Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]([CH2:34][CH:35]([CH3:37])[CH3:36])[C@H:13]1[CH2:18][C@@H:17]([C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])[CH2:16][N:15]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:14]1)=[O:11].Br[CH2:39][C:40]([O:42][CH3:43])=[O:41].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:43][O:42][C:40](=[O:41])[CH2:39][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]([CH2:34][CH:35]([CH3:37])[CH3:36])[C@H:13]1[CH2:18][C@@H:17]([C:19]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)=[O:20])[CH2:16][N:15]([C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])[CH2:14]1)=[O:11]
Reactant: CC(C)CN(C(=O)c1nc2ccccc2[nH]1)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)Cn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCOCC3)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Temperature: 55 °C
Reaction time: 1 h

Procedure:
tert-Butyl (3S,5R)-3-{(1H-benzimidazol-2-ylcarbonyl)(2-methylpropyl)amino}-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (1.06 g) was dissolved in dimethylformamide (20 ml), methyl bromoacetate (390 μl) and cesium carbonate (2.02 g) were added and the mixture was stirred at 55° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, and a fraction eluted with ethyl acetate-hexane (1:9)-ethyl acetate was concentrated under reduced pressure to give the object product (1.19 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[C:5](O)=[O:6].[H-].[H-].[H-].[H-].[Li+].[Al+3]>CCOCC>[F:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1
Reactant: COc1cc(F)cc(C(=O)O)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: COc1cc(F)cc(CO)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 104.6 %

Procedure:
To a solution of 3-fluoro-5-methoxybenzoic acid (5.1 g, 30 mmol) in dry ether at 0° C., LiAlH4 (3.44 g, 90 mmol) was added slowly. The reaction mixture was stirred at room temperature for 3 h, and quenched by slow addition of 1 M aqueous HCl solution (30 mL). The mixture was extracted with ethyl acetate (3×15 mL). The organic phase was dried over Na2SO4 and concentrated to give 4.9 g of (3-fluoro-5-methoxyphenyl)methanol. 1H NMR (CDCl3): δ 6.67-6.70 (m, 2H), 6.50-6.55 (m, 1H), 4.64 (d, 2H), 3.79 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[O:6][CH2:7][C:8]1[O:12][C:11]([C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2C(OC(C)(C)C)=O)=[N:10][N:9]=1.[ClH:30].CCOC(C)=O>CCOC(C)=O>[ClH:30].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[O:6][CH2:7][C:8]1[O:12][C:11]([C@@H:13]2[CH2:17][CH2:16][CH2:15][NH:14]2)=[N:10][N:9]=1
Reactant: COc1ccc(OCc2nnc([C@@H]3CCCN3C(=O)OC(C)(C)C)o2)cc1OC
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1ccc(OCc2nnc([C@@H]3CCCN3)o2)cc1OC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To an AcOEt (200 ml) solution of the compound (42.0 g) obtained in Example 8-(2), 4N HCl-AcOEt solution (200 ml) was added and the mixture was stirred at room temperature for 4 hours. The solvent was distilled off under reduced pressure to give a crude form of the titled compound (35.0 g).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@H:12]2[C@@H:17]([CH2:18][O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:16][CH:15]=[CH:14][CH2:13]2)(=O)=O)=CC=1.[C-:28]#[N:29].[K+].O>CS(C)=O>[C:28]([CH2:11][C@H:12]1[C@@H:17]([CH2:18][O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:16][CH:15]=[CH:14][CH2:13]1)#[N:29]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CC=CC[C@@H]2COCc2ccccc2)cc1
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#CC[C@@H]1CC=CC[C@@H]1COCc1ccccc1
Temperature: 100 °C
Yield: 86.8 %

Procedure:
The p-toluene sulphonyl ester/benzyl ether (3) (12 g) in dimethylsulphoxide (DMSO) (15 ml) is added with stirring to potassium cyanide (3 g) in DMSO (20 ml). The mixture is heated at 100° C. under nitrogen for 6 hours and is then cooled, poured into water and the product extracted with ether. The solvent is removed and the residue purified on a Florisil column, eluting with petroleum ether-benzene (1:1) to give the title compound as an oil (6.5 g, ca. 80%) νmax (film) 2220 and 1600 cm-1.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4]1.O=[C:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=2[C:18]#[N:19])[CH2:12][CH2:11]1>>[OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=3[C:18]#[N:19])[CH2:12][CH2:11]2)[CH2:4]1
Reactant: N#Cc1ccccc1N1CCC(=O)CC1
Reactant: OCC1CCCNC1
Product: N#Cc1ccccc1N1CCC(N2CCCC(CO)C2)CC1

Procedure:
The title compound was prepared from 21 (1.13 g, 5.6 mmol) and 5 (750 mg, 3.75 mmol) using the procedure described in 16 to give the title compound.
Reaction SMILES: S1C(C=[O:7])=CC=C1C=O.C(O)(=O)C.[CH2:14]([CH:16]([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:17][O:18][C:19](=[O:28])[C:20]1[CH:25]=[CH:24][C:23]([NH:26][OH:27])=[CH:22][CH:21]=1)[CH3:15]>O>[CH2:14]([CH:16]([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:17][O:18][C:19](=[O:28])[C:20]1[CH:21]=[CH:22][C:23]([N+:26]([O-:7])=[O:27])=[CH:24][CH:25]=1)[CH3:15]
Reactant: O=Cc1ccc(C=O)s1
Reactant: CCCCC(CC)COC(=O)c1ccc(NO)cc1
Solvent: O
Solvent: CC(=O)O
Product: CCCCC(CC)COC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 160.6 %

Procedure:
To a 250 ml 3-necked flask was added 0.5 gm 2,5-thiophenedicarboxaldehyde, 30 ml acetic acid, 5.6 gm 2-ethylhexylesterphenyl hydroxylamine 3 and stirred for 20 hrs at room temperature. To the reaction mixture, 100 ml water was added and the mixture was filtered. The filtered product was washed with water and dried. A yield of about 1.6 gm of 2, 5-thiophene bis-2-ethylhexylesterphenyl dinitrone of Ex.2 was obtained with a HPLC purity of 98% (DSC: 205° C.).
Reaction SMILES: [CH2:1]([SnH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[C:10]([O:13][CH:14]=[CH2:15])(=[O:12])[CH3:11]>C1CCCCC1>[C:10]([O:13][CH2:14][CH2:15][Sn:5]([CH2:15][CH2:14][O:13][C:10](=[O:12])[CH3:11])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:1][CH2:2][CH2:3][CH3:4])(=[O:12])[CH3:11]
Reactant: CCCC[SnH2]CCCC
Reactant: C=COC(C)=O
Solvent: C1CCCCC1
Product: CCCC[Sn](CCCC)(CCOC(C)=O)CCOC(C)=O
Reaction time: 3 h

Procedure:
2.349 g (0.01 mole) of dibutyltin dihydride, 1.722 g (0.02 mole) of distilled vinyl acetate, and 2 g of anhydrous cyclohexane were placed in aPyrex® bowl thermostated at 25° C. The solution was exposed to ultraviolet radiation for 3 hours. The cyclohexane was then eliminated under vacuum at ambient temperature. The expected product was obtained pure in quantitative yield
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:8]=[CH:9][C:10]2[O:14][CH:13]=[C:12]([CH3:15])[C:11]=2[CH:16]=1.CN([CH:20]=[O:21])C>C1COCC1>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]2[O:14][C:13]([CH:20]=[O:21])=[C:12]([CH3:15])[C:11]=2[CH:16]=1
Reactant: CN(C)C=O
Reactant: Cc1coc2ccc(Cl)cc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1c(C=O)oc2ccc(Cl)cc12
Temperature: -78 °C
Reaction time: 1 h
Yield: 95.9 %

Procedure:
n-Butyl lithium (2.5 M in hexane, 6.6 mmol, 2.6 mL) was added dropwise over 15 minutes to a solution of 5-chloro-3-methyl benzofuran (6.0 mmol, 1 g) in THF (8 mL) cooled to −78° C. To this was added DMF (12 mmol, 0.6 mL) and stirred for one hour. The reaction mixture was allowed to come to room temperature overnight and then quenched with EtOAc (20 mL) and H2O (10 mL). The organic portion was collected, dried, filtered and the filtrate was evaporated to dryness to obtain 5-chloro-3-methyl benzofuran-2-carboxaldehyde (96%, 1.12 g), which-was carried on without further purification.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[NH2:13][C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:13][C:14]1[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=1)[O:20][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Nc1cccc(O)c1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cc([N+](=O)[O-])ccc1Oc1cccc(N)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 66.3 %

Procedure:
To a solution of 2-fluoro-5-nitrobenzonitrile (5.00 g, 30.1 mmol) and 3-aminophenol (3.28 g, 30.1 mmol) in N,N-dimethylformamide (30 ml) was added potassium carbonate (6.23 g, 45.2 mmol), and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was cooled to room temperature, insoluble material was filtered off and washed with ethyl acetate (150 mL). The filtrate and washings were combined and the mixture was concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate (200 mL), washed with 5% aqueous sodium hydrogen carbonate solution (100 mL) and saturated brine (100 mL), successively, and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/n-hexane=20/80→70/30) and the obtained solution was concentrated under reduced pressure. The residue was crystallized from ethyl acetate/n-hexane to give the title compound (5.09 g, 66%) as a yellow powder.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:42][N:43]([CH:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1)[C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47]>ClCCl.C(OCC)(=O)C>[CH3:42][N:43]([CH:51]1[CH2:52][CH2:53][N:54]([C:9](=[O:11])[CH2:8][CH2:7][N:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH2:55][CH2:56]1)[C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:47])[CH3:48]
Reactant: O=C(O)CCN1CCCCC1
Reactant: CN(C(=O)OC(C)(C)C)C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)OC(C)(C)C)C1CCN(C(=O)CCN2CCCCC2)CC1
Temperature: 0 °C
Reaction time: 15 h
Yield: 78 %

Procedure:
3-(Piperidin-1-yl)propanoic acid (3.183 mmol, 1.0 eq) was dissolved in dichloromethane (40 ml) and DIPEA (7.958 mmol, 2.5 eq) and cooled to 0° C.; EDCI (3.82 mmol, 1.2 eq) and HOBT (0.637 mmol, 0.2 eq) were added and stirring was carried out for 15 hours at RT. The mixture was then cooled to 0° C. again, tert-butyl methyl(piperidin-4-yl)carbamate (3.183 mmol, 1.0 eq) was added, and the reaction mixture was stirred for 16 hours at RT. Then the reaction mixture was diluted with ethyl acetate, washed with 10% ammonium chloride solution, sat. NaHCO3 solution and with sat. NaCl solution, dried over magnesium sulfate and concentrated. The crude product was purified by column chromatography (silica gel, ethyl acetate/ethanol). Yield: 78%
Reaction SMILES: [NH2:1][C:2](=[S:13])[C:3]1[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=1[CH3:8].Br[CH:15]([CH3:29])[C:16]([C:18]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([F:28])[CH:19]=1)=O.FC1C=C(C2N=C(C3C(C)=C(C(OC)=S)SC=3)SC=2C)C=C(C(F)(F)F)C=1.C1C(/C=C(/C(O)=O)\C#N)=CC=C(O)C=1>>[F:28][C:20]1[CH:19]=[C:18]([C:16]2[N:1]=[C:2]([C:3]3[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=3[CH3:8])[S:13][C:15]=2[CH3:29])[CH:23]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:21]=1
Reactant: COC(=S)c1cc(C(N)=S)c(C)s1
Reactant: CC(Br)C(=O)c1cc(F)cc(C(F)(F)F)c1
Agent: COC(=S)c1scc(-c2nc(-c3cc(F)cc(C(F)(F)F)c3)c(C)s2)c1C
Agent: N#C/C(=C\c1ccc(O)cc1)C(=O)O
Product: COC(=S)c1cc(-c2nc(-c3cc(F)cc(C(F)(F)F)c3)c(C)s2)c(C)s1

Procedure:
A solution of 75 mg (0.3 mmol) of methyl 4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (Maybridge, Cornwall, UK) was reacted with 90 mg (0.3 mmol) of 2-bromo-1-[3-fluoro-5-(trifluoromethyl)phenyl]propan-1-one in a manner similar to Example 8, step (a) to give, methyl 4-{4-[3-fluoro-5-(trifluoromethyl)phenyl]-5-methyl(1,3-thiazol-2-yl)}-methylthiothiophene-2-carboxylate (31.9 mg, 24%) as a solid. 1H-NMR (DMSO-d6; 300 MHz) δ8.17 (s, 1H), 7.98 (m, 1H), 7.95 and 7.92 (m, 1H, 1:1 ratio conformers), 7.77 and 7.74 (m, 1H, 1:1 ratio conformers), 3.87 (s, 3H), 2.75 (s, 3H), 2.70 (s, 3H). Mass spectrum (MALDI-TOF, CHCA matrix, m/z): Calcd. for C18H13NO2S3F4, 448.0 (M+H), found 448.0.
Reaction SMILES: [C:1]([C:4]1[C:9]([NH:10][C:11]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)=O)=[CH:8][CH:7]=[CH:6][C:5]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:3])[NH2:2].C[O-].[Na+]>CO>[O:3]=[C:1]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][C:5]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:10]=[C:11]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[NH:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2cccc(-c3ccccc3)c2C(N)=O)CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2nc3cccc(-c4ccccc4)c3c(=O)[nH]2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 61.7 %

Procedure:
To a solution tert-butyl 4-(2-carbamoylbiphenyl-3-ylcarbamoyl)piperidine-1-carboxylate (1.0 g, 2.4 mmol) in methanol was added NaOMe (2.6 mL, 25% in MeOH, 12.3 mmol). The resulting reaction mixture was stirred at RT for 14 h. After this time, the reaction mixture was concentrated under reduced pressure and the resulting residue was diluted with ethyl acetate and then washed with water. The organic portion was dried, concentrated under reduced pressure to yield a residue. The residue was purified by ISCO chromatography (30% EtOAc in hexanes) to yield tert-butyl 4-(4-oxo-5-phenyl-3,4-dihydroquinazolin-2-yl)piperidine-1-carboxylate (0.60 g, 67% yield) as a white solid. LCMS Method W: retention time 2.07 min; [M+1]=422.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:25])[NH:10][O:11][CH:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[ClH:26]>O1CCOCC1>[ClH:26].[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:10][O:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:25])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(ONC(=O)Nc2ccc(F)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(NOC1CCNCC1)Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
A mixture of tert-butyl 4-(3-(4-fluorophenyl)ureidooxy)piperidine-1-carboxylate (1.5 g, 4.2 mmol) and 1 N HCl solution in dioxane (25 ml) was stirred at room temperature for 3 hours and concentrated in vauo. The residual solid was triturated with diethyl ether (100 ml) to give 1-(4-fluorophenyl)-3-(piperidin-4-yloxy)urea hydrochloride (1.1 g, 90%) as a white solid.
Reaction SMILES: [OH-].[Li+].C([O:5][C:6]([C:8]1[S:12][C:11]2=[N:13][C:14]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[CH:15][N:10]2[C:9]=1[CH3:23])=[O:7])C>C(O)C.O>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:14]2[N:13]=[C:11]3[N:10]([CH:15]=2)[C:9]([CH3:23])=[C:8]([C:6]([OH:7])=[O:5])[S:12]3)=[CH:17][CH:18]=1
Reactant: CCOC(=O)c1sc2nc(-c3ccc(F)cc3)cn2c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1c(C(=O)O)sc2nc(-c3ccc(F)cc3)cn12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To lithium hydroxide (184.4 mg, 7.7 mmol) in 100 ml of ethanol and 100 ml of water was added 6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic acid ethyl ester (example 1, 2.13 g, 7 mmol). After stirring 24 hours at RT the mixture was filtered and the filtrate partially evaporated. The aqueous solution was acidified with hydrochloric acid to pH 4 and the separated product filtered and dried. Yield: 1.11 g (57%). MS: M+H+=277.01.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([Br:24])[CH:9]=[C:10]([CH:11]3CCN(C(OC(C)(C)C)=O)C[CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1.NC1C2=CC=C(CC[OH:37])N2N=CN=1>>[NH2:1][C:2]1[C:7]2=[C:8]([Br:24])[CH:9]=[C:10]([CH2:11][CH2:12][OH:37])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(Br)c3c(N)ncnn23)CC1
Reactant: Nc1ncnn2c(CCO)ccc12
Product: Nc1ncnn2c(CCO)cc(Br)c12

Procedure:
This compound was prepared in a manner similar to the bromination procedure described for the preparation of tert-butyl 4-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate, using 2-(4-amino-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-ethanol as the starting material. 1H NMR (300 MHz, DMSO-d6) δ 7.83 (s, 1H), 6.64 (s, 1H), 4.75 (t, 1H), 3.65 (q, 2H), 2.96 (t, 2H); ES-MS m/z 257.3/259.2 [M+H]+, RT (min) 0.35.
Reaction SMILES: P(O[CH2:10][C:11]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]([O:19][CH3:20])[CH:12]=1)(OCC)(OCC)=O.[C:21]([O:24][C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([O:37][C:38](=[O:40])[CH3:39])[C:32]=1[O:33][C:34](=[O:36])[CH3:35])[CH:28]=O)(=[O:23])[CH3:22]>>[CH3:20][O:19][C:13]1[CH:12]=[C:11](/[CH:10]=[CH:28]/[C:27]2[CH:26]=[C:25]([O:24][C:21](=[O:23])[CH3:22])[C:32]([O:33][C:34](=[O:36])[CH3:35])=[C:31]([O:37][C:38](=[O:40])[CH3:39])[CH:30]=2)[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=1
Reactant: CC(=O)Oc1cc(C=O)cc(OC(C)=O)c1OC(C)=O
Reactant: CCOP(=O)(OCC)OCc1cc(OC)cc(OC)c1
Product: COc1cc(/C=C/c2cc(OC(C)=O)c(OC(C)=O)c(OC(C)=O)c2)cc(OC)c1
Yield: 75 %

Procedure:
Use diethyl 3,5-dimethoxybenzyl phosphate and 3,4,5-triacetoxybenzaldehyde as materials, and follow the method described in Example 5 to obtain a white solid as the target product (75%). 1H NMR (400 MHz, DMSO-d6): 2.08 (s, 9H), 3.77 (s, 6H), 6.22 (s, 1H), 6.84 (s, 2H), 6.91 (d, J=16.0 Hz, 1H), 6.92 (d, J=16.0 Hz, 1H), 7.01 (s, 2H).
Reaction SMILES: [CH2:1]([C:3]1([CH2:14][C:15]([OH:17])=[O:16])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12]C)[CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].CN1C(=O)CCC1.[OH-].[Na+].C(S)CCCCCCCCCCC>Cl>[CH2:1]([C:3]1([CH2:14][C:15]([OH:17])=[O:16])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCC1(CC(=O)O)CCc2ccc(OC)cc21
Agent: CCCCCCCCCCCCS
Agent: Cl
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCC1(CC(=O)O)CCc2ccc(O)cc21
Temperature: 125 °C
Reaction time: 8 h
Yield: 64.9 %

Procedure:
A screw-cap vial was charged with 42.2 (0.195 g, 0.832 mmol), NMP (0.8 mL), sodium hydroxide (0.150 g, 3.75 mmol), and 1-dodecanethiol (available from Aldrich) (0.699 mL, 2.91 mmol). The mixture was stirred overnight at 125° C. (sealed vial) and cooled to room temperature. Additional NMP (0.8 mL), sodium hydroxide (0.150 g, 3.75 mmol), and 1-dodecanethiol (0.699 mL, 2.91 mmol) were added, and the mixture was stirred for 72 hours at 125° C. and cooled to room temperature. The solidified mixture was fractured with a spatula, diluted with 1 N HCl, and extracted with EtOAc. The combined organic layers were washed with water and brine, dried (MgSO4), and concentrated. The residue was purified by silica gel flash chromatography (20-50% EtOAc/hexanes) to afford 42.3 (0.119 g, 65% yield) as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[CH3:19][N:20]1[CH2:28][CH2:27][C:23]2([CH2:26][NH:25][CH2:24]2)[CH2:22][CH2:21]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][N:25]3[CH2:26][C:23]4([CH2:27][CH2:28][N:20]([CH3:19])[CH2:21][CH2:22]4)[CH2:24]3)=[CH:8][C:6]=2[N:7]=1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CN1CCC2(CC1)CNC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: CN1CCC2(CC1)CN(Cc1cc3nc(Cl)nc(N4CCOCC4)c3s1)C2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 29.9 %

Procedure:
To a solution of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde (72 mg, 0.254 mmol) in DCE (7 mL) was added 7-methyl-2,7-diaza-spiro[3.5]nonane (45 mg, 0.321 mmol). The mixture was stirred at RT for 10 min, then sodium triacetoxyborohydride (81 mg, 0.382 mmol) was added and stirring was continued for 3 h. To the reaction mixture was added water and the resulting solution was loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the desired product was eluted with 2 M NH3 in MeOH an concentrated in vacuo. The resultant residue was purified by column chromatography to give the title compound as a yellow oil (31 mg, 30%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[N:14]2[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]2=[N:12][C:11]=1[C:20]1[CH:33]=[CH:32][CH:31]=[CH:30][C:21]=1[C:22]([NH:24][NH:25][C:26]([NH:28][CH3:29])=S)=[O:23]>CO.C([O-])(=O)C.[Hg+2].C([O-])(=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[N:14]2[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]2=[N:12][C:11]=1[C:20]1[CH:33]=[CH:32][CH:31]=[CH:30][C:21]=1[C:22]1[O:23][C:26]([NH:28][CH3:29])=[N:25][N:24]=1
Reactant: CNC(=S)NNC(=O)c1ccccc1-c1nc2ccc(F)cn2c1Nc1c(C)cccc1C
Agent: CC(=O)[O-]
Agent: [Hg+2]
Solvent: CO
Product: CNc1nnc(-c2ccccc2-c2nc3ccc(F)cn3c2Nc2c(C)cccc2C)o1
Yield: 26 %

Procedure:
3.2 117 mg (0.253 mmol) of 1-{2-[3-(2,6-dimethylphenylamino)-6-fluoroimidazo[1,2-a]pyridin-2-yl]benzoyl}-4-methyl-3-thiosemicarbazide and 96 mg (0.300 mmol) of mercury(II) acetate are warmed at 80° C. for 1 hour in 10 ml of methanol in a sealed screw-lid bottle. The mixture is filtered through kieselguhr, rinsed with MeOH, and the filtrate is evaporated to dryness. Purification by silica-gel chromatography (heptane/ethyl acetate) gives 28 mg of (2,6-dimethylphenyl)-{6-fluoro-2-[2-(5-methylamino-1,3,4-oxadiazol-2-yl)phenyl]imidazo[1,2-a]pyridin-3-yl}amine, corresponding to a yield of 26%; MS-FAB (M+H+)=429.8; Rf (HPLC, polar method): 1.58 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[S:7][CH2:6][CH2:5][N:4]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]#[C:20][CH2:21][CH2:22][O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:3]1[C:30]([O:32]C)=[O:31].[OH-].[Na+].CO>C1COCC1>[CH3:1][C:2]1([CH3:34])[S:7][CH2:6][CH2:5][N:4]([S:8]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:18][C:19]#[C:20][CH2:21][CH2:22][O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)=[CH:15][CH:16]=2)(=[O:10])=[O:9])[CH:3]1[C:30]([OH:32])=[O:31]
Reactant: COC(=O)C1N(S(=O)(=O)c2ccc(OCC#CCCOC3CCCCO3)cc2)CCSC1(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC1(C)SCCN(S(=O)(=O)c2ccc(OCC#CCCOC3CCCCO3)cc2)C1C(=O)O
Yield: 84.1 %

Procedure:
A solution of 0.418 g (0.817 mmol) of methyl 2,2-dimethyl-4-[(4-{[5-(tetrahydro-2H-pyran-2-yloxy)-2-pentynyl]oxy}phenyl)sulfonyl]-3-thiomorpholine carboxylate, 4.0 mL (4.08 mmol) of 1N NaOH, 4.0 mL of methanol and 4.0 mL of THF was heated to reflux for 5 h. The reaction was concentrated and the residue was diluted with water, acidified to pH5 and extracted with ethyl acetate. The organics were washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo to provide 0.342 g (84%) of 2,2-dimethyl-4-[(4-{[5-(tetrahydro-2H-pyran-2-yloxy)-2-pentynyl]oxy}phenyl)sulfonyl]-3-thiomorpholine carboxylic acid as a colorless oil. Electrospray Mass Spec: 496.5 (M−H)−.