Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([CH2:10][C:11]([O:13]CC)=O)=O)=[C:6]([F:16])[C:5]([F:17])=[C:4]([F:18])[C:3]=1[F:19].[C:20]1([NH:26][NH2:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl>CO>[C:20]1([N:26]2[C:11]([OH:13])=[CH:10][C:8]([C:7]3[C:6]([F:16])=[C:5]([F:17])[C:4]([F:18])=[C:3]([F:19])[C:2]=3[F:1])=[N:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NNc1ccccc1
Reactant: CCOC(=O)CC(=O)c1c(F)c(F)c(F)c(F)c1F
Agent: Cl
Solvent: CO
Product: Oc1cc(-c2c(F)c(F)c(F)c(F)c2F)nn1-c1ccccc1
Temperature: 110 °C
Yield: 54 %

Procedure:
A mixture of 2.82 g (10 mmol) of ethyl pentafluorobenzoylacetate, phenylhydrazine (1.08 g; 10 mmol), and 0.33 ml of conc. HCl in 10 ml of methanol was refluxed for 18 hours. The mixture was concentrated in vacuo, the residue was diluted with toluene and heated at 110° C. for 20 hours and cooled. The mixture was diluted with sodium bicarbonate solution and extracted with ethyl acetate (3×). The combined organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica gel; 20-50% ethyl acetate/hexane) and recrystallized from ethyl acetate/hexane to afford 1.76 g (54%) of 1-phenyl-3-(pentafluorophenyl)-5-hydroxypyrazole as a white solid, mp 149-151° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][C:5]([CH3:8])=[CH:6][N:7]=1.[CH2:11]([O:13][CH2:14][C:15](N)=[NH:16])[CH3:12]>>[NH2:10][C:9]1[C:3]2[C:2](=[N:7][CH:6]=[C:5]([CH3:8])[N:4]=2)[N:1]=[C:15]([CH2:14][O:13][CH2:11][CH3:12])[N:16]=1
Reactant: Cc1cnc(N)c(C#N)n1
Reactant: CCOCC(=N)N
Product: CCOCc1nc(N)c2nc(C)cnc2n1

Procedure:
A suspension of 15.1 g (0.113 mole) of 3-amino-6-methyl-2-pyrazinecarbonitrile [prepared according to E. C. Taylor et al., J. Am. Chem. Soc. 1973, 95, 6413] in the above ethanolic solution of 2-ethoxyacetamidine is refluxed for 2 hours. After cooling, the solution obtained is concentrated to dryness under reduced pressure. The residue is purified by washing with acetone and recrystallization from a mixture of acetone and isopropyl ether. Yld: 8.4 g (34%), m.p. 166°-168° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:16]=2[C:17](Cl)=[O:18])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O.[NH2:26][NH2:27].NN>ClCCl>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:16]=2[C:17]([NH:26][NH2:27])=[O:18])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)Cl)cc1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)NN)cc1
Temperature: -10 °C
Yield: 85 %

Procedure:
The crude 2-(4-tert-butyl-benzenesulfonylamino)-5-chlorobenzoyl chloride was dissolved in dichloromethane (300 mL) and transferred to an addition funnel. Hydrazine hydrate (212 mL, 4.35 mol), dissolved in 1.2 L dichloromethane in a 4 L Erlenmeyer flask, was cooled to −10° C. in a dry ice-acetone bath and the acyl chloride solution was added in a slow stream to the stirring hydrazine solution over a 15 minute period. The cold bath was subsequently removed following the addition and LCMS analysis at 15 minutes indicated the reaction was complete. The resultant reaction mixture was quenched with water (500 mL), resulting in a voluminous white precipitate that was collected by vacuum filtration. The precipitate was slurried in 800 mL ethyl acetate and acetic acid was added while stirring until a homogeneous solution was formed. The solution was transferred to a separatory funnel and extracted with 3×100 mL of water. The aqueous phases were discarded and the organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo to produce 4-tert-butyl-N-(4-chloro-2-hydrazinocarbonyl-phenyl)benzenesulfonamide (71 g) in an 85% yield: HPLC retention time=2.49 minutes; MS (ES) M+H expected 382.0, found 382.0.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:28](=[O:29])[N:7]2[CH:8]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=3)[C:9]3[NH:10][C:11]4[C:16]([C:17]=3[CH2:18][C:6]2([CH3:30])[C:5]1=[O:31])=[CH:15][C:14]([O:19][CH3:20])=[CH:13][CH:12]=4.[CH2:32]([NH2:36])[CH:33]([CH3:35])[CH3:34]>>[OH:27][C:23]1[CH:22]=[C:21]([CH:8]2[C:9]3[NH:10][C:11]4[C:16](=[CH:15][C:14]([O:19][CH3:20])=[CH:13][CH:12]=4)[C:17]=3[CH2:18][C:6]3([CH3:30])[C:5](=[O:31])[N:4]([CH2:3][CH2:2][NH:36][CH2:32][CH:33]([CH3:35])[CH3:34])[C:28](=[O:29])[N:7]23)[CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)CN
Reactant: COc1ccc2[nH]c3c(c2c1)CC1(C)C(=O)N(CCBr)C(=O)N1C3c1cccc(O)c1
Product: COc1ccc2[nH]c3c(c2c1)CC1(C)C(=O)N(CCNCC(C)C)C(=O)N1C3c1cccc(O)c1

Procedure:
The title compound is prepared similarly as described for example 30 using (3aSR,10RS)-2-(2-Bromoethyl)-10-(3-hydroxy-phenyl)-6-methoxy-3a-methyl-3a,4,9,10-tetrahydro-2,9,10a-triaza-cyclopenta[b]-fluorene-1,3-dione (example 24) and isobutyl amine as starting materials. MS: m/z (MH+)=477.2
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][CH2:11][CH:12]=[CH:13][CH2:14][CH2:15]I)=[CH:4][C:3]=2[O:2]1.[Li].[CH3:18][CH2:19][C:20](=[O:26])[CH2:21][C:22](=[O:25])[CH2:23][CH3:24]>CN(C)C=O>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][CH2:11][CH:12]=[CH:13][CH2:14][CH2:15][CH:21]([C:20](=[O:26])[CH2:19][CH3:18])[C:22](=[O:25])[CH2:23][CH3:24])=[CH:4][C:3]=2[O:2]1
Reactant: CCC(=O)CC(=O)CC
Reactant: ICCC=CCCc1ccc2c(c1)OCO2
Agent: [Li]
Solvent: CN(C)C=O
Product: CCC(=O)C(CCC=CCCc1ccc2c(c1)OCO2)C(=O)CC

Procedure:
[I; Ar is 3,4-methylenedioxyphenyl, R0 is H, R' and R" are CH3CH2CO, Y is CH=CHCH2CH2 ] was prepared from 12.5 g. of 6-(3,4-methylenedioxyphenyl)-3-hexenyl iodide (Preparation D2) and 12.5 g. of the lithium salt of 3,5-heptanedione in 175 ml. of dimethylformamide. The product was chromatographed on silica gel and eluted with pentane-benzene (1:1) and then with chloroform-benzene (7:3). The latter brought out 7.0 g. of 4-[6-(3,4-methylenedioxyphenyl)-3-hexenyl]-3,5-heptanedione as a light amber oil.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([N:14]2[CH2:19][CH2:18][CH:17]([N:20]3[CH2:25][CH2:24][NH:23][C:22](=[O:26])[CH2:21]3)[CH2:16][CH2:15]2)[CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12].[F:27][CH2:28][CH2:29]I>CN(C=O)C.C1COCC1>[F:27][CH2:28][CH2:29][N:23]1[CH2:24][CH2:25][N:20]([CH:17]2[CH2:18][CH2:19][N:14]([C:7]3[CH:8]=[CH:9][C:10]([N+:11]([O-:13])=[O:12])=[C:5]([O:4][CH3:3])[CH:6]=3)[CH2:15][CH2:16]2)[CH2:21][C:22]1=[O:26]
Reactant: COc1cc(N2CCC(N3CCNC(=O)C3)CC2)ccc1[N+](=O)[O-]
Reactant: FCCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cc(N2CCC(N3CCN(CCF)C(=O)C3)CC2)ccc1[N+](=O)[O-]
Reaction time: 0.75 h
Yield: 75.6 %

Procedure:
NaH (60% dispersion in mineral oil, 0.174 g, 4.35 mmol) was washed two times with hexanes. 10 mL of DMF and 5 mL of THF was added via syringe. 4-{1-[3-(Methyloxy)-4-nitrophenyl]-4-piperidinyl}-2-piperazinone (0.970 g, 2.90 mmol) in 20 mL of DMF and 10 mL of THF was added slowly via syringe. The reaction was stirred for 45 min, and 1-fluoro-2-iodoethane (0.28 mL, 3.4 mmol) was added via syringe. The reaction was stirred overnight and quenched by the addition of H2O. The mixture was poured into EtOAc and H2O, and the layers were separated. The organic layer was washed with brine, and the combined aqueous layers were extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography to afford 0.834 g (76%) of the title compound of step B. 1H NMR (400 MHz, DMSO-d6) δ 7.83 (d, J=9.0 Hz, 1H), 6.55 (dd, J=9.4, 2.5 Hz, 1H), 6.46 (d, J=2.4 Hz, 1H), 4.55 (t, J=4.9 Hz, 1H), 4.44 (t, J=4.9 Hz, 1H), 4.07-3.94 (m, 2H), 3.86 (s, 3H), 3.58 (t, J=4.9 Hz, 1H), 3.51 (t, J=5.1 Hz, 1H), 3.34-3.22 (m, 2H), 3.11 (s, 2H), 2.99-2.86 (m, 2H), 2.68 (t, J=5.2 Hz, 2H), 2.57-2.46 (m, 1H), 1.89-1.76 (m, 2H), 1.49-1.32 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:10]([C:35]#[N:36])=[C:11]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:34])[CH3:33])[CH:26]=3)[S:12][C:13]=2[C:14]2[N:18]=[CH:17][N:16]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][O:20]3)[N:15]=2)=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:45])C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([C:9]2[C:10]([C:35]#[N:36])=[C:11]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:34])[CH3:33])[CH:26]=3)[S:12][C:13]=2[C:14]2[N:18]=[CH:17][N:16]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][O:20]3)[N:15]=2)=[O:45])=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)Nc1cc(-c2sc(-c3ncn(C4CCCCO4)n3)c(Sc3ccc(Cl)cc3)c2C#N)ccn1
Solvent: ClCCl
Product: CC(=O)Nc1cc(-c2sc(-c3ncn(C4CCCCO4)n3)c(S(=O)c3ccc(Cl)cc3)c2C#N)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.8 %

Procedure:
N-(4-{4-[(4-chlorophenyl)sulfanyl]-3-cyano-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-2-thienyl}pyridin-2-yl)acetamide (0.0575 g, 0.107 mmol) was dissolved in methylene chloride (5.00 mL), followed by addition of m-chloroperbenzoic acid (0.0194 g, 0.112 mmol). The reaction mixture was stirred at room temperature for 1 hr. The solution was concentrated, and purified by column chromatography. The eluent was 50-100% ethyl acetate in hexane to yield a solid product (0.0324 g, 54.7%) LCMS: (AA) ES+ 553, 555. 1H NMR (300 MHz, CDCl3) δ: 8.47 (m, 2H), 8.41 (s, 1H), 8.36 (d, 1H), 8.06 (dd, 2H), 7.46 (dd, 2H), 7.45 (d, 1H), 5.53-5.59 (dd, 1H), 4.08-4.16 (m, 1H), 3.73-3.81 (m, 1H), 2.25 (s, 3H), 2.10-2.18 (m, 1H), 2.00-2.07 (m, 2H), 1.69-1.80 (m, 3H).
Reaction SMILES: Cl[C:2]1[S:10][C:9]2[C:8]([C:11]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[O:12])=[N:7][C:6]([NH:18][CH2:19][C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[N:5][C:4]=2[CH:3]=1.[CH3:26][NH:27][CH3:28].O>CC(N(C)C)=O>[CH3:26][N:27]([CH3:28])[C:2]1[S:10][C:9]2[C:8]([C:11]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[O:12])=[N:7][C:6]([NH:18][CH2:19][C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[N:5][C:4]=2[CH:3]=1
Reactant: O=C(c1cccs1)c1nc(NCc2cccnc2)nc2cc(Cl)sc12
Reactant: CNC
Solvent: CC(=O)N(C)C
Solvent: O
Product: CN(C)c1cc2nc(NCc3cccnc3)nc(C(=O)c3cccs3)c2s1
Temperature: 170 °C
Reaction time: 0.25 h
Yield: 42 %

Procedure:
A stirred solution of Example 5 (0.02 g, 0.052 mmol) in dimethylacetamide (1.5 ml) was treated with dimethylamine (2.0M in THF, 0.52 mmol). The solution was heated to 170° C. for 30 min in a microwave reactor. The cooled solution was poured onto stirred iced water (20 ml). After 15 min stirring, an orange solid was filtered. Recrystallisation from hot ethyl acetate gave the title compound in 42% yield, >95% purity. LC-MS m/z=396.0 [M+H]+; RT=2.97; LC-MS method 1. 1H NMR: δH (400 MHz, D6-DMSO) 3.13 (6H, s), 4.68 (2H, bd), 5.91 (1H, s), 7.26-8.61 (8H, m).
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]3[NH:23][CH2:22][CH2:21][C:20]([C:24]([O:26][CH3:27])=[O:25])=[CH:19][C:18]=3[CH:28]=2)=[CH:10][CH:9]=1)[CH2:2][CH3:3].[CH:29]1([CH:32]=O)[CH2:31][CH2:30]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCCl.O>[CH:29]1([CH2:32][N:23]2[C:17]3[CH:16]=[CH:15][C:14]([C:11]4[CH:12]=[CH:13][C:8]([O:7][CH2:6][CH2:5][O:4][CH2:1][CH2:2][CH3:3])=[CH:9][CH:10]=4)=[CH:28][C:18]=3[CH:19]=[C:20]([C:24]([O:26][CH3:27])=[O:25])[CH2:21][CH2:22]2)[CH2:31][CH2:30]1
Reactant: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3)cc1
Reactant: O=CC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3CC2CC2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.3 %

Procedure:
In 1,2-dichloroethane (5 ml) were dissolved methyl 7-[4-(2-propoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.3 g) and cyclopropanecarboaldehyde (0.22 g). To the solution was added sodium triacetoxyborohydride (0.33 g), and the mixture was stirred under nitrogen atmosphere at room temperature for 4 hours, poured into water, neutralized with sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated to give methyl 1-cyclopropylmethyl-7-[4-(2-propoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.34 g) as yellow oil.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:42])[NH:17][CH2:18][C:19]3[N:20]([CH2:38][CH:39]([CH3:41])[CH3:40])[C:21](=[O:37])[C:22]4[C:27]([C:28]=3[O:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:26][C:25]([C:34]([NH2:36])=[S:35])=[CH:24][CH:23]=4)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[CH2:44][C:45](=O)[C:46]([O:48][CH2:49][CH3:50])=[O:47].O>C(O)C>[CH2:30]([O:29][C:28]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:34]3[S:35][CH:44]=[C:45]([C:46]([O:48][CH2:49][CH3:50])=[O:47])[N:36]=3)[CH:26]=2)[C:21](=[O:37])[N:20]([CH2:38][CH:39]([CH3:41])[CH3:40])[C:19]=1[CH2:18][NH:17][C:16]([O:15][CH2:14][CH:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)=[O:42])[CH2:31][CH2:32][CH3:33]
Reactant: CCCCOc1c(CNC(=O)OCC2c3ccccc3-c3ccccc32)n(CC(C)C)c(=O)c2ccc(C(N)=S)cc12
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCO
Solvent: O
Product: CCCCOc1c(CNC(=O)OCC2c3ccccc3-c3ccccc32)n(CC(C)C)c(=O)c2ccc(-c3nc(C(=O)OCC)cs3)cc12
Yield: 88.3 %

Procedure:
A solution of 9H-fluoren-9-ylmethyl[6-(aminocarbothioyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.29 g, 0.5 mmol) and ethyl bromopyruvate (0.19 g, 1 mmol) in ethanol (10 ml) was refluxed under heating for 1 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from ethyl acetate-diisopropyl ether to give ethyl 2-[4-butoxy-3-[[[(9H-fluoren-9-ylmethoxy)carbony]amino]methyl]-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-1,3-thiazole-4-carboxylate (0.30 g, 90.9%) as crystals.
Reaction SMILES: [CH3:1][CH:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)[N:3]1[S:25]([C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=1)(=[O:27])=[O:26].[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39]>C(Cl)Cl>[F:41][C:40]([F:43])([F:42])[C:38]([OH:44])=[O:39].[CH3:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]2)[N:3]1[S:25]([C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=1)(=[O:27])=[O:26]
Reactant: CC1C=Cc2c(N3CCN(C(=O)OC(C)(C)C)CC3)cccc2N1S(=O)(=O)c1ccc2ccccc2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1CCc2c(N3CCNCC3)cccc2N1S(=O)(=O)c1ccc2ccccc2c1
Reaction time: 0.5 h

Procedure:
The compound prepared in example 8 (260 mg, 0.62 mmol) was dissolved in a mixture of 1 mL TFA and 4 mL CH2Cl2 and stirred for 30 min. The solvent was evaporated and the crude product was purified by a short silica gel column (using CH2Cl2-MeOH 98:2 as eluent). Yield: 180 mg (85.6%) Rf=0.38 (CH2Cl2-MeOH 9:1).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:17]2[CH:26]=[C:25]3[C:20]([C:21](=[O:35])[N:22]([CH2:27][O:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[CH:23]=[N:24]3)=[CH:19][C:18]=2[O:36][CH3:37])[CH2:10][CH2:9]1)=O)(C)(C)C.O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:17]2[CH:26]=[C:25]3[C:20]([C:21](=[O:35])[N:22]([CH2:27][O:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:31])[CH3:32])[CH:23]=[N:24]3)=[CH:19][C:18]=2[O:36][CH3:37])[CH2:10][CH2:9]1
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCCC1CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
A solution of 7-(2-(1-tertbutoxycarbonylpiperidin-4-yl)ethoxy)-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (10.5 g, 20 mmol) in methylene chloride (100 ml) containing TPA (25 ml) was stirred for 1 hour at ambient temperature. Water (50 ml) and methylene chloride (100 ml) were added and the pH of the aqueous layer was adjusted to 8 with solid sodium hydrogen carbonate. The organic layer was separated, washed with water, brine, dried (MgSO4) and evaporated. The residue was triturated with ether and the solid was filtered and dried under vacuum to give 7-(2-(piperidin-4-yl)ethoxy)-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (8.3 g, 100%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]23[CH2:24][CH:16]([C:17]4[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][C:22]=42)[C:15]2[C:10]3=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:4][CH2:3]1.N1C=CC=CC=1.[CH:31]1([CH2:36][C:37](Cl)=[O:38])[CH2:35][CH2:34][CH2:33][CH2:32]1.[OH-].[Na+]>C(Cl)Cl>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]2[CH:16]3[CH2:24][C:9]([CH2:8][N:5]4[CH2:6][CH2:7][CH:2]([NH:1][C:37](=[O:38])[CH2:36][CH:31]5[CH2:35][CH2:34][CH2:33][CH2:32]5)[CH2:3][CH2:4]4)([C:10]4[C:15]3=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:22]=2[CH:21]=1
Reactant: NC1CCN(CC23CC(c4ccccc42)c2ccc(Cl)cc23)CC1
Reactant: O=C(Cl)CC1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(CC1CCCC1)NC1CCN(CC23CC(c4ccccc42)c2ccc(Cl)cc23)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71.9 %

Procedure:
To a stirred cold (ice bath) solution of 4-amino-1-[2-chloro-9,10-dihydro-9,10-methanoanthracen-9-ylmethyl]piperidine (339 mg, 1 mmol, described in Example 7b) and pyridine (158 mg, 2 mmol) in methylene chloride (6.7 mL) was added cyclopentylacetyl chloride (161 mg, 1.1 mmol). After 15 min, the reaction was allowed to warm to ambient temperature and stirred for 18 h. The reaction was added methylene chloride (75 mL) and 1N sodium hydroxide (50 mL). The aqueous layer was extracted with methylene chloride (50 mL). The organic layers were combined and washed with 1N sodium hydroxide (2×50 mL), brine (35 mL) and dried (sodium sulfate). The solution was filtered and concentrated to give a foam. This material was chromatographed over silica gel (eluting in sequence with 1) methylene chloride; 2) 3:97 methanol:methylene chloride) and crystallized with ether to give the title compound as a white solid (323 mg, 72%), mp 149.5°-150.5° C.; MS(CI): 449 (M+H); NMR (300 MHz,DMSO-d6): 1.02-1.17(m, 2H), 1.26-1.74(m, 10H), 2.01(d, 2H, 2H, J=6.0 Hz), 2.09(m, 1H), 2.18-2.32(m, 2H), 2.47(m, 2H), 2.86-3.00(m, 2H), 3.28(d, 1H, J=14 Hz), 3.37(d, 1H, J=14 Hz), 3.54(m, 1H), 4.33(s, 1H), 6.89-7.00(m, 3H), 7.15-7.31(m, 4H), 7.61(d, 1H, J=7.7 Hz).
Reaction SMILES: Br.[CH2:2]([NH:4][C:5](=[O:16])[C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11](=[O:15])[C@H:12]([CH3:14])[NH2:13])[CH3:3].[OH-].[Na+].[CH:19]1([C:25](Cl)=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>ClCCl>[CH2:2]([NH:4][C:5](=[O:16])[C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11](=[O:15])[C@H:12]([CH3:14])[NH:13][C:25]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:26])[CH3:3]
Reactant: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](C)N
Reactant: O=C(Cl)C1CCCCC1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)C1CCCCC1
Reaction time: 1 h
Yield: 60 %

Procedure:
1.25 g (0.00425 mol) of L-alanyl-L-proline ethylamide hydrobromide were suspended in 20 ml of dichloromethane and to the suspension were added 17.84 ml (0.00892 mol) of 0.5-N sodium hydroxide solution followed by 0.62 ml (1.1 equivalents) of cyclohexane carboxylic acid chloride. The mixture was stirred vigorously for 1 hour. The solution was diluted with 80 ml of dichloromethane, the organic layer was separated, washed with 60 ml of brine, dried over magnesium sulphate and evaporated to give a solid. Recrystallisation from ethyl acetate yielded 0.83 g (60%) of N-cyclohexylcarbonyl-L-alanyl-L-proline ethylamide of melting point 190.5°-191.5° C.; [α]D20 =-116.0° (c=1.055% in methanol).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([CH2:16][C:17]4[CH:18]=[C:19]([NH2:24])[C:20]([NH2:23])=[CH:21][CH:22]=4)=[N:14][N:15]=3)[N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:25](O)=O>>[N:23]1[C:20]2[CH:21]=[CH:22][C:17]([CH2:16][C:13]3[N:11]4[N:12]=[C:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[CH:8]=[CH:9][C:10]4=[N:15][N:14]=3)=[CH:18][C:19]=2[NH:24][CH:25]=1
Reactant: O=CO
Reactant: Nc1ccc(Cc2nnc3ccc(-c4ccccc4)nn23)cc1N
Product: c1ccc(-c2ccc3nnc(Cc4ccc5nc[nH]c5c4)n3n2)cc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 73 %

Procedure:
A suspension of 4-(6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylmethyl)-benzene-1,2-diamine (20 mg, 0.063 mmol) in formic acid (0.5 mL) was stirred at 100° C. for 5 h. The reaction mixture was cooled to room temperature and filtered through a 0.45 micron filter. The filtrate was concentrated in vacuo. The residue was purified by preparative HPLC on Xbridge prep C18 column (5 microns, 19×150 mm) using a formic acid buffered gradient of acetonitrile in water to return the title compound as an off-white solid (15 mg, 0.046 mmol, 73% yield). Analytical data presented in Table 1.
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([O:10][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][C:3]1([CH3:20])[CH3:19].[C:21]1([CH3:37])[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[N:29][C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)=[CH:23][CH:22]=1>C1COCC1>[C:33]1([CH3:36])[CH:34]=[CH:35][C:30]([NH:29][C:28]([O:1][N:2]2[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([O:10][C:11](=[O:18])[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:4][C:3]2([CH3:20])[CH3:19])=[N:27][C:24]2[CH:23]=[CH:22][C:21]([CH3:37])=[CH:26][CH:25]=2)=[CH:31][CH:32]=1
Reactant: Cc1ccc(N=C=Nc2ccc(C)cc2)cc1
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1O
Solvent: C1CCOC1
Product: Cc1ccc(N=C(Nc2ccc(C)cc2)ON2C(C)(C)CC(OC(=O)c3ccccc3)CC2(C)C)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 63.3 %

Procedure:
1-Hydroxy-4-benzoyloxy-2,2,6,6-tetramethylpiperidine (5.75 g, 20.7 mmol) [prepared as described in Example 6] and di-p-tolylcarbodiimide (4.8 g, 21.6 mmol) are dissolved in THF (40 ml) and the solution is stirred at room temperature for 17 hours. The solvent is evaporated and the residue is chromatographed on silica gel with hexane-ethyl acetate (9:1). The pure fractions are recrystallized from acetonitrile to afford 6.55 g of the title compound as a colorless solid, mp. 124-128° C.