Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5]1([C:8]([OH:10])=O)[CH2:7][CH2:6]1)(=[O:3])[CH3:2].O1CCCC1.C(Cl)(=O)C(Cl)=O.Cl.[NH2:23][C:24]1[N:25]=[C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]3[CH:34]=[CH:35][C:36]([CH3:49])=[C:37]([NH:39][C:40]([C:42]4[N:46]([CH3:47])[N:45]=[C:44]([CH3:48])[CH:43]=4)=[O:41])[CH:38]=3)=[N:28][N:27]2[CH:50]=1>CN(C)C=O.CN(C)C(=O)C>[C:1]([O:4][C:5]1([C:8]([NH:23][C:24]2[N:25]=[C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]4[CH:34]=[CH:35][C:36]([CH3:49])=[C:37]([NH:39][C:40]([C:42]5[N:46]([CH3:47])[N:45]=[C:44]([CH3:48])[CH:43]=5)=[O:41])[CH:38]=4)=[N:28][N:27]3[CH:50]=2)=[O:10])[CH2:6][CH2:7]1)(=[O:3])[CH3:2]
Reactant: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(N)cn4n3)ccc2C)n(C)n1
Reactant: CC(=O)OC1(C(=O)O)CC1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(=O)OC1(C(=O)Nc2cn3nc(Oc4ccc(C)c(NC(=O)c5cc(C)nn5C)c4)ccc3n2)CC1
Yield: 74.5 %

Procedure:
In the same manner as in Example 279 and using 1-acetoxycyclopropanecarboxylic acid (90 mg, 0.63 mmol), tetrahydrofuran (1.5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride (54 μL, 0.63 mmol), N-{5-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]-2-methylphenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide hydrochloride (200 mg, 0.48 mmol) and N,N-dimethylacetamide (5 mL) as starting materials, the title compound (180 mg, 74%) was obtained as a white solid.
Reaction SMILES: Cl[CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22].Cl>CN(C=O)C.O>[F:14][C:15]1[CH:20]=[C:19]([CH:2]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22]
Reactant: CCOC(=O)C(Cl)c1ccccc1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(c1ccccc1)c1ccc([N+](=O)[O-])c(F)c1
Temperature: -45 °C
Reaction time: 0.33 h
Yield: 44.4 %

Procedure:
9.8 g of potassium tert. butylate were dissolved in 90 ml of DMF and cooled to −45° C. For this purpose, a mix of ethyl 2-chloro-2-phenylacetate (43.8 mmol, 8.7 g) and 1-fluoro-2-nitrobenzene (43.8 mmol, 4.6 ml) was carefully added dropwise and the mixture was stirred for a further 20 minutes. The reaction mix was set to pH 4 using 16% HCl, diluted with 25 ml of water and extracted with EE (3×50 ml). Once combined, the organic phases were washed with water and sat. aq. NaCl sol., dried over MgSO4 and concentrated under vacuum. The residue obtained was purified by column chromatography (silica gel: mesh 100-200, eluent: 10% EE in cyclohexane) and produced 5.9 g (44.9%) of product.
Reaction SMILES: [F:1][C:2]1[C:10]([N+:11]([O-])=O)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[H][H]>CO.[Pd]>[NH2:11][C:10]1[C:2]([F:1])=[C:3]([CH:7]=[CH:8][CH:9]=1)[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1F
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1cccc(C(=O)O)c1F
Temperature: 25 °C
Reaction time: 40 h
Yield: 99 %

Procedure:
To 2-fluoro-3-nitro-benzoic acid (70, 6.77 g, 36.6 mmol) in 150 mL of methanol, Palladium on carbon (5:95 Palladium:Carbon, 0.338 g, 0.159 mmol) is added under a balloon of hydrogen. The reaction is stirred at room temperature for 40 hours, then a new balloon of hydrogen is attached, and the reaction continued for 5 hours. The reaction is filtered and the filtrate is concentrated under vacuum to provide the desired compound (71, 5.62 g). MS (ESI) [M−H+]−=154.1.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20](O)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH:25]12[CH:30]([NH:31][C:32](=[O:48])[O:33][CH2:34][CH:35]3[C:47]4[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=4[C:41]4[C:36]3=[CH:37][CH:38]=[CH:39][CH:40]=4)[CH:29]1[CH2:28][NH:27][CH2:26]2.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:24][C:2]([F:1])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([N:27]3[CH2:26][CH:25]4[CH:29]([CH:30]4[NH:31][C:32](=[O:48])[O:33][CH2:34][CH:35]4[C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][C:41]=5[C:42]5[C:47]4=[CH:46][CH:45]=[CH:44][CH:43]=5)[CH2:28]3)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: O=C(NC1C2CNCC21)OCC1c2ccccc2-c2ccccc21
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NC1C2CN(C(=O)/C=C\n3cnc(-c4cc(C(F)(F)F)cc(C(F)(F)F)c4)n3)CC21)OCC1c2ccccc2-c2ccccc21
Temperature: -60 °C
Reaction time: 1 h
Yield: 67.7 %

Procedure:
(Z)-3-(3-(3,5-Bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (1.0 g, 1.0 eq.) was dissolved in DCM (50 mL) and cooled to −60° C. where (9H-fluoren-9-yl)methyl 3-azabicyclo[3.1.0]hexan-6-ylcarbamate (1.09 g, 1.2 eq.), T3P (50% in EtOAc) (2.02 mL, 1.2 eq.) and DIPEA (0.95 mL, 2 eq.) was added. The clear reaction mixture was stirred at −60° C. for 1 h, quenched with water, and extracted with DCM. The organic layer was dried over sodium sulphate, concentrated under reduced pressure (25° C., 20 mm Hg) to afford the crude product, which was purified by chromatography (2% Methanol in DCM) to yield (Z)-(9H-fluoren-9-yl)methyl (3-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)-3-azabicyclo[3.1.0]hexan-6-yl)carbamate (1.26 g, 69% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][OH:26])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([O:8][C:9]1[N:14]=[CH:13][N:12]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][OH:26])=[CH:21][CH:20]=2)[C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1cc(OCc2ccccc2)nc[nH]1
Reactant: OCc1ccc(CCCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1cc(OCc2ccccc2)ncn1CCc1ccc(CO)cc1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To 3.00 g (14.8 mmol) 6-benzyloxy-3H-pyrimidin-4-one in 15 mL DMF is added 2.66 g (15.6 mmol) [4-(2-chloro-ethyl)-phenyl]-methanol (preparation 1b) and 5.13 g (37.1 mmol) potassium carbonate. The reaction mixture is stirred 3 h at 100° C., filtered and the solvent is evaporated. The residue is put on silica gel and is purified by chromatography (silica gel; PE/EtOAc 1:1 to 2.5:7.5)
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][C:5]=2[N:6]=1.CCN(CC)CC.[CH:20]1([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH2:22][CH2:21]1>CCO>[CH:20]1([N:23]2[CH2:28][CH2:27][N:26]([C:2]3[O:3][C:4]4[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][C:5]=4[N:6]=3)[CH2:25][CH2:24]2)[CH2:22][CH2:21]1
Reactant: N#Cc1ccc2oc(Cl)nc2c1
Reactant: C1CN(C2CC2)CCN1
Solvent: CCO
Solvent: CCN(CC)CC
Product: N#Cc1ccc2oc(N3CCN(C4CC4)CC3)nc2c1
Yield: 52.6 %

Procedure:
To a solution of 2-chlorobenzooxazole-5-carbonitrile (1.69 g, 9.5 mmol) in EtOH (34 mL) was added Et3N (4.8 g, 47.5 mmol), followed by 1-cyclopropylpiperazine (1.44 g, 11.4 mmol) and the mixture was heated at reflux for 12 h. Then the volatiles were evaporated to remove EtOH and water (120 mL) was added. The mixture was extracted with CH2Cl2 (3×50 mL). The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated. The residue was purified by column chromatography on silica gel (elute: 10% ethyl acetate in petroleum ether, 0.1% NH4OH added) to give 1.34 g (53%) of 2-(4-cyclopropylpiperazin-1-yl)benzooxazole-5-carbonitrile.
Reaction SMILES: [BH4-].[Na+].[NH2:3][C@@H:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C@H:5]1[NH:10][C:11]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:12]=1[C:13]#[N:14].[C:23](O)(=O)[CH3:24]>>[CH2:23]([NH:3][C@@H:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C@H:5]1[NH:10][C:11]1[CH:18]=[C:17]([C:19]([F:20])([F:21])[F:22])[CH:16]=[CH:15][C:12]=1[C:13]#[N:14])[CH3:24]
Reactant: CC(=O)O
Reactant: N#Cc1ccc(C(F)(F)F)cc1N[C@@H]1CCCC[C@H]1N
Agent: [BH4-]
Agent: [Na+]
Product: CCN[C@@H]1CCCC[C@H]1Nc1cc(C(F)(F)F)ccc1C#N
Temperature: 60 °C

Procedure:
Under ice-cooling, sodium borohydride was slowly added in small portions to an acetic acid solution of 2-{[(1R,2R)-2-aminocyclohexyl]amino}-4-(trifluoromethyl)benzonitrile, followed by heating at 60° C. for 6 hours. By post-treating the reaction liquid, 2-{[(1R,2R)-2-(ethylamino)cyclohexyl]amino}-4-(trifluoromethyl)benzonitrile was obtained. A formalin aqueous solution and sodium triacetoxyborohydride were added to a THF solution of this, followed by stirring. By post-treating the reaction liquid, 2-({(1R,2R)-2-[ethyl(methyl)amino]cyclohexyl}amino)-4-(trifluoromethyl)benzonitrile was obtained.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:11]=[C:10](Cl)[CH:9]=[C:8]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[N:7]=1)[CH2:2][CH2:3][CH3:4].[NH2:19][NH2:20]>O1CCOCC1>[CH2:1]([O:5][C:6]1[N:11]=[C:10]([NH:19][NH2:20])[CH:9]=[C:8]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1nc(Cl)cc(N2CCOCC2)n1
Reactant: NN
Solvent: C1COCCO1
Product: CCCCOc1nc(NN)cc(N2CCOCC2)n1
Temperature: 95 °C
Reaction time: 12 h
Yield: 80.7 %

Procedure:
To a solution of 2-n-butoxy-4-chloro-6-(morpholin-4-yl)pyrimidine (1.38 g, 5.1 mmol) in dioxane (50 ml), anhydrous hydrazine (1.6 mL, 50 mmol) was added. The obtained reaction mixture was heated to 95° C., and stirred for 12 h under N2. After cooling to room temperature, the reaction mixture was quenched with ice-brine and extracted with EtOAc (200 mL). The organic extract was washed with brine, water, and dried over Na2SO4. The solvent was removed under reduced pressure. The crude residue was recrystallized from methanol to obtain 2-n-butoxy-4-hydrazino-6-(morpholin-4-yl)pyrimidine as white crystals (1.10 g, 81%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][C@@H:6]([C:19]1[CH:20]=[N:21][C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:7]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][CH2:14]C(=O)C)[C:8]1=[O:18])[CH3:2].[NH2:30][C:31]1[C:36]([CH:37]=O)=[CH:35][CH:34]=[CH:33][N:32]=1.N1CCC[C@H:40]1[C:41](O)=O>C(O)C>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][C@@H:6]([C:19]1[CH:20]=[N:21][C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:7]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][CH2:14][C:33]2[CH:34]=[CH:35][C:36]3[C:31](=[N:30][CH:40]=[CH:41][CH:37]=3)[N:32]=2)[C:8]1=[O:18])[CH3:2]
Reactant: CCOC(=O)C[C@@H](c1cnc2ccccc2c1)N1CCC(CCCC(C)=O)C1=O
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: Nc1ncccc1C=O
Solvent: CCO
Product: CCOC(=O)C[C@@H](c1cnc2ccccc2c1)N1CCC(CCCc2ccc3cccnc3n2)C1=O

Procedure:
A mixture of 6-2 (396 mg, 1.0 mmol), 2-amino-3-formylpyridine (138 mg, 1.2 mmol; for prep. see JOC 1983,48, 3401) and proline (218 mg, 2.0 mmol) in absolute ethanol (15 mL) was heated at reflux for 12 h. Following evaporative removal of the solvent, the residue was chromatographed (silica gel, 50% ethyl acetate/chloroform to 70:25:5 chloroform/ethyl acetate/MeOH) to give 6-3 as a yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:16]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34]Cl)=[CH:28][CH:27]=3)[C:17]3[C:22]([C:23]=2[CH3:24])=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1.[I-].[K+].C([O:47][CH2:48][CH3:49])(=O)C>CN(C=O)C>[CH2:48]([O:47][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH2:25][C:26]1[CH:27]=[CH:28][C:29]([O:32][CH2:33][CH2:34][N:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)=[CH:30][CH:31]=1)[C:15]([C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:10]=1)=[C:23]2[CH3:24])[C:49]1[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: CCOC(C)=O
Reactant: Cc1c(-c2cccc(OCc3ccccc3)c2)n(Cc2ccc(OCCCl)cc2)c2ccccc12
Reactant: C1CCNCC1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(-c2cccc(OCc3ccccc3)c2)n(Cc2ccc(OCCN3CCCCC3)cc2)c2ccc(OCc3ccccc3)cc12
Temperature: 45 °C

Procedure:
To a solution of 1.1 g (0.00953 mol) of 5-benzyloxy-2-(3-benzyloxy-phenyl-1-[4(2-chloro-ethoxy)-benzyl]-3-methyl-1H-indole (example No. 58) in 10 mL of DMF was added 1.1 mL (0.0112 mol) of piperidine, and 0.93 g (00561 mol) of potassium iodide. The reaction mixture was heated to ˜40-50° C. for 4 hours. After cooling the reaction mixture to room temperature, 150 mL of ethyl acetate were added and the mixture was washed with water (3×100 mL). The organic solution was collected, washed with saturated brine, removed, dried over magnesium sulfate, filtered and evaporated to yield 1.0 g of product of the product after purification. Mp=125-126° C.; 1H NMR (DMSO) 7.48-7.45 (d, 2H, J=7.2 Hz), 7.41-7.35 (m, 7H), 7.33-7.28 (m, 2H), 7.23-7.21 (d, 1H, J=9.0 Hz), 7.13-7.12 (d, 1H, J=2.4 Hz), 7.06-7.03 (m, 1H), 6.95-6.91 (m, 2H), 6.83-6.80 (dd, 1H, J=2.4 Hz, J=6.3 Hz), 6.75-6.70 (m, 4H), 5.13 (s, 2H), 5.11 (s, 2H), 5.02 (s, 2H), 3.93-3.90 (t, 2H, J=6.0 Hz), 2.56-2.53 (t, 2H, J=5.9 Hz), 2.49-2.48 (m, 4H), 2.14 (s, 3H), 1.46-1.40 (m, 4H), 1.35-1.31 (m, 2H); IR (KBr) 3400, 2900 cm−1; MS eI m/z 636 (M+); CHN calcd for C43H44N2O3+0.25 H2O.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:51])[C@@H:9]([CH3:50])[C:10]([NH:12][C@@H:13]([C:46]([CH3:49])([CH3:48])[CH3:47])[C:14]([N:16]1[C@H:20]([C:21](=[O:33])[NH:22][C@H:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26][CH2:25][CH2:24]2)[CH2:19][C@H:18]([O:34][CH2:35][C:36]2[CH:45]=[CH:44][C:39]([C:40]([O:42]C)=[O:41])=[CH:38][CH:37]=2)[CH2:17]1)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>C1COCC1.CO.O>[C:1]([O:5][C:6]([N:8]([CH3:51])[C@@H:9]([CH3:50])[C:10]([NH:12][C@@H:13]([C:46]([CH3:49])([CH3:48])[CH3:47])[C:14]([N:16]1[C@H:20]([C:21](=[O:33])[NH:22][C@H:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26][CH2:25][CH2:24]2)[CH2:19][C@H:18]([O:34][CH2:35][C:36]2[CH:45]=[CH:44][C:39]([C:40]([OH:42])=[O:41])=[CH:38][CH:37]=2)[CH2:17]1)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(CO[C@H]2C[C@@H](C(=O)N[C@@H]3CCCc4ccccc43)N(C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(C)(C)C)C2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](C(=O)N[C@H](C(=O)N1C[C@@H](OCc2ccc(C(=O)O)cc2)C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.2 %

Procedure:
To a solution of methyl 4-((((3S,5S)-1-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-3,3-dimethylbutanoyl)-5-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-3-yl)oxy)methyl)benzoate (1.35 g, 1.91 mmol) in THF (5 mL) and MeOH (3 mL) was added a solution of NaOH (0.31 g, 7.64 mmol) in water (6 mL). The reaction mixture was stirred at rt for 4 h, acidified with 1N HCl and extracted with ethyl acetate. The organic layer was separated, washed with brine, and dried over MgSO4. The filtrate was concentrated in vacuo to give the title compound as a white solid (1.30 g, 98%). 1H NMR (DMSO-d6) δ 8.01 (d, J=8.6 Hz, 0.5H), 7.91 (d, J=8.4 Hz, 1.5H), 7.43 (d, J=8.4 Hz, 2H), 7.24 (d, J=7.7 Hz, 1H), 7.15-6.98 (m, 3H), 4.98-4.83 (m, 1H), 4.60 (s, 2H), 4.47 (d, J=9.0 Hz, 1H), 4.34 (t, J=7.7 Hz, 1H), 4.21 (t, J=6.2 Hz, 1H), 4.12-4.05 (m, 1H), 3.86-3.71 (m, 1H), 3.54 (dd, J=10.2, 6.1 Hz, 1H), 2.81-2.65 (m, 5H), 2.45-2.36 (m, 1H), 2.02-1.92 (m, 1H), 1.86-1.56 (m, 4H), 1.40 (br. s., 9H), 1.26-1.15 (m, 3H), 1.03-0.86 (m, 9H); MS(ESI+) m/z 693.6 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([OH:26])=[C:5]([C:15]([NH:17][CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])=[O:16])[C:6](=[O:14])[C:7]2([CH3:13])[CH3:12].C(O)(C(F)(F)F)=O>O>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([OH:26])=[C:5]([C:15]([NH:17][CH2:18][C:19]([OH:21])=[O:20])=[O:16])[C:6](=[O:14])[C:7]2([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2c(Cl)cccc2C(C)(C)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC1(C)C(=O)C(C(=O)NCC(=O)O)=C(O)c2c(Cl)cccc21
Yield: 97.2 %

Procedure:
tert-Butyl N-((5-chloro-4-hydroxy-1,1-dimethyl-2-oxo-naphthalen-3-yl)carbonyl)glycinate (204 mg, 537 μmol) was stirred in TFA (2 mL, 26924 μmol) for 25 minutes. Water was added. The resulting precipitate was filtered and washed with water to give a white solid (169 mg). MS m/e=324 (M+H)+. Calculated for C15H14ClNO5 323.06.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:9][I:10]>>[I-:10].[NH2:1][C:2]1[CH:3]=[N+:4]([CH3:9])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Nc1cnccc1Cl
Reactant: CI
Product: C[n+]1ccc(Cl)c(N)c1
Product: [I-]
Reaction time: 1 h

Procedure:
The starting material was prepared by allowing a mixture of 3-amino-4-chloropyridine and excess methyl iodide (no solvent) to stand at ambient temperature for 1 hour to give 3-amino-4-chloro-1-methylpyridinium iodide as a solid, n.m.r. in solvent F:-4.2(s, 3H); 7.9-8.3(m, 3H).
Reaction SMILES: [OH-].[Li+].[Br:3][C:4]1[N:5]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]([CH:27]3[CH2:29][CH2:28]3)=[CH:19][CH:18]=2)[C:6]([S:9]CCC(OCC)=O)=[N:7][N:8]=1.Cl>C1COCC1.CO>[Br:3][C:4]1[N:5]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]([CH:27]3[CH2:29][CH2:28]3)=[CH:19][CH:18]=2)[C:6]([SH:9])=[N:7][N:8]=1
Reactant: CCOC(=O)CCSc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Sc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.1 %

Procedure:
Aqueous lithium hydroxide solution (1M, 437 mL, 0.437 mmol, 3 eq.) was added to a solution of ethyl 3-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)propanoate (65 mg, 0.146 mmol) in THF (1.5 mL) and methanol (1 mL). The mixture was stirred at room temperature for ˜2 hours, and HCl (1N, 584 μL, 0.584 mmol, 4 eq.) added. The mixture was concentrated, a little water added, sonicated and the off-white solids isolated by filtration. The isolated material was placed into small amount of methanol, sonicated again, and then filtered to give 5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole-3-thiol as an off-white solid (39 mg, 78%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:16]([NH:18][C@H:19]([C@H:27]1[O:31][C:30](=[O:32])[C@H:29]([CH3:33])[CH2:28]1)[CH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:34][NH2:35]>>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:16]([NH:18][C@@H:19]([CH2:20][CH:21]1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1)[C@@H:27]([OH:31])[CH2:28][C@@H:29]([CH3:33])[C:30]([NH:35][CH3:34])=[O:32])=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CN
Reactant: C[C@@H]1C[C@@H]([C@H](CC2CCCCC2)NC(=O)[C@H](Cc2cscn2)NC(=O)OC(C)(C)C)OC1=O
Product: CNC(=O)[C@H](C)C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
A solution of 500 mg (1.04 mmole) of (3R, 5S)-5-{(1S)-1-[N-(t-butoxycarbonyl)-3-(4-thiazolyl)-L-alanyl]amino-2-cyclohexylethyl}-3-methyldihydrofuran-2(3H)-one (prepared as described in Preparation 25) in 2.5 ml of a 40% by volume methanolic solution of methylamine was allowed to stand at room temperature for 1 hour. At the end of this time, any excess of the methylamine and the methanol were removed by distillation under reduced pressure. The resulting residue was recrystallized from ethyl acetate to afford 405 mg of the title compound as white crystals, melting at 158°-160° C.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[Br:13][C:14]1[CH:15]=[C:16]([C:22](=[O:52])[CH2:23][N:24]2[C:29](=[O:30])[C:28]3[CH:31]=[C:32]([CH2:34][CH3:35])[S:33][C:27]=3[N:26]([CH2:36][C:37]3[CH:42]=[CH:41][C:40]([C:43]4[C:44]([C:49]#[N:50])=[CH:45][CH:46]=[CH:47][CH:48]=4)=[CH:39][CH:38]=3)[C:25]2=[O:51])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]>C(Cl)(Cl)Cl>[Br:13][C:14]1[CH:15]=[C:16]([C:22](=[O:52])[CH2:23][N:24]2[C:29](=[O:30])[C:28]3[CH:31]=[C:32]([CH2:34][CH3:35])[S:33][C:27]=3[N:26]([CH2:36][C:37]3[CH:42]=[CH:41][C:40]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=4[C:49]4[NH:3][C:4](=[O:7])[O:5][N:50]=4)=[CH:39][CH:38]=3)[C:25]2=[O:51])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: CCc1cc2c(=O)n(CC(=O)c3ccc(OC)c(Br)c3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Product: CCc1cc2c(=O)n(CC(=O)c3ccc(OC)c(Br)c3)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 15.5 %

Procedure:
A mixture of hydroxylammonium chloride (1.8 g), sodium hydrogencarbonate (2.75 g) and dimethyl sulfoxide (20 mL) was stirred at 40° C. for 30 min, 4′-{[3-[2-(3-bromo-4-methoxyphenyl)-2-oxoethyl]-6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile (1 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with chloroform, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography and dissolved in methylene chloride (40 mL). N,N′-Carbonyldiimidazole (0.26 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.22 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with chloroform, washed successively with saturated aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in methylene chloride (50 mL), iodine acid (0.51 g) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by preparative HPLC to give the title compound as a colorless amorphous solid (0.17 g, 16%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][NH:8][CH:9]=1)=[O:4].[H-].[Na+].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C@@H:19]2[C@:21]3([C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]([CH2:30][C:31]4C=CN=CC=4)[C:22]3=[O:37])[CH2:20]2)=[CH:15][CH:14]=1.BrCCN1C2C(=CC=CC=2)[C@@]2(C[C@@H]2C2C=CC(Cl)=CC=2)C1=O>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][N:8]([CH2:31][CH2:30][N:23]2[C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@:21]3([CH2:20][C@H:19]3[C:16]3[CH:15]=[CH:14][C:13]([Cl:12])=[CH:18][CH:17]=3)[C:22]2=[O:37])[CH:9]=1)=[O:4]
Reactant: O=C1N(Cc2ccncc2)c2ccccc2[C@@]12C[C@@H]2c1ccc(Cl)cc1
Reactant: COC(=O)c1c[nH]cn1
Agent: O=C1N(CCBr)c2ccccc2[C@@]12C[C@@H]2c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cn(CCN2C(=O)[C@@]3(C[C@H]3c3ccc(Cl)cc3)c3ccccc32)cn1
Reaction time: 1 h
Yield: 35 %

Procedure:
To a solution of methyl-imidazole-4-carboxylate (100 mg, 0.2 mmol) in 1 mL of anhydrous DMF was added NaH (60% disp.) (8.8 mg, 0.22 mmol) at room temperature. The reaction mixture was stirred for 1 hour at that temperature. To the mixture was added a solution of racemic (1R,2S) and (1S,2R)-1′-(2-bromoethyl)-2-(4-chlorophenyl)spiro[cyclopropane-1,3′-indolin]-2′-one (75.2 mg, 0.2 mmol) in 1 mL of DMF. The reaction was stirred at room temperature for 14 hours and then concentrated under reduced pressure. The residue was dissolved in EtOAc and washed with saturated aqueous NaHCO3. The layers were separated and the aqueous layer was extracted with EtOAc. The organic layers were combined and washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound as white solid (30 mg, 35%). LC/MS m/e calcd. for C23H20ClN3O3: 421, observed (M+H)+: 422.3.