Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH:18]2[CH2:20][CH2:19]2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:5]2=[N:21][CH:22]=[C:23]([C:24]#[N:25])[N:4]2[N:3]=1.[NH2:26][C:27]1[CH:28]=[C:29]([CH:32]=[C:33]([N:36]2[CH2:41][CH2:40][CH:39]([O:42][Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44])[CH2:38][CH2:37]2)[C:34]=1[Cl:35])[C:30]#[N:31].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>CC([O-])=O.CC([O-])=O.[Pd+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].O1CCOCC1>[Si:43]([O:42][CH:39]1[CH2:38][CH2:37][N:36]([C:33]2[C:34]([Cl:35])=[C:27]([NH:26][C:2]3[N:7]=[C:6]([N:8]([CH:18]4[CH2:20][CH2:19]4)[CH2:9][C:10]4[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=4)[C:5]4=[N:21][CH:22]=[C:23]([C:24]#[N:25])[N:4]4[N:3]=3)[CH:28]=[C:29]([C:30]#[N:31])[CH:32]=2)[CH2:41][CH2:40]1)([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:44])[CH3:45]
Reactant: CC(C)(C)[Si](C)(C)OC1CCN(c2cc(C#N)cc(N)c2Cl)CC1
Reactant: COc1ccc(CN(c2nc(Cl)nn3c(C#N)cnc23)C2CC2)cc1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCC(O[Si](C)(C)C(C)(C)C)CC4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Temperature: 100 °C
Yield: 74.7 %

Procedure:
(I13C): 2-Chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Intermediate 1) (0.646 g, 1.820 mmol), 3-amino-5-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-4-chlorobenzonitrile (I13B) (0.666 g, 1.820 mmol), Pd(OAc)2 (0.123 g, 0.546 mmol), DPPF (0.101 g, 0.182 mmol), Xantphos (0.105 g, 0.182 mmol), and cesium carbonate (1.186 g, 3.64 mmol) were combined in a round bottom flask and dioxane (12.13 ml) was added. The flask was evacuated and backfilled with nitrogen (3×), then heated at 100° C. 10 h. The reaction mixture was diluted with ethyl acetate and vacuum filtered through a pad of Celite. The filtrate was concentrated in vacuo and the crude material purified by column chromatography on the ISCO system (40 g, 0-100% EtOAc/Hex). 2-((3-(4-((tert-Butyldimethylsilyl)oxy)piperidin-1-yl)-2-chloro-5-cyanophenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (0.9309 g) was isolated as a dark yellow solid.
Reaction SMILES: [C-:1]#[N:2].[Na+].O.Cl[CH2:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[CH3:14]>C(O)C>[F:13][C:11]1[CH:10]=[CH:9][C:8]([CH3:14])=[C:7]([CH2:6][C:1]#[N:2])[CH:12]=1
Reactant: Cc1ccc(F)cc1CCl
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1ccc(F)cc1CC#N
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred and refluxing mixture of 71 parts of sodium cyanide, 99 parts of ethanol and 85 parts of water is added dropwise a solution of 134 parts of 2-(chloromethyl)-4-fluoro-1-methylbenzene in 99 parts of ethanol. Upon completion, stirring is continued first for 6 hours at reflux and further overnight at room temperature. The ethanol is evaporated and the residue is taken up in 4-methyl-2-pentanone and water. The layers are separated and the aqueous phase is extracted three times with 4-methyl-2-pentanone. The combined organic phases are washed twice with water, dried, filtered and evaporated. The residue is distilled, yielding 98 parts of 5-fluoro-2-methylbenzeneacetonitrile; bp. 124°-128° C. at 10 mm. pressure.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[CH2:27][C:28]1[O:29][CH:30]=[CH:31][CH:32]=1.[Cl-].[NH4+]>O1CCCC1.CN(C)C=O.C(OCC)(=O)C.CCCCCC>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:16]([CH2:27][C:28]3[O:29][CH:30]=[CH:31][CH:32]=3)[C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCc1ccco1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3[nH]2)CC1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3n2Cc2ccco2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Combine 1-t-butoxycarbonyl-4-(1H-benzimidazol-2-yl)[1,4]diazepane (1.70 g, 5.4 mmol) in tetrahydrofuran (45 mL) and dimethylformamide (5 mL). Cool in an ice bath. Add sodium hydride (0.32 g, 60% in oil, 8.1 mmol) portionwise. After 15 minutes, warm to ambient temperature. After about 30 minutes, when the gas evolution ceases, add 2-(chloromethyl)furan (0.94 g, 8.1 mmol). After 18 hours, cool in an ice bath, add ice and then a saturated aqueous solution of ammonium chloride. Evaporate the reaction mixture to remove most of the tetrahydrofuran, dilute with ethyl acetate and extract with a saturate aqueous solution of sodium bicarbonate and then brine. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 50% ethyl acetate/hexane to give 1-t-butoxycarbonyl-4-(1-(fur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepane: Rf =0.47 (silica gel, ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[C:10]([OH:11])=[CH:9][C:8]([I:12])=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:13].C(=O)([O-])[O-].[K+].[K+].[C:20]([O:24][C:25](=[O:31])[NH:26][CH2:27][CH2:28][CH2:29]Br)([CH3:23])([CH3:22])[CH3:21].O>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:1][C:2]1[C:10]([O:11][CH2:29][CH2:28][CH2:27][NH:26][C:25]([O:24][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:31])=[CH:9][C:8]([I:12])=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:13]
Reactant: O=C1NCc2c(Cl)c(O)cc(I)c21
Reactant: CC(C)(C)OC(=O)NCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCCCOc1cc(I)c2c(c1Cl)CNC2=O
Yield: 81.9 %

Procedure:
In a similar manner to Step 1 of Example 429, 4-chloro-5-hydroxy-7-iodoisoindolinone (283 mg, 0.916 mmol) was dissolved in DMF (8.4 mL), and the solution was treated with potassium carbonate (190 mg, 1.37 mmol), tetrabutylammonium iodide (33.8 mg, 0.092 mmol) and 3-bromopropylcarbamic acid tert-butyl ester (654 mg, 2.75 mmol). The reaction mixture was added with water. The obtained solid was collected by filtration and purified by slurry using hexane and diisopropylether to obtain 4-chloro-5-[3-(tert-butoxycarbonylamino)propoxy]-7-iodoisoindolinone (350 mg, yield 84%).
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]2[CH2:11][CH:10](O)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.C(OC(C)C)(C)C.[OH-].[Na+].[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([SH:47])=[CH:43][CH:42]=1>C1(C)C=CC=CC=1.O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([S:47][CH:10]2[CH2:11][N:8]([CH:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:9]2)=[CH:43][CH:42]=1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: Sc1ccc(Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CS(=O)(=O)Cl
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: Clc1ccc(SC2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Reaction time: 16 h

Procedure:
A stirred mixture of 48 g (0.2 mole) of 1-diphenylmethyl-3-azetidinol, and 22 g (28 ml) (0.22 mole) of triethylamine in 800 ml of toluene under nitrogen was cooled in a water bath then treated with 27.5 g (0.22 mole) of methanesulfonyl chloride added dropwise. After stirring for 16 hr, the reaction mixture was diluted by adding 200 ml of isopropyl ether. The triethylamine hydrochloride was removed by filtration and washed with 200 ml of (50/50) toluene/isopropyl ether. The filtrates were combined, washed with 2×200 ml of water and returned to the reaction mixture. The reaction mixture was treated with 24 g (0.6 mole) of sodium hydroxide in 100 ml of water, 6.5 g (0.02 mole) of tetrabutylammonium bromide and 31.8 g (0.22 mole) of 4-chlorothiophenol then heated at reflux while stirring vigorously. After 96 hr, TLC showed the expected product to be approximately 80% of the reaction mixture. After cooling, the organic phase was separated, washed with water (3×200 ml) and treated with 25 g of oxalic acid dihydrate in 100 ml of methanol. The precipitated product was collected by filtration, yielding 75 g of crude oxalate salt. The oxalate salt was suspended in warm water and treated with 0.4 mole (26 g) of potassium hydroxide. The solid which precipitated from the basic solution was collected and recrystallized from methanol with charcoal treatment to yield 17.6 g of white granular crystals, m.p. 84°-86° C. A second crop of crystals was obtained from the filtrate after standing (8.6 g). The yield was 36%.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([NH:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.S([O-])([O-])(=O)=O.[Mg+2].[CH:24]1([CH:27]=O)[CH2:26][CH2:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClC(Cl)C.C(O)(=O)C>[CH:24]1([CH2:27][NH:1][CH2:2][CH:3]([NH:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:26][CH2:25]1
Reactant: CCOC(=O)CCNC(CN)c1ccccc1
Reactant: O=CC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CCOC(=O)CCNC(CNCC1CC1)c1ccccc1
Reaction time: 1 h
Yield: 40 %

Procedure:
A mixture of ethyl 3-[(2-amino-1-phenylethyl)amino]propanoate (6.38 g, 27.0 mmol), magnesium sulfate (10 g, 83.1 mmol), and cyclopropanecarboxaldehyde (2.02 mL, 27.2 mmol) in dichloroethane (200 mL) was adjusted to pH 6 with acetic acid. After 1 h, sodium triacetoxyborohydride (5.72 g, 27.0 mmol) was added. After an additional 30 min, saturated aqueous sodium bicarbonate was added and the mixture was extracted with dichloromethane (3×). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated. Purification by silica gel chromatography [100% dichloromethane→95% dichloromethane/5% (10% ammonium hydroxide/methanol)] gave the title compound (3.14 g). MS 291 (M+1).
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH3:14])=[CH:9][C:8]=1[F:15].CC([O-])(C)C.[K+].[C:22](=[O:24])=[O:23]>C1COCC1.O>[Cl:6][C:7]1[C:8]([F:15])=[C:9]([C:10]([NH:13][CH3:14])=[CH:11][CH:12]=1)[C:22]([OH:24])=[O:23]
Reactant: CNc1ccc(Cl)c(F)c1
Reactant: O=C=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CNc1ccc(Cl)c(F)c1C(=O)O
Temperature: -75 °C
Reaction time: 0.08 h
Yield: 11 %

Procedure:
n-Butyllithium solution (1.6 M in hexane, 4.95 mL, 8.0 mmol) was added at −78° C. to THF (10 ml) under nitrogen. A solution of (4-chloro-3-fluoro-phenyl)-methyl-amine (575 mg, 4.0 mmol) in THF (3 mL) was added dropwise keeping the temperature below −70° C. The solution was stirred for 5 min at −75° C. Potassium tert-butylate (889 mg, 8 mmol) dissolved in THF (2 ml) was added within 15 min. The reaction was stirred at −75° C. for 2 h and treated with a large excess of dry ice. Within 30 min the reaction was warmed to RT. Water was added and the reaction was extracted twice with diethyl ether. The aqueous layer was acidified to pH1 with 1N aq. HCl solution and extracted twice with diethyl ether. The combined organic layers were washed with sat. aq. NaCl solution, dried over sodium sulfate, filtered and the solvent was removed in vacuo to yield 3-chloro-2-fluoro-6-methylamino-benzoic acid (83 mg, 11%). Light brown solid, 1HNMR (DMSO-d6, 300 MHz): δ 81 (s, 3H), 6.52 (d, J=9.2 Hz, 1H), 7.45 (t, J=9.1 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:35]=[CH:34][C:5]([C:6](=[O:33])[CH2:7][CH2:8][NH:9][C:10]2[C:18]3[C:13](=[CH:14][C:15]([Cl:20])=[CH:16][C:17]=3[Cl:19])[N:12](C(OC(C)(C)C)=O)[C:11]=2[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6](=[O:33])[CH2:7][CH2:8][NH:9][C:10]2[C:18]3[C:13](=[CH:14][C:15]([Cl:20])=[CH:16][C:17]=3[Cl:19])[NH:12][C:11]=2[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:34][CH:35]=1
Reactant: CCOC(=O)c1c(NCCC(=O)c2ccc(F)cc2)c2c(Cl)cc(Cl)cc2n1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1NCCC(=O)c1ccc(F)cc1

Procedure:
Dissolve 3-[(p-fluorophenacyl)methylamino]-2-carbethoxy-4,6-dichloro-1-(tert-butyloxycarbonyl)-indole (1.2 g, 2.35 mmol) in methylene chloride. Add trifluoracetic acid and stir for 2 hours. Concentrate the reaction in vacuo and recrystallize the residue from hot ethyl acetate/hexane to yieldthe title compound (720 mg, 74%).
Reaction SMILES: Cl[C:2]1[C:3](=[O:8])[NH:4][CH2:5][CH2:6][CH:7]=1.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.C(N(CC)CC)C>C1COCC1>[N:9]1([C:2]2[C:3](=[O:8])[NH:4][CH2:5][CH2:6][CH:7]=2)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: C1COCCN1
Reactant: O=C1NCCC=C1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1NCCC=C1N1CCOCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 43 %

Procedure:
A solution of 3-chloro-5,6-dihydro-1H-pyridin-2-one (44, 1.0 g, 7.6 mmol) in THF (4 mL) was treated with morpholine (663 mg, 0.67 mL, 7.6 mmol, 1.0 equiv) and triethylamine (TEA, 1.54 g, 2.1 mL, 15.2 mmol, 2.0 equiv) at room temperature, and the resulting reaction mixture was warmed up to reflux for 6 h. When HPLC and TLC showed the reaction was deemed complete, the reaction mixture was quenched with water (10 mL) and EtOAc (20 mL), and the resulting mixture was stirred at room temperature for 10 min. The two layers were separated, and the aqueous layer was extracted with EtOAc (3×20 mL). The combined organic extracts were washed with saturated NaCl aqueous solution (5 mL), dried over MgSO4, and concentrated in vacuo. The residue was then purified by flash column chromatography (SiO2, 15-40% EtOAc/hexane gradient elution) to afford the desired 3-morpholin-4-yl-5,6-dihydro-1H-pyridin-2-one (45, 595 mg, 1.384 g theoretical, 43%) as pale-yellow oil, which solidified upon standing at room temperature in vacuo and was found to be essentially pure to do the following reaction without further purification. For 45, CIMS m/z 181 (M+−H, C9H14N2O2).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:2]1.CCN(C(C)C)C(C)C.F[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1.C([O-])([O-])=O.[Na+].[Na+]>CO.N1C=CC=CC=1.C(O)(C)(C)C>[N:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:2]1
Reactant: Fc1ccccn1
Reactant: O=C(OCc1ccccc1)C1CCCNC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OCc1ccccc1)C1CCCN(c2ccccn2)C1
Temperature: 25 °C

Procedure:
Pure benzyl piperidine-3-carboxylate (170 mg, 0.776 mmol; Example 31) was placed in a microwave tube. DIPEA (0.50 mL), tert-BuOH (1.5 mL) and 2-fluoropyridine (Aldrich, 0.40 mL) were added to the tube via syringes before the tube was subjected to microwave irradiation at 180° C. for 20 min. LC/MS showed partial conversion to the desired pyridine derivative. The tube was subjected to further microwave irradiation at 220° C. for 20 min and then it was allowed to cool to room temperature. The volatiles were removed by rotary evaporation to provide 229 mg of crude oil which was dissolved in MeOH (8.0 mL) and then subjected to reverse phase HPLC. The pure fractions were poured into Na2CO3 (10%, 75 mL) and extracted with EtOAc (3×50 mL), washed with brine (sat, 150 mL), dried with sodium sulfate, filtered and concentrated to provide 90 mg of benzyl 1-(pyridin-2-yl)piperidine-3-carboxylate. MS m/z: 297 (M+1)
Reaction SMILES: Br[O:2][CH2:3][CH:4]([O:24][O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:5][O:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[CH3:42][NH:43][CH3:44].C(OCC)(=O)C>C(Cl)(Cl)Cl.CCCCCC>[CH2:8]([O:7][O:6][CH2:5][CH:4]([CH2:3][O:2][N:43]([CH3:44])[CH3:42])[O:24][O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CNC
Reactant: CCCCCCCCCCCCCCCCOOCC(COBr)OOCCCCCCCCCCCCCCCC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCOOCC(CON(C)C)OOCCCCCCCCCCCCCCCC
Reaction time: 8 h

Procedure:
900 mg of 3-bromo-1,2-dihexadecyloxy glycerol was dissolved in 30 ml chloroform in a 100 ml round bottom flask. 720 mg dimethylamine was added to yield an approximately 10 fold molar excess, and the reaction mixture stirred at room-temperature overnight. The progress of the reaction was measured by thin-layer-chromatography (30% ethyl acetate in hexane).
Reaction SMILES: [CH:1]([C:4]1([CH3:17])[C:8](=[S:9])[NH:7][C:6]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[N:5]1)([CH3:3])[CH3:2].C([Li])(CC)C.[Cl:23]C(Cl)(Cl)C(Cl)(Cl)Cl.[Cl-].[Na+].S(=O)(=O)(O)O.ClC1C=C(N2C(=S)C(C(C)C)(C)N=C2)C=CC=1C>O1CCCC1.C1CCCCC1>[Cl:23][C:12]1[CH:11]=[C:10]([C:6]2[NH:7][C:8](=[S:9])[C:4]([CH:1]([CH3:3])[CH3:2])([CH3:17])[N:5]=2)[CH:15]=[CH:14][C:13]=1[CH3:16]
Reactant: Cc1ccc(C2=NC(C)(C(C)C)C(=S)N2)cc1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: Cc1ccc(N2C=NC(C)(C(C)C)C2=S)cc1Cl
Agent: O=S(=O)(O)O
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: Cc1ccc(C2=NC(C)(C(C)C)C(=S)N2)cc1Cl
Temperature: 25 °C

Procedure:
A mechanically stirred solution of 20.0 g of 4-isopropyl-4-methyl-2-p-tolyl-2-imidazolin-5-thione in 200 mL of dry tetrahydrofuran is treated dropwise with 160 mL of a 1.2M solution of sec-butyl lithium (0.191 mol) in cyclohexane over a 40 minute period at -72° to -65° C. After stirring the resulting solution at -40° to -35° for one and one-half hours, a solution of 21.4 g (0.090 mol) of hexachloroethane in 125 mL of dry tetrahydrofuran is added dropwise. Addition temperature is allowed to reach -20° C. After warming to room temperature over a 16 hour period, the reaction is treated with 200 mL of ice water plus 200 mL of a saturated sodium chloride solution. The mixture is carefully acidified to pH 3 with concentrated sulfuric acid. The phases are separated and the aqueous phase is extracted with 200 mL ether. The organic phases are combined, dried over magnesium sulfate and concentrated to an oily residue. The residue is purified by chromatography on silica gel to give pure 2.(2-chloro-p- tolyl)-4-isopropyl-4-methyl-2-imidazolin-5-thione.
Reaction SMILES: O.[NH2:2]N.CO[N:6]=[CH:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:18][CH2:17][N:16]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][C:24]=3[CH3:25])[C:15]2=[O:26])=[CH:10][C:9]=1F.CO>C(Cl)(Cl)Cl>[NH:2]1[C:9]2[C:8](=[CH:13][CH:12]=[C:11]([N:14]3[CH2:18][CH2:17][N:16]([C:19]4[CH:20]=[N:21][CH:22]=[CH:23][C:24]=4[CH3:25])[C:15]3=[O:26])[CH:10]=2)[CH:7]=[N:6]1
Reactant: NN
Reactant: CON=Cc1ccc(N2CCN(c3cnccc3C)C2=O)cc1F
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1ccncc1N1CCN(c2ccc3cn[nH]c3c2)C1=O
Temperature: 200 °C
Yield: 39.17 %

Procedure:
Hydrazine hydrate (5 mL) was added to solution of 2-fluoro-4-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-benzaldehyde O-methyl-oxime (I-121b: 350 mg, 0.917 mmol) in 2-methoxy methanol (10 mL). The resulting mixture was heated to 200° C. and maintained for 2 days. The reaction was monitored by TLC (5% MeOH in CHCl3). The reaction mixture was cooled to room temperature and concentrated. The crude product was purified by column chromatography on silica gel (4% MeOH in CHCl3), washed with ether and dried to afford 105 mg of the product (39.17% yield).
Reaction SMILES: [N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:16][CH:15]=[C:14]([CH3:17])[N:9]2[C:10](=[O:13])[C:11]=1Br)[CH3:5])=[N+:2]=[N-:3].[F:18][C:19]1[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)(P(C(C)(C)C)(C(C)(C)C)C1C=CC(N(C)C)=CC=1)P(C1C=CC(N(C)C)=CC=1)(C(C)(C)C)C(C)(C)C>[N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:16][CH:15]=[C:14]([CH3:17])[N:9]2[C:10](=[O:13])[C:11]=1[C:23]1[CH:22]=[CH:21][CH:20]=[C:19]([F:18])[C:24]=1[F:25])[CH3:5])=[N+:2]=[N-:3]
Reactant: OB(O)c1cccc(F)c1F
Reactant: Cc1csc2nc(C(C)N=[N+]=[N-])c(Br)c(=O)n12
Agent: CN(C)c1ccc([PH](C(C)(C)C)(C(C)(C)C)[Pd](Cl)(Cl)[PH](c2ccc(N(C)C)cc2)(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: Cc1csc2nc(C(C)N=[N+]=[N-])c(-c3cccc(F)c3F)c(=O)n12
Temperature: 100 °C
Reaction time: 8 h
Yield: 62.9 %

Procedure:
To a mixture of 7-(1-azidoethyl)-6-bromo-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.12 g, 0.38 mmol) and (2,3-difluorophenyl)boronic acid (0.072 g, 0.46 mmol) in 1,4-dioxane (3 mL) was added a 1 N solution of sodium carbonate in water (0.57 mL, 0.57 mmol) and dichloro(bis{di-tert-butyl[4-(dimethylamino)phenyl]phosphoranyl})palladium (0.014 g, 0.019 mmol). The mixture was stirred at 100° C. overnight. After cooling, the mixture was diluted with ethyl acetate, washed with water, dried over Na2SO4, concentrated, and purified on silica gel (0-30% ethyl acetate/hexane) to give the desired product (83 mg). LCMS calculated for C15H12F2N5OS (M+H)+: m/z=348.1. Found: 348.0.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:4]=2[N:5]=[CH:6][N:7]=1.O1CCOCC1.C(OCN1C2N=CN=C([C:42]3[CH:43]=[N:44][N:45](C(OCC)C)[CH:46]=3)C=2C=C1)(=O)C(C)(C)C.C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)(=O)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.CCCCCCC.C(OCC)(=O)C>[NH:44]1[CH:43]=[C:42]([C:2]2[C:3]3[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH:46]=[N:45]1
Reactant: CCOC(C)n1cc(-c2ncnc3c2ccn3COC(=O)C(C)(C)C)cn1
Reactant: C[Si](C)(C)CCOCn1ccc2c(Cl)ncnc21
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
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Temperature: 90 °C
Yield: 64 %

Procedure:
Method A. To a flask equipped with a reflux condenser, a nitrogen inlet, mechanical stirrer, and a thermowell was added 4-chloro-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine (3a, 817 g, 2.88 mol) and dioxane (8 L). To this solution was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (4, 728 g, 3.75 mol, 1.30 equiv) followed by a solution of potassium carbonate (K2CO3, 1196 g, 8.67 mol, 3.0 equiv) in water (4 L). The solution was degassed by passing a stream of nitrogen through the solution for 15 minutes before being treated with tetrakis(triphenylphosphine)palladium(0) (167 g, 0.145 mol, 0.05 equiv) and the resulting reaction mixture was heated at reflux (about 90° C.) for 2 hours. When the reaction was deemed complete by TLC (1:1 heptane/ethyl acetate) and LCMS, the reaction mixture was cooled to room temperature, diluted with ethyl acetate (24 L) and water (4 L). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (4 L). The combined organic layers were washed with water (2×2 L), brine (2 L), dried over sodium sulfate (Na2SO4), and concentrated under reduced pressure. The residue was suspended in toluene (4 L) and the solvent was removed under reduced pressure. The residue was finally triturated with methyl tert-butyl ether (MTBE, 3 L) and the solids were collected by filtration and washed with MTBE (1 L) to afford 4-(1H-pyrazol-4-yl)-7-(2-trimethylsilanyl-ethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine (5, 581.4 g, 908.5 g theoretical, 64% yield) as white crystalline solids. For 5: 1H NMR (DMSO-d6, 400 MHz) δ ppm 13.41 (bs, 1H), 8.74 (s, 1H), 8.67 (bs, 1H), 8.35 (bs, 1H), 7.72 (d, 1H, J=3.7 Hz), 7.10 (d, 1H, J=3.7 Hz), 5.61 (s, 2H), 3.51 (t, 2H, J=8.2 Hz), 0.81 (t, 2H, J=8.2 Hz), 0.13 (s, 9H); C15H21N5OSi (MW, 315.45), LCMS (EI) m/e 316 (M++H).