Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C1N(CC(C)C)C(=O)N(C)C(=O)C=1)N.ClC1C=C2C(=CC=1)NC=C2C=O.C(C1C=C(C=O)N(C)C=1)(=O)C.[C:39]([C:42]1[CH:43]=[C:44]([C:48]2[N:49]([CH2:64][C:65]3[C:73]4[C:68](=[CH:69][CH:70]=[C:71]([Cl:74])[CH:72]=4)[NH:67][CH:66]=3)[N:50]=[C:51]3[C:56]=2[C:55](=[O:57])[N:54]([CH3:58])[C:53](=[O:59])[N:52]3[CH2:60][CH:61]([CH3:63])[CH3:62])[N:45]([CH3:47])[CH:46]=1)(=O)[CH3:40].Cl.[NH2:76][OH:77]>>[Cl:74][C:71]1[CH:72]=[C:73]2[C:68](=[CH:69][CH:70]=1)[NH:67][CH:66]=[C:65]2[CH2:64][N:49]1[C:48]([C:44]2[N:45]([CH3:47])[CH:46]=[C:42](/[C:39](=[N:76]/[OH:77])/[CH3:40])[CH:43]=2)=[C:56]2[C:51]([N:52]([CH2:60][CH:61]([CH3:62])[CH3:63])[C:53](=[O:59])[N:54]([CH3:58])[C:55]2=[O:57])=[N:50]1
Reactant: CC(=O)c1cc(-c2c3c(=O)n(C)c(=O)n(CC(C)C)c3nn2Cc2c[nH]c3ccc(Cl)cc23)n(C)c1
Reactant: NO
Agent: CC(=O)c1cc(C=O)n(C)c1
Agent: CC(C)Cn1c(NN)cc(=O)n(C)c1=O
Agent: Cl
Product: C/C(=N\O)c1cc(-c2c3c(=O)n(C)c(=O)n(CC(C)C)c3nn2Cc2c[nH]c3ccc(Cl)cc23)n(C)c1

Procedure:
This compound was made in one pot following the procedure described above, starting with 6-hydrazino-1-isobutyl-3-methylpyrimidine-2,4(1H,3H)-dione, and condensing first 5-chloro-1H-indole-3-carbaldehyde, followed by 4-acetyl-1-methyl-1H-pyrrole-2-carbaldehyde. To the crude 3-(4-acetyl-1-methyl-1H-pyrrol-2-yl)-2-[(5-chloro-1H-indol-3-yl)methyl]-7-isobutyl-5-methyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione was treated with hydroxylamine hydrochloride and heated at 80° C. in N,N′Dimethylacetamide for 18 h. The crude reaction product was purified by semi-prep RPHPLC eluting with water/acetonitrile/trifluoroacetic acid mixtures. 522 (M+H).
Reaction SMILES: [CH3:1][C:2]12[CH:17]([CH3:18])[CH:15]3[NH:16][C:11]4[CH:12]([CH2:14]3)[CH2:13][C:4](=[C:5]([CH:10]=4)[CH:6]=[CH:7][CH2:8][NH:9]1)[CH2:3]2.C(N(C(C)C)CC)(C)C.Br[CH2:29][CH:30]=[C:31]([CH3:33])[CH3:32].O>CN(C)C=O.C(OCC)(=O)C>[CH3:1][C:2]12[CH:17]([CH3:18])[CH:15]3[NH:16][C:11]4[CH:12]([CH:14]3[CH2:29][CH:30]=[C:31]([CH3:33])[CH3:32])[CH2:13][C:4](=[C:5]([CH:10]=4)[CH:6]=[CH:7][CH2:8][NH:9]1)[CH2:3]2
Reactant: CC(C)=CCBr
Reactant: CC1C2CC3CC4=C(C=CCNC1(C)C4)C=C3N2
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)=CCC1C2CC3=C4C=CCNC(C)(C3)C(C)C1NC2=C4
Temperature: 0 °C
Reaction time: 1.25 h
Yield: 34.6 %

Procedure:
To a stirred solution of 1.42 g of 6,12-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-8H-pyrrolo[2,3-i][3]benzazocine and 40 ml of dimethylformamide was added 1.54 ml of diisopropylethyl amine. The mixture was cooled to 0° C. and 0.97 g of 4-bromo-2-methyl-2-butene in 8 ml of dimethylformamide was added, under nitrogen. The mixture was stirred at 0° C. for an additional 1.25 hr, and was poured into water and ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate and ether. The combined organic layers were washed with brine, dried over anhydrous potassium carbonate, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 2% triethylamine/ethyl acetate) to afford 0.63 g (35%) of product, mp 62°-65° C.
Reaction SMILES: [CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][C@H:13]3[O:17][C:16]([NH2:18])=[N:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1O[C@H]1CCl.C1(C2C=CC(O)=CC=2)CCCCC1.C([O:41][C:42](=O)[CH:43]([CH:47]=O)[CH:44]([CH3:46])[CH3:45])C>C(O)C>[CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][C@H:13]3[O:17][C:16]4=[N:18][C:42](=[O:41])[C:43]([CH:44]([CH3:46])[CH3:45])=[CH:47][N:15]4[CH2:14]3)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)C(C=O)C(C)C
Reactant: NC1=NC[C@@H](COc2ccc(C3CCCCC3)cc2)O1
Agent: ClC[C@H]1CO1
Agent: Oc1ccc(C2CCCCC2)cc1
Solvent: CCO
Product: CC(C)c1cn2c(nc1=O)O[C@H](COc1ccc(C3CCCCC3)cc1)C2
Yield: 22.5 %

Procedure:
To a solution of (S)-5-(4-cyclohexyl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine (0.48 g, 1.74 mmol) (prepared in accordance with the procedures described in Steps 1 and 2 of Example 1 and starting from R-epichlorohydrin and 4-cyclohexylphenol) in ethanol (16 mL) was added 2-formyl-3-methyl-butyric acid ethyl ester (0.33 g, 2.1 mmol). The reaction mixture was heated at reflux for 24 hours. It was then concentrated to remove solvent and loaded on silica gel column. Chromatography with (1-5%) 2-propanol/methylene chloride gave 0.144 g of the title compound. [α]D25 −15.80 (c 0.5, CHCl3).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][C:8]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2].O[N:21]1[C:25]2C=[CH:27][CH:28]=[CH:29][C:24]=2N=N1.CCN=C=NCCCN(C)C.N1CCCCC1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:19])[C:7]1[CH:15]=[CH:14][C:10]([C:11]([N:21]2[CH2:27][CH2:28][CH2:29][CH2:24][CH2:25]2)=[O:13])=[CH:9][C:8]=1[N+:16]([O-:18])=[O:17])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)c1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Solvent: C1CCNCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(C(=O)N2CCCCC2)cc1[N+](=O)[O-]

Procedure:
2-Nitro-terephthalic acid 1-tert-butyl ester (500 mg, 1.88 mmol) in DCM (18 mL), was treated with 1-hydroxybenzotriazole (0.39 g, 2.43 mmol), EDCI (0.47 g, 2.43 mmol) and piperidine (0.24 mL, 2.43 mmol). After 3 hours the reaction was diluted with DCM (50 mL) and washed with aqueous NaHCO3 (30 mL), water (30 mL) and finally with brine. After drying over sodium sulphate and evaporation of the solvent the title compound was obtained as a colourless oil in quantitative yield. The crude was employed in the following reaction without any further purification.
Reaction SMILES: Cl[C:2]1[CH:17]=[C:16]([F:18])[C:15]([N:19]2[C:24](=[O:25])[CH:23]=[C:22]([CH3:26])[N:21]([CH3:27])[C:20]2=[O:28])=[CH:14][C:3]=1[C:4]([O:6][C:7]([C:10]([O:12][CH3:13])=[O:11])([CH3:9])[CH3:8])=[O:5].[Cu][C:30]#[N:31]>CN1CCCN(C)C1=O>[C:30]([C:2]1[CH:17]=[C:16]([F:18])[C:15]([N:19]2[C:24](=[O:25])[CH:23]=[C:22]([CH3:26])[N:21]([CH3:27])[C:20]2=[O:28])=[CH:14][C:3]=1[C:4]([O:6][C:7]([C:10]([O:12][CH3:13])=[O:11])([CH3:9])[CH3:8])=[O:5])#[N:31]
Reactant: COC(=O)C(C)(C)OC(=O)c1cc(-n2c(=O)cc(C)n(C)c2=O)c(F)cc1Cl
Reactant: N#C[Cu]
Solvent: CN1CCCN(C)C1=O
Product: COC(=O)C(C)(C)OC(=O)c1cc(-n2c(=O)cc(C)n(C)c2=O)c(F)cc1C#N
Temperature: 220 °C

Procedure:
A mixture of 1.5 g of 1-methoxycarbonyl-1-methylethyl 2-chloro-5-[3,6-dihydro-3 4-dimethyl-2,6-dioxo-1(2H)-pyrimidinyl]-4-fluorobenzoate and 0.4 g of copper(I) cyanide in 20 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone is heated to 220° C. under nitrogen for 6 hours. After cooling to room temperature the mixture is filtered and the filtrate is dissolved in 200 ml of ethyl acetate. The solution is washed four times with 50 ml of water each time, the combined organic phases are dried and concentrated under reduced pressure. In this manner there is obtained 1-methoxycarbonyl-1-methylethyl 2-cyano-5-[3,6-dihydro-3,4-dimethyl-2,6-dioxo-1(2H)-pyrimidinyl]-4-fluorobenzoate, mass spectrum (m/e); 403 10) M+.
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[CH2:10][C:11]1[C:15](=[CH2:16])[CH:14]=[CH:13][CH:12]=1.B(F)(F)F.CCOCC.O>C(Cl)Cl>[CH3:8][O:7][C:1]1[CH:6]=[CH:5][C:4]([CH2:16][C:15]2[C:11](=[CH2:10])[CH:12]=[CH:13][CH:14]=2)=[CH:3][CH:2]=1
Reactant: COc1ccccc1
Reactant: C=C1C=CC=C1CO
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Solvent: O
Product: C=C1C=CC=C1Cc1ccc(OC)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Anisole (0.04 mL, 0.37 mmol) was added to a solution of hydroxymethylfulvene (10 mg, 0.04 mmol) in dry CH2Cl2 (5 mL). The mixture was cooled to -78° C. and boron triflouride etherate (0.04 mL, 0.36 mmol) was added dropwise. The reaction was stirred at that temperature for 1 hour and water was added to quench the reaction. The organic layer was washed with H2O, saturated NaHCO3 and brine, and dried over MgSO4. Concentration of the solution gave a residue which was dried in vacuo, yielding the product in quantitative yield (14 mg). 1H NMR δ0.59-1.40 (m, 4 H). 1.36 (s, 3 H), 1.76 (s, 3 H), 2.07 (s, 3 H), 3.78 (s, 3 H), 3.95 (s, 1 H), 3.99 (d, J=16.12 Hz, 2 H), 6.81 (d, J-8.8 Hz, 2 H), 6.96 (d, J=8.3 Hz, 2 H), 7.22 (s, 1 H). MS m/Z 336 (M+), 308 (M+-CH2CH2), 215, 121 ((CH2 -Ph-OCH3)+). UV 410 nm (2.7×103), 325 nm (7.0×103), 267 nm (1.0×104), 245 nm (inflection), 226 nm (1.9×104), 203 nm (1.4×104). The compound has the structure: ##STR17##
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[C:29]([CH2:34][OH:35])[CH:28]=1)[CH2:10][NH:11][C@H:12]([CH3:26])[CH2:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18]([C:23]([OH:25])=O)=[CH:17]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.[CH3:65][O:66][C:67]1[CH:74]=[CH:73][CH:72]=[CH:71][C:68]=1[CH2:69][NH2:70]>CN(C)C=O>[Si:1]([O:8][C@H:9]([C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[C:29]([CH2:34][OH:35])[CH:28]=1)[CH2:10][NH:11][C@H:12]([CH3:26])[CH2:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18]([C:23]([NH:70][CH2:69][C:68]1[CH:71]=[CH:72][CH:73]=[CH:74][C:67]=1[O:66][CH3:65])=[O:25])=[CH:17]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: COc1ccccc1CN
Reactant: C[C@H](Cc1ccc2[nH]c(C(=O)O)cc2c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c(CO)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccccc1CNC(=O)c1cc2cc(C[C@@H](C)NC[C@H](O[Si](C)(C)C(C)(C)C)c3ccc(O)c(CO)c3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 24.6 %

Procedure:
A solution of 5-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]-1H-indole-2-carboxylic acid (Preparation 5, 0.25 g, 0.50 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (106 mg, 0.55 mmol), hydroxybenzotriazole (75 mg, 0.55 mmol) in N,N-dimethylformamide (5 ml) was treated with triethylamine (0.15 ml, 0.55 mmol) and 2-methoxybenzylamine (0.07 ml, 0.55 mmol) and the resulting suspension left to stir at room temperature under a nitrogen atmosphere for 18 hours. The solvent was removed in vacuo and the residue partitioned between dichloromethane (50 ml) and saturated aqueous sodium bicarbonate (20 ml). The organic phase was separated, dried (sodium sulphate) and the solvent removed in vacuo. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane:methanol (95:5 changing to 90:10, by volume) to give the title compound as a colourless foam (76 mg).
Reaction SMILES: OC(C(F)(F)F)=O.[NH2:8][C@@H:9]([CH3:35])[C:10]([NH:12][C@@H:13]([CH2:31][CH:32]1[CH2:34][CH2:33]1)[C:14]([NH:16][C@@H:17]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:18]([C@@:20]1([CH3:23])[CH2:22][O:21]1)=[O:19])=[O:15])=[O:11].[O:36]1[CH2:41][CH2:40][N:39]([CH2:42][C:43](O)=[O:44])[CH2:38][CH2:37]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:32]1([CH2:31][C@H:13]([NH:12][C:10](=[O:11])[C@@H:9]([NH:8][C:43](=[O:44])[CH2:42][N:39]2[CH2:40][CH2:41][O:36][CH2:37][CH2:38]2)[CH3:35])[C:14]([NH:16][C@@H:17]([CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:18]([C@@:20]2([CH3:23])[CH2:22][O:21]2)=[O:19])=[O:15])[CH2:34][CH2:33]1
Reactant: O=C(O)CN1CCOCC1
Reactant: C[C@H](N)C(=O)N[C@@H](CC1CC1)C(=O)N[C@@H](Cc1ccccc1)C(=O)[C@@]1(C)CO1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](NC(=O)CN1CCOCC1)C(=O)N[C@@H](CC1CC1)C(=O)N[C@@H](Cc1ccccc1)C(=O)[C@@]1(C)CO1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.8 %

Procedure:
To (S)-2-((S)-2-aminopropanamido)-3-cyclopropyl-N-((S)-1-((R)-2-methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-yl)propanamide TFA salt (377 mg, 0.779 mmol) was added 2-morpholinoacetic acid (226 mg, 1.56 mmol), HATU (622 mg, 1.64 mmol), and DMF (4 mL). The mixture was cooled to 0° C. and DIEA (0.68 mL, 3.9 mmol) was added. The reaction mixture was stirred at ambient temperature for 30 min then quenched with sodium bicarbonate (sat.), extracted with ethyl acetate (2×), dried with sodium sulfate, filtered, and concentrated. Purification by column chromatography (3:1 DCM/ethyl acetate+0-10% methanol) provided (S)-3-cyclopropyl-N-((S)-1-((R)-2-methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-yl)-2-((S)-2-(2-morpholinoacetamido)propanamido)propanamide (320 mg, 80%) as a colorless solid. 1H NMR (400 MHz, CDCl3): δ 7.54 (d, J=7.6 Hz, 1H), 7.32-7.22 (m, 3H), 7.16-7.14 (m, 2H), 6.67 (d, J=7.6 Hz, 1H), 6.47 (d, J=7.6 Hz, 1H), 4.86-4.81 (m, 1H), 4.43 (q, J=6.8 Hz, 2H), 4.34 (dd, J=14.4, 6.8 Hz, 1H), 3.74-3.72 (m, 4H), 3.30 (d, J=4.8 Hz, 1H), 3.14 (dd, J=14.0, 5.2 Hz, 1H), 3.04 (d, J=4.8 Hz, 2H), 2.92 (d, J=4.8 Hz, 1H), 2.83 (dd, J=14.0, 7.8 Hz, 1H), 2.54-2.52 (m, 4H), 1.56 (t, J=6.8 Hz, 2H), 1.50 (s, 3H), 1.35 (d, J=7.2 Hz, 3H), 0.41-0.36 (m, 2H), 0.05-0.00 (m, 2H). MS (EI) for C27H38N4O6, found 515.4 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[OH-].[Na+].C[SH-][C:13]([SH-]C)=[N:14][C:15]1[S:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=1>CN(C=O)C.O>[S:16]1[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=[C:15]1[NH:14][C:13]1[O:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: Nc1ccccc1O
Reactant: C[SH-]C(=Nc1nc2ccccc2s1)[SH-]C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc2oc(Nc3nc4ccccc4s3)nc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.1 %

Procedure:
2-aminophenol (21.8 g (0.20 mol)) was dissolved in 944 g of DMF, thereto was added 40 mL of 5 mol/L aqueous sodium hydroxide solution (equivalent to 0.20 mol of sodium hydroxide), the resulting mixture was stirred at room temperature for 30 minutes, and then thereto was added a solution obtained by dissolving 50.9 g (0.20 mol) of the obtained S,S′-dimethyl-N-(2-benzothiazolyl)carbonimidodithioate in 1416 g of DMF. The resulting mixture was then heated to 153° C., refluxed under a nitrogen atmosphere for 6 hours, and then cooled to room temperature, and the reaction liquid was added dropwise in 2000 g of water. A precipitate was filtered off, washed with water, and dried to obtain 30.0 g of 2-(2-benzothiazolylamino)benzoxazole (L5: see Table 1 below). The yield was 56.1% based on 2-aminophenol.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([CH3:19])[N:13]=2)[CH:3]=1.[NH2:20][C@@H:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C@@H:22]1[NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31].CN1C(=O)CCC1.CO>ClCCl>[C:8]([C:5]1[N:6]=[N:7][C:2]([NH:20][C@@H:21]2[CH2:26][CH2:25][CH2:24][CH2:23][C@@H:22]2[NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[CH:3][C:4]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([CH3:19])[N:13]=1)(=[O:9])[NH2:10]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Reactant: Cc1nc(Nc2cc(Cl)nnc2C(N)=O)ccc1Cl
Solvent: ClCCl
Solvent: CO
Solvent: CN1CCCC1=O
Product: Cc1nc(Nc2cc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)nnc2C(N)=O)ccc1Cl
Temperature: 140 °C
Reaction time: 60 h
Yield: 25.3 %

Procedure:
A pressure tube was charged with 6-chloro-4-(5-chloro-6-methylpyridin-2-ylamino)pyridazine-3-carboxamide (600 mg, 2.01 mmol), tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (863 mg, 4.03 mmol) and NMP (6 mL) to give a yellow suspension. The reaction mixture was stirred at 140° C. for 2.5 days. After cooling to room temperature, the NMP was distilled off using a Kugelrohr to afford a brown, viscous oil. This crude material was dissolved in dichloromethane and methanol and adsorbed onto silica gel. Purification by chromatography (spherical silica 20-45 m, 50 g, Versaflash column from Supelco, eluting from 100% dichloromethane to 84:15.2:0.8 dichloromethane/methanol/NH4OH), to give tert-butyl (1S,2R)-2-(6-carbamoyl-5-(5-chloro-6-methylpyridin-2-ylamino)pyridazin-3-ylamino)cyclohexylcarbamate (242.3 mg) as a brown solid. The product was then dissolved in dichloromethane (3 mL) and TFA (2.96 g, 2 mL, 26.0 mmol) was added. The mixture was stirred at room temperature for 2 h. The excess TFA and the dichloromethane were removed in vacuo and the residue obtained was purified by chromatography (spherical silica 20-45 μm, 50 g, Versaflash from Supelco, eluting with a gradient of 0.05:0.95:99 NH4OH:methanol:dichloromethane up to 0.6:11.4:88 NH4OH:methanol:dichloromethane over 40 min) to give 6-((1R,2S)-2-aminocyclohexylamino)-4-(5-chloro-6-methylpyridin-2-ylamino)pyridazine-3-carboxamide (152 mg, 4%) as a light brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.77 (br. s., 1H), 8.42 (br. s., 1H), 8.05 (br. s., 1H), 7.59-7.80 (m, 2H), 6.78-6.99 (m, 2H), 3.18 (br. s., 1H), 2.57 (br. s., 4H), 1.21-1.42 (m, 2H), 1.20-1.81 (m, 8H), LC-MS 376 [M+H]+.
Reaction SMILES: [Br-:1].C1(C(C2C=CC=CC=2)(C)C(O[C@@H]2C3CC[N+](CC(=O)NC4C=CON=4)(CC3)C2)=O)C=CC=CC=1.[Br-].O[C@@H]1C2CC[N+](CC(=O)NC3C=CON=3)(CC2)C1.[Br-].[OH:56][C@@H:57]1[CH:62]2[CH2:63][CH2:64][N+:59]([CH2:65][C:66](=[O:79])[NH:67][C:68]3[C:72]([C:73]4[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=4)=[CH:71][O:70][N:69]=3)([CH2:60][CH2:61]2)[CH2:58]1.[CH:80]1([C:86]([OH:96])([C:90]2[CH:95]=[CH:94][CH:93]=[CH:92][CH:91]=2)[C:87](O)=[O:88])[CH2:85][CH2:84][CH2:83][CH2:82][CH2:81]1>>[Br-:1].[CH:90]1([C:86]([OH:96])([C:80]2[CH:81]=[CH:82][CH:83]=[CH:84][CH:85]=2)[C:87]([O:56][C@@H:57]2[CH:62]3[CH2:63][CH2:64][N+:59]([CH2:65][C:66](=[O:79])[NH:67][C:68]4[C:72]([C:73]5[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=5)=[CH:71][O:70][N:69]=4)([CH2:60][CH2:61]3)[CH2:58]2)=[O:88])[CH2:95][CH2:94][CH2:93][CH2:92][CH2:91]1
Reactant: O=C(C[N+]12CCC(CC1)[C@@H](O)C2)Nc1nocc1-c1ccccc1
Reactant: O=C(O)C(O)(c1ccccc1)C1CCCCC1
Agent: CC(C(=O)O[C@H]1C[N+]2(CC(=O)Nc3ccon3)CCC1CC2)(c1ccccc1)c1ccccc1
Agent: O=C(C[N+]12CCC(CC1)[C@@H](O)C2)Nc1ccon1
Agent: [Br-]
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C(O)(c1ccccc1)C1CCCCC1)C2)Nc1nocc1-c1ccccc1

Procedure:
This compound is prepared analogously to (R)-3-(2,2-diphenyl-propionyloxy)-1-(isoxazol-3-ylcarbamoylmethyl)-1-azonia-bicyclo[2.2.2]octane bromide (Example 4), substituting (R)-3-hydroxy-1-(isoxazol-3-ylcarbamoylmethyl)-1-azonia-bicyclo[2.2.2]octane bromide (Intermediate A) with (R)-3-hydroxy-1-[(4-phenyl-isoxazol-3-ylcarbamoyl)-methyl]-1-azonia-bicyclo[2.2.2]octane bromide (Intermediate I) and by replacing 2,2′-diphenylpropionic acid with cyclohexyl-hydroxy-phenyl-acetic acid, yielding the titled compound as a diastereomeric mixture. (M+544.4)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]([CH2:12][CH2:13][O:14][C:15]1[N:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[C:5]2=[O:21].[F:22][C:23]([F:35])([F:34])[O:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[N:16]1[CH:17]=[CH:18][CH:19]=[N:20][C:15]=1[O:14][CH2:13][CH2:12][N:6]1[C:5](=[O:21])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:28]3[CH:27]=[CH:26][C:25]([O:24][C:23]([F:22])([F:34])[F:35])=[CH:30][CH:29]=3)[CH:3]=2)[N:8]=[CH:7]1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: O=c1c2cc(Br)ccc2ncn1CCOc1ncccn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Product: O=c1c2cc(-c3ccc(OC(F)(F)F)cc3)ccc2ncn1CCOc1ncccn1
Temperature: 90 °C
Reaction time: 1 h
Yield: 75.6 %

Procedure:
A mixture of 60 mg 6-bromo-3-(2-(pyrimidin-2-yloxy)ethyl)quinazolin-4(3H)-one Compound 178-C (0.25 mmol), 53 mg 4-(trifluoromethoxy)phenyl boronic acid (0.38 mmol), 18 mg potassium carbonate (0.15 mmol), and 3 mg Pd(dppf)Cl2 in 5 mL of degassed 9:1 DMF:water solution was heated at 90° C. After 1 h, the reaction mixture was filtered through celite and the filtrate concentrated and purified by reverse-phase (ACN/H2O with 0.1% TFA) followed by neutralization on resin column to produce 56 mg of 3-(2-(pyrimidin-2-yloxy)ethyl)-6-(4-(trifluoromethoxy)phenyl)quinazolin-4(3H)-one Compound IV-25.
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:19]3[CH:20]=[C:21]([CH2:23][O:24][C:25]4[CH:34]=[CH:33][C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[N:26]=4)[N:22]=[C:18]3[C:17]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[N:16][CH:15]=2)[CH2:10][CH2:9]1.CCN(C(C)C)C(C)C.Br[CH2:51][C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53]>C1COCC1>[O:38]1[CH2:39][CH2:40][N:35]([C:17]2[C:18]3[N:19]([CH:20]=[C:21]([CH2:23][O:24][C:25]4[CH:34]=[CH:33][C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[N:26]=4)[N:22]=3)[C:14]([CH:11]3[CH2:10][CH2:9][N:8]([CH2:51][C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:13][CH2:12]3)=[CH:15][N:16]=2)[CH2:36][CH2:37]1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: c1ccc2nc(OCc3cn4c(C5CCNCC5)cnc(N5CCOCC5)c4n3)ccc2c1
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CN1CCC(c2cnc(N3CCOCC3)c3nc(COc4ccc5ccccc5n4)cn23)CC1
Temperature: 25 °C

Procedure:
Compound 111 (50 mg, 0.06 mmol, Example 26), DIEA (53 μL, 0.38 mmol) and tert-butyl bromoacetate (12 μL, 0.07 mmol) in THF (1 mL) was heated at 120° C. in a microwave for 10 min. The reaction mixture was allowed to cool to rt and concentrated. The residue obtained was purified by flash column chromatography on silica gel (0:1-1:0 EtOAc/hexanes) to obtain compound 27a. Mass Spectrum (LCMS, ESI pos.) Calcd. For C31H38N6O4: 559.3 (M+H). Found 559.3.
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:35])[CH2:15][NH:16][C:17]([C:19]2[CH:23]=[C:22]([O:24][CH2:25][C:26](O)=[O:27])[N:21]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:20]=2)=[O:18])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].FC1C(O)=C(F)C(F)=C(F)C=1F.[CH:48]1([NH:52][C:53]([C@@H:55]2[CH2:59][C@@H:58]([OH:60])[CH2:57][NH:56]2)=[O:54])[CH2:51][CH2:50][CH2:49]1.C(N1CCOCC1)C>CN(C=O)C.C(Cl)Cl.C(Cl)CCl>[CH2:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:35])[CH2:15][NH:16][C:17]([C:19]2[CH:23]=[C:22]([O:24][CH2:25][C:26]([N:56]3[CH2:57][C@H:58]([OH:60])[CH2:59][C@H:55]3[C:53](=[O:54])[NH:52][CH:48]3[CH2:51][CH2:50][CH2:49]3)=[O:27])[N:21]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:20]=2)=[O:18])[CH2:12][CH2:13]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)N1CCN(C(=O)CNC(=O)c2cc(OCC(=O)O)n(-c3ccccc3)n2)CC1
Reactant: O=C(NC1CCC1)[C@@H]1C[C@@H](O)CN1
Agent: CCN1CCOCC1
Agent: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCOC(=O)N1CCN(C(=O)CNC(=O)c2cc(OCC(=O)N3C[C@H](O)C[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1

Procedure:
To a solution of 700 mg 4-{2-[(5-Carboxymethoxy-1-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetyl}-piperazine-1-carboxylic acid butyl ester in 10 ml DMF were added 317 mg pentafluorophenol and 330 mg EDC. The mixture was stirred under exclusion of moisture until LCMS indicated complete conversion to the corresponding pentafluorophenolester. (2S,4R)-4-Hydroxy-pyrrolidine-2-carboxylic acid cyclobutylamide hydrotrifluoroacetate (455 mg) was mixed with 0.55 ml N-ethylmorpholine and 5 ml DMF and this mixture added dropwise to the solution of the pentafluorophenolester. After 12 h the reaction mixture was diluted with DCM and washed with aqueous LiCl (4%), saturated aqueous NaHCO3 and brine. The crude product obtained after evaporation of the solvent was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were immediately lyophilized to yield the pure product which was taken up in dichloromethane and washed once with aqueous NaHCO3. The residue obtained after evaporation of the solvent was lyophilized again to give the title compound. Yield: 454 mg MS (ES+): m/e=654.