Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C@@H:8]([C:12](=[NH:21])[NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:9]([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.C([O:32][C:33](=O)[CH:34]([C:36](Cl)=[O:37])[CH3:35])C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:22])[NH:7][CH:8]([C:12]1[N:13]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:33](=[O:32])[C:34]([CH3:35])=[C:36]([OH:37])[N:21]=1)[CH:9]([CH3:11])[CH3:10])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=N)NCc1ccccc1
Reactant: CCOC(=O)C(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(O)nc(C(NC(=O)OC(C)(C)C)C(C)C)n(Cc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 40.5 %

Procedure:
To a stirred solution of [(R)-1-(N-Benzyl-carbamimidoyl)-2-methyl-propyl]-carbamic acid t-butyl ester (16.37 g, 53.6 mMol) in CH2Cl2 (150 mL) with cooling at 0° C. was added Et3N (9 mL, 64.3 mMol) followed by 2-chlorocarbonyl-propionic acid ethyl ester (10 g, 60.8 mMol) dropwise over 15 minutes. The reaction was allowed to warm to RT and stirred for 4 h, poured into a separatory funnel, washed with water, brine, dried (Na2SO4), and evaporated to dryness under vacuum. The unpurified acylamidine (˜90% pure by LCMS, MS (ES) m/e (M+H)+434.4) was taken up in DMF (150 mL) and heated to 100° C. with stirring for 18 h. The reaction was concentrated under vacuum and purified by flash chromatography (90:10:1, CH2Cl2:EtOAc:HOAc) then (30:70:1, EtOAc:hexane:HOAc) to give the title compound (8.42 g, 41%) as an off-white solid: MS (ES) m/e 388.2 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.[CH:7]1([NH:10][C:11]([C:13]2[CH:14]=[CH:15][C:16]([CH3:32])=[C:17]([NH:19][C:20](=[O:31])[C:21]3[CH:26]=[C:25](F)[CH:24]=[CH:23][C:22]=3[N+:28]([O-:30])=[O:29])[CH:18]=2)=[O:12])[CH2:9][CH2:8]1>>[CH:7]1([NH:10][C:11]([C:13]2[CH:14]=[CH:15][C:16]([CH3:32])=[C:17]([NH:19][C:20](=[O:31])[C:21]3[CH:26]=[C:25]([N:1]4[CH2:6][CH2:5][S:4][CH2:3][CH2:2]4)[CH:24]=[CH:23][C:22]=3[N+:28]([O-:30])=[O:29])[CH:18]=2)=[O:12])[CH2:9][CH2:8]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(F)ccc1[N+](=O)[O-]
Reactant: C1CSCCN1
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(N2CCSCC2)ccc1[N+](=O)[O-]

Procedure:
Using an analogous procedure to that described paragraph (A) in the portion of Example 13 which is concerned with the preparation of starting materials thiomorpholine was reacted with N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-fluoro-2-nitrobenzamide to give N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-nitro-5-thiomorpholin-4-ylbenzamide; NMR Spectrum: (DMSOd6) 0.56 (m, 2H), 0.67 (m, 2H), 2.30 (s, 3H), 2.67 (m, 4H), 2.82 (m, 1H), 3.91 (m, 4H), 7.06 (m, 2H), 7.27 (d, 1H), 7.55 (d, 1H), 7.97 (s, 1H), 8.04 (d, 1H), 8.37 (s, 1H), 9.90 (s, 1H); Mass Spectrum: M+Na+ 463.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[C:17]([Cl:18])[N:11]2[N:10]=[C:9]1[CH:19]([CH:21]1[CH2:23][CH2:22]1)O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:24]=[N+]=[N-].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.CCOC(C)=O>[NH2:24][CH:19]([CH:21]1[CH2:23][CH2:22]1)[C:9]1[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[C:17]([Cl:18])[N:11]2[N:10]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=c1c2ccc(Cl)n2nc(C(O)C2CC2)n1Cc1ccccc1
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NC(c1nn2c(Cl)ccc2c(=O)n1Cc1ccccc1)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.4 %

Procedure:
A mixture of 3-benzyl-7-chloro-2-(cyclopropyl-hydroxy-methyl)-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one (Example 17 G, 0.10 g, 0.29 mmol) and sodium azide (30 mg, 0.46 mmol) in DMF (2 mL) was stirred at rt under nitrogen overnight. The reaction mixture was diluted with EtOAc to 40 mL, washed with water and brine, dried over MgSO2 and concentrated to a pale oil. The oil was dissolved in THF (6 mL) and water (0.2 mL), flushed with nitrogen and treated with triphenylphosphine (0.15 g, 0.58 mmol). The reaction mixture was heated at 66° C. for 5 h. The solvents were removed under reduced pressure. Purification of the residue by flash column chromatography (SiO2, EtOAc/hexane/MeOH/NH4OH 500:500:50:5) gave the title compound as a colorless oil (69 mg, 73%): 1H NMR (CDCl3) δ 7.35 (m, 4H), 7.22 (d, 1H, J=7.7 Hz), 7.11 (m, 1H), 6.54 (m, 1H), 5.65 (m, 1H), 5.37 (m, 1H), 3.73 (m 1H), 2.00 (m, 1H),1.60 (m, 1H), 1.33 (m, 1H), 0.58 (m, 1H), 0.29 (m, 2H); MS (ESI+) 329.09, 331.07 (M++H).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][N:15]=1.C([O:24][B:25](OCCC)[O:26]CCC)CC>C1COCC1>[F:13][C:14]1[C:19]([B:25]([OH:26])[OH:24])=[CH:18][C:17]([CH3:20])=[CH:16][N:15]=1
Reactant: Cc1ccc(F)nc1
Reactant: CCCOB(OCCC)OCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Cc1cnc(F)c(B(O)O)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 94.3 %

Procedure:
n-Butyllithium (2.5M solution in hexane, 9.6 mL, 24 mmol) was added to a mixture of diisopropylamine (3.4 mL, 24 mmol) in THF (5.00 mL, 61 mmol) at 0° C. and the resulting pale yellow solution was stirred at the same temperature for 30 min and then cooled down to −78° C. A suspension of 2-fluoro-5-methylpyridine (Aldrich, St. Louis, Mo.) (2.22 g, mmol) in THF (5.00 mL, not complete dissolved) was slowly added. The resulting bright yellow solution was stirred at −78° C. for 1 h, treated with a solution of tri-1-propylborate (6.9 mL, 30 mmol) in THF (10.00 mL) and then allowed to warm up to room temperature. The yellow suspension was quenched with 1 N NaOH until basic (pH about 10) and the organic layer was separated. The aqueous layer was collected and carefully acidified with 6N aqueous HCl until slightly acidic, and then extracted with EtOAc(×3). The combined organic layers were dried (Na2SO4), filtered and concentrated. The resulting white solid was washed with ether to give 2-fluoro-5-methylpyridin-3-ylboronic acid (2.9196 g, 94% yield) as a white solid. LCMS (API-ES) m/z 156 (M+H)+.
Reaction SMILES: N1C=CC=CC=1.[O:7]=[C:8]1[N:13]([CH2:14][C:15]#[CH:16])[C:12]2[CH:17]=[C:18]([N:21]3[C:26](=[O:27])[CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[NH:23][C:22]3=O)[CH:19]=[CH:20][C:11]=2[O:10][CH2:9]1.P(Cl)(Cl)([Cl:35])=O>C1(C)C=CC=CC=1>[Cl:35][C:22]1[N:21]([C:18]2[CH:19]=[CH:20][C:11]3[O:10][CH2:9][C:8](=[O:7])[N:13]([CH2:14][C:15]#[CH:16])[C:12]=3[CH:17]=2)[C:26](=[O:27])[CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[N:23]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: C#CCN1C(=O)COc2ccc(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)cc21
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: C#CCN1C(=O)COc2ccc(-n3c(Cl)nc(C(F)(F)F)cc3=O)cc21
Temperature: 100 °C

Procedure:
16.61 g of pyridine are added at 25° C. while stirring to a suspension of 25.55 g of 3-[3,4-dihydro-3-oxo-4-(2-propynyl)-2H-1,4-benzoxazin-6-yl]-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione (see Example 3) and 32.13 g of phosphorus oxychloride in 250 ml of toluene. The reaction mixture is heated to 100° C. for 6 hours, cooled to 25° C. and poured on to 500 g of ice. Subsequently, the aqueous mixture is extracted three times with 150 ml of ethyl acetate each time and the organic phase is washed neutral with water, dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure. The resinous product is purified by chromatography on a silica gel column with ethyl acetate/n-hexane (1:3) as the eluent. Finally, the product is recrystallized from diethyl ether/n-hexane. In this manner there is obtained 6-[2-chloro-6-oxo-4-trifluoromethyl-1(6H)-pyrimidinyl]-4-(2-propynyl)-2H-1,4-benzoxazin-3(4H)-one, m.p. 143°-145° C. (see Example 78).
Reaction SMILES: [K].C([O-])(C)(C)C.[O:7]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:21]([N:23]([CH2:30][CH3:31])[C:24](=[O:29])[CH:25](Cl)[CH2:26][CH3:27])[CH3:22].C(OCC)C>CS(C)=O>[CH2:21]([N:23]([CH2:30][CH3:31])[C:24](=[O:29])[CH2:25][CH2:26][CH2:27][O:20][C:17]1[CH:16]=[CH:15][C:14]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:19][CH:18]=1)[CH3:22]
Reactant: CCC(Cl)C(=O)N(CC)CC
Reactant: Oc1ccc(Oc2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K]
Solvent: CCOCC
Solvent: CS(C)=O
Product: CCN(CC)C(=O)CCCOc1ccc(Oc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
17 g of potassium-tert.-butanolate is added at 10° C to a solution of 28 g of 4-phenoxy-phenol in 100 ml of anhydrous dimethylsulphoxide. After the base has completely dissolved, an addition is made dropwise in the course of 2 hours, with stirring, of 26.5 g of chlorobutyric acid diethylamide dissolved in 20 ml of dimethylsulphoxide and the whole is further stirred overnight at room temperature. For further processing, the reaction mixture is poured into ice water, and extraction is repeatedly performed with diethyl ether. The combined ether phases are washed four times with cold 10% potassium hydroxide solution and subsequently repeatedly with water; they are then dried by means of sodium sulphate. After the ether has been distilled off, there is obtained crude 4-[(4-phenoxy)-phenoxy]-butyric acid diethylamide, which is purified by chromatography on silica gel (eluant: ether/hexane 1:3), and recrystallised from isopropanol/hexane, M.P. 73°-74° C.
Reaction SMILES: [C:1]([O:4][C:5]12[CH2:9][C:7]([NH2:10])([CH2:8]1)[CH2:6]2)(=[O:3])[CH3:2].[C:11](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[C:1]([O:4][C:5]12[CH2:9][C:7]([NH:10][CH3:11])([CH2:8]1)[CH2:6]2)(=[O:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)OC12CC(N)(C1)C2
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CNC12CC(OC(C)=O)(C1)C2

Procedure:
To an anhydrous DMF (5 mL) solution of 3-aminobicyclo[1.1.1]pentan-1-yl acetate (1 mmol; prepared as described in Example 1, Step 2) is potassium carbonate (3 mmol) followed by the addition of methyl iodide (1 mmol) by syringe at room temperature. The reaction is monitored by LCMS and TLC. After consumption of starting material, the reaction mixture is quenched by adding water (3 mL) and extracted with ethyl acetate (3×). The organic layers are combined, dried (magnesium sulfate), filtered, and concentrated. The crude residue is subjected to flash chromatography (silica gel, EtOAc/hexanes) to afford 3-(methylamino)bicyclo[1.1.1]pentan-1-yl acetate.
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8](OC)=[O:9])=[C:6]([OH:12])[C:5]2[S:13][C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=3[C:4]=2[S:3]1(=[O:22])=[O:21].[NH2:23][C:24]1[C:29]([OH:30])=[CH:28][CH:27]=[CH:26][N:25]=1>>[CH3:1][N:2]1[C:7]([C:8]([NH:23][C:24]2[C:29]([OH:30])=[CH:28][CH:27]=[CH:26][N:25]=2)=[O:9])=[C:6]([OH:12])[C:5]2[S:13][C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=3[C:4]=2[S:3]1(=[O:22])=[O:21]
Reactant: COC(=O)C1=C(O)c2sc3cc(C)ccc3c2S(=O)(=O)N1C
Reactant: Nc1ncccc1O
Product: Cc1ccc2c3c(sc2c1)C(O)=C(C(=O)Nc1ncccc1O)N(C)S3(=O)=O
Yield: 38 %

Procedure:
Prepared analogous to Example 1 from methyl 2,7-dimethyl-4-hydroxy-2H-[1]-benzothieno-[2,3-e]-1,2-thiazine-3-carboxylate-1,1-dioxide and 2-amino-3-hydroxy-pyridine with a yield of 38% of theory.
Reaction SMILES: [C:1]([OH:12])(=O)[CH:2]=[CH:3][CH2:4][CH2:5][CH:6]=[CH:7][CH:8]=[CH:9][CH3:10].COC(=O)CC(OS(C)(=O)=O)CCC[Cl:21].COC(=O)CC(O)CCCCl>>[C:1]([Cl:21])(=[O:12])[CH:2]=[CH:3][CH2:4][CH2:5][CH:6]=[CH:7][CH:8]=[CH:9][CH3:10]
Reactant: CC=CC=CCCC=CC(=O)O
Reactant: COC(=O)CC(CCCCl)OS(C)(=O)=O
Agent: COC(=O)CC(O)CCCCl
Product: CC=CC=CCCC=CC(=O)Cl

Procedure:
GC/MS (m/e); 184 (M+, 6%), 149 (7), 121 (3), 105 (2), 93 (3), 81 (100), 68 (14), 53 (15), 41 (14)
Reaction SMILES: [H-].[Na+].[N:3]1[CH:4]=[CH:5][N:6]2[CH2:11][CH2:10][NH:9][CH2:8][C:7]=12.Cl[C:13]1[O:14][C:15]2[C:16](=[C:18]([C:22]([O:24][CH3:25])=[O:23])[CH:19]=[CH:20][CH:21]=2)[N:17]=1>C1COCC1>[N:3]1[CH:4]=[CH:5][N:6]2[CH2:11][CH2:10][N:9]([C:13]3[O:14][C:15]4[C:16](=[C:18]([C:22]([O:24][CH3:25])=[O:23])[CH:19]=[CH:20][CH:21]=4)[N:17]=3)[CH2:8][C:7]=12
Reactant: COC(=O)c1cccc2oc(Cl)nc12
Reactant: c1cn2c(n1)CNCC2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1cccc2oc(N3CCn4ccnc4C3)nc12
Reaction time: 0.17 h
Yield: 37.2 %

Procedure:
To a solution of NaH (60% dispersion in mineral oil, 0.130 g, 3.25 mmol) in THF (10 mL) was added 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (0.33 g, 2.71 mmol) and the reaction mixture stirred for 10 min. Methyl 2-chlorobenzoxazole-4-carboxylate (478 mg, 2.26 mmol), in THF (10 mL) was added and the reaction mixture was allowed to stir at room temperature 17 h. The reaction mixture was quenched with CH3OH (3 mL), and adsorbed onto silica gel (2 g). The crude product was purified by column chromatography (silica gel, 0.5 to 10% CH3OH in CH2Cl2) to afford methyl 2-(5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)benzoxazole-4-carboxylate (251 mg, 37%) as an orange oil. 1H NMR and MS consistent.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])/[CH:4]=[C:5](\[NH:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)/[CH3:6].[C:18](#[N:21])[CH2:19][CH3:20]>CC([O-])=O.CC([O-])=O.[Cu+2]>[CH3:1][O:2][C:3]([C:4]1[C:18]([CH2:19][CH3:20])=[N:21][N:7]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[C:5]=1[CH3:6])=[O:17]
Reactant: CCC#N
Reactant: COC(=O)/C=C(/C)Nc1ccc([N+](=O)[O-])cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Product: CCc1nn(-c2ccc([N+](=O)[O-])cc2)c(C)c1C(=O)OC
Yield: 65 %

Procedure:
According to AVV A, (Z-3-(4-nitrophenylamino)-but-2-enoic acid methylester (236.2 mg, 1.0 mmol, 1.0 equiv.) was stirred with Cu(OAc)2 (544.9 mg, 3.0 mmol, 3.0 equiv.) into propionitrile (3.0 ml, 41.9 mmol, 41.9 equiv.) for 21 hours at 120° C. The green solid obtained as raw product 100:0→90:10→0:100), whereby the pure product was obtained in the form of a slightly yellowish solid (188.3 mg, 0.65 mmol, 65%).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]([OH:7])=O)[CH3:2].[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:18])=[C:13]([N:15]=[C:16]=[S:17])[CH:14]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:18])=[C:13]([N:15]2[C:5](=[O:7])[CH2:4][N:3]([CH2:1][CH3:2])[C:16]2=[S:17])[CH:14]=1
Reactant: CCNCC(=O)O
Reactant: Cc1ccc(Cl)cc1N=C=S
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCN1CC(=O)N(c2cc(Cl)ccc2C)C1=S
Yield: 56.6 %

Procedure:
A mixture of the crude N-ethyl glycine (9.23 g), 5-chloro-2-methylphenylisothiocyanate (9.18 g), triethyl amine (10 g) and chloroform (250 mL) was heated at reflux for 18 hours. The solvent was evaporated. The residue was dissolved in ethyl acetate (400 mL) and water (300 mL). The organic phase was washed with 1N HCl (2×300 mL), then evaporated to dryness. Purification was achieved through crystallization from ethanol. The title compound (7.6 g) was obtained as a light pink solid, m.p. 152°-154° C. Anal. Calcd. for. C12H13Cl N2O S: C, 53.63; H, 4.88; N, 10.42. Found: C, 53.36; H, 4.79; N, 10.35. Mass spectrum (EI, M.+) m/z 268/270.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:14]S(C2C=CC=CC=2)(=O)=O)=[C:6]([CH:13]=1)/[CH:7]=[CH:8]/[C:9]([O:11]C)=[O:10].Br.Br[CH2:26][C:27]([C:29]1[CH:34]=[C:33]([CH3:35])[CH:32]=[CH:31][N:30]=1)=[O:28]>>[Cl:1][C:2]1[CH:13]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:14][C:26]([C:27]([C:29]1[CH:34]=[C:33]([CH3:35])[CH:32]=[CH:31][N:30]=1)=[O:28])=[C:7]2[CH2:8][C:9]([OH:11])=[O:10]
Reactant: Cc1ccnc(C(=O)CBr)c1
Reactant: COC(=O)/C=C/c1cc(Cl)ccc1NS(=O)(=O)c1ccccc1
Agent: Br
Product: Cc1ccnc(C(=O)c2[nH]c3ccc(Cl)cc3c2CC(=O)O)c1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 8 (Method A) from methyl trans-5-chloro-2-(phenylsulfonylamino)cinnamate (step 3) and 2-bromoacetyl-4-methylpyridine hydrobromide (F. H. Case et al., J. Am. Chem. Soc., 1956, 78, 5842).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[C:31]([NH:36][C:37](=[O:41])[CH:38]([CH3:40])[CH3:39])[CH:32]=[CH:33][C:34]=2[F:35])[CH2:25][CH2:24]1>>[F:18][C:15]1[CH:16]=[CH:17][C:12]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:9]([NH:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:30]=[C:31]([NH:36][C:37](=[O:41])[CH:38]([CH3:39])[CH3:40])[CH:32]=[CH:33][C:34]=3[F:35])[CH2:25][CH2:24]2)=[O:11])=[CH:13][CH:14]=1
Reactant: O=C(O)C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CC(C)C(=O)Nc1ccc(F)c(C2CCN(CCCN)CC2)c1
Product: CC(C)C(=O)Nc1ccc(F)c(C2CCN(CCCNC(=O)C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c1

Procedure:
Example 35 was prepared from bis(4-fluorophenyl)acetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-fluorophenyl}-2-methylpropanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.58 (dd, 1H, J=2.8, 6.4 Hz), 7.53 (s, 1H), 7.49 (br s, 1H), 7.31–6.92 (m, 10H), 4.81 (s, 1H), 3.40 (dd, 2H, J=5.6, 11.2 Hz), 2.93 (d, 2H, J=11.6 Hz), 2.76 (m, 1H), 2.49 (m, 1H), 2.42 (t, 2H, J=6.0 Hz), 2.02–1.96 (m, 2H), 1.77 (d, 2H, J=11.6 Hz), 1.69–1.62 (m, 4H), 1.22 (d, 6H, J=6.8 Hz); ESMS m/e: 552.3 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:24][CH2:23][C:8]3([C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:9]3=[O:22])[C:6]=2[CH:7]=1.BrC1C=CC=C2C=1C1(C3=CC4OCOC=4C=C3OC1)[CH2:29][N:30]2CCCCC>>[O:22]=[C:9]1[C:8]2([C:6]3[CH:7]=[C:2]([C:29]#[N:30])[CH:3]=[CH:4][C:5]=3[O:24][CH2:23]2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]1[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCN1CC2(COc3cc4c(cc32)OCO4)c2c(Br)cccc21
Reactant: CCCCCN1C(=O)C2(COc3ccc(Br)cc32)c2ccccc21
Product: CCCCCN1C(=O)C2(COc3ccc(C#N)cc32)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 30, and making non-critical variations using 5-bromo-1′-pentylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace 4′-bromo-1′-pentylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′(1′H)-one, the title compound was obtained (78%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.51 (dt, 1H), 7.34 (dt, 1H), 7.12-6.91 (m, 5H), 5.01 (d, 1H), 4.76 (d, 1H), 3.86-3.63 (m, 2H), 1.80-1.68 (m, 2H), 1.43-1.32 (m, 4H), 0.92 (t, 3H); 13C NMR (75 MHz, CDCl3) δ 176.2, 164.1, 142.6, 134.8, 131.4, 130.8, 129.6, 127.8, 123.9, 123.5, 118.8, 111.5, 109.1, 104.7, 80.6, 57.3, 40.6, 29.0, 27.1, 22.3, 14.0; MS (ES+) m/z 333.5 (M+1).
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1C=CN=C1.[I:25]I.[CH2:27]([O:34][C:35]1[C:40]([F:41])=[CH:39][C:38]([F:42])=[CH:37][C:36]=1[CH2:43][CH2:44]O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(Cl)Cl>[CH2:27]([O:34][C:35]1[C:36]([CH2:43][CH2:44][I:25])=[CH:37][C:38]([F:42])=[CH:39][C:40]=1[F:41])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: II
Reactant: OCCc1cc(F)cc(F)c1OCc1ccccc1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Fc1cc(F)c(OCc2ccccc2)c(CCI)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.6 %

Procedure:
A solution of Ph3P (750 mg, 2.86 mmol) and imidazole (195 mg, 2.86 mmol) in DCM (15 mL) was cooled to 0° C. Added to this was iodine (726 mg, 2.86 mmol) and the resulting mixture was stirred at 0° C. for 30 min. Then, 2-(2-(benzyloxy)-3,5-difluorophenyl)ethanol (630 mg, 2.384 mmol) was added portionwise over several minutes and the resulting mixture was stirred at room temp. After 5 h, the mixture was filtered washing the solids with DCM. The filtrate was washed with aq Na2S2O3 and the organic phase was dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (5%-30% EtOAc/hexane) to give 2-(benzyloxy)-1,5-difluoro-3-(2-iodoethyl)benzene (630 mg, 1.684 mmol, 70.6% yield) as light yellow viscous oil. 1H NMR (500 MHz, CDCl3) δ 7.46-7.34 (m, 5H), 6.83 (ddd, J=11.3, 8.2, 3.0 Hz, 1H), 6.69 (dt, J=8.6, 2.3 Hz, 1H), 5.10 (s, 2H), 3.21 (d, J=7.7 Hz, 2H), 3.13-3.00 (m, 2H).
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:18](OC([O-])=O)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>ClCCl>[CH2:4]1[C:5]2([CH2:10][CH2:9][N:8]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:7][CH2:6]2)[CH2:1][CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: C1CCC2(C1)CCNCC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC2(CCCC2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.3 %

Procedure:
To a solution of 8-azaspiro[4.5]decane (which has been described in WO 9800404 A1 6.2 g, 44.5 mmol) in dichloromethane (130 ml), which was cooled to 0° C., triethylamine (7.5 ml, 53.4 mmol) was added then a solution of tert-butyl dicarbonate (10.68 g, 48.9 mmol) in dichloromethane (50 ml) was added in 20 minutes. The clear solution was maintained under stirring at room temperature for 18 hours, then dichloromethane (50 ml) was added and the organic solution was washed with water (2×20 ml), HCl 0.1N (20 ml) then water (2×20 ml). The organic solvent was anhydrified (Na2SO4) and evaporated to give a crude that was purified on silica gel column (Hexane/AcOEt 95/5) to give 6 g of the title compound (light yellow solid).
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=O)[CH:19]([CH3:24])[CH2:20][C:21](O)=[O:22])=[CH:14][C:13]=1[OH:26])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(O)(=O)C>[CH2:4]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]([CH3:24])[CH2:20][C:21](=[O:22])[NH:2][N:3]=2)=[CH:14][C:13]=1[OH:26])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: NN
Reactant: CC(CC(=O)O)C(=O)c1ccc(NCc2ccccc2)c(O)c1
Solvent: O
Solvent: CC(=O)O
Product: CC1CC(=O)NN=C1c1ccc(NCc2ccccc2)c(O)c1
Temperature: 110 °C
Reaction time: 1.5 h

Procedure:
While cooling with the ice bath 69.9 ml (1396 mmol) hydrazine hydrate are added dropwise to 220 ml glacial acetic acid, then 54.7 g (175 mmol) 4-(4-benzylamino-3-hydroxy-phenyl)-3-methyl-4-oxo-butyric acid are added and the mixture is stirred for 1.5 h at 110° C. Then the mixture is cooled somewhat and poured onto ice water, the precipitated product is suction filtered, washed first with copious amounts of water, then with a little acetone and then dried in the vacuum dryer.
Reaction SMILES: [CH:1]1[C:14]2[CH:13]([C:15]([OH:17])=[O:16])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.CN(C=O)C.[CH3:29][N:30]1[CH2:34][CH2:33][C@@H:32](O)[CH2:31]1>C(Cl)(Cl)Cl>[CH3:29][N:30]1[CH2:34][CH2:33][C@@H:32]([O:16][C:15]([CH:13]2[C:14]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[O:6][C:7]3[C:12]2=[CH:11][CH:10]=[CH:9][CH:8]=3)=[O:17])[CH2:31]1
Reactant: CN1CC[C@@H](O)C1
Reactant: O=C(O)C1c2ccccc2Oc2ccccc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CN1CC[C@@H](OC(=O)C2c3ccccc3Oc3ccccc32)C1
Temperature: 0 °C
Yield: 92.9 %

Procedure:
2 g of 9H-Xanthene-9-carboxylic acid (0.0088 mol) were dissolved in 30 ml of CHCl3 (ethanol free). The solution was cooled at 0° C. and 1.08 ml (0.0123 mol) of oxalyl chloride and a drop of DMF was added. The mixture was stirred and allowed to warm to room temperature. After an hour at this temperature the solvents were evaporated and the residue was dissolved in CHCl3 and evaporated again. This procedure was repeated two times. The solid obtained (2.19 g) was dissolved in 20 ml of CHCl3 and added to a solution of 0.975 g (0.0097 mol) of (3R)-1-methylpyrrolidin-3-ol (Intermediate I-19) in 15 ml of CHCl3 cooled at 0–5° C. The reaction mixture was allowed to warm to room temperature and stirred overnight. The solvent was evaporated and the residue was dissolved in toluene and extracted with HCl 2N. The aqueous layer was basified with K2CO3 and extracted with CHCl3. The organic layer was washed with brine, dried over Na2SO4 and evaporated to dryness to yield 2.53 g (93%) of the title product as an oil.