Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][C:9]1[C:10]([F:28])=[C:11]([C:21]2[N:22]=[CH:23][C:24]([NH2:27])=[N:25][CH:26]=2)[CH:12]=[CH:13][C:14]=1[CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[NH2:27][C:24]1[N:25]=[CH:26][C:21]([C:11]2[C:10]([F:28])=[C:9]([OH:8])[C:14]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[CH:13][CH:12]=2)=[N:22][CH:23]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1c(C2CCCCC2)ccc(-c2cnc(N)cn2)c1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Nc1cnc(-c2ccc(C3CCCCC3)c(O)c2F)cn1
Reaction time: 16 h
Yield: 60.2 %

Procedure:
A solution consisting of 5-(3-((tert-butyldimethylsilyl)oxy)-4-cyclohexyl-2-fluorophenyl)pyrazin-2-amine (936 mg, 2.33 mmol) and THF (15 mL) was treated with tetrabutylammonium fluoride (5 mL, 5 mmol, 1 M in THF). The reaction mixture was stirred for 16 hours at which point it was concentrated to dryness and purified by FCC to yield the title compound (0.403 g, 60%) which was used without further purification. MS (ESI): mass calcd. for C16H18FN3O, 287.14; m/z found, 288.1 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.47-8.45 (m, 1H), 8.09 (d, J=1.5, 1H), 7.32 (m, 1H), 7.06-7.03 (m, 1H), 5.60 (d, J=6.3, 1H), 4.65 (s, 2H), 3.00-2.92 (m, 1H), 1.94-1.81 (m, 4H), 1.80-1.74 (m, 1H), 1.52-1.38 (m, 4H), 1.33-1.25 (m, 1H).
Reaction SMILES: [P:1]([O:5][CH2:6][C@H:7]1[O:11][C@@H:10]([N:12]2[C:21]3[N:20]=[CH:19][N:18]=[C:16]([NH2:17])[C:15]=3[N:14]=[C:13]2[NH:22][CH2:23][CH2:24][NH2:25])[C@H:9]([OH:26])[C@@H:8]1[OH:27])([OH:4])([OH:3])=[O:2].[OH-].[Na+].C(=O)(O)[O-].[Na+].F[C:36]1[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][C:37]=1[N+:45]([O-:47])=[O:46].Cl>O.C(O)C.CC(C)=O>[P:1]([O:5][CH2:6][C@H:7]1[O:11][C@@H:10]([N:12]2[C:21]3[N:20]=[CH:19][N:18]=[C:16]([NH2:17])[C:15]=3[N:14]=[C:13]2[NH:22][CH2:23][CH2:24][NH:25][C:40]2[CH:41]=[CH:36][C:37]([N+:45]([O-:47])=[O:46])=[CH:38][C:39]=2[N+:42]([O-:44])=[O:43])[C@H:9]([OH:26])[C@@H:8]1[OH:27])([OH:3])([OH:4])=[O:2]
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Reactant: NCCNc1nc2c(N)ncnc2n1[C@@H]1O[C@H](COP(=O)(O)O)[C@@H](O)[C@H]1O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: CCO
Product: Nc1ncnc2c1nc(NCCNc1ccc([N+](=O)[O-])cc1[N+](=O)[O-])n2[C@@H]1O[C@H](COP(=O)(O)O)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
8-(2-aminoethyl)aminoadenosine-5'-monophosphate from Part A of this Example (0.64 mmol) was dissolved in 20 ml water by addition of sodium hydroxide to pH 8.0. Then 168 mg sodium bicarbonate was added, followed by 0.2 ml 1-fluoro-4-dinitrobenzene (1.58 mmol dissolved in 2 ml ethanol). The reaction was stirred for 18 hr at room temperature and then 0.1 ml 1-fluoro-2,4-dinitrobenzene in 1 ml ethanol was added. After stirring for an additional 4 hrs, the mixture was adjusted to pH 2.0 with hydrochloric acid and poured into 200 ml cold acetone (-10° C.). The yellow precipitate which formed was collected by filtration, dissolved in 200 ml water and passed into a 2.5×45 cm column of DEAE-cellulose in the bicarbonate form. The chromatogram was developed with a linear salt gradient generated with 2 liters water and 2 liters 0.7M ammonium carbonate. A peak of yellow material with an absorption maximum at 275 nm eluted between 2 and 3 liters of the gradient. Ammonium bicarbonate was removed from this material by evaporation under vacuum and the yield of the desired intermediate was 37 percent. Optical absorption maxima measured in 0.02N hydrochloric acid occurred at 275 and 363 nm and the millimolar extinction coefficients were 21.8 and 15.5, respectively. Further analyses showed 1.07 phosphate residue per ribose residue.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH2:13][N:14]3[C:26]4[C:25]5[N:24]=[CH:23][CH:22]=[CH:21][C:20]=5[N:19]=[C:18]([NH2:27])[C:17]=4[N:16]=[CH:15]3)[O:10][N:9]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>[Pt](=O)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[C:11]([CH2:13][N:14]3[C:26]4[C:25]5[NH:24][CH2:23][CH2:22][CH2:21][C:20]=5[N:19]=[C:18]([NH2:27])[C:17]=4[N:16]=[CH:15]3)[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: Nc1nc2cccnc2c2c1ncn2Cc1cc(-c2ccc(F)cc2)no1
Agent: O=[Pt]=O
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc2c(c3c1ncn3Cc1cc(-c3ccc(F)cc3)no1)NCCC2
Reaction time: 0.5 h
Yield: 12.6 %

Procedure:
1-{[3-(4-Fluorophenyl)isoxazol-5-yl]methyl}-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine (Example 11, 0.300 g, 0.833 mmol) was combined with platinum (IV) oxide (0.03 g) and trifluoroacetic acid (5 mL), and the mixture was placed under hydrogen pressure (45 psi, 3.1×105 Pa) for 24 hours. An analysis by liquid chromatography/mass spectrometry indicated the presence of starting material. The catalyst was removed by filtration, and the trifluoroacetic acid was removed under reduced pressure. The residue was combined with trifluoroacetic acid (5 mL) and platinum (IV) oxide (0.10 g), and the reaction was again placed under hydrogen pressure (45 psi, 3.1×105 Pa) for 24 hours. The catalyst was removed by filtration, and the trifluoroacetic acid was removed under reduced pressure. The resulting oil was dissolved in 6 N hydrogen chloride in ethanol and stirred for 30 minutes. The solvent was removed under reduced pressure, and the residue was dissolved in water. The solution was adjusted to pH 14 with the addition of a few drops of 50% w/w sodium hydroxide, and the resulting mixture was stirred for 30 minutes. A precipitate was present and was isolated by filtration, purified by column chromatography on silica gel (5% to 10% CMA in chloroform), triturated with diethyl ether, filtered, and dried to provide 0.0382 g of 1-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-6,7,8,9-tetrahydro-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine as a white powder, mp 227.0-228.0° C.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].C(O)(=O)C.[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4])=[CH:15][CH:14]=1
Reactant: CC(C)(N)CO
Reactant: COc1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1ccc(CNC(C)(C)CO)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 60.7 %

Procedure:
To a solution of 2-amino-2-methyl-1-propanol (8.4, 94 mmol) in 1,2-dichloroethane (150 mL) and acetic acid (4.3 mL, 77 mmol) was added 4-methoxy benzaldehyde (11.5 mL, 94 mmol). After stirring for 10 min, sodium triacetoxyborohydride (49.9 g, 235.5 mmol) was added portion-wise over 20 min. The resulting mixture was stirred at 60° C. for 2 h then cooled to room temperature and quenched with saturated NaHCO3. The aqueous layer was washed with dichloromethane and made basic by the addition of 10N NaOH. The product was extracted with ethyl acetate, concentrated and crystallized from Et2O/hexane to give the title compound as a white solid (11.95 g, 61% yield). 1H NMR (300 MHz, CDCl3) δ: 7.32-7.20 (2H, m), 6.86-6.80 (2H, m), 3.76 (3H, s), 3.58 (2H, s), 3.30 (2H, s), 1.11 (6H, s). LCMS (M+H) calcd for C12H20NO2: 210.14; found: 210.20.
Reaction SMILES: [C:1]([NH:5][C:6]1[N:11]=[C:10](Cl)[C:9]([C:13]#[N:14])=[CH:8][C:7]=1[F:15])([CH3:4])([CH3:3])[CH3:2].[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN1CCCC1=O>[CH2:16]([NH:23][C:10]1[C:9]([C:13]#[N:14])=[CH:8][C:7]([F:15])=[C:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])[N:11]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)Nc1nc(Cl)c(C#N)cc1F
Solvent: CN1CCCC1=O
Product: CC(C)(C)Nc1nc(NCc2ccccc2)c(C#N)cc1F
Temperature: 160 °C
Reaction time: 3 h
Yield: 25.4 %

Procedure:
To 40 ml of N-methylpyrrolidone solution of 6 g 6-t-butylamino-2-chloro-3-cyano-5-fluoropyridine was added 6.3 g of benzylamine, and the mixture was stirred under nitrogen atmosphere at 160° C. for 3 hours and allowed to cool. The reaction solution was separated by adding chloroform and water, and the organic layer was dried over magnesium sulfate, and the solvent was distilled off. The precipitated crystals were collected from the residue by filtration to obtain 2 g of the title compound as a pale yellow powder.
Reaction SMILES: [NH:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1.[C:14](Cl)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>CC#N>[C:14]([N:3]1[C:4]2[CH:5]=[N:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]=2[N:1]=[CH:2]1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: c1ccc2c(c1)ncc1nc[nH]c12
Solvent: CCN(CC)CC
Solvent: CC#N
Product: c1ccc(C(c2ccccc2)(c2ccccc2)n2cnc3c4ccccc4ncc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
To a suspension of 5.2 g of 1H-imidazo[4,5-c]quinoline (II-1) in 180 ml of MeCN were added 10.3 g of trityl chloride and 4.2 g of triethylamine, and the mixture was stirred at room temperature for 8 hours. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate. The organic layer was washed with water and brine, and then dried. The ethyl acetate was removed and the residue was chromatographed on a column of silica gel with ethyl acetate-n-hexane (1:1 v/v). Crystallization of the resulting oily substance from n-hexane gave 12.4 g (yield: 98%) of the titled compound (III-1). This was recrystallized from ethyl acetate-n-hexane to give colorless crystals melting at 190°~192° C.
Reaction SMILES: NCC(O)=O.[OH-].[Na+].[F:8][CH2:9][CH2:10][CH2:11][CH:12]([CH2:15][CH2:16][OH:17])[CH2:13][OH:14].C1C=[N+]([C@@H]2O[C@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](O)[C@@H]3O)(O)=O)([O-])=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1.COC1C=CC(C=O)=CC=1>O.CC(C)=O.C(O)C.C(Cl)Cl>[F:8][CH2:9][CH2:10][CH2:11][C@@H:12]1[CH2:15][CH2:16][O:17][C:13]1=[O:14]
Reactant: OCCC(CO)CCCF
Agent: COc1ccc(C=O)cc1
Agent: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)([O-])OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: NCC(=O)O
Solvent: CC(C)=O
Solvent: O
Solvent: ClCCl
Product: O=C1OCC[C@H]1CCCF

Procedure:
Glycine (18.8 grams) is dissolved in 2 liters of deionized water, and the pH is adjusted by the addition of 10% sodium hydroxide to 9.0. 2-(3-fluoropropyl)-1,4-butanediol (10.0 grams) is dissolved in 150 ml of acetone added to the glycine solution with stirring, followed by the addition of β-NAD+ (Sigma, 0.5 grams). To the resulting solution is added horse liver alcohol dehydrogenase (Sigma, 250 mg, approximately 400 units). After the enzyme has dissolved the pH is readjusted to 9.0 with 10% sodium hydroxide, and the reaction mixture is stirred at 30° C. During the reaction, the pH is maintained at 9.0 with a pH-stat by the addition of 10% sodium hydroxide. Progress of the reaction is monitored by thin layer chromatography (Silica gel plates, eluent methylene chloride; visualization by dipping in a solution of 5% anisaldehyde in ethanol and heating). When the reaction is complete as judged by thin layer chromatography, the reaction mixture is adjusted to a pH of 13 with 10 M sodium hydroxide and then extracted 3 times with 250 ml of methylene chloride. The pH of the aqueous mixture is then adjusted to 3 with concentrated HCl, followed by continuous extraction with 1 liter of ethyl acetate for 24 hours. The ethyl acetate extract is dried over anhydrous magnesium sulfate and evaporated under reduced pressure to yield (2R)-2-(3-fluoropropyl)butyrolactone as a yellowish oil.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[CH:12])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].I[C:14]1[C:19]([CH3:20])=[CH:18][C:17](Br)=[CH:16][C:15]=1[CH3:22]>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:14]2[C:19]([CH3:20])=[CH:18][C:17]([C:12]#[C:11][C:8]3[CH:9]=[CH:10][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[CH:6][CH:7]=3)=[CH:16][C:15]=2[CH3:22])=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Cc1cc(Br)cc(C)c1I
Reactant: C#Cc1ccc(CCCC)cc1
Product: CCCCc1ccc(C#Cc2cc(C)c(C#Cc3ccc(CCCC)cc3)c(C)c2)cc1

Procedure:
1,4-bis(4-n-Butylphenylethynyl)-2,6-dimethylbenzene is prepared from 4-n-butylphenylacetylene and 1-iodo-4-bromo-2,6-dimethylbenzene analogously to the synthesis described under 1A.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])=[O:16])=[CH:13][N:12]=[C:11]([NH:26][CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[N:10]=1.[N:33]1([CH2:39][C:40](O)=[O:41])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>>[NH2:8][C:9]1[C:14]([C:15](=[O:16])[C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])=[CH:13][N:12]=[C:11]([NH:26][CH:27]2[CH2:28][CH2:29][N:30]([C:40](=[O:41])[CH2:39][N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[CH2:31][CH2:32]2)[N:10]=1
Reactant: O=C(O)CN1CCOCC1
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCNCC2)nc1N
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(C(=O)CN3CCOCC3)CC2)nc1N

Procedure:
The same procedure as described in Example 81 was used, starting from [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone trifluoroacetic acid salt, Example 59, and morpholin-4-yl-acetic acid (Aldrich) to give 1-[4-[4-amino-5-(5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidin-1-yl]-2-morpholin-4-yl-ethanone. MS (M+H)+: 473.
Reaction SMILES: [N-:1]=[C:2]=[O:3].[CH:4]1([CH2:10][CH2:11][CH2:12][CH2:13]N)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1>>[N:1]([CH2:13][CH2:12][CH2:11][CH2:10][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)=[C:2]=[O:3]
Reactant: [N-]=C=O
Reactant: NCCCCC1CCCCC1
Product: O=C=NCCCCC1CCCCC1
Yield: 91 %

Procedure:
Following the synthetic procedure of 4b′ as described in Example 17, isocyanate 4d′ (91% yield) was synthesized from 4-(cyclohexyl)butylamine as an oil. 1H-NMR (CDCl3) δ0.80-0.95 (m, 2H), 1.10-1.30 (m, 6H), 1.32-1.45 (m, 2H), 1.52-1.75 (m, 7H), 3.28 (t, J=6.6 Hz, 2H).
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[CH3:22][C:23]1[CH:32]=[C:31]([CH2:33][O:34][C:35]2[CH:59]=[CH:58][C:38]([C:39]([NH:41][CH2:42][C:43]3([N:52]4[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]4)[C:48](=[O:49])[NH:47][C:46](=[O:50])[NH:45][C:44]3=[O:51])=[O:40])=[CH:37][CH:36]=2)[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1.[N:60]1[CH:65]=[CH:64][CH:63]=[C:62]([CH:66]=O)[CH:61]=1>>[CH3:22][C:23]1[CH:32]=[C:31]([CH2:33][O:34][C:35]2[CH:36]=[CH:37][C:38]([C:39]([NH:41][CH2:42][C:43]3([N:52]4[CH2:53][CH2:54][N:55]([CH2:66][C:62]5[CH:61]=[N:60][CH:65]=[CH:64][CH:63]=5)[CH2:56][CH2:57]4)[C:44](=[O:51])[NH:45][C:46](=[O:50])[NH:47][C:48]3=[O:49])=[O:40])=[CH:58][CH:59]=2)[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1
Reactant: O=Cc1cccnc1
Reactant: Cc1cc(COc2ccc(C(=O)NCC3(N4CCNCC4)C(=O)NC(=O)NC3=O)cc2)c2ccccc2n1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(COc2ccc(C(=O)NCC3(N4CCN(Cc5cccnc5)CC4)C(=O)NC(=O)NC3=O)cc2)c2ccccc2n1
Yield: 51 %

Procedure:
Following the procedure analogous to that used in reaction (9), the compound from Example 8 was reacted with 3-pyridine-carboxaldehyde for 2 days to provide the title compound (7.6 mg, 51%). MS found: (M+H)+=608.4.
Reaction SMILES: Br[C:2]1[C:3]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C([Li])(C)(C)C.[O:23]1[C:28](=[O:29])[CH2:27][CH2:26][CH2:25][C:24]1=[O:30].O>CCOCC>[CH2:12]([C:3]1[C:2]([C:28](=[O:29])[CH2:27][CH2:26][CH2:25][C:24]([OH:30])=[O:23])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCc1nc2ccccc2cc1Br
Reactant: O=C1CCCC(=O)O1
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: CCOCC
Product: CCCCCCc1nc2ccccc2cc1C(=O)CCCC(=O)O
Temperature: -100 °C
Reaction time: 2 h

Procedure:
To the solution of 3-bromo-2-hexyl-quinoline in ether was added tert-butyl lithium at −100° C. The reaction mixture was stirred for 2 hours at −100° C. To the reaction mixture a solution of dihydro-pyran-2,6-dione in ether was added at −100° C. and stirred for 30 minutes and was allowed to warm up to RT. The stirring was continued for 3 hours. The water was added to the reaction mixture and was stirred for 20 minutes. Solvent was evaporated under vacuum and water was added to the crude mixture. It was then acidified by using dilute HCl and was extracted with ether. The product was purified by column chromatography.
Reaction SMILES: Cl.[OH:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[N:12]2[CH:13]=[CH:14][N:15]=[C:11]2[CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25].C(=O)([O-])O.[Na+]>ClCCl>[CH3:23][S:24]([O:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[N:12]2[CH:13]=[CH:14][N:15]=[C:11]2[CH:10]=[CH:9][CH:8]=1)(=[O:26])=[O:25]
Reactant: OCCCCc1cccc2nccn12
Reactant: CS(=O)(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCCCc1cccc2nccn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1.59 g (7.0 mmol) of 5-(4-hydroxybutyl)imidazo[1,2-a]pyridine hydrochloride and 2.25 ml (16 mmol) of triethylamine in 30 ml of dichloromethane, 0.62 ml (8.0 mmol) of methanesulfonyl chloride was added at 0° C. After stirring at room temperature for 1 hour, saturated aqueous sodium hydrogen carbonate was added. The reaction mixture was extracted with dichloromethane and dried, after which the solvent was distilled off to yield 5-(4-methanesulfonyloxybutyl)imidazo[1,2-a]pyridine.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:12]([CH2:13][NH:14][C:15]3[C:20]([F:21])=[CH:19][CH:18]=[C:17]([O:22][CH2:23][CH3:24])[C:16]=3[F:25])=[CH:11][N:10]=[C:9]([S:26][CH3:27])[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].C1N=CN([C:35](N2C=NC=C2)=[O:36])C=1>C1COCC1>[CH:1]1([N:6]2[C:7]3=[N:8][C:9]([S:26][CH3:27])=[N:10][CH:11]=[C:12]3[CH2:13][N:14]([C:15]3[C:20]([F:21])=[CH:19][CH:18]=[C:17]([O:22][CH2:23][CH3:24])[C:16]=3[F:25])[C:35]2=[O:36])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOc1ccc(F)c(NCc2cnc(SC)nc2NC2CCCC2)c1F
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOc1ccc(F)c(N2Cc3cnc(SC)nc3N(C3CCCC3)C2=O)c1F
Reaction time: 0.5 h
Yield: 80.8 %

Procedure:
A solution of 1.00 g (2.53 mmol) of cyclopentyl-{5-[(3-ethoxy-2,6-difluoro-phenylamino)-methyl]-2-methylsulfanyl-pyrimidin-4-yl }-amine in 20 mL of dry THF was cooled to 0C. To this solution was added 0.25 g (6.33 mmol, 2.5 equivalents) of NaH as a 60% oil suspension. The reaction was stirred for 0.5 hour, the ice bath was removed, and the reaction was stirred for another 0.5 hour. To the reaction was added 1.24 g (7.60 mmol, 3.0 equivalents) of CDI. After 0.5 hour the reaction was warmed to reflux for 24 hours. The reaction was concentrated in vacuo and the residue was partitioned between dichloromethane and a saturated solution of ammonium chloride. The dichloromethane layer was washed again with ammonium chloride and then once with a saturated solution of NaCl, dried, and concentrated in vacuo. The crude material was eluted onto a Biotage 90 g silica gel column that had been pre-equilibrated with 3:1 hexane/ethyl acetate using the same solvent mixture. Fractions of pure product were combined and concentrated in vacuo to give 0.86 g (81%) of the title compound as a foam: mp 45° C. dec. MS (APCI) (m+1)/z 421.2 Analysis calculated for C20H22F2N4SO2: C, 57.13; H, 5.27; N, 13.32. Found: C, 57.12; H, 5.08; N, 13.21.
Reaction SMILES: [N+](C1C=CC(C[O:11][C:12]([C:14]2[N:15]3[CH:18]([CH:19]([CH3:32])[C:20]=2[S:21][CH:22]2[CH2:26][CH:25]([CH2:27][O:28][C:29]([NH2:31])=[O:30])[O:24][CH2:23]2)[CH:17]([CH:33]([OH:35])[CH3:34])[C:16]3=[O:36])=[O:13])=CC=1)([O-])=O.C(=O)(O)[O-].[Na+:41].O>[Pd].O1CCOCC1>[Na+:41].[NH2:31][C:29]([O:28][CH2:27][CH:25]1[O:24][CH2:23][CH:22]([S:21][C:20]2[CH:19]([CH3:32])[CH:18]3[N:15]([C:16](=[O:36])[CH:17]3[CH:33]([OH:35])[CH3:34])[C:14]=2[C:12]([O-:13])=[O:11])[CH2:26]1)=[O:30]
Reactant: CC(O)C1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3COC(COC(N)=O)C3)C(C)C12
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(O)C1C(=O)N2C(C(=O)[O-])=C(SC3COC(COC(N)=O)C3)C(C)C12
Yield: 55.7 %

Procedure:
The title compound is prepared by the procedure of Example 18 using 0.126 g of product from Example 20, 0.0223 g of sodium bicarbonate, 1.4 ml of water, 7.8 ml of dioxane, and 0.070 g of 10% palladium/carbon to give 0.055 g of the desired product as a yellow solid.
Reaction SMILES: Br[C:2]1[C:3]([C:13]#[N:14])=[C:4]([N+:10]([O-:12])=[O:11])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O>C1(C)C=CC=CC=1.CCO.C(=O)([O-])[O-].[Na+].[Na+].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>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:2]1[C:3]([C:13]#[N:14])=[C:4]([N+:10]([O-:12])=[O:11])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: COc1cc(Br)c(C#N)c([N+](=O)[O-])c1
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc(-c2ccccc2Cl)c(C#N)c([N+](=O)[O-])c1
Yield: 100 %

Procedure:
5-Bromo-4-cyano-3-nitroanisole [prepared by the method of Harrison et al, J. Chem. Soc. C, 1769 (1966)] (250 mg, 0.86mmol) and 2-chlorophenylboronic acid (150 mg, 0.96 mmol) were dissolved in a mixture of toluene (10 ml), EtOH (5.6 ml), and 1N aqueous sodium carbonate (1.7 ml). The solution was placed under a nitrogen atmosphere and tetrakis(triphenylphosphine)palladium (30 mg, 0.03 mmol) added. After refluxing for 3 h, the solvent was removed from the reaction mixture under reduced pressure. The residue was partitioned between H2O (50 ml) and EtOAc (50 ml) and the EtOAc layer washed with H2O (2×50 ml), and dried over MgSO4. Following removal of the solvent, the crude material was purified on silica gel, eluting with hexane/ether (1/1, v/v). This gave the subtitle compound as a colourless gum (252 mg, 100%). Rf 0.38 (hexane/ether 1:1, v/v). MS m/z 306 and 308 (MNH4+).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([N+]([O-])=O)[CH:12]=[C:11]([Cl:18])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-:19].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.O.C(OCC)(=O)C>CN(C)C=O>[CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([F:19])[CH:12]=[C:11]([Cl:18])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [F-]
Reactant: O=[N+]([O-])c1cc(Cl)nc(NCc2ccccc2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: Fc1cc(Cl)nc(NCc2ccccc2)c1
Temperature: 65 °C

Procedure:
A solution of Example 212A (70 mg, 0.265 mmol) in 3 mL of N,N-dimethylformamide was treated with 1M tetra-n-butyl ammonium fluoride in tetrahydrofuran (0.531 mL, 0.531 mmol) and the mixture was heated at 65° C. for 12 hours. The mixture was poured into 30 mL 1:1 water/ethyl acetate and the organic layer was washed with water and brine, dried over sodium sulfate, filtered, and concentrated. Purification by column chromatography (silica, 5% ethyl acetate-hexane) afforded the title compound. LCMS: 236.8 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C:8]2([CH:15]([F:17])[F:16])[NH:13][C:12](=O)[CH2:11][O:10][CH2:9]2)[CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:28])=CC=1>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C:8]2([CH:15]([F:17])[F:16])[NH:13][C:12](=[S:28])[CH2:11][O:10][CH2:9]2)[CH:7]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1COCC(c2cc(Br)ccc2F)(C(F)F)N1
Solvent: C1CCOC1
Product: Fc1ccc(Br)cc1C1(C(F)F)COCC(=S)N1

Procedure:
A mixture of 7.34 g (22.65 mmol) 5-(5-bromo-2-fluoro-phenyl)-5-difluoromethyl-morpholin-3-one and 5.19 g (12.46 mmol) Lawesson's reagent in 73 ml of THF was refluxed for 1 h. The mixture was concentrated and crystallized from DCM/hexane and recrystallized from EtOH to yield the desired product as colorless crystals.