Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH:3]1[O:20][C:7]2([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[CH2:6][NH:5][CH2:4]1.Cl[C:22]1[N:27]=[CH:26][CH:25]=[CH:24][N:23]=1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C.CCCCCC>CS(C)=O.C(OCC)(=O)C>[OH:1][CH2:2][CH:3]1[O:20][C:7]2([CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[CH2:11][CH2:12]2)[CH2:6][N:5]([C:22]2[N:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:4]1
Reactant: Clc1ncccn1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNCC(CO)O2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CN(c1ncccn1)CC(CO)O2
Yield: 80.8 %

Procedure:
A solution of tert-butyl 10-(hydroxymethyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (3.10 g, 10.8 mmol), 2-chloropyrimidine (1.86 g, 16.2 mmol) and sodium carbonate (2.30 g, 21.7 mmol) in DMSO (15 mL) was heated at 110° C. for 1 h. The reaction mixture was diluted with ethyl acetate (200 mL), washed with water (4×100 mL), dried over Na2SO4, and concentrated in vacuo. Silica gel column chromatography (0-60% ethyl acetate/hexane) provided tert-butyl 10-(hydroxymethyl)-8-pyrimidin-2-yl-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (3.18 g, 8.73 mmol, 80%). ESI-MS m/z calc. 364.2. Found 365.3 (M+1)+; Retention time: 1.21 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 8.29 (d, J=4.7 Hz, 2H), 6.50 (t, J=4.7 Hz, 1H), 4.64 (ddd, J=16.0, 8.5, 1.5 Hz, 2H), 3.90-3.80 (m, 1H), 3.79-3.56 (m, 4H), 3.44-3.22 (m, 1H), 3.13 (t, J=10.6 Hz, 1H), 2.90-2.71 (m, 2H), 2.19 (d, J=8.9 Hz, 1H), 1.98 (dd, J=10.6, 3.6 Hz, 1H), 1.69-1.58 (m, 2H), 1.45 (s, 9H).
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH2:8][C:7](=[O:9])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=2[F:17])[C:5]1=[O:18])[CH3:3].Cl[CH2:20][C:21]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:22]=1[O:23][CH:24]([CH3:29])[C:25]([O:27][CH3:28])=[O:26].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[F:17][C:11]1[CH:12]=[C:13]([CH:14]=[CH:15][C:10]=1[N:6]1[C:7](=[O:9])[CH2:8][N:4]([CH:2]([CH3:1])[CH3:3])[C:5]1=[O:18])[O:16][CH2:20][C:21]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:22]=1[O:23][CH:24]([CH3:29])[C:25]([O:27][CH3:28])=[O:26]
Reactant: COC(=O)C(C)Oc1cc(Cl)ccc1CCl
Reactant: CC(C)N1CC(=O)N(c2ccc(O)cc2F)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)C(C)Oc1cc(Cl)ccc1COc1ccc(N2C(=O)CN(C(C)C)C2=O)c(F)c1
Yield: 90.5 %

Procedure:
By the method of Example 1, Step I, 0.60 g (0.0024 mole) of 1-(1-methylethyl)-3-(2-fluoro-4-hydroxyphenyl)imidazolidin-2,4-dione, 1.24 g (0.0048 mole) of methyl 2-(2-chloromethyl-5-chlorophenoxy)propionate (Example 2, Step E), and 0.5 g (0.0036 mole) of potassium carbonate were reacted in 25 mL of 2-butanone. After purification, 1.04 g of methyl 2-[2-[3-fluoro-4[1-(1-methylethyl)imidazolidin-2,4-dion-3-yl]phenoxymethyl]-5-chlorophenoxy]propionate was isolated as a yellow oil. The NMR and IR spectra were consistent with the proposed structure. NMR: 1.24 (d, 6H, JHH =8 Hz); 1.64 (d, 3H, JHH =8 Hz); 3.68 (s, 3H); 3.96 (s, 1H); 4.44 (septet, 1H, JHH =8.0 Hz); 5.04 (q, 1H, JHH =8.0 Hz); 5.24 (s, 2H); 6.80-7.34 (m, 5H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][N:14]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:10]=3[N:11]=[CH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.[CH:39]1[N:43]=C[N:41]([C:44](N2C=NC=C2)=[O:45])[CH:40]=1.NCC#N>C(Cl)Cl>[C:39]([CH2:40][NH:41][C:44](=[O:45])[NH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][N:14]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:28])([CH3:27])[CH3:29])[C:10]=3[N:11]=[CH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1)#[N:43]
Reactant: CCOC(=O)c1cn(COCC[Si](C)(C)C)c2ncnc(-c3cccc(N)c3)c12
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N#CCN
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1cn(COCC[Si](C)(C)C)c2ncnc(-c3cccc(NC(=O)NCC#N)c3)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of ethyl 4-(3-aminophenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (103 mg, 0.250 mmol), DIPEA (0.131 mL, 0.749 mmol) in DCM (1 mL) was added CDI (81 mg, 0.50 mmol). The reaction mixture was stirred at room temperature overnight. At that point aminoacetonitrile (70.0 mg, 1.25 mmol) was added and the reaction mixture was stirred at room temperature for 5 hours. The resulting mixture was concentrated and purified by chromatography on silica eluting with 0-100% ethyl acetate/hexanes to give ethyl 4-(3-(3-(cyanomethyl)ureido)phenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate as a pale yellow solid. LRMS (ESI) calc'd for C24H31N6O4Si [M+H]+: 495, found 495.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH2:10][CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.C1C=C(Cl)C=C(C(OO)=[O:19])C=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[N:7]=[CH:6][N+:5]([O-:19])=[C:4]2[CH2:8][CH2:9][CH2:10][C:3]=12
Reactant: Clc1ncnc2c1CCC2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: [O-][n+]1cnc(Cl)c2c1CCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.7 %

Procedure:
To a solution of 4-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (5.69 g, 36.8 mmol) in chloroform (200 mL) was added MCPBA (19 g, 84.8 mmol) in chloroform (50 mL) dropwise. The mixture was stirred at room temperature for 16 hour. After cooling with ice-water, the mixture was quenched with Na2S2O3 (27.5 g) in water (110 mL) dropwise and followed by Na2CO3 (14 g) in water (52 mL) dropwise. The organic phase was separated and the aqueous phase was extracted with chloroform (3×200 mL). The organic phase was dried and concentrated at low temperature (<25° C.). The residue was subject to chromatography on silica gel, eluting by ethyl acetate to afford 4-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine 1-oxide (2.93 g, 47%). MS (APCI+) [M+H] +171.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([N:8]2[Si](C)(C)CC[Si]2(C)C)[CH:5]=[CH:6][CH:7]=1.C([Li])(CC)C.C([N:32]1[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]1)(OCC1C=CC=CC=1)=O.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[N:32]1([C:3]2[CH:2]=[CH:7][CH:6]=[CH:5][C:4]=2[NH2:8])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: C[Si]1(C)CC[Si](C)(C)N1c1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: Nc1ccccc1N1CCCCC1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A solution of 1-(3-fluorophenyl)-2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane (EXAMPLE 20, Step 1, 1.00 g) in dry tetrahydrofuran (9.8 mL) at -78° C. under N2 is treated with sec-butyllithium (1.3M in cyclohexane, 3.64 mL) dropwise over 3 mins, and the resulting mixture is stirred at -78° C. for 2 hrs. The mixture is then treated with a solution of N-(carbobenzyloxy)-4-piperidone (919 mg) in dry tetrahydrofuran (3.9 mL) dropwise over 2 mins and is stirred at -78° C. for 2 hrs. The mixture is then warmed to -20° C. over 1 hr and quenched with saturated aqueous ammonium chloride (5 mL), diluted with water (20 mL), the layers are separated, the aqueous phase is extracted with diethyl ether (20 mL), and the combined organic phase is washed with saline (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is dissolved in methanol (15 mL) and treated with anhydrous potassium carbonate (544 mg, 3.94 mmol), and the mixture is stirred at ambient temperature for 30 mins, concentrated under reduced pressure, diluted with diethyl ether (30 mL), washed with water (20 mL) and saline (10 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the crude 4-hydroxy)piperidinyl benzenamine intermediate (Rf =0.25 by TLC, ethyl acetate/hexane (50/50). A mixture of this intermediate and N,N-dimethylaniline (1.00 mL) in tetrahydrofuran (20 mL) is cooled to -20° C. and treated with benzyl chloroformate (0.59 mL), and the resulting mixture is stirred at -20° C. for 1 hr. The mixture is then diluted with saturated aqueous potassium carbonate (5 mL), water (25 mL) and diethyl ether (25 mL) and saline (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is chromatographed on silica gel (230-400 mesh, 150 g), eluting with a gradient of ethyl acetate/hexane (25/75-50/50), and those fractions with an Rf =0.47 by TLC (ethyl acetate/hexane, 50/50) are pooled and concentrated to give the title compound, NMR (400 MHz, CDCl3) 7.35, 7.00, 6.92, 5.20, 5.16, 4.10, 3.32, 2.15 and 1.79 δ and Anal. calculated for C27H27FN2O5 : C, 67.77; H, 5.69; N, 5.85. Found: C, 67.44; H, 5.83; N, 5.65.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([CH2:11][CH:12]=[CH2:13])[C:6](OCC)=[O:7])C.C[O-].[Na+].C(O)(=O)C.[CH:22]([NH2:24])=[NH:23]>C(O)C>[CH2:11]([C:5]1[C:6](=[O:7])[NH:24][CH:22]=[N:23][C:4]=1[OH:3])[CH:12]=[CH2:13]
Reactant: N=CN
Reactant: C=CCC(C(=O)OCC)C(=O)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: C=CCc1c(O)nc[nH]c1=O
Reaction time: 0.17 h
Yield: 57 %

Procedure:
2-Allyl-malonic acid diethyl ester (Preparation 205, 100 g, 0.5 mol) was added dropwise to a mixture of sodium methoxide (27 g, 0.5 mol) in ethanol (1 L) at 0-5° C. and the mixture was stirred at this temperature for 10 min. Formamidine acetate (51.9 g, 0.5 mol) was added and the mixture was stirred at room temperature overnight. The solvent was removed in vacuo, and aqueous hydrochloric acid (36.5%) and water were added to adjust the pH to approximately 3 at 0-20° C. The resulting mixture was filtered to afford the title compound as a colorless solid in 57% yield, 87.12 g.
Reaction SMILES: [Na].CS([O:6][CH2:7][C@@H:8]1[O:25][CH2:24][C@:11]2([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[F:32])[N:12]=[C:13]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[S:14][CH2:15][C@@H:10]2[CH2:9]1)(=O)=O.[Cl-].[NH4+].[CH3:35][CH:36](O)[CH3:37]>>[F:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[C@:11]12[CH2:24][O:25][C@@H:8]([CH2:7][O:6][CH:36]([CH3:37])[CH3:35])[CH2:9][C@H:10]1[CH2:15][S:14][C:13]([NH:16][C:17](=[O:18])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[N:12]2
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3ccccc3F)CO[C@@H](COS(C)(=O)=O)C[C@H]2CS1
Reactant: CC(C)O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Product: CC(C)OC[C@H]1C[C@H]2CSC(NC(=O)OC(C)(C)C)=N[C@@]2(c2ccccc2F)CO1
Reaction time: 18 h

Procedure:
The sodium salt of 2-propanol (34 mg, 0.41 mmol) was dissolved in 2-propanol (1.5 mL), and this was added to a solution of [(4aR,6R,8aS)-2-[(tert-butoxycarbonyl)amino]-8a-(2-fluorophenyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-6-yl]methyl methanesulfonate (C19) (40 mg, 0.084 mmol) in 2-propanol (0.5 mL). After 18 hours, additional sodium salt (34 mg, 0.41 mmol) was added, and stirring was continued for 66 hours. After addition of aqueous ammonium chloride solution, the mixture was extracted three times with ethyl acetate. The combined organic layers were washed with water, washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Purification was carried out via preparative thin layer chromatography on silica gel (Eluent: 1:1 ethyl acetate/heptane) to provide the product as a white foam. Yield: 11.2 mg, 0.255 mmol, 30%. LCMS m/z 439.4 (M+1). 1H NMR (400 MHz, CDCl3) δ 1.19 (br d, J=6.2 Hz, 6H), 1.54 (s, 9H), 1.63-1.71 (br m, 1H), 1.83-1.97 (br m, 1H), 2.50-2.59 (m, 1H), 2.93 (dd, J=13, 4 Hz, 1H), 3.07-3.18 (br m, 1H), 3.41 (dd, J=9.9, 4.8 Hz, 1H), 3.58-3.68 (m, 2H), 3.72-3.89 (m, 2H), 4.20 (br d, J=12 Hz, 1H), 7.05-7.12 (m, 1H), 7.17-7.23 (m, 1H), 7.30-7.40 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:17]([O-])([O-])=O.[Cs+].[Cs+].CI>CN(C=O)C.O>[CH3:17][N:11]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[S:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: COC(=O)CNS(=O)(=O)c1ccc(C)cc1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CN(C)S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
To a stirred solution of methyl 2-(4-methylphenylsulfonamido)acetate (3.10 g, 12.8 mmol) and Cs2CO3 (8.31 g, 25.5 mmol) in DMF (0.1 M) was added MeI (877 μL, 14.1 mmol). The reaction was allowed to stir overnight at rt. The reaction was then diluted with water and repeatedly extracted with CH2Cl2. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to furnish 6 (2.80 g, 85%): δH (400 MHz, CDCl3) 2.42 (s, 3H, CH3), 2.87 (s, 3H, CH3), 3.66 (s, 3H, CH3), 3.97 (s, 2H, CH2), 7.31 (d, J=8.4 Hz, 2H, CH), 7.69 (d, J=8.4 Hz, 2H, CH); LRMS (ES+) calcd for [C11H15NO4S+H] 258.08. found 258.06 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:24][N:25]=[C:26]([C:35]([NH:37][C:38](=[O:42])OCC)=[O:36])[C:27]([NH:29][C:30](=[O:34])[O:31][CH2:32][CH3:33])=[O:28])[CH:5]=[C:6]([Cl:23])[C:7]=1[C:8]([C:11]1[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[O:13][N:12]=1)([CH3:10])[CH3:9].C([O-])(=O)C.[Na+].O>C(O)(=O)C>[Cl:23][C:6]1[CH:5]=[C:4]([N:24]2[C:38](=[O:42])[NH:37][C:35](=[O:36])[C:26]([C:27]([NH:29][C:30](=[O:34])[O:31][CH2:32][CH3:33])=[O:28])=[N:25]2)[CH:3]=[C:2]([Cl:1])[C:7]=1[C:8]([C:11]1[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[O:13][N:12]=1)([CH3:9])[CH3:10]
Reactant: CCOC(=O)NC(=O)C(=NNc1cc(Cl)c(C(C)(C)c2noc(-c3ccccc3C)n2)c(Cl)c1)C(=O)NC(=O)OCC
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)NC(=O)c1nn(-c2cc(Cl)c(C(C)(C)c3noc(-c4ccccc4C)n3)c(Cl)c2)c(=O)[nH]c1=O

Procedure:
A solution of intermediate (20) (0.0302 mole) and sodium acetate (0.0302 mole) in acetic acid (200 ml) was stirred and refluxed for 3 hours. The reaction mixture was poured out into water and this mixture was extracted with CH2Cl2. The separated organic layer was dried, filtered and the solvent evaporated. Toluene was added and azeotroped on the rotary evaporator, yielding ethyl [[2-[3,5-dichloro-4-[1-[5-(2-methylphenyl)-1,2,4-oxadiazol-3-yl]-1-methylethyl]phenyl]-2,3,4,5-tetrahydro-3,5-dioxo-1,2,4-triazin-6-yl]carbonyl]carbamate (intermediate 21).
Reaction SMILES: C(O[C:4]([N:6]=[C:7]=[S:8])=[O:5])C.[CH2:9]([O:11][C:12]([CH3:24])([CH3:23])[CH2:13][NH:14][C:15]1[N:16]=[CH:17][NH:18][C:19]=1C(N)=O)[CH3:10]>C(Cl)Cl>[CH2:9]([O:11][C:12]([CH3:23])([CH3:24])[CH2:13][N:14]1[C:15]2[N:16]=[CH:17][NH:18][C:19]=2[C:4](=[O:5])[NH:6][C:7]1=[S:8])[CH3:10]
Reactant: CCOC(=O)N=C=S
Reactant: CCOC(C)(C)CNc1nc[nH]c1C(N)=O
Solvent: ClCCl
Product: CCOC(C)(C)Cn1c(=S)[nH]c(=O)c2[nH]cnc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 47 %

Procedure:
Ethoxycarbonyl isothiocyanate (0.171 g, 1.30 mmol) was added to a stirred solution of 4-[(2-Ethoxy-2-methylpropyl)amino]-1H-imidazole-5-carboxamide (0.246 g, 1.09 mmol), which had been obtained from Example 1(c), in CH2Cl2 (1.1 mL) at r.t. for 0.5 h, then the reaction was left unstirred at 4° C. for 16 h. The reaction mixture was heated to r.t. for 1 h and the solvent was evaporated, the residue was dissolved in 2% sodium hydroxide (aq.) (27 mL) and the reaction was heated at 50° C. for 5.5 h. The pH was adjusted to neutral with conc. HCl and 1M HCl. The precipitate was collected by filtration, washed with water and purified by flash silica gel chromatography (CHCl3/MeOH; 20:1), to give the title compound in 47% yield (96 mg).
Reaction SMILES: COP([CH2:7][C:8](=[O:21])[CH2:9][CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[CH2:17][CH2:16][CH2:15][NH:14][C:13]=2[N:12]=1)(=O)OC.[CH2:22]([O:24][C:25](=[O:38])[CH2:26][CH:27]([C:31]1[CH:32]=[N:33][C:34]([CH3:37])=[N:35][CH:36]=1)[CH2:28][CH:29]=O)[CH3:23].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:22]([O:24][C:25](=[O:38])[CH2:26][CH:27]([C:31]1[CH:32]=[N:33][C:34]([CH3:37])=[N:35][CH:36]=1)[CH2:28][CH:29]=[CH:7][C:8](=[O:21])[CH2:9][CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[CH2:17][CH2:16][CH2:15][NH:14][C:13]=2[N:12]=1)[CH3:23]
Reactant: CCOC(=O)CC(CC=O)c1cnc(C)nc1
Reactant: COP(=O)(CC(=O)CCc1ccc2c(n1)NCCC2)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC(CC=CC(=O)CCc1ccc2c(n1)NCCC2)c1cnc(C)nc1
Temperature: 50 °C

Procedure:
To a mixture of 4-10 (100 mg, 0.42 mmol) and 4-6 (160 mg, 0.54 mmol) in DMF (3 mL) was added K2CO3 (87 mg, 0.63 mmol) followed by heating to 50° C. for 18 hours. Following evaporative removal of the solvent, the residue was chromatographed (silica gel, 70:25:5 CHCl3/EtOAc/MeOH) to give 4-11 as a clear oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([C:6]#[N:7])[CH2:5][CH2:4]1.[Br:8][C:9]1[N:10]=[C:11]([CH:29]2[CH2:31][CH2:30]2)[N:12]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:13]=1[C:14]1[CH:19]=[CH:18][N:17]=[C:16](Cl)[N:15]=1.CCN(C(C)C)C(C)C.C([O-])([O-])=O.[Na+].[Na+]>CN1C(=O)CCC1>[Br:8][C:9]1[N:10]=[C:11]([CH:29]2[CH2:31][CH2:30]2)[N:12]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:26])([CH3:27])[CH3:28])[C:13]=1[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([NH:7][CH2:6][C:3]2([C:2]#[N:1])[CH2:5][CH2:4]2)[N:15]=1
Reactant: C[Si](C)(C)CCOCn1c(C2CC2)nc(Br)c1-c1ccnc(Cl)n1
Reactant: N#CC1(CN)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1c(C2CC2)nc(Br)c1-c1ccnc(NCC2(C#N)CC2)n1
Temperature: 110 °C
Yield: 65.1 %

Procedure:
A mixture of 1-(aminomethyl)cyclopropanecarbonitrile (0.67 g, 7.0 mmol), 4-(4-bromo-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-2-chloropyrimidine (2.01 g, 4.7 mmol), DIEA (1.64 ml, 9.35 mmol), Na2CO3 (0.99 g, 9.4 mmol) and NMP (2 mL) was heated at 110° C. for 25 hours. The reaction mixture was allowed to cool to room temperature and partitioned between EtOAc (10 mL) and water (20 mL). The layers were separated and the organic portion was sequentially washed with water (20 mL), brine (10 mL), and concentrated. The resulting residue was purified by flash chromatography on silica gel eluting with an EtOAc-heptane (0-50%) gradient to provide 1-((4-(4-bromo-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)methyl)cyclopropanecarbonitrile (1.50 g, 3.06 mmol, 66%) as a white foam. LCMS (m/z) 491.1 (MH+), tR=0.99 minute.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[N:3]=1.[Se](=O)=[O:13]>O1CCOCC1>[N:3]1[C:4]2[C:9](=[N:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[CH:1]=[O:13]
Reactant: O=[Se]=O
Reactant: Cc1ccc2ncccc2n1
Solvent: C1COCCO1
Product: O=Cc1ccc2ncccc2n1
Temperature: 25 °C

Procedure:
A 100 mL round bottom flask equipped with a condenser (with a calcium sulfate drying tube) and a magnetic stirbar was charged with 2-methyl-1,5-naphthyridine (CAS#7675-32-3, Synchem-OHG #CDP146FP1, 433 mg, 3.0 mmol). Dioxane (10 mL) was added to give a stirred solution, then selenium dioxide (366 mg, 3.3 mmol) was added and the reaction mixture was heated to reflux with an oil bath. The stirred reaction mixture was maintained at reflux for 2 h, then cooled to ambient temperature and filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on an Analogix IF-280 (Varian SF25-60 g, 100:0 to 0:100 hexane/EtOAc). Fractions #10-17 were combined and concentrated under reduced pressure to give a white solid that was dried overnight in a vacuum oven at ambient temperature. The dried solid Intermediate 4B, 1,5-naphthyridine-2-carbaldehyde weighed 229 mg (48%). 1H NMR (300 MHz, CDCl3) δ 10.25 (d, J=0.9 Hz, 1H), 9.12 (dd, J=4.2, 1.6 Hz, 1H), 8.60-8.54 (m, 2H), 8.28 (d, J=8.7 Hz, 1H), 7.77 (dd, J=8.6, 4.2 Hz, 1H). MS (DCI—NH3) m/z=159 (M+H)+, m/z=176 (M+NH4)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:18][C:19]3[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=3)=[N:8][C:9]([C:13]([O:15]CC)=O)=[N:10]2)=[CH:5][CH:4]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([Mg]Br)=[CH:28][CH:27]=1.C1COCC1>CC(N(C)C)=O>[F:25][C:26]1[CH:31]=[CH:30][C:29]([C:13]([C:9]2[N:8]=[C:7]([NH:18][C:19]3[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=3)[C:6]3[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[N:10]=2)=[O:15])=[CH:28][CH:27]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: CCOC(=O)c1nc(Nc2cc(C)[nH]n2)c2ccc(OC)cc2n1
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: COc1ccc2c(Nc3cc(C)[nH]n3)nc(C(=O)c3ccc(F)cc3)nc2c1
Yield: 95 %

Procedure:
To ethyl 7-methoxy-4-(5-methyl-1H-pyrazol-3-ylamino)quinazoline-2-carboxylate (379 mg, 1.16 mmol) in dry DMA (16 mL) cooled in a −30° C. bath was added dropwise 1N 4-fluorophenylmagnesium bromide in THF (4.05 mL, 4.05 mmol). After 4 h the reaction mixture was quenched by addition of a saturated ammonium chloride solution. The solution was concentrated and H2O was added. The precipitate was washed with water and diethyl ether to give a yellow solid (415 mg, 95%). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.18 (br. s., 3H) 3.92 (br. s., 3H) 6.48 (br. s., 1H) 7.27 (br. s., 2H) 7.39 (br. s., 2H) 8.07 (br. s., 2H) 8.62 (br. s., 1H) 10.50 (br. s., 1H) 12.15 (br. s., 1H) LC-MS (ESI) m/z 378 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][CH:5]=[C:6]([CH3:8])[N:7]=1.Cl.[NH2:10][CH2:11][CH2:12][SH:13].C[O-].[Na+].[C:17]([N:19]=[C:20](SC)[S:21][CH3:22])#[N:18]>>[C:17]([NH:19][C:20](=[N:10][CH2:11][CH2:12][S:13][CH2:2][C:3]1[S:4][CH:5]=[C:6]([CH3:8])[N:7]=1)[S:21][CH3:22])#[N:18]
Reactant: Cc1csc(CCl)n1
Reactant: CSC(=NC#N)SC
Reactant: NCCS
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: CSC(=NCCSCc1nc(C)cs1)NC#N

Procedure:
When 2-chloromethyl-4-methylthiazole [prepared from 2-hydroxymethyl-4-methylthiazole and thionyl chloride] is reacted with cysteamine hydrochloride and about two equivalents of a strong base such as sodium methoxide and the resultant amine treated with dimethyl cyanodithioimidocarbonate there is produced N-cyano-N'-{2-[(4-methylthiazol-2-yl)methylthio]ethyl}-S-methylisothiourea. When the latter compound is reacted with propargylamine according to the general procedure of Example 4, there is produced N-cyano-N'-(2-propyn-1-yl)-N"-{2-[(4-methylthiazol-2-yl)methylthio]ethyl}guanidine.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:12](=[O:15])[CH:13]=[CH2:14])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[OH:23][CH:24]([C:29]1[S:33][C:32]([CH:34]=[O:35])=[N:31][CH:30]=1)[C:25]([OH:28])([CH3:27])[CH3:26].C(N(CC)CC)C.O1CCCC1>[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(O)C>[OH:23][CH:24]([C:29]1[S:33][C:32]([C:34](=[O:35])[CH2:14][CH2:13][C:12](=[O:15])[CH:11]([C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:10][CH:9]=2)[CH2:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[N:31][CH:30]=1)[C:25]([OH:28])([CH3:27])[CH3:26]
Reactant: C=CC(=O)C(CC1CCOCC1)c1ccc(S(C)(=O)=O)cc1
Reactant: CC(C)(O)C(O)c1cnc(C=O)s1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(O)C(O)c1cnc(C(=O)CCC(=O)C(CC2CCOCC2)c2ccc(S(C)(=O)=O)cc2)s1
Yield: 62.8 %

Procedure:
A mixture of 4-[4-(methylsulfonyl)phenyl]-5-(tetrahydro-2H-pyran-4-yl)pent-1-en-3-one (0.50 g), 5-(1,2-dihydroxy-2-methylpropyl)-1,3-thiazole-2-carbaldehyde (0.32 g), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (43 mg), triethylamine (0.09 mL), tetrahydrofuran (6 mL) and ethanol (6 mL) was stirred with heating under reflux for 1 hr. The reaction mixture was concentrated, the residue was subjected to basic silica gel column chromatography, and eluted with tetrahydrofuran, and the fraction was concentrated. The residue was subjected to silica gel column chromatography, and the title compound (0.51 g, yield 61%) was obtained as a colorless oil from a fraction eluted with ethyl acetate. MS: 524 (MH+).