Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[NH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(N(C(C)C)CC)(C)C>C1COCC1>[Br:8][C:5]1[CH:4]=[N:3][C:2]([NH:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[N:7][CH:6]=1
Reactant: NCCN1CCOCC1
Reactant: Clc1ncc(Br)cn1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Brc1cnc(NCCN2CCOCC2)nc1
Temperature: 85 °C

Procedure:
A resealable tube was charged with a solution of 2-chloro-5-bromopyrimidine (1.00 g, 5.17 mmol), N-(2-aminoethyl)morpholine (0.808 g, 6.20 mmol), diisopropylethylamine (0.801 g, 1.1 mL, 6.20 mmol), and THF (40 mL). The mixture was heated at 85° C. for 20 h. The reaction mixture was concentrated and then purified via column chromatography on silica gel (gradient elution with 0-100% (90:10:1, dichloromethane/methanol/ammonium hydroxide)-dichloromethane) to afford 5-bromo-N-(2-morpholinoethyl)pyrimidin-2-amine as a light yellow solid. MS m/z=288 [M+H]+. Calc'd for C10H15BrN4O: 287.
Reaction SMILES: Cl[C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6](=[O:14])[N:5]([CH3:15])[C:4](=[O:16])[CH:3]=1.[CH3:17][NH2:18]>CC(O)C>[CH3:15][N:5]1[C:4](=[O:16])[CH:3]=[C:2]([NH:18][CH3:17])[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6]1=[O:14]
Reactant: CN
Reactant: Cn1c(=O)cc(Cl)n(-c2ccccc2)c1=O
Solvent: CC(C)O
Product: CNc1cc(=O)n(C)c(=O)n1-c1ccccc1
Temperature: 90 °C
Yield: 89.1 %

Procedure:
The obtained 6-chloro-3-methyl-1-phenyluracil (4.26 g, 18 mM) was added to 100 ml of 2-propanol. A 40% aqueous solution of methylamine (17 g, 0.22M) was added to the resulting solution and the mixture was heated at 90° C. for 5 hours while stirring. After being left to cool, a precipitated crystal was obtained by filtration and washed successively with ethanol and water to yield 3-methyl-6-methylamino-1-phenyluracil (yield: 3.71 g, or 89% based on 6-chloro-3-methyl-1-phenyluracil).
Reaction SMILES: [C:1]([BH3-])#[N:2].[Na+].[CH:5]1([N:11]2[C:15]([CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[C:14]([C:22]3[O:26][N:25]=[C:24]([C:27]4[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=4)[N:23]=3)[CH:13]=[N:12]2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[C:35]([OH:38])(=[O:37])[CH3:36]>CO>[CH:5]1([N:11]2[C:15]([CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[C:14]([C:22]3[O:26][N:25]=[C:24]([C:27]4[CH:28]=[CH:29][C:30]([CH2:31][NH:2][CH2:1][CH2:36][C:35]([OH:38])=[O:37])=[CH:33][CH:34]=4)[N:23]=3)[CH:13]=[N:12]2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: [BH3-]C#N
Reactant: CC(=O)O
Reactant: O=Cc1ccc(-c2noc(-c3cnn(C4CCCCC4)c3C3CCOCC3)n2)cc1
Agent: [Na+]
Solvent: CO
Product: O=C(O)CCNCc1ccc(-c2noc(-c3cnn(C4CCCCC4)c3C3CCOCC3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium cyanoborohydride (28 mg; 0.440 mmol) was added to a solution of 4-(5-(1-cyclohexyl-5-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)benzaldehyde (163 mg; 0.40 mmol), obtained as described in Example 88, steps 1 and 2, and R-alanine (71.3 mg; 0.80 mmol) in methanol (3 mL) and acetic acid (69 μL; 1.20 mmol) and the mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue purified by reverse-phase preparative HPLC. The residue was dissolved in methanol and loaded onto an SCX-2 column. The product was eluted with 0-20% NH3/methanol in DCM. The residue was then recrystallised from acetone to give Example 102 a white solid. 1H NMR: (Acetone-d6, 400 MHz) δ 7.99 (2 H, d, J=8.0 Hz), 7.94 (1 H, s), 7.46 (2 H, d, J=8.0 Hz), 4.46-4.37 (1 H, m), 3.92 (2 H, dd, J=11.5, 4.3 Hz), 3.84 (2 H, s), 3.75 (1 H, t, J=12.3 Hz), 3.43 (2 H, t, J=11.7 Hz), 2.82 (2 H, t, 6.0 Hz), 2.51-2.32 (4 H, m), 1.85-1.70 (6 H, m), 1.61 (1 H, d, J=12.9 Hz), 1.53 (2 H, d, J=12.9 Hz), 1.47-1.32 (2 H, m), 1.23-1.10 (1 H, m). LC/MS: 480 (M+H)+. HPLC (Method D) Rt 15.428 min (Purity: 99.4%).
Reaction SMILES: N12CCC(CC1)/C(=[CH:9]\[N:10]1[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[S:17][C:16]3[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=3)/C2.[C:24](O)(=O)[CH3:25].[H][H]>[C].[Pd].CO>[CH:13]1[CH:14]=[CH:15][C:16]2[S:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=3[N:10]([CH2:9][C:24]34[CH2:25][CH2:9][N:10]([CH2:23][CH2:18]3)[CH2:11][CH2:12]4)[C:11]=2[CH:12]=1
Reactant: [H][H]
Reactant: CC(=O)O
Reactant: C(=C1/CN2CCC1CC2)\N1c2ccccc2Sc2ccccc21
Agent: [Pd]
Solvent: CO
Product: c1ccc2c(c1)Sc1ccccc1N2CC12CCN(CC1)CC2

Procedure:
(E)-10-(1-Azabicyclo[2.2.2]oct-3-ylidenemethyl)phenothiazine (10.00 g, 0.0312 mol), acetic acid (2.25 g, 0.0374 mol) and 10% palladium carbon (2.00 g, water content 50%) were added to methanol (158 g) and the mixture was stirred under pressurization with hydrogen (3-5 kg/cm2, hydrogen gas amount:equimolar amount relative to starting material) at 45-50° C. for 8 hr. The obtained reaction mixture was subjected to HPLC. As a result, the starting material was not detected but highly pure mequitazine was quantitatively obtained.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH2:8][CH2:9][CH2:10][CH:11]([N:12]3C(=O)C4C(=CC=CC=4)C3=O)[C:6]2=[N:5][C:4]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[CH:3]1.O.NN>C(O)C>[NH2:12][CH:11]1[C:6]2=[N:5][C:4]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)=[CH:3][C:2](=[O:1])[N:7]2[CH2:8][CH2:9][CH2:10]1
Reactant: O=C1c2ccccc2C(=O)N1C1CCCn2c1nc(-c1ccncc1)cc2=O
Agent: NN
Solvent: CCO
Solvent: O
Product: NC1CCCn2c1nc(-c1ccncc1)cc2=O
Yield: 65.8 %

Procedure:
To a solution of 3.2 g (8.59 mmol) of (+/−)2-(4-oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)-1H-isoindole-1,3(2H)-dione dissolved in 24 mL of ethanol was added 2.09 mL (43 mmol) of hydrazine hydrate and the resulting mixture was stirred under reflux for 2 h. The mixture was filtered and the solid obtained was triturated with dichloromethane for 24 h, filtered, and the resulting filtrates were evaporated to dryness. The resulting residue was purified on silica gel eluting with a mixture of dichloromethane/methanol in the proportions 98/2 to 96/4 to give 1.37 g (66%) of the desired compound as a brown powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH2:11][C:12]([NH:16][C:17](=[O:29])[C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=1)([C:14]#[N:15])[CH3:13])[C:6]=2[O:30][CH3:31].[C:32](Cl)(=[O:34])[CH3:33]>>[C:32]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH2:11][C:12]([NH:16][C:17](=[O:29])[C:18]1[CH:19]=[CH:20][C:21]([O:24][C:25]([F:28])([F:26])[F:27])=[CH:22][CH:23]=1)([C:14]#[N:15])[CH3:13])[C:6]=2[O:30][CH3:31])(=[O:34])[CH3:33]
Reactant: CC(=O)Cl
Reactant: COc1c2ccc(N)cc2nn1CC(C)(C#N)NC(=O)c1ccc(OC(F)(F)F)cc1
Product: COc1c2ccc(NC(C)=O)cc2nn1CC(C)(C#N)NC(=O)c1ccc(OC(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using N-[2-(6-amino-3-methoxy-2H-indazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide (23 mg, described in Example 129) and acetyl chloride, the title compound was isolated as a white solid (8 mg, 32%). MS (ES): M/Z [M+H]=476. 1H NMR: (400 MHz, DMSO-d6): 1.71 (s, 3H), 2.05 (s, 3H), 4.16 (s, 3H), 4.71 (d, 1H), 4.82 (d, 1H), 6.88 (dd, J=9.2, 1.6 Hz, 1H), 7.52 (d, J=8.0 Hz, 2H), 7.74 (d, J=9.1 Hz, 1H), 7.86 (s, 1H), 7.99 (d, J=8.8 Hz, 2H), 8.95 (s, 1H) and 9.89 (s, 1H). 19F NMR (376 MHz, DMSO-d6): −57.1 (s, 3F).
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]([NH:11][C:12]1[S:16][N:15]=[C:14]([C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)[C:13]=1[C:24]([NH2:26])=[O:25])=[O:10])(=O)C>[Pd].O1CCCC1.CN(C)C=O.CCOCC>[NH2:23][C:20]1[CH:21]=[CH:22][C:17]([C:14]2[C:13]([C:24]([NH2:26])=[O:25])=[C:12]([NH:11][C:9]([NH:8][CH2:7][CH2:6][CH2:5][OH:4])=[O:10])[S:16][N:15]=2)=[CH:18][CH:19]=1
Reactant: CC(=O)OCCCNC(=O)Nc1snc(-c2ccc(N)cc2)c1C(N)=O
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: NC(=O)c1c(-c2ccc(N)cc2)nsc1NC(=O)NCCCO
Yield: 99 %

Procedure:
3-[({[4-(aminocarbonyl)-3-(4-aminophenyl)isothiazol-5-yl]amino}carbonyl)amino]propyl acetate (10.0 g) and 10% palladium on carbon (3 g) in tetrahydrofuran (400 mL) and dimethylformamide (100 mL) was hydrogenated at 80 psi over 24 hr. in metal bomb. The catalyst was removed by filtration through celite and washed with tetrahydrofuran. The filtrate was concentrated in vacuo to give a yellow solid, which was stirred in ether (100 mL) and collected by filtration to give the title compound as a light yellow solid (8.8 g, 96%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:19]=[C:18]([NH:20][C:21]3[CH2:25][C:24]([CH3:26])=[N:23][N:22]=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[O:9])=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].CC(O)(C)C.[H][H]>CC(O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:10]2[N:19]=[C:18]([NH:20][C:21]3[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[OH:9])=[CH:4][CH:3]=1
Reactant: CC1=NN=C(Nc2nc(C(=O)c3ccc(F)cc3)nc3ccccc23)C1
Reactant: [H][H]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Solvent: CC(C)(C)O
Product: Cc1cc(Nc2nc([C@@H](O)c3ccc(F)cc3)nc3ccccc23)n[nH]1
Temperature: 40 °C
Reaction time: 18 h
Yield: 82.3 %

Procedure:
A stirred mixture of (4-fluorophenyl)(4-(5-methyl-4H-pyrazol-3-ylamino)quinazolin-2-yl)methanone (16.66 g, 48 mmol) and [(R)—P-Phos RuCl2(R)-DAIPEN] (217 mg, 0.192 mmol) at room temperature was subjected to five cycles of pressurizing with nitrogen to 40 psi followed by depressurization. Then 1M KOtBu/tBuOH (576 μL, 0.0.576 mmol) in 9:1 i-PrOH/H2O (4 mL) was added and the mixture was subjected to five cycles of pressurizing with nitrogen to 40 psi followed by depressurization. The stirred mixture was then subjected to ten cycles of pressurizing with hydrogen to 435 psi followed by depressurization. The mixture was then stirred at 900 rpm under hydrogen (435 psi) at 40° C. for 18 hrs. The mixture was allowed to cool to room temperature and then carefully vented. The resulting precipitate was collected by filtration and washed with cold MeOH (100 mL) to afford (S)-(4-fluorophenyl)(4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)methanol as a white solid (13.8 g). Chiral HPLC indicated a >99% enantiomeric excess of the earlier eluting enantiomer.
Reaction SMILES: C([C:3]1[C:4]([C:9]([OH:11])=[O:10])=[C:5]([NH2:8])[S:6][CH:7]=1)C.[C:12]1(C)[CH:17]=CC(S(O)(=O)=O)=C[CH:13]=1.CO[C:25](OC)(C)[CH3:26].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[CH3:13][CH:12]([NH:8][C:5]1[S:6][CH:7]=[CH:3][C:4]=1[C:9]([O:11][CH2:25][CH3:26])=[O:10])[CH3:17]
Reactant: CCc1csc(N)c1C(=O)O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COC(C)(C)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccsc1NC(C)C
Reaction time: 72 h

Procedure:
A solution of ethyl 2-aminothiophene-3-carboxylic acid (Chem.Ber.; 1965; 98; 3571-3577, 98.8 g), 4-toluenesulfonic acid (1 g) and 2,2-dimethoxypropane (158 ml) in anhydrous toluene (650 ml) was heated at reflux under nitrogen for 5 hours. The solution was allowed to cool and was then added to saturated aqueous sodium bicarbonate solution (500 ml) and extracted with ether (500 ml). The organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated. The residual oil was dissolved in ethanol (250 ml) containing sodium borohydride (8 g). The mixture was stirred for 3 days and then further sodium borohydride (8 g) was added. The mixture was stirred for 1 further day, then sodium borohydride (4 g) was added. After a further 2 days stirring, saturated aqueous sodium bicarbonate solution (750 ml) was added and the mixture was extracted with ether (2×750 ml). The organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated. The residual oil was purified by column chromatography over silica, eluting with dichloromethane/isohexane (1:1) to give the subtitle compound (24.65 g) as an oil.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]2)OCC1.[C:12]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])#[N:13].C([O-])(=O)C.[NH4+].C(O)(=O)C>C1(C)C=CC=CC=1.O>[C:12]([C:14](=[C:5]1[CH2:6][CH2:7][C:8](=[O:11])[CH2:9][CH2:10]1)[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])#[N:13]
Reactant: CC(C)(C)OC(=O)CC#N
Reactant: O=C1CCC2(CC1)OCCO2
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)C(C#N)=C1CCC(=O)CC1

Procedure:
A solution of 1,4-dioxaspiro[4.5]decan-8-one (5 g, 32.0 mmol), tert-butyl 2-cyanoacetate (4.97 g, 35.2 mmol), ammonium acetate (0.2 g) and acetic acid (1.0 mL) in toluene (75 ml) was refluxed using Dean-Stark water separator to isolate water formed for 16 hours. After cooling, the reaction mixture was washed twice with water, dried over Na2SO4, filtered, and concentrated in vacuo. The crude material (4.18 g, 14.96 mmol) was treated with acetic acid (80% in water, 42.8 mL, 599 mmol) at 65° C. overnight. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography on Analogix IntelliFlash280 eluting with 5 to 100% ethyl acetate/hexanes to give the title compound. 1H NMR (501 MHz, CDCl3) δ 1.54 (s, 9H), 2.49-2.62 (m, 4H), 3.05-3.16 (m, 2H), 3.37 (t, J=7.0 Hz, 2H).
Reaction SMILES: [Mg].[CH:2]([C:5]1[CH:10]=[C:9]([CH:11]([CH3:13])[CH3:12])[CH:8]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:6]=1Br)([CH3:4])[CH3:3].BrCCBr.F[C:23]1[CH:24]=[C:25]([O:29][CH3:30])[CH:26]=[CH:27][CH:28]=1.[Li]CCCC.[I:36]I>C1COCC1>[I:36][C:24]1[C:25]([O:29][CH3:30])=[CH:26][CH:27]=[CH:28][C:23]=1[C:6]1[C:5]([CH:2]([CH3:4])[CH3:3])=[CH:10][C:9]([CH:11]([CH3:13])[CH3:12])=[CH:8][C:7]=1[CH:14]([CH3:16])[CH3:15]
Reactant: II
Reactant: CC(C)c1cc(C(C)C)c(Br)c(C(C)C)c1
Reactant: COc1cccc(F)c1
Agent: [Li]CCCC
Agent: [Mg]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: COc1cccc(-c2c(C(C)C)cc(C(C)C)cc2C(C)C)c1I
Temperature: 25 °C

Procedure:
An oven-dried three-neck round bottom flask, which was equipped with a magnetic stir bar and charged with magnesium shavings (2.4 equiv), was fitted with a reflux condenser, glass stopper, and rubber septum. The flask was purged with argon and then THF (1 mL/mmol) and 2,4,6-triisopropylbromobenzene (2 equiv) were added via syringe. The reaction mixture was heated to reflux and 1,2-dibromethane (40 uL) was added via syringe. The reaction was allowed to stir at reflux for 1.5 h and was then cooled to room temperature. A separate oven-dried round bottom flask, which was equipped with a magnetic stir bar and fitted with a septum, was purged with argon and then THF (10 mL/mmol) and 3-fluoroanisole (1 equiv) were added to the flask via syringe. The reaction mixture was cooled to −78° C. and n-BuLi (1.05 equiv) was added in a dropwise fashion over a 40 min period. The solution was stirred for 1 h and the Grignard reagent, which was prepared in the first reaction vessel, was added via cannula over a 30 min period and allowed to stir at −78° C. for 1 h. The reaction mixture was warmed to room temperature slowly where it was stirred for an additional 12 h. The mixture was then cooled to 0° C. and a solution of Iodine in THF (1 M, 2 equiv) was added via syringe over a 15 min period and then the dark red solution was warmed to room temperature and stirred for 1 h. The solvent was removed via a rotary evaporator, and the remaining dark brown oil was taken up in Et2O, washed with a saturated solution of sodium sulfite, and washed with brine. The organic layer was then dried over MgSO4, filtered, and the solvent was removed via rotary evaporator to give a yellow solid. The crude material was recrystallized to give the desired product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:5]([Cl:20])=[CH:4][N:3]=1.[C:21](=O)([O-])[O-].[Cs+].[Cs+].CI>CC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[N:15]([CH3:21])[S:16]([CH3:19])(=[O:18])=[O:17])[C:5]([Cl:20])=[CH:4][N:3]=1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CC(C)=O
Product: CN([C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (490 mg, 1.4 mmol) in Acetone (5 mL), Cesium Carbonate (706 mg, 2.17 mmol)was added; after 15 min, Methyl iodide (95.0 uL, 1.53 mmol) was added and the mixture stirred at room temperature. After 4 h, a second aliquot of Methyl iodide (15 uL, 0.24 mmol) was added to drive the reaction to completion. After 30 min, the mixture was partitioned between 20 mL DCM/20 mL water, extracted 2×20 mL DCM. The combined organics were dried over sodium sulfate, filtered and con. in vacuo to afford N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-N-methyl-methanesulfonamide as an oil in quantitative yield. 1H-NMR (CDCl3): 8.02 (s, 1H), 5.94 (d, 1H, J=7.6 Hz), 4.11 (m, 1H), 3.74 (m, 1H), 2.84 (s, 3H), 2.80 (s, 3H), 2.35 (m, 1H), 1.84 (m, 3H), 1.71 (m, 1H), 1.42 (m, 2H), 1.27 (m, 1H).
Reaction SMILES: [Br:1][CH2:2][C:3]([O:5]C)=O.C1(C2NC=C([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([CH3:25])[CH:19]=3)N=2)CCCCC1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][CH2:2][C:3]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[C:20]([CH3:25])[CH:19]=1)=[O:5]
Reactant: COC(=O)CBr
Reactant: Cc1cc(-c2c[nH]c(C3CCCCC3)n2)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)CBr)ccc1F
Temperature: 25 °C

Procedure:
0.38 mL methyl bromoacetate was added to 940 mg 2-cyclohexyl-4-(4-fluoro-3-methyl-phenyl)-1H-imidazole and 1.52 g potassium carbonate in 10 mL DMF. The reaction was stirred over night at RT and evaporated. Methanol and 1 mol/L sodiumhydroxide solution was added and the mixture was stirred 2 h at RT. The solvent was removed. The residue was dissolved in water and acidified with 1 mol/L HCL solution. The precipitate was filtered and dried to give 700 mg desired product. Rt: 0.92 min (method A), (M+H)+: 317
Reaction SMILES: [Li]CCCC.[CH3:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[N+:12]([CH2:15][CH2:16]C)([O-:14])=[O:13].C1C[O:21][CH2:20]C1>>[C:8]1([CH:20]([OH:21])[CH:15]([N+:12]([O-:14])=[O:13])[CH3:16])[CH:7]=[CH:6][CH:11]=[CH:10][CH:9]=1
Reactant: CCC[N+](=O)[O-]
Reactant: CCCCCC
Reactant: C1CCOC1
Agent: [Li]CCCC
Product: CC(C(O)c1ccccc1)[N+](=O)[O-]
Temperature: 25 °C
Yield: 28 %

Procedure:
n-BuLi (1.6 M hexane soln, 3.12 mL) was added dropwise with stirring to a solution of nitropropane (0.45 mL, 5 mmol) in THF (4 mL at -78° C. After 20 minutes the complex (as prepared above) was added and the solution allowed to warm to room temperature. After a further 4 hours the reaction was quenched at 0° C. with an aqueous slurry of disodium EDTA (1.86 g in 10 mL water). The mixture was diluted with water (50 mL) and extracted with Et2O (3×50 mL). The combined Et2O extracts were washed with hydrochloric acid (2 M, 50 mL), aqueous sodium bicarbonate (saturated, 50 mL) and water (50 mL, dried and evaporated in vacuo. Flash column chromatography [SiO2 hexane, Et2O 6:1] gave 1-phenyl-2-nitro-1-propanol (0.271 g, 28%) Erythro:threo ratio 4.6:1.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:6][C:5](=O)[C:4](=O)[CH2:3]1.COP([CH2:16][C:17](=O)[CH2:18][CH:19]1[CH2:21][CH2:20]1)(=O)OC.O.[NH2:24][NH2:25]>>[CH:19]1([CH2:18][C:17]2[N:25]=[N:24][C:4]3[CH2:3][C:2]([CH3:9])([CH3:1])[CH2:6][C:5]=3[CH:16]=2)[CH2:21][CH2:20]1
Reactant: COP(=O)(CC(=O)CC1CC1)OC
Reactant: CC1(C)CC(=O)C(=O)C1
Reactant: NN
Solvent: O
Product: CC1(C)Cc2cc(CC3CC3)nnc2C1

Procedure:
Prepared from 4,4-dimethyl-cyclopentane-1,2-dione, (3-cyclopropyl-2-oxo-propyl)-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH3:21])=[N:11][C:12](N)=[N:13][C:14]=1[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]=O.[BH3-][C:25]#[N:26].[Na+]>CO>[CH2:1]([O:8][C:9]1[C:10]([CH3:21])=[N:11][C:12]([N:26]([CH3:25])[CH3:22])=[N:13][C:14]=1[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=O
Reactant: CCCCCc1nc(N)nc(C)c1OCc1ccccc1
Reactant: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCCCCc1nc(N(C)C)nc(C)c1OCc1ccccc1
Temperature: 23 °C
Reaction time: 3 h

Procedure:
To a stirred solution containing 334 mg (1.17 mmol) of 5-(benzyloxy)-4-methyl-6-pentylpyrimidin-2-amine in 4 mL of methanol were added 4 mL of 35% aq. formaldehyde followed by 588 mg (9.35 mmol) of NaCNBH3. The reaction mixture was stirred at 23° C. for 3 h. The reaction mixture was quenched with acetic acid until bubbling ceased then poured into 20 mL of water and extracted with two 40-mL portions of ethyl acetate. The combined organic layer was washed with one 40-mL portion of saturated aq. NaHCO3 and one 40-mL portion of brine. The organic solution was dried (MgSO4) and then concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column (8×3 cm). Elution with 2:1 hexanes-ethyl acetate afforded the expected product as colorless oil: yield 150 mg (41%); silica gel TLC Rf 0.7 (2:1 hexanes-ethyl acetate); 1H NMR (CDCl3) δ 0.88 (t, 3H, J=7.2 Hz), 1.33 (m, 4H), 1.69 (quint, 2H, J=7.6 Hz), 2.32 (s, 3H), 2.62 (dd, 2H, J=8.0, 8.0 Hz), 3.15 (s, 6H), 4.70 (s, 2H) and 7.33-7.44 (m, 5H); 13C NMR (CDCl3) δ 14.00, 19.31, 22.54, 27.52, 31.67, 31.81, 37.22, 37.22, 75.73, 127.94, 128.13, 128.13, 128.55, 128.55, 137.15, 141.26, 158.60, 160.01 and 163.48; mass spectrum (APCI), m/z 314.2224 (M+H)1 (C19H28N3O requires 314.2232).
Reaction SMILES: N1C=CN=C1.[Cl:6][C:7]1[S:11][C:10]([CH:12](O)[CH2:13][OH:14])=[CH:9][CH:8]=1.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].CN(C)C=[O:27]>>[Si:16]([O:27][CH:13]([OH:14])[CH2:12][C:10]1[S:11][C:7]([Cl:6])=[CH:8][CH:9]=1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: OCC(O)c1ccc(Cl)s1
Reactant: CN(C)C=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Product: CC(C)(C)[Si](C)(C)OC(O)Cc1ccc(Cl)s1
Reaction time: 1 h

Procedure:
Imidazole (0.45 g) was added to a solution of 1(5-chloro-2-thienyl)-1,2-ethanediol (1.0 g, 5.6 mmol) and tert-butyldimethylsilyl chloride (0.80 g) in N,N-dimethylformamide (5 ml) at 5°. The reaction mixture was allowed to come to room temperature and stirred 1 hour, extracted with ethyl acetate, washed with 0.5N aqueous hydrochloric acid, saturated sodium bicarbonate and brine. The extracts were dried over sodium sulfate, filtered, concentrated in vacuo. 1-tert-butyldimethylsilyloxy-2-(5-chloro-2-thienyl)ethan-1-ol (1.14 g) was obtained as a colorless oil after a chromatographic purification. 1,1′-Carbonyldiimidazole (0.95 g) was added to a solution of the foregoing alcohol (1.14 g 3.9 mmol) in dichloromethane (20 mL) at 5°. The reaction mixture was allowed to come to room temperature and stirred 1 hour. Ammonium hydroxide (equivalent to 28% ammonia in water, 10 ml) was added at 5°. The reaction mixture was stirred for 1 hour at room temperature, extracted with ethyl acetate, washed with 0.5N aqueous hydrochloric acid, saturated sodium bicarbonate and brine. The extracts were dried over sodium sulfate, filtered, concentrated in vacuo. 1-tert-butyldimethylsilyloxy-2-(5-chloro-2-thienyl)-2-carbamoyloxyethane (0.47 g) was obtained as a colorless oil after a chromatographic purification.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7]([O:9]CC)=O.C(O)(=O)C.[CH:16](N)=[NH:17]>CCO>[CH:5]1[N:4]=[C:3]2[C:7]([N:17]=[CH:16][NH:1][N:2]2[CH:6]=1)=[O:9]
Reactant: N=CN
Reactant: CCOC(=O)c1nccn1N
Solvent: CC(=O)O
Solvent: CCO
Product: O=c1nc[nH]n2ccnc12
Temperature: 25 °C

Procedure:
A mixture of ethyl 1-amino-1H-imidazole-2-carboxylate (C-4) (800 mg, 5.16 mmol, 1.0 eq) and formamidine acetate (2.68 g, 25.78 mmol, 5.0 eq) in EtOH (100 mL) is stirred at reflux overnight. The resulting mixture is cooled to RT. The solid is collected by filtration, rinsed with EtOH (3×2 mL) and petroleum ether (2 mL×3), and then dried in vacuo to afford the product, imidazo[1,2-f][1,2,4]triazin-4-ol (C-5).