Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C:9]1[C:10]([CH3:24])=[C:11]([CH3:23])[C:12]2[O:16][CH:15]([CH2:17][CH2:18][CH2:19]Cl)[S:14][C:13]=2[C:21]=1[CH3:22])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[I-:25].[Na+]>CC(C)=O>[Si:1]([O:8][C:9]1[C:10]([CH3:24])=[C:11]([CH3:23])[C:12]2[O:16][CH:15]([CH2:17][CH2:18][CH2:19][I:25])[S:14][C:13]=2[C:21]=1[CH3:22])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Cc1c(C)c2c(c(C)c1O[Si](C)(C)C(C)(C)C)SC(CCCCl)O2
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Cc1c(C)c2c(c(C)c1O[Si](C)(C)C(C)(C)C)SC(CCCI)O2

Procedure:
A mixture of 1.06 g of 5-t-butyldimethylsilyloxy-2-(3-chloropropyl)-4,6,7-trimethyl-1,3-benzoxathiole (prepared as described in Example 78), 4.1 g of sodium iodide and 40 ml of acetone was heated under reflux for 10 hours. The reaction product was then cooled, after which it was treated in the same manner as described in (a) above, to give the title compound having the same Rf value, infrared absorption spectrum and mass spectrum as the product of (a) above.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([SH:11])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][CH2:28][CH:29]1[O:33][CH2:32][CH2:31][O:30]1>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:27][CH2:28][CH:29]2[O:33][CH2:32][CH2:31][O:30]2)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1nc(S)nc2c1nc(O)n2Cc1ccccc1
Reactant: BrCCC1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc(SCCC2OCCO2)nc2c1nc(O)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.8 %

Procedure:
Crude 6-amino-9-benzyl-8-hydroxy-2-mercaptopurine (200 mg, 0.73 mmol) was suspended in dimethylformamide (80 ml). To the suspension were added potassium carbonate (150 mg, 1.1 mmol) and 2-(2-bromoethyl)-1,3-dioxolane (0.14 ml, 1.1 mmol) in order. The mixture was stirred at room temperature for 3 hours. The solvent was removed in vacuo, and the residue was purified by silica gel chromatography (3% methanol/chloroform) to give the subject compound (163 mg, yield 60%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])[CH3:7])=[O:5])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[N:26]1[CH:31]=[CH:30][CH:29]=[N:28][C:27]=1[NH:32][CH2:33][C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35]>O1CCCC1>[CH2:1]([O:3][C:4]([C@@H:6]([NH:8][C@H:9]([C:11]([N:32]([C:27]1[N:26]=[CH:31][CH:30]=[CH:29][N:28]=1)[CH2:33][C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35])=[O:13])[CH3:10])[CH3:7])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H](C)N[C@@H](C)C(=O)O
Reactant: O=C(CNc1ncccn1)OCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](C)N[C@@H](C)C(=O)N(CC(=O)OCc1ccccc1)c1ncccn1

Procedure:
N-[1-(S)-Ethoxycarbonylethyl]alanine and 1,1'-Carbonyldiimidazole were added to dry tetrahydrofuran. The resulting mixture was refluxed for fifteen minutes. To the resulting solution was added benzyl N-(2-pyrimidyl)glycinate. The resulting mixture was refluxed for three hours. The product was purified by HPLC chromatography to yield benzyl N-[1-(S)ethoxycarbonylethyl]alanyl-N-(2-pyrimidyl)glycinate.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=3)[O:10][C:3]=12.[NH2:23][CH2:24][C:25]1[C:26]([N:31]([CH3:36])[S:32]([CH3:35])(=[O:34])=[O:33])=[N:27][CH:28]=[CH:29][CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:36][N:31]([C:26]1[C:25]([CH2:24][NH:23][C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[CH:8]=[C:9]([C:11]4[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=4)[O:10][C:3]=23)=[CH:30][CH:29]=[CH:28][N:27]=1)[S:32]([CH3:35])(=[O:34])=[O:33]
Reactant: CN(c1ncccc1CN)S(C)(=O)=O
Reactant: COc1cc(-c2cc3nccc(Cl)c3o2)cc(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(-c2cc3nccc(NCc4cccnc4N(C)S(C)(=O)=O)c3o2)cc(OC)c1OC
Temperature: 110 °C
Reaction time: 1 h
Yield: 33.8 %

Procedure:
To a dry 10 mL microwave vial with stirbar was added 7-chloro-2-(3,4,5-trimethoxyphenyl)furo[3,2-b]pyridine (50.00 mg; 0.16 mmol; 1.00 eq.), N-(3-aminomethyl-pyridin-2-yl)-N-methyl-methanesulfonamide (40.40 mg; 0.19 mmol; 1.20 eq.), chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) methyl-tert.-butyl ether adduct (2.59 mg; 0.003 mmol; 0.02 eq.), and potassium carbonate (30.26 mg; 0.22 mmol; 1.40 eq.). The vial was sealed and flushed with N2. The reagents were suspended in tert.-BuOH (1.00 ml) and the reaction mixture was heated to 110° C. with stirring for 1 h. The reaction mixture was cooled to room temperature and concentrated on a rotary evaporator. The crude mixture was purified by Biotage chromatography (20-100% EtOAc/hex KP-NH SNAP column) to afford the title compound as a beige solid (27 mg, 34%). (HPLC (method F): 90%, RT: 4.62 min); MS (m/z) 499 [M+H]+, RT: 2.5 min.
Reaction SMILES: [CH:1]([C:3]1[N:4]=[C:5]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:9][CH:8]=[N:7][N:6]2[C:17]=1[C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)=[N:22][CH:23]=1)=O.[NH2:37][C:38]1[CH:47]=[CH:46][C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[N:39]=1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[O:14]1[CH2:15][CH2:16][N:11]([C:10]2[C:5]3[N:6]([C:17]([C:18]4[CH:19]=[CH:20][C:21]([N:24]5[CH2:25][CH2:26][N:27]([C:30]([O:32][C:33]([CH3:34])([CH3:36])[CH3:35])=[O:31])[CH2:28][CH2:29]5)=[N:22][CH:23]=4)=[C:3]([CH2:1][NH:37][C:38]4[CH:47]=[CH:46][C:45]5[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=5)[N:39]=4)[N:4]=3)[N:7]=[CH:8][CH:9]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3c(C=O)nc4c(N5CCOCC5)ccnn34)cn2)CC1
Reactant: Nc1ccc2ccccc2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3c(CNc4ccc5ccccc5n4)nc4c(N5CCOCC5)ccnn34)cn2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Crude compound 21b (140 mg, 0.284 mmol) was placed in a 50 mL round bottom flask equipped with a stir bar and then 2-aminoquinoline (49.1 mg, 0.340 mmol) was added. DCE (10 mL) and AcOH (32.5 μL, 0.567 mmol) were added and then NaBH(OAc)3 (180 mg, 0.851 mmol) was added as a solid. The reaction was stirred at rt for 20 h and then additional NaBH(OAc)3 (60.0 mg, 0.283 mmol) was added. After 24 h, more NaBH(OAc)3 (60.0 mg, 0.283 mmol) was added and the reaction was stirred for an additional 20 h. The reaction was poured into saturated NaHCO3 solution (30 mL) and extracted with DCM (3×10 mL), and then the combined organic extracts were dried over MgSO4 and filtered. The solvent was removed under reduced pressure. The crude product was chromatographed on a 12 g SiO2 pre-packed column eluting with 0-100% ACN/DCM to afford compound 21c. 1H-NMR (400 MHz, CDCl3) δ (ppm): 8.52 (d, J=2.0 Hz, 1H), 8.00 (d, J=5.4 Hz, 1H), 7.88 (dd, J=8.8, 2.2 Hz, 1H), 7.80 (d, J=9.0 Hz, 1H), 7.69 (d, J=8.3 Hz, 1H), 7.58 (d, J=7.8 Hz, 1H), 7.52 (t, J=7.7 Hz, 1H), 7.21 (t, J=7.5 Hz, 1H), 6.76 (d, J=8.8 Hz, 1H), 6.71 (d, J=9.0 Hz, 1H), 6.08 (d, J=5.9 Hz, 1H), 5.49 (br. s., 1H), 4.87 (d, J=4.9 Hz, 2H), 3.88-4.01 (m, 8H), 3.52-3.65 (m, 8H), 1.50 (s, 9H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C34H39N9O3: 622.3 (M+H). Found: 622.3.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([SH:23])=[CH:19][CH:18]=1.C(N(CC)CC)C>CN(C=O)C>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23][C:2]2[N:6]([CH3:7])[CH:5]=[N:4][C:3]=2[C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)=[CH:19][CH:18]=1
Reactant: Cn1cnc(-c2ccc(C#N)cc2)c1Cl
Reactant: Sc1ccc(Cl)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1cnc(-c2ccc(C#N)cc2)c1Sc1ccc(Cl)cc1

Procedure:
4-(5-Chloro-1-methyl-1H-imidazol-4-yl)benzonitrile (1 g), 4-chlorobenzenethiol (797 mg), and 1.3 ml of triethylamine in 20 mL of DMF were heated in a microwave tube at 180° C. for 90 min. The reaction mixture was purified by reverse phase HPLC with MS detector to afford the title compound. 1H NMR (500 MHz, (CDCl3): 8.21 (d, 2H), 7.83 (s, 1H), 7.66 (d, 2H), 7.45 (d, 2H), 6.98 (d, 2H), 3.63 (s, 3H). LCMS: [M+1]=326.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].[CH:11]([N:14]1[CH2:19][CH2:18][CH:17]([NH:20][S:21]([CH2:24][CH2:25][NH:26][C:27]([C:29]2[S:30][C:31]([Cl:34])=[CH:32][CH:33]=2)=[O:28])(=[O:23])=[O:22])[CH2:16][CH2:15]1)([CH3:13])[CH3:12]>>[CH:11]([N:14]1[CH2:19][CH2:18][CH:17]([N:20]([CH2:2][C:3]([N:5]2[CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)=[O:4])[S:21]([CH2:24][CH2:25][NH:26][C:27]([C:29]2[S:30][C:31]([Cl:34])=[CH:32][CH:33]=2)=[O:28])(=[O:22])=[O:23])[CH2:16][CH2:15]1)([CH3:13])[CH3:12]
Reactant: CC(C)N1CCC(NS(=O)(=O)CCNC(=O)c2ccc(Cl)s2)CC1
Reactant: O=C(CCl)N1CCOCC1
Product: CC(C)N1CCC(N(CC(=O)N2CCOCC2)S(=O)(=O)CCNC(=O)c2ccc(Cl)s2)CC1

Procedure:
5-Chloro-thiophene-2-carboxylic acid {2-[(1-isopropyl-piperidin-4-yl)-(2-morpholin-4-yl-2-oxo-ethyl)-sulfamoyl]-ethyl}-amide was prepared by an analogous procedure as described in example 15 starting from 83 mg (2 equiv.) 2-chloro-1-morpholin-4-yl-ethanone and 100 mg (0.25 mmol) 5-chloro-thiophene-2-carboxylic acid [2-(1-isopropyl-piperidin-4-ylsulfamoyl)-ethyl]-amide. Final purification by preparative RP-HPLC (CH3CN/H2O gradient+0.1% TFA) gave pure 5-chloro-thiophene-2-carboxylic acid {2-[(1-isopropyl-piperidin-4-yl)-(2-morpholin-4-yl-2-oxo-ethyl)-sulfamoyl]-ethyl}-amide. The title compound was obtained as its trifluoroacetate in form of a colorless amorphous material, which turned out to be hygroscopic with time.
Reaction SMILES: [CH3:1][NH:2][C:3](=O)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:1][NH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CNC(=O)CCCCCCCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNCCCCCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.2 %

Procedure:
To a solution of N-methyl-8-phenyloctanamide (25.2 g, 108.0 mmol, 1 eq) in THF (500 mL) cooled to 0° C. was added lithium aluminum hydride (12.3 g, 466.8 mmol, 4.3 eq) portionwise over 20 minutes. The cold bath was removed and the reaction was stirred at rt 3 hours. The reaction was then heated at reflux for 2-hours. It was then cooled to rt and quenched by the slow addition of H2O (30 mL). EtOAc (300 mL) was added, followed by 2 M NaOH (40 mL). The solids were then filtered off and washed with EtOAc. The filtrate was dried over MgSO4 and concentrated in vacuo to afford N-methyl-N-(8-phenyloctyl)amine (19.7 g, 83%) as a light yellow oil. 1H NMR (CDCl3) δ 7.30-7.14 (m, 5H); 2.63-2.52 (m, 4H); 2.43 (s, 3H); 2.05 (s, 1H); 1.62 (m, 4H); 1.30 (m, 8H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)=[O:13])=[CH:2]1.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>>[CH3:26][S:27]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)=[O:13])=[CH:2]1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(C(=O)/C=C/c2c[nH]c3ccccc23)cc(OC)c1OC
Product: COc1cc(C(=O)/C=C/c2cn(S(C)(=O)=O)c3ccccc23)cc(OC)c1OC
Yield: 80.2 %

Procedure:
Substantially the same procedure as in Example 3 was repeated using Compound 1 (1.69 g) obtained in Example 1 and methanesulfonyl chloride (0.86 g) except that the reaction product was purified by silica gel column chromatography and that the obtained crude crystals were recrystallized from ethanol, to give Compound 9 (1.67 g).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].[CH3:10][O:11][CH2:12][C:13](O)=[O:14]>>[CH3:10][O:11][CH2:12][C:13]([NH:4][C:3]1[C:5]([CH3:9])=[CH:6][CH:7]=[CH:8][C:2]=1[CH3:1])=[O:14]
Reactant: COCC(=O)O
Reactant: Cc1cccc(C)c1N
Product: COCC(=O)Nc1c(C)cccc1C

Procedure:
According to the process described in the HU-PS 202,481, after acylating 2,6-dimethylaniline with methoxyacetic acid, the N-methoxyacetyl-2,6-dimethylaniline obtained is heated together with a twofold excess of methyl DL-α-bromopropionate to 120° C., and after adding sodium methoxide in small portions to the reaction mixture obtained, the alkylation is carried out at 140° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([OH:12])[C:9]([NH2:11])=[O:10])=[CH:4][CH:3]=1.Cl[C:14](OCC)=[O:15].O>[OH-].[Na+]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:9](=[O:10])[NH:11][C:14](=[O:15])[O:12]2)=[CH:6][CH:7]=1
Reactant: NC(=O)N(O)c1ccc(F)cc1
Reactant: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=c1[nH]c(=O)n(-c2ccc(F)cc2)o1
Reaction time: 1 h

Procedure:
1-(4-Fluorophenyl)-1-hydroxyurea (0.2 mole) dissolved in aqueous sodium hydroxide (200 ml; 2 N) is charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The solution is cooled to a temperature of about 10°C and ethyl chloroformate (0.21 mole) is slowly added with stirring. After the addition is completed stirring is continued for a period of about one hour. The reaction mixture is then poured into 2 liters of water. The resulting aqueous solution is then filtered and the filtrate is cooled and acidified with concentrated hydrochloric acid to form a precipitate. The precipitate is recovered by filtration and is dried. The dried product is then dissolved in a methylene chloridetetrahydrofuran mixture and the resulting solution is dried over anhydrous magnesium sulfate, filtered and stripped of solvent to yield the desired product 2-(4-fluorophenyl)-1,2,4-oxadiazolidin-3,5-dione as the residue.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=2)[CH:6]=1.[C:18]([C:21]1[CH:22]=[CH:23][C:24]([F:30])=[C:25](B(O)O)[CH:26]=1)(=[O:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+]>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.O1CCOCC1>[F:30][C:24]1[CH:25]=[CH:26][C:21]([C:18](=[O:20])[CH3:19])=[CH:22][C:23]=1[C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=2)[CH:6]=1
Reactant: CC(=O)c1ccc(F)c(B(O)O)c1
Reactant: FC(F)(F)Oc1ccc(-n2cnc(Br)c2)cc1
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: C1COCCO1
Product: CC(=O)c1ccc(F)c(-c2cn(-c3ccc(OC(F)(F)F)cc3)cn2)c1
Reaction time: 0.33 h
Yield: 88 %

Procedure:
4-Bromo-1-(4-trifluoromethoxyphenyl)-1H-imidazole (200 mg, 0.651 mmol), 5-acetyl-2-fluorophenylboronic acid (178 mg, 0.977 mmol), tetrakis(triphenylphosphine)palladium(0) (7 mg, 0.007 mmol), a 2 N aqueous solution of potassium carbonate (0.651 mL) and dioxane (8 mL) were combined and added to a microwave vessel. The reaction mixture was heated in the microwave with stiffing to 150° C. for 20 min. LC-MS indicated 88% anticipated product; TLC (1:1 hexanes:EtOAc) indicated the presence of starting material plus 3 other materials. EtOAc and water were added to the reaction mixture. The aqueous layer was extracted with EtOAc and the organic extracts were washed with brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by chromatography with gradient elution (100% hexanes to 100% EtOAc) resulting in 90 mg of an off-white solid. ESIMS 265.0 (M+H); mp 129° C.
Reaction SMILES: Cl[CH2:2][CH2:3][Si:4]([O:9][CH3:10])([O:7][CH3:8])[O:5][CH3:6].[N-:11]=[N+:12]=[N-:13].[Na+]>C(#N)C>[N:11]([CH2:2][CH2:3][Si:4]([O:9][CH3:10])([O:7][CH3:8])[O:5][CH3:6])=[N+:12]=[N-:13]
Reactant: CO[Si](CCCl)(OC)OC
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC#N
Product: CO[Si](CCN=[N+]=[N-])(OC)OC

Procedure:
1.0 mole of 2-chloroethyltrimethoxysilane and 1.1 moles of sodium azide in 500 ml of acetonitrile were heated in the presence of 3 mole percent of the catalyst described in Example 1 (a) for ten hours under stirring and reflux. After separation of the salt the subsequent distillation under reduced pressure gave the 2-azidoethyltrimethoxysilane in a yield of 61 weight percent with the following characteristics:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-])=O)=[CH:4][CH:3]=1>C(O)(=O)C.CO.[Zn]>[Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([NH2:9])=[CH:4][CH:3]=1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CO
Solvent: CC(=O)O
Product: Nc1ccc(Cl)nc1N
Reaction time: 18 h

Procedure:
Add zinc (4.0 g) to a solution of 6-chloro-3-nitropyridin-2-yl-amine (1.0 g, 5.76 mmol) in acetic acid (1.5 mL) and methanol (40 mL). Stir the resulting mixture is at room temperature for 18 hours, and filter through a pad of celite. Evaporate the filtrate to dryness under reduced pressure. Treat the resulting residue with 1N aqueous NaOH and extract with EtOAc. Wash the EtOAc extract with water and saturated aqueous NaCl. Separate the organic layer, dry over Na2SO4, filter and concentrate. Purify by flash column chromatography (50% EtOAc-hexane) to obtain 6-chloro-pyridine-2,3-diamine. C. 5-Chloro-1,3-dihydro-imidazole[4,5-b]pyridin-2-one
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2/[CH:14]=[CH:15]/[C:16]([O:18]C)=[O:17])[N:3]=[CH:2]1.[OH-].[Na+].[ClH:22]>CO>[ClH:22].[ClH:22].[NH:1]1[CH:5]=[C:4]([CH2:6][NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2/[CH:14]=[CH:15]/[C:16]([OH:18])=[O:17])[N:3]=[CH:2]1
Reactant: COC(=O)/C=C/c1ccccc1NCc1c[nH]cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)/C=C/c1ccccc1NCc1c[nH]cn1
Reaction time: 20 h

Procedure:
To a solution of methyl (E)-3-[2-(4-imidazolylmethylamino)phenyl]propenoate (0.7 g) in methanol (7 ml) was added 1N sodium hydroxide aqueous solution (3 ml) and the mixture was stirred for 20 hours. After removal of methanol from the reaction mixture, water was added to the residue. The mixture was adjusted to pH 6 with acetic acid. The mixture was salted out and extracted with ethyl acetate 8 times. The extracts were combined and dried over magnesium sulfate. Removal of the solvent afforded an orange oil, which was dissolved in methanol (5 ml). To the solution was added an ethereal solution of hydrogen chloride. The resultant precipitate was collected by filtration, washed with ether twice and dried to give (E)-3-[2-(4-imidazolylmethylamino)phenyl] propenoic acid dihydrochloride (0.29 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]1[N:11]=[C:12]2[N:16]([CH:17]=1)[CH:15]=[CH:14][O:13]2.CN(C=O)C.C1C(=O)N([I:30])C(=O)C1>O>[I:30][C:17]1[N:16]2[C:12]([O:13][CH:14]=[CH:15]2)=[N:11][C:10]=1[C:3]1[CH:4]=[C:5]([F:9])[C:6]([F:8])=[CH:7][C:2]=1[F:1]
Reactant: Fc1cc(F)c(-c2cn3ccoc3n2)cc1F
Reactant: O=C1CCC(=O)N1I
Solvent: O
Solvent: CN(C)C=O
Product: Fc1cc(F)c(-c2nc3occn3c2I)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.3 %

Procedure:
To a round bottom flask containing 6-(2,4,5-trifluorophenyl)imidazo[2,1-b]oxazole (11.7 g, 49.1 mmol) and DMF (120 mL) was added NIS (11.4 g, 50.6 mmol). The reaction mixture was stirred at ambient temperature for about 1 h. The reaction mixture was poured into water (300 mL) and the resulting precipitate was collected by vacuum filtration. The solid was dissolved into DCM (500 mL) and the organic suspension was washed sequentially with saturated NaHCO3 solution, 5% sodium thiosulfate solution, and brine. The resulting solution was dried over MgSO4, filtered, and concentrated to dryness under reduced pressure to give the title compound as a pale yellow solid (13.1 g, 73%): LC/MS (Table 1, Method b) Rt=2.17 min; MS m/z 365.0 (M+H)+.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[I:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH2:16])[CH3:15])=[CH:9][CH:8]=1.N1C=CC=CC=1>C(Cl)Cl>[I:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH:14]([NH:16][C:2](=[O:3])[O:4][CH3:5])[CH3:15])=[CH:11][CH:12]=1
Reactant: COC(=O)Cl
Reactant: CC(N)Cc1ccc(I)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)NC(C)Cc1ccc(I)cc1
Reaction time: 1 h

Procedure:
0.53 ml (6.89 mmol) methyl chloroformate are added to a mixture of 1.50 g (5.75 mmol) 1-(4-iodophenyl)propane-2-amine and 1.16 ml pyridine (14.3 mmol) in 30 ml DCM at 0° C. and the reaction mixture is stirred for 1 h at constant temperature. Further DCM is added and the organic solution is consecutively washed with aq. HCl-solution (0.5 mol/l) and water, dried with MgSO4 and the solvent is removed under reduced pressure. The crude product is used without further purification.
Reaction SMILES: Cl[CH:2]([C:8](=O)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[N:18]1([C:24](=[Se:26])[NH2:25])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>C(O)(C)C>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][C:8]2[N:25]=[C:24]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[Se:26][C:2]=2[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:11][CH:12]=1
Reactant: NC(=[Se])N1CCOCC1
Reactant: CCOC(=O)C(Cl)C(=O)Cc1ccc(Cl)cc1
Solvent: CC(C)O
Product: CCOC(=O)c1[se]c(N2CCOCC2)nc1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.6 %

Procedure:
In a round bottomed flask were placed ethyl 2-chloro-4-(4-chlorophenyl)-3-oxobutanoate (84.4 mg, 0.3069 mmol), isopropyl alcohol (5 mL), and morpholine-4-carboselenoamide (80.0 mg, 0.414 mmol). The resulting mixture was brought to reflux under an atmosphere of nitrogen (all solids dissolved to give a clear pale pink solution). After ˜1 hour reflux, TLC analysis indicated that all starting materials had been consumed with the production of one major product. The reaction was allowed to cool to room temperature and stir overnight. The solvent was removed on the rotovap then the residue was dissolved in minimal dichloromethane and purified by column chromatography on silica gel (gradient 100% hexane to 35% ethyl acetate) to afford 35 mg (28% yield) product as a white solid. LC/MS (FA) ES+ 413/415/417. NMR (400 MHz, DMSO) δ 7.37-7.23 (m, 4H), 4.25-4.14 (m, 4H), 3.72-3.62 (t, J=4.9 Hz, 4H), 3.50-3.41 (t, J=4.8 Hz, 4H), 1.27-1.20 (t, J=7.1 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[NH:21][N:20]=[CH:19]4)=[C:11]([F:25])[CH:10]=2)[CH:5]=[C:4](Cl)[N:3]=1>C(O)C.[Pd]>[F:25][C:11]1[CH:10]=[C:9]([NH:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[N:7]=2)[CH:14]=[CH:13][C:12]=1[O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][N:20]=[CH:19]2
Reactant: Nc1nc(Cl)cc(Nc2ccc(Oc3ccc4[nH]ncc4c3)c(F)c2)n1
Agent: [Pd]
Solvent: CCO
Product: Nc1nccc(Nc2ccc(Oc3ccc4[nH]ncc4c3)c(F)c2)n1
Reaction time: 8 h

Procedure:
50 mg (0.135 mmol) of 6-chloro-N4-[3-fluoro-4-(1H-indazol-5-yloxy)phenyl]pyrimidine-2,4-diamine (from example 8) are dissolved in ethanol. 50 mg of 10% palladium-on-carbon are added, and the suspension is stirred overnight under an atmosphere of hydrogen. The palladium catalyst is filtered off with suction and the filtrate is concentrated.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][C:11]([OH:13])=O.[Br:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:30]=1[C:24]1([CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[CH2:23][CH:22]2[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>>[Br:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:30]=1[C:24]1([CH2:25][CH2:26][N:27]([C:11](=[O:13])[CH2:10][CH2:9][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:2]([F:1])([F:15])[F:14])[CH2:28][CH2:29]1)[CH2:23][CH:22]2[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]
Reactant: O=C(O)CCc1ccccc1C(F)(F)F
Reactant: CCOC(=O)CC1CC2(CCNCC2)c2c(Br)cccc21
Product: CCOC(=O)CC1CC2(CCN(C(=O)CCc3ccccc3C(F)(F)F)CC2)c2c(Br)cccc21

Procedure:
The title compound was prepared following a procedure analogous to that described in Example 1 using 3-(2-(trifluoromethyl)phenyl)propanoic acid and ethyl 2-(7-bromo-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate. LC-MS Method 1 tR=2.27, min, m/z=554, 552