Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]2[C:13]([C:14]#[N:15])=[C:12]([O:16][C:17]3[CH:18]=[C:19]([NH:23]C(=O)C(F)(F)F)[CH:20]=[CH:21][CH:22]=3)[CH:11]=[CH:10][C:8]=2[N:9]=1)(=[O:3])[CH3:2].O.[OH-].[Li+]>O1CCCC1.CO.O.C(OCC)(=O)C>[NH2:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[O:16][C:12]1[CH:11]=[CH:10][C:8]2[N:9]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[S:6][C:7]=2[C:13]=1[C:14]#[N:15]
Reactant: CC(=O)Nc1nc2ccc(Oc3cccc(NC(=O)C(F)(F)F)c3)c(C#N)c2s1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1nc2ccc(Oc3cccc(N)c3)c(C#N)c2s1
Temperature: 25 °C
Reaction time: 20 h
Yield: 38.1 %

Procedure:
N-(3-{[2-(Acetylamino)-7-cyano-1,3-benzothiazol-6-yl]oxy}phenyl)-2,2,2-trifluoroacetamide (6.8 g, 16.2 mmol) was dissolved in a mixed solvent of tetrahydrofuran (75 mL)/methanol (25 mL)/water (25 mL), lithium hydroxide monohydrate (1.99 g, 48.5 mmol) was added, and the mixture was stirred at room temperature for 20 hr. The reaction mixture was diluted with ethyl acetate (600 mL) and tetrahydrofuran (200 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (300 mL) and saturated brine (300 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was suspended in N,N-dimethylformamide/ethyl acetate (1:1), and the insoluble material was collected by filtration to give the title compound (2.00 g, 38%) as a white powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[O:7][C:6]2[CH:8]=[CH:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][C:5]=2[N:4]2[C:15](=[O:18])[NH:16][N:17]=[C:3]12.I[CH3:21].[H-].[Na+].O>CN(C=O)C>[CH3:21][N:16]1[C:15](=[O:18])[N:4]2[C:5]3[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:6]=3[O:7][C:2]([CH3:19])([CH3:1])[C:3]2=[N:17]1
Reactant: CC1(C)Oc2ccc([N+](=O)[O-])cc2-n2c1n[nH]c2=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nc2n(c1=O)-c1cc([N+](=O)[O-])ccc1OC2(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
4,4-Dimethyl-8-nitro-2,4-dihydro-1H-benzo[b][1,2,4]triazolo[4,3-d][1,4]oxazin-1-one, iodomethane (73 μL, 1.2 eq.) were dissolved in DMF (4 mL). Sodium hydride (58 mg, 60% suspension in oil, 1.5 eq.) was added to the solution in an ice bath. The reaction mixture was stirred at room temperature for two hours. Water (15 mL) was added to the reaction. White precipitation was filtered and washed with water to give 2,4,4-trimethyl-8-nitro-2,4-dihydro-1H-benzo[b][1,2,4]triazolo[4,3-d][1,4]oxazin-1-one (249 mg, 92% yield in two steps).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.C([O:15][C:16](=O)[CH2:17][C:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:30]=[CH:29][N:28]=[C:27]([CH2:31][O:32]C3CCCCO3)[CH:26]=2)[CH:20]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C1(C)C(C)=CC=CC=1.C(Cl)Cl>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[NH:9][C:16](=[O:15])[CH2:17][C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]4[CH:30]=[CH:29][N:28]=[C:27]([CH2:31][OH:32])[CH:26]=4)[CH:20]=3)=[N:10][C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccnc(COC3CCCCO3)c2)c1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1C
Solvent: ClCCl
Product: O=C1CC(c2cccc(-c3ccnc(CO)c3)c2)=Nc2cc(Cl)c(Cl)cc2N1

Procedure:
The title compound was prepared from commercially available 4,5-dichloro-1,2-phenylendiamine (177 mg, 1.0 mmol) and (RS)-3-oxo-3-{3-[2-(tetrahydro-pyran-2-yloxymethyl)-pyridin-4-yl]-phenyl}-propionic acid tert-butyl ester (Example K40) (412 mg, 1.0 mmol) in xylene (15 ml) under reflux conditions for 1.5 h according to the general procedure M and subsequent treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (220 mg, 53%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]([OH:14])=[CH:12][CH:13]=2)=[CH:4][C:3]=1[O:15][C@@H:16]([C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[N:25]1[N:29]=[CH:28][CH:27]=[N:26]1)[CH3:17].CS(O[CH:35]1[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH2:36]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>[Cl-].[Na+].O>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]([O:14][CH:35]3[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH2:36]3)=[CH:12][CH:13]=2)=[CH:4][C:3]=1[O:15][C@@H:16]([C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[N:25]1[N:29]=[CH:28][CH:27]=[N:26]1)[CH3:17]
Reactant: C[C@@H](Oc1cc(-c2ccc(O)nc2)cnc1N)c1cc(F)ccc1-n1nccn1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: O
Product: C[C@@H](Oc1cc(-c2ccc(OC3CCN(C(=O)OC(C)(C)C)CC3)nc2)cnc1N)c1cc(F)ccc1-n1nccn1
Yield: 66 %

Procedure:
A mixture of example 121 (125 mg, 0.308 mmol), tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate (129 mg, 0.462 mmol) and cesium carbonate (301 mg, 0.924 mmol) was heated at 90° C. for 24 hr. LCMS indicated ˜90% completion of the reaction. Two products were observed. The mixture was dropped into brine and the resulting precipitate was collected by filtration and rinsed with water. The partially dried solids were taken up in EtOAc, dried over magnesium sulfate and concentrated. The residue was purified with a Biotage silica gel cartridge eluting with 50-100% EtOAc/Heptane to give tert-butyl 4-[(6′-amino-5′-{(1R)-1-[5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl]ethoxy}-3,3′-bipyridin-6-yl)oxy]piperidine-1-carboxylate (117 mg).
Reaction SMILES: C[O:2][C:3](=[O:39])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][O:34]3)[CH:27]=2)[S:13]([C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=2[CH3:24])(=[O:15])=[O:14])=[CH:8][CH:7]=1.[OH-].[Na+].Cl.C(OCC)(=O)C>O1CCCC1.O>[O:34]1[CH2:35][CH2:36][CH2:37][CH2:38][CH:33]1[O:32][C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=1)[CH2:25][N:12]([S:13]([C:16]1[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=1[CH3:24])(=[O:15])=[O:14])[C:9]1[CH:8]=[CH:7][C:6]([CH:5]=[CH:4][C:3]([OH:39])=[O:2])=[CH:11][CH:10]=1
Reactant: COC(=O)C=Cc1ccc(N(Cc2cccc(OC3CCCCO3)c2)S(=O)(=O)c2c(C)cc(C)cc2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C)c(S(=O)(=O)N(Cc2cccc(OC3CCCCO3)c2)c2ccc(C=CC(=O)O)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.4 %

Procedure:
To a solution of 3-{4-[[3-(tetrahydro-pyran-2-yloxy)-benzyl]-(2,4,6-trimethyl-benzenesulfonyl)-amino]-phenyl}-acrylic acid methyl ester (1.83 g, 3.33 mmol) in 4 mL tetrahydrofuran was added sodium hydroxide (0.399 g, 9.98 mmol) in 3 mL water. The reaction mixture was stirred at room temperature overnight. The reaction mixture was adjusted to a pH of 4 with 1 N HCl and ethyl acetate and water were added. The layers were separated and the organic layer was washed with two portions of water and then with saturated aqueous sodium chloride. The combined aqueous layers were back-extracted with ethyl acetate. The combined organic layers were dried (magnesium sulfate) and concentrated to afford 1.756 g (98%) of the title compound. MS 534.3 (M−1)−
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27](/[CH:30]=[CH:31]/[CH2:32]O)=[C:26]([N+:34]([O-:36])=[O:35])[CH:25]=1.N1C=CC=CC=1>C(Cl)Cl>[Br:20][CH2:32][CH:31]=[CH:30][C:27]1[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][C:26]=1[N+:34]([O-:36])=[O:35]
Reactant: COc1ccc(/C=C/CO)c([N+](=O)[O-])c1
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(C=CCBr)c([N+](=O)[O-])c1
Reaction time: 0.25 h
Yield: 58.5 %

Procedure:
To a stirred slurry of triphenyl phosphine (16.4 g, 0.627 mol) in dry DCM (150 mL) under nitrogen at 0° C., is added dropwise a solution of bromine (3.2 mL, 0.0627 mol) in DCM (30 mL). After stirring for 15 min, a solution of (2E)-3-(4-methoxy-2-nitrophenyl)prop-2-en-1-ol (10 g, 0.044 mol) in dry DCM (100 mL) is added dropwise to the reaction mixture followed by a dropwise addition of pyridine (5.05 mL, 0.06 mol) at 0° C. After stirring at room temperature for another 4 h, the reaction mixture is quenched with ice and the product extracted with DCM. The organic layer is washed with water then brine and dried over Na2SO4. The solvent is removed under reduced pressure and the residue is purified by chromatography using silica-gel (60-120 mesh) and petrol ether/EtOAc as eluent to afford (7 g, 53%) of the title compound as a yellow solid. 1H NMR (CDCl3, 400 MHz) δ 7.52-7.55 (m, 1H), 7.42-7.47 (m, 1H), 7.11-7.16 (m, 1H), 7.06-7.09 (m, 1H), 6.23-6.29 (m, 1H), 4.15-4.18 (m, 2H), 3.88 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Br:10])[CH:9]=1)[CH:5]=O.[C@@H:11]1([NH2:21])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1>>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Br:10])[CH:9]=1)[CH2:5][NH:21][C@@H:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1
Reactant: N[C@H]1CCCc2ccccc21
Reactant: O=Cc1cc(Br)cc(Br)c1
Product: Brc1cc(Br)cc(CN[C@H]2CCCc3ccccc32)c1

Procedure:
3,5-Dibromobenzaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][C:14]([OH:16])=[O:15])=O)(C)(C)C.O1CCO[CH2:19][CH2:18]1.[ClH:23]>>[ClH:23].[CH2:18]([O:16][C:14](=[O:15])[CH2:13][C@H:9]1[CH2:10][CH2:11][CH2:12][NH:8]1)[CH3:19]
Reactant: C1COCCO1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CC(=O)O
Agent: Cl
Product: CCOC(=O)C[C@H]1CCCN1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (R)-2-carboxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester in 2 N hydrogen chloride in dioxane (250 mg, 1.1 mmol) in 4 N hydrogen chloride in dioxane (2 ml, 8 mmol) was stirred for 2 h at 25° C. and evaporated to dryness and redissolved in ethanol. After addition of a few drops of 12 M aqueous hydrochloric acid the mixture was stirred at 25° C. overnight. Solvents were evaporated to give 200 mg (95%) of (R)-pyrrolidin-2-yl-acetic acid ethyl ester hydrochloride (25 mg, 55%).
Reaction SMILES: Cl.[C:2]1([C@H:12]([NH:14][C@H:15]2[CH2:19][CH2:18][N:17]([C:20]3[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=3)[CH2:16]2)[CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.Cl.[CH3:30][O:31][C:32](=[O:36])[C@H:33]([CH3:35])[NH2:34].ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C.O>[CH3:30][O:31][C:32]([C@@H:33]([NH:34][C:24](=[O:25])[C:23]1[CH:27]=[CH:28][C:20]([N:17]2[CH2:18][CH2:19][C@H:15]([NH:14][C@@H:12]([C:2]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[CH:5]=[CH:4][CH:3]=3)[CH3:13])[CH2:16]2)=[CH:21][CH:22]=1)[CH3:35])=[O:36]
Reactant: C[C@@H](N[C@H]1CCN(c2ccc(C(=O)O)cc2)C1)c1cccc2ccccc12
Reactant: COC(=O)[C@H](C)N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](C)NC(=O)c1ccc(N2CC[C@H](N[C@H](C)c3cccc4ccccc34)C2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 18.9 %

Procedure:
To a solution of 150 mg of 4-[(S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidin-1-yl]benzoic acid hydrochloride of Example 3.001 and 58 mg of (1)-alanine methyl ester hydrochloride in 5 ml of DMF were added 163 mg of 1-[3-(dimethylaminopropyl)]-3-ethylcarbodiimide hydrochloride, 115 mg of 1-hydroxybenzotriazole and 125 μl of triethylamine, and the reaction mixture was stirred at room temperature for 1 day. To the reaction mixture were added water and ethyl acetate, the mixture was stirred and then the liquids were separated. The organic layer was dried and concentrated under reduced pressure, then, the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=65:35→35:65) to obtain 31.9 mg of N—[(S)-1-methoxycarbonylethyl]-4-[(S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidin-1-yl]benzamide.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[N:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH:24]1([C:27]([NH2:29])=[O:28])[CH2:26][CH2:25]1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>[N+:15]([C:12]1[N:11]=[CH:10][C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:29][C:27]([CH:24]3[CH2:26][CH2:25]3)=[O:28])[CH:7]=2)=[CH:14][CH:13]=1)([O-:17])=[O:16]
Reactant: NC(=O)C1CC1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc(Cl)c2)cn1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])nc2)ccn1)C1CC1
Temperature: 25 °C
Yield: 63.7 %

Procedure:
A suspension of Example A1 (2.00 g, 7.95 mmol), Cs2CO3 (5.00 g, 15.35 mmol), XPhos (0.200 g, 0.420 mmol), Pd2(dba)3 (0.200 g, 0.218 mmol) and cyclopropylcarboxamide (1.00 g, 11.75 mmol) in dioxane (20 mL) was heated at 90° C. under argon overnight. The mixture was cooled to RT and the solids removed via filtration and washed with DCM and THF. The filtrate was concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex) to afford N-(4-((6-nitropyridin-3-yl)oxy)pyridin-2-yl)cyclopropanecarboxamide (1.52 g, 64%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.01 (s, 1H), 8.57 (dd, J=2.8, 0.5 Hz, 1H), 8.40 (m, 1H), 8.31 (d, J=5.7 Hz, 1H), 7.98 (dd, J=8.9, 2.8 Hz, 1H), 7.85 (d, J=2.4 Hz, 1H), 6.89 (dd, J=5.7, 2.4 Hz, 1H), 1.97 (m, 1H), 0.77 (m, 4H); MS (ESI) m/z: 301.1 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[C:22]4[N:23]([CH:28]=[CH:29][N:30]=4)[CH:24]=[C:25](Br)[N:26]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].S(O)(O)(=O)=O.[NH2:36][C:37]1[CH:38]=[C:39](B(O)O)[CH:40]=[CH:41][CH:42]=1.NC1C=C(B(O)O)C=CC=1.C(=O)([O-])[O-].[Na+].[Na+].C(COC)OC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[C:22]4[N:23]([CH:28]=[CH:29][N:30]=4)[CH:24]=[C:25]([C:41]4[CH:40]=[CH:39][CH:38]=[C:37]([NH2:36])[CH:42]=4)[N:26]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1cccc(B(O)O)c1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3nc(Br)cn4ccnc34)cc2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3nc(-c4cccc(N)c4)cn4ccnc34)cc2)CC1
Temperature: 95 °C

Procedure:
A mixture of 4-(6-bromoimidazo[1,2-a]pyrazin-8-ylamino)benzoic acid ethyl ester (13) (4,33 mmol), 3-aminophenylboronic acid hemisulfate (5,63 mmol), tetrakis(triphenylphosphine)palladium (0.2 mmol), 1N aqueous sodium carbonate solution (13 mL), and dimethoxyethane (70 mL) is heated at 95° C. for 2 days. The mixture is allowed to cool, treated with water (100 mL), and extracted with ethyl acetate (3×80 mL). The extracts are washed with water (2×75 mL) and brine (1×75 mL), dried over magnesium sulfate, and evaporated in vacuo. The residue is chromatographed over silica gel, eluting with ethyl acetate, to give 4-{4-[6-(3-amino-phenyl)-imidazo[1,2-a]pyrazin-8-ylamino]-phenyl}-piperazine-1-carboxylic acid tert-butyl ester (14) as a cream solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH:19]1([NH2:22])[CH2:21][CH2:20]1.C(N(CC)CC)C>C(Cl)Cl.O.CN(C)C=O>[CH:19]1([NH:22][C:10](=[O:12])[CH2:9][CH2:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:21][CH2:20]1
Reactant: NC1CC1
Reactant: O=C(O)CCc1ccc(F)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCc1ccc(F)cc1)NC1CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.9 %

Procedure:
To a stirred solution of 3-(4-fluorophenyl)propionic acid (5 g, 31 mmoles) and 0.1 mL of dimethylformamide in 50 mL of anhydrous CH2Cl2 at 0° C. was added oxalyl chloride (2.84 mL, 32.6 mmoles) and the mixture was stirred for 1 hour at 0° C. and for 1 hour at room temperature. After cooling to 0° C. were added cyclopropylamine (2.6 mL, 37.2 mmoles) and triethylamine (6.5 mL, 46.5 mmoles), and the mixture was stirred for 1 hour while warming to room temperature gradually. Then water was added and the product was extracted with CH2Cl2. The extract was washed with water, dried over MgSO4 and evaporated to give a solide residue. It was recrystallized from CH2Cl2 and hexane to give 4.94 g of N-cyclopropyl-3-(4-fluorophenyl)propionamide.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][C:21]1=[O:26].N12CCN(CC1)CC2.Cl>O.CS(C)=O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([N:23]4[CH2:24][CH2:25][NH:20][C:21](=[O:26])[CH2:22]4)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Reactant: O=C1CNCCN1
Agent: C1CN2CCN1CC2
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Product: O=C1CN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CCN1
Yield: 72.4 %

Procedure:
5.3 g (20 mmol) of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are initially introduced into 50 ml of DMSO and heated with 2.4 g (24 mmol) of 2-piperazinone and 4.4 g (40 mmol) of 1,4-diazabicyclo[2.2.2]octane at 130° C. for 1 hour. After cooling, the suspension is adjusted to pH 5 with 2 N hydrochloric acid, 50 ml of water are added, and the precipitate is filtered off with suction, washed with water and methanol, and then boiled in 50 ml of methanol. 5 g (72% of theory) of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(3-oxo-1-piperazinyl)-3-quinolinecarboxylic acid of melting point 342°-348° C. (decomposition) and purity 97% (HPLC) are isolated. Mass spectrum: m/e 345 (M+), 301 (94%, M+--CO2), 231 (M+--C 3 H4NO), 202, 44 (100%, CO2). NMR (CF3COOH)=δ1.45 and 1.7 broad (4H in the cyclopropyl radical), 3.9 and 4.0 broad (5H, N--CH in the cyclopropyl radical, N--CH2CH2 --N), 4.6 broad (2H, CO--CH2 --N), 7.85 d (1H, on C-8), 8.28 d (1H, on C-5), 9.3 s (1H, on C-2).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[CH:12][N:11]=2.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>N1C=CC=CC=1>[C:17]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[CH:12][N:11]=2)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccccc1-c1nc2cccnc2o1
Solvent: c1ccncc1
Product: O=C(Nc1ccccc1-c1nc2cccnc2o1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
An ice cold solution of 1 gram of 2-(2-aminophenyl)oxazolo[5,4-b]pyridine in 15 ml. of dry pyridine was treated with 1 gram of benzoyl chloride slowly. The reaction mixture was diluted with ice-water and stirred for 10 minutes and the resulting solid was collected on a filter and recrystallized from benzene to give 2-(2-benzoylaminophenyl)oxazolo[5,4-b]pyridine, m.p. 197°-198° C.
Reaction SMILES: CCCP(=O)=O.[CH3:7][NH:8][C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][CH:17]=2)[CH:10]=1.[CH2:25]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[CH3:26].CCN(CC)CC>CN(C1C=CN=CC=1)C.CN(C=O)C.CCOC(C)=O>[CH2:25]([N:27]1[CH2:32][CH2:31][N:30]([C:20]([C:19]2[CH:18]=[CH:17][C:16]([NH:15][C:11]3[CH:10]=[C:9]([NH:8][CH3:7])[N:14]=[CH:13][N:12]=3)=[CH:24][CH:23]=2)=[O:22])[CH2:29][CH2:28]1)[CH3:26]
Reactant: CCN1CCNCC1
Reactant: CNc1cc(Nc2ccc(C(=O)O)cc2)ncn1
Agent: CCCP(=O)=O
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCN1CCN(C(=O)c2ccc(Nc3cc(NC)ncn3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Propylphosphonic anhydride (50% in DMF, 2.72 mL, 4.7 mmol, 2 equiv) is added to a solution of 4-(6-methylamino-pyrimidin-4-ylamino)-benzoic acid (0.570 g, 2.33 mmol), N-ethyl-piperazine (0.33 mL, 2.57 mmol, 1.1 equiv), DMAP (7 mg), and Et3N (3.3 mL, 23.3 mmol, 10 equiv) in DMF (25 mL), at RT and under an argon atmosphere. The reaction mixture is stirred at RT for 1 h, diluted with EtOAc and washed with H2O. The aqueous layer is extracted with EtOAc. The combined organic phase is washed with brine, dried (Na2SO4), filtered and concentrated. The residue is purified by silica gel column chromatography (DCM→DCM/2 N NH3 in MeOH, 86:14) to provide the title compound as a yellow foam: ES-MS: 341.2 [MH]+; tR=1.00 min (system 1); Rf=0.33 (CH2Cl2/2 N NH3 in MeOH, 9:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:37][CH2:38][CH3:39])=[C:5]([CH:27]=[CH:28][C:29]=1[C:30]([N:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:31])[O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[C:12]([CH2:24][CH2:25][CH3:26])=[C:13]([CH:21]=[CH:22][CH:23]=1)[O:14][CH2:15][C:16]([O:18]CC)=[O:17].[OH-].[Li+]>CO>[CH3:1][O:2][C:3]1[C:4]([CH2:37][CH2:38][CH3:39])=[C:5]([CH:27]=[CH:28][C:29]=1[C:30]([N:32]1[CH2:33][CH2:34][CH2:35][CH2:36]1)=[O:31])[O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[C:12]([CH2:24][CH2:25][CH3:26])=[C:13]([CH:21]=[CH:22][CH:23]=1)[O:14][CH2:15][C:16]([OH:18])=[O:17]
Reactant: CCCc1c(OCCCOc2ccc(C(=O)N3CCCC3)c(OC)c2CCC)cccc1OCC(=O)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CCCc1c(OCCCOc2ccc(C(=O)N3CCCC3)c(OC)c2CCC)cccc1OCC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound of Example 49 (150 mg, 0.2769 mmol) and 1 M lithium hydroxide (554 μl, 0.5538 mmol) were added to 2.0 ml of methanol and the reaction mixture was stirred at room temperature overnight. The solvent was removed under vacuum, 2.0 ml of water was added, then the solution was acidified with 10% hydrochloric acid. The solution was extracted three times with ethyl acetate and the combined extracts were dried and filtered. The solvent was removed under vacuum to give the product as a gum.
Reaction SMILES: [CH:1]1([OH:9])[CH2:6][CH:5]([OH:7])[CH2:4][CH:3]([OH:8])[CH2:2]1.[CH:10]1([C:16](Cl)=[O:17])[CH2:15][CH2:14][CH:13]=[CH:12][CH2:11]1.Cl>N1C=CC=CC=1>[CH:10]1([C:16]([O:7][CH:5]2[CH2:6][CH:1]([O:9][C:16]([CH:10]3[CH2:15][CH2:14][CH:13]=[CH:12][CH2:11]3)=[O:17])[CH2:2][CH:3]([O:8][C:16]([CH:10]3[CH2:15][CH2:14][CH:13]=[CH:12][CH2:11]3)=[O:17])[CH2:4]2)=[O:17])[CH2:15][CH2:14][CH:13]=[CH:12][CH2:11]1
Reactant: OC1CC(O)CC(O)C1
Reactant: O=C(Cl)C1CC=CCC1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(OC1CC(OC(=O)C2CC=CCC2)CC(OC(=O)C2CC=CCC2)C1)C1CC=CCC1
Temperature: 2.5 °C
Reaction time: 4 h
Yield: 100.8 %

Procedure:
To 1.32 g (10 mmol) of cyclohexane-1,3,5-triol (a mixture of cis- and trans-isomers) dissolved in 20 ml of pyridine was added dropwise 6.51 g (45 mmol) of 3-cyclohexene carbonyl chloride within 30 minutes at 5° C. or lower, followed by stirring at 0 to 5° C. for 4 hours to allow the reaction to proceed. After the reaction, the reaction solution was poured into a mixture of 50 ml of 10% hydrochloric acid and 50 ml of ice water, and the resultant was extracted with 30 ml of chloroform three times. The combined organic layers were washed twice with 30 ml of saturated sodium bicarbonate solution and then with 30 ml of saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 4.6 g of the desired 1,3,5-tris(3-cyclohexene carbonyloxy)cyclohexane as a pale yellow oil.