Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[NH2:2][C:3]1[N:8]=[C:7]([NH:9][C@@H:10]2[CH2:14][C@H:13]([CH2:15][OH:16])[CH:12]=[CH:11]2)[C:6]([N:17]=NC2C=CC(Cl)=CC=2)=[C:5]([Cl:26])[N:4]=1.[C:27](O)(=O)C.O>O1CCCC1.[Zn]>[NH2:2][C:3]1[N:8]=[C:7]2[C:6]([N:17]=[CH:27][N:9]2[C@@H:10]2[CH2:14][C@H:13]([CH2:15][OH:16])[CH:12]=[CH:11]2)=[C:5]([Cl:26])[N:4]=1
Reactant: Nc1nc(Cl)c(N=Nc2ccc(Cl)cc2)c(N[C@H]2C=C[C@@H](CO)C2)n1
Reactant: CC(=O)O
Agent: [Zn]
Solvent: O
Solvent: C1CCOC1
Product: Nc1nc(Cl)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 65 %

Procedure:
A suspension of (1 S,4R)-4-((2-Amino-6-chloro-5-((4chlorophenyl)azo)-4-pyrimidinyl)amino)-2-cyclopentene-1-methanol hydrate (1.96 g, 5 mmol) in tetrahydrofuran (15 mL) was treated with acetic acid/water (1:1, 5 mL), then with zinc dust (1.63g, 25 mmol) in portions so as to keep the pot temperature below 35° C. The deep yellow color faded after 10 min, and after an additional 50 min the solution was filtered to remove precipitated zinc salts. The filter cake was rinsed with tetrahydrofuran and the filtrate was refiltered to remove additional zinc salts, then concentrated in vacuo with addition of toluene to facilitate removal of water and acetic acid. The residue was rinsed with toluene/hexane to separate some of the 4-chloroaniline byproduct, taken up in triethyl orthoformate (40 mL), cooled on an ice bath (5° C.), and treated dropwise with concentrated hydrochloric acid (1.9 mL). The mixture was stirred at 5° C. for 5 h (tan suspension soon formed), slowly warmed to room temperature, and stirred for an additional 18 h, then cooled on an ice bath and filtered. The filter cake was rinsed with ether (save filtrate), and this solid was taken up in water (30 mL), filtered, and the solids washed with water. The aqueous filtrate was basified with sodium carbonate to pH-9, then extracted with 5% isopropanol-hloroform (3×25 mL) The combined extracts were dried (Na2SO4) and concentrated in vacuo to a residual tan foam (0.85 g). The organic filtrate from above was concentrated in vacuo and the residue taken up in 1N hydrochloric acid (30 mL), stirred for 1h, filtered, and the filtrate adjusted to pH-6 with 5 N sodium hydroxide (6 mL, then basified with sodium carbonate. This aqueous suspension was extracted with 5% isopropanol-chloroform (3×25 mL), and the combined organic extracts were dried (Na2SO4) and concentrated in vacuo to a tan foam (0.55 g ). The two batches were combined, dissolved in warm chloroform, and loaded onto a silica gel column, which was eluted with 7% methanol-chloroform to afford pure fractions containing the subject compounds. These were concentrated in vacuo and the residual foam crystallized from ethyl acetate(2 crops) to afford 0.86 g (65%) of the title compound as a pale tan solid; mp 160°-162° C. 1H-NMR (DMSO-d6)δ: 8.04(s,1H); 6.91(s,2H); 6.15(m,1H); 5.90 (m,1H); 5.45 (m,1H); 4.73 (t, 1H,J =5 Hz); 3.45 (t,2H,J=5 Hz); 2.80-2.95(m, 1H); 2.55-2.70(m,1H); 1.60-1.70(m,1H). Ms(Cl): m/z 170 (m-C5ring, 100); 230 (m-Cl, 50); 266 (m+H+, 100). [α]20589 -104°, [α]20436 -267°(c=0.29, methanol).
Reaction SMILES: [CH2:1]([C@H:4]1[N:11]([S:12]([C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:24]=2[N:23]=[CH:22][CH:21]=[CH:20]3)(=[O:14])=[O:13])[CH2:10][C:9]2[CH:25]=[CH:26][CH:27]=[CH:28][C:8]=2[CH2:7][O:6][CH2:5]1)[CH:2]=[CH2:3].[CH2:29]([Zn]CC)C.ICI.[Cl-].[NH4+]>C1COCC1>[CH:2]1([CH2:1][C@H:4]2[N:11]([S:12]([C:15]3[CH:16]=[CH:17][CH:18]=[C:19]4[C:24]=3[N:23]=[CH:22][CH:21]=[CH:20]4)(=[O:14])=[O:13])[CH2:10][C:9]3[CH:25]=[CH:26][CH:27]=[CH:28][C:8]=3[CH2:7][O:6][CH2:5]2)[CH2:29][CH2:3]1
Reactant: CC[Zn]CC
Reactant: C=CC[C@@H]1COCc2ccccc2CN1S(=O)(=O)c1cccc2cccnc12
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: ICI
Product: O=S(=O)(c1cccc2cccnc12)N1Cc2ccccc2COC[C@H]1CC1CC1
Temperature: 0 °C
Reaction time: 6 h
Yield: 31 %

Procedure:
To a stirred solution of compound 18 (100 mg, 0.25 mmol) in dry THF (5 mL) was added diethyl zinc (1M solution in hexane, 2.5 mL) at 0° C. under nitrogen atmosphere followed by diiodomethane (667 mg, 2.5 mmol). The reaction was stirred at 0° C. for 6 h and poured over cold aqueous solution of ammonium chloride. The organic layer was separated and the aqueous layer extracted repeatedly with EA. The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by Prep-TLC to afford the compound 20 (32 mg, 31% yield). 1H NMR (500 MHz, CDCl3) δ 8.94 (m, 1H), 8.47 (d, J=7.5 Hz, 1H), 8.13 (d, J=8.0 Hz, 1H), 7.93 (d, J=8.5 Hz, 1H), 7.55 (t, J=8.0 Hz, 1H), 7.43 (dd, J=8.0 Hz, 4.0 Hz 1H), 7.17 (d, J=7.5 Hz, 1H), 6.98 (t, J=7.5 Hz, 1H), 6.89 (m, 1H), 6.80 (d, J=7.5 Hz, 1H), 5.07 (d, J=15.5 Hz, 1H), 4.95 (d, J=15.0 Hz, 1H), 4.86 (d, J=15.5 Hz, 1H), 4.60 (d, J=15.0 Hz, 1H), 4.49 (m, 1H), 4.14 (d, J=12.0 Hz, 1H), 3.75 (d, J=12.0 Hz, 1H), 1.71 (m, 1H), 1.10 (m, 1H), 0.63 (m, 1H), 0.33 (m, 2H), −0.11 (m, 2H). MS (ESI+) m/z: 409 [M+H]+. LCMS (m/z): 409.2 (MH+).
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2.[NH2:29][CH2:30][C:31]1([OH:37])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[CH3:28][N:4]1[C:3]([CH2:2][NH:29][CH2:30][C:31]2([OH:37])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)=[N:11][C:10]2[C:5]1=[N:6][C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])=[N:8][C:9]=2[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: NCC1(O)CCCCC1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CNCC3(O)CCCCC3)n(C)c2n1

Procedure:
4-(8-(Bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine (50 mg) was reacted with 1-(aminomethyl)cyclohexanol via General Procedure E to give 22 mg of 273 following reverse phase purification. MS (Q1) 491.3 (M)+
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[N:4]=1.[Cl:12][C:13]1[N:18]=[C:17](Cl)[N:16]=[C:15]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[N:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Cl:12][C:13]1[N:14]=[C:15]([N:20]2[CH2:21][CH2:22][O:23][CH2:24][CH2:25]2)[N:16]=[C:17]([N:7]2[C:6]3[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=3[N:4]=[C:3]2[S:2][CH3:1])[N:18]=1
Reactant: Clc1nc(Cl)nc(N2CCOCC2)n1
Reactant: CSc1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1nc2ccccc2n1-c1nc(Cl)nc(N2CCOCC2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
A mixture of 2-(methylsulfanyl)-1H-benzimidazole (1.64 g, 10 mmol), 2,4-dichloro-6-(4-morpholinyl)-1,3,5-triazine (2.35 g, 10 mmol), and powdered K2CO3 (11 g, 80 mmol) in DMF (50 mL) was stirred at room temperature for 1 hr. The mixture was diluted with water and the resulting precipitate was collected, washed with water and then ethanol, and dried to give 3.56 g (98% yield) of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(methylsulfanyl)-1H-benzimidazole: mp (CHCl3/EtOH) 260-261° C.; 1H NMR (CDCl3) δ 8.42 (br dd, J=7.0, 1.9 Hz, 1H), 7.65 (br dd, J=6.8, 1.9 Hz, 1H), 7.30 (m, 2H), 4.06 (m, 2H), 3.95 (m, 2H), 3.84 (m, 2H), 3.80 (m, 2H), 2.74 (s, 3H); Anal. Calcd. for C1sH15ClN6OS: C, 49.65; H, 4.2; N, 23.2. Found: C, 49.8; H, 4.1; N, 23.1%.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].FC(F)(F)S(O[C:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH:18]=1)(=O)=O.[C:28]([NH:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1)(=[O:30])[CH3:29]>C(COC)OC>[C:28]([NH:31][C:32]1[CH:37]=[C:36]([C:13]2[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH:18]=2)[CH:35]=[CH:34][CH:33]=1)(=[O:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(=O)Nc1cccc(C2=CCN(C(=O)OC(C)(C)C)CC2)c1

Procedure:
A mixture of saturated of aqueous Na2CO3 solution (25 mL), tert-butyl 4-{[(trifluoromethyl)sulfonyl]oxy}-1,2,3,6-tetrahydro-1-pyridine-carboxylate (20 mmol), 3-acetamidophenylboronic acid (30 mmol) and tetrakis-triphenylphosphine palladium (0) (1.15 g) and dimethoxyethane (40 mL) was heated at reflux temperature overnight. The organic layer of the cooled reaction mixture was separated and the aqueous layer was washed with ethyl acetate (3×). The combined organic extracts were dried and concentrated in vacuo. The crude product was chromatograghed, giving the desired product 1H NMR δ 8.11 (br s, 1 H), 7.57 (br s, 1 H), 7.41 (br d, 1 H, J=7.8 Hz), 7.25 (apparent t, 1 H, J=7.8 Hz), 7.08 (br d, 1 H, J=7.8 Hz), 5.99 (b s, 1 H), 4.03 (br m, 2 H, J=2.7 Hz), 3.59 (t, 2 H, J=5.7 Hz), 2.46 (m, 2 H,), 2.16 (s, 3 H), 1.49 (s, 9 H).
Reaction SMILES: [C:1]1([C:7](=[CH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[C:8](=[O:10])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:18].[Na+].OO.[Cl-].[Na+]>CO>[C:1]1([C:7]2([O:18][CH:11]2[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[C:8](=[O:10])[CH3:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [OH-]
Reactant: CC(=O)C(=Cc1ccncc1)c1ccccc1
Agent: OO
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)C1(c2ccccc2)OC1c1ccncc1
Reaction time: 2 h
Yield: 71.8 %

Procedure:
To a stirred solution of 3-phenyl-4-(4-pyridyl)-3-butene-2-one (step 1) (500 mg, 2.24 mmol) in methanol (10 ml) at room temperature was added an aqueous solution (9 ml) of sodium hydroxide (100 mg, 2.24 mmol) and hydrogen peroxide (0.5 ml of 30% aqueous solution, 4.4 mmol). After stirring for 2 hours, sodium chloride was added and the reaction was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo to provide the crude 3-phenyl-4-(4-pyridyl)-3,4-epoxy-2-butanone (385 mg, 65%) as an oil. This was used in the next step without further purification.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]=[CH:21][N:22]([CH2:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:23]=2)=[CH:15][CH:14]=1.[C:33]([NH:38][C:39](=[O:44])[O:40][CH:41]([CH3:43])[CH3:42])(=[O:37])/[CH:34]=[CH:35]/[CH3:36]>C(#N)C>[CH3:36][CH:35]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]=[CH:21][N:22]([CH2:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:23]=2)=[CH:15][CH:14]=1)[CH2:34][C:33]([NH:38][C:39]([O:40][CH:41]([CH3:42])[CH3:43])=[O:44])=[O:37]
Reactant: C/C=C/C(=O)NC(=O)OC(C)C
Reactant: CC(C)(C)OC(=O)CCn1cnc(-c2ccc(N)cc2)c1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(CC(=O)NC(=O)OC(C)C)Nc1ccc(-c2cn(CCC(=O)OC(C)(C)C)cn2)cc1
Temperature: 50 °C
Reaction time: 48 h
Yield: 53 %

Procedure:
DBU (954 mg, 944 μl, 6.26 mmol) was added to a stirred solution of 1,1-dimethylethyl 3-[4-(4-aminophenyl)-1H-imidazol-1-yl]propanoate (for a preparation see Intermediate 96) (1.8 g, 6.26 mmol) and 1-methylethyl (2E)-2-butenoylcarbamate (for a preparation see Intermediate 49) (1.34 g, 7.83 mmol) in acetonitrile (25 mL). The reaction mixture was stirred at 50° C. for 48 h then was cooled to room temperature and most of the solvent was removed in vacuo. Purification of the residue by flash chromatography on silica gel (gradient: 0 to 5% MeOH in AcOEt) gave 1,1-dimethylethyl 3-[4-(4-{[1-methyl-3-({[(1-methylethyl)oxy]carbonyl}amino)-3-oxopropyl]amino}phenyl)-1H-imidazol-1-yl]propanoate (1.53 g, 3.34 mmol, 53%) as an orange oil.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11](CCCNC(C3C(C4C=CC=CC=4)=NOC=3C)=O)[CH2:10][CH2:9]2)=[C:4]([CH3:32])[CH:3]=1.[Cl:33]C1C=CC(N)=C(C)C=1>>[Cl:33][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[C:4]([CH3:32])[CH:3]=1
Reactant: Cc1cc(F)ccc1N1CCN(CCCNC(=O)c2c(-c3ccccc3)noc2C)CC1
Reactant: Cc1cc(Cl)ccc1N
Product: Cc1cc(Cl)ccc1N1CCNCC1
Yield: 73 %

Procedure:
The title compound was prepared following the method described for the Compound 31A of Example 31 but starting from 4-chloro-2-methylaniline instead of 4-fluoro-2-methylaniline. Purification by flash chromatography (chloroform-2N ammonia in methanol 100:3 to 100:5) afforded the title compound (73%) as an oil.
Reaction SMILES: [CH3:1][C:2]1[C:7](=[O:8])[CH2:6][CH:5]([C:9]([CH3:11])=[CH2:10])[CH2:4][CH:3]=1.[OH:12]O.[OH-].[Na+]>CO.O>[C:9]([C@@H:5]1[CH2:6][C@@H:7]2[C@@:2]([CH3:1])([O:8]2)[C:3](=[O:12])[CH2:4]1)([CH3:11])=[CH2:10]
Reactant: C=C(C)C1CC=C(C)C(=O)C1
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C=C(C)[C@H]1CC(=O)[C@]2(C)O[C@@H]2C1
Reaction time: 5 h

Procedure:
(R)-Carvone was epoxidized according to a modification of the method of E. Klein and G. Ohloff (Tetrahedron, 1963, 11, 1091-1099). Thus H2O2 (31%, 95 mL, 836 mmol, 1.3 equivalents) was added to a solution of (L)-carvone (100 mL, 640 mmol) in 650 mL of methanol at <5° C. After cooling to <0° C., 6N NaOH (10.5 mL, 63 mmol, 0.1 equivalents) was added. The reaction temperature was maintained at <5° C. After 5 hours, the reaction was diluted with 650 mL water, then quenched with 0.5 N KH2PO4 (250 mL) and 325 mL of 1 molal Na2SO3, keeping the temperature at <25° C. The reaction was extracted with 2×750 mL tert-butyl methyl ether. The combined tert-butyl methyl ether extracts were washed with 500 mL each of 20% aqueous NaCl then 10% then 25% to provide a clear organic layer which was dried over MgSO4, then filtered and concentrated, then chased with 100 mL of methanol. The resulting solution assayed (GC) at 101.3 g (96%) of the titled compound, which contained 5% of the minor isomer. 1H NMR (400 MHz, CDCl3) δ ppm 1.40 (s, 3 H) 1.70 (s, 3 H) 1.89 (ddd, J=14.75, 11.11, 1.17 Hz, 1 H) 2.02 (dd, J=17.56, 11.66 Hz, 1 H) 2.31 -2.41 (m, 1 H) 2.58 (ddd, J=17.56, 4.67, 1.37 Hz, 1 H) 2.65-2.76 (m, 1 H) 3.44 (dd, J=3.09, 1.03 Hz, 1 H) 4.70 (d, J=0.69 Hz, 1 H) 4.75-4.80 (m, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:29]=C[CH:31]=1)[C:5]([NH:7][CH:8]([C:10]1[N:15]=[N:14][C:13]([NH:16][C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=2)=[N:12][CH:11]=1)[CH3:9])=[O:6].[NH2:32]C(C1N=NC(NC2C=C(OC)C(OC)=C(OC)C=2)=NC=1)C.BrC1C=NC=C(C=1)C(O)=O.C(N(CC)CC)C>CN(C)C=O>[Br:1][C:2]1[CH:31]=[N:32][CH:29]=[C:4]([CH:3]=1)[C:5]([NH:7][CH:8]([C:10]1[N:15]=[N:14][C:13]([NH:16][C:17]2[CH:18]=[C:19]([O:27][CH3:28])[C:20]([O:25][CH3:26])=[C:21]([O:23][CH3:24])[CH:22]=2)=[N:12][CH:11]=1)[CH3:9])=[O:6]
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3cccc(Br)c3)nn2)cc(OC)c1OC
Reactant: COc1cc(Nc2ncc(C(C)N)nn2)cc(OC)c1OC
Agent: O=C(O)c1cncc(Br)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(Nc2ncc(C(C)NC(=O)c3cncc(Br)c3)nn2)cc(OC)c1OC

Procedure:
In a similar manner as described for Intermediate 18, 6-(1-aminoethyl)-N-(3,4,5-trimethoxyphenyl)-1,2,4-triazin-3-amine (Intermediate 9) (0.10 g, 033 mmol), 5-bromonicotinic acid (0.073 g, 0.36 mmol), O-(7-azabenzotriazol-1-yl-N,N,N′N′-tetramethyluronium hexafluorophospahte (0.14 g, 0.36 mmol) and triethylamine (0.10 mL, 0.72 mmol) in N,N-dimethylformamide (5 mL) gave 5-bromo-N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)nicotinamide (0.15 g) as a white solid. MS m/z 489, 491 (M+1, M+3).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:14])[N:5]=[C:4]([CH:15]([CH3:17])[CH3:16])[C:3]=1[C:18]([NH2:20])=[O:19].[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]([O-])=O)=[CH:24][CH:23]=1.[O-]CC.[Na+]>C(O)C>[Cl:14][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]([CH3:13])[C:7]=1[N:6]1[C:2]2=[N:1][C:29]([CH2:28][C:25]3[CH:26]=[CH:27][C:22]([NH2:21])=[CH:23][CH:24]=3)=[N:20][C:18](=[O:19])[C:3]2=[C:4]([CH:15]([CH3:17])[CH3:16])[NH:5]1
Reactant: Nc1ccc(CC(=O)[O-])cc1
Reactant: Cc1cccc(Cl)c1-n1nc(C(C)C)c(C(N)=O)c1N
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cccc(Cl)c1-n1[nH]c(C(C)C)c2c(=O)nc(Cc3ccc(N)cc3)nc1-2
Temperature: 25 °C
Reaction time: 18 h
Yield: 37.9 %

Procedure:
Part D: To a stirred solution of 1.4 g (4.8 mmol) 5-amino-3-isopropyl-1-(2-chloro-6-methyl-phenyl)pyrazole-4-carboxamide in 100 mL absolute ethanol was added 5.14 g (28.8 mmol) of 4-amino-phenylacetate followed by 10.7 mL (28.8 mmol) of 2.66 M sodium ethoxide in ethanol. The solution was stirred 18 h at reflux and the heating mantle was then removed. The reaction was treated with water and 10% aq. HOAc, cooled to ambient temperature, and filtered. The solid purified by coloumn chromatography on silica gel using 1:1 hexanes-EtOAc as eluant to afford 743 mg (38%) of 1-(2-chloro-6-methylphenyl)-3-isopropyl-6-(4-aminobenzyl)-pyrazolo[3,4-d]pyrimidin-4-one, mp 206-207° C. Mass Spec.(CI+): 408 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=2)[CH2:9]1)=O)(C)(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH:44]12[CH2:52][CH2:51][CH:48]([CH2:49][CH2:50]1)[CH2:47][NH:46][CH2:45]2.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:44]12[CH2:52][CH2:51][CH:48]([CH2:49][CH2:50]1)[CH2:47][N:46]([C:20]([C:17]1[CH:16]=[CH:15][C:14]([O:13][CH:10]3[CH2:11][CH2:12][NH:8][CH2:9]3)=[CH:19][CH:18]=1)=[O:22])[CH2:45]2
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C(=O)O)cc2)C1
Reactant: C1CC2CCC1CNC2
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1ccc(OC2CCNC2)cc1)N1CC2CCC(CC2)C1
Reaction time: 0.17 h
Yield: 53.6 %

Procedure:
To a solution of 3-(4-carboxy-phenoxy)-pyrrolidine-1-carboxylic acid t-butyl ester (2.0 g, 6.53 mmol) in DMF (75 mL) was added HOBt (1.1 g, 7.83 mmol) and EDAC (1.5 g, 7.83 mmol) and the resulting mixture was stirred for 10 min. 3-Aza-bicyclo-[3.2.2]nonane (1 g, 7.83 mmol) and DIPEA (1.4 mL) were added and stirring was continued for 16 hrs at ambient temperature. The volatiles were evaporated in vacuo and to the residue was added water (50 mL) and diethyl ether (25 mL). A precipitate was forme, filtered off and redissolved in DCM (25 mL) followed by addition of TFA (10 mL). The mixture was stirred at room temperature for 16 hrs and the volatiles evaporated in vacuo. The residue was dissolved in water (50 mL) and washed with diethyl ether (2×10 mL). The pH of the aqueous phase was adjusted to ˜11 by addition of 32% NaOH followed by extraction with diethyl ether (2×50 mL). The combined organic phases were dried (Na2SO4), filtered and evaporated in vacuo. The crude residue was stirred with EtOAc (20 mL) and the precipitate formed was filtered off. The filtrate was evaporated to dryness affording crude 1.1 g (55%) of (3-aza-bicyclo[3.2.2]non-3-yl)-[4-(pyrrolidin-3-yloxy)-phenyl]-methanone which was used without further purification.
Reaction SMILES: N[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[Cl:10].[N:11]([O-:13])=[O:12].[Na+]>Cl.O.[Cu-]=O>[N+:11]([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[Cl:10])([O-:13])=[O:12]
Reactant: N#Cc1ccc(N)c(Cl)c1
Reactant: O=N[O-]
Agent: O=[Cu-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: N#Cc1ccc([N+](=O)[O-])c(Cl)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To an ice cold solution of 4-amino-3-chlorobenzonitrile (1 g, 6.6 mmol) in concentrated HCl (2.5 mL) plus water (2.5 mL) a chilled solution of sodium nitrite (0.74 g, 1.62 eq) in water (3.6 mL) is added dropwise to maintain the reaction temperature <0° C. After stirring at 0° C. for 10 min, the mixture is added portion-wise to an ice cold solution of sodium nitrite (3.29 g, 7.22 eq) and copper(I) oxide (349 mg, 0.37 eq) in water 14.5 mL). Stirring is continued at 0° C. for 40 min, and then at room temperature for 0.5 h. The reaction mixture is extracted with dichloromethane (2×), the combined organic layers washed with saturated aqueous sodium chloride, dried (MgSO4), concentrated, and purified by silica gel chromatography to give 4-nitro-3-chlorobenzonitrile. 1H NMR (CDCl3): δ 7.96 (d, J=8.24 Hz, 1 h), 7.88 (d, T=1.65 Hz, 1H), 7.63 (dd, J=1.65, 8.24 Hz, 1H.
Reaction SMILES: Cl[C:2]1[C:7](=[O:8])[C:6]([Cl:9])=[N:5][S:4][N:3]=1.[OH:10][C:11]1[CH:12]=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=1.C(N(CC)CC)C>O1CCCC1>[Cl:9][C:6]1[C:7](=[O:8])[C:2]([O:10][C:11]2[CH:12]=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=2)=[N:3][S:4][N:5]=1
Reactant: Cc1ccc(O)cn1
Reactant: O=c1c(Cl)nsnc1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(Oc2nsnc(Cl)c2=O)cn1
Yield: 77.2 %

Procedure:
This compound was prepared in the manner of Example 3, using 14.6 grams (0.08 mole) of 3,5-dichloro-4H-1,2,6-thiadiazin-4-one, 8.7 grams (0.08 mole) of 3-hydroxy-6-methylpyridine and 8.9 grams (0.088 mole) of triethylamine in 300 ml of tetrahydrofuran. The crude product was recrystallized from ethanol to give 15.8 grams (77%) of 3-chloro-5-(6-methyl-3-pyridyloxy)-4H-1,2,6-thiadiazin-4-one; m.p. 155°-156° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][N:8]([CH2:20][CH3:21])[CH2:9][CH2:10][CH2:11][CH2:12][N:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])=[CH:5][CH:4]=1.C(OC)(OC)OC.[NH:31]1[CH:35]=[CH:34][N:33]=[C:32]1[CH:36]=O.[BH4-].[Na+]>CO>[CH2:20]([N:8]([CH2:7][C:6]1[CH:22]=[CH:23][C:3]([CH2:2][NH:1][CH2:36][C:32]2[NH:31][CH:35]=[CH:34][N:33]=2)=[CH:4][CH:5]=1)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])[CH3:21]
Reactant: O=Cc1ncc[nH]1
Reactant: CCCN(CCC)CCCCN(CC)Cc1ccc(CN)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: COC(OC)OC
Product: CCCN(CCC)CCCCN(CC)Cc1ccc(CNCc2ncc[nH]2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 115.7 %

Procedure:
The compound (219 mg) obtained in Example 23-6 was dissolved in anhydrous methanol (5.0 ml) and added with trimethyl orthoformate (112 μl) and 2-imidazole carboxaldehyde (72.4 mg) and the whole was stirred overnight at room temperature, under a nitrogen atmosphere. Subsequently, sodium borohydride (12.3 mg) was added thereto in an ice bath, and the whole was stirred at room temperature for 1 hour. After completion of the reaction, distilled water was added thereto and the whole was stirred for a while. The resultant was subjected to extraction with chloroform and washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated saline solution. The organic layer obtained was dried with anhydrous sodium sulfate. The solvent was distilled off, thereby obtaining the subject compound (317 mg) as a yellow oily substance.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][NH:4][C@@H:3]1[C:7]([OH:9])=[O:8].CCN(C(C)C)C(C)C.Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>CN(C=O)C>[CH2:23]([O:22][C:20]([N:4]1[CH2:5][CH2:6][C@H:2]([OH:1])[C@H:3]1[C:7]([OH:9])=[O:8])=[O:21])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)[C@H]1NCC[C@@H]1O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)[C@@H]1[C@@H](O)CCN1C(=O)OCc1ccccc1
Temperature: 0 °C

Procedure:
(2S,3S)-3-Hydroxy-pyrrolidine-2-carboxylic acid (254.5 mg, 1.9 mmol) was dissolved in DMF (15 mL) and distilled water (6 mL). The solution was cooled to 0° C., and DIEA (500 μL, 2.9 mmol) was added followed by benzyl chloroformate (410 μL, 2.9 mmol). The reaction was stirred at 0° C. and allowed to warm to ambient temperature overnight. The reaction was filtered and purified by reverse phase HPLC to give the desired product.