Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14](OC)=[CH:13][C:12]=1[N+:19]([O-:21])=[O:20])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[CH2:22]([Sn](CCCC)(CCCC)C=C)[CH2:23]CC>CN(C=O)C.[Cl-].[Cl-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd+2]>[CH2:7]([O:6][P:4]([CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:22]=[CH2:23])=[CH:13][C:12]=1[N+:19]([O-:21])=[O:20])([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CCOP(=O)(COc1ccc(OC)cc1[N+](=O)[O-])OCC
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: [Pd+2]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=Cc1ccc(OCP(=O)(OCC)OCC)c([N+](=O)[O-])c1
Temperature: 60 °C

Procedure:
A solution of 2-diethylphosphonomethyloxy-5-bromonitrobenzene (1 mmole, prepared as in Example 37, Step A) in DMF (5 mL) was treated with tributyl(vinyl)tin (1.2 mmole) and palladium bis(triphenylphosphine) dichloride (0.1 mmole), and the mixture was heated at 60° C. under nitrogen for 6 h. Evaporation and chromatography gave 2-diethylphosphonomethyloxy-5-vinylnitrobenzene as an oil which was subjected to Step B of Example 38, Step B of Example 36, and Step D of Example 34 to give 2-amino-7-ethyl-6-thiocyano-4-phosphonomethoxybenzothiazole (41.1). mp>167° C.(dec.). Anal. Calcd. for C11H12N3O4PS2: C, 38.26; H, 3.50; N, 12.17. Found: C, 37.87; H, 3.47; N, 11.93.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]=[C:10]=[S:11].[NH2:12][CH2:13][C:14]([NH2:16])=[O:15]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10](=[S:11])[NH:12][CH2:13][C:14]([NH2:16])=[O:15]
Reactant: NCC(N)=O
Reactant: S=C=Nc1c(Cl)cccc1Cl
Product: NC(=O)CNC(=S)Nc1c(Cl)cccc1Cl

Procedure:
2-[3-(2,6-Dichlorophenyl)-thioureido]-acetamide was prepared by the procedure described in Example 2 using 40.8 g of 2,6-dichlorophenyl-isothiocyanate and 29.6 g of glycinamide. The product was obtained (54 g) as a solid, m.p. 189°-191° C. Mass spectrum (+FAB, [M+H]+) m/z 278/280/282. This intermediate was used in the next paragraph without further purification.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[NH:10][CH2:9][CH2:8]2)[CH:2]=[CH2:3].Br[CH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1.[H-].[Na+].O>CN(C)C=O>[F:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][CH2:18][CH2:17][N:10]2[CH2:9][CH2:8][C:7]3[C:12](=[CH:13][CH:14]=[C:5]([O:4][CH2:1][CH:2]=[CH2:3])[CH:6]=3)[C:11]2=[O:15])=[CH:21][CH:22]=1
Reactant: C=CCOc1ccc2c(c1)CCNC2=O
Reactant: Fc1ccc(CCCBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1ccc2c(c1)CCN(CCCc1ccc(F)cc1)C2=O

Procedure:
To a solution of 6-allyloxy-1-oxo-1,2,3,4-tetrahydroisoquinoline (10.6 g, 52 mmol) and 1-bromo-3-(4-fluorophenyl)-propane (17 g, 78 mmol) and KI (430 mg, 2.6 mmol) in dimethyl formamide (DMF) (125 mL) is added NaH (3.1 g, 78 mmol). After 4 hours the reaction mixture is poured into H2O (500 mL) and the resulting suspension is extracted with EtOAc (3×300 mL). The combined organic extracts are washed with H2O (5×200 mL), saturated NaCl solution (2×200 mL), dried over MgSO4 and concentrated in vacuo. The residue is chromatographed (silica gel, 1:1 EtOAc/hexane) to yield 2-[3-(4-fluorophenyl)-propyl]-6-allyloxy-1-oxo-1,2,3,4-tetrahydroisoquinoline as a brown oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:6](=[O:7])[C:5]2[CH:8]=[C:9]([N+:14]([O-])=O)[C:10]([CH3:13])=[C:11]([CH3:12])[C:4]=2[O:3]1.C([O-])=O.[NH4+]>CO.[C].[Pd]>[NH2:14][C:9]1[C:10]([CH3:13])=[C:11]([CH3:12])[C:4]2[O:3][C:2]([CH3:1])([CH3:17])[C:6](=[O:7])[C:5]=2[CH:8]=1
Reactant: Cc1c([N+](=O)[O-])cc2c(c1C)OC(C)(C)C2=O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Cc1c(N)cc2c(c1C)OC(C)(C)C2=O
Yield: 92 %

Procedure:
A mixture of 2,2,6,7-tetramethyl-5-nitro-1-benzofuran-3 (2H)-one obtained in Reference Example 46 (5.0 g, 21.3 mmol), 10%-palladium carbon (50% hydrous, 500 mg) and ammonium formate (7.06 g, 85.0 mmol) in methanol (100 mL) was heated under reflux for two hours. The solid material was removed and the filtrate was concentrated under reduced pressure. Water and ethyl acetate were added to the residue to separate the organic layer, and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water, dried over magnesium sulfate and then concentrated under reduced pressure. The solvent was distilled off under reduced pressure to obtain a residue, which was crystallized with ethyl acetate-hexane to obtain 4.0 g (yield 92%) of the title compound. Melting point: 149-150° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][NH:9][CH2:10]2)=[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:4]=1.[CH:19]([O:22][C:23]1[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][C:24]=1[C:25](O)=[O:26])([CH3:21])[CH3:20]>>[CH:19]([O:22][C:23]1[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][C:24]=1[C:25]([N:9]1[CH2:8][CH2:7][C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:10]1)=[O:26])([CH3:21])[CH3:20]
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: COc1cc2c(c(-c3ccccc3)c1)CCNC2
Product: COc1cc2c(c(-c3ccccc3)c1)CCN(C(=O)c1cc(S(C)(=O)=O)ccc1OC(C)C)C2

Procedure:
Prepared in analogy to example 1.1 from 7-methoxy-5-phenyl-1,2,3,4-tetrahydro-isoquinoline and 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.1).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CC#N>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([O:10][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:9])=[CH:11][CH:12]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(OCc1ccccc1)c1ccc([N+](=O)[O-])cc1
Yield: 89.1 %

Procedure:
15.01 g (89.9 mmol) 4-nitrobenzoic acid are suspended in 500 mL MeCN and then combined with 15.03 g (108.7 mmol, 1.2 eq) potassium carbonate. 15.4 g (90.4 mmol, 1.01 eq) benzylbromide are added dropwise with stirring and the reaction mixture is heated for 5 h with stirring at 60° C. It is combined with 750 mL distilled water, extracted 4 times with 250 mL of EE and after the organic phases have been combined dried on sodium sulphate. After all the volatile constituents have been eliminated in vacuo the crude product is suspended twice in succession in toluene and evaporated down in vacuo. 20.6 g (80.1 mmol) benzyl 4-nitrobenzoate are obtained, which is used in the next step without any further purification.
Reaction SMILES: [CH3:1][Mg]Br.[CH3:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12](=O)[C:11](=[CH:17][C:18]([O:20][CH3:21])=[O:19])[CH2:10][CH2:9]2.Cl>C(OCC)C>[CH3:1][C:12]1[C:13]2[C:8](=[CH:7][C:6]([O:5][CH3:4])=[CH:15][CH:14]=2)[CH:9]=[CH:10][C:11]=1[CH2:17][C:18]([O:20][CH3:21])=[O:19]
Reactant: C[Mg]Br
Reactant: COC(=O)C=C1CCc2cc(OC)ccc2C1=O
Agent: Cl
Solvent: CCOCC
Product: COC(=O)Cc1ccc2cc(OC)ccc2c1C
Temperature: 180 °C
Reaction time: 1 h

Procedure:
To a mixture of 12 g. of methyl magnesium bromide and 200 ml. of diethyl ether, 25 g. of 6-methoxy-2-(methoxycarbonylmethylene)-1-tetralone are added. The alkylating mixture is refluxed for one hour after it has been allowed to stand for one hour; the mixture is made acidic to litmus by the addition of 1 N methanolic HCl, filtered, and evaporated. The residue, containing methyl 1-methyl-6-methoxy-3,4-dihydro-2-naphthylacetate, is added to 1 g. of 10% palladium-on-charcoal and the resulting mixture is heated to 180° C. for six hours. The mixture is cooled, diluted with 200 ml. of chloroform, filtered, and evaporated to yield methyl 1-methyl-6-methoxy-2-naphthylacetate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.CS([C:21]1[N:26]=[C:25]([C:27]2[C:28]([CH3:34])=[N:29][C:30]([NH2:33])=[N:31][CH:32]=2)[CH:24]=[CH:23][N:22]=1)=O>C1COCC1>[CH3:34][C:28]1[C:27]([C:25]2[CH:24]=[CH:23][N:22]=[C:21]([NH:1][C:2]3[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=3)[N:26]=2)=[CH:32][N:31]=[C:30]([NH2:33])[N:29]=1
Reactant: Nc1ccncc1
Reactant: Cc1nc(N)ncc1-c1ccnc(S(C)=O)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc(N)ncc1-c1ccnc(Nc2ccncc2)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 1.8 %

Procedure:
To a solution of 4-aminopyridine (423 mg, 4.49 mmol) in THF (0.562 mL) cooled to −10° C. was added LHMDS (1M in THF) (1.123 mL, 1.123 mmol). The resulting suspension was warmed to rt and stirred for 15 minutes, after which time it was cooled back to −10° C. and 2-Methanesulfinyl-4′-methyl-[4,5′]bipyrimidinyl-2′-ylamine (20) (70 mg, 0.281 mmol) was then added. The reaction mixture was again warmed to rt and stirred for 1.5 hours. The reaction was quenched by slow addition of saturated ammonium chloride and the volatiles evaporated. The mixture was then diluted with DCM, the layers separated, and the organic layer washed with brine, dried with sodium sulfate, and concentrated. The crude residue was purified by flash column chromatography with a gradient of 2-20% MeOH in DCM. The product was further purified by reverse phase HPLC with a gradient of 10-90% MeCN in water over 15 minutes, to give the desired product as a white solid (1.39 mg, 0.44%). 1H NMR (400 MHz, MeOD) δ ppm 2.57 (s, 3H) 7.13 (d, J=5.56 Hz, 1H) 7.84 (d, J=6.57 Hz, 2H) 8.30 (d, J=6.57 Hz, 2H) 8.50 (s, 1H) 8.57 (d, J=5.05 Hz, 1H). HRMS (ES+) for C14H13N7.H+ [MH+]: calcd, 280.1311; found, 280.1318. UV-LC: 100/100% UV purity at 214/254 nm; tR=2.93 minutes over 7.75 minutes.
Reaction SMILES: F[C:2]1[CH:15]=[C:14]2[C:5]([N:6]3[C:11]([CH2:12][O:13]2)=[N:10][NH:9][C:8](=[O:16])[CH:7]3[CH3:17])=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19].C([O-])([O-])=O.[K+].[K+].[C:27]1([OH:33])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CC(C)=O>[CH3:17][CH:7]1[N:6]2[C:11]([CH2:12][O:13][C:14]3[C:5]2=[CH:4][C:3]([N+:18]([O-:20])=[O:19])=[C:2]([O:33][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:15]=3)=[N:10][NH:9][C:8]1=[O:16]
Reactant: Oc1ccccc1
Reactant: CC1C(=O)NN=C2COc3cc(F)c([N+](=O)[O-])cc3N21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC1C(=O)NN=C2COc3cc(Oc4ccccc4)c([N+](=O)[O-])cc3N21
Temperature: 25 °C
Reaction time: 48 h
Yield: 23.7 %

Procedure:
A mixture of 7-fluoro-4-methyl-6-nitro-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (0.30 g, 1.07 mmol), K2CO3 (0.296 g, 2.14 mmol) and phenol (0.151 g, 1.61 mmol) in acetone (10 mL) was stirred at ambient temperature for 48 h and then heated to reflux for 3 h. After cooling to ambient temperature, the solvent was removed in vacuo and the residue was partitioned between EtOAc (30 mL) and water (10 mL). The organic portion was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silical gel (eluting with 15% EtOAc in petroleum ether) to give 4-methyl-6-nitro-7-phenoxy-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (0.090 g, 24%) as an orange solid. LC/MS (Table 1, Method 2) Rt=1.117 min; MS m/z: 355 [M+H]+
Reaction SMILES: [CH2:1]([N:3]([CH2:24][CH3:25])[C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]([OH:22])[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:21]=2[N:20]=[CH:19][CH:18]=[CH:17]3)=[CH:7][CH:6]=1)[CH3:2].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl.CCCCCCC>[CH2:24]([N:3]([CH2:1][CH3:2])[C:4](=[O:23])[C:5]1[CH:6]=[CH:7][C:8]([C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:21]=2[N:20]=[CH:19][CH:18]=[CH:17]3)=[O:22])=[CH:9][CH:10]=1)[CH3:25]
Reactant: CCN(CC)C(=O)c1ccc(C(O)c2cccc3cccnc23)cc1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCCCCCC
Product: CCN(CC)C(=O)c1ccc(C(=O)c2cccc3cccnc23)cc1
Reaction time: 24 h
Yield: 60.2 %

Procedure:
16 (3.0 g, 9.0 mmol) was dissolved in CH2Cl2 (25 mL) and powdered pyridinium dichromate (PDC) (5.0 g, 13 mmol) was added portionwise at 25° C. Two more portions of PDC (0.5 g) were added after 3 h and 12 h. After 24 h, the solution was diluted with heptane and filtered through silica gel. Eluton with EtOAc and evaporation in vacuo gave 17 (1.8 g, 60%). MS: 332, 303, 275, 260, 232, 204, 176, 156, 128, 115. 1H NMR (CDCl3): δ1.1, 1.3 (2m, 6H), 3.22, 3.55 (2m, 4H), 7.39 (d, J=8 Hz, 2H), 7.43 (m, 1H), 7.65 (m, 1H), 7.75 (m, 1H), 7.86 (d, J=8 Hz, 2H), 7.98 (m, 1H), 8.23 (m, 1H), 8.83 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([N+:16]([O-:18])=[O:17])=[C:12]([F:15])[CH:13]=2)[NH:8][C:7]=1[CH:19]([CH3:21])[CH3:20])=[O:5])[CH3:2].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([N:8]1[C:9]2[C:14](=[CH:13][C:12]([F:15])=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=2)[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:7]1[CH:19]([CH3:20])[CH3:21])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1c(C(C)C)[nH]c2cc([N+](=O)[O-])c(F)cc12
Product: CCOC(=O)c1c(C(C)C)n(Cc2ccccc2)c2cc([N+](=O)[O-])c(F)cc12

Procedure:
The title compound was prepared from ethyl5-fluoro-2-isopropyl-6-nitro-1H-indole-3-carboxylate (Compound 168) and benzyl bromide by General Procedure J.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.I[CH2:27][C:28]#[N:29]>O1CCCC1>[C:28]([CH2:27][N:16]1[C:17]2[C:12](=[N:11][CH:10]=[C:9]([CH2:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH:18]=2)[C:13]([OH:25])=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]1=[O:19])#[N:29]
Reactant: N#CCI
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC#N)c1=O
Yield: 101.8 %

Procedure:
In a similar manner to that described in example 316 step 1, from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (29 mg, 0.085 mmol) lithium (bis-trimethylsilyl)amide (0.17 mL of a 1 M solution in tetrahydrofuran) and iodoacetonitrile (0.04 mL, 0.51 mmol) was prepared ethyl 1-(cyanomethyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (33 mg, 95% yield) as a yellow oil. Product was carried on without further purification. 1H NMR (CDCl3) δ 8.51 (s, 1 H), 7.40 (s, 1 H), 7.15-7.09 (m, 2 H), 7.01-6.96 (m, 2 H), 5.10 (s, 2 H), 4.46 (m, 2 H), 4.13 (s, 2 H), 1.41 (m, 3 H); MS m/z 404 (M+23).
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:13])=[C:4]([S:9]([NH2:12])(=[O:11])=[O:10])[C:5]([Cl:8])=[CH:6][CH:7]=1.[Cl:14][C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1[N:22]=[C:23]=[O:24]>CN(C)C=O.C(OCC)(=O)C>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:23]([NH:22][C:16]2[CH:17]=[CH:18][CH:19]=[C:20]([Cl:21])[C:15]=2[Cl:14])=[O:24])=[C:3]([OH:13])[C:4]=1[S:9]([NH2:12])(=[O:11])=[O:10]
Reactant: Nc1ccc(Cl)c(S(N)(=O)=O)c1O
Reactant: O=C=Nc1cccc(Cl)c1Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1c(Cl)ccc(NC(=O)Nc2cccc(Cl)c2Cl)c1O
Yield: 73.7 %

Procedure:
A solution of 3-amino-6-chloro-2-hydroxybenzenesulfonamide (0.88 g, 3.9 mmol) and 2,3-dichlorophenylisocyanate (0.62 mL, 4.6 mmol) in 5 mL of N,N-dimethyl-formamide was stirred at room temperature for 20 hours. The mixture was diluted with ethyl acetate and washed with water to give the crude material. Purification by column chromatography on silica gel, eluting with ethyl acetate/hexane (30/70 to 50/50, v/v), followed by recrystallization from dichloromethane and hexane, gave the desired product (1.18 g, 74%). mp 241-242° C.
Reaction SMILES: [CH2:1]=[C:2]1[CH:4]([CH2:5][O:6][C:7](=[O:14])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:3]1[CH2:15][O:16][C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[OH-:25].[Na+].OO>O1CCCC1.C(OCC)(=O)C>[OH:25][CH2:1][CH:2]1[CH:3]([CH2:15][O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:4]1[CH2:5][O:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C=C1C(COC(=O)c2ccccc2)C1COC(=O)c1ccccc1
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(OCC1C(CO)C1COC(=O)c1ccccc1)c1ccccc1
Temperature: 5 °C
Reaction time: 0.33 h
Yield: 46.3 %

Procedure:
A solution of 8.36 g (26 mmol) of 3-Methylene-1,2-bis(benzoyloxymethyl)cyclopropane (from Step C) in tetrahydrofuran (THF) was cooled in an ice-water bath. To this solution was added 26 mL (26 mmol) of a 1 M THF solution of borane-THF complex, and the resultant solution was stirred at 5° C. for 2 h. 3N Sodium hydroxide solution (8.67 mL, 26 mmol) was then added slowly to the reaction mixture at 5° C., followed by 7.8 mL (78 mmol) of 30% aqueous hydrogen peroxide solution. The reaction mixture was stirred for 20 min at 5° C., allowed to warm to ambient temperature and stirred for 30 min at ambient temperature. The reaction mixture was diluted with ethyl acetate, washed 3 times with brine (until the pH of the aqueous layer was approximately 7) and concentrated in vacuo. The residue was purified by column chromatography on a 3×65 cm silica gel column eluted with 2% methanol in chloroform. Fractions numbered 35-47 were combined and concentrated in vacuo to give 4.1 g (46% yield) of 3-Hydroxymethyl-1,2-bis((benzoyl)oxymethyl)cyclopropane. DCI NH3MS, M/Z: 341 (M+H)+, 358 (M+NH4)+.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[CH:5]=[C:4]([C:22]#[N:23])[CH:3]=1.[C:24]([CH2:27][C:28](=O)[CH3:29])(=O)[CH3:25].Cl.C(=O)(O)[O-].[Na+]>C(O)C>[F:14][C:11]1[CH:10]=[CH:9][C:8]([CH:7]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[N:6]2[C:2]3=[N:1][C:24]([CH3:25])=[CH:27][C:28]([CH3:29])=[C:3]3[C:4]([C:22]#[N:23])=[CH:5]2)=[CH:13][CH:12]=1
Reactant: N#Cc1cc(N)n(C(c2ccc(F)cc2)c2ccc(F)cc2)c1
Reactant: CC(=O)CC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(C)c2c(C#N)cn(C(c3ccc(F)cc3)c3ccc(F)cc3)c2n1

Procedure:
To a solution of 5-amino-1-[bis(4-fluorophenyl)methyl]-1H-pyrrole-3-carbonitrile (13.9 g, 45.1 mmol) in ethanol (200 ml) was sequentially added acetylacetone (5.02 g, 50.2 mmol) and concentrated hydrochloric acid (2.0 ml). The mixture was heated under reflux for 3 hours, poured into saturated sodium bicarbonate solution and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give the objective product as a solid material.
Reaction SMILES: [C:1](N1[C@@H](C2C=CC=CC=2)COC1=O)(=O)/C=C/CC.[C:19]([CH2:21][C@@H:22]1[N:26]([C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)[N:25]=[C:24]([C:34]2[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[CH:36][CH:35]=2)[C@H:23]1[CH3:42])#[N:20]>>[C:19]([CH2:21][C@@H:22]1[N:26]([C:27]2[CH:28]=[CH:29][C:30]([OH:33])=[CH:31][CH:32]=2)[N:25]=[C:24]([C:34]2[CH:35]=[CH:36][C:37]([C:38]#[N:39])=[CH:40][CH:41]=2)[C@H:23]1[CH2:42][CH3:1])#[N:20]
Reactant: CC/C=C/C(=O)N1C(=O)OC[C@@H]1c1ccccc1
Reactant: C[C@@H]1C(c2ccc(C#N)cc2)=NN(c2ccc(O)cc2)[C@H]1CC#N
Product: CC[C@@H]1C(c2ccc(C#N)cc2)=NN(c2ccc(O)cc2)[C@H]1CC#N

Procedure:
4-((4S,5S)-5-(Cyanomethyl)-4-ethyl-1-(4-hydroxyphenyl)-4,5-dihydro-1H-pyrazol-3-yl)benzonitrile was prepared from (S,E)-3-(pent-2-enoyl)-4-phenyloxazolidin-2-one following the procedure for the preparation of 4-((4S,5S)-5-(cyanomethyl)-1-(4-hydroxyphenyl)-4-methyl-4,5-dihydro-1H-pyrazol-3-yl)benzonitrile (91G): LC-MS [M+H] 331.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:17](=[O:19])[N:16]([CH2:20][C@@H:21]([OH:24])[CH2:22][OH:23])[CH:15]=[N:14][C:13]=3[N:12]([CH3:25])[C:11](=[O:26])[CH:10]=2)=[C:4]([F:27])[CH:3]=1.C1C(=O)N([Cl:35])C(=O)C1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:17](=[O:19])[N:16]([CH2:20][C@@H:21]([OH:24])[CH2:22][OH:23])[CH:15]=[N:14][C:13]=3[N:12]([CH3:25])[C:11](=[O:26])[C:10]=2[Cl:35])=[C:4]([F:27])[CH:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cn1c(=O)cc(Nc2ccc(Br)cc2F)c2c(=O)n(C[C@@H](O)CO)cnc21
Solvent: ClCCl
Product: Cn1c(=O)c(Cl)c(Nc2ccc(Br)cc2F)c2c(=O)n(C[C@@H](O)CO)cnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Compound 20C (60 mg, 0.136 mmol) was dissolved in 2 mL DCM. NCS (22 mg, 0.165 mmol) was added. The mixture was stirred at room temperature overnight. Example 29 (35.3 mg, 54%) was isolated by preparative HPLC separation. 1H NMR (400 MHz, MeOD) δ 8.50 (s, 1 H) 7.45 (d, J=8.0 Hz, 1 H) 7.38 (d, J=8.0 Hz, 1 H) 7.10 (t, J=8.0 Hz, 1 H) 4.51 (m, 1 H) 4.03 (m, 1 H) 3.88 (m, 1 H), 3.82 (s, 3 H) 3.68 (d, J=4 Hz, 2 H). [M+H] calc'd for C17H15BrClFN4O4, 475; found, 475.
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([NH:24][CH:25]([CH3:27])[CH3:26])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[N:6][CH:5]=1.Cl.O>CO.[OH-].[Na+]>[CH:25]([NH:24][C:23]1[C:18]([N:15]2[CH2:16][CH2:17][N:12]([C:10]([C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:28])=[O:2])=[CH:5][N:6]=3)=[O:11])[CH2:13][CH2:14]2)=[N:19][CH:20]=[CH:21][CH:22]=1)([CH3:27])[CH3:26]
Reactant: COC(=O)c1ccc(C(=O)N2CCN(c3ncccc3NC(C)C)CC2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)O)cn2)CC1
Reaction time: 2 h
Yield: 91 %

Procedure:
6-[1-[3-(Isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]nicotinic acid methyl ester (3 g) was dissolved in methanol (30 ml) and with the addition of aqueous 1N sodium hydroxide (16 ml), the mixture was hydrolyzed at 25°C. for 2 hours. 2N hydrochloric acid was slowly added to the mixture for neutralization (pH=˜5), followed by the slow addition of excess of water to precipitate. After 2-hours stirring, the precipitate was filtered, washed with water and dried to give a desired compound of 2.63 g (yield: 91%).
Reaction SMILES: Cl.[CH2:2]=[C:3]1[C:8](=[O:9])[CH:7]2[CH2:10][CH2:11][N:4]1[CH2:5][CH2:6]2.O.C([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:3]([N:4]([CH2:2][CH:3]1[C:8](=[O:9])[CH:7]2[CH2:10][CH2:11][N:4]1[CH2:5][CH2:6]2)[CH2:5][C:6]1[CH:17]=[CH:16][N:15]=[CH:18][CH:19]=1)[CH3:2]
Reactant: C=C1C(=O)C2CCN1CC2
Reactant: CCN(CC)CC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Solvent: O
Product: CCN(Cc1ccncc1)CC1C(=O)C2CCN1CC2
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 2-methylene-3-quinuclidinone hydrochloride (0.5 g, 0.0036 mol) in water (3 ml) N-(4-pyridylmethyl)ethylamine (0.49 g, 0.0036 mol), triethylamine (1.09 g, 0.0108 mol) and tetra-n-butyl ammonium bromide (116 mg, 0.00036 mol) were added and the reaction mixture were allowed to stir at 80° C. for 18 h. The completion of reaction was monitored by tlc. The reaction mixture was quenched with ice-cold water (10 ml), extracted with dichloromethane (2×50 ml), organic layers were washed with 10% NaHCO3 solution, brine and dried over sodium sulphate, filtered and concentrated to get the crude product which was purified as yellow solids (200 mg, 22%) by flash column chromatography on neutral silica gel using chloroform as eluent.