Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([CH2:5][N:6]1[C:14]2[C:9](=[N:10][CH:11]=[N:12][C:13]=2[NH2:15])[N:8]=[CH:7]1)=O.O.[BH4-].[Na+].Cl>C1COCC1>[OH:2][CH2:3][CH2:5][N:6]1[C:14]2[C:9](=[N:10][CH:11]=[N:12][C:13]=2[NH2:15])[N:8]=[CH:7]1
Reactant: COC(=O)Cn1cnc2ncnc(N)c21
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Nc1ncnc2ncn(CCO)c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 55.1 %

Procedure:
To a stirred solution containing 16 (0.207 g, 0.999 mmol) and water (0.50 mL) in THF (12 mL) was added NaBH4 (0.38 g, 10.0 mmol). After stirring for 4 h at 25° C., the reaction mixture was neutralized to pH=7.0 by use of 10% HCl aqueous solution. Solvent was evaporated under reduced pressure and the residue was purified by column chromatography (EtOAc/hexanes=9:1) to give 18 (0.10 g, 0.55 mmol) in 55% yield: mp 132-133° C.; Rf(hexanes/EtOAc=1:2) 0.09; UV (EtOH) λmax 265 (ε 14,110); 1H NMR (CD3OD) δ 3.68 (t, J=5.9 Hz, 2 H, CH2O), 3.66 (t, J=5.9 Hz, 2 H, CH2N), 8.34 (s, 1 H, HC2), 8.68 (s, 1 H, HC8); MS m/z 179 (M+). Anal (C7H9N5O) C, H, N; calcd (%): 46.92, 5.06, 39.08; found (%): 47.01, 5.12, 39.11.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[CH:11]=O.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:26][CH2:25][N:24]([CH2:11][C:3]2[N:2]([CH3:1])[C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:23][CH2:22]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: Cn1c(C=O)cc2ccccc21
Product: COc1ccccc1N1CCN(Cc2cc3ccccc3n2C)CC1

Procedure:
1-Methyl-1H-indole-2-carbaldehyde and 1-(2-methoxyphenyl)piperazine were processed as described in Example 7 to provide the title compound. 1H NMR (CD3OD, 300 MHz) δ 3.0 (m, 2H), 3.45 (m, 2H), 3.74 (m, 4H), 3.86 (s, 3H), 3.88 (s, 2H), 4.70 (s, 3H), 6.83 (s, 1H), 6.90-7.14 (m, 5H), 7.28 (m, 1H), 7.48 (d, 1H, J=7.8 Hz), 7.62 (d, 1H, J=7.8 Hz). MS (DCI/NH3) m/z 336.1 (M+H)+. Anal. Calcd for C21H25N3O: C, 75.19;H, 7.51; N, 12.53. Found: C, 74.45;H, 7.43; N, 12.37.
Reaction SMILES: [CH2:1]([C:3]1([CH2:16][CH3:17])[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[C:6](=[O:15])[CH2:5][CH2:4]1)[CH3:2].C(O[CH:21](OCC)[N:22]([CH3:24])[CH3:23])C>>[CH2:16]([C:3]1([CH2:1][CH3:2])[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[C:6](=[O:15])[C:5](=[CH:21][N:22]([CH3:24])[CH3:23])[CH2:4]1)[CH3:17]
Reactant: CCOC(OCC)N(C)C
Reactant: CCC1(CC)CCC(=O)c2cc(OC)ccc21
Product: CCC1(CC)CC(=CN(C)C)C(=O)c2cc(OC)ccc21

Procedure:
4,4-Diethyl-3,4-dihydro-2-dimethylaminomethylene-7-methoxy-1(2H) naphthalenone was prepared from 4,4-diethyl-3,4-dihydro-7-methoxy-1(2H)naphthalenone (1.50 g, 6.5 mmol) and N,N-dimethylformamide diethyl acetal (3.3 ml, 19.5 mmol) to give the compound as a golden yellow oil (1.72 g) δH (CDCl3) 7.76 (1H, s), 7.63 (1H, d, J 2.9 Hz), 7.11 (1H, d, J 8.6 Hz), 6.96 (1H, dd, J 2.9, 8.6 Hz), 3.84 (3H, s), 3.13 (6H, s), 2.78 (2H, s), 1.66 (4H, q, J 7.5 Hz) and 0.77 (6H, t, J 7.4 Hz). MS (ES+) 288 (MH+, 100%).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:27]=[CH:26][CH:25]=[CH:24][C:5]=1[CH2:6][N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]2[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=2)[CH2:9][CH2:8]1.C(Cl)Cl.[CH2:31]([N:33]([CH2:37][CH3:38])[CH2:34][CH2:35][OH:36])[CH3:32]>C(OCC)C>[Cl:3][C:4]1[CH:27]=[CH:26][CH:25]=[CH:24][C:5]=1[CH2:6][N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]2[CH:23]=[CH:22][C:18]([C:19]([O:36][CH2:35][CH2:34][N:33]([CH2:37][CH3:38])[CH2:31][CH3:32])=[O:20])=[CH:17][CH:16]=2)[CH2:9][CH2:8]1
Reactant: CCN(CC)CCO
Reactant: O=C(Cl)c1ccc(CCN2CCN(Cc3ccccc3Cl)CC2)cc1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CCN(CC)CCOC(=O)c1ccc(CCN2CCN(Cc3ccccc3Cl)CC2)cc1

Procedure:
A mixture of 9.45 g. (21 mmole) 4-{2-[1-(2-chlorobenzyl)-piperazin-4-yl]-ethyl}-benzoyl chloride dihydrochloride, 50 ml. methylene chloride and 3.3 g. (28 mmole) 2-diethylaminoethanol is maintained at reflux temperature for 3 hours, then cooled and mixed with diethyl ether until turbidity appears. A thick precipitate is slowly deposited. This is filtered off with suction, washed with sec.-butanol and dissolved in a hot mixture of sec.-butanol and ethanol. Upon cooling and partial concentration, there are obtained 5.0 g. (35% of theory) of the desired compound in the form of its dihydrochloride; m.p. 220°-221° C.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:12](=[O:17])[NH:13][CH2:14][CH2:15][SH:16])[CH:9]([CH3:11])[CH3:10])(C)(C)C.C(Cl)Cl.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>>[NH2:7][C@@H:8]([CH:9]([CH3:11])[CH3:10])[C:12]([NH:13][CH2:14][CH2:15][SH:16])=[O:17]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)NCCS
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H](N)C(=O)NCCS
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To 26g (222.0 mg, 0.80 mmol) in a 100 mL round-bottom flask purged with argon were added CH2Cl2 (2.00 mL, 31.2 mmol), triethylsilane (1.28 mL, 8.0 mmol), and trifluoroacetic acid (616 μL, 8.0 mmol). The reaction was stirred for 2.5 hours at room temperature, then concentrated in vacuo. The crude product was purified by silica gel chromatography using 10% methanolic CH2Cl2 as eluant. Clean fractions were combined, and concentrated in vacuo to afford 27g as a colorless oil.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])[CH:2]=[CH2:3].Cl[C:12]1[C:13](Cl)=[C:14]([CH3:19])[CH:15]=[CH:16][C:17]=1[CH3:18]>>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:18][C:17]1[CH:16]=[CH:15][C:14]([CH2:19][O:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:1]=[CH:2][CH3:3])=[CH:13][CH:12]=1)=[CH:2][CH3:3]
Reactant: Cc1ccc(C)c(Cl)c1Cl
Reactant: C=CCc1ccccc1O
Product: CC=Cc1ccccc1OCc1ccc(COc2ccccc2C=CC)cc1

Procedure:
α,α'-bis-(ortho-propenylphenoxy)-para-xylene is prepared in a procedure similar to Example I, except that 459.3 grams (3.4 moles) of 2-allylphenol is employed along with 300 grams (1.7 mole) of dichloro-para-xylene to yield 597 grams (95% yield) of a white crystalline solid having a melting point of 50°-53° C.
Reaction SMILES: S([O-])(O[O-])(=O)=[O:2].[K+].[K+].[CH3:9][C:10]1[C:11]2[CH:18]=[CH:17][CH:16]=[C:15]([S:19][CH2:20][N+:21]([O-:23])=[O:22])[C:12]=2[S:13][CH:14]=1>O.COCCOC>[CH3:9][C:10]1[C:11]2[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([CH2:20][N+:21]([O-:23])=[O:22])=[O:2])[C:12]=2[S:13][CH:14]=1
Reactant: O=S(=O)([O-])O[O-]
Reactant: Cc1csc2c(SC[N+](=O)[O-])cccc12
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Cc1csc2c(S(=O)C[N+](=O)[O-])cccc12
Temperature: 5 °C
Reaction time: 18 h
Yield: 84.1 %

Procedure:
A solution of potassium peroxymonosulphate (`oxane` trade mark; 1.0 g, 1.63 mmol) in water (20 ml) was added in one portion to a stirred solution of 3-methyl-7-(nitromethylthio)benzo[b]thiophene (0.7 g, 2.93 mmol) in 1,2-dimethoxyethane (40 ml) cooled to 5° C. The mixture was allowed to warm to ambient temperature and stirred for 18 hours. The reaction mixture was diluted with water (50 ml) and extracted with ethyl acetate (3×50 ml). These extracts were washed with water, dried (MgSO4), and evaporated to leave an oil, which was purified by flash chromatography using 4:1 v/v dichloromethane/hexane as eluant, to give 3-methyl-7-(nitromethylsulphinyl)benzo[b]thiophene as a pale yellow solid (0.35 g); NMR:2.5(s, 3H), 5.55(s, 2H), 7.25(s, 1H), 7.6-8.0(m, 3H).
Reaction SMILES: [N:1]([CH2:4][C:5]1[S:6][S:7][C:8]([CH2:11]O[Si](C(C)(C)C)(C)C)=[CH:9][CH:10]=1)=[N+:2]=[N-:3].O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:40]C(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[N:1]([CH2:4][C:5]1[S:6][S:7][C:8]([CH2:11][Cl:40])=[CH:9][CH:10]=1)=[N+:2]=[N-:3]
Reactant: CC(C)(C)[Si](C)(C)OCC1=CC=C(CN=[N+]=[N-])SS1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: [N-]=[N+]=NCC1=CC=C(CCl)SS1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.2 %

Procedure:
To a stirred solution of the silyloxyazide 15 (100 mg; 0.31 mmol) in distilled THF (5 mL) was added at room temperature water (6.7 μL), followed by the sequential addition, in one portion, of triphenylphosphine (97 mg; 0.37 mmol) and triphosgene (460 mg; 1.55 mmol). The reaction mixture was shielded from light and stirred at room temperature overnight. The reaction mixture was chromatographed on silica gel, eluting with 10% ethyl acetate in hexane, to afford 27.4 mg (40.4%) of the title chloride 28. 1H NMR (CDCl3) δ6.425 (dd, J=6.4, 6.0 Hz, 2H, C=CH), 4.267 (s, 2H, CH2), 4.004 (s, 2H, CH2); 13C NMR (CDCl3) δ128.538, 28.417, 127.719, 127.582, 54.864, 46.634.
Reaction SMILES: CC([NH:5][S:6]([C:9]1[CH:13]=[CH:12][N:11]([CH3:14])[C:10]=1[C:15]([N:17]([CH3:19])[CH3:18])=[O:16])(=[O:8])=[O:7])(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:5][S:6]([C:9]1[CH:13]=[CH:12][N:11]([CH3:14])[C:10]=1[C:15]([N:17]([CH3:19])[CH3:18])=[O:16])(=[O:8])=[O:7]
Reactant: CN(C)C(=O)c1c(S(=O)(=O)NC(C)(C)C)ccn1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)C(=O)c1c(S(N)(=O)=O)ccn1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.9 %

Procedure:
To a solution of 5.63 g of 3-[[(1,1-dimethylethyl)amino]sulfonyl]-N,N,1-trimethyl-1H-pyrrole-2-carboxamide in 75 ml, of methylene chloride was added 75 mL of TFA. The reaction mixture was allowed to stir at room temperature overnight ca. 16 hours. The reaction mixture was concentrated in vacuo. Three portions of diethyl ether were added to the residue and removed by evaporation to remove residual TFA, affording 4.21 g of the title compound as a gray solid, m.p. 185°-190.5° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)=[O:6].[Cl:14][C:15]1[CH:20]=[C:19]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:18]=[CH:17][C:16]=1[CH2:27][OH:28]>CC(C)=O.C(N(CC)CC)C>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5](=[O:6])[CH2:4][CH2:3][CH2:2][N:24]2[CH2:23][CH2:22][N:21]([C:19]3[CH:18]=[CH:17][C:16]([CH2:27][OH:28])=[C:15]([Cl:14])[CH:20]=3)[CH2:26][CH2:25]2)=[CH:8][CH:9]=1
Reactant: O=C(CCCCl)c1ccc(Cl)cc1
Reactant: OCc1ccc(N2CCNCC2)cc1Cl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: O=C(CCCN1CCN(c2ccc(CO)c(Cl)c2)CC1)c1ccc(Cl)cc1

Procedure:
A solution of 4,4'-dichlorobutyrophenone (4.5 g, 20.7 mmole) in 25 ml of acetone was added to a warm suspension of 2-chloro-4-(1-piperazinyl)benzenemethanol (4.7 g, 20.7 mole) in 50 ml acetone and 2.5 ml of triethylamine. The reaction mixture was refluxed for four days, cooled at -10° for three hours, and then filtered. The product was washed with a little acetone, triturated on the filter with water (four times, 50 ml), and air dried. Recrystallization from acetonitrile (65 ml) gave 3.0 g (35%), mp 137°-139°.
Reaction SMILES: [C:1]([C:3]1[CH:31]=[CH:30][C:6]2[N:7]([CH2:10][CH2:11][CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][N:17]([C:20]4[CH:29]=[CH:28][C:23]5[O:24][CH2:25][CH2:26][O:27][C:22]=5[CH:21]=4)[CH2:16][CH2:15]3)[CH:8]=[N:9][C:5]=2[CH:4]=1)#[N:2].[OH-].[Na+].C([O:36]CCOCCO)C>O>[C:1]([C:3]1[CH:31]=[CH:30][C:6]2[N:7]([CH2:10][CH2:11][CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][N:17]([C:20]4[CH:29]=[CH:28][C:23]5[O:24][CH2:25][CH2:26][O:27][C:22]=5[CH:21]=4)[CH2:16][CH2:15]3)[CH:8]=[N:9][C:5]=2[CH:4]=1)(=[O:36])[NH2:2]
Reactant: CCOCCOCCO
Reactant: N#Cc1ccc2c(c1)ncn2CCCCN1CCN(c2ccc3c(c2)OCCO3)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NC(=O)c1ccc2c(c1)ncn2CCCCN1CCN(c2ccc3c(c2)OCCO3)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 4.16 g of 6-[4-(4-(5-cyanobenzimidazol-1-yl)butyl)piperazino]-1,4-benzodioxane, 2.4 g of NaOH, 50 ml of H2O and 40 ml of diethylene glycol monoethyl ether is stirred at a bath temperature of 140° for 3 hours. The mixture is then cooled to room temperature, worked up in the conventional manner and gives 6-[4-(4-(5-carbamoylbenzimidazol-1-yl)butyl)piperazino]-1,4-benzodioxane.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][C:6]2[N:7]([CH3:33])[C:8]3[C:13]([N:14]=2)=[C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:11]=[C:10]([N:21]2[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[C:22]2[C@H:30]([OH:32])[CH3:31])[N:9]=3)[CH2:2]1.[OH:34][C:35]([CH3:40])([CH3:39])[C:36](O)=[O:37].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C>C(Cl)Cl>[OH:34][C:35]([CH3:40])([CH3:39])[C:36]([N:1]1[CH2:4][CH:3]([CH2:5][C:6]2[N:7]([CH3:33])[C:8]3[C:13]([N:14]=2)=[C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:11]=[C:10]([N:21]2[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[C:22]2[C@H:30]([OH:32])[CH3:31])[N:9]=3)[CH2:2]1)=[O:37]
Reactant: C[C@@H](O)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CNC3)n(C)c2n1
Reactant: CC(C)(O)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C[C@@H](O)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CN(C(=O)C(C)(C)O)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.1 %

Procedure:
To a solution of (R)-1-[1-(8-azetidin-3-ylmethyl-9-methyl-6-morpholin-4-yl-9H-purin-2-yl)-1H-benzoimidazol-2-yl]ethanol (57 mg, 0.13 mmol) in DCM (2 mL) was added 2-hydroxy-2-methyl-propionic acid (15 mg, 0.14 mmol), HOBt (19 mg, 0.14 mmol), NMM (31 μL, 0.28 mmol) and EDCI (27 mg, 0.14 mmol) and the resulting mixture stirred at r.t. for 1 h. The reaction mixture was partitioned between DCM and H2O, the organic phase dried (phase separator) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:DCM, 0-10%) affording 861 (14 mg, 21%). LCMS (method I): RT 3.05 min, [M+H]+ 535.3. 1H NMR (DMSO, 400 MHz): δ 7.97-7.94 (1 H, m), 7.71-7.68 (1 H, m), 7.30-7.26 (2 H, m), 5.58-5.57 (1 H, m), 5.39 (1 H, d, J=6.33 Hz), 5.02 (1 H, s), 4.57-4.56 (1 H, m), 4.39-4.14 (4 H, brd s), 4.18 (1 H, dd, J=10.39, 5.70 Hz), 4.04-4.02 (1 H, m), 3.80-3.75 (4 H, m), 3.72 (3 H, s), 3.68 (1 H, dd, J=9.67, 5.21 Hz), 3.23-3.20 (2 H, m), 1.60 (3 H, d, J=6.48 Hz), 1.25 (6 H, s)
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:3]=1[CH2:12][CH2:13][CH3:14].[C:15](OCC)(=[O:20])[CH2:16][C:17]([CH3:19])=O>C(O)(=O)C>[CH3:19][C:17]1[NH:1][C:2]2[N:6]([N:5]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:3]=2[CH2:12][CH2:13][CH3:14])[C:15](=[O:20])[CH:16]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: CCCc1c(C(=O)OCC)n[nH]c1N
Solvent: CC(=O)O
Product: CCCc1c(C(=O)OCC)nn2c(=O)cc(C)[nH]c12
Yield: 96.4 %

Procedure:
A mixture of 11.5 g of ethyl 5-amino-4-propylpyrazole-3-carboxylate, 11.3 g of ethyl acetoacetate, and 100 mL of acetic acid is refluxed overnight. The solvent is removed in vacuo, and the residue triturated with hexane/ether (1:1) to give 14.8 g of off-white solid. 1H NMR (CD3OD) δ: 0.97 (t, 3H), 1.40 (t, 3H), 1.61 (m, 2H), 2.42 (s, 3H), 2.85 (t, 2H), 4.40 (q, 2H), 5.73 (s, 1H). LC-MS (APCI, m/z): 264 (M+1).
Reaction SMILES: O(P(O[C:18]1[C@H:19]([CH3:42])[C@H:20]2[C@@H:37]([C@H:38]([OH:40])[CH3:39])[C:36](=[O:41])[N:21]2[C:22]=1[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:24])(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[SH:43][C@@H:44]1[CH2:48][N:47]([C:49]([O:51][CH2:52][C:53]2[CH:58]=[CH:57][C:56]([N+:59]([O-:61])=[O:60])=[CH:55][CH:54]=2)=[O:50])[C@H:46]([CH:62]2[CH2:66][NH:65][C:64](=[O:67])[CH:63]2[NH:68][C:69]([O:71][CH2:72][C:73]2[CH:78]=[CH:77][C:76]([N+:79]([O-:81])=[O:80])=[CH:75][CH:74]=2)=[O:70])[CH2:45]1>>[OH:40][C@@H:38]([C@H:37]1[C:36](=[O:41])[N:21]2[C:22]([C:23]([O:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=3)=[O:24])=[C:18]([S:43][C@@H:44]3[CH2:48][N:47]([C:49]([O:51][CH2:52][C:53]4[CH:58]=[CH:57][C:56]([N+:59]([O-:61])=[O:60])=[CH:55][CH:54]=4)=[O:50])[C@H:46]([CH:62]4[CH2:66][NH:65][C:64](=[O:67])[CH:63]4[NH:68][C:69]([O:71][CH2:72][C:73]4[CH:74]=[CH:75][C:76]([N+:79]([O-:81])=[O:80])=[CH:77][CH:78]=4)=[O:70])[CH2:45]3)[C@H:19]([CH3:42])[C@H:20]12)[CH3:39]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(Oc3ccccc3)Oc3ccccc3)[C@H](C)[C@@H]12
Reactant: O=C(NC1C(=O)NCC1[C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1)OCc1ccc([N+](=O)[O-])cc1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C4CNC(=O)C4NC(=O)OCc4ccc([N+](=O)[O-])cc4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Yield: 48.9 %

Procedure:
The same procedure as in Example 1-1 was carried out by using p-nitrobenzyl (1R,5S,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (155.4 mg, 0.26 mmol) and (2S,4S)-4-mercapto-N-(p-nitrobenzyloxycarbonyl)-2-[3-[(p-nitrobenzyloxycarbonyl)amino]-2-pyrrolidon-4-yl]pyrrolidine (110 mg, 0.197 mmol, compound of Reference Example 20-6) to obtain p-nitrobenzyl (1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-N-(p-nitrobenzyloxycarbonyl)-2-[3-[(p-nitrobenzyloxycarbonyl)amino]-2-pyrrolidon-4-yl]pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylate (87 mg, yield: 48.9%).
Reaction SMILES: C([O:3][C:4]([C:6]1([S:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C.CO.[OH-].[Na+]>C1COCC1>[CH2:29]([O:28][C:25]1[CH:26]=[CH:27][C:22]([S:19]([C:6]2([C:4]([OH:5])=[O:3])[CH2:7][CH2:8][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[CH2:10][CH2:11]2)(=[O:20])=[O:21])=[CH:23][CH:24]=1)[CH2:30][CH2:31][CH3:32]
Reactant: CCCCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(Cc3ccncc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(Cc3ccncc3)CC2)cc1

Procedure:
4-(4-Butoxy-benzenesulfonyl)-1-pyridin-4-ylmethyl-piperidine-4-carboxylic acid was prepared starting from 4-(4-Butoxy-benzenesulfonyl)-1-pyridin-4-ylmethyl-piperidine-4-carboxylic acid ethyl ester (3.0 g, 6.5 mmol) dissolved in THF:Methanol (75: 50 ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 1.2 g (42%); off white solid; MS: 433.0 (M+H)+
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([NH2:10])=[CH:8][CH:9]=1.C(N(CC)CC)C.[Br:18][C:19]1[N:23]2[N:24]=[C:25]([Cl:29])[CH:26]=[C:27](Br)[C:22]2=[N:21][CH:20]=1>CCO>[Br:18][C:19]1[N:23]2[N:24]=[C:25]([Cl:29])[CH:26]=[C:27]([NH:10][C:7]3[CH:8]=[CH:9][C:4]([O:3][CH2:2][CH3:1])=[CH:5][CH:6]=3)[C:22]2=[N:21][CH:20]=1
Reactant: Clc1cc(Br)c2ncc(Br)n2n1
Reactant: CCOc1ccc(N)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOc1ccc(Nc2cc(Cl)nn3c(Br)cnc23)cc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
p-Phenetidine (0.38 ml, 2.9 mmol) and triethylamine (0.8 ml, 5.8 mmol) were added to a mixture of 3,8-dibromo-6-chloroimidazo[1,2-b]pyridazine (0.83 g, 2.67 mmol) from 1a in EtOH (10 mL). The mixture was heated to 80° C. and stirred for 16 hrs. The solution was then concentrated in vacuo to give crude 3-bromo-6-chloro-N-(4-ethoxyphenyl)imidazo[1,2-b]pyridazin-8-amine.
Reaction SMILES: CC1(C)C[O:35][C:5]2([CH2:9][C@@H:8]([CH2:10][C@H:11]([C:26]3[CH:31]=[CH:30][C:29]([S:32][CH3:33])=[C:28]([CH3:34])[CH:27]=3)[C:12](N([C@H](C)[C@H](O)C3C=CC=CC=3)C)=[O:13])[CH2:7][CH2:6]2)OC1.S(=O)(=O)(O)[OH:39]>O1CCOCC1.O>[CH3:34][C:28]1[CH:27]=[C:26]([C@@H:11]([CH2:10][C@H:8]2[CH2:7][CH2:6][C:5](=[O:35])[CH2:9]2)[C:12]([OH:39])=[O:13])[CH:31]=[CH:30][C:29]=1[S:32][CH3:33]
Reactant: CSc1ccc([C@@H](C[C@H]2CCC3(C2)OCC(C)(C)CO3)C(=O)N(C)[C@H](C)[C@H](O)c2ccccc2)cc1C
Reactant: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: O
Product: CSc1ccc([C@@H](C[C@H]2CCC(=O)C2)C(=O)O)cc1C
Temperature: 110 °C
Yield: 90 %

Procedure:
A solution of (R)-3-((R)-8,8-dimethyl-6,10-dioxa-spiro[4.5]dec-2-yl)-N-((1R,2R)-2-hydroxy-1-methyl-2-phenyl-ethyl)-N-methyl-2-(3-methyl-4-methylsulfanyl-phenyl)-propionamide (1.35 g, 2.57 mmol) in dioxane (14 mL) was treated with a 9 N aqueous sulfuric acid solution (8 mL). The resulting solution was then heated at 110° C. for 16 h. The reaction was then cooled and diluted with water (150 mL) and extracted with a chloroform/methanol solution (3:2, 2×50 mL) and then combined the organic extracts and concentrated. The resulting residue was then dissolved in acetonitrile and concentrated with silica gel (3 g) and purified on Biotage Flash chromatography system (40 L column, silica gel, 60% ethyl acetate/hexanes) to afford (R)-2-(3-methyl-4-methylsulfanyl-phenyl)-3-((R)-3-oxo-cyclopentyl)-propionic acid (674 mg, 90%) as a pale yellow gum: [α]28958−115.4° (c=0.35, methanol); ES-HRMS m/e calcd for C16H20O3S (M+Na)+ 315.1025, observed 315.1025; 1H NMR (300 MHz, DMSO-d6) δ 1.46 (m, 1H, CH), 1.76-2.32 (m, 8H, 4×CH2), 2.22 (s, 3H, ArCH3), 2.44 (s, 3H, SCH3), 3.48 (m, 1H, ArCHCO), 7.14 (m, 3H, Ar), 12.31 (s, 1H, CO2H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.C(Cl)(=O)C(Cl)=O.[NH2:20][CH2:21][C:22]([N:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:23]>C(N(CC)CC)C>[C:25]1([N:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:22]([CH2:21][NH:20][C:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[O:13])=[O:23])[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: NCC(=O)N(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1ccc2ccccc2c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Product: O=C(NCC(=O)N(c1ccccc1)c1ccccc1)c1ccc2ccccc2c1
Yield: 59.5 %

Procedure:
Working in a manner similar to that described in Example 9, but starting with 2-naphthalenecarboxylic acid (0.95 g), oxalyl dichloride (0.7 g), 2-amino-N,N-diphenylacetamide (1.2 g) and triethylamine (0.8 g), and after recrystallization in acetonitrile, N-(diphenylcarbamoylmethyl)-2-naphthalenecarboxamide (1.2 g), m.p. 205° C., is obtained.
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[N:6]2[N:5]=1)=O.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1.CN1CCCC1=O>CO>[CH3:22][S:19]([C:16]1[CH:17]=[CH:18][C:13]([C:12]2[N:6]3[C:7]([CH:8]=[N:9][C:4]([NH:36][C:33]4[CH:32]=[CH:31][C:30]([N:27]5[CH2:26][CH2:25][N:24]([CH3:23])[CH2:29][CH2:28]5)=[CH:35][CH:34]=4)=[N:5]3)=[CH:10][CH:11]=2)=[CH:14][CH:15]=1)(=[O:21])=[O:20]
Reactant: CS(=O)c1ncc2ccc(-c3ccc(S(C)(=O)=O)cc3)n2n1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: CN1CCCC1=O
Solvent: CO
Product: CN1CCN(c2ccc(Nc3ncc4ccc(-c5ccc(S(C)(=O)=O)cc5)n4n3)cc2)CC1
Temperature: 150 °C

Procedure:
Into a 30 mL vial, 2-Methanesulfinyl-7-(4-methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (80 mg, 0.0002 mol), 4-(4-Methyl-piperazin-1-yl)-phenylamine (0.100 g, 0.000525 mol) and N-Methylpyrrolidinone (0.25 mL, 0.0026 mol) were added. The reaction mixture was heated at 150° C. for 90 minutes. The reaction was cool to room temperature. Methanol (15 mL) was added. The solid was filtered and washed with hot MeOH (10 mL) to afford [7-(4-Methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine as a light brown solid. MP 234-238° C. LCMS (E/I+) 373.18 (M+H). NMR 1H (DSMO-d6)-9.31 (s, 1H), 9.00 (s, 1H), 8.48 (d, 2H, J=8.48 Hz), 8.02 (d, 2H, J=8.16 Hz), 7.57 (d, 2H, J=8.79 Hz), 7.33 (d, 1H, J=4.77 Hz), 6.95 (d, 1H, J=4.76 Hz), 6.95-7.04 (m, 3H), 3.28 (s, 3H), 3.09 (bs, 4H), 2.40-2.56 (m, 4H), 2.22 (s, 3H).