Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:7]([O:14][N:15]1[C:24](=[O:25])[C:23]2[CH:26]=[C:27]([Br:32])[C:28]([N+:29]([O-])=O)=[C:21]3[C:22]=2[C:17](=[CH:18][CH:19]=[CH:20]3)[C:16]1=[O:33])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:34]([O:41][N:42]1[C:51](=[O:52])[C:50]2[CH:53]=[C:54]([Br:56])[CH:55]=[C:48]3[C:49]=2[C:44](=[CH:45][CH:46]=[C:47]3[N+:57]([O-])=O)[C:43]1=[O:60])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C=O)C>[CH2:7]([O:14][N:15]1[C:24](=[O:25])[C:23]2[CH:26]=[C:27]([Br:32])[C:28]([N:29]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[C:21]3[C:22]=2[C:17](=[CH:18][CH:19]=[CH:20]3)[C:16]1=[O:33])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:34]([O:41][N:42]1[C:51](=[O:52])[C:50]2[CH:53]=[C:54]([Br:56])[CH:55]=[C:48]3[C:49]=2[C:44](=[CH:45][CH:46]=[C:47]3[N:57]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:43]1=[O:60])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: C1CCNCC1
Reactant: O=C1c2ccc([N+](=O)[O-])c3cc(Br)cc(c23)C(=O)N1OCc1ccccc1
Reactant: O=C1c2cccc3c([N+](=O)[O-])c(Br)cc(c23)C(=O)N1OCc1ccccc1
Solvent: CN(C)C=O
Product: O=C1c2ccc(N3CCCCC3)c3cc(Br)cc(c23)C(=O)N1OCc1ccccc1
Product: O=C1c2cccc3c(N4CCCCC4)c(Br)cc(c23)C(=O)N1OCc1ccccc1
Temperature: 120 °C

Procedure:
To a solution of piperidine (0.40 g, 4.7 mmol) in 5 mL of DMF was added a mixture of 2-benzyloxy-5-bromo-6-nitro-benzo[de]isoquinoline-1,3-dione (A) and 2-benzyloxy-5-bromo-7-nitro-benzo[de]isoquinoline-1,3-dione (B) (0.50 g, 1.2 mmol, from Example S1-A,B). The reaction was heated to 120° C. for 4 hours, cooled, and the solvent removed under vacuum. The residue was chromatographed using chloroform/ethyl acetate (10:1) to give a mixture of the title compounds which were separated by crystallization from chloroform/hexane/ethyl acetate (5:5:1) to give 0.27 g of 2-benzyloxy-5-bromo-6-(piperidin-1-yl)-benzo[de]isoquinoline-1,3-dione (A) and 0.10 g of 2-benzyloxy-5-bromo-7-(piperidin-1-yl)-benzo[de]isoquinoline-1,3-dione (B).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][O:15][C:14]2[CH:18]=[C:19]([S:22]([NH:25][C:26]3[S:30][N:29]=[CH:28][N:27]=3)(=[O:24])=[O:23])[CH:20]=[CH:21][C:13]1=2.B1([C:40]2[CH2:45][CH2:44][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:42][CH:41]=2)OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[S:30]1[C:26]([NH:25][S:22]([C:19]2[CH:20]=[CH:21][C:13]3[N:12]([C:3]4[CH:4]=[CH:5][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]=4[C:40]4[CH2:45][CH2:44][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:42][CH:41]=4)[CH2:17][CH2:16][O:15][C:14]=3[CH:18]=2)(=[O:24])=[O:23])=[N:27][CH:28]=[N:29]1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: O=S(=O)(Nc1ncns1)c1ccc2c(c1)OCCN2c1ccc(C(F)(F)F)cc1Br
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC=C(c2cc(C(F)(F)F)ccc2N2CCOc3cc(S(=O)(=O)Nc4ncns4)ccc32)CC1
Temperature: 100 °C
Yield: 29.2 %

Procedure:
A microwave vial was charged with INTERMEDIATE D (0.100 g, 0.192 mmol), (N-tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (Maybridge Chemicals, Cornwall, UK, 0.059 mL, 0.192 mmol), tetrakis(triphenylphosphine)palladium(0) (0.022 g, 0.019 mmol), and K2CO3 (0.133 g, 0.959 mmol). The solids were diluted with dioxane (1.279 mL) and water (0.639 mL), and the reaction was heated under microwave irradiation at 100° C. for 10 minutes (starting material remained, but moved forward). The reaction mixture was diluted with water, and washed with DCM. Equal partitioning between both layers was observed (and an emulsion formed), so the organic and aqueous were combined and concentrated until just the water remained. The aqueous was washed with DCM (×3) and the organics were then combined and dried using a phase separator. After concentration, the material was purified by reverse-phase preparative HPLC (Column: Phenomenex 150×30 mm, 5 micron, C18 column; 0.1% TFA in CH3CN/H2O, gradient 25% to 90% over 20 min) to provide tert-butyl 4-(2-(7-(N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-2H-benzo[b][1,4]oxazin-4(3 H)-yl)-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2 H)-carboxylate (0.035 g, 0.056 mmol) as a light-yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.37 (s, 9 H) 2.16-2.37 (m, 2 H) 3.51-3.72 (m, 4 H) 3.81-3.90 (m, 2 H) 4.22-4.34 (m, 2 H) 5.84 (br. s., 1 H) 6.38-6.46 (m, 1 H) 7.10-7.17 (m, 2 H) 7.56 (d, J=8.31 Hz, 1 H) 7.65 (d, J=2.05 Hz, 1 H) 7.72 (dd, J=8.41, 2.15 Hz, 1 H) 8.42 (s, 1 H). m/z (ESI) 524.0 (Boc group falls off in LCMS).
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:4]([C:5](F)=[O:6])[C:3]=1[C:14](F)=[O:15].FC1(F)C2C(=C(F)C(F)=C(F)C=2F)C(=O)[O:19]1>C(O)(=O)C>[F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:4]2[C:5](=[O:19])[O:6][C:14](=[O:15])[C:3]=12
Reactant: O=C1OC(F)(F)c2c(F)c(F)c(F)c(F)c21
Reactant: O=C(F)c1c(F)c(F)c(F)c(F)c1C(=O)F
Solvent: CC(=O)O
Product: O=C1OC(=O)c2c(F)c(F)c(F)c(F)c21
Yield: 64.3 %

Procedure:
Into a 200 ml glass reactor equipped with a reflux condenser and a stirrer, 50 g (0.207 mol) of the mixture (1:1) of the 3,4,5,6-tetrafluorophthaloyldifluoride and the 3,3,4,5,6,7-hexafluoro-1-[3H]-isobenzofuranone of Example 2, and 50 ml of acetic acid were charged, and the mixture was refluxed for 16 hours with vigorous stirring. Then, the reaction mixture was separated by distillation to obtain 29.3 g of tetrafluorophthalic anhydride. The yield was 64.3%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:18]2[CH:22]=[CH:21][N:20]=[C:19]2[CH2:23]O)=[C:8]([CH:17]=1)[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10])([O-:3])=[O:2].[C:25]1(=[O:35])[NH:29][C:28](=[O:30])[C:27]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:18]2[CH:22]=[CH:21][N:20]=[C:19]2[CH2:23][N:29]2[C:25](=[O:35])[C:26]3=[CH:34][CH:33]=[CH:32][CH:31]=[C:27]3[C:28]2=[O:30])=[C:8]([CH:17]=1)[C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:10])([O-:3])=[O:2]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=C(c1ccccc1)c1cc([N+](=O)[O-])ccc1-n1ccnc1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C(c1ccccc1)c1cc([N+](=O)[O-])ccc1-n1ccnc1CN1C(=O)c2ccccc2C1=O

Procedure:
In the manner given in Example 17, 5-nitro-2-[2-(hydroxymethyl)imidazol-1-yl]benzophenone is treated with phthalimide and triphenylphosphine and finally with diethyl azodicarboxylate to give 5-nitro-2-[2-(phthalimidomethyl)imidazol-1-yl]benzophenone.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[O:12][C:11]([CH3:17])([CH3:16])[CH:10](OC(=O)C)[CH:9]2[N:22]([CH3:27])[S:23]([CH3:26])(=[O:25])=[O:24])[CH2:2][CH2:3][CH3:4].C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1.CC(=O)OCC>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[O:12][C:11]([CH3:16])([CH3:17])[CH:10]=[C:9]2[N:22]([CH3:27])[S:23]([CH3:26])(=[O:24])=[O:25])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc2c(c1)C(N(C)S(C)(=O)=O)C(OC(C)=O)C(C)(C)O2
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCOc1ccc2c(c1)C(N(C)S(C)(=O)=O)=CC(C)(C)O2

Procedure:
A solution of 0.5 g (1.3 mmol) of N-(6-butoxy-3-acetoxy-2,2-dimethylchroman-4-yl)-N-methyl-methanesulfonamide (Example 6) and 1.1 g (7.5 mmol) of DBU in 2.5 ml of toluene was heated at 105° C. for 60 h. The reaction mixture was diluted with EA and washed with hydrochloric acid until the aqueous phase gave an acidic reaction. The mixture was washed with sodium bicarbonate solution, dried over magnesium sulfate and concentrated i. vac., giving 0.3 9 of N-(6-butoxy-2,2-dimethyl-2H-chromen-4-yl)-N-methyl-methanesulfonamide; m.p. 114-116° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[NH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[N:10]1([CH2:6][C:5]2[CH:8]=[CH:9][C:2]([OH:1])=[CH:3][CH:4]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: C1CCNC1
Reactant: O=Cc1ccc(O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Oc1ccc(CN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 4-hydroxylbenzaldehyde (10 g, 81.9 mmol) in anhydrous CH2Cl2 (500 mL) at RT, under N2, pyrrolidine (10.2 mL, 122.9 mmol) was added, followed by NaBH(OAc)3 (34.6 g, 163.9 mmol) and AcOH (19.7 g, 327.8 mmol). After the mixture was stirred at RT for 24 h, a saturated solution of NaHCO3(aq) (150 mL) was added. The mixture was vigorously stirred for an additional 1 h and then extracted with CH2Cl2 (3×200 mL). The combined organic layer was washed with brine (300 mL), dried over MgSO4, filtered and concentrated under reduced pressure to yield the title compound as amber oil. This was used crude in the next step. MS m/z: 178 (M+1). Calc'd for C11H15NO-177.2.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[C:14]([O:18][CH2:19][CH3:20])(=[O:17])[C:15]#[CH:16].CCN(CC)CC>C1(C)C=CC=CC=1.CCOC(C)=O>[CH2:19]([O:18][C:14]([C:15]1[O:1][N:2]=[C:3]([C:4]2[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=2)[CH:16]=1)=[O:17])[CH3:20]
Reactant: C#CC(=O)OCC
Reactant: O=[N+]([O-])c1ccc(C(Cl)=NO)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(-c2ccc([N+](=O)[O-])cc2)no1
Temperature: 80 °C
Yield: 51.5 %

Procedure:
To a solution of N-hydroxy-4-nitro-benzimidoyl chloride (2.0 g; 10 mmol) and ethyl propiolate (2.02 ml; 20 mmol) in toluene (25 ml) was added Et3N (1.46 ml; 10.5 mmol) drop wise for 10 minutes. The resulting reaction mixture was heated at 80° C. for 2.5 hours, and then diluted with EtOAc (50 ml) and transferred in a separating funnel. The EtOAc layer was washed with 0.1N HCl (10 ml) followed by water (3×10 ml) and brine (10 ml). The EtOAc layer was dried over anhydrous Na2SO4, solvent was evaporated and the residue was crystallized from CHCl3 and light petroleum to afford the title compound of step 1 (1.35 g; 51.7%). Mass (ES+), 263 (M++1); 1H NMR (CDCl3) δ: 1.45 (t, 3H), 4.48 (q, 2H), 7.26 (s, 1H), 8.02 (d, 2H), 8.35 (d, 2H).
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3C(OC(C)(C)C)=O)[S:11][CH:12]=2)=[CH:4][C:3]1=[O:25].[ClH:26]>C(Cl)Cl.O1CCOCC1>[ClH:26].[CH3:1][N:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C@H:13]3[CH2:17][CH2:16][CH2:15][NH:14]3)[S:11][CH:12]=2)=[CH:4][C:3]1=[O:25]
Reactant: Cn1ccc(-c2csc([C@H]3CCCN3C(=O)OC(C)(C)C)n2)cc1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cn1ccc(-c2csc([C@H]3CCCN3)n2)cc1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(R)-tert-butyl 2-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)thiazol-2-yl)pyrrolidine-1-carboxylate (131 mg,) was dissolved in CH2Cl2 (5 mL) and 4 M HCl in dioxane (5 mL) was added. The mixture was stirred at rt for 3 h and concentrated to afford (R)-1-methyl-4-(2-(pyrrolidin-2-yl)thiazol-4-yl)pyridin-2(1H)-one HCl salt (127 mg) as an off-white solid. LC-MS Method 1 tR=0.40 min, m/z=262.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:21])[CH:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH3:14])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:23]1[CH2:28][CH2:27][CH2:26][C@@H:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:24]1>C(O)(CC)C>[Br:1][C:2]1[C:3]([N:23]2[CH2:28][CH2:27][CH2:26][C@@H:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])[CH2:24]2)=[C:4]2[C:10]([NH:11][C:12](=[O:21])[CH:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH3:14])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: CC(C(=O)Nc1c[nH]c2ncc(Br)c(F)c12)c1ccccc1
Solvent: CCC(C)O
Product: CC(C(=O)Nc1c[nH]c2ncc(Br)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)c12)c1ccccc1
Yield: 55.8 %

Procedure:
N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-phenylpropanamide (170 mg, 0.469 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (282 mg, 1.41 mmol) in s-BuOH (5 mL) were heated to 135° C. in a sealed tube for 24 hours. After cooling down, the residue was concentrated and purified by reverse phase chromatography (SP4, 25M, water/ACN 80/20→0/100, 30 CV) to yield tert-butyl (3R)-1-(5-bromo-3-(2-phenylpropanamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (142 mg, 55.8% yield) as a solid.
Reaction SMILES: [CH:1]1([C:4](OC)=O)C[CH2:2]1.[Cl:8][C:9]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=O.[NH2:18][C:19]1[CH:23]=[CH:22][NH:21][N:20]=1>>[C:19]([C:23]1[CH:11]([C:10]2[CH:13]=[CH:14][CH:15]=[C:16]([Cl:17])[C:9]=2[Cl:8])[C:23]2[C:19](=[N:20][NH:21][CH:22]=2)[NH:18][C:22]=1[CH:4]1[CH2:1][CH2:2]1)#[N:18]
Reactant: O=Cc1cccc(Cl)c1Cl
Reactant: COC(=O)C1CC1
Reactant: Nc1cc[nH]n1
Product: N#CC1=C(C2CC2)Nc2n[nH]cc2C1c1cccc(Cl)c1Cl

Procedure:
The title compound was prepared from methyl cyclopropanecarboxylate, 2,3-dichlorobenzaldehyde and 3-aminopyrazole in the same manner as in Example 94.
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[Br:7][C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[C:15]=1O)[C:11]#[N:12]>CN(C=O)C>[Br:7][C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[C:15]=1[Cl:4])[C:11]#[N:12]
Reactant: N#Cc1cc(Br)c(O)c([N+](=O)[O-])c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: N#Cc1cc(Br)c(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 79.9 %

Procedure:
(I1C): DMF (2 mL) was cooled to −20° C. and treated gradually in dropwise manner with oxalyl chloride (0.216 mL, 2.469 mmol). After 10 min, a solution of 3-bromo-4-hydroxy-5-nitrobenzonitrile (200 mg, 0.823 mmol) in DMF (2 mL) was added slowly via syringe while maintaining internal temperature below −10° C. After addition, the mixture was allowed to warm to room temperature and then heated at 100° C. for 1.5 h. The reaction mixture was cooled and poured into ice-water; the solid was collected by filtration, rinsed with water and dried to give 172 mg of 3-bromo-4-chloro-5-nitrobenzonitrile as tan solid. 1H NMR (400 MHz, CHLOROFORM-d) ppm 8.13 (1H, d, J=1.76 Hz), 8.02 (1H, d, J=1.98 Hz)
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1.CO[CH:14](OC)[CH2:15][C:16](=O)[CH3:17].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[CH:15][C:16]([CH3:17])=[N:11]2)=[CH:6][CH:5]=1
Reactant: COc1ccc(NN)cc1
Reactant: COC(CC(C)=O)OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COc1ccc(-n2ccc(C)n2)cc1

Procedure:
A mixture of 17 parts of (4-methoxyphenyl)hydrazine hydrochloride, 14 parts of 4,4-dimethoxy-2-butanone, 14 parts of potassium carbonate and 240 parts of ethanol is stirred and refluxed for 2 hours. The reaction mixture is evaporated and the residue is stirred and refluxed for 1 hour with 200 parts of a hydrochloric acid solution 10%. The solvent is evaporated and the residue is neutralized with ammonium hydroxide. The product is extracted three times with 2,2'-oxybispropane. The combined extracts are washed with water, dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using trichlormethane as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from hexane. The product is filtered off and dried, yielding 2.4 parts of 1-(4-methoxyphenyl)-3-methyl-1H-pyrazole.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[CH2:17][CH2:16][C@@:15]2([CH3:23])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1.C(N(CC)CC)C.[F:31][C:32]([F:40])([C:36]([F:39])([F:38])[F:37])[C:33](Cl)=[O:34].Cl>CN(C)C1C=CN=CC=1.ClCCl.CCOCC>[F:31][C:32]([F:40])([C:36]([F:39])([F:38])[F:37])[C:33]([O:1][C@@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[CH2:17][CH2:16][C@@:15]2([CH3:23])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1)=[O:34]
Reactant: O=C(Cl)C(F)(F)C(F)(F)F
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOCC
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](OC(=O)C(F)(F)C(F)(F)F)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 0 °C

Procedure:
To an ice-cooled, stirred mixture of 3α-hydroxy-5α-pregnan-20-one (260 mg, 318.5 g/m, 0.82 mmol), triethylamine (0.17 mL), and 4-dimethylaminopyridine (DMAP catalytic, 10 mg, 122.17 g/m, 82 umol) dissolved in 17 mL of dry dichloromethane under a nitrogen atmosphere was added pentafluoropropionyl chloride (168 mg, 182.5 g/m 0.92 mmol). The reaction was stirred at 0° C. for 10 hours and then poured into 100 mL of 10% HCl and 200 mL of ether. The organic phase was washed once more with acid, twice with saturated sodium bicarbonate, and then dried over magnesium sulfate. After removal of solvent in vacuo, the crude product was purified by filtration through a bed of silica gel with hexane/ethyl acetate (15:35) elution. The product was isolated from the two earliest fractions (100 mL each) to give (330 mg, 464.5 g/m, 0.71 mmol, 87%).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][CH2:8][C:7]([C:18]3[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=3)([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[CH2:6]2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:32](Cl)(=[O:35])[CH2:33][CH3:34]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][CH2:8][C:7]([C:18]3[CH:19]=[C:20]([O:24][C:32](=[O:35])[CH2:33][CH3:34])[CH:21]=[CH:22][CH:23]=3)([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[CH2:6]2)[CH2:3][CH2:2]1
Reactant: CCC(=O)Cl
Reactant: Cc1ccc(C2(c3cccc(O)c3)CCCN(CC3CC3)C2)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)Oc1cccc(C2(c3ccc(C)cc3)CCCN(CC3CC3)C2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 102.4 %

Procedure:
To a solution of 3-(1-cyclopropylmethyl-3-p-tolyl-piperidin-3-yl)-phenol (65 mg, 0.15 mmol) in CH2Cl2 (2 ml) at room temperature were added DMAP (18 mg, 0.15 mmol), triethylamine (0.071 mL, 0.52 mmol) and propionyl chloride (0.038 mL, 0.45 mmol). The reaction mixture was stirred at room temperature for 12 hours. The reaction was partitioned between 5 mL CH2Cl2 and 5 mL of aqueous saturated NaHCO3. The aqueous layer was washed with CH2Cl2 (3×5 mL), dried over Na2SO4 and concentrated. Purification by flash chromatography with hexanes/EtOAc (1:1) afforded 58 mg of propionic acid 3-(1-cyclopropylmethyl-3-p-tolyl-piperidin-3-yl)-phenyl ester. 1HNMR (400 MHz, CDCl3) δ 7.33 (d, 2H), 7.26-7.19 (comp, 3H), 7.16-7.03 (comp, 2H), 6.89-6.86 (m, 1H), 3.59-3.43 (comp, 2H), 3.35-3.19 (comp, 2H), 2.59-2.53 (q, 2H), 2.52-2.41 (comp, 2H), 2.27-2.18 (comp, 4H), 1.57-1.44 (comp, 2H), 1.31-1.19 (t, 3H), 1.18-1.09 (comp, 3H), 1.08-1.01 (comp, 3H), 100-0.91 (m, 1H), 0.59-0.49 (comp, 2H), 0.19-0.11 (comp, 1H); MS (M+1) 463.3.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:26]=[C:25]([O:27][C@@H:28]3[CH2:32][C@H:31]([O:33]C4CCCCO4)[CH:30]=[CH:29]3)[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>C(O)(=O)C.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][N:14]([C:17]2[N:26]=[C:25]([O:27][C@@H:28]3[CH2:32][C@H:31]([OH:33])[CH:30]=[CH:29]3)[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)N1CCN(c2nc(O[C@H]3C=C[C@@H](OC4CCCCO4)C3)c3ccccc3n2)CC1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: O=C(OCc1ccccc1)N1CCN(c2nc(O[C@H]3C=C[C@@H](O)C3)c3ccccc3n2)CC1
Yield: 59.7 %

Procedure:
A solution of 2-[4-(benzyloxycarbonyl)piperazin-1-yl]-4-[(1R,4S)-[4-[(RS)-(tetrahydropyran-2-yl)oxy]cyclopent-2-en-1-yl]oxy]quinazoline (12.57 g) in acetic acid (50 ml)--water (12.6 ml) is stirred at 60° C. for 4.5 hours. The reaction mixture is diluted with ethyl acetate and washed with aqueous sodium hydrogen carbonate and water, and then dried over anhydrous magnesium sulfate. The solution is evaporated to dryness under reduced pressure, and the resulting residue is purified by medium pressure liquid column chromatography [eluent, chloroform, (chloroform:methanol=500:1, v/v)] to give 2-[4-(benzyloxycarbonyl) piperazin-1-yl]-4-[(1R,4S)-(4-hydroxycyclopent-2-en-1-yl) oxy] quinazoline (6.31 g) as crystals.
Reaction SMILES: [C:1]([C:9]1[C:10](=[O:20])[N:11]([CH3:19])[C:12](=[O:18])[N:13]([CH3:17])[C:14]=1[CH2:15]Br)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:22][O:23][C:24](=[O:28])[CH2:25][CH2:26][NH2:27].C(N(CC)CC)C>CCO.C(Cl)Cl>[CH3:17][N:13]1[C:14]2=[CH:15][N:27]([CH2:26][CH2:25][C:24]([O:23][CH3:22])=[O:28])[C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:9]2[C:10](=[O:20])[N:11]([CH3:19])[C:12]1=[O:18]
Reactant: COC(=O)CCN
Reactant: Cn1c(CBr)c(C(=O)c2ccccc2)c(=O)n(C)c1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: ClCCl
Product: COC(=O)CCn1cc2c(c1-c1ccccc1)c(=O)n(C)c(=O)n2C

Procedure:
5-Benzoyl-6-(bromomethyl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione (Intermediate C) (3 g, 8.90 mmol), beta alanine methyl ester hydrochloride (1.242 g, 8.90 mmol) and triethylamine (2.480 mL, 17.80 mmol) in EtOH (63.6 mL) was heated to 100° C. for 90 min using microwave radiation. The reaction mixture was diluted with of DCM (80 ml) and washed with water and 0.1M HCl. The organic portion was dried by passing through a phase separating cartridge and concentrated in vacuo to yield the title compound as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]1[N:14]=[C:15]([C:24]([CH3:28])([CH3:27])[CH2:25][NH2:26])[NH:16][C:17]=1[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)[CH:7]=[CH:6]2.[CH3:29][C:30]([N:32]=[C:33]=[O:34])=[O:31]>>[CH3:29][C:30]([NH:32][C:33]([NH:26][CH2:25][C:24]([C:15]1[NH:16][C:17]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[C:13]([C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:9]=2)[N:14]=1)([CH3:28])[CH3:27])=[O:34])=[O:31]
Reactant: COc1ccc2cc(-c3nc(C(C)(C)CN)[nH]c3-c3ccncc3)ccc2c1
Reactant: CC(=O)N=C=O
Product: COc1ccc2cc(-c3nc(C(C)(C)CNC(=O)NC(C)=O)[nH]c3-c3ccncc3)ccc2c1
Yield: 51 %

Procedure:
The title compound (13 mg, 51%) was prepared starting from the product of Example 2 and methylformyl isocyanate using the method described in Example 4; MS(ES) m/e 474 [M+H]+.