Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([NH:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[N:6]2[CH2:11][CH2:12]O.O=S(Cl)[Cl:23]>>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([NH:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[N:6]2[CH2:11][CH2:12][Cl:23]
Reactant: Nc1ncnc2c1nc(Nc1cccnc1)n2CCO
Reactant: O=S(Cl)Cl
Product: Nc1ncnc2c1nc(Nc1cccnc1)n2CCCl
Reaction time: 12 h
Yield: 27 %

Procedure:
0.11 g of 2-(6-amino-8-(pyridin-3-ylamino)-purin-9-yl)ethanol were cooled to −20° C. and 2 ml of SOCl2 were added. The temperature was gradually risen to 50° C. and the mixture was stirred at this temperature for 12 hours. The excess of SOCl2 was evaporated and aqueous ammonia was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was separated and evaporated. The crude product was purified by flash chromatography on silica gel (ethyl acetate:MeOH 20:1) to give 30 mg (27%) of the desired product. 1H-NMR (DMSO-d6): 9.10 (s, 1H); 9.0 (s, 1H); 8.35 (d, 1H); 8.20 (d, 1H); 8.05 (s, 1H); 7.30 (m, 1H); 6.65 (s, 2H, —NH2); 4.55 (t, 2H); 4.0 (t, 2H).
Reaction SMILES: Cl.[CH:2]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([OH:16])[CH:10]=1)=[O:8])([CH3:4])[CH3:3].[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=1>>[CH:2]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=2)=[C:11]([OH:16])[CH:10]=1)=[O:8])([CH3:4])[CH3:3]
Reactant: CC(C)NCC(=O)c1ccc(O)c(O)c1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Product: CC(C)NCC(=O)c1ccc(OC(=O)c2cccnc2)c(O)c1

Procedure:
Following a procedure similar to that described above in Example 58A but using 3,4-dihydroxyphenyl isopropylaminomethyl ketone hydrochloride instead of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride, and nicotinoyl chloride instead of isovaleryl chloride, there is obtained 3-hydroxy-4-(nicotinoyloxy)phenyl isopropylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using a procedure similar to that described above in Example 2B, there is obtained 3-hydroxy-4-(nicotinoyloxy)-alpha-(isopropylaminomethyl)benzyl alcohol hydrochloride.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14](Br)[C:15]([O:17][CH3:18])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4].[C:22]([Cu])#[N:23]>CN(C)C=O.O>[F:1][C:2]([F:21])([F:20])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([C:22]#[N:23])[C:15]([O:17][CH3:18])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: COc1cc2c(cc1Br)C(C)CN(C(=O)C(F)(F)F)CC2
Reactant: N#C[Cu]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(cc1C#N)C(C)CN(C(=O)C(F)(F)F)CC2
Yield: 64 %

Procedure:
A solution of N-trifluoroacetyl-8-bromo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (18 mg, 0.05 mmol) in dimethylformamide (1 mL) was treated with CuCN (20 mg, 0.24 mmol) and the mixture was microwaved at 200 C for 0.5. hours. The product mixture was diluted with water (5 mL), extracted twice with EtOAc (5 mL), the combined organic phases were washed with brine (5 mL), dried with Na2SO4 and concentrated. Flash chromatography (35% EtOAc in hexane, silica) resulted in 10 mg of a clear oil. MS calculated for C15H15F3N2O2+H: 313, observed: 313.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[C:5]([N:10]=1)=[N:6][CH:7]=[CH:8][CH:9]=2.Cl.[CH2:12]([NH:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19]Cl)[CH:13]([CH3:15])[CH3:14].C(OCC)C>C(O)C>[CH2:12]([NH:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19][S:1][C:2]1[NH:3][C:4]2[C:5]([N:10]=1)=[N:6][CH:7]=[CH:8][CH:9]=2)[CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)CNc1ccccc1CCl
Reactant: Sc1nc2ncccc2[nH]1
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: CC(C)CNc1ccccc1CSc1nc2ncccc2[nH]1
Yield: 49.3 %

Procedure:
To a dispersion of 0.96 of 2-mercaptoimidazo[4,5-b]pyridine in 30 ml of ethanol was added at once 1.5 g of 2-(isobutylamino)benzyl chloride hydrochloride at room temperature under stirring. The resulting mixture was further stirred for one hour. To the mixture was added 30 ml of diethyl ether, and the precipitated crystals were collected by filtration and washed with a mixture of ethanol and diethyl ether (1/1 in volume). The obtained powdery product was added portionwise to a mixture of 30 ml o fchloroform and 30 ml of a saturated NaHCO3 solution for neutralization. The organic phase was separated, washed with a saturated aqueous sodium chloride solution, and dried over sodium sulfate. The solvent was then distilled off under reduced pressure and the residue was crystallized by addition of diethyl ether and hexane. The crystalline product was collected by filtration, washed with a mixture of diethyl ether and hexane (1/1 in volume) and dried to give 985 mg (yield: 49.3%) of 2-[2-(isobutylamino)benzylthio]imidazo[4,5-b]pyridine as a white crystalline powder.
Reaction SMILES: [C:1]([C:3]1[O:10][C:9]2[CH:8]=[C:7]([C:11]([OH:13])=O)[NH:6][C:5]=2[CH:4]=1)#[N:2].Cl.[NH2:15][C@@H:16]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:17]([N:19]1[CH2:22][CH:21]([OH:23])[CH2:20]1)=[O:18]>>[CH2:24]([C@H:16]([NH:15][C:11]([C:7]1[NH:6][C:5]2[CH:4]=[C:3]([C:1]#[N:2])[O:10][C:9]=2[CH:8]=1)=[O:13])[C:17]([N:19]1[CH2:22][CH:21]([OH:23])[CH2:20]1)=[O:18])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)N1CC(O)C1
Reactant: N#Cc1cc2[nH]c(C(=O)O)cc2o1
Agent: Cl
Product: N#Cc1cc2[nH]c(C(=O)N[C@@H](Cc3ccccc3)C(=O)N3CC(O)C3)cc2o1

Procedure:
2-Cyano-4H-furo[3,2-b]pyrrole-5-carboxylic acid and (2S)-amino-1-(3-hydroxy-azetidin-1-yl)-3-phenyl-propan-1-one hydrochloride were coupled according to Procedure B (reaction mixture partitioned between ethyl acetate and water prior to acidic washing).
Reaction SMILES: Br[CH2:2][CH:3]=[CH:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH:6]=1.CN1C=CN=C1CC=CC1C=CC(C(OC)=O)=C(C2C=CC(F)=CC=2)C=1.[CH2:48]([N:55]1[CH:59]=[CH:58][N:57]=[CH:56]1)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>>[CH2:48]([N:55]1[CH:59]=[CH:58][N:57]=[C:56]1[CH2:2][CH:3]=[CH:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH:6]=1)[C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1
Reactant: c1ccc(Cn2ccnc2)cc1
Reactant: COC(=O)c1ccc(C=CCBr)cc1-c1ccc(F)cc1
Agent: COC(=O)c1ccc(C=CCc2nccn2C)cc1-c1ccc(F)cc1
Product: COC(=O)c1ccc(C=CCc2nccn2Cc2ccccc2)cc1-c1ccc(F)cc1
Yield: 76 %

Procedure:
Methyl 4-[3-(1-benzylimidazol-2-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzoate was prepared from methyl 4-(3-bromoprop-1-en-1-yl)-2-(4-fluorophenyl)benzoate as described for methyl 4-[3-(1-methylimidazol-2-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzoate in Example 19, but using N-benzylimidazole. Yield: 76%
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[CH:5]1([C:11]2[C:19]3[C:14](=[CH:15][C:16]([C:20]([O:22][CH3:23])=[O:21])=[CH:17][CH:18]=3)[NH:13][C:12]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH:30]=O)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>>[C:1]([C:2]1[CH2:30][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[C:12]2=[C:11]([CH:5]3[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]3)[C:19]3[CH:18]=[CH:17][C:16]([C:20]([O:22][CH3:23])=[O:21])=[CH:15][C:14]=3[N:13]2[CH:3]=1)#[N:4]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3C=O)[nH]c2c1
Reactant: C=CC#N
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C=C(C#N)Cc1ccccc1-3
Temperature: 100 °C

Procedure:
Acrylonitrile (2 mL of 1.52 M in 1,4-dioxane, 3.04 mmol) was added to methyl 3-cyclohexyl-2-(2-formylphenyl)-1H-indole-6-carboxylate (200 mg, 0.55 mmol) in a microwave vial. The vial was sealed and Triton® B (50□L, 0.11□mol) was added via syringe. The vial was heated in a microwave apparatus for 1 hr at 100° C. The solution was concentrated and the residue dissolved in methylene chloride. The solution was applied to a silica gel thick layer plate. The plated was eluted with hexanes-ethyl acetate (8:2). The product containing band was extracted with methylene chloride-methanol (3×). The combined extracts were concentrated and the residue recrystallized from methanol to afford the titled compound as a tan solid. MS m/z 397 (MH); 1H NMR (300 MHz, CHLOROFORM-D) □ ppm 1.16–2.25 (m, 10 H) 2.90–3.10 (m, 1 H) 3.20–3.34 (m, 1 H) 3.60–3.75 (m, 1 H) 3.95 (s, 3 H) 7.28–7.49 (m, 4 H) 7.76 (s, 1 H) 7.86–7.97 (m, 2 H) 8.13 (s, 1 H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].CS[C:17](SC)=[CH:18][N+:19]([O-:21])=[O:20].C(N(CC)CC)C>C(#N)C>[C:11]([O:10][C:8]([NH:7][CH2:6][CH2:5][N:4]1[CH2:3][CH2:2][NH:1][C:17]1=[CH:18][N+:19]([O-:21])=[O:20])=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)NCCNCCN
Reactant: CSC(=C[N+](=O)[O-])SC
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCN1CCNC1=C[N+](=O)[O-]
Yield: 64.6 %

Procedure:
A stirred mixture of 2.03 gram (0.010 mole) of N-{2-[(2-aminoethyl)amino]ethyl}(tert-butoxy)carboxamide (commercially available), 1.18 gram (0.010 mole) of 1,1-di(methylthio)-2-nitroethene and 2 mL (excess) of triethylamine in 40 mL of acetonitrile was warmed to reflux where it was maintained for four hours. After this time the reaction mixture was concentrated under reduced pressure to a solid residue. The residue was washed with diethyl ether and dried, yielding 1.76 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([O:9]CC)=[O:8])=[C:5]([CH3:12])[NH:4][N:3]=1.BrC[CH:15]([O:18][CH3:19])[CH2:16][CH3:17]>>[CH3:19][O:18][CH2:15][CH2:16][CH2:17][N:4]1[C:5]([CH3:12])=[C:6]([C:7]([OH:9])=[O:8])[C:2]([CH3:1])=[N:3]1
Reactant: CCOC(=O)c1c(C)n[nH]c1C
Reactant: CCC(CBr)OC
Product: COCCCn1nc(C)c(C(=O)O)c1C
Yield: 12 %

Procedure:
Prepared by following the same method as the preparation of intermediate 42: ethyl 3,5-dimethyl-1H-pyrazole-4-carboxylate (280 mg) was reacted with 1-bromo-2-methoxybutane (337 mg) to afford white solid (42 mg, 0.20 mmol, 10%). ESI-MS m/z 213.2 (M+H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([NH:10][C:11]2[CH:16]=[C:15]([NH:17][C:18]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[CH:21]=3)=[O:19])[CH:14]=[CH:13][C:12]=2[CH3:32])=[O:9])[CH:5]=[CH:4][N:3]=1.[CH3:33][N:34]([CH3:39])[CH2:35][CH2:36][NH:37][CH3:38]>>[CH3:33][N:34]([CH3:39])[CH2:35][CH2:36][N:37]([C:2]1[CH:7]=[C:6]([C:8]([NH:10][C:11]2[CH:16]=[C:15]([NH:17][C:18]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([N:26]4[CH2:27][CH2:28][O:29][CH2:30][CH2:31]4)[CH:21]=3)=[O:19])[CH:14]=[CH:13][C:12]=2[CH3:32])=[O:9])[CH:5]=[CH:4][N:3]=1)[CH3:38]
Reactant: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1NC(=O)c1ccnc(Cl)c1
Reactant: CNCCN(C)C
Product: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1NC(=O)c1ccnc(N(C)CCN(C)C)c1
Yield: 44 %

Procedure:
Using an analogous procedure to that described in Example 21, 2-chloro-N-[2-methyl-5-(2-morpholinopyrid-4-ylcarbonylamino)phenyl]pyridine-4-carboxamide was reacted with N-(2-dimethylaminoethyl)-N-methylamine to give the title compound in 44% yield; NMR Spectrum: (DMSOd6) 2.17 (s, 6H), 2.19 (s, 31), 2.4 (t, 2H), 3.05 (s, 3H), 3.5-3.54 (m, 4H) 3.65-3.72 (m, 6H), 6.75 (s, 1H), 6.94 (d, 1H), 7.02 (s, 1H), 7.1 (d, 1H), 7.24 (d, 2H), 7.58 (d, 1H), 7.78 (s, 1H), 8.19 (d, 1H), 8.26 (d, 1H), 9.96 (s, 1H), 10.28 (s, 1H); Mass Spectrum: M+H+ 518.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CI.[C:25](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:25])[C:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1cc2cc(OCc3ccccc3)ccc2[nH]1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)c1cc2cc(OCc3ccccc3)ccc2n1C
Temperature: 150 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 5-(benzyloxy)-1H-indole-2-carboxylate (5.00 g, 16.93 mmol) and methyl iodide (1.14 mL, 18.28) in 17 mL dimethylformamide was added potassium carbonate (2.57 g, 18.62 mmol). The resulting suspension was stirred for 2 h at 150° C. in a sealed reaction vessel. Solids were filtered and the liquor concentrated to give crude ethyl 5-(benzyloxy)-1-methyl-1H-indole-2-carboxylate. Used without further purification or characterization.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]2[C:3]=1[C:4](=O)[O:5][C:6]2=[O:12].C([O-])(=O)C.[Na+].C(O)(=O)C.[NH2:23][NH2:24]>O>[F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]2[C:3]=1[C:4](=[O:5])[NH:23][NH:24][C:6]2=[O:12]
Reactant: NN
Reactant: O=C1OC(=O)c2c(F)ccc(F)c21
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH][nH]c(=O)c2c(F)ccc(F)c12
Temperature: 25 °C

Procedure:
To 4,7-difluoroisobenzofuran-1,3-dione (1.00 g, 5.43 mmol) and sodium acetate (0.535 g, 6.52 mmol) was added water (14 mL), acetic acid (7.15 ml, 125 mmol) and hydrazine (0.205 ml, 6.52 mmol) (slowly). A water condenser was attached and the mixture was heated to reflux for 20 hours. Cooled to RT and filtered the resulting solid. Washed with water and dried to yield 5,8-difluoro-2,3-dihydrophthalazine-1,4-dione as a white solid. MS m/z=199 [M+1]+. Calc'd for C8H4P2N2O2: 198.13.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=3)=[CH:11][C:10]([NH2:24])=[N:9]2)=[CH:4][CH:3]=1.[CH3:25][C@H:26]1[C:30](=[O:31])[NH:29][CH2:28][C@@H:27]1[C:32](O)=[O:33].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C)C=O.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:22])([F:21])[F:23])[CH:14]=3)=[CH:11][C:10]([NH:24][C:32]([C@@H:27]3[C@@H:26]([CH3:25])[C:30](=[O:31])[NH:29][CH2:28]3)=[O:33])=[N:9]2)=[CH:4][CH:3]=1
Reactant: C[C@H]1C(=O)NC[C@@H]1C(=O)O
Reactant: Nc1cc(-c2cccc(OC(F)(F)F)c2)n(-c2ccc(F)cc2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H]1C(=O)NC[C@@H]1C(=O)Nc1cc(-c2cccc(OC(F)(F)F)c2)n(-c2ccc(F)cc2)n1
Yield: 64.8 %

Procedure:
To a solution of 1-(4-fluorophenyl)-5-(3-(trifluoromethoxy)phenyl)-1H-pyrazol-3-ylamine (90 mg) in N,N-dimethylformamide (0.9 ml) were added (3R,4R)-4-methyl-5-oxopyrrolidine-3-carboxylic acid (50 mg) prepared in Preparation 1, HOBt.H2O (61 mg) and WSC.HCl (77 mg), and the mixture was stirred at room temperature for 2 hours. To this mixture were added water and a saturated aqueous solution of sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The separated organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel thin-layer chromatography (eluent: chloroform/methanol=10/1) to give the titled compound (80 mg).
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].C(N(C(C)C)C(C)C)C.N1(C(N2C=CN=C2)=O)C=CN=C1.[Cl:27][C:28]1[CH:29]=[C:30]([C@@H:34]2[C@@H:39]([C:40]3[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=3)[N:38]([C@H:47]([CH2:53][CH3:54])[C:48]([O:50][CH2:51][CH3:52])=[O:49])[C:37](=[O:55])[C@@H:36]([CH2:56][C:57](O)=[O:58])[CH2:35]2)[CH:31]=[CH:32][CH:33]=1.[NH4+].[Cl-]>C1COCC1>[Cl:27][C:28]1[CH:29]=[C:30]([C@H:34]2[CH2:35][C@H:36]([CH2:56][C:57]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[O:58])[C:37](=[O:55])[N:38]([C@@H:47]([CH2:53][CH3:54])[C:48]([O:50][CH2:51][CH3:52])=[O:49])[C@@H:39]2[C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=2)[CH:31]=[CH:32][CH:33]=1
Reactant: CCOC(=O)[C@@H](CC)N1C(=O)[C@@H](CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reactant: CS(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](CC)N1C(=O)[C@@H](CC(=O)NS(C)(=O)=O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Methanesulfonamide (0.02 g, 0.2 mmol), N-ethyl-N-isopropylpropan-2-amine (0.05 ml, 0.3 mmol), di(1H-imidazol-1-yl)methanone (0.04 g, 0.2 mmol) and 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((R)-1-ethoxy-1-oxobutan-2-yl)-2-oxopiperidin-3-yl)acetic acid (Example 3, 0.030 g, 0.06 mmol) were combined in 2 mL of THF. After being stirred at 25° C. for 12 h, sat. NH4Cl solution was added and the reaction mixture was extracted with EtOAc. The combined organic layers were successively washed with sat. aq. NaHCO3 solution and sat. aq. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by reversed phase HPLC (10 to 90% AcCN/H2O with 0.1% TFA in 45 min) to give the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[C:4]([I:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:17][CH3:18]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([I:9])[C:5]([O:8][CH2:17][CH3:18])=[CH:6][N:7]=1
Reactant: CCI
Reactant: Oc1cnc(Cl)cc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cnc(Cl)cc1I
Temperature: 25 °C

Procedure:
6-Chloro-4-iodo-pyridin-3-ol (0.41 g, 1.62 mmol) was dissolved in anhydrous DMF (4 mL) and stirred at room temperature. Potassium carbonate (0.67 g, 4.9 mmol) and iodoethane (0.40 mL, 4.9 mmol) were added sequentially. The mixture was heated to 60° C. and maintained for 2 hours. The mixture was cooled to room temperature and filtered. The filtrate was diluted with diethyl ether (25 mL) and washed with 20% aqueous citric acid (25 mL). The aqueous was extracted with diethyl ether (2×20 mL). The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was triturated with hexane resulting in a tan solid (0.42 g, 91%). 1H NMR (400 MHz, CDCl3): δ 7.80 (s, 1H), 7.74 (s, 1H) 4.18 (q, J=7.1 Hz, 2H), 1.51 (t, J=7.1 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])=[C:4]([CH2:17]Br)[N:3]=1.[CH3:19][NH:20][CH3:21]>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])=[C:4]([CH2:17][N:20]([CH3:21])[CH3:19])[N:3]=1
Reactant: CNC
Reactant: Nc1nc(N)c(-c2ccc(Cl)cc2Cl)c(CBr)n1
Solvent: CCO
Product: CN(C)Cc1nc(N)nc(N)c1-c1ccc(Cl)cc1Cl

Procedure:
This compound was prepared from 2,4-diamino-5-(2,4-dichlorophenyl)-6-bromomethyl-pyrimidine (Example 53) by reaction with dimethylamine in ethanol at room temperature, mp. 170°-172° C.
Reaction SMILES: [CH:1]([C:9]1=[CH:10][C:11]([O:13][C:14]1=[O:15])=[O:12])=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C[OH:17]>>[CH:1](/[C:9](/[C:14]([OH:13])=[O:15])=[CH:10]/[C:11]([OH:17])=[O:12])=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C1C=C(C=Cc2ccccc2)C(=O)O1
Reactant: CO
Product: O=C(O)/C=C(/C=Cc1ccccc1)C(=O)O
Temperature: 100 °C
Reaction time: 30 h

Procedure:
1.8 g of the styrene-maleic anhydride polymer (molecular weight: 1600) was mixed with 5.4 g of the polyethyleneoxyglycol (molecular weight: 600). The mixture was dropped on a glass substrate and heated in an oven at 100° C. under nitrogen stream. After 30 hours, the mixture was cooled down to room temperature, immersed into methanol and dried. A thin membrane of the styrene-maleic acid polyethyleneoxy ester crosslinked copolymer of an excellent adhesive strength and mechanical strength was prepared.
Reaction SMILES: [NH2:1][CH:2]1[C:17](=[O:18])[N:4]2[C:5]([C:14]([OH:16])=[O:15])=[C:6]([CH2:9][O:10][C:11](=[O:13])[CH3:12])[CH2:7][S:8][C@H:3]12.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.S1C2C=CC=CC=2N=C1S[C:41](=[O:50])[C:42]([C:44]1[N:45]=[C:46]([NH2:49])[S:47][CH:48]=1)=[O:43]>ClCCl>[NH2:49][C:46]1[S:47][CH:48]=[C:44]([C:42](=[O:43])[C:41]([NH:1][CH:2]2[C:17](=[O:18])[N:4]3[C:5]([C:14]([OH:16])=[O:15])=[C:6]([CH2:9][O:10][C:11](=[O:13])[CH3:12])[CH2:7][S:8][C@H:3]23)=[O:50])[N:45]=1
Reactant: Nc1nc(C(=O)C(=O)Sc2nc3ccccc3s2)cs1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Solvent: ClCCl
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=O)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5.44 g of 7-amino-3-acetoxymethylceph-3-em-4-carboxylic acid are suspended under a nitrogen atmosphere in 50 ml of dry dichloromethane, and mixed with 5.4 ml of N,O-bis(trimethylsilyl)acetamide. The preparation is stirred at room temperature until a clear solution is present, and then cooled to -15°. 8.4 g of 2-(2-amino-4-thiazolyl)-2-oxothioacetic-acid-S-benzothiazol-2-ylester are added, and stirred for two hours at -15° and then for two hours at 0°. The solvent is carefully drawn off in a rotary evaporator, and the oily residue is rubbed with 50 ml of ethanol, whereby the title compound precipitates. 6.3 g are obtained in the form of a yellow powder.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][CH:6]([N:13]1[C:21]2[C:16](=[CH:17][C:18]([O:22][CH2:23][CH2:24][OH:25])=[CH:19][CH:20]=2)[CH:15]=[CH:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].O[N:28]1[C:32](=[O:33])[C:31]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]2[C:29]1=[O:38].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][CH:6]([N:13]1[C:21]2[C:16](=[CH:17][C:18]([O:22][CH2:23][CH2:24][O:25][N:28]3[C:32](=[O:33])[C:31]4[C:30](=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:29]3=[O:38])=[CH:19][CH:20]=2)[CH:15]=[CH:14]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)CC(c1ccccc1)n1ccc2cc(OCCO)ccc21
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)CC(c1ccccc1)n1ccc2cc(OCCON3C(=O)c4ccccc4C3=O)ccc21
Reaction time: 0.17 h
Yield: 96 %

Procedure:
3-[5-(2-hydroxy-ethoxy)-indol-1yl]-3-phenyl-propionic acid ethyl ester (0.77 g, 2.10 mmol), N-hydroxyphthalimide (0.40 g, 2.40 mmol) and triphenylphosphine (0.85 g, 3.24 mmol) were dissolved in tetrahydrofuran (5 mL). The mixture was placed under an argon atmosphere at 0° C. and stirred for 10 minutes. Diisopropylazodicarboxylate (0.65 g, 3.24 mmol) was added all at once. After stirring overnight (16 h), the solvent was removed under vacuum, and the crude mixture was purified via column chromatogpraphy to afford the title compound (96% yield). 1H NMR (CDCl3) δ 7.79 (m, 2H), 7.70 (m, 2H), 7.15-7.29 (m, 7H), 7.03 (d, 1H, J=2.3 Hz), 6.69 (dd, 1H, J=2.5, 9.0 Hz), 6.43 (d, 1H, J=3.7 Hz), 5.99 (t, 1H, J=7.7 Hz), 4.56 (m, 2H), 4.34 (m, 2H), 4.02 (c, 2H, J=7.2 Hz), 3.27 (m, 2H), 1.06 (t, 3H, J=7.2 Hz).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[NH:12][C:13]2[CH:19]=[C:18]([C:20]([OH:22])=O)[CH:17]=[CH:16][C:14]=2[N:15]=1)([CH3:3])[CH3:2].[N:23]1([CH2:29][CH2:30][O:31][C:32]2[C:40]3[C:35](=[CH:36][C:37]([NH2:41])=[CH:38][CH:39]=3)[NH:34][N:33]=2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[N:23]1([CH2:29][CH2:30][O:31][C:32]2[C:40]3[C:35](=[CH:36][C:37]([NH:41][C:20]([C:18]4[CH:17]=[CH:16][C:14]5[N:15]=[C:11]([NH:10][C:5]6[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=6[CH:1]([CH3:2])[CH3:3])[NH:12][C:13]=5[CH:19]=4)=[O:22])=[CH:38][CH:39]=3)[NH:34][N:33]=2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: CC(C)c1ccccc1Nc1nc2ccc(C(=O)O)cc2[nH]1
Reactant: Nc1ccc2c(OCCN3CCOCC3)n[nH]c2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CC(C)c1ccccc1Nc1nc2ccc(C(=O)Nc3ccc4c(OCCN5CCOCC5)n[nH]c4c3)cc2[nH]1

Procedure:
2-(2-Isopropylphenylamino)-3H-benzimidazole-5-carboxylic acid (0.3 mmol; see Example 66) was coupled with aforementioned 3-(2-morpholin-4-ylethoxy)-1H-indazol-6-ylamine (0.3 mmol) using HBTU as described in general procedure D to afford the desired product, 2-(2 isopropylphenylamino)-3H-benzimidazole-5-carboxylic acid [3-(2-morpholin-4-ylethoxy)-1H-indazol-6-yl]amide. MS: m/z 540 (M+H)+.