Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH2:10][CH2:11][N:12]1[C:24]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=[C:16]([NH2:25])[C:15]=2[N:14]=[C:13]1[CH2:26][O:27][CH2:28][CH3:29].O[N:31]1[C:52](=[O:53])[NH:51][C@H:50]2[C@@H:32]1[CH2:33][S:34][C@H:35]2[CH2:36][CH2:37][CH2:38][CH:39](N1C(=O)CCC1=O)[C:40](=O)[OH:41]>C(Cl)(Cl)Cl>[NH2:25][C:16]1[C:15]2[N:14]=[C:13]([CH2:26][O:27][CH2:28][CH3:29])[N:12]([CH2:11][CH2:10][NH:9][C:40](=[O:41])[CH2:39][CH2:38][CH2:37][CH2:36][CH:35]3[CH:50]4[CH:32]([NH:31][C:52](=[O:53])[NH:51]4)[CH2:33][S:34]3)[C:24]=2[C:23]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:17]=1
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CCN
Reactant: O=C(O)C(CCC[C@@H]1SC[C@H]2[C@@H]1NC(=O)N2O)N1C(=O)CCC1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CCNC(=O)CCCCC1SCC2NC(=O)NC21
Temperature: 25 °C
Yield: 13.3 %

Procedure:
Triethylamine (1.2 g, 11.4 mmol) was added in a single portion to a slurry of 1-(2-aminoethyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine hydrochloride (3.39 g, 10.53 mmol) in chloroform (150 mL). The reaction mixture became clear. N-hydroxysuccinimidobiotin (3.0 g, 8.79 mmol) was then slowly added. After 2 hours the turbid reaction mixture was heated to reflux. The reaction mixture was maintained at reflux overnight and became clear. The reaction mixture was allowed to cool to ambient temperature and then it was quenched with water. The layers were separated. The organic layer was dried over magnesium sulfate and then concentrated to provide an off-white solid. This material was recrystallized from 8:2 ethanol:water to provide a white solid. A portion of this material was purified by prep HPLC eluting with water/acetonitrile/trifluoroacetic acid to provide 0.6 g of N1-[2-(4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]-5-(2-oxoperhydrothieno[3,4-d]imidazol-4-yl)pentanamide as the ditrifluoroacetate salt, m.p. 171-175° C. Analysis: Calculated for: C25H33N7O3S.2 C2HF3O2: %C, 47.09; %H, 4.77; %N, 13.26; Found: %C, 47.06; %H, 5.17; %N, 13.31.
Reaction SMILES: C([Li])CCC.CC(C)([O-])C.[Li+].[C:12]([Li])([CH3:15])([CH3:14])[CH3:13].[CH:17]1([CH2:23][CH2:24][C:25](Cl)=[O:26])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>O1CCCC1.C(O)CCC>[CH3:13][C:12]([CH3:15])([C:25]([CH2:24][CH2:23][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:26])[CH3:14]
Reactant: [Li]C(C)(C)C
Reactant: O=C(Cl)CCC1CCCCC1
Agent: CC(C)(C)[O-]
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CCCCO
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)CCC1CCCCC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Stage 1 of the preparation was carried out under an argon atmosphere. To a stirred solution of t butyl alcohol (4.92 g) in tetrahydrofuran (20 ml) at -30° C. was added dropwise n-butyl lithium (41.8 ml of 1.6 molar solution). The resultant lithium t-butoxide solution was allowed to warm to 0° C. and was added to a stirred solution of cuprous iodide (12.65 g) in tetrahydrofuran (50 ml). After about 15 minutes, the grey cuprous iodide was replaced by a beige solid, and the reaction mixture turned brown. The reaction mixture was then cooled to -70° C. and t-butyl lithium (34.0 ml of 1.9 molar solution) was added dropwise. A cooled (-40° C.) solution of 3-cyclohexyl propionic acid chloride (10 .0 g) in tetrahydrofuran (20 ml) was added rapidly. After 11/2 hours, the reaction was quenched by the addition of methanol (30 ml) and the reaction mixture was allowed to stand overnight at room temperature. The mixture was then poured into saturated ammonium chloride (200 ml) and insolubles were filtered off. The aqueous layer was extracted with ether (300 ml) and the extract was washed with 1% sodium thiosulphate solution (200 ml) and then dried over magnesium sulphate in the presence of charcoal. Concentration yielded an amber oil which was distilled to give a colourless liquid (5.56 g) which turned yellow on standing.
Reaction SMILES: [N:1]1([C:6](Cl)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:9]([O:13][C:14]([NH:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(N(CC)CC)C>ClCCl>[C:9]([O:13][C:14]([NH:16][CH:17]1[CH2:18][CH2:19][N:20]([C:6]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:7])[CH2:21][CH2:22]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: O=C(Cl)N1CCCC1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCN(C(=O)N2CCCC2)CC1
Reaction time: 72 h

Procedure:
1-Pyrrolidine carbonylchloride (1.10 g, 9.99 mmol) was dissolved in 400 ml if dichloromethane under N2. (Tert-butoxy)-N-(4-piperidyl)carboxamide (2.0 g, 9.99 mmol) and triethyl amine (1.40 mL, 9.99 mmol) were added and the reaction mixture was stirred for three days. The reaction was quenched with sat. NaHCO3 solution and extracted with dichlorormethane. The combined organic phases were dried over MgSO4 and the solvent evaporated to give the product as a white solid. (2.63 g, 8.84 mmol, 89%).
Reaction SMILES: [C:1](NNP(OCC)(OCC)=O)(=[O:3])[CH3:2].[CH:14]([O:17][P:18]([NH:24][NH2:25])(=[O:23])[O:19][CH:20]([CH3:22])[CH3:21])([CH3:16])[CH3:15]>N1C=CC=CC=1>[C:1]([NH:25][NH:24][P:18]([O:17][CH:14]([CH3:15])[CH3:16])([O:19][CH:20]([CH3:21])[CH3:22])=[O:23])(=[O:3])[CH3:2]
Reactant: CC(C)OP(=O)(NN)OC(C)C
Reactant: CCOP(=O)(NNC(C)=O)OCC
Solvent: c1ccncc1
Product: CC(=O)NNP(=O)(OC(C)C)OC(C)C

Procedure:
This compound was prepared in a similar manner to the compound of Example 1, but using diisopropylphosphorohydrazidate instead of diethylphosphorohydrazidate, and pyridine in place of triethylamine. The product distilled at 130°-140° C./0.07 mm.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[NH2:10][CH2:11][C@@H:12]1[O:16][C:15](=[O:17])[N:14]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[CH2:13]1.Cl[CH:26](Cl)[C:27](=[N:29][NH:30]S(C1C=CC(C)=CC=1)(=O)=O)[CH3:28]>CO>[F:24][C:20]1[CH:19]=[C:18]([N:14]2[CH2:13][C@H:12]([CH2:11][N:10]3[CH:26]=[C:27]([CH3:28])[N:29]=[N:30]3)[O:16][C:15]2=[O:17])[CH:23]=[CH:22][CH:21]=1
Reactant: CC(=NNS(=O)(=O)c1ccc(C)cc1)C(Cl)Cl
Reactant: NC[C@H]1CN(c2cccc(F)c2)C(=O)O1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cn(C[C@H]2CN(c3cccc(F)c3)C(=O)O2)nn1
Temperature: 0 °C
Reaction time: 8 h
Yield: 70.2 %

Procedure:
N,N-Diisopropylethylamine (3.20 mL, 18.35 mM) was added to a solution of (5S)-5-(aminomethyl)-3-(3-fluorophenyl)-1,3-oxazolidin-2-one (0.77 g, 3.57 mM; see Dong Pharmaceuticals WO 0194342) in anhydrous methanol (25 mL). The solution was cooled to 0° C., and N′-[2,2-dichloro-1-methylethylidene]-4-methylbenzenesulfonohydrazide (1.28 g, 4.58 mM) was added. The solution was warmed to room temperature and stirred overnight. The reaction mixture was then concentrated under vacuum and chromatographed on silica gel using 2% methanol/dichloromethane to give 0.71 g of the title product.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[C:6]([CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1.Cl>CC(O)=O>[N:1]1[C:10]2[C:5](=[C:6]([CH2:11][C:12]([OH:14])=[O:13])[CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)Cc1cccc2nccnc12
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)Cc1cccc2nccnc12
Temperature: 80 °C

Procedure:
To a stirring mixture of tert-butyl 2-(quinoxalin-5-yl)acetate (200 mg) in HOAc (5 mL) was added 6N HCl (5 mL). The reaction mixture was warmed to 80° C. for 2 h. The crude product mixture was concentrated under reduced pressure to give 2-(quinoxalin-5-yl)acetic acid, which was used in the next reaction without further purification. Method[1], MS (ESI) 189.0 [M+H], Retention time=0.722 min.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([CH3:13])=[CH:6][C:3]=1[CH:4]=[O:5].B(O[O-])=[O:15].[Na+].C(OCC)(=O)C>C(O)(=O)C>[Cl:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([CH3:13])=[CH:6][C:3]=1[C:4]([OH:15])=[O:5]
Reactant: O=BO[O-]
Reactant: Cc1cc(C=O)c(Cl)cc1[N+](=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1cc(C(=O)O)c(Cl)cc1[N+](=O)[O-]
Yield: 77.1 %

Procedure:
A solution of 2-chloro-5-methyl-4-nitrobenzaldehyde (1.72 g, 8.6 mmol) in acetic acid (20 ml) at 80° C. was treated with sodium perborate (2.64 g, 17.2 mmol). After 0.5 h a further portion of sodium perborate (1.32 g, 8.6 mmol) was added. After 0.25 h the reaction mixture was added to ethyl acetate--half saturated brine, and the organic extract dried (Na2SO4) and evaporated, affording the title product as a white solid (1.43 g, 77%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:20]2[CH2:25][C:24]([CH3:27])([CH3:26])[CH2:23][C:22]([CH3:29])([CH3:28])[CH2:21]2)[C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17](O)=[O:18])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[NH3:36]>C(Cl)Cl.CN(C=O)C>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:20]2[CH2:25][C:24]([CH3:27])([CH3:26])[CH2:23][C:22]([CH3:29])([CH3:28])[CH2:21]2)[C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([NH2:36])=[O:18])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(/C=C/C(=O)O)cc2)CC(C)(C)C1
Reactant: N
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(/C=C/C(N)=O)cc2)CC(C)(C)C1
Reaction time: 1 h
Yield: 15 %

Procedure:
To a stirred suspension of (2E)-3-{4-[(4-hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}-2-propenoic acid (16) (0.18 g, 0.46 mmol) in CH2Cl2 (6 mL) at room temperature was added oxalyl chloride (0.15 mL, 0.218 g, 1.72 mmol, 3.7 eq) followed by several drops of DMF (Note: vigorous bubbling occurred upon addition of DMF). The reaction mixture was stirred under a nitrogen atmosphere for 1 h and concentrated in vacuo. Toluene was added to the crude acid chloride and the solvent was removed in vacuo. To the crude acid chloride was added ammonia (0.5 M in 1,4-dioxane) (6 mL) and the turbid reaction mixture stirred at room temperature under a nitrogen atmosphere for 3 h. Ammonia (0.5 M in 1,4-dioxane) (2 mL) was added to the reaction mixture and stirring was continued overnight at room temperature under a nitrogen atmosphere. The reaction mixture was concentrated in vacuo. Ammonia (0.5 M in 1,4-dioxane) (8 mL) and CH2Cl2 (8 mL) were added to the residue. The flask was equipped with a rubber septum and the reaction mixture was stirred at room temperature for 2 d. The reaction mixture was transferred to a separatory funnel and partitioned between CH2Cl2 and H2O. The layers were separated and the aqueous phase was extracted with CH2Cl2. The organic extracts were combined, washed with brine, dried (MgSO4) filtered, and the filtrate was concentrated to give the crude product as an amorphous solid. The crude product was purified by flash chromatography on silica gel with CH2Cl2:MeOH (100:0 to 19:1) as eluant to provide the product which was dried to give 0.026 g (15%) of compound 17 as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 0.87 (s, 6H), 0.88 (s, 6H), 1.25 (s, 2H), 1.89 (s, 2H), 1.92 (s, 2H), 6.53 (d, J=15.8 Hz, 1H), 6.66 (d, J=8.5 Hz, 2H), 6.93 (d, J=8.5 Hz, 2H), 7.06 (br s, 1), 7.14 (d, J=8.1 Hz, 2H), 7.35 (d, J=15.9 Hz, 1H), 7.45 (d, J=8.1 Hz, 2H), 7.50 (br s, 1H), 9.30 (s, 1). HRMS (ESI) Calcd for C26H32NO2: 390.2433 (M+H)+. Found: 390.2427.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][N:5]([CH2:7][C:8]2[CH:9]=NC(C)=NC=2)[CH2:4][C@H:3]1[C:15]1[NH:16][C:17](=[O:30])[C:18]2[CH:23]=[N:22][N:21]([CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:19]=2[N:20]=1.[N:31]1[S:32][N:33]=[C:34]2[CH:39]=C(C=O)C=[CH:36][C:35]=12>>[N:31]1[S:32][N:33]=[C:34]2[CH:39]=[C:8]([CH2:7][N:5]3[CH2:6][C@@H:2]([CH3:1])[C@H:3]([C:15]4[NH:16][C:17](=[O:30])[C:18]5[CH:23]=[N:22][N:21]([CH:24]6[CH2:29][CH2:28][O:27][CH2:26][CH2:25]6)[C:19]=5[N:20]=4)[CH2:4]3)[CH:9]=[CH:36][C:35]=12
Reactant: O=Cc1ccc2nsnc2c1
Reactant: Cc1ncc(CN2C[C@@H](C)[C@H](c3nc4c(cnn4C4CCOCC4)c(=O)[nH]3)C2)cn1
Product: C[C@@H]1CN(Cc2ccc3nsnc3c2)C[C@H]1c1nc2c(cnn2C2CCOCC2)c(=O)[nH]1

Procedure:
Following the procedure for the preparation of 6-{(3S,4S)-4-methyl-1-[(2-methylpyrimidin-5-yl)methyl]pyrrolidin-3-yl}-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one but substituting benzo[c][1,2,5]thiadiazole-5-carbaldehyde provided the title compound. 400 MHz 1H NMR (CDCl3) δ 10.97 (brs, 1H), 8.02-8.00 (m, 2H), 7.86 (s, 1H), 7.77 (d, J=1.2 Hz, 1H), 4.81-4.75 (m, 1H), 4.12-4.06 (m, 2H), 3.96-3.92 (m, 1H), 3.81-3.78 (m, 1H), 3.60-3.52 (m, 2H), 3.38 (t, J=8.3 Hz, 1H), 3.03 (d, J=9.9 Hz, 1H), 2.88-2.85 (m, 1H), 2.68-2.63 (m, 1H), 2.47-2.45 (m, 1H), 2.37-2.28 (m, 2H), 2.04 (t, J=8.7 Hz, 1H), 1.90-1.80 (m, 2H), 1.21 (d, J=7.1 Hz, 3H). MS: (M+H m/z 452.1).
Reaction SMILES: C(OC([N:11]1[CH2:15][C@@H:14]([F:16])[C@@H:13]([CH2:17][NH:18][CH:19]2[CH2:21][CH2:20]2)[CH2:12]1)=O)C1C=CC=CC=1.[H][H]>C(O)C.[C].[Pd]>[CH:19]1([NH:18][CH2:17][C@@H:13]2[C@H:14]([F:16])[CH2:15][NH:11][CH2:12]2)[CH2:21][CH2:20]1
Reactant: [H][H]
Reactant: O=C(OCc1ccccc1)N1C[C@H](CNC2CC2)[C@H](F)C1
Agent: [Pd]
Solvent: CCO
Product: F[C@@H]1CNC[C@@H]1CNC1CC1
Yield: 92 %

Procedure:
(3S,4S)-1-Benzyloxycarbonyl-3-cyclopropylaminomethyl-4-fluoropyrrolidine (2.29 g) was dissolved in ethanol (25 mL). To this solution, 10% palladium carbon (229 mg) was added and the mixture was stirred at room temperature for 1.5 hours under a stream of hydrogen gas. The catalyst in the reaction mixture was filtered and was washed with ethanol. The filtrate and the washings were combined and concentrated under reduced pressure. The resulting residue was distilled under reduced pressure to give (3R,4S)-3-cyclopropylaminomethyl-4-fluoropyrrolidine as a colorless oil (1.14 g). This compound was identical to the compound obtained in Reference Example 8 (Process I).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[C:4]([F:9])[CH:3]=1.[CH3:10][S-:11].[Na+]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[C:6]([S:11][CH3:10])[CH:5]=[C:4]([F:9])[CH:3]=1
Reactant: Fc1cc(F)cc(Br)c1
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1cc(F)cc(Br)c1
Temperature: 150 °C

Procedure:
To a solution of 1-bromo-3,5-difluorobenzene (5.0 g, 25.9 mmol) in dimethylformamide (40 ml) was added sodiumthiomethylate (1.81 g, 25.9 mmol), and the mixture was heated to 150° C. for 10 min. The reaction mixture was brought to ambient temperature, quenched with saturated aqueous ammonium chloride (100 ml) and extracted with ethylacetate (3×100 ml). The combined organic phases was dried and concentrated in vacuo to receive the pure title compound (3.84 g). MS m/z (rel. intensity, 70 eV) 222 (M+, 100), 220 (M+, 100), 189 (49), 187 (50), 126 (75).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:8]([CH2:9][CH3:10])=[N:7][C:6]2[N:11]([CH2:14][CH3:15])[N:12]=[CH:13][C:5]=2[C:4]=1[NH:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.[CH3:23][O:24][C:25]([C:27]1[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=1)=[O:26].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl>[CH2:14]([N:11]1[C:6]2=[N:7][C:8]([CH2:9][CH3:10])=[C:3]([CH2:2][NH:1][C:31]([C:30]3[CH:34]=[CH:35][C:27]([C:25]([O:24][CH3:23])=[O:26])=[CH:28][CH:29]=3)=[O:32])[C:4]([NH:16][CH:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[C:5]2[CH:13]=[N:12]1)[CH3:15]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 23 h
Yield: 100.2 %

Procedure:
To a solution of 5-(aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine-4-amine (1.02 g, 3.0 mmol) in DCM (30 mL) was added 4-[(methyloxy)carbonyl]benzoic acid (0.541 g, 3.0 mmol), HBTU (1.37 g, 3.6 mmol), and Et3N (0.843 mL, 6.0 mmol) This mixture was stirred at room temperature for 23 h. It was diluted with DCM (30 mL), which was washed with H2O (30 mL) and dried over Na2SO4, filtered, concentrated and the concentrate purified by CombiFlash chromatograph to afford the title compound 1.40 g (quantitative). LC-MS m/z 466 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][CH3:16])[N:10]=2)[CH:3]=1.[O:17]([C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>Cl.C(O)CCC>[CH3:16][NH:15][C:11]1[N:10]=[C:9]([NH:8][C:4]2[CH:3]=[C:2]([NH:28][C:27]3[CH:26]=[CH:25][C:24]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:30][CH:29]=3)[N:7]=[CH:6][N:5]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Nc1ccc(Oc2ccccc2)cc1
Reactant: CNc1cccc(Nc2cc(Cl)ncn2)n1
Agent: Cl
Solvent: CCCCO
Product: CNc1cccc(Nc2cc(Nc3ccc(Oc4ccccc4)cc3)ncn2)n1
Yield: 41 %

Procedure:
A solution of N2-(6-chloropyrimidin-4-yl)-N6-methylpyridine-2,6,diamine (0.3 g 1.27 mmol), 4-phenoxy aniline (0.28 g, 1.52 mmol) and conc. HCl (2 drops) in n-butanol (2 mL) was subjected to microwave irradiation (120° C., 1 h). The reaction mixture was cooled, was concentrated under reduced pressure, and the residue was diluted with CH2Cl2 (5 mL). The dichloromethane solution was washed with NaHCO3 (2 mL), water (2 mL), and brine (2 mL), and was dried over Na2SO4. Filtration followed by concentration under reduced pressure gave a residue which was purified by column chromatography (SiO2, 60-120, chloroform/methanol, 9/1) to give N4-(6-(methylamino)pyridine-2-yl)-N6-(4-phenoxyphenyl)pyrimidine-4,6-diamine (0.2 g, 41%) as a light brown solid.
Reaction SMILES: C([Li])CCC.Br[C:7]1[N:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][CH:8]=1.[CH3:15][C:16]([O:19][C:20](=[O:30])[NH:21][CH2:22][CH2:23][C:24](NCOC)=[O:25])([CH3:18])[CH3:17]>O1CCCC1>[CH3:18][C:16]([O:19][C:20](=[O:30])[NH:21][CH2:22][CH2:23][C:24]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([O:13][CH3:14])[N:12]=1)=[O:25])([CH3:15])[CH3:17]
Reactant: COCNC(=O)CCNC(=O)OC(C)(C)C
Reactant: COc1cccc(Br)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cccc(C(=O)CCNC(=O)OC(C)(C)C)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 73.1 %

Procedure:
Butyl lithium (2.5M solution in hexanes, 1.4 ml) was added to a solution of 6-bromo-2-methoxypyridine (690 mg, 4.0 mmol) in tetrahydrofuran (4 ml) at −78° C. and stirred for 1 h. A solution of [3-(methoxymethylamino)-3-oxopropyl carbamic acid 1,1-dimethylethyl ester (344 mg, 1.42 mmol) in tetrahydrofuran (3 ml) was added and the mixture was warmed to 0° C. over 3 h. The mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate (three times) The combined organic extracts were dried (sodium sulphate), evaporated and purified by chromatography on silica eluting with petrol-acetone to give the sub-title compound as a colourless oil (291 mg, 73%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.Cl.[S:11]([C:15]1[CH:20]=[CH:19][C:18]([NH:21][NH2:22])=[CH:17][CH:16]=1)(=[O:14])(=[O:13])[NH2:12]>>[S:11]([C:15]1[CH:16]=[CH:17][C:18]([NH:21][N:22]=[CH:6][C:5]2[CH:8]=[CH:9][C:2]([Br:1])=[CH:3][CH:4]=2)=[CH:19][CH:20]=1)(=[O:14])(=[O:13])[NH2:12]
Reactant: O=Cc1ccc(Br)cc1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Product: NS(=O)(=O)c1ccc(NN=Cc2ccc(Br)cc2)cc1
Yield: 66 %

Procedure:
A solution of 4-bromobenzaldehyde (5 mmol) and 4-sulfamylphenyl-hydrazine hydrochloride was subjected to the General Procedure. The title compound, melting point 190–192° C., was obtained in 66% yield.
Reaction SMILES: [CH2:1]([O:17][CH2:18][C@H:19](O)[CH2:20][OH:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[Si]([N:60]=[N+:61]=[N-:62])(C)(C)C>C(Cl)Cl>[N:60]([C@H:19]([CH2:18][O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:20][OH:21])=[N+:61]=[N-:62]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CCCCCCCCCCCCCCCCOC[C@H](O)CO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCOC[C@H](CO)N=[N+]=[N-]
Reaction time: 3 h

Procedure:
To a solution of 3.17 g (10.0 mmol) of 3-O-hexadecyl-sn-glycerol (2) and 3.42 g (13.0 mmol) of Ph3P in 180 mL of CH2Cl2 was added 3.2 mL (15 mmol) of diisopropyl azodicarboxylate (DIAD) at 0° C. After the mixture was stirred for 3 h under nitrogen, Me3SiN3 was added. The mixture was stirred at the same temperature for 3 h, and then at room temperature until glycerol 2 had reacted completely. The reaction mixture was concentrated to give a yellow residue, which was dissolved in a minimum volume of CH2Cl2 and passed through a pad of silica gel in a sintered glass funnel. The pad was rinsed with hexane/EtOAc (50:1) until the excess yellow DIAD began to elute. After concentration of the eluted silyloxy azide, the residue was dissolved in 30 mL of THF and treated with 25 mL of a 1 M (n-Bu)4NF solution in THF. The mixture was stirred at room temperature until all of the silyloxy azides were consumed completely, and then was diluted with 250 mL of Et2O and washed with water and brine. The organic layer was separated, dried over Na2SO4, and concentrated The crude product was purified by column chromatography on silica gel (elution first 150 mL of 50:1 hexane/EtOAc and then with 6:1 hexane/EtOAc) to give 2.60 (76%) of azido alcohol 3 as a white solid: mp 37-39° C., (Ponpipom and Bugianesi, 1984). 38-29° C.; [α]25D +14.50 (c 1.0, CHCl3), (Ponpipom and Bugianesi 1984. [α]27D +14.1° (c 1.0, CHCl3); 1H NMR (CDCl3) δ 0.88 (t, 3H, J=6.4 Hz), 1.26 (s, 26H), 1.52-1.62 (m, 2H), 2.19 (br s, 1H), 3.47 (t, 2H, J=6.8 Hz), 3.55-3.63 (m, 4H), 3.65-3.80 (m, 1H); 13C NMR (CDCl3) δ 14.1, 22.7, 26.0, 29.3, 29.4, 29.5, 29.6, 29.7, 31.9, 62.3, 63.0, 70.9, 71.9.
Reaction SMILES: [C:1]([O:5][CH2:6][CH:7]1[O:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[CH3:10][C:11]([NH2:22])([CH3:21])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1>>[OH:9][CH:7]([CH2:6][O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:8][NH:22][C:11]([CH3:21])([CH3:10])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1
Reactant: COc1ccc(CC(C)(C)N)cc1
Reactant: CC(C)(C)OCC1CO1
Product: COc1ccc(CC(C)(C)NCC(O)COC(C)(C)C)cc1
Yield: 34.3 %

Procedure:
Using the method of Example 15, supra, t-butylglycidyl ether (142 mg, 1.0 mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (197 mg, 1.1 mmol) were used to prepare 106 mg of the title compound as a clear, colorless oil: GC/EI-MS, m/z (rel. int.) 310 (M+1. 0.3), 294 (0.5), 222 (1.8), 188 (67.9), 163 (14.6), 132 (100), 121 (19.1); 1H-NMR (CDCl3) δ 7.09 (2H, d, J=8.6), 6.82 (2H, d, J=8.6), 3.78 (3H, s), 3.68 (1H, m), 3.37 (2H, m), 2.27 (1H, dd, J=11.5 and 4.2), 2.63 (3H, m), 1.19 (9H, s), 1.05 (3H, s), 1.03 (3H, s); 13C-NMR (CDCl3) δ 156.0, 131.3, 130.3, 113.3, 72.9, 69.7, 64.5, 55.1, 52.9, 46.6, 44.7, 27.4, 26.9, 26.8.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[N:6][C:5]=1Cl.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:19][CH:20]([SH:22])[CH3:21]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[N:6][C:5]=1[S:22][CH:20]([CH3:21])[CH3:19]
Reactant: COC(=O)c1ccc(C)nc1Cl
Reactant: CC(C)S
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C)nc1SC(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.8 %

Procedure:
2-Chloro-6-methyl-nicotinic acid methyl ester (1.39 g, 7.44 mmol) obtained in Step A was dissolved in DMF (15 mL). Cs2CO3(4.88 g, 14.99 mmol) and propane-2-thiol (1.39 mL, 14.99 mmol) were added to the solution, and the mixture was stirred at room temperature for 2 hours. The reactant was concentrated under reduced pressure to remove the solvent. The residue was added with water and then extracted with EtOAc. The organic layer was dried with MgSO4, filtered and concentrated under reduced pressure. The obtained residue was purified by column chromatography (eluent EtOAc/Hex=1/5) to obtain the title compound (1.17 g, 69%).