=O)NCC(F)(F)F)nn1
Yield: 71 %

Procedure:
As described for example 73c, 6-[(5-methyl-3-phenyl-isoxazol-4-ylmethyl)-amino]-pyridazine-3-carboxylic acid methyl ester (100 mg, 0.3 mmol) was converted, using 2,2,2-trifluoroethylamine instead of aminomethylcyclopropane, to the title compound (86 mg, 71%) which was obtained as a light yellow foam. MS: m/e=428.1 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH2:7].C([Mg]Cl)(C)C.[N:13]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16][CH2:15][C@H:14]1[C:17](OC)=[O:18]>C1COCC1>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:7][C:17]([C@@H:14]1[CH2:15][CH2:16][N:13]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:18]
Reactant: COC(=O)[C@@H]1CCN1C(=O)OC(C)(C)C
Reactant: Nc1cnccn1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H]1C(=O)Nc1cnccn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of pyrazin-2-amine (1.626 g, 17.10 mmol) in THF (40 mL) was added isopropylmagnesium chloride (8.44 mL, 16.88 mmol) at 0° C. under N2. The resulting slurry was stirred at RT for 30 min. A solution of (S)-1-tert-butyl 2-methyl azetidine-1,2-dicarboxylate (0.92 g, 4.27 mmol) in THF (5 ml) was added to the reaction slurry. The reaction mixture was stirred at RT for 4 h. and concentrated. The residue was dissolved in EtOAc and washed with 1N HCl, water, and brine. The organic layer was dried over Na2SO4 and filtered. The crude product (1.05 g, 88%) was used in the next step without purification. 1H NMR (400 MHz, MeOD) δ ppm 1.38 (s, 9H) 2.31 (br s, 1H) 2.53 (ddd, J=8.81, 6.17, 2.39 Hz, 1H) 3.89-4.00 (m, 2H) 4.81-4.86 (m, 1H) 8.30-8.37 (m, 2H) 9.41 (s, 1H); LC/MS [M+H]+: 279; Ret time (Method F): 2.27 min.
Reaction SMILES: Br[C:2]1[C:3]([CH2:12][CH2:13][CH:14]=[CH2:15])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[CH2:15]=[C:14]1[C:2]2[CH:11]=[CH:10][CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[C:3]=2[CH2:12][CH2:13]1
Reactant: C=CCCc1c(Br)cccc1C(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: C=C1CCc2c1cccc2C(=O)OC
Temperature: 120 °C

Procedure:
To a microwave tube charged with methyl 3-bromo-2-but-3-en-1-ylbenzoate (800 mg, 3.0 mmol) and a stir bar was added palladium(II) acetate (67 mg, 0.30 mmol), triphenylphosphine (310 mg, 1.19 mmol), potassium carbonate (2.46 g, 18.0 mmol), and acetonitrile (20 mL). The reaction tube was sealed, and the solution was purged three times with nitrogen, and heated in a microwave apparatus to 120° C. for 10 minutes. TLC showed a big blue spot right below the SM. The product was isolated by silica gel chromatography. LC-MS M+1 (calc. 189, found 189).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4C=[CH:20][NH:21][C:15]=4[CH:14]3[CH3:22])=[O:12])[CH:10]=2)[CH:7]=1.CC1C2N=C[O:32]C=2CCN1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4[O:32][CH:20]=[N:21][C:15]=4[CH:14]3[CH3:22])=[O:12])[CH:10]=2)[CH:7]=1
Reactant: CC1c2[nH]ccc2CCN1C(=O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2ocnc21
Product: CC1c2ncoc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(7-methyl-1,4,5,7-tetrahydro-pyrrolo[2,3-c]pyridin-6-yl)-methanone is reacted with 4-methyl-4,5,6,7-tetrahydro-oxazolo[4,5-c]pyridine to provide the title compound.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:27])[C@@H:6]([O:24][CH2:25][CH3:26])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)=[CH:10][CH:9]=1)[CH3:3].C(N(CC)CC)C.[C:35]1([CH2:41][S:42](Cl)(=[O:44])=[O:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.O>ClCCl>[CH2:2]([O:4][C:5](=[O:27])[C@@H:6]([O:24][CH2:25][CH3:26])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([NH:23][S:42]([CH2:41][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)(=[O:44])=[O:43])=[CH:21][CH:22]=2)=[CH:10][CH:9]=1)[CH3:3]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCc2ccc(N)cc2)cc1)OCC
Reactant: O=S(=O)(Cl)Cc1ccccc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](Cc1ccc(OCCc2ccc(NS(=O)(=O)Cc3ccccc3)cc2)cc1)OCC
Temperature: 0 °C
Reaction time: 8 h
Yield: 37.7 %

Procedure:
3-{4-[2-(4-Aminophenyl)ethoxy]phenyl}-(S)-2-ethoxypropanoic acid ethyl ester hydro chloride (described in Example 41b) (0.5 g; 1.27 mmole) was dissolved in dichloromethane (10 ml) and triethylamine (0.39 ml; 2.8 mmole) was added. The mixture was cooled to 0° C., Phenylmethanesulphonyl chloride (0.32 g; 1.68 mmole) was added. The reaction mixture was then stirred overnight and the temperature was allowed to reach room temperature. Water was added and the phases were separated. The organic phase was washed with water, dried with magnesium sulfate and evaporated. Chromatography of the residue on silica gel using ethyl acetate/heptane as eluant gave 0.245 g (38% yield) of 3-[4-{2-(4-benzylsulfonylaminophenyl)ethoxy}phenyl]-2-(S)-ethoxypropanoic acid ethyl ester.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[N:10]=[CH:9][N:8]([CH2:12][CH3:13])[C:7]=2[C:6](=[O:14])[NH:5][C:4]1=[O:15])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:23][CH2:24][CH2:25][CH:26]=[CH:27][CH3:28]>CN(C)C=O>[CH2:1]([N:3]1[C:11]2[N:10]=[CH:9][N:8]([CH2:12][CH3:13])[C:7]=2[C:6](=[O:14])[N:5]([CH2:28][CH2:27][CH2:26][CH:25]=[CH:24][CH3:23])[C:4]1=[O:15])[CH3:2]
Reactant: CCn1cnc2c1c(=O)[nH]c(=O)n2CC
Reactant: CC=CCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC=CCCCn1c(=O)c2c(ncn2CC)n(CC)c1=O
Yield: 94.7 %

Procedure:
2.8 g (0.1 mole) of 3,7-diethylxanthine, 15.2 g (0.11 mole) of potassium carbonate and 13.0 g (0.11 mole) of 1-chloro-4-hexene in 600 ml of dimethylformamide were stirred at 110° C. for 18 hours. After cooling down, the mixture was filtered, the filtrate was evaporated under reduced pressure and the residue was taken up in chloroform. The unreacted 3,7-diethylxanthine was removed by extracting with 1N sodium hydroxide solution by shaking, the organic phase was washed to neutrality with water, dried over sodium sulfate and the solvent was distilled off in a rotary evaporator. After drying the solid residue from evaporation, 27.5 g (94.7% of theory) of crude 3,7-diethyl-1-(4-hexenyl)xanthine were obtained, ##STR29## which, after dissolving in 350 ml of chloroform and adding 23.1 g (0.114 mole) of 3-chloroperbenzoic acid (85% pure), was stirred under a nitrogen atmosphere at room temperature for 48 hours. The mixture was then initially extracted by shaking with 10% strength sodium dithionite solution until the iodine-starch reaction disappeared, and then with 10% strength sodium bicarbonate solution, and the solution was washed with water until neutral and free of salt, dried and evaporated under reduced pressure. 29.0 g (100% of theory) of crude 3,7-diethyl-1-(4,5-epoxyhexyl)xanthine were obtained ##STR30## which, after being taken up in a solvent mixture composed of 150 ml of tetrahydrofuran and 100 ml of water and addition of 0.46 ml of perchloric acid (70% strength), was stirred at room temperature for 90 hours. The mixture was then neutralized with saturated sodium bicarbonate solution, the solvent was distilled off under reduced pressure and the residue was chromatographed on silica gel with chloroform as the mobile phase. This produced 26.4 g (86% of theory) of a crystalline product, which was recrystallized from ethyl acetate/petroleum ether, and which was almost pure by thin-layer chromatography.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[F:28][C:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[CH:31][N:30]=1>>[F:28][C:29]1[CH:34]=[C:33]([C:2]2[N:3]=[C:4]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=2)[CH:32]=[CH:31][N:30]=1
Reactant: OB(O)c1ccnc(F)c1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: CS(=O)(=O)N1CCN(Cc2cc3nc(-c4ccnc(F)c4)nc(N4CCOCC4)c3s2)CC1

Procedure:
2-Chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine was reacted with 2-fluoropyridine-4-boronic acid in General Procedure A. Purification on silica yielded 2-(2-fluoro-pyridin-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C@:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][O:11]2)[CH:7]=1.[Li].[F-].[CH2:22]([N+](CCCC)(CCCC)CCCC)[CH2:23]CC.[Cl-].[NH4+]>CS(C)=O.C1COCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C@@:10]([C:13]([F:16])([F:15])[F:14])([OH:11])[CH2:12][C:22]#[CH:23])[CH:7]=1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: Cc1ccc(F)cc1C(C)(C)C[C@]1(C(F)(F)F)CO1
Agent: [Cl-]
Agent: [F-]
Agent: [Li]
Solvent: O
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: C#CC[C@](O)(CC(C)(C)c1cc(F)ccc1C)C(F)(F)F
Temperature: 25 °C
Reaction time: 5 h
Yield: 65.2 %

Procedure:
To a solution of (R)-2-[2-(5-fluoro-2-methylphenyl)-2-methylpropyl]-2-trifluoromethyloxirane (18.5 g, 67.0 mmol) in 200 mL of anhydrous DMSO was added lithium trimethylsilylacetylide (0.5 M in THF, 201 mL, 101 mmol). The resulting brown solution was stirred at room temperature for 5 hours. The reaction mixture was poured into 500 mL of water and extracted with three 500 mL portions of 10% ethyl acetate/hexanes. The combined organic phases were washed with two 500 mL portions of water and one 500 mL portion of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude material was redissolved in 200 mL of THF and cooled to 0° C. A solution of tetrabutylammonium fluoride (1.0 M in THF, 67.0 mL, 67.0 mmol) was added over 5 minutes. The reaction mixture was stirred for 1 hour, poured into 150 mL of saturated aqueous ammonium chloride solution, and extracted with three 300 mL portions of diethyl ether. The combined organic phases were washed with 300 mL of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification by column chromatography with silica gel (eluted with 0%-3% EtOAc/hexanes) afforded (S)-6-(5-fluoro-2-methylphenyl)-6-methyl-4-trifluoromethylhept-1-yn-4-ol as a yellow oil (13.2 g, 65%).
Reaction SMILES: [N:1]([CH2:4][C:5]([C:8]1[N:13]=[CH:12][CH:11]=[CH:10][N:9]=1)([F:7])[F:6])=[N+]=[N-].[OH-].[Na+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl.O1CCOCC1>C1COCC1>[F:7][C:5]([F:6])([C:8]1[N:9]=[CH:10][CH:11]=[CH:12][N:13]=1)[CH2:4][NH2:1]
Reactant: [N-]=[N+]=NCC(F)(F)c1ncccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: NCC(F)(F)c1ncccn1
Temperature: 25 °C
Yield: 84.4 %

Procedure:
A portion of the 2-(2-azido-1,1-difluoro-ethyl)-pyrimidine (578 mg, 3.12 mmol) was taken up in THF (8 mL), 0.1 M NaOH (aq) (0.6 mL), and PPh3 (982 mg, 3.74 mmol) and stirred at 50° C. for 29 h. The resulting pale yellow solution was allowed to cool to rt, dried (2×Na2SO4), and treated with 4 M HCl/dioxane (2 mL; approximately 8 mmol HCl). The precipitate was collected by decantation, and washed with dry ether (3×15 mL). The solid was then partitioned with 4 M NaCl (4 mL) and EtOAc (4 mL), and the aqueous layer was washed with EtOAc (1×4 mL). The aqueous layer was then brought to a pH greater than 10 with 2.5 M NaOH, and extracted with equal volumes of DCM (3×5 mL). The combined organic layers were dried (Na2SO4) and concentrated under rotary evaporation at 35° C. to provide the title compound as a pale yellow oil (419 mg, 85% over two steps).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][N:9]=[C:10]([C:16]#[N:17])[C:11]([NH:13][CH2:14][CH3:15])=[O:12].[Cl-].[Al+3].[Cl-].[Cl-].[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[NH2:17][C:16]1[C:4]2[C:3](=[C:2]([Br:1])[CH:7]=[CH:6][CH:5]=2)[N:8]=[N:9][C:10]=1[C:11]([NH:13][CH2:14][CH3:15])=[O:12]
Reactant: CCNC(=O)C(C#N)=NNc1ccccc1Br
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCNC(=O)c1nnc2c(Br)cccc2c1N
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 69.3 %

Procedure:
To a stirred solution of 2-[(2-bromophenyl)-hydrazono]-N-ethyl-2-cyanoacetamide (260 mg, 0.88 mmol) in anhydrous toluene (10 mL) was added aluminum chloride (370 mg, 2.78 mmol). The reaction was heated with vigorous stirring at 90° C. for 1.5 hours, cooled, diluted with ethyl acetate (40 mL), and treated with Rochelle's salt (saturated aqueous solution). After stirring for 30 minutes, the organic layer was decanted into a separator funnel. (The white precipitate was rinsed with ethyl acetate three times.) The organic layer was washed with 1:1 brine:Rochelle's salt solution, dried over sodium sulfate, and concentrated to a light brown solid. The solid was slurred in ether and filtered to afford the title compound as a brown solid (180 mg, 69%). 1H NMR (300.132 MHz, CDCl3) δ 8.52 (s, 1H), 8.13 (dd, J=7.4, 1.1 Hz, 1H), 7.82 (dd, J=8.4, 1.1 Hz, 1H), 7.51 (dd, J=8.4, 7.5 Hz, 1H), 3.56 (dq, J=5.8, 7.3 Hz, 2H), 1.31 (t, J=7.3 Hz, 3H). MS APCI, m/z=395/397 (M+H). HPLC 1.90 min.